Current therapeutic paradigm in pediatric atopic dermatitis: Practical guidance from a national expert panel

Main Article Content

A. Chiricozzi
A. Belloni Fortina
E. Galli
G. Girolomoni
I. Neri
G. Ricci
M. Romanelli
D. Peroni

Keywords

Atopic dermatitis, Atopy, Therapy, Management, Probiotics

Abstract

Introduction and Objectives: Atopic dermatitis (AD) is the most common cutaneous inflammatory disease in both adults and children. Although emerging therapeutic approaches are being investigated for the management of pediatric AD, it still needs to be managed with conventional treatments. This consensus document is aimed at providing an update on general management and therapies of pediatric AD, defining practical recommendations for using both topical and systemic agents.


Material and Methods: A panel of experts consisting of dermatologists and pediatricians were convened in order to define statements, through a Delphi process, standardizing the management of AD in pediatric subjects in a real-world setting.
Results: A set of practical recommendations obtaining an at least 75% agreement was presented.


Conclusions: This set of practical recommendations represents a simple and fast snapshot on the pediatric use of common anti-AD therapeutics.

Abstract 508 | PDF Downloads 485

References

1. Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387:1109-22.

2. Flohr C, Mann J. New insights into the epidemiology of childhood atopic dermatitis. Allergy. 2014;69:3-16.

3. Barbarot S, Auziere S, Gadkari A, Girolomoni G, Puig L, Simpson EL, et al. Epidemiology of atopic dermatitis in adults: results from an international survey. Allergy. 2018, http://dx.doi.org/10.1111/all.13401 [Epub ahead of print].

4. Roduit C, Frei R, Depner M, Karvonen AM, Renz H, BraunFahrländer C, et al. Phenotypes of atopic dermatitis depending on the timing of onset and progression in childhood. JAMA Pediatr. 2017;171:655-62.

5. Cantarutti A, Donà D, Visentin F, Borgia E, Scamarcia A, Cantarutti L, et al. Epidemiology of frequently occurring skin diseases in Italian children from 2006 to 2012: a retrospective, population-based study. Pediatr Dermatol. 2015;32:668-78.

6. Kim JP, Chao LX, Simpson EL, Silverberg JI. Persistence of atopic dermatitis (AD): a systematic review and meta-analysis. J Am Acad Dermatol. 2016;75:681-7.

7. Abuabara K, Yu AM, Okhovat JP, Allen IE, Langan SM. The prevalence of atopic dermatitis beyond childhood: a systematic review and meta-analysis of longitudinal studies. Allergy. 2018;73:696-704.

8. Thyssen JP, Andersen YMF, Zhang H, Gislason G, Skov L, Egeberg A. Incidence of pediatric atopic dermatitis following thymectomy: a Danish register study. Allergy. 2018, http://dx.doi.org/10.1111/all.13457 [Epub ahead of print].

9. Tuckman A. The potential psychological impact of skin conditions. Dermatol Ther (Heidelb). 2017;7:53-7.

10. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh). 1980;92:44-7.

11. Pugliarello S, Cozzi A, Gisondi P, Girolomoni G. Phenotypes of atopic dermatitis. J Dtsch Dermatol Ges. 2011;9:12-20.

12. [No authors listed]. Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology 1993;186:23-31.

13. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol. 2001;10:11-8.

14. Leshem YA, Hajar T, Hanifin JM, Simpson EL. What the eczema area and severity index score tells us about the severity of atopic dermatitis: an interpretability study. Br J Dermatol. 2015;172:1353-7.

15. Coutanceau C, Stalder JF. Analysis of correlations between patient-oriented SCORAD (PO-SCORAD) and other assessment scores of atopic dermatitis severity and quality of life. Dermatology. 2014;229:248-55.

16. Schmitt J, Spuls PI, Thomas KS, Simpson E, Furue M, Deckert S, et al. The Harmonising Outcome Measures for Eczema (HOME) statement to assess clinical signs of atopic eczema in trials. J Allergy Clin Immunol. 2014;134:800-7.

17. Khan SJ, Dharmage SC, Matheson MC, Gurrin LC. Is the atopic march related to confounding by genetics and early-life environment? A systematic review of sibship and twin data. Allergy. 2018;73:17-28.

