corticosteroids. The effort to slow the progression of RA includes diseasemodifying (DMARDs), which include gold salts,

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1 Rituximab for Patients with Refractory Rheumatoid Arthritis Patty Ghazvini, PharmD, Angela Singh, PharmD, Phillip Treadwell, PharmD, Marlon Honeywell, PharmD, and Natosha Canty, MD Dr. Ghazvini and Dr. Singh are Assistant Professors of Pharmacy Practice,and Dr.Honeywell is Associate Professor of Pharmacy Practice,all in the College of Pharmacy at Florida A&M University in Tallahassee, Florida. Dr.Treadwell is Associate Director of Clinical Pharmacology and Dr. Canty is a first-year medical resident,both in the Family Medicine Residency Program at Tallahassee Memorial HealthCare in Tallahassee. Drug Forecast is a regular department coordinated by Alan Caspi,PhD,PharmD,MBA,President of Caspi & Associates in New York. INTRODUCTION Rheumatoid arthritis (RA) is a chronic, degenerative autoimmune disease that affects 1% to 2% of the U.S. population. It occurs more often in women than in men, and there is no racial predilection. The onset is usually during the fourth and fifth decade of life; 8% of all new patients with RA are between 35 and 5 years of age. 1 RA is characterized by joint inflammation and degeneration, which leads to joint deformity and immobility. Although joint manifestations are seen as the hallmark features of RA, extra-articular manifestations can occur; these include rheumatoid nodules, vasculitis, eye inflammation, neurological dysfunction, cardiopulmonary disease, and splenomegaly. 1 Although RA can appear abruptly, its onset is usually insidious or subtle, occurring over a period of weeks to months. The prodromal period is characterized by fatigue, weakness, low-grade fever, anorexia, and arthralgias. Joint involvement, which may be preceded by stiffness and myalgias, is generally symmetrical and most commonly involves the small joints of the hands, wrists, and feet. RA is not limited to these smaller joints, however, and may be present in the knees, spine, elbow, ankle, and temporomandibular joint. As the disease progresses, joint deformities lead to alterations in strength and motor movements. These changes result in functional impairment and are associated with increased morbidity and mortality. 1 The specific pathogenic mechanism of RA remains unclear, although one theory suggests that exogenous or endogenous antigenic triggers, acting in the presence of a genetic predisposition, initiate a self-perpetuating autoimmune response within the synovial compartment. 2 This series of events leads to an increased presence of lymphocytes, macrophages, and fibroblasts within the synovium with a corresponding increase in the number of cytokines and chemokines produced, such as interferongamma (IFN-γ), interleukin-1 (IL-1), and tumor necrosis factor (TNF). The increased presence of these pro-inflammatory agents contributes to the clinical manifestations of RA, including synovial tissue inflammation, synovial fluid inflammation, and synovial proliferation, resulting in subsequent cartilage and bone damage. 3 Pharmacological strategies used in the treatment of RA address two goals: (1) alleviating symptoms associated with the disease and (2) altering the progressive nature of the disease. Alleviation of symptoms is achieved through the use of nonsteroidal antiinflammatory drugs (NSAIDs) and corticosteroids. The effort to slow the progression of RA includes diseasemodifying anti-rheumatic drugs (DMARDs), which include gold salts, D-penicillamine, hydroxychloroquine sulfate (Plaquenil, Sanofi Synthelabo), azathioprine (Imuran, Prometheus Laboratories), cyclosporine (Sandimmune, Neoral, Novartis) sulfasalazine (Azulfidine, Pfizer) and methotrexate (MTX) (Rheumatex, Wyeth; Trexall, Barr). Advances in our understanding of the pathogenesis of RA have more recently prompted the use of agents that target the pathogenic elements of the disease. 4 These agents include those that target TNF, such as infliximab (Remicade, Centocor), etanercept (Enbrel, Amgen/ Wyeth), and adalimumab (Humira, Abbott), and anakinra (Kineret, Amgen), which targets IL-1. Treatment of RA is successful in approximately two thirds of patients, leaving the remaining one third to suffer from the debilitating effects of the disease. New hope for these patients was recently discussed in anecdotal reports of remission of RA in patients receiving the monoclonal antibody rituximab (Rituxan, Biogen/Genentech) as a therapy for lymphoma. 5 These reports led to randomized, double-blind, controlled trials that showed major clinical benefit. 6 Rituximab offers a new approach to the management of RA by targeting the cellular elements (i.e., B cells) that function as a driving force behind the autoimmune responses seen in RA. 4 THE ROLE OF B CELLS IN RHEUMATOID ARTHRITIS The immune system functions by means of complex mechanisms, many of which involve the bone marrow derived B cells and the thymus-derived T cells. Until recently, RA was believed to be a T-cell mediated autoimmune disorder. This hypothesis was based on several factors, such as the association with HLA- DR allotypes, the dominant presence of T cells over B cells, and an assumed dependence of macrophage cytokine production on T-cell activation. 7 Although T cells play a crucial role in the pathogenesis of RA, newer evidence suggests that B cells exert some degree of control over T-cell activity. Recent studies involving patients with autoimmune disorders demonstrate that depletion of B cells in the peripheral bloodstream results in a decrease in disease activity despite unchanged levels of immunoglobulins. 8 This suggests that the role of Vol. 31 No. 4 April 26 P&T 21

2 B cells in autoimmune disorders extends beyond the antibody-dependent mechanisms. The current hypothesis implies that B cells participate in the pathogenesis of RA via three specific mechanisms. First, and most significantly, B cells located in the synovium produce the autoantibody rheumatoid factor (RF). The chronic inflammatory process seen in RA is perpetuated by rheumatoid factor through multiple mechanisms, including the formation of immune complexes, the production of TNF-α, T-cell involvement, and complement activation. 9 Second, B cells located within the synovium also secrete pro-inflammatory cytokines and chemokines, which contribute to the inflammation and joint destruction seen in RA. Last, B cells function as efficient antigen-presenting cells (APCs) and provide important costimulatory signals required for T-cell activation. Once activated, the T cells further stimulate the proliferation and differentiation of B cells through the secretion of cytokines, resulting in a vicious circle that is manifested clinically as RA. 5 The Target: CD2 Antigen The CD2 antigen is highly expressed on B cells, excluding stem cells, pro-b lymphocytes, and plasma cells. This feature makes CD2 an attractive target for monoclonal antibody therapy, whereas its absence from stem cells, pro-b lymphocytes, and plasma cells allows for the regeneration of the B-cell population as well as the production of immunoglobulins. Decreased immunoglobulin levels are seen with prolonged anti-cd2 antibody therapy because plasma cells are derived from activated B cells. 8 Other favorable characteristics include these facts: 1 CD2 does not modulate its own expression. CD2 is not shed from cell surfaces, and it is not internalized upon antibody binding. No membrane or secreted molecules interfere with its function. CD2 antigen is not found in the circulation. The Antibody: Rituximab Rituximab is a genetically engineered chimeric monoclonal anti-cd2 antibody. 22 P&T April 26 Vol. 31 No. 4 It is the only anti-cd2 antibody that the Food and Drug Administration (FDA) has approved for use in humans. 11 Rituximab, by targeting CD2, produces a selective transient depletion of the B-cell population through multiple mechanisms, including antibody-dependent cellular toxicity, complement-dependent cytotoxicity, the induction of apoptosis, and alterations in the ability of B cells to respond to antigens. 12 APPROVAL STATUS Rituximab was originally approved for use in patients with relapsed or refractory CD2-positive, B-cell non-hodgkin s lymphoma. On August 29, 25, Biogen and Genentech submitted a supplemental Biologics License Application (sbla) for the use of rituximab in patients with active RA who were responding inadequately to anti-tnf therapy. As a result of its Priority Review designation, the FDA approved the agent for the treatment of RA on February 28, LITERATURE REVIEW Protherae et al. 14 Early case reports of remission of coexisting RA in patients with non- Hodgkin s lymphoma (NHL) who were given rituximab provided encouraging results that this agent might lead to clinical improvement in patients with active RA. The case report described a 53-year-old man with NHL who subsequently developed arthropathy. He was treated with 7 mg of chimeric monoclonal anti-cd2 antibody for four weeks. An initial improvement of symptoms was noted at the third week of treatment. During the following weeks, symptoms resolved completely. 