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Randomized Controlled Trial
. 2024 Feb;6(2):e92-e104.
doi: 10.1016/S2665-9913(23)00298-9. Epub 2023 Dec 12.

Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial

Abhishek Abhishek  1 , Nicholas Peckham  2 , Corinna Pade  3 , Joseph M Gibbons  3 , Lucy Cureton  2 , Anne Francis  2 , Vicki Barber  2 , Jennifer A E Williams  2 , Duncan Appelbe  2 , Lucy Eldridge  2 , Patrick Julier  2 , Daniel M Altmann  4 , James Bluett  5 , Tim Brooks  6 , Laura C Coates  7 , Ines Rombach  8 , Amanda Semper  6 , Ashley Otter  6 , Ana M Valdes  9 , Jonathan S Nguyen-Van-Tam  10 , Hywel C Williams  10 , Rosemary J Boyton  11 , Áine McKnight  3 , Jonathan A Cook  2 ; VROOM study investigators
Collaborators, Affiliations
Free article
Randomized Controlled Trial

Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial

Abhishek Abhishek et al. Lancet Rheumatol. 2024 Feb.
Free article

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.

Funding: National Institute for Health and Care Research.

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Conflict of interest statement

Declaration of interests The institutions of the authors received funding from the National Institute for Health and Care Research (NIHR)–MRC–Efficacy Mechanism Evaluation (EME) programme (award number NIHR 134607) towards conducting this research. LCC is funded by a NIHR Clinician Scientist award. HW worked for the NIHR between 2015 and 2021. He played no part in the funding decision for this study. LCC has received grants or research support from AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; worked as a paid consultant for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Moonlake, Novartis, Pfizer, and UCB; and has been paid as a speaker for AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Medac, Novartis, Pfizer, and UCB in the past 36 months. JB reports research grants from Pfizer and travel or conference fees from Fresenius Kabi, UCB, Pfizer, and Eli Lilly. AA reports personal payments from UpToDate (royalty), Springer (royalty), Cadilla Pharmaceuticals (lecture fees), NGM Bio (consulting), Limbic (consulting), and Inflazome (consulting), unrelated to the work. JSN-V-T was seconded to the Department of Health and Social Care, England until March 31, 2022. Subsequent to that date, he has received one-off lecture fees from AstraZeneca and Sanofi Pasteur and performed consulting for Janssen, all unrelated to the presented work. He began general paid consulting for Moderna in May 2023. DMA has received honoraria for consultancy work with Novavax, Pfizer, and AstraZeneca. AMK is a shareholder of Raphael Labs. All other authors declare no competing interests.

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