This review of combined methotrexate/sulfasalazine therapy for rheumatoid arthritis compared with either agent alone concluded that combination therapy may benefit patients who did not respond to sulfasalazine, but not patients naive to either drug. The conclusions appear to reflect the results, but their reliability is unclear due to potential biases in the review process and the limited synthesis of results.

To compare the combination of methotrexate with sulfasalazine with either drug alone in patients with rheumatoid arthritis who were naive to, or did not respond to, either drug.

MEDLINE was searched from 1966 to April 2007 and the Cochrane Register of Controlled Trials (CENTRAL) Issue 2, 2007 was searched. Search terms were reported. Only English language articles were included.

To be included studies had to be randomised controlled trials of at least 12 weeks duration, of a parallel or add-on design, that compared a combination of methotrexate and sulfasalazine to either agent alone. Included patients had to fulfil the American College of Rheumatology (ACR) 1987 revised criteria for rheumatoid arthritis and could be naive to methotrexate and sulfasalazine (parallel trials) or had failed to respond to either agent (add-on trials). Open extensions of a randomised controlled trial or retrospective studies were excluded.

The outcomes measured were the Disease Activity Score (DAS - a composite index of the Ritchie articular index or joint pain count, the joint swelling count and the erythrocyte sedimentation rate) and/or ACR response criteria. ASR responses were defined by at least 20, 50 or 70% improvement in joint swelling, tenderness counts and three of five other variables (erythrocyte sedimentation rate; Health Assessment Questionnaire (HAQ); pain score; assessors' global assessment; and patient’s global assessment).

Two of the included trials were of patients naive to both agents; two trials included patients classed as sulfasalazine treatment failures. The age of included patients ranged from 51 to 56 years, the duration of disease from three to 60 months, and the percentage of females ranged from 65 to 80%. Three trials compared the combination therapy to both agents alone; the remaining trial compared the combination to methotrexate alone. Doses of methotrexate ranged from 7.5 to 15mg per week and 2 to 3grams/day of sulfasalazine. None of the trials allowed concomitant corticosteroids; all trials allowed a stable dose of non-steroidal anti-inflammatory drugs.

The authors did not state how studies were selected.

The authors did not report that trial quality was formally assessed, but aspects of trial quality including follow-up, blinding, and randomisation were reported.

The authors did not state how the validity assessment was performed.

Data were extracted to enable the calculation of effect sizes and 95% confidence intervals (CI), comparing mean changes in DAS for combination and single therapies. The proportion of patients fulfilling ACR 20, 50 and 70% responses and adverse events were also extracted for each group. All trials reported intention-to-treat data, and individual patient data were available for one study.

All data were extracted by one reviewer.

A limited narrative synthesis of results was provided.

Four randomised controlled trials, with 515 participants, were identified. Three trials were double-blind and placebo-controlled; one trial was single-blind. The loss to follow-up ranged from 5 to 28%, and the length of follow-up was from 24 to 52 weeks.

In the two trials of treatment of patients naive to sulfasalazine and methotrexate, the Disease Activity Score (DAS) effect sizes for the combination therapy compared with methotrexate alone were 0.2 (95% CI -0.3 to 0.7) and 0.3 (95% CI 0.1 to 0.8), and for the combination therapy compared with sulfasalazine alone were 0.3 (95% CI -0.2 to 0.8) and 0.1 (95% CI -0.2 to 0.4).

For the two trials that included sulfasalazine treatment-failure patients, the effect sizes for combination therapy were 1.8 (95% CI 1.0 to 2.5) and 0.5 (95% CI 0.1 to 0.9) compared to methotrexate alone, and 0.5 (95% CI 0.1 to 0.9) for sulfasalazine alone.

The proportion of patients fulfilling ACR 20, 50 and 70% responses were also reported in two trials. One trial was of treatment-naive patients and the other trial was of patients who failed to respond to sulfasalazine. In four of the six data sets from these two trials, the response rates were higher in the combination therapy group compared with either treatment alone.

Significantly more nausea was reported with the combination therapy in the two trials of patients naive to treatment.

In rheumatoid arthritis, the addition of methotrexate to sulfasalazine was a therapeutic option in patients who have failed to respond to sulfasalazine, but had no added value to sulfasalazine alone in patients naive to either drug.

The review question and inclusion criteria were clear. However, the search was limited to two databases and the restriction to published English language studies meant that publication and language biases were possible, and that relevant studies may have been missed.

Information about the participants, interventions and design of each trial were reported in detail, along with some quality criteria. Although the conclusions appear to reflect the results of the review, their reliability is compromised as all data were extracted by one author, the methods used to select studies and assess validity were not described, the synthesis was limited, and conclusions were largely based on single trial data.

Practice: The authors stated that the addition of methotrexate to sulfasalazine is therapeutic option for patients with suboptimal responses to sulfasalazine, and that the combination in naive patients has no added value unless combined with corticosteroids.

Research: The authors did not state any implications for research.

Not stated.

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.