INTRODUCTION — Atopic 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".)
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, sleep, impact on daily activities, and persistence of disease [4]. Several disease severity scales (eg, the Scoring of Atopic Dermatitis [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 [4]. 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 [5].
A practical guide to visual assessment of eczema severity that also includes the evaluation of disease impact on quality of life and psychosocial well-being has been proposed by the United Kingdom National Institute for Health and Care Excellence:
●Mild – Areas of dry skin, infrequent itching (with or without small areas of redness); little impact on everyday activities, sleep, and psychosocial well-being
●Moderate – Areas of dry skin, frequent itching, redness (with or without excoriation and localized skin thickening); moderate impact on everyday activities and psychosocial well-being, frequently disturbed sleep
●Severe – Widespread areas of dry skin, incessant itching, redness (with or without excoriation, extensive skin thickening, bleeding, oozing, cracking, and alteration of pigmentation); severe limitation of everyday activities and psychosocial functioning, nightly loss of sleep
GENERAL APPROACH — The 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) [6].
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 [7]. 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 [8]. The program consisted of two-hour weekly sessions covering medical, nutritional, and psychologic 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 of the Scoring of Atopic Dermatitis (SCORAD) score 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.
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 [9,10]. 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 [11]:
●Avoid trigger factors such as heat and 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)
●Manage 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, Dermatophagoides farinae), animal danders, molds, and pollens is thought to be associated with flares of atopic dermatitis [12,13]. However, although many atopic dermatitis patients are sensitized to house dust mites, reduction of house dust mite antigens in the atopic dermatitis patient's environment does not seem to be useful for disease control [14,15].
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 immunoglobulin E (IgE) to one or more food allergens (in particular, cow's milk, egg, wheat, and peanut), food sensitization is clinically irrelevant in most cases [16]. 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 [17]. Moreover, food restriction in toddlers may result in lower Z-scores of weight, height, head circumference, and body mass index for age [18]. One trial suggests that an egg-free diet may be helpful for infants with proven sensitivity to eggs [19].
Contact allergens — Atopic individuals are at an increased risk for developing allergic contact dermatitis (ACD) to nickel as well as to many components of topical treatments (eg, fragrances, preservatives, neomycin) [20,21]. 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. To maintain skin hydration, emollients should be applied at least two times per day and immediately after bathing or hand washing.
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, but some patients may complain that they are greasy. Lotions, although less effective than thick creams and ointments, can be an alternative for these patients.
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 but 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 [22].
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 [23,24]:
●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
Frequency of bathing — 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 [25-27]. 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 daily bathing to most patients. Whether bath or shower is preferred, rapid application of emollients and/or prescribed topical preparations immediately after is important.
A small, randomized, single-blind, crossover trial examined the effect of frequent versus infrequent bathing on atopic dermatitis. In this study, 42 children (median age 3.9 years, range 6 months to 11.5 years) with moderate to severe atopic dermatitis were randomized to two groups. Group 1 was assigned to twice-weekly, soak-and-seal baths for 10 minutes or less for two weeks (infrequent bathing) followed by twice-daily, soak-and-seal baths for 15 to 20 minutes for two weeks (frequent bathing); group 2 did the inverse [28]. 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]).
Bath additives — 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 [29,30]. 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 [2,31].
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 [32,33]. 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 [34,35]. Similar results were obtained at 52 weeks.
CONTROLLING PRURITUS — The management of atopic pruritus requires a multipronged approach that addresses the multiple factors involved in its pathogenesis [36-41]. These include:
●Skin barrier disruption
●Aberrant type 2 immune response, with increased IgE production, eosinophilia, mast cell activation, and overexpression of T helper type 2 (Th2) cytokines
●Itch mediators, such as histamine, nerve growth factor (NGF), substance P (SP), proteases, and cytokines/chemokines (eg, thymic stromal lymphopoietin [TSLP], 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 cornerstone of atopic itch management.
Tepid baths to hydrate and cool the skin, followed by application of emollients, can relieve itching. In more severe cases, the use of wet dressings (wet wraps) helps soothe the skin, reduce pruritus, and interrupts 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 [42]. 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. Antipruritic ingredients, such as phenol, menthol, and camphor, are found in some moisturizers.
Psychologic interventions, including habit reversal training, relaxation training, and cognitive behavioral therapy, have been reported as beneficial in patients with chronic pruritus [43-45].
Topical treatments — Topical anti-inflammatory therapy with topical corticosteroids or topical calcineurin 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) [46].
Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of mild to moderate atopic dermatitis in patients aged ≥3 months, appears to be effective in reducing pruritus [47]. Inhibition of PDE4 results in an increase in intracellular cyclic adenosine monophosphate, which causes a decrease in the production of pruritogenic cytokines [48].
