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Pathogenesis of inflammatory myopathies

Steven A Greenberg, MD
Section Editors
Ira N Targoff, MD
Jeremy M Shefner, MD, PhD
Deputy Editor
Monica Ramirez Curtis, MD, MPH


The inflammatory myopathies are a group of disorders sharing the common feature of immune-mediated muscle injury. Clinical and histopathological distinctions between these conditions suggest that different pathogenic processes underlie each of the inflammatory myopathies. The most common of these disorders include:

Dermatomyositis (DM)

Overlap syndromes (with another systemic rheumatic disease)

Inclusion body myositis (IBM)

Polymyositis (PM)


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Literature review current through: Sep 2016. | This topic last updated: May 31, 2016.
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  1. Hoogendijk JE, Amato AA, Lecky BR, et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands. Neuromuscul Disord 2004; 14:337.
  2. van der Meulen MF, Bronner IM, Hoogendijk JE, et al. Polymyositis: an overdiagnosed entity. Neurology 2003; 61:316.
  3. Greenberg SA. Type 1 interferons and myositis. Arthritis Res Ther 2010; 12 Suppl 1:S4.
  4. Greenberg SA. Dermatomyositis and type 1 interferons. Curr Rheumatol Rep 2010; 12:198.
  5. Greenberg SA. Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications. Neurology 2007; 69:2008.
  6. Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003; 362:971.
  7. Dalakas MC. Inflammatory disorders of muscle: progress in polymyositis, dermatomyositis and inclusion body myositis. Curr Opin Neurol 2004; 17:561.
  8. Salajegheh M, Kong SW, Pinkus JL, et al. Interferon-stimulated gene 15 (ISG15) conjugates proteins in dermatomyositis muscle with perifascicular atrophy. Ann Neurol 2010; 67:53.
  9. Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol 1984; 16:193.
  10. McDouall RM, Dunn MJ, Dubowitz V. Nature of the mononuclear infiltrate and the mechanism of muscle damage in juvenile dermatomyositis and Duchenne muscular dystrophy. J Neurol Sci 1990; 99:199.
  11. Greenberg SA, Pinkus JL, Pinkus GS, et al. Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis. Ann Neurol 2005; 57:664.
  12. López de Padilla CM, Vallejo AN, McNallan KT, et al. Plasmacytoid dendritic cells in inflamed muscle of patients with juvenile dermatomyositis. Arthritis Rheum 2007; 56:1658.
  13. Siegal FP, Kadowaki N, Shodell M, et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 1999; 284:1835.
  14. Wenzel J, Schmidt R, Proelss J, et al. Type I interferon-associated skin recruitment of CXCR3+ lymphocytes in dermatomyositis. Clin Exp Dermatol 2006; 31:576.
  15. Casciola-Rosen L, Nagaraju K, Plotz P, et al. Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy. J Exp Med 2005; 201:591.
  16. Gallardo E, de Andrés I, Illa I. Cathepsins are upregulated by IFN-gamma/STAT1 in human muscle culture: a possible active factor in dermatomyositis. J Neuropathol Exp Neurol 2001; 60:847.
  17. Nagaraju K, Casciola-Rosen L, Lundberg I, et al. Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum 2005; 52:1824.
  18. Pedrol E, Grau JM, Casademont J, et al. Idiopathic inflammatory myopathies. Immunohistochemical analysis of the major histocompatibility complex antigen expression, inflammatory infiltrate phenotype and activation cell markers. Clin Neuropathol 1995; 14:179.
  19. Banwell BL, Engel AG. AlphaB-crystallin immunolocalization yields new insights into inclusion body myositis. Neurology 2000; 54:1033.
  20. Sato S, Hoshino K, Satoh T, et al. RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: Association with rapidly progressive interstitial lung disease. Arthritis Rheum 2009; 60:2193.
  21. Fiorentino D, Chung L, Zwerner J, et al. The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study. J Am Acad Dermatol 2011; 65:25.
  22. Greenberg SA, Sanoudou D, Haslett JN, et al. Molecular profiles of inflammatory myopathies. Neurology 2002; 59:1170.
  23. Raju R, Dalakas MC. Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIg and biological validation of clinically relevant genes. Brain 2005; 128:1887.
  24. Greenberg SA. A gene expression approach to study perturbed pathways in myositis. Curr Opin Rheumatol 2007; 19:536.
  25. Walsh RJ, Kong SW, Yao Y, et al. Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis. Arthritis Rheum 2007; 56:3784.
