Engineering the IL-4/IL-13 axis for targeted immune modulation.

The structurally and functionally related interleukin-4 (IL-4) and IL-13 cytokines play pivotal roles in shaping immune activity. The IL-4/IL-13 axis is best known for its critical role in T helper 2 (Th2) cell-mediated Type 2 inflammation, which protects the host from large multicellular pathogens, such as parasitic helminth worms, and regulates immune responses to allergens. In addition, IL-4 and IL-13 stimulate a wide range of innate and adaptive immune cells, as well as non-hematopoietic cells, to coordinate various functions, including immune regulation, antibody production, and fibrosis. Due to its importance for a broad spectrum of physiological activities, the IL-4/IL-13 network has been targeted through a variety of molecular engineering and synthetic biology approaches to modulate immune behavior and develop novel therapeutics. Here, we review ongoing efforts to manipulate the IL-4/IL-13 axis, including cytokine engineering strategies, formulation of fusion proteins, antagonist development, cell engineering approaches, and biosensor design. We discuss how these strategies have been employed to dissect IL-4 and IL-13 pathways, as well as to discover new immunotherapies targeting allergy, autoimmune diseases, and cancer. Looking ahead, emerging bioengineering tools promise to continue advancing fundamental understanding of IL-4/IL-13 biology and enabling researchers to exploit these insights to develop effective interventions.

Increased Muc5AC and Decreased Ciliated Cells in Severe Asthma Partially Restored by Inhibition of IL-4Rα Receptor.

BACKGROUND: The role of IL-13 on the airway epithelium in severe asthma leading to airway remodeling remains poorly understood. OBJECTIVE: To study IL-13 induced airway remodeling on goblet cells and cilia in the airway epithelium in severe asthma and the impact of an anti-IL4Rα antibody, dupilumab, in vitro. METHODS: Quantitative CT (qCT) lungs and endobronchial biopsies and brushings were obtained in 51 participants (22 severe, 11 non-severe asthma and 18 healthy participants) in the Severe Asthma Research Program (SARPIII) and measured for mucin and cilia related proteins. Epithelial cells were differentiated in air-liquid interphase (ALI) with IL-13 +/-dupilumab and assessed for mucin, cilia, cilia beat frequency (CBF) and epithelial integrity (transepithelial electrical resistance, TEER). RESULTS: Increased Muc5AC (Δ+263.2±92.7 lums/EpiArea) and decreased ciliated cells (Δ-0.07±0.03 Foxj1+cells/EpiArea) were observed in biopsies from severe asthma when compared to healthy (p<0.01 and p=0.047 respectively). RNAseq of epithelial cell brushes confirmed a Muc5AC increase with a decrease in a 5-gene cilia-related mean in severe asthma compared to healthy (all p<0.05). IL-13 (5 ng/mL) differentiated ALI cultures of healthy and asthmatic (severe and non-severe participants) increased Muc5AC, decreased cilia (α-acytl-tubulin) in healthy (Δ+6.5±1.5%, Δ-14.1±2.7%; all p<0.001 respectively) and asthma (Δ+4.4±2.5%, Δ-13.1±2.7%; p=0.084, p<0.001 respectively); decreased epithelial integrity (TEER) in healthy (-140.9±21.3 [ohms], p<0.001) while decreasing CBF in asthma (Δ-4.4±1.7 [Hz], p<0.01). When dupilumab was added to ALI with IL-13, there was no significant decrease in Mu5AC but there was restoration of cilia in healthy and asthma participants (absolute increase of 67.5% and 32.5% cilia, all p<0.05 respectively) while CBF increased (Δ+3.6±1.1 [Hz], p<0.001) and TEER decreased (only in asthma Δ-37.8±16.2 [ohms] p<0.05). CONCLUSIONS: IL-13 drives features of airway remodeling in severe asthma which are partially reversed by inhibiting IL-4Rα receptor in vitro.

Unexpected connections of the IL-23/IL-17 and IL-4/IL-13 cytokine axes in inflammatory arthritis and enthesitis.

