Treatment of atopic dermatitis (eczema)

INTRODUCTION — Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease that occurs most frequently in children but also affects adults [1]. Clinical features of AD include skin dryness, scaling, erythema, oozing, crusting, and lichenification. Pruritus is a hallmark of the condition and is responsible for much of the disease burden for patients and their families and caregivers. The goals of treatment include reducing symptoms and signs, preventing exacerbations and minimizing therapeutic risks. Standard treatment modalities for the management of these patients are centered on the use of topical anti-inflammatory preparations and moisturization of the skin, but patients with severe disease may require phototherapy or systemic treatment [2,3].

This topic discusses the approach to the management of AD. The management of severe, refractory AD in children and adults and the epidemiology, pathogenesis, clinical manifestations, and diagnosis of AD are discussed separately.

●(See "Management of severe, refractory atopic dermatitis (eczema) in children".)

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

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

ASSESSMENT OF SEVERITY — For the management of the individual patient, it is important that clinicians evaluate the extent and characteristics of the rash (eg, presence of erythema, excoriations, oozing, lichenification, clinical signs of bacterial superinfection) and ask general questions about itch, skin pain, sleep, impact on daily activities, frequency of flares, and persistence of disease [4]. Importantly, erythema is difficult to assess in patients with darkly pigmented skin, and therefore, severity of AD can be underestimated in these patients. Marked lichenification indicates that itching or rubbing has been chronic and may reflect undertreatment.

Several disease severity scales and patient-reported, quality-of-life measurement scales have been tested and validated for use in clinical trials, but are not commonly used in clinical practice [4]. These include:

●The physician-reported Eczema Area and Severity Index (EASI; 0 to 72)

●The Investigator Global Assessment (IGA; 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, and 4 = severe)

●The joint-reported Scoring of Atopic Dermatitis (SCORAD; 0 to 103)

●The patient-reported Patient-Oriented Eczema Measure (POEM; 0 to 28)

●The Peak Pruritus Numeric Rating Scale (0 to 10)

POEM, which assesses how frequently the patient experienced seven symptoms (itch, sleep disturbance, dryness, flaking, weeping or oozing, bleeding, and cracking) in the previous seven days, typically takes less than two minutes to complete and is available from the Centre of Evidence Based Dermatology [5]. The Peak Pruritus Numeric Rating Scale may be a useful addition to POEM to assess pruritus intensity.

The Investigator Global Assessment and Body Surface Area (IGAxBSA) obtained by multiplying the IGA score by the percentage of the BSA involved may be a simpler alternative to EASI [6,7].

A practical guide to the visual assessment of AD 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

GENERAL APPROACH — The optimal management of AD requires a multipronged approach that involves patient education, hydration of the skin and restoration of the skin barrier function, pharmacologic treatment of skin inflammation, and elimination of exacerbating factors (algorithm 1) [8].

Patient education — Patient education is an important component of the management of AD. A systematic review of nine randomized trials (>2000 participants) of educational interventions for AD suggests that children and their parents/caregivers may benefit from structured education provided by nurses or multidisciplinary teams [9]. In the largest of these trials, which included 992 children and adolescents with AD and their families, a six-week education program was compared with no intervention [10]. The program consisted of two-hour weekly sessions (covering medical, nutritional, and psychologic issues) led by a multidisciplinary team of dermatologists or pediatricians, psychologists, and dietitians. After one year, the decrease in the severity (based on the Scoring of Atopic Dermatitis [SCORAD] score) was greater in the intervention groups than in the control groups for all ages groups (from 3 months to 18 years). There was also improvement in subjective assessment of severity, itching behavior, and emotional coping for patients aged 8 to 12 years (not assessed in younger children and not significant for ages 13 to 17 years).

In two randomized trials, the addition to standard care of two online behavioral interventions for AD, targeting parents and caregivers of children <12 years or adolescents and young adults aged 13 to 25 years, was associated with a modest but sustained improvement in AD severity at 52 weeks [11].

Maintaining skin hydration

Bathing practices

Frequency of bathing — Most experts recommend a hydrating bath using mild or soap-free cleansers followed by immediate emollient application to prevent skin drying, but others recommend a shower of short duration. We feel that either option is reasonable but suggest less frequent bathing in infants and up to daily bathing/showering in older children and adults. Only a few, small trials have addressed this controversy [12-14].

●A small, randomized, single-blind, crossover trial examining the effect of frequent (twice daily) versus infrequent (twice weekly) soak-and-seal baths in 42 children with moderate to severe AD found that frequent bathing was associated with a greater decrease of SCORAD score from baseline compared with infrequent bathing (mean difference in SCORAD 21.2 [95% CI 4.9-27.6]) [15].

●Another study of 1303 infants showed higher transepidermal water loss and higher prevalence of AD at three months of age in those who bathed at least daily versus two to four times weekly; however, the risk of developing AD at 12 months was similar in the two groups [16].

In patients with Staphylococcus aureus skin infection, daily bathing or showering is needed. Regardless of the preference for bath or shower and frequency, the application of emollients and/or prescribed topical preparations immediately after emerging from the bath or shower is critical.

Bath additives

Emollient additives — Despite the lack of high-quality studies providing evidence of benefit, bath emollient additives (eg, liquid paraffin, oils with or without emulsifiers, colloidal oatmeal) are widely used to improve skin hydration and supported by national and international guidelines [2,17,18].

A large, well-designed, pragmatic, randomized trial demonstrated that emollient bath additives provide no additional benefits beyond standard care in the management of AD [19,20]. In this study, 463 children aged 1 to 11 years with mild to moderate AD were assigned to use bath emollient additives or no bath additives in addition to standard care (ie, leave-on emollients and topical corticosteroid as needed) for 52 weeks. At 16 weeks, there was no significant difference between groups in the mean Patient-Oriented Eczema Measure (POEM) score. After adjusting for potential confounders (eg, baseline severity, use of topical corticosteroid, use of soap substitutes), the POEM score in the no bath additives group was marginally higher than in the bath additives group, and far below the accepted minimal clinically important difference [21,22]. Similar results were obtained at 52 weeks.

Of note, most bath additives increase the risk for slipping in the bath, adding an element of potential danger to infants and young children.

Bleach baths — Diluted bleach baths 0.005% (obtained by adding 0.5 cup or 120 mL of 6% bleach in a full bathtub [40 gallons or 150 L] of lukewarm water; or 1 scant teaspoon of bleach in 1 gallon/4 L of lukewarm water) have been widely suggested as an adjunctive therapy for AD to reduce the cutaneous load of S. aureus and improve symptoms [23].

However, data from a limited number of small studies suggest that the impact of diluted bleach baths is more a direct anti-inflammatory effect rather than an antibacterial effect [24].

●A 2022 meta-analysis of 10 small randomized trials with 307 participants with moderate to severe AD found that bleach baths were associated with a modest improvement in the severity of AD compared with no bleach baths, with 32 percent of patients achieving a 50 percent reduction in the Eczema Area and Severity Index (EASI-50) in the bleach bath group versus 22 percent in the no bleach bath group [25]. Beach baths were also associated with a slight and transient decrease in the cutaneous load of S. aureus.

●In an open-label 12-week study, daily bleach baths improved AD severity, itch, and the skin barrier function but did not reduce the S. aureus skin load and did not alter the skin microbiome [26].

These findings support the use of diluted bleach baths as an inexpensive adjunct to the skin care routine for patients with moderate to severe AD [27]. They are generally well tolerated; adverse effects are mild and include skin dryness and irritation.

Emollients and moisturizers — Skin hydration is a key component of the overall management of patients with AD. To maintain skin hydration, emollients should be applied at least two times per day and preferably immediately after bathing or hand washing, when the skin is well hydrated.

●Choice of emollients

•Formulation – Thick creams, which have a low water content, or ointments (eg, petroleum jelly), which have zero water content, are generally preferred as they better protect against xerosis. However, some patients and families/caregivers may complain that they are greasy. Emollient creams, lotions, or oils (eg, safflower, sunflower, or coconut) can be an alternative for these patients. In hot, humid environments, ointments and, less commonly, other emollient bases can increase the risk of folliculitis.

•Avoid fragranced emollients – Fragranced emollients or those with potential sensitizers (eg, essential oils from plants such as ylang-ylang and tea tree oil) should be avoided. Studies show that emollients that are marketed as being "hypoallergenic" may contain potent sensitizers [28]. Particular attention should be paid to labeling. Fragrance-free labeling indicates that fragrance materials or masking scents are not used in the product. However, unscented products may contain chemicals that neutralize or mask the odors of other ingredients.

•Moisturizers containing ceramides – The stratum corneum of patients with AD is deficient in certain lipids (especially ultralong chain ceramides) and "natural moisturizing factor" (a mixture of hygroscopic amino acids resulting from filaggrin breakdown). Moisturizers may contain a small fraction of the deficient ceramides and, although beneficial in theory, have had little evidence to support their use [29]. Furthermore, it is unclear whether supplementation truly replaces deficiencies. Moisturizers with added "ceramide" are unlikely to replenish the hundreds of ceramide species recognized to be deficient in AD or even the most critical ones.

●Efficacy

•In a 2023 United Kingdom pragmatic randomized trial, 550 children (median age four years, interquartile range two to eight years) with mild AD (mean POEM score at baseline 9 to 10; mean Eczema Area and Severity Index [EASI] score 3) were assigned to use emollients formulated as lotion, cream, gel, or ointment for 16 weeks along with usual eczema care [30]. Gels were nonalcohol based and contained liquid paraffin and isopropyl myristate as main ingredients. There was no difference in the primary outcome (repeated measure analysis of weekly POEM scores) among the different groups or in any of the pairwise comparisons over 16 weeks. No difference was reported in the secondary outcomes (EASI score, Atopic Dermatitis Quality of Life score) nor in the median reported daily use of topical corticosteroids or other emollients. Overall satisfaction was highest with lotions and gels. Application site reactions (eg, worsening of eczema, stinging) occurred with similar frequency in all groups.

•A 2017 systematic review of 77 studies and 6603 participants (mean age 19 years) with mostly mild to moderate eczema evaluated the efficacy of emollients and moisturizers in reducing the signs and symptoms of eczema and the frequency of flares [31,32]:

-Based on both physician and patient assessment, the use of any moisturizers reduced eczema severity and itch compared with no use, resulted in fewer flares, and reduced the need for topical corticosteroids.

-In three studies, patients found that a moisturizer containing glycyrrhetinic acid (a natural anti-inflammatory agent) was four times more effective than vehicle in reducing eczema severity.

-In four studies, patients using a cream containing urea (a humectant agent) reported improvement more often than those using a control cream without urea.

-Three studies assessed a moisturizer containing glycerol (a humectant agent) versus control. More patients in the glycerol group experienced skin improvement, both by physician and patient assessment.

-Four studies examined oat-containing moisturizers versus no treatment or control. No significant difference in skin improvement was noted between groups, although patients using oat moisturizers tended to have fewer flares and reduced need for topical corticosteroids.

Elimination of exacerbating factors

General considerations — Exacerbating factors that disrupt an already abnormal epidermal barrier include [33-35]:

●Excessive bathing without subsequent moisturization

●Low-humidity environments

●Emotional stress

●Xerosis (dry skin)

●Overheating and sweating

●Use of hard water

●Exposure to solvents and detergents

Avoiding these situations helps reduce acute flares as well and maintain remission. Climatic changes affect skin barrier function, and winter worsening is common in the northern hemisphere.

Adjunctive measures that can be useful in all patients with dermatitis include [36]:

●Avoiding pruritogens and irritants, such as rough wool clothing, fragranced soaps, perfumes, detergents, household cleaning products, chemical substances

●Treating skin infections (see 'Management of infection' below)

●Managing stress and anxiety

Aeroallergens and food allergens — Whether environmental or food allergens are exacerbating factors in patients with AD is controversial. (See "Role of allergy in atopic dermatitis (eczema)".)

●Environmental allergens – Hypersensitivity to house dust mites (eg, Dermatophagoides pteronyssinus, Dermatophagoides farinae), animal danders, molds, and pollens is thought to be associated with flares of AD and disease severity [37-40]. In one study, a linear relationship was observed between the degree of sensitization to dust mite and cat dander and severity of AD [39].

However, despite the hypersensitivity of many individuals with AD to house dust mites, reduction of house dust mite antigens in the patient's environment has not been found useful for disease control [41,42].

●Food allergens – Exacerbation of AD by food allergens is uncommon. Although approximately 50 percent of children with AD have positive skin prick tests or specific immunoglobulin E (IgE) to one or more food allergens (in particular, cow's milk, egg, wheat, and peanut), food sensitization is clinically irrelevant for the course of AD in most cases [43]. Thus, dietary interventions are not helpful in reducing the severity or preventing flares in unselected patients.

A systematic review of nine randomized trials including 421 children and adults with AD indicated lack of benefit of either milk and egg exclusion, a few-foods diet, or an elemental diet in unselected patients with AD [44]. Moreover, food restriction in toddlers may result in lower Z-scores of weight, height, head circumference, and body mass index for age [45]. One trial suggests that an egg-free diet may be helpful for infants with proven sensitivity to eggs [46].

Little is known on the role of food allergy in adults with AD, but adults with AD and birch allergy may experience worsening if they ingest birch pollen-related foods [47].

Contact irritants and allergens — Patients with AD are more susceptible to both irritant and allergic contact dermatitis and would benefit from identification of triggers and avoidance. An example of irritant contact dermatitis in patients with AD is the lip licker's dermatitis of the perioral area due to contact with saliva (picture 1) or dermatitis on the palmar and dorsal aspects of the hands due to frequent hand washing or use of hand sanitizers.

Ingredients found in emollients and topical treatments may cause allergic contact dermatitis in patients with AD [48]. Allergic contact dermatitis should be suspected in patients who do not respond to appropriate topical therapy, especially at sites exposed to contact allergens (eg, face, periorbital area, hands and feet, periumbilical area) [49].

Patch testing is required for the identification of relevant allergens (see "Patch testing"). However, patch testing can be difficult in patients with AD due to increased skin reactivity and possibility of false-positive reactions.

