Safety of dupilumab in T2 airways conditions: focus on eosinophilia across trials and real-life evidence.

INTRODUCTION: Dupilumab, a monoclonal antibody targeting the IL-4 receptor alpha subunit, effectively blocks both IL-4 and IL-13 mediated pathways. Its introduction has represented a significant advancement in the treatment of severe asthma and other Type 2 (T2) conditions, including nasal polyps, atopic dermatitis, and eosinophilic esophagitis. To date, Dupilumab has demonstrated optimal efficacy and safety profile. AREAS COVERED: The safety profile of dupilumab has been extensively studied, especially for its effects on blood eosinophil count. Transient eosinophil increase during treatment is typically insignificant from a clinical point of view and related to its mechanism of action. Rare cases of hyper-eosinophilia associated with clinical conditions like eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES) have been reported. Those cases are often related to the drug's steroid-sparing effect or the natural trajectory of the underlying disease rather than a direct cause-effect relationship with dupilumab. EXPERT OPINION: The management of hyper-eosinophilia during dupilumab treatment requires comprehensive diagnostic work-up and strict follow-up monitoring for early detection of systemic disease progression in order to avoid unnecessary discontinuation of an effective treatment. This approach highlights the importance of a personalized treatment.

Dupilumab for the Treatment of Prurigo Nodularis.

Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by the presence of pruritic nodules. Dupilumab was approved by the US Food and Drug Administration in September 2022 and Health Canada in July 2023 for the treatment of PN. Dupilumab is a human monoclonal immunoglobulin G4 antibody that binds the interleukin (IL)-4 receptor alpha subunit, blocking intercellular signalling of IL-4 and IL-13. Inhibition of these cytokines downregulates the inflammatory response and improves disease severity and pruritus. Two randomized controlled trials have shown dupilumab to be effective in reducing pruritus and lesion count in patients with PN. The approval of dupilumab for PN represents the first approved therapy for PN and may indicate a paradigm shift in the way this condition is treated.

Anti-interleukin 4 receptor α antibody for the treatment of Chinese bullous pemphigoid patients with diverse comorbidities and a 1-year follow-up: a monocentric real-world study.

Background: Bullous pemphigoid (BP) is a common subepidermal bullous disorder that lacks adequate treatment alternatives. Dupilumab, an anti-interleukin (IL) 4 receptor α antibody blocking Th2 molecules IL-4 and 13, has been used off-label and shown to be effective in refractory BP cases. Methods: BP patients with various disease severities and comorbidities were included in this case series. All patients received dupilumab alone or in combination with immunosuppressants in a real-world setting. Complete remission (CR) was defined as the absence of pruritus symptoms and previous BP eruptions, with only hyperpigmentation patches and without newly occurring lesions for at least 4 weeks. Disease relapse was classified as the appearance of three or more new lesions within 1 month or at least one large urticarial or eczematous lesion that did not resolve within a week. Findings: Ten individuals were enrolled in this case series. Pruritus symptoms and BP eruptions improved significantly in nine patients (90%). Seven patients (70%) attained CR, including all mild-to-moderate (100%) cases and three of six (50%) severe BP cases. At the dupilumab monotherapy stage, eosinophilia was observed in two severe cases. One patient out of seven (14.3%) relapsed after 1 year of follow-up after CR. Conclusion: Treatment of BP with diverse comorbidities with anti-IL-4 receptor α antibody provides further credentials to a prospective randomized study. More impressive efficacy and safety profiles were observed in patients with mild-to-moderate disease after 1 year of follow-up. Eosinophilia may occur in patients receiving dupilumab monotherapy.

Identification of clinical predictors for dupilumab dose spacing in adults with atopic dermatitis: a real-world study.

