Atopic dermatitis: an expanding therapeutic pipeline for a complex disease

Nature Reviews Drug Discovery, Год журнала: 2021, Номер 21(1), С. 21 - 40

Опубликована: Авг. 20, 2021

Язык: Английский

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Advances and highlights in biomarkers of allergic diseases

Allergy, Год журнала: 2021, Номер 76(12), С. 3659 - 3686

Опубликована: Сен. 14, 2021

During the past years, there has been a global outbreak of allergic diseases, presenting considerable medical and socioeconomical burden. A large fraction diseases is characterized by type 2 immune response involving Th2 cells, innate lymphoid eosinophils, mast M2 macrophages. Biomarkers are valuable parameters for precision medicine as they provide information on disease endotypes, clusters, diagnoses, identification therapeutic targets, monitoring treatment efficacies. The availability powerful omics technologies, together with integrated data analysis network-based approaches can help clinically useful biomarkers. These biomarkers need to be accurately quantified using robust reproducible methods, such reliable point-of-care systems. Ideally, samples should collected quick, cost-efficient noninvasive methods. In recent plethora research directed toward finding novel diseases. Promising include sputum serum periostin exhaled nitric oxide. Several other biomarkers, pro-inflammatory mediators, miRNAs, eicosanoid molecules, epithelial barrier integrity, microbiota changes diagnosis in serum, body fluids air. Herein, we review studies asthma, chronic urticaria, atopic dermatitis, rhinitis, rhinosinusitis, food allergies, anaphylaxis, drug hypersensitivity allergen immunotherapy. addition, discuss COVID-19 within perspective recommendations management asthmatic patients during pandemic.

Язык: Английский

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Two Phase 3 Trials of Lebrikizumab for Moderate-to-Severe Atopic Dermatitis

New England Journal of Medicine, Год журнала: 2023, Номер 388(12), С. 1080 - 1091

Опубликована: Март 15, 2023

Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of interleukin-4Rα-interleukin-13Rα1 heterodimer receptor signaling complex.We conducted two identically designed, 52-week, randomized, double-blind, placebo-controlled, phase 3 trials; both trials included 16-week induction period and 36-week maintenance period. Eligible patients with moderate-to-severe atopic dermatitis (adults [≥18 years age] adolescents [12 to <18 age, weighing ≥40 kg]) were randomly assigned in 2:1 ratio receive either lebrikizumab at dose 250 mg (loading 500 baseline week 2) or placebo, administered subcutaneously every 2 weeks. Outcomes for assessed up 16 weeks are this report. The primary outcome was an Investigator's Global Assessment (IGA) score 0 1 (indicating clear almost skin; range, 4 [severe disease]) reduction improvement) least points from 16. Secondary outcomes 75% improvement Eczema Area Severity Index (EASI-75 response) assessments itch interference sleep. Safety also assessed.In trial 1, met 43.1% 283 group 12.7% 141 placebo (P<0.001); EASI-75 response occurred 58.8% 16.2%, respectively (P<0.001). In 2, 33.2% 281 10.8% 146 52.1% 18.1%, Measures sleep indicated therapy. incidence conjunctivitis higher among who received than those placebo. Most adverse events during mild moderate severity did not lead discontinuation.In trials, treatment effective adults dermatitis. (Funded by Dermira; ADvocate1 ADvocate2 ClinicalTrials.gov numbers, NCT04146363 NCT04178967, respectively.).

