Inflammatory Myopathies

Abstract

Idiopathic inflammatory myopathies are relatively rare diseases. Polymyositis and dermatomyositis are more common in women than men (2:1 ratio), while inclusion body myositis is twice as common in men. Inflammatory myopathies are a heterogeneous group of chronic systemic autoimmune diseases with an annual incidence of two to five cases per million, characterized by muscle inflammation and progressive muscle weakness. There are three major diseases which includes Dermatomyositis (DM) including a distinct juvenile subtype (JDM), Polymyositis (PM), and Inclusion Body Myositis. DM is a compliment mediated microangiopathy affecting skin and muscle. PM and IBM are T-cell mediated disorders, where CD8 positive cytotoxic T cells invade muscle fibers expressing MHC class I antigens, this leading to fiber necrosis. In IBM, vacuolar formation with amyloid deposits are also present. This article summarizes the clinical, histochemical and immunological features as well as the treatment options of the inflammatory myopathies.

Dermatomyositis

Dermatomyositis (DM) is a multisystem autoimmune disease that affects children and adults, characterized clinically by progressive symmetrical proximal muscle weakness and specific skin manifestations, including Gottron’s papules, heliotrope rash, and macular erythema.¹ The skin manifestations may precede myositis onset by months or years and can be worsened by sun exposure. Major differences between juvenile and adult DM include the presence of subcutaneous calcinosis affecting the elbows and knees with or without ulceration in Juvenile DM.² Other manifestations including, arthralgia, dysphagia, Raynaud’s phenomenon, and pulmonary symptoms.⁹ About 20 to 25% of the times it can be associated with an underlying malignancy, in particular lung, ovarian or gastrointestinal tract, as well as with other connective tissue diseases.

Immunopathogenesis

DM is a humorally mediated autoimmune disorder. Complement dependent attack leads to destruction of capillaries in muscle and other tissues. The etiology is not well understood, it has been suggested that genetically susceptible individuals probably develop myositis in response to particular environmental stimuli. Characteristic of DM is persisting damage to the vascular endothelium of endomysial capillaries and lesser extent of larger blood vessels. Membrane attack complex deposits, are noted on small arterioles and capillaries supplying the muscle fibers (compliment mediated).² The result is a marked reduction in the number of capillaries fallowed by dilation of remaining capillaries. The endothelial cells become swollen and necrotic, and develop tubuloreticular inclusions and microvacuoles. These changes results in perivascular inflammation, muscle ischemia and the characteristic perifascicular atrophy.

Polymyositis

The Polymyositis (PM) is an immune mediated syndrome secondary to defective cellular immunity that is most commonly associated with other systemic autoimmune diseases. PM rarely effects people under the age of 20, with the peak onset between the ages of 30 and 60. The proximal muscle weakness develops as a sub-acute myopathy, usually over weeks to months. Patients present with neck flexor and symmetric proximal upper and lower extremity weakness that develops slowly.² Distal muscle may become involved but to a lesser degree. Dysphagia occurs in a third of patients due to oropharyngeal and esophageal involvement. Usually extraocular muscles are spared. Weakness of neck flexors also occurs.

Extra muscular manifestations of polymyositis:

• Constitutional symptoms, such as fever and fatigue

• Articular symptoms of polymyositis: rheumatoid like arthropathy

• Severe interstitial lung disease (ILD)

• Cardiac manifestations: are unusual, rhythm disturbances, conduction defects, congestive heart failure, pericarditis, pulmonary hypertension and myocarditis can occur

• Cutaneous manifestations: mechanic’s hands

Pathogenesis

Polymyositis is characterized by T-cell mediated injury. Class I and II MHC upregulation is an early and consistent finding in the skeletal muscle of PM patients, the interaction of muscle with infiltrating CD8+ and CD4+ T cells. CD138− positive plasma cells are also abundant in endomysial areas and are probably the main source of autoantibodies in PM muscle.² IFN-γ transcript expression has been shown up-regulated in PM muscle compared to other IIM and also control muscle, emphasizing the involvement of IFN-γ is also involved in the induction of MHC class II molecules present on muscle fibers in PM muscle.⁷ IFN-γ is also involved in the synthesis of important chemotactic γ cytokine that govern leukocyte migration from blood to sites of inflammation (CCL2, CXCL9 and CXCL10) and sustain the active invasion of nonnecrotic myofibers by inflammatory cells. The high levels of IFN-γ, as well as of IL-4 and IL-17, present in PM muscle, suggest involvement of activated CD4+ T cells in the pathophysiology of this disorder.

