Management of severe atopic dermatitis (eczema) in children

INTRODUCTION — Atopic dermatitis (AD) is a common, chronic, inflammatory skin disorder characterized by the presence of pruritic, eczematous dermatitis. In most patients, the disorder is managed with careful skin care practices, barrier repair strategies, topical therapies for inflammation, and the elimination of exacerbating factors. Patients with severe disease that fails to improve with conventional therapy may benefit from second-line therapies, such as phototherapy or systemic medications.

This topic reviews the causes and treatment of severe, refractory AD in children. The standard management of AD, including maintenance of skin hydration, control of pruritus, topical anti-inflammatory therapies, and management of infection, is discussed separately. The clinical manifestations and diagnosis of AD and the role of allergy in AD are also discussed separately.

●(See "Treatment of atopic dermatitis (eczema)".)

●(See "Evaluation and management of severe refractory atopic dermatitis (eczema) in adults".)

●(See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

●(See "Role of allergy in atopic dermatitis (eczema)".)

DEFINITION OF SEVERE ATOPIC DERMATITIS — Most patients with AD have mild to moderate disease. However, a subpopulation of patients develops severe symptoms. Severe AD may be loosely described as the presence of widespread skin lesions, unremitting itching, or physically or emotionally disabling disease that significantly compromises a patient's quality of life (picture 1 and picture 2). Patients with severe AD that does not respond to first-line topical therapies may be classified as having severe, refractory disease.

ASSESSMENT OF SEVERITY — Clinical studies have utilized scales for defining the severity of AD, such as the Investigator Global Assessment (IGA), the Scoring of Atopic Dermatitis (SCORAD) index, and the Eczema Area and Severity Index (EASI) [1]. Although such scales are useful for standardizing the results of research studies, they are not routinely used in clinical practice. Moreover, these measures may not reflect the disease severity as perceived by the individual patients. The Patient-Oriented Eczema Measure (POEM), a fully patient-derived and patient-assessed scale, has been proposed as a core instrument to complement the clinician-assessed scales in the evaluation of disease severity and response to treatment in patients with AD [2].

An international study involving over 1000 patients or parents of children with AD from 34 countries found that the symptoms considered to be important by 80 percent of the participants included itch, pain/soreness, skin feeling hot or inflamed, bleeding, involvement of visible or sensitive body sites, cracks, sleep difficulties, amount of the body affected, and weeping/oozing [3]. A practical guide to visual assessment of eczema severity that also includes the evaluation of disease impact on quality of life and psychosocial well-being has been proposed by the United Kingdom National Institute for Health and Care Excellence:

●Mild – Areas of dry skin, infrequent itching (with or without small areas of redness); little impact on everyday activities, sleep, and psychosocial well-being.

●Moderate – Areas of dry skin, frequent itching, redness (with or without excoriation and localized skin thickening); moderate impact on everyday activities and psychosocial well-being, frequently disturbed sleep.

●Severe – Widespread areas of dry skin, incessant itching, redness (with or without excoriation, extensive skin thickening, bleeding, oozing, cracking, and alteration of pigmentation); severe limitation of everyday activities and psychosocial functioning, nightly loss of sleep.

POTENTIAL CAUSES OF REFRACTORY DISEASE — Circumstances that may contribute to severe or refractory AD include financial considerations, poor adherence or incorrect use of medications, presence of environmental exacerbating factors, secondary infection, and hypersensitivity reactions to topical treatments or other allergens (table 1). Prior to initiating second-line treatments for AD, clinicians should ensure that severe, refractory disease is not a result of the presence of an avoidable or treatable factor.

Poor adherence/incorrect medication use — For many patients, a lack of adherence to the treatment regimen and basic skin care techniques contributes to persistent disease. Over 50 percent of patients with AD do not administer treatment as recommended by their clinicians [4-6]. Specific reasons for inadequate application of treatment include financial considerations, concerns about medication side effects, patient dislike of topical preparations, and insufficient time for clinicians to educate patients about skin care [7].

Topical corticosteroid phobia, defined as a concern or fear about using topical corticosteroids, is common, with a prevalence among patients and caregivers ranging from 20 to over 80 percent worldwide [8-10]. Corticosteroid phobia is likely a contributing cause of poor adherence to treatment and treatment failure among patients with AD.

Exacerbating factors/environmental triggers — Prior to initiating second-line treatments for AD, clinicians should ensure that severe, refractory disease is not a result of the presence of an avoidable or treatable exacerbating factor. Circumstances that may contribute to severe or refractory AD include noncompliance with conventional therapy, secondary infection, hypersensitivity reactions to topical treatments, and exposure to triggers of disease flares.

Exacerbating factors for AD may include low humidity environments, xerosis (dry skin), overheating of skin, emotional stress, and exposure to irritating substances, such as harsh chemicals or soaps. Avoiding these factors is helpful for avoiding acute flares as well as for long-term management, although this is not always possible. (See "Treatment of atopic dermatitis (eczema)".)

Infection — Patients with AD are at an increased risk for secondary cutaneous bacterial, viral, and dermatophyte infections. The possibility of secondary infection should be considered in patients with skin lesions that appear refractory to conventional therapy. In particular, clinicians should be aware of the possibility of Staphylococcus aureus and herpes simplex virus (HSV) infections.

Colonization with S. aureus occurs more frequently in individuals with AD than in the general population, and S. aureus is a common cause of secondary infection in these patients. The presence of purulence or honey-colored crusts suggests S. aureus infection. Even in the absence of overt infection, colonization by S. aureus may be an exacerbating factor for AD. (See "Treatment of atopic dermatitis (eczema)", section on 'Staphylococcus aureus'.)

Secondary HSV infection (eczema herpeticum) may also occur and, rarely, may lead to life-threatening dissemination of HSV in patients with AD. Punched-out erosions, hemorrhagic crusts, and vesicles are indicators of this infection. Rarely, coxsackie virus and vaccinia virus (in smallpox vaccine) can give a similar clinical picture [11,12]. (See "Treatment of atopic dermatitis (eczema)", section on 'Viral infections'.)

Hypersensitivity reactions to treatment — Delayed hypersensitivity reactions to contact allergens in topical emollients or medications are another cause of an apparent lack of response to treatment. Allergic contact dermatitis can be caused by vehicles or active ingredients in emollients (eg, lanolin, propylene glycol, fragrances, preservatives), topical immunosuppressive medications (eg, corticosteroids, calcineurin inhibitors), and topical antibiotics (eg, bacitracin, neomycin) [13-19].

Contact allergy to a topical emollient, medication, or other allergen (eg, nickel) should be considered when patients present with AD that fails to respond to, or appears to worsen, with these therapies [19,20]. The identification and elimination of a contact allergen can lead to rapid clinical improvement in affected individuals. If a contact allergy is suspected, patch testing should be performed to identify the responsible allergen. (See "Overview of dermatitis (eczematous dermatoses)", section on 'Allergic contact dermatitis' and "Contact dermatitis in children".)

Food and environmental allergies — In some cases, patients with refractory AD may have undiagnosed food or environmental allergies that are worsening their disease. It is therefore important to exclude immediate and delayed hypersensitivity through allergy testing (skin prick testing, specific immunoglobulin E [IgE] measurement, and patch testing). However, evidence of allergen sensitization is not proof of clinically relevant allergy. Confirming clinical reactivity is especially important when food allergies are suspected in young children since avoidance of food allergens can result in less than optimal nutritional intake. Additionally, there is some evidence that food avoidance may actually induce sensitization, including an increased risk of developing anaphylaxis [21,22].

The role of allergy in AD is discussed in detail separately. (See "Role of allergy in atopic dermatitis (eczema)", section on 'Food allergies' and "Role of allergy in atopic dermatitis (eczema)", section on 'Environmental allergies'.)

Incorrect diagnosis — An incorrect diagnosis may account for a failure to respond to conventional therapy. The possibility of other disorders that may present with clinical features that resemble AD should be considered. These may include conditions such as cutaneous T cell lymphoma, autoimmune disorders, and nutritional or immune system deficiencies (table 2).

REFERRAL — Patients with refractory AD should be seen by a specialist (eg, dermatologist, allergist) familiar with second-line treatments, such as phototherapy and systemic immunosuppressive and immunomodulating agents. Because of the paucity of randomized trials addressing the management of refractory AD in the pediatric age group, however, there is a wide variability among clinicians in the use of second-line therapies for children with severe disease [23,24].

OUR APPROACH

Initial management — Because most of the second-line therapies for AD have potential adverse effects and nearly all are off-label for this indication in children, patients should be selected for these treatments only when conventional topical therapy does not provide sufficient improvement. Thus, after excluding the factors potentially associated with recalcitrant disease, we attempt a more intensive topical treatment with wet wraps for several days (see 'Potential causes of refractory disease' above). This will help identify those children who are candidates for second-line therapies.

Wet wraps — For children with persistent, severe AD despite optimal treatment with topical corticosteroids and/or topical calcineurin inhibitors and for children with an acute, generalized exacerbation of AD, we suggest wet wrap therapy with diluted medium-potency topical corticosteroids (table 3) once to twice daily for 2 to 14 days. Wet wraps can be maintained for two or more hours, as tolerated, and even overnight if patients feel comfortable. Wet wraps can also be applied for a shorter time (eg, 15 to 30 minutes) two or three times per day.

Wet wraps consist of a bottom wet layer and top dry layer. They are generally applied on top of emollients or topical corticosteroids and left in place for up to 24 hours [25]. Cotton clothing in two layers may be sufficient for some cases, but elasticated cotton tubular bandages of appropriate size, which can be cut to cover any part of the body, may be more convenient in some situations [26]. Special bodysuits for wet wrap therapy for infants and toddlers are also commercially available.

Because of the increased systemic absorption of topical corticosteroids with wet wraps, some experts suggested that diluting low- to mid-potency topical corticosteroids in emollients (eg, 1:19 for face and body in infants and young children) and limiting the duration of treatment to a few days may reduce the risk of hypothalamic-pituitary-adrenal axis suppression [27,28]. Measurement of early morning fasting serum cortisol before and after treatment may be used to assess systemic absorption, although it is not generally performed for short-term use.

Data on the efficacy of wet wraps are sparse and inconsistent, due to a wide variability across studies in the treatment modality (eg, type of bandage used, frequency of application, treatment duration) and patient characteristics (eg, AD severity, body area involved) [29]. While several observational studies and a few small randomized trials support their efficacy as a short-term treatment (2 to 14 days) to induce a rapid remission in children with severe disease, other studies suggest that wet wraps are as effective as conventional treatment with topical corticosteroids and emollients [25,30,31]. Adverse effects include increased systemic absorption of topical corticosteroids, general discomfort, chills, and folliculitis. Temporary decreases in early morning serum cortisol levels have been reported, although short courses (<2 weeks) of use of diluted low- to mid-potency corticosteroids have not been associated with prolonged adrenal suppression [25].

Proactive therapy — Once the flare has subsided, patients can resume topical therapy with a medium-potency topical corticosteroid and/or topical calcineurin inhibitor (tacrolimus 0.03 or 0.1% or pimecrolimus 1%) and/or topical crisaborole twice daily for two weeks and then intermittently (eg, for two consecutive days per week or every other day) as a proactive therapy to prevent exacerbations [32].

Topical ruxolitinib (a Janus kinase [JAK] inhibitor) has been approved for short-term treatment of mild to moderate AD in children 12 years and older and represents another topical nonsteroidal agent that may be useful prior to consideration of systemic therapy [33,34]. Importantly, there are significant warnings and limitations of use, both in terms of body surface area and continuous therapy. (See "Treatment of atopic dermatitis (eczema)", section on 'Topical ruxolitinib'.)

Emollients should be liberally used multiple times per day. (See "Treatment of atopic dermatitis (eczema)", section on 'Maintenance and prevention of relapses'.)

If a patient does not respond to proactive therapy, our next line of therapy is dupilumab.

Dupilumab — For children older than six months of age with refractory AD, we suggest dupilumab therapy rather than other immunosuppressive therapy. There are three dosing schedules based on weight. For children 60 kg and over, a 600 mg loading dose followed by 300 mg every two weeks is approved, exactly as is recommend for adults. For those in the 30 to 59 kg range, a 400 mg loading dose is administered, followed by 200 mg every two weeks. Finally, for those in the 15 to 29 kg range, a 600 mg loading dose is administered, followed by 300 mg every four weeks. The dosing for children six months to five years is 200 mg every four weeks for children weighing 5 to 15 kg and 300 mg for children weighing 15 to 30 kg, notably without any loading dose.

Dupilumab is an interleukin (IL) 4 and IL-13 receptor-alpha antagonist that is approved by the US Food and Drug Administration for the treatment of children aged six months and older with moderate to severe AD not adequately controlled with topical prescription therapies. Data on the use of dupilumab in children aged six months and older and adolescents are now available [35-39]. The results of clinical trials evaluating the safety, pharmacokinetics, and efficacy of dupilumab in toddlers, children, and adolescents are comparable with those seen in the adult studies. (See "Treatment of atopic dermatitis (eczema)", section on 'Dupilumab'.)

Second-line therapies

Phototherapy — For older children (eg, older than six years who can cooperate with treatment) and adolescents with refractory AD for whom dupilumab is undesirable, not accessible, or ineffective, we suggest phototherapy with narrowband ultraviolet B (NBUVB), if feasible. NBUVB is usually administered three times per week, with a progressive protocol that increases the dose with each treatment, as tolerated. The patient is usually reassessed after 20 to 25 treatments. (See "UVB phototherapy (broadband and narrowband)", section on 'Dosimetry and treatment protocols'.)

Because of its favorable safety profile and wide availability, NBUVB is a more appropriate initial choice than other forms of phototherapy (eg, ultraviolet A1 [UVA1], psoralens plus ultraviolet A [PUVA], broadband ultraviolet B [UVB]) for the treatment of severe, refractory AD in children. (See "UVA1 phototherapy" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)

Data on the efficacy of NBUVB phototherapy in children with AD are limited to a few retrospective case series and one prospective study [40-43]. In a small study, 77 children (age 4 to 16 years) with psoriasis or AD were treated with NBUVB phototherapy [40]. Of 25 children with AD, 17 achieved minimal residual disease after a median of 24 treatments. In another retrospective study, 50 children with severe AD received more than 10 exposures to NBUVB [43]. Complete clearance or good improvement was reported in 30 children.

Data on the short- and long-term safety of NBUVB phototherapy in children are sparse. In one study, adverse effects included erythema, blistering, herpes simplex reactivation, and anxiety [40]. There are no studies evaluating the carcinogenic risk of phototherapy in children with AD. Although a systematic review of four studies assessing the risk of skin cancer among adults and children with psoriasis treated with NBUVB did not find an increased risk of melanoma or nonmelanoma skin cancer, patients receiving NBUVB phototherapy should be monitored with yearly skin examination [44,45].

Cyclosporine — For children and adolescents with refractory AD for whom dupilumab or phototherapy are inaccessible, undesirable, or ineffective, cyclosporine is our first-choice immunosuppressive agent. Cyclosporine has a rapid onset of action, and its effects can be noticed in the first few weeks of treatment. Cyclosporine is given at the dose of 3 to 5 mg/kg/day in two divided doses for two to four months. The dose can then be gradually tapered over several months (eg, by 1 mg/kg/day every one to three months) and stopped once stable improvement is achieved. Thereafter, intermittent therapy with 3 mg/kg or 5 mg/kg per day given twice weekly (eg, on Saturdays and Sundays) may be an option to prevent relapses while minimizing toxicity [46].

Cyclosporine has been shown to be effective in inducing remission in adults and children with severe AD [47]. In a systematic review and meta-analysis of 15 controlled and uncontrolled clinical trials including 602 adult and pediatric patients with AD who were treated with cyclosporine, the mean relative decrease in AD severity (based on AD severity scores) from baseline was 55 percent (95% CI 48-62) after six to eight weeks of continuous treatment [47]. After the first two weeks of treatment, disease severity decreased by 22 percent (95% CI 8-36) in patients treated with low-dose cyclosporine (2.5 to 3 mg/kg) and by 40 percent (95% CI 29-51) in those treated with high-dose cyclosporine (4 to 5 mg/kg). However, there was considerable heterogeneity among the individual trials regarding the dose and duration of cyclosporine therapy and the comparator (for studies that included a control group). Adverse events reported in these studies included gastrointestinal symptoms (40 percent), elevations in creatinine (11 percent), and newly diagnosed infections (6 percent). Headache and paresthesias were also common. Adverse events were more common in patients receiving higher doses of cyclosporine. In the three trials that reported on relapse rates after stopping therapy, approximately 50 percent of patients relapsed within two weeks.

Renal and hepatic function must be monitored during treatment. Cyclosporine trough levels should be monitored if the clinical response is inadequate [48]. Adverse effects include nephrotoxicity, hepatotoxicity, hypertension, hypertrichosis, increased risk of infection, and malignancy. (See "Pharmacology of cyclosporine and tacrolimus".)

Methotrexate — For children with severe AD in whom treatment with cyclosporine is contraindicated or not tolerated, methotrexate is an alternative treatment option. Methotrexate has a slow onset of action, and its effects become apparent after six to eight weeks of treatment.

We usually start with a dose of 0.5 mg/kg given orally once weekly. The dose can be gradually increased as tolerated, up to a maximum of 25 mg per week. Oral supplementation with folic acid 1 mg per day is recommended to reduce methotrexate toxicity without loss of efficacy [49]. (See "Major side effects of low-dose methotrexate".)

Methotrexate is a folic acid antagonist that inhibits transmethylation reactions and promotes release of adenosine. The anti-inflammatory effects of methotrexate may be due to the inhibition of lymphocyte proliferation and to the anti-inflammatory activity of adenosine. Methotrexate is generally well tolerated. Adverse effects include gastrointestinal upset, hepatotoxicity, bone marrow suppression, and, very rarely, acute idiopathic pulmonary fibrosis.

Studies of methotrexate for the treatment of AD in children are limited to a few retrospective studies [50-55] and one small randomized trial [56]. The quality of these studies is generally low, with high variability in the dose and duration of treatment, outcome measurement, and length of follow-up [57]. Of note, in the only randomized trial, the doses of methotrexate and cyclosporine were likely subtherapeutic [56]:

●In a small randomized unblinded trial, low-dose methotrexate (7.5 mg/week) was compared with low-dose cyclosporine (2.5 mg/kg/day) in 40 children aged 8 to 14 years with severe AD (who had failed topical therapy) [56]. The primary outcome was the mean change in Scoring of Atopic Dermatitis (SCORAD) after 12 weeks of treatment. At week 12, the mean absolute reduction in SCORAD was similar in the methotrexate and cyclosporine groups (26 and 25 points, respectively). Treatment was well tolerated in both groups.

●In a retrospective study, 47 children 2 to 18 years old with severe AD were treated with a weekly dose of methotrexate 0.2 to 0.5 mg/kg [50]. The 44 patients who had completed at least three months of methotrexate treatment reported improvement of eczema, reduced itch, and reduced use of topical corticosteroids, as assessed by the Investigator Global Assessment (IGA) score, at three to five months. Sustained improvement was reported at 10 to 14 months among the 30 children who completed at least 10 months of treatment. Approximately 70 percent of patients experienced a mild flare-up during methotrexate therapy that was treated with topical corticosteroids, minor methotrexate dose adjustment, or both. Adverse effects were reported in 83 percent of the patients and included mild elevation of transaminases and transient hematologic abnormalities. Gastrointestinal adverse effects, including nausea, vomiting, and abdominal pain, occurred in nearly 30 percent of patients.

●In another retrospective study of 55 children (age 3 to 19.5 years) with severe, longstanding AD treated with methotrexate at a mean starting dose of 0.37 mg/kg, 42 patients (76 percent) showed improvement, with a reduction of the mean baseline IGA score from 4.2 to 2.9 after six to nine months of treatment [54]. Adverse effects occurred in 51 percent of patients, most commonly gastrointestinal discomfort and nausea (31 percent), followed by fatigue (26 percent) and headache (16 percent).

Other therapies

Systemic corticosteroids — We generally avoid using systemic corticosteroids in children with severe AD. Although frequently used in clinical practice for the treatment of severe AD in children and adults [58-60], there are no high-quality studies evaluating their role in the management of AD [61]. A consensus statement published by the International Eczema Council, an international panel of 77 experts, reports that systemic corticosteroids should be generally avoided, particularly in children and adolescents, but can be occasionally used for a short period of time in the following circumstances [62]:

●When other options are not available or contraindicated

●As a bridge therapy to other systemic therapies or phototherapy

●For the immediate relief of acute flares

●In the most severe cases

These principles are in agreement with most clinical practice guidelines [48,63-66]. However, the dose and duration of a "short course" of systemic corticosteroids have not been determined. The European Task Force on Atopic Dermatitis/European Academy of Dermatology and Venereology Task Force position statement on the treatment of AD suggests that a typical regimen of systemic corticosteroids might be methylprednisolone 0.5 mg/kg per day for one to two weeks tapered over one month [64].

Because of the many and potentially severe adverse effects of systemic corticosteroids in children, including adrenal suppression, weight gain, growth suppression, and increased susceptibility to infection, their use is not recommended for the long-term control of AD [67,68]. (See "Major side effects of systemic glucocorticoids".)

Mycophenolate mofetil — Mycophenolate mofetil inhibits T and B cell proliferation via the inhibition of inosine monophosphatase dehydrogenase, a key enzyme involved in de novo purine synthesis. Studies of mycophenolate mofetil for the treatment of AD in children are limited. A number of small, uncontrolled studies have reported efficacy in adults with AD [69-72]. Two retrospective case series evaluated the use of the drug in children [73]:

●In one report of 14 children treated with an initial dose of mycophenolate mofetil of 12 to 40 mg/kg per day and up to 75 mg/kg per day (maximum dose 3 g/day), disease improvement occurred in all but one; the initial response was noted within eight weeks of treatment [73]. Treatment was well tolerated in all patients. Two patients experienced transient, mild gastrointestinal disturbance during the initial week of treatment, one patient had a history of recurrent herpes simplex viral infections, and two had recurrent bacterial superinfections requiring systemic antibiotic therapy.

●In another report, 12 children were treated with mycophenolate mofetil 20 to 40 mg/kg per day for 0.5 to 20 months [74]. Significant improvement was reported in eight patients and no response in four. Adverse effects included decreased hemoglobin level in one patient and cutaneous infections in three.

Adverse effects of mycophenolate mofetil include gastrointestinal disturbances, myelosuppression, and infections.

Azathioprine — Azathioprine is an antagonist of purine metabolism that inhibits T cell proliferation. Its catabolism and concurrent production of active metabolites is regulated by the levels of thiopurine methyltransferase (TPMT), which vary among individuals according to common allelic polymorphisms. Evidence supporting the use of azathioprine in children with AD is limited to a few observational studies [74-78]:

●In a small prospective study, 12 children with severe, recalcitrant AD (baseline SCORAD >40) started treatment with azathioprine 1 to 2.5 mg/kg per day, depending on their baseline red blood cell TPMT activity, for up to 16.5 months [75]. Considerable improvement was reported in 11 of 12 children, with a mean decrease in SCORAD of 27.7 points. Treatment was generally well tolerated. One child had a transitory decrease in the absolute neutrophil count, and another had a mild increase in serum transaminase level.

●In a retrospective study, 28 children aged 3 to 17 years were treated with azathioprine for 1 to 29 months [74]. Seventeen (61 percent) of patients reported significant improvement, six some improvement, and five no response. Seven patients experienced laboratory abnormalities (eg, abnormal liver function test, decreased hemoglobin concentration and white blood cell count) requiring dose adjustment. Twelve patients were transitioned to mycophenolate mofetil for an average of 10 months after starting azathioprine. Of these patients, eight reported significant improvement, and four reported no improvement.

Azathioprine has numerous adverse effects, including myelosuppression, hepatotoxicity, gastrointestinal disturbances, increased susceptibility to infection, and increased risk of cancer (squamous cell carcinoma, non-Hodgkin lymphoma) especially for long-term treatments. Pretreatment determination of TPMT activity may be helpful to determine the appropriate dose and reduce the risk of myelotoxicity [79].

Hematologic parameters and liver function tests must be monitored. In a series of 82 children (mean age 8.3 years) treated with azathioprine for an average time of approximately two years, 33 (40 percent) had transaminase levels ≥50 international unit/L and/or lymphocyte count <1 x 10⁹/L or neutrophils <1.5 x 10⁹/L after a median time of five months [78]. Five children discontinued azathioprine because of adverse effects.

Omalizumab — Omalizumab is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody that binds IgE with high affinity and is approved for the treatment of moderate to severe asthma inadequately controlled by inhaled corticosteroids in children aged six years or older with IgE levels up to 1500 international units/mL. Limited studies of omalizumab for AD have provided conflicting results [80].

A previous small, randomized trial including eight children with severe, refractory AD showed that omalizumab given at a dose of 150 to 375 mg every two to four weeks was no more effective than placebo in improving the clinical symptoms of AD, as measured with SCORAD, despite a marked reduction in the blood levels of IgE and T helper type 2 (Th2) inflammatory markers [81]. In a subsequent randomized trial including 62 children with severe AD and elevated IgE levels treated with omalizumab or placebo for 24 weeks, omalizumab was more effective than placebo in improving the clinical signs of AD (mean difference in the objective SCORAD index between the omalizumab group and placebo group -6.9, 95% CI -12.2 to -1.5, after adjusting for baseline SCORAD score, serum IgE level [≤1500 or >1500 international units/mL] and age [<10 or ≥10 years]) [82]. However, in this trial, omalizumab was used at much higher doses (up to 1200 mg per month), and all patients were allowed to use potent topical corticosteroids as needed throughout the study.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atopic dermatitis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Eczema (atopic dermatitis) (The Basics)")

●Beyond the Basics topics (see "Patient education: Eczema (atopic dermatitis) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Potential causes of refractory disease – Severe atopic dermatitis (AD) remains a difficult condition to treat. Before initiating second-line treatments for AD, factors potentially associated with recalcitrant diseases should be assessed and treated. These include poor adherence to treatment, presence of environmental triggers or allergens, infected eczema, and incorrect diagnosis. (See 'Potential causes of refractory disease' above.)

●Initial management:

•For children of any age with persistent, severe AD or acute, generalized exacerbation of AD, we attempt a more intensive topical treatment with wet wrap therapy with diluted, medium-potency topical corticosteroids (table 3) rather than systemic treatments. Wet wraps consist of a bottom wet layer and a top dry layer. They are applied once or twice daily and can be maintained for two or more hours, as tolerated, and even overnight if patients feel comfortable. Wet wraps can be used until improvement occurs, usually for a few days and up to 14 days, if tolerated. Topical therapy is resumed once the flare has subsided. (See 'Wet wraps' above and 'Proactive therapy' above.)

•For children ≥6 months and adolescents who do not respond to or refuse wet wraps, we suggest dupilumab as first-line therapy rather than other treatments (Grade 2B). The dosing schedules in children 6 months to 17 years of age are based on weight. (See 'Dupilumab' above.)

●Second-line therapies:

•Children six months to six years of age – For children six months to six years of age with severe AD for whom dupilumab is undesirable, not accessible, or ineffective, conventional systemic immunosuppressive therapy is warranted. In this setting, we suggest oral cyclosporine as the first-choice immunosuppressive agent rather than other immunosuppressive agents (Grade 2C). Cyclosporine is given at the dose of 3 to 5 mg/kg in two divided doses for two to four months and then gradually tapered. (See 'Cyclosporine' above.)

For children in whom treatment with cyclosporine is contraindicated or not tolerated, other treatment options include methotrexate, mycophenolate mofetil, and azathioprine. (See 'Other therapies' above.)

•Children older than six years – For children ≥6 years and adolescents for whom dupilumab is undesirable, not accessible, or ineffective, we suggest narrowband ultraviolet B (NBUVB) phototherapy rather than conventional immunosuppressive agents (Grade 2C). NBUVB is usually administered three times per week, with a progressive protocol that increases the dose with each treatment, as tolerated. (See 'Phototherapy' above.)

If phototherapy is inaccessible, undesirable, or ineffective, alternative therapies include oral cyclosporine or other conventional immunosuppressants (eg, methotrexate, mycophenolate mofetil, azathioprine). (See 'Cyclosporine' above and 'Methotrexate' above and 'Other therapies' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jonathan M Spergel, MD, PhD, FAAAAI, who contributed to earlier versions of this topic review.