Available via license: CC BY-NC-SA 4.0
Content may be subject to copyright.
Advances in Dermatology and Allergology 2, April / 2020 129
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0).
License (http://creativecommons.org/licenses/by-nc-sa/4.0/)
Special paper
Address for correspondence: Prof. Roman J. Nowicki MD, PhD, Department of Dermatology, Venereology, and Allergology,
Medical University of Gdansk, 17 Smoluchowskiego St, 80-214 Gdansk, Poland, phone: +48 58 584 40 10, e-mail: rnowicki@gumed.edu.pl
Received: 18.09.2019 accepted: 4.10.2019.
Atopic dermatitis. Interdisciplinary diagnostic and
therapeutic recommendations of the Polish Dermatological
Society, Polish Society of Allergology, Polish Pediatric
Society and Polish Society of Family Medicine.
Part II. Systemic treatment and new therapeutic methods
Roman J. Nowicki1, Magdalena Trzeciak1, Maciej Kaczmarski2, Aleksandra Wilkowska1, Magdalena Czarnecka-Operacz3,
Cezary Kowalewski4, Lidia Rudnicka5, Marek Kulus6, Agnieszka Mastalerz-Migas7, Jarosław Peregud-Pogorzelski8,
Małgorzata Sokołowska-Wojdyło1, Radosław Śpiewak9, Zygmunt Adamski3, Joanna Czuwara5, Monika Kapińska-Mrowiecka10,
Andrzej Kaszuba11, Dorota Krasowska12, Beata Kręcisz13, Joanna Narbutt11, Sławomir Majewski14, Adam Reich15,
Zbigniew Samochocki5, Jacek Szepietowski16, Katarzyna Woźniak4
1Department of Dermatology, Venereology, and Allergology, Medical University of Gdansk, Gdansk, Poland
2Department of Paediatrics, Paediatric Gastroenterology and Allergology, Medical University of Bialystok, Bialystok, Poland
3Department of Dermatology, Poznan University of Medical Sciences, Poznan, Poland
4Department of Dermatology and Immunodermatology, Medical University of Warsaw, Warsaw, Poland
5Department of Dermatology, Medical University of Warsaw, Warsaw, Poland
6Department of Paediatric Pneumonology and Allergology, Medical University of Warsaw, Warsaw, Poland
7Department of Family Medicine, Medical University of Wroclaw, Wroclaw, Poland
8Department of Paediatrics and Paediatric Oncology, Pomeranian Medical University, Szczecin, Poland
9Department of Experimental Dermatology and Cosmetology, Jagiellonian University Medical College, Krakow, Poland
10Dermatology Ward, Stefan Żeromski Specialist Hospital, Krakow, Poland
11Department of Dermatology, Paediatric and Oncological Dermatology, Medical University of Lodz, Lodz, Poland
12Department of Dermatology, Venereology and Paediatric Dermatology, Medical University, Lublin, Poland
13Department of Dermatology, Faculty of Medicine and Health Sciences, Jan Kochanowski University, Kielce, Poland
14Department of Dermatology and Venereology, Medical University of Warsaw, Warsaw, Poland
15Department of Dermatology, University of Rzeszow, Rzeszow, Poland
16Department of Dermatology, Venereology and Allergology, Medical University of Wroclaw, Wroclaw, Poland
Adv Dermatol Allergol 2020; XXXVII (2): 129–134
DOI: https://doi.org/10.5114/ada.2020.94829
Abstract
The treatment goal in atopic dermatitis is eliminating clinical symptoms of the disease, preventing exacerbations
and complications, as well as improving patients’ quality of life. In cases of severe atopic dermatitis and lack of
response it is recommended to introduce systemic therapy. Patients ofter require multi-specialist consultations, and
occasionally hospitalization. It is not recommended to use acupuncture, acupressure, bioresonance, homeopathy,
or Chinese herbs in the treatment of atopic dermatitis.
Key words: atopic dermatitis, immunosuppressive drugs, biological treatment, dupilumab, allergen-specic immu-
notherapy, probiotics, alternative therapy.
