Generic placeholder image

Current Pharmaceutical Biotechnology


ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Mini-Review Article

Novel Therapeutic Approaches and Targets for the Treatment of Atopic Dermatitis

Author(s): Leonardo Pescitelli, Elia Rosi, Federica Ricceri , Nicola Pimpinelli and Francesca Prignano *

Volume 22, Issue 1, 2021

Published on: 11 June, 2020

Page: [73 - 84] Pages: 12

DOI: 10.2174/1389201021666200611112755

Price: $65


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.

Keywords: Atopic dermatitis, new treatment, dupilumab, lebrikizumab, tralokinumab, nemolizumab, tezepelumab, fezakinumab, small molecules.

Graphical Abstract
Fölster-Holst, R. Management of atopic dermatitis: Are there differences between children and adults? J. Eur. Acad. Dermatol. Venereol., 2014, 28(Suppl. 3), 5-8.
[] [PMID: 24702444]
Mortz, C.G.; Andersen, K.E.; Dellgren, C.; Barington, T.; Bindslev-Jensen, C. Atopic dermatitis from adolescence to adulthood in the TOACS cohort: Prevalence, persistence and comorbidities. Allergy, 2015, 70(7), 836-845.
[] [PMID: 25832131]
Barbarot, S.; Auziere, S.; Gadkari, A.; Girolomoni, G.; Puig, L.; Simpson, E.L.; Margolis, D.J.; de Bruin-Weller, M.; Eckert, L. Epidemiology of atopic dermatitis in adults: Results from an international survey. Allergy, 2018, 73(6), 1284-1293.
[] [PMID: 29319189]
Wollenberg, A.; Barbarot, S.; Bieber, T.; Christen-Zaech, S.; Deleuran, M.; Fink-Wagner, A.; Gieler, U.; Girolomoni, G.; Lau, S.; Muraro, A.; Czarnecka-Operacz, M.; Schäfer, T.; Schmid-Grendelmeier, P.; Simon, D.; Szalai, Z.; Szepietowski, J.C.; Taïeb, A.; Torrelo, A.; Werfel, T.; Ring, J. European Dermatology Forum (EDF), the European Academy of Dermatology and Venereology (EADV), the European Academy of Allergy and Clinical Immunology (EAACI), the European Task Force on Atopic Dermatitis (ETFAD), European Federation of Allergy and Airways Diseases Patients’ Associations (EFA), the European Society for Dermatology and Psychiatry (ESDaP), the European Society of Pediatric Dermatology (ESPD), Global Allergy and Asthma European Network (GA2LEN) and the European Union of Medical Specialists (UEMS). Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: Part I. J. Eur. Acad. Dermatol. Venereol., 2018, 32(5), 657-682.
[] [PMID: 29676534]
Kay, J.; Gawkrodger, D.J.; Mortimer, M.J.; Jaron, A.G. The prevalence of childhood atopic eczema in a general population. J. Am. Acad. Dermatol., 1994, 30(1), 35-39.
[] [PMID: 8277028]
Alexander, H.; Patton, T.; Jabbar-Lopez, Z.K.; Manca, A.; Flohr, C. Novel systemic therapies in atopic dermatitis: What do we need to fulfil the promise of a treatment revolution? F1000Research [Internet].2019 Jan 31 [cited 2019 Oct 6]; 8. Available from: 2019.
Guttman-Yassky, E.; Lowes, M.A.; Fuentes-Duculan, J.; Zaba, L.C.; Cardinale, I.; Nograles, K.E.; Khatcherian, A.; Novitskaya, I.; Carucci, J.A.; Bergman, R.; Krueger, J.G. G Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis. J. Immunol.Baltim. Md., 1950, 2008, 15181(10), 7420-7427.
Eyerich, K.; Eyerich, S. Immune response patterns in non-communicable inflammatory skin diseases. J. Eur. Acad. Dermatol. Venereol., 2018, 32(5), 692-703.
[] [PMID: 29114938]
Brunner, P.M.; Guttman-Yassky, E.; Leung, D.Y.M. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J. Allergy Clin. Immunol., 2017, 139(4S), S65-S76.
[] [PMID: 28390479]
Moyle, M.; Cevikbas, F.; Harden, J.L.; Guttman-Yassky, E. Understanding the immune landscape in atopic dermatitis: The era of biologics and emerging therapeutic approaches. Exp. Dermatol., 2019, 28(7), 756-768.
[] [PMID: 30825336]
Suárez-Fariñas, M.; Tintle, S.J.; Shemer, A.; Chiricozzi, A.; Nograles, K.; Cardinale, I.; Duan, S.; Bowcock, A.M.; Krueger, J.G.; Guttman-Yassky, E. Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin. Immunol. 2011, 127(4), 954-964.e1-4.
Gittler, J.K.; Shemer, A.; Suárez-Fariñas, M.; Fuentes-Duculan, J.; Gulewicz, K.J.; Wang, C.Q.F.; Mitsui, H.; Cardinale, I.; de Guzman Strong, C.; Krueger, J.G.; Guttman-Yassky, E. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J. Allergy Clin. Immunol., 2012, 130(6), 1344-1354.
