Atopic march refers to the development of several atopic clinical manifestations in the same patient. AD is the initial manifestation of the atopic march and it may represent the most relevant risk factor for the development of the other manifestations, including food allergy, asthma, allergic rhinitis and conjunctivitis. It is thus possible that the adequate control of AD reduces the risk for the other atopic disorders. However, the progression of the atopic march is complex and multifactorial, predominantly driven by genetic susceptibility, and it does not necessarily occur in all AD subjects.17 Indeed, PRICK-tested allergic sensitization, demonstrating the presence of specific IgE, correlated with a higher risk for the progression of the atopic march, having strong interactive effects on both asthma and food allergy risk at three years of age.18 In addition to the abovementioned atopic and allergic comorbidities, AD has been linked to other, non-allergic comorbid conditions, similarly to what has been shown in psoriasis. Adult AD patients showed increased cardiovascular risk factors, including higher body mass index, higher odds of heavy smoking, sedentary lifestyle, arterial hypertension, autoimmune disorders, lifetime prediabetes, increased alcohol intake, and decreased rates of vigorous physical activity compared with individuals without AD.19,20 Although it is still debated whether AD may represent an independent risk factor for cardiovascular disease, patients with severe AD without any history of cardiovascular events were reported to show more than two-fold greater prevalence of coronary artery disease compared with healthy control subjects, assessed by coronary computed tomographic angiography.21,22 Moreover, neuropsychiatric disorders such as depression, anxiety, suicidal ideation, attention-deficit/hyperactivity disorder, and autism spectrum disorder might be associated to AD.

Moisturizers and emollients are essential in the treatment of skin xerosis and in the improvement of skin barrier function. Their use is indicated independently from disease severity and topical/systemic immunomodulant therapies. Indeed, an optimal skin hydration lessens skin inflammation, improves barrier function, reduces flare frequency and the use of topical corticosteroids. Emollients, including Vaseline do not simply delay water evaporation from stratum corneum but also induce metabolic changes in keratinocytes favoring the synthesis of essential components of the epidermal barrier.35–37

Skin barrier repair products might consist of occlusive components (i.e., Vaseline) dampening trans-epidermal water loss (TEWL), humectants to attract and retain water (i.e., analogs of natural moisturizing factor), or both. Petrolatum is the most efficacious occlusive component, producing a near-immediate reduction in TEWL, although its cosmetic acceptability as well as the adherence to treatment is limited as it appears greasy and messy.38 Hydrophilic bases and silicates are cosmetically more acceptable as they may have some occlusivity beside a favorable emolliency and cosmetic acceptability. Hyaluronic acid is an endogenous humectant that is used in some barrier repair products and moisturizers. Other commonly used humectants include glycerol, glycyrrhetinic acid, urea, propylene glycol, and sodium lactate. Such products are available in a wide array of different formulations. In infants, particularly in subjects younger than two-year-old, both propylene glycol-based and high-concentration urea products may be irritating or toxic, and in general avoided. According to skin conditions, lipophilic bases as well as barrier ointments, bath oil, shower gel, emulsions or micellar solutions might be also helpful.39 In patients with acute, oozing and erosive lesions, emollients could be poorly tolerated.

Conversely to oil-containing emulsions, pure oil products such as coconut or almond oil, may induce skin dryness and are therefore not recommended. Topical compounds containing intact proteic allergens or haptens (i.e., peanut- or oat meal-derived proteins) as well as plant extracts,40,41 such as Mahonia aquifolium, Hypericum perforatum, Glycyrrhiza glabra, and Perilla, or Gram-negative bacterial lysates from Vitreoscilla filiformis or Aquaphilus dolomiae are available on the market.42–44 These lysates-containing products have demonstrated some efficacy in AD and they may also have beneficial effects on skin microbiome.44,45 Compounds containing proteic allergens or haptens should not be used before the age of two years because of the potential risk of skin sensitization and allergy.43–50

Cleansing is always recommended for patients with AD, particularly when oozing with or without bacterial superinfections occurs.51 When eczematous lesions are covered by crusts, skin must be cleansed in order to gently remove crusts, bacterial contaminants, allergens (i.e., dust mites), mechanically. Nevertheless, the skin barrier could be damaged by the use of overly aggressive cleansers, therefore, non-irritant and anallergic products, preferably with a pH of 5.5–6, in peculiar formulations (non-soap aqueous cleansers, syndets, oily cleansers, free or relatively free of preservatives and perfumes) are preferred in order to maintain acid skin pH (4–6), preserving microbial equilibrium, stratum corneum integrity, lipid metabolism, and epidermal differentiation.51 Baths should last no more than 5min and the addition of bath oil could help in contrasting epidermal dehydration. Frequency in bathing is irrelevant whether an optimal hydration is achieved. Daily short baths with lukewarm water followed by gentle drying with smooth cloths and application of emollients while the skin is still slightly humid is recommended. In case of superinfection cleanser containing antiseptics could be useful.38,51 Salt baths as well as bath-water added with sodium hypochlorite or 0.005% bleached baths showed controversial beneficial effects on AD.52–55

Corticosteroids represent the milestone in the therapeutic approach of AD.51,56,57 Based on their strength, corticosteroids could be divided into four or seven classes distinguishing mild from superpotent steroids, marketed in different formulations. If appropriately used they usually result effective in treating AD. Disease severity, previous therapies, and body localization primarily affect the choice of potency and formulation.38,51 The usually recommended amount of corticosteroids (either mild or super-potent) for mild disease is 15g monthly for infants, 30g for children, and up to 60–90g in adolescents and adults, to be administered daily, preferably night-time administration, until resolution of lesions occur and then twice to three times weekly as a maintenance treatment for up to six months. Super-potent topical corticosteroids are not recommended, especially in children, because of the risk of adverse events whereas mid-potency and potent molecules with higher benefit/risk ratio, such as methylprednisolone aceponate, fluticasone propionate, and mometasone furoate, are preferred.58,59 The use of wet-wrap dressings with diluted corticosteroids (‘wet-wraps’ medications) has been advocated as a relatively safe and effective treatment modality in children with severe and/or refractory atopic dermatitis. It is a short-term treatment for up to 14 days.

The main side-effects of topical corticosteroids are represented by skin atrophy, telangiectasias, striae distensae, hyperticosis, and peculiarly, by granuloma gluteale infantum occurring in infants, in the diaper area. Contact allergy to corticosteroids may occur but is very rare and limited to some compounds (e.g. budesonide and hydrocortisone). The use of potent topical corticosteroids in sensitive skin areas (face, neck, folds) should be limited in time to avoid skin atrophy.60

Corticophobia is the main limitation to the use of corticosteroids, and it is associated with undertreatment and poor adherence.61–64 Corticophobia is a very relevant issue and should be adequately addressed by speaking to the parents about the differences with the new corticosteroid molecule, and the proper application procedures. Corticosteroid addiction refers to topical corticosteroid uncontrolled, long-term, self-managed therapy that could result for instance, in rosacea-like perioral dermatitis (“red-face syndrome”), and steroidal-induced folliculitis in genital areas.65

Corticosteroids are best applied under a medication (either simple or occlusive) to fasten the therapeutic effect. Dose tapering is usually applied to avoid withdrawal rebound, although no controlled studies have demonstrated its usefulness. Tapering strategies consist of either reducing the frequency of application, maintaining the same corticosteroid potency, or switching to a less potent corticosteroid with the same frequency.

Pimecrolimus and tacrolimus are indicated for the treatment of mild-to-moderate and moderate-to-severe AD, respectively, in children older than two years.66–69 [50–52]. Both agents have proved more effective than both vehicle and mild-potency corticosteroids, in several short- and long-term studies, up to a four-year period for tacrolimus and five years for pimecrolimus.66,68–76 Conversely to 0.1% tacrolimus ointment showing similar anti-inflammatory effects compared to a mid-potency corticosteroid,77,78 pimecrolimus 1% cream results less effective.79 Tacrolimus 0.1% is more effective than the 0.03% formulation and is licensed only for adolescents older than 16 years, but it can also be safely used in younger patients. Because of their capability in preserving tight junctions (TJs) formation and their lower permeation through the skin (due to their molecular weight), pimecrolimus and tacrolimus are preferred to treat the face and sensitive areas, over corticosteroids.80–82

The most common adverse events are represented by pruritus and a “skin burning” sensation that is transitory, lasting a few days, which could be lessened with prior use of corticosteroids.66,71,79 In some cases, worsening of erythema is observed following the first application. Neither skin atrophy, nor increased risk of lymphoma or non-melanoma skin cancer, is associated with topical calcineurin inhibitors.76,83–90

Bacterial skin infections are usually caused by S. aureus or S. pyogenes.91 Although S. aureus colonization could be detected in 60–100% of AD patients, correlating with disease severity and exacerbation, the beneficial effect of antiseptics and antimicrobials indiscriminately used for the daily management of AD is still debated. Super-antigens and exotoxins released by S. aureus may sustain inflammatory reactions and promote tachyphylaxis, thus, the occurrence of bacterial infections should implicate the use of topical antibiotics. The most commonly prescribed for mild/moderate secondary infections are gentamicin, fusidic acid and mupirocin that could be also used in combination with diluted bleach and corticosteroids.92

Cyclosporine is the only approved conventional systemic agent for AD in various countries for adults, although it can be used from the age of 2.104–106 The initial dosage ranges from 2.5 to 5mg/kg/day, which could be tapered to 1.5–3mg/kg/day, once a satisfactory clinical response is achieved.51,103 An alternative therapeutic scheme was proposed, consisting in a high starting dose of 5mg/kg/day in two separate doses, reduced by 1mg/kg/day twice weekly till 3mg/kg/day or minimum effective dose, once remission is obtained.107 The overall treatment duration may last 3–12 months, although long-term cyclosporine therapy is not recommended for the risk of kidney toxicity. It is rapidly and highly effective in treating AD as highlighted in a meta-analysis collecting data from more than 600 children and adult patients with AD, wherein cyclosporine dose-dependently markedly reduced the severity of AD.108 Overall, pediatric trials indicate that side effects might be frequent but mild, being more common in patients after longer treatment periods; kidney toxicity and hypertension are rare in children.103 Notably, cyclosporine 5mg/kg/day administered as multiple 12-week courses versus continuous therapy for up to one year, was not associated with an increase in serum creatinine or blood pressure in 43 patients aged 2–16 years, with no significant difference between groups. In order to reduce drug exposure, and thus, the potential occurrence of drug-related adverse events, weekend therapy regimen has also been reported as showing beneficial effects and a reduced risk of relapse.109–111

Oral corticosteroids are more commonly used by European (30.7%) than American (5.2%) pediatricians as first-line systemic agents for severe pediatric AD.112,113 A recent position paper on systemic corticosteroids in both adult and pediatric AD patients indicated that routine use of systemic corticosteroids for AD is generally discouraged and should be reserved for cases of severe AD under special circumstances, including a lack of other treatment options, as a bridge to other systemic therapies or phototherapy, during acute flares in need of immediate relief, or in anticipation of a major life event.114 If used, this treatment should be limited to short-term. Most panelists agreed that systemic corticosteroids should never be used in children.114 In particular, the use of systemic corticosteroids could be avoided if physicians consider that most children will have fewer comorbidities complicating the use of immunomodulatory agents such as cyclosporine.

The efficacy of methotrexate resulted high, although its use in pediatric AD patients is limited in a real-life setting. Indeed, in a head-to-head trial evaluating efficacy and safety of methotrexate and cyclosporine in the treatment of 40 children with severe AD, no significant differences in terms of efficacy have been detected.111 Patients were randomly assigned 1:1 to methotrexate (7.5mg/week) or cyclosporine (2.5mg/kg/day). Clinical improvement was similar in both treatment groups with no statistically significant difference in mean SCORAD score reduction. Mild and temporary adverse events were reported in some patients in both groups.111 Other clinical studies reported good-to-excellent response to three-month methotrexate therapy. The most commonly reported side effects include dose-dependent nausea, mouth ulcers and transient raised liver enzymes. No toxicity on pulmonary, renal, dermatologic, developmental or cardiac systems has been described in children and adolescents treated with methotrexate for dermatologic and rheumatologic diseases. Methotrexate may be prescribed in children at the initial dose of 5mg/week with subsequent weekly increment of 2.5–5mg until the achievement of a clinical response.51,103 Once a satisfactory clinical response is obtained, dosage could be reduced by 2.5mg/week maintaining disease control with the minimal effective dose.51,103 Dose could also be calculated as 10–20mg/m2/week or 0.2–0.7mg/kg/week.51,115–117 The effective methotrexate dosage might also be adjusted based on patient's age: 7.5mg/week for children aged <5 years, 10mg/week for children aged 6–10 years, and 15mg/week for children aged >11 years.116

In children (and adults) there is no recommendation for liver biopsy in the case of long-term, continuous methotrexate treatment while the use of non-invasive methods (FibroScan) needs further standardization and serum markers (i.e., procollagen-3 N-terminal peptide) correlating with hepatic fibrosis may not be indicative because of the serum level variability in children. Liver elastography is an option to monitor liver fibrosis but rarely required in children.118

It is considered as effective as methotrexate in the treatment of adult AD. The dose regimen is 2–3mg/kg/day. Similarly to methotrexate, azathioprine may require up to two months to show efficacy. Its safety profile and efficacy is dependent upon the functional activity of the main metabolizing enzyme, thiopurine methyltransferase (TPMT). In a small fraction (<2%) of the population there are genetic polymorphisms which render the enzyme not active (homozygous or heterozygous) exposing the patient to high risk of side effects, mostly hematological. The best strategy is to adjust the dose according to the enzymatic activity; however, TMPT testing is not available in many countries. An alternative strategy is to start treatment with a low dose and perform a blood test (blood cell counts with differential and liver function test) after 7–10 days, and if tests are normal increase the dose to the therapeutic range.119–121 Azathioprine dosage at 1.5–2.5mg/kg/day was found to be as effective as methotrexate 10–22.5mg/week after 12 weeks of treatment in adults with severe AD in a prospective, randomized, controlled trial.122 Similar to other studies reporting positive clinical outcomes but having a smaller population, a retrospective study on childhood subjects showed good or excellent response to azathioprine treatment in 85% (41/48) of cases.120,121,123 Some adverse events such as malaise, myalgia, fever, gastrointestinal symptoms, skin reactions, vasculitis, headaches, recurrent chest infections, recurrent herpes simplex infections, lymphopoenia, neutropaenia or increased transaminase levels have been associated with the use of azathioprine.

Mycophenolate mofetil is an immunosuppressive drug that may be initially prescribed at 10–40mg/kg/day, divided in two doses. Incremental doses by 500mg every 2–4 weeks are usually recommended in order to achieve the effective dose of 20–50mg/kg/day or 600–1200mg/m2/day.124,125 A few studies described the efficacy and safety of MMF in pediatric AD subjects showing good or excellent responses, also in azathioprine-unresponsive subjects. Testing MMF in 14 children affected by severe refractory AD, Heller et al. reported successful response associated with no severe adverse events.125 The most common adverse events, occurring in 10–30% of patients, were nausea, vomiting, diarrhea and abdominal discomfort. A head-to-head study testing mycophenolate mofetil vs. cyclosporine in the long-term showed similar efficacy.126

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The authors obtained informed consent of patients and/or subjects referred to in the article consent. The corresponding author maintains responsibility for this manuscript.

The authors declare that all procedures were carried out according to the ethical standards of the responsible committee on human experimentation and in accordance with World Medical Association and Declaration of Helsinki.