I n the past, analgesics and nonsteroidal

Transcription

1 Rituximab in advanced rheumatoid arthritis Michael Guida BSc, MA Rheumatoid arthritis (RA) continues to have a major impact on public health. Costs to the individual and to the NHS are high, and treatment options for RA are by no means perfect. This article reviews, an agent that interrupts inflammatory events via a novel mode of action, and shows promise as a new intervention in cases of moderate to severe RA. I n the past, analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) have been the mainstay of RA treatment to control pain and inflammation. However, these agents did nothing to affect the course of the disease. More recently disease-modifying anti-rheumatic drugs (DMARDs), like methotrexate and sulfasalazine, were favoured because of their ability to slow the processes that result in joint destruction. Good evidence began to emerge 1 years ago to support the early use of DMARDs to achieve better long-term outcomes and disease remission. 1 DMARDs are now used as first-line treatment, with NSAIDs and analgesics as adjuncts. However, RA continues to be a disease associated with significant morbidity and mortality 2 and is a major burden to the health service. 3 Advances in understanding the pathological processes underlying RA have led, over recent years, to the development of new and better therapies. Today, patients with evidence of highly active disease, who have failed to respond to, or who have had significant side-effects with at least two DMARDs, including methotrexate, are eligible for antitumour necrosis factor-α (anti- TNF-α) therapy, based on the recommendations of the British Society for Rheumatology and the National Institute for Health and Clinical Excellence (NICE). 4 Anti-TNF-α agents, such as etanercept, infliximab and adalimumab, along with interleukin-based treatments such as anakinra, aim to limit inflammatory processes mediated by joint synovial cell populations 5 and the effects of cytokines. THE NEED FOR NEW AGENTS Although these newer biological treatments have been shown to be very effective, overcoming many of the limitations of traditional DMARDs, they do not work in all patients. In some 3 per cent of patients, anti-tnf-α agents have no efficacy at all, or initial efficacy is soon lost. Yet no good explanation has emerged as to why some patients respond poorly to anti-tnf-α therapy. These agents cannot be used in those with immunological profiles suggestive of connective tissue disease as well as RA, or in patients at risk of infections. In addition, concerns have been expressed about the reactivation of tuberculosis and the occurrence of serious bacterial infections such as histoplasmosis and Pneumocystis carinii pneumonia following anti-tnf-α therapy. 6 Symptoms of congestive heart failure and demyelinating disease must be monitored and long-term safety of these agents is unproven. 6 Investigation into the pathophysiology of RA points to multiple exogenous and/or endogenous antigenic triggers that act, in the presence of a background genetic predisposition, to initiate a self- EXPERT OPINION Paul Emery, Professor of Rheumatology, Molecular Medicine Unit, University of Leeds Despite the enormous impact of anti-tnf-α therapy on the treatment of RA, approximately one-third of patients who are eligible for this therapy will not benefit. Some patients initially respond to anti-tnf-α treatment and then relapse, while others appear to have disease entirely unresponsive to such therapy. A significant number of patients also develop toxicity with anti-tnf-α agents, such as infusion reactions and serious infections, including reactivation of tuberculosis. Furthermore, many patients have contraindications to anti-tnf-α therapy due to comorbid conditions. There is, therefore, a significant unmet need in the treatment of RA. Rituximab represents a major breakthrough in RA treatment, especially for patients with severe disease and limited therapeutic options. Questions remain, particularly regarding the timing of re-treatment and the best dosing strategy. Rituximab s novel therapeutic approach may eventually justify its use earlier in RA. It is the focus of a broad, ongoing research programme, which aims to underpin its increasing clinical use. FUTURE PRESCRIBER VOL 7(2) 5

