Network analysis of associations between serum interferon-α activity, autoantibodies, and clinical features in systemic lupus erythematosus

Abstract

Objective: Interferon-α (IFNα) is a primary pathogenic factor in systemic lupus erythematosus (SLE), and high IFNα 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 IFNα 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 IFNα 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 IFNα activity was associated with anti-Ro and anti-double-stranded DNA antibodies (P = 4.6 × 10(-18) and P = 2.9 × 10(-16) , respectively). Younger age, non-European ancestry, and anti-RNP were also independently associated with increased serum IFNα activity (P ≤ 6.7 × 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-IFNα relationships were similar across backgrounds. IFNα activity and autoantibodies were not associated with ACR clinical features in multivariate models.

Conclusion: Our findings indicate that serum IFNα activity is strongly and consistently associated with autoantibodies, and not independently associated with clinical features in SLE. IFNα may be more relevant to humoral tolerance and initial pathogenesis than later clinical disease manifestations.

Figure 1

Serum IFN-α alpha activity in SLE patients stratified by self-reported ancestry. Serum IFN-α activity is represented in relative units on the Y-axis, as described in the Methods. Line is drawn at the median, boxes show the interquartile range, and error bars represent the 90^th and 10^th percentiles respectively. Two-column t-tests and p-value calculations were done using the non-parametric Mann-Whitney U test.

Figure 2

Network diagram showing significant associations between ACR clinical criteria, autoantibodies, and serum IFN-α activity in SLE patients of each ancestral background. A. shows African-American patients, B. shows European-American patients, and C. shows Hispanic-American patients. Each of the boxes indicates the presence of the given feature, and IFN indicates high IFN-α activity, and the odds ratios indicate the direction of the association. Thus, an odds ratio greater than one for an association between “Anti-Ro” and “IFN” means that the presence of anti-Ro antibodies is associated with high IFN-α activity. Connecting lines indicate associations, and arrowheads indicate directionality of the associations (arrowhead touching the box of the outcome variable that is associated with the given predictor variable, most are bidirectional associations). OR = Odds ratio, Photosens. = photosensitivity, anti-DNA = anti-dsDNA