Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials

Nature Medicine, Год журнала: 2023, Номер 29(5), С. 1180 - 1190

Опубликована: Май 1, 2023

Prurigo nodularis (PN) is a chronic inflammatory skin disease with intensely pruritic nodules. The LIBERTY-PN PRIME and PRIME2 phase 3 trials enrolled adults PN ≥20 nodules severe itch uncontrolled topical therapies. Dupilumab, fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 IL-13. Patients were randomized 1:1 to 300 mg dupilumab or placebo subcutaneously every 2 weeks 24 weeks. primary endpoint was pruritus improvement, measured by proportion of patients ≥4-point reduction in Worst Itch Numeric Rating Scale (WI-NRS) from baseline at week (PRIME) 12 (PRIME2). Key secondary endpoints included nodule number ≤5 24. 151 160 patients, respectively. Both met all pre-specified key endpoints. A WI-NRS arms achieved 60.0% 18.4% respectively, (95% confidence interval (CI), 27.8-57.7 difference, P < 0.001) 37.2% 22.0% CI, 2.3-31.2; = 0.022). Dupilumab demonstrated clinically meaningful statistically significant improvements lesions versus PN. Safety consistent known safety profile.ClinicalTrials.gov identifiers: NCT04183335 NCT04202679 .

Язык: Английский

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Peripheral itch sensitization in atopic dermatitis

Allergology International, Год журнала: 2022, Номер 71(3), С. 265 - 277

Опубликована: Май 25, 2022

Atopic dermatitis is a skin disorder caused by dryness and barrier dysfunction, resulting in inflammation chronic itch (or pruritus). The pathogenesis of atopic thought to be initiated lowering the threshold due dry skin. This at least partially increase intraepidermal nerve fibers sensitization sensory nerves interleukin (IL)-33 produced secreted keratinocytes. Such easily prone mechanical stimuli, such as rubbing clothing chemical stimuli from mediators. In patients with dermatitis, once occurs, further induced scratching, associated scratching breaks down barrier. Disruption allows entry into epidermis external foreign substances, allergens derived house dust mites, leading an increased induction type 2 inflammatory responses. As result, cytokines IL-4, IL-13, IL-31 are mainly Th2 cells, their action on causes sensitization. These sequences events occur simultaneously vicious itch-scratch cycle. cycle becomes negative spiral that leads disease burden. Therefore, controlling essential for treatment dermatitis. this review, we summarize discuss advances mechanisms peripheral focusing barrier-neuro-immune triadic connectivity.

Язык: Английский

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Chronic Pruritus

JAMA, Год журнала: 2024, Номер 331(24), С. 2114 - 2114

Опубликована: Май 29, 2024

Chronic pruritus, defined as itch experienced for 6 weeks or longer, affects approximately 22% of people in their lifetime. Approximately 1% physician visits are the chief concern chronic pruritus. pruritus is associated with adverse outcomes, including impaired sleep and reduced quality life.

Язык: Английский

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Atopic dermatitis

The Lancet, Год журнала: 2025, Номер 405(10478), С. 583 - 596

Опубликована: Фев. 1, 2025

Язык: Английский

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Neuroimmune interplay during type 2 inflammation: Symptoms, mechanisms, and therapeutic targets in atopic diseases

Journal of Allergy and Clinical Immunology, Год журнала: 2023, Номер 153(4), С. 879 - 893

