Rheumatoid Arthritis: Haraoui B

Haraoui B, Keystone E. · Université de Montréal, RDU CHUM, Hôpital Notre-Dame, Montreal, Quebec, Canada. · Curr Opin Rheumatol. · Pubmed #16344625 No free full text.

Abstract: PURPOSE OF REVIEW: The anti-tumor necrosis factor agents are now widely used in the management of patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile inflammatory arthritis. One of the most common observations made during their use is the development of autoantibodies. The purpose of this paper is to review this phenomenon and its clinical implications. RECENT FINDINGS: While the development of different autoantibodies is a common encounter, rare cases of lupus-like syndromes have been reported. On the other hand, a variety of immune-mediated clinical manifestations have been described, including vasculitis and demyelinating syndromes. Rare cases of cytopenia and non-specific lung injuries have also been reported. SUMMARY: While these clinical complications are rare and isolated events, clinicians must be aware of their occurrence. The experience with the anti-tumor necrosis factor agents is rather short and new, unusual immune-mediated complications may still appear. Clinicians should be prepared to recognize them.

Haraoui B. · Centre Hospitalier de l'Université de Montréal, Canada. · Semin Arthritis Rheum. · Pubmed #15852248 No free full text.

Abstract: The tumor necrosis factor inhibitors are a diverse group of biologic agents. Although there are no studies that directly compare these agents, data from noncomparative trials suggest that all 3 agents have therapeutic activity in rheumatoid arthritis. Etanercept and infliximab have also demonstrated beneficial activity in other inflammatory arthritides (ie, psoriatic arthritis and ankylosing spondylitis [both agents] and juvenile rheumatoid arthritis [etanercept only]) and inflammatory diseases (ie, psoriasis and uveitis). Their effects in granulomatous diseases are more variable, with only infliximab demonstrating clear efficacy in the treatment of Crohn's disease, sarcoidosis, and Wegener's granulomatosis. The purpose of this brief review is to summarize current efficacy data and explore possible explanations for observed clinical differences.

Haraoui B. · Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada. · J Rheumatol Suppl. · Pubmed #15742457 No free full text.

Abstract: Blockade of tumor necrosis factor (TNF) has emerged as one of the most promising therapies in rheumatoid arthritis (RA). Three agents are currently available as specific TNF antagonists, etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira). Data from noncomparative trials suggest that all 3 agents have comparable therapeutic activity in RA. Etanercept and infliximab have also demonstrated beneficial activity in other inflammatory arthritides [i.e., psoriatic arthritis and ankylosing spondylitis (both agents) and juvenile rheumatoid arthritis (etanercept only)] and inflammatory diseases (i.e., psoriasis and uveitis). Their effects in granulomatous diseases are more variable, with only infliximab demonstrating clear efficacy in the treatment of Crohn's disease, sarcoidosis, and Wegener's vasculitis. In this brief review current efficacy data are summarized and possible explanations for observed clinical differences are explored.

Haraoui B. · University of Montreal, Montreal, Quebec, Canada. · J Rheumatol Suppl. · Pubmed #15660467 No free full text.

Abstract: Despite optimization of the use of the traditional disease modifying antirheumatic drugs (DMARD) as mono- or combination therapy, between 25% and 50% of patients with rheumatoid arthritis (RA) still have clinically active synovitis with progressive structural articular damage. Several clinical trials with the anti-tumor necrosis factor (TNF) agents etanercept, infliximab, and adalimumab, used alone or in combination with methotrexate, in patients with early or established RA have shown consistent improvement in signs and symptoms as well as function, with a dramatic slowing of radiographic damage. The anti-TNF agents combined with optimal doses of MTX currently constitute the best therapeutic regimen for the management of patients with RA failing to adequately respond to traditional DMARD.

Keystone E, Haraoui B. · Division of Advanced Therapeutics, The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Mount Sinai Hospital, 60 Murray Street, University of Toronto, Toronto, Ontario, Canada M5G 1X5. · Rheum Dis Clin North Am. · Pubmed #15172045 No free full text.

Abstract: Adalimumab is a recombinant human immunoglobulin G1 monoclonal antibody that is specific for human tumor necrosis factor.Based on the data presented in this article, adalimumab administered alone or in patients partially responsive to methotrexate exhibits a rapid onset of action, provides a substantial reduction in signs and symptoms, and results in an improvement in physical function and health-related quality of life. Adalimumab has been demonstrated to inhibit progression of structural joint damage in patients who have long-standing rheumatoid arthritis. Taken together, the data support adalimumab as a new therapeutic option for patients with moderate to severe rheumatoid arthritis.

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.