BACKGROUND: Dupilumab is a monoclonal antibody against the IL-4/IL-13 receptor-subunit approved for the treatment of moderate-severe atopic dermatitis (AD). Some attempts to increase dose interval have been described in both trial and real-world settings. OBJECTIVE: This study aimed to identify predictive clinical and demographic factors affecting patient selection for dose spacing or treatment withdrawal due to satisfactory response. MATERIALS AND METHODS: This retrospective study included adult patients with moderate-to-severe AD treated with dupilumab for at least 16 weeks. Descriptive statistics were performed to analyze demographic and clinical variables. Logistic regression models were used to identify predictor variables. RESULTS: A total of 818 adult patients with moderate-to-severe AD was included in the study and 12% (97/818) of them performed dose spacing to 3-4 weeks or treatment withdrawal (8%, 67/818). The presence of non-cutaneous atopic manifestations (OR = 1.59, 95%CI = 1.06-2.38, p = 0.024), prurigo nodularis phenotype (OR = 4.5, 95%CI = 1.87-10.9, p = 0.001) and the age at treatment initiation (OR = 1.82, 95%CI = 1.12-2.94, p = 0.015) were confirmed as the strongest predictors of dose spacing or treatment withdrawal while maintaining dupilumab effectiveness. CONCLUSION: Our findings contribute to define the patient profile that could maintain the therapeutic response after dose spacing or treatment withdrawal.

Predicting factors identified patients with dupilumab who could benefit of dose spacing or treatment withdrawal.

IL-4Rα signalling in B cells and T cells play differential roles in acute and chronic atopic dermatitis.

Atopic dermatitis (AD) is a common pruritic inflammatory skin disease with complex environmental and genetic predisposing factors. Primary skin barrier dysfunction and aberrant T helper 2 (TH2) responses to common allergens, together with increased serum IgE antibodies, characterise the disease. B and T cells are essential in the disease manifestation, however, the exact mechanism of how these cells is involved is unclear. Targeting interleukin 4 receptor alpha (IL-4Rα), an IL-4/IL-13 signalling axis, with dupilumab shows efficacy in AD. We investigated the importance of IL-4Rα signalling specifically on B and T cells during acute and chronic models of AD. We used House dust mite (HDM) and Ovalbumin (OVA) in chronic models and a low-calcemic analog of vitamin D (MC903) for acute models of AD. We used mb1creIL-4Rα-/lox, iLCKcreIL-4Rα-/lox, LCKcreIL-4Rα-/lox, CD4creIL-4Rα-/lox, Foxp3creIL-4Rα-/lox and IL-4Rα-/lox littermate controls. IL-4Rα-responsive B cells were essential in serum IgE levels, but not in epidermal thickening in both chronic and acute models. IL-4Rα-responsive T cells were essential in epidermal thickening in the pan-T cell, but not CD4 or CD8 T cells suggesting the importance of γδT cells during acute AD. Our results suggest that IL-4Rα responsiveness on innate T cells regulates acute atopic dermatitis, while on B cells it regulates IgE.

Interleukin-3 stabilizes CD124/IL-4α surface expression in mast cells via Tyk2 and STAT6.

Interleukin (IL)-4 signals can modulate mast cells, which express the IL-4Rα chain. The IL-4Rα can heterodimerise with the common γ-chain and utilizes JAK1 and JAK2 for signal transduction, while complexes of IL-4Rα with IL-13Rα1 subunit mediates signals via JAK2 and Tyk2. Here, we report that IL-3 is an essential factor for the continuous expression of the IL-4Rα chain on mast cells, which did not express the IL-13Rα1 chain. We demonstrate that the signals induced by IL-3 important for IL-4Rα expression are mediated by Tyk2 and STAT6 activation and the subsequent maintenance of HSP90 levels. In line with that, inhibition of either Tyk2, STAT6 or HSP90 impaired the IL-3-induced IL-4Rα upregulation. Consequently, the IL-3 maintained IL-4Rα surface expression via Tyk2 is essential for the costimulatory effect of IL-4 on the IL-33-induced production of IL-6 and IL-13.

IgG memory B cells expressing IL4R and FCER2 are associated with atopic diseases.

BACKGROUND: Atopic diseases are characterized by IgE antibody responses that are dependent on cognate CD4 T cell help and T cell-produced IL-4 and IL-13. Current models of IgE cell differentiation point to the role of IgG memory B cells as precursors of pathogenic IgE plasma cells. The goal of this work was to identify intrinsic features of memory B cells that are associated with IgE production in atopic diseases. METHODS: Peripheral blood B lymphocytes were collected from individuals with physician diagnosed asthma or atopic dermatitis (AD) and from non-atopic individuals. These samples were analyzed by spectral flow cytometry, single cell RNA sequencing (scRNAseq), and in vitro activation assays. RESULTS: We identified a novel population of IgG memory B cells characterized by the expression of IL-4/IL-13 regulated genes FCER2/CD23, IL4R, IL13RA1, and IGHE, denoting a history of differentiation during type 2 immune responses. CD23+ IL4R+ IgG+ memory B cells had increased occurrence in individuals with atopic disease. Importantly, the frequency of CD23+ IL4R+ IgG+ memory B cells correlated with levels of circulating IgE. Consistently, in vitro stimulated B cells from atopic individuals generated more IgE+ cells than B cells from non-atopic subjects. CONCLUSIONS: These findings suggest that CD23+ IL4R+ IgG+ memory B cells transcribing IGHE are potential precursors of IgE plasma cells and are linked to pathogenic IgE production.

