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8th Annual European Congress of Rheumatology (EULAR)

Barcelona, Spain / June 13-16, 2007

A series of new substudies derived from the BeSt (Behandel-Strategieen) trial (Goekoop-Ruiterman et al. Ann Intern Med 2007;146:406-15) have provided additional support for a combination of the tumour necrosis factor alpha (TNF-a) inhibitor infliximab and disease-modifying antirheumatic drug (DMARD) methotrexate as initial therapy for rheumatoid arthritis (RA). In the initial publication, more aggressive therapies provided more rapid remission than the less aggressive ones. In new data, an initial methotrexate/infliximab combination relative to a combination of DMARDs plus prednisone was associated with a higher proportion of patients in remission and off therapy at the end of four years of follow-up.

In BeSt, four treatment strategies were compared: DMARD monotherapy (group 1); combination DMARDs with up to three agents (group 2); initial combination therapy with two DMARDs plus tapered high-dose prednisone (group 3); or initial combination methotrexate/infliximab therapy (group 4). Trimonthly treatment adjustments were made to achieve low disease activity.

While the more aggressive groups 3 and 4 strategies produced faster remissions than the groups 1 and 2 strategies in the initial report of results, an update comparing strategies 3 and 4 demonstrated an advantage for initiating a combination containing infliximab. In group 3, 40% of patients were considered treatment failures and 36% were off prednisone at the end of three years. In contrast, the failure rate in group 4 was 26% and 53% were off infliximab at the end of three years. Fourteen per cent of those who initiated the TNF-a inhibitor were off all medications vs. 7% in group 3 at the end of three years.

“There is a large group of patients started on combination therapy early in RA who are able to maintain remission after discontinuing infliximab,” stated Dr. Sjoerd M. van der Kooij, Research Physician, Rheumatology Staff Centre, Leiden University Medical Centre, The Netherlands.

In the BeSt trial, which randomized 508 patients with early-onset RA, clinical remission was defined as a disease activity score (DAS) <1.6. The primary end points were progression of radiological joint damage with the Sharp-van der Heijde Score (SHS) and functional ability with the Health Assessment Questionnaire (HAQ). Independent physicians assessed X-rays of the patients’ hands and feet in random order at baseline and after four years’ follow-up. Initial combination therapies were associated with earlier clinical improvement and less progression of joint damage. Although all treatment strategies eventually showed similar clinical improvements, the study demonstrated that combination therapy can be withdrawn successfully after disease remission is achieved, resulting in fewer treatment adjustments than with initial monotherapies.

Aiming for Remission

According to new detailed analyses of the clinical and radiological outcomes in the 120 patients who were treated with initial infliximab, Dr. van der Kooij and co-investigators reported that high remission rates have been sustained in long-term follow-up. In this group, the TNF-a inhibitor was started at 3 mg/kg/week and methotrexate was initiated at 25 mg/week. The DAS was calculated one to two weeks before each infliximab infusion. Dosage was tapered incrementally every eight weeks, depending on DAS achieved.

After four years, 51% of the 120 patients randomized to the methotrexate/infliximab combination maintained a DAS of =2.4 even though infliximab had been discontinued an average of 35 months (almost three years) earlier. Furthermore, 17% of these patients had stopped all antirheumatic drugs and maintained a DAS below 1.6. They were able to discontinue DMARDs for an average of 12 months. During the fourth year, an additional six patients who were on methotrexate monotherapy had a DAS below 1.6 and were able to discontinue that therapy. Four patients who had previously stopped all DMARDs had DAS of at least 1.6 and consequently restarted methotrexate. Four patients who had previously discontinued infliximab had a DAS above 2.4 despite treatment with methotrexate 25 mg/week and consequently had to restart the TNF-a inhibitor. Therefore, 22 patients were on the combination therapy after four years. The combination failed for 30 patients, who proceeded to the next step in the study design.

The investigators found that radiologic progression was highest in the patients for whom the combination failed and minimal in the 20 patients who discontinued all treatment. At baseline, the 20 patients off treatment had an average DAS of 4.1; 45% were rheumatoid factor-positive and 74% had erosions.

Early vs. Delayed Treatment Results

In another analysis of BeSt results, investigators compared clinical outcomes after nine months in the group of combination therapy patients who were initially started on the TNF-a inhibitor (group 4) and in the 86 patients who received it after a delay (49, 12 and 25 patients from groups 1, 2 and 3, respectively). Nine months was chosen as the timeframe because after this point, per protocol patients were allowed to switch to other DMARDs after failure on methotrexate/infliximab. All 86 patients started the combination after at least three previous DMARDs had failed them. The average time from inclusion in the study to starting the combination was 18 months.

Not surprisingly, the average DAS and HAQ scores in the 120 patients who had initiated therapy with infliximab were more improved than the scores in the 86 patients on a DMARD combination at the time that they were switched to the TNF-a inhibitor. Nine months after conversion to the TNF-a inhibitor, the latter group still experienced more disease activity than patients initiated with infliximab suggesting that starting with the biologic provided better long-term disease control than stepping up therapy downstream. In addition, a higher proportion of the patients initiated on infliximab had achieved a DAS of <1.6 than patients on delayed treatment. Two years after the start of combination therapy, more patients who received infliximab from the beginning had tapered and discontinued it due to a sustained DAS of no more than 2.4. Of these, more patients retained a DAS of <1.6 for at least one year, compared to patients for whom it was delayed.

Gauging Response by DAS

BeSt investigators also assessed the value of using DAS as a gauge for response to treatment. They found that more patients (44% in the immediate infliximab group) maintained a DAS of no more than 2.4 than in the other three groups, and that 16% of such patients were in clinical remission (DAS <1.6) compared to 11% of those on sequential monotherapy, 6% of those on step-up monotherapy, and 7% of those on delayed combination therapy (P<0.05 for immediate infliximab compared to step-up and delayed combination therapy). The median SHS progression in the 438 patients (86%) for whom X-rays were available was 3.8 in the sequential group, 3.0 in the step-up group, 1.8 in the delayed combination group, and 1.5 in the immediate TNF-a inhibitor group (P<0.05 for the monotherapy groups vs. the combination groups).

In another BeSt substudy (Goekoop-Ruiterman et al. Ann Rheum Dis, published online Apr 2007), a questionnaire was administered to all 508 participants asking them to evaluate their preferences and dislikes about the assigned regimen. Although half of the 440 respondents did not express a strong opinion about their treatment, it is notable that 50% of patients in group 3, which included DMARDs plus prednisone, expressed dislike for the steroid. In contrast, 8% of patients receiving the TNF-a inhibitor expressed dislike for going to the hospital for intravenous therapy. Although investigators cautioned that this was a retrospective analysis, they reported that patients clearly preferred initial combination therapy with infliximab and disliked taking prednisone.

Summary

In new data from the BeSt trial, which compared four different regimens in early RA and found the combination regimens more likely to produce rapid and sustained radiological and clinical remission, initial use of infliximab was found to provide better long-term outcomes than delayed use. The sustained benefit at four years was observed even though 51% were off the TNF-a inhibitor and 17% were off all medications. The data provide compelling evidence for early aggressive treatment regimens to rapidly gain control, reduce risk of progressive radiological damage, and produce sustained remissions.