Immune-Mediated Inflammatory Myopathies

Immune-mediated inflammatory myopathies include polymyositis, dermatomyositis, myositis resulting from a rheumatic disease or overlap syndrome, inclusion body myositis (IBM), and immune-mediated necrotizing myopathy.

These disorders are characterized by progressive muscle weakness, and all but IBM demonstrate an inflammatory infiltrate in muscle tissue.

Polymyositis and dermatomyositis are systemic disorders of unknown cause whose principal manifestation is muscle weakness.

Although their clinical presentations (aside from the presence of certain skin findings in dermatomyositis, some of which are pathognomonic) and treatments are similar, the two diseases are pathologically distinct.

They affect persons of any age group, but the peak incidence is in the fifth and sixth decades of life and women are affected twice as commonly as men.

There is an increased risk of malignancy, especially in dermatomyositis. Indeed, up to one patient in four with dermatomyositis has an occult malignancy. Malignancies may be evident at the time of presentation with the muscle disease but may not be detected until months afterward in some cases. The malignancies most commonly associated with dermatomyositis are lung, ovarian, breast, colorectal, cervical, bladder, nasopharyngeal, esophageal, pancreatic, and renal cancer.

Patients may have skin disease without overt muscle involvement, a condition termed dermatomyositis sine myositis; these patients can have aggressive interstitial lung disease.

Myositis may also overlap with other connective tissue diseases, especially systemic sclerosis, SLE, mixed connective tissue disease, and Sjögren syndrome.

IBM affects older men and is characterized by more distal weakness in the upper extremities and is generally less symmetric.

Immune-mediated necrotizing myopathies include those associated with the signal recognition particle or with anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) autoantibodies in the setting of statin use.

This latter entity is distinct from the more common statin-induced myopathy, which occurs in about 1% of statin users. Unlike anti-HMGCR necrotizing myopathy, statin-induced myopathy generally resolves within 6 months of drug discontinuation.

Diagnostic Essentials

• Progressive muscle weakness.
• Dermatomyositis: characteristic cutaneous manifestations (Gottron papules, heliotrope rash); increased risk of malignancy.
• Elevated creatine kinase, myositis-specific antibodies, diagnostic muscle biopsy.
• Mimics include infectious, metabolic, or drug-induced myopathies.

Clinical Findings

Symptoms and Signs

Polymyositis may begin abruptly, but the usual presentation is one of progressive muscle weakness over weeks to months.

The weakness chiefly involves proximal muscle groups of the upper and lower extremities and the neck.

Leg weakness (eg, difficulty in rising from a chair or climbing stairs) typically precedes arm symptoms.

In contrast to myasthenia gravis, polymyositis and dermatomyositis do not cause facial or ocular muscle weakness.

In contrast to polymyalgia rheumatica (PMR), pain and tenderness of affected muscles occur in only one-fourth of cases, and these are rarely the chief complaints.

About one-fourth of patients have dysphagia. In contrast to systemic sclerosis, which affects the smooth muscle of the lower esophagus and can cause a “sticking” sensation below the sternum, polymyositis or dermatomyositis involves the striated muscles of the upper pharynx and can make initiation of swallowing difficult.

Clinically significant myocarditis is uncommon even though there is often creatine kinase-MB elevation.

Respiratory muscle weakness can be severe enough to cause CO2 retention and respiratory failure.

Dermatomyositis has a characteristic rash that is dusky red and may appear in a malar distribution, mimicking the classic rash of SLE. Facial erythema beyond the malar distribution is also characteristic of dermatomyositis.

Erythema also occurs over other areas of the face, neck, shoulders, and upper chest and back (“shawl sign”).

Periorbital edema and a purplish (heliotrope) suffusion over the eyelids are typical signs (Figure 1–6ck). Coloration of the heliotrope and other rashes of dermatomyositis can be affected by skin tone. In Black persons, the rashes may appear more hyperpigmented than erythematous or violaceous.

Periungual erythema, dilations of nailfold capillaries, Gottron papules (raised violaceous lesions overlying the dorsa of DIP, PIP, and MCP joints), and Gottron sign (erythematous rash on the extensors surfaces of the fingers, elbows, and knees) are highly suggestive.