Topical doxepin, a tricyclic antidepressant with potent H1- and H2-blocking properties, may be used as a second-line treatment if others fail [49]. However, allergic contact dermatitis to this agent is common [50].
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 [36,51,52]. 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 [53]. However, high-dose UVA1 may be more effective in reducing pruritus and other symptoms of atopic dermatitis in individuals with darker skin types [51].
Oral antihistamines — Oral H1 antihistamines are widely used as a therapeutic adjunct in patients with atopic dermatitis to alleviate pruritus [54]. 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 [55]. In one of the trials including 795 children aged one to two years with eczema, 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 (from 24.9 to 15.2 in the cetirizine group and from 25.1 to 15.7 in the placebo group) [56]. 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) [57].
Cyclosporine — The efficacy of oral cyclosporine in improving pruritus and other symptoms of atopic dermatitis has been demonstrated in several randomized trials [58,59]. Cyclosporine may be especially useful for the rapid control of pruritus associated with atopic dermatitis. However, recurrence is common upon discontinuation of treatment.
Dupilumab — Dupilumab, a fully human monoclonal antibody inhibiting IL-4 and IL-13, has been shown to rapidly and substantially improve atopic pruritus, even in patients with an unsatisfactory cutaneous response. In an analysis of patients from two randomized trials who were not clear or almost clear (Investigator's Global Assessment >1) after 16 weeks of treatment with dupilumab or placebo [60], dupilumab was more effective than placebo in improving secondary outcome measures, including pruritus (numerical rating scale -35 versus -9 percent) [61]. (See 'Dupilumab' below.)
An analysis of data from 1505 adult and adolescent patients from four randomized trials showed that the least squares mean percent change from baseline of daily Peak Pruritus Numerical Rating Scale scores was approximately -48 to -57 percent in the dupilumab groups compared with -19 to -31 percent in the placebo groups. 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 [62].
PATIENTS WITH MILD TO MODERATE DISEASE
Topical corticosteroids — 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:
●Mild disease – For patients with mild atopic dermatitis, we suggest a low-potency (groups 5 and 6 (table 1)) corticosteroid cream or ointment (eg, desonide 0.05%, hydrocortisone 2.5%). 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 [63]. (See 'Emollients and moisturizers' above.)
●Moderate disease – For patients with moderate disease, we suggest medium- to high-potency (groups 3 and 4 (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 (groups 1 to 3 (table 1)) can be used for up to two weeks and then replaced with lower-potency preparations until the lesions resolve.
●Face and skin folds – 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 6 (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. Topical calcineurin inhibitors, which do not cause skin atrophy, are an alternative to topical corticosteroids. (See 'Topical calcineurin inhibitors' below.)
●Ear canal – Topical corticosteroid-based ophthalmic solutions can be used for the treatment of atopic dermatitis involving the ear canal. (See "External otitis: Treatment", section on 'Glucocorticoids'.)
Efficacy and adverse effects — A systematic review of randomized trials identified 83 studies of topical corticosteroids for atopic dermatitis [64]. 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 [65-67].
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 [68,69].
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 those >15 years old), 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 [70,71]. (See 'Safety' below.)
Efficacy and minor side effects — Topical tacrolimus is generally recognized as being equal in strength to medium-potency (groups 4 and 5 (table 1)) topical steroids and should be considered a second-line therapy [72]. 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 [73]. Pimecrolimus 1% cream is a calcineurin inhibitor, like tacrolimus, that was developed specifically to treat inflammatory skin conditions. Although less effective than topical tacrolimus, pimecrolimus has a mechanism of action similar to topical tacrolimus and does not appear to have systemic immune effects [74]. Transient burning, erythema, and pruritus are the most common adverse effects [75].
The efficacy of tacrolimus has been demonstrated in several randomized trials and systematic reviews [68,76,77]. 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 >90 percent versus 20 percent in the vehicle group) [68]. 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) [77]. 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 [78]. However, pimecrolimus was less effective than medium-potency topical corticosteroids (triamcinolone acetonide 0.1% and betamethasone valerate 0.1%) and tacrolimus 0.1%.
Safety — Topical calcineurin inhibitors in controlled trials have appeared to be safe in adults and children [75,79-82]. Despite concerns about a possible link between topical calcineurin inhibitors and cancer [83], no definite causal relationship has been established [84], and two case-control studies did not detect an increased risk of lymphoma among patients treated with topical calcineurin inhibitors [85,86].
The results of subsequent 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 [87]. The standardized incidence ratio, 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 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 [88], 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) [89].
