For early rheumatoid arthritis, aggressive combination therapy can slow progression of joint damage.?That has been an approach that physicians believe is the right one but have not been able to prove until the results of a recent study.

Which works better for rheumatoid arthritis: a single drug given sequentially (start with one drug and if that doesn抰 work, go to another) or multiple drugs given at the same time.?A recent study answered this question. European investigators instituted a large multi-center trial. The trial involved 508 patients with early active RA who were treated at 20 medical centers.

The patients, all 18 or older, had a disease duration of two years or less, and active disease with at least six of 66 swollen joints and at least six of 68 tender joints. They had an erythrocyte sedimentation rate of 28 mm/hour or greater, or a global health score of 20 mm or more on a visual analog scale of 0 mm best) to 100 mm (worst). In other words, these patients all had pretty active disease.

The patients were randomized into four groups:

• Sequential monotherapy (single drug at a time), consisting of methotrexate followed by sulfasalazine, leflunomide, methotrexate with infliximab, gold with methylprednisolone (intramuscular), methotrexate with cyclosporine and prednisone, and azathioprine with prednisone (group 1).
• Methotrexate, followed by methotrexate with sulfasalazine, methotrexate with sulfasalazine and hydroxychloroquine, methotrexate with sulfasalazine, hydroxychloroquine and prednisone, methotrexate with infliximab, methotrexate with cyclosporine and prednisone, leflunomide, and azathioprine with prednisone (group 2).
• Combination of methotrexate, sulfasalazine, and tapered high-dose prednisone, followed by methotrexate with cyclosporine and prednisone, methotrexate with infliximab, leflunomide, gold with methylprednisolone, and azathioprine with prednisone (group 3).
• Combination of methotrexate and infliximab, followed by sulfasalazine, leflunomide, methotrexate with cyclosporine and prednisone, gold with methylprednisolone, and azathioprine with prednisone (group 4).

The treating physician adjusted therapy every three months, with the goal of achieving low disease activity.

The primary study end points were functional ability as assessed by the Health Assessment Questionnaire, and Sharp-van der Heijde score for x-ray measurement of joint damage.

The authors found that patients in both groups 3 and 4 (started on combination therapy) had more rapid clinical improvement and regained physical function (as gauged by change in Health Assessment Questionnaire score) significantly earlier during the first year than the patients in groups 1 and 2 (single drug therapy).

During the second year of follow-up, physical function improved further in all groups.

After one year, 31% of patients were in clinical remission, and 42% were in remission by the end of the second year. In all, low disease activity scores were maintained from six months to two years by 22% of patients in group 1, 21% in group 2, 28% in group 3, and 40% in group 4.

On x-ray evaluation, the authors found that patients in groups 3 and 4 had less progression of joint damage at two years than those in groups 1 and 2.

There were no significant differences in side-effects among the four groups.

The combination therapy with prednisone or infliximab was better at suppressing progression of joint damage in the early stages of disease, but by two years about 42% of patients in all treatment groups were in remission, and many were being maintained on only one disease-modifying anti-rheumatic drug (DMARD), or none.

In all, 79% of patients across all groups had low disease activity.

揑f clinicians are allowed the flexibility to change or escalate therapy, the vast majority of patients will be doing very well at two years regardless of which initial therapy they received," noted James R. O'Dell, M.D., of the University of Nebraska Medical Center in Omaha, in an accompanying editorial.

He added, "most patients can achieve excellent outcomes when clinicians escalate therapy until the patient achieves a low level of disease activity" and that "therapy should be individualized because patients with excellent responses were receiving a wide variety of DMARDs and combinations of drugs."

The results of this study point out several valuable lessons. 燜irst, the treating rheumatologist must see the patient frequently early on to make the necessary adjustments in medications. 燬econd, all patients should receive a DMARD (in most cases methotrexate) as soon as possible. Third, rheumatologists should adjust therapy in a timely fashion (increasing doses or adding other DMARDs) until patients have achieved low levels of disease activity (or are in remission), and finally, it appears that multi-drug combination can slow disease progression and the associated joint damage better than single drug therapy with comparable safety.

(Yvonne P.M. Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, 燗llaart CF, van Zeben D, Kerstens PJSM, et al. Comparison of Treatment Strategies in Early Rheumatoid Arthritis: A Randomized Trial. Annals Int Med. 2007; 146: 406-415)