The article was published in the journal "Dermatology Review/Przegląd Dermatologiczny" 2019, 106, 475–485,
DOI: https://doi.org/10.5114/dr.2019.89995.
Advances in Dermatology and Allergology 2, April / 2020130
R.J. Nowicki, M. Trzeciak, M. Kaczmarski, A. Wilkowska, M. Czarnecka-Operacz, C. Kowalewski, L. Rudnicka, M. Kulus,
A. Mastalerz-Migas, J. Peregud-Pogorzelski, M. Sokołowska-Wojdyło, R. Śpiewak, Z. Adamski, J. Czuwara, M. Kapińska-Mrowiecka,
A. Kaszuba, D. Krasowska, B. Kręcisz, J. Narbutt, S. Majewski, A. Reich, Z. Samochocki, J. Szepietowski, K. Woźniak
Introduction
In cases of severe atopic dermatitis (AD) and lack of re-
sponse to topical treatment, it is recommended to consid-
er administration of the following: cyclosporine A (CyA) or
dupilumab, methotrexate (MTX), azathioprine (AZA), my-
cophenolate mofetil (MMF), glucocorticoids (GCs) [1–10].
Prior to administration of immunosuppressive treat-
ment it is recommended to:
• conrm the diagnosis of AD;
• excluding:
– disease-exacerbating factors,
– possibility of infections,
– comorbidities,
– contact eczema.
Cyclosporine A (CyA) is recommended as the rst-line
drug in severe cases of chronic AD in adults. In children
and youths its application should be considered only in
severe AD cases by a physician with appropriate experi-
ence. Recommendations regarding the use of the drug
in children are based on results of single cohort stud-
ies and individual randomized cohort studies (o-label
recommendations) [3, 11, 12]. Cyclosporine A decreases
inflammation, area of lesions, and pruritus intensity,
as well as improves the quality of sleep. An initial rec-
ommended drug dose is 5 mg/kg body weight/day
with a reduction of 0.5–1 mg/kg body weight/day every
2 weeks, when clinical ecacy has been reached. Ben-
ecial eects of CyA include a decrease in pruritus and
skin inflammation, and is observed already within 2–
6 weeks of treatment introduction [3, 11, 12]. It is recom-
mended to administer CyA in cycles that last 12 weeks
on average. Discontinuation of the drug is associated
with recurrence of skin lesions within several weeks
since the discontinuation of the treatment, however, it
is assessed that condition of patients’ skin does not re-
turn to the same condition as before the CyA treatment
[11, 12]. Dose decrease should be considered with regard
to clinical ecacy. In some cases it may be recommended
to opt for a long-term treatment with the lowest clinically
eective dose [3]. The drug may also be administered in
a long-term continuous therapy. CyA treatment duration
depends on the clinical ecacy and drug tolerance, how-
ever, the treatment should not exceed 2 years and must
be accompanied with thorough monitoring of possible
serious adverse reactions. Despite the fact that many pa-
tients tolerate a much longer than 2 years therapy with
a low CyA dose, after 2 years of the CyA therapy is should
be attempted to discontinue the treatment or change the
drug to another one that is administered generally [3]. In
some patients a so-called weekend therapy is eective;
it allows for decreasing an accumulative dose. A close
monitoring of patients is recommended. Frequent ad-
verse reactions of CyA (e.g. nephrotoxicity, hypertension)
speak against the long-term AD treatment with CyA, and
3–6-month intervals are suggested [3].
Despite unquestionable ecacy of CyA in AD treat-
ment, the use of this drug is associated with the risk of
serious adverse reactions. Most of the side eects appear
during the therapy, and subside after the drug is discontin-
ued. In order to prevent them or decrease the risk for their
appearance, it is recommended to monitor the treatment
closely. Patients taking the drug should undergo regu-
lar exams with regard to arterial pressure and nephritic
parameters. The risk for nephrotoxic activity increases
when the drug dose exceeds 5 mg/kg body weight/day,
increased creatinine values are maintained, and in the el-
derly. Kidneys may be permanently damaged (tubulopathy,
vasculopathy) in individuals who take CyA continually for
over 2 years [12]. In short-term intermittent CyA therapy,
renal dysfunction is usually transient. The risk for occur-
rence of nephrotoxic activity is lower in children than in
adults. Less common adverse reactions occurring during
CyA therapy include neurological symptoms, such as head-
ache, convulsions, paraesthesia, as well as disorders of
the gastrointestinal tract, infections, gingival hypertrophy,
hypertrichosis, hyperlipidaemia, disorders in electrolyte
levels, an increased risk for developing skin cancers and
lymphoproliferative hyperplasia. Measurements of CyA
blood concentration during the therapy with this drug is
not required since CyA concentration correlated with ef-
cacy and toxicity only in a slight degree.