2 A ACR Patients (%) B ACR 5 38 p=.25 p=.1 p=.3 p= Week 24 Week 48 p=.1 65 perpetuating series of autoimmune responses in the joint synovial compartment. 7,8 Many cell populations, including monocytes, macrophages, B-cells, T-cells, endothelial cells and fibroblasts, are believed to participate in the ongoing inflammatory processes. 7 In recent years there has been growing interest in the contribution of B-cells to the pathogenesis of RA. A number of mechanisms for B-cell involvement have been proposed 8 1 and, in particular, strong evidence for a critical role of B-cells in RA has come from a 1 report of a small study of in combination with cyclophosphamide and corticosteroids. 11 In this study, sustained improvement in RA was observed following the treatment, which was designed to deplete B-cells. Patients (%) p= p=.5 41 p=.5 43 Methotrexate alone (n=4) Rituximab alone (n=4) Rituximab and cyclophosphamide (n=41) Rituximab and methotrexate (n=4) 5 15 Week 24 Week 48 p=.1 27 p=.2 ACR denotes at least a per cent improvement in disease symptoms according to the American College of Rheumatology (ACR); ACR 5, a 5 per cent improvement. p values are for comparisons with the methotrexate monotherapy (control) group. Figure 1. American College of Rheumatology clinical responses to at weeks 24 and 48 in the randomised, double-blind, controlled phase II study of PHARMACOLOGY Rituximab is a genetically engineered chimeric anti-cd monoclonal antibody comprising human and mouse-derived elements. CD is an antigenic phosphoprotein that is chiefly expressed by B-cells. 5 Rituximab works by several mechanisms, all of which trigger CD+ B-cell lysis or apoptosis and, ultimately, a substantial depletion of circulating B-cells that lasts for up to 6 months. 5 Thereafter, B-cell levels return to normal within 9 12 months. 12 As T-cells are unaffected by therapy, opportunistic infections rarely occur. 13 In addition, treatment is associated with a rapid and sustained decrease in rheumatoid factor levels; increased rheumatoid factor is associated with aggressive disease. 14,15 Rituximab is not currently licensed for use in RA in the UK. However, as MabThera, it was the first monoclonal antibody to be widely approved and marketed 6 FUTURE PRESCRIBER VOL 7(2)

3 Median CD19+ B-cells (x1-3 /µl) Figure 2. Median levels of peripheral CD19+ B-cells during the 24-week study period in the randomised, controlled, key phase II study of. 16 for the treatment of cancer. Since 1997, has been available for the treatment of CD+ B-cell non-hodgkin s lymphoma (NHL) at a standard dose regimen of 375mg per m 2 given as intravenous (iv) infusions every 4 or 8 weeks. Dosing considerations In the key published phase II randomised, controlled, clinical trial of in RA, the dosage schedule was a mg iv infusion on days 1 and 15, alone or in combination with cyclophosphamide or methotrexate. 16 In most published trials, has been administered with concomitant high-dose corticosteroids to suppress troublesome infusion-related skin reactions. How best to use corticosteroids with remains to be clarified, but it appears that lower doses (such as mg methylprednisolone) will suppress infusion-related reactions and the Methotrexate alone (n=4) Rituximab alone (n=4) Rituximab and cyclophosphamide (n=41) Rituximab and methotrexate (n=4) Weeks use of additional oral steroids is unnecessary. CLINICAL EFFICACY Key controlled phase II study Only one randomised, controlled trial of in RA has been published to date. 16 This international study of 161 patients showed that, in those with active disease, despite methotrexate treatment, a single course of two infusions of, alone or in combination with cyclophosphamide or continued methotrexate, achieved significant improvement in disease symptoms. At 24 weeks the proportion of patients who had at least a 5 per cent improvement in disease symptoms (ACR criteria) was significantly greater with the -methotrexate combination (43 per cent, p=.5) and the -cyclophosphamide combination (41 per cent, p=.5) than with the control group taking methotrexate alone, 13 per cent (see Figure 1). Rituximab was also related to nearly complete depletion of peripheral-blood B-cells, which lasted throughout the 24- week study period (see Figure 2). 16 In all groups treated with, a significantly higher proportion of patients had a per cent improvement in disease symptoms (65 to 76 per cent vs 38 per cent, p.25), or had European League Against Rheumatism responses (83 to 85 per cent vs 5 per cent, p.4), compared with patients in the control group. All ACR responses were maintained at week 48 in the methotrexate group. 