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Review

Atopic dermatitis: a review of evolving targeted therapies

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Pages 275-288 | Received 22 Aug 2018, Accepted 14 Dec 2018, Published online: 14 Jan 2019

References

  • Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387:1109–1122.
  • Bieber T, D’Erme AM, Akdis CA, et al. Clinical phenotypes and endophenotypes of atopic dermatitis: where are we, and where should we go? J Allergy Clin Immunol. 2017;139(4S):S58–S64.
  • Dharmage SC, Lowe AJ, Matheson MC, et al. Atopic dermatitis and the atopic march revisited. Allergy. 2014;69(1):17–27.
  • Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab. 2015;66(Suppl 1):8–16.
  • Mu Z, Zhao Y, Liu X, et al. Molecular biology of atopic dermatitis. Clin Rev Allergy Immunol. 2014;47(2):193–218.
  • Nograles KE, Zaba LC, Shemer A, et al. IL-22-producing “T22ʹ’ T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol. 2009;123(6):1244–1252.
  • D’Erme AM, Romanelli M, Chiricozzi A. Spotlight on dupilumab in the treatment of atopic dermatitis: design, development, and potential place in therapy. Drug Des Devel Ther. 2017;11:1473–1480.
  • Zheng Y, Danilenko DM, Valdez P, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007;445(7128):648–651.
  • Kaminishi K, Soma Y, Kawa Y, et al. Flow cytometric analysis of IL-4, IL-13 and IFN-gamma expression in peripheral blood mononuclear cells and detection of circulating IL-13 in patients with atopic dermatitis provide evidence for the involvement of type 2 cytokines in the disease. J Dermatol Sci. 2002;29(1):19–25.
  • Akkoc T, de Koning PJ, RüCkert B, et al. Increased activation-induced cell death of high IFN-gamma producing T(H)1 cells as a mechanism of T(H)2 predominance in atopic diseases. J Allergy Clin Immunol. 2008;121(3):652–658.e1.
  • Megna M, Napolitano M, Patruno C, et al. Systemic treatment of adult atopic dermatitis: a review. Dermatol Ther (Heidelb). 2017;7(1):1–23.
  • Garritsen FM, Roekevisch E, van der Schaft J, et al. Ten years experience with oral immunosuppressive treatment in adult patients with atopic dermatitis in two academic centres. J Eur Acad Dermatol Venereol. 2015;29(10):1905–1912.
  • Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population-based study. J Allergy Clin Immunol. 2013;132(5):1132–1138.
  • Napolitano M, Megna M, Patruno C, et al. Adult atopic dermatitis: a review. G Ital Dermatol Venereol. 2016;151(4):403–411.
  • Vakharia PP, Silverberg JI. New therapies for atopic dermatitis: additional treatment classes. J Am Acad Dermatol. 2018;78(3S1):S76–S83.
  • Howell MD, Parker ML, Mustelin T, et al. Past, present, and future for biologic intervention in atopic dermatitis. Allergy. 2015;70(8):887–896.
  • DaVeiga SP. Epidemiology of atopic dermatitis: a review. Allergy Asthma Proc. 2012;33(3):227–234.
  • Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol. 2010;105(2):99–106.
  • Bieber T. Atopic dermatitis. N Engl J Med. 2008;358:1483–1494.
  • Suarez-Farinas M, Dhingra N, Gittler J, et al. 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.
  • Martel BC, Litman T, Hald A, et al. Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis. Exp Dermatol. 2016;25(6):453–459.
  • Gooderham M, Lynde CW, Papp K, et al. Review of systemic treatment options for adult atopic dermatitis. J Cutan Med Surg. 2017;21(1):31–39.
  • Harskamp CT, Armstrong AW. Immunology of atopic dermatitis: novel insights into mechanisms and immunomodulatory therapies. Semin Cutan Med Surg. 2013;32(3):132–139.
  • Mansouri Y, Guttman-Yassky E. Immune pathways in atopic dermatitis, and definition of biomarkers through broad and targeted therapeutics. J Clin Med. 2015;4(5):858–873.
  • Lauffer F, Ring J. Target-oriented therapy: emerging drugs for atopic dermatitis. Expert Opin Emerg Drugs. 2016;21(1):81–89.
  • Suárez-Fariñas M, Tintle SJ, Shemer A, et al. Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin Immunol. 2011;127(4):954–64.e1–e4.
  • Hamilton JD, Suárez-Fariñas M, Dhingra N, et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2014;134(6):1293–1300.