Despite the lack of clinical proofs, it is recommended
to discontinue CyA 2 weeks before planned vaccination,
and start taking it again 4–6 weeks after the vaccination
[2, 3]. During the CyA therapy, an eective UV protection
should be used.
Dupilumab is an IL-4/IL-13 receptor α antagonist and
the rst biological drug in the world registered for treat-
ment of moderate and server AD, which is not adequate-
ly controlled by recommended topical treatment or when
such treatment is not recommended.
Dupilumab may be used as the second-line treatment
in severe AD after the rst failure of general therapy. The
drug may be used with or without local glucocorticoste-
roids (GCs). Clinical studies conrmed its statistically sig-
nificant clinical efficacy with regard to improvements in
disease symptoms measured with the use of EASI (75%)
and IGA scoring systems, and an improvement with
≥ 4 points of pruritus evaluation according to Numeric Rat-
ing Scale (NRS) as compare with the placebo control group.
A decrease in sleep disorders, an improvement in quality
of life, and good drug tolerance were conrmed. The most
commonly observed adverse events included: local reaction
after subcutaneous drug administration, and conjunctivitis.
A high safety prole of the drug and lack of dose-dependent
toxicity were presented. The drug is administered accord-
ing to the following scheme: 600 mg in two injections with
300 mg, and then 300 mg subcutaneously every 2 weeks.
There is available data that indicates its long-term ecacy
and safety [13–15].
Advances in Dermatology and Allergology 2, April / 2020
Atopic dermatitis. Interdisciplinary diagnostic and therapeutic recommendations of the Polish Dermatological Society,
Polish Society of Allergology, Polish Pediatric Society and Polish Society of Family Medicine.
Part II. Systemic treatment and new therapeutic methods
131
Oral glucocorticosteroids (GCs) are allowed for AD
treatment with a limitation, mainly in adult patients, to
the period of 1 week, in rigidly selected cases, and in dis-
ease exacerbation periods [2, 3]. An equivalent of 0.5 mg
of prednisone/kg body weight should not be exceeded
[3]. In everyday practice (dierent from published clinical
study results) the most common reasons for discontinu-
ation of treatment involving oral GCs are: adverse reac-
tions, lack of treatment ecacy, lack of patient’s co-oper-
ation, or abandonment of treatment by the patient after
improvements in clinical condition have been achieved.
During 10-year observational studies of AD-patients in
the Netherlands, the lowest number of adverse reac-
tions was noted during the treatment of oral GCs (5%),
MMF (22%), and CyA (24%). More adverse reactions were
observed after the treatment with AZA (38%) and MTX
(41%) – these adverse reactions regarded the gastroin-
testinal track in most cases. Then, the treatment was not
eective in 15% of CyA and AZA cases, 20% of oral GCs
cases, 44% of MMF cases, and 65% of MTX cases [16].
Methotrexate, AZA, and MMF may be used o-label
in AD-patients if CyA is ineective or there exist contra-
indications for its use [3].
Methotrexate (MTX) is recommended for treatment
of severe AD cases resistant to other treatment methods.
It is highlighted that it is the second, after CyA, most fre-
quently used drug in treatment of severe AD. Referenced
literature included a number of reports on safety and ef-
cacy of MTX in AD. The studies most often regard adults.
There are also single reports on efficacy and safety of
MTX usage in children [16–19].
