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62 Immunologically Mediated Skin Diseases

slow to heal, but when they do, irregularly shaped white scars form. The majority of cases are secondary to venous hypertension, but pos­ sible underlying illnesses include disorders of hypercoagulability, for example, antiphospholipid syndrome and factor V Leiden (Chaps. 122 and 369). In pyoderma gangrenosum, the border of untreated active ulcers has a characteristic appearance consisting of an undermined necrotic violaceous edge and a peripheral erythematous halo. The ulcers often begin as pustules that then expand rather rapidly to a size as large as 20 cm. Although these lesions are most commonly found on the lower extremities, they can arise anywhere on the surface of the body, including at sites of trauma (pathergy). An estimated 30–50% of cases are idiopathic, and the most common associated disorder is inflamma­ tory bowel disease. Less commonly, pyoderma gangrenosum is asso­ ciated with seropositive rheumatoid arthritis, myelodysplasia, acute myelogenous leukemia, a monoclonal gammopathy (usually IgA), or an autoinflammatory disorder. Because the histology of pyoderma gan­ grenosum may be nonspecific (dermal infiltrate of neutrophils when in untreated state), the diagnosis requires clinicopathologic correlation, in particular, the exclusion of similar-appearing ulcers such as vasculitis, Meleney’s ulcer (synergistic infection at a site of trauma or surgery), dimorphic fungi, cutaneous amebiasis, spider bites, and factitial. In the hematologic disorders, the ulcers may be more superficial with a pustulobullous border, and these lesions provide a connection between classic pyoderma gangrenosum and acute febrile neutrophilic derma­ tosis (Sweet syndrome). FEVER AND RASH The major considerations in a patient with a fever and a rash are inflammatory diseases versus infectious diseases. In the hospital set­ ting, the most common scenario is a patient who has a drug rash plus a fever secondary to an underlying infection. However, it should be emphasized that a drug reaction can lead to both a cutaneous eruption and a fever (“drug fever”), especially in the setting of DRESS, AGEP, or serum sickness–like reaction. Additional inflammatory diseases that are often associated with a fever include pustular psoriasis, erythro­ derma, and Sweet syndrome. Lyme disease, secondary syphilis, and viral and bacterial exanthems (see “Exanthems,” above) are examples of infectious diseases that produce a rash and a fever. Lastly, it is impor­ tant to determine whether or not the cutaneous lesions represent septic emboli (see “Purpura,” above). Such lesions usually have evidence of ischemia in the form of purpura, necrosis, or impending necrosis (gunmetal-gray color). In the patient with thrombocytopenia, however, purpura can be seen in inflammatory reactions such as morbilliform drug eruptions and infectious lesions. In addition, because of venous hypertension, lesions of a morbilliform drug eruption that are below the knee can be purpuric. ■ ■FURTHER READING Bolognia JL, Schaffer JV, Cerroni L (eds): Dermatology, 5th ed. Philadelphia, Elsevier, 2024. Callen JP et al (eds): Dermatological Signs of Systemic Disease, 5th ed. Edinburgh, Elsevier, 2017. Fazel N (ed): Oral Signs of Systemic Disease. Switzerland, Springer, 2019. Kurtzman D: Rheumatologic dermatology. Clin Dermatol 36:439, 2018. Taylor SC et al (eds): Taylor and Kelly’s Dermatology for Skin of Color, 2nd ed. New York, McGraw-Hill, 2016.

Kim B. Yancey, Benjamin F. Chong,

Thomas J. Lawley

Immunologically

Mediated Skin Diseases A number of immunologically mediated skin diseases and immuno­ logically mediated systemic disorders with cutaneous manifestations are now recognized as distinct entities with consistent clinical, his­ tologic, and immunopathologic findings. Clinically, these disorders are characterized by morbidity (pain, pruritus, disfigurement) and, in some instances, risk of mortality (largely due to loss of epidermal barrier function and/or secondary infection). The major features of the more common immunologically mediated skin diseases are sum­ marized in this chapter (Table 62-1), as are autoimmune systemic disorders with cutaneous manifestations. Immunologically Mediated Skin Diseases CHAPTER 62 AUTOIMMUNE CUTANEOUS DISEASES ■ ■PEMPHIGUS VULGARIS Pemphigus refers to a group of autoantibody-mediated intraepidermal blistering diseases characterized by loss of cohesion between epidermal cells (a process termed acantholysis). Manual pressure to the skin of these patients may elicit the separation of the epidermis (Nikolsky’s sign). This finding, while characteristic of pemphigus, is not specific to this group of disorders and is also seen in toxic epidermal necrolysis, Stevens-Johnson syndrome, and a few other skin diseases. Pemphigus vulgaris (PV) is a mucocutaneous blistering disease that predominantly occurs in patients >40 years of age. PV typically begins on mucosal surfaces and often progresses to involve the skin. This dis­ ease is characterized by fragile, flaccid blisters that rupture to produce extensive denudation of mucous membranes and skin (Fig. 62-1). The mouth, scalp, face, neck, axilla, groin, and trunk are typically involved. PV may be associated with severe skin pain; some patients experience pruritus as well. Lesions usually heal without scarring except at sites complicated by secondary infection or mechanically induced dermal wounds. Postinflammatory hyperpigmentation is usually present for some time at sites of healed lesions. Biopsies of early lesions demonstrate intraepidermal vesicle formation secondary to loss of cohesion between epidermal cells (i.e., acantholytic blisters). Blister cavities contain acantholytic epi­ dermal cells, which appear as round homogeneous cells containing hyperchromatic nuclei. Basal keratinocytes remain attached to the epidermal basement membrane; hence, blister formation takes place within the suprabasal portion of the epidermis. Lesional skin may contain focal collections of intraepidermal eosinophils within blister cavities; dermal alterations are slight, often limited to an eosino­ phil-predominant leukocytic infiltrate. Direct immunofluorescence microscopy of lesional or intact patient skin shows deposits of IgG on the surface of keratinocytes; deposits of complement components are typically found in lesional but not in uninvolved skin. Deposits of IgG on keratinocytes are derived from circulating autoantibodies to cell-surface autoantigens. Such circulating autoantibodies can be demonstrated in 80–90% of PV patients by indirect immunofluores­ cence microscopy; monkey esophagus is the optimal substrate for these studies. Patients with PV have IgG autoantibodies to desmo­ gleins (Dsgs), transmembrane desmosomal glycoproteins that belong to the cadherin family of calcium-dependent adhesion molecules. Such autoantibodies can be precisely quantitated by enzyme-linked immunosorbent assay (ELISA). Patients with early PV (i.e., mucosal disease) have IgG autoantibodies to Dsg3; patients with advanced PV (i.e., mucocutaneous disease) have IgG autoantibodies to both Dsg3 and Dsg1. Experimental studies have shown that autoanti­ bodies from patients with PV are pathogenic (i.e., responsible for blister formation) and that their titer correlates with disease activity.

