Management of Moderate to Severe Atopic Dermatitis in Adults
Abstract
Atopic dermatitis is a chronic inflammatory skin condition characterized by relapsing pruritic, scaly, erythematous papules and plaques frequently associated with superinfection. It is one of the most common skin diseases affecting 10%-20% of children and 1%-3% of adults, and it is a significant cause of morbidity, quality-of-life impairment and health-care costs. Although many patients can be treated satisfactorily with topical medications and phototherapy, a smaller subset requires more aggressive systemic therapies to control skin inflammation, reduce symptoms, prevent flares, and improve quality of life. Besides, severe atopic dermatitis has a profound effect on many aspects of the patient's life, and a combination of topical and systemic treatment is often required to control the disease, after ensuring all treatment failure causes are adequately excluded. Despite the available classical options, effective and safe treatments for patients with moderate-to-severe atopic dermatitis are limited due to toxicity and side effects. This article reviews the use and the scientific evidence of these medications in the treatment of adult moderate to severe atopic dermatitis, as well as several promising targeted therapies currently in development.
Downloads
References
Williams HC. Epidemiology of atopic dermatitis. Clin
Exp Dermatol. 2000;25:522-9. doi:10.1046/j.1365-
2000.00698.x.
Hanifin JM, Reed ML. A population-based survey of
eczema prevalence in the United States. Dermat Contact
Atopic Occup Drug. 2007;18:82-91.
Carroll CL, Balkrishnan R, Feldman SR, Fleischer
ABJ, Manuel JC. The burden of atopic
dermatitis: impact on the patient, family, and society. Pediatr
Dermatol. 2005;22:192-9. doi:10.1111/j.1525-
2005.22303.x.
Kemp AS. Cost of illness of atopic dermatitis in children:
a societal perspective. Pharmacoeconomics.
;21:105-113.
Lapidus CS, Kerr PE. Social impact of atopic dermatitis.
Med Health R I. 2001;84:294-5.
Chamlin SL, Frieden IJ, Williams ML, Chren M-M.
Effects of atopic dermatitis on young American children
and their families. Pediatrics. 2004;114:607-11.
doi:10.1542/peds.2004-0374.
Fivenson D, Arnold RJG, Kaniecki DJ, Cohen JL, Frech F,
Finlay AY. The effect of atopic dermatitis on total burden
of illness and quality of life on adults and children in a
large managed care organization. J Manag Care Pharm.
;8:333-42. doi:10.18553/jmcp.2002.8.5.333.
Finlay AY, Khan GK. Dermatology Life Quality Index
(DLQI)-a simple practical measure for routine clinical
use. Clin Exp Dermatol. 1994;19:210-6.
Kiebert G, Sorensen S V, Revicki D, et al. Atopic dermatitis
is associated with a decrement in health-related quality
of life. Int J Dermatol. 2002;41:151-8.
Weidinger S, Novak N. Atopic dermatitis. Lancet.
;387:1109-122. doi:10.1016/S0140-
-6736(15)00149-X.
Kunz B, Oranje AP, Labreze L, Stalder JF, Ring J, Taieb
A. Clinical validation and guidelines for the SCORAD
index: consensus report of the European Task Force on
Atopic Dermatitis. Dermatology. 1997;195:10-9.
Schmitt J, Langan S, Deckert S, et al. Assessment of
clinical signs of atopic dermatitis: a systematic review
and recommendation. J Allergy Clin Immunol.
;132:1337-47. doi:10.1016/j.jaci.2013.07.008.
Chopra R, Silverberg JI. Assessing the severity of atopic
dermatitis in clinical trials and practice. Clin
Dermatol. 2018;36:606-15. doi:10.1016/j.clindermatol.
05.012.
Arkwright PD, Motala C, Subramanian H, Spergel J,
Schneider LC, Wollenberg A. Management of difficult-
-to-treat atopic dermatitis. J Allergy Clin Immunol Pract.
;1:142-51. doi:10.1016/j.jaip.2012.09.002.
Ring J, Alomar A, Bieber T, et al. Guidelines for treatment
of atopic eczema (atopic dermatitis) Part I. J
Eur Acad Dermatology Venereol. 2012;26:1045-60.
doi:10.1111/j.1468-3083.2012.04635.x.
Ring J, Alomar A, Bieber T, et al. Guidelines for treatment
of atopic eczema (atopic dermatitis) Part II. J
Eur Acad Dermatology Venereol. 2012;26:1176-93.
doi:10.1111/j.1468-3083.2012.04636.x.
Baumer JH. Atopic eczema in children, NICE. Arch
Dis Child Educ Pract Ed. 2008;93:93-7. doi:10.1136/
adc.2008.139626.
Silverberg NB. A practical overview of pediatric atopic
dermatitis, part 2: triggers and grading. Cutis.
;97:326-9.
Kiken DA, Silverberg NB. Atopic dermatitis in children,
part 1: epidemiology, clinical features, and complications.
Cutis. 2006;78:241-7.
Breuer K, HAussler S, Kapp A, Werfel T. Staphylococcus
aureus: colonizing features and influence of an antibacterial
treatment in adults with atopic dermatitis. Br J
Dermatol. 2002;147:55-61.
Bjerre RD, Bandier J, Skov L, Engstrand L, Johansen JD.
The role of the skin microbiome in atopic dermatitis: a
systematic review. Br J Dermatol. 2017;177:1272-8.
doi:10.1111/bjd.15390.