Russell A, Haraoui B, Keystone E, Klinkhoff A. · Department of Medicine, University of Alberta Hospital Site, Heritage Medical Research Centre, Edmonton, Canada. · Clin Ther. · Pubmed #11768835 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis (RA) is a physically debilitating disease that places an enormous burden not only on individuals and their families but also on the economy. Affecting -1% of the Canadian population, RA is characterized by pain and swelling of joints. Without effective treatment, RA results in joint destruction that often requires surgery. OBJECTIVE: This review summarizes the effect of current and new RA treatments on joint damage, with a focus on infliximab. The health-economic repercussions and potential impact of arresting the joint destruction of RA are discussed. METHODS: Information for inclusion in this review was identified through searches of the MEDLINE and HealthStar databases from 1995 to 2000. Search terms included rheumatoid arthritis, treatment guidelines, economics, and individual drug names. RESULTS: Standard initial RA drug therapy has been aimed at reducing pain and inflammation, whereas use of the more potent disease-modifying antirheumatic drugs (DMARDs) has been reserved for later stages of disease. More aggressive RA treatment involves introducing DMARDs at the earliest stage. The largest single direct cost of RA involves hospital admissions for the correction of joint deformities. Among newer therapies, the anti-tumor necrosis factor-alpha agent infliximab has been shown to arrest radiographic measures of disease progression. CONCLUSIONS: With early and aggressive treatment involving new drugs and drug combinations, it may be possible to ameliorate the physical, social, and economic effects of RA.

Haraoui B, Strand V, Keystone E. · Université de Montreal, Rheumatic Disease Unit, CHUM, Canada. · Curr Pharm Biotechnol. · Pubmed #11469381 No free full text.

Abstract: Advances in the understanding of the pathogenesis of rheumatoid arthritis (RA) as well as improved biotechnology has enabled selective targeting of the pathogenic elements of disease. Targeting cell recruitment through adhesion molecules has been shown to be successful in pre-clinical murine models. Results of studies of an anti-ICAM-1 monoclonal antibody and anti-sense oligonucleotides have been encouraging. An alternate approach to inhibiting recruitment has been the targeting of chemoattractant molecules ie. chemokines. Important advances have been made in cytokine directed therapy targeting TNFalpha and IL-1. TNF antagonists (anti-TNF monoclonal antibody/soluble TNF receptor Fc fusion protein) have resulted in rapid and substantial improvement in signs and symptoms of disease as well as disease modification, shown by slowing of radiological progression. IL-1 receptor antagonist protein appears to have a significant effect on radiological progression despite a modest effect on symptoms and signs. Studies using anti-inflammatory cytokines such as IL-10 are in progress. A more recent therapeutic approach has been to target T-cell activation by interfering with co-stimulatory complexes such as CD40L/CD40 and CD28/CD80 and CD86. Both pre-clinical and preliminary clinical studies in human subjects support the concept. Another approach involving T-cell receptor peptide vaccination with VB peptides over-utilized in RA synovium has shown to be beneficial. Targeting the cytokines driving T-cells in the RA synovium ie. IL-12 & IL-15 has also proven beneficial in animal studies. Recent attention has also been directed toward the invading synovial fibroblast using Fas-FasL mediated apoptosis. Pre-clinical studies in which angiogenesis and osteoclast activation are targeted have been encouraging. In conclusion, the proof of principle has been established that selective targeting of pathogenic elements of disease results in substantial improvement in signs and symptoms as well as disease progression. Improved efficacy is expected with more aggressive targeting of the pathogenic elements.

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.

Haraoui B, Keystone EC, Thorne JC, Pope JE, Chen I, Asare CG, Leff JA. · Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, 1560 Sherbrooke East, Montréal, Quebec H2L 4M1, Canada. · J Rheumatol. · Pubmed #15570634 No free full text.

Abstract: OBJECTIVE: To assess the efficacy and monitor serious adverse events in patients with rheumatoid arthritis (RA) switching treatment from infliximab to etanercept. METHODS: Adult patients with active RA who were discontinuing treatment with infliximab were eligible to enroll in this prospective, 12-week, open label, single-arm, observational study. Four to 10 weeks after their last infusion of infliximab, patients began treatment with etanercept (twice weekly subcutaneous injections of 25 mg). Clinical assessments using the American College of Rheumatology (ACR) criteria for improvement were performed at baseline and at Weeks 6 and 12, and serious adverse events were monitored throughout the study. RESULTS: Twenty-five patients were enrolled, 18 of whom had discontinued infliximab because of lack of efficacy, and 22 completed 12 weeks of etanercept treatment. After 12 weeks, 14 of 22 patients (64%) achieved at least a 20% improvement in ACR criteria (ACR20), 13 (59%) experienced improvements in physical function that were considered clinically important (> or = 0.22 point decrease in overall Health Assessment Questionnaire score), and mean values of all individual components of the ACR criteria had improved. No serious adverse events were reported during the study and no patient discontinued because of lack of efficacy. CONCLUSION: Etanercept, a soluble tumor necrosis factor (TNF) receptor, provided a well tolerated and effective treatment option for some patients even when infliximab, a monoclonal antibody to TNF, had been ineffective.

