Association between seropositivity and discontinuation of tumor necrosis factor inhibitors due to ineffectiveness in rheumatoid arthritis

  • Yoshikazu OgawaEmail author
  • Nobunori Takahashi
  • Atsushi Kaneko
  • Yuji Hirano
  • Yasuhide Kanayama
  • Yuichiro Yabe
  • Takeshi Oguchi
  • Takayoshi Fujibayashi
  • Hideki Takagi
  • Masahiro Hanabayashi
  • Koji Funahashi
  • Masatoshi Hayashi
  • Seiji Tsuboi
  • Shuji Asai
  • Nobuyuki Asai
  • Takuya Matsumoto
  • Yasumori Sobue
  • Naoki Ishiguro
  • Toshihisa Kojima
Original Article



Discontinuation of biologic therapy in rheumatoid arthritis is attributable to various reasons, with the most important cause being insufficient response. In this study, we investigated the association between rheumatoid factor (RF) and anti-citrullinated protein autoantibody (ACPA) status and the discontinuation of tumor necrosis factor inhibitors (TNFi) therapy due to insufficient response in bio-naïve rheumatoid arthritis (RA) patients.


This study included patients enrolled in the Tsurumai Biologic Communication Registry in Japan. The crude comparison of TNFi discontinuation due to ineffectiveness between seropositive and seronegative patients was analyzed using the cumulative incidence function of competing events and Gray test. We assessed the associations between baseline patient characteristics and discontinuation of TNFi therapy due to insufficient response using Fine-Gray proportional hazard regression. Fine-Gray proportional hazard analysis considered competing events of interest, including insufficient response, adverse event, palliation, and personal reasons.


Of 1237 patients evaluated, 79.3% were positive for RF and 85.4% for ACPA; 72.6% were double positive and 11.1% were double negative. TNFi therapy had been discontinued because of insufficient response at 200 weeks in 19.8% RF-positive, 16.7% RF-negative, 23.0% ACPA-positive, and 13.8% ACPA-negative patients. There was a significantly higher discontinuation rate due to insufficient response in ACPA-positive patients than in ACPA-negative patients using Gray test, with a similar trend as that for RF status. RF positivity was significantly predictive of the discontinuation of TNFi therapy due to ineffectiveness using Fine-Gray proportional hazard regression analysis after adjusting for baseline characteristics, including age, sex, stage, class, disease activity at baseline, methotrexate use, and prednisolone use [hazard ratio 1.73 (95% confidence interval 1.07–2.80)].


Using Fine-Gray proportional hazard regression, we demonstrated that RF positivity was related to a higher discontinuation rate of TNFi therapy due to ineffectiveness in bio-naïve RA patients.

Key Points

• RF positivity is related to a higher discontinuation rate of TNFi therapy due to ineffectiveness.

• ACPA is not predictive of a discontinuation of TNFi therapy due to ineffectiveness.


Biological therapy Rheumatoid factor Tumor necrosis factor Survival analysis 



The authors would like to thank Crimson Interactive Pvt. Ltd. for English proofreading.

Compliance with ethical standards

Conflict of interest

N.T. has received speaking fees from Abbott Japan Co. Ltd., Eisai Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Bristol-Myers Squibb, Abbott Japan, Chugai Pharmaceutical Co. Ltd., and Pfizer Co. Ltd. N.I. has received lecture fees including service on speaker bureaus from Daiichi Sankyo Company Ltd., Takeda Pharmaceutical Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., Kaken Pharmaceutical Co. Ltd., Eisai Co. Ltd., Janssen Pharmaceutical KK, Bristol-Myers Squibb, Abbott Japan, Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharmaceutical, UCB Japan, and Astellas Pharma Inc. T.K. has received lecture fees from Mitsubishi Tanabe Pharma Corporation, Takeda Pharma Corporation, Bristol-Myers Squibb, Abbott Japan, Chugai Pharmaceutical Co. Ltd., and Eisai Pharma Corporation. All other authors have declared no conflicts of interest.


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Copyright information

© International League of Associations for Rheumatology (ILAR) 2019

Authors and Affiliations

  • Yoshikazu Ogawa
    • 1
    Email author
  • Nobunori Takahashi
    • 2
  • Atsushi Kaneko
    • 3
  • Yuji Hirano
    • 4
  • Yasuhide Kanayama
    • 5
  • Yuichiro Yabe
    • 6
  • Takeshi Oguchi
    • 7
  • Takayoshi Fujibayashi
    • 8
  • Hideki Takagi
    • 9
  • Masahiro Hanabayashi
    • 10
  • Koji Funahashi
    • 11
  • Masatoshi Hayashi
    • 12
  • Seiji Tsuboi
    • 13
  • Shuji Asai
    • 2
  • Nobuyuki Asai
    • 2
  • Takuya Matsumoto
    • 2
  • Yasumori Sobue
    • 2
  • Naoki Ishiguro
    • 2
  • Toshihisa Kojima
    • 2
  1. 1.Department of Orthopaedic SurgeryNakatsugawa Municipal General HospitalNakatsugawaJapan
  2. 2.Department of Orthopaedic SurgeryNagoya University Graduate School of MedicineNagoyaJapan
  3. 3.Department of Orthopedic Surgery and RheumatologyNagoya Medical CenterNagoyaJapan
  4. 4.Department of RheumatologyToyohashi Municipal HospitalToyohashiJapan
  5. 5.Department of Orthopedic SurgeryToyota Kosei HospitalToyotaJapan
  6. 6.Department of RheumatologyTokyo Shinjuku Medical CenterTokyoJapan
  7. 7.Department of Orthopedic SurgeryAnjo Kosei HospitalAnjoJapan
  8. 8.Department of Orthopedic SurgeryKonan Kosei HospitalKonanJapan
  9. 9.Department of Orthopedic SurgeryNagoya Central HospitalNagoyaJapan
  10. 10.Department of Orthopedic SurgeryIchinomiya Municipal HospitalIchinomiyaJapan
  11. 11.Department of Orthopedic SurgeryKariya–Toyota General HospitalKariyaJapan
  12. 12.Department of RheumatologyNagano Red Cross HospitalNaganoJapan
  13. 13.Department of Orthopedic SurgeryShizuoka Kosei HospitalShizuokaJapan

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