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Purpose of Review: While sporadic inclusion body myositis (sIBM) is the most common acquired muscle disease after age 50, the pathogenesis of this disease is still poorly understood. In this review, we discuss our current state of knowledge in sIBM and provide an update on our current understanding of its pathophysiology and management., Recent Findings: Lines of evidence in support of an inflammatory pathogenesis include inflammatory infiltrates in the target organ, NFκB activation, cytokine response, MHC I upregulation, and cN1A antibody. Refractoriness to immunotherapies has led to suggestion of a degenerative pathophysiology. Evidence for impaired protein homeostasis with misfolding burden is coupled with findings of endoplasmic reticulum stress, proteasome dysfunction, and mitochondrial lesion. Recent treatment trials have focused more on correcting the degenerative process or muscle growth rather than controlling the inflammation. There has been growing evidence toward degeneration as the primary process in sIBM. This is consistent with the refractory nature of this disease. Improving our understanding of this disease pathogenesis will propel efforts to find an effective therapy.

Purpose of Review: Our goal is to review the recent literature pertaining to the genetics of sporadic inclusion body myositis (IBM)., Recent Findings: In a study of 252 IBM patients, the class II MHC allele HLA-DRB1*03:01 showed the most significant association with IBM, and that risk could be largely attributed to amino acids within the peptide-binding pocket. Candidate gene sequencing identified rare missense variants in proteins regulating protein homeostasis including VCP and SQSTM1. An unbiased approach employing exome sequencing of genes encoding rimmed vacuole proteins identified FYCO1 variants in IBM. Ongoing GWAS approaches may shed new light on genetic risk factors for IBM. Many variants have been reported at an increased frequency in IBM in small studies; however, only HLA association has shown genome-wide significance. Future studies are needed to validate variants in larger cohorts and to understand the molecular roles these risk factors play in IBM.

Degenerative mechanisms such as protein accumulation and vacuolar transformation in the skeletal muscle distinguish inclusion body myositis (IBM) from other inflammatory myopathies. IBM is particularly common in patients over the age of 50 years and inevitably leads to progressive muscle weakness and atrophy. Conventional immunotherapies, albeit effective in other forms of myositis, seem to have only a transient or no beneficial effect on disease progression of IBM. So far, no established evidence-based treatment exists and therapy recommendations are based on expert opinion. Recent clinical trials using monoclonal antibodies such as alemtuzumab or etanercept have failed to demonstrate efficacy. Different treatment studies with drugs that aim at degenerative disease mechanisms are planned or ongoing. This review aims to provide an overview of the current treatment options for IBM.

Intravenous immunoglobulin (IVIG) is a unique immune-modulating therapy that has a wide range of effects on the immune system at multiple levels. This allows it to be used successfully in a variety of immune-mediated, systemic, and neurological disorders, including the inflammatory myopathies. It is likely that the specific action of IVIG varies depending on the underlying pathogenesis of a given disease. In dermatomyositis (DM), IVIG has been shown to diminish the activity of complement and deposition of membrane attack complex on capillaries and muscle fibers, the expression of adhesion molecules, and cytokine production. IVIG also appears to modify gene expression in the muscle of DM patients. The mechanism by which IVIG affects muscle in polymyositis and inclusion body myositis has not been well-studied. However, it may work via suppression of T-cell activation (including cytotoxic T cells) and migration into muscle tissue and alterations in cytokine production. IVIG generally yields the greatest therapeutic benefit in DM and is often of marginal utility in inclusion body myositis. It is generally considered as second-line or adjunctive therapy in the inflammatory myopathies.