Adachi J, Endo K, Fukuzumi T, Tanigawa N, Aoki T. Increasing
incidence of streptococcal impetigo in atopic
dermatitis. J Dermatol Sci. 1998;17:45-53.
Wollenberg A, Zoch C, Wetzel S, Plewig G, Przybilla
B. Predisposing factors and clinical features of eczema
herpeticum: a retrospective analysis of 100 cases. J Am
Acad Dermatol. 2003;49:198-205.
Roul S, Ducombs G, Taieb A. Usefulness of the European
standard series for patch testing in children. A 3-year
single-centre study of 337 patients. Contact Dermatitis.
;40:232-5.
Brasch J, Geier J. Patch test results in schoolchildren.
Results from the Information Network of Departments
of Dermatology (IVDK) and the German Contact Dermatitis
Research Group (DKG). Contact Dermatitis.
;37:286-93.
Tada J, Toi Y, Arata J. Atopic dermatitis with severe facial
lesions exacerbated by contact dermatitis from topical
medicaments. Contact Dermatitis. 1994;31:261-3.
Giordano-Labadie F, Rance F, Pellegrin F, Bazex J, Dutau
G, Schwarze HP. Frequency of contact allergy in children
with atopic dermatitis: results of a prospective study of
cases. Contact Dermatitis. 1999;40:192-5.
Mailhol C, Lauwers-Cances V, Rancé F, Paul C, Giordano-
Labadie F. Prevalence and risk factors for allergic
contact dermatitis to topical treatment in atopic dermatitis:
a study in 641 children. Allergy. 2009;64:801-6.
doi:10.1111/j.1398-9995.2008.01890.x.
Eichenfield LF, Hanifin JM, Beck LA, et al. Atopic dermatitis
and asthma: parallels in the evolution of treatment.
Pediatrics. 2003;111:608-16.
Naldi L, Parazzini F, Gallus S. Prevalence of atopic
dermatitis in Italian schoolchildren: factors affecting
its variation. Acta Derm Venereol. 2009;89):122-5.
doi:10.2340/00015555-0591.
Schafer T. The impact of allergy on atopic eczema
from data from epidemiological studies. Curr Opin
Allergy Clin Immunol. 2008;8:418-22. doi:10.1097/
ACI.0b013e32830e71a7.
Flohr C, Johansson SGO, Wahlgren C-F, Williams H.
How atopic is atopic dermatitis? J Allergy Clin Immunol.
;114:150-8. doi:10.1016/j.jaci.2004.04.027.
Breuer K, Heratizadeh A, Wulf A, et al. Late eczematous
reactions to food in children with atopic dermatitis. Clin
Exp Allergy. 2004;34:817-24. doi:10.1111/j.1365-
2004.1953.x.
Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the
diagnosis and management of food allergy in the United
States: report of the NIAID-sponsored expert panel.
J Allergy Clin Immunol. 2010;126(6 Suppl):S1-58.
doi:10.1016/j.jaci.2010.10.007.
Bath-Hextall F, Delamere FM, Williams HC. Dietary exclusions
for established atopic eczema. Cochrane Database
Syst Rev. 2008;1:CD005203. doi:10.1002/14651858.
CD005203.pub2.
Tupker RA, De Monchy JG, Coenraads PJ, Homan
A, van der Meer JB. Induction of atopic dermatitis by
inhalation of house dust mite. J Allergy Clin Immunol.
;97:1064-70.
Nankervis H, Pynn E V, Boyle RJ, Rushton L, Williams
HC, Hewson DM, et al. House dust mite reduction
and avoidance measures for treating eczema.
Cochrane Database Syst Rev. 2015;1:CD008426.
doi:10.1002/14651858.CD008426.pub2.
Krejci-Manwaring J, Tusa MG, Carroll C, Camacho
F, Kaur M, Carr D, et al. Stealth monitoring of adherence
to topical medication: Adherence is very poor in
children with atopic dermatitis. J Am Acad Dermatol.
;56:211-6. doi:10.1016/j.jaad.2006.05.073.
Ohya Y, Williams H, Steptoe A, Saito H, Iikura Y, Anderson
R, et al. Psychosocial factors and adherence to
treatment advice in childhood atopic dermatitis. J Invest
Dermatol. 2001;117):852-7. doi:10.1046/j.0022-
x.2001.01475.x.
Misery L, Ortonne J-P, Cambazard F, Guillet G, Thomas
L, Lorette G, et al. PPAD: a tool for presumption of atopic
dermatitis. J Dermatol. 2012;39:151-5. doi:10.1111/
j.1346-8138.2011.01381.x.
Hanifin J. Diagnostic features of atopic dermatitis. Acta
Dermatovener. 1980;92:44-7.
Williams HC, Burney PG, Hay RJ, Archer CB, Shipley MJ,
Hunter JJ, et al. The U.K. Working Party’s Diagnostic Criteria
for Atopic Dermatitis. I. Derivation of a minimum
set of discriminators for atopic dermatitis. Br J Dermatol.
;131:383-96.
Eichenfield LF, Hanifin JM, Luger TA, Stevens SR, Pride
HB. Consensus conference on pediatric atopic dermatitis.
J Am Acad Dermatol. 2003;49:1088-95. doi:10.1067/
S0190.
Meduri NB, Vandergriff T, Rasmussen H, Jacobe
H. Phototherapy in the management of
atopic dermatitis: a systematic review. Photodermatol Photoimmunol
Photomed. 2007;23:106-12. doi:10.1111/
j.1600-0781.2007.00291.x.
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. doi:10.1016/j.
jaad.2014.03.030.
Reynolds NJ, Franklin V, Gray JC, Diffey BL, Farr PM.
Narrow-band ultraviolet B and broad-band ultraviolet A
phototherapy in adult atopic eczema: a randomised controlled
trial. Lancet. 2001;357:2012-6. doi:10.1016/
S0140-6736(00)05114-X.
Fernandez-Guarino M, Aboin-Gonzalez S, Barchino
L, Velazquez D, Arsuaga C, Lazaro P. Treatment of
moderate and severe adult chronic atopic dermatitis with
narrow-band UVB and the combination of narrow-band
UVB/UVA phototherapy. Dermatol Ther. 2016;29:19-
doi:10.1111/dth.12273.
Hjerppe M, Hasan T, Saksala I, Reunala T. Narrow-band
UVB treatment in atopic dermatitis. Acta Derm Venereol.
;81:439-40.
Dayal S, Pathak K, Sahu P, Jain VK. Narrowband UV-B
phototherapy in childhood atopic dermatitis: efficacy
and safety. An Bras Dermatol. 2017;92:801-6.
doi:10.1590/abd1806-4841.20175958.
Majoie IML, Oldhoff JM, van Weelden H, Laaper-Ertmann
M, Bousema MT, Sigurdsson V, et al. Narrowband
ultraviolet B and medium-dose ultraviolet A1 are
equally effective in the treatment of moderate to severe
atopic dermatitis. J Am Acad Dermatol. 2009;60:77-84.
doi:10.1016/j.jaad.2008.08.048.
Gambichler T, Othlinghaus N, Tomi NS, Holland-
-Letz T, Boms S, Skrygan M,et al. Medium-dose ultraviolet
(UV) A1 vs. narrowband UVB phototherapy
in atopic eczema: a randomized crossover study. Br J
Dermatol. 2009;160:652-8. doi:10.1111/j.1365-
2008.08984.x.
Garritsen FM, Brouwer MW, Limpens J, Spuls PI.
Photo(chemo)therapy in the management of atopic dermatitis:
an updated systematic review with implications
for practice and research. Br J Dermatol. 2014;170:501-
doi:10.1111/bjd.12645.
Tzaneva S, Kittler H, Holzer G, Reljic D, Weber M, Hönigsmann
H, et al. 5-Methoxypsoralen plus ultraviolet (UV)
A is superior to medium-dose UVA1 in the treatment of
severe atopic dermatitis: a randomized crossover trial.
Br J Dermatol. 2010;162:655-60. doi:10.1111/j.1365-
2009.09514.x.
Der-Petrossian M, Seeber A, Honigsmann H, Tanew A.
Half-side comparison study on the efficacy of 8-methoxypsoralen
bath-PUVA versus narrow-band ultraviolet B
phototherapy in patients with severe chronic atopic dermatitis.
Br J Dermatol. 2000;142:39-43.
Stern RS. The risk of melanoma in association with
long-term exposure to PUVA. J Am Acad Dermatol.
;44:755-61. doi:10.1067/mjd.2001.114576.
Nijsten TEC, Stern RS. The increased risk of skin cancer
is persistent after discontinuation of psoralen+ultraviolet
A: a cohort study. J Invest Dermatol. 2003;121:252-8.
doi:10.1046/j.1523-1747.2003.12350.x.
Patel R V, Clark LN, Lebwohl M, Weinberg JM. Treatments
for psoriasis and the risk of malignancy. J Am
Acad Dermatol. 2009;60:1001-17. doi:10.1016/j.
jaad.2008.12.031.
Gambichler T. Management of atopic dermatitis using
photo(chemo)therapy. Arch Dermatol Res. 2009;301:197-
doi:10.1007/s00403-008-0923-5.
Eichenfield LF, Tom WL, Berger TG, Krol A, Paller AS,
Schwarzenberger K, et al. Guidelines of care for the management
of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies.
J Am Acad Dermatol. 2014;71:116-32. doi:10.1016/j.
jaad.2014.03.023.
Devillers AC, Oranje AP. Wet-wrap treatment in children
with atopic dermatitis: a practical guideline.
Pediatr Dermatol. 2012;29:24-7. doi:10.1111/j.1525-
2011.01691.x.
Oranje AP, Devillers ACA, Kunz B, Jones SL, DeRaeve
L, Van Gysel D, et al. Treatment of patients with
atopic dermatitis using wet-wrap dressings with diluted
steroids and/or emollients. An expert panel’s
opinion and review of the literature. J Eur Acad Dermatol
Venereol. 2006;20:1277-6. doi:10.1111/j.1468-
2006.01790.x.
Devillers ACA, de Waard-van der Spek FB, Mulder
PG, Oranje AP. Treatment of refractory atopic dermatitis
using “wet-wrap” dressings and diluted corticosteroids:
results of standardized treatment in both
children and adults. Dermatology. 2002;204:50-5.
doi:10.1159/000051810.
Foelster-Holst R, Nagel F, Zoellner P, Spaeth D. Efficacy
of crisis intervention treatment with topical corticosteroid
prednicarbat with and without partial wet-wrap dressing
in atopic dermatitis. Dermatology. 2006;212:66-9.
doi:10.1159/000089025.
Xu W, Li Y, Chen Z, Liu T, Wang S, Li L. Wet-wrap therapy
with halometasone cream for severe adult atopic dermatitis.
Postgrad Med. 2018 (in press). doi:10.1080/00
2018.1478108.
Gonzalez-Lopez G, Ceballos-Rodriguez RM, Gonzalez-
-Lopez JJ, Feito Rodriguez M, Herranz-Pinto P. Efficacy
and safety of wet wrap therapy for patients with atopic
dermatitis: a systematic review and meta-analysis. Br J
Dermatol. 2017;177:688-95. doi:10.1111/bjd.15165.
Amor KT, Ryan C, Menter A. The use of cyclosporine in
dermatology: part I. J Am Acad Dermatol. 2010;63:925-
doi:10.1016/j.jaad.2010.02.063.
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. doi:10.1111/
j.1468-3083.2006.02023.x.
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.
doi:10.1159/000051694.
Brazzelli V, Prestinari F, Chiesa MG, Borroni RG, Ardigo
M, Borroni G. Sequential treatment of severe atopic dermatitis
with cyclosporin A and low-dose narrow-band
UVB phototherapy. Dermatology. 2002;204:252-4.
doi:10.1159/000057893.
Zonneveld IM, De Rie MA, Beljaards RC, Van Der Rhee
HJ, Wuite J, Zeegelaar J, et al. The long-term safety and
efficacy of cyclosporin in severe refractory atopic dermatitis:
a comparison of two dosage regimens. Br J Dermatol.
;135 Suppl:15-20.
Berth-Jones J, Graham-Brown RA, Marks R, Camp RD,
English JS, Freeman K, et al. Long-term efficacy and safety
of cyclosporin in severe adult atopic dermatitis. Br J
Dermatol. 1997;136:76-81.
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.
Haeck IM, Knol MJ, Ten Berge O, van Velsen SGA, de
Bruin-Weller MS, Bruijnzeel-Koomen CAFM. 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. doi:10.1016/j.
jaad.2010.04.027.
Granlund H, Erkko P, Remitz A, Langeland T, Helsing P,
Nuutinen M,et al. Comparison of cyclosporin and UVAB
phototherapy for intermittent one-year treatment of atopic
dermatitis. Acta Derm Venereol. 2001;81:22-7.
Kim C-H, Cheong KA, Park CD, Lee A-Y. Glucosamine
improved atopic dermatitis-like skin lesions in NC/
Nga mice by inhibition of Th2 cell development. Scand
J Immunol. 2011;73:536-45. doi:10.1111/j.1365-
2011.02526.x.
Kwon H-B, Ahn B-J, Choi Y, Jin SY, Cheong KA, Lee J, et
al. Combination of glucosamine improved therapeutic
effect of low-dose cyclosporin A in patients with atopic
dermatitis: a pilot study. J Dermatol. 2013;40:207-10.
doi:10.1111/1346-8138.12003.
Jin S-Y, Lim W-S, Sung NH, Cheong KA, Lee A-Y. Combination
of glucosamine and low-dose cyclosporine for
atopic dermatitis treatment: a randomized, placebo-
-controlled, double-blind, parallel clinical trial. Dermatol
Ther. 2015;28:44-51. doi:10.1111/dth.12163.
Goujon C, Viguier M, Staumont-Salle D, Bernier C, Guillet
G, Lahfa M, et al. Methotrexate versus cyclosporine
in adults with moderate-to-severe atopic dermatitis: a
phase III randomized noninferiority trial. J allergy Clin
Immunol Pract. 2018; 6:562-9.e3. doi:10.1016/j.
jaip.2017.07.007.
Law Ping Man S, Bouzille G, Beneton N, Safa G, Dupuy
A, Droitcourt C. Drug survival and postdrug survival of
first-line immunosuppressive treatments for atopic dermatitis:
comparison between methotrexate and cyclosporine.
J Eur Acad Dermatol Venereol. 2018 (in press).
doi:10.1111/jdv.14880.
Flohr C, Irvine AD. Systemic therapies for severe atopic
dermatitis in children and adults. J Allergy Clin Immunol.
;132:774-4.e6. doi:10.1016/j.jaci.2013.03.016.
Holme SA, Duley JA, Sanderson J, Routledge PA, Anstey
AV. Erythrocyte thiopurine methyl transferase assessment
prior to azathioprine use in the UK. QJM. 2002;95:439-
Schram ME, Borgonjen RJ, Bik CMJM, van der Schroeff
JG, van Everdingen JJE, Spuls PI. Off-label use of
azathioprine in dermatology: a systematic review. Arch Dermatol. 2011;147:474-88. doi:10.1001/archdermatol.
79.
Berth-Jones J, Takwale A, Tan E, Barclay G, Agarwal S,
Ahmed I, et al. Azathioprine in severe adult atopic dermatitis:
a double-blind, placebo-controlled, crossover
trial. Br J Dermatol. 2002;147:324-30.
Meggitt SJ, Gray JC, Reynolds NJ. Azathioprine dosed by
thiopurine methyltransferase activity for moderate-to-severe
atopic eczema: a double-blind, randomised controlled
trial. Lancet. 2006;367:839-46. doi:10.1016/
S0140-6736(06)68340-2.
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. doi:10.1016/j.
jaci.2011.03.024.
Gerbens LA, Hamann SA, Brouwer MW, Roekevisch E,
Leeflang MM, Spuls PI. Methotrexate and azathioprine
in severe atopic dermatitis: a 5-year follow up study
of a randomised controlled trial. Br J Dermatol. 2018;
:1288-96. doi:10.1111/bjd.16240.
Fuggle NR, Bragoli W, Mahto A, Glover M, Martinez AE,
Kinsler VA. The adverse effect profile of oral azathioprine
in pediatric atopic dermatitis, and recommendations
for monitoring. J Am Acad Dermatol. 2015;72:108-14.
doi:10.1016/j.jaad.2014.08.048.
Orvis AK, Wesson SK, Breza TSJ, Church AA, Mitchell
CL, Watkins SW. Mycophenolate mofetil in dermatology.
J Am Acad Dermatol. 2009;60:182-3. doi:10.1016/j.
jaad.2008.08.049.
Salvadori M, Bertoni E, Budde K, Holzer H, Civati
G, Lien B, et al. Superior efficacy of enteric-coated
mycophenolate vs mycophenolate mofetil in de
novo transplant recipients: pooled analysis. Transplant
Proc. 2010;42:1325-8. doi:10.1016/j.transproceed.
03.044.
Murray ML, Cohen JB. Mycophenolate mofetil therapy
for moderate to severe atopic dermatitis. Clin
Exp Dermatol. 2007;32:23-7. doi:10.1111/j.1365-
2006.02290.x.
Garritsen FM, Roekevisch E, van der Schaft J, Deinum J,
Spuls PI, de Bruin-Weller MS. Ten years experience with
oral immunosuppressive treatment in adult patients with
atopic dermatitis in two academic centres. J Eur Acad
Dermatol Venereol. 2015;29:1905-12. doi:10.1111/
jdv.13064.
Bangert CA, Costner MI. Methotrexate in dermatology.
Dermatol Ther. 2007;20:216-28. doi:10.1111/j.1529-
2007.00135.x.
Dogra S, Mahajan R. Systemic methotrexate therapy for
psoriasis: past, present and future. Clin Exp Dermatol.
;38:573-88. doi:10.1111/ced.12062.
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.
doi:10.1007/s00431-012-1893-3.
Weatherhead SC, Wahie S, Reynolds NJ, Meggitt SJ.
An open-label, dose-ranging study of methotrexate
for moderate-to-severe adult atopic eczema. Br J
Dermatol. 2007;156:346-51. doi:10.1111/j.1365-
2006.07686.x.
Lyakhovitsky A, Barzilai A, Heyman R, Baum S, Amichai
B, Solomon M, et al. Low-dose methotrexate treatment
for moderate-to-severe atopic dermatitis in adults. J Eur
Acad Dermatol Venereol. 2010;24:43-9. doi:10.1111/
j.1468-3083.2009.03351.x.
Goujon C, Berard F, Dahel K, Guillot I, Hennino A, Nosbaum
A, et al. Methotrexate for the treatment of adult
atopic dermatitis. Eur J Dermatol. 2006;16:155-8.
Heddle RJ, Soothill JF, Bulpitt CJ, Atherton DJ. Combined
oral and nasal beclomethasone diproprionate in children
with atopic eczema: a randomised controlled trial.
Br Med J. 1984;289:651-4.
Galli E, Chini L, Moschese V, Paone F, Menichelli A, Fraioli
G, et al. Methylprednisolone bolus: a novel therapy for
severe atopic dermatitis. Acta Paediatr. 1994;83:315-7.
Schmitt J, Schakel K, Folster-Holst R, Bauer A, Oertel
R, Augustin M, et al. Prednisolone vs. ciclosporin
for severe adult eczema. An investigator-initiated
double-blind placebo-controlled multicentre trial. Br
J Dermatol. 2010;162:661-8. doi:10.1111/j.1365-
2009.09561.x.
Schadt CR, Jackson SM. Glucocorticoids. In: Bolognia
JL, Schaffer J V, Cerroni L, editors. Dermatology. 4th Ed.
Amsterdam: Elsevier; 2018:2186-99.
Akdis CA, Akdis M, Bieber T, Boguniewicz M, Eigenmann
P, Hamid Q, et al. Diagnosis and treatment of
atopic dermatitis in children and adults: European Academy
of Allergology and Clinical Immunology/American
Academy of Allergy, Asthma and Immunology/
PRACTALL Consensus Report. Allergy. 2006;61:969-87.
doi:10.1111/j.1398-9995.2006.01153.x.
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.
doi:10.1111/bjd.15928.
Hanifin JM, Chan SC. Monocyte phosphodiesterase
abnormalities and dysregulation of lymphocyte function
in atopic dermatitis. J Invest Dermatol. 1995;105(1
Suppl):84S-88S.
Samrao A, Berry TM, Goreshi R, Simpson EL. A
pilot study of an oral phosphodiesterase inhibitor
(apremilast) for atopic dermatitis in adults. Arch
Dermatol. 2012;148:890-7. doi:10.1001/archdermatol.
812.
Volf EM, Au SC, Dumont N, Scheinman P, Gottlieb AB. 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;11:341-6.
Abrouk M, Farahnik B, Zhu TH, Nakamura M, Singh
R, Lee K, et al. Apremilast treatment of atopic dermatitis
and other chronic eczematous dermatoses. J Am
Acad Dermatol. 2017;77:177-80. doi:10.1016/j.
jaad.2017.03.020.
Saporito RC, Cohen DJ. Apremilast use for moderate-to-
-severe atopic dermatitis in pediatric patients. Case Rep
Dermatol. 2016;8:179-84. doi:10.1159/000446836.
Farahnik B, Beroukhim K, Nakamura M, Abrouk M, Zhu
TH, Singh R, et al. Use of an oral phosphodiesterase-4
inhibitor (apremilast) for the treatment of chronic, severe
atopic dermatitis: a case report. Dermatol Online J.
;23.
Simon D, Hosli S, Kostylina G, Yawalkar N, Simon
HU. Anti-CD20 (rituximab) treatment improves atopic
eczema. J Allergy Clin Immunol. 2008;121:122-8.
doi:10.1016/j.jaci.2007.11.016.
Ponte P, Lopes MJ. Apparent safe use of single dose rituximab
for recalcitrant atopic dermatitis in the first
trimester of a twin pregnancy. J Am Acad Dermatol.
;63:355-6. doi:10.1016/j.jaad.2009.05.015.
Sedivá A, Kayserová J, Vernerová E, Poloucková A, Capková
S, Spísek R, et al. Anti-CD20 (rituximab) treatment
for atopic eczema. J Allergy Clin Immunol.
;121:1515-7. doi:10.1016/j.jaci.2008.03.007.
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;41:45-7.
doi:10.1111/ced.12691.
Simon D, Wittwer J, Kostylina G, Buettiker U, Simon HU,
Yawalkar N. Alefacept (lymphocyte function-associated
molecule 3/IgG fusion protein) treatment for atopic
eczema. J Allergy Clin Immunol. 2008;122:423-4.
doi:10.1016/j.jaci.2008.06.010.
Moul DK, Routhouska SB, Robinson MR, Korman NJ. Alefacept
for moderate to severe atopic dermatitis: a pilot
study in adults. J Am Acad Dermatol. 2008;58:984-9.
doi:10.1016/j.jaad.2008.02.007.
Jacobi A, Antoni C, Manger B, Schuler G, Hertl M. Infliximab
in the treatment of moderate to severe atopic
dermatitis. J Am Acad Dermatol. 2005;52:522-6.
doi:10.1016/j.jaad.2004.11.022.
Vestergaard C, Deleuran M, Kragballe K. Two cases
of atopic dermatitis-like conditions induced in psoriasis
patients treated with infliximab. J Eur Acad
Dermatol Venereol. 2007;21:1272-4. doi:10.1111/
j.1468-3083.2007.02165.x.
Ruiz-Villaverde R, Galan-Gutierrez M. Exacerbation of
atopic dermatitis in a patient treated with infliximab.
Actas Dermosifiliogr. 2012;103:743-6. doi:10.1016/j.
ad.2011.11.013.
Wright RC. Atopic dermatitis-like eruption precipitated
by infliximab. J Am Acad Dermatol. 2003;49:160-1.
doi:10.1067/mjd.2003.252.
Fernandez-Anton Martinez MC, Leis-Dosil V, Alfageme-
Roldan F, Paravisini A, Sanchez-Ramon S, Suarez
Fernandez R. Omalizumab for the treatment of atopic
dermatitis. Actas Dermosifiliogr. 2012;103:624-8.
doi:10.1016/j.ad.2011.07.013.
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;80:38-40.
Vigo PG, Girgis KR, Pfuetze BL, Critchlow ME, Fisher J,
Hussain I. Efficacy of anti-IgE therapy in patients with
atopic dermatitis. J Am Acad Dermatol. 2006;55:168-
doi:10.1016/j.jaad.2005.12.045.
Garmhausen D, Hagemann T, Bieber T, Dimitriou I,
Fimmers R, Diepgen T,et al. Characterization of different
courses of atopic dermatitis in adolescent and adult
patients. Allergy. 2013;68:498-506. doi:10.1111/
all.12112.
Kim DH, Park KY, Kim BJ, Kim MN, Mun SK. Anti-
-immunoglobulin E in the treatment of refractory atopic
dermatitis. Clin Exp Dermatol. 2013;38:496-500.
doi:10.1111/j.1365-2230.2012.04438.x.
Belloni B, Ziai M, Lim A, Lemercier B, Sbornik M, Weidinger
S, et al. Low-dose anti-IgE therapy in patients
with atopic eczema with high serum IgE levels. J Allergy
Clin Immunol. 2007;120:1223-5. doi:10.1016/j.
jaci.2007.08.060.
Hotze M, Baurecht H, Rodriguez E, Chapman-Rothe
N, Ollert M, Fölster-Holst R, et al. Increased efficacy of
omalizumab in atopic dermatitis patients with wild-type
filaggrin status and higher serum levels of phosphatidylcholines.
Allergy. 2014;69:132-5. doi:10.1111/
all.12234.
Sheinkopf LE, Rafi AW, Do LT, Katz RM, Klaustermeyer
WB. Efficacy of omalizumab in the treatment of atopic
dermatitis: a pilot study. Allergy asthma Proc.
;29:530-7. doi:10.2500/aap.2008.29.3160.
Velling P, Skowasch D, Pabst S, Jansen E, Tuleta I, Grohe
C. 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.
;16:407-10.
Heil PM, Maurer D, Klein B, Hultsch T, Stingl G. 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;8:990-8. doi:10.1111/j.1610-
2010.07497.x.
Oldhoff JM, Darsow U, Werfel T, Katzer K, Wulf A, Laifaoui
J,et al. Anti-IL-5 recombinant humanized monoclonal
antibody (mepolizumab) for the treatment of atopic dermatitis.
Allergy. 2005;60:693-6. doi:10.1111/j.1398-
2005.00791.x.
Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting
pathogenesis of atopic dermatitis and psoriasis--part I:
clinical and pathologic concepts. J Allergy Clin Immunol.
;127:1110-8. doi:10.1016/j.jaci.2011.01.053.
Boguniewicz M, Leung DY. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol
Rev. 2011;242:233-246. doi:10.1111/j.1600-
X.2011.01027.x.
Borges AS, Pinheiro R, Brasileiro A. Dermite atópica : os
novos conhecimentos sobre a fisiopatologia da doença.
Rev Soc Port Dermatol Venereol. 2017;75:117-122.
Shirley M. Dupilumab: First Global Approval. Drugs.
;77:1115-21. doi:10.1007/s40265-017-0768-3.
Beck LA, Thaci D, Hamilton JD, Graham NM, Bieber
T, Rocklin R, et al. Dupilumab treatment in adults with
moderate-to-severe atopic dermatitis. N Engl J Med.
;371:130-9. doi:10.1056/NEJMoa1314768.
Simpson EL, Gadkari A, Worm M, Soong W, Blauvelt
A, Eckert L, et al. Dupilumab therapy provides clinically
meaningful improvement in patient-reported outcomes
(PROs): A phase IIb, randomized, placebo-controlled,
clinical trial in adult patients with moderate to severe atopic
dermatitis (AD). J Am Acad Dermatol. 2016;75:506-
doi:10.1016/j.jaad.2016.04.054.
Hamilton JD, Suarez-Farinas M, Dhingra N, Cardinale I,
Li X, Kostic A, et al. Dupilumab improves the molecular
signature in skin of patients with moderate-to-severe atopic
dermatitis. J Allergy Clin Immunol. 2014;134:1293-
doi:10.1016/j.jaci.2014.10.013.
Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt
A, Cork MJ,et al. Two phase 3 trials of dupilumab
versus placebo in atopic dermatitis. N Engl J Med.
;375:2335-48. doi:10.1056/NEJMoa1610020.
Blauvelt A, de Bruin-Weller M, Gooderham M, Cather
JC, Weisman J, Pariser D, et al. Long-term management
of moderate-to-severe atopic dermatitis with dupilumab
and concomitant topical corticosteroids (LIBERTY AD
CHRONOS): a 1-year, randomised, double-blinded, placebo-
controlled, phase 3 trial. Lancet. 2017;389:2287-
doi:10.1016/S0140-6736(17)31191-1.
Sanofi, Regeneron Pharmaceuticals. Study to Assess the
Long-term Safety of Dupilumab Administered in Participants
≥6 Months to <18 Years of Age With Atopic
Dermatitis (AD). NCT02612454 @ clinicaltrials.gov.
[Accessed September 26, 2018]Available from:https://
clinicaltrials.gov/ct2/show/NCT02612454. 2018.
Sanofi, Regeneron Pharmaceuticals. Efficacy and Safety
of Dupilumab in Patients ≥12 to <18 Years of Age, With
Moderate-to-Severe Atopic Dermatitis. NCT03054428
@ clinicaltrials.gov. [Accessed September 26, 2018]
Available from:https://clinicaltrials.gov/ct2/show/record/
NCT03054428. 2018.
Sanofi, Regeneron Pharmaceuticals. Study to Investigate
the Efficacy and Safety of Dupilumab Administered
With Topical Corticosteroids (TCS) in Participants
≥6 to <12 Years With Severe Atopic Dermatitis (AD).
NCT03345914 @ clinicaltrials.gov. [Accessed September
, 2018]Available from:https://clinicaltrials.gov/
ct2/show/record/NCT03345914. 2018.
Sanofi, Regeneron Pharmaceuticals. Safety, Pharmacokinetics
and Efficacy of Dupilumab in Patients ≥6 Months
to <6 Years With Severe Atopic Dermatitis (Liberty AD
PRESCHOOL). NCT03346434 @ clinicaltrials.gov. [Accessed
September 26, 2018]Available from:https://clinicaltrials.
gov/ct2/show/NCT03346434. 2018.
Simpson E. Dupilumab Efficacy and Safety in Adolescents
with Moderate-to-Severe Atopic Dermatitis: Results
from a Multicenter, Randomized, Placebo-Controlled,
Double-Blind, Parallel-Group, Phase 3 Study. In: 27th
European Academy of Dermatology and Venereology
(EADV) Congress. Paris; 2018:Abstract D3T01.1L. Presented
September 15, 2018.
Jolles S. A review of high-dose intravenous immunoglobulin
treatment for atopic dermatitis. Clin Exp Dermatol.
;27:3-7.
Bemanian MH, Movahedi M, Farhoudi A, Gharagozlou
M, Seraj MH, Pourpak Z,et al. High doses intravenous
immunoglobulin versus oral cyclosporine in the treatment
of severe atopic dermatitis. Iran J Allergy Asthma
Immunol. 2005;4:139-43. doi:04.03/ijaai.139143.
Gorgun G, Miller KB, Foss FM. Immunologic mechanisms
of extracorporeal photochemotherapy in chronic
graft-versus-host disease. Blood. 2002;100:941-7.
doi:10.1182/blood-2002-01-0068.
Chiricozzi A, Faleri S, Lanti A, Adorno G, Lorè B, Chimenti
S, et al. Apheresis in the treatment of recalcitrant
atopic dermatitis: case series and review of the literature.
Eur J Dermatol. 2014;24:545-50. doi:10.1684/
ejd.2014.2383.
Radenhausen M, Michelsen S, Plewig G, Bechara
FG, Altmeyer P, Hoffmann K. Bicentre experience in
the treatment of severe generalised atopic dermatitis
with extracorporeal photochemotherapy. J Dermatol.
;31:961-70.
Koppelhus U, Poulsen J, Grunnet N, Deleuran MS, Obitz
E. Cyclosporine and extracorporeal photopheresis are
equipotent in treating severe atopic dermatitis: a randomized
cross-over study comparing two efficient treatment
modalities. Front Med. 2014;1:33. doi:10.3389/
fmed.2014.00033.