TABLE 62-1  Immunologically Mediated Blistering Diseases DISEASE CLINICAL MANIFESTATIONS HISTOLOGY IMMUNOPATHOLOGY AUTOANTIGENSa Pemphigus vulgaris Oromucosal lesions, flaccid blisters, denuded skin Acantholytic blister formed in suprabasal layer of epidermis Pemphigus foliaceus Crusts and shallow erosions on scalp, central face, upper chest, and back Acantholytic blister formed in superficial layer of epidermis Paraneoplastic pemphigus Painful stomatitis with papulosquamous or lichenoid eruptions that may progress to blisters Acantholysis, keratinocyte necrosis, and vacuolar interface dermatitis PART 2 Cardinal Manifestations and Presentation of Diseases Bullous pemphigoid Large tense blisters on flexor surfaces and trunk Subepidermal blister with eosinophil-rich infiltrate Pemphigoid gestationis Pruritic, urticarial plaques rimmed by vesicles and bullae on the trunk and extremities Teardrop-shaped, subepidermal blisters in dermal papillae; eosinophil-rich infiltrate Dermatitis herpetiformis Extremely pruritic small papules and vesicles on elbows, knees, buttocks, and posterior neck Subepidermal blister with neutrophils in dermal papillae Linear IgA disease Pruritic papulovesicles on extensor surfaces; occasionally larger, arciform blisters Subepidermal blister with neutrophil-rich infiltrate Epidermolysis bullosa acquisita Blisters, erosions, scars, and milia on sites exposed to trauma; widespread, inflammatory, tense blisters may be seen initially Subepidermal blister that may or may not include a leukocytic infiltrate Mucous membrane pemphigoid Erosive and/or blistering lesions of mucous membranes and possibly the skin; scarring of some sites Subepidermal blister that may or may not include a leukocytic infiltrate aAutoantigens bound by these patients’ autoantibodies are defined as follows: Dsg1, desmoglein 1; Dsg3, desmoglein 3; BPAG1, bullous pemphigoid antigen 1; BPAG2, bullous pemphigoid antigen 2. Abbreviation: BMZ, basement membrane zone. Recent studies have shown that the anti-Dsg autoantibody profile in these patients’ sera as well as the tissue distribution of Dsg3 and Dsg1 determine the site of blister formation in patients with PV. Coexpression of Dsg3 and Dsg1 by epidermal cells protects against pathogenic IgG antibodies to either of these cadherins but not against pathogenic autoantibodies to both. PV can be life-threatening. Prior to the availability of glucocor­ ticoids, mortality rates ranged from 60% to 90%; the current figure is ~5%. Common causes of morbidity and death are infection and complications of treatment. Bad prognostic factors include advanced age, widespread involvement, and the requirement for high doses of glucocorticoids (with or without other immunosuppressive agents) for control of disease. The course of PV in individual patients is variable and difficult to predict. Some patients experience remis­ sion, while others may require long-term treatment or succumb to complications of their disease or its treatment. The mainstay of treatment is systemic glucocorticoids alone or in combination with other immunosuppressive agents. Patients with moderate to severe PV are usually started on prednisone at doses ≤1 mg/kg per day (single morning dose). If new lesions continue to appear after 1–2 weeks of treatment, the dose of prednisone may need to be increased and/ or combined with another immunosuppressive agent. Among these, rituximab in combination with prednisone often achieves remission (though maintenance therapy may be required to prevent relapse). Other immunosuppressive agents sometimes combined with pred­ nisone to treat PV include azathioprine, mycophenolate mofetil, or cyclophosphamide. Patients with severe, treatment-resistant disease may derive benefit from plasmapheresis (six high-volume exchanges [i.e., 2–3 L per exchange] over ~2 weeks) and/or IV immunoglobulin (IVIg). It is important to bring severe or progressive disease under control quickly in order to lessen the severity and/or duration of this disorder. Increasingly, rituximab and daily glucocorticoids are used early in PV patients to avert the development of advanced and/or treatment-resistant disease.

