P0054Shared pathways, unequal engagement: skin transcriptomics distinguish paradoxical anti-TNF induced from conventional psoriasis in IBD

Abstract Background Anti–tumour necrosis factor (anti-TNF) therapy is widely used as first-line treatment for inflammatory bowel diseases (IBD). Although generally safe, ∼6% of patients develop paradoxical psoriasiform lesions (PP), sometimes necessitating therapy withdrawal.1,2 The underlying mechanisms remain unclear. This study compared molecular profiles of PP with conventional psoriasis (PsO). Methods Paired lesional and non-lesional biopsies were obtained from 7 IBD patients with anti-TNF–induced PP, alongside 10 PsO lesional biopsies. RNA-seq (Illumina TruSeq) was performed, complemented by public datasets from 9 healthy controls (HC) and 10 PsO lesions.3 Differentially expressed genes (DEG) were identified with DESeq. Weighted gene co-expression network analysis (WGCNA) defined modules associated with PP and PsO, followed by pathway analysis (IPA, GSEA). Results PP and PsO shared 1420 DEGs relative to HC (556 up, 864 down), with an additional 404 DEGs unique to PP and 2175 unique to PsO (Figure 1A). However, the more informative distinction emerged from WGCNA, which revealed modules showing similar directionality in PP and PsO, but consistently stronger correlations in PsO (Figure 1B). The most strongly disease-associated module (M2) was enriched for IFNα/β (p = 1.6 × 10−18), IFNγ (p = 2.1 × 10−17) and IL-17A signalling (p = 6.5 × 10−¹²) (Figure 2), with TNF and IFNγ as major upstream regulators. A second module (M3) highlighted enhanced proliferation programmes—cell-cycle (p = 4.0 × 10−66) and mitotic processes (p = 1.6 × 10−50)—driven by MYC, TP53 and TGFB1. A third (M4) showed enrichment for sphingolipid metabolism (p = 6.8 × 10−10) and keratinization (p = 1.5 × 10−3), indicating disrupted barrier and differentiation pathways, mediated by OSM. Two modules (M5, M6) were downregulated in both PP and PsO, again with a stronger association in PsO, enriched for WNT (p = 2.0 × 10−7) and NF1–RAS signalling (p = 1.55 × 10−7), respectively, suggesting reduced epithelial regulatory control. A single PsO-specific module (M1), enriched for TREM1 signalling (p = 0.016), was uniquely downregulated in PsO, but showed a weak, opposite trend in PP. Conclusion PP and PsO share key inflammatory, proliferative, and differentiation-related pathways, but WGCNA reveals that these modules are more strongly engaged in PsO. Persistence of TNF as a predicted upstream regulator in PP despite anti-TNF therapy supports the proposed secondary inflammatory loop involving IL-36γ.4 References: 1. Xie W, Xiao S, Huang H, et al. Incidence of and Risk Factors for Paradoxical Psoriasis or Psoriasiform Lesions in Inflammatory Bowel Disease Patients Receiving Anti-TNF Therapy: Systematic Review With Meta-Analysis. Front Immunol 2022;13:847160. doi: 10.3389/fimmu.2022.847160 published Online First: 20220301 2. Cleynen I, Van Moerkercke W, Billiet T, et al. Characteristics of Skin Lesions Associated With Anti-Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease: A Cohort Study. Ann Intern Med 2016;164(1):10-22. doi: 10.7326/M15-0729 published Online First: 20151208 3. Liu J, Chang HW, Grewal R, et al. Transcriptomic Profiling of Plaque Psoriasis and Cutaneous T-Cell Subsets during Treatment with Secukinumab. JID Innov 2022;2(3):100094. doi: 10.1016/j.xjidi.2021.100094 published Online First: 20211230 4. Friedrich M, Tillack C, Wollenberg A, et al. IL-36gamma sustains a proinflammatory self-amplifying loop with IL-17C in anti-TNF-induced psoriasiform skin lesions of patients with Crohn’s disease. Inflamm Bowel Dis 2014;20(11):1891-901. doi: 10.1097/MIB.0000000000000198 Conflict of interest: Dr. D’hooghe, Anna-Teresa: No conflicts. Hillary, Tom: Consultancy from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Janssen, Leo Pharma, Eli Lilly, Novartis, Sandoz, UCB Pharma speaker fees from AbbVie, Almirall, Amgen, Biogen, Bristol Myers Squibb, Celgene, Janssen, Leo Pharma, L’Oréal, Eli Lilly, Novartis, Sanofi, UCB Pharma research funding from AbbVie, Almirall, Amgen, Janssen, Leo Pharma, Eli Lilly, Novartis, UCB Pharma. Moens, Annick: No conflicts. Verstockt, Sare: Grant: Postdoctoral fellowship of the Research foundation – Flanders (FWO), Belgium Abdurahiman, Saeed: None to declare Guedelha Sabino, João: Speaker’s fees: Lilly, Pfizer, Abbvie, Ferring, Falk, Takeda, Janssen, Fresenius, and Galapagos. Consultancy fees: Takeda, Pfizer, Janssen, Ferring, Fresenius, Abbvie, Galapagos, Celltrion, Pharmacosmos, and Pharmanovia. Research support: Galapagos, Viatris, and Eurogenerics. JS is supported by a Senior Clinical researcher grant from the Research foundation – Flanders. Van Hoeve, Karen: Lecture fee from Menarini and Takeda Vermeire, Séverine: No conflict of interest Ferrante, Marc: Research grants from AbbVie, EG Pharma, Celltrion, Janssen, Pfizer, Takeda and Viatris Consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, MRM Health, Merck Sharp and Dohme, Pfizer, Takeda and ThermoFisher Speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, Janssen-Cilag, Merck Sharp and Dohme, Pfizer, Takeda, Truvion Healthcare and Viatris Verstockt, Bram: - Research support from AbbVie, Biora Therapeutics, Celltrion, Landos, Pfizer, Sanofi, Sossei Heptares/Nxera and Takeda. - Speaker’s fees from Abbvie, Agomab, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Eli Lily, Falk, Ferring, Galapagos, Materia Prima, Johnson and Johnson, Pfizer, Sandoz, Takeda, Tillots Pharma, Truvion and Viatris. - Consultancy fees from Abbvie, Alfasigma, Alimentiv, Anaptys Bio, Applied Strategic, Astrazeneca, Atheneum, BenevolentAI, Biora Therapeutics, Boxer Capital, Bristol Myers Squibb, Domain Therapeutics, Eli Lily, Galapagos, Guidepont, Landos, Merck, Mirador Therapeutics, Mylan, Nxera, Inotrem, Ipsos, Johnson and Johnson, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris. - Stock options Vagustim and Thethis Pharma.