The inflammatory myopathies represent the largest group of acquired and potentially treatable causes of skeletal muscle weakness. They are classified into three major groups: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM).
Clinical Features
The prevalence of the inflammatory myopathies is estimated at 1 in 100,000. PM as a stand-alone entity is a rare disease affecting adults. DM affects both children and adults and women more often than men. IBM is three times more frequent in men than in women, more common in Caucasians than blacks, and is most likely to affect persons >50 years of age.
These disorders present as progressive and symmetric muscle weakness except for IBM, which can have an asymmetric pattern. Patients usually report increasing difficulty with everyday tasks requiring the use of proximal muscles, such as getting up from a chair, climbing steps, stepping onto a curb, lifting objects, or combing hair. Fine-motor movements that depend on the strength of distal muscles, such as buttoning a shirt, sewing, knitting, or writing, are affected only late in the course of PM and DM, but fairly early in IBM. Falling is common in IBM because of early involvement of the quadriceps muscle with buckling of the knees. Ocular muscles are spared, even in advanced, untreated cases; if these muscles are affected, the diagnosis of inflammatory myopathy should be questioned. Facial muscles are unaffected in PM and DM, but mild facial muscle weakness is common in patients with IBM. In all forms of inflammatory myopathy, pharyngeal and neck-flexor muscles are often involved, causing dysphagia or difficulty in holding up the head (head drop). In advanced and rarely in acute cases, respiratory muscles may also be affected. Severe weakness, if untreated, is almost always associated with muscle wasting. Sensation remains normal. The tendon reflexes are preserved but may be absent in severely weakened or atrophied muscles, especially in IBM where atrophy of the quadriceps and the distal muscles is common. Myalgia and muscle tenderness may occur in a small number of patients, usually early in the disease, and particularly in DM associated with connective tissue disorders.Weakness in PM and DM progresses subacutely over a period of weeks or months and rarely acutely; by contrast, IBM progresses very slowly, over years, simulating a late-life muscular dystrophy or slowly progressive motor neuron disorder.
Specific Features
Polymyositis
The actual onset of PM is often not easily determined, and patients typically delay seeking medical advice for several months.
TABLE 16-1
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FEATURES ASSOCIATED WITH INFLAMMATORY MYOPATHIES |
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|
CHARACTERISTIC |
POLYMYOSITIS |
DERMATOMYOSITIS |
INCLUSION BODY MYOSITIS |
|
Age at onset |
>18 yr |
Adulthood and childhood |
>50 yr |
|
Familial association |
No |
No |
Yes, in some cases |
|
Extramuscular manifestations |
Yes |
Yes |
Yes |
|
Associated conditions |
|||
|
Connective tissue diseases |
Yesa |
Scleroderma and mixed connective tissue disease (overlap syndromes) |
Yes, in up to 20% of casesa |
|
Systemic autoimmune diseasesb Frequent |
Infrequent |
Infrequent |
|
|
Malignancy |
No |
Yes, in up to 15% of cases |
No |
|
Viruses |
Yesc |
Unproven |
Yesc |
|
Drugsd |
Yes |
Yes, rarely |
No |
|
Parasites and bacteriae |
Yes |
No |
No |
aSystemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, systemic sclerosis, mixed connective tissue disease.
bCrohn’s disease, vasculitis, sarcoidosis, primary biliary cirrhosis, adult celiac disease, chronic graft-versus-host disease, discoid lupus, ankylosing spondylitis, Behget’s syndrome, myasthenia gravis, acne fulminans, dermatitis herpetiformis, psoriasis, Hashimoto’s disease, granulomatous diseases, agammaglobulinemia, monoclonal gammopathy, hypereosinophilic syndrome, Lyme disease, Kawasaki disease, autoimmune thrombocytopenia, hypergammaglobulinemic purpura, hereditary complement deficiency, IgA deficiency.
cHIV (human immunodeficiency virus) and HTLV-I (human T cell lymphotropic virus type I).
dDrugs include penicillamine (dermatomyositis and polymyositis), zidovudine (polymyositis), and contaminated tryptophan (dermatomyositis-like illness). Other myotoxic drugs may cause myopathy but not an inflammatory myopathy (see text for details).
eParasites (protozoa, cestodes, nematodes), tropical and bacterial myositis (pyomyositis).
This is in contrast to DM, in which the rash facilitates early recognition (see below). PM mimics many other myopathies and is a diagnosis of exclusion. It is a subacute inflammatory myopathy affecting adults, and rarely children, who do not have any of the following: rash, involvement of the extraocular and facial muscles, family history of a neuromuscular disease, history of exposure to myotoxic drugs or toxins, endocrinopathy, neurogenic disease, muscular dystrophy, biochemical muscle disorder (deficiency of a muscle enzyme), or IBM as excluded by muscle biopsy analysis (see below). As an isolated entity, PM is a rare (and overdiagnosed) disorder; more commonly, PM occurs in association with a systemic autoimmune or connective tissue disease, or with a known viral or bacterial infection. Drugs, especially D-penicillamine or zidovudine (AZT), may also produce an inflammatory myopathy similar to PM.
Dermatomyositis
DM is a distinctive entity identified by a characteristic rash accompanying, or more often preceding, muscle weakness. The rash may consist of a blue-purple discoloration on the upper eyelids with edema (heliotrope rash), a flat red rash on the face and upper trunk, and erythema of the knuckles with a raised violaceous scaly eruption (Gottron’s sign).The erythematous rash can also occur on other body surfaces, including the knees, elbows, malleoli, neck and anterior chest (often in a V sign), or back and shoulders (shawl sign), and may worsen after sun exposure. In some patients the rash is pruritic, especially on the scalp, chest, and back. Dilated capillary loops at the base of the fingernails are also characteristic. The cuticles may be irregular, thickened, and distorted, and the lateral and palmar areas of the fingers may become rough and cracked, with irregular, “dirty” horizontal lines, resembling mechanic’s hands. The weakness can be mild, moderate, or severe enough to lead to quadriparesis. At times, the muscle strength appears normal, hence the term dermatomyositis sine myositis. When muscle biopsy is performed in such cases, however, significant perivascular and perimysial inflammation is often seen.
DM usually occurs alone but may overlap with scleroderma and mixed connective tissue disease. Fasciitis and thickening of the skin, similar to that seen in chronic cases of DM, have occurred in patients with the eosinophilia-myalgia syndrome associated with the ingestion of contaminated L-tryptophan.
Inclusion Body Myositis
In patients >50 years of age, IBM is the most common of the inflammatory myopathies. It is often misdiagnosed as PM and is suspected only later when a patient with presumed PM does not respond to therapy. Weakness and atrophy of the distal muscles, especially foot extensors and deep finger flexors, occur in almost all cases of IBM and may be a clue to early diagnosis. Some patients present with falls because their knees collapse due to early quadriceps weakness. Others present with weakness in the small muscles of the hands, especially finger flexors, and complain of inability to hold objects such as golf clubs or perform tasks such as turning keys or tying knots. On occasion, the weakness and accompanying atrophy can be asymmetric and selectively involve the quadriceps, iliopsoas, triceps, biceps, and finger flexors, resembling a lower motor neuron disease. Dysphagia is common, occurring in up to 60% of IBM patients, and may lead to episodes of choking. Sensory examination is generally normal; some patients have mildly diminished vibratory sensation at the ankles that presumably is age related. The pattern of distal weakness, which superficially resembles motor neuron or peripheral nerve disease, results from the myopathic process affecting distal muscles selectively. Disease progression is slow but steady, and most patients require an assistive device such as a cane, walker, or wheelchair within several years of onset.
In at least 20% of cases, IBM is associated with systemic autoimmune or connective tissue diseases. Familial aggregation of typical IBM may occur; such cases have been designated as familial inflammatory IBM. This disorder is distinct from hereditary inclusion body myopathy (h-IBM), which describes a heterogeneous group of recessive, and less frequently dominant, inherited syndromes; the h-IBMs are noninflammatory myopathies. A subset of h-IBM that spares the quadriceps muscles has emerged as a distinct entity. This disorder, originally described in Iranian Jews and now seen in many ethnic groups, is linked to chromosome 9p1 and results from mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene.
Associated Clinical Findings
Extramuscular Manifestations
These may be present to a varying degree in patients with PM or DM, and include:
1. Systemic symptoms, such as fever, malaise, weight loss, arthralgia, and Raynaud’s phenomenon, especially when inflammatory myopathy is associated with a connective tissue disorder.
