Exploring the Association Between Atopic Dermatitis and Malignancy: A Comprehensive Review with Therapeutic Strategies.

Atopic dermatitis (AD) is a prevalent dermatologic condition affecting both children and adults, and the debate surrounding its association as either a risk or protective factor for malignancies has garnered significant attention. Proposed mechanisms suggest that AD may act protectively against cancer formation through chronic immune system activation or create an inflammatory state conducive to cancer development. This review discusses the relationship between AD and various skin cancers, solid tumors, and hematologic malignancies. Additionally, the authors explore the impact of AD treatments, particularly novel biologic drugs targeting molecular pathways such as JAK-STAT, IL-4, and IL-13 in association with malignancies.

Exploiting the potential of dupilumab in the treatment of eosinophilic COPD.

Chronic obstructive pulmonary disease (COPD) often involves type 1 (T1) inflammation, but 40% of patients have T2 inflammation, which worsens outcomes. Dupilumab, targeting interleukin (IL)-4 and IL-13, shows promise in phase 3 trials. The new NOTUS trial1 showed effectiveness in reducing exacerbations and improving lung function. However, its predominantly white population limits generalizability. Future research should include diverse populations and assess different therapies combined with dupilumab to improve outcomes.

Dupilumab: Mechanism of action, clinical, and translational science.

Allergic disease prevalence has increased globally with the subset of type 2 inflammatory diseases playing a substantial role. Type 2 inflammatory diseases may differ in clinical presentation, but they exhibit shared pathophysiology that is targeted by the unique pharmacology of dupilumab. Dupilumab binds to the interleukin (IL)-4 receptor alpha subunit (IL-4Rα) that blocks IL-4 and IL-13 signaling, two key drivers of type 2 inflammation. Herein, we review the mechanism of action and pharmacology of dupilumab, and the clinical evidence that led to the regulatory approvals of dupilumab for the treatment of numerous type 2 inflammatory diseases: atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis.

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.

Dupilumab for Eosinophilic Esophagitis in Patients 1 to 11 Years of Age.

BACKGROUND: Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2 inflammation, including eosinophilic esophagitis in adults and adolescents. METHODS: In this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups) (Part A). At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered in one of four doses tiered according to baseline body weight. The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤6 per high-power field) at week 16. Key secondary end points were tested hierarchically. RESULTS: In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group (difference between the higher-exposure regimen and placebo, 65 percentage points [95% confidence interval {CI}, 48 to 81; P<0.001]; difference between the lower-exposure regimen and placebo, 55 percentage points [95% CI, 37 to 73; P<0.001]). The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo. The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A. In Part A, the incidence of coronavirus disease 2019, nausea, injection-site pain, and headache was at least 10 percentage points higher among the patients who received dupilumab (at either dose) than among those who received placebo. Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B. CONCLUSIONS: Dupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher-exposure dupilumab regimen also led to improvements in measures of key secondary end points as compared with placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; EoE KIDS ClinicalTrials.gov number, NCT04394351.).

Global influence of dupilumab on Quality of Life in a severe asthma patient with T2 multimorbidities: a case report on atopic dermatitis, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis.

INTRODUCTION: Interleukin (IL)-4 and IL-13 are considered key drivers of type 2 inflammatory diseases. Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for IL-4 and IL-13, thus inhibiting signaling of both cytokines. CASE STUDY: We report a case of a patient with uncontrolled severe asthma and other T2 inflammatory diseases (atopic dermatitis, chronic rhinosinusitis with nasal polyposis and eosinophilic esophagitis) treated with dupilumab. RESULTS: After one year of treatment, dupilumab improved asthma control together with lung function parameters and airway inflammation. Additionally, a positive impact on quality of life (QoL), evaluated by validated questionnaires, across all the diseases was observed. CONCLUSION: In this case report, a positive and objectively measurable of global improvement on QoL across all four T2 comorbidities was observed after treatment with dupilumab, demonstrating the important role of IL-4 and IL-13 and the existence of a unifying pathological mechanism in T2 diseases.

Dupilumab: Advances in the off-label usage of IL4/IL13 antagonist in dermatoses.

Type 2 immune response refers to a complicated series of immune responses characterized by Th2 polarization and Th2 cytokines secretion. The IgE secretion, airway hypersensitivity, and effector cell recruitment (eosinophils, mast cells, basophils) in skin lesion and peripheral blood stream could be upregulated during the activation of type 2 immune response. Th1/Th2 ratio, also referred as Th1/Th2 balance, represent the T lymphocytes immune pattern to a certain degree: Th1-dominated responses are often involved in intracellular infections (e.g., mycobacterium tuberculosis) and autoimmune diseases (e.g., Graves' disease) while Th2-dominated responses are involved in allergic conditions (e.g., atopic dermatitis, eczema), IgE mediated diseases (e.g., urticaria), and fibrotic dermatoses (e.g., keloids). Dupilumab, as one of the most widely applied Th2 cytokine inhibitors, could block the bioactivity of IL-14/IL-13 via competitively binding to the common IL-4Rα subunit shared by IL-4 and IL-13 receptors. In addition to the direct inhibition of type 2 response, dupilumab is also effective in autoimmune and some infectious skin diseases through indirect regulation of type 1 immune response. The pathological mechanism of Th2 responses and advanced clinical application of dupilumab in skin diseases will be summarized and discussed in the review.