  • Beck LA, Thaci D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371(2):130–139.
  • Wollenberg A, Bieber T. Proactive therapy of atopic dermatitis – an emerging concept. Allergy. 2009;64(2):276–278.
  • Thaci D, Simpson EL, Beck LA, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo- controlled, dose-ranging phase 2b trial. Lancet. 2016;387(10013):40–52.
  • Brunner PM, Guttman-Yassky E, Leung DYM. The immunology of atopic dermatitis and its reversibility with broad spectrum and targeted therapies. J Allergy Clin Immunol. 2017;139(4S):S65–S76.
  • Hamilton JD, Ungar B, Guttman-Yassky E. Drug evaluation review: dupilumab in atopic dermatitis. Immunotherapy. 2015;7(10):1043–1058.
  • Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335–2348.
  • Blakely K, Gooderham M, Papp K. Dupilumab, a monoclonal antibody for atopic dermatitis: a review of current literature. Skin Therapy Lett. 2016;21(2):1–5.
  • D’Erme AM. The beginning of biological treatment era in the atopic dermatitis management. Dermatol Ther. 2016;29(3):208–209.
  • Antoniu SA. Pitrakinra, a dual IL-4/IL-13 antagonist for the potential treatment of asthma and eczema. Curr Opin Invest Drugs. 2010;11(11):1286–1294.
  • McGregor S, Farhangian ME, Feldman SR. Dupilumab for the treatment of atopic dermatitis: a clinical trial review. Expert Opin Biol Ther. 2015;15(11):1657–1660.
  • Hambly N, Nair P. Monoclonal antibodies for the treatment of refractory asthma. Curr Opin Pulm Med. 2014;20(1):87–94.
  • Montes-Torres A, Llamas-Velasco M, Pérez-Plaza A, et al. Biological treatments in atopic dermatitis. J Clin Med. 2015;4(4):593–613. a.
  • Clinicaltrials.gov [Internet]. A phase 2a study to investigate the effects of repeated administration of Aeroderm in subjects with atopic eczema. Bethesda (MD): ClinicalTrials.gov; 2008 May 13 [cited 2017 Dec 17]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT00676884
  • Hamann CR, Thyssen JP. Monoclonal antibodies against IL-13 and IL-31RA in development for atopic dermatitis. J Am Acad Dermatol. 2018;78(3):S37–S42. a.
  • Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2009;124(3 Suppl 2):R7–R12.
  • Wollenberg A, Howell MD, Guttman-Yassky E, et al. A phase 2b dose-ranging efficacy and safety study of tralokinumab in adult patients with moderate to severe atopic dermatitis (AD). J Am Acad Dermatol. 2017;76(6, Supplement 1):AB20.
  • Renert-Yuval Y, Guttman-Yassky E. The changing landscape of alopecia areata: the therapeutic paradigm. Adv Ther. 2017;34(7):1594–1609.
  • Popovic B, Breed J, Rees DG, et al. Structural characterisation reveals mechanism of IL-13-neutralising monoclonal antibody tralokinumab as inhibition of binding to IL-13Rα1 and IL-13Rα2. J Mol Biol. 2017;429(2):208–219.
  • Gandhi NA, Pirozzi G, Graham NMH. Commonality of the IL-4/IL-13 pathway in atopic diseases. Expert Rev Clin Immunol. 2017;13(5):425–437.
  • Clinicaltrials.gov [Internet]. Tralokinumab monotherapy for moderate to severe atopic dermatitis - ECZTRA 1 (ECZema tralokinumab trial no. 1) (ECZTRA 1). Bethesda (MD): ClinicalTrials.gov; 2017 Apr 27 [cited 2017 Jul 17]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT03131648?view=results
  • Piper E, Brightling C, Niven R, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41(2):330–338.
  • Ultsch M, Bevers J, Nakamura G, et al. Structural basis of signaling blockade by anti-IL-13 antibody Lebrikizumab. J Mol Biol. 2013;425(8):1330–1339.
  • Simpson E, Flohr C, Eichenfield L. Efficacy and safety of lebrikizumab in patients with atopic dermatitis: a Phase II randomized, controlled trial (TREBLE). J Am Acad Dermatol. 2018;78(5):863–871.
  • Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365(12):1088–1098.
  • Oldhoff JM, Darsow U, Werfel T, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy. 2005;60(5):693–696.
  • Molfino NA, Gossage D, Kolbeck R, et al. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin Exp Allergy. 2012;42(5):712–737.
