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Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial
  1. Jin Kyun Park1,
  2. Min Ah Lee1,
  3. Eun Young Lee1,
  4. Yeong Wook Song1,
  5. Yunhee Choi2,
  6. Kevin L Winthrop3,
  7. Eun Bong Lee1
  1. 1 Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
  2. 2 Division of Medical Statistics, Medical Research Collaborating Center, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
  3. 3 Division of Infectious Diseases, Oregon Health and Science University, Portland, Oregon, USA
  1. Correspondence to Dr Eun Bong Lee, Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea; leb7616{at}


Objective To investigate whether temporary discontinuation of methotrexate (MTX) improves the efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis (RA).

Methods In this prospective randomised parallel-group trial, patients with RA taking stable dose of MTX were randomly assigned at a ratio of 1:1:1:1 to continue MTX (group 1), suspend MTX for 4 weeks before vaccination (group 2), suspend MTX for 2 weeks before and 2 weeks after vaccination (group 3) or suspend MTX for 4 weeks after vaccination (group 4). All participants were vaccinated with trivalent influenza vaccine containing H1N1, H3N2 and B-Yamagata. The primary outcome was frequency of satisfactory vaccine response (≥4-fold titre increase 4 weeks postvaccination). Secondary endpoints included fold change in antibody titres from baseline.

Results The per-protocol population consisted of 199 patients (n=54, 44, 49 and 52 in groups 1, 2, 3 and 4, respectively). Group 3 achieved higher satisfactory vaccine response against all three antigens than group 1 (51.0% vs 31.5%, p=0.044). The anti-H3N2 antibody fold increase (95% CI) was significantly higher in groups 3 and 4 (12.2 (8.4 to 17.5), p <0.001 and 10.0 (6.8 to 14.8), p=0.043, respectively) than group 1 (5.9 (4.3 to 8.1)). The anti-B-Yamagata antibody responses of groups 3 and 4 were higher (4.7 (3.3 to 6.7), p=0.048; 6.1 (4.2 to 8.8), p <0.001, respectively) than group 1 (2.9 (2.2 to 3.8)). RA flare occurred in 24.1%, 21.2%, 34.1% and 38.8% in groups 1, 2, 3 and 4, respectively (p=NS).

Conclusions Temporary MTX discontinuation improves the immunogenicity of seasonal influenza vaccination in patients with RA.

Trial registration Trial registration number is:, NCT02748785.

  • rheumatoid arthritis
  • methotrexate
  • vaccination
  • influenza.

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  • Contributors EBL had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. EBL and JKP: study concept and design. JKP, MAL, EYL, YC, YWS, KLW and EBL: acquisition, analysis or interpretation of data. EBL, KLW and JKP: drafting of the manuscript. JKP, KHL, EYL, YWS, YC, KW and EBL: critical revision of the manuscript for important intellectual content. EBL, JKP, YC and KLW: statistical analysis. EBL: obtained funding, study supervision.

  • Funding This research was partly supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2016R1D1A1A02937044).

  • Competing interests EBL has acted as a consultant to Pfizer. The other authors declare no conflicts of interest.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the institutional review board of the Seoul National University Hospital [IRB 1508-050-694] and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent.

  • Provenance and peer review Not commissioned; externally peer reviewed.