Pinter, Andreas

ABSTRACT Tissue‐resident memory T cells (TRMs) are a distinct memory T‐cell subset that permanently reside in tissues such as the skin. In chronic immune‐mediated dermatoses, including psoriasis, atopic dermatitis, and vitiligo, TRMs are implicated in site‐specific “disease memory,” contributing to persistence and relapse at previously affected sites. This review synthesizes emerging concepts on TRMs in chronic inflammatory skin diseases and discusses clinical and translational implications, including TRM‐targeted therapies. Original human, animal, or in vitro studies evaluating TRMs in the pathogenesis or persistence of dermatologic diseases were included. In psoriasis, CD8 + TRMs (CD69 + CD103 + ) persisted in clinically healed skin. For atopic dermatitis, both CD4 + and CD8 + TRMs are implicated in maintaining Th2/Th22 inflammation. In vitiligo, autoreactive CD8 + TRMs at lesional margins mediate melanocyte destruction. Across dermatological diseases, TRMs share three core features: persistence in previously affected skin after clinical resolution, rapid reactivation by diverse triggers (stress, autoantigens, allergens, or cytokines) leading to site‐specific recurrence, and relative resistance to conventional therapies. Together, these properties provide a unifying framework linking tissue immune memory to the chronic, relapsing nature of inflammatory skin diseases. However, the dominant TRM pathways vary by disease, reflecting differences in immune polarization and antigen specificity. Targeting TRMs represents a promising strategy for disease control and serves as a biomarker of residual disease or flare. image

Abstract Background The results of a previous phase IIa trial suggested efficacy of the anti-C5a compound vilobelimab in a small number of patients with severe hidradenitis suppurativa (HS) refractory to adalimumab treatment. Objectives To study the efficacy of vilobelimab in a larger-scale randomized phase IIb trial (SHINE) of patients with moderate-to-severe HS. Methods In total, 177 patients with moderate-to-severe HS were treated either with placebo or one of four doses of vilobelimab, a monoclonal antibody that targets the complement split product C5a. Hidradenitis Suppurativa Clinical Response (HiSCR) at 16 weeks was the primary endpoint. Those who achieved HiSCR switched to open-label low-dose vilobelimab; those who did not were switched to medium-dose vilobelimab. The trial was registered with the EU Clinical Trials Register (EudraCT number 2017-004501-40) and ClinicalTrials.gov (NCT03487276). Results The study did not meet the primary endpoint, perhaps due, in part, to an unexpectedly high HiSCR placebo response rate of 47.1%. HS flares decreased and post hoc analysis showed that high-dose vilobelimab significantly decreased the median draining tunnel counts and IHS4 score by 63%. Following the switch to medium-dose vilobelimab at week 16, 45.5% of those who did not respond to treatment achieved HiSCR at week 40. Conclusions Compared with placebo, vilobelimab treatment did not result in significant HiSCR improvements in patients with moderate-to-severe HS. Post hoc analysis revealed significant effects for the highest tested dose on draining tunnel reduction and IHS4 score, which captures reductions in draining tunnels. These findings warrant further investigation.

AbstractBackgroundNemolizumab is a humanized anti‐IL‐31 receptor blocker in phase 3 for atopic dermatitis (AD).ObjectiveAnalyse onset of action of nemolizumab 30 mg and compare efficacy and safety vs placebo (SC q4wk plus loading dose) in moderate‐to‐severe AD.MethodsPost hoc analysis of patients with Eczema Area and Severity Index (EASI) scores ≥ 16 from a phase 2b trial of moderate‐to‐severe AD. Endpoints were change in EASI score at week 16, peak pruritus numeric rating scale (PP‐NRS), Investigator’s Global Assessment (IGA), changes in sleep and responders with ≥ 4‐point improvement on PP‐NRS.ResultsThere was a significantly greater itch relief apparent by Day 2 (−22.8% vs –12.3% PP‐NRS; P = 0.005) which continued to improve through week 16 (−68.5% vs −30.9% PP‐NRS; P < 0.001). At week 16, PP‐NRS ≥ 4‐point response of itch was observed in 68.0% nemolizumab vs 15.9% placebo patients (P ≤ 0.001). There was also a rapid improvement of sleep disturbance with nemolizumab 30 mg, with a significant separation from placebo by Day 3 (−26.6% vs –9.0%; P < 0.001) which further improved till week 16 (−76.0% vs −36.5%; P < 0.001). Also for the EASI score a separation between groups in favour of nemolizumab was observed by week 1 (P ≤ 0.001), which increased through week 16 (−68.6% vs. −42.6%; P = 0.002). Finally, the degree of response was greater in nemolizumab‐treated patients; clinically relevant reductions of 75% EASI were observed in 50.0% of nemolizumab patients versus 15.9% of placebo patients, while 90% reductions were reported for 36.0% and 6.8% of patients, respectively (P < 0.001 for both). IGA success (score of 0/1) was 32.0% for nemolizumab vs 6.8% for placebo (P = 0.002).Nemolizumab was safe and well‐tolerated in this population; nasopharyngitis and upper respiratory tract infection were the most common adverse events.ConclusionsNemolizumab resulted in very rapid, sustained improvements of inflammation, pruritus and sleep in patients with EASI ≥ 16 at baseline.