[] [PMID: 22951056]
Tazawa, T.; Sugiura, H.; Sugiura, Y.; Uehara, M. Relative importance of IL-4 and IL-13 in lesional skin of atopic dermatitis. Arch. Dermatol. Res., 2004, 295(11), 459-464.
[] [PMID: 15014952]
Hamid, Q.; Boguniewicz, M.; Leung, D.Y. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J. Clin. Invest., 1994, 94(2), 870-876.
[] [PMID: 8040343]
Chan, L.S.; Robinson, N.; Xu, L. Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: An experimental animal model to study atopic dermatitis. J. Invest. Dermatol., 2001, 117(4), 977-983.
[] [PMID: 11676841]
Hamid, Q.; Naseer, T.; Minshall, E.M.; Song, Y.L.; Boguniewicz, M.; Leung, D.Y. In vivo expression of IL-12 and IL-13 in atopic dermatitis. J. Allergy Clin. Immunol., 1996, 98(1), 225-231.
[] [PMID: 8765838]
Howell, M.D.; Kim, B.E.; Gao, P.; Grant, A.V.; Boguniewicz, M.; Debenedetto, A.; Schneider, L.; Beck, L.A.; Barnes, K.C.; Leung, D.Y. Cytokine modulation of atopic dermatitis filaggrin skin expression. J. Allergy Clin. Immunol., 2007, 120(1), 150-155.
[] [PMID: 17512043]
Kim, B.E.; Leung, D.Y.M.; Boguniewicz, M.; Howell, M.D. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin. Immunol., 2008, 126(3), 332-337.
[] [PMID: 18166499]
Sehra, S.; Yao, Y.; Howell, M.D.; Nguyen, E.T.; Kansas, G.S.; Leung, D.Y.M.; Travers, J.B.; Kaplan, M.H. IL-4 regulates skin homeostasis and the predisposition toward allergic skin inflammation. J. Immunol. Baltim. Md., 1950, 2010, 184(6), 3186-3190.
Kisich, K.O.; Carspecken, C.W.; Fiéve, S.; Boguniewicz, M.; Leung, D.Y.M. Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human beta-defensin-3. J. Allergy Clin. Immunol., 2008, 122(1), 62-68.
[] [PMID: 18538383]
Nograles, K.E.; Zaba, L.C.; Guttman-Yassky, E.; Fuentes-Duculan, J.; Suárez-Fariñas, M.; Cardinale, I.; Khatcherian, A.; Gonzalez, J.; Pierson, K.C.; White, T.R.; Pensabene, C.; Coats, I.; Novitskaya, I.; Lowes, M.A.; Krueger, J.G. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br. J. Dermatol., 2008, 159(5), 1092-1102.
[] [PMID: 18684158]
Boniface, K.; Bernard, F.-X.; Garcia, M.; Gurney, A.L.; Lecron, J.-C.; Morel, F. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J. Immunol. Baltim. Md. 1950, 2005, 174(6), 3695-3702.
Silverberg, J.I.; Kantor, R. The role of interleukins 4 and/or 13 in the pathophysiology and treatment of atopic dermatitis. Dermatol. Clin., 2017, 35(3), 327-334.
[] [PMID: 28577802]
Akdis, C.A.; Akdis, M. Immunological differences between intrinsic and extrinsic types of atopic dermatitis. Clin. Exp. Allergy, 2003, 33(12), 1618-1621.
[] [PMID: 14656345]
Suárez-Fariñas, M.; Dhingra, N.; Gittler, J.; Shemer, A.; Cardinale, I.; de Guzman Strong, C.; Krueger, J.G.; Guttman-Yassky, E. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J. Allergy Clin. Immunol., 2013, 132(2), 361-370.
[] [PMID: 23777851]
Noda, S.; Suárez-Fariñas, M.; Ungar, B.; Kim, S.J.; de Guzman Strong, C.; Xu, H.; Peng, X.; Estrada, Y.D.; Nakajima, S.; Honda, T.; Shin, J.U.; Lee, H.; Krueger, J.G.; Lee, K.H.; Kabashima, K.; Guttman-Yassky, E. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J. Allergy Clin. Immunol., 2015, 136(5), 1254-1264.
[] [PMID: 26428954]
Margolis, D.J.; Apter, A.J.; Gupta, J.; Hoffstad, O.; Papadopoulos, M.; Campbell, L.E.; Sandilands, A.; McLean, W.H.; Rebbeck, T.R.; Mitra, N. The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort. J. Allergy Clin. Immunol., 2012, 130(4), 912-917.
[] [PMID: 22951058]
Czarnowicki, T.; Krueger, J.G.; Guttman-Yassky, E. Skin barrier and immune dysregulation in atopic dermatitis: an evolving story with important clinical implications. J. Allergy Clin. Immunol. Pract., 2014, 2(4), 371-379.
[] [PMID: 25017523]
Kezic, S.; O’Regan, G.M.; Lutter, R.; Jakasa, I.; Koster, E.S.; Saunders, S.; Caspers, P.; Kemperman, P.M.; Puppels, G.J.; Sandilands, A.; Chen, H.; Campbell, L.E.; Kroboth, K.; Watson, R.; Fallon, P.G.; McLean, W.H.; Irvine, A.D. Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency. J. Allergy Clin. Immunol., 2012, 129(4), 1031-9.e1.
