Consensus on the therapeutic management of atopic dermatitis - Brazilian Society of Dermatology

Abstract

BACKGROUND

Atopic dermatitis is a highly prevalent inflammatory and pruritic dermatosis with a multifactorial etiology, which includes skin barrier defects, immune dysfunction, and microbiome alterations. Atopic dermatitis is mediated by genetic, environmental, and psychological factors and requires therapeutic management that covers all the aspects of its complex pathogenesis.

OBJECTIVES

The aim of this article is to present the experience, opinions, and recommendations of Brazilian dermatology experts regarding the therapeutic management of atopic dermatitis.

METHODS

Eighteen experts from 10 university hospitals with experience in atopic dermatitis were appointed by the Brazilian Society of Dermatology to organize a consensus on the therapeutic management of atopic dermatitis. The 18 experts answered an online questionnaire with 14 questions related to the treatment of atopic dermatitis. Afterwards, they analyzed the recent international guidelines on atopic dermatitis of the American Academy of Dermatology, published in 2014, and of the European Academy of Dermatology and Venereology, published in 2018. Consensus was defined as approval by at least 70% of the panel.

RESULTS/CONCLUSION

The experts stated that the therapeutic management of atopic dermatitis is based on skin hydration, topical anti-inflammatory agents, avoidance of triggering factors, and educational programs. Systemic therapy, based on immunosuppressive agents, is only indicated for severe refractory disease and after failure of topical therapy. Early detection and treatment of secondary bacterial and viral infections is mandatory, and hospitalization may be needed to control atopic dermatitis flares. Novel target-oriented drugs such as immunobiologicals are invaluable therapeutic agents for atopic dermatitis.

INTRODUCTION

Atopic dermatitis (AD) is a chronic inflammatory skin disease, with lesions showing typical morphology and distribution, and whose hallmark is intense pruritus. AD presents in patients with a personal or family history of atopic diseases such as asthma, rhinitis, or AD itself. It is one of the most frequent diseases of childhood, and its prevalence reaches up to 20% in infants and 2.1 to 4.9% in adults in Europe, North America, and Japan.^1-3 Annual incidence of new cases of AD in patients below the age of 17 in the US is 11%; 85% of AD patients first manifest the disease before the age of 5, but 20-40% of children with AD persist with the skin disease in adulthood. ^4,5 In the Brazilian population, prevalence of AD symptoms according to Solé et al. was 8.2% in children and 5.0% in adolescents. ⁶

Due to the complex pathogenesis of AD, which involves skin barrier defects, immune dysfunction, and microbiome alterations mediated by genetic, environmental, and psychological triggers, a single therapeutic approach is hardly capable of achieving disease control. ⁷ Increased transepidermal water loss (TEWL), decreased stratum corneum water content, and reduced expression of skin barrier proteins such as filaggrin and claudin 1 are the main alterations of the skin barrier in individuals with AD. ^8-10

Of note is the cytokine dysregulation, leading to Th2, Th1, Th17, and Th22 polarization, which varies according to age, ethnicity, and AD phase. ^11-13

Skin microbiome plays a crucial role in AD; about 90% of the skin of atopic individuals is colonized by Staphylococcus aureus (S. aureus). ¹⁴ The diversity of skin microbiome of AD patients shows temporal shifts, with a predominance of S. aureus during flares and Streptococcus, Propionibacterium, and Corynebacterium after treatment. ¹⁵

AD remains a challenging disease. Ideal treatment is targeted to long-term disease control with reduction of flares and maintenance of good quality of life. Moreover, treatment approaches depend on geographic, economic, and genotypic/phenotypic variations.

This paper aims to communicate the experience, opinions, and recommendations of Brazilian dermatology experts on atopic dermatitis treatment.

METHODS

Eighteen faculty members from 10 university hospitals with expertise in AD were appointed by the Brazilian Society of Dermatology. The first step was the application of an online questionnaire with 14 questions regarding the management of AD patients by the experts at university hospitals. Table 1 shows the compiled answers.

Table 1.

Atopic dermatitis (AD) treatment: Brazilian Society of Dermatology position paper

		answers/total
Number of AD patients seen per month	<50	9/18
	>50	9/18
Number of patients seen in public institutions	< 50	2 / 18
	>50	16 / 18
Number of patients seen in private practice	< 50	4 / 18
	>50	13 / 18
Treatment based on published guidelines (12/18)	American	5 / 12
	European	5 / 12
	Other	2 / 12
Topical therapy:	Topical corticosteroids	17 / 18
	Calcineurin inhibitors	16 / 18
	Topical antibiotics	6 / 18
	Other-moisturizers	7 / 18
Systemic therapy:	Cyclosporine	14 / 18
	Azathioprine	3 / 18
	Methotrexate	11 / 18
	Mycophenolatemofetil	1 / 18
	Oral steroids	5 / 18
	Immunobiologicaltherapy	0 / 18
Phototherapy (narrow-band UVB)	Yes	15 / 18
	No	3 / 18
Use of antimicrobials during flares	Topical	10 / 18
	Systemic	16 / 18

The second step was the analysis of recent international guidelines (American Academy of Dermatology, published in 2014, and the European Academy of Dermatology and Venereology, published in 2018). ^16-21 All sections and recommendations regarding AD treatment were discussed with the 18 experts, and consensus was defined as approval by at least 70% of the panel. This paper expresses their opinions regarding international guidelines for AD treatment and provides practical guidance for dermatologists in Brazil.

RESULTS/DISCUSSION

Table 1 shows the data obtained from the applied questionnaire. The majority of experts (17/18) who answered the questionnaire work in public and private institutions. About 50% of the specialists see more than 50 AD patients/month, mostly at public hospitals. Twelve out of 18 of the dermatologists follow published consensuses, with emphasis on the American and European guidelines. The most widely used topical treatments are corticosteroids, followed by calcineurin inhibitors. The first choice for systemic therapy was cyclosporin, followed by methotrexate and azathioprine.

Baseline therapy and preventive measures

The recent guidelines are in accordance regarding baseline therapy. Key steps include maintenance of the skin barrier through the constant use of emollients, which recover the function of the damaged skin barrier in AD and consequently protect the skin from allergen penetration and subsequent inflammation. ²²

Skin hydration improves xerosis and reduces pruritus, sparing topical corticosteroid use. Cleansing eliminates crusts and reduces bacterial contamination. The use of substances with physiological pH is recommended, and baths should last no longer than five minutes. ²³ Sodium hypochlorite baths (bleach) may not always change the severity of AD but appear to reduce the need for topical anti-inflammatory drugs and antibiotics. ²⁴

Daily bathing is possible for regular skin hydration, and emollients should be applied on slightly wet skin, immediately after drying; application twice daily is usually sufficient. ²⁵ Some emollients have additional ingredients such as urea and propylene glycol, which may lead to skin irritation, and there is still inconclusive evidence about superiority of emollients enhanced with components of the skin barrier such as ceramides. ^25,26

Recent concepts regarding the microbiome and the skin highlight that the cutaneous microbiome in AD is not as heterogeneous as in healthy individuals, with the predominance of Staphylococcus aureus (S. aureus). ^15,27 Recovery of the skin barrier by adjusting the inflammatory response reestablishes the skin microbiome in AD patients. ^28,29 Bacterial lysates or topical application of commensal bacteria are promising, but skin hydration itself is able to recover the skin microbiome. ^15,30

There is evidence for early use of emollients in atopic dermatitis-prone children (three months of age and older) in the prevention of AD. ^28,29

Recommendations by the dermatology experts for baseline therapy:

Daily cleansing for up to 5 minutes with mild agents with adequate pH

Emollient application twice daily on slightly wet skin is the main component of baseline therapy

Aeroallergens

Aeroallergens are relevant triggering factors of AD flares.^31-33 Exacerbation of an eczematous lesion after skin contact or inhalation has been reported, but studies are still inconclusive. ³² The skin prick test and specific IgE are routinely utilized but have a low positive predictive value. ³²

In the present panel of dermatology experts, 89% do not perform the skin prick test or RAST as part of routine practice.

Food allergy

One-third of the children with moderate/severe AD have associated food allergy; however, food allergy is not the cause of AD. ³⁴ Restrictive diets should only be prescribed for children with proven food allergy. ^34,35 The published guidelines recommend restrictive diets only for those patients with a positive oral challenge test, the gold standard assay for food allergy. ^19,34-36

The detection of specific IgE to food through prick or serological tests does not prove food allergy, and their positive predictive value is low. ³⁷

The present panel of dermatology experts does not recommend restrictive diets, but considers that food allergy may be investigated in children with severe, treatment-resistant AD and in those with a history of flares following ingestion of specific foods.

Contact dermatitis

Contact dermatitis is present in 40-65% of AD patients, usually exacerbating the existing eczema. ³⁸ The patch test is recommended for refractory AD with atypical skin lesions. ³⁹

Patients should be tested for fragrances, preservatives, topical corticosteroids, and other topical components. ³⁸ Patients are more prone to develop occupational dermatoses, since AD exacerbates the irritant effect of allergens in certain professions such as hairdressers, mechanics, metalworkers, janitorial workers, and nurses, in whom hand eczema is commonly reported. ⁴⁰ Preventive measures should be taken in order to reduce the incidence of AD in such patients.

Fifty percent of the expert group recommend patch tests. The main problem is the difficulty in performing the test, since ideal sites are usually limited in AD patients.

Topical anti-inflammatory therapy

Topical anti-inflammatory therapy is the mainstay of AD treatment. Anti-inflammatory agents must have sufficient potency and should be applied on the skin lesions according to the recommendations and not exceeding the allowed amount per day. ⁴¹

Topical corticosteroids (TC)

TC are the first line treatment for AD, with strong evidence of their superiority over placebo. ⁴² They are classified according to their potency based on vasoconstrictive effects, and every clinician should be aware of their potential local and systemic adverse effects, such as cutaneous atrophy and adrenal suppression.^43,44

Strategies defining the use of TC vary according to their potency, but the suggested applied amounts of topical corticosteroids follow the fingertip unit rule.^19,20 In the European guidelines, the approximate total amount of TC per month is 15g in infants, 30g in children, and 60-90g in adolescents and adults.²⁰ The choice of corticosteroid and its vehicle depend on the affected site, the patients’ age and the severity and clinical phase of AD. Wet-wrap dressings may improve AD flares, and ultrahigh potent topical corticosteroids should be applied for up to two weeks.^29,45

TC use depends on the vehicle; as a cream, they should be applied 15 minutes before the moisturizer, and as an ointment, applied 15 minutes prior to the moisturizer.⁴¹

Corticosteroid phobia is a relevant matter that should be addressed, especially due to its influence on adherence to treatment; it varies according to the country and culture.⁴⁶

Topical corticosteroids are the first-line topical treatment for AD, according to the experts.

Calcineurin inhibitors (topical immunomodulators or TIM)

Tacrolimus and pimecrolimus are second-line non-corticosteroid, anti-inflammatory therapies for AD with proven efficacy.^20,47 The most widely reported adverse effect is burning sensation during the initial days of use (especially with tacrolimus); they do not induce skin atrophy, which makes them useful for application on eyelids, perioral lesions, axillae, and genitals.⁴⁸

Despite a black box warning in the package insert, studies have not reported an increased risk of lymphoma with the topical use of TIM at therapeutic doses.⁴⁹ Intermittent use of TIM is recommended above two years of age.²⁰

Eighty percent of the Brazilian experts use TIM as a second-line therapy for AD.

Proactive treatment

Proactive treatment has been proposed in published guidelines. It consists of long-term use of topical anti-inflammatory agents, either TC or TIM (tacrolimus), twice a week in previously affected areas, combined with moisturizers. ^29,45,50,51 The rationale for proactive treatment is based on its efficacy and long-term safety (up to one year), reducing the number of flares and improving the quality of life of atopic patients. ^50,51

The Brazilian experts recommend proactive treatment with TC or TIM in AD patients.

Topical antimicrobial therapy

Colonization by S. aureus is frequent on the skin of AD patients and is much higher than in non-atopic individuals (100% vs. 30%). ^52-54Fortunately, the skin and nares of AD patients are not frequently colonized by methicillin-resistant S. aureus (MRSA) (7.4 and 4%, respectively). ⁵⁴

The American Academy of Dermatology does not recommend the use of topical antibiotics, since they do not show clear benefits for AD patients. However, the use of 0.005% sodium chlorine in bathwater may be helpful in children and is recommended by the EADV. ^17,20

During flares, 100% of the Brazilian experts use antibiotics. About 1/3 of the experts use topical antibiotics in acute phases of AD for short periods (up to one week).

Recommendations for topical therapy in AD:

TC are the first-line treatment for AD patients and must be carefully prescribed according to their potency and vehicle. Patient’s age, site, and phase of AD lesions are key factors when choosing TC.

TIM constitute the second-line treatment for AD and are suitable for application on areas with high risk of corticosteroid-induced atrophy.

Proactive therapy with either TC or TIM is safe, reduces flares and AD severity, and is indicated as long-term maintenance therapy.

The use of topical antibiotics and antiseptics is still variable. Topical antibiotics can be used for short periods, and bleachers (0.005% sodium hypochlorite may be useful for pediatric AD).

Wet-wrap bandages or occlusive treatment during hospitalization are helpful measures for improving flares.

In patients that fail to respond to topical treatment, the following should be considered:

• -differential diagnoses of AD

• -lack of adherence

• -contact dermatitis

• -secondary infection (bacterial, viral, or fungal)

• -indication for systemic therapy

Systemic treatment

Systemic treatment of AD is recommended in moderate to severe cases that fail to respond topical therapies. Before initiating systemic treatment, it is mandatory to avoid aggravating factors, to diagnose and treat secondary infections, and to rule out differential diagnoses. The option for systemic therapy should also include the impact of the disease on the patient’s quality of life and a careful balance of risks and benefits with the chosen medication. ^55,56

Phototherapy

Phototherapy is a valid adjuvant therapeutic option, especially for chronic AD and in adults. It improves pruritus, thus reducing insomnia. ⁵⁷ Ultraviolet B (UVB), narrow-band UVB, and psoralen + UVA (PUVA) are the main modalities. ^12,57 UVB-NB (311-313nm) is the most widely used form and can be indicated for children. UVA1 (340-400nm) is seldom used in Brazil but is useful for flares. ^21,57

In the Brazilian consensus group, 83% recommend this treatment modality, especially for the chronic phase of AD. Phototherapy improves clinical signs and reduces pruritus and bacterial colonization, thus being a steroid-sparing measure. It is important to avoid this treatment in patients with recurrent herpes simplex infection or history of eczema herpeticum. A limiting factor for this therapeutic modality is lack of adherence to long-term treatment.

Antihistamines

Oral antihistamines that block the histamine 1 receptor (H1R) have been prescribed for AD patients for decades; however, there are few randomized studies that evaluate their real efficacy in AD. ²¹

The aim of systemic antihistamines in AD is to allow better quality of sleep, since their role as anti-inflammatory agents in AD is controversial. There is no evidence of improvement of severity scores in randomized studies, and first-generation drugs are prescribed due to their sedative effect and to the relief of other conditions related to AD, such as asthma, rhinoconjunctivitis, dermographism, and urticaria. ^21,58 However, our group stresses that the quality of sleep induced by anti-H1R drugs is not ideal, since they do not alter the REM phase. ^21,58

Our group recommends the use of first-generation antihistamines (hydroxyzine and chlorpheniramine) based only on their sedative effect.

Anti-inflammatory agents

Cyclosporin A (CyA)

Cyclosporin A is approved in many European countries and in Brazil for severe AD. The U.S. FDA approves it for psoriasis. The initial dose for children and adults varies from 3 to 5 mg/kg/day, and the maintenance dose is from 2.5 to 3 mg/kg/day. ^{55, 59-61} Clinical improvement can be observed after 2-8 weeks; CyA is recommended for up to 2 years with constant monitoring of blood pressure and kidney function. ^55,59-61 Periodic intervals of 3-6 months off therapy decreases the occurrence of side effects. 62 The average length of treatment with CyA is 3-12 months, and the drug is usually considered first-line treatment for treatment-resistant AD and in acute flares. ⁶³ Pregnancy is not a contraindication to CyA use. ⁶³

Although CyA leads to prompt improvement in severity scores after 2 weeks from the initial dose, reactivation of AD after the drug’s suspension is equally rapid, occurring in 2 weeks. ⁶³

Methotrexate (MTX)

MTX can be indicated as initial treatment for moderate/severe AD, recalcitrant to topical treatment with corticosteroids. The drug has a good safety profile and is indicated for long-term maintenance; clinical efficacy is reached after 8-12 weeks of administration.^21,61,63

The therapeutic dose varies from 15 to 25mg/week for adults and 10-15mg/m2/week for children (oral, intravenous, or subcutaneous), and folate should be added to the treatment, usually 1-2 days after MTX. ^21,61,63 Average length of treatment ranges from 6 to 12 months, and clinical improvement is seen at 8-12 weeks from the initial dose. Side effects include hematological disorders, liver enzyme alterations, and gastrointestinal discomfort. Its use is recommended for up to 2 years, with constant monitoring of bone marrow and liver function. ^21,61,63,64 Contraception is mandatory, since the drug is considered category X. ^61,63

Azathioprine (AZA)

AZA can be indicated as systemic treatment for refractory AD. Peak efficacy of AZA is reached after 8-12 weeks of use. ⁶³ The initial dose is usually 50 mg/day for 1-2 weeks, increased thereafter to 2-3 mg/kg/day. ^63,65 It can increase the risk of non-melanoma skin cancer and lymphoma. ^66,67 Thiopurine methyltransferase enzyme (TPMT) levels should be measured whenever possible, since TPMT deficiency while in use of AZA can lead to bone marrow aplasia. ⁶⁵ It can be prescribed for children (off label for AD) and is subject to restricted indication during pregnancy. ^63,68

Mycophenolate mofetil (MMF)

Clinical efficacy of MMF is reached after 8-12 weeks of use (off label in AD), and the drug has a good safety profile. ^21,63 The recommended doses in adults are 1-2g/day (starting dose) and 2-3g/ day (maintenance); the pediatric doses are 20-50mg/kg/day (starting dose) and 30-50mg/kg/day (maintenance).^21,68 Gastrointestinal and hematological side effects have been reported. ^21,63

Systemic corticosteroids (SC)

There are few randomized controlled studies regarding the use of systemic corticosteroids in AD. In the 2018 European consensus, SC are used in exceptional cases of AD, but only for one week.²¹ There is a rapid clear up of skin lesions , but severe rebound tends to occur in 2 weeks. ²¹ One controlled trial indicates lower efficacy of systemic prednisolone in comparison to CyA in severe AD.^21,69

Position/recommendations for the use of systemic anti-inflammatory drugs in AD:

CyA and MTX are the most widely used systemic drugs for severe refractory AD.

CyA leads to fast improvement of AD severity scores after 2 weeks of initial treatment, but reactivation of AD after drug suspension is equally fast, occurring in 2 weeks.

MTX can be used as the initial systemic medication for refractory moderate/severe AD and is indicated for long-term maintenance. Clinical efficacy is reached after 8-12 weeks of administration.

Oral corticosteroids are used in exceptional cases for short periods (up to 1 week).

Few dermatologists have experience with mycophenolate mofetil or azathioprine.

Treatment of secondary infections (bacterial, viral, or fungal)

S. aureus and Streptococcus pyogenes are the most common bacterial agents in AD. They are detected in more than 90% of AD lesions.⁵³ Systemic antibiotics are reserved for patients with clinical evidence of infection, and cephalosporins are the first choice of treatment.^21,70

Extensive viral infections such as eczema herpeticum (EH) are seen in AD patients. Skin barrier defects, including mutations of the filaggrin and claudin1 genes or abnormalities in IFN-gamma response may increase the risk of EH. ^12,71 Risk factors for EH include early severe AD, high IgE levels, eosinophilia, and associated food allergy and asthma.^14,45,63,72

Treatment for localized EH is oral acyclovir. Systemic involvement with fever, lethargy, headache, nausea, and dizziness requires hospitalization and intravenous acyclovir. ⁷²

As for fungal infections in patients with AD, Malassezia spp. appears to contribute to skin inflammation during flares, and there is an anti-IgE response to immunogenic proteins released by some Malassezia species. ⁷³

Recommendations by the Brazilian experts:

oral antibiotics are indicated when there are signs of bacterial superinfection of the skin; cephalosporins are the first choice, followed by sulfamethoxazole-trimethoprim.

Eczema herpeticum must be treated with systemic antiviral drugs; when it is followed by systemic symptoms and signs, hospitalization and intravenous antiviral therapy are indicated.

AD patients with head and neck involvement may benefit from treatment with antifungal agents.

Education and AD

AD has a strong impact on the quality of life of patients and caregivers due to its chronic course and intense pruritus. ^21,45,74 Sleep loss, school and work absenteeism, social isolation, depression, and suicidal ideation may be present. ^56,74 Low treatment adherence is common in AD, and educational programs are needed to reinforce the patient’s understanding of the disease complexity and therapeutic approaches. ⁷⁵

Various models focusing on AD education and with multidisciplinary approaches have shown subjective and objective improvement of AD worldwide. ^75-79

Future perspectives

Immunobiologicals and small molecules are targeted therapies that have been developed for many inflammatory, autoimmune, and oncologic diseases.

Crisaborole ointment is a topical phosphodiesterase 4 (PDE4) inhibitor that was approved in the USA in 2017 for patients above the age of 2 years with mild/moderate AD. ⁸⁰

Dupilumab is a human monoclonal antibody for AD that blocks the alfa-chain receptor for IL-4 and IL-13 (dupilumab) and is approved for adults with moderate/severe AD. ⁸¹ Its efficacy after 16 weeks as monotherapy (initial dose: 600 mg, followed by 300 mg every 2 weeks, SC), measured by the reduction of eczema severity scores (EASI) was 82.5% (EASI 50), 60.3% (EASI 75), and 36.5% (EASI 90).^81-83 Improvement of skin lesions and reduction of pruritus improved 2 weeks after initiating treatment. ^81-83The studies show sustained long-term efficacy (one year) with dupilumab combined with TC in AD patients.^84,85 The main adverse event reported with dupilumab was conjunctivitis, detected in 25-50% of AD patients.^85,86

There are ongoing studies (phases 2-3) with novel immunobiologicals and small molecules for AD treatment. See Chart 1. ^87,88

Chart 1.

Novel immunobiologicals and small molecules for atopic dermatitis

Agent	Target	Administration	Phase
Tralokinumab	IL-13	SC	3
Lebrikizumab	IL-13	SC	2
Nemolizumab	IL-31Ra	SC	3
Apremilast	PDE4	PO	2
ILV-094	IL-22	IV	terminated
Secukinumab	IL-17	SC	2
Baricitinib	JAK1/2	PO	2
Upadacitinib	JAK1	SC	2
ZPL389	H4R	PO	2
Tezepelumab	TSLP	SC	2
Serlopitant	NKR1	PO	2

IL=interleukin; R=receptor PDE=phosphodiesterase; JAK= janus kinase; H=histamine; TSLP=thymic stromal lymphopoietin; NKR=neurokinin receptor; SC= subcutaneously; PO= per oral; IV= intravenously

Source: Wang, et al, 2016⁸⁷ and Lee, et al, 2018.⁸⁸

Chart 1: New systemic drugs for AD treatment. ^87,88

CONCLUSIONS

Despite the cultural and economic differences between Brazil, USA, and Europe, including in access to immunobiological therapies, the ideal management of AD is based on a better understanding of disease pathogenesis and knowledge of treatment strategies.

Basic treatment for AD includes skin hydration, topical anti-inflammatory therapy, avoidance of aggravating factors, and educational programs with a multidisciplinary approach. Systemic therapy should be only indicated for refractory or severe disease after attempts with topical therapy. Secondary infections must be diagnosed early and treated promptly, and hospitalization may be necessary to control flares (Figure 1).

Figure 1.

Consensus-based recommendations of topical and systemic treatments for patients with atopic dermatitis (AD)

Novel target-oriented drugs are invaluable tools for AD treatment.