The efficacy of anti-TNF in rheumatoid arthritis, a comparison between randomised controlled trials and clinical practice

Abstract

Background: Randomised controlled trials (RCTs) evaluating the efficacy of antagonists to tumour necrosis factor a (TNFa) showed high response percentages in the groups treated with active drugs. Objective: To compare the efficacy of anti-TNF treatments for rheumatoid arthritis (RA) patients in RCTs and in daily clinical practice, with an emphasis on the efficacy for patients eligible and not eligible for RCTs of anti-TNF treatments. Methods: First, randomised placebo-controlled trials written in English for etanercept, infliximab and adalimumab for patients with RA were selected by a systematic review. Second, the DREAM (Dutch Rheumatoid Arthritis Monitoring) register with patients starting for the first time on one of the TNF-blocking agents was used. Patient characteristics, doses of medication and co-medication as well as the ACR20 response percentages were compared between RCTs and DREAM data, stratified for trial eligibility. Results: In 10 of 11 comparisons, the ACR20 response percentages were lower in daily clinical practice than in the RCT active drug group, which was significant in five of 11 comparisons. Only 34-79% of DREAM patients fulfilled the selection criteria for disease activity in the several RCTs examined. DREAM patients eligible for RCTs had higher response percentages than ineligible DREAM patients. ACR20 response percentages of eligible DREAM patients were comparable with the ACR20 response percentages of the RCT active drug group in 10 of 11 comparisons. Conclusion: The efficacy of TNF-blocking agents in RCTs exceeded the efficacy of these drugs in clinical practice. However, in clinical practice more patients with lower disease activity were treated with TNFblocking agents compared with those treated in RCTs. For daily practice patients who were eligible for RCTs, responses were more similar to responses reached in RCTs.

Generalization and Extrapolation of Treatment Effects From Clinical Studies in Rheumatoid Arthritis

“…This suggests that using a prediction model with variables commonly used for inclusion/exclusion criteria to adjust results from RCTs to a specific daily practice situation can be feasible. In line with Wolfe et al (13), who concluded that the design in RCTs exaggerated the treatment effect because of the selection of patients, and Hyrich et al (57), we also found that a higher DAS28 and older age increased the probability of response next to the treatment. Kievit et al (13) suggested that selection toward high disease activity and continued use of comedication in RCTs could be the probable explanations for the difference in effects of anti-TNF in clinical practice and in RCTs, in line with the findings of our regression analyses.…”

“…95% CI ϭ 95% confidence interval; anti-IL-1 ϭ anti-interleukin-1; anti-TNF␣ ϭ anti-tumor necrosis factor ␣; DMARD ϭ disease-modifying antirheumatic drug; HAQ ϭ Health Assessment Questionnaire; DAS28 ϭ Disease Activity Score in 28 joints. † Golimumab (a TNF blocker) showed a different treatment effect from the other TNF blockers (as also found earlier by Kievit et al [13]), which led us to the decision to classify this drug separately.…”

“…It has been suggested that, in patients who are eligible (according to inclusion/exclusion criteria) for RCTs from daily practice, the responses are similar to patients in RCTs (13). This suggests that using a prediction model with variables commonly used for inclusion/exclusion criteria to adjust results from RCTs to a specific daily practice situation can be feasible.…”

“…Fixed-effects regression analysis was used and a multivariate analysis of selected variables was performed using a backward selection strategy based on the statistical significance and size of the regression coefficient. The final models included the type of biologic agent used, with golimumab used as a separate class because it has previously been found to have a different clinical efficacy form other tumor necrosis factor (TNF)-blocking agents (13), and the control treatment type.…”

“…In the past decade, many new treatments have been introduced, mainly the so-called biologic agents (11). It has been recognized that the results of phase II/III RCTs for these drugs are not in line with the results as observed in daily practice for patients treated with these drugs (12,13). No systematic evaluation regarding the population and disease characteristics of these RCTs in relation to the obtained treatment effect has been performed.…”