IFN-λ1 with Th17 axis cytokines and IFN-α define different subsets in systemic lupus erythematosus (SLE)

Background: Interferon (IFN)-alpha is thought to have a pivotal role in systemic lupus erythematosus (SLE), and type III IFNs (IFN-lambda) were recently also associated with SLE. In this study, we measured levels of IFN-alpha, IFN-lambda 1, and related cytokines, such as IL-17A, IL-23, and interferon-gamma-induced protein 10 (IP-10), in a Karolinska University Hospital cohort of patients with SLE and control subjects. The objective of the study was to investigate if cytokine measurements could identify different subsets of patients with active SLE and higher disease damage. Methods: We included 261 patients with SLE and 261 population control subjects. All participants underwent a standardized clinical examination. Medical files were reviewed. Patients with SLE were assessed for current organ manifestations, disease activity, and damage. Routine blood parameters, complement levels, and serology were analyzed at the time of inclusion. Levels of IFN-lambda 1, IFN-alpha, IL-17A, IL-23, and IP-10 were measured by enzyme-linked immunosorbent assay. Results: IFN-lambda 1 and IFN-alpha were detected in 29% and 44% of patients, respectively, but their levels did not correlate. High serum levels of IFN-lambda 1 were positively associated with antinucleosome antibodies and lymphopenia but negatively with musculoskeletal damage. Positive correlations between levels of IFN-lambda 1, IL-17A, and IL-23 were observed. Patients with high levels of these three cytokines had more disease damage, especially renal impairment. High levels of IFN-a were associated with mucocutaneous disease; leukopenia; and low complement, Ro/SSA, and La/SSB. Vascular events and antiphospholipid antibodies were uncommon. We identified two subgroups with high disease activity: one with double-high IFN-lambda 1 and IFN-alpha and another with IP-10(high). The former had more neuropsychiatric manifestations, and the latter had more arthritis. Increased levels of both types I and III IFNs were found in a proportion of population control subjects. Therefore, high IFN levels do not seem to be SLE-specific biomarkers. Conclusions: Measurements of circulating IFN-lambda 1 and IFN-alpha define subsets of patients with SLE with different characteristics. Levels of IFN-lambda 1 correlate with T-helper type 17 cytokines and identify a subgroup with more damage. High disease activity is associated with either simultaneous upregulation of IFN-lambda 1 and IFN-alpha or independently with IP-10. Our findings could be of major importance when tailoring therapy for patients with SLE with agents targeting IFN pathways.