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Journal ArticleDOI

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

TL;DR: 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].

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Citations
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Journal ArticleDOI
TL;DR: The four main types of inflammatory muscle disease — dermatomyositis, polymyositis," necrotizing autoimmune myositis", and inclusion-bodyMyositis — are summarized.
Abstract: The four main types of inflammatory muscle disease — dermatomyositis, polymyositis, necrotizing autoimmune myositis, and inclusion-body myositis — are summarized. Pathogenesis, differential diagnosis, and treatment approaches are discussed.

525 citations

Journal ArticleDOI
TL;DR: In this article, the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICP) was discussed. But, the authors did not provide guidance on recommended management.
Abstract: PURPOSETo increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICP...

286 citations

Journal ArticleDOI
TL;DR: Treatment is still largely based on expert opinion, but several studies have shown effectiveness of different therapies in various subsets of inflammatory myopathies, and advances will undoubtedly improve the outcomes of patients with inflammatory myopathy.
Abstract: Inflammatory myopathies, collectively known as myositis, are heterogeneous disorders characterised by muscle inflammation, and frequently accompanied by extramuscular manifestations that affect the skin, lung, and joints. Patients with inflammatory myopathies were previously classified as having dermatomyositis if characteristic rashes accompanied the muscle involvement, and as having polymyositis if no rashes were present. Five main types of inflammatory myopathies are now widely recognised: dermatomyositis, immune-mediated necrotising myopathy, sporadic inclusion-body myositis, overlap myositis (including antisynthetase syndrome), and polymyositis. The discovery of autoantibodies that are specifically associated with characteristic clinical phenotypes has been instrumental to the understanding of inflammatory myopathies. Treatment is still largely based on expert opinion, but several studies have shown effectiveness of different therapies in various subsets of inflammatory myopathies. These advances will undoubtedly improve the outcomes of patients with inflammatory myopathies.

225 citations

Journal ArticleDOI
24 Feb 2016-BMJ
TL;DR: Despite similarities in clinical and pathologic presentation, the prognosis and treatment of CTD associated ILD (CTD-ILD) can differ greatly from that of other forms of ILD, such as idiopathic pulmonary fibrosis.
Abstract: The lung is a common site of complications of systemic connective tissue disease (CTD), and lung involvement can present in several ways. Interstitial lung disease (ILD) and pulmonary hypertension are the most common lung manifestations in CTD. Although it is generally thought that interstitial lung disease develops later on in CTD it is often the initial presentation (“lung dominant” CTD). ILD can be present in most types of CTD, including rheumatoid arthritis, scleroderma, systemic lupus erythematosus, polymyositis or dermatomyositis, Sjogren’s syndrome, and mixed connective tissue disease. Despite similarities in clinical and pathologic presentation, the prognosis and treatment of CTD associated ILD (CTD-ILD) can differ greatly from that of other forms of ILD, such as idiopathic pulmonary fibrosis. Pulmonary hypertension (PH) can present as a primary vasculopathy in pulmonary arterial hypertension or in association with ILD (PH-ILD). Therefore, detailed history, physical examination, targeted serologic testing, and, occasionally, lung biopsy are needed to diagnose CTD-ILD, whereas both non-invasive and invasive assessments of pulmonary hemodynamics are needed to diagnose pulmonary hypertension. Immunosuppression is the mainstay of treatment for ILD, although data from randomized controlled trials (RCTs) to support specific treatments are lacking. Furthermore, treatment strategies vary according to the clinical situation—for example, the treatment of a patient newly diagnosed as having CTD-ILD differs from that of someone with an acute exacerbation of the disease. Immunosuppression is indicated only in select cases of pulmonary arterial hypertension related to CTD; more commonly, selective pulmonary vasodilators are used. For both diseases, comorbidities such as sleep disordered breathing, symptoms of dyspnea, and cough should be evaluated and treated. Lung transplantation should be considered in patients with advanced disease but is not always feasible because of other manifestations of CTD and comorbidities. Clinical trials of novel therapies including immunosuppressive therapies are needed to inform best treatment strategies.

216 citations

Journal ArticleDOI
TL;DR: To identify the clinical and laboratory predictors of clinical improvement in a cohort of myositis patients treated with rituximab, a large number of patients with the disease were diagnosed with atypical central giant cell granuloma.
Abstract: The idiopathic inflammatory myopathies (IIM) are a group of acquired, heterogeneous, systemic connective tissue diseases (CTD) that include polymyositis (PM), adult dermatomyositis (DM), childhood myositis (predominantly juvenile DM), myositis associated with cancer or another connective tissue disease, and inclusion body myositis (IBM) (1, 2). Over the last few decades, survival has improved in IIM, with patients experiencing less cumulative damage and better health related quality of life. Despite an improvement in survival, our knowledge about clinical and serological predictors of clinical improvement in IIM is limited by the lack of well-designed, long–term epidemiological studies and clinical trials. IIM patients have heterogeneous features from a mild rash to life threatening muscle weakness or lung involvement. Their course can be self-limited or may require long-term glucocorticoids and multiple immunosuppressive medications. The response to immunosuppressive drugs is quite variable and current data do not allow the accurate prediction of clinical improvement, which poses a significant challenge to treating physicians, as well as investigators. The varying clinical features of myositis are closely linked to myositis autoantibodies, some of which may contribute to the pathogenesis of IIM (3). Although these autoantibodies provide useful prognostic information on patient outcomes (4–6), this relationship has not been established in prospective cohorts with uniform treatment. Previous evidence suggested that patients possessing anti-Mi-2 autoantibodies had a better prognosis, while patients with anti-SRP fared worse and those with anti-synthetase autoantibodies had intermediate outcomes (6, 7). In addition, there is a paucity of literature regarding predictors of clinical improvement by IIM disease subgroups. IBM is associated with poor treatment responses but studies differentiating responses between PM, DM and JDM are lacking (6). Treatment delay, muscle damage and longer disease duration have also been shown to be associated with poor prognosis (7–10). However, published studies are limited by small sample sizes, retrospective design and a limited assessment of prognostic factors. The availability of targeted therapies and validated outcome measures (11–13) spearheaded the recently completed Rituximab in Myositis (RIM) trial that was designed to evaluate the safety and efficacy of B cell depletion in adult and pediatric myositis patients (14). Rituximab has been studied in a wide variety of autoimmune diseases, as B cells play a critical role in the initiation and propagation of the immune response and are specifically implicated in the pathogenesis of myositis (15). As biologic agents are increasingly utilized in autoimmune diseases, it is important to elucidate the factors that predict a favorable outcome so that clinical trials can be designed with stratification of patients with a good and poor likelihood of improvement. The aim of this study was to identify the clinical and laboratory predictors of clinical improvement in a trial of refractory myositis subjects treated with B cell depletion. This is the first comprehensive study in myositis to evaluate factors associated with clinical improvement in a large prospective cohort.

213 citations

References
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Journal ArticleDOI
TL;DR: (First of Two Parts)
Abstract: Laboratory Features Elevation of sarcoplasmic enzymes in serum (creatine phosphokinase, aldolase, transaminases and lactic dehydrogenase) is valuable both for diagnosis and for following the clinic...

4,394 citations

Journal ArticleDOI
TL;DR: A structure for representation of patient outcome is presented, together with a method for outcome measurement and validation of the technique in rheumatoid arthritis, and these techniques appear extremely useful for evaluation of long term outcome of patients with rheumatic diseases.
Abstract: A structure for representation of patient outcome is presented, together with a method for outcome measurement and validation of the technique in rheumatoid arthritis. The paradigm represents outcome by five separate dimensions: death, discomfort, disability, drug (therapeutic) toxicity, and dollar cost. Each dimension represents an outcome directly related to patient welfare. Quantitation of these outcome dimensions may be performed at interview or by patient questionnaire. With standardized, validated questions, similar scores are achieved by both methods. The questionnaire technique is preferred since it is inexpensive and does not require interobserver validation. These techniques appear extremely useful for evaluation of long term outcome of patients with rheumatic diseases.

4,253 citations

Journal ArticleDOI
TL;DR: In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotRexate, provided significant improvement in disease symptoms at both weeks 24 and 48.
Abstract: Background An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study. Methods We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (≥10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). Results At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab–methotre...

2,469 citations

Journal ArticleDOI
TL;DR: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease.
Abstract: Background Cyclophosphamide and glucocorticoids have been the cornerstone of remissioninduction therapy for severe antineutrophil cytoplasmic antibody (ANCA)−associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. Methods We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. Results Nine centers enrolled 197 ANCA-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P = 0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. Conclusions Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

2,100 citations