Опубликована: Авг. 25, 2023

Type 2 inflammation is characterized by overexpression and heightened activity of type cytokines, mediators, cells that drive neuroimmune activation sensitization to previously subthreshold stimuli. The consequences altered differ tissue disease; they include skin inflammation, pruritogens, itch amplification in atopic dermatitis prurigo nodularis; airway and/or hyperresponsiveness, loss expiratory volume, airflow obstruction increased mucus production asthma; sense smell chronic rhinosinusitis with nasal polyps; dysphagia eosinophilic esophagitis. We describe the interactions underlie various sensory autonomic pathologies inflammatory diseases present recent advances targeted treatment approaches reduce its associated symptoms these diseases. Further research needed better understand mechanisms chronic, sustained related inflammation. immunity a specialized, evolutionarily conserved arm immune system combats ectoparasitic endoparasitic helminths, expels toxins, promotes repair.1Gandhi N.A. Bennett B.L. Graham N.M.H. Pirozzi G. Stahl N. Yancopoulos G.D. Targeting key proximal drivers disease.Nat Rev Drug Discov. 2016; 15: 35-50Crossref PubMed Scopus (392) Google Scholar, 2Gandhi N.M. Commonality IL-4/IL-13 pathway diseases.Expert Clin Immunol. 2017; 13: 425-437Crossref (276) 3Kopp E.B. Agaronyan K. Licona-Limon I. Nish S.A. Medzhitov R. Modes response initiation.Immunity. 2023; 56: 667-694Abstract Full Text PDF (1) 4Molofsky A.B. Locksley R.M. ins outs innate adaptive immunity.Immunity. 704-722Abstract (0) Scholar When epithelial barrier breached, alarmin cytokines (eg, thymic stromal lymphopoietin [TSLP], IL-25, IL-33) activate tissue-resident (such as mast cells, dendritic group lymphoid [ILC2s]) while simultaneously recruiting granulocytes, including eosinophils basophils. Collectively, orchestrate polarized through histamine, other mediators neutralize expel parasitic helminths toxins repair turnover, remodeling, fibrosis. Although processes are protective intended restore homeostasis, setting allergy continuous stress become pathologic, resulting variety Mechanical reflexes such scratching, constriction, coughing, sneezing, gastrointestinal motility also protect surfaces triggered direct neurons, often concert input target organs. Many manifestations pathologically dysregulation (Fig 1), (but not limited to) (AD), nodularis (PN), asthma, food allergy, polyps (CRSwNP), esophagitis (EoE).1Gandhi Scholar,2Gandhi Scholar,5Hamilton J.D. Harel S. Swanson B.N. Brian W. Chen Z. Rice M.S. et al.Dupilumab suppresses biomarkers across multiple atopic, allergic diseases.Clin Exp Allergy. 2021; 51: 915-931Crossref (59) Scholar,6Le Floc'h A. Allinne J. Nagashima Scott Birchard D. Asrat al.Dual blockade IL-4 IL-13 dupilumab, an IL-4Rα antibody, required broadly inhibit inflammation.Allergy. 2020; 75: 1188-1204Crossref (163) extent similarities among pathways regulating mechanical responses remains be fully defined (Table I7Kulka M. Sheen C.H. Tancowny B.P. Grammer L.C. Schleimer R.P. Neuropeptides human cell degranulation chemokine production.Immunology. 