# 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