Background Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease affecting multiple organ systems, making clinical trial design challenging. Biomarkers that can identify patients with specific clinical manifestations could allow for more targeted approaches in clinical development. Utilizing biomarker data from a phase III study of ustekinumab in participants with active SLE,¹ we sought to explore the dysregulation of cytokines in association with disease characteristics at baseline.

Methods The phase 3 randomized, placebo-controlled study enrolled 516 autoantibody-positive participants with SLE whose disease remained active despite standard-of-care therapy.¹ Participants were randomized in a 3:2 ratio to receive ustekinumab or placebo through week 48. Baseline serum levels of inflammatory cytokines were assessed using the Meso Scale Discovery platform (IFNγ, p40, TNFα, IL-10, IL-15, IL-16), Quanterix’s single molecule array (Simoa) technology (IFNα), and the high-sensitivity Single Molecule Counting Erenna Immunoassay (IL-17F and IL-22) in a biomarker subgroup with similar baseline characteristics as the overall study population (n=201). Samples from demographically matched healthy subjects (n=30) were procured independently as a control group for biomarker analyses. In this post hoc exploratory analysis, statistical significance is defined as fold change >1.5 and p<0.05.

Results Compared to healthy subjects, trial participants with SLE had significantly elevated serum levels of IFNα, IFNγ, IL-12/23 p40, TNFα, IL-10, IL-15, and IL-16, but not IL-17F or IL-22. Among participants with SLE, elevated serum IFNα levels were associated with higher levels of anti-dsDNA (>75 IU/mL) and with the presence of other autoantibodies, including anti-RNP, -SSA, -SSB, and -Sm. Similar associations with each autoantibody were found with IFNγ except for anti-SSA. Clinically, both IFNα and IFNγ were found to be associated with higher overall baseline disease activity, as measured by SLEDAI-2K scores (>10 vs ≤10) and with active lupus nephritis. Skin disease was not associated with IFNα levels. However, lower IFNγ levels were found in participants with more severe skin manifestations (CLASI>6 vs ≤6). No clear difference in either IFNα or IFNγ levels were observed in patients with more arthritis activity (active joint count >6 vs ≤6).

Conclusion Inflammatory cytokines are dysregulated in individuals with SLE participating in a phase 3 clinical trial, similar to previously reported findings. Serum levels of IFNα and IFNγ were associated with autoantibodies, consistent with their roles in B lymphocyte regulation. While IFNs were associated with overall disease activity and renal disease, skin disease activity was not associated with IFNα and was instead associated with lower levels of IFNγ, consistent with a regulatory function. If confirmed in future studies, these findings suggest that cytokine levels have potential to identify patients with significantly high organ-specific disease activity.

Reference

1. van Vollenhoven RF, Kalunian KC, Dörner T, et al. Annals of the Rheumatic Diseases 2022;81:1556–1563.