18. Tran MM, Lefebvre DL, Dharma C, Dai D, Lou WYW, Subbarao P, et al. Predicting the atopic march: results from the Canadian Healthy Infant Longitudinal Development Study. J Allergy Clin Immunol. 2018;141:601-7, e8.

19. Cipriani F, Marzatico A, Ricci G. Autoimmune diseases involving skin and intestinal mucosa are more frequent in adolescents and young adults suffering from atopic dermatitis. J Dermatol. 2017;44:1341-8.

20. Brunner PM, Leung DYM, Guttman-Yassky E. Immunologic, microbial, and epithelial interactions in atopic dermatitis. Ann Allergy Asthma Immunol. 2018;120:34-41.

21. Brunner PM, Silverberg JI, Guttman-Yassky E, Paller AS, Kabashima K, Amagai M, et al. Increasing comorbidities suggest that atopic dermatitis is a systemic disorder. J Invest Dermatol. 2017;137:18-25.

22. Brunner PM, Suárez-Farinas ˜ M, He H, Malik K, Wen HC, Gonzalez J, et al. The atopic dermatitis blood signature is characterized by increases in inflammatory and cardiovascular risk proteins. Sci Rep. 2017;7:8707.

23. Bin L, Leung DY. Genetic and epigenetic studies of atopic dermatitis. Allergy Asthma Clin Immunol. 2016;12:52.

24. Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol. 2010;105:99-106.

25. Flohr C, England K, Radulovic S, McLean WH, Campbel LE, Barker J, et al. Filaggrin loss-of-function mutations are associated with early-onset eczema, eczema severity and transepidermal water loss at 3 months of age. Br J Dermatol. 2010;163:1333-6.

26. Kelleher M, Dunn-Galvin A, Hourihane JO, Murray D, Campbell LE, McLean WH, et al. Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year. J Allergy Clin Immunol. 2015;135:930-5.

27. Clausen ML, Agner T, Lilje B, Edslev SM, Johannesen TB, Andersen PS. Association of disease severity with skin microbiome and filaggrin gene mutations in adult atopic dermatitis. JAMA Dermatol. 2018;154:293-300.

28. Lee MJ, Kang MJ, Lee SY, Lee E, Kim K, Won S, et al. Perturbations of gut microbiome genes in infants with atopic dermatitis according to feeding type. J Allergy Clin Immunol. 2018;141:1310-9.

29. Meylan P, Lang C, Mermoud S, Johannsen A, Norrenberg S, Hohl D, et al. Skin colonization by Staphylococcus aureus precedes the clinical diagnosis of atopic dermatitis in infancy. J Invest Dermatol. 2017;137:2497-504.

30. Nakatsuji T, Chen TH, Narala S, Chun KA, Two AM, Yun T, et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci Transl Med. 2017;9:378.

31. Werfel T, Heratizadeh A, Niebuhr M, Kapp A, Roesner LM, Karch A, et al. Exacerbation of atopic dermatitis on grass pollen exposure in an environmental challenge chamber. J Allergy Clin Immunol. 2015;136:96-103, e9.

32. Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol. 2017;139: S65-76.

33. Furue M, Yamamura K, Kido-Nakahara M, Nakahara T, Fukui Y. Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis. Allergy. 2018;73:29-36.

34. Paller AS, Kabashima K, Bieber T. Therapeutic pipeline for atopic dermatitis: end of the drought? J Allergy Clin Immunol. 2017;140:633-43.

35. Buraczewska I, Berne B, Lindberg M, Lodén M, Törmä H. Long-term treatment with moisturizers affects the mRNA levels of genes involved in keratinocyte differentiation and desquamation. Arch Dermatol Res. 2009;301:175-81.

36. Buraczewska I, Berne B, Lindberg M, Lodén M, Törmä H. Moisturizers change the mRNA expression of enzymes synthesizing skin barrier lipids. Arch Dermatol Res. 2009;301:587-94.

37. Czarnowicki T, Malajian D, Khattri S, Correa da Rosa J, Dutt R, Finney R, et al. Petrolatum: Barrier repair and antimicrobial responses underlying this ‘‘inert’’ moisturizer. J Allergy Clin Immunol. 2016;137:1091-102.

38. Galli E, Neri I, Ricci G, Baldo E, Barone M, Belloni Fortina A, et al. Consensus conference on clinical management of pediatric atopic dermatitis. Ital J Pediatr. 2016;42:26.

