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Anti-cyclic citrullinated peptide antibody and pain sensitisation in patients with rheumatoid arthritis: a cross-sectional analysis
  1. Yoon Y Qiu1,
  2. Tuhina Neogi2,
  3. Lutfiyya N Muhammad3,
  4. Jing Song3,
  5. Marcy B Bolster4,
  6. Wendy Marder5,
  7. Andrew C Heisler6,
  8. Alyssa Wohlfahrt7,
  9. Dorothy Dunlop8,
  10. Yvonne C Lee3,8
  1. 1 Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
  2. 2 Clinical Epidemiology Research and Training Uni, Boston University School of Medicine, Boston, Massachusetts, USA
  3. 3 Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  4. 4 Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  5. 5 Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  6. 6 Medicine, Western Michigan University, Kalamazoo, Michigan, USA
  7. 7 Tufts University School of Medicine, Boston, Massachusetts, USA
  8. 8 Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  1. Correspondence to Dr Yvonne C Lee, Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA; yvonne.lee{at}

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Pain and inflammation are often discordant among patients with rheumatoid arthritis (RA). In a mouse model, systemic injection of polyclonal autoantibodies against citrullinated proteins (ACPA) induced pain-like behaviours.1 A recent study also suggested that specific monoclonal ACPAs may be responsible for tenosynovitis and pain behaviours in mice.2 Given these findings, our goal was to examine the association between a subset of ACPA, anti-cyclic citrullinated peptides (anti-CCP) and pain in humans with RA.

Patients with active RA were enrolled in the Central Pain in RA study. Anti-CCP positivity was categorised as positive/negative and into quantiles . Experimental measures of peripheral sensitivity were pressure pain thresholds (PPTs) at the wrists and knees. Measures of central sensitivity were PPT at the trapezius muscles, PPT at the thumbnails, temporal summation (TS) and conditioned pain modulation (CPM). Patient-reported measures included pain intensity on a Numeric Rating Scale and pain interference assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) computerised adaptive test. Associations between anti-CCP positivity and pain were examined using multiple linear regression and linear trend tests. Exploratory subgroup analyses were performed, stratified by sex, high sensitivity C-reactive protein (hsCRP) (≤ or >3 mg/L) and swollen joint count (SJC ≤or >1) (see online supplemental materials).

Supplemental material


Among the 255 participants, 159 (62.4%) were positive for anti-CCP antibody. Mean (SD) DAS-28 score was 4.4 (1.2) (online supplemental table 1). Comparing …

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  • Handling editor Josef S Smolen

  • Twitter @Lee_Yvonne_C

  • Contributors YYQ, TN and YCL conceived the design of this study. TN, MBB, WM, AW and YCL participated in acquisition of data. LNM, JS and DD contributed to the analysis of data. YYQ and YCL drafted the manuscript. All authors contributed to data interpretation, revised the manuscript for intellectual content, and provided final approval of the version to be published.

  • Funding This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health (R01 AR064850; K24AR 080840, P30 AR072579 to YCL, LNM, JS; K24 AR070892, P30 AR072571 to TN), and the Rheumatology Research Foundation Resident Research Preceptorship (award number N/A) to YYQ.

  • Competing interests TN discloses consulting fees from Novartis, Pfizer, Lilly and Regeneron. JS discloses grant support from the NIH/NIAMS and Rheumatology Research Foundation. MBB discloses grant support from the Rheumatology Research Foundation, Mitsubishi, Corbus, Cumberland and Genentech, honorarium from Elsevier/Practice Update, participation on a data safety monitoring board for Novartis, leadership roles in the American College of Rheumatology and American Board of Internal Medicine, and stock in Johnson and Johnson. YCL discloses grant support from the NIH/NIAMS and Rheumatology Research Foundation, and Pfizer, stock ownership in Cigna-Express Scripts, and receipt of medical writing services from Eli Lilly and Sanofi Genzyme. The remainder of the authors have no relevant competing interests.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.