Inclusion body myositis: clinical features and pathogenesis

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Abstract

Inclusion body myositis (IBM) is often viewed as an enigmatic disease with uncertain pathogenic mechanisms and confusion around diagnosis, classification and prospects for treatment. Its clinical features (finger flexor and quadriceps weakness) and pathological features (invasion of myofibres by cytotoxic T cells) are unique among muscle diseases. Although IBM T cell autoimmunity has long been recognized, enormous attention has been focused for decades on several biomarkers of myofibre protein aggregates, which are present in <1% of myofibres in patients with IBM. This focus has given rise, together with the relative treatment refractoriness of IBM, to a competing view that IBM is not an autoimmune disease. Findings from the past decade that implicate autoimmunity in IBM include the identification of a circulating autoantibody (anti-cN1A); the absence of any statistically significant genetic risk factor other than the common autoimmune disease 8.1 MHC haplotype in whole-genome sequencing studies; the presence of a marked cytotoxic T cell signature in gene expression studies; and the identification in muscle and blood of large populations of clonal highly differentiated cytotoxic CD8+ T cells that are resistant to many immunotherapies. Mounting evidence that IBM is an autoimmune T cell-mediated disease provides hope that future therapies directed towards depleting these cells could be effective.

Key points

  • Inclusion body myositis (IBM) progresses slowly and is commonly misdiagnosed initially as arthritis or polymyositis; IBM is associated with cardiovascular complications and other autoimmune diseases and has a high economic cost.

  • IBM has unique physical examination features (such as finger flexor and knee extensor weakness) that distinguish it from most other muscle diseases.

  • IBM has a greater range of autoimmune T cell abnormalities than any other muscle disease; treatment refractoriness has paradoxically given rise to the view that IBM is not an autoimmune disease.

  • Degenerative abnormalities that can occur in IBM include numerous myofibre protein aggregates associated with endoplasmic reticulum stress.

  • Degenerative abnormalities might occur following autoimmunity in cell culture and mouse models and following immune cell dysfunction in patients infected with HIV or human T cell lymphotropic virus type 1.

  • Treatment refractoriness probably reflects the inability of current therapies to inhibit or deplete the highly differentiated population of effector memory and terminally differentiated effector T cells present in IBM.

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Fig. 1: Evolution of inflammatory myopathy classification and history of IBM.
Fig. 2: IBM physical examination and imaging features.
Fig. 3: Pattern of muscle involvement in IBM and other inflammatory myopathies.
Fig. 4: IBM muscle pathology.
Fig. 5: IBM muscle inflammation.
Fig. 6: Proposed pathogenesis of IBM: highly differentiated cytotoxic T cells drive IBM myofibre injury.

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Correspondence to Steven A. Greenberg.

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S.A.G. is an inventor of intellectual property related to myositis diagnostics and therapeutics, owned and managed by Brigham and Women’s Hospital; he receives sponsored research from Pfizer, Inc. and is a founder of Abcuro, Inc.

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