title: Rheumatoid factor isotypes in relation to antibodies against citrullinated peptides and carbamylated proteins before the onset of rheumatoid arthritis.
abstract: BACKGROUND
  The presence of rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and antibodies against citrullinated protein and peptides (ACPA) precedes the onset of symptoms of rheumatoid arthritis (RA) by several years. Relationships between the development of these antibodies are not obvious.
  
  
  METHODS
  Three isotypes [immunoglobulin A (IgA), IgG and IgM) of RF were analysed in 321 pre-symptomatic individuals who provided 598 samples collected a median of 6.2 (interquartile range 7.2) years before the onset of symptoms, and in 492 population control subjects. All samples were donated to the Biobank of Northern Sweden. RF isotypes were analysed using the EliA system (Phadia GmbH, Freiburg, Germany) with 96 % specificity according to receiver operating characteristic curves. Ten ACPA specificities were analysed using the ImmunoCAP ISAC system, and anti-CCP2 and anti-CarP antibodies were evaluated using enzyme-linked immunosorbent assays.
  
  
  RESULTS
  The frequencies of RF isotypes in pre-symptomatic individuals were significantly increased compared with control subjects (p < 0.0001). In samples collected ≥15 years before the onset of symptoms, the IgA-RF isotype was significantly more prevalent than the most frequent ACPAs. Combinations of IgM- and IgA-RF isotypes with ACPA specificities [α-enolase (CEP-1/Eno5-21)], fibrinogen (Fib)β36-52, Fibα580-600, filaggrin (CCP-1/Fil307-324) and anti-CCP2 antibodies were associated with a significantly shorter time to onset of symptoms (p < 0.001-0.05). Using conditional inference tree analysis, anti-CCP2 in combination with anti-filaggrin antibodies gave the highest probability, 97.5 %, for disease development.
  
  
  CONCLUSIONS
  RF isotypes predicted the development of RA, particularly in combination with ACPA, anti-CCP2 or anti-CarP antibodies. The highest probability for disease development was the presence of anti-CCP2 and anti-filaggrin antibodies.
authors: Division of Rheumatology, Department of Public Health and Clinical Medicine, Umeå University, SE-90185, Umeå, Sweden. mikael.brink@umu.se.
authors: Mikael
authors: M
authors: Brink
authors: Rheumatology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden. monika.hansson@ki.se.
authors: Monika
authors: M
authors: Hansson
authors: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. linda.mathsson-alm@thermofisher.com.|Thermo Fisher Scientific, Uppsala, Sweden. linda.mathsson-alm@thermofisher.com.
authors: Linda
authors: L
authors: Mathsson-Alm
authors: Department of Statistics, Umeå University, Umeå, Sweden. priyantha.wijayatunga@stat.umu.se.
authors: Priyantha
authors: P
authors: Wijayatunga
authors: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands. m.k.verheul@lumc.nl.
authors: Marije K
authors: MK
authors: Verheul
authors: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands. l.a.trouw@lumc.nl.
authors: Leendert A
authors: LA
authors: Trouw
authors: Medical Inflammation Research, Medical Biophysics and Biochemistry, Karolinska Institute, Solna, Stockholm, Sweden. rikard.holmdahl@ki.se.
authors: Rikard
authors: R
authors: Holmdahl
authors: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. johan.ronnelid@igp.uu.se.
authors: Johan
authors: J
authors: Rönnelid
authors: Rheumatology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden. lars.klareskog@ki.se.
authors: Lars
authors: L
authors: Klareskog
authors: Division of Rheumatology, Department of Public Health and Clinical Medicine, Umeå University, SE-90185, Umeå, Sweden. solbritt.rantapaa.dahlqvist@umu.se.
authors: Solbritt
authors: S
authors: Rantapää-Dahlqvist
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000175:diagnosis; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002956:Citrulline / Q000097:blood*; D015331:Cohort Studies; D005260:Female; D000091344:Filaggrin Proteins; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000097:blood*; D012217:Rheumatoid Factor / Q000097:blood*
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007132:Immunoglobulin Isotypes; D010456:Peptides, Cyclic; D002956:Citrulline; D012217:Rheumatoid Factor