REVIEW Targeting B cells to treat systemic lupus erythematosus B cells play a central role in the pathogenesis of systemic lupus erythematosus. Of late, there has been growing interest in utilizing B cells as targets for the development of new treatments for this frequently devastating disease. In addition to producing (auto)antibodies, B cells are involved in a variety of autoantibody-independent pathogenic mechanisms, such as effector functions, cytokine production and costimulation. Therefore, depleting B cells or inhibiting their actions can suppress the immune hyperactivity that is characteristic of systemic lupus erythematosus. This article examines the latest advances in novel B-cell-directed therapies for patients with systemic lupus erythematosus. 1 KEYWORDS: B-cell depletion n B-cell -directed therapies n B-lymphocyte stimulator n Arlene T Tieng , CD20 n CD22 n costimulation n systemic lupus erythematosus Gisele Zandman-Goddard2,3 & Elena Peeva†1 Systemic lupus erythematosus (SLE) is a chronic are hyperactive and display a variety of abnor- 1Rheumatology Division, Department of Medicine, Albert Einstein College of autoimmune disorder that can induce a variety malities; lupus B cells have increased calcium Medicine, Bronx, NY, USA of nonspecific constitutional symptoms such as influx upon B-cell receptor engagement, reduced 2Department of Medicine, fatigue, malaise, fever and weight loss, but also levels of Lyn kinase and increased CD45 in lipid Wolfson Medical Center, Holon, Israel 3Sackler Faculty of Medicine, Tel-Aviv can involve various organs such as the skin, rafts, and decreased expression of FcgRIIB on University, Tel Aviv, Israel - + † joints, heart, kidneys, nervous, hematologic IgM CD27 memory cells [7]. Author for correspondence: Arthritis Clinic, Montefiore Hospital, and musculoskeletal systems. Lupus nephritis is Despite the multitude of studies testing vari- DTC Bldg 440,111 E 210th St, Bronx, the key predictor of poor outcome. Some of the ous therapies, there are only a few drugs that are NY 10467, USA Tel.: +1 718 920 5584 SLE manifestations have an unpredictable clini- approved for treatment of SLE [8]. The current Fax: +1 718 798 3029 cal course and can be life-threatening. Genetics treatments are nonspecific immunosuppressants [email protected] seem to play an important role in lupus severity that can induce multiple side effects including as ethnicity predisposes people more to renal and severe infections and ovarian failure. The ratio- neuropsychiatric damage than socioeconomic nale for developing B-cell-directed therapies for factors [1]. Furthermore, SLE manifestations are SLE is based on the aforementioned critical role usually more severe in African and Asian patients of B cells in the pathogenesis of lupus. The aim is than in those of European ancestry [1]. Compared to develop novel focused drugs that will be devoid with the general population, SLE patients have a of the significant side effects of the broad-spec- three- to five-fold increased mortality [2]. trum immunosuppressants. Better specificity and The fundamental immunologic characteris- improved efficacy are the major characteristics tic of SLE is a broad dysregulation of immune expected of the new drugs, with the goal being responses that includes hyperactivity of CD4+ amelioration of SLE disease activity and preven- helper T cells and B cells, leading to the forma- tion of sequels without significant side effects. tion of autoantibodies [3,4]. Antinuclear anti- This article will highlight the newest treatments bodies (ANAs), the hallmark autoantibodies that target B cells in lupus (FIGURE 1). Despite the in SLE, are directed against dsDNA and other fact that some of the trials that target B cells have nuclear components [5]. Although historically, the been disappointing, they have provided valuable production of autoantibodies has been thought of information that can help improve the design of as the only mechanism of B-cell-mediated effects, future trials. this notion is now archaic, as B cells have been found to exert a handful of other functions, such Therapies directed to B-cell surface as the presentation of autoantigens to T cells, reg- markers CD20 & CD22 ulation of dendritic cell differentiation, mainte- Rituximab is the most commonly used mono- nance of lymphoid organization, and secretion clonal antibody for rapid B-cell depletion. of cytokines that can affect inflammation and It is a chimeric antibody directed against the lymphopoesis, and play other effector roles in B-cell-specific surface marker CD20, which is immune responses [2,6]. B cells in SLE patients expressed on immature and mature B cells, but 10.2217/IJR.10.95 © 2010 Future Medicine Ltd Int. J. Clin. Rheumatol. (2010) 5(6), 627–636 ISSN 1758-4272 627 REVIEW Tieng, Zandman-Goddard & Peeva Targeting B cells to treat systemic lupus erythematosus REVIEW IL-10 B-N10 Tocilizumab IL-6 AMG 557 B7RP-1/ICOS Epratuzumab CD22 B7/CTLA4 Rituximab Ocrelizumab CD20 B cell SBI-087 T cell Abatacept Belimumab BAFF BAFF Atacicept APRIL Figure 1. Presentation of the novel B-cell-directed therapies for systemic lupus erythematosus. APRIL: A proliferation-inducing ligand; BAFF: B-cell-activating factor; ICOS: Inducible costimulator. not on early pre-B cells or plasma cells (TABLE 1). clinical response, but the difference did not Rituximab depletes CD20+ B cells through anti- reach statistical significance (29.6 vs 28.4%). body-dependent cell-mediated and complement- However, the decrease and increase in the levels mediated cytotoxicity [9]. Rituximab has been of anti-dsDNA autoantibodies and complement, approved for the treatment of non-Hodgkin’s respectively, were significantly different between B-cell lymphoma and, more recently, rheuma- the rituximab- and the placebo-treated patients. toid arthritis. In case reports and case series, Furthermore, patients with baseline thrombo- rituximab has benefited SLE patients with cytopenia had improved platelet counts when refractory vasculitic ulcers, shrinking lung syn- treated with rituximab [18]. It is also worthwhile drome, refractory thrombotic thrombocytopenic noting that the subgroup ana lysis showed that purpura, bilateral retinal vasculitis and recur- the African–American and Hispanic patients, rent enteritis [10–14]. Although open-label trials who comprised approximately a third of the also implied the efficacy of rituximab in SLE study population, did have significant benefit [15,16], two moderate-sized, randomized, pla- from rituximab (33.8 vs 15.7%). In addition, an cebo-controlled trials of rituximab in extrarenal ad hoc ana lysis demonstrated that the subgroup and renal lupus (Exploratory Phase II/III SLE of patients who received rituximab on back- Evaluation of Rituximab [EXPLORER] and ground therapy with methotrexate had improved Lupus Nephritis Assessment with Rituximab mean global British Isles Lupus Assessment [LUNAR] trials, respectively) disappointingly Group (BILAG) scores compared with placebo. failed to meet their primary and secondary end Serious adverse events occurred at a similar per- points. The EXPLORER trial was a 52-week- centage of patients in both the rituximab and long study that randomly assigned 257 SLE placebo groups (37.9 vs 36.4%). patients with moderate to severe disease activity The LUNAR trial was a Phase III, random- in a 2:1 ratio to rituximab or placebo [17]. The ized, double-blind, placebo-controlled, multi- patients were administered intravenous infu- center study in which 144 patients with active sions as two 1000-mg doses on days 1, 15, 168 proliferative nephritis (class III/IV) were ran- and 182, as well as daily prednisone (as per trial domly assigned in a 1:1 ratio to rituximab or regimen) and their baseline immunosuppressive placebo, in the same dose and regimen that was regimen, which could have included azathio- administered in EXPLORER [19]. Background prine, mycophenolate mofetil or methotrexate. therapy of steroids and mycophenolate mofetil Compared with placebo, slightly more patients was permitted. Patients who took prednisone at in the rituximab group showed a major or partial a dose greater than 20 mg daily for more than 628 Int. J. Clin. Rheumatol. (2010) 5(6) future science group REVIEW Tieng, Zandman-Goddard & Peeva Targeting B cells to treat systemic lupus erythematosus REVIEW 2 weeks prior to screening were excluded. The The fact that EXPLORER and LUNAR primary end point, assessed at 52 weeks, was the studies did not reach their end points has pro- percentage of patients who achieved a complete voked multiple discussions regarding their study or partial renal response. There were numerically designs, end points and background immuno- more responders in the rituximab group than in suppressive therapies [20,21]. Concerns regarding the placebo group (57 vs 46%), but the differ- glucocorticoids and other immunosuppressants ence did not reach statistical significance in the masking rituximab’s effects have been expressed. end points – complete or partial renal responses In addition, some lupologists believe that the at week 52. Despite this, the rituximab group variability caused by SLE heterogeneity may displayed a significantly greater improvement have had a negative impact on the results of the in the levels of anti-dsDNA and complement rituximab studies and advocate that new clini- than the placebo group. The numbers of serious cal trials focus on patient subsets with specific adverse events were similar between the treat- organ system involvement and/or specific