Rituximab — Shadow, illusion or light?

Abstract

Rituximab (Rituxan, Mabthera) is a monoclonal therapeutic anti-CD20 antibody approved for use in lymphoma and rheumatoid arthritis but not for use in systemic lupus erythematosus (SLE). Nonetheless, over the past decade many reports based on case series and observational studies have suggested benefits in selected groups of SLE patients with this monoclonal. It is also clear that off-label use of rituximab in SLE is not uncommon in many countries in the world. However, two randomized controlled clinical trials of rituximab failed to demonstrate a benefit for this agent, raising important questions on how to assess the potential role of rituximab in SLE. In this article I will review the available data and provide some comments that may be of use for the practicing clinician.

Introduction

Rituximab (Rituxan, Mabthera) is a monoclonal anti-CD20 antibody that was originally developed as a therapeutic for B-cell lymphoma in the 1990s. Following its approval for use in this disease it has rapidly become one of the most widely used biologic agents based on its ability to provide benefit for patients with low-grade non-Hodgkin B-cell lymphomas, a patient group for whom few other options are available; its ability to synergize with other anti-neoplastic therapies for the treatment of high-grade lymphoma; and, perhaps most importantly for the clinician, a relatively benign side-effect profile given the seriousness of the diseases under treatment. In the late 1990s Professor Jonathan Edwards in London suggested that rituximab might also be of benefit for patients with rheumatoid arthritis (RA), a suggestion that at the time was not at all intuitive in that the role of B-cells in RA pathogenesis was poorly defined. Despite that fact, subsequent large-scale randomized clinical trials in RA clearly demonstrated that rituximab had important therapeutic efficacy in that disease, and it was subsequently approved for use in patients who had failed anti-TNF agents. Largely based on these encouraging results various groups of investigators began to explore the possibility of treating other autoimmune diseases with rituximab as well. Because SLE is characterized by a range of autoantibodies, some of which are clearly pathophysiologically important, it was not illogical to consider the use of this B-cell agent in SLE. Thus, Leandro et al. [1] initially published data demonstrating important clinical improvements in a group of patients with moderate to severe and refractory SLE who were given a single course of rituximab in the dosage approved for lymphoma, 375 mg/m² × 4 at weekly intervals. In our own unit at the Karolinska University Hospital we also treated a large number of patients in this manner and reported on the results in several publications. Specifically, an initial report of two cases demonstrated dramatic clinical improvements in patients with a prior manifest failure of treatment with cyclophosphamide (CyX) [2]. Both patients suffered from lupus nephritis and in both cases biopsies taken before and after rituximab treatment demonstrated remarkable improvements in renal histology. Later we reported on a larger group of patients with refractory lupus nephritis demonstrating similar responses, all confirmed by biopsies [3]. It should be noted that our patients were treated with the combination of rituximab in the above referenced dosage plusCyX 500 mg given twice and glucocorticoids as intravenous boluses and/or higher oral dose with subsequent tapering. In a separate report we also described patients with both renal and non-renal lupus who because of various organ manifestations that had remained refractory to conventional immunosuppressive treatments were given treatment with rituximab [4]. The vast majority of our patients had improvements after rituximab treatment that were clinically meaningful and relatively long-lasting. Throughout these uncontrolled observations the safety profile of rituximab appeared adequate. Additional groups of investigators also reported on the results of rituximab treatment in SLE. Among these reports can be named the dose-ranging studies in mild SLE by Looney et al. [5] where some improvements were seen; a large series of patients with lupus nephritis studied in Greece [6]; more follow-up on the large cohort in London [7]; a large cohort of patients in France [8], [9]; and other published case series which also supported these general impressions. In a recent meta-analysis, data on 188 cases were included [10].

Based on the multiple uncontrolled observational data and the a priori plausibility of rituximab treatment in SLE it was decided by the manufacturers of this drug to initiate two relatively large controlled clinical trials of rituximab in SLE, nicknamed Explorer for patients with predominantly non-renal lupus and Lunar for patients with lupus nephritis. The results of the Explorer trial, in which patients with predominantly non-renal lupus were randomized to receive rituximab versus placebo on top of standard immunosuppressive background therapy, were published by Merrill et al. [11] and did not demonstrate any benefit for the active treatment over placebo. It can be noted that most patients in Explorer had musculoskeletal, mucocutaneous, or generalized lupus, with other lupus manifestations being represented in only small or very small numbers. In this trial, despite the lack of positive findings in the primary and secondary outcomes, a robust biological effect for rituximab was demonstrated (i.e., B-cells were depleted and anti-DNA titers decreased) and some exploratory analyses suggested that certain subsets of patients might have benefitted from treatment. Specifically, in a recent sub-analysis, it was shown that when analyzing only the occurrence of severe flares (defined as a new ‘BILAG A’ lupus manifestation), there was a clear advantage for rituximab over placebo [12]. Nevertheless, the overall conclusion of that trial was decidedly negative.

The results of Lunar have been presented at scientific meetings but not yet published [13]. Nevertheless, it is clear that the trial was also negative without a convincing demonstration of clinical benefit for patients who received rituximab versus placebo on a background of immunosuppressive therapy with mycophenolic acid mofetyl (MMF) — not CyX.

Thus, while observational studies and a plausible mechanism made clinicians and clinical scientists confident that rituximab would demonstrably be an effective treatment for SLE, the results of two randomized trials were decidedly negative. This leads to two opposite views on rituximab for SLE. The staunch optimist, choosing to ignore the randomized trial data, could argue that rituximab remains an excellent treatment for SLE because: it depletes autoreactive B-cells, it decreases autoantibodies and it has been shown to work in observational studies of hundreds of patients. On the other hand, the more pessimistic but perhaps also the more evidence-based reaction would be something like “Rituximab has failed in two well-controlled randomized clinical trials which represent the highest level of scientific evidence. We have all been fooled by the uncontrolled data.”