Rheumatoid Arthritis: Keystone EC

Keystone EC. · No affiliation provided · Nat Clin Pract Rheumatol. · Pubmed #18235535 No free full text.

This publication has no abstract.

Keystone EC, Kavanaugh A. · No affiliation provided · Expert Opin Drug Saf. · Pubmed #15794709 No free full text.

Abstract: The introduction of TNF inhibitors into the clinic for the treatment of patients with rheumatoid arthritis and other systemic inflammatory conditions has revolutionised the approach to these diseases. Despite the substantial efficacy of these agents, a subset of patients either does not respond or has a suboptimal clinical response. Defining what constitutes 'failure' of this type of therapy is important in both clinical research and practice. For patients who fail to respond to TNF inhibitors, a number of promising avenues targeting other aspects of the immune system are under study, and may be brought to the clinic in the near future.

Leombruno JP, Einarson TR, Keystone EC. · University of Toronto, Department of Pharmaceutical Sciences, Toronto, Ontario, Canada. · Ann Rheum Dis. · Pubmed #18753157 No free full text.

Abstract: OBJECTIVE: To evaluate the safety of biological treatments for rheumatoid arthritis (RA) using results from randomised controlled trials (RCT). METHODS: The literature was searched to December 2007 for RCT evaluating inhibitors of tumour necrosis factor alpha (anti-TNF) for RA. Safety data were abstracted and risk estimates were calculated using three approaches, meta-analysis with and without adjustment for exposure and simple exposure-adjusted pooling. RESULTS: Eighteen randomised trials involving 8808 RA subjects were included. Treatment with recommended doses of anti-TNF found no increase in the odds of death (odds ratio (OR) 1.39; 95% CI 0.74 to 2.62), serious adverse events (OR 1.11; 95% CI 0.94 to 1.32), serious infection (OR 1.21; 95% CI 0.89 to 1.63), lymphoma (OR 1.26; 95% CI 0.52 to 3.06), non-melanoma skin cancers (OR 1.27; 95% CI 0.67 to 2.42) or the composite endpoint of non-cutaneous cancers plus melanomas (OR 1.31; 95% CI 0.69 to 2.48) when evaluated using the unadjusted meta-analytic method. Risk estimates were similar with the other methods. For subjects who received two to three times the recommended doses of anti-TNF the risk of serious infection was increased with the unadjusted meta-analytic and pooled analysis, (OR 2.07; 95% CI 1.31 to 3.26) and (risk ratio (RR) 1.83; 95% CI 1.18 to 2.85), respectively, but not increased in the exposure-adjusted meta-analysis (RR 1.99; 95% CI 0.90 to 4.37). Meta-regression identified that the risk of serious infection with anti-TNF therapy decreases with increasing trial duration (p = 0.035). CONCLUSION: Meta-analytic and exposure-adjusted pooled analyses on over 8800 RA subjects in RCT treated over an average of 0.8 years did not identify an increased risk of serious adverse events with recommended doses. High-dose anti-TNF therapy was associated with a twofold increase in the risk of serious infections.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Sieper J, Emery P, Keystone EC, Schiff MH, Mease P, van Riel PL, Fleischmann R, Weisman MH, Weinblatt ME. · David Geffen School of Medicine, UCLA - RM 32-59, 1000 Veteran Avenue, Los Angeles, CA 90025, USA. · Ann Rheum Dis. · Pubmed #17934088 No free full text.

This publication has no abstract.

Keystone EC. · University of Toronto, Canada. · Nat Clin Pract Rheumatol. · Pubmed #17075598 No free full text.

Abstract: Recent data have shown that disability and joint destruction in rheumatoid arthritis (RA) occur early on in the course of the disease and progress rapidly. It has been shown that in the early stages of RA, disability is attributed to increased disease activity, whereas later in the course of the disease, disability results from irreversible joint damage. These findings support the need to develop treatment strategies that will rapidly bring the disease under control, with the ultimate goal of alleviating symptoms and halting progressive joint damage. A number of such strategies have been evaluated, including the early administration of a biologic agent alone or in combination with high-dose methotrexate. Other, more recent treatment strategies include the tight control of disease activity by targeting specific outcomes necessary for decision making; the use of biologic agents for the treatment of moderate disease; and the induction of remission with a biologic agent early in the course of disease, followed by maintenance therapy using a conventional disease-modifying antirheumatic drug. The substantial positive effect these strategies have on patient outcomes supports the concept that the optimal management of RA involves aggressive early therapy combined with close monitoring of disease progression and modification of ineffective therapeutic strategies.

