Chronic spontaneous urticaria (CSU) and atopic dermatitis (AD) are pruritic inflammatory skin diseases that share partly overlapping mast-cell-related pathways, including IgE/FcεRI signaling, type 2 inflammation, neuroimmune signaling, and lipid mediator pathways. Yet they usually produce distinct phenotypes: transient wheals and angioedema in CSU and persistent eczematous lesions with inflammation in AD. Whether disease activity in the two conditions fluctuates concordantly or independently within the same patient has not been directly tested. This Perspective proposes that phenotypic divergence reflects the tissue-response network in which mast cell activation is embedded rather than mediator identity alone. In CSU, autoimmune and autoallergic FcεRI-dependent activation, MRGPRX2-related neuropeptide pathways, coagulation/fibrinolysis-C5a signaling, and platelet-activating factor (PAF)/lipid mediators may preferentially converge on mast cells and basophils poised for rapid degranulation within the dermal vascular/perivascular unit. This network favors histamine bursts, endothelial hyperpermeability, neurovascular itch, and feedback-limited wheal formation. In AD, mast cells are embedded in a barrier-disrupted, alarmin-rich neuroepidermal niche, producing a multicellular inflammatory network involving keratinocyte activation, cytokine and chemokine production, neuronal sensitization, itch-scratch cycling, and tissue remodeling, although degranulation and vascular effects may also occur. Neuropeptides and PAF illustrate how shared mediators may be preferentially routed toward vascular leakage in CSU or neuroepidermal inflammatory amplification in AD. This tissue-addressed mast cell output model is proposed as a testable hypothesis for how overlapping inflammatory mediators may generate feedback-limited vascular whealing in CSU but sustained neuroepidermal inflammation in AD. The model emphasizes that shared pathways are preferentially weighted toward different tissue-level outcomes in CSU and AD.
Hereditary alpha-tryptasemia (H α T) has emerged over the past decade as an important genetic modifier of mast cell–mediated disease and anaphylaxis. First described in 2016 by Lyons and colleagues, H α T is an autosomal dominant genetic trait caused by increased germline copy numbers of the TPSAB1 gene encoding α -tryptase. It affects approximately 4%–6% of Western populations and is now recognized as the most common cause of elevated basal serum tryptase (BST) levels in otherwise healthy individuals. Despite its high prevalence, the clinical penetrance of H α T is remarkably heterogeneous. Approximately one-third of individuals carrying the trait remain asymptomatic, whereas others develop multisystem manifestations that include flushing, pruritus, gastrointestinal symptoms, and recurrent systemic reactions. While associations with connective tissue abnormalities, dysautonomia, joint hypermobility, and postural orthostatic tachycardia syndrome (POTS) were initially reported, these were later disproven. Importantly, H α T is best understood as a genetic trait rather than a disease entity, with clinical relevance that depends strongly on context.
Chronic spontaneous urticaria is a common, mast cell driven condition that presents with wheals, angioedema, or both, and a substantial proportion of patients remain inadequately controlled despite guideline-directed antihistamine therapy. The 2026 guideline has expanded the advanced-treatment options to include omalizumab, dupilumab and remibrutinib, while ciclosporin remains an alternative later-line immunosuppressive option, yet it is organised around treatment response rather than prognosis, so patients with difficult-to-control disease are often recognised only after months of sequential escalation. This narrative review examines the scoring systems and biomarkers available in urticaria and angioedema and considers whether they can support early risk stratification and help identify patients at increased risk of difficult-to-control disease. The validated instruments in routine use, namely the Urticaria Activity Score, the Urticaria Control Test, the Chronic Urticaria Quality of Life Questionnaire, and their angioedema counterparts, measure current disease activity, control, and quality of life rather than long term outcome. A separate body of work has described biomarkers associated with the autoimmune type IIb endotype and with response to omalizumab, including low total IgE, a high ratio of IgG anti-thyroid peroxidase to total IgE, basopenia, and raised inflammatory markers, although most of this evidence is associative rather than prospectively predictive. The distinction between markers of current burden, markers of prognosis, and markers of treatment response is emphasised. Composite models integrating clinical characteristics, patient-reported outcomes, and biomarkers represent a promising approach toward precision management of CSU, although no validated prognostic tool is currently available for routine clinical use.
