INTRODUCTIONAtopic dermatitis is a chronic, pruritic, inflammatory skin disease that occurs most frequently in children, but also affects many adults [1]. Clinical features of atopic dermatitis include skin dryness, erythema, oozing and crusting, and lichenification. Pruritus is a hallmark of the condition and is responsible for much of the disease burden for patients and their families.

The goals of treatment are to reduce symptoms (pruritus and dermatitis), prevent exacerbations, and minimize therapeutic risks. Standard treatment modalities for the management of these patients are centered around 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].

Conventional therapy for atopic dermatitis is reviewed here. The management of severe, refractory atopic dermatitis in children and adults and the epidemiology, pathogenesis, clinical manifestations, and diagnosis of atopic dermatitis are discussed separately.

●(See «Management of severe 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».)

GENERAL APPROACHThe optimal management of atopic dermatitis requires a multipronged approach that involves the 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) [4].

Elimination of exacerbating factors — Exacerbating factors in atopic dermatitis that disrupt an already abnormal epidermal barrier include excessive bathing without subsequent moisturization, low humidity environments, emotional stress, xerosis (dry skin), overheating of skin, and exposure to solvents and detergents [5,6]. Avoiding these situations is helpful for acute flares as well as for long-term management. Since atopic individuals tend to respond more readily to pruritic stimuli, anything that tends to induce itch in an individual should be avoided.

Adjunctive measures that can be useful in all patients with dermatitis include [7]:

●Avoid trigger factors such as heat, low humidity

●Treat skin infections such as Staphylococcus aureus and herpes simplex (see ‘Management of infection’ below)

●Use antihistamines for sedation and control of itching (see ‘Controlling pruritus’ below)

●Treat stress and anxiety

Aeroallergens and food allergens — There is controversy regarding whether environmental or food allergies are exacerbating factors in patients with atopic dermatitis. (See «Role of allergy in atopic dermatitis (eczema)».)

Hypersensitivity to house dust mites (eg, Dermatophagoides pteronyssinus, D. farinae), animal danders, molds, and pollens is thought to be associated with flares of atopic dermatitis [8,9]. However, although many atopic dermatitis patients are sensitized to house dust mites, reduction of house dust mite antigens in the atopic patient’s environment does not seem to be useful for disease control [10,11].

There is a lack of evidence that dietary interventions are helpful in reducing the severity or preventing flares of atopic dermatitis in unselected patients. Although approximately 50 percent of children with atopic dermatitis may have positive skin prick tests or specific IgE to one or more food allergens (in particular, cow’s milk, egg, wheat, and peanut), food sensitization is clinically irrelevant in most cases [12]. A systematic review of nine randomized trials including 421 children and adults with atopic eczema indicates that either milk and egg exclusion, a few-foods diet, or an elemental diet are not beneficial in unselected patients with atopic dermatitis [13]. One study suggests that an egg-free diet may be helpful for infants with proven sensitivity to eggs [14].

Contact allergens — Atopic individuals are at an increased risk for developing allergic contact dermatitis (ACD) to nickel as well as many components of topical treatments (eg, fragrances, preservatives, neomycin) [15,16]. ACD should be suspected when patients do not respond to appropriate topical therapy or when affected areas continue to spread beyond the usual flexural locations.

Maintaining skin hydration

Emollients and moisturizers — Skin hydration is a key component of the overall management of patients with atopic dermatitis. Lotions, which have a high water and low oil content, can worsen xerosis via evaporation and trigger a flare of the disease. In contrast, thick creams, which have a low water content, or ointments (eg, petroleum jelly), which have zero water content, better protect against xerosis, but some patients may complain that they are greasy. To maintain skin hydration, emollients should be applied at least two times per day and immediately after bathing or hand-washing.

Since atopic skin is deficient in stratum corneum lipids (especially ceramide) and «natural moisturizing factor» (a mixture of hygroscopic amino acids resulting from filaggrin breakdown), moisturizers that contain those ingredients may be beneficial. There are a number of topical moisturizers available in the United States by prescription. These agents contain a variety of components intended to improve skin barrier function and are expensive. There are few data demonstrating their efficacy, but one randomized trial suggests that they are no more effective than over-the-counter emollients [17].

A 2017 systematic review of 77 studies including 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 [18,19]:

●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.

Emollients are best applied immediately after bathing when the skin is well hydrated.

Bathing practices — Warm soaking baths or showers using mild or soap-free cleansers should be part of the routine skin care for patients with atopic dermatitis. Some controversy exists concerning the frequency of bathing and whether showering or bathing is preferable in patients with atopic dermatitis [20-22]. Most experts recommend a hydrating bath followed by immediate emollient application, but others recommend a shower of short duration. No well-designed studies have been published to address this controversy. We feel that either option is reasonable but suggest bathing to most patients. Whether bath or shower is preferred, rapid application of emollients and/or prescribed topical preparations immediately after is important.

We do not support the use of bath additives for atopic dermatitis. However, despite a 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 in children and adults with atopic dermatitis, especially in Europe, where their use is supported by national and international guidelines [23,24]. In the United States, while the American Academy of Allergy, Asthma, and Immunology’s practice parameter for atopic dermatitis supports the use of bath additives, the American Academy of Dermatology guidelines recommend against them [2,25].

A large, well-designed, pragmatic, randomized trial demonstrated that emollient bath additives provide no additional benefits beyond standard care in the management of atopic dermatitis [26,27]. In this study, 463 children aged 1 to 11 years with mild to moderate atopic dermatitis were assigned to use bath emollient additives or no bath additives, in addition to standard care (ie, leave-on emollients and topical corticosteroids as needed) for 52 weeks. The primary outcome was eczema severity assessed weekly by the patient-oriented eczema measure (POEM) over 16 weeks. At 16 weeks, there was no significant difference between the mean POEM score in the bath additives group and that in the no bath additives group (7.5 versus 8.4). After adjusting for potential confounders (eg, baseline severity, use of topical corticosteroids, use of soap substitutes), the POEM score in the no bath additives group was 0.41 (95% CI -0.27 to 1.10) points higher than in the bath additives group, which is markedly lower than the accepted minimal clinically important difference of three points [28,29]. Similar results were obtained at 52 weeks.

