Wanruchada Katchamart

Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative

Objectives: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. Methods: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007–8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005–7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. Results: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. Conclusions: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.

Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis

Objective: To evaluate the efficacy and toxicity of methotrexate (MTX) monotherapy compared with MTX combination with non-biological disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis. Method: A systematic review of randomised trials comparing MTX alone and in combination with other non-biological DMARDs was carried out. Trials were identified in Medline, EMBASE, the Cochrane Library and ACR/EULAR meeting abstracts. Primary outcomes were withdrawals for adverse events or lack of efficacy. Results: A total of 19 trials (2025 patients) from 6938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (relative risk (RR) = 1.16; 95% CI 0.70 to 1.93). Trials in MTX or non-MTX DMARD inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups (RR = 0.86; 95% CI 0.49 to 1.51 and RR = 0.75; 95% CI 0.41 to 1.35), but in one study the specific combination of MTX with sulfasalazine and hydroxychloroquine showed a better efficacy/toxicity ratio than MTX alone with RR = 0.3 (95% CI 0.14 to 0.65). Adding leflunomide to MTX non-responders improved efficacy but increased the risk of gastrointestinal side effects and liver toxicity. Withdrawals for toxicity were most significant with ciclosporin and azathioprine combinations. Conclusion: In DMARD naive patients the balance of efficacy/toxicity favours MTX monotherapy. In DMARD inadequate responders the evidence is inconclusive. Trials are needed that compare currently used MTX doses and combination therapies.

Indirect comparisons of the efficacy of biological antirheumatic agents in rheumatoid arthritis in patients with an inadequate response to conventional disease-modifying antirheumatic drugs or to an anti-tumour necrosis factor agent: a meta-analysis

Background The availability of increasing numbers of biological agents for the treatment of rheumatoid arthritis (RA) offers several therapeutic options. While all biologicals have proven effective in trials, very limited direct comparisons are available. The objective of the present work was to compare the efficacy of biologicals (anti-tumour necrosis factor (TNF) agents, rituximab, abatacept, tocilizumab) in patients with RA with active disease and (i) an inadequate response (IR) to methotrexate (IR-MTX), (ii) an IR to anti-TNF agents (IR-anti-TNFs) using indirect comparisons. Methods Randomised clinical trials were identified examining the efficacy of a biological agent in RA at 6 months in patients with an IR-MTX or with an IR-anti-TNF. To compare the relative efficacy of biologicals, adjusted indirect comparison meta-analytic methods to estimate the ORs of achieving a 50% improvement according to American College of Rheumatology criteria (ACR50) response at 6 months were used. Results A total of 18 published trials and 1 abstract were included in the analyses. In IR-MTX, anti-TNFs had the same probability of reaching an ACR50 compared to ‘non-anti-TNF biologicals’ taken together (OR 1.30, 95 % CI 0.91 to 1.86). However, when compared to specific biological agents, anti-TNFs demonstrated a higher probability of reaching an ACR50 than abatacept (OR 1.52, 95 % CI 1.0 to 2.28), but not in comparison to rituximab and tocilizumab. In IR-anti-TNF, rituximab demonstrated a higher probability of achieving an ACR50 than tocilizumab (OR 2.61, 95% CI 1.10 to 6.37), but no significant differences existed between rituximab, tocilizumab, abatacept and golimumab. Conclusions In a meta-analysis of randomised clinical trials of patients with IR-MTX, anti-TNFs demonstrated a higher probability of achieving an ACR50 response than abatacept. In IR-anti-TNF, no difference was found between rituximab, tocimizumab, abatacept and golimumab.

Predictors for remission in rheumatoid arthritis patients: A systematic review.

To summarize the potential predictors of remission in patients with rheumatoid arthritis (RA).

