Combination Drug Therapy Retards Early RA Damage

LEIDEN, The Netherlands, March 20 -- For early rheumatoid arthritis, aggressive combination therapy can slow progression to joint damage, investigators here found.

Among 508 patients treated in a randomized multicenter trial, initial combination therapy plus either tapered prednisone or infliximab (Remicade) and other medications outperformed monotherapy in the first year, reported Yvonne P.M. Goekoop-Ruiterman, M.D., of the University of Leiden, and colleagues and other centers.

"We conclude that the difference in disease activity during the first year is clinically relevant and will probably have an economic impact," the investigators wrote in the March 20 issue of the Annals of Internal Medicine.

The combination therapy with prednisone or infliximab was also better at suppressing progression to 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 antirheumatic drug (DMARD), or none, the authors noted.

In all, 79% of patients across all groups had low disease activity, as defined by a disease activity score of less than 2.4.

The results of the long-running BeSt (a Dutch acronym for Behandel-Strategieen, or "treatment strategies") study show that "if 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.

The study also demonstrates that "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," Dr. O'Dell added.

The BeSt 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).

The patients were randomized into four groups:

• Sequential monotherapy, 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 radiographic 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.

During the second year of follow-up, physical function improved further in all groups, resulting in a change from baseline of 0.7 for group 1, 0.8 for group 2, and 0.9 each for groups 3 and 4 (P=0.257).

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 radiography, 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. The median increase in total Sharp-van der Heijde score was 2.0 each in groups 1 and 2, and 1.0 each in groups 3 and 4 (group 1 versus group 2, P=0.850; group 1 versus group 3, P=0.043; group 1 versus group 4, P=0.014; group 2 versus. group 3, P=0.006; group 2 versus group 4, P=0.004; group 3 versus group 4; P=0.798)

There were no significant differences in toxicity among the four groups. Serious adverse events were reported in eight, nine, 17, and six patients in groups 1 through 4, respectively, during the first year. During the second year, 56 serious adverse events were reported (16 events [13 patients] in group 1, 10 events [10 patients] in group 2, 17 events [11 patients] in group 3, and 13 events [eight patients] in group 4).

"With our current knowledge and the results of the BeSt trial, how should we treat patients with newly diagnosed RA?," Dr. O'Dell wrote in his editorial. "First, with the ever-increasing complexity, expense, and toxicity of modern therapy, a rheumatologist should be actively involved in the care of all patients with RA in conjunction with the primary care physician. Second, all patients should receive a DMARD (in most cases methotrexate) as soon as possible. Finally, 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)."

The BeSt investigators noted that their study was limited by the open-label design, although assessors were blinded as to treatment group.

Co-author Ferdinand C. Breedveld, M.D., is a consultant to Schering-Plough, Centocor, and other companies. Co-author Cornelia F. Allart, M.D. has received grants and honoraria from Schering-Plough.