BERLIN — Studies of anti-tumor necrosis factor therapy for rheumatoid arthritis are growing in size and enrolling more “real world” patient populations, compared with the earlier pivotal trials that won marketing approval for the biologic agents.
Results of two such studies presented at the annual European Congress of Rheumatology reaffirm the safety and efficacy of adalimumab and infliximab; earlier trials for these drugs had been criticized for their highly restrictive eligibility requirements and unrepresentative patient populations.
The biggest of these “real life” trials, which are intended to more accurately mirror clinical practice, is the ongoing Research in Active Rheumatoid Arthritis (ReAct) trial, an open-label study that to date has enrolled 6,500 patients at more than 430 sites in 11 European countries.
Participants in ReAct have long-standing moderate to severe rheumatoid arthritis (RA) of a mean 11 years' duration that has responded inadequately to at least one traditional disease-modifying antirheumatic drug (DMARD). Comorbid illnesses—commonplace among patients with RA—are no exclusion to participation in ReAct. Patients received 40 mg of adalimumab subcutaneously every other week in addition to any preexisting but inadequate therapy, most often methotrexate.
Gerd R. Burmester, M.D., presented data on treatment efficacy and safety at week 12 in the first 2,008 participants in ReAct, sponsored by Abbott Laboratories.
Median tender joint count fell from a baseline of 13 to 3. The swollen joint count dropped from 10 to 3. Clinical remission at 12 weeks, as defined by a Disease Activity Score-28 of less than 2.6, was achieved by 24% of patients; mean baseline DAS-28 was 6.0. Similarly, from a mean baseline Health Assessment Questionnaire score of 1.6, 25% of patients dropped below 0.5, a rate indicative of normal physical functioning.
Also at 12 weeks, 67% of patients obtained at least a 20% reduction in disease signs and symptoms, or ACR 20. Adalimumab's onset of action was swift: Two-thirds of patients who achieved an ACR 20 by 12 weeks did so within 2 weeks of their first dose, reported Dr. Burmester, at Humboldt University, Berlin.
Of particular clinical interest was the efficacy of adalimumab in patients, regardless of whether they had previously failed therapy with other biologic agents. (See chart.) Also, efficacy was quite similar regardless of how many concomitant DMARDs patients were taking.
The 4.9% rate of serious infections in ReAct was similar to that of pivotal trials. “There were no new alerting signals,” he said. Seven cases of tuberculosis occurred during 2,259 patient-years of follow-up.
In a separate presentation, Rene Westhovens, M.D., reported on 1,084 participants in the Safety and Efficacy of Infliximab Therapy in Rheumatoid Arthritis (START) trial. START was a multicenter study designed specifically to assess the infection risk associated with combined infliximab-methotrexate therapy in everyday practice and included 15 patients with previous active TB and another 45 with latent TB.
All participants were on methotrexate, and they were randomized to the standard 3 mg/kg of IV infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter for 22 weeks, or to 10 mg/kg of the TNF antagonist, or to placebo.
The rate of serious infections—defined as those resulting in death, hospitalization, or threat to life—was 1.7% among patients on placebo, 1.7% in those on standard-dose infliximab, and 5.3% in those on 10 mg/kg of infliximab. The adjusted relative risk of serious infection was 3.3-fold greater in patients on high-dose infliximab, said Dr. Westhovens of the Catholic University of Leuven (Belgium).
None of the patients with latent TB or prior active TB developed a relapse or flare of active TB during the Schering-Plough-sponsored study, he added.