Inclusion Body Myositis: Update on Pathogenesis and Treatment

Abstract

Inclusion body myositis is the most common acquired myopathy after the age of 50. It is characterized by progressive asymmetric weakness predominantly affecting the quadriceps and/or finger flexors. Loss of ambulation and dysphagia are major complications of the disease. Inclusion body myositis can be associated with cytosolic 5'-nucleotidase 1A antibodies. Muscle biopsy usually shows inflammatory cells surrounding and invading non-necrotic muscle fibers, rimmed vacuoles, congophilic inclusions, and protein aggregates. Disease pathogenesis remains poorly understood and consists of an interplay between inflammatory and degenerative pathways. Antigen-driven, clonally restricted, cytotoxic T cells represent a main feature of the inflammatory component, whereas abnormal protein homeostasis with protein misfolding, aggregation, and dysfunctional protein disposal is the hallmark of the degenerative component. Inclusion body myositis remains refractory to treatment. Better understanding of the disease pathogenesis led to the identification of novel therapeutic targets, addressing both the inflammatory and degenerative pathways.

Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial

“…2b). There was no difference between the bimagrumab and placebo groups at 52 weeks (LS mean treatment difference for bimagrumab 10 Fig. 2c; Table 2d).…”

“…6 Recent reviews on IBM provide understanding of pathogenesis of this disease and effective therapeutic targets. [7][8][9][10][11] To date, there are no effective drug treatments for IBM. 12 Bimagrumab (BYM338) is a novel fully human monoclonal antibody that binds competitively to activin type II receptors (ActRII) with greater affinity than the natural ligands activin and myostatin, which usually function to limit muscle mass growth.…”

“…RESILIENT, A Randomized, double-blind, placebo-controlled, multicenter, parallel group, dose-finding, pivotal, phase IIb/III study to evaluate the Efficacy, Safety and tolerability of Intravenous BYM338 at 52 weeks on Lean body mass, muscle strength, physical function and mobility and additional long-term safety up to 2 years in patIENTs with sporadic inclusion body myositis Findings: At Week 52, there were no statistically significant differences in 6MWD change from baseline for any of the bimagrumab groups (10,3 Interpretation: Bimagrumab demonstrated a good safety profile in the IBM population but did not improve 6MWD. Strengths of the study are that it is the largest RCT conducted in IBM and provides important natural history data over 12 months.…”

Diagnostic Challenge and Neuromuscular Junction Contribution to ALS Pathogenesis

“…Myopathies hold a list of pathologies (Table 1) where muscle weakness can begin in the hands and feet (distal muscles) as well as in the muscles near the center of the body (proximal muscles) sometimes mimicking ALS features, confusing the diagnostic and the treatment decision. Among them, Inclusion Body Myositis (IBM) (94) is the most common ALS-mimic disease. It is the most common adult myopathy in 50 year-old persons and older, and its incidence is 3.5 per 100,000 (95).…”

Myopathy: Recent Progress, Current Therapies, and Future Directions

“…Although muscle biopsies from those with inclusion body myositis also have prominent cellular infiltrates, these patients do not usually improve with immunosuppressive therapy. To help explain this, Naddaf et al present recent work showing that many patients with inclusion body myositis have circulating populations of abnormal T cells that also infiltrate skeletal muscle; these T cells may be especially resistant to current immunosuppressive therapies [15]. In addition, degenerative pathways leading to the abnormal accumulation of cellular proteins may play a role in inclusion body myositis pathogenesis and help explain the refractory nature of this disease.…”