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Inflammatory Myopathies PowerPoint Presentation

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Description : This medical presentation titled "Inflammatory Myopathies" talks about inflammatory myopathies, a rare heterogeneous group of acquired diseases characterized by inflammatory infiltrate of skeletal muscle.

Tags : Idiopathic, Inflammatory Myopathies, Polymyositis, Dermatomyositis, Juvenile dermatomyositis, Inclusion body myositis, Myositis associated with collagen vascular disease, Myositis associated with malignancy

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Inflammatory Myopathies Susan Wallis, MD
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Idiopathic inflammatory myopathies Polymyositis Dermatomyositis Juvenile dermatomyositis Inclusion body myositis Myositis associated with collagen vascular disease Myositis associated with malignancy
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Idiopathic inflammatory myopathies Polymyositis Dermatomyositis Juvenile dermatomyositis Inclusion body myositis Myositis associated with collagen vascular disease Myositis associated with malignancy
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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.
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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
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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
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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
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Criteria to define polymyositis and dermatomyositis proposed by Bohan and Peter 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
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Elevation of levels of serum skeletal muscle enzymes 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.
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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
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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.
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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
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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
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Deforming arthritis of anti-Jo 1 antibody patient
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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.
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Dermatologic manifestations www.jfponline.com/Pages.asp?AID=2763&UID=
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Nailfold capillaries www.hakeem-sy.com/main/files/images/20_2.jpg
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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
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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
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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
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GI Tract Pharyngeal muscle involvement Dyphonia Dysphagia Postprandial symptoms of bloating, pain and distension Pneumatosis cystoides intestinalis
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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.
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Pathology
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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
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Polymyositis Endomysial inflammatory infiltrate surrounding and invading non-necrotic muscle fibers www.neuropathologyweb.org/chapter13/chapter13 pleiad.umdnj.edu/.../muschtml/musc008.htm
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Dermatomyositis Necrotic and regenerating muscle fibers in perifascicular regions www.phoenixneurology.com www.neuro.wustl.edu/.../pathol/dermmyo.htm
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Chronic dermatomyositis
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Inclusion body myositis
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Pathogenesis Humoral Autoantibodies Directed against cell components Directed at intracellular, ususally intracytoplasmic molecules Usually part of the protein synthesis machinery Cellular Genetic
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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.
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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
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Autoimmunity, May 2006; 39(3): 161–170
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Clinical syndromes associated with specific antibodies
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Antisynthetase syndrome Aminoacyl-tRNA-synthetase is a cytoplasmic enzyme involved in aminoacylation. The most common ARS is histidyl-RNA-synthetase, also called Jo-1. www.arodia.com/.../orderByAttribute__caption
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Common characteristics Myopathy Interstitial lung disease Raynaud’s phenomenon Polyarthritis Fever Mechanic’s hands
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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 ILD Autoimmunity 2006; 39(3):233-241
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Autoimmunity 2006; 39(3):233-241 Prevalence of symptoms of patients with antisynthetase syndrome
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Interstitial lung disease Autoimmunity 2006; 39(3): 233-241
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Autoimmunity 2006; 39(3): 233-241
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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.
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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
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Anti-Mi-2 Antibodies directed to a nuclear macromolecular complex involved in transcription. Strong specificity for dermatomyositis. Usually good response to treatment.