Activation of iNKT Cells Facilitates Liver Repair After Hepatic Ischemia Reperfusion Injury Through Acceleration of Macrophage Polarization.

Macrophage polarization is critical for liver tissue repair following acute liver injury. However, the underlying mechanisms of macrophage phenotype switching are not well defined. Invariant natural killer T (iNKT) cells orchestrate tissue inflammation and tissue repair by regulating cytokine production. Herein, we examined whether iNKT cells played an important role in liver repair after hepatic ischemia-reperfusion (I/R) injury by affecting macrophage polarization. To this end, we subjected male C57BL/6 mice to hepatic I/R injury, and mice received an intraperitoneal (ip) injection of α-galactosylceramide (α-GalCer) or vehicle. Compared with that of the vehicle, α-GalCer administration resulted in the promotion of liver repair accompanied by acceleration of macrophage differentiation and by increases in the numbers of Ly6Chigh pro-inflammatory macrophages and Ly6Clow reparative macrophages. iNKT cells activated with α-GalCer produced interleukin (IL)-4 and interferon (IFN)-γ. Treatment with anti-IL-4 antibodies delayed liver repair, which was associated with an increased number of Ly6Chigh macrophages and a decreased number of Ly6Clow macrophages. Treatment with anti-IFN-γ antibodies promoted liver repair, associated with reduced the number of Ly6Chigh macrophages, but did not change the number of Ly6Clow macrophages. Bone marrow-derived macrophages up-regulated the expression of genes related to both a pro-inflammatory and a reparative phenotype when co-cultured with activated iNKT cells. Anti-IL-4 antibodies increased the levels of pro-inflammatory macrophage-related genes and decreased those of reparative macrophage-related genes in cultured macrophages, while anti-IFN-γ antibodies reversed the polarization of macrophages. Cd1d-deficient mice showed delayed liver repair and suppressed macrophage switching, compared with that in wild-type mice. These results suggest that the activation of iNKT cells by α-GalCer facilitated liver repair after hepatic I/R injury by both IL-4-and IFN-γ-mediated acceleration of macrophage polarization. Therefore, the activation of iNKT cells may represent a therapeutic tool for liver repair after hepatic I/R injury.

Dual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice.

Allergic asthma is characterized by elevated levels of IgE antibodies, type 2 cytokines such as interleukin-4 (IL-4) and IL-13, airway hyperresponsiveness (AHR), mucus hypersecretion and eosinophilia. Approved therapeutic monoclonal antibodies targeting IgE or IL-4/IL-13 reduce asthma symptoms but require costly lifelong administrations. Here, we develop conjugate vaccines against mouse IL-4 and IL-13, and demonstrate their prophylactic and therapeutic efficacy in reducing IgE levels, AHR, eosinophilia and mucus production in mouse models of asthma analyzed up to 15 weeks after initial vaccination. More importantly, we also test similar vaccines specific for human IL-4/IL-13 in mice expressing human IL-4/IL-13 and the related receptor, IL-4Rα, to find efficient neutralization of both cytokines and reduced IgE levels for at least 11 weeks post-vaccination. Our results imply that dual IL-4/IL-13 vaccination may represent a cost-effective, long-term therapeutic strategy for the treatment of allergic asthma as demonstrated in mouse models, although additional studies are warranted to assess its safety and feasibility.

Retrospective analysis of adverse events with dupilumab reported to the United States Food and Drug Administration.

BACKGROUND: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases and has aesthetic, physical, and emotional-social sequelae when left untreated. OBJECTIVE: To classify the most common adverse reactions associated with dupilumab treatment in patients with AD. METHODS: The United States Food and Drug Administration Adverse Event Reporting (FAERS) database was analyzed for common adverse reactions associated with dupilumab, topical pimecrolimus, and topical tacrolimus. Phase III clinical trial data were used to compare the rate of herpes infections between the treatment group and placebo group. RESULTS: The most common adverse reaction associated with dupilumab was ocular complications. Herpes infections were extremely rare in the patients with AD being treated with dupilumab. LIMITATIONS: Prescribing information for dupilumab, topical pimecrolimus, and topical tacrolimus is not available. Adverse effects are reported by patients, health care providers, and pharmaceutical companies, they have not been corroborated. CONCLUSIONS: Ocular complications are the most common complication associated with dupilumab. The rate of herpes infection is low in patients being treated with dupilumab, topical pimecrolimus, and topical tacrolimus. There is no significant difference for the rate of herpes infection between, placebo, dupilumab, topical pimecrolimus, and the topical tacrolimus treatment group, suggesting that dupilumab does not affect herpes infection rates.

