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A New Era with the Development of Cytokine-Based Therapy for Pruritus

  • Rintaro Shibuya
    Affiliations
    Department of Dermatology, Faculty of Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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  • Riko Takimoto-Ito
    Affiliations
    Department of Dermatology, Faculty of Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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  • Naotomo Kambe
    Correspondence
    Correspondence: Naotomo Kambe, Department of Dermatology, Faculty of Medicine, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
    Affiliations
    Department of Dermatology, Faculty of Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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  • Kenji Kabashima
    Affiliations
    Department of Dermatology, Faculty of Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Singapore Immunology Network, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore

    Skin Research Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
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Published:November 17, 2021DOI:https://doi.org/10.1016/j.jid.2021.09.023
      Pruritus is a common dermatological condition and negatively impacts QOL. Persistent pruritus and excessive scratching behavior can lead to the itch–scratch cycle that exacerbates inflammatory skin diseases. Conventional antipruritic drugs, such as antihistamines, corticosteroids, or anticonvulsants, are sometimes insufficient. Recently, however, molecularly targeted drugs, such as IL-31 or IL-4 receptor–targeting antibodies, have become available or are under clinical trials, dramatically changing the clinical situation. In fact, some of these drugs can improve pruritus without the need for topical steroids. Taken together, these observations point to the importance of cytokine-mediated pruritus, further understanding of which may guide improved therapies.

      Abbreviations:

      5-D (five-domain), AD (atopic dermatitis), DC (dendritic cell), EASI (Eczema Area and Severity Index), KC (keratinocyte), NRS (numerical rating scale), STAT (signal transducer activator of transcription), VAS (visual analog scale)
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      References

        • Beck K.M.
        • Yang E.J.
        • Sekhon S.
        • Bhutani T.
        • Liao W.
        Dupilumab treatment for generalized prurigo Nodularis.
        JAMA Dermatol. 2019; 155: 118-120
        • Bieber T.
        • Simpson E.L.
        • Silverberg J.I.
        • Thaçi D.
        • Paul C.
        • Pink A.E.
        • et al.
        Abrocitinib versus placebo or dupilumab for atopic dermatitis.
        N Engl J Med. 2021; 384: 1101-1112
        • Campion M.
        • Smith L.
        • Gatault S.
        • Métais C.
        • Buddenkotte J.
        • Steinhoff M.
        Interleukin-4 and interleukin-13 evoke scratching behaviour in mice.
        Exp Dermatol. 2019; 28: 1501-1504
        • Cevikbas F.
        • Wang X.
        • Akiyama T.
        • Kempkes C.
        • Savinko T.
        • Antal A.
        • et al.
        A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1.
        J Allergy Clin Immunol. 2014; 133: 448-460
        • Chee A.
        • Branca L.
        • Jeker F.
        • Vogt D.R.
        • Schwegler S.
        • Navarini A.
        • et al.
        When life is an itch: what harms, helps, and heals from the patients' perspective? Differences and similarities among skin diseases.
        Dermatol Ther. 2020; 33: e13606
        • Chen Y.L.
        • Gutowska-Owsiak D.
        • Hardman C.S.
        • Westmoreland M.
        • MacKenzie T.
        • Cifuentes L.
        • et al.
        Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis.
        Sci Transl Med. 2019; 11eaax2945
        • Cornelissen C.
        • Lüscher-Firzlaff J.
        • Baron J.M.
        • Lüscher B.
        Signaling by IL-31 and functional consequences.
        Eur J Cell Biol. 2012; 91: 552-566
        • Cornelissen C.
        • Marquardt Y.
        • Czaja K.
        • Wenzel J.
        • Frank J.
        • Lüscher-Firzlaff J.
        • et al.
        IL-31 regulates differentiation and filaggrin expression in human organotypic skin models.
        J Allergy Clin Immunol. 2012; 129: 426-433.e4338
        • Dillon S.R.
        • Sprecher C.
        • Hammond A.
        • Bilsborough J.
        • Rosenfeld-Franklin M.
        • Presnell S.R.
        • et al.
        Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice [published correction appears in Nat Immunol 2004;6:114].
        Nat Immunol. 2004; 5: 752-760
        • Drucker A.M.
        • Wang A.R.
        • Li W.Q.
        • Sevetson E.
        • Block J.K.
        • Qureshi A.A.
        The burden of atopic dermatitis: summary of a report for the National Eczema Association.
        J Invest Dermatol. 2017; 137: 26-30
        • Fowler E.
        • Yosipovitch G.
        A new generation of treatments for itch.
        Acta Derm Venereol. 2020; 100adv00027
        • Giura M.T.
