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Treatment of atopic dermatitis (eczema)

Authors: William L Weston, MD, William Howe, MD
Section Editors: Robert P Dellavalle, MD, PhD, MSPH, Moise L Levy, MD, Joseph Fowler, MD
Deputy Editor: Rosamaria Corona, MD, DSc

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jun 2021. | This topic last updated: Apr 15, 2021.

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 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

Initial treatment — Topically applied corticosteroids and emollients are the mainstay of

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

Topical corticosteroids — For patients with mild atopic dermatitis, we suggest a low-

potency (groups 5 and 6 ( table 1)) corticosteroid cream or ointment (eg, desonide 0.05%,
hydrocortisone 2.5%) ( algorithm 1). Topical corticosteroids are applied one or two times per
day for two to four weeks. Emollients should be liberally used multiple times per day in
conjunction with topical corticosteroids. Emollients can be applied before or after topical
corticosteroids [63]. (See 'Emollients and moisturizers' above.)

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.

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 corticosteroid-based ophthalmic solutions can be used for the treatment of atopic
dermatitis involving the ear canal. (See "External otitis: Treatment".)

Maintenance therapy that includes intermittent use of a topical corticosteroid or a topical

calcineurin inhibitor may help prevent relapse. (See 'Maintenance and prevention of relapses'
below.)
 Efficacy and adverse effects — A systematic review of randomized trials identified 83
studies of topical corticosteroids for atopic dermatitis [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 'Long-term safety concerns' 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%.

Long-term safety concerns — Although the topical calcineurin inhibitors in controlled

trials have appeared to be safe in adults and children [75,79-82], in 2005, based upon case
reports, animal studies, and the known risks with systemic calcineurin inhibitors, the FDA issued
warnings about a possible link between the topical calcineurin inhibitors and cancer [83] and, in
2006, placed a boxed warning on the prescribing information for these medications [84].

Issues of concern include:

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

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

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

However, no definite causal relationship has been established [85], and two case-control studies
did not detect an increased risk of lymphoma among patients treated with topical calcineurin
inhibitors [86,87]. 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 [88]. 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 [89], 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) [90].

● A 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 subsequent, 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).

Although most cohort studies do not indicate an increased risk of lymphoma or other cancers
with topical calcineurin inhibitors, the following FDA recommendations seem reasonable
precautions [94,95]:

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

other treatments.

● Avoid the use of these agents in children <2 years of age.

● Continuous, long-term use of topical calcineurin inhibitors in any age group should be
avoided, and application should be limited to areas of involvement with atopic dermatitis.

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

Providers and patients will need to weigh the risks and benefits of topical calcineurin inhibitors
in comparison with those of other therapies. In particular, calcineurin inhibitors may continue
to have an important role in the management of atopic dermatitis in areas at high risk for skin
atrophy when treated with corticosteroids (eg, face) [96].

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 [97].

A five-year, industry-sponsored, randomized trial evaluated the safety and long-term efficacy of
pimecrolimus 1% cream compared with low-potency (1% hydrocortisone) or medium-potency
(0.1% hydrocortisone butyrate) topical corticosteroids in over 2400 infants 3 to 12 months of
age with mild to moderate atopic dermatitis [98]. After five years, overall treatment success,
measured by an investigator global assessment score, was achieved in approximately 89
percent of children in the pimecrolimus group and 92 percent in the topical corticosteroid
group. Vaccine responsiveness, growth, immune function, and cancer rates were similar in the
two groups. The overall rates of adverse events were also similar in the two groups, although
episodes of bronchitis, infected eczema, impetigo, and nasopharyngitis were slightly more
frequent in the pimecrolimus group than in the topical corticosteroid group.

Since the rates of cutaneous adverse events (eg, skin irritation, atrophy, telangiectasias) were
not reported in this trial, the advantage of using pimecrolimus rather than low- to mid-potency
topical corticosteroids for infants with mild to moderate atopic dermatitis remains unclear.