A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants.

PARP14 has been implicated by genetic knockout studies to promote protumor macrophage polarization and suppress the antitumor inflammatory response due to its role in modulating interleukin-4 (IL-4) and interferon-γ signaling pathways. Here, we describe structure-based design efforts leading to the discovery of a potent and highly selective PARP14 chemical probe. RBN012759 inhibits PARP14 with a biochemical half-maximal inhibitory concentration of 0.003 µM, exhibits >300-fold selectivity over all PARP family members, and its profile enables further study of PARP14 biology and disease association both in vitro and in vivo. Inhibition of PARP14 with RBN012759 reverses IL-4-driven protumor gene expression in macrophages and induces an inflammatory mRNA signature similar to that induced by immune checkpoint inhibitor therapy in primary human tumor explants. These data support an immune suppressive role of PARP14 in tumors and suggest potential utility of PARP14 inhibitors in the treatment of cancer.

Metformin alleviates allergic airway inflammation and increases Treg cells in obese asthma.

Obesity increases the morbidity and severity of asthma, with poor sensitivity to corticosteroid treatment. Metformin has potential effects on improving asthma airway inflammation. Regulatory T cells (Tregs) play a key role in suppressing the immunoreaction to allergens. We built an obese asthmatic mouse model by administering a high-fat diet (HFD) and ovalbumin (OVA) sensitization, with daily metformin treatment. We measured the body weight and airway inflammatory status by histological analysis, qRT-PCR, and ELISA. The percentage of Tregs was measured by flow cytometry. Obese asthmatic mice displayed more severe airway inflammation and more significant changes in inflammatory cytokines. Metformin reversed the obese situation and alleviated the airway inflammation and remodelling with increased Tregs and related transcript factors. The anti-inflammatory function of metformin may be mediated by increasing Tregs.

Novel Therapeutic Approaches and Targets for the Treatment of Atopic Dermatitis.

BACKGROUND: Atopic Dermatitis is one of the most common inflammatory skin diseases, with an estimated prevalence of 2.1-4.9% in adults. Recently, advances in Atopic Dermatitis understanding have highlighted the role of inappropriate Th2 cell activation as principally involved in its pathogenesis. Other immune pathways seem to play a key role in the complex Atopic Dermatitis pathophysiology. The anti-IL-4/IL-13 was the first monoclonal antibody approved for the treatment of moderate to severe atopic dermatitis in adult patients whose disease is resistant to other therapies. Following its interesting results in terms of efficacy and safety, new therapies are in development. METHODS: Monoclonal antibodies targeting IL-5, IL-13, IL-17, IL-22, IL-23, IL-31 and TSLP are currently under investigation on patients with moderate to severe Atopic Dermatitis patients. Moreover, small molecules like anti-PDE4 and JAK inhibitors may also represent other treatment possibilities. RESULTS: In this section, we present data available on the efficacy and safety of newer molecules for the treatment of Atopic Dermatitis. CONCLUSION: The extreme clinical heterogeneity and the chronic progression of Atopic Dermatitis need for newer, safer and more effective treatments, able to control the disease and to improve the quality of life of affected patients. Dupilumab, and the other monoclonal antibodies and small molecules currently under investigation aim to improve the clinical management of Atopic Dermatitis.

Biologics and Allergy Immunotherapy in the Treatment of Allergic Diseases.

Allergic diseases represent some of the most chronic and costly chronic conditions. Medical management may require long-term pharmacotherapy, which is often associated with poor adherence. Although medications provide symptomatic control, they do not modify the allergic disease. Patients may prefer disease-modifying treatments that provide lasting benefits after discontinuation. To date, allergy immunotherapy is the only proved disease modification therapy associated with lasting benefits after discontinuation. However, allergy immunotherapy safety and efficacy has only been established in allergic rhinitis, mild to moderate asthma, and some patients with atopic dermatitis.

Weight gain in patients with severe atopic dermatitis treated with dupilumab: a cohort study.

