Tofacitinib-methotrexate trial extended as first randomized controlled trial of tofacitinib monotherapy for psoriatic arthritis.
Results from the first randomized control trial of tofacitinib monotherapy for psoriatic arthritis, an extension substudy of a long-term tofacitinib-methotrexate combination trial, suggest that some patients can discontinue methotrexate from the combination treatment without exacerbation of disease activity or reduction in health-related quality of life.
Peter Nash, MD, Griffith University, Brisbane, Queensland, Australia, and colleagues note that the 2019 European League Against Rheumatology (EULAR) guidelines recommend continuing methotrexate with advanced therapies in patients who tolerate it, and reducing the dosage in patients demonstrating good response to biological treatment, particularly if there are concerns with toxicity.
Nash and colleagues note, however, “treat-to-target, including withdrawal or tapering of medication in patients who achieve treatment goals, is still an emerging concept In psoriatic arthritis.”
To evaluate whether methotrexate can be discontinued without loss of treatment efficacy, they conducted a 12-month extension substudy of the OPAL Balance long-term study in patients who had been on a stable dose of tofacitinib. The study of tofacitinib monotherapy after methotrexate withdrawal was designed as a phase 3, randomized, double-blind, placebo-controlled parallel-group, 12-month estimation study with patients from 50 clinics across 14 countries.
A total of 180 patients were recruited from the OPAL Balance trial between October 2017 and May 2019. Eligibility criteria included having received tofacitinib treatment for at least 24 months, maintained at 5mg twice daily for at least 3 months; and a stable dose of oral methotrexate of 7.5-20mg/week for at least 4 weeks. Candidates were excluded if they were receiving other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), or methotrexate at a dose less than 7.5mg/week or more than 20mg/week.
The participants were maintained on open label tofacitinib 5mg twice daily, and randomized to either maintain methotrexate or receive a placebo of matching appearance. The primary endpoints at 6 months were changes from baseline in psoriatic arthritis disease activity score (PASDAS) and health assessment questionnaire-disability index (HAQ-DI); and safety measures of disease status and treatment tolerance were assessed throughout the study period.
The investigators reported that, on average, there were no appreciable differences in disease activity and physical function at 6 months between patients who continued or discontinued methotrexate. They noted a numerical difference in psoriatic arthritis disease activity score at month 9 favoring those who maintained the methotrexate, but that outcomes were similar in both treatment groups by month 12.
Nash and colleagues also found a similar safety profile between the groups, with the exception of elevated liver enzymes in a greater proportion of the patients who maintained methotrexate with tofacitinib.
In accompanying commentary, Roy Fleischmann, MD, University of Texas Southwestern Medical Center, Dallas, Texas, characterized the study as "an interesting and clinically important analysis," but offered several concerns about the design and interpretation of the results.
He noted that the 2019 EULAR guidelines recommend methotrexate dosage of 25mg/week, but that the mean dose of methotrexate before withdrawal in this study was 15mg/week, and the maximum was 20mg/week.
"There is a possibility that many of the patients who maintained their response with tofacitinib monotherapy did so because they were treated with a suboptimal, ineffective dose of methotrexate before inclusion," Fleischmann posited.
He also points out that the trial report does not specify what percentage of patients transitioning to tofacitinib monotherapy had maintained effective disease control. In addition, the report does not indicate whether psoriasis flared when methotrexate was discontinued; or whether there was arthritis flare with the tofacitinib monotherapy.
"What cannot be answered by this substudy," Fleishchmann remarked, "are the basic questions of whether front-line tofacitinib monotherapy is superior, non-inferior, not non-inferior, or inferior to an optimal dose methotrexate in any of the multiple manifestations of psoriatic arthritis."
Nash and colleagues consider the results as suggestive rather than definitive, however, and conclude "some patients receiving tofacitinib 5mg twice daily with background methotrexate who are in a stable disease state might be able to discontinue methotrexate to receive tofacitinib monotherapy, without an adverse effect on their overall disease activity or health-related quality of life."
The study, “Tofacitinib as Monotherapy Following Methotrexate Withdrawal in Patients with Psoriatic Arthritis Previously Treated with Open-Label Tofacitinib Plus Methotrexate: A Randomized, Placebo-controlled Substudy of OPAL Balance,” was published online in The Lancet Rheumatology.