Clinical Presentation of Polymyositis and Dermatomyositis

Muscle pain and tenderness are present in half of the patients. They can have arthralgia, fatigue, anorexia, weight loss, and fever. Pulmonary and cardiac manifestations may occur at any time during the course of the disease. Interstitial pneumonitis may cause dyspnea, cough, hypoxemia, and fatal respiratory failure. Aspiration pneumonia can complicate the disease course due to esophageal dysmotility. Heart block, supraventricular arrhythmia or cardiomyopathy may develop, may cause syncope, palpitations or congestive heart failure. In dermatomyositis, besides myositis that is similar to polymyositis, plus cutaneous manifestations are seen. Rash is often the presenting compliant. A variety of skin changes can be seen. The pathognomonic skin manifestation is Gottron’s papules. These are symmetric, lacy, and pink to violaceous raised or macular areas typically found on the dorsal aspect of interphalangeal joints, elbows, patellae and medial malleoli. Other changes include heliotrope (violaceous) discoloration of the eyelids, often with associated periorbital edema, macular erythema of the posterior shoulders and neck (shawl-sign), anterior neck and upper chest (V-sign), face and forehead. Periungual telangiectasias, dystrophic cuticles and nail fold capillary changes are frequently seen. Darkened or dirty-appearing horizontal lines may be noted across the lateral and palmar aspects of the fingers. These changes are termed mechanic’s hands. Cutaneous vasculitis can occur with livedo reticularis, digital infarcts or palpable, white centered petechia. Periungual erythema, cuticular overgrowth, and dilated capillary loops seen in nail folds. See Figures 1 and 2.

Figure 1.

Dilated capillary loops and cuticular overgrowth in the nail beds

Figure 2.

Gottron papules: erythematous lichenoid popular scaly rash over the extensor surface of the hands and fingers.

Laboratory Testing

Serologic testing can indicate muscle damage, includes elevations in creatinine phosphokinase (CPK) aldolase, lactate dehydrogenase (LDH, and liver function enzymes.⁶ Specific autoantibody testing is helpful to determine prognosis and rule out associated conditions. Anti Jo-1 antibodies are found in 15–20% of patients, associated with ILD, anti- Mi-2 is marker for DM and associated with good response to steroid treatment with good prognosis. Anti-SRP is specific for PM and associated with treatment-resistant myopathy. Antibodies to transcription intermediary factor 1γ/α (TIF1γ/α, ρ 155/140) are frequently found in DM associated with malignancy while anti-melanoma differentiation-associated gene 5 (MDA5; CADM140) are associated with clinically amyopathic DM (CADM) complicated by rapidly progressive ILD.

Electro-Diagnostic Studies

The electromyogram (EMG) is an electrical study of the nerves and muscles that plays an important role in confirming the presence, duration and severity of a myopathy. In PM increased insertional activity, fibrillations and sharp positive waves, spontaneous, bizarre high frequency discharges and polyphasic motor unit potentials of low amplitude and short duration seen in 40% of the patients. EMG can be normal in mild myopathies, therefore normal EMG does not exclude the presence of a myopathy.

Magnetic Resonance Imaging (MRI) Scanning

MRI of the muscle can be helpful to direct muscle biopsy.⁸ Areas of inflamed muscle demonstrate increased signal on T2-weighted images with fat suppression (STIR) images denoting areas of inflammation/edema. In chronic cases of myositis MRI can show fatty degeneration on T1 weighted images. Muscle biopsies from sites which are affected by MRI have a higher intensity of inflammatory infiltrates as compared to those obtained from nonaffected MRI locations, thus the performance of both MRI and biopsy has a superior diagnostic yield.

Muscle Biopsy

Histopathologic examination is very helpful in determining the specific type of muscle disease. Muscle fibers are found to be in varied stages of necrosis and regeneration. The inflammatory cell infiltrate is predominantly focal and endomysial. T-lymphocytes, especially T8+ cytotoxic cells accompanied by a smaller number of macrophages are found surrounding and invading initially non necrotic fibers. Destroyed fibers are replaced by fibrous connective tissue and fat. In dermatomyositis perivascular distribution of inflammatory cells, composed of higher percentages of B lymphocytes and helper T4+ lymphocytes. Perifascicular atrophy also seen.

Treatment

Oral and intravenous steroids are most commonly used, regimens of daily prednisone at a dose of 1.5 mg/kg per day or intravenous methylprednisolone at 500 to 1000 mg for three to five days are recommended depends on severity of the disease.¹ Methotrexate, azathioprine, mycophenolate mofetil are help full for rash, muscle disease and ILD as steroid sparing agents, Hydroxychloroquine is help full for the rash. Cyclophosphamide is helpful in refractory cases. Intravenous immune globulin (IVIG), (2 g/kg over five days initially and followed by a monthly three-day courses is effective. Tacrolimus is effective in resistant PM. Cyclosporine has also been used. Rituximab has recently been shown to be effective DM and PM patients with myositis specific antibodies.

Repository corticotropin injection (H.P.Acthar gel): this is FDA approved for treatment with DM/PM (80 USP units subcutaneously twice a week) for three months then decrease the dose.

Inclusion Body Myositis

Inclusion Body Myositis (IBM) is a subset of inflammatory myopathy, most commonly seen in an older population, over 50 years, and is more common in men. It is a gradual onset myositis and it may take several months to years from the onset of symptoms, till the diagnosis is made. It exists in sporadic and familial farm. IBM usually affects proximal as well as distal muscles, the most frequent symptom is frequent falls. Muscle atrophy and swallowing difficulty are also seen in IBM. It is associated with changes identical to polymyositis but also demonstrates lined vacuoles and deposits of beta-amyloid and ubiquitin.² It is associated with other connective tissue diseases in about 15% of patients. About 30% of patients can have myositis specific abs and serum CK levels are only slightly elevated in most patients. EMG may show neurogenic or mixed neurogenic and myopathic changes.

Pathogenesis

IBM is a multifactorial disease with autoimmune and degenerative features. Histologic changes include necrosis and inflammation, ragged red fibers and angulated atrophic fibers may be seen. The characteristic change is the presence of intracellular lined vacuoles. Electronic microscopy reveals either intracytoplasmic or intranuclear tubular or filamentous inclusions.

Treatment

Patients respond poorly to immunosuppressive therapy, and the course is typically progressive. Rarely patients will respond to prednisone alone or in combination with other immunosuppressive medications like methotrexate and azathioprine, so they should be treated for at least four to six months.

The Antisynthetase Syndrome (AS)

The antisynthetase syndrome is a triad of polymyositis, diffuse interstitial lung disease (ILD), and serum autoantibodies to aminoacyl transfer RNA synthetase. Anti jo-1 anibody is the most common antibody found. ILD is the clinical hall mark of AS. Usually, the myositis is less severe than in DM and PM without anti AS antibodies. At onset of disease, respiratory symptoms are present in 40–60% of patients, they may also present with constitutional symptoms such as fever, loss of appetite, and weight loss. Joint pain, arthritis, tenosynovitis and Raynaud’s phenomenon.³ Most reports indicate that the frequency of ILD in the AS is in the range of 70–95%. ILD seems to be highest in patients with antibodies to PL-12.

All the patients with AS in addition to evaluation for ILD should be evaluated for pulmonary hypertension (ECHO), and barium esophageal X-ray to assess for esophageal dysmotility

Treatment

In acute and subacute farms corticosteroids are helpful, either high dose IV methylprednisolone (500–1000 mg/day for three days), or oral corticosteroids (1mg/kg/day). In moderate to mild cases a combination of oral glucocorticoids and either cyclophosphamide, azathioprine, or methotrexate may be recommended. In some retrospective case series, they recommend a combination of oral corticosteroids, cyclophosphamide, and the anti-CD-20 monoclonal antibody rituximab as induction therapy in AS are recommended. Cyclosporine A, mycophenolate mofetil and tacrolimus are also showed efficacy.

Statin-Induced Necrotizing Autoimmune Myopathy

Necrotizing autoimmune myopathy (NAM) is relatively newly recognized subgroup of idiopathic inflammatory myopathies. Patients may present with a subacute severe symmetrical proximal myopathy, associated with a markedly elevated creatine kinase level. It can be associated with an antibody against the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) protein, which is upregulated in regenerating fibers ⁴. This may suggest that NAM is an antibody-mediated disease, and may explain the continuing progression of disease despite cessation of the statin.

NAM can be distinguished from the other inflammatory infiltrates with macrophages rather than T-cells being the effector cells.⁵ Immunostaining of muscle biopsies shows macrophages around necrotic fibers without many lymphocytes. An antibody dependent complement-mediated lysis may be responsible, with macrophages as seen on muscle biopsies.

Patients with statin-induced myopathy can have symptoms years after starting or even stopping the treatment. They can have persistence or progression of symptoms despite stopping statins. Treatment is oral corticosteroids 1mg/kg/day and depends on severity of symptoms. Steroid sparing agents, such as methotrexate, azathioprine, mycophenolate, and IVIG can be used as an adjunct. Rituximab was also shown to be effective when used with corticosteroids.

Biography

Rama Bandlamudi Atluri, MD, CCD, is Associate Professor of Internal Medicine, Certified Clinical Densitometrist, Division of Rheumatology, at Saint Louis University.

Contact: bandlar@slu.edu