Cell surface deposits of IgG on keratinocytes Dsg3 (plus Dsg1 in patients with skin involvement) Cell surface deposits of IgG on keratinocytes Dsg1 Cell surface deposits of IgG and C3 on keratinocytes and (variably) similar immunoreactants in epidermal BMZ Plakin protein family members and desmosomal cadherins (see text for details) Linear band of IgG and/or C3 in epidermal BMZ BPAG1, BPAG2 Linear band of C3 in epidermal BMZ BPAG2 (plus BPAG1 in some patients) Granular deposits of IgA in dermal papillae Epidermal transglutaminase Linear band of IgA in epidermal BMZ BPAG2 (see text for specific details) Linear band of IgG and/or C3 in epidermal BMZ Type VII collagen Linear band of IgG, IgA, and/or C3 in epidermal BMZ BPAG2, laminin-332, or others ■ ■PEMPHIGUS FOLIACEUS Pemphigus foliaceus (PF) is distinguished from PV by several features. In PF, acantholytic blisters are located high within the epidermis, usu­ ally just beneath the stratum corneum. Hence, PF is a more superfi­ cial blistering disease than PV. The distribution of lesions in the two disorders is much the same, except that in PF mucous membranes are almost always spared. Patients with PF rarely have intact blisters but rather exhibit shallow erosions associated with erythema, scale, and crust formation. Mild cases of PF can resemble severe seborrheic dermatitis; severe PF may cause extensive exfoliation. Sun exposure (ultraviolet irradiation) may be an aggravating factor. PF has immunopathologic features in common with PV. Specifically, direct immunofluorescence microscopy of perilesional skin demon­ strates IgG on the surface of keratinocytes. Similarly, patients with PF have circulating IgG autoantibodies directed against the surface of keratinocytes. In PF, autoantibodies are directed against Dsg1, a 160kDa desmosomal cadherin. These autoantibodies can be quantitated by ELISA. As noted for PV, the autoantibody profile in patients with PF (i.e., anti-Dsg1 IgG) and the tissue distribution of this autoantigen (i.e., expression in oral mucosa that is compensated by coexpression of Dsg3) are thought to account for the distribution of lesions in this disease. Endemic forms of PF are found in south-central rural Brazil, where the disease is known as fogo salvagem (FS), as well as in selected sites in Latin America and Tunisia. Endemic PF, like other forms of this disease, is mediated by IgG autoantibodies to Dsg1. Clusters of FS overlap with those of leishmaniasis, a disease transmitted by bites of the sand fly Lutzomyia longipalis. Studies have shown that sand fly salivary antigens (specifically, the LJM11 salivary protein) are recognized by IgG autoantibodies from FS patients (as well as by monoclonal anti­ bodies to Dsg1 derived from these patients). The demonstration that mice immunized with LJM11 produce antibodies to Dsg1 suggests that insect bites may deliver salivary antigens, initiate a cross-reactive humoral immune response, and lead to FS in genetically susceptible individuals.

A B FIGURE 62-1  Pemphigus vulgaris. A. Flaccid bullae are easily ruptured, resulting in multiple erosions and crusted plaques. B. Involvement of the oral mucosa, which is almost invariable, may present with erosions on the gingiva, buccal mucosa, palate, posterior pharynx, or tongue. (Courtesy of Robert Swerlick, MD; with permission.) Although pemphigus has been associated with several autoimmune diseases, its association with thymoma and/or myasthenia gravis is particularly notable. To date, >30 cases of thymoma and/or myasthenia gravis have been reported in association with pemphigus, usually with PF. Patients may also develop pemphigus as a consequence of drug exposure; drug-induced pemphigus usually resembles PF rather than PV. Drugs containing a thiol group in their chemical structure (e.g., penicillamine, captopril, enalapril) are most commonly associated with drug-induced pemphigus. Nonthiol drugs linked to pemphigus include penicillins, cephalosporins, and piroxicam. Some cases of drug-induced pemphigus are durable and require treatment with systemic glucocor­ ticoids and/or immunosuppressive agents. PF is generally a less severe disease than PV and usually carries a better prognosis. Localized disease can sometimes be treated with topical or intralesional glucocorticoids; more active cases can usually be controlled with systemic glucocorticoids either alone or in com­ bination with other immunosuppressive agents. Patients with severe, treatment-resistant disease may require more aggressive interventions, as described above for patients with PV.

■ ■PARANEOPLASTIC PEMPHIGUS Paraneoplastic pemphigus (PNP) is an autoimmune acantholytic mucocutaneous disease associated with an occult or confirmed neoplasm. Patients with PNP typically have painful stomatitis in association with papulosquamous and/or lichenoid eruptions that often progress to blisters. Palm and sole involvement are common in these patients and raise the possibility that prior reports of neoplasia-

associated erythema multiforme may have represented unrecognized cases of PNP. Biopsies of lesional skin from these patients show varying combinations of acantholysis, keratinocyte necrosis, and vacuolar-interface dermatitis. Direct immunofluorescence microscopy of a patient’s skin shows deposits of IgG and complement on the surface of keratinocytes and (variably) similar immunoreactants in the epidermal basement membrane zone. Patients with PNP have IgG autoantibodies to cytoplasmic proteins that are members of the pla­ kin family (e.g., desmoplakins I and II, bullous pemphigoid antigen [BPAG] 1, envoplakin, periplakin, and plectin) and to other proteins (e.g., Dsg1, Dsg3, and α2-macroglobulin like-1). Passive transfer studies have shown that autoantibodies from patients with PNP are pathogenic in animal models.

