Journal of Allergy and Clinical Immunology最新文献

Background: Ataxia Telangiectasia (A-T) is a DNA repair disorder with cancer predisposition.

Objective: Characterize the prevalence and outcomes of hematologic and solid cancers and treatment-associated toxicities in individuals with A-T.

Methods: Data was retrospectively analyzed from the Johns Hopkins Ataxia Telangiectasia Clinical Center cohort. Cumulative incidence and standardized incidence ratios of cancer, survival probability after cancer diagnosis, and standardized mortality ratios were calculated. Cox regression estimated risk of death based on chemotherapy (standard v reduced) dosing and multivariable logistic regression evaluated cancer risk associations with ATM exons and variants.

Results: Eighty-four (16.5%) of 508 individuals were diagnosed with a primary cancer, 62 (74%) were hematologic in origin and 22 (26%) were solid organ cancers. The cumulative incidence of cancer was 29% by age 35 years. Non-Hodgkin lymphoma occurred most frequently (n=39), while solid cancers disproportionately affected those ≥18 years old (n=22). The standardized mortality ratio was 24.6 (95% CI:21.1-28.4) overall and 232.9 (95% CI:178.1-299.2) among individuals with cancer. Risk of death was higher when treated with standard/unknown versus modified chemotherapy (HR 2.2, 95% CI:1.1-4.4, p=0.024). Chemotherapy-associated toxicities developed in 58% of individuals, predominantly neurologic (n=14) and gastrointestinal (n=10) systems. Three exons were enriched for cancer-associated variants.

Conclusion: Individuals with A-T experience a wide array of blood and solid organ malignancies, high mortality rates, and treatment related toxicities, highlighting need for targeted therapies to mitigate toxicity and optimize survival.

Clinical implication: A-T patients with cancer face elevated mortality rates, underscoring the urgency for tailored therapies to minimize toxicity and improve survival outcomes.

Background: Clinical trials and real-world experience have provided evidence for the clinical benefit of mepolizumab, an anti-IL-5 biologic, in severe asthma. However, limited data exists regarding the impact of mepolizumab on airway remodelling.

Objective: We thus investigated the effect of mepolizumab on airway structural remodelling in patients treated for severe asthma in routine clinical care.

Methods: MESILICO is a multicenter study involving 8 Pulmonology Departments in Greece. This study focused on patients who initiated mepolizumab for severe asthma with an eosinophilic phenotype and had late-onset disease with obstructive patterns (impaired reversibility). Forty-seven patients were recruited, of whom 41 were enrolled in the bronchoscopy sub-study. The findings were related to clinical outcome.

Results: After 12 months, mepolizumab treatment was associated with significant improvements in lung function and ACT score, along with a significant decrease in severe exacerbation events (p<0.001). Thirty four of the 41 participants (83%) had paired biopsies for comparative analysis. There was a significant reduction from baseline in sub-basement membrane thickness, airway smooth muscle area, airway smooth muscle layer thickness and extent of epithelial damage, as well as a decrease in tissue eosinophil numbers (all p<0.001). The extent of ASMLT reduction positively correlated with the submucosal eosinophil reduction (r= 0.599, p<0.001).

Conclusion: This study identifies that 12 month of mepolizumab treatment in patients with late-onset severe asthma, who are also characterized by eosinophilic and impaired reversibility phenotypes, leads not only to clinical improvement but also reduces indices of airway tissue remodelling suggestive of a disease modifying effect.

Background: T helper 2 (Th2) cells crucially contribute to the pathogenesis of atopic dermatitis (AD) by secreting high levels of IL-13 and IL-22. Yet, the upstream regulators that activate Th2 cells in AD skin remain unclear. IL-18 is a putative upstream regulator of Th2 cells as it is implicated in AD pathogenesis and has the capacity to activate T cells.

Objective: To decipher the role of IL-18 in Th2 responses in blood and skin of AD patients.

Methods: PBMCs and skin biopsies from AD patients and healthy donors were used. Functional assays were performed ex vivo using stimulation or blocking experiments. Analysis was performed using flow cytometry, bead-based multiplex assays, RT-qPCR, RNA-seq, western blotting, and spatial sequencing.

Results: IL-18Rα⁺ Th2 cells were enriched in blood and lesional skin of AD patients. Of all the cytokines for which Th2 cells express the receptor, only IL-9 was able to induce IL-18R via an IL-9R-JAK1/JAK3-STAT1 signaling pathway. Functionally, stimulation of circulating Th2 cells with IL-18 induced secretion of IL-13 and IL-22, an effect that was enhanced by co-stimulation with IL-9. Mechanistically, IL-18 induced Th2 cytokines via activation of IRAK4, NF-κB, and AP-1 signaling in Th2 cells, and neutralization of IL-18 inhibited these cytokines in cultured explants of AD skin lesions. Finally, IL-18 protein levels correlated positively with disease severity in lesional AD skin.