The IL-23/IL-17 cytokine axis is related to spondyloarthropathy (SpA) pattern diseases that target the skin, eye, gut and joints. These share overlapping target tissues with Th2 type or allergic diseases, including the skin, eye and gut but SpA diseases exhibit distinct microanatomical topography, molecular characteristics, and clinical features including uveitis, psoriasis, apical pulmonary involvement, lower gastrointestinal involvement with colitis, and related arthritides including psoriatic arthritis and ankylosing spondylitis. Inflammatory arthritis is conspicuously absent from the Th2 diseases which are characterised IL-4/IL-13 dependent pathway activation including allergic rhino-conjunctivitis, atopic eczema, allergic asthma and food allergies. This traditional understanding of non-overlap of musculoskeletal territory between that atopic diseases and the IL-17 -mediated SpA diseases is undergoing a critical reappraisal with the recent demonstration of IL-4/IL-13 blockade, may be associated with the development of SpA pattern arthritis, psoriasiform skin disease and occasional anterior uveitis. Given the known plasticity within Th paradigm pathways, these findings suggest dynamic Th2 cytokine and Th17 cytokine counter regulation in vivo in humans. Unexpected, this is the case in peripheral enthesis and when the IL-4/13 immunological brake on IL-23/17 cytokines is removed, a SpA phenotype may emerge. We discuss hitherto unexpected observations in SpA, showing counter regulation between the Th17 and Th2 pathways at sites including the entheses that collectively indicate that the emergent reverse translational therapeutic data is more than coincidental and offers new insights into the "Th paradigms" in atopy and SpA.

Anti-IL-4R versus anti-IL-5/5R after anti-IL-5/5R failure in asthma: An emulated target trial.

BACKGROUND: Switching biologics is now common practice in severe eosinophilic asthma. After insufficient response to anti-IL-5 or 5 receptor (anti-IL-5/5R), the optimal switch between an anti-IL-4R mAb (interclass) or another anti-IL-5/5R drug (intraclass) remains unknown. OBJECTIVE: We sought to compare the effectiveness of these 2 strategies in asthma control in patients with severe eosinophilic asthma and insufficient response to an anti-IL-5/5R mAb. METHODS: We emulated a target randomized trial using observational data from the Recherche sur les AsthMes SEvèreS (RAMSES) cohort. Eligible patients were switched to an anti-IL-4R mAb or another anti-IL-5/5R drug after insufficient response to an anti-IL-5/5R mAb. The primary outcome was the change in Asthma Control Test score at 6 months. RESULTS: Among the 2046 patients in the cohort, 151 were included in the study: 103 switched to an anti-IL-4R mAb and 48 to another anti-IL-5/5R. At 6 months, the difference in Asthma Control Test score improvement was not statistically significant (mean difference groups, 0.82 [-0.47 to 2.10], P = .213). The interclass group exhibited greater cumulative reduction in oral corticosteroid dose (Pinter-intra, -1.05 g [-1.76 to -0.34], P = .041). The interclass group had a better effect, although not significantly, on reducing exacerbations (Δinter-intra, -0.37 [-0.77 to 0.02], P = .124) and increasing lung function (FEV1) (126.8 mL [-12.7 to 266.4], P = .124). CONCLUSIONS: After anti-IL-5/5R mAb insufficient response, switching to dupilumab demonstrated similar improvement in Asthma Control Test scores compared with intraclass switching. However, it appeared more effective in reducing oral corticosteroid use. Larger studies are warranted to confirm these results.

Influence of pathogenic filaggrin variants on dupilumab treatment in atopic dermatitis.