  • Menzies-Gow A, Ying S, Phipps S, et al. Interactions between eotaxin, histamine and mast cells in early microvascular events associated with eosinophil recruitment to the site of allergic skin reactions in humans. Clin Exp Allergy. 2004;34(8):1276–1282.
  • Wang HH, Li YC, Huang YC. Efficacy of omalizumab in patients with atopic dermatitis: a systematic review and meta-analysis. J Allergy Clin Immunol. 2016;138(6):1719–1722.e1.
  • Simon D, Braathen LR, Simon HU. Eosinophils and atopic dermatitis. Allergy. 2004;59(6):561–570.
  • Phipps S, Flood-Page P, Menzies-Gow A, et al. Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and tenascin deposition in allergen-challenged human atopic skin. J Invest Dermatol. 2004;122(6):1406–1412.
  • ClinicalTrials.gov [Internet]. Efficacy and safety study of mepolizumab in subjects with moderate to severe atopic dermatitis. Bethesda (MD): ClinicalTrials.gov; 2017. [cited 2018 Jun 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT03055195?term=NCT03055195&rank=1
  • Grimstad O, Sawanobori Y, Vestergaard C, et al. Anti-interleukin-31 antibodies ameliorate scratching behaviour in NC/Nga mice: A model of atopic dermatitis. Exp Dermatol. 2009;18(1):35–43.
  • Gittler JK, Shemer A, Suarez-Farinas M, et al. 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.
  • Nobbe S, Dziunycz P, MüHleisen B, et al. IL-31 expression by inflammatory cells is preferentially elevated in atopic dermatitis. Acta Derm Venereol. 2012;92(1):24–28.
  • Rabenhorst A, Hartmann K. Interleukin-31: a novel diagnostic marker of allergic diseases. Curr Allergy Asthma Rep. 2014;14(4):423.
  • ClnicalTrials.gov [Internet]. A two-part, Phase 1, randomized, double-blind, placebo-controlled, single-dose, dose- escalation study of subcutaneous and intravenous administration of IL-31 mAb (Anti- Interleukin 31 monoclonal antibody; BMS-981164) in healthy subjects and adult subjects with atopic dermatitis. Bethesda (MD): ClinicalTrials.gov; 2012 [cited 2017 Jan 2]. Available from: https://clinicaltrials.gov/ct2/show/NCT01614756
  • Ruzicka T, Hanifin JM, Furue M, et al. Anti-interleukin-31 receptor A antibody for atopic dermatitis. N Engl J Med. 2017;376(9):826–835.
  • Nemoto O, Furue M, Nakagawa H, 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(2):296–304.
  • Saleem M, Oussedik E, D’Amber V, et al. Interleukin-31 pathway and its role in atopic dermatitis: a systematic review. J Dermatol Treat. 2017;28(7):591–599.
  • Nakajima S, Igyarto BZ, Honda T, et al. Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling. J Allergy Clin Immunol. 2012;129(4):1048–1055.
  • Kubo T, Kamekura R, Kumagai A, et al. ∆Np63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis. PLoS ONE. 2014;9(8):e105498.
  • Ziegler SF, Liu YJ. Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nat Immunol. 2006;7(7):709–714.
  • Wang YH, Liu YJ. Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses. Clin Exp Allergy. 2009;39(6):798–806.
  • Liu YJ. 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.
  • Tidwell WJ, Fowler JF Jr. T-cell inhibitors for atopic dermatitis. J Am Acad Dermatol. 2018;78(3S1):S67–S70.
  • Gauvreau GM, O’Byrne PM, Boulet LP, et al. Effects on an anti-TSLP antibody on allergen- induced asthmatic response. N Engl J Med. 2014;370(22):2102–2110.
  • AstraZeneca [Internet]. Year-to-date and Q3 2017 results. Cambridge: AstraZenea; 2017 Nov 9 [cited 2018 Aug 10]. Available from: https://www.astrazeneca.com/content/dam/az/PDF/2017/Q3/Year-to-date_and_Q3_2017_Results_Announcement.pdf
  • Holm JG, Agner T, Sand C, et al. Omalizumab for atopic dermatitis: case series and a systematic review of the literature. Int J Dermatol. 2017;56(1):18–26.
  • Godse K, Mehta A, Patil S, et al. Omalizumab—a review. Indian J Dermatol. 2015;60(4):381–384.
  • Heil PM, Maurer D, Klein B, et al. Omalizumab therapy in atopic dermatitis: depletion of IgE does not improve the clinical course—a randomized, placebo-controlled and double blind pilot study. J Dtsch Dermatol Ges. 2010;8(12):990–998.
