Methotrexate Plus Leflunomide Shows Significant Improvements in Disease Activity in Patients With Psoriatic Arthritis

psoriatic arthritis of hand
psoriatic arthritis of hand
Researchers assessed whether combination therapy with methotrexate plus leflunomide was superior to methotrexate monotherapy in improving disease activity in patients with psoriatic arthritis.

Based on psoriatic arthritis (PsA) disease activity score (PASDAS), a combination of methotrexate (MTX) plus leflunomide vs MTX monotherapy showed greater improvements in disease activity, according to study results published in Lancet Rheumatology.

According to treatment guidelines for PsA, conventional synthetic disease-modifying antirheumatic drugs (DMARDs) are the preferred first-line treatment after local glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs). However, limited data are available regarding the efficacy of these agents, especially when used in combination.

To examine whether the combination of MTX and leflunomide was superior to MTX monotherapy in improving disease activity in PsA, researchers conducted a single center, investigator-initiated, double-blind, randomized, placebo-controlled trial.

Eligible patients were aged 16 years and older with a clinical diagnosis of PsA and active disease (defined as ≥2 swollen joints; dactylitis counting as 1 swollen joint). Patients were randomly assigned and stratified by high disease activity (PASDAS ≥5.4) to receive MTX plus leflunomide (combination therapy) or MTX plus placebo (monotherapy).

The PASDAS calculation included swollen joint count for 66 joints (SJC66), tender joint count for 68 joints (TJC68), Leeds enthesitis index, dactylitis count, patient and physician global visual analog scale (VAS), C-reactive protein (CRP), and the physical component summary score of the 36-item short form health survey (SF-36).

Between February 2019, and March 2021, 78 patients with clinically diagnosed PsA were enrolled to receive MTX plus leflunomide (n=39) or MTX plus placebo (n=39).

The adjusted PASDAS at week 16 improved significantly in the MTX plus leflunomide group vs the MTX monotherapy group (3.1 vs 3.7; treatment difference, -0.6; 90% CI, -1 to -0.1; P =.025). Similar results were seen for PASDAS low disease activity (59% vs 34%; P =.019) and minimal disease activity (59% vs 32%; P =.013).

Other significant between-group differences at week 16 included change in SJC66 (P =.049) and physician global VAS (P =.021).

Nausea and vomiting, tiredness, and elevated alanine aminotransferase were the most frequently occurring adverse events. Overall, 3 patients had serious adverse events in the combination group; however, no deaths occurred.

Study limitations included that fact that certain patient characteristics, including sex, skin disease, inflammatory back pain, and dactylitis, were slightly unbalanced; the lack of a placebo group that may have been beneficial to understand the efficacy of MTX monotherapy; the inability to reach conclusions regarding leflunomide monotherapy; and the single-center nature of the study, which could have reduced external generalizability.

However, the researchers recommended, “We believe that prescribing this combination [MTX plus leflunomide] in routine practice is viable when combined with shared decision making and strict monitoring of side-effects.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Mulder M L M, Vriezekolk JE, van Hal TW, et al. Comparing methotrexate monotherapy with methotrexate plus leflunomide combination therapy in psoriatic arthritis (COMPLETE-PsA): a double-blind, placebo-controlled, randomised, trial. Lancet Rheumatology. Published online February 28, 2022. doi:10.1016/S2665-9913(22)00028-5