[] [PMID: 22322004]
Irvine, A.D.; McLean, W.H.I.; Leung, D.Y.M. Filaggrin mutations associated with skin and allergic diseases. N. Engl. J. Med., 2011, 365(14), 1315-1327.
[] [PMID: 21991953]
Esaki, H.; Brunner, P.M.; Renert-Yuval, Y.; Czarnowicki, T.; Huynh, T.; Tran, G.; Lyon, S.; Rodriguez, G.; Immaneni, S.; Johnson, D.B.; Bauer, B.; Fuentes-Duculan, J.; Zheng, X.; Peng, X.; Estrada, Y.D.; Xu, H.; de Guzman Strong, C.; Suárez-Fariñas, M.; Krueger, J.G.; Paller, A.S.; Guttman-Yassky, E. Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin. J. Allergy Clin. Immunol., 2016, 138(6), 1639-1651.
[] [PMID: 27671162]
Silverberg, J.I. Association between adult atopic dermatitis, cardiovascular disease, and increased heart attacks in three population-based studies. Allergy, 2015, 70(10), 1300-1308.
[] [PMID: 26148129]
Brunner, P.M.; Silverberg, J.I.; Guttman-Yassky, E.; Paller, A.S.; Kabashima, K.; Amagai, M.; Luger, T.A.; Deleuran, M.; Werfel, T.; Eyerich, K.; Stingl, G. Councilors of the International Eczema Council. Increasing comorbidities suggest that atopic dermatitis is a systemic disorder. J. Invest. Dermatol., 2017, 137(1), 18-25.
[] [PMID: 27771048]
Simpson, E.L.; Bieber, T.; Guttman-Yassky, E.; Beck, L.A.; Blauvelt, A.; Cork, M.J.; Silverberg, J.I.; Deleuran, M.; Kataoka, Y.; Lacour, J.P.; Kingo, K.; Worm, M.; Poulin, Y.; Wollenberg, A.; Soo, Y.; Graham, N.M.; Pirozzi, G.; Akinlade, B.; Staudinger, H.; Mastey, V.; Eckert, L.; Gadkari, A.; Stahl, N.; Yancopoulos, G.D.; Ardeleanu, M. SOLO 1 and SOLO 2 Investigators. Two phase 3 trials of Dupilumab versus Placebo in atopic dermatitis. N. Engl. J. Med., 2016, 375(24), 2335-2348.
[] [PMID: 27690741]
Fishbein, A.B.; Silverberg, J.I.; Wilson, E.J.; Ong, P.Y. Update on atopic dermatitis: Diagnosis, severity assessment, and treatment selection. J. Allergy Clin. Immunol. Pract., 2020, 8(1), 91-101.
[PMID: 31474543]
Blauvelt, A.; de Bruin-Weller, M.; Gooderham, M.; Cather, J.C.; Weisman, J.; Pariser, D. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (Liberty Ad Chronos): A 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet Lond. Engl., 2017, 10389(10086), 2287-2303.
Simpson, E.; Paller, A.S.; Siegfried, E.; Boguniewicz, M.; Pariser, D.; Blauvelt, A.; Hultsch, T.; Staudinger, H.; Zhang, R.; Kamal, M.A. Dupilumab Efficacy and Safety in Adolescents with Moderate- to-Severe Atopic Dermatitis: Results from a Multicenter, Randomized,Placebo-Controlled, Double-Blind, Parallel-Group,Phase 3 Study. In Proceedings of the European Academy of Dermatology and Venereology, Paris, France, September 2018.pp. 12-16 .
Cline, A.; Bartos, G.J.; Strowd, L.C.; Feldman, S.R. Biologic treatment options for pediatric psoriasis and atopic dermatitis. Child Basel Switz., 2019, 6(9), 103.
Deleuran, M.; Thaçi, D.; Beck, L.A.; de Bruin-Weller, M.; Blauvelt, A.; Forman, S.; Bissonnette, R.; Reich, K.; Soong, W.; Hussain, I.; Foley, P.; Hide, M.; Bouaziz, J.D.; Gelfand, J.M.; Sher, L.; Schuttelaar, M.L.A.; Wang, C.; Chen, Z.; Akinlade, B.; Gadkari, A.; Eckert, L.; Davis, J.D.; Rajadhyaksha, M.; Staudinger, H.; Graham, N.M.H.; Pirozzi, G.; Ardeleanu, M. Dupilumab shows long-term safety and efficacy in moderate-to-severe atopic dermatitis patients enrolled in a phase 3 open-label extension study. J. Am. Acad. Dermatol., 2020, 82(2), 377-388.
[PMID: 31374300]
Renert-Yuval, Y.; Guttman-Yassky, E. Monoclonal antibodies for the treatment of atopic dermatitis. Curr. Opin. Allergy Clin. Immunol., 2018, 18(4), 356-364.
