Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial

Abstract

Objective: B cells are likely to contribute to the pathogenesis of systemic lupus erythematosus (SLE), and rituximab induces depletion of B cells. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial tested the efficacy and safety of rituximab versus placebo in patients with moderately-to-severely active extrarenal SLE.

Methods: Patients entered with >or=1 British Isles Lupus Assessment Group (BILAG) A score or >or=2 BILAG B scores despite background immunosuppressant therapy, which was continued during the trial. Prednisone was added and subsequently tapered. Patients were randomized at a ratio of 2:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182.

Results: In the intent-to-treat analysis of 257 patients, background treatment was evenly distributed among azathioprine, mycophenolate mofetil, and methotrexate. Fifty-three percent of the patients had >or=1 BILAG A score at entry, and 57% of the patients were categorized as being steroid dependent. No differences were observed between placebo and rituximab in the primary and secondary efficacy end points, including the BILAG-defined response, in terms of both area under the curve and landmark analyses. A beneficial effect of rituximab on the primary end point was observed in the African American and Hispanic subgroups. Safety and tolerability were similar in patients receiving placebo and those receiving rituximab.

Conclusion: The EXPLORER trial enrolled patients with moderately-to-severely active SLE and used aggressive background treatment and sensitive cutoffs for nonresponse. No differences were noted between placebo and rituximab in the primary and secondary end points. Further evaluation of patient subsets, biomarkers, and exploratory outcome models may improve the design of future SLE clinical trials.

Trial registration: ClinicalTrials.gov NCT00137969.

Figures

Figure 1

A, Study design. B, Disposition of patients. AE = adverse event.

Figure 2

A, Proportion of patients experiencing a major clinical response (MCR), a partial clinical response (PCR), and no clinical response (NCR) at 52 weeks. B, Responders with African American/Hispanic backgrounds. C, Responders, according to the background immunosuppressive drug. BILAG = British Isles Lupus Assessment Group; AZA = azathioprine; MMF = mycophenolate mofetil; MTX = methotrexate.

Figure 3

A, Mean British Isles Lupus Assessment Group (BILAG) index global scores over time. B, Kaplan-Meier curve showing the time to moderate/severe flare over 52 weeks. Scr = screening; HR = hazard ratio.

Figure 4

A, B cell depletion over time. Values are the means. B, Changes in the level of anti–double-stranded DNA (anti-dsDNA) over time. C and D, Changes in complement C3 and C4 levels over time in patients with low baseline levels of C3 and C4.