Crisaborole — Crisaborole is a boron-based, small molecule, topical phosphodiesterase 4

(PDE4) inhibitor approved by the FDA for the treatment of mild to moderate atopic dermatitis in
adults and children three months of age and older [99]. 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 [47,100-102]. 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) [102].

Two subsequent, phase III, 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 [103]. 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 [48,104]. 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.

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 [105-108].

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 [106].

Maintenance and prevention of relapses — We suggest proactive therapy to prevent relapse

in adolescents and adults with moderate to severe atopic dermatitis ( picture 1A-B) that
responds to continuous therapy with topical corticosteroids or calcineurin inhibitors (
algorithm 1). After induction of remission, we suggest intermittent therapy with moderate-
to high-potency topical corticosteroids (groups 3 to 5) ( table 1). 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. 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 [2,31,109-111].
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 [112]. 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 [113]. 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) [113]. 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) [113]. Adverse effects included pruritus, burning
sensation, skin infections, and bronchopneumonia. In addition, four patients developed a
cancer. (See 'Long-term safety concerns' above.)

Treatment of acute exacerbations — In adolescents and adults, an acute exacerbation of

chronic atopic dermatitis can sometimes be aborted by a short course of systemic
glucocorticoids (eg, prednisone 40 to 60 mg/day for three to four days, then 20 to 30 mg/day
for three to four days). 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

Patients with persistent, moderate to severe disease despite optimal topical therapy may
require phototherapy or systemic immunomodulatory therapy to achieve adequate disease
control [3,58,114]. (See 'Phototherapy' below and 'Systemic therapies' below.)
Evidence on the efficacy and safety of phototherapy and systemic therapies for young children
is limited. These treatments should be used only when other management options have failed
and the disease has a significant impact on the quality of life [115]. (See "Management of severe
atopic dermatitis (eczema) in children".)

Phototherapy — Narrowband ultraviolet B (NBUVB), broadband ultraviolet B (UVB), ultraviolet

A1 (UVA1), or psoralens plus ultraviolet A (PUVA) radiation phototherapy are treatment options
for moderate to severe atopic dermatitis [3,116,117]. (See "UVB therapy (broadband and
narrowband)" and "UVA1 phototherapy" and "Psoralen plus ultraviolet A (PUVA)
photochemotherapy".)

We suggest NBUVB phototherapy rather than other forms of phototherapy as first-line therapy
for adult patients with moderate to severe atopic dermatitis that is not controlled with topical
therapy ( algorithm 1). Phototherapy is usually administered 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.

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

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 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].

Disadvantages of phototherapy include cost and need for multiple office visits per week.
Moreover, prolonged treatment may lead to an increased risk of melanoma and nonmelanoma
skin cancer [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'.)

Dupilumab — We suggest dupilumab, rather than conventional immunosuppressant

agents, for patients with moderate to severe disease unresponsive to topical therapy alone for
whom phototherapy is not feasible or acceptable. 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 [127,128]. However, cost may be a
major consideration with dupilumab.

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
years and in adolescents, dosing is based on body weight. For patients <60 kg, the initial dose is
400 mg, followed by a maintenance dose of 200 mg every other week; for patients ≥60 kg, the
initial dose is 600 mg, followed by a maintenance dose of 300 mg every other week.

Topical corticosteroids are usually continued as needed during treatment with dupilumab.

Efficacy and adverse effects — Dupilumab is a fully human monoclonal antibody that

binds to the alpha subunit of the interleukin (IL) 4 receptor and inhibits downstream signaling
of IL-4 and IL-13, cytokines of type 2 helper T lymphocytes (Th2) that are believed to play a key
role in atopic diseases, including asthma and atopic dermatitis. 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 III trials of identical design, SOLO1 and SOLO2, which included
671 and 708 adult patients with long-standing, moderate to severe atopic dermatitis not
controlled by topical treatments, respectively [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) [127]. 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 [128].
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 [129]. 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 [130-132]:

● In a phase III, 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 [130]. 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 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 III, randomized trial examined the efficacy and safety of dupilumab plus
topical corticosteroids in children [132]. 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).

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 [133-
135]. This reaction has also been reported in children and adolescents treated with dupilumab
[136,137].