        • Viola R.
        • Fierro M.T.
        • Ribero S.
        • Ortoncelli M.
        Efficacy of dupilumab in prurigo nodularis in elderly patient.
        Dermatol Ther. 2020; 33: e13201
        • Guttman-Yassky E.
        • Blauvelt A.
        • Eichenfield L.F.
        • Paller A.S.
        • Armstrong A.W.
        • Drew J.
        • et al.
        Efficacy and safety of lebrikizumab, a high-affinity interleukin 13 inhibitor, in adults with moderate to severe atopic dermatitis: a phase 2b randomized clinical trial.
        JAMA Dermatol. 2020; 156: 411-420
        • Guttman-Yassky E.
        • Teixeira H.D.
        • Simpson E.L.
        • Papp K.A.
        • Pangan A.L.
        • Blauvelt A.
        • et al.
        Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials.
        Lancet. 2021; 397: 2151-2168
        • Hänel K.H.
        • Pfaff C.M.
        • Cornelissen C.
        • Amann P.M.
        • Marquardt Y.
        • Czaja K.
        • et al.
        Control of the physical and antimicrobial skin barrier by an IL-31-IL-1 signaling network.
        J Immunol. 2016; 196: 3233-3244
        • Hawro T.
        • Przybyłowicz K.
        • Spindler M.
        • Hawro M.
        • Steć M.
        • Altrichter S.
        • et al.
        The characteristics and impact of pruritus in adult dermatology patients: a prospective, cross-sectional study.
        J Am Acad Dermatol. 2021; 84: 691-700
        • Howell M.D.
        • Kim B.E.
        • Gao P.
        • Grant A.V.
        • Boguniewicz M.
        • DeBenedetto A.
        • et al.
        Cytokine modulation of atopic dermatitis filaggrin skin expression.
        J Allergy Clin Immunol. 2009; 124: R7-R12
        • Imai Y.
        Interleukin-33 in atopic dermatitis.
        J Dermatol Sci. 2019; 96: 2-7
        • Jafferany M.
        • Davari M.E.
        Itch and psyche: psychiatric aspects of pruritus.
        Int J Dermatol. 2019; 58: 3-23
        • Kabashima K.
        • Furue M.
        • Hanifin J.M.
        • Pulka G.
        • Wollenberg A.
        • Galus R.
        • et al.
        Nemolizumab in patients with moderate-to-severe atopic dermatitis: randomized, phase II, long-term extension study.
        J Allergy Clin Immunol. 2018; 142: 1121-1130.e7
        • Kabashima K.
        • Irie H.
        Interleukin-31 as a clinical target for pruritus treatment.
        Front Med (Lausanne). 2021; 8: 638325
        • Kabashima K.
        • Matsumura T.
        • Komazaki H.
        • Kawashima M.
        • Nemolizumab-JP01 Study Group
        Trial of nemolizumab and topical agents for atopic dermatitis with pruritus.
        N Engl J Med. 2020; 383: 141-150
        • Kim B.S.
        • Siracusa M.C.
        • Saenz S.A.
        • Noti M.
        • Monticelli L.A.
        • Sonnenberg G.F.
        • et al.
        TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation.
        Sci Transl Med. 2013; 5: 170ra16
        • Kini S.P.
        • DeLong L.K.
        • Veledar E.
        • McKenzie-Brown A.M.
        • Schaufele M.
        • Chen S.C.
        The impact of pruritus on quality of life: the skin equivalent of pain.
        Arch Dermatol. 2011; 147: 1153-1156
        • Liu B.
        • Tai Y.
        • Achanta S.
        • Kaelberer M.M.
        • Caceres A.I.
        • Shao X.
        • et al.
        IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy.
        Proc Natl Acad Sci USA. 2016; 113: E7572-E7579
        • Lu J.
        • Wu K.
        • Zeng Q.
        • Xiang Y.
        • Gao L.
        • Huang J.
        Serum interleukin-31 level and pruritus in atopic dermatitis: a meta-analysis.
        Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2018; 43: 124-130
        • Luk K.M.
        • Shaw F.M.
        • Zhang C.
        • Culler S.D.
        • Chen S.C.
        The annual direct and indirect health care costs for patients with chronic pruritus and their determining factors.
        J Invest Dermatol. 2020; 140: 699-701.e5
        • Mack M.R.
        • Kim B.S.
        The itch-scratch cycle: a neuroimmune perspective.
        Trends Immunol. 2018; 39: 980-991
        • Naafs B.
        • Alemu Belachew W.
        Comments to the letter to the editor by Dr Sweta Subhadarshani.
