No significant differences were observed between patients with rheumatoid arthritis (RA) who received tofacitinib and methotrexate combination therapy or adalimumab and methotrexate combination therapy after failing methotrexate monotherapy, according to results published in The Lancet.
“[T]ofacitinib 5 mg twice daily with methotrexate showed efficacy and safety similar to adalimumab with methotrexate in patients with rheumatoid arthritis who had an inadequate response to methotrexate therapy. Tofacitinib monotherapy did not achieve statistical non-inferiority to either combination regimen,” Roy Fleischmann, MD, from the University of Texas Southwestern Medical Center and Metroplex Clinical Research Center in Dallas, and colleagues wrote. “These results suggest that in patients with an inadequate response to methotrexate, the addition of tofacitinib or adalimumab is equally efficacious and more effective than switching to tofacitinib monotherapy.”
Dr Fleishmann and colleagues enrolled 1146 patients with RA from 194 centers in 25 countries in the Oral Rheumatoid Arthritis trial (ORAL) Strategy trial, a double-blind, phase 3b/4, randomized controlled trial assessing superiority of tofacitinib and methotrexate combination therapy or adalimumab and methotrexate combination therapy. The investigators randomly assigned patients to receive twice daily oral tofacitinib (5 mg), twice daily oral tofacitinib (5 mg) with methotrexate, or subcutaneous adalimumab every other week (40 mg) with methotrexate. Patients were minimum 18 years old with RA and had had an inadequate response to methotrexate monotherapy.
At 6 months, 38% of patients (n=147) in the tofacitinib group, 46% of patients (n=173) in the tofacitinib and methotrexate group, and 44% (n=169) of patients in the adalimumab and methotrexate group reached American College of Rheumatology 50% response criteria (ACR50). Non-inferiority was present when comparing tofacitinib and methotrexate combination therapy with adalimumab and methotrexate combination therapy (difference 2%; 98.34% CI, −6 to 11), but not when comparing tofacitinib monotherapy with adalimumab and methotrexate combination therapy (difference −6; 98.34% CI, −14 to 3) or tofacitinib and methotrexate combination therapy (difference −8; 98.34% CI, −16 to 1).
Overall, 6% of patients (n=23) in the tofacitinib group, 7% of patients (n=26) in the tofacitinib with methotrexate group, and 9% of patients (n=36) in the adalimumab with methotrexate group discontinued therapy because of adverse events, with 2 deaths reported in the tofacitinib group.
The investigators noted that the study provides evidence that the use of a targeted synthetic disease-modifying anti-rheumatic drug (DMARD) such as tofacitinib, as outlined in the recent 2016 update of the European League Against Rheumatism (EULAR) recommendations, may be indicated in cases in which methotrexate monotherapy has failed.
“ORAL Strategy was designed to answer clinically relevant questions faced by clinicians in routine clinical practice when presented with a patient with rheumatoid arthritis and an inadequate response to methotrexate who might have also had an inadequate response to other conventional synthetic DMARDs: to either add tofacitinib or a [tumor necrosis factor] TNF inhibitor, such as adalimumab, to the methotrexate regimen, or to switch methotrexate to tofacitinib monotherapy,” Dr Fleischmann and colleagues wrote. “The results of ORAL Strategy suggest that the addition of tofacitinib to methotrexate is preferable to switching to tofacitinib monotherapy.”
Limitations & Disclosures
The investigators noted the lack of generalization to other patients with TNF therapies, lack of radiographic follow-up, and the lack of a placebo group as limitations of the study.
The investigators report various disclosures. Please see the full study for the complete list of disclosures.
Fleischmann R, Mysler E, Hall S, et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial [published online June 16, 2017]. Lancet. doi:10.1016/S0140-6736(17)31618-5