●A 2021 meta-analysis of eight cohort studies with over 400,000 treated participants and over 1,700,000 controls and three case-control studies with nearly 4000 cases and 14,000 controls found no association between use of topical calcineurin inhibitors and cancer overall [90]. 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 [RR] 1.86, 95% CI 1.39-2.49, and RR 1.35, 95% CI 1.13-1.61, respectively).
●A 2018, European, multicenter, cohort study that included over 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 [IRR] 3.74, 95% CI 1.00-14.06 and IRR 1.76, 95% CI 0.81-3.79, respectively) [91].
●A 2020, international, cohort study of nearly 8000 children (mean age at enrollment 7.1 years) with atopic dermatitis 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) [92].
●The risk of keratinocyte carcinoma associated with topical calcineurin inhibitors was evaluated in a 2020, United States, cohort study that included over 93,000 patients (mean age at cohort entry 58.5 years) diagnosed with atopic dermatitis from 2002 to 2013 who received at least two prescriptions for topical calcineurin inhibitors (n = 7033) or topical corticosteroids (n = 73,674) [93]. A multivariate analysis, adjusted for demographic variables, immunosuppression, exposure to systemic treatment for atopic dermatitis, ultraviolet (UV) treatment, and radiation treatment, did not show an increased risk of either squamous cell carcinoma or basal cell carcinoma among patients exposed to topical calcineurin inhibitors compared with those exposed to topical corticosteroids and unexposed patients (hazard ratio [HR] 1.02, 95% CI 0.93-1.13 and HR 1.03, 95% CI 0.92-1.14, respectively).
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 [94].
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 over 2400 infants 3 to 12 months of age with mild to moderate atopic dermatitis [95]. After five years, overall treatment success, measured by an Investigator Global Assessment (IGA) 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.
Other 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 atopic dermatitis in adults and children three months of age and older [96]. 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 [47,97-99]. 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) [99].
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 [48]. 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 endpoint (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, were mild, and were 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 [100]. 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 [48,101]. 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.
Topical ruxolitinib — Topical ruxolitinib is a Janus kinase (JAK) inhibitor approved in September 2021 by the US FDA for the short-term treatment of mild to moderate atopic dermatitis in immunocompetent patients older than 12 years whose disease is not controlled with topical prescription therapies. 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 atopic dermatitis (IGA score of 2/3) involving up to 20 percent of the body area surface [102]. 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 1 or 2 (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. No adverse events were suggestive of systemic inhibition of JAK1/JAK2 kinase.
Although topical ruxolitinib appears promising for the short-term management of atopic dermatitis, data on long-term safety and potential adverse effects due to systemic absorption are lacking. A pharmacokinetic study performed in the setting of the two clinical trials described above 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 [103].
Assessing adherence to topical treatment — Poor adherence to prescribed topical therapies is a major cause of exacerbation of atopic dermatitis. 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, the use of inadequate amounts of emollients needs consideration as an additional obstacle to treatment success [104-107].
In a Scottish, population-based study that included 844 patients with moderate to severe atopic dermatitis who failed treatment in a primary care setting, the analysis of nearly 30,000 verified prescriptions of relevant topical medications showed significant underuse. The median daily amount of emollients used was 9.6 g in adults and 17.5 g in children, and the median monthly amount of topical corticosteroids used was 47 g for male patients and 30 g for female patients, roughly corresponding to an average daily use of 0.5 to 2 g [105].
Maintenance and prevention of relapses — 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 in adolescents and adults with mild to moderate atopic dermatitis (picture 1A-B) that responds to continuous therapy with topical corticosteroids or calcineurin inhibitors (algorithm 1). The steroid or topical calcineurin inhibitor should be applied once daily to previously affected skin areas for two consecutive days per week (eg, 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 [2,31,108-110].
In infants and young children with moderate to severe atopic dermatitis (picture 2) who have frequent flares, proactive, intermittent therapy with low-potency topical corticosteroids (groups 6 and 7 (table 1)) may be beneficial in preventing relapse [111]. The steroid should be applied once daily to previously affected skin areas for two consecutive days per week (eg, 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 [112]. 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) [112]. 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) [112]. Adverse effects included pruritus, burning sensation, skin infections, and bronchopneumonia. In addition, four patients developed a cancer. (See 'Safety' 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). To avoid rebound flare, topical therapy should be resumed while tapering systemic glucocorticoids. 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 DISEASE
Our approach — Patients with persistent, moderate to severe disease despite optimal topical therapy will require a systemic treatment to achieve adequate disease control [3,58,113]. The choice of treatment is based on evidence of efficacy, safety, availability, patient preference, and cost considerations. Our approach is illustrated in the algorithm (algorithm 1):
●We suggest dupilumab rather than other systemic agents as first-line therapy in most adult and pediatric patients with moderate to severe atopic dermatitis that is not controlled by topical therapies.
