RT Journal Article SR Electronic T1 251 Type II but not type I interferon signifies clinical response to ustekinumab in patients with systemic lupus erythematosus JF Lupus Science & Medicine JO Lupus Sci & Med FD Lupus Foundation of America SP A185 OP A185 DO 10.1136/lupus-2019-lsm.251 VO 6 IS Suppl 1 A1 Jordan, Jarrat A1 Sweet, Kristen A1 Cesaroni, Matteo A1 Ma, Keying A1 Franks, Carol A1 Seridi, Loqmane A1 Schreiter, Jessica A1 Gordon, Robert A1 Lipsky, Peter A1 Vollenhoven, Ronald van A1 Tsokos, George C A1 Hahn, Bevra H A1 Rose, Shawn A1 Baribaud, Frédéric A1 Loza, Matthew J A1 Campbell, Kim YR 2019 UL http://lupus.bmj.com/content/6/Suppl_1/A185.1.abstract AB Background 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 trial of patients with active SLE (NCT02349061).1 Type I interferon (IFN-I) and type II IFN (IFN-gamma) are elevated in a subset of SLE patients. Although targeting IFN-I (anifrolumab) has demonstrated inconsistent efficacy and a preliminary study with anti-IFN-gamma mAb (AMG811) failed to establish benefit,2 3 we sought to determine if UST affects either pathway and if those effects correlated with a positive SRI-4 response at wk24.Methods A phase-2, PBO-controlled study enrolled 102 adults with seropositive SLE (SLICC criteria) and active disease (baseline SLEDAI score 6 and 1 BILAG A and/or 2 BILAG B scores) despite standard-of-care therapy.1 Gene expression analysis using a 21 gene IFN-I gene signature (IGS)4 or IFN-gamma signature5 was performed by microarray analysis using whole blood PAXgene RNA samples. Serum IFN-gamma and IFN- levels were assessed using MSD (IFN-gamma) and Quanterix (IFN-).Results Serum IFN-gamma and IFN- and the IGS were elevated at baseline in SLE compared to healthy controls (p<0.0001). IGS was increased in approximately 67% of the SLE patients at baseline. No decrease was observed with IFN- protein or IGS levels after treatment with either UST or PBO. Whereas the proportion of patients achieving an SRI-4 response at wk24 was numerically greater in the IGS low patients (81.8% UST vs. 54.5% PBO) versus IGS high (48.6% UST vs. 20% PBO), the magnitude of the treatment effect (UST vs. PBO) was similar in both subsets (IGS low effect size=27.3% vs. IGS high effect size=28.6%). Despite similar baseline levels, UST-treated patients achieving an SRI-4 response at wk24 exhibited a significant decrease in IFN-gamma protein versus non-responders (p<0.05) at 4 and 8 wks and IFN-gamma gene signature at 4 wks (p<0.0001) and 24 wks (p<0.05) post-dosing.Conclusions In this SLE trial population which had significant upregulation of IFN-I at baseline, clinical response to UST was not associated with IFN-I reduction. In contrast, a significant decrease in IFN-gamma protein and gene signature was associated with UST response. These findings suggest that a broad population of SLE patients may respond to UST regardless of baseline IFN-I status. Moreover, UST may have affected TH1 responses in SLE since IFN-gamma levels decreased following treatment.Funding Source(s): Janssen Research and Development, LLC supported this studyReferencesVanVollenhoven RF. Lancet 2018;392:1330.Furie R. Arthritis Rheumatol 2017;69:376.Boedigheimer MJ. Lupus Sci Med 2017;4:e000226.Yao Y. Human Genomics Proteomics 2009. doi:10.4061/2009/374312Welcher AA. Arthritis & Rheumatol 2015;67:2713.