  26. Grimley PM, Rutherford MN, Kang YH, et al. Formation of tubuloreticular inclusions in human lymphoma cells compared to the induction of 2'-5'-oligoadenylate synthetase by leucocyte interferon in dose-effect and kinetic studies. Cancer Res 1984; 44:3480.
  27. Feldman D, Goldstein AL, Cox DC, Grimley PM. Cultured human endothelial cells treated with recombinant leukocyte A interferon. Tubuloreticular inclusion formation, antiproliferative effect, and 2',5' oligoadenylate synthetase induction. Lab Invest 1988; 58:584.
  28. Kuyama J, Kanayama Y, Mizutani H, et al. Formation of tubuloreticular inclusions in mitogen-stimulated human lymphocyte cultures by endogenous or exogenous alpha-interferon. Ultrastruct Pathol 1986; 10:77.
  29. Rich SA, Owens TR, Bartholomew LE, Gutterman JU. Immune interferon does not stimulate formation of alpha and beta interferon induced human lupus-type inclusions. Lancet 1983; 1:127.
  30. Grimley PM, Davis GL, Kang YH, et al. Tubuloreticular inclusions in peripheral blood mononuclear cells related to systemic therapy with alpha-interferon. Lab Invest 1985; 52:638.
  31. Norton WL, Velayos E, Robison L. Endothelial inclusions in dermatomyositis. Ann Rheum Dis 1970; 29:67.
  32. De Visser M, Emslie-Smith AM, Engel AG. Early ultrastructural alterations in adult dermatomyositis. Capillary abnormalities precede other structural changes in muscle. J Neurol Sci 1989; 94:181.
  33. Banker BQ. Dermatomyostis of childhood, ultrastructural alteratious of muscle and intramuscular blood vessels. J Neuropathol Exp Neurol 1975; 34:46.
  34. Fuchsberger M, Hochrein H, O'Keeffe M. Activation of plasmacytoid dendritic cells. Immunol Cell Biol 2005; 83:571.
  35. Vallin H, Blomberg S, Alm GV, et al. Patients with systemic lupus erythematosus (SLE) have a circulating inducer of interferon-alpha (IFN-alpha) production acting on leucocytes resembling immature dendritic cells. Clin Exp Immunol 1999; 115:196.
  36. Mimori T, Imura Y, Nakashima R, Yoshifuji H. Autoantibodies in idiopathic inflammatory myopathy: an update on clinical and pathophysiological significance. Curr Opin Rheumatol 2007; 19:523.
  37. Mammen AL. Dermatomyositis and polymyositis: Clinical presentation, autoantibodies, and pathogenesis. Ann N Y Acad Sci 2010; 1184:134.
  38. Gunawardena H, Betteridge ZE, McHugh NJ. Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression. Rheumatology (Oxford) 2009; 48:607.
  39. Friedman AW, Targoff IN, Arnett FC. Interstitial lung disease with autoantibodies against aminoacyl-tRNA synthetases in the absence of clinically apparent myositis. Semin Arthritis Rheum 1996; 26:459.
  40. Tillie-Leblond I, Wislez M, Valeyre D, et al. Interstitial lung disease and anti-Jo-1 antibodies: difference between acute and gradual onset. Thorax 2008; 63:53.
  41. Stone KB, Oddis CV, Fertig N, et al. Anti-Jo-1 antibody levels correlate with disease activity in idiopathic inflammatory myopathy. Arthritis Rheum 2007; 56:3125.
  42. Soejima M, Kang EH, Gu X, et al. Role of innate immunity in a murine model of histidyl-transfer RNA synthetase (Jo-1)-mediated myositis. Arthritis Rheum 2011; 63:479.
  43. Karpati G, Carpenter S, Melmed C, Eisen AA. Experimental ischemic myopathy. J Neurol Sci 1974; 23:129.
  44. Hathaway PW, Engel WK, Zellweger H. Experimental myopathy after microarterial embolization; comparison with childhood x-linked pseudohypertrophic muscular dystrophy. Arch Neurol 1970; 22:365.
  45. Greenberg SA, Amato AA. Uncertainties in the pathogenesis of adult dermatomyositis. Curr Opin Neurol 2004; 17:359.
  46. Kissel JT, Halterman RK, Rammohan KW, Mendell JR. The relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis. Arch Neurol 1991; 48:26.
