B cells as a therapeutic target in autoimmune diseases other than rheumatoid arthritis

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1 Rheumatology 2005;44(Suppl. 2):ii13 ii17 B cells as a therapeutic target in autoimmune diseases other than rheumatoid arthritis doi: /rheumatology/keh618 Selective B-cell depletion with anti-cd20 therapy is a promising novel treatment option for patients with refractory autoimmune disease. The anti-cd20 antibody, rituximab, is the first therapeutic monoclonal antibody to have been approved by the European Medical Agency (EMEA) and the US Food and Drug Administration (FDA) for the treatment of relapsed, low-grade, follicular non-hodgkin s lymphoma. Rituximab is now being studied in a range of autoimmune diseases, most notably rheumatoid arthritis, but also chronic immune thrombocytopenic purpura and systemic lupus erythematosus. Current data obtained from studies of rituximab single-agent therapy for autoimmune disease show good tolerability and sustained improvement in disease symptoms, although the precise mechanisms of action in autoimmunity remain to be fully clarified. Future research is likely to be focused on the optimization of responses with rituximab-based therapy. However, early observations suggest that this approach is likely to yield significant clinical benefits in a wide range of organ-specific and systemic autoimmune diseases. KEY WORDS: Autoimmune disease, B cells, CD20, Monoclonal antibody, Rituximab. In recent years, our understanding of the role of B cells in the regulation of the immune system has expanded and it is now thought that B cells have a more extensive role than was previously appreciated [1 4]. B cells are, by definition, the source of all immunoglobulins, and in this capacity they play a critical role in antibody-mediated autoimmunity. B cells should not, however, be viewed as passive producers of immunoglobulins, with other cells (especially helper T cells) making the important decisions. B cells also play a key role in determining the responses to antigens, both directly as antigen-presenting cells (APCs) and indirectly by influencing other APCs (such as dendritic cells). As B cells could potentially contribute to the pathogenesis of autoimmune conditions, their depletion may be a highly beneficial therapeutic goal [5, 6]. Novel targeted therapies for autoimmune disorders have been developed that can affect B cells either directly or indirectly. To date, the only directly targeted B-cell therapy that has been evaluated in the clinical setting is rituximab, which targets the CD20 antigen expressed on the surface of B cells [5, 7]. Indirect strategies involve disrupting the interaction between B cells and T cells, such as with inhibitors of the immunoregulatory cytokines IL-10 and IL-6 [8 10]. CTLA4-Ig and anti-cd154 (the ligand for CD40) monoclonal antibodies have also been shown to affect the interaction between B cells and T cells [11]. Another approach has been to target molecules belonging to the tumour necrosis factor (TNF) family (e.g. BLyS and its BAFFR receptor, which seems to be specific for B cells, and CD137, which is found on T cells [12, 13]). Rituximab (MabThera Õ /Rituxan Õ ): anti-cd20 monoclonal antibody Anti-cell surface receptor molecules such as rituximab, which targets CD20, may offer certain advantages over the other strategies targeting B cells in autoimmune disease. CD20 is highly specific to B cells, whereas other indirect strategies (that interfere with the interaction between B cells and T cells) lack this specificity. A lack of specificity can result in other unexpected effects which means that it is difficult for this potential strategy to be used as a tool to gain insight into the pathophysiology of the disease. The advantages of CD20 as a target, together with the mechanisms of anti-b-cell therapy, are described in greater detail in the article by Keystone in this supplement [14]. Rituximab is the first therapeutic monoclonal antibody to have been approved by the European Medical Agency (EMEA) and the US Food and Drug Administration (FDA) for the treatment of relapsed or refractory CD20þ B-cell non-hodgkin s lymphoma (NHL). Since its introduction in 1997, rituximab has been used to treat more than patients with NHL; it is generally well tolerated with serious adverse events being uncommon [6, 15 17]. Emerging experience in neurology Rituximab as a treatment for autoimmune disease was first investigated in the neurological setting. It has been suggested that rituximab could be used to treat patients with neuropathies that are associated with monoclonal gammopathies of undetermined significance (MGUS), otherwise referred to as paraproteinaemic neuropathies [18]. There is also interest in evaluating rituximab for the treatment of myasthenia gravis and multiple sclerosis; however, data from only a few case reports are currently available [19 21]. Figure 1 shows the results obtained by Levine and Pestronk [22], who used rituximab in an open-label pilot study to treat five patients with IgM antibody-related polyneuropathies. Within 3 to 6 months of treatment, all five patients treated showed improved function, significantly improved quantitative strength measurements and reduced titres of serum autoantibodies. A subsequent controlled trial [23], which included 21 patients who were treated University of Rochester School of Medicine, Rochester, NY, USA. Submitted 2 July 2004; revised version accepted 24 February Correspondence to:, University of Rochester, 601 Elmwood Avenue, Rm G-6454, Rochester, NY 14642, USA. john_looney@urmc.rochester.edu ii13 ß The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oupjournals.org

