Rituximab (Mabthera), a new approach for the treatment of rheumatoid arthritis. A systematic review

378 Finger E, Scheinberg MA Review Rituximab (Mabthera), a new approach for the treatment of rheumatoid arthritis. A systematic review Rituximab (M...
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Finger E, Scheinberg MA

Review

Rituximab (Mabthera), a new approach for the treatment of rheumatoid arthritis. A systematic review Rituximab (Mabthera), uma nova abordagem para tratamento da artrite reumatóide. Uma revisão sistemática Eduardo Finger1, Morton Aaron Scheinberg2

ABSTRACT Rituximab is a chimeric monoclonal antibody capable of depleting B cells expressing CD20. Clinical trials carried out in patients diagnosed with active, established RA confirm that a single cycle of rituximab given as two infusions a week apart, together with once weekly oral methotrexate, produces enduring clinical responses comparable to that observed with TNF blockade and may slow the rate of structural damage to joints. Rituximab, which has recently been approved for use in active rheumatoid arthritis refractory to TNF inhibitors, exhibits an acceptable safety record in rheumatoid arthritis  trials, but its infusion can be followed by reactions of variable frequency and severity which, in most instances, can be prevented by intravenous administration of corticosteroids and anti-histamines prior to the infusion. The long-term safety record of rituximab as observed from the follow-up of patients treated for non-Hodgkin’s lymphoma is favorable and reassuring. Current uncertainties regarding rituximab usage in rheumatoid arthritis are: (a) management of rituximab treatment failures, and (b) lack of reliable biomarkers to rationally indicate the best choice of the biologic agent. Keywords: Arthritis, rheumatoid/drug therapy; Antibodies, monoclonal/ therapeutic use; Antigens CD20  

RESUMO Rituximab é um anticorpo monoclonal quimérico capaz de reduzir o repertório de linfócitos B que expressam CD20. Estudos clínicos realizados em pacientes com diagnóstico definido de artrite reumatóide ativa confirmaram que um ciclo único de rituximab aplicado por meio de duas infusões no intervalo de uma semana, associado a um regime semanal de metotrexato, produz resposta clínica duradoura comparável àquela observada com o bloqueio do TNF e pode reduzir a velocidade de dano estrutural nas articulações. Rituximab foi recentemente aprovado para tratamento de artrite reumatóide ativa não-responsiva ao tratamento com agentes inibidores do TNF e apresenta um bom

histórico de segurança, mas sua infusão pode gerar reações com freqüência e gravidade variáveis que, na maior parte dos casos, podem ser evitadas com a administração intravenosa de corticóides e anti-histamínicos antes da infusão. O perfil de segurança do rituximab a longo prazo, a julgar pelo acompanhamento de pacientes tratados em decorrência de linfomas não-Hodgkin, é favorável e motivador. As dúvidas atuais sobre o uso do rituximab na artrite reumatóide são: a) como tratar falhas de resposta ao rituximab e b) falta de marcadores confiáveis para indicar de forma racional a melhor opção de agente biológico a ser utilizado. Descritores: Artrite reumatóide/quimioterapia; Anticorpos monoclonais/uso terapêutico; Antígenos CD20

INTRODUCTION The outlook for rheumatoid arthritis (RA) has improved considerably in recent years. A number of factors have contributed to this: 1) appreciation of the gravity of the social and economic burden imposed by RA has grown, as has the recognition that more favorable clinical outcomes are achieved when synovitis is optimally suppressed; 2) there is now compelling evidence that intervention with disease-modifying combination therapy early in the course of rheumatoid arthritis results in improved rates of remission, magnitude of clinical benefit, and slowing of structural damage to joints(1-8); and 3) the dramatic impact that has been made over the last decade or so with the introduction and widespread use of biologic tumoral necrosis factor (TNFα) inhibitors leading to improvements in patient care with particularly marked benefit with respect to inhibition of structural damage to joints. However, the costs associated with

 PhD Immunology, Hospital Israelita Albert Einstein – HIAE, São Paulo (SP), Brazil.

1

 Researcher in Rheumatology and Immunology , Instituto Israelita de Ensino e Pesquisa Albert Einstein – IIEP, São Paulo (SP),  Brazil.

