title: Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden.
abstract: BACKGROUND
  Autoantibodies have a central role in systemic lupus erythematosus (SLE). The presence of autoantibodies preceding disease onset by years has been reported both in patients with SLE and in those with rheumatoid arthritis, suggesting a gradual development of these diseases. Therefore, we sought to identify autoantibodies in a northern European population predating the onset of symptoms of SLE and their relationship to presenting symptoms.
  
  
  METHODS
  The register of patients fulfilling the American College of Rheumatology criteria for SLE and with a given date of the onset of symptoms was coanalysed with the register of the Medical Biobank, Umeå, Sweden. Thirty-eight patients were identified as having donated blood samples prior to symptom onset. A nested case-control study (1:4) was performed with 152 age- and sex-matched controls identified from within the Medical Biobank register (Umeå, Sweden). Antibodies against anti-Sjögren's syndrome antigen A (Ro/SSA; 52 and 60 kDa), anti-Sjögren's syndrome antigen B, anti-Smith antibody, ribonucleoprotein, scleroderma, anti-histidyl-tRNA synthetase antibody, double-stranded DNA (dsDNA), centromere protein B and histones were analysed using the AtheNA Multi-Lyte ANA II Plus Test System on a Bio-Plex Array Reader (Luminex200). Antinuclear antibodies test II (ANA II) results were analysed using indirect immunofluorescence on human epidermal 2 cells at a sample dilution of 1:100.
  
  
  RESULTS
  Autoantibodies against nuclear antigens were detected a mean (±SD) of 5.6 ± 4.7 years before the onset of symptoms and 8.7 ± 5.6 years before diagnosis in 63% of the individuals who subsequently developed SLE. The sensitivity (45.7%) was highest for ANA II, with a specificity of 95%, followed by anti-dsDNA and anti-Ro/SSA antibodies, both with sensitivities of 20.0% at specificities of 98.7% and 97.4%, respectively. The odds ratios (ORs) for predicting disease were 18.13 for anti-dsDNA (95% confidence interval (95% CI), 3.58 to 91.84) and 11.5 (95% CI, 4.54 to 28.87) for ANA. Anti-Ro/SSA antibodies appeared first at a mean of 6.6 ± 2.5 years prior to symptom onset. The mean number of autoantibodies in prediseased individuals was 1.4, and after disease onset it was 3.1 (P < 0.0005). The time predating disease was shorter and the number of autoantibodies was greater in those individuals with serositis as a presenting symptom in comparison to those with arthritis and skin manifestations as the presenting symptoms.
  
  
  CONCLUSIONS
  Autoantibodies against nuclear antigens were detected in individuals who developed SLE several years before the onset of symptoms and diagnosis. The most sensitive autoantibodies were ANA, Ro/SSA and dsDNA, with the highest predictive OR being for anti-dsDNA antibodies. The first autoantibodies detected were anti-Ro/SSA.
authors.affiliation: Department of Clinical Immunology, Umeå University, SE-90185 Umeå, Sweden.
authors.forename: Catharina
authors.initials: C
authors.lastname: Eriksson
authors.forename: Heidi
authors.initials: H
authors.lastname: Kokkonen
authors.forename: Martin
authors.initials: M
authors.lastname: Johansson
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.forename: Göran
authors.initials: G
authors.lastname: Wadell
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
mesh_terms: D000293:Adolescent; D000328:Adult; D000974:Antibodies, Antinuclear / Q000097:blood* / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D016022:Case-Control Studies; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000175:diagnosis* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012680:Sensitivity and Specificity; D013548:Sweden; D055815:Young Adult
chemical_list: D000974:Antibodies, Antinuclear; D001324:Autoantigens