2124: Immunological Differences Between PsA Patients Who Are Tumor Necrosis Factor Inhibitor-Naïve and Who Have Inadequate Response to Tumor Necrosis Factor Inhibitors

Stefan Siebert¹, Laura Coates², Georg Schett³, Siba P. Raychaudhuri⁴, Warner Chen⁵, Sheng Gao⁵, Soumya Chakravarty⁶, May Shawi⁷, Frederic Lavie⁸, Elke Theander⁹, Marlies Neuhold¹⁰, Alexa Kollmeier¹¹, Xie L Xu¹², Proton Rahman¹³, Philip J Mease¹⁴ and Atul Deodhar¹⁵, ¹Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom, ²Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK, Oxford, England, United Kingdom, ³Universitätsklinikum Erlangen, Erlangen, Germany, ⁴Rheumatology, Allergy, and Clinical Immunology, University of California Davis, School of Medicine, Sacramento, CA, ⁵Janssen Research and Development, LLC, Spring House, PA, ⁶Janssen Scientific Affairs, LLC; Drexel University College of Medicine, Villanova, PA, ⁷Immunology Global Medical Affairs, Janssen Pharmaceutical Companies of Johnson & Johnson, Horsham, PA, ⁸The Janssen Pharmaceutical Companies of Johnson & Johnson, Paris, France, Paris, France, ⁹Janssen Cilag, Lund, Sweden, ¹⁰Janssen, Zug, Switzerland, ¹¹Janssen-Cilag, Research & Development, LLC, San Diego, CA, ¹²Janssen Research & Development, LLC, San Diego, CA, USA, San Marcos, CA, ¹³Memorial University, St. John's, NL, Canada, ¹⁴Swedish Medical Center/Providence St. Joseph Health, Seattle, WA, ¹⁵Oregon Health & Science University, Portland, OR, USA, Portland, OR

Background/Purpose: A better understanding of the immunological differences between psoriatic arthritis (PsA) patients (pts) who are tumor necrosis factor inhibitor (TNFi)-naïve and who have inadequate response to TNFi (TNFi-IR) may guide treatment choices. In DISCOVER-1, benefit of the IL-23p19 subunit inhibitor guselkumab (GUS) every-four-weeks (Q4W) and Q8W over placebo (PBO) in improving PsA signs and symptoms was seen in adults with active PsA.¹ The Phase 3b COSMOS study of GUS Q8W vs PBO in TNFi-IR PsA pts corroborated these findings.² We assessed baseline (BL) molecular differences between TNFi-naïve and TNFi-IR PsA pts and investigated GUS pharmacodynamic 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] and TNFi-IR [n=17]), DISCOVER-2³ (TNFi-naïve [n=150]), and COSMOS² (TNFi-IR [n=76]) were analyzed for selected serum cytokine levels. TNFi-IR pts in this post-hoc analysis had active PsA and discontinued 1-2 TNFi due to inadequate efficacy; these pts required a TNFi-specific washout period prior to starting GUS. Pharmacodynamic effect of GUS Q8W on cytokine levels was assessed. Differential BL cytokine expression, associations between BL cytokine levels and clinical response (Psoriasis [PsO] Area and Severity Index 75% improvement from BL [PASI75] and American College of Rheumatology 20% improvement [ACR20]), and GUS effect on cytokine levels were analyzed with a General linear model and Spearman linear regression.

Results: BL pt demographics, disease characteristics, and conventional synthetic disease-modifying antirheumatic drug (csDMARD) use were comparable between TNFi-naïve (DISCOVER-1 and DISCOVER-2, N=251) and TNFi-IR (DISCOVER-1 and 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 years), and PsO duration (16.7 v 20.4 years; Table). BL serum IL-22 and TNFα levels for pooled treatment groups were higher in TNFi-IR than TNFi‑naïve pts (p< 0.05). At W24, GUS reduced IL-22, IL-17A, IL-17F, IL-6, C-reactive protein (CRP), and serum amyloid A protein to similar levels in both cohorts (p< 0.05; Figure). W24 PASI75 responders in GUS arm had higher BL IL-17F levels in both cohorts (p< 0.05) and 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 treated with GUS (p=0.07).

Conclusion: Elevated BL IL-22 expression and association between BL IL-22 levels and W24 PASI75 response, and a W24 trend for an association between upregulated BL IL-22 and 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 and significant pharmacodynamic effects for TNFi-naïve and TNFi-IR pts, consistent with observed clinical responses.

References:
¹Deodhar A, et al. Lancet. 2020;395:1115-25
²Coates LC, et al. Ann Rheum Dis. 2021;80:140-1
³Mease P, et al. Lancet. 2020;395:1126-36



Disclosures: S. Siebert, AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Janssen, Novartis, UCB, Biogen; L. Coates, AbbVie, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb (BMS), Eli Lilly, Gilead, Galapagos, Janssen, Medac, Novartis, Pfizer, UCB, Celgene, Biogen, Moonlake, GlaxoSmithKlein (GSK); G. Schett, None; S. P. Raychaudhuri, AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, UCB; W. Chen, Janssen Research & Development, LLC, Johnson & Johnson; S. Gao, Janssen Research & Development, LLC; S. Chakravarty, Janssen Scientific Affairs, LLC, Johnson & Johnson; M. Shawi, Janssen Pharmaceutical Companies of Johnson and Johnson; F. Lavie, Janssen; E. Theander, Janssen Pharmaceutical Companies of Johnson and Johnson; M. Neuhold, Janssen Scientific Affairs, Johnson & Johnson; A. Kollmeier, Janssen Research & Development, LLC, Johnson & Johnson; X. Xu, Janssen Research & Development, LLC, Johnson & Johnson; P. Rahman, Janssen, Novartis, AbbVie, Eli Lilly and Company, Pfizer; P. Mease, AbbVie, Amgen, Janssen, Novartis, Pfizer Inc, UCB, Sun Pharma, Eli Lilly, Bristol-Myers Squibb(BMS), Celgene, Genentech; A. Deodhar, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Pfizer Inc, UCB Pharma, Aurinia, Moonlake.