Methotrexate Plus Leflunomide Proves Effective for PsA

Steve Cimino

March 08, 2022

A new study has found that methotrexate plus leflunomide outperforms methotrexate alone as a treatment option for patients with psoriatic arthritis (PsA).

Dr Michelle Mulder

"We believe that prescribing this combination in routine practice is viable when combined with shared decision-making and strict monitoring of side effects," write Michelle L. M. Mulder, MD, of the Department of Rheumatology at Sint Maartenskliniek in Nijmegen, the Netherlands, and her co-authors. Their findings were published in Lancet Rheumatology.

The latest treatment guidelines from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the European Alliance of Associations for Rheumatology (EULAR) recommend conventional synthetic disease-modifying antirheumatic drugs for patients with active PsA, but Mulder and her colleagues note a distinct lack of information on their effectiveness, especially this particular combination.

To assess the efficacy and safety of methotrexate plus leflunomide, they launched a single-center, double-blind, randomized trial that incuded 78 Dutch patients with PsA. The majority of the participants in this trial ― dubbed COMPLETE-PsA ― were men (64%), and the median age of the patients was 55 years. All had active disease at baseline; the median swollen joint count (SJC) and tender joint count were 4.0 in both groups.

Participants were assigned to receive either methotrexate plus leflunomide (n = 39) or methotrexate plus placebo (n = 39). After 16 weeks, mean Psoriatic Arthritis Disease Activity Score (PASDAS) had improved for patients in the combination therapy group in comparison with the monotherapy group (3.1 [standard deviation (SD), 1.4] vs 3.7 [SD, 1.3]; treatment difference, -0.6; 90% CI, -1.0 to -0.1; P = .025). The combination therapy group also achieved PASDAS low disease activity at a higher rate (59%) than did the monotherapy group (34%; P = .019).

Other notable differences after 16 weeks included improvements in SJC for 66 joints (-3.0 in the combination therapy group vs -2.0 in the monotherapy group) and significantly better skin and nail measures ― such as active psoriasis and change in body surface area ― in the methotrexate plus leflunomide group.

When asked who should be prescribed the combination therapy and who should be prescribed methotrexate going forward, Mulder told Medscape Medical News, "At the moment, we have insufficient knowledge on who will benefit most or who will develop clinically relevant side effects. It seems warranted to discuss with every patient which approach they would prefer. This could be a step-down or -up approach.

"We hope to be able to better predict treatment response and side effects in the future via post hoc analysis of our study and via extensive flow-cytometric phenotyping of immune blood cells taken at baseline," she added.

Three patients in the combination therapy group experienced serious adverse events, two of which were deemed unrelated to leflunomide. The most frequently occurring adverse events were nausea or vomiting, tiredness, and elevated alanine aminotransferase. Mild adverse events more common in the methotrexate plus leflunomide group. No participants died, and all patients with adverse events recovered completely.

"It appears good practice to do blood draws for laboratory tests on liver enzymes at least monthly for the first 4 months and every 4 months after that once stable dosing is achieved, as well as have a telephone consultation after 6 to 8 weeks to talk about possible side effects a patient might experience and change or add therapy if necessary," Mulder added.

Study Turns Perception of Combination Therapy Into Reality

It had already been perceived by rheumatologists that methotrexate plus leflunomide was an effective combo for PsA, and this study reinforces those beliefs, Clementina López-Medina, MD, PhD, and colleagues from the University of Cordoba (Spain), write in an accompanying editorial.

They highlight this study's notable strengths, one of which was defining "active disease" as two or more swollen joints, which opened the study up to a larger patient population. The editorialists also underline the confirmation that leflunomide plus methotrexate reduces both joint symptoms and skin involvement in this subset of patients, which had also been found in a previous study.

"Leflunomide is usually considered as a second-line option after methotrexate is unsuccessful," they note, "despite the fact that methotrexate did not show superiority over placebo in previous trials."

The editorialists were not surprised that the combination therapy was more toxic than the monotherapy. Rheumatologists could use these data to individualize treatment accordingly, they write, while keeping an eye on "gastrointestinal disturbances."

Overall, López-Medina and colleagues say that the study results should "be considered not only in daily clinical practice but also in the development of future recommendations."

Leflunomide: Forgotten No Longer, at Least for PsA

"I think we probably underutilize leflunomide," Arthur Kavanaugh, MD, professor of medicine and director of the Center for Innovative Therapy at the University of California, San Diego, told Medscape Medical News. "Sometimes medicines get 'old,' for lack of a better term, and fall a little bit of out of favor, sometimes unnecessarily. Leflunomide falls into that category. Because it's older, it doesn't get as much buzz as what's new and shiny.

Dr Arthur Kavanaugh

"I was not surprised by the results on the joints," he said, "because we know from previous studies that leflunomide works in that regard. What did surprise me is that the skin got better, especially with the combination."

Regarding the side effects for the combination therapy, he commended the authors for limiting potential uncertainty by using such a high dose of methotrexate.

"By going with a dose of 25 mg [per week], no one can say, 'They pulled their punches and methotrexate monotherapy would've been just as good if it was given at a higher dose,' " he said. "And they also used leflunomide at a high dose. It makes you wonder: Could you use lower doses, and do lower doses mean fewer lab test abnormalities? This positive study does lend itself to some other permutations in terms of study design.

"Even though this was a small study," he added, "it brings us right back to: We should really consider leflunomide in the treatment of PsA."

The authors acknowledge their study's limitations, including the fact that it was conducted in a single country and the absence of a nontreatment placebo group. They also note the higher percentage of women in the methotrexate plus leflunomide group, "which might have lowered the treatment response and increased the adverse event rate, resulting in bias."

The study was funded by a Regional Junior Researcher Grant from Sint Maartenskliniek. The authors reported numerous potential conflicts of interest, including receiving payment, research grants, and consulting and speaker fees from various pharmaceutical companies.

Lancet Rheumatol. Published online February 28, 2022. Abstract

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