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Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial.

ABSTRACT: To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase trial in adult and pediatric myositis patients.Adults with refractory polymyositis (PM) and adults and children with refractory dermatomyositis (DM) were enrolled. Entry criteria included muscle weakness and ?2 additional abnormal values on core set measures (CSMs) for adults. Juvenile DM patients required ?3 abnormal CSMs, with or without muscle weakness. Patients were randomized to receive either rituximab early or rituximab late, and glucocorticoid or immunosuppressive therapy was allowed at study entry. The primary end point compared the time to achieve the International Myositis Assessment and Clinical Studies Group preliminary definition of improvement (DOI) between the 2 groups. The secondary end points were the time to achieve ?20% improvement in muscle strength and the proportions of patients in the early and late rituximab groups achieving the DOI at week 8.Among 200 randomized patients (76 with PM, 76 with DM, and 48 with juvenile DM), 195 showed no difference in the time to achieving the DOI between the rituximab late (n = 102) and rituximab early (n = 93) groups (P = 0.74 by log rank test), with a median time to achieving a DOI of 20.2 weeks and 20.0 weeks, respectively. The secondary end points also did not significantly differ between the 2 treatment groups. However, 161 (83%) of the randomized patients met the DOI, and individual CSMs improved in both groups throughout the 44-week trial.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. The role of B cell-depleting therapies in myositis warrants further study, with consideration for a different trial design.

SUBMITTER: Oddis CV

PROVIDER: S-EPMC3558563 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial.

Oddis Chester V CV Reed Ann M AM Aggarwal Rohit R Rider Lisa G LG Ascherman Dana P DP Levesque Marc C MC Barohn Richard J RJ Feldman Brian M BM Harris-Love Michael O MO Koontz Diane C DC Fertig Noreen N Kelley Stephanie S SS Pryber Sherrie L SL Miller Frederick W FW Rockette Howard E HE

Arthritis and rheumatism 20130201 2

<h4>Objective</h4>To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase trial in adult and pediatric myositis patients.<h4>Methods</h4>Adults with refractory polymyositis (PM) and adults and children with refractory dermatomyositis (DM) were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal values on core set measures (CSMs) for adults. Juvenile DM patients required ≥3 abnormal CSMs, with or without muscle weakness. Patients were r ...[more]

PMID: 23124935

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Project description:ObjectiveTo identify the clinical and laboratory predictors of clinical improvement in a cohort of myositis patients treated with rituximab.MethodsWe analyzed data for 195 patients with myositis (75 with adult polymyositis [PM], 72 with adult dermatomyositis [DM], and 48 with juvenile DM) in the Rituximab in Myositis trial. Clinical improvement was defined as 20% improvement in at least 3 of the following 6 core set measures of disease activity: physician's and patient's/parent's global assessment of disease activity, manual muscle testing, physical function, muscle enzymes, and extramuscular disease activity. We analyzed the association of the following baseline variables with improvement: myositis clinical subgroup, demographics, myositis damage, clinical and laboratory parameters, core set measures, rituximab treatment, and myositis autoantibodies (antisynthetase, anti-Mi-2, anti-signal recognition particle, anti-transcription intermediary factor 1γ [TIF-1γ], anti-MJ, other autoantibodies, and no autoantibodies). All measures were univariately assessed for association with improvement using time-to-event analyses. A multivariable time-dependent proportional hazards model was used to evaluate the association of individual predictive factors with improvement.ResultsIn the final multivariable model, the presence of an antisynthetase, primarily anti-Jo-1 (hazard ratio [HR] 3.08, P < 0.01), anti-Mi-2 (HR 2.5, P < 0.01), or other autoantibody (HR 1.4, P = 0.14) predicted a shorter time to improvement compared to the absence of autoantibodies. A lower physician's global assessment of damage (HR 2.32, P = 0.02) and juvenile DM (versus adult myositis) (HR 2.45, P = 0.01) also predicted improvement. Unlike autoantibody status, the predictive effect of physician's global assessment of damage and juvenile DM diminished by week 20. Rituximab treatment did not affect these associations.ConclusionOur findings indicate that the presence of antisynthetase and anti-Mi-2 autoantibodies, juvenile DM subset, and lower disease damage strongly predict clinical improvement in patients with refractory myositis.

Project description:Orbital inflammation is a potentially blinding and disfiguring disease process that is often treated with systemic corticosteroids and immunosuppression; better treatments are needed.To determine whether rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20, is effective in the treatment of refractory orbital inflammation.A dose-ranging, randomized, double-masked phase 1/2 clinical trial was conducted at a tertiary referral ophthalmology clinic. Ten individuals with orbital inflammation refractory to systemic corticosteroids and at least 1 other immunosuppressive agent were enrolled from January 2007 to March 2010.Rituximab infusions were administered on study days 1 and 15 at doses of either 500 mg or 1000 mg. Initial responders with recurrent inflammation after week 24 were permitted reinfusion with an additional cycle of 2 open-label 1000-mg rituximab infusions.The primary outcomes were reduction of inflammation measured with a validated orbital disease grading scale and corticosteroid dose reduction by at least 50%. The secondary outcomes were visual acuity, reduction in pain, and participant- and physician-reported global health assessment.Of 10 enrolled patients, 7 demonstrated improvement on the orbital disease grading scale at the 24-week end point with rituximab therapy. Of these 7 individuals, 4 were receiving corticosteroids at study inception and all achieved successful dose reduction. For the secondary outcome measures in the 10 participants, 7 patients and 8 patients improved in self-rated and physician global health scores, respectively, and 7 patients had reduction in pain by 25% or more at 24 weeks. Four patients who were positive responders at the week 24 end point experienced breakthrough inflammation after week 24 and received reinfusions between 24 and 48 weeks. Vision remained stable in all participants. Three of 10 patients had short-term objective or subjective worsening 2 to 8 weeks after receiving rituximab infusions, which was averted in subsequent patients with oral corticosteroids administered during the infusion and did not affect the eventual positive treatment outcome. No significant differences with regard to efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms.Rituximab was safe and effective in 7 of 10 patients with noninfectious orbital disease, although 4 required reinfusion with rituximab to maintain control of orbital inflammation. Substantial toxicity was not noted. Rituximab should be considered in the treatment of refractory orbital inflammation.clinicaltrials.gov Identifier: NCT00415506.

Dataset Information

Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial.

Publications

Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial.

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