Anti-cancer activity of microbubble conjugated with Sorafenib containing liposome and IL4R-targeting peptide in kidney cancer cells.

Microbubble-based cancer treatment is a promising new approach that utilizes tiny gas-filled bubbles to deliver cancer drugs directly to tumor sites. This study aims to investigate the anti-cancer effect of the novel microbubble (MB) complex conjugated with sorafenib containing liposome and interleukin 4 receptor (IL4R) targeting peptide in kidney cancer cells. MBs were synthesized by using a solvent with an emulsion evaporation technique. To target kidney tumor cells, the produced MBs were conjugated with sorafenib (SOR) loaded liposomes and peptide ligands for (IL4RTP). The anti-cancer effect of the MB complex was accessed by WST-1 assay, confocal microscopy analysis, and western blotting analysis. The finally prepared IL4RTP (MB-Lipo(SOR)-IL4RTP) showed an average size of 1,600 nm. A498, a kidney cancer cell line that expresses IL4Rα strongly, had an uptake of the MB-Lipo(SOR)-IL4RTP when exposed to frequency ultrasonic energy. Additionally, MB-Lipo(SOR)-IL4RTP suppressed the growth of A498 cells in an IL4R-dependent manner. This cell proliferation assay results were validated by western blotting analysis of the signal transduction proteins such as FOXO3, phosphorylated Erk, total Erk, and p27. Taken together, these findings show that MB-Lipo(SOR)-IL4RTP exerts the effective targeting capacity for A498 kidney cancer cells via regulation of Erk phosphorylation as a promising ultrasound contrast and therapeutic agent for treating kidney cancers.

Atopic Dermatitis Mediates the Association Between an IL4RA Variant and Food Allergy in School-Aged Children.

BACKGROUND: Atopic dermatitis (AD) and food allergy (FA) may share genetic risk factors. It is unknown whether genetic factors directly cause FA or are mediated through AD, as the dual-allergen hypothesis suggests. OBJECTIVE: To test the hypothesis that AD mediates the relationship between an IL-4 receptor alpha chain gene (IL4RA) variant, the human IL-4 receptor alpha chain protein-R576 polymorphism, and FA. METHODS: A total of 433 children with asthma enrolled in the School Inner-City Asthma Study underwent genotyping for the IL4RA576 allele. Surveys were administered to determine FA, AD, and associated allergic responses. Mediation analysis was performed adjusting for race and ethnicity, age, sex, and household income. Multivariate models were used to determine the association between genotype and FA severity. RESULTS: AD was reported in 193 (45%) and FA in 80 children (19%). Each risk allele increased odds of AD 1.39-fold ([1.03-1.87], P = .03), and AD increased odds of FA 3.67-fold ([2.05- 6.57], P < .01). There was an indirect effect of genotype, mediated by AD, predicting FA; each risk allele increased the odds of FA by 1.13 (odds ratio [95% CI], Q/R = 1.13 [1.02-1.24], R/R = 1.28 [1.04-1.51]; P < .01). Each risk allele increased the odds of severe FA symptoms 2.68-fold ([1.26-5.71], P = .01). CONCLUSIONS: In a cohort of children with asthma, AD is part of the causal pathway between an IL4RA variant and FA. This variant is associated with increased risk of severe FA reactions. Addressing AD in children with an IL4RA polymorphism may modulate the risk of FA.

Dupilumab ocular side effects in patients with atopic dermatitis: a systematic review.