        J Eur Acad Dermatol Venereol. 2020; 34: e73-e74
        • Nakagawa H.
        • Nemoto O.
        • Igarashi A.
        • Saeki H.
        • Kaino H.
        • Nagata T.
        Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: a phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study.
        J Am Acad Dermatol. 2020; 82: 823-831
        • Nakajima S.
        • Kabata H.
        • Kabashima K.
        • Asano K.
        Anti-TSLP antibodies: targeting a master regulator of type 2 immune responses.
        Allergol Int. 2020; 69: 197-203
        • Neis M.
        • Peters B.
        • Dreuw A.
        • Wenzel J.
        • Bieber T.
        • Mauch C.
        • et al.
        Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis.
        J Allergy Clin Immunol. 2006; 118: 930-937
        • Nemoto O.
        • Furue M.
        • Nakagawa H.
        • Shiramoto M.
        • Hanada R.
        • Matsuki S.
        • et al.
        The first trial of CIM331, a humanized antihuman interleukin-31 receptor A antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-controlled study.
        Br J Dermatol. 2016; 174: 296-304
        • Niyonsaba F.
        • Ushio H.
        • Hara M.
        • Yokoi H.
        • Tominaga M.
        • Takamori K.
        • et al.
        Antimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells.
        J Immunol. 2010; 184: 3526-3534
        • Oetjen L.K.
        • Mack M.R.
        • Feng J.
        • Whelan T.M.
        • Niu H.
        • Guo C.J.
        • et al.
        Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch.
        Cell. 2017; 171: 217-228.e13
        • O'Shea J.J.
        • Plenge R.
        JAK and STAT signaling molecules in immunoregulation and immune-mediated disease.
        Immunity. 2012; 36: 542-550
        • Palmer C.N.
        • Irvine A.D.
        • Terron-Kwiatkowski A.
        • Zhao Y.
        • Liao H.
        • Lee S.P.
        • et al.
        Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.
        Nat Genet. 2006; 38: 441-446
        • Papp K.
        • Szepietowski J.C.
        • Kircik L.
        • Toth D.
        • Eichenfield L.F.
        • Leung D.Y.M.
        • et al.
        Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: results from 2 phase 3, randomized, double-blind studies.
        J Am Acad Dermatol. 2021; 85: 863-872
        • Patel S.P.
        • Khanna R.
        • Choi J.
        • Williams K.A.
        • Roh Y.S.
        • Hong M.S.
        • et al.
        Sleep disturbance in adults with chronic pruritic dermatoses is associated with increased C-reactive protein levels.
        J Am Acad Dermatol. 2021; 84: 265-272
        • Petra A.I.
        • Tsilioni I.
        • Taracanova A.
        • Katsarou-Katsari A.
        • Theoharides T.C.
        Interleukin 33 and interleukin 4 regulate interleukin 31 gene expression and secretion from human laboratory of allergic diseases 2 mast cells stimulated by substance P and/or immunoglobulin E.
        Allergy Asthma Proc. 2018; 39: 153-160
        • Raap U.
        • Gehring M.
        • Kleiner S.
        • Rüdrich U.
        • Eiz-Vesper B.
        • Haas H.
        • et al.
        Human basophils are a source of - and are differentially activated by - IL-31.
        Clin Exp Allergy. 2017; 47: 499-508
        • Ruzicka T.
        • Hanifin J.M.
        • Furue M.
        • Pulka G.
        • Mlynarczyk I.
        • Wollenberg A.
        • et al.
        Anti-interleukin-31 receptor A antibody for atopic dermatitis.
        N Engl J Med. 2017; 376: 826-835
        • Silverberg J.I.
        • Gelfand J.M.
        • Margolis D.J.
        • Boguniewicz M.
        • Fonacier L.
        • Grayson M.H.
        • et al.
        Patient burden and quality of life in atopic dermatitis in US adults: a population-based cross-sectional study.
        Ann Allergy Asthma Immunol. 2018; 121: 340-347
        • Silverberg J.I.
        • Pinter A.
        • Pulka G.
        • Poulin Y.
        • Bouaziz J.D.
        • Wollenberg A.
        • et al.
        Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus.
        J Allergy Clin Immunol. 2020; 145: 173-182
        • Silverberg J.I.
        • Simpson E.L.
        • Thyssen J.P.
        • Gooderham M.
        • Chan G.
        • Feeney C.
        • et al.
        Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial.
        JAMA Dermatol. 2020; 156: 863-873
        • Silverberg J.I.
        • Yosipovitch G.
        • Simpson E.L.
        • Kim B.S.
