Molecular and Cellular Profiling of Psoriatic Scar: Exploring Early vs Late Intervention

Background and aim: Psoriasis is a chronic, immune-mediated inflammatory skin disorder associated with numerous comorbidities. Medications for psoriasis, especially biologic agents, are designed to inhibit the inflammatory response. While these agents can clear skin lesions, discontinuing the treatment leads to the recurrence of psoriasis in the same locations. Indeed, even after effective treatment, cleared lesions leave behind a "molecular scar" composed of pathogenic immune cells, which can lead to a relapse after the cessation of therapy. Currently, biologic agents are prescribed after inadequate response to topical or conventional systemic agents. However, evidence from rheumatoid arthritis and Crohn’s disease has demonstrated that the early use of targeted therapies improves long-term outcomes. In this study, we aimed to investigate the molecular and cellular signatures of the disease and assess whether an early intervention with biologic drugs might modify its natural course at both cutaneous and systemic levels. Methods: This is a single-center, open-label study involving eighteen patients with moderate to severe psoriasis treated with anti IL-23 and anti TNFa biologic drugs according to the European Guidelines. Based on disease duration, patients were classified into early (within 5 years from onset) or late (after 5 years from the disease onset) intervention groups. Clinical evaluations, blood samples, and skin biopsies were taken before and after 24 weeks of treatment and analyzed via Luminex Multiplex assay, Multiparametric Flow Cytometry, immunofluorescence. Results: Early intervention with anti IL-23 and anti TNFa led to a greater clinical improvement and lower disease severity. Both groups showed systemic inflammation through elevated serum levels of cytokines. A positive correlation was observed between IL-17A and IL-23p40 and disease severity. The treatment with both anti IL-23 and anti TNFa normalized cytokine levels, with early-intervention group showing a significant drop in IL-17A. Multiparameter flow cytometry analysis of the T-cell compartment in skin biopsies revealed an increase in T-cell infiltration and permanence in the psoriatic skin as compared to non-lesional and post-lesional skin, with a predominance of the memory compartment, that was strongly decreased by the treatment. Tissue resident memory cells, which are believed to be involved in psoriasis memory and recurrence, were especially reduced in early- intervention group, with trends suggesting better outcomes with anti IL-23 treatment. A unique T-cell subpopulation that expressed both naive and memory markers was identified within the psoriatic skin, along with the presence of aggregates of B and T cells, pointing to the presence of tertiary lymphoid organs (TLOs). Conclusions: Early intervention, particularly with biologics targeting the IL-23/Th17 axis, proved superior to late intervention in terms of improving clinical outcomes, mitigating the systemic inflammatory milieu, and modulating the "disease memory" within the skin. Psoriatic skin exhibited intricate T-cell activity, hinting at its potential role as TLO.