Immunologically Mediated Skin Diseases CHAPTER 62 The predominant neoplasms associated with PNP are non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, thymoma, spindle cell tumors, Waldenström’s macroglobulinemia, and Castleman’s disease; the last-mentioned neoplasm is particularly common among children with PNP. Rare cases of seronegative PNP have been reported in patients with B-cell malignancies previously treated with rituximab. In addition to severe skin lesions, many patients with PNP develop life-threatening bronchiolitis obliterans. PNP is generally resistant to conventional therapies (i.e., those used to treat PV); rarely, a patient’s disease may ameliorate or even remit following ablation or removal of underlying neoplasms. ■ ■BULLOUS PEMPHIGOID Bullous pemphigoid (BP) is a polymorphic autoimmune subepidermal blistering disease usually seen in the elderly. Initial lesions may consist of urticarial plaques; most patients eventually display tense vesicles or blisters on either normal-appearing or erythematous skin (Fig. 62-2). The lesions are usually distributed over the lower abdomen, groin, and flexor surface of the extremities; oral mucosal lesions are found in some patients. Pruritus may be nonexistent or severe. As lesions evolve, tense blisters tend to rupture and be replaced by erosions with or with­ out surmounting crust. Nontraumatized blisters heal without scarring. FIGURE 62-2  Bullous pemphigoid with tense vesicles and bullae on erythematous, urticarial bases. (Courtesy of the Yale Resident’s Slide Collection; with permission.)

The major histocompatibility complex class II allele HLA-DQβ1∗0301 is prevalent in patients with BP. Though most cases occur sporadically, BP can be triggered by medications (e.g., furosemide, dipeptidyl peptidase-4 inhibitors, immune checkpoint inhibitors), ultraviolet light, or ionizing radiation. Several studies have shown that BP is associated with neurologic diseases (e.g., stroke, dementia, Parkinson’s disease, and multiple sclerosis).

Biopsies of early lesional skin demonstrate subepidermal blisters and histologic features that roughly correlate with the clinical character of the lesion under study. Lesions on normal-appearing skin generally contain a sparse perivascular leukocytic infiltrate with some eosino­ phils; conversely, biopsies of inflammatory lesions typically show an eosinophil-rich infiltrate at sites of vesicle formation and in perivas­ cular areas. In addition to eosinophils, cell-rich lesions also contain mononuclear cells and neutrophils. It is not possible to distinguish BP from other subepidermal blistering diseases by routine histologic studies alone. PART 2 Cardinal Manifestations and Presentation of Diseases Direct immunofluorescence microscopy of normal-appearing per­ ilesional skin from patients with BP shows linear deposits of IgG and/ or C3 in the epidermal basement membrane. The sera of ~70% of these patients contain circulating IgG autoantibodies that bind the epidermal basement membrane of normal human skin in indirect immunofluo­ rescence microscopy. IgG from an even higher percentage of patients reacts with the epidermal side of 1 M NaCl split skin (an alternative immunofluorescence microscopy test substrate used to distinguish circulating IgG autoantibodies to the basement membrane in patients with BP from those in patients with similar, yet different, subepidermal blistering diseases; see below). In BP, circulating autoantibodies recog­ nize 230- and 180-kDa hemidesmosome-associated proteins in basal keratinocytes (i.e., BPAG1 and BPAG2, respectively). Autoantibodies to BPAG2 are thought to deposit in situ, activate complement, produce dermal mast-cell degranulation, and generate granulocyte-rich infil­ trates that cause tissue damage and blister formation. BP may persist for months to years, with exacerbations or remis­ sions. Extensive involvement may result in widespread erosions and compromise cutaneous integrity; elderly and/or debilitated patients may die. Local or minimal disease can sometimes be controlled with potent topical glucocorticoids alone; more extensive lesions generally respond to systemic glucocorticoids either alone or in combination with other agents. Adjuncts to systemic glucocorticoids include doxy­ cycline, azathioprine, mycophenolate mofetil, and rituximab. ■ ■PEMPHIGOID GESTATIONIS Pemphigoid gestationis (PG), also known as herpes gestationis, is a rare, nonviral, subepidermal blistering disease of pregnancy and the puerperium. PG may begin during any trimester of pregnancy or present shortly after delivery. Lesions are usually distributed over the abdomen, trunk, and extremities; mucous membrane lesions are rare. Skin lesions in these patients may be quite polymorphic and consist of erythematous urticarial papules and plaques, vesiculopapules, and/ or frank bullae. Lesions are almost always extremely pruritic. Severe exacerbations of PG frequently follow delivery, typically within 24–48 h. PG tends to recur in subsequent pregnancies, often beginning earlier during such gestations. Brief flare-ups of disease may occur with resumption of menses and may develop in patients later exposed to oral contraceptives. Occasionally, infants of affected mothers have transient skin lesions. Biopsies of early lesional skin show teardrop-shaped subepidermal vesicles forming in dermal papillae in association with an eosinophil-rich leukocytic infiltrate. Differentiation of PG from other subepidermal bullous diseases by light microscopy is difficult. However, direct immunofluorescence microscopy of perilesional skin from PG patients reveals the immunopathologic hallmark of this disorder: linear depos­ its of C3 in the epidermal basement membrane. These deposits develop as a consequence of complement activation produced by low-titer IgG anti–basement membrane autoantibodies directed against BPAG2, the same hemidesmosome-associated protein that is targeted by auto­ antibodies in patients with BP—a subepidermal bullous disease that resembles PG clinically, histologically, and immunopathologically.

