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.

Keywords: Inclusion body myositis; idiopathic inflammatory myopathies; immunotherapy; muscle homeostasis; neurodegenerative disorder..

Fig. 1

Clinical characteristics of inclusion body myositis. (A) Patient attempting to make a fist with both hands: asymmetric weakness of finger flexors, severe on the left. (B) Patient in a wheelchair with severe quadriceps weakness and atrophy

Fig. 2

Histopathological features of inclusion body myositis. (A, B) Hematoxylin & eosin stain: (A) predominantly endomysial inflammatory infiltration; (B) inflammatory cells invading a non-necrotic muscle fiber (arrow) splitting off a small portion of the fiber (arrowhead) and an adjacent necrotic fiber (star). (C) Acid phosphatase stain: mononuclear cells (likely lymphocytes) invading a non-necrotic muscle fiber (arrowhead), backed up by a macrophage (arrow) identified by its acid phosphatase reactivity, as well as myriad endomysial inflammatory cells, some of which are macrophages, surrounding and occasionally focally invading muscle fibers. (D) Trichrome stain: rimmed vacuoles (star). (E) Cytochrome c oxidase stain: multiple cytochrome c oxidase negative fibers (star) in various regions of the specimen. (F) Congo red stain viewed under rhodamine optics: 2 fibers with intravacuolar congophilic inclusions (arrowheads) and 1 fiber with extravacuolar congophilic inclusions (star)