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 Th17^2,3, 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.

1. VanVollenhovenR Lancet. 2018;392:1330.
2. ZhangW. PLoS One. 2012;7:e38510.
3. ZhangH. JAllergyClinImmunol. 2013;132:1005.
4. WelcherAA. ArthritisRheumatol. 2015;67:2713.
5. YaoY. HumGenomicsProteomics. 2009;doi:10.4061/2009/374312.

« Back to ACR/ARP Annual Meeting 2019

ACR Meeting Abstracts - https://acrabstracts.org/abstract/biomarker-profiling-reveals-novel-mechanistic-insights-into-ustekinumab-therapeutic-responses-in-systemic-lupus-erythematosus/