The goals of therapy in patients with PG are to prevent the devel­ opment of new lesions, relieve intense pruritus, and care for erosions at sites of blister formation. Many patients require treatment with moderate doses of daily glucocorticoids (i.e., 20–40 mg of prednisone) at some point in their course. Mild cases (or brief flare-ups) may be controlled by vigorous use of potent topical glucocorticoids. Infants born of mothers with PG appear to be at increased risk of being born slightly premature or “small for dates.” Current evidence suggests that there is no difference in the incidence of uncomplicated live births between PG patients treated with systemic glucocorticoids and those managed more conservatively. If systemic glucocorticoids are admin­ istered, newborns are at risk for development of reversible adrenal insufficiency. ■ ■DERMATITIS HERPETIFORMIS Dermatitis herpetiformis (DH) is an intensely pruritic, papulovesicular skin disease characterized by lesions symmetrically distributed over extensor surfaces (i.e., elbows, knees, buttocks, back, scalp, and pos­ terior neck) (see Fig. 59-8). Primary lesions in this disorder consist of papules, papulovesicles, or urticarial plaques. Because pruritus is prominent, patients may present with excoriations and crusted papules but no observable primary lesions. Patients sometimes report that their pruritus has a distinctive burning or stinging component; the onset of such local symptoms reliably heralds the development of distinct clinical lesions 12–24 h later. Almost all DH patients have associated, usually subclinical, gluten-sensitive enteropathy (Chap. 336), and

90% express the HLA-B8/DRw3 and HLA-DQw2 haplotypes. DH may present at any age, including in childhood; onset in the second to fourth decades is most common. The disease is typically chronic. Biopsy of early lesional skin reveals neutrophil-rich infiltrates within dermal papillae. Neutrophils, fibrin, edema, and microvesicle forma­ tion at these sites are characteristic of early disease. Older lesions may demonstrate nonspecific features of a subepidermal bulla or an excori­ ated papule. Because the clinical and histologic features of this disease can be variable and resemble those of other subepidermal blistering disorders, the diagnosis is confirmed by direct immunofluorescence microscopy of normal-appearing perilesional skin. Such studies dem­ onstrate granular deposits of IgA (with or without complement com­ ponents) in the papillary dermis and along the epidermal basement membrane zone. IgA deposits in the skin are unaffected by control of disease with medication; however, these immunoreactants diminish in intensity or disappear in patients maintained for long periods on a strict gluten-free diet (see below). Patients with DH have granular deposits of IgA in their epidermal basement membrane zone and should be distinguished from individuals with linear IgA deposits at this site (see below). Although most DH patients do not report overt gastrointestinal symptoms or have laboratory evidence of malabsorption, biopsies of the small bowel usually reveal blunting of intestinal villi and a lympho­ cytic infiltrate in the lamina propria. As is true for patients with celiac disease, this gastrointestinal abnormality can be reversed by a glutenfree diet. Moreover, if maintained, this diet alone may control the skin disease and eventuate in clearance of IgA deposits from these patients’ epidermal basement membrane zones. Subsequent gluten exposure in such patients alters the morphology of their small bowel, elicits a flare-up of their skin disease, and is associated with the reappearance of IgA in their epidermal basement membrane zones. As in patients with celiac disease, dietary gluten sensitivity in patients with DH is associated with IgA anti-endomysial autoantibodies that target tissue transglutaminase. Studies indicate that patients with DH also have high-avidity IgA autoantibodies to epidermal transglutaminase and that the latter is co-localized with granular deposits of IgA in the papil­ lary dermis of DH patients. Patients with DH also have an increased incidence of thyroid abnormalities, achlorhydria, atrophic gastritis, and autoantibodies to gastric parietal cells. These associations likely relate to the high frequency of the HLA-B8/DRw3 haplotype in these patients, since this marker is commonly linked to autoimmune disor­ ders. The mainstay of treatment of DH is dapsone, a sulfone. Patients respond rapidly (24–48 h) to dapsone but require careful pretreatment