2

Corresponding author: Eduardo Finger – Avenida Albert Einstein, 627 – conj. 1209 – Morumbi – CEP 05652-000 – São Paulo (SP), Brazil – Tel.: 11 3747-3209 – e-mail: [email protected] Received on Jan 21, 2007 – Accepted on Oct 01, 2007

einstein. 2007; 5(4):378-386

Rituximab (Mabthera), a new approach for the treatment of rheumatoid arthritis. A systematic review

biologic drugs is high and rationing of these agents is required in most health care economies, and TNFα inhibitors are generally not available at the earliest stages of disease where there is the highest potential to prevent joint damage(9-15). Indeed, sufficient data exist to suggest that early treatment with an anti-TNF agent may permit induction of biologic-free remission(16-17). Cost-effective and optimal clinical use of expensive biologic agents is further complicated by the fact that a significant proportion of RA patients are refractory to TNFα blockade, suggesting that other pro-inflammatory molecules or immunological pathways drive the clinical syndrome in this population. Furthermore, serious adverse events, although relatively uncommon, can and do occur in an unpredictable manner(18-20). In light of these considerations, the recent approval in Brazil of a new, efficacious biologic therapy for patients with active RA who fail to respond to, or are intolerant of, TNFα inhibitors is timely. The biologic in question is rituximab (Rituxan; Genentech Inc. and Biogen Idec Inc.; and MabThera; F-Hoffman LaRoche Ltd.), a B celldepleting, monoclonal anti-CD20 monoclonal antibody (mAb).

OBJECTIVES To systematically review and analyze available peerreviewed evidence regarding the usage of Rituximab in the treatment of rheumatoid arthritis in terms of its rationale, clinical efficacy, safety, likely mechanism of action and future perspectives. METHODS Utilizing the PUBMED database, we gathered 20 publications with appropriate presentation and discussion of evidence regarding the treatment of RA with rituximab comprising case reports, original articles, reviews and preliminary reports and full reports. This evidence was analyzed, summarized and discussed. RESULTS Introduction to rituximab Rituximab is a chimeric mouse-human monoclonal antibody, directed against the extracellular domain of the CD20 antigen. It initiates complement-mediated B cell lysis and may permit antibody-dependent, cellmediated cytotoxicity when the Fc portion of the antibody is recognized by corresponding receptors on cytotoxic cells. Rituximab may also initiate apoptosis(21) and influence the ability of B cells to respond to antigen or other stimuli(22). Rituximab initially found a role in

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clinical practice as a single-agent treatment for relapsed or refractory low-grade or follicular CD20 + B cell non-Hodgkin’s lymphoma, for which it was approved. There was, therefore, a wide experience of rituximab in hematology-oncology prior to clinical trials of this drug in rheumatoid arthritis and its recent approval in the USA and Europe for treatment TNF inhibitor-refractory RA patients with active disease.

B cell depletion therapy: a new approach to the treatment of rheumatoid arthritis B cells arise from stem cells in the bone marrow where they acquire an antibody receptor bearing a unique variable region. A number of maturation and activation steps take place as the B cells migrate from the marrow compartment through blood to perifollicular germinal centers and memory compartments in lymphoid tissue before returning to the marrow as mature plasma cells. Successful maturation and survival of cells is tightly regulated and dependent on a number of trophic signals delivered via cell surface ligands such as the vascular cell adhesion molecule-1 (VCAM-1), and soluble factors such as the B lymphocyte stimulator (BLyS). The role of B cells in the pathogenesis of RA is not fully understood. Nonetheless, there are a number of known B cell functions of likely relevance, including their role in antigen presentation, secretion of proinflammatory cytokines, and production of rheumatoid factor, and thus, their role in immune complex formation and co-stimulation of T cells. B cells are also implicated in the process of ectopic lymphoid organogenesis in the rheumatoid synovium. In the late 1990’s, Edwards and colleagues suggested that the (assumed) underlying autoreactive response in RA might be driven by self-perpetuating B cells and that initiation of inflammation results from ligation of the low affinity IgG receptor, FcRγIIIa, by immune complexes(23-24) and their antibody products. Because CD20 is not internalized and is highly expressed on a range of B lineage cells including pre-B cells, immature B cells, activated cells, and memory cells, but is not found on stem, dendritic, or plasma cells (Figure 1), it is an ideal target for B cell depletion by monoclonal antibodies. The hypothesis that B cells represent a therapeutic target in RA is also being tested in clinical practice using other strategies for B cell inhibition, as discussed below. The CD20 antigen is located in the B cell membrane with 44 amino acids exposed to the intracellular space. Its function is unknown, although it may have a role in cell signaling or in calcium mobilization(24). Interestingly, CD20 knock-out mice do not have a clear-cut phenotype einstein. 2007; 5(4):378-386

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or obvious B cell defect(25). In the majority of patients, CD20-positive B cells represent a prominent population in the rheumatoid synovial tissue.

Cell surface antigens

Stem

Pro B

Pre B

Immature

Activated

Memory

Plasma

CD19 CD20 CD24 CD38 CD39

Figure 1. CD20 expression during the maturation of B cells

Clinical studies of rituximab in RA The clinical effects of B cell depletion therapy using rituximab in a number of different treatment regimes have been reported in patients with active RA over the last five years with the emergence of encouraging data. In 2001, Edwards and Cambridge reported their findings in five patients with severe, long-standing refractory RA, despite treatment with at least 5 previous disease-modifying anti-rheumatic drugs (DMARDs), following treatment with rituximab used in combination with oral prednisolone and pulsed intravenous cyclophosphamide based on a schedule derived from the rituximab-CHOP regimen used in nonHodgkin’s lymphoma patients(26). Up to four intravenous rituximab infusions were administered at 300 mg on day 2, and 600 mg on days 8, 15, 22. Oral prednisone was given from 30-60 mg on days 1-22 and intravenous 750 mg cyclophosphamide on days 4 and 17. At 6 months, all five patients achieved an ACR 50 response, and of these, three patients achieved the more stringent ACR 70 level response. All three maintained this response at 1 year. The two patients with ACR 50 responses relapsed and both achieved ACR 70 on re-treatment. In this small series, there were no major adverse events and no infusion-related events. However, the use of steroids and cyclophosphamide precluded any conclusions regarding the contribution of rituximab to the observed benefit. The findings of two further small open-label studies were published in 2002. De Vita et al. used rituximab (4 weekly intravenous infusions of 375 mg/m2) to treat 5 patients with active RA despite combination treatment with methotrexate and cyclosporine, of whom 2 were non-responders to anti-TNF therapy(27). In this study, one patient had an ACR 70 response (lasting 10 months) and einstein. 2007; 5(4):378-386

one had an ACR 50 response (lasting 1 year). Two further patients had an ACR 20 response. Leandro et al. reported their findings following treatment with one of five different combinations of rituximab, cyclophosphamide and oral prednisone in 22 patients with long-standing active RA despite treatment with at least 2 previous DMARDs(28). At 6 months, ACR 20, 50 and 70 responses were achieved by 16, 13 and 8 patients, respectively. No major adverse events were reported, but non-serious infections occurred in five patients and mild to moderate nausea in seven patients. These encouraging early efficacy findings with an acceptable safety profile pointed to a possible therapeutic potential for rituximab in RA. Confirmation of benefit required a randomized, double-blind, controlled study. In a phase IIa study, the efficacy of rituximab in active rheumatoid arthritis was tested in 161 patients who had failed to respond adequately to treatment with methotrexate at a dose of at least 10 mg once weekly for at least 16 weeks. Patients were assigned to one of four treatment regimens: a 1 g infusion of intravenous rituximab alone on days 1 and 15; methotrexate alone as a comparator arm; intravenous rituximab with cyclophosphamide infusions at a dose of 750 mg on days 3 and 17; or rituximab and methotrexate. All patients received 100 mg methylprednisolone just before each treatment, in addition to prednisolone 60 mg daily on day 2 and days 4-7, and 30 mg daily on days 8-14. The primary endpoint was the proportion of patients achieving an ACR 50 response at week 24, and exploratory analyses were undertaken at week 48(29). At week 24, a significantly greater proportion of patients achieved an ACR 50 in the rituximab and methotrexate combination group (43%; p = 0.005), and the rituximab and cyclophosphamide combination group (41%; p = 0.005) than in the group receiving methotrexate as monotherapy (13%). Thirtythree percent of the patients receiving rituximab alone achieved an ACR 50 response, but this failed to reach statistical significance as compared with methotrexate alone (p = 0.059). In all the rituximab groups, the mean change from baseline in disease activity score was significant as compared with methotrexate alone. At 48 weeks, an exploratory analysis of the ACR responses in the rituximab and methotrexate group demonstrated 35% of patients responding at the ACR 50 level, and 15% at the ACR 70 level, significantly greater than the 5% and 0% responses at ACR 50 and 70% levels, respectively, in the methotrexate group. In the rituximab and cyclophosphamide treatment arm, 27% of patients achieved an ACR 50 response. Rituximab treatment was associated with nearcomplete peripheral blood B cell depletion persisting throughout the 24-week period of the primary analysis.

