|A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness
|Chen Y F, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, Fry-Smith A, Burls A
This review concluded that adalimumab, etanercept and infliximab are effective treatments compared with placebo for patients with rheumatoid arthritis who are not well-controlled by disease-modifying antirheumatic drugs. Combination with methotrexate seems more effective in early rheumatoid arthritis. An increased risk of infection may occur when adalimumab or infliximab are combined with methotrexate. Despite some limitations, these conclusions are likely to be reliable.
To evaluate the clinical and cost-effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis (RA).
MEDLINE (1966 to February 2005), EMBASE (1980 to February 2005), the Cochrane Library (Issue 1, 2005), the Science Citation Index (1981 to 2005), the National Research Register (Issue 1, 2005), internet sites of the U.S. Food and Drug Administration and the European Medicines Agency, manufacturers' submissions to the National Institute for Clinical Excellence (NICE) appraisal process, and bibliographies were searched without language restrictions, and experts and researchers contacted. The search strategies were reported. Abstracts were excluded.
Study designs of evaluations included in the review
Randomised controlled trials (RCTs) where recruitment was complete were eligible for inclusion. Observational studies of tumour necrosis factor (TNF) inhibitor therapies without a control group were only used to inform the incidence of adverse events.
Specific interventions included in the review
Studies of adalimumab, etanercept or infliximab compared with an active comparator or placebo were eligible for inclusion. Trials evaluating only different doses or routes of administration of the intervention of interest were excluded. The included studies evaluated a range of doses and modes of administration, which were reported in full in the review.
Participants included in the review
Studies of adults with RA were eligible for inclusion. Studies of patients with juvenile arthritis, Crohn's disease, psoriatic arthritis or spondyloarthritis were excluded. Where reported, the mean age of the participants ranged from 48 to 62 years, the disease duration from 0.5 to 19.8 years, and the number of previous disease-modifying antirheumatic drugs used from 0 to 3.8.
Outcomes assessed in the review
A range of outcomes of interest were identified, relating to efficacy, tolerability and safety. Studies not reporting clinical outcomes were excluded. A range of criteria and scales were used to assess efficacy.
How were decisions on the relevance of primary studies made?
Two independent reviewers selected the studies; any discrepancies were resolved by discussion.
Assessment of study quality
Two independent reviewers assessed RCT quality in terms of randomisation, allocation concealment, blinding, withdrawals and the use of an intention-to-treat analysis; any discrepancies were resolved by discussion.
The data from studies used in a previous report were taken directly from that report. Two independent reviewers extracted the data from new studies and for additional outcomes using a pre-specified data extraction form; any discrepancies were resolved by discussion. Relative risks (RRs) and risk differences (RDs) were extracted or calculated for dichotomous data, and weighted mean differences (WMDs) were used for continuous data, along with 95% confidence intervals (CIs) for each study.
Methods of synthesis
How were the studies combined?
Each TNF inhibitor was analysed separately and studies were further grouped by comparator (placebo or active comparator) and outcome measure. The primary analysis was for the licensed dose of each drug. Pooled RRs, RDs or WMDs and 95% CIs were calculated, generally using a fixed-effect model.
How were differences between studies investigated?
Heterogeneity was evaluated using the chi-squared and I-squared tests. Sensitivity analyses to investigate the effect of doses above and below the licensed indication, and sub-group analyses to investigate the effect of disease duration were planned.
Results of the review
Twenty-nine RCTs (n=9,939) were included in the review.
Of the 29 included RCTs, 20 reported adequate randomisation, 21 reported allocation concealment, 27 reported blinding of the participants, 26 reported blinding of the investigators, 23 reported blinding of the outcome assessors, 26 had important differences in withdrawal rates and 23 used intention-to-treat.
Adalimumab (9 RCTs; n=3,387).
Adalimumab had a significantly smaller increase in the modified Sharp score, but no significant difference for any other efficacy outcome compared with methotrexate (1 RCT). It was significantly more effective for all efficacy outcomes at the licensed dose compared with placebo (5 RCTs), and with methotrexate alone when combined with methotrexate (1 RCT). Adalimumab was not associated with a significant difference in withdrawal due to adverse events when compared with placebo, or when combined with methotrexate and compared with methotrexate alone. Adalimumab was associated with a significant increase in the risk of infection when compared with placebo.
Etanercept (11 RCTs; n=3,717).
Compared with methotrexate, etanercept was slightly more effective at improving RA symptoms and physical function, and appeared to be better tolerated, with no differences in the number of adverse events (2 RCTs). Compared with placebo, etanercept was significantly more effective when a licensed dose was used, was better tolerated and had no increase in the incidence of adverse events (8 RCTs). Compared with methotrexate alone, etanercept plus methotrexate was significantly more effective for all efficacy outcomes, was better tolerated and had no increase in the number of adverse events (1 RCT).
Infliximab (9 RCTs; n=2,835).
Compared with placebo (2 RCTs) or methotrexate alone (2 RCTs), infliximab plus methotrexate was significantly more effective for all efficacy outcomes when a licensed dose was used. Infliximab plus methotrexate was better tolerated than methotrexate alone in one placebo controlled trial, but not a second. Infliximab plus methotrexate was associated with a statistically significant increase in the risk of infection, but not for other adverse events (2 RCTs). Results for comparison with placebo were similar when 3 trials using unlicensed doses were included in the analysis.
TNF inhibitors were more cost-effective when used as a last active therapy, with etanercept possibly being the TNF inhibitor of choice if all other factors were equal.
Adalimumab, etanercept and infliximab are effective treatments compared with placebo for RA patients who are not well-controlled by disease-modifying antirheumatic drugs. The combination of TNF inhibitors with methotrexate seems more effective than TNF inhibitors alone in early RA. An increased risk of serious infection cannot be ruled out when adalimumab or infliximab are combined with methotrexate.
The authors addressed a clear review question. An extensive search was undertaken, with efforts made to locate unpublished studies and no language restrictions being applied, thus reducing the potential for language and publication bias. The review process was conducted in duplicate, thereby decreasing the potential for error and bias. Study quality was assessed using appropriate criteria and the results of individual criteria reported for each study, although differences in study quality were not accounted for in the analyses. The authors often pooled highly statistically significantly heterogeneous studies, which may not be appropriate, particularly when using a fixed-effect meta-analysis. The authors do not seem to have explored the reasons for the apparent heterogeneity. The main analyses were based on the few studies where licensed doses were administered, and might not, therefore, be adequately powered. Although the review has limitations, the conclusions are likely to be reliable.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors suggested that RCTs of direct comparisons of TNF inhibitors should be conducted, as well as trials of different anti-TNFs in patients who have failed a previous TNF inhibitor, and longer-term studies of quality of life, the incidence of joint replacement, other disease, morbidity and mortality.
NHS R&D Health Technology Assessment (HTA) Programme, project number 04/26/01.
Chen Y F, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, Fry-Smith A, Burls A. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. Health Technology Assessment 2006; 10(42): 1-248
Subject indexing assigned by NLM
Antibodies, Monoclonal /administration & dosage /economics /therapeutic use; Antirheumatic Agents /administration & dosage /economics /therapeutic use; Arthritis, Rheumatoid /drug therapy /economics; Cost-Benefit Analysis; Drug Costs; Great Britain; Immunoglobulin G /administration & dosage /economics /therapeutic use; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Receptors, Tumor Necrosis Factor /administration & dosage /therapeutic use; Treatment Outcome
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.