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Shared epitope defines distinct associations of cigarette smoking with levels of anticitrullinated protein antibody and rheumatoid factor
  1. Yuki Ishikawa1,2,
  2. Katsunori Ikari3,
  3. Motomu Hashimoto4,
  4. Koichiro Ohmura5,
  5. Masao Tanaka4,
  6. Hiromu Ito6,
  7. Atsuo Taniguchi7,
  8. Hisashi Yamanaka7,
  9. Tsuneyo Mimori5,
  10. Chikashi Terao2,8
  1. 1 Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
  2. 2 Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
  3. 3 Department of Orthopaedic Surgery, Tokyo Women’s Medical University, Tokyo, Japan
  4. 4 Department of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine Faculty of Medicine, Kyoto, Japan
  5. 5 Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine Faculty of Medicine, Kyoto, Japan
  6. 6 Department of Orthopeadic Surgery, Kyoto University Graduate School of Medicine Faculty of Medicine, Kyoto, Japan
  7. 7 Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan
  8. 8 Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
  1. Correspondence to Dr Chikashi Terao, Laboratory for Statistical and Translational Genetics, Center for Integrative Medical Sciences, Riken, Yokohama 230-0045, Japan; a0001101{at}kuhp.kyoto-u.ac.jp

Abstract

Objects Although the association of cigarette smoking (CS) with susceptibility to rheumatoid arthritis (RA) has been established, the impact of CS on anticitrullinated cyclic peptide/protein antibody (ACPA) and rheumatoid factor (RF) levels in RA has yet been clear, especially in relation to shared epitope (SE) alleles.

Methods A total of 6239 subjects, the largest Asian study ever, from two independent Japanese cohorts were enrolled. Precise smoking histories, levels of ACPA and RF, and HLA-DRB1 allele status were withdrawn from databases. Associations between CS and high ACPA or RF levels, defined by the top quartiles, were evaluated. The effect of HLA-DRB1 alleles on the association was further investigated.

Results CS at RA onset conferred the risks of high levels of both antibodies, especially RF (OR 2.06, p=7.4×10–14; ACPA, OR 1.29, p=0.012), suggesting that RF level is more sensitive to CS than ACPA level. The patients who had quitted CS before RA onset showed a trend of decreased risks of developing high levels of ACPA or RF, and the risks steadily decreased according to the cessation years. The association of CS with high ACPA level was observed only in subjects carrying SE alleles, while the association of high RF level was observed regardless of SE.

Conclusions CS confers the risks of high autoantibody levels in RA in different manners; CS interacts with SE alleles on ACPA level, while CS impacts on RF level despite SE allele. These data suggest novel distinct production mechanisms of RF and ACPA.

  • rheumatoid arthritis
  • rheumatoid factor
  • anti-CCP
  • smoking
  • epidemiology
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Footnotes

  • Handling editor Josef S Smolen

  • Contributorship Statement YI analysed and interpreted data and wrote the manuscript. KI, MH, KO, MT, HI, AT, HY and TM interpreted data and edited the manuscript. CT conceived the project, analysed and interpreted data, and wrote the manuscript.

  • Funding KI received scholarship donations from three pharmaceutical companies (Eisai, Chugai and Eli-Lilly). MH received scholarship donations from three pharmaceutical companies (Astellas, Bristol-Myers Squibb and Eisai). MT received scholarship donations from seven pharmaceutical companies (Pfizer Japan Inc., Astellas, Takeda Pharmaceutical, AbbVie GK Inc., Taisho-Toyama Pharmaceutical, Eisai and Asahi-Kasei). HI received scholarship donations from three pharmaceutical companies (Astellas, Bristol-Myers Squibb and Asahi-Kasei). AT received scholarship donations from two pharmaceutical companies (Eisai and Mitsubishi-Tanabe Pharma). TM received scholarship donations from thirteen pharmaceutical companies (Pfizer Japan Inc., Mitsubishi-Tanabe, Eisai, Astellas, AYUMI, Chugai, Daiichi Sankyo, Nippon Shinyaku, Takeda Pharmaceutical, Eli-Lilly, Asahi-Kasei Pharma, Nippon Kayaku and Sanofi).

  • Competing interests KI received speaker fee from fifteen pharmaceutical companies (Asahi-Kasei Pharma, Astellas Pharma, Abbvie GK Inc., AYUMI, Eisai, Otsuka, Kaken, Takeda, Mitsubishi-Tanabe, Chugai, Eli-Lilly, Bristol-Myers Squibb, Pfizer Japan Inc., Janssen and UCB Japan). MH, HI and MT belong to a department that has been financially supported by four pharmaceutical companies (Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan). TM received personal fees from fourteen pharmaceutical companies (Pfizer Japan Inc., Mitsubishi-Tanabe, Eisai, Astellas, AYUMI, Chugai, Daiichi Sankyo, Nippon Shinyaku, Takeda Pharmaceutical, Eli-Lilly, Asahi-Kasei Pharma, Sanofi, Bristol-Myers Squibb and GlaxoSmithKline). KURAMA cohort study is supported by grant from Daiichi Sankyo Co. Ltd. This study is conducted as investigator initiate study. These companies had no role in the design of the study, the collection or analysis of the data, the writing of the manuscript or decision to submit the manuscript for the publication. IORRA cohort study is supported by grant by twenty pharmaceutical companies (Daiichi Sankyo Co. Ltd., Mitsubishi-Tanabe, Chugai, Bristol-Myers Squibb, AYUMI, Astellas, Pfizer Japan Inc., Takeda Pharmaceutical, Eisai, Nippon Shinyaku, YL Biologics Ltd., AbbVie, Novartis Pharmaceutical K.K., Kaken Pharmaceutical Co., Ltd., UCB Japan, Ono Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Teijin Pharma, Torii Pharmaceutical Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd.). These sponsors were not involved in the: study design; collection, analysis and interpretation of data; writing of the paper; and/or decision to submit for publication.

  • Patient and public involvement statement This research was done without patient involvement. Patients were not invited to comment on the study design and were not consulted to develop patient relevant outcomes or interpret the results. Patients were not invited to contribute to the writing or editing of this document for readability or accuracy.

  • Patient consent for publication Not required.

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

  • Data availability statement Individual-level deidentified patient data, survey results, interview transcripts, statistical code and spreadsheets would be available from Chikashi Terao (ORCID 0000-0002-6452-4095) at any time only on reasonable request. There is no additional information available.

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