PATIENTS WITH MILD TO MODERATE DISEASE

Topical corticosteroids — Topical corticosteroids as monotherapy and emollients are the mainstay of therapy for mild to moderate AD (algorithm 1) [2,50]. Regardless of disease severity, emollients should be liberally used multiple times per day as they soothe the skin and reduce the need for topical corticosteroids. Emollients can be applied before or after topical corticosteroids [51]. (See 'Emollients and moisturizers' above.)

●Selection of topical corticosteroid potency and formulation – The choice of topical corticosteroid potency should be based on the patient's age, body area involved, and degree of skin inflammation. It should be noted that ointment formulations tend to be more potent and have superior emollient properties than their cream counterparts. Cream formulations contain more additives than ointments and are more likely to burn or sting. Oil formulations spread more easily and are useful for scalp or large body surface areas. However, the choice of formulation should also be based on patient's preference.

●Administration – Published guidelines recommend twice-daily application for most topical corticosteroids during acute flares, but there is evidence suggesting that once-daily application may result in similar efficacy [52-54].

•Mild disease – For patients with mild AD, we suggest a low-potency (groups 5 and 6 (table 1)) topical corticosteroid ointment (eg, desonide 0.05%, hydrocortisone 2.5%) once to twice daily until three to five days after clearance or up to two weeks. Following clearance, maintenance treatment with emollients alone is usually sufficient.

•Moderate disease – For patients with moderate to severe disease, we suggest medium- to high-potency (groups 2 to 4 (table 1)) topical corticosteroids (eg, mometasone furoate 0.1%, fluocinolone 0.025%, triamcinolone 0.1%). In patients with acute flares, high-potency topical corticosteroids (groups 2 to 3 (table 1)) can be used for up to two weeks and then replaced with lower-potency topical steroid preparations, nonsteroidal agents, or proactive therapy to maintain control as needed. (See 'Maintenance and prevention of relapses' below.)

•Face and skin folds – The face and skin folds are areas at higher risk for atrophy with corticosteroids. Initial therapy in these areas should start with a low-potency steroid (group 6 (table 1)), such as alclometasone 0.05% or desonide 0.05% ointment. High-potency topical corticosteroids are generally avoided in skin folds and on the face. However, limited, brief use (eg, four to five days) of medium- to high-potency corticosteroids (groups 2 to 4 (table 1)) may produce a more rapid response, after which patients can be switched to lower-potency preparations.

Topical calcineurin inhibitors, which do not cause skin atrophy or ocular toxicity, are an alternative to topical corticosteroids (see 'Topical calcineurin inhibitors' below). Other nonsteroidal topical treatments such as crisaborole and topical ruxolitinib are also safe for sensitive areas. (See 'Crisaborole' below and 'Topical ruxolitinib' below.)

•Ear canal – Fluocinolone 0.01% oil or topical corticosteroid-based ophthalmic solutions (eg, prednisolone 1% ophthalmic solution) can be used for the treatment of AD involving the ear canal. If using a cream or ointment, a cotton-tipped stick may facilitate the application. (See "External otitis in adults: Treatment", section on 'Glucocorticoids'.)

●Efficacy – In a network meta-analysis of 219 randomized trials with nearly 32,000 patients evaluating 68 topical interventions for the treatment of AD, high-potency topical corticosteroids were ranked among the best treatments for improving AD severity (high-certainty evidence) [55]. Mid- to high-potency topical corticosteroids and topical tacrolimus 0.1% were among the best treatments for improving itch severity. Mid-potency topical corticosteroids were best effective for long-term control of AD, followed by topical tacrolimus and pimecrolimus. Crisaborole, topical ruxolitinib, topical delgocitinib, and topical difamilast were of intermediate efficacy in improving AD severity (high-certainty evidence).

●Adverse effects – Long-term use of topical corticosteroids, especially high- or super high-potency preparations, on large body areas may lead to systemic absorption with adrenal suppression and other systemic adverse events, such as osteoporosis and type 2 diabetes [56,57]. Local adverse effects include skin thinning (including striae), telangiectasias, hypertrichosis, folliculitis, and contact dermatitis but are generally limited to chronic use of stronger topical corticosteroids. The use of topical corticosteroids on the eyelids, where the skin is thinnest, can lead to adverse ocular effects (eg, glaucoma or cataracts). (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

●Topical corticosteroid withdrawal – The term "topical steroid withdrawal" (also called topical corticosteroid addiction) refers to a constellation of symptoms that have been described in some patients after inappropriate, prolonged use of mid- to high-potency topical corticosteroids, especially on the face or genitals [58-60]. Symptoms usually begin within days; may persist for days to weeks after steroid discontinuation; and include erythema, edema, papulopustular eruption, burning or stinging, and itching.

Although uncommon, increasing awareness of topical steroid withdrawal among the general public has been driven by the wide circulation on social media of patients' experiences and potentially misleading information promoting steroid phobia [61,62]. This prompted the British Association of Dermatologists, National Eczema Society, and British Dermatological Nursing Group to issue a joint statement that acknowledges topical steroid withdrawal as an entity despite the lack of diagnostic criteria and reliable data on prevalence, pathogenetic mechanisms, and management [63].

Topical calcineurin inhibitors — The topical calcineurin inhibitors tacrolimus and pimecrolimus are nonsteroidal, immunomodulating agents that do not cause skin atrophy or other corticosteroid-induced adverse effects [64]. They can be used as an alternative to topical corticosteroids for the treatment of mild to moderate AD involving the face, including the eyelids, neck, and skin folds [65,66].

●Available formulations – Tacrolimus ointment comes in two strengths: 0.1% and 0.03%. Both are approved for moderate to severe AD but are frequently used for milder disease as well. Topical tacrolimus 0.1% is approved for patients >16 years in the United States, Canada, and Europe but has been extensively used off-label in younger children. The 0.03% formulation is approved for children ≥2 years but has been widely used off-label in younger children over the past 20 years.

Pimecrolimus 1% cream is approved for mild to moderate AD in children >2 years of age in the United States and Europe and in children >3 months in Canada.

●Administration – Tacrolimus ointment and pimecrolimus cream are applied twice daily to the affected areas.

●Efficacy – Topical tacrolimus 0.1% is equal in strength to a medium-potency (group 4 (table 1)) topical corticosteroid; topical tacrolimus 0.03% is equal in strength to a group 4 to 5 topical corticosteroid [67]. Pimecrolimus 1% cream is comparable in efficacy to a low-potency topical corticosteroid and is slightly less effective than tacrolimus 0.03% [68].

The efficacy of topical calcineurin inhibitors has been demonstrated in several randomized trials and meta-analyses [55,65,69,70]. Tacrolimus ointment (particularly the 0.1% preparation) may be more effective than pimecrolimus cream, although it may also cause greater local irritation.

•A meta-analysis of 25 randomized trials that included nearly 7000 patients showed that tacrolimus 0.1% was more effective than vehicle for the treatment of patients with moderate to severe AD [65]. Both tacrolimus 0.03% and 0.1% were more effective than hydrocortisone acetate 1%. Tacrolimus 0.1% was comparable in efficacy with hydrocortisone butyrate 0.1%, but tacrolimus 0.03% was less effective. Pimecrolimus was more effective than vehicle in the treatment of mild to moderate AD and in preventing flares but was less effective than betamethasone valerate 0.1%. None of the included trials compared pimecrolimus with topical hydrocortisone.

•In a subsequent meta-analysis of four randomized trials comparing tacrolimus with pimecrolimus in more than 1800 patients with AD, tacrolimus 0.1% ointment was more effective than pimecrolimus 1% cream after six weeks of therapy in adult patients (relative risk 0.58, 95% CI 0.46-0.72) [70]. Tacrolimus 0.03% was superior to pimecrolimus 1% (relative risk 0.65, 95% CI 0.57-0.75) in children with moderate to severe AD, but the two agents were equally effective in those with mild to moderate AD.

•In a meta-analysis of 31 randomized trials, pimecrolimus was significantly better than vehicle in preventing flares at six months [71]. However, pimecrolimus was less effective than medium-potency topical corticosteroids (triamcinolone acetonide 0.1% and betamethasone valerate 0.1%) and tacrolimus 0.1%.

●Adverse effects – Transient burning, stinging, erythema, and pruritus at the application site are the only adverse effects (including in real world experience) [72]. Because burning and stinging are more intense when applied to severely inflamed skin, a topical corticosteroid is often used first for several days to reduce inflammation before introducing a topical calcineurin inhibitor. Tacrolimus 0.03% or pimecrolimus 0.1% are generally better tolerated than tacrolimus 0.1%. Refrigerating topical calcineurin tube for 15 to 20 minutes prior to skin application may reduce the burning sensation [73]

●Safety – Because of early concerns raised by the US Food and Drug Administration (FDA) about a theoretical link between the use of topical tacrolimus and pimecrolimus and cancer (particularly lymphoma and nonmelanoma skin cancer), based on the cancer risk associated with systemic tacrolimus at immunosuppressive doses [74], this group of topical immunomodulators was given a boxed warning. However, randomized trials in adults and children [75-77] and several long-term studies have shown no evidence of a link to internal malignancies or skin cancer [77-80]. In 2021, the boxed warning was removed in Canada, but it remains in the United States.

The results of additional safety studies are summarized below:

•The Pediatric Eczema Elective Registry (PEER) is an industry-sponsored, ongoing, cohort study established in 2004 as part of the postmarketing commitments for the approval of pimecrolimus to evaluate the risk of malignancy in children. Among 7500 children enrolled between 2004 and 2014, five malignancies (two leukemias, one osteosarcoma, and two lymphomas) were reported [81]. The standardized incidence ratio, based upon the age-standardized Surveillance, Epidemiology, and End Results (SEER) Program population, was 1.2 (95% CI 0.5-2.8) for all malignancies, 2.9 (95% CI 0.7-11.7) for lymphoma, and 2.0 (95% CI 0.5-8.2) for leukemia. Although the excess risk of lymphoma and leukemia is not statistically significant, the authors acknowledge that the small sample size and the resulting wide confidence interval may not allow the exclusion of all risk.

•A 2015 meta-analysis did not find a statistically significant association between the use of topical calcineurin inhibitors and risk of lymphoma [82], although an included cohort study reported a fivefold increased risk of T cell lymphoma in patients exposed to topical tacrolimus (relative risk 5.44, 95% CI 2.51-11.79) [83].

•A 2018 European, multicenter, cohort study that included more than 147,000 adults and children initiating tacrolimus or pimecrolimus, nearly 600,000 users of topical corticosteroids, and 257,000 untreated subjects found an increased risk of lymphoma (of borderline statistical significance) associated with tacrolimus compared with topical corticosteroids in children but not in adults (incidence rate ratio 3.74, 95% CI 1.00-14.06 and incidence rate ratio 1.76, 95% CI 0.81-3.79, respectively) [75].

•A 2020 international, cohort study of nearly 8000 children (mean age at enrollment 7.1 years) with AD exposed to tacrolimus ointment before the age of 16 years did not demonstrate an increased incidence of any cancers among tacrolimus users compared with the general population (standardized incidence ratio 1, 95% CI 0.37-2.20) [77]. There were no instances of lymphoma.

•A 2021 meta-analysis of eight cohort studies with more than 400,000 treated participants and more than 1,700,000 controls and three case-control studies with nearly 4000 cases and 14,000 controls found no association between the use of topical calcineurin inhibitors and cancer overall [84]. However, the risk of lymphoma was higher among patients treated with topical calcineurin inhibitors compared with controls treated with either vehicle or topical corticosteroids (risk ratio 1.86, 95% CI 1.39-2.49 and risk ratio 1.35, 95% CI 1.13-1.61, respectively).

●Off-label use in infants – In the absence of long-term studies evaluating their efficacy and safety compared with low- or mid-potency topical corticosteroids, both tacrolimus and pimecrolimus have been used off-label in children as first-line treatment for AD and in children <2 years [85]. Several studies have demonstrated their safety in this age group [86].

A five-year, randomized trial evaluated the safety and long-term efficacy of pimecrolimus 1% cream compared with low-potency (1% hydrocortisone) or medium-potency (0.1% hydrocortisone butyrate) topical corticosteroids in more than 2400 infants 3 to 12 months of age with mild to moderate AD [76]. At five years, the overall treatment success, measured by an Investigator Global Assessment (IGA) score, was achieved in approximately 89 percent of children in the pimecrolimus group and in 92 percent of children in the topical corticosteroid group. Vaccine responsiveness, growth, immune function, and cancer rates were similar in the two groups. The overall rates of adverse events were also similar in the two groups, although episodes of bronchitis, infected eczema, impetigo, and nasopharyngitis were slightly more frequent in the pimecrolimus group. Since the rates of cutaneous adverse events (eg, skin irritation, atrophy, telangiectasias) were not reported in this trial, the advantage of using pimecrolimus rather than low- to mid-potency topical corticosteroids for infants with mild to moderate AD remains unclear.

Other topical treatments

Crisaborole — Crisaborole is a boron-based, small molecule, topical phosphodiesterase 4 (PDE4) inhibitor approved by the FDA for the treatment of mild to moderate AD in adults and children three months of age and older [87-91].

●Administration – Crisaborole 2% ointment is applied twice daily to the affected areas.

●Efficacy – In two phase 3, multicenter, randomized trials that included 1522 patients ≥2 years of age with mild to moderate AD receiving crisaborole 2% ointment or vehicle twice daily for 28 days, more patients in the crisaborole groups than in the vehicle groups achieved an investigator global assessment (IGA) score of clear/almost clear at day 29 (32.8 and 31.4 percent versus 25.4 and 18.0 percent ) [92]. Crisaborole-related adverse events occurred in 4.4 percent of patients and were limited to burning or stinging at the site of application.

In a 48-week, open-label, extension study that included 517 patients (60 percent children) who had completed the trials above, adverse events, most frequently exacerbation of AD, burning/stinging, and infection at the application site occurred in 10 percent of patients [93]. Diarrhea or vomiting, side effects observed with oral PDE4 inhibitors, were reported by 1 to 2 percent of patients throughout the study. Rescue therapy with topical corticosteroids or topical calcineurin inhibitors was needed by 22 percent of children, 26 percent and adolescents, and 13 percent of adults. Although crisaborole seems to be generally safe for long-term use, its efficacy remains uncertain due to the strong placebo effect noted in trials [92,94].

