Objective. Interferon-␣ (IFN␣) is a primary pathogenic factor in systemic lupus erythematosus (SLE), and high IFN␣ 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␣ 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␣ 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␣ activity was associated with anti-Ro and anti-doublestranded 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 IFN␣ 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-IFN␣ relationships were similar across backgrounds. IFN␣ activity and autoantibodies were not associated with ACR clinical features in multivariate models.Conclusion. Our findings indicate that serum IFN␣ activity is strongly and consistently associated with autoantibodies, and not independently associated with clinical features in SLE. IFN␣ may be more relevant to humoral tolerance and initial pathogenesis than later clinical disease manifestations.

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Increased IFN-α signaling is a heritable risk factor for systemic lupus erythematosus (SLE). IFN induced with helicase C domain 1 (IFIH1) is a cytoplasmic dsRNA sensor that activates IFN-α pathway signaling. We studied the impact of the autoimmune-disease–associated IFIH1 rs1990760 (A946T) single nucleotide polymorphism upon IFN-α signaling in SLE patients in vivo. We studied 563 SLE patients (278 African-American, 179 European-American, and 106 Hispanic-American). Logistic regression models were used to detect genetic associations with autoantibody traits, and multiple linear regression was used to analyze IFN-α–induced gene expression in PBMCs in the context of serum IFN-α in the same blood sample. We found that the rs1990760 T allele was associated with anti-dsDNA Abs across all of the studied ancestral backgrounds (meta-analysis odds ratio = 1.34, p = 0.026). This allele also was associated with lower serum IFN-α levels in subjects who had anti-dsDNA Abs (p = 0.0026). When we studied simultaneous serum and PBMC samples from SLE patients, we found that the IFIH1 rs1990760 T allele was associated with increased IFN-induced gene expression in PBMCs in response to a given amount of serum IFN-α in anti-dsDNA–positive patients. This effect was independent of the STAT4 genotype, which modulates sensitivity to IFN-α in a similar way. Thus, the IFIH1 rs1990760 Tallele was associated with dsDNA Abs, and in patients with anti-dsDNA Abs this risk allele increased sensitivity to IFN-α signaling. These studies suggest a role for the IFIH1 risk allele in SLE in vivo.

Objective. Interferon-␣ (IFN␣) is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variation near IRF7 is implicated in SLE susceptibility. SLE-associated autoantibodies can stimulate IFN␣ production through the Toll-like receptor/IRF7 pathway. This study was undertaken to determine whether variants of IRF7 act as risk factors for SLE by increasing IFN␣ production and whether autoantibodies are important to this phenomenon.Methods. We studied 492 patients with SLE (236 African American, 162 European American, and 94 Hispanic American subjects). Serum levels of IFN␣ were measured using a reporter cell assay, and singlenucleotide polymorphisms (SNPs) in the IRF7/PHRF1 locus were genotyped.Results. In a joint analysis of European American and Hispanic American subjects, the rs702966 C allele was associated with the presence of anti-doublestranded DNA (anti-dsDNA) antibodies (odds ratio [OR] 1.83, P ‫؍‬ 0.0069). The rs702966 CC genotype was only associated with higher serum levels of IFN␣ in European American and Hispanic American patients with anti-dsDNA antibodies (joint analysis P ‫؍‬ 4.1 ؋ 10 ؊5 in anti-dsDNA-positive patients and P ‫؍‬ 0.99 in anti-dsDNA-negative patients). In African American subjects, anti-Sm antibodies were associated with the rs4963128 SNP near IRF7 (OR 1.95, P ‫؍‬ 0.0017). The rs4963128 CT and TT genotypes were associated with higher serum levels of IFN␣ only in African American patients with anti-Sm antibodies (P ‫؍‬ 0.0012). In African American patients lacking anti-Sm antibodies, an effect of anti-dsDNA-rs702966 C allele interaction on serum levels of IFN␣ was observed, similar to the other patient groups (overall joint analysis P ‫؍‬ 1.0 ؋ 10 ؊6 ). In European American and Hispanic American patients, the IRF5 SLE risk haplotype showed an additive effect with the rs702966 C allele on IFN␣ level in anti-dsDNA-positive patients.Conclusion. Our findings indicate that IRF7/ PHRF1 variants in combination with SLE-associated autoantibodies result in higher serum levels of IFN␣, providing a biologic relevance for this locus at the protein level in human SLE in vivo.Systemic lupus erythematosus (SLE) is characterized by multisystem involvement commonly affecting the skin, renal, musculoskeletal, and hematopoietic systems. SLE is caused by interactions between susceptibility genes and environmental factors, which can include ultraviolet light, infections, and viruses, resulting in an irreversible loss of immunologic self tolerance (1). SLE incidence is highest in women of childbearing age (2); however, people of both sexes and all ages and ethnic backgrounds are susceptible. Disease features range from mild manifestations, such as rash or arthritis, to life-threatening end-organ manifestations, such as glomerulonephritis or thrombosis, and it is difficult to predict which manifestations will affect a given patient.

The SF-6D and EQ-5D exhibited satisfactory psychometric properties for use among US patients with SLE. Measures of disease activity and damage were weakly correlated with HRQOL, suggesting that HRQOL is an important complementary source of information about patients with SLE.