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Extended report
Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial
  1. Jin Kyun Park1,
  2. Yun Jong Lee2,
  3. Kichul Shin3,
  4. You-Jung Ha2,
  5. Eun Young Lee1,
  6. Yeong Wook Song1,
  7. Yunhee Choi4,
  8. Kevin L Winthrop5,
  9. Eun Bong Lee1
  1. 1 Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
  2. 2 Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Gyeonggi-do, Korea
  3. 3 Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea
  4. 4 Division of Medical Statistics, Medical Research Collaborating Center, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
  5. 5 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, Seoul 03080, Korea; leb7616{at}


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.

  • rheumatoid arthritis
  • methotrexate
  • discontinuation
  • vaccination
  • influenza

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  • Handling editor Josef S Smolen

  • Contributors All authors contributed to the acquisition, analysis or interpretation of data and critical revision of the manuscript for important intellectual content. 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, KLW and JKP were responsible for the study concept and design and drafting of the manuscript. EBL, JKP, YC and KLW were responsible for the statistical analysis.

  • Funding This study was sponsored by GC Pharma (formerly known as Green Cross Corporation) Yongin-si, South Korea. The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the study and final responsibility for the decision to submit for publication.

  • Competing interests EBL has acted as a consultant to Pfizer and received research grants from Green Cross Corporation and Hanmi Pharm.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the institutional review board of the Seoul National University Hospital (IRB 1608-158-787).

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

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