Inflammatory Myopathies

Susan Wallis, MD

Idiopathic inflammatory myopathies• Polymyositis

• Dermatomyositis• Juvenile dermatomyositis• Inclusion body myositis

• Myositis associated with collagen vascular disease

• Myositis associated with malignancy

Idiopathic inflammatory myopathies• Polymyositis

• Dermatomyositis• Juvenile dermatomyositis• Inclusion body myositis

• Myositis associated with collagen vascular disease

• Myositis associated with malignancy

Inflammatory myopathies• Rare heterogeneous group of acquired

diseases characterized by inflammatory infiltrate of skeletal muscle.

• Incidence of about 2-10 per 1 million people per year in the United States.

• Potentially treatable.

Polymyositis/Dermatomyositis

• Heliotrope rash was first described in 1875 in France.

• In 1888 the first American biopsy documented polymyositis in ruling out Trichinella.

• 1930 Gottron reported skin lesions• 1967 the pathology of inclusion body

myositis was described.

Hochberg et al. Rheumatology 3rd ed. 2003

Epidemiology

• Bimodal age distribution in PM/DM– Between 10-15 years in children– Between 45-60 in adults

• Inclusion body– More common after age 50 years

• Female predominance

Differential diagnosis• Drugs and toxins:

– Chloroquine– Colchicine– Corticosteroids– Heroin– Alcohol– Fibrates/statins– AZT

• Metabolic

• Malignancy

• Genetic– HLA-DRB1– HLA-DQA1– TNF2(-308)

• Infectious agents:– Bacteria

• Staphylococci• Clostridia• Rickettsias• Mycobacteria

– Parasites• Toxoplasma• Trichnella• Schistosoma• Cysticerca• Borrelia

– Viruses• Coxsackie• Echo• Influenze• Adeno

Criteria to define polymyositis and dermatomyositis proposed by Bohan and Peter

1. Symmetric weakness of limb girdle muscles and anterior neck flexors.

2. Skeletal muscle histologic examination

showing evidence of necrosis of types I and II muscle fibers, phagocytosis, regeneration with basophilia, large sarcolemmal nuclei and prominent nucleoli, atrophy in a perifascicular distribution, variation in fiber size, and an inflammatory exudate.

N Engl J Med 292:344, 1975

3. Elevation of levels of serum skeletal muscle enzymes

4. Electromyographic (EMG) triad of short, small polyphasic motor units; fibrillations, positive waves, and insertional irritability; and bizarre high-frequency discharges.

5. Dermatologic features including a heliotrope rash with periorbital edema; a scaly, erythematous dermatitis over the dorsa of the hands, especially over the MCP and PIP joints (Gottron's sign); and involvement of the knees, elbows, medial malleoli, face, neck, and upper torso.

Diagnostic criteria for IBM• Pathologic criteria

– Electron microscopy: Microtubular filaments in the inclusions.

– Light microscopy: • Lined vacuoles

• Intranuclear or intracytoplasmic inclusions or both

• Clinical criteria– Proximal muscle

weakness– Distal weakness– EMG evidence of

generalized myopathy– Increase in serum muscle

enzymes– Failure of muscle

weakness to improve on high-dose steroids

Polymyositis/Dermatomyositis

• Occur sporadically or in association with other systemic autoimmune disease

• More common in women than men.• DM common than PM.• DM can clinically manifest with heliotrope

rash, Grotton’s papules, shawl rash, erythematous nailfolds, dermatomyositis sine myositis.

Clinical features

• Progressive painless weakness– Difficulty lifting above head/combing hair– Difficulty arising from a low chair or toilet– Nasal regurgitation or choking when eating– Hoarseness, change in voice– *Ocular/facial muscle involvement is very

uncommon• Fatigue• Fever

Other clinical features

• Weight loss• Nonerosive inflammatory polyarthritis in

rheumatoid-like distribution– Except in Jo-1 positive, can be erosive and

deforming.• Raynaud’s phenomenon• Interstitial lung disease• Cardiac abnormalities• Amyopathic dermatomyositis

Deforming arthritis of anti-Jo 1 antibody patient

Inclusion body myositis

• Can present with features identical to PM.• Onset is typically insidious and

progression is slow.• May differ from PM in that it may include

focal, distal or asymmetric weakness.• Dyspagia is a late occurrence.• CK only slightly increased and can be

normal in up to 25% of patients.

