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Identification of anticitrullinated protein antibody reactivities in a subset of anti-CCP-negative rheumatoid arthritis: association with cigarette smoking and HLA-DRB1 'shared epitope' alleles.

AbstractINTRODUCTION:
A hallmark of rheumatoid arthritis (RA) is the development of autoantibodies targeting proteins that contain citrulline. Anticitrullinated protein antibodies (ACPAs) are currently detected by the commercial cyclic citrullinated peptide (CCP) assay, which uses a mix of cyclised citrullinated peptides as an artificial mimic of the true antigen(s). To increase the sensitivity of ACPA detection and dissect ACPA specificities, we developed a multiplex assay that profiles ACPAs by measuring their reactivity to the citrullinated peptides and proteins derived from RA joint tissue.
METHODS:
We created a bead-based, citrullinated antigen array to profile ACPAs. This custom array contains 16 citrullinated peptides and proteins detected in RA synovial tissues. We used the array to profile ACPAs in sera from a cohort of patients with RA and other non-inflammatory arthritides, as well as sera from an independent cohort of RA patients for whom data were available on carriage of HLA-DRB1 'shared epitope' (SE) alleles and history of cigarette smoking.
RESULTS:
Our multiplex assay showed that at least 10% of RA patients who tested negative in the commercial CCP assay possessed ACPAs. Carriage of HLA-DRB1 SE alleles and a history of cigarette smoking were associated with an increase in ACPA reactivity-in anti-CCP(+) RA and in a subset of anti-CCP(-) RA.
CONCLUSIONS:
Our multiplex assay can identify ACPA-positive RA patients missed by the commercial CCP assay, thus enabling greater diagnostic sensitivity. Further, our findings suggest that cigarette smoking and possession of HLA-DRB1 SE alleles contribute to the development of ACPAs in anti-CCP(-) RA.
AuthorsCatriona A Wagner, Jeremy Sokolove, Lauren J Lahey, Camilla Bengtsson, Saedis Saevarsdottir, Lars Alfredsson, Michelle Delanoy, Tamsin M Lindstrom, Roger P Walker, Reuven Bromberg, Piyanka E Chandra, Steven R Binder, Lars Klareskog, William H Robinson
JournalAnnals of the rheumatic diseases (Ann Rheum Dis) Vol. 74 Issue 3 Pg. 579-86 (Mar 2015) ISSN: 1468-2060 [Electronic] England
PMID24297382 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightPublished by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Chemical References
  • Autoantibodies
  • Autoantigens
  • Epitopes
  • HLA-DRB1 Chains
  • Peptides
  • Peptides, Cyclic
  • cyclic citrullinated peptide
  • Citrulline
Topics
  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Arthritis, Psoriatic (immunology)
  • Arthritis, Rheumatoid (immunology)
  • Autoantibodies (immunology)
  • Autoantigens (immunology)
  • Case-Control Studies
  • Citrulline (immunology)
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes (genetics)
  • Female
  • Gout (immunology)
  • HLA-DRB1 Chains (genetics)
  • Humans
  • Lupus Erythematosus, Systemic (immunology)
  • Male
  • Middle Aged
  • Peptides (immunology)
  • Peptides, Cyclic (immunology)
  • Smoking (immunology)
  • Young Adult

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