BACKGROUND: Pathogenic variants in filaggrin (FLG) are associated with an increased risk of atopic dermatitis (AD). OBJECTIVE: We evaluated the influence of FLG variants on the effectiveness of dupilumab treatment in AD. METHODS: This prospective observational study included adult AD patients treated with dupilumab from the BioDay registry. FLG was analyzed with single-molecule molecular inversion probe-targeted sequencing. Novel mutations were confirmed by Sanger sequencing. Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), numeric rating scale (NRS) pruritus, Dermatology Quality of Life Index (DLQI), and Patient-Oriented Eczema Measure (POEM) were assessed at baseline and at weeks 16 and 52. The study was registered at ClinicalTrials.gov as NCT03549416. RESULTS: Genetic analysis of the 285 included patients showed biallelic pathogenic variants (FLG-/-) in 41 (14%), monoallelic pathogenic variants (FLG-/+) in 64 (23%), and wild-type alleles (FLG+/+) in 180 patients (63%). Three novel pathogenic variants were found. We observed no clinically relevant differences in EASI, IGA, NRS pruritus, DLQI, or total POEM scores for patients with and without pathogenic FLG variants at all time points. The FLG-/- group showed significantly higher POEM flaking and dryness scores at week 16 (P < .001 and P = .002, respectively) and week 52 (P < .001 and P = .016, respectively) compared to FLG+/+ as well as significant differences compared to FLG-/+, while differences in delta scores were nonsignificant. CONCLUSION: The effectiveness of dupilumab treatment in AD patients was not influenced by pathogenic FLG variants. However, patients with biallelic pathogenic FLG variants tended to have drier skin before and during dupilumab treatment compared to patients with monoallelic pathogenic variants or wild-type alleles.

Dupilumab in patients with chronic spontaneous urticaria (LIBERTY-CSU CUPID): Two randomized, double-blind, placebo-controlled, phase 3 trials.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a chronic inflammatory disease characterized by recurrent pruritic wheals (hives) and/or angioedema. Patients with CSU could remain symptomatic despite standard-of-care H1 antihistamines (H1-AH) or anti-IgE (omalizumab) treatment. Dupilumab blocks IL-4/IL-13 signaling and is approved for multiple type 2/atopic indications. OBJECTIVE: We conducted two phase 3, randomized, placebo-controlled, double-blind trials comparing dupilumab with placebo in patients with symptomatic CSU despite H1-AH. METHODS: In LIBERTY-CSU CUPID Study A, patients were omalizumab-naive (n = 138, aged ≥6 years). In Study B, patients were omalizumab-intolerant/incomplete responders (n = 108, aged ≥12 years). The primary end point was either change from baseline over 7 days in the Urticaria Activity Score (UAS7) or Itch Severity Score (ISS7) at week 24, with the other as a key secondary end point, depending on regional regulatory requirements. Studies were pooled for safety assessment. RESULTS: In Study A, UAS7 and ISS7 improved with dupilumab versus placebo (difference -8.5 [95% CI, -13.2 to -3.9; P = .0003] and -4.2 [95% CI, -6.6 to -1.8; P = .0005]). In Study B, tested at α = 0.043 after interim analysis, UAS7 improved (difference -5.8 [95% CI, -11.4 to -0.3; P = .0390]), with a numerical trend in ISS7 (difference -2.9 [95% CI, -5.7 to -0.07; nominal P = .0449, not significant]). Pooled safety data were consistent between dupilumab and placebo and with the known dupilumab safety profile. CONCLUSIONS: Dupilumab reduced urticaria activity by reducing itch and hives severity in omalizumab-naive patients with CSU uncontrolled with H1-AH. Although the primary end point for Study B was not met, dupilumab effects were small in patients who were omalizumab-intolerant/incomplete responders.

Patients taking benralizumab, dupilumab, or mepolizumab have lower postvaccination SARS-CoV-2 immunity.

BACKGROUND: Biologic therapies inhibiting the IL-4 or IL-5 pathways are very effective in the treatment of asthma and other related conditions. However, the cytokines IL-4 and IL-5 also play a role in the generation of adaptive immune responses. Although these biologics do not cause overt immunosuppression, their effect in primary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization has not been studied completely. OBJECTIVE: Our aim was to evaluate the antibody and cellular immunity after SARS-CoV-2 mRNA vaccination in patients on biologics (PoBs). METHODS: Patients with severe asthma or atopic dermatitis who were taking benralizumab, dupilumab, or mepolizumab and had received the initial dose of the 2-dose adult SARS-CoV-2 mRNA vaccine were enrolled in a prospective, observational study. As our control group, we used a cohort of immunologically healthy subjects (with no significant immunosuppression) who were not taking biologics (NBs). We used a multiplexed immunoassay to measure antibody levels, neutralization assays to assess antibody function, and flow cytometry to quantitate Spike-specific lymphocytes. RESULTS: We analyzed blood from 57 patients in the PoB group and 46 control subjects from the NB group. The patients in the PoB group had lower levels of SARS-CoV-2 antibodies, pseudovirus neutralization, live virus neutralization, and frequencies of Spike-specific B and CD8 T cells at 6 months after vaccination. In subgroup analyses, patients with asthma who were taking biologics had significantly lower pseudovirus neutralization than did subjects with asthma who were not taking biologics. CONCLUSION: The patients in the PoB group had reduced SARS-CoV-2-specific antibody titers, neutralizing activity, and virus-specific B- and CD8 T-cell counts. These results have implications when considering development of a more individualized immunization strategy in patients who receive biologic medications blocking IL-4 or IL-5 pathways.

