Systemic Treatment for Severe Atopic Dermatitis

  • Mara Giavina-Bianchi
  • Pedro Giavina-BianchiEmail author


Atopic dermatitis (AD) is a chronic inflammatory, relapsing disease of the skin, characterized by intense pruritus, maculopapular or vesicular erythematous lesions and scaling, sometimes accompanied by oozing, crusts and/or lichenification that has a negative impact on patients’ quality of life. Prevalence is higher in children, around 15%, and approximately 5% in adults. Before introducing systemic therapy, it is mandatory to review patients’ adherence to the correct use of topical treatments (corticosteroids, calcineurin inhibitors or cresoborole) and/or phototherapy. Ensure that environmental measures are being taken care of, irritant or proven allergic substances are not in use and even if the diagnostic is correct. If all is being done and topical treatment with corticosteroid, emollients and phototherapy have not been sufficient to achieve a good control in AD of adults or children patients, it is time to consider systemic agents. Up to now, most of systemic treatments were based on immunosuppressive therapies, being cyclosporine A, the usually first choice for moderate-to-severe AD. Recently, biologic drugs have been developed and approved for AD, as dupilumab, and a whole new group of drugs is giving much hope for patients to have a better control of the disease with less side effects.


Systemic treatment Atopic dermatitis Review Immunosuppressive agents Biologic agents 



Atopic dermatitis


Cyclosporine A


Systemic corticosteroids






Mycophenolate mofetil


Enteric-coated mycophenolate sodium


Janus-associated kinase


Thymic stromal lymphopoietin


  1. 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 44:1371–1385CrossRefGoogle Scholar
  2. Balal M, Demir E, Paydas S et al (2005) Uncommon side effect of MMF in renal transplant recipients. Ren Fail 27:591–594CrossRefGoogle Scholar
  3. Bantz SK, Zhu Z, Zheng T (2014) The atopic March: progression from atopic dermatitis to allergic rhinitis and asthma. J Clin Cell Immunol 5:202Google Scholar
  4. Benson AA, Toh JA, Vernon N et al (2012) The role of vitamin D in the immunopathogenesis of allergic skin diseases. Allergy 67:296–301CrossRefGoogle Scholar
  5. Berth-Jones J, Takwale A, Tan E et al (2002) Azathioprine in severe adult atopic dermatitis: a double-blind, placebo-controlled, crossover trial. Br J Dermatol 147:324–330CrossRefGoogle Scholar
  6. Bieber T (2008) Atopic dermatitis. N Engl J Med 358:1483–1494CrossRefGoogle Scholar
  7. Doege K, Grajecki D, Zyriax BC et al (2012) Impact of maternal supplementation with probiotics during pregnancy on atopic eczema in childhood—a meta-analysis. Br J Nutr 107:1–6CrossRefGoogle Scholar
  8. Eichenfield LF, Ahluwalia J, Waldman A et al (2017) 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 139:S49–S57CrossRefGoogle Scholar
  9. El-Khalawany MA, Hassan H, Shaaban D et al (2013) Methotrexate versus cyclosporine in the treatment of severe atopic dermatitis in children: a multicenter experience from Egypt. Eur J Pediatr 172:351–356CrossRefGoogle Scholar
  10. Fala L (2015) Otezla (Apremilast), an oral PDE-4 inhibitor, receives FDA approval for the treatment of patients with active psoriatic arthritis and plaque psoriasis. Am Health Drug Benefits 8:105–110Google Scholar
  11. 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 105:312–313CrossRefGoogle Scholar
  12. Flohr C, Mann J (2014) New insights into the epidemiology of childhood atopic dermatitis. Allergy 69:3–16CrossRefGoogle Scholar
  13. Garmhausen D, Hagemann T, Bieber T et al (2013) Characterization of different courses of atopic dermatitis in adolescent and adult patients. Allergy 68:498–506CrossRefGoogle Scholar
  14. Gooderham M, Lynde CW, Papp K et al (2017) Review of systemic treatment options for adult atopic dermatitis. J Cutan Med Surg 21:31–39CrossRefGoogle Scholar
  15. Goujon C, Bérard F, Dahel K et al (2006) Methotrexate for the treatment of adult atopic dermatitis. Eur J Dermatol 16:155–158Google Scholar
  16. Grahovac M, Molin S, Prinz JC et al (2010) Treatment of atopic eczema with oral alitretinoin. Br J Dermatol 162:217–218CrossRefGoogle Scholar
  17. Grundmann-Kollmann M, Podda M, Ochsendorf F et al (2001) Mycophenolate mofetil is effective in the treatment of atopic dermatitis. Arch Dermatol 137:870–873Google Scholar
  18. Haeck IM, Knol MJ, Ten Berge O et al (2011) Enteric-coated mycophenolate sodium versus cyclosporin A as long-term treatment in adult patients with severe atopic dermatitis: a randomized controlled trial. J Am Acad Dermatol 64:1074–1084CrossRefGoogle Scholar
  19. Hamilton JD, Suárez-Fariñas M, Dhingra N et al (2014) Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol 134:1293–1300CrossRefGoogle Scholar
  20. Hanifin JM, Reed ML (2007) A population-based survey of eczema prevalence in the United States. Dermatitis 18:82–91CrossRefGoogle Scholar
  21. Hata TR, Audish D, Kotol P et al (2014) A randomized controlled double-blind investigation of the effects of vitamin D dietary supplementation in subjects with atopic dermatitis. J Eur Acad Dermatol Venereol 28:781–789CrossRefGoogle Scholar
  22. Heller M, Shin HT, Orlow SJ et al (2007) Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol 157:127–132CrossRefGoogle Scholar
  23. Hoare C, Li Wan Po A, Williams H (2000) Systematic review of treatments for atopic eczema. Health Technol Assess 4:1–191CrossRefGoogle Scholar
  24. 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 69:132–135CrossRefGoogle Scholar
  25. Howell MD, Kim BE, Gao P et al (2007) Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 120:150–155CrossRefGoogle Scholar
  26. Irvine AD, Jones AP, Beattie P et al (2018) A randomised controlled trial protocol assessing the effectiveness, safety and cost-effectiveness of methotrexate versus ciclosporin in the treatment of severe atopic eczema in children: the treatment of severe Atopic eczema Trial (TREAT). Br J Dermatol. Google Scholar
  27. 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 162:89–93CrossRefGoogle Scholar
  28. Javanbakht MH, Keshavarz SA, Djalali M et al (2011) Randomized controlled trial using vitamins E and D supplementation in atopic dermatitis. J Dermatol Treat 22:144–150CrossRefGoogle Scholar
  29. Katsarou A, Armenaka M (2011) Atopic dermatitis in older patients: particular points. J Eur Acad Dermatol Venereol 25:12–18CrossRefGoogle Scholar
  30. Kay J, Gawkrodger DJ, Mortimer MJ et al (1994) The prevalence of childhood atopic eczema in a general population. J Am Acad Dermatol 30:35–39CrossRefGoogle Scholar
  31. Khan N, Abbas AM, Lichtenstein GR et al (2013) Risk of lymphoma in patients with ulcerative colitis treated with thiopurines: a nationwide retrospective cohort study. Gastroenterology 145:1007–1015.e3CrossRefGoogle Scholar
  32. Kim DH, Park KY, Kim BJ et al (2013) Anti-immunoglobulin E in the treatment of refractory atopic dermatitis. Clin Exp Dermatol 38:496–500CrossRefGoogle Scholar
  33. Kim JE, Kim HJ, Lew BJ et al (2015) Consensus guidelines for the treatment of atopic dermatitis in Korea (Part II): systemic treatment. Ann Dermatol 27:578–592CrossRefGoogle Scholar
  34. Kirby B, Owen CM, Blewitt RW et al (2002) Cutaneous T-cell lymphoma developing in a patient on cyclosporin therapy. J Am Acad Dermatol 47(2 Suppl):S165–S167CrossRefGoogle Scholar
  35. Klein PA, Clark RA (1999) An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis. Arch Dermatol 135:1522–1525CrossRefGoogle Scholar
  36. Laube S, Stephens M, Smith AG et al (2005) Lymphomatoid papulosis in a patient with atopic eczema on long-term ciclosporin therapy. Br J Dermatol 152:1346–1348CrossRefGoogle Scholar
  37. Leung DY, Boguniewicz M, Howell MD et al (2004) New insights into atopic dermatitis. J Clin Invest 113:651–657CrossRefGoogle Scholar
  38. Levy LL, Urban J, King BA (2015) Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate. J Am Acad Dermatol 73:395–399CrossRefGoogle Scholar
  39. Lyakhovitsky A, Barzilai A, Heyman R et al (2010) Low-dose methotrexate treatment for moderate-to-severe atopic dermatitis in adults. J Eur Acad Dermatol Venereol 24:43–49CrossRefGoogle Scholar
  40. Meggitt SJ, Gray JC, Reynolds NJ (2006) Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial. Lancet 367:839–846CrossRefGoogle Scholar
  41. Megna M, Napolitano M, Patruno C et al (2017) Systemic treatment of adult atopic dermatitis: a review. Dermatol Ther 7:1–23CrossRefGoogle Scholar
  42. Moreno AS, McPhee R, Arruda LK et al (2016) Targeting the T helper 2 inflammatory axis in atopic dermatitis. Int Arch Allergy Immunol 171:71–80CrossRefGoogle Scholar
  43. Moul DK, Routhouska SB, Robinson MR et al (2008) Alefacept for moderate to severe atopic dermatitis: a pilot study in adults. J Am Acad Dermatol 58:984–989CrossRefGoogle Scholar
  44. Mutgi K, Koo J (2013) Update on the role of systemic vitamin D in atopic dermatitis. Pediatr Dermatol 30:303–307CrossRefGoogle Scholar
  45. Napolitano M, Megna M, Patruno C et al (2016) Adult atopic dermatitis: a review. Dermatol Venereol 151:403–411Google Scholar
  46. Nguyen RH, Cruz PD Jr (2014) Hepatitis due to mycophenolate mofetil used to treat atopic dermatitis and allergic contact dermatitis. Dermatitis 25:284–285CrossRefGoogle Scholar
  47. Notaro ER, Sidbury R (2015) Systemic agents for severe atopic dermatitis in children. Paediatr Drugs 17:449–457CrossRefGoogle Scholar
  48. Oldhoff JM, Darsow U, Werfel T et al (2005) Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy 60:693–696CrossRefGoogle Scholar
  49. Pelucchi C, Chatenoud L, Turati F et al (2012) Probiotics supplementation during pregnancy or infancy for the prevention of atopic dermatitis: a meta-analysis. Epidemiology 23:402–414CrossRefGoogle Scholar
  50. Peyrin-Biroulet L, Khosrotehrani K, Carrat F et al (2011) Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology 141:1621–1628 (e1–5) CrossRefGoogle Scholar
  51. Politiek K, van der Schaft J, Coenraads PJ et al (2016) Drug survival for methotrexate in a daily practice cohort of adult patients with severe atopic dermatitis. Br J Dermatol 174:201–203CrossRefGoogle Scholar
  52. Puya R, Alvarez-López M, Velez A et al (2012) Treatment of severe refractory adult atopic dermatitis with ustekinumab. Int J Dermatol 51:115–116CrossRefGoogle Scholar
  53. Ring J, Alomar A, Bieber T et al (2012) Guidelines for treatment of atopic eczema (atopic dermatitis) Part II. J Eur Acad Dermatol Venereol 26:1176–1193CrossRefGoogle Scholar
  54. Roekevisch E, Spuls PI, Kuester D et al (2014) Efficacy and safety of systemic treatments for moderate-to-severe atopic dermatitis: a systematic review. J Allergy Clin Immunol 133:429–438CrossRefGoogle Scholar
  55. Ruzicka T, Lynde CW, Jemec GB et al (2008) Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial. Br J Dermatol 158:808–817CrossRefGoogle Scholar
  56. Saeki H, Nakahara T, Tanaka A et al (2016) Clinical practice guidelines for the management of atopic dermatitis 2016. J Dermatol 43:1117–1145CrossRefGoogle Scholar
  57. Saeki H, Kabashima K, Tokura Y et al (2017) Efficacy and safety of ustekinumab in Japanese patients with severe atopic dermatitis: a randomized, double-blind, placebo-controlled, phase II study. Br J Dermatol 177:419–427CrossRefGoogle Scholar
  58. 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 30:522–523CrossRefGoogle Scholar
  59. 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 148:890–897CrossRefGoogle Scholar
  60. Sánchez-Pérez J, Daudén-Tello E, Mora AM et al (2013) Impact of atopic dermatitis on health-related quality of life in Spanish children and adults: the PSEDA study. Actas Dermosifiliogr 104:44–52CrossRefGoogle Scholar
  61. Schmitt J, Schmitt N, Meurer M (2007) Cyclosporin in the treatment of patients with atopic eczema—a systematic review and meta-analysis. J Eur Acad Dermatol Venereol 21:606–619Google Scholar
  62. Schmitt J, Schäkel K, Fölster-Holst R et al (2010) Prednisolone vs. ciclosporin for severe adult eczema. An investigator-initiated double-blind placebo-controlled multicentre trial. Br J Dermatol 162:661–668CrossRefGoogle Scholar
  63. Schram ME, Roekevisch E, Leeflang MM et al (2011) A randomized trial of methotrexate versus azathioprine for severe atopic eczema. J Allergy Clin Immunol 128:353–359CrossRefGoogle Scholar
  64. Sedivá A, Kayserová J, Vernerová E et al (2008) Anti-CD20 (rituximab) treatment for atopic eczema. J Allergy Clin Immunol 121:1515–1516CrossRefGoogle Scholar
  65. Shaw TE, Currie GP, Koudelka CW et al (2011) Eczema prevalence in the United States: data from the 2003 National Survey of Children’s Health. J Invest Dermatol 131:67–73CrossRefGoogle Scholar
  66. Sheldon E, Schwickart M, Li J et al (2016) Pharmacokinetics, pharmacodynamics, and safety of MEDI4212, an anti-IgE monoclonal antibody, in subjects with atopy: a phase I study. Adv Ther 33:225–251CrossRefGoogle Scholar
  67. Sidbury R, Davis DM, Cohen DE et al (2014a) Guidelines of care for the management of atopic dermatitis: Sect. 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol 71:327–349CrossRefGoogle Scholar
  68. Sidbury R, Tom WL, Bergman JN (2014b) Guidelines of care for the management of atopic dermatitis: Sect. 4. Prevention of disease flares and use of adjunctive therapies and approaches. J Am Acad Dermatol 71:1218–1233CrossRefGoogle Scholar
  69. Silverberg JI, Hanifin JM (2013) Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population-based study. J Allergy Clin Immunol 132:1132–1138CrossRefGoogle Scholar
  70. Simon D, Bieber T (2014) Systemic therapy for atopic dermatitis. Allergy 69:46–55CrossRefGoogle Scholar
  71. Simon D, Hösli S, Kostylina G et al (2008) Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol 121:122–128CrossRefGoogle Scholar
  72. Simpson EL, Bieber T, Eckert L et al (2016) Patient burden of moderate to severe atopic dermatitis (AD): insights from a phase 2b clinical trial of dupilumab in adults. J Am Acad Dermatol 74:491–498CrossRefGoogle Scholar
  73. Simpson EL, Akinlade B, Ardenalu M (2017) Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 376:1090–1091CrossRefGoogle Scholar
  74. Sinha A, Velangi S, Natarajan S (2004) Non-Hodgkin’s lymphoma following treatment of atopic eczema with cyclosporin A. Acta Derm Venereol 84:327–328CrossRefGoogle Scholar
  75. Sollinger HW (2005) Enteric-coated mycophenolate sodium—current and future use in transplant patients. Expert Rev Clin Immunol 1:203–211CrossRefGoogle Scholar
  76. Soumelis V, Reche PA, Kanzler H et al (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3:673–680CrossRefGoogle Scholar
  77. Spergel JM, Mizoguchi E, Oettgen H et al (1999) Roles of TH1 and TH2 cytokines in a murine model of allergic dermatitis. J Clin Invest 103:1103–1111CrossRefGoogle Scholar
  78. Van der Schaft J, van Zuilen AD, Deinum J et al (2015) Serum creatinine levels during and after long-term treatment with cyclosporine A in patients with severe atopic dermatitis. Acta Derm Venereol 95:963–967CrossRefGoogle Scholar
  79. Volf EM, Au SC, Dumont N et al (2012) 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 11:341–346Google Scholar
  80. Wang YH, Liu YJ (2009) Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses. Clin Exp Allergy 39:798–806CrossRefGoogle Scholar
  81. Waxweiler WT, Agans R, Morrell DS (2011) Systemic treatment of pediatric atopic dermatitis with azathioprine and mycophenolate mofetil. Pediatr Dermatol 28:689–694CrossRefGoogle Scholar
  82. Weatherhead SC, Wahie S, Reynolds NJ et al (2007) An open-label, dose-ranging study of methotrexate for moderate-to-severe adult atopic eczema. Br J Dermatol 156:346–351CrossRefGoogle Scholar
  83. Weidinger S, Novak N (2016) Atopic dermatitis. Lancet 387:1109–1122CrossRefGoogle Scholar
  84. Werfel T, Aberer W, Augustin M et al (2009) [Atopic dermatitis: S2 guidelines]. J Dtsch Dermatol Ges 7(Suppl 1):S1–S46Google Scholar
  85. Wilson SR, Thé L, Batia LM et al (2013) The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155:285–295CrossRefGoogle Scholar
  86. Wollenberg A, Bieber T (2009) Proactive therapy of atopic dermatitis—an emerging concept. Allergy 64:276–278CrossRefGoogle Scholar
  87. Wollenberg A, Oranje A, Deleuran M et al (2016) ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients. J Eur Acad Dermatol Venereol 30:729–747CrossRefGoogle Scholar
  88. Wollenberg A, Barbarot S, Bieber T et al (2018) Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II. J Eur Acad Dermatol Venereol 32:850–878CrossRefGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018

Authors and Affiliations

  1. 1.Division of Clinical Immunology and AllergyUniversity of São Paulo School of MedicineSão PauloBrazil

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