39. van Zuuren EJ, Fedorowicz Z, Arents BWM. Emollients and moisturizers for eczema: abridged Cochrane systematic review including GRADE assessments. Br J Dermatol. 2017;177:1256-71.

40. Lack G, Fox D, Northstone K, Golding J. Avon Longitudinal Study of Parents and Children Study Team. Factors associated with the development of peanut allergy in childhood. N Engl J Med. 2003;348:977-85.

41. Boussault P, Léauté-Labrèze C, Saubusse E, Maurice-Tison S, Perromat M, Roul S, et al. Oat sensitization in children with atopic dermatitis: prevalence, risks and associated factors. Allergy. 2007;62:1251-6.

42. Gueniche A, Knaudt B, Schuck E, Volz T, Bastien P, Martin R, et al. Effects of nonpathogenic gram-negative bacterium Vitreoscilla filiformis lysate on atopic dermatitis: a prospective, randomized, double-blind, placebo-controlled clinical study. Br J Dermatol. 2008;159:1357-63.

43. Aries MF, Hernandez-Pigeon H, Vaissiere C, Delga H, Caruana A, Leveque M, et al. Anti-inflammatory and immunomodulatory effects of Aquaphilus dolomiae extract on in vitro models. Clin Cosmet Investig Dermatol. 2016;9:421-34.

44. Mahe YF, Perez MJ, Tacheau C, Fanchon C, Martin R, Rousset F, et al. A new Vitreoscilla filiformis extract grown on spa water enriched medium activates endogenous cutaneous antioxidant and antimicrobial defenses through a potential Toll-like receptor 2/protein kinase C, zeta transduction pathway. Clin Cosmet Investig Dermatol. 2013;6:191-6.

45. Bianchi P, Theunis J, Casas C, Villeneuve C, Patrizi A, Phulpin C, et al. Effects of a new emollient-based treatment on skin microflora balance and barrier function in children with mild atopic dermatitis. Pediatr Dermatol. 2016;33:165-71.

46. Seite S, Bieber T. Barrier function and microbiotic dysbiosis in atopic dermatitis. Clin Cosmet Investig Dermatol. 2015;8:479-83.

47. Reuter J, Wölfle U, Weckesser S, Schempp C. Which plant for which skin disease? Part 1: Atopic dermatitis, psoriasis, acne, condyloma and herpes simplex. J Dtsch Dermatol Ges. 2010;8:788-96.

48. Seité S, Zelenkova H, Martin R. Clinical efficacy of emollients in atopic dermatitis patients - relationship with the skin microbiota modification. Clin Cosmet Investig Dermatol. 2017;10:25-33.

49. Kaplan DH, Igyártó BZ, Gaspari AA. Early immune events in the induction of allergic contact dermatitis. Nat Rev Immunol. 2012;12:114-24.

50. Fostini AC, Georgescu V, Decoster CJ, Girolomoni G. A cream based on Aquaphilus dolomiae extracts alleviates non-histaminergic pruritus in humans. Eur J Dermatol. 2017;27:317-8.

51. Wollenberg A, Oranje A, Deleuran M, Simon D, Szalai Z, Kunz B, et al. 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. 2016;30:729-47.

52. Ryan C, Shaw RE, Cockerell CJ, Hand S, Ghali FE. Novel sodium hypochlorite cleanser shows clinical response and excellent acceptability in the treatment of atopic dermatitis. Pediatr Dermatol. 2013;30:308-15.

53. Wong SM, Ng TG, Baba R. Efficacy and safety of sodium hypochlorite (bleach) baths in patients with moderate to severe atopic dermatitis in Malaysia. J Dermatol. 2013;40:874-80.

54. Hon KL, Tsang YC, Lee VW, Pong NH, Ha G, Lee ST, et al. Efficacy of sodium hypochlorite (bleach) baths to reduce Staphylococcus aureus colonization in childhood-onset moderate-to-severe eczema: a randomized, placebo-controlled cross-over trial. J Dermatolog Treat. 2016;27:156-62.

55. Ludwig G. On the topical effect of seawater tub-baths with and without addition of an oil emulsion. Z Haut Geschlechtskr. 1968;43:683-8.

56. R. Intermittent dosing of fluticasone propionate cream for reducing the risk of relapse in atopic dermatitis patients. Br J Dermatol. 2002;147:528-37.

57. Berth-Jones J, Damstra RJ, Golsch S, Livden JK, Van Hooteghem O, Allegra F, et al. Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double-blind, parallel-group study. BMJ. 2003;326:1367.

58. Walsh P, Aeling JL, Huff L, Weston WL. Hypothalamus-pituitary adrenal axis suppression by superpotent topical steroids. J Am Acad Dermatol. 1993;29:501-3.

59. Rafanelli A, Rafanelli S, Stanganelli I, Marchesi E. Mometasone furoate in the treatment of atopic dermatitis in children. J Eur Acad Dermatol Venereol. 1993;2:225-30.

60. Barnes L, Kaya G, Rollason V. Topical corticosteroid-induced skin atrophy: a comprehensive review. Drug Saf. 2015;38:493-509.

61. Aubert-Wastiaux H, Moret L, Le Rhun A, Fontenoy AM, Nguyen JM, Leux C, et al. Topical corticosteroid phobia in atopic dermatitis: a study of its nature, origins and frequency. Br J Dermatol. 2011;165:808-14.

62. Li AW, Yin ES, Antaya RJ. Topical corticosteroid phobia in atopic dermatitis: a systematic review. JAMA Dermatol. 2017;153:1036-42.

63. Müller SM, Tomaschett D, Euler S, Vogt DR, Herzog L, Itin P. Topical corticosteroid concerns in dermatological outpatients: a cross-sectional and interventional study. Dermatology. 2016;232:444-52.

64. Belloni Fortina A, Neri L. Topical steroids and corticophobia. G Ital Dermatol Venereol. 2013;148:651-4.

65. Hajar T, Leshem YA, Hanifin JM, Nedorost ST, Lio PA, Paller AS, et al. A systematic review of topical corticosteroid withdrawal (‘‘steroid addiction’’) in patients with atopic dermatitis and other dermatoses. J Am Acad Dermatol. 2015;72:541-9, e2.

66. Luger T, Boguniewicz M, Carr W, Cork M, Deleuran M, Eichenfield L, et al. Pimecrolimus in atopic dermatitis: consensus on safety and the need to allow use in infants. Pediatr Allergy Immunol. 2015;26:306-15.

67. Leung DY, Hanifin JM, Pariser DM, Barber KA, Langley RG, Schlievert PM, et al. Effects of pimecrolimus cream 1% in the treatment of patients with atopic dermatitis who demonstrate a clinical insensitivity to topical corticosteroids: a randomized, multicenter vehicle-controlled trial. Br J Dermatol. 2009;161:435-43.

68. Baldo A, Cafiero M, Di Caterino P, Di Costanzo L. Tacrolimus ointment in the management of atopic dermatitis. Clin Cosmet Investig Dermatol. 2009;2:1-7.

69. Cury Martins J, Martins C, Aoki V, Gois AF, Ishii HA, da Silva EM. Topical tacrolimus for atopic dermatitis. Cochrane Database Syst Rev. 2015 Jul 1;7. CD009864.

70. Huang X, Xu B. Efficacy and safety of tacrolimus versus pimecrolimus for the treatment of atopic dermatitis in children: a network meta-analysis. Dermatology. 2015;231:41-9.

71. Ruzicka T, Bieber T, Schöpf E, Rubins A, Dobozy A, Bos J, et al. A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med. 1997;337:816-21.

72. Van Leent EJ, Graber M, Thurston M, Wagenaar A, Spuls PI, Bos JD. Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis. Arch Dermatol. 1998;134:805-9.

73. Reitamo S, Wollenberg A, Schopf E, Perrot JL, Marks R, Ruzicka T, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. Arch Dermatol. 2000;136:999-1006.

74. Meurer M, Folster-Holst R, Wozel G, Weidinger G, Junger M, Brautigam M, et al. Pimecrolimus cream in the long-term management of atopic dermatitis in adults: a six-month study. Dermatology. 2002;205:271-7.

75. Reitamo S, Rustin M, Harper J, Kalimo K, Rubins A, Cambazard F, et al. A 4-year follow-up study of atopic dermatitis therapy with 0.1% tacrolimus ointment in children and adult patients. Br J Dermatol. 2008;159:942-51.

76. Sigurgeirsson B, Boznanski A, Todd G, Vertruyen A, Schuttelaar ML, Zhu X, et al. Safety and efficacy of pimecrolimus in atopic dermatitis: a 5-year randomized trial. Pediatrics. 2015;135:597-606.

