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Differences in the symptomatic phase preceding ACPA-positive and ACPA-negative RA: a longitudinal study in arthralgia during progression to clinical arthritis
  1. Leonie E Burgers,
  2. Hanna W van Steenbergen,
  3. Robin M ten Brinck,
  4. Tom WJ Huizinga,
  5. Annette HM van der Helm-van Mil
  1. Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Leonie E Burgers, Department of Rheumatology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands; l.e.burgers{at}


Objective Although anticitrullinated protein antibody (ACPA)-positive and ACPA-negative rheumatoid arthritis (RA) have different aetiopathology, the clinical presentation at the time of diagnosis is similar. This study evaluated whether there are phenotypic differences in the symptomatic pre-RA phase.

Methods Patients with arthralgia included in the Leiden clinically suspect arthralgia cohort who developed arthritis during follow-up were studied (n=67). Symptoms at symptom onset, symptoms and signs at presentation with arthralgia and time to arthritis development were compared between ACPA-positive and ACPA-negative patients.

Results In ACPA-negative patients (n=37), the location of initial symptoms less often included the lower extremities (22% vs 50%, p=0.014). At presentation with arthralgia, ACPA-positive patients had a longer symptom duration (median 22 vs 14 weeks, p=0.005), less tender joints (mean 5 vs 9, p=0.007) and less difficulty making a fist (11% vs 43%, p=0.004). However, after presentation with arthralgia, ACPA-positive patients developed arthritis more quickly (median 6 vs 18 weeks, p=0.015). A partial least squares regression analysis showed clustering of ACPA-positive and ACPA-negative patients based on the above-mentioned clinical variables.

Conclusion This study is the first showing that ACPA-positive and ACPA-negative patients have clinical differences in the symptomatic phase preceding clinical arthritis. This contributes to the notion that ACPA-positive and ACPA-negative RA develop differently.

  • early rheumatoid arthritis
  • arthritis
  • anti-CCP
  • autoantibodies

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  • Contributors All authors contributed to the design of the study, the interpretation of the results and gave feedback on the manuscript. All authors approved the final version and agreed to be accountable for all aspects of the work. HWvS, RMtB and LEB contributed to the acquistion of data. LEB analysed the data. LEB and AvdH-vM drafted the manuscript.

  • Funding The research leading to these results was funded by a Vidi-grant of the Netherlands Organisation for Scientific Research, a grant of the Dutch Arthritis Foundation, a grant of the Dutch Organization of Health Research and the FP7 grant TEAM.

  • Competing interests None declared.

  • Ethics approval Local medical ethical committee Leiden University Medical Center.

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