Controlling pruritus — Oral H1 antihistamines are widely used as a therapeutic adjunct in patients with atopic dermatitis to alleviate pruritus [30]. The evidence supporting their use is relatively weak since no large, randomized, placebo-controlled trials with definitive conclusions have been performed. Nevertheless, first-generation, sedating antihistamines (eg, diphenhydramine, hydroxyzine, and cyproheptadine) may be beneficial for patients with disturbed sleep secondary to itch, although optimal doses and length of treatment have not been determined [3].

The efficacy of second-generation, less sedating, H1 antihistamines, such as fexofenadine, cetirizine, or loratadine, as an adjunct to topical treatment in adults and children with atopic dermatitis remains uncertain, and 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 these agents are effective in improving the symptoms of atopic dermatitis [31]. In one of the trials including 795 children aged 1 to 2 years with eczema, cetirizine 0.5 mg/kg per day for 18 months was no more effective than placebo in reducing the score of atopic dermatitis (SCORAD) score (from 24.9 to 15.2 in the cetirizine group and from 25.1 to 15.7 in the placebo group) [32]. Another study including 400 adult patients with atopic dermatitis found that 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) [33].

Topical doxepin, a tricyclic antidepressant with potent H1 and H2 blocking properties, may be used as a second-line treatment if others fail [34]. However, allergic contact dermatitis to this agent is common [35]. Topical calcineurin inhibitors appear to be 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) [36].

Tepid baths to hydrate and cool the skin can also temporarily relieve itching. Wet dressings (wet wraps) help soothe the skin, reduce pruritus, reduce redness, débride crusts, and limit 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 [37]. The patient may use these dressings overnight if tolerated or change them every few hours during the day. Anti-pruritic ingredients such as phenol, menthol, and camphor are found in some moisturizers. (See «Pruritus: Overview of management».)

Patient education — Patient education is an important component of the management of atopic dermatitis. A systematic review of nine randomized trials (2003 participants) of educational interventions for atopic dermatitis suggests that children and their parents or caregivers may benefit from structured education provided by nurses or multidisciplinary teams [38]. In the largest of these trials including 992 children and adolescents with atopic dermatitis and their families, a six-week education program was compared with no intervention [39]. The program consisted of two-hour weekly sessions covering medical, nutritional, and psychological issues, and were carried out by a multiprofessional team of dermatologists or pediatricians, psychologists, and dietitians. After one year, the decrease in the total severity SCORAD was greater in the intervention group than in the control group. There was also a significant improvement in subjective assessment of severity, itching behavior, and emotional coping.

ASSESSMENT OF SEVERITYFor 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, sleep, impact on daily activities, and persistence of disease [40]. Several disease severity scales (eg, the SCORAD index, the eczema area and severity index [EASI], and the patient-oriented eczema measure [POEM]) and patient quality of life measurement scales have been tested and validated for use in clinical trials, but they are not commonly used in clinical practice [40]. However, POEM, which asks about the frequency of 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 [41].

A practical guide to visual assessment of eczema severity that also includes the evaluation of disease impact on quality of life and psychosocial wellbeing 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 wellbeing

●Moderate – Areas of dry skin, frequent itching, redness (with or without excoriation and localized skin thickening); Moderate impact on everyday activities and psychosocial wellbeing, 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

PATIENTS WITH MILD TO MODERATE DISEASE

Initial treatment — Topically applied corticosteroids and emollients are the mainstay of therapy for atopic dermatitis (algorithm 1) [2]. The choice of the corticosteroid potency should be based upon the patient’s age, body area involved, and degree of skin inflammation. Topical calcineurin inhibitors may be an alternative to topical corticosteroids, in particular for the treatment of the face, including the eyelids, neck, and skin folds.

Topical corticosteroids — For patients with mild atopic dermatitis, we suggest a low potency (groups five and six (table 1)) corticosteroid cream or ointment (eg, desonide 0.05%, hydrocortisone 2.5%) (algorithm 1). Topical corticosteroids are applied one or two times per day for two to four weeks. Emollients should be liberally used multiple times per day in conjunction with topical corticosteroids. Emollients can be applied before or after topical corticosteroids [42]. (See ‘Emollients and moisturizers’ above.)

For patients with moderate disease, we suggest medium to high potency (groups three and four (table 1)) corticosteroids (eg, fluocinolone 0.025%, triamcinolone 0.1%, betamethasone dipropionate 0.05%). In patients with acute flares, super high or high potency topical corticosteroids (group one to three (table 1)) can be used for up to two weeks and then replaced with lower potency preparations until the lesions resolve.

The face and skin folds are areas that are at high risk for atrophy with corticosteroids. Initial therapy in these areas should start with a low potency steroid (group VI (table 1)), such as desonide 0.05% ointment. High potency topical corticosteroids are generally avoided in skin folds and on the face; however, limited brief use (five to seven days) of potent corticosteroids may produce a rapid response after which patients can be switched to lower potency preparations.

Maintenance therapy that includes intermittent use of a topical corticosteroid or a topical calcineurin inhibitor may help prevent relapse. (See ‘Maintenance and prevention of relapses’ below.)

Efficacy and adverse effects — A systematic review of randomized trials identified 83 studies of topical corticosteroids for atopic dermatitis [43]. Although studies were of poor methodologic quality and short duration (<4 weeks), all indicated a large therapeutic efficacy of topical corticosteroids compared with placebo. No clear benefit has been demonstrated with more than once daily application [44-46].

Long-term use of topical corticosteroids, especially high or super high potency preparations, on large body areas may lead to adrenal suppression. Other adverse effects include skin thinning, telangiectasias, folliculitis, and contact dermatitis. (See «Topical corticosteroids: Use and adverse effects», section on ‘Adverse effects’.)

Topical calcineurin inhibitors — Topical calcineurin inhibitors are nonsteroidal immunomodulating agents that, unlike topical corticosteroids, do not cause skin atrophy or other corticosteroid adverse effects. They can be used as an alternative to topical corticosteroids for the treatment of mild to moderate atopic dermatitis involving the face, including the eyelids, neck, and skin folds [47,48].

Tacrolimus ointment and pimecrolimus cream are applied twice a day. Tacrolimus comes in two strengths; the 0.1% formulation is appropriate initial therapy for adults, and the 0.03% formulation is appropriate for children and for adults who do not tolerate the higher dose. In patients who do not tolerate tacrolimus because of burning or stinging, pimecrolimus may be better tolerated.

Both tacrolimus and pimecrolimus topical preparations are approved by the US Food and Drug Administration (FDA) for use in children over the age of two years. However, concerns have been raised by the FDA about a possible link to cancers, in particular lymphoma and skin cancer [49,50]. (See ‘Long-term safety concerns’ below.)

Efficacy and minor side effects — Topical calcineurin inhibitors are generally recognized as being equal in strength to medium potency (groups four and five (table 1)) topical steroids, and should be considered a second-line therapy [51]. In addition to its inhibitory effect on cytokine production, topical tacrolimus causes alterations in epidermal antigen-presenting dendritic cells that may result in decreased immunologic response to antigens [52]. Pimecrolimus 1% cream is a calcineurin inhibitor like tacrolimus that was developed specifically to treat inflammatory skin conditions. Its mechanism of action is similar to topical tacrolimus, and it does not appear to have systemic immune effects [53]. Transient burning, erythema, and pruritus are the most common adverse effects [54].

The efficacy of tacrolimus has been demonstrated in several randomized trials and systematic reviews [47,55,56]. 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 including 6897 patients showed that tacrolimus 0.1% was more effective than vehicle for the treatment of patients with moderate to severe atopic dermatitis (44 percent of patients in the tacrolimus group improved by greater than 90 percent, versus 20 percent in the vehicle group) [47]. Tacrolimus was more effective than hydrocortisone acetate and comparable in efficacy to hydrocortisone butyrate. Pimecrolimus was more effective than vehicle in the treatment of mild to moderate atopic dermatitis (33 percent of patients were clear or almost clear at three weeks versus 10 percent of those who used the vehicle) and in preventing flares. Pimecrolimus was less effective than betamethasone valerate, but its potency compared with hydrocortisone was not evaluated in any of the included trials.

●A subsequent meta-analysis of four randomized trials comparing tacrolimus with pimecrolimus for the treatment of atopic dermatitis, including more than 1800 patients, found that 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) [56]. In pediatric patients with moderate to severe eczema, tacrolimus 0.03% was superior to pimecrolimus 1% (relative risk 0.65, 95% CI 0.57-0.75). However, in the group of pediatric patients with mild to moderate eczema, there was no significant difference between tacrolimus 0.03% and 1% pimecrolimus.

●In a systematic review of 31 randomized trials, pimecrolimus was significantly better than vehicle in preventing flares at six months [57]. However, pimecrolimus was less effective than medium potency topical corticosteroids (triamcinolone acetonide 0.1% and betamethasone valerate 0.1%) and tacrolimus 0.1%.

Long-term safety concerns — Although in controlled trials the topical calcineurin inhibitors have appeared to be safe in adults and children [54,58-61], in 2005, based upon case reports, animal studies, and the known risks with systemic calcineurin inhibitors, the FDA issued warnings about a possible link between the topical calcineurin inhibitors and cancer [62], and in 2006 placed a boxed warning on the prescribing information for these medications [63].

Issues of concern include:

●Animal studies in mice, rats, and monkeys have found an increased risk of lymphoma and skin cancers with topical or oral exposure to calcineurin inhibitors.

●As of December 2004, the FDA had received 29 reports of cancers in adults and children treated with topical calcineurin inhibitors; approximately half the cases were lymphomas and the other half were cutaneous tumors.

●Between January 2004 and January 2009, the FDA received 46 reports of new cancer cases among children 0 to 16 years old who used topical pimecrolimus and/or topical tacrolimus (30 lymphomas/leukemias, 8 skin cancers, and 8 other cancers).

However, no definite causal relationship has been established [64], and two case-control studies did not detect an increased risk of lymphoma among patients treated with topical calcineurin inhibitors [65,66]. The Pediatric Eczema Elective Registry (PEER) is an industry-sponsored, ongoing cohort study established in 2004 as part of the post-marketing 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 [67]. The standardized incidence ratio (SIR) based upon the age-standardized Surveillance, Epidemiology, and End Results 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 to exclude all risk.

A subsequent meta-analysis [68] did not find a statistically significant association between the use of topical calcineurin inhibitors and risk of lymphoma, 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) [69].

Waiting for more reassuring data from larger studies, the following FDA recommendations seem reasonable precautions [70,71]:

●Use these agents only as second-line therapy in patients unresponsive to or intolerant of other treatments.

●Avoid the use of these agents in children younger than two years of age; clinical studies have found higher rates of upper respiratory infections in children younger than two years who were treated with pimecrolimus.

●Use these agents only for short periods of time and use the minimum amount necessary to control symptoms; avoid continuous use.

●Avoid the use of these agents in patients with compromised immune systems.

Providers and patients will need to weigh the risks and benefits of topical calcineurin inhibitors in comparison to those of other therapies. In particular, calcineurin inhibitors may continue to have an important role in the management of atopic dermatitis in areas at high risk for skin atrophy when treated with corticosteroids (eg, face) [72].

Off-label use in infants — Topical calcineurin inhibitors have been approved in the United States as second-line therapies for the short and intermittent treatment of mild to moderate atopic dermatitis in adults and children aged ≥2 years. However, they have been used off-label in children as first-line treatment for atopic dermatitis, and in children <2 years, in the absence of long-term studies evaluating their efficacy and safety compared with low- or mid-potency topical corticosteroids [73].

A five-year industry-sponsored 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 over 2400 infants 3 to 12 months of age with mild to moderate atopic dermatitis [74]. After 5 years, overall treatment success, measured by an investigator global assessment score, was achieved in approximately 89 percent of children in the pimecrolimus group and 92 percent 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 than in the topical corticosteroid 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 atopic dermatitis remains unclear.

Crisaborole — Crisaborole is a boron-based, small-molecule, topical phosphodiesterase 4 (PDE4) inhibitor that was approved by the FDA in December 2016 [75] for the treatment of mild to moderate atopic dermatitis. Preliminary studies in adolescents and adults indicated that crisaborole 2% ointment may improve the clinical signs of atopic dermatitis, including erythema, excoriation, exudation, lichenification, and, in particular, pruritus [76-79]. Adverse effects of topical crisaborole were mild and mainly limited to application site reactions (pain, paresthesia). Systemic exposure to crisaborole has been shown to be limited even after maximal use (3 mg/cm²) [79].

Two subsequent phase 3, multicenter randomized trials (AD-301 and AD-302) were performed to assess the efficacy and safety of topical crisaborole in patients with mild to moderate atopic dermatitis [80]. In these trials, a total of 1522 patients ≥2 years of age were randomized to receive crisaborole 2% ointment twice daily for 28 days. The primary efficacy end point (success) was defined as an investigator’s static global assessment (ISGA) score of 0 (clear) or 1 (almost clear) with a two-grade or more improvement from baseline. At day 29, more patients in the crisaborole groups than in the vehicle groups achieved success (32.8 versus 25.4 percent in AD-301 and 31.4 versus 18 percent in AD-302). Improvement was noted in pruritus, skin inflammation, excoriation, and lichenification. Crisaborole-related adverse events occurred in 4.4 percent of patients and were mild and limited to burning or stinging at the site of application.

The long-term safety of crisaborole was evaluated in a 48-week, open-label, extension study including 517 patients (60 percent children) who had completed the AD-301 and AD-302 trials without experiencing adverse effects [81]. Patients with an ISGA score ≥2 initiated crisaborole treatment twice daily for 28 days. Participants underwent an average of six treatment periods and used an average of 133 g of crisaborole ointment per month. Adverse events, of which 86 percent were mild or moderate, occurred in 10 percent of patients. The most frequently reported adverse events were exacerbation of atopic dermatitis, burning or stinging in the application site, and application site infection. Diarrhea or vomiting, side effects observed with oral PDE4 inhibitors, were reported by approximately 1 to 2 percent of patients throughout the study. Rescue therapy with topical corticosteroids or topical calcineurin inhibitors was needed by 22 and 26 percent of children and adolescents, respectively, 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 [80,82]. Head-to-head studies comparing crisaborole with established therapies for atopic dermatitis are needed to better define its role in the management of mild to moderate atopic dermatitis.

Maintenance and prevention of relapses — We suggest proactive therapy to prevent relapse in adolescents and adults with moderate to severe (picture 1A-B) atopic dermatitis that responds to continuous therapy with topical corticosteroids or calcineurin inhibitors (algorithm 1). After induction of remission, we suggest intermittent therapy with moderate to high potency topical corticosteroids (group three to five) (table 1). The steroid should be applied once daily to previously affected skin areas for two consecutive days per week (ie, weekends) and may be continued for up to 16 weeks. Emollients can be liberally used multiple times per day.

Flares of atopic dermatitis that occur during intermittent treatment may be treated by resuming continuous use of topical corticosteroids or calcineurin inhibitors that have been effective for the patient in the past. Similar strategies for proactive therapy are recommended in multiple national and international guidelines for the management of atopic dermatitis [2,25,83-85].

In infants and young children with moderate to severe atopic dermatitis (picture 2A-B) who have frequent flares, proactive intermittent therapy with low potency (groups six and seven) topical corticosteroids (table 1) may be beneficial in preventing relapse [86]. The steroid should be applied once daily to previously affected skin areas for two consecutive days per week (ie, weekends) and may be continued for up to 16 weeks. Flares of atopic dermatitis that occur during intermittent treatment may be treated by resuming continuous use of topical corticosteroids that have been effective for the patient in the past.

In meta-analyses of randomized trials, proactive, intermittent therapy with moderate to high potency corticosteroids or tacrolimus, after achieving disease control with continuous use of these agents, was effective in reducing the risk of subsequent flares [87]. However, there were fewer adverse effects with corticosteroids, as illustrated below:

●In a meta-analysis of four randomized trials, 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 0.46, 95% CI 0.38-0.55) [87]. No serious adverse events were reported.

●In a meta-analysis of three randomized trials, 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 (relative risk 0.78, 95% CI 0.60-0.78) [87]. Adverse effects included pruritus, burning sensation, skin infections, and bronchopneumonia. In addition, four patients developed a cancer. (See ‘Long-term safety concerns’ above.)

Treatment of acute exacerbations — In adolescents and adults, an acute exacerbation of chronic atopic dermatitis can sometimes be aborted by a short course of systemic glucocorticoids (eg, prednisone 40 to 60 mg/day for three to four days, then 20 to 30 mg/day for three to four days). This strategy is not recommended for infants and young children. (See «Major side effects of systemic glucocorticoids» and «Management of severe atopic dermatitis (eczema) in children», section on ‘Systemic corticosteroids’.)

PATIENTS WITH MODERATE TO SEVERE DISEASEAdult patients with moderate to severe atopic dermatitis that is not controlled with optimal topical therapy may require phototherapy or systemic immunosuppressant treatment to achieve adequate disease control (algorithm 1) [3,88,89]. Evidence on the efficacy and safety of phototherapy and systemic immunosuppressants for children is limited. Thus, these treatments should be used only in older children in whom other management options have failed and the disease has a significant impact on the quality of life [90].

Phototherapy

In adults — Ultraviolet light therapy (phototherapy) with PUVA (psoralens plus ultraviolet A radiation), broadband UVA, broadband UVB, combined UVA and UVB, narrow-band UVB, or UVA1 is a treatment option for moderate to severe atopic dermatitis that is not adequately controlled with topical therapy [91-93]. (See «UVB therapy (broadband and narrowband)» and «Psoralen plus ultraviolet A (PUVA) photochemotherapy» and «UVA1 phototherapy».)

We suggest narrowband UVB phototherapy rather than other forms of phototherapy for adult patients with moderate to severe atopic dermatitis that is not controlled with topical therapy. Phototherapy is usually administered three times per week. Topical corticosteroids can be continued as needed during phototherapy. Additional emollients may be necessary since phototherapy may increase skin dryness.

Phototherapy for the treatment of moderate to severe atopic dermatitis has been evaluated in randomized trials and systematic reviews. In a 2013 systematic review of 19 randomized trials including 905 patients, medium dose UVA1 (30 to 60 J/cm²) and narrow-band UVB were more effective than other phototherapy modalities in reducing the clinical signs and symptoms of atopic dermatitis, as measured with several clinical scores [94]. However, phototherapy is expensive ($25 to $100 per treatment) and prolonged treatment may lead to an increased risk of melanoma and nonmelanoma skin cancer [95-97].

In children — Phototherapy is not suitable for infants and young children. In older children and adolescents with atopic dermatitis not controlled with topical therapies, narrowband UVB phototherapy may be a therapeutic option, if available. However, the benefits of phototherapy must be weighed against potential adverse effects. (See «Management of severe atopic dermatitis (eczema) in children», section on ‘Phototherapy’.)

Oral cyclosporine

In adults — Oral cyclosporine is a short-term treatment option for patients with moderate to severe atopic dermatitis that is not adequately controlled with topical therapy, when phototherapy is not available or contraindicated [88,89]. For adult patients, cyclosporine is given at dose of 3 to 5 mg/kg per day in two divided doses for six weeks. The dose is then lowered to the minimum effective dose and maintained until stable improvement is achieved, or for up to one year. After cyclosporine withdrawal, treatment with topical corticosteroids and emollients can be resumed. (See ‘Initial treatment’ above and ‘Maintenance and prevention of relapses’ above.)

The efficacy of oral cyclosporine for the treatment of atopic dermatitis has been evaluated in randomized trials and systematic reviews. In a 2013 systematic review of 34 randomized trials including 1653 patients with moderate to severe atopic dermatitis, cyclosporine was more effective than placebo in five trials, with a mean improvement of 50 to 95 percent in different clinical severity scores after short-term treatment (10 day to 8 weeks) [88]. In head-to-head trials, cyclosporine was more effective than prednisolone, intravenous immunoglobulins, and phototherapy with UVA/UVB. Higher doses (5 mg/kg per day) lead to a more rapid response than lower doses (2.5 to 3 mg/kg).

Side effects of cyclosporine include nephrotoxicity, hypertension, hypertrichosis, gum hyperplasia, and increased susceptibility to serious infections. Monitoring of patients receiving cyclosporine includes 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. (See «Pharmacology of cyclosporine and tacrolimus».)

In children — Oral cyclosporine is not recommended in infants and young children with atopic dermatitis. In older children and adolescents, the use of cyclosporine should be reserved to the most severe cases that failed to respond to topical treatment and where there is a significant negative impact on quality of life. (See «Management of severe atopic dermatitis (eczema) in children», section on ‘Cyclosporine’.)

Other systemic immunosuppressants — Second-line systemic immunosuppressive agents for the treatment of atopic dermatitis include methotrexate, azathioprine, and mycophenolate mofetil. Their use in children and adults with severe atopic dermatitis is discussed in detail separately. (See «Management of severe atopic dermatitis (eczema) in children» and «Evaluation and management of severe refractory atopic dermatitis (eczema) in adults».)

Dupilumab — Dupilumab is a fully human monoclonal antibody that binds to the alpha subunit of the interleukin (IL)-4 receptor and inhibits downstream signaling of IL-4 and IL-13, cytokines of type 2 helper T lymphocytes (Th2) that are believed to play a key role in atopic diseases, including asthma and atopic dermatitis. Dupilumab was approved by the US Food and Drug Administration (FDA) in March 2017 and by the European Medicine Agency in July 2017 for the treatment of adult patients with moderate to severe atopic dermatitis not adequately controlled with topical prescription therapies [98,99]. In a March 2019 modification of the prescribing information, the FDA approved dupilumab (with or without topical corticosteroids) for the treatment of adolescents aged 12 years or older with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable [100].

Dupilumab was initially evaluated in four small, industry-sponsored, randomized trials in adult patients with moderate to severe atopic dermatitis [101]. In a subsequent phase IIb, randomized trial, 379 adult patients with chronic moderate to severe atopic dermatitis present for ≥3 years were treated with dupilumab 300 mg once a week, 300 mg every two weeks, 200 mg every two weeks, 300 mg every four weeks, 100 mg every four weeks, or placebo once a week for 16 weeks [102]. The primary efficacy endpoint was the percentage change in the eczema area and severity index (EASI) score from baseline to week 16. At 16 weeks, patients in all the dupilumab treatment groups had a greater improvement in the EASI score compared with baseline than patients in the placebo group. The improvement was dose-dependent, with the largest effect seen in the 300 mg once-a-week and 300 mg every-two-weeks groups (-74 and -68 percent, respectively, versus -18 percent in the placebo group). Serious treatment-related adverse events occurred in 12 of 318 (4 percent) patients in the dupilumab groups combined and in 4 of 61 (7 percent) in the placebo group. In an analysis of patient-reported outcomes, dupilumab was also associated with a dose-dependent improvement in pruritus, sleep, symptoms of anxiety and depression, and health-related quality of life [103].

The efficacy of dupilumab 300 mg or placebo given by subcutaneous injection weekly or every other week was also evaluated in two phase III trials of identical design, SOLO1 and SOLO2, which included 671 and 708 adult patients with long-standing moderate to severe atopic dermatitis not controlled by topical treatments, respectively [104]. The primary endpoint was the proportion of patients with an investigator general assessment (IGA) score of 0 or 1 (clear or almost clear) and a reduction from baseline of at least two points in the score at week 16. The secondary endpoint was the proportion of patients who achieved at least a 75 percent improvement from baseline in the eczema area and severity index (EASI-75). At week 16, more patients in the dupilumab groups than in the placebo groups achieved the primary endpoint (approximately 40 versus 10 percent). There were no differences between trials and between weekly or biweekly dupilumab regimens. EASI-75 was achieved by 44 to 52 percent of patients receiving dupilumab versus 12 and 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. Exacerbation of atopic dermatitis was reported overall in three patients receiving dupilumab and in eight receiving placebo.

The results of these trials indicate that dupilumab may be an alternative systemic therapy for long-standing atopic dermatitis in adults, despite the relatively low proportion of patients achieving complete or near-complete clearance after 16 weeks of treatment. The long-term efficacy and safety of dupilumab was subsequently evaluated in a randomized, double-blind, multicenter trial (LIBERTY AD CHRONOS) [105]. In this study, 740 patients were treated with dupilumab 300 mg once weekly, dupilumab 300 mg every 2 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 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). Serious adverse events occurred less frequently in the dupilumab plus topical corticosteroids groups than in the placebo plus topical corticosteroids group (7 and 16 percent, respectively); however, patients in the dupilumab groups experienced an approximately twofold higher frequency of eye disorders and noninfectious conjunctivitis. The results of this study support the use of dupilumab for the treatment of moderate to severe atopic dermatitis in adult patients who do not respond to topical therapies alone and in whom other systemic treatments are contraindicated.

PATIENTS WITH SEVERE REFRACTORY DISEASEThe management of severe refractory atopic dermatitis in children and adults is discussed separately. (See «Management of severe atopic dermatitis (eczema) in children» and «Evaluation and management of severe refractory atopic dermatitis (eczema) in adults».)

PREGNANT WOMENThe management of atopic dermatitis during pregnancy is discussed separately [106]. (See «Recognition and management of allergic disease during pregnancy» and «Recognition and management of allergic disease during pregnancy», section on ‘Atopic dermatitis’ and «Dermatoses of pregnancy», section on ‘Atopic eruption of pregnancy’.)

MANAGEMENT OF INFECTIONPatients with atopic dermatitis 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 3), honey-colored crusting (picture 4), 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 atopic dermatitis. A meta-analysis of 95 observational studies found that 70 percent of patients with atopic dermatitis carried S. aureus on lesional skin (95% CI 66-74) and 39 percent on the nonlesional skin (95% CI 31-47) [107]. 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 indicate that a relationship between heavy colonization and eczema severity does exist [108]. An analysis of data from studies including patients with mild or severe atopic dermatitis found a pooled colonization rate of 43 percent (95% CI 31-57) in patients with mild atopic dermatitis, compared with 83 percent (95% CI 74-89) in those with severe atopic dermatitis [107].

Clinically infected skin — Because of the universal skin colonization with S. aureus in patients with atopic dermatitis, routine skin swabs for bacteriologic culture are not recommended. However, skin and nasal swabs may be useful for recurrent infection, infection that does not respond to treatment, or if there is concern about antimicrobial resistance or clinical suspicion of unusual organisms [109].

For patients with localized clinical infection, we suggest topical mupirocin. Mupirocin 2% cream is applied twice a day for one to two weeks. A prolonged use of topical antibiotics should be avoided because of the risk of inducing bacterial resistance. For patients with more extensive infection, we suggest oral antibiotic therapy with cephalosporins or penicillinase-resistant penicillins [83]. Oral antibiotics are given for two weeks. (See «Impetigo», section on ‘Treatment’.)

Clinically uninfected skin — Multiple observations indicate that in patients with atopic dermatitis without frank clinical infection there is a relationship between the epidermal density of S. aureus and eczema severity or flare frequency [110-112]. Since sodium hypochlorite 6% solution (liquid chlorine bleach) has activity against S. aureus, including methicillin-resistant S. aureus (MRSA), diluted bleach baths (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 one-half of a teaspoon of bleach in one gallon or four liters of lukewarm water) have been suggested as an adjunct to topical treatment between episodes of clinical infection to reduce the cutaneous load of S. aureus and improve symptoms [113].

However, studies evaluating the efficacy of bleach baths for atopic dermatitis have been scarce and inconsistent [114-116]. A meta-analysis of four small randomized trials (116 participants) found that bleach baths were not more effective than plain water baths at four weeks in decreasing the severity of atopic dermatitis as assessed by the eczema area and severity index (EASI) and by the body surface area involved [117]. Emollients and topical corticosteroids were permitted in all studies. Three of the four included studies also found a decrease in S. aureus density after both bleach and normal baths, without a significant difference between groups. Moreover, one of the included trials found that the addition of bleach baths to topical corticosteroids was not more effective than corticosteroids alone in reducing the skin colonization in children with moderate to severe atopic dermatitis [118].

The results of this meta-analysis indicate that bathing per se (with or without bleach) may be effective in reducing the skin colonization from S. aureus and improving symptoms. However, since bleach baths are inexpensive, well tolerated, and devoid of adverse effects, we continue to suggest their use in patients with atopic dermatitis and frequent flares of clinically infected eczema.

The efficacy of other topical antiseptics or 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 atopic dermatitis in the absence of clinical infection [119,120]. The same review found that topical antibiotics or antiseptics reduced colonization with S. aureus in patients with atopic dermatitis, but could not conclude that treatment with these agents in combination with topical corticosteroids induced greater clinical improvement than topical corticosteroids alone. However, the systematic review primarily was based on poor quality studies, and cannot definitively discount antimicrobial therapies for patients without overt infection.

Viral infections — Atopic dermatitis patients with lesions that are infected with herpes simplex (called eczema herpeticum or Kaposi’s 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. The diagnosis should be considered in patients who fail to respond to oral antibiotics [121]. Cases of life-threatening dissemination have been reported, and intravenous antiviral therapy may be necessary in severe cases [121]. (See «Treatment of herpes simplex virus type 1 infection in immunocompetent patients».)

Patients with atopic dermatitis may also develop widespread molluscum contagiosum infections (picture 6). (See «Molluscum contagiosum».)

Fungal infections — Dermatophyte infections are more common in patients with atopic dermatitis, and can be treated with standard regimens of topical or oral antifungals. (See «Dermatophyte (tinea) infections».)

In addition, the Malassezia furfur yeast (a normal component of skin flora) may be an exacerbating factor in patients with head/neck atopic dermatitis [122]. Elevated Malassezia-specific IgE levels have been reported in these patients [122]. Treatment may result in improvement. (See «Role of allergy in atopic dermatitis (eczema)», section on ‘Malassezia’.)

IMMUNOTHERAPYAllergen-specific immunotherapy (SIT) with dust mite extract in sensitized patients with atopic dermatitis has been studied using both subcutaneous (SCIT) and sublingual (SLIT) administration with conflicting results [123-126]. A meta-analysis of eight randomized trials, including 385 patients, that compared SIT (mostly using house dust mite allergens) with placebo found that patients in the SIT group were more likely to experience treatment success, as assessed by patients or investigators, than those in the placebo group (odds ratio [OR] 5.35, 95% CI 1.61-17.77) [127]. However, there was considerable heterogeneity among studies regarding types, doses, and pharmaceutical preparations of allergens; treatment schedules and duration; patients’ age and disease severity; and assessment of outcome. Although this meta-analysis suggests that SIT improves the course of atopic eczema, it is unclear which patients may benefit from this form of treatment. SIT may be a treatment option for patients with proven sensitization to house dust mites (eg, positive allergen-specific test; exacerbation upon natural exposure to the allergen) and severe eczema that is not controlled with conventional therapies [128]. (See «Subcutaneous immunotherapy for allergic disease: Indications and efficacy».)

EXPERIMENTAL AGENTS

JAK inhibitors — Tofacitinib and baricitinib are oral small-molecule Janus kinase (JAK) inhibitors approved for the treatment of rheumatoid arthritis that block multiple cytokine signaling, including interleukin (IL)-4, IL-5, and IL-13, involved in immune response and inflammation. A topical formulation of tofacitinib has been shown to have a modest beneficial effect in the treatment of mild to moderate plaque psoriasis [129]. The efficacy of topical tofacitinib for the treatment of atopic dermatitis has been evaluated in a phase IIa randomized trial [130]. In this study, 69 adult patients with clinically stable, mild to moderate atopic dermatitis were treated with tofacitinib 2% ointment or placebo twice daily for four weeks. The primary end point was the percentage change from baseline in the Eczema Area and Severity Index (EASI). At week 4, the mean percentage change from baseline in the EASI score was significantly greater in patients treated with topical tofacitinib than in those treated with placebo (-82 and -30 percent, respectively). Moreover, the proportion of patients with a physician general assessment score of clear or almost clear was higher in the tofacitinib group than in the placebo group (73 versus 22 percent). Adverse effects, including infection, increased blood creatine phosphokinase, and contact dermatitis, were mild and occurred in 31 percent of patients treated with tofacitinib and 60 percent of those treated with placebo.

A phase 2 randomized trial evaluated the efficacy of oral baricitinib plus topical corticosteroids compared with placebo plus topical corticosteroids for the treatment of moderate to severe atopic dermatitis in 124 adults [131]. At 16 weeks, more patients treated with baricitinib 4 mg achieved EASI-50 from baseline (61 versus 37 percent). Baricitinib also improved pruritus and sleep. Adverse events occurred in 71 percent of patients in the baricitinib 4 mg group, 46 percent of those in the 2 mg group, and 49 percent of those in the placebo group. Adverse events related to baricitinib included headache, increased blood levels or creatine phosphokinase, decrease in the neutrophil count, and nasopharyngitis.

Although topical and oral JAK inhibitors seem to be promising treatments for atopic dermatitis, larger studies of longer duration are needed to evaluate their long-term efficacy and safety.

Anti-IL-31 antibodies — Nemolizumab is a humanized monoclonal antibody against the receptor A of IL-31, a newly discovered cytokine associated with chronic skin inflammation and pruritus [132]. A phase 2 12-week randomized trial evaluated the efficacy of nemolizumab for the treatment of adult patients with moderate to severe atopic dermatitis not controlled by topical corticosteroids or topical calcineurin inhibitors [133]. In this study, 264 patients received subcutaneous nemolizumab at a dose of 0.1 mg, 0.5 mg, or 2 mg per kilogram of body weight or placebo every four weeks or nemolizumab at a dose of 2 mg per kilogram every eight weeks with placebo given at week 4. The primary outcome was the percentage improvement from baseline in the score on the pruritus visual-analogue scale. At 12 weeks, pruritus was reduced by 44, 60, and 63 percent in the 0.1 mg, 0.5 mg, and 2 mg groups, respectively, versus 21 percent in the placebo group. The body surface area affected by atopic dermatitis decreased by 8, 20, and 19 percent in the 0.1 mg, 0.5 mg, 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 atopic dermatitis and respiratory tract infections.

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

Anti-IL-13 antibodies — Lebrikizumab is a monoclonal antibody that binds specifically to soluble IL-13, a pleiotropic T helper 2 cytokine that is likely to play a role in the pathogenesis of barrier dysfunction and inflammation in atopic dermatitis, asthma, and pulmonary fibrosis [134]. Lebrikizumab has been investigated for the treatment of asthma with inconsistent results [135-137].

In a proof-of-concept, phase 2, multicenter, randomized trial, 209 patients with moderate to severe atopic dermatitis received subcutaneous injections of lebrikizumab 125 or 250 mg or placebo every four weeks as an add-on to topical corticosteroid treatment [138]. At 12 weeks, more patients in the lebrikizumab 125 mg every four weeks group achieved the primary endpoint (a 50 percent reduction in the Eczema Area and Severity Index score [EASI-50]) compared with the placebo group (82 versus 62 percent). Lebrikizumab was generally well tolerated; nonsevere infection was the most common adverse event and occurred with similar frequency in all groups.

The results of this study indicate that lebrikizumab in combination with topical corticosteroids may provide some additional benefit compared with topical corticosteroids alone; however, its efficacy as monotherapy for atopic dermatitis remains to be determined.

Anti-IL-22 antibodies — A small phase 2 randomized trial evaluated the efficacy and safety of intravenous fezakinumab, an IL-22 antagonist, for the treatment of atopic dermatitis [139]. Sixty adult patients with at least a six-month history of moderate to severe atopic dermatitis received fezakinumab (a loading dose of 600 mg at baseline, followed by 300 mg every two weeks) or placebo for 12 weeks and were followed for 8 additional weeks. At 12 and 20 weeks, the mean Scoring of Atopic Dermatitis (SCORAD) decrease from baseline was greater in the fezakinumab group than in the placebo group (13.8 and 18.8 points, respectively, in the fezakinumab group versus 8 and 11.7 points, respectively, in the placebo group). Adverse events occurred with similar frequency in the active treatment and placebo groups and were considered mild to moderate.

UNPROVEN THERAPIES

Complementary and alternative therapies

Probiotics — Probiotic therapy with Lactobacillus and other organisms has been studied for the treatment of atopic dermatitis in infants and children, but has proven to be of limited benefit [140-144]. In a 2009 meta-analysis of 12 randomized trials including 781 participants, probiotics were not more effective than placebo in reducing eczema symptoms and sleep disturbance [143]. 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) [145].

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 eczema [146]. 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 atopic dermatitis (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 atopic dermatitis [147-149]. 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 atopic dermatitis as a complementary and alternative medicine remedy [150,151]. However, studies of supplementation of gamma-linolenic acid for eczema have provided conflicting results [152]. 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 the placebo group [149].

Melatonin — Melatonin is a hormone produced in the pineal gland involved in the regulation of sleep and circadian rhythms (see «Physiology and available preparations of melatonin»). It has also been suggested that melatonin has antioxidant, anti-inflammatory, and immunomodulating properties [153,154]. In children and adults with atopic dermatitis, abnormal melatonin levels have been correlated with disease severity and degree of sleep disturbance [155-157].

In two small randomized trials, melatonin supplementation reduced disease severity and improved sleep in children and adolescents with atopic dermatitis [158,159]:

●In a crossover trial, 48 children with atopic dermatitis 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 [158]. 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 including 70 children of 6 to 12 years of age with atopic dermatitis 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 [159]. 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 immunoglobulin E (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 atopic dermatitis in children and adolescent.

Chinese herbal medicine — Chinese herbal medications for atopic dermatitis have been used for many years, but their efficacy and safety have not been adequately evaluated in clinical trials [160,161]. A systematic review found three small randomized trials and one open-label trial of a commercial preparation of 10 traditional Chinese herbs (Zemaphyte, no longer available) [162]. 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 significant difference between the active treatment and placebo. However, all studies were small (less than 50 patients) and had methodologic flaws. (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 atopic dermatitis 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 atopic dermatitis 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) [163]. The main outcome measure was a reduction in disease severity assessed by using validated score systems (ie, SCORAD; eczema area and severity index [EASI]; six area, six sign atopic dermatitis [SASSAD]). The pooled analysis of three studies did not show a difference between montelukast and placebo in improving disease severity (standardized mean difference 0.29, 95% CI -0.23 to 0.81) 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 [164,165]. All trials were of low quality with a significant risk of bias.

Because of the limited and low-quality available evidence, the role of leukotriene receptor antagonists in the management of atopic dermatitis remains uncertain. While waiting for larger and well-designed studies, we do not support the use of this class of agents for adults or children with atopic dermatitis.

REFERRALMany patients with atopic dermatitis 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

●When patients have failed to respond to appropriate therapy

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

●If treatment with systemic immunosuppressive agents is being considered

PREVENTION

Skin barrier enhancement — Epidermal barrier dysfunction is recognized as a key factor in the initiation and progression of atopic dermatitis. Two 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 reduce the incidence of atopic dermatitis in infants at increased risk (ie, those with a parent or sibling with atopic dermatitis) [166,167].

In the United States and United Kingdom trial, 124 neonates received daily emollients (oil, cream/gel, or ointment) on the entire body surface. At 24 weeks, the cumulative incidence of atopic dermatitis was 22 percent in the emollient group versus 43 percent in the control group, with a relative risk reduction of 49 percent.

In the Japanese study, 118 neonates at increased risk of atopic dermatitis received a daily application of an emulsion-type emollient from the first week of life or no treatment [167]. At 32 weeks, 19 of 59 infants in the emollient group and 28 of 59 in the control group had developed atopic dermatitis (32 versus 43 percent, relative risk reduction 26 percent). There were no differences between the two groups in the levels of IgE against egg white.

Although the long-term efficacy of this treatment needs to be evaluated in larger studies with extended follow-up, emollient therapy from birth is a simple, inexpensive, and safe intervention that may prevent the onset of atopic dermatitis in the first year of life. A cost-effectiveness analysis indicated that daily skin moisturization in the first six months of life is likely a cost-effective strategy for the prevention of atopic dermatitis; among several emollient products examined in the study, petrolatum was the most cost-effective [168].

Probiotics and dietary supplements — Probiotic supplementation in pregnant mothers and infants at risk for atopic dermatitis may prevent the development of the disease in children younger than three years [169]. A 2014 meta-analysis of 16 randomized trials including approximately 3500 participants found that probiotics given in the prenatal and postnatal period reduced the risk of atopic dermatitis in the first years of life in both children at high risk of atopic dermatitis and in those from the general population (pooled odds ratio [OR] 0.56, 95% CI 0.52-0.60) [170].

However, two subsequent randomized trials did not confirm this finding [171,172]. In one study, a multispecies probiotic preparation or placebo was given to 454 unselected women at 36 weeks gestation and their infants to age six months [171]. At two years, the cumulative frequency of eczema was similar in the probiotic and placebo groups (34 versus 32 percent; OR 1.07, 95% CI 0.7-1.6). In another 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 [HR] 0.95, 95% CI 0.59-1.53) [172]. The cumulative incidences of asthma at five years were also not significantly different in the two groups (10 versus 17 percent; HR 0.88, 95% CI 0.41-1.87). (See «Prebiotics and probiotics for prevention of allergic disease».)

A few small randomized trials have evaluated the role of vitamin D supplementation in the prevention of winter-related exacerbation of atopic dermatitis [173-175]. In the largest study, 107 children with a history of atopic dermatitis worsening during winter were treated with 1000 IU daily of vitamin D or placebo for one month [173]. 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.

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

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 [176,177]. However, the results of a 2016 systematic review and 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 [178]. 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 LINKSLinks 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 PATIENTSUpToDate 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

●The goals of treatment for atopic dermatitis are to reduce symptoms (pruritus and dermatitis), prevent exacerbations, and minimize therapeutic risks. (See ‘Introduction’ above.)

●The optimal management requires a multipronged approach that involves the 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 ‘General approach’ above.)

●We suggest that patients with mild to moderate atopic dermatitis be initially treated with topical corticosteroids and emollients (Grade 2B). The choice of the corticosteroid potency should be based upon the patient’s age, body area involved, and degree of skin inflammation.

•For patients with mild atopic dermatitis, we suggest a low potency (groups five and six (table 1)) corticosteroid cream or ointment (eg, desonide 0.05%, hydrocortisone 2.5%). Topical corticosteroids can be applied once or twice daily for two to four weeks.

•For patients with moderate disease, we suggest medium to high potency (groups three and four (table 1)) corticosteroids (eg, fluocinolone 0.025%, triamcinolone 0.1%, betamethasone dipropionate 0.05%). (See ‘Topical corticosteroids’ above.)

•The face and skin folds are areas that are at high risk for atrophy with corticosteroids. Initial therapy in these areas should start with a low potency corticosteroid (group VI (table 1)), such as desonide 0.05% ointment for up to three weeks. (See ‘Topical corticosteroids’ above.)

●We suggest that patients with atopic dermatitis involving the face or skin folds that is not controlled with topical corticosteroids, be treated with a topical calcineurin inhibitor (ie, tacrolimus or pimecrolimus) (Grade 2B). (See ‘Topical calcineurin inhibitors’ above.)

●We suggest proactive therapy to prevent relapse in adolescents and adults with moderate to severe (picture 1A-B) atopic dermatitis that responds to continuous therapy with topical corticosteroids or calcineurin inhibitors (Grade 2A). We suggest medium to high potency topical corticosteroids (groups three to five) (table 1) rather than topical calcineurin inhibitors for proactive intermittent therapy (Grade 2B). Topical corticosteroids are applied once daily for two consecutive days per week for up to 16 weeks. (See ‘Maintenance and prevention of relapses’ above.)

●Patients with moderate to severe atopic dermatitis that is not controlled with optimal topical therapy may require phototherapy or systemic immunosuppressant treatment to achieve adequate disease control (algorithm 1). These treatments are not suitable for infants and young children. In older children and adolescents, they should be used when other management options have failed and the disease has a significant impact on the quality of life. (See ‘Patients with moderate to severe disease’ above.)