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Myositis Associated Antibodies Anti-PM-Scl Anti-RNP Anti-Ro Anti-La Anti-Ku
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Autoimmunity, May 2006; 39(3): 161–170 Myositis-associated antigens
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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.
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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.
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Joint, Bone, Spine. 2006;73:646-654.
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Cellular Immunity Lymphocyte accumulation T cell receptor restriction in inflamed muscle Cytokine activation Increased expression of antigen presenting cells
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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.
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Dermatomyositis Complement activation C5b-C9 deposition in endomysial capillares Capillary necrosis Perivascular inflammation Ischemia Muscle fiber destruction
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Immunopathological changes in dermatomyositis Neuromuscular Disorders 16 (2006) 223–236
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Polymyositis CD8+ invade healthy non-necrotic muscle fibers. MHC-class I antigen expressing muscle cells.
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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
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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
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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.
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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
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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.
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Arthritis and rheumatism 2007;56(1)372-383 Muscle biopsies showing localization of CD4, CD8 and BV3-expressing cells (brown cells).
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Conclusion Restricted accumulation of T lymphocytes expressing selected TCR V-gene segments. Positive results from lung and muscle. Suggests common target antigens. Unidentified
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Patient evaluation
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Diagnosis Biopsy is gold standard EMG MRI STIR images for active myositis Confirmation of amyopathic dermatomyositis Documentation of flare
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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
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If we do not know what causes it, how do we treat it? Immunotherapy
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Anti-inflammatory and immunosuppressive Steroids Azathioprine CellCept Methotrexate Cytoxan Cyclosporin
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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.
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Other treatments Steroid sparing Methotrexate Imuran Non-responders Rituxan IVIG Cyclosporin Cellcept Cyclophosphamide (also for ILD) Plasmapheresis ?TNF inhibitors
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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.
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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.
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Poor prognostic factors Older age Malignancy Delayed steroid treatment Dysphagia with aspiration ILD
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Bibliography Bradshaw EM, Orihuela A, McArdel S, Salajegheh M, Amato A, Hafler D, Greenberg S, O’Connor K. A local antigen-driven humoral response is present in the inflammatory myopathies. J of Immun. 2007;178:547-556. Ghirardello A, Zampieri S, Tarricone E, Iaccarino L, Bendo R, Briani c, rondinone R, Sarzi-Puttini P, Todesco S, Doria A. Clinical implications of autoantibody screening in patients with autoimmune myositis. Autoimmunity 2006; 39(3):217-221. Chinoy H, et al. In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype. Arthritis Research and Therapy 2006;8(1):R13. Chinoy H, Ollier W, Cooper R. Have recent immunogenetic investigations increased our understanding of disease mechanisms in the idiopathic inflammatory myopathies? Curr Opin Rheumatol 2004;16:707-713. Chong B, Wong H. Immunobiologics in the treatment of psoriasis. Cin. Immunol 2007. Dalakas MC. Therapeutic targets in patients with inflammatory myopathies: present approaches and a look to the future. Neuromuscular Disorders 2006;16:223-236. Englund P, Wahlstrom J, Fathi M, Rasmussen E, Grunewald J, Tornling G, Lundberg I. Restricted T cell receptor BV gene usage in the lungs and muscles of patients with idiopathic inflammatory myopathies. Arthritis and Rheumatism 2007;56(1):372-383. Hassan AB, Nikitina-Zake L, Sanjeevi CB, et al. Association of the proinflammatory haplotypes (MICA5.1/TNF2/TNFa2/DRB103) with polymyositis and dermatomyositis. Arthritis Rheum 2004;50:1013-1015. Hochberg et al, eds. Rheumatology 2003. Kanneboyina N, Raben N, Loeffler L, et al. Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies. Nagaraju K, Raben N, Loeffler L, et al. Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies. PNAS 2000;97(16):9209-9214. Sordet C, Goetz J, Sibilia J. Contribution of autoantibodies to the diagnosis and nosology of inflammatory muscle disease. Joint Bone Spine 2006; 73:646-654 Wiendl H, Mitsdoerffer M, Hofmeister V, et al. The non-classical MHC molecule HLA-G protects human muscle cells from immune-mediated lysis; implications for myoblast transplantation and gene therapy. Brain 2003; 126:176-185. Van der Pas J, Hengstman GJ, Laak HJ, Borm GF, van Engelen BGM. Diagnositc value of MHC class I staining in idiopathic inflammatory myopathies. J Neurol., Neursurg., Psychiatry 2004; 75:136-139. Volkland J, et al. A humanized monoclonal antibody against interleukin-2 that can inactivate the cytokine/receptor complex. Molec Immunol. 2007;44:1743-1753.