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Factors associated with progression to inflammatory arthritis in first-degree relatives of individuals with RA following autoantibody positive screening in a non-clinical setting
  1. Elizabeth A Bemis1,
  2. M Kristen Demoruelle2,
  3. Jennifer A Seifert1,2,
  4. Kristen J Polinski1,
  5. Michael H Weisman3,
  6. Jane H Buckner4,
  7. Peter K Gregersen5,
  8. Ted R Mikuls6,7,
  9. James R ODell6,7,
  10. Richard M Keating8,
  11. Kevin D Deane2,
  12. V Michael Holers2,
  13. Jill M Norris1
  1. 1 Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA
  2. 2 Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, Colorado, USA
  3. 3 Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA
  4. 4 Department of Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
  5. 5 Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA
  6. 6 Division of Rheumatology, University of Nebraska Medical Center, Omaha, Nebraska, USA
  7. 7 Division of Rheumatology, Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
  8. 8 Division of Rheumatology, Scripps Clinic/Scripps Green Hospital, San Diego, California, USA
  1. Correspondence to Dr Jill M Norris, Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA; jill.norris{at}


Objectives Little is known about the likelihood of developing inflammatory arthritis (IA) in individuals who screen autoantibody positive (aAb+) in a non-clinical research setting.

Methods We screened for serum cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor isotype aAbs in subjects who were at increased risk for rheumatoid arthritis (RA) because they are a first-degree relative of an individual with classified RA (n=1780). We evaluated combinations of aAbs and high titre aAbs, as defined by 2-times (2 x) the standard cut-off and an optimal cut-off, as predictors of our two outcomes, aAb+ persistence and incident IA.

Results 304 subjects (17.1%) tested aAb+; of those, 131 were IA-free and had at least one follow-up visit. Sixty-four per cent of these tested aAb+ again on their next visit. Anti-CCP+ at levels ≥2 x the standard cut-off was associated with 13-fold higher likelihood of aAb +persistence. During a median of 4.4 years (IQR: 2.2–7.2), 20 subjects (15.3%) developed IA. Among subjects that screened anti-CCP+ at ≥ 2 x or ≥an optimal cut-off, 32% and 26% had developed IA within 5 years, respectively. Both anti-CCP cut-offs conferred an approximate fourfold increased risk of future IA (HR 4.09 and HR 3.95, p<0.01).

Conclusions These findings support that aAb screening in a non-clinical setting can identify RA-related aAb+ individuals, as well as levels and combinations of aAbs that are associated with higher risk for future IA. Monitoring for the development of IA in aAb+ individuals and similar aAb testing approaches in at-risk populations may identify candidates for prevention studies in RA.

  • rheumatoid arthritis
  • synovitis
  • ant-CCP
  • rheumatoid factor
  • epidemiology

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  • Handling editor Josef S Smolen

  • Presented at This work was previously presented at 2019 American College of Rheumatology/Association of Rheumatology Professionals Annual Meeting. Abstract available at (accessed 2 Dec 2019).

  • Contributors All authors contributed to drafting or critically revising the article for intellectual content and approved the final version of the article. EAB had access to all data and analyses. Study conception and design: JMN and VMH. Acquisition of data: VMH, JMN, KDD, MKD, MHW, JRO, TRM, JAS, JHB, PKG and RK. Analysis and interpretation of data: EAB, JMN, KDD, KP and VMH.

  • Funding This work is supported by the NIH Autoimmunity Prevention Center U19 AI050864 and U01 AI101981; the NIH (grants R01 AR051394, M01 RR00069, M01 RR00425, K23 AR051461, and T32 AR007534); the General Clinical Research Centers Program, National Center for Research Resources, NIH; National Center for Research Resources (grant UL1RR033176), now the National Center for Advancing Translational Sciences (grant UL1TR000124), the Walter S. and Lucienne Driskill Foundation, the Research Support Fund grant from the Nebraska Medical Center, and the University of Nebraska Medical Center.

  • Competing interests MKD reports grants from Pfizer, outside the submitted work; JHB reports grants from NIH, during the conduct of the study; in addition, JHB reports grants from Jannsen and from BMS, outside the submitted work; PKG reports grants from NIH, during the conduct of the study; KDD reports non-financial support from Inova Diagnostic, outside the submitted work; in addition, KDD has a patent on biomarkers in rheumatoid arthritis with royalties paid; VMH reports grants from NIH, a grant from Pfizer, and grants and personal fees from Janssen Research and Development and personal fees from Celgene, all outside of the submitted work. JMN reports a grant from Pfizer, outside the submitted work; in addition, JMN reports grants from NIH, during the conduct of the study.

  • 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.

  • Patient consent for publication Not required.

  • Ethics approval The study protocol was approved by the following institutional review boards (IRBs) at each SERA site: Colorado Multiple IRB, University of Nebraska Medical Center IRB, Benaroya Research Institute at Virginia Mason IRB, Cedars-Sinai Medical Center’s IRB, North Shore-LIJ IRB and the Chicago Biomedicine IRB.

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

  • Data availability statement Data are available on reasonable request.