Keystone EC. · University of Toronto, Canada. · Nat Clin Pract Rheumatol. · Pubmed #17075592 No free full text.

This publication has no abstract.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Bijlsma JW, Dougados M, Emery P, Keystone EC, Klareskog L, Mease PJ. · 1000 Veteran Avenue Rehabilitation Centre, Room 32-59, Los Angeles, CA 90024, USA. · Ann Rheum Dis. · Pubmed #16239380 links to  free full text

This publication has no abstract.

Keystone EC. · The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Mount Sinai Hospital, The Joseph and Wolf Lebovic Building, 2nd Floor, Room 2-006, 60 Murray Street, Toronto, Ontario M5G 1X5, Canada. · Rheumatology (Oxford). · Pubmed #15851525 links to  free full text

Abstract: Rituximab (MabThera/Rituxan) is a therapeutic monoclonal antibody against CD20, an antigen expressed by B cells but not B-cell progenitor or plasma cells. It is currently approved for the treatment of relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) and is well tolerated and efficacious. A small open-label study (conducted by Edwards and Cambridge) indicated that selective depletion of B cells using rituximab led to sustained benefits for patients with active rheumatoid arthritis. A 24-week, double-blind, randomized controlled trial was carried out to confirm these initial observations. In total, 161 patients with active rheumatoid arthritis were randomized to one of four treatment groups: rituximab monotherapy; rituximab plus methotrexate (R+MTX); rituximab plus cyclophosphamide (R+CTX); or methotrexate alone (MTX). Rituximab was administered as two 1000 mg infusions on days 1 and 15. An analysis at 24 weeks showed that the proportion of patients achieving an ACR20 response was significantly greater (P < or = 0.025 for all three comparisons) in all the rituximab groups compared with the MTX control group (rituximab alone, 65%; R+CTX, 76%; R+MTX, 73%; MTX alone, 38%). Both ACR50 (43 vs 13%; P = 0.005) and ACR70 (23 vs 5%; P = 0.048) responses were also significantly higher for the R+MTX group compared with the MTX group. The rituximab groups showed no significant safety differences compared with the MTX arm. The majority of adverse events were of mild to moderate intensity. Rituximab is a novel targeted therapy for the treatment of rheumatoid arthritis and it appears to be highly effective, safe and well tolerated.

Keystone EC. · Division of Advanced Therapeutics, The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Mount Sinai Hospital and the University of Toronto, Toronto, Canada. · J Rheumatol Suppl. · Pubmed #15742458 No free full text.

Abstract: Tumor necrosis factor (TNF) antagonists have set a new therapeutic standard for rheumatoid arthritis (RA). Agents including infliximab, etanercept, and adalimumab have demonstrated substantial improvement in signs and symptoms, disability, and quality of life, while significantly inhibiting joint damage in early and long-standing RA. Safety issues in concert with efficacy determine risk/benefit ratio and hence a position in the therapeutic algorithm. This brief review focuses on infection, congestive heart, and malignancy.

Bykerk VP, Keystone EC. · Mount Sinai Hospital, 2005-60, Murray Street, Toronto, Ont., Canada M5G 1X5. · Best Pract Res Clin Rheumatol. · Pubmed #15588976 No free full text.

Abstract: The management of patients with new-onset rheumatoid arthritis (RA) requires an awareness of the potential issues and needs that are unique to each patient with regards to their perceptions of their disease, physical needs and nutritional issues. Arthritis specialists should have a clear approach to the goals of management that are specific to patients with early rheumatoid arthritis (ERA). In this chapter, evidence for the goals and principles of management in the early treatment of RA is discussed. Patient education, the role of self-management, physical therapies, exercise, diet and drug management are addressed. This chapter aims to provide clinicians with a clear understanding of which interventions have supporting evidence and where further research is required. Where evidence for patients with ERA is lacking, evidence from patients with established RA is reviewed.

