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Sporadic inclusion body myositis—diagnosis, pathogenesis and therapeutic strategies

Nature Clinical Practice Neurology volume 2, pages 437–447 (2006)Cite this article

Abstract

Sporadic inclusion body myositis (sIBM) presents with a characteristic clinical phenotype of slow-onset weakness and atrophy, affecting proximal and distal limb muscles and facial and pharyngeal muscles. Histologically, sIBM is characterized by chronic myopathic features, lymphocytic infiltrates invading non-vacuolated fibers, vacuolar degeneration, and accumulation of amyloid-related proteins. The cause of sIBM is unclear, but two processes—one autoimmune and the other degenerative—appear to occur in parallel. In contrast to dystrophies, in sIBM the autoinvasive CD8+ T cells are cytotoxic and antigen-driven, invading muscle fibers expressing major histocompatibility complex class I antigen and costimulatory molecules. The concurrent degenerative features include vacuolization, filamentous inclusions and intracellular accumulations of amyloid-β-related molecules. Although viruses have not been amplified from the muscle fibers, at least 12 cases of sIBM have been seen in association with retroviral infections, indicating that a chronic persistent viral infection might be a potential triggering factor. Emerging data imply that continuous upregulation of cytokines and major histocompatibility complex class I on the muscle fibers causes an endoplasmic reticulum stress response, resulting in intracellular accumulation of misfolded glycoproteins and activation of the transcription factor NFκB, leading to further cytokine activation. In spite of the brisk, antigen-driven T-cell infiltrates, sIBM does not respond to immunotherapies. New therapies using monoclonal antibodies against lymphocyte signaling pathways might prove helpful in arresting disease progression.

Key Points

  • Sporadic inclusion body myositis (sIBM) is a slowly progressive myopathy that affects proximal and distal muscles; its histopathology is characterized by autoimmune inflammatory features combined with degenerative features

  • Involvement of quadriceps and deep finger flexors are clues to early diagnosis; neck flexors and extensors are also frequently affected

  • The clinical diagnosis of sIBM is confirmed by muscle biopsy, and is aided by electromyography and determination of serum muscle enzyme levels

  • The cause of sIBM is unclear, but two processes—one autoimmune and the other degenerative—appear to occur in parallel

  • Several cases of sIBM have been seen in association with retroviral infections, indicating that a chronic persistent viral infection might be a potential triggering factor

  • Despite the involvement of primary immune factors in the pathogenesis of sIBM, this disease remains resistant to most immunotherapies; a study using alemtuzumab, a T-cell-depleting monoclonal antibody, is currently in progress

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Figure 1: Characteristic histological features in cross-sections of muscle biopsies in patients with sporadic inclusion body myositis.
Figure 2: Sequence of immunopathological changes in sporadic inclusion body myositis.
Figure 3: Assembly of MHC class I peptide complexes in the ER of the muscle fiber for antigen presentation, and translocation of misfolded MHC class I heavy chain glycoproteins to the cytoplasm.
Figure 4: Proposed mechanism for the pathogenesis of inclusion body myositis.

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Acknowledgements

This research was supported by the Intramural Research Program of the NIH, NINDS.

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  1. Chief of the Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, and Professor of Clinical Neurology at George Washington University, Washington, DC, USA

    Marinos C Dalakas

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Dalakas, M. Sporadic inclusion body myositis—diagnosis, pathogenesis and therapeutic strategies. Nat Rev Neurol 2, 437–447 (2006). https://doi.org/10.1038/ncpneuro0261

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