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., Barber, V., Williams, J. A. E., Appelbe, D., Eldridge, L., Julier, P., Altmann, D. M., Bluett, J., Brooks, T., Coates, L. C., Rombach, I., Semper, A., Otter, A., Valdes, A. M., Nguyen-Van-Tam, J. S., …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.