Canadian Recommendations for Use of Methotrexate in Patients with Rheumatoid Arthritis

Objective. To develop recommendations for the use of methotrexate (MTX) in patients with rheumatoid arthritis. Methods. Canadian rheumatologists who participated in the international 3e Initiative in Rheumatology (evidence, expertise, exchange) in 2007–2008 formulated 5 unique Canadian questions. A bibliographic team systematically reviewed the relevant literature on these 5 topics. An expert committee consisting of 26 rheumatologists from across Canada was convened, and a set of recommendations was proposed based on the results of systematic reviews combined with expert opinions using a nominal group consensus process. Results. The 5 questions addressed drug interactions, predictors of response, strategies to reduce non-serious side effects, variables to assess clinical response, and incorporating patient preference into decision-making. The systematic review retrieved 93 pertinent articles; this evidence was presented to the expert committee during the interactive workshop. After extensive discussion and voting, a total of 9 recommendations were formulated: 2 on drug interactions, 1 on predictors of response, 2 on strategies to reduce non-serious side effects, 3 on variables to assess clinical response, and 1 on incorporating patient preferences into decision-making. The level of evidence and the strength of recommendations are reported. Agreement among panelists ranged from 85% to 100%. Conclusion. Nine recommendations pertaining to the use of MTX in daily practice were developed using an evidence-based approach followed by expert/physician consensus with high level of agreement.

Systematic Monitoring of Disease Activity Using an Outcome Measure Improves Outcomes in Rheumatoid Arthritis

Objective. To systematically review the literature on the value of outcome measures to monitor treatment response in patients with rheumatoid arthritis (RA). Methods. Canadian rheumatologists participating in the International 3e (evidence expertise exchange) Initiative formulated the question “Which parameters should be recommended for use in the management of RA patients to assess a clinically meaningful response in clinical practice?”. Searches in 3 electronic databases, Medline, Embase, and Cochrane Central Register of Controlled Trials, yielded no relevant study addressing this question. Experts in the field proposed to extrapolate evidence from 3 randomized controlled trials of systematic monitoring or tight control strategy in the management of RA. Results. Three studies were included in this review. The TICORA study showed that intensive management using systematic monitoring with the Disease Activity Score (DAS) aiming at least low disease activity, monthly followup, and more aggressive disease-modifying antirheumatic drug (DMARD) treatment improves outcomes with higher remission rates (65% vs 16%; p < 0.0001). Fransen, et al demonstrated that targeted therapy aimed at low disease activity (DAS28 < 3.2) led to more changes in DMARD treatment, resulting in a larger number of patients with low disease activity (31% vs 16%; p = 0.028). The CAMERA study showed that systematic monitoring using the objective computer decision program evaluation and monthly followup yielded a greater remission rate (50% vs 37%; p = 0.0001). Conclusion. Systematic monitoring of disease activity, aiming for at least low disease activity, and frequent followup improves outcome in RA.

PubMed had a higher sensitivity than Ovid-MEDLINE in the search for systematic reviews

OBJECTIVE To compare the performance of Ovid-MEDLINE vs. PubMed for identifying randomized controlled trials of methotrexate (MTX) in patients with rheumatoid arthritis (RA). STUDY DESIGN AND SETTING We created search strategies for Ovid-MEDLINE and PubMed for a systematic review of MTX in RA. Their performance was evaluated using sensitivity, precision, and number needed to read (NNR). RESULTS Comparing searches in Ovid-MEDLINE vs. PubMed, PubMed retrieved more citations overall than Ovid-MEDLINE; however, of the 20 citations that met eligibility criteria for the review, Ovid-MEDLINE retrieved 17 and PubMed 18. The sensitivity was 85% for Ovid-MEDLINE vs. 90% for PubMed, whereas the precision and NNR were comparable (precision: 0.881% for Ovid-MEDLINE vs. 0.884% for PubMed and NNR: 114 for Ovid-MEDLINE vs. 113 for PubMed). CONCLUSION In systematic reviews of RA, PubMed has higher sensitivity than Ovid-MEDLINE with comparable precision and NNR. This study highlights the importance of well-designed database-specific search strategies.

Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis

Objectives: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. Methods: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007–8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005–7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. Results: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. Conclusions: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.

Multinational evidence-based recommendations for the use of methotrexate inrheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel ofrheumatologists in the 3E Initiative

Objectives: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. Methods: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007–8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005–7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. Results: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. Conclusions: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.

Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders: Integrating systematic literature research and expert opinion of a broad panel of rheumatologists in the 3E initiative

Objectives: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. Methods: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007–8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005–7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. Results: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. Conclusions: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.