BACKGROUND: Dupilumab, targeting the interleukin-4α receptor and inhibiting the action of interleukin-4 and interleukin-13, was recently approved for treatment of moderate to severe atopic dermatitis. There is limited data on long-term effects and safety among patients with severe atopic dermatitis treated with dupilumab. Weight gain was observed among patients treated with dupilumab in our clinic. The aim was to describe weight change in a cohort study of patients with severe atopic dermatitis treated with dupilumab from baseline to follow-up after 12 months, and to analyze if weight change was associated with effect of treatment, reported appetite, and/or disturbed night sleep due to itching. METHODS: All patients with atopic dermatitis receiving systemic treatment at the Unit of Dermatology, Karolinska University Hospital, have been registered and monitored consecutively since January 2017. This cohort constituted all patients who started treatment on dupilumab or methotrexate between 10 January 2017 and 30 June 2019 with at least 6 months of follow-up within the study period. The following variables were monitored at start of and during treatment: Eczema Severity Score Index, Patient-Oriented Eczema Measure, visual analogue scale for pruritus 10 cm, Montgomery-Åsberg Depression Rating Scale, Dermatology Life Quality Index, and weight. Data analyses were performed using two-sample Wilcoxon-Mann-Whitney rank-sum test, or the Wilcoxon matched-pairs sign-rank test with a p-value < 0.05 considered as statistically significant. RESULTS: Patients treated with dupilumab (n = 12) gained weight (mean 6.1 kg, range [0.1-18.0], p = 0.002) after 1 year on treatment. The majority of patients showed a good response to treatment with dupilumab (n = 11); at follow-up at 6, 9, or 12 months, they reached EASI-90 (n = 6), EASI-75 (n = 4), or EASI-50 (n = 1). There was no significant association between weight gain and treatment response, reported appetite, or disturbed night-sleep due to itch. Patients treated with methotrexate showed no significant weight change (n = 8). CONCLUSIONS: To our knowledge, this is the first report on a possible association between weight gain and dupilumab treatment; the extent of the association is yet to be seen, as is the mechanism behind this finding.

A randomised, double-blind, placebo-controlled, 24-week, phase II, proof-of-concept study of romilkimab (SAR156597) in early diffuse cutaneous systemic sclerosis.

OBJECTIVES: Recent advances in systemic sclerosis (SSc) show that it involves a T-helper type-2-oriented immune response with interleukin (IL)-4 and IL-13. Romilkimab is an engineered, humanised, bispecific immunoglobulin-G4 antibody that binds and neutralises IL-4/IL-13 making it ideal for exploration in fibrosis. METHODS: Patients aged ≥18 years diagnosed with diffuse cutaneous SSc (dcSSc), and with or without immunosuppressive background therapy, were randomised (1:1) to subcutaneous romilkimab 200 mg or placebo one time per week for 24 weeks in this double-blind, proof-of-concept, phase II study. The primary endpoint was change in modified Rodnan skin score (mRSS) from baseline to week 24. RESULTS: Ninety-seven patients were randomised to romilkimab (n=48) or placebo (n=49) for 24 weeks. Least-squares mean (SE) change in mRSS was -4.76 (0.86) for romilkimab versus -2.45 (0.85) for placebo yielding a mean (SE) (90% CI) difference of -2.31 (1.21) (-4.32 to -0.31; p=0.0291, one-sided). Treatment-emergent AEs were balanced between placebo (n=41; 84%) and romilkimab (n=40; 80%). Most were mild-to-moderate and discontinuations were low (three overall). There were two deaths (one scleroderma renal crisis (romilkimab) and one cardiomyopathy (placebo)), neither were considered treatment related. Two patients in the placebo group had a cardiovascular treatment-emergent SAE (one cardiac failure, one cardiomyopathy), but there were no cardiac safety signals with romilkimab. CONCLUSION: This study demonstrated significant effects on skin changes with romilkimab in early dcSSc that require confirmation with a longer and more comprehensive phase III study to determine clinical relevance. TRIAL REGISTRATION NUMBER: NCT02921971.

A Small-Molecule Inhibitor to the Cytokine Interleukin-4.

Interleukin-4 (IL-4) is a multifunctional cytokine and an important regulator of inflammation. When deregulated, IL-4 activity is associated with asthma, allergic inflammation, and multiple types of cancer. While antibody-based inhibitors targeting the soluble cytokine have been evaluated clinically, they failed to achieve their end points in trials. Small-molecule inhibitors are an attractive alternative, but identifying effective chemotypes that inhibit the protein-protein interactions between cytokines and their receptors remains an active area of research. As a result, no small-molecule inhibitors to the soluble IL-4 cytokine have yet been reported. Here, we describe the first IL-4 small-molecule inhibitor identified and characterized through a combination of binding-based approaches and cell-based activity assays. The compound features a nicotinonitrile scaffold with micromolar affinity and potency for the cytokine and disrupts type II IL-4 signaling in cells. Small-molecule inhibitors of these important cell-signaling proteins have implications for numerous immune-related disorders and inform future drug discovery and design efforts for these challenging protein targets.