Biological therapies have transformed the management of psoriasis, but clinical response is variable and there is an unmet clinical need to identify predictive biomarkers. Whilst newer biologics have been licensed, the anti-TNF drug adalimumab remains a first-line intervention in psoriasis, given its effectiveness, well-established safety profile and, with the advent of biosimilars, significantly reduced costs. Nevertheless, the cellular and molecular mechanisms underpinning its clinical efficacy are ill understood and no companion diagnostic exists to guide prescription. We performed in-depth immunomonitoring of 67 psoriasis patients, before and during adalimumab therapy to identify immune biomarkers of response. Clinical response was assessed applying a binary model, using 75% reduction in baseline psoriasis area severity index (PASI75) at week 12, or a continuous model, where the outcome is residual disease at week 12. We assessed proximal TNF signalling events, such as NF-κB nuclear translocation and phosphorylation, and downstream effects, such as immune cell phenotype in blood and skin. We found that LPS-induced NF-κBp65 phosphorylation in type-2 dendritic cells (DC) before therapy, significantly correlated with lack of clinical response to adalimumab after 12 weeks (r2=0.573, FDR=104). In vitro DC maturation and frequency of circulating IL-17+T cells were increased in PASI75 non-responders before therapy. Moreover, lesional skin of non-responders contained more activated dermal DC and increased numbers of IL-17+T cells. Finally, we clinically validated LPS-induced NF-κBp65 phosphorylation at baseline as a predictive biomarker of non-response to adalimumab (93.3% accuracy, 100 % sensitivity and 90.1 % specificity) in an independent cohort of an additional 15 patients. Our study has uncovered key molecular and cellular players in adalimumab’s mechanism of action in psoriasis and identified a blood biomarker for predicting clinical outcome before commencing therapy

ESDR045 - NF-κB phosphorylation in type-2 dendritic cells at baseline is a blood predictive biomarker of clinical response to adalimumab in psoriasis

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