[] [PMID: 29870461]
Castro, M.; Corren, J.; Pavord, I.D.; Maspero, J.; Wenzel, S.; Rabe, K.F.; Busse, W.W.; Ford, L.; Sher, L.; FitzGerald, J.M.; Katelaris, C.; Tohda, Y.; Zhang, B.; Staudinger, H.; Pirozzi, G.; Amin, N.; Ruddy, M.; Akinlade, B.; Khan, A.; Chao, J.; Martincova, R.; Graham, N.M.H.; Hamilton, J.D.; Swanson, B.N.; Stahl, N.; Yancopoulos, G.D.; Teper, A. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N. Engl. J. Med., 2018, 378(26), 2486-2496.
[] [PMID: 29782217]
Bachert, C.; Mannent, L.; Naclerio, R.M.; Mullol, J.; Ferguson, B.J.; Gevaert, P.; Hellings, P.; Jiao, L.; Wang, L.; Evans, R.R.; Pirozzi, G.; Graham, N.M.; Swanson, B.; Hamilton, J.D.; Radin, A.; Gandhi, N.A.; Stahl, N.; Yancopoulos, G.D.; Sutherland, E.R. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: A randomized clinical trial. JAMA, 2016, 315(5), 469-479.
[] [PMID: 26836729]
Werfel, T.; Allam, J-P.; Biedermann, T.; Eyerich, K.; Gilles, S.; Guttman-Yassky, E.; Hoetzenecker, W.; Knol, E.; Simon, H.U.; Wollenberg, A.; Bieber, T.; Lauener, R.; Schmid-Grendelmeier, P.; Traidl-Hoffmann, C.; Akdis, C.A. Cellular and molecular immunologic mechanisms in patients with atopic dermatitis. J. Allergy Clin. Immunol., 2016, 138(2), 336-349.
[] [PMID: 27497276]
Choy, D.F.; Hsu, D.K.; Seshasayee, D.; Fung, M.A.; Modrusan, Z.; Martin, F.; Liu, F.T.; Arron, J.R. Comparative transcriptomic analyses of atopic dermatitis and psoriasis reveal shared neutrophilic inflammation. J. Allergy Clin. Immunol., 2012, 130(6), 1335-43.e5.
[] [PMID: 22920495]
Ultsch, M.; Bevers, J.; Nakamura, G.; Vandlen, R.; Kelley, R.F.; Wu, L.C.; Eigenbrot, C. Structural basis of signaling blockade by anti-IL-13 antibody Lebrikizumab. J. Mol. Biol., 2013, 425(8), 1330-1339.
[] [PMID: 23357170]
Hanania, N.A.; Noonan, M.; Corren, J.; Korenblat, P.; Zheng, Y.; Fischer, S.K.; Cheu, M.; Putnam, W.S.; Murray, E.; Scheerens, H.; Holweg, C.T.; Maciuca, R.; Gray, S.; Doyle, R.; McClintock, D.; Olsson, J.; Matthews, J.G.; Yen, K. Lebrikizumab in moderate-to-severe asthma: Pooled data from two randomised placebo-controlled studies. Thorax, 2015, 70(8), 748-756.
[] [PMID: 26001563]
Hanania, N.A.; Korenblat, P.; Chapman, K.R.; Bateman, E.D.; Kopecky, P.; Paggiaro, P.; Yokoyama, A.; Olsson, J.; Gray, S.; Holweg, C.T.; Eisner, M.; Asare, C.; Fischer, S.K.; Peng, K.; Putnam, W.S.; Matthews, J.G. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir. Med., 2016, 4(10), 781-796.
[] [PMID: 27616196]
Simpson, E.L.; Flohr, C.; Eichenfield, L.F.; Bieber, T.; Sofen, H.; Taïeb, A.; Owen, R.; Putnam, W.; Castro, M.; DeBusk, K.; Lin, C.Y.; Voulgari, A.; Yen, K.; Omachi, T.A. Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: A randomized, placebo-controlled phase II trial (TREBLE). J. Am. Acad. Dermatol., 2018, 78(5), 863-871.e11.
[] [PMID: 29353026]
May, R.D.; Monk, P.D.; Cohen, E.S.; Manuel, D.; Dempsey, F.; Davis, N.H.E.; Dodd, A.J.; Corkill, D.J.; Woods, J.; Joberty-Candotti, C.; Conroy, L.A.; Koentgen, F.; Martin, E.C.; Wilson, R.; Brennan, N.; Powell, J.; Anderson, I.K. Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma. Br. J. Pharmacol., 2012, 166(1), 177-193.
[] [PMID: 21895629]
Chandriani, S.; DePianto, D.J.; N’Diaye, E.N.; Abbas, A.R.; Jackman, J.; Bevers, J.; Ramirez-Carrozzi, V.; Pappu, R.; Kauder, S.E.; Toy, K.; Ha, C; Modrusan, Z.; Wu, L.C.; Collard, H.R.; Wolters, P.J.; Egen, J.G.; Arron, J.R. Endogenously expressed IL-13Rα2 attenuates IL-13-mediated responses but does not activate signaling in human lung fibroblasts. J. Immunol. Baltim. Md. 1950, 2014, 193(1), 111-119.
Braddock, M.; Hanania, N.A.; Sharafkhaneh, A.; Colice, G.; Carlsson, M. Potential risks related to modulating interleukin-13 and interleukin-4 signalling: A systematic review. Drug Saf., 2018, 41(5), 489-509.