16 In order to suppress infusionrelated events, all patients, including those in the control group, received a short course of oral and iv corticosteroids. The authors acknowledged the anti-inflammatory contribution such concomitant treatment might have and highlighted earlier work suggesting the possibility that corticosteroids may contribute to B-cell death by encouraging apoptosis or direct cytolysis. 11 Efficacy with concomitant corticosteroids The most recent data, presented in Europe and the USA in 5, appear to indicate that the effectiveness of with methotrexate is not dependent on either concomitant iv or oral corticosteroid treatment, although the latter are useful in suppressing infusion-related reactions. 17,18 These recent data from a large controlled trial also appear to confirm the efficacy of a single course of (mg x 2) over 24 weeks in patients with moderate to severe RA of about 1 years standing with an inadequate response to methotrexate FUTURE PRESCRIBER VOL 7(2) 7

4 Efficacy in anti-tnf-α therapy failure The recent REFLEX phase III study by Cohen et al reported positive results of in RA patients with long-standing active disease who had responded inadequately to anti-tnf-α therapy and methotrexate. 19 Currently, patients suffering from severe to moderate RA, who may represent more than 3 per cent of all those treated with biological therapies, are left with few treatment alternatives. In a patient group of 5, with an average duration of RA of 12 years, in combination with methotrexate produced significantly higher response rates compared with methotrexate plus placebo at 24 weeks. A per cent improvement in disease symptoms (ACR criteria) was achieved in 51 per cent of patients on compared with 18 per cent on methotrexate alone (p<.1). A 5 per cent improvement in disease symptoms was observed in 27 per cent of patients taking vs 5 per cent taking methotrexate (p<.1). Rituximab was given at a dose of mg by iv infusion on days 1 and 15. Once again, all patients received iv and oral corticosteroids. 19 Knowing when and how to retreat with, based on clinical signs or B-cell levels, is an important outstanding question. Also of interest is the effect of combining biological therapies with, an area of study yet to be explored. SAFETY AND TOLERABILITY The safety profile of in patients with CD+ B-cell NHL is well characterised. Since its market launch in 1997, it is estimated that over 73 patients have received at a standard dosage regimen of 375mg per m 2 given as Number of patients Figure 3. Incidence of treatment-related adverse events in the pivotal study of in relapsed and refractory indolent non-hodgkin s lymphoma, stratified by infusion number. 13 iv infusions every 4 or 8 weeks. While serious adverse reactions have occurred in a small minority of patients, for the great majority, has proved to be safe and well-tolerated. 13 The vast majority of adverse events reported with are associated with infusions. Reactions generally occur within 3 1 minutes and are characterised by fever, chills or rigors, nausea, headache and transient hypotension. Seventy to 8 per cent of patients with NHL experience a reaction during their first infusion, and this declines to about 3 per cent with subsequent infusions (see Figure 3). Such events are predominantly brief, and mild to moderate in severity, gradually resolving when the infusion is either slowed or interrupted briefly. 13 Experience in RA The overall safety profile observed Grade 1 Grade 2 Grade 3 or 4 1st 2nd 3rd 4th Infusion in the randomised, controlled, phase II study carried out by Edwards et al 16 was consistent with that reported previously with in patients with lymphoma. 12 The majority (85 9 per cent) of adverse events associated with infusions were characterised as mild or moderate. The following adverse events generally occurred during or within 24 hours after the first infusion of and tended to be less frequent with the subsequent infusion: transient hypotension or hypertension, cough, pruritus and rash. Although the events that occurred during infusions were similar to those that occur in NHL, the incidence and severity seem to be reduced in patients with RA. From 7 8 per cent of patients with NHL report adverse events during their first infusion, 21 compared with just 36 per cent of patients in this RA study. The reasons for this difference are unproven 8 FUTURE PRESCRIBER VOL 7(2)

