Ultrasensitive quantification of serum IFN-α and IFN-γ in systemic lupus erythematosus: A cross-sectional observational study.

BACKGROUND

Interferon (IFN) has been implicated in the pathogenesis of patients with systemic lupus erythematosus (SLE). However, its measurement in serum has been limited by low circulating levels that fall below the detection threshold of standard laboratory assays. In this study, we measured serum levels of IFN-alpha (IFN-α) and IFN-gamma (IFN-γ) using a novel ultrasensitive assay. We then aimed to analyze the relationship between these IFN levels and a broad spectrum of disease characteristics, including indices of disease activity and remission, and autoantibodies profiles.

METHODS AND FINDINGS: From an initial cohort of 400 patients, a total of 313 patients with SLE were recruited in this cross-sectional study from September 2023 to February 2024. A comprehensive characterization of the patients was performed, including autoantibody profiles and indices of disease activity (SLE-DAS, SLEDAI-2K, and LLDAS), damage (SLICC-DI), and remission (DORIS). IFN-α and IFN-γ serum levels were measured using Simoa (Single Molecule Array) technique. A multivariable linear regression analysis was performed to examine the associations between the disease characteristics and circulating IFN-α and IFN-γ as the dependent variables. Besides, the diagnostic capacity of serum IFN levels to discriminate between high and low disease activity was studied using area under the curve analysis and determination of optimal cutoff points. Serum levels of IFN-α and IFN-γ showed a significant, albeit weak, correlation (Pearson's r = 0.369, p < 0.001). Both IFNs exhibited minimal associations with demographic characteristics (such as age, sex, and body mass index) and traditional cardiovascular risk factors (including hypertension, diabetes, dyslipidemia, smoking status, obesity, and metabolic syndrome). After multivariable adjustment, IFN-α-but not IFN-γ-was significantly and positively associated with acute-phase reactants (C-reactive protein and interleukin-6), disease activity indices (SLEDAI-2K, beta coefficient: 0.20 [95% confidence interval 0.09, 0.32] log pg/ml, p < 0.001 and SLE-DAS, beta coefficient: 0.15 [95% confidence interval 0.05, 0.25] log pg/ml, p = 0.003) and the presence of antinuclear antibodies. In contrast, remission (as defined by DORIS) and low disease activity (LLDAS) were negatively and significantly associated with IFN-α levels after adjustment for covariates. However, when attempts were made to define IFN cutoff values to discriminate between active and inactive disease or remission, they exhibited a poor balance between sensitivity and specificity. The cross-sectional design of this study limits our ability to infer causality and raises the possibility of reverse causation.

CONCLUSIONS

In this study, we observed that IFN-α, but not IFN-γ, significantly associates with inflammation, indices of disease activity and remission, and autoantibody status in SLE. Investigating the potential of IFN-α as a biomarker for treatment response and long-term outcomes is warranted.