IL-4Rα signaling promotes barrier-altering oncostatin M and IL-6 production in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a severe disease involving dysregulated type 2 inflammation. However, the role other inflammatory pathways play in AERD is poorly understood. OBJECTIVE: We sought to broadly define the inflammatory milieu of the upper respiratory tract in AERD and to determine the effects of IL-4Rα inhibition on mediators of nasal inflammation. METHODS: Twenty-two AERD patients treated with dupilumab for 3 months were followed over 3 visits and compared to 10 healthy controls. Nasal fluid was assessed for 45 cytokines and chemokines using Olink Target 48. Blood neutrophils and cultured human mast cells, monocytes/macrophages, and nasal fibroblasts were assessed for response to IL-4/13 stimulation in vitro. RESULTS: Of the nasal fluid cytokines measured, nearly one third were higher in AERD patients compared to healthy controls, including IL-6 and the IL-6 family-related cytokine oncostatin M (OSM), both of which correlated with nasal albumin levels, a marker of epithelial barrier dysregulation. Dupilumab significantly decreased many nasal mediators, including OSM and IL-6. IL-4 stimulation induced OSM production from mast cells and macrophages but not from neutrophils, and OSM and IL-13 stimulation induced IL-6 production from nasal fibroblasts. CONCLUSION: In addition to type 2 inflammation, innate and IL-6-related cytokines are also elevated in the respiratory tract in AERD. Both OSM and IL-6 are locally produced in nasal polyps and likely promote pathology by negatively affecting epithelial barrier function. IL-4Rα blockade, although seemingly directed at type 2 inflammation, also decreases mediators of innate inflammation and epithelial dysregulation, which may contribute to dupilumab's therapeutic efficacy in AERD.

Nasal Brushing Molecular Endotyping Distinguishes CRSwNP Patients with Better Response to Dupilumab.

BACKGROUND: There is evidence of pathophysiologic diversity in chronic rhinosinusitis with nasal polyps (CRSwNP), but data characterizing the molecular endotypes of CRSwNP and their association with treatment is lacking. OBJECTIVES: To identify gene signatures associated with CRSwNP endotypes, clinical features, and dupilumab treatment response. METHODS: Nasal brushing samples were collected from 89 patients randomized to dupilumab 300 mg every 2 weeks or placebo in the SINUS-52 trial (NCT02898454). Microarrays were used to identify transcriptional clusters and assess the relationship between gene expression and baseline clinical features and clinical response to dupilumab. Endotype signatures were determined using differential expression analysis. RESULTS: Two distinct transcriptional clusters (C1 and C2) were identified, both with elevated type 2 biomarkers. At baseline, C2 patients had higher mean Nasal Polyp Score and higher type 2 biomarker levels than C1 patients. At Week 24, significant improvements in clinical outcomes (dupilumab vs placebo) were observed in both clusters, although the magnitude of improvements was significantly greater in C2 than C1, and more C2 patients demonstrated clinically meaningful responses. Gene sets enrichment analyses supported the existence of two molecular endotypes: C2 was enriched in genes associated with type 2 inflammation (including periostin, cadherin-26, and type 2 cysteine protease inhibitors), while C1 was enriched in genes associated with T cell activation and interleukin-12 production. CONCLUSION: Two distinct gene signatures associated with CRSwNP clinical features were identified; the endotype signatures were associated with clinical outcome measures and magnitude of dupilumab response.

Characterization of Inflammatory Mediators and Metabolome in Interstitial Fluid Collected with Dermal Open Flow Microperfusion before and at the End of Dupilumab Treatment in Atopic Dermatitis.