14 Felson et al. 15 Several small, open-label trials and one double-blind, randomized, controlled trial were conducted to evaluate the efficacy and safety of rituximab for patients with refractory RA. All of the trials used the American College of Rheumatology s (ACR s) definition of criteria for improvement. The target percentage for improvement of individual criteria has traditionally been set at 2% (ACR 2). An ACR 2 response is defined as an improvement of at least 2% from baseline in counts of both tender and swollen joints, as well as three of the remaining disease-activity measures of the ACR core set: (1) the physician s assessment of disease activity, (2) the patient s assessment of physical function, and (3) the value for one acute-phase reactant. Targets of improvement of 5% and 7% (ACR 5 and 7 responses, respectively), however, have increasingly been used in clinical trials. 15 Edwards and Cambridge 16 The first indication of the therapeutic potential of rituximab in RA was provided in a small, open-label study of five patients who had not responded to treatment consisting of at least five DMARDs. Patients received a combination of rituximab (3 mg on day 2 and 6 mg on days 8, 15, and 22), cyclophosphamide (75 mg on days 4 and 17), and oral prednisolone (3 6 mg/day for 22 days). All patients achieved an ACR 5 response, and three patients received an ACR 7 response at six months. None of the patients experienced major adverse drug events (ADEs). Leandro et al. 7 Another pilot study reported outcomes achieved in 22 patients with RA that was considered refractory to standard DMARDs. The results supported earlier data on the effectiveness of different treatment regimens in which dosages of rituximab, cyclophosphamide, and corticosteroids were varied. Cohort I. Five patients received rituximab as four intravenous (IV) infusions. On day 2, the patients were given 3 mg; on days 8, 15, and 22, they received 6 mg. They also received cyclophosphamide 75 mg as an IV infusion on days 4 and 17 and oral prednisolone 6 mg on days 1 to 23. Cohort II. Four patients received either one or two 3-mg/m 2 doses of rituximab 14 days apart without cyclophosphamide. Cohort III. Ten patients received two 3- to 35-mg/m 2 doses of rituximab and, in most cases, two doses of cyclophosphamide 75 mg. Cohort IV. Six patients were given the same protocol as those in Cohort I but without a prednisolone cover. Cohort V. Four patients received 5 mg/m 2 of rituximab, with two 75-mg doses of cyclophosphamide under variable prednisolone cover (Table 1). continued on page 25

3 continued from page 22 Table 1 Interventions and Efficacy Outcomes in Patients with Rheumatoid Arthritis Who Were Treated with Rituximab Cohort No. No. of Patients I 5 3 mg then 3 x 6 mg (2 x 6 mg in one patient) Rituximab Dosage (by IV Infusion) Other Treatments* Efficacy Outcomes Prednisolone for three to six weeks and cyclophosphamide, 2 x 75 mg II mg/m 2 Prednisolone 65 or 64 mg (in two patients only) III 1 6 or 7 mg/m 2 Cyclophosphamide 1, 1,5 mg (2,25 mg in one patient) IV 6 2 x 6 mg Cyclophosphamide, 2 x 75 mg (2 x 6 mg in two patients) V 4 5 mg/m 2 Cyclophosphamide, 2 x 75 mg ACR 7 in three of five patients ACR 5 in two of five patients at 26 weeks ACR 7 in three of five patients at 18 months ACR 2 in one patient only at six months ACR 7 in six of 1 patients ACR 5 in two of 1 patients at six months ACR 7 in two of six patients ACR 5 in two of six patients ACR 2 in two of six patients at six months Short-duration benefit only; all patients experienced relapse at six months. * Prednisolone and prednisone were given orally; cyclophosphamide was given by IV infusion. ACR = American College of Rheumatology. Adapted from Leandro M, Edwards J, Cambridge G. Ann Rheum Dis 22;61: With permission from BMJ Medical Publishing Group. 7 Of the 2 patients in this study who achieved an ACR 2 response by six months, only 19 had received both rituximab and cyclophosphamide therapy. As with the other pilot studies, no major ADEs were reported; only two infusionrelated reactions were observed. 7 DeVita et al. 17 Another trial investigated the use of rituximab without cyclophosphamide for patients with RA refractory to DMARDs and biological agents. 