[] [PMID: 29411337]
Wollenberg, A.; Howell, M.D.; Guttman-Yassky, E.; Silverberg, J.I.; Kell, C.; Ranade, K.; Moate, R.; van der Merwe, R. Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb. J. Allergy Clin. Immunol., 2019, 143(1), 135-141.
[] [PMID: 29906525]
Panettieri, R.A., Jr; Sjöbring, U.; Péterffy, A.; Wessman, P.; Bowen, K.; Piper, E.; Colice, G.; Brightling, C.E. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respir. Med., 2018, 6(7), 511-525.
[] [PMID: 29792288]
Nakashima, C.; Otsuka, A.; Kabashima, K. Interleukin-31 and interleukin-31 receptor: New therapeutic targets for atopic dermatitis. Exp. Dermatol., 2018, 27(4), 327-331.
[] [PMID: 29524262]
Dillon, S.R.; Sprecher, C.; Hammond, A.; Bilsborough, J.; Rosenfeld-Franklin, M.; Presnell, S.R.; Haugen, H.S.; Maurer, M.; Harder, B.; Johnston, J.; Bort, S.; Mudri, S.; Kuijper, J.L.; Bukowski, T.; Shea, P.; Dong, D.L.; Dasovich, M.; Grant, F.J.; Lockwood, L.; Levin, S.D.; LeCiel, C.; Waggie, K.; Day, H.; Topouzis, S.; Kramer, J.; Kuestner, R.; Chen, Z.; Foster, D.; Parrish-Novak, J.; Gross, J.A. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat. Immunol., 2004, 5(7), 752-760.
[] [PMID: 15184896]
Baron, J.M.; Lüscher, B. IL-31 expression by inflammatory cells is preferentially elevated in atopic dermatitis. Acta Derm. Venereol., 2012, 92(1), 5-6.
[] [PMID: 22215012]
Nemoto, O.; Furue, M.; Nakagawa, H.; Shiramoto, M.; Hanada, R.; Matsuki, S.; Imayama, S.; Kato, M.; Hasebe, I.; Taira, K.; Yamamoto, M.; Mihara, R.; Kabashima, K.; Ruzicka, T.; Hanifin, J.; Kumagai, Y. 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(2), 296-304.
[] [PMID: 26409172]
Ruzicka, T.; Hanifin, J.M.; Furue, M.; Pulka, G.; Mlynarczyk, I.; Wollenberg, A.; Galus, R.; Etoh, T.; Mihara, R.; Yoshida, H.; Stewart, J.; Kabashima, K. XCIMA study group. Anti-interleukin-31 receptor A antibody for atopic dermatitis. N. Engl. J. Med., 2017, 376(9), 826-835.
[] [PMID: 28249150]
Kabashima, K.; Furue, M.; Hanifin, J.M.; Pulka, G.; Wollenberg, A.; Galus, R.; Etoh, T.; Mihara, R.; Nakano, M.; Ruzicka, T. Nemolizumab in patients with moderate-to-severe atopic dermatitis: Randomized, phase II, long-term extension study. J. Allergy Clin. Immunol., 2018, 142(4), 1121-1130.e7.
[] [PMID: 29753033]
Suárez-Fariñas, M.; Ungar, B.; Correa da Rosa, J.; Ewald, D.A.; Rozenblit, M.; Gonzalez, J.; Xu, H.; Zheng, X.; Peng, X.; Estrada, Y.D.; Dillon, S.R.; Krueger, J.G.; Guttman-Yassky, E. RNA sequencing atopic dermatitis transcriptome profiling provides insights into novel disease mechanisms with potential therapeutic implications. J. Allergy Clin. Immunol., 2015, 135(5), 1218-1227.
[] [PMID: 25840722]
Cavaliere, C.; Frati, F.; Ridolo, E.; Greco, A.; de Vincentiis, M.; Masieri, S.; Makri, E.; Incorvaia, C. The spectrum of therapeutic activity of mepolizumab. Expert Rev. Clin. Immunol., 2019, 15(9), 959-967.
[] [PMID: 31424304]
Oldhoff, J.M.; Darsow, U.; Werfel, T.; Katzer, K.; Wulf, A.; Laifaoui, J.; Hijnen, D.J.; Plötz, S.; Knol, E.F.; Kapp, A.; Bruijnzeel-Koomen, C.A.; Ring, J.; de Bruin-Weller, M.S. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy, 2005, 60(5), 693-696.
[] [PMID: 15813818 Kang, E.G.; Narayana, P.K.; Pouliquen, I.J.; Lopez, M.C.; Ferreira-Cornwell, M.C.; Getsy, J.A. Efficacy and safety of mepolizumab administered subcutaneously for moderate to severe atopic dermatitis. Allergy, 2020, 75(4), 950-953.] [PMID: 31515809]
Liu, Y.J. Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation. J. Allergy Clin. Immunol., 2007, 120(2), 238-244.
[] [PMID: 17666213]
Tidwell, W.J.; Fowler, J.F. Jr. T-cell inhibitors for atopic dermatitis. J. Am. Acad. Dermatol., 2018, 78(3)(Suppl. 1), S67-S70.