2008; 123: 398-410Crossref (340) 8Liang Y. Marcusson J.A. Jacobi H.H. Haak-Frendscho Johansson O. Histamine-containing their relationship NGFr-immunoreactive nerves nodularis: reappraisal.J Cutan Pathol. 1998; 25: 189-198Crossref (49) 9Sonkoly E. Muller Lauerma A.I. Pivarcsi Soto H. Kemeny L. al.IL-31: new link between T pruritus inflammation.J Allergy 2006; 117: 411-417Abstract (759) 10Tominaga Takamori Peripheral dermatitis.Allergol Int. 2022; 71: 265-277Crossref (19) 11Garcovich Maurelli Gisondi P. Peris Yosipovitch Girolomoni Pruritus distinctive feature inflammation.Vaccines (Basel). 9: 303Crossref (50) 12Kim Y.J. Granstein R.D. Roles calcitonin gene-related peptide skin, physiological pathophysiological functions.Brain Behav Immun Health. 18100361PubMed 13Wang F. Trier A.M. Li Kim Chai J.N. al.A basophil-neuronal axis itch.Cell. 184: 422-440.e17Abstract (95) 14Liu B. Tai Achanta Kaelberer M.M. Caceres Shao X. al.IL-33/ST2 signaling excites neurons mediates mouse model poison ivy contact allergy.Proc Natl Acad Sci U S 113: E7572-E7579Crossref (179) 15Wilson S.R. Thé Batia L.M. Beattie Katibah G.E. McClain S.P. al.The cell-derived cytokine TSLP activates induce 2013; 155: 285-295Abstract (676) 16Trier Mack M.R. Fredman Tamari Ver Heul Zhao al.IL-33 promoted dry itch.J 149: 1473-1480Abstract 17Simpson E.L. Parnes J.R. She Crouch Rees Mo al.Tezepelumab, anti–thymic monoclonal moderate severe dermatitis: randomized phase 2a clinical trial.J Am Dermatol. 2019; 80: 1013-1021Abstract 18Oetjen L.K. Feng Whelan T.M. Niu Guo C.J. al.Sensory co-opt classical mediate 171: 217-228.e13Abstract (581) 19Cevikbas Wang Akiyama Kempkes C. Savinko T. Antal neuron-expressed IL-31 receptor helper cell-dependent itch: involvement TRPV1 TRPA1.J 2014; 133: 448-460Abstract (482) 20Blauvelt de Bruin-Weller Gooderham Cather J.C. Weisman Pariser al.Long-term management moderate-to-severe dupilumab concomitant topical corticosteroids (LIBERTY AD CHRONOS): 1-year, randomized, double-blinded, placebo-controlled, 3 trial.Lancet. 389: 2287-2303Abstract (786) 21Silverberg J.I. Simpson Ardeleanu Thaçi Barbarot Bagel provides important benefits patients who do achieve clear or almost according Investigator's Global Assessment: pooled analysis data from two III trials.Br J 181: 80-87Crossref (39) 22Simpson Bieber Guttman-Yassky Beck L.A. Blauvelt Cork M.J. al.Two trials versus placebo dermatitis.N Engl Med. 375: 2335-2348Crossref (1254) 23Thaçi Deleuran Kataoka Gadkari al.Efficacy safety monotherapy adults SOLO 1 LIBERTY 2).J Dermatol Sci. 94: 266-275Abstract 24Simpson Paller A.S. Siegfried E.C. Boguniewicz Sher adolescents uncontrolled trial.JAMA 156: 44-56Crossref (254) 25Paller Wollenberg Arkwright P.D. children 6 11 years old placebo-controlled 83: 1282-1293Abstract (174) 26Paller ages months younger than randomised, double-blind, 400: 908-919Abstract 27Wollenberg Worm Lynde Lacour J.P. al.Tralokinumab for results 52-week, multicentre, (ECZTRA ECZTRA 2).Br 437-449Crossref (214) 28Wollenberg Howell M.D. Silverberg Kell Ranade al.Treatment tralokinumab, anti-IL-13 mAb.J. Clin. 143: 135-141Abstract (252) 29Gutermuth Pink A.E. Soldbro Bjerregård Øland Weidinger Tralokinumab plus inadequate intolerance ciclosporin A: trial 7).Br 186: 440-452Crossref (26) 30Silverberg Toth Alexis A.F. Elewski B.E. trial.Br 450-463Crossref (133) 31Simpson Carsten Flohr Eichenfield L.F. Sofen Taïeb lebrikizumab (an antibody) inadequately controlled corticosteroids: II (TREBLE).J 2018; 78: 863-871.e11Abstract (239) 32Guttman-Yassky Armstrong A.W. Drew lebrikizumab, high-affinity interleukin 13 inhibitor, dermatitis. A 2b 411-420Crossref 33Silverberg Irvine A.D. Stein Gold 388: 1080-1091Crossref (16) 34Silverberg Pinter Pulka Poulin Bouaziz al.Phase 2B study nemolizumab pruritus.J 145: 173-182Abstract (159) 35Kabashima Matsumura Komazaki Kawashima Nemolizumab JP01 JP02 Study Group. agents (AD) provide improvement signs up 68 weeks: III, long-term studies.Br 642-651Crossref 36Ständer Legat F.J. Paul Narbutt al.Trial nodularis.N 382: 706-716Crossref (144) 37Kamata Tada Optimal use Jak inhibitors biologics on basis current evidence.JID Innov. 3100195Abstract 38Bieber Kabashima al.Atopic pathomechanisms lessons learned novel systemic therapeutic options.JEADV. 36: 1432-1449Google 39Lee K.P. Plante Korte J.E. Elston D.M. Oral Janus kinase systematic review meta-analysis.Skin Health Dis. 3: e133Crossref 40Rodriguez-Roy Ficheux A.-S. Misery Brenaut Efficacy treatments pruritus: literature meta-analysis.Front 91079323Google 41Huang I.-H. Chung W.-H. Wu P.-C. C.-B. JAK-STAT pathogenesis An updated review.Front 131068260Crossref (12) 42Haas Capellino Phan N.Q. Böhm Luger T.A. Straub R.H. al.Low density sympathetic nerve fibers relative substance P-positive lesional nodularis.J 2010; 58: 193-197Abstract (73) 43Liang Reimert C.M. CGRP-immunoreactive nodularis—an exploration neurogenic 2000; 27: 359-366Crossref (62) 44Williams K.A. Huang A.H. Belzberg Kwatra S.G. Prurigo management.J 1567-1575Abstract 45Molina F.A. Burrows N.P. Jones R.R. Terenghi Polak J.M. Increased neuropeptides nodular prurigo: quantitative immunohistochemical analysis.Br 1992; 127: 344-351Crossref 46Kabata Artis Neuro-immune crosstalk Invest. 129: 1475-1482Crossref (88) 47Teresiak-Mikołajczak Czarnecka-Operacz Jenerowicz Silny Neurogenic markers process relation severity pruritus.Postepy Alergol. 30: 286-292Crossref (33) 48Yang T.B. B.S. Clinical Review: immunology.J 144: 353-360Abstract 49Hashimoto Nattkemper H.S. al.Itch intensity closely dermal interleukin-31, oncostatin M, alpha M beta.Exp 804-810Crossref (44) 50Stott Lavender Lehmann Pennino Durham Schmidt-Weber C.B. Human induced Th2-driven 132: 446-454Abstract (134) 51Macdonald L.E. Karow Stevens Auerbach Poueymirou W.T. Jason Yasenchak al.Precise situ genetic humanization Mb immunoglobulin genes.Proc 111: 5147-5152Crossref (237) 52Ständer Reich al.Nemolizumab efficacy onset action sleep disturbances.J Eur Venereol. 