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Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity
  1. Eirik Hornes Halvorsen (eirikhha{at}
  1. Institute of Immunology, University of Oslo, Norway
    1. Sylvie Pollmann (s.m.pollmann{at}
    1. Institute of Immunology, University of Oslo, Norway
      1. Inge-Margrethe Gilboe (inge-margrethe.gilboe{at}
      1. Dept of Rheumatology, Rikshospitalet University Hospital, Oslo, Norway
        1. Désirée van der Heijde (d.vanderheijde{at}
        1. Dept of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
          1. Robert Landewé (rlan{at}
          1. Dept of Rheumatology, University Hospital Maastricht, Maastricht, Netherlands
            1. Sigrid Ødegård (sigrid.odegard{at}
            1. Dept of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway
              1. Tore Kristian Kvien (t.k.kvien{at}
              1. Dept of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway
                1. Øyvind Molberg (oyvind.molberg{at}
                1. Institute of Immunology, University of Oslo, Oslo, Norway


                  Background: Antibodies targeting citrullinated antigens are specific for rheumatoid arthritis (RA). Citrullination is catalyzed 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 auto-antibodies against human recombinant PAD4 (hPAD4) in Caucasian RA patients.

                  Methods: A time-resolved fluorometric immunoassay based on hPAD4 was developed to analyze sera from two RA cohorts (n=237 and n=177), one 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-CCP and 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 HLA-DRB1 variants.

                  Conclusion: 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.

                  • auto-antibodies
                  • citrullination
                  • peptidylarginine deiminase 4
                  • rheumatoid arthritis

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                      Dose-dependent inhibition of serum anti-hPAD4 IgG binding to solid-phase hPAD4 by incubation with liquid-phase hPAD4. Human albumin was used as a control inhibitor. A pool of five anti-hPAD4 positive RA sera diluted 1:2000 in TBS-T was incubated for 1 hour at 37�C with equal volumes of hPAD4 (▲) or human albumin (▼) in increasing concentrations. Serum pools were then applied to the microtiter plate after the blocking of the plate with 1% BSA.
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