●Narrowband ultraviolet B (NBUVB) phototherapy is an alternative first-line therapy for adults and adolescents with moderate to severe atopic dermatitis, if available and acceptable to the patient (see 'Phototherapy' below). Phototherapy is not suitable for infants and young children. Disadvantages of phototherapy include cost and need for multiple office visits per week.
Phototherapy — NBUVB is a treatment option for moderate to severe atopic dermatitis in adults and adolescents [3,114,115] (see "UVB therapy (broadband and narrowband)"):
●Administration – Phototherapy is usually administered in the office two to three times per week. Topical corticosteroids can be 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. (See "Treatment of psoriasis in adults", section on 'Home phototherapy'.)
●Efficacy – Phototherapy for the treatment of moderate to severe atopic dermatitis has been evaluated in a limited number of randomized trials and systematic reviews. In a 2013 systematic review of 19 randomized trials including 905 patients, medium-dose ultraviolet A1 (UVA1; 30 to 60 J/cm2) and NBUVB were more effective than other phototherapy modalities in reducing the clinical signs and symptoms of atopic dermatitis as measured with several clinical scores [51]. Observational studies indicate that NBUVB is associated with long-term remission and reduced use of topical corticosteroids as well as oral corticosteroids and antihistamines following NBUVB treatment [116,117].
●Adverse effects – Short-term adverse effects of UVB phototherapy include erythema, skin dryness, pruritus, blistering, and increased frequency of recurrent herpes simplex. Prolonged treatment may lead to an increased risk of melanoma and nonmelanoma skin cancer (table 2) [118-120].
Systemic therapies — Several systematic reviews and meta-analyses have evaluated the efficacy of systemic therapies for atopic dermatitis [121-123]:
●A network meta-analysis of 74 randomized trials with over 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 and improving the Patient-Oriented Eczema Measure (POEM) score during short-term follow-up when compared with placebo (risk ratio [RR] 3.04, 95% CI 2.51-3.69 and mean difference 7.3, 95% CI 6.61-8.00, respectively) [121]. 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.
●Another network meta-analysis of 39 randomized trials (6360 patients) indicated that higher-dose cyclosporine (3 to 5 mg/kg per day) and dupilumab (600 mg as first dose, then 300 mg every two weeks) were similarly effective compared with placebo in clearing the clinical signs of atopic dermatitis and may be superior to methotrexate and azathioprine [122].
Impact of COVID-19 pandemic — The coronavirus disease 2019 (COVID-19) pandemic has led medical professional organizations, including the American Academy of Dermatology, to issue provisional guidelines regarding the use of systemic immunomodulatory drugs and biologic agents during the pandemic [124-126]. General information on the use of systemic immunomodulatory therapies during the COVID-19 pandemic is provided elsewhere. (See "COVID-19: Management in hospitalized adults", section on 'Immunomodulatory agents'.)
Biologic agents
Dupilumab — Dupilumab is an interleukin (IL) 4/IL-13 receptor antagonist approved by the US Food and Drug Administration (FDA) for the treatment of adults and children aged six months and older with moderate to severe atopic dermatitis that is not adequately controlled with topical prescription therapies [127].
Dupilumab is also an option for patients who are not candidates for or failed previous treatment with conventional immunosuppressive agents, such as cyclosporine, methotrexate, mycophenolate mofetil, or azathioprine. Compared with conventional immunosuppressive agents, dupilumab has a favorable safety profile and may be used for long-term treatment of atopic dermatitis [128-130]. However, cost may be a major consideration with dupilumab.
Administration — Dupilumab is administered as subcutaneous injections two weeks apart. In adults, an initial 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 [127].
Topical corticosteroids are usually continued as needed during treatment with dupilumab.
Efficacy — 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 are believed to play a key role in atopic diseases, including asthma and atopic dermatitis. Multiple randomized trials in adults and children have documented its efficacy in the treatment of moderate to severe atopic dermatitis:
●Studies in adults – The efficacy of dupilumab for the treatment of atopic dermatitis in adults has been evaluated in several randomized trials, prospective cohort studies, and meta-analyses:
•Dupilumab 300 mg or placebo given by subcutaneous injection weekly or every other week was evaluated in two phase 3 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 [60]. At 16 weeks, more patients in the dupilumab groups than in the placebo groups achieved the primary endpoint of an Investigator's Global Assessment (IGA) score of clear or almost clear (approximately 40 versus 10 percent). 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. Exacerbation of atopic dermatitis was reported overall in three patients receiving dupilumab and in eight patients receiving placebo.