evaluation (e.g., screening for glucose-6-phosphate dehydrogenase deficiency) and close follow-up to ensure that complications are avoided or controlled. All patients taking dapsone at ≥100 mg/d will have some hemolysis and methemoglobinemia, which are expected pharmacologic side effects of this agent. Gluten restriction can control DH and lessen dapsone requirements; this diet must rigidly exclude gluten to be of maximal benefit. Many months of dietary restriction may be necessary before a beneficial result is achieved. Good dietary counseling by a trained dietitian is essential. ■ ■LINEAR IGA DISEASE Linear IgA disease, once considered a variant form of DH, is actually a separate and distinct entity. Clinically, patients with linear IgA disease may resemble individuals with DH, BP, or other subepidermal blister­ ing diseases. Lesions typically consist of papulovesicles, bullae, and/or urticarial plaques that develop predominantly on central or flexural sites. Oral mucosal involvement occurs in some patients. Severe pru­ ritus resembles that seen in patients with DH. Patients with linear IgA disease do not have an increased frequency of the HLA-B8/DRw3 hap­ lotype or an associated enteropathy and therefore are not candidates for treatment with a gluten-free diet. Histologic alterations in early lesions may be virtually indistinguish­ able from those in DH. However, direct immunofluorescence micros­ copy of normal-appearing perilesional skin reveals a linear band of IgA (and often C3) in the epidermal basement membrane zone. Most patients with linear IgA disease have circulating IgA anti-basement membrane autoantibodies directed against neoepitopes in the pro­ teolytically processed extracellular domain of BPAG2. These patients generally respond to treatment with dapsone (50–200 mg/d) alone or in combination with low daily doses of prednisone. ■ ■EPIDERMOLYSIS BULLOSA ACQUISITA Epidermolysis bullosa acquisita (EBA) is a rare, noninherited, poly­ morphic, chronic, subepidermal blistering disease. (The inherited form is discussed in Chap. 425.) Patients with classic or noninflam­ matory EBA have blisters on noninflamed skin, atrophic scars, milia, nail dystrophy, hair loss, and oral lesions. Because lesions generally occur at sites exposed to minor trauma, classic EBA is considered a mechanobullous disease. Other patients with EBA have widespread inflammatory scarring and bullous lesions that resemble severe BP. Inflammatory EBA may evolve into the classic, noninflammatory form of this disease. Rarely, patients present with lesions that pre­ dominate on mucous membranes. The HLA-DR2 haplotype is found with increased frequency in EBA patients. Studies suggest that EBA is sometimes associated with inflammatory bowel disease (especially Crohn’s disease). The histology of lesional skin varies with the character of the lesion being studied. Noninflammatory bullae are subepidermal, feature a sparse leukocytic infiltrate, and resemble the lesions in patients with porphyria cutanea tarda. Inflammatory lesions consist of

neutrophil-rich subepidermal blisters. EBA patients have continu­ ous deposits of IgG (and frequently C3) in a linear pattern within the epidermal basement membrane zone. Ultrastructurally, these immunoreactants are found in the sublamina densa region in associa­ tion with anchoring fibrils. Approximately 50% of EBA patients have demonstrable circulating IgG anti-basement membrane autoantibodies directed against type VII collagen—the collagen species that makes up anchoring fibrils. Such IgG autoantibodies bind the dermal side of 1 M NaCl split skin (in contrast to IgG autoantibodies in patients with BP). Studies have shown that passive transfer of experimental or patient IgG against type VII collagen can produce lesions in mice that clinically, histologically, and immunopathologically resemble those in patients with EBA. Treatment of EBA is generally unsatisfactory. Some patients with inflammatory EBA may respond to systemic glucocorticoids, either alone or in combination with immunosuppressive agents. Other patients (especially those with neutrophil-rich inflammatory lesions) may respond to dapsone. The chronic, noninflammatory form of EBA is largely resistant to treatment, although some patients may respond

to prednisone in combination with rituximab, cyclosporine, mycophe­ nolate mofetil, azathioprine, or IVIg.

■ ■MUCOUS MEMBRANE PEMPHIGOID Mucous membrane pemphigoid (MMP) is a rare, acquired, subepithe­ lial immunobullous disease characterized by erosive lesions of mucous membranes and skin that result in scarring of at least some sites of involvement. Common sites include the oral mucosa (especially the gingiva) and conjunctiva; other sites that may be affected include the nasopharyngeal, laryngeal, esophageal, and anogenital mucosa. Skin lesions (present in about one-third of patients) tend to predominate on the scalp, face, and upper trunk and generally consist of a few scat­ tered erosions or tense blisters on an erythematous or urticarial base. MMP is typically a chronic and progressive disorder. Serious compli­ cations may arise as a consequence of ocular, laryngeal, esophageal, or anogenital lesions. Erosive conjunctivitis may result in shortened fornices, symblepharon, ankyloblepharon, entropion, corneal opaci­ ties, and (in severe cases) blindness. Similarly, erosive lesions of the larynx may cause hoarseness, pain, and tissue loss that, if unrecognized and untreated, may eventuate in complete destruction of the airway. Esophageal lesions may result in stenosis and/or strictures that could place patients at risk for aspiration. Strictures may also complicate anogenital involvement. Immunologically Mediated Skin Diseases CHAPTER 62 Biopsies of lesional tissue generally show subepithelial vesicu­ lobullae and a mononuclear leukocytic infiltrate. Neutrophils and eosinophils may be seen in biopsies of early lesions; older lesions may demonstrate a scant leukocytic infiltrate and fibrosis. Direct immu­ nofluorescence microscopy of perilesional tissue typically reveals deposits of IgG, IgA, and/or C3 in the epidermal basement membrane. Because many patients with MMP exhibit no evidence of circulating anti-basement membrane autoantibodies, testing of perilesional skin is important diagnostically. Although MMP was once thought to be a single nosologic entity, it is now largely regarded as a disease pheno­ type that may develop as a consequence of an autoimmune reaction to a variety of molecules in the epidermal basement membrane (e.g., BPAG2, laminin-332, type VII collagen, α6β4 integrin) and other anti­ gens yet to be completely defined. Studies suggest that MMP patients with autoantibodies to laminin-332 have an increased relative risk for cancer. Treatment of MMP is largely dependent upon the sites of involvement. Due to potentially severe complications, patients with ocular, laryngeal, esophageal, and/or anogenital involvement require aggressive systemic treatment with dapsone, prednisone, or the latter in combination with other immunosuppressive agents (e.g., rituximab, azathioprine, mycophenolate mofetil, or cyclophosphamide), or IVIg. Less threatening forms of the disease may be managed with topical or intralesional glucocorticoids. AUTOIMMUNE SYSTEMIC DISEASES WITH PROMINENT CUTANEOUS FEATURES ■ ■DERMATOMYOSITIS The cutaneous manifestations of dermatomyositis (Chap. 377) are often distinctive but at times may resemble those of systemic lupus erythematosus (SLE) (Chap. 368), scleroderma (Chap. 372), or other overlapping connective tissue diseases (Chap. 372). The extent and severity of cutaneous disease may or may not correlate with the extent and severity of the myositis. The cutaneous manifestations of dermato­ myositis are similar, whether the disease appears in children or in the elderly, except that calcification of subcutaneous tissue is a common late sequela in childhood dermatomyositis. Dermatomyositis may be associated with interstitial lung disease or cancer. The cutaneous signs of dermatomyositis may precede or follow the development of myositis by weeks to years. Cases lacking muscle involvement (i.e., dermatomyositis sine myositis or amyopathic derma­ tomyositis) have been reported. The most common manifestation is a purple-red discoloration of the upper eyelids, sometimes associated with scaling (“heliotrope” erythema; Fig. 62-3) and periorbital edema. Erythema on the cheeks and nose in a “butterfly” distribution may resemble the malar eruption of SLE. Erythematous or violaceous thin,