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 [135].

Topical corticosteroids, topical calcineurin inhibitors, and topical and systemic antifungals have
been used in a few patients with dupilumab facial redness with variable results [134,135,138].
No worsening or progression to a generalized reaction has been noted upon continuation of
dupilumab therapy.

Cyclosporine — Oral cyclosporine is a short-term treatment option for patients with

moderate to severe atopic dermatitis ( algorithm 1) [58,114]. 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 'Initial treatment' 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 [139]. 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 [139-142].

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 Scoring of Atopic Dermatitis
(SCORAD) score at five years [141]. 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) [140].

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 immunosuppressive 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 WOMEN

The management of atopic dermatitis during pregnancy is discussed separately [143]. (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) [144]. 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 [145]. 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 [144].

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 [146].

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 [109]. 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 [147-149]. 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 [150].

However, studies evaluating the efficacy of bleach baths for atopic dermatitis have been scarce
and inconsistent [151-153]. 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 [154]. 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 [155].

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
[156,157]. 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 [158]. Cases of life-threatening dissemination have been reported, and intravenous
antiviral therapy may be necessary in severe cases [158]. (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 [159]. Elevated Malassezia-
specific IgE levels have been reported in these patients [159]. Treatment may result in
improvement. (See "Role of allergy in atopic dermatitis (eczema)", section on 'Malassezia'.)

IMMUNOTHERAPY

Allergen-specific immunotherapy (SIT) with dust mite extract in sensitized patients with atopic
dermatitis has been studied using both subcutaneous immunotherapy (SCIT) and sublingual
immunotherapy (SLIT) administration with conflicting results [160-163]. A meta-analysis of eight
randomized trials including 385 patients that compared SIT (mostly using house dust mite
allergens) with placebo found that patients in the SIT group were more likely to experience
treatment success, as assessed by patients or investigators, than those in the placebo group
(odds ratio [OR] 5.35, 95% CI 1.61-17.77) [164]. However, there was considerable heterogeneity
among studies regarding types, doses, and pharmaceutical preparations of allergens;
treatment schedules and duration; patients' age and disease severity; and assessment of
outcome. Although this meta-analysis suggests that SIT improves the course of atopic eczema,
it is unclear which patients may benefit from this form of treatment. SIT may be a treatment
option for patients with proven sensitization to house dust mites (eg, positive allergen-specific
test, exacerbation upon natural exposure to the allergen) and severe eczema that is not
controlled with conventional therapies [165]. (See "Subcutaneous immunotherapy (SCIT) for
allergic disease: Indications and efficacy".)

EXPERIMENTAL AGENTS

JAK inhibitors — Tofacitinib and baricitinib are oral small-molecule Janus kinase (JAK) inhibitors
approved for the treatment of rheumatoid arthritis that block multiple cytokine signaling,
including interleukin (IL) 4, IL-5, and IL-13, involved in immune response and inflammation.
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 IIa, randomized trial [166]. 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.

● Abrocitinib − Abrocitinib, an oral JAK-1 selective inhibitor, has been investigated for the
treatment of atopic dermatitis in adults and adolescents [167,168]:

• In a phase III, 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 [167]. At 12 weeks, more patients in the abrocitinib 100
and 200 mg groups than in the placebo group achieved the Investigator's Global
Assessment (IGA) of clear or almost clear (24, 44, and 8 percent, respectively) and a 75
percent reduction in the Eczema Area and Severity Index (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 12-week, phase III, 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 [169]. 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, and conjunctivitis.

● Baricitinib – In a 16-week, phase II, 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)
[170]. 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 III 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) [171]. 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.  

● Upadacitinib − A 16-week, randomized trial evaluated the efficacy of the selective JAK-1
inhibitor upadacitinib given orally at the dose of 7.5, 15, or 30 mg or placebo in 167 patients
with moderate to severe atopic dermatitis [172]. The percentage improvement of EASI from
baseline was 39, 62, and 74 percent for the upadacitinib 7.5, 15, and 30 mg groups,
respectively, versus 23 percent for the placebo group. Adverse events occurred in 71 to 79
percent of patients in the upadacitinib groups and 63 percent in the placebo group and
included respiratory infections, worsening of atopic dermatitis, and acne.