Dupilumab is a monoclonal antibody approved for the treatment of atopic dermatitis (AD); however, its effects on molecular, cellular, and immunological levels remain to be elucidated. In this study, blood and dermal interstitial fluid (ISF) from nonlesional (NL) and lesional (L) skin were collected from eight patients with moderate to severe AD, before (visit 2-v2) and at the end of a 16-week treatment with dupilumab (visit 10-v10). Clinical treatment effect was demonstrated by significantly decreased AD severity scores at the end of treatment. At v10 versus v2, the percentages of CD4+ interleukin-producing cells showed a decreasing trend in ISF L and NL, unbound IL-4 levels in plasma were increased, IL-5 levels in ISF L reduced, and levels of factors involved in anti-inflammatory pathways and re-epithelization increased. At v2, ISF L showed that AD lesions might have altered amino acid pathways and lipid signaling compared to ISF NL. At v10, ISF L exhibited raised levels of long- and very-long-chain fatty acids and lipids compared to v2. Furthermore, dupilumab administration caused reduced expression of miR-155-5p and miR-378a-3p in ISF L. In conclusion, results from the present study provided novel knowledge by linking local immune and metabolic alterations to AD pathogenesis and treatment response.

Management of Atopy with Dupilumab and Omalizumab in CADINS Disease.

The caspase activation and recruitment domain 11 (CARD11) gene encodes a scaffold protein required for lymphocyte antigen receptor signaling. Dominant-negative, loss-of-function (LOF) pathogenic variants in CARD11 result in CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease. Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity. We assessed the response of dupilumab in five patients and omalizumab in one patient with CADINS for the treatment of severe atopic symptoms. CARD11 mutations were validated for pathogenicity using a T cell transfection assay to assess the impact on activation-induced signaling to NF-κB. Three children and three adults with dominant-negative CARD11 LOF mutations were included. All developed atopic disease in infancy or early childhood. In five patients, atopic dermatitis was severe and recalcitrant to standard topical and systemic medications; one adult suffered from chronic spontaneous urticaria. Subcutaneous dupilumab was initiated to treat atopic dermatitis and omalizumab to treat chronic spontaneous urticaria. All six patients had rapid and sustained improvement in atopic symptoms with no complications during the follow-up period. Previous medications used to treat atopy were able to be decreased or discontinued. In conclusion, treatment with dupilumab and omalizumab for severe, refractory atopic disease in patients with CADINS appears to be effective and well tolerated in patients with CADINS with severe atopy.

Real-World Efficacy of Dupilumab in Severe, Treatment-Refractory, and Fibrostenotic Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Dupilumab is approved for treatment of eosinophilic esophagitis (EoE), but real-world data are lacking. We aimed to determine the real-world efficacy of dupilumab in patients with severe, treatment-refractory, and fibrostenotic EoE. METHODS: We conducted a retrospective cohort study of EoE patients prescribed dupilumab and who were treatment-refractory to standard modalities. Patient demographics, clinical characteristics, EoE history, and procedural data (including the histologically worst, predupilumab, and postdupilumab endoscopies) were extracted from medical records. Symptomatic, endoscopic, and histologic responses were assessed for the worst and predupilumab endoscopies compared with the postdupilumab endoscopy. RESULTS: We identified 46 patients with refractory fibrostenotic EoE who were treated with dupilumab. Patients showed endoscopic, histologic, and symptomatic improvement on dupilumab compared with both the worst and the predupilumab esophagogastroduodenoscopies. The peak eosinophil counts decreased markedly, and postdupilumab histologic response rates were 80% and 57% for fewer than 15 eosinophils per high-power field and 6 or fewer eosinophils per high-power field, respectively, and the Endoscopic Reference Score decreased from 5.01 to 1.89 (P < .001 for all). Although the proportion of strictures was stable, there was a significant increase in the predilation esophageal diameter (from 13.9 to 16.0 mm; P < .001). Global symptom improvement was reported in 91% (P < .001). CONCLUSIONS: In this population of severe, refractory, and fibrostenotic EoE patients, most achieved histologic, endoscopic, and symptom improvement with a median of 6 months of dupilumab, and esophageal stricture diameter improved. Dupilumab has real-world efficacy for a severe EoE population, most of whom would not have qualified for prior clinical trials.

