TY - JOUR T1 - OP0278 BIOMARKER PROFILING REVEALS NOVEL MECHANISTIC INSIGHTS INTO USTEKINUMAB THERAPEUTIC RESPONSES IN SYSTEMIC LUPUS ERYTHEMATOSUS JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 220 LP - 221 DO - 10.1136/annrheumdis-2019-eular.2452 VL - 78 IS - Suppl 2 AU - Matteo Cesaroni AU - Loqmane Seridi AU - Jarrat Jordan AU - Kristen Sweet AU - MA Keying AU - Carol Franks AU - Jessica Schreiter AU - Peter Lipsky AU - Ronald van Vollenhoven AU - Bevra H. Hahn AU - Shawn Rose AU - Frederic Baribaud AU - Matthew J Loza AU - Kim Campbell AU - George Tsokos Y1 - 2019/06/01 UR - http://ard.bmj.com/content/78/Suppl_2/220.3.abstract N2 - Background 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.Objectives 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 therapy.1Patients 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-γ, 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-α ELISA was utilized to quantify the IFN-I pathway. Whole blood RNA was assessed for gene expression by microarray. Two Th172,3, an IFN-γ4 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-γ protein and IFN-γ 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-α 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 (Δ=27%) and high (Δ=28%) patients.Conclusion Response to UST was associated with reductions in IFN-γ 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.References [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.Disclosure of Interests Matteo Cesaroni Employee of: Janssen Research & Development, LLC, Loqmane Seridi Employee of: Janssen Research & Development, LLC, Jarrat Jordan Employee of: Janssen Research & Development, LLC, Kristen Sweet Employee of: Janssen Research & Development, LLC, Keying Ma Employee of: Janssen Research & Development, LLC, Carol Franks Employee of: Janssen Research & Development, LLC, Jessica Schreiter Employee of: Janssen Research & Development, LLC, Peter Lipsky Consultant for: Consulting fees from Horizon Pharma, Ronald van Vollenhoven Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, and UCB, Consultant for: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex., Speakers bureau: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex., Bevra H. Hahn Grant/research support from: Janssen Research & Development, LLC, Shawn Rose Employee of: Janssen Research & Development, LLC, Frederic Baribaud Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Matthew J Loza Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Kim Campbell Employee of: Janssen Research & Development, LLC, George Tsokos Grant/research support from: Janssen Research & Development, LLC ER -