Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial

Abstract

Objective: To determine whether a 2-week methotrexate (MTX) discontinuation after vaccination improves the efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis (RA).

Methods: In this prospective randomised parallel-group multicentre study, patients with RA on stable dose of MTX were randomly assigned at a ratio of 1:1 to continue MTX or to hold MTX for 2 weeks after 2016-2017 quadrivalent seasonal influenza vaccine containing H1N1, H3N2, B-Yamagata and B-Victoria. The primary outcome was frequency of satisfactory vaccine response, defined as greater than or equal to fourfold increase of haemagglutination inhibition (HI) antibody titre at 4 weeks after vaccination against ≥2 of four vaccine strains. Secondary endpoints included seroprotection (ie, HI titre ≥1:40) rate, fold change in antibody titres.

Results: The modified intention-to-treat population included 156 patients in the MTX-continue group and 160 patients in the MTX-hold group. More patients in MTX-hold group achieved satisfactory vaccine response than the MTX-continue group (75.5% vs 54.5%, p<0.001). Seroprotection rate was higher in the MTX-hold group than the MTX-continue group for all four antigens (H1N1: difference 10.7%, 95% CI 2.0% to 19.3%; H3N2: difference 15.9%, 95% CI 5.9% to 26.0%; B-Yamagata: difference13.7%, 95% CI 5.2% to 22.4%; B-Victoria: difference 14.7%, 95% CI 4.5% to 25.0%). The MTX-hold group showed higher fold increase in their antibody titres against all four influenza antigens (all p<0.05). Change in disease activity was similar between groups.

Conclusions: A temporary MTX discontinuation for 2 weeks after vaccination improves the immunogenicity of seasonal influenza vaccination in patients with RA without increasing RA disease activity.

Trial registration: NCT02897011.

Keywords: discontinuation; influenza; methotrexate; rheumatoid arthritis; vaccination.

Figure 1

Patient flow. MTX, methotrexate; mITT, modified intention-to-treat.

Figure 2

Frequency of vaccination responses to the influenza antigens. Satisfactory vaccine response, defined as greater than or equal to four fold increase of haemagglutination inhibition antibody titre at 4 weeks after vaccination against ≥2 of 4 vaccine strains (A) and against ≥1 of 4, ≥3 of 4 and 4 of 4 vaccine strains (B). Numbers in the bars indicate the percentage of satisfactory responders. Error bar represents 95% CI. P values were generated by Χ² test. MTX, methotrexate.

Figure 3

Impact of baseline methotrexate (MTX) dose on vaccination responses to the influenza antigens. Log-transformed fold change in antibody titre against each vaccine strain relative to baseline was depicted according to the baseline MTX dose per week (mg/week). Bar and whiskers represent mean and SD, respectively. P values were generated by t-test.