ABSTRACT
OBJECTIVE: Autoantibodies to complement factor H (FH) are associated with atypical hemolytic uremic syndrome, but can also be detected in patients with rheumatoid arthritis and in patients positive for lupus anticoagulants and thus potentially antiphospholipid syndrome (APS). To our knowledge, no data are available on the association between the presence of FH autoantibodies in APS and clinical manifestations. METHODS: We determined FH autoantibody levels using ELISA in 2 cohorts of patients with primary (PAPS) and secondary APS (SAPS) from Serbia and Italy, and an additional cohort including patients with venous thromboembolism (VTE) from Sweden. RESULTS: FH autoantibodies were detected in 13.7% of patients (n = 73) with PAPS and 30.3% of patients (n = 33) with SAPS in the Serbian cohort. FH autoantibody frequency in the Italian cohort was 33.3% (n = 15) and 36% (n = 25) in PAPS and SAPS, respectively. Both FH autoantibody levels and frequencies observed in both APS cohorts were significantly higher than in matched healthy controls (5%). Further, patients with PAPS with venous thrombosis in the Serbian cohort had significantly higher levels of FH autoantibodies. Therefore, we analyzed a dedicated Swedish thrombosis cohort and found that patients with FH autoantibody positivity had higher risk of VTE recurrence (HR 2.0, 95% CI 1.2-3.3, p = 0.011) compared with the reference group of FH autoantibody-negative patients. CONCLUSION: Overall, the data indicate that in patients with APS and recurrent venous thrombosis, there are increased levels of FH autoantibodies, a finding associated with poor clinical outcome.
Subject(s)
Antiphospholipid Syndrome/blood , Autoantibodies/blood , Complement Factor H/metabolism , Venous Thrombosis/blood , Adult , Aged , Antiphospholipid Syndrome/physiopathology , Autoantibodies/immunology , Biomarkers/blood , Case-Control Studies , Cohort Studies , Complement Factor H/immunology , Disease Progression , Female , Humans , Italy , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Recurrence , Reference Values , Risk Assessment , Serbia , Severity of Illness Index , Statistics, Nonparametric , Sweden , Venous Thrombosis/physiopathology , Young AdultABSTRACT
INTRODUCTION: Complement activation is involved in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and atypical hemolytic uremic syndrome (aHUS). Autoantibodies to complement inhibitor factor H (FH), particularly in association with deletions of the gene coding for FH-related protein 1 (CFHR1), are associated with aHUS. METHODS: Autoantibodies against FH, factor I (FI) and C4b-binding protein (C4BP) were measured by ELISA, while CFHR1 homozygous deletion was determined with Western blotting of sera. Epitopes for FH autoantibodies were mapped using recombinant fragments of FH. RESULTS: FH autoantibodies were detected in SLE (6.7%, n = 60, RA patients (16.5%, n = 97 in the Swedish cohort and 9.2%, n = 217 in the Dutch cohort) and thrombosis patients positive for the lupus anticoagulants (LA+) test (9.4%, n = 64) compared with aHUS patients (11.7%, n = 103). In the control groups (n = 354), an average of 4% of individuals were positive for FH autoantibodies. The frequencies observed in both RA cohorts and LA+ patients were statistically significantly higher than in controls. We also found that an average of 15.2% of the FH-autoantibody positive individuals in all studied disease groups had homozygous deficiency of CFHR1 compared with 3.8% of the FH autoantibody negative patients. The levels of FH autoantibodies varied in individual patients over time. FH autoantibodies found in LA+, SLE and RA were directed against several epitopes across FH in contrast to those found in aHUS, which bound mainly to the C-terminus. Autoantibodies against FI and C4BP were detected in some patients and controls but they were not associated with any of the diseases analyzed in this study. CONCLUSIONS: Autoantibodies against FH are not specific for aHUS but are present at a significant frequency in rheumatic diseases where they could be involved in pathophysiological mechanisms.
Subject(s)
Atypical Hemolytic Uremic Syndrome/blood , Autoantibodies/blood , Complement C3b Inactivator Proteins/metabolism , Gene Deletion , Rheumatic Diseases/blood , Adolescent , Adult , Aged , Aged, 80 and over , Atypical Hemolytic Uremic Syndrome/diagnosis , Atypical Hemolytic Uremic Syndrome/genetics , Autoantibodies/genetics , Biomarkers/blood , Cohort Studies , Complement C3b Inactivator Proteins/genetics , Complement Factor H/genetics , Complement Factor H/metabolism , Female , HEK293 Cells , Humans , Male , Middle Aged , Rheumatic Diseases/diagnosis , Rheumatic Diseases/genetics , Young AdultABSTRACT
BACKGROUND: Glutamic acid decarboxylase antibodies (GADA) and tyrosine phosphatase antibodies (islet antigen-2 antibodies; IA-2A) are used in clinical practise to identify type 1 diabetes. METHODS: GADA and IA-2A were measured with RSR-ELISA kits in samples from 76 newly diagnosed type 1 diabetic children and 120 healthy controls. The aim was to evaluate performance of RSR-ELISA kits for GADA and IA-2A when serum and Ca2+ treated plasma were used. RESULTS: GADA achieved high area under the curve (AUC) both for serum 0.95 (95% CI 0.90-0.99) and for Ca2+ treated plasma 0.95 (95% CI 0.91-0.99). At specificity 98%, sensitivity was 84% for serum and 87% for Ca2+ treated plasma. IA-2A achieved AUC 0.92 (95% CI 0.87-0.97) for serum and 0.94 (95% CI 0.90-0.98) for Ca2+ treated plasma. Using the lowest standard (15 WHO-Units/ml) as cut-off, specificity for serum was 100% and for Ca2+ treated plasma 99% with sensitivity 74% in both cases. Sensitivity was higher in ELISA compared to RIA (74%; p = 0.0080) for GADA measurement and similar for ELISA and RIA IA-2A measurements (76%; p = 0.50). CONCLUSION: Both RSR-ELISAs, GADA and IA-2A showed excellent performance for serum as well as for Ca2+ treated plasma.