77. Reitamo S, Rustin M, Ruzicka T, Cambazard F, Kalimo K, Friedmann PS, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with atopic dermatitis. J Allergy Clin Immunol. 2002;109:547-55.

78. Cury Martins J, Martins C, Aoki V, Gois AF, Ishii HA, da Silva EM. Topical tacrolimus for atopic dermatitis. Cochrane Database Syst Rev. 2015;7:CD009864.

79. Chen SL, Yan J, Wang FS. Two topical calcineurin inhibitors for the treatment of atopic dermatitis in pediatric patients: a meta-analysis of randomized clinical trials. J Dermatolog Treat. 2010;21:144-56.

80. Jens-Michael Jensen, MD, Stephan Pfeiffer, Dipl Ing, Magdalena Witt, MD, Matthias Bräutigam, MD, Claudia Neumann, BTA, Michael Weichenthal, MD, Thomas Schwarz, MD, Regina Fölster-Holst, MD, Ehrhardt Proksch, MD. Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis. 2009 124 (3) Supplement 2, pp. R19-R28.

81. Lee SE, Choi Y, Kim SE, Noh EB, Kim SC. Differential effects of topical corticosteroid and calcineurin inhibitor on the epidermal tight junction. Exp Dermatol. 2013;22:59-61.

82. Billich A, Aschauer H, Aszódi A, Stuetz A. Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus. Int J Pharm. 2004;269:29-35.

83. Reitamo S, Rissanen J, Remitz A, Granlund H, Erkko P, Elg P, et al. Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized trial. J Invest Dermatol. 1998;111:396-8.

84. Queille-Roussel C, Paul C, Duteil L, Lefebvre MC, Rapatz G, Zagula M, et al. The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study. Br J Dermatol. 2001;144:507-13.

85. Legendre L, Barnetche T, Mazereeuw-Hautier J, Meyer N, Murrell D, Paul C. Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: a systematic review and meta-analysis. J Am Acad Dermatol. 2015;72:992-1002.

86. Ring J, Barker J, Behrendt H, Braathen L, Darsow U, Dubertret L, et al. Review of the potential photo-cocarcinogenicity of topical calcineurin inhibitors: position statement of the European Dermatology Forum. J Eur Acad Dermatol Venereol. 2005;19:663-71.

87. Margolis DJ, Hoffstad O, Bilker W. Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults. Dermatology. 2007;214:289-95.

88. Thaci D, Salgo R. Malignancy concerns of topical calcineurin inhibitors for atopic dermatitis: facts and controversies. Clin Dermatol. 2010;28:52-6.

89. Margolis DJ, Abuabara K, Hoffstad OJ, Wan J, Raimondo D, Bilker WB. Association between malignancy and topical use of
pimecrolimus. JAMA Dermatol. 2015;151:594-9.

90. Deleuran M, Vestergaard C, Vølund A, Thestrup-Pedersen K. Topical calcineurin inhibitors, topical glucocorticoids and cancer in children: a nationwide study. Acta Derm Venereol. 2016;96:834-5.

91. Belloni Fortina A, Neri I. Antibiotic therapy in the management of atopic dermatitis. G Ital Dermatol Venereol. 2015;150:321-5.

92. Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS. Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics. 2009;123:e808-14.

93. Paller AS, Tom WL, Lebwohl MG, Blumenthal RL, Boguniewicz M, Call RS, et al. 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;75:494-503.

94. Stein Gold LF, Spelman L, Spellman MC, Hughes MH, Zane LT. A Phase 2, randomized, controlled, dose-ranging study evaluating crisaborole topical ointment, 0.5% and 2% in adolescents with mild to moderate atopic dermatitis. J Drugs Dermatol. 2015;14:1394-9.

95. Hanifin JM, Ellis CN, Frieden IJ, Fölster-Holst R, Stein Gold LF, Secci A, et al. OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): a phase-II randomized, double-blind, placebo-controlled study. J Am Acad Dermatol. 2016;75:297-305.

96. Ohba F, Matsuki S, Imayama S, Matsuguma K, Hojo S, Nomoto M, et al. Efficacy of a novel phosphodiesterase inhibitor, E6005, in patients with atopic dermatitis: an investigator-blinded, vehicle-controlled study. J Dermatolog Treat. 2016;27:467-72.

97. Bissonnette R, Papp KA, Poulin Y, Gooderham M, Raman M, Mallbris L, et al. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br J Dermatol. 2016;175:902-11.

98. 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;178:424-32.

99. Darné S, Leech SN, Taylor AE. Narrowband ultraviolet B phototherapy in children with moderate-to-severe eczema: a comparative cohort study. Br J Dermatol. 2014;170:150-6.

100. Tintle S, Shemer A, Suárez-Farinas ˜ M, Fujita H, Gilleaudeau P, Sullivan-Whalen M, et al. Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response. J Allergy Clin Immunol. 2011;128:583-93, e1-4.

101. Jury CS, McHenry P, Burden AD, Lever R, Bilsland D. Narrowband ultraviolet B (UVB) phototherapy in children. Clin Exp Dermatol. 2006;31:196-9.

102. Clayton TH, Clark SM, Turner D, Goulden V. The treatment of severe atopic dermatitis in childhood with narrowband ultraviolet B phototherapy. Clin Exp Dermatol. 2007;32:28-33.

103. Chong JH, Koh MJA. Non-topical management of recalcitrant paediatric atopic dermatitis. Arch Dis Child. 2017;102:681-6.

104. Harper JI, Ahmed I, Barclay G, Lacour M, Hoeger P, Cork MJ, et al. Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy. Br J Dermatol. 2000;142:52-8.

105. Lee SS, Tan AW, Giam YC. Cyclosporin in the treatment of severe atopic dermatitis: a retrospective study. Ann Acad Med Singapore. 2004;33:311-3.

106. Berth-Jones J, Finlay AY, Zaki I, Tan B, Goodyear H, Lewis-Jones S, et al. Cyclosporine in severe childhood atopic dermatitis: a multicenter study. J Am Acad Dermatol. 1996;34:1016-21.

107. Harper JI, Berth-Jones J, Camp RD, Dillon MJ, Finlay AY, Holden CA, et al. Cyclosporin for atopic dermatitis in children. Dermatology. 2001;203:3-6.

108. Schmitt J, Schmitt N, Meurer M. Cyclosporin in the treatment of patients with atopic eczema-a systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2007;21:606-19.

109. Hernández-Martín A, Noguera-Morel L, Bernardino-Cuesta B, Torrelo A, Pérez-Martin MA, Aparicio-López C, et al. Cyclosporine A for severe atopic dermatitis in children efficacy and safety in a retrospective study of 63 patients. J Eur Acad Dermatol Venereol. 2017;31:837-42.

110. Garrido Colmenero C, Blasco Morente G, Tercedor Sánchez J. Oral cyclosporine weekend therapy: a new maintenance therapeutic option in patients with severe atopic dermatitis. Pediatr Dermatol. 2015;32:551-2.

111. El-Khalawany MA, Hassan H, Shaaban D, Ghonaim N, Eassa B. Methotrexate versus cyclosporine in the treatment of severe atopic dermatitis in children: a multicenter experience from Egypt. Eur J Pediatr. 2013;172:351-6.

112. Proudfoot LE, Powell AM, Ayis S, Barbarot S, Baselga Torres E, Deleuran M, et al. The European TREatment of severe Atopic eczema in children Taskforce (TREAT) survey. Br J Dermatol. 2013;169:901-9.

113. Totri CR, Eichenfield LF, Logan K, Proudfoot L, Schmitt J, LaraCorrales I, et al. Prescribing practices for systemic agents in the treatment of severe pediatric atopic dermatitis in the US and Canada: The PeDRA TREAT survey. J Am Acad Dermatol. 2017;76:281-5.

114. Drucker AM, Eyerich K, de Bruin-Weller MS, Thyssen JP, Spuls PI, Irvine AD, et al. Use of systemic corticosteroids for atopic
dermatitis: International Eczema Council consensus statement. Br J Dermatol. 2018;178:768-75.

115. Rahman SI, Siegfried E, Flanagan KH, Armbrecht ES. The methotrexate polyglutamate assay supports the efficacy of methotrexate for severe inflammatory skin disease in children. J Am Acad Dermatol. 2014;70:252-6.

116. Sidbury R, Davis DM, Cohen DE, Cordoro KM, Berger TG, Bergman JN, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71:327-49.