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 62-3  Dermatomyositis. Periorbital violaceous erythema characterizes the classic heliotrope rash. (Courtesy of James Krell, MD; with permission.) scaly plaques are common on the upper trunk and neck (shawl sign), the scalp, lateral aspects of the thighs (holster sign), and the extensor surfaces of the forearms and hands (tendon streaking). Approximately one-third of patients have violaceous, flat-topped papules over the dor­ sal interphalangeal joints that are pathognomonic of dermatomyositis (Gottron’s papules) (Fig. 62-4). Thin violaceous papules and plaques on the elbows and knees of patients with dermatomyositis are referred to as Gottron’s sign. These lesions can be contrasted with the erythema and scaling on the dorsum of the fingers that spares the skin over the interphalangeal joints of some SLE patients. Periungual telangiectasias and edema may be prominent in patients with dermatomyositis. Other patients, particularly those with long-standing disease, develop areas of hypopigmentation, hyperpigmentation, mild atrophy, and telangi­ ectasia known as poikiloderma. Poikiloderma is rare in both SLE and FIGURE 62-4  Dermatomyositis showing involvement of the hands with erythematous flat-topped papules over the joints (i.e., Gottron’s papules) as well as periungual erythema and telangiectasias. (Courtesy of Justin Cheeley, MD; with permission.)

scleroderma and thus can serve as a clinical sign that distinguishes dermatomyositis from these two diseases. Cutaneous changes may be similar in dermatomyositis and various overlap syndromes where thickening and binding down of the skin of the hands (sclerodactyly) as well as Raynaud’s phenomenon can be seen. However, the presence of severe muscle disease, Gottron’s papules, heliotrope erythema, and poikiloderma serves to distinguish patients with dermatomyositis. Skin biopsy of the erythematous, scaling lesions of dermatomyositis may reveal only mild nonspecific inflammation, but sometimes may show changes indistinguishable from those found in cutaneous lupus erythe­ matosus (LE), including epidermal atrophy, hydropic degeneration of basal keratinocytes, and dermal changes consisting of interstitial mucin deposition and a mild mononuclear cell perivascular infiltrate. Direct immunofluorescence microscopy of lesional skin is usually negative, although granular deposits of immunoglobulin(s) and complement in the epidermal basement membrane zone have been described in some patients. Treatment should be stratified based on the relative severity of disease. Topical treatments include glucocorticoids, sunscreens, and aggressive photoprotective measures. Treatment of systemic disease includes antimalarials (though some patients may develop a drug eruption upon initiation of therapy) or systemic glucocorticoids in conjunction with methotrexate, mycophenolate mofetil, azathioprine, rituximab, or IVIg. ■ ■LUPUS ERYTHEMATOSUS The cutaneous manifestations of LE (Chap. 368) can be divided into acute, subacute, and chronic types. Acute cutaneous LE is characterized by erythema of the nose and malar eminences in a “butterfly” distribu­ tion (Fig. 62-5A). The erythema is often sudden in onset, accompanied by edema and fine scale, and correlated with systemic involvement. Patients may have widespread involvement of the face as well as ery­ thema and scaling of the extensor surfaces of the extremities and upper chest (Fig. 62-5B). These acute lesions, while sometimes evanescent, usually last for days and are often associated with exacerbations of systemic disease. Skin biopsy of acute lesions typically shows hydropic degeneration of basal keratinocytes, dermal edema, and (in some cases) a sparse perivascular infiltrate of mononuclear cells in the upper dermis as well as dermal mucin. Direct immunofluorescence micros­ copy of lesional skin frequently reveals deposits of immunoglobulin(s) and complement in the epidermal basement membrane zone. Treat­ ment of cutaneous disease includes topical glucocorticoids, aggressive photoprotection, antimalarials, and control of systemic disease. Treat­ ment of systemic disease associated with acute cutaneous LE includes systemic glucocorticoids in conjunction with antimalarials and other immunosuppressive agents. Subacute cutaneous lupus erythematosus (SCLE) is characterized by a widespread photosensitive, nonscarring eruption. In most patients, renal and central nervous system involvement is mild or absent. SCLE may present as a papulosquamous eruption that resembles psoriasis or as annular polycyclic lesions. In the papulosquamous form, discrete erythematous papules arise on the upper back, upper chest, shoulders, extensor surfaces of the arms, and dorsum of the hands; lesions are uncommon on the central face and the flexor surfaces of the arms as well as below the waist. These slightly scaling papules tend to merge into plaques. The annular form involves the same areas and presents with erythematous papules that evolve into oval, circular, or poly­ cyclic lesions. The lesions of SCLE are more widespread than those in patients with discoid LE and have less tendency for scarring. In many patients with SCLE, drugs (e.g., hydrochlorothiazide, calcium channel blockers, antifungals, proton pump inhibitors) may induce or exacerbate disease. Skin biopsy typically reveals epidermal changes that include atrophy, hydropic degeneration of basal keratinocytes, and apoptosis accompanied by an infiltrate of mononuclear cells in the upper dermis. Direct immunofluorescence microscopy of lesional skin reveals deposits of immunoglobulin(s) in the epidermal basement membrane zone in about one-half of these cases. A particulate pattern of IgG deposition throughout the epidermis has been associated with SCLE. Most SCLE patients have anti-Ro autoantibodies. Local therapy alone is usually unsuccessful. Most patients require treatment with