1820-1825Crossref 53Fryer L.H. Nie Curtis D.E. Evans Hodgson S.T. al.Neuronal eotaxin effects CCR3 antagonist hyperreactivity M2 dysfunction.J 116: 228-236Crossref (122) 54Grunig Warnock Wakil Venkayya Brombacher Rennick al.Requirement independently experimental asthma.Science. 282: 2261-2263Crossref (1748) 55Wills-Karp Luyimbazi K.J. Xu Schofield Neben T.Y. Karp C.L. al.Interleukin-13: central mediator 2258-2261Crossref (2410) 56Manson M.L. Jesper Säfholm James Johnsson Bergman Al-Ameri al.IL-13 IL-4, but IL-5 nor IL-17A, hyperresponsiveness isolated small airways.J 808-817Abstract (66) 57Brightling C.E. Bradding Symon Holgate Wardlaw A.J. Pavord I.D. Mast-cell infiltration smooth muscle asthma.N 2002; 346: 1699-1705Crossref (1079) 58Weigand Myers A.C. Meeker Undem B.J. Mast cell-cholinergic interaction Physiol. 2009; 587: 3355-3362Crossref (55) 59Klose C.S.N. Mahlakõiv Moeller J.B. Rankin Flamar A.L. Kabata neuropeptide neuromedin stimulates inflammation.Nature. 549: 282-286Crossref (350) 60Cardoso V. Chesné Ribeiro García-Cassani Carvalho Bouchery regulation via U.Nature. 277-281Crossref (368) 61Perner Flayer Zhu Aderhold P.A. Dewan Z.N.A. Voisin al.Substance P release triggers migration initiates type-2 allergens.Immunity. 53: 1063-1077Abstract 62Moriyama Brestoff Klose al.β2-adrenergic receptor-mediated negative responses.Science. 359: 1056-1061Crossref (236) 63Sui Wiesner D.L. Zhang Lee Van Dyken al.Pulmonary neuroendocrine amplify asthma 360eaan8546Crossref (228) 64Hara Jha M.K. Mattoo Nash Khan Orengo al.Interleukin 4 directly olfactory induces mice.J 151: AB128Abstract 65Rouyar Classe Gorski Bock Le-Guern Roche al.Type 2/Th2-driven impairs neurogenesis model.Allergy. 74: 549-559Crossref (14) 66Backaert Steelant Hellings P.W. Talavera Gerven TRiP roles transient potential cation channels upper inflammation.Curr Asthma Rep. 21: 20Crossref 67Li Jiang Shen al.Sneezing reflex mediated peptidergic nose brainstem.Cell. 3762-3773Abstract (23) 68Samivel D.W. Son H.R. role CD4+ cell-mediated rhinitis.Oncotarget. 2015; 7: 148-160Crossref 69Yu Chang Yu Capsaicin-sensitive vagal afferent nerve-mediated interoceptive signals esophagus.Molecules. 26: 3929Crossref (3) 70O'Shea K.M. Aceves S.S. Dellon E.S. Pathophysiology esophagitis.Gastroenterology. 154: 333-345Abstract 71Akiho Ihara Motomura Nakamura Cytokine-induced alterations disorders.World Gastrointest Pathophysiol. 2011; 2: 72-81Crossref 72Hu Liu al.Increased acid responsiveness guinea pig esophagitis.Am Physiol Liver 307: G149-G157Crossref (21) 73Zhang Shoda Arva N.C. Chehade Collins M.H. al.Mast cell-pain connection esophagitis.Allergy. 77: 1895-1899Crossref (8) Scholar).Table INeuroimmune affecting AD, PN, CRSwNP, EoEConditionSymptomsNeuroimmune interactionsType profileADPruritus•Colocalization cells7Kulka Scholar,8Liang Scholar•Type OSM promote pruritogen sensitization9Sonkoly Scholar•Neuropeptide proinflammatory basophils)7Kulka Scholar,10Tominaga Scholar•Scratching causes alarmins IL-33), which can act neurons9Sonkoly Scholar,11Garcovich Scholar,14Liu Scholar•Some express receptors IL-13, IL-31, TRPA1, TRPV118Oetjen Scholar,19Cevikbas Scholar•Reducing reduces itch20Blauvelt

