POS0074 IMMUNOLOGICAL DIFFERENCES BETWEEN PsA PATIENTS WHO ARE TUMOR NECROSIS FACTOR INHIBITOR-NAIVE AND WHO HAVE INADEQUATE RESPONSE TO TUMOR NECROSIS FACTOR INHIBITORS

Abstract

Background: A better understanding of the immunological differences between psoriatic arthritis (PsA) patients (pts) who are tumor necrosis factor inhibitor (TNFi)‐naïve & who have inadequate response to TNFi (TNFi‐IR) may guide treatment choices. In DISCOVER‐1, beneft of the IL‐23p19 subunit inhibitor guselkumab (GUS) every‐four‐weeks (Q4W) & Q8W vs placebo (PBO) in improving PsA signs & symptoms was seen in adults with active PsA.1 The Ph3b COSMOS study of GUS Q8W vs PBO in TNFi‐IR PsA pts corroborated these fndings.2 Objectives: Assess baseline (BL) molecular differences between TNFi‐naïve &‐IR PsA pts & investigate GUS pharmacodynamic (PD) effect on cytokine expression over time in these cohorts. Methods: Serum samples collected from consenting biomarker substudy pts in DISCOVER‐11 (TNFi‐naïve [n=101] &‐IR [n=17]), DISCOVER‐23 (TNFi‐naïve [n=150]), & COSMOS2 (TNFi‐IR [n=76]) were analyzed for selected serum cytokine levels. TNFi‐IR pts in this post‐hoc analysis had active PsA & discontinued 1‐2 TNFi due to inadequate efficacy; these pts required a TNFi‐specifc washout period prior to starting GUS. PD effect of GUS Q8W on cytokine levels was assessed. Differential BL cytokine expression, associations between BL cytokine levels & clinical response (Psoriasis [PsO] Area & Severity Index 75% improvement from BL [PASI75] & American College of Rheumatology 20% improvement [ACR20]), & GUS effect on cytokine levels were analyzed with a General linear model & Spearman linear regression. Results: BL pt demographics, disease characteristics, & conventional synthetic disease‐modifying antirheumatic drug (csDMARD) use were comparable between TNFi‐naïve (DISCOVER‐1 &‐2, N=251) &‐IR (DISCOVER‐1 & COSMOS, N=93) pts, with differences in mean PASI score (8.9 v 12.5), swollen joint count (SJC) (11.7 v 10.3), PsA duration (5.8 v 9.8 yrs), & PsO duration (16.7 v 20.4 yrs; Table 1). BL serum IL‐22 & TNFα levels for pooled treatment groups were higher in TNFi‐IR than‐naïve pts (p<0.05). At W24, GUS reduced IL‐22, IL‐17A/F, IL‐6, C‐reactive protein (CRP), & serum amyloid A protein to similar levels in both cohorts (p<0.05; Figure 1). W24 PASI75 responders had higher BL IL‐17F levels with GUS in both cohorts (p<0.05) & higher IL‐22 levels in TNFi‐IR pts only (p<0.05). A trend of upregulated BL IL‐22 expression in W24 ACR20 responders was seen for TNFi‐IR pts with GUS (p=0.07). Conclusion: Elevated BL IL‐22 expression & association between BL IL‐22 levels & W24 PASI75 response, & a W24 trend for an association between upregulated BL IL‐22 & ACR20 response, in TNFi‐IR pts seen in this exploratory analysis may suggest increased involvement of the IL‐23 pathway in TNFi‐IR pts. GUS showed comparable & signifcant PD effects for TNFi‐naïve &‐IR pts, consistent with observed clinical responses.