  • Thaiwat S, Sangasapaviliya A. Omalizumab treatment in severe adult atopic dermatitis. Asian Pac J Allergy Immunol. 2011;29(4):357–360.
  • Park SY, Choi MR, Na JI, et al. Recalcitrant atopic dermatitis treated with omalizumab. Ann Dermatol. 2010;22(3):349–352.
  • El-Qutob D. Off-label uses of omalizumab. Clin Rev Allergy Immunol. 2016;50(1):84–96.
  • Amrol D. Anti-immunoglobulin e in the treatment of refractory atopic dermatitis. South Med J. 2010;103(6):554–558.
  • Fernandez-Anton Martinez MC, Leis-Dosil V, Alfageme-Roldan F, et al. Omalizumab for the treatment of atopic dermatitis. Actas Dermosifiliogr. 2012;103(7):624–628.
  • Forman SB, Garrett AB. Success of omalizumab as monotherapy in adult atopic dermatitis: case report and discussion of the high-affinity immunoglobulin E receptor, FcepsilonRI. Cutis. 2007;80(1):38–40.
  • Belloni B, Ziai M, Lim A, et al. Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels. J Allergy Clin Immunol. 2007;120(5):1223–1225.
  • Quist SR, Ambach A, Go ̈Ppner D, et al. Long-term treatment of severe recalcitrant atopic dermatitis with omalizumab, an anti-immunoglobulin E. Acta Derm Venereol. 2013;93(2):206–208.
  • Vigo PG, Girgis KR, Pfuetze BL, et al. Efficacy of anti-IgE therapy in patients with atopic dermatitis. J Am Acad Dermatol. 2006;55(1):168–170.
  • Incorvaia C, Pravettoni C, Mauro M, et al. Effectiveness of omalizumab in a patient with severe asthma and atopic dermatitis. Monaldi Arch Chest Dis. 2008;69(2):78–80.
  • Lee E, Sheinkopf LE, Asif W, et al. Efficacy of anti-IgE therapy in patients with atopic dermatitis. J Am Acad Dermatol. 2006;55(1):168–170.
  • Kim DH, Park KY, Kim BJ, et al. Anti-immunoglobulin E in the treatment of refractory atopic dermatitis. Clin Exp Dermatol. 2013;38(5):496–500.
  • Sheinkopf LE, Rafi AW, Do LT, et al. Efficacy of omalizumab in the treatment of atopic dermatitis: a pilot study. Allergy Asthma Proc. 2008;29(5):530–537.
  • Zink A, Gensbaur A, Zirbs M, et al. Targeting IgE in severe atopic dermatitis with a combination of immunoadsorption and omalizumab. Acta Derm Venereol. 2016;96(1):72–76.
  • Toledo F, Silvestre JF, Mun ̃oz C. Combined therapy with low-dose omalizumab and intravenous immunoglobulin for severe atopic dermatitis. Report of four cases. J Eur Acad Dermatol Venereol. 2012;26(10):1325–1327.
  • Hotze M, Baurecht H, Rodríguez E, et al. Increased efficacy of omalizumab in atopic dermatitis patients with wild-type filaggrin status and higher serum levels of phosphatidylcholines. Allergy. 2014;69(1):132–135.
  • Krathen RA, Hsu S. Failure of omalizumab for treatment of severe adult atopic dermatitis. J Am Acad Dermatol. 2005;53(2):338–340.
  • Iyengar SR, Hoyte EG, Loza A, et al. Immunologic effects of omalizumab in children with severe refractory atopic dermatitis: a randomized, placebo-controlled clinical trial. Int Arch Allergy Immunol. 2013;162(1):89–93.
  • Lane JE, Cheyney JM, Lane TN, et al. Treatment of recalcitrant atopic dermatitis with omalizumab. J Am Acad Dermatol. 2006;54(1):68–72.
  • Sanchez-Ramon S, Eguíluz-Gracia I, Rodríguez- Mazariego ME, et al. Sequential combined therapy with Omalizumab and Rituximab: a new approach to severe atopic dermatitis. J Investig Allergol Clin Immunol. 2013;23(3):190–196.
  • Velling P, Skowasch D, Pabst S, et al. Improvement of quality of life in patients with concomitant allergic asthma and atopic dermatitis: one year follow-up of omalizumab therapy. Eur J Med Res. 2011;16(9):407.
  • Romano C, Sellitto A, De Fanis U, et al. Omalizumab for difficult-to-treat dermatological conditions: clinical and immunological features from a retrospective real-life experience. Clin Drug Investig. 2015;35(3):159–168.