Язык: Английский

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The hidden sentinel of the skin: An overview on the role of interleukin-13 in atopic dermatitis

Frontiers in Medicine, Год журнала: 2023, Номер 10

Опубликована: Апрель 18, 2023

Recent evidence suggests that interleukin (IL)-13 is a crucial cytokine involved in the pathogenesis of atopic dermatitis (AD). It central driver type-2 T-helper inflammation and overexpressed lesional skin AD patients. Upon release peripheral skin, IL-13 activates its receptors, recruits inflammatory cells, modifies microbiome. also reduces expression epidermal barrier proteins sensory nerve mediating itch transmission signal. Novel therapeutics target seem to be efficacious safe for treatment patients with moderate-to-severe AD. The aim our manuscript review role plays immunopathogenesis.

Язык: Английский

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The immunological and structural epidermal barrier dysfunction and skin microbiome in atopic dermatitis-an update

Frontiers in Molecular Biosciences, Год журнала: 2023, Номер 10

Опубликована: Авг. 16, 2023

Atopic dermatitis (AD) is a common, chronic and relapsing inflammatory skin disease with various clinical presentations combinations of symptoms. The pathophysiology AD complex multifactorial. There are several factors involved in the etiopathogenesis including structural immunological epidermal barrier defect, imbalance microbiome, genetic background environmental factors. Alterations proteins, lipids, proteases, their inhibitors, lead to impairment stratum corneum which associated increased penetration transepidermal water loss. elevated serum immunoglobulin E levels blood eosinophilia have been shown majority patients. Type 2 T-helper cell immune pathway expression interleukin (IL)-4, IL-5, IL-13, has an important role AD. Both T cells keratinocytes contribute via dynamic interaction cytokines chemokines. microbiome another factor relevance It that during flares, Staphylococcus aureus (S. aureus) colonization increased, while epidermidis epidermidis) decreased. On contrary, S. species Streptococcus, Corynebacterium Propionibacterium remision phases. However, it not clear whether dysbiosis one symptoms or causes therapeutic options, targeting these pathways play critical Although topical steroids mainstay treatment AD, new biological therapies IL-4, IL-31 as well Janus kinase inhibitors (JAKi), increasingly gain more importance advances therapy In this review, we summarize dysfunction, abnormalities, filaggrin mutation options for effects on abnormalities skin.

Язык: Английский

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IL-33 potentiates histaminergic itch

Journal of Allergy and Clinical Immunology, Год журнала: 2023, Номер 153(3), С. 852 - 859.e3

Опубликована: Ноя. 18, 2023

Itch is a common symptom that can greatly diminish quality of life. Histamine potent endogenous pruritogen, and while antihistamines are often the first-line treatment for itch, in conditions like chronic spontaneous urticaria (CSU), many patients remain symptomatic receiving maximal doses. Mechanisms drive resistance to poorly defined.

Язык: Английский

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Updated Review on Treatment of Atopic Dermatitis

Journal of Investigational Allergology and Clinical Immunology, Год журнала: 2023, Номер 33(3), С. 158 - 167

Опубликована: Июнь 15, 2023

Atopic dermatitis (AD) is a chronic or chronically recurrent Inflammatory dermatosis associated with multiple triggers that has complex pathophysiological mechanism. It characterized by heterogeneous clinical expression, signs, and symptoms. Its etiology pathogenesis are influenced immune-mediated factors. Treatment of AD can also be complex, given the high number available drugs therapeutic targets. In this review, we summarize current literature on efficacy safety topical systemic to treat moderate-to-severe AD. We begin treatments such as corticosteroids calcineurin inhibitors subsequently address latest treatments, Janus kinase (upadacitinib, baricitinib, abrocitinib, gusacitinib) interleukin (IL) inhibitors, which have proven efficacious in AD, namely, dupilumab (IL-4 IL-13), tralokinumab (IL-13), lebrikizumab nemolizumab (IL-31). Given large available, pivotal trials for each drug, evaluate recent real-world experience terms purposes compilation, provide evidence guide optimal choice therapy.

Язык: Английский

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Molecular mechanisms of pruritus in prurigo nodularis

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Ноя. 23, 2023

Pruritus is the most common symptom of dermatological disorders, and prurigo nodularis (PN) notorious for intractable severe itching. Conventional treatments often yield disappointing outcomes, significantly affecting patients’ quality life psychological well-being. The pathogenesis PN associated with a self-sustained “itch-scratch” vicious cycle. Recent investigations PN-related itch have partially revealed intricate interactions within cutaneous neuroimmune network; however, underlying mechanism remains undetermined. Itch mediators play key role in pruritus amplification understanding their action will undoubtedly lead to development novel targeted antipruritic agents. In this review, we describe series pruritogens receptors involved mediating itching PN, including cytokines, neuropeptides, extracellular matrix proteins, vasculogenic substances, ion channels, intracellular signaling pathways. Moreover, provide prospective outlook on potential therapies based existing findings.

Язык: Английский

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