[] [PMID: 29248519]
Simpson, E.L.; Parnes, J.R.; She, D.; Crouch, S.; Rees, W.; Mo, M.; van der Merwe, R. Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase IIa clinical trial. J. Am. Acad. Dermatol., 2019, 80(4), 1013-1021.
[] [PMID: 30550828]
Guttman-Yassky, E.; Pavel, A.B.; Zhou, L.; Estrada, Y.D.; Zhang, N.; Xu, H.; Peng, X.; Wen, H.C.; Govas, P.; Gudi, G.; Ca, V.; Fang, H.; Salhi, Y.; Back, J.; Reddy, V.; Bissonnette, R.; Maari, C.; Grossman, F.; Wolff, G. GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis. J. Allergy Clin. Immunol., 2019, 144(2), 482-493.e7.
[] [PMID: 30738171]
Koga, C.; Kabashima, K.; Shiraishi, N.; Kobayashi, M.; Tokura, Y. Possible pathogenic role of Th17 cells for atopic dermatitis. J. Invest. Dermatol., 2008, 128(11), 2625-2630.
[] [PMID: 18432274]
Molinelli, E.; Campanati, A.; Brisigotti, V.; Offidani, A. Biologic therapy in psoriasis (Part II): Efficacy and safety of new treatment targeting IL23/IL-17 pathways. Curr. Pharm. Biotechnol., 2017, 18(12), 964-978.
[] [PMID: 29299984]
Vakharia, P.P.; Silverberg, J.I. New therapies for atopic dermatitis: Additional treatment classes. J. Am. Acad. Dermatol., 2018, 78(3)(Suppl. 1), S76-S83.
[] [PMID: 29248520]
Vandeghinste, N.; Klattig, J.; Jagerschmidt, C.; Lavazais, S.; Marsais, F.; Haas, J.D.; Auberval, M.; Lauffer, F.; Moran, T.; Ongenaert, M.; Van Balen, M.; Dupont, S.; Lepescheux, L.; Garcia, T.; Härtle, S.; Eyerich, K.; Fallon, P.G.; Brys, R.; Steidl, S. Neutralization of IL-17C reduces skin inflammation in mouse models of psoriasis and atopic dermatitis. J. Invest. Dermatol., 2018, 138(7), 1555-1563.
[] [PMID: 29474945]
Brunner, P.M.; Pavel, A.B.; Khattri, S.; Leonard, A.; Malik, K.; Rose, S.; Jim On, S.; Vekaria, A.S.; Traidl-Hoffmann, C.; Singer, G.K.; Baum, D.; Gilleaudeau, P.; Sullivan-Whalen, M.; Fuentes-Duculan, J.; Li, X.; Zheng, X.; Estrada, Y.; Garcet, S.; Wen, H.C.; Gonzalez, J.; Coats, I.; Cueto, I.; Neumann, A.U.; Lebwohl, M.G.; Krueger, J.G.; Guttman-Yassky, E. Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab. J. Allergy Clin. Immunol., 2019, 143(1), 142-154.
[] [PMID: 30121291]
Ungar, B.; Garcet, S.; Gonzalez, J.; Dhingra, N.; Correa da Rosa, J.; Shemer, A.; Krueger, J.G.; Suarez-Farinas, M.; Guttman-Yassky, E. An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease. J. Invest. Dermatol., 2017, 137(3), 603-613.
[] [PMID: 27825969]
Jones, B.C.; Logsdon, N.J.; Walter, M.R. Structure of IL-22 bound to its high-affinity IL-22R1 chain. Structure, 2008, 16(9), 1333-1344.
[] [PMID: 18599299]
Peng, W.; Novak, N. Recent developments in atopic dermatitis. Curr. Opin. Allergy Clin. Immunol., 2014, 14(5), 417-422.
[] [PMID: 25090248]
Guttman-Yassky, E.; Brunner, P.M.; Neumann, A.U.; Khattri, S.; Pavel, A.B.; Malik, K.; Singer, G.K.; Baum, D.; Gilleaudeau, P.; Sullivan-Whalen, M.; Rose, S.; Jim On, S.; Li, X.; Fuentes-Duculan, J.; Estrada, Y.; Garcet, S.; Traidl-Hoffmann, C.; Krueger, J.G.; Lebwohl, M.G. Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: A randomized, double-blind, phase 2a trial. J. Am. Acad. Dermatol., 2018, 78(5), 872-881.e6.
[] [PMID: 29353025]
Thibodaux, R.J.; Triche, M.W.; Espinoza, L.R. Ustekinumab for the treatment of psoriasis and psoriatic arthritis: A drug evaluation and literature review. Expert Opin. Biol. Ther., 2018, 18(7), 821-827.
[] [PMID: 29949399]
Pan, Y.; Xu, L.; Qiao, J.; Fang, H. A systematic review of ustekinumab in the treatment of atopic dermatitis. J. Dermatolog. Treat., 2018, 29(6), 539-541.
[] [PMID: 29164954]
Khattri, S.; Brunner, P.M.; Garcet, S.; Finney, R.; Cohen, S.R.; Oliva, M.; Dutt, R.; Fuentes-Duculan, J.; Zheng, X.; Li, X.; Bonifacio, K.M.; Kunjravia, N.; Coats, I.; Cueto, I.; Gilleaudeau, P.; Sullivan-Whalen, M.; Suárez-Fariñas, M.; Krueger, J.G.; Guttman-Yassky, E. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. Exp. Dermatol., 2017, 26(1), 28-35.