Keystone EC. · University of Toronto, Canada. · Clin Exp Rheumatol. · Pubmed #15552529 No free full text.

Abstract: Several novel biologic therapies for rheumatoid arthritis (RA) are emerging that target aspects of the immune system other than tumor necrosis factor (TNF). Two such therapies currently in development include CTLA4Ig (Abatacept) and anti-CD20 monoclonal antibody (Rituximab). CTLA4Ig has been demonstrated to be well tolerated with a good short-term safety profile. Rituximab has also been shown to have a good safety profile in a limited number of RA patients. Further safety data with larger numbers of RA patients treated with Rituximab is required.

Keystone EC. · Department of Medicine, University of Toronto, Ontario, Canada. · Ann Rheum Dis. · Pubmed #15479879 links to  free full text

Abstract: A variety of rheumatic disorders have been successfully treated with tumour necrosis factor (TNF) blockers. However, TNF blockade may be useful in a number of rare diseases. Preliminary data suggest that several forms of vasculitis appear responsive to TNF antagonists-Behcet's disease, Churg-Strauss vasculitis, polyarteritis nodosa, and giant cell arteritis, among others. Wegener's granulomatosis and sarcoidosis have been shown to improve with infliximab but not with etanercept. These results lend further support for the concept of differential mechanism(s) of action of the two antagonists with infliximab being more effective for the treatment of granulomatous diseases. Polymyositis/dermatomyositis may also be responsive to TNF blockade. TNF likely plays little role in Sjogren's syndrome as evidenced by the lack of efficacy of both TNF antagonists. Etanercept has been shown to be useful in the treatment of hepatitis C both in reducing the viral load and improving liver function. A number of other more rare disorders also may be responsive to TNF blockade. Further studies with larger numbers of well characterised patients and treatment regimens are necessary to provide more definitive evidence of the utility of the TNF antagonists in these serious and often life threatening diseases.

Kavanaugh A, Keystone EC. · Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, California, USA. · Clin Exp Rheumatol. · Pubmed #14969079 No free full text.

Abstract: Accompanying the excitement surrounding the prominent efficacy of biologic agents in rheumatoid arthritis (RA) has been concern regarding potential adverse effects. Data from clinical trials and pharmacovigilance has provided an assessment of their safety in patients with established RA. As biologic agents are utilized in patients with earlier disease, optimal determination of the risk/benefit will depend on continued careful monitoring, collection, reporting and analysis of safety information.

Keystone EC, Haraoui B, Bykerk VP. · Department of Medicine, University of Toronto, Ontario, Canada. · Clin Exp Rheumatol. · Pubmed #14969078 No free full text.

Abstract: Data has been generated that infliximab may be more effective when initiated earlier in the course of disease. A subset analysis of the Attract trial has demonstrated better efficacy of infliximab in reducing joint damage in an early rheumatoid arthritis (RA) population. Recently a randomized double-blind controlled trial revealed that infliximab in combination with methotrexate (MTX) in an early RA population improved signs and symptoms as well as inhibition in radiographic progression compared with patients receiving infliximab or MTX alone. The possibility of withdrawing infliximab after induction of remission with a combination of infliximab and MTX has been shown in a small pilot trial. Taken together, the results support the early use of infliximab in the treatment of patients with moderate to severe disease.

Keystone EC. · Centre for Advanced Therapeutics in Arthritis, Mount Sinai Hospital, and University of Toronto, Toronto, Canada. · Drugs Today (Barc). · Pubmed #14668928 No free full text.

Abstract: There are several unmet needs for the appropriate and effective control of rheumatoid arthritis (RA), namely rapid onset of action; effectiveness in disease-modifying antirheumatic drug (DMARD)-resistant disease, including improvements in signs and symptoms, disability, quality of life and radiographic progression; sustainability of response; and a good risk/benefit ratio. Tumor necrosis factor (TNF) antagonists appear to address these needs and consequently have set a new therapeutic standard for the treatment of RA and have made it possible for rheumatologists to target remission as a primary therapeutic goal.