  • Gauvreau GM, Arm JP, Boulet LP, et al. Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses. J Allergy Clin Immunol. 2016;138(4):1051–1059.
  • Lee DE, Clark AK, Tran KA, et al. New and emerging targeted systemic therapies: a new era for atopic dermatitis. J Dermatolog Treat. 2018;29(4):364–374.
  • ClinicalTrials.gov [Internet]. A study evaluating the safety and efficacy of QGE031 in atopic dermatitis patients. Bethesda (MD): ClinicalTrials.gov; 2017 [cited 2017 Jun 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT01552629?term=NCT01552629&rank=1
  • Simon D, Hosli S, Kostylina G, et al. Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol. 2008;121(1):122–128.
  • Sediva A, Kayserova J, Vernerova E, et al. Anti-CD20 (rituximab) treatment for atopic eczema. J Allergy Clin Immunol. 2008;121(1):1515–1516.
  • McDonald BS, Jones J, Rustin M. Rituximab as a treatment for severe atopic eczema: failure to improve in three consecutive patients. Clin Exp Dermatol. 2016;41(1):45–47.
  • Pene J, Chevalier S, Preisser L, et al. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J Immunol. 2008;180(11):7423–7430.
  • Dhingra N, Guttman-Yassky E. A possible role for IL-17A in establishing Th2 inflammation in murine models of atopic dermatitis. J Invest Dermatol. 2014;134(8):2071–2074.
  • Batista DI, Perez L, Orfali RL, et al. Profile of skin barrier proteins (filaggrin, claudins 1 and 4) and Th1/Th2/Th17 cytokines in adults with atopic dermatitis. J Eur Acad Dermatol Venereol. 2015;29(6):1091–1095.
  • Floudas A, Saunders SP, Moran T, et al. IL-17 receptor A maintains and protects the skin barrier to prevent allergic skin inflammation. J Immunol. 2017;199(2):707–717.
  • Koga C, Kabashima K, Shiraishi N, et al. Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol. 2008;128(11):2625–2630.
  • Noda S, Hashim PW, Khattri S, et al. Successful use of secukinumab in an Asian patient with severe refractory atopic dermatitis. J Invest Dermatol. 2016;136(5):S40.
  • ClinicalTrials.gov [Internet]. Secukinumab for treatment of atopic dermatitis. Bethesda (MD): ClinicalTrials.gov; 2017 [cited 2017 Jun 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT02594098?term=NCT02594098&rank=1
  • Nograles KE, Zaba LC, Guttman-Yassky E, et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol. 2008;159(5):1092–1102.
  • US Food and Drug Administration [Internet]. Secukinumab. Silver Spring (MD): FDA; 2015 [cited 2017 Dec 27]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125504s016lbl.pdf
  • Ibler K, Dam TN, Gniadecki R, et al. Efalizumab for severe refractory atopic eczema: retrospective study on 11 cases. J Eur Acad Dermatol Venereol. 2010;24(7):837–839.
  • Chacko M, Weinberg JM. Efalizumab. Dermatol Ther. 2007;20(4):265–269.
  • Takiguchi R, Tofte S, Simpson B, et al. Efalizumab for severe atopic dermatitis: a pilot study in adults. J Am Acad Dermatol. 2007;56(2):222–227.
  • Lebwohl M. New developments in the treatment of psoriasis. Arch Dermatol. 2002;138(5):686–688.
  • Lebwohl M, Tyring SK, Hamilton TK, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med. 2003;349(21):2004–2013.
  • Baniandrés O, Pulido A, Silvente C, et al. Clinical outcomes in patients with psoriasis following discontinuation of efalizumab due to suspension of marketing authorization. Actas Dermosifiliogr. 2010;101(5):421–427.
  • Fernández Vozmediano JM, Armario Hita JC. Nuevas perspectivas terapéuticas en dermatitis atópica (Atopic dermatitis. New therapies for the future). Med Cutan Iber Lat Am. 2011;39(1):30–36.
  • Simon D, Wittwer J, Kostylina G, et al. Alefacept (lymphocyte function-associated molecule 3/IgG fusion protein) treatment for atopic eczema. J Allergy Clin Immunol. 2008;122(2):423.
  • Johnson JG, Jenkins MK. Accessory cell-derived signals required for T cell activation. Immunol Res. 1993;12(1):48–64.
  • Miller GT, Hochman PS, Meier W, et al. Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses. J Exp Med. 1993;178(1):211–222.
