Session Type: ACR Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease that causes progressive organ damage. The cytokines type I interferon (IFN-I), IL-12 and IL-23 have all been shown to contribute to SLE pathogenesis. We previously reported that treatment with ustekinumab (UST), an anti-IL-12/23 p40 neutralizing monoclonal antibody, improved global and organ-specific measures of disease activity in a randomized, placebo (PBO)-controlled study of patients with active SLE (NCT02349061)1. Here, we utilized biomarker data from this clinical study to elucidate the mechanism of action of UST in SLE.
We aimed to determine whether modulation of IL-12, IL-23, or both cytokines was associated with clinical efficacy, and to ascertain whether UST treatment could modulate IFN-I or improve disease activity in patients exhibiting an elevated IFN-I signature at baseline.
Methods: A Phase 2, placebo (PBO)-controlled study enrolled 102 patients with seropositive SLE and active disease despite standard-of-care therapy1. Patients were randomized 3:2 to receive UST IV ~6 mg/kg or PBO at week 0, then subcutaneous injections of 90mg UST q8w or PBO. Whole blood RNA from PAXgene tubes and serum were collected over 24 weeks. Age and sex-matched healthy controls were also studied. Serum IFN-g, and IL-17A, IL-17F and IL-22 levels were quantified by ELISA as indicative of the IL-12 and IL-23 pathways, respectively and an IFN-a ELISA was utilized to quantify the IFN-I pathway. Whole blood RNA was assessed for gene expression by microarray. Two Th172,3, an IFN-g4 gene signature and 21-gene IFN-I signature (IGS)5 were analyzed. SLE Responder Index (SRI)-4 at week 24 was used to define UST response (UST-R) and non-response (UST-NR).
Results: Serum IL-17A, IL-17F and IL-22 levels and Th17 gene signature levels in blood remained largely stable over the course of 24 weeks in all treatment groups. In contrast, UST-R was associated with a durable reduction in IFN-g protein and IFN-g gene signature levels relative to baseline, which was not observed in UST-NR or PBO patients. IGS levels were elevated in 67% of patients at baseline versus healthy controls. Serum IFN-a levels and IGS levels in blood were not modulated by UST treatment through week 24. Baseline IFN-I signature status did not associate with response to UST, as the treatment effect size (UST vs PBO) was similar in IGS low (∆=27%) and high (∆=28%) patients.
Conclusion: Response to UST was associated with reductions in IFN-g levels, whereas IL-17A, IL-17F, IL-22 and IFN-I remained largely unchanged. While these findings require confirmation in an ongoing Phase 3 study, these data implicate the involvement of the IL-12 pathway and suggest a novel mechanism of action for UST-R in SLE.
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To cite this abstract in AMA style:Cesaroni M, Seridi L, Jordan J, Sweet K, Ma K, Franks C, Schreiter J, Lipsky P, van Vollenhoven R, Hahn B, Rose S, Baribaud F, Loza M, Campbell K, Tsokos G. Biomarker Profiling Reveals Novel Mechanistic Insights into Ustekinumab Therapeutic Responses in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/biomarker-profiling-reveals-novel-mechanistic-insights-into-ustekinumab-therapeutic-responses-in-systemic-lupus-erythematosus/. Accessed April 13, 2021.
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