Akdis CA. Therapies for allergic inflammation: refining
strategies to induce tolerance. Nat Med. 2012;18:736-
doi:10.1038/nm.2754.
Compalati E, Rogkakou A, Passalacqua G, Canonica
GW. Evidences of efficacy of allergen immunotherapy
in atopic dermatitis: an updated review. Curr Opin Allergy
Clin Immunol. 2012;12:427-33. doi:10.1097/
ACI.0b013e328354e540.
Darsow U, Forer I, Ring J. Allergen-specific immunotherapy
in atopic eczema. Curr Allergy Asthma Rep.
;11:277-83. doi:10.1007/s11882-011-0194-7.
Tam H, Calderon MA, Manikam L, Nankervis H, García
Núñez I, Williams HC, et al. Specific allergen immunotherapy
for the treatment of atopic eczema.
Cochrane Database Syst Rev. 2016;2:CD008774.
doi:10.1002/14651858.CD008774.pub2.
Wegner J, Weinmann-Menke J, von Stebut E. Immunoadsorption for treatment of severe atopic dermatitis.
Atheroscler Suppl. 2017; 30:264-70. doi:10.1016/j.
atherosclerosissup.2017.05.043.
Cotter DG, Schairer D, Eichenfield L. Emerging therapies
for atopic dermatitis: JAK inhibitors. J Am Acad Dermatol.
;78:S53-S62. doi:10.1016/j.jaad.2017.12.019.
Guttman-Yassky E, Silverberg JI, Nemoto O, Forman SB,
Wilke A, Prescilla R, et al. Baricitinib in adult patients
with moderate-to-severe atopic dermatitis: a phase 2
parallel, double-blinded, randomized placebo-controlled
multiple-dose study. J Am Acad Dermatol. 2018.
doi:10.1016/j.jaad.2018.01.018.
Fraser KA. American Academy of Dermatology Annual
Meeting: San Diego, CA, USA, 16-20 Feb 2018. Am J
Clin Dermatol. 2018;19:287-90. doi:10.1007/s40257-
-0351-z.
Damsky W, King BA. JAK inhibitors in dermatology:
The promise of a new drug class. J Am Acad Dermatol.
;76:736-44. doi:10.1016/j.jaad.2016.12.005.
Levy LL, Urban J, King BA. Treatment of recalcitrant atopic
dermatitis with the oral Janus kinase inhibitor tofacitinib
citrate. J Am Acad Dermatol. 2015;73:395-9.
doi:10.1016/j.jaad.2015.06.045.
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.
;175:902-911. doi:10.1111/bjd.14871.
Kim BE, Leung DYM, Boguniewicz M, Howell MD. Loricrin
and involucrin expression is down-regulated by Th2
cytokines through STAT-6. Clin Immunol. 2008;126:332-
doi:10.1016/j.clim.2007.11.006.
Simpson EL, Flohr C, Eichenfield LF, Bieber T, Sofen
H, Taïeb A, et al. Efficacy and safety of lebrikizumab
(an anti-IL-13 monoclonal antibody) in adults with
moderate-to-severe atopic dermatitis inadequately
controlled by topical corticosteroids: A randomized,
placebo-controlled phase II trial (TREBLE). J Am Acad
Dermatol. 2018;78:863-871.e11. doi:10.1016/j.
jaad.2018.01.017.
Andreas Wollenberg, Michael D. Howell, Emma Guttman-
Yassky, Jonathan I. Silverberg, Claire Birrell, Chris
Kell, Michelle Dawson R van der M. 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):AB20.
doi:10.1016/j.jaad.2017.04.099.
Nemoto O, Furue M, Nakagawa H, Shiramoto M, Hanada
R, Matsuki S, 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-
-co. Br J Dermatol. 2016;174:296-304. doi:10.1111/
bjd.14207.
Cornelissen C, Marquardt Y, Czaja K, Wenzel J, Frank
J, Lüscher-Firzlaff J, et al. IL-31 regulates differentiation
and filaggrin expression in human organotypic skin models.
J Allergy Clin Immunol. 2012;129:426-33, 433-8.
doi:10.1016/j.jaci.2011.10.042.
Ruzicka T, Hanifin JM, Furue M, Pulka G, Mlynarczyk I,
Wollenberg A, et al. Anti-Interleukin-31 receptor A antibody
for atopic dermatitis. N Engl J Med. 2017;376:826-
doi:10.1056/NEJMoa1606490.
Kabashima K, Furue M, Hanifin JM, Pulka G, Wollenberg
A, Galus R, et al. Nemolizumab in patients with
moderate-to-severe atopic dermatitis: Randomized,
phase II, long-term extension study. J Allergy Clin Immunol.
(in press). doi:10.1016/j.jaci.2018.03.018.
Novartis, Icahn School of Medicine at Mount Sinai.
Secukinumab for Treatment of Atopic Dermatitis.
NCT02594098 @ clinicaltrials.gov. [Accessed September
, 2018]Available from:https://clinicaltrials.gov/
ct2/show/NCT02594098. P2018.
Novartis, GWT-TUD GmbH. Investigation of Efficacy of Secukinumab
in Patients With Moderate to Serve Atopic Dermatitis
(Secu_in_AD). NCT03568136 @ clinicaltrials.gov.
[Accessed September 26, 2018]Available from:https://
clinicaltrials.gov/ct2/show/NCT03568136. 2018.
All articles in this journal are Open Access under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).