Atopic dermatitis (AD) is a chronic, inflammatory skin disorder that most frequently occurs in children, but it can also affect adults. Even though most AD cases can be managed with topical treatments, moderate-to-severe forms require systemic therapies. Dupilumab is the first human monoclonal antibody approved for the treatment of AD. Its action is through IL-4 receptor alpha subunit inhibition, thus blocking IL-4 and IL-13 signaling pathways. It has been shown to be an effective, well-tolerated therapy for AD, as well as for asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and eosinophilic esophagitis (EoE). However, an increasing incidence of dupilumab-induced ocular surface disease (DIOSD) has been reported in patients treated with dupilumab, as compared to placebo. The aim of this study was to summarize scientific data regarding DIOSD in AD patients treated with dupilumab. A search of PubMed and clinicaltrials.gov databases was performed. There was no limit to study design. All AD cases were moderate-to-severe. DIOSD was either dermatologist-, allergist-, or ophthalmologist-assessed. Evidence shows that DIOSD occurs most frequently in patients with atopic dermatitis and not in other skin conditions, neither in patients with asthma, CRSwNP, nor EoE who are on dupilumab treatment. Further studies are warranted in order to establish a causal relationship between dupilumab and ocular surface disease. Nevertheless, ophthalmological evaluations prior to dupilumab initiation can benefit AD patients with previous ocular pathology or current ocular symptomatology. Also, patch testing for ocular allergic contact dermatitis might be advantageous in patients with a history of allergic conjunctivitis. Furthermore, TARC, IgE, and circulating eosinophils levels might be important biomarkers for a baseline assessment of future candidates to dupilumab treatment. However, TARC measurements should be resumed for research purposes only.

Successful use of dupilumab for the treatment of atopic dermatitis on the genitals, a neglected anatomical site.

Atopic dermatitis (AD) is a chronic inflammatory disease that may involve any cutaneous site; involvement of the genital area may greatly impair patients' quality of life but, as the inspection of genitals is not usually conducted during the routine physical examination of patients with AD, the genital presentation of AD is frequently neglected and under-reported. We decided to evaluate the incidence of genital AD in patients with moderate-severe AD and the relative response to anti-interleukin (IL)-4/IL-13 dupilumab. In our study, a high incidence of genital AD emerged but the use of dupilumab allowed a generalized improvement.

CircIL4R activates the PI3K/AKT signaling pathway via the miR-761/TRIM29/PHLPP1 axis and promotes proliferation and metastasis in colorectal cancer.

BACKGROUND: Accumulating studies have revealed that aberrant expression of circular RNAs (circRNAs) is widely involved in the tumorigenesis and progression of malignant cancers, including colorectal cancer (CRC). Nevertheless, the clinical significance, levels, features, biological function, and molecular mechanisms of novel circRNAs in CRC remain largely unexplored. METHODS: CRC-related circRNAs were identified through bioinformatics analysis and verified in clinical specimens by qRT-PCR and in situ hybridization (ISH). Then, in vitro and in vivo experiments were performed to determine the clinical significance of, functional roles of, and clinical characteristics associated with circIL4R in CRC specimens and cells. Mechanistically, RNA pull-down, fluorescence in situ hybridization (FISH), luciferase reporter, and ubiquitination assays were performed to confirm the underlying mechanism of circIL4R. RESULTS: CircIL4R was upregulated in CRC cell lines and in sera and tissues from CRC patients and was positively correlated with advanced clinicopathological features and poor prognosis. Functional experiments demonstrated that circIL4R promotes CRC cell proliferation, migration, and invasion via the PI3K/AKT signaling pathway. Mechanistically, circIL4R was regulated by TFAP2C and competitively interacted with miR-761 to enhance the expression of TRIM29, thereby targeting PHLPP1 for ubiquitin-mediated degradation to activate the PI3K/AKT signaling pathway and consequently facilitate CRC progression. CONCLUSIONS: Our findings demonstrate that upregulation of circIL4R plays an oncogenic role in CRC progression and may serve as a promising diagnostic and prognostic biomarker for CRC detection and as a potential therapeutic target for CRC treatment.

Dupilumab for the treatment of nivolumab-induced bullous pemphigoid: a case report and review of the literature.

Immune checkpoint inhibitors, a relatively new class of drugs, are used to treat a variety of malignancies. These drugs have a known association with cutaneous side effects, such as bullous pemphigoid. Bullous pemphigoid is a pruritic blistering disorder that is caused by autoantibodies forming against the basement membrane of the epidermis. New research has shown that interleukin-4, interleukin-13, and eosinophils play a significant role in the pathogenesis of bullous pemphigoid. Dupilumab, an IL4 alpha receptor antagonist has been shown to reduce IL4 and IL13 in atopic dermatitis. We present a case of nivolumab-induced bullous pemphigoid that was successfully treated with dupilumab.