特应性皮炎（AD）前沿文献精读特辑（J Am Acad Dermatol / Dermatol Ther (Heidelb) / Acta Derm Venereol）

INTRODUCTION: Both tralokinumab and dupilumab have shown efficacy in atopic dermatitis (AD) with moderate-to-severe hand involvement in double-blind phase 3 trials. As there are no head-to-head studies of tralokinumab and dupilumab, an anchored matching-adjusted indirect comparison (MAIC) was conducted. METHODS: In the ADHAND trial, adults with AD with moderate-to-severe hand involvement were randomised to tralokinumab 300 mg or placebo every 2 weeks for 16 weeks. In the LIBERTY-AD-HAFT trial, adults and adolescents (≥ 12 years) with moderate-to-severe AD with hand and/or foot involvement were randomised to dupilumab 300 mg or placebo every 2 weeks for 16 weeks. An anchored MAIC was conducted using individual patient data from ADHAND weighted to match aggregate data for age, sex, race, and baseline Hand Eczema Severity Index (HECSI) score from LIBERTY-AD-HAFT, with placebo as the common anchor. Endpoints compared at week 16 were proportions of patients with Investigator's Global Assessment scores of 0/1, HECSI-75 and HECSI-90, and percent reductions in HECSI and the Routine Activity Impairment domain of the Work Productivity and Activity Index. Reductions in itch and pain and proportions of patients with ≥ 4-point itch improvement were also compared. RESULTS: LIBERTY-AD-HAFT included 133 patients (dupilumab, n = 67, placebo, n = 66) while ADHAND included 235 patients (tralokinumab, n = 156; placebo, n = 79). The effective sample size after matching was 99 (tralokinumab, n = 76, placebo, n = 23). Anchor-adjusted relative treatment differences significantly favoured tralokinumab compared with dupilumab for the proportions of patients achieving HECSI-90 (17.5% [95% CI 0.8, 34.2]; p = 0.040) and decrease in percent routine activity impairment (16.0% [95% CI 4.8, 27.1]; p = 0.005). Relative differences for other endpoints favoured tralokinumab over dupilumab but were not significantly different between treatments. CONCLUSION: In this anchored MAIC, tralokinumab was associated with a higher placebo-adjusted response than dupilumab, with a higher proportion achieving HECSI-90, and a significantly greater improvement in ability to perform regular daily activities versus dupilumab. Other endpoints were numerically in favour of tralokinumab. Graphical abstract and video abstract available for this article. CLINICAL TRIAL REGISTRATION: NCT05958407, NCT04417894. Video Abstract (MP4 112997 KB).

Corrigendum to article: https://doi.org/10.2340/actadv.v105.43523.

INTRODUCTION: Real-world evidence on long-term effectiveness and safety of oral Janus kinase (JAK) inhibitors in atopic dermatitis (AD) remains limited. This study evaluated sustained long-term clinical and patient-reported disease control and safety during continuous treatment with upadacitinib 30 mg or baricitinib 4 mg. METHODS: This monocentric retrospective study included adults with moderate-to-severe AD treated at IRCCS Humanitas Research Hospital. Eligible patients had baseline assessments and completed longitudinal follow-ups while remaining on their assigned JAK inhibitor. Outcomes were assessed through week 260 for upadacitinib and week 312 for baricitinib and included Eczema Area and Severity Index (EASI) 75/90/100, EASI ≤ 7/≤ 3, Investigator Global Assessment (IGA) 0/1, mean EASI, Peak Pruritus Numerical Rating Scale (PP-NRS), Sleep Disturbance Numerical Rating Scale (SD-NRS) improvement and remission endpoints, and safety. Between-treatment comparisons were considered exploratory only. RESULTS: The long-term cohort included 41 patients: 34 received upadacitinib and 7 baricitinib. At week 260, EASI 75, EASI 90, EASI ≤ 7, and EASI ≤ 3 were achieved by 97.1%, 91.2%, 100.0%, and 91.2% of upadacitinib-treated patients, respectively. In the baricitinib group, EASI 75 was maintained by all patients from week 32 to week 312, and EASI 90, EASI ≤ 7, and EASI ≤ 3 were achieved by all patients at week 312. IGA 0/1 and mean EASI indicated sustained low disease activity during follow-up. At week 260, ΔPP-NRS ≥ 4 and ΔSD-NRS ≥ 4 were maintained in 82.4% and 73.5% of upadacitinib-treated patients and in 85.7% and 71.4% of baricitinib-treated patients, with corresponding baricitinib rates maintained at week 312. Adverse events were infrequent, with no serious adverse events, treatment interruptions, or permanent discontinuations in the long-term cohort. CONCLUSIONS: In selected patients remaining on continuous treatment, upadacitinib and baricitinib were associated with sustained long-term clinical and patient-reported control of moderate-to-severe AD. Larger prospective studies are needed to clarify outcomes after dose reduction or discontinuation and the potential for deeper disease remodeling.

Atopic dermatitis is a complex and relapsing inflammatory skin disease attributed to skin barrier dysfunction and immune dysregulation. Because of the heterogeneous and unpredictable nature of the disease, moderate to severe atopic dermatitis remains challenging to treat, with a continued need for therapeutics capable of modulating multiple inflammatory pathways. Antigen-presenting cells (APCs) drive T cell activation through both primary and secondary signals. As part of the secondary, costimulatory signals, OX40 ligand (OX40L), expressed on activated APCs, binds the OX40 receptor expressed on T cells. The OX40L/OX40 signaling pathway is active during a dynamic phase of atopic dermatitis pathogenesis, representing the immune system's preparatory state that precedes the onset of the overt immune imbalance. During this critical period, defined here as the inflammatory prequel, OX40L/OX40 interactions promote T cell proliferation, survival, and cytokine production and release, therefore priming and amplifying inflammatory pathways central to atopic dermatitis pathogenesis and development of the disease. Sustained OX40L/OX40 signaling further promotes the generation of memory T cells and inhibits regulatory T cell function, contributing to chronic inflammation. Uniquely positioned at the crossroads of inflammatory pathways, OX40L/OX40 represents an alternative therapeutic target for atopic dermatitis and potentially other T cell-driven inflammatory diseases. Clinical trials evaluating antibodies targeting OX40L or OX40 are ongoing, with new evidence still emerging. Clinical studies have demonstrated efficacy in skin clearance and pruritus that persists beyond active treatment, supporting the role of this pathway in atopic dermatitis. Targeting the inflammatory prequel and intervening during the activation of the inflammatory cascade may therefore offer an opportunity to modulate immune dysregulation and achieve more sustained disease control in patients with atopic dermatitis.Graphical abstract available for this article.