2 ii14 FIG. 1. Changes in strength in patients with IgM antibody-related polyneuropathy before and after B-cell depletion therapy with rituximab [22]. The strength of each patient was evaluated quantitatively, and then divided by the expected strength of an adult of the same sex and multiplied by 100 to derive a per cent of normal. Reprinted from Levine and Pestronk [22] by permission of Lippincott Williams and Wilkins. ß1999 Lippincott Williams and Wilkins. with rituximab and 13 untreated patients (control group) with IgM antibody-related polyneuropathies, showed that treatment with rituximab was followed by improved strength, a reduction in serum IgM autoantibodies and a reduction in total IgM levels. There was no change in levels of serum IgG antibodies and there were no major side-effects associated with rituximab treatment, even though B cells were depleted from the circulation for periods of up to 2 yr. Emerging experience in haematology Autoimmune therapy is also attracting intense interest from haematologists. Small series and case studies in patients treated with rituximab have been reported in thrombocytopenic purpura [24 30], autoimmune haemolytic anaemia [31 39], acquired haemophilia A and von Willebrand s disease [40, 41]. Rituximab has shown good efficacy in a study of 25 patients with chronic idiopathic thrombocytopenic purpura (ITP) who had demonstrated resistance to conventional therapy [42, 43]. In this study, five patients achieved platelet counts of more than /l, and a further five achieved counts of (50 100) 10 9 /l, after 4 weeks of therapy with rituximab 375 mg/m 2 once weekly. A further three patients showed minor responses, with stabilization of their platelet counts (to less than /l). Seven of the responses were sustained for 6 months or longer and the infusions were generally well tolerated. Following these encouraging results [42, 43], a joint US Italian group conducted a study in 57 patients with ITP refractory to conventional management [44]. A total of 41 patients (72%) achieved a response (defined as a platelet increment of > /l) to four infusions of rituximab. Of these, 18 patients (32%) achieved a complete response (platelet count raised to above /l); 13 patients (23%) had a partial response (platelet count raised to above /l but below /l); and 10 patients (18%) had a minor response (platelet count raised to above /l but below /l). Of particular note in this study was the duration of response observed in some of the patients (2 partial and 16 complete responders): after 3 yr, approximately 90% of these individuals maintained the initial response. Overall, rituximab appears to confer response rates comparable or superior to those achieved with conventional second-line agents, such as vinca alkaloids, danazol, oral cyclophosphamide and azathioprine, which are associated with response rates of up to 40 50%. However, sustained remissions with these therapies are generally seen in fewer than 20% of cases [45 48]. The response to therapy with rituximab was not immediate in a large proportion of patients; some individuals showed a complete or partial response several months after the rituximab infusions [44]. The reason for this remains unclear, although there are a number of potential factors that might determine the time it takes for a patient to achieve a clinical response. Firstly, the speed at which B-cell depletion is achieved may simply vary from patient to patient and from one immune disorder to another. Secondly, the half-life of the plasma cells may affect the time it takes for an individual to respond, as plasma cells do not carry CD20 and are therefore not targeted by rituximab (i.e. if an individual has long-lived plasma cells, it may be some time before the benefits of therapy become apparent). Finally, in certain patients, autoantibodies may be able to exert an effect even at very low levels, which could delay the clinical manifestation of response to therapy. Experience in autoimmune conditions, including systemic lupus erythematosus Rituximab has been used in a variety of rheumatological diseases. However, rheumatoid arthritis remains the only condition in which a double-blind, randomized, controlled trial the results of which indicate substantial clinical benefit of rituximab has been conducted [49]. Other diseases for which rituximab therapy has been used include type II mixed cryoglobulinaemia [50, 51], Wegener s granulomatosis [52] and Goodpasture s syndrome [7]. Interim results of a Phase I/II open-label clinical study in patients with systemic lupus erythematosus (SLE) have been presented recently [53, 54]. This study is currently ongoing in individuals with clinically active SLE but without organthreatening disease (i.e. SLE Disease Activity Measure [SLAM] score <6). In this study, rituximab was given at different doses to