Dermatologic manifestations

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Nailfold capillaries

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Cardiac

• Myocarditis– With secondary arrhythmias and CHF– Myocardial fibrosis

• Cor pulmonale– Secondary to ILD

• Accelerated atherosclerosis associated with prolonged steroid use

Dyspnea

• Non-pulmonary: respiratory muscle weakness, cardiac involvement

• Pulmonary:– ILD: NSIP, UIP, diffuse alveolar damage,

cryptogenic organizing pneumonia– Pulmonary hypertension– Alveolar hemorrhage– Infection: with or without aspiration– Drug induced

Pulmonary evaluation

• CT scan– Increased interstitial markings

• PFTs– Decreased TLV and DLCO

• BAL– Abnormal number of leukocytes

• Biopsy– Mononuclear cell infiltration, destruction of

alveolar spaces and fibrosis

GI Tract

• Pharyngeal muscle involvement– Dyphonia– Dysphagia

• Postprandial symptoms of bloating, pain and distension

• Pneumatosis cystoides intestinalis

Malignancy risk

• Strong association between malignancy and dermatomyositis, but less clearly with polymyositis.– Ovarian, lung, pancreatic, stomach and

colorectal and non-Hodgkin lymphoma• The overall risk is greatest in the first 3

years after diagnosis but is still increased through all years of follow-up.

Pathology

Inflammation• Dermatomyositis

– B cells and CD4 are abundant in the pervascular region.

– MAC found in the perivascular areas and within intrafascicular capillaries

– Damage to intrafascicular capillaries• Polymyositis and inclusion body myositis

– Normal appearing muscle cells are invaded by T cells• PM/DM

– Increased expression of costimulatory molecules

Polymyositis

Endomysial inflammatory infiltrate surrounding and invading non-necrotic muscle fibers

www.neuropathologyweb.org/chapter13/chapter13

pleiad.umdnj.edu/.../muschtml/musc008.htm

DermatomyositisNecrotic and regenerating muscle fibers in

perifascicular regions

www.phoenixneurology.com

www.neuro.wustl.edu/.../pathol/dermmyo.htm

Chronic dermatomyositis

Inclusion body myositis

Pathogenesis• Humoral

– Autoantibodies• Directed against cell components• Directed at intracellular, ususally intracytoplasmic

molecules• Usually part of the protein synthesis machinery

• Cellular• Genetic

Autoantibodies

• Autoantibodies have been identified in patients with myositis.– Not seen in inclusion body myositis

• Can help predict specific syndromes.• Differentiate between types of idiopathic

myositis versus myositis associated with other conditions.

Autoantibodies• Myositis specific antibodies (MSA)• Present in 30-60% of patients with PM/DM• Anti-aminoacyl-tRNA synthetases (ARS).• Anti-SRP• Anti-Mi-2

Autoimmunity, 2006;39(3):161-170

Autoimmunity, May 2006; 39(3): 161–170

Clinical syndromes associated with specific antibodies

Antisynthetase syndrome

• Aminoacyl-tRNA-synthetase is a cytoplasmic enzyme involved in aminoacylation.

• The most common ARS is histidyl-RNA-synthetase, also called Jo-1.

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Common characteristics

• Myopathy• Interstitial lung disease• Raynaud’s phenomenon• Polyarthritis• Fever• Mechanic’s hands

Anti-aminoacyl-tRNA synthetase antibodies in clinical course prediction of interstitial lung disease complicated

with idiopathic inflammatory myopathies

• Aim of the study to determine if these antibodies were predictive of clinical course of ILD in idiopathic inflammatory myositis patients.

• Retrospective study of 74 patients who met Peter-Bohan criteria.

• The patients with ILD have a worse prognosis than those without.

• Anti-ARS are strongly associated with ILDAutoimmunity 2006; 39(3):233-241

Autoimmunity 2006; 39(3):233-241

Prevalence of symptoms of patients with antisynthetase syndrome

Interstitial lung disease

Autoimmunity 2006; 39(3): 233-241

Autoimmunity 2006; 39(3): 233-241

Anti-SRP Antibodies

• Cytoplasmic antibody

• SRP is an RNA-protein complex that binds newly synthesized proteins and guides them to the endoplasmic reticulum for translocation.

Clinical

• Very rare• Chiefly proximal muscle involvement with

rhabdomyolysis • Usually poor response to steroids• ILD possible but uncommon• Skin and joints spared

Joint, Bone, Spine. 2006;73:646-654

Anti-Mi-2

• Antibodies directed to a nuclear macromolecular complex involved in transcription.

• Strong specificity for dermatomyositis.• Usually good response to treatment.

Myositis Associated Antibodies

• Anti-PM-Scl• Anti-RNP• Anti-Ro• Anti-La• Anti-Ku

Autoimmunity, May 2006; 39(3): 161–170

Myositis-associated antigens

Anti-PM-Scl antibodies

• Directed against a nucleolar macromolecular complex

• Primarily polymyositis or dermatomyositis/scleroderma overlap

• Strongly associated with HLA-DR3

• Seen in 5-25% of patients with myositis.

Anti-U1-RNP

• Sm-RNPs are ribonucleoproteins composed of 11 peptides and five small RNAs called U1, U2, U4, U5 and U6.– Anti-U1-RNP is primary marker of an overlap

syndrome.• Found in 5-60% of patients with

connective tissue disease and myositis.

Joint, Bone, Spine. 2006;73:646-654.

Cellular Immunity

• Lymphocyte accumulation• T cell receptor restriction in inflamed

muscle• Cytokine activation• Increased expression of antigen

presenting cells

• Factors that activate complement and the antigenic targets are unknown.

• Lymphocytic infiltrates are B cells, CD4+ cells and plasmacytoid/dendritic cells.

• Complement activation upregulates cytokines, chemokines and adhesion molecules.

DermatomyositisComplement activation

C5b-C9 deposition in endomysial capillares

Capillary necrosis

Perivascular inflammation

Ischemia

Muscle fiber destruction

Immunopathological changes in dermatomyositis

Neuromuscular Disorders 16 (2006) 223–236

Polymyositis

• CD8+ invade healthy non-necrotic muscle fibers.

• MHC-class I antigen expressing muscle cells.

MHC-class I

• MHC-class I expression is absent in normal muscle

• Strongly up-regulated in pathologic conditions, especially in inflammatory myopathies.

• A mouse model of overexpression of MHC class I molecules alone in skeletal muscle led to a self-sustaining inflammatory process. PNAS 2000;97(16):9209-9214

Genetic Factors• HLA-DRB1*0301, HLA-DQA1• Non-HLA class II genetic polymorphisms

including IL-1 receptor antagonist and TNF-α.

• Gene studies have been difficult to perform given rarity of disease.

• Previous studies have combined DM and PM patients to increase power.

Current Opinion in Rheumatology 2004;16:707-713

T cell receptors

• All the inflammatory myopathies are characterized by the presence of T cells and macrophages in muscle tissue.

• Exogenous or endogenous antigen?

• Previous studies looking at the TCR repertoire in myositis patients has been inconclusive.

Restricted T Cell Receptor BV Gene Usage in the Lungs and Muscles of Patients with Idiopathic

Inflammatory Myopathies

• Aim of study to compare TCR expression in 3 compartments that could be involved in patients with myositis: muscle, lung and peripheral blood.

• Identify a common TCR

Englund P et al. Arthritis and Rheumatism 2007; 56(1);372-383

• T cells recognize an antigen via complementary region of T cell receptors.

• TCR is a heterodimer of two α and two β variable chain lesions.

• TCR genes are restricted and amino acid sequences are conserved when T cells are selectively recruited by specific autoantigens.

Arthritis and rheumatism 2007;56(1)372-383

Muscle biopsies showing localization of CD4, CD8 and BV3-expressing cells (brown cells).

Conclusion

• Restricted accumulation of T lymphocytes expressing selected TCR V-gene segments.

• Positive results from lung and muscle.• Suggests common target antigens.

– Unidentified

Patient evaluation

Diagnosis

• Biopsy is gold standard• EMG• MRI

– STIR images for active myositis– Confirmation of amyopathic dermatomyositis– Documentation of flare

Disease activity assessment• Global activity- VAS• Muscle strength

– Proximal and distal muscle evaluation• Physical function

– HAQ• Laboratory assessment

– >2 serum muscle enzymes• Extramuscular disease

– Assess cutaneous, GI, articular, cardiac and pulmonary activity

If we do not know what causes it, how do we treat it?

Immunotherapy

Anti-inflammatory and immunosuppressive

• Steroids• Azathioprine• CellCept• Methotrexate• Cytoxan• Cyclosporin

Corticosteroids is mainstay of treatment in most cases

• Start 1-2 mg/kg/day• Continue until CPK returns to normal, then

slow taper.• For severe acute disease, consider pulse

dose steroids.

Other treatments

• Steroid sparing– Methotrexate– Imuran

• Non-responders– Rituxan– IVIG– Cyclosporin– Cellcept– Cyclophosphamide

(also for ILD)– Plasmapheresis– ?TNF inhibitors

Additional follow-up

• Cancer screening– Age appropriate– CAP CT scan– CA-125 and CA19-9

• Aggressive risk factor modification for atherosclerosis.

• PT tailored to patient’s needs starting with passive ROM, stretching advancing to aerobic activity after recovery.

Prognosis

• Older studies (before the availability of steroids) revealed a 50% mortality from complications.

• Current estimates of mortality, excluding patients with malignancy, is less than 10% at 5 years after initial diagnosis.

Poor prognostic factors

• Older age• Malignancy• Delayed steroid treatment• Dysphagia with aspiration• ILD

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Clinical implications of autoantibody screening in patients with autoimmune myositis. Autoimmunity 2006; 39(3):217-221.

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