Infrequently, the cutaneous findings of this disease precede the muscle inflammation by weeks or months.

Diagnosing polymyositis in patients over age 70 years can be difficult because weakness may be overlooked or attributed erroneously to idiopathic frailty.

A subset of patients with polymyositis and dermatomyositis have the “antisynthetase syndrome,” a group of findings including inflammatory nonerosive arthritis, fever, Raynaud phenomenon, “mechanic’s hands” (hyperkeratosis along the radial and palmar aspects of the fingers), interstitial lung disease, and often severe muscle disease associated with certain autoantibodies (eg, anti-Jo-1 antibodies).

IBM, because of its tendency to mimic polymyositis, is a common cause of “treatment-resistant polymyositis.” The typical patient with IBM is a man > 50 years.

The onset of IBM is more insidious than that of polymyositis or dermatomyositis (eg, occurring over years rather than months), and the distal motor weakness is commonly asymmetric. Creatine kinase levels are often minimally elevated and are normal in 25%. Electromyography may show a mixed picture of myopathic and neurogenic abnormalities. The disease is associated with antibodies to cytoplasmic 5’-nucleotidase 1A (cN1A). IBM is less likely to respond to therapy.

Immune-mediated necrotizing myopathy, although similar to polymyositis, is distinct because of the presence of muscle necrosis. Autoantibodies aid in diagnosis; anti-SRP antibodies are associated with severe muscle weakness, pain, and cardiac involvement. Anti-HMGCR antibodies occur in the setting of statin use and are associated with proximal muscle weakness and marked creatine kinase elevations. Many patients have a severe and unrelenting disease course with persistent weakness, unlike other statin-induced myopathies, which are generally self-limited after drug discontinuation.

Laboratory Findings

Measurement of serum levels of muscle enzymes, especially creatine kinase and aldolase, is most useful in diagnosis and in assessment of disease activity.

Inflammatory myositis can be misdiagnosed as hepatitis because of elevations in serum levels of muscle-derived ALT and AST levels.

Anemia is uncommon.

The ESR and CRP are often normal and are not reliable indicators of disease activity.

Rheumatoid factor is found in a minority of patients.

Antinuclear antibodies can be present, especially when there is an associated connective tissue disease.

A number of autoantibodies are seen exclusively in patients with myositis and are associated with distinctive clinical features (Table 1–10ck).

Examples of myositis-specific antibodies include (1) anti-Jo-1 antibody (antisynthetase syndrome), (2) anti-Mi-2 (dermatomyositis), (3) anti-155/140 (dermatomyositis with malignancy), (4) anti-MDA5 (melanocyte differentiation-associated protein 5, linked to dermatomyositis with cutaneous ulcerations and rapidly progressive interstitial lung disease), and (5) anti-signal recognition particle (immune-mediated necrotizing myopathy).

Chest radiographs are usually normal unless there is associated interstitial lung disease.

Electromyographic abnormalities can point toward a myopathic, rather than a neurogenic, cause of weakness.

MRI can detect early and patchy muscle involvement, can guide biopsies, and often is more useful than electromyography.

The search for an occult malignancy should begin with a history and physical examination, supplemented with a CBC, comprehensive biochemical panel, and UA and should include age- and risk-appropriate cancer screening tests.

Given the especially strong association of ovarian carcinoma and dermatomyositis, transvaginal ultrasonography, CT scanning, and CA-125 levels may be useful in women.

No matter how extensive the initial screening, some malignancies will not become evident for months after the initial presentation of the myopathy.

Muscle Biopsy

Biopsy of clinically involved muscle is often required. The pathology findings in polymyositis and dermatomyositis are distinct.

In dermatomyositis, the cellular infiltrate is mostly perifascicular and perivascular, while in polymyositis, the inflammatory infiltrate involves the fascicle itself.

The presence of prominent necrosis with a paucity of inflammatory cells suggests an immune-mediated necrotizing myopathy.

Muscle biopsy in IBM shows characteristic intracellular vacuoles by light microscopy and either tubular or filamentous inclusions in the nucleus or cytoplasm by electron microscopy.