Although topical and oral JAK inhibitors seem to be promising treatments for atopic dermatitis,
larger 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 [173]. Several studies indicated that nemolizumab may be effective
in controlling pruritus associated with atopic dermatitis [174-176]:

● A phase II, 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 [175]. 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 [176]. 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 2 cytokine that is likely to play a role in the pathogenesis of
barrier dysfunction and inflammation in atopic dermatitis, asthma, and pulmonary fibrosis
[177]. Lebrikizumab has been investigated for the treatment of asthma with inconsistent results
[178-180].

In a proof-of-concept, phase II, 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 [181]. 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 II, 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 [182]. 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 II, randomized trial evaluated the efficacy and safety of
intravenous fezakinumab, an IL-22 antagonist, for the treatment of atopic dermatitis [183]. 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
[184-188]. 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
[187]. 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)
[189].

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 [190]. 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 [191-
193]. 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 [194,195]. However, studies of supplementation of gamma-
linolenic acid for eczema have provided conflicting results [196]. 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 [193].

Melatonin — Melatonin is a hormone produced in the pineal gland involved in the

regulation of sleep and circadian rhythms (see "Physiology and available preparations of
melatonin"). It has also been suggested that melatonin has antioxidant, anti-inflammatory, and
immunomodulating properties [197,198]. In children and adults with atopic dermatitis,
abnormal melatonin levels have been correlated with disease severity and degree of sleep
disturbance [199-201].

In two small, randomized trials, melatonin supplementation reduced disease severity and
improved sleep in children and adolescents with atopic dermatitis [202,203]:

● 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 [202].
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 [203]. 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 [204,205]. 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) [206]. 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) [207]. 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 [208,209]. 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

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) [210,211]. In a cost-
effectiveness analysis, petrolatum was the most cost-effective emollient [212].
However, several subsequent, randomized trials, including the large United Kingdom BEEP
multicenter trial and the Norwegian PreventADALL trial, did not confirm these findings [213-
216]. 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 [217,218]:

● 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 [219]. 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) [220].

However, two subsequent, randomized trials did not confirm this finding [221,222]. 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 [221]. 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) [222].
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 [223-225]. 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 [223]. 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 [226,227]. 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 [228]. 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

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

● The optimal management requires a multipronged approach that involves the elimination
of exacerbating factors, restoration of the skin barrier function and hydration of the skin,
patient education, and pharmacologic treatment of skin inflammation ( algorithm 1). (See
'General approach' above.)

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

• For patients with mild atopic dermatitis, we suggest a low-potency (groups 5 and 6 (
table 1)) corticosteroid cream or ointment (eg, desonide 0.05%, hydrocortisone
2.5%). Topical corticosteroids can be applied once or twice daily for two to four weeks.

• For patients with moderate disease, we suggest medium- to high-potency (groups 3

and 4 ( table 1)) corticosteroids (eg, fluocinolone 0.025%, triamcinolone 0.1%,
betamethasone dipropionate 0.05%). (See 'Topical corticosteroids' above.)

• The face and skin folds are areas that are at high risk for atrophy with corticosteroids.
Initial therapy in these areas should start with a low-potency corticosteroid (group 6 (
table 1)), such as desonide 0.05% ointment for up to three weeks. (See 'Topical
corticosteroids' above.)

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

● We suggest proactive therapy to prevent relapse in adolescents and adults with moderate
to severe atopic dermatitis ( picture 1A-B) that responds to continuous therapy with
topical corticosteroids or calcineurin inhibitors (Grade 2A). We suggest medium- to high-
potency topical corticosteroids (groups 3 to 5 ( table 1)) rather than topical calcineurin
inhibitors for proactive, intermittent therapy (Grade 2B). Topical corticosteroids are applied
once daily for two consecutive days per week for up to 16 weeks. (See 'Maintenance and
prevention of relapses' above.)

● We suggest dupilumab, rather than conventional immunosuppressant agents, for patients

with moderate to severe disease unresponsive to topical therapy alone for whom
phototherapy is not feasible or acceptable (Grade 2A). Dupilumab is also an option for
patients who are not candidates for or failed previous treatment with conventional
immunosuppressive agents ( algorithm 1). Dupilumab, phototherapy, and conventional
immunosuppressive agents are not suitable for infants and young children. In children
older than six years and adolescents, they should be used when optimal topical therapy has
failed and the disease has a significant impact on the quality of life. (See 'Patients with
moderate to severe disease' above.)

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Topic 1730 Version 86.0
GRAPHICS

Management of atopic dermatitis

For examples of low-, medium-, and high-potency topical corticosteroids, please refer to the UpToDate table on topical
corticosteroids.

TCS: topical corticosteroid; TCI: topical calcineurin inhibitor.

* Trigger/exacerbating factors:
Irritants (soaps, detergents)
Skin infections (Staphylococcus aureus, herpes simplex)
Contact, inhalant, or food allergens
¶ Mild atopic dermatitis – Areas of dry skin, infrequent itching (with or without small areas of redness); little impact on everyday
activities, sleep, and psychosocial wellbeing.

Δ Moderate atopic dermatitis – Areas of dry skin, frequent itching, redness (with or without excoriation and localized skin thickening);
moderate impact on everyday activities and psychosocial wellbeing, frequently disturbed sleep.

◊ Severe atopic dermatitis – 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.

§ Crisaborole is approved for mild to moderate atopic dermatitis in adults and children >3 months.

¥ TCIs are approved for mild to moderate atopic dermatitis in adults and children >2 years. TCIs include tacrolimus and pimecrolimus.

‡ Dupilumab is approved for moderate to severe atopic dermatitis in adults and children ≥12 years whose disease is not adequately
controlled with topical prescription therapies.

Graphic 115549 Version 4.0

Comparison of representative topical corticosteroid preparations (classified according to the
United States system)

Available
Brand names
strength(s),
Potency group* Corticosteroid Vehicle type/form
(United States) percent

(except as noted)

Super-high potency
Betamethasone Gel, lotion, ointment Diprolene 0.05
(group 1) dipropionate, (optimized)
augmented

Clobetasol propionate Cream, gel, ointment, Temovate 0.05

solution (scalp)

Cream (emollient base) Temovate E ¶ 0.05

Lotion, shampoo, spray Clobex 0.05

aerosol

Foam aerosol Olux, Olux-E, Tovet 0.05

Lotion Impeklo 0.05

Ointment Clobetavix 0.05

Shampoo Clodan 0.05

Solution (scalp) Cormax ¶ 0.05

Diflucortolone valerate Ointment, oily cream Nerisone Forte (United 0.3

(not available in United Kingdom, others)
States)

Fluocinonide Cream Vanos 0.1

Flurandrenolide Tape (roll) Cordran 4 mcg/cm 2

Halobetasol propionate Cream, lotion, Ultravate 0.05

ointment

High potency
Amcinonide Ointment Cyclocort ¶, Amcort ¶ 0.1
(group 2)
Betamethasone Ointment Diprosone ¶ 0.05
dipropionate
Cream, augmented Diprolene AF 0.05
formulation (AF)

Clobetasol propionate Cream Impoyz 0.025

Desoximetasone Cream, ointment, spray Topicort 0.25

Gel Topicort 0.05

Diflorasone diacetate Ointment ApexiCon ¶, Florone ¶ 0.05

Cream, emollient ApexiCon E 0.05

Fluocinonide Cream, gel, ointment, Lidex ¶ 0.05

solution

Halcinonide Cream, ointment, Halog 0.1

solution

Halobetasol propionate Lotion Bryhali 0.01

High potency
Amcinonide Cream Cyclocort ¶, Amcort ¶ 0.1
(group 3)
Lotion Amcort ¶ 0.1