●Adverse effects – In clinical practice, the burning and stinging associated with application is reported much more frequently. In a retrospective study of 41 patients using crisaborole for AD, 32 percent reported skin pain [95]. Fifty percent of patients using crisaborole exclusively on the face reported skin pain. To increase tolerance, a topical corticosteroid can be used for a few days before starting crisaborole. Refrigerating the medication tube or diluting crisaborole with an emollient may help decreasing pain at the application site. Regardless, the high incidence of application-related discomfort decreases compliance and can preclude use.

Systemic exposure to crisaborole has been shown to be limited even after maximal use (3 mg/cm²) [90].

Topical ruxolitinib — Topical ruxolitinib 1.5% is a Janus kinase (JAK) inhibitor (JAK1/2) approved in September 2021 by the US FDA for the short-term treatment of mild to moderate AD in immunocompetent patients older than 12 years whose disease is not controlled with topical prescription therapies.

●Administration – Topical ruxolitinib is applied twice daily to affected areas of the skin. The application area should not exceed 20 percent of the body surface area. Maximum dose is 60 g per week or 100 g per two weeks.

●Efficacy – The efficacy of topical ruxolitinib was evaluated in two eight-week, randomized, phase 3 trials with identical design (TRuE-AD1 and TRuE-AD2) that included 631 and 618 adolescent and adult patients, respectively, with mild to moderate AD (IGA score of 2/3) involving up to 20 percent of the body area surface [96]. Patients were treated with 0.75% ruxolitinib cream, 1.5% ruxolitinib cream, or vehicle twice daily. At eight weeks, more patients in the ruxolitinib groups than in the vehicle group achieved the primary endpoint of an IGA score of 0/1 (clear or almost clear) in both trials (50 and 39 percent, respectively, in the 0.75% cream groups; 54 and 51 percent, respectively, in the 1.5% cream groups; and 15 and 8 percent, respectively, in the vehicle group). More patients in both ruxolitinib groups than in the vehicle group achieved a 75 percent reduction in the Eczema Area and Severity Index (EASI-75) and a clinically relevant reduction in pruritus. Adverse events occurred in approximately 30 percent of patients in each group. Burning and pruritus at application site, upper respiratory infection, and headache were the most common.

●Safety – Although topical ruxolitinib appears promising for the short-term management of AD, data on long-term safety and potential adverse effects due to systemic absorption are lacking. A pharmacokinetic study performed in the setting of TRuE-AD1 and TRuE-AD2 found that at eight weeks the mean steady state plasma concentrations of ruxolitinib after applications of 0.75% and 1.5% cream were low (<20 percent of the half-maximal inhibitory concentration for JAK2 inhibition in human whole blood assays), and the drug bioavailability was approximately 6 percent [97]. Nonetheless, a boxed warning for serious infections, major cardiovascular events, thrombosis, malignancies, and all-cause mortality, reflecting the risk of patients taking JAK inhibitors orally (and specifically tofacitinib in older adults with rheumatoid arthritis), was issued for topical ruxolitinib.

Topical delgocitinib — Delgocitinib is a topical pan-JAK inhibitor that is approved in Japan (0.5% ointment) for adult patients with AD.

●In a four-week randomized trial, 137 patients aged 2 through 15 years (one-half of whom had moderate AD) received delgocitinib 0.25% ointment or vehicle [98]. The least squares mean percent change from baseline in a modified Eczema Area and Severity Index (EASI) score was -39.3 percent for delgocitinib ointment and 10.9 percent for vehicle. Improvements were maintained a 52-week extension period.

●Similar results were obtained in a Japanese randomized trial that included 158 patients aged 16 years or older with moderate or severe AD assigned to four-week treatment with delgocitinib 0.5% ointment or vehicle [99]. The least squares mean percent change from baseline in a modified EASI score showed significantly greater reductions in the delgocitinib group compared with the vehicle group (-44.3 versus 1.7 percent). The effect was maintained in a 24-week extension period. In both study periods, adverse events were reported to be mild and unrelated to delgocitinib.

Experimental topical therapies — Several topical therapies are in clinical trials for treating AD.

●Roflumilast – Roflumilast is a topical PDE4 inhibitor that is reportedly more potent than crisaborole and without the associated stinging or burning. In a pivotal phase 3, four-week, randomized trial evaluating roflumilast 0.15% cream once daily in patients ≥6 years, more patients in the roflumilast group than in the vehicle group achieved the primary endpoint of IGA 0/1 with a two-grade improvement from baseline (32 versus 15 percent, respectively) [100].

●Difamilast – Topical difamilast is a selective topical PDE4 inhibitor evaluated for the treatment of AD in children and adults with mild to moderate AD. In a randomized trial, 251 children (mean age seven years) with mild to moderate AD were assigned to treatment with difamilast 0.3% or 1% ointment or vehicle twice daily [101]. At four weeks, more patients in the difamilast groups achieved the primary endpoint of IGA 0/1 than patients in the placebo group (45, 47, and 18 percent, respectively). Adverse events occurred with similar frequency in all groups and included nasopharyngitis, impetigo, and worsening AD. In another study that included 364 patients aged 15 to 70 years, more patients in the difamilast 1% ointment group achieved the primary endpoint of IGA 0/1 at four weeks than patients in the vehicle group (38 versus 13 percent, respectively) [102].

●Tapinarof – Tapinarof is an aryl hydrocarbon receptor agonist that has been shown to improve barrier function, reduce inflammation, and reduce itch. In a phase 2, dose-finding trial in patients aged 12 to 65 years with AD, more patients receiving tapinarof 1% cream twice daily achieved an IGA score of 0/1 at week 12 compared with dose receiving vehicle (53 versus 24 percent) [103]. Similar results were seen in a subsequent phase 2b randomized trial in adolescents and adults with AD [104].

Topical formulations of roflumilast and tapinarof were both approved by the FDA in 2022 for the treatment of plaque psoriasis.

●Topical brepocitinib – Brepocitinib is an investigative small molecule tyrosine kinase 2/JAK1 inhibitor that can block the IL-12 and IL-23 pathways. A topical formulation of brepocitinib 0.1, 0.3, 1, or 3% applied once or twice daily was evaluated in a six-week, phase 2b, randomized trial in 292 adolescents and adults with mild or moderate AD (mean baseline EASI score 7.3) [105]. At six weeks, patients in the brepocitinib 1% groups had a greater mean percentage reduction of EASI score from baseline (-70 and -75 percent for once-daily and twice-daily application, respectively) compared with vehicle (-44 and -47 percent, respectively). Adverse events occurred in 34 percent of patients, with the most common being nasopharyngitis and worsening of AD. Plasma levels of brepocitinib were generally low but showed a dose-related increase.

●Bacteriotherapy – Bacteriotherapy using the commensal organism Staphylococcus hominis A9 (ShA9) isolated from healthy human skin has been investigated as a topical therapy for AD. ShA9 kills S. aureus and inhibits the expression of a staphylococcal pro-inflammatory toxin. In a phase 1 randomized trial, application of topical ShA9 versus vehicle on the forearm skin of 54 adults with S. aureus-positive AD for one week was shown to be safe and resulted in a significant decrease in S. aureus density and increase in ShA9 DNA [106].

Assessing adherence to topical treatment — Poor adherence to prescribed topical therapies is a major cause of exacerbation of AD [107]. (See "Evaluation and management of severe refractory atopic dermatitis (eczema) in adults", section on 'Identifying the causes of recalcitrant disease'.)

Assessing the patient's adherence to topical therapy is thus critical when evaluating the response to initial treatment and need for additional therapy. While "steroid phobia" resulting in insufficient use of prescribed topical corticosteroids is a common cause of treatment failure [108-111] and associated with lower education [112], the use of inadequate amounts of emollients needs consideration as an additional obstacle to treatment success.

In a small Danish study that included 15 dermatology outpatients who were prescribed topical corticosteroids, patients used a median of 35 percent of the prescribed dose, with only one patient using the full dose [113]. In a larger Danish study analyzing primary prescription adherence, one-third of 322 patients from a hospital-based dermatology outpatient clinic never picked up their prescription medication [114].

Adherence can also be affected by prescription of insufficient amount of topical medication. It should be remembered that 30 g are needed to cover an adult body once in its entirety. Thus, the smaller tubes of topical corticosteroids given to patients for the month may be inadequate for adherence to the prescribed treatment regimen. Hydrocortisone 2.5% ointment and triamcinolone 0.1% ointment are the only topical corticosteroids commercially available in 454 g size jars, which may ensure that an adequate topical corticosteroid is available to the patient.

Maintenance and prevention of relapses — While many patients with mild AD respond well to intermittent, anti-inflammatory therapy for flares, those with moderate to severe disease typically require more chronic suppression of the cutaneous immune activation. For patients with dermatitis recurring at the same limited areas, we suggest proactive, intermittent therapy with mid- to high-potency topical corticosteroids (groups 3 to 5 (table 1)) or topical calcineurin inhibitors to prevent relapse (picture 2A-B) and limit more severe flares (algorithm 1).

Topical corticosteroid or topical calcineurin inhibitor should be applied once or twice daily to reach clear or almost clear status, and then the frequency of application is tapered during the subsequent weeks to two to three times per week to the areas prone to recurrent flares [115,116]. We prefer to evenly space the two- to three-times-per-week application, but others just apply treatment on weekends with success.

Flares of AD that occur during intermittent treatment may be treated by resuming continuous use of topical corticosteroids or topical calcineurin inhibitors and tapering again to maintenance. In infants and young children with moderate to severe AD (picture 3) who have frequent flares but respond to lower-strength corticosteroids, proactive, intermittent therapy with low-potency topical corticosteroids (groups 6 and 7 (table 1)) may be beneficial in preventing relapse [117]. This proactive therapy can be continued long term as needed. Similar strategies for maintenance therapy are recommended in multiple national and international guidelines for the management of AD [2,118-120].

In a meta-analysis of randomized trials, proactive, intermittent therapy with moderate- to high-potency topical corticosteroids or tacrolimus was effective in reducing the risk of subsequent flares after achieving disease control with continuous use of these agents [121]:

●Pooled data from four randomized trials showed that topical fluticasone propionate once daily for two consecutive days per week for 16 weeks reduced the risk of a subsequent flare by 54 percent (relative risk [RR] 0.46, 95% CI 0.38-0.55; number needed to treat [NNT] 2). No serious adverse events were reported.

●Pooled data from three randomized trials showed that topical tacrolimus once daily two to three days per week for 10 to 12 months reduced the risk of a subsequent flare by 22 percent (RR 0.78, 95% CI 0.60-0.78; NNT 4).

Of note, an application of two to three times per week may be insufficient to control disease for patients with moderate severity AD. In some, proactive, intermittent topical corticosteroids can be combined with intermittent topical calcineurin inhibitors or other nonsteroidal topical medication to maintain control while avoiding daily use of topical corticosteroids.

Patients with moderate disease that is not controlled with a proactive regimen are candidates for systemic therapy. (See 'Patients with moderate to severe disease' below.)

Use of systemic corticosteroids for acute exacerbations — In general, use of systemic corticosteroids should be avoided for treatment of AD, given their many adverse effects, the high risk of rebound on discontinuation, and the availability of newer systemic therapies that are safer than conventional immunosuppressants [122]. (See "Major adverse effects of systemic glucocorticoids" and "Management of severe, refractory atopic dermatitis (eczema) in children", section on 'Systemic corticosteroids'.)

However, a short course of systemic corticosteroids (eg, prednisone 40 to 60 mg/day for three to four days, then 20 to 30 mg/day for three to four days, then 10 mg/day for four days) can be used occasionally for adults or adolescents with an acute exacerbation who require rapid relief of symptoms. To reduce the risk of rebound flare, topical therapy should be continued while tapering systemic glucocorticoids. Systemic corticosteroids should virtually never be used for pediatric patients, except in unusual situations as a bridging therapy. (See "Management of severe, refractory atopic dermatitis (eczema) in children", section on 'Systemic corticosteroids'.)

PATIENTS WITH MODERATE TO SEVERE DISEASE

Choice of systemic treatment and supporting evidence — Patients with persistent, moderate to severe disease despite optimal topical therapy require a systemic treatment to achieve adequate disease control [3,123-128]. Before starting systemic therapies, it is good clinical practice to re-evaluate patients to exclude concurrent diseases or reactions that may influence response (eg, infection, contact dermatitis) and to confirm the diagnosis of AD.

●Our approach – The choice of treatment is based on evidence of efficacy, safety, availability, patient preference, and cost considerations [129-131]. Our approach is illustrated in the algorithm (algorithm 1).

•We suggest dupilumab or tralokinumab as first-line therapy for most adult and pediatric patients with moderate to severe AD that is not controlled by topical therapies.

Dupilumab or tralokinumab are also options for patients who have failed previous treatment with conventional immunosuppressive agents, such cyclosporine, methotrexate, mycophenolate mofetil, or azathioprine.

•Oral Janus kinase (JAK) inhibitors (upadacitinib, abrocitinib, baricitinib) may be considered for short-term treatment in select patients who do not have contraindications to their use (eg, age >65 years, cardiovascular risk factors, previous cancer, previous major adverse cardiovascular events, or thromboembolic event) in the following situations:

-Control of seasonal flares

-AD that does not respond to biologics

-Patients who have concomitant alopecia areata or vitiligo

•Narrowband ultraviolet B (NBUVB) phototherapy, if available and acceptable to the patient, is an alternative first-line therapy in combination with topical corticosteroids for adults and adolescents with moderate to severe AD (see 'Phototherapy' below). Phototherapy is generally not suitable for infants and young children. Disadvantages of phototherapy include cost, the need for multiple office visits per week and related risk of poor adherence, and poor tolerance when the skin is very inflamed.

●Evidence

•A 2023 network meta-analysis of 149 randomized trials (28,686 patients with moderate to severe AD) evaluated the efficacy of 75 interventions (including investigational agents) for six patient-important outcomes (AD severity measured using the Eczema Area and Severity Index [EASI]): itch severity, sleep disturbance, AD-related quality of life, patient anxiety and depression, number of patients experiencing AD flares, and adverse events [129]. The study demonstrated the following:

-Upadacitinib 30 mg per day (high dose) was most effective in reducing AD severity, pruritus, and number of flares (high-certainty evidence). Upadacitinib 15 mg per day (low dose) was of intermediate/superior efficacy. High-dose upadacitinib was associated with high frequency of any adverse events. Because few serious adverse events were reported in the trials and the median duration of the studies was four months, direct evidence of serious adverse effects associated with upadacitinib in the AD population was uncertain. Similar considerations also apply to other JAK inhibitors (baricitinib and abrocitinib).

-Dupilumab and tralokinumab were of intermediate/superior efficacy in reducing AD severity, pruritus, and number of flares (high-certainty evidence). The frequency of any adverse events and serious adverse events reported with these agents was similar to that reported with placebo.

-High-dose cyclosporine (at a dose of 4 to 5 mg/kg per day) was among the most effective in reducing AD severity (low-certainty evidence).

-There was low-certainty evidence on the efficacy and safety of oral corticosteroids, other nontargeted immunosuppressants (eg, azathioprine, methotrexate, mycophenolate), and phototherapy, all of which were less effective than the JAK inhibitors and biologics noted above.

•A 2020 network meta-analysis of 74 randomized trials with more than 8000 participants indicated (with a high degree of certainty) dupilumab as the most effective treatment in achieving a 75 percent reduction in the Eczema Area and Severity Index (EASI-75) score (risk ratio 3.04, 95% CI 2.51-3.69) and improving the Patient-Oriented Eczema Measure (POEM) score (mean difference 7.3, 95% CI 6.61-8.00) during short-term follow-up when compared with placebo [126]. Dupilumab was also ranked first among other investigational and noninvestigational biologics in terms of achieving EASI-75 and improving POEM scores during short-term follow-up. However, due to the lack of comparative data, the ranking of conventional immunosuppressive treatments for efficacy compared with dupilumab and other biologic agents remained uncertain.

Phototherapy — NBUVB, if feasible and acceptable to the patient, is a treatment option for moderate to severe AD in adults and adolescents [132]. (See "UVB phototherapy (broadband and narrowband)".)

●Administration – Phototherapy is usually administered in the office two to three times per week. Topical corticosteroids are typically continued as needed during phototherapy. Additional emollients may be necessary, since phototherapy may increase skin dryness. An alternative to office-based phototherapy is the use of a home ultraviolet B (UVB) phototherapy unit prescribed by the treating clinician. However, insurance coverage of these units varies.

●Efficacy – Phototherapy for the treatment of moderate to severe AD has been evaluated in a several randomized trials and systematic reviews. In a 2021 systematic review of 32 randomized trials that included 1219 patients, NBUVB was effective in reducing the clinical signs and symptoms of AD (low-certainty evidence) [133]. Observational studies indicate that NBUVB is associated with long-term remission and reduced use of topical corticosteroids, oral corticosteroids, and antihistamines [134,135].

●Adverse effects – Short-term adverse effects of UVB phototherapy include erythema, skin dryness, pruritus, blistering, and increased frequency of recurrent herpes simplex. Data are conflicting on whether prolonged exposure leads to an increased risk of melanoma and nonmelanoma skin cancer, but the risk is assumed to be very small (table 2) [136-139].

Biologic agents

Dupilumab — Dupilumab is a fully human monoclonal antibody that binds to the alpha subunit of the IL-4 receptor and inhibits downstream signaling of IL-4 and IL-13, cytokines of T helper type 2 (Th2) lymphocytes that play a key role in atopic diseases (including asthma and AD). In the United States and Europe, dupilumab is approved for the treatment of adults and children aged six months and older with moderate to severe AD that is not adequately controlled with topical prescription therapies; in Canada, it is approved for adults and children older than six years [140]. Compared with conventional immunosuppressive agents, dupilumab has a favorable safety profile and may be used for long-term treatment of AD [141-143]. However, cost and access may limit its use. In some cases, contact allergy testing may be required for patients prior to initiation.

Administration — Dupilumab is administered as subcutaneous injections every two to four weeks. In adults, an initial loading dose of 600 mg is followed by a maintenance dose of 300 mg every other week. In children ≥6 months and in adolescents, dosing is based on body weight [140]. In children aged six months to six years, a loading dose is not necessary. The full dose is maintained until dermatitis is cleared.  

●Concurrent use of topical therapies – Topical corticosteroids and other topical agents are usually continued as needed during treatment with dupilumab unless they are no longer needed to maintain disease control.

●Tapering – In patients who are clear, the administration of dupilumab may be shifted to a longer interval (eg, every three or four weeks) and even stopped. A few patients may achieve a long-term remission. In case of flare, administration every two weeks can be resumed.

A few observational studies have described strategies and outcomes of dose reduction in patients on stable clinical response after long-term use of dupilumab [144-146]. In a multicenter study that included 595 adult patients with AD from the Dutch BioDay registry who had been treated with dupilumab 300 mg every two weeks for at least one year, 401 patients switched to dupilumab every three to four weeks [144]. The mean EASI and pruritus Numeric Rating Scale scores remained low during the tapering period. Overall, 334 of 401 patients (83 percent) continued dupilumab treatment at a prolonged interval.

Efficacy — Multiple randomized trials in adults and children have documented dupilumab efficacy in the treatment of moderate to severe AD.

●Trials in adults

•Dupilumab 300 mg or placebo given by subcutaneous injection weekly or every other week was evaluated in two, phase 3 randomized trials of identical design (SOLO1 and SOLO2) that included 671 and 708 adult patients, respectively, with longstanding, moderate to severe AD uncontrolled by topical treatments [147]. At 16 weeks, more patients on dupilumab achieved the primary endpoint of an Investigator's Global Assessment (IGA) score of clear or almost clear (approximately 40 versus 10 percent) compared with placebo. There were no differences between trials and between weekly or biweekly dupilumab regimens. An EASI-75 score was achieved by 44 to 52 percent of patients receiving dupilumab versus 12 to 15 percent of those receiving placebo. Rescue treatment was required in approximately 50 percent of patients receiving placebo and 15 to 20 percent of those receiving dupilumab. Serious adverse events were rare in all groups. However, injection site reactions and conjunctivitis occurred more frequently in the dupilumab groups than in the placebo group.

•In the SOLO1 and SOLO2 trials, patients who failed to achieve IGA score of clear or almost clear with dupilumab at week 16 [147] often had greater improvement in secondary outcome measures, including pruritus (numerical rating scale -35 versus -9 percent) and quality of life (Dermatology Life Quality Index [DLQI] score ≥4-point improvement, 59 versus 24 percent) [148].

•The long-term efficacy and safety of dupilumab was subsequently evaluated in a randomized, double-blind, multicenter trial (LIBERTY AD CHRONOS) [141]. In this study, 740 patients were treated with dupilumab 300 mg once weekly, dupilumab 300 mg every two weeks, or placebo for 52 weeks. All patients received concurrent treatment with topical corticosteroids (or topical calcineurin inhibitors, if indicated) and were allowed to receive rescue treatments (topical or systemic medications or phototherapy) after two weeks of dupilumab. The two coprimary endpoints were the proportion of patients with both an IGA score of 0/1 (clear/almost clear) or a two-point or higher reduction from baseline at week 52 and the proportion of patients achieving EASI-75 from baseline to week 52. At week 52, more patients in the dupilumab plus topical corticosteroids groups achieved the IGA endpoint and EASI-75 compared with those receiving placebo plus topical corticosteroids (approximately 40 versus 13 percent, and 65 versus 22 percent, respectively). The rates of adverse events were similar in the three groups (83 to 88 percent). However, patients in the dupilumab groups experienced an approximately twofold higher frequency of eye disorders and noninfectious conjunctivitis.

•An open-label, extension study of patients enrolled in previous randomized trials who continued treatment with dupilumab 300 mg weekly confirmed a sustained efficacy of dupilumab, with more than 60 percent of patients achieving a 90 percent reduction in the Eczema Area and Severity Index (EASI-90) score at 56 and 76 weeks [142]. Approximately 50 percent of patients received additional treatment with topical corticosteroids (44 percent) and topical calcineurin inhibitors (13 percent). Four percent of patients required rescue systemic therapy.

•In a study evaluating the efficacy of dupilumab in 138 consecutive adult patients with difficult-to-treat AD in a real-life setting, treatment with dupilumab for 16 weeks induced a mean reduction of the EASI score of 73 percent [149]. A 50 percent reduction in the Eczema Area and Severity Index (EASI-50), EASI-75, and EASI-90 scores was achieved by 86, 62, and 24 percent of patients, respectively. Improvement also occurred in patient-reported outcomes, including POEM score, pruritus, and quality of life. The most frequent adverse effects were conjunctivitis and eye irritation in 34 and 25 percent of patients, respectively [150].

●Trials in children and adolescents

•In a phase 3, randomized trial, 251 adolescents aged 12 to 18 years with moderate to severe AD were treated with dupilumab 200 or 300 mg every two weeks, dupilumab 300 mg every four weeks, or placebo for 16 weeks [151]. Most participants had associated comorbidities, including allergic rhinitis (66 percent), asthma (54 percent), and food allergy (61 percent). The coprimary endpoints (proportion of patients with ≥75 percent improvement from baseline in the EASI and an IGA score of 0/1 [clear or almost clear]) were achieved by a higher proportion of patients in both the every-two-weeks and every-four-weeks groups compared with the placebo group (EASI-75: 42, 38, and 8 percent, respectively; IGA 0/1: 24, 18, and 2 percent, respectively). The most common adverse events were worsening of AD, skin infection, upper respiratory infection, and conjunctivitis. The last was more frequent in the dupilumab groups than in the placebo group (10 to 11 versus 5 percent, respectively).

•A 16-week, phase 3, randomized trial examined the efficacy and safety of dupilumab plus topical corticosteroids in children [152]. In this study, 367 children aged 6 to 11 years with severe AD inadequately controlled with topical medications were treated with dupilumab 300 mg every four weeks, a weight-based regimen of 100 to 200 mg every two weeks, or placebo, in combination with a medium-potency topical corticosteroid. More patients in the dupilumab 300 mg and 100 or 200 mg groups achieved the coprimary endpoints (IGA score of 0 to 1 or EASI-75) at week 16 than in the placebo group (33, 30, and 11 percent; and 67, 70, and 27 percent, respectively). Adverse events occurred in 73 percent of patients in the placebo group and in 65 to 67 percent of patients in the dupilumab groups. Injection site reactions and conjunctivitis were more common with dupilumab.

•A 16-week, phase 3, randomized trial examined the efficacy and safety of dupilumab given at the dose of 200 mg if 5 to <15 kg or 300 mg if 15 to <30 kg plus a very low-potency topical corticosteroid in 162 children aged six months to six years [153]. At 16 weeks, more patients in the dupilumab group than in the placebo group achieved the primary endpoint of IGA 0/1 (28 versus 4 percent). Approximately 10 percent of patients in the dupilumab group experienced conjunctivitis. Both groups had similar incidences of injection site reactions. Across various ages, the frequency of skin infections in the group on placebo was approximately twice that with dupilumab.

•A phase 3, open-label extension study provided long-term data on dupilumab treatment in 294 adolescents [154]. By 52 weeks, 43 percent of patients on 300 mg of dupilumab every two or four weeks had an IGA score of 0/1 and 29 percent had maintained IGA 0/1 for 12 consecutive weeks (weeks 40 to 52), after which dupilumab was discontinued per protocol. After a mean of 18 weeks, 57 percent of patients relapsed and required dupilumab reinitiation.

●Postapproval studies have shown that IL-4 and IL-13 blockade reduces skin infections and S. aureus colonization, and improves atopic comorbidities [155-157].

Adverse effects — Frequent adverse effects of dupilumab include injection site reactions, conjunctivitis, and facial redness. Less common adverse effects include psoriasiform dermatitis and seronegative arthritis/enthesitis. Eosinophilia is frequent, often starting approximately four weeks after dupilumab initiation and tends to decrease by 16 weeks. Increased frequency of herpes simplex virus infection was reported in some but not all trials. A psoriasis-like eruption, development of psoriasis during therapy, and arthritis have been rarely reported [158]. Concomitant treatment of these adverse events often allows for dupilumab continuation. Of note, no worsening or progression to a generalized reaction has been noted upon continuation of dupilumab therapy.

●Ocular adverse effects – Dupilumab-associated ocular surface disease (DAOSD) has been reported in approximately 11 percent of patients with AD participating in randomized trials of dupilumab and in up to 26 percent of patients in prospective or real-life studies [159-161]. Of note, AD is the only disorder treated by dupilumab in which ocular surface disease has been linked to drug administration, suggesting inherent subclinical ocular disease in a subset of patients with AD that is unmasked by use. Although the mechanism is not fully understood, use of biologics that target type 2 immunity has been associated with reduction in the goblet cells that lubricate the ocular surface and a shift in the cytokine pattern from a Th2/T helper type 17 (Th17) profile toward a T helper type 1 (Th1)/Th17 profile [162]. Ocular surface disease includes conjunctivitis and, infrequently, keratitis, eye dryness, burning or stinging, pruritus, blepharitis, and blurred vision [163]. In most cases, ocular surface disease appeared in the first weeks or months of treatment, was generally mild or moderate, and resolved with continued dupilumab treatment [159].

Lubricant, preservative-free eye drops may be beneficial for the treatment and prevention of ocular surface disease. For persisting conjunctivitis, referral to an ophthalmologist is advised for evaluation and treatment [164]. (See "Atopic keratoconjunctivitis".)  

●Dupilumab facial redness – Exacerbation or new onset of head and neck dermatitis ("dupilumab facial redness") has been reported in approximately 4 to 10 percent of adult patients treated with dupilumab after a median time of 65 days after initiating dupilumab [165-167]. This reaction has also been reported in up to 29 percent of children and adolescents treated with dupilumab [168,169]. In a Danish real-world study, head and neck dermatitis was still present in most patients after 104 weeks of treatment [170].

The pathogenesis of dupilumab-induced head and neck dermatitis is unclear. It may represent site-specific treatment failure, unmasking of existing allergic contact dermatitis or psoriasis [171], topical steroid withdrawal [172], dupilumab-induced Malassezia hypersensitivity reaction, or Demodex proliferation resulting in rosacea. Patch testing can be helpful to uncover potential contact allergens.

Topical corticosteroids, topical calcineurin inhibitors, topical and systemic antifungals, and ivermectin have been used in a few patients with dupilumab facial redness with variable results [166,167,173-177].

●Seronegative arthritis and enthesitis/enthesopathy – There have been several reports of inflammatory arthritis and enthesitis associated with dupilumab treatment, in most cases occurring during the first few months of treatment [178,179]. It has been hypothesized that the blockade of IL-4 and IL-13, critical cytokines of the Th2 immune response, may activate the IL-23/IL-17 axis, resulting in the paradoxical emergence of Th17 diseases, including spondyloarthropathy-pattern arthritis and occasional anterior uveitis.

An analysis of nearly 38,000 dupilumab adverse reactions reported to VigiBase (the World Health Organization's global pharmacovigilance database of adverse drug reactions) found that musculoskeletal and connective tissue were the third most affected systems (n = 3452, 9.1 percent) [180]. Specifically, dupilumab was associated with diseases sharing Th17 immunogenetics, including seronegative arthritis (odds ratio [OR] 9.6, 95% CI 3.1-30.1), enthesitis/enthesopathy (OR 12.7, 95% CI 6.5-24.5), and iridocyclitis (OR 3.8, 95% CI 1.0-7.6). Dupilumab was not associated with humoral-mediated autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and scleroderma. These data suggest that all patients initiating treatment with dupilumab should be counseled about the risk of new-onset joint pain, and that if it occurs, it is generally mild and can be conservatively managed without a need to discontinue dupilumab [178].

●Psoriasis/psoriasiform dermatitis – Suppression of the Th2 pathway in patients with AD may lead to the development of psoriasis in predisposed patients, due to a shift towards a skewed Th1/Th17 pathway. There is some thought that this reaction is distinct from classical psoriasis [181,182]. In a postapproval systematic review, 47 adult patients on dupilumab developed psoriasis at a median time of 3.7 months after its initiation [181]. Nearly one-half (48 percent) discontinued dupilumab, leading to complete resolution in 40 percent and variable improvement in another 48 percent with use of typical psoriasis treatments. In a pediatric retrospective review, six children developed psoriasiform lesions at a median time of eight months after dupilumab initiation [171]. Most experienced full clearance of their psoriasiform lesions with the initiation of concomitant topical corticosteroids and continuation of dupilumab, suggesting that the management in adults versus children is different.

Diagnosis of mycosis fungoides following dupilumab treatment — There are several reports of patients who were treated with dupilumab for AD and were subsequently diagnosed with mycosis fungoides or Sézary syndrome [183-185]. A 2023 systematic review found 11 reports with 23 cases (19 adults with onset of AD during adulthood) diagnosed with mycosis fungoides/Sézary syndrome after treatment with dupilumab for presumed AD [186]. Dupilumab has also been associated with the rapid progression of mycosis fungoides in patients with mycosis fungoides who received off-label dupilumab for the management of pruritus associated with mycosis fungoides [187,188].

Whether dupilumab unmasks underlying mycosis fungoides by accelerating its progression or promotes the development of a lymphoid reaction/mycosis fungoides has not been determined [189]. However, it is of utmost importance to exclude the diagnosis of early mycosis fungoides before starting treatment with dupilumab, especially in adults with late-onset AD [190]. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Diagnosis'.)

Tralokinumab — Tralokinumab is a fully human monoclonal anti-IL-13 antibody. It is approved for the treatment of moderate to severe AD that is not adequately controlled with topical prescription therapies in adults and adolescents 12 years and older in the United States and Europe.

●Administration – In adults, tralokinumab is administered subcutaneously with a loading dose of 600 mg followed by 300 mg every other week.

●Efficacy – The efficacy of tralokinumab as monotherapy or in combination with topical corticosteroids has been evaluated in several randomized trials:

•In two identical, randomized trials (ECZTRA 1 and ECZTRA 2), 1596 adult patients with AD who were candidates for systemic therapy received subcutaneous tralokinumab 300 mg as monotherapy or placebo every other week for 16 weeks [191]. An IGA score of 0/1 (clear/almost clear) was achieved by 16 and 22 percent of patients in the tralokinumab groups in ECZTRA 1 and ECZTRA 2, respectively, compared with 7 and 11 percent of patients in the placebo groups, respectively. EASI-75 was achieved by 25 and 33 percent of patients in the tralokinumab groups, respectively, versus 13 and 11 percent of those in the placebo groups, respectively. Tralokinumab was also more effective than placebo in reducing the Scoring of Atopic Dermatitis (SCORAD) score, improving pruritus, and improving quality of life. The majority of tralokinumab responders at week 16 maintained response at week 52 with continued treatment. Adverse events, most commonly AD flares and viral upper respiratory infections, occurred with similar frequency in the tralokinumab and placebo groups and were nonserious in most cases. Conjunctivitis was two- to over threefold more common in patients receiving tralokinumab compared with those receiving placebo.

•In the ECZTRA 3 trial, 380 patients were treated with tralokinumab 300 mg every two weeks or placebo in combination with a mid-potency topical corticosteroid (mometasone furoate 0.1%) applied as needed [192]. At 16 weeks, more patients in the tralokinumab group than in the placebo group achieved an IGA score of 0/1 (39 versus 26 percent, respectively) and EASI-75 (56 versus 36 percent, respectively). The overall frequency of adverse events, including viral upper respiratory infection, headache, and exacerbation of AD (in most cases mild or moderate), was similar in both groups. Conjunctivitis was more common in patients receiving tralokinumab than in those receiving placebo (11.1 versus 3.2 percent, respectively). Similar trends were observed with concomitant topical corticosteroid use in the ECZTRA 7 trial of adults who were previously on cyclosporine therapy.

•In the ECZTRA 6 study that included 289 patients aged 12 to 17 years with moderate to severe AD, more patients receiving tralokinumab 150 or 300 mg than patients receiving placebo achieved an IGA score of 0/1 (21.4 and 17.5 percent, respectively, versus 4.3 percent) and EASI-75 (28.6 and 27.8 percent, respectively, versus 6.4 percent) by week 16 [193]. Similar to adult studies, the most common adverse events were viral upper respiratory tract infections, exacerbation of AD, injection site reactions, asthma, and headache. Conjunctivitis occurred in 3 to 4 percent of patients taking tralokinumab versus 2 percent of patients taking placebo.

•In a network meta-analysis of 60 randomized trials with over 16,000 participants, tralokinumab at the approved dosing of 600 then 300 mg every two weeks was found to be slightly less effective than dupilumab in reducing EASI at the same dose during 16 weeks [194].

●Adverse events – In a pooled analysis of five randomized trials with 2285 participants, adverse events occurred with similar frequencies in the tralokinumab and placebo groups (66 and 67 percent, respectively) [195]. The most common adverse events occurring with higher frequency with tralokinumab than with placebo included: viral upper respiratory tract infection (15.7 versus 12.2 percent); conjunctivitis (5.4 versus 1.9 percent); and injection-site reaction (3.5. versus 0.3 percent). Skin infections requiring systemic treatment occurred with lower frequency in the tralokinumab groups compared with placebo groups (2.6 versus 5.5 percent).

Experimental biologics — Lebrikizumab, nemolizumab, eblasakimab, and OX40/OX40L targeting biologics are being evaluated for the treatment of AD in clinical trials. Lebrikizumab was approved in Europe (2023), the United Kingdom (2023), and Japan (2024) for the treatment of adults and adolescents ≥12 years with moderate to severe AD who are candidates for systemic therapy.

●Lebrikizumab – Lebrikizumab is a monoclonal antibody that binds specifically to soluble IL-13 [196].

•In a phase 3, randomized trial that included 211 adults and adolescent patients with moderate to severe AD, more patients receiving subcutaneous lebrikizumab (loading dose of 500 mg at baseline and week 2, followed by 250 mg every two weeks thereafter) in combination with low- to mid-potency topical corticosteroids achieved an IGA score of 0/1 at week 16 than those receiving placebo plus topical corticosteroids (41 and 22 percent, respectively) [197]. Adverse events were more frequent in the lebrikizumab group than in the placebo group (43 versus 35 percent) and included conjunctivitis, headache, herpes infection, hypertension, and injection site reaction.

•In two identical phase 3 randomized trials (ADvocate1 and ADvocate2) that included 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 than in the placebo groups achieved an IGA score of 0/1 at week 16 (43 and 33 percent versus 13 and 11 percent, respectively) [198]. Lebrikizumab-related adverse events included conjunctivitis and mild eosinophilia.

•In a 52-week extension study of the ADvocate1 and ADvocate2 trials, 71 percent of patients receiving lebrikizumab 250 mg every two weeks, 77 percent of those receiving lebrikizumab 250 mg every four weeks, and 48 percent of those receiving placebo maintained an IGA score of 0/1 [199]. Treatment-related adverse effects included worsening of AD (9 percent), conjunctivitis (8 percent), and nasopharyngitis (8 percent).

●Eblasakimab – Eblasakimab is an IL-13R-alpha-1 monoclonal antibody that is being evaluated in a phase 2b randomized trial for the treatment of moderate to severe AD in adult patients.

●Nemolizumab – Nemolizumab is a humanized monoclonal antibody against the receptor of IL-31, a cytokine known to be associated with pruritus via IL-31 receptor activation [200-202]. Several studies indicate that nemolizumab may be effective in controlling pruritus associated with AD [203-205].

•A phase 2, 12-week, randomized trial evaluated the efficacy of nemolizumab for the treatment of adult patients with moderate to severe AD not controlled by topical corticosteroids or topical calcineurin inhibitors [204]. In this study, 264 patients received subcutaneous nemolizumab at a dose of 0.1, 0.5, or 2 mg per kg of body weight or placebo every four weeks or nemolizumab at a dose of 2 mg per kg every eight weeks with placebo given at week 4. At 12 weeks, pruritus was reduced by 44, 60, and 63 percent in the 0.1, 0.5, and 2 mg groups, respectively, versus 21 percent in the placebo group. The body surface area affected by AD decreased by 8, 20, and 19 percent in the 0.1, 0.5, and 2 mg groups, respectively, compared with 16 percent in the placebo group. Adverse events occurred in approximately 70 percent of patients in all study groups and were generally mild, with the most frequent being exacerbation of AD and respiratory tract infections.

•The efficacy of nemolizumab in reducing pruritus associated with AD was confirmed in a subsequent Japanese randomized trial that included 215 patients aged 13 years or older with AD and moderate to severe pruritus [205]. Patients received subcutaneous nemolizumab 60 mg or placebo every four weeks for 16 weeks plus topical therapy for AD (eg, medium-potency topical glucocorticoids, topical calcineurin inhibitors). At week 16, the least squares mean of the pruritus visual analogue scale score (primary endpoint) was reduced by 43 percent in the nemolizumab group compared with 21 percent in the placebo group. Adverse events occurred in 71 percent of patients in both groups and were generally mild. In the nemolizumab group, four treatment-related adverse events (AD exacerbation, Meniere disease, alopecia, and peripheral edema) occurred in three patients.

Although nemolizumab appears to be a promising agent for the treatment of pruritus associated with AD and the interruption of the itch-scratch cycle, larger studies of longer durations are needed to evaluate its long-term efficacy and safety.

●Agents targeting OX40/OX40L – Agents that bind to OX40, a costimulatory receptor on activated T cells (telazorlimab/GBR 830 and rocatinlimab/AMG 451/KHK4083) or to the OX40 ligand (amlitelimab) have been evaluated in phase 2 studies in adults with promising results [206-209].

In a multicenter randomized trial, 274 patients with moderate to severe AD were randomized to subcutaneous rocatinlimab 150 mg every 4 weeks, 600 mg every 4 weeks, 300 mg every 2 weeks, 600 mg every 2 weeks, or subcutaneous placebo for 18 weeks [209]. At 16 weeks, a least-squares mean percent reduction of approximately 60 percent in the EASI score was observed in all rocatinlimab groups compared with a 15 percent reduction in the placebo group.

JAK inhibitors — Given their ability to suppress multiple immune pathways, Janus kinase (JAK) inhibitors provide more rapid improvement in signs and symptoms of AD compared with biologics. Oral administration is an additional advantage of systemic JAK inhibitors over biologics, which require subcutaneous injection. However, because of the potential risk of associated serious adverse events, benefits and risks should be carefully evaluated in the individual patient prior to initiating treatment with oral JAK inhibitors.

Abrocitinib — Abrocitinib is an oral Janus kinase 1 (JAK1) selective inhibitor approved in Europe, the United States, and Japan for the treatment of moderate to severe AD in adults whose disease is not controlled with other systemic therapies (including biologics) or when the use of those therapies is not indicated. In the United States, abrocitinib is also approved for children ≥12 years.

●Administration – Abrocitinib is administered orally at a dose of 100 mg daily, with the option to increase to 200 mg daily if there is an inadequate response.

●Efficacy – Several randomized trials have evaluated the efficacy of abrocitinib in adults and adolescents with moderate to severe AD. In head-to-head trials, abrocitinib 100 mg daily showed efficacy similar to that of dupilumab.

•In a phase 3, randomized trial, 387 patients aged 12 years or older with moderate to severe AD received oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks [210]. At 12 weeks, more patients in the abrocitinib 100 and 200 mg groups than in the placebo group achieved the IGA of clear or almost clear (24, 44, and 8 percent, respectively) and an EASI-75 response (40, 63, and 12 percent, respectively). Adverse events, including exacerbation of AD, nasopharyngitis, nausea, and headache, were reported in 69 and 78 percent of patients in the 100 and 200 mg abrocitinib groups, respectively, and in 57 percent of patients in the placebo group.

•In a 16-week, phase 3, randomized trial, 838 adult patients with AD unresponsive to topical treatments were randomized to receive abrocitinib 200 mg daily, abrocitinib 100 mg daily, dupilumab 300 mg subcutaneously every other week (after a loading dose of 600 mg), or placebo [211]. All patients also received topical therapy. An IGA response of clear or almost clear at week 12 was observed in 48, 37, 37, and 14 percent of participants in the 200 mg abrocitinib group, 100 mg abrocitinib group, dupilumab group, and placebo group, respectively. An EASI-75 response at week 12 was observed in 70, 59, 58, and 27 percent of participants, respectively. The overall rate of adverse events was higher in the 200 mg abrocitinib group than in the other groups; the most frequent were nausea, acne, headache, and nasopharyngitis.

•In a 26-week, phase 3, randomized trial that included 727 patients comparing abrocitinib 200 mg daily with dupilumab 300 mg every other week, more patients in the abrocitinib group achieved the primary outcomes of a four-point or higher improvement in the Peak Pruritus Numerical Rating Scale at week 2 (48 versus 26 percent; difference 22.6 percent, 95% CI 15.8-29.5) and EASI-90 at week 4 (29 versus 15 percent; difference 14.1 percent, 95% CI 8.2-20.05) [212]. However, the differences between the two treatments were not statistically significant at week 26. Adverse effects occurred in 74 percent of patients in the abrocitinib group and included two fatalities (COVID-19 infection and cardiorespiratory arrest and intracranial hemorrhage). Serious adverse effects in the dupilumab group included nephrotic syndrome in one patient and rhabdomyolysis in another patient.

•In a double-blind, randomized, placebo-controlled, 12-week trial for moderate to severe AD in 256 adolescents (JADE TEEN), 46.2 percent of patients on abrocitinib 200 mg and 41.6 percent of those on abrocitinib 100 mg achieved an IGA 0/1 response versus 24.5 percent of adolescents treated with placebo [213]. EASI-75 response was met in 72 percent of those on abrocitinib 200 mg, 68.5 percent on abrocitinib 100 mg, and 41.5 percent on placebo. Consistently, 55.4 percent of patients on abrocitinib 200 mg reached a Peak Pruritus Numerical Rating Scale response of at least 4 compared with 52.6 percent of patients on abrocitinib 100 mg and 29.8 percent on placebo.

Upadacitinib — Upadacitinib is an oral selective JAK1 inhibitor approved in the United States, Europe, and other countries for the treatment of AD in adults and children older than 12 years whose disease is not adequately controlled with other systemic drug products (including biologics) or when the use of those therapies is inadvisable.

●Administration – Upadacitinib is administered orally at the dose of 15 mg once daily. The dose can be increased to 30 mg daily if response is not adequate after three months of treatment.

●Efficacy – Three multicenter, randomized trials have evaluated the efficacy of upadacitinib in adults and adolescents with moderate to severe AD as monotherapy or in combination with topical corticosteroids versus placebo [214,215] and versus dupilumab [216]:

•In two replicate, multicenter trials, 847 and 836 patients with moderate to severe AD were randomized to receive oral upadacitinib 15 or 30 mg daily or placebo as monotherapy [214]. At 16 weeks in both studies, more patients in the upadacitinib groups achieved the primary endpoint of EASI-75 than patients in the placebo groups (60 and 70 percent in the 15 mg groups and 73 and 80 percent in the 30 mg groups versus 47 and 46 percent in the placebo groups, respectively). In both trials, the proportion of patients who had a clinically meaningful improvement in pruritus was higher in the upadacitinib groups than in placebo groups, with improvements observed by day 2 in the upadacitinib 30 mg groups and by day 3 in the upadacitinib 15 mg groups. Treatment was well tolerated. The most frequently reported, treatment-emergent adverse events were acne (up to 17 percent in the upadacitinib 30 mg groups versus 2 percent in placebo groups), upper respiratory infections, nasopharyngitis, headache, and elevation of creatine phosphokinase.

•In a separate multicenter trial, 901 adults and adolescents with moderate to severe AD were randomized to receive upadacitinib 15 or 30 mg daily plus once-daily, moderate-potency topical corticosteroids or placebo plus once-daily, moderate-potency topical corticosteroids [215]. At 16 weeks, more patients in the upadacitinib 15 and 30 mg plus topical corticosteroids groups achieved EASI-75 than patients in the placebo plus topical corticosteroids group (65, 77, and 26 percent, respectively). Clinically significant improvement in pruritus at week 16 occurred in 52 and 64 percent of patients in the upadacitinib groups versus 15 percent in the placebo group. Median time to discontinuation of topical corticosteroids was shorter in the upadacitinib groups than in the placebo group (88, 57, and ≥120 days, respectively). Adverse events were more frequent in the upadacitinib groups than in the placebo group.

•In a separate analysis of 552 adolescents aged 12 to 17 years enrolled in the three randomized trials summarized above [214,215], a greater proportion of adolescents achieved EASI-75 at week 16 with upadacitinib 15 and 30 mg compared with placebo (73, 69, and 63 percent with upadacitinib 15 mg; 78, 73, and 84 percent with upadacitinib 30 mg; and 12, 13, and 30 percent with placebo) [217]. The most frequently reported adverse events in the upadacitinib groups were acne (up to 16 percent), upper respiratory infections (up to 13 percent), headache (up to 8 percent), and elevation of creatine phosphokinase (up to 10 percent).

•Versus dupilumab – In a subsequent randomized trial, 692 adult patients with moderate to severe AD were randomized to receive upadacitinib 30 mg orally once daily or subcutaneous dupilumab 300 mg every 2 weeks for 24 weeks as monotherapy [216]. More patients in the upadacitinib group than patients in the dupilumab group achieved the primary endpoint of EASI-75 at 16 weeks (71 versus 61 percent) and the secondary endpoints of EASI-75 at 2 weeks (44 versus 17 percent), EASI-90 at 16 weeks (61 versus 39 percent), and a 100 percent reduction in the Eczema Area and Severity Index (EASI-100) at 16 weeks (28 versus 8 percent). The proportion of patients achieving a clinically significant reduction in pruritus at week 16 was also higher for those treated with upadacitinib compared with those treated with dupilumab (55 versus 36 percent). Overall, adverse events occurred in 72 percent of patients receiving upadacitinib and 63 percent of those receiving dupilumab and included acne (more frequently in the upadacitinib group), conjunctivitis (more frequently in the dupilumab group), upper respiratory infection, and worsening of AD. Serious infections, including herpes zoster and eczema herpeticum, were rare and occurred more frequently in the upadacitinib group. One patient in the upadacitinib group died of influenza-related pneumonia.

In a 52-week open-label extension of this trial, patients switching from dupilumab to upadacitinib (n = 239) experienced a further improvement in EASI score, with the proportion of patients achieving EASI-75 increasing from 88 to 99 percent [218]. Upadacitinib further improved AD severity and pruritus in patients with either a prior adequate or inadequate response to dupilumab.

Baricitinib — Baricitinib is an oral JAK1/2 selective inhibitor approved in Europe, but not in the United States, for adults with AD. Baricitinib is approved in the United States for adults with severe alopecia areata. Multiple phase 3 studies have been completed in adults with AD, but only one phase 3 trial has been performed in children.

●A multicenter, randomized, phase 3 trial evaluated the efficacy and safety of baricitinib combined with topical corticosteroids in children with moderate to severe AD [219]. In this study, 483 patients aged 2 to <18 years were randomized to once-daily oral baricitinib 1 mg equivalent (low dose), 2 mg equivalent (medium dose), 4 mg equivalent (high dose), or placebo plus low- to medium-potency topical corticosteroids. At 16 weeks, more patients in the 4 mg baricitinib group achieved a validated IGA score of 0/1 (clear/almost clear) compared with those in the placebo group (42 versus 16 percent). There was no statistically significant difference in the proportion of patients achieving an IGA score of 0/1 in the baricitinib 1 mg, 2 mg, and placebo groups (18, 26, and 16 percent, respectively). Adverse events occurred with similar frequency (approximately 50 percent in all groups) and were mild or moderate in severity. Treatment-emergent adverse events included abdominal pain, acne, and headache.

●In two 16-week, phase 3 trials (BREEZE-AD1 and BREEZE-AD2) including a total of 1239 adults with moderate to severe AD, more patients treated with baricitinib 2 and 4 mg per day as monotherapy achieved a validated IGA score of 0/1 (clear or almost clear) compared with placebo (11.4, 16.8, and 4.8 percent for baricitinib 2 mg, baricitinib 4 mg, and placebo, respectively, in BREEZE-AD1; 10.6, 13.8, and 4.5 percent for baricitinib 2 mg, baricitinib 4 mg, and placebo, respectively, in BREEZE-AD2) [220]. Adverse events occurred in approximately 60 percent of patients in all groups. The most frequent adverse events reported in the baricitinib groups were nasopharyngitis and headache.

●In a 52-week extension study of two randomized clinical trials (BREEZE-AD3), baricitinib 4 and 2 mg demonstrated sustained long-term efficacy in adults [221].

Safety concerns — The benefit of broader immune suppression comes at the cost of more potential adverse events, which requires close clinical surveillance and diligent laboratory monitoring. Long-term studies of the safety of oral JAK inhibitors in patients with AD are lacking. Data from a large, randomized safety trial of patients with rheumatoid arthritis (older than 50 years of age and with cardiovascular risk factors) indicated that the pan-JAK inhibitor tofacitinib may increase the risk of serious infections, major cardiovascular events (eg, heart attack, stroke), cancer (eg, lymphoma, lung cancer), thrombosis, and death [222]. In the United States, Canada, and Europe, warnings regarding these risks have been added to prescription drug information.

These increased risks have not been noted in clinical trials for AD.

●A systematic review and meta-analysis of 20 randomized trials with over 10,000 participants with AD treated with various systemic JAK inhibitors evaluated the short-term risk of major adverse cardiovascular events (MACE) [223]. Overall, 5 of 6531 patients (0.08 percent) with AD receiving JAK inhibitors had a MACE compared with 0 of 3576 participants receiving placebo or dupilumab, a nonstatistically significant difference.

●Another systematic review and meta-analysis of 35 randomized trials with over 20,000 patients with AD, psoriasis/psoriatic arthritis, alopecia areata, and vitiligo did not find a statistically significant difference in the rates of composite MACE and all-cause mortality among patients treated with JAK inhibitors and those treated with placebo or active comparator (OR 0.83, 95% CI 0.44-1.57) [224]. Similar results were obtained when excluding pediatric trials and in subgroup analyses based on oral versus topical JAK inhibitors or dermatologic condition. No statistically significant difference was found in the rate of venous thromboembolism between JAK inhibitors and placebo/active comparator (OR 0.52, 95% CI 0.26-1.04).

It should be noted, however, that most of the included trials had a duration ≤6 months. Longer-term postmarketing data are awaited to support the safety of JAK inhibitors for AD and other dermatologic conditions.

Nontargeted immunosuppressive agents

Cyclosporine — Oral cyclosporine is rarely used for infants and young children with AD. In older children and adolescents, the use of cyclosporine should be reserved for the most severe cases that failed to respond to optimal topical treatment and dupilumab and have a negative impact on quality of life. Cyclosporine is an on-label medication for adult AD in some European countries. (See "Management of severe, refractory atopic dermatitis (eczema) in children", section on 'Cyclosporine'.)

●Administration – Oral cyclosporine is a short-term treatment option for patients with moderate to severe AD [124,225]. Cyclosporine (preferably the modified formulation) is typically given at a dose of 3 to 5 mg/kg per day in two divided doses for four to eight weeks or longer (until improvement is noted). The dose is then lowered to the minimum effective dose and maintained until stable improvement is achieved. After cyclosporine withdrawal, treatment with topical corticosteroids and emollients can be continued. Cyclosporine is best tapered before discontinuation because of a possible rebound effect. (See 'Topical corticosteroids' above and 'Maintenance and prevention of relapses' above.)

●Efficacy and adverse effects – The efficacy of oral cyclosporine for the treatment of AD has been evaluated in several randomized trials and systematic reviews.

In a 2021 meta-analysis of 19 randomized trials, most of which considered at high risk of bias, cyclosporine was more effective than placebo in improving nonvalidated clinical scores and patient-reported scores of itch, sleep loss, and quality of life; in head-to-head trials, cyclosporine was superior to ultraviolet A and B phototherapy, intravenous immunoglobulins, and oral prednisolone and was equally effective as methotrexate and mycophenolate sodium [128].

Adverse effects of cyclosporine include nephrotoxicity, hypertension, hypertrichosis, gum hyperplasia, and increased susceptibility to serious infections. Monitoring of patients receiving cyclosporine involves measuring blood pressure and serum creatinine every two weeks for three months, followed by monthly monitoring. Significant elevations of either are an indication to lower the dose or stop treatment. Tracking complete blood counts and liver function are also important. (See "Pharmacology of calcineurin inhibitors".)

Methotrexate — Methotrexate is a treatment option for the long-term control of moderate to severe AD in adults and, less frequently, in adolescents and children [226].

●Administration – In adults and adolescents, methotrexate is usually administered in a single weekly dose of 7.5 to 25 mg. Supplementation with folic acid 1 mg is given six to seven times per week or 5 mg as a single weekly dose to reduce the risk of several common methotrexate toxicities [227]. One international study of children using methotrexate for psoriasis found a higher risk of gastrointestinal toxicity with the weekly administration, despite approximately the same weekly total dose [228]. Methotrexate has a slow onset of action, and benefit may not be noted in the first few months of treatment.

The use and dosing of methotrexate in children with severe AD is discussed separately. (See "Management of severe, refractory atopic dermatitis (eczema) in children", section on 'Methotrexate'.)

●Efficacy and adverse effects – There is limited high-quality evidence for the use of methotrexate for the treatment of AD [226,229-231].

•In an open-label, follow-up study that included 35 of 43 adult participants of a randomized trial comparing methotrexate and azathioprine for the treatment of moderate to severe AD [226], both agents were equally effective in reducing the SCORAD score at five years [230]. The median drug survival was longer for methotrexate than for azathioprine (29 versus 12 months). Viral respiratory infections were the most common adverse events in both treatment groups. Serious adverse events requiring hospitalization occurred in 7 of 14 patients in the methotrexate group and 1 of 11 patients in the azathioprine group and included pneumonia, myocardial infarction, surgical wound abscess, bladder carcinoma, and exacerbation of AD.

•In a randomized trial comparing oral methotrexate 15 mg per week with cyclosporine 2.5 mg/kg per day in 97 adult patients with moderate to severe AD, more patients in the cyclosporine group achieved the primary endpoint of a 50 percent reduction of SCORAD at eight weeks compared with patients in the methotrexate group (42 versus 8 percent, respectively) [229].

Common adverse effects of methotrexate include nausea and stomach upset, increased liver enzyme levels, headache, fatigue, and malaise. Periodic routine laboratory testing, including complete blood count and liver function, is required to monitor hematologic toxicity and hepatotoxicity. (See "Major adverse effects of low-dose methotrexate".)

Other agents — Other systemic immunosuppressive agents for the long-term treatment of AD include azathioprine and mycophenolate mofetil. Their use in children and adults with severe AD is discussed separately. (See "Management of severe, refractory atopic dermatitis (eczema) in children" and "Evaluation and management of severe refractory atopic dermatitis (eczema) in adults".)

PATIENTS WITH SEVERE REFRACTORY DISEASE — The management of severe refractory AD in children and adults is discussed separately. (See "Management of severe, refractory atopic dermatitis (eczema) in children" and "Evaluation and management of severe refractory atopic dermatitis (eczema) in adults".)

TREATING PREGNANT PATIENTS — The management of AD during pregnancy is discussed separately. A position article from the European Task Force on Atopic Dermatitis provided clear and pragmatic guidance for clinicians on management of AD in pregnancy [232]. In most cases, pregnant patients can be treated with topical corticosteroids and broadband and narrowband ultraviolet B (UVB) phototherapy. There are limited or no data on the safety of systemic immunosuppressants and biologics (eg, dupilumab) during pregnancy.(See "Recognition and management of allergic disease during pregnancy", section on 'Atopic dermatitis' and "Dermatoses of pregnancy", section on 'Atopic eruption of pregnancy'.)

CONTROLLING PRURITUS — The management of atopic pruritus requires a multipronged approach that addresses the multiple factors involved in its pathogenesis [233-238]. These include:

●Skin barrier disruption

●Aberrant type 2 immune response, with increased immunoglobulin E (IgE) production, eosinophilia, mast cell activation, and overexpression of T helper type 2 (Th2) cytokines

●Itch mediators, such as histamine, nerve growth factor, substance P, proteases, and cytokines/chemokines (eg, thymic stromal lymphopoietin, interleukin [IL] 2, IL-4, IL-13, and IL-31)

●Hyperinnervation of skin and central sensitization of itch

Nonpharmacologic interventions — Optimal skin hydration and moisturization and treatment with topical anti-inflammatory therapy are the cornerstones of atopic itch management. Tepid baths to hydrate and cool the skin followed by the application of emollients can relieve itching; some patients report better itch relief if the emollient is kept refrigerated.

In more severe cases, wet dressings (wet wraps) help soothe the skin, reduce pruritus, and interrupt the itch-scratch cycle by limiting access to the skin. Emollients are applied to the skin, and dampened cotton garments are worn over the affected area and covered with a dry garment [239]. The wet layer should not be allowed to dry out. The patient may use these dressings overnight if tolerated or change them every few hours during the day.

Psychologic interventions, including habit reversal training, relaxation training, and cognitive behavioral therapy, have been reported as beneficial in patients with chronic pruritus [240-242].

Topical treatments — Topical anti-inflammatory therapy with topical corticosteroids, topical calcineurin inhibitors, or topical Janus kinase (JAK) inhibitors is effective in controlling pruritus. In a meta-analysis of 22 randomized trials including 481 adult patients, pimecrolimus 1% cream or tacrolimus 0.03% to 0.1% ointment were more effective than vehicle in reducing pruritus (odds ratio [OR] 0.64, 95% CI 0.61-0.68) [243].

Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of mild to moderate AD in patients aged ≥3 months, appears to be effective in reducing pruritus [87]. Inhibition of PDE4 results in an increase in intracellular cyclic adenosine monophosphate, which causes a decrease in the production of pruritogenic cytokines [92].

Pramoxine is a topical anesthetic with antipruritic properties now available over the counter as 1% lotions or creams. Pramoxine provides rapid and long-lasting itch relief and has generally a good safety profile [244]. (See "Pruritus: Therapies for localized pruritus", section on 'Topical anesthetics'.)

Phototherapy — In patients with diffuse pruritus that is not controlled with topical therapy alone, narrowband ultraviolet B (NBUVB) or ultraviolet A1 (UVA1) phototherapy are therapeutic options [233,245,246]. The mechanism of action involves a reduced production of histamine from mast cells and basophils. Moreover, as ultraviolet A (UVA) light penetrates deeper into the skin (compared with ultraviolet B [UVB]), it may also cause damage to Schwann and perineural cells, resulting in decreased sensitivity to pruritus.

Both NBUVB and medium-dose UVA1 have been shown to be equally effective in reducing atopic pruritus [247]. However, high-dose UVA1 may be more effective in reducing pruritus and other symptoms of AD in individuals with darkly pigmented skin [245].

Oral antihistamines — Despite lack of evidence for their efficacy, oral H1 antihistamines are widely used as a therapeutic adjunct in patients with pruritus and AD [248]. First-generation, sedating antihistamines (eg, diphenhydramine, hydroxyzine, and cyproheptadine) may be beneficial for patients with disturbed sleep due to itch, although optimal doses and length of treatment have not been determined [3].

The efficacy of second-generation, less-sedating H1 antihistamines (eg, fexofenadine, cetirizine, or loratadine) as an adjunct to topical treatment in adults and children with AD remains uncertain. Their use should be limited to patients with concurrent symptoms of urticaria or allergic rhinitis.

●A 2019 systematic review of 25 randomized trials, most of which were of low methodologic quality, did not find evidence that antihistamines improve the symptoms of AD [249]. In one of the included trials with 795 children aged one to two years, cetirizine 0.5 mg/kg per day for 18 months was no more effective than placebo in reducing the Scoring of Atopic Dermatitis (SCORAD) score (-25 to -15 in the cetirizine group versus -25 to -16 in the placebo group) [250].

●In another randomized trial that included 400 adult patients with AD, fexofenadine 120 mg daily for one week reduced patient-assessed pruritus more than placebo, although the reduction was probably not clinically significant (mean change -0.75 in the fexofenadine group versus -0.5 in the placebo group on a pruritus scale of 0 to 8) [251].

Cyclosporine — The efficacy of oral cyclosporine in rapidly improving pruritus and other symptoms of AD has been demonstrated in several randomized trials [124,252]. However, recurrence is common upon discontinuation of treatment.

Dupilumab — Based on studies in mouse models, it has been suggested that dupilumab, a fully human monoclonal antibody inhibiting IL-4 and IL-13, exerts a direct effect on sensory dorsal root ganglion activation by pruritogens (eg, IL-31) [253]. In clinical trials, dupilumab has been shown to substantially improve atopic pruritus, even in patients with an unsatisfactory cutaneous response and in patients as young as six months [153].

●In a pooled analysis of data from two randomized trials [147], dupilumab was more effective than placebo in improving the secondary outcome of pruritus (numerical rating scale -35 versus -9 percent) in patients who were not clear/almost clear after 16 weeks of treatment with dupilumab [148].

●An analysis of data from 1505 adult and adolescent patients from four randomized trials showed a least squares mean percent change from baseline of daily Peak Pruritus Numerical Rating Scale scores of approximately -48 to -57 percent in the dupilumab groups compared with -19 to -31 percent in the placebo groups [254]. The improvement in the dupilumab groups occurred by day 2 in adults and day 5 in adolescents and was sustained through the end of treatment.

Tralokinumab — Tralokinumab, an IL-13-inhibiting biologic, also provides itch relief and improvement in other signs and symptoms of AD in adults and adolescents, especially in combination with topical corticosteroids.

In the ECZTRA1 and ECZTRA2 trials, a reduction of the weekly average worst daily pruritus Numerical Rating Scale by ≥4 points from baseline was noted at week 16 in 20 and 25 percent of patients treated with tralokinumab versus 10 and 9.5 percent of patients treated with placebo [191].

JAK inhibitors — In randomized trials, abrocitinib and upadacitinib provided rapid itch reduction [212,216]. Their efficacy in reducing pruritus is presumably due to their ability to suppress multiple pruritogens, including IL-31 receptor signaling [255].

MANAGEMENT OF INFECTION — Patients with AD are at increased risk for cutaneous bacterial, viral, and fungal infections. Clinical signs of bacterial superinfection, most often from S. aureus, include weeping, pustules (picture 4A), honey-colored crusting (picture 4B), worsening of dermatitis, or failure to respond to therapy. The presence of vesicles and punched-out erosions may be a sign of eczema herpeticum.

Staphylococcus aureus — S. aureus is a frequent skin colonizer in patients with AD. A meta-analysis of 95 observational studies found that 70 percent of patients with AD carried S. aureus on lesional skin (95% CI 66-74) and 39 percent carried S. aureus on nonlesional skin (95% CI 31-47) [256]. However, in patients without frank clinical infection, the role of staphylococcal colonization in driving the disease severity is still unclear, although multiple lines of evidence suggest a relationship between heavy colonization and AD severity [257]. Studies in patients with the range of severities found a pooled colonization rate of 43 percent (95% CI 31-57) in patients with mild AD compared with 83 percent (95% CI 74-89) in those with severe AD [256].

Clinically infected skin — Because of the universal skin colonization with S. aureus in patients with AD, routine skin swabs for bacteriologic culture are not recommended. However, skin and nasal swabs may be useful for assessing antimicrobial resistance or when there is clinical suspicion of unusual organisms.

●Extensive infection – For patients with extensive clinical infection with weeping, pustules, and honey-colored crusting (picture 4A-B), we suggest oral antibiotic therapy with cephalosporins (typically cephalexin two to three times daily) or penicillinase-resistant penicillins for five to seven days (table 3) [258]. (See "Impetigo", section on 'Treatment'.)

●Localized infection – More localized crusting suggestive of infection can be handled with topical antiseptics, such as diluted bleach baths 0.005% (obtained by adding 0.5 cup or 120 mL of 6% bleach in a full bathtub [40 gallons or 150 L]) and optimal topical anti-inflammatory therapy [258].

Clinically uninfected skin — Multiple observations indicate that in patients with AD without frank clinical infection, there is a relationship between the epidermal density of S. aureus and eczema severity or flare frequency [259-261].

●Bleach baths – Diluted bleach baths 0.005% (obtained by adding 0.5 cup or 120 mL of 6% bleach in a full bathtub [40 gallons or 150 L] of lukewarm water; or 1 scant teaspoon of bleach in 1 gallon/4 L of lukewarm water) have been widely suggested as an adjunctive therapy for AD to reduce the cutaneous load of S. aureus. However, it has been demonstrated that the 0.005% bleach concentration does not exert a bactericidal effect on S. aureus strains in vitro [24] and does not decrease the cutaneous bacterial load in patients with AD [26]. (See 'Bleach baths' above.)

●Oral or topical antibiotics – The efficacy of oral or topical antibiotics in improving the severity of dermatitis is uncertain. A systematic review found insufficient evidence to recommend the use of oral antibiotics for the treatment of AD in the absence of clinical infection [262,263]. The same review found that topical antibiotics or antiseptics reduced colonization with S. aureus in patients with AD but could not conclude that treatment with these agents in combination with topical corticosteroids induced greater clinical improvement than topical corticosteroids alone.

Viral infections — Patients with AD and multifocal lesions that are infected with herpes simplex (called eczema herpeticum or Kaposi varicelliform eruption) should be treated immediately with oral antiviral therapy. Examination reveals skin with punched-out erosions, hemorrhagic crusts, and/or vesicles (picture 5A-C). Involved skin may be pruritic or painful, and lesions may be widespread. Eczema herpeticum is often misdiagnosed as bacterial infection and treated with oral antibiotics, although secondary bacterial infection of eczema herpeticum can occur. Cases of life-threatening dissemination have been reported, and intravenous antiviral therapy may be necessary in severe cases [264,265]. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults".)

"Eczema coxsackium" (picture 6) refers to widespread vesicobullous lesions usually caused by coxsackievirus A6 occurring in children and, less often, in young adults with AD [266,267]. In addition to the typical areas of hand, foot, and mouth disease (palms, soles, buttocks), the face (especially perioral area), extremities, and trunk can be involved. Eczema coxsackium is self-limited and does not require treatment. (See "Atypical exanthems in children", section on 'Atypical hand, foot, and mouth disease' and "Hand, foot, and mouth disease and herpangina", section on 'Hand, foot, and mouth disease'.)

Patients with AD may also develop widespread molluscum contagiosum infections (picture 7). (See "Molluscum contagiosum".)

Fungal infections — Dermatophyte infections are more common in patients with AD and can be treated with standard regimens of topical or oral antifungals. (See "Dermatophyte (tinea) infections".)

Hypersensitivity to Malassezia furfur yeast (a normal component of skin flora) may be an exacerbating factor in patients with head/neck AD [268]. Elevated Malassezia-specific IgE levels have been reported in these patients. Oral antifungal treatment may result in improvement. (See "Role of allergy in atopic dermatitis (eczema)", section on 'Malassezia'.)

ROLE OF ALLERGEN IMMUNOTHERAPY — Allergen immunotherapy (AIT) is a treatment option for patients with proven sensitization to an allergen, such as house dust mites (eg, positive, allergen-specific in vitro testing or skin testing; exacerbation upon natural exposure to the allergen), and dermatitis that is not controlled with conventional therapies. AIT may be administered by either subcutaneous or sublingual routes and should be supervised by an allergy specialist.

Although previous studies of AIT have shown controversial results, including worsening of AD, a meta-analysis of 23 randomized trials suggested a beneficial effect [269]. This study compared subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT), mostly using house dust mite extract, with placebo in 1957 children and adults receiving standard topical therapy with topical corticosteroids or calcineurin inhibitors [269]. Specifically, patients receiving add-on AIT were more likely to experience a 50 percent reduction of Scoring of Atopic Dermatitis (SCORAD; risk ratio 1.53, 95% CI 1.31-1.78) and improvement in Dermatology Life Quality Index (DLQI) of ≥4 points (risk ratio 1.44, 95% CI 1.03-2.01). SCIT and SLIT had similar relative and absolute beneficial effects. Effects on sleep disturbance and dermatitis flare were uncertain. Both forms of AIT were associated with known adverse effects, which were mostly mild irritation at the site of administration, although SCIT carries a small risk of systemic allergic reactions and must be administered in a health care setting.

AIT has the advantages of not containing any drug (just the allergen to which the patient is sensitized) and having lasting effects after therapy is stopped because the underlying immune response to the allergen is modified. AIT may be particularly relevant for patients with AD and concomitant allergic rhinoconjunctivitis or asthma. (See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy" and "Sublingual immunotherapy for allergic rhinitis and conjunctivitis: SLIT-tablets".)

UNPROVEN THERAPIES

Complementary and alternative therapies

Probiotics — Probiotic therapy with Lactobacillus and other organisms has been studied for the treatment of AD in infants and children but has proven to be of limited benefit [270-274]. In a 2009 meta-analysis of 12 randomized trials including 781 participants, probiotics were not more effective than placebo in reducing AD symptoms and sleep disturbance [273]. In addition, the use of probiotics did not reduce the need for other treatments, such as topical corticosteroids. A subsequent meta-analysis of 25 randomized trials including 1600 participants found that probiotics were associated with a modest, clinically insignificant reduction of the baseline Scoring of Atopic Dermatitis (SCORAD) score (-4.5, 95% CI -6.8 to -2.2) [275].

A 2018 systematic review of 39 randomized trials (2599 participants) evaluated the efficacy of oral live probiotics or placebo for the treatment of adults and children with mild to severe AD [276]. The probiotics used were bacteria of the Lactobacillus and Bifidobacteria species taken alone or in combination with other probiotics for a period of four weeks to six months. A pooled analysis did not show a difference between probiotics and placebo in participant- or parent-rated severity of AD (mean difference in SCORAD part C [pruritus plus sleep loss] score at the end of treatment -0.44, 95% CI -1.22 to 0.33) or quality of life. Similarly, no difference between treatments was noted when using clinician-rated disease severity (mean difference in SCORAD part A/B [eczema extent and intensity] -2.24, 95% CI -4.69 to 0.20). An analysis using the total SCORAD score suggested only a modest reduction in eczema severity of uncertain clinical significance (mean difference -3.91, 95% CI -5.86 to -1.96) in patients taking probiotics compared with placebo. (See "Prebiotics and probiotics for treatment of allergic disease".)

Dietary supplements — Dietary supplements, including vitamins, fish oil, and plant-derived essential fatty acids, do not appear to be beneficial for the treatment of AD [277-279]. Evening primrose oil and borage oil, which are rich in the essential fatty acid gamma-linolenic acid, have been widely used for the treatment of AD as a complementary and alternative medicine remedy [280,281]. However, studies of supplementation of gamma-linolenic acid for eczema have provided conflicting results [282]. A meta-analysis of 19 randomized trials of evening primrose oil for the treatment of eczema in children and adults did not find a significant difference in global eczema symptoms (assessed by both the participants and clinicians) between the active treatment and placebo groups [279].

Melatonin — Melatonin is a hormone produced in the pineal gland involved in the regulation of sleep and circadian rhythms (see "Pharmacotherapy for insomnia in adults", section on 'Melatonin'). It has also been suggested that melatonin has antioxidant, anti-inflammatory, and immunomodulating properties [283,284]. In children and adults with AD, abnormal melatonin levels have been correlated with disease severity and degree of sleep disturbance [285-287].

In two small, randomized trials, melatonin supplementation reduced disease severity and improved sleep in children and adolescents with AD [288,289]:

●In a crossover trial, 48 children with AD involving >5 percent of the body surface area and a history of sleep disturbance interfering with daytime activities more than three days per week in the previous three months were treated with oral melatonin 3 mg per day or placebo at bedtime for four weeks, and then after a washout period of two weeks, were switched to the alternate treatment for an additional four weeks [288]. Compared with placebo, melatonin was associated with a greater decrease from the baseline in the total SCORAD score (-9.9 versus -0.7 points) and a greater decrease of the sleep-onset latency time (-23 versus -1.2 minutes). No adverse effects were reported.

●Similar results were provided by another randomized trial that included 70 children aged 6 to 12 years who received oral melatonin 6 mg or placebo an hour before bedtime for six weeks, while continuing their usual treatment with topical corticosteroids and emollients [289]. At the end of the study, children in the melatonin supplementation group compared with those in the placebo group had a greater improvement in the total SCORAD score from baseline (-6.6 versus -2.6 points) and in the total Children's Sleep Habits Questionnaire (CSHQ) score (-5.5 versus -2.7 points) but not in the pruritus score. A decrease in the total IgE level and an increase in the total sleep time per night were also noted in the melatonin group but not in the placebo group. No adverse effects associated with treatment were reported.

Larger studies with longer follow-up are needed to establish the role and safety of long-term melatonin supplementation in the management of AD in children and adolescents.

Chinese herbal medicine — Chinese herbal medications for AD have been used for many years, but their efficacy and safety have not been adequately evaluated in clinical trials [290,291]. A systematic review found three randomized trials and one open-label of a commercial preparation of 10 traditional Chinese herbs [292]. Two trials showed a reduction in erythema and skin surface damage and improvement in sleep in the active treatment group but not in the placebo group. Another trial did not find any difference between the active treatment and placebo groups. All studies were small (less than 50 patients) and of poor methodologic quality. (See "Chinese herbal medicine for the treatment of allergic diseases", section on 'Therapy for atopic dermatitis'.)

Leukotriene receptor antagonists — Montelukast, an oral leukotriene receptor antagonist approved for the treatment of asthma and allergic rhinitis in children and adults, has been evaluated for the treatment of AD in a few randomized trials with conflicting results.

A systematic review of five randomized trials including 202 adults and children older than six years with moderate to severe AD evaluated the efficacy of oral montelukast (10 mg/day in adults and 5 mg/day in children aged 6 to 14 years) given for four to eight weeks compared with placebo (three studies) or conventional treatment with oral antihistamines and topical corticosteroids (two studies) [293]. The pooled analysis of three studies did not show a difference between montelukast and placebo in improving disease severity and pruritus and in reducing the need for topical corticosteroids. In the two studies comparing montelukast with conventional treatment, participants using montelukast experienced improvement in disease severity in one study but no effect in the other study [294,295]. All trials were of low quality with a significant risk of bias.

We do not support the use of this class of agents for adults or children with AD.

REFERRAL — Many patients with AD can initially be treated by a nonspecialist. We suggest that patients be referred to a specialist (eg, dermatologist, allergist) in the following circumstances:

●When the diagnosis is uncertain or contact allergy needs to be ruled out

●When disease has not responded to appropriate topical therapy

●If treatment of AD of the face or skin folds with high-potency topical corticosteroids is being contemplated

●If treatment with phototherapy or systemic agents is being considered

●If allergen immunotherapy (AIT) is being considered (refer to an allergist specifically)

PREVENTION

Skin barrier enhancement — Epidermal barrier dysfunction is recognized as a key factor in the initiation and progression of AD. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis", section on 'Epidermal barrier dysfunction'.)

Two small, randomized trials (one performed in Japan and the other in the United States and United Kingdom) found that the enhancement of a defective skin barrier with daily application of emollients in the first months of life reduced the incidence of AD in infants at increased risk (ie, those with a parent or sibling with AD) [296,297]. In a cost-effectiveness analysis, petrolatum was the most cost-effective emollient [298]. However, several subsequent, randomized trials (including the large United Kingdom BEEP multicenter trial with subsequent five-year follow-up and the Norwegian PreventADALL trial) did not confirm these findings [299-303].

A 2022 meta-analysis that used individual participant data from 11 randomized trials (5217 participants) concluded that:

●Skin moisturizing in infancy does not change the risk of developing AD by age 1 to 3 years (relative risk [RR] 1.03, 95% CI 0.81-1.31; moderate-certainty evidence) [304].

●Subgroup analysis showed that the type of emollient or the duration of emollient use, patient age, FLG mutation, chromosome 11 risk variant, or family history of atopy did not have an impact on the risk of developing AD.

●Skin care interventions using emollients may increase the risk of developing an IgE-mediated food allergy by one to three years when compared with standard care (RR 2.53, 95% CI 0.99-6.49; low-certainty evidence).

●The use of emollients may increase the risk of skin infections (risk ratio 1.33, 95% CI 1.01-1.75, moderate-certainty evidence).

Based on the results of this meta-analysis, daily skin moisturization in infancy probably does not influence the risk of developing AD and may be associated with an increased risk of food allergies and skin infections. However, sensible skin care, which may include emollient use, should be continued for newborns at high risk of AD, especially in dry and cold climate conditions. Caregivers should adopt appropriate hygiene measures when applying emollients to the skin of infants to avoid local skin infections (eg, washing hands and using emollients in tubes rather than jars, which can be more easily contaminated) [304].

A subsequent Irish randomized trial examined the effect of emollients applied twice daily for the first eight weeks of life in 321 infants at high-risk for AD versus standard care [305]. The cumulative incidence of AD defined by the United Kingdom Working Party Diagnostic Criteria at 12 months was 32.8 percent in the emollient group versus 46.4 percent in the standard care group (RR 0.71, 95% CI 0.52-0.97).

These data indicate a window of opportunity for emollient use during the first weeks of life. Indeed, a Danish birth cohort study showed that phytosphingosine levels at eight weeks were significantly reduced in infants who developed AD in the first 12 months compared with those who did not [306]. A reduction in phytosphingosine levels was the most sensitive predictive marker for AD (sensitivity 75.6 percent).

Probiotics and dietary supplements

●Probiotics – In several meta-analyses, probiotic supplementation in pregnant mothers and infants at risk for AD was found effective in reducing the risk of AD in children younger than three years [274,307-309]. However, subsequent randomized trials did not confirm this finding [310-312]. (See "Prebiotics and probiotics for prevention of allergic disease".)

In a randomized trial including 184 children at high risk for allergic disease, probiotic supplementation with Lactobacillus rhamnosus GG during the first six months of life did not decrease the cumulative incidence of eczema at two years of age compared with placebo (29 versus 31 percent; hazard ratio 0.95, 95% CI 0.59-1.53) [311]. The cumulative incidences of asthma at five years were also not significantly different in the two groups (10 versus 17 percent; hazard ratio 0.88, 95% CI 0.41-1.87).

●Vitamin D

•A few small, randomized trials evaluated the role of vitamin D supplementation in the prevention of winter-related exacerbation of AD with conflicting results [313-315]. In the largest study, 107 children with a history of AD worsening during winter were treated with 1000 international units daily of vitamin D or placebo for one month [313]. The primary outcome was a reduction in the clinician-measured Eczema Area and Severity Index (EASI). At the end of the study, the mean decrease in the EASI score was 6.5 in the vitamin D group and 3.3 in the placebo group.

•A large, randomized trial that included 703 pregnant women found that maternal supplementation with vitamin D reduced the incidence of AD in the first year of life [316]. In this study, infants born to mothers who received vitamin D 1000 international units per day during pregnancy had a lower risk of AD at age 12 months (odds ratio [OR] 0.55, 95% CI 0.32-0.97) compared with infants whose mothers had received placebo. However, this effect was not statistically significant at ages 24 or 48 months (OR 0.76, 95% CI 0.47-1.23 and OR 0.75, 95% CI 0.37-1.52, respectively).

Although the results of these trials suggest that winter supplementation of vitamin D may be beneficial for patients with AD, larger, well-designed studies are needed to clarify the role of vitamin D in the prevention and treatment of AD.

Nutritional interventions — Previous international guidelines recommended the use of hydrolyzed formula for the prevention of allergic diseases in high-risk infants who cannot be exclusively breastfed [317,318]. However, the results of a 2016 meta-analysis of 37 randomized trials evaluating the effect of hydrolyzed formula in infancy on the risk of childhood eczema, wheezing, allergic rhinitis, or food allergy do not support this recommendation [319]. This meta-analysis did not find a significant difference between hydrolyzed formula and standard cow's milk formula in the risk of eczema at age 0 to 4 years (OR 0.84, 95% CI 0.67-1.07) or 5 to 14 years (OR 0.86, 95% CI 0.72-1.02). (See "Introducing formula to infants at risk for allergic disease".)

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)" and "Patient education: Giving your child over-the-counter medicines (The Basics)" and "Patient education: Topical corticosteroid medicines (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

●Goals and principles of treatment – The goals of the treatment of atopic dermatitis (AD) are to reduce symptoms (pruritus and dermatitis), prevent exacerbations, and minimize therapeutic risks. Management involves elimination of exacerbating factors, restoration of the skin barrier function and hydration of the skin, patient education, and pharmacologic treatment of skin inflammation (algorithm 1). (See 'Introduction' above and 'General approach' above.)

●Patients with mild to moderate atopic dermatitis:

•Topical therapies – Patients with mild to moderate symptoms (picture 2A-B) are generally managed with topical therapies. For most patients with AD, we suggest topical corticosteroids and emollients rather than other topical anti-inflammatory agents (Grade 2C). The choice of the corticosteroid potency should be based upon the patient's age, body area involved, and degree of skin inflammation. (See 'Topical corticosteroids' above.)

However, for patients with AD in areas at high risk of atrophy (eg, face, skin folds), topical calcineurin inhibitors are an alternative to topical corticosteroids. (See 'Topical calcineurin inhibitors' above.)

Second-line treatment options include topical crisaborole (adults and children) and topical ruxolitinib (adults and children older than 12 years). (See 'Crisaborole' above and 'Topical ruxolitinib' above.)

•Maintenance/proactive therapy – For patients with mild to moderate AD that responds to continuous topical therapy, we suggest maintenance/proactive therapy with topical corticosteroids or topical calcineurin inhibitors to prevent relapse (Grade 2B). Topical corticosteroids or topical calcineurin inhibitors are applied once daily for two to three days per week. (See 'Maintenance and prevention of relapses' above.)

●Patients with moderate to severe disease – For patients with moderate to severe disease who have an inadequate response to topical therapies, we suggest dupilumab or tralokinumab rather than other immunosuppressants or phototherapy (algorithm 1) (Grade 2C). Use of these agents is standard practice; however, abrocitinib, and upadacitinib are newly approved agents that may be alternative options for adult patients with inadequate response to dupilumab or tralokinumab. (See 'Biologic agents' above and 'Dupilumab' above.)

For adults and adolescents with moderate to severe disease, narrowband ultraviolet B (NBUVB) phototherapy is an alternative first-line treatment if available and acceptable to the patient, but adherence can be challenging. Phototherapy is usually administered in the office two to three times per week. (See 'Phototherapy' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges William L Weston, MD, and Jacob P Thyssen, MD, who contributed to earlier versions of this topic review.