[] [PMID: 27304428]
Saeki, H.; Kabashima, K.; Tokura, Y.; Murata, Y.; Shiraishi, A.; Tamamura, R.; Randazzo, B.; Imanaka, K. Efficacy and safety of ustekinumab in Japanese patients with severe atopic dermatitis: A randomized, double-blind, placebo-controlled, phase II study. Br. J. Dermatol., 2017, 177(2), 419-427.
[] [PMID: 28338223]
Howell, M.D.; Fitzsimons, C.; Smith, P.A. JAK/STAT inhibitors and other small molecule cytokine antagonists for the treatment of allergic disease. Ann. Allergy Asthma Immunol., 2018, 120(4), 367-375.
[] [PMID: 29454096]
Paller, A.S.; Tom, W.L.; Lebwohl, M.G.; Blumenthal, R.L.; Boguniewicz, M.; Call, R.S.; Eichenfield, L.F.; Forsha, D.W.; Rees, W.C.; Simpson, E.L.; Spellman, M.C.; Stein Gold, L.F.; Zaenglein, A.L.; Hughes, M.H.; Zane, L.T.; Hebert, A.A. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal Phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J. Am. Acad. Dermatol., 2016, 75(3), 494-503.e6.
[] [PMID: 27417017]
Nemoto, O.; Hayashi, N.; Kitahara, Y.; Furue, M.; Hojo, S.; Nomoto, M.; Shima, S. Japanese E6005 Study Investigators. Effect of topical phosphodiesterase 4 inhibitor E6005 on Japanese children with atopic dermatitis: Results from a randomized, vehicle-controlled exploratory trial. J. Dermatol., 2016, 43(8), 881-887.
[] [PMID: 26703371]
Ohba, F.; Matsuki, S.; Imayama, S.; Matsuguma, K.; Hojo, S.; Nomoto, M.; Akama, H. Efficacy of a novel phosphodiesterase inhibitor, E6005, in patients with atopic dermatitis: An investigator-blinded, vehicle-controlled study. J. Dermatolog. Treat., 2016, 27(5), 467-472.
[] [PMID: 27080209]
Furue, M.; Kitahara, Y.; Akama, H.; Hojo, S.; Hayashi, N.; Nakagawa, H. JAPANESE E6005 Study Investigators. Safety and efficacy of topical E6005, a phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis: Results of a randomized, vehicle-controlled, multicenter clinical trial. J. Dermatol., 2014, 41(7), 577-585.
[] [PMID: 24942594]
Seif, F.; Khoshmirsafa, M.; Aazami, H.; Mohsenzadegan, M.; Sedighi, G.; Bahar, M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun. Signal., 2017, 15(1), 23.
[] [PMID: 28637459]
Banerjee, S.; Biehl, A.; Gadina, M.; Hasni, S.; Schwartz, D.M. JAKSTAT signalling as a target for inflammatory and autoimmune diseases: Current and future prospects. Drugs, 2017, 77(5), 521-546.
[] [PMID: 28255960]
Villarino, A.V.; Kanno, Y.; O’Shea, J.J. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol., 2017, 18(4), 374-384.
[] [PMID: 28323260]
Samadi, A.; Ahmad Nasrollahi, S.; Hashemi, A.; Nassiri Kashani, M.; Firooz, A. Janus Kinase (JAK) inhibitors for the treatment of skin and hair disorders: A review of literature. J. Dermatolog. Treat., 2017, 28(6), 476-483.
[] [PMID: 28024126]
Vu, M.; Heyes, C.; Robertson, S.J.; Varigos, G.A.; Ross, G. Oral tofacitinib: A promising treatment in atopic dermatitis, alopecia areata and vitiligo. Clin. Exp. Dermatol., 2017, 42(8), 942-944.
[] [PMID: 29034491]
Wollenhaupt, J.; Silverfield, J.; Lee, E.B.; Curtis, J.R.; Wood, S.P.; Soma, K.; Nduaka, C.I.; Benda, B.; Gruben, D.; Nakamura, H.; Komuro, Y.; Zwillich, S.H.; Wang, L.; Riese, R.J. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J. Rheumatol., 2014, 41(5), 837-852.
[] [PMID: 24692527]
Bissonnette, R.; Papp, K.A.; Poulin, Y.; Gooderham, M.; Raman, M.; Mallbris, L.; Wang, C.; Purohit, V.; Mamolo, C.; Papacharalambous, J.; Ports, W.C. Topical tofacitinib for atopic dermatitis: A phase IIa randomized trial. Br. J. Dermatol., 2016, 175(5), 902-911.
[] [PMID: 27423107]
Guttman-Yassky, E.; Silverberg, J.I.; Nemoto, O.; Forman, S.B.; Wilke, A.; Prescilla, R.; de la Peña, A.; Nunes, F.P.; Janes, J.; Gamalo, M.; Donley, D.; Paik, J.; DeLozier, A.M.; Nickoloff, B.J.; Simpson, E.L. Baricitinib in adult patients with moderate-to-severe atopic dermatitis: A phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. J. Am. Acad. Dermatol., 2019, 80(4), 913-921.e9.
