特应性皮炎（AD）前沿文献精读特辑（J Eur Acad Dermatol Venereol / J Invest Dermatol / JID Innov / Allergy）

INTRODUCTION: Janus kinase signal transducer and transcription activator (JAK-STAT) inhibitors have revolutionized the treatment of immune-mediated inflammatory diseases (IMIDs) of the skin, such as in atopic dermatitis, alopecia areata and vitiligo. Although several meta-analyses have confirmed their efficacy, concerns remain about the risk of infection, as the JAK-STAT pathway plays a key role in immune defence. Previous meta-analyses examined only selected, pre-specified infection categories and have not comprehensively evaluated all reported infection types or compared systemic and topical agents. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that reported infection-related adverse events in patients treated with systemic or topical JAK-STAT inhibitors for IMIDs of the skin. The study followed the PRISMA 2020 and Cochrane guidelines (PROSPERO: CRD 42024615839). Overall risk ratios (RRs) with 95% confidence intervals (CI) were calculated using a random-effects model. RESULTS: Seventy-four RCTs were included, involving more than 29,000 patients. JAK-STAT inhibitors were associated with an increased risk of influenza (RR = 2.12, 95% CI 1.03-4.36), bronchitis (RR = 2.03, 95% CI 1.43-2.88) and herpes zoster (RR = 1.67, 95% CI 1.29-2.15) compared to a placebo. The risk was particularly elevated in patients with atopic dermatitis (influenza: 3.22, 95% CI 2.03-5.10, herpes zoster: RR = 2.00, 95% CI 1.34-2.99). No significant risks were identified for serious, fungal or opportunistic infections, and topical JAK-STAT inhibitors demonstrated a favourable safety profile comparable to vehicle controls. CONCLUSIONS: This meta-analysis provides a comprehensive assessment of the risk of infection associated with JAK-STAT inhibitors in IMIDs of the skin. Although overall safety is acceptable, clinicians should be aware of the higher infection risk of influenza and herpes zoster and should consider vaccination and preventive strategies for high-risk patients with atopic dermatitis. The main limitation is that the included studies involved highly selected populations with few comorbidities and short follow-up.

Atopic dermatitis (AD) is increasingly recognized as a systemic inflammatory disease associated with increased cardiovascular risk, yet the mechanisms linking AD to atherosclerosis and clinically relevant biomarkers of early vascular involvement remain poorly defined. We characterized the circulating proteomic profile of moderate-to-severe AD and identified biomarkers associated with subclinical atherosclerosis. In this cross-sectional study, serum samples from patients with AD (n=34), psoriasis (n=34), and healthy controls (n=20) were analyzed using proteomic panels targeting inflammatory and cardiovascular pathways. Participants underwent carotid and femoral ultrasound to detect atheromatous plaques. Compared with controls, AD showed increased circulating Th2 (CCL13, ST2, IL-13), innate (IL-6, IL-18), Th1 (IFN-γ), and Th17 (IL-17RA) markers, together with cardiovascular-related proteins including CCL19, FGF21, HGF, and P-selectin, with enrichment of atherosclerosis-related pathways. In AD, plaques were associated with higher LDL receptor, CDH5, transferrin receptor, CCL19, and CCL25, and lower IGFBP-2 levels, which also correlated with atherosclerosis burden. A composite proteomic score showed good discrimination of plaques (AUC 0.94) and outperformed traditional cardiovascular risk factors. Proteomic profiles and plaque-associated proteins differed markedly from psoriasis. These findings identify a disease-specific systemic proteomic signature in AD linked to early atherosclerosis and highlight circulating biomarkers with potential relevance for cardiovascular risk stratification.

Alopecia areata (AA) is an immune-mediated hair loss disorder that frequently co-occurs with chronic inflammatory skin disorders, such as atopic dermatitis, vitiligo, and psoriasis. Emerging evidence suggest that such comorbidity profiles represent clinical AA subtypes with distinct etiological underpinnings. However, mechanistic insights remain limited owing to a lack of molecular datasets from comorbid patient cohorts. In this study, we addressed this gap by leveraging publicly available case-control gene expression datasets from AA, atopic dermatitis, vitiligo, and psoriasis for an integrative analysis. Our results revealed a statistically significant overlap between gene expression signatures of AA and each chronic inflammatory skin disorder, suggesting that their co-occurrence is not coincidental. Downstream analyses of shared gene expression signatures suggested catecholamine signaling and hair/skin-pigmentation-related processes as possible drivers of AA and vitiligo codevelopment, whereas skin barrier defects and dysregulation of specific immune response pathways may underlie the comorbid development of AA with atopic dermatitis or psoriasis. This study provides a foundation for future mechanistic investigations into skin, hair follicle, and immune system interactions that drive distinct comorbid AA subtypes.

BACKGROUND: Atopic dermatitis (AD) and psoriasis (PsO) are chronic inflammatory skin diseases with distinct features, but clinical and molecular overlap exists. These ambiguous phenotypes complicate diagnosis and treatment, and their immunologic basis remains poorly defined. This study aimed to delineate compartment-specific immune profiles in AD-PsO overlap lesions and explore candidate markers associated with molecular stratification. METHODS: Spatial transcriptomic profiling (GeoMx) was performed on 14 biopsies (AD = 4, PsO = 4, clinically ambiguous AD-PsO overlap = 6), followed by immunohistochemical (IHC) analysis of candidate markers in an expanded cohort (n = 35; AD = 9, PsO = 9, overlap = 17) to support the transcriptomic findings. RESULTS: AD-PsO overlap lesions demonstrated intermediate Th2 and Th17 signatures relative to AD and PsO and showed relative alignment toward AD-like or PsO-like molecular patterns rather than forming a single uniform state. Patient-level analyses showed distinct pathway profiles, with AD-like alignment associated with epidermal barrier-related pathways and dermal neural/sensory signaling, whereas the PsO-like alignment was associated with Th1, Th17, interferon, IL-15, and neutrophil-related pathways. Candidate genes associated with AD-like alignment included CCL13, CCL19, P2RY4, CXCR4, IL4I1, and EBI3, whereas MAVS and C1orf43 showed relative association with PsO-like alignment. IL36G, which was not used for alignment assignment, showed higher staining in PsO and PsO-like overlap cases than in AD and AD-like overlap cases, providing additional biological support for the observed molecular alignment. CONCLUSIONS: AD-PsO overlap lesions are molecularly heterogeneous and align toward AD-like or PsO-like inflammatory patterns. Compartment-resolved profiling provides a hypothesis-generating framework for molecular characterization of clinically ambiguous cases that merits validation in larger independent cohorts.