Keystone EC. · Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Mount Sinai Hospital, The Joseph and Wolf Lebovic Building, 2nd Floor, Room 2-006, 60 Murray Street, Toronto, Ontario M5G 1X5, Canada. · Ann Rheum Dis. · Pubmed #14532146 links to  free full text

This publication has no abstract.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Dougados M, Emery P, Gibofsky A, Kavanaugh AF, Keystone EC, Klareskog L, Russell AS, van de Putte LB, Weisman MH, Kavenaugh AF. · University of California, UCLA, Rheumatology, Division Los Angeles, USA. · Ann Rheum Dis. · Pubmed #14532138 links to  free full text

This publication has no abstract.

Keystone EC. · Department of Medicine, University of Toronto, Ontario, Canada. · Curr Opin Rheumatol. · Pubmed #12707578 No free full text.

Abstract: The capability of selectively targeting pathogenic elements of disease with biologic therapies has created a new therapeutic repertoire. Although a substantial number of biologic agents have been developed for treatment of rheumatoid arthritis, few have been approved for use. Most of the agents have failed to reach the approval stage because of inadequate clinical benefit. Despite this, studies of these agents have provided extremely valuable lessons in study design, immunobiology, pharmacodynamic evaluation, and the utility of animal models in the development of biologic agents. These insights have laid the groundwork for future development of other novel therapeutic agents in the treatment of rheumatoid arthritis.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Antoni CE, Bijlsma JW, Burmester GR, Cronstein B, Keystone EC, Kavanaugh A, Klareskog L. · University of California, Los Angeles, CA, USA. · Ann Rheum Dis. · Pubmed #12379612 links to  free full text

This publication has no abstract.

Furst DE, Keystone EC, Breedveld FC, Kalden JR, Smolen JS, Antoni CE, Burmester GR, Crofford LJ, Kavanaugh A. · Arthritis Clinical Research Unit, Virginia Mason Research Centre, Seattle, WA 98101, USA. · Ann Rheum Dis. · Pubmed #11890647 links to  free full text

Abstract: TNF blocking agents have proved to be effective DMARDs and they have been a major advance in the treatment of RA. Their use is expanding to other rheumatic diseases. However, rare to uncommon and unexpected toxicities have been found and others may yet be found during their use. Studies in selected areas of efficacy, toxicity, and general use of TNF blocking agents are needed to help further define the most appropriate use of these agents. Use of these drugs will require doctors experienced in the diagnosis, treatment, and assessment of RA and other rheumatic diseases. These doctors will need to make long term observations of efficacy and toxicity. Further considerations which must be made when using TNF blocking agents in this disease include the cost and a recognition that data in subgroups are still being acquired. It is hoped that this statement, which is based upon the best evidence available at the time of its creation, and modified by expert opinion, will facilitate the optimal use of these agents for our patients with RA and other rheumatic diseases.

Keystone EC. · Centre for Advanced Therapeutics in Arthritis, Mount Sinai Hospital, Toronto, Ontario, Canada. · Rheum Dis Clin North Am. · Pubmed #11396102 No free full text.

Abstract: The use of TNF alpha antagonists in RA has been extremely instructive. They have taught us that selective targeting of a pathogenic element can provide substantial clinical benefit. They have reinforced the concept of TNF alpha as a pivotal cytokine in the pathogenesis of RA. Pharmacodynamic studies of TNF alpha antagonists have further clarified the pathogenic processes involved in the disease. TNF alpha antagonists have set a new therapeutic standard for RA. Indeed, they are one of the most important advances in the history of the treatment of the disorder. If clinical efficacy is sustained and the safety profile remains benign over the long term, TNF alpha antagonists may replace MTX as the gold standard and become the agent of choice for combination therapy in RA. Further studies are needed to clarify their ultimate position in the therapeutic algorithm.

Furst DE, Breedveld FC, Burmester GR, Crofford JJ, Emery P, Feldmann M, Kalden JR, Kavanaugh AF, Keystone EC, Klareskog LG, Lipsky PE, Maini RN, Russell AS, Scott DL, Smolen JS, Van de Putte LB, Visher TL, Weisman MH. · No affiliation provided · Ann Rheum Dis. · Pubmed #11053077 links to  free full text

This publication has no abstract.