•Of note, in an analysis of patients from the two trials described above who were not clear or almost clear (IGA >1) at week 16 [60], dupilumab, compared with placebo, induced a 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) [61].
•The long-term efficacy and safety of dupilumab was subsequently evaluated in a randomized, double-blind, multicenter trial (LIBERTY AD CHRONOS) [128]. 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 including patients enrolled in previous randomized trials who continued treatment with dupilumab 300 mg weekly confirmed a sustained efficacy of dupilumab over time, 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 [129]. 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 atopic dermatitis in a real-life setting, treatment with dupilumab for 16 weeks induced a mean reduction of the EASI score of 73 percent [131]. A 50 percent reduction in the Eczema Area and Severity Index (EASI-50) score, EASI-75, and EASI-90 were 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.
●Studies in children and adolescents – Studies of dupilumab in children and adolescents with atopic dermatitis are limited [132-134]:
•In a phase 3, randomized trial, 251 adolescents aged 12 to 18 years with moderate to severe atopic dermatitis were treated with dupilumab 200 or 300 mg every two weeks, dupilumab 300 mg every four weeks, or placebo for 16 weeks [132]. 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 atopic dermatitis, 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).
•A 16-week, phase 3, randomized trial examined the efficacy and safety of dupilumab plus topical corticosteroids in children [134]. In this study, 367 children aged 6 to 11 years with severe atopic dermatitis 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 than in the placebo group achieved the coprimary endpoints (IGA score of 0 to 1 or EASI-75) at week 16 (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 65 to 67 percent in the dupilumab groups. Injection site reactions and conjunctivitis were more common with dupilumab; severe reactions leading to treatment discontinuation occurred in two patients in the placebo group (asthma and exacerbation of atopic dermatitis) and in two patients in the dupilumab groups (food allergy and urinary tract infection).
Adverse effects — Frequent adverse effects of dupilumab include injection site reactions, conjunctivitis, and facial redness. Other adverse events include antibody development against the drug, eosinophilia, herpes simplex virus infection, joint pain, and a psoriasis-like eruption [135]:
●Ocular adverse effects – Dupilumab-induced ocular surface disease (DIOSD) has been reported in approximately 11 percent of patients with atopic dermatitis participating in randomized trials of dupilumab and in up to 26 percent of patients in prospective or real-life studies [136-138]. DIOSD includes conjunctivitis and, infrequently, keratitis, eye dryness, burning or stinging, pruritus, blepharitis, and blurred vision [139]. In most cases, DIOSD appeared in the first weeks or months of treatment, was generally mild or moderate, and resolved with continued dupilumab treatment [136].
●Seronegative arthritis and enthesitis/enthesopathy – There have been several reports of psoriasis and inflammatory arthritis and enthesitis associated with dupilumab treatment, in most cases occurring during the first few months of treatment [140-142]. 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 T helper type 17 (Th17) diseases, including spondyloarthropathy-pattern arthritis, psoriasiform skin disease, and occasional anterior uveitis [143].
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) [144]. 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 [141].
●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 [145-147]. This reaction has also been reported in children and adolescents treated with dupilumab [148,149].
The pathogenesis of the dupilumab-induced head and neck dermatitis is unclear. It may represent a hypersensitivity reaction, a site-specific treatment failure, a seborrheic dermatitis-like or rosacea-like reaction, or an allergic contact dermatitis [147].
Topical corticosteroids, topical calcineurin inhibitors, and topical and systemic antifungals have been used in a few patients with dupilumab facial redness with variable results [146,147,150]. No worsening or progression to a generalized reaction has been noted upon continuation of dupilumab therapy.
Tralokinumab — Tralokinumab is a fully human monoclonal anti-IL-13 antibody approved in Europe and the United States for the treatment of adults with moderate to severe atopic dermatitis that is not adequately controlled with topical prescription therapies.
The efficacy of tralokinumab as monotherapy or in combination with topical corticosteroids has been evaluated in randomized trials:
●In two identical, randomized trials (ECZTRA 1 and ECZTRA 2), 1596 adult patients with atopic dermatitis who were candidates for systemic therapy received subcutaneous tralokinumab 300 mg as monotherapy or placebo every other week for 16 weeks [151]. 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 atopic dermatitis 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 [152]. 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 atopic dermatitis, 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).
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 atopic dermatitis in adults whose disease is not controlled with other systemic therapies, including biologics, or when the use of those therapies is not indicated:
●In a phase 3, randomized trial, 387 patients aged 12 years or older with moderate to severe atopic dermatitis received oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks [153]. 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 atopic dermatitis, 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 atopic dermatitis 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 [154]. 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 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) [155]. 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.
Upadacitinib — Upadacitinib is an oral selective Janus kinase (JAK) inhibitor approved in the United States, Europe, and other countries for the treatment of atopic dermatitis 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 [156].
Three multicenter, randomized trials evaluated the efficacy of upadacitinib in adults and adolescents with moderate to severe atopic dermatitis as monotherapy or in combination with topical corticosteroids versus placebo [157,158] and versus dupilumab [159]:
●In two replicate, multicenter trials, 847 and 836 patients with moderate to severe atopic dermatitis were randomized to receive oral upadacitinib 15 or 30 mg daily or placebo as monotherapy [157]. At 16 weeks in both studies, more patients in the upadacitinib groups than in the placebo groups achieved the primary endpoint of EASI-75 (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, elevation of creatine phosphokinase, and worsening of atopic dermatitis.
●In a separate multicenter trial, 901 adults and adolescents with moderate to severe atopic dermatitis 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 [158]. At 16 weeks, more patients in the upadacitinib 15 and 30 mg plus topical corticosteroids groups than in the placebo plus topical corticosteroids group achieved EASI-75 (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 and included acne, upper respiratory infections, nasopharyngitis, headache, elevation of creatine phosphokinase, and worsening of atopic dermatitis.
●In a subsequent randomized trial, 692 adult patients with moderate to severe atopic dermatitis were randomized to receive upadacitinib 30 mg orally once daily or subcutaneous dupilumab 300 mg every 2 weeks for 24 weeks as monotherapy [159]. More patients in the upadacitinib group than those 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 atopic dermatitis. 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.
Safety concerns — Long-term studies of the safety of oral JAK inhibitors in patients with atopic dermatitis are lacking. Data from a large, randomized safety trial of patients with rheumatoid arthritis indicate that oral JAK inhibitors (eg, tofacitinib, abrocitinib, upadacitinib) may increase the risk of serious infections, major cardiovascular events (eg, heart attack, stroke), cancer (eg, lymphoma, lung cancer), thrombosis, and death [160]. In the United States and Canada, warnings regarding these risks have been added to prescription drug information [156,161-163]. Benefits and risks should be evaluated in individual patients prior to initiating treatment with oral JAK inhibitors.
Nontargeted immunosuppressive agents
Cyclosporine — Oral cyclosporine is a short-term treatment option for patients with moderate to severe atopic dermatitis (algorithm 1) [58,113]. Cyclosporine 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. (See 'Topical corticosteroids' above and 'Maintenance and prevention of relapses' above.)
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 for the most severe cases that failed to respond to optimal 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'.)
Efficacy and adverse effects — 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 days to 8 weeks) [58]. In head-to-head trials, cyclosporine was more effective than prednisolone, intravenous immunoglobulins, and phototherapy with ultraviolet A (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".)
Methotrexate — Methotrexate is a treatment option for the long-term control of moderate to severe atopic dermatitis in adults and, less frequently, in adolescents and children [164]. In adults and adolescents, methotrexate is usually administered in a single weekly dose of 7.5 to 25 mg in combination with daily supplementation with folic acid 1 mg to reduce the risk of several common methotrexate toxicities. 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 atopic dermatitis is discussed separately. (See "Management of severe 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 atopic dermatitis [164-167].
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 atopic dermatitis, both agents were equally effective in reducing the SCORAD score at five years [166]. 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 atopic dermatitis.
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 atopic dermatitis, more patients in the cyclosporine group than in the methotrexate group achieved the primary endpoint of a 50 percent reduction of SCORAD at eight weeks (42 versus 8 percent, respectively) [165].
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 side effects of low-dose methotrexate".)
Other agents — Second-line systemic immunosuppressive agents for the long-term treatment of atopic dermatitis include 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".)
PATIENTS WITH SEVERE REFRACTORY DISEASE — The 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 PATIENTS — The management of atopic dermatitis during pregnancy is discussed separately [168]. (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 INFECTION — Patients 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 nonlesional skin (95% CI 31-47) [169]. 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 [170]. 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 [169].
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, for infection that does not respond to treatment, or if there is concern about antimicrobial resistance or clinical suspicion of unusual organisms [171].
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 [108]. 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 [172-174]. Since sodium hypochlorite 6% solution (liquid chlorine bleach) has activity against S. aureus, including methicillin-resistant Staphylococcus 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 [175].
However, studies evaluating the efficacy of bleach baths for atopic dermatitis have been scarce and inconsistent [176-178]. 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 [179]. 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 [180].
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 [181,182]. 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 was primarily 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 [183]. Cases of life-threatening dissemination have been reported, and intravenous antiviral therapy may be necessary in severe cases [183]. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults".)
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 [184]. Elevated Malassezia-specific IgE levels have been reported in these patients [184]. Treatment may result in improvement. (See "Role of allergy in atopic dermatitis (eczema)", section on 'Malassezia'.)
ALLERGEN IMMUNOTHERAPY — Allergen immunotherapy (AIT) is a treatment option for patients with proven sensitization to house dust mites (eg, positive, allergen-specific in vitro test or skin testing; exacerbation upon natural exposure to the allergen) and eczema 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.
In a meta-analysis of 23 randomized trials that 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, AIT resulted in significant patient-important improvements [185]. Specifically, patients receiving add-on AIT were more likely to experience a 50 percent reduction of Scoring of Atopic Dermatitis (SCORAD; risk ratio [RR] 1.53, 95% CI 1.31-1.78) and improvement in Dermatology Life Quality Index (DLQI) of ≥4 points (RR 1.44, 95% CI 1.03-2.01). SCIT and SLIT had similar relative and absolute beneficial effects. Effects on sleep disturbance and eczema 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 atopic dermatitis 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".)
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. Tofacitinib, baricitinib, and other JAK inhibitors are being investigated for the treatment of atopic dermatitis:
●Topical tofacitinib – The efficacy of topical tofacitinib for the treatment of atopic dermatitis has been evaluated in a phase 2a, randomized trial [186]. 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 endpoint 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.
●Baricitinib – In a 16-week, phase 2, randomized trial that included 124 adults with moderate to severe atopic dermatitis, more patients treated with baricitinib 4 mg per day plus topical corticosteroids achieved a 50 percent reduction in the Eczema Area and Severity Index (EASI-50) score from baseline compared with placebo (61 versus 37 percent) [187]. Baricitinib also improved pruritus and sleep. Adverse events related to baricitinib included headache, increased blood levels or creatine phosphokinase, decrease in the neutrophil count, and nasopharyngitis.
In two subsequent, 16-week, phase 3 trials (BREEZE-AD1 and BREEZE-AD2) including a total of 1239 adults with moderate to severe atopic dermatitis, more patients treated with baricitinib 2 mg and 4 mg per day 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) [188]. 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.
Topical and oral JAK inhibitors seem to be promising treatments for atopic dermatitis. Studies of longer durations are needed to evaluate their long-term efficacy and safety.
Anti-IL-31 antibodies (nemolizumab) — Nemolizumab is a humanized monoclonal antibody against the receptor A of IL-31, a newly discovered cytokine associated with chronic skin inflammation and pruritus [189]. Several studies indicated that nemolizumab may be effective in controlling pruritus associated with atopic dermatitis [190-192]:
●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 [191]. In this study, 264 patients received subcutaneous nemolizumab at a dose of 0.1, 0.5, 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, 0.5, 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, 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 atopic dermatitis and respiratory tract infections.
●The efficacy of nemolizumab in reducing pruritus associated with atopic dermatitis was confirmed in a subsequent Japanese randomized trial that included 215 patients aged 13 years or older with atopic dermatitis and moderate to severe pruritus [192]. Patients received subcutaneous nemolizumab 60 mg or placebo every four weeks for 16 weeks, plus topical therapy for atopic dermatitis (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 occurred in three patients (atopic dermatitis exacerbation, Meniere's disease, alopecia, and peripheral edema).
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 type 2 (Th2) cytokine that is likely to play a role in the pathogenesis of barrier dysfunction and inflammation in atopic dermatitis, asthma, and pulmonary fibrosis [193]. Lebrikizumab has been investigated for the treatment of asthma with inconsistent results [194-196].
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 (single dose), or 125 mg or placebo every four weeks as an add-on to topical corticosteroid treatment [197]. At 12 weeks, more patients in the lebrikizumab 125 mg every four weeks group achieved the primary endpoint (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.
In a phase 2, randomized trial, 280 adult patients with moderate to severe atopic dermatitis were treated with lebrikizumab 125 mg every four weeks, 250 mg every four weeks, 250 mg every two weeks, or placebo every two weeks for 16 weeks [198]. Rescue therapy with topical corticosteroids was allowed. Compared with placebo, all lebrikizumab groups showed a dose-dependent, statistically significant reduction in the EASI score at week 16. Common adverse effects in the lebrikizumab groups included upper respiratory tract infection, nasopharyngitis, headache, injection site pain, and fatigue.
The results of these studies indicate that lebrikizumab in combination with topical corticosteroids may provide some additional benefit compared with topical corticosteroids alone; however, its efficacy as long-term monotherapy for atopic dermatitis needs further confirmation.
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 [199]. 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) score 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 [200-204]. 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 [203]. 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) [205].
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 [206]. 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 [207-209]. 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 [210,211]. However, studies of supplementation of gamma-linolenic acid for eczema have provided conflicting results [212]. 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 groups [209].
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 [213,214]. In children and adults with atopic dermatitis, abnormal melatonin levels have been correlated with disease severity and degree of sleep disturbance [215-217].
In two small, randomized trials, melatonin supplementation reduced disease severity and improved sleep in children and adolescents with atopic dermatitis [218,219]:
●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 [218]. 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 [219]. 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 atopic dermatitis in children and adolescents.
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 [220,221]. 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) [222]. 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 groups. 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) [223]. 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 [224,225]. 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.
REFERRAL — Many 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
●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 atopic dermatitis. (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 reduces the incidence of atopic dermatitis in infants at increased risk (ie, those with a parent or sibling with atopic dermatitis) [226,227]. In a cost-effectiveness analysis, petrolatum was the most cost-effective emollient [228].
However, several subsequent, randomized trials, including the large United Kingdom BEEP multicenter trial and the Norwegian PreventADALL trial, did not confirm these findings [229-232]. A 2021 meta-analysis that used individual participant data from 10 randomized trials or parallel group studies (5154 participants), most of which were at low risk of bias, concluded that skin moisturizing in the early weeks of life is not effective in the prevention of eczema and food allergy at age one to three years [233,234]:
●For the primary outcome of eczema diagnosis at one to two years, the analysis of pooled individual patient data from 3075 participants in seven studies showed no effect of emollients on the risk of atopic dermatitis (relative risk [RR] 1.03, 95% CI 0.81-1.31, moderate quality of evidence).
●Subgroup analysis showed that family history of allergic disease, FLG mutation, type of emollient, and duration of emollient use did not have an impact on the risk of developing eczema.
●For the coprimary outcome of IgE-mediated food allergy by age one to two years, confirmed by oral food challenge at two years of age, data were available for 996 participants in one study and favored standard care (RR 2.53, 95% CI 0.99-6.47). The quality of evidence was considered very low, due to missing data and imprecision due to the small number of events from a single study and wide confidence interval.
●For adverse events, skin infections occurred more frequently in children in the emollient group than in those in the standard care group (RR 1.34, 95% CI 1.02-1.77, pooled data from 2728 participants in six studies).
Based on the results of this meta-analysis, daily skin moisturization in the first months of life probably does not influence the risk of developing atopic dermatitis and may be associated with an increased risk of skin infections. However, sensible skin care, which may include emollient use, should be continued for newborns at high risk of atopic dermatitis, 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, using emollients in tubes rather than jars, which can be more easily contaminated).
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 [235]. 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) [236].
However, two subsequent, randomized trials did not confirm this finding [237,238]. 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 [237]. 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) [238]. 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 [239-241]. In the largest study, 107 children with a history of atopic dermatitis worsening during winter were treated with 1000 international units daily of vitamin D or placebo for one month [239]. 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 [242,243]. 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 [244]. 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 5th to 6th 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 10th to 12th 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 treatment of atopic dermatitis 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:
•Initial treatment – 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. (See 'Topical corticosteroids' above.)
For patients with atopic dermatitis involving areas at high risk of atrophy (eg, face, skin folds), we suggest treatment with topical calcineurin inhibitors (Grade 2B). (See 'Topical calcineurin inhibitors' above.)
•Second-line therapies – Second-line treatment options for mild to moderate disease include crisaborole (adults and children) and topical ruxolitinib (adults and children older than 12 years). (See 'Other treatments' above.)
•Proactive therapy – We suggest proactive therapy with topical corticosteroids or topical calcineurin inhibitors to prevent relapse in adolescents and adults with mild to moderate atopic dermatitis (picture 1A-B) that responds to continuous topical therapy (Grade 2B). Topical corticosteroids or topical calcineurin inhibitors 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 disease – We suggest dupilumab rather than nontargeted immunosuppressant agents (eg, cyclosporine, methotrexate) as first-line treatment for adult and pediatric patients with moderate to severe disease unresponsive to topical therapy alone (algorithm 1) (Grade 2A). Tralokinumab, abrocitinib, and upadacitinib are newly approved agents that may be an alternative treatment option for adult patients with inadequate response to dupilumab. (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. Phototherapy is usually administered in the office two to three times per week. Topical corticosteroids and emollients can be continued as needed during phototherapy. (See 'Phototherapy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William L Weston, MD, who contributed to an earlier version of this topic review.
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28 : Frequent Versus Infrequent Bathing in Pediatric Atopic Dermatitis: A Randomized Clinical Trial.
79 : Successful treatment of resistant facial lesions of atopic dermatitis with 0.1% FK506 ointment.
80 : Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part I, efficacy.