  47. Greenberg SA. Theories of the pathogenesis of inclusion body myositis. Curr Rheumatol Rep 2010; 12:221.
  48. Fukuchi K, Pham D, Hart M, et al. Amyloid-beta deposition in skeletal muscle of transgenic mice: possible model of inclusion body myopathy. Am J Pathol 1998; 153:1687.
  49. Jin LW, Hearn MG, Ogburn CE, et al. Transgenic mice over-expressing the C-99 fragment of betaPP with an alpha-secretase site mutation develop a myopathy similar to human inclusion body myositis. Am J Pathol 1998; 153:1679.
  50. Capsoni S, Ruberti F, Di Daniel E, Cattaneo A. Muscular dystrophy in adult and aged anti-NGF transgenic mice resembles an inclusion body myopathy. J Neurosci Res 2000; 59:553.
  51. Sugarman MC, Yamasaki TR, Oddo S, et al. Inclusion body myositis-like phenotype induced by transgenic overexpression of beta APP in skeletal muscle. Proc Natl Acad Sci U S A 2002; 99:6334.
  52. Strazielle C, Dumont M, Fukuchi K, Lalonde R. Transgenic mice expressing the human C99 terminal fragment of betaAPP: effects on cytochrome oxidase activity in skeletal muscle and brain. J Chem Neuroanat 2004; 27:237.
  53. Kitazawa M, Green KN, Caccamo A, LaFerla FM. Genetically augmenting Abeta42 levels in skeletal muscle exacerbates inclusion body myositis-like pathology and motor deficits in transgenic mice. Am J Pathol 2006; 168:1986.
  54. Moussa CE, Fu Q, Kumar P, et al. Transgenic expression of beta-APP in fast-twitch skeletal muscle leads to calcium dyshomeostasis and IBM-like pathology. FASEB J 2006; 20:2165.
  55. Sugarman MC, Kitazawa M, Baker M, et al. Pathogenic accumulation of APP in fast twitch muscle of IBM patients and a transgenic model. Neurobiol Aging 2006; 27:423.
  56. Chen X, Ghribi O, Geiger JD. Rabbits fed cholesterol-enriched diets exhibit pathological features of inclusion body myositis. Am J Physiol Regul Integr Comp Physiol 2008; 294:R829.
  57. Delaunay A, Bromberg KD, Hayashi Y, et al. The ER-bound RING finger protein 5 (RNF5/RMA1) causes degenerative myopathy in transgenic mice and is deregulated in inclusion body myositis. PLoS One 2008; 3:e1609.
  58. Kitazawa M, Trinh DN, LaFerla FM. Inflammation induces tau pathology in inclusion body myositis model via glycogen synthase kinase-3beta. Ann Neurol 2008; 64:15.
  59. Rebolledo DL, Minniti AN, Grez PM, et al. Inclusion body myositis: a view from the Caenorhabditis elegans muscle. Mol Neurobiol 2008; 38:178.
  60. Kitazawa M, Vasilevko V, Cribbs DH, LaFerla FM. Immunization with amyloid-beta attenuates inclusion body myositis-like myopathology and motor impairment in a transgenic mouse model. J Neurosci 2009; 29:6132.
  61. Greenberg SA, Bradshaw EM, Pinkus JL, et al. Plasma cells in muscle in inclusion body myositis and polymyositis. Neurology 2005; 65:1782.
  62. Bradshaw EM, Orihuela A, McArdel SL, et al. A local antigen-driven humoral response is present in the inflammatory myopathies. J Immunol 2007; 178:547.
  63. Needham M, Mastaglia FL, Garlepp MJ. Genetics of inclusion-body myositis. Muscle Nerve 2007; 35:549.
  64. Tian L, Greenberg SA, Kong SW, et al. Discovering statistically significant pathways in expression profiling studies. Proc Natl Acad Sci U S A 2005; 102:13544.
  65. Greenberg SA, Pinkus GS, Amato AA, Pinkus JL. Myeloid dendritic cells in inclusion-body myositis and polymyositis. Muscle Nerve 2007; 35:17.
  66. Salajegheh M, Lam T, Greenberg SA. Autoantibodies against a 43 KDa muscle protein in inclusion body myositis. PLoS One 2011; 6:e20266.
  67. Larman HB, Salajegheh M, Nazareno R, et al. Cytosolic 5'-nucleotidase 1A autoimmunity in sporadic inclusion body myositis. Ann Neurol 2013; 73:408.
  68. Pluk H, van Hoeve BJ, van Dooren SH, et al. Autoantibodies to cytosolic 5'-nucleotidase 1A in inclusion body myositis. Ann Neurol 2013; 73:397.
