BIRMINGHAM, ENGLAND – Combinations of conventional antirheumatic drugs are as clinically effective as more expensive biologic agents in managing patients with active, established rheumatoid arthritis, randomized trial data suggest.
Health Assessment Questionnaire (HAQ) scores at 12 months were lower in patients given conventional disease-modifying antirheumatic drugs (cDMARDs) as compared to a tumor necrosis factor inhibitor (TNFi) after failure of methotrexate and at least one other DMARD (1.35 vs. 1.60, P = .046).
Dr. David L. Scott
Nevertheless, the two approaches were "clinically equivalent," said trial investigator Dr. David L. Scott at the annual meeting of the British Society for Rheumatology.
"In patients with methotrexate-resistant rheumatoid arthritis [RA], giving the cDMARD intensive therapy and starting off with a TNFi achieves similar outcomes, causes comparable harms, but the cDMARDs cost less," said Dr. Scott, who is professor of clinical rheumatology at King’s College London.
These data, from the TACIT (Tumor Necrosis Factor Inhibitors or Conventional Drugs in Rheumatoid Arthritis) trial, suggest that combination DMARD therapy could be an alternative approach for patients with established RA, reserving anti-TNF agents for those who fail intensive DMARD treatment.
Dr. Scott noted that the findings might warrant a change in practice in the United Kingdom, where anti-TNFs are currently recommended as the next choice in patients who do not respond to treatment with two individual DMARDs, one of which must be methotrexate. Such an approach is based on evidence from placebo-controlled, rather than head-to-head, trials, however, and such a "one size fits all" approach perhaps needs reevaluation.
The TACIT trial was conducted in 24 centers in the United Kingdom and involved 205 patients who had RA for a median duration of 4 years. The aim of the trial was to directly compare two different treatment strategies: a TNFi (infliximab, etanercept, or adalimumab) given to patients after failing methotrexate and a subsequent DMARD versus methotrexate followed by combination cDMARDs and then a TNFi.
Combinations of cDMARDs used in the trial included triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine; other methotrexate combinations (methotrexate-cyclosporin, methotrexate-leflunomide, and methotrexate-gold); and one sulfasalazine combination (sulfasalazine-leflunomide).
At 12 months’ follow-up, there was no significant difference between the treatment strategies in terms of quality of life measured using the EuroQol instrument, radiographic progression assessed using Larsen scores, or disease activity assessed via monthly Disease Activity Score-28 (DAS28).
The mean change in DAS28 score was initially greater in TNFi-treated patients (–2.07 vs. –1.45, P = .007) at 6 months, Dr. Scott said, but this difference was lost with longer follow-up. "This simply shows that, as we’ve always known, TNFi’s act rapidly and DMARDs are slow acting," he observed.
Economic analysis showed a clear advantage for the use of cDMARDs over anti-TNF agents, with an annual estimated saving of health and social care costs of £5,552 (U.S.$8,400) per patient. Taking lost productivity and social security payments into account did not change the findings.
Safety is a concern of using multiple cDMARDs, particularly older combinations, but the TACIT data showed that there were a comparable number of adverse reactions. The total number of events was 635 for cDMARDs and 465 in the TNFi group. Of these, there were more digestive adverse events in the cDMARD arm than in the TNFi group (148 vs. 60), but more infections in the anti-TNF-treated patients than in the cDMARD group (54 vs. 30).
Serious adverse events were noted in 10 and 18 of cDMARD- and TNFi-treated patients, respectively, with 10 and 6 patients in each group withdrawing as a result of experiencing a side effect. There was one death, due to pneumonia and multiple organ failure, in the anti-TNF arm.
"We should think about the treatment strategy in terms of intensive DMARDs first of all and then moving onto biologics," Dr. Scott said. Remission needs to be a target of treatment, he added, although this is rarely achieved by either strategy. Remission rates at 12 months seen in TACIT are comparable to rates reported from several registries, including CORRONA (Consortium of Rheumatology Researchers of North America) in the United States, DANBIO in Denmark, RABBIT in Germany, and BSRBR-RA (British Society for Rheumatology Biologics Register-Rheumatoid Arthritis) in the United Kingdom.
Dr. Scott concluded by noting that there are three unresolved questions. First, it is not clear what the best combination of cDMARDs is; second, the optimum way to use biologics is currently unknown; and third, it is not clear how to convert patients with intermediate disease activity into patients who may achieve clinical remission.
The TACIT trial was supported by a Health Technology Assessment grant from the U.K. National Institute for Health Research. Dr. Scott and his coinvestigators reported having no conflicts of interest.