Rituximab (Mabthera), a new approach for the treatment of rheumatoid arthritis. A systematic review

methylprednisolone on day 1 reduced the incidence and severity of the first rituximab infusion reactions by about one-third (Figure 2). Both rituximab doses were efficacious. At the lower dose, 55% of recipients achieved ACR20% responses as did 54% of those at the higher rituximab dose, in both cases highly significantly greater than the 28% of those receiving placebo infusions. Similarly, there were significantly higher proportions of patients achieving ACR50, ACR70% and according to the European League Against Rheumatism (EULAR) criteria good responses at 24 weeks at both rituximab doses as compared to patients randomized to placebo infusions. At the most stringent ACR70% response level, the difference between the percentages of responders in the placebo, lower and higher rituximab groups was most marked at the higher rituximab dose of one gram two weeks apart (5%, 13% and 20% respectively, p < 0.05). Adverse events reported up to 24 weeks were largely infusion-related, particularly at the time of the first infusion. First infusion

50

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Patients in the rituximab groups were noted to have a substantial and rapid reduction in the concentration of rheumatoid factor levels in serum, but despite peripheral B cell depletion, immunoglobulin levels did not change substantially(29). Surprisingly, in view of the profound peripheral B cell depletion, the overall incidence of infection reported was similar in the control and rituximab groups, at 24 and 48 weeks. By week 24, four patients in the rituximab groups and one in the control group had suffered a serious infection. Two further serious infections were reported during the extended 48-week period in the rituximab groups, one of which was fatal. Infusion reactions were reported in 36% of patients receiving rituximab and 30% of patients receiving placebo, although most were characterized as mild or moderate. Infusion reactions included hypotension, hypertension, flushing, pruritus, and rash. These features are thought to be caused by a cytokine-release syndrome associated with marked cell lysis. In summary, the findings of the phase IIa study indicated that a single course of treatment with rituximab, particularly in combination with MTX, produces an enduring response in patients with severe, seropositive, active RA. Furthermore, treatment with rituximab was well tolerated, with a favorable safety profile over 48 weeks of follow-up. Following the success of the phase IIa study, a phase IIb study was undertaken to examine the efficacy and safety of rituximab at different doses, with or without glucocorticorticoids, in patients with active RA resistant to DMARDs, including biologics. The findings of this phase IIb study, the Dose-ranging Assessment: International Clinical Evaluation of Rituximab in RA (DANCER) trial have recently been reported(30). Four hundred and sixty-five patients with active disease were recruited. They had to have failed at least one DMARD other than methotrexate, but no more than five, and/or biologic response modifiers, and to have been treated with methotrexate as a single DMARD for at least 12 weeks, with four weeks of stable therapy at a dose of at least 10 mg once weekly. All other DMARDs were withdrawn at least four weeks prior to randomization and eight weeks for infliximab, adalimumab, or leflunomide. Patients were randomized to receive either placebo infusions or rituximab at a dose of 500 mg or 1 g on days 1 and 15, together with one of three glucocorticoid options, comprising glucocorticoid placebo, 100 mg of intravenous methylprednisolone prior to each rituximab infusion, or 100 mg of methylprednisolone prior to each infusion in addition to an oral corticosteroid. The results at 24 weeks confirmed the significant efficacy of a single course of rituximab in active rheumatoid arthritis when combined with continuing methotrexate. This benefit was independent of glucocorticoids, although

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Based on data in Emery P, et al. Arthritis Rheum. 2006;54:1390-400.