  • Ibler KS, Jemec GB. Novel investigational therapies for atopic dermatitis. Expert Opin Investig Drugs. 2015;24(1):61–68.
  • Cooper JC, Morgan G, Harding S, et al. Alefacept selectively promotes NK cell-mediated deletion of CD45RO1 human T cells. Eur J Immunol. 2003;33(3):666–675.
  • Moul DK, Routhouska SB, Robinson MR, et al. Alefacept for moderate to severe atopic dermatitis: a pilot study in adults. J Am Acad Dermatol. 2008;58(6):984.
  • Akdis CA, Akdis M, Simon HU, et al. Regulation of allergic inflammation by skin-homing T cells in allergic eczema. Int Arch Allergy Immunol. 1999;118(2–4):140–144.
  • Boniface K, Bernard FX, Garcia M, et al. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol. 2005;174(6):3695–3702.
  • Guttman-Yassky E, Khattri S, Brunner P, et al. A pathogenic role for Th22/IL-22 in atopic dermatitis is established by a placebo-controlled trial with an anti IL- 22/ILV-094 mAb. J Invest Dermatol. 2017;137(5):S53.
  • ClinicalTrials.gov [Internet]. Randomized placebo controlled study to determine safety, pharmacodynamics and efficacy of ILV- 094 in atopic dermatitis. Bethesda (MD): ClinicalTrials.gov; 2013 [cited 2018 Aug 6] Available from: https://clinicaltrials.gov/ct2/show/NCT01941537
  • Guttman-Yassky E, Brunner PM, Neumann AU, et al. 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.
  • Landells I, Marano C, Hsu MC, et al. Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: results of the randomized phase 3 CADMUS study. J Am Acad Dermatol. 2015;73(4):594–603.
  • Fernandez-Anton Martinez MC, Alfageme Roldan F, Ciudad Blanco C, et al. Ustekinumab in the treatment of severe atopic dermatitis: a preliminary report of our experience with 4 patients. Actas Dermosifiliogr. 2014;105(3):312–313.
  • Puya R, Alvarez-Lo ́pez M, Velez A, et al. Treatment of severe refractory adult atopic dermatitis with ustekinumab. Int J Dermatol. 2012;51(1):115–116.
  • Nast A, Jacobs A, Rosumeck S, et al. Efficacy and safety of systemic long-term treatments for moderate-to-severe psoriasis: a systematic review and meta-analysis. J Invest Dermatol. 2015;135(11):2641–2648.
  • Khattri S, Brunner PM, Garcet S, et al. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. Exp Dermatol. 2016;26(1):28–35.
  • Shroff A, Guttman-Yassky E. Successful use of ustekinumab therapy in refractory severe atopic dermatitis. JAAD Case Rep. 2014;1(1):25–26.
  • Weiss D, Schaschinger M, Ristl R, et al. Ustekinumab treatment in severe atopic dermatitis: down-regulation of T-helper 2/22 expression. J Am Acad Dermatol. 2016;76(1):945–973.
  • Samorano LP, Hanifin JM, Simpson EL, et al. Inadequate response to ustekinumab in atopic dermatitis—a report of two patients. J Eur Acad Dermatol Venereol. 2016;30(3):522–523.
  • Lis-Swiety A, Skrzypek-Salamon A, Arasiewicz H, et al. Atopic dermatitis exacerbated with ustekinumab in a psoriatic patient with childhood history of atopy. Allergol Int. 2015;64(4):382–383.
  • Navarini AA, French LE, Hofbauer GFL. Interrupting IL-6–receptor signaling improves atopic dermatitis but associates with bacterial superinfection. J Allergy Clin Immunol. 2011;128(5):1128–1130.
  • Lebas D, Staumont-Sallé D, Solau-Gervais E, et al. Cutaneous manifestations during treatment with TNF-alpha blockers: 11 cases. Ann Dermatol Venereol. 2007;134(4 Pt 1):337–342.
  • Jacobi A, Antoni C, Manger B, et al. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol. 2005;52(3 Pt 1):522–526.
  • Chan JL, Davis-Reed L, Kimball AB. Counter-regulatory balance: atopic dermatitis in patients undergoing infliximab infusion therapy. J Drugs Dermatol. 2004;3(3):315–318.
  • Wright RC. Atopic dermatitis-like eruption precipitated by infliximab. J Am Acad Dermatol. 2003;49(1):160–161.
  • Buka RL, Resh B, Roberts B, et al. Etanercept is minimally effective in 2 children with atopic dermatitis. J Am Acad Dermatol. 2005;53(2):358–359.
  • Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT. 2013;2(3):e24137.
  • Amano W, Nakajima S, Kunugi H, et al. The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. J Allergy Clin Immunol. 2015;136(3):667–677.
  • Bissonnette R, Papp KA, Poulin Y, et al. Topical tofacitinib for atopic dermatitis: a phase 2a randomised trial. Br J Dermatol. 2016;175(5):902–911.
  • Levy LL, Urban J, King BA. Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate. J Am Acad Dermatol. 2015;73(3):395–399.
  • ClinicalTrials.gov [Internet]. A study to evaluate ASN002 in subjects with atopic dermatitis. Bethesda (MD): ClinicalTrials.gov; 2017 [cited 2017 Jul 1]. Available from: https://clinicaltrials.gov/ct2/show/NCT03139981?term=NCT03139981&rank=1
  • Samrao A, Berry TM, Goreshi R, et al. A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol. 2012;148(8):890–897.
  • Jin SL, Ding SL, Lin SC. Phosphodiesterase 4 and its inhibitors in inflammatory diseases. Chang Gung Med J. 2012;35(3):197–210.
  • Hanifin JM, Chan SC, Cheng JB, et al. Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol. 1996;107(1):51–56.
  • Chan SC, Li SH, Hanifin JM. Increased interleukin-4 production by atopic mononuclear leukocytes correlates with increased cyclic adenosine monophosphate-phosphodiesterase activity and is reversible by phosphodiesterase inhibition. J Invest Dermatol. 1993;100(5):681–684.
  • Chan SC, Kim JW, Henderson WR, et al. Altered prostaglandin E2 regulation of cytokine production in atopic dermatitis. J Immunol. 1993;151(6):3345–3352.
  • Chan SC, Reifsnyder D, Beavo JA, et al. Immunochemical characterization of the distinct monocyte cyclic AMP phosphodiesterase from patients with atopic dermatitis. J Allergy Clin Immunol. 1993;91(6):1179–1188.
  • Butler JM, Chan SC, Stevens S, et al. Increased leukocyte histamine release with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis. J Allergy Clin Immunol. 1983;71(5):490–497.
  • Cooper KD, Kang K, Chan SC, et al. Phosphodiesterase inhibition by Ro 20-1724 reduces hyper-IgE synthesis by atopic dermatitis cells in vitro. J Invest Dermatol. 1985;84(6):477–482.
  • Zebda R, Paller AS. Phosphodiesterase 4 inhibitors. J Am Acad Dermatol. 2018;78(3S1):S43–S52.
  • Volf EM, Au SC, Dumont N, et al. A phase 2, open-label, investigator-initiated study to evaluate the safety and efficacy of apremilast in subjects with recalcitrant allergic contact or atopic dermatitis. J Drugs Dermatol. 2012;11(3):341–346.
  • ClinicalTrials.gov [Internet]. Efficacy and safety study of apremilast in subjects with moderate to severe atopic dermatitis. Bethesda (MD): ClinicalTrials.gov; 2017 [cited 2018 Jun 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT02087943?term=NCT02087943&rank=1
  • Murata Y, Song M, Kikuchi H, et al. Phase 2a, 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.
  • Gutzmer R, Mommert S, Gschwandtner M, et al. The histamine H4 receptor is functionally expressed on T(H)2 cells. J Allergy Clin Immunol. 2009;123(3):619–625.
  • ClinicalTrials.gov [Internet]. A study of JNJ-39758979 in adult Japanese patients with moderate atopic dermatitis. Bethesda (MD): ClinicalTrials.gov; 2017 [cited 2018 Jul 1]. Available from: https://clinicaltrials.gov/ct2/show/NCT01497119?term=NCT01497119&rank=1
  • Stander S, Siepmann D, Herrgott I, et al. Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One. 2010;5(6):e10968.
  • Salomon J, Baran E. The role of selected neuropeptides in pathogenesis of atopic dermatitis. J Eur Acad Dermatol Venereol. 2008;22(2):223–228.
