Paradigm shift in the pathomechanisms and treatment of inclusion body myositis: at the crossroads of cell-autonomous muscle degeneration and immune activation
Naoki Suzuki, Rumiko Izumi, Kensuke IkedaPurpose of review
Inclusion body myositis (IBM) is the most prevalent acquired myopathy in adults over 50 years of age, yet effective disease-modifying therapy has remained elusive. The longstanding debate over whether degeneration or inflammation is the primary driver has now given way to a model of bidirectional interplay. This review critically appraises advances published between January 2025 and June 2026, encompassing molecular pathomechanisms, early diagnostic strategies, disease-modifying therapies, and rehabilitation.
Recent findings
A pivotal mechanistic advance is the demonstration that TDP-43 nuclear depletion in IBM myonuclei generates cryptic exon-derived neoantigens that directly activate CD8 + T cells, molecularly unifying cell-autonomous degeneration and adaptive immune activation. In parallel, mitochondrial DNA leakage activates the cGAS–STING innate immune pathway prior to T cell infiltration. An endogenous compensatory mechanism involving the NORAD–Pumilio regulatory axis has also been identified. Clinically, preliminary data from the Phase 2/3 MUSCLE trial suggest a potential 50% slowing of progression in mild-to-moderate IBM with the anti-KLRG1 antibody ulviprubart, pending full peer-reviewed publication, while novel diagnostic and rehabilitation strategies further advance personalized care.
Summary
A molecular cascade from cell-autonomous TDP-43 dysfunction to cryptic epitope-driven immune activation could underlie the pathogenesis of IBM. Personalized multidisciplinary care integrating early diagnosis, targeted disease-modifying therapy, and advanced rehabilitation represents the emerging treatment paradigm.