Figure 2. DANCER – infusion reactions Figure 2

Very recently, preliminary data from a phase III trial has been published or presented at international meetings(3132) . This trial, known by the acronym Randomized Evaluation of Long-term Efficacy of Rituximab in RA (REFLEX) was designed to determine the efficacy and safety of rituximab when used in combination with methotrexate in patients with active rheumatoid arthritis who have an inadequate response to one or more antiTNF therapies, either because of lack of efficacy (90% of patients recruited) or because of toxicity (10% of patients recruited) (Figure 3). In addition, all patients recruited had radiographic evidence of at least one joint with definite erosion attributable to rheumatoid arthritis. The recruited cohort comprised 520 patients, of mean disease duration 12 years, on a background regime of 10-25 mg of once weekly methotrexate. After a washout period during which other DMARDs and anti-TNFs were withdrawn, patients were randomized to receive a single course of einstein. 2007; 5(4):378-386

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1g rituximab, or placebo, infusions on days 1 and 15. All patients were given 100 mg, IV, methylprednisolone prior to each infusion and a brief course of oral prednisolone between the two doses: 60 mg daily from days 2-7 and 30 mg daily from days 8-14.

Screen: anti-TNF and/or DMARD withdrawal period

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Day Day Wk Wk Wk Wk Wk Wk 1 15 4 8 12 16 20 24

Visits every 2 months Month 24

Rescue therapy

Rituximab or placebo infusion Clinic visit

Group B: Rituximab + MTX Group A: Standard of care

* Primary efficacy timepoint Figure 3. REFLEX study design Figure 3

Of the patients assigned to rituximab, 82% completed 6 months compared with only 54% assigned to placebo. The major reason given for study withdrawal was lack of response reported in 40% of placebo and 12% of rituximab treated patients. At 6 months, significantly more patients receiving rituximab achieved ACR20, 50% and 70% responses at 51%, 27% and 12% compared with 18%, 5% and 1% of patients receiving placebo infusions. In terms of change in disease activity score (DAS28), intentionto-treat analyses showed that in patients administered placebo infusions, the reduction from baseline was 0.34, less than the 0.6 point reduction from baseline considered to clinically meaningful, as contrasted with a reduction of 1.83 in the rituximab group. The ACR response evaluates RA treatment based on a 20, 50 or 70 percentage improvement in 5 of 7 core components. However, from the patient perspective, it is not straightforward to determine where the actual benefit of an ACR 20 improvement lies. In fact, in the REFLEX study there were significantly greater improvements in all components of the ACR core set measures in the rituximab group. Rituximab demonstrated a clinically meaningful benefit for RA pts in physical function evaluated by a health assessment questionnaire (HAQ) in all non-overlapping ACR response categories. In the active treatment arm, both clinical and subjective parameters of the ACR core components contributed to the assignment of an ACR 20% response, whereas on placebo, the subjective parameters dominated(32). The extraordinary success of TNF blockade with respect to inhibition of structural damage to joints has set a level to which all new biologics must aspire in the treatment of RA. Preliminary analyses of REFLEX einstein. 2007; 5(4):378-386

radiographic data set at one year have been presented recently with encouraging findings(33). At week 56, the mean change in Genant-modified Sharp score in the placebo plus methotrexate arm was 2.31 compared to 1.0 in the rituximab plus methotrexate group (p = 0.0043). Significant differences were also reported for joint space narrowing and bone erosions, comprising both components of the score. The proportion of patients with no progression in erosion score was 61% in the rituximab arm, significantly higher than the 52% in the placebo arm. These represent the first data that B cell depletion therapy can inhibit progressive destruction to joints in a population refractory to anti-TNF treatment.

