Anti-tumour necrosis factor (TNFi) therapy is widely used to treat immune-mediated inflammatory diseases including psoriasis. However, 2-5% of patients receiving TNFi may develop de novo psoriasis-like lesions, including pustular phenotypes, or have an exacerbation of existing psoriasis. This is termed paradoxical psoriasis (PXP). Mechanistically, TNF-blockade has been linked to aberrant production of type I interferon (IFN) in the skin by immature plasmacytoid dendritic cells (pDCs). Nevertheless, PXP is still ill-understood and prognostic biomarkers are not available. Thus, to gain further insights into PXP pathogenesis, we investigated molecular and cellular players putatively involved in PXP in the blood of patients with PXP (n=15, of which 5 with resolved PXP) and age, sex and ethnicity-matched controls groups of healthy donors (HD, n=15) and psoriasis patients before (Ps) and after 12 weeks of receiving TNFi without developing PXP (Ps TNFi). IFNA1 mRNA expression was significantly lower in PXP versus Ps TNFi (p<0.05), with a downward trend in the level of IFNa protein in the serum of PXP patients versus each control groups. However, IFN-induced genes MX1 (p<0.001) and STAT1 (p<0.05) were significantly upregulated in PXP versus Ps TNFi. Next, we used an 11-colour flow cytometry panel inclusive of skin homing, maturation and pDC subset markers to deep-phenotype PBMCs of PXP patients. A higher frequency of PXP pDCs expressed the tissue-homing markers CHERMR23 (p<0.001 vs HD) and CXCR3 (p<0.01 vs HD). Taken together, our data suggests that the type I IFN pathway is dysregulated in PXP, with pDCs expressing tissue-homing markers favouring their migration to the skin, where they may contribute to disease development. Investigation of skin pDC phenotype and function using imaging mass cytometry may elucidate mechanisms underpinning PXP and uncover potential prognostic biomarkers to aid patient stratification and treatment.

ESDR056 - Dissecting the pathogenesis of anti-TNF-induced paradoxical psoriasis

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING