Abstract
Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. The number of people affected by AD is relatively high and seems to be rising. Although mild and moderate forms of the disease can be well controlled by the use of emollients, topical corticosteroids, and topical calcineurin inhibitors, treatment of severe is still a huge challenge. The new hope is biologic drugs, magic bullets in allergy, targeted at different points of the complex pathomechanism of inflammation in AD. In this review, novel biologic therapies are discussed, including recombinant monoclonal antibodies directed against various interleukin pathways (such as IL-4, IL-13, TSLP, IL-31, and IL-12/23), on immunoglobulin E, molecules acting as T cells, B cells, etc. Of biological drugs, the most promising seems to be anti-IL-4/IL-13 therapy (dupilumab—the biological agent) and phosphodiesterase-4 inhibitor (crisaborole—a small molecule). A deep understanding of the AD pathomechanism provides a new perspective for tailor-made treatment of severe atopic dermatitis.
Similar content being viewed by others
References
Agusti-Mejias A, Messeguer F, García R et al (2013) Severe refractory atopic dermatitis in an adolescent patient successfully treated with ustekinumab. Ann Dermatol 25:368–370
Arm JP, Bottoli I, Skerjanec A et al (2014) Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects. Clin Exp Allergy 44:1371–1385
Batista DI, Perez L, Orfali RL et al (2015) 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 29:1091–1095
Beck LA, Thaçi D, Hamilton JD et al (2014) Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med 371:130–139
Bieber T, Straeter B (2015) Off-label prescriptions for atopic dermatitis in Europe. Allergy 70:6–11
Boniface K, Bernard FX, Garcia M et al (2005) IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol 174:3695–3702
Brough HA, Liu AH, Sicherer S et al (2015) Atopic dermatitis increases the effect of exposure to peanut antigen in dust on peanut sensitization and likely peanut allergy. J Allergy Clin Immunol 135:164–170
Buka RL, Resh B, Roberts B et al (2005) Etanercept is minimally effective in 2 children with atopic dermatitis. J Am Acad Dermatol 53:358–359
Chan SC, Reifsnyder D, Beavo JA et al (1993) Immunochemical characterization of the distinct monocyte cyclic AMP-phosphodiesterase from patients with atopic dermatitis. J Allergy Clin Immunol 91:1179–1188
Czarnowicki T, Gonzalez J, Bonifacio KM et al (2016) Diverse activation and differentiation of multiple B-cell subsets in patients with atopic dermatitis but not in patients with psoriasis. J Allergy Clin Immunol 137(118–129):e115
Eyerich K, Novak N (2013) Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy 68:974–982
Eyerich K, Eyerich S, Biedermann T (2015) The multi-modal immune pathogenesis of atopic eczema. Trends Immunol 36:788–801
Fernández-Antón Martínez MC, Leis-Dosil V, Alfageme-Roldán F et al (2012) Omalizumab for the treatment of atopic dermatitis. Actas Dermosifiliogr 103:624–628
Fernández-Antón Martínez MC, Alfageme Roldán F, Ciudad Blanco C et al (2014) Ustekinumab in the treatment of severe atopic dermatitis: a preliminary report of our experience with 4 patients. Actas Dermosifiliogr 105:312–313
Gittler JK, Shemer A, Suárez-Fariñas M et al (2012) Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol 130:1344–1354
Hanania NA, Noonan M, Corren J et al (2015) Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax 70:748–756
Heil PM, Maurer D, Klein B et al (2010) 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 8:990–998
Hotze M, Baurecht H, Rodríguez E et al (2014) Increased efficacy of omalizumab in atopic dermatitis patients with wild-type filaggrin status and higher serum levels of phosphatidylcholines. Allergy 69:132–135
Howell MD, Kim BE, Gao P et al (2009) Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 124(3 Suppl 2):R7–R12
Ibler KS, Jemec GB (2015) Novel investigational therapies for atopic dermatitis. Expert Opin Investig Drugs 24:61–68
Itazawa T, Adachi Y, Okabe Y et al (2003) Developmental changes in interleukin-12-producing ability by monocytes and their relevance to allergic diseases. Clin Exp Allergy 33:525–530
Iyengar SR, Hoyte EG, Loza A et al (2013) Immunologic effects of omalizumab in children with severe refractory atopic dermatitis: a randomized, placebo-controlled clinical trial. Int Arch Allergy Immunol 162:89–93
Jacobi A, Antoni C, Manger B et al (2005) Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol 52:522–526
Kasperkiewicz M, Sufke S, Schmidt E et al (2014) IgE-specific immunoadsorption for treatment of recalcitrant atopic dermatitis. JAMA Dermatol 150:1350–1351
Kim DH, Park KY, Kim BJ et al (2013) Anti-immunoglobulin E in the treatment of refractory atopic dermatitis. Clin Exp Dermatol 38:496–500
Kwiek B, Novak N (2010) Immunosuppressants as treatment for atopic dermatitis. In: Pawankar R, Holgate S et al (eds) Allergy frontiers: therapy and prevention, vol V. Springer, Berlin, pp 291–310
Kwiek B, Peng WM, Allam JP et al (2008) Tacrolimus and TGF-beta act synergistically on the generation of Langerhans cells. J Allergy Clin Immunol 122:126–132.e1
Lacombe Barrios J, Begin P, Paradis L et al (2013) Anti-IgE therapy and severe atopic dermatitis: a pediatric perspective. J Am Acad Dermatol 69:832–834
Lauffer F, Ring J (2016) Target-oriented therapy: emerging drugs for atopic dermatitis. Expert Opin Emerg Drugs 21:81–89
Leitch CS, Chu R, Ray R et al (2015) Preventing atopic eczema from birth using emollients. J Allergy Clin Immunol 135:1663–1664
Mangge H, Gindl S, Kenzian H et al (2003) Atopic dermatitis as a side effect of anti-tumor necrosis factor-alpha therapy. J Rheumatol 30:2506–2507
McDonald BS, Jones J, Rustin M (2016) Rituximab as a treatment for severe atopic eczema: failure to improve in three consecutive patients. Clin Exp Dermatol 41:45–47
NCT00676884 (2008) A phase 2a study to investigate the effects of repeated administration of aeroderm in subjects with atopic eczema. https://clinicaltrials.gov/ct2/show/NCT00676884. Accessed 4 Jan 2017
NCT01614756 (2012) A two-part, phase 1, single-dose study of IL-31 mAb (anti-interleukin 31 monoclonal antibody); in healthy subjects and adults with atopic dermatitis. https://clinicaltrials.gov/ct2/show/NCT01614756. Accessed 4 Jan 2017
NCT01806662 (2013) Pilot study of ustekinumab for subjects with chronic atopic dermatitis. https://clinicaltrials.gov/ct2/show/NCT01806662. Accessed 4 Jan 2017
NCT01941537 (2013) Randomized Placebo Controlled Study to Determine Safety, Pharmacodynamics and Efficacy of ILV-094 in Atopic Dermatitis. https://clinicaltrials.gov/ct2/show/NCT01941537. Accessed 4 Jan 2017
NCT02087943 (2014) Efficacy and safety study of apremilast in subjects with moderate to severe atopic dermatitis. https://clinicaltrials.gov/ct2/show/NCT02087943. Accessed 24 Mar 2017
NCT02340234 (2015) A study of lebrikizumab in patients with persistent moderate to severe atopic dermatitis. https://clinicaltrials.gov/ct2/show/NCT02340234. Accessed 4 Jan 2017
NCT02407756 (2015) A study to determine the safety and tolerability of dupilumab in patients aged ≥6 to <18 years with atopic dermatitis (eczema). https://clinicaltrials.gov/ct2/show/study/NCT02407756. Accessed 4 Jan 2017
NCT02525094 (2015) Phase 2a study to evaluate the efficacy and safety of MEDI9929 in adults with atopic dermatitis (ALLEVIAD). https://clinicaltrials.gov/ct2/show/NCT02525094. Accessed 4 Jan 2017
NCT02594098 (2015) Secukinumab for Treatment of Atopic Dermatitis. https://clinicaltrials.gov/ct2/show/NCT02594098. Accessed 4 Jan 2017
Novak N, Kwiek B, Bieber T (2005) The mode of topical immunomodulators in the immunological network of atopic dermatitis. Clin Exp Dermatol 30:160–164
Oldhoff JM, Darsow U, Werfel T et al (2005) Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy 60:693–696
Paller AS, Tom WL, Lebwohl MG et al (2016) 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 75(494–503):e6
Pazyar N, Feily A, Yaghoobi R (2012) An overview of interleukin-1 receptor antagonist, anakinra, in the treatment of cutaneous diseases. Curr Clin Pharmacol 7:271–275
Puya R, Alvarez-Lopez M, Velez A et al (2012) Treatment of severe refractory adult atopic dermatitis with ustekinumab. Int J Dermatol 51:115–116
Raap U, Wichmann K, Bruder M et al (2008) Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol 122:421–423
Ruzicka T, Hanifin JM, Furue M et al (2017) Anti-interleukin-31 receptor a antibody for atopic dermatitis. N Engl J Med 376:826–835
Samorano LP, Hanifin JM, Simpson EL et al (2016) Inadequate response to ustekinumab in atopic dermatitis—a report of two patients. J Eur Acad Dermatol Venereol 30:522–523
Samrao A, Berry TM, Goreshi R et al (2012) A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol 148:890–897
Sanchez-Ramon S, Eguíluz-Gracia I, Rodríguez-Mazariego ME et al (2013) Sequential combined therapy with omalizumab and rituximab: a new approach to severe atopic dermatitis. J Investig Allergol Clin Immunol 23:190–196
Schafer PH, Parton A, Gandhi AK et al (2010) Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol 159:842–855
Sediva A, Kayserova J, Vernerova E et al (2008) Anti-CD20 (rituximab) treatment for atopic eczema. J Allergy Clin Immunol 121:1515–1516 (author reply 1516–1517)
Shirakawa I, Deichmann KA, Izuhara I et al (2000) Atopy and asthma: genetic variants of IL-4 and IL-13 signalling. Immunol Today 21:60–64
Shroff A, Guttman-Yassky E (2014) Successful use of ustekinumab therapy in refractory severe atopic dermatitis. JAAD Case Rep 1:25–26
Simon D, Hosli S, Kostylina G et al (2008a) Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol 121:122–128
Simon D, Wittwer J, Kostylina G et al (2008b) Alefacept (lymphocyte function-associated molecule 3/IgG fusion protein) treatment for atopic eczema. J Allergy Clin Immunol 122:423–424
Simpson EL, Bieber T, Guttman-Yassky E et al (2016) Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 375:2335–2348
Sonkoly E, Muller A, Lauerma AI et al (2006) IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol 117:411–417
Strowd LC, Feldman SR (2017) Dupilumab for atopic dermatitis. Lancet 10(389):2265–2266
Tatsuno K, Fujiyama T, Yamaguchi H et al (2015) TSLP directly interacts with skin-homing Th2 cells highly expressing its receptor to enhance IL-4 production in atopic dermatitis. J Invest Dermatol 135:3017–3024
Terabe M, Park JM, Berzofsky JA (2004) Role of IL-13 in regulation of anti-tumor immunity and tumor growth. Cancer Immunol Immunother 53:79–85
Thaci D, Simpson EL, Beck LA et al (2016) 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 387:40–52
Toledo F, Silvestre JF, Munoz C (2012) Combined therapy with low-dose omalizumab and intravenous immunoglobulin for severe atopic dermatitis. Report of four cases. J Eur Acad Dermatol Venereol 26:1325–1327
Torley D, Futamura M, Williams HC et al (2013) What’s new in atopic eczema? An analysis of systematic reviews published in 2010–11. Clin Exp Dermatol 38:449–456
Wang HH, Li YC, Huang YC (2016) Efficacy of omalizumab in patients with atopic dermatitis: a systematic review and meta-analysis. J Allergy Clin Immunol 138(1719–1722):e1
Weidinger S, Novak N (2016) Atopic dermatitis. Lancet 387:1109–1122
Wenzel S, Wilbraham D, Fuller R et al (2007) Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 370:1422–1431
Wenzel S, Ford L, Pearlman D et al (2013) Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 368:2455–2466
Wlodek C, Hewitt H, Kennedy CT (2016) Use of ustekinumab for severe refractory atopic dermatitis in a young teenager. Clin Exp Dermatol 41:625–627
Wright RC (2003) Atopic dermatitis-like eruption precipitated by infliximab. J Am Acad Dermatol 49:160–161
Yayli S, Irla N, Yawalkar N (2013) Adalimumab in recalcitrant severe psoriasis associated with atopic dermatitis. Case Rep Dermatol 5:332–335
Zane LT, Chanda S, Jarnagin K et al (2016) Crisaborole and its potential role in treating atopic dermatitis: overview of early clinical studies. Immunotherapy 8:853–866
Ziegler SF, Roan F, Bell BD et al (2013) The biology of thymic stromal lymphopoietin (TSLP). Adv Pharmacol 66:129–155
Zink A, Gensbaur A, Zirbs M et al (2016) Targeting IgE in severe atopic dermatitis with a combination of immunoadsorption and omalizumab. Acta Derm Venereol 96:72–76
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
There are no conflicts of interest to declare. All authors have approved the manuscript and agree with submission.
About this article
Cite this article
Osinka, K., Dumycz, K., Kwiek, B. et al. Novel Therapeutic Approaches to Atopic Dermatitis. Arch. Immunol. Ther. Exp. 66, 171–181 (2018). https://doi.org/10.1007/s00005-017-0487-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00005-017-0487-1