Atopic dermatitis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Atopic dermatitis is a chronic, relapsing disease, and educating patients and their families is necessary so that they develop an understanding of basic skin care and how to avoid trigger factors.[77][78] Pay specific attention to adolescents with atopic dermatitis and ensure they are aware of the principles of topical treatment and its proper use.[79]

Treatment is carried out in a stepwise approach starting with emollients and typically progressing to topical corticosteroids and/or calcineurin inhibitors.[45][80] [ ] Newer options for topical therapy include the phosphodiesterase-4 (PDE4) inhibitor crisaborole and the topical Janus kinase (JAK) inhibitor ruxolitinib.[81] Symptom control is achieved in most patients following this approach, but those with treatment-resistant dermatitis require ultraviolet (UV) light therapy or systemic therapies. Systemic therapy options include oral drugs (immunosuppressants, corticosteroids, JAK inhibitors) and injectables (biologics).[81] Most patients will use evidence-based topical therapies, including emollients and topical anti-inflammatory medications, concomitantly with phototherapy and systemic therapies.[81]

If a patient has a history of allergy to food (e.g., exacerbation of atopic dermatitis after consumption of egg), is under 5 years old with moderate to severe atopic dermatitis, and has not responded to initial treatment (i.e., patient education and optimal skin care, including topical corticosteroids), food allergy testing using oral food challenge or trial elimination diet should be considered.[51][54][55] Food allergy testing independent of a history of allergy is not recommended.[51][54][55]

Repeated courses of oral corticosteroids are not advocated in the treatment of atopic dermatitis; systemic corticosteroid use should be reserved exclusively for acute, severe exacerbations and as a short-term bridge to other systemic corticosteroid-sparing therapies.[81] Adverse effects of systemic corticosteroid therapy include hypertension, weight gain, glucose intolerance, adrenal suppression, and potential decreased linear growth in children.[82]

Optimizing treatment

Poorly managed disease has a significant impact on mood, sleep, relationships, school, and work life.[83] Patients, parents, and caregivers should be offered information on how to recognize flares of atopic dermatitis, and given clear instructions on how to manage flares.[45]

One systematic review and synthesis of qualitative studies reported four analytical themes expressed by people with atopic dermatitis:[84]

Atopic dermatitis is often not viewed as a chronic condition, which impairs effective management
The significant psychosocial impact of atopic dermatitis is not acknowledged by others
Hesitancy on the part of healthcare providers is communicated to patients with regards to treating atopic dermatitis
There is insufficient information and advice about treatments available.

The conclusions of the systematic review suggested that self-management of atopic dermatitis could be improved by addressing beliefs and concerns about treatments, including a promotion of a "control not cure" message.[84]

Emollients for all patients

Emollients rehydrate and improve the barrier function of the skin, and are an essential part of the daily skincare regimen for all patients.[80][85] [ ] Emollients alone may be sufficient to manage symptoms in a few patients. In all other patients, they are used in combination with other treatments. Emollients should be used in large amounts and more often than other treatments, both when atopic dermatitis is clear and while using all other treatments.[45] Regular use of emollient therapy has a demonstrated corticosteroid-sparing effect.[50]

Emollients may contain a humectant (e.g., glycol or urea) that promotes hydration of the stratum corneum and an occlusive agent (e.g., petrolatum) that reduces evaporation. Newer emollients may contain lipids at levels that mimic endogenous composition, or ceramides or filaggrin breakdown products.

By decreasing the dryness and improving the barrier function of the skin, emollients can improve symptoms of itch and pain, in addition to decreasing exposure to bacteria and sensitizing antigens. Individual preference determines choice; the selected emollient should not contain additives or sensitizing agents (e.g., fragrances or perfumes).[50]

There is insufficient evidence to determine whether one emollient is better than another.[80][85] However, increased lipid content is associated with improved hydration of the skin. Petrolatum effectively prevents water loss and may reduce T-cell-associated inflammation in atopic skin.[86]

Addition of wet wrap therapy

In children and adults with moderate to severe atopic dermatitis, the addition of wet wrap therapy to the topical regimen can result in faster resolution of symptoms.[85][87] Wet wrap therapy may help by occluding the topical agent for increased penetration, reducing water loss, and acting as a physical barrier against scratching.[85]

American Academy of Dermatology (AAD) guidelines make a conditional recommendation for the use of wet wrap therapy in adults with moderate to severe atopic dermatitis experiencing a flare, caveating that most data are from pediatric populations. They note that wet wrap therapy requires increased time and effort, as well as patient education, so the benefit in mild disease relative to the effort required is questionable.[85]

UK guidelines recommend that occlusive dressings (including wet wrap therapy) can be used for localized or whole-body treatment of chronic lichenified atopic dermatitis in children in addition to emollients, or emollients and topical corticosteroids.[45]

Localized dressings with emollients and corticosteroids should only be used for the short term (7-14 days).
Whole-body dressing should only be initiated by a specialist, using topical corticosteroids for 7-14 days, but can be continued with emollients alone until the symptoms are controlled.

