Randomized controlled trial of rituximab in patients with Graves' orbitopathy

Abstract

Context: Graves' orbitopathy (GO) is a potentially sight-threatening disease for which available medical therapy is not uniformly successful. Multiple case series suggest that rituximab (RTX) may be effective therapy for GO patients.

Objective: To determine the efficacy of RTX in GO.

Design: It is a prospective, randomized, double-masked, placebo-controlled trial.

Setting: The study was conducted at a large academic private practice.

Patients: Twenty five patients with active moderate to severe GO were enrolled, and 21 completed the study to the primary endpoint.

Interventions: Two RTX infusions (1000 mg each) or two saline infusions were given 2 weeks apart.

Main outcome measures: The primary endpoint was a reduction in clinical activity score (CAS) assessed as a continuum and separately as improvement by ≥ 2 points at 24 weeks. Secondary endpoints included success and failure rates, proportions showing clinically significant improvement in proptosis, lid fissure width, diplopia score, lagophthalmos and disease severity, and changes in those parameters, orbital fat/ muscle volume and quality-of-life.

Results: The treatment groups were similar in all parameters at baseline. The last observation was carried forward if the patient discontinued prematurely. No differences were found in the proportions of patients showing CAS improvement at 24 weeks (25% placebo; 31% RTX, P = .75) or in CAS decrease from baseline to 24 or 52 weeks [mean 1.5 points (1.8 SD) placebo; 1.2 (2 SD) RTX at 24 weeks, P = .73]. Similarly, there were no differences between groups in any of the secondary endpoints at either 24 or 52 weeks. There were four adverse events (AE) in 3/12 placebo patients and 11 AE in 8/13 RTX-treated patients; 5/6 moderate or severe AE occurred in the RTX group.

Conclusion: RTX offered no additional benefit over placebo to our patients with active and moderate to severe GO and carried with it non-negligible adverse effects.

Trial registration: ClinicalTrials.gov NCT00595335.

Figures

Figure 1.

Flow chart of patient participation in the trial from enrollment to primary endpoint (per protocol) at 24 weeks and trial completion at 52 weeks.

Figure 2.

Change in CAS and TRAb levels over the course of the study showing individual patient data for (A) CAS - placebo group; (B) CAS - rituximab-treated group; (C) mean CAS ± SD for each group; and (D) median TRAb levels for each group. Patients who discontinued the trial prior to week 52 were evaluated before discontinuation and those data were carried forward to either 24 weeks (for the 5 patients who discontinued prior to or at week 24) or 52 weeks (for the single patient discontinued from the trial after 24 weeks) as the final evaluation for that patient. There were no significant differences in mean CAS or TRAb levels between the study groups at any time point.

Figure 3.

Proportion of patients in each study group showing clinically significant improvement from baseline to 24 weeks (A and B) or baseline to 52 weeks (C and D). Improvement was defined as decrease in any of the following: (CAS) ≥ 2 points; proptosis ≥ 2 mm; diplopia score from 3 or 4 to 0, 1 or 2; lid fissure width ≥ 3 mm; and NOSPECS classification by 1 or 2 classes (A and C). Success and failure rates (B and D) were defined as a composite of decrease in CAS ≥ 2 points and no need for additional therapy (success) or either CAS decrease of