5 but could either be due to lower levels of CD+ lymphocytes in patients with RA, or premedication with corticosteroids. The difference may also be accounted for by the absence of cytokine release syndrome associated with tumour cell lysis seen in patients with B-cell cancers. 13 Patients receiving in the randomised, controlled phase II study had profound and prolonged depletion of peripheral-blood B-cells, but did not appear to be more susceptible to infection at weeks 24 or Immunoglobulin levels were only minimally affected, and anti-tetanus antibody titres were unchanged. By week 24, serious infections had occurred in one patient (2.5 per cent) in the control group and in a total of four patients (3.3 per cent) in the groups. Two additional serious infections were reported by week 48. The authors of this study suggested that the incidence of infection be carefully monitored together with the long-term effects of on acquired immunity. 16 Prolonged use of Extended dosing with does not appear to have revealed any significant safety issues in patients treated for NHL. Multiple courses of do not result in an increased incidence of adverse events or an increase in the incidence of infections. 13 In a report of a group of 36 patients with NHL who had received four courses of treatment at 6-month intervals, no cumulative or additional safety concerns were identified during the maintenance treatment period, even though the patients may have Figure 4. Coloured X-ray showing erosion of knee joints due to RA. been B-cell depleted throughout the 2-year study period. 22 Long-term follow up of the use of as monotherapy, or in combination with other therapies for NHL, has not revealed any consistent pattern of adverse events. 13 In RA there is unpublished evidence from the controlled phase II study that repeat treatment with in patients who have previously responded is safe and effective, the median time to re-treat being 48 weeks. 23 COST EFFECTIVENESS OF NEW TREATMENTS RA affects over 4 people in the UK, many of whom are of working age. 3 Disabling pain, stiffness and reduced joint function diminish quality of life for patients and their families. RA shortens life expectancy by 6 1 years, which is equivalent to the impact of diabetes, Hodgkin s disease, stroke or triple vessel coronary artery disease. 3 There is no shortage of evidence concerning the major impact the disease has on direct and indirect costs, as well as EXPERT OPINION Robert Moots, Professor of Rheumatology, Division of Infection and Immunity, University of Liverpool RA is a serious condition that causes major morbidity and increased mortality. The cost to both patients and society is high with loss of earnings and a need for extensive medical care. Breakthroughs in our understanding of the pathological processes that underlie RA have led to the development of new and better therapies, such as anti-tnf-α agents, and the chance of remission for many patients. However, these drugs are not effective in all patients, and may be associated with an increased risk of infection, and are certainly expensive. There is, therefore, still a place for other therapies in the armament of the rheumatologist. Rituximab depletes cells expressing CD. It is given as a course of two iv infusions that may result in significant clinical improvements for many months. Rituximab has been shown to be effective in patients who have failed on anti-tnf-α agents and is set to play an important role in the care of RA. SPL FUTURE PRESCRIBER VOL 7(2) 9

6 quality of life. In, there were 1.9 million GP consultations for inflammatory arthritis and nearly 46 hospital admissions. 3 The cost to the NHS of managing RA and the complications of treatment is an estimated 24 million per year, and the total annual cost of treating RA (including health costs and lost working days) is estimated to be 1.3 billion. 3 Thanks to the progress made with anti-tnf-α therapy, the goals of treatment have been raised remission is now feasible, with these agents attenuating progression of joint damage, improving quality of life and preserving functional status. 