A B FIGURE 62-5  Acute cutaneous lupus erythematosus (LE). A. Acute cutaneous LE on the face, showing prominent, scaly, malar erythema. Involvement of other sun-exposed sites is also common. B. Acute cutaneous LE on the upper chest, demonstrating brightly erythematous and slightly edematous papules and plaques. (Courtesy of Robert Swerlick, MD; with permission.) aminoquinoline antimalarial drugs. Low-dose therapy with oral glu­ cocorticoids is sometimes necessary. Photoprotective measures against both ultraviolet B and ultraviolet A wavelengths are very important. Chronic cutaneous LE has multiple subtypes; discoid LE (DLE) is the most common. DLE is characterized by discrete lesions, most often found on the face, scalp, and/or external ears. It is unusual to see DLE lesions below the neck without lesions above the neck. The lesions are erythematous papules or plaques with a thick, adherent scale that occludes hair follicles (follicular plugging). When the scale is removed, its underside shows small excrescences that correlate with the openings of hair follicles (so-called “carpet tacking”), a finding relatively specific for DLE. Long-standing lesions develop central atrophy, scarring, and hypopigmentation but frequently have erythematous, sometimes raised borders (Fig. 62-6). These lesions persist for years and tend to expand slowly. Up to 20% of patients with DLE eventually meet the American College of Rheumatology criteria for SLE, but lower percentages of DLE patients develop SLE under the Systemic Lupus International Collaborating Clinics classification criteria and European League Against Rheumatism and American College of Rheumatology classification criteria. Typical discoid lesions are frequently seen in patients with SLE. Biopsy of DLE lesions shows hyperkeratosis, follicular plugging, atrophy of the epidermis, hydropic degeneration of basal keratinocytes, thickening of the epidermal basement membrane zone,

Immunologically Mediated Skin Diseases CHAPTER 62 FIGURE 62-6  Discoid lupus erythematosus (DLE). Erythematous to violaceous, dyspigmented, atrophic plaques with scarring of the face and scalp. (Courtesy of Robert Swerlick, MD; with permission.) dermal mucin, and a mononuclear cell infiltrate adjacent to epidermal, adnexal, and microvascular basement membranes. Direct immuno­ fluorescence microscopy demonstrates immunoglobulin(s) and com­ plement deposits at the basement membrane zone in ~90% of cases. Treatment is focused on control of local cutaneous disease and consists mainly of photoprotection and topical or intralesional glucocorticoids. If local therapy is ineffective, use of aminoquinoline antimalarial agents may be indicated. ■ ■SCLERODERMA AND MORPHEA The skin changes of scleroderma (Chap. 372) may be limited or dif­ fuse. In both instances, disease usually begins on the fingers, hands, toes, feet, and face, with episodes of recurrent nonpitting edema. Sclerosis of the skin commences distally on the fingers (sclerodac­ tyly) and spreads proximally, usually accompanied by resorption of bone of the fingertips, which may have punched out ulcers, stellate scars, or areas of hemorrhage (Fig. 62-7). The fingers may shrink and become sausage-shaped, and, because the fingernails are usually unaffected, they may curve over the end of the fingertips. Periungual telangiectasias are usually present, but periungual erythema is rare. In diffuse disease, the extremities show contractures and calcinosis cutis; facial involvement includes a smooth, unwrinkled brow, taut skin over the nose, shrinkage of tissue around the mouth, and perioral radial FIGURE 62-7  Scleroderma showing acral sclerosis, matlike telangiectasias, and focal digital ulcers.  (Courtesy of Justin Cheeley, MD; with permission.)