        • Wu J.J.
        • Eckert L.
        • et al.
        Dupilumab treatment results in early and sustained improvements in itch in adolescents and adults with moderate to severe atopic dermatitis: analysis of the randomized phase 3 studies SOLO 1 and SOLO 2, AD ADOL, and CHRONOS.
        J Am Acad Dermatol. 2020; 82: 1328-1336
        • Simpson E.L.
        • Lacour J.P.
        • Spelman L.
        • Galimberti R.
        • Eichenfield L.F.
        • Bissonnette R.
        • et al.
        Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.
        Br J Dermatol. 2020; 183: 242-255
        • Simpson E.L.
        • Parnes J.R.
        • She D.
        • Crouch S.
        • Rees W.
        • Mo M.
        • et al.
        Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: a randomized phase 2a clinical trial.
        J Am Acad Dermatol. 2019; 80: 1013-1021
        • Ständer S.
        • Weisshaar E.
        • Mettang T.
        • Szepietowski J.C.
        • Carstens E.
        • Ikoma A.
        • et al.
        Clinical classification of itch: a position paper of the International Forum for the Study of Itch.
        Acta Derm Venereol. 2007; 87: 291-294
        • Ständer S.
        • Yosipovitch G.
        • Legat F.J.
        • Lacour J.P.
        • Paul C.
        • Narbutt J.
        • et al.
        Trial of nemolizumab in moderate-to-severe prurigo nodularis.
        N Engl J Med. 2020; 382: 706-716
        • Szegedi K.
        • Kremer A.E.
        • Kezic S.
        • Teunissen M.B.
        • Bos J.D.
        • Luiten R.M.
        • et al.
        Increased frequencies of IL-31-producing T cells are found in chronic atopic dermatitis skin.
        Exp Dermatol. 2012; 21: 431-436
        • Tsakok T.
        • Woolf R.
        • Smith C.H.
        • Weidinger S.
        • Flohr C.
        Atopic dermatitis: the skin barrier and beyond.
        Br J Dermatol. 2019; 180: 464-474
        • Usoskin D.
        • Furlan A.
        • Islam S.
        • Abdo H.
        • Lönnerberg P.
        • Lou D.
        • et al.
        Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.
        Nat Neurosci. 2015; 18: 145-153
        • Wang F.
        • Kim B.S.
        Itch: a paradigm of neuroimmune crosstalk.
        Immunity. 2020; 52: 753-766
        • Wang F.
        • Morris C.
        • Bodet N.D.
        • Kim B.S.
        Treatment of refractory chronic pruritus of unknown origin with tofacitinib in patients with rheumatoid arthritis.
        JAMA Dermatol. 2019; 155: 1426-1428
        • Whang K.A.
        • Gabriel S.
        • Chavda R.
        • Kwatra S.G.
        Emergency department use by patients with prurigo nodularis in the United States.
        J Am Acad Dermatol. 2021; 84: 1138-1140
        • Whang K.A.
        • Kang S.
        • Kwatra S.G.
        Inpatient burden of prurigo nodularis in the United States.
        Medicines (Basel). 2019; 6: 88
        • Whang K.A.
        • Khanna R.
        • Williams K.A.
        • Mahadevan V.
        • Semenov Y.
        • Kwatra S.G.
        Health-related QOL and economic burden of chronic pruritus.
        J Invest Dermatol. 2021; 141: 754-760.e1
        • Wilson S.R.
        • Thé L.
        • Batia L.M.
        • Beattie K.
        • Katibah G.E.
        • McClain S.P.
        • et al.
        The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.
        Cell. 2013; 155: 285-295
        • Wollenberg A.
        • Howell M.D.
        • Guttman-Yassky E.
        • Silverberg J.I.
        • Kell C.
        • Ranade K.
        • et al.
        Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb.
        J Allergy Clin Immunol. 2019; 143: 135-141
        • Wong L.S.
        • Wu T.
        • Lee C.H.
        Inflammatory and noninflammatory itch: implications in pathophysiology-directed treatments.
        Int J Mol Sci. 2017; 18: 1485
        • Yang G.
        • Seok J.K.
        • Kang H.C.
        • Cho Y.Y.
        • Lee H.S.
        • Lee J.Y.
        Skin barrier abnormalities and immune dysfunction in atopic dermatitis.
        Int J Mol Sci. 2020; 21: 2867
        • Yang X.
        • Kambe N.
        • Takimoto-Ito R.
        • Kabashima K.
        Advances in the pathophysiology of atopic dermatitis revealed by novel therapeutics and clinical trials.
        Pharmacol Ther. 2021; 224: 107830