The latest results from the BeSt study show that initial combination therapy with either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year among early rheumatoid arthritis (RA) patients when compared with either sequential monotherapy or step-up combination therapy, according to a new study published in the November issue of Arthritis & Rheumatism.¹

Patients who had received initial combination therapy of methotrexate (MTX), sulfasalazine, and prednisone or MTX plus infliximab had significantly less progression of radiographic joint damage than did patients treated with MTX and disease-modifying antirheumatic drugs (DMARDs) or patients assigned to a step-up combination protocol, starting with MTX only and adding other DMARDs and prednisone, according to a multicenter study led by YPM Goekoop-Ruiterman, MD, of Leiden University Medical Center in the Netherlands.

However, at 1 year, participants in all groups demonstrated measurable improvements, with 32% of the entire cohort achieving clinical remission (DAS₄₄ of <1.6).  

The Dutch researchers compared the four most widely used treatment strategies for very early RA in 508 patients. Group 1 (126 patients) received standard DMARD therapy, starting with MTX. Group 2 (121 patients) was assigned to step-combination therapy, beginning with MTX only and adding other DMARDs and prednisone. Group 3 (133 patients) started with a combination of MTX, sulfasalazine, and prednisone. Group 4 (128 patients) started with a combination of MTX and infliximab. For all groups, drug dosages were increased or switched to other agents to achieve an adequate clinical response (DAS₄₄ < 2.4).

Study participants were primarily women (mean age 54) who had suffered disease symptoms for an average of 23 weeks before entering the trial. Participants were monitored for 1 year.

Improvements in radiographic assessments and D-HAQ
 
After 1 year, median increases in Sharp/Van der Heijde radiographic joint scores were 2.0, 2.5, 1.0, and 0.5, in groups 1 to 4, respectively (P <.001). Though statistically significant, these radiographic differences were not as important from a clinical perspective, study authors point out.

RA patients in both initial combination therapy groups also experienced earlier functional improvement than did patients in either the DMARD monotherapy or step-up combination therapy group, according to scores of the Dutch version of the Health Assessment Questionnaire (D-HAQ).  

Overall, patients who received initial combination therapy experienced no more side effects than patients in the other two groups.

"What is interesting is that when one is focused on improving outcome, it doesn't matter which strategy you use, you seem to get there eventually," Salahuddin Kazi, MBBS, chief of the rheumatology section at Dallas VA Medical Center in Texas, tells CIAOMed.
"Another way of looking at having the same end result is the ‘opportunity cost' of getting there: the quality-of-life issues, the prednisone side effects, and the possibility that even though signs and symptoms and radiographic change looked similar, perhaps future disability will be different," Dr. Kazi says.

A sustained adequate suppression of disease activity was achieved with MTX monotherapy in over 40% of patients in groups 1 and 2, the study found, indicating that a large proportion of patients would be overtreated if all patients started with initial combination therapy, according to the study authors.

Yet while patients in groups 3 and 4 experienced more rapid symptom relief and improvement in physical function than those in groups 1 and 2, the study authors note that there is the additional possibility that "the suppression of disease activity during the early phases of the disease may ameliorate long-term joint damage and poor physical function and, ideally, even induce true clinical remission without the need for ongoing DMARD treatment."

Validation of early, aggressive therapy

According to Dr. Kazi, the findings are "in a sense a validation that we should be treating early RA aggressively and people do get better." However, he adds, "I think [the BeSt researchers] were hoping to find that one [treatment] was clearly superior to the other, and part of the surprise was that patients started to look similar in many of the endpoints we measure." Dr. Kazi feels this begs the question of whether these endpoints are fully valid. "If signs and symptoms get better, but somehow the disease progresses, then the signs and symptoms are not adequate to address true outcomes in disease," he observes.

Dr. Kazi also questioned the withdrawal of the study drugs as soon as patients reached remission. "Maybe if we hadn't withdrawn infliximab at the first sign of remission, we could have seen more benefits," he says. "The race is over when everybody reaches the finish line, but maybe the finish line is not where we think it is."  In all of the study groups, patients who maintained a consistent clinical response (DAS₄₄ <2.4) for the first 6 months went on a monotherapy maintenance dose. Prednisone and infliximab were the first drugs in the protocols to be withdrawn entirely.

Dr. Kazi says he would have liked to have seen a fifth arm in the trial that looked at continuation of biologics in patients. More data from the BeSt trial is slated to be presented at the upcoming meeting of the American College of Rheumatology in San Diego, California, on November 12–17, 2005.

Reference

1. Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Allaart CR, et al.  Clinical and radiographic outcomes of four different treatment strategies in patients with early
rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum.  2005;52:3381–3390.