Keystone EC, Haraoui B, Bykerk VP. · Department of Medicine, University of Toronto, Ontario, Canada. · Clin Exp Rheumatol. · Pubmed #14969077 No free full text.

Abstract: Adalimumab, a recent addition to the therapeutic armamentarium in rheumatoid arthritis (RA), has been evaluated in patients with early RA. The DE019 study, a double blind randomized placebo controlled trial of adalimumab given 20 mg once a week or 40 mg every other week demonstrated both clinical and radiographic efficacy. A subset analysis of patients with early disease revealed that early treatment with adalimumab may be more efficacious than therapy later in the course of disease, particularly with regard to radiographic progression. The findings support early aggressive intervention in RA.

Haraoui B. · Dr. B. Haraoui, CHUM, Campus Notre-Dame, 1560 Sherbrooke est, Montreal, Quebec H2L 1S6. E-mail: · J Rheumatol Suppl. · Pubmed #19509324 No free full text.

Abstract: The goal of treatment for patients with rheumatoid arthritis (RA) is to achieve remission, or at least a low disease activity state. A variety of useful and practical tools are available to rheumatologists to assess patient prognosis and evaluate response to treatment in clinical practice. Frequent assessments, ideally every 1 to 3 months, allow rheumatologists to adjust therapy according to patient outcomes. For patients who fail to respond to treatment with classic disease modifying antirheumatic drugs, combination therapies with biologic agents offer improved outcomes.

Keystone EC, Haraoui B. · Dr. E. Keystone, the Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Mount Sinai Hospital, The Joseph and Wolf Lebovic Building, 60 Murray Street, 2nd Floor, Room 2-006, Toronto, Ontario M5T 3L9. E-mail: · J Rheumatol Suppl. · Pubmed #19509323 No free full text.

This publication has no abstract.

Russell A, Beresniak A, Bessette L, Haraoui B, Rahman P, Thorne C, Maclean R, Dupont D. · University of Alberta, Edmonton, Canada. · Clin Rheumatol. · Pubmed #19089488 No free full text.

Abstract: To assess the cost-effectiveness of abatacept compared to different biologic treatment strategies for moderate to severe rheumatoid arthritis based on current medical practices in Canada. A model was constructed to assess the cost-effectiveness of various biologic treatments over a 2-year time horizon, using two effectiveness endpoints: "low disease activity state" (LDAS) and "remission". Abatacept, as first biologic agent after an inadequate response to DMARDs, provides greater treatment success rate for achieving LDAS (29.4% versus 15.6%) and remission (14.8% versus 5.2%), and appears significantly more cost-effective compared to the sequential use of anti-TNF agents (p<0.001). Abatacept, as second biologic agent after an inadequate response to one anti-TNF agent, provides greater treatment success rate for achieving LDAS (17.1% versus 10.2%) and remission (7.4% versus 3.9%) and appears significantly more cost-effective compared to the sequential use of anti-TNF agents (p<0.001). Abatacept is a cost-effective strategy in patients with an inadequate response to DMARDs or to one anti-TNF agent.

Haraoui B, Bykerk V. · No affiliation provided · Ther Clin Risk Manag. · Pubmed #18360618 links to  free full text

Abstract: Etanercept (ETN) is the first anti-tumor necrosis factor (TNF) agent to be approved for the treatment of rheumatoid arthritis (RA). Over the last 8 years, several clinical trials have shown its efficacy and safety in established and early RA, as well as a monotherapy or in combination with methotrexate. ETN not only reduces the signs and symptoms of RA, but also retards the progression of radiographic damage and improves the quality of life and function of patients. Its safety profile has been predictable since the first clinical trials with no new major safety concerns. Beyond its efficacy in RA, ETN is also indicated for the treatment of psoriatic arthritis. This current report reviews the evidence and the data in RA and psoriatic arthritis (PsA).

Beresniak A, Russell AS, Haraoui B, Bessette L, Bombardier C, Duru G. · LIRAES, University Paris-Descartes, Paris, France. · J Rheumatol. · Pubmed #17937471 No free full text.