Mahnaz Jamee, Roba Maher Al-Gaweesh, Amirhossein Hajialigol, Sally Gouda Mohammed, Peyman Tirandazi, Abdullah A. Alangari, Rasha El-Owaidy
Atopy might be the initial or dominant manifestation in patients with inborn errors of immunity (IEIs). Biologics and Janus kinase (JAK) inhibitors have emerged as targeted options for atopic disorders in IEIs refractory to conventional treatment. We conducted a systematic review of PubMed, Web of Science, and Scopus for human studies reporting biologics or JAK inhibitors used specifically to treat atopic manifestations in IEIs. Data on genotypes, clinical phenotypes, treatments, outcomes, adverse events, and laboratory changes were extracted and synthesized. The databases were last searched in April 2026. Study quality was appraised with the Joanna Briggs Institute checklists and the certainty of evidence was rated following GRADE principles. Eighty-one studies comprising 172 patients were included. The most common IEIs were STAT3 loss-of-function (LOF) disease (n = 52, 30.2%), Netherton syndrome (n = 32, 18.6%), and DOCK8 deficiency (n = 19, 11.0%). Dupilumab (n = 120, 69.8%) was the most frequently reported agent, followed by JAK inhibitors (n = 21, 12.2%) and omalizumab (n = 16, 9.3%). A complete or major clinical response was described in most published patients treated with dupilumab, together with improvement in skin disease in some patients. Omalizumab was also associated with a favorable outcome in atopic dermatitis and asthma, with steroid-sparing effects and few reported adverse events. Responses to JAK inhibitors were most often described in patients with JAK-STAT pathway defects, although adverse events such as anemia were reported in some cases. All proportions are descriptive frequencies among published patients with available outcome information and are not estimates of treatment effectiveness. Published case reports and small series suggest that biologics and JAK inhibitors may provide clinically meaningful control of selected atopic or atopic-like manifestations in some patients with IEIs. Dupilumab has the largest published experience, while JAK inhibitors may be particularly relevant when the underlying disorder involves JAK-STAT pathway activation. Due to the lack of evidence, treatment should remain individualized, genotype-informed, and accompanied by careful infection surveillance and longitudinal outcome assessment.
Jinguo Chen, J. Joanna Yu, Jing Yu, Lili Wan, Joseph Chiao, Athena Economides, Dingfen Han, H. Henry Li
Peanut oral immunotherapy (pOIT) can achieve desensitization, yet patients with high peanut-sIgE may experience more adverse reactions and treatment failure. We evaluated a conservative pOIT protocol in children with high Ara h 2-sIgE (≥40 kU/L) and examined longitudinal basophil activation test (BAT) and sIgE/sIgG4 trajectories as candidate biomarkers. Thirty-two peanut-allergic children underwent pOIT, including 16 with high and 16 with lower Ara h 2-sIgE. All received low-dose initiation and slow up-dosing. Clinical outcomes, safety, and immunologic markers were evaluated longitudinally for up to 36 months. Effective desensitization (≥300 mg peanut protein) was achieved in 68.8% of high-sIgE and 62.5% of lower-sIgE participants. One severe adverse event occurred in each subgroup, with no treatment-related discontinuations. Peanut and Ara h 2/6-sIgE levels rose transiently before gradually declining, whereas sIgG4 increased early, leading to a reduced sIgE/sIgG4 ratio. A ratio <50 was associated with effective desensitization. BAT responses initially increased and subsequently declined, with progressive increase in the activation threshold. Baseline BAT and sIgE were not associated with desensitization. However, BAT area under the curve (AUC) <100 was significantly associated with effective desensitization with ROC AUC of 0.784 (bootstrap 95% CI 0.536–0.983). Exploratory time-lagged analyses did not establish prospective predictive utility. Low-dose initiation, slow-escalation pOIT achieved effective desensitization in patients with high Ara h 2-sIgE, without treatment-related discontinuations. Longitudinal reductions in BAT and sIgE/sIgG4 ratio were associated with increased ingested dose. These exploratory biomarkers may provide adjunctive information during pOIT, but prospective validation is required.