  • ClinicalTrials.gov [Internet]. Proof of concept of VLY-686 in subjects with treatment-resistant pruritus associated with atopic dermatitis. Bethesda (MD): ClinicalTrials.gov; 2017 [cited 2018 Mar 1]. Available from: https://clinicaltrials.gov/ct2/show/NCT02004041?term=NCT02004041&rank=1
  • ClinicalTrials.gov [Internet]. Tradipitant in treatment-resistant pruritus associated with atopic dermatitis. Bethesda (MD): ClinicalTrials.gov; 2017 [cited 2018 Apr 28]. Available from: https://clinicaltrials.gov/ct2/show/NCT02651714?term=NCT02651714&rank=1
  • ClinicalTrials.gov [Internet]. A randomized placebo-controlled study of the neurokinin-1 (NK1) receptor antagonist serlopitant prurigo nodularis (PN). Bethesda (MD): ClinicalTrials.gov; 2017 [cited 2018 Jan 7]. Available from: https://clinicaltrials.gov/ct2/show/NCT02196324?term=NCT02196324&rank=1
  • Tominaga M, Ogawa H, Takamori K. Possible roles of epidermal opioid systems in pruritus of atopic dermatitis. J Invest Dermatol. 2007;127(9):2228–2235.
  • Bishop KM, Visonneau S, McGuire D Development of asimadoline,a selective kappa opioid receptor agonist, for the treatment of pruritus. Paper presented at: 8th World Congress on Itch (WCI); 2015 Oct 27–29; Nara, Japan.
  • Tey HL, Yosipovitch G. Targeted treatment of pruritus: a look into the future. Br J Dermatol. 2011;165(1):5–17.
  • Cowan A, Kehner GB, Inan S. Targeting itch with ligands selective for j opioid receptors. Handb Exp Pharmacol. 2015;226:291–314.
  • ClinicalTrials.gov [Internet]. Safety, pharmacokinetics and preliminary efficacy of asimadoline in pruritus associated with atopic dermatitis. Bethesda (MD): ClinicalTrials.gov;2017 [cited 2018 Feb 05]. Available from: https://clinicaltrials.gov/ct2/show/NCT02475447?term=NCT02475447&rank=1
  • Fajas L, Auboeuf D, Raspe E, et al. The organization, promoter analysis, and expression of the human PPAR-γ gene. J Biol Chem. 1997;272(30):18779–18789.
  • Kuenzli S, Saurat JH. Peroxisome proliferator-activated receptors in cutaneous biology. Br J Dermatol. 2003;149(2):229–236.
  • Behshad R, Cooper KD, Korman NJ. A retrospective case series review of the peroxisome proliferator-activated receptor ligand rosiglitazone in the treatment of atopic dermatitis. Arch Dermatol. 2008;144(1):84–88.
  • Martin H. Role of PPAR-γ in inflammation. Prospects for therapeutic intervention by food components. Mutat Res. 2010;690(1–2):57–63.
  • Pappas A. Epidermal surface lipids. Dermatoendocrinol. 2009;1(2):72–76.
  • Manku MS, Horrobin DF, Morse N, et al. Reduced levels of prostaglandin precursors in the blood of atopic patients: defective delta-6-desaturase function as a biochemical basis for atopy. Prostaglandins Leukot Med. 1982;9(6):615–628.
  • Kawashima H, Tateishi N, Shiraishi A, et al. Oral administration of dihomo-gamma-linolenic acid prevents development of atopic dermatitis in NC/Nga mice. Lipids. 2008;43(1):37–43.
  • dsbiopharma.com [Internet]. DS biopharma announces positive top-line phase IIa trial results for DS107 as an oral treatment for moderate to severe atopic dermatitis. Dublin: (Ireland): dsbiopharma.com; 2016 [cited 2018 Jul 10]. Available from: http://www.dsbiopharma.com/2016/01/07/ds-biopharma-announces-positive-top-line-phase-iia-trial-results-for-ds107-as-an-oral-treatment-for-moderate-to-severe-atopic-dermatitis/
  • ClinicalTrials.gov [Internet]. Oral DS107G in moderate to severe atopic dermatitis. Bethesda (MD): ClinicalTrials.gov; 2017. [cited 2018 Mar 19]. Available from: https://clinicaltrials.gov/ct2/show/NCT02211417?term=NCT02211417&rank=1
  • ClinicalTrials.gov [Internet]. Efficacy and safety study of orally administered DS107 in moderate to severe atopic dermatitis patients. Bethesda (MD): ClinicalTrials.gov; 2017 [cited 2018 May 16]. Available from: https://clinicaltrials.gov/ct2/show/NCT02864498?term=NCT02864498&rank=1
  • Eichenfield LF, Ahluwalia J, Waldman A, et al. Current guidelines for the evaluation and management of atopic dermatitis: A comparison of the joint task force practice parameter and American Academy of Dermatology guidelines. J Allergy Clin Immunol. 2017;139(4S):S49–S57.

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