Conclusion: Our data identify a novel IL-9-IL-18 axis that contributes to Th2 responses in AD. Our findings suggest that both IL-9 and IL-18 could represent upstream targets for future treatment of AD.

Background: There have been multiple reports of the anti-IL4Rα agent, dupilumab, as associated with the onset and/or progression of cutaneous T-cell lymphoma (CTCL).

Objective: We sought to evaluate safety signals associated with dupilumab, with a focus on CTCL, and to evaluate possible underlying mechanism(s) for the potential association.

Methods: First, we used the FDA pharmacovigilance database, FAERS, to evaluate if dupilumab was associated with CTCL including both positive controls (conjunctivitis, eosinophilia, and arthralgia) and exposure controls (other medications with similar indications including JAK-inhibitors and the anti-IL13, tralokinumab,) to reduce and evaluate confounding bias. Thereafter, we used publicly available bulk and single cell-RNA seq datasets to probe possible underlying mechanisms through which dupilumab might be associated with CTCL.

Results: Between January 2019 and Q2 of 2023, there were 181,575 unique reports of dupilumab related adverse events (AE) in FAERS with 606 of these being for a neoplasm. Dupilumab had 30.0 times the proportional reporting ratio (PRR) (95% CI: 25.0 - 35.9) for CTCL compared to all other medications in FAERS. The risk was highest in males aged 45-65. The PRR for conjunctivitis, eosinophilia, and arthralgia, known side effects of dupilumab, were 35.6 (34.4 - 36.8), 2.15 (2.00 - 2.31), and 2.14 (2.07 - 2.18) respectively. Using the log-count normalized PRR (AE score) to account for PRR inflation when reports were small, the top safety signals included conjunctivitis (AEscore 8.3) and CTCL (AEscore 4.9). Bulk RNA sequencing data showed changes in IL4RA and IL13RA1 expression in CTCL and in epidermal layers of atopic dermatitis (AD) biopsies. Single-cell transcriptomic studies revealed that this change was similar in AD and CTCL, and that keratinocytes seemed to be the most divergent cell type with regards to IL4R and IL13RA1. An effect on keratinocyte specific gene expression was also independently observed in available bulk RNA sequencing data.

Conclusion: These data suggest that dupilumab might be causing an unmasking or progression of CTCL via the same mechanism through which it improves atopic dermatitis: IL13 receptor blockade, which leads to increased IL13 in the local milieu, driving CTCL stimulation and progression. However, these associations need further evaluation given the inherent limitations of the FAERS database and our non-experimental approach.

Background: The mental health conditions of allergic diseases has been investigated, but the consistency and magnitude of their effects are unclear. The aim of this umbrella review is to systematically evaluate the published evidence on allergic diseases and mental health conditions to establish a new hierarchy of evidence and identify gaps in this area of research.

Methods: We systematically searched PubMed, Embase, Web of Science and the Cochrane Database of Systematic Reviews from database inception to April 30, 2024. We included systematic reviews that conducted meta-analyses that examined the association of allergic diseases and mental health conditions. We calculated summary effect estimates (odds ratio [OR]), 95% confidence intervals, I²statistic, 95% prediction interval, small study effects, and excess significance biases. We used AMSTAR 2 to appraise the methodological quality of the included studies.

Results: We identified 21 eligible articles which yielded 37 associations (38,4405,029 total population) of allergic diseases and mental health conditions. The credibility of evidence was convincing (class I) for asthma and risk of attention deficit/hyperactivity disorder (ADHD) (OR 1.34, 1.24-1.44); and highly suggestive (class II) for allergic rhinitis and risk of tic disorders (OR 2.61, 1.90-3.57), allergic rhinitis and risk of sleep disorders (OR 2.17, 1.87-2.53), food allergy and risk of autism spectrum disorder (ASD) (OR 2.79, 2.08-3.75), atopic dermatitis and risk of depression (OR 1.60, 1.43-1.79), atopic dermatitis and risk of anxiety (OR 1.62 1.42-1.85), atopic dermatitis and risk of ADHD (OR 1.28, 1.18-1.40), atopic dermatitis and risk of suicidal ideation (OR 1.44, 1.25-1.65), asthma and risk of depression (OR 1.64, 1.50-1.78), asthma and risk of anxiety (OR 1.95, 1.68-2.26), asthma and risk of tic disorders (OR 1.90, 1.57-2.30), asthma and risk of suicidal ideation (OR 1.52, 1.37-1.70), and asthma and risk of suicide attempts (OR 1.60, 1.33-1.92).

Conclusions: Allergic diseases are associated with increased risk of a range of mental health conditions, with the most convincing evidence that asthma. However, these associations do not imply causality, and there is large heterogeneity in these associations, which requires high-quality preliminary studies to identify causality and strength of evidence.