False-negative biopsies sometimes occur in these disorders because of the sometimes patchy distribution of pathologic abnormalities.

Differential Diagnosis

Muscle inflammation may occur as a component of SLE, systemic sclerosis, Sjögren syndrome, and overlap syndromes. In those cases, associated findings usually permit the precise diagnosis of the primary condition.

Hypothyroidism is a common cause of proximal muscle weakness associated with elevations of serum creatine kinase.

Hyperthyroidism and Cushing disease may both be associated with proximal muscle weakness with normal levels of creatine kinase.

Patients with polymyalgia rheumatica are > age of 50 and—in contrast to patients with polymyositis—have pain but no objective weakness; creatine kinase levels are normal.

Disorders of the peripheral nervous system and CNS (eg, chronic inflammatory polyneuropathy, multiple sclerosis, myasthenia gravis, Lambert-Eaton disease, and amyotrophic lateral sclerosis) can produce weakness but are distinguished by characteristic symptoms and neurologic signs and often by distinctive electromyographic abnormalities.

A number of systemic vasculitides (polyarteritis nodosa, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis, and mixed cryoglobulinemia) can produce profound weakness through vasculitic neuropathy. The muscle weakness associated with these disorders, however, is typically distal and asymmetric, at least in the early stages.

Limb-girdle muscular dystrophy can present in early adulthood with a clinical picture that mimics polymyositis: proximal muscle weakness, elevations in serum creatine kinase, and inflammatory cells on muscle biopsy. Failure to respond to treatment for polymyositis or the presence of atypical clinical features such as scapular winging or weakness of ankle plantar flexors should prompt genetic testing for limb-girdle muscular dystrophy.

Many drugs, including corticosteroids, alcohol, clofibrate, penicillamine, tryptophan, and hydroxychloroquine, can produce proximal muscle weakness. Long-term use of colchicine at doses as low as 0.6 mg bid in patients with moderate CKD can produce a mixed neuropathy-myopathy that mimics polymyositis. The weakness and muscle enzyme elevation reverse with cessation of the drug.

HIV is associated with a myopathy indistinguishable from polymyositis.

Statins can cause myopathy and rhabdomyolysis, in addition to the anti-HMGCR myopathy described above. Although only about 0.1% of patients taking a statin drug alone develop myopathy, concomitant administration of other drugs (especially gemfibrozil, cyclosporine, niacin, macrolide antibiotics, azole antifungals, and protease inhibitors) increases the risk.

The use of immune checkpoint inhibitors to treat cancer can cause rheumatic and musculoskeletal symptoms, including myalgia and myositis.

Treatment

Most patients respond to corticosteroids. Initially, prednisone, 40–60 mg or more po od is often required. The dose is then adjusted downward while monitoring muscle strength and serum levels of muscle enzymes. Long-term use of corticosteroids is often needed, and the disease may recur when they are withdrawn.

Patients with an associated neoplasm have a poor prognosis, although remission may follow treatment of the tumor; corticosteroids may or may not be effective in these patients.

Immunosuppressive drugs like methotrexate (15–25 mg po weekly), azathioprine (1.5 mg/kg po od) or mycophenolate mofetil (1–1.5 g po bid) are often started to reduce cumulative corticosteroid exposure.

Intravenous immunoglobulin is effective for dermatomyositis resistant to prednisone and anti-HMGCR myopathy. Intravenous immunoglobulin is FDA-approved for the treatment of dermatomyositis.

Rituximab is effective in some patients with inflammatory myositis unresponsive to prednisone.

Since the rash of dermatomyositis is often photosensitive, patients should limit sun exposure.

Hydroxychloroquine (200–400 mg/day po not to exceed 5 mg/kg) can help ameliorate the skin disease.

When to Refer

• All patients with myositis should be referred to a rheumatologist or neurologist.
• Severe lung disease may require consultation with a pulmonologist.

When to Admit

• Signs of rhabdomyolysis.
• New onset of dysphagia.
• Respiratory insufficiency with hypoxia or carbon dioxide retention.