Abstract: Utility assessment and cost-utility analyses such as costs/quality-adjusted life-years (QALY) are frequently presented to demonstrate the value of new treatment options in rheumatoid arthritis (RA). However, utility indicators require various methods that introduce significant methodological challenges, which directly influence the results and ensuing reimbursement decisions. Our objective was to review and discuss these challenges and the validity of frequently used utility assessment techniques in the context of RA. Coding the intensity of preferences or variations in patient satisfaction in order to assess utility implies extreme mathematical assumptions about a patient's rationality regarding his/her preferences towards different given health states. The construction and assumptions of commonly used "direct approaches" (standard gamble, time tradeoff, visual analog scale) and indirect approaches (EQ5D, HUI, SF6D) are presented. Other approaches such as transformation in utility of data from clinical (Health Assessment Questionnaire) or quality of life instruments ("mapping technique") are analyzed as they appear to generate uncertainty and a wide variation in estimated utility values in the context of RA. Utility assessment and cost-utility analyses in RA, which form the basis of the QALY, are frequently published and often requested by health technology assessment agencies to assist -reimbursement decisions. However, when interpreting the results, the medical community must take into consideration the limitations and significant uncertainty of these approaches.In light of these findings, real cost-effectiveness analyses based on observed clinical outcomes appear to be more robust and reliable to assist decision-making, particularly in the context of RA.

Villeneuve E, St-Pierre A, Haraoui B. · Department of Rheumatology, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada. · J Rheumatol. · Pubmed #16622902 No free full text.

Abstract: Interstitial pneumonitis is a well documented, rare complication of methotrexate (MTX). We describe a patient with rheumatoid arthritis (RA) taking MTX for more than 3 years who then developed severe interstitial pneumonitis after a third infliximab infusion. Other similar cases are reviewed. Infliximab may potentiate pulmonary toxicity of MTX.

Haraoui B, Cameron L, Ouellet M, White B. · Department of Rheumatology, Centre Hospitalier de l'Université de Montréal, and Groupe de recherche des maladies rhumatismales du Québec, Montréal, Quebec, Canada. · J Rheumatol. · Pubmed #16395747 No free full text.

Abstract: OBJECTIVE: To determine whether the need to use doses of infliximab greater than 3 mg/kg every 8 weeks to achieve or maintain clinical response in patients with rheumatoid arthritis (RA) is associated with differences in baseline clinical characteristics or anti-infliximab antibodies. METHODS: Baseline clinical characteristics and anti-infliximab levels were evaluated retrospectively in a cohort of 51 consecutive patients with RA treated with infliximab at a single center. Patients were divided into 2 groups for comparison: Group 1 patients achieved and maintained clinical responses with infliximab 3 mg/kg every 8 weeks; Group 2 patients required higher doses. RESULTS: Thirty-two (63%) patients required infliximab dose escalation (Group 2). There were no statistically significant differences in baseline or clinical characteristics between Group 1 and Group 2 patients. Anti-infliximab antibodies occurred in 47% of Group 2 versus 27% of Group 1 patients, with higher anti-infliximab antibody concentrations in Group 2 patients (mean +/- SD: 18.3 +/- 8.9 g/ml vs 7.5 +/- 4.8 g/ml; p = 0.02). Patients who developed anti-infliximab antibodies were younger and receiving less prednisone at the time of infliximab initiation than patients who did not. CONCLUSION: Finding higher anti-infliximab antibody concentrations in patients who needed dose escalation of infliximab to achieve or maintain clinical responses with lower serum trough levels of infliximab suggests that development of anti-infliximab antibodies may reduce clinical efficacy of infliximab in some patients with RA.

Beauparlant P, Papp K, Haraoui B. · Immunology/Biotechnology Unit, Novartis Pharmaceuticals Canada, Inc, Quebec. · Semin Arthritis Rheum. · Pubmed #10622679 No free full text.

Abstract: OBJECTIVES: The treatment of rheumatoid arthritis (RA) targets inflammation either by inhibiting the activation of immune cells or their clonal expansion. We evaluated the available evidence concerning the risk of cancer associated with RA treatment. METHOD: Articles published between 1966 and 1998 reporting the incidence of cancer in RA patients were reviewed. RESULTS: Large follow-up studies suggest the relative risk (RR) of lymphomas associated with RA is about twofold higher than in the general population. A role for azathioprine in the development of lymphomas and a role for cyclophosphamide in cancers, particularly bladder cancer, has been suggested. However, no studies have shown that methotrexate increases the risk of cancer in RA patients. Studies that showed an increased risk of cancer associated with gold or cyclosporine therapy in RA patients are inconclusive as they have used cancer incidence in the general population as the reference. One study measured the RR of cancer in a group of cyclosporine-treated RA patients (1.6 year on average) using RA patients as a control and found no enhanced risk. CONCLUSIONS: Although evidence suggests an increased risk of specific cancers associated with the use of some treatments, this may be outweighed by the potential benefit of therapy, especially in patients with severe disease.