The use of a wet wrap therapy in addition to calcineurin inhibitors should only be undertaken with specialist advice.[45]

Topical corticosteroids

Topical corticosteroids have been the mainstay of atopic dermatitis treatment for decades, and are the definitive standard to which all other treatments are compared.[85] The use of adequate topical corticosteroid therapy is considered when lesions do not respond to regular moisturizer use and appropriate skin care alone, and an assessment of all topical therapy has been completed.[85]

Topical corticosteroids reduce inflammation and pruritus, and are often used in short bursts for flares of atopic dermatitis. Patients are started on low- to medium-potency topical corticosteroids and may only require intermittent use on affected areas.[85] Patients who do not respond may require a higher-potency corticosteroid preparation during flares and continuous use of milder forms for maintenance therapy.[88] If symptoms are not controlled, a higher-potency corticosteroid preparation may have to be used for maintenance therapy.

While some guidelines recommend once-daily dosing of topical corticosteroids, many of the medications are approved for twice-daily (or more frequent) dosing by the Food and Drug Administration (FDA), depending on the corticosteroid. Similar efficacy has been reported for once-daily and twice-daily (or more frequent) use of potent topical corticosteroids to treat flares.[89]

Topical corticosteroids should be applied once or twice daily; the potency of the preparation should be tailored to the severity of atopic dermatitis, and may vary according to body site:[45][85]

Mild potency for mild atopic dermatitis
Moderate potency for moderate atopic dermatitis
Potent for severe atopic dermatitis
Face and neck: use mild potency, except for short-term (3-5 days) use of moderate potency for severe flares
Flares in vulnerable sites (e.g., axillae and groin): moderate or potent preparations for short periods only (7-14 days)
Very high-potency topical corticosteroids can be effective in short courses for controlling flares of severe atopic dermatitis in adults. Very potent preparations should not be used for children without specialist advice.

A different topical corticosteroid of the same potency should be considered as an alternative to stepping up treatment if tachyphylaxis is suspected.[45] Once the flare has settled, treating problem areas with topical corticosteroids twice weekly to prevent further flares could be considered for patients who experience frequent flares (e.g., 2 or 3 per month).[45][85][89] Available data indicate fewer relapses and increased time between relapses with this strategy.[85]

Concordance

Parents and caregivers may express concern regarding the use of topical corticosteroids and be reluctant to use these agents on their child's skin.[90][91] Ensuring that caregivers are aware of the mechanism of action of the corticosteroid, its efficacy and safety, and how to reduce the dose may contribute to improved treatment.[92] Patients can be informed that the FDA has approved several formulations of topical corticosteroid for infants ≥3 months of age who have atopic dermatitis.

Adverse effects of topical corticosteroids

The incidence of adverse events with topical corticosteroids is low.[85] Using the lowest-potency formulation that effectively treats a patient's dermatitis will help to minimize these. Hydrocortisone butyrate lotion has been shown to be safe and effective in children ages over 3 months.[93]

Cutaneous adverse effects of topical corticosteroids include skin atrophy, hypopigmentation, striae, purpura, focal hypertrichosis, acneiform eruptions, and telangiectasias.[85] Skin atrophy is generally the most concerning for physicians and patients. Risk factors for atrophy include higher-potency topical corticosteroid use, occlusion, use on thinner and intertriginous skin, older patient age, and long-term continuous use. Allergic contact dermatitis to topical corticosteroids or other ingredients in their formulations can be determined via patch testing.[85] The related concepts of topical steroid addiction (TSA) and topical steroid withdrawal (TSW) are less clearly characterized in the literature, with low strength of evidence reported in systematic reviews.[94][95]

Systemic adverse effects associated with topical corticosteroid use are rare, but may include hypothalamic-pituitary-adrenal axis suppression, reduction of linear growth rate, diabetes, Cushing syndrome, and reduction of bone density.[85][96] These events usually occur in patients using large amounts of potent corticosteroids continuously for prolonged periods.[85] An association with cataracts or glaucoma is unclear, but minimizing periocular corticosteroid use is advised.[85] Children are at increased risk of systemic adverse effects because of their increased body surface area to weight ratio, and lower-potency formulations should be used whenever possible.

