10.5826/dpc.1201a155
Atopic dermatitis is a Th2 disease, due to relapse of IL-4 and IL-13 by Th2 cells. Despite the approval by FDA of dupilumab, the first monoclonal antibody for the severe forms, traditional drugs remain a milestone for the treatment of this dermatosis. Dermatologists need a good knowledge of all therapies for an integrated and personalized management of patients.
text/xml
2160-9381
2310
en
Giuseppe Argenziano
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
systemic therapy
Topical and Conventional Systemic Treatments in Atopic Dermatitis: Have They Gone Out of Fashion?
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2022-02-02
2022-01-12
2022-02-02
2022-02-09
e2022155
Dermatol Pract Concept
Atopic dermatitis is a Th2 disease, due to relapse of IL-4 and IL-13 by Th2 cells. Despite the approval by FDA of dupilumab, the first monoclonal antibody for the severe forms, traditional drugs remain a milestone for the treatment of this dermatosis. Dermatologists need a good knowledge of all therapies for an integrated and personalized management of patients.
Giuseppe Argenziano
2022/02/02
10.5826/dpc.1201a155
e2022155
Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
2160-9381
systemic therapy
en
e2022155
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; 367:839–846. DOI: 10.1016/S0140-6736(06)68340-2. PMID: 16530578.
Topical and Conventional Systemic Treatments in Atopic Dermatitis: Have They Gone Out of Fashion?
https://dpcj.org/index.php/dpc/article/download/2310/1502
 Topical and Conventional Systemic Treatments in
Atopic Dermatitis: Have They Gone Out of Fashion?
Giulia Calabrese1, Gaetano Licata1, Alessio Gambardella1, Alina De Rosa1, Roberto Alfano2,
                                  Giuseppe Argenziano1


1 Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli,
  Naples, Italy
2 Department of Anesthesiology Surgery and Emergency, University of Campania Luigi Vanvitelli, Naples, Italy.



Keywords: atopic dermatitis, treatments, therapy, topicals, systemic therapy
Citation: Calabrese G, Licata G, Gambardella A, De Rosa A, Alfano R, Argenziano G. Dermatol Pract Concept. 2022;12(1):e2022155.
DOI: https://doi.org/10.5826/dpc.1201a155
Accepted: January 7, 2022; Published: January 2022
Copyright: ©2022 Calabrese et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Giulia Calabrese, MD, Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine,
University of Campania Luigi Vanvitelli, E-mail: allergologiavanvitel-li@gmail.com




   This article is part of a series of reviews dedicated to Atopic Dermatitis, guest edited by Prof Anna Balato.

   Guest Editor

   Prof. Anna Balato, MD, PhD

   Associate Professor of Dermatology, Dermatology Unit, University of Campania, Naples, Italy




  ABSTRACT                 Atopic dermatitis is a Th2 disease, due to relapse of IL-4 and IL-13 by Th2 cells. Despite the approval
                           by FDA of dupilumab, the first monoclonal antibody for the severe forms, traditional drugs remain a
                           milestone for the treatment of this dermatosis. Dermatologists need a good knowledge of all therapies
                           for an integrated and personalized management of patients.




Introduction                                                                        IL-13 by Th2 cells. IL-4 and IL-13 are involved in the survival
                                                                                    of Th2 cells, differentiation and activation of myeloid and den-
Atopic dermatitis (AD) is a chronic, inflammatory skin disease,                     dritic cell, B-cell maturation, stimulation of IgE class switching,
characterized by a multifactorial pathogenesis. AD is consid-                       eosinophil chemotaxis and down-regulation of genes involved
ered a prototypical Th2 disease, due to relapse of IL-4 and                         in skin barrier function (fillagrin, locrin, and involucrin).



Review | Dermatol Pract Concept. 2022;12(1):e2022155                                                                                                 1
    Conventional treatments represent a cornerstone of AD         maintenance treatment. There are few studies that have com-
therapy and are the first-line therapy for the mild-moder-        pared moisturizers, but results are overlapping. Therefore,
ate forms. With biological drugs rapidly emerging, it is im-      the choice of moisturizing agent is highly dependent on indi-
portant for clinicians to combine the new treatments with         vidual preference [5].
the traditional ones to improve the response of the patients         In AD, the alteration of skin barrier is associated with
[1-4,17].                                                         reduced ceramide levels, with a consequential increase in
                                                                  trans-epidermal water loss (TEWL) and reduction in skin
Conventional therapy for AD                                       hydration.
Conventional treatments for AD can be differentiated in              It is not yet known whether dupilumab restores skin
topical and systemic. Topical agents are moisturizers, cor-       barrier function. The latter can be investigated using TEWL
ticosteroids, calcineurin inhibitors and antimicrobials/anti-     (that is the water evaporization rate in g/h/m2) and stratum
septics, used in monotherapy or in combination. In the field      corneum hydration (SCH) (the water content in the stratum
of topical therapies, wet wrap therapy must also be men-          corneum measured by Corneometer®).
tioned [5-9].                                                        According to a recent study, following treatment with
    Systemic treatments, used for severe and recalcitrant         dupilumab, TEWL decreases quickly in the skin interested
forms, consist in phototherapy, systemic corticosteroids, cyc-    by AD, while SCH does not improve. Because of the small
losporine, methotrexate, mycophenylate mofetil and azathi-        sample size in this study, further papers are needed but it
oprine [10].                                                      seems that dupilumab have no effects for dry skin conditions
                                                                  and patients have to continue the use of moisturizers [12].
Moisturizers
Moisturizers are used to combat xerosis (one of the cardi-        Topical corticosteroids
nal clinical features of AD and the result of a dysfunctional     Topical corticosteroids (TCS) inhibit the antigen processing
epidermal barrier) and transepidermal water loss. They re-        and suppress the release of pro-inflammatory cytokines, act-
duce disease severity, the need for pharmacologic interven-       ing on a variety of immune cells, including T lymphocytes,
tion and should be applied soon after bathing, almost once        monocytes, macrophages, and dendritic cells. Their efficacy
a day [5-7].                                                      has been demonstrated, with more than 110 different ran-
    Moisturizers can be classified in traditional (glycol and     domized controlled trials [5]. Twice daily application of
glyceryl stearate, soy sterols, petrolatum, dimethicone, min-     corticosteroids is generally recommended for the treatment
eral oil, glycerol, lactic acid, urea) and prescription emol-     of AD; however, evidence suggests that once daily applica-
lient devices (PEDs). Traditional agents contain varying          tion may be sufficient. As maintenance therapy to reduce
amounts of emollient, occlusive and humectant ingredients.        the number of relapses, a “proactive” approach can be pre-
Emollients (eg glycol and glyceryl stearate, soy sterols) lu-     script. It consists of applying TCS intermittently once or
bricate and soften the skin, occlusive agents (eg petrolatum,     twice a week in the areas most prone to relapse, even when
dimethicone, mineral oil) form a layer to reduce evaporation      no inflammatory lesions are visible. The CHRONOS study
of water, while humectants (.g glycerol, lactic acid, urea) at-   examined the use of dupilumab combined with topical corti-
tract and hold water. Several clinical trials have shown that     costeroids versus placebo in 52 weeks of treatment. Thanks
they lessen symptoms and signs of AD, including pruritus,         to the combination with topical corticosteroids, 10% of
erythema, fissuring, and lichenification [5-7].                   patients more than in the SOLO studies (that have tested
    The term PED has been introduced to identify a new            just dupilumab versus placebo) achieved a 75% reduction in
class of topical agents designed to target the specific defects   EASI score [13].
in skin barrier function observed in AD. They include prepa-
rations having distinct ratios of lipids that mimic endoge-       Wet Wrap Therapy
nous compositions and containing palmitoylethanolamide,           The wet wrap therapy (WWT) is a method to quickly reduce
glycyrrhetinic acid, or other hydrolipids. PEDs may contain       AD severity, used for significant flares and recalcitrant dis-
an antioxidant agent, such as furfuryl palmitate or furfuryl      ease. It consists in the application of topical agent (TCS or
derivatives. PEDs lessen xerosis and inflammation but they        moisturizers or combination of both) covered by a wetted
have been tested in a small number of controlled studies [11].    first layer of tubular bandages, gauze, or a cotton suit, fol-
    Moisturizers are the main primary treatment for mild          lowed by a second dry layer.
forms and should be part of the regimen for moderate and             WWT increases the penetration of topical therapy and
severe ones because they reduce inflammation, the prescrip-       reduces the water loss. The wrap can be worn from several
tion of topical corticosteroids and prevent the flares in the     hours to 24 hours at a time, depending on patient tolerance




2                                                                              Review | Dermatol Pract Concept. 2022;12(1):e2022155
and the application can be repeated for several days up to             Multiple forms of light therapy are beneficial for disease
2 weeks. The major limitation of this technique is repre-           and symptom control, including: natural sunlight, narrow-
sented by the lack of practicality and the low tolerance for        band (NB) UVB, BB-UVB, UVA, topical and systemic PUVA.
patients, especially if children [8,9].                             Home phototherapy under the direction of a physician may
                                                                    be considered for patients who are unable to receive photo-
Topical Calcineurin Inhibitors                                      therapy in a medical office setting.
Topical calcineurin inhibitors (TCIs) inhibit calcineurin-de-          The light modality chosen should be guided by factors
pendent T-cell activation, blocking the production of pro-in-       such as availability, cost, patient skin type, skin cancer his-
flammatory cytokines. Two types of TCIs are available:              tory, and patient use of photosensitizing medications (for
tacrolimus ointment (0.03% and 0.1% strengths) and pi-              example calcineurine inhibitor). The dosing and scheduling
mecrolimus cream (1% strength). TCIs are recommended                of light should be based on minimal erythema dose and Fitz-
and effective for acute and chronic treatment, twice a day,         patrick skin type. Phototherapy is usually administered 3
as well as maintenance, in both adults and children with            times a week.
AD. They can be used as steroid-sparing agents in long term            NB-UVB is generally the most commonly recommended
therapy because they do not cause cutaneous atrophy and             light treatment, considering its low risk profile and the rela-
can be used in sensitive areas, such as the face, skin folds        tive efficacy. Several common adverse effects include: actinic
and genitals. Tacrolimus 0.03% ointment and pimecrolimus            damage, local erythema and tenderness, pruritus and burn-
cream are indicated for use in individuals aged 2 years and         ing [10].
older, while tacrolimus 0.1% strength is only approved in
those over age 15 years. Proactive, intermittent use of TCIs        Systemic Corticosteroids
as maintenance therapy (2–3 times a week) on areas that             The management of AD with systemic corticosteroids should
commonly flare is recommended to prevent relapses and is            generally be avoided because of short- and long-term adverse
more effective than the use of emollients alone. This strategy      effects. Their use should be exclusively reserved for acute,
has been tested for up to 1 year, without significant adverse       severe exacerbations and as a short-term bridge therapy to
events. The most common side effects are local reactions            other systemic, steroid-sparing therapy [10].
such as stinging and burning. TCIs may be combined with
TCS [5].                                                            Cyclosporine
   For patients undergoing dupilumab injections, tacroli-           Cyclosporine (CSA) is an immunosuppressant of T-cells
mus ointment and pimecrolimus cream may be helpful to               and interleukin-2 production, used for adult and pedi-
treat facial eczema (that responds later to dupilumab) and          atric patients with severe or refractory form of AD. The
peripalpebral dermatitis (as a prevention of dupilumab as-          dosage of CSA (available in oral capsules and solution)
sociated conjunctivitis). Conjunctivitis is the most common         ranges from 3 to 6 mg/kg/d, standardly 150 to 300 mg/
side effect of dupilumab [14]. The prescription of trehalose/       day in adults, divided in two doses. The initial and main-
hyaluroate tear substitute and the treatment of peripalpebral       tenance dose of CSA should be based on multiple factors,
and facial eczema with topical therapy reduce the incidence         including the patient’s disease severity and other medical
of dupilumab-associated conjunctivitis (incidence equal to          morbidities. Potential adverse effects include: hyperten-
5% with preventive therapy versus an incidence of 8% and            sion, infection, nephrotoxicity, hypertension, tremor, hy-
8-23% without preventive therapy, according to trial stud-          pertrichosis, headache, gingival hyperplasia, and increased
ies and real life studies respectively) [15]. Moreover, new         risk of skin cancer and lymphoma. Thus, patients receiving
emerging problems are reported in literature: recalcitrant          CSA should be monitored for such potential consequences.
(pre-existing biological therapy) and dupilumab-associated          The recommended time limit for consecutive use of CSA
(probably induced by biological therapy) face and neck der-         is currently 1 year. Before starting therapy, the following
matitis are described and can benefit by topical therapy (an-       tests should be prescribed: blood count, renal and liver
tifungal-corticosteroids and tacrolimus ointment). Various          function, lipids, electrolytes, uric acid, hepatitis B and C
etiopathogenic mechanisms for these new regional derma-             markers, HIV and human chorionic gonadotropin (HCG)
toses have been proposed but more studies are needed [16].          if indicated. During therapy, blood pressure should be
                                                                    measured twice a week and blood tests should be tested
Phototherapy                                                        monthly [10]. CSA can be associated with dupilumab
Phototherapy is used as second-line treatment, after failure        in the initial phase of therapy to induce faster the clini-
of first-line treatment (emollients, topical steroids, and TCIs),   cal remission or in patients recalcitrant to dupilumab in
or as maintenance therapy in patients with chronic disease.         monotherapy [17].




Review | Dermatol Pract Concept. 2022;12(1):e2022155                                                                             3
Methotrexate                                                      individual’s thiopurine S-methyltransferase (TPMT) activity
Methotrexate (MTX) is an antifolate metabolite and blocks         level, a principal enzyme in the thiopurine pathway. Genetic
the synthesis of DNA, RNA, and purines. It is also thought        polymorphisms in TPMT activity are linked to a patient’s
to negatively affect T-cell function. Its many off-label uses     susceptibility to AZA toxicity, such that the homozygous
include treatment of refractory AD. MTX is available in           carrier state of low or absent enzyme capacity poses the
solution (for intramuscular or subcutaneous injection) and        greatest toxicity risk. Thus, baseline TPMT level testing is
oral tablet form. MTX is usually given as a single weekly         strongly recommended before AZA initiation, with avoid-
dose. The dose range for MTX in patients with AD is ex-           ance of use in those with very low or absent enzyme ac-
trapolated from its use in psoriasis and it is between 7.5        tivity. Concomitant phototherapy is not advised because of
and 25 mg weekly. Folate supplementation is recommended           increased risk of DNA damage and possible photocarcino-
during treatment with MTX. Nausea and other gastroin-             genicity. Nausea, vomiting and other gastrointestinal symp-
testinal symptoms may preclude oral administration. Se-           toms (bloating, anorexia, cramping) are common adverse
vere adverse effects, including bone-marrow suppression           effects. Other side effects include headache, hypersensitivity
and pulmonary fibrosis, can occur. Literature suggests that       reactions, elevated liver enzymes, and leukopenia. AZA can
bone-marrow suppression is often reversible upon MTX              be used for pediatric population in case of recalcitrant der-
dose reduction or discontinuation. Risk for skin cancer           matitis but there are not sufficient data to recommend an
and lymphoma has been reported, although some cases               optimal dose, duration of therapy, or to predict the relapse
of lymphoma arising during low-dose treatment have re-            rate upon discontinuation. However, the most common
gressed on drug discontinuation. Pulmonary fibrosis may           dosage given is 2.5 mg/kg/d, with a higher treatment range
occur with short- or long-term use of the medication, such        maximum of 4 mg/kg/d relative to adult dosing (maximum
that patients with pulmonary diseases (eg asthma, chronic         3 mg/kg/d) [10].
cough) may not be candidates. Before starting therapy, the
following tests should be prescribed: blood count, renal and      Mycophenolate Mofetil
liver function, lipids, electrolyte, uric acid, hepatitis B and   Mycophenolate mofetil (MMF) is an immunosuppressant
C markers, HIV and HCG if indicated. During the therapy,          that blocks the purine biosynthesis pathway of cells via the
blood tests should be tested monthly. There are no data           inhibition of inosine monophosphate dehydrogenase, selec-
about use of MTX in children affected by AD. Multiple             tively affecting B- and T-cells. It is recognized as an off-label
studies regarding its use in pediatric patients with psoriasis    therapy in patients with refractory forms of AD. Insufficient
show MTX as a safe, effective, and well-tolerated medica-         data exist to make recommendations regarding the opti-
tion [10]. Like cCSA, MTX can be associated with dupi-            mal MMF dosing or duration of therapy for patients with
lumab in recalcitrant patients, maintaining a good safety         AD. Dosing ranges from 0.5 to 3 g/d. MMF is available in
profile [17].                                                     oral suspension, capsules, and tablets, and it is given twice
                                                                  daily. MMF is generally well tolerated, with nausea, vomit-
                                                                  ing, and abdominal cramping being the most common side
Azathioprine
                                                                  effects. Rarely, hematologic (anemia, leukopenia, thrombo-
Azathioprine (AZA) is a purine analog that inhibits DNA
                                                                  cytopenia) and genitourinary (urgency, frequency, dysuria)
production, thus preferentially affecting cells with high pro-
                                                                  toxicities have been reported. There is a theoretical risk of
liferation rates, such as B-cells and T-cells during inflamma-
                                                                  increased susceptibility to viral and bacterial infections while
tory disease states. It is used off-label to treat inflammatory
                                                                  taking MMF, as it is clearly observed in patients with organ
cutaneous and systemic disorders, including refractory AD
                                                                  transplantation. Cutaneous malignancy and lymphoma are
with moderate improvement of dermatitis (equal to a 37%
                                                                  potential risks [10].
reduction of disease, measured by the Six Area, Six Sign AD
scoring system after 12 weeks) [18]. A delayed effect may be
noted, with some patients needing a treatment for 12 weeks
                                                                  Conclusions
or longer to achieve full clinical benefit. The dose range is
variable between 1 to 3 mg/kg/d. AZA is available in tablet       The introduction of dupilumab has changed the manage-
form only and may be given once daily.                            ment of patients with severe forms of AD but traditional
    Graduated dosing to maximize benefit while l­imiting          drugs remain a milestone for the treatment of mild-moderate
side effects is preferred, as a considerable number of pa-        AD and for combined therapies. Therefore, dermatologists
tients develops intolerable nausea and vomiting at higher         need a good knowledge of both fields of interest for an inte-
doses. The metabolism of AZA is dependent on an                   grated and personalized management of patients.




4                                                                             Review | Dermatol Pract Concept. 2022;12(1):e2022155
                                                            Table 1. Key points
 Moisturizers          Integral part of AD therapy, including in patients on biological treatment since it is able to reduce
                       inflammation and itching but not xerosis.
 Topical               Recommended for mild-to-moderate forms; they can be also helpful to accelerate the response to
 corticosteroids       systemic drugs, including biologics, to increase the efficacy and to control the flares.
 Topical               Recommended as steroid-sparing agents in long term therapy and mostly for the sensitive areas (face,
 calcineurin           skin folds and genitals). Useful to treat facial dermatitis (not responsive to dupilumab or dupilumab
 inhibitors            associated) and to prevent dupilumab associated conjunctivitis, if peripalpebral eczema is present.
 Phototherapy          Used as second-line treatment, after failure of first-line treatment (emollients, topical steroids, and
                       topical calcineurin inhibitors), or as maintenance therapy in patients with chronic disease.
 Traditional           First line therapy for severe forms and a valid choice in combination with dupilumab and in case of
 systemic drugs        inadequate response to biological drug, maintaining a good safety profile.


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Review | Dermatol Pract Concept. 2022;12(1):e2022155                                                                                             5