Keystone EC. · Department of Medicine, University of Toronto, Centre for Advanced Therapeutics in Arthritis, Mount Sinai Hospital, Ontario, Canada. · J Rheumatol Suppl. · Pubmed #10328139 No free full text.

Abstract: The armamentarium for the treatment of rheumatoid arthritis (RA) includes several classes of therapeutics that induce symptomatic relief and reduce disease activity. The early addition of disease modifying antirheumatic drugs (DMARD) is now the standard of care in treatment. Methotrexate (MTX) is a cornerstone of contemporary management of RA, and the treatment paradigm for RA includes the early use of MTX and combination DMARD. Unfortunately, second-line treatments alone or in combination rarely induce complete disease remission. Advances in the understanding of the pathogenesis of RA have opened the way for more directed therapy, and new therapies that target the cytokine tumor necrosis factor alpha (TNF-alpha) have demonstrated rapid action and substantial benefit with few adverse effects. This article discusses the pivotal role of MTX in combination with DMARD. The use of leflunomide and cyclosporine as single agents and with MTX is evaluated. The role of TNF-alpha antagonism in the treatment of rheumatologic illnesses is examined, with particular attention to etanercept, a recombinant human TNF receptor (p75)-Fc fusion protein, and infliximab, a chimeric TNF monoclonal antibody (CA2). Data on the efficacy and toxicity of etanercept and infliximab are summarized, including their use in combination therapy with MTX.

Bingham CO, Ince A, Haraoui B, Keystone EC, Chon Y, Baumgartner S. · Johns Hopkins University, Baltimore, MD 21224, USA. · Curr Med Res Opin. · Pubmed #19317607 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Tumor necrosis factor (TNF) antagonists, including etanercept (a soluble TNF receptor) and infliximab (an anti-TNF monoclonal antibody) are used in the treatment of patients with rheumatoid arthritis (RA). The purpose of this study was to evaluate the effectiveness and safety of 50 mg etanercept weekly in subjects with RA who have failed infliximab therapy. METHODS: This phase 4, multicenter, open-label, single-arm, 16-week observational study enrolled subjects who had experienced primary (failure to achieve an initial response) or secondary (failure to maintain an initial response) infliximab failures. Effectiveness was measured using European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) response criteria and laboratory assessments were used to evaluate levels of inflammation, lymphotoxin alpha, drug concentrations, and antibodies to infliximab. Safety endpoints included incidence of serious adverse events. Clinical trial registration: This trial was registered under U.S. National Institutes of Health ClinicalTrials.gov identifier NCT00099554. RESULTS: At week 16, over half (62%; 95% CI = 55, 69) of all subjects in the trial achieved a good or moderate EULAR response (DAS28) with etanercept. Using ACR criteria, after 16 weeks of etanercept therapy, 45% (95% CI = 38, 52) of all subjects had achieved an ACR20 response. Benefits were noted in tender and swollen joint counts, subject and physician global assessments, joint pain, and the Health Assessment Questionnaire. Outcomes were similar between subjects with primary and secondary infliximab failures. Levels of lymphotoxin alpha did not appear to affect response to etanercept. Potential limitations included the lack of a washout period, short duration of the trial, and the number of subjects who did not receive all doses of etanercept. CONCLUSION: In this open-label, uncontrolled study, subjects with moderate to severe RA who failed to respond or who lost their initial response to infliximab safely benefited from receiving etanercept.

Keystone EC, Genovese MC, Klareskog L, Hsia EC, Hall ST, Miranda PC, Pazdur J, Bae SC, Palmer W, Zrubek J, Wiekowski M, Visvanathan S, Wu Z, Rahman MU, Anonymous00045. · University of Toronto and Mount Sinai Hospital, Ontario, Canada. · Ann Rheum Dis. · Pubmed #19066176 links to  free full text

Abstract: OBJECTIVE: The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy. METHODS: Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n = 133), golimumab 100 mg injections plus placebo capsules (group 2, n = 133), golimumab 50 mg injections plus methotrexate capsules (group 3, n = 89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n = 89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24. RESULTS: The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively. CONCLUSION: The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function.