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Introduction & Objectives Alopecia areata (AA) is a chronic inflammatory skin disorder resulting in patchy, non-scaring hair loss. The pathogenesis for AA involves loss of immune privilege for the hair follicle through overactivity of the Th1 and Th17 cells and dysfunction of regulatory T cells (Treg).1 Rezpegaldesleukin (REZPEG: NKTR-358) is a polyethylene glycol (PEG)-conjugated recombinant human interleukin 2 (rhIL-2) with the ability to selectively promote the activation and up-to 12-fold expansion of Tregs, while having relatively minimal effect on conventional T cells (Tcons).2 REZPEG is a biologic therapy and represents a potential novel therapeutic approach for patients with severe to very-severe AA. There are currently no biologic therapies approved for the treatment of AA. REZPEG has previously demonstrated clinical activity in patients with chronic inflammatory skin conditions, including atopic dermatitis (AD), psoriasis, and systemic lupus erythematous. Specifically, a Phase 1b study of REZPEG for patients with moderate-to-severe AD demonstrated a rapid time to response (2-4 weeks) during induction therapy and a prolonged durability of response, i.e. throughout the 36-week follow-up after cessation of therapy. These results support further development of REZPEG for patients with moderate to severe AD (phase 2b study ongoing, NCT06136741) and other inflammatory skin diseases, including AA. Objective Evaluate the efficacy and safety of REZPEG in patients with severe alopecia areata. Materials & Methods We are conducting a Phase 2b, randomized, double-blinded, placebo-controlled, international, multicenter study of REZPEG vs placebo for JAK-inhibitor naïve patients with severe to very severe AA. Eligibility requires adult males (aged 18-60 years) or adult females (aged 18-70) with severe to very severe AA with the following inclusion criteria: baseline Severity Alopecia Tool (SALT) score ≥ 50, stable hair loss for 6-months, current episode of severe AA of less than 8-years, and no hair loss from causes other than AA. Patients will be randomly assigned in a 3:3:2 ratio to 2 different REZPEG dosing regimens vs. placebo, administered subcutaneously, during the treatment period and all patients will undergo an extended follow-up. The primary endpoint for this study is the percent change from baseline in SALT score at end of treatment period. Key secondary/exploratory endpoints include the following: percent change from baseline in SALT score at other assessed timepoints, proportions with ≥ 50%, 75%, 90% reduction in SALT at end of treatment period and other assessed timepoints, proportion of patients with absolute SALT score ≤ 10, ≤ 20, ≤ 30, ≤ 50 at end of treatment period and other assessed timepoints, safety/tolerability, various patient reported outcomes (PROs), pharmacokinetics, and pharmacodynamics. Results Trial ongoing (NCT 06340360). Conclusion REZPEG is a novel regulatory T cell stimulating therapy that may confer prolonged therapeutic benefit for patients with chronic inflammatory skin conditions, including AA and AD. This phase 2b trial is evaluating the efficacy and safety of multiple dosing regimens of REZPEG in JAK-inhibitor and biologic-therapy naïve patients with severe to very severe alopecia areata. [ABSTRACT FROM AUTHOR]

Background: The proportion of dendritic cell subpopulations in the skin is important for the severity of atopic dermatitis because topical treatment with tacrolimus leads to rapid depletion of inflammatory dendritic epidermal cells, whereas Langerhans cells (LCs) predominate in cured sites., Objectives: The effects of tacrolimus and TGF-beta1 on LC differentiation and the idea of tacrolimus skewing the differentiation of epidermal precursors to LCs were evaluated., Methods: The presence of LC markers, MHC, and costimulatory molecules and stimulatory capacity toward T cells of monocyte-derived LCs were analyzed. Skin samples of patients with atopic dermatitis were assessed by means of immunofluorescence microscopy before and after tacrolimus treatment. TGF-beta production of skin cells was analyzed., Results: Tacrolimus and TGF-beta1 act synergistically on the generation of LCs and the expression of CD40, CD80, CD86, CD83, and MHC II; stabilize TGF-beta receptor II expression; and decrease the stimulatory capacity of LCs toward T cells. In vivo the number of epidermal LCs in tacrolimus-treated skin increased., Conclusion: The synergism between TGF-beta1 and tacrolimus leads to the generation of LCs, reduced expression of costimulatory and MHC II molecules, and reduced stimulatory activity. Shifting the balance of the dendritic cell population to LCs might be of major importance for the therapeutic effect of tacrolimus.