[] [PMID: 29410014]
Guttman-Yassky, E.; Silverberg, J.I.; Nemoto, O.; Forman, S.B.; Wilke, A.; Prescilla, R. Efficacy and safety of upadacitinib treatment over 32 weeks for patients with atopic dermatitis from a phase 2b, randomized, placebo-controlled trial. In: 27th European Academy of Dermatology and Venerology (EADV) Congress, France, Paris, September 12, 2018.
Kim, B.S.; Nasir, A.; Papp, K.; Parish, L.C.; Kuligowski, M.; Venturanza, M. A phase II randomized, dose-ranging, vehicle- and active-controlled study to evaluate the safety and efficacy of topical ruxolitinib in adult patients with atopic dermatitis. In: 27th European Academy of Dermatology and Venerology; France Paris, September 12, 2018.
Tanimoto, A.; Ogawa, Y.; Oki, C.; Kimoto, Y.; Nozawa, K.; Amano, W.; Noji, S.; Shiozaki, M.; Matsuo, A.; Shinozaki, Y.; Matsushita, M. Pharmacological properties of JTE-052: A novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm. Res., 2015, 64(1), 41-51.
[] [PMID: 25387665]
Nakagawa, H.; Nemoto, O.; Yamada, H.; Nagata, T.; Ninomiya, N. Phase 1 studies to assess the safety, tolerability and pharmacokinetics of JTE-052 (a novel Janus kinase inhibitor) ointment in Japanese healthy volunteers and patients with atopic dermatitis. J. Dermatol., 2018, 45(6), 701-709.
[] [PMID: 29665062]
Nakagawa, H.; Nemoto, O.; Igarashi, A.; Nagata, T. Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: A phase II, multicentre, randomized, vehicle-controlled clinical study. Br. J. Dermatol., 2018, 178(2), 424-432.
[] [PMID: 28960254]
Nakagawa, H.; Nemoto, O.; Igarashi, A.; Nagata, T. Phase 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis. J. Allergy Clin. Immunol., 2019.S0091-6749(19)31045-0.
Yanes, D.A.; Mosser-Goldfarb, J.L. Emerging therapies for atopic dermatitis: The prostaglandin/leukotriene pathway. J. Am. Acad. Dermatol., 2018, 78(3)(Suppl. 1), S71-S75.
[] [PMID: 29248523]
[100] [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29, Identifier: NCT02002208, Effect of OC000459 on Moderate to Severe Atopic Dermatitis. 2018 Mar 26 [cited 2018 Apr 12]; Available from:
[101] [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29, Identifier: NCT01785602, Efficacy and Safety Study of QAW039 in the Treatment of Patients With Moderate to Severe Atopic Dermatitis. 2015 Dec 15 [cited 2018 Apr 12]; Available from:
[102] [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29, Identifier: NCT02590289, A Pharmacokinetic Study to Evaluate BBI-5000 Capsules and Food Effect in Healthy Adult Subjects, 2000. Dec 2 [cited 2018 July 15]; Available from:
Ohsawa, Y.; Hirasawa, N. The role of histamine H1 and H4 receptors in atopic dermatitis: from basic research to clinical study. Allergol. Int., 2014, 63(4), 533-542.
[] [PMID: 25249063]
Ko, K.; Kim, H.J.; Ho, P.S.; Lee, S.O.; Lee, J.E.; Min, C.R.; Kim, Y.C.; Yoon, J.H.; Park, E.J.; Kwon, Y.J.; Yun, J.H.; Yoon, D.O.; Kim, J.S.; Park, W.S.; Oh, S.S.; Song, Y.M.; Cho, W.K.; Morikawa, K.; Lee, K.J.; Park, C.H. Discovery of a novel highly selective histamine H4 receptor antagonist for the treatment of atopic dermatitis. J. Med. Chem., 2018, 61(7), 2949-2961.
[] [PMID: 29579390]
Suga, H.; Sato, S. Novel topical and systemic therapies in atopic dermatitis. Immunol. Med., 2019, 42(2), 84-93.
[] [PMID: 31318324]
Werfel, T.; Layton, G.; Yeadon, M.; Whitlock, L.; Osterloh, I.; Jimenez, P.; Liu, W.; Lynch, V.; Asher, A.; Tsianakas, A.; Purkins, L. Efficacy and safety of the histamine H4 receptor antagonist ZPL-3893787 in patients with atopic dermatitis. J. Allergy Clin. Immunol., 2019, 143(5), 1830-1837.e4.
[] [PMID: 30414855]
Murata, Y.; Song, M.; Kikuchi, H.; Hisamichi, K.; Xu, X.L.; Greenspan, A.; Kato, M.; Chiou, C.F.; Kato, T.; Guzzo, C.; Thurmond, R.L.; Ohtsuki, M.; Furue, M. Phase IIa, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of a H4 R-antagonist (JNJ-39758979) in Japanese adults with moderate atopic dermatitis. J. Dermatol., 2015, 42(2), 129-139.
[] [PMID: 25491792]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy