Narrative review on the management of moderate-severe atopic dermatitis in pediatric age of the Italian Society of Pediatric Allergology and Immunology (SIAIP), of the Italian Society of Pediatric Dermatology (SIDerP) and of the Italian Society of Pediatrics (SIP).

Currently, there are a few detailed guidelines on the overall management of children and adolescents with moderate-severe atopic dermatitis. AD ​​is a complex disease presenting with different clinical phenotypes, which require an individualized and multidisciplinary approach. Therefore, appropriate interaction between primary care pediatricians, pediatric allergists, and pediatric dermatologists is crucial to finding the best management strategy. In this manuscript, members of the Italian Society of Pediatric Allergology and Immunology (SIAIP), the Italian Society of Pediatric Dermatology (SIDerP), and the Italian Society of Pediatrics (SIP) with expertise in the management of moderate-severe atopic dermatitis have reviewed the latest scientific evidence in the field. This narrative review aims to define a pathway to appropriately managing children and adolescents with moderate-severe atopic dermatitis.

Introduction

Atopic dermatitis (AD) represents the most frequent chronic inflammatory skin disease in pediatric age with an estimated between 16 and 20%. The health and social costs of the disease are relevant not only for the complexity of pharmacological treatments, but also for the very frequent complications, for the strong impact on the psychological balance of families and on the times of assistance required, on the quality of life of the sick and family members, on sleep disorders and on attention disorders and irritability that follow [1]. Erythematous lesions, papules and vesicles, crusty scratching lesions for severe itching, lichenification and xerosis are the clinical features whose severity is measured through various objective scales such as the SCORAD index [2] (Severity ScoRing of Atopic Dermatitis) or EASI [3] (Eczema Area and severity index)

AD displayed a growing body of new comorbidities also in dermatology and oral diseases (4-%). An observational study conducted by Perugia et al [4, 5], found a higher prevalence of atopic dermatitis in pediatric dentistry patients compared to the general population suggesting that dental diseases could be involved in the pathogenesis of AD. Furthermore that actually Italia guidelinestend [6, 7] to be more anymore inclusive for pediatrics, however a dedicated document is mandatory to highlight knowledge gaps.

Experts of the Italian Society of Pediatric Allergology and Immunology (SIAIP), the Italian Society of Pediatric Dermatology (SIDerP), and the Italian Society of Pediatrics (SIP) have updated the management of AD in the light of the most recent pathogenetic and therapeutic findings

Methods

A joint Task Force of experts of the SIAIP, SIDerP, and SIP defined the topics to address in the review (appendix 1)

A literature search was performed in September 2021 across MEDLINE/PUBMED to identify studies investigating the management of moderate-to-severe AD in the pediatric age. We included randomized controlled trials (RCTs), observational (cross-sectional and cohort), case-control studies, and systematic review and meta-analyses, which [8] were written in English, [9] included patients 0-18 years of age with moderate-severe AD, either isolated or associated with other atopic comorbidities, [10] reported systemic monotherapy or systemic therapy with topical anti-inflammatory therapy (combination therapy) or topical anti-inflammatory therapy alone, and [11] reported efficacy and/or safety. The search criteria were atopic dermatitis* OR atopic eczema* OR eczema* AND severe* OR moderate-severe* OR therapy* OR treatment* OR azathioprine* OR ciclosporin* OR methotrexate* OR mycophenolate* OR interferon-gamma* OR upadacitinib* OR baricitinib* OR dupilumab* OR dupixent* OR abrocitinib* or tralokinumab* OR nemolizumab* OR lebrikizumab* OR biologic* OR biological* OR topical* OR corticosteroid* OR glucocorticoid* OR calcineurin inhibitor* OR immunomodulator* OR immunosuppressant* OR tacrolimus* OR pimecrolimus* OR wet-wrap* OR Janus Kinase inhibitor* OR antibodies* OR monoclonal* OR antimicrobial* OR antibiotic* OR antiviral* OR antihistamine* OR emollient* OR moisturizer* OR phototherapy* OR immunotherapy* OR education* OR intervention*. Titles and abstracts of citations identified from searches and content of relevant full texts were evaluated. Studies that did not specifically measure the severity of AD, using either the Eczema Area and Severity Index (EASI), or Investigator’s Global Assessment (IGA), or the SCORing Atopic Dermatitis (SCORAD), were excluded. The special interest was in studies published within the last 36 months. The screening was conducted by 2 investigators (one pediatric allergist and one pediatric dermatologist), with a third investigator (EG) resolving any disagreements.

Conclusions

In recent years, important insights into the pathogenesis of AD have been observed; this aspect was evidently reflected in drug therapy; in particular the moderate-severe forms are those in which we have had the greatest therapeutic innovations. The purpose of this narrative review was to update knowledge in the management of AD with a particular reflection on those situations where biological drugs may be involved. Having combined the knowledge of pediatricians, allergists and dermatologists should allow us to have a valid document for all those who deal with AD in pediatric age.

Table 1

Potency classification of topical corticosteroids (from patrizi et al, [13])

Group/Potency	Active ingredient	Vehicle	Concentration (%)
Group I - Mild	Hydrocortisone	cream	0.5
	Hydrocortisone acetate	cream	0.5
Group II - Moderate	Aclomethasone dipropionatea
	Clobethasone butyrate	cream	0.5
	Dexamethasone sodium phosphate	ointment	0.2
	Dexamethasone valerate	cream	0.1
	Desonidea
	Fluocortinbutylestera
	Hydrocortisone butyrate	cream, cream hydrophilic, emulsion, cutaneous solution, ointment	0.1
Group III - Potent	Beclomethasone dipropionate	cream	0.025
	Betamethasone benzonate	cream	0.025
		cream, skin emulsion, gel	0.1
	Beclomethasone dipropionate	cutaneous solution	0.05
		cream, skin emulsion, ointment	0.1
	Betamethasone dipropionate	cream, cutaneous solution, ointment	0.05
	Budesonide	cream, oinment	0.025
	Deoxymethasone	emulsion	0.25
	Diflucortolone valerate	cream, cream hydrophobic, cutaneous solution, ointment	0.1
		cream hydrophobic, ointment	0.3
	Diflucortone valerianatea
	Fluocinolone acetonide	cream	0.025
		cutaneous solution	0.01
	Fluocinonide	cream, gel, cutaneous solution	0.05
	Fluocortolone pivalate / caproate	cream hydrophobic	0.25
		cream	0.25
	Fluticasone propionate	oinment	0.005
		cream	0.05
	Methylprednisolone aceponate	cream, cream hydrophobic, emulsion, cutaneous solution ointment	0.1
	Mometasone furoate	cream, cutaneous solution, ointment	0.1
	Prednicarbato	cream	0,25
Group IV – Very potent	Alcinonide	cream	0.1
	Clobetasol propionate	oinment	0.05

amolecules not available in Italy

Table 2

Adequate doses of topical corticosteroids to be applied in finger tip unit (ftu) (modified from katoh et al, [2])

1 FTU = 0.5 g
Child	Face and neck	Upper limb	Lower limb	Trunk	Back
3-6 months	1	1	1,5	1	1,5
1-2 years	1,5	1,5	2	2	3
3-5 years	1,5	2	3	3	3,5
6-10 years	2	2,5	4,5	3,5	5
Adult	Face and neck	Upper limb	Lower limb	Trunk	Back
	2,5	3+1	6 + 2	7	7

Table 3

Main effects of topical calcineurin inhibitors compared to topical corticosteroids

Parameter	Topical Pimecrolimus (810 Da)	Topical Tacrolimus (822 Da)	Topical Corticosteroids (<500 Da)
Activity on cells	T Lymphocytes, Mast cells,	T Lymphocytes, Mast cells, Eosinophils, Basophils, Langherans cells,	T Lymphocytes, Mast cells, Eosinophils, Basophils, Langherans cells, Keratinocytes, Endothelial cells, Fibroblasts
Cytokines	IL-2, IL-3, IL-4, IL-5,IL-13,IL-33, TNF-α, INF-γ, GM-CSF	IL-2, IL-3, IL-4, IL-5,IL-13,IL-31,IL-33, TNF-α, INF-γ, GM-CSF	IL-1,IL-2, IL-3, IL-4, IL-5,IL-6, IL-13,IL-31,TNF-α, INF-γ, GM-CSF,TSLP
Inhibition function and Apoptosis of Langherans cells	-	+	++
Absorption through the skin	+	++	+++
Atrophogenic activity	-	-	+++

Table 4

Indications and contraindications for topical tacrolimus (ttac) 0.03% and 0.1% ointment

Indications

• Moderate to severe dermatitis in sensitive body sites (first choice)

• Moderate to severe atopic dermatitis in which (one of the following applies): a) there is no response to first-line therapy with TCSs; b) there are contraindications to treatment with TCSs; c) undesirable effects induced by the use of TCSs may occur, such as skin atrophy or telangiectasia; d) Long-term maintenance therapy is required. Tacrolimus is approved for maintenance therapy to prevent relapses of AD and prolong intervals without flare-ups in patients experiencing a high frequency of relapses. In all these patients, sunscreen should be encouraged to reduce a hypothetical risk of photocarcinogenesis.

Contraindications

Absolute

Hypersensitivity to tTAC or other components of the ointment

Relative

a) children aged <2 years (0.03% concentration is indicated for age 2- <16 years; 0.1% concentration is indicated for ≥ 16 years). The use in this age group is off-label, but with various studies supporting the safety of use at age <2 years.

b) active skin infections (viral and/or bacterial) in place at the application site

c) eroded or ulcerated surfaces at the application site (if they were present in multiple forms, the application of this ointment should be started after the improvement of the lesions obtained with TCSs).

d) immunocompromised patients primitively, secondarily, or taking immunosuppressive drugs and/or with neoplasms

e) any lymphadenopathies present at the time of starting therapy should be evaluated and kept under observation

f) should not be used under occlusive dressing

g) the combination with phototherapy is not recommended

tTCA should not be applied to the skin within two hours of applying an emollient cream

Table 5

Indications and contraindications for topical pimecrolimus (tpim) 1% cream

Indications

• Mild to moderate dermatitis in sensitive body sites (first choice)

• Moderate to severe atopic dermatitis in which (one of the following applies): a) there is no response to first-line therapy with TCSs; b) there are contraindications to treatment with TCSs; c) undesirable effects induced by the use of TCSs may occur, such as skin atrophy or telangiectasia; d) Long-term maintenance therapy is required. Pimecrolimus is approved for maintenance therapy to prevent re-ignition and prolong intervals without flare-ups in patients experiencing high relapse rates. In all these subjects, sunscreen should be encouraged to reduce a hypothetical risk of photocarcinogenesis

Contraindications

Absolute

Hypersensitivity to tPIM or other components of the cream

Relative

a) children aged <2 years (0.03% concentration is indicated for age 2- <16 years; 0.1% concentration is indicated for ≥ 16 years). The use in this age group is off-label, but with various studies supporting the safety of use at age <2 years.

b) active skin infections (viral and/or bacterial) in place at the application site

c) eroded or ulcerated surfaces at the application site (if they were present in multiple forms, the application of this ointment should be started after the improvement of the lesions obtained with TCSs).

d) immunocompromised patients primitively, secondarily, or taking immunosuppressive drugs and/or with neoplasms

e) any lymphadenopathies present at the time of starting therapy should be evaluated and kept under observation

f) should not be used under occlusive dressing

g) the combination with phototherapy is not recommended

tPIM should not be applied to the skin within two hours of applying an emollient cream

Table 6

Characteristics of the main fabrics on the market

Fabric type	Features
Sea Cell Active fibers® Smart Fiber AG, Thuringia, Germanya	Made using Lyocell, dried algae are crushed, ground, and incorporated into cellulose fiber. The antibacterial effect is obtained through the activation of metal ions.
SkinDoctor® Ventex Co., Ltd., Korea	It is a silver-associated cellulose fabric made with algae, with a moisture control system. To produce the fabric, a semi-permanent antibacterial (titanium dioxide-silver) is applied to the regenerated rayon (Lyocell; Lenzing AG, Lenzing, Austria). This rayon represents 60% of the final fabric and the remaining 40% is made up of polyester.
Skintoskin® New Textiles, Ltd, London	It is a fabric of cellulose fibers with algae enriched with silver ions.
Chitosan	Chitosan is a product of the waste from the crustacean food industry. It is a biopolymer with biological, physiological, and pharmacological properties, such as biodegradability, non-toxicity, and strong antibacterial activity against both Gram-positive and Gram-negative bacteria thanks to the combined bactericidal and bacteriostatic action.
MICROAIR DermaSilk ® (AlPreTec Srl, San Donà di Piave, Italya	Fabric is made of 100% silk fibroin, an animal protein composed of the same amino acids (glycine, alanine, serine, etc.) that form the stratum corneum, with added ammonium quaternary.
DreamSkin TM (DreamSkin Health Ltd, Hatfield, UK)	Fabric made with silk fiber finished with DreamSkin® polymer and a zinc-based antibacterial. It is based on the same technology used for contact lenses.
Padycare® Texamed GmbH	It is made of silver-coated polyamide fibers.
Binamed® Binamed Moll GmbH	It consists of two different yarns, the micro modal fiber, and the silver thread.

aAvailable in Italy

Table 7

History of approvals of dupilumab for atopic dermatitis by international regulatory agencies

Approval date	FDA	EMA	AIFA
Adults with moderate to severe AD inadequately controlled	March 2017	September 2017	August 2018a
Adolescents 12-17 years, with moderate to severe AD inadequately controlled	March 2019	August 2019	November 2020b
Children 6-11 years, with moderate to severe AD inadequately controlled	May 2020	October 2020	January 2022c

aAdult patients with EASI score ≥ 24, for whom cyclosporine therapy is contraindicated, ineffective, or not tolerated. Reimbursement class: H, medicinal product subject to restrictive medical prescription, to be renewed from time to time, sold to the public on prescription from hospitals or dermatologist specialists (RNRL)

bAdolescents eligible for systemic therapy without prior use of cyclosporine; medicine subject to a limited medical prescription, to be renewed from time to time, sold to the public on prescription from hospitals or specialists - dermatologist, pulmonologist, allergist, otolaryngologist, immunologist and pediatrician (RNRL)

cFrom 20 December 2022 it is possible to use dupilumab in a reimbursable regime as an innovative non-oncological drug for the treatment of severe AD in children aged 6 to 11 eligible for systemic therapy who have an EASI score ≥24 or one of the following characteristics: localization in visible and / or sensitive areas; evaluation of pruritus with NRS ≥7 scale; quality of life assessment with CDLQI index ≥10

Table 8

Dupilumab in adolescents with moderate to severe dermatitis

Main clinical trials
Phase 2 open-label study R 668-AD1412
Pharmacokinetics, safety, efficacy in patients aged 6 to 17 years
Liberty ADOL
Phase 3 pilot monotherapy study R 668-AD 1526
Safety and efficacy in patients aged 12 to 17 years
Liberty AD PED OLE
Phase 3 study Open-Label Extension (OLE) R 668-AD 1434
Safety and efficacy in patients 6 months to <18 years

Table 9

Recommended dose of dupulumab for the treatment of pediatric atopic dermatitis

Adolescents between the ages of 12 and 17
Bodyweight	Starting dose	Subsequent doses
Less than 60 kg	400 mg (two 200 mg injections)	200 mg every 2 weeks
60 kg or more	600 mg (two 300 mg injections)	300 mg every 2 weeks
Children between the ages of 6 and 11
Bodyweight	Starting dose	Subsequent doses
15 to less than 60 kg	300 mg (one 300 mg injection) on day 1, followed by 300 mg on day 15	300 mg every 4 weeksa, starting 4 weeks after the day 15 dose
60 kg or more	600 mg (two 300 mg injections)	300 mg every 2 weeks

aThe dose may be increased to 200 mg every 2 weeks in patients weighing 15 kg to less than 60 kg based on the physician's assessment

Table 10

Flow chart for the possible multidisciplinary management of pediatric moderate-severe atopic dermatitis in italy

	Healthcare facility	Actor	Action
Phase 1	General Practice	Primary Care Pediatrician and General Practitioner	• Management of mild AD, • Promotion of basic management strategies of AD (i.e. moisturizing, mild-moderate potency topical steroids, antibiotics) • Refer moderate-severe AD patients to specialists
Phase 2	Community or 1-2nd levels Hospitals	Pediatric Allergist and/or Dermatologist	• Management of mild to moderate AD (SCORAD <50) using I-II line therapy (eg. Wet-wrap therapy; phototherapy) • Specific testing, if needed (eg. skin prick test and/or serum specific IgE testing, patch test, biopsy) • Educational therapy • To refer the patient to a University or 3rd level Hospital if severe AD (SCORAD >50) or difficult to treat AD patient
Phase 3	University or 3rd level Hospitals	Pediatric allergist AND dermatologist	• Re-evaluation of differential diagnosis and comorbidities • Definition of the baseline severity (SCORAD and EASI) and further specific testing, if needed • To start III line therapies for severe AD (eg. add on immunosuppressants, biologics) and management of eventual comorbidities • Involvement of other specialist health care professionals (eg. immunologist, psychologist, dietician)