17 Five women with RA who fulfilled the ACR criteria gave informed consent to treatment with rituximab. Therapy consisted of four weekly IV infusions of 375 mg/m 2. Only low-dose steroids, NSAIDs, or antimalarial drugs could be continued during the trial. Only two patients demonstrated a response of at least ACR 5 by 1 months; however, reductions in C-reactive protein and serum rheumatoid factor levels were observed in four patients. No significant ADEs were noted. 17 Moore et al. 18 A phase 2 trial examined the efficacy and safety of rituximab in patients who had not successfully responded to hematopoietic stem cell transplantation (HSCT) as a therapy for RA. Ten patients were enrolled in this trial. All of them received rituximab 1 g, two weeks apart, with no major adverse sequelae. They were observed for 12 months. Eligible patients received cyclophosphamide 1 to 2 mg/kg as part of their transplantation protocol, and all were able to continue with DMARDs and steroid therapy for at least the first two months of the trial. A total of eight out of 1 patients experienced major clinical responses, achieving a 5% to 7% improvement in disease parameters. 18 Edwards et al. 12 Because the open-label pilot trials of rituximab in RA patients had demonstrated encouraging results, a randomized, double-blind, controlled study was conducted. A total of 161 patients with active RA that was inadequately controlled by conventional DMARDs, including methotrexate at median doses of 12.5 to 15 mg/week, were recruited into the study. The baseline characteristics and measures of disease activity were similar in all four treatment groups (Table 2). Patients were randomly assigned to receive one of four treatments: oral methotrexate 1 mg weekly; rituximab 1, mg on days 1 and 15; rituximab plus IV cyclophosphamide 1, mg on days 1 and 15 and 75 mg on days 3 and 17, respectively; or rituximab 1, mg on days 1 and 15 plus oral methotrexate at a dose of 1 mg weekly. They were allowed to take NSAIDs at stable doses or corticosteroids at doses that did not exceed 12.5 mg/day of prednisolone, and they were followed for 48 weeks. The primary endpoint of the study was the proportion of patients with an ACR 5 response at week 24. Secondary outcomes included ACR 2 and ACR 7 responses (2% and 7% improvement, respectively, according to the ACR criteria). The proportion of patients achieving an ACR 5 response at week 24 was greater (P =.5) in the groups of patients receiving the regimens of rituximab in combination with either methotrexate or cyclophosphamide than in the control group. The ACR 5 response with rituximab monotherapy was numerically higher than the response for the control group (which received only methotrexate), but the difference did not reach statistical significance (P =.59). The proportions of patients achieving ACR 2 and ACR 7 responses at week 24 were higher for the rituximab patients than for the controls. Exploratory analyses at week 48 revealed ACR 7, ACR 5, and ACR 2 responses in %, 5%, and 2% of patients in the methotrexate control group, Vol. 31 No. 4 April 26 P&T 25

4 Table 2 Baseline Characteristics of Patients (N = 4) Rituximab (N = 4) Cyclophosphamide (N = 41) (N = 4) Age (years) 54 ± ± 1 53 ± 1 54 ± 12 Female sex (%) Duration of disease (years) 11 ± 7 9 ± 6 1 ± 6 12 ± 7 Previous DMARDs (No.) 2.6 ± ± ± ± 1.4 Swollen joints (No.) 19 ± 1 21 ± ± 1 23 ± 13 Tender joints (No.) 32 ± ± ± ± 16 Serum C-reactive protein (mg/liter) 32 ± ± 22 4 ± 4 29 ± 32 Erythrocyte sedimentation rate (mm/hour) 52 ± ± ± ± 23 Adapted from Edwards J, et al. N Engl J Med 24;35(25): Copyright Massachusetts Medical Society. 12 Table 3 Summary of Adverse Drug Events Adverse Event Any event Up to week 24 Up to week 48 Serious adverse event Up to week 24 Up to week 48 (N = 4) 32 (8) 34 (85) Rituximab (N = 4) 32 (8) 36 (9) Cyclophosphamide (N = 41) 3 (73) 35 (85) 7 (17) (N = 4) 34 (85) 35 (88) Any event associated with the first infusion 12 (3) 18 (45) 13 (32) 13 (33) Specific event Hypotension* 7 (18) 12 (3) 12 (29) 7 (18) Exacerbation of RA 16 (4) Hypertension* 3 (7) 1 (25) Nasopharyngitis Arthralgia 1 (2) Rash Back pain 3 (7) Cough Pruritus Nausea Dyspnea 5 (13) 1 (2) * A change of more than 3 mm Hg in systolic and diastolic blood pressure from the pressure at screening was classified as hypotension (if a decrease) or hypertension (if an increase). Adapted from Edwards J, et al. N Engl J Med 24;35(25): Copyright Massachusetts Medical Society P&T April 26 Vol. 31 No. 4

