Comparison of azathioprine, methotrexate, and the combination of the two in the treatment of rheumatoid arthritis

Rf, Willkens; Jt, Sharp; Stablein, D; Marks, Cara R.; Wortmann, Robert L.

doi:10.1002/art.1780381213

Cited by 58 publications

(16 citation statements)

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“…Other agents there are other agents that are used less frequently in rheumatology today: these include various injectible gold salts, with excellent efficacy in certain patients, f o C u s o n t h e f u t u r e o f t h e r a P y f o r r a but with unpredictable toxicities and a slow onset of action; the oral gold drug auranofin, which in practice did not have the same efficacy as the parenteral gold salts; ciclosporin a, which is used mostly in combination with metho trexate; azathioprine, which probably has a lower efficacy than methotrexate and somewhat greater toxicity; 12 and in the us, minocycline, which has an overall weaker efficacy than methotrexate. 38 Biologic agents the terms biologic agents or biologics refer to complex pro tein molecules that are created using molecular biology methods and produced in prokaryotic or eukaryotic cell cultures.…”

Section: The Antirheumatic Arsenalmentioning

confidence: 99%

“…11 not all such combinations were successful: a large controlled trial demon strated that the combination of methotrexate plus azathioprine was not more effective-but was more toxic-than methotrexate alone. 12 randomized clinical trials the science of clinical trials in ra improved during this time, including the development of the extraordinarily successful american College of rheumatology (aCr) 20, aCr50, and aCr70 outcomes, 13 as well as response criteria based on the Disease activity score 28-joint count (Das28) 14 that were adopted by the european league against rheumatism (eular). scoring systems for radiographs became available that transformed the radiological assessment of ra into a quantitative science, 15 and the development of the stanford Health assessment Questionnaire Disability index (usually, but somewhat incorrectly, abbreviated HaQ) allowed for the accurate assessment of functional status.…”

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confidence: 99%

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Treatment of rheumatoid arthritis: state of the art 2009

2009

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Few, if any, areas of medical therapeutics have witnessed such dramatic changes as those that have occurred in the therapy of rheumatoid arthritis (RA) during the past two decades. Improvements in clinical trials methodologies, the introduction of no fewer than nine biologic agents with distinct mechanisms of action, and the development of better strategies for the use of such agents have all contributed to the new age in RA therapeutics. Here, we review these developments and attempt to describe the current landscape of RA therapy in terms of available treatments, agreed-upon principles of RA management, as well as some important controversies in this field. Despite the great pace at which developments are moving, a treatment-free remission for patients with RA remains an elusive goal and unmet medical needs remain. The quest for better therapies for this potentially devastating disease is still as important as ever; research in this exciting area is ongoing, and it is reasonable to hope that, during the next decade, developments will lead to improved, rationally designed, targeted therapies for RA.

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Section: The Antirheumatic Arsenalmentioning

confidence: 99%

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confidence: 99%

Treatment of rheumatoid arthritis: state of the art 2009

2009

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“…The overall OR for withdrawal with combination therapy was 1.51 (95% CI 1.02 to 2.25). Seven 66,67,222,223,225,227,229 of these studies used methotrexate as the monotherapy arm; the OR for withdrawal was 1.58 (95% CI 0.97 to 2.59).…”

Section: Toxicitymentioning

confidence: 99%

“…For cDMARDs, all 10 trials 66,67,[222][223][224][225][226][227][228][229] reported patient withdrawals because of toxicity. The overall OR for withdrawal with combination therapy was 1.51 (95% CI 1.02 to 2.25).…”

Section: Toxicitymentioning

confidence: 99%

“…Of these, nine studies were excluded: in four patients were treatment naive, in two patients had not received DMARDs for > 3 months, two did not specify previous DMARD treatment and one was a duplicate of an included study. The remaining 19 studies 66,67,170,[222][223][224][225][226][227][228][229][230][231][232][233][234][235][236][237] were included in the systematic review and are summarised in …”