Global IL4Rα blockade exacerbates heart failure after an ischemic event in mice and humans.

Ischemic heart failure continues to be a highly prevalent disease among westernized countries and there is great interest in understanding the mechanisms preventing or exacerbating disease progression. The literature suggests an important role for the activation of interleukin-13 or interleukin-4 signaling in improving ischemic heart failure outcomes after myocardial infarction in mice. Dupilumab, a neutralizing antibody that inhibits the shared IL13/IL4 receptor subunit IL4Rα, is widely used for conditions such as ectopic dermatitis in humans. If global depletion of IL4Rα influences ischemic heart failure, either in mice or in humans taking dupilumab, is unknown. Here, we investigated the pathophysiological effects of global IL4Rα genetic deletion in adult mice after surgically induced myocardial infarction (MI). We also determined heart failure risk in patients with ischemic heart disease and concomitant usage of dupilumab using the collaborative patient data network TriNetX. Global deletion of IL4Rα results in exacerbated cardiac dysfunction associated with reduced capillary size after myocardial infarction in mice. In agreement with our findings in mice, dupilumab treatment significantly increased the risk of heart failure development in patients with preexisting diagnosis of ischemic heart disease. Our results indicate that systemic IL4Rα signaling is protective against heart failure development in adult mice and human patients specifically following an ischemic event. Thus, the compelling evidence presented hereby advocates for the development of a randomized clinical trial specifically investigating heart failure development after myocardial ischemia in patients taking dupilumab for another underlying condition.NEW & NOTEWORTHY A body of literature suggests a protective role for IL4Rα signaling postmyocardial infarction in mice. Here, our observational study demonstrates that humans taking the IL4Rα neutralizing antibody, dupilumab, have increased incidence of heart failure following an ischemic event. Similarly, global IL4Rα deletion in mice exacerbates heart failure postinfarct. To our knowledge, this is the first study reporting an adverse association in humans of dupilumab use with heart failure following a cardiac ischemic event.

Ocular surface disease in moderate-to-severe atopic dermatitis patients and the effect of biological therapy.

Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate-to-severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate-to-severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD-related severity biomarkers in tear fluid. The second part of this review highlights that pre-existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab-associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new-onset OSD or worsening of pre-existing OSD) is observed in approximately one-third of the dupilumab-treated AD patients. Anti-inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate-to-severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab-treated AD patients with moderate-to-severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate-to-severe AD patients, and a low-threshold referral to an ophthalmologist is recommended.

Impact of 1-year treatment with dupilumab on work productivity in Japanese patients with atopic dermatitis.

Atopic dermatitis (AD) places a burden on work productivity. Recently, dupilumab was approved for AD, but its impact on work productivity in Japanese patients has not been reported. Furthermore, data on the effect of long-term treatment with dupilumab on work productivity are limited. We investigated the work productivity and activity in Japanese patients with moderate-to-severe AD, utilizing the Japanese version of the Work Productivity and Activity Impairment (WPAI-AD-Japan) questionnaire. Furthermore, we examined the impact of dupilumab on work productivity. Adult moderate-to-severe AD patients treated with dupilumab for more than 12 months from March 2020 to June 2022 who filled out the WPAI-AD-Japan questionnaire were included. Twenty-eight adult AD patients were analysed. Absenteeism was low (mean: 5.3%), but presenteeism, work productivity loss and activity impairment were high (36.8%, 39.7%, 48.9%, respectively). Significant positive correlations were observed between work productivity loss and visual analogue scale (VAS) score of pruritus and between activity impairment and dermatology life quality index (DLQI). Dupilumab treatment significantly reduced presenteeism, work productivity loss and activity impairment at both 6 and 12 months. The extent of their amelioration was numerically higher at 12 months than at 6 months. The reduction rates in presenteeism, work productivity loss and activity impairment were positively correlated with the reduction rates in DLQI and VAS score of pruritus at 12 months. Dupilumab improved work productivity in Japanese AD patients. Long-term remission of pruritus and improved quality of life are important for comprehensive improvement of work productivity.

Differential modulation of allergic rhinitis nasal transcriptome by dupilumab and allergy immunotherapy.