  69. Salajegheh M, Lin YY, Parker KC, et al. Using humoral immunity for the identification of candidate antigens in inclusion body myositis. Neurology 2007; 68(Suppl 1):A361.
  70. Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. IV: Cell-mediated cytotoxicity and muscle fiber necrosis. Ann Neurol 1988; 23:168.
  71. Greenberg SA, Pinkus JL, Amato AA, et al. Association of inclusion body myositis with T cell large granular lymphocytic leukaemia. Brain 2016; 139:1348.
  72. Greenberg SA, Pinkus JL, Amato AA. Nuclear membrane proteins are present within rimmed vacuoles in inclusion-body myositis. Muscle Nerve 2006; 34:406.
  73. Chou SM. Myxovirus-like structures and accompanying nuclear changes in chronic polymyositis. Arch Pathol 1968; 86:649.
  74. Carpenter S, Karpati G, Heller I, Eisen A. Inclusion body myositis: a distinct variety of idiopathic inflammatory myopathy. Neurology 1978; 28:8.
  75. Nalbantoglu J, Karpati G, Carpenter S. Conspicuous accumulation of a single-stranded DNA binding protein in skeletal muscle fibers in inclusion body myositis. Am J Pathol 1994; 144:874.
  76. Carpenter S. Inclusion body myositis, a review. J Neuropathol Exp Neurol 1996; 55:1105.
  77. Karpati G, Carpenter S. Pathology of the inflammatory myopathies. Baillieres Clin Neurol 1993; 2:527.
  78. Nakano S, Shinde A, Fujita K, et al. Histone H1 is released from myonuclei and present in rimmed vacuoles with DNA in inclusion body myositis. Neuromuscul Disord 2008; 18:27.
  79. Salajegheh M, Pinkus JL, Taylor JP, et al. Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis. Muscle Nerve 2009; 40:19.
  80. Küsters B, van Hoeve BJ, Schelhaas HJ, et al. TDP-43 accumulation is common in myopathies with rimmed vacuoles. Acta Neuropathol 2009; 117:209.
  81. Olivé M, Janué A, Moreno D, et al. TAR DNA-Binding protein 43 accumulation in protein aggregate myopathies. J Neuropathol Exp Neurol 2009; 68:262.
  82. Weihl CC, Temiz P, Miller SE, et al. TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia. J Neurol Neurosurg Psychiatry 2008; 79:1186.
  83. Greenberg SA. How citation distortions create unfounded authority: analysis of a citation network. BMJ 2009; 339:b2680.
  84. Askanas V, Engel WK. Inclusion-body myositis: a myodegenerative conformational disorder associated with Abeta, protein misfolding, and proteasome inhibition. Neurology 2006; 66:S39.
  85. Greenberg SA. Inclusion body myositis: review of recent literature. Curr Neurol Neurosci Rep 2009; 9:83.
  86. Sarkozi E, Askanas V, Johnson SA, et al. Expression of beta-amyloid precursor protein gene is developmentally regulated in human muscle fibers in vivo and in vitro. Exp Neurol 1994; 128:27.
  87. Schmidt J, Barthel K, Wrede A, et al. Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle. Brain 2008; 131:1228.
  88. Sarkozi E, Askanas V, Johnson SA, et al. beta-Amyloid precursor protein mRNA is increased in inclusion-body myositis muscle. Neuroreport 1993; 4:815.
  89. Salajegheh M, Pinkus JL, Nazareno R, et al. Nature of "Tau" immunoreactivity in normal myonuclei and inclusion body myositis. Muscle Nerve 2009; 40:520.
  90. Engel AG, Arahata K. Monoclonal antibody analysis of mononuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol 1984; 16:209.
  91. Hohlfeld R, Engel AG. The immunobiology of muscle. Immunol Today 1994; 15:269.
  92. Emslie-Smith AM, Arahata K, Engel AG. Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies. Hum Pathol 1989; 20:224.
  93. Amato AA, Barohn RJ. Evaluation and treatment of inflammatory myopathies. J Neurol Neurosurg Psychiatry 2009; 80:1060.
  94. Grable-Esposito P, Katzberg HD, Greenberg SA, et al. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve 2010; 41:185.
  95. Valiyil R, Casciola-Rosen L, Hong G, et al. Rituximab therapy for myopathy associated with anti-signal recognition particle antibodies: a case series. Arthritis Care Res (Hoboken) 2010; 62:1328.