Язык: Английский

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An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study

The Lancet, Год журнала: 2022, Номер 401(10372), С. 204 - 214

Опубликована: Дек. 9, 2022

Язык: Английский

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Exploring causal correlations between inflammatory cytokines and systemic lupus erythematosus: A Mendelian randomization

Frontiers in Immunology, Год журнала: 2023, Номер 13

Опубликована: Янв. 19, 2023

Previous studies have reported that a few inflammatory cytokines associations with systemic lupus erythematosus (SLE)-for example, IL-6, IL-17, and macrophage protein (MIP). This Mendelian randomization was conducted to further assess the causal correlations between 41 SLE.The two-sample utilized genetic variances of SLE from large publicly available genome-wide association study (GWAS) (7,219 cases 15,991 controls European ancestry) GWAS summary containing 8,293 healthy participants. Causalities exposures outcomes were explored mainly using inverse variance weighted method. In addition, multiple sensitivity analyses including MR-Egger, median, simple mode, MR-PRESSO simultaneously applied strengthen final results.The results indicated cutaneous T cell-attracting chemokine (CTACK) IL-17 may be suggestively associated risk (odds ratio, OR: 1.21, 95%CI: 1.04-1.41, p = 0.015; 1.37, 1.03-1.82, 0.029). beta nerve growth factor, basic fibroblast IL-4, interferon gamma-induced 10, monokine induced by interferon-gamma, MIP1b, stromal cell-derived factor-1 alpha, tumor necrosis factor-alpha are suggested consequences disease (Beta: 0.035, 0.014; Beta: 0.021, 0.032; 0.024, 0.013; 0.019, 0.042; 0.040, 0.005; 0.046, 0.001; 0.029; 0.045; 0.029, 0.048).This CTACK probably factors correlated etiology, while couple more likely involved in development downstream.

Язык: Английский

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Multiple Roles for Cytokines in Atopic Dermatitis: From Pathogenic Mediators to Endotype-Specific Biomarkers to Therapeutic Targets

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(5), С. 2684 - 2684

Опубликована: Фев. 28, 2022

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, which generally presents with intense itching and recurrent eczematous lesions. AD affects up to 20% children 10% adults in high-income countries. The prevalence incidence have increased recent years. onset mostly occurs childhood, although some cases may persist adult life or even manifest middle age (adult-onset AD). pathophysiology made a complex net, genetic background, barrier dysfunction, innate adaptive immune responses, as well itch contribute disease development, progression, chronicization. One important features dehydration, mainly caused by filaggrin mutations that determine trans-epidermal water loss, pH alterations, antigen penetration. In accordance "outside-inside" theory pathogenesis, context an altered epidermal barrier, antigens encounter presentation cells (APCs), such Langerhans dendritic cells, leading their maturation Th-2 cell-mediated inflammation. APCs also bear trimeric high-affinity receptors for immunoglobulin E (IgE), induce IgE-mediated sensitizations part pathogenic mechanisms AD. this review, we discuss role cytokines pathogenesis AD, considering patients various clinical phenotypes. Moreover, describe cytokine patterns at different phases evolution, relation phenotypes/endotypes, including age, race, intrinsic/extrinsic subtypes. We outcomes current biologics corroborate presence multiple axes involved background A deep insight into correlation between related forms crucial step towards increasingly personalized, therefore more efficient therapy.

Язык: Английский

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Type 2 chronic inflammatory diseases: targets, therapies and unmet needs

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 22(9), С. 743 - 767

Опубликована: Авг. 1, 2023

Язык: Английский

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Rhinitis associated with asthma is distinct from rhinitis alone: The ARIA‐MeDALL hypothesis

Allergy, Год журнала: 2023, Номер 78(5), С. 1169 - 1203

Опубликована: Фев. 17, 2023

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach links between upper- lower-airway allergic diseases. With new data, it time to reassess concept. This article reviews (i) observations led Allergic Rhinitis its Impact on Asthma (ARIA), (ii) insights into polysensitization multimorbidity, (iii) advances mHealth for novel phenotype definitions, (iv) confirmation canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, (vii) concepts onset rhinitis multimorbidity. One recent concept, bringing together diseases with skin, gut, neuropsychiatric multimorbidities, "Epithelial Barrier Hypothesis." review determined "one-airway-one-disease" does not always hold true several disease can be defined. These include an extreme "allergic" (asthma) combining asthma, conjunctivitis. alone asthma multimorbidity represent two distinct following differences: transcriptomic background (Toll-Like Receptors IL-17 as local disease; IL-33 IL-5 non-allergic systemic disease), allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), severity symptoms, response. In conclusion, (local disease) (systemic should considered diseases, possibly modulated by microbiome, may model understanding epidemics chronic autoimmune

