Concomitant Methotrexate Does Not Increase Efficacy of Ustekinumab in Patients with Psoriatic Arthritis

Ustekinumab, an interleukin (IL)-12 and IL-23 inhibitor, effectively treated psoriatic arthritis (PsA), regardless of methotrexate co-therapy, based on changes in the Disease Activity Score 28 (DAS28). The benefits of adding or maintaining methotrexate when initiating ustekinumab is unsubstantiated, according to a study published in The Lancet.¹

“Methotrexate is thought to have several mechanisms of action that could help to ameliorate inflammatory arthritis, including inhibition of interleukin (IL)-12and IL-23 pathways,” investigators explained.

In the randomized, multicenter, placebo-controlled, phase 3b Impact of Concomitant Methotrexate on Efficacy, Safety, and Adherence of Ustekinumab Treatment in Patients with Active Psoriatic Arthritis (MUST) trial (NCT03148860), investigators evaluated the role methotrexate, in combination with ustekinumab, plays in the treatment of PsA. Eligible patients were naïve to ustekinumab treatment, met the classification criteria for PsA, and had active PsA.

Performed in 22 centers in Germany between January 2017 and April 2021, patients were randomized 1:1 to receive either open-level subcutaneous ustekinumab (45 mg; 90 mg for patients with a body weight >100 kg) plus either placebo (15 mg, weekly) or methotrexate (15 mg, weekly). The primary outcome was non-inferiority of mean Disease Activity Score-28 joints (DAS28) based on erythrocyte sedimentation rate (ESR) at week 24 for ustekinumab monotherapy compared with ustekinumab plus concomitant methotrexate, which was further stratified by current methotrexate treatment and no previous methotrexate treatment. The secondary outcome was non-inferiority of DAS28 at week 52. Both adverse events (AEs) and serious AEs (SAEs) were reported.

Ultimately, 173 adult patients with active PsA were included in the study and assigned to receive concomitant methotrexate (n = 88) or placebo (n = 85). At baseline, 84 patients were currently receiving methotrexate therapy, while 89 patients had no history of methotrexate treatment. The majority (96%, n = 166) were included in the safety and efficacy analyses at 24 weeks. The mean age was 48.2 years and 58% of patients were male.

Results showed that ustekinumab monotherapy was non-inferior to ustekinumab plus methotrexate regarding DAS28 at week 24 (2.9 [SD 1.31] vs 3.1 [1.42]). The stratified Mann-Whitney estimator for comparison between treatment groups was 0.5426 (2-sided 95% CI 0.4545–0.6307). Similarly, at week 52, mean DAS28 was 2.8 (SD 1.4) for those receiving monotherapy and 3.1 (SD 1.6) for those in the methotrexate co-therapy group. The stratified Mann-Whitney estimator was 0.5461 (95% CI 0.4579 to 0.6344). The difference in DAS28 between the 2 treatment arms at week 24 was 0.29. Further, 44% of patients in the methotrexate cohort and 46% of patients in the monotherapy cohort achieved DAS28 remission at week 24.

SAEs were reported in 9% (n = 7) of patients in the monotherapy group and 9% (n = 8) in the co-therapy group.

The study was slightly underpowered, as 173 patients were ultimately included from the original sample size of 196. Investigators also note that the DAS28 does not include the full range of PsA disease activity signs and symptoms. Incorrect stratification may have occurred in those with prior methotrexate exposure who had not been adherent to therapy. Lastly, patients may have been able to determine the blinded treatment due to common methotrexate-related side effects, such as nausea.

“Analyses suggest that ustekinumab remains highly effective in reducing disease symptoms in multiple domains in the presence or absence of concomitant methotrexate,” investigators concluded. “Although methotrexate use at baseline may be an indicator for more severe disease or longer disease duration in some patients, it does not appear to be of benefit when used in combination with ustekinumab for the treatment of psoriatic arthritis. Removing methotrexate from ustekinumab therapy has the potential to reduce patient costs and burden.”

Reference:

Koehm M, Rossmanith T, Foldenauer AC, et al. Methotrexate plus ustekinumab versus ustekinumab monotherapy in patients with active psoriatic arthritis (MUST): a randomised, multicentre, placebo-controlled, phase 3b, non-inferiority trial. The Lancet Rheumatology. 2023;5(1):e14-e23. doi:10.1016/S2665-9913(22)00329-0