117. Deo M, Yung A, Hill S, Rademaker M. Methotrexate for treatment of atopic dermatitis in children and adolescents. Int J Dermatol. 2014;53:1037-41.

118. Gisondi P, Barba E, Girolomoni G. Non-alcoholic fatty liver disease fibrosis score in patients with psoriasis. J Eur Acad Dermatol Venereol. 2016;30:282-7.

119. Murphy LA, Atherton DJ. Azathioprine as a treatment for severe atopic eczema in children with a partial thiopurine methyl transferase (TPMT) deficiency. Pediatr Dermatol. 2003;20:531-4.

120. Caufield M, Tom WL. Oral azathioprine for recalcitrant pediatric atopic dermatitis: clinical response and thiopurine monitoring. J Am Acad Dermatol. 2013;68:29-35.

121. Murphy LA, Atherton D. A retrospective evaluation of azathioprine in severe childhood atopic eczema, using thiopurine methyltransferase levels to exclude patients at high risk of myelosuppression. Br J Dermatol. 2002;147:308-15.

122. Schram ME, Roekevisch E, Leeflang MM, Bos JD, Schmitt J, Spuls PI. A randomized trial of methotrexate versus azathioprine for severe atopic eczema. J Allergy Clin Immunol. 2011;128:353-9.

123. Hon KL, Ching GK, Leung TF, Chow CM, Lee KK, Ng PC. Efficacy and tolerability at 3 and 6 months following use of azathioprine for recalcitrant atopic dermatitis in children and young adults. J Dermatolog Treat. 2009;20:141-5.

124. Waxweiler WT, Agans R, Morrell DS. Systemic treatment of pediatric atopic dermatitis with azathioprine and mycophenolate mofetil. Pediatr Dermatol. 2011;28:689-94.

125. Heller M, Shin HT, Orlow SJ, Schaffer JV. Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol. 2007;157:127-32.

126. Haeck IM, Knol MJ, Ten Berge O, van Velsen SG, de Bruin-Weller MS, Bruijnzeel-Koomen CA. 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. 2011;64: 1074-84.

127. He A, Feldman SR, Fleischer AB Jr. An assessment of the use of antihistamines in the management of atopic dermatitis. J Am Acad Dermatol. 2018 Jan 6, http://dx.doi.org/10.1016/j.jaad.2017.12.077, pii: S0190-9622(18)30020-3, [Epub ahead of print].

128. La Rosa M, Ranno C, Musarra I, Guglielmo F, Corrias A, Bellanti JA. Double-blind study of cetirizine in atopic eczema in children. Ann Allergy. 1994;73:117-22.

129. Munday J, Bloomfield R, Goldman M, Robey H, Kitowska GJ, Gwiezdziski Z, et al. Chlorpheniramine is no more effective than placebo in relieving the symptoms of childhood atopic dermatitis with a nocturnal itching and scratching component. Dermatology. 2002;205:40-5.

130. Isolauri E, Arvola T, Sutas Y, Moilanen E, Salminen S. Probiotics in the management of atopic eczema. Clin Exp Allergy. 2000;30:1604-10.

131. Fölster-Holst R, Müller F, Schnopp N, Abeck D, Kreiselmaier I, Lenz T, et al. Prospective, randomized controlled trial on Lactobacillus rhamnosus in infants with moderate to severe atopic dermatitis. Br J Dermatol. 2006;155:1256-61.

132. Rosenfeldt V, Benfeldt E, Nielsen SD, Michaelsen KF, Jeppesen DL, Valerius NH, et al. Effect of probiotic Lactobacillus strains in children with atopic dermatitis. J Allergy Clin Immunol. 2003;111:389-95.

133. Gruber C. Probiotics and prebiotics in allergy prevention and treatment: future prospects. Expert Rev Clin Immunol. 2012;8:17-9.

134. Cuello-Garcia CA, Brozek JL, Fiocchi A, Pawankar R, YepesNunez JJ, Terracciano L, et al. Probiotics for the prevention of allergy: a systematic review and meta-analysis of randomized controlled trials. J Allergy Clin Immunol. 2015;136: 952-61.

135. Navarro-López V, Ramírez-Boscá A, Ramón-Vidal D, RuzafaCostas B, Genovés-Martínez S, Chenoll-Cuadros E, et al. Effect of oral administration of a mixture of probiotic strains on SCORAD index and use of topical steroids in young patients with moderate atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2018;154:37-43.