The future is finally here: Advances in
the treatment of atopic dermatitis
Matthew J. Zirwas, MD
Columbus, Ohio
Key word: atopic dermatitis.
A great deal has been written and said about
how the new drugs for atopic dermatitis are
changing patients’ lives, and those who have
used dupilumab have seen it with their own eyes. But
these drugs are not just changing patients’ lives, they
are also changing dermatologists’ lives. Many of the
most frustrating patients, the ones who do not get
better and who make providers the most nervous
about side effectsdthe ones who make physicians
feel like failuresdare finally getting better.
Looking back at the last 20 yearsdand at all the
agents that have been reported as therapies for adult
atopic dermatitisdis probably the best way to put
these new protocols into context. This context shows
just how desperately these drugs have been needed.
As a medical student rotating in dermatology
20 years ago, I knew the state-of-the-art treatment
for adults with moderate atopic dermatitis by the end
of my second week. ‘‘Use the triamcinolone oint-
ment twice a day, once right after showering, for
2 weeks, then take 1 week off and just use petroleum
jelly, and keep repeating this cycle. Only use a
syndet soap bar, do not take hot showers, and avoid
wearing wool. When you moisturize after shower-
ing, you need to get the emollient on within
4 minutes of getting out of the shower. Take hy-
droxyzine before bed, if you are having trouble
sleeping because of the itch.’’
Phototherapy was an option, but because almost
all of my patients worked, it usually was not a
realistic option. Short courses of oral steroids would
help, but the benefits were extremely short-lived and
Publication of this article was supported by Leo Pharma, Bayer,
and Sanofi/Regeneron.
From the Department of Medicine, The Ohio State University,
Columbus.
Funding sources: Supported by Bayer, LEO Pharma, and Sanofi.
Disclosure: Dr Zirwas MD, has served on speakers’ bureaus for
Regneron, Sanofi, and Genentech. He has received compensa-
tion for consulting for Regeneron, Sanofi, and Valean and
provided contract research for LEO Pharma, Regeneron, Jans-
sen, Incyte, Foamix, Sanofi, and UCB Biopharma.
Downloaded for Dilip Dilip (dilip.derma@aiimsrishikesh.edu.in) at Teerthanker Mahaveer Medical College And Research Centre from ClinicalKey.com by Elsevier on February 21, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
the side effects, such as a 5 times greater risk of
sepsis, are too great to allow us to consider repetitive
use.1 Organ transplantation helped move atopic
dermatitis treatment forward with the discovery
that drugs such as azathioprine,2-4 cyclosporine,5,6
and mycophenolate7-9 had efficacy. Dermatologists
also repurposed methotrexate10-12 for use in indica-
tions from psoriasis to eczema.
The problem was that none of these treatments
worked well enoughdif working ‘‘well enough’’ is
defined to mean that the expectation is that the
patient would have a relatively normal life while
taking the medication, and if those who responded
could expect to remain that way safely and indefi-
nitely. Cyclosporine delivered on the ‘‘relatively
normal life’’ part but is generally not a long-term
option (although, out of desperation, many atopic
patients were taking it for years), and the others did
not deliver either on the ‘‘relatively normal life’’ or on
‘‘safely and indefinitely’’ factor.
Dermatologists were faced with treating a life-
ruining disease without any truly effective therapies.
Even more dishearteningly, the patients also knew
that none of these agents worked well enough, and
that they were not going to have normal lives.
In the interest of giving patients hope, there were
‘‘innovative, outside-the-box’’ treatments that were
reported. Things such as ceramides,13,14 peppermint
oil,15 coconut oil,16,17 oral itraconazole,18,19 glucos-
amine20,21 combined with cyclosporine, vitamin
D,22,23 melatonin,24,25 glycopyrrolate,26,27 and pro-
biotics28,29 all sound good to patients and offered
Accepted for publication December 9, 2017.
Reprint requests: Matthew J. Zirwas, MD, The Ohio State
University, Department of Medicine, 2359 E Main St,
Columbus, OH 43209. E-mail: matt.zirwas@gmail.com.
J Am Acad Dermatol 2018;78:S25-7.