Язык: Английский

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Treatment of atopic dermatitis: Recently approved drugs and advanced clinical development programs

Allergy, Год журнала: 2024, Номер 79(6), С. 1501 - 1515

Опубликована: Янв. 8, 2024

Atopic dermatitis (AD) represents the most common skin disease characterized by heterogeneous endophenotypes and a high burden. In Europe, six new systemic therapies for AD have been approved: biologics dupilumab (anti-interleukin-4 receptor (IL-4R) α in 2017), tralokinumab (anti-IL-13 2021), lebrikizumab 2023), oral janus kinase (JAK) inhibitors (JAKi) targeting JAK1/2 (baricitinib 2020 EU) or JAK1 (upadacitinib 2021 abrocitinib 2022). Herein, we give an update on approvals, long-term safety, efficacy. Upadacitinib highest short-term efficacy among approved therapies. responders, catch up regarding incremental clinical benefit within continuous use. Recently, European Medicines Agency has released recommendations use of JAKi patients at risk (cardiovascular thromboembolic diseases, malignancies, (former) smoking, age ≥65 years). Furthermore, overview emerging currently Phase III trials. Among topical therapies, tapinarof (aryl hydrocarbon receptor), ruxolitinib (JAK1/2i), delgocitinib (pan-JAKi), asivatrep (anti-transient potential vanilloid), phosphodiesterase-4-inhibitors (roflumilast, difamilast) are discussed. current data cord-blood-derived mesenchymal stem cells, CM310 (anti IL-4Rα), nemolizumab (anti-IL-31RA), anti-OX40/OX40L-antibodies, neurokinin-receptor-1-antagonists, difelikefalin (κ-opioid-R) reported.

Язык: Английский

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Safety and efficacy of amlitelimab, a fully human nondepleting, noncytotoxic anti-OX40 ligand monoclonal antibody, in atopic dermatitis: results of a phase IIa randomized placebo-controlled trial

British Journal of Dermatology, Год журнала: 2023, Номер 189(5), С. 531 - 539

Опубликована: Июль 18, 2023

Abstract Background Atopic dermatitis (AD) is an inflammatory skin disease with significant unmet need. Blockade of the OX40–OX40 ligand (OX40L) costimulation pathway by targeting OX40L on antigen-presenting cells (APCs) a fully human noncytotoxic, nondepleting anti-OX40L monoclonal antibody (amlitelimab; SAR445229; KY1005) novel way to modulate persistent inflammation. Objectives To assess safety and efficacy amlitelimab over 16 weeks in adults AD phase IIa double-blind placebo-controlled study. Methods The study was conducted at 19 hospitals Germany, Poland, Spain UK. Eligible patients moderate-to-severe were randomized (1 : 1 1) low-dose intravenous (IV) (200 mg), high-dose IV (500 mg) or placebo, followed three maintenance doses (50% loading dose) 4, 8 12 weeks, follow-up week 36. co-primary endpoints incidence treatment-emergent adverse events (all who received ≥ dose drug) mean percentage change Eczema Area Severity Index (EASI) (full analysis set). Results Between 13 December 2018 May 2020, 89 randomly assigned low- (n = 29) 30) placebo 29), whom 88 proceeded treatment [37 women (42%), 51 (58%) men; (SD) age 33.6 (11.9) years]. Amlitelimab generally well tolerated unremarkable profile; no hypersensitivity reported. For primary endpoint, least square EASI from baseline –80.12% [95% confidence interval (CI) –95.55 –64.68; P 0.009 vs. placebo] –69.97% (95% CI –85.04 –54.60; 0.07 placebo) for 27) groups, respectively, –49.37% –66.02 –32.72) 24). Numerically greater reductions observed 2 16. Conclusions Novel OX40L-expressing APCs resulted clinically meaningful improvements AD.

Язык: Английский

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