Betamethasone Cream, hydrophilic Diprosone ¶ 0.05

dipropionate emollient

Betamethasone Ointment Valisone ¶ 0.1

 valerate Foam Luxiq 0.12

Desoximetasone Cream Topicort LP ¶ 0.05

Diflorasone diacetate Cream Florone ¶ 0.05

Diflucortolone valerate Cream, oily cream, Nerisone (Canada, 0.1

(not available in United ointment United Kingdom,
States) others)

Fluocinonide Cream aqueous Lidex-E ¶ 0.05

emollient

Fluticasone propionate Ointment Cutivate ¶ 0.005

Mometasone furoate Ointment Elocon 0.1

Triamcinolone Cream, ointment Aristocort HP ¶, 0.5

acetonide Kenalog ¶, Triderm

Medium potency
Betamethasone Spray Sernivo 0.05
(group 4) dipropionate

Clocortolone pivalate Cream Cloderm 0.1

Fluocinolone acetonide Ointment Synalar ¶ 0.025

Flurandrenolide Ointment Cordran 0.05

Fluticasone propionate Cream Cutivate ¶ 0.05

Hydrocortisone Ointment Westcort 0.2

valerate

Mometasone furoate Cream, lotion, Elocon ¶ 0.1

ointment, solution

Triamcinolone Cream Kenalog ¶, Triderm 0.1

acetonide
Ointment Kenalog ¶ 0.1

Ointment Trianex 0.05

Aerosol spray Kenalog 0.2 mg per 2 second

spray

Dental paste Oralone 0.1

Lower-mid potency
Betamethasone Lotion Diprosone ¶ 0.05
(group 5) dipropionate

Betamethasone Cream Beta-Val, Valisone ¶ 0.1

valerate

Desonide Ointment DesOwen, Tridesilon ¶ 0.05

Gel Desonate 0.05

Fluocinolone acetonide Cream Synalar ¶ 0.025

Flurandrenolide Cream, lotion Cordran 0.05

Fluticasone propionate Lotion Cutivate 0.05

Hydrocortisone Cream, lotion, Locoid, Locoid 0.1

butyrate ointment, solution Lipocream

Hydrocortisone Cream Pandel 0.1

probutate

Hydrocortisone Cream Westcort ¶ 0.2

valerate

Prednicarbate Cream (emollient), Dermatop 0.1

ointment

Triamcinolone Lotion Kenalog ¶ 0.1

acetonide
Ointment Kenalog ¶ 0.025
 Low potency
Alclometasone Cream, ointment Aclovate 0.05
(group 6) dipropionate

Betamethasone Lotion Beta-Val ¶, Valisone ¶ 0.1

valerate

Desonide Cream DesOwen, Tridesilon ¶ 0.05

Lotion DesOwen, LoKara 0.05

Foam Verdeso 0.05

Fluocinolone acetonide Cream, solution Synalar ¶ 0.01

Shampoo Capex 0.01

Oil Δ Derma-Smoothe/FS 0.01

Body, Derma-
Smoothe/FS Scalp

Triamcinolone Cream, lotion Kenalog ¶, Aristocort ¶ 0.025

acetonide

Least potent
Hydrocortisone (base, Cream, ointment Hytone, Nutracort ¶ 2.5
(group 7) ≥2%)
Lotion Hytone, Ala Scalp, 2
Scalacort

Solution Texacort 2.5

Hydrocortisone (base, Ointment Cortaid, Cortizone 10, 1

<2%) Hytone, Nutracort

Cream Cortaid ¶, Cortizone 10, 1

Hytone, Synacort

Gel Cortizone 10 1

Lotion Aquanil HC, Sarnol-HC, 1

Cortizone 10

Spray Cortaid 1

Solution Cortaid, Noble, Scalp 1

Relief

Cream, ointment Cortaid 0.5

Hydrocortisone acetate Cream MiCort-HC 2.5

Lotion Nucort 2

* Listed by potency according to the United States classification system: group 1 is the most potent, group 7 is the least potent. Other
countries use a different classification system with only 4 or 5 groups.

¶ Inactive United States brand name for specific product; brand may be available outside United States. This product may be available
generically in the United States.

Δ 48% refined peanut oil.