0190-9622/$36.00
Ó 2018 by the American Academy of Dermatology, Inc.
https://doi.org/10.1016/j.jaad.2017.12.025
S25
 S26 Zirwas
temporary hope, but none of these were the magic
bullet (and some were proved in later reports to not
work at all).30
Over time, enough evidence was available to
provide a picture of the risk-benefit ratio for existing
therapies utilized in treating moderate-to-severe
atopic dermatitis. Cyclosporine leads to a 50%
reduction in severity on average, with improved
efficacy at higher doses, but it should be used only
for relatively short periods and has a well-known,
significant side effect profile that is best known for
renal impairment.31-33 Azathioprine is less effective,
giving an average improvement closer to 35%, but it
also has a significant side effect profile and can be
used long-term in those for whom it is effective.31-33
Methotrexate and azathioprine were not statistically
different when compared head to head, but metho-
trexate was also shown to be ‘‘noninferior’’ to
cyclosporine.34,35 Methotrexate, then, is in between
azathioprine and cyclosporine in terms of efficacy,
with average improvement in the 40% to 50% range,
but it arguably has a better side effect profile than
either of the others.31-33 Mycophenolate does not
have adequate data to allow an estimation of average
efficacy, but it is likely in the same range as
methotrexate and azathioprine, with a relatively
good side effect profile that predominantly features
increased risk for common infections.36,37 Adding
topical therapy and an occasional short course of
systemic steroids increases the efficacy of all of the
aforementioned, but there is no solid evidence
regarding just how much.
To summarize and simplify, aggressive therapy
with systemic immunosuppressive agents combined
with topicals, on average, reduces the severity of
moderate-to-severe atopic dermatitis by about 1
gradedthat is, a patient with severe disease at
baseline could be moved to the moderate category
and one with moderate disease could be move to the
mild disease category (with careful laboratory moni-
toring; acceptance of the risk of hepatic, renal, and/
or immunologic side effects; and treatment with
systemic steroids during flares). Individual patients
would occasionally have exceptional responses to 1
of the aforementioned therapies, but for the majority
of patients with moderate-to-severe atopic derma-
titis, the best these individuals could hope for was to
be less miserable.
That changed on March 28, 2017, when dupilu-
mab received US Food and Drug Administration
approval. In a matter of days after the first dose,
many patients’ lives changed dramatically and there
were no serious side effects reported in those treated
with the drug compared with those who were not.
Interestingly, about 10% of patients treated with
Downloaded for Dilip Dilip (dilip.derma@aiimsrishikesh.edu.in) at Teerthanker Mahaveer Medical College And Research Centre from ClinicalKey.com by Elsevier on February 21, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
J AM ACAD DERMATOL
MARCH 2018
dupilumab do get ocular inflammation, the mecha-
nism of which has not been elucidated, but there
have been no reports of visual impairment or other
major ocular side effects, and thus far there has been
only 1 report of a patient discontinuing dupilumab
therapy as a result of ocular side effects. The most
substantial ‘‘side effect’’ reported is that dupilumab
reduces the risk of Staphylococcus infections for
patients.38 Obviously, as with all new drugs, long-
term data in large numbers of patients are still
lacking. Although it is expensive, dupilumab has
been shown to be cost-effective for the benefit it
provides, and it costs substantially less than any of
the psoriasis biologics currently on the market (more
than $1,000 per month less than adalimumab,
ustekinumab, guselkumab, ixekizumab, or
secukinumab).39,40
And dupilumab is just the beginning. As the rest of
this Supplement will show, there are dozens of new
agents in the pipeline, both topical and oral. Some,
the interleukin 13 inhibitors, have mechanisms of
action related to dupilumab, but most are new
mechanisms of action that you may be hearing about
as atopic dermatitis treatments for the first time in this
Supplement: Janus kinase inhibitors, phosphodies-
terase 4 inhibitors, transient receptor potential cation
channel subfamily V member 1 inhibitors, neuro-
kinin inhibitors, T-cell inhibitors, arachidonic acid,
leukotriene, and prostaglandin inhibitors, 5HT2B
antagonists, liver X receptor agonists, and more.
Some of them are stunningly effective over a wide
range of types of dermatitis, whereas others will fill
relatively specific niches.
With all of these emerging therapeutic options, no
one knows exactly how atopic dermatitis will be
treated 5 years from now. But for the first time in the
history of dermatology, skin specialists candwith a
high level of confidenced tell their patients with
atopic dermatitis that they are going to get better.
Welcome to the future.
REFERENCES
1. Waljee AK, Rogers MA, Lin P, et al. Short term use of oral
corticosteroids and related harms among adults in the
United States: population based cohort study. BMJ. 2017;
357:j1415.
2. Gunnar SO, Johansson K, Juhlin L. Immunoglobulin E in
‘‘healed’’ atopic dermatitis and after treatment with cortico-
steroids and azathioprine. Br J Dermatol. 1970;82(1):10-13.
3. Buckley DA, Baldwin P, Rogers S. The use of azathioprine in
severe adult atopic eczema. J Eur Acad Dermatol Venereol.
1998;11(2):137-140.
4. Morrison JG, Schulz EJ. Treatment of eczema with cyclophos-
phamide and azathioprine. Br J Dermatol. 1978;98(2):203-207.
5. van Joost T, Stolz E, Heule F. Efficacy of low-dose cyclosporine
in severe atopic skin disease. Arch Dermatol. 1987;123(2):
166-167.
 J AM ACAD DERMATOL
VOLUME 78, NUMBER 3
6. Taylor RS 3rd, Cooper KD, Headington JT, et al. Cyclosporine
therapy for severe atopic dermatitis. J Am Acad Dermatol.
1989;21(3 Pt 1):580-583.
7. Grundmann-Kollmann M, Korting HC, Behrens S, et al. Suc-
cessful treatment of severe refractory atopic dermatitis with
mycophenolate mofetil. Br J Dermatol. 1999;141(1):175-176.
8. Hansen ER, Buug S, Deleuran M, et al. Treatment of atopic
dermatitis with mycophenolate mofetil. Br J Dermatol. 2000;
143(6):1324-1326.
9. Neuber K, Schwartz I, Itschert G, et al. Treatment of atopic
eczema with oral mycophenolate mofetil. Br J Dermatol. 2000;
143(2):385-391.
10. Pankovich NM. Methotrexate in complex treatment of eczema
and neurodermatitis. Vestn Dermatol Venerol. 1977;(1):56-59.
11. Balasubramaniam P, Ilchyshyn A. Successful treatment of
severe atopic dermatitis with methotrexate. Clin Exp Dermatol.
2005;30(4):436-437.
12. Goujon C, Berard F, Dahel K, et al. Methotrexate for the
treatment of adult atopic dermatitis. Eur J Dermatol. 2006;
16(2):155-158.
13. Murata Y, Ogata J, Higaki Y, et al. Abnormal expression of
sphingomyelin acylase in atopic dermatitis: an etiologic factor
for ceramide deficiency? J Invest Dermatol. 1996;106(6):
1242-1249.
14. Gehring W, Wenz J, Gloor M. Influence of topically applied
ceramide/phospholipid mixture on the barrier function of
intact skin, atopic skin and experimentally induced barrier
damage. Int J Cosmet Sci. 1997;19(4):143-156.
15. Elsaie LT, El Mohsen AM, Ibrahim IM, et al. Effectiveness of
topical peppermint oil on symptomatic treatment of chronic
pruritus. Clin Cosmet Investig Dermatol. 2016;9:333-338.
16. Verallo-Rowell VM, Dillague KM, Syah-Tjundawan BS. Novel
antibacterial and emollient effects of coconut and virgin olive
oils in adult atopic dermatitis. Dermatitis. 2008;19(6):308-315.
17. Evangelista MT, Abad-Casintahan F, Lopez-Villafuerte L. The
effect of topical virgin coconut oil on SCORAD index, trans-
epidermal water loss, and skin capacitance in mild to moder-
ate pediatric atopic dermatitis: a randomized, double-blind,
clinical trial. Int J Dermatol. 2014;53(1):100-108.
18. Ikezawa Z, Kindo M, Okajima M, et al. Clinical usefulness of oral
itraconazole, an antimycotic drug, for refractory atopic derma-
titis. Eur J Dermatol. 2004;14(6):400-406.
19. Takechi M. Minimum effective dosage in the treatment of
chronic atopic dermatitis with itraconazole. J Int Med Res.
2005;33(3):273-283.
20. Kwon HB, Ann BJ, Choi Y, 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(3):207-210.
21. Kim CH, Choi YN, Cheong KA, et al. Mechanism underlying the
effect of combined therapy using glucosamine and low-dose
cyclosporine A on the development of atopic dermatitis-like
skin lesions in NC/Nga mice. Int Immunopharmacol. 2013;15(2):
424-432.
22. Hata TR, Kotoi P, Jackson M, et al. Administration of oral
vitamin D induces cathelicidin production in atopic individ-
uals. J Allergy Clin Immunol. 2008;122(4):829-831.
23. Sidbury R, Sullivan AF, Thadhani RI, et al. Randomized
controlled trial of vitamin D supplementation for
Downloaded for Dilip Dilip (dilip.derma@aiimsrishikesh.edu.in) at Teerthanker Mahaveer Medical College And Research Centre from ClinicalKey.com by Elsevier on February 21, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
Zirwas S27
winter-related atopic dermatitis in Boston: a pilot study. Br J
Dermatol. 2008;159(1):245-247.
24. Marseglia L, D’Angelo G, Manti S, et al. Melatonin and atopy:
role in atopic dermatitis and asthma. Int J Mol Sci. 2014;15(8):
1382-1393.
25. Chang YS, Lin MH, Lee JH, et al. Melatonin supplementa-
tion for children with atopic dermatitis and sleep distur-
bance: a randomized clinical trial. JAMA Pediatr. 2016;170(1):
35-42.
26. Adachi K, Aoki T. IgE antibody to sweat in atopic dermatitis.
Acta Derm Venereol Suppl (Stockh). 1989;144:83-87.
27. Kaneko S, Murota H, Murata S, et al. Usefulness of sweat
management for patients with adult atopic dermatitis, regard-
less of sweat allergy: a pilot study. Biomed Res Int. 2017;
114(87):46-51.
28. Kirjavainen PV, Salminen SJ, Isolauri E. Probiotic bacteria in
the management of atopic disease: underscoring the impor-
tance of viability. J Pediatr Gastroenterol Nutr. 2003;36(2):
223-227.
29. Matsumoto M, Ebata T, Hirooka J, et al. Antipruritic effects of
the probiotic strain LKM512 in adults with atopic dermatitis.
Ann Allergy Asthma Immunol. 2014;113(2):209-216.e7.
30. Hata TR, Audish D, Kotol P, et al. A randomized controlled
double-blind investigation of the effects of vitamin D dietary
supplementation in subjects with atopic dermatitis. J Eur Acad
Dermatol Venereol. 2014;28(6):781-789.
31. Cookson H, Smith C. Systemic treatment of adult atopic
dermatitis. Clin Med (Lond). 2012;12(2):172-176.
32. Roekevisch E, Spuls PI, Kuester D, et al. Efficacy and safety of
systemic treatments for moderate-to-severe atopic dermatitis: a
systematic review. J Allergy Clin Immunol. 2014;133(2):429-438.
33. Gooderham M, Lynde CW, Papp K, et al. Review of systemic
treatment options for adult atopic dermatitis. J Cutan Med
Surg. 2017;21(1):31-39.
34. Schram ME, Roekevisch E, Leeflang MM, et al. A randomized
trial of methotrexate versus azathioprine for severe atopic
eczema. J Allergy Clin Immunol. 2011;128(2):353-359.
35. Goujon C, Viquier M, Staumont-Salle D, et al. Methotrexate
versus cyclosporine in adults with moderate-to-severe
atopic dermatitis: a phase III randomized noninferiority trial.
J Allergy Clin Immunol Pract. 2017 Sept 26 [Epub ahead of
print].
36. Subedi A, Magder LS, Petri M. Effect of mycophenolate mofetil
on the white blood cell count and the frequency of infection
in systemic lupus erythematosus. Rheumatol Int. 2015;35(10):
1687-1692.
37. Koo S, Gagne LS, Lee P, et al. Incidence and risk factors for
herpes zoster following heart transplantation. Transpl Infect
Dis. 2014;16(1):17-25.
38. Fleming P, Drucker AM. Risk of infection in patients with
atopic dermatitis treated with dupilumab: a meta-analysis of
randomized controlled trials. J Am Acad Dermatol. 2018;78:
62-69.
39. Kuznik A, Bego-Le-Bagousse G, Eckert L, et al. Economic
evaluation of dupilumab for the treatment of moderate-
to-severe atopic dermatitis in adults. Dermatol Ther (Heidelb).
2017;7:493-505.
40. Good Rx. Stop paying too much for your prescriptions.
Available from: www.goodrx.com. Accessed October 20, 2017.