# 18 - PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders # 02 - 360 Introduction to the Immune System ### 360 Introduction to the Immune System Immune-Mediated, Inflammatory, and Rheumatologic Disorders PART 11 Section 1 The Immune System in Health and Disease Barton F. Haynes, Kelly A. Cuttle, Anthony S. Fauci Introduction to the Immune System ■ ■DEFINITIONS • Adaptive immune system—recently evolved system of immune responses mediated by T and B lymphocytes. Immune responses by these cells are based on specific antigen recognition by clonotypic receptors that are products of genes that rearrange during devel­ opment and throughout the life of the organism. Additional cells of the adaptive immune system include various types of antigenpresenting cells (APCs). • Antibody—B cell–produced molecules encoded by genes that rear­ range during B-cell development consisting of immunoglobulin heavy and light chains that together form the central component of the B-cell receptor (BCR) for antigen. Antibody can exist as B cell– surface antigen-recognition molecules or as secreted molecules in plasma and other body fluids. • Antigens—foreign or self-molecules that are recognized by the adap­ tive and innate immune systems resulting in immune cell triggering, T-cell activation, and/or B-cell antibody production. • Antigen-presenting cells (APCs)—a group of immune cells that process antigens to mediate both adaptive immune responses and the maintenance of peripheral tolerance. Classical APCs include dendritic cells, macrophages, and B cells. • Apoptosis—the process of programmed cell death whereby signal­ ing through “death receptors” on the surface of cells (e.g., tumor necrosis factor [TNF] receptors, CD95) leads to signaling cascades that involve activation of the caspase family of molecules and leads to DNA cleavage and cell death. Apoptosis, which does not lead to induction of inordinate inflammation, is to be contrasted with cell necrosis, which does lead to induction of inflammatory responses. • Autoimmune diseases—diseases such as systemic lupus erythemato­ sus and rheumatoid arthritis in which cells of the adaptive immune system such as autoreactive T and B cells become overreactive and produce pathogenic T-cell and antibody responses. • Autoinflammatory diseases—hereditary disorders such as heredi­ tary periodic fevers (HPFs) characterized by recurrent episodes of severe inflammation and fever due to mutations in controls of the innate inflammatory response, i.e., the inflammasome (see below and Table 360-5). Patients with HPFs also have rashes and serosal and joint inflammation, and some can have neurologic symptoms. Autoinflammatory diseases are different from autoimmune diseases in that evidence for activation of adaptive immune cells such as autoreactive B cells is not present. • Autophagy—lysosomal degradation pathway mechanism of cells to dispose of intracellular debris and damaged organelles. Autophagy by cells of the innate immune system is used to control intracel­ lular infectious agents such as mycobacteria, in part by initiation of phagosome maturation and enhancing major histocompatibility complex (MHC) class II antigen presentation to CD4 T cells. • B-cell receptor (BCR) for antigen—complex of surface molecules that rearrange during postnatal B-cell development, made up of surface immunoglobulin (Ig) and associated Ig αβ chain molecules that recognize nominal antigen via Ig heavy- and light-chain variable regions, and signal the B cell to terminally differentiate to make antigen-specific antibody. • B lymphocytes—bone marrow–derived lymphocytes that express surface immunoglobulin (the BCR for antigen) and secrete specific antibody after interaction with antigen. • B regulatory cells—a population of suppressive B cells that aid in the inhibition of inflammation through the release of cytokines such as interleukin-(IL) 10. • CD classification of human lymphocyte differentiation antigens—the development of monoclonal antibody technology led to the discov­ ery of a large number of new leukocyte surface molecules. From a series of International Workshop on Leukocyte Differentiation Antigens has come the cluster of differentiation (CD) classification of leukocyte antigens. • CD4 T cell—T lymphocyte subset that participates in adaptive immunity and helps B cells make antibody. • CD8 T cell—cytotoxic T lymphocyte subset that kills tumor cells and cells infected with pathogens. • Chemokines—soluble molecules that direct and determine immune cell movement and circulation pathways. • Complement—cascading series of plasma enzymes and effector proteins that function to lyse pathogens and/or target them to be phagocytized by neutrophils and monocyte/macrophage lineage cells of the reticuloendothelial system. • Co-stimulatory molecules—molecules of APCs (such as B7-1, B7-2, or CD40) that lead to T-cell activation when bound by ligands on activated T cells (such as CD28 or CD40 ligand). • Crystallopathies—nanoparticle- or microparticle-sized deposits of crystals, misfolded proteins, or airborne particulate matter that can stimulate the inflammasome and initiate inflammation and tissue damage. • Cytokines—soluble proteins that interact with specific cellular recep­ tors that are involved in the regulation of the growth and activation of immune cells and mediate normal or pathologic inflammatory and immune responses. • Dendritic cells—myeloid and/or lymphoid lineage APCs of the adaptive immune system. Immature dendritic cells (DCs), or DC precursors, are key components of the innate immune system by responding to infections with production of high levels of cytokines. DCs are key initiators of innate immune responses via cytokine pro­ duction and mediators of adaptive immune responses via presenta­ tion of antigen to T lymphocytes. • Ig fragment crystallizable (Fc) receptors (Rs)—receptors found on the surface of certain cells including B cells, natural killer (NK) cells, macrophages, neutrophils, and mast cells. Fc receptors bind to the Fc domains of antibodies that have attached to invading pathogen-infected cells. FcRs stimulate cytotoxic cells to destroy microbe-infected cells through antibody-dependent cell-mediated cytotoxicity (ADCC). Examples of important FcRs include CD16 (FcγRIIIa), CD23 (FcεR), CD32 (FcγRII), CD64 (FcγRI), and CD89 (FcαR). • Inflammasome—large cytoplasmic complexes of intracellular pro­ teins that link the sensing of microbial products and cellular stress to the proteolytic activation of IL-1β and IL-18 inflammatory cytokines. Activation of molecules in the inflammasome is a key step in the response of the innate immune system for intracellular recognition of microbial and other danger signals in both health and pathologic states. • Innate immune system—ancient immune recognition system of host cells bearing germline-encoded pattern recognition receptors (PRRs) that recognize pathogens and trigger a variety of mecha­ nisms of pathogen elimination. Cells of the innate immune system include NK cell lymphocytes, monocytes/macrophages, DCs, neu­ trophils, basophils, eosinophils, tissue mast cells, and epithelial cells. • Innate lymphoid cells (ILCs)—lymphocytes that do not express the type of diversified antigen receptors on T cell and B cells. ILC1s, ILC2s, and ILC3s are tissue resident cells and functionally may be analogous to CD4 TH1, TH2, and TH17 cells, respectively. • Natural killer (NK) cells—a type of ILC that kills target cells express­ ing few or no human leukocyte antigen (HLA) class I molecules, such as malignantly transformed cells and virally infected cells. NK cells express receptors that inhibit killer cell function when self-MHC class I is present. Innate NK cells mirror the cytolytic functions of CD8 cytotoxic T cells of the adaptive immune system. • NK T cells—innate-like lymphocytes that use an invariant T-cell PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders receptor (TCR)-α chain combined with a limited set of TCR-β chains and coexpress receptors commonly found on NK cells. NK T cells recognize lipid antigens of bacterial, viral, fungal, and protozoal infectious agents. • Pathogen-associated molecular patterns (PAMPs)—invariant molec­ ular structures expressed by large groups of microorganisms that are recognized by host cellular PRRs in the mediation of innate immunity. • Pattern recognition receptors (PRR)—germline-encoded receptors expressed by cells of the innate immune system that recognize PAMPs. • T lymphocytes—thymus-derived lymphocytes that mediate adaptive cellular immune responses including T helper, T regulatory, and cytotoxic T lymphocyte effector cell functions. • T-cell exhaustion—state of T cells when the persistence of antigen disrupts memory T-cell function, resulting in defects in memory T-cell responses. Most frequently occurs in malignancies and in chronic viral infections such as HIV-1 and hepatitis C. • TCR for antigen—complex of surface molecules that rearrange during postnatal T-cell development made up of clonotypic TCR-α and -β chains that are associated with the CD3 complex composed of invariant γ, δ, ε, ζ, and η chains. TCR-α and -β chains recognize peptide fragments of protein antigen physically bound in APC MHC class I or II molecules, leading to signaling via the CD3 complex to mediate effector functions. • T follicular helper T cells (TFH)—CD4 T cells regulated by bcl-6 in B-cell follicle germinal centers that produce IL-4 and IL-21 and drive B-cell differentiation and affinity maturation in peripheral lymphoid tissues such as lymph node and spleen. • TH1 T cells—CD4 helper T-cell subset regulated by transcription factor T-bet that produces interferon (IFN)-γ, IL-2, and TNF-β and participates in cell-mediated immunity. • TH2 T cells—CD4 helper T-cell subset regulated by transcription fac­ tors STAT6 and GATA3 that produces IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13 and regulates antibody and eosinophil responses. • T regulatory cells (Treg)—CD4 or CD8 T cells regulated by the tran­ scription factor forkhead box P3 (FOXP3) that play roles in modulat­ ing immune responses to prevent harmful immune activation. Treg cells that prevent autoimmunity can arise in the thymus (thymic Tregs) after exposure to self-antigens on thymic epithelial cells or can arise outside the thymus and are called peripheral Tregs. Intestinal Tregs are essential to preventing pathogenic immune responses to the gut microbiome, thus preventing intestinal inflammation. • TH9 T cells—CD4 T cells regulated by the transcription factor PU.1 that secrete IL-9 and enhance inflammation in atopic disease and inflammatory bowel disease as well as mediate antitumor immunity. • TH13 T cells—T follicular helper cells (TFH) regulated by the GATA3 transcription factor that produce IL-4, IL-5, and IL-13. TH13 TFH induce high-affinity IgE antibody responses that cause anaphy­ lactic reactions to allergens. • TH17 T cells—CD4 T cells regulated by the transcription factor RORγt that secrete IL-17, IL-22, and IL-26 and play roles in autoim­ mune inflammatory disorders as well as defend against bacterial and fungal pathogens. • Tolerance—B- and T-cell nonresponsiveness to antigens that results from encounter with foreign or self-antigens by B and T lympho­ cytes in the absence of expression of APC co-stimulatory molecules. Tolerance to antigens may be induced and maintained by multiple mechanisms either centrally (B-cell deletion in the thymus for T cells or bone marrow for B cells) or peripherally (by cell deletion or anergy at sites throughout the peripheral immune system). • Trained immunity—the epigenetic, transcriptional, and functional reprogramming of innate immune cells to adapt to previous encoun­ ters with pathogens and respond to a second challenge in an altered manner. ■ ■INTRODUCTION The human immune system has evolved over millions of years from both invertebrate and vertebrate organisms to develop sophisticated defense mechanisms that protect the host from microbes and their virulence factors. The normal immune system has three key properties: a highly diverse repertoire of antigen receptors that enables recognition of a nearly infinite range of pathogens; immune memory, to mount rapid recall immune responses; and immunologic tolerance, to avoid immune damage to self-tissues. From invertebrates, humans have inherited the innate immune sys­ tem, an ancient defense system that uses germline-encoded proteins to recognize pathogens. Cells of the innate immune system, such as macrophages, DCs, and NK lymphocytes, recognize PAMPs that are highly conserved among many microbes and use a diverse set of PRR molecules. Important components of the recognition of microbes by the innate immune system include recognition by germline-encoded host molecules, recognition of key microbe virulence factors but not recognition of self-molecules, and nonrecognition of benign foreign molecules or microbes such as are found in mucosal or other bar­ rier microbiomes. Upon contact with pathogens, cells of the innate immune system may kill pathogens directly or, in concert with DCs, activate a series of events that both slow the infection and recruit the more recently evolved arm of the human immune system, the adaptive immune system. In addition, innate immune cells undergo epigenetic, transcriptional, and functional changes that allow adapted (either enhanced or reduced) innate cell responses to repeat encounters with pathogens, called trained immunity. Adaptive immunity is found only in vertebrates and is based on the generation of antigen receptors on T and B lymphocytes by gene rear­ rangements, such that individual T or B cells express unique antigen receptors on their surface capable of specifically recognizing diverse antigens of infectious agents in the environment. Coupled with specific recognition mechanisms that maintain tolerance (nonreactivity) to selfantigens or nonpathogenic microbes (Chap. 361), T and B lymphocytes bring both specificity and immune memory to vertebrate host defenses. This chapter describes the cellular components, key molecules (Table 360-1), and mechanisms that make up the innate and adaptive immune systems and describes how adaptive immunity is recruited to the defense of the host by innate immune responses. An appreciation of the cellular and molecular bases of innate and adaptive immune responses is critical to understanding the pathogenesis of inflam­ matory, autoimmune, infectious, and immunodeficiency diseases, as well as a wide range of diseases associated with inflammation such as atherosclerotic cardiovascular disease and neurodegenerative diseases. ■ ■THE INNATE IMMUNE SYSTEM All multicellular organisms, including humans, have developed the use of surface and intracellular germline-encoded molecules that recognize pathogens. Because of the myriad of human pathogens, host molecules of the human innate immune system sense “danger signals” and either recognize PAMPs, the common molecular structures shared by many pathogens, or recognize host cell molecules produced in response to infection such as heat shock proteins and fragments of the extracel­ lular matrix. PAMPs must be conserved structures vital to pathogen virulence and survival, such as bacterial endotoxin, so that pathogens cannot mutate molecules of PAMPs to evade human innate immune responses. PRRs are host proteins of the innate immune system that recognize PAMPs as host danger signal molecules (Tables 360-2 and 360-3). Thus, recognition of pathogen molecules by hematopoietic and nonhematopoietic cell types leads to activation/production of the complement cascade, cytokines, or antimicrobial peptides as effector molecules. In addition, pathogen PAMPs as host danger signal mol­ ecules activate DCs to mature and to express molecules on the DC sur­ face that optimize antigen presentation to respond to foreign antigens. TABLE 360-1  Human Leukocyte Surface Antigens—The CD Classification of Leukocyte Differentiation Antigens SURFACE ANTIGEN (OTHER NAMES) FAMILY MOLECULAR MASS, kDa DISTRIBUTION LIGAND(S) FUNCTION CD1a (T6, HTA-1) Ig CD, cortical thymocytes, Langerhans type of DCs CD1b Ig CD, cortical thymocytes, Langerhans type of DCs CD1c Ig DC, cortical thymocytes, subset of B cells, Langerhans type of DCs CD1d Ig Cortical thymocytes, intestinal epithelium, Langerhans type of DCs CD2 (T12, LFA-2) Ig T, NK CD58, CD48, CD59, CD15 CD3 (T3, Leu-4) Ig γ:25–28, δ:21– 28, ε:20–25, η:21–22, ζ:16 T, NK T Associates with the TCR CD4 (T4, Leu-3) Ig T, myeloid MHC-II, HIV gp120, IL-16, SABP CD7 (3A1, Leu-9) Ig T, NK K-12 (CD7L) T- and NK-cell signal transduction and regulation of IFN-γ, TNF-α production CD8 (T8, Leu-2) Ig T, subset of NK MHC-I T-cell selection, T-cell activation, signal transduction with p56lck CD14 (LPS-receptor) LRG 53–55 M, G (weak), not by myeloid progenitors CD16a (FcγRIIIa) Ig 50–80 NK, macrophages, neutrophils CD19 B4 Ig B (except plasma cells), FDC CD20 (B1) Unassigned 33–37 B (except plasma cells) Not known Cell signaling, may be important for B-cell activation and proliferation CD21 (B2, CR2, EBV-R, C3dR) RCA Mature B, FDC, subset of thymocytes CD22 (BL-CAM) Ig 130–140 Mature B CDw75 Cell adhesion, signaling through association with p72sky, p53/56lyn, PI3 kinase, SHP1, fLCγ C-type lectin 45 B, M, FDC IgE, CD21, CD11b, CD11c CD23 (FcεRII, B6, Leu-20, BLAST-2) CD28 Ig T, plasma cells CD80, CD86 Co-stimulatory for T-cell activation; involved in the decision between T-cell activation and anergy CD32a (FcγRIIa) Ig NK, macrophages, neutrophils CD40 TNFR 48–50 B, DC, EC, thymic epithelium, MP, cancers CD45 (LCA, T200, B220) PTP 180, 200, 210, All leukocytes Galectin-1, CD2, CD3, CD4 CD45RA PTP 210, 220 Subset T, medullary thymocytes, “naive” T CD45RB PTP 200, 210, 220 All leukocytes Galectin-1, CD2, CD3, CD4 CD45RC PTP 210, 220 Subset T, medullary thymocytes, “naive” T CD45RO PTP Subset T, cortical thymocytes, “memory” T CD64 (FcγRI) Ig 45–55 Macrophages and monocytes CD80 (B7-1, BB1) Ig Activated B and T, MP, DC CD28, CD152 (CTLA-4) Co-regulator of T-cell activation; signaling through CD28 stimulates and through CD152 inhibits T-cell activation CD86 (B7-2, B70) Ig Subset B, DC, EC, activated T, thymic epithelium CD89 (FCαR) Ig 55–100 Neutrophils, eosinophils, monocytes, and MP CD1 molecules present lipid antigens of intracellular bacteria such as Mycobacterium leprae and M. tuberculosis to TCRγδT cells or NK T cells TCRγδ T cells, NK T cells CHAPTER 360   TCRγδ T cells, NK T cells   TCRγδ T cells, NK T cells Introduction to the Immune System   TCRγδ T cells, NK T cells Alternative T-cell activation, T-cell anergy, T-cell cytokine production, T- or NK-mediated cytolysis, T-cell apoptosis, cell adhesion T-cell activation and function; ζ is the signal transduction component of the CD3 complex T-cell selection, T-cell activation, signal transduction with p56lck, primary receptor for HIV-1 Endotoxin (lipopolysaccharide), lipoteichoic acid, PI TLR4 mediates with LPS and other PAMP activation of innate immunity Fc portion of IgG Mediates phagocytosis and ADCC Not known Associates with CD21 and CD81 to form a complex involved in signal transduction in B-cell development, activation, and differentiation C3d, C3dg, iC3b, CD23, EBV Associates with CD19 and CD81 to form a complex involved in signal transduction in B-cell development, activation, and differentiation; Epstein-Barr virus receptor Regulates IgE synthesis, cytokine release by monocytes Fc portion of IgG Mediates phagocytosis and ADCC CD154 (CD40L) B-cell activation, proliferation, and differentiation; formation of GCs; isotype switching; rescue from apoptosis T and B activation, thymocyte development, signal transduction, apoptosis Galectin-1, CD2, CD3, CD4 Isoforms of CD45 containing exon 4 (A), restricted to a subset of T cells Isoforms of CD45 containing exon 5 (B) Galectin-1, CD2, CD3, CD4 Isoforms of CD45 containing exon 6 (C), restricted to a subset of T cells Galectin-1, CD2, CD3, CD4 Isoforms of CD45 containing no differentially spliced exons, restricted to a subset of T cells Fc portion of IgG Mediates phagocytosis and ADCC CD28, CD152 (CTLA-4) Co-regulator of T-cell activation; signaling through CD28 stimulates and through CD152 inhibits T-cell activation Fc portion of IgG Mediates phagocytosis and ADCC of IgA-coated pathogens (Continued) TABLE 360-1  Human Leukocyte Surface Antigens—The CD Classification of Leukocyte Differentiation Antigens SURFACE ANTIGEN (OTHER NAMES) FAMILY MOLECULAR MASS, kDa DISTRIBUTION LIGAND(S) FUNCTION CD95 (APO-1, Fas) TNFR Activated T and B Fas ligand Mediates apoptosis CD112 (nekton-2, PVRL2) Ig Epithelial cells, endothelial cells, other tissues PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders CD134 (OX40) TNFR Activated T OX40L (CD252) T-cell survival, cytokine stimulation CD137 (4-1BB) TNFR Activated T, DCs, B, NK CD137L (41BBL) T-cell co-stimulation CD155 (PVR) Ig 50–65 DCs, NK, epithelial cells TIGIT, CD96, DNAM-1 T-cell inhibition (TIGIT, CD96), T-cell activation (DNAM-1) CD223 (LAG-3) Ig NK, B, activated T MHC class II T-cell inhibition CD226 (DNAM-1) Ig NK, monocytes, T CD112, CD155 T-cell activation (CD112), T-cell activation (CD155) CD252 (OX40L) TNFR 16–25 Antigen-presenting cells, endothelial cells CD272 (BTLA) Ig Activated T HVEM T-cell inhibition CD274 (PD-L1) Ig T, NK, myeloid, B, tumor cells CD278 (ICOS) Ig 55–60 Activated T ICOSL T-cell activation CD357 (GTTR) TNFR Activated T, Tregs GITRL T-cell activation CD152 (CTLA-4) Ig 30–33 Activated T CD80, CD86 Inhibits T-cell proliferation CD154 (CD40L) TNF Activated CD4+ T, subset CD8+ T, NK, M, basophil CD279 (PD-1) Ig 50–55 B, T, TFH PD-L1 (CD274), PD-L2 (CD273) Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; BTLA, band T lymphocyte attenuators; CTLA, cytotoxic T lymphocyte–associated protein; DC, dendritic cells; DNAM-1, DNAX accessory molecule-1; EBV, Epstein-Barr virus; EC, endothelial cells; ECM, extracellular matrix; Fcγ RIII, low-affinity IgG receptor isoform A; FDC, follicular dendritic cells; G, granulocytes; GC, germinal center; GITR, glucocorticoid-induced TNFR-related protein; GPI, glycosyl phosphatidylinositol; HTA, human thymocyte antigen; HVEM, herpesvirus entry mediator; ICOS, inducible T-cell co-stimulator; Ig, immunoglobulin; IgG, immunoglobulin G; LAG-3, lymphocyte-activation gene 3; LCA, leukocyte common antigen; LPS, lipopolysaccharide; MHC-I, major histocompatibility complex class I; MP, macrophages; Mr, relative molecular mass; NK, natural killer cells; P, platelets; PBT, peripheral blood T cells; PD-1, programmed cell death-1; PI, phosphatidylinositol; PI3K, phosphatidylinositol 3-kinase; PLC, phospholipase C; PTP, protein tyrosine phosphatase; PVR, polio virus receptor; PVRL2, polio virus receptor-related 2; RCA, regulators of complement activation; SABP, seminal actin binding protein; TCR, T-cell receptor; TFH, T follicular helper cells; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor. Note: For an expanded list of cluster of differentiation (CD) human antigens, see Harrison’s Online at accessmedicine.com; and for a full list of CD human antigens from the most recent Human Workshop on Leukocyte Differentiation Antigens (VII), D Mason, P Andre, A Bensussan, et al (eds): Leucocyte Typing VII. Oxford: Oxford University Press, 2002. Source: Compiled from T Kishimoto et al (eds): Leukocyte Typing VI. New York: Garland Publishing, 1997; R Brines et al: Immunol Today 18S:1, 1997; and D Mason et al: CD antigens 2002. Blood 99:3877, 2002. ■ ■PATTERN RECOGNITION Major PRR families of proteins include transmembrane proteins, such as the Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), and cytoplasmic proteins, such as the retinoic acid–inducible gene (RIG)- 1-like receptors (RLRs) and NOD-like receptors (NLRs) (Table 360-4). A major group of PRR collagenous glycoproteins with C-type lectin domains are termed collectins and include the serum protein mannosebinding lectin (MBL). MBL and other collectins, as well as two other protein families—the pentraxins (such as C-reactive protein and serum amyloid P) and macrophage scavenger receptors—all have the property of opsonizing (coating) bacteria for phagocytosis by macrophages and TABLE 360-2  Major Components of the Innate Immune System Pattern recognition receptors (PRRs) Toll-like receptors (TLRs), C-type lectin receptors (CLRs), retinoic acid–inducible gene (RIG)-1-like receptors (RLRs), and NOD-like receptors (NLRs) Antimicrobial peptides α-Defensins, β-defensins, cathelin, protegrin, granulysin, histatin, secretory leukoprotease inhibitor, and probiotics Cells Macrophages, dendritic cells, innate lymphoid cells (ILC1, ILC2, ILC3, NK cells, lymphoid tissue inducer [LTi] cells), mucosal-associated invariant T (MAIT) cells, NK-T cells, neutrophils, eosinophils, mast cells, basophils, and epithelial cells Complement components Classic and alternative complement pathway, and proteins that bind complement components Cytokines Autocrine, paracrine, endocrine cytokines that mediate host defense and inflammation, as well as recruit, direct, and regulate adaptive immune responses Abbreviation: NK, natural killer. (Continued) DNAM-1 (CD226), TIGIT T-cell activation (DNAM-1), T-cell inhibition (TIGIT) OX40 T-cell survival, cytokine stimulation PD-1 (CD279) Inhibit TCR activation CD40 Co-stimulatory for T-cell activation, B-cell proliferation and differentiation Inhibits T-cell proliferation can also activate the complement cascade to lyse bacteria. Integrins are cell-surface adhesion molecules that affect attachment between cells and the extracellular matrix and mediate signal transduction that reflects the chemical composition of the cell environment. For example, integrins signal after cells bind bacterial lipopolysaccharide (LPS) and activate phagocytic cells to ingest pathogens. There are multiple connections between the innate and adaptive immune systems; these include (1) a plasma protein, LPS-binding protein, that binds and transfers LPS to the macrophage LPS recep­ tor, CD14; (2) the human family of proteins called Toll-like receptor proteins (TLRs), some of which are associated with CD14, bind LPS, and signal epithelial cells, DCs, and macrophages to produce cytokines and upregulate cell-surface molecules that signal the initiation of adaptive immune responses (Fig. 360-1, Table 360-3); and (3) families of intracellular microbial sensors called NLRs and RLRs. Proteins in the Toll family can be expressed on macrophages, DCs, and B cells as well as on a variety of nonhematopoietic cell types, including respira­ tory epithelial cells. Eleven TLRs have been identified in humans (Table 360-3). Upon ligation, TLRs activate a series of intracellular events that lead to the killing of bacteria- and viral-infected cells as well as to the recruitment and ultimate activation of antigen-specific T and B lymphocytes (Fig. 360-1). Importantly, signaling by massive amounts of LPS through TLR4 leads to the release of high levels of cytokines that mediate LPS-induced shock. Mutations in TLR4 proteins in mice pro­ tect from LPS shock, and TLR mutations in humans can protect from LPS-induced inflammatory diseases such as LPS-induced asthma. Table 360-4 lists diseases caused by gene variants in nucleic acid–sensing Toll family and related receptors. Two other families of cytoplasmic PRRs are the NLRs and the RLRs. These families, unlike the TLRs, are composed primarily of soluble TABLE 360-3  Pattern Recognition Receptors (PRRs) and Their Ligands PRR LOCALIZATION LIGAND ORIGIN OF THE LIGAND TLR         TLR1 Plasma membrane Triacyl lipoprotein Bacteria   TLR2 Plasma membrane Lipoprotein Bacteria, viruses, parasite, self   TLR3 Endolysosome dsRNA Virus   TLR4 Plasma membrane LPS Bacteria, viruses, self   TLR5 Plasma membrane Flagellin Bacteria   TLR6 Plasma membrane Diacyl lipoprotein Bacteria, viruses   TLR7 (human TLR8) Endolysosome ssRNA Virus, bacteria, self   TLR9 Endolysosome CpG-DNA Virus, bacteria, protozoa, self   TLR10 Endolysosome Unknown Unknown   TLR11 Plasma membrane Profilin-like molecule Protozoa RLR         RIG-I Cytoplasm Short dsRNA, triphosphate dsRNA RNA viruses, DNA virus   MDA5 Cytoplasm Long dsRNA RNA viruses (Picornaviridae)   LGP2 Cytoplasm Unknown RNA viruses NLR         NOD1 Cytoplasm iE-DAP Bacteria   NOD2 Cytoplasm MDP Bacteria CLR         Dectin-1 Plasma membrane β2-Glucan Fungi   Dectin-2 Plasma membrane β2-Glucan Fungi   MINCLE Plasma membrane SAP130 Self, fungi Abbreviations: CLR, C-type lectin receptors; dsRNA, double-strand RNA; iE-DAP, D-glutamyl-meso-diaminopimelic acid moiety; LGP2, Laboratory of Genetics and Physiology 2 protein encoded by the gene DHX58; MDA5, melanoma differentiation-associated protein 5; MDP, MurNAc-L-Ala-D-isoGln, also known as muramyl dipeptide; MINCLE, macrophage-inducible C-type lectin; NLR, NOD-like receptor; NOD, NOTCH protein domain; RIG, retinoic acid–inducible gene; RLR, RIG-like receptors; SAP130, Sin-3 associated protein 130; TLR, Toll-like receptor. Source: Reproduced with permission from O Takeuchi: Pattern recognition receptors and inflammation. Cell 140:805, 2010. Triacylated lipopeptides Diacylated lipopeptides Flagellin Unknown LPS CD14 TLR4 TLR2 TLR1 TLR2 TLR6 TLR5 TLR10 MYD88 MYD88 TIRAP TRIF TRAM TRIF IRF3 TLR3 dsRNA Endosome IRF3 Inflammatory cytokines and/ or chemokines Nucleus IFN-β FIGURE 360-1  Overview of major TLR signaling pathways. All TLRs signal through MYD88, with the exception of TLR3. TLR4 and the TLR2 subfamily (TLR1, TLR2, TLR6) also engage TIRAP (Toll-interleukin 1 receptor domain-containing adapter protein). TLR3 signals through TRIF (Toll-interleukin 1 receptor domain-containing adapter-inducing interferon-β). TRIF is also used in conjunction with TRAM (TRIF-related adaptor molecule) in the TLR4-MYD88-independent pathway. Dashed arrows indicate translocation into the nucleus. dsRNA, double-strand RNA; IFN, interferon; IRF3, interferon regulatory factor 3; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor-κB; ssRNA, single-strand RNA; TLR, Toll-like receptor. (Reproduced with permission from D Van Duin et al: Triggering TLR signaling in vaccination. Trends Immunol 27:49, 2006.) CHAPTER 360 Introduction to the Immune System Flagellin TLR11 Plasma membrane MYD88 TLR9 CpG IRAK ssRNA Endosome TLR7 or TLR8 TRAF-6 NF-κB MAPK NF-κB TABLE 360-4  Diseases Caused by Gene Variants in Nucleic Acid-Sensing Receptors and Related Proteins CHANGE IN FUNCTION LOCATION LIGAND OR PARTNER GENE PROTEIN DNASE1 DNASE1 LOF Extracellular dsDNA (NETs) SLE Yes PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders DNASE1L3 DNASE1L3 LOF Extracellular Nucleosomes exposed on microparticles or apoptotic bodies TLR7 TLR7 GOF Endosomal ssRNA, 2’3’cGMP SLE 17 Yes TLR9 TLR9 – Endosomal CpG dsDNA N/A – No MyD88 MyD88 – Endosomal TLRs N/A (GOF) – No ADA2 ADA2 LOF Endolysosomal Adenosine, Sneddon syndrome No         2’-deoxyadenosine Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome (DADA2) DNASE2 DNASE2 LOF Lysosomal Exogenous DNA Autoinflammatory-pancytopenia syndrome TREX1 TREX1 LOF Cytoplasmic DNA (retroviral/retrotransposon) AGS 1 Yes         Chilblain lupus Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations           Susceptibility to SLE TMEM173 STING LOF Cytoplasmic cGAMP and excess DNA STING-associated vasculopathy, infantile-onset CGAS cGAS – Cytoplasmic Cytosolic DNA N/A (GOF) – No SAMHD1 SAMHD1 LOF Cytoplasmic dNTPs Chilblain lupus? Yes           AGS 5 RNASEH2A RNASEH2A LOF Cytoplasmic RNA in RNA-DNA hybrids AGS 4 Yes RNASEH2B RNASEH2B LOF Cytoplasmic RNA in RNA-DNA hybrids AGS 2 Yes RNASEH2C RNASEH2C LOF Cytoplasmic RNA in RNA-DNA hybrids AGS 3 Yes IFIH1 MDA5 GOF Cytoplasmic Long dsRNA AGS 7 Yes RIGI DDX58 GOF Cytoplasmic Short dsRNA Singleton-Merten syndrome 2 No MAVS MAVS – Cytoplasmic – N/A (GOF) – No AIM2 AIM2 – Cytoplasmic Cytosolic dsDNA N/A – No IFI16 IFI16 – Nuclear Viral DNA or damaged self-DNA N/A (GOF) – No Note: See the online catalogue of human genes and genetic disorders (OMIM) at https://omim.org. Abbreviations: GOF, gain of function; LOF, loss of function; N/A, not applicable; SLE, systemic lupus erythematosus. Source: Reproduced with permission from CG Vinuesa CG et al: Innate virus-sensing pathways in B cell systemic autoimmunity. Science 380:478, 2023. intracellular proteins that scan host cell cytoplasm for intracellular pathogens (Tables 360-2 and 360-3). The intracellular microbial sensors, NLRs, after triggering, form large cytoplasmic complexes termed inflammasomes, which are aggre­ gates of molecules including NOD-like receptor pyrin (NLRP) proteins (Table 360-5). Inflammasomes activate inflammatory caspases and IL-1β in the presence of nonbacterial danger signals (cell stress) and bacterial PAMPs. Mutations in inflammasome proteins can lead to chronic inflammation in a group of periodic febrile diseases called autoinflammatory syndromes. Polymorphisms in inflammasome com­ ponents can either protect or enhance risk of infections or autoimmune/ autoinflammatory diseases (Table 60-4). Inflammasomes are activated upon sensing of PAMPs. Crystallopathies are diseases caused by tissue crystal deposition such as monosodium urate that can activate the inflammasome and, in the case of urate deposition, can lead to gout with arthritis or renal disease. ■ ■EFFECTOR CELLS OF INNATE IMMUNITY Cells of the innate immune system and their roles in the first line of host defense are listed in Table 360-6. Equally important as their roles in the mediation of innate immune responses are the roles that each cell type plays in recruiting T and B lymphocytes of the adaptive immune system to engage in specific pathogen responses. Monocytes-Macrophages  Monocytes arise from precursor cells within bone marrow (Fig. 360-2) and circulate with a half-life ranging AUTOIMMUNE OR AUTOINFLAMMATORY DISEASE IN OMIM LUPUS SUSCEPTIBILITY ALLELES OMIM NUMBER SLE16 Yes No Yes Singleton-Merten syndrome 1 from 1 to 3 days. Monocytes leave the peripheral circulation via capil­ laries and migration into a vast extravascular cellular pool. Tissue macrophages arise from monocytes that have migrated out of the circulation and by in situ proliferation of macrophage precursors in tis­ sue. Common locations where tissue macrophages (and certain of their specialized forms) are found are lymph node, spleen, bone marrow, perivascular connective tissue, serous cavities such as the peritoneum, pleura, skin connective tissue, lung (alveolar macrophages), liver (Kupffer cells), bone (osteoclasts), central nervous system (microglia cells), and synovium (type A lining cells). In general, monocytes-macrophages are on the first line of defense associated with innate immunity and ingest and destroy microorgan­ isms through the release of toxic products such as hydrogen peroxide (H2O2) and nitric oxide (NO). Inflammatory mediators produced by macrophages attract additional effector cells such as neutrophils to the site of infection. Macrophage mediators include prostaglandins; leukotrienes; platelet activating factor; cytokines such as IL-1, TNF-α, IL-6, and IL-12; and chemokines (Tables 360-7 and 360-8). Although monocytes-macrophages were originally thought to be the major APCs of the immune system, it is now clear that cell types called dendritic cells are the most potent and effective classical APCs in the body (see below). Monocytes-macrophages mediate innate immune effector functions such as destruction of antibody-coated bac­ teria, tumor cells, or even normal hematopoietic cells in certain types of autoimmune cytopenias. Monocytes-macrophages ingest bacteria TABLE 360-5  Mutations in Innate Inflammasome Molecules Associated with Clinical Disease Inherited Inflammasomopathies INHERITED PATTERN AND EFFECT PHENOTYPE MUTATED GENE DISEASE NLRP1 NLRP1-associated autoinflammation with arthritis and dyskeratosis Autosomal dominant GoF Hyperkeratotic ulcerative skin lesions, fever, arthritis, ANA NLRP3 Cryopyrin-associated periodic syndromes (CAPS) Autosomal dominant GoF Spectrum from cold-induced urticaria and fever to CNS inflammation and bone overgrowth NLRC4 Autoinflammatory infantile fever with enterocolitis (AIFEC) Autosomal dominant GoF Recurrent MAS, enterocolitis, cold-induced fever and urticaria, CNS inflammation MEFV Familial Mediterranean fever (FMF) Autosomal recessive LoF or gene-dosage-dependent autosomal dominant GoF Genetic Polymorphisms in Inflammasome Components and Human Infectious Diseases INFECTIOUS AGENT/DISEASE GENE VARIANT ID Candida albicans (recurrent vulvovaginal candidiasis) NLRP3 rs74163773 Increased Risk Chlamydia trachomatis NLRP3 rs12065526 Unknown Risk HCV NLRP3 rs1539019; rs35829419 Unknown; increased Protection HIV-1 NLRP3 rs10754558 Increased Protection   IFI16 rs1417806 Increased Protection HPV NLRP1 rs11651270 Increased Protection   NLRP3 rs10754558 Increased Protection HSV-2 IFI16 rs2276404 Increased Protection HTLV NLRP3 rs10754558 Increased Protection Microbial infection in lungs NLRC4 rs212704 Decreased Risk Mycobacterium leprae NLRP1 rs2670660, rs12150220 Increased Protection     rs2137722 (Haplotype)   Mycobacterium tuberculosis NLRP3 rs10754558 Increased Protection     rs10754558 Increased Risk   CARD8 rs6509365 Unknown Risk   NLRC4 rs385076 Decreased Protection Plasmodium vivax NLRP1 rs12150220 Increased Risk Renal parenchymal infections NLRP3 rs4612666 Increased Protection Streptococcus pneumoniae NLRP1 rs11651270 Increased Risk   CARD8 rs2043211 Increased   Trypanosoma cruzi NLRP1 rs11691270 Increased Risk   CASP1 rs501192 Unknown Risk Genetic Polymorphisms in Inflammasome Components and Autoimmune in Polygenic Autoinflammatory Diseases Addison disease NLRP1 rs12150220 Increased Risk Ankylosing spondylitis NLRP3 rs4612666 Increased Risk   MEFV rs224204 Unknown Risk   CARD8 rs2043211 Increased Protection Autoimmune thyroiditis NLRP1 rs12150220, rs2670660 Increased Risk   AIM2 rs855873 Unknown Risk Behçet disease AIM2 rs855873 Unknown Risk   IFI16 rs6940 Decreased   Celiac disease NLRP3 rs35829419 Increased Protection; risk IBD: Crohn’s disease (CD) and ulcerative colitis (UC) NLRP3 rs35829419 Increased Risk (men)     Increased Protection     rs10754558 Increased Risk     rs10925019 Unknown Risk     rs4925648 Unknown Risk     rs4353135, rs55646866; rs4266924, rs6672995, rs10733113 PREDOMINANT EFFECTOR CELLS CHAPTER 360 Keratinocytes Monocytes, granulocytes (neutrophils), chondrocytes Introduction to the Immune System Monocytes/macrophages Fever, serositis, rash, SAA amyloidosis Neutrophils, monocytes, serosal and synovial fibroblasts EFFECT ON INFLAMMASOME ACTIVATION ASSOCIATION Decreased; unknown Risk (Continued) TABLE 360-5  Mutations in Innate Inflammasome Molecules Associated with Clinical Disease INFECTIOUS AGENT/DISEASE GENE VARIANT ID IBD: Crohn’s disease (CD) and ulcerative colitis (UC) (Cont.) MEFV rs182674, rs224217, rs224225, rs224224, rs224223, rs224222 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders   CARD8 rs2043211 Increased Risk         Protection     rs1972619 Unknown Risk HS purpura MEFV rs3743930 Unknown Risk Kawasaki disease NLRP1 rs11651270, rs8079034, rs3744717, rs11078571, rs16954813, rs8079727 Multiple sclerosis NLRP3 rs3806265, rs10754557 Unknown Risk     rs35829419 Increased Risk   NLRC4 rs479333 Decreased Protection PFAPA CARD8 rs140826611 Unknown Risk Psoriasis NLRP1 rs8079034 Unknown Risk   NLRP3 rs3806265, rs10754557 Unknown Risk     rs10733113 Unknown Risk   CARD8 rs2043211 Increased Risk   AIM2 rs2276405 Unknown Protection Psoriatic JIA NLRP3 rs4353135 Decreased Risk     rs3806265 Unknown Risk   MEFV rs224204 Unknown Risk Rheumatoid arthritis NLRP1 rs878329 Unknown Risk   NLRP3 rs35829419 Increased Risk     rs10754558 Increased Risk     rs10159239, rs4925648, rs4925659   CASP5 rs9651713 Unknown Risk SLE NLRP1 rs12150220, rs2670660 Increased Risk Systemic sclerosis NLRP1 rs8182352 Unknown Risk Type 1 diabetes NLRP1 rs12150220 Increased Risk     rs2670660, rs11651270 Increased Protection   NLRP3 rs10754558 Increased Protection Vitiligo NLRP1 rs12150220 Increased Risk     rs2670660 Increased Risk     rs8182352 Unknown Risk     rs6502867 Unknown Risk     rs1008588 Unknown Risk Note: Mutated gene and respective syndrome name are reported for inflammasomopathies, as well as inheritance pattern and effect of mutations, clinical phenotype, and predominant disease effector cells. Inflammasome variants previously associated with infectious agents and/or diseases are briefly resumed from literature (https://www .ncbi.nlm.nih.gov/pubmed). Significantly associated polymorphisms were grouped according to the infectious agent/disease. Infectious agent or disease (in alphabetical order), gene name (gene), identification number of polymorphism (ID), resulting effect on inflammasome activation (“increased,” “decreased,” or “unknown”), cohort origin (cohort) and eventually specifications (severity, etc.), sample size (n), and type (case/control or cases only), association result (“risk” or “protection”), and respective reference are reported. Abbreviations: ANA, antinuclear antibodies; CNS, central nervous system; GoF, gain-of-function; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HPV, human papillomavirus; HS, Henoch-Schönlein; HSV, herpes simplex virus; HTLV, human T-lymphotropic virus; IBD, inflammatory bowel disease; JIA, juvenile idiopathic arthritis; LoF, loss-of-function; MAS, macrophage activation syndrome; PFAPA, periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis; SAA, serum amyloid A; SLE, systemic lupus erythematosus. Source: Reproduced with permission from FP Fernandes et al: Inflammasome genetics and complex diseases: A comprehensive review. Eur J Hum Genet 28:1307, 2020. or are infected by viruses, and in doing so, they frequently undergo programmed cell death or apoptosis. Macrophages that are infected by intracellular infectious agents are recognized by DCs as infected and apoptotic cells and are phagocytosed by DCs. In this manner, DCs “cross-present” infectious agent antigens of macrophages to T cells. Activated macrophages can also mediate antigen-nonspecific lytic activity and eliminate cell types such as tumor cells in the absence of antibody. This activity is largely mediated by cytokines (i.e., TNF-α and IL-1). Monocytes-macrophages express lineage-specific molecules (e.g., the cell-surface LPS receptor, CD14) as well as surface receptors for a number of molecules, including the Fc region of IgG, activated complement components, and various cytokines (Table 360-7). (Continued) EFFECT ON INFLAMMASOME ACTIVATION ASSOCIATION Unknown Risk Increased (haplotype) Risk Unknown Risk Dendritic Cells  Human DCs contain several subsets, including myeloid DCs and plasmacytoid DCs. Myeloid DCs can differentiate into either macrophages-monocytes or tissue-specific DCs. In contrast to myeloid DCs, plasmacytoid DCs are potent producers of TLR-7 dependent type I IFN (e.g., IFN-α) in response to free virus and virusinfected cells. The maturation of DCs is regulated through cell-to-cell contact and soluble factors, and DCs attract immune effectors through secretion of chemokines. When DCs come in contact with bacterial products, viral proteins, or host proteins released as danger signals from distressed host cells (Fig. 360-2), infectious agent molecules bind to various TLRs and activate DCs to release cytokines and chemokines that drive cells of the innate immune system to become activated to TABLE 360-6  Cells of the Innate Immune System and Their Major Roles in Triggering Adaptive Immunity CELL TYPE MAJOR ROLE IN INNATE IMMUNITY MAJOR ROLE IN ADAPTIVE IMMUNITY Macrophages Phagocytose and kill bacteria; produce antimicrobial peptides; bind LPS; produce inflammatory cytokines Plasmacytoid dendritic cells (DCs) of lymphoid lineage Produce large amounts of interferon-α (IFN-α), which has antitumor and antiviral activity, and are found in T-cell zones of lymphoid organs; they circulate in blood Myeloid DCs are of two types: interstitial and Langerhans-derived Interstitial DCs are strong producers of IL-12 and IL-10 and are located in T-cell zones of lymphoid organs, circulate in blood, and are present in the interstices of the lung, heart, and kidney; Langerhans DCs are strong producers of IL-12; are located in T-cell zones of lymph nodes, skin epithelia, and the thymic medulla; and circulate in blood ILC1 cells Weakly cytotoxic, dependent on T-bet transcription factor, first line of defense against viruses and bacteria ILC2 cells Mediate innate responses to parasites/helminths, repair damaged tissues by producing amphiregulin ILC3 cells Innate immune response to extracellular bacteria and gut microbiome Lymphoid tissue inducer (LTi) cells Critical for formation of secondary lymphoid tissue during embryogenesis Natural killer (NK) cells Kill foreign and host cells that have low levels of MHC+ selfpeptides. Express NK receptors that inhibit NK function in the presence of high expression of self-MHC. NK-T cells Lymphocytes with both T-cell and NK surface markers that recognize lipid antigens of intracellular bacteria such as Mycobacterium tuberculosis by CD1 molecules and kill host cells infected with intracellular bacteria Neutrophils Phagocytose and kill bacteria, produce antimicrobial peptides Produce nitric oxide synthase and nitric oxide, which inhibit apoptosis in lymphocytes and can prolong adaptive immune responses Eosinophils Kill invading parasites Produce IL-5, which recruits Ig-specific antibody responses Mast cells and basophils Release TNF-α, IL-6, and IFN-γ in response to a variety of bacterial PAMPs Epithelial cells Produce antimicrobial peptides; tissue-specific epithelia produce mediator of local innate immunity; e.g., lung epithelial cells produce surfactant proteins (proteins within the collectin family) that bind and promote clearance of lung-invading microbes Abbreviations: GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-4, IL-5, IL-6, IL-10, and IL-12, interleukin 4, 5, 6, 10, and 12, respectively; ILC, innate lymphoid cell; MHC, major histocompatibility complex: LPS, lipopolysaccharide; PAMP, pathogen-associated molecular patterns; TGF, transforming growth factor; TH, helper T cell; TNF-α, tumor necrosis factor-alpha. Source: Reproduced with permission from R Medzhitov, CA Janeway: Curr Opinion Immunol 9:4-9; 1997. respond to invading organisms, and recruit T and B cells of the adap­ tive immune system to respond. Plasmacytoid DCs produce antiviral IFN-α that activates NK cell killing of pathogen-infected cells; IFN-α also activates CD8 T cells to mature into antipathogen cytotoxic (killer) T cells. Following contact with pathogens, both plasmacytoid and myeloid DCs produce chemokines that attract helper and cytotoxic T cells, B cells, polymorphonuclear cells, and naïve and memory T cells as well as regulatory T cells to ultimately dampen the immune response once the pathogen is controlled. TLR engagement on DCs upregulates MHC class II, B7-1 (CD80), and B7-2 (CD86), which enhance DCspecific antigen presentation and induce cytokine production. Thus, DCs are important bridges between early (innate) and later (adaptive) immunity. DCs also modulate and determine the types of immune responses induced by pathogens via the TLRs expressed on DCs (TLR7–9 in plasmacytoid DCs, TLR4 on monocytoid DCs) and via the TLR adapter proteins that are induced to associate with TLRs (Fig. 360-1, Table 360-1). In addition, other PRRs, such as C-type lectins, NLRs, and mannose receptors, upon ligation by pathogen products, activate cells of the adaptive immune system and, like TLR stimulation, by a variety of factors, determine the type and quality of the adaptive immune response that is triggered. Produce IL-1 and TNF-α to upregulate lymphocyte adhesion molecules and chemokines to attract antigen-specific lymphocyte. Produce IL-12 to recruit TH1 T helper cell responses; upregulate co-stimulatory and MHC molecules to facilitate T and B lymphocyte recognition and activation. Macrophages and dendritic cells, after LPS signaling, upregulate co-stimulatory molecules B7-1 (CD80) and B7-2 (CD86) that are required for activation of pathogen-specific T cells. There are also Toll-like proteins on B cells and dendritic cells that, after LPS ligation, induce CD80 and CD86 on these cells for T-cell antigen presentation. CHAPTER 360 Introduction to the Immune System IFN-α is a potent activator of macrophage and mature DCs to phagocytose invading pathogens and present pathogen antigens to T and B cells. Interstitial DCs are potent activators of macrophage and mature DCs to phagocytose invading pathogens and present pathogen antigens to T and B cells. Produce IFN-γ to recruit CD4 TH1 T cells Produce IL-4, IL-5, IL-13; recruit CD4 TH2 T cells Produce IL-22, IL-17, GM-CSF, lymphotoxin; recruit CD4 TH17 T cells Produce lymphotoxin for lymph node and Peyer’s patch development in which adaptive immune responses occur Produce TNF-α and IFN-γ, which recruit TH1 helper T-cell responses Produce IL-4 to recruit TH2 helper T-cell responses, IgG1 and IgE production Produce IL-4, which recruits TH2 helper T cell responses, and recruit IgG1- and IgE-specific antibody responses Produces TGF-β, which triggers IgA-specific antibody responses Innate Lymphoid Cells  ILCs are comprised of ILC1, ILC2, ILC3, lymphoid tissue inducer (LTi), and NK cells. ILC1, ILC2, ILC3, and LTi are primarily tissue resident cells. ILCs develop from a common lymphoid precursor in the bone marrow and then differentiate into one of five ILC types—ILC1, ILC2, ILC3, LTi, or NK cells—based on their development (Fig. 360-3A) and function (Fig. 360-3B). NK cells and ILC1s depend on T-bet transcription factor for their development and function and produce IFN-γ. NK cells are innate analogues to CD8 cytotoxic T cells in that they both mediate granzyme and perforinbased cytotoxic cell activity. ILC1s mirror CD4 TH1 lymphocytes and react to intracellular pathogens such as viruses and to tumors. ILC2s are the analogues of TH2 CD4 T cells and are dependent on GATA3 and RORα factors and produce type 2 cytokines, such as IL-5 and IL-13. ILC2s respond to extracellular parasites and allergens. ILC3s and LTi cells are dependent on transcription factor retinoic acid receptor-related orphan receptor γt (RORγt) and produce IL-17. ILC3s are analogues of CD4 TH17 lymphocytes and attack extracellular pathogens such as bacte­ ria and fungi. LTi cells are critical for the formation of lymph nodes and Peyer’s patches in gut during fetal development (Fig. 360-3B). In the intestine, a critical function of the immune system is not only to quickly respond to pathogens but also to ignore benign Stem cell PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders B cell Plasmacytoid dendritic cell Natural killer cell Monocyte/ macrophage Dendritic cell Neutrophilic, eosinophilic, or basophilic granulocyte Antibodies antigen presentation IL-12 antigen presentation IL-1, IL-6 phagocytosis of microbes IFN-α antigen presentation GATA3 GATA3 RORγt PU 1 Fox3p Tbet Bcl6 TFH13 cell TH1 cell TH2 cell TH17 cell TH9 cell T regulatory cell T follicular helper cell (TFH) IL-13 IFN-γ IL-4 IL-5 IL-13 IL-17 IL-22 IL-9 IL-10 TGF-β IL-21 Cytotoxic T-cell responses B-cell affinity maturation in germinal centers IgE allergic reaction FIGURE 360-2  Model of immune effector cell development. Hematopoietic stem cells differentiate into T cells, antigen-presenting dendritic cells, natural killer cells, macrophages, granulocytes, or B cells. Foreign antigen is processed by dendritic cells, macrophages, and B cells, and peptide fragments of foreign antigen are presented to CD4+ and/or CD8+ T cells. CD8+ T-cell activation leads to induction of cytotoxic T lymphocyte (CTL) or killer T-cell generation, as well as induction of cytokine-producing CD8+ cytotoxic T cells. Granulocytes (neutrophils, eosinophils, or basophils) are effector cells of the innate immune system and mediate anti-infectious agent activity by cytokine production, infectious agent killing, or both. TH1 CD4+ T cells play an important role in defense against intracellular microbes and help in the generation of CD8+ cytotoxic T cells. TH2 CD4+ T cells producing interferon (IFN) γ or interleukin (IL) 4, IL-5, or IL-13 regulate Ig class switching and determine the type of antibody produced. TH17 cells secrete IL-17 and IL-22, TH9 cells secrete IL-9, and TFH13 cells secrete IL-4, IL-5, and IL-13. TH17 and TH9 CD4 T cells are linked to mediation of autoimmune disease, and TFH13 cells are linked to IgE-mediated anaphylaxis. CD4+ T regulatory cells produce IL-10 and transforming growth factor (TGF)-β and downregulate T- and B-cell responses once the microbe has been eliminated. Each of the types of CD4+ T cells are regulated by different transcription factors, and the key transcription factors are shown in the circles above each CD4+ T-cell type. Lymphoid precursor T cell IFN-α antigen presenting Antibodydependent cellular cytotoxicity tumor cell killing CD4+ T cell CD8+ cytotoxic T cell Kill pathogeninfected cells Differentiation/ activation Kill tumor cells Linked to autoimmune disease mediation T-cell function downregulation; prevent autoimmune disease Antibody responses; stimulate eosinophils TABLE 360-7  Cytokines and Cytokine Receptors CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY IL-1α, β Type I IL-1r, type II IL-1r Monocytes/macrophages, B cells, fibroblasts, most epithelial cells including thymic epithelium, endothelial cells IL-2 IL-2r α, β, common γ T cells T cells, B cells, NK cells, monocytes-macrophages IL-3 IL-3r, common β T cells, NK cells, mast cells Monocytes-macrophages, mast cells, eosinophils, bone marrow progenitors IL-4 IL-4r α, common γ T cells, mast cells, basophils T cells, B cells, NK cells, monocytes-macrophages, neutrophils, eosinophils, endothelial cells, fibroblasts IL-5 IL-5r α, common γ T cells, mast cells, eosinophils Eosinophils, basophils, murine B cells IL-6 IL-6r, gp130 Monocytes-macrophages, B cells, fibroblasts, most epithelium including thymic epithelium, endothelial cells IL-7 IL-7r α, common γ Bone marrow, thymic epithelial cells IL-8 CXCR1, CXCR2 Monocytes-macrophages, T cells, neutrophils, fibroblasts, endothelial cells, epithelial cells IL-9 IL-9r α, common γ T cells Bone marrow progenitors, B cells, T cells, mast cells IL-10 IL-10r Monocytes-macrophages, T cells, B cells, keratinocytes, mast cells IL-11 IL-11r α, gp130 Bone marrow stromal cells Megakaryocytes, B cells, hepatocytes IL-12 (35-kDa and 40-kDa subunits) IL-12r Activated macrophages, dendritic cells, neutrophils IL-13 IL-13r/IL-4r α T cells (TH2) Monocytes-macrophages, B cells, endothelial cells, keratinocytes IL-14 Unknown T cells Normal and malignant B cells Induces B-cell proliferation, inhibits antibody secretion, and expands selected B-cell subgroups IL-15 IL-15r α, common γ, IL2r β Monocytes-macrophages, epithelial cells, fibroblasts IL-16 CD4 Mast cells, eosinophils, CD8+ T cells, respiratory epithelium IL-17 IL-17r CD4+ T cells Fibroblasts, endothelium, epithelium, macrophages IL-18 IL-18r (IL-1Rrelated protein) Keratinocytes, macrophages T cells, B cells, NK cells Upregulates IFN-γ production, enhances NK cell cytotoxicity IL-21 IL-δγ chain/IL-21R CD4 T cells NK cells Downregulates NK cell–activating molecules, NKG2D/ DAP10; produced by T follicular helper cells in B-cell germinal centers that stimulate B-cell maturation IL-22 IL-22 R1/IL-10R2 DC, T cells Epithelial cells Innate responses against bacterial pathogens; promotes hepatocyte survival IL-23 IL-12Rb1/IL23R Macrophages, other cell types T cells Opposite effects of IL-12 (↑IL-17, ↑IFN-γ) IL-24 IL-20R1/IL-20R2 IL-22R1/IL-20R2 Macrophages, TH2 cells All cells Upregulates adhesion molecule expression, neutrophil and macrophage emigration, mimics shock, fever, upregulates hepatic acute-phase protein production, facilitates hematopoiesis CHAPTER 360 Promotes T-cell activation and proliferation, B-cell growth, NK-cell proliferation and activation, enhanced monocyte/macrophage cytolytic activity Stimulates hematopoietic progenitors Introduction to the Immune System Stimulates TH2 helper T-cell differentiation and proliferation; stimulates B-cell Ig class switch to IgG1 and IgE anti-inflammatory action on T cells, monocytes; produced by T follicular helper cells in B-cell germinal centers that stimulate B-cell maturation Regulates eosinophil migration and activation T cells, B cells, epithelial cells, hepatocytes, monocytes-macrophages Induces acute-phase protein production, T- and B-cell differentiation and growth, myeloma cell growth, and osteoclast growth and activation T cells, B cells, bone marrow cells Differentiates B-, T-, and NK-cell precursors, activates T and NK cells Neutrophils, T cells, monocytes-macrophages, endothelial cells, basophils Induces neutrophil, monocyte, and T-cell migration, induces neutrophil adherence to endothelial cells and histamine release from basophils, and stimulates angiogenesis; suppresses proliferation of hepatic precursors Induces mast cell proliferation and function, synergizes with IL-4 in IgG and IgE production and T-cell growth, activation, and differentiation Monocytes-macrophages, T cells, B cells, NK cells, mast cells Inhibits macrophage proinflammatory cytokine production, downregulates cytokine class II antigen and B7-1 and B7-2 expression, inhibits differentiation of TH1 helper T cells, inhibits NK cell function, stimulates mast cell proliferation and function, B-cell activation, and differentiation Induces megakaryocyte colony formation and maturation, enhances antibody responses, stimulates acute-phase protein production T cells, NK cells Induces TH1 T helper cell formation and lymphokineactivated killer cell formation; increases CD8+ CTL cytolytic activity; ↓IL-17, ↑IFN-γ Upregulates VCAM-1 and C-C chemokine expression on endothelial cells and B-cell activation and differentiation, and inhibits macrophage proinflammatory cytokine production T cells, NK cells Promotes T-cell activation and proliferation, angiogenesis, and NK cells CD4+ T cells, monocytes- macrophages, eosinophils Promotes chemoattraction of CD4+ T cells, monocytes, and eosinophils; inhibits HIV-1 replication; inhibits T-cell activation through CD3/T-cell receptor Enhances cytokine/chemokine secretion; promotes delayed-type reactions Nonhematopoietic cells such as fibroblasts Promotes wound healing (Continued) TABLE 360-7  Cytokines and Cytokine Receptors (Continued) CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY IL-25 (also called IL-17E) IL-17RB CD4 T cells, mast cells Fibroblasts, endothelium, epithelium, macrophages IL-26 IL-20R1/IL-10R2 TH1, TH17 T cells, synovial cells Epithelial cells Proinflammatory; induces cytokine production PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders IL-27 gp130t wsx-1 Myeloid cells such as macrophages and DCs Myeloid lineage cells; epithelial cells IL-28A (IFN-λ2) IFN-λ receptor 1, IL-28Rα, IL-10Rβ Myeloid lineage cells; epithelial cells IL-28B (IFN-λ3) IFN-λ receptor 1, IL-28Rα, IL-10Rβ Myeloid lineage cells; epithelial cells IL-29 (IFN-λ1) IFN-λ receptor 1, IL-28Rα, IL-10Rβ IL-30 (p28 of IL-27) Activated macrophages and DCs; epithelial malignancies IL-27Rα; gp130+wsx-1 IL-31 IL-31RA/ oncostatin MRβ Eosinophils, CD4 T cells Epithelial cells, monocytes Pruritis, proinflammatory IL-32 (NK4) ? Monocytes, T cells, NK cells, epithelial cells IL-33 (NF-HEV; IL-1 F11) ST-2 Endothelial cells, epithelial cells, fibroblasts, mucosal epithelium IL-34 (C16of77) CSF-1R, PTP-E, CD138 Neurons, Treg, myeloid cells   Anti-inflammatory myeloid cell proliferation IL-35 IL-12Rβ2/ IL-12Rβ2, gp130/ gp130, IL-12Rb2/ gp130 Tregs, Bregs Macrophages, T cells Prevents TH1 and TH17 proliferation; induced Treg/Breg proliferation/anti-inflammatory IL-36R Keratocytes Mucosal epithelial cells Monocytes-macrophages Langerhans cells CD4 T cells IL-36α IL36β IL36γ IL36RA (IL-1 F5) IL-38 IL-10 F10 IL-1R, IL-36R, IL-1RA PL1 Epithelial cells, B cells Epithelial cells, macrophages, DCs, T cells, B cells, plasma cells IL-39 ? Macrophages, DCs, B cells Neutrophils Proinflammatory IL-40 ? B cells, bone marrow/stroma B cells Involved in IgA production, B-cell homeostasis and development IFN-α Type I interferon receptor All cells All cells Promotes antiviral activity; stimulates T-cell, macrophage, and NK-cell activity; direct antitumor effects; upregulates MHC class I antigen expression; used therapeutically in viral and autoimmune conditions IFN-β Type I interferon receptor All cells All cells Antiviral activity; stimulates T-cell, macrophage, and NK-cell activity; direct antitumor effects; upregulates MHC class I antigen expression; used therapeutically in viral and autoimmune conditions IFN-γ Type II interferon receptor T cells, NK cells All cells Regulates macrophage and NK-cell activations; stimulates immunoglobulin secretion by B cells; induction of class II histocompatibility antigens; TH1 T-cell differentiation TNF-α TNFrI, TNFrII Monocytes-macrophages, mast cells, basophils, eosinophils, NK cells, B cells, T cells, keratinocytes, fibroblasts, thymic epithelial cells TNF-β TNFrI, TNFrII T cells, B cells All cells except erythrocytes Cell cytotoxicity, lymph node and spleen development LT-β LTβR T cells All cells except erythrocytes Cell cytotoxicity, normal lymph node development G-CSF G-CSFr; gp130 Monocytes-macrophages, fibroblasts, endothelial cells, thymic epithelial cells, stromal cells GM-CSF GM-CSFr, common β T cells, monocytes-macrophages, fibroblasts, endothelial cells, thymic epithelial cells Proinflammatory; induces cytokine production T cells Collaborates with other cytokines to activate T-cell differentiation Epithelial cells Enhanced clearance of viral infections Epithelial cells Enhanced clearance of viral infections Epithelial cells Enhanced clearance of viral infections Monocytes Anti-inflammatory cytokines; upregulation of breast and prostate cancer metastasis Monocytes, macrophages, bone marrow stroma Angiogenesis, IL-2 production in bone marrow, proinflammatory T cells, mast cells eosinophils, basophils, ILC2s Alarmin cytokine, proinflammatory Epithelial cells, macrophages, DCs, T cells, B cells, plasma cells TH responses, proinflammatory Blocks IL-36; anti-inflammatory All cells except erythrocytes Fever, anorexia, shock, capillary leak syndrome, enhanced leukocyte cytotoxicity, enhanced NK-cell function, acute phase protein synthesis, proinflammatory cytokine induction Myeloid cells, endothelial cells Regulates myelopoiesis; enhances survival and function of neutrophils; clinical use in reversing neutropenia after cytotoxic chemotherapy Monocytes-macrophages, neutrophils, eosinophils, fibroblasts, endothelial cells Regulates myelopoiesis; enhances macrophage bactericidal and tumoricidal activity; mediator of dendritic cell maturation and function; upregulates NK-cell function; clinical use in reversing neutropenia after cytotoxic chemotherapy (Continued) (Continued) TABLE 360-7  Cytokines and Cytokine Receptors CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY M-CSF M-CSFr (c-fms protooncogene) Fibroblasts, endothelial cells, monocytes-macrophages, T cells, B cells, epithelial cells including thymic epithelium LIF LIFr-α; gp130 Activated T cells, bone marrow stromal cells, thymic epithelium OSM OSMr; LIFr; gp130 Activated monocytesmacrophages and T cells, bone marrow stromal cells, some breast carcinoma cell lines, myeloma cells SCF SCFr (c-kit protooncogene) Bone marrow stromal cells and fibroblasts Type I, II, III TGF-β receptor Most cell types Most cell types Downregulates T-cell, macrophage, and granulocyte responses; stimulates synthesis of matrix proteins; stimulates angiogenesis TGF-β (3 isoforms) Lymphotactin/ SCM-1 XCR1 NK cells, mast cells, doublenegative thymocytes, activated CD8+ T cells MCP-1 CCR2 Fibroblasts, smooth-muscle cells, activated PBMCs MCP-2 CCR1, CCR2 Fibroblasts, activated PBMCs Monocytes-macrophages, T cells, eosinophils, basophils, NK cells MCP-3 CCR1, CCR2 Fibroblasts, activated PBMCs Monocytes-macrophages, T cells, eosinophils, basophils, NK cells, dendritic cells MCP-4 CCR2, CCR3 Lung, colon, small intestinal epithelial cells, activated endothelial cells Eotaxin CCR3 Pulmonary epithelial cells, heart Eosinophils, basophils Potent chemoattractant for eosinophils and basophils; induces allergic airways disease; acts in concert with IL-5 to activate eosinophils; antibodies to eotaxin inhibit airway inflammation TARC CCR4 Thymus, dendritic cells, activated T cells MDC CCR4 Monocytes-macrophages, dendritic cells, thymus MIP-1α CCR1, CCR5 Monocytes-macrophages, T cells Monocytes-macrophages, T cells, dendritic cells, NK cells, eosinophils, basophils MIP-1β CCR5 Monocytes-macrophages, T cells Monocytes-macrophages, T cells, NK cells, dendritic cells RANTES CCR1, CCR2, CCR5 Monocytes-macrophages, T cells, fibroblasts, eosinophils CCR6 Dendritic cells, fetal liver cells, activated T cells LARC/MIP-3α/ Exodus-1 ELC/MIP-3β CCR7 Thymus, lymph node, appendix Activated T cells and B cells Chemoattractant for B and T cells; receptor upregulated on EBV-infected B cells and HSV-infected T cells I-309/TCA-3 CCR8 Activated T cells Monocytes-macrophages, T cells SLC/TCA-4/ Exodus-2 CCR7 Thymic epithelial cells, lymph node, appendix, and spleen DC-CK1/PARC Unknown Dendritic cells in secondary lymphoid tissues Monocytes-macrophages Regulates monocyte-macrophage production and function CHAPTER 360 Megakaryocytes, monocytes, hepatocytes, possibly lymphocyte subpopulations Induces hepatic acute-phase protein production; stimulates macrophage differentiation; promotes growth of myeloma cells and hematopoietic progenitors; stimulates thrombopoiesis Introduction to the Immune System Neurons, hepatocytes, monocytes-macrophages, adipocytes, alveolar epithelial cells, embryonic stem cells, melanocytes, endothelial cells, fibroblasts, myeloma cells Induces hepatic acute-phase protein production; stimulates macrophage differentiation; promotes growth of myeloma cells and hematopoietic progenitors; stimulates thrombopoiesis; stimulates growth of Kaposi’s sarcoma cells Embryonic stem cells, myeloid and lymphoid precursors, mast cells Stimulates hematopoietic progenitor cell growth, mast cell growth; promotes embryonic stem cell migration T cells, NK cells Chemoattractant for lymphocytes; only known chemokine of C class Monocytes-macrophages, NK cells, memory T cells, basophils Chemoattractant for monocytes, activated memory T cells, and NK cells; induces granule release from CD8+ T cells and NK cells; potent histamine-releasing factor for basophils; suppresses proliferation of hematopoietic precursors; regulates monocyte protease production Chemoattractant for monocytes, memory and naïve T cells, eosinophils,? NK cells; activates basophils and eosinophils; regulates monocyte protease production Chemoattractant for monocytes, memory and naïve T cells, dendritic cells, eosinophils,? NK cells; activates basophils and eosinophils; regulates monocyte protease production Monocytes-macrophages, T cells, eosinophils, basophils Chemoattractant for monocytes, T cells, eosinophils, and basophils T cells, NK cells Chemoattractant for T and NK cells Activated T cells Chemoattractant for activated T cells; inhibits infection with T-cell tropic HIV-1 Chemoattractant for monocytes, T cells, dendritic cells, and NK cells, and weak chemoattractant for eosinophils and basophils; activates NK-cell function; suppresses proliferation of hematopoietic precursors; necessary for myocarditis associated with coxsackievirus infection; inhibits infection with monocytotropic HIV-1 Chemoattractant for monocytes, T cells, and NK cells; activates NK-cell function; inhibits infection with monocytotropic HIV-1 Monocytes-macrophages, T cells, NK cells, dendritic cells, eosinophils, basophils Chemoattractant for monocytes-macrophages, CD4+, CD45Ro+ T cells, CD8+ T cells, NK cells, eosinophils, and basophils; induces histamine release from basophils; inhibits infections with monocytotropic HIV-1 T cells, B cells Chemoattractant for lymphocytes Chemoattractant for monocytes; prevents glucocorticoid-induced apoptosis in some T-cell lines T cells Chemoattractant for T lymphocytes; inhibits hematopoiesis Naïve T cells May have a role in induction of immune responses (Continued) TABLE 360-7  Cytokines and Cytokine Receptors (Continued) CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY TECK CCR9 Dendritic cells, thymus, liver, small intestine GRO-α/MGSA CXCR2 Activated granulocytes, monocytemacrophages, and epithelial cells PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders GRO-β/MIP-2α CXCR2 Activated granulocytes and monocyte-macrophages NAP-2 CXCR2 Platelets Neutrophils, basophils Derived from platelet basic protein; neutrophil chemoattractant and activator IP-10 CXCR3 Monocytes-macrophages, T cells, fibroblasts, endothelial cells, epithelial cells MIG CXCR3 Monocytes-macrophages, T cells, fibroblasts SDF-1 CXCR4 Fibroblasts T cells, dendritic cells,? basophils,? endothelial cells Fractalkine CX3CR1 Activated endothelial cells NK cells, T cells, monocytes-macrophages PF-4 Unknown Platelets, megakaryocytes Fibroblasts, endothelial cells Chemoattractant for fibroblasts; suppresses proliferation of hematopoietic precursors; inhibits endothelial cell proliferation and angiogenesis Abbreviations: B7-1, CD80; B7-2, CD86; Breg, regulatory B cells; CCR, CC-type chemokine receptor; CXCR, CXC-type chemokine receptor; DC, dendritic cell; DC-CK, dendritic cell chemokine; EBV, Epstein-Barr virus; ELC, EB11 ligand chemokine (MIP-1b); G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; GRP, growth-related peptide; HSV, herpes simplex virus; IFN, interferon; Ig, immunoglobulin; IL, interleukin; IP-10, IFN-γ-inducible protein-10; LARC, liver- and activation-regulated chemokine; LIF, leukemia inhibitory factor; MCP, monocyte chemotactic protein; M-CSF, macrophage colony-stimulating factor; MDC, macrophage-derived chemokine; MGSA, melanoma growth-stimulating activity; MHC, major histocompatibility complex; MIG, monokine induced by IFN-γ; MIP, macrophage inflammatory protein; NAP, neutrophil-activating protein; NK, natural killer; OSM, oncostatin M; PARC, pulmonary- and activation-regulated chemokine; PBMC, peripheral blood mononuclear cells; PF, platelet factor; RANTES, regulated on activation, normally T cell–expressed and –secreted; SCF, stem cell factor; SDF, stromal cell–derived factor; SLC, secondary lymphoid tissue chemokine; TARC, thymus- and activation-regulated chemokine; TCA, T-cell activation protein; TECK, thymus-expressed chemokine; TGF, transforming growth factor; TH1 and TH2, helper T cell subsets; TNF, tumor necrosis factor; Treg, regulatory T cells; VCAM, vascular cell adhesion molecule. Sources: Data from JS Sundy et al: Appendix B, in Inflammation, Basic Principles and Clinical Correlates, 3rd ed. J Gallin, R Snyderman (eds). Philadelphia, Lippincott Williams and Wilkins, 1999; J Ye et al: Frontiers in Pharmacology 11; HM Lazear et al: Immunity 43:15, 2015; J Catalan-Dibene et al: J Interferon and Cytokine Research 38:423, 2018. microorganisms or environmental antigens. Inability to prevent immune responses to the gut microbiome can be a factor in the cause of inflammatory bowel diseases (Chap. 337). In healthy individuals, a subset of RORγt+ ILCs, possibly ILC3s, stimulate naïve CD4 T cells to differentiate into peripheral Tregs that suppress immune responses to microbiome organisms. NK cells express surface receptors for the Fc portion of IgG (FcR) (CD16) and for NCAM-I (CD56), and many NK cells express T lineage markers, particularly CD2, CD7, and CD8, and proliferate in response to IL-2. NK cells arise in both bone marrow and thymic microenviron­ ments. In addition to mediating cytotoxicity to foreign or malignant cells, NK cells also mediate ADCC. ADCC is the binding of an opso­ nized (antibody-coated) target cell to an Fc receptor-bearing effector cell via the Fc region of antibody, resulting in target cell lysis. NK cell cytotoxicity is the MHC-unrestricted, non-antibody-mediated killing of target cells, which are usually malignant cell types, transplanted for­ eign cells, or virus-infected cells. Thus, NK cell cytotoxicity may play an important role in immune surveillance and destruction of malig­ nant and virus-infected host cells. NK cell hyporesponsiveness is also observed in patients with Chédiak-Higashi syndrome, an autosomal recessive disease associated with fusion of cytoplasmic granules and defective degranulation of neutrophil lysosomes. NK cells have a variety of surface receptors that have inhibitory or activating functions (Table 360-9). NK immunoglobulin superfamily receptors include the killer cell immunoglobulin-like activating or inhibitory receptors (KIRs), many of which have been shown to have HLA class I ligands. The KIRs are made up proteins with either two (KIR2D) or three (KIR3D) extracellular immunoglobulin domains (D). Moreover, their nomenclature designates their function as either inhibitory KIRs with a long (L) cytoplasmic tail and immunoreceptor tyrosine-based inhibitory motif (ITIM) (KIRDL) or activating KIRs T cells, monocytesmacrophages, dendritic cells Thymic dendritic cell–derived cytokine, possibly involved in T-cell development Neutrophils, epithelial cells,? endothelial cells Neutrophil chemoattractant and activator; mitogenic for some melanoma cell lines; suppresses proliferation of hematopoietic precursors; angiogenic activity Neutrophils and? endothelial cells Neutrophil chemoattractant and activator; angiogenic activity Activated T cells, tumorinfiltrating lymphocytes,? endothelial cells,? NK cells IFN-γ-inducible protein that is a chemoattractant for T cells; suppresses proliferation of hematopoietic precursors Activated T cells, tumorinfiltrating lymphocytes IFN-γ-inducible protein that is a chemoattractant for T cells; suppresses proliferation of hematopoietic precursors Low-potency, high-efficacy T-cell chemoattractant; required for B lymphocyte development; prevents infection of CD4+, CXCR4+ cells by T-cell tropic HIV-1 Cell-surface chemokine/mucin hybrid molecule that functions as a chemoattractant, leukocyte activator, and cell adhesion molecule with a short (S) cytoplasmic tail (KIRDS). NK cell inactivation by KIRs is a central mechanism to prevent damage to normal host cells. Genetic studies have demonstrated the association of KIRs with viral infection outcome, or to outcomes in autoimmune or malignant diseases (Table 360-10). In addition to the KIRs, a second set of immunoglobulin superfam­ ily receptors includes the natural cytotoxicity receptors (NCRs), which include NKp46, NKp30, and NKp44. These receptors help to mediate NK cell activation against target cells. The ligands to which NCRs bind on target cells have been recently recognized to be comprised of mol­ ecules of pathogens such as influenza, cytomegalovirus, and malaria, as well as host molecules expressed on tumor cells. Signaling lym­ phocytic activating molecule (SLAM) family receptors are expressed on hematopoietic cells, with SLAMF2 (CD48), SLAMF4 (2B4), and SLAMF7/CD2-like receptor activating cytotoxic cells (CRACCs) the most prominent on NK cells (Table 360-9). NK cell signaling is, therefore, a highly coordinated series of inhibit­ ing and activating signals that prevent NK cells from responding to uninfected, nonmalignant self-cells; however, they are activated to attack malignant and virally infected cells (Fig. 360-4). Recent evidence suggests that NK cells, although not possessing rearranging immune recognition genes, may be able to mediate recall for NK cell responses to viruses and for immune responses such as contact hypersensitivity. Some NK cells express CD3 and invariant TCR-α chains and are termed NK T cells. TCRs of NK T cells recognize lipid molecules of intracellular bacteria when presented in the context of CD1 molecules on APCs. Upon activation, NK T cells secrete effector cytokines such as IL-4 and IFN-γ. This mode of recognition of intracellular bacteria such as Listeria monocytogenes and Mycobacterium tuberculosis by NK T cells leads to induction of activation of DCs and is thought to be an important innate defense mechanism against these organisms. TABLE 360-8  CC, CXC1, CX3, C1, and XC Families of Chemokines and Chemokine Receptors CHEMOKINE RECEPTOR CHEMOKINE LIGANDS CELL TYPES DISEASE CONNECTION CCR1 CCL3 (MIP-1α), CCL5 (RANTES), CCL7 (MCP-3), CCL14 (HCC1) T cells, monocytes, eosinophils, basophils CCR2 CCL2 (MCP-1), CCL8 (MCP-2), CCL7 (MCP-3), CCL13 (MCP-4), CCL16 (HCC4) Monocytes, dendritic cells (immature), memory T cells CCR3 CCL11 (eotaxin), CCL13 (eotaxin-2), CCL7 (MCP-3), CCL5 (RANTES), CCL8 (MCP-2), CCL13 (MCP-4) Eosinophils, basophils, mast cells, TH2, platelets CCR4 CCL17 (TARC), CCL22 (MDC) T cells (TH2), dendritic cells (mature), basophils, macrophages, platelets CCR5 CCL3 (MIP-1α), CCL4 (MIP-1α), CCL5 (RANTES), CCL11 (eotaxin), CCL14 (HCC1), CCL16 (HCC4) T cells, monocytes HIV-1 co-receptor (T cell–tropic strains), transplant rejection CCR6 CCL20 (MIP-3α, LARC) T cells (T regulatory and memory), B cells, dendritic cells CCR7 CCL19 (ELC), CCL21 (SLC) T cells, dendritic cells (mature) Transport of T cells and dendritic cells to lymph nodes, antigen presentation, and cellular immunity CCR8 CCL1 (1309) T cells (TH2), monocytes, dendritic cells Dendritic cell migration to lymph node, type 2 cellular immunity, granuloma formation CCR9 CCL25 (TECK) T cells, IgA+ plasma cells Homing of T cells and IgA+ plasma cells to the intestine, inflammatory bowel disease CCR10 CCL27 (CTACK), CCL28 (MEC) T cells T-cell homing to intestine and skin CXCR1 CXCL8 (interleukin-8), CXCL6 (GCP2) Neutrophils, monocytes Inflammatory lung disease, COPD CXCR2 CXCL8, CXCL1 (GROα), CXCL2 (GROα), CXCL3 (GROα), CXCL5 (ENA-78), CXCL6 Neutrophils, monocytes, microvascular endothelial cells CXCR3-A CXCL9 (MIG), CXCL10 (IP-10), CXCL11 (I-TAC) Type 1 helper cells, mast cells, mesangial cells CXCR3-B CXCL4 (PF4), CXCL9 (MIG), CXCL10 (IP-10), CXCL11 (I-TAC) Microvascular endothelial cells, neoplastic cells CXCR4 CXCL12 (SDF-1) Widely expressed HIV-1 co-receptor (T cell–tropic), tumor metastases, hematopoiesis CXCR5 CXCL13 (BCA-1) B cells, follicular helper T cells Formation of B-cell follicles CXCR6 CXCL16 (SR-PSOX) CD8+ T cells, natural killer cells, and memory CD4+ T cells CX3CR1 CX3CL1 (fractalkine) Macrophages, endothelial cells, smooth-muscle cells XCR1 XCL1 (lymphotactin), XCL2 T cells, natural killer cells Rheumatoid arthritis, IgA nephropathy, tumor response Abbreviations: BCA-1, B-cell chemoattractant 1; COPD, chronic obstructive pulmonary disease; CTACK, cutaneous T cell–attracting chemokine; ELC, Epstein-Barr I1-ligand chemokine; ENA, epithelial cell–derived neutrophil-activating peptide; GCP, granulocyte chemotactic protein; GRO, growth-regulated oncogene; HCC, hemofiltrate chemokine; IP-10, interferon inducible 10; I-TAC, interferon-inducible T-cell alpha chemoattractant; LARC, liver- and activation-regulated chemokine; MCP, monocyte chemoattractant protein; MDC, macrophage-derived chemokine; MEC, mammary-enriched chemokine; MIG, monokine induced by interferon-γ; MIP, macrophage inflammatory protein; PF, platelet factor; SDF, stromal cell–derived factor; SLC, secondary lymphoid-tissue chemokine; SR-PSOX, scavenger receptor for phosphatidylserinecontaining oxidized lipids; TARC, thymus- and activation-regulated chemokine; TECK, thymus-expressed chemokine; TH2, type 2 helper T cells. Source: From IF Charo, RM Ranshohoff: The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354:610, 2006. Copyright © (2006) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. The receptors for the Fc portion of IgG (FcγRs) are present on NK cells, B cells, macrophages, neutrophils, and mast cells and mediate interactions of IgG with antibody-coated target cells, such as virally infected cells. Antibody-NK interaction via antibody Fc and NK cell FcR links the adaptive and innate immune systems and regulates the mediation of IgG antibody effector functions such as ADCC. There are both activation and inhibitory FcγRs. Activation FcRs, such as FcγRI (CD64), FcγRIIa (CD32a), and FcγRIIIa (CD16a), are characterized by the presence of an immunoreceptor tyrosine-based activating motif (ITAM) sequence, whereas inhibitory FcRs, such as FcγRIIb (CD32b), contain an ITIM sequence. There is evidence that dysregulation in IgG-FcγR interactions plays roles in arthritis, multiple sclerosis, and systemic lupus erythematosus. Neutrophils, Eosinophils, and Basophils  Granulocytes are present in nearly all forms of inflammation and are amplifiers and effectors of innate immune responses (Fig. 360-2). Unchecked accu­ mulation and activation of granulocytes can lead to host tissue damage, as seen in neutrophil- and eosinophil-mediated systemic necrotizing vasculitis. Granulocytes are derived from stem cells in bone marrow. Rheumatoid arthritis, multiple sclerosis CHAPTER 360 Atherosclerosis, rheumatoid arthritis, multiple sclerosis, resistance to intracellular pathogens, type 2 diabetes mellitus Allergic asthma and rhinitis Introduction to the Immune System Parasitic infection, graft rejection, T-cell homing to skin Mucosal humoral immunity, allergic asthma, intestinal T-cell homing Inflammatory lung disease, COPD, angiogenic for tumor growth Inflammatory skin disease, multiple sclerosis, transplant rejection Angiostatic for tumor growth Inflammatory liver disease, atherosclerosis (CXCL16) Atherosclerosis Each type of granulocyte (neutrophil, eosinophil, or basophil) is derived from a different subclass of progenitor cell that is stimulated to proliferate by colony-stimulating factors (Table 360-6). During termi­ nal maturation of granulocytes, class-specific nuclear morphology and cytoplasmic granules appear that allow for histologic identification of granulocyte type. Neutrophils express Fc receptor IIIa for IgG (CD16a) as well as receptors for activated complement components (C3b or CD35). Upon interaction of neutrophils with antibody-coated (opsonized) bacteria or immune complexes, azurophilic granules (containing myeloper­ oxidase, lysozyme, elastase, and other enzymes) and specific granules (containing lactoferrin, lysozyme, collagenase, and other enzymes) are released, and microbicidal superoxide radicals (O2 –) are generated at the neutrophil surface. The generation of superoxide leads to inflam­ mation by direct injury to tissue and by alteration of macromolecules such as collagen and DNA. Eosinophils are potent cytotoxic effector cells for various para­ sitic organisms. In Nippostrongylus brasiliensis helminth infection, eosinophils are important cytotoxic effector cells for removal of these parasites. Key to regulation of eosinophil cytotoxicity to N. brasiliensis worms are antigen-specific T helper cells that produce IL-4, thus pro­ viding an example of regulation of innate immune responses by adap­ tive immunity antigen-specific T cells. Intracytoplasmic contents of eosinophils, such as major basic protein, eosinophil cationic protein, and eosinophil-derived neurotoxin, are capable of directly damaging tissues and may be responsible in part for the organ system dysfunction in the hypereosinophilic syndromes (Chap. 67). Because the eosinophil granule contains anti-inflammatory types of enzymes (histaminase, arylsulfatase, phospholipase D), eosinophils may also downregulate or terminate ongoing inflammatory responses. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders TOX NFIL3 ID2 ETS1 NKP T-BET EOMES T-BET NFIL3 RUNX3 NK A ILC1 ILC2 FIGURE 360-3  Development and function of innate lymphoid cells (ILCs). A. ILC development, mainly based on mouse ILC differentiation paths, is schematized. ILCs develop from common innate lymphoid progenitors (CILPs), which themselves differentiate from common lymphoid progenitors (CLPs). CILPs can differentiate into natural killer (NK) cell precursor (NKP) cells or into common helper innate lymphoid progenitors (CHILPs), which themselves give rise to lymphoid tissue inducer progenitors (LTiPs) and innate lymphoid cell precursors (ILCPs). LTiPs differentiate into lymphoid tissue inducers (LTis) and ILCPs into ILC1, ILC2, or ILC3. Each stage of differentiation is dependent on the expression of the indicated transcription factors: NFIL3 (nuclear factor IL-3 induced), Id2 (inhibitor of DNA binding 2), TOX (thymocyte selection-associated high mobility group box protein), TCF-1 (T-cell factor 1), ETS1 (avian erythroblastosis virus E26 homolog-1), GATA3 (GATA binding protein 3), PLZF (promyelocytic leukemia zinc finger), T-bet (T-box transcription factor), Eomes (eomesodermin), RUNX3 (runt-related transcription factor 3), RORα (RAR-related orphan receptor α), Bcl11b (B cell lymphoma/ leukemia 11B), RORγt (RAR-related orphan receptor γt), and AHR (Aryl hydrocarbon receptor). It has been shown in humans that ILC1 subsets may originate from precursors other than ILCPs, but the identity of these precursors remains unknown at this time. B. Some of the most well-known immune functions of each ILC subset are shown: NK cells and ILC1s react to intracellular pathogens, such as viruses, and to tumors; ILC2s respond to large extracellular parasites and allergens; ILC3s combat extracellular microbes, such as bacteria and fungi; and Lutes are involved in the formation of secondary lymphoid structures. For each ILC subset, effector molecules that can be produced upon activation are indicated AREG, amphiregulin; RANK, receptor activation of nuclear factor kB; RANK-L, RANK-ligand. (Reproduced with permission from E Vivier et al: Innate lymphoid cells: 10 years on. Cell 174:1054, 2018.) Basophils and tissue mast cells are potent reservoirs of cytokines such as IL-4 and can respond to bacteria and viruses with cytokine production through multiple TLRs expressed on their surface. Mast cells and basophils can also mediate antipathogen immunity through the binding of antibodies. This is a particularly important host defense mechanism against parasitic diseases. Basophils express high-affinity surface receptors for IgE (FcεRII) (CD23) and, upon cross-linking of basophil-bound IgE by antigen, can release histamine, eosinophil chemotactic factor of anaphylaxis, and neutral proteases—all media­ tors of allergic immediate (anaphylaxis) hypersensitivity responses. CLP NFIL3 ID2 TOX TCF-1 ETS1 CILP GATA3 CHILP LTiP PLZF ROR γT TOX ID2 ILCP ROR γT AHR ID2 ROR α Bci11B GATA3 ILC3 LTi Stimuli Mediators Immune function Tumors, intracellular microbes (virus, bacteria, parasites) NK Large extracellular parasites and allergens Mesenchymal organizer cells (retinoic acid, CXCL13, RANK-L) Extracellular microbes (bacteria, fungi) B FIGURE 360-3  (Continued) In addition, basophils express surface receptors for activated comple­ ment components (C3a, C5a), through which mediator release can be directly effected. Thus, basophils, like most cells of the immune sys­ tem, can be activated in the service of host defense against pathogens, or they can be activated for mediator release and cause pathogenic responses in allergic and inflammatory diseases. For further discus­ sion of tissue mast cells, see Chap. 366. The Complement System  The complement system, an impor­ tant soluble component of the innate immune system, is a series of plasma enzymes, regulatory proteins, and proteins that are activated in a cascading fashion, resulting in cell lysis. There are four pathways of the complement system: the classic activation pathway activated by antigen/antibody immune complexes, the MBL (a serum collectin) activation pathway activated by microbes with terminal mannose groups, the alternative activation pathway activated by microbes or tumor cells, and the terminal pathway that is common to the first three pathways and leads to the membrane attack complex that lyses cells (Fig. 360-5). The series of enzymes of the complement system are serine proteases. Activation of the classic complement pathway via immune complex binding to C1q links the innate and adaptive immune systems via specific antibody in the immune complex. The alternative complement activation pathway is antibody-independent and is activated by bind­ ing of C3 directly to pathogens and “altered self” such as tumor cells. In the renal glomerular inflammatory disease IgA nephropathy, IgA activates the alternative complement pathway and causes glomerular damage and decreased renal function. Activation of the classic comple­ ment pathway via C1, C4, and C2 and activation of the alternative path­ way via factor D, C3, and factor B both lead to cleavage and activation of C3. C3 activation fragments, when bound to target surfaces such as bacteria and other foreign antigens, are critical for opsonization (coat­ ing by antibody and complement) in preparation for phagocytosis. The MBL pathway substitutes MBL-associated serine proteases (MASPs) 1 and 2 for C1q, C1r, and C1s to activate C4. The MBL activation path­ way is activated by mannose on the surface of bacteria and viruses. CHAPTER 360 IFN-γ Granzymes Perforin Type 1 immunity (macrophage activation, cytotoxicity) ILC1 Introduction to the Immune System Type 2 immunity (alternative macrophage activation) IL-4 IL-5 IL-13 IL-9 AREG ILC2 RANK Lymphotoxin TNF IL-17 IL-22 Formation of secondary lymphoid structures LTi Type 3 immunity (phagocytosis, antimicrobial peptides) IL-22 IL-17 GM-CSF Lymphotoxin ILC3 The three pathways of complement activation all converge on the final common terminal pathway. C3 cleavage by each pathway results in activation of C5, C6, C7, C8, and C9, resulting in the membrane attack complex that physically inserts into the membranes of target cells or bacteria and lyses them. Thus, complement activation is a critical component of innate immunity for responding to microbial infection. The functional conse­ quences of complement activation by the three initiating pathways and the terminal pathway are shown in Fig. 360-5. In general, the cleavage products of complement components facilitate microbe or damaged cell clearance (C1q, C4, C3), promote activation and enhancement of inflammation (anaphylatoxins, C3a, C5a), and promote microbe or opsonized cell lysis (membrane attack complex). ■ ■CYTOKINES Cytokines are soluble proteins produced by a wide variety of cell types (Tables 360-7 and 360-8). They are critical for both normal innate and adaptive immune responses, and their expression may be perturbed in most immune, inflammatory, and infectious disease states. Cytokines are involved in the regulation of the growth, develop­ ment, and activation of immune system cells and in the mediation of the inflammatory response. In general, cytokines are characterized by considerable redundancy in that different cytokines have similar functions. In addition, many cytokines are pleiotropic in that they are capable of acting on many different cell types. This pleiotropism results from the expression on multiple cell types of receptors for the same cytokine (see below), leading to the formation of “cytokine networks.” The action of cytokines may be (1) autocrine when the target cell is the same cell that secretes the cytokine, (2) paracrine when the target cell is nearby, and (3) endocrine when the cytokine is secreted into the circulation and acts distal to the source. Cytokines have been named based on presumed targets or based on presumed functions. Those cytokines that are thought to primarily target leukocytes have been named IL-1, -2, -3, etc. Many cytokines that were originally described as having a certain function have retained those names (e.g., granulocyte colony-stimulating factor [G-CSF]). Cytokines TABLE 360-9  NK-Cell Receptors, Cognate Ligands, and Their Known Signaling Domains/Proximal Adapters SIGNALING DOMAINS AND PROXIMAL ADAPTERS Inhibitory KIR   Conserved epitopes on HLA I (“KIR ligands”) ITIM, Src phosphatases KIR2DL1 KIR2DL1 HLA-C2 alleles (Lys80)   KIR2DL2 KIR2DL2 HLA-C1 alleles (Asp80); HLA-C2 alleles (Lys80)   KIR2DL3 KIR2DL3 HLA-C1 alleles (Asp80)   KIR3DL1 KIR3DL1 HLA-B alleles carrying the Bw4 motif; HLA-A alleles carrying the Bw4 motif RECEPTOR GENE LIGAND PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders KIR3DL2 KIR3DL2 HLA-A*03, HLA-A*11 carrying specific peptides   KIR2DL4 KIR2DL4 HLA-G   KIR2DL5   CD155   Activating KIR   HLA-C2, HLA-C1, HLA-F, certain configurations of HLApeptide combinations KIR2DS1 KIR2DS1 HLA-C2 alleles (Lys80) carrying specific peptides KIR2DS2 KIR2DS2 HLA-C1 (Asp80) HLA-A*11 KIR2DS3 KIR2DS3 Unknown KIR3DS1   HLA-F KIR2DS5   Unknown Natural cytotoxicity receptors (NCRs)   NKp30 NCR3 B7-H6, BAT-3, heparan sulfates   NKp44 NCR2 PDGF, heparan sulfates, PCNA   NKp46 NCR1 Viral hemagglutinins, heparan sulfates, vimentin, ecto-calreticulin SLAM family receptors ITSM, SAP, EAT SLAMF1 (SLAM, CD150, IPO-3) SLAMF1 SLAMF1   SLAMF2 (CD48, BLAST-1) CD48 SLAMF4, CD2   SLAMF3 (CD229, Ly9) LY9 SLAMF3   SLAMF4 (CD244, 2B4, ERT) CD244 SLAMF2   SLAMF6 (NTB-A, Ly108, CD352) SLAMF6 SLAMF6   SLAMF7 (CRACC, CD319) SLAMF7 SLAMF7   SLAMF8 (BLAME, CD353) SLAMF8 Unknown   Abbreviations: BAT-3, human leukocyte antigen-B-associated transcript 3; EAT, Ewing sarcoma associated transcript; HLA, human leukocyte antigens; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; ITSM, immunoreceptor tyrosine-based switch motif; KIR, killer cell immunoglobulin-like receptor; NCRs, natural cytotoxicity receptors; NK, natural killer cell; SAP, SLAM-associated protein; SFK, Src family kinase; SLAM, signalling lymphocyte activating molecule. Source: Reproduced from S Nersesian et al: Killer instincts: Natural killer cells as multifactorial cancer immunotherapy. Front Immunol. 2023; 14:1269614. TABLE 360-10  Association of KIRS with Disease DISEASE KIR ASSOCIATION OBSERVATION Psoriatic arthritis KIR2DS1/KIR2DS2; HLA-Cw group homozygosity Susceptibility Spondylarthritides Increased KIR3DL2 expression Interaction of HLA-B27 homodimers with KIR3DL1/KIR3DL2; independent of peptide Ankylosing spondylitis KIR3DL1/3DS1; HLA-B27 genotypes Susceptibility Rheumatoid vasculitis KIR2DS2; HLA-Cw*03 Increased KIR2L2/2DS2 in patients with extraarticular manifestations Susceptibility Clinical manifestations may have different genetic backgrounds with respect to KIR genotype Rheumatoid arthritis Decreased KIR2DS1/3DS1 in patients without bone erosions KIR2DS4; HLA-Cw4 Susceptibility  Susceptibility Scleroderma KIR2DS2+/KIR2DL2– Susceptibility Behçet’s disease Altered KIR3DL1 expression Associated with severe eye disease Psoriasis vulgaris 2DS1; HLA-Cw*06 2DS1; 2DL5; haplotype B Susceptibility Susceptibility IDDM KIR2DS2; HLA-C1 Susceptibility Type 1 diabetes KIR2DS2; HLA-C1 and no HLA-C2, no HLA-Bw4 Increased disease progression Preeclampsia KIR2DL1 with fewer KIR2DS (mother); HLA-C2 (fetus) Increased disease progression AIDS KIR3DS1; HLA-Bw4Ile80 KIR3DS1 homozygous; no HLA-Bw4Ile80 Decreased disease progression Increased disease progression HCV infection KIR2DL3 homozygous; HLA-C1 homozygous Decreased disease progression Cervical neoplasia (HPV induced) KIR3DS1; HLA-C1 homozygous and no HLA-Bw4 Increased disease progression Malignant melanoma KIR2DL2 and/or KIR2DL3; HLA-C1 Increased disease progression Abbreviations: HCV, hepatitis C virus; HLA, human leukocyte antigen; HPV, human papillomavirus; IDDM, insulin-dependent diabetes mellitus; KIR, killer cell immunoglobulin-like receptor. Source: Reproduced with permission from R Diaz-Pena et al: KIR genes and their role in spondyloarthropathies. Adv Exp Med Biol 649:286, 2009.   ITAM, SFK   May contribute to disease pathology May contribute to disease pathogenesis Inhibitory receptor A No response No HLA class I No activating ligands Target NK Activating receptor B No response HLA class I No activating ligands NK Target C NK attacks target cells No HLA class I Activating ligands NK Target D Outcome determined by balance of signals HLA class I Activating ligands NK Target FIGURE 360-4  Encounters between natural killer (NK) cells: Potential targets and possible outcomes. The amount of activating and inhibitory receptors on the NK cells and the amount of ligands on the target cell, as well as the qualitative differences in the signals transduced, determine the extent of the NK response. A. When target cells have no HLA class I or activating ligands, NK cells cannot kill target cells. B. When target cells bear self-HLA, NK cells cannot kill targets. C. When target cells are pathogen-infected and have downregulated HLA and express activating ligands, NK cells kill target cells. D. When NK cells encounter targets with both self-HLA and activating receptors, then the level of target killing is determined by the balance of inhibitory and activating signals to the NK cell. HLA, human leukocyte antigen. (Republished with permission of Annual Review of Immunology, from NK Cell Recognition, L Lanier 23:225,2005: permission conveyed through Copyright Clearance Center, Inc.) belong in general to three major structural families: the hematopoietin family; the TNF, IL-1, platelet-derived growth factor (PDGF), and trans­ forming growth factor (TGF) β families; and the CXC and C-C chemo­ kine families. Chemokines are cytokines that regulate cell movement and trafficking; they act through G protein–coupled receptors and have a distinctive three-dimensional structure (Table 360-7). In general, cytokines exert their effects by influencing gene activa­ tion that results in cellular activation, growth, differentiation, functional cell-surface molecule expression, and cellular effector function. In this regard, cytokines can have dramatic effects on the regulation of immune responses and the pathogenesis of a variety of diseases. Indeed, T cells have been categorized on the basis of the pattern of cytokines that they secrete, which results in either humoral immune response (TH2) or cellmediated immune response (TH1). A third type of T helper cell is the TH17 cell that contributes to host defense against extracellular bacteria and fungi, particularly at mucosal sites (Fig. 360-2). Cytokine receptors can be grouped into five general families based on similarities in their extracellular amino acid sequences and conserved structural domains. The immunoglobulin (Ig) superfamily represents a large number of cell-surface and secreted proteins. The IL-1 receptors (type 1, type 2) are examples of cytokine receptors with extracellular Ig domains. The hallmark of the hematopoietic growth factor (type 1) receptor family is that the extracellular regions of each receptor contain two conserved motifs. One motif, located at the N terminus, is rich in Mannose-binding Classic activation pathway Bacteria, fungi, virus, or tumor cells Alternative lectin activation pathway activation pathway Microbes with terminal mannose groups Antigen/antibody immune complex CHAPTER 360 C3 (H2O) MBL-MASP1-MASP2 C1q-C1r-C1s C4 B C4 D C2 C2 Introduction to the Immune System P Anaphylatoxin C3 Opsonin Immune complex modification Lymphocyte activation C3b Clearance of apoptotic cells C5 C6 Anaphylatoxin C7 Terminal pathway C8 Lysis poly-C9 Membrane perturbation FIGURE 360-5  The four pathways and the effector mechanisms of the complement system. Dashed arrows indicate the functions of pathway components. (Reproduced with permission from BJ Morley, MJ Walport: The Complement Facts Books. London, Academic Press, 2000.) cysteine residues. The other motif is located at the C terminus proximal to the transmembrane region and comprises five amino acid residues, tryptophan-serine-X-tryptophan-serine (WSXWS). This family can be grouped on the basis of the number of receptor subunits they have and on the utilization of shared subunits. A number of cytokine receptors, i.e., IL-6, IL-11, IL-12, and leukemia inhibitory factor, are paired with gp130. There is also a common 150-kDa subunit shared by IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors. The gamma chain (γc) of the IL-2 receptor is common to the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors. Thus, the specific cytokine receptor is responsible for ligand-specific binding, whereas the sub­ units such as gp130, the 150-kDa subunit, and γc are important in sig­ nal transduction. The γc gene is on the X chromosome, and mutations in the γc protein result in the X-linked form of severe combined immune deficiency syndrome (X-SCID) (Chap. 362). The members of the interferon (type II) receptor family include the receptors for IFN-γ and -β, which share a similar 210-amino-acid binding domain with conserved cysteine pairs at both the amino and carboxy termini. The members of the TNF (type III) receptor family share a common binding domain composed of repeated cysteine-rich regions. Members of this family include the p55 and p75 receptors for TNF (TNF-R1 and TNF-R2, respectively); CD40 antigen, which is an important B-cell surface marker involved in immunoglobulin isotype switching; fas/Apo-1, whose triggering induces apoptosis; CD27 and CD30, which are found on activated T cells and B cells; and nerve growth factor receptor. The common motif for the seven transmembrane helix family was originally found in receptors linked to GTP-binding proteins. This family includes receptors for chemokines (Table 360-8), β-adrenergic receptors, and retinal rhodopsin. It is important to note that two mem­ bers of the chemokine receptor family, CXC chemokine receptor type 4 (CXCR4) and β chemokine receptor type 5 (CCR5), have been found to serve as the two major co-receptors for binding and entry of HIV-1 into CD4-expressing host cells (Chap. 208). Significant advances have been made in defining the signaling pathways through which cytokines exert their intracellular effects. The Janus family of protein tyrosine kinases (JAK) is a critical ele­ ment involved in signaling via the hematopoietin receptors. Four JAK kinases, JAK1, JAK2, JAK3, and Tyk2, preferentially bind different cytokine receptor subunits. Cytokine binding to its receptor brings the cytokine receptor subunits into apposition and allows a pair of JAKs to transphosphorylate and activate one another. The JAKs then phosphorylate the receptor on the tyrosine residues and allow signal­ ing molecules to bind to the receptor, whereby the signaling mol­ ecules become phosphorylated. Signaling molecules bind the receptor because they have domains (SH2, or src homology 2 domains) that can bind phosphorylated tyrosine residues. There are a number of these important signaling molecules that bind the receptor, such as the adapter molecule SHC, which can couple the receptor to the acti­ vation of the mitogen-activated protein kinase pathway. In addition, an important class of substrate of the JAKs is the signal transducers and activators of transcription (STAT) family of transcription factors. STATs have SH2 domains that enable them to bind to phosphorylated receptors, where they are then phosphorylated by the JAKs. It appears that different STATs have specificity for different receptor subunits. The STATs then dissociate from the receptor and translocate to the nucleus, bind to DNA motifs that they recognize, and regulate gene expression. The STATs preferentially bind DNA motifs that are slightly different from one another and thereby control transcription of specific genes. The importance of this pathway is particularly relevant to lym­ phoid development. Mutations of JAK3 itself also result in a disorder identical to X-SCID; however, because JAK3 is found on chromosome 19 and not on the X chromosome, JAK3 deficiency occurs in boys and girls (Chap. 362). A new class of immunosuppressive drugs of JAK inhibitors has been developed that are approved to treat chronic inflammatory diseases such as rheumatoid arthritis (Chap. 370), psoriatic arthritis (Chap. 374), ulcerative colitis (Chap. 337), atopic dermatitis (Chap. 59), and alopecia areata (Chap. 61). PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders ■ ■THE ADAPTIVE IMMUNE SYSTEM Adaptive immunity is characterized by antigen-specific responses to a foreign antigen or pathogen. A key feature of adaptive immunity is that following the initial contact with antigen (immunologic priming), subsequent antigen exposure leads to more rapid and vigorous immune responses (immunologic memory). The adaptive immune system con­ sists of dual limbs of cellular and humoral immunity. The principal effectors of cellular immunity are T lymphocytes, whereas the principal effectors of humoral immunity are B lymphocytes. Both B and T lym­ phocytes derive from a common stem cell (Fig. 360-6). The proportion and distribution of immunocompetent cells in various tissues reflect cell traffic, homing patterns, and functional capabilities. Bone marrow is the major site of maturation of B cells, monocytes-macrophages, DCs, and granulocytes and contains pluripo­ tent stem cells that, under the influence of various colony-stimulating factors, can give rise to all hematopoietic cell types. T-cell precursors also arise from hematopoietic stem cells and home to the thymus for maturation. Mature T lymphocytes, B lymphocytes, monocytes, and DCs enter the circulation and home to peripheral lymphoid organs (lymph nodes, spleen) and mucosal surface-associated lymphoid tis­ sue (gut, genitourinary, and respiratory tracts) as well as the skin and mucous membranes and await activation by foreign antigen. T Cells  The pool of effector T cells is established in the thymus early in life and is maintained throughout life both by new T-cell production in the thymus and by antigen-driven expansion of virgin peripheral T cells into “memory” T cells that reside in peripheral lymphoid organs. The thymus exports ~2% of the total number of thymocytes per day throughout life, with the total number of daily thymic emigrants decreasing by ~3% per year during the first four decades of life. Mature T lymphocytes constitute 70–80% of normal peripheral blood lymphocytes (only 2% of the total-body lymphocytes are contained in peripheral blood), 90% of thoracic duct lymphocytes, 30–40% of lymph node cells, and 20–30% of spleen lymphoid cells. In lymph nodes, T cells occupy deep paracortical areas around B-cell germinal centers, and in the spleen, they are located in periarteriolar areas of white pulp (Chap. 70). T cells are the primary effectors of cell-mediated immunity, with subsets of T cells maturing into CD8+ cytotoxic T cells capable of lysis of virus-infected or foreign cells (short-lived effector T cells) and CD4+ T cells capable of T-cell help for CD8+ T-cell and B-cell development. Two populations of long-lived memory T cells are triggered by infections: effector memory and cen­ tral memory T cells. Effector memory T cells reside in nonlymphoid organs and respond rapidly to repeated pathogenic infections with cytokine production and cytotoxic functions to kill virus-infected cells. Central memory T cells home to lymphoid organs where they replenish long- and short-lived and effector memory T cells as needed. In general, CD4+ T cells are the primary regulatory cells of T and B lymphocyte and monocyte function by the production of cytokines and by direct cell contact (Fig. 360-2). In addition, T cells regulate erythroid cell maturation in bone marrow and, through cell contact (CD40 ligand), have an important role in activation of B cells and induc­ tion of Ig isotype switching. Considerable evidence now exists that colonization of the gut by commensal bacteria (the gut microbiome) is responsible for expansion of the peripheral CD4+ T-cell compartment in normal children and adults. Human T cells express cell-surface proteins that mark stages of intrathymic T-cell maturation or identify specific functional subpopu­ lations of mature T cells. Many of these molecules mediate or partici­ pate in important T-cell functions (Table 360-1, Fig. 360-6, Chap. 361). The earliest identifiable T-cell precursors in bone marrow are CD34+ pro-T cells (i.e., cells in which TCR genes are neither rear­ ranged nor expressed). In the thymus, CD34+ T-cell precursors begin cytoplasmic (c) synthesis of components of the CD3 complex of TCRassociated molecules (Fig. 360-6). Within T-cell precursors, TCR for antigen gene rearrangement yields two T-cell lineages, expressing either TCR-αβ chains or TCR-γδ chains. T cells expressing the TCR-αβ chains constitute the majority of peripheral T cells in blood, lymph node, and spleen and terminally differentiate into either CD4+ or CD8+ cells. Cells expressing TCR-γδ chains circulate as a minor popu­ lation in blood; their functions have been postulated to be those of immune surveillance at epithelial surfaces and cellular defenses against mycobacterial organisms and other intracellular bacteria through rec­ ognition of bacterial lipids. In the thymus, the recognition of self-peptides on thymic epithelial cells, thymic macrophages, and DCs plays an important role in shap­ ing T-cell repertoire. As immature cortical thymocytes begin to express surface TCR for antigen, thymocytes with TCRs capable of interacting with self-peptides in the context of self-MHC antigens with low affinity are activated and survive (positive selection). Thymocytes with TCRs that are incapable of binding to self-MHC antigens or bind with high affinity die of attrition (no selection) or by apoptosis (negative selec­ tion). Thymocytes that are positively selected undergo maturation into CD4 or CD8 single positive T cells, and then migrate to the thymus medulla where they interact with self-peptide–self-MHC molecules, where they can again undergo selection. The purpose of negative and positive thymocyte selection is to eliminate potential pathogenic auto­ reactive T cells, and at the same time, select a repertoire of mature T cells capable of recognizing foreign antigens. Mature TCRab thymocytes that are positively selected are func­ tional MHC class II–restricted CD4+ T cells (Fig. 360-2), or they are CD8+ T cells destined to become CD8+ MHC class I–restricted cytotoxic T cells. MHC class I or class II restriction means that T cells recognize antigen peptide fragments only when they are presented in the antigen-recognition site of a class I or class II MHC molecule, respectively. After thymocyte maturation and selection, CD4 and CD8 thymocytes leave the thymus and migrate to the peripheral immune system. The thymus can continue to be a contributor to the periph­ eral immune system well into adult life, both normally and when the peripheral T-cell pool is damaged, such as occurs in AIDS and cancer chemotherapy. MOLECULAR BASIS OF T-CELL RECOGNITION OF ANTIGEN  The TCR for antigen is a complex of molecules consisting of an antigen-binding heterodimer of either αβ or γδ chains noncovalently linked with five CD3 subunits (γ, δ, ε, ζ, and η) (Fig. 360-7). The CD3 ζ chains are either disulfide-linked homodimers (CD3-ζ2) or disulfide-linked Pro-T Pro-T Pro-T Immature T Mature T CD34+ CD7lo+ or - α,β Germline CD34+ Hematopoietic α,β Germline CD7 CD2 CD3 α-Germline β-VDJ Rearranged Hematopoietic stem cell CD34+ Early pro-B cell Late pro-B cell Large pre-B cell Small pre-B cell Immature B cell Mature B cell Heavy-chain genes VDJ rearranging D-J rearranging Light-chain genes Germline Germline Surface Ig Absent Absent Surface marker proteins CD34 CD10 CD38 CD10 CD19 CD38 CD40 FIGURE 360-6  Development stages of T and B cells. Elements of the developing T- and B-cell receptor for antigen are shown schematically. The classification into the various stages of B-cell development is primarily defined by rearrangement of the immunoglobulin (Ig) heavy (H) and light (L) chain genes and by the absence or presence of specific surface markers. The classification of stages of T-cell development is primarily defined by cell-surface marker protein expression (sCD3, surface CD3 expression; cCD3, cytoplasmic CD3 expression; TCR, T-cell receptor). For B-cell development, the pre-B-cell receptor is shown as a blue-orange B-cell receptor. (Adapted from Janeway’s Immunobiology, 9th ed by Kenneth Murphy and Casey Weaver. Copyright © 2017 by Garland Science, Taylor & Francis Group, LLC. Used by permission of W. W. Norton & Company, Inc.) heterodimers composed of one ζ chain and one η chain. TCR-αβ or TCR-γδ molecules must be associated with CD3 molecules to be inserted into the T-cell surface membrane, TCR-α being paired with TCR-β and TCR-γ being paired with TCR-δ. Molecules of the CD3 complex mediate transduction of T-cell activation signals via TCRs, whereas TCR-α and -β or -γ and -δ molecules combine to form the TCR antigen-binding site. The α, β, γ, and δ TCR for antigen molecules have amino acid sequence homology and structural similarities to immunoglobulin heavy and light chains and are members of the immunoglobulin gene superfamily of molecules. The genes encoding TCR molecules are encoded as clusters of gene segments that rearrange during T-cell mat­ uration. This creates an efficient and compact mechanism for housing the diversity requirements of antigen receptor molecules. The TCR-α chain is on chromosome 14 and consists of a series of V (variable), J (joining), and C (constant) regions. The TCR-β chain is on chromo­ some 7 and consists of multiple V, D (diversity), J, and C TCR-β loci. The TCR-γ chain is on chromosome 7, and the TCR-δ chain is in the middle of the TCR-α locus on chromosome 14. Thus, molecules of the TCR for antigen have constant (framework) and variable regions, and Thymus medulla and peripheral T-cell pools CHAPTER 360 CD7 CD2 cCD3, TCRαβ CD1 CD4, CD8 α-VJ Rearranged β-VDJ Rearranged CD7 CD2 CD3, TCRαβ CD4 Mature T Introduction to the Immune System CD7 CD2 CD3, TCRαβ CD8 Mature T CD7 CD2 CD3, TCRγδ CD8 IgM IgD VDJ rearranged VDJ rearranged VDJ rearranged VDJ rearranged VJ rearranged VJ rearranged VJ rearranging Germline µ H-chain in cytoplasm µ H-chain at surface as part of the pre-B receptor (orange) containing surrogate light chain (SLC). Receptor is mainly intracellular IgM expressed on cell surface IgD and IgM made from alternatively spliced H-chain transcripts CD19 CD20 CD19 CD20 CD21 CD19 CD20 CD38 CD19 CD20 CD38 the gene segments encoding the α, β, γ, and δ chains of these molecules are recombined and selected in the thymus, culminating in synthesis of the completed molecule. In both T- and B-cell precursors (see below), DNA rearrangements of antigen receptor genes involve the same enzymes, recombinase activating gene RAG1 and RAG2, both DNAdependent protein kinases. TCR diversity is created by the different V, D, and J segments that are possible for each receptor chain by the many permutations of V, D, and J segment combinations, by “N-region diversification” due to the addition of nucleotides at the junction of rearranged gene seg­ ments, and by the pairing of individual chains to form a TCR dimer. As T cells mature in the thymus, the repertoire of antigen-reactive T cells is modified by selection processes that eliminate many autoreactive T cells, enhance the proliferation of cells that function appropriately with self-MHC molecules and antigen, and allow T cells with nonpro­ ductive TCR rearrangements to die. TCR-αβ cells do not recognize native protein or carbohydrate anti­ gens. Instead, T cells recognize only short (~9–13 amino acids) peptide fragments derived from protein antigens taken up or produced in APCs. Foreign antigens may be taken up by endocytosis into acidified PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders PtdIns (4,5)P3 Lipid raft InsP3 Release of Ca2+ Translocation of NFAT to the nucleus DAG PKC RASGRP Activation of downstream effectors such as NFkB, AP1, and NFAT to induce specific gene transcription leading to cell proliferation and differentiation MAPK activation FIGURE 360-7  Signaling through the T-cell receptor. Activation signals are mediated via immunoreceptor tyrosine-based activation (ITAM) sequences in LAT and CD3 chains (blue bars) that bind to enzymes and transduce activation signals to the nucleus via the indicated intracellular activation pathways. Ligation of the T-cell receptor (TCR) by MHC complexed with antigen results in sequential activation of LCK and γ-chain-associated protein kinase of 70 kDa (ZAP70). ZAP70 phosphorylates several downstream targets, including LAT (linker for activation of T cells) and SLP76 (SCR homology 2 [SH2] domain-containing leukocyte protein of 76 kDa). SLP76 is recruited to membrane-bound LAT through its constitutive interaction with GADS (GRB2-related adaptor protein). Together, SLP76 and LAT nucleate a multimolecular signaling complex, which induces a host of downstream responses, including calcium flux, mitogen-activated protein kinase (MAPK) activation, integrin activation, and cytoskeletal reorganization. APC, antigen-presenting cell; NFAT, nuclear factor of activated T cells. (Reproduced with permission from GA Koretzky, F Abtahian, MA Silverman. SLP76 and SLP65: Complex regulation of signalling in lymphocytes and beyond. Nat Rev Immunol 6:67, 2006.) intracellular vesicles or by phagocytosis and degraded into small pep­ tides that associate with MHC class II molecules (exogenous antigenpresentation pathway). Other foreign antigens arise endogenously in the cytosol (such as from replicating viruses) and are broken down into small peptides that associate with MHC class I molecules (endogenous antigen-presenting pathway). Thus, APCs proteolytically degrade for­ eign proteins and display peptide fragments embedded in the MHC class I or II antigen-recognition site on the MHC molecule surface, where foreign peptide fragments are available to bind to TCR-αβ or TCR-γδ chains of reactive T cells. CD4 molecules act as adhesives and, by direct binding to MHC class II (DR, DQ, or DP) molecules, stabilize the interaction of TCR with peptide antigen (Fig. 360-7). Similarly, CD8 molecules also act as adhesives to stabilize the TCR-antigen inter­ action by direct CD8 molecule binding to MHC class Ia (HLA A, B, or C) molecules or to MHC class Ib (HLA E). Antigens that arise in the cytosol and are processed via the endog­ enous antigen-presentation pathway are cleaved into small peptides by a complex of proteases called the proteasome. From the proteasome, antigen peptide fragments are transported from the cytosol into the lumen of the endoplasmic reticulum by a heterodimeric complex termed transporters associated with antigen processing or TAP proteins. There, MHC class I molecules in the endoplasmic reticulum mem­ brane physically associate with processed cytosolic peptides. Following peptide association with class I molecules, peptide–class I complexes are exported to the Golgi apparatus, and then to the cell surface, for recognition by CD8+ T cells. Antigens taken up from the extracellular space via endocytosis into intracellular acidified vesicles are degraded by vesicle proteases into peptide fragments. Intracellular vesicles containing MHC class II molecules fuse with peptide-containing vesicles, thus allowing peptide fragments to physically bind to MHC class II molecules. Peptide–MHC APC ICAM-1 LFA-3 CD28 B7-1 β α CD3 TCR LFA-1 CD2 RAS LCK Cytoskeletal reorganization ZAP70 LAT GRB2 SOS ITK VAV1 PLCγ NCK GADS HPK1 ADAP Integrin activation class II complexes are then transported to the cell surface for recogni­ tion by CD4+ T cells. Whereas it is generally agreed that the TCR-αβ receptor recognizes peptide antigens in the context of MHC class I or class II molecules, lipids in the cell wall of intracellular bacteria such as M. tuberculosis can also be presented to a wide variety of T cells, including subsets of TCR-γδ T cells, and a subset of CD8+ TCR-αβ T cells. Importantly, bacterial lipid antigens are not presented in the context of MHC class I or II molecules, but rather are presented in the context of MHC-related CD1 molecules. Some γδ T cells that recognize lipid antigens via CD1 molecules have very restricted TCR usage, do not need antigen prim­ ing to respond to bacterial lipids, and may be a form of innate rather than acquired immunity to intracellular bacteria. Just as foreign antigens are degraded and their peptide fragments presented in the context of MHC class I or class II molecules on APCs, endogenous self-proteins also are degraded, and self-peptide frag­ ments are presented to T cells in the context of MHC class I or class II molecules on APCs. In peripheral lymphoid organs, there are T cells that are capable of recognizing self-protein fragments but normally are anergic or tolerant, i.e., nonresponsive to self-antigenic stimulation, due to lack of self-antigen upregulating APC co-stimulatory molecules such as B7-1 (CD80) and B7-2 (CD86) (see below and Chap. 361). Once engagement of mature T-cell TCR by foreign peptide occurs in the context of self-MHC class Ia (A, B, or C), class 1b (E), or class II molecules, binding of non-antigen-specific adhesion ligand pairs such as CD54-CD11/CD18 and CD58-CD2 stabilizes MHC peptide-TCR binding, and the expression of these adhesion molecules is upregu­ lated. Once antigen ligation of the TCR occurs, the T-cell membrane is partitioned into lipid membrane microdomains, or lipid rafts, that coalesce the key signaling molecules TCR/CD3 complex, CD28, CD2, LAT (linker for activation of T cells), intracellular activated (dephosphorylated) src family protein tyrosine kinases (PTKs), and the key CD3ζ-associated protein-70 (ZAP-70) PTK (Fig. 360-7). Impor­ tantly, during T-cell activation, the CD45 molecule, with protein tyro­ sine phosphatase activity, is partitioned away from the TCR complex to allow activating phosphorylation events to occur. The coalescence of signaling molecules of activated T lymphocytes in microdomains has suggested that T cell–APC interactions can be considered immunologic synapses, analogous in function to neuronal synapses. After TCR-MHC binding is stabilized, activation signals are trans­ mitted through the cell to the nucleus and lead to the expression of gene products important in mediating the wide diversity of T-cell func­ tions such as the secretion of IL-2. The TCR does not have intrinsic signaling activity but is linked to a variety of signaling pathways via ITAMs expressed on the various CD3 chains that bind to proteins that mediate signal transduction. Each of the pathways results in the activa­ tion of particular transcription factors that control the expression of cytokine and cytokine receptor genes. Thus, antigen-MHC binding to the TCR induces the activation of the src family of PTKs, Fyn and Lck (Lck is associated with CD4 or CD8 co-stimulatory molecules); phos­ phorylation of CD3ζ chain; activation of the related tyrosine kinases ZAP-70 and Syk; and downstream activation of the calcium-dependent calcineurin pathway, the ras pathway, and the protein kinase C path­ way. Each of these pathways leads to activation of specific families of transcription factors (including NF-AT, fos and jun, and rel/NF-κB) that form heteromultimers capable of inducing expression of IL-2, IL-2 receptor, IL-4, TNF-α, and other T-cell mediators. In addition to the signals delivered to the T cell from the TCR complex and CD4 and CD8, molecules on the T cell, such as CD28 and inducible co-stimulator (ICOS), and molecules on DCs, such as B7-1 (CD80) and B7-2 (CD86), also deliver important co-stimulatory signals that upregulate T-cell cytokine production and are essential for T-cell activation. If signaling through CD28 or ICOS does not occur, or if CD28 is blocked, the T cell becomes anergic rather than activated (see “Immune Tolerance and Autoimmunity” below and Chap. 361). CTLA-4 (CD152) is similar to CD28 in its ability to bind CD80 and CD86. Unlike CD28, CTLA-4 transmits an inhibitory signal to T cells, acting as an off switch. T-CELL EXHAUSTION IN VIRAL INFECTIONS AND CANCER  In chronic viral infections such as HIV-1, hepatitis C virus, and hepatitis B virus and in chronic malignancies, the persistence of antigen disrupts mem­ ory T-cell function, resulting in defects in memory T-cell responses. This has been defined as T-cell exhaustion and is associated with T-cell programmed cell death protein 1 (PD-1) (CD279) expression. Exhausted T cells have compromised proliferation and lose the ability to produce effector molecules, like IL-2, TNF-α, and IFN-γ. PD-1 and CTLA-4 activation downregulates T-cell responses and is associated with T-cell exhaustion and tumor progression. Inhibition of T-cell PD-1 or CTLA-4 activity to enhance effector T-cell killing of tumor cells has become a critical component of therapy for certain malignan­ cies (Chap. 361). T-CELL SUPERANTIGENS  Conventional antigens bind to MHC class I or II molecules in the groove of the αβ heterodimer and bind to T cells via the V regions of the TCR-α and -β chains. In contrast, superantigens bind directly to the lateral portion of the TCR-β chain and MHC class II β chain and stimulate T cells based solely on the Vβ gene segment used independent of the D, J, and Vα sequences present. Superantigens are protein molecules capable of activating up to 20% of the peripheral T-cell pool, whereas conventional antigens activate <1 in 10,000 T cells. T-cell superantigens include staphylococcal enterotox­ ins and other bacterial products. Superantigen stimulation of human peripheral T cells occurs in the clinical setting of staphylococcal toxic shock syndrome, leading to massive overproduction of T-cell cytokines that leads to hypotension and shock (Chap. 152). B CELLS  Mature B cells constitute 5–10% of human peripheral blood lymphocytes, 20–30% of lymph node cells, 50% of splenic lympho­ cytes, and ~10% of bone marrow lymphocytes. B cells express on their surface intramembrane immunoglobulin (Ig) molecules that function as BCRs for antigen in a complex of Ig-associated α and β signaling molecules with properties similar to those described in T cells (Fig. 360-8). Unlike T cells, which recognize only processed peptide fragments of conventional antigens embedded in the notches of MHC class I and class II antigens of APCs, B cells are capable of recognizing and proliferating to whole unprocessed native antigens via antigen binding to B-cell surface Ig (sIg) receptors. B cells also express surface receptors for the Fc region of IgG molecules (CD32) as well as receptors for activated complement components (C3d or CD21, C3b or CD35). The primary function of B cells is to produce antibodies. B cells also serve as APCs and are highly efficient at antigen processing. Their antigen-presenting function is enhanced by a variety of cytokines. Mature B cells are derived from bone marrow precursor cells that arise continuously throughout life (Fig. 360-6). CHAPTER 360 Introduction to the Immune System B lymphocyte development can be separated into antigen-inde­ pendent and antigen-dependent phases. Antigen-independent B-cell development occurs in primary lymphoid organs and includes all stages of B-cell maturation up to the sIg+ mature B cell. Antigendependent B-cell maturation is driven by the interaction of antigen with the mature B-cell sIg, leading to memory B-cell induction, Ig class switching, and plasma cell formation. Antigen-dependent stages of B-cell maturation occur in secondary lymphoid organs, including lymph node, spleen, and gut Peyer’s patches. In contrast to the T-cell repertoire that is generated intrathymically before contact with foreign antigen, the repertoire of B cells expressing diverse antigen-reactive sites is modified by further alteration of Ig genes by the enzyme acti­ vation-induced cytidine deaminase after stimulation by antigen—a process called somatic hypermutation—that occurs in lymph node germinal centers. During B-cell development, diversity of the antigen-binding variable region of Ig is generated by an ordered set of Ig gene rearrangements that are similar to the rearrangements undergone by TCR α, β, γ, and δ genes. For the heavy chain, there is first a rearrangement of D segments to J segments, followed by a second rearrangement between a V gene segment and the newly formed D-J sequence; the C segment is aligned to the V-D-J complex to yield a functional Ig heavy chain gene (V-D-JC). During later stages, a functional κ or γ light chain gene is generated by rearrangement of a V segment to a J segment, ultimately yielding an intact Ig molecule composed of heavy and light chains. The process of Ig gene rearrangement is regulated and results in a single antibody specificity produced by each B cell, with each Ig molecule comprising one type of heavy chain and one type of light chain. Although each B cell contains two copies of Ig light and heavy chain genes, only one gene of each type is productively rearranged and expressed in each B cell, a process termed allelic exclusion. There are ~300 Vκ genes and 5 Jκ genes, resulting in the pairing of Vκ and Jκ genes to create >1500 different kappa light chain combinations. There are ~70 Vλ genes and 4 Jλ genes for >280 different lambda light chain combinations. The number of distinct light chains that can be generated is increased by somatic mutations within the V and J genes, thus creating large numbers of possible specificities from a limited amount of germline genetic information. As noted above, in heavy chain Ig gene rearrangement, the VH domain is created by the joining of three types of germline genes called VH, DH, and JH, thus allowing for even greater diversity in the variable region of heavy chains than of light chains. The most immature B-cell precursors (early pro-B cells) lack cyto­ plasmic Ig (cIg) and sIg (Fig. 360-6). The large pre-B cell is marked by the acquisition of the surface pre-BCR composed of μ heavy (H) chains and a pre-B light chain, termed V pre-B. V pre-B is a surrogate light chain receptor encoded by the non-rearranged V pre-B and the γ5 light chain locus (the pre-BCR). Pro- and pre-B cells are driven to proliferate and mature by signals from bone marrow stroma—in particular, IL-7. Light chain rearrangement occurs in the small pre-B-cell stage such that the full BCR is expressed at the immature B-cell stage. Imma­ ture B cells have rearranged Ig light chain genes and express sIgM. As immature B cells develop into mature B cells, sIgD is expressed as well as sIgM. At this point, B lineage development in bone marrow is complete, and B cells exit into the peripheral circulation and migrate to secondary lymphoid organs to encounter specific antigens. Heavy chain Fab region PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders BCR RAS LYN Igβ MAPK activation Cytoskeletal reorganization a VAV1 PLCγ NCK SOS FIGURE 360-8  B-cell receptor (BCR) activation results in the sequential activation of protein tyrosine kinases, which results in the formation of a signaling complex and activation of downstream pathways as shown. Whereas SLP76 is recruited to the membrane through GADS and LAT, the mechanism of SLP65 recruitment is unclear. Studies have indicated two mechanisms: (a) direct binding by the SH2 domain of SLP65 to immunoglobulin (Ig) of the BCR complex or (b) membrane recruitment through a leucine zipper in the amino terminus of SLP65 and an unknown binding partner. ADAP, adhesion- and degranulation-promoting adaptor protein; AP1, activator protein 1; BTK, Bruton’s tyrosine kinase; DAG, diacylglycerol; GRB2, growth factor receptor-bound protein 2; HPK1, hematopoietic progenitor kinase 1; InsP3, inositol-1,4,5-trisphosphate; ITK, interleukin-2-inducible T-cell kinase; NCK, noncatalytic region of tyrosine kinase; NF-B, nuclear factor B; PKC, protein kinase C; PLC, phospholipase C; PtdIns(4,5)P2, phosphatidylinositol-4,5-bisphosphate; RASGRP, RAS guanyl-releasing protein; SOS, son of sevenless homologue; SYK, spleen tyrosine kinase. (Reproduced with permission from GA Koretzky et al: SLP76 and SLP65: Complex regulation of signalling in lymphocytes and beyond. Nat Rev Immunol 6:67, 2006.) Random rearrangements of Ig genes occasionally generate selfreactive antibodies, and mechanisms must be in place to correct these mistakes. One such mechanism is BCR editing, whereby autoreactive BCRs are mutated to not react with self-antigens. If receptor editing is unsuccessful in eliminating autoreactive B cells, then autoreactive B cells may undergo negative selection in the bone marrow through induction of apoptosis after BCR engagement of self-antigen. After leaving the bone marrow, B cells populate peripheral B-cell sites, such as lymph node and spleen, and await contact with foreign antigens that react with each BCR. Antigen-driven B-cell activation occurs through the BCR, and somatic hypermutation takes place whereby point mutations in rearranged H- and L-genes give rise to mutant sIg molecules, some of which bind antigen better than the original sIg molecules. Somatic hypermutation, therefore, is a process whereby memory B cells in peripheral lymph organs have the best binding or the highest-affinity antibodies. This overall process of generating the best antibodies is called affinity maturation of antibody. Lymphocytes that synthesize IgG, IgA, and IgE are derived from sIgM+, sIgD+ mature B cells. Ig class switching occurs in lymph node and other peripheral lymphoid tissue germinal centers. CD40 on B cells and CD40 ligand on T cells constitute a critical co-stimulatory receptorligand pair of immune-stimulatory molecules. Pairs of CD40+ B cells and CD40 ligand+ T cells bind and drive B-cell Ig class switching via T cell–produced cytokines such as IL-4 and TGF-β. IL-1, -2, -4, -5, and -6 synergize to drive mature B cells to proliferate and differentiate into Ig-secreting cells. Humoral Mediators of Adaptive Immunity: Immunoglobulins  Immunoglobulins are the products of differentiated B cells and mediate Light chain Igα PtdIns(4,S)P3 SYK b InsP3 Release of Ca2+ DAG BTK SLP65 PKCβ RASGRP GRB2 Activation of downstream effectors the humoral arm of the immune response. The primary functions of antibodies are to bind specifically to antigen and bring about the inac­ tivation or removal of the offending toxin, microbe, parasite, or other foreign substance from the body. The structural basis of Ig molecule function and Ig gene organization has provided insight into the role of antibodies in normal protective immunity, pathologic immunemediated damage by immune complexes, and autoantibody formation against host determinants. All immunoglobulins have the basic structure of two heavy and two light chains (Fig. 360-8). Immunoglobulin isotype (i.e., G, M, A, D, E) is determined by the type of Ig heavy chain present. IgG and IgA iso­ types can be divided further into subclasses (G1, G2, G3, G4, and A1, A2) based on specific antigenic determinants on Ig heavy chains. The characteristics of human immunoglobulins are outlined in Table 360-11. The four chains are covalently linked by disulfide bonds. Each chain is made up of a V region and C regions (also called domains), themselves made up of units of ~110 amino acids. Light chains have one variable (VL) and one constant (CL) unit; heavy chains have one variable unit (VH) and three or four constant (CH) units, depending on isotype. As the name suggests, the constant, or C, regions of Ig molecules are made up of homologous sequences and share the same primary structure as all other Ig chains of the same isotype and subclass. Constant regions are involved in biologic functions of Ig molecules. The CH2 domain of IgG and the CH4 units of IgM are involved with the binding of the C1q portion of C1 during complement activation. The CH region at the carboxy-terminal end of the IgG molecule, the Fc region, binds to surface Fc receptors (CD16, CD32, CD64) of macrophages, DCs, NK cells, B cells, neutrophils, and eosinophils. The Fc of IgA binds to FcαR (CD89), and the Fc of IgE binds to FcεR (CD23). TABLE 360-11  Physical, Chemical, and Biologic Properties of Human Immunoglobulins PROPERTY IgG IgA IgM IgD IgE Usual molecular form Monomer Monomer, dimer Pentamer, hexamer Monomer Monomer Other chains None J chain, SC J chain None None Subclasses G1, G2, G3, G4 A1, A2 None None None Heavy chain allotypes Gm (=30) No A1, A2m (2) None None None Molecular mass, kDa 160, 400 950, 1150 Serum level in average adult, mg/mL 9.5–12.5 1.5–2.6 0.7–1.7 0.04 0.0003 Percentage of total serum Ig 75–85 7–15 5–10 0.3 0.019 Serum half-life, days 2.5 Synthesis rate, mg/kg per day 0.4 0.016 Antibody valence 2, 4 10, 12 Classical complement activation +(G1, 2?, 3) – ++ – – Alternate complement activation +(G4) + – + – Binding cells via Fc Macrophages, neutrophils, large granular lymphocytes Biologic properties Placental transfer, secondary antibody for most antipathogen responses Source: Reproduced with permission from L Carayannopoulos, JD Capra, in WE Paul (ed): Fundamental Immunology, 3rd ed. New York, Raven, 1993. Variable regions (VL and VH) constitute the antibody-binding (Fab) region of the molecule. Within the VL and VH regions are hypervari­ able regions (extreme sequence variability) that constitute the antigenbinding site unique to each Ig molecule. The idiotype is defined as the specific region of the Fab portion of the Ig molecule to which antigen binds. Antibodies against the idiotype portion of an antibody molecule are called anti-idiotype antibodies. The formation of such antibodies in vivo during a normal B-cell antibody response may generate a negative (or “off”) signal to B cells to terminate antibody production. IgG constitutes ~75–85% of total serum immunoglobulin. The four IgG subclasses are numbered in order of their level in serum, IgG1 being found in greatest amounts and IgG4 the least. IgG subclasses have clinical relevance in their varying ability to bind macrophage and neutrophil Fc receptors and to activate complement (Table 360-11). Moreover, selective deficiencies of certain IgG subclasses give rise to clinical syndromes in which the patient is inordinately susceptible to bacterial infections. IgG antibodies are frequently the predominant antibody made after rechallenge of the host with antigen (secondary antibody response). IgM antibodies normally circulate as a 950-kDa pentamer with 160-kDa bivalent monomers joined by a molecule called the J chain, a 15-kDa nonimmunoglobulin molecule that also effects polymerization of IgA molecules. IgM is the first immunoglobulin to appear in the immune response (primary antibody response) and is the initial type of antibody made by neonates. Membrane IgM in the monomeric form also functions as a major antigen receptor on the surface of mature B cells (Table 360-11). IgM is an important component of immune com­ plexes in autoimmune diseases. For example, IgM antibodies against IgG molecules (rheumatoid factors) are present in high titers in rheu­ matoid arthritis, other collagen diseases, and some infectious diseases (subacute bacterial endocarditis). IgA constitutes only 7–15% of total serum immunoglobulin but is the predominant class of immunoglobulin in secretions. IgA in secretions (tears, saliva, nasal secretions, gastrointestinal tract fluid, and human milk) is in the form of secretory IgA (sIgA), a polymer consisting of two IgA monomers, a joining molecule, again termed the J chain, and a glycoprotein called the secretory protein. Of the two IgA subclasses, IgA1 is primarily found in serum, whereas IgA2 is more prevalent in secretions. IgA fixes complement via the alternative complement pathway and has potent antiviral activity in humans by prevention of virus binding to respiratory and gastrointestinal epithe­ lial cells. IgD is found in minute quantities in serum and, together with IgM, is a major receptor for antigen on the naïve B-cell surface. IgE, which is present in serum in very low concentrations, is the major class of CHAPTER 360 Introduction to the Immune System Lymphocytes Lymphocytes None Mast cells, basophils, B cells Secretory immunoglobulin Primary antibody responses Marker for mature B cells Allergy, antiparasite responses immunoglobulin involved in arming mast cells and basophils by bind­ ing to these cells via the Fc region. Antigen cross-linking of IgE mol­ ecules on basophil and mast cell surfaces results in release of mediators of the immediate hypersensitivity (allergic) response (Table 360-11). ■ ■CELLULAR INTERACTIONS IN REGULATION OF NORMAL IMMUNE RESPONSES The net result of activation of the humoral (B-cell) and cellular (T-cell) arms of the adaptive immune system by foreign antigen is the elimina­ tion of antigen directly by specific effector T cells or in concert with specific antibody. The expression of adaptive immune cell function is the result of a complex series of immunoregulatory events that occur in phases. Both T and B lymphocytes mediate immune functions, and each of these cell types, when given appropriate signals, passes through stages, from activation and induction through proliferation, differentiation, and ultimately effector functions. The effector function expressed may be at the end point of a response, such as secretion of antibody by a differentiated plasma cell, or it might serve a regulatory function that modulates other functions, such as is seen with CD4 and CD8 T lym­ phocytes that modulate both differentiation of B cells and activation of CD8 cytotoxic T cells. TH1 CD4+ T cells, through elaboration of IFN-γ, have a central role in mediating intracellular killing by a variety of pathogens. TH1 CD4+ T cells also provide T-cell help for generation of cytotoxic T cells and some types of opsonizing antibody, and they generally respond to antigens that lead to delayed hypersensitivity types of immune responses for many intracellular viruses and bacteria (such as HIV-1 or M. tuberculosis). In contrast, TH2 cells have a primary role in regula­ tory humoral immunity and isotype switching. TH2 cells, through production of IL-4 and IL-10, have a regulatory role in limiting proin­ flammatory responses mediated by TH1 cells (Fig. 360-2). In addition, TH2 CD4+ T cells provide help to B cells for specific Ig production and respond to antigens that require high antibody levels for foreign antigen elimination (extracellular encapsulated bacteria such as Strep­ tococcus pneumoniae and certain parasite infections). TH17 cells secrete cytokines IL-17, -22, and -26 and have been shown to play a role in autoimmune inflammatory disorders in addition to defense against extracellular bacteria and fungi, particularly at mucosal surfaces. TH9 cells are defined by their secretion of IL-9 and have been shown to play a role in atopic disease, inflammatory bowel disease, and antitumor immunity. Moreover, the TFH subset of helper T cells secrete IL-21 and is crucial for providing the necessary signals to B cells in germinal centers to undergo affinity maturation. TFH13 cells secrete IL-4, IL-5, and IL-13 in response to allergens and and have been postulated to mediate anaphylaxis reactions (Fig. 360-2). In summary, the type of T-cell response generated in an immune response is determined by the microbe PAMPs presented to the DCs, the TLRs on the DCs that become activated, the types of DCs that are activated, and the cytokines that are produced (Table 360-7). Commonly, myeloid DCs produce IL-12 and activate TH1 T-cell responses that result in IFN-γ and cytotoxic T-cell induction, and plasmacytoid DCs produce IFN-α and lead to TH2 responses that result in IL-4 production and enhanced antibody responses. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders As shown in Fig. 360-2, upon activation by DCs, T-cell subsets that produce IL-2, IL-3, IFN-γ, and/or IL-4, -5, -6, -10, and -13 are gener­ ated and exert positive and negative influences on effector T and B cells. For B cells, trophic effects are mediated by a variety of cytokines, particularly T cell–derived IL-3, -4, -5, and -6, that act at sequential stages of B-cell maturation, resulting in B-cell proliferation, differentia­ tion, and ultimately antibody secretion. For cytotoxic T cells, trophic factors include inducer T-cell secretion of IL-2, IFN-γ, and IL-12. Important types of immunomodulatory T cells that control immune responses are CD4 and CD8 Treg cells. These cells express the α chain of the IL-2 receptor (CD25), produce IL-10, and suppress both T- and B-cell responses. T regulatory cells (Tregs) are induced by immature DCs and play key roles in maintaining tolerance to self-antigens. Loss of Treg cells is the cause of organ-specific autoimmune disease in mice such as autoimmune thyroiditis, adrenalitis, and oophoritis and plays a role in inflammatory bowel disease (see “Immune Tolerance and Auto­ immunity” below, Chap. 361). Tregs also play key roles in controlling the magnitude and duration of immune responses to microbes. Nor­ mally, after the initial immune response to a microbe has eliminated the invader, Tregs are activated to suppress the antimicrobe response and prevent host injury. Some microbes have adapted to induce Treg activation at the site of infection to promote parasite infection and sur­ vival. In Leishmania infection, the parasite induces Treg accumulation at skin infection sites that dampens anti-Leishmania T-cell responses and prevents parasite elimination. Although B cells recognize native antigen via B-cell surface Ig receptors, B cells require T-cell help to produce high-affinity antibody of multiple isotypes that are the most effective in eliminating foreign antigen. In B-cell germinal centers, CD4 T cells that promote B-cell maturation and affinity maturation are termed T follicular helper (TFH) cells. T cell–B cell interactions that lead to high-affinity antibody production require (1) processing of native antigen by B cells and expression of peptide fragments on the B-cell surface for presentation to TH cells, (2) the ligation of B cells by both the TCR complex and the CD40 ligand, (3) induction of the pro­ cess termed antibody isotype switching in antigen-specific B-cell clones, and (4) induction of the process of affinity maturation of antibody in the germinal centers of B-cell follicles of lymph node and spleen. Naïve B cells express cell-surface IgD and IgM, and initial contact of naïve B cells with antigen is via binding of native antigen to B-cell surface IgM. T-cell cytokines, released following TH2 cell contact with B cells or by a “bystander” effect, induce changes in Ig gene conforma­ tion that promote recombination of Ig genes. These events then result in the switching of expression of heavy chain exons in a triggered B cell, leading to the secretion of IgG, IgA, or, in some cases, IgE antibody with the same V region antigen specificity as the original IgM antibody, for response to a wide variety of extracellular bacteria, protozoa, and helminths. CD40 ligand expression by activated T cells is critical for induction of B-cell antibody isotype switching and for B-cell respon­ siveness to cytokines. Patients with mutations in T-cell CD40 ligand have B cells that are unable to undergo isotype switching, resulting in lack of memory B-cell generation and the immunodeficiency syn­ drome of X-linked hyper-IgM syndrome (Chaps. 361 and 362). ■ ■IMMUNE TOLERANCE AND AUTOIMMUNITY Immune tolerance is defined as the absence of activation of pathogenic autoreactivity to self-antigens. Mechanisms of immune tolerance can be classified as cell intrinsic or cell extrinsic. Cell intrinsic mechanisms of tolerance include apoptosis and induction of cell unresponsiveness (anergy). Mechanisms of cell extrinsic tolerance include suppression of immune responses by immunomodulatory cells such as Tregs. Autoimmune diseases are syndromes caused by the activation of T or B cells or both, with no evidence of other causes such as infections or malignancies (Chaps. 361 and 367). Low levels of autoreactivity of T and B cells with self-antigens in the periphery are critical to T- and B-cell survival. Similarly, low levels of autoreactivity and thymocyte recognition of self-antigens in the thymus are the mechanisms whereby normal T cells are positively selected to survive and leave the thymus to respond to foreign microbes in the periphery and T cells highly reac­ tive to self-antigens are negatively selected and die to prevent overly self-reactive T cells from migrating to the periphery (central toler­ ance). Unlike the presentation of microbial antigens by mature DCs, the presentation of self-antigens by immature DCs neither activates nor matures the DCs to express high levels of co-stimulatory molecules such as B7-1 (CD80) or B7-2 (CD86). When peripheral T cells are stimulated by DCs expressing self-antigens in the context of HLA mol­ ecules, sufficient stimulation of T cells occurs to keep them alive, but otherwise, they remain anergic, or nonresponsive, until T cells contact a DC with high levels of co-stimulatory molecules expressing microbial antigens and become activated to respond to the microbe. If B cells have high self-reactive BCRs, they normally undergo either deletion in the bone marrow or receptor editing to express a less autoreactive receptor. Although many autoimmune diseases are characterized by abnormal or pathogenic autoantibody production (see Chap. 361, Table 361-4), most autoimmune diseases are caused by a combination of excess T- and B-cell reactivity. Multiple factors contribute to the genesis of autoimmune disease syndromes, including genetic susceptibility (e.g., HLA-B27 with anky­ losing spondylitis), environmental immune stimulants such as drugs (e.g., procainamide and phenytoin [Dilantin] with drug-induced systemic lupus erythematosus), infectious agent triggers (e.g., EpsteinBarr virus and autoantibody production against red blood cells and platelets), and loss of Treg cells (leading to thyroiditis, adrenalitis, and oophoritis). Immunity at Mucosal Surfaces  Mucosa covering the respiratory, digestive, and urogenital tracts; the eye conjunctiva; the inner ear; and the ducts of all exocrine glands contain cells of the innate and adaptive mucosal immune system that protect these surfaces against pathogens. In the healthy adult, mucosa-associated lymphoid tissue (MALT) contains 80% of all immune cells within the body and constitutes the largest mammalian lymphoid organ system. MALT has three main functions: (1) to protect the mucous mem­ branes from invasive pathogens; (2) to prevent uptake of foreign anti­ gens from food, commensal organisms, and airborne pathogens and particulate matter; and (3) to prevent pathologic immune responses from foreign antigens if they do cross the mucosal barriers of the body. MALT is a compartmentalized system of immune cells that func­ tions independently from systemic immune organs. Whereas the systemic immune organs are essentially sterile under normal condi­ tions and respond vigorously to pathogens, MALT immune cells are continuously bathed in foreign proteins and commensal bacteria, and they must select those pathogenic antigens that must be eliminated. MALT contains anatomically defined foci of immune cells in the intestine, tonsil, appendix, and peribronchial areas that are inductive sites for mucosal immune responses. From these sites, immune T and B cells migrate to effector sites in mucosal parenchyma and exocrine glands where mucosal immune cells eliminate pathogen-infected cells. In addition to mucosal immune responses, all mucosal sites have strong mechanical and chemical barriers and cleansing functions to repel pathogens. Key components of MALT include specialized epithelial cells called “membrane” or “M” cells that take up antigens and deliver them to DCs or other APCs. Regulatory cells that maintain gut homeostasis include ILC APCs, likely ILC3, that drive the development of CD4 Tregs that suppress pathogenic immune responses to benign commensal micro­ biota. Effector cells in MALT include B cells producing antipathogen neutralizing antibodies of secretory IgA as well as IgG isotype, T cells producing similar cytokines as in systemic immune responses, and T helper and cytotoxic T cells that respond to pathogen-infected cells. Secretory IgA is produced in amounts of >50 mg/kg of body weight per 24 h and functions to inhibit bacterial adhesion, inhibit macromol­ ecule absorption in the gut, neutralize viruses, and enhance antigen elimination in tissue through binding to IgA and receptor-mediated transport of immune complexes through epithelial cells. Recent studies have demonstrated the importance of commensal gut and other mucosal bacteria to the health of the human immune system. Normal commensal flora induces anti-inflammatory events in the gut and protects epithelial cells from pathogens through TLRs and other PRR signaling. When the gut is depleted of normal com­ mensal flora, the immune system becomes abnormal, with loss of TH1 T-cell function. Restoration of the normal gut flora can reestablish the balance in Treg and T helper cell ratios characteristic of the normal immune system. Diet also has an impact on the gut microbiome. Altered microbiome composition has been etiologically related to obesity, insulin resistance, inflammatory bowel disease, and diabetes. When the gut barrier is intact, either antigens do not transverse the gut epithelium or, when pathogens are present, a self-limited, protec­ tive MALT immune response eliminates the pathogen. However, when the gut barrier breaks down, immune responses to commensal flora antigens can contribute to Crohn’s disease and, perhaps, ulcerative colitis (Chap. 337). Uncontrolled MALT immune responses to food antigens, such as gluten, can cause celiac disease (Chap. 337). ■ ■THE CELLULAR AND MOLECULAR CONTROL OF PROGRAMMED CELL DEATH The process of apoptosis (programmed cell death) plays a crucial role in regulating normal immune responses to antigen. In general, a wide variety of stimuli trigger one of several apoptotic pathways to eliminate microbe-infected cells, eliminate cells with damaged DNA, or eliminate activated immune cells that are no longer needed. The largest known family of “death receptors” is the TNF receptor (TNF-R) family (TNF-R1, TNF-R2, Fas [CD95], death receptor 3 [DR3], death receptor 4 [DR4; TNF-related apoptosis-including ligand receptor 1, or TRAIL-R1], and death receptor 5 [DR5, TRAIL-R2]); their ligands are all in the TNF-α family. Binding of ligands to these death recep­ tors leads to a signaling cascade that involves activation of the caspase family of molecules that leads to DNA cleavage and cell death. Two other pathways of programmed cell death involve nuclear p53 in the elimination of cells with abnormal DNA and mitochondrial cytochrome c to induce cell death in damaged cells. A number of human diseases have now been described that result from, or are associated with, mutated apoptosis genes. These include mutations in the Fas and Fas ligand genes in autoimmune and lymphoproliferation syndromes, and multiple associations of mutations in genes in the apoptotic pathway with malignant syndromes (Chap. 361). ■ ■MECHANISMS OF IMMUNE-MEDIATED DAMAGE TO MICROBES OR HOST TISSUES Several responses by the host innate and adaptive immune systems to foreign microbes culminate in rapid and efficient elimination of microbes. In these scenarios, the classic weapons of the adaptive immune system (T cells, B cells) interface with cells (macrophages, DCs, NK cells, neutrophils, eosinophils, basophils) and soluble prod­ ucts (microbial peptides, pentraxins, complement and coagulation systems) of the innate immune system (Chaps. 67 and 363). There are five general phases of host defenses: (1) migration of leukocytes to sites of antigen localization; (2) antigen-nonspecific rec­ ognition of pathogens by macrophages and other cells and systems of the innate immune system; (3) specific recognition of foreign antigens mediated by T and B lymphocytes; (4) amplification of the inflamma­ tory response with recruitment of specific and nonspecific effector cells by complement components, cytokines, kinins, arachidonic acid metabolites, and mast cell–basophil products; and (5) macrophage, neutrophil, and lymphocyte participation in destruction of antigen with ultimate removal of antigen particles by phagocytosis (by macro­ phages or neutrophils) or by direct cytotoxic mechanisms (involving macrophages, neutrophils, DCs, or lymphocytes). Under normal cir­ cumstances, orderly progression of host defenses through these phases results in a well-controlled immune and inflammatory response that protects the host from the offending antigen. However, dysfunction of any of the host defense systems can damage host tissue and produce clinical disease. Furthermore, for certain pathogens or antigens, the nor­ mal immune response itself might contribute substantially to the tissue damage. For example, the immune and inflammatory response in the brain to certain pathogens such as M. tuberculosis may be responsible for much of the morbidity rate of this disease in that organ system (Chap. 183). In addition, the morbidity rate associated with certain pneumonias such as that caused by Pneumocystis jirovecii may be associated more with inflammatory infiltrates than with the tissuedestructive effects of the microorganism itself (Chap. 227). CHAPTER 360 Introduction to the Immune System Molecular Basis of Lymphocyte–Endothelial Cell Interac­ tions  The control of lymphocyte circulatory patterns between the bloodstream and peripheral lymphoid organs operates at the level of lymphocyte–endothelial cell interactions to control the specificity of lymphocyte subset entry into organs. Similarly, lymphocyte–endothelial cell interactions regulate the entry of lymphocytes into inflamed tissue. Adhesion molecule expression on lymphocytes and endothelial cells regulates the retention and subsequent egress of lymphocytes within tissue sites of antigenic stimulation, delaying cell exit from tissue and preventing reentry into the circulating lymphocyte pool (Fig. 360-9). All types of lymphocyte migration begin with lymphocyte attachment to specialized regions of vessels, termed high endothelial venules (HEVs). An important concept is that adhesion molecules do not generally bind their ligand until a conformational change (ligand activation) occurs in the adhesion molecule that allows ligand binding. Induction of a conformation-dependent determinant on an adhesion molecule can be accomplished by cytokines or via ligation of other adhesion molecules on the cell. The first stage of lymphocyte–endothelial cell interactions, attach­ ment and rolling, occurs when lymphocytes leave the stream of flowing blood cells in a postcapillary venule and roll along venule endothelial cells (Fig. 360-9). Lymphocyte rolling is mediated by the l-selectin molecule (LECAM-1, LAM-1, CD62L) and slows cell transit time through venules, allowing time for activation of adherent cells. The second stage of lymphocyte–endothelial cell interactions, firm adhesion with activation-dependent stable arrest, requires stimulation of lymphocytes by chemoattractants or by endothelial cell–derived cytokines. Cytokines thought to participate in adherent cell activa­ tion include members of the IL-8 family, platelet-activation factor, leukotriene B4, and C5a. In addition, HEVs express chemokines, SLC (CCL21) and ELC (CCL19), which participate in this process. Fol­ lowing activation by chemoattractants, lymphocytes shed l-selectin from the cell surface and upregulate cell CD11b/18 (MAC-1) or CD11a/18 (LFA-1) molecules, resulting in firm attachment of lym­ phocytes to HEVs. Lymphocyte homing to peripheral lymph nodes involves adhesion of l-selectin to glycoprotein HEV ligands collectively referred to as peripheral node addressin (PNAd), whereas homing of lymphocytes to intestine Peyer’s patches primarily involves adhesion of the a4β7 integrin to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on the Peyer’s patch HEVs. However, for migration to mucosal Peyer’s patch lymphoid aggregates, naïve lymphocytes primarily use l-selectin, whereas memory lymphocytes use α4β7 integrin. α4β1 integrin (CD49d/CD29, VLA-4)–VCAM-1 interactions are important in the initial interaction of memory lymphocytes with HEVs of multiple organs in sites of inflammation. The third stage of leukocyte emigration in HEVs is sticking and arrest. Sticking of the lymphocyte to endothelial cells and arrest at the site of sticking are mediated predominantly by ligation of a1β2 integrin LFA-1 to the integrin ligand ICAM-1 on HEVs. Whereas the first three stages of lymphocyte attachment to HEVs take only a few seconds, the fourth stage of lymphocyte emigration, transendothelial migration, takes ~10 min. Although the molecular mechanisms that control lymphocyte transendothelial migration are not fully character­ ized, the HEV CD44 molecule and molecules of the HEV glycocalyx (extracellular matrix) are thought to play important regulatory roles in Blood vessel lumen 1. Tethering and rolling 2. Chemokine signal 3. Arrest 4. Polarization and diapedesis PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Basement membrane DC Lymph vessel 8. DC migration to draining LN Inflammatory chemoattractants Selectin sialomucin Resting actve integrins Collagen FIGURE 360-9  Key migration steps of immune cells at sites of inflammation. Inflammation due to tissue damage or infection induces the release of cytokines (not shown) and inflammatory chemoattractants (red arrowheads) from distressed stromal cells and “professional” sentinels, such as mast cells and macrophages (not shown). The inflammatory signals induce upregulation of endothelial selectins and immunoglobulin “superfamily” members, particularly ICAM-1 and/or VCAM-1. Chemoattractants, particularly chemokines, are produced by or translocated across venular endothelial cells (red arrow) and are displayed in the lumen to rolling leukocytes. Those leukocytes that express the appropriate set of trafficking molecules undergo a multistep adhesion cascade (steps 1–3) and then polarize and move by diapedesis across the venular wall (steps 4 and 5). Diapedesis involves transient disassembly of endothelial junctions and penetration through the underlying basement membrane (step 6). Once in the extravascular (interstitial) space, the migrating cell uses different integrins to gain “footholds” on collagen fibers and other ECM molecules, such as laminin and fibronectin, and on inflammation-induced ICAM-1 on the surface of parenchymal cells (step 7). The migrating cell receives guidance cues from distinct sets of chemoattractants, particularly chemokines, which may be immobilized on glycosaminoglycans (GAG) that “decorate” many ECM molecules and stromal cells. Inflammatory signals also induce tissue dendritic cells (DCs) to undergo maturation. Once DCs process material from damaged tissues and invading pathogens, they upregulate CCR7, which allows them to enter draining lymph vessels that express the CCR7 ligand CCL21 (and CCL19). In lymph nodes (LNs), these antigen-loaded mature DCs activate naïve T cells and expand pools of effector lymphocytes, which enter the blood and migrate back to the site of inflammation. T cells in tissue also use this CCR7-dependent route to migrate from peripheral sites to draining lymph nodes through afferent lymphatics. (Reproduced with permission from AD Luster et al: Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 6:1182, 2005.) this process (Fig. 360-10). Finally, expression of matrix metalloprote­ ases capable of digesting the subendothelial basement membrane, rich in nonfibrillar collagen, appears to be required for the penetration of lymphoid cells into the extravascular sites. Abnormal induction of HEV formation and use of the molecules discussed above have been implicated in the induction and mainte­ nance of inflammation in a number of chronic inflammatory diseases. In animal models of type 1 diabetes mellitus, MAdCAM-1 and GlyCAM-1 have been shown to be highly expressed on HEVs in inflamed pancre­ atic islets, and treatment of these animals with inhibitors of l-selectin and a4 integrin function blocked the development of type 1 diabetes mellitus (Chap. 415). A similar role for abnormal induction of the adhesion molecules of lymphocyte emigration has been suggested in rheumatoid arthritis (Chap. 370), Hashimoto’s thyroiditis (Chap. 394), Graves’ disease (Chap. 394), multiple sclerosis (Chap. 455), Crohn’s disease (Chap. 337), and ulcerative colitis (Chap. 337). Immune-Complex Formation  Clearance of antigen by immunecomplex formation between antigen, complement, and antibody is a highly effective mechanism of host defense. However, depending 5. Junctional rearrangement 6. Proteolysis Cytokinestimulated parenchymal cell Damaged or inflamed tissue 7. Interstitial migration ECM with GAG GPCR CCL19 CCL21 CCR7 ICAM-1 or VCAM-1 on the level of immune complexes formed and their physicochemi­ cal properties, immune complexes may or may not result in host and foreign cell damage. After antigen exposure, certain types of soluble antigen-antibody complexes freely circulate and, if not cleared by the reticuloendothelial system, can be deposited in blood vessel walls and in other tissues such as renal glomeruli and cause vasculitis or glomerulonephritis syndromes (Chaps. 326 and 375). Deficiencies of early complement components are associated with inefficient clearance of immune complexes and immune complex–mediated autoimmune syndromes or encapsulated bacterial infections such as S. pneumoniae, whereas deficiencies of the later complement components are associ­ ated with susceptibility to recurrent Neisseria infections (Table 360-12). Immediate-Type Hypersensitivity  Helper T cells that drive antiallergen IgE responses are usually TH2-type inducer T cells that secrete IL-4, IL-5, IL-6, and IL-10. A subset of TFH, TFH13, cells have been identified that produce IL-4, IL-5, and IL-13, which play a key role in responses to allergens that induce IgE and mediate ana­ phylaxis. Mast cells and basophils have high-affinity receptors for the Fc portion of IgE (FcRI), and cell-bound antiallergen IgE effectively TABLE 360-12  Complement Deficiencies and Associated Diseases COMPONENT ASSOCIATED DISEASES Classic Pathway Clq, Clr, Cls, C4 Immune-complex syndromes,a pyogenic infections C2 Immune-complex syndromes,a few with pyogenic infections C1 inhibitor Rare immune-complex disease, few with pyogenic infections C3 and Alternative Pathway C3 C3 Immune-complex syndromes,a pyogenic infections D Pyogenic infections Properdin Neisseria infections I Pyogenic infections H Hemolytic-uremic syndrome Membrane Attack Complex C5, C6, C7, C8 Recurrent Neisseria infections, immune-complex disease C9 Rare Neisseria infections aImmune-complex syndromes include systemic lupus erythematosus (SLE) and SLE-like syndromes, glomerulonephritis, and vasculitis syndromes. Source: After JA Schifferli, DK Peters: Lancet 322:957, 1983. Copyright 1983. “arms” basophils and mast cells. Mediator release is triggered by antigen (allergen) interaction with Fc receptor-bound IgE, and the mediators released are responsible for the pathophysiologic changes of allergic diseases. Mediators released from mast cells and basophils can be divided into three broad functional types: (1) those that increase vascular permeability and contract smooth muscle (histamine, plateletactivating factor, SRS-A, BK-A), (2) those that are chemotactic for or activate other inflammatory cells (ECF-A, NCF, leukotriene B4), and (3) those that modulate the release of other mediators (BK-A, plateletactivating factor) (Chap. 363). Cytotoxic Reactions of Antibody  In this type of immunologic injury, complement-fixing (C1-binding) antibodies against normal or foreign cells or tissues (IgM, IgG1, IgG2, IgG3) bind complement via the classic pathway and initiate a sequence of events similar to that initiated by immune-complex deposition, resulting in cell lysis or tissue injury. Examples of antibody-mediated cytotoxic reactions include red cell lysis in transfusion reactions, Goodpasture’s syndrome with anti–glomerular basement membrane antibody formation, and pemphigus vulgaris with anti-epidermal antibodies inducing blistering skin disease. Delayed-Type Hypersensitivity Reactions  Inflammatory reactions initiated by mononuclear leukocytes and not by antibody alone have been termed delayed-type hypersensitivity reactions. The term delayed has been used to contrast a secondary cellular response that appears 48–72 h after antigen exposure with an immediate hyper­ sensitivity response generally seen within 12 h of antigen challenge and initiated by basophil mediator release or preformed antibody. For example, in an individual previously infected with M. tuberculo­ sis organisms, intradermal placement of tuberculin purified protein derivative as a skin test challenge results in an indurated area of skin at 48–72 h, indicating previous exposure to tuberculosis. The cellular events that result in classic delayed-type hypersensitiv­ ity responses are centered on T cells (predominantly, although not exclusively, IFN-γ, IL-2, and TNF-α-secreting TH1-type helper T cells) and macrophages. Recently, NK cells have been suggested to play a major role in the form of delayed hypersensitivity that occurs follow­ ing skin contact with immunogens. First, local immune and inflam­ matory responses at the site of foreign antigen upregulate endothelial cell adhesion molecule expression, promoting the accumulation of lymphocytes at the tissue site. In the scheme outlined in Fig. 360-2, antigen is processed by DCs and presented to small numbers of CD4+ T cells expressing a TCR specific for the antigen. IL-12 produced by APCs induces T cells to produce IFN-γ (TH1 response). Macrophages frequently undergo epithelioid cell transformation and fuse to form multinucleated giant cells in response to IFN-γ. This type of mono­ nuclear cell infiltrate is termed granulomatous inflammation. Examples of diseases in which delayed-type hypersensitivity plays a major role are fungal infections (histoplasmosis; Chap. 218), mycobacterial infec­ tions (tuberculosis, leprosy; Chaps. 183 and 184), chlamydial infections (lymphogranuloma venereum; Chap. 194), helminth infections (schis­ tosomiasis; Chap. 241), reactions to toxins (berylliosis; Chap. 300), and hypersensitivity reactions to organic dusts (hypersensitivity pneumoni­ tis; Chap. 299). In addition, delayed-type hypersensitivity responses play important roles in tissue damage in autoimmune diseases such as rheumatoid arthritis, temporal arteritis, and granulomatosis with poly­ angiitis (Chaps. 370 and 375). CHAPTER 360 Introduction to the Immune System Autophagy  Autophagy is a process that involves a lysosomal deg­ radation pathway mechanism of cells to dispose of intracellular debris and damaged organelles. Autophagy by cells of the innate immune sys­ tem is used to control intracellular infectious agents such as M. tuber­ culosis, in part by initiation of phagosome maturation and enhancing MHC class II antigen presentation to CD4 T cells. ■ ■CLINICAL EVALUATION OF IMMUNE FUNCTION Clinical assessment of immunity requires investigation of the four major components of the immune system that participate in host defense and in the pathogenesis of autoimmune diseases: (1) humoral immunity (B cells); (2) cell-mediated immunity (T cells, monocytes); (3) phagocytic cells of the reticuloendothelial system (macrophages), as well as polymorphonuclear leukocytes; and (4) complement. Clini­ cal problems that require an evaluation of immunity include chronic infections, recurrent infections, unusual infecting agents, and certain autoimmune syndromes. The type of clinical syndrome under evalu­ ation can provide information regarding possible immune defects (Chap. 362). Defects in cellular immunity generally result in viral, mycobacterial, and fungal infections. An extreme example of defi­ ciency in cellular immunity is AIDS (Chap. 208). Antibody deficien­ cies result in recurrent bacterial infections, frequently with organisms such as S. pneumoniae and Haemophilus influenzae (Chap. 362). Dis­ orders of phagocyte function are frequently manifested by recurrent skin infections, often due to Staphylococcus aureus (Chap. 67). Finally, deficiencies of early and late complement components are associated with autoimmune phenomena and recurrent Neisseria infections (Table 360-12). Artificial intelligence/machine learning algorithms are now being tested for improving the diagnosis of infectious, immune deficiency, and autoimmune diseases. For further discussion of useful initial screening tests of immune function, see Chap. 362. ■ ■IMMUNOTHERAPY Many therapies for autoimmune and inflammatory diseases involve the use of nonspecific immune-modulating or immunosuppressive agents such as glucocorticoids or cytotoxic drugs. The goal of development of new treatments for immune-mediated diseases is to design ways to specifically interrupt pathologic immune responses, leaving nonpatho­ logic immune responses intact (Chap. 361). Novel ways to interrupt pathologic immune responses that are under investigation include the use of anti-inflammatory cytokines or specific cytokine inhibitors as anti-inflammatory agents, the use of monoclonal antibodies against T or B lymphocytes as therapeutic agents, the use of intravenous Ig for certain infections and immune complex–mediated diseases, the use of specific cytokines to reconstitute components of the immune system, and bone marrow transplantation to replace the pathogenic immune system with a more normal immune system (Chaps. 67, 208, 361, and 362). CTLA-4 inhibitors such as ipilimumab and tremelimumab and anti-PD-1 antibodies such as nivolumab are termed checkpoint inhibitors and have been shown to reverse CD8 T-cell exhaustion in melanoma and other solid tumors and induce immune cell control of tumor growth (Chap. 361). A technique that engineers autologous T cells to express antibody receptors that target leukemic cells, termed chimeric antigen receptor T cells (CAR T cells), has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of certain types of leukemias and lymphomas (Chap. 361). Cell-based therapies have been studied for many years, includ­ ing ex vivo activation of NK cells for reinfusion into patients with # 07 - 364 Anaphylaxis ### 364 Anaphylaxis PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Anaphylaxis David Hong, Joshua A. Boyce ■ ■BACKGROUND Anaphylaxis is a potentially life-threatening systemic allergic reac­ tion involving one or more organ systems that typically occurs within seconds to minutes of exposure to the anaphylactic trigger, most often a drug, food, or Hymenoptera sting. The term anaphylaxis was first described in 1902 by Charles Richet and Paul Portier who attempted to immunize dogs against sea anemone toxin in the same way Pasteur was able to vaccinate individuals against the smallpox virus. To their surprise, repeated administration of small, sublethal doses of sea anem­ one toxin reliably induced acute-onset death when readministered 2–3 weeks after initial “vaccination” to the toxin. The phenomenon was termed ana (anti)-phylaxis (“protection or guarding”) because vaccination with anemone toxin resulted in the opposite intended immune effect. Charles Richet was awarded the Nobel Prize in Physiol­ ogy or Medicine in 1913 for this work which led to further insights into hypersensitivity and mast cell biology. ■ ■CLINICAL MANIFESTATIONS While 80–90% of anaphylactic episodes are uniphasic, about 10–20% of cases are biphasic, in which anaphylactic symptoms return about an hour or longer after resolution of initial symptoms. Anaphylactic reactions are particularly dangerous when hypotension or hypoxia occurs, leading potentially to cardiovascular collapse or respiratory failure, respectively. There may be upper or lower airway obstruc­ tion or both. Laryngeal edema may be experienced as a “lump” in the throat, hoarseness, or stridor, whereas bronchial obstruction is associ­ ated with a feeling of tightness in the chest and/or audible wheezing. Patients with underlying asthma are predisposed to severe involvement of the lower airways and increased mortality associated with anaphy­ laxis. In fatal cases with clinical bronchial obstruction, the lungs show marked hyperinflation on gross and microscopic examination. The microscopic findings in the bronchi, however, are limited to luminal secretions, peribronchial congestion, submucosal edema, and eosino­ philic infiltration, and the acute emphysema is attributed to intractable bronchospasm that subsides with death. Angioedema resulting in death by mechanical obstruction occurs in the epiglottis and larynx. This process can also be evident in the hypopharynx and trachea. On microscopic examination, there is wide separation of the collagen fibers and the glandular elements. Vascular congestion and eosino­ philic infiltration may also be present. Patients dying of vascular col­ lapse without antecedent hypoxia from respiratory insufficiency have visceral congestion with a presumed loss of intravascular fluid volume. The associated electrocardiographic abnormalities in some patients, with or without infarction, may reflect a primary cardiac event medi­ ated by mast cells (which are prominent near the coronary vessels) or may be secondary to a critical reduction in intravascular volume. Gastrointestinal manifestations represent another severe presenta­ tion of anaphylaxis and include nausea, vomiting, crampy abdominal pain, and/or fecal incontinence. Angioedema of the bowel wall may also cause sufficient intravascular volume depletion to precipitate car­ diovascular collapse. Cutaneous manifestations are among the most common presenta­ tions of anaphylaxis (>90% of cases). Symptoms include urticarial eruptions, flushing with diffuse erythema, and/or a feeling of general­ ized warmth. Urticarial eruptions are intensely pruritic and may be localized or disseminated. They may coalesce to form large urticarial plaques but seldom persist beyond 48 h. ■ ■PATHOPHYSIOLOGY Many of the important early mediators of anaphylaxis are derived from mast cells, basophils, and eosinophils. Mast cells contain preformed granules comprised of histamine, proteases (tryptase, chymase), pro­ teoglycans (heparin, chondroitin sulfate), and tumor necrosis factor-α, which are rapidly released into surrounding tissue upon cell activation, a process known as degranulation. Basophils, like mast cells, contain and release histamine. Mast cells, basophils, and eosinophils are also sources of arachidonic acid–derived products, which include cysteinyl leukotrienes, prostaglandins, and platelet-activating factor (PAF). Histamine release results in flushing, urticaria, pruritus, and, in high concentrations, hypotension and tachycardia. Cysteinyl leukotrienes and prostaglandin D2 cause bronchoconstriction and increased micro­ vascular permeability. Prostaglandin D2 causes cutaneous flushing and attracts eosinophils and basophils to the site of mast cell activation. Serum PAF levels correlate with anaphylaxis severity and are inversely proportional to the constitutive level of PAF acetylhydrolase, which is necessary for PAF inactivation. Tryptase and chymase can activate complement and coagulation pathways. Activation of these pathways results in production of the anaphylatoxins, C3a and C5a, and activa­ tion of the kallikrein-kinin system, which regulates blood pressure and vascular permeability. The actions of these anaphylactic mediators are likely additive or synergistic at the target tissues. ■ ■PREDISPOSING FACTORS AND MECHANISMS Because the most dangerous manifestations of anaphylaxis involve the cardiovascular and/or respiratory systems, preexisting asthma and underlying cardiovascular disease could lead to more rapid decompen­ sation from anaphylaxis. Atopy is not generally thought to be a risk fac­ tor for anaphylaxis from drug reactions or Hymenoptera stings, but it is associated with radiocontrast sensitivity, exercise-induced anaphylaxis, idiopathic anaphylaxis, and allergy to foods or latex. Severe Hyme­ noptera-induced anaphylaxis (generally with prominent hypotension) is the most common initial presentation for patients with underlying systemic mastocytosis. For this reason, it is important to check a base­ line tryptase (a reflection of mast cell burden) in patients who present with sting-induced anaphylaxis to screen for this condition. Hyme­ noptera allergy is also more likely in patients whose occupations (i.e., beekeepers, trash haulers, and landscape workers) place them in regu­ lar proximity to stinging insects. Most commonly, allergen-induced cross-linking of IgE-bound FcεRI receptors on mast cells and basophils initiates the signal transduction events leading to hypersensitivity syndromes, including anaphylaxis. The generation of allergen-specific IgE is the end result of sensitization via the adaptive immune system. While the mechanisms underlying sensitization are beyond the scope of this chapter, environmental factors, innate immune responses, and cytokines are among the many variables leading to antigen-specific IgE production by B cells and plasma cells. IgE-mediated drug allergies are most common with antibiotics and certain chemotherapy drugs, though theoretically, they can occur with almost any medication. As is the case with environmental allergies, repeated exposure to the allergy-causing antigen is an important risk factor to keep in mind when evaluating patients with anaphylaxis. In the case of allergy to carboplatin, the incidence of hypersensitivity is 27% in patients who have had ≥7 lifetime infusions and as high as 46% in patients who have had ≥15 lifetime infusions. Similarly, patients with cystic fibrosis have a relatively high incidence of allergic reactions to IV antibiotics, particularly beta-lactams, that they receive periodically for intermittent “clean-outs” to maintain airway clearance. Drugs can also function as haptens that form immunogenic conjugates with host proteins. The conjugating hapten may be the parent compound, a nonenzymatically derived storage product, or a metabolite formed in the host. Recom­ binant biologics in some cases can also induce the formation of IgE against the proteins or against glycosylated structures that serve as immunogens. Outbreaks of anaphylaxis to the epidermal growth factor receptor (EGFR) antibody, cetuximab, have been reported in associa­ tion with elevated titers of serum IgE to alpha-1,3-galactose (alphagal), an oligosaccharide found in nonprimate mammals. Cetuximab is derived from a mouse cell line expressing a transferase that tags the Fab′ portion of the cetuximab heavy chain with alpha-gal. Interestingly, patients with a history of multiple bites from Amblyomma americanum ticks commonly found in the Carolinas, Arkansas, and Tennessee are more likely to have anti-alpha-gal IgE as compared to patients living outside those states. A subset of individuals with anti-alpha-gal IgE can develop episodes of delayed-onset anaphylaxis about 3–6 h after consuming mammalian meat (beef, lamb, or pork) in a condition now known as alpha-gal syndrome (AGS). The mechanisms behind AGS are not yet well understood. It is also important to remember that allergic reactions caused by the effector cells and mediators described previously can be triggered by a variety of mechanisms that may not require the presence of sensitizing IgE. Non-IgE-mediated mast cell activation secondary to certain drugs is clinically indistinguishable from classical IgE-mediated hypersensi­ tivity reactions but can occur with first known exposure since there is no prior need for mast cell sensitization by IgE. MRGPRX2, a G protein–coupled receptor that is highly expressed in skin mast cells, has been shown in mouse models and in vitro studies using human cells to induce mast cell activation and mediator release secondary to neuromuscular blocking drugs (NMBDs), quinolones, and icatibant. These findings are clinically significant since NMBDs are needed for procedures done under general anesthesia while quinolones are a commonly used antibiotic family. Icatibant, a bradykinin-2 receptor antagonist administered by subcutaneous injection for the treatment of acute attacks of hereditary angioedema, is known to frequently result in local injection site reactions. Another example of non-IgE-mediated anaphylaxis is demonstrated with paclitaxel, a chemotherapy agent most commonly used in combination with carboplatin to treat ovar­ ian cancer. It is derived from yew tree bark and needles that require polyethoxylated castor oil (Cremophor) to be solubilized into aqueous solution. Cremophor has been shown in vitro to activate the comple­ ment cascade, resulting in complement-dependent histamine release from mast cells and basophils. A version of paclitaxel that is solubilized by being bound to albumin nanoparticles, Abraxane, has a far lower rate of hypersensitivity, especially for patients who have had infusion reactions to Cremophor-solubilized paclitaxel. Reactions such as flush­ ing, hives, angioedema, and/or anaphylaxis to radiocontrast, opiates, vancomycin, and nonsteroidal anti-inflammatory drugs (NSAIDs) are other examples of non-IgE-mediated hypersensitivity. An example of non-IgE-mediated food anaphylaxis is scombroid poisoning, caused by the ingestion of a pharmacologically significant dose of histamine from contaminated fish. This is most commonly associated with fish that are rich in histidine, such as mahi-mahi, mackerel, and tuna. If improperly stored, surface contaminant bacteria expressing histidine decarboxylase convert histidine into histamine, which is not broken down by baking or broiling. Scombroid poison­ ing leads to symptoms including flushing, oropharyngeal pruritis/ angioedema, nausea/vomiting, and lightheadedness. Symptoms are often self-limited but still treatable with antihistamines and, if needed, epinephrine. Because the source of histamine is exogenous, tryptase levels are not elevated. A final example of non-IgE-mediated anaphylaxis occurred in clustered cases of anaphylaxis to IV unfractionated heparin in Europe and North America in 2008. Cases were attributable to specific lots of heparin found to be enriched in a contaminant, oversulfated chon­ droitin sulfate (OSCS). OSCS is able to activate the contact activation system, leading to the generation of bradykinin and the anaphylatoxins C3a and C5a, which led to the anaphylactic symptoms. Heparin is now routinely screened for this contaminant to prevent further outbreaks. ■ ■DIAGNOSIS The diagnosis of an anaphylactic reaction depends primarily on a his­ tory revealing the onset of symptoms and signs within seconds to min­ utes after the putative trigger is encountered. An exception is delayed anaphylaxis to mammalian meats in patients with AGS. Table 364-1 lists other possibilities to consider on the differential for IgE-mediated anaphylaxis. Every attempt to identify the specific cause or causes should be made to minimize the risk of recurrent anaphylaxis. If a particular drug or food is suspected, skin or serum-specific IgE testing can be useful to confirm clinical suspicions. If a specific trigger cannot be identified by history or testing, a workup of underlying baseline atopic diatheses may be useful to identify risk factors that could play potential contributory roles alone or in concert. In the acute setting, laboratory biomarkers of mast cell degranulation may be useful to TABLE 364-1  Differential Diagnoses for IgE-Mediated Anaphylaxis CONDITION DISTINGUISHED BY Mastocytosis Elevated baseline tryptase, spindleshaped mast cells (MCs) on bone marrow CHAPTER 364 Pheochromocytoma Elevated urine metanephrines Carcinoid syndrome Elevated urine 5-hydroxyindoleacetic acid Hereditary angioedema Decreased C4 during attacks Acquired angioedema Decreased C1q Anaphylaxis Systemic capillary leak syndrome Severe hypotension on presentation with lack of response to firstline hypersensitivity medications (epinephrine, antihistamines) Scombroid poisoning Tryptase not elevated; negative skin test and oral challenge to fish Drugs (opiates, neuromuscular blocking agents, vancomycin), computed tomography radiocontrast Direct MC degranulation triggered through MRGPRX2 receptor or other as-yet-undetermined mechanism document the severity of an anaphylactic episode. The most obvious serum biomarker to assay, histamine, has an extremely short serum half-life with a measurable time-window that expires <1 h from the onset of anaphylaxis. A more practical and reliable biomarker is serum tryptase, which is released from mast cells, peaks 60–90 min after the onset of anaphylaxis, and can be measured as long as 5 h after the onset of anaphylaxis. It may be useful to follow up an elevated tryptase mea­ surement in the acute setting with another measurement when the patient is clinically stable to establish a baseline reference since there is considerable variability of baseline serum tryptase (BST) within the general population. For example, ~6% of Western populations have hereditary alpha-tryptasemia (HAT), a mostly benign condition featuring elevated BST due to expression of an extra allele of TPSAB1, the gene that encodes alpha-tryptase. Some studies suggest that HAT may be a risk factor for severe anaphylaxis and is also overrepresented in patients with indolent mastocytosis. Another cause for temporarily elevated BST is high environmental allergen exposure, something that can occur, for example, in regions with distinct pollen seasons. A work­ ing group on mast cell disorders in 2010 came up with a formula to better interpret tryptase levels since (1) the range of “normal” BST is wide within the general population and (2) an acutely elevated tryptase for a given patient may still fall within normal parameters if their BST is low. The “20% + 2” rule stipulates that a tryptase level drawn in the setting of possible anaphylaxis that is 20% above the patient’s baseline plus 2 ng/mL is diagnostic for an acute event involving a clinically significant degree of mast cell activation. ■ ■TREATMENT Early recognition of an anaphylactic reaction and appropriate interven­ tion are critically important because severe, even fatal, complications can occur within minutes after symptoms first appear. The treatment of first choice is intramuscular administration of 0.3–0.5 mL of 1:1000 (1 mg/mL) epinephrine, with repeated doses at 5- to 20-min intervals as needed for a severe reaction. The failure to use epinephrine within the first 20 min of symptoms is a risk factor for poor clinical outcomes in various studies of anaphylaxis. IV fluids and vasopressor agents may be administered in the acute medical setting if intractable hypoten­ sion occurs. Epinephrine provides both α- and β-adrenergic effects, resulting in vasoconstriction, bronchial smooth-muscle relaxation, and attenuation of enhanced venular permeability. Beta blockers may attenuate this response; therefore, an alternative antihypertensive may be considered in patients at high risk of needing emergency epineph­ rine. Oxygen alone via a nasal catheter or with nebulized albuterol may be helpful; however, either endotracheal intubation or a tracheostomy is mandatory for oxygen delivery if progressive hypoxia develops. Ancillary agents such as antihistamines, glucocorticoids, and broncho­ dilators are also useful therapeutics to treat urticaria/angioedema and bronchospasm once the patient is hemodynamically stable. # 08 - 365 Desensitization ### 365 Desensitization ■ ■PREVENTION Avoidance  The simplest and most straightforward approach to the long-term management of a patient with a history of anaphylaxis is strict avoidance of known anaphylactic triggers and education on acute management, specifically, instructing the patient on proper use and indications for use of self-administered epinephrine. Lifelong avoid­ ance is not easy if the trigger is an occupational exposure, Hymenop­ tera sting, a common food (i.e., peanut), or a drug representing the sole or best therapeutic option for the patient. Special management options may exist for these patients. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Venom Immunotherapy  Patients of any age who have had docu­ mented anaphylaxis from Hymenoptera sting should be formally eval­ uated and started on venom immunotherapy (VIT) if skin or serologic IgE testing confirms the history. Immunotherapy is a means of “toler­ izing” patients to allergen by means of serial subcutaneous administra­ tion of escalating doses of extract containing relevant allergen until a target maintenance dose is achieved. Anaphylaxis can sometimes occur during the course of administering immunotherapy extracts, so formulating extracts and administering them is typically done under the care of a specialist familiar with this type of treatment. In the case of Hymenoptera allergy, patients receive VIT extracts containing actual Hymenoptera venom with a maintenance dose equivalent to 2–5 stings. The recommended duration of treatment is 3–5 years; however, some patients who have experienced severe respiratory or cardiovascu­ lar anaphylaxis are put on lifelong therapy. Patients with mastocytosis may also require such lifelong treatment. Preventative Tolerance Induction to Peanuts  IgE sensitiza­ tion to foods occurs most frequently in infants and young children, especially those with atopic dermatitis, and is a risk factor for anaphy­ laxis (although detection of specific IgE through skin or serum testing has relatively poor predictive value). While most allergy to egg, milk, soy, and/or wheat resolves spontaneously during childhood, ~80% of children with peanut allergy remain sensitive for life. A sharp rise in the prevalence of peanut allergy was also observed in the late 1990s to early 2000s, especially in countries with Western diets where the aver­ age age of peanut introduction was age ≥3 years. Curiously, in cultures where peanut was introduced much earlier into children’s diets, the prevalence of peanut allergy remained low. The landmark Learning Early About Peanut Allergy (LEAP) study demonstrated that early introduction of peanut protein to the diet of high-risk infants (4–11 months of age with atopic dermatitis and/or egg allergy) prevented the development of most (80% or more) peanut allergy compared with children who did not consume peanuts (avoidance group), even when IgE sensitization (based on positive skin test) had already developed at the time of study entry. While the induction of tolerance at an early age seems to be key to preventing clinical reactivity later in life, it is not yet clear if this principle holds true for other foods commonly associated with hypersensitivity reactions. A relatively new treatment for patients who already suffer from severe peanut allergy is peanut oral immunotherapy (OIT) in which patients receive a titrating regimen of precisely dosed peanut protein in the form of an oral capsule. The goal of peanut OIT is to raise a patient’s threshold tolerance for accidental peanut exposure before anaphylaxis occurs, and it is not a cure for peanut allergy. At the current time, pea­ nut is the only food for which a U.S. Food and Drug Administration (FDA)-approved treatment exists, but research on developing OIT for other foods, such as milk and egg, remains ongoing. Desensitization  For patients who have experienced anaphylaxis from drug allergy and whose treatment regimen requires the admin­ istration of the offending drug, desensitization may be a short-term treatment option to prevent reactions. Desensitization elicits a tem­ porary state of tolerance to the drug in sensitized, clinically reactive patients. While it has been a proven technique for penicillin-allergic patients for decades, desensitization has more recently been proven to be effective for certain chemotherapy agents, especially platin-based chemotherapy agents that can induce IgE-mediated sensitization with repeated exposures. The exact mechanisms underlying desensitiza­ tion are not fully understood; however, temporary tolerance can be achieved through the serial administration of gradually escalating doses of drug, starting from extremely low doses, over the course of hours. As long as the patient continues to receive the drug in question at regular intervals based on drug half-life, a “desensitized” state can also be maintained until the drug is no longer needed. While drug desensitization certainly works for IgE-mediated reactions, it has been performed in cases of non-IgE-mediated anaphylaxis from Cremophor- solubilized paclitaxel as described earlier in this chapter. Drug desensitization has also been shown by multiple groups to work for non-IgE-mediated reactions from a variety of biologic agents, various chemotherapy drugs, and NSAIDs. Given the complexity and variety of possible drug reactions, the decision to desensitize, challenge, or avoid should be made in conjunction with an allergy specialist for complete evaluation and proper risk stratification of the different pos­ sible approaches to take. ■ ■FURTHER READING Brennan PJ et al: Hypersensitivity reactions to mAbs: 105 desensiti­ zations in 23 patients, from evaluation to treatment. J Allergy Clin Immunol 124:1259, 2009. Castells MC et al: Hypersensitivity reactions to chemotherapy: Out­ comes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 122:574, 2008. Chung CH et al: Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med 358:1109, 2008. Du Toit G et al: LEAP Study Team. Randomized trial of peanut con­ sumption in infants at risk for peanut allergy. N Engl J Med 373:803, 2015. Du Toit G et al: Immune Tolerance Network LEAP-On Study Team. Effect of avoidance on peanut allergy after early peanut consumption. N Engl J Med 374:1435, 2016. Lieberman P et al: Anaphylaxis—A practice parameter update 2015. Ann Allergy Asthma Immunol 115:341, 2015. McNeil BD et al: Identification of a mast cell-specific receptor crucial for pseudoallergic drug reactions. Nature 519:237, 2015. Valent P et al: Why the 20% + 2 tryptase formula is a diagnostic gold standard for severe systemic mast cell activation and mast cell activa­ tion syndrome. Int Arch Allergy Immunol 180:44, 2019. Mariana Castells Desensitization DRUG ALLERGY AND THE NEED FOR DRUG DESENSITIZATION Drug allergy is a rising problem, paralleling the worldwide increased use of medications, the plethora of new targeted therapies, and the greater longevity of patients. Allergic drug reactions decrease patients’ quality of life, limit treatment options, and can lead to vaccine hesi­ tancy, as seen for the COVID-19 mRNA vaccines. The first cases of reported drug-induced anaphylaxis occurred shortly after the dis­ covery and therapeutic applications of penicillin in 1945, and today, 10–20% of the world’s population engaged in health care claims to have a penicillin allergy. Truly allergic patients cannot use penicillin and are negatively impacted by the decreased efficacy, increased costs, and limited availability of second-line antibiotics. Similarly, the need to avoid the offending medications in allergic patients with malignancies and chronic inflammatory diseases can increase morbidity and impact life expectancy. To address the needs of drug-allergic patients, a novel modality of drug delivery aimed at curtailing allergic symptoms has culminated in drug desensitization (DD), a treatment option that takes advantage of immune inhibitory mechanisms. Rapid multistep protocols that deliver sequential small doses of drug until the target therapeutic dose is reached in a few hours have shown outstanding safety, efficacy, and wide applicability in thousands of patients with infections, chronic inflammatory diseases, malignancies, and other conditions. ■ ■DRUG ALLERGY DEFINITIONS AND RISK FACTORS Drug allergy and drug hypersensitivity are interchangeable terms that refer to acute and delayed symptoms occurring after exposure to medications. While there is a need to address drug-allergic patients, those with unconfirmed allergy labels should be dela­ beled, and single-dose oral challenges have been shown to be safe in children and adults at low risk for penicillin allergy. Drug allergy is multifactorial and associated with female gender, specific human leukocyte antigen (HLA) haplotypes, atopy, polypharmacy, older age, chronic diseases, microbiome changes, and drug-dependent factors such as the route of administration, repeated and high doses, excipients, and glycosylation. ■ ■CLASSIFYING HYPERSENSITIVITY REACTIONS The modern classification of reactions has incorporated timing, sever­ ity, biomarkers, and new presentations to the classical Gell and Coombs definitions. Acute or immediate reactions occur during or within 1–6 h of drug exposure, while delayed reactions occur 6 h to several days or weeks after drug exposure. Reactions can be mild (affecting one organ; grade 1), moderate (affecting two or more organs; grade 2), or severe (associated with changes in vital signs; grade 3). ■ ■PHENOTYPES, ENDOTYPES, AND BIOMARKERS The symptom presentation (phenotype) depends on the mechanisms of the reactions (endotype). Acute reactions include infusion reactions, type I IgE-dependent and -independent reactions, cytokine release reactions (CRRs), and mixed reactions (type I and CRR symptoms). Delayed reactions include type II antibody-mediated cytotoxicity; type III immune complex–mediated reactions; and type IV reactions, which include benign reactions, typically skin limited, and severe cutaneous reactions with systemic symptoms (SCARS) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized eosinophilic pustulosis (AGEP) (Fig. 365-1). Symptoms are drug specific, and acute musculoskeletal pain is common in reactions to taxanes, oxaliplatin, doxorubicin, and rituximab. Type I Reactions  Type I reactions result from the activation of mast cells and basophils through IgE-dependent and -independent mechanisms. While IgE sensitization requires repeated exposures and is typical for antibiotics, chemotherapy, and some biologicals, IgE-independent reactions typically occur at first exposure through either complement activation, inhibition of COX-1, or activation of the MRGPRX2 receptor by quinolones, vancomycin, icatibant, and general anesthetics with THIQ binding motif and by basic compounds. Symp­ toms of type I reactions include itching, flushing, hives, angioedema, dyspnea, wheezing, oxygen desaturation, throat tightening, nausea, vomiting, and hypotension with cardiovascular collapse and are associ­ ated with elevated serum tryptase, a specific biomarker of anaphylaxis released from mast cells and basophils granules. Tryptase levels above the normal range (11.4 ng/mL) or above a patient’s baseline (× 1.6) obtained within 30 min to 4 h of initial symptoms are diagnostic of type I and mixed reactions. Patients with baseline levels of 7.5 ng/mL or higher may have duplications of the TPSAB1 tryptase gene located on chromosome 16, known as hereditary alpha tryptasemia (HαT), a familial autosomal dominant trait present in 4–6% of Caucasian populations, which modulates anaphylaxis severity. Other mast cell– derived mediators include urine N-methylhistamine, prostaglandins, and leukotrienes. Cytokine Release Reactions  CRRs can occur at first exposure or after several exposures and are thought to be due to activation of T cells and other immune cells. Patients present with fever; chills; back, chest, or pelvic pain; headache; oxygen desaturation; and hyper- or hypoten­ sion; these reactions are associated with a transient serum elevation of interleukin (IL) 6. CHAPTER 365 Mixed Reactions  Mixed reactions present with symptoms of type I and CRR reactions and are associated with tryptase and IL-6 elevations (Fig. 365-1). Desensitization Delayed Type IV Reactions  Delayed type IV reactions amenable to DD present as benign maculopapular rashes without associated systemic symptoms, whereas SCARS, type II, type III, vasculitis, and single-organ toxic reactions are contraindications for DD because min­ ute amounts of medication can trigger severe reactions. DIAGNOSTIC TESTING Skin testing (ST) elicits a local wheal-and-flare reaction upon epicuta­ neous or intradermal injection of drugs inducing IgE-mediated reac­ tions. Its use is limited by the availability of drug components including excipients, skin toxicity, costs, and the time elapsed since the patient’s initial reaction (the longer the time, the lower the likelihood that an ST will be positive) and the severity of the reaction (anaphylactic reactions can deplete mediators inducing false-negative ST). Positive and nega­ tive predictive values are drug specific, and anaphylaxis to penicillin or carboplatin has not been reported in ST-negative patients. The basophil activation test (BAT) provides evidence of IgE sensi­ tization by challenging the patient’s basophils in vitro with the culprit drug, eliminating the need for direct ST, which has a small risk for anaphylaxis. Serum-specific IgE antibodies to penicillin and platins are found in allergic patients with low sensitivity. Skin patch testing is helpful to evaluate β-lactams, anticonvulsants, corticosteroids, and other drugs that cause delayed type IV reactions with high specific but low sensitivity. Lymphocyte transformation tests (LTTs) measure the activation and/or cytokine release of lymphocytes exposed to culprit drugs and can be used to identify drugs inducing SCARS. Certain HLA haplotypes place patients at risk for SCARS when exposed to abacavir, anticonvulsants, allopurinol, vancomycin, and other drugs, and geno­ typing is available. DRUG DESENSITIZATION ■ ■DEFINITIONS AND MECHANISMS DD is a temporary immunotherapy modality, delivered through multi­ step protocols to safely and timely reintroduce a drug that has induced an acute or delayed allergic reaction. IgE-mediated desensitization takes advantage of inhibitory mast cell/basophil pathways, which are activated by low doses of drug antigens. Rapid delivery of incremental doses recruit phosphatases to IgE receptors, blocking signal transduc­ tion and the release of mediators when reaching the target dose and protecting against anaphylaxis. Desensitized patients have transient conversion from positive to negative ST. ■ ■PROTOCOLS Based on inhibitory pathways in mast cell models, human protocols have been generated for type I phenotypes with low starting doses and multiple steps that progress by doubling the dose administered in the previous step at constant time intervals. The first standardized and most used protocol contains three bags of 1/100, 1/10, and undiluted concentrations of the target dose and 12 doubling steps delivered every 15 min so that the target dose is reached in 5.7 h (Fig. 365-2), which has been adapted for IV, PO, SC, IM, intraperitoneal, intraocular, and intrathecal use. Protocols with four bags (starting with a 1/1000 dilution bag) are used for patients with severe initial reactions and associated comorbidities. The recent use of one-bag protocols for type I reactions has produced mixed outcomes, with an increased use of epinephrine during breakthrough reactions (BTRs) and inability to complete treatments in highly sensitized patients. Cytokine Release Phenotype Infusion Reaction Type I IgE/non-IgE Type II Type III Mixed Mast cell T cell NK cell Lymphocyte PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Endotype Opsonization Both TNF-α, IL-6, IL-1β TNF-α, IL-6, IL-1β IL-6, IL-1β Histamine, tryptase Biomarkers Both Flushing Pruritus Rash Urticaria Throat tightness Shortness of breath Nausea and/or vomiting Anaphylaxis and cardiovascular collapse Fever, Chills/rigors Nausea Pain Headache Dyspnea Hyper/ hypotension Back pain Fever Chills/rigors Nausea Pain Headache Both Symptoms Indicated Indicated Indicated Indicated Non indicated, regular infusion Desensitization Type IV Severe Cutaneous Adverse Reactions (SCARS); Not Indicated, Avoid Medication Eosinophils Antigen presenting cell Interferon-γ Granzyme B Granulysin Perforin HLA-1 Penicillin hapten-carrier complex TCR Neutrophils CD4+ or CD8+ cell FIGURE 365-1  Drug allergy phenotypes, endotypes, and biomarkers and indications for desensitization. AGEP, acute generalized eosinophilic pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; IL, interleukin; SJS-TEN, Stevens-Johnson syndrome–toxic epidermal necrolysis; TNF, tumor necrosis factor. (From The New England Journal of Medicine, Penicillin Allergy, M Castells, DA Khan et al: 381: 2338. Copyright @2019 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.) The mechanisms of desensitization for other phenotypes are poorly understood, and CRRs have been successfully treated with multistep one-bag protocols, whereas multiple doses over several days have been used for delayed reactions (see specific drugs). Premedications are tailored to the initial symptoms, and steroids do not protect against anaphylaxis. Omalizumab, a monoclonal anti-IgE antibody, has been used as an adjuvant in highly sensitized patients with type I severe IgE-mediated reactions, including life-threatening anaphylaxis. Desensitization is a temporary phenomenon that does not lead to sustained tolerance and must be repeated with each exposure or if there has been a pause between doses equal to two or more half-lives of the drug. However, the desensitized state can be maintained by continued drug exposure as with antibiotics and aspirin/COX-1 inhibitors. Some Type IV T cell Neutrophil MΦ C3a Antibody dependent cell cytotoxicity C3a C3a Antigen/ antibody complexes T cell Specific antibody or antibody/antigen complex deposition IFN-γ, IL-4, IL-5 Autoimmune Thrombocytopenia Anemia Neutropenia Serum sickness Urticaria vasculitis Arthus reaction Nephritis Fever Delayed maculopapular rash Not indicated, avoid medication Not indicated, avoid medication Clinical Phenotype Interleukin-4 Interleukin-5 Eotaxin DRESS, 2- to 8-week delay: Epidermal edema, fever, lymphadenopathy, eosinophilia, atypical lymphocytosis, and infiltration of skin and internal organs Keratinocyte death SJS–TEN, 4- to 28-day delay: Epidermal necrosis, subepidermal bullae, and involvement of multiple mucous membranes AGEP, 24- to 48-hour delay Fever, neutrophilic leukocytosis, sterile pustules in stratum corneum and epidermis, dermal edema, and infiltration of neutrophils, CD4+ T cells, CD8+ T cells, and some eosinophils Neutrophils home to the skin Interferon-γ CXCL8 GM-CSF patients reactive to taxanes and certain biologicals with uneventful DD protocols may eventually return to regular infusions. INDICATIONS, BREAKTHROUGH REACTIONS, AND OUTCOMES ■ ■INDICATIONS (FIG. 365-2) Qualifications for DD depend on the need of the medication as firstline therapy, the initial reaction phenotype, and its severity. Infusion reactions, mild CRRs, and mild delayed reactions can be addressed by symptoms targeting adjuvant medications. DD is indicated for type I IgE-dependent and IgE-independent, CRR, mixed, and nonsevere delayed type IV phenotypes. Type I and mixed reactions BWH desensitization 1/1000 Rate (Ml/h) 2.5 X 15min 5 X 15min 10 X 15min 20 X 15min A Clinical Vignette 1: Rituximab Rituximab Carboplatin 59–year old, ovarian cancer, six courses of carboplatin and paclitaxel with remission 61-year old, male Marginal zone lymphoma Reaction on 8th lifetime exposure Immediate sweating, flushing, chest pain Infusion stopped and resumed after 10 minutes but symptoms recurred Treated with steroids and infusion discontinued Allergy evaluation for desensitization Change for a second-line treatment? Skin test positive (ID 1 mg/mL) Grade 2 Mixed reaction 3-bag 12-step protocol Premedication: Certirizine 10 mg Aspirin 325 mg Methylprednisolone 40 mg Famotidine 20 mg Acetaminophen 650 mg Montelukast 10 mg Tryptase 10.2 ng/mL (baseline 6.1 ng/mL) Desens # 1: step 12: Flushing, chills, restlessness Fluids (nl saline 250 mL/h) Fever of 102.4F: Acetaminophen 650 mg : Meperidine 25 mg IV : Diphenhydramine 25 mg : Famotidine 20 mg Complete rest of steps IL-6 >3000 pg/mL (normal, <17.4 pg/mL; baseline <2.9 pg/mL) B FIGURE 365-2  Desensitization: protocols and applications. A. Multibag, multistep intravenous desensitization protocols. B. Rituximab allergic reaction with mixed phenotype, positive skin test, and elevated tryptase and interleukin (IL) 6 biomarkers and successful treatment with a three-bag 12-step protocol. C. Carboplatin allergic reaction with type I phenotype, positive skin test, and elevated tryptase biomarker and successful treatment with a three-bag 12-step protocol. (Reproduced with permission from L Campos et al: Curr Treat Options Allergy 6:519, 2019.) 4-bag 16-step protcol (6.7h) 3-bag 12-step protcol (5.7h) CHAPTER 365 2-bag, 8-step protocol and 1-bag, 4-step protocol Rate (Ml/h) 1/100 Rate (Ml/h) 1/10 Rate (Ml/h) Full dose Desensitization 2.5 X 15min 5 X 15min 10 X 15min 20 X 15min 5 X 15min 10 X 15min 20 X 15min 40 X 15min 10 X 15min 20 X 15min 40 X 15min 80 X 2.9h Clinical Vignette 2: Carboplatin Two years later, CA125 increase, mass in abdomen, stage 4, restart carboplatin and paclitaxel Second carboplatin: (8th exposure) Itchy hands Third carboplatin: (9th exposure) Flushing Generalized pruritus Shortness of breath Dizziness Hypotension O2 desaturation with syncopal episode Fluids Antihistamines Steroids Epinephrine IM: Tryptase 52 ng/mL (normal level 11.4 ng/mL) Change chemotherapy for a second-line treatment? Allergy evaluation for desensitization ANAPHYLAXIS Positive skin test to carboplatin Epinephrine 3-bag 12-step protocol Grade 3 Type reaction Tryptase Completed rest of treatment cycle via desensitization to carboplatin C in patients with multiple exposures to antibiotics, chemotherapeutic drugs, and biologicals indicate IgE sensitization. ST-positive patients require DD for reexposure since the risk for anaphylaxis is high. In patients with mild reactions and negative biomarkers, controlled drug challenges are indicated to assess tolerance. Large clinical series sup­ port outpatient settings for the majority of DD, which decreases the starting treatment time and costs and improves patients’ experiences. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders ■ ■DD BREAKTHROUGH REACTIONS AND OUTCOMES BTRs are typically mild with symptoms similar to the initial reaction. They occur in 10–30% of protocols and require symptom-specific management including epinephrine for severe reactions. BTRs do not preclude the completion of the DD protocols in 99% of cases, and no deaths due to DD have been reported. Comorbidities such as pregnancy, cystic fibrosis, decreased lung function, cardiac diseases, advanced cancer, beta blocker and/or angiotensin-converting enzyme inhibitor use, and prior severe reactions increase the risk during BTRs (Fig. 365-3). The administration of antibiotics, monoclonal antibod­ ies, and chemotherapy drugs through DD has shown equal efficacy as for standard administration, with the expected clearance of infec­ tions, decreased inflammation, and similar cancer responses. Kounis syndrome and takotsubo cardiomyopathy resulting from drug-induced anaphylaxis are contraindications for DD (Fig. 365-3). APPROACH TO SPECIFIC DRUGS ■ ■ANTIBIOTICS Antibiotics can induce all the reactions in Fig. 365-1, but the most common are type I IgE-dependent and type IV non-SCARS reactions, both of which can be addressed by DD. β-Lactams  The first description of penicillin desensitization was in a World War II allergic soldier who presented with wheezing and hypotension after penicillin injection and received oral incremental Principles of Drug Desensitization No desensitization; avoid culprit drug Indications/Phenotypes Contraindications Risk Factors • SCARS* (SJS/TEN/DRESS/AGEP) • Organ specific toxicity • Cytopenias • Serum sickness • Vasculitis • Kounis and Tako Tsubo • Severe reactions • Pregnancy • Pulmonary diseases • Acute cardiac diseases • β-blockers • ACE inhibitors • Atopy • HLA haplotypes • Female gender • Polypharmacy • Advanced age • Alpha-Gal syndrome • Type 1 lgE/non-lgE • Cytokine release reaction (CRR) • Mixed reaction • Type IV +Severe cutaneous adverse reaction ‡‡Non-steroidal anti-inflammatory drugs ^Cystic fibrosis transmembrane conductance regulator potentiator FIGURE 365-3  Principles of drug desensitization: Indications, contraindications, risk factors, and drugs with successful desensitizations. ACE, angiotensin-converting enzyme; AGEP, acute generalized eosinophilic pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; HLA, human leukocyte antigen; SJS-TEN, Stevens-Johnson syndrome–toxic epidermal necrolysis. doses over 30 days until he was able to tolerate a treatment course. The initial success led to shorter protocols to treat patients with bacterial endocarditis and pregnant women with syphilis who had a history of penicillin-induced anaphylaxis and positive ST. Safe rapid PO and IV desensitization protocols are currently available for all antibiotic classes and can treat high-risk patients, including cystic fibrosis patients with low pulmonary function. Sulfonamides  Delayed type IV rashes to trimethoprim- sulfamethoxazole occurred in up to 40% of patients with <100 total CD4 T cells/µL during the early 1990s HIV/AIDS epidemic, and DD included incremental doses over multiple days. Reactions have decreased since retroviral treatments, and shorter protocols have evolved. One-day PO and IV multidose protocols have shown consis­ tent safety and efficacy for delayed reactions in non-HIV patients. ■ ■CHEMOTHERAPY Taxanes  Over 40% of patients exposed to paclitaxel and docetaxel presented with acute reactions, which have been reduced to 1% by antihistamine and corticosteroid premedication. Moderate to severe reactions attributed to lipid excipients (Cremophor and polysorbate 80) and to IgE sensitization through cross-reactive foods and envi­ ronmental allergens occur typically at first or second exposure with type I, mixed, and delayed phenotypes. Patients with delayed rashes can convert to acute reactions including anaphylaxis upon subsequent exposures. The first DD to paclitaxel was reported in 2002, and an early study of 940 DDs to paclitaxel and docetaxel in 138 patients described BTRs in 20% of cases, and 22% of desensitized patients returning to standard infusions. A review of 25 studies with 976 patients and 2396 DDs to paclitaxel and docetaxel, completed in 95–100% of cases, the majority with three-bag 12-step protocols, showed 32% paclitaxel and 20% docetaxel mild BTRs and no deaths. Platinums  Platinum drug (carboplatin, cisplatin, and oxaliplatin) IgE sensitization requires multiple exposures (typically six or more; Desensitization Drug Formulation • Platins: carboplatin, cisplatin, oxaliplatin • Taxanes: paclitaxel, docetaxel, cabazitaxel, nab-paclitaxel • Monoclonals: rituximab, cetuximab, tocilizumab, bevacizumab, ofatumumab, alemtuzumab, pertuzumab, nivolumab; sacituzumab, etanercept, adalimumab, infliximab, ustekinumab, vedolizumab, tezepelumab, golimumab, daratumumab, ocrelizumab, obinutuzumab, trastuzumab, margetuximab, pembrolizumab • Antibiotics: β-lactams, cephalosporins, sulfonamides, quinolones, macrolides, vancomycin, aminoglycosides, doxycycline, rifampin, metronidazole • CFTCRP^: elexacaftor/tezacaftor/ivacaftor • Enzymes: laronidase, elosulfase alfa, galsulfase, alglucosidease alfa, imiglucerase, taliglucerase alfa, sebelipase alfa, idursulfase • Iron: sodium ferric gluconate, ferumoxytol, iron sucrose, iron dextran • NSAIDS‡‡: aspirin, naproxen • Hormones: progesterone, aromatase inhibitor, letrozole • Small molecules: lenalidomide, imatinib, osimertinib, olaparib # 09 - 366 Mastocytosis ### 366 Mastocytosis less for BRCA mutation carriers), and sensitized patients typically have type I symptoms with pruritus, flushing, urticaria, throat tightening, and hypotension with elevated tryptase (Fig. 365-2). ST is positive in >85% of patients with recent reactions. In a prospective study of 126 women who received six or more carboplatin treatments, repeat ST before each exposure identified reactors, with seven anaphylactic reactions in seven patients who agreed to be reexposed to carboplatin despite positive ST. Oxaliplatin reaction phenotypes include CRR and mixed reactions with conversion from type I to CRR and mixed phenotypes during DD. Oxaliplatin-induced immune-mediated thrombocytopenia (OIIT) with bleeding is a rare complication that precludes further DD. Carboplatin DD started in early 2000 and a large study in 2016 with 370 patients (212 carboplatin-allergic and 13 cisplatin-allergic patients), who underwent 2177 DDs, mostly in the outpatient setting with three- or four-bag protocols, showed 20% mild BTRs, non­ superior costs compared to regular infusions, and a life expectancy advantage at 5 years in ovarian cancer patients compared to nonallergic patients. A study of 272 patients allergic to platins, taxanes, and mono­ clonals who underwent 1471 DDs with three-bag 12-step protocols reported similar safety. Oxaliplatin DD poses challenges due to the heterogeneity of phenotypes and phenotype switching. A study of 48 patients with 200 DDs who underwent three-bag 12-step protocols showed mild to moderate BTRs in 18 patients, 1 patient with OIIT, and 2 patients with hemolytic anemia. A study of patients with type I, CRR, and mixed reactions who underwent 273 DDs indicated a switch from type I to CRR and mixed reactions during DD, with elevated IL-6, and two patients developed OIIT. The survival of platinum-desensitized patients is noninferior to nonallergic patients. Doxorubicin and Other Chemotherapy Drugs  Doxorubicin reactions are rare, occurring at first exposure, and a study of 30 patients and 128 DDs, mostly with three-bag 12-step protocols, showed 16% mild BTRs, and one patient required epinephrine. DDs for etoposide, cyclophosphamide, methotrexate, gemcitabine, and other chemother­ apy drugs have shown similar safety. ■ ■MONOCLONALS/BIOLOGICALS Infusion reactions of the type I IgE/non-IgE mediated, CRR, mixed, and delayed-reaction phenotypes have been reported for monoclonal antibodies (MoAbs). Hypersensitivity reactions can occur on first exposure or after multiple exposures (Fig. 365-2). Reactions are more frequent with chimeric MoAbs but also occur with humanized and fully humanized MoAbs. Skin testing is limited by cost. Patients with cetuximab-induced anaphylaxis react to galactose-alpha-1-3-galactose, a nonhuman carbohydrate in the Fab chain of cetuximab, due to pre­ existing IgE acquired through tick bite sensitization. DDs have been reported for most IV and SC available MoAbs (Fig. 365-3). The first series of MoAb desensitizations included 23 patients with moderate to severe type I and mixed reactions to trastuzumab, infliximab, and ritux­ imab who underwent 105 DDs with three bags and 12 steps and had 29% mild BTRs. A study of 104 patients who reacted to 16 MoAbs with type I, CRR, mixed, and delayed reactions and received 526 DDs, mostly with three bags and 12 steps in the outpatient setting, presented with 23% mild BTRs. Tryptase was elevated in type I and IL-6 in CRR BTRs. ■ ■SMALL MOLECULES Epidermal growth factor receptor and tyrosine kinase inhibitors such as imatinib, osimertinib, and olaparib can induce type I and type IV reac­ tion phenotypes, and successful DDs with multiple oral doubling doses have been reported, allowing for continued long-term maintenance. ■ ■NONSTEROIDAL ANTINFLAMMATORY DRUGS (NSAIDS) Aspirin (ASA) and other NSAIDs can induce type I reactions with urticaria and anaphylaxis thought to be IgE-mediated and, in patients with asthma and dysregulated lipid metabolism, a syndrome termed aspirin-exacerbated respiratory disease (AERD) with bronchospasm. Patients with AERD have universal intolerance to COX-1 inhibitors but tolerate COX-2 inhibitors. The American Academy of Allergy, Asthma, and Immunology Work Group Report in 2020 reviewed 14 series of ASA DDs with intranasal ketorolac or oral aspirin in >900 AERD patients. More than 70% of patients reported improvement of asthma, lack of polyp recurrence, recovery of sense of smell, and less steroid usage, with cross-desensitization and tolerance to all COX-1 inhibitors while maintained on daily ASA. For type I reactions in car­ diac and neurologic patients, DD with rapid doubling doses has been proven safe and effective. CHAPTER 366 ■ ■OTHER DRUGS Symptoms of progestogen hypersensitivity (PH) are cyclical and include type I and delayed phenotypes. PH can lead to miscarriage, and oral and vaginal DD protocols have resulted in viable pregnancies. Reactions to iron formulations include type I, CRR, mixed, and delayed phenotypes that are responsive to DD. Allopurinol-induced delayed rashes respond to PO and IV DD protocols. Corticosteroids, glatiramer acetate, vaccines, and other medication DDs have been reported with doubling multistep PO, IV, and SC protocols. Mastocytosis IMPACT Discontinuing drugs inducing allergic symptoms affects patients for whom second-line therapies may not be available, are more expensive, or do not provide similar therapeutic benefits. DD protocols allow for the safe reintroduction of first-line therapies, and their use should be extended to all patients in need. ■ ■FURTHER READING Adnan A, Acharya S: Multistep IgE mast cell desensitization is a dose- and time-dependent process partially regulated by SHIP-1. J Immunol 210:709, 2023. Castells M et al: Penicillin allergy. N Engl J Med 381:2338, 2019. Dhopeshwarkar N: Drug-induced anaphylaxis documented in elec­ tronic health records. J Allergy Clin Immunol Pract 7:103, 2019. Isabwe GAC: Hypersensitivity reactions to therapeutic monoclonal antibodies: Phenotypes and endotypes. J Allergy Clin Immunol 142:159, 2018. Sloane D: Safety, costs, and efficacy of rapid drug desensitizations to chemotherapy and monoclonal antibodies. J Allergy Clin Immunol Pract 4:497, 2016. Matthew P. Giannetti, Joshua A. Boyce Mastocytosis ■ ■DEFINITION AND EPIDEMIOLOGY Mastocytosis is defined by accumulation of clonally expanded mast cells in tissues such as skin, bone marrow, liver, spleen, and gut. Diag­ nostically, mast cell expansion is most readily identified in skin and/ or bone marrow. Mastocytosis occurs at any age, although it is most commonly diagnosed in infancy and young adulthood. The prevalence of mastocytosis is estimated at ~1 in 10,000 people. Most forms of the disease are characterized by somatic gain-of-function mutations in the stem cell factor receptor (KIT) gene, and >90% of patients carry the KIT D816V mutation. Familial occurrence is rare, and atopy is not increased compared with the general population. ■ ■CLASSIFICATION AND PATHOPHYSIOLOGY A consensus classification for mastocytosis recognizes cutaneous mas­ tocytosis with variants, systemic mastocytosis with five variants, and mast cell sarcoma (Table 366-1). Cutaneous mastocytosis is the most common diagnosis in children and indicates disease limited to skin with absence of pathologic infil­ trates in internal organs. It is usually diagnosed within the first year TABLE 366-1  Classification of Mastocytosis Cutaneous mastocytosis (CM)   Maculopapular cutaneous mastocytosis (MPCM)   Solitary mastocytoma of skin   Diffuse cutaneous mastocytosis Systemic mastocytosis   Indolent systemic mastocytosis (ISM)   Smoldering systemic mastocytosis   Systemic mastocytosis with associated clonal hematologic non–mast cell PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders lineage disease (SM-AHNMD)   Aggressive systemic mastocytosis (ASM)   Mast cell leukemia (MCL) Mast cell sarcoma (MCS) Source: Modified from DA Arber et al: International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood 140:1200, 2022. of life with demonstration of fixed, maculopapular, polymorphic, and hyperpigmented lesions (known as maculopapular cutaneous mas­ tocytosis [MPCM]), solitary mastocytoma(s), or diffuse cutaneous mastocytosis. Although mast cell accumulation is limited to the skin, children often have systemic symptoms. Systemic mastocytosis (SM) refers to involvement of an extracutaneous site (most often bone mar­ row). There are five distinct variants of SM. Indolent systemic mastocy­ tosis (ISM) accounts for >70% of adult patients. ISM is diagnosed when there is no evidence of organ dysfunction due to mast cell infiltration, an associated hematologic disorder, or mast cell leukemia. ISM is asso­ ciated with a normal life expectancy. Smoldering systemic mastocytosis (SSM) is characterized by high mast cell burden including bone mar­ row infiltration of >30% and a baseline serum tryptase >200 ng/mL (B findings), but absence of systemic mastocytosis associated with clonal hematologic non–mast cell lineage disease (SM-AHNMD) or aggressive systemic mastocytosis (ASM) (Table 366-2). In SM-AHNMD, the prog­ nosis is determined by the nature of the associated disorder, which can range from dysmyelopoiesis to leukemia. In ASM, mast cell infiltration may occur in multiple organs such as liver, spleen, gut, bone, and bone marrow resulting in one or more C findings and a poor prognosis (Table 366-2). Mast cell leukemia (MCL) is the rarest form of SM and is invariably fatal at present; the peripheral blood contains circulating, metachromatically staining, atypical mast cells. An aleukemic form of MCL is recognized without circulating mast cells when the percentage of high-grade immature mast cells in bone marrow smears exceeds 20% in a nonspicular area. Mast cell sarcoma is a rare solid mast cell tumor with malignant invasive features. TABLE 366-2  B and C Findings for Diagnosis of SSM and ASM B Findings (2 or more in the absence of any C findings are required for a diagnosis of SSM): 1. High MC burden: MC infiltration in bone marrow of >30%, basal serum tryptase level >200 ng/mL, and/or KIT D816V >10% VAF in bone marrow 2. Hypercellular bone marrow with signs of dysmyelopoiesis but without cytopenias meeting C criteria or WHO criteria for an MDS or MPN 3. Palpable hepatomegaly, palpable splenomegaly, or lymphadenopathy (on CT or ultrasound: >2 cm) without impaired liver function or hypersplenism C Findings (1 or more required for a diagnosis of ASM). C findings should be reasonably attributable to high tissue MC infiltration: 1. Cytopenia(s): ANC <1000/μL or Hb <10 g/dL or PLT <100,000/μL 2. Hepatomegaly with ascites and impaired liver function 3. Palpable splenomegaly with associated hypersplenism 4. Malabsorption with hypoalbuminemia and weight loss 5. Skeletal lesions: large area(s) of osteolysis with pathologic fractures (presence of osteoporosis alone without osteolytic lesions does not satisfy this criterion) Abbreviations: ANC, absolute neutrophil count; ASM, aggressive systemic mastocytosis; CT, computed tomography; Hb, hemoglobin; MC, mast cells; MDS, myelodysplastic syndromes; MPN, myeloproliferative disorders; PLT, platelets; SSM, smoldering systemic mastocytosis; VAF, variant allele frequency; WHO, World Health Organization. Somatic activating mutations in the KIT gene are characteristic of mastocytosis. KIT D816V is most common, although other mutations have been reported. KIT mutations are found in mast cells and some­ times in other cell lineages in patients with mastocytosis. KIT muta­ tions are observed in patients with all forms of SM but are also present in some children with cutaneous mastocytosis in lesional skin. Addi­ tional mutations in genes such as TET2, SRSF2, ASLX1, and RUNX1 known to be associated with other hematologic neoplastic disorders can be detected in patients, usually with advanced variants of SM. The life expectancy for patients with cutaneous mastocytosis and for most patients with ISM is normal, whereas that for patients with SMAHNMD is determined by the non–mast cell component. ASM and MCL have a poor prognosis, while patients with SSM have an inter­ mediate prognosis. Progression from ISM to a more advanced form is uncommon (~5% lifetime risk); however, patients should be monitored for emergence of hematologic disease and end-organ manifestations of ASM. In infants and children with cutaneous manifestations, namely, maculopapular cutaneous mastocytosis, mastocytoma(s), or bullous lesions, visceral involvement is usually lacking, and spontaneous reso­ lution is common prior to adolescence. Polymorphic maculopapular cutaneous mastocytosis usually resolves spontaneously. Progression from cutaneous mastocytosis (CM) to ISM may occur in ~10% of chil­ dren, especially in those with high mast cell burden (diffuse cutaneous mastocytosis) or hematologic abnormalities and those who present with smaller uniform lesions with diameters measuring <2 cm (mono­ morphic MPCM). ■ ■CLINICAL MANIFESTATIONS The clinical manifestations of SM are due to the release of bioactive substances acting at both local and distal sites, tissue infiltration by mast cells, and the tissue response to the cellular infiltrate. Clinical manifestations include intermittent urticaria, flushing, tachycardia and vascular collapse, gastric acid hypersecretion, crampy lower abdominal pain, and diarrhea. The increased local mast cell burden in the skin (MPCM), bone marrow, and gastrointestinal tract may be a direct cause of pruritus, bone pain, and malabsorption, respectively. Mast cell–mediated fibrotic changes may occur in liver, spleen, and bone marrow but not in gastrointestinal tissue or skin. The cutaneous lesions of MPCM are reddish-brown macules, pap­ ules, or plaques that respond to trauma with urtication and erythema (Darier’s sign). Two distinct forms of MPCM are recognized: poly­ morphic MPCM and monomorphic MPCM. Children with CM may present with MPCM, mastocytomas, or diffuse cutaneous mastocyto­ sis (DCM). Mastocytomas are generally solitary elevated lesions that are yellow, brown, or red in color. Their size may vary from a few millimeters to several centimeters. Rubbing or irritation of a masto­ cytoma lesion may lead to systemic symptoms such as flushing and urticaria. Children with DCM present without distinct lesions, but rather a generalized thickening of skin and “peau d’orange” appear­ ance due to diffuse mast cell infiltration. DCM is associated with bul­ lae formation and more severe systemic symptoms, including upper gastrointestinal irritation and vascular collapse in the first few years of life. Maculopapular skin lesions of mastocytosis may be present in patients with adult-onset systemic disease. The apparent incidence of cutaneous lesions is ≥80% in patients with ISM and <50% in those with SM-AHNMD or ASM. In the upper gastrointestinal tract, gas­ tritis and peptic ulcer are significant problems. In the lower intestinal tract, the occurrence of diarrhea and abdominal pain is attributed to increased motility due to mast cell mediators. The periportal fibrosis associated with mast cell infiltration may lead to portal hypertension and ascites. In some patients, anaphylaxis may occur with rapid and life-threatening vascular collapse. Anaphylaxis is most commonly induced by Hymenoptera stings and nonsteroidal anti-inflammatory drugs (NSAIDs). The neuropsychiatric disturbances are clinically most evident as impaired recent memory, decreased attention span, and “migraine-like” headaches. Patients may experience exacerbation of a specific clinical sign or symptom variably with alcohol ingestion, temperature changes, stress, use of mast cell–interactive opioids, or ingestion of NSAIDs. # 11 - 368 Systemic Lupus Erythematosus ### 368 Systemic Lupus Erythematosus thyroiditis. Cancers commonly associated with autoimmunity include melanoma, thyroid cancer, and non-small-cell lung cancer. One spe­ cific example is the development of encephalitis through generation of Abs to N-methyl-d-aspartate glutamate receptor in women affected by ovarian cancer. In some cases, these events may be associated with favorable disease outcomes that may suggest a beneficial effect from the autoimmune response. The autoimmune manifestations can be severe, and management of these patients is difficult given the coexis­ tent malignancy. ■ ■IATROGENIC AUTOIMMUNITY Checkpoint Inhibitors  Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. They act by blocking inhibitory mole­ cules involved in regulating T lymphocytes, promoting the destruction of tumors by the adaptive immune system. Immune-related adverse events (irAEs) have been described as toxic complications related to tissue-specific autoimmunity from the use of ICIs, and they can persist after withholding therapy and using immunomodulatory therapy to control them. Among these complications, DM, arthritis, thyroiditis, and colitis are prevalent. Up to 85% of individuals treated with an ICI may develop irAEs. Most of these are mild, and overall survival and time to malignancy progression are not influenced by the development of these immune complications. Drug-Induced Autoimmunity  In addition to ICIs, many drugs have been linked to the development of autoimmunity. These include antibiotics, antihypertensives, antiarrhythmics, TNF inhibitors, and antiseizure medications, among many others. Drug-induced lupus is a well-described entity, and patients developing this condition have characteristic detection of antihistone Abs. In many cases, discontinu­ ation of the drug may be sufficient for symptoms to be abrogated or decreased. ■ ■PREVENTION AND TREATMENT OF AUTOIMMUNITY The hope is that better understanding of the pathophysiology of overt development of ADs and their associated organ damage will lead to primary or secondary prevention strategies in conditions such as T1DM, RA, and SLE. One promising example is where infants at risk of developing multiple T1DM autoAbs and clinical disease are being studied to determine if certain interventions (oral insulin) can delay or stop progression to overt disease. Studies have also been performed on people considered at risk for RA to assess delayed disease progression, but more studies are needed to better characterize the utility of these preventive strategies. Overall, opportunities to initiate early therapy depend on the availability of serologic tests that can predict disease, to initiate treatments that have a good efficacy-to-safety ratio. Specific treatments for ADs are included in chapters focusing on individual diseases and include a variety of immunomodulatory agents (e.g., antimalarials) and immunosuppressive drugs (spanning those drugs with broad effects on the immune system, such as corticosteroids or cyclophosphamide, to highly specific biologic agents targeting spe­ cific cytokines or immune cells). It is the hope that the development of personalized medicine approaches will lead in the future to the specific targeting of dysregulated immune cell components while sparing other critical cells and functions of the immune system. ■ ■FURTHER READING Enhancing NIH Research on Autoimmune Diseases. Consensus Study Report. The National Academies of Sciences, Engineering, Medicine, 2022. Gupta S, Kaplan MJ: Bite of the wolf: Innate immune responses propagate autoimmunity in lupus. J Clin Immunol 131:e144918, 2021. Johnson D, Jang W: Infectious diseases, autoantibodies and autoim­ munity. J Autoimm 137:102962, 2023. Singh N et al: Immune-related adverse events after immune check point inhibitors: Understanding the intersection with autoimmunity. Immunol Rev 318:81, 2023. Chelsey J.F. Smith, Paul J. Hoover, Kenneth Kalunian Systemic Lupus Erythematosus CHAPTER 368 DEFINITION, PREVALENCE, AND EPIDEMIOLOGY Systemic lupus erythematosus (SLE) is an autoimmune disease in which overactive innate and adaptive immune systems cause tissue damage through the effects of autoantibodies and immune complexes. Many organ systems can be affected, with cutaneous, musculoskeletal, and renal systems most involved, followed by pulmonary, hematologic, cardiovascular, serosal, and central nervous system involvement. Con­ stitutional symptoms are often present. Autoantibodies can be detected years prior to a clinical diagnosis. Approximately 90% of affected indi­ viduals are women, most of childbearing age; however, the disease can also affect neonates and older children, men, and elderly individuals. Certain ethnic and racial groups are at higher risk for more prevalent disease and more severe disease. The Centers for Disease Control and Prevention (CDC) National Lupus Registry estimates the prevalence in the United States to be 204,295 cases, with overall prevalence being nine times higher in women compared to men. The highest prevalence is seen in Black women, followed by Hispanic, White, and Asian/ Pacific Islander women. Among men with SLE, Black men have the highest prevalence and White men have the lowest. Prognosis and survival from SLE can vary widely by geographic region, race, ethnicity, and access to both care and medications. Systemic Lupus Erythematosus DIAGNOSIS AND CLASSIFICATION For the diagnosis of SLE, an individualized approach should be taken based on available clinical data and excluding other disease entities. Classification criteria for SLE have been developed for the purposes of enrollment of patients into clinical trials rather than criteria for diagnosis. Currently, the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE and the 2012 Systemic Lupus International Collabo­ rating Clinics (SLICC) SLE classification criteria are both utilized for enrollment of patients into clinical trials. For the EULAR/ACR criteria, an antinuclear antibody (ANA) titer of at least 1:80 is required. Clinical criteria are then weighed by points within several clinical domains, and a patient requires at least 10 points to meet criteria. No single clinical or laboratory value leads to 10 points except for a renal biopsy revealing class III or IV lupus nephritis. Certain subsets of patients with SLE are currently not included in clinical trials, including patients with incomplete lupus or features of SLE without an established diagnosis and the ~5% of SLE patients who are ANA negative. Researchers have suggested that if predictive or diagnostic biomarkers for progression are developed, then early treatment for patients with incomplete lupus could prevent progression to SLE. Furthermore, because the EULAR/ACR criteria exclude ANAnegative patients from participating in clinical trials, the opportunity to understand whether new drugs have a role in this disease subset is also underserved. SLE has been classified into two broad categories based on symp­ toms. Those with predominant classic findings of SLE that have a clear relationship to immune dysregulation, such as nephritis, arthritis, and vasculitis, have been categorized as having type 1 lupus, whereas those with predominant symptoms of fatigue, diffuse body pain, depres­ sion, cognitive dysfunction, sleep disturbances, anxiety, and/or brain fog have been categorized as having type 2 lupus. Type 1 symptoms arise from autoimmune inflammation and/or organ damage and often respond to standard immunosuppression, whereas type 2 patients are less responsive to immunosuppressive therapy. This categorization presents an opportunity to explore the genetic and immune association of each category as well as develop biomarkers and treatments for the distinct types. PATHOGENESIS ■ ■OVERVIEW SLE reflects multiple immunoregulatory defects and is characterized by the production of autoantibodies to cellular components, especially nucleic acids and nuclear proteins, that promote inflammation and tis­ sue damage. The interaction of environmental factors with the stochas­ tic dysregulation of genes controlled by common genetic variations underpins the development of SLE (Fig. 368-1). PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders ■ ■GENETICS SLE has a strong genetic component as evidenced by familial cluster­ ing, a greater incidence in monozygotic twins versus dizygotic (24% vs 2%), and the identification of >150 susceptibility loci from genomewide association studies (GWAS). Genetic studies have identified groups of immunoregulatory genes associated with SLE, reflecting common pathways that may contribute to pathogenesis. It is pos­ sible that each pathway differentially contributes to the expression of disease, accounting for clinical heterogeneity. The most common genetic association is within the major histocompatibility complex that contains genes for antigen presentation molecules (class I and class II), several complement components, and cytokines. Nearly half of the susceptibility loci are associated with type 1 interferon (IFN) production or its downstream signaling. For example, some suscep­ tibility genes lead to increased IFN through defects in nucleic acid sensing and metabolism (TLR7, ADAR, IFIH1, SAMHD1, RNASEH2B, TREX1) or nucleic acid degradation (DNASE1, DNASE1L3), whereas other IFN-related susceptibility genes amplify the IFN response (IRF5, IRF7, IRF8, STAT4). Many predisposing genes are immune cell type specific, affecting activation and survival of T cells (OX40L) or B cells (BANK1, BACH2). The complement cascade (C1Q, C1r, C1s, C2, C4), Neutrophils and dying cells release debris NETosis Predisposing Factors Environmental triggers and potential mechanism UV light - induces apoptosis and autoantigen release. Crystalline silica - induces inflammation. Smoking - causes autoantigen release. Sex hormones - regulate development and function of adaptive immune cells. Microbes (EBV, microbiome) - induce nucleic acid response, increase gut permeability. Toxins (i.e., mercury, diet) - induce cell death, inflammation, epigenetic changes. Cell death Key immunologic SLE pathways and selected susceptibility genes Antigen presentation (MHC) - HLA-DR, HLA-DQ IFN induction - IRAK1, SLC15A4, SPP1, TNIP1, UBE2L3 Nucleic acid sensing - TLR7, ADAR, IFIH1, SAMHD1, RNASEH2B, TREX1 Nucleic acid degradation - DNASE1, DNASE1L3 Response to IFN - IRF5, IRF7, IRF8, STAT4, TYK2 Phagocytosis - FCGR2A, C1Q, C1r, C1s, C2, C4 T-cell activation ETS1, IL21, IKZF1, IKZF2, PTPN22, STAT4, TCF7, OX40L B-cell activation - ARID5B, BANK1, BACH2, BLK, CD40, CSK, IKZF3, IRF5 Monocytes infiltrate tissue and are activated by immune complexes binding to FcGR, inducing tissue inflammation FcGR Classic monocyte Non-classical monocyte anti-dsDNA: Anti double-stranded DNA anti-Sm: anti-Smith FcGR: Fc gamma receptor IFN: Type 1 interferon MHC: Major histocompatibility complex Epigenetic changes DNA methylation and histone acetylation can affect the IFN response of T, B, and myeloid subsets. FIGURE 368-1  Pathogenesis of systemic lupus erythematosus (SLE). Autoantigens from neutrophil NETosis and cellular turnover overwhelm clearance mechanisms regulated by the innate immune system in SLE. Consequently, these autoantigens accumulate and induce an immune response. Nucleic acid activates TLR signaling in plasmacytoid dendritic cells (DCs), producing type 1 IFN, sensitizing the innate and adaptive immune responses. DCs present autoantigens to autoreactive T cells, leading to B-cell stimulation and the production of immune complexes against these autoantigens. Immune complexes deposit in tissue and induce local immune responses that lead to inflammation and repair and, eventually, fibrosis after recurrent SLE flares. EBV, Epstein-Barr virus. which is essential for clearance of apoptotic cellular debris and immune complexes, is often affected in monogenic cases, leading to severe SLE. ■ ■ENVIRONMENT About a quarter of monozygotic twins are clinically concordant for SLE, implicating environmental factors in disease expression. Low socioeconomic status is associated with the development of SLE and may include exposures to environmental toxins, including mercury, pesticides, and diet. Viral infections such as Epstein-Barr virus likely contribute to disease development by inducing the IFN response dur­ ing an acute infection or by expressing viral proteins that activate SLE susceptibility genes. Ultraviolet light can impact DNA methylation, generate self-stimulatory nucleic acids, activate keratinocyte immune responses, and produce autoreactive T cells. Finally, emerging evidence suggests that the gut microbiome may increase gut permeability, pro­ moting the translocation of certain gut microbes into the blood with the development of lupus-specific autoantibodies contributing to SLE pathogenesis. ■ ■INNATE IMMUNITY Multiple innate immune cell defects contribute to increased cellular breakdown and reduced cell debris clearance, culminating in the pro­ duction of autoantibodies. Neutrophils are typically short-lived and abundant immune cells, representing a large burden of cellular debris that is usually cleared without inducing an immune response. Patients with SLE, however, have neutrophils with higher turnover, delivering a large load of stimulatory nucleic acids and autoantigens. Cellular debris and immune complexes are typically cleared by macrophages and dendritic cells through complement-mediated phagocytosis and nucleic acid digestion; these mechanisms are dysregulated in SLE. In turn, the burden of cellular debris exceeds that which can be cleared in SLE, triggering nucleic acid sensors and toll-like receptors (TLRs) in plasmacytoid dendritic cells to express type 1 IFN. Consequently, IFN primes neutrophils for further turnover and sensitizes the adaptive Cellular debris induces IFN response that sensitizes the immune response The innate immune system processes debris FcGR TLR Endosome Macrophage phagocytosis Dendritic cell antigen presentation (MHC) to T-cells IFN Plasmacytoid DC Autoreactive B cells produce autoantibody with activation signals from T-helper cells. Autoreactive T cell Autoreactive B cell Autoantibodies Immune complexes deposit in tissue Autoantibodies (i.e., anti-dsDNA, anti-Sm autoantibodies) against cellular debris form immune complexes Legend NETosis: Program for formation of neutrophil extracellular traps (NETs) Plasmacytoid DC: Plasmacytoid dendritic cell TLR: Toll-like receptor immune system. Other innate immune cells with aberrant function in SLE include classical monocytes that infiltrate and repair injured tissue due to immune complex deposition and nonclassical monocytes that patrol the vascular lumen for injury. Sustained activation of these sub­ sets from SLE leads to tissue inflammation and scarring. ■ ■ADAPTIVE IMMUNITY B cells play a central role in the SLE pathogenesis based on the production of autoantibodies due to their loss of tolerance. Autoantibodies, especially those complexed with nucleic acid, are pathogenic mediators of tissue inflammation and damage in SLE. These autoantibodies induce type 1 IFN and other inflammatory mediators and activate patrolling monocytes in tissue. A subset of circulating age-associated B cells (ABCs) expands in SLE patients and eventually matures into autoantibody-secreting plasma cells, indicating that SLE patients have an increased population of B cells primed to generate pathogenic autoantibodies. Similar to B cells, T cells lose tolerance and play a central role in the autoimmune response. In particular, both T follicular and T peripheral helper cells promote B-cell differentiation into pathogenic, high-affinity, autoantibody-secreting plasma cells. T regulatory cells meant to maintain tolerance in both T and B cells are defective in SLE. CLINICAL MANIFESTATIONS ■ ■OVERVIEW AND SYSTEMIC MANIFESTATIONS The initial presentation of SLE is variable and may present as nonspe­ cific constitutional symptoms with or without single-organ or mul­ tiorgan involvement. Autoantibody presence is helpful in attributing nonspecific symptoms to SLE. Symptoms can be mild to severe at any time over the course of the disease, including at initial presentation. Patients with severe disease often have systemic symptoms such as fever, anorexia, and unintentional weight loss. Approximately 15% of patients have relatively mild disease, which may or may not be accom­ panied by fatigue, brain fog, and/or mild arthralgia. The majority of SLE patients have active disease despite therapy or have frequent flares of their disease requiring treatment adjustment. Goals for SLE treat­ ment are low-level disease activity or remission on ongoing therapy. (See “Outcomes” section for more details.) ■ ■MUSCULOSKELETAL MANIFESTATIONS Nonspecific arthralgia and myalgia are common in SLE. Lupus arthritis is characterized by a polyarthritis most commonly involving the wrists, the metacarpal-phalangeal and proximal interphalangeal joints of the hands, and the knees. In some cases, damage of the periarticular liga­ ments may lead to Jaccoud-like changes (Fig. 368-2A). Rheumatoid arthritis and SLE can occur simultaneously, and this overlap is denoted by the term rhupus. While radiographs rarely demonstrate erosive changes in lupus arthritis, emerging studies with magnetic resonance imaging (MRI) and ultrasound imaging suggest a possible erosive pat­ tern that is less severe than that seen with rheumatoid arthritis. Pain in a single hip, shoulder, or knee out of proportion to other joints should prompt consideration of avascular necrosis of bone, particularly with history of corticosteroid usage. Inflammatory muscle disease is also seen in lupus, characterized by symmetrical proximal weakness, ele­ vated creatine kinase and aldolase levels, and inflammatory changes on muscle biopsy. Corticosteroids used to treat SLE may cause myopathy, as can antimalarials, although this is rare. ■ ■CUTANEOUS MANIFESTATIONS Three major categories of SLE skin manifestations include acute cuta­ neous lupus erythematosus (ACLE), subacute cutaneous lupus erythe­ matosus (SCLE), and chronic cutaneous lupus (Fig. 368-2B-F). ACLE occurs with SLE disease activity, whereas SCLE and certain forms of chronic cutaneous lupus may be seen in the absence of systemic dis­ ease. The most classic form of ACLE is the malar rash, which appears in a “butterfly” distribution across the cheeks of the face with nasolabial sparing. Due to its photosensitive nature, slightly raised lesions, and location on the face, this may be confused with rosacea, which involves the nasolabial folds. ACLE may also present as a generalized macu­ lopapular rash in sun-exposed areas of the body, bullous lupus, toxic epidermal necrolysis variant, and generalized photosensitivity. SCLE is a photosensitive rash associated with anti-Ro or SSA antibodies that is characterized by flat, red-rimmed annular or psoriasiform lesions. Discoid lesions are rough, circular lesions that are slightly raised, scaly, and hyperpigmented with depigmented, atrophic centers and erythematous rims, and are the most common chronic dermatitis seen in SLE. Other chronic forms of cutaneous lupus include hypertrophic or verrucous lupus, lupus panniculitis, tumid lupus, chilblains lupus, and discoid lupus/lichen planus overlap. Nonspecific cutaneous mani­ festations that may be seen in SLE include nonscarring alopecia, oral and nasal painful or nonpainful mucosal ulcers, and the less common leukocytoclastic and urticarial vasculitides. Approximately one-third of SLE patients also experience Raynaud’s phenomenon, a condition in which small blood vessels undergo vasospasm with exposure to cold environment or stress, causing a classically triphasic color change of the fingers and/or toes, inducing white (blanching), blue (cyanosis), and red (hyperemia) coloring of the extremities. CHAPTER 368 Systemic Lupus Erythematosus ■ ■RENAL MANIFESTATIONS Nephritis occurs in ~35% of patients with SLE and is more severe in non-White patients, more frequently leading to end-stage renal dis­ ease (ESRD) despite therapy. Nephritis can be seen with or without extrarenal SLE disease and may be present in an asymptomatic patient. Patients should therefore be screened at regular 3-month intervals with a random urine protein-to-creatinine ratio (UPCr) or a 24-h urine pro­ tein and creatinine determination. Usually, nephritis is seen in patients with elevated serum anti–double-stranded DNA (dsDNA) antibody titers and decreased serum levels of C3 and/or C4, and trends of these biomarkers over time may serve as warning signs of impending active nephritis. Renal biopsy is generally prompted by a UPCr of >0.5 and/ or declining kidney function. Classification is based on renal pathol­ ogy from a renal biopsy and is defined by the International Society of Nephrology/Renal Pathology Society criteria. Aggressive therapy is generally reserved for patients with class III (focal proliferative glo­ merulonephritis), class IV (diffuse proliferative glomerulonephritis), or a combination of class III or IV with class V disease (membranous) (Fig. 368-3, Chap. A4). Approximately 20% of lupus nephritis patients with significant proteinuria tend to have class V disease and more often have nephrotic syndrome. Patients with class V lupus nephritis have a better overall prognosis than patients with class III or IV lupus nephri­ tis and are treated in the same manner as class III and IV. Patients who do not respond to treatment may require a repeat biopsy to evaluate for a change in class. In the United States, ~20% of SLE patients with class IV lupus nephritis die or develop ESRD within 10 years. Newer approaches are being developed to both increase renal survival and spare patients from accelerated atherosclerosis, hypertension, hyper­ glycemia, and hyperlipidemia, all of which can be accelerated by renal disease and corticosteroid usage. ■ ■NERVOUS SYSTEM MANIFESTATIONS Lupus patients experience neuropsychiatric manifestations of disease that are characterized by diffuse or focal symptoms. The most com­ mon diffuse symptom is “brain fog,” a cognitive dysfunction or slow­ ing of thought. The etiology is not well understood but may be related to autoantibodies crossing the blood-brain barrier, leading to local inflammation and neuronal damage. Headache is common and often severe, although it may be difficult to distinguish from migraine or tension headache. Seizures of any type may be seen in neuropsychiat­ ric lupus. Acute psychosis and confusional states are uncommon but can occur in SLE without any structural abnormalities. In these cases, glucocorticoid-induced psychosis and infectious encephalitis should be ruled out. Transverse myelitis is a rare SLE complication that mani­ fests as bilateral neurologic deficits such as symmetric motor weakness and decreased sensation due to spinal cord inflammation. ■ ■VASCULAR OCCLUSION: MYOCARDIAL INFARCTIONS AND STROKE Coronary heart disease from accelerated atherosclerosis in SLE is a significant cause of morbidity and premature death, especially in young patients without other risk factors. Vascular injury due to excessive PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders A B C D E F FIGURE 368-2  Characteristic musculoskeletal and cutaneous manifestations seen in systemic lupus erythematosus (SLE). A. Jaccoud arthropathy, characterized by chronic, nonerosive, and reversible deviations caused by joint capsule inflammation with subsequent fibrotic retraction and metacarpophalangeal joint subluxation. B. Patchy, nonscarring alopecia. C. Patchy scarring alopecia. D. Patchy alopecia associated with chronic, scarring discoid lupus changes. E. Classic photosensitive malar rash. F. Subacute cutaneous lupus erythematosus (SCLE) with widespread, nonscarring photosensitive features. (Panels B–E reproduced with permission from Victoria Werth, MD. Panels A and F reproduced with permission from DoQuyen Huynh, MD.) type 1 IFN and cellular death may predispose to atherosclerosis. The risk of coronary artery disease and vascular thrombosis is further increased in SLE patients with antiphospholipid syndrome (APS), an autoimmune syndrome that commonly occurs in SLE and is character­ ized by arterial, venous, or small vessel thromboembolic events in the presence of antiphospholipid antibodies with prothrombotic proper­ ties (Chap. 369). Stroke has been reported in up to 19% of patients with SLE, a result of atherosclerosis and increased risk from APS. In addition to stroke, APS appears to be a significant risk factor for other focal central nervous system manifestations including seizures and transverse myelitis. ■ ■PULMONARY MANIFESTATIONS The most common pulmonary manifestation of SLE is pleuritis, which can occur with or without exudative pleural effusions. Acute pneumonitis may present in active SLE, with pulmonary infiltrates often appearing indistinguishable from infection on imaging. Diffuse alveolar hemorrhage with capillaritis and interstitial lung disease may also be seen. Restrictive lung defect from reduced lung volumes, also known as shrinking lung syndrome, is uncommon but may occur. Pulmonary arterial hypertension and pulmonary embolism may be present with or without APS. ■ ■CARDIAC MANIFESTATIONS All layers of the heart may be involved in SLE, with pericardial involvement being the most frequent. Pericarditis can typically be managed with anti-inflammatory medications, colchicine, and anti-IL-1–directed therapies, or without glucocorticoids, and rarely leads to tamponade physiology. Myocarditis is rarer and may lead to left-sided heart failure and/or arrhythmia. Libman-Sacks endocarditis, a fibrinous sterile form of endocarditis that may be associated with antiphospholipid antibod­ ies, may increase the risk for embolic events. Right-sided heart failure may be present with pulmonary arterial hypertension or chronic lung disease. ■ ■HEMATOLOGIC MANIFESTATIONS Cytopenias in SLE are often multifactorial and may be associated with disease activity, medication use, or infection. Anemia is the most common hematologic manifestation of SLE and is present in >50% of SLE cases, with anemia of chronic disease representing approximately Class I Class II Class III/IV Class V Class III/IV + V FIGURE 368-3  Ultrastructural features of lupus glomerulonephritis. Class I: Mesangial immune deposits (black) without mesangial cell (red) hypercellularity or leukocyte infiltration. Class II: Mesangial immune deposits with mesangial cell hypercellularity, no leukocyte infiltration. Class III/IV: Subendothelial immune deposits visible by light microscopy, with infiltration of mesangial and capillary leukocytes (dark green neutrophils and light green monocytes/macrophages). Class III/IV + V: Leukocyte infiltration with subepithelial and subendothelial immune deposits. Class V: Subepithelial immune deposits, no leukocyte infiltration. (Reproduced with permission from IM Bajema et al: Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: Clarification of definitions, and modified National Institutes of Health activity and chronicity indices. Kidney Int 93:789, 2018, Figure 2.) one-third of cases; other causes for anemia in SLE include iron deficiency, autoimmune hemolytic anemia, aplastic anemia, micro­ angiopathic hemolytic anemia, and medication effect. Leukopenia (<4000/µL) is common, occurring in about half of SLE patients, and usually consists of lymphopenia (<1500/µL), rather than neutropenia. Thrombocytopenia (<150,000/µL) is usually mild but can also be severe (<50,000/µL) and pose significant bleeding risk. It is most com­ monly due to immune mechanisms and may be associated with APS or antiphospholipid antibodies against platelet antigens. Splenomegaly, splenic atrophy, and asplenism may all be seen in SLE. Depending on severity of the abnormal blood counts, treatment considerations include glucocorticoids, anti-CD20 biologic agents, platelet growth factors, intravenous immunoglobulin, and/or splenectomy in resistant cases. Rarely, atypical hemolytic-uremic syndrome (formerly des­ ignated as thrombotic thrombocytopenic purpura or the syndrome of microvascular thrombotic crisis) may occur. This is a condition that presents with hemolysis, thrombocytopenia, and microvascular thrombosis, as well as brain and other tissue involvement. Laboratory testing shows schistocytes in the peripheral blood smear, low levels of ADAMTS13 activity, and elevated serum lactate dehydrogenase levels. ■ ■GASTROINTESTINAL MANIFESTATIONS Lupus can involve any part of the gastrointestinal tract. Flaring SLE activity has been associated with nonspecific gastrointestinal symptoms including nausea, vomiting, and diarrhea. Abdominal pain may be caused by lupus peritonitis, enteritis, pancreatitis, or vasculitis. Mesen­ teric vasculitis can lead to intestinal perforation, bleeding, and ischemia and requires high doses of glucocorticoids for treatment. Impaired intestinal motility and protein-losing enteropathy may also occur. CHAPTER 368 Systemic Lupus Erythematosus Elevated liver enzymes are common and may be associated with flaring disease activity, medications, and/or coexisting autoimmune hepato­ biliary disease. Mesenteric thrombosis, Budd-Chiari syndrome, and hepatic venoocclusive disease can be observed with concomitant APS. ■ ■OCULAR MANIFESTATIONS Keratoconjunctivitis sicca is common in SLE, even in the absence of secondary Sjögren’s syndrome. Retinal vasculitis, optic neuritis, uveitis, scleritis, peripheral ulcerative keratitis, episcleritis, and nonspecific conjunctivitis may all be seen. Retinal vasculitis is rare but, when present, requires aggressive immunosuppression to prevent blindness. Adverse ocular effects from medications include cataracts and glau­ coma from glucocorticoid treatment and hydroxychloroquine (HCQ)- induced maculopathy (Table 368-1). LABORATORY TESTS ■ ■AUTOANTIBODIES An elevated titer of ANA reflects the underlying immune dysregulation in SLE. Measuring ANA presence and titer is the best screening test for SLE because ANAs are seen in almost all SLE patients. Repeated nega­ tive tests by immunofluorescence make a diagnosis unlikely, but rare cases of ANA-negative SLE do occur. Classification of SLE by current EULAR/ACR criteria requires the presence of an ANA titer of 1:80 for enrollment of patients into SLE clinical trials; however, the diagnosis is based on clinical and laboratory features and ultimately, clinical judgement (see “Diagnosis and Classification” section). Numerous ANAs have been identified that target nuclear antigens; in particu­ lar, components of the nucleosome (DNA wrapped around a histone TABLE 368-1  Clinical Manifestations of Systemic Lupus Erythematosus Constitutional Fatigue, malaise, fever, weight loss, anorexia Cutaneous    Generalized Photosensitivity, oral and nasal ulcers, alopecia   Acute cutaneous Malar rash, maculopapular rash, bullous lupus, toxic epidermal necrolysis variant PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders lupus   Subacute cutaneous   lupus   Chronic forms of Discoid rash, panniculitis, tumid lupus, chilblains, verrucous lupus, cutaneous vasculitis cutaneous lupus Musculoskeletal Arthralgia, myalgia, polyarthritis, Jaccoud hand deformity, inflammatory myopathy, avascular necrosis of bone Hematologic Anemia, leukopenia, lymphopenia, thrombocytopenia, lymphadenopathy, splenomegaly, venous or arterial thrombosis, atypical hemolytic-uremic syndrome Cardiopulmonary Pleurisy, pericarditis, pleural and pericardial effusions, myocarditis, endocarditis, pneumonitis, coronary artery disease, interstitial fibrosis, pulmonary hypertension, diffuse alveolar hemorrhage, shrinking lung syndrome Vascular Pulmonary hypertension, stroke, myocardial infarction, peripheral arterial disease, pulmonary embolism, deep vein thrombosis, Raynaud’s phenomenon Neurologic Cognitive dysfunction, mood disorder, depression, headache, seizures, mononeuropathy, polyneuropathy, stroke, transient ischemic attack, psychosis, aseptic meningitis, transverse myelitis Renal Proteinuria ≥500 mg/24 h, cellular casts, nephrotic syndrome, end-stage renal disease Gastrointestinal Nausea, abdominal pain, diarrhea, elevated liver enzymes, lupus peritonitis or enteritis, vasculitis, pancreatitis Ocular Sicca syndrome, conjunctivitis, episcleritis, scleritis, uveitis, retinal vasculitis octamer) or RNA-binding proteins (RBPs). In SLE, the most common antinucleosome antibodies are anti-dsDNA antibodies that are pres­ ent in ~40–60% of patients and highly specific (75–99%). Anti-Smith (anti-Sm) antibodies are the most common anti-RBP, present in ~30% of patients, and are highly specific for SLE (55–100%). Given their high specificity, both anti-dsDNA and anti-Sm antibodies are the only ANA subtypes that are included in the current EULAR/ACR criteria. Anti-Ro (SS-A) antibodies, which recognize a protein complexed pri­ marily to 60-kDa and 52-kDa RNAs, are often seen in ANA-negative SLE patients and are associated with risk for neonatal lupus, sicca symptoms, photosensitivity, and SCLE. Antihistone antibodies may be associated with drug-induced lupus (see “Drug-Induced Lupus” section). Antiphospholipid antibodies, as measured by IgG, IgM, and IgA isotypes of anticardiolipin and anti–beta-2 glycoprotein-1 antibod­ ies (anti-β2GP-1), and the lupus anticoagulant usually obtained using the dilute Russell venom viper time (dRVVT) are present in ~50% of SLE patients. These antibodies, especially the IgG and IgA isotypes of cardiolipin and β2GP-1, and the lupus anticoagulant are associated with arterial and venous thrombosis, thrombocytopenia, and recurrent fetal loss (Table 368-2). Many ANA subtypes can be present in SLE and other systemic autoimmune diseases including myositis, rheumatoid arthritis, Sjögren’s syndrome, and systemic scleroderma, as well as organ-specific autoimmune diseases such as autoimmune hepatitis, Hashimoto’s thyroiditis, and primary biliary cholangitis. ■ ■STANDARD DIAGNOSTIC TESTS Immunologic, renal, and hematologic domains make up the laboratory testing for the diagnosis of SLE. Among the immunologic domain, elevated titers of ANA confer a high likelihood of SLE. Although ANAs are present at low levels in healthy patients, the threshold for a positive test of 1:80 or higher favors SLE. In the setting of ANA negativity with a clinical presentation highly suggestive of SLE, anti-Ro (SSA) confers a high likelihood of SLE. Further immunologic testing for anti-dsDNA TABLE 368-2  Autoantibodies in Systemic Lupus Erythematosus PREVALENCE, % CLINICAL ASSOCIATIONS ANTIBODY ANA Titers of 1:80 or higher are considered positive and are sensitive for SLE but not specific. Anti-dsDNA Higher titers are more specific for SLE. Levels correlate with disease activity and nephritis. Anti-Sm Most specific autoantibody for SLE and more common in black and Asian patients. May correlate with CNS manifestations and incidence of nephritis. Anti-RNP Not SLE-specific. Associated with overlap syndromes and increased risk for pulmonary hypertension. Correlates with high interferon gene signature. Anti-Ro (SS-A) Not SLE-specific. Associated with sicca syndrome, neonatal lupus and congenital heart block, and subacute cutaneous lupus. Anti-La (SS-B) Associated with anti-Ro. Antiribosomal P May be associated with CNS involvement. Specific for SLE but not sensitive. Antihistone Associated with drug-induced lupus. Anti–U1-RNP Associated with musculoskeletal and lung impairment. Antiphospholipid   Anticardiolipin   Anti–b2-glycoprotein   Lupus anticoagulant Arterial or venous thrombosis, pregnancy morbidity and fetal loss, thrombocytopenia. Associated with CNS manifestations, LibmanSacks endocarditis, hypertension, pulmonary hypertension. Abbreviations: ANA, antinuclear antibody; CNS, central nervous system; dsDNA, double-stranded DNA; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; Sm, Smith. and anti-Sm autoantibodies confers specificity. Anti-dsDNA antibod­ ies and reduced levels of complement components C3 and C4 suggest a propensity for lupus nephritis, as these tests indirectly reflect the pathogenic production of autoantibodies and the high load of cellular debris. Laboratory testing is required at initial presentation to screen for hematologic abnormalities including leukopenia, lymphopenia, thrombocytopenia and anemia of chronic inflammation, hemolytic anemia, and atypical hemolytic-uremic syndrome. Initial testing for renal abnormalities is necessary to determine an estimated glomerular filtration rate (eGFR), serum creatinine, and either a random or 24-h UPCr. When commercially available, consideration should be given to measuring urinary biomarkers recently noted to be associated with renal inflammatory and fibrotic disease, including urinary interleukin 16, CD163, type 1 IFN, and transforming growth factor-beta (TGF-β). ■ ■TESTS FOR FOLLOWING DISEASE COURSE Clinical manifestations of SLE vary over time, likely in response to the aberrant immunologic mechanisms that are driving disease. In particular, anti-dsDNA antibody titers are important to track disease activity. These autoantibodies are produced by a short-lived population of B-cell plasmablasts that turn over rapidly, reflecting the presence or absence of immunologic activity. Levels of the complement factors C3 and C4 can drop during episodes of high disease activity, as these are affected by the formation of autoimmune immune complexes and apoptotic cells. In lupus nephritis, the extent of proteinuria and the eGFR are also frequently monitored. Quarterly testing is suggested in asymptomatic patients because hematologic and renal manifesta­ tions can be present in the absence of symptoms. Testing should be performed to consider the presence of leukopenia, lymphopenia, thrombocytopenia, anemia (both anemia of chronic inflammation and hemolytic anemia), and rarely, atypical hemolytic-uremic syndrome. Testing for eGFR, serum creatinine, and a random or 24-h UPCr level is essential for routine follow-up care with consideration of a renal biopsy when urinary protein exceeds a new level of UPCr of 0.5 to rule out active lupus nephritis. Consideration should be given to measuring urinary biomarkers on a quarterly basis when available. MANAGEMENT EULAR recently updated recommendations for the management of SLE and lupus nephritis. Goals for SLE treatment include improved disease activity with minimal symptoms, prevention of damage, and improved quality of life (Figs. 368-4 and 368-5). Adherence to treat­ ment plans is essential. Achieving these goals with safe treatments and minimal corticosteroids is an integral aspect of achieving low levels of disease activity and remission. If corticosteroids are utilized for active or flaring disease, the goal should be to utilize the lowest possible dos­ age to suppress disease activity. Aggressive therapy should be reserved for life-threatening manifestations or those that could lead to damage. Consideration should be given to minimize both the effects of active disease and complications from treatment. Renal treatment goals based on EULAR recommendations include (1) a goal that all patients should at least achieve a state of low disease activity, defined by a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of 0–4; or (2) remission, defined as a SLEDAI score of 0, both with stable use of HCQ, immunosuppressives or biologics, and a daily dose of 5 mg of prednisone (or glucocorticoid equivalent) or less (see “Outcomes” section). Treatment of Non-Renal Systemic Lupus Erythematosus Mild* Moderate* Severe* 1st line 2nd line 1st line 2nd line 1st line 2nd line General measures HCQ (all patients unless contraindicated) Sun protection Exercise No smoking Balanced diet Vaccinations Normal body weight Blood pressure, lipid, glucose control GC PO/IV (if needed, short-term use to control active disease; taper to ≤5 mg/day as quickly as possible and discontinue, if possible) MTX AZA MMF MMF Acetylsalicylic acid, VKA (in aPL+/APS) Immunosuppressive or biological agents at stable, tolerated dose Assess adherence to treatment Grade A Grade B Grade C Grade D FIGURE 368-4  Treatment of nonrenal systemic lupus erythematosus (SLE). Notes: Top-to-bottom sequence does not imply order of preference (e.g., MTX, AZA, and MMF are equal options for second-line therapy in mild disease or first-line therapy in moderate disease). *Mild disease: constitutional symptoms; mild arthritis; rash ≤9% body surface area; platelet count (PLTs) 50–100 × 109/L; SLEDAI ≤6; BILAG C or ≤1 BILAG B manifestation. *Moderate disease: moderate-to-severe arthritis (“rheumatoid arthritis–like”; rash 9–18% body surface area [BSA]; PLTs 20–50 × 109/L; serositis; SLEDAI 7–12; ≥2 BILAG B manifestations). *Severe disease: major organ-threatening disease (e.g., cerebritis, myelitis, pneumonitis, mesenteric vasculitis); thrombocytopenia with platelets <20 × 109/L; thrombotic thrombocytopenic purpura–like disease or acute hemophagocytic syndrome; rash >18% BSA; SLEDAI >12; ≥1 BILAG A manifestation. †Recommendation of belimumab and anifrolumab as first-line therapy in severe disease refers to cases of extrarenal SLE with nonmajor organ involvement but extensive disease from skin, joints, and so on. The use of anifrolumab as add-on therapy in severe disease refers mainly to severe skin disease. For patients with severe neuropsychiatric disease, anifrolumab and belimumab are not recommended. ANI, anifrolumab; aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; AZA, azathioprine; BEL, belimumab; BILAG, British Isles Lupus Assessment Group; CNI, calcineurin inhibitor; CYC, cyclophosphamide; GC, glucocorticoids; HCQ, hydroxychloroquine; IV, intravenous; MMF, mycophenolate mofetil; MTX, methotrexate; PO, per os; RTX, rituximab; SLEDAI, SLE Disease Activity Index; VKA, vitamin K antagonists. (Reproduced with permission from A Fanouriakis et al: Ann Rheum Dis 83:15, 2024.) ■ ■ESSENTIAL LUPUS THERAPEUTIC APPROACHES AND ANTIMALARIALS All SLE patients should use daily sunscreen on sun-exposed areas, maintain a healthy diet and weight, avoid smoking, exercise regularly, maintain compliance with vaccination recommendations, and regu­ larly monitor and achieve control of their blood pressure, lipid, and glucose levels. Antimalarials should be used in all patients unless con­ traindicated, as they have been shown to prevent flares, increase overall survival, and decrease the risk of developing renal disease and acceler­ ated atherosclerosis, among other benefits. HCQ, one of the first drugs approved by the U.S. Food and Drug Administration (FDA) for use in SLE, is the most common antimalarial used and is first-line therapy for patients with skin manifestations and arthritis. It is the most use­ ful drug to improve fatigue in SLE. Use during pregnancy and during breastfeeding has been demonstrated to be safe. Appropriate dosing of HCQ is under investigation, as higher doses may be associated with better disease control. Current recommendations are for dosing up to 5 mg/kg per day (actual body weight) with performance of retinal evaluations at baseline and at yearly intervals to monitor for macular effects, which are associated with prolonged usage. Risk factors for retinal toxicity from HCQ include higher dose and longer duration of use; however, higher doses may also confer better disease control, and overall risk for maculopathy remains low. The most appropri­ ate dose of HCQ for SLE treatment thus remains unclear. Other side effects of HCQ may include rash, nausea, vomiting and diarrhea, and skin dyspigmentation. Tobacco use may interfere with the efficacy of antimalarials. Alternative antimalarials include chloroquine, which has a higher risk of retinal toxicity, and quinacrine, which has a higher CHAPTER 368 Systemic Lupus Erythematosus Target Remission Clinical SLEDAI = 0 HCQ GC ≤5 mg/day or Low disease activity SLEDAI ≤4 HCQ GC ≤5 mg/day BEL† ANI† CNI CNI CYC RTX RTX Treatment of Lupus Nephritis Initial Subsequent HCQ (all patients unless contraindicated) Adjunct treatment for kidney protection# PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders GC PO/IV (consider pulse IV MP, then 0.3–0.5 mg/kg/day depending on severity; taper to ≤5 mg/day as quickly as possible) ACEi/ARBs Consider SGLT2i (if decreased eGFR) Low-dose CYC VKA, heparin (if concomitant APS nephropathy) MMF/AZA + BEL§ MMF/low-dose CYC + BEL§ MMF + CNI (esp. VOC, TAC)^ High-dose CYC *,¶ Any of the above– mentioned unless contraindicated^ RTX† Assess adherence to treatment Grade A Grade B Grade C Grade D FIGURE 368-5  Treatment of lupus nephritis. Notes: Top-to-bottom sequence does not imply order of preference. #In addition to general protective measures, as outlined in Figure 368-3. §BEL should always be given in combination with MMF or low-dose CYC as initial therapy and with MMF or AZA as maintenance therapy. ˆCNIs should be given in combination with MMF. *Particularly recommended in the presence of poor prognostic factors: reduced eGFR, histologic presence of cellular crescents or fibrinoid necrosis, or severe interstitial inflammation. ¶Extension of high-dose CYC to subsequent phase refers to severe lupus nephritis cases, in which bimonthly or quarterly CYC pulses may be given following 6 monthly pulses. †In relapsing/refractory disease, especially after failure of CYC-based regimens. ACEi, angiotensin-converting enzyme inhibitors; APS, antiphospholipid syndrome; ARB, angiotensin receptor blockers; AZA, azathioprine; BEL, belimumab; CNI, calcineurin inhibitor; CYC, cyclophosphamide; eGFR, estimated glomerular filtration rate; GC, glucocorticoids; HCQ, hydroxychloroquine; IV, intravenous; MMF, mycophenolate mofetil; MP, methylprednisolone; PO, per os; RTX, rituximab; SGLT2i, sodium-glucose cotransporter 2 inhibitors; TAC, tacrolimus; Upr, urine protein; VKA, vitamin K antagonists; VOC, voclosporin. (Reproduced with permission from A Fanouriakis et al: Ann Rheum Dis 83:15, 2024.) risk of skin dyspigmentation. Quinacrine can be used as alternative therapy in cases of toxic retinopathy or as add-on therapy to HCQ for patients with inadequate response. For arthritis and arthralgia, non­ steroidal anti-inflammatory drugs (NSAIDs) can be useful but should be used with caution in SLE patients due to increased risk for aseptic meningitis, hypertension, renal dysfunction, elevated serum transami­ nases, and increased myocardial infarction risk with cyclooxygenase-2 inhibition. ■ ■GLUCOCORTICOIDS Glucocorticoid dosing is based on the organ-specific needs and sever­ ity of disease. While effective at reducing inflammation quickly, their use is associated with dose-dependent side effects including cushin­ goid metabolic effects, hyperglycemia, hypertension, osteoporosis, and avascular necrosis. If needed, corticosteroids should be tapered as quickly as possible to maintenance doses of 5 mg or less of daily predni­ sone or its equivalent, and withdrawn as soon as feasible. Use of intra­ venous methylprednisolone (usually 125–1000 mg daily for 1–3 days) is limited to emergent needs such as active nephritis, severe central nervous system or vascular involvement, and hematologic manifesta­ tions such as life-threatening hemolytic anemia or thrombocytopenia. A major goal of novel SLE therapies is the ability to develop treatment algorithms that are less dependent on chronic glucocorticoid use. ■ ■SKIN AND MUSCULOSKELETAL MANIFESTATIONS: IMMUNOMODULATING AND IMMUNOSUPPRESSANT DRUGS All SLE patients and especially those with skin manifestations of disease should be treated with topical sunscreens and antimalarials. If unresponsive to these approaches, topical glucocorticoids and/ or calcineurin inhibitors can be utilized. Persistent mucocutane­ ous disease and/or arthritis may prompt consideration of additional oral immunomodulating drugs such as azathioprine (6-thioguanine purine analogue), leflunomide (lymphocyte-specific pyrimidine syn­ thesis inhibitor), mycophenolate mofetil (MMF), or mycophenolic acid (purine synthesis inhibitors). Biological drugs such as belimumab Targets 3 months ≥25% reduction in UPr MMF 6 months ≥50% reduction in UPr to <3 gr/day AZA/MMF 12 to 24 months UPr <0.5–0.7 gr/day (all with eGFR within 10% from baseline) (anti-BAFF, administered intravenously or subcutaneously) and ani­ frolumab (anti–type 1 IFN receptor, administered intravenously) are FDA-approved approaches shown to improve outcomes in these clini­ cal domains, with better ability to taper glucocorticoids. Thalidomide and lenalidomide may be used for some cutaneous subtypes but with caution due to risk for polyneuropathy and teratogenicity. Methotrex­ ate (a folinic acid antagonist) is another option for arthritis associated with SLE. ■ ■RENAL DISEASE: SUCCESSES WITH COMBINATION THERAPIES Treatment approaches have been recommended by EULAR for class III and IV lupus nephritis, as well as combination of class V lupus nephritis with either class III or IV (Fig. 368-5). The recommended targets are a 3-month target of 25% or more reduction in UPCr level, a 6-month target of 50% or more reduction in UPCr to <3 g/d, and a 12- to 24-month target in UPCr to <0.5–0.7 g/d, with each of these targets associated with an eGFR within 10% from baseline. All patients with class III, IV, or V nephritis should receive an angiotensinconverting enzyme (ACE) inhibiting agent or an angiotensin receptor blocking (ARB) agent to decrease proteinuria and reduce systemic and glomerular hypertension. With a baseline decreased eGFR, use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor should be considered to reduce glomerular hyperfiltration, lower blood pressure, and decrease proteinuria. Patients with active lupus nephritis with concomitant antiphospholipid nephropathy as noted by biopsy should receive a vitamin K antagonist or heparin. Current initial regimens include either cyclophosphamide (an alkylating agent administered intravenously) or MMF (administered orally) plus glucocorticoids to reduce progression to ESRD and death. Rates of infection and death are similar in both treatment approaches. Induction in Black or Hispanic patients with MMF 2–3 g daily is appro­ priate given better response to MMF in these ethnic groups, while use of either MMF or cyclophosphamide may be an option for White and Asian patients. Low doses of cyclophosphamide (500 mg every 2 weeks for six doses) followed by either azathioprine or MMF maintenance are as effective as standard high doses of cyclophosphamide with improved tolerability. High-dose cyclophosphamide monthly for 6 months fol­ lowed by azathioprine or MMF may be more appropriate for patients with crescentic proliferative glomerulonephritis or rapidly progressive glomerulonephritis. Ovarian failure is a potential consequence of high-dose cyclophosphamide, and therefore, a gonadotropin-releasing hormone agonist may be given prior to each cyclophosphamide dose. Dosing of glucocorticoids as part of the initial therapeutic approach is controversial, with more recent data suggesting the use of intermediate doses for shorter periods of time with more rapid dose reduction. For subsequent therapy, MMF is superior to azathioprine in maintaining renal function and survival, but both may be used, and azathioprine is the preferred agent for lupus nephritis in pregnancy. Patients using azathioprine should be screened for homozygous deficiency of the thiopurine S-methyltransferase (TMPT) gene, which increases the risk for severe bone marrow suppression, as this gene is responsible for the TPMT enzyme necessary for metabolizing thiopurine drugs. Calcineu­ rin inhibitors such as tacrolimus and cyclosporine may be beneficial for decreasing proteinuria, and tacrolimus can be used in pregnancy. Two immunomodulating therapies have recently been approved by the FDA for use in lupus nephritis for patients on standard therapy for active nephritis: belimumab, approved in 2020, and the cyclosporine analogue voclosporin, approved in 2021. The randomized controlled trials for these medications demonstrate favorable outcomes without the use of high-dose steroids. Voclosporin-based triple immunotherapy (with MMF and glucocorticoids) or belimumab-based triple therapy (with either low-dose cyclophosphamide or MMF and glucocorticoids) can be considered as an initial approach in active lupus nephritis. Patients with active lupus nephritis and inadequate response to con­ ventional therapies may also consider alternative biologics targeting B cells such as rituximab. While rituximab studies in lupus nephritis did not demonstrate efficacy compared to standard therapies, issues with the trial designs may have hampered the demonstration of an effect. Treatment approaches for patients with pure class V membranous glomerulonephritis have not been well studied, and commonly patients with this presentation are treated only in the setting of significant proteinuria. All patients with class III, IV, or V nephritis, including combinations of class III or IV with class V, should be considered for treatment with ARB or ACE inhibition to reduce proteinuria. ■ ■THERAPIES FOR OTHER ORGAN-BASED SYSTEMS Few studies have focused on central and peripheral nervous system, cardiac, pulmonary, serosal, gastrointestinal, or hematologic manifes­ tations of SLE. Anti-CD20 agents such as rituximab are used for lupusrelated hemolytic anemia and severe thrombocytopenia. Colchicine can be used to treat pleural, pericardial, or peritoneal inflammatory symptoms. MMF, cyclophosphamide, and rituximab plus corticoste­ roids are the mainstay of treatment for serious central and peripheral inflammatory nervous system presentations including psychosis, vas­ culitis, and transverse myelitis. Plasmapheresis and high levels of glu­ cocorticoids can be lifesaving in atypical hemolytic-uremic syndrome. In refractory patients, rituximab and a C5 inhibitor, eculizumab, are used. Concomitant APS should be treated with warfarin for long-term anticoagulation rather than direct oral anticoagulants (Chap. 369). ■ ■EMERGING THERAPIES AND TREATMENT APPROACHES SGLT2 inhibitors are being studied in lupus nephritis for their effects on preserving function through tubular protection with effects on inflammation and fibrosis. Obinutuzumab, a CD20-targeted mono­ clonal antibody that is commercially available for oncologic indi­ cations, has recently demonstrated efficacy in a phase 3 study for lupus nephritis, and is also being investigated for use in SLE without nephritis. Anecdotal experience with obinutuzumab by rheumatolo­ gists in treating SLE patients off-label suggests that this drug may be more clinically effective than rituximab due to improved CD20 tissue depletion. Deucravacitinib, an oral Tyk2 inhibitor, is in phase 3 study for SLE. Telitacicept, a TACI-Fc fusion protein that targets BLyS and APRIL growth factors for B cells, has been approved in China for use in patients with SLE, and global phase 3 studies are underway. Litifilimab, a drug in late-stage development with initial promising results, is a monoclonal antibody targeting BDCA2, a protein expressed on plas­ macytoid dendritic cells, that suppresses activation of type I interferons and other proinflammatory cytokines. Initial results show achievement of remission, according to the Definition of Remission in Systemic Lupus Erythematosus (DORIS), from nonrandomized CD19-directed chimeric antigen receptor T-cell treatment, which has prompted inter­ est in further study of this approach. Other cell-based therapeutic programs under investigation include both allogenic and autologous natural killer cell–based programs and mesenchymal embryonic stem cell transplantation for severe SLE. CHAPTER 368 Systemic Lupus Erythematosus ■ ■GUIDELINES Besides the recent EULAR (2013) and Pan-American League of Associations for Rheumatology (2018) guidelines for SLE and lupus nephritis, the ACR (2012) and the Kidney Disease Improving Global Outcomes (KDIGO) organization (2021) have published guidelines specifically for lupus nephritis. These guidelines address medicationbased, lifestyle, and nonpharmacologic approaches, as well as infection screening and vaccination recommendations. The KDIGO guidelines include recommendations prior to the approval of belimumab and voclosporin. An important concept that the KDIGO group emphasizes is the unsettled question of duration of immunosuppression. The group notes that the risk of lupus relapse should be balanced with risk of adverse events secondary to immunosuppressive drugs. They suggest that for patients who have achieved a complete renal response and have no ongoing extrarenal SLE manifestations, the total duration of immunosuppression (initial plus maintenance) should not be <36 months. The EULAR guidelines provide consensus guidance for SLE management that combines evidence and expert opinion concerning the use of HCQ, glucocorticoids, immunosuppressive drugs, calcineu­ rin inhibitors, and biologics, with suggestions for treatment strategies, response assessment, combination approaches, and therapy tapering (see Figures 368-4 and 368-5). Most of the concepts and strategies pre­ sented in these guidelines are described in the sections above. DRUG-INDUCED LUPUS Drug-induced lupus (DIL) is an autoimmune phenomenon in which a positive ANA and clinical features of SLE arise from a drug exposure. DIL accounts for ~6–12% of all lupus cases. Symptoms may include fever, rash, arthralgia, myalgia, and serositis. Antihistone antibodies are commonly associated with DIL, with dsDNA antibodies occurring less frequently. DIL tends to be less severe than SLE, rarely involving kidneys or brain, and symptoms typically resolve within several weeks after discontinuation of the offending agent. The first agent identified to cause lupus symptoms was hydralazine in 1954. Over the years, >100 drugs have been identified as potential triggers for DIL. The highest incidence of DIL occurs with the anti­ arrhythmic procainamide, with risk reported to be as high as 30%. Other substances associated with DIL include the antihypertensives hydralazine and methyldopa; other antiarrhythmics; antibiotics includ­ ing minocycline, isoniazid, rifampin, and nitrofurantoin; the anti­ rheumatic drug sulfasalazine; anticonvulsants such as phenytoin and carbamazepine; antipsychotics including chlorpromazine and lithium; several ACE inhibitors and beta blockers; the diuretic hydrochloro­ thiazide; the antithyroid propylthiouracil; proton pump inhibitors; NSAIDs; and oral contraceptives. Biologic agents include antitumor necrosis factor α medications, particularly infliximab and etanercept, and IFN-α. Diagnosis can be difficult, as DIL symptoms may start weeks to several months after drug initiation. Furthermore, skin biopsy may be indistinguishable from SLE, and laboratory characteristics including histone antibody may be seen in the majority of SLE cases. In DIL, the ANA pattern is most commonly homogeneous, and histone is posi­ tive in 75% of DIL cases. Cytopenias may be present but are typically mild. The presence of other autoantibodies may help to distinguish SLE from DIL, as these are rarely seen in DIL. The ANA test typically appears before symptoms, although many of the same medications will induce a positive ANA in patients who never develop symptoms. If DIL is suspected, these laboratory tests should help to inform the clinical picture to decide if medication discontinuation is appropriate. If symp­ toms resolve after medication discontinuation, this helps to confirm a diagnosis of DIL. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders PREGNANCY AND REPRODUCTIVE HEALTH ■ ■FERTILITY Lupus activity can affect the menstrual and ovulation cycle. Lower measures of ovarian reserve are seen in SLE patients compared to healthy controls. Women with SLE have a higher risk for infertility if they have active disease, comorbidities such as APS or nephritis, and prior exposure to treatments such as cyclophosphamide. Cyclophos­ phamide use may lead to amenorrhea, ovarian insufficiency, and early menopause. ■ ■CONTRACEPTION/HORMONE REPLACEMENT Contraception and family planning should be discussed with all women of reproductive age with SLE. SLE patients with antiphospholipid anti­ bodies and those with moderate-to-severe or active lupus should avoid estrogen compounds due to increased risk for thromboembolism. Progestin-only contraceptive options such as the levonorgestrel intra­ uterine device or etonogestrel implant, as well as emergency contracep­ tion, may be used safely in women with SLE. Estrogen compounds as a part of postmenopausal hormone replacement therapy should similarly be avoided in the presence of antiphospholipid antibodies. ■ ■PREGNANCY SLE pregnancies are high risk. Disease activity in pregnancy is unpre­ dictable, and the disease can flare during any trimester. Active disease at time of conception is associated with more flares during pregnancy. HCQ reduces the risk of flares during pregnancy and postpartum. Women with SLE are at a higher risk for adverse pregnancy outcomes including pregnancy loss, preterm birth, preeclampsia and pregnancyinduced hypertension, intrauterine growth restriction, cesarean sec­ tion, and maternal death. Flaring or active disease increases the risk for these adverse outcomes. The presence of maternal hypertension, use of glucocorticoids during pregnancy, maternal renal disease, discontinu­ ation of HCQ, non-White ethnicity, and lupus anticoagulant positivity are all associated with worse pregnancy outcomes. SLE patients at the highest risk for maternal death are those with pulmonary arterial hypertension, prior arterial thrombosis, and severe end-organ damage, and these patients should strongly consider avoiding pregnancy. Outcomes are generally favorable for women with SLE with mildto-moderate disease activity on pregnancy-compatible medications. Low-dose aspirin is used during pregnancy for preeclampsia preven­ tion. HCQ is safe and the standard of care for all SLE pregnancies. Azathioprine and tacrolimus may be used safely in pregnancy for more severe disease and/or renal disease. MMF and methotrexate are terato­ genic and should be avoided. Belimumab, anifrolumab, and voclospo­ rin should currently be avoided due to lack of safety data. Patients who get pregnant on these medications may be switched to azathioprine or tacrolimus. Rituximab should be discontinued at conception but may be used during pregnancy in organ-threatening disease. Predni­ sone may be used for disease flares and can suppress disease activity, but the dose should be tapered to the lowest effective dose by adding pregnancy-compatible immunosuppressant medications. Warfarin is teratogenic; low-molecular-weight heparin is used in SLE pregnancies with APS or prior pregnancy morbidity. ■ ■NEONATAL LUPUS SS-A (Ro) antibodies may cross the placenta into the fetal circulation and put the infant at risk for neonatal lupus. Neonatal lupus can consist of a transient cutaneous rash or lab abnormalities that present after birth or, less commonly, congenital heart block that presents in utero. The presence of Ro antibodies, particularly in high titer, should prompt referral to high-risk obstetricians who can perform fetal echocardiog­ raphy to screen for congenital heart block. The use of fluorinated steroids may be considered if first- or second-degree heart block is detected. The use of HCQ in pregnancy significantly reduces the risk of congenital heart block in women who have had a prior fetus with congenital heart block. OUTCOMES Measuring SLE outcomes both in clinical trials and in clinical practice is complex given the multisystem nature of the disease. Various aspects of disease require unique treatment approaches and often at differing rates, which makes measuring response challenging. Modern SLE treatment outcomes include improvement in inflammatory type 1 and chronic type 2 symptoms, quality of life, and the prevention of frailty and damage. New drugs and interventions are constantly being explored as potential treatments for SLE in clinical trials. Goals of clinical trials for novel therapies include improved disease activity and acceptable safety. Long-term extension studies focus on long-term safety and mainte­ nance of improved disease activity. The Systemic Lupus Erythematosus Responder Index (SRI) and the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) are validated instruments for use in clinical trials. The Cutaneous Lupus Disease Area and Severity Index (CLASI) is also utilized specifically for trials involv­ ing cutaneous lupus. Several instruments are utilized in clinical trials to assess quality of life and fatigue, although few are specific to SLE. ■ ■TREAT-TO-TARGET APPROACHES Treat-to-target goals for clinical trials and clinical practice have been developed and validated, including the definition of a lupus low dis­ ease activity state (LLDAS) and remission (DORIS). Both LLDAS and DORIS remission scoring utilize the SLEDAI-2K instrument, a vali­ dated instrument that measures SLE disease activity. Achievement of remission by these measures is defined by low disease activity (LLDAS) or no disease activity (DORIS), with minimal use of steroids and stable use of antimalarials, immunosuppressants, and/or biologics and by low levels (LLDAS) or no evidence of disease activity (DORIS) as assessed by the evaluating physician. LLDAS has been shown to be attainable in up to 80% of patients, and the achievement of sustained LLDAS for 2 more years is associated with significantly less overall damage. ■ ■DAMAGE Organ or structural damage occurs in SLE due to the use of medica­ tions to treat the disease or because of persistent disease activity. Use of glucocorticoids is associated with the development of irrevers­ ible organ damage that is independent of disease activity. Cataracts, osteoporosis-associated fractures, avascular necrosis, and diabetes mellitus are the complications from glucocorticoid treatment that are most commonly observed. Development of damage accrues in a dose-dependent manner, but even low doses of 5 mg of prednisone or equivalent appear to be associated with damage accrual. Accelerated atherosclerosis is a major cause of death after 5 years of SLE disease duration. Increased myocardial infarction and cerebrovascular event rates are due to both traditional cardiovascular risk factors and non­ traditional factors including presence of antiphospholipid antibodies, increased disease activity, low C3 levels, high glucocorticoid dose, and high homocysteine and leptin levels. Statin use has been demonstrated to reduce all-cause mortality in SLE patients with renal transplantation. Studies of malignancy rates in SLE have been inconsistent; however, recent meta-analyses suggest an increased risk of overall cancer and cancer-related death in SLE patients. Seventeen site-specific cancers noted include digestive cancers (esophagus, colon, anus, hepatobiliary, liver, and pancreas), hematologic cancers (lymphoma, Hodgkin’s lym­ phoma, non-Hodgkin’s lymphoma, leukemia, and multiple myeloma), and cancer involving lung, larynx, cervix, vagina/vulva, kidney, blad­ der, skin, and thyroid. ■ ■FURTHER READING Aringer M et al: 2019 European League Against Rheumatism/Ameri­ can College of Rheumatology classification for systemic lupus erythe­ matosus. Ann Rheum Dis 78:1151, 2019. Aringer M et al: A glimpse into the future of systemic lupus erythe­ matosus. Ther Adv Musculoskelet Dis 14:1759720X221086719, 2022. # 12 - 369 Antiphospholipid Syndrome ### 369 Antiphospholipid Syndrome Barber MRW et al: Global epidemiology of systemic lupus erythema­ tosus. Nat Rev Rheumatol 17: 515, 2021. Fanouriakis A et al: EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis 83:15, 2024. Izmirly PM et al: Prevalence of systemic lupus erythematosus in the United States: Estimates from a meta-analysis of the centers for Disease Control and Prevention National Lupus Registries. Arthritis Rheumatol 73:991, 2021. Morand EF et al: Advances in the management of systemic lupus ery­ thematosus. BMJ 383:e073980, 2023. Petri M et al: Derivation and validation of Systemic Lupus Interna­ tional Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 64:2677, 2012. Pisetsky DS et al: A novel system to categorize the symptoms of systemic lupus erythematosus. Arthritis Care Res (Hoboken) 71:735, 2019. Shumilova A, Vital EM: Musculoskeletal manifestations of systemic lupus erythematosus. Best Pract Res Clin Rheumatol 22:101859, 2023. Vale ECSD, Garcia LC: Cutaneous lupus erythematosus: A review of etiopathogenic, clinical, diagnostic and therapeutic aspects. An Bras Dermatol 98:355, 2023. Haralampos M. Moutsopoulos, Maria G. Tektonidou Antiphospholipid Syndrome ■ ■DEFINITIONS Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or venous thrombosis, microvascular manifestations, and/or pregnancy morbid­ ity. It affects primarily young females. APS may occur alone (primary) or in association with other autoimmune diseases, mainly systemic lupus erythematosus (SLE). Catastrophic APS (CAPS) is a rare, lifethreatening, rapidly progressive thromboembolic disease involving simultaneously three or more organs. The major autoantibodies detected in APS patients are directed against phospholipid-binding plasma proteins such as β2-glycoprotein I (β2GPI) and prothrombin. The plasma protein β2GPI is a 43-kDa plasma apolipoprotein, which consists of 326 amino acids arranged in five domains (I through V). The presence of anti–domain I IgG antibodies has been associated with increased thrombotic risk. Recent evidence from animal studies has shown that the antithrombotic func­ tion of β2GPI is dependent on its fifth domain (domain V). Another group of antibodies against phospholipid-binding proteins, termed lupus anticoagulant (LA), prolongs clotting time in vitro, which is not corrected by adding normal plasma. Anticardiolipin and anti-β2GPI IgG/IgM antibodies are measured by standardized enzyme-linked immunosorbent assays (ELISA); β2GPI in combination with cardiolipin or β2GPI in the absence of cardiolipin serve as target antigens, respectively. LA testing includes a threestep procedure: (1) screening including testing with activated partial thromboplastin time (aPTT) and dilute Russel viper venom test (DRVVT); (2) mixing study; and (3) confirmation. In patients receiv­ ing anticoagulation treatment, LA test positivity should be interpreted with caution. In patients with features highly reminiscent of APS in the absence of classical antiphospholipid antibodies (aPL), testing for antiphosphatidylserine/prothrombin antibodies may have a valuable diagnostic role. ■ ■EPIDEMIOLOGY The incidence of APS is estimated to be 1–2 cases per 100,000 persons per year. The prevalence of APS in the general population is estimated to be 40–50 per 100,000. APL antibodies occur in 1–5% of the general population. Their prevalence increases with age; however, it is ques­ tionable whether they are able to induce thrombotic events in elderly individuals. Moreover, one-third of patients with SLE (Chap. 368) pos­ sess these antibodies and 10–15% of them develop APS. CHAPTER 369 ■ ■PATHOGENESIS The initiating events for the induction of antibodies to phospholipidbinding proteins seem to be endothelial injury induced by infections, oxidative stress, and major physical stresses such as surgery or trauma in an appropriate genetic background, given the previously demonstrated associations with alleles within the human leukocyte antigen (HLA) locus. These contributors seem to induce increased apoptosis of the ves­ sel endothelial cells, autoantigen presentation, and subsequent initiation of autoimmune response. The binding of aPL to the disrupted endothe­ lial cells leads to a proinflammatory and prothrombotic state involving monocytes and platelets activation, adhesion molecules and proinflam­ matory cytokines production, complement and neutrophil activation, neutrophil extracellular trap (NET) formation, and thrombus formation. Recently, type I interferon pathway activation and an imbalance between type I and III interferons have been proposed as potential mechanisms of thrombotic events and APS-related obstetric complications. Antiphospholipid Syndrome ■ ■CLINICAL MANIFESTATIONS AND LABORATORY FINDINGS Clinical manifestations include venous or arterial thrombosis, micro­ vascular events, and/or pregnancy morbidity (Table 369-1). Deep venous thrombosis occurs primarily in the lower extremities and often causes pulmonary emboli. Thrombosis of the pulmonary arteries leads to pulmonary hypertension and thrombosis of hepatic veins to BuddChiari syndrome. Cerebral venous thrombosis presents with signs and symptoms of intracranial hypertension and focal neurologic deficits. Other venous thrombosis manifestations include retinal vein throm­ bosis and renal, mesenteric, or splanchnic vein thrombosis. Arterial thrombosis affects more commonly the arteries of the brain and is manifested as transient ischemic attack, stroke, migraines, or cognitive dysfunction. Peripheral artery thrombosis presents with acute limb ischemia, ischemic leg ulcers, or digital gangrene. Thrombosis of other arteries leads to myocardial infarction, retinal artery occlusion, renal artery stenosis, and infarcts of spleen, liver, and adrenals. Microvascular manifestations include livedo reticularis, which con­ sists of a mottled reticular vascular pattern that appears as a lace-like, purplish discoloration of the skin; livedo racemosa, characterized by a broken, irregular, and asymmetric pattern; and livedoid vasculopathy, which presents with painful papules or lower limb ulcers. Another microvascular feature of APS is the so-called aPL-nephropathy, mani­ fested with hypertension, proteinuria (mild to nephrotic range), hematuria, and mild renal insufficiency. Histologically, the acute phase is characterized by thrombotic microangiopathy lesions in the glomerular capillaries and/or arterioles. In a chronic phase, fibrous intima hyperplasia, fibrous and/or fibrocellular arteriolar occlusions, and focal cortical atrophy are present (Table 369-1). Additional rare microvascular manifestations are pulmonary hemorrhage, myocardial disease confirmed by magnetic resonance imaging or histologically, and adrenal hemorrhage. Pregnancy morbidity manifests with prefetal (<10 weeks of gesta­ tion) or fetal death, preeclampsia, eclampsia, and placental insuffi­ ciency with intrauterine fetal growth restriction, abnormal umbilical arterial Doppler, and/or infarctions of the placenta Cardiac valve manifestations include valve thickening or veg­ etations. Libman-Sacks endocarditis consists of small (usually <1 cm) valve vegetations, histologically characterized by organized plateletfibrin microthrombi surrounded by growing fibroblasts and mac­ rophages. Premature atherosclerosis has been also recognized as a feature of APS. Thrombocytopenia and autoimmune hemolytic anemia are the main hematologic manifestations of APS. Musculoskeletal TABLE 369-1  Clinical Features of Antiphospholipid Syndrome MANIFESTATION % Venous Thrombosis and Skin Manifestations Deep-vein thrombosis Livedo reticularis Pulmonary embolism Superficial thrombophlebitis Thrombosis in various other sites PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Arterial Thrombosis and Cardiac Manifestations Stroke Cardiac valve thickening/dysfunction and/or Libman-Sacks vegetations Transient ischemic attack Myocardial ischemia (infarction or angina) and coronary bypass graft thrombosis Leg ulcers and/or digital gangrene Arterial thrombosis in the extremities Retinal artery thrombosis/amaurosis fugax Ischemia of visceral organs or avascular necrosis of bone Multi-infarct dementia Neurologic Manifestations of Uncertain Etiology Migraine Epilepsy Chorea Cerebellar ataxia Transverse myelopathy 0.5 Renal Manifestations Due to Various Reasons (Renal Artery/Renal Vein/Glomerular Thrombosis, Fibrous Intima Hyperplasia) Musculoskeletal Manifestations Arthralgias Arthritis Obstetric Manifestations (Referred to the Number of Pregnancies) Preeclampsia Eclampsia Fetal Manifestations (Referred to the Number of Pregnancies) Early fetal loss (<10 weeks) Late fetal loss (≥10 weeks) Premature birth among the live births Hematologic Manifestations Thrombocytopenia Autoimmune hemolytic anemia Source: Adapted from R Cervera et al: Arthritis Rheum 46:1019, 2002. manifestations may also occur in APS including arthralgias/arthritis, avascular bone necrosis, bone marrow necrosis, nontraumatic frac­ tures, and osteoporosis. ■ ■DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The diagnosis of APS should be seriously considered in cases of throm­ bosis, cerebral vascular accidents in individuals <55 years of age, or pregnancy morbidity, in the presence of livedo reticularis or thrombo­ cytopenia. In these cases, aPL antibodies should be measured. Accord­ ing to the 2023 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for APS, the presence of at least 3 points from clinical domains and 3 points from laboratory domains is required to classify APS. Clinical manifestations with other equally or more likely explanations than APS will not be counted. Clinical domains include (1) venous throm­ boembolism; (2) arterial thrombosis; (3) microvascular events; (4) obstetric complications; (5) cardiac valve disease; and (6) hematologic manifestations, as shown in Table 369-2. Laboratory domains include (1) LA, (2) anticardiolipin (aCL), and/or (3) anti-β2GPI antibodies, at moderate (40-79 units) or high titers (≥ 80 units) on two occasions 12 weeks apart. Differential diagnosis is based on the exclusion of other inherited or acquired causes of thrombophilia (Chap. 121), Coombs-positive hemolytic anemia (Chap. 105), and thrombocytopenia (Chap. 120). Livedo reticularis with or without a painful ulceration on the lower extremities may be also a manifestation of disorders affecting (1) the vascular wall, such as atherosclerosis, polyarteritis nodosa, SLE, cryoglobulinemia, and lymphomas; or (2) the vascular lumen, such as TABLE 369-2  2023 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) Classification Criteria for Antiphospholipid Syndrome Clinical Domains  DOMAINS/CRITERIA POINTS Venous thromboembolism (VTE) • With high-risk VTE profile • Without a high-risk VTE profile Microvascular events Suspected (any of below) • Livedo racemosa (exam) • Livedoid vasculopathy lesions (exam) • Acute/chronic aPL-nephropathy (exam or lab) • Pulmonary hemorrhage (symptoms and imaging)  Established (any of below) • Livedoid vasculopathy (pathology) • Acute/chronic aPL-nephropathy (pathology) • Pulmonary hemorrhage (BAL or pathology) • Myocardial disease (imaging or pathology) • Adrenal hemorrhage (imaging or pathology) Cardiac valve disease • Thickening • Vegetation Arterial thrombosis • With high-risk CVD profile • Without high-risk CVD profile Obstetric complications • >3 consecutive prefetal (<10 w) and/or early fetal deaths (10w0d–15w6d) • Fetal death (16w0d–33w6d) in the absence of preeclampsia (PEC) with severe features or placental insufficiency (PI) with severe features • PEC with severe features (<34w0d) or PI with severe features (<34w0d) with/without fetal death • PEC with severe features (<34w0d) and PI with severe features (<34w0d) with/without fetal death Hematologic manifestations • Thrombocytopenia (otherwise unexplained lowest platelet count ever between 20 and 130 × 109/L) Laboratory Domains (aPL) DOMAINS/CRITERIA POINTS Lupus anticoagulant (LA) test • One time positive • Persistent Anticardiolipin (aCL) and/or anti-β2GPI antibodies (persistent) • Moderate (40–79 units) or high (≥80 units) IgM aCL and/or   anti-β2GPI • Moderate (40–79 units) IgG aCL and/or anti-β2GPI • High (≥80 units) positive IgG aCL or anti-β2GPI • High (≥80 units) IgG aCL and anti-β2GPI Abbreviations: aPL, antiphospholipid antibody; anti-β2GPI, anti-β2-glycoprotein I; BAL, bronchoalveolar lavage; CVD, cardiovascular disease; Exam, physical examination; Lab, laboratory tests. Source: Modified with permission from R Zuo et al: The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria. Arthritis Rheumatol 75:1687, 2023. # 13 - 370 Rheumatoid Arthritis ### 370 Rheumatoid Arthritis myeloproliferative disorders, hypercholesterolemia, or other causes of thrombophilia. Diagnosis of CAPS should be considered in patients with mainly microvascular thrombotic disease involving multiple organs in a short time period. A patient is classified as definite CAPS if all four of the following criteria are fulfilled and as probable CAPS when a combina­ tion of these criteria is present: (1) thrombosis in three or more organs/ systems; (2) development in less than a week; (3) histologic evidence of small-vessel thrombosis in at least one organ; and (4) aPL presence. Because thrombotic microangiopathy (microangiopathic hemolytic anemia and severe thrombocytopenia) is a typical finding in CAPS, the differential diagnosis includes thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, disseminated intravascular coagulation, and heparin-induced thrombocytopenia. TREATMENT Antiphospholipid Syndrome It has been increasingly appreciated that the risk of thrombotic and obstetric events is closely related to the underlying aPL profile. The latter depends on the type of autoantibodies (IgG high risk vs IgM low risk), the number of aPL antibodies (simultaneous presence of two or three classical autoantibodies vs a single antibody denotes a higher risk profile), their titer (moderate-high titer vs low), and the persistence of aPL positivity in repeated measurements. Following the first thrombotic event, APS patients should be placed on vitamin K antagonists (VKAs) for life, aiming to achieve an international normalized ratio (INR) ranging from 2.0 to 3.0 in case of an unprovoked venous thrombosis. For patients with arte­ rial thrombosis, the corresponding INR target should be 3.0–4.0 or 2.0–3.0 with or without low-dose aspirin (LDA, 75–100 mg daily), depending on the thrombotic/hemorrhagic patient profile. Administration of direct oral anticoagulants (DOACs) recently has been shown to increase the risk of arterial events, especially in patients with triple positivity or previous arterial thrombosis. A recent meta-analysis of four open-label randomized controlled trials showed that prior thrombosis type (arterial vs venous) did not affect the increased odds of arterial thrombosis associated with DOACs compared to VKAs in APS. In pregnant women with a history of obstetric APS, combination treatment with LDA and prophylactic dose of low-molecular-weight heparin (LMWH) is recommended, whereas in cases of thrombotic APS, LDA plus therapeutic LMWH dose should be administered. When recurrent obstetric complications occur despite standard treatment, increas­ ing the LMWH dose (from prophylactic to therapeutic) or adminis­ tering oral hydroxychloroquine 400 mg/d or low-dose prednisolone in the first trimester are alternative options. For asymptomatic individuals or SLE patients with a high-risk aPL profile and no evidence of a previous thrombotic event or pregnancy morbidity, prophylactic treatment with LDA is recom­ mended. In nonpregnant women with a history of APS-related obstetric complications, independently of the presence of underly­ ing SLE diagnosis, treatment with LDA seems to reduce the risk of a subsequent thrombotic event. Patients with CAPS should be treated with combination therapy including glucocorticoids, heparin, and plasma exchange or intra­ venous immunoglobulin (IVIG) together with appropriate manage­ ment of triggering events such as infections. For refractory CAPS, B-cell depletion (e.g., with rituximab) or complement inhibition (e.g., with eculizumab) therapies are alternative options. ■ ■FURTHER READING Barbhaiya M et al: 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Arthritis Rheumatol 75:1687, 2023. Knight JS et al: Antiphospholipid syndrome: Advances in diagnosis, pathogenesis, and management. BMJ 380:e069717, 2023. Tektonidou MG et al: EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 78:1296, 2019. Ankoor Shah, E. William St. Clair Rheumatoid Arthritis CHAPTER 370 INTRODUCTION Rheumatoid arthritis (RA) is a chronic inflammatory disease charac­ terized by a symmetric, erosive polyarthritis. It is the most common form of chronic inflammatory arthritis. Since persistently active RA often results in articular cartilage and bone destruction and functional disability, it is vital to diagnose and treat this disease early and aggres­ sively before damage ensues. Although predominately affecting joints, RA is a systemic disease that may lead to a variety of extraarticular manifestations, including fatigue, subcutaneous nodules, lung involve­ ment, pericarditis, peripheral neuropathy, vasculitis, and hematologic abnormalities. Rheumatoid Arthritis Insights gained over the past two decades have revolutionized the contemporary paradigms for the diagnosis and management of RA. Testing for serum antibodies to anti-citrullinated protein antibodies (ACPA) and rheumatoid factor continues to be valuable in the diagnos­ tic evaluation of patients with suspected RA, and these autoantibodies serve as biomarkers of prognostic significance. Advances in imaging modalities assist clinical decision-making by improving the detection of joint inflammation and monitoring the progression of damage. The science of RA has taken major leaps forward by illuminating new disease-related genes, environmental interactions, and the molecu­ lar components and pathways of disease pathogenesis. The relative contribution of these cellular and inflammatory mediators in disease pathogenesis has been further brought to light by the efficacy of the approved biologic and targeted synthetic disease-modifying therapies. Despite these major strides, incomplete understanding of the initiating events of RA and the factors perpetuating the chronic inflammatory response remains a barrier to finding a cure. The past 20 years have witnessed a remarkable improvement in the outcomes of RA. The crippling arthritis of years past is encountered much less frequently today. Much of this progress can be traced to the expanded therapeutic armamentarium and the renewed sense of urgency to identify patients earlier in the disease process, enabling prompt treatment intervention. This shift in treatment strategy dic­ tates a new mindset for primary care practitioners—namely, one that demands early referral of patients with inflammatory arthritis to a rheumatologist for confirmation of the diagnosis and initiation of dis­ ease-modifying therapy, since delays in starting effective treatment are associated with worse outcomes. Reaching a clinical state of low disease activity and remission is now an achievable goal for most patients. CLINICAL FEATURES The incidence of RA increases between 25 and 55 years of age, after which it plateaus until the age of 75 and then decreases. The presenting symptoms are typically related to inflammation of the joints, tendons, and bursae. Patients often complain of early morning joint stiffness lasting >1 h that eases with physical activity. The earliest involved joints are mostly the small joints of the hands and feet. The initial pattern of joint involvement may be monoarticular, oligoarticular (≤4 joints), or polyarticular (>5 joints), usually in a symmetric distribution. Some patients with inflammatory arthritis will present with too few affected joints to be classified as having RA—so-called undifferentiated inflam­ matory arthritis. Those with an undifferentiated arthritis who are most likely to be diagnosed later with RA have a higher number of tender and swollen joints, test positive for serum rheumatoid factor (RF) or ACPA, and have higher scores for physical disability. In established RA, the most frequently involved joints are the wrists and metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints (Fig. 370-1). Distal interphalangeal (DIP) joint involvement may occur in patients with RA, but it is usually due to coexistent osteoarthritis. Flexor tendon tenosynovitis is a frequent hallmark of RA and leads to decreased range of motion, reduced grip strength, PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders FIGURE 370-1  Metacarpophalangeal joint swelling and subluxation. (Reproduced with permission from RP Usatine, MA Smith, EJ Mayeaux: The Color Atlas and Synopsis of Family Medicine, 3rd ed. New York, McGraw Hill, 2019; Fig. 97.5.) and “trigger” fingers. Flexor tendon involvement may also lead to tendon rupture, most commonly the flexor pollicis longus. Progres­ sive destruction of the joints and soft tissues may result in chronic, irreversible deformities. Ulnar deviation is a common deformity of long-standing RA that is caused by subluxation of the MCP joints, with subluxation, or partial dislocation, of the proximal phalanx to the volar side of the hand. Hyperextension of the PIP joint with flexion of the DIP joint (“swan-neck deformity”), flexion of the PIP joint with hyper­ extension of the DIP joint (“boutonnière deformity”), and subluxation of the first MCP joint with hyperextension of the first interphalangeal (IP) joint (“Z-line deformity”) also may result from damage to the tendons, joint capsule, and other soft tissues. Inflammation about the ulnar styloid and tenosynovitis of the extensor carpi ulnaris may cause subluxation of the distal ulna, resulting in a “piano-key movement” of the ulnar styloid. Although metatarsophalangeal (MTP) joint involve­ ment is an early feature of disease, chronic inflammation of the ankle and midtarsal regions usually comes later and may lead to pes pla­ novalgus (“flat feet”). Large joints, including the knees and shoulders, are often affected in established disease and may remain asymptomatic for many years after onset. Atlantoaxial involvement of the cervical spine is clinically note­ worthy because of its potential to cause compressive myelopathy and neurologic dysfunction. Neurologic manifestations are rarely a present­ ing sign or symptom of atlantoaxial disease, but they may slowly evolve over time with progressive instability of C1 on C2. The prevalence of atlantoaxial subluxation has been declining in recent years and occurs now in <10% of patients. Unlike the spondyloarthritides (Chap. 374), RA rarely affects the thoracic and lumbar spine. Extraarticular manifestations may develop during the clinical course of RA in up to 40% of patients, even prior to the onset of arthritis (Fig. 370-2). Patients most likely to develop extraarticular disease have a history of cigarette smoking, have early onset of significant physi­ cal disability, and test positive for serum RF or ACPA. Subcutaneous nodules, Sjögren’s disease, interstitial lung disease (ILD), pulmonary nodules, and anemia are among the most frequently observed extraar­ ticular manifestations. Recent studies have shown a decrease in the incidence and severity of at least some extraarticular manifestations, particularly Felty’s syndrome and vasculitis. The most common systemic and extraarticular features of RA are described in more detail in the sections below. ■ ■CONSTITUTIONAL These signs and symptoms include weight loss, fever, fatigue, malaise, depression, and in the most severe cases, cachexia; they generally reflect a high degree of inflammation and may even precede the onset of joint symptoms. In general, the presence of a fever of >38.3°C (101°F) at any time during the clinical course should raise suspicion of systemic vasculitis (see below) or infection. ■ ■NODULES Subcutaneous nodules have been reported to occur in 30–40% of patients and more commonly in those with the highest levels of disease activity, who carry the disease-related shared epitope (SE) (see below), who have a positive test for serum RF, and who show radiographic evidence of joint erosions. However, more recent cohort studies sug­ gest a declining prevalence of subcutaneous nodules, perhaps related to early and more aggressive disease-modifying therapy. When palpated, the nodules are generally firm; nontender; and adherent to periosteum, tendons, or bursae; they develop in areas of the skeleton subject to repeated trauma or irritation such as the forearm, sacral prominences, and Achilles tendon. They may also occur in the lungs, pleura, peri­ cardium, and peritoneum. Nodules are typically benign, although they can be associated with infection, ulceration, and gangrene. Accelerated growth of smaller nodules may occur in up to 10% of patients taking long-term methotrexate, although the mechanisms behind this phe­ nomenon are unclear. ■ ■SJÖGREN’S SYNDROME Secondary Sjögren’s syndrome, or Sjögren’s disease (Chap. 373), is defined by the presence of either keratoconjunctivitis sicca (dry eyes) or xerostomia (dry mouth) in association with another connective tis­ sue disease, such as RA. Approximately 10% of patients with RA have secondary Sjögren’s syndrome. ■ ■PULMONARY Pleuritis, the most common pulmonary manifestation of RA, may result in pleuritic chest pain and dyspnea, as well as a finding of a pleu­ ral friction rub and radiographic evidence of a pleural effusion. Pleural effusions tend to be exudative with increased numbers of monocytes and neutrophils. ILD may also occur in patients with RA and is her­ alded by symptoms of dry cough and progressive shortness of breath. ILD can be associated with cigarette smoking and is generally found in patients with higher disease activity, although it may be diagnosed in up to 3.5% of patients prior to the onset of joint symptoms. Recent studies have shown the overall prevalence of ILD in RA to be as high as 12%. Diagnosis is readily made by high-resolution chest computed tomography (CT) scan, which shows infiltrative opacification, or ground-glass opacities, in the periphery of both lungs. Usual intersti­ tial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP) are the main histologic and radiologic patterns of ILD. UIP causes progressive scarring of the lungs that, on chest CT scan, produces hon­ eycomb changes in the periphery and lower portions of the lungs. In contrast, the most common radiographic changes in NSIP are relatively symmetric and bilateral ground-glass opacities with associated fine reticulations, volume loss, and traction bronchiectasis. In both cases, pulmonary function testing shows a restrictive pattern (e.g., reduced total lung capacity) and a reduced diffusing capacity for carbon mon­ oxide (DLCO). The presence of ILD confers a poor prognosis. The prog­ nosis of ILD in RA, however, is not quite as poor as that of idiopathic pulmonary fibrosis (e.g., usual interstitial pneumonitis) and responds better to immunosuppressive therapy (Chap. 304). Pulmonary nodules are also common in patients with RA and may be solitary or multiple. Caplan’s syndrome is a rare subset of pulmonary nodulosis character­ ized by the development of nodules and pneumoconiosis following silica exposure. Less commonly, RA may be associated with respiratory bronchiolitis and bronchiectasis. ■ ■CARDIAC The most frequent site of cardiac involvement in RA is the pericar­ dium. However, clinical manifestations of pericarditis occur in <10% of patients with RA despite pericardial involvement being detectable in nearly one-half of cases by echocardiogram or at autopsy. Up to 20% of patients with RA may have asymptomatic pericardial effusions on echocardiography. Cardiomyopathy, another clinically important manifestation of RA, may result from necrotizing or granulomatous myocarditis, coronary artery disease, or diastolic dysfunction. This Ocular: Keratoconjunctivitis sicca, episcleritis, scleritis Neurologic: Cervical myelopathy Hematologic: Anemia of chronic disease, neutropenia, splenomegaly, Felty’s syndrome, large granular lymphocyte leukemia, lymphoma GI: Vasculitis Skeletal: Osteoporosis FIGURE 370-2  Extraarticular manifestations of rheumatoid arthritis. involvement, too, may be subclinical and only identified by echocar­ diography or cardiac magnetic resonance imaging (MRI). Rarely, the heart muscle may contain rheumatoid nodules or be infiltrated with amyloid. ■ ■VASCULITIS Rheumatoid vasculitis (Chap. 375) typically occurs in patients with long-standing disease, a positive test for serum RF or ACPA, and hypo­ complementemia. The overall incidence has decreased significantly in the past decade to <1% of patients. The cutaneous signs vary and include petechiae, purpura, digital infarcts, gangrene, livedo reticularis, and in severe cases large, painful lower extremity ulcerations. Vascu­ litic ulcers, which may be difficult to distinguish from those caused by venous insufficiency, may be treated successfully with immuno­ suppressive agents including cytotoxic treatment and skin grafting in severe cases. Sensorimotor polyneuropathies, such as mononeuritis multiplex, may occur in association with systemic rheumatoid vasculi­ tis; they usually present with new onset of numbness, tingling, or focal muscle weakness. ■ ■HEMATOLOGIC A normochromic, normocytic anemia often develops in patients with RA and is the most common hematologic abnormality. The degree of anemia parallels the degree of inflammation, correlating with the levels of serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Platelet counts may also be elevated in RA as an acute-phase reactant; immune-mediated thrombocytopenia is rare. CHAPTER 370 Oral: Xerostomia, periodontitis Pulmonary: Pleural effusions, pulmonary nodules, interstitial lung disease, pulmonary vasculitis, organizing pneumonia Rheumatoid Arthritis Cardiac: Pericarditis, ischemic heart disease, myocarditis, cardiomyopathy, arrhythmia, mitral regurgitation Renal: Membranous nephropathy, secondary amyloidosis Endocrine: Hypoandrogenism Skin: Rheumatoid nodules, purpura, pyoderma gangrenosum Felty’s syndrome is defined by the clinical triad of neutropenia, sple­ nomegaly, and nodular RA and is seen in <1% of patients, although its incidence appears to be declining in the face of more aggressive treatment of the joint disease. It typically occurs in the late stages of severe RA and is more common in whites than other racial groups. T-cell large granular lymphocyte leukemia (T-LGL) may have a similar clinical presentation and often occurs in association with RA. T-LGL is characterized by a chronic, indolent clonal growth of LGL cells, lead­ ing to neutropenia and splenomegaly. As opposed to Felty’s syndrome, T-LGL may develop early in the course of RA. Leukopenia apart from these disorders is uncommon and most often a side effect of drug therapy. ■ ■LYMPHOMA Large cohort studies have shown a two- to fourfold increased risk of lymphoma in RA patients compared with the general population. The most common histopathologic type of lymphoma is a diffuse large B-cell lymphoma. The risk of developing lymphoma increases if the patient has high levels of disease activity or Felty’s syndrome. ■ ■ASSOCIATED CONDITIONS In addition to extraarticular manifestations, several conditions asso­ ciated with RA contribute to disease morbidity and mortality rates. They are worthy of mention because they affect chronic disease management. Cardiovascular Disease  The most common cause of death in patients with RA is cardiovascular disease. The incidence of coronary artery disease and carotid atherosclerosis is higher in RA patients than in the general population even when controlling for traditional cardiac risk factors, such as hypertension, obesity, hypercholesterol­ emia, diabetes, and cigarette smoking. Furthermore, congestive heart failure (including both systolic and diastolic dysfunction) occurs at an approximately twofold higher rate in RA than in the general popula­ tion. The presence of elevated serum inflammatory markers appears to confer an increased risk of cardiovascular disease. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Osteoporosis  Osteoporosis is more common in patients with RA than an age- and sex-matched population, with an incidence rate of nearly double that of the healthy population and a prevalence of approximately one-third in postmenopausal women with RA. There is also an increased risk of fragility fracture, with a greater risk among women. The inflammatory milieu of the joint promotes generalized bone loss by activating osteoclasts. Both trabecular and cortical bone are affected by the inflammatory response, with cortical sites more susceptible to bone loss. Chronic use of glucocorticoids and disabilityrelated immobility also contribute to osteoporosis. Hip fractures are more likely to occur in patients with RA and are significant predictors of increased disability and mortality rate in this disease. EPIDEMIOLOGY RA affects ~0.5–1% of the adult population worldwide, although the majority of epidemiologic studies have been done in Western coun­ tries. There is evidence that the overall incidence of RA has been decreasing in recent decades, whereas the prevalence has remained the same because individuals with RA are living longer. The incidence and prevalence of RA vary based on geographic location, both globally and among certain ethnic groups within a country (Fig. 370-3). For example, the indigenous Yakima, Pima, and Chippewa tribes of North America have reported prevalence rates in some studies of nearly 7%. In contrast, many population studies from Africa and Asia show lower prevalence rates for RA in the range of 0.2–0.4%. Like many other autoimmune diseases, RA occurs more commonly in females than in males, with a 2–3:1 ratio. Interestingly, studies of RA from some of the Latin American and African countries show an even greater predominance of disease in females compared to males, with ratios of 6–8:1. Given this preponderance of females, various theories have been proposed to explain the possible role of estrogen in disease pathogenesis. Broadly speaking, most of the theories center on the role of estrogens and androgens in enhancing and suppressing the immune European ancestry: HLA-DRB1: *0401 *0404 *0301 *0101 PTPN22: European US: 0.7–1.3% STAT4: North American TNFAIP3: North American TRAFI/CF: North American CTLA4: European Asian ancestry: HLA-DRB1: Brazil: 0.4–1.4% *0401 (East Asian) *0405 *0901 (Japanese, Malaysian, Korean) PADI4 CD244 Other: CD40 FIGURE 370-3  Global prevalence rates of rheumatoid arthritis (RA) with genetic associations. Listed are the major genetic alleles associated with RA. Although human leukocyte antigen (HLA)-DRB1 mutations are found globally, some alleles have been associated with RA in only certain ethnic groups. response, respectively. However, estrogens have both stimulatory and inhibitory effects on the immune system, and their role, if any, on the development of RA is unknown. GENETIC CONSIDERATIONS It has been recognized for >30 years that genetic factors contrib­ ute to the occurrence of RA as well as to its severity. The likeli­ hood that a first-degree relative of a patient will share the diagnosis of RA is 2–10 times greater than in the general population. There remains, however, some uncertainty in the extent to which genetics plays a role in the causative mechanisms of RA. Heritability estimates range from 40 to 60%, although this may be higher in ACPApositive patients compared to those without ACPA. The estimate of genetic influence has varied across studies, probably due to gene– environment interactions. The alleles known to confer the greatest risk of RA are located within the major histocompatibility complex (MHC) and, in particular, those encoding the MHC class II molecules. MHC class II molecules are typi­ cally expressed on antigen-presenting cells and are comprised of α and β chains. Most, but probably not all, of this risk is associated with allelic variation in the HLA-DRB1 gene, which encodes the MHC II β-chain molecule. The disease-associated HLA-DRB1 alleles share an amino acid sequence at positions 70–74 in the third hypervariable regions of the HLA-DR β-chain, termed the shared epitope (SE). These amino acids are located in the antigen-binding grove within the hypervariable regions of the HLA-DRβ1 molecule. These hypervariable regions are important not only for determining antigen recognition but also for binding of the MHC-peptide complex to the T-cell receptor (TCR). Peptides derived from posttranslationally modified proteins (via citrullination, acetylation, or carbamylation, for example) may bind with greater avidity to the SE, providing a potential explanation for increased disease risk at a molecular level. The risk of RA is four times higher in persons carrying a single SE allele and eight times higher in those carrying two alleles compared to SE-negative individuals. Carriership of the SE alleles is associated with production of ACPAs and worse disease outcomes. Some HLA-DRB1 alleles bestow a high risk of disease (∗0401), whereas others confer a more moderate risk (∗0101, 0404, 1001, and 0901). Over 90% of patients with RA express at least one of these variants. Interestingly, HLA-DRB1∗1301 and to a lesser extent HLA-DRB1∗1302 confer protection from ACPA-positive RA. Additionally, there is geographic variation in disease susceptibility and the identity of the HLA-DRB1 risk alleles. In Greece, for example, Norway: 0.4% Bulgaria: 0.2–0.6% UK: 0.8–1.1% Iraq: 0.4–1.5% India: 0.1–0.4% Japan: 0.2–0.3% Spain: 0.2–0.8% Greece: 0.3–1% Jamaica: 1.9–2.2% Hong Kong: 0.1–0.5% Saudi Arabia: 0.1–0.2% Liberia: 2–3% Java: 0.1–0.2% Lesotho: 1.7–4.5% South Africa: 2.5–3.6% where RA tends to be milder than in western European countries, RA susceptibility has been associated with the ∗0101 SE allele. By com­ parison, the ∗0401 or ∗0404 alleles are found in ~50–70% of northern Europeans and are the predominant risk alleles in this group. The most common disease susceptibility SE alleles in Asians, namely the Japanese, Koreans, and Chinese, are ∗0405 and ∗0901. Lastly, disease susceptibility of Native American populations such as the Pima and Tlingit Indians, where the prevalence of RA can be as high as 7%, is associated with the SE allele ∗1042. The risk of RA conferred by these SE alleles is less in African and Hispanic Americans than in individuals of European ancestry. Genome-wide association studies (GWAS) have made possible the identification of several non-MHC-related genes that contribute to RA susceptibility. GWASs are based on the detection of single nucleotide polymorphisms (SNPs), which allow for examination of the genetic architecture of complex diseases such as RA. Overall, several themes have emerged from GWAS in RA. First, among the >100 non-MHC loci identified as risk alleles for RA, they individually have only a modest effect on risk; they also contribute to the risk for developing other autoimmune diseases, such as type 1 diabetes mellitus, systemic lupus erythematosus, and multiple sclerosis. Second, although most of the non-HLA associations are described in patients with ACPApositive disease, there are several risk loci that are unique to ACPAnegative disease. Third, risk alleles vary among ethnic groups. And fourth, the risk loci mostly reside in genes encoding proteins involved in the regulation of the immune response. However, the risk alleles identified by GWAS only account at present for ~5% of the genetic risk, suggesting that rare variants or other classes of DNA variants, such as variants in copy number, may be yet found that significantly contribute to the overall risk model. Among the best examples of the non-MHC genes contributing to the risk of RA is the gene encoding protein tyrosine phosphatase nonreceptor 22 (PTPN22). This gene varies in frequency among patients from different parts of Europe (e.g., 3–10%) but is absent in patients of East Asian ancestry. PTPN22 encodes lymphoid tyrosine phosphatase, a protein that regulates T- and B-cell function. Inheritance of the risk allele for PTPN22 produces a gain-of-function in the protein that is hypothesized to result in the abnormal thymic selection of autoreactive T and B cells and appears to be associated exclusively with ACPApositive disease. The peptidyl arginine deiminase type IV (PADI4) gene is another risk allele that encodes an enzyme involved in the conversion of arginine to citrulline and is postulated to play a role in the develop­ ment of antibodies to citrullinated antigens. A polymorphism in PADI4 has been associated with a twofold increase in the risk of RA, primarily in those of East Asian descent. Recently, polymorphisms in apolipo­ protein M (APOM) in an East Asian population were found confer an increased risk for RA as well as risk for dyslipidemia, independent of RA disease activity. Epigenetics is the study of heritable traits that affect gene expres­ sion but do not modify DNA sequence. Epigenetic mechanisms are theoretically involved in three important aspects of RA: contribution to disease etiology, perpetuation of chronic inflammatory responses, and disease severity. The best-studied epigenetic mechanisms are those regulating posttranslational histone modifications and DNA methyla­ tion. DNA methylation patterns have been shown to differ between RA patients and healthy controls, including monozygotic twins, as well as from patients with osteoarthritis. Epigenetics may also offer a mecha­ nistic explanation for how cigarette smoking confers an increased risk for ACPA-positive RA (see below) as those patients with the SE have higher levels of DNA methylation compared to nonsmokers. MicroR­ NAs, which are noncoding RNAs that function as posttranscriptional regulators of gene expression, represent an additional epigenetic mechanism that may potentially influence cellular responses. ENVIRONMENTAL FACTORS In addition to genetic predisposition, a host of environmental factors have been implicated in the pathogenesis of RA. The most reproducible of these environmental links is cigarette smoking. Numerous cohort and case-control studies have demonstrated that smoking confers a relative risk for developing RA of 1.5–3.5 times. Smoking-related risk interacts in a synergistic manner with MHC risk alleles. The classic SE alleles alone increase the likelihood of developing RA by four- to sixfold; however, this risk increases to 20- to 40-fold when combined with smoking. In particular, women who smoke cigarettes have a nearly 2.5 times greater risk of RA, a risk that persists even 15 years after smoking cessation. A twin who smokes will have a significantly higher risk for RA than their monozygotic co-twin, theoretically with the same genetic risk, who does not smoke. Interestingly, the risk from smoking is almost exclusively related to RF and ACPA-positive disease. However, it has not been shown that smoking cessation, while having many health benefits, reduces the severity or extent of joint inflammation. Inhalant-related occupations and silica inhalants also may increase RA risk. These observations have led to the theory that subclinical lung disease may play a critical early role in the initial devel­ opment of autoreactive immune cells and account for the occurrence of autoantibodies more than a decade prior to the clinical development of joint disease. CHAPTER 370 Rheumatoid Arthritis Researchers began to aggressively seek an infectious etiology for RA after the discovery in 1931 that sera from patients with this dis­ ease could agglutinate strains of streptococci. Certain viruses such as Epstein-Barr virus (EBV) have garnered the most interest over the past 30 years given their ubiquity, ability to persist for many years in the host, and frequent association with arthritic complaints. For example, titers of IgG antibodies against EBV antigens in the peripheral blood and saliva are significantly higher in patients with RA than in the general population. EBV DNA has also been found in synovial fluid and synovial cells of RA patients. Because the evidence for these links is largely circumstantial, it has not been possible to directly implicate infection as a causative factor in RA. An attractive hypothesis raised by newer studies is that microbial dysbiosis of the oral or gut microbiome may predispose to the devel­ opment of RA. Recent work suggests that periodontitis in the oral cavity may play a role in disease mechanisms. Multiple studies provide evidence for a link between ACPA-positive RA and cigarette smoking, periodontal disease, and the oral microbiome, specifically Porphyromo­ nas gingivalis. It has been hypothesized that the immune response to P. gingivalis may trigger the development of RA and the bacterial enzyme peptidyl arginine deiminase (PAD) induces ACPA by catalyzing the citrullination of arginine residues on the stimulating autoantigens. Interestingly, P. gingivalis is the only oral bacterial species known to harbor this enzyme. Some studies have shown a relationship between the presence of circulating antibodies to P. gingivalis and RA, as well as with first-degree relatives at risk for this disease. However, it remains unproven whether the observed dysbiosis in the oral cavity precedes the development of disease. There are also limited data suggesting a role for the gut microbiome in the etiology of RA. Some studies have found that the gut microbiome is different in patients with early RA compared with controls. In par­ ticular, Prevotella copri was reported to be enriched in early untreated RA as well as in an “at-risk” population. On the other hand, a common dysbiotic signature does not seem to predominate in patients with RA, and evidence is lacking for a direct immune-modulating effect. PATHOLOGY RA affects the synovial lining tissue of the diarthrodial joints and the underlying cartilage and bone. The synovial membrane, which covers most articular surfaces, tendon sheaths, and bursae, normally is a thin layer of connective tissue. In joints, it faces the bone and cartilage, bridging the opposing bony surfaces and inserting at periosteal regions close to the articular cartilage. It consists primarily of two cell types— type A synoviocytes (macrophage-derived) and type B synoviocytes (fibroblast-derived). The synovial fibroblasts are the most abundant and produce the structural components of joints, including collagen, fibronectin, and laminin, as well as other extracellular constituents of the synovial matrix. The sublining layer consists of blood vessels and a sparse population of mononuclear cells within a loose network of connective tissue. Synovial fluid, an ultrafiltrate of blood, diffuses through the subsynovial lining tissue across the synovial membrane and into the joint cavity. Its main constituents are hyaluronan and lubricin. Hyaluronan is a glycosaminoglycan that contributes to the viscous nature of synovial fluid, which, along with lubricin, lubricates the surface of the articular cartilage. The pathologic hallmarks of RA are synovial inflammation and proliferation, focal bone erosions, and thinning of articular cartilage. Chronic inflammation leads to synovial lining hyperplasia and the formation of pannus, a thickened cellular membrane consisting of multiple layers of fibroblast-like synoviocytes and granulation-reactive fibrovascular tissue that has a propensity for invading underlying car­ tilage and bone. The inflammatory infiltrate is made up of no less than six cell types: T cells, B cells, plasma cells, dendritic cells, mast cells, and, to a lesser extent, granulocytes. The T cells compose 30–50% of the infiltrate, with the other cells accounting for the remainder. The topographical organization of these cells is complex and may vary among individuals with RA. Most often, the lymphocytes are diffusely organized among the tissue resident cells; however, in some cases, the B cells, T cells, and dendritic cells may form higher levels of organization, such as lymphoid follicles and germinal center–like structures. Growth factors secreted by synovial fibroblasts and macrophages promote the formation of new blood vessels in the synovial sublining that supply the increasing demands for oxygenation and nutrition required by the infiltrating leukocytes and expanding synovial tissue. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders The structural damage to the mineralized cartilage and subchondral bone is mediated by the osteoclast. Osteoclasts are multinucleated giant cells that appear at the pannus-bone interface where they eventually form resorption lacunae. These lesions typically localize where the synovial membrane inserts into the periosteal surface at the edges of bone close to the rim of articular cartilage and at the attachment sites of ligaments and tendon sheaths. This process most likely explains why bone erosions usually develop at the radial sites of the MCP joints jux­ taposed to the insertion sites of the tendons, collateral ligaments, and synovial membrane. Periarticular osteopenia, another form of bone loss, occurs in joints with active inflammation. It is associated with substantial thinning of the bony trabeculae along the metaphyses of bones from inflammation of the bone marrow cavity. These lesions can be visualized on MRI scans, where they appear as signal alterations in the bone marrow adjacent to inflamed joints. Their signal characteris­ tics show they are water-rich with a low-fat content and are consistent with highly vascularized inflammatory tissue. These bone marrow lesions are often the forerunner of bone erosions. The cortical bone layer that separates the bone marrow from the invading pannus is rela­ tively thin and susceptible to penetration by the inflamed synovium. The bone marrow lesions visualized on MRI scans are associated with an endosteal bone response characterized by the accumulation of osteoblasts and deposition of osteoid. Finally, generalized osteoporosis, which results in the thinning of trabecular bone throughout the body, is a third form of bone loss found in patients with RA and can lead to fragility fractures. Articular cartilage is an avascular tissue comprised of a specialized matrix of collagens, proteoglycans, and other proteins. It is organized in four distinct regions (superficial, middle, deep, and calcified carti­ lage zones)—chondrocytes constitute the unique cellular component in these layers. Originally, cartilage was considered to be an inert tis­ sue, but it is now known to be a highly responsive tissue that reacts to inflammatory mediators and mechanical factors, which, in turn, alter the balance between cartilage anabolism and catabolism. In RA, the initial areas of cartilage degradation are juxtaposed to the synovial pannus. The cartilage matrix is characterized by a generalized loss of proteoglycan, most evident in the superficial zones adjacent to the synovial fluid. Degradation of cartilage may also take place in the peri­ chondrocytic zone and in regions adjacent to the subchondral bone. PATHOGENESIS The pathogenic mechanisms of synovial inflammation are likely the result of a complex interplay of genetic, environmental, and immuno­ logic factors that cause immune system dysregulation and a breakdown in self-tolerance (Fig. 370-4). Precisely what triggers these initiating events and what genetic and environmental factors disrupt the immune system remains a mystery. However, a detailed molecular picture is emerging of the mechanisms underlying the chronic inflammatory response and the resulting destruction of the articular cartilage and bone. In RA, the preclinical stage appears to be characterized by a break­ down in self-tolerance. This idea is supported by the finding that auto­ antibodies, such as RF and ACPA, may be found in sera from patients many years before onset of clinical disease. However, the antigenic tar­ gets of ACPA and RF are not restricted to the joint. ACPAs are directed against deaminated peptides, which result from posttranslational mod­ ification by the enzyme PADI4. They recognize citrulline-containing regions of several different matrix proteins, including filaggrin, keratin, fibrinogen, and vimentin, and are present at higher levels in the joint fluid compared to the serum. Antibodies binding to carbamylated pep­ tides and mutant citrullinated vimentin, as well as the 14-3-3 family of proteins, have also been detected in a minority of RA patients. In theory, environmental triggers may synergize with other factors to bring about inflammation in RA. People who smoke display higher citrullination of proteins in bronchoalveolar fluid than those who do not smoke. Thus, it has been speculated that long-term exposure to tobacco smoke might induce citrullination of cellular proteins via increased PADI expression in the lung and generate a neoepitope capable of inducing self-reactivity, which in turns, leads to formation of immune complexes that trigger joint inflammation and joint damage. Microbiota may also be involved in the initiating events of RA. The immune system is alerted to the presence of microbial infections when pathogen-associated molecular patterns (PAMPs) on their surface bind to Toll-like receptors (TLRs) on host cells. There are 10 TLRs in humans that recognize a variety of microbial products, including bacterial cell-surface lipopolysaccharides and heat-shock proteins (TLR4), lipoproteins (TLR2), double-strand RNA viruses (TLR3), and unmethylated CpG DNA from bacteria (TLR9). TLR2, 3, and 4 are abundantly expressed by synovial fibroblasts in early RA and, when bound by their ligands, upregulate the cell’s production of proinflam­ matory cytokines. Although TLR ligands may theoretically amplify inflammatory pathways in RA, their specific role in disease pathogen­ esis remains uncertain. The pathogenesis of RA is built upon the concept that self-reactive T cells drive the chronic inflammatory response. In theory, self-reactive T cells might arise in RA from abnormal central (thymic) selection or intrinsic defects lowering the threshold in the periphery for T-cell activation. Either mechanism might result in abnormal expansion of a self-reactive T-cell repertoire and a breakdown in T-cell tolerance. The support for these ideas comes mainly from studies of arthritis in mouse models. It has not been shown that patients with RA have abnormal thymic selection of T cells or defective apoptotic pathways regulating cell death. At least some antigen stimulation inside the joint seems likely, owing to the fact that T cells in the synovium express a cell-surface phenotype indicating prior antigen exposure and show evidence of clonal expansion. There is substantial evidence of a role for CD4+ T cells in the patho­ genesis of RA. First, the co-receptor CD4 on the surface of T cells binds to invariant sites on MHC class II molecules, stabilizing the MHCpeptide–T-cell receptor complex during T-cell activation. Because the SE on MHC class II molecules is a risk factor for RA, it follows that CD4+ T-cell activation plays a role in the pathogenesis of this disease. Second, CD4+ memory T cells are enriched in the synovial tissue from patients with RA and therefore are implicated through “guilt by association.” Third, CD4+ T cells have been shown to be important in the initiation of arthritis in animal models. Fourth, some, but not all, T cell–directed therapies have shown clinical efficacy in this disease. Taken together, these lines of evidence suggest that CD4+ T cells play an important role in orchestrating the chronic inflammatory response in RA. However, other cell types, such as CD8+ T cells, natural killer (NK) cells, and B cells are present in synovial tissue and may also influ­ ence pathogenic responses. In the rheumatoid joint, by mechanisms of cell-cell contact and release of soluble mediators, activated T cells stimulate macro­ phages and fibroblast-like synoviocytes to generate proinflammatory Genetics Environment TLR APC MHC II TCR TH1 IFN-γ, TNF-α lymphotoxin-β TH CD40L CD40 IFN-γ, IL17 IL15, GM-CSF, TNF-α B M RF, Anti-CCP Ab Pre-OB OB FIGURE 370-4  Pathophysiologic mechanisms of inflammation and joint destruction. Genetic predisposition along with environmental factors may trigger the development of rheumatoid arthritis (RA), with subsequent synovial T-cell activation. CD4+ T cells become activated by antigen-presenting cells (APCs) through interactions between the T-cell receptor and class II MHC-peptide antigen (signal 1) with co-stimulation through the CD28-CD80/86 pathway, as well as other pathways (signal 2). In theory, ligands binding Toll-like receptors (TLRs) may further stimulate activation of APCs inside the joint. Synovial CD4+ T cells differentiate into TH1 and TH17 cells, each with their distinctive cytokine profile. CD4+ TH cells in turn activate B cells, some of which are destined to differentiate into autoantibody-producing plasma cells. Immune complexes, possibly comprised of rheumatoid factors (RFs) and anti–cyclic citrullinated peptides (CCP) antibodies, may form inside the joint, activating the complement pathway and amplifying inflammation. T effector cells stimulate synovial macrophages (M) and fibroblasts (SF) to secrete proinflammatory mediators, among which is tumor necrosis factor α (TNF-α). TNF-α upregulates adhesion molecules on endothelial cells, promoting leukocyte influx into the joint. It also stimulates the production of other inflammatory mediators, such as interleukin 1 (IL-1), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). TNF-α has a critically important function in regulating the balance between bone destruction and formation. It upregulates the expression of dickkopf-1 (DKK-1), which can then internalize Wnt receptors on osteoblast precursors. Wnt is a soluble mediator that promotes osteoblastogenesis and bone formation. In RA, bone formation is inhibited through the Wnt pathway, presumably due to the action of elevated levels of DKK-1. In addition to inhibiting bone formation, TNF-α stimulates osteoclastogenesis. However, it is not sufficient by itself to induce the differentiation of osteoclast precursors (Pre-OC) into activated osteoclasts capable of eroding bone. Osteoclast differentiation requires the presence of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB (RANK) ligand (RANKL), which binds to RANK on the surface of Pre-OC. Inside the joint, RANKL is mainly derived from stromal cells, synovial fibroblasts, and T cells. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL, thereby inhibiting osteoclastogenesis and bone loss. FGF, fibroblast growth factor; IFN, interferon; MMP, matrix metalloproteinase; TGF, transforming growth factor. CHAPTER 370 Rheumatoid Arthritis CD80 CD28 T TH17 IL-17A, IL-17F, TNF-α, IL-6, GM-CSF Teff Teff SF IL-6, IL-8 FGF, TGF-β IL-1, IL-6, IL-18 TNF-` MMP + Wnt TH + St Dkk-1 OPG RANK-L + RANK OC Pre-OC Cathepsin K mediators and proteases that drive the synovial inflammatory response and destroy the cartilage and bone. CD4+ T-cell activation is depen­ dent on two signals: (1) T-cell receptor binding to peptide-MHC on antigen-presenting cells; and (2) CD28 binding to CD80/86 on antigen-presenting cells. This interaction then leads to downstream signals that differentiate CD4+ T cells into effector and memory cell populations, as well as activate CD8+ T cells. Certain subsets of CD4+ T cells, called T helper cells, enable B cells to differentiate into antibody-secreting cells. An earlier T cell–centric model for the patho­ genesis of RA was based on a TH1-driven paradigm, which came from studies indicating that CD4+ T helper (TH) cells differentiated into TH1 and TH2 subsets, each with their distinctive cytokine profiles. TH1 cells were found to mainly produce interferon γ (IFN-γ), lymphotoxin β, and tumor necrosis factor (TNF)-α, whereas TH2 cells predominately secreted interleukin (IL)-4, IL-5, IL-6, IL-10, and IL-13. In humans, naïve T cells may also be induced to differentiate into TH17 cells by exposure to transforming growth factor β (TGF-β), IL-1, IL-6, and IL-23. Upon activation, TH17 cells secrete a variety of proinflamma­ tory mediators such as IL-17, IL-21, IL-22, TNF-α, IL-26, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Sub­ stantial evidence now exists from studies in both animal models and humans that IL-17 plays an important role not only in promoting joint inflammation but also in destroying cartilage and subchondral bone. However, therapeutic antibodies that interfere with the IL-17/IL-17 receptor pathway were not particularly effective in clinical trials for reducing joint inflammation in RA. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders The immune system has evolved mechanisms to counterbalance the potentially harmful immune-mediated inflammatory responses provoked by infectious agents and other triggers. Among these nega­ tive regulators are regulatory T (Treg) cells, which are produced in the thymus and induced in the periphery to suppress immune-mediated inflammation. They are characterized by the surface expression of CD25 and the expression of the transcription factor forkhead box P3 (FOXP3). Tregs orchestrate dominant tolerance through contact with other immune cells and secretion of inhibitory cytokines, such as TGF-β, IL-10, and IL-35. They are heterogeneous and capable of suppressing distinct classes (TH1, TH2, TH17) of the immune response, although data supporting their role in suppressing inflammation in RA are inconclusive. Cytokines, chemokines, antibodies, and endogenous danger sig­ nals bind to receptors on the surface of immune cells and stimulate a cascade of intracellular signaling events that can amplify the inflam­ matory response. Examples of signaling molecules in these critical inflammatory pathways include Janus kinase (JAK)/signal transducers and activators of transcription (STAT), spleen tyrosine kinase (Syk), mitogen-activated protein kinases (MAPKs), and nuclear factor-κB (NF-κB). These pathways exhibit significant crosstalk and are found in many cell types. Some signal transducers, such as the JAKs, are expressed in hematopoietic cells and play an important role in the inflammatory response in RA. Activated, autoreactive B cells are also important players in the chronic inflammatory process. B cells give rise to plasma cells, which, in turn, produce antibodies, including RF and ACPA. RFs may form large immune complexes inside the joint that contribute to the patho­ genic process by fixing complement and promoting the release of pro­ inflammatory cytokines and chemokines. In mouse models of arthritis, RF-containing immune complexes and ACPA-containing immune complexes synergize with other mechanisms to exacerbate the synovial inflammatory response. RA is often considered to be a macrophage-driven disease because this cell type is the predominant source of proinflammatory cyto­ kines inside the joint. Key proinflammatory cytokines released by macrophage-like synoviocytes include TNF-α, IL-1, IL-6, IL-12, IL-15, IL-18, and IL-23. Synovial fibroblasts, the other major cell type in this microenvironment, produce the cytokines IL-1 and IL-6 as well as TNF-α. TNF-α is a pivotal cytokine in the pathobiology of synovial inflammation and has many proinflammatory effects. It upregulates adhesion molecules on endothelial cells, promoting the influx of leukocytes into the synovial microenvironment; activates synovial fibroblasts; stimulates angiogenesis; promotes pain receptor sensitiz­ ing pathways; and drives osteoclastogenesis. Fibroblasts secrete matrix metalloproteinases (MMPs) as well as other proteases that are chiefly responsible for the breakdown of articular cartilage; they also promote inflammation and synovial proliferation by secreting cytokines such as IL-6, IL-1, IL-18, and GM-CSF, chemokines, and vascular endothelial growth factor. Recent studies of synovial tissue samples from patients with RA have combined histology and single-cell RNA expression data to identify distinct cell populations that drive joint inflammation. These studies reveal that synovial tissue samples can be distinguished among patients with RA by the relative abundance of myeloid cells, T cells, B cells, synovial fibroblasts, and endothelial cells and hence can be divided into different subsets. Thus far, these data highlight the importance of IFN-γ-secreting granzyme K+ CD8+ T cells, peripheral helper CD4+ T cells, activated sublining fibroblasts, and proinflammatory mono­ cytes as key mediators of joint inflammation. In these studies, most of the synovial tissue samples were found to be populated by T cells, fibroblasts, and myeloid cells and had cellular phenotypes classified as predominately myeloid, T and B cell, and T cell and myeloid, while oth­ ers had a paucity of immune cells and were dominated by endothelial cells and fibroblasts. Further research along these lines will enrich our understanding of the active immune pathways in RA and may help to determine in the future if knowledge of these cellular phenotypes can be used to guide a personalized treatment approach. Osteoclast activation at the site of the pannus is closely tied to the presence of focal bone erosion. Receptor activator of nuclear factor-κB ligand (RANKL) is expressed by stromal cells, synovial fibroblasts, and T cells. Upon binding to its receptor RANK on osteoclast progenitors, RANKL stimulates osteoclast differentiation and bone resorption. RANKL activity is regulated by osteoprotegerin (OPG), a decoy recep­ tor of RANKL that blocks osteoclast formation. Monocytic cells in the synovium serve as the precursors of osteoclasts and, when exposed to macrophage colony-stimulating factor (M-CSF) and RANKL, fuse to form polykaryons termed preosteoclasts. These precursor cells undergo further differentiation into osteoclasts with a characteristic ruffled membrane. Cytokines such as TNF-α, IL-1, IL-6, and IL-17 can pro­ mote osteoclastogenesis by increasing the expression of RANKL inside the joint. Osteoclasts also secrete cathepsin K, a cysteine protease that degrades the bone matrix by cleaving collagen and thus contributes to generalized bone loss and osteoporosis. Increased bone loss is only part of the story in RA, as decreased bone formation plays a crucial role in bone remodeling at sites of inflam­ mation. Recent evidence shows that inflammation suppresses bone formation. TNF-α plays a key role in actively suppressing bone forma­ tion by enhancing the expression of dickkopf-1 (DKK-1). DKK-1 is an important inhibitor of the Wnt pathway, which acts to promote osteo­ blast differentiation and bone formation. The Wnt system is a family of soluble glycoproteins that binds to cell-surface receptors known as frizzled (fz) and low-density lipoprotein (LDL) receptor–related proteins (LRPs) and promotes cell growth. In animal models, increased levels of DKK-1 are associated with decreased bone formation, whereas inhibition of DKK-1 protects against structural damage in the joint. Wnt proteins also induce the formation of OPG and thereby shut down bone resorption, emphasizing their key role in tightly regulating the balance between bone resorption and formation. DIAGNOSIS The clinical diagnosis of RA is largely made by recognizing the signs and symptoms of a chronic inflammatory arthritis and the typical pattern of joint involvement, with laboratory and radiographic results providing important corroborating information. In 2010, a collab­ orative effort between the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) revised the 1987 ACR classification criteria for RA in an effort to improve early diagnosis with the goal of identifying patients who would benefit from early introduction of disease-modifying therapy (Table 370-1). The items in the newly revised criteria yield a score of 0–10, with a score of ≥6 fulfilling the requirements for definite RA. The new classification TABLE 370-1  Classification Criteria for Rheumatoid Arthritis     SCORE Joint involvement 1 large joint (shoulder, elbow, hip, knee, ankle) 2–10 large joints 1–3 small joints (MCP, PIP, thumb IP, MTP, wrists) 4–10 small joints >10 joints (at least 1 small joint) Serology Negative RF and negative ACPA Low-positive RF or low-positive anti-CCP antibodies (≤3 times ULN) High-positive RF or high-positive anti-CCP antibodies (>3 times ULN) Acute-phase reactants Normal CRP and normal ESR Abnormal CRP or abnormal ESR Duration of symptoms <6 weeks ≥6 weeks Note: These criteria are aimed at classification of newly presenting patients who have at least one joint with definite clinical synovitis that is not better explained by another disease. A score of ≥6 fulfills requirements for definite RA. Abbreviations: ACPA, anti-citrullinated peptide antibodies; CCP, cyclic citrullinated peptides; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IP, interphalangeal joint; MCP, metacarpophalangeal joint; MTP, metatarsophalangeal joint; PIP, proximal interphalangeal joint; RF, rheumatoid factor; ULN, upper limit of normal. Source: Reproduced with permission from D Aletaha et al: 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62:2569, 2010. criteria differ in several ways from the older criteria sets. Previous classification schemes required symptoms to be present for >6 weeks. There are several conditions, including virus-related syndromes, that may cause a polyarthritis mimicking RA and be associated with tran­ sient production of RF. Such conditions usually last only 2–3 weeks. The 2010 criteria, however, do not mandate symptoms be present for >6 weeks. They also include as an item a positive test for serum ACPA, which carries greater specificity for the diagnosis of RA than a positive test for RF. About three-fourths of patients with the clini­ cal and radiographic features of RA test positive for RF and/or ACPA (seropositive), while the remaining one-fourth of patients with RA test negative for RF and/or ACPA (seronegative). The presence of rheuma­ toid nodules or radiographic joint damage as items were not included as they occur only rarely in early RA. It is important to emphasize that the 2010 ACR-EULAR criteria are “classification criteria” as opposed to “diagnostic criteria” and serve to distinguish patients at the onset of disease who have a high likelihood of evolution to chronic disease with persistent synovitis and joint damage. The presence of radiographic joint erosions or subcutaneous nodules may inform the diagnosis in the later stages of the disease. The differential diagnosis for RA includes all types of acute and chronic inflammatory arthritides, many of which may be differentiated from RA based on the clinical course, pattern of joint involvement, the presence of disease in other organ systems, and ancillary laboratory studies. Patients with primary Sjögren’s syndrome whose predominate clinical manifestations are dry eyes and dry mouth often also have symptoms of polyarthralgia and may show a mild inflammatory syno­ vitis similar to RA. Moreover, 50% of patients with primary Sjögren’s syndrome test positive for RF and, therefore, may be confused with early RA. However, most patients with primary Sjögren’s syndrome test positive for ANA and approximately two-thirds have detectable anti-Ro/SSA antibodies. Spondyloarthropathies, such as psoriatic arthritis or enteropathy-associated arthritis, may present similarly to RA and may be distinguished by the presence of sacroiliitis, other enthesopathic features, and the presence of psoriasis or inflammatory bowel disease, respectively. In elderly patients, seronegative RA may be difficult at times to distinguish from polymyalgia rheumatica (PMR), a chronic inflammatory condition of the elderly characterized by neck/ shoulder girdle and lower back/hip girdle pain and stiffness (Chap. 375). While PMR may occasionally feature distal limb involvement, RA predominately affects the wrists/hands and ankles/feet, especially at disease onset. Similarly, the relatively rare condition called remitting seronegative symmetrical synovitis with pitting edema (RS3PE) and paraneoplastic syndromes may also be confused with early RA. RS3PE is typically characterized by prominent distal limb pitting edema, which is unusual in RA, and responds promptly to treatment with low doses of prednisone. Chronic tophaceous gout may mimic severe RA in some cases, and tophi may be confused with rheumatoid nodules. Hepatitis C–related arthropathy often involves the small joints of the hands and is associated in half the cases with a positive RF, but generally not ACPA. CHAPTER 370 Rheumatoid Arthritis LABORATORY FEATURES Patients with systemic inflammatory diseases such as RA will often present with elevated nonspecific inflammatory markers such as an ESR or CRP. Testing for serum RF and anti-cyclic citrullinated peptide (CCP) antibodies is important in differentiating RA from other poly­ articular diseases, although RF lacks diagnostic specificity and may be found in association with other chronic inflammatory diseases in which arthritis figures in the clinical manifestations. IgM, IgG, and IgA isotypes of RF occur in sera from patients with RA, although the IgM isotype is the one most frequently measured by commercial laboratories. Serum IgM RF has been found in 75% of patients with RA; therefore, a negative result does not exclude the pres­ ence of this disease. It is also found in other connective tissue diseases, such as primary Sjögren’s syndrome, systemic lupus erythematosus, and type II mixed essential cryoglobulinemia, as well as chronic infec­ tions such as subacute bacterial endocarditis and hepatitis B and C. Serum RF, mostly at low levels, may also be detected in 1–5% of the healthy population. The presence of serum anti-CCP antibodies has about the same sensitivity as serum RF for the diagnosis of RA. However, its diagnostic specificity approaches 95%, so a positive test for anti-CCP antibodies in the setting of an early inflammatory arthritis is useful for distinguish­ ing RA from other forms of arthritis. There is some incremental value in testing for the presence of both RF and anti-CCP, as some patients with RA are positive for RF but negative for anti-CCP and vice versa. The presence of RF or anti-CCP antibodies also has prognostic signifi­ cance, with anti-CCP antibodies showing the most value for predicting worse outcomes. Patients with RA may also have other antibodies associated with autoimmune disease. Approximately 30% of patients with RA test positive for antinuclear antibodies (ANAs), and some sera from some patients contain antineutrophil cytoplasmic antibodies (ANCAs; par­ ticularly p-ANCAs). However, patients with RA would not be expected to test positive for anti-MPO or anti-PR3 antibodies as they would if they had an ANCA-associated vasculitis. ■ ■SYNOVIAL FLUID ANALYSIS Typically, the cellular composition of synovial fluid from patients with RA reflects an acute inflammatory state. Synovial fluid white blood cell (WBC) counts can vary widely but generally range between 5000 and 50,000 WBC/μL, compared with <2000 WBC/μL for a noninflamma­ tory condition such as osteoarthritis. In contrast to the synovial tissue, the overwhelming cell type in the synovial fluid is the neutrophil. Clinically, the analysis of synovial fluid is most useful for confirming an inflammatory arthritis (as opposed to osteoarthritis), while at the same time excluding infection or a crystal-induced arthritis such as gout or pseudogout (Chap. 384). ■ ■JOINT IMAGING Joint imaging is a valuable tool not only for diagnosing RA but also for tracking progression of any joint damage. Plain x-ray is the most common imaging modality, but it is limited to visualization of the bony structures and inferences about the state of the articular carti­ lage based on the amount of joint space narrowing. MRI and ultra­ sound techniques offer the added value of detecting changes in the soft tissues such as synovitis, tenosynovitis, and effusions, as well as providing greater sensitivity for identifying bony abnormalities. Plain PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders FIGURE 370-5  X-ray of the right hand demonstrating features of advanced rheumatoid arthritis. This x-ray is notable for carpal crowding of the wrist (yellow arrow), loss of joint space and subluxation of the fifth metacarpophalangeal joint (green arrow), and an erosion of the fourth proximal interphalangeal joint (red arrow). radiographs are usually relied upon in clinical practice for the purpose of diagnosis and monitoring affected joints. However, in selected cases, MRI and ultrasound can provide additional diagnostic information that may guide clinical decision-making. Musculoskeletal ultrasound with power Doppler is increasingly used in rheumatology clinical prac­ tice for detecting synovitis and bone erosion. Plain Radiography  Classically in RA, the initial radiographic finding is periarticular osteopenia. Practically speaking, however, this finding is difficult to appreciate on plain films and particularly their digitalized images. Other findings on plain radiographs include soft tissue swelling, symmetric joint space loss, and juxtaarticular and subchondral erosions, most frequently in the wrists and hands (MCPs and PIPs) and the feet (MTPs). In the feet, the lateral aspect of the fifth MTP is often targeted first, but other MTP joints may be involved at the same time. X-ray imaging of advanced RA may reveal signs of severe destruction, including joint subluxation and collapse (Fig. 370-5). MRI  MRI offers the greatest sensitivity for detecting synovitis and joint effusions, as well as early bone and bone marrow changes. These soft tissue abnormalities often occur before osseous changes are noted on x-ray. Presence of bone marrow edema has been recognized to be an early sign of inflammatory joint disease and can predict the subsequent development of erosions on plain radiographs as well as MRI scans. Cost and availability of MRI are the main factors limiting its routine clinical use. Ultrasound  Ultrasound, including power color Doppler, can detect more erosions than plain radiography, especially in easily accessible joints. It can also reliably detect synovitis, including increased joint vascularity indicative of inflammation. The usefulness of ultrasound is dependent on the experience of the sonographer; however, it does offer the advantages of portability, lack of radiation, and low expense relative to MRI, factors that make it attractive as a clinical tool (Fig. 370-6). See Videos 370-1, 370-2, and 370-3. CLINICAL COURSE The natural history of RA is complex and affected by a number of fac­ tors including age of onset, gender, genotype, phenotype (i.e., extraar­ ticular manifestations or variants of RA), and comorbid conditions, which make for a truly heterogeneous disease. It is important to realize FIGURE 370-6  Ultrasound demonstrating an effusion (arrow) within the metacarpophalangeal joint. (Courtesy of Dr. Ryan Jessee.) that as many as 10% of patients with inflammatory arthritis fulfilling ACR classification criteria for RA will undergo a spontaneous remis­ sion within 6 months (particularly seronegative patients). However, the vast majority of patients will exhibit a pattern of persistent and progressive disease activity that waxes and wanes in intensity over time. A minority of patients will show intermittent and recurrent explosive attacks of inflammatory arthritis interspersed with periods of disease quiescence. Finally, an aggressive form of RA may occur in an unfor­ tunate few with inexorable progression of severe erosive joint disease, although this highly destructive course is less common in the modern treatment era. Disability, as measured by the Health Assessment Questionnaire (HAQ), shows gradual worsening over time in the face of poorly con­ trolled disease activity and disease progression. Disability may result from both a disease activity–related component that is potentially reversible with therapy and a joint damage–related component owing to the cumulative and largely irreversible effects of soft tissue, cartilage, and bone breakdown. Early in the course of disease, the extent of joint inflammation is the primary determinant of disability, while in the later stages of disease, the amount of joint damage is the dominant contrib­ uting factor. Previous studies have shown that more than one-half of patients with RA are unable to work 10 years after the onset of their disease; however, increased employability and less work absenteeism have been reported recently with the use of newer therapies and earlier treatment intervention. The overall mortality rate in RA is two times greater than in the general population. In particular, patients are at significantly increased risk for death due to respiratory illness, cardiovascular disease, and infection. Median life expectancy is shortened by an average of 7 years for men and 3 years for women compared with control populations. Patients at higher risk for shortened survival are those with systemic extraarticular involvement, low functional capacity, low socioeco­ nomic status, low education, and chronic prednisone use. TREATMENT Rheumatoid Arthritis The amount of clinical disease activity in patients with RA reflects the overall burden of inflammation and is the variable that most influences treatment decisions. Joint inflammation is the main driver of joint damage and is the most important cause of functional disability in the early stages of disease. Several composite indices have been developed to assess clinical disease activity. The ACR 20, 50, and 70 improvement criteria (which correspond to a 20, 50, and 70% improvement, respectively, in joint counts, physician/ patient assessment of disease severity, pain scale, serum levels of acute-phase reactants [ESR or CRP], and a functional assessment of disability using a self-administered patient questionnaire) are a composite index with a dichotomous response variable. The ACR improvement criteria are commonly used in clinical trials as an endpoint for comparing the proportion of responders between treatment groups. In contrast, the Disease Activity Score (DAS), Simplified Disease Activity Index (SDAI), the Clinical Disease Activity Index (CDAI), and the Routine Assessment of Patient Index Data 3 (RAPID3) are continuous measures of disease activ­ ity that are used in clinical practice for tracking disease status and documenting treatment response. The identification of genetic and environmental risk factors as well as the presence of autoantibodies creates a phenotype of a per­ son who may be at higher risk for development of RA, or “preclini­ cal RA.” Several trials have enrolled patients meeting a definition of preclinical RA in an attempt to prevent development of disease with disease-modifying therapies approved for the treatment of RA. While some of these disease-modifying therapies may delay the development of RA compared to a placebo, no strategy has yet been successful in preventing disease. Several developments during the past two decades have changed the therapeutic landscape in RA. They include (1) the emer­ gence of methotrexate as the disease-modifying antirheumatic drug (DMARD) of first choice for the treatment of early RA; (2) the development of novel highly efficacious biologicals that can be used alone or in combination with methotrexate; and (3) the proven superiority of combination DMARD regimens over metho­ trexate alone. The medications used for the treatment of RA may be divided into broad categories: nonsteroidal anti-inflammatory drugs (NSAIDs); glucocorticoids, such as prednisone and meth­ ylprednisolone; conventional DMARDs; and biologic DMARDs (Table 370-2). Although disease for some patients with RA is man­ aged adequately with a single DMARD, such as methotrexate, it calls in most cases for the use of a combination DMARD regimen that may vary in its components over the treatment course depend­ ing on fluctuations in disease activity, loss of treatment efficacy, and emergence of drug-related toxicities and comorbidities. NSAIDS NSAIDs were formerly viewed as the core of RA therapy, but they are now considered to be adjunctive agents for management of symptoms uncontrolled by other measures. NSAIDs exhibit both analgesic and anti-inflammatory properties. The anti-inflammatory effects of NSAIDs derive from their ability to nonselectively inhibit cyclooxygenase (COX)-1 and COX-2. Although the results of clini­ cal trials suggest that NSAIDs are roughly equivalent in their effi­ cacy, experience suggests that some individuals may preferentially respond to a particular NSAID. Chronic use should be minimized due to the possibility of side effects, particularly gastritis and peptic ulcer disease and kidney injury. GLUCOCORTICOIDS Glucocorticoids may serve in several ways to control disease activ­ ity in RA. First, they may be administered in low to moderate doses to achieve rapid disease control before the onset of fully effective DMARD therapy, which often takes several weeks or even months. Second, a 1- to 2-week burst of glucocorticoids may be prescribed for the management of acute disease flares, with dose and duration guided by the severity of the exacerbation. Chronic administra­ tion of low doses (5–10 mg/d) of prednisone (or its equivalent) may also be warranted to control disease activity in patients with an inadequate response to DMARD therapy. As much as possible, chronic glucocorticoid therapy should be avoided in favor of find­ ing an effective DMARD regimen that adequately controls the disease. Best practices minimize chronic use of low-dose predni­ sone therapy owing to the risk of osteoporosis and other long-term complications; however, the use of chronic prednisone therapy is unavoidable in some cases. High-dose glucocorticoids may be necessary for the treatment of severe extraarticular manifestations of RA, such as ILD. Finally, if a patient exhibits one or a few actively inflamed joints, the clinician may consider intraarticular injection of an intermediate-acting glucocorticoid such as triamcinolone ace­ tonide. This approach may allow for rapid control of inflammation in a limited number of affected joints. Caution must be exercised to appropriately exclude joint infection as it often mimics a monoar­ ticular RA flare. CHAPTER 370 Osteoporosis ranks as an important long-term complication of chronic prednisone use. Based on a patient’s risk factors, including total prednisone dosage, length of treatment, gender, race, and bone density, treatment with an oral (e.g., alendronate, risedronate) or parenteral (e.g., zoledronic acid) bisphosphonate may be appropri­ ate for primary prevention of glucocorticoid-induced osteoporosis. Other agents, including denosumab and teriparatide, have also been approved for the treatment of steroid-induced osteoporosis and may be indicated in certain cases. Although prednisone use is known to increase the risk of peptic ulcer disease, especially with concomitant NSAIDs, no evidence-based guidelines recommend routine co-administration of proton pump inhibitors for gastroin­ testinal ulcer prophylaxis. DMARDS DMARDs are so named because of their ability to slow or prevent structural progression of RA. The conventional DMARDs include hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide; they exhibit a delayed onset of action of ~6–12 weeks or longer. Methotrexate is the DMARD of choice for the treatment of RA and is the anchor drug for most combination therapies. It was approved for the treatment of RA in 1988 and remains a benchmark for comparison with the newer disease-modifying therapies. At the dosages used for the treatment of RA, methotrexate has been shown to stimulate adenosine release from cells, producing an anti-inflammatory effect. Methotrexate is administered weekly by the oral or subcutaneous route. Folic acid is taken as co-therapy to mitigate some of methotrexate’s side effects. The clinical efficacy of leflunomide, an inhibitor of pyrimidine synthesis, appears similar to that of methotrexate; it has been shown in well-designed trials to be effective for the treatment of RA as monotherapy or in combina­ tion with methotrexate and other DMARDs. Rheumatoid Arthritis Although similar to the other DMARDs in its slow onset of action, hydroxychloroquine has not been shown to delay radio­ graphic progression of disease and thus is not considered to be a true DMARD. In clinical practice, hydroxychloroquine is generally used for treatment of early, mild disease or as adjunctive therapy in combination with other DMARDs. It is prescribed at a dosage of 5 mg/kg of body weight or less to decrease the risk of retinal toxicity. Sulfasalazine has been shown in randomized, controlled trials to reduce joint inflammation and radiographic progression of disease. A regimen termed oral triple therapy, which is comprised of hydroxychloroquine, sulfasalazine, and methotrexate, is an effec­ tive combination regimen often used in patients with an inadequate response to treatment with methotrexate alone. BIOLOGICALS Biologic DMARDs have revolutionized the treatment of RA over the past two decades (Table 370-2). They are protein therapeutics designed to target cytokines and cell-surface molecules. The TNF inhibitors were the first biologicals approved for the treatment of RA, but several others have come to market since their introduc­ tion in 1999. Additionally, biosimilars are agents that have been designed with the same active properties as the licensed biophar­ maceutical product. Several of these biosimilars have been studied for the treatment of RA and demonstrate a similar efficacy and side-effect profile to the reference biological. Anti-TNF Agents  The development of TNF inhibitors was origi­ nally spurred by the experimental finding that TNF-α is a critical upstream mediator of joint inflammation. Five original “innovator” TNF inhibitors with various molecular designs have been approved for the treatment of RA. Three of these products are anti-TNF TABLE 370-2  DMARDs Used for the Treatment of Rheumatoid Arthritis DRUG DOSAGE SERIOUS TOXICITIES Hydroxychloroquine 200–400 mg/d orally (≤5 mg/kg) Irreversible retinal damage Cardiotoxicity Blood dyscrasia PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Sulfasalazine Initial: 500 mg orally twice daily Maintenance: 1000–1500 mg twice daily Granulocytopenia Hemolytic anemia (with G6PD deficiency) Methotrexate 10–25 mg/week orally or SQ Folic acid 1 mg/d to reduce toxicities Hepatotoxicity Myelosuppression Infection Interstitial pneumonitis Pregnancy category X Leflunomide 10–20 mg/d Hepatotoxicity Myelosuppression Infection Pregnancy category X TNF-α inhibitors Infliximab: 3 mg/kg IV at weeks 0, 2, 6, then every 8 weeks. May increase dose up to 10 mg/kg every 4 weeks ↑ Risk bacterial, fungal infections Reactivation of latent tuberculosis ↑ Lymphoma risk (controversial) Drug-induced lupus Neurologic deficits   Etanercept: 50 mg SQ weekly, or 25 mg SQ biweekly As above Injection site reaction Tuberculosis screening   Adalimumab: 40 mg SQ every other week As above Injection site reaction Tuberculosis screening   Golimumab: 50 mg SQ monthly As above Injection site reaction Tuberculosis screening   Certolizumab: 400 mg SQ weeks 0, 2, 4, then 200 mg every other week As above Injection site reaction Tuberculosis screening Abatacept Weight based: <60 kg: 500 mg 60–100 kg: 750 mg >100 kg: 1000 mg IV dose at weeks 0, 2, and 4, and then every 4 weeks OR 125 mg SQ weekly ↑ Risk bacterial, viral infections Anakinra 100 mg SQ daily ↑ Risk bacterial, viral infections Reactivation of latent tuberculosis Neutropenia Rituximab 1000 mg IV × 2, days 0 and 14 May repeat course every 24 weeks or more Premedicate with methylprednisolone 100 mg to decrease infusion reaction ↑ Risk bacterial, viral infections Infusion reaction Cytopenia Hepatitis B reactivation Interleukin-6 inhibitors Tocilizumab: 4–8 mg/kg IV monthly OR 162 mg SQ every other week (<100 kg weight) 162 mg SQ every week (≥100 kg weight) Sarilumab: 200 mg SQ every other week Risk of infection Infusion reaction LFT elevation Dyslipidemia Cytopenias OTHER COMMON SIDE EFFECTS INITIAL EVALUATION MONITORING Nausea Diarrhea Headache Rash Eye examination if >40 years old or prior ocular disease Optical coherence tomography and visual field testing every 12 months Nausea Diarrhea Headache CBC, LFTs G6PD level CBC every 2–4 weeks for first 3 months, then every 3 months Nausea Diarrhea Stomatitis/mouth ulcers Alopecia Fatigue CBC, LFTs Viral hepatitis panela CBC, creatinine, LFTs every 2–3 months Chest x-ray Alopecia Diarrhea CBC, LFTs Viral hepatitis panela CBC, creatinine, LFTs every 2–3 months Infusion reaction ↑ LFTs Tuberculosis screeningb LFTs periodically Monitor for injection site reactions Monitor for injection site reactions Monitor for injection site reactions Monitor for injection site reactions Headache Nausea Tuberculosis screening Monitor for infusion reactions Injection site reaction Headache Tuberculosis screening CBC with differential CBC every month for 3 months, then every 4 months for 1 year Monitor for injection site reactions Rash Fever CBC Viral hepatitis panela CBC at regular intervals   Tuberculosis screening CBC and LFTs at regular intervals (Continued) TABLE 370-2  DMARDs Used for the Treatment of Rheumatoid Arthritis DRUG DOSAGE SERIOUS TOXICITIES JAK inhibitors Tofacitinib: 5 mg orally twice daily OR 11 mg orally daily Upadacitinib: 15 mg orally daily Baricitinib: 2 mg orally daily Risk of infection LFT elevation Dyslipidemia Neutropenia Thrombosis aViral hepatitis panel: hepatitis B surface antigen, hepatitis C viral antibody. bTuberculosis screening can be performed using a Mantoux tuberculin skin test or blood interferon-gamma release assay. Abbreviations: CBC, complete blood count; DMARDs, disease-modifying antirheumatic drugs; G6PD, glucose-6-phosphate dehydrogenase; IV, intravenous; LFTs, liver function tests; JAK, Janus kinase; SQ, subcutaneous. monoclonal antibodies: infliximab, a chimeric (part mouse and human) monoclonal antibody; and adalimumab and golimumab, humanized monoclonal antibodies. Certolizumab pegol, a fourth product, is a pegylated Fab′ fragment of a humanized monoclonal antibody, while the other, etanercept, is a soluble fusion protein consisting of the TNF receptor 2 in covalent linkage with the Fc portion of IgG1. All of these TNF inhibitors have been shown in randomized controlled clinical trials to reduce the signs and symptoms of RA, slow radiographic progression of joint damage, and improve physical function and quality of life. Anti-TNF drugs may be used alone or in combination with background methotrex­ ate therapy. Patients with RA who have an inadequate response to methotrexate therapy are often treated with a TNF inhibitor, usually in combination with methotrexate. Anti-TNF agents should be avoided in patients with active infec­ tion or a history of hypersensitivity to these agents and are contra­ indicated in patients with chronic hepatitis B infection or class III/ IV congestive heart failure. A major concern is the increased risk for infection, including serious bacterial infections, opportunistic fungal infection, and reactivation of latent tuberculosis infection (LTBI). For this reason, all patients are screened for LTBI accord­ ing to national guidelines with either an intradermal injection of purified protein derivative (PPD) or an IFN-γ release assay prior to starting anti-TNF therapy (Chap. 183). If positive, treatment for LTBI is given for at least 1 month prior to starting anti-TNF therapy. Anakinra  Anakinra is the recombinant form of the naturally occurring IL-1 receptor antagonist. Anakinra has seen limited use for the treatment of RA because other biologic DMARDs have seen greater efficacy in practice. Abatacept  Abatacept is a soluble fusion protein consisting of the extracellular domain of human CTLA-4 linked to the modified portion of human IgG. It inhibits the co-stimulation of T cells by blocking CD28-CD80/86 interactions and may also inhibit the function of antigen-presenting cells by reverse signaling through CD80 and CD86. Abatacept has been shown in clinical trials to reduce disease activity, slow radiographic progression of damage, and improve functional disability. Most patients receive abatacept in combination with a conventional DMARD. Abatacept therapy has been associated with an increased risk of infection and can inhibit a vaccine response. Rituximab  Rituximab is a chimeric monoclonal antibody directed against CD20, a cell-surface molecule expressed by most mature B lymphocytes. It works by depleting B cells, which, in turn, leads to a reduction in the inflammatory response by unknown mechanisms. These mechanisms may include a reduction in autoantibodies, inhi­ bition of T-cell activation, and alteration of cytokine production. Rituximab has been approved for the treatment of refractory RA (failure of treatment with a TNF-α inhibitor) in combination with methotrexate and has been shown to be more effective for patients with seropositive than seronegative disease. Its administration has (Continued) OTHER COMMON SIDE EFFECTS INITIAL EVALUATION MONITORING Upper respiratory tract infections Diarrhea Headache Nasopharyngitis Tuberculosis screening CBC, LFTs, and lipids at regular intervals CHAPTER 370 Rheumatoid Arthritis been associated with mild to moderate infusion reactions, as well as an increased risk of infection. Notably, there have been rare isolated reports of a potentially lethal brain disorder, progressive multifocal leukoencephalopathy (PML), in association with rituximab therapy, although the absolute risk of this complication appears to be very low in patients with RA (~1:25,000). Most of these cases have occurred on a background of previous or current exposure to other potent immunosuppressive drugs. Studies in recent years have also demonstrated that rituximab significantly inhibits a vaccine response (e.g., response to SARS-CoV-2 vaccination). Anti-IL-6 Receptor Agents  IL-6 is a proinflammatory cytokine implicated in the pathogenesis of RA, with effects on both joint inflammation and damage. IL-6 binding to its receptor acti­ vates intracellular signaling pathways that affect the acute-phase response, cytokine production, and osteoclast activation. Tocili­ zumab and sarilumab are both monoclonal antibodies directed against the membrane and soluble forms of the IL-6 receptor. Clinical trials attest to the clinical efficacy of these therapies for RA, both as monotherapy and in combination with methotrexate and other conventional DMARDs. Anti-IL-6 receptor agents have been associated with an increased risk of infection, neutropenia, and thrombocytopenia; the hematologic abnormalities appear to be reversible upon stopping the drug. In addition, this agent has been shown to increase LDL cholesterol. However, it is not known if this effect on lipid levels increases the risk for atherosclerotic disease. Anti-IL-6 receptor agents have also been associated with an increased rate of gastrointestinal perforation and should be avoided if possible in patients with a history of diverticulitis and a recent gastric or duodenal ulcer. TARGETED SYNTHETIC DMARDs Because treatment with conventional DMARDs and/or biologic therapies may not result in optimal disease control, other therapeu­ tic strategies have been investigated to fill this gap. The so-called targeted synthetic DMARDs have been designed to target intracel­ lular signaling pathways, which transduce the positive signals from cell-surface receptors activated by cytokines and other inflamma­ tory mediators. They have an advantage over biologics in their oral formulation. JAK Inhibitors  Although several different kinases have been evaluated as potential treatment targets, only inhibitors of the JAKs have demonstrated safety and efficacy for the treatment of RA. The JAK family comprises four members (JAK1, JAK2, JAK3, and tyrosine kinase 2 [Tyk2]) and link a host of extracellular cytokine receptors with their intracellular signaling domains. They form homodimeric and heterodimeric duplexes that mediate signaling of the receptors for the common γ-chain-related cytokines IL-2, -4, -7, -9, -15, and -21, as well as IFN-γ, IL-6, IL-12, IL-23, IL-10, the type I IFNs, and the hemopoietic cytokines and growth factors. Many of these cytokines play critical roles in promoting T- and B-cell activa­ tion as well as chronic inflammation in RA. Tofacitinib is a potent JAK1 and JAK3 inhibitor with minor inhibitory effects on JAK2 and Tyk2; baricitinib is a JAK1 and JAK2 inhibitor with moderate inhibition of Tyk2 and minimal inhibition of JAK3; and upadacitinib is a predominately selective inhibitor of JAK1. Each of the JAK inhibitors can be used as monotherapy or in combination with methotrexate. However, they are associated with an increased risk of infections, including bacterial infections and herpes zoster. Other possible side effects of these agents include elevated liver transaminases, neutropenia, increased cholesterol levels, hypertension, and elevations in serum creatinine. Recent studies have also found an increased risk of thrombosis, major adverse cardiovascular events, and malignancies in patients taking tofacitinib compared with TNF inhibitors, with the highest of these risks in the elderly. TREATMENT OF EXTRAARTICULAR MANIFESTATIONS In general, treatment of the underlying RA favorably modifies its extraarticular manifestations, and observational studies suggest aggressive management of early disease can potentially prevent their occurrence in established disease. The treatment of patients with RA-ILD, however, can be particularly challenging because some of the DMARDs used for the treatment of RA are also associ­ ated with pulmonary toxicity, such as methotrexate and lefluno­ mide. RA-ILD is often treated with high doses of corticosteroids and adjunctive immunosuppressive agents, such as azathioprine, mycophenolate mofetil, or rituximab. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders APPROACH TO THE PATIENT Rheumatoid Arthritis The treatment of RA adheres to the following principles and goals: (1) early, aggressive therapy to prevent joint damage and disability; (2) frequent modification of DMARD therapy to achieve treatment goals with utilization of combination therapy where appropriate; (3) individualization of DMARD therapy in an attempt to maximize response and minimize side effects; (4) minimal use of long-term glucocorticoid therapy; and (5) achieving, whenever possible, low disease activity or clinical remission. A considerable amount of evidence supports this intensive treatment approach and has been termed “treat to target,” with a target of achieving low disease activ­ ity or remission. As mentioned earlier, methotrexate is the DMARD of first choice for initial treatment of moderate to severe RA. Failure to achieve adequate improvement with methotrexate therapy calls for a change in DMARD therapy, usually a transition to an effective combination regimen. Effective combinations include methotrexate, sulfasala­ zine, and hydroxychloroquine (oral triple therapy); methotrexate and leflunomide; and methotrexate plus a biological. The combina­ tion of methotrexate and an anti-TNF agent, for example, has been shown in randomized controlled trials to be superior to methotrex­ ate alone, not only for reducing signs and symptoms of disease but also for retarding the progression of structural joint damage. Pre­ dicting which patients are at higher risk for developing radiologic joint damage is imprecise at best, although some factors such as an elevated serum level of acute-phase reactants, high burden of joint inflammation, and the presence of erosive disease are associated with increased likelihood of developing structural injury. In 2021, the ACR updated their guidelines for the treatment of RA. These recommendations do not make a distinction between the treatment of patients with early (<6 months of disease dura­ tion) or established disease and highlight the use of a treat-to-target approach and the need to switch or add therapies for worsening or persistent moderate/high disease activity. For example, in patients with early RA who have persistent moderate/high disease activity despite DMARD monotherapy, providers should consider escala­ tion to combination DMARD therapy or switching to an antiTNF +/– methotrexate or a non-TNF biologic +/– methotrexate. Since a more intensive initial approach (e.g., combination DMARD therapy) has been shown to produce superior long-term outcomes compared with starting methotrexate alone, the usual approach is to begin with methotrexate and, in the absence of an adequate therapeutic response, rapidly step up (e.g., after 3–6 months) to a combination of conventional DMARDs or add an anti-TNF or nonTNF biological agent. Some patients may not respond to an anti-TNF drug or may be intolerant of its side effects. Initial responders to an anti-TNF agent who later experience worsening of their condition may benefit from switching to another anti-TNF agent or an alternative biological with a different mechanism of action. Indeed, some studies suggest that switching to an alternative biological such as abatacept is more effective than switching to another anti-TNF drug. Unacceptable toxicity from an anti-TNF agent may also call for switching to another biological or targeted synthetic DMARD with a different mechanism of action or a conventional DMARD regimen. Studies have also shown that oral triple therapy (hydroxychloro­ quine, methotrexate, and sulfasalazine) may be used effectively for the treatment of early RA. Treatment may be initiated with metho­ trexate alone and, lacking an adequate treatment response, followed within 6 months by a step-up to oral triple therapy. A clinical state defined as low disease activity or remission is the optimal goal of therapy, although most patients never achieve com­ plete remission despite every effort to achieve it. Composite indices, such as the Disease Activity Score-28 (DAS-28), are useful for clas­ sifying states of low disease activity and remission; however, they are imperfect tools due to the limitations of the clinical joint exami­ nation in which low-grade synovitis may escape detection. Com­ plete remission has been stringently defined as the total absence of all articular and extraarticular inflammation and immunologic activity related to RA. However, evidence for this state can be dif­ ficult to demonstrate in clinical practice. In an effort to standardize and simplify the definition of remission for clinical trials, the ACR and EULAR developed two provisional operational definitions of remission in RA (Table 370-3). A patient may be considered in remission if the patient (1) meets all the clinical and laboratory criteria listed in Table 370-3 or (2) has a composite SDAI score of <3.3. The SDAI is calculated by taking the sum of a tender joint and swollen joint count (using 28 joints), patient global assessment (0–10 scale), physician global assessment (0–10 scale), and CRP (in mg/dL). This definition of remission does not consider the pos­ sibility of subclinical synovitis or that damage alone may produce a tender or swollen joint. Ignoring the semantics of these definitions, the aforementioned remission criteria are nonetheless useful for setting a level of disease control that will likely result in minimal or no progression of structural damage and disability. With an early, aggressive approach to treatment, a significant number of patients who reach remission may have a reduction in treatment without an increased risk of flare or loss of remission. However, complete withdrawal of DMARD therapy during established disease almost invariably leads to a relapse. TABLE 370-3  ACR/EULAR Provisional Definition of Remission in Rheumatoid Arthritis At any time point, patient must satisfy all of the following:   Tender joint count ≤1   Swollen joint count ≤1   C-reactive protein ≤1 mg/dL   Patient global assessment ≤1 (on a 0–10 scale) OR At any time point, patient must have a Simplified Disease Activity Index score of ≤3.3 Abbreviations: ACR, American College of Rheumatology; EULAR, European League Against Rheumatism. Source: Reproduced with permission from DT Felson et al; American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum 63:573, 2011. PHYSICAL ACTIVITY AND ASSISTIVE DEVICES In principle, all patients with RA should receive a prescription for exercise and physical activity. The ACR has developed guidelines for integrative interventions to accompany disease-modifying therapy and includes evidence-based recommendations for diet and exercise. Dynamic strength training, community-based comprehensive phys­ ical therapy, and physical-activity coaching (emphasizing achieving 150 min of moderate-to-vigorous physical activity per week) have all been shown to improve muscle strength and perceived health status, as well as improve DAS-28 scores and inflammatory markers. Foot orthotics for painful valgus deformity decrease foot pain and may reduce disability and functional limitations. Judicious use of wrist splints can also decrease pain; however, their benefits may be offset by decreased dexterity and variably curb grip strength. SURGERY Surgical procedures may improve pain and disability in RA with varying degrees of reported long-term success—most notably for the hands, wrists, and feet. For large joints, such as the knee, hip, shoul­ der, or elbow, the preferred option for advanced joint disease may be total joint arthroplasty. A few surgical options exist for dealing with the smaller hand joints. Silicone implants are the most com­ mon prosthetic for MCP arthroplasty and are generally implanted in patients with severe decreased arc of motion, marked flexion contrac­ tures, MCP joint pain with radiographic abnormalities, and severe ulnar drift. Arthrodesis and total wrist arthroplasty are reserved for patients with severe disease who have substantial pain and functional impairment. Numerous surgical options exist for correction of hallux valgus in the forefoot, including arthrodesis and arthroplasty, as well as primarily arthrodesis for refractory hindfoot pain. OTHER MANAGEMENT CONSIDERATIONS Pregnancy  Up to 75% of female RA patients will note overall improvement in symptoms during pregnancy but they will often flare shortly after delivery. Flares during pregnancy are gener­ ally treated with low doses of prednisone. Hydroxychloroquine and sulfasalazine are probably the safest DMARDs to use during pregnancy, although anti-TNF agents are generally accepted to be safe in this setting. However, current guidelines call for anti-TNF drugs to be discontinued during the third trimester of pregnancy. Methotrexate and leflunomide therapy are contraindicated during pregnancy due to their teratogenicity in animals and humans. The experience with other biologic agents, such as abatacept, anti-IL-6 receptor antibodies, rituximab, and JAK inhibitors has been insuf­ ficient to make specific recommendations for their use during pregnancy and are discontinued at conception. Active inflamma­ tory disease is associated with worse pregnancy outcomes, and thus, controlling disease activity remains a priority. Elderly Patients  RA presents in up to one-third of patients after the age of 60; however, older individuals may receive less aggressive treatment due to concerns about increased risks of drug toxicity. Studies suggest that conventional DMARDs and biological agents are equally effective and safe in younger and older patients (with the possible exception of JAK inhibitors). Due to comorbidities, many elderly patients have an increased risk of infection. Aging also leads to a gradual decline in renal function that may raise the risk for side effects from NSAIDs and some DMARDS, such as methotrexate. Renal function must be taken into consideration before prescribing methotrexate, which is mostly cleared by the kidneys. To reduce the risks of side effects, methotrexate doses may need to be adjusted downward for the drop in renal function that usually comes with the seventh and eighth decades of life. GLOBAL CHALLENGES Developing countries are finding an increase in the incidence of non­ communicable, chronic diseases such as diabetes, cardiovascular dis­ ease, and RA in the face of ongoing poverty, rampant infectious disease, and poor access to modern health care facilities. In these areas, patients tend to have a greater delay in diagnosis and limited access to special­ ists and, thus, greater disease activity and disability at presentation. In addition, infection risk remains a significant issue for the treatment of RA in developing countries because of the immunosuppression associ­ ated with the use of glucocorticoids and most DMARDs. For example, in some developing countries, patients undergoing treatment for RA have a substantial increase in the incidence of tuberculosis, which demands the implementation of far more comprehensive screening practices and liberal use of isoniazid prophylaxis than in developed countries. The increased prevalence of hepatitis B and C, as well as human immunodeficiency virus (HIV), in these developing countries also poses challenges. Reactivation of viral hepatitis has been observed in association with some of the DMARDs, such as rituximab. Also, reduced access to antiretroviral therapy may limit the control of HIV infection and therefore the choice of DMARD therapies. CHAPTER 370 Rheumatoid Arthritis Despite these challenges, one should attempt to initiate early treat­ ment of RA in the developing countries with the resources at hand. Hydroxychloroquine, sulfasalazine, and methotrexate are all reason­ ably accessible throughout the world where they can be used as both monotherapy and in combination with other drugs. The availability of biological agents is increasing in the developed countries as well as in other areas around the world, although their use is limited by high cost; national protocols restrict their use, and concerns remain about the risk for opportunistic infections. SUMMARY Improved understanding of the pathogenesis of RA and its treat­ ment has dramatically revolutionized the management of this disease. The outcomes of patients with RA are vastly superior to those of the prebiologic modifier era; more patients than in years past are able to avoid significant disability and continue working, albeit with some job modifications. The need for early and aggressive treatment of RA as well as frequent follow-up visits for monitoring of drug therapy has implications for our health care system. Primary care physicians and rheumatologists must be prepared to work together as a team to imple­ ment a treat-to-target approach with the goal of reaching remission or low disease activity. In many settings, rheumatologists have reengi­ neered their practice in a way that places high priority on consultations for any new patient with early inflammatory arthritis. The therapeutic regimens for RA are becoming increasingly com­ plex with the rapidly expanding armamentarium. Patients receiving these therapies must be carefully monitored by both the primary care physician and the rheumatologist to minimize the risk of side effects and identify quickly any complications of chronic immunosuppression. Also, prevention and treatment of RA-associated conditions such as ischemic heart disease and osteoporosis will likely benefit from a team approach owing to the value of multidisciplinary care. Research will continue to search for new therapies with superior efficacy and safety profiles and investigate treatment strategies that can bring the disease under control more rapidly and nearer to remis­ sion. However, prevention and cure of RA will likely require new breakthroughs in our understanding of disease pathogenesis. Several prevention trials in RA are currently underway and focus on a variety of prevention strategies in individuals who have serologic and/or clini­ cal features at higher risk than the general population for developing RA. Equally important is the identification of predictive biomarkers in RA that will enable a personalized approach to DMARD therapy, a foreseeable goal in the future that will take advantage of the advances in technology and scientific understanding of the disease. ■ ■FURTHER READING Aletaha D, Smolen JS: Diagnosis and management of rheumatoid arthritis: A review. JAMA 320:1360, 2018. Catrina AI et al: Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis. Nat Rev Rheumatol 13:79, 2017. Erickson AR et al: Clinical features of rheumatoid arthritis, in Kelley and Firestein’s Textbook of Rheumatology, 10th ed. Firestein GS et al (eds). Philadelphia, Elsevier, 2017, pp 1167–1186. # 14 - 371 Acute Rheumatic Fever ### 371 Acute Rheumatic Fever Fraenkel L et al: 2021 American College of Rheumatology guide­ line for the treatment of rheumatoid arthritis. Arthritis Rheumatol 73:1108, 2021. Gravallese EM, Firestein GS: Rheumatoid arthritis: Common ori­ gins, divergent mechanisms. N Engl J Med 388:529, 2023. Karimi J et al: Genetic implications in the pathogenesis of rheumatoid PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders arthritis; an updated review. Gene 702:8, 2019. Moreland LW et al: A randomized comparative effectiveness study of oral triple therapy versus methotrexate plus etanercept in early aggressive rheumatoid arthritis: The Treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum 64:2824, 2012. VIDEO 370-1  Transverse view of 2nd MCP demonstrating synovial hypertrophy with abnormal power doppler signal (yellow) consistent with synovitis. Synovial proliferation is displacing the overlying extensor tendon of the digit above the joint space. This view demonstrates small erosions of the dorsal metacarpal head. (Courtesy of Dr. Philip Chu.) VIDEO 370-2  Longitudinal dorsal view of the 2nd MCP demonstrating synovial hypertrophy with abnormal power doppler signal (yellow) consistent with synovitis. (Courtesy of Dr. Philip Chu) VIDEO 370-3  Transverse view of 2nd MCP demonstrating synovial hypertrophy and intrasynovial effusion with abnormal power doppler signal (yellow) consistent with synovitis. Fluid and synovial proliferation is displacing the overlying extensor tendon of the digit above the joint space. (Courtesy of Dr. Philip Chu.) Joseph Kado, Jonathan Carapetis Acute Rheumatic Fever Acute rheumatic fever (ARF) is a multisystem disease resulting from an autoimmune reaction to infection with group A Streptococcus. Although many parts of the body may be affected, almost all of the manifestations resolve completely. The major exception is cardiac valvular damage (rheumatic heart disease [RHD]), which may persist after the other features have disappeared. GLOBAL CONSIDERATIONS ARF and RHD are diseases of poverty. They were common in all coun­ tries until the early twentieth century, when their incidence began to decline in industrialized nations. This decline was largely attributable to improved living conditions—particularly less crowded housing and better hygiene—which resulted in reduced transmission of group A streptococci. The introduction of antibiotics and improved systems of medical care had a supplemental effect. The virtual disappearance of ARF and reduction in the incidence of RHD in high-income countries during the first half of the twentieth century unfortunately was not replicated in low- and middle-income countries (LMICs), where these diseases continue unabated. RHD is the most common cause of acquired heart disease in children in LMICs and is a major cause of mortality and morbidity in adults as well. It is estimated that >40 million people worldwide are affected by RHD, with >300,000 deaths occurring each year. Some 95% of ARF cases and RHD deaths now occur in developing countries, with particularly high burdens in sub-Saharan Africa, Pacific nations, Australasia, China, and South and Central Asia. The pathogenetic pathway from exposure to group A Streptococcus followed by pharyngeal or superficial skin infection and subsequent development of ARF, ARF recurrences, and development of RHD and its complications is associated with a range of risk factors and, therefore, potential interventions at each point (Fig. 371-1). In affluent countries, many of these risk factors are well controlled, and where needed, interventions are in place. Unfortu­ nately, the greatest burden of disease is found in LMICs, most of which do not have the resources, capacity, and/or interest to tackle this multi­ faceted disease. In particular, few of these countries have coordinated, register-based RHD control programs, which have been proven to be cost-effective in reducing the burden of RHD. Enhancing awareness of RHD and mobilizing resources for its control in LMICs are issues requiring international attention. In 2018, member states of the World Health Organization (WHO) unanimously adopted a Global Resolu­ tion on Rheumatic Fever and Rheumatic Heart Disease, calling on all states as well as international stakeholders and the WHO itself to take practical actions to control these diseases. EPIDEMIOLOGY ARF is mainly a disease of children aged 5–14 years. Initial episodes become less common in older adolescents and young adults and are rare in persons aged >30 years. By contrast, recurrent episodes of ARF remain relatively common in adolescents and young adults. This pattern con­ trasts with the prevalence of RHD, which peaks between 25 and 40 years. There is no clear gender association for ARF, but RHD more commonly affects females, sometimes up to twice as frequently as males. PATHOGENESIS ■ ■ORGANISM FACTORS Conventional teaching has it that ARF is exclusively caused by infection of the upper respiratory tract with group A streptococci (Chap. 153). Although classically, certain M-serotypes (particularly types 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29) were associated with ARF, recent evidence demonstrates that many more M-serotypes are rheumatogenic and that so-called “rheumatogenic motifs” are found in only a minority of serotypes associated with rheumatic fever. This epidemiologic evidence also points to a clear role of skin infection in the pathogenesis of ARF. The potential role of groups C and G streptococci is unclear at this time. ■ ■HOST FACTORS Based on epidemiologic evidence, ~3–6% of any population may be sus­ ceptible to ARF, and this proportion does not vary dramatically between populations. Findings of familial clustering of cases and concordance in monozygotic twins—particularly for chorea—confirm that suscep­ tibility to ARF is an inherited characteristic, with 44% concordance in monozygotic twins compared to 12% in dizygotic twins and heritability more recently estimated at 60%. Most evidence for host factors focuses on immunologic determinants. Initial studies found associations with human leukocyte antigen (HLA) class II alleles, some protective and some associated with increased susceptibility, as well as polymorphisms in tumor necrosis factor and mannose binding lectin. Recent genomewide association studies and genomic sequencing analyses have identi­ fied associations with a range of genes including the immunoglobulin heavy chain (IGH) locus (specifically the IGHV4-61*02 allele), comple­ ment factor H, and some HLA class II (a range of HLA-DQ A and B alleles) and III loci. The associations are often population dependent, although increasing consistency is being found across populations in meta-analyses of genomic studies. Over coming years, further genomic analyses are expected to provide additional insights into ARF and RHD pathogenesis, as well as host protective and susceptibility factors. ■ ■THE IMMUNE RESPONSE The most widely accepted theory of rheumatic fever pathogenesis is based on the concept of molecular mimicry, whereby an immune response targeted at streptococcal antigens (mainly thought to be on the M protein) also recognizes human tissues. In this model, antigen processing cells of the innate immune system present streptococcal antigens after throat (and possibly skin) group A streptococcal infec­ tion to T cells, which then lead to activation of both humoral and cellu­ lar immunity. Cross-reactive antibodies bind to endothelial cells on the heart valve, leading to activation of the adhesion molecule VCAM-1, with resulting recruitment of activated lymphocytes and lysis of endo­ thelial cells in the presence of complement. The latter leads to release of peptides including laminin, keratin, and tropomyosin, which, in turn, activates cross-reactive T cells that invade the heart, amplifying the damage and causing epitope spreading. An alternative hypothesis proposes that the initial damage is due to streptococcal invasion of epithelial surfaces, with binding of M protein to type IV collagen Asymptomatic infection Overcrowded living conditions Failure to seek health care for sore throat Risk factors Poverty Inadequate diagnosis and treatment of streptococcal pharyngitis Rural residence Urban slum residence Treatment failure Exposure to group A streptococcus Group A streptococcal upper respiratory tract infection* Better diagnosis and treatment of sore throat in primary care Better primary care Economic development Good evidence base Better living conditions Opportunities for Intervention Systematic sore throat screening and treatment programs Unproven/ Hypothesized/ Future (Vaccine) (Skin infection control programs) *Increasing evidence of the role of streptococcal skin infection FIGURE 371-1  Pathogenetic pathway for acute rheumatic fever and rheumatic heart disease (RHD), with associated risk factors and opportunities for intervention at each step. Interventions in parentheses are either unproven or currently unavailable. allowing it to become immunogenic, but not through the mechanism of molecular mimicry. CLINICAL FEATURES There is a latent period of ~3 weeks (1–5 weeks) between the precipitat­ ing group A streptococcal infection and the appearance of the clinical features of ARF. The exceptions are chorea and indolent carditis, which may follow prolonged latent periods lasting up to 6 months. Although many patients report a prior sore throat, the preceding group A strep­ tococcal infection is commonly subclinical; in these cases, it can only be confirmed using streptococcal antibody testing. The most common clinical features are polyarthritis (present in 60–75% of cases) and car­ ditis (50–75%). The prevalence of chorea in ARF varies substantially between populations, ranging from <2 to 30%. Erythema marginatum and subcutaneous nodules are now rare, being found in <5% of cases. ■ ■HEART INVOLVEMENT Up to 75% of patients with ARF progress to RHD. The endocardium, pericardium, or myocardium may be affected. Valvular damage is the hallmark of rheumatic carditis. The mitral valve is almost always affected, sometimes together with the aortic valve; isolated aortic valve involvement is rare. Damage to the pulmonary or tricuspid valves is usually secondary to increased pulmonary pressures resulting from left-sided valvular disease. Early valvular damage leads to regurgita­ tion. Over ensuing years, usually as a result of recurrent episodes, leaf­ let thickening, scarring, calcification, and valvular stenosis may develop (Fig. 371-2). See Videos 371-1 and 371-2. Therefore, the characteristic manifestation of carditis in previously unaffected individuals is mitral Poor access to health care Poor access to health care Inherited susceptibility Lack of medication Poor delivery of secondary prophylaxis Female gender (chorea) CHAPTER 371 Lack of cardiac surgical facilities Poor access to health care Asymptomatic or undiagnosed acute rheumatic fever Acute Rheumatic Fever Recurrent acute rheumatic fever Heart failure Rheumatic heart disease (RHD) Surgery Disability Death Acute rheumatic fever Stroke Endocarditis Improved access to health care Secondary prophylaxis Register-based programs Register-based control programs Integration of RHD control into primary care, childhealth, and noncommunicable disease programs Specialist services • Cardiology • Cardiac surgery Echocardiographic screening (Immunotherapies) regurgitation, sometimes accompanied by aortic regurgitation. Myo­ cardial inflammation may affect electrical conduction pathways, lead­ ing to P-R interval prolongation (first-degree atrioventricular block or rarely higher-level block) and softening of the first heart sound. People with RHD are often asymptomatic for many years before their valvular disease progresses to cause cardiac failure. Moreover, particularly in resource-poor settings, the diagnosis of ARF is often not made, so children, adolescents, and young adults may have RHD but not know it. These cases can be diagnosed using echocardiography; auscultation is poorly sensitive and specific for RHD diagnosis in asymptomatic patients. Echocardiographic screening of school-aged children in populations with high rates of RHD is becoming more widespread and has been facilitated by improving technologies in portable echocardiography and the avail­ ability of consensus guidelines for the diagnosis of RHD on echocardiog­ raphy (Table 371-1). These guidelines replace the previous “definite,” “borderline,” and “latent” diagnostic category terms with a classification based on the risk of progression to more advanced valvular heart disease and provide recommendations on secondary prophylaxis for each group. ■ ■JOINT INVOLVEMENT The most common form of joint involvement in ARF is arthritis, i.e., objective evidence of inflammation, with hot, swollen, red, and/or ten­ der joints, and involvement of more than one joint (i.e., polyarthritis). Polyarthritis is typically migratory, moving from one joint to another over a period of hours. ARF almost always affects the large joints— most commonly the knees, ankles, hips, and elbows—and is asymmet­ ric. The pain is severe and usually disabling until anti-inflammatory medication is commenced. RV PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders LV AV MV LA FIGURE 371-2  Transthoracic echocardiographic image from a 5-year-old boy with chronic rheumatic heart disease. This diastolic image demonstrates leaflet thickening, restriction of the anterior mitral valve leaflet tip, and doming of the body of the leaflet toward the interventricular septum. This appearance (marked by the arrowhead) is commonly described as a “hockey stick” or an “elbow” deformity. AV, aortic valve; LA, left atrium; LV, left ventricle; MV, mitral valve; RV, right ventricle. (Courtesy of Dr. Bo Remenyi, Department of Paediatric and Congenital Cardiac Services, Starship Children’s Hospital, Auckland, New Zealand.) Less severe joint involvement is also relatively common and has been recognized as a potential major manifestation in high-risk populations in the most recent revision of the Jones criteria. Arthralgia without objective joint inflammation usually affects large joints in the same migratory pattern as polyarthritis. In some populations, aseptic monoarthritis may be a presenting feature of ARF, which may, in turn, result from early commencement of anti-inflammatory medication before the typical migratory pattern is established. The joint manifestations of ARF are highly responsive to salicylates and other nonsteroidal anti-inflammatory drugs (NSAIDs). ■ ■CHOREA Sydenham’s chorea commonly occurs in the absence of other manifes­ tations, follows a prolonged latent period after group A streptococcal infection, and is found mainly in females. The choreiform movements affect particularly the head (causing characteristic darting movements of the tongue) and the upper limbs (Chap. 447). They may be gen­ eralized or restricted to one side of the body (hemi-chorea). In mild cases, chorea may be evident only on careful examination, whereas in the most severe cases, the affected individuals are unable to perform activities of daily living. There is often associated emotional lability or obsessive-compulsive traits, which may last longer than the chorei­ form movements (which usually resolve within 6 weeks but sometimes may take up to 6 months). More than 50% of patients presenting with chorea will have carditis, for which reason echocardiography should be part of the workup. ■ ■SKIN MANIFESTATIONS The classic rash of ARF is erythema marginatum (Chap. 21), which begins as pink macules that clear centrally, leaving a serpiginous, spreading edge. The rash is evanescent, appearing and disappearing before the examiner’s eyes. It occurs usually on the trunk, sometimes on the limbs, but almost never on the face. Subcutaneous nodules occur as painless, small (0.5–2 cm), mobile lumps beneath the skin overlying bony prominences, particularly of the hands, feet, elbows, occiput, and occasionally the vertebrae. They are a delayed manifestation, appearing 2–3 weeks after the onset of disease, last for just a few days up to 3 weeks, and are commonly associated with carditis. TABLE 371-1  Staging of Rheumatic Heart Disease Detected by Echocardiographya,b Stage A: Minimal Echocardiographic Criteria for RHD Applies only to individuals aged ≤20 years old • Clinical risk: might be at risk of valvular heart disease progression • Echocardiographic features: the presence of mildc MR or AR without morphologic features Stage B: Mild RHD Can apply to any age • Clinical risk: at moderate or high risk of progression and at risk of developing symptoms of valvular heart disease • Echocardiographic features: evidence of mildc valvular regurgitation plus at least one morphologic feature in individuals aged ≤20 years and at least two morphologic features in individuals aged >20 yearsd; or mild regurgitation in both mitral and aortic valves Stage C: Advanced RHD at Risk of Clinical Complications Can apply to any age • Clinical risk: at high risk of developing clinical complications that require medical or surgical intervention • Echocardiographic features: moderate or severe MR, moderate or severe AR, any MS or ASe, pulmonary hypertension, and decreased LV systolic function Stage D: Advanced RHD with Clinical Complications Can apply to any age • Clinical risk: established clinical complications include cardiac surgery, heart failure, arrhythmia, stroke, and infective endocarditis • Echocardiographic features: moderate or severe MR, moderate or severe AR, any MS or ASe, pulmonary hypertension, and decreased LV systolic function aTo be applied in high-risk settings and requires other causes of valvular heart disease to have been excluded. bAfter the application of the confirmatory echocardiographic criteria, diagnostic categories might include “normal” and “other,” which encompasses other diseases such as congenital heart disease, cardiomyopathies, and pericardial effusion. cFulfilling the confirmatory criteria for pathologic regurgitation (see Source). dThis cutoff value is derived from expert consensus. eAortic stenosis is defined in accordance with international guidelines on valvular heart disease. A diagnosis of rheumatic aortic stenosis requires the exclusion of other causes, including bicuspid aortic valve and degenerative calcific AS. Abbreviations: AR, aortic regurgitation; AS, aortic stenosis; LV, left ventricular; MR, mitral regurgitation; MS, mitral stenosis, RHD, rheumatic heart disease. Source: Reproduced with permission from J Rwebembera et al: 2023 World Heart Federation guidelines for the echocardiographic diagnosis of rheumatic heart disease. Nat Rev Cardiol 21:250; 2023. ■ ■OTHER FEATURES Fever occurs in most cases of ARF, although rarely in cases of pure chorea. Although high-grade fever (≥39°C) is the rule, lower grade temperature elevations are not uncommon. Elevated acute-phase reac­ tants are also present in most cases. ■ ■EVIDENCE OF A PRECEDING GROUP A STREPTOCOCCAL INFECTION With the exception of chorea and low-grade carditis, both of which may become manifest many months later, evidence of a preceding group A streptococcal infection is essential in making the diagnosis of ARF. Because most cases do not have a positive throat swab culture or rapid antigen test, serologic evidence is usually needed. The most com­ mon serologic tests are the anti-streptolysin O (ASO) and anti-DNase B (ADB) titers. Where possible, age-specific reference ranges should be determined in a local population of healthy people without a recent group A streptococcal infection. ■ ■CONFIRMING THE DIAGNOSIS Because there is no definitive test, the diagnosis of ARF relies on the presence of a combination of typical clinical features together with evidence of the precipitating group A streptococcal infection, and the exclusion of other diagnoses. This uncertainty led Dr. T. Duckett Jones in 1944 to develop a set of criteria (subsequently known as the Jones criteria) to aid in the diagnosis. The most recent revision of the Jones criteria (Table 371-2) requires the clinician to determine if the patient is from a setting or population known to experience low rates of ARF. TABLE 371-2  Jones Criteria A. For All Patient Populations with Evidence of Preceding Group A Streptococcal Infection Diagnosis: initial ARF 2 major manifestations or 1 major plus 2 minor manifestations Diagnosis: recurrent ARF 2 major or 1 major and 2 minor or 3 minor B. Major Criteria Low-risk populationsa Moderate- and high-risk populations   Carditisb   Carditis • Clinical and/or subclinical • Clinical and/or subclinical Arthritis Arthritis • Polyarthritis only • Monoarthritis or polyarthritis • Polyarthralgiac   Chorea Chorea   Erythema marginatum Erythema marginatum   SC nodules SC nodules C. Minor Criteria Low-risk populationsa Moderate- and high-risk populations   Polyarthralgia   Monoarthralgia   Fever (≥38.5°C)   Fever (≥38°C)   ESR ≥60 mm in the first hour and/or CRP ≥3.0 mg/dLd   ESR ≥30 mm/h and/or CRP ≥3.0 mg/dLd   Prolonged PR intervale, after   Prolonged PR intervale, after accounting for age variability (unless carditis is a major criterion) accounting for age variability (unless carditis is a major criterion) aLow-risk populations are those with ARF incidence ≤2 per 100,000 school-age children or all-age rheumatic heart disease prevalence of ≤1 per 1000 population per year. bSubclinical carditis indicates echocardiographic valvulitis. (See source document.) cPolyarthralgia should only be considered as a major manifestation in moderate- to high-risk populations after exclusion of other causes. As in past versions of the criteria, erythema marginatum and SC nodules are rarely “standalone” major criteria. Additionally, joint manifestations can only be considered in either the major or minor categories but not both in the same patient. (See source document for more information.) dCRP value must be greater than upper limit of normal for laboratory. Also, because ESR may evolve during the course of ARF, peak ESR values should be used. eProlonged PR interval can only be considered in the absence of carditis as a major criterion. Abbreviations: ARF, acute rheumatic fever; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; SC, subcutaneous. Source: Reproduced with permission from MH Gewitz et al: Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: A scientific statement from the American Heart Association. Circulation 131(20):1806, 2015. https://www.ahajournals.org/doi/full/10.1161/ CIR.0000000000000205. For this group, there is a set of “low-risk” criteria; for all others, there is a set of more sensitive criteria. TREATMENT Acute Rheumatic Fever Patients with possible ARF should be followed closely to ensure that the diagnosis is confirmed, treatment of heart failure and other symptoms is undertaken, and preventive measures including com­ mencement of secondary prophylaxis, inclusion on an ARF registry, and health education are commenced. Echocardiography should be performed on all possible cases to aid in making the diagnosis and to determine the severity at baseline of any carditis. Other tests that should be performed are listed in Table 371-3. There is no treatment for ARF that has been proven to alter the likelihood of developing, or the severity of, RHD. With the excep­ tion of treatment of heart failure, which may be lifesaving in cases of severe carditis, the treatment of ARF is symptomatic. ANTIBIOTICS All patients with ARF should receive antibiotics sufficient to treat the precipitating group A streptococcal infection (Chap. 153). Penicil­ lin is the drug of choice and can be given orally (as phenoxymethyl TABLE 371-3  Testing and Monitoring of ARF in the Acute Setting Investigations Always request: • Electrocardiogram (ECG) • Echocardiogram • Complete blood count (CBC) • C-reactive protein (CRP) • Streptococcal serology (antistreptolysin and anti-DNase B) In relevant situations: • Throat swab • Skin sore swab • Blood cultures • Synovial fluid aspirate CHAPTER 371 Acute Rheumatic Fever • Ensure sample does not clot by using correct tubes that have been well mixed and transported promptly to the laboratory • Include request for cell count, microscopy, culture, and gonococcal polymerase chain reaction (PCR) • Pregnancy test • Creatinine test (UEC [urea, electrolytes, creatinine]) since nonsteroidal anti-inflammatory drugs can affect renal function Tests to exclude alternative diagnoses, depending on clinical presentation and locally endemic infections: • Autoantibodies, double-stranded DNA, anti–cyclic citrullinated peptide (anti-CCP) antibodies • Urine for Neisseria gonorrhoeae molecular test • Urine for Chlamydia trachomatis molecular test • Serologic or other testing for viral hepatitis, Yersinia spp., cytomegalovirus (CMV), parvovirus B19, respiratory viruses, Ross River virus, Barmah Forest virus Source: Reproduced with permission from RDHAustralia, Menzies School of Health Research. RHDAustralia (ARF/RHD writing group). The 2020 Australian guideline for prevention, diagnosis and management of acute rheumatic fever and rheumatic heart disease (3rd edition); 2020. Available at https://www.rhdaustralia.org.au/ arf-rhd-guideline. penicillin, 500 mg [250 mg for children ≤27 kg] PO twice daily, or amoxicillin, 50 mg/kg [maximum, 1 g] daily, for 10 days) or as a single dose of 1.2 million units (600,000 units for children ≤27 kg) IM benzathine penicillin G. SALICYLATES AND NSAIDS These may be used for the treatment of arthritis, arthralgia, and fever once the diagnosis is confirmed. They are of no proven value in the treatment of carditis or chorea. Aspirin has traditionally been the first-line choice, delivered at a dose of 50–60 mg/kg per day, up to a maximum of 80–100 mg/kg per day (4–8 g/d in adults) in 4–5 divided doses. At higher doses, the patient should be monitored for symptoms of salicylate toxicity such as nausea, vomiting, or tinnitus; if symptoms appear, lower doses should be used. Owing to the frequency of gastrointestinal side effects and the potential of more severe adverse effects of aspirin, many clini­ cians now prefer to use naproxen at a dose of 10–20 mg/kg per day because it may be safer than aspirin and has the advantage of twicedaily dosing. When the acute symptoms are substantially resolved, usually within the first 2 weeks, patients on higher doses of antiinflammatory medications can have the dose reduced for a further 2–4 weeks. Fever, joint manifestations, and elevated acute-phase reactants sometimes recur up to 3 weeks after the medication is discontinued. This does not indicate a recurrence and can be man­ aged by recommencing anti-inflammatory agents for a brief period. CONGESTIVE HEART FAILURE Glucocorticoids  The use of glucocorticoids in ARF remains con­ troversial. Two meta-analyses have failed to demonstrate a benefit of glucocorticoids compared to placebo or salicylates in improving the short- or longer-term outcome of carditis. However, the studies included in these meta-analyses all took place >40 years ago and did not use medications in common usage today. There are some recent data that suggest corticosteroids improve laboratory, radiologic, and echocardiographic parameters in carditis. Many clinicians treat cases of severe carditis (causing heart failure) with glucocorticoids in the belief that they may reduce the acute inflammation and result in more rapid resolution of failure. However, the potential benefits of this treatment should be balanced against the possible adverse effects. If used, prednisone or prednisolone is recommended at a dose of 1–2 mg/kg per day (maximum, 80 mg), usually for a few days or up to a maximum of 3 weeks. MANAGEMENT OF HEART FAILURE See Chap. 265. BED REST Traditional recommendations for long-term bed rest, once the cor­ nerstone of management, are no longer widely practiced. Instead, bed rest should be prescribed as needed while arthritis and arthral­ gia are present and for patients with heart failure. Once symptoms are well controlled, gradual mobilization can commence as tolerated. CHOREA Medications to control the abnormal movements do not alter the duration or outcome of chorea. Milder cases can usually be man­ aged by providing a calm environment. In patients with severe cho­ rea, carbamazepine or sodium valproate is preferred to haloperidol. A response may not be seen for 1–2 weeks, and medication should be continued for 1–2 weeks after symptoms subside. There is recent evidence that corticosteroids are effective and lead to more rapid symptom reduction in chorea. They should be considered in severe or refractory cases. Prednisone or prednisolone may be commenced at 0.5 mg/kg daily, with weaning as early as possible, preferably after 1 week if symptoms are reduced, although slower weaning or temporary dose escalation may be required if symptoms worsen. INTRAVENOUS IMMUNOGLOBULIN (IVIG) Small studies have suggested that IVIg may lead to more rapid reso­ lution of chorea but have shown no benefit on the short- or longterm outcome of carditis in ARF without chorea. In the absence of better data, IVIg is not recommended except in cases of severe chorea refractory to other treatments. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders PROGNOSIS Untreated, ARF lasts on average 12 weeks. With treatment, patients are usually discharged from hospital within 1–2 weeks. Inflammatory markers should be monitored every 1–2 weeks until they have normal­ ized (usually within 4–6 weeks), and an echocardiogram should be performed after 1 month to determine if there has been progression of carditis. Cases with more severe carditis need close clinical and echo­ cardiographic monitoring in the longer term. Once the acute episode has resolved, the priority in management is to ensure long-term clinical follow-up and adherence to a regimen of secondary prophylaxis. Patients should be entered onto the local ARF registry (if present) and contact made with primary care practitioners to ensure a plan for follow-up and administration of secondary prophy­ laxis before the patient is discharged. Patients and their families should also be educated about their disease, emphasizing the importance of adherence to secondary prophylaxis. PREVENTION ■ ■PRIMARY PREVENTION Ideally, primary prevention would entail elimination of the major risk factors for streptococcal infection, particularly overcrowded housing. This is difficult to achieve in most places where ARF is common but must remain a priority in ongoing efforts to achieve global control of ARF and RHD. Concerted international efforts are underway to develop a vaccine against group A Streptococcus that would prevent infection of the throat or skin and consequently prevent ARF in the absence of a suitable vac­ cine; however, the mainstay of primary prevention for ARF remains primary prophylaxis (i.e., the timely and complete treatment of group A streptococcal sore throat with antibiotics). If commenced within 9 days of sore throat onset, a course of penicillin (as outlined above for treatment of ARF) will prevent almost all cases of ARF that would oth­ erwise have developed. In settings where ARF and RHD are common but microbiologic diagnosis of group A streptococcal pharyngitis is not available, such as in resource-poor countries, primary care guidelines sometimes recommend that all patients with sore throat be treated with penicillin (an approach that has the potential drawbacks that come from antibiotic overuse, including side effects and increasing pres­ sure on antimicrobial resistance in group A Streptococcus or bystander pathogens) or, alternatively, that a clinical algorithm be used to identify patients with a higher likelihood of group A streptococcal pharyngitis. Although imperfect, such approaches recognize the importance of ARF prevention at the expense of overtreating many cases of sore throat that are not caused by group A Streptococcus. Although there is no proof that antibiotic treatment of group A streptococcal skin infections can prevent ARF, the increasing evidence that impetigo is strongly associ­ ated with ARF in some populations argues for a focus on treatment and prevention of group A streptococcal skin infections as part of a comprehensive ARF control strategy in regions with endemic impetigo. ■ ■SECONDARY PREVENTION The mainstay of controlling ARF and RHD is secondary prevention. Because patients with ARF are at dramatically higher risk than the gen­ eral population of developing a further episode of ARF after a group A streptococcal infection, they should receive long-term penicillin prophylaxis to prevent recurrences. The best antibiotic for secondary prophylaxis is benzathine penicillin G (1.2 million units, or 600,000 units if ≤27 kg) delivered intramuscularly every 4 weeks. It can be given every 3 weeks, or even every 2 weeks, to persons considered to be at particularly high risk, although in settings where good compliance with an every-4-week dosing schedule can be achieved, more frequent dosing is rarely needed. Evidence has emerged recently that subcutane­ ous delivery of benzathine penicillin G provides more optimal pharma­ cokinetics than intramuscular delivery and may have added advantages of reducing pain and allowing for larger doses to be delivered less frequently, although this approach is yet to be recommended in clinical guidelines. Oral penicillin V (250 mg) can be given twice daily instead but is less effective than benzathine penicillin G. Penicillin-allergic patients can receive erythromycin (250 mg) twice daily. The duration of secondary prophylaxis is determined by many fac­ tors, in particular the duration since the last episode of ARF (recur­ rences become less likely with increasing time), age (recurrences are less likely with increasing age), and the severity of RHD (if severe, it may be prudent to avoid even a very small risk of recurrence because of the potentially serious consequences) (Table 371-4). Secondary prophylaxis is best delivered as part of a coordinated RHD control pro­ gram, based around a registry of patients. Registries improve the ability to follow patients and identify those who default from prophylaxis and to institute strategies to improve adherence. TABLE 371-4  American Heart Association Recommendations for Duration of Secondary Prophylaxisa CATEGORY OF PATIENT DURATION OF PROPHYLAXIS Rheumatic fever without carditis For 5 years after the last attack or 21 years of age (whichever is longer) Rheumatic fever with carditis but no residual valvular disease For 10 years after the last attack, or 21 years of age (whichever is longer) Rheumatic fever with persistent valvular disease, evident clinically or on echocardiography For 10 years after the last attack, or 40 years of age (whichever is longer); sometimes lifelong prophylaxis aThese are only recommendations and must be modified by individual circumstances as warranted. Note that some organizations recommend a minimum of 10 years of prophylaxis after the most recent episode, or until 21 years of age (whichever is longer), regardless of the presence of carditis with the initial episode. Source: Reproduced with permission from MA Gerber et al: Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis. Circulation 119:1541, 2009. https://www.ahajournals.org/doi/10.1161/ CIRCULATIONAHA.109.191959?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref. org&rfr_dat=cr_pub%20%200pubmed. # 16 - 373 Sjögren’s Disease ### 373 Sjögren’s Disease dermatomyositis (heliotrope rash on the eyelids, erythematous rash on knuckles) may occur. Arthralgia is common, and some patients develop erosive polyarthritis. Pulmonary fibrosis and isolated or sec­ ondary PAH may develop. Other manifestations include esophageal dysmotility, pericarditis, Sjögren’s syndrome, and renal disease, espe­ cially membranous glomerulonephritis. Laboratory evaluation shows elevated ESR and hypergammaglobulinemia. In contrast to SSc, MCTD often responds to glucocorticoids, and the long-term prognosis is bet­ ter than that of SSc. Whether MCTD is truly a distinct entity or is a subset of SLE or SSc remains controversial. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders EOSINOPHILIC FASCIITIS (DIFFUSE FASCIITIS WITH EOSINOPHILIA) Eosinophilic fasciitis is a rare idiopathic disorder of adults associated with abrupt skin induration. The skin characteristically shows a coarse cobblestone “peau d’orange” appearance. In contrast to SSc, Raynaud’s phenomenon and SSc-associated internal organ involvement and autoantibodies are absent. Furthermore, skin involvement spares the fingers. Full-thickness biopsy of the lesional skin reveals fibrosis of the subcutaneous fascia, with variable inflammation and eosinophil infil­ tration. In the acute phase of the illness, peripheral blood eosinophilia may be prominent. MRI appears to be a sensitive tool for the diagnosis of eosinophilic fasciitis. Eosinophilic fasciitis can occur in association with, or preceding, various myelodysplastic syndromes or multiple myeloma. Although glucocorticoids cause prompt resolution of eosin­ ophilia, the skin shows slow and variable improvement. The prognosis of patients with eosinophilic fasciitis is generally good. ■ ■FURTHER READING Allanore Y et al: Systemic sclerosis. Nat Rev Dis Primers 1:15002, 2015. Herzog EL et al: Interstitial lung disease associated with systemic sclerosis and idiopathic pulmonary fibrosis: How similar or distinct? Arthritis Rheum 66:1967, 2014. Joseph CG et al: Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343:152, 2014. Martyanov V, Whitfield ML: Molecular stratification and precision medicine in systemic sclerosis from genomic and proteomic data. Curr Opin Rheumatol 28:83, 2016. Tashkin DP et al: Mycophenolate mofetil versus oral cyclophospha­ mide in scleroderma-related interstitial lung disease (SLS II): A ran­ domised controlled, double-blind, parallel group trial. Lancet Respir Med 4:708, 2016. Haralampos M. Moutsopoulos, Clio P. Mavragani Sjögren’s Disease ■ ■DEFINITION, INCIDENCE, AND PREVALENCE Sjögren’s disease is a prototype autoimmune disease characterized by lymphocytic infiltration of the exocrine glands resulting in xerostomia, dry eyes (keratoconjunctivitis sicca), and profound B-cell hyperactivity. The disease has unique features since it presents with a wide clinical spectrum from organ-specific to systemic disease; can occur alone or in association with other systemic rheumatic diseases, more com­ monly rheumatoid arthritis, limited scleroderma, and systemic lupus erythematosus; and displays high probability of the development of lymphoma. Because of all these characteristics, it is an ideal model to study not only autoimmunity but also lymphoid malignancy. Middle-aged women (female-to-male ratio 10–20:1) are primarily affected, although Sjögren’s disease may occur at any age, including childhood. Patients with earlier disease onset express a more aggres­ sive disease phenotype manifested by a high occurrence of systemic manifestations and serum autoantibodies. The prevalence of Sjögren’s disease is ~0.5–1%, while 5–20% of patients with other autoimmune diseases can express sicca manifestations. ■ ■PATHOGENESIS The autoimmune phenomena observed in Sjögren’s disease include lymphocytic infiltration of the exocrine glands (primarily salivary and lachrymal glands) and B lymphocyte hyperreactivity. The latter is mainly manifested by hypergammaglobulinemia and the pres­ ence of serum autoantibodies toward non-organ-specific antigens such as immunoglobulins (rheumatoid factors) and extractable cel­ lular antigens (Ro52, Ro60, and La). The major infiltrating cells in the affected exocrine glands are activated T lymphocytes. In labial minor salivary gland tissues with extensive lymphocytic infiltrations, B-cell populations prevail. Other cellular subsets detected in the labial minor salivary gland histopathologic lesion of Sjogren’s disease include follicular, myeloid, and plasmacytoid dendritic cells, as well as macrophages. The latter along with inflammasome activation have been shown to be associated with increased risk for lymphoma development. The interplay of endogenous (e.g., intracellular stress, inappropriate overexpression of endogenous nucleic acids) and exogenous triggers (e.g., viruses, hormonal triggers, stressful life events) in a background of a genetically determined hyperactive immune response seems to be crucial for the initiation and perpetuation of the disease. Ductal and acinar epithelial cells appear to play a significant role in the initiation and perpetuation of autoimmune injury. These cells (1) express inap­ propriately costimulatory molecules and the intracellular autoantigens Ro and La on their cell surfaces, acquiring the capacity to provide sig­ nals essential for lymphocytic activation; (2) produce proinflammatory cytokines and lymphocyte-attracting chemokines necessary for sus­ taining the autoimmune lesion and allowing the formation of ectopic germinal centers; (3) express functional receptors of innate immunity, particularly Toll-like receptors (TLRs) 3, 7, and 9 molecules, which may account for the initiation of the autoimmune reactivity; and (4) display immunoregulatory molecules such as ICAM and CD40. Glan­ dular epithelial cells also seem to have an active role in the production of B cell–activating factor (BAFF), which is induced after stimulation with type I and II interferons. Circulating BAFF has been found to be elevated also in the serum of Sjögren’s disease patients, especially those with hypergammaglobulinemia and serum autoantibodies, and prob­ ably accounts for the antiapoptotic effect on B lymphocytes. In contrast to B and T lymphocytes, glandular epithelial cells dis­ play increased rates of apoptotic death. Established risk genetic loci implicated in Sjögren’s disease include the human leukocyte antigen DQA1∗0501 allele, variations involved in the interferon/BAFF axis (IRF5, STAT4, BAFF) and B-cell function (EBF1, BLK), as well as com­ bined genetic deficiencies in the classical complement pathway. CLINICAL MANIFESTATIONS Most patients with Sjögren’s disease have symptoms related to impaired exocrine gland, particularly lacrimal and salivary gland, function. The disease evolution is slow and, in the majority of patients, runs a benign course. Studies have shown that prior to disease onset, patients with Sjögren’s disease experience major stressful life events with which they cannot cope adequately. The principal oral symptom of Sjögren’s disease is dryness (xero­ stomia). Patients report difficulty in swallowing dry food, a burning mouth sensation, an increase in dental caries, and problems in wearing complete dentures. Physical examination shows a dry, erythematous sticky oral mucosa. In patients with severe oral dryness, the filiform papillae on the tongue dorsum are atrophic, and the tongue is deeply fissured (Fig. 373-1). Furthermore, saliva from the major glands is either not expressible or cloudy. Intermittent or persistent enlargement of the parotid or other major salivary glands occurs in two-thirds of patients with Sjögren’s disease. Diagnostic tests include sialometry and several imaging techniques, including ultrasound, magnetic resonance FIGURE 373-1  A dry deeply fissured tongue from a patient with Sjögren’s disease. imaging (MRI), and magnetic resonance sialography of the major salivary glands. In particular, salivary gland ultrasound is an emerg­ ing tool of both diagnostic and prognostic utility. Biopsy of the labial minor salivary gland allows histopathologic confirmation of focal lymphocytic infiltrates. Ocular involvement is the other major manifestation of Sjögren’s disease. Patients usually report a sandy or gritty feeling under the eye­ lids. Other ocular symptoms include burning, accumulation of secre­ tions in thick strands at the inner canthi, decreased tearing, redness, itching, eye fatigue, and increased photosensitivity. These symptoms are attributed to the destruction of corneal and bulbar conjunctival epithelium, a pathology termed keratoconjunctivitis sicca. Diagnostic evaluation of keratoconjunctivitis sicca includes measurement of tear flow by Schirmer’s I test, determination of tear composition by tear breakup time or tear lysozyme content, and slit-lamp examination of the cornea and conjunctiva after lissamine green or Rose Bengal stain­ ing that reveals punctuate corneal and bulbar conjunctival ulcerations and attached filaments. Involvement of other exocrine glands, which occurs less frequently, includes a decrease in mucous gland secretions of the upper and lower respiratory tree, resulting in dry nose, throat, and trachea (xerotra­ chea). In addition, diminished secretion of the exocrine glands of the gastrointestinal tract leads to esophageal mucosal dysmotility and atro­ phic gastritis. Dyspareunia, in premenopausal women, due to dryness of the external genitalia and dry skin also may occur. Extraglandular (systemic) manifestations are seen in one-third of patients with Sjögren’s disease (Table 373-1) and can be classified as follows: nonspecific, periepithelial (surrounding of epithelial tissues by lymphocytes), immune complex–mediated, and lymphoma. Nonspecific manifestations include fatigability, low-grade fever, Raynaud’s phe­ nomenon, myalgias, arthralgias, and arthritis. Arthritis in patients with primary Sjögren’s disease is nonerosive. Periepithelial pathology due to periepithelial accumulation of lymphocytes results from the involvement of parenchymal organs such as the lungs, kidneys, and liver. On the basis of this observation, one of the authors (H.M.M.) has coined the term autoimmune epithelitis. Lung involvement is usually manifested with dry cough and rarely with dyspnea. The underlying lung pathology includes peribronchial infiltrates (bronchitis sicca) and interstitial pneumonitis. Renal involvement includes interstitial TABLE 373-1  Prevalence of Extraglandular Manifestations in Primary Sjögren’s disease CLINICAL MANIFESTATION PERCENT REMARKS Nonspecific CHAPTER 373 Fatigability/myalgias Fibromyalgia Arthralgias/arthritis Usually nonerosive, leading to Jaccoud’s arthropathy Raynaud’s phenomenon In one-third of patients, precedes sicca manifestations Sjögren’s Disease Periepithelial Lung involvement Small airway disease/lymphocyte interstitial pneumonitis Kidney involvement Interstitial kidney disease is usually asymptomatic Liver involvement Primary biliary cirrhosis stage I Immune complex–mediated Small vessel vasculitis Purpura, urticarial lesions Peripheral neuropathy Polyneuropathy, either sensory or sensorimotor Glomerulonephritis Membranoproliferative Lymphoma Lymphoma Glandular MALTa lymphoma is most common aMucosa-associated lymphoid tissue. nephritis, clinically manifested by hyposthenuria and renal tubular dysfunction with or without acidosis. Untreated acidosis may lead to nephrocalcinosis. Immune complex–mediated disease is expressed with vasculitis affecting primarily small-sized vessels, mainly manifested with purpura and rarely with urticarial rash, skin ulcerations, mono­ neuritis multiplex, and membranoproliferative glomerulonephritis associated with mixed type II or III cryoglobulinemia. Central nervous system involvement is rarely recognized. A few cases of myelitis associ­ ated with antibodies to aquaporin 4 have been described. Sjögren’s disease is characterized by the highest risk for lymphoma development among all autoimmune diseases with clinical, labora­ tory, and histopathologic features being designated as risk factors (Fig. 373-2). Despite that the pathogenesis of lymphoma in the set­ ting of Sjögren’s disease remains to be elucidated, genetic alterations involved in chronic inflammatory, B-cell activation, and the type I and II interferon pathways, as well as epigenetic abnormalities, have been shown to be significant contributors. Of interest, B cells producing cryoglobulins were shown to harbor mutations in genes recurrently mutated in B-cell malignancies. Most lymphomas are extranodal, low-grade, marginal zone B-cell lymphomas and are usually detected incidentally during evaluation of the labial minor salivary gland biopsy. The affected lymph nodes are usually peripheral. Survival rates are decreased in patients with B symptoms, lymph node mass >7 cm in diameter, and high or intermediate histologic grade. Fluorodeoxyglu­ cose positron emission tomography (FDG-PET)/computed tomogra­ phy (CT) can be a useful tool to exclude lymphoma when suspected. In line with observations in rheumatoid arthritis and systemic lupus erythematosus, patients with Sjögren’s disease also display an increased risk of cardiovascular disease. Routine laboratory tests in Sjögren’s disease can reveal leukopenia and infrequently lymphopenia. In two-thirds of patients, elevated erythrocyte sedimentation rate, hypergammaglobulinemia, antinuclear antibodies, rheumatoid factors, and antibodies against Ro52/Ro60 and La autoantigens are detected. Anticentromere autoantibodies are pres­ ent in Sjögren’s patients with a clinical picture similar to that of limited scleroderma (Chap. 372), while the presence of antimitochondrial antibodies may connote liver involvement in the form of autoim­ mune cholangitis (Chap. 357). Autoantibodies to 21-hydroxylase are found in patients with a blunted adrenal response, while autoan­ tibodies to citrullinated peptides are seen in Sjögren’s patients with Hematologic/Serologic Leukopenia Autoantibodies (Rheumatoid factor, against Ro/SSA and La/SSB autoantigens) PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Low C4 complement levels Monoclonal gammopathy Cryoglobulins Clinical Parotid gland enlargement Severe tongue atrophy Palpable purpura FIGURE 373-2  Sjögren’s disease risk factors for lymphoma development. arthritis. Anticalponin-3 antibodies have been recently associated with the occurrence of peripheral neuropathies. ■ ■DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS Sjögren’s disease should be suspected if a patient presents with eye and/or mouth dryness, major salivary gland enlargement, or systemic manifestations such as Raynaud’s phenomenon, palpable purpura, or symptomatology of renal tubular acidosis. A careful history of medica­ tions causing dryness should be obtained. Recently, cases of Sjögren’s disease were triggered by PD-1/PD-L1 checkpoint inhibitors. The workup should include eye tests that might reveal keratocon­ junctivitis sicca, salivary flow tests or ultrasonography, and serum TABLE 373-2  Differential Diagnosis of Sicca Symptoms BILATERAL PAROTID GLAND ENLARGEMENT XEROSTOMIA DRY EYE Viral infections (HCV, HIV) Drugs   Psychotherapeutic   Parasympatholytic   Antihypertensive Psychogenic origin Irradiation Diabetes mellitus Trauma Sjögren’s disease Amyloidosis Autoimmune thyroid disease   Inflammation   Stevens-Johnson Viral infections   Mumps   Influenza   Epstein-Barr virus   Coxsackievirus A   Cytomegalovirus   HIV, HCV Sarcoidosis, tuberculosis IgG4-related disease Sjögren’s disease Metabolic disorders   Diabetes mellitus   Hyperlipoproteinemias syndrome   Pemphigoid   Chronic conjunctivitis   Chronic blepharitis   Sjögren’s Disease Toxicity   Burns   Drugs Neurologic conditions   Impaired lacrimal gland function   Impaired eyelid (types IV and V)   Chronic pancreatitis   Hepatic cirrhosis Endocrine   Acromegaly   Gonadal hypofunction Eosinophilic sialodochitis Lymphoma function Miscellaneous   Trauma   Hypovitaminosis A   Blink abnormality   Anesthetic cornea   Lid scarring   Epithelial irregularity   Autoimmune thyroid disease Abbreviation: HCV, hepatitis C virus. Histopathologic (salivary gland tissues) Germinal center formation Heavy focal lymphocytic infiltrates Lymphoma related to Sjögren’s disease evaluation for specific autoantibodies. Testing for chronic viral infec­ tions (hepatitis C virus, HIV), chest x-ray to rule out sarcoidosis, protein electrophoresis, IgG4 serum levels, and autoantibodies to thyroid antigens can be also offered. Labial biopsy is valuable to rule out conditions that may cause dry mouth, dry eyes, or parotid gland enlargement (Tables 373-2 and 373-3). A diagnostic algorithm based on recent classification criteria (2016 American College of Rheumatology– European League Against Rheumatism [EULAR] Classification Crite­ ria) is presented in Fig. 373-3. TREATMENT Sjögren’s Disease Treatment of Sjögren’s disease aims to relieve symptoms and limit the damage from chronic xerostomia and keratoconjunctivitis sicca through substitution or stimulation of impaired secretions. To replace deficient tears, several ophthalmic preparations are readily available (hydroxypropyl methylcellulose; polyvinyl alcohol; 0.5% methylcellulose; Hypo Tears). If corneal ulcerations are present, eye patching and boric acid ointments are recommended, as well as cyclosporine eye drops. Certain drugs that may decrease lacrimal and salivary secretions, such as diuretics, antihypertensive drugs, anticholinergics, and antidepressants, should be avoided. For xerostomia, the best replacement is water. Propionic acid gels may be used to treat vaginal dryness. To stimulate secretions, orally administered pilocarpine (5 mg thrice daily) or cevimeline (30 mg TABLE 373-3  Differential Diagnosis of Sjögren’s disease HIV INFECTION AND SICCA SYNDROME SJÖGREN’S DISEASE SARCOIDOSIS Predominant in young males Predominant in middleaged women No age or sex preference Lack of autoantibodies to Ro and/or La Presence of autoantibodies Lack of autoantibodies to Ro and/or La Lymphoid infiltrates of salivary glands by CD8+ T lymphocytes Lymphoid infiltrates of salivary glands by CD4+ T lymphocytes Granulomas in salivary glands Association with HLA-DR5 Association with HLA-DR3 and DRw52 Unknown Positive serologic tests for HIV Negative serologic tests for HIV Negative serologic tests for HIV # 17 - 374 Spondyloarthritis ### 374 Spondyloarthritis Dry eyes and/or dry mouth1 And/or Major salivary gland enlargement, fatigue, Raynaud’s phenomenon, arthralgias/arthritis (particularly small hand joints), palpable purpura/urticarial lesions, renal tubular acidosis/membranoproliferative glomerulonephritis, ILD/small airways disease, autoimmune cholangitis, peripheral neuropathy, MS-like lesions Ocular staining score ≥5 (or van Bijsterveld’s score ≥4) on at least one eye2 Unstimulated whole saliva flow rate ≤0.1 mL/min Schirmer’s test ≤5 mm/5 min on at least one eye If any of those present If any of those present + Sjögren’s disease FIGURE 373-3  Diagnostic algorithm for Sjögren’s disease. 1Defined as a positive response to at least one of the following questions: (a) Have you had daily, persistent, troublesome dry eyes for more than 3 months? (b) Do you have a recurrent sensation of sand or gravel in the eyes? (c) Do you use tear substitutes more than three times a day? (d) Have you had a daily feeling of dry mouth for more than 3 months? (e) Do you frequently drink liquids to aid in swallowing dry food? 2Ocular staining score described in Whitcher et al. van Bijsterveld score described in van Bijsterveld et al. 3Focus score count ≥1 (based on the number of foci per 4 mm2 of salivary gland tissue) following a protocol described in Daniels et al. ILD, interstitial lung disease; MS, multiple sclerosis. thrice daily) appears to improve sicca manifestations, and both are well tolerated. Hydroxychloroquine (200 to 400 mg daily) and/or methotrexate (0.2–0.3 mg/kg body weight/weekly) are helpful for arthralgias and mild arthritis. Patients with renal tubular acidosis should receive sodium bicar­ bonate by mouth (0.5–2 mmol/kg in four divided doses). Gluco­ corticoids and monoclonal antibody to CD20 (rituximab) appear to be effective in patients with systemic disease, particularly in those with purpura and persistent arthritis. Novel monoclonal antibodies targeting the CD40L/CD40 costimulatory pathway or the BAFF receptor or sequential treatment of belimumab and rituximab seem to be promising therapeutic strategies. Data for a beneficial role of other conventional immunosuppressants are limited. Treatment of lymphoma in the setting of Sjögren’s disease follows the general guidelines for lymphoma management in the general population. Detailed recommendations on Sjögren’s disease management have been issued by EULAR and British Society of Rheumatology. ■ ■FURTHER READING Daniels TE et al: Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjögren’s syndrome among 1,726 registry participants. Arthritis Rheum 63:2021, 2011. Fragkioudaki S et al: Predicting the risk for lymphoma develop­ ment in Sjogren syndrome: An easy tool for clinical use. Medicine (Baltimore) 95:e3766, 2016. Mavragani CP, Moutsopoulos HM: Sjögren’s syndrome. CMAJ 186:579, 2014. Mavragani CP, Moutsopoulos HM: Sjogren’s syndrome: Old and new therapeutic targets. J Autoimmun 110:102364, 2020. Moutsopoulos HM: Sjögren’s syndrome: A forty-year scientific jour­ ney. J Autoimmun 51:1, 2014. Nocturne G, Mariette X: Expert perspective: Challenges in Sjögren’s disease. Arthritis Rheumatol 75:2078, 2023. Price EJ et al: British Society for Rheumatology guideline on man­ agement of adult and juvenile onset Sjögren disease. Rheumatology (Oxford)16:keae152, 2024. Shiboski CH et al: 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary CHAPTER 374 Exclude History of head and neck radiation treatment Active hepatitis C infection Acquired immunodeficiency syndrome Sarcoidosis Amyloidosis Graft-versus-host disease IgG4-related disease Spondyloarthritis + Serum antibodies against Ro antigen + Minor salivary gland biopsy3 Sjögren’s Syndrome: A consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol 69:35, 2017. van Bijsterveld OP: Diagnostic tests in the Sicca syndrome. Arch Ophthalmol 82:10, 1969. Whitcher JP et al: A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjögren’s Syndrome International Registry. Am J Ophthalmol 149:405, 2010. Atul Deodhar, Dirk Elewaut Spondyloarthritis Spondyloarthritis (SpA) refers to a family of immune-mediated inflammatory arthritis disorders that share many clinical, genetic, and pathologic characteristics. Moll and Wright are credited in recogniz­ ing these diseases in 1974 as distinct from rheumatoid arthritis (RA), a well-recognized inflammatory arthritis at that time. While axial skeletal involvement is hinted at in the word “spondyloarthritis,” it is not mandatory. The musculoskeletal manifestations of SpA include sacroiliitis, inflammatory spinal lesions, peripheral inflammatory arthritis, enthesitis (inflammation at the attachment of tendons and ligaments to the bones), tendonitis, tenosynovitis, and dactylitis (“sau­ sage digits”). Other clinical manifestations include uveitis, skin pso­ riasis, inflammatory bowel disease (IBD, Crohn’s, or ulcerative colitis), absence of rheumatoid factor (RF) and nodules (to differentiate from RA), familial correlation, and association with the gene human leuko­ cyte antigen (HLA)-B27. The 2009 Assessment of Spondyloarthritis International Society (ASAS) classification criteria divided SpA under “axial” (axSpA) and “peripheral” (pSpA). “Peripheral” SpA may seem a misnomer, but it simply indicates that peripheral musculoskeletal TABLE 374-1  Spectrum of Spondyloarthritis SPONDYLOARTHRITIS (SPA) AXIAL SPONDYLOARTHRITIS (axSpA) PERIPHERAL SPONDYLOARTHRITIS (pSpA) CONDITION CLINICAL FEATURES CONDITION CLINICAL FEATURES     Conditions commonly included under pSpA PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Radiographic axSpA (r-axSpA, also called ankylosing spondylitis [AS]) Sacroiliitis grade 2 (bilateral), grade 3 or 4 (unilateral or bilateral) Psoriatic arthritis Skin psoriasis and nail involvement usually preceding arthritis, enthesitis, dactylitis Nonradiographic axSpA (nr-axSpA) Sacroiliitis grade 1 (unilateral or bilateral) or grade 2 (unilateral) Inflammatory bowel disease–associated arthritis     Reactive arthritis Urethritis, history of preceding infection with Salmonella, Shigella, Yersinia, Campylobacter, and Chlamydia, mucosal ulcers, conjunctivitis, keratoderma blennorrhagica     Undifferentiated peripheral SpA Enthesitis, dactylitis, family history of SpA, HLA-B27, acute anterior uveitis, and not fitting in any of the other conditions mentioned above     Conditions sometimes included under pSpA     SAPHO syndrome Synovitis, acne, pustulosis, hyperostosis, and osteitis; typical involvement of anterior chest wall joints     Acne-associated arthritis Acne conglobata, peripheral arthritis     Hidradenitis suppurativa–associated arthritis manifestations are predominant and more troublesome to the patient than the spinal involvement. AxSpA is further divided into radiographic (r-axSpA, also known as ankylosing spondylitis [AS]), and nonradiographic (nr-axSpA). The conditions included under pSpA are psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis associated with IBD, and undifferentiated SpA, where patients cannot be classified under any known categories. Patients with axSpA can have peripheral musculoskeletal manifes­ tations, and patients with pSpA may have additional axial skeletal involvement at presentation or may develop it later in the course of their disease. Other conditions sometimes included under pSpA are SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syn­ drome, acne-associated arthritis, and arthritis associated with hidrad­ enitis suppurativa. Table 374-1 shows the full spectrum of conditions included under “spondyloarthritis.” Pattern recognition is important for the diagnosis of SpA. Typical patterns include asymmetric, mono- or oligoarticular (four or less joints) inflammatory arthritis of large joints in the lower limb (usu­ ally knee), with enthesitis, tendonitis, and dactylitis. This contrasts with RA, where polyarticular symmetric involvement of metacarpo­ phalangeal (MCP)/proximal interphalangeal (PIP) joints predomi­ nates. The cumulative prevalence of all conditions under SpA is 2–3% of the population, much more common than RA. PATHOLOGY OF SPONDYLOARTHRITIS SpA is a prototypic chronic immune-mediated inflammatory disease that couples inflammation to structural damage. A unique feature of SpA is that inflammation-induced bone loss coexists with pathologic new bone formation, which occurs at specific sites in the skeleton. These sites include not only the sacroiliac joint but also the anterior spinal ligaments or at entheses in the peripheral skeleton. If uncon­ trolled, axSpA may ultimately lead to a complete ankylosis of the sacroiliac joints and the spine, termed “bamboo spine.” With increas­ ing awareness of SpA resulting from early diagnosis and treatment, there has been a steady decrease in the amount of structural damage observed over the past decades with a gradual shift of higher preva­ lence from r-AxSpA to nr-AxSpA. While histopathologic studies have led to an increased under­ standing of local inflammatory and structural changes, the acces­ sibility to target tissue particularly in the axial skeleton and tendons/ entheses has been hampered by technical issues. Most of the informa­ tion to date comes from surgically derived specimens from patients with longstanding disease. Accordingly, many of the described Crohn’s disease or ulcerative colitis with inflammatory arthritis Hidradenitis suppurativa, peripheral arthritis, rarely asymmetric sacroiliitis features represent disease under treatment, which inevitably impacts histopathology. Obtaining synovial tissue from an array of joints such as knees, wrists, and small joints in fingers has become much more readily accessible through ultrasound-guided synovial tissue biopsy, which permits study of synovial tissue alterations in an early treatment-naïve stage. PATHOGENESIS OF SPONDYLOARTHRITIS Although the exact mechanisms that initiate the disease are not fully delineated, genetic and environmental risk factors and molecular and cellular alterations at key disease sites have been implicated in the pathophysiology of SpA (Fig. 374-1). At these sites, which include the axial and peripheral joints, entheses, skin, and gut, variation is seen in the disease mechanisms and perturbations of the key cytokine path­ ways. These tissue-based variations are most likely associated with the dissimilar clinical responses observed between the spine, peripheral joints, and gut during treatment with cytokine inhibitors. ■ ■GENETIC ASSOCIATIONS IN AXIAL SPONDYLOARTHRITIS AND OTHER SPONDYLOARTHRITIS: HLA-B27 AND BEYOND HLA-B27 is a major histocompatibility complex (MHC) class I allele that forms the strongest genetic risk factor for SpA and specifically axSpA. MHC class I molecules are expressed on the surface of nucle­ ate cells and can present peptides to CD8+ T cells. HLA-B27 is present in 85–90% of the patients with r-axSpA and 50–90% in nr-axSpA, in contrast to about 5% of the healthy Caucasian population. Besides HLA-B27, other MHC class I genes and non-MHC coding genes have been identified in large genome-wide association stud­ ies (GWAS) in axSpA. Within the group of non-MHC coding genes, genes linked to innate immune processes, interleukin (IL)-23/IL-17 immunity, joint and bone remodeling, epithelial function, and antigen presentation are seen, which are processes relevant in the immuno­ pathogenesis of axSpA. Whether all of these represent independent risk factors is still not clear, although some appear to be interconnected. For example, genetic epistatic interaction has been suggested between ERAP1, a peptide-trimming enzyme, of which single nucleotide poly­ morphisms (SNPs) are associated with AS and HLA-B27. How HLAB27 fosters development of SpA remains unclear despite the discovery of this strong genetic association 50 years ago. At present, several theories exist with limitations to each of them. The “arthritogenic peptide” theory proposes that HLA-B27 pres­ ents pathological microbial peptides to CD8+ cytotoxic T cells that Genetic predisposition e.g., HLA-B27 Gut Gut iNKT MAIT Urogenital system Tc17 Th17 γδT ILC3 Joint Skin IL-17 Axial SpA IBD PsA PsO Fibroblast Fibroblast Fibroblast Fibroblast MAIT ILC3 T17 T17 T17 T17 ILC3 γδT γδT Mø Mø Mø Neutrophil Neutrophil Neutrophil Neutrophil DC AntiIL-17 AntiIL-17 Anti-IL-17 JAKi JAKi JAKi JAKi AntiIL-23 AntiIL-23 Anti-IL-23 Anti-TNF Anti-TNF Anti-TNF AntiTNF FIGURE 374-1  Pathogenesis and signature cytokines across different disease domains in spondyloarthritis (SpA). In genetically predisposed individuals, SpA may arise from mechanical stress, a well-known disease precipitator in psoriatic arthritis and axial SpA, or by altered host-microbial interplay at inner (gut, urogenital tract) or outer (skin) surfaces culminating in a cytokine crosstalk characterized by both tumor necrosis factor (TNF)- and interleukin (IL)-17-driven immune responses. Drivers of disease include cells of both innate and adaptive immune system, along with tissue-resident stromal cells. Different disease domains (gut, spin, peripheral joints, and skin) harbor overlapping (e.g., TNF-α) but also distinct (e.g., IL-17, IL-23) signature cytokines, which has major therapeutic implications. Janus kinase (JAK) inhibitors, which interfere with signaling of several cytokines, are effective across all domains. then target cross-reactive human peptides leading to inflammation and resulting in molecular mimicry. Presumably, this first antigenic exposure could take place in the gut or at the urogenital tract. Several allotypes of HLA-B27 exist, but not all of them represent risk factors for axSpA. For example, HLA-B*2704 and HLA-B*2705 subtypes confer a genetic risk, whereas the HLA-B*2706 and HLA-B*2709 allotypes are not associated with axSpA even though they only differ in one peptide Mechanical strain Barrier integrity loss CHAPTER 374 Urogenital system Spondyloarthritis Skin Neutrophil Mø T cell Joint TNF-α Disease domains ILC3 γδT Mø γδT residue or amino acid. This would suggest that there could be spe­ cific peptides that can only be presented by the pathogenic HLA-B27 subtypes to induce the “arthritogenic” response. In the arthritogenic peptide hypothesis, inflammation is driven by antigen presentation to CD8+ T cells. Existence of HLA-B27-restricted CD8+ T cells in the synovial fluid of AS patients was shown three decades ago, whereas more recent next-generation sequencing T-cell receptor (TCR) studies showed expansion of both CD4+ and CD8+ TCR clonotypes in blood and synovium of HLA-B27-positive SpA. Expansion of CD8+ TCR clonotypes with the CAS **STDTQYF CDR3 motif were found in AS patients versus HLA-B27-positive controls in blood and synovium, which was recently suggested as a target for therapeutic intervention. The second theory relates to the ability of HLA-B27 to homodimer­ ize. These HLA-B27 homodimers can be expressed at the cell surface and interact with innate immune receptors, such as the KIR3DL2 receptor, on T and natural killer (NK) cells resulting in IL-17 produc­ tion, one of the key pathogenic cytokines in axSpA. However, there is still some controversy regarding whether various allotypes of HLA-B27 differ in their ability to form homodimers. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders A third theory links HLA-B27 to unfolded protein responses (UPR) and autophagy, which may promote type 17 immune responses through release of IL-23. Support comes from the HLA-B27 transgenic rat model, while no evidence for an increase in UPR in synovial tissue or blood of HLA-B27-positive AS patients was found in steady state, which questions its role in humans. Although HLA-B27 has the strongest genetic link, other MHC class I associations have also been found, for example (HLA-Cw6) in PsA. IL-23R gene polymorphisms are shared across most forms of SpA. This suggests overlapping yet distinct features across different disease domains. ■ ■FACTORS INSTIGATING THE ONSET OF SPONDYLOARTHRITIS IN GENETICALLY PREDISPOSED INDIVIDUALS Despite the strong genetic association between HLA-B27 and AS, only a minority of HLA-B27-positive subjects develop disease. In addition, the risk of developing AS in HLA-B27-positive first-degree relatives of AS patients is only 20%. This indicates that additional factors are needed to induce disease. Because SpA affects seemingly distinct tis­ sues (spine, peripheral joints, enthesis, anterior eye chamber, intestine, skin), it has been a challenge to seek a common denominator between these different organs. Two main mechanisms are currently under con­ sideration: the role of intestinal microbiota following a loss of barrier integrity and an aberrant response to mechanical stress. Barrier Integrity Loss and the Intestinal Microbiota in SpA  In view of the link between gut inflammation and SpA, much attention has been focused on barrier integrity loss in the intestine and the role of the intestinal microbiota. Evidence supporting this mecha­ nism has been the development of ReA following an infectious gas­ troenteritis with Salmonella typhimurium, Shigella enteritidis, Yersinia enterocolitica, or Campylobacter enteritidis. Studies have highlighted the loss of barrier integrity, which may facilitate translocation of bac­ teria and microbial peptides that can elicit an immune response. The human microbiome is shaped by genetic and environmental factors. Changes in diversity and composition of the gut microbiome have been identified in SpA, pinpointing an intestinal dysbiosis that is similar to patients with IBD. While most information on host-microbial interplay in SpA relates to the intestine, other mucosal surfaces and particularly the urogenital tract (e.g., Chlamydia) may serve as an entry route for pathogens to instigate the onset of SpA. Germ-free HLA-B27 transgenic rats fail to develop SpA, suggest­ ing a crucial pathogenic role for intestinal microbiota. In humans, microbiome profiling in stool and biopsy samples of HLA-B27–positive individuals found that HLA-B27 affects the gut microbiome even in the absence of disease. This supports the concept that in HLA-B27– positive individuals, intestinal dysbiosis occurs prior to the onset of clinical manifestations and may contribute to the risk of disease. Earlier research suggested that HLA-B27 may promote intracellular survival and persistence of pathogens such as Chlamydia trachomatis in monocytes, which could travel to joints and promote synovial inflam­ mation. More recent studies indicate that not all preclinical models of combined gut and joint disease mimicking SpA impact these sites similarly: in a tumor necrosis factor (TNF) cytokine-dependent model with Crohn’s-like ileitis and peripheral arthritis, gut inflammation was found to be microbiota dependent but not joint inflammation. This suggests that intestinal microbiota may play a role in some, but not all, SpA patients or disease features. The skin, as the outer barrier of the body, is also vulnerable to the development of immune-mediated inflammatory disease. Like the inner barriers of the intestines and joints, the skin plays a key role in preserving tissue homeostasis at a site exposed to microbial, chemical, and mechani­ cal challenges. Alterations in the cutaneous microbiome of patients with psoriasis and PsA have been described with striking similarities between nonlesional and lesional skin. However, the functional impact of skin microbiota on the disease trajectory is still ill defined. Mechanical Stress as Gateway to Joint Disease in SpA  The entheses in SpA and PsA are key inflammatory target tissues, and patients can present with both axial and peripheral entheseal inflam­ mation. In both SpA patients and in individuals without inflammatory conditions, mechanical stress in entheses may lead to microdamage that leads to immune activation and tissue repair. The importance of mechanical strain in the pathophysiology of enthesitis in SpA is supported by observations in patients and animal models. Enthesitis occurs more often in the lower limbs, which are subject to higher mechanical strain. In patients with AS, exposure to physical labor was related to more structural damage. In mouse models, mechanical strain was shown to be causally related to development of enthesitis and SpA-related new bone formation through mechanisms that support chronicity of inflammation. Responses to mechanical stress are physiologic and self-limited, but they appear to be enhanced and prolonged in SpA. The reason for this is unclear, but this may be influenced by genetic factors and/or impaired intestinal barrier function. Chronic entheseal inflammation in axSpA also leads to excessive local bone responses. This is associated with osteoblast differentia­ tion initiated by prostaglandin E2, IL-17-A and -F, and IL-22 followed by activation of downstream bone morphogenic proteins and Wnt proteins, which are thought to play a role in pathological new bone formation. This culminates in the generation of bony spurs at vertebral bodies and sacroiliac joints, eventually leading to ankylosis. Common Versus Private Cytokine Hubs in Disease Domains in SpA  Regardless of the route of disease initiation, several common effector pathways have emerged, with TNF and IL-17 representing sig­ nature cytokines in the immunologic basis of axSpA. The impact of TNF-α as a common effector pathway that acts down­ stream in the inflammatory process has been long recognized given its broad therapeutic efficacy across all disease domains (gut, enthesis, skin, eye, spine, and joints). TNF-α is an important activator and prod­ uct of macrophages that stimulates cytokine production in immune cells and activates fibroblasts. TNF-α can also be made by neutrophils and activated T cells in the inflamed synovium, enthesis, and intestine. By activating osteoclasts, it promotes inflammation-induced bone loss and bone erosions in SpA. Even though axSpA and IBD share a similar genetic predisposi­ tion in IL-23R polymorphisms, the two disorders differ substantially in their cytokine dependency. IL-17A blockade is effective in axSpA, whereas IL-23 inhibition does not provide benefit. Conversely, IL-23 blockers are approved in IBD, but agents targeting IL-17A are contra­ indicated in active IBD, due to the barrier protective roles of IL-17. In PsA, IL-23 and IL-17 inhibitors both appear to be effective. These observations instigated a search into cellular sources of IL-17 in SpA and their dependency on IL-23. Several IL-17A–producing cell types, including T17 cells (consisting of both CD4+ TH17 and CD8+ cytotoxic T17 [Tc17] cells), γ/δ T cells, and ILC3, are present at enthe­ seal sites in steady-state conditions. In synovial fluid of SpA patients, innate-like T cells such as γδ T cells were found to be the major T-cell source of IL-17 in the presence or absence of IL-23. This is of particu­ lar interest as these γδ T cells also survey epithelial sites such as skin or intestine. Thus, entheses, synovium, and mucosal sites appear to harbor cells that may boost IL-17A responses in the absence of IL-23. Janus kinase (JAK) inhibitors, which block signaling of several cytokines, are effective in a wide range of SpA including all clinical domains (Fig. 374-1). AXIAL SPONDYLOARTHRITIS AxSpA is a chronic, immune-mediated inflammatory disorder pre­ dominantly involving the axial skeleton (sacroiliac joints and the spine) and also the peripheral skeleton. The axial skeleton is always involved, and involvement of the peripheral joints occurs in ~30–40% of patients. The hips, historically considered “root joints,” are the most common nonspinal joints affected. Enthesitis in the axial and peripheral skel­ eton is a common feature, but dactylitis is relatively rare. Extraarticular manifestations include psoriasis, acute anterior uveitis, and IBD. Some patients with axSpA experience gradual spinal bony fusion over several years, which leads to reduced spine and neck flexibility. Despite these osteoproliferative changes in the skeleton, osteoporosis is a common morbidity. AxSpA significantly affects patients’ well-being, function, productivity, and health-related quality of life. ■ ■DEFINITIONS AND NOMENCLATURE AxSpA is divided into r-axSpA (also called AS) and nr-axSpA, the dif­ ference based on the presence or absence of definitive sacroiliitis on plain radiographs. “Definitive sacroiliitis” is defined by the modified New York criteria (Table 374-2) as grade 2 bilateral or grade 3 or 4 unilateral or bilateral (Table 374-3). Patients with sacroiliitis of lower grade are classified as nr-axSpA. Since the differentiation between r-axSpA and nr-axSpA is based on the degree of sacroiliitis, it is open to disagreements even between trained musculoskeletal radiologists. The interreader reliability as measured by the kappa statistic is between 0.35 and 0.45. nr-axSpA and r-axSpA have the same clinical features and share similar disease burden, though in late-stage r-axSpA, fusion of spine and hip involvement can add to functional loss. ■ ■EPIDEMIOLOGY The male-to-female ratio is 2:1 for r-axSpA and 1:1 for nr-axSpA. The population prevalence of axSpA depends on the prevalence of HLAB27 in that geographic region. In Europe, HLA-B27 frequency in the population increases from south to north, and so does the prevalence of axSpA. For example, the prevalence of HLA-B27 in Spain and Nor­ way is 7 and 9%, respectively, and the prevalence of AS and axSpA in these two countries is 0.1 and 0.56%. The 2009–2010 National Health and Nutritional Examination Survey (NHANES) estimated that in the United States, the population prevalence of HLA-B27 is 6% and that of axSpA is between 0.9 and 1.4%, of which 0.5% were reported to have AS. The population prevalence of axSpA in the rest of the world is not well studied and is believed to be between 0.02 and 1.5%. Diagnostic prevalence of axSpA in the United States, which includes only the diag­ nosed cases in a population, is one-tenth that of population prevalence, suggesting a large undiagnosed population. Based on insurance claims databases in the United States, the diagnostic prevalence of axSpA increased between 2006 to 2019, which could be attributed to increased disease awareness. The incidence rates of AS are 0.005–0.01 per 100 patient-years globally and are not available for nr-axSpA. The risk of axSpA is 5% in HLA-B27-positive people but increases to 20% in HLA-B27-positive first-degree relatives of affected individuals with axSpA. TABLE 374-2  Modified New York Classification Criteria for Ankylosing Spondylitis (AS) Clinical Criteria 1. Low back pain >3 months   Improved with exercise   Not relieved by rest 2. Limited lumbar motion in fontal and lateral planes 3. Reduced chest expansion  Radiographic Criteria 1. Bilateral grade >2 sacroiliitis on x-ray 2. Unilateral or bilateral grade 3 or 4 on x-ray  Definite AS requires ≥1 clinical criterion plus 1 radiographic criterion Source: Adapted from S van der Linden et al: Arthritis Rheum 27:361, 1984. TABLE 374-3  Grading of Sacroiliitis GRADE DESCRIPTION Grade 0 Normal Grade 1 Suspicious change CHAPTER 374 Grade 2 Minimum abnormality (small, localized areas with erosions or sclerosis, without alterations in the joint width) Grade 3 Unequivocal abnormality (moderate or advanced sacroiliitis with erosions, evidence of sclerosis, widening, narrowing, or partial ankylosis) Grade 4 Severe abnormality (total ankylosis) Spondyloarthritis Source: Reproduced with permission from S van der Linden et al: Evaluation of diagnostic criteria for ankylosing spondylitis. Arthritis Rheum 27:361, 1984. ■ ■CLINICAL MANIFESTATIONS The most common first manifestation of axSpA is low back, hip, or buttock pain, which starts before the age of 40–45 years, usually in the 20s to 30s. The typical characteristics of this back pain include any combination of the following: insidious onset, chronicity (>3 months’ duration), age of onset <45 years, improvement with exercise or activ­ ity and no improvement with rest, worse back pain in the second half of the night with improvement after getting out of bed and walking around, and prolonged (>30 min) morning stiffness. Back pain with these characteristics is termed “inflammatory back pain” (IBP) to dif­ ferentiate it from the common “mechanical back pain” (Table 374-4), but the term is a misnomer because only 15% of patients with IBP have demonstrable inflammation in their axial skeleton. Rarely, thoracic or neck pain can be a presenting feature, and when present, it is more commonly seen in women. Fatigue and stiffness are the two most both­ ersome symptoms after back pain in axSpA. Fatigue is multifactorial, secondary to sleep disturbance, active inflammation, and anemia, and may also indicate underlying depression and anxiety of chronic disease. Peripheral arthritis is seen in 30–40% of patients with axSpA. Typi­ cally, this is an asymmetric, oligoarticular inflammatory arthritis involv­ ing the large joints of the lower extremities and rarely the small joints of hands and feet. Hip involvement, presenting as pain in the groin with radiation to medial thigh or the knee, is common and is associated with significant functional impairment. Enthesitis is a common manifesta­ tion of axSpA. Enthesitis may present as heel pain (plantar fasciitis, Achilles tendon insertion pain), chest wall pain, intercostal muscle insertions, medial or lateral epicondylitis, quadriceps or patellar tendon insertion pain around knees, or pelvic rim pain. Dactylitis is an uncom­ mon manifestation of axSpA. Persistent axial inflammation may lead to bony fusion of sacroiliac joints, apophyseal joints, and development of syndesmophytes by osteoproliferation in the outer fibers of the annulus fibrosus of the intervertebral disks. These bony changes lead to limitation of spinal, including neck, mobility in all directions and are a major cause of significant functional impairment in late stages of the disease. Extramusculoskeletal manifestations of axSpA, such as psoriasis, IBD, and acute anterior uveitis, can also be the presenting symptom of axSpA in some patients, and such patients may first present to a der­ matologist, gastroenterologist, or an ophthalmologist. Uveitis, the most TABLE 374-4  Clinical Features of Inflammatory Versus Mechanical Back Pain MECHANICAL BACK PAIN FEATURE INFLAMMATORY BACK PAIN Age at onset Before 40–45 years 20–65 years Onset Insidious Acute or insidious Morning stiffness Prolonged (more than 30 min) Less than 30 min Pain at night Yes, usually after midnight No, usually late in the day Exercise/activity Improves pain and stiffness Worsens pain Rest/inactivity Worsens pain and stiffness Improves pain Duration Chronic Acute or chronic Response to fulldose NSAIDs More than 50% relief in 48 hours Limited relief Note: Not all features are required for diagnosis of inflammatory back pain, nor are they present in every patient. Abbreviation: NSAIDs: nonsteroidal anti-inflammatory drugs. common extramusculoskeletal manifestation, is seen in 40% of patients with axSpA and presents as eye discomfort followed by redness, pain, photophobia, and miosis. The typical phenotype of uveitis associated with axSpA is acute, anterior, unilateral, and episodic. While frank IBD is seen in 10%, histologic evidence of subclinical gut inflammation is seen in up to 50% of patients. Psoriasis is seen in 10%, and osteoporosis can be present in 40%. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders AxSpA can affect multiple organ systems. The two renal manifesta­ tions of axSpA are IgA nephropathy, which can present at any time in the disease course as microscopic hematuria, and nephrotic syndrome secondary to renal (AA) amyloidosis, which is a late complication only seen after prolonged uncontrolled inflammation. Conduction abnor­ malities (heart blocks) can be seen at any stage of the disease, whereas aortic valve insufficiency and cauda equina syndrome presenting as urinary hesitancy and/or saddle anesthesia are late complications. Pulmonary manifestations of axSpA include apical fibrosis, cavitary lung lesion, or fibrotic parenchymal lesions. Sleep apnea syndrome and restrictive lung disease seen in late-stage axSpA are mostly related to osteoproliferative structural changes of the cervical spine and rib cage. The course of axSpA can be variable, with close to 50% of patients progressing from nonradiographic to radiographic stage over 20 years and <10% progressing to significant spinal involvement with bamboo spine. Risk factors for osteoproliferation include male sex, persistent inflammation (seen on magnetic resonance imaging [MRI] of sacro­ iliac joints and spine, high C-reactive protein [CRP]), syndesmophytes, presence of HLA-B27, and smoking. ■ ■DIAGNOSIS A diagnostic delay of 5–14 years from symptom onset of axSpA reported in various parts of the world is mostly related to the common­ ality of mechanical back pain in the general population. Traditionally, Chronic back pain >3 months, Insidious onset <45 years, common causes such as mechanical back pain, fibromyalgia ruled out SI joint x-ray positive for definite sacroiliitis Yes No Presence of SpA features: IBP, inflammatory arthritis, uveitis, dactylitis, enthesitis, psoriasis, IBD, family history, good response to NSAIDs, high CRP AS (R-axSpA) ≥ 4 SpA Features Compelling clinical picture Yes Nr-axial SpA Nr-axSpA FIGURE 374-2  Schema for the diagnosis of axial spondyloarthritis in a patient complaining of chronic back pain (back pain lasting >3 months). AS is thought to be a disease of males, and back pain and enthesitis in women are commonly mistaken for fibromyalgia. This delays the diagnosis in females even further. Lower prevalence of HLA-B27 in nonwhite populations also adds to the delay in diagnosis. The diagnosis of axSpA is based on pattern recognition, ruling out common causes for the symptoms, and clinical reasoning. Figure 374-2 shows a schema for the diagnosis of axSpA in a patient complaining of chronic (>3 months) back pain. While elevated inflammatory mark­ ers, erythrocyte sedimentation rate (ESR), and CRP help in making the diagnosis of axSpA, these tests are neither sensitive (seen in only 30–40% of patients with active axSpA) nor specific for axSpA. Imaging plays a very important role in the diagnosis of axSpA. A single anteroposterior (AP) view or a Ferguson view x-ray of the pelvis is sufficient to image sacroiliac joints. Multiple views (e.g., oblique) of the sacroiliac joints add little in making the diagnosis; in addition, they increase radiation risk to gonads. Radiographic features of sacroiliitis include marginal sclerosis, erosions, narrowing and widening of the joints, and in late stages, fusion (Fig. 374-3A and Table 374-3). As a gen­ eral rule, plain radiographs of the spine should be avoided in patients with chronic back pain. However, there are some characteristic changes of axSpA seen in the lateral radiograph of the spine, and they include Romanus lesions or the shiny corner sign and squaring of the vertebral body seen as a result of erosions at the attachments of the spinal liga­ ments at the vertebral corners. Andersson lesion is an uncommon find­ ing and is characterized by vertebral body erosion and sclerosis at the intervertebral disk level. In the late stages, ossification of the outer layer of annulus fibrosus leads to syndesmophyte formation (Fig. 374-3B). Typical syndesmophyte orientation is vertical, differentiating it from the horizontal orientation of osteophytes, which is commonly seen with osteoarthritis (OA) of the spine. Bamboo spine, or ankylosis of the entire spine, is seen in a very small percentage of late-stage AS patients. <4 SpA Features MRI SI Joints positive for sacroiliitis Yes No Compelling clinical picture plus HLA-B27 positive Clinical picture not compelling and/or HLA-B27 negative Nr-axSpA Not axSpA A B FIGURE 374-3  Radiographic axial spondyloarthritis. A. Bilateral sacroiliitis (modified New York grade 3) with sclerosis and erosions. B. Lateral view cervical spine in advanced radiographic axial spondyloarthritis showing anterior syndesmophytes and fused facet joints. Low-dose computed tomography (CT) of the sacroiliac joints and spine in the diagnosis of axSpA is emerging as an alternative to plain radiog­ raphy for diagnosis and assessing progression (Fig. 374-4). Magnetic resonance imaging (MRI) of the sacroiliac joints and spine has evolved as an important tool in making the diagnosis of axSpA. During the early stage of disease, MRI of the sacroiliac joints may show evidence of active inflammation, or “osteitis,” and that may be the only abnormality. As time passes, the active inflammatory changes transition to fatty metaplasia, and this may further transform to new bone forma­ tion. The structural changes of sclerosis, fat metaplasia, erosions, fat metaplasia in an erosion cavity (backfill), and new bone formation, in addition to the inflammatory changes seen on MRI, aid in making the diagnosis of axSpA (Fig. 374-5). Sole presence of inflammatory lesions in early stages or sole presence of ankylosis in very late stage may be enough for the diagnosis of axSpA, but as a general rule, multiple types of inflammatory and structural lesions increase the suspicion of axSpA. In the spine, multiple corner inflammatory lesions and/or multiple cor­ ner fatty lesions increase the confidence of axSpA diagnosis. MRI is a very sensitive imaging technique, and mechanical stress on the sacroiliac joints in professional athletes, postpartum women, and even in normal individuals, especially above the age of 40, may show changes of osteitis. Fat metaplasia-type changes in the sacroiliac joints are also seen in degenerative arthritis as well as in normal individuals. Inappropriate utilization of MRI can lead to overdiagnosis. CHAPTER 374 Spondyloarthritis FIGURE 374-4  Computed tomography of the thoracic spine sagittal view in radiographic axial spondyloarthritis showing anterior and posterior syndesmophytes. ■ ■DIFFERENTIAL DIAGNOSIS Chronic nonspecific “mechanical” back pain is common in the general population, and axSpA is the etiology in only 4–5% of such patients. Mechanical causes of back pain therefore should be considered first in a patient presenting with chronic back pain. The so-called “red flag” A B FIGURE 374-5  Magnetic resonance images of spondyloarthritis. A. T1-weighted image of sacroiliac joints with bilateral erosions (left-sided erosions marked by **), left fatty metaplasia (single *), and right bone marrow edema (marked with white arrows). B. Short tau inversion recovery (STIR) image with bilateral bone marrow edema suggestive of joint space inflammation (shown by *) and anterior capsulitis (shown by a white arrow). signs of fever, weight loss, advanced age, and past history of malig­ nancy should alert the examiner to look for osteomyelitis, osteoporotic fracture, or metastatic disease. In young patients with generalized body pain, fibromyalgia, central sensitization, hypermobility, hypothyroid­ ism, and hypovitaminosis D may be considered. Abnormalities on incidental imaging in a patient with or even without chronic back pain lead to other differential diagnoses such as diffuse idiopathic skeletal hyperostosis (DISH) or osteitis conden­ sans ilii (OCI). DISH is a noninflammatory, degenerative condition affecting the spine, with exuberant new bone formation in the form of anterior and posterior longitudinal ligament ossification of at least four contiguous vertebral bodies and bulky “flowing” osteophytes typically on the right side of the thoracic spine, but normal sacroiliac joints. It is generally seen in obese, diabetic males, often older than 50 years of age. DISH is sometimes mistaken for bamboo spine of AS. OCI is usually an asymptomatic condition of multiparous women character­ ized by radiographic findings of a triangular area of dense sclerosis on the lower and inferior part of the iliac side of the sacroiliac joints. This can be mistaken for sacroiliitis, and in early stages, MRI of the sacroiliac joints may be indistinguishable from that of axSpA. Lack of erosions should help distinguish OCI from axSpA. OCI can be seen in nulliparous women and even men. While DISH and OCI are generally asymptomatic, some patients with either condition may present with chronic back pain. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Inflammatory back pain with sclerotic changes on sacroiliac joint radiographs can also be seen in conditions such as postpartum insuf­ ficiency fracture of the sacrum; septic sacroiliitis from tuberculosis, brucellosis, fungi, and other infectious agents; and rarely, malignancies such as acute lymphoblastic leukemia. ■ ■MONITORING AxSpA patients should be monitored at every visit for disease activ­ ity, function, and medication safety. The frequency of monitoring is individualized. Assessment of disease activity can be performed by using the Bath Ankylosing Spondylitis Disease Activity Index (BAS­ DAI) or the Ankylosing Spondylitis Disease Activity Score (ASDAS). Functional impairment can be measured by the Bath Ankylosing Spondylitis Functional Index (BASFI). This is a patient-administered questionnaire that includes 10 activities of daily living. The Bath Ankylosing Spondylitis Metrology Index is an index of spinal and hip mobility in patients with AS. The ESR and CRP may be useful in monitoring disease activity. MRI of the sacroiliac joints or spine is expensive and is not indicated to monitor disease activity of AxSpA. Spine radiographs and MRI are not used for monitoring purposes in daily practice, although they may be used if back pain persists or relapses to rule out active inflammation despite therapy or complications such as spinal fractures. TREATMENT Axial Spondyloarthritis Principles of treatment of nr-axSpA and r-axSpA are identical and are described as one disease. Some agents are approved to treat only AS (r-axSpA) and are mentioned below. The targets for treatment include low disease activity or remis­ sion. Traditionally, the treatment of axSpA was limited to exer­ cise, physical therapy, and nonsteroidal anti-inflammatory drugs (NSAIDs), but with the advent of biologics and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), great strides have been made in in the last two decades. Shared decision-making regarding all modes of therapy is the key to success. Treatment of axSpA can be divided into nonpharmacologic, pharmacologic, and surgical. NONPHARMACOLOGIC INTERVENTIONS Physical exercise in the form of active physical therapy (on land or aquatic) and self-directed physical exercise are strongly recom­ mended by all international guidelines and should be promoted. Physical therapy improves fatigue, mobility, and posture. Smoking cessation is encouraged in all patients. PHARMACOLOGIC INTERVENTIONS The American College of Rheumatology (ACR), Spondylitis Associ­ ation of America (SAA), Spondyloarthritis Research and Treatment Network (SPARTAN) treatment guidelines, and ASAS-EULAR (European Alliance of Associations for Rheumatology) treatment recommendations have many commonalities regarding the order of treatments, choices of agents, and precautions. Table 374-5 outlines pharmacologic interventions for the treatment of axSpA. The use of immunosuppressive biologics and tsDMARDs has been associated with an increased risk of serious infections. While bacterial infections are seen in both classes, herpes zoster is mostly seen with JAK inhibitors (JAKis), and reactivation of latent tubercu­ losis is mostly seen with TNF inhibitors (TNFis). Mucosal and skin Candida infections are associated with IL-17 inhibitor (IL-17i) use. Other side effects of biologic therapy include injection-site reac­ tions with subcutaneous injections or infusion reactions with intra­ venous (IV) medication. TNFi adverse effects include development of demyelinating disease, worsening of congestive heart failure, and paradoxical development of psoriasis-like skin lesions. Adverse events associated with IL-17i therapy include leukopenia and devel­ opment or worsening of IBD. JAKis have a higher risk of major cardiovascular adverse events and cancers (lymphoma and lung cancers), especially in patients aged 65 years or older and in those with current or past history of smoking, with history of cardiovas­ cular disease, or with malignancy. As a result, the U.S. Food and Drug Administration (FDA) suggests reserving these medicines for patients who have had an inadequate response or intolerance to one or more TNFi. SURGICAL INTERVENTIONS Hip involvement in axSpA leads to significant functional impair­ ment, and total hip arthroplasty should be considered in patients with refractory hip pain or functional decline in the presence of radiographic evidence of structural damage. Spinal osteoto­ mies should be reserved for severe fixed kyphotic deformities in advanced AS that affect horizontal vision and should be performed in centers of expertise. ■ ■COMPLICATIONS The prevalence of osteoporosis is ~25% after 10 years of axSpA. Verte­ bral fractures are seen in ~10% of patients with AS. The lower cervical spine is the most commonly involved area, where there is often also neurologic compromise. One should consider vertebral fractures in patients with neck and back pain that has changed in intensity or character from baseline. Another rare complication is the cauda equina syndrome from long-standing AS resulting from inflammation of the lumbosacral nerve roots caused by arachnoiditis. Cardiac manifesta­ tions include aortic valve insufficiency and conduction abnormali­ ties. Pulmonary manifestations are rare and include chest expansion restriction from ossification of costovertebral joints and upper lobe– predominant interstitial lung disease. Patients with AS can have IgA nephropathy or, in late stages, renal amyloidosis if the disease is left untreated. Cardiovascular disease is being recognized as a common comorbidity in patients with AS and is linked to chronic inflammation. All patients with AS should be counseled about the traditional risk factors for cardiovascular disease, and appropriate treatment should be instituted if necessary. PSORIATIC ARTHRITIS PsA is a relatively common immune-mediated inflammatory condition that may lead to progressive joint damage. If left untreated, it is associ­ ated with poor quality of life, loss of function, and increased morbid­ ity and mortality. PsA, associated with cutaneous and nail psoriasis, involves peripheral joints, axial skeleton (sacroiliac joints and spine), entheses, and tendon sheaths. In addition, uveitis and inflammatory bowel disease may coexist with PsA. Common comorbidities of PsA TABLE 374-5  Pharmacologic Management of Axial Spondyloarthritis (axSpA) • Nonsteroidal anti-inflammatory drugs (NSAIDs) should be used in highest tolerable doses continuously in active disease and on an as-needed basis if the disease is stable. No particular NSAID is preferred over any other. Side effects to monitor are gastric ulcer disease, hypertension, renal insufficiency, and cardiovascular disease. • Conventional synthetic DMARDs like sulfasalazine, up to 3 g/d, and methotrexate, up to 25 mg/wk, are useful for the treatment of peripheral joint and entheses involvement, but not for axial disease in axSpA. • If the disease remains active despite a 4-week trial of full-dose NSAIDs, treatment should be escalated to start a biologic from either the TNFi or IL-17i class. • Before initiating therapy with biologics or JAKi, screening for latent tuberculosis, hepatitis B, and hepatitis C should be performed. • All five TNFi agents are approved for the treatment of AS, while selective TNFis are approved for nr-axSpA in various countries. • Soluble receptor of TNF–etanercept 50 mg subcutaneous (SC) injection once weekly. • TNFi monoclonal antibodies: • Adalimumab 40 mg SC every 2 weeks. • Certolizumab pegol 200 mg SC twice a month or 400 mg SC once a month. • Golimumab 50 mg SC once a month or golimumab 2 mg/kg intravenous (IV) at weeks 0, 4, and then every 8 weeks thereafter. • Infliximab 5 mg/kg IV infusion at weeks 0, 2, 6, and then every 6 weeks. • No TNFi is preferred, except in patients with concomitant uveitis or IBD in whom TNF monoclonal antibodies are preferred over soluble receptor TNFi therapy. • In the case of primary failure of TNFi, treatment can be switched to IL-17i or JAKi. In the case of secondary failure of TNFi therapy (failing after initial benefit), an alternative TNFi can be used. • Two IL-17Ais are approved for the treatment of nr-axSpA and AS. • Secukinumab 150 mg SC at weeks 0, 1, 2, 3, and 4, followed by 150 or 300 mg every 4 weeks. • Ixekizumab 160 mg SC once, followed by 80 mg every 4 weeks. • In case of primary failure of IL-17Ai, treatment can be switched to TNFi or JAKi. In the case of secondary failure of IL-17Ai therapy, an alternative IL-17i can be used. • Two JAKis are approved for the treatment of AS, while only one is approved for nr-axSpA. JAKi should be used in patients who have failed TNFi. • Tofacitinib 5 mg orally two times a day is approved for the treatment of AS only. • Upadacitinib 15 mg once a day is approved for the treatment of AS and nr-axSpA. • One IL-17A and IL-17F inhibitor is approved in certain parts of the world to treat both nr-axSpA and radiographic axSpA. • Bimekizumab 160 mg SC every 4 weeks. • Local glucocorticoid injections for upper extremity enthesitis or intraarticular injections for peripheral arthritis are indicated. Injections around lower limb weightbearing entheses are not recommended because of the risk of rupture. • Systemic glucocorticoids do not have any efficacy in axSpA and should be avoided.  Abbreviations: AS, ankylosing spondylitis; DMARDs, disease-modifying antirheumatic drugs; IBD, inflammatory bowel disease; IL-17i, interleukin 17 inhibitor; JAKi, Janus kinase inhibitor; nr-axSpA, nonradiographic axial spondyloarthritis; TNFi, tumor necrosis factor inhibitor. include depression, metabolic syndrome, diabetes mellitus, and car­ diovascular disease. Sometimes the term “psoriatic disease” is used to emphasize these varied manifestations. In 1973 Moll and Wright defined PsA as an inflammatory arthritis (peripheral arthritis and/or sacroiliitis or spondylitis), with presence of cutaneous psoriasis and absence of RF. They demonstrated the association between PsA and the gene HLA-B*27 and described five phenotypes of PsA, namely asymmetric oligoarticular inflammatory arthritis, symmetric polyarticular arthritis, distal interphalangeal joint arthritis, spondylitis, and arthritis mutilans. Over the years, enthesitis and dactylitis have been added to these musculoskeletal manifesta­ tions. It is important to remember that these clinical phenotypes are not exclusive and frequently coexist. ■ ■EPIDEMIOLOGY With a prevalence of 2–3%, skin psoriasis is one of the most common immune-mediated diseases. The prevalence of PsA in patients with psoriasis is 30% (range, 6–42%). The incidence of PsA in patients with psoriasis is 3 per 100 patient-years (range 2–10) and depends on the severity of skin psoriasis. The likelihood of developing PsA in psoriasis patients does not change over time. ■ ■CLINICAL FEATURES Clinical features of PsA include peripheral arthritis, axial arthritis (spondylitis), enthesitis, dactylitis, and tenosynovitis. Inflammatory arthritis presents with joint pain, swelling, prolonged stiffness, and reduced mobility. Typically, early PsA is oligoarticular (<4 joints) and often asymmetric, and as the number of affected joints increases, the disease becomes polyarticular and the distribution becomes more sym­ metric. Distal interphalangeal joint involvement is typical of PsA and is associated with psoriatic nail changes since the nail bed is closely linked to the distal interphalangeal (DIP) joints. Inflammatory arthritis of the axial skeleton occurs in 5% of PsA patients in early stage and can be seen in 50% of patients after 20 years CHAPTER 374 Spondyloarthritis of disease. Axial inflammatory arthritis presents with inflammatory back and/or neck pain and stiffness, which is typically worse after peri­ ods of prolonged inactivity and improves with activity. However, axial arthritis can be asymptomatic or overshadowed by patients’ peripheral arthritis symptoms. Most patients with axial involvement have sacroi­ liitis, although axial involvement without sacroiliitis may distinguish axial PsA from axial SpA. While many of the radiographic features may resemble AS, presence of asymmetric sacroiliitis, nonmarginal and asymmetric bulky syndesmophytes, and frequent involvement of cervical spine have been more often assigned to axial PsA then AS. These phenotypic differences have led to the suggestion that this may reflect potential pathogenic distinctions. Whether axial PsA pathogen­ esis differs substantially from axSpA and especially whether this has therapeutic consequences are the subjects of investigations by several international consortia. Other important musculoskeletal manifestations of PsA include dactylitis, enthesitis, and tenosynovitis. Dactylitis is defined as inflam­ matory swelling of an entire finger or toe. Dactylitis is due to inflam­ mation of the joints, tendons, bones, and soft tissues within the digit. Dactylitis is a marker of severity of PsA, and persistent dactylitis leads to structural damage to the joints within that digit. Arthritis mutilans is an end manifestation of a severe arthritis process. Enthesitis is another important manifestation of PsA. The most common sites affected by enthesitis are the plantar fascia and Achil­ les tendon insertion on the calcaneum (plantar fasciitis and Achilles enthesitis). Other common sites for enthesitis include quadriceps tendon insertion on the patella, patellar tendon insertion on tibia, medial and lateral epicondyle, pelvic rim, spinous processes, and intercostal muscle insertion on ribs. Tenosynovitis, or inflammation of the tendon sheath, may affect tendons in the hands, wrists, and around the ankles. Most patients with PsA have psoriasis vulgaris. In ~80% of people with PsA, psoriasis develops first, and the musculoskeletal mani­ festations develop after a variable duration. In ~10%, both arthritis and psoriasis develop simultaneously. While patients with PsA have psoriasis by definition, in 10% of patients, the arthritis develops first and cutaneous psoriasis manifests a few years later. Diagnosis of PsA is challenging in such patients, and family history of psoriasis, with typical musculoskeletal involvement, can help make the diagnosis. Although 40% of patients with psoriasis without PsA have nail lesions, nail involvement is much more frequent in patients with PsA, affect­ ing close to 90% of patients. Psoriatic nail manifestations may be classified into nail matrix disease and nail bed disease. Nail pitting, leukonychia, crumbling, and red spots in the lunula are manifestations of nail matrix disease, whereas onycholysis, subungual hyperkeratosis, oil drop change, and splinter hemorrhages are manifestations of nail bed disease. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Patients with PsA may also have involvement of the eye and gastro­ intestinal tract. Uveitis may occur in 5% of patients, and conjunctivitis is rarely seen. While unilateral acute anterior uveitis is the commonest form, posterior uveitis and bilateral eye involvement are also reported. IBD (Crohn’s disease or rarely ulcerative colitis) may coexist in patients with PsA. Mucous membrane inflammation presents with painful mouth ulcers and rarely urethritis. The disease course of PsA is variable. Whereas some patients do well with few joints involved and no significant damage, others progress very quickly to develop marked joint damage within a few months. Patients with PsA have a worse quality of life and function compared with the general population as well as to patients with psoriasis without PsA. Patients with psoriasis and PsA have an increased risk of cardiovas­ cular disease, as high as the risk in people with diabetes mellitus. The increased risk is independent of cardiovascular risk factors and cor­ relates with more severe skin disease, disease duration, and increased inflammatory markers. Patients with PsA have more severe subclinical atherosclerosis compared with psoriasis patients without PsA. The prevalence of hypertension, type 2 diabetes, obesity, metabolic syn­ drome, fatty liver disease, angina, and myocardial infarction is higher among patients with PsA compared with the general population. Obesity has an additional adverse impact on PsA disease activity and treatment response. Patients with psoriasis and PsA have increased rates of depression and suicidality compared to the general population. The prevalence of malignancy in PsA is not increased, and mortality studies have shown conflicting results. ■ ■DIAGNOSIS The diagnosis of PsA is based on clinical features of cutaneous psoriasis with inflammatory musculoskeletal disease such as arthritis, dactylitis, enthesitis, or spondylitis. Presence of dactylitis is an important sign, and careful examination of feet is important since dactylitis of a single toe or enthesitis around the heel may be the only musculoskeletal man­ ifestation of PsA in a patient with psoriasis. Psoriasis may be hidden in areas such as the scalp, umbilicus, below breasts, or in the natal cleft, or it may be present in the nail only and should be looked for carefully. Typical involvement of the joints of the fingers or toes is in a “ray” dis­ tribution (involvement of all joints in a finger or toe), with one finger showing dactylitis, another with bony ankylosis, and the neighboring finger showing arthritis mutilans. The pattern of involvement in PsA is often asymmetric compared with RA, in which the pattern tends to be symmetric. The presence of spondylitis with asymmetric oligoarticular peripheral arthritis would virtually rule out RA and would make the diagnosis of PsA more likely. The diagnosis of PsA may sometimes be made even in the absence of psoriasis if the above characteristic features are present and if there is a family history of psoriasis or PsA. Laboratory tests only play a minor role in the diagnosis of PsA. Tests for acute-phase reactants such as ESR or CRP are abnormal in ~50% of patients despite clinically active disease. High levels of ESR or CRP are markers of severe disease and are predictors of radiographic damage and mortality. RF is typically negative, but low titer RF or low titer anticyclic citrullinated peptide antibody may be positive in <10% of patients. HLA-B27 is positive in 20% of all patients with PsA and 50% of patients with axial PsA. A patient with PsA may present with monoarticular arthritis of knee or ankle, and in this situation, synovial fluid analysis will differentiate between infection (“septic arthritis”), crystal-induced arthritis, OA, or immune-mediated inflam­ matory arthritis such as PsA. White blood cell counts of >2000/mL of synovial fluid with no crystals and negative Gram stain and culture are diagnostic of inflammatory arthritis and, in this clinical scenario, should raise the suspicion of SpA such as PsA, reactive arthritis, or IBD-associated arthritis. Routine laboratory tests such as complete blood counts or kidney or liver function tests do not help in making the diagnosis of PsA but can be useful for monitoring treatment or assessing comorbidities. ■ ■IMAGING FEATURES Imaging is an important modality in the assessment of PsA and may help in confirming the diagnosis and determining disease severity. Radiographs of the hands, feet, pelvis, spine, and other affected joints should be performed to look for changes suggestive of PsA. In early disease, x-rays of the hands and feet show soft tissue swelling around the involved joints. Periarticular osteopenia is generally absent. Mar­ ginal erosions are markers of disease severity and predict further radio­ graphic progression, deformity, and disability. In PsA, erosions are often accompanied by “fluffy” new bone formation. The combination of ero­ sions at joint margins with new bone formation is characteristic of PsA (Fig. 374-6). New bone formation may also cause ankylosis of the joints. There also may be joint space narrowing, “pencil-in-cup” deformity, and in late stages, such as arthritis mutilans, total joint destruction or joint lysis and acro-osteolysis (resorption of the terminal phalanx) are seen. Certain characteristic radiographic features such as “pencil-in-cup” deformity, bony ankylosis in a ray distribution, or “fluffy” new bone formation close to sites of erosions can be pathognomonic of PsA. X-ray of the pelvis (anteroposterior view) may show changes of sac­ roiliitis. Sacroiliitis in PsA is more likely to be unilateral compared to axSpA, where it is usually bilateral. Axial involvement in PsA may show changes of shiny vertebral corners, erosions, squaring of vertebrae, and syndesmophyte formation on the lateral view of the spine. While this may mimic radiographic axSpA, often in PsA, the syndesmophytes are chunky and “nonmarginal” and develop from sites away from the vertebral corners (Fig. 374-7). The presence of such syndesmophytes is characteristic of PsA. Cervical and lumbar vertebrae are frequently involved. Rarely, atlantoaxial subluxation develops with potentially serious consequences. Ultrasound combined with Doppler evaluation can help in differ­ entiating enthesitis from fibromyalgia tender points or in differenti­ ating mechanical versus inflammatory etiology. Ultrasound can also detect erosions before they appear on x-rays, especially in the hand joints. Some of the findings in inflammatory enthesitis in PsA include thickening of the tendon with loss of the regular fibrillar architecture, hypoechoic lesion, and neovascularization around insertions of ten­ dons, ligaments, and joint capsules at the bone. Bony irregularities and erosions would distinguish inflammatory from mechanical enthesitis. Ultrasound, however, is highly operator dependent and is useful in expert hands only, which remains a limitation. MRI with IV contrast of the peripheral joints can detect synovitis, and MRI without contrast in axial joints may show bone marrow edema (on the short tau inver­ sion recovery [STIR] image) suggestive of active inflammation before any abnormality is visualized on x-rays. MRI can also show erosions in the joints even before they are seen on plain x-rays. MRI is also very useful in visualizing enthesitis. CT scans are useful when an MRI is unavailable or contraindicated, although the risk of considerable radia­ tion exposure needs to be balanced with the benefits. Nuclear medicine bone scans are neither specific nor sensitive to diagnose PsA. Use of fluorodeoxyglucose positron emission tomography scans to assess inflammatory burden in PsA is experimental. ■ ■CLASSIFICATION CRITERIA The Classification of Psoriatic Arthritis (CASPAR) criteria (Table 374-6) have a specificity of 98.7% and sensitivity of 91.4%. To meet the CASPAR criteria for PsA, individuals must first have inflammatory articular dis­ ease (joint, spine, or entheseal) and must have at least three points from the five categories described in Table 374-6. A   FIGURE 374-6  A. X-ray of the feet in psoriatic arthritis. These images show erosions, loss of cartilage in bilateral first metatarsophalangeal (MTP) joints, bilateral interphalangeal joint of great toes, and right fifth MTP joint. There are changes of secondary osteoarthritis with sclerosis and osteophyte formation in these joints and early pencil-in-cup deformity in the left fifth MTP joint. B. X-ray of the hands in psoriatic arthritis. Left thumb interphalangeal joint showing early pencil-in-cup deformity (marked with **). Right third finger has dactylitis and shows periosteal new bone formation in the third proximal phalanx (white arrow), along with erosions in the proximal (marked with *) and distal interphalangeal joints (marked with *). This combination of periosteal new bone formation and erosions in “ray” distribution is typical of psoriatic arthritis. ■ ■DIFFERENTIAL DIAGNOSIS OA, the most common form of arthritis, occurs in ~5% of the popu­ lation, and it may coexist with psoriasis especially in the DIP joints. Thus, the presence of Heberden nodules in the context of patients with hand OA with concomitant psoriasis is an important differential diagnosis to be made. Psoriatic nail involvement would differentiate PsA from inflammatory OA of the DIP joints, along with imaging abnormalities such as on ultrasonography. Patients with “seronegative RA” should be carefully examined for presence of psoriasis in hidden areas (scalp, umbilicus, gluteal cleft, genitals, below breasts, and nails) and questioned about family history of psoriasis. Many patients with seronegative RA may have pSpA such as PsA, ReA, or IBD-associated arthritis. The high skin turnover in psoriasis can lead to hyperuri­ cemia, and gout can coexist with PsA. Flare of monoarticular PsA should be assessed with synovial fluid analysis to rule out gout or septic arthritis. PsA shares several clinical, laboratory, and imaging features with other SpA conditions such as ReA, IBD-associated FIGURE 374-7  X-ray of the lumbar spine anteroposterior view in psoriatic arthritis. The images show nonmarginal “chunky” syndesmophytes (marked with white arrows). CHAPTER 374 Spondyloarthritis B arthritis, and axSpA, and patients may fulfill classification criteria of multiple SpAs simultaneously. Calcium pyrophosphate deposition disease (CPPD) arthritis affecting the MCP joints may coexist in the elderly with skin psoriasis. Chondrocalcinosis of the triangular fibrocartilage in the wrist, “hook-like” osteophytes in the MCP joints, and absence of erosions or fluffy new bone formation should rule out PsA. Synovitis, acne, pustulosis, SAPHO, and rarely hidradenitis sup­ purativa may mimic palmer plantar psoriasis and PsA. ■ ■ASSESSING DISEASE ACTIVITY IN PSORIATIC ARTHRITIS Disease Activity in Psoriatic Arthritis (DAPSA) and Minimal Disease Activity (MDA) are the most common instruments used to assess dis­ ease activity in clinical practice. A simple scale used to assess plaque psoriasis is to ask the patient, “How many palms will be covered by the current psoriasis on your body?” With one palm of the patient counted as 1% body surface area (BSA), the total BSA involved by active psoriasis can be assessed. Nail psoriasis and dactylitis can be TABLE 374-6  Classification Criteria for Psoriatic Arthritis (CASPAR) Patients with Inflammatory Articular Disease (Joint, Spine, or Entheseal) Plus ≥3 Points Meet CASPAR Criteria for Psoriatic Arthritis CATEGORY DESCRIPTION POINT VALUE Psoriasisa Current psoriasis as determined by a rheumatologist or dermatologist Personal history of psoriasis obtained from patient or qualified health care provider A family history of psoriasis as reported by patient in a first- or second-degree relative Nail changes Typical psoriatic nail dystrophy (onycholysis, pitting, and hyperkeratosis) present at assessment Rheumatoid factor Rheumatoid factor negative Dactylitis (swelling of entire digit) Current dactylitis or history of dactylitis recorded by a rheumatologist Radiographic evidence Juxtaarticular new bone formation (excluding osteophyte formation) on plain radiograph of hand or foot; appears as illdefined ossification near joint margins aPsoriasis should account for only one of the three descriptors. Source: Adapted from WJ Taylor et al: Arthritis Rheum 54: 2665, 2006. assessed by simply counting the digits with affected fingernails or with dactylitis. A number of enthesitis indices have been developed, such as the Spondyloarthritis Research Consortium of Canada Index and the Leeds Enthesitis Index. Axial arthritis is assessed using tools borrowed from axSpA assessment. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders TREATMENT Psoriatic Arthritis The treatment target is remission or low disease activity. This is achieved by nonpharmacologic and pharmacologic interven­ tions including novel advanced therapies. A multidisciplinary team consisting of rheumatologists, physical and occupational thera­ pists, dermatologists, and depending upon the domains involved, gastroenterologists, ophthalmologists, psychologists/psychiatrists, dieticians, endocrinologists, and cardiologists may be needed to manage common comorbidities. All pharmacologic interventions need to be based on shared decision-making between the patient and their provider. The four main classes of pharmacotherapy used in the man­ agement of PsA include NSAIDs, conventional synthetic diseasemodifying antirheumatic drugs (csDMARDs), biologic DMARDs, and tsDMARDs. Biologic and tsDMARDs have revolutionized the management of PsA by effectively controlling signs and symptoms, decreasing joint damage progression, and improving health-related quality of life. Biologic DMARDs used in the man­ agement of PsA include TNFi (etanercept, adalimumab, inflix­ imab, certolizumab, or golimumab), antibodies against IL-12/23 (ustekinumab), IL-17A (secukinumab, ixekizumab), IL-17A and IL-17F (bimekizumab), IL-23 (guselkumab, risankizumab), and costimulatory blockade agent (abatacept). tsDMARDs include the phosphodiesterase-4 (PDE4) inhibitor apremilast; JAKis such as tofacitinib, baricitinib, and upadacitinib; and the tyrosine kinase 2 (TYK2) inhibitor deucravacitinib. The IL-17A and IL-17A+F inhibitor nanobodies izokibep and sonelokimab are currently undergoing clinical trials. TREATMENT RECOMMENDATIONS The ACR along with National Psoriasis Foundation (ACR-NPF), EULAR, and Group for the Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) have published separate recom­ mendations for the pharmacologic management of PsA, though there are many similarities. They all recommend that the treat­ ment should be tailored according to the disease activity assessed by level of symptoms and clinical findings in peripheral joints, skin, nails, axial skeleton, entheses, and presence of dactylitis. Individual clinical features (age, gender, concomitant medica­ tions, and psychosocial factors), comorbidities (especially IBD, uveitis, metabolic syndrome, and heart disease), prognostic indi­ cators, and patient preferences, values, and cultural background need to be considered in this shared decision-making process. Patients should be monitored at regular intervals and treatment adjusted as appropriate. Treatment is generally continued indefi­ nitely for this lifelong disease since there is high risk of flare once treatment is discontinued. Principles and recommendations for PsA management from these recommendations are summarized in Table 374-7. For musculoskeletal manifestations of PsA, TNFi and IL-17i have demonstrated comparable efficacy, whereas IL-17i, IL-12/23i, and IL-23i have shown superior efficacy in clearing skin psoriasis compared to TNFi in head-to-head studies. JAKis have comparable efficacy to TNFis for musculoskeletal manifestations of PsA. All biologics except abatacept, and JAKis have shown efficacy in reduc­ ing radiographic progression in PsA, but none of the csDMARDs, PDE-4 inhibitors, or TYK2 inhibitors have shown this. While there are no comparative studies on safety, IL-17i, IL-12/23i, IL-23i, PDE-4 inhibitors, and TYK2 inhibitors are perceived to be safer than TNFis in clinical practice. REACTIVE ARTHRITIS The interrelation between infection and arthritic disease has been established for many decades. ReA refers to the development of arthri­ tis following urogenital or gastrointestinal infection involving welldefined triggering microorganisms that are normally not cultivable from the joints affected. Prototypical inducers of reactive arthritis include Yersinia, Campylobacter, Salmonella, Shigella, and Chlamydia. ■ ■CLINICAL FEATURES A crucial factor in the diagnosis relates to recognition of the clinical pic­ ture and the identification of causative organisms. A hallmark feature is the time delay between initial infection and onset of arthritis: the interval ranges between 1 day and 4 weeks after infection. Inflammatory mus­ culoskeletal disease (joint, spine, or entheseal) is essential for the diag­ nosis of ReA. The clinical spectrum may include a typical asymmetrical oligoarticular arthritis preferentially involving lower limbs, enthesitis, tendonitis, bursitis, dactylitis, inflammatory back pain, and sacroiliitis. Mucocutaneous lesions may also occur in addition to the musculoskel­ etal manifestations and include uveitis/conjunctivitis, erythema nodo­ sum, oral ulcers, circinate balanitis, and keratoderma blenorrhagica. ReA is strongly associated with the presence of HLA-B27, with up to 50–80% of all reactive arthritis patients carrying HLA-B27. Accordingly, prevalence of ReA matches the prevalence of HLA-B27, which has a clear North-South gradient; e.g., the highest prevalence of HLA-B27 is observed in the Northern Hemisphere, which was reflected by historical large out­ breaks of ReA in, for example, Scandinavian regions. However, over the past decades, there has been a steady decline in the number of such out­ breaks with improved hygiene and changes in microbiota. Recent updates on incidence of reactive arthritis point to an overall incidence rate estimate of 3.4 cases per 100,000 person-years. Overall, the estimated percentage of cases to develop ReA following an enteric infection with Campylobacter, Salmonella, Shigella, or Yersinia is estimated around 2.6%. Expert consensus refers to ReA only if clinical picture and causative microbes are HLA-B27 and SpA related. Hence many other infections that trigger onset of arthritis fall outside of the SpA construct. These “infection-related arthritides” constitute all forms of arthritis associated with infections except septic arthritis. They include, among others, acute rheumatic fever, meningococcus, Mycoplasma genitalium, Ureaplasma urealyticum, Chlamydia pneumoniae, beta-hemolytic streptococci, and some live vaccines and COVID. These should not be described as ReA since the clinical pattern does not fit the SpA spectrum and is unrelated to HLA-B27. Thus, the term ReA should be restricted to an acute SpA that is linked to an acute genitourinary or gastrointestinal infection. The other forms should be referred to as postinfectious arthritides and will not be discussed further in this chapter. ■ ■DIAGNOSIS ReA is diagnosed based on clinical features and identification of an antecedent infection from medical history and laboratory tests and exclusion of other different diagnosis. While diagnostic procedures are focused around HLA-B27 and molecular testing for Chlamydia tracho­ matis infection, additional individualized diagnostic tests must also be considered to rule out other causes (e.g., postinfectious arthritides). Laboratory tests such as stool cultures to test for Salmonella, Shigella, Campylobacter, and Yersinia can sometimes confirm a preceding or concomitant infection with a causative pathogen, but since gastrointes­ tinal symptoms often have resolved when rheumatic features develop, pathogens may no longer be retrievable. Serology for enteric pathogens is used primarily in epidemiologic studies to test for preceding infec­ tions, but there are some questions on its utility in daily clinical prac­ tice given the overall low yield of positive results. All patients should be offered screening for Chlamydia. TREATMENT Reactive Arthritis Treatment of ReA is oriented to management of SpA features, but treatment guidelines for ReA do not exist currently. While antibiot­ ics are not used in the routine care of ReA, one study demonstrated TABLE 374-7  Pharmacologic Management of Psoriatic Arthritis (PsA)  PRINCIPLES AND RECOMMENDATIONS   1.  The primary goal of treating patients with PsA is to maximize long-term health-related quality of life through control of symptoms, abrogation of inflammation, prevention of structural damage, normalization of function, and social participation.   2.  PsA requires multidisciplinary treatment (rheumatologist, dermatologist, psychiatrist, gastroenterologist, ophthalmologist, dietician, endocrinologist, cardiologist, and physical/occupational therapists), and it should be based on a shared decision-making between the patient and the rheumatologist.   3.  “Treat to target” is recommended, with the target being minimal disease activity or remission. Patients should be regularly monitored, and treatment should be adjusted appropriately to reach the target.   4.  NSAIDs may be used as an initial short-term treatment to relieve symptoms related to peripheral arthritis, enthesitis, dactylitis, and axial disease. NSAIDs alone are very rarely sufficient to treat PsA but can be combined with cs-, b-, or tsDMARDs.   5.  Local injections of glucocorticoids should be considered for active arthritis, enthesitis, and/or dactylitis. Glucocorticoid injections around lower extremity weightbearing entheses should be avoided due to the risk of tendon rupture.   6.  Systemic glucocorticoids should be avoided. In rare circumstances such as acute flares of arthritis, they may be used with caution at the lowest effective dose for the shortest period.   7.  In patients with active disease with peripheral arthritis, enthesitis, and/or dactylitis, treatment with csDMARDs, such as methotrexate, sulfasalazine, or leflunomide, should be considered at an early stage. Methotrexate is preferred if clinically relevant psoriasis is present.   8.  PDE-4 inhibitor or TYK-2 inhibitor may be considered as the initial treatment instead of csDMARD for active musculoskeletal disease (except axial disease) or active skin disease.   9.  In patients with predominant axial disease, csDMARDs should be avoided, and either bDMARDs or JAKi should be considered after inadequate response to NSAIDs. 10.  In rare circumstances, in patients with very active musculoskeletal disease (multiple swollen joints, structural damage in the presence of active inflammation, and/ or clinically relevant extraarticular manifestations such as IBD or uveitis) or extensive skin involvement, treatment with bDMARDs can be started before csDMARDs at the discretion of the treating provider. 11.  The choice of initial biologic for active musculoskeletal disease (TNF, IL-12/23, IL-17, or IL-23 inhibitors) should be based on pros and cons of each therapy class, patients’ comorbidities, and their comfort with risks/benefit. 12.  For patients with predominant skin disease along with musculoskeletal disease, IL-12/23, IL-17, or IL-23 inhibitors are preferred over TNF inhibitors. 13.  For PsA patients with comorbid IBD, monoclonal antibodies against TNF, IL-12/23 inhibitors, IL-23 inhibitors, or JAKi therapy is preferred. IL-17 inhibitors should be avoided in patients with active IBD but can be used in patients with history of IBD. 14.  For PsA patients with comorbid uveitis, therapy with monoclonal antibodies against TNF is preferred. 15.  JAKi should be used after failure of TNF inhibitors according to the black-box warning issued by regulatory authorities based on their CV risk. Comorbidities of metabolic syndrome and CV disease should be considered before JAKi treatment. 16.  Combination of methotrexate with bDMARDs such as TNF inhibitors has not been shown to improve efficacy compared to bDMARDs alone. 17.  Abatacept has no efficacy against the disease domains of skin, nail, and the axial skeleton. Its efficacy against peripheral arthritis is modest. 18.  Agents that effectively treat skin and nail involvement (but with minimal efficacy on the musculoskeletal domains) include topical glucocorticoids such as clobetasol, retinoic acid derivatives, PUVA, and cyclosporin. 19.  Biosimilars may be used in place of the original biologics. 20.  Tapering of DMARDs in a PsA patient with long-term minimal disease activity or remission should be a shared decision. Stopping DMARD therapy is not recommended. Abbreviations: bDMARDs, biologic disease-modifying antirheumatic drugs; csDMARDs, conventional synthetic disease-modifying antirheumatic drugs; CV, cardiovascular; IBD, inflammatory bowel disease; IL, interleukin; JAKi, Janus kinase inhibitor; NSAIDs, nonsteroidal anti-inflammatory drugs; PUVA, psoralene plus ultraviolet light A; TNF, tumor necrosis factor; tsDMARDs, targeted synthetic disease-modifying antirheumatic drugs. that a 6-month course of combination antibiotics (doxycycline or azithromycin, combined with rifampicin) yielded higher response rates then placebo in chronic Chlamydia-induced ReA. However, these results have not been replicated, and the routine use of longterm antibiotics to treat chronic ReA is not recommended. In acute ReA, management of joint symptoms include NSAIDs, intraarticular glucocorticoids for monoarthritis or oligoarthritis, and short-term low-dose systemic glucocorticoids for polyarticular joint involvement. While ReA is thought to be self-limiting and resolving in a large proportion of patients, ReA may also evolve into a chronic phase. The presence of HLA-B27 has been linked to the evolution into chronicity in part because HLA-B27 has been sug­ gested to promote intracellular survival of causative microorgan­ isms in infected macrophages, providing a roadmap to chronicity. In chronic forms of ReA (e.g., lasting longer than 6 months and with inadequate response to management outline in acute ReA), DMARDs such as sulfasalazine and methotrexate and even TNFis can be considered. Overall, the management of chronic forms of ReA follows treatment principles of peripheral SpA. IBD-ASSOCIATED ARTHRITIS An intriguing relationship between bowel and joint inflammation has emanated for >50 years that points to a prominent role of barrier integ­ rity loss and dysbiosis in SpA, initially recognized by uncovering the CHAPTER 374 Spondyloarthritis occurrence of arthritis in IBD patients. The link between gut and joint inflammation, however, is reciprocal. Hence, patients with a diagnosis of SpA but without associated gastrointestinal symptoms were also found to display histologic signs of inflammation in ileocolonoscopic studies, primarily in the terminal ileum. Here, two types of lesions were described: an acute type of inflammation resembling an infectious enterocolitis and a chronic type of inflammation with many features of Crohn’s disease. Overall, the frequency of microscopic inflammatory lesions mounts up to 50% of new-onset treatment-naïve SpA patients and is associated with higher degrees of bone marrow edema in MRI of sacroiliac joints. Furthermore, the presence of chronic lesions rep­ resents a risk factor for evolution into full-blown Crohn’s disease and progression to AS. These microscopic lesions are accompanied by elevated fecal calprotectin and CRP levels. Both ulcerative colitis and Crohn’s disease are associated with SpA. AxSpA as well as pSpA commonly occur in both of them, with pSpA being the most prevalent form. R-axSpA develops in up to 10% of IBD patients, whereas prevalence of pSpA varies largely according to vari­ ous studies, ranging from 10 to 30%. Conversely, patients with axSpA have a substantially higher risk of developing IBD, with a prevalence varying between 5 and 10% and with an observed increase with disease duration. This reciprocal rela­ tionship between IBD and AS is reflected by a considerable overlap in the genetic predisposition between these diseases, including polymor­ phisms in genes linked to type 3 immunity (e.g., IL-23R, IL-12p40, RORc), innate immunity (TNFAIP3, TLR4), and epithelial integrity (GPR35, PTGER4). However, HLA-B27 is not a risk factor for IBD. ■ ■CLINICAL FEATURES Axial skeletal involvement associated with IBD is clinically similar to idiopathic axSpA. There may be, however, a disconnect in time in the occurrence of both. Thus, axSpA may develop after diagnosis of IBD but, in other cases, precedes onset of IBD. Peripheral involvement in IBD resembles the clinical picture of peripheral SpA, which may include more acute forms of oligoarthritis that co-occur with relapses of IBD. More chronic forms of SpA may also occur that may cause substantial structural damage if not appropriately treated. A rare sym­ metric polyarticular arthritis that runs an independent course has also been described. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders In addition to IBD patients with a firm diagnosis of SpA, a compara­ ble fraction of IBD patients have arthralgias or fibromyalgia symptoms. ■ ■DIAGNOSIS IBD-related arthritis is diagnosed based on clinical and imaging fea­ tures in patients with a history of IBD and follows the same diagnostic principles as other forms of SpA. It is important to note, however, that most patients with IBD-related arthritis are seen while being treated for IBD. Thus, special caution should be taken in interpretation of imag­ ing in patients treated with biologics, immune suppressive drugs, and glucocorticoids. TREATMENT IBD-Associated Arthritis Management of IBD-related arthritis follows the general prin­ ciples of axSpA and pSpA treatment with some special consid­ erations, given the observed disconnect that may occur between gut and joint symptoms with some targeted therapies. Within the targeted therapies, the monoclonal antibodies, but not the soluble receptor, blocking TNF-α are effective in IBD as well as in both axial and peripheral SpA. Other biologics with efficacy in IBD that may have proven efficacy in peripheral SpA include ustekinumab (anti-IL12/23p40), guselkumab, and risankizumab (anti-IL23p19), but anti-IL17 therapy is contraindicated. The JAKi tofacitinib and upadacitinib are approved in ulcerative colitis and upadacitinib in Crohn’s disease and are also effective in axSpA and pSpA. Other treatments for IBD include sulfasalazine and related drugs as well as systemic and local glucocorticoids. NSAIDs, especially COX2-selective formulations, are helpful for arthritis and generally well tolerated but may induce IBD flares, so they should be considered only for temporary use. Vedolizumab is a gut-selective integrin inhibitor approved for both Crohn’s disease and ulcerative colitis. However, up to 15% of IBD patients treated with vedolizumab may develop new-onset disease or flare of axSpA or pSpA. UNDIFFERENTIATED PERIPHERAL SPONDYLOARTHRITIS The term “undifferentiated pSpA” is used to describe patients who do not fit into any of the above well-defined conditions such as axSpA, PsA, ReA, or IBD-associated arthritis but have the typical SpA phe­ notype (oligoarticular inflammatory arthritis, usually involving lower limbs, asymmetric, or peripheral enthesitis or dactylitis). The ASAS group developed classification criteria for pSpA in 2011 (Table 374-8). These criteria allow the classification of a patient with peripheral enthesitis or dactylitis but without peripheral arthritis. The prevalence and incidence of undifferentiated pSpA are not known since there are no epidemiologic studies available. Some of these patients are likely to have ReA, where the inciting infection is silent, and in some patients, features of psoriasis and/or IBD may develop later. Treatment of pSpA TABLE 374-8  Assessment of Spondyloarthritis International Society (ASAS) Criteria for Peripheral Spondyloarthritis (SpA) Arthritis or enthesitis or dactylitis Plus ≥1 of: - Psoriasis - Inflammatory bowel disease - Preceding infection - HLA-B27 - Uveitis - Sacroiliitis on imaging (radiographs Plus ≥2 of the remaining: - Arthritis - Enthesitis - Dactylitis - IBP in the past - Positive family history for SpA   or MRI)  Note: Peripheral arthritis: usually lower limb, asymmetric arthritis; enthesitis: clinically assessed; dactylitis: clinically assessed. Abbreviations: IBP, Inflammatory back pain; MRI, magnetic resonance imaging. should be individualized based on the predominant musculoskeletal manifestation. SPONDYLOARTHRITIS ASSOCIATED WITH SAPHO SYNDROME AND HIDRADENITIS SUPPURATIVA SAPHO is a clinical entity that is sometimes associated with Propioni­ bacterium acne infection on bone biopsies. It is included under SpA since some patients have asymmetric inflammatory arthritis (typi­ cally sternoclavicular joints and chest wall costochondral junctions), sacroiliitis, and spinal hyperostosis. The skin manifestations include acne conglobate and palmoplantar pustular lesions that are patho­ logically identical to psoriasis. Some consider SAPHO as the adult phenotype of juvenile chronic recurrent multifocal osteomyelitis (CRMO), where the osteomyelitis is sterile. Apart from TNFi, IL-17i, and JAKi, there are case reports of pamidronate, a bisphosphonate, being effective in treatment. Hidradenitis suppurativa patients may develop a SpA phenotype of musculoskeletal involvement, including asymmetric sacroiliitis. ■ ■FURTHER READING Coates L et al: Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA): Updated treatment recommendations for psoriatic arthritis 2021. Nat Rev Rheumatol 18:465, 2022. Danve A et al: Treatment of axial spondyloarthritis: An update. Nat Rev Rheumatol 18:205, 2022. Gracey E et al. Revisiting the gut-joint axis: Links between gut inflam­ mation and spondyloarthritis. Nat Rev Rheumatol 16:415, 2020. Gracey E et al: Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis. Nat Rev Rheumatol 16:193, 2020. Maksymowych WP et al: Data-driven definitions for active and structural MRI lesions in the sacroiliac joint in spondyloarthritis and their predictive utility. Rheumatology (Oxford) 60:4778, 2021. Moll JM et al: Psoriatic arthritis. Semin Arthritis Rheum 3:55, 1973. Rudwaleit M et al: The development of assessment of SpondyloAr­ thritis International Society classification criteria for axial spondy­ loarthritis (part II): Validation and final selection. Ann Rheum Dis 68:777, 2009. Schett G et al: Reframing immune-mediated inflammatory diseases through signature cytokine hubs. N Engl J Med 385:628, 2021. van der Linden S et al: Evaluation of diagnostic criteria for ankylos­ ing spondylitis: A proposal for modification of the New York criteria. Arthritis Rheum 27:361, 1984. Ward MM et al: 2019 update of the American College of Rheumatology/ Spondylitis Association of America/Spondyloarthritis Research and Treatment Network recommendations for the treatment of ankylosing spondylitis and non-radiographic axial spondyloarthritis. Arthritis Rheumatol 71:1519, 2019. # 18 - 375 The Vasculitis Syndromes ### 375 The Vasculitis Syndromes Carol A. Langford, Anthony S. Fauci The Vasculitis Syndromes DEFINITION Vasculitis is a clinicopathologic process characterized by inflammation of and damage to blood vessels. The vessel lumen is usually compro­ mised, and this is associated with ischemia of the tissues supplied by the involved vessel. A broad and heterogeneous group of syndromes may result from this process, since any type, size, and location of blood vessel may be involved. Vasculitis and its consequences may be the primary or sole manifestation of a disease; alternatively, vasculitis may be a secondary component of another disease. Vasculitis may be confined to a single organ, such as the skin, or it may simultaneously involve several organ systems. CLASSIFICATION The vasculitic syndromes as a group have a great deal of heterogeneity while also possessing a considerable degree of overlap. Table 375-1 lists the major vasculitis syndromes. The distinguishing and overlapping features of these syndromes are discussed below. PATHOPHYSIOLOGY AND PATHOGENESIS Generally, most of the vasculitic syndromes are assumed to be medi­ ated at least in part by immunopathogenic mechanisms that occur in response to certain antigenic stimuli. However, evidence supporting this hypothesis is for the most part indirect and may reflect epiphe­ nomena as opposed to true causality. Furthermore, it is unknown why some individuals might develop vasculitis in response to certain antigenic stimuli, whereas others do not. It is likely that a number of factors are involved in the ultimate expression of a vasculitic syndrome. These include the genetic predisposition, environmental exposures, and the regulatory mechanisms associated with immune response to certain antigens. Although immune complex formation, antineutro­ phil cytoplasmic antibodies (ANCA), and pathogenic T lymphocyte responses (Table 375-2) have been among the prominent hypothesized mechanisms, the pathogenesis of individual forms of vasculitis remains complex and varied. TABLE 375-1  Vasculitis Syndromes SECONDARY VASCULITIS SYNDROMES PRIMARY VASCULITIS SYNDROMES Granulomatosis with polyangiitis Microscopic polyangiitis Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) IgA vasculitis (Henoch-Schönlein) Cryoglobulinemic vasculitis Polyarteritis nodosa Kawasaki disease Giant cell arteritis Takayasu arteritis Behçet’s disease Cogan’s syndrome Single-organ vasculitis   Cutaneous leukocytoclastic angiitis   Cutaneous arteritis   Primary central nervous system Vasculitis associated with probable etiology   Drug-induced vasculitis   Hepatitis C virus–associated cryoglobulinemic vasculitis   Hepatitis B virus–associated vasculitis   Cancer-associated vasculitis Vasculitis associated with systemic disease   Lupus vasculitis   Rheumatoid vasculitis   Sarcoid vasculitis   Others vasculitis   Isolated aortitis Source: Adapted from JC Jennette et al: Arthritis Rheum 65:1, 2013. TABLE 375-2  Potential Mechanisms of Vessel Damage in Vasculitis Syndromes Pathogenic immune-complex formation and/or deposition   IgA vasculitis (Henoch-Schönlein)   Lupus vasculitis   Serum sickness and cutaneous vasculitis syndromes   Hepatitis C virus–associated cryoglobulinemic vasculitis   Hepatitis B virus–associated vasculitis Production of antineutrophilic cytoplasmic antibodies   Granulomatosis with polyangiitis   Microscopic polyangiitis   Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) Pathogenic T lymphocyte responses and granuloma formation   Giant cell arteritis   Takayasu arteritis   Granulomatosis with polyangiitis   Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) CHAPTER 375 The Vasculitis Syndromes Source: Reproduced with permission from MC Sneller, AS Fauci: Pathogenesis of vasculitis syndromes. Med Clin North Am 81:221, 1997. ■ ■PATHOGENIC IMMUNE-COMPLEX FORMATION Deposition of immune complexes was the first and most widely accepted pathogenic mechanism of vasculitis. However, the causal role of immune complexes has not been clearly established in most of the vasculitic syndromes. Circulating immune complexes need not result in deposition of the complexes in blood vessels with ensuing vasculitis, and many patients with active vasculitis do not have demonstrable circulating or deposited immune complexes. The actual antigen con­ tained in the immune complex has only rarely been identified in vascu­ litic syndromes. In this regard, hepatitis B antigen has been identified in both the circulating and deposited immune complexes in a subset of patients who have features of a systemic vasculitis clinically similar to polyarteritis nodosa (see “Polyarteritis Nodosa”). Cryoglobulinemic vasculitis is strongly associated with hepatitis C virus infection; hepa­ titis C virions and hepatitis C virus antigen-antibody complexes have been identified in the cryoprecipitates of these patients (see “Cryo­ globulinemic Vasculitis”). The mechanisms of tissue damage in immune complex–mediated vasculitis resemble those described for serum sickness. In this model, antigen-antibody complexes are formed in antigen excess and are deposited in vessel walls whose permeability has been increased by vasoactive amines such as histamine, bradykinin, and leukotrienes released from platelets or from mast cells as a result of IgE-triggered mechanisms. The deposition of complexes results in activation of com­ plement components, particularly C5a, which is strongly chemotactic for neutrophils. These cells then infiltrate the vessel wall, phagocytose the immune complexes, and release their intracytoplasmic enzymes, which damage the vessel wall. As the process becomes subacute or chronic, mononuclear cells infiltrate the vessel wall resulting in com­ promise of the vessel lumen with ischemic changes in the tissues sup­ plied by the involved vessel. Several variables may explain why only certain types of immune complexes cause vasculitis and why only cer­ tain vessels are affected in individual patients. These include the ability of the reticuloendothelial system to clear circulating complexes from the blood, the size and physicochemical properties of immune com­ plexes, the relative degree of turbulence of blood flow, the intravascular hydrostatic pressure in different vessels, and the preexisting integrity of the vessel endothelium. ■ ■ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES ANCA are antibodies directed against certain proteins in the cytoplasmic granules of neutrophils and monocytes. These auto­ antibodies are present in a high percentage of patients with active granulomatosis with polyangiitis and microscopic polyangiitis and in a lower percentage of patients with eosinophilic granulomatosis with polyangiitis. Because these diseases share the presence of ANCA and small-vessel vasculitis, they have been grouped collectively as “ANCA-associated vasculitis.” However, since these diseases possess unique clinical phenotypes, they should continue to be viewed as separate entities. There are two major categories of ANCA based on different targets for the antibodies. The terminology of cytoplasmic ANCA (cANCA) refers to the diffuse, granular cytoplasmic staining pattern observed by immunofluorescence microscopy when serum antibodies bind to indicator neutrophils. Proteinase-3, a 29-kDa neutral serine protein­ ase present in neutrophil azurophilic granules, is the major cANCA antigen. More than 90% of patients with active granulomatosis with polyangiitis have detectable antibodies to proteinase-3 (see below). The terminology of perinuclear ANCA (pANCA) refers to the more localized perinuclear or nuclear staining pattern of the indicator neu­ trophils. The major target for pANCA is the enzyme myeloperoxidase; other targets that can produce a pANCA pattern include elastase, cathepsin G, lactoferrin, lysozyme, and bactericidal/permeabilityincreasing protein. However, only antibodies to myeloperoxidase have been convincingly associated with vasculitis. Antimyeloperoxidase antibodies have been reported in a variable percentage of patients with microscopic polyangiitis, eosinophilic granulomatosis with polyangi­ itis, isolated necrotizing crescentic glomerulonephritis, and granulo­ matosis with polyangiitis (see below). A pANCA pattern that is not due to antimyeloperoxidase antibodies has been associated with non­ vasculitic entities such as rheumatic and nonrheumatic autoimmune diseases, inflammatory bowel disease, certain drugs, and infections such as endocarditis and bacterial airway infections in patients with cystic fibrosis. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders It is unclear why patients with these vasculitis syndromes develop antibodies to myeloperoxidase or proteinase-3 or what role these antibodies play in disease pathogenesis. There are a number of in vitro observations that suggest possible mechanisms whereby these antibod­ ies can contribute to the pathogenesis of the vasculitis syndromes. Proteinase-3 and myeloperoxidase reside in the azurophilic granules and lysosomes of resting neutrophils and monocytes, where they are apparently inaccessible to serum antibodies. However, when neutro­ phils or monocytes are primed by tumor necrosis factor α (TNF-α) or interleukin 1 (IL-1), or activation of the alternative complement cascade, proteinase-3 and myeloperoxidase translocate to the cell membrane, where they can interact with extracellular ANCA. The neu­ trophils then degranulate and produce reactive oxygen species that can cause tissue damage. Furthermore, ANCA-activated neutrophils can adhere to and kill endothelial cells in vitro. Activation of neutrophils and monocytes by ANCA also induces the release of proinflamma­ tory cytokines such as IL-1 and IL-8. Adoptive transfer experiments in genetically engineered mice provide further evidence for a direct pathogenic role of ANCA in vivo. In contradiction, however, a number of clinical and laboratory observations argue against a primary patho­ genic role for ANCA. Patients may have active granulomatosis with polyangiitis in the absence of ANCA; the absolute height of the anti­ body titers does not correlate well with disease activity; and patients with granulomatosis with polyangiitis in remission may continue to have high ANCA levels for years (see below). ■ ■PATHOGENIC T LYMPHOCYTE RESPONSES AND GRANULOMA FORMATION The histopathologic feature of granulomatous vasculitis has provided evidence to support a role of pathogenic T lymphocyte responses and cell-mediated immune injury. Vascular endothelial cells can express human leukocyte antigen (HLA) class II molecules following activa­ tion by cytokines such as interferon (IFN) γ. This allows these cells to participate in immunologic reactions such as interaction with CD4+ T lymphocytes in a manner similar to antigen-presenting macrophages. Endothelial cells can secrete IL-1, which may activate T lymphocytes and initiate or propagate in situ immunologic processes within the blood vessel. In addition, IL-1 and TNF-α are potent inducers of endothelial-leukocyte adhesion molecule 1 (ELAM-1) and vascular cell adhesion molecule 1 (VCAM-1), which may enhance the adhesion of leukocytes to endothelial cells in the blood vessel wall. APPROACH TO THE PATIENT General Principles of Diagnosis The diagnosis of vasculitis should be considered in any patient with an unexplained systemic illness. However, there are certain clinical features that should suggest a diagnosis of vasculitis. These include palpable purpura, pulmonary infiltrates and microscopic hematuria, chronic sinusitis, mononeuritis multiplex, unexplained ischemic events, and glomerulonephritis with evidence of multi­ system disease. As a number of nonvasculitic diseases may also produce these abnormalities, the first step in the workup of a patient with suspected vasculitis is to exclude other diseases that can mimic vasculitis (Table 375-3). It is particularly important to exclude infectious diseases with features that overlap those of vasculitis, especially if the patient’s clinical condition is deteriorat­ ing rapidly and empirical immunosuppressive treatment is being contemplated. Once diseases that mimic vasculitis have been excluded, the workup should follow a series of progressive steps that establish the diagnosis of vasculitis and determine, where possible, the category of the vasculitis syndrome (Fig. 375-1). This approach is of consid­ erable importance since several of the vasculitis syndromes require aggressive therapy with glucocorticoids and other immunosuppres­ sive agents, whereas other syndromes usually resolve spontaneously and require symptomatic treatment only. The definitive diagnosis of vasculitis is usually made based on biopsy of involved tissue. The yield of “blind” biopsies of organs with no subjective or objec­ tive evidence of involvement is very low and should be avoided. TABLE 375-3  Conditions That Can Mimic Vasculitis Infectious Diseases   Bacterial endocarditis   Disseminated gonococcal infection   Pulmonary histoplasmosis   Coccidioidomycosis   Syphilis   Lyme disease   Rocky Mountain spotted fever   Whipple’s disease Coagulopathies/Thrombotic Microangiopathies   Antiphospholipid syndrome   Thrombotic thrombocytopenic purpura Neoplasms   Atrial myxoma   Lymphoma   Carcinomatosis Drug Toxicity   Cocaine   Levamisole   Amphetamines   Ergot alkaloids   Methysergide   Arsenic Other   Sarcoidosis   Atheroembolic disease   Antiglomerular basement membrane disease (Goodpasture’s syndrome)   Amyloidosis   Migraine   Fibromuscular dysplasia   Heritable disorders of connective tissue   Segmental arterial mediolysis (SAM)   Reversible cerebral vasoconstrictive syndrome Presentation of patient with suspected vasculitis Clinical findings Biopsy Establish diagnosis Angiogram where appropriate Laboratory workup Properly categorize to a specific vasculitis syndrome Determine pattern and extent of disease Look for offending antigen Look for underlying disease Characteristic syndrome (i.e., granulomatosis with polyangiitis PAN, Takayasu arteritis) Yes No Yes No Treat underlying disease Remove antigen Syndrome resolves Treat vasculitis Yes No No further action Treat vasculitis FIGURE 375-1  Algorithm for the approach to a patient with suspected diagnosis of vasculitis. PAN, polyarteritis nodosa. When syndromes such as polyarteritis nodosa, Takayasu arteri­ tis, or primary central nervous system (CNS) vasculitis are sus­ pected, arteriogram of organs with suspected involvement should be performed. GENERAL PRINCIPLES OF TREATMENT Once a diagnosis of vasculitis has been established, a decision regarding therapeutic strategy must be made (Fig. 375-1). If an offending antigen that precipitates the vasculitis is recognized, the antigen should be removed where possible. If the vasculitis is associated with an underlying disease such as an infection, neo­ plasm, or connective tissue disease, the underlying disease should be treated. If the syndrome represents a primary vasculitic disease, treatment should be initiated according to the category of the vasculitis syndrome. Specific therapeutic regimens are discussed below for the individual vasculitis syndromes; however, certain general principles regarding therapy should be considered. Deci­ sions regarding treatment should be based on the use of regimens for which there has been published literature supporting efficacy for that particular vasculitic disease. Since the potential toxic side effects of certain therapeutic regimens may be substantial, the riskversus-benefit ratio of any therapeutic approach should be weighed carefully. Glucocorticoids and/or other immunosuppressive agents should be instituted immediately in diseases where irreversible organ system dysfunction and high morbidity and mortality rates have been clearly established. Granulomatosis with polyangiitis is the prototype of a severe systemic vasculitis requiring such a therapeutic approach (see below). Conversely, aggressive therapy should be avoided for vasculitic manifestations that rarely result in irreversible organ system dysfunction such as isolated idiopathic cutaneous vasculitis. Glucocorticoids should be initiated in those systemic vasculitides that cannot be specifically categorized or for which there is no established standard therapy, with other immu­ nosuppressive agents being added if an adequate response does not result or if remission can only be achieved and maintained with an unacceptably toxic regimen of glucocorticoids. Following improve­ ment, one should continually attempt to taper glucocorticoids and discontinue when possible. When using other immunosuppressive regimens, one should base the choice of agent upon the available therapeutic data supporting efficacy in that disease, the site and severity of organ involvement, and the toxicity profile of the drug. CHAPTER 375 Most forms of vasculitis carry the potential for relapse such that treatment planning needs to include assessment of relapse risk for that vasculitis and the medication regimen being used. Physicians should be thoroughly aware of the acute and longterm side effects associated with the agents that are commonly used to treat different forms of vasculitis (Table 375-4). The Vasculitis Syndromes Morbidity and mortality can occur as a result of treatment, and strategies to monitor for and prevent toxicity represent an essential part of patient care. Addressing the risk of bone loss is important in all patients receiving glucocorticoids. Daily cyclophosphamide should be taken all at once in the morning with a large amount of fluid throughout the day to reduce the risk of bladder injury, and monitoring for bladder cancer should continue indefinitely. Maintaining the white blood cell (WBC) count at >3000/μL and the neutrophil count at >1500/μL is essential to reduce the risk of life-threatening infections. Monitoring of the complete blood count every 1–2 weeks for as long as the patient receives cyclo­ phosphamide can effectively prevent cytopenias. Methotrexate, azathioprine, and mycophenolate mofetil are also associated with bone marrow suppression, and complete blood counts should be obtained every 1–2 weeks for the first 1–2 months after their initia­ tion and once a month thereafter. To lessen toxicity, methotrexate is often given together with folic acid, 1 mg daily, or folinic acid, 5–10 mg once a week 24 h following methotrexate. Methotrexate is eliminated by the kidney and contraindicated in renal insufficiency as this increases the risk for toxicity. Prior to initiation of azathio­ prine, thiopurine methyltransferase (TPMT), an enzyme involved in the metabolism of azathioprine, should be assayed because inad­ equate levels may result in severe cytopenia. Rituximab can be associated with infusion reactions. In addition to administering this within a skilled infusion center, these reac­ tions can be lessened by the use of premedications. There is a risk of hepatitis B reactivation with rituximab such that all patients should be screened for this infection prior to its use. Immunoglobulins should be monitored with rituximab use. Tocilizumab and sarilumab are associated with cytopenias, hepa­ totoxicity, and hyperlipidemia. Laboratory monitoring for drug toxicity should be performed 4–8 weeks after start of therapy and every 3 months thereafter. Infection represents a significant toxicity for all vasculitis patients treated with immunosuppressive therapy. Infections with Pneumo­ cystis jirovecii and certain fungi can be seen even when the WBC count is within normal limits, particularly in patients receiving glucocorticoids. Use of prophylactic therapy to prevent P. jirovecii infection should be based on the treatment regimen being used. Patients with granulomatosis with polyangiitis or microscopic poly­ angiitis who are receiving induction treatment with glucocorticoids in combination with another immunosuppressive agent should receive trimethoprim-sulfamethoxazole (TMP-SMX) or a different preventive medication. Continuation of Pneumocystis prophylaxis during maintenance therapy should be strongly considered in most patients, particularly for those receiving rituximab or who have persistent lymphopenia. In recent years, national and regional organizations have pub­ lished treatment guidelines that can provide additional direction to clinicians. It should be emphasized that each patient is unique and requires individual decision-making. Information from guidelines as well as this chapter should serve as a framework for the applica­ tion of evidence-based approaches with incorporation of patientspecific goals to provide maximal therapeutic efficacy with minimal toxic side effects. TABLE 375-4  Major Toxic Side Effects of Drugs Used in the Treatment of Vasculitisa CONVENTIONAL IMMUNOSUPPRESSIVE AGENTS Glucocorticoids Osteoporosis Cataracts Glaucoma Diabetes mellitus Electrolyte abnormalities Metabolic abnormalities Severe and opportunistic infections Cushingoid features Growth suppression in children Hypertension Avascular necrosis of bone Myopathy Alterations in mood Psychosis Pseudotumor cerebri Peptic ulcer diathesis Pancreatitis PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Cyclophosphamide Bone marrow suppression Cystitis Bladder carcinoma Gonadal suppression Gastrointestinal intolerance Hypogammaglobulinemia Pulmonary fibrosis Myelodysplasia Oncogenesis Teratogenicity Severe and opportunistic infections Methotrexate Gastrointestinal intolerance Stomatitis Bone marrow suppression Hepatotoxicity (may lead to fibrosis or cirrhosis) Pneumonitis Teratogenicity Severe and opportunistic infections Azathioprine Gastrointestinal intolerance Bone marrow suppression Hepatotoxicity Severe and opportunistic infections Hypersensitivity Mycophenolate mofetil Bone marrow suppression Gastrointestinal intolerance Severe and opportunistic infections Teratogenicity BIOLOGIC AGENTS AND SMALL-MOLECULE INHIBITORS Rituximab (granulomatosis with polyangiitis and microscopic polyangiitis) Infusion reactions Progressive multifocal leukoencephalopathy Mucocutaneous reactions Hypogammaglobulinemia Impaired vaccine response Severe and opportunistic infections Hepatitis B reactivation Tumor lysis syndrome Late-onset neutropenia Tocilizumab (giant cell arteritis) Sarilumab (polymyalgia rheumatica) Bone marrow suppression Hepatotoxicity Hyperlipidemia Severe and opportunistic infections Gastrointestinal perforation Hypersensitivity reactions Mepolizumab (eosinophilic granulomatosis with polyangiitis [Churg-Strauss]) Hypersensitivity reactions Opportunistic infections: herpes zoster Apremilast (Behçet’s syndrome; see Chap. 376) Diarrhea, nausea, and vomiting Depression Weight decrease Avacopan (severe granulomatosis with polyangiitis and microscopic polyangiitis) Hepatotoxicity Hypersensitivity reactions Hepatitis B reactivation Serious infections aConsult the drug package insert for a full listing of side effects. FIGURE 375-2  Lung histology in granulomatosis with polyangiitis. This area of geographic necrosis has a serpiginous border of histiocytes and giant cells surrounding a central necrotic zone. Vasculitis is also present with neutrophils and lymphocytes infiltrating the wall of a small arteriole (upper right). (Courtesy of William D. Travis, MD; with permission.) GRANULOMATOSIS WITH POLYANGIITIS ■ ■DEFINITION Granulomatosis with polyangiitis is a distinct clinicopathologic entity characterized by granulomatous vasculitis of the upper and lower respiratory tracts together with glomerulonephritis. In addition, vari­ able degrees of disseminated vasculitis involving both small arteries and veins may occur. ■ ■INCIDENCE AND PREVALENCE Granulomatosis with polyangiitis has an estimated prevalence of 3 per 100,000. It is extremely rare in blacks compared with whites; the male-to-female ratio is 1:1. The disease can be seen at any age; ~15% of patients are <19 years of age, but only rarely does the disease occur before adolescence; the mean age of onset is 40–60 years. ■ ■PATHOLOGY AND PATHOGENESIS The histopathologic hallmarks of granulomatosis with polyangiitis are necrotizing vasculitis of small arteries and veins together with granu­ loma formation, which may be either intravascular or extravascular (Fig. 375-2). Lung involvement typically appears as multiple, bilateral, nodular or cavitary infiltrates (Fig. 375-3), which on biopsy can reveal necrotizing granulomatous vasculitis. Upper airway lesions, particu­ larly those in the sinuses and nasopharynx, typically reveal inflamma­ tion, necrosis, and granuloma formation, with or without vasculitis. In its earliest form, renal involvement is characterized by a focal and segmental glomerulitis that may evolve into a rapidly progressive cres­ centic glomerulonephritis. Granuloma formation is only rarely seen on FIGURE 375-3  Computed tomography scan of a patient with granulomatosis with polyangiitis. The patient developed multiple, bilateral, and cavitary infiltrates. renal biopsy. In contrast to other forms of glomerulonephritis, immune complex deposition is not found in the renal lesion of granulomatosis with polyangiitis (pauci-immune glomerulonephritis). In addition to the classic triad of disease of the upper and lower respiratory tracts and kidney, virtually any organ can be involved with vasculitis, granuloma, or both. The immunopathogenesis of this disease is unclear, although the involvement of upper airways and lungs with granulomatous vasculitis suggests an aberrant cell-mediated immune response to an exogenous or even endogenous antigen that enters through or resides in the upper airway. Chronic nasal carriage of Staphylococcus aureus has been reported to be associated with a higher relapse rate of granulomatosis with polyangiitis; however, there is no evidence for a role of this organ­ ism in the pathogenesis of the disease. Peripheral blood mononuclear cells obtained from patients with granulomatosis with polyangiitis manifest increased secretion of IFN-γ but not of IL-4, IL-5, or IL-10 compared to healthy controls. In addition, TNF-α production from peripheral blood mononuclear cells and CD4+ T cells is elevated and monocytes from patients with granulomatosis with polyangiitis produce increased amounts of IL-12. These findings indicate an unbalanced TH1-type T-cell cytokine pat­ tern in this disease that may have pathogenic and perhaps therapeutic implications. A high percentage of patients with granulomatosis with polyangiitis develop ANCA, and these autoantibodies may play a role in the patho­ genesis of this disease (see above). ■ ■CLINICAL AND LABORATORY MANIFESTATIONS Involvement of the upper airways occurs in 95% of patients with gran­ ulomatosis with polyangiitis. Patients often present with severe upper respiratory tract findings such as paranasal sinus pain and drainage and purulent or bloody nasal discharge, with or without nasal mucosal ulceration (Table 375-5). Nasal septal perforation may follow, leading to saddle nose deformity. Serous otitis media may occur as a result of eustachian tube blockage. Subglottic stenosis resulting from active disease or scarring occurs in ~16% of patients and may result in severe airway obstruction. Pulmonary involvement (85–90% of patients) may be clinically expressed as cough, hemoptysis, dyspnea, and chest discomfort, or active disease may be asymptomatic in up to 30% of cases. Endobron­ chial disease, either in its active form or as a result of fibrous scarring, may lead to obstruction with atelectasis. Eye involvement (52% of patients) may range from a mild conjunc­ tivitis to dacryocystitis, episcleritis, scleritis, granulomatous sclerou­ veitis, ciliary vessel vasculitis, and retroorbital mass lesions leading to proptosis. Skin lesions (46% of patients) appear as papules, vesicles, palpable purpura, ulcers, or subcutaneous nodules; biopsy reveals vasculitis, granuloma, or both. Cardiac involvement (8% of patients) mani­ fests as pericarditis, coronary vasculitis, or, rarely, cardiomyopathy. Nervous system manifestations (23% of patients) include cranial neuritis, mononeuritis multiplex, or, rarely, cerebral vasculitis and/ or granuloma. Renal disease (77% of patients) generally dominates the clinical pic­ ture and, if left untreated, accounts directly or indirectly for most of the mortality in this disease. Although it may smolder in some cases as a mild glomerulitis with proteinuria, hematuria, and red blood cell casts, once clinically detectable renal functional impairment occurs, rapidly progressive renal failure usually ensues unless appropriate treatment is instituted. While the disease is active, most patients have nonspecific symp­ toms and signs such as malaise, weakness, arthralgias, anorexia, and weight loss. Fever may indicate activity of the underlying disease but more often reflects secondary infection, usually of the upper airway. Characteristic laboratory findings include an elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP), anemia and leukocytosis, and mild hypergammaglobulinemia. Thrombocy­ tosis may be seen as an acute-phase reactant. Approximately 90% of patients with active granulomatosis with polyangiitis have a positive TABLE 375-5  Granulomatosis with Polyangiitis: Frequency of Clinical Manifestations in 158 Patients Studied at the National Institutes of Health PERCENTAGE THROUGHOUT COURSE OF DISEASE CHAPTER 375 PERCENTAGE AT DISEASE ONSET MANIFESTATION Kidney Glomerulonephritis Ear/Nose/Throat The Vasculitis Syndromes Sinusitis Nasal disease Otitis media Hearing loss Subglottic stenosis Ear pain Oral lesions Lung Pulmonary infiltrates Pulmonary nodules Hemoptysis Pleuritis Eyes Conjunctivitis Dacryocystitis Scleritis Proptosis Eye pain Visual loss Retinal lesions Corneal lesions Iritis Othera Arthralgias/arthritis Fever Cough Skin abnormalities Weight loss (>10% body weight) Peripheral neuropathy Central nervous system disease Pericarditis Hyperthyroidism aFewer than 1% had parotid, pulmonary artery, breast, or lower genitourinary (urethra, cervix, vagina, testicular) involvement. Source: GS Hoffman et al: Ann Intern Med 116:488, 1992. antiproteinase-3 ANCA. However, in the absence of active disease, the sensitivity drops to ~60–70%. A small percentage of patients with granulomatosis with polyangiitis may have antimyeloperoxidase rather than antiproteinase-3 antibodies, and up to 20% may lack ANCA. Patients with granulomatosis with polyangiitis have been found to have an increased incidence of venous thrombotic events. Although routine anticoagulation for all patients is not recommended, a height­ ened awareness for any clinical features suggestive of deep-vein throm­ bosis or pulmonary emboli is warranted. ■ ■DIAGNOSIS The diagnosis of granulomatosis with polyangiitis can be established by the demonstration of necrotizing granulomatous vasculitis on tis­ sue biopsy in a patient with compatible clinical features. Pulmonary tissue offers the highest diagnostic yield, almost invariably revealing granulomatous vasculitis. Biopsy of upper airway tissue usually reveals acute and chronic inflammation but can show granulomas and/or vas­ culitis. Renal biopsy can confirm a pauci-immune glomerulonephritis (Chaps. A4 and A14), which differentiates this from other causes of glomerular disease (Chap. 326). The utility of ANCA in diagnosis varies based on the clinical pre­ sentation. The predictive value of a positive ANCA is 90% in patients with active glomerulonephritis. However, in patients who present with sinus and/or lung disease where renal disease is absent, this decreases to 30–60%. Tissue biopsy is typically necessary in these settings to rule out infection or malignancy, which can have a similar presentation and be associated with a false-positive ANCA. Biopsy should also be pur­ sued when clinically inconsistent features are present or when ANCA is absent. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders In its typical presentation, the clinicopathologic complex of granu­ lomatosis with polyangiitis usually provides ready differentiation from other disorders. However, if all the typical features are not present at once, it needs to be differentiated from the other vasculitides, anti­ glomerular basement membrane disease (Goodpasture’s syndrome) (Chap. 326), relapsing polychondritis (Chap. 378), tumors of the upper airway or lung, and infectious diseases such as histoplasmosis (Chap. 218), endocarditis (Chap. 133), mucocutaneous leishmaniasis (Chap. 233), and rhinoscleroma (Chap. 166) as well as noninfectious granulomatous diseases. Of particular note is the differentiation from other midline destruc­ tive diseases. These diseases lead to extreme tissue destruction and mutilation localized to the midline upper airway structures including the sinuses; erosion through the skin of the face commonly occurs, a feature that is extremely rare in granulomatosis with polyangiitis. Although blood vessels may be involved in the intense inflammatory reaction and necrosis, primary vasculitis is not seen. Upper airway neo­ plasms and specifically extranodal natural killer (NK)/T-cell lymphoma (nasal type) are important causes of midline destructive disease. These lesions are diagnosed based on histology, which reveals polymorphous atypical lymphoid cells with an NK cell immunophenotype, typi­ cally Epstein-Barr virus (Chap. 199). Such cases are treated based on their degree of dissemination, and localized lesions have responded to irradiation. Upper airway lesions should never be irradiated in granulomatosis with polyangiitis. Cocaine-induced tissue injury can be another important mimic of granulomatosis with polyangiitis in patients who present with isolated midline destructive disease. ANCA that target human neutrophil elastase can be found in patients with cocaine-induced midline destructive lesions and can complicate the differentiation from granulomatosis with polyangiitis. This has been further confounded by the high frequency of levamisole adulteration of cocaine, which can result in cutaneous infarction and serologic changes that may mimic vasculitis. Granulocytopenia is a common finding in levamisole-induced disease that is not associated with granulomatosis with polyangiitis. Granulomatosis with polyangiitis must also be differentiated from lymphomatoid granulomatosis, which is an Epstein-Barr virus–positive B-cell proliferation that is associated with an exuberant T-cell reaction. Lymphomatoid granulomatosis is characterized by lung, skin, CNS, and kidney involvement in which atypical lymphocytoid and plasma­ cytoid cells infiltrate nonlymphoid tissue in an angioinvasive manner. In this regard, it clearly differs from granulomatosis with polyangiitis in that it is not an inflammatory vasculitis in the classic sense but an angiocentric perivascular infiltration of atypical mononuclear cells. Up to 50% of patients may develop a true malignant lymphoma. TREATMENT Granulomatosis with Polyangiitis Prior to the introduction of effective therapy, granulomatosis with polyangiitis was universally fatal within a few months of diagnosis. Glucocorticoids alone led to some symptomatic improvement, with little effect on the ultimate course of the disease. The develop­ ment of treatment with cyclophosphamide dramatically changed patient outcome such that marked improvement was seen in >90% of patients, complete remission was seen in 75% of patients, and 5-year patient survival was seen in >80%. Despite the ability to successfully induce remission, 50–70% of remissions are later associated with one or more relapses. The determination of relapse should be based on objective evidence of disease activity, taking care to rule out other features that may have a similar appearance such as infection, medication toxicity, or chronic disease sequelae. Many patients who achieve remission continue to have a positive ANCA for years, and changes in ANCA should not be used as a measure of disease activity. Results from a large prospective study found that only 43% of patients relapsed within 1 year of an increase in ANCA levels. Thus, a rise in ANCA by itself is not a harbinger of immediate disease relapse and should not lead to reinstitution or increase in immunosuppressive therapy. Reinduction of remission after relapse is almost always achieved; however, a high percentage of patients ultimately have some degree of damage from irreversible features of their disease, such as vary­ ing degrees of renal insufficiency, neurologic impairment, hearing loss, subglottic stenosis, saddle nose deformity, and chronic sinus dysfunction. Patients who developed irreversible renal failure but who achieved subsequent remission have undergone successful renal transplantation. Treatment of granulomatosis with polyangiitis is viewed as hav­ ing two phases: induction, where active disease is put into remis­ sion, followed by maintenance. Decisions regarding induction and maintenance agents are guided by published data, individual patient factors that include contraindications, relapse history, and comor­ bidities, and stratification based on disease severity. Severe disease is associated with life- or organ-threatening manifestations and is based not only on the degree of involvement but also the organ affected. Pulmonary involvement can be nonsevere when present­ ing as nodular disease without respiratory compromise or severe in the setting of alveolar hemorrhage. In contrast, active glomerulo­ nephritis is always considered to be severe disease even when renal function remains normal. REMISSION INDUCTION OF SEVERE DISEASE Regimens to induce remission of severe active disease consist of either cyclophosphamide or rituximab given in combination with glucocor­ ticoids and consideration of adjunctive avacopan. Glucocorticoids were historically given as prednisone 1 mg/kg per day for the first month, followed by tapering. In a randomized trial, use of a reduceddose glucocorticoid regimen was noninferior to a standard-dose regi­ men and was associated with a lower rate of serious infection. Avacopan (a C5a receptor inhibitor) was investigated in a ran­ domized trial as an alternative to glucocorticoids in patients receiv­ ing induction with either cyclophosphamide or rituximab. At 52 weeks, sustained remission was higher in those who received avacopan as compared to prednisone with a similar rate of serious adverse events. Although glucocorticoids were given within the first few weeks to most patients receiving avacopan, glucocorticoid exposure in the avacopan group remained markedly less than those randomized to the prednisone treatment arm. This supported that glucocorticoids can be rapidly withdrawn in patients with severe active disease receiving avacopan together with either rituximab or cyclophosphamide. In patients presenting with disease that is life-threatening, meth­ ylprednisolone 1000 mg daily for 3 days has been used. Adjunctive plasma exchange was found to provide no added benefit in reduc­ ing the composite outcome of end-stage renal disease or death in a large, randomized trial. Whether it may still play a role in selected patients with the most fulminant disease remains controversial. Although a low number of patients in this trial were enrolled with alveolar hemorrhage requiring mechanical ventilation, a retrospec­ tive study also showed no benefit. From a meta-analysis, patients with active glomerulonephritis and serum creatinine >5.7 mg/dL who received plasma exchange had improvement in renal func­ tion but an increased risk of serious infection. Plasma exchange should be used in patients with granulomatosis with polyangiitis or microscopic polyangiitis who are also positive for antiglomerular basement membrane autoantibody (Chap. 326). When plasma exchange is used concurrently with rituximab, these treatments must be separated by at least 48 h to avoid removal of rituximab. CYCLOPHOSPHAMIDE INDUCTION FOR SEVERE DISEASE Daily cyclophosphamide combined with glucocorticoids was the first regimen proven to effectively induce remission and prolong survival. Cyclophosphamide is given in doses of 2 mg/kg per day orally, but because it is renally eliminated, dosage reduction should be consid­ ered in patients with renal insufficiency. Although we continue to favor the use of daily cyclophosphamide, a randomized trial found IV cyclophosphamide 15 mg/kg, three infusions given every 2 weeks, then every 3 weeks thereafter, to have a similar rate of remission but higher frequency of relapse compared to cyclophosphamide 2 mg/kg daily given for 3 months followed by 1.5 mg/kg daily. Although leu­ kopenia occurred more often with daily cyclophosphamide, this was likely related to a reduced frequency of blood count monitoring after the first month. RITUXIMAB INDUCTION FOR SEVERE DISEASE Rituximab (anti-CD20) has been of proven effectiveness for the treatment of granulomatosis with polyangiitis and microscopic poly­ angiitis. In two randomized trials that enrolled patients with severe active granulomatosis with polyangiitis or microscopic polyangiitis, rituximab 375 mg/m2 once a week for 4 weeks in combination with glucocorticoids was found to be as effective as cyclophosphamide with glucocorticoids for inducing disease remission. In the trial that also enrolled patients with relapsing disease, rituximab was found to be statistically superior to cyclophosphamide. Although rituximab does not have the bladder toxicity or infertility risks of cyclophospha­ mide, in both randomized trials, the rate of adverse events was similar in the rituximab and cyclophosphamide arms. The decision about whether to utilize cyclophosphamide or rituximab for remission induction must be individually based. Factors to consider include disease severity, whether the patient has newly diagnosed or relapsing disease, medication contraindica­ tions, and individual patient factors particularly fertility concerns and risk factors for toxicity. In patients with rapidly progressive glomerulonephritis with a creatinine >4.0 mg/dL or pulmonary hemorrhage requiring mechanical ventilation, daily cyclophospha­ mide and glucocorticoids may be favored. There has been no evidence to date that using cyclophosphamide and rituximab together for induction is more efficacious, and com­ bined use raises concern for additive toxicity, particularly infection. However, in instances of toxicity or rare occurrences of inefficacy, there may be a need to switch from cyclophosphamide to rituximab or vice versa. REMISSION MAINTENANCE OF SEVERE DISEASE When cyclophosphamide is given for induction, it should be stopped after 3–6 months and switched to another agent for remis­ sion maintenance. Medications used in this setting with which there has been published experience from randomized trials are rituximab, azathioprine, methotrexate, and mycophenolate mofetil. A lower rate of relapse was seen with rituximab given at 500 mg for two doses followed by 500 mg every 6 months when compared to azathioprine 2 mg/kg per day. In a randomized trial comparing methotrexate to azathioprine for remission maintenance, similar rates of toxicity and relapse were seen. Methotrexate is administered orally or subcutaneously at a starting dose of 15 mg/week, which is increased by 2.5 mg every 2 weeks up to a dosage of 20–25 mg/week. In patients who are unable to receive methotrexate or azathioprine or who have experienced relapse on such treatment, mycophenolate mofetil 1000 mg twice a day may also sustain remission, but it is associated with a higher rate of relapse compared to azathioprine. For patients who receive rituximab for remission induction, a randomized trial found that rituximab had a lower rate of relapse compared to azathioprine. Although rituximab maintenance doses have not been directly compared, use of 1000 mg every 4 months in this trial was not found to be associated with a longer length of sustained remission after discontinuation. The optimal duration of maintenance therapy is uncertain. With regard to glucocorticoids, it has been unclear whether maintaining patients on prednisone 5 mg/d has greater risks or benefits. Main­ tenance therapy with azathioprine, methotrexate, or mycophenolate mofetil is usually given for a minimum of 2 years. Because there is evidence that the risk of relapse is higher once maintenance medi­ cation has been stopped, the decision is individualized regarding whether to continue treatment or taper these agents over a 6- to 12-month period until discontinuation. Patients with significant organ damage or a history of relapse may benefit from longer-term maintenance therapy. Although rituximab has been found to have a lower relapse rate, studies have similarly shown that relapses occur once treatment is discontinued. Longer term use of rituximab can be associated with hypogammaglobulinemia such that the decision for how long to continue this agent beyond 2 years must be weighed in each patient. REMISSION INDUCTION AND MAINTENANCE OF NONSEVERE DISEASE For patients whose disease is not immediately organ- or life-threat­ ening, methotrexate or mycophenolate mofetil together with gluco­ corticoids, often initiated at a lower dose, may be given to induce and then maintain remission. Rituximab can also be used in this setting weighing the risks and benefits. Treatment with cyclophos­ phamide is rarely, if ever, justified for the treatment of nonsevere granulomatosis with polyangiitis. There have been no published studies to date with the use of avacopan in nonsevere disease. OTHER BIOLOGIC AGENTS Etanercept (TNF inhibitor) was not found to sustain remission when used adjunctively to standard therapy and should not be used in granulomatosis with polyangiitis. Belimumab (anti-B lymphocyte stimulator) was examined as an adjunctive therapy to azathioprine for remission maintenance but showed no added benefit in reducing the risk of relapse. Abatacept (CTLA4-Ig) was examined in a randomized trial in patients with nonsevere relaps­ ing disease where it did not reduce the risk of relapse, disease worsening, or failure to achieve remission. ORGAN-SPECIFIC TREATMENT Not all manifestations of granulomatosis with polyangiitis require or respond to immunosuppressive therapy, and differentiation of active disease from damage is necessary. As sinus disease can dis­ rupt the mucociliary barrier, patients should be instructed on the use of local care with moisturization and humidification. Although certain reports have indicated that TMP-SMX may be of benefit in the treatment of granulomatosis with polyangiitis isolated to the sinonasal tissues, it should never be used alone to treat active granulomatosis with polyangiitis involving other organs. Subglot­ tic stenosis can often scar and responds optimally to nonmedical intervention with dilation and glucocorticoid injection. CHAPTER 375 The Vasculitis Syndromes MICROSCOPIC POLYANGIITIS ■ ■DEFINITION The term microscopic polyarteritis was introduced into the literature by Davson in 1948 in recognition of the presence of glomerulonephritis in patients with polyarteritis nodosa. In 1992, the Chapel Hill Consen­ sus Conference on the Nomenclature of Systemic Vasculitis adopted the term microscopic polyangiitis to connote a necrotizing vasculitis with few or no immune complexes affecting small vessels (capillar­ ies, venules, or arterioles). Glomerulonephritis is very common in microscopic polyangiitis, and pulmonary capillaritis often occurs. The absence of granulomatous inflammation in microscopic polyangiitis is said to differentiate it from granulomatosis with polyangiitis. ■ ■INCIDENCE AND PREVALENCE The incidence of microscopic polyangiitis is estimated to be 3–5/100,000. The mean age of onset is ~57 years, and males are slightly more frequently affected than females. ■ ■PATHOLOGY AND PATHOGENESIS Microscopic polyangiitis has a predilection to involve capillaries and venules in addition to small- and medium-sized arteries. Immunohis­ tochemical staining reveals a paucity of immunoglobulin deposition in the vascular lesion of microscopic polyangiitis, suggesting that immune-complex formation does not play a role in the pathogenesis of this syndrome. The renal lesion seen in microscopic polyangiitis is histologically identical to that of granulomatosis with polyangiitis. Like granulomatosis with polyangiitis, microscopic polyangiitis is highly associated with ANCA, which may play a role in pathogenesis of this syndrome (see above). PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders ■ ■CLINICAL AND LABORATORY MANIFESTATIONS Because of its predilection to involve the small vessels, microscopic polyangiitis and granulomatosis with polyangiitis share similar clinical features. Disease onset may be gradual, with initial symptoms of fever, weight loss, and musculoskeletal pain; however, it is often acute. Glo­ merulonephritis occurs in at least 79% of patients and can be rapidly progressive, leading to renal failure. Hemoptysis may be the first symp­ tom of alveolar hemorrhage, which occurs in 12% of patients. Other manifestations include mononeuritis multiplex and gastrointestinal tract and cutaneous vasculitis. Upper airway disease and pulmonary nodules are not typically found in microscopic polyangiitis and, if pres­ ent, suggest granulomatosis with polyangiitis. Features of inflammation may be seen, including an elevated ESR and/or CRP, anemia, leukocytosis, and thrombocytosis. ANCA are present in 75% of patients with microscopic polyangiitis, with antimy­ eloperoxidase antibodies being the predominant antigen association. ■ ■DIAGNOSIS The diagnosis is based on histologic evidence of vasculitis or pauciimmune glomerulonephritis in a patient with compatible clinical features of multisystem disease. Although microscopic polyangiitis is strongly ANCA-associated, tissue biopsy should continue to be pur­ sued in patients who do not have a clinically compatible picture. TREATMENT Microscopic Polyangiitis The 5-year survival rate for patients with treated microscopic poly­ angiitis is 74%, with disease-related mortality occurring from alveo­ lar hemorrhage or gastrointestinal, cardiac, or renal disease. Studies on treatment have come from trials that have included patients with granulomatosis with polyangiitis or microscopic polyangiitis. Currently, the treatment approach for microscopic polyangiitis is the same as is used for granulomatosis with polyangiitis (see “Granulomatosis with Polyangiitis” for a detailed description of this therapeutic regimen). Disease relapse has been observed in at least 34% of patients. Treatment for such relapses would be based on site and severity of disease. EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (CHURG-STRAUSS) ■ ■DEFINITION Eosinophilic granulomatosis with polyangiitis was described in 1951 by Churg and Strauss and is characterized by asthma, peripheral and tissue eosinophilia, extravascular granuloma formation, and vasculitis of multiple organ systems. ■ ■INCIDENCE AND PREVALENCE Eosinophilic granulomatosis with polyangiitis is an uncommon disease with an estimated annual incidence of 1–3 per million. The disease can occur at any age with the possible exception of infants. The mean age of onset is 48 years, with a female-to-male ratio of 1.2:1. ■ ■PATHOLOGY AND PATHOGENESIS The necrotizing vasculitis of eosinophilic granulomatosis with polyan­ giitis involves small- and medium-sized muscular arteries, capillaries, veins, and venules. A characteristic histopathologic feature of eosino­ philic granulomatosis with polyangiitis is granuloma that may be present in the tissues or even within the walls of the vessels them­ selves. These are usually associated with infiltration of the tissues with eosinophils. This process can occur in any organ in the body; lung involvement is predominant, with skin, cardiovascular system, kidney, peripheral nervous system, and gastrointestinal tract also commonly involved. Although the precise pathogenesis of this disease is uncer­ tain, its strong association with asthma and its clinicopathologic mani­ festations, including eosinophilia, granuloma, and vasculitis, point to aberrant immunologic phenomena. ■ ■CLINICAL AND LABORATORY MANIFESTATIONS Patients with eosinophilic granulomatosis with polyangiitis often exhibit nonspecific manifestations such as fever, malaise, anorexia, and weight loss, which are characteristic of a multisystem disease. The pulmonary findings in eosinophilic granulomatosis with polyangiitis dominate the clinical picture with asthmatic attacks and the presence of pulmonary infiltrates. Mononeuritis multiplex is the second most common manifestation and occurs in up to 72% of patients. Allergic rhinitis and sinusitis develop in up to 61% of patients and are often observed early in the course of disease. Clinically recognizable heart disease with myocarditis, pericarditis, endocarditis, or coronary vascu­ litis occurs in ~14% of patients and is an important cause of mortality. Skin lesions occur in ~51% of patients and include purpura in addition to cutaneous and subcutaneous nodules. Renal disease in eosinophilic granulomatosis with polyangiitis is less common than that of granulo­ matosis with polyangiitis and microscopic polyangiitis. The characteristic laboratory finding in virtually all patients with eosinophilic granulomatosis with polyangiitis is a striking eosinophilia, which reaches levels >1000 cells/μL in >80% of patients. Evidence of inflammation as evidenced by elevated ESR and/or CRP, fibrinogen, or α2-globulins can be found in 81% of patients. The other laboratory findings reflect the organ systems involved. Approximately 48% of patients with eosinophilic granulomatosis with polyangiitis have circu­ lating ANCA that is usually antimyeloperoxidase. ■ ■DIAGNOSIS Although the diagnosis of eosinophilic granulomatosis with polyan­ giitis is optimally made by biopsy in a patient with the characteristic clinical manifestations (see above), histologic confirmation can be challenging because the pathognomonic features often do not occur simultaneously. In order to be diagnosed with eosinophilic granulo­ matosis with polyangiitis, a patient should have evidence of asthma, peripheral blood eosinophilia, and clinical features consistent with vasculitis. TREATMENT Eosinophilic Granulomatosis with Polyangiitis The prognosis of untreated eosinophilic granulomatosis with poly­ angiitis is poor, with a reported 5-year survival of 25%. With treat­ ment, prognosis is favorable, with one study finding a 78-month actuarial survival rate of 72%. Myocardial involvement is the most frequent cause of death and is responsible for 39% of patient mor­ tality. Echocardiography should be performed in all newly diag­ nosed patients because this may influence therapeutic decisions. Glucocorticoids alone appear to be effective in many patients. Dosage tapering is often limited by asthma, with asthma often persisting after clinical recovery from vasculitis. In patients who present with fulminant multisystem disease, particularly cardiac involvement, the treatment of choice is daily cyclophosphamide and prednisone followed by azathioprine or methotrexate (see “Granulomatosis with Polyangiitis” for a detailed description of this therapeutic regimen). Use of rituximab and prednisone can be considered, particularly in ANCA-positive patients who have glo­ merulonephritis or other features of severe small-vessel vasculitis. Mepolizumab (anti-IL-5 antibody) 300 mg given subcutane­ ously once a month was studied in a randomized trial and found to be more effective than placebo, with a higher number of weeks in remission (28% vs 3%) and a higher proportion of patients in remission (32% vs 3%). Patients with life-threatening eosinophilic granulomatosis with polyangiitis were excluded from this trial, and mepolizumab should not be used for the treatment of severe disease. Mepolizumab may have a particularly beneficial role in the setting of relapsing or resistant asthma requiring glucocorticoids, sinus disease, mild to moderate eosinophilic disease features, or mild vasculitis. In a recent study, benralizumab, which also inhibits IL-5, demonstrated noninferior rates of remission compared to mepolizumab in patients with relapsing or refractory, non-lifethreatening eosinophilic granulomatosis with polyangiitis. POLYARTERITIS NODOSA ■ ■DEFINITION Polyarteritis nodosa was described in 1866 by Kussmaul and Maier. It is a multisystem, necrotizing vasculitis of small- and medium-sized mus­ cular arteries characteristically involving the renal and visceral arteries. Polyarteritis nodosa does not involve pulmonary arteries, although bronchial vessels may be involved; glomerulonephritis, granuloma, and significant eosinophilia are not seen. ■ ■INCIDENCE AND PREVALENCE It is difficult to establish an accurate incidence of polyarteritis nodosa because previous reports have included microscopic polyangiitis as well as other related vasculitides. Polyarteritis nodosa, as currently defined, is felt to be a very uncommon disease. ■ ■PATHOLOGY AND PATHOGENESIS The vascular lesion in polyarteritis nodosa is a necrotizing inflamma­ tion of small- and medium-sized muscular arteries. The lesions are segmental and tend to involve bifurcations and branchings of arteries. They may spread circumferentially to involve adjacent veins. However, involvement of venules is not seen in polyarteritis nodosa and, if pres­ ent, suggests microscopic polyangiitis (see below). In the acute stages of disease, polymorphonuclear neutrophils infiltrate all layers of the vessel wall and perivascular areas, which results in intimal prolifera­ tion and degeneration of the vessel wall. Mononuclear cells infiltrate the area as the lesions progress to the subacute and chronic stages. Fibrinoid necrosis of the vessels ensues with compromise of the lumen, thrombosis, infarction of the tissues supplied by the involved vessel, and, in some cases, hemorrhage. As the lesions heal, there is collagen deposition, which may lead to further occlusion of the vessel lumen. Aneurysmal dilations up to 1 cm in size along the involved arteries are characteristic. Multiple organ systems are involved, and the clinicopathologic findings reflect the degree and location of vessel involvement and the resulting ischemic changes. As mentioned above, pulmonary arteries are not involved, and bronchial artery involvement is uncommon. The pathology in the kidney is that of arteritis without glomerulonephritis. In patients with significant hypertension, typical pathologic features of glomerulosclerosis may be seen. In addition, pathologic sequelae of hypertension may be found elsewhere in the body. The presence of a polyarteritis nodosa–like vasculitis in patients with hepatitis B together with the isolation of circulating immune complexes composed of hepatitis B antigen and immunoglobulin and the demonstration by immunofluorescence of hepatitis B antigen, IgM, and complement in the blood vessel walls strongly suggest the role of immunologic phenomena in the pathogenesis of this disease. A polyarteritis nodosa–like vasculitis has also been reported in patients with hepatitis C. Hairy cell leukemia can be associated with polyarteritis nodosa; the pathogenic mechanisms of this association are unclear. A polyarteritis nodosa–like vasculitis has been described in con­ junction with deficiency of adenosine deaminase type 2 (DADA2). Patients with DADA2 usually present in childhood with a variable pattern of clinical features and vascular pathology that is respon­ sive to TNF inhibitors. As this differs from the usual treatment for TABLE 375-6  Clinical Manifestations Related to Organ System Involvement in Polyarteritis Nodosa PERCENT INCIDENCE CLINICAL MANIFESTATIONS ORGAN SYSTEM CHAPTER 375 Renal Renal failure, hypertension Musculoskeletal Arthritis, arthralgia, myalgia Peripheral nervous system Peripheral neuropathy, mononeuritis multiplex Gastrointestinal tract Abdominal pain, nausea and vomiting, bleeding, bowel infarction and perforation, cholecystitis, hepatic infarction, pancreatic infarction The Vasculitis Syndromes Skin Rash, purpura, nodules, cutaneous infarcts, livedo reticularis, Raynaud’s phenomenon Cardiac Congestive heart failure, myocardial infarction, pericarditis Genitourinary Testicular, ovarian, or epididymal pain Central nervous system Cerebral vascular accident, altered mental status, seizure Source: Reproduced with permission from TR Cupps, AS Fauci: The vasculitides. Major Probl Intern Med 21:1, 1981. polyarteritis nodosa, DADA2 should be considered in patients with suggestive clinical features, particularly those with early-onset disease. ■ ■CLINICAL AND LABORATORY MANIFESTATIONS Nonspecific signs and symptoms are the hallmarks of polyarteritis nodosa. Fever, weight loss, and malaise are present in over one-half of cases. Patients usually present with vague symptoms such as weak­ ness, malaise, headache, abdominal pain, and myalgias that can rapidly progress to a fulminant illness. Specific complaints related to the vas­ cular involvement within a particular organ system may also dominate the presenting clinical picture as well as the entire course of the illness (Table 375-6). Renal involvement most commonly manifests as hyper­ tension, renal insufficiency, or hemorrhage due to microaneurysms. There are no diagnostic serologic tests for polyarteritis nodosa. In >75% of patients, the leukocyte count is elevated with a predominance of neutrophils. Eosinophilia is rare and, when present at high levels, suggests the diagnosis of eosinophilic granulomatosis with polyangiitis. The anemia of chronic disease may be seen, and an elevated ESR and/ or CRP is almost always present. Other laboratory findings reflect the particular organ involved. Hypergammaglobulinemia may be present, and all patients should be screened for hepatitis B and C. ANCA are rarely found. ■ ■DIAGNOSIS The diagnosis of polyarteritis nodosa is based on the demonstration of characteristic findings of vasculitis on biopsy material of involved organs. Biopsy of symptomatic organs such as nodular skin lesions, painful testes, and nerve/muscle provides the highest diagnostic yields. In the absence of easily accessible tissue for biopsy, the arteriographic demonstration of involved vessels, particularly in the form of aneu­ rysms of small- and medium-sized arteries in the renal, hepatic, and visceral vasculature, is sufficient to make the diagnosis. This should consist of a catheter-directed dye arteriogram because magnetic resonance and computed tomography arteriograms do not have suf­ ficient resolution at the current time to visualize the affected vessels. Aneurysms of vessels are not pathognomonic of polyarteritis nodosa; furthermore, aneurysms may not always be present, and arteriographic findings may be limited to stenotic segments and obliteration of vessels. TREATMENT Polyarteritis Nodosa The prognosis of untreated polyarteritis nodosa is extremely poor, with a reported 5-year survival rate between 10 and 20%. Death usu­ ally results from gastrointestinal complications, particularly bowel infarcts and perforation, and cardiovascular causes. Intractable hypertension often compounds dysfunction in other organ systems, such as the kidneys, heart, and CNS, leading to additional late morbidity and mortality. The combination of prednisone and cyclo­ phosphamide has been found to significantly improve the survival rate (see “Granulomatosis with Polyangiitis” for a description of this therapeutic regimen). In less severe cases, glucocorticoids alone have resulted in disease remission. Treatment of hypertension can lessen vascular complications. Following remission, relapse has been esti­ mated to occur in 10–20% of patients. In patients with hepatitis B or C who have a polyarteritis nodosa–like vasculitis, antiviral therapy is an essential part of management, with immunosuppression being given concurrently for severe vasculitis and then withdrawn once the vasculitis is controlled. Plasma exchange has been used in some series of hepatitis virus-associated polyarteritis nodosa. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders GIANT CELL ARTERITIS AND POLYMYALGIA RHEUMATICA ■ ■DEFINITION Giant cell arteritis, historically referred to as temporal arteritis, is an inflammation of medium- and large-sized arteries. It characteristically involves one or more branches of the carotid artery, particularly the temporal artery. However, it is a systemic disease that can involve arter­ ies in multiple locations, particularly the aorta and its main branches. Giant cell arteritis is closely associated with polymyalgia rheumatica, which is characterized by stiffness, aching, and pain in the muscles of the neck, shoulders, lower back, hips, and thighs. Most commonly, polymyalgia rheumatica occurs in isolation, but it may be seen in 40–50% of patients with giant cell arteritis. In addition, ~10–20% of patients who initially present with features of isolated polymyalgia rheumatica later go on to develop giant cell arteritis. A careful his­ tory and physical examination at initial and subsequent visits should be performed in patients with polymyalgia rheumatica to look for features suggestive of giant cell arteritis. This strong clinical associa­ tion together with data from pathophysiologic studies has supported that giant cell arteritis and polymyalgia rheumatica represent differing clinical spectrums of a single disease process. ■ ■INCIDENCE AND PREVALENCE Giant cell arteritis occurs almost exclusively in individuals aged >50 years. It is more common in women than in men and is rare in blacks. The incidence of giant cell arteritis varies widely in different studies and in different geographic regions. A high incidence has been found in Scandinavia and in regions of the United States with large Scandinavian populations, compared to a lower incidence in southern Europe. The annual incidence rates in individuals aged ≥50 years range from 6.9 to 32.8 per 100,000 population. Familial aggregation has been reported, as has an association with HLA-DR4. In addition, genetic link­ age studies have demonstrated an association of giant cell arteritis with alleles at the HLA-DRB1 locus, particularly HLA-DRB1∗04 variants. In Olmsted County, Minnesota, the annual incidence of polymyalgia rheumatica in individuals aged ≥50 years is 58.7 per 100,000 population. ■ ■PATHOLOGY AND PATHOGENESIS Although the temporal artery is most frequently involved in giant cell arteritis, patients often have a systemic vasculitis of multiple medium- and large-sized arteries, which may go undetected. Histopathologically, the disease is a panarteritis with inflammatory mononuclear cell infil­ trates within the vessel wall with frequent giant cell formation. There is proliferation of the intima and fragmentation of the internal elastic lamina. Pathophysiologic findings in organs result from the ischemia related to the involved vessels. Experimental data support that giant cell arteritis is an antigendriven disease in which activated T lymphocytes, macrophages, and dendritic cells play a critical role in pathogenesis. Sequence analysis of the T-cell receptor of tissue-infiltrating T cells in lesions of giant cell arteritis indicates restricted clonal expansion, suggesting the presence of an antigen residing in the arterial wall. Giant cell arteritis is believed to be initiated in the adventitia where CD4+ T cells enter through the vasa vasorum, become activated, and orchestrate macrophage differentiation. T cells recruited to vasculitic lesions in patients with giant cell arteritis produce predominantly IL-2 and IFN-γ, and the latter has been suggested to be involved in the progression to arteritis. Laboratory-based data demonstrate that at least two separate lineages of CD4 T cells—IFN-γ-producing TH1 cells and IL-17-producing TH17 cells—participate in vascular inflammation and may have differing levels of responsiveness to glucocorticoids. ■ ■CLINICAL AND LABORATORY MANIFESTATIONS Giant cell arteritis is most commonly characterized clinically by the complex of fever, anemia, high ESR and/or CRP, and headaches in a patient aged >50 years. Four phenotypic manifestations can be seen including cranial arteritis, polymyalgia rheumatica, large-vessel dis­ ease, and features of systemic inflammation. These can occur together, in isolation, or at different times. In patients with involvement of the cranial arteries, headache is the predominant symptom and may be associated with a tender, thick­ ened, or nodular artery, which may pulsate early in the disease but may become occluded later. Scalp pain and claudication of the jaw and tongue may occur. A well-recognized and dreaded complication of giant cell arteritis, particularly in untreated patients, is ischemic optic neuropathy, which may lead to serious visual symptoms, including sudden blindness in some patients. However, most patients have com­ plaints relating to the head or eyes before visual loss. Attention to such symptoms with institution of appropriate therapy (see below) lessens the risk of this complication. Other cranial ischemic complications include strokes and scalp or tongue infarction. Up to one-third of patients can have large-vessel disease that can be the primary presentation of giant cell arteritis or can emerge at a later point in patients who have had previous cranial arteritis features or polymyalgia rheumatica. Manifestations of large-vessel disease can include subclavian artery stenosis that can present as arm claudication or aortic aneurysms involving the thoracic and to a lesser degree the abdominal aorta, which carry risks of rupture or dissection. Clinical features of systemic inflammation can include malaise, fatigue, anorexia, weight loss, and sweats. Laboratory findings can also support an inflammatory process. An elevated ESR and/or CRP will be seen in most patients. Therapeutic blockade of IL-6 signaling prevents the hepatic production of CRP and other acute-phase pro­ teins like ESR. These values will therefore normalize in patients who are treated with an IL-6 inhibitor, eliminating the ability to utilize CRP and ESR in monitoring disease activity or infection assessment in this setting. Other laboratory features include a normochromic or slightly hypochromic anemia. Liver function abnormalities are common, par­ ticularly increased alkaline phosphatase levels. Increased levels of IgG and complement have been reported. ■ ■DIAGNOSIS The diagnosis of giant cell arteritis can often be suggested clinically by the demonstration of the complex of fever, anemia, and high ESR and/or CRP with or without symptoms of polymyalgia rheumatica in a patient >50 years old. The diagnosis can be confirmed by biopsy of the temporal artery but may not be positive in all patients due to patchy histologic findings. Since involvement of the vessel may be segmental, positive yield is increased by obtaining a biopsy seg­ ment of 3–5 cm together with serial sectioning of biopsy specimens. Ultrasonography of the temporal arteries alone or in combination with the axillary arteries demonstrating a noncompressible “halo” sign has been used in supporting the diagnosis. Therapy should not be delayed pending the performance of diagnostic studies. In this regard, it has been reported that temporal artery biopsies may show vasculitis even after ~14 days of glucocorticoid therapy. A dramatic clinical response to a trial of glucocorticoid therapy can further sup­ port the diagnosis. Large-vessel disease may be suggested by symptoms and findings on physical examination such as diminished pulses or bruits. It is confirmed by vascular imaging, most commonly through magnetic resonance or computed tomography. Positron emission tomography has become increasingly investigated, although its role in diagnosis and monitoring remains unclear. Isolated polymyalgia rheumatica is a clinical diagnosis made by the presence of typical symptoms of stiffness, aching, and pain in the muscles of the hip and shoulder girdle, an increased ESR and/or CRP, the absence of clinical features suggestive of giant cell arteritis, and a prompt therapeutic response to low-dose prednisone. Polymyalgia rheumatica can be associated with a peripheral arthritis that can mimic rheumatoid arthritis (Chap. 370). Rheumatoid factor and anti– cyclic citrullinated peptide (CCP) should be negative. In patients who develop a worsening pattern of peripheral arthritis, the potential for a seronegative rheumatoid arthritis or other inflammatory arthropathy should be considered. Levels of enzymes indicative of muscle damage such as serum creatine kinase are not elevated. TREATMENT Giant Cell Arteritis Acute disease–related mortality directly from giant cell arteritis is uncommon, with fatalities occurring from cerebrovascular events or myocardial infarction. However, patients are at risk of late mor­ tality from aortic aneurysm rupture or dissection as patients with giant cell arteritis are 18 times more likely to develop thoracic aortic aneurysms than the general population. The goals of treatment in giant cell arteritis are to reduce symp­ toms and, most importantly, to prevent visual loss. The treatment approach for cranial arteritis and large-vessel disease in giant cell arteritis is currently the same. Giant cell arteritis and its associated symptoms are responsive to glucocorticoid therapy. Treatment should begin with predni­ sone 40–60 mg/d for ~1 month, followed by a gradual tapering. When ocular signs and symptoms occur, consideration should be given for the use of methylprednisolone 1000 mg daily for 3 days to protect remaining vision. Although the optimal duration of glucocorticoid therapy has not been established, most series have found that patients require treatment for ≥2 years. Symptom recurrence during prednisone tapering develops in 60–85% of patients with giant cell arteritis, requiring a dosage increase. For patients treated with prednisone alone, the ESR and/or CRP can serve as an indicator of inflammatory disease activity in monitor­ ing and tapering therapy and can be used to guide the tapering schedule. However, minor increases in the ESR and/or CRP can occur as glucocorticoids are being tapered and do not necessar­ ily reflect an exacerbation of arteritis, particularly if the patient remains symptom-free. Under these circumstances, the tapering should continue with caution. An increase in ESR and/or CRP can also occur for other reasons, including infection. Glucocorticoid toxicity occurs in 35–65% of patients and represents an important cause of patient morbidity. Tocilizumab (anti-IL-6 receptor) 162 mg given subcutaneously once every week or once every other week combined with a 26-week prednisone taper was found to be superior to prednisone alone in sustaining glucocorticoid-free remission in a randomized trial. The decision about when to use tocilizumab in giant cell arteritis is indi­ vidually based, taking into account comorbidities, glucocorticoid toxicity, and the side effects of tocilizumab. Pharmacokinetic stud­ ies supported that tocilizumab 6 mg/kg given intravenously every 4 weeks could also be used as a treatment option in giant cell arteritis. The use of methotrexate as a glucocorticoid-sparing agent was examined in two randomized placebo-controlled trials that reached conflicting conclusions. It may be considered in select patients with glucocorticoid toxicity who are unable to take or are intolerant of tocilizumab. Abatacept (CTLA4-Ig) was examined in a small randomized trial in giant cell arteritis and demonstrated greater efficacy than gluco­ corticoids alone. Infliximab, a monoclonal antibody to TNF, was studied in a randomized trial and was not found to provide benefit. Aspirin 81 mg daily has been found in retrospective studies to reduce the occurrence of cranial ischemic complications in giant cell arteritis, and adjunctive use should be considered in patients who do not have contraindications. Polymyalgia Rheumatica CHAPTER 375 Patients with isolated polymyalgia rheumatica respond promptly to prednisone given at a dose of 10–20 mg/d. Similar to giant cell arte­ ritis, the ESR and/or CRP can serve as a useful indicator in moni­ toring prednisone reduction in those treated with glucocorticoids alone. Recurrent polymyalgia symptoms develop in the majority of patients during prednisone tapering. The Vasculitis Syndromes Sarilumab (anti-IL-6 receptor) was found to be effective in a randomized trial of patients with glucocorticoid-resistant polymy­ algia rheumatica who relapsed on prednisone ≥7.5 mg/d. In this trial, sarilumab 200 mg given subcutaneously every 2 weeks plus a 14-week glucocorticoid taper was associated with a higher rate of sustained remission compared to glucocorticoids alone. As most patients with polymyalgia rheumatica can be successfully treated with glucocorticoids alone, use of sarilumab should be restricted to those who have had an inadequate response to glucocorticoids or who relapse with a glucocorticoid taper. One study of methotrexate found that this reduced the prednisone dose on average by only 1 mg and did not decrease prednisonerelated side effects. A randomized trial in polymyalgia rheumatica did not find infliximab to lessen relapse or glucocorticoid requirements. TAKAYASU ARTERITIS ■ ■DEFINITION Takayasu arteritis is an inflammatory disease of large-sized arteries char­ acterized by a strong predilection for the aortic arch and its branches. ■ ■INCIDENCE AND PREVALENCE Takayasu arteritis is an uncommon disease with an estimated annual incidence rate of 1.2–2.6 cases per million. It is most prevalent in ado­ lescent girls and young women. Although it is more common in Asia, it is neither racially nor geographically restricted. ■ ■PATHOLOGY AND PATHOGENESIS The disease involves large-sized arteries, with a strong predilection for the aortic arch and its branches; the pulmonary artery may also be involved. The most commonly affected arteries seen by arteriography are listed in Table 375-7. The involvement of the major branches of TABLE 375-7  Frequency of Arteriographic Abnormalities and Potential Clinical Manifestations of Arterial Involvement in Takayasu Arteritis PERCENTAGE OF ARTERIOGRAPHIC ABNORMALITIES POTENTIAL CLINICAL MANIFESTATIONS ARTERY Subclavian Arm claudication, Raynaud’s phenomenon Common carotid Visual changes, syncope, transient ischemic attacks, stroke Abdominal aortaa Abdominal pain, nausea, vomiting Renal Hypertension, renal failure Aortic arch or root Aortic insufficiency, congestive heart failure Vertebral Visual changes, dizziness Coeliac axisa Abdominal pain, nausea, vomiting Superior mesenterica Abdominal pain, nausea, vomiting Iliac Leg claudication Pulmonary 10–40 Atypical chest pain, dyspnea Coronary <10 Chest pain, myocardial infarction aArteriographic lesions at these locations are usually asymptomatic but may potentially cause these symptoms. Source: G Kerr et al: Ann Intern Med 120:919, 1994. the aorta is much more marked at their origin than distally. The disease is a panarteritis with inflammatory mononuclear cell infiltrates and occasionally giant cells. There are marked intimal proliferation and fibrosis, scarring and vascularization of the media, and disruption and degeneration of the elastic lamina. The vasa vasorum are frequently involved. Narrowing of the lumen occurs with or without thrombosis. Pathologic changes in various organs typically reflect reduced blood flow through these vascular stenoses. Aneurysms can also occur due to weakening of the vessel wall. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Immunopathogenic mechanisms, the precise nature of which is uncertain, are suspected in this disease. As with several of the vasculitis syndromes, circulating immune complexes have been demonstrated, but their pathogenic significance is unclear. ■ ■CLINICAL AND LABORATORY MANIFESTATIONS Takayasu arteritis is a systemic disease with generalized as well as vascular symptoms. The generalized symptoms include malaise, fever, night sweats, arthralgias, anorexia, and weight loss, which may occur months before vessel involvement is apparent. These symptoms may merge into those related to vascular compromise and organ ischemia. Pulses are commonly absent in the involved vessels, particularly the subclavian artery. The frequency of arteriographic abnormalities and the potentially associated clinical manifestations are listed in Table 375-7. Hypertension occurs in 32–93% of patients and contributes to renal, cardiac, and cerebral injury. Characteristic laboratory findings include an elevated ESR and/or CRP, mild anemia, and elevated immunoglobulin levels. ■ ■DIAGNOSIS The diagnosis of Takayasu arteritis should be suspected strongly in a young woman who develops a decrease or absence of peripheral pulses, a discrepancy in blood pressure between arms, or arterial bruits. The diagnosis is confirmed by the characteristic pattern on arteriography, which includes irregular vessel walls, stenosis, poststenotic dilation, aneurysm formation, occlusion, and evidence of increased collateral circulation. Complete imaging of the aorta and its major branches by magnetic resonance or computed tomography arteriography should be obtained to fully delineate the distribution and degree of arterial disease. Because of the involvement of the large vessels, tissue is rarely available or necessary as a means of diagnosis and obtained only if vascular surgery is necessary. IgG4-related disease (Chap. 380) is a potential cause of aortitis and periaortitis that is histologically differen­ tiated from Takayasu arteritis by a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, a storiform pattern of fibrosis, and obliterative phlebitis. TREATMENT Takayasu Arteritis The long-term outcome of patients with Takayasu arteritis has var­ ied widely between studies. Although two North American reports found overall survival to be ≥94%, the 5-year mortality rate from other studies has ranged from 0 to 35%. Disease-related mortality most often occurs from congestive heart failure, cerebrovascular events, myocardial infarction, aneurysm rupture, or renal failure. Even in the absence of life-threatening disease, Takayasu arteritis can be associated with significant morbidity. The course of the dis­ ease is variable, and although spontaneous remissions may occur, Takayasu arteritis is most often chronic and relapsing. Although glucocorticoids, given as prednisone 40–60 mg/d followed by a taper, alleviate symptoms, there are no convincing studies that indi­ cate that it increases survival. The combination of glucocorticoid therapy for acute signs and symptoms and an aggressive surgical and/or arterioplastic approach to stenosed vessels has markedly improved outcome and decreased morbidity by lessening the risk of stroke, correcting hypertension due to renal artery stenosis, and improving blood flow to ischemic viscera and limbs. Unless it is urgently required, surgical correction of stenosed arteries should be undertaken only when the vascular inflammatory process is well controlled with medical therapy. In individuals who are refractory to or unable to taper glucocor­ ticoids, methotrexate in doses up to 25 mg per week has been used with positive results. Retrospective series with anti-TNF therapies have shown benefit, but these agents have not been studied through randomized trials to determine efficacy. Tocilizumab has been investigated in a randomized trial where it did not reach its primary efficacy endpoint, although it was found to be associated with glucocorticoid-sparing effects and improve­ ments in well-being. Encouraging results have also been seen in retrospective studies such that the utility of this agent remains an active question. Abatacept was examined in a randomized trial in Takayasu arteritis but did not demonstrate efficacy beyond gluco­ corticoids alone. IGA VASCULITIS (HENOCH-SCHÖNLEIN) ■ ■DEFINITION IgA vasculitis (Henoch-Schönlein) is a small-vessel vasculitis charac­ terized by palpable purpura (most commonly distributed over the buttocks and lower extremities), arthralgias, gastrointestinal signs and symptoms, and glomerulonephritis. ■ ■INCIDENCE AND PREVALENCE IgA vasculitis is usually seen in children ages 4–7 years; however, the disease may also be seen in infants and adults. It is not a rare disease; in one series, it accounted for between 5 and 24 admissions per year at a pediatric hospital. The male-to-female ratio is 1.5:1. A seasonal varia­ tion with a peak incidence in spring has been noted. ■ ■PATHOLOGY AND PATHOGENESIS The presumptive pathogenic mechanism for IgA vasculitis is immunecomplex deposition. A number of inciting antigens have been sug­ gested including upper respiratory tract infections, various drugs, foods, insect bites, and immunizations. IgA is the antibody class most often seen in the immune complexes and has been demonstrated in the renal biopsies of these patients. ■ ■CLINICAL AND LABORATORY MANIFESTATIONS In pediatric patients, palpable purpura is seen in virtually all patients; most patients develop polyarthralgias in the absence of frank arthritis. Gastrointestinal involvement, which is seen in almost 70% of pediatric patients, is characterized by colicky abdominal pain usually associated with nausea, vomiting, diarrhea, or constipation, and is frequently accompanied by the passage of blood and mucus per rectum; bowel intussusception may occur. Renal involvement occurs in 10–50% of patients and is usually characterized by mild glomerulonephritis lead­ ing to proteinuria and microscopic hematuria, with red blood cell casts in the majority of patients; it usually resolves spontaneously without therapy. Progressive glomerulonephritis rarely develops. In adults, presenting symptoms are most frequently related to the skin and joints, while initial complaints related to the gut are less common. Although certain studies have found that renal disease is more frequent and more severe in adults, this has not been a consistent finding. However, the course of renal disease in adults may be more insidious and thus requires close follow-up. Myocardial involvement can occur in adults but is rare in children. Laboratory studies generally show a mild leukocytosis, a normal platelet count, and occasionally eosinophilia. Serum complement components are normal, and IgA levels are elevated in about one-half of patients. ■ ■DIAGNOSIS The diagnosis of IgA vasculitis is based on clinical signs and symptoms. Skin biopsy specimen can be useful in confirming leukocytoclastic vasculitis with IgA and C3 deposition by immunofluorescence. Renal biopsy is rarely needed for diagnosis but may provide prognostic infor­ mation in some patients. TREATMENT IgA Vasculitis The prognosis of IgA vasculitis is excellent. Mortality is exceed­ ingly rare, and 1–5% of children progress to end-stage renal disease, although renal failure may be more common in adults. Most patients recover completely, and some do not require therapy. When glucocor­ ticoids are required, prednisone, 1 mg/kg per day and tapered accord­ ing to clinical response, has been shown to be useful in decreasing tissue edema, arthralgias, and abdominal discomfort; however, it has not proved beneficial in the treatment of skin or renal disease and does not appear to shorten the duration of active disease or lessen the chance of recurrence. Patients with rapidly progressive glomerulone­ phritis have been anecdotally reported to benefit from glucocorticoids used in combination with another immunosuppressive agent. Disease recurrences have been reported in 10–40% of patients. CRYOGLOBULINEMIC VASCULITIS ■ ■DEFINITION Cryoglobulins are cold-precipitable monoclonal or polyclonal immu­ noglobulins. Cryoglobulinemia may be associated with a systemic vasculitis characterized by palpable purpura, arthralgias, weakness, neuropathy, and glomerulonephritis. The most common association has been with hepatitis C, although cryoglobulinemia can be observed in association with a variety of underlying disorders including multiple myeloma, lymphoproliferative disorders, connective tissue diseases, infection, and liver disease and can be idiopathic. ■ ■INCIDENCE AND PREVALENCE The incidence of cryoglobulinemic vasculitis has not been established. It has been estimated that 5% of patients with chronic hepatitis C will develop cryoglobulinemic vasculitis. ■ ■PATHOLOGY AND PATHOGENESIS Skin biopsies in cryoglobulinemic vasculitis reveal an inflammatory infiltrate surrounding and involving blood vessel walls, with fibrinoid necrosis, endothelial cell hyperplasia, and hemorrhage. Deposition of immunoglobulin and complement is common. Abnormalities of uninvolved skin including basement membrane alterations and deposits in vessel walls may be found. Membranoproliferative glo­ merulonephritis is responsible for 80% of all renal lesions in cryo­ globulinemic vasculitis. The association between hepatitis C and cryoglobulinemic vasculitis has been supported by the high frequency of documented hepatitis C infection, the presence of hepatitis C RNA and anti–hepatitis C anti­ bodies in serum cryoprecipitates, evidence of hepatitis C antigens in vasculitic skin lesions, and the effectiveness of antiviral therapy. Cur­ rent evidence suggests that in the majority of cases, cryoglobulinemic vasculitis occurs when an aberrant immune response to hepatitis C infection leads to the formation of immune complexes consisting of hepatitis C antigens, polyclonal hepatitis C–specific IgG, and monoclo­ nal IgM rheumatoid factor. The deposition of these immune complexes in blood vessel walls triggers an inflammatory cascade that results in cryoglobulinemic vasculitis. ■ ■CLINICAL AND LABORATORY MANIFESTATIONS The most common clinical manifestations of cryoglobulinemic vas­ culitis are cutaneous vasculitis, arthritis, peripheral neuropathy, and glomerulonephritis. Renal disease develops in 10–30% of patients. Life-threatening rapidly progressive glomerulonephritis or vasculitis of the CNS, gastrointestinal tract, or heart occurs infrequently. The presence of circulating cryoprecipitates is the fundamental find­ ing in cryoglobulinemic vasculitis. Rheumatoid factor is almost always found and may be a useful clue to the disease when cryoglobulins are not detected. Hypocomplementemia occurs in 90% of patients. An elevated ESR and/or CRP and anemia occur frequently. Evidence for hepatitis C infection must be sought in all patients by testing for hepa­ titis C antibodies and hepatitis C RNA. TREATMENT Cryoglobulinemic Vasculitis Acute mortality directly from cryoglobulinemic vasculitis is uncom­ mon, but the presence of glomerulonephritis is a poor prognostic sign for overall outcome. In such patients, 15% progress to endstage renal disease, with 40% later experiencing fatal cardiovascular disease, infection, or liver failure. As indicated above, the majority of cases are associated with hepatitis C infection. In such patients, treatment with antiviral therapy (Chap. 352) is first-line therapy for hepatitis C–associated cryoglobulinemic vasculitis, particularly given the efficacy of current hepatitis C therapies. Clinical improve­ ment with antiviral therapy is dependent on the virologic response. Patients who clear hepatitis C from the blood have objective improvement in their vasculitis along with significant reductions in levels of circulating cryoglobulins, IgM, and rheumatoid factor. While transient improvement can be observed with glucocorti­ coids, a complete response is seen in only 7% of patients. Plasma exchange and cytotoxic agents have been used in anecdotal reports. These observations have not been confirmed, and such therapies carry significant risks. Randomized trials with rituximab in hepa­ titis C–associated cryoglobulinemic vasculitis showed evidence of benefit such that this should be considered in patients with active vasculitis either in combination with antiviral therapy or alone in patients who have relapsed through, are intolerant to, or have con­ traindications to antiviral agents. CHAPTER 375 The Vasculitis Syndromes SINGLE-ORGAN VASCULITIS Single-organ vasculitis has been defined as vasculitis in arteries or veins of any size in a single organ that has no features that indicate that it is a limited expression of a systemic vasculitis. Examples include isolated aortitis, testicular vasculitis, vasculitis of the breast, isolated cutaneous vasculitis, and primary CNS vasculitis. In some instances, this may be discovered at the time of surgery such as orchiectomy for a testicular mass where there is concern for neoplasm that is found instead to be vasculitis. Some patients originally diagnosed with single-organ vas­ culitis may later develop additional manifestations of a more systemic disease. In instances where there is no evidence of systemic vasculitis and the affected organ has been removed in its entirety, the patient may be followed closely without immunosuppressive therapy. In other instances, such as primary CNS vasculitis, medical intervention is necessary. IDIOPATHIC CUTANEOUS VASCULITIS ■ ■DEFINITION The term cutaneous vasculitis is defined broadly as inflammation of the blood vessels of the dermis. Because of its heterogeneity, cutaneous vasculitis has been described by a variety of terms including hypersen­ sitivity vasculitis and cutaneous leukocytoclastic angiitis. However, cuta­ neous vasculitis is not one specific disease but a manifestation that can be seen in a variety of settings. In >70% of cases, cutaneous vasculitis occurs either as part of a primary systemic vasculitis or as a second­ ary vasculitis related to an inciting agent or an underlying disease (see “Secondary Vasculitis,” below). In the remaining 30% of cases, cutane­ ous vasculitis occurs idiopathically. ■ ■INCIDENCE AND PREVALENCE Cutaneous vasculitis represents the most commonly encountered vas­ culitis in clinical practice. The exact incidence of idiopathic cutaneous vasculitis has not been determined due to the predilection for cutane­ ous vasculitis to be associated with an underlying process and the vari­ ability of its clinical course. ■ ■PATHOLOGY AND PATHOGENESIS The typical histopathologic feature of cutaneous vasculitis is the pres­ ence of vasculitis of small vessels. Postcapillary venules are the most commonly involved vessels; capillaries and arterioles may be involved less frequently. This vasculitis is characterized by a leukocytoclasis, a term that refers to the nuclear debris remaining from the neutrophils that have infiltrated in and around the vessels during the acute stages. In the subacute or chronic stages, mononuclear cells predominate; in certain subgroups, eosinophilic infiltration is seen. Erythrocytes often extravasate from the involved vessels, leading to palpable purpura. Cutaneous arteritis can also occur, which involves slightly larger-sized vessels within the dermis. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders ■ ■CLINICAL AND LABORATORY MANIFESTATIONS The hallmark of idiopathic cutaneous vasculitis is the predominance of skin involvement. Skin lesions may appear typically as palpable purpura; however, other cutaneous manifestations of the vasculitis may occur, including macules, papules, vesicles, bullae, subcutaneous nodules, ulcers, and recurrent or chronic urticaria. The skin lesions may be pru­ ritic or painful, with a burning or stinging sensation. Lesions most com­ monly occur in the lower extremities in ambulatory patients or in the sacral area in bedridden patients due to the effects of hydrostatic forces on the postcapillary venules. Edema may accompany certain lesions, and hyperpigmentation often occurs in areas of recurrent or chronic lesions. There are no specific laboratory tests diagnostic of idiopathic cuta­ neous vasculitis. A mild leukocytosis with or without eosinophilia is characteristic, as is an elevated ESR and/or CRP. Laboratory studies should be aimed toward ruling out features to suggest an underlying disease or a systemic vasculitis. ■ ■DIAGNOSIS The diagnosis of cutaneous vasculitis is made by the demonstration of vasculitis on biopsy. An important diagnostic principle in patients with cutaneous vasculitis is to search for an etiology of the vasculitis—be it an exogenous agent, such as a drug or an infection, or an endogenous underlying disease (Fig. 375-1). In addition, a careful history, physical, and laboratory examination should be performed to rule out the pos­ sibility of coexisting systemic vasculitis. TREATMENT Idiopathic Cutaneous Vasculitis When an antigenic stimulus is recognized as the precipitating fac­ tor in the cutaneous vasculitis, it should be removed; if this is a microbe, appropriate antimicrobial therapy should be instituted. If the vasculitis is associated with another underlying disease, treat­ ment of the latter often results in resolution of the former. In situ­ ations where disease is apparently self-limited, no therapy, except possibly symptomatic therapy, is indicated. When cutaneous vas­ culitis persists and when there is no evidence of an inciting agent, an associated disease, or an underlying systemic vasculitis, the decision to treat should be based on weighing the balance between the degree of symptoms and the risk of treatment. Some cases of idiopathic cutaneous vasculitis resolve spontaneously, whereas oth­ ers remit and relapse. In patients with persistent vasculitis, a variety of therapeutic regimens have been tried with variable results. In general, the treatment of idiopathic cutaneous vasculitis has not been satisfactory. Fortunately, since the disease is generally limited to the skin, this lack of consistent response to therapy usually does not lead to a life-threatening situation. Agents with which there have been anecdotal reports of success include dapsone, colchicine, hydroxychloroquine, and nonsteroidal anti-inflammatory agents. Glucocorticoids are often used in the treatment of idiopathic cutaneous vasculitis. Therapy is usually instituted with the lowest effective dose of prednisone with rapid tapering to discontinuation. In cases that prove refractory to glucocorticoids, a trial of another immunosuppressive agent may be indicated. Patients with chronic vasculitis isolated to cutaneous venules rarely respond dramatically to any therapeutic regimen, and other immunosuppressive agents should be used only as a last resort in these patients. Methotrexate and azathioprine have been used in such situations in anecdotal reports. Cyclophosphamide should almost never be used for idio­ pathic cutaneous vasculitis because of the potential toxicity. PRIMARY CENTRAL NERVOUS SYSTEM VASCULITIS Primary CNS vasculitis is an uncommon clinicopathologic entity characterized by vasculitis restricted to the vessels of the CNS without other apparent systemic vasculitis. The inflammatory process is usually composed of mononuclear cell infiltrates with or without granuloma formation. Patients may present with headaches, altered mental function, and focal neurologic defects. Systemic symptoms are generally absent. Devastating neurologic abnormalities may occur depending on the extent of vessel involvement. The diagnosis can be suggested by abnor­ mal magnetic resonance imaging of the brain, an abnormal lumbar puncture, and/or demonstration of characteristic vessel abnormalities on arteriography (Fig. 375-4), but it is confirmed by biopsy of the brain parenchyma and leptomeninges. In the absence of a brain biopsy, care should be taken not to misinterpret as true primary vasculitis arteriographic abnormalities that might actually be related to another cause. An important entity in the differential diagnosis is reversible cerebral vasoconstrictive syndrome, which typically presents with “thunderclap” headache and is associated with reversible arteriographic abnormalities that mimic primary CNS vasculitis. Other diagnostic considerations include infection, atherosclerosis, emboli, connective tissue disease, sarcoidosis, malignancy, and drug-associated causes. The prognosis of granulomatous primary CNS vasculitis is poor; however, some reports indicate that glucocorticoid therapy, alone or together with cyclophosphamide administered as described above, has induced clinical remissions. Following disease remission, cyclophos­ phamide should be switched to azathioprine or mycophenolate mofetil as these have good penetration into the CNS. BEHÇET’S DISEASE Behçet’s disease is a clinicopathologic entity characterized by recurrent episodes of oral and genital ulcers, iritis, and cutaneous lesions. The underlying pathologic process is a leukocytoclastic venulitis, although vessels of any size and in any organ can be involved. This disorder is described in detail in Chap. 376. COGAN’S SYNDROME Cogan’s syndrome is characterized by interstitial keratitis together with vestibuloauditory symptoms. It may be associated with a systemic vasculitis, particularly aortitis with involvement of the aortic valve. FIGURE 375-4  Cerebral arteriogram from a 32-year-old man with primary central nervous system vasculitis. Dramatic beading (arrow) typical of vasculitis is seen. Glucocorticoids are the mainstay of treatment. Initiation of treatment as early as possible after the onset of hearing loss improves the likeli­ hood of a favorable outcome. KAWASAKI’S DISEASE Kawasaki’s disease is an acute, febrile, multisystem disease of children. Some 80% of cases occur prior to the age of 5, with the peak incidence occurring at ≤2 years. It is characterized by nonsuppurative cervi­ cal adenitis and changes in the skin and mucous membranes such as edema; congested conjunctivae; erythema of the oral cavity, lips, and palms; and desquamation of the skin of the fingertips. Although the disease is generally benign and self-limited, it is associated with coro­ nary artery aneurysms in ~25% of cases, with an overall case-fatality rate of 0.5–2.8%. These complications usually occur between the third and fourth weeks of illness during the convalescent stage. Vasculitis of the coronary arteries is seen in almost all the fatal cases that have been autopsied and can cause complications into adulthood. There is typical intimal proliferation and infiltration of the vessel wall with mononuclear cells. Beadlike aneurysms and thromboses may be seen along the artery. Other manifestations include pericarditis, myocardi­ tis, myocardial ischemia and infarction, and cardiomegaly. Apart from the up to 2.8% of patients who develop fatal complica­ tions, the prognosis of this disease for uneventful recovery is excellent. High-dose IV γ-globulin (2 g/kg as a single infusion over 10 h) together with aspirin (100 mg/kg per day for 14 days followed by 3–5 mg/kg per day for several weeks) has been shown to be effective in reducing the prevalence of coronary artery abnormalities when administered early in the course of the disease. Surgery may be necessary for Kawasaki disease patients who have giant coronary artery aneurysms or other coronary complications. Surgical treatment most commonly includes thromboendarterectomy, thrombus clearing, aneurysmal reconstruc­ tion, and coronary artery bypass grafting. Multisystem inflammatory syndrome (MIS-C), a serious condition that may resemble Kawasaki’s disease, has been observed with infections due to SARS-CoV-2 (Chap. 205). Although clinical features consistent with Kawasaki’s disease have been observed, these patients can also have manifestations atypical for Kawasaki’s disease, including gastrointestinal symptoms, myocarditis, neurocognitive symptoms, and shock. Any patient who presents with a clinical picture suggestive of Kawasaki’s dis­ ease should be tested for SARS-CoV-2 to guide management. POLYANGIITIS OVERLAP SYNDROMES Some patients with systemic vasculitis manifest clinicopathologic characteristics that do not fit into a specific disease but have overlap­ ping features of different vasculitides. The diagnostic and therapeutic considerations as well as the prognosis for these patients depend on the sites and severity of active vasculitis. Patients with vasculitis that could cause irreversible damage to a major organ system should be treated as described under “Granulomatosis with Polyangiitis.” SECONDARY VASCULITIS ■ ■DRUG-INDUCED VASCULITIS Vasculitis associated with drug reactions usually presents as palpable purpura that may be generalized or limited to the lower extremities or other dependent areas; however, urticarial lesions, ulcers, and hemor­ rhagic blisters may also occur (Chap. 63). Signs and symptoms may be limited to the skin, although systemic manifestations such as fever, malaise, and polyarthralgias may occur. Although the skin is the pre­ dominant organ involved, systemic vasculitis may result from drug reac­ tions. Drugs that have been implicated in vasculitis include allopurinol, thiazides, gold, sulfonamides, phenytoin, and penicillin (Chap. 63). An increasing number of drugs have been reported to cause vas­ culitis associated with ANCA. Of these, the best evidence of causality exists for hydralazine and propylthiouracil. The clinical manifestations in ANCA-positive drug-induced vasculitis can range from cutaneous lesions to glomerulonephritis and pulmonary hemorrhage. Outside of drug discontinuation, treatment should be based on the severity of the vasculitis. Patients with immediately life-threatening small-vessel vasculitis should initially be treated with glucocorticoids and cyclo­ phosphamide as described for granulomatosis with polyangiitis. Fol­ lowing clinical improvement, consideration may be given for tapering such agents along a more rapid schedule. CHAPTER 375 ■ ■SERUM SICKNESS AND SERUM SICKNESS–LIKE REACTIONS These reactions are characterized by the occurrence of fever, urticaria, polyarthralgias, and lymphadenopathy 7–10 days after primary expo­ sure and 2–4 days after secondary exposure to a heterologous protein (classic serum sickness) or a nonprotein drug such as penicillin or sulfa (serum sickness–like reaction). Most manifestations are not due to vasculitis; however, occasional patients will have typical cutaneous venulitis that may progress rarely to a systemic vasculitis. The Vasculitis Syndromes ■ ■VASCULITIS ASSOCIATED WITH OTHER UNDERLYING DISEASES Certain infections may directly trigger an inflammatory vasculitic process. For example, rickettsias can invade and proliferate in the endothelial cells of small blood vessels causing a vasculitis (Chap. 192). In addition, the inflammatory response around blood vessels associ­ ated with certain systemic fungal diseases such as histoplasmosis (Chap. 218) may mimic a primary vasculitic process. A cutaneous leukocytoclastic vasculitis with occasional involvement of other organs may be a component of some infections. These include subacute bac­ terial endocarditis, Epstein-Barr virus infection, HIV infection, and a number of other infections. Vasculitis can be associated with certain malignancies, particularly leukemic, lymphoid, or reticuloendothelial neoplasms. Leukocytoclas­ tic venulitis confined to the skin is the most common finding; however, systemic vasculitis may occur. A number of connective tissue diseases have vasculitis as a second­ ary manifestation of the underlying primary process. Foremost among these are systemic lupus erythematosus (Chap. 368), rheumatoid arthritis (Chap. 370), inflammatory myositis (Chap. 377), relapsing polychondritis (Chap. 378), and Sjögren’s syndrome (Chap. 373). The most common form of vasculitis in these conditions is the small-vessel venulitis isolated to the skin. However, certain patients may develop a fulminant systemic necrotizing vasculitis. Secondary vasculitis has also been observed in association with ulcerative colitis, congenital deficiencies of various complement compo­ nents, sarcoidosis, primary biliary cirrhosis, α1-antitrypsin deficiency, and intestinal bypass surgery. ■ ■FURTHER READING Finkielman JD et al: Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis. Ann Intern Med 147:611, 2007. Jayne D et al: A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 349:36, 2003. Jayne DRW et al: Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 18:599, 2021. Jennette JC et al: 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 65:1, 2013. Smith RM et al: Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: An international randomised controlled trial. Ann Rheum Dis 82:937, 2023. Spiera RF et al: Sarilumab for relapse of polymyalgia rheumatica dur­ ing glucocorticoid taper. N Engl J Med 389:1263, 2023. Stone JH et al: Rituximab versus cyclophosphamide for ANCAassociated vasculitis. N Engl J Med 363:221, 2010. Stone JH et al: Trial of tocilizumab in giant-cell arteritis. N Engl J Med 377:317, 2017. Walsh M et al: Plasma exchange and glucocorticoids in severe ANCAassociated vasculitis. N Engl J Med 382:622, 2020. Wechsler ME et al: Mepolizumab or placebo for eosinophilic granu­ lomatosis with polyangiitis. N Engl J Med 376:1921, 2017. # 19 - 376 Behçet Syndrome ### 376 Behçet Syndrome Yusuf Yazici Behçet Syndrome PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Behçet syndrome is a systemic vasculitis, first described by Hulusi Behçet, a Turkish dermatologist. It can present with oral and genital ulcers, skin lesions, uveitis, arthritis, major arterial and venous ves­ sel disease, and gastrointestinal and neurologic manifestations. These manifestations can be present in various combinations and sequences over time. Patients are most commonly from the Middle East, the Mediterranean region, and the Far East; it is most prevalent in Turkey, with a prevalence of 1 in 250 adults. It is relatively rare before the late teens and after age 50. Males and females are equally affected; however, males frequently have more severe disease and poorer outcomes. Some manifestations may show regional differences; for example, gastroin­ testinal involvement, rare in Turkey, is more common in Japan and is seen in ~30% of patients in the United States. ■ ■DIAGNOSIS Behçet syndrome is diagnosed clinically. There are no specific labora­ tory, imaging, or histologic features that can help in the diagnosis of a patient with suggestive symptoms. However, these can be used in rul­ ing out conditions that may mimic Behçet syndrome and the diagnosis is based on a combination of clinical features in the setting of ruling out other potential causes. In this regard, some patients may require months to years to develop the array of symptoms that would lead to a definitive diagnosis, although a tentative diagnosis may be made well before. The most commonly used and best performing diagnostic criteria are the International Study Group (ISG) criteria (sensitivity ~95%, specificity ~96%); patients need to have recurrent oral ulcers plus two of the following four clinical manifestations: recurrent genital ulcers, skin lesions, eye lesions, or a positive pathergy test (Table 376-1). Additional clinical manifestations may involve various organ systems, including the gastrointestinal, vascular, pulmonary, and central ner­ vous systems. Up to 50–60% of patients, depending on where they are from, can be positive for HLA B∗51; however, it is not used as a diagnostic test because it is also found in around 20% of the normal population. ■ ■PATHOGENESIS The pathogenesis and etiology of Behçet syndrome are unknown. Family studies show a possible genetic predisposition, and increased inflammation and immunologic mechanisms play a role. Both innate and adaptive immune systems may be involved. Unlike other auto­ immune diseases, however, Behçet syndrome is not typically associated with autoantibodies, Raynaud’s phenomenon, Sjögren’s syndrome, thrombocytopenia, hemolytic anemia, sun hypersensitivity, serosal involvement, or an increased risk for other autoimmune diseases. On the other hand, features that separate it from autoinflammatory conditions include tendency to abate with time, absence of mutations TABLE 376-1  International Study Group Criteria for the Diagnosis of Behçet Syndrome CRITERIA FREQUENCY COMMENTS Oral ulcers ~98% At least 3 times in a 12-month period Plus 2 out of 4 from below:     Recurrent genital ulcers ~80% Usually scarring Skin lesions ~80% Erythema nodosum, pseudofolliculitis, papulopastular or acneiform nodules (postadolescent, not receiving corticosteroids) Eye lesions ~50% Anterior or posterior uveitis, cells in vitreous or retinal vasculitis Pathergy ~50% Evaluated in 24–48 h, after dermal insertion of a 20-gauge needle associated with autoinflammatory diseases, and higher prevalence than typical autoinflammatory diseases such as familial Mediterranean fever (Chap. 381). There is neutrophil hyperreactivity; however, it is not clear whether this is primary or secondary to cytokine-directed activation. There is also evidence from retrospective patient cohort analyses that there may be different clusters of disease presentation; for example, acne lesions are more commonly seen with arthritis and associated with enthesitis, and each of these clusters may have a differ­ ent pathogenesis. ■ ■CLINICAL PRESENTATION The most common symptoms are associated with mucocutaneous tis­ sues. Oral ulcers are seen in virtually all patients and are commonly the first manifestation (Fig. 376-1). Commonly, like ordinary canker sores, they are usually multiple. They last around 10 days but recur unless treated. Only the uncommon, major ulcers tend to scar. Beneficial effects of dental and periodontal therapies suggest that decreased oral health is associated with disease severity. Genital ulcers are the most specific lesions, most commonly occur­ ring on the scrotum or labia (Fig. 376-1). They are larger and deeper and take longer to heal than oral ulcers and tend to form scars. Acne-like or papulopustular lesions are indistinguishable from acne vulgaris in appearance and pathology. They are seen both at the usual acne sites as well as at uncommon sites such as lower extremities. Other skin findings are the nodular lesions, which are of two types: erythema nodosum lesions due to panniculitis and superficial vein thromboses. Superficial thrombophlebitis often occurs in men and is associated with deep-vein thrombosis; it should trigger workup for other vascular involvement, including pulmonary artery aneurysms. Pathergy reaction is a nonspecific hyperreactivity of the skin to trauma. Typically, a papule or pustule forms in 24–48 h after a A B FIGURE 376-1  Clinical findings in Behçet syndrome. A. Behçet oral ulcer. B. Behçet scrotal ulcer. # 20 - 377 Inflammatory Myopathies ### 377 Inflammatory Myopathies 20–21-gauge needle prick. It is rather unique for Behçet syndrome and is part of the ISG diagnostic criteria. Arthralgia or arthritis is seen in about half of patients; it is usually a mono- or oligoarthritis in the lower extremities and does not usually cause erosions or deformity. Eye involvement is seen in half of all patients and may be seen in up to ~70% of males. It is most commonly a bilateral panuveitis. A hypopyon, seen in ~10% of patients with eye disease, is an intense inflammation in the anterior chamber and is quite specific for Behçet syndrome. Ocular involvement develops usually in the first 2 years after fulfillment of diagnostic criteria and is most severe during the first few years and then tends to abate. Male gender, posterior involvement, frequent attacks (>3 per year), strong vitreous opacity, and macular edema are poor prognostic factors. Vascular disease is seen in up to 40% of patients. It is associated with intensive thrombosis and runs a relapsing course. Several welldefined venous vascular associations are seen; superficial and deepvein thrombosis, Budd-Chiari syndrome, inferior vena cava syndrome, pulmonary artery involvement, intracardiac thrombosis, and cerebral venous sinus thrombosis frequently cluster in various combinations. Pulmonary artery aneurysms carry a 5-year mortality rate of 20–25%. Prevalence of neurologic involvement is ~5%, with about threequarters of patients presenting with parenchymal involvement, while the remaining cases present with cerebral venous sinus thrombosis. These two forms rarely occur together. Parenchymal involvement usu­ ally affects the telencephalic-diencephalic junction, brainstem, and spinal cord. Patients may present with a subacute onset of severe head­ ache, cranial nerve palsy, dysarthria, ataxia, and hemiparesis. Prevalence of gastrointestinal involvement changes significantly across different populations (up to 50% in the Far East but rare in the Middle East). Clinical and endoscopic appearance of intestinal involve­ ment can be similar to, and thus cannot easily be differentiated from, Crohn’s disease. Ulcers tend to be single or less than five, are usually confined to the ileocecal area, are more likely to be deep and round, and are prone to perforate; perianal and rectal area involvement are rare. In practice, it is difficult to distinguish Behçet syndrome from Crohn’s disease unless extraintestinal manifestations are present. TREATMENT Behçet Syndrome Treatment is guided by type and severity of involvement, with the goal of preventing long-term damage. Most new manifestations tend to present within the first 5 years, and for most patients, the natural course is one of diminishing symptoms culminating in potential remission, frequently not requiring ongoing treatment with medications. Patient characteristics, such as being young and male, need to be kept in mind when making treatment decisions, as these patients tend to have a worse prognosis. In most patients, tapering and/or stopping their medications in 2–3 years after the symptoms have improved should be attempted. Oral ulcers can be managed with topical glucocorticoids and on an as-needed basis if mild. Lesions resistant to local measures may require systemic treatment with colchicine, oral glucocorti­ coids, immunosuppressants such as apremilast, azathioprine, or a tumor necrosis factor (TNF)-α inhibitor such as infliximab. A similar treatment approach can be used for genital ulcers and other mucocutaneous manifestations. Patients may need a combination of medications, at least initially, to control disease activity. Eye involvement, given its frequency and potential morbid­ ity, requires early and aggressive treatment with brief courses of glucocorticoids and longer-term treatment with an immunosup­ pressant. Azathioprine is usually the preferred agent in clinical practice. TNF inhibitors infliximab or adalimumab can also be used, either as first-line monotherapy or more commonly in com­ bination with systemic glucocorticoids and azathioprine, for control of disease activity. Cyclosporine can also be considered in combi­ nation regimens; monotherapy with interferon is another option. Glucocorticoids can be tapered in many patients after active disease has been controlled, whereas immunosuppressants are generally continued for at least 2 years with plans to potentially taper them also based on treatment response and ongoing disease activity. Gastrointestinal involvement is treated with glucocorticoids plus an immunosuppressant such as azathioprine alone or in combina­ tion with infliximab. CHAPTER 377 Venous thrombotic events are treated by controlling systemic inflammation with immunosuppressive medications (usually azathio­ prine or, for more severe cases, cyclophosphamide), rather than using anticoagulants. However, if venous thrombotic events occur, standard anticoagulation treatment can be given, provided there is a low risk of bleeding and there are no coexistent pulmonary artery aneurysms. For central nervous system involvement, the combina­ tion of azathioprine and a TNF inhibitor is usually the first choice. Inflammatory Myopathies ■ ■FURTHER READING Hatemi G et al: 2018 update of the EULAR recommendations for the management of Behçet’s syndrome. Ann Rheum Dis 77:808, 2018. Kural-Seyahi E et al: The long-term mortality and morbidity of Behçet syndrome: A 2-decade outcome survey of 387 patients followed at a dedicated center. Medicine (Baltimore) 82:60, 2003. Yazici H et al: Behçet syndrome: A contemporary view. Nat Rev Rheumatol 14:107, 2018. Yazici Y et al: Behçet syndrome. Nat Rev Dis Primers 7:67, 2021. Steven A. Greenberg, Anthony A. Amato Inflammatory Myopathies This chapter focuses on the major types of inflammatory myopathies (IMs), including dermatomyositis (DM), polymyositis (PM), immunemediated necrotizing myopathy (IMNM), antisynthetase syndrome (ASyS), and inclusion body myositis (IBM) (Table 377-1). Other IMs include those caused by infection, eosinophilic myositis, granuloma­ tous myositis, and myositis triggered by checkpoint inhibitors. Of note, inflammatory cell infiltrates can also be occasionally seen in muscle biopsies of hereditary myopathies (e.g., muscular dystrophies, meta­ bolic myopathies), sporadic late-onset nemaline myopathy (SLONM), and toxic myopathies. Epidemiologic studies suggest that the incidence of IM grouped together is up to 16 cases per 100,000 with prevalence in the range of 14–32 per 100,000. Defining the actual incidence and prevalence of the individual myositides is limited, however, by different diagnostic criteria employed in various epidemiologic studies, an increasing rec­ ognition of ASyS and IMNM, as well as the frequent misdiagnosis of IBM. Idiopathic PM without signs of an overlap syndrome is quite rare compared to DM, ASyS, IBM, and IMNM that occur in roughly simi­ lar frequencies. DM can occur in children (juvenile DM), while IBM always occurs in adults and is the most common cause of myopathy in those aged >50. DM, PM, and ASyS are more common in women, while IBM is more common in men. DIAGNOSTIC APPROACH AND DIFFERENTIAL DIAGNOSIS The approach to patients with suspected myopathy is detailed in Chap. 460. In any patient presenting with weakness, the first step is to localize the site of the lesion by history and clinical findings (Chap. 26). Weakness could be caused by a process in the cerebral hemispheres, spi­ nal cord (Chap. 453), anterior horn cell (Chap. 448), peripheral nerve TABLE 377-1  Inflammatory Myopathies: Clinical and Laboratory Features AGE OF ONSET RASH PATTERN OF WEAKNESS LABORATORY FEATURES MUSCLE BIOPSY DISORDER SEX DM F > M Childhood and adult Yes Proximal > distal Normal or increased CK (up to 50× normal or higher); various MSAs (anti-MDA5, anti-TIF1, anti-Mi-2, anti-NXP2) PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders PM F > M Adult No Proximal > distal Increased CK (up to 50× normal or higher) IMNM M = F Children and adults No Proximal > distal Elevated CK (>10× normal or higher); anti-HMGCR or antiSRP antibodies ASyS F > M Children and adults Sometimes Proximal > distal Elevated CK (>10× normal or higher); antisynthetase antibodies IBM M > F Older adults (>50 years) No Proximal and distal; predilection for: finger/ wrist flexors, knee extensors Normal or mildly increased CK (usually <10× normal); anticN-1A antibodies; large granular lymphocytes on flow cytometry and reduced CD4/CD8 ratio with increased CD8 count Abbreviations: CK, creatine kinase; cN-1A, cytosolic 5′-nucleotidase 1A; CTDs, connective tissue diseases; COX, cytochrome oxidase; DM, dermatomyositis; F, female; g, immunoglobulin; IBM, inclusion body myositis; IFN-1, type 1 interferon; ILD, interstitial lung disease; IS, immunosuppressive; M, male; MAC, membrane attack complex; MDA5, melanoma differentiation antigen; MHC-1, major histocompatibility antigen 1; MSA, myositis-specific autoantibodies; NCP2, nuclear matrix protein 2 (NXP2); NM, necrotizing myopathy; PM, polymyositis; TIF1, transcriptional intermediary factor 1. Source: Reproduced with permission from AA Amato, JA Russell (eds): Neuromuscular Disorders. 2nd ed. New York: McGraw-Hill Education; 2016. (Chaps. 457–458), neuromuscular junction (Chap. 459), or muscle (Chap. 460). Past medical history, medication use, and family history, combined with a detailed clinical examination and an appreciation for the pattern of muscle involvement (e.g., what muscles are weak and atrophic or hypertrophic as well as the presence of scapular winging, early contractures, sensory abnormalities, fasciculations, or rash), help differentiate myopathies from other neuromuscular disorders and the different types of myopathies from each other (see Chap. 460). For example, atrophy with fasciculations suggests a neurogenic process such as amyotrophic lateral sclerosis, fatigable weakness on examination points to a neuromuscular junction defect such as myasthenia gravis, and concomitant sensory symptoms suggest a central process such as a spinal cord disorder or a polyneuropathy. Scapular winging, calf hypertrophy or atrophy, and early contractures before significant weak­ ness develops would strongly suggest a muscular dystrophy, particularly if there is a positive family history. A heliotrope rash combined with Gottron papules (below) and dilated nailfold capillaries is diagnostic for DM. The presence of atrophy and weakness of the flexor forearm muscles and quadriceps in a person aged >50 years is most likely IBM. When the site of the lesion cannot be localized based on history and clinical examination alone, laboratory testing is required. Serum creatine kinase (CK) is the most sensitive laboratory marker of muscle destruction. Not all myopathies are associated with elevated CK levels, but a markedly elevated CK (e.g., >2000 U/L) is almost always due to a myopathy. A slightly elevated CK can also be seen in neurogenic RESPONSE TO IS THERAPY COMMON ASSOCIATED CONDITIONS CELLULAR INFILTRATE Perimysial and perivascular inflammation; IFN-1 regulated proteins (MHC-1, MxA), MAC deposition on capillaries CD4+ dendritic cells; B cells; macrophages Yes Myocarditis, ILD, malignancy, vasculitis, other CTDs Endomysial and perivascular inflammation; ubiquitous expression of MHC-1 CD8+ T cells; macrophages; plasma cells Yes Myocarditis, ILD, other CTDs Necrotic muscle fibers; minimal inflammatory infiltrate; MHC-I and MAC deposition on sarcolemma of scattered nonnecrotic muscle fibers Macrophages in necrotic fibers undergoing phagocytosis Yes Malignancy, CTD, HMGCR antibody cases can be triggered by statin use Perimysial and perivascular inflammation; perimysial fragmentation with alkaline phosphatase staining; perimysial muscle damage with necrosis; MHC-I, HLA-DR, and MAC deposition on sarcolemma of perifascicular muscle fibers CD4+ dendritic cells; B cells; macrophages Yes Nonerosive arthritis, ILD, Raynaud’s phenomenon, mechanic hands, and fever Endomysial and perivascular inflammation; ubiquitous expression of MHC-1 and HLA-DR; rimmed vacuoles; p62, LC3, TDP-43 aggregates; EM: 15–18 nm tubulofilaments; ragged red and COXnegative fibers CD8+ T cells; macrophages; plasma cells; myeloid dendritic cells; large granular lymphocytes None or minimal Granular lymphocytic leukemia/ lymphocytosis, sarcoidosis, sicca or Sjögren’s syndrome disorders, however. Myositis-associated and myositis-specific antibod­ ies (MSAs) help to distinguish subtypes of IM, as discussed below. Electromyography (EMG) and nerve conductions studies (NCS) are useful in localizing the site of the lesion but are less specific in helping to determine the actual cause of a myopathy. EMG can be useful at times in guiding what muscle to biopsy, especially if muscles typically biopsied are normal on clinical examination. Imaging skeletal muscle can be helpful in assessing muscle involvement and revealing fatty replacement, atrophy, or edema within muscle or surrounding fascia. A muscle biopsy is often required to definitively distinguish one myopathy from another, if there is no characteristic dermatomyositis rash or myositis specific autoantibody. However, a muscle biopsy should be performed in every case of suspected PM to exclude IBM (if not clinically apparent) and other causes of myopathy. Diagnosis of IMNM is by definition based upon histologic findings but again is not needed if a patient has clinical features and anti-3-hydroxy-3-methylglutaryl-coenzyme reductase (HMGCR) or anti–signal recognition particle (SRP) antibodies. It is important to biopsy a muscle that is clinically affected but not too weak (e.g., Medical Research Council grade 4 out of 5 in strength); otherwise, one may just see end-stage muscle. A biopsy should always be coordinated with an experienced muscle histopathology laboratory. Patients with severe muscle pain, subjective weakness, and fatigue with normal strength and function on examination are not likely to have an IM. Polymyalgia rheumatica should be considered in older individuals with an elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) but normal CK and EMG. Fibromyalgia is likely in patients with a normal laboratory workup. In general, a muscle biopsy is not indicated unless there is objective weakness, an abnormal EMG, or elevated CK. SPECIFIC DISORDERS ■ ■DERMATOMYOSITIS Clinical Features  DM manifests with symmetric, proximal greater than dis­ tal weakness along with a characteristic rash that includes the heliotrope rash (erythematous discoloration of eyelids with periorbital edema), Gottron sign (erythematous rash over the extensor surfaces of joints such as the knuck­ les, elbows, knees, and ankles), Gottron papules (raised erythematous rash over knuckles) (Fig. 377-1), V-sign (rash on the sun-exposed anterior neck and chest), shawl sign over the back of the neck and shoulders, nail bed telangiectasias, and subcutaneous calcium deposits. The weakness and rash usually accompany one another but can be separated by sev­ eral months. Furthermore, beyond “clas­ sic DM” with prominent muscle and skin manifestations, there is a spectrum of involvement such that some patients have skin-predominant disease (only with a rash called amyopathic DM, or mini­ mal muscle disease called hypomyopathic DM), while others may present mainly with weakness and little or no visible skin changes. Patients may also have myalgias, arthralgias, dysphagia, and dysarthria. Cutaneous dis­ ease activity is highly relevant in DM; in comparison to other debilitat­ ing skin diseases including cutaneous lupus erythematosus, psoriasis, and atopic dermatitis, skin symptoms in DM patients are associated with an overall reduction in life quality. Pruritus can be especially debilitating. Dyspnea can occur from ventilatory muscle weakness or intrinsic lung involvement including interstitial lung disease (ILD), bronchopneumonia, and alveolitis. Pulmonary manifestations are often associated with anti-MDA-5 antibodies or with antisynthetase antibodies; myositis associated with the ASyS is now considered a dis­ tinct disorder (discussed below). DM can present in children (juvenile DM) or in adults. There is a higher risk for malignancy in adult-onset cases, ~15% within the first 2–3 years. A B FIGURE 377-1  Cutaneous manifestations of dermatomyositis. A. Macular erythema plaques (Gottron sign) and erythematous papules (Gottron papules) on extensor surface of fingers and B. elbow. C. Macular erythema plaques over anterior neck and chest (V-sign) and D. the posterior neck, shoulder, and upper back (Shawl sign). E. Nail bed changes with dilated capillaries. Laboratory Features  Serum CK levels are elevated in 70–80% of patients; in 10% of those with normal CK, serum aldolase may be increased. Antinuclear antibodies can be positive but are a nonspecific finding. The myositis-specific antibodies (MSAs) that are specific for DM include anti–complex nucleosome remodeling histone deacetylase (anti-Mi-2), anti–transcription intermediary factor 1-γ (anti-TIF1-γ), anti–melanoma differentiation-associated gene 5 (anti-MDA5), anti– nuclear matrix protein 2 (anti-NXP-2), and anti–small ubiquitin-like modifier activating enzyme (anti-SAE). These antibodies are usually associated with characteristic clinical features, and recent studies sug­ gest that they are also directly involved in the pathogenesis of DM. Mi-2 antibodies are found in 15–20% of patients with DM and are typically associated with an acute onset, a florid rash, and prominent weakness but a good response to therapy and a favorable prognosis. Anti-MDA5 antibodies are found in 10–20% of DM patients and up to 65% of patients with clinically amyopathic DM. This antibody is associated with palmar rash, severe skin ulcerations from ischemia, CHAPTER 377 Inflammatory Myopathies C D E and rapidly progressive ILD. Anti-TIF1-γ, also known as p155, anti­ bodies are found in adult cancer-associated DM with an 89% specificity and 70% sensitivity. Thus, enhanced vigilance for underlying cancer is especially important in these patients. Anti-NXP-2 antibodies are found in as many as 17% of patients with DM and are also associated with calcinosis, subcutaneous edema, distal weakness, and dysphagia, as well as with cancer. Anti-SAE antibodies are present in 1.5–8% of DM and are associated with an underlying cancer in 14–57% of patients. Most manifest with a skin rash alone, and CK is often normal, but approximately one-third of patients have elevated aldolase levels. ILD can also be seen in anti-SAE DM, but unlike anti-MDA-5 amyo­ pathic DM, the ILD is usually mild. EMG of weak muscles shows increased insertional and spontaneous activity in the form of positive sharp waves and fibrillation potentials, or complex repetitive discharges along with early recruitment of smallamplitude, short-duration, polyphasic motor units. These findings are nonspecific and can also be seen in other myopathies. Skeletal muscle magnetic resonance imaging (MRI muscle) reveals edema in affected muscles and sometimes more specific findings of abnormalities of fascia suggesting fasciitis. Histopathology and Pathogenesis  The characteristic histo­ pathologic abnormality on muscle biopsy is perifascicular atrophy (Fig. 377-2A); however, this finding is present in perhaps only 50% of patients. Immunohistochemical staining for myxovirus resistance protein A (MxA) is diagnostically more sensitive and highly specific (Fig. 377-2B). The inflammatory cell infiltrate is predominantly peri­ vascular and located in the perimysium and is composed primarily of macrophages, B cells, and plasmacytoid dendritic cells. Recent studies have highlighted some variability in histologic abnormalities associated with different MSAs. Skin biopsies reveal cell-poor interface dermati­ tis, which is analogous to the perifascicular atrophy in that the basal PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders A B FIGURE 377-2  Perifascicular atrophy and myxovirus resistance protein A (MxA) expression in dermatomyositis. A. Perifascicular myofibers (black arrows) bordering on disrupted perimysial connective tissue are atrophic and basophilic on hematoxylin and eosin (H&E) stains. B. Perifascicular myofibers (white arrows) show intense staining for MxA protein along a gradient from superficial to deep; all capillaries show intense MxA expression (white arrowheads). layer of keratinocytes is most damaged; the inflammatory infiltrate is typically absent or minimal and, when present, is located mainly at the border zone of the dermis and epidermis. The pathogenesis of DM was traditionally attributed to an antibody-mediated attack on endothelial cells, followed by complementmediated destruction of capillaries and watershed ischemia of muscle fibers. However, subsequent studies suggest that this is not likely the case. Immunoglobulin deposition is largely absent on endothelial cells, and complement deposition may be a secondary phenomenon. There is increasing evidence that the microvasculopathy and skin and muscle damage associated with DM are primarily due to toxicity from type I interferon (IFN)–mediated pathways, most likely IFN-β. As mentioned, there is increasing evidence that the MSAs are directly pathogenic. For example, anti-Mi-2 antibodies appear to be capable of entering myonuclei and inhibiting the CHD4/NuRD complex in the nucleosome. Prognosis  In the absence of malignancy, prognosis is generally favorable in patients with DM, with 5-year survival rates ranging from 70 to 93%. Poor prognostic features are increased age, associated ILD, cardiac disease, and late or previous inadequate treatment. ■ ■POLYMYOSITIS Clinical Features  PM is a heterogenous group of disorders that usually presents with symmetric and proximal weakness that worsens over several weeks to months. As with DM, there can be associated heart, lung, and joint involvement as well as an increased risk of cancer. Some epidemiologic studies suggest that the risk of cancer in PM is less than that in DM, but these older series likely included patients with IBM and dystrophies with inflammation who were misdiagnosed as having PM. Laboratory Features  CK levels are always elevated in uncontrolled PM. A normal CK should alert clinicians to the possibility of IBM. EMG and skeletal muscle imaging can be abnormal, but the findings are not specific (Fig. 377-3). Histopathology and Pathogen­ esis  Because PM is a heterogeneous category, muscle pathology varies sub­ stantially. Most often, patients with nonspecific inflammatory cells present in perimysial more often than endo­ mysial locations have been categorized as PM. A small minority of patients have a mononuclear inflammatory infiltrate that surrounds fibers with sarcolemmal expression of major histocompatibility complex (MHC-I) molecules (Fig. 377-4). FIGURE 377-3  Skeletal muscle magnetic resonance imaging (MRI) with short T1 inversion recovery (STIR) imaging in polymyositis. MRI of the thigh demonstrates bright signal indicative of edema/inflammation, particularly in the rectus femoris muscle. This contrasts with MRI in inclusion body myositis in which there is more selective involvement of the vastus lateralis and medialis with relative sparing of the rectus femoris (see Fig. 377-7F and G). There is debate as to whether a true inva­ sion of myofibers occurs in PM or rather always indicates IBM. The inflamma­ tory infiltrate predominantly consists of CD8+ T cells and macrophages located in the endomysial, perimysial, and peri­ vascular regions. PM is heterogeneous, and its varied forms of pathogenesis are poorly understood. Prognosis  Most patients with PM improve with immunotherapies but usually require lifelong treatment. Some retrospective studies suggest that PM does not respond as well as DM to these therapies. However, many of these older series of “PM” likely included patients who actually had IMNM, IBM, or other myopathies (including muscular dystro­ phies) that do not respond to immunotherapies. As in DM, poor prog­ nostic features are cancer, increased age, lung or cardiac involvement, and late or previously inadequate treatment. ■ ■OVERLAP SYNDROMES The term overlap syndrome is applied when an inflammatory myopa­ thy is associated with other well-defined connective tissue diseases (CTDs) such as scleroderma, mixed connective tissue disease (MCTD), Sjögren’s syndrome, systemic lupus erythematosus (SLE), or rheuma­ toid arthritis. Overlap syndromes are usually responsive to immuno­ therapies. The exception is Sjogren’s syndrome with coexisting IBM. ■ ■IMMUNE-MEDIATED NECROTIZING MYOPATHY Clinical Features  IMNM, or autoimmune necrotizing myopathy, is characterized by the acute or insidious onset of symmetric, proximal more than distal weakness. Dysphagia, dysarthria, or myalgia may occur. Patients may have an underlying CTD (usually scleroderma or MCTD) or cancer (paraneoplastic necrotizing myopathy), or the condition may be idiopathic. There are at least two distinct forms of IMNM associated with specific autoantibodies (anti-HMGCR and anti-SRP). Anti-HMGCR myopathy can be seen in patients receiving statins, inhibitors of HMGCR, particularly in those aged >50 years. However, anti-HMGCR myopathy can develop in children and young adults without a history of statin use and can mimic a limb girdle mus­ cular dystrophy. Unlike the more common “toxic” myopathy associated with statin use, anti-HMGCR myopathy does not improve when statins are discontinued. Anti-SRP myopathies are notable for the presence of anti-SRP antibodies and a typically subacute, aggressive, and relatively refractory course. FIGURE 377-4  Pathology of polymyositis. Muscle biopsy demonstrates endomysial infiltrates surrounding nonnecrotic muscle fibers. Laboratory Features  CK levels are markedly elevated (usually >10 × normal) in IMNM and are associated with titers of anti-HMGCR or anti-SRP antibodies. EMG often shows increased insertional and spontaneous activity, including myotonic discharges. Skeletal muscle imaging findings are nonspecifically abnormal. Histopathology and Pathogenesis  Muscle biopsies reveal multi­ focal necrotic and regenerating muscle fibers with a paucity of inflam­ matory cells (Fig. 377-5). However, some patients with anti-HMGCR myopathy have endomysial, macrophage-predominant infiltrates simi­ lar to what is seen in PM. Overexpression of MHC-I and membrane attack complex (MAC) molecules may be evident on sarcolemma of nonnecrotic fibers, and MAC deposition present on capillaries. The pathogenesis of IMNM is not completely understood and likely varies depending on subtype. A trial of a complement inhibitor in both antiHMGCR and anti-SRP myopathies failed to demonstrate any efficacy, so IMNM in these subtypes does not appear to be primarily comple­ ment driven. Interestingly, pathogenic biallelic variants in the HMGCR gene result in proximal weakness, myalgias, high CK, and dystrophic changes on skeletal muscle MRI and biopsies. Recent studies suggest that HMGCR antibodies may bind to the receptor on the sarcolemma and lead to accumulation of acetyl-CoA and subsequently an increase in lipids within muscle fibers. Recent studies also suggest that anti-SRP antibodies are directly causal to the associated IMNM. Prognosis  Anti-HMGCR myopathy is often responsive to intra­ venous immunoglobulin (IVIG) monotherapy. However, anti-SRP FIGURE 377-5  Pathology of immune-mediated necrotizing myopathy. Muscle biopsy demonstrates scattered necrotic fibers with inflammatory infiltrate confined to those fibers undergoing myophagocytosis along with a few regenerating fibers. myopathy and seronegative IMNM are generally much more difficult to treat, and aggressive immunotherapy is usually required. The pro­ gressive course despite immunotherapy and the marked weakness with atrophy can lead to a misdiagnosis of a limb girdle muscular dystro­ phy. There may be an increased incidence of cancer in patients with anti-HMGCR myopathy; thus, patients should undergo a malignancy workup. CHAPTER 377 ■ ■ANTISYNTHETASE SYNDROME Clinical Features  The presence of myositis, nonerosive arthritis, ILD, Raynaud’s phenomenon, mechanic hands, and fever associated with antibodies against aminoacyl-tRNA synthetase constitute the ASyS. Some patients have an erythematous rash, and muscle biopsies share histopathologic features of DM, which likely accounts for many of these patients being classified as having DM. Inflammatory Myopathies Laboratory Features  Antibodies against aminoacyl-tRNA syn­ thetases are the most common MSA, present in 25–35% of patients with myositis. These include anti-Jo-1 (histidyl), anti-PL-7 (threo­ nyl), anti-PL-12 (alanyl), anti-EJ (glycyl), anti-OJ (isoleucyl), anti-KS (asparaginyl), anti-Ha (tyrosyl), anti-Zo (phenylalanyl), and other less common antibodies. The most common aminoacyl-tRNA syn­ thetase antibody is anti-Jo-1. CK is usually elevated in patients with ASyS and myositis. Those with ILD demonstrate reduced forced vital capacity and diffusion capacity on pulmonary function tests. Spiral chest computed tomography (CT) scans are best at demonstrating the honeycomb pattern of ILD. Skeletal muscle MRI and EMG show abnormalities similar to DM, PM, and IMNM. Histopathology and Pathogenesis  Muscle biopsies demonstrate a predilection for perimysial damage including perimysial fragmenta­ tion and staining with alkaline phosphatase (Fig. 377-6), plasmacytoid dendritic cells and macrophages in the perimysium and around blood vessels, and MAC deposition on capillaries. Also similar to DM, there is perifascicular muscle fiber damage, but with ASyS, there is more perifascicular muscle fiber necrosis compared to DM, in which peri­ fascicular atrophy is more prominent. MHC-I, MHC-II (HLA-DR), and MAC deposits on muscle fibers may be seen on sarcolemma of perifascicular muscle fibers. The HLA-DR expression on muscle fibers suggests that ASyS is more driven by gamma-IFN than type 1 IFN. Recent studies suggest that the various antibodies may be directly pathogenic by binding to specific aminoacyl-tRNA synthetases thereby impairing protein synthesis. More work needs to be done to confirm these observations. Prognosis  Most patients respond to treatment, although ASyS can be difficult to treat, in particular for patients with interstitial lung disease. Aggressive treatment, often with early rituximab, is war­ ranted in such cases. There does not appear to be an increased risk of malignancy. ■ ■INCLUSION BODY MYOSITIS Clinical Features  IBM usually manifests in patients over the age of 50 years and is slightly more common in men than women. It is associated with slowly progressive weakness and muscle atrophy that has a predilection for early involvement of the wrist and finger flexors in the arms and quadriceps in the legs (Fig. 377-7). Weakness is often asymmetric. Dysphagia is common and rarely can be the presenting feature. These clinical features can help distinguish IBM from PM and other forms of myopathy. The mean duration from onset of symptoms to use of wheelchair or scooter is ~15 years. There is no known increase in risk of malignancy. Laboratory Features  CK levels can be normal or only slightly elevated (usually <10 times normal). Antibodies targeting cytosolic 5′-nucleotidase 1A (cN-1A) are detected in the blood in a third to more than two-thirds of IBM patients and are a highly specific diag­ nostic biomarker for IBM among patients with myopathy. Other blood biomarkers for IBM include the presence of an abnormal population of large granular lymphocytes on flow cytometry and a reduced CD4/CD8 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders A B C FIGURE 377-6  Pathology of myositis with anti-Jo-1 antibodies (antisynthetase syndrome). A. Perifascicular/perimysial muscle fiber atrophy and necrosis (thin arrow) associated with perimysial connective tissue is edematous and fragmented in appearance (thick arrow), hematoxylin and eosin stain. B. The perimysial connective tissue intensely stains red with alkaline phosphatase stain (arrowhead). C. Immunostaining demonstrates deposition of membrane attack complex (MAC) deposits on the sarcolemma of nonnecrotic perifascicular muscle fibers (open arrow). ratio with an increased CD8 count. Needle EMG may demonstrate large-amplitude, long-duration motor unit potentials that can be mis­ interpreted as neurogenic but reflect the chronicity of the myopathy. Muscle MRI may show a predilection for involvement of the flexor digitorum profundus in the arms and the vastus medialis and lateralis muscles with sparing of the rectus femoris muscle. Histopathology and Pathogenesis  Muscle biopsies demon­ strate endomysial inflammatory infiltrates predominantly composed of highly differentiated CD8+ CD57+ T cells that express killer cell lectin-like receptor G1 (KLRG1) molecules, plus macrophages, that A B D E FIGURE 377-7  Muscle manifestations of inclusion body myositis (IBM; A–C). Finger flexor weakness can be (A) subtle and multifocal (black arrows), (B) moderate, or (C) severe. Note that even with complete paralysis of deep and superficial finger flexors, metacarpophalangeal joint flexion (arrows) is often maintained due to preservation of lumbricals. D. Ventral forearm atrophy (arrows). E. Atrophy of medial thighs due to loss of vastus medialis (arrows). F. Early IBM, with relatively preserved vastus medialis (arrows), in contrast to (G) advanced IBM with marked fibrous replacement of vastus medialis (arrows). 100.00 µm surround and invade nonnecrotic muscle fibers expressing MHC-I and MHC-II on the sarcolemma, along with fibers with rimmed vacuoles, cytochrome oxidase (COX)–negative fibers, and inclusions on light or electron microscopy (Fig. 377-8). The inclusions contain betasheet misfolded proteins (amyloid) but are difficult to appreciate with routine Congo red stain (they are seen on frozen but not paraffin sec­ tions). Immunostaining for p62 appears to be the most sensitive stain for detection of these inclusions. Importantly, rimmed vacuoles may not be seen in as many as 20–30% of muscle biopsies. In such cases, the presence of mitochondrial abnormalities (ragged red and COXnegative fibers) and immunostaining demonstrating p62 inclusions are C F G A C FIGURE 377-8  Pathology of inclusion body myositis. A. Scattered muscle fibers with rimmed vacuoles and rare fibers with eosinophilic inclusions (arrow), hematoxylin and eosin stain. B. Cytochrome oxidase stain demonstrates an increased number of pale-staining or COX-negative muscle fibers. C. Cytoplasmic inclusions stain positive with p62 within a muscle fiber (thick arrow). D. Electromicroscopy reveals 15- to 21-nm tubulofilamentous inclusions within a myonucleus. helpful in distinguishing IBM from PM (aside from the clinical pattern of muscle weakness). Immunostaining also demonstrates that TAR DNA-binding protein 43 (TDP-43), an intranuclear RNA/DNA-binding protein involved in the regulation of RNA processing, is extruded from the myonuclei in IBM. This is similar to what is found in neurons of patients with neurodegenerative disorders such as frontotemporal dementia (Chap. 443) and amyotrophic lateral sclerosis (Chap. 448). The pathogenesis of IBM is poorly understood. The prominent adaptive immune system abnormalities related to T-cell inflamma­ tion and the presence of a relatively specific autoantibody against a muscle protein indicate an autoimmune attack on muscle. The chronic and highly inflammatory environment within muscles in IBM may alter protein synthesis and degradation pathways in part via aber­ rant immunoproteasome expression. Additional histologic features, typically referred to as “degenerative,” include aggregation of various proteins including markers of endoplasmic reticulum (ER) stress and autophagy (e.g., p62 and LC3). Involvement of ER stress and autophagy has also been observed in other autoimmune diseases, such as primary biliary cholangitis (PBC), inflammatory bowel disease, and ankylosing spondylitis, some of which can be highly refractory to immunotherapy. As noted above, TDP-43, which is important for normal splicing of messenger RNA, is extruded from myonuclei in IBM; loss of TDP43–mediated splicing repression likely leads to abnormal inclusion of cryptic exons in skeletal muscle and aberrant translation of muscle proteins. Whether this tissue damage results directly from a pathogenic immune response or a secondary neurodegenerative process is unclear at this time. Prognosis  The myopathy is slowly progressive and is not typically responsive to immunotherapies. Most patients require a scooter or wheelchair within 10–15 years of onset of symptoms. TREATMENT OF INFLAMMATORY MYOPATHIES (TABLE 377-2) DM, PM, ASyS, and IMNM are typically responsive to immuno­ therapy. High-dose glucocorticoids are considered the first-line treat­ ment. There is uncertainty regarding when to start second-line CHAPTER 377 Inflammatory Myopathies B D agents (e.g., methotrexate, azathioprine, mycophenolate, immuno­ globulin, or rituximab). The clinician must weigh with the patient the increased risks of immunosuppression versus possible benefits (e.g., faster improvement, steroid-sparing effects, and/or avoidance of morbidities associated with long-term glucocorticoid use). It is our general practice to start a second-line agent (typically methotrexate) with glucocorticoids in patients with severe weakness or other organ system involvement (e.g., myocarditis, ILD), those with increased risk of steroid complications (e.g., diabetics, osteoporosis, or postmenopausal women), and patients with IMNM who are known to have difficultto-treat myositis. When treatment is initiated with prednisone alone, a second-line agent is added in patients who fail to significantly improve after 2–4 months of treatment or in those who cannot be tapered to a low dose of prednisone. Many patients with IMNM do not respond to prednisone alone or even prednisone plus a second-line agent in combi­ nation. Many require triple therapy with prednisone, methotrexate, and IVIG and, if this fails, rituximab. In our experience and that of others, anti-HMGCR myopathy often responds to monotherapy with IVIG. Unfortunately, IBM does not typically respond to any known immu­ notherapy. The mainstay of treatment is physical and occupational therapy to improve function, and swallowing therapy (and sometimes esophageal dilation or cricopharyngeal myotomy) in those with dysphagia. ■ ■GENERAL GUIDELINES FOR USE OF SPECIFIC IMMUNOTHERAPIES Glucocorticoids  Treatment is initiated with prednisone (0.75–1.5 mg/kg up to 100 mg) administered as a daily morning single dose (the most common dose used in adults is 60 mg daily). In patients with severe weakness or comorbidities (e.g., ILD, myocarditis), treatment with a short course of intravenous methylprednisolone (1 g daily for 3 days) is recommended prior to starting oral glucocorticoids. Patients are generally maintained on high-dose prednisone until strength normal­ izes or until improvement in strength has reached a plateau (usually 3–6 months). Subsequently, prednisone can be tapered by 5 mg every 2–4 weeks. Once the dose is reduced to 20 mg every day or every other day, TABLE 377-2  Immunotherapies for Inflammatory Myopathies THERAPY ROUTE DOSE SIDE EFFECTS MONITOR Prednisone Oral 0.75–1.5 mg/kg per day to start Hypertension, fluid and weight gain, hyperglycemia, hypokalemia, cataracts, gastric irritation, osteoporosis, infection, aseptic femoral necrosis PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Methylprednisolone Intravenous 1 g in 100 mL/normal saline over 1–2 h, daily or every other day for 3–6 doses Azathioprine Oral 2–3 mg/kg per day; single a.m. dose Flu-like illness, hepatotoxicity, pancreatitis, leukopenia, macrocytosis, neoplasia, infection, teratogenicity Methotrexate Oral 7.5–20 mg weekly, single or divided doses; 1 day a week dosing   Subcutaneously 20–50 mg weekly; 1 day a week dosing Same as oral Same as oral Cyclophosphamide Oral Intravenous 1.5–2 mg/kg per day; single a.m. dose 0.5–1.0 g/m2 per month × 6–12 months Cyclosporine Oral 4–6 mg/kg per day, split into two daily doses Tacrolimus Oral 0.1–0.2 mg/kg per day in two divided doses Nephrotoxicity, hypertension, infection, hepatotoxicity, hirsutism, tremor, gum hyperplasia, teratogenicity Mycophenolate mofetil Oral Adults (1–1.5 g BID) Children (600 mg/m2 per dose BID) (no >1 g/d in patients with renal failure) Intravenous immunoglobulin Intravenous 2 g/kg over 2–5 days; then 1 g/kg every 4–8 weeks as needed Rituximab Intravenous A course is typically 750 mg/m2 (up to 1 g) and repeated in 2 weeks Courses are then repeated usually every 6–18 months Abbreviations: BUN, blood urea nitrogen; IVIG, intravenous immunoglobulin. Source: Reproduced with permission from AA Amato, JA Russell (eds): Neuromuscular Disorders. 2nd ed. New York: McGraw-Hill Education; 2016. the taper is slowed to 2.5 mg every 2–4 weeks. The goal is to taper pred­ nisone to ≤10 mg daily. Although most patients improve, the response may not be complete and many will require at least a small dose of pred­ nisone or a second-line agent to have a sustained remission. Serum CK levels are monitored; however, dose adjustments of prednisone and other immunotherapies are primarily based on the objective clinical examina­ tion and not the CK levels or the patients’ subjective response. When no response is noted after an adequate trial of high-dose prednisone, alter­ native diagnoses (e.g., IBM or an inflammatory muscular dystrophy) and a repeat muscle biopsy should be considered. Relapse of the myositis needs to be distinguished from steroid myopathy. Features suggesting a steroid myopathy include weakness developing while on high dosage, a normal serum CK, clinical features of steroid excess such as ecchymoses and “moon facies,” and absence of muscle membrane irritability on EMG. By contrast, patients experi­ encing relapses of myositis may become weaker during the prednisone taper, have increasing serum CK levels, and display abnormal sponta­ neous activity on EMG. Intravenous Immunoglobulin  IVIG is most often used in patients refractory to prednisone and at least one second-line immuno­ suppressive agent. However, the ProDERM Trial Group found IVIG to be effective in a randomized, controlled trial in patients with DM, lead­ ing to U.S. Food and Drug Administration (FDA) approval. Thus, IVIG can be administered as first-line therapy in DM. In addition, IVIG is effective as a monotherapy in anti-HMGCR myopathy and may be the treatment of choice. A dose of 2 g/kg is divided over 2–5 days, and repeat infusions are given at monthly intervals for at least 3 months. Subsequently, intervals can be lengthened or dosage decreased: 2 g/kg every 2 months or 1 g/kg per month. Weight, blood pressure, serum glucose/potassium, cataract formation Arrhythmia, flushing, dysgeusia, anxiety, insomnia, fluid and weight gain, hyperglycemia, hypokalemia, infection Heart rate, blood pressure, serum glucose/potassium Blood count, liver enzymes Hepatotoxicity, pulmonary fibrosis, infection, neoplasia, infertility, leukopenia, alopecia, gastric irritation, stomatitis, teratogenicity Liver enzymes, blood count Bone marrow suppression, infertility, hemorrhagic cystitis, alopecia, infections, neoplasia, teratogenicity Blood count, urinalysis Nephrotoxicity, hypertension, infection, hepatotoxicity, hirsutism, tremor, gum hyperplasia, teratogenicity Blood pressure, creatinine/ BUN, liver enzymes, cyclosporine levels Blood pressure, creatinine/ BUN, liver enzymes, tacrolimus levels Bone marrow suppression, hypertension, tremor, diarrhea, nausea, vomiting, headache, sinusitis, confusion, amblyopia, cough, teratogenicity, infection, neoplasia Blood count Hypotension, arrhythmia, diaphoresis, flushing, nephrotoxicity, headache, aseptic meningitis, anaphylaxis, stroke Heart rate, blood pressure, creatinine/BUN Infusion reactions (as per IVIG), infection, progressive multifocal leukoencephalopathy Some check B-cell count prior to subsequent courses (but this may not be warranted) ■ ■SECOND-LINE THERAPIES Methotrexate  Methotrexate is usually the second-line treatment of choice because most authorities believe it works faster than other agents. An oral dose of 5 or 7.5 mg/week is initiated and then gradually increased as needed up to 25 mg/week. If there is no improvement after 1 month of 25 mg/week of oral methotrexate, a switch to weekly par­ enteral (usually subcutaneous) methotrexate is the next step, with dose escalation by 5 mg weekly; only rarely is a dose >35 mg/week used. The major side effects of methotrexate are alopecia, stomatitis, ILD, terato­ genicity, oncogenicity, risk of infection, and pulmonary fibrosis, along with bone marrow, renal, and liver toxicity. Patients are concomitantly treated with folate or folinic acid. Azathioprine  A recommended initial dose is 50 mg/d in adults, which can be increased by 50 mg every 2 weeks up to 2–3 mg/kg per day. Approximately 12% of patients develop a systemic reaction char­ acterized by fever, abdominal pain, nausea, vomiting, and anorexia that requires discontinuation of the drug. The major practical limitation of azathioprine is that 6–18 months of treatment are usually required before benefit can be seen. Patients can be prescreened for thiopurine methyltransferase (TPMT) deficiency that is associated with severe bone marrow toxicity from this drug. Mycophenolate Mofetil  This drug inhibits the proliferation of T and B lymphocytes by blocking purine synthesis. It appears to be effec­ tive in different forms of myositis and is the second-line treatment of choice for myositis patients with ILD. The starting dose is 1.0 g twice daily and can be increased to 3 g daily in divided doses, if necessary. Mycophenolate is excreted through the kidneys; therefore, the dose should be decreased in patients with renal insufficiency. An advantage # 21 - 378 Relapsing Polychondritis ### 378 Relapsing Polychondritis of mycophenolate compared to other immunosuppressive agents is the lack of renal or hepatic toxicity. Rituximab  Rituximab is a monoclonal antibody directed against CD20+ B cells. A large randomized controlled trial found no benefit, but there were flaws in the study design. Most authorities feel that rituximab can be beneficial in some patients who are refractory to prednisone and at least one of the other second-line agents. The typi­ cal dosage is 750 mg/m2 (up to 1 g) IV with a second infusion 2 weeks later and with repeat courses (375 mg/m2 as a single infusion or with a second infusion 2 weeks apart) every 6–18 months as needed. Drugs in Clinical Trials  Trials of a monoclonal antibody to block IFN-β and drugs to target downstream pathways (e.g., JAK-1) are ongoing in DM and other forms of myositis. Studies targeting the neo­ natal Fc receptor (FcRn) to decrease myositis-specific antibodies are underway in DM, ASyS, and IMNM, as are trials with chimeric antigen receptor (CAR) T-cell therapy. Ongoing trials in IBM include rapamy­ cin as well as a trial of a monoclonal antibody binding to KLRG1 to deplete highly differentiated muscle-invading T cells. MYOSITIS ASSOCIATED WITH CHECKPOINT INHIBITORS Autoimmune neurologic complications, including inflammatory neu­ ropathy (Chap. 458), myasthenia gravis (Chap. 459), and myositis, can occur with use of immune checkpoint inhibitors (anti-CTLA-4, antiPD-1, and anti-PD-L1) to treat various cancers. Patients with myosi­ tis often develop muscle pain and weakness (axial musculature and proximal limbs) after one or two cycles. Myocarditis can also develop. Additionally, diplopia with extraocular weakness along with dysphagia and dysarthria suggesting the co-occurrence of myasthenia gravis (MG) may be present. In such cases, an elevated CK level helps sup­ port the diagnosis of myositis, while acetylcholine receptor antibod­ ies or decremental response on slow repetitive nerve stimulation can establish the diagnosis of MG. Endomysial inflammatory cell infiltrates composed of macrophages expressing PD-L1 and CD8+ lymphocytes expressing PD-1, overexpression of MHC-I on sarcolemma of muscle fibers, and scattered necrotic and regenerating fibers can be found on muscle biopsies. The immune checkpoint inhibitor should be discontinued, but most patients require concurrent treatment with glucocorticoids or IVIG. Patients generally improve over several months, during which time immunotherapy can be tapered. There are rare reports of patients with mild myositis who were able to be successfully re-treated with an immune checkpoint inhibitor. MYOSITIS ASSOCIATED WITH COVID-19 INFECTION Early series of patients hospitalized with COVID-19 report that as many as 44% of patients experience muscle pain or fatigue and 33% have elevated CK levels. Rare cases are complicated by myoglobinuria. Histopathology can demonstrate inflammatory cell infiltration and necrotic muscle fibers. In autopsy series, SARS-CoV-2 has not been demonstrated in muscle fibers, and the myositis is felt in most, if not all, to be due to cytokine storm. Whether COVID-19 infection can induce a chronic autoimmune myositis is controversial; there have been a number of reports of various types of IM, some with MSA, in patients following COVID-19 infection, but temporal associations do not equal causation. GLOBAL ISSUES There is a lack of epidemiologic data with regard to the incidence and prevalence of various subtypes of IM throughout the world. Compli­ cating the issue is disease awareness and the inability to obtain and process muscle biopsies and MSAs, particularly in less developed countries. Nevertheless, each of these disorders occurs throughout the world. The specific environmental triggers and genetic risk factors are likely variable. Interestingly, a report from Japan found that 28% of IBM patients had evidence of exposure to hepatitis C, which was much higher than seen in the Western Hemisphere and also more common than seen in PM and healthy population controls in Japan. HIV-associated PM and IBM are more commonly encountered in areas endemic for HIV, and recent studies suggest most of these “PM” patients turn out to have IBM and can develop symptoms at an earlier age (e.g., in the 30s). Interestingly, while most cases of anti-HMGCR myopathy in North America and Europe are associated with prior statin use, the major­ ity of such cases in Asia are not. Pyomyositis and parasitic myositis are clearly more common in the tropics. The prevalence of different types of cancers varies in different parts of the world, an important consideration with respect to paraneoplastic myositis. For example, nasopharyngeal cancer is particularly common in Asia; thus, assess­ ment for this type of cancer should be considered in the workup of patients from high-risk regions. CHAPTER 378 Relapsing Polychondritis ■ ■FURTHER READING Aggarwal R et al: ProDERM Trial Group. Trial of intravenous immune globulin in dermatomyositis. N Engl J Med 387:1264, 2022. Allenbach Y et al: Immune-mediated necrotizing myopathy: Clinical features and pathogenesis. Nat Rev Rheumatol 16:689, 2020. Amato AA, Russell JA (eds): Neuromuscular Disorders, 2nd ed. New York, McGraw-Hill Education, 2016, pp. 827–871. Britson KA et al: Loss of TDP-43 function and rimmed vacuoles persist after T cell depletion in a xenograft model of sporadic inclusion body myositis. Sci Transl Med 14:eabi9196, 2022. Greenberg SA: Inclusion body myositis: clinical features and patho­ genesis. Nat Rev Rheumatol 15:257, 2019. Julien S et al: Immune-mediated necrotizing myopathy (IMNM): A story of antibodies. Antibodies (Basel) 13:12, 2024. Mariampillai K et al: Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurol 75:1528, 2018. Müller F et al: CD19 CAR T-cell therapy in autoimmune disease: A case series with follow-up. N Engl J Med 390:687, 2024. Pinal-Fernandez I et al: Pathogenic autoantibody internalization in myositis. medRxiv [Preprint]. 17:2024.01.15.24301339, 2024. Puwanant A et al: Clinical spectrum of neuromuscular complications after immune checkpoint inhibition. Neuromuscul Disord 29:127, 2019. Suh J et al: Skeletal muscle and peripheral nerve histopathology in COVID-19. Neurology 97:e849, 2021. Marcela A. Ferrada, Peter C. Grayson Relapsing Polychondritis Relapsing polychondritis (RP) is a rare systemic disease characterized by recurrent inflammation in cartilaginous structures. Involvement of the ears, nose, respiratory tract, and joints are hallmark features of the disease; however, other organs can be affected including the eyes, inner ear, nervous system, skin, and cardiovascular system. Some patients with RP may be concomitantly diagnosed with other rheumatologic diseases, such as Sjögren’s syndrome or systemic lupus erythematosus. Recurrent chondritis of the ears and nose in older male patients with severe systemic inflammation and progressive bone marrow failure is associated with acquired hematologic mutations in UBA1, a condition now known as the VEXAS (vacuoles, E1 enzyme, X-linked, autoin­ flammatory, somatic) syndrome. Prompt recognition and accurate diagnosis of RP or VEXAS syndrome are essential to prevent lifethreatening complications of these diseases. The epidemiology of RP is poorly characterized. The disease is commonly reported to primarily affect middle-aged adults without a strong sex predilection; some cohort studies report female predilection, but large, population-based studies typically show equal sex distribu­ tion. Children can be affected; however, these data are limited to case reports. Rare instances of familial aggregation have also been reported. The estimated incidence rate of disease is 0.7–3.5 cases per million per year, and prevalence estimates range from 4.5–25 cases per million. Epidemiologic data in RP are limited to older studies, typically evalu­ ating population distributions more than three decades ago in cohorts from Europe and North America. Given the diagnostic challenges encountered in this condition, these data may underestimate the true prevalence of disease. Although RP has been reported in many regions of the world, whether racial or ethnic differences are associated with variable clinical features or outcomes is not known. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders ■ ■PATHOLOGY AND PATHOPHYSIOLOGY Histologic findings from biopsy of affected cartilage are dependent on the timing of tissue sampling. In acute disease, a mixed inflammatory infiltrate of myeloid and lymphoid populations is observed at the car­ tilage interface. Over time, cartilage destruction is marked by lacunar breakdown and loss of chondrocytes, replaced by fibrosis. Biopsy of affected cartilage may cause morbidity, and there are no features on histology that are specifically diagnostic for RP. Therefore, biopsy is often reserved when there is a high suspicion of conditions that mimic RP, particularly infectious diseases and malignancies. Although genetic, environmental, and immunologic aspects of the disease have been studied in humans and in animal models, the exact mechanisms that drive the disease are unclear. Limited studies in animal models support the concept that autoimmunity to cartilage components may play a role in RP. Immunization of specific animals to type II col­ lagen, type IX collagen, or matrillin-1 can recapitulate various aspects of the clinical phenotypes observed in patients with RP; however, the performance characteristics of these antibodies in clinical practice are poor to differentiate RP from other diseases. Autoantibodies to type II collagen have been reported in small cohorts of patients with RP but are neither sensitive nor specific to be considered as an acceptable diag­ nostic marker of disease. Observational cohort data suggest that B-cell– depleting therapies are not particularly effective to treat the condition, arguing against a strong primary role of antibody-mediated disease. Acute phase reactants (e.g., erythrocyte sedimentation rate or C-reactive protein) are not reliably elevated in patients with RP. Proinflammatory cytokines and chemokines related to both innate and adaptive immunity have been identified in association with RP; A   FIGURE 378-1  Representation of ear involvement in relapsing polychondritis. A and B. Examples of typical ear chondritis, with significant inflammation of the pinnae. C. Mild ear cartilage inflammation. D. Cartilage damage. however, these findings are not consistent and, therefore, are not rou­ tinely measured to guide management in clinical practice. ■ ■CLINICAL MANIFESTATIONS AND ORGAN INVOLVEMENT RP is associated with a wide range of clinical manifestations. In the absence of a diagnostic blood test, a detailed medical history and physical examination are the most essential tools for diagnosis and, most importantly, further management. Because disease activity is intermittent and patients may not exhibit clear signs of inflammation during direct evaluation, it is crucial to consider the patient’s symptoms over time and to review any provided photographic documentation of disease features. Ears, Nose, and Throat  Ear involvement is one of the most common clinical manifestations of relapsing polychondritis, affecting 80–90% of the patients. However, there are no clear definitions of ear chondritis, and patient descriptions of pain and associated symptoms are variable. The typical description includes involvement of only the cartilaginous aspect of the ear (pinnae) (Fig. 378-1A and B). However, a subset of patients may report pain in the ears with minimal associ­ ated findings visualized on physical examination, such as mild swell­ ing or erythema (Fig. 378-1C). Although damage to the cartilaginous portion of the external ear (i.e., “cauliflower ear”) is observed in RP (Fig. 378-1D), it is present only in a small number of patients, usually in the setting of recurrent episodes of ear inflammation. Questions that can be helpful to elicit the nature of ear pain include asking about onset, duration, and triggers. Common triggers include minimal trauma to the ear (such as from lying on the effected side or wearing glasses) or temperature changes. Patients usually describe a sensation of pressure at the bridge of the nose that may not be accompanied by other associated symptoms. Some patients may have overt redness and swelling of the bridge or tip of nose, but this is less common (Fig. 378-2A). While a “saddle nose” has been described as a typical clinical finding in RP, many patients will not develop an obvious nasal deformity (Fig. 378-2B). The nasal septum and nasal passages should always be evaluated in patients with suspected RP, as many patients can have septal ulcers and mucosal inflammation. In contrast to granulomatosis with polyangiitis (GPA) where a saddle nose deformity is usually associated with a septal perforation (Chap. 375), patients with RP who have a saddle nose deformity usually do not have B C   FIGURE 378-1  (Continued) a septal perforation, as most of the nasal perforations in patients with RP are located anteriorly. Patients can have complaints of throat pain or a sensation of globus, usually described as a “choking sensation.” Patients can also report pain on the anterior aspect of the neck, in some cases associated with erythema, usually located at the level of the thyroid cartilage. Upper and Lower Airway  Conditions like subglottic stenosis may manifest acutely or subacutely, leading to cough, voice changes, or breathlessness. Severe narrowing can result in stridor, requiring urgent medical attention to avoid mortality (Fig. 378-3A). Often misdiag­ nosed as adult-onset asthma, timely recognition of airway involvement is important to prevent chronic damage to the large airways, which can result in tracheomalacia, bronchomalacia, or tracheal calcification (Fig. 378-3B and C). Patients with intermittent episodes of wheezing A   FIGURE 378-2  Nose involvement in relapsing polychondritis. A. Redness and swelling of the base and tip of the nose. B. Saddle nose deformity. CHAPTER 378 Relapsing Polychondritis D and with a review of symptoms positive for possible RP should be fol­ lowed closely and further evaluated for lower airway involvement. Musculoskeletal  •  JOINTS  RP is associated with a nonerosive inflammatory arthritis that can affect small and large peripheral joints and as well as the axial skeleton. Erosions have been described in the sacroiliac joints but not in other joints. The most common large joint affected is the knees, often presenting with effusions. The pattern of small joint involvement emulates rheumatoid arthritis, without ero­ sions or deformities. TENOSYNOVITIS  Different tendons can be affected including Achilles and peroneal tendons. COSTOCHONDRAL JOINTS  Located at the rib-sternum junction, these joints are frequently inflamed in RP, producing constant pain that B PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders A   B C FIGURE 378-3  Airway involvement in relapsing polychondritis. A. Subglottic stenosis. B and C. Computed tomography demonstrating tracheal calcification and tracheomalacia. stands out due to its unique severe quality. Pain due to costochondritis can be so severe that patients will seek evaluation in the emergency room due to concerns for an acute coronary event. The pain is bilateral, reproducible with palpation, and not associated with movement of the affected rib. Inner Ear  All patients with RP should undergo hearing tests to evaluate for conductive and sensorineural hearing loss. During the physical exam, the ear canal should be evaluated as some patients can have severe inflammation or eustachian tube dysfunction leading to conductive hearing loss. The presence of dizziness necessitates further evaluation through maneuvers like finger-to-nose, Romberg, and nys­ tagmus to rule out vestibular involvement. Ocular Involvement  Episcleritis is the most frequent type of ocu­ lar inflammation in RP. It might coincide with other flare symptoms or occur independently. Although rare, features suggesting scleritis man­ date urgent ophthalmologic evaluation due to its potential catastrophic outcomes, including vision loss, scleromalacia, or global rupture neces­ sitating enucleation (Fig. 378-5A). Cardiovascular  Patients with mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome may exhibit symptoms seen in Behçet’s syndrome (Chap. 376), including pathergy and gastrointes­ tinal involvement. These patients can also have large-vessel vasculitis involving the aorta. Neurologic  The diagnosis of neurologic involvement due to RP is one of exclusion. All possible etiologies including infection and malig­ nancy should be ruled out before attributing the clinical findings to RP; however, encephalitis and meningitis can be seen in RP. ■ ■DIAGNOSIS There are no circulating or tissue-based biomarkers with adequate performance characteristics to function as a diagnostic test for RP. As such, diagnosis is based primarily on clinical pattern recognition informed by a comprehensive review of systems and physical examina­ tion. Several diagnostic criteria have been proposed; however, these criteria were developed in small cohorts, are largely based on expert opinion, and have not been formally validated. McAdam’s criteria require presence of three of six symptoms, including bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, or ves­ tibular/cochlear dysfunction. Damiani and Levine modified McAdam’s criteria to include either three clinical features or one clinical feature with histologic evidence of chondritis or two clinical features with clinical response to glucocorticoids, dapsone, or both. Michet’s criteria propose three major criteria (inflammation of ear, nose, or respira­ tory tract) and four minor criteria (ocular inflammation, hearing loss, vestibular dysfunction, and seronegative inflammatory arthritis) and require fulfillment of two major criteria or one major plus two minor criteria to establish the diagnosis. Another important limitation of these criteria is the lack of precise definitions of organ involvement. The differential diagnosis for RP includes conditions that mimic chondritis in specific cartilaginous organs and systemic diseases for which chondritis may be a manifestation. Ear chondritis can be mim­ icked by infectious and cutaneous diseases of the external ear, trau­ matic otohematoma, or red ear syndrome. Various infectious diseases and angiocentric centrofacial lymphoma can mimic nasal chondritis. Asthma, traumatic airway stenosis, infectious diseases, and congenital disorders involving the airway can mimic airway chondritis. Systemic diseases that mimic RP include GPA (Chap. 375) and autoinflamma­ tory diseases (Chap. 381). GPA can be differentiated from RP in part by the presence of antineutrophil cytoplasmic autoantibodies (ANCA) and glomerulonephritis, which are not features of RP. Presence of cytopenia, most notably macrocytosis and lymphopenia, in older male patients should trigger consideration of genetic testing and bone mar­ row assessment for VEXAS. Audiometry to assess hearing loss and dynamic expiratory phase computed tomography of the chest to assess tracheobronchomalacia are critical studies that should be performed in all patients with suspected # 22 - 379 Sarcoidosis ### 379 Sarcoidosis RP to define the extent of disease involvement. Direct laryngoscopy can be useful to visualize cartilage damage and inflammation in the upper airway; however, bronchoscopy to visualize the lower airway can exacerbate disease and should be performed with caution. Echocardiog­ raphy can assess valvular heart disease. Fluorodeoxyglucose–positron emission tomography may have utility to detect inflammation in the large arteries and the larger airways. Biopsy of affected cartilage often yields nonspecific findings and should be reserved to exclude mimick­ ing conditions. TREATMENT Relapsing Polychondritis Patients with RP can present to diverse specialists prior to diagnosis that can include multiple emergency room visits. Internal medicine doctors are typically among the first to encounter patients who present with the initial manifestations of RP and are instrumental in starting the initial treatment regimen. Because RP is a systemic and heterogeneous disease, clini­ cal management should typically involve multidisciplinary teams, including otolaryngologists (ear, nose, and throat specialists) and pulmonologists. Given the disease’s propensity to progressively involve various organs, it is crucial to perform initial testing to define organ damage. If possible, patients should be referred to a rheumatologist for comprehensive evaluation, diagnosis confirma­ tion, and the establishment of a tailored treatment plan. Glucocorticoids are the cornerstone of initial treatment for inflammation in RP, with dosages tailored to the severity of the disease and the specific organs involved. In cases where life-threat­ ening organ involvement, such as the airway, is present, high doses of glucocorticoids (e.g., 1 mg/kg of prednisone or an equivalent glucocorticoid) should be rapidly initiated. For patients with milder disease, lower doses of glucocorticoids can be trialed. Different disease-modifying agents can be used to treat the disease including methotrexate, leflunomide, mycophenolate, anti-interleukin-6, or tumor necrosis factor inhibitors. Due to the heterogeneity of the disease, treatment strategies are often determined by the predomi­ nant clinical phenotype. ■ ■FURTHER READING Beck DB et al: Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med 383:2628, 2020. Ferrada M et al: Defining clinical subgroups in relapsing polychon­ dritis: A prospective observational cohort study. Arthritis Rheum 72:1396, 2020. Alicia K. Gerke Sarcoidosis Sarcoidosis is a systemic inflammatory disease of unknown cause char­ acterized by the formation of nonnecrotizing granulomatous inflam­ mation. Sarcoidosis affects the lung in >90% of cases but can afflict almost any other organ system as well. The disease was first described >150 years ago by Dr. Jonathan Hutchinson of London, England, as a skin malady of symmetrical purple plaques (later termed lupus pernio) and raised red lesions (Mortimer’s malady). In 1899, the skin lesions were noted to be “sarkoid” by Caeser Boeck, a Norwegian dermatolo­ gist, as they resembled sarcoma, albeit the lesions were largely benign and granulomatous in their histology. The advent of imaging and other clinical technology later unveiled the multiorgan involvement associated with sarcoidosis. However, despite even modern advances in immunology, genetics, and genomics, there is still considerable mys­ tery regarding the exact etiology of the inflammation and the factors that contribute to variability of disease presentation and clinical course. Because of this considerable heterogeneity and lack of large, random­ ized treatment trials, decisions regarding diagnosis and management continue to be challenging. CHAPTER 379 EPIDEMIOLOGY Sarcoidosis occurs throughout the world, affecting all genders, races, and ages. Epidemiologic studies regarding the incidence, prevalence, and mortality rates of sarcoidosis are difficult to conduct and compare; this is due to the potential for nonstandardized case definition, differ­ ing methods of case acquisition, and lack of known etiology. Regional variabilities due to race and gender, as well as phenotypic variability, further confound epidemiologic measurements. Taken as a whole, epi­ demiologic studies highlight the variation in disease globally. Sarcoidosis ■ ■INCIDENCE AND PREVALENCE The incidence and prevalence of sarcoidosis vary by race, gender, geographic region, ethnicity, and season. An increased familial risk has been noted. The highest incidence in the world occurs in African Americans (35.5 per 100,000) and Northern European populations (24 per 100,000) as described by studies from the United States and Sweden. A higher incidence occurring in women is consistent across most studies, although the ratio does not usually exceed 2:1. The U.S. Black Women’s Health Study cohort found a particularly high annual incidence of 71 per 100,000 and a prevalence of 2%. Some studies suggest an increase in incidence over time in the populations of some countries such as the United States and Japan. Peak incidence of the disease occurs between 35 and 45 years of age, but a significant proportion of cases do happen after age 55, with men manifesting disease earlier than women. The overall perceived incidence rate may be underestimated, as identification of subclinical sarcoidosis may only be possible in screening population studies or at autopsy. Certain occupations and exposures and an elevated body mass index have been identified as risk factors for development of sarcoidosis, whereas smok­ ing is associated with reduced odds of incident sarcoidosis. Seasonal variation is also reported, with a predominance of diagnoses occurring in the springtime. Differences in presentation and severity are also seen among popu­ lations. Cardiac and ocular involvement are more commonly observed in Japanese populations, whereas Europeans tend to develop erythema nodosum, which is uncommon among Japanese and black populations. Several studies suggest that overall severity is higher in black popula­ tions, with black patients presenting with more frequent involvement of extrapulmonary disease and three times the likelihood of familial disease. Women are at increased risk for developing erythema nodo­ sum and ocular, musculoskeletal, and neurologic disease, while men are at higher risk for hypercalcemia. While most sarcoidosis patients have lung involvement, black and female patients tend to have more severe lung disease. Finally, lower income has also been associated with severity of disease and potentially greater disability and impairment (particularly increased dyspnea and onset of new organ involvement), suggesting that socioeconomic status may impact disease course. ■ ■MORTALITY Mortality rates vary considerably based on the study setting, with popu­ lation screenings noting lower rates of mortality than those reported from referral centers. These occurrences may reflect differences in disease severity. Analysis of death certificates from the United States shows an average age- and gender-adjusted mortality rate of 4.32 per 1,000,000. Mortality rates are higher in women and in African Ameri­ cans. Pulmonary fibrosis is the leading cause of death in this population. Lower mortality rates are seen in Japan, with estimates at 0.1 per million people. In Japan, mortality from sarcoidosis itself is usually attributed to cardiac involvement, whereas in Europeans and Americans, respiratory mortality predominates. ETIOLOGY The cause of sarcoidosis is unknown; however, current evidence strongly indicates a heightened host immune response to an undeter­ mined environmental exposure in a genetically susceptible individual. It is unknown if there are multiple different antigens that induce the same disease process. The immunologic response in sarcoidosis appears to be physiologic, although it is either exaggerated or is defi­ cient in its regulatory mechanisms. The transmissibility of the immune response also supports the presence of an antigen. For example, the Kveim-Siltzbach reagent (historically used to diagnose sarcoidosis) is a homogenate of human splenic tissue from patients with sarcoidosis that, when injected into the skin, induces a systemic granulomatous response in patients with early sarcoidosis. In a similar fashion, trans­ plant recipients can develop a sarcoid-like inflammatory response after receiving organ tissue from another person with sarcoidosis. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Histologic inflammatory responses like sarcoidosis occur in the lungs of patients with known inorganic and organic exposures such as beryllium, mycobacteria, or fungi, resulting in these antigens being studied as potential causes. Mycobacterial proteins (e.g., mKatG, ESAT-6, mycobacterial superoxide dismutase A, antigen 85A, heat shock pro­ teins) have been found disproportionately in sarcoidosis granulomas. Heightened macrophage immune responses against these peptides within blood and bronchoalveolar lavage (BAL) have also been noted in patients with sarcoidosis. In a similar manner in other cohorts, Cuti­ bacterium acnes (formerly Propionibacterium acnes) has been impli­ cated. A genetic predisposition is also suspected, as antigen recognition and presentation molecule polymorphisms have been associated with sarcoidosis development and phenotype. Similarly, gene–environment interactions have been identified, suggesting a complex interaction of a susceptible host in a predisposing environment. Epidemiologically, the role of antigens in pulmonary sarcoidosis is further supported by case-cluster events and occupational association. Whereas numerous familial case clusters support a genetic predisposi­ tion to sarcoidosis in at least a proportion of cases, spatial clustering of nonrelated sarcoidosis cases suggests exposure to an inciting envi­ ronmental antigen. For example, a baseline higher incidence is noted in U.S. firefighters, with an annual incidence of sarcoidosis occurring in 13–15 per 100,000 individuals. Following the World Trade Center event and building collapses, the rates of “sarcoid-like” disease were 86 per 100,000 in the first year and 22 per 100,000 over the next 4 years, with the highest risk associated with working in the debris piles. Inter­ estingly, the cases included not only those with lung disease but also those with multisystem involvement, which would not be expected from a localized inhalational exposure. Additionally, employment in agriculture, teaching, metalworking, radiation, cotton ginning, and automobiles has also been associated with sarcoidosis. Increased rates of sarcoidosis have been found in association with environmental exposures. Musty or humid environments, mold and mildew, insecticides, air conditioning, raising birds, and exposure to wood stoves/burning and fireplaces have been associated with increased risk of sarcoidosis. On the other hand, smoking is con­ sistently a negative predictor of disease; the mechanism of this is unknown, although it is perhaps related to immunomodulatory effects of nicotine and smoke. These epidemiologic studies would indicate that the inciting exposure may be a bioaerosol or an inorganic agent, which may explain some of the epidemiologic variability of clinical presentation by race, age, gender, and ethnicity. Additionally, the incit­ ing antigen may not be a single agent; rather, differing antigens may exist for each individual or population. PATHOGENESIS Like other granulomatous processes, granulomas of sarcoidosis are presumably forming around a poorly degradable or insoluble material that is identified and presented to lymphocytes by dendritic cells or macrophages via the major histocompatibility complex (Fig. 379-1). The initial innate immune response triggers the production of cytokines and chemokines that begin the cascade of granulomatous inflamma­ tion, attracting cells of the adaptive immune response. Activated lym­ phocytes and mononuclear cells migrate to the site of granulomatous Antigen Presentation MHC Unknown antigen TCR CD4+ T cell (activated) T Cell Response Th-1 response TH17 cell Granulomatous Inflammation Regulatory Response Treg Resolution Fibrosis FIGURE 379-1  Immunopathogenesis of sarcoidosis. Granulomatous inflammation of sarcoidosis is presumed to be due to a heightened immune response to an undetermined antigen in a genetically predisposed individual. The antigen presentation via the major histocompatibility complex (MHC) activates CD4+ T cells, leading to a polarized TH1 response. Activated lymphocytes, macrophages, and monocytes migrate to sites of inflammation, leading to a cascade of tightly formed noncaseating granulomas. Altered T-regulatory (Treg) and TH17 responses are thought to be involved in lack of resolution of granulomatous inflammation or progression to fibrosis in some cases. inflammation in a process driven by amplification of oligoclonal T cells of undefined antigenic specificity. Type 1 (TH1) immune polarization is the immunopathogenic hallmark of sarcoidosis, characterized by highly polarized CD4+ TH1 lymphocytes and less so by CD8+ lymphocytes, producing interferon-gamma (IFN-γ). TH1-promoting immunoregula­ tory cytokines and chemokines (interleukin [IL]-1, IL-2, IL-15, IL-18, CXCR3) are consistently upregulated at sites of inflammation, propa­ gating the immune response, activating macrophages, and forming granulomas. The accumulation of inflammatory cells at granuloma formation sites appears to be the result of both in situ proliferation and redistribution of the peripheral blood to the lung. Alterations in regula­ tory T cells and TH17 cells may also play a role in the body’s inability to control the inflammation. Although most patients with sarcoidosis eventually recover, the critical step as to why some patients with sar­ coidosis transition to fibrosis is not understood. CLINICAL PRESENTATION The clinical presentation of patients varies considerably from asymp­ tomatic to progressive organ dysfunction. Acute-onset presentation is seen in Löfgren syndrome in up to 10% of sarcoidosis cases (fever, erythema nodosum, ankle arthralgias, bilateral hilar lymphadenopa­ thy) and, less commonly, Heerfordt syndrome (facial nerve palsy, fever, anterior uveitis, and bilateral enlargement of the parotid glands). These acute presentations typically have an excellent prognosis with full spontaneous resolution. In subacute or chronic cases, symptoms such as chronic cough, dyspnea, atypical chest pain, or intermittent joint or muscle pain tend to have a more insidious onset. In rare cases, presentation of sarcoidosis can be fatal, usually related to heart failure, sudden cardiac death, or neurologic involvement. Symptoms vary depending on organ involvement and intensity of inflammatory response; therefore, patients can present to different clinical specialists. Nonspecific symptoms of fevers, malaise, night sweats, and weight loss are often present. More fulminant and organthreatening symptoms can include acute hypercalcemia, blindness, arrhythmias, heart block, or neurologic demise, necessitating hospi­ talization. Cardiopulmonary symptoms such as cough, chest pain, or shortness of breath can mimic more common diseases, contributing to delays in diagnosis. In many cases, findings of sarcoidosis are found incidentally on imaging, prompting further workup. ESTABLISHING A DIAGNOSIS The diagnosis of sarcoidosis is made using three main criteria: (1) a compatible clinical presentation, (2) the presence of nonnecrotizing granulomatous inflammation in one or more tissues, and (3) exclusion of alternative causes of granulomatous inflammation. The diagnostic workup for sarcoidosis should also include assessment of extent and severity of organ involvement, a review of prognostic factors, and a determination of whether therapy will benefit the patient. If a compatible clinical picture or radiographic finding suggests sarcoidosis, then biopsy should be considered as the next step. There are no well-established, clinically useful diagnostic serum biomarkers that can secure a diagnosis. Noninvasive sites for biopsy can include A B C FIGURE 379-2  Comparison of granulomas. (A) The sarcoidosis granuloma is tightly formed and nonnecrotizing. (B) The infectious granuloma as seen in tuberculosis or fungal infections is tightly formed but with a necrotizing center. (C) The granuloma in hypersensitivity pneumonitis is loosely formed and without necrosis. skin, conjunctiva, or superficial lymph nodes, but in cases where lung involvement and mediastinal/hilar lymphadenopathy are the promi­ nent feature, bronchoscopy is the preferred method for diagnosis. Endobronchial ultrasound-guided lymph node sampling has high diagnostic yield and low procedural risk. BAL studies of lymphocyte subpopulations can be performed and characteristically reveal an elevated percentage of lymphocytes. A CD4:CD8 lymphocyte ratio >3.5 supports a diagnosis of sarcoidosis, particularly when combined with consistent clinical and radiographic findings (albeit a normal ratio does not exclude sarcoidosis). BAL is also important to exclude infection. Granulomas can line all segments of airway walls, providing the “cobblestone” appearance seen during bronchoscopy. If needed, transbronchial lung tissue biopsies can also be done to confirm sar­ coidosis with lung infiltrates. Endoscopic ultrasound through the esophagus can be considered as an alternative biopsy approach based on clinical presentation and location of inflammation. Rarely, surgical lung biopsy or mediastinoscopy may be indicated when less invasive procedures have proven nondiagnostic and no other accessible sites for biopsy have been identified. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)–computed tomography (CT) can also be helpful to identify active tissue inflammation and a site to biopsy in difficult cases. CHAPTER 379 Sarcoidosis In some cases, the clinical presentation can be so compelling that lymph node sampling may not be necessary. For example, this can occur in patients with classic Löfgren syndrome, Heerfordt syndrome, or lupus pernio. Similarly, deferring biopsy in asymptomatic patients with symmetrical bilateral hilar lymphadenopathy may be considered based on patient-oriented discussions. In all cases, however, close clini­ cal follow-up is still recommended, as the diagnosis of sarcoidosis is never fully secure. PATHOLOGY The sarcoidosis granuloma is an organized collection of macro­ phages, epithelioid cells, and multinucleated giant cells (which form as the epithelioid cells fuse). These cells are surrounded by a wellcircumscribed rim of lymphocytes and fibroblasts. CD4+ T lympho­ cytes are also found interspersed within the granuloma center, while CD8+ T lymphocytes and B lymphocytes reside at the periphery. Sarcoidosis granulomas are nonnecrotizing; however, punctuate necrosis may be present on rare occasions. More abundant necrosis strongly indicates alternative causes of granulomatous inflammation such as infection, and loosely formed nonnecrotizing granulomas would suggest an alternative diagnosis such as hypersensitivity pneu­ monitis (Fig. 379-2). Additionally, inclusions occasionally appear in sarcoidosis granulomas; these can include asteroid bodies, birefrin­ gent calcium carbonate or oxalate crystals, Schaumann bodies, and Hamazaki-Wesenberg bodies (especially in lymph nodes). Although most inflammatory granulomas tend to resolve, hyalinization and fibrosis of the granulomas can occur. TABLE 379-1  Common Exclusionary Causes of Granulomatous Disease in the Diagnosis of Sarcoidosis OTHER INFLAMMATORY DISEASES MALIGNANCY RELATED INFECTIONS Mycobacterial infection • Tuberculosis • Atypical Environmental exposure • Hypersensitivity Malignancy • Local PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders pneumonitis • Aspiration pneumonitis • Chronic beryllium disease • Silicosis • Talc inhalation or injection • Local or systemic reaction granulomatous reaction surrounding tumor • Systemic sarcoidmycobacteria Fungal infection • Histoplasmosis • Coccidiomycosis • Blastomycosis • Aspergillosis • Cryptococcus Parasitic infection • Toxoplasmosis • Schistosomiasis Other bacterial and viral infection (less common) • Herpes zoster • Tularemia (Francisella like reaction to malignancy Chemotherapy or immunotherapy • Sarcoid-like to tattoo ink Medication sarcoid-like reaction • Immune checkpoint reaction inhibitors • Antiretroviral therapy • Interferon • TNF-α antagonist Autoimmune/Inflammatory • ANCA-associated vasculitis • Granulomatous-lymphocytic tularensis) • Q fever (Coxiella interstitial lung disease (associated with common variable immunodeficiency) • IgG4-related disease • Rheumatoid nodules • Inflammatory bowel disease • Bronchocentric burnetii) • Bartonella henselae granulomatosis Abbreviations: ANCA, antineutrophil cytoplasmic antibodies; TNF, tumor necrosis factor. A histopathologic examination of the involved organ tissue reveals granulomas in sarcoidosis; however, diagnosis heavily relies on exclu­ sion of other causes of granulomas. The differential diagnosis can be broad and must be considered in the clinical context (Table 379-1). A careful history assessment for environmental exposures or other inflammatory diseases is imperative to secure confidence in the diag­ nosis of sarcoidosis. Infections can be difficult to differentiate from sarcoidosis and require special histologic stains and cultures. Necro­ tizing sarcoidosis granulomatosis, characterized by necrosis, is a rare and less well-established entity that often involves vasculitis. Given the numerous causes of granulomatous inflammation and disease mimics, the diagnosis of sarcoidosis is never made with absolute certainty, and new symptoms or signs that occur during the disease process should be fully evaluated. DIAGNOSTIC EVALUATION The initial evaluation of sarcoidosis patients includes a complete his­ tory and physical exam, as well as assessment of organ involvement and severity of disease. Once diagnosis is suspected, a full review of symptoms is warranted to elucidate any potential pulmonary and extrapulmonary involvement, as about half of patients will have extrapulmonary involvement. Almost every organ system in the body can be affected by sarcoidosis (Fig. 379-3). A baseline set of testing (at minimum) should be done in all patients on initial evaluation, including pulmonary function tests, chest imaging, a baseline oph­ thalmologic investigation to evaluate for clinically silent uveitis, and an electrocardiogram (ECG) (Table 379-2). Serum tests for abnormal calcium metabolism and any significant hepatic, renal, or hematologic involvement should also be performed. Hematologic abnormalities are frequent and can be attributed to redistribution of T cells to sites of disease, splenic sequestration, granulomatous bone marrow involve­ ment, or immune mediation. Routine asymptomatic follow-up testing is more controversial regarding its utility, but repeat testing should be Neurologic: 5% Eyes: 12% Salivary/Parotid Glands: 4% Ear/Nose/Throat: 3% ä Calcium: 4% Peripheral Lymph Nodes: 15% Lungs: 95% Heart: 2% Liver: 12% Spleen: 7% Kidneys: 1% Skin: 16% Bones/Joints/ Muscles: 1% FIGURE 379-3  Frequency of organ involvement in sarcoidosis. Organ involvement upon presentation. (RP Baughman et al: Am J Respir Crit Care Med 164:1885, 2001.) done to evaluate the onset of any new signs or symptoms as the disease evolves. Abnormal initial testing may require further workup. ORGAN INVOLVEMENT ■ ■LUNGS The lungs are involved in >90% of patients with sarcoidosis. Pulmo­ nary function tests are important to measure initial lung impairment and to assess improvement or deterioration over time. Many patients have normal lung function testing or a normal lung exam despite the presence of granulomatous inflammation and abnormal imag­ ing findings. A restrictive pattern is often seen in those with more TABLE 379-2  Baseline Testing upon Initial Diagnosis of Sarcoidosis Full history, review of systems, physical exam Pulmonary function testing Chest imaging Eye exam Serum creatinine, alkaline phosphatase, calcium level, complete blood counts 25- and 1,25-hydroxyvitamin D levels if assessing vitamin D metabolism Electrocardiogram Note: Further testing is dependent upon signs or symptoms indicating potential organ involvement. advanced disease, and airflow obstruction can occur in up to one-third of patients. Sarcoidosis tends to be upper-lobe predominant on lung imaging. Chest x-rays are classically used to “stage,” or describe the pattern of presentation in the lungs, known as Scadding stages (Fig. 379-4). Although chest CT is not indicated in every patient, it is commonly performed to determine extent of lung disease and to guide biopsies. Sarcoidosis granulomas have a lymphangitic distribution in the lung along the pleural and subpleural areas and interlobular septa and around the bronchovascular bundles. Classic findings of sarcoidosis on chest CT scans are widespread small nodules with a bronchovascular and subpleural distribution (Fig. 379-5A, B), thickened interlobular septa, mediastinal and hilar lymphadenopathy, and conglomerate masses with architectural distortion (Fig. 379-5C). In advanced cases of pulmonary involvement, CT findings include honeycombing, cyst or cavity formation, and bronchiectasis. Nodular sarcoidosis or nec­ rotizing sarcoid granulomatosis can present with nodular masses. Pleural effusions tend to be indirectly related (e.g., infections, heart failure), but rarely, sarcoidosis can cause lymphocytic, exudative STAGE 1: Bilateral hilar lymphadenopathy without parenchymal lung involvement STAGE 2: Bilateral hilar lymphadenopathy and parenchymal lung involvement STAGE 3: Parenchymal lung involvement without lymphadenopathy STAGE 4: Pulmonary fibrosis with architectural distortion and volume loss FIGURE 379-4  Scadding stages in sarcoidosis.   pleural effusions. Upper respiratory tract involvement can also occur rarely within the larynx, pharynx, and sinuses and is associated with more chronic severe disease. Progressive pulmonary fibrosis with irreversible scarring is a sig­ nificant cause of complications and death in patients with sarcoidosis. Fibrosis can be complicated by cavitary lung disease, chronic pul­ monary aspergillosis or aspergillomas, and pulmonary hypertension. Airflow obstruction is common in these patients due to central airway scarring and distortion of the lung structure. Fibrosis can occur even in the setting of anti-inflammatory therapy. CHAPTER 379 Sarcoidosis ■ ■HEART Granulomas can infiltrate any part of the heart, causing rhythm abnor­ malities, heart failure, pericardial effusion, and even sudden death. In the broader general population, cardiac sarcoidosis is the cause of a significant proportion of cases of new-onset atrioventricular block, cardiomyopathy, and ventricular dysrhythmias, particularly in younger age groups. Clinical evidence of cardiac involvement in patients with RESOLUTION RATE: 55–90% 40–70% 10–20% 0% PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders A B C FIGURE 379-5  Imaging findings in sarcoidosis. (A and B) Chest computed tomography images of sarcoidosis show widespread small nodules in a perilymphatic and subpleural distribution and prominent bronchovascular bundle thickening. (C) Large peribronchovascular mass-like consolidations extending along the hila along with partially calcified mediastinal and hilar lymphadenopathy in a patient with sarcoidosis. known sarcoidosis is found in <5% of U.S. sarcoidosis patients and 23% of Japanese patients, although autopsy studies suggest a higher rate of subclinical involvement. Severity of pulmonary involvement does not appear to predict the presence of cardiac sarcoidosis, and therefore every patient should be queried for potential cardiac symptoms, as cardiac sarcoidosis can have life-threatening complications. Isolated cardiac sarcoidosis can also rarely occur. Sudden death is the most common cause of death among cardiac sarcoidosis patients, and it can occur as the initial presentation of the disease. Ventricular tachycardia is the most frequent tachyarrhythmia, but atrial tachycardias are also found in relation to ventricular dysfunc­ tion, dilated atria, or severe pulmonary disease. Heart failure is most often due to involvement of the myocardium but can also be caused by infiltration of valves or papillary muscles. Predictors of sudden death include severity of heart failure, left ventricular end-diastolic diameter, and sustained ventricular tachycardia. Diagnosis of cardiac sarcoidosis can be difficult, since gold-standard biopsies lack sensitivity due to the patchy presence of granulomas in cardiac tissue, predominant location at base of the heart, and the lack of right ventricular involvement. ECG should be obtained on initial evaluation of every patient with sarcoidosis to reveal the presence of any conduction block, ST-T wave abnormalities, Q waves, frequent premature ventricular complexes, or resting tachycardia. Symptoms or unexpected abnormalities on ECG should prompt further cardiac evaluation, which can include a Holter monitor, signal-averaged ECG, or further cardiac imaging. Several imaging tests are used for evaluating and diagnosing cardiac sarcoidosis. Historically, thallium-201 scintigraphy or technetium-sestamibi single-photon emission CT nuclear scans have been used to identify segmental defects that correspond either to a granulomatous disease or a fibrous scar. In contrast to coronary artery disease, patients with cardiac sarcoidosis have perfusion defects that reverse with exercise or dipyri­ damole, termed reverse redistribution. More current imaging studies now support the use of enhanced cardiac magnetic resonance imaging (MRI) as a preferred diagnostic tool due to its superior resolution and ability to detect early myocardial involvement with high sensitivity and specificity. Cardiac PET/CT can also be used in some cases to detect the presence of active inflammation in cases where cardiac MRI is unavailable, unable to be done (noncompatible devices or claustrophobia), or inconclusive. The use of these imaging techniques has largely obviated the need for myocar­ dial biopsy in the diagnosis of cardiac involvement. In patients with rhythm disturbances, prompt referral to an electrophysi­ ologist is warranted for consideration of potential mapping or implantation of cardiac devices. Echocardiography can help identify ventricular dysfunc­ tion, valve dysfunction, abnormal septal wall thickness, or wall motion abnormalities that may also be contributing to the clinical picture. Traditional treatments for cardiac arrhythmias and heart failure are indicated depending on the presentation, as well as immunosuppres­ sive medications. The optimal amount of time dedicated to the course of immunosuppressive therapy is unclear, although the presence of cardiac sarcoidosis generally portends a more chronic and protracted course. Serial imaging and response to therapy can help guide potential therapy duration. Heart transplantation can be considered for refractory severe cardiac sarcoidosis, resulting in better short- and intermediateterm survival rates as compared to other transplant recipients. ■ ■PULMONARY ARTERY HYPERTENSION Pulmonary hypertension (PH) in sarcoidosis, classified as a World Health Organization group 5 cause of PH, can complicate the clinical course and contribute significantly to morbidity and mortality. Pulmo­ nary hypertension in sarcoidosis may be due to granulomatous vascu­ litis, pulmonary arterial occlusion by lymphadenopathy, thrombosis, pulmonary venous occlusion, destruction of the vascular bed, left heart dysfunction due to myocardial involvement, portopulmonary hyper­ tension from associated liver cirrhosis, or hypoxic vasoconstriction related to parenchymal abnormalities. In some cases, precapillary PH can occur in the absence of other cardiopulmonary disease, resembling idiopathic PH. Evaluation for PH should be sought in patients who have symptoms that are disproportionate to the amount of parenchy­ mal disease, have extensive parenchymal abnormalities, desaturate on 6-min walk test, or have a low diffusing capacity. Echocardiography is a useful noninvasive technique screening test to evaluate pulmonary pressures, systolic or diastolic function, and val­ vular disease; however, right heart catheterization is the gold standard for diagnosis. Treating granulomatous disease with corticosteroids may result in the improvement of pulmonary pressures in some, but not all, cases, and pulmonary vasodilator therapy can be considered on a case-by-case basis. ■ ■NERVOUS SYSTEM INVOLVEMENT Sarcoidosis affecting the nervous system is highly associated with systemic disease but also can occur in the absence of significant pul­ monary or systemic disease. Cranial nerve involvement, particularly with the facial and optic nerves, is the most common manifestation and can be a result of granulomatous basal meningitis or direct involve­ ment of the nerve. Facial nerve palsy is associated with good prognosis compared to other neurologic findings. Neurosarcoidosis has a predi­ lection for the base of the brain. Inflammation of the hypothalamus and pituitary gland can cause neuroendocrine abnormalities that can persist even after immunosuppressive treatment. Other findings can include space-occupying masses, acute or chronic meningitis, periph­ eral neuropathy, and neuromuscular or spinal cord involvement. Rare presentations include seizures or neuropsychiatric symptoms. Gadolinium-enhanced MRI is the preferred test for evaluating brain parenchyma, meninges, dura, and the spinal cord. MRI findings of leptomeningeal or parenchymal enhancement or multiple white matter lesions in a periventricular distribution are the more common abnor­ malities and are sensitive diagnostic findings. However, the appearance of sarcoidosis lesions is often nonspecific, mimicking malignancies or infections. Chest imaging can be helpful in diagnosis since many patients will have a pulmonary abnormality that can be biopsied. Cerebrospinal fluid (CSF) analysis most often reveals mononuclear cell pleocytosis and/or elevated proteins. Elevated CSF angiotensinconverting enzyme, high soluble IL-2 receptor, increased lysozyme, decreased glucose, and oligoclonal bands can also be seen but are not diagnostic. CSF analysis is important to help exclude infection. Histo­ logic confirmation of disease in the brain or spinal cord is occasionally necessary when significant diagnostic uncertainty exists or a patient is not responding to therapy. Otherwise, a diagnosis can be established with an acceptable degree of certainty by biopsy of a nonneurologic site, such as the lung, together with consistent clinical features and imaging and exclusion of other causes. Peripheral nerves can also be affected in sarcoidosis. Pain is a common symptom among sarcoidosis patients and may be related to neuropathic or fibromyalgia syndromes. Small-fiber neuropathy has increasingly been noted to be a cause of pain and autonomic dysfunc­ tion. Large-fiber neuropathies can be evaluated by performing nerve biopsy or nerve conduction studies. Unfortunately, pain syndromes, regardless of their underlying cause, often do not respond well to immunosuppressive medications. ■ ■CUTANEOUS Sarcoidosis causes many forms of skin lesions, with maculopapular, nodular eruptions and plaques being the most common types involv­ ing granulomatous inflammation of the tissue itself. Other skin lesions include infiltration of old scars or tattoos, hypo- and hyperpigmented areas, scales, annular lesions, ulcerations, and subcutaneous nod­ ules or masses. Most of the time, lesions are not painful or pruritic. Nonspecific, nongranulomatous lesions of erythema nodosum are a well-established manifestation of sarcoidosis, commonly found in Europeans and women. Lesions are raised, tender, erythematous bumps or nodules found on the anterior legs and often a prominent feature of Löfgren syndrome. Lupus pernio is a distinctive chronic lesion and consists of indurated plaques and violaceous discoloration of the nose, cheeks, lips, and ears, and frequently involves the nasal mucosa (Fig. 379-6). This lesion appears most commonly among members of the African-American female population. Lupus pernio is often associated with more severe disease including bone cysts, pulmo­ nary fibrosis, and a prolonged clinical course. Overall, skin lesions can be treated with topical or injected corticosteroids, although disfiguring or symptomatic lesions may need systemic therapy. ■ ■EYE INVOLVEMENT Ocular sarcoidosis can affect any part of the eye or orbit, with clinical manifestations ranging from asymptomatic to permanent vision loss. Given the potential for permanent vision loss, ophthalmologic exami­ nation is recommended on initial exam in sarcoidosis patients and with any change in visual symptoms. Uveitis (anterior, posterior, or panuve­ itis) is the most common manifestation and is often bilateral. Chronic uveitis may lead to synechiae formation, glaucoma, cataracts, cystoid macular edema, and blindness. Optic neuropathy can lead to sudden permanent vision loss and should be treated as an emergency with immediate initiation of immunosuppressive therapy. Other eye lesions FIGURE 379-6  Cutaneous sarcoidosis. Extensive involvement of the nose and philtrum extending onto the cheeks is seen. The lesions include confluent papules and plaques, some of which are vaguely annular on the philtrum. (Courtesy of Dr. Misha Rosenbach, MD.) include conjunctival or eyelid granulomas, lacrimal gland enlarge­ ment, keratoconjunctivitis sicca, dacryocystitis, retinal vasculitis, and periorbital swelling. If conjunctival nodules are present, biopsy can be a relatively noninvasive way to obtain diagnostic tissue. CHAPTER 379 ■ ■LIVER Hepatic granulomas are found very frequently in patients with pulmo­ nary sarcoidosis (up to 80% in some autopsy studies) but are much less often clinically significant (up to 15%). Conversely, hepatic sarcoidosis can occur without involving the lungs. Liver function tests are abnor­ mal in up to one-third of sarcoidosis cases, with an elevated alkaline phosphatase as the most common lab abnormality. Elevated trans­ aminases are also frequent, while elevated bilirubin levels are more indicative of significant progressive sarcoidosis liver disease. Hepato­ megaly is commonly seen. Patients who do present with symptoms experience abdominal pain, pruritus, fevers, weight loss, and jaundice. Hepatic sarcoidosis can infrequently progress to chronic cholestasis, hepatocellular disease, portal hypertension, Budd-Chiari syndrome, or cirrhosis. The pattern of presentation depends on the extent and location of granulomatous inflammation and fibrosis in the liver. Imag­ ing of the liver often shows hepatomegaly and/or small, innumerable nodules of low attenuation. Extensive evaluation of alternative causes should be performed when cases of isolated hepatic granulomas are involved, because liver granulomas are associated with a large differ­ ential diagnosis. Immunosuppressives may be effective when a patient experiences symptomatic liver dysfunction, but not in every case. Liver transplantation remains a viable option when hepatic failure occurs. Sarcoidosis ■ ■MUSCULOSKELETAL Acute arthritis (such as that seen in Löfgren syndrome) is common in sarcoidosis, especially early in the course of disease. Pain is a potential indication to treat. Chronic arthritis or synovitis is rarer than the acute presentations. The most common joints affected by sarcoidosis are the ankles, knees, elbows, wrists, and small joints of the hands and feet. Bone lesions, characteristically identified as lacy, reticular osteolytic lesions on radiographs, can be frequently asymptomatic but occasion­ ally cause pain. Bone marrow involvement can cause hematologic abnormalities such as anemia and lymphopenia. Cases of symptomatic muscle involvement present with pain, ten­ derness, or weakness and have physical findings that are consistent with myositis, chronic myopathy, or muscle nodules. Myopathy is more commonly found in women and can be the sole presentation of disease. MRI or nuclear bone scans are useful to identify active inflammation in patients with musculoskeletal symptoms or to differentiate nonsarcoid­ osis causes. Electromyogram studies and biopsy may also be helpful in the diagnostic workup. ■ ■HYPERCALCEMIA Hypercalcemia occurs in only about 10–20% of patients with sarcoid­ osis, but hypercalciuria is much more frequent and is seen in up to 50% of patients. High calcium levels are due to dysregulated production of the active form of vitamin D (1,25-hydroxyvitamin D3 or calcitriol) by activated macrophages and granulomas in the setting of abundant cytokines such as IFN-γ. Normally, conversion of vitamin D to its active form is a highly regulated process that occurs in the kidney via the action of 1-alpha-hydroxylase (CYP27B1) controlled by parathy­ roid gland. The conversion of vitamin D to calcitriol by macrophages occurs unregulated, causing increased intestinal absorption and bone resorption and thereby raising serum calcium despite low parathyroid hormone levels. Hypercalcemia, left untreated, leads to nephrocal­ cinosis and subsequent renal dysfunction. Patients with evidence of hypercalcemia should monitor vitamin D intake, avoid excessive sunlight, and maintain hydration. In severe acute symptomatic cases, hypercalcemia is a cause of hospital admission requiring more urgent corticosteroid therapy. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders ■ ■KIDNEY Renal dysfunction is mostly related to hypercalcemia and nephrocal­ cinosis associated with sarcoidosis, rather than direct granulomatous infiltration. However, sarcoidosis can cause interstitial nephritis (with and without granulomas), which is generally responsive to treatment. Urinalysis usually reveals sterile pyuria, bland sediment, or mild proteinuria. ■ ■LYMPHOID SYSTEM Peripheral lymphadenopathy can be the presenting sign of sarcoid­ osis in a minority of cases. The extrathoracic glands most frequently involved are the cervical, axillary, epitrochlear, and inguinal glands. Enlarged glands are discrete, movable, and nontender without ulcer­ ation or drainage. Splenomegaly in sarcoidosis is common but is usually clinically silent. Hypodense nodules can be seen on imag­ ing. Infrequently, splenic involvement may cause pressure, pain, constitutional symptoms, or hematologic abnormalities that require splenectomy. ■ ■PAROTID GLANDS Parotid or salivary involvement occurs in 4% of sarcoidosis patients, often associated with Heerfordt syndrome (parotitis, uveitis, fever, facial palsy). Patients with parotid gland involvement can be asymp­ tomatic or present with painful, swollen glands or xerostomia. Parotid enlargement is self-limiting in many cases and can present like Sjögren’s syndrome. ■ ■GASTROINTESTINAL TRACT Gastrointestinal tract involvement is a rare manifestation of sarcoid­ osis and most commonly involves the stomach than any other parts. Patients may present with dysphagia, bleeding, nausea or vomiting, pain, weight loss, or obstructive symptoms. ■ ■REPRODUCTIVE ORGANS Granulomas may occur in the reproductive system, most commonly appearing within the female uterus or the male epididymis. Given the rarity of involvement, any new nodules or masses in these organs require careful attention to exclude malignancy. CLINICAL COURSE AND PROGNOSIS In just over half of patients, the disease resolves spontaneously; how­ ever, a significant proportion (30–40%) of patients will have chronic disease that threatens vital organs or causes debilitating symptoms, necessitating treatment. Chronic symptoms can be progressive or waxing and waning. Predicting clinical course on presentation in any one individual is difficult, given lack of known prognostic biomarkers. Research studies are often confounded by the variable clinical course and the lack of correlation of serum and radiographic measures to the intensity of granulomatous response. Most cases of sarcoidosis will show improvement in chest radiography or spirometry after 2 years of follow-up, including treated and untreated. Serious extrapulmonary involvement (e.g., cardiac, central nervous system, hepatic) occurs in 4–7% of sarcoidosis patients at presentation and can develop as the disease evolves. Relapses are common and are associated with shorter treatment duration. Acute exacerbations of pulmonary sarcoidosis are thought to occur in over one-third of patients, although they are not well-defined. Death related to sarcoidosis itself does occur in 1–5% patients because of progressive respiratory insufficiency, complications of pulmonary scarring (e.g., hemoptysis, infection, aspergilloma), central nervous system involvement, liver failure, or myocardial involvement (heart failure, cardiac block, sudden cardiac death, or arrhythmias). Differing mortality rates reflect variances in disease severity, referral bias, and diverse genetic and epidemiologic factors of the populations studied. For instance, most deaths occurring in the United States and Northern Europe are due to pulmonary complications, whereas a vast majority of deaths due to sarcoidosis in Japanese patients are from cardiac involvement. Complications of immunosuppressive therapies can also contribute indirectly to mortality. Transplantation of the lungs, heart, liver, or kidneys can be lifesaving in severe progressive cases. ■ ■CLINICAL FACTORS OF PROGNOSTIC SIGNIFICANCE Overall, patients with a more robust initial immune response have a better prognosis than those with more subacute or chronic presentation. Patients that present with Löfgren or Heerfordt syndromes tend to have an excellent prognosis with spontaneous remission in up to 80%. Löfgren syndrome occurs in 20–30% of Caucasians with sarcoidosis, particularly Northern Europeans, and <5% of Asians and African Americans. Ery­ thema nodosum and fever usually remit spontaneously within 6 weeks, while resolution of lymphadenopathy may be delayed for over a year. Immunosuppressive therapy is rarely necessary. On the other hand, adverse clinical prognostic factors include lupus pernio, chronic uveitis, older age, chronic hypercalcemia, nephrocalcinosis, African origins, pulmonary hypertension, fibrotic pulmonary sarcoidosis, sinus involve­ ment, cystic bone lesions, neurosarcoidosis, and cardiac involvement. Parenchymal infiltrates associated with Scadding radiographic stages do not predict activity, progression of lung disease, or extrapulmonary involvement but do reveal overall resolution rates (Fig. 379-4). ■ ■PREDICTIVE VALUE OF SERUM, BRONCHOALVEOLAR LAVAGE, AND GENETICS There are no current clinically used biomarkers that can predict clinical course in any one case. Serum angiotensin-converting enzyme (ACE) levels, derived from macrophages, are not largely useful as a diagnostic or prognostic tool due to low sensitivity. However, ACE levels have been employed to monitor systemic disease activity, as they correlate roughly with the granulomatous burden. Similarly, the T-cell–derived soluble IL-2 receptor lacks sensitivity for diagnosis but correlates with disease activity and may predict relapse rate. In BAL fluid, the high CD4:CD8 ratio, although supporting a diagnosis, does not correlate with disease progression or need for treatment, but higher values seem to implicate a better overall prognosis. Increased percentages of BAL neutrophils (or eosinophils) appear to be present in a higher propor­ tion of individuals with progression. In genetics, certain human leu­ kocyte antigen (HLA) haplotypes have been associated with acute and chronic phenotypes. Similarly, variants of butyrophilin-like 2 (BTNL2), tumor necrosis factor alpha (TNF-α), and annexin A11 (ANXA11) genes have been associated with worse prognosis. Unfortunately, these and multiple other serum and BAL markers lack generalizability and utility in the clinical realm for any one individual. FOLLOW-UP AND MONITORING To assess prognosis and determine the need for therapy, longitudinal surveillance of sarcoidosis should be most intensive during the 2-year period following presentation with decreasing frequency as time goes on. When therapy has started, follow-up of response and side effects should be done in 1–3 months and, once stable on therapy, every 3–6 months. Once in full remission, patients should be followed for a few years to assess for relapses; however, lengthier observation may be necessary based on severity of disease or residual organ dysfunction. Follow-up testing should include symptoms, a complete physical exam, imaging of affected organs, periodic pulmonary function testing, and markers of specific organ dysfunction. Choice of imaging depends on clinical scenario and can include chest x-rays, CT scans, and in some rarer cases, PET/CT or MRI. Any development of new symptoms over time should prompt full evaluation of that organ system. TREATMENT Sarcoidosis Treatment decisions in sarcoidosis are complex, and medication options tend to be guided by expert opinion, uncontrolled trials, and only a few larger randomized controlled trials. There is no cure for sarcoidosis; the goal of treatment is to suppress granu­ lomatous inflammation, prevent irreversible organ fibrosis, and alleviate debilitating symptoms as the disease evolves. With the high side effect profile of corticosteroids and other immunosup­ pressive therapy, it is first important to identify those cases in which therapy is indicated. For example, treatment is not indicated for asymptomatic stage I disease, which has an inherent high rate of spontaneous resolution. Mild symptoms may be closely monitored, and topical immunosuppressive therapies are preferred for skin disease if possible. Oral immunosuppressive therapy should be reserved for those who have significant symptoms, disfigurement, or dangerous impending organ damage. In pulmonary disease, this may include worsening cough and shortness of breath, moderate to severe parenchymal lung involvement, or a progressive decline in pulmonary function. In each case of sarcoidosis, the risks and toxicity of immunosuppression must be considered in comparison to the potential benefit of treatment. Corticosteroids remain the mainstay of first-line treatment, although controversy exists regarding whether they alter the natural history. Oral steroids have been shown to improve chest x-ray imag­ ing scores, symptoms, and spirometry in the short term. There are limited data beyond 2 years to indicate whether oral steroids have any modifying effect on long-term disease progression or mortal­ ity. In cases of intolerance or toxicity to corticosteroids, inability to taper corticosteroids, or refractory disease, alternative steroidsparing immunosuppressives can be considered (Table 379-3). In TABLE 379-3  Treatments for Sarcoidosis DRUG NAME DOSE RANGE CONSIDERATIONS Initial therapy Corticosteroids (prednisone, prednisolone) 20–40 mg/d initial, tapered to 7.5–15 mg/d Consider taper early based on clinical improvement Monitor bone health Consider implications of weight gain Assess risk of diabetes Monitor eye exams (glaucoma and cataracts) Common second-line therapies Methotrexate 7.5–20 mg/wk orally or subcutaneously Concurrent administration with folic acid Monitor liver and renal function and blood counts Contraindicated with significant alcohol use Leflunomide 10–20 mg/d Monitor liver and renal function and blood counts In cases of toxicity, consider cholestyramine to accelerate clearance Azathioprine 50–200 mg/d or 1–2 mg/kg/d Mycophenolate 1000–3000 mg/d Monitor blood counts Enteric-coated option available (note: different dose range) Hydroxychloroquine 200–400 mg/d Periodic eye exams for retinopathy Assess QT (monitor drug interactions) Effective for skin or hypercalcemia, but not for pulmonary Refractory disease or inability to taper corticosteroids Infliximab 3–5 mg/kg intravenously at weeks 0 and 2, and then every 4–8 weeks Adalimumab 40 mg subcutaneous every 1–2 weeks (exact dose unknown) choosing a therapy, clinicians should take into consideration the presence of comorbid conditions such as osteoporosis, diabetes, cataracts, or glaucoma that may be aggravated by corticosteroids. Organ transplantation is occasionally necessary in cases of progres­ sive organ damage including lungs, liver, heart, and kidney. Sarcoid­ osis can recur in transplanted organs but is rarely a cause of organ failure after transplant. CORTICOSTEROIDS When it is determined that treatment is indicated, corticosteroids are generally used as first-line therapy given efficacy and ease of use. Generally, prednisone or an equivalent corticosteroid is started at 0.5 mg/kg per day or ~20–40 mg/d for 4 weeks, and then reduced to a maintenance dose that will control symptoms and disease progression, ideally below 10 mg/d. Higher starting doses are not largely effective in most cases of sarcoidosis and are associated with increased morbidity. Lower induction doses can be considered based on severity of presentation, side effect tolerance, and rate of disease progression. More aggressive therapeutic approaches with higher doses or in association with other immunosuppression can be considered in life- or organ-threatening situations such as seen in central nervous system involvement, ocular involvement leading to vision loss, or extensive myocardial inflammation. In a subgroup of cases with very mild pulmonary symptoms such as cough, inhaled corticosteroids may be considered for symptom control but have not been shown to be of benefit in the larger sarcoidosis population. CHAPTER 379 Sarcoidosis STEROID-SPARING THERAPIES As the landscape of drug development broadens, treatment options have expanded beyond corticosteroids to include several antiinflammatories drawn from treatment of other rheumatologic con­ ditions (Table 379-3). The choice of steroid-sparing agent often depends on several clinical factors (e.g., alcohol use, desire for pregnancy, known pharmacogenetic profiles, comorbidities such as liver or renal dysfunction), but methotrexate is the most recom­ mended second-line therapy due to its efficacy and favorable side effect profile. Azathioprine appears to be equally effective, although Monitor liver and renal function and blood counts Consider thiopurine methyltransferase activity level Tuberculosis screening prior to use Avoid use in heart failure Allergic reactions possible with infusion Longer term association with demyelination syndrome and malignancy Can induce sarcoid-like reactions Similar precautions and adverse events as infliximab # 23 - 380 IgG4-Related Disease ### 380 IgG4-Related Disease potentially has higher rates of infectious complications. Other medications that can be considered second-line treatment include leflunomide or mycophenolate mofetil. Hydroxychloroquine can also be an effective immunomodulator, particularly for skin disease or hypercalcemia, but is not recommended for lung disease. If all second-line therapies have been exhausted due to intoler­ ance, inefficacy, or inability to taper corticosteroids, tumor necrosis factor (TNF) inhibitors can be considered. TNF-α is produced by the activated macrophages of the granuloma and contributes to propagation of inflammation in sarcoidosis. Infliximab and adali­ mumab are monoclonal antibodies that target TNF-α. Infliximab has garnered the most supporting data, with randomized controlled trials and larger case series showing positive effects on pulmonary function, imaging, and inflammatory cytokine levels, particularly in those with more severe disease. Adalimumab has shown efficacy in smaller series, particularly in ocular sarcoidosis. Etanercept, on the other hand, a TNF receptor antagonist, has been shown to be ineffective for sarcoidosis and should not be used for treatment. Other therapies targeting different aspects of the immune response are also considered at times in refractory cases including anti-B-cell therapy and antifibrotic medications. IMMUNOSUPPRESSIVE MONITORING While on immunosuppressive therapy, close attention to preven­ tion of toxicity is important in the care plan, and monitoring should follow published rheumatologic guideline recommenda­ tions. Bisphosphonates should be considered to minimize steroidinduced osteoporosis, and regular eye exams should be obtained with corticosteroid use and hydroxychloroquine. When assessing a medication choice, it is also important to consider pregnancy risk, as many second-line agents have adverse reproductive effects. DURATION OF TREATMENT The exact duration of treatment may differ between individuals based on severity of disease but is ~1 year for most patients. Shorter courses of therapy have been associated with higher relapse rates, although they can be considered for particularly responsive cases. For pulmonary involvement, the greatest amount of improvement is seen within the first weeks to months of therapy; therefore, tapering of corticosteroids to a lower maintenance dose should be considered with early follow-up to minimize long-term toxicity. Longer courses of treatment may be necessary for life-threatening or refractory disease. Relapses are treated with the last known effec­ tive dosing regimen. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders APPROACH TO THE PATIENT Sarcoidosis Comprehensive treatment of the patient with sarcoidosis includes not only suppression of granulomatous inflammation but also consideration of medication side effects and evaluation of fatigue, psychological health, and pain. Up to 80% of patients with sarcoid­ osis experience multifactorial fatigue, which can persist even after treatment and remission. Fatigue can be due to medications, sleep disorders, pain, and the granulomatous inflammation itself. It is associated with extrapulmonary involvement. Neuropathic pain or autonomic dysfunction may require symptomatic care. Formal­ ized physical training has been shown to improve exercise capacity, strength, and fatigue in patients with sarcoidosis. Depression is also highly prevalent in chronic sarcoidosis, associated with female sex, dyspnea, and poor access to care. Cognitive impairment contribut­ ing to decreased quality of life is well-noted but poorly understood. Patient-centered care of the entire constellation of effects of sarcoid­ osis can include neuropsychiatric evaluation, sleep therapy, exercise therapy, pain relief, and lifestyle modifications. An individualized plan is necessary for every patient to address the benefits of antiinflammatory treatments, associated comorbidities, and mainte­ nance of quality of life while living with sarcoidosis. ■ ■FURTHER READING Baughman RP et al: Clinical characteristics of patients in a case con­ trol study of sarcoidosis. Am J Respir Crit Care Med 164:1885, 2001. Baughman RP et al: European Respiratory Society clinical practice guidelines on treatment of sarcoidosis. Eur Respir J 58: 2004079, 2021. Crouser ED et al: Diagnosis and Detection of Sarcoidosis. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 201:e26, 2020. Drent M et al: Challenges of sarcoidosis and its management. N Engl J Med 385:1018, 2021. Judson MA: Environmental risk factors for sarcoidosis. Front Immu­ nol 11:1340, 2020. John H. Stone IgG4-Related Disease IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by a tendency to form tumefactive lesions. The clinical manifestations of this disease, however, are protean, as IgG4-RD can affect virtually any organ system. The disease has a particular predilec­ tion for targeting blood vessels of any size on either the venous or arte­ rial side of the circulation and is therefore regarded as a variable-vessel vasculitis. Commonly affected organs are the pancreas, biliary tree, major salivary glands (submandibular, parotid), periorbital tissues, kidneys, lungs, lymph nodes, and retroperitoneum. In addition, IgG4RD involvement of the meninges, aorta, prostate, thyroid, pericardium, skin, and other organs is well described. The disease affects the brain parenchyma, the joints, the bone marrow, and the bowel mucosa only rarely. The pathologic findings are consistent across all affected organs. These findings include a lymphoplasmacytic infiltrate with a high percentage of IgG4-positive plasma cells; a characteristic pattern of fibrosis termed “storiform” (from the Latin storea, for “woven mat”); a tendency to target blood vessels, particularly veins, through an oblit­ erative process (“obliterative phlebitis”); and a mild to moderate tissue eosinophilia. Although the pathology is consistent from organ to organ, it is essentially never diagnostic in and of itself. Classification criteria emphasize the importance of careful correlation among clinical, sero­ logic, radiologic, and pathologic findings in deciding whether a patient should be classified as having IgG4-RD. Biopsy is not required in order to establish the diagnosis in classic cases, but most patients undergo a biopsy at some point in the evaluation in order to exclude malignancy. IgG4-RD encompasses a number of conditions previously regarded as separate, organ-specific entities. A condition once known as “lym­ phoplasmacytic sclerosing pancreatitis” became the paradigm of IgG4RD in 2000, when Japanese investigators recognized that these patients had elevated serum concentrations of IgG4. This form of sclerosing pancreatitis is now termed type 1 (IgG4-related) autoimmune pancre­ atitis (AIP). By 2003, extrapancreatic disease manifestations had been identified in patients with type 1 AIP, and descriptions of IgG4-RD in other organs followed. Mikulicz’s disease, once considered to be a subset of Sjögren’s syndrome that affected the lacrimal, parotid, and subman­ dibular glands, is one of the most common presentations of IgG4-RD. ■ ■CLINICAL FEATURES The major organ lesions are summarized in Table 380-1. IgG4-RD usually presents subacutely, and even in the setting of multiorgan dis­ ease, most patients do not have fevers or high elevations of C-reactive protein levels. Some patients, however, experience substantial weight loss over periods of months. This is generally because of exocrine TABLE 380-1  Organ Manifestations of IgG4-Related Disease ORGAN MAJOR CLINICAL FEATURES Orbits and periorbital tissues Painless eyelid or periocular tissue swelling; orbital pseudotumor; dacryoadenitis; dacryocystitis; orbital myositis; and mass lesions extending into the pterygopalatine fossa and infiltrating along the trigeminal nerve Ears, nose, and sinuses Allergic phenomena (nasal polyps, asthma, allergic rhinitis, peripheral eosinophilia); nasal obstruction, rhinorrhea, anosmia, chronic sinusitis; occasional bone-destructive lesions Salivary glands Submandibular and/or parotid gland enlargement (isolated bilateral submandibular gland involvement more common); minor salivary glands sometimes involved Meninges Headache, radiculopathy, cranial nerve palsies, or other symptoms resulting from spinal cord compression; tendency to form mass lesions; magnetic resonance imaging (MRI) shows marked thickening and enhancement of dura Hypothalamus and pituitary Clinical syndromes resulting from involvement of the hypothalamus and pituitary, e.g., anterior pituitary hormone deficiency, central diabetes insipidus, or both; imaging reveals thickened pituitary stalk or mass formation on the stalk, swelling of the pituitary gland, or mass formation within the pituitary Lymph nodes Generalized lymphadenopathy or localized disease adjacent to a specific affected organ; the lymph nodes involved are generally 1–2 cm in diameter and nontender Thyroid gland Riedel’s thyroiditis; fibrosing variant of Hashimoto’s thyroiditis Lungs Asymptomatic finding on lung imaging; cough, hemoptysis, dyspnea, pleural effusion, or chest discomfort; associated with parenchymal lung involvement, pleural disease, or both; four main clinical lung syndromes: inflammatory pseudotumor, paravertebral mass often extending over several vertebrae, central airway disease, localized or diffuse interstitial pneumonia; pleural lesions have severe, nodular thickening of the visceral or parietal pleura with diffuse sclerosing inflammation, sometimes associated with pleural effusion Aorta Asymptomatic finding on radiologic studies; surprise finding at elective aortic surgery; aortic dissection; clinicopathologic syndromes described include lymphoplasmacytic aortitis of thoracic or abdominal aorta, aortic dissection, periaortitis and periarteritis, and inflammatory abdominal aneurysm Retroperitoneum Backache, lower abdominal pain, lower extremity edema, hydronephrosis from ureteral involvement, asymptomatic finding on radiologic studies. Classic radiologic appearance is periaortic inflammation extending caudally to involve the iliac vessels. Kidneys Tubulointerstitial nephritis; membranous glomerulonephritis in a small minority; asymptomatic tumoral lesions, typically multiple and bilateral, are sometimes detected on radiologic studies; renal involvement strongly associated with hypocomplementemia Pancreas Type 1 autoimmune pancreatitis, presenting as mild abdominal pain; weight loss; acute, obstructive jaundice, mimicking adenocarcinoma of the pancreas (including a pancreatic mass); between 20 and 50% of patients present with acute glucose intolerance; imaging shows diffuse (termed “sausage-shaped pancreas”) or segmental pancreatic enlargement, with loss of normal lobularity; a mass often raises the suspicion of malignancy Biliary tree and liver Obstructive jaundice associated with autoimmunity in most cases; weight loss; steatorrhea; abdominal pain; and new-onset diabetes mellitus; mimicker of primary sclerosing cholangitis and cholangiocarcinoma Other organs involved Gallbladder, liver (mass), breast (pseudotumor), prostate (prostatism), pericardium (constrictive pericarditis), mesentery (sclerosing mesenteritis), mediastinum (fibrosing mediastinitis), skin (erythematous or flesh-colored papules), peripheral nerve (perineural inflammation) pancreatic failure and the resulting inability of the pancreas to produce sufficient quantities of digestive enzymes. Failure of the endocrine pancreas, resulting in diabetes mellitus, is also common. Clinically apparent disease can evolve over months, years, or even decades before the manifestations within a given organ become sufficiently severe to bring the patient to medical attention. Some patients have disease that is marked by the appearance and then resolution or temporary improvement in symptoms within a particular organ. Other patients accumulate new organ involvement as their disease persists in previ­ ously affected organs. Initial misdiagnosis, particularly of cancer, is extremely common because of the disease’s tendency to cause mass lesions in the organs it affects. IgG4-RD is also often identified inci­ dentally through radiologic findings. Multiorgan disease may be evident at diagnosis but can also evolve over months to years. Some patients, however, have disease that appears to be confined to a single organ at the time of diagnosis. Others have subclinical involvement of other organs when the major clini­ cal feature presents. For example, patients with type 1 AIP may have their major disease focus in the pancreas, but thorough investigation through the history and physical examination, blood tests, and crosssectional imaging may demonstrate disease in multiple other organs. Two common characteristics of IgG4-RD are allergic disease and the tendency to form tumefactive lesions that mimic malignancies (Fig. 380-1). Many IgG4-RD patients have allergic features such as atopy, eczema, asthma, nasal polyps, sinusitis, and modest peripheral eosinophilia. IgG4-RD also appears to account for a significant propor­ tion of tumorous swellings—pseudotumors—in many organ systems (Fig. 380-2). Some patients undergo major surgeries (e.g., modified Whipple procedures or thyroidectomy) for the purpose of resecting malignancies before the correct diagnosis is identified. IgG4-RD often causes major morbidity and can lead to organ failure; however, its general pattern is to cause damage in a subacute manner. CHAPTER 380 IgG4-Related Disease Destructive bone lesions in the sinuses, head, and middle ear spaces that mimic granulomatosis with polyangiitis occur occasionally in IgG4-RD, but less aggressive lesions are the rule in most organs. In regions such as the retroperitoneum, substantial fibrosis often occurs before the diagnosis is established, leading to ureteral entrapment, hydronephrosis, postobstructive uropathy, and renal atrophy. Undiag­ nosed or undertreated IgG4-related sclerosing cholangitis can lead to hepatic failure within months. Similarly, IgG4-related aortitis can cause aneurysms and dissections. Substantial renal dysfunction and even renal failure can ensue from IgG4-related tubulointerstitial nephritis, and renal atrophy is a frequent sequel to this disease complication even following apparently effective immunosuppressive therapy. IgG4related membranous glomerulonephropathy, a less common renal manifestation than tubulointerstitial nephritis, must be distinguished from idiopathic membranous glomerulonephropathy. As a variablevessel vasculitis, IgG4-RD can target small-, medium-, and large-sized arteries and veins. Patients with longstanding IgG4-RD marked by substantial elevations of serum IgG4 concentrations and other bio­ markers are at risk for developing coronary arteritis, marked by wall thickening, periarterial soft tissue encasement, stenosis, calcification, and aneurysms or ectasia. ■ ■SEROLOGIC FINDINGS The majority of patients with IgG4-RD have elevated serum IgG4 con­ centrations; however, the range of elevation varies widely. Serum con­ centrations of IgG4 as high as 30 or 40 times the upper limit of normal sometimes occur, usually in patients with disease that affects multiple organ systems simultaneously. Approximately 30% of patients have normal serum IgG4 concentrations despite classic histopathologic and immunohistochemical findings. Such patients tend to have disease that affects fewer organs. Patients with IgG4-related retroperitoneal fibrosis often have normal serum IgG4 concentrations, perhaps because the PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders A B FIGURE 380-1  A major clinical feature of IgG4-related disease is its tendency to form tumefactive lesions. Shown here are mass lesions of the lacrimal glands, causing supraorbital swelling (A) and the submandibular glands (B). process has advanced to a fibrotic stage by the time the diagnosis is considered. Correlations between serum IgG4 concentrations, disease activity, and the need for treatment are imperfect. Serum IgG4 concentrations typically decline swiftly with the institution of therapy but often do not normalize completely. Patients can achieve clinical remissions yet have persistently elevated serum IgG4 concentrations. Following treatment and a disease response, however, steadily rising serum IgG4 concentra­ tions are useful in identifying patients at risk for clinical flares who should be considered for re-treatment. Clinical relapses occur in some patients despite persistently normal IgG4 concentrations. IgG4 concentrations in serum are usually measured by nephelome­ try assays. In the setting of extremely high serum IgG4 concentrations, these assays can generate spuriously low IgG4 values because of the prozone effect. Failure to identify dramatic serum IgG4 elevations can have a substantial impact on patients, because that subset of patients is at greatest risk for multiorgan disease and substantial end-organ injury. The prozone effect should be considered when the results of serologic testing for IgG4 concentrations are normal despite the presence of clinical features that strongly suggest IgG4-RD. This effect can be cor­ rected by dilution of the serum sample in the laboratory. ■ ■EPIDEMIOLOGY The typical patient with IgG4-RD is a middle-aged to elderly man. This epidemiology stands in stark contrast to that of many classic autoimmune conditions, which tend to affect young women. Male patients are approximately 5 years older at the time of diagnosis com­ pared to female patients and have higher degrees of serologic activity, e.g., IgG4 hypergammaglobulinemia or hypocomplementemia. The male-to-female ratio appears to be on the order of 2:1, with even more striking male predominance reported in certain types of internal organ A B FIGURE 380-2  Thickening of extraocular muscles and meninges. (A) Magnetic resonance imaging study of the orbits, showing enhancement and enlargement of extraocular muscles in a patient with IgG4-related orbital disease (orbit axial T1 postcontrast fat-saturated image). (B) Magnetic resonance imaging study of the brain, showing thickening of the pachymeninges. There is nodular pachymeningeal enhancement at the base of the brain (blue dot), anterior to the pons. There is also abnormal enhancement and thickening of the tentorium cerebelli, interposed between the superior cerebellum and the occipital lobes (sagittal MPRAGE volumetric T1 postcontrast image). involvement (e.g., the pancreas, kidneys, or retroperitoneum). Among IgG4-RD manifestations that involve organs of the head and neck—the orbits, lacrimal glands, and major salivary glands—the sex ratio may be closer to 1:1. ■ ■PATHOLOGY The key histopathology characteristics of IgG4-RD are a dense lym­ phoplasmacytic infiltrate (Fig. 380-3) that is organized in a storiform pattern, obliterative phlebitis, and a mild to moderate eosinophilic infiltrate. Lymphoid follicles and germinal centers are frequently observed. The infiltrate tends to aggregate around ductal structures when it affects glands. The inflammatory lesion often aggregates into tumefactive masses that destroy the involved tissue. Obliterative arteritis is observed in some organs, particularly the lung; however, venous involvement is more common (and is indeed a hall­ mark of IgG4-RD). Several histopathology features are uncommon in IgG4-RD and, when detected, mitigate against the diagnosis of IgG4-RD. These include intense neutrophilic infiltration, leukocytoclasis, granulo­ matous inflammation, multinucleated giant cells, and fibrinoid necrosis. FIGURE 380-3  Hallmark histopathology characteristics of IgG4-related disease (IgG4-RD) are a dense lymphoplasmacytic infiltrate and a mild to moderate eosinophilic infiltrate. The cellular inflammation is often encased in a distinctive type of fibrosis termed “storiform,” which often has a basket weave pattern. Abundant fibroblasts and strands of fibrosis accompany the lymphoplasmacytic infiltrate in this figure. Outlined by the arrowheads is a vein demonstrating obliterative phlebitis, underscoring the vascular tropism of this disease, which is classified as a variable-vessel vasculitis. This biopsy is from a patient with IgG4related hypertrophic pachymeningitis. However, the findings are identical to the pathology found in the pancreas, kidneys, lungs, salivary glands, and other organs affected by IgG4-RD. The inflammatory infiltrate is composed of an admixture of B and T lymphocytes. B cells are typically organized in germinal centers. Plasma cells staining for CD19, CD138, and IgG4 appear to radiate from the germinal centers. In contrast, the T cells, usually CD4+, are distributed more diffusely throughout the lesion and generally represent the most abundant cell type. Fibroblasts, histiocytes, and eosinophils can all be observed in moderate numbers. Some biopsy samples are particularly enriched with eosinophils. In other samples, particularly from longstanding cases, fibrosis predominates. The histologic appearance of IgG4-RD, although characteristic, should be supplemented by immunohistochemical stains for IgG4 and IgG. IgG4-positive plasma cells predominate within the lesion, but plasma cells containing immunoglobulins from each subclass can be found. The number of IgG4-positive plasma cells can be quantified by either counting the number of cells per high-power field (HPF) or by calculating the ratio of IgG4- to IgG-bearing plasma cells. Tissue fibrosis predominates in the latter phases of organ involvement, and in this relatively acellular phase of inflammation, both the IgG4:total IgG ratio and the pattern of tissue fibrosis are more important than the number of IgG4-positive cells per HPF in establishing the diagnosis. No matter how strongly the histopathology and immunohistochem­ istry studies favor a diagnosis of IgG4-RD, however, the pathology findings must always be interpreted in the context of clinical, serologic, and radiologic findings. Pathology findings alone are never sufficient for the diagnosis. ■ ■PATHOPHYSIOLOGY Despite the emphasis of IgG4 in the name of this disease, the IgG4 molecule is not believed to play a direct role in the pathophysiology of disease within most organs. The IgG4 molecule can undergo Fab exchange, a phenomenon in which the two halves of the molecule dis­ sociate from each other and reassociate with hemi-molecules of differ­ ent antigen specificity that have originated from other dissociated IgG4 molecules. Partly as a result of this Fab exchange, IgG4 antibodies do not bind antigen tightly. Moreover, the molecules have low affinities for Fc receptors and C1q and are regarded generally as noninflammatory immunoglobulins. The low affinities for Fc receptors and C1q impair the ability of IgG4 antibodies to induce phagocyte activation, antibodydependent cellular cytotoxicity, and complement-mediated damage. It is possible, therefore, that the role of IgG4 in this disease is actually as a counterregulatory mechanism rather than part of the primary inflam­ matory process. Next-generation sequencing studies of CD4+ effector T cells have demonstrated a unique CD4+ cytotoxic T cell. This cell, also found in abundance at tissue sites of disease, makes interferon gamma, T-cell growth factor-beta, and interleukin-1, all of which may contribute to the storiform fibrosis found in this condition. The cells also elaborate per­ forin, granzyme A and B, and granulysin, products capable of inducing cytotoxicity. The pronounced oligoclonal expansion of this CD4+ cyto­ toxic T cell at tissue sites suggests that this cell is a major disease driver. CHAPTER 380 IgG4-Related Disease Oligoclonal expansions of plasmablasts are also present within the blood of patients with IgG4-RD. Continuous antigen presentation by B cells and plasmablasts may support CD4+ cytotoxic T cells, which in turn produce profibrotic cytokines and other molecules, thereby directly mediating tissue injury. ■ ■TREATMENT Vital organ involvement must be treated aggressively, because IgG4-RD can lead to serious organ dysfunction and failure. Aggressive disease can lead quickly to end-stage liver disease, permanent impairment of pancreatic function, renal atrophy, aortic dissection or aneurysms, and destructive lesions in the sinuses and nasopharynx. Not every disease manifestation of IgG4-RD requires immediate treatment, however, because the disease may take an indolent form in some patients. IgG4related lymphadenopathy, for example, can be asymptomatic for years, without evolution to other disease manifestations. Watchful waiting is prudent in some cases, but monitoring is essential because serious organ involvement may evolve over time, particularly in the setting of persistently rising serum IgG4 concentrations. Glucocorticoids are the first line of therapy. Treatment regimens, extrapolated from experience with the management of type 1 AIP, generally begin with 40 mg/d of prednisone, with tapering to dis­ continuation or maintenance doses of 5 mg/d within 2 or 3 months. Although the clinical response to glucocorticoids is usually swift and striking, prolonged steroid-free remissions are uncommon and the risk of steroid-induced morbidity in this middle-aged to elderly patient population is high, particularly in those with baseline comorbidities and pancreatic involvement by IgG4-RD. Few data exist to support the utility of conventional glucocorticoid-sparing agents in this disease. For patients with relapsing or glucocorticoid-resistant disease, B-cell depletion with rituximab is an excellent second-line therapy. Ritux­ imab treatment (two doses of 1 g IV, separated by ~15 days) leads to a swift decline in serum IgG4 concentrations, suggesting that rituximab achieves its effects in part by preventing the repletion of short-lived plasma cells that produce IgG4. More important than its effects on IgG4 concentrations, however, may be the effect of B-cell depletion on T-cell function. Specific effects of rituximab on the CD4+ cytotoxic T cell described above have been documented in IgG4-RD. The rapidly evolving understanding of the pathophysiology of IgG4-RD suggests several novel targeted approaches to treating the disease, some of which are in clinical trials. Phase 3 clinical trials of treatments target­ ing CD19+ B lymphocytes are now at advanced stages of recruitment. B-cell–targeted treatment strategies may be appropriate first-line ther­ apy options for some patients following confirmation of their efficacy in clinical trials, particularly for patients at high risk for glucocorticoid toxicity and for those with immediately organ-threatening disease. ■ ■FURTHER READING Jha I et al: Sex as a predictor of clinical phenotype and determinant of immune response in IgG4-Related disease: A retrospective study of 328 patients fulfilling the American College of Rheumatology/ European League Against Rheumatism classification criteria. Lancet Rheumatol 6:E460, 2024. Katz G et al: IgG4-related disease as a variable-vessel vasculitis: A case series of 13 patients with medium-sized coronary artery involvement. Semin Arthritis Rheum 60:152184, 2023. Katz G et al: Proliferative features of IgG4-related disease. Lancet Rheu­ matol 6:e481, 2024. # 27 - 383 Osteoarthritis ### 383 Osteoarthritis David T. Felson, Tuhina Neogi Osteoarthritis Osteoarthritis (OA) is the most common type of arthritis. Its high prevalence, especially in the elderly, and its negative impact on physi­ cal function make it a leading cause of disability in the elderly. Because of the aging of Western populations and because obesity, a major risk factor, is increasing in prevalence, the occurrence of OA is on the rise. OA affects certain joints yet spares others (Fig. 383-1). Commonly affected joints include the hip, knee, and first metatarsal phalangeal joint (MTP) and cervical and lumbosacral spine. In the hands, the distal and proximal interphalangeal joints and the base of the thumb are often affected. Usually spared are the wrist, elbow, and ankle. Our joints were designed, in an evolutionary sense, for brachiating apes, animals that still walked on four limbs. We thus develop OA in joints that were ill designed for human tasks such as pincer grip (OA in the thumb base) and walking upright (OA in knees and hips). Some joints, like the ankles, may be spared because their articular cartilage may be uniquely resistant to loading stresses. OA can be diagnosed based on structural abnormalities or on the symptoms these abnormalities evoke. According to cadaveric studies, by elderly years, structural changes of OA are nearly universal. These include cartilage loss (seen as joint space loss on x-rays) and osteophytes. Many persons with x-ray evidence of OA have no joint symptoms, and although the prevalence of structural abnormalities is of interest in understanding disease pathogenesis, what matters more from a clinical perspective is the prevalence of symptomatic OA. Symptoms, usually joint pain, determine disability, visits to clinicians, and disease costs. Symptomatic OA of the knee (pain on most days of a recent month plus x-ray evidence of OA in that knee) occurs in ~12% of persons age ≥60 in the United States and 6% of all adults age ≥30. Symptomatic hip OA is roughly one-third as common as disease in the knee. Although radiographic hand OA and the appearance of bony enlargement in affected hand joints (Fig. 383-2) are extremely common in older Distal and proximal First carpometacarpal interphalangeal Cervical vertebrae Lower lumbar vertebrae Hip Knee First metatarsophalangeal FIGURE 383-1  Joints commonly affected by osteoarthritis.   CHAPTER 383 Osteoarthritis FIGURE 383-2  Severe osteoarthritis of the hands affecting the distal interphalangeal joints (Heberden’s nodes) and the proximal interphalangeal joints (Bouchard’s nodes). There is no clear bony enlargement of the other common site in the hands, the thumb base. persons, most affected persons have no pain. Even so, painful hand OA occurs in ~10% of elderly individuals and often produces measurable limitation in function. The prevalence of OA rises strikingly with age, being uncommon in adults aged <40 and highly prevalent in those aged >60. It is also a disease that, at least in middle-aged and elderly persons, is much more common in women than in men. X-ray evidence of OA is common in the lower back and neck, but back pain and neck pain have not been tied to findings of OA on x-ray. Thus, back pain and neck pain are treated separately (Chaps. 18 and 19). ■ ■GLOBAL CONSIDERATIONS With the aging of the populations, both the prevalence of OA and the amount of disability worldwide related to OA have been increasing, especially in developed countries where many are living into old age. Hip OA is rare in China and in immigrants from China to the United States. Anatomic differences between Chinese and white hips may account for much of the difference in hip OA prevalence, with white hips having a higher prevalence of anatomic predispositions to the development of OA. However, OA in the knees is at least as common, if not more so, in Chinese as in whites from the United States, and knee OA represents a major cause of disability in China, especially in rural areas. DEFINITION OA is joint failure, a disease in which all structures of the joint have undergone pathologic change, often in concert. The pathologic sine qua non of disease is hyaline articular cartilage loss, present in a focal and, initially, nonuniform manner. This is accompanied by increasing thickness and sclerosis of the subchondral bony plate, by outgrowth of osteophytes at the joint margin, by stretching of the articular capsule, by variable degrees of synovitis, and by weakness of muscles bridging the joint. In knees, meniscal degeneration is part of the disease. There are numerous pathways that lead to joint failure, but the initial step is often joint injury in the setting of a failure of protective mechanisms. JOINT PROTECTIVE MECHANISMS AND THEIR FAILURE Joint protectors include joint capsule and ligaments, muscle, sensory afferents, and underlying bone. Joint capsule and ligaments serve as joint protectors by providing a limit to excursion, thereby fixing the range of joint motion. Synovial fluid reduces friction between articulating cartilage sur­ faces, thereby serving as a protector against friction-induced cartilage wear. This lubrication function depends on hyaluronic acid and on lubricin, a mucinous glycoprotein secreted by synovial fibroblasts whose concentration diminishes after joint injury and in the face of synovial inflammation. The ligaments, along with overlying skin and tendons, contain mechanoreceptor sensory nerves. These mechanoreceptors fire at different frequencies throughout a joint’s range of motion, provid­ ing feedback by way of the spinal cord to muscles and tendons. As a consequence, these muscles and tendons assume the right tension at appropriate points in joint excursion to act as optimal joint protectors, anticipating joint loading. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Muscles and tendons that bridge the joint are key joint protectors. Focal stress across the joint is minimized by muscle contraction that decelerates the joint before impact and assures that when joint impact arrives, it is distributed broadly across the joint surface. Failure of these joint protectors increases the risk of joint injury and OA. For example, in animals, OA develops rapidly when a sensory nerve to the joint is sectioned and joint injury induced. Similarly, in humans, Charcot’s arthropathy, a severe and rapidly progressive OA, develops when minor joint injury occurs in the presence of posterior column peripheral neuropathy. Another example of joint protector failure is rup­ ture of ligaments, a well-known cause of the early development of OA. ■ ■CARTILAGE AND ITS ROLE IN JOINT FAILURE A thin rim of tissue at the ends of two opposing bones, cartilage is lubri­ cated by synovial fluid to provide an almost frictionless surface across which these two bones move. The compressible stiffness of cartilage compared to bone provides the joint with impact-absorbing capacity. The earliest changes of OA may occur in cartilage, and abnormali­ ties there can accelerate disease development. The two major macro­ molecules in cartilage are type 2 collagen, which provides cartilage its tensile strength, and aggrecan, a proteoglycan macromolecule linked with hyaluronic acid, which consists of highly negatively charged gly­ cosaminoglycans. In normal cartilage, type 2 collagen is woven tightly, constraining the aggrecan molecules in the interstices between collagen strands, forcing these highly negatively charged molecules into close proximity. The aggrecan molecule, through electrostatic repulsion of its negative charges, gives cartilage its compressive stiffness. Chondrocytes, the cells within this avascular tissue, synthesize all elements of the matrix and produce enzymes that break it down (Fig. 383-3). Cartilage matrix synthesis and catabolism are in a dynamic equilibrium influenced by the cytokine and growth factor environment. Mechanical and osmotic stress on chondrocytes induces these cells to alter gene expression and Articular cartilage Cartilage degradation Synovium Macrophage Neuropeptides Neuron Chondrocyte Mechanoflammation Apidokines Adipose tissue Osteoblast FIGURE 383-3  Selected factors involved in the osteoarthritic process including chondrocytes, bone, and synovium. Synovitis causes release of cytokines, alarmins, damage-associated molecular pattern (DAMP) molecules, and complement, which activate chondrocytes through cell-surface receptors. Chondrocytes produce matrix molecules (collagen type 2, aggrecan) and the enzymes responsible for the degradation of the matrix (e.g., ADAMTS-5 and matrix metalloproteinases [MMPs]). Bone invasion occurs through the calcified cartilage, triggered by vascular endothelial growth factor (VEGF) and other growth factors. (Reproduced with permission from De Roover A et al: Fundamentals of osteoarthritis: Inflammatory mediators in osteoarthritis. Osteoarthritis Cart 31:1303, 2023.) increase production of inflammatory cytokines and matrix-degrading enzymes. While chondrocytes synthesize numerous enzymes, matrix metalloproteinases (MMPs; especially collagenases and ADAMTS-5) are critical enzymes in the breakdown of cartilage matrix. Local inflammation accelerates the development and progression of osteoarthritis and increases the likelihood that an osteoarthritic joint will be painful. Some of this inflammation may be induced by mechan­ ical stimuli, so called mechanoinflammation. The synovium, carti­ lage, and bone all influence disease development through cytokines, chemokines, and even complement activation (Fig. 383-3). Matrix fragments released from cartilage stimulate synovium, which releases inflammatory cytokines, and they, in turn, induce chondrocytes to synthesize other proinflammatory molecules. Ultimately, the combina­ tion of effects on chondrocytes triggers matrix degradation. Growth factors are also part of this complex network, with bone morphogenetic protein 2 (BMP-2) and transforming growth factor β (TGF-β) playing prominent roles in stimulating the development of osteophytes. Trig­ gered by local vascular endothelial growth factor (VEGF) synthesis, blood vessels invade cartilage and, with them, come nerves that may bring nociceptive innervation. With aging, articular chondrocytes develop a senescence-associated secretory phenotype, exhibiting a decline in synthetic capacity and pro­ ducing proinflammatory mediators and matrix-degrading enzymes. These chondrocytes are unable to maintain tissue homeostasis (such as after insults of a mechanical or inflammatory nature). Thus, with age, cartilage is easily damaged by minor sometimes unnoticed injuries, including those that are part of daily activities. OA cartilage is characterized by gradual depletion of aggrecan, an unfurling of the tightly woven collagen matrix, and loss of type 2 col­ lagen. With these changes comes increasing vulnerability of cartilage, which loses its compressive stiffness. RISK FACTORS Risk factors for OA can be understood in terms of their effect either on joint vulnerability or joint loading. On the one hand, a vulnerable joint whose protectors are dysfunctional can develop OA with minimal lev­ els of loading, perhaps even levels encountered during everyday activi­ ties. On the other hand, in a young joint with competent protectors, a DAMPs Cytokines Synoviocyte Osteophyte Growth factors Subchondral bone Activated osteoblast Intrinsic joint vulnerabilities (local environment) Previous damage (e.g., meniscectomy) Bridging muscle weakness Increasing bone density Malalignment Proprioceptive deficiences Systemic factors affecting joint vulnerability Use (loading) factors acting on joints Increased age Female gender Racial/ethnic factors Genetic susceptibility Nutritional factors Obesity Injurious physical activities Susceptibility to OA Osteoarthritis or its progression FIGURE 383-4  Risk factors for osteoarthritis (OA) either contribute to the susceptibility of the joint (systemic factors or factors in the local joint environment) or increase risk by the load they put on the joint. Usually, a combination of loading and susceptibility factors is required to cause disease or its progression. major acute injury or long-term overloading is necessary to precipitate disease (Fig. 383-4). ■ ■SYSTEMIC RISK FACTORS THAT AFFECT JOINT VULNERABILITY Age is the most potent risk factor for OA. Radiographic evidence of OA is rare in individuals aged <40; however, in some joints, such as the hands, OA occurs in >50% of persons aged >70. Aging increases joint vulnerability through several mechanisms. Whereas dynamic loading of joints stimulates matrix synthesis by chondrocytes in young cartilage, aged cartilage is less responsive to these stimuli. As a conse­ quence of this failure to synthesize matrix with loading, cartilage thins with age, and thinner cartilage experiences higher shear stress and is at greater risk of damage. Also, joint protectors fail more often with age. Muscles that bridge the joint become weaker with age and respond less quickly to oncoming impulses. Sensory nerve input slows with age, retarding the feedback loop of mechanoreceptors to muscles and tendons related to their tension and position. Ligaments stretch with age, making them less able to absorb impulses. These factors work in concert to increase the vulnerability of older joints to OA. Older women are at high risk of OA in all joints, a risk that increases as women reach their sixth decade. Although hormone loss with meno­ pause may contribute to this risk, there is little understanding of the unique vulnerability of older women versus men. ■ ■HERITABILITY AND GENETICS AND THEIR RELATION TO JOINT VULNERABILITY OA is a heritable disease, but its heritability is mostly joint specific. Nearly 60–65% of OA in hips or hands may be attributed to shared genetics within a family. However, heritability of knee OA is, at most, 30%, with some studies suggesting no heritability at all. Knees are susceptible to nongenetic factors like activities that affect joint loading and risk of injury. On the other hand, many people with OA develop “generalized OA” or multisite OA, but the involvement of multiple joints with OA is usually a consequence of aging rather than genetics. The best replicated genetic variant known to increase OA risk lies in the locus for growth differentiation factor 5 (GDF5). It affects epigen­ etic regulation of GDF5 activity, resulting in reduction in GDF5 expres­ sion. GDF5 probably affects joint shape, a mechanism by which genes increase disease risk. Minor abnormalities in joint shape can make a joint vulnerable to damage if focal stresses across the joint increase. ■ ■RISK FACTORS IN THE JOINT ENVIRONMENT Some risk factors increase vulnerability of the joint through local effects on the joint environment. With changes in joint anatomy, for example, load across the joint is no longer distributed evenly across the joint surface, but rather shows an increase in focal stress. In the hip, three uncommon developmental abnormalities occurring in utero or in childhood—congenital dysplasia, Legg-Perthes disease, and slipped capital femoral epiphysis—leave a child with distortions of hip joint anatomy that often lead to OA later in life. Girls are predominantly affected by acetabular dysplasia, a mild form of congenital dysplasia, whereas the other abnormalities more often affect boys. Depending on the severity of the anatomic abnormalities, hip OA occurs either in young adulthood (severe abnormalities) or middle age (mild abnormalities). Femoroacetabular impingement can develop during adolescence. It is a clinical syndrome in which an outgrowth of bone at the femur’s head/neck junction thought to develop during closure of the growth plate results in abnormal contact between the femur and acetabulum, especially during hip flexion and rotation. This leads to cartilage and labral damage, to hip pain, and ultimately in later life, to an increased risk of hip OA. CHAPTER 383 Osteoarthritis Major injuries to a joint also can produce anatomic abnormalities that leave the joint susceptible to OA. For example, a fracture through the joint surface often causes OA in joints in which the disease is oth­ erwise rare such as the ankle and the wrist. Avascular necrosis can lead to collapse of dead bone at the articular surface, producing anatomic irregularities and subsequent OA. Tears of ligamentous and fibrocartilaginous structures that protect the joints, such as the anterior cruciate ligament or meniscus in the knee and the labrum in the hip, can lead to premature OA. Meniscal tears increase with age and, when chronic, are often asymptomatic but lead to adjacent cartilage damage and accelerated OA. Even recalled injuries in which the affected person never received a diagnosis may increase risk of OA. For example, in the Framingham Study subjects, men with a history of major knee injury, but no surgery, had a 3.5-fold increased risk for subsequent knee OA. Another source of anatomic abnormality is malalignment across the joint (Fig. 383-5), a factor best studied in the knee. Varus (bow­ legged) knees with OA are at exceedingly high risk of cartilage loss in the medial or inner compartment of the knee, whereas valgus (knockkneed) malalignment predisposes to rapid cartilage loss in the lateral compartment. Malalignment causes this effect by increasing stress on a focal area of cartilage, which then breaks down; it also causes dam­ age to bone underlying the cartilage, producing bone marrow lesions seen on magnetic resonance imaging (MRI). Malalignment in the knee often produces such a substantial increase in focal stress within the knee (as evidenced by its destructive effects on subchondral bone) that severely malaligned knees may be destined to progress regardless of the status of other risk factors. Weakness in the quadriceps muscles bridging the knee increases the risk of the development of painful OA in the knee, especially in women. Normal Varus Knock knees (valgus) FIGURE 383-5  The two types of limb malalignment in the frontal plane: varus, in which the stress is placed across the medial compartment of the knee joint, and valgus, which places excess stress across the lateral compartment of the knee. High bone density also increases OA risk, especially risk of a subtype of OA characterized by large osteophytes. ■ ■LOADING FACTORS Obesity  Three to six times body weight is transmitted across the knee during single-leg stance. Any increase in weight may be multiplied by this factor to reveal the excess force across the knee in overweight per­ sons during walking. Obesity is a potent risk factor for the development of knee OA and, less so, for hip OA. It is a stronger risk factor for disease in women than in men, and for women, the relationship of weight to the risk of disease is linear, so that with each pound increase in weight, there is a commensurate increase in risk. Not only is obesity a risk factor for OA in weight-bearing joints, but obese persons have more pain from the disease. Weight loss greater than 10% of body weight reduces cartilage loss and, in most affected persons, alleviates pain. PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Obesity’s effect on the development and progression of disease, especially in knees, is mediated mostly through the increased loading in weight-bearing joints that occurs in overweight persons. However, high levels of leptin, an adipokine, are associated with increasing pain severity in OA regardless of the joint affected. Repeated Use of Joint and Exercise  There are two categories of repetitive joint use: occupational use and leisure time physical activities. Workers who, over many years, perform repetitive tasks as part of their occupations are at high risk of developing OA in joints they use repeatedly. Workers whose jobs require regular knee bending or lifting or carrying heavy loads have a high rate of knee OA. One reason why workers may get disease is that during long days at work, their muscles may gradually become exhausted, no longer serving as effective joint protectors. It is widely recommended for people to adopt an exercise-filled life­ style, and long-term studies of exercise suggest no consistent associa­ tion of exercise with OA risk in most persons. However, persons who already have injured joints may put themselves at greater risk by engag­ ing in certain types of exercise. For example, persons who have already sustained major knee injuries are at increased risk of progressive knee OA as a consequence of running. In addition, compared to nonrun­ ners, elite runners (professional runners and those on Olympic teams) have high risks of both knee and hip OA. Lastly, although recreational runners are not at increased risk of knee OA, studies suggest that they have a modest increased risk of disease in the hip. PATHOLOGY The pathology of OA provides evidence of the involvement of many joint structures in disease. Cartilage initially shows surface fibrillation and irregularity. As disease progresses, focal erosions develop there, and these eventually extend to the subjacent bone. With further pro­ gression, cartilage erosion down to bone expands to involve a larger proportion of the joint surface, even though OA remains a focal disease with nonuniform loss of cartilage. After an injury to cartilage, chondrocytes undergo mitosis and clus­ tering. Although the metabolic activity of these chondrocyte clusters is high, the net effect of this activity is to promote proteoglycan depletion in the matrix surrounding the chondrocytes. This is because the catabolic activity is greater than the synthetic activity. As disease develops, colla­ gen matrix becomes damaged, the negative charges of proteoglycans get exposed, and cartilage swells from ionic attraction to water molecules. Because in damaged cartilage proteoglycans are no longer forced into close proximity, cartilage does not bounce back after loading as it did when healthy, and cartilage becomes vulnerable to further injury. With loss of cartilage comes alteration in subchondral bone. Stimu­ lated by growth factors and cytokines, osteoclasts and osteoblasts in the bony plate just underneath cartilage become activated. Bone forma­ tion produces a thickening of the subchondral plate that occurs even before cartilage ulcerates. Trauma to bone during joint loading may be the primary factor driving this bone response, with healing from injury (including microcracks) inducing remodeling. Small areas of osteonecrosis usually exist in joints with advanced disease. Bone death may also be caused by bone trauma with shearing of microvasculature, leading to a cutoff of vascular supply to some bone areas. At the margin of the joint, near areas of cartilage loss, osteophytes form. These start as outgrowths of new cartilage, and with neurovas­ cular invasion from the bone, this cartilage ossifies. Osteophytes are an important radiographic hallmark of OA. The synovium produces lubricating fluids that minimize shear stress during motion. In healthy joints, the synovium consists of a single dis­ continuous layer filled with fat and containing two types of cells, macro­ phages and fibroblasts, but in OA, it can sometimes become edematous and inflamed. There is a migration of macrophages from the periphery into the tissue, and cells lining the synovium proliferate. Inflammatory cytokines and alarmins secreted by the synovium activate chondrocytes to produce enzymes that accelerate destruction of matrix. Additional pathologic changes occur in the capsule, which stretches, becomes edematous, and can become fibrotic. The pathology of OA is not identical across joints. In hand joints with severe OA, for example, there are often cartilage erosions in the center of the joint probably produced by bony pressure from the oppo­ site side of the joint. Basic calcium phosphate and calcium pyrophosphate dihydrate crystals are present microscopically in most joints with end-stage OA. Their role in osteoarthritic cartilage is unclear, but their release from cartilage into the joint space and joint fluid likely triggers synovial inflammation, which can, in turn, produce release of cytokines and trigger nociceptive stimulation. SOURCES OF PAIN Because healthy cartilage is aneural, cartilage loss alone is not accom­ panied by much pain. Thus, pain in OA likely arises from structures outside the cartilage. Innervated structures in the joint include the synovium, ligaments, joint capsule, muscles, and subchondral bone. Most of these are not visualized by x-ray, and the severity of x-ray changes in OA correlates poorly with pain severity. However, in later stages of OA, loss of cartilage integrity accompanied by neurovascular invasion may contribute more to pain. Based on MRI studies in osteoarthritic knees comparing those with and without pain and on studies mapping tenderness in unanesthetized joints, likely sources of pain include synovial inflammation, joint effu­ sions, and bone marrow edema. Modest synovitis develops in many but not all osteoarthritic joints. The presence of synovitis on MRI is cor­ related with the presence and severity of knee pain, and potentially with pain sensitization. Capsular stretching from fluid in the joint stimulates nociceptive fibers there, inducing pain. Increased focal loading as part of the disease not only damages cartilage but probably also injures the underlying bone. As a consequence, bone marrow edema appears on the MRI; histologically, this edema signals the presence of microcracks and scar, which are the consequences of trauma. These lesions may stimu­ late bone nociceptive fibers. Pain may arise from outside the joint also, including bursae near the joints. Common sources of pain near the knee are anserine bursitis and iliotibial band syndrome. Much of the pain experienced in OA occurs when nociceptors in the joint are stimulated during weight-bearing activities. However, the pain may eventually become more constant and present at rest, and this suggests other mechanisms contribute to the pain experience. The pathologic changes of OA may lead to alterations in nervous system signaling (Chap. 18). Specifically, peripheral nociceptors can become more responsive to sensory input, known as peripheral sensitization, and there can also be an increase in facilitated central ascending noci­ ceptive signaling, known as central sensitization. Individuals with OA may also have insufficient descending inhibitory modulation. Some individuals may be genetically predisposed to becoming sensitized; however, regardless of the etiology, these nervous system alterations are associated with more severe pain, contribute to the presence of allodynia and hyperalgesia in patients with OA, and may predispose to development of chronic pain. CLINICAL FEATURES Joint pain from OA is primarily activity-related in the early stages of the disease. Pain comes on either during or just after joint use and then gradually resolves. Examples include knee or hip pain with going up or FIGURE 383-6  X-ray and magnetic resonance imaging (MRI) of knee with medial osteoarthritis. X-ray shows osteophytes at the medial and lateral tibia and femur and joint space narrowing of the medial tibiofemoral joint. Coronal intermediate-weighted fat-suppressed MRI confirms the presence of medial and lateral osteophytes and the medial tibiofemoral joint space narrowing. There is diffuse denuded area with no cartilage remaining at the weight-bearing medial tibiofemoral joint (arrows). There is also a severe medial meniscus extrusion (arrowhead). Bone marrow lesions, which provide evidence of bone injury, are present at medial tibia, medial femur, and intraspinous tibial region. Cartilage focal defects are also seen at the lateral weight-bearing femur and tibia. down stairs, pain in weight-bearing joints when walking, and, for hand OA, pain when cooking. Early in disease, pain is episodic, triggered often by overactive use of a diseased joint, such as a person with knee OA taking a long run and noticing a few days of pain thereafter. As disease progresses, the pain becomes continuous and even begins to be bothersome at night. Stiffness of the affected joint may be prominent, but morning stiffness is usually brief (<30 min). In knees, buckling may occur, in part, from weakness of muscles crossing the joint. Mechanical symptoms, such as buckling, catching, or locking, could also signify internal derangement, like an anterior cruciate ligament or meniscal tear; however, these symptoms, which are common in persons with knee OA, need to be further evaluated only if they develop after an acute knee injury. In the knee, pain with activities requiring knee flexion, such as stair climbing and arising from a chair, often emanates from the patellofemoral compartment of the knee, which does not actively articulate until the knee is bent ~35°. OA is the most common cause of chronic knee pain in persons aged >45, but the differential diagnosis is long. Inflammatory arthritis is likely if there is prolonged morning stiffness, and many other joints are affected. Bursitis occurs commonly around knees and hips. A physical examination should focus on whether tenderness is over the joint line (at the junction of the two bones around which the joint is articulat­ ing) or outside of it. Anserine bursitis, medial and distal to the knee, is an extremely common cause of chronic knee pain that may respond to a glucocorticoid injection. Prominent nocturnal pain in the absence of end-stage OA merits a distinct workup. For hip pain, OA can be detected by loss of internal rotation on passive movement, and pain isolated to an area lateral to the hip joint usually reflects the presence of trochanteric bursitis. No blood tests are routinely indicated for workup of patients with OA unless symptoms and signs suggest inflammatory arthritis. Exami­ nation of the synovial fluid is often more helpful diagnostically than CHAPTER 383 Osteoarthritis an x-ray. If the synovial fluid white count is >1000/μL, inflammatory arthritis or gout or pseudogout is likely, the latter two being also identi­ fied by the presence of crystals. Radiographs are not indicated in the workup of OA. They should be ordered only when joint pain and physical findings are not typical of OA or if pain persists after inauguration of treatment effective for OA. In OA, imaging findings (Fig. 383-6) correlate poorly with the pres­ ence and severity of pain. Further, in both knees and hips, radiographs may be normal in early disease as they are insensitive to cartilage loss and other early findings. Although MRI may reveal the extent of pathology in an osteo­ arthritic joint, it is not indicated as part of the diagnostic workup. Findings such as meniscal tears and cartilage and bone lesions occur not only in most patients with OA in the knee but also in most older persons without joint pain. MRI findings rarely warrant a change in therapy. TREATMENT Osteoarthritis The goals of the treatment of OA are to alleviate pain and minimize loss of physical function. To the extent that pain and loss of function are consequences of inflammation, of weakness across the joint, and of laxity and instability, the treatment of OA involves addressing each of these impairments. Comprehensive therapy consists of a multimodality approach including physical modalities and phar­ macologic elements. Foundational to OA management is patient education and self-management strategies. Patients with mild and intermit­ tent symptoms may need only symptomatic management and/ or treatments aimed at weight loss, physical activity, exercise, and self-management strategies. Patients with ongoing, disabling pain are likely to need both physical modalities and pharmacotherapy. Treatments for knee OA have been more completely evaluated than those for hip and hand OA or for disease in other joints. Thus, although the principles of treatment are identical for OA in all joints, we shall focus below on the treatment of knee OA, not­ ing specific recommendations for disease in other joints, especially when they differ from those for the knee. PHYSICAL MANAGEMENT MODALITIES Because OA is a mechanically driven disease, the mainstay of treat­ ment involves altering loading across the painful joint and improv­ ing the function of joint protectors, so they can better distribute load across the joint. Ways of lessening focal load across the joint include: PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders 1. Avoiding painful activities as these are usually activities that overload the joint 2. Improving the strength and conditioning of muscles that bridge the joint to optimize their function 3. Unloading the joint, either by redistributing load within the joint with a brace or a splint or by unloading the joint during weight bearing with a cane or a crutch The simplest treatment for many patients is to avoid activities that precipitate pain. For example, for the middle-aged patient whose long-distance running brings on symptoms of knee OA, a less demanding form of weight-bearing activity may alleviate all symptoms. For an older person whose daily walks up and down hills bring on knee pain, routing these away from hills might elimi­ nate symptoms. Weight loss is a central strategy for those who are overweight or obese, particularly for knee OA. Each pound of weight loss has a multiplier effect, unloading both knees and hips and probably relieving pain in those joints. Depending on how much weight loss occurs, bariatric surgery and drugs that cause weight loss such as glucagon-like peptide 1 receptor agonists (GLP1R agonists) often reduce pain and may slow structural disease progression. In hand joints affected by OA, splinting, by limiting motion, often minimizes pain for patients with involvement especially in the base of the thumb. Weight-bearing joints such as knees and hips can be unloaded by using a cane in the hand opposite the affected joint for partial weight bearing. A physical therapist can help teach the patient how to use the cane optimally, including ensuring that its height is optimal for unloading. Crutches or walkers can serve a similar beneficial function. Exercise  Osteoarthritic pain in knees or hips during weight bear­ ing results in lack of activity and poor mobility, and because OA is so common, the inactivity that results increases the risk of cardio­ vascular disease and obesity. Aerobic capacity is poor in most elders with symptomatic knee OA, worse than others of the same age. Weakness in muscles that bridge osteoarthritic joints is multi­ factorial in etiology. First, there is a decline in strength with age. Second, with limited mobility comes disuse muscle atrophy. Third, patients with painful knee or hip OA alter their gait to lessen load­ ing across the affected joint, and this further diminishes muscle use. Fourth, “arthrogenous inhibition” may occur, whereby contrac­ tion of muscles bridging the joint is inhibited by a nerve afferent feedback loop emanating in a swollen and stretched joint capsule; this prevents attainment of voluntary maximal strength. Because adequate muscle strength and conditioning are critical to joint pro­ tection, weakness in a muscle that bridges a diseased joint makes the joint more susceptible to further damage and pain. The degree of weakness correlates strongly with the severity of joint pain and the degree of physical limitation. One of the cardinal elements of the treatment of OA is to improve the functioning of muscles sur­ rounding the joint. Trials in knee and hip OA have shown that exercise lessens pain and improves physical function. Most effective exercise regimens consist of aerobic and/or resistance training, the latter of which focuses on strengthening muscles across the joint. Treatment guide­ lines strongly recommend exercise for knee and hip OA with no hierarchy regarding type of exercise due to lack of sufficient headto-head data. Exercises are likely to be effective especially if they train muscles for the activities a person performs daily. Activities that increase pain in the joint should be avoided. Range-of-motion exercises, which do not strengthen muscles, and isometric exer­ cises that strengthen muscles, but not through range of motion, are unlikely to be effective by themselves. Low-impact exercises, including water aerobics and water resistance training, are often better tolerated by patients than exercises involving impact load­ ing, such as running or treadmill exercises. Evidence suggests that high-intensity strengthening is no more effective in reducing knee pain than less aggressive strengthening regimens. The exercise regimen needs to be individualized to optimize effectiveness, and patients should be referred to an exercise class or a therapist who can create an individualized regimen. In addition to conventional exercise regimens, tai chi may be effective for knee OA. However, there is no strong evidence that patients with hand OA benefit from therapeutic exercise. Adherence over the long term is the major challenge to an exer­ cise prescription. In trials involving patients with knee OA who were engaged in exercise treatment, from a third to over half of patients stopped exercising by 6 months. Less than 50% continued regular exercise at 1 year. The strongest predictor of a patient’s con­ tinued exercise is a previous personal history of successful exercise. Physicians should reinforce the exercise prescription at each clinic visit, help the patient recognize barriers to ongoing exercise, and identify convenient times for exercise to be done routinely. Mobile health and wearable technologies are increasingly being used to encourage adherence to exercise. The combination of exercise with calorie restriction and weight loss is especially effective in lessening pain. Correction of Malalignment  Malalignment in the frontal plane (varus-valgus) markedly increases the stress across the joint, which can lead to progression of disease and to pain and disability (Fig. 383-5). Correcting varus-valgus malalignment, either surgically or with bracing, may relieve pain in persons whose knees are malaligned. However, correcting malalignment is often challenging. Fitted braces that straighten varus knees by putting valgus stress across the knee can be effective. Unfortunately, many patients are unwilling to wear a realigning knee brace; in addition, in patients with obese legs, braces may slip with usage and lose their realigning effect. Braces are indicated for willing patients who can learn to put them on correctly and on whom they do not slip. Shoes modified with rubber hemispheres on the sole that alter alignment of the proximal knee have shown efficacy in trials especially if worn for brief periods daily over several months. Pain from the patellofemoral compartment of the knee can be caused by tilting of the patella or patellar malalignment with the patella riding laterally in the femoral trochlear groove. Using a patel­ lar brace to realign the patella, or tape to pull the patella back into the trochlear sulcus or reduce its tilt, can lessen patellofemoral pain. However, patients may find it difficult to apply tape, with skin irrita­ tion common, and, like realigning braces, patellar braces may slip. Although their effect on malalignment is questionable, neoprene sleeves pulled up to cover the knee lessen pain and are easy to use and popular among patients. The explanation for their therapeutic effect on pain is unclear. In patients with knee OA, acupuncture produces modest pain relief compared to placebo needles and may be an adjunctive treat­ ment, though placebo effect is likely high. In patients with refrac­ tory joint pain from OA, radiofrequency ablation of the nerves innervating the joint has been shown to provide prolonged pain relief, although long-term safety is unknown. PHARMACOTHERAPY Although approaches involving physical modalities constitute its mainstay, pharmacotherapy serves an important adjunctive role in OA treatment for symptom management. Available drugs are administered using oral, topical, and intraarticular routes. To date, there are no available drugs that alter the disease process itself. Acetaminophen, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), and Cyclooxygenase-2 (COX-2) Inhibitors  The treatment effect of acetaminophen (paracetamol) in OA is small and not considered clinically meaningful (Table 383-1). However, for a minority of patients, it is adequate to control symptoms, in which case more toxic drugs such as oral NSAIDs can be avoided. NSAIDs are the most popular drugs to treat osteoarthritic pain. They can be administered either topically or orally. In clinical trials, oral NSAIDs produce ~30% greater improvement in pain than high-dose acetaminophen. Response to NSAIDs varies greatly across patients. Occasional patients treated with NSAIDs experience dramatic pain relief, whereas others experience little improvement. Initially, NSAIDs should be administered topically or taken orally on an “as-needed” basis because side effects are less frequent with low intermittent doses. For those with mild symp­ toms, topical NSAIDs may be sufficient to reduce pain. If topicals or occasional oral medication use is insufficiently effective, then daily treatment may be indicated, with an anti-inflammatory dose selected (Table 383-1). Topical NSAIDs absorbed through the skin have plasma concen­ trations an order of magnitude lower than the same amount of drug administered orally. However, when these drugs are administered TABLE 383-1  Pharmacologic Treatment for Osteoarthritis MAXIMAL DOSAGE COMMENTS TREATMENT Take with food. Increased risk of myocardial infarction and stroke for some NSAIDs. High rates of gastrointestinal side effects, including ulcers and bleeding. Patients at high risk for gastrointestinal side effects should also take either a proton pump inhibitor or misoprostol.a There is an increase in gastrointestinal side effects or bleeding when taken with acetylsalicylic acid. Can also cause edema and renal insufficiency. Oral NSAIDs and COX-2 inhibitors   Naproxen   Salsalate   Ibuprofen   Celecoxib 375–500 mg bid 1500 mg bid 600–800 mg qid/tid 100–200 mg qd Acetaminophen Up to 2 g/d Of limited efficacy; conditionally recommended. Opiates Common side effects include dizziness, sedation, nausea, vomiting, dry mouth, constipation, urinary retention, and pruritus. Addiction risk. Less efficacious than oral NSAIDs. Topical NSAIDs Rub onto hands/knees. Few systemic side effects. Diclofenac Na 1% gel 4 g qid Skin irritation common. Capsaicin 0.025–0.075% cream tid/qid Can irritate mucous membranes. Intraarticular injections   Steroids Various   Hyaluronans Varies from 3 to 5 weekly injections Mild to moderate pain at injection site. Controversy exists regarding efficacy. aPatients at high risk include those with previous gastrointestinal events, persons ≥60 years, and persons taking glucocorticoids. Trials have shown the efficacy of proton pump inhibitors and misoprostol in the prevention of ulcers and bleeding. Misoprostol is associated with a high rate of diarrhea and cramping; therefore, proton pump inhibitors are more widely used to reduce NSAID-related gastrointestinal symptoms. Abbreviations: COX-2, cyclooxygenase-2; NSAIDs, nonsteroidal anti-inflammatory drugs. Source: From DT Felson: Osteoarthritis of the Knee. N Engl J Med 354:841, 2006. Copyright © 2006 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. topically over a superficial joint (knees, hands, but not hips), the drug can be found in joint tissues such as the synovium and car­ tilage. Generally, topical NSAIDs are slightly less efficacious than oral agents, but have far fewer gastrointestinal (GI) and systemic side effects. Topical NSAIDs often cause local skin irritation where the medication is applied, inducing redness, burning, or itching (see Table 383-1). CHAPTER 383 Oral NSAIDs are often effective in reducing moderate or severe joint pain, but they have substantial and frequent side effects, the most common of which is upper GI toxicity, including dyspepsia, nausea, bloating, GI bleeding, and ulcer disease. Certain oral agents including celecoxib and nabumetone are safer to the stomach than others. Major NSAID-related GI side effects can occur in patients who do not complain of upper GI symptoms. Patients should be reminded to take low-dose aspirin and ibuprofen or naproxen at different times during the day to avoid a drug interaction. Osteoarthritis Because of the increased rates of cardiovascular events associated with conventional NSAIDs such as diclofenac, many of these drugs are not appropriate long-term treatment choices for older persons with OA, especially those at high risk of heart disease or stroke. The American Heart Association has identified COX-2 inhibitors as putting patients at high risk, although low doses of celecoxib (≤200 mg/d) are not associated with an elevation of risk. Naproxen is a safe NSAID from a cardiovascular perspective, but it does have GI toxicity. There are other common side effects of NSAIDs, including the tendency to develop edema because of prostaglandin inhibition of afferent blood supply to glomeruli in the kidneys and, for similar reasons, a predilection toward reversible renal insufficiency. Blood pressure may increase modestly in some NSAID-treated patients. Oral NSAIDs should not be used in patients with stage 3, 4, or 5 renal disease. Intraarticular Injections: Glucocorticoids, Hyaluronic Acid, and Other Products  Because synovial inflammation is likely to be a major cause of pain in patients with OA, local anti-inflammatory treatments administered intraarticularly may be effective in ame­ liorating pain for up to 3 months. Glucocorticoid injections provide such efficacy, but response is variable, with some patients having little relief of pain, whereas most experience pain relief lasting up to several months. Synovitis, a major cause of joint pain in OA, may abate after an injection, and this correlates with the reduction in knee pain severity. Glucocorticoid injections are useful to get patients over acute flares of pain. Repeated injections may cause minor amounts of cartilage loss, but these do not appear to increase risk of disease progression, worsening pain, functional limitations, or the need for surgery. Hyaluronic acid injections can be given for treatment of symp­ toms in knee and hip OA, but most evidence suggests they have little efficacy versus placebo (Table 383-1). Few rigorous studies of intraarticular stem cell therapy and platelet-rich plasma (PRP) have been conducted to date. Further, the composition of the injected biologic materials reflecting stem cells or PRP has not been standardized, making it challenging to compare across studies due to variability in formulation. Other Classes of Drugs and Nutraceuticals  Opioids have only modest short-term efficacy in treating pain in hip or knee OA without evidence of long-term benefit and, given concerns about opioid dependency, should be avoided. If NSAIDs are ineffective, one option is the use of duloxetine, which is U.S. Food and Drug Administration approved for OA. Duloxetine may be particularly efficacious when knee pain is part of a syndrome of widespread pain. Biologic agents and disease-modifying agents used for rheuma­ toid arthritis have been tested for OA, but trials have mostly been negative. Notable exceptions are two randomized trials for hand OA, one of 6 weeks of prednisolone and the other of 6 months of methotrexate. Both trials demonstrated reductions in hand pain compared with placebo. In a large randomized trial, GLP1R ago­ nists reduced knee pain in obese patients. # 29 - 385 Fibromyalgia ### 385 Fibromyalgia Leslie J. Crofford Fibromyalgia ■ ■DEFINITION Fibromyalgia (FM) is characterized by chronic widespread musculo­ skeletal pain and tenderness. Although FM is defined primarily as a pain syndrome, patients also commonly report associated neuropsy­ chological symptoms of fatigue, unrefreshing sleep, cognitive dysfunc­ tion, anxiety, and depression. Patients with FM have an increased prevalence of other syndromes associated with pain and fatigue, including myalgic encephalitis/chronic fatigue syndrome (Chap. 461), temporomandibular disorder, chronic headaches, irritable bowel syn­ drome, interstitial cystitis/painful bladder syndrome, and other pelvic pain syndromes. These are collectively referred to as chronic primary or chronic overlapping pain conditions. Available evidence implicates the central nervous system as key to maintaining pain and other core symptoms of FM and related conditions. The presence of FM is asso­ ciated with substantial negative consequences for physical and social functioning. ■ ■EPIDEMIOLOGY Worldwide prevalence is ~2%, with a prevalence of ~4% in women and <1% in men. There is some variability depending on the method of ascertainment; however, the prevalence data are similar across world regions and socioeconomic classes. Cultural factors may play a role in determining whether patients with FM symptoms seek medical atten­ tion; however, even in cultures in which secondary gain is not expected to play a significant role, the prevalence of FM remains in this range. In clinical settings, a diagnosis of FM is far more common in women than in men, with a ratio of ~8:1. In population studies, the ratio of women to men is closer to 3:1. The prevalence of FM is much higher in patients with rheumatic diseases such as rheumatoid arthritis or systemic lupus erythematosus, where up to 30% have comorbid FM. Additional risk factors include sleep disturbances, physical inactivity, and overweight or obesity. ■ ■CLINICAL MANIFESTATIONS Pain and Tenderness  At presentation, patients with FM most commonly report “pain all over.” Widespread pain is operationalized as being present both above and below the waist on both sides of the body and involving the axial skeleton (neck, back, or chest). The pain attributable to FM is poorly localized, difficult to ignore, severe in its intensity, and associated with a reduced functional capacity. For a diag­ nosis of FM, pain should have been present most of the day on most days for at least 3 months. The pain of FM is associated with tenderness and increased evoked pain sensitivity. In clinical practice, this elevated sensitivity may be identified by pain induced by the pressure of a blood pressure cuff or skin roll tenderness. More formally, an examiner may complete a tender-point examination in which the examiner uses the thumbnail to exert pressure of ~4 kg/m2 (or the amount of pressure leading to blanching of the tip of the thumbnail) on well-defined musculoten­ dinous sites. Previously, the classification criteria of the American College of Rheumatology required that 11 of 18 sites be perceived as painful on exam for a diagnosis of FM. In practice, tenderness is a continuous variable, and strict application of a categorical threshold for diagnosis is not necessary. Newer criteria eliminate the need for identi­ fication of tender points and focus instead on patient-reported clinical symptoms of widespread or multisite pain and neuropsychological symptoms (Fig. 385-1). The newer criteria perform well in clinical set­ tings in comparison to the older, tender-point criteria. When subjective criteria are applied to populations, the result is an increase in preva­ lence of FM and a change in the sex ratio (see “Epidemiology,” earlier). Patients with FM often have peripheral pain generators that are thought to serve as triggers for the more widespread pain attributed to central nervous system factors. Potential pain generators such as arthritis, bursitis, tendinitis, neuropathies, and other inflammatory or degenerative conditions should be identified by history and physical examination. More subtle pain generators may include joint hypermo­ bility and scoliosis. In addition, patients may have chronic myalgias triggered by infectious, metabolic, or psychiatric conditions that can serve as triggers for the development of FM. These conditions are often identified in the differential diagnosis of patients with FM, and a major challenge is to distinguish the ongoing pain of a triggering condition from FM pain that is occurring as a consequence of a comorbid condi­ tion and that should itself be treated. CHAPTER 385 Fibromyalgia Neuropsychological Symptoms  In addition to widespread pain, FM patients typically report fatigue, stiffness, sleep disturbance, cogni­ tive dysfunction, anxiety, and depression. These symptoms are present to varying degrees in most FM patients but are not present in every patient or at all times in a given patient. Relative to pain, such symp­ toms may, however, have an equal or even greater impact on function and quality of life. Fatigue is highly prevalent in patients in primary care who ultimately are diagnosed with FM. Pain, stiffness, and fatigue often are worsened by exercise or unaccustomed activity. The sleep complaints include difficulty falling asleep, difficulty staying asleep, and early-morning awakening. Regardless of the specific complaint, patients awake feeling unrefreshed. Patients with FM may meet criteria for restless legs syndrome and sleep-disordered breathing; frank sleep apnea can also be documented. Cognitive issues are characterized as difficulties with attention or concentration, problems with word retrieval, and short-term memory loss. Studies have demonstrated altered cognitive function in these domains in patients with FM, although speed of processing is age appropriate. Symptoms of anxiety and depression are common, and the lifetime prevalence of mood disorders in patients with FM approaches 80%. Although depression is neither necessary nor sufficient for the diagnosis of FM, it is important to screen for major depressive disorders by querying for depressed mood and anhedonia. Analysis of genetic factors that are likely to pre­ dispose to FM reveals shared neurobiologic pathways with mood dis­ orders, providing the basis for comorbidity (see later in this chapter). Overlapping Syndromes  FM is considered as part of a group of conditions called chronic overlapping pain syndromes because of the propensity to coexist with other syndromes that may share underlying mechanisms. Review of systems often reveals headaches, facial/jaw pain, regional myofascial pain particularly involving the neck or back, and arthritis. Visceral pain involving the gastrointestinal tract, bladder, and pelvic or perineal region is often present as well. It is important for patients to understand that shared pathways may mediate symptoms and treatment strategies effective for one condition may help with global symptom management. Comorbid Conditions  FM is often comorbid with chronic mus­ culoskeletal, infectious, metabolic, or psychiatric conditions. Whereas FM affects only ~2% of the general population, it occurs in ~10–30% of patients with degenerative or inflammatory rheumatic disorders, likely because these conditions serve as peripheral pain generators to alter central pain-processing pathways. The proposition that there may be an inflammatory or autoimmune etiology for FM in some patients has not been rigorously tested to date. It is particularly important for clinicians to be sensitive to pain management of these comorbid con­ ditions so that when FM emerges—characterized by pain outside the boundaries of what could reasonably be explained by the triggering condition, development of neuropsychological symptoms, or tender­ ness on physical examination—treatment of central pain processes will be undertaken as opposed to a continued focus on treatment of peripheral or inflammatory causes of pain. Psychosocial Considerations  Symptoms of FM often have their onset and are exacerbated during periods of perceived stress. This pattern may reflect an interaction among central stress physiol­ ogy, vigilance or anxiety, and central pain-processing pathways. An understanding of current psychosocial stressors will aid in patient Generalized pain - do not count jaws, chest, or abdomen Widespread Pain Index (WPI score 0-19) Pain and tenderness during the past week Neck Region 5 Right jaw PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Left jaw Right shoulder Left shoulder Upper back Chest or breast Right upper arm Left upper arm Lower back Abdomen Right lower arm Left lower arm Left hip or buttocks Right hip or buttocks Right upper leg Left upper leg Left lower leg Right lower leg Widespread Pain Index (WPI) Total (maximum 19) All of the following criteria must be met to make a diagnosis of fibromyalgia = 3 = 3 = 3 No No = 0 1. WPI ≥ 7 and SSS ≥ 5 OR WPI 4 to 6 and SSS ≥ 9 Yes 2. Generalized pain: at least 4/5 regions Yes 3. Have the symptoms in section 3 and pain been present at a similar clinical level for at least 3 months? No Yes Fulfills all diagnostic criteria for FM No Yes FIGURE 385-1  Fibromyalgia (FM) 2016 diagnostic criteria. (Figure created using data from F Wolfe et al: Semin Arthritis Rheum 46:319, 2016.) management, as many factors that exacerbate symptoms cannot be addressed by pharmacologic approaches. Furthermore, there is a high prevalence of exposure to previous interpersonal and other forms of violence in patients with FM and related conditions. If posttraumatic stress disorder is an issue, the clinician should be aware of it and con­ sider treatment options. Functional Impairment  It is crucial to evaluate the impact of FM symptoms on function and role fulfillment. In defining the success of a management strategy, improved function is a key measure. Functional assessment should include physical, mental, and social domains. Rec­ ognition of the ways in which role functioning falls short will be helpful in establishing treatment goals. ■ ■DIFFERENTIAL DIAGNOSIS Because musculoskeletal pain is such a common complaint, the dif­ ferential diagnosis of FM is broad. Table 385-1 lists some of the more common conditions that should be considered. Patients with inflam­ matory causes for widespread pain should be identifiable on the basis of specific history, physical findings, and laboratory or radiographic tests. ■ ■LABORATORY OR RADIOGRAPHIC TESTING Routine laboratory and radiographic tests yield normal results in FM without comorbidities. Thus, diagnostic testing is focused on iden­ tification of other diagnoses and evaluation for pain generators or comorbid conditions (Table 385-2). Most patients with new chronic widespread pain should be assessed for the most common entities in the differential diagnosis. Radiographic testing should be used very sparingly and only for diagnosis of inflammatory arthritis. After the patient has been evaluated thoroughly, repeat testing is discouraged Region 1 Region 2 Region 4 Region 3 Generalized Pain Total (maximum 5) Sympton Severity Score (SSS range 0-12) Over the past week: No problem Slight or mild problem: generally mild or intermittent Moderate problem: considerable problems; often present and/or at a moderate level Severe problem: continuous, life-disturbing No problem Slight/mild Moderate Severe • Fatigue • Trouble thinking or remembering • Waking up tired (unrefreshed) = 1 = 1 = 1 = 2 = 2 = 2 = 0 = 0 During the past 6 months: • Pain or cramps in the abdomen • Depression • Headache No = 0 No = 0 No = 0 Yes = 1 Yes = 1 Yes = 1 Symptom Severity Score Total (maximum 12) unless the symptom complex changes. Particularly to be discouraged is magnetic resonance imaging (MRI) of the spine unless there are fea­ tures suggesting inflammatory spine disease or neurologic symptoms. ■ ■GENETICS AND PHYSIOLOGY As in most complex diseases, it is likely that a number of genes contribute to vulnerability to the development of FM. To date, these genes appear to be in pathways controlling pain and stress responses. Some of the genetic underpinnings of FM are shared across other chronic pain conditions. Genes associated with metabolism, transport, and receptors of serotonin and other monoamines have been implicated in FM and overlapping conditions. Genes associated with other pathways involved in pain transmission have also been described as vulnerability factors for FM. Taken together, the pathways in which polymorphisms have been identified in FM patients further implicate central factors in mediation of the physiology that leads to the clinical manifestations of FM. Psychophysical testing of patients with FM has demonstrated altered sensory afferent pain processing and impaired descending noxious inhibitory control leading to hyperalgesia and allodynia. Functional MRI and other research imaging procedures clearly demonstrate activation of the brain regions involved in the experience of pain in response to stimuli that are innocuous in study participants without FM. Pain perception in FM patients is influenced by the emotional and cognitive dimensions, such as catastrophizing and perceptions of control, providing a solid basis for recommendations for cognitive and behavioral treatment strategies. Studies have indicated that some patients meeting criteria for FM may have a small fiber neuropathy. There have also been early reports of a possible autoimmune etiology for changes in the TABLE 385-1  Common Conditions in the Differential Diagnosis of Fibromyalgia Inflammatory Polymyalgia rheumatica Inflammatory arthritis: rheumatoid arthritis, spondyloarthritides Connective tissue diseases: systemic lupus erythematosus, Sjögren’s syndrome Infectious Hepatitis C HIV infection Lyme disease Parvovirus B19 infection Epstein-Barr virus infection Noninflammatory Degenerative joint/spine/disk disease Myofascial pain syndromes Bursitis, tendinitis, repetitive strain injuries Endocrine Hypo- or hyperthyroidism Hyperparathyroidism Neurologic Diseases Multiple sclerosis Neuropathic pain syndromes Psychiatric Disease Major depressive disorder Drugs Statins Aromatase inhibitors peripheral nervous system in patients with FM. Other studies have identified alterations in expressed gene or metabolic signatures in peripheral blood. These studies raise the possibility that confirma­ tory diagnostic testing could be developed in the future to assist in the diagnosis of FM. APPROACH TO THE PATIENT Fibromyalgia FM is common and has an extraordinary impact on the patient’s function and health-related quality of life. Optimal management requires prompt diagnosis and assessment of pain, function, and psychosocial context. Physicians and other health professionals can be helpful in managing some of the symptoms and impact TABLE 385-2  Laboratory and Radiographic Testing in Patients with Fibromyalgia Symptoms Routine Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) Complete blood count (CBC) Thyroid-stimulating hormone (TSH) Guided by History and Physical Examination Complete metabolic panel Antinuclear antibody (ANA) Anti-SSA (anti–Sjögren’s syndrome A) and anti-SSB Rheumatoid factor and anti–cyclic citrullinated peptide (anti-CCP) Creatine phosphokinase (CPK) Viral (e.g., hepatitis C, HIV) and bacterial (e.g., Lyme) serologies Spine and joint radiographs Source: LM Arnold et al: J Women’s Health 21:231, 2012; MA Fitzcharles et al: J Rheumatol 40:1388, 2013. of FM. Developing a partnership with patients is essential for improving the outcome of FM, with a goal of understanding the factors involved, implementing a treatment strategy, and choosing appropriate nonpharmacologic and pharmacologic treatments. CHAPTER 385 TREATMENT Fibromyalgia Fibromyalgia NONPHARMACOLOGIC TREATMENT Patients with chronic pain, fatigue, and other neuropsychological symptoms require a framework for understanding the symptoms that have such an important impact on their function and qual­ ity of life. Explaining the genetics, triggers, and physiology of FM can be an important adjunct in relieving associated anxiety and in reducing the overall cost of health care resources. In addition, patients must be educated regarding expectations for treatment. The physician should focus on improved function and quality of life rather than elimination of pain. Illness behaviors, such as frequent physician visits, should be discouraged and behaviors that focus on improved function strongly encouraged. Treatment strategies should include physical conditioning, with encouragement to begin at low levels of aerobic exercise and to proceed with slow but consistent advancement. Physical activity and exercise are consistently found to be the most helpful strategies. Exercise programs are helpful in reducing tenderness and enhanc­ ing self-efficacy. Patients who have been physically inactive may do best in supervised or water-based programs at the start. Strength training may be recommended after patients reach their aerobic goals. The U.S. Food and Drug Administration has approved devices including a laser therapy device and a transcutaneous electric nerve stimulation (TENS) device. A large randomized, placebo-controlled trial showed that TENS reduces movementevoked pain and fatigue. Meditative movement therapies, such as qigong, yoga, or Tai Chi, may be helpful to manage symptoms. Other defined physical therapies such as acupuncture or hydro­ therapy may also be considered. Cognitive-behavioral strategies to improve sleep hygiene and reduce illness behaviors can also be helpful in management. PHARMACOLOGIC APPROACHES It is essential for the clinician to treat any comorbid triggering condi­ tion and to clearly delineate for the patient the treatment goals for each medication. For example, glucocorticoids or nonsteroidal antiinflammatory drugs may be useful for management of inflammatory triggers but are not effective against FM-related symptoms. At present, the treatment approaches that have proved most successful in FM patients target afferent or descending pain pathways. Table 385-3 lists the drugs with demonstrated effectiveness. It should be emphasized that strong opioid analgesics are to be avoided in patients with FM. These agents have no demonstrated efficacy in FM and are associated with adverse effects that can worsen both symptoms and function. Tramadol, an opioid with mild serotonin-noradrenaline reuptake inhibitor activity, has been studied in this population with indication of efficacy, however its use is generally discouraged due to opioid-related adverse effects. Use of single agents to treat multiple symptom domains is strongly encouraged. For example, if a patient’s symptom complex is dominated by pain and sleep distur­ bance, use of an agent that exerts both analgesic and sleep-promoting effects is desirable. These agents include cyclobenzaprine, sedating antidepressants such as amitriptyline, and alpha-2-delta ligands such as gabapentin and pregabalin. For patients whose pain is associated with fatigue, anxiety, or depression, drugs that have both analgesic and antidepressant/anxiolytic effects, such as duloxetine or milnacipran, may be the best first choice.