24 However, the cost to the NHS of anti-tnf-α agents are a concern (running at 9 to 13 per patient for the first year) despite approval of infliximab and etanercept by NICE in 2. Currently these two agents, together with adalimumab, are being reviewed again by NICE for use in adults with active RA who have not responded adequately to at least two DMARDs, including methotrexate. In comparison, two mg infusions of cost approximately 35, based on current pricing for the NHL indication. Any newcomers including will be subject to the scrutiny of NICE and the medical community for real benefits to patients and the healthcare system. WHICH PATIENTS MIGHT BENEFIT FROM RITUXIMAB? Those who do not respond to anti- TNF-α treatment at all (although it is not possible to predict who they might be) or who cannot tolerate anti-tnf-α treatment. Patients with established, moderate to severe RA who have inadequate response on anti-tnf-α treatment. Those with advanced disease who are failing on DMARDs including methotrexate. Those who require early, aggressive treatment. REGULATORY STATUS IN RA Rituximab has been developed by Roche together with Genentech and Biogen Idec. This year, the companies received approval in the USA for the use of in adult patients with active RA, who have had an inadequate response to current biologic therapy. A submission to the European Agency for Evaluation of Medicinal Products (EMEA) was made in September 5. Michael Guida is a medical writer REFERENCES 1. Fries JF, Williams CA, Morfeld D, et al. Reduction in long-term disability in patients with rheumatoid arthritis by diseasemodifying antirheumatic drug-based treatment strategies. Arthritis Rheum 1996;39: Pincus T, Callahan LF. Reassessment of twelve traditional paradigms concerning the diagnosis, prevalence, morbidity and mortality of rheumatoid arthritis. Scand J Rheumatol 1989(suppl);79: Arthritis and Musculoskeletal Alliance. Standards of care for people with inflammatory arthritis National Institute for Health and Clinical Excellence. Guidance on the use of etanercept and infliximab for the treatment of rheumatoid arthritis NICE Technology Appraisal No 36. London: NICE 2. [ page.aspx?o=ta36; accessed 2.3.6] 5. Shaw T, Quan J, Totoritis MC. B cell therapy for rheumatoid arthritis: the (anti- CD) experience. Ann Rheum Dis 3;62: Goldblatt F, Isenberg DA. New therapies for rheumatoid arthritis. Clin Exp Immunol 5;14: Panayi GS. The immunopathogenesis of rheumatoid arthritis. Br J Rheumatol 1993; 32(suppl 1): Edwards JC, 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. Bio-Drugs 1;15: Zhang Z, Bridges SL Jr. Pathogenesis of rheumatoid arthritis: role of B lymphocytes. Rheum Dis Clin North Am 1;27: Edwards JC, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology 1;4: McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-cd monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16: Kimby E. Tolerability and safety of (MabThera). Cancer Treat Rev 5; 31: Tighe H, Carson DA. Rheumatoid factors. In: Kelley WN, Harris ED Jr, Ruddy S, Sledge CB, eds. Textbook of rheumatology. 5th edition. Philadelphia: WB Saunders, 1997: van Zeben D, Hazes JM, Zwinderman AH, et al. Clinical significance of rheumatoid factors in early rheumatoid arthritis: results of a follow up study. Ann Rheum Dis 1992;51: Edwards JCW, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with in patients with rheumatoid arthritis. N Engl J Med 4;35: van Vollenhoven RF, Schechtman J, Szczepanski LJ, et al. Safety and tolerability of in patients with moderate to severe rheumatoid arthritis: results from the dose-ranging assessment international clinical evaluation of in rheumatoid arthritis (DANCER) Study. ACR 5, abstract Emery P, Fleischmann RM, Filipowicz- Sosnowska A, et al. The efficacy and safety of in patients with active rheumatoid arthritis despite methotrexate treatment. Arthritis Rheum 6;54: Cohen S, Emery P, Greenwald M, et al. Rituximab for Rheumatoid Arthritis Refractory to Anti-Tumor Necrosis Factor Therapy (REFLEX). Arthritis Rheum (re-submitted).. Data on file Roche. 21. McLaughlin P, Hagemeister FB, Grillo- Lopez AJ. Rituximab in indolent lymphoma: the single-agent pivotal trial. Semin Oncol 1999; 26(suppl 14): Hainsworth JD, Litchy S, Burris HA, et al. Rituximab as first-line and maintenance therapy for patients with indolent non- Hodgkin s lymphoma. J Clin Oncol 2;: Pavelka K. Prevention of surgical joint replacement in the long-term follow-up of recent disease-modifying drug trials in osteoarthritis.oral Presentation, European League Against Rheumatism Congress, Vienna, 1 June Kavanaugh A. Health economics: implications for novel antirheumatic therapies. Ann Rheum Dis 5;64(suppl 4): FUTURE PRESCRIBER VOL 7(2)