Safety issues A common concern regarding all therapies directed at B cells is the potential for toxicities related to modulation of humoral immunity. Unlike other newly introduced biologic therapies for an RA indication, rituximab has the considerable advantage of an oncology safety database based on more than 350,000 non-Hodgkin’s lymphoma patient treatments since 1997(34). The overall safety conclusions are that serious adverse events are infrequent and often associated with well-defined risk factors such as cardiopulmonary disease or a high number of circulating cancer cells. Of note, in this lymphoma population, prolonged peripheral B cell depletion has not been associated with cumulative toxicity or increased occurrence of opportunist infections(35-37). In RA open-label (38) phase II (29-30) and III (31) studies there has been no evidence of severe humoral immunodeficiency although there is some anecdotal evidence that this may represent a significant difficulty in those patients receiving multiple cycles of rituximab treatment over a number of years in open-label studies(23). In phase II studies, most adverse events were mild to moderate and included headache, nausea and rigors. In the DANCER trial, adverse events associated with rituximab were largely associated with the first infusion, occurring in 39% of patients treated with 500mg (without steroid) and 46% receiving 1g compared with 17% of those administered placebo infusions. The corresponding incidence decreased with the second infusion to 5%, 8% and 10%, respectively [Figure 2]. Two serious infusion reactions, hypersensitivity and generalized edema, occurred on day 1. Pre-treatment with methylprednisolone prior to rituximab infusions reduced the incidence and severity of reactions by about one-third. Infectious adverse events (largely upper respiratory tract infections) were reported in 28% of placebo and 35% of rituximab patients. There were six serious infections: two in the placebo group, four in patients receiving rituximab

Rituximab (Mabthera), a new approach for the treatment of rheumatoid arthritis. A systematic review

1000 mg, and none in patients receiving rituximab 500 mg. No opportunistic infections or TB reactivations were reported. Immunoglobulin levels in patients receiving rituximab were slightly decreased at week 24, but remained within normal limits. In our experience, infusion reactions have not constituted a factor limiting the indication of Rituximab. Infusion reactions can mostly be prevented by treatment with intravenous hydrocortisone (100 mg) and diphenhydramine (50 mg) shortly before the infusion (Figure 4), but sometimes, even with this recommended pre-treatment, during the beginning of the first infusion, some patients develop tachycardia, hypotension, diaphoresis, weakness, dizziness, headache and dyspnea. These symptoms can be controlled by immediate interruption of the infusion, which can be restarted at a slower rate with no recurrence of the symptoms after the patient recovers.

100 mg of intravenous

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Figure 4. Prophylactic protocol applied prior to rituximab infusion at Hospital Israelita Albert Einstein with the purpose of preventing infusion reactions Figure 4

In some patients, a late serum-sickness-like reaction to Rituximab has been reported, especially in those presenting high baseline levels of immunoglobulins at the initiation of the treatment (Chart 1)(18). This reaction presents as a disseminated urticarial rash, low fever and increased inflammatory markers resembling classical serum sickness. This is mostly a self-limited reaction and the symptoms can be controlled by anti-histamines, or in case of severe symptoms, corticosteroids. Chart 1. Development of serum-sickness-like reactions following infusion of Rituximab(18) Age/Sex Diagnosis Triggering infusion 45/M Refractory Autoimmune Polyneuropathy 1 48/F Refractory Autoimmune Thrombocytopenia 2 23/F Systemic Lupus Erythematosus 2 28/F Systemic Lupus Erythematosus 1 28/F Systemic Lupus Erythematosus 2 43/F Primary Sjögren’s Syndrome 2 41/F Primary Sjögren’s Syndrome 2 39/F Primary Sjögren’s Syndrome 2 27/F Primary Sjögren’s Syndrome 2 60/F Mixed Cryoglobulinemia 1 38/F Hypergammaglobulinemic Purpura 4 45/F Primary Sjögren’s Syndrome 1 12/M Chronic immune thrombocytopenic purpura 2 11/F Chronic immune thrombocytopenic purpura 2

