Periarticular myositis and muscle fibrosis are cytokine-dependent complications of inflammatory arthritis

The deleterious consequences of chronic synovitis on cartilage, tendon, and bone in rheumatoid arthritis (RA) are well described. In contrast, its effects on periarticular skeletal muscle are under-studied. Furthermore, while TNF inhibition is an effective therapy for RA synovitis, it exacerbates fibrosis in muscle injury models. We aimed to investigate whether myositis and muscle fibrosis are features of inflammatory arthritis and evaluate whether targeted RA therapies influence these disease features. Periarticular muscle was analyzed in murine models of poly- and monoarticular inflammatory arthritis: serum transfer-induced arthritis, collagen-induced arthritis, K/BxN, and antigen-induced arthritis (AIA). Periarticular myositis and an increase in muscle fibroadipocyte progenitors (FAPs) were observed in all models, despite diverse arthritogenic mechanisms. Periarticular muscle fibrosis was observed from day 15 in AIA. Neither etanercept nor baricitinib suppressed periarticular myositis or subsequent fibrosis compared to vehicle, despite reducing arthritis. Notably, etanercept failed to prevent muscle fibrosis even when initiated early, but this was not linked to increased FAP survival or collagen production. Corroborating these data, radiographic and histological analyses revealed periarticular myositis in patients with RA. We conclude that periarticular myositis and fibrosis are under-recognized features of inflammatory arthritis. Targeted RA therapies may not prevent periarticular muscle sequelae, despite controlling arthritis.