BACKGROUND: Nasal epithelial cells are important regulators of barrier function and immune signaling; however, in allergic rhinitis (AR) these functions can be disrupted by inflammatory mediators. We aimed to better discern AR disease mechanisms using transcriptome data from nasal brushing samples from individuals with and without AR. METHODS: Data were drawn from a feasibility study of individuals with and without AR to Timothy grass and from a clinical trial evaluating 16 weeks of treatment with the following: dupilumab, a monoclonal antibody that binds interleukin (IL)-4Rα and inhibits type 2 inflammation by blocking signaling of both IL-4/IL-13; subcutaneous immunotherapy with Timothy grass (SCIT), which inhibits allergic responses through pleiotropic effects; SCIT + dupilumab; or placebo. Using nasal brushing samples from these studies, we defined distinct gene signatures in nasal tissue of AR disease and after nasal allergen challenge (NAC) and assessed how these signatures were modulated by study drug(s). RESULTS: Treatment with dupilumab (normalized enrichment score [NES] = -1.73, p = .002) or SCIT + dupilumab (NES = -2.55, p < .001), but not SCIT alone (NES = +1.16, p = .107), significantly repressed the AR disease signature. Dupilumab (NES = -2.55, p < .001), SCIT (NES = -2.99, p < .001), and SCIT + dupilumab (NES = -3.15, p < .001) all repressed the NAC gene signature. CONCLUSION: These results demonstrate type 2 inflammation is an important contributor to the pathophysiology of AR disease and that inhibition of the type 2 pathway with dupilumab may normalize nasal tissue gene expression.

Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after mRNA vaccination.

BACKGROUND: The noninflammatory immunoglobulin G4 (IgG4) is linked to tolerance and is unique to humans. Although poorly understood, prolonged antigenic stimulation and IL-4-signaling along the T helper 2-axis may be instrumental in IgG4 class switching. Recently, repeated SARS-CoV-2 mRNA vaccination has been linked to IgG4 skewing. Although widely used immunosuppressive drugs have been shown to only moderately affect humoral responses to SARS-CoV-2 mRNA vaccination, the effect on IgG4 switching has not been investigated. METHODS: Here we study the impact of such immunosuppressive drugs, including the IL-4 receptor-blocking antibody dupilumab, on IgG4 skewing upon repeated SARS-CoV-2 mRNA vaccination. Receptor-binding domain (RBD) specific antibody responses were longitudinally measured in 600 individuals, including patients with immune-mediated inflammatory diseases treated with a TNF inhibitor (TNFi) and/or methotrexate (MTX), dupilumab, and healthy/untreated controls, after repeated mRNA vaccination. RESULTS: We observed a substantial increase in the proportion of RBD-specific IgG4 antibodies (median 21%) in healthy/untreated controls after third vaccination. This IgG4 skewing was profoundly reduced in dupilumab-treated patients (<1%). Unexpectedly, an equally strong suppression of IgG4 skewing was observed in TNFi-treated patients (<1%), whereas MTX caused a modest reduction (7%). RBD-specific total IgG levels were hardly affected by these immunosuppressive drugs. Minimal skewing was observed, when primary vaccination was adenoviral vector-based. CONCLUSIONS: Our results imply a critical role for IL-4/IL-13 as well as TNF in vivo IgG4 class switching. These novel findings advance our understanding of IgG4 class switch dynamics, and may benefit humoral tolerance induction strategies, treatment of IgG4 pathologies and mRNA vaccine optimization.

Dupilumab-associated ocular surface disease is characterized by a shift from Th2/Th17 toward Th1/Th17 inflammation.