5 respectively, compared with 15%, 35%, and 65% of patients in the rituximab/ methotrexate group (P =.3, P =.2, and P <.1, respectively). In the rituximab/cyclophosphamide group, 27% of patients had ACR 5 responses and 49% achieved ACR 2 responses (P =.1 for both comparisons). All other comparisons of ACR responses at week 48 favored rituximab therapy, but this difference did not reach statistical significance. 12 ADVERSE DRUG EVENTS Safety evaluations from the Edwards study showed that rituximab was generally well tolerated in patients with RA. 12 The treated patients demonstrated a similar overall incidence of ADEs, with 73% to 85% of patients reporting at least one ADE; 3% to 45% of patients in each group experienced ADEs associated with the first infusion (Table 3). 6 During the initial 24 weeks, a total of 16 serious ADEs were reported in 14 patients, with the highest incidence among patients receiving rituximab plus cyclophosphamide. During the extended observation to week 48, three patients withdrew from the trial because of ADEs: one control and two rituximab monotherapy patients. The profile of ADEs remained the same as those observed during the initial 24 weeks. It was concluded that because using rituximab in combination with either cyclophosphamide or methotrexate led to substantial clinical responses yet did not result in an observed increased risk for developing life-threatening infections this treatment approach should be considered a viable option for refractory RA. CONCLUSION B cells have an important role in the pathogenesis of RA. This is documented not only by in vitro data but also by in vivo data of B-cell depleting biological agents. The therapeutic efficacy of rituximab in RA suggests that this agent affects B cells in the synovium and causes clinically significant disruption of the inflammatory process. According to the published studies, patients do not appear to become immunocompromised by short-term treatment with anti-cd2 antibody. However, treatment is likely to involve maintenance doses after the proposed two induction doses and, possibly, additional treatment with immunosuppressive or immunomodulatory agents. Many unanswered questions exist regarding response rates, optimal dosing, comparative long-term efficacy, and placement in the RA treatment algorithm. Further controlled trials need to be conducted to answer these questions. REFERENCES 1. Shuna A. Rheumatoid arthritis. In: Talbert RL, DiPiro JT, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiological Approach, 5th ed. New York: McGraw- Hill; 22: Shaw T, Quan J, Totoritis MC. B cell therapy for rheumatoid arthritis: The rituximab (anti-cd2) experience. Ann Rheum Dis 23;62: Lipsky PE. Rheumatoid arthritis. In: Kasper D, Braunwald E, Fauci A, eds. Harrison s Principles of Internal Medicine, 16th ed. New York: McGraw-Hill; 25: Keystone E. B-cells targeted therapy. Arthritis Res Ther 25;7:S13 S Puppo F, Murdaca G, Ghio M, Indiveri F. Emerging biologic drugs for the treatment of rheumatoid arthritis. Autoimmunity Rev 25;4: Edwards J, Leandro M, Cambridge G. B lymphocyte depletion therapy with rituximab in rheumatoid arthritis. Rheum Dis Clin North Am 24;3: Leandro M, Edwards J, Cambridge G. Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum Dis 22; 61: Tsokos G. B cells, be gone: B-cell depletion in the treatment of rheumatoid arthritis. N Engl J Med 24;35(25): Cohen S. B-cell depletion for rheumatic diseases: Where are we? Medscape. Available at: Accessed January 24, Keystone E. B cells in rheumatoid arthritis: From hypothesis to the clinic. Rheumatology. 25;44(Suppl 2):ii8 ii Eisenberg R, Looney R. The therapeutic potential of anti-cd2: What do B cells do? Clin Immunol 25;117: Edwards J, Szczepanski L, Szechinski J, et al. Efficacy of B-cell targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 24;35(25): Biogen Idec and Genentech Announce FDA Acceptance of Supplemental Biologics License Application and Priority Review Designation for Rituxan in Rheumatoid Arthritis. Available at: www. biogen.com/news/biogenidecpr_99. htm. Accessed February 15, Protherae A, Edwards J, Simmons A, et al. Remission of inflammatory arthropathy in association with anti-cd2 therapy for non-hodgkin s lymphoma. Rheumatology 1999;38: Felson D, Anderson J, Boers M, et al. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38: Edwards J, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology 21;4: De Vita S, Zaja F, Sacco S, et al. Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis. Arthritis Rheum 22;46: Moore J, Ma D, Will R, et al. A phase II study of rituximab in rheumatoid arthritis patients with recurrent disease following hematopoietic stem cell transplantation. Bone Marrow Transplant 24;34: Vol. 31 No. 4 April 26 P&T 27