Abstract
Background:Pneumococcal vaccination is recommended for patients with chronic inflammatory rheumatism treated with immunosuppressants. Methotrexate (MTX) is the first-line treatment used in rheumatoid arthritis (RA), but can decrease the immune response of anti-pneumococcal vaccination in RA patients. It is recommended to vaccine before initiation of MTX but it is also recommended to start MTX as soon as the diagnosis of RA is made.Objectives:The main objective of VACIMRA study was then to compare, in the context of a prospective, randomized, multicenter, open trial, the rate of immunological response in RA patients receiving the pneumococcal 13 -valent conjugate vaccine (PCV13) either 1 month before MTX initiation (group DELAY: GD) or simultaneously with MTX (group IMMEDIATE: GI).Methods:RA patients (ACR/EULAR 2010 criteria) were vaccinated with PCV13 at randomization and two months later with 23-valent pneumococcal polysaccharide vaccine (PPV23). Ig G concentrations of the 13 serotypes contained in PCV13 were measured at baseline and during follow-up at 1, 3, 6 and 12 months. After randomization 1:1, MTX was initiated immediately in GI or at one month in GD. Oral steroids were allowed but less than 10mg/day. Disease activity, infections and side effects were collected throughout the study. Outcomes were serotype-specific IgG concentrations of the 13 pneumococcal serotypes contained in PCV13 using ELISA and functional antibody activity using an opsonophagocytic killing assay (OPA), reported as the opsonisation indices (OIs). Positive antibody response was defined as ≥ 2-fold increase in the IgG concentration by ELISA. For OI, response was defined as a value ≥ to the serotype threshold provided by the laboratory. Main outcome was the responder rates at one month after PCV13, defined by at least 3 positives antibody responses out of 5 of the target serotypes (1, 3, 5, 7F, 19A) by ELISA or OPA. The main analysis was performed in the full analysis set (FAS) with a logistic mixed model.Results:276 RA patients were randomized: 188 in GI and 188 in GD. For the primary end point, data of 249 patients were analyzed in FAS and 224 for per protocol (PP). Characteristics of the RA patients at baseline were similar between the two groups: 70% female, mean age 55.6 years, RA duration 2 months, 69% ACPA+, 21% erosive, DAS28-CRP 4.6. Compared to GI, the rates of responders were significantly higher in GD: 88% versus 75% (p<0.01) and 96% versus 88% (p=0.02) by ELISA and OPA respectively, in FAS. These differences were also observed without imputation of missing values in FAS and PP analysis. The proportions of responders at 12 months were still higher in GD with ELISA or OPA tests. Evolution of geometric mean concentrations during the year of follow-up were higher for most of the 13 serotypes in GD compared to GI. The cumulative doses of steroids were similar between GI and GD during the follow-up. As expected, cumulative dose of MTX was higher in GI than in GD during follow-up. However, the weekly mean doses of MTX were similar at 3, 6 and 12 months between the two groups. The use of targeted DMARDs at 1 year was comparable between the two groups. There was no difference in terms of serious adverse events between groups with one pneumococcal infection in the GD during follow-up. There were no unexpected side effects observed with PCV13 and PPV23. At 1 month, DAS28 scores were higher in GD than in GI: 3.95 vs 3.38 for DAS28-ESR and 3.54 vs 3.01 for DAS28-CRP (p<0.01). Beyond the 1st month, DAS28 scores were similar between the two groups.Conclusion:This study clearly demonstrates that in RA, PCV13 vaccine administered 1 month prior starting MTX, allows a significantly higher immunological response at 1 month, in comparison to patients vaccinated simultaneously with MTX. The proportions of responders were also significantly higher in GD at 1 year with no differences on disease control and treatments used for RA such as glucocorticoids or targeted DMARDs. These results strongly support to vaccinate patients before MTX initiation.