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

Abstract

Objective: To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase trial in adult and pediatric myositis patients.

Methods: 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.

Results: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT00106184.

Figure 1. Schematic diagram of the design of the Rituximab in Myositis Study demonstrating the Randomized Placebo Phase Design

Subjects were randomly assigned to the ‘Rituximab (Rtx) Early’ or ‘Rituximab (Rtx) Late’ arm. The unshaded boxes indicate the early arm where drug was administered at weeks 0 and 1 and placebo infusions were given at weeks 8 and 9. Conversely, the shaded boxes signify the late rituximab arm receiving placebo infusions at weeks 0 and 1 and rituximab at weeks 8 and 9. The measurement at Week 8 can be regarded as the final endpoint of an 8-week parallel group, placebo-controlled randomized clinical trial. There were 14 visits over 44 weeks where the Core Set Measures and adverse events were assessed and biologic specimens obtained.

Figure 2. Participant Flow Diagram: RIM Study

After adjudicating all polymyositis patients (see text), 239 subjects were screened and 200 randomized. Most excluded patients either did not meet criteria for muscle weakness or had immunoglobulin levels that were too low. Of the 200 randomized subjects, 195 were included in the final analysis. ** Reasons for exclusion (n=35) include: Definite diagnosis not met (n=1); Other form of myositis (n=1); Prednisone dose stable < 4 weeks (n=1); MMT Score > 125 (n=10); IgG or IgM below lower limit normal (n=11); Hematologic abnormality (n=2); Concomitant illness (n=2); Other (n=7): 1 each for prior CNS toxoplasmosis, muscle atrophy and damage, chronic lymphocytic leukemia, hypercholesterolemia, hypercalcemia/high hemoglobin, current use of adalimumab, disease flare

Figure 3. Peripheral Blood B cell Numbers Prior to and Following Rituximab Treatment of IIM Subjects in the RIM Study

Peripheral blood samples were obtained at baseline (week 0) and at time points (weeks 4, 8, 12, 20, 32 and 44) following the baseline visit. Whole blood white blood cell counts and a differential were obtained at each time point and used in conjunction with flow cytometry to estimate the number of B cells/uL of blood at each time point (Methods). Median B cell numbers are displayed as a horizontal line with the distribution of B cells represented by boxes (25-75% of each sample set) and whiskers (10-90% of each sample set). Subjects treated at weeks 0 and 1 with rituximab (n=85) are represented by white boxes and subjects treated with rituximab at weeks 8 and 9 are represented by shaded boxes (n=98). The number of subjects represented in this figure (n=183) does not match up with those analyzed (n=195; Results) for either technical reasons or performance of flow cytometry locally at European sites.

Figures 4A-4D. DOI-free Survival for the Entire Cohort and Individual Myositis Subsets

The graphs depict the probability of DOI-free survival; Rtx Late is represented by a solid black line and Rtx Early by a solid grey line. The x-axis represents time in weeks from randomization and the y-axis represents the percentage of patients without a DOI where DOI is the definition of improvement. Figure 4A Entire Cohort Rtx Late (87 DOI; 17 Cens; Median =20.2 wks); Rtx Early (74 DOI; 22 Cens; Median =20.0 wks); Rtx Late vs. Rtx Early; p = 0.74. Figure 4B Juvenile DM Subset Rtx Late (20 DOI; 5 Cens; Median=19.6 wks); Rtx Early (20 DOI; 3 Cens; Median=11.7 wks); Rtx Late vs. Rtx Early = 0.32. Figure 4C Adult PM Subset Rtx Late (33 DOI; 6 Cens; Median=24.0 wks); Rtx Early (26 DOI; 11 Cens; Median=21.9 wks); Rtx Late vs. Rtx Early = 0.43. Figure 4D Adult DM Subset Rtx Late (34 DOI; 6 Cens; Median=20.3 wks); Rtx Early (28 DOI; 8 Cens; Median=20.4 wks); Rtx Late vs. Rtx Early = 0.70.