Section: Trialsmentioning

confidence: 99%

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Randomised controlled trial of Tumour necrosis factor inhibitors Against Combination Intensive Therapy with conventional disease-modifying antirheumatic drugs in established rheumatoid arthritis: the TACIT trial and associated systematic reviews

Scott

Ibrahim

Farewell

et al. 2014

Health Technology Assessment

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BackgroundRheumatoid arthritis (RA) is initially treated with methotrexate and other disease-modifying antirheumatic drugs (DMARDs). Active RA patients who fail such treatments can receive tumour necrosis factor inhibitors (TNFis), which are effective but expensive.ObjectiveWe assessed whether or not combination DMARDs (cDMARDs) give equivalent clinical benefits at lower costs in RA patients eligible for TNFis.DesignAn open-label, 12-month, pragmatic, randomised, multicentre, two-arm trial [Tumour necrosis factor inhibitors Against Combination Intensive Therapy (TACIT)] compared these treatment strategies. We then systematically reviewed all comparable published trials.SettingThe TACIT trial involved 24 English rheumatology clinics.ParticipantsActive RA patients eligible for TNFis.InterventionsThe TACIT trial compared cDMARDs with TNFis plus methotrexate or another DMARD; 6-month non-responders received (a) TNFis if in the cDMARD group; and (b) a second TNFi if in the TNFi group.Main outcome measuresThe Heath Assessment Questionnaire (HAQ) was the primary outcome measure. The European Quality of Life-5 Dimensions (EQ-5D), joint damage, Disease Activity Score for 28 Joints (DAS28), withdrawals and adverse effects were secondary outcome measures. Economic evaluation linked costs, HAQ changes and quality-adjusted life-years (QALYs).ResultsIn total, 432 patients were screened; 104 started on cDMARDs and 101 started on TNFis. The initial demographic and disease assessments were similar between the groups. In total, 16 patients were lost to follow-up (nine in the cDMARD group, seven in the TNFi group) and 42 discontinued their intervention but were followed up (23 in the cDMARD group and 19 in the TNFi group). Intention-to-treat analysis with multiple imputation methods used for missing data showed greater 12-month HAQ score reductions with initial cDMARDs than with initial TNFis [adjusted linear regression coefficient 0.15, 95% confidence interval (CI) −0.003 to 0.31;p = 0.046]. Increases in 12-month EQ-5D scores were greater with initial cDMARDs (adjusted linear regression coefficient −0.11, 95% CI −0.18 to −0.03;p = 0.009) whereas 6-month changes in HAQ and EQ-5D scores and 6- and 12-month changes in joint damage were similar between the initial cDMARD group and the initial TNFi group. Longitudinal analyses (adjusted general estimating equations) showed that the DAS28 was lower in the initial TNFi group in the first 6 months (coefficient −0.63, 95% CI −0.93 to −0.34;p < 0.001) but there were no differences between the groups in months 6–12. In total, 36 patients in the initial cDMARD group and 44 in the initial TNFi group achieved DAS28 remission. The onset of remission did not differ between groups (p = 0.085 on log-rank test). In total, 10 patients in the initial cDMARD group and 18 in the initial TNFi group experienced serious adverse events; stopping therapy because of toxicity occurred in 10 and six patients respectively. Economic evaluation showed that the cDMARD group had similar or better QALY outcomes than TNFi with significantly lower costs at 6 and 12 months. In the systematic reviews we identified 32 trials (including 20–1049 patients) on early RA and 19 trials (including 40–982 patients) on established RA that compared (1) cDMARDs with DMARD monotherapy; (2) TNFis/methotrexate with methotrexate monotherapy; and (3) cDMARDs with TNFis/methotrexate. They showed that cDMARDs and TNFis had similar efficacies and toxicities.ConclusionsActive RA patients who have failed methotrexate and another DMARD achieve equivalent clinical benefits at a lower cost from starting cDMARDs or from starting TNFis (reserving TNFis for non-responders). Only a minority of patients achieve sustained remission with cDMARDs or TNFis; new strategies are needed to maximise the frequency of remission.Trial registrationCurrent Control Trials ISRCTN37438295.FundingThis project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 18, No. 66. See the NIHR Journals Library website for further project information.

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