Rituximab Anti-B-Cell Therapy in Systemic Lupus Erythematosus: Pointing to the Future

Petros P. Sfikakis; John N. Boletis; George C. Tsokos

Disclosures

Curr Opin Rheumatol. 2005;17(5):550-557. 

Abstract and Introduction

Abstract

Purpose of Review: To discuss the clinical effects and the immunologic consequences of transient B-cell depletion using the anti-CD20 monoclonal antibody rituximab in systemic lupus erythematosus.
Recent Findings: A total of 100 rituximab-treated patients with severe disease, refractory to major immunosuppressive treatment, have been reported so far. Within a median follow-up period of 12 months rituximab was well tolerated, which is compatible with the experience accumulated from its use in more than 500 000 lymphoma patients. About 80% of patients achieved marked and rapid reductions in global disease activity. Because of the clinical heterogeneity, dosing differences, and concomitant treatments, including cyclophosphamide in 35% of patients, a proper evaluation of the clinical efficacy or rituximab is difficult. Variable degrees of clinical benefit have been reported for all clinical systemic lupus erythematosus manifestations, including active proliferative nephritis. Whereas 4-weekly infusions of 375 mg/m2 of rituximab result in complete B-cell depletion lasting most often from 3 to 8 months, a prolonged depletion does not always correlate with a more favorable clinical response. Total immunoglobulin levels and protective antibodies are preserved, but anti-dsDNA antibody titers decrease, often independently of the clinical response.
Summary: The findings reviewed point to a growing optimism for targeting B cells in the treatment of systemic lupus erythematosus; therefore double-blind studies comparing rituximab with existing immunosuppressive therapies are needed. Moreover, careful assessments of the effects of transient B-cell depletion on distinct autoimmune pathogenetic processes will enable optimization of therapeutic single or combined therapeutic schemes.

Introduction

Systemic lupus erythematosus (SLE) B cells produce antibodies directed against self-antigens to form immune complexes that deposit to tissues and, with the help of local factors, instigate an inflammatory process.[1,2*,3*] SLE B cells are hyperactive following the engagement of the B-cell receptor that may be driven not only by extrinsic factors but also by intrinsic defects resulting in an excessive response to immunologic stimulation.[2*,4,5] In addition to the production of autoantibodies, B cells have a central role in the activation of the immune system through the production of various cytokines and serving as potent antigen-presenting cells.[6] Therefore, a drug that specifically targets B cells may represent an ideal therapeutic approach for SLE patients. Indeed, interest is increasing in the exploration of the therapeutic potential of rituximab in SLE[7**] and other autoimmune systemic diseases.[8]

Rituximab is a chimeric monoclonal antibody against the B-cell marker CD20. CD20 is expressed throughout the stages of B-cell development, but not on plasma cells, and provides a stable target for rituximab because it is neither internalized nor shed.[9*] Rituximab was approved for the treatment of B-cell malignancies in 1997 and has been administered to more than 500 000 lymphoma patients, with a highly acceptable safety profile. The biology of CD20 and the mode of action of rituximab have been recently reviewed in detail elsewhere.[9*] Here we briefly review the information generated in murine models of SLE following B-cell depletion and present critically the published experience on the use of rituximab in patients with SLE. In addition, we present immune studies performed in patients who received rituximab that provide additional in-vivo insights on the role of B cells in the pathogenesis of human SLE.

Lessons from lupus animal models The hypothesis that transient B-cell depletion can provide therapeutic benefit to SLE patients is supported by experiments indicating that Fas-intact, MRL lupus mice in a B-cell-deficient background do not develop nephritis at a time when the B-cell-intact littermates have severe disease.[10] B cells that cannot secrete circulating immunoglobulin in genetically engineered MRL/lpr lupus mice, however, can still induce glomerulonephritis, suggesting that antibodies are not required for the development of the disease.[11] Also, breaking tolerance to dsDNA and chromatin is not required for the pathogenesis of chronic glomerulonephritis in the NZM2328 lupus-prone mouse.[12] These studies confirm that aberrant interactions between autoreactive B and T cells are crucial for the development of autoimmune tissue injury and that this process is independent of the production of autoantibodies. Moreover, experiments in lupus-prone MRL-lpr/lpr mice that lack B cells indicate that expansion of activated T cells is highly B cell dependent.[13] Along these lines, experiments in rituximab-treated immunodeficient mice that were implanted with human rheumatoid synovium have shown that local T-cell activation depends on the presence of B cells.[14] These Results are compatible with the notion that B cells exert an important pathogenic role as autoantigen-presenting cells supporting the activation of autoreactive T cells.[6,15]

Although the lifespan of autoantibody-producing plasma cells is not known for any human autoimmune disease, recent experiments in lupus-prone mice have shown that certain plasma cells are short or long lived. Even following antiproliferative immunosuppressive therapy, the long-lived, nondividing plasma cells survive and continue to produce autoantibodies.[16*] Because CD20 is not expressed on autoantibody-producing long-lived plasma cells, rituximab may not remove such existing cells. In a murine model for human CD20 expression, in which treatment with rituximab mimics B-cell depletion observed in humans, distinct sensitivities of B-cell subsets to rituximab depend on factors derived from the cellular microenvironment, including the B-lymphocyte stimulator (BlyS) survival factor.[17*] Because an anti-BLyS monoclonal antibody (belimumab) is currently under study in patients with autoimmune disease,[18*] such experiments advance our understanding on the potential of combined anti-B-cell therapy in lupus patients. We can foresee that rituximab will be the proper drug to induce remission in patients with active disease (induction phase), whereas biologic agents such as belimumab will be sufficient to consolidate the therapeutic affect (consolidation phase).

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