Effect of a 1-month methotrexate delay on pneumococcal vaccine immunogenicity and disease control in patients with early rheumatoid arthritis (VACIMRA): an open-label randomised trial

Abstract

Background: Pneumococcal vaccination is recommended for patients with rheumatoid arthritis. Because immunosuppressant therapies for rheumatoid arthritis hinder vaccine efficacy, vaccination should be administered before initiating immunosuppressive drugs. We aimed to compare humoral responses in patients with rheumatoid arthritis receiving the pneumococcal 13-valent conjugate vaccine (PCV13) before methotrexate initiation or simultaneously.

Methods: In this randomised, multicentre, open-label trial, patients were recruited from 26 rheumatology departments in 22 university hospitals and four general hospitals in France. Adult patients (aged 18-80 years) with active rheumatoid arthritis (Disease Activity Score in 28 joints >3·2), who were naive to targeted disease-modifying anti rheumatic drugs (DMARDs), had not had methotrexate or leflunomide in the past 3 months, and had no previous pneumococcal vaccinations were included. Patients were excluded in case of treatment with methotrexate or with leflunomide within the previous 3 months and absolute or relative contraindications to methotrexate. Patients were vaccinated with PCV13 at randomisation, before being randomly assigned (1:1) to either the immediate group (methotrexate treatment [maximum dose 15 mg per week] initiated at the same time as PCV13 vaccine) or the delay group (methotrexate initiated 1 month after PCV13 vaccine). Randomisation was stratified by sex (self-reported) and DMARD naive status. 2 months later, patients in both groups were vaccinated with the 23-valent pneumococcal polysaccharide vaccine. Humoral responses, disease activity, infections, and adverse events were assessed at baseline and at 1, 3, 6, and 12 months after PCV13. The primary outcome was the responder rate at 1 month, defined by positive responses against at least three of five target serotypes (ie, 1, 3, 5, 7F, and 19A). Responders were defined according to a 2 or more-fold increase in IgG concentrations with ELISA or opsonophagocytic assay compared with baseline. The main analysis was performed in the modified intention-to-treat population, including all randomly assigned patients with a valid measure of the primary endpoint, analysed in their assigned group. There was no involvement of people with lived experience in the study design or implementation. The trial was registered at ClinicalTrials.gov (NCT01942174) and is completed.

Findings: Between Sept 27, 2013, and Oct 10, 2019, 276 patients with rheumatoid arthritis were randomly assigned. 27 patients were excluded, of whom four patients dropped out, and 249 patients were included in the modified intention-to-treat population (126 [51%] in the delay group and 123 [49%] in the immediate group). 174 (70%) patients were female and 75 (30%) were male, the mean age at enrolment was 55·6 years (SD 14·8). Responder rates were higher in the delay group compared with the immediate group for IgG concentrations (relative risk 1·46 [95% CI 1·10-1·92]; p=0·02) and for opsonophagocytic assay activity (1·65 [1·25-2·19]; p=0·01), adjusted for sex and true DMARD naive status. At 12 months, antibody functional activity was significantly higher for eight of 13 serotypes in the delay group. Cumulative doses of corticosteroids and the number of patients who had targeted DMARDs were similar between groups throughout. 72 (11%) of 649 adverse events were serious (including one vaccine-related serious adverse event) in both groups and were equally frequent between groups, and the rheumatoid arthritis disease activity score remained comparable during follow-up.

Interpretation: In patients with early rheumatoid arthritis, the PCV13 vaccine administered 1 month before methotrexate allowed for improved immunological responses without significant effect on disease control during one year of follow-up. Future steps are to confirm these results with PCV20 or PCV21 and assess the best time frame for the booster vaccine.

Funding: Government of France and Pfizer.

Translation: For the French translation of the abstract see Supplementary Materials section.