Network Analysis of Associations Between Serum Interferon-α Activity, Autoantibodies, and Clinical Features in Systemic Lupus Erythematosus

Objective. Interferon-alpha (IFN alpha) is a primary pathogenic factor in systemic lupus erythematosus (SLE), and high IFN alpha levels may be associated with particular clinical manifestations. The prevalence of individual clinical and serologic features differs significantly by ancestry. This study was undertaken to detect associations between clinical and serologic disease manifestations and serum IFN alpha activity in a large diverse SLE cohort, using multivariate and network analyses. Methods. We studied 1,089 SLE patients (387 African American, 186 Hispanic American, and 516 European American patients). The presence or absence of individual American College of Rheumatology (ACR) clinical criteria for SLE, autoantibodies, and serum IFN alpha activity data were analyzed in univariate and multivariate models. Iterative multivariate logistic regression was performed in each ancestral background group separately to establish the network of associations between variables that were independently significant following Bonferroni correction. Results. In all ancestral backgrounds, high IFN alpha activity was associated with anti-Ro and anti-doublestranded DNA antibodies (P = 4.6 x 10(-18) and P = 2.9 x 10(-16), respectively). Younger age, non-European ancestry, and anti-RNP were also independently associated with increased serum IFN alpha activity (P <= 6.7 x 10(-4)). We found 14 unique associations between variables in network analysis, and only 7 of these associations were shared among > 1 ancestral background. Associations between clinical criteria were different for different ancestral backgrounds, while autoantibody-IFN alpha relationships were similar across backgrounds. IFN alpha activity and autoantibodies were not associated with ACR clinical features in multivariate models. Conclusion. Our findings indicate that serum IFN alpha activity is strongly and consistently associated with autoantibodies, and not independently associated with clinical features in SLE. IFN alpha may be more relevant to humoral tolerance and initial pathogenesis than later clinical disease manifestations.