Treatment of Rheumatoid Arthritis with Methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications

Deb Bynum, MD

Date: Sept 30, 1997

Clinical Bottom Lines:

1) Significantly more patients treated with the three drug combination of methotrexate, sulfasalazine, and hydroxychloroquine had at least a 50% improvement in symptoms (as defined by morning stiffness less than 30 minutes or decreased by 50%, decreased joint tenderness by 50%, decreased joint swelling by 50%, and decrease in ESR to less than 30) when compared to patients receiving methotrexate alone or the combination of sulfasalazine and hydroxychloroquine.

2) Treatment with all three medications was not more toxic than treatment with methotrexate alone during the two year course of the study.

The Evidence: Double-blind, randomized study of 102 patients with active rheumatoid arthritis (defined as ESR greater than 28, morning stiffness greater than 45 minutes, eight or more tender joints, and three or more swollen joints); 36 patients were randomized to receive methotrexate alone, 35 to receive sulfasalazine and hydroxychloroquine, and 31 to receive all three drugs.

Comments:

1) Patients were evaluated at 9 months and if they had not had a greater than 50% improvement as defined above were discontinued from the study because of "lack of efficacy". The main goal was to demonstrate clinically important treatment benefits, but the primary endpoint of the study was completion of the 2 year study. Although only 50 total patients completed the 2 year study, some patients were discontinued from the study because of toxic effects or protocol violations and not only because of lack of improvement-- this has potential bias of course. However, there were not significantly more drop-outs for these reasons between groups with 13 total discontinuing because of toxicity and 2 because of protocol violations. Overall 3 patients in the 3 drug group, 18 in the sulfasalazine-hydroxychoroquine group, and 16 in the methotrexate group were discontinued because of treatment failure alone (total of 37).

2) Differences between groups in symptoms and ESR may be difficult to compare at 24 months due to the high drop-out rate by that time in the methotrexate and sulfasalazine+hydroxychloroquine groups--the authors point out that benefits seen in the three drug group at 24 months may therefore actually be even more impressive since the comparison is made to patients in the other groups who were overall doing well enough to be included in the study to that point.

3) The endpoints are mainly subjective with the largest benefits seen for "global assessment scores" -- both per patient and per physician; there were no significant differences in ESR for example. Although possibly more difficult to work with, these outcomes of overall well-being are the most relevant clinically.

4) Overall 33% of patients receiving methotrexate alone, 40% on hydroxychloroquine, and 77% on all three had a "good response"--therefore the NNT with triple drug therapy is only 2.3!

Reference: N Engl J Med 1996; 334:1287-91.