Currently MTX is recommended in AD treatment in
adults in doses similar to the ones used in treatment of
psoriasis, i.e. 10–20 mg/week. The drug may be used in
one dose once a week, but it is more often used in three
doses of 2.5–7.5 mg every 12 h once a week [17–19]. Other
authors recommend to use MTX in the dose of 7.5–25 mg/
week in adults, and 0.2–0.7 mg/kg/week in children [17].
The treatment is usually tolerated well, but it should be
remembered that severe adverse reactions may occur. It
is believed that frequency and intensity of adverse re-
actions is associated with the dose. Adverse reactions
were reported mainly after the use of large MTX doses.
More common ones included: hepatotoxicity, bone mar-
row suppression, pneumonocirrhosis, and renal insu-
ciency. Methotrexate is teratogenic – women and men
should use eective contraception during the treatment
and, according to SPC, for 6 months after its discontinu-
ation [16–19].
Azathioprine (AZA) is used o-label in treatment of
severe atopic dermatitis cases in adults resistant to other
treatment methods, i.e. when CyA is noneective or con-
traindicated. AZA may be also used o label in children
[3]. A precise mechanism of AZA in AD has not been fully
examined. In vitro studies suggest that AZA exerts sup-
pressive and toxic influence on Langerhans cells. It is
emphasized that AZA is really eective in AD treatment,
however, due to AZA’s mechanism, therapeutic eects
of the drug may be delayed. In some patients, full thera-
peutic eects are reached even after 12 weeks or later.
It is recommended to use AZA in the dose of 1–3 mg/kg
body weight/day. Prior to commencement of the treat-
ment, thiopurine methyl transferase (TPMT) activity
should be determined, since this enzyme participates in
metabolism of 6-mercaptopurine, and in individuals with
a congenital insuciency of this enzyme, an increased
myelosuppression may occur [3]. Thiopurine methyl
transferase gene mutations may inuence the ecacy
and safety of treatment with AZA. Measuring the TPMT
level allows for adjusting an individual dose to the pa-
tient, and decreasing the risk of bone marrow damage
[20–26]. Individual authors used the drugs in severe AD
in children and showed that it was effective. Toxic in-
uence exerted on the bone marrow was not observed
[24, 25]. Furthermore, it was showed that AZA not only
improves the clinical conditions, but also decreases the
level of total IgE in children and youths with AD [26].
Azathioprine shows a number of adverse reactions.
The most commonly observed include bone marrow
damage and disorders of the immune system. Moreover,
the following are also observed: vascular disorders (vas-
culitis), gastrointestinal disorders (nausea, emesis), and
disorders involving the liver. Therefore, it is necessary to
monitor transaminases and complete blood count dur-
ing the treatment. According to the summary of product
characteristics, within rst 8 weeks of treatment, com-
plete blood count examination should be performed once
a week. During a later treatment period, the frequency of
tests may be decreased to one test per month, and then,
to one test per 3 months. In case the level of leucocytes
or blood platelets drops below the normal limit, and in
case other adverse reactions occur, the drug dose should
be lowered.
While using AZA, patients should not be vaccinated
with vaccines containing live microorganisms. Since AZA
exhibits teratogenic activity, it should not be used dur-
ing pregnancy. Furthermore, the drug should not be used
during breastfeeding period. Azathioprine should not be
combined with UV – an eective protection against UV
should be used [3, 26].
Mycophenolate mofetil may be used o label in treat-
ment of adults with AD in the dose of up to 3 g/day if CyA
is ineective or contraindicated. Mycophenolate mofetil
may be used in treatment of children and youths with
AD. Mycophenolate mofetil is teratogenic – men and
women must use eective contraception [3].
Antihistamines
There is no sucient proof to use rst- and second-
generation antihistamines for treating pruritus in AD.
First-generation antihistamines may inhibit histamine
Advances in Dermatology and Allergology 2, April / 2020132
R.J. Nowicki, M. Trzeciak, M. Kaczmarski, A. Wilkowska, M. Czarnecka-Operacz, C. Kowalewski, L. Rudnicka, M. Kulus,
A. Mastalerz-Migas, J. Peregud-Pogorzelski, M. Sokołowska-Wojdyło, R. Śpiewak, Z. Adamski, J. Czuwara, M. Kapińska-Mrowiecka,
A. Kaszuba, D. Krasowska, B. Kręcisz, J. Narbutt, S. Majewski, A. Reich, Z. Samochocki, J. Szepietowski, K. Woźniak
activity in subcortical regions of the central nervous sys-
tem, and simultaneously exert anti-pruritic and sedative
influence, what may be beneficial in case of patients
with AD, who have problems with falling asleep and
suer from sleep disorders. Second-generation antihis-
tamines are especially useful in patient with AD that
is accompanied by conjunctivitis or allergic rhinitis [3].
A higher specificity of the bond to histamine receptor
H1, a longer halife period, and hydrophilic structure of
second-generation antihistamines contributed to an in-
creased ecacy and safety of use of second-generation
antihistamines [7, 27].
Allergen-specic immunotherapy
Allergen-specic immunotherapy is the only causal
treatment for AD-patients. Indications for allergen-specif-
ic immunotherapy in AD-patients include cases with in-
sucient response to existing treatment and document-
ed allergy to IgE-dependent airborne allergens [3, 28–31].
Allergen-specic immunotherapy for AD shows consid-
erable clinical efficacy in treatment of patients with
signs of being allergic to both year-round and seasonal
airborne allergens, especially in patients allergic to one
allergen group [3, 31]. So far, clinical eects with the use
of allergen-specic immunotherapy in patients allergic to
dust mites and pollens have been documented best [30,
31]. There are no contraindications to deallergize patients
with AD or concomitant other atopic diseases, such as
allergic rhinitis or mild bronchial asthma [3, 31]. Eec-
tive allergen-specic immunotherapy depends on proper
patient qualication, proper choice of the vaccine com-
position, and proper execution of the therapy. Vaccine
composition should be based on results of a detailed
physical examination, interview, and reliable diagnostics
based on skin prick tests and measurement of serum
asIgE. Proper choice of vaccine composition, and the or-
der of their administration in cases of patients suering
from AD with polyvalent allergies determined the success
of allergen-specic immunotherapy. While planning the
therapy for AD-patients, allergological diagnostics should
not be limited to skin prick tests, but should be supple-
mented with measurement of asIgE levels for proper al-
lergens by means of brand new diagnostic methods, e.g.
component-resolved [29–31].
Adverse reactions occur mainly during an induction
phase of the allergen-specic immunotherapy, and are
of mild as well as transient nature. Most often they take
a form of erythema and skin oedema at site when the
vaccine was administered. Systemic reactions are less
common and occur as focal reactions distant from the
allergen administration site, or there are general symp-
toms. Exacerbations of rhinitis or asthma as well as
occurrence of skin pruritus and urticaria are observed.
Non-specic symptoms, such as increased temperature,
headaches, dizziness, fatigue, and muscle tiredness, are
less frequently reported. Individual cases can involve
a drop in arterial blood pressure, laryngeal oedema, or
even anaphylactic shock. Usually, adverse reactions of
allergen-specic immunotherapy are mild as well as tran-
sient, and include, rst and foremost, the skin. However,
while using allergen-specic immunotherapy, one should
always be prepared for a pharmacological intervention
and have anaesthesiologic protection [31]. This therapy
should be conducted systematically for at least 4–
5 years by an expert physician, with satisfaction of safety
requirements, and allowing for occurrence of adverse re-
actions [30, 31].
Probiotics
Probiotics were examined with regard to possible ap-
plication in AD treatment. A justication of the use of
probiotics is that bacteria they contain induce immu-
nological response type Th1 instead of Th2, what is to
inhibit production development of IgE antibodies. Some
reports show an enormous benet associated with the
use of probiotics in AD prevention and treatment. These
studies show inconsistent results and require to be con-
rmed [32–36].
Alternative treatment
Balneotherapy with thermal water may be taken into
consideration in treatment of mild and moderate AD. Co-
hort studies show that balneotherapy with thermal water
with/without phototherapy may be eective in mild and
moderate AD [3, 37].
There is no proof of ecacy for acupuncture, acupres-
sure, bioresonance, Chinese herbs, homeopathy, and mas-
sage/aromatherapy in the treatment of AD [3]. Yet, a risk
for developing a secondary contact allergy is observed
after e.g. application of lavender oil that contains up to
40% of linalool [38, 39]. Acupuncture, acupressure, biores-
onance, homeopathy, and Chinese herbs are not recom-
mended in AD treatment [3].
New methods of therapy
A phosphodiesterase 4 (PDE4) inhibitor for topical
application in AD therapies that since 2016 has been
available only in the US. In clinical studies including
children above the age of 2 with mild and moderate
AD, crisaborole was used twice a day for 4 weeks with
the following results: a reduction of lesions on IGA scale
was achieved, and pruritus was signicantly reduced
after 2 days of treatment. The studies lasted 48 weeks
and conrmed ecacy and safety of crisaborole. Ob-
served adverse reactions included pain, and infections
at the sited of administration [40–42].
Currently, a number of new drugs for AD therapies
are at the clinical study phase, including biological drugs,
Advances in Dermatology and Allergology 2, April / 2020
Atopic dermatitis. Interdisciplinary diagnostic and therapeutic recommendations of the Polish Dermatological Society,
Polish Society of Allergology, Polish Pediatric Society and Polish Society of Family Medicine.
Part II. Systemic treatment and new therapeutic methods
133
phosphodiesterase 4 (PDE4) antagonists, and protein ki-
nase inhibitors (JAK) [43–46]. It appears that personalized/
individual medicine is the future of AD therapies. On the
basis of measuring biomarkers specic for particular dis-
ease endotypes, it will be possible to qualify patients to
proper therapeutic groups, and implement eective tar-
geted treatment [47].
Conclusions
While treating AD-patients the following factors are
of key importance: experience and close co-operation
with patients and/or their families, education, prophy-
laxis, avoidance of factors exacerbating the disease, re-
storing dysfunctional skin barrier functions, containing
pruritus, and elimination of inammatory lesions as well
as skin infections. The patients require frequent multi-
specialist consultations, and in serious cases, hospital-
izations at wards dealing with treatments of this disease.
Conict of interest
The authors declare no conict of interest.
References
1. Wollenberg A, Oranje A, Deleuran M, et al. ETFAD/EADV Ec-
zema task force 2015 position paper on diagnosis and treat-
ment of atopic dermatitis in adult and paediatric patients.
J Eur Acad Dermatol Venereol 2016; 30: 729-47.
2. Wollenberg A, Barbarot S, Bieber T, et al. Consensus-based
European guidelines for treatment of atopic eczema (atopic
dermatitis) in adults and children: part I. J Eur Acad Dermatol
Venereol 2018; 32: 657-82.
3. Wollenberg A, Barbarot S, Bieber T, et al. Consensus-based
European guidelines for treatment of atopic eczema (atopic
dermatitis) in adults and children: part II. J Eur Acad Derma-
tol Venereol 2018; 32: 850-78.
4. Akdis CA, Akdis M, Bieber T, et al. Diagnosis and treatment of
atopic dermatitis in children and adults. European Academy
of Allergology and Clinical immunology/PRACTALL consensus
report. Allergy 2006; 61: 969-87.
5. Hanin JM, Cooper KD, Ho VC, et al. Guidelines of care for
atopic dermatitis. J Am Acad Dermatol 2004; 50: 391-404.
6. Sidbury R, Davis DM, Cohen DE, et al. Guideline of care
for the management of atopic dermatitis Section 3. Man-
agement and treatment with phototherapy and systemic
agents. J Am Acad Dermatol 2014; 71: 327-49.
7. Johnson BB, Franco AI, Beck LA, Prezzano JC. Treatment-resis-
tant atopic dermatitis: challenges and solutions. Clin Cosmet
Investig Dermatol 2019; 12: 181-92.
8. 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.
9. Simpson EL, Bruin-Weller M, Flohr C, et al. When does atopic
dermatitis warrant systemic therapy? Recommendations
from an expert panel of the International Eczema Council.
J Am Acad Dermatol 2017; 77: 623-33.
10. Hoare C, Li Wan Po A, Williams H. Systematic review of treat-
ments for atopic eczema. Health Technol Assess 2000; 4:
1-191.
11. Harper J, Ahmed I, Barclay G, et al. Cyclosporin for severe
childhood atopic dermatitis: short course versus continuous
therapy. Br J Dermatol 2000; 142: 52-8.
12. 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.
13. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase
3 trials of dupilumab versus placebo in atopic dermatitis.
N Engl J Med 2016; 375: 2335-48.
14. Blauvelt A, de Bruin-Weller M, Gooderham M, 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:
2287-303.
15. de Bruin-Weller M, Thaci D, Smith CH, et al. Dupilumab with
concomitant topical corticosteroid treatment in adults with
atopic dermatitis with an inadequate response or intoler-
ance to ciclosporin A or when this treatment is medically in-
advisable: a placebo-controlled, randomized phase III clinical
trial (LIBERTY AD CAFE). Br J Dermatol 2018; 178: 1083-101.
16. Garritsen FM, Roekevisch E, van der Schaft J, et al. 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.
17. El-Khalawany MA, Hassan H, Shaaban D, et al. Methotrexate
versus cyclosporine in the treatment of severe atopic der-
matitis in children; multicenterexperience from Egypt. Eur
J Pediatr 2013; 172: 351-6.
18. Schramm ME, Roekevisch E, Leeang MMG, et al. A random-
ized trial of methotrexate vs. azathioprine for severe atopic
eczema. J Allergy Clin Immunol 2011; 128: 353-9.
19. Jenerowicz D, Silny W. Leczenie ogólne atopowego zapalenia
skóry. In: Atopowe zapalenie skóry. Silny W (ed.). Termedia,
Poznań 2012; 260-70.
20. Megitt SJ, Gray JC, Reynolds NI. Azathioprine dosed by thio-
purine methyltransferase activit for moderate to severe
atopic eczema: double blind, randomisswd, controlled trial.
Lancet 2006; 367: 839-46.
21. Berth-Jones J, Takwale A, Tan E, et al. Azathioprine in severe
adult atopic dermatitis: double- blind, placebo-controlled,
crossover trial. Br J Dermatol 2002; 147: 324-30.
22. Patel AN, Langan SM, Batchelor JM. A randomized trial of
methotrexate vs. azathioprine for severe atopic eczema:
a critical appraisal. Br J Dermatol 2012; 166: 701-4.
23. Roekevisch E, Spuls PI, Keuster D, et al. Ecacy and safety
of systemic treatments for moderate-to-severe atopic der-
matitis: a systemic review. J Allergy Clin Immunol 2014; 133:
429-38.
24. Murphy LA, Atherton D. A retrospective evaluation of aza-
thioprine in severe childhood atopic eczema using thiopurine
methyltransferase levels to exclude patients at high risk my-
elosuppression. Br J Dermatol 2002; 147: 308-15.
25. Caueld M, Tom WL. Oral azathiopryne for recalcitrant pe-
diatric atopic dermatitis: clinical response and thiopurine
monitoring. J Am Acad Dermatol 2013; 68: 29-35.
26. Hon KL, Ching GK, Leung TF, et al. Ecacy and tolerability
at 3 and 6 months following use of azathiopryne for recalci-
trant atopic dermatitis in children and young adults. J Der-
matol Treat 2009; 20: 141-5.
27. 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; 79: 92-6.
Advances in Dermatology and Allergology 2, April / 2020134
R.J. Nowicki, M. Trzeciak, M. Kaczmarski, A. Wilkowska, M. Czarnecka-Operacz, C. Kowalewski, L. Rudnicka, M. Kulus,
A. Mastalerz-Migas, J. Peregud-Pogorzelski, M. Sokołowska-Wojdyło, R. Śpiewak, Z. Adamski, J. Czuwara, M. Kapińska-Mrowiecka,
A. Kaszuba, D. Krasowska, B. Kręcisz, J. Narbutt, S. Majewski, A. Reich, Z. Samochocki, J. Szepietowski, K. Woźniak
28. Czarnecka-Operacz M, Silny W. Specic immunotherapy in
atopic dermatitis. Acta Dermatovenerol Croat 2006; 14: 52-9.
29. Jutel M, Solarewicz-Madejek K, Węgrzyn A. Allergen-specic
immunotheraphy in atopic dermatitis. Adv Dermatol Allergol
2011; 28: 389-95.
30. Silny W, Czamecka-Operacz M. Spezische Immuntherapie
bei der Behandlung von Patienten mit atopischer Dennatitis.
Ergeb-nisse einer placebokontrollierten Doppelblindstudie.
Allergologie 2006; 29: 171-83.
31. Silny W, Jenerowicz D. Immunoterapia swoista. In: Atopowe
zapalenie skóry. Silny W (ed.). Termedia, Poznań 2012; 271-8.
32. Kim SO, Ah YM, Yu YM, et al. Effects of probiotics for the
treatment of atopic dermatitis: a meta-analysis of random-
ized controlled trials. Ann Allergy Asthma Immunol 2014; 113:
217-26.
33. Lee J, Seto D, Bielory L. Meta-analysis of clinical trials of pro-
biotics for prevention and treatment of pediatric atopic der-
matitis. J Allergy Clin Immunol 2008; 121: 116e.
34. Li L, Han Z, Niu X, et al. Probiotic supplementation for pre-
vention of atopic dermatitis in infants and children: a sys-
tematic review and meta-analysis. Am J Clin Dermatol 2019;
20: 367-77.
35. Folster-Holst R, Müller F, Schnopp N, et al. Prospective, ran-
domized controlled trial on Lactobacillus rhamnosus in in-
fants with moderate tosevere atopic dermatitis. Br J Derma-
tol 2006; 155: 1256-61.
36. Cuello-Garcia CA, Brożek JL, Fiocchi A, 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.
37. Farina S, Gisondi P, Zanoni M, et al. Balneotherapy for atopic
dermatitis in children at Comano spa in Trentino, Italy. J Der-
matolog Treat 2011; 22: 366-71.
38. Lee MS, Choi J, Posadzki P, Ernst E. Aromatherapy for health
care: an overview of systematic reviews. Maturitas 2012; 71:
257-60.
39. Posadzki P, Alotaibi A, Ernst E. Adverse eects of aromather-
apy: a systematic review of case reports and case series. Int
J Risk Saf Med 2012; 24: 147-61.
40. Vestergaard C, Wollenberg A, Barbarot S, et al. European
task force on atopic dermatitis position paper: treatment of
parental atopic dermatitis during preconception, pregnancy
and lactation period. J Eur Acad Dermatol Venereol 2019; 33:
1644-59.
41. Paller AS, Tom WL, Lebwohl MG, et al. Ecacy and safety
of crisaborole ointment, a novel, nonsteroidal phosphodies-
terase 4 (PDE4) inhibitor for the topical treatment of atopic
dermatitis (AD) in children and adults. J Am Acad Dermatol
2016; 75: 494-503.
42. Eicheneld LF, Call RS, Forsha DW, et al. Long-term safety
of crisaborole ointment 2% in children and adults with mild
to moderate atopic dermatitis. J Am Acad Dermatol 2017;
77: 641-9.
43. Zhong CS, Elmariah SB. Novel therapies in the treatment of
atopic dermatitis. Semin Cutan Med Surg 2018; 37: 190-7.
44. Hon KL, Leung AKC, Leung TNH, Lee VWY. Investigational
drugs for atopic dermatitis. Expert Opin Investig Drugs 2018;
27: 637-47.
45. Chiricozzi A, Peroni D, Girolomoni G. Testing biologics and in-
tracellular signaling inhibitors on pediatric atopic dermatitis:
a stairway to modern therapeutic approaches. Expert Opin
Investig Drugs 2018; 27: 699-707.
46. Edwards T, Patel NU, Blake A, et al. Insights into future thera-
peutics for atopic dermatitis. Expert Opin Pharm 2018; 19:
265-78.
47. Thijs JL, Strickland I, Bruijnzeel-Koomen CA, et al. Moving
toward endotypes in atopic dermatitis: Identication of pa-
tient clusters based on serum biomarker analysis. J Allergy
Clin Immunol 2017; 140: 730-7.