2. Joint contractures, mostly in DM and especially in children.
3. Dysphagia and gastrointestinal symptoms, due to involvement of oropharyngeal striated muscles and upper esophagus, especially in DM and IBM.
4.Cardiac disturbances, including atrioventricular conduction defects, tachyarrhythmias, dilated cardiomyopathy, a low ejection fraction, and congestive heart failure, which may rarely occur, either from the disease itself or from hypertension associated with longterm use of glucocorticoids.
5. Pulmonary dysfunction, due to weakness of the thoracic muscles, interstitial lung disease, or drug-induced pneumonitis (e.g., from methotrexate), which may cause dyspnea, nonproductive cough, and aspiration pneumonia. Interstitial lung disease may precede myopathy or occur early in the disease and develops in up to 10% of patients with PM or DM, most of whom have antibodies to t-RNA synthetases, as described below.
6. Subcutaneous calcifications, in DM, sometimes extruding on the skin and causing ulcerations and infections.
7. Arthralgias, synovitis, or deforming arthropathy with subluxation in the interphalangeal joints can occur in some patients with DM and PM who have Jo-1 antibodies (see below).
Association with Malignancies
Although all the inflammatory myopathies can have a chance association with malignant lesions, especially in older age groups, the incidence of malignant conditions appears to be specifically increased only in patients with DM and not in those with PM or IBM. The most common tumors associated with DM are ovarian cancer, breast cancer, melanoma, colon cancer, and non-Hodgkin’s lymphoma. The extent of the search that should be conducted for an occult neoplasm in adults with DM depends on the clinical circumstances. Tumors in these patients are usually uncovered by abnormal findings in the medical history and physical examination and not through an extensive blind search. The weight of evidence argues against performing expensive, invasive, and nondirected tumor searches. A complete annual physical examination with pelvic, breast (mammogram, if indicated), and rectal examinations (with colonoscopy according to age and family history); urinalysis; complete blood count; blood chemistry tests; and a chest film should suffice in most cases. In Asians, nasopharyngeal cancer is common, and a careful examination of ears, nose, and throat is indicated.
Overlap Syndromes
These describe the association of inflammatory myopathies with connective tissue diseases. A well-characterized overlap syndrome occurs in patients with DM who also have manifestations of systemic sclerosis or mixed connective tissue disease, such as sclerotic thickening of the dermis, contractures, esophageal hypomotility, microangiopathy, and calcium deposits (Table 16-1). By contrast, signs of rheumatoid arthritis, systemic lupus erythematosus, or Sjögren’s syndrome are very rare in patients with DM. Patients with the overlap syndrome of DM and systemic sclerosis may have a specific antinuclear antibody, the anti-PM/Scl, directed against a nucleolar-protein complex.
Pathogenesis
An autoimmune etiology of the inflammatory myopathies is indirectly supported by an association with other autoimmune or connective tissue diseases; the presence of various autoantibodies; an association with specific major histocompatibility complex (MHC) genes; demonstration of T cell-mediated myocytotoxicity or complement-mediated microangiopathy; and a response to immunotherapy.
Autoantibodies and Immunogenetics
Various autoantibodies against nuclear antigens (antinu-clear antibodies) and cytoplasmic antigens are found in up to 20% of patients with inflammatory myopathies. The antibodies to cytoplasmic antigens are directed against ribonucleoproteins involved in protein synthesis (anti-synthetases) or translational transport (anti-signal- recognition particles).The antibody directed against the histidyl-transfer RNA synthetase, called anti-Jo-1, accounts for 75% of all the anti-synthetases and is clinically useful because up to 80% of patients with anti-Jo-1 antibodies have interstitial lung disease. Some patients with the anti-Jo-1 antibody also have Raynaud’s phenomenon, nonerosive arthritis, and the MHC molecules DR3 and DRw52. DR3 haplotypes (molecular designation DRB1*0301,DQB1*0201) occur in up to 75% of patients with PM and IBM, whereas in juvenile DM there is an increased frequency of DQA1*0501 (Chap. 2).
Immunopathologic Mechanisms
In DM, humoral immune mechanisms are implicated, resulting in a microangiopathy and muscle ischemia (Fig. 16-1). Endomysial inflammatory infiltrates are composed of B cells located in proximity to CD4 T cells, dendritic cells, and macrophages; there is a relative absence of lymphocytic invasion of nonnecrotic muscle fibers.
FIGURE 16-1
Immunopathogenesis of dermatomyositis. Activation of complement, possibly by autoantibodies (Y), against endothelial cells and formation of C3 via the classic or alternative pathway. Activated C3 leads to formation of C3b, C3bNEO, and membrane attack complexes (MAC), which are deposited in and around the endothelial cell wall of the endomysial capillaries. Deposition of MAC leads to destruction of capillaries, ischemia, or microinfarcts most prominent in the periphery of the fascicles, and perifascicular atrophy. B cells, CD4 T cells, and macrophages traffic from the circulation to the muscle. Endothelial expression of vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) is induced by cytokines released by the mononuclear cells. Integrins, specifically very late activation antigen (VLA)-4 and leukocyte function-associated antigen (LFA)-1, bind VCAM and ICAM and promote T-cell and macrophage infiltration of muscle through the endothelial cell wall.
Activation of the complement C5b-9 membranolytic attack complex is thought to be a critical early event that triggers release of proinflammatory cytokines and chemokines, induces expression of vascular cell adhesion molecule (VCAM) 1 and intracellular adhesion molecule (ICAM) 1 on endothelial cells, and facilitates migration of activated lymphoid cells to the perimysial and endomysial spaces. Necrosis of the endothelial cells, reduced numbers of endomysial capillaries, ischemia, and muscle-fiber destruction resembling microinfarcts occur. The remaining capillaries often have dilated lumens in response to the ischemic process. Larger intramuscular blood vessels may also be affected in the same pattern. Residual perifascicular atrophy reflects the endofascicular hypoperfusion that is prominent in the periphery of the muscle fascicles.
By contrast, in PM and IBM a mechanism of T cell-mediated cytotoxicity is likely. CD8 T cells, along with macrophages, initially surround and eventually invade and destroy healthy, nonnecrotic muscle fibers that aberrantly express class I MHC molecules. MHC-I expression, absent from the sarcolemma of normal muscle fibers, is probably induced by cytokines secreted by activated T cells and macrophages. The CD8/MHC-I complex is characteristic of PM and IBM; its detection can aid in confirming the histologic diagnosis of PM, as discussed below. The cytotoxic CD8 T cells contain perforin and granzyme granules directed towards the surface of the muscle fibers and capable of inducing myonecrosis. Analysis of T-cell receptor molecules expressed by the infiltrating CD8 cells have revealed clonal expansion and conserved sequences in the antigen-binding region, both suggesting an antigen-driven T-cell response. Whether the putative antigens are endogenous (e.g., muscle) or exogenous (e.g., viral) sequences is unknown. Viruses have not been identified within the muscle fibers. Co-stimulatory molecules and their counterreceptors, which are fundamental for T-cell activation and antigen recognition, are strongly upregu-lated in PM and IBM. Key molecules involved in T cell-mediated cytotoxicity are depicted in Fig. 16-2.
FIGURE 16-2
Cell-mediated mechanisms of muscle damage in polymyositis (PM) and inclusion body myositis (IBM).
Antigen-specific CD8 cells are expanded in he periphery, cross the endothelial barrier, and bind directly to muscle fibers via T-cell receptor (TCR) molecules that recognize aberrantly expressed MHC-I. Engagement of co-stimulatory molecules (BB1 and ICOSL) with their ligands (CD28, CTLA-4, and ICOS) along with ICAM-1/LFA-1, stabilize the CD8-muscle fiber interaction. Metalloproteinases (MMP) facilitate the migration of T cells and their attachment to the muscle surface. Muscle fiber necrosis occurs via perforin granules released by the autoaggressive T cells. A direct myocytotoxic effect exerted by the cytokines interferon (IFN) γ, interleukin (IL) 1, or tumor necrosis factor (TNF) α may also play a role. Death of the muscle fiber is mediated by necrosis. MHC class I molecules consist of a heavy chain and a light chain [ß2 microglobulin (ß2m)] complexed with an antigenic peptide that is transported into the endoplasmic reticulum by TAP proteins.