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Immunodynamics Among RA patients achieving clinical responses to rituximab treatment, the time to clinical relapse is heterogeneous. In some patients, relapse is closely correlated to the reappearance of peripheral blood B cells, but in others, it may be delayed by years(39). Clinical relapse is more closely associated with increases in autoantibody levels, but a need remains for better biomarkers reliably informing optimal management strategies on an individual patient basis. All B cell populations are depleted following rituximab therapy, with more than 80% of residual B lineage cells exhibiting memory or a plasma cell precursor phenotype(40). B cell repopulation occurs at a mean of 8 months after rituximab treatment, and depends on the formation of naïve B cells of immature phenotype as found in umbilical cord blood. Peripheral B cell depletion is accompanied by substantial increases in blood BLyS concentrations which tend to fall with B cell repopulation(41). However, in cases of prolonged clinical responses, more gradual reductions in BLyS concentrations have been observed to extend beyond the period of B cell depletion. Thus, BLyS may contribute to survival or regeneration of pathogenic, autoreactive B cells. This hypothesis predicts a potential therapeutic role for blockade of BLyS in addition to B cell depletion. DISCUSSION General comments Recent advances in the understanding of the pathogenesis of rheumatoid arthritis emphasize the critical role played by peripheral blood B cells in self-sustaining chronic inflammatory processes. The available data suggest that rituximab is most effective in a proportion of rheumatoid factor positive patients and that this drug will be a promising addition to the therapeutic armamentarium for the treatment of rheumatoid arthritis. It is likely that its major short-term use in clinical practice will be confined to the TNF inhibitorrefractory population until there is broader experience and confidence regarding potential adverse effects. At the present time there are uncertainties regarding the implications of long-term peripheral B cell depletion and the timing and need for re-dosing with rituximab in patients who respond. Current research suggests that restoration of peripheral B cell numbers takes about 8 months after depletion treatment, and further studies are needed to identify the optimum regimes that can be used for maintenance therapy that will provide efficacy and limit toxicity. Although the available safety data for rituximab in RA is reassuring, the data need to be interpreted with caution until larger numbers of patients have been treated and long-term safety and re-treatment data become available. However, antibody titers against common recall antigens einstein. 2007; 5(4):378-386

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such as tetanus toxoid appear to be unaffected by a single course of rituximab treatment(42). Furthermore, there is also a substantial body of safety data for rituximab in treatment of non-Hodgkin’s lymphoma where similarly low infection rates have been reported. In oncology, some of the associated adverse events are related to circulating tumor loads. Overall, this is reassuring with regard to the rheumatoid population, although close monitoring of immunocompetence and for the possibility of rare opportunistic infections is advisable.

The future of B cell therapy Initially, rituximab, in combination with methotrexate, will be used as a second-line biologic, after one or more anti-TNFs, in the treatment of active RA. However, as physicians become more experienced with its use, it is likely that interest in its potential as a first-line biologic will increase over the next few years. It is believed that competitive health economic data in comparison to TNF inhibitors and efficacy data in early phase disease will be a decision factor in these circumstances. A key issue will be the most effective strategy in early stages of RA to induce a biologic-free remission and whether this can be achieved safely and effectively with rituximab. The longer-term success of rituximab will also depend on clinical trial data for fully human antibodies targeting CD20, and in particular, whether delivery of such antibodies has a lower rate of infusion (or injection) reactions. Although many other approaches to B cell targeted therapy are in clinical testing, it is unlikely that any of these will significantly affect the rituximab niche over the next 5-year time span. Alternative strategies to target the B cell compartment include the use of antibodies to B lymphocyte stimulator or BlyS (Figure 5). BLyS is a naturally occurring protein required for the development of B-lymphocytes into mature plasma cells. Elevated levels of BLyS in rheumatoid arthritis are believed to contribute to the production of autoantibodies. Belimumab, or LymphoStat-B, is a human anti-BLyS monoclonal antibody currently in clinical development for the treatment of rheumatoid arthritis and other rheumatic

indications. An alternative approach to BLyS inhibition in early stages of clinical development is to block signaling through BLyS receptors using a soluble receptor such as transmembrane activator and calcium modulator and cyclophilin ligand interactor immunoglobulin (TACI-Ig). Preliminary results of a phase II double-blind, placebocontrolled study of belimumab in 283 active RA patients has been presented(43). Patients were randomized to receive intravenous belimumab at a dose of 1, 4, or 10 mg per kg or placebo infusions on days 0, 14, and 28, then every 28 days through 24 weeks. The ACR 20 response at week 24 in the combined belimumab groups was 29% compared to 16% in the placebo group, with no dose response observed. The antibody was well tolerated(43). These preliminary findings with a functional inhibitor of B cells are surprising, given the effectiveness of rituximab. This may simply represent a pharmacokinetic problem and signify that too low a dose of belimumab was used. An alternative explanation might be that the effectiveness of rituximab is not directly related to its effects on B cells. BONE MARROW Stem Cell

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Figure5.5 Targeting B cells in RA Figure

In conclusion, the rituximab clinical trial data available indicate that CD20 is a therapeutic target in RA and endorses B cell depletion as a successful approach to treatment that has an acceptable safety profile without an unacceptable reduction in humoral immunity after a single treatment cycle. Our experience with anti B cell therapy at Hospital Israelita Albert Einstein dates back to 2003 and is summarized in Chart 2(44).