  96. Miller T, Al-Lozi MT, Lopate G, Pestronk A. Myopathy with antibodies to the signal recognition particle: clinical and pathological features. J Neurol Neurosurg Psychiatry 2002; 73:420.
  97. Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011; 63:713.
  98. Cirigliano G, Della Rossa A, Tavoni A, et al. Polymyositis occurring during alpha-interferon treatment for malignant melanoma: a case report and review of the literature. Rheumatol Int 1999; 19:65.
  99. Dietrich LL, Bridges AJ, Albertini MR. Dermatomyositis after interferon alpha treatment. Med Oncol 2000; 17:64.
  100. John A, El Emadi S, Al Kaabi S, et al. Polymyositis during pegylated alpha-interferon ribavirin therapy for chronic hepatitis. Indian J Gastroenterol 2007; 26:147.
  101. Kälkner KM, Rönnblom L, Karlsson Parra AK, et al. Antibodies against double-stranded DNA and development of polymyositis during treatment with interferon. QJM 1998; 91:393.
  102. Lee SW, Kim KC, Oh DH, et al. A case of polymyositis with dilated cardiomyopathy associated with interferon alpha treatment for hepatitis B. J Korean Med Sci 2002; 17:141.
  103. Matsuya M, Abe T, Tosaka M, et al. The first case of polymyositis associated with interferon therapy. Intern Med 1994; 33:806.
  104. Dastmalchi M, Grundtman C, Alexanderson H, et al. A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies. Ann Rheum Dis 2008; 67:1670.
  105. Hall HA, Zimmermann B. Evolution of dermatomyositis during therapy with a tumor necrosis factor alpha inhibitor. Arthritis Rheum 2006; 55:982.
  106. Hengstman GJ, De Bleecker JL, Feist E, et al. Open-label trial of anti-TNF-alpha in dermato- and polymyositis treated concomitantly with methotrexate. Eur Neurol 2008; 59:159.
  107. Ramos-Casals M, Brito-Zerón P, Muñoz S, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore) 2007; 86:242.
  108. Jego G, Pascual V, Palucka AK, Banchereau J. Dendritic cells control B cell growth and differentiation. Curr Dir Autoimmun 2005; 8:124.
  109. Hollander D, Adelman LS. Eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan: muscle biopsy findings in 4 patients. Neurology 1991; 41:319.
  110. Somani AK, Swick AR, Cooper KD, McCormick TS. Severe dermatomyositis triggered by interferon beta-1a therapy and associated with enhanced type I interferon signaling. Arch Dermatol 2008; 144:1341.
  111. Amato AA. Adults with eosinophilic myositis and calpain-3 mutations. Neurology 2008; 70:730.
  112. Krahn M, Lopez de Munain A, Streichenberger N, et al. CAPN3 mutations in patients with idiopathic eosinophilic myositis. Ann Neurol 2006; 59:905.
  113. Le Roux K, Streichenberger N, Vial C, et al. Granulomatous myositis: a clinical study of thirteen cases. Muscle Nerve 2007; 35:171.
  114. Bagdasaryan R, Donahue JE. Granulomatous myositis in association with chronic graft vs. host disease. Med Health R I 2007; 90:287.
  115. Kaushik S, Flagg E, Wise CM, et al. Granulomatous myositis: a manifestation of chronic graft-versus-host disease. Skeletal Radiol 2002; 31:226.
  116. Prayson RA. Granulomatous myositis. Clinicopathologic study of 12 cases. Am J Clin Pathol 1999; 112:63.
  117. Arin MJ, Scheid C, Hübel K, et al. Chronic graft-versus-host disease with skin signs suggestive of dermatomyositis. Clin Exp Dermatol 2006; 31:141.
  118. Ollivier I, Wolkenstein P, Gherardi R, et al. Dermatomyositis-like graft-versus-host disease. Br J Dermatol 1998; 138:558.
  119. Allen JA, Greenberg SA, Amato AA. Dermatomyositis-like muscle pathology in patients with chronic graft-versus-host disease. Muscle Nerve 2009; 40:643.
  120. Nozaki K, Pestronk A. High aldolase with normal creatine kinase in serum predicts a myopathy with perimysial pathology. J Neurol Neurosurg Psychiatry 2009; 80:904.
  121. Stevens AM, Sullivan KM, Nelson JL. Polymyositis as a manifestation of chronic graft-versus-host disease. Rheumatology (Oxford) 2003; 42:34.