Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis: A Randomized, Placebo-phase Trial

TLDR: Although there were no significant differences in the 2 treatment arms for the primary and secondary end points, 83% of adult and juvenile myositis patients with refractory disease met the DOI, and individual CSMs improved in both groups throughout the 44-week trial.

Abstract: The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of acquired disorders characterized by chronic inflammation of striated muscle leading to predominantly proximal muscle weakness. The most common subsets of IIM include adult polymyositis (PM), adult and juvenile dermatomyositis (DM), myositis in overlap with cancer or another connective tissue disease and inclusion body myositis (IBM). The IIM are frequently associated with constitutional symptoms and commonly involve other organ systems including the skin, joints, lungs, gastrointestinal tract and heart. They are rare with an estimated incidence of 4-10 cases/million population per year and a bimodal incidence pattern reflecting childhood onset of juvenile DM (JDM) and a later peak in adulthood [1]. Although the precise pathogenesis is unknown, the IIM likely result from immune-mediated processes initiated by environmental factors in genetically susceptible individuals [2]. Factors strongly supporting their autoimmune basis include: the association of myositis with other autoimmune diseases such as Hashimoto thyroiditis, Grave’s disease and various connective tissue diseases, the high frequency of circulating serum autoantibodies, and their response to immunosuppressive (IS) or immunomodulatory therapy. The treatment of IIM is challenging, complicated by its rarity and heterogeneity as well as the lack of controlled trials and partially validated outcome measures. Most studies involve single referral centers using cross-sectional and retrospective analyses of small numbers of treatmentrefractory patients observed for relatively short time periods. In addition, widely disparate inclusion criteria have complicated the assessment of treatment response, as disease damage and the inclusion of misdiagnosed patients contribute to suboptimal therapeutic outcomes. Although glucocorticoids have not been formally tested in controlled trials, expert consensus is that they are the primary therapy to be followed by a variety of immunosuppressive or immunomodulatory agents alone or in combination [2]. Rituximab, a B cell depleting agent long recognized as an effective therapy for B cell lymphomas, has gained increased favor in the treatment of many autoimmune diseases and is FDA-approved for use in rheumatoid arthritis [3] as well as granulomatosis with polyangiitis and microscopic polyangiitis [4]. The effectiveness of rituximab in PM and DM has been suggested by case reports and case series in adult and pediatric patients with refractory disease [5-9]. B cells play a critical role in the initiation and propagation of the immune response and are implicated in the pathogenesis of myositis. They localize to the perivascular region of DM muscle and are found in the inflammatory infiltrates of both PM and DM [10]. In addition to functioning as the precursor of autoantibody-producing plasma cells, B cells present antigen to T cells and secrete proinflammatory cytokines [10]. Therefore, based on the autoimmune characteristics of myositis and the aforementioned immunopathogenic role of the B cell, the Rituximab in Myositis (RIM) trial assessed the effectiveness of rituximab in refractory adult PM and adult and juvenile DM using validated measures of myositis disease activity and damage, a consensus-driven definition of improvement [11-13] and a unique randomized placebo-phase trial design [14, 15].