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Inclusion Body Myositis: A Final Word
Abstract & Commentary
By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports that he receives grant/research support from Pfizer and is on the speaker's bureau of Athena Diagnostics.
Synopsis: Inclusion body myositis remains a mystery the underlying cause and pathogenesis have yet to be fully understood.
Source: Karpati G, O'Ferrall EK. Sporadic inclusion body myositis: pathogenic considerations. Ann Neurol 2009;65: 7-11.
Sporadic inclusion body myositis (IBM) is the most common acquired myopathy with onset over the age of 50 years. Unresponsive to therapy, its etiology remains a puzzle. In this paper, the last published in his lifetime, George Karpati, who in 1978 first described IBM as a distinct clinical and pathological entity, offers a final word on its pathogenesis.
Categorized as an inflammatory myopathy, both degenerative and inflammatory changes are seen pathologically. Myonuclear abnormalities, including the presence of 18-nm tubular filaments, rimmed vacuoles, small-caliber muscle fibers, increased endomysial connective tissue, muscle fiber hypertrophy, and ragged red fibers suggesting mitochondrial abnormalities, comprise the degenerative changes reported. Cytoplasmicamyloid accumulation, reputedly myotoxic, has been described by some, but not found by others. None of these findings are diagnostic in isolation but the constellation of these features is characteristic. Endomysial CD8+ lymphocyte and macrophage collections with partial invasion of these cells into nonnecrotic muscle fibers, as well as endomysial dendritic and CD138+ plasma cells, encompass the inflammatory features of IBM.
Proposed pathogenic paradigms ascribe either a primary role to inflammation with degenerative changes the resulting byproduct, or the reverse, with degenerative changes believed to be primary, and inflammation a secondary phenomenon. The firm skeptic (George Karpati) accepts neither scenario. Inflammation-first advocates suggest that an antigenic trigger, perhaps a virus, provokes a process, including clonal expansion of CD8+ lymphocytes and release of proinflammatory cytokines and chemokines, which results in cell injury and death. Arguing against this scenario is the lack of therapeutic benefit with immunosuppression, the paucity of necrosis and regeneration in sporadic IBM, and the absence of inflammatory changes in the inherited form. Degeneration-first advocates offer that, well before clinical symptoms begin, alterations of the myonuclear matrix putatively develops, resulting in transcriptional or RNA-handling dysregulation and nuclear membrane dissolution, with rimmed vacuole and tubular filament formation. Subsequent inflammatory changes may be immune mediated. Hereditary IBM lacks these inflammatory changes, arguing against this theory as well. Most plausibly, inflammatory and degenerative changes occur independently, the consequence of hitherto undiscovered agents, and it is to these agent(s) provocateurs that future research should best be directed to resolve the controversy and ultimately offer efficacious treatment.
George Karpati, 19342009, was a man of epic achievements. Husband, father, teacher, mentor, physician, scientist, Chevalier de l'ordre National du Québec, andhis proudest accomplishment (personal communication)officer of the Order of Canada, Canada's highest civilian honor, George Karpati still had much to contribute. This writer had the privilege to be trained under him and owes his professional advancement, at least in part, to him. Always available for counsel and advice, either professional or personal, by phone or email, he was able to quickly recognize the issue at hand, direct listeners on the best course of action, and intervening himself if he felt it warranted. Many will miss him.