Management of severe, refractory 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 topical therapy may benefit from systemic medications or phototherapy.

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 eczematous 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 and may not reflect the disease severity as perceived by the individual patients.

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 [2].

A few severity assessment tools that incorporate the patient's perception of severity and disease control associated with treatments have been developed:

●POEM – 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 [3].

●ADCT – A similar tool called the Atopic Dermatitis Control Tool (ADCT) has been validated for patients 12 years of age and older [4]. This six-question scale is designed for clinical use and seeks to determine if the condition is under control, something perhaps more relevant than the disease severity from a patient perspective. A version for younger patients is being validated as well [5].

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.

ASSESSMENT OF 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 additional 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 [6-8]. 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 [9].

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 [10-12]. Corticosteroid phobia is likely a contributing cause of poor adherence to treatment and treatment failure among patients with AD.

Exacerbating factors/environmental triggers — Circumstances that may contribute to severe or refractory AD include noncompliance with conventional therapy, secondary infection, hypersensitivity reactions to topical treatments, and persistent exposure to triggers of disease flares.

Exacerbating factors for AD may include low humidity environments; xerosis (dry skin); sweat and overheating of skin; emotional or physiologic 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 [13,14]. (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 vehicle or active ingredients in emollients (eg, lanolin, propylene glycol, fragrances, preservatives), topical immunosuppressive medications (eg, corticosteroids, calcineurin inhibitors), and topical antibiotics (eg, bacitracin, neomycin) [15-21].

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 [21,22]. 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 "Allergic contact dermatitis in children".)

Food and environmental allergies — In some cases, patients with refractory AD may have undiagnosed food or environmental allergies that may worsen the symptoms of their disease. It is important to exclude immediate and delayed hypersensitivity through allergy testing (eg, skin prick testing, specific immunoglobulin E [IgE] measurement, patch testing).

However, clinicians should be cognizant that evidence of allergen sensitization is not proof of clinically relevant allergy. Moreover, even a clinically relevant food allergy is often not the trigger of the persistent eczema, as food allergies most often present with urticaria and angioedema and not dermatitis.

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 [23]. Additionally, there is some evidence that food avoidance may actually induce sensitization, including an increased risk of developing anaphylaxis [24,25].

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 current treatment guidelines and use of second-line treatments, such as biologics, other systemic agents, and phototherapy. Because of the paucity of randomized trials addressing the management of refractory AD in the pediatric age group, there is a wide variability among clinicians in the use of second-line therapies for children with severe disease [26,27].

MANAGEMENT — A number of systemic treatments are available for the treatment of refractory AD in children and adolescents. However, it is important to note that AD is a lifelong disease, and initiation of systemic therapy should be carefully considered.

Optimizing topical therapy

Basic principles — After excluding the factors potentially associated with recalcitrant disease (see 'Assessment of potential causes of refractory disease' above), our initial approach is to attempt to optimize topical treatment for several weeks. This will help identify those children who are candidates for second-line therapies. To optimize topical treatment:

●Ensure that the appropriate strength topical medication expected to clear the flare in approximately 5 to 10 days is being used

●Initiate treatment at the first sign of a flare

●Continue treatment until there is complete clearance of skin lesions

Wet wraps and proactive therapy are additional techniques that help to optimize topical treatments and, in many situations, can prolong the interval between flares.

Wet wrap therapy — 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.

●Application – Wet wraps consist of a bottom wet layer and top dry layer. They are generally applied on top of emollients and/or topical corticosteroids and left in place for up to 24 hours [28]. 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 [29]. 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, 1:20 for the 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 [30,31]. 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.

●Efficacy – 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) [32]. 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 [28,33,34].

●Adverse effects – 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 [28].

Proactive (maintenance) topical therapy — Once the flare has subsided, patients can continue using topical therapy with a medium-potency topical corticosteroid (table 3) or topical calcineurin inhibitor (tacrolimus 0.03% or 0.1% or pimecrolimus 1%) intermittently in the area of previously flared skin to prevent exacerbations and prolong the interval in-between flares [23,35]. The frequency of application of proactive therapy varies, with some clinicians recommending every other day or twice weekly for two to four weeks.

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 and adolescents with refractory AD that is not controlled with optimized topical therapy and for children who refuse wet wraps, we suggest dupilumab rather than other systemic therapies. (See 'Conventional immunosuppressants' below.)

Dupilumab is an interleukin (IL) 4 and IL-13 receptor-alpha antagonist that is approved by the US Food and Drug Administration (FDA) for the treatment of children ≥6 months with moderate to severe AD.

●Administration – There are three dosing schedules based on weight for children >6 years and based on age and weight for children <6 years.

•Children 60 kg and over – 600 mg loading dose followed by 300 mg every two weeks

•Children 30 to 59 kg – 400 mg loading dose followed by 200 mg every two weeks

•Children 15 to 29 kg – 600 mg loading dose is administered, followed by 300 mg every four weeks

•Children six months to five years – 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

●Efficacy – Data on the use of dupilumab in children aged six months and older and adolescents are available [36-41]. The results of randomized trials evaluating the safety, pharmacokinetics, and efficacy of dupilumab in toddlers, children, and adolescents are comparable with those seen in the adult studies [41]. Compared with conventional immunosuppressive agents, dupilumab has a favorable safety profile and may be used for long-term treatment of AD [42]. (See "Treatment of atopic dermatitis (eczema)", section on 'Dupilumab'.)

Second-line therapies

Children six months to six years of age

Conventional immunosuppressants — Broader action immunosuppressants are less commonly used as second-line therapies for severe AD. However, they are an option for children aged six months to six years whose dermatitis is not controlled by optimal topical therapy or dupilumab and for those who cannot access dupilumab.

Cyclosporine — Cyclosporine is our first-choice immunosuppressive agent for children and adolescents with refractory AD for whom dupilumab, other approved systemic agents, and phototherapy are inaccessible, undesirable, or ineffective. Cyclosporine has a rapid onset of action, and its effects can be noticed in the first few weeks of treatment.

●Administration – 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 [43].

●Monitoring – Renal and hepatic function must be monitored during treatment. Cyclosporine trough levels should be monitored if the clinical response is inadequate [44]. Adverse effects include nephrotoxicity, hepatotoxicity, hypertension, hypertrichosis, increased risk of infection, and malignancy. (See "Pharmacology of calcineurin inhibitors".)

●Efficacy – A 2023 randomized trial compared oral cyclosporine 4 mg/kg/day and oral methotrexate 0.4 mg/kg/week for 36 weeks in 103 children aged 2 to 16 years with severe, recalcitrant AD (Scoring of Atopic Dermatitis [SCORAD] index ≥30 and inadequate response to potent topical treatment, with no previous exposure to systemic immunosuppressants or biologics) [45]. At week 12, patients in the cyclosporine group experienced a greater improvement in SCORAD from baseline compared with those in the methotrexate group. However, there was no difference between the two treatments at week 36. After stopping treatment, flares were more common in the cyclosporine group. The most frequent adverse events were AD flares (43 percent), headache (27 percent), and abnormal glomerular filtration rate (27.5 percent) in the cyclosporine group and nausea (43 percent), AD flares (29 percent), and fatigue (23 percent) in the oral methotrexate group.

Methotrexate — For children with severe AD in whom treatment with cyclosporine is contraindicated or not tolerated, methotrexate is an alternative treatment option [46,47]. Methotrexate has a slow onset of action, and its effects become apparent after six to eight weeks of treatment.

●Administration – 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 [48]. (See "Major adverse effects of low-dose methotrexate".)

●Efficacy – Studies of methotrexate for the treatment of AD in children are limited to a few retrospective studies [49-54] and small clinical trials [45,55].

•In a randomized trial of 103 children 2 to 16 years with severe AD, methotrexate 0.1 mg/kg/week at week 0 and then 0.4 mg/kg/week (maximum dose 25 mg orally per week) was as effective as cyclosporine 4 mg/kg/daily at 36 weeks [45]. Patient-reported flares after treatment cessation occurred less frequently in the methotrexate group than in the cyclosporine group (29 versus 43 percent). Nausea and fatigue were the most common adverse effects of methotrexate.

•In a retrospective study including 47 children 2 to 18 years old with severe AD, methotrexate at the dose of 0.2 to 0.5 mg/kg/week induced improvement of eczema, reduced itch, and reduced use of topical corticosteroids at three to five months [49]. 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, nausea, vomiting, and abdominal pain.

•In another retrospective study of 55 children aged 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 Investigator Global Assessment (IGA) score from 4.2 to 2.9 after six to nine months of treatment [53]. 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).

●Adverse effects – 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.

Children >6 years

Phototherapy — For children >6 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 and acceptable to the patients or caregivers. Because of its favorable safety profile, 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]). (See "UVA1 phototherapy" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)

The treatment is generally well tolerated. However, given the impracticality of frequent visits to a clinician's office for this treatment and the availability of newer systemic modalities, phototherapy is now used less often.

●Administration – 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'.)

●Efficacy – Data on the efficacy of NBUVB phototherapy in children with AD are limited to a few retrospective case series and one prospective study [56-58]. In one study that included 25 children with AD, 17 achieved almost clear or clear skin with a median of 24 treatments [56].

●Adverse effects – Short-term adverse effects of NBUVB include erythema, blistering, herpes simplex reactivation, and anxiety [56]. 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 [59,60].

Children >12 years

Other biologics

Tralokinumab — Tralokinumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to IL-13 and is approved by the FDA for the treatment of adolescents ≥12 years with moderate to severe AD not adequately controlled with topical prescription therapies.

Tralokinumab is an option for adolescents who have skin-limited disease and have developed intolerable adverse effects or have not seen improvement with dupilumab. Unlike dupilumab, tralokinumab is not indicated for asthma or eosinophilic esophagitis in children. No laboratory tests are required before or during treatment with tralokinumab.

In a phase 3 clinical trial of adolescents 12 to 17 years old with moderate to severe AD, more patients achieved clear or almost clear skin with tralokinumab 300 and 150 mg compared with placebo after 16 weeks of treatment (21.4, 17.5, and 4.3 percent, respectively) [61]. The most frequent adverse events were upper respiratory tract infection, injection site reaction, asthma, and headache. The incidence of conjunctivitis was low and similar in the tralokinumab and placebo arms at week 16, with no increases seen for up to 52 weeks.

Lebrikizumab — In Europe, lebrikizumab, a humanized IgG4 monoclonal antibody that binds soluble IL-13, is approved in adults and adolescents ≥12 years with moderate to severe AD who are candidates for systemic therapy.

In two identical phase 3 randomized trials (ADvocate1 and ADvocate2) with a total of 851 adults and adolescents with moderate to severe AD receiving lebrikizumab (loading dose of 500 mg at baseline followed by 250 mg every other week) or placebo, more patients in the lebrikizumab groups achieved an IGA score of 0/1 at week 16 than patients in the placebo groups (43 and 33 percent versus 13 and 11 percent, respectively) [62].

JAK inhibitors

Overview and dosing — Janus kinases (JAKs) are a family of intracellular enzymes (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]) that are necessary for the successful signaling of numerous inflammatory cytokines, including IL-4 and IL-13. In children ≥12 years, we use oral JAK inhibitors as a second-line treatment when dupilumab or another biologic fails to control signs and symptoms of refractory AD.

●Upadacitinib – Upadacitinib is an oral small molecule JAK1 inhibitor that decreases proinflammatory cytokines in the skin and is indicated for moderate to severe AD in adolescents ≥12 years with refractory, moderate to severe AD whose disease is not adequately controlled with other systemic drugs, including biologics, or when use of those therapies is inadvisable.

•Administration – In patients ≥12 years who weigh >40 kg, the recommended starting dose is 15 mg once daily. The dose can be titrated up to 30 mg if an inadequate response is achieved after two to three months of treatment.

•Efficacy – In the phase 3 clinical trials involving adolescents with moderate to severe AD, more patients treated with upadacitinib 30 and 15 mg experienced clear or almost clear skin at 16 weeks compared with placebo (45, 59 to 64, and 5 to 7 percent, respectively) [63]. In addition, more patients treated with upadacitinib achieved a 75 percent improvement in their Eczema Area and Severity Index (EASI-75) score at 16 weeks compared with placebo (73 to 78 percent in the 30 mg group, 69 to 73 percent in the 15 mg group, and 12 to 13 percent in the placebo group). Significant improvements in itch versus placebo were seen as early as two days.

•Adverse effects – The safety profile of upadacitinib in adolescents was similar to that seen in adults. The most common side effects seen in the AD clinical trials were acne, headache, nasopharyngitis and upper respiratory tract infection, and creatine phosphokinase (CPK) elevations.

●Abrocitinib – Abrocitinib is an oral small molecule JAK1 inhibitor that is approved by the FDA for the treatment of adolescents ≥12 years with refractory, moderate to severe AD that is not adequately controlled with other systemic drugs, including biologics, or when use of those therapies is inadvisable.

•Administration – Abrocitinib is taken orally at the dose of 100 mg once daily. If inadequate control is achieved with 100 mg, the dose can be titrated up to 200 mg daily.

•Efficacy – In a phase 3 clinical trial that included 256 adolescents with moderate to severe AD, more patients treated with topical corticosteroids and abrocitinib 100 and 200 mg daily had clear or almost clear skin at 12 weeks compared with patients treated with placebo (46.2, 41.6, and 24.5 percent, respectively) [64]. In addition, 68.5 percent of the patients treated with abrocitinib 100 mg and 72 percent of those treated with 200 mg achieved an EASI-75 score at 12 weeks compared with 41.5 percent of patients treated with placebo. Improvement in itch was also greater in the abrocitinib groups than in the placebo group (53 and 55 percent versus 30 percent) and was noted in the abrocitinib groups within two days of the first dose.

•Adverse effects – The safety profile of abrocitinib in adolescents was similar to that seen in adults. The most common side effects seen in the adolescent AD clinical trials were nausea, nasopharyngitis and upper respiratory tract infection, acne/folliculitis, increased CPK levels, and headache.

●Baricitinib – Baricitinib, an oral selective JAK1/JAK2 inhibitor, is approved in Europe, but not in the United States, in children ≥2 years with refractory, moderate to severe AD when topical treatments are not sufficient. In a randomized trial that included 483 children aged 2 to <18 years assigned to once daily treatment with baricitinib 1, 2 , or 4 mg, more patients in the baricitinib 4 mg group achieved a clear/almost clear score at 16 weeks compared with placebo (42 versus 16 percent) [65].

Safety concerns — A boxed warning exists on upadacitinib, abrocitinib, and other oral JAK inhibitors in the United States. The alerts listed (including major adverse cardiovascular events, venous thromboembolism, cancer, serious infection, and mortality) were not seen as adverse events in the AD adolescent clinical trials. Nonetheless, the presence of the warning requires discussion of the context of the origin of the warnings with patients and families/caregivers. In addition, oral JAK inhibitors require laboratory monitoring at baseline and ongoing laboratory monitoring for latent tuberculosis, hepatitis infection, renal and hepatic function, and lipids.

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 [66-68], there are no high-quality studies evaluating their role in the management of AD [69]. 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 [70]:

●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 [44,71-74]. 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 [72].

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 [75,76]. (See "Major adverse effects of systemic glucocorticoids".)

Other agents infrequently used

●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 [77-80]. Two retrospective case series evaluated the use of the drug in children [81]:

•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, and the initial response was noted within eight weeks of treatment [81]. 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 [82]. Significant improvement was reported in eight patients, and no response was reported in four. Adverse effects included decreased hemoglobin level in one patient and cutaneous infections in three patients.

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

●Azathioprine – While historically used in some cases of refractory disease, azathioprine is rarely used for AD in children. Compared with other systemic treatments, azathioprine has limited efficacy for AD and is associated with potentially serious adverse effects (eg, myelosuppression, hepatotoxicity) that require laboratory monitoring during treatment [83]. Guidelines recommend against its use for AD [23].

●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 [84,85].

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".)

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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

●Assess 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 'Assessment of potential causes of refractory disease' above.)

●Approach to management

•Optimize topical therapy – For children of any age with persistent, severe AD or acute, widespread exacerbation of AD, we suggest optimizing topical treatments before starting systemic therapy. This includes:

-Ensuring that a topical corticosteroid of appropriate strength is being used for sufficient time to allow for complete clearance of the skin lesions (see 'Basic principles' above)

-Instructing patients/caregivers to use wet wraps with diluted medium-potency topical corticosteroids (table 3) (see 'Wet wrap therapy' above)

-Educating patients/caregivers about the importance of maintenance (proactive) therapy with intermittent topical corticosteroids or topical calcineurin inhibitors (see 'Proactive (maintenance) topical therapy' above)

•Dupilumab – For children ≥6 months and adolescents who do not respond to optimal topical therapy or refuse wet wraps, we suggest dupilumab rather than other systemic therapies (Grade 2C). Dupilumab has a favorable safety profile and can be used for long-term treatment of AD. 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, methotrexate is an alternative treatment option. (See 'Other therapies' above.)

•Children >6 years of age – 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 methotrexate. (See 'Cyclosporine' above and 'Methotrexate' above and 'Other therapies' above.)

•Children older than 12 years – For children older than 12 years for whom dupilumab is undesirable, inaccessible, or ineffective, alternative therapies may also include tralokinumab, upadacitinib, or abrocitinib. (See 'Children >12 years' above.)

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