Two-week break in methotrexate treatment and COVID-19 vaccine response: a prospective, open label, two-arm parallel-group, multicentre, superiority, randomised controlled trial

Abhishek, Abhishek; Peckham, Nicholas; Pade, Corinna; Gibbons, Joseph M.; Cureton, Lucy; Francis, Anne; Barber, Vicki; Williams, Jennifer A. E.; Appelbe, Duncan; Eldridge, Lucy; Julier, Patrick; Altmann, Daniel M.; Bluett, James; Brooks, Tim; Coates, Laura C.; Rombach, Ines; Semper, Amanda; Otter, Ashley; Valdes, Ana M.; Nguyen-Van-Tam, Jonathan S.; Williams, Hywel C.; Boyton, Rosemary J.; McKnight, Áine; Cook, Jonathan A.; Study investigators, VROOM

Abstract

Background
Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases.
Method
We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early.
Finding
Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227–29 056) in the suspend methotrexate group and 12 326 U/mL (10 538–14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59–2·70; p<0·0001). No intervention-related serious adverse events occurred.
Interpretation
2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19.

Citation

Abhishek, A., Peckham, N., Pade, C., Gibbons, J. M., Cureton, L., Francis, A., …Study investigators, V. (2024). Two-week break in methotrexate treatment and COVID-19 vaccine response: a prospective, open label, two-arm parallel-group, multicentre, superiority, randomised controlled trial. The Lancet Rheumatology, 6(2), E92-E104. https://doi.org/10.1016/S2665-9913%2823%2900298-9

• Journal Article Type: Article
• Acceptance Date: Oct 30, 2023
• Online Publication Date: Dec 12, 2023
• Publication Date: 2024-02
• Deposit Date: Nov 1, 2023
• Publicly Available Date: Dec 12, 2023
• Journal: The Lancet Rheumatology
• Electronic ISSN: 2665-9913
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 2
• Pages: E92-E104
• DOI: https://doi.org/10.1016/S2665-9913%2823%2900298-9
• Public URL: https://nottingham-repository.worktribe.com/output/26803329
• Publisher URL: https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(23)00298-9/fulltext
• Related Public URLs: https://www.sciencedirect.com/science/article/pii/S2665991323002989
• Additional Information: Authors on behalf of the VROOM Study investigators.