BACKGROUND: Dupilumab is used for the treatment of atopic dermatitis (AD). Approximately one third of AD patients develop a dupilumab-associated ocular surface disease (DAOSD), of which the pathomechanism is poorly understood. This study aimed at investigating inflammatory markers in tear fluids of patients on dupilumab therapy. METHODS: Tear fluids were collected from AD patients with DAOSD (ADwDAOSD), AD patients without DAOSD (ADw/oDAOSD), and non-AD patients before and during dupilumab therapy, and analyzed using a specialized proteomic approach quantifying inflammatory markers. The ocular surface microbiome was determined by next generation sequencing technology. RESULTS: Upon dupilumab therapy, an upregulation of 31 inflammatory markers was observed in DAOSD tear fluids compared to baseline in AD patients. While IL-12B was upregulated in both ADwDAOSD and ADw/oDAOSD groups, the pattern of inflammatory markers significantly differed between groups and over time. In the ADwDAOSD group, a shift from a mixed Th2/Th17 pattern at baseline toward a Th1/Th17 profile under dupilumab was observed. Furthermore, an upregulation of remodeling and fibrosis markers was seen in DAOSD. Semantic map and hierarchical cluster analyses of baseline marker expression revealed four clusters distinguishing between AD and non-AD as well as ADwDAOSD and ADw/oDAOSD patient groups. In a pilot study, dupilumab therapy was associated with a decrease in richness of the ocular surface microbiome. CONCLUSIONS: DAOSD is characterized by a Th1/Th17 cytokine profile and an upregulation of markers known to promote remodeling and fibrosis. The expression pattern of inflammatory markers in tear fluids at baseline might serve as a prognostic factor for DAOSD.

An updated reappraisal of dupilumab in children and adolescents with moderate-severe atopic dermatitis.

Atopic dermatitis (AD) is still a demanding challenge in clinical practice. Type 2 inflammation is the most common inflammatory pathway in children and adolescents with AD. Anti-inflammatory drugs, mainly corticosteroids (CS) and immunomodulant agents are the primary therapeutic approach to dampening type 2 inflammation. However, AD patients may require long-term high CS doses or drug combinations with possibly significant adverse effects to achieve and maintain disease control. In this regard, the advent of biologics constituted a breakthrough in managing this condition. Dupilumab is a monoclonal antibody directed against the IL-4 receptor α-subunit (IL-4Rα), antagonizing both IL-4 and IL-13 and is approved for pediatric severe AD. This review presents and discusses the most recent published studies on dupilumab in children and adolescents with AD. There is convincing evidence that dupilumab is safe and effective in managing AD. It can reduce skin lesions and associated itching, reduce the need for additional medications, and improve disease control and quality of life. However, a thorough diagnostic pathway is mandatory, especially considering the different AD phenotypes. The ideal eligible candidate is a child or adolescent with AD requiring systemic treatment because of severe clinical manifestations and impaired quality of life.

Effect of dupilumab on asthma and aeroallergen sensitization in pediatric atopic dermatitis patients: Results of the BioDay registry.

BACKGROUND: Atopic dermatitis (AD) is frequently associated with asthma and allergic rhinitis (AR). Dupilumab is an effective treatment for pediatric AD, although the effect on atopic comorbidities in pediatric AD patients is limited. OBJECTIVE: To investigate the prevalence of asthma and AR in pediatric AD patients starting dupilumab treatment and to evaluate the effect of dupilumab on these comorbidities. METHODS: This study included pediatric AD patients (aged 3-17 years) treated with dupilumab between 2019 and 2023. Patients were screened at baseline by a pulmonologist for the presence of asthma and AR. Screening included evaluation of medical history and current symptoms, spirometry (including Forced Expiratory Volume in 1 s (FEV1)), Fractional exhaled Nitric Oxide (FeNO), and measurement of aeroallergen-specific IgE levels. In patients diagnosed with comorbid asthma and/or AR, measurements were repeated at weeks 16 and 52. Spirometry measurements, FeNO, and aeroallergen-specific IgE levels during treatment were analyzed using a covariance pattern model. RESULTS: Eighty-four patients were included. Asthma was diagnosed in 50 patients (59.5%) and AR in 72 patients (85.7%). Baseline FeNO levels were elevated in both patients with (29.0 ppb (95% CI 22.0-54.0)) and without asthma (26.0 ppb (95% CI 22.0-30.0)). During treatment, FeNO levels decreased (p < .001) and FEV1 scores increased (p < .001) in patients with asthma. In patients with asthma and/or AR, all aeroallergen-specific IgE levels decreased between 61.3% and 89.1% at 52 weeks of treatment. CONCLUSION: One year of dupilumab treatment, primarily indicated for AD, resulted in a significant improvement in comorbid asthma and a profound decrease in aeroallergen-specific IgE levels in patients with asthma and/or AR.