Methotrexate safety and efficacy in combination therapies in patients with early rheumatoid arthritis: A Post Hoc Analysis of a Randomized Controlled Trial

Kristina Lend*, Frieda A Koopman, Jon Lampa, Gerrit Jansen, Merete L Hetland, Till Uhlig, Dan Nordström, Michael Nurmohamed, Bjorn Gudbjornsson, Anna Rudin, Mikkel Østergaard, Marte S Heiberg, Tuulikki Sokka-Isler, Kim Hørslev-Petersen, Espen A Haavardsholm, Gerdur Grondal, Jos W R Twisk, Ronald van Vollenhoven

*Corresponding author for this work

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Abstract

Objective: We investigated methotrexate safety and the influence of dose on efficacy outcomes in combination with three different biologic treatments and with active conventional treatment (ACT) in early rheumatoid arthritis (RA). Methods: This post hoc analysis included 812 treatment-naïve patients with early RA who were randomized (1:1:1:1) in the NORD-STAR trial to receive methotrexate in combination with ACT, certolizumab-pegol, abatacept, or tocilizumab. Methotrexate safety, doses, and dose effects on Clinical Disease Activity Index (CDAI) remission were assessed after 24 weeks of treatment. Results: Compared with ACT, the prevalence of methotrexate-associated side effects was higher when methotrexate was combined with tocilizumab (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.20–1.84) but not with certolizumab-pegol (HR 0.99, 95% CI 0.79–1.23) or with abatacept (HR 0.93, 95% CI 0.75–1.16). With ACT as the reference, the methotrexate dose was significantly lower when used in combination with tocilizumab (β −4.65, 95% CI −5.83 to −3.46; P < 0.001) or abatacept (β −1.15, 95% CI −2.27 to −0.03; P = 0.04), and it was numerically lower in combination with certolizumab-pegol (β −1.07, 95% CI −2.21 to 0.07; P = 0.07). Methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the treatment combinations. Conclusion: Methotrexate was generally well tolerated in combination therapies, but adverse events were a limiting factor in receiving the target dose of 25 mg/wk, and these were more frequent in combination with tocilizumab versus ACT. On the other hand, methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the four treatment combinations at 24 weeks. (Figure presented.).

Original languageEnglish
JournalArthritis & Rheumatology
Volume76
Issue number3
Pages (from-to)363-376
ISSN0004-3591
DOIs
Publication statusPublished - Mar 2024

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