Chart 2. Demographic and clinical data on patients with rheumatoid arthritis treated with rituximab Patient Sex Age (years) Disease duration (years) Rituximab schedule DAS28 Before After 1 F 71 5 1.0 g x 2 – – 2 F 62 8 1.0 g x 2 – – 3 F 38 10 1.0 g x 2 – – 4 F 56 10 1.0 g x 2 6.2 1.8 5 F 42 6 1.0 g x 2 5.2 1.6 6 F 50 8 1.0 g x 2 7.3 2.1 7 F 48 10 375 mg/m2 x 4 5.3 1.5 8 F 38 15 375 mg/m2 x 4 6.0 2.1 9 F 35 6 1.0 g x 2 5.1 1.6 10 F 58 11 1.0 g x 2 – –

Prednisone dose (mg) Before After 20 5.0 20 2.5 40 5.0 20 – 10 – 20 5 10 – 10 5 20 2.5 15 5

DAS = disease activity score; F = female; M = male. *Evaluation after 3 months. Efficacy was defined as a significant reduction in disease activity score when available, or by a reduction in signs, symptoms and daily prednisone dose. TNF failures described by the individual physician after prolonged use (“n” refers to the number of infliximab infusions administered before introducing rituximab).

einstein. 2007; 5(4):378-386

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Rituximab (Mabthera), a new approach for the treatment of rheumatoid arthritis. A systematic review

CONCLUSIONS The long-term safety record of rituximab as observed from the follow-up of patients treated with it for nonHodgkin’s lymphoma is favorable, and the current uncertainties regarding rituximab usage in rheumatoid arthritis are: a) how to treat rituximab failures, and b) lack of reliable biomarkers to inform a rational choice of biologic agent REFERENCES 1. Egsmose C, Lund B, Borg G, Pettersson H, Berg E, Brodin U, et al. Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5 year followup of a prospective double blind placebo controlled study. J Rheumatol. 1995;22(12):2208-13. 2. van der Heide A, Jacobs JW, Bijlsma JW, Heurkens AH, van Booma-Frankfort C, van der Veen MJ, et al. The effectiveness of early treatment with “secondline” antirheumatic drugs. A randomized, controlled trial. Ann Intern Med. 1996;124(8):699-707. 3. Lard LR, Visser H, Speyer I, vander Horst-Bruinsma IE, Zwinderman AH, Breedvel FC, et al. Early versus delayed treatment in patients with recentonset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. Am J Med. 2001;111(6):446-51. 4. van Aken J, Lard LR, le Cessie S, Hazes JM, Breedveld FC, Huizinga TW. Radiological outcome after four years of early versus delayed treatment strategy in patients with recent onset rheumatoid arthritis. Ann Rheum Dis. 2004;63(3):274-9. 5. Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet. 1997;350(9074):309-18. 6. Mottonen T, Hannonen P, Leirisalo-Repo M, Nissila M, Kautiainen H, Korpela M, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet. 1999;353(9164):1568-73. 7. Puolakka K, Kautiainen H, Mottonen T, Hannonen P, Korpela M, Hakala M, et al. Early suppression of disease activity is essential for maintenance of work capacity in patients with recent-onset rheumatoid arthritis: five-year experience from the FIN-RACo trial. Arthritis Rheum. 2005;52(1):36-41. 8. Grigor C, Capell H, Stirling A,  McMahon AD, Lock P, Vallance R, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364(9430):263-9. 9. Breedveld FC, Emery P, Keystone E, Patel K, Furst DE, Kalden JR, et al. Infliximab in active early rheumatoid arthritis. Ann Rheum Dis. 2004;63(2):149-55. 10. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: A multicenter, randomized, doubleblind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54(1):26-37. 11. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343(22):1586-93. 12. Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff M, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum. 2002;46(6):1443-50. 13. St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432-43.

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