Data from:
1. Lexicomp Online. Copyright © 1978-2021 Lexicomp, Inc. All Rights Reserved.
2. Tadicherla S, Ross K, Shenefelt D. Topical corticosteroids in dermatology. Journal of Drugs in Dermatology 2009; 12:1093.
3. U.S. Food & Drug Administration Approved Drug Products with Therapeutic Equivalence (Orange Book). Available at:
https://www.accessdata.fda.gov/scripts/cder/ob/default.cfm (Accessed on June 18, 2017).
4. The British Association of Dermatologists' information on topical corticosteroids – established and alternative proprietary names,
potency, and discontinuation. British Association of Dermatologists. Available at: https://www.bad.org.uk/shared/get-file.ashx?
id=3427&itemtype=document (Accessed on April 26, 2021).

Graphic 62402 Version 61.0

Adult atopic dermatitis

Chronic atopic dermatitis with lichenification (skin thickening and enhancement of skin markings)
of the knee flexures in a 22-year-old female.

Copyright © Monica Standish, RN, Dermatlas; http://www.dermatlas.org.

Graphic 64525 Version 5.0

Adult chronic atopic dermatitis

Lichenified, hyperpigmented plaque in the elbow flexure of a 35-year-old female with atopic

dermatitis.

Copyright © Yusoff Saifuzzaman, MD, Dermatlas; http://www.dermatlas.org.

Graphic 55375 Version 6.0

Atopic dermatitis: Infantile

Confluent erythema, microvesiculation, scaling, and crusting on the face, with similar
involvement (to a lesser degree) on the trunk and arms.

Reproduced with permission from: Fitzpatrick TB, Johnson RA, Wolff K, et al (Eds). Color Atlas and
Synopsis of Clinical Dermatology, 3rd ed, McGraw-Hill, New York, 1997. Copyright © McGraw-Hill.

Graphic 77457 Version 7.0

Staphylococcus aureus infection in atopic dermatitis

Pustules and honey-colored crusting are seen on the dorsal hand of this patient with
infected atopic dermatitis.

Courtesy of Joseph Morelli, MD.

Graphic 74056 Version 3.0

Staphylococcus aureus infection in atopic dermatitis

Honey-colored crusts are seen on the postauricular skin of this patient with infected
atopic dermatitis.

Courtesy of Joseph Morelli, MD.

Graphic 62234 Version 3.0

Eczema herpeticum

Punched-out ulcers are due to herpes simplex virus infection present on the arm of
this patient with underlying atopic dermatitis.

Reproduced with permission from: Fleisher GR, Ludwig S, Baskin MN. Atlas of Pediatric Emergency
Medicine, Lippincott Williams & Wilkins, Philadelphia 2004. Copyright ©2004 Lippincott Williams &
Wilkins.

Graphic 51337 Version 4.0

Eczema herpeticum

Hemorrhagic crusts and vesicles due to herpes simplex virus infection are present on
the hand of this infant with underlying atopic dermatitis.

Reproduced with permission from: Fleisher GR, Ludwig S, Baskin MN. Atlas of Pediatric Emergency
Medicine, Lippincott Williams & Wilkins, Philadelphia 2004. Copyright © 2004 Lippincott Williams
& Wilkins.

Graphic 74838 Version 5.0

Eczema herpeticum

Hemorrhagic crusts and vesicles due to herpes simplex virus infection are present on
the face of this infant with underlying atopic dermatitis.

Reproduced with permission from: Fleisher GR, Ludwig S, Baskin MN. Atlas of Pediatric Emergency
Medicine, Lippincott Williams & Wilkins, Philadelphia 2004. Copyright © 2004 Lippincott Williams
& Wilkins.

Graphic 64142 Version 5.0

Molluscum contagiosum in a patient with atopic dermatitis

Lesions are present on a background of atopic dermatitis of the flexural creases.

Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of Common Skin
Disorders, 2nd ed, Lippincott Williams & Wilkins 2003. Copyright © 2003 Lippincott Williams &
Wilkins.

Graphic 57836 Version 3.0

