Background/Purpose: 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. This post-hoc analysis explored the dysregulation of cytokines in association with disease characteristics at baseline using biomarker data from a phase 3 study of ustekinumab in participants with active SLE.¹

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 (IFN-γ, p40, TNF-α, IL-10, IL-15, IL-16), Quanterix’s single molecule array (Simoa) technology (IFN-α), and the high-sensitivity Single Molecule Counting Erenna Immunoassay (IL-17F and IL-22) in a biomarker subgroup (n=201) with similar baseline characteristics as the overall study population. Samples from demographically matched healthy subjects (n=30) were procured independently as a control group for biomarker analyses. Statistical significance was defined as fold change >1.5 and p< 0.05 in this exploratory analysis.

Results: Compared to healthy subjects, trial participants with SLE had significantly elevated serum levels of IFN-α, IFN-γ, IL-12/23 p40, TNF-α, IL-10, IL-15, and IL-16, but not IL-17F or IL-22. Among participants with SLE, elevated serum IFN-α 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 IFN-γ except for anti-SSA. Clinically, both IFN-α and IFN-γ 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 IFN-α levels. However, lower IFN-γ levels were found in participants with more severe skin manifestations (Cutaneous Lupus Erythematosus Disease Area and Severity Index [CLASI] >6 vs ≤6). No clear difference in either IFN-α or IFN-γ levels were observed in patients with more arthritis activity (active joint count >6 vs ≤6).

Conclusion: Inflammatory cytokines are dysregulated in participants with SLE in a phase 3 clinical trial, similar to previously reported findings. Serum levels of IFN-α and IFN-γ 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 IFN-α and was instead associated with lower levels of IFN-γ, 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.

¹van Vollenhoven RF, et al. Ann Rheum Dis. 2022;81:1556-1563.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dysregulated-serum-cytokines-in-association-with-clinical-manifestations-in-patients-with-systemic-lupus-erythematosus/