3 B cells as a target in autoimmune diseases ii15 three groups of six patients as follows: one dose of rituximab 100 mg/m 2 (low dose), one dose of 375 mg/m 2 (medium dose) and four weekly doses of 375 mg/m 2 (full dose). Results to date show that the extent of B-cell depletion varies between patients, although full-dose treatment has resulted in more consistent and prolonged depletion than has been seen with the other two regimens. It is interesting to note that analysis of rituximab levels in the peripheral blood of patients 2 months after the infusions showed that there was an inverse relationship between rituximab levels and the proportion of B cells present. However, the variability in B-cell response could not be fully explained by dose variation. It is possible that genetic factors may have contributed to the variation in B-cell response, as suggested by differences between individuals FcRIIIa genotypes [55]. FcR is an IgG receptor that is involved in the regulation of immune responses and inflammation. FcRIIIa is a subclass of FcR that exhibits functional polymorphisms, which can affect the efficiency of FcR-mediated functions [55, 56]. Relative to patients with the high-affinity allele, those with the low-affinity FcRIIIa allele required higher levels of rituximab in peripheral blood to achieve equivalent levels of B-cell depletion. As expected, no improvement in the SLAM score was observed in patients with partial B-cell depletion, whereas patients with good B-cell depletion (<1% of CD19þ lymphocytes) showed significant improvement in their SLAM scores 2 3 months after treatment with rituximab. Similarly, the joint and skin score components of SLAM also showed significant improvement in patients with B-cell depletion. Of additional interest is the observation that there were no significant changes in anti-double-stranded DNA titres or serum complements after 12 months follow-up. This poor serological response further supports the hypothesis that B cells are involved in mechanisms other than autoantibody production. It also suggests that in patients with SLE, B-cell depletion may be more difficult to achieve (perhaps owing to blockade of FcRIIIa or decreased natural killer cell activity and/or the presence of plasma cells with long half-lives [53, 54]). Future directions in SLE After depletion of the susceptible mature B cells, it is possible that plasma cells (which do not bear CD20) may continue to produce autoantibodies, and elusive lymphoid cells may retain the immunological memory of the autoantigen (see reviews [6, 55]). It might be hypothesized that early treatment would help to prevent the establishment of long-lived plasma cells. Recent reports of studies with rituximab in combination with other agents in patients with rheumatoid arthritis or SLE suggest that the addition of a second agent (such as a standard chemotherapeutic agent, e.g. cyclophosphamide or methotrexate) may improve efficacy [56 58]. In one study, six female patients with SLE resistant to standard immunosuppressive therapy were treated with two infusions of rituximab 500 mg, two infusions of cyclophosphamide 750 mg and with oral prednisolone [58]. All of these individuals had active disease, with elevated levels of anti-native DNA antibodies and depressed complement levels. Five patients showed improvement, as indicated by a change in median British Isles Lupus Assessment Group (BILAG) global score from 14 to 6 after 6 months (Fig. 2) [58]. One of the patients showed no improvement after 3 months and was then lost to follow-up. Manifestations of SLE, such as fatigue, arthralgia or arthritis and serositis, responded particularly well to this protocol. Haemoglobin levels increased in four patients, and the erythrocyte sedimentation rate decreased or stabilized in all participants. Serum levels of C3 increased in all five patients who had low levels at baseline, and were normal in two individuals after 6 months. Levels of anti-double-stranded DNA varied across time among the patients, but B-cell depletion was consistent and persistent in this study. FIG. 2. British Isles Lupus Assessment Group (BILAG) global scores over 6 months follow-up in female patients receiving combination therapy based on rituximab for SLE [58]. Reprinted from Leandro et al. [58] by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. ß2002 Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. Conclusions The efficacy of rituximab in a variety of autoimmune diseases shows that B cells play a key role in these disorders, and it is now generally accepted that the various functions of B cells are intimately interlinked with the actions of the other immunocytes and inflammatory cells that participate in the autoimmune process. Future therapeutic advances and optimal results are likely to be achieved with the combination of rituximab with other agents. It should also be noted that the long-term efficacy of short treatment courses with rituximab suggests that treatments directed at B cells may be capable of inducing long-lasting responses or even remission. Pending further research aimed at the identification of regimens that are likely to optimize clinical responses, it is clear that selective B-cell depletion with rituximab promises to be an important treatment option for severe autoimmune disease refractory to standard therapy. The author has completed a phase I/II trial of Rituxan Õ / MabThera Õ in SLE. The trial was partly supported by a grant from Genentech/IDEK. In addition the author has served as a consultant to Roche/Genentech/IDEK for the use of anti-cd20 in SLE and received an honorarium for participating in the symposium on which the article is based. References 1. Edwards JCW, Cambridge G, Abrahams VM. Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology 1999;97: Gause A, Berek C. The role of B cells in the pathogenesis of rheumatoid arthritis. Potential implications for treatment. BioDrugs 2001;15: Looney RJ. Treating human autoimmune diseases by depleting B cells. Ann Rheum Dis 2002;10: Takemura S, Klimiuk PA, Braun A et al. T cell activation in rheumatoid synovium is B cell dependent. J Immunol 2001;167: Do rner T, Burmester GR. The role of B cells in rheumatoid arthritis: mechanisms and therapeutic targets. Curr Opin Rheumatol 2003;15: Silverman GJ, Weisman S. 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