The authors concluded there was no evidence that intensive therapy in early rheumatoid arthritis caused unacceptable toxicity compared with methotrexate monotherapy. This conclusion did not appear to reflect the evidence presented; together with potential methodological limitations in the search and review process, the authors' conclusion and recommendation for practice is unreliable.

To compare the effects of combinations of disease-modifying antirheumatic drugs and/or tumour necrosis factor inhibitors combined with methotrexate versus methotrexate alone in patients with rheumatoid arthritis.

MEDLINE, EMBASE, and the Cochrane Library were searched for English language articles from 1960 to March 2010. Search terms were reported.

Randomised controlled trials (RCTs) that compared methotrexate monotherapy versus combinations of disease-modifying antirheumatic drugs and/or a combination of tumour necrosis factor inhibitors (infliximab, adalimumab, or etanercept) plus methotrexate were eligible for inclusion. Eligible patients had to meet the American College of Rheumatology criteria for rheumatoid arthritis and have disease duration of less than three years. Eligible outcomes were patient withdrawal due to toxicity, total adverse events, serious adverse events (total and by physiological system), nausea, malignancy, and death.

In included trials, the proportion of female patients ranged from 53 to 93%. The mean age of participants ranged from 47 to 57 years; duration of disease ranged from less than six months to less than 36 months.

The authors did not state how many reviewers carried out the study selection.

Trial quality was assessed using the Jadad scale, which covered randomisation, allocation concealment, blinding, and withdrawals. The maximum possible score was 5 points.

The authors did not state how many reviewers carried out the quality assessment.

All outcomes were binary, so data were extracted to enable the calculation of odds ratios (OR) and 95% confidence intervals (CI).

The authors did not state how many reviewers carried out the data extraction.

Odds ratios and 95% confidence intervals were pooled in meta-analyses, using a random-effects model (for total adverse events) and the Peto fixed-effect model for all other outcomes (as these were considered rare). Statistical heterogeneity was assessed using X² and I². Sensitivity analysis was carried out according to length of follow-up.

Fifteen RCTs were included (with at least 4,008 patients, range 20 to 1,049). Eight trials evaluated combination disease-modifying antirheumatic drugs; eight trials evaluated tumour necrosis factor inhibitors/methotrexate (one trial included both combination groups). Follow-up ranged between 12 and 24 months. The average Jadad score was 3.93 (range 2 to 5).

Pooled analysis showed that there were significantly more withdrawals due to toxicity in the combination arms compared with methotrexate alone (15 RCTs). For combination disease-modifying antirheumatic drugs, the odds ratio was 2.33 (95% CI 1.43 to 3.77) and for tumour necrosis factor inhibitors/methotrexate, the odds ratio was 1.44 (95% CI 1.05 to 1.98). The authors stated there was no statistical heterogeneity. The only statistically significant impact of combination treatments on adverse events were an increase in serious adverse events with tumour necrosis factor inhibitors/methotrexate (OR 1.66, 95% CI 1.26 to 2.20; four RCTs) and nausea with combination disease-modifying antirheumatic drugs (OR 2.06, 95% CI 1.30 to 3.27; three RCTs). There were discrepancies between results reported in the tables and text.

Sensitivity analysis showed that patients receiving combination disease-modifying antirheumatic drugs had significantly higher withdrawals due to toxicity at 24 months (OR 2.44, 95% CI 1.28 to 4.66; three RCTs), and had significantly more episodes of nausea during the first 12 months (OR 3.48, 95% CI 2.00 to 6.08).

There was no evidence that intensive therapy in early rheumatoid arthritis caused unacceptable toxicity compared with methotrexate monotherapy. Short follow-up may have led to an inability to detect new malignancies.

The review question was clear, and this was supported by potentially replicable inclusion criteria. The search strategy included three relevant data sources. The restriction to articles in English and no apparent search for unpublished material, meant that relevant studies might have been overlooked; language and publication biases were possible. The absence of reporting on the review process conduct meant that errors and bias could not be ruled out.

A recognised instrument was used to assess trial quality, and although results indicated that quality was reasonably good, there were no review-specific criteria. Trial details were presented. Statistical heterogeneity was reported to be assessed. The absence of results for heterogeneity assessment made it difficult to confirm the suitability of the chosen method of synthesis. The total number of patients recruited into a three-arm trial was unclear. The small sample sizes for several of the included trials may mean that there was inadequate statistical power to detect rare events.

The authors' conclusion on toxicity did not appear to reflect the evidence presented. Together with the potential methodological limitations identified, the authors' conclusion and recommendation for practice is likely to be unreliable.

Practice: The authors stated that intensive therapies in patients with early rheumatoid arthritis appear to be justified.

Research: The authors stated that further reseach is needed using large registries with longer follow-up periods to evaluate the toxicity outcomes of combination therapies for patients with rheumatoid arthritis.

Arthritis Research Campaign (ARC); National Institute of Health Research (NIHR).

Ma MH, Kingsley GH, Scott DL. A systematic comparison of combination DMARD therapy and tumour necrosis inhibitor therapy with methotrexate in patients with early rheumatoid arthritis. Rheumatology 2010; 49(1): 91-98.

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.