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Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity
  1. E H Halvorsen1,
  2. S Pollmann1,
  3. I-M Gilboe2,
  4. D van der Heijde3,
  5. R Landewé4,
  6. S Ødegård5,
  7. T K Kvien5,
  8. Ø Molberg2
  1. 1
    Institute of Immunology, University of Oslo, Rikshospitalet University Hospital, Oslo, Norway
  2. 2
    Department of Rheumatology, Rikshospitalet University Hospital, Oslo, Norway
  3. 3
    Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  4. 4
    Department of Internal Medicine, Division of Rheumatology, University Hospital Maastricht, Maastricht, The Netherlands
  5. 5
    Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway
  1. E Hornes Halvorsen, Institute of Immunology, University of Oslo, Rikshospitalet University Hospital, 0027 Oslo, Norway; eirikhha{at}medisin.uio.no

Abstract

Background: Antibodies targeting citrullinated antigens are specific for rheumatoid arthritis (RA). Citrullination is catalysed by the peptidylarginine deiminase (PAD) enzyme family. Critical enzymes are often targeted by disease-specific antibodies in complex immune-mediated diseases. Here, we have tested for autoantibodies against human recombinant PAD4 (hPAD4) in Caucasian RA patients.

Methods: A time-resolved fluorometric immunoassay based on hPAD4 was developed to analyse sera from two RA cohorts (n = 237 and n = 177), one systemic lupus erythaematosus (SLE) cohort (n = 84) and 148 healthy controls. Simple and multiple analyses were performed to examine possible associations between anti-hPAD4 and disease variables.

Results: Raised levels of anti-hPAD4 IgG were found in both RA cohorts compared to the controls, and 23% of the RA patients were anti-hPAD4 IgG positive. Anti-hPAD4 was associated with anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF), as well as increased physical disability. Anti-hPAD4 was also associated with higher longitudinal radiographic damage scores and increased clinical joint pathology, but weaker than anti-CCP. No associations were found between anti-hPAD4 and selected Human leukocyte antigen (HLA)-DRB1 variants.

Conclusions: Approximately 23% of Caucasian RA patients have serum IgG antibodies against hPAD4.The presence of serum anti-hPAD4 IgG was in simple analyses associated with a more severe disease phenotype, and the association with physical disability was maintained in multiple analyses.

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Footnotes

  • Additional data are published online only at http://ard.bmj.com/content/vol67/issue3

  • Funding: This work was supported by grants from Rikshospitalet University Hospital and the Research Council of Norway. EHH was financed by a PhD stipend from the University of Oslo

  • Competing interests: None.

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