Potency

Percentages included in the name of the corticosteroid do not correlate with its strength, so it is important to understand the potency of the individual corticosteroids.[97] Topical corticosteroids are graded according to their potency.[98]

Low-potency: hydrocortisone, desonide
Mid-potency: fluticasone, triamcinolone, fluocinolone
High-potency: mometasone, betamethasone, desoximetasone
Very high-potency: clobetasol, halobetasol, diflorasone.

Topical calcineurin inhibitors

If there is a need for daily topical corticosteroids to maintain control of atopic dermatitis (and particularly if there is facial atopic dermatitis with eyelid involvement), a topical calcineurin inhibitor (e.g., pimecrolimus, tacrolimus) may be considered, either as monotherapy or in combination with a topical corticosteroid.[85]

Topical calcineurin inhibitors should be used by physicians who are experienced in treating atopic dermatitis. Pimecrolimus 1% and tacrolimus 0.03% can be used in patients ages 2 years or older, and tacrolimus 0.1% can be used in patients ages 16 years or older.

In one meta-analysis, calcineurin inhibitors were found to be the most effective topical agent in lessening pruritus associated with atopic dermatitis.[99] Another systematic review of 20 trials reported that tacrolimus (0.1%) was more effective than pimecrolimus, tacrolimus (0.03%), and low-potency corticosteroids.[100] In addition, tacrolimus (0.03%) was found to be superior to mild corticosteroids and pimecrolimus.[100] [ ]

Adverse effects of topical calcineurin inhibitors

The most common adverse reactions seen with the use of calcineurin inhibitors are erythema, pruritus and skin irritation, or skin burning at the site of application.[50]

There is a theoretical risk of malignancy in patients using topical calcineurin inhibitors. The FDA recognizes that a causal relationship has not been confirmed, while advising that the long-term safety of these drugs has not been established, and recommending limiting their use to affected areas and avoiding long-term use when possible.

A prospective evaluation of the long-term safety of topical calcineurin inhibitors in approximately 8000 pediatric patients with atopic dermatitis (44,629 person-years) reported six confirmed incident cancers.[101] The cancer incidence was as expected, given matched background data (standardized incidence ratio 1.01, 95% CI 0.37 to 2.20); no lymphomas were reported. The study concluded that pediatric patients using a calcineurin inhibitor for atopic dermatitis are not at increased risk of developing malignancies.[101] Conversely, a subsequent systematic review to evaluate the risk of lymphoma associated with topical calcineurin inhibitor treatment concluded that the use of either topical tacrolimus or topical pimecrolimus significantly increased the risk of lymphoma.[102] Subgroup analyses showed that both topical tacrolimus and topical pimecrolimus significantly increased risk of non-Hodgkin lymphoma, but found no increased risk of Hodgkin lymphoma.[102]

Topical crisaborole

Crisaborole, a topical nonsteroidal anti-inflammatory PDE4 inhibitor, is approved in the US for the management of mild to moderate atopic dermatitis in patients ages 3 months and older.[85] It does not have marketing authorization in Europe or the UK. It has been shown to improve disease severity and pruritus.[103][104][105] Adverse effects include application-site reactions (pain, burning, pruritus, stinging, and erythema); treatment-related adverse reactions are typically mild to moderate.[104] Crisaborole is typically used twice daily; however, one randomized controlled trial found that, compared with ointment containing no drug, long-term maintenance treatment with once-daily application of crisaborole resulted in delayed onset of first flare, greater number of flare-free days, and decreased number of flares in patients who had previously responded to twice-daily application, suggesting that once-daily application could be a potential long-term maintenance treatment option.[106]

Topical ruxolitinib

Ruxolitinib is a topical JAK inhibitor. Medications in this group have the potential to reduce inflammation and improve pruritus, without the skin thinning associated with topical corticosteroid use.[107][108][109][110]

Topical ruxolitinib is approved in the US for the short-term and noncontinuous chronic treatment of mild to moderate atopic dermatitis in immunocompetent patients older than 12 years whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.[111]

US guidelines differ in their recommendations regarding ruxolitinib. American Academy of Dermatology (AAD) guidelines include it in their treatment algorithm, whereas American College of Allergy, Asthma and Immunology guidelines do not recommend it, citing concerns about the potential for serious adverse effects due to systemic absorption.[75][85][111] The body surface area limitation for topical ruxolitinib is up to 20% due to these safety concerns.[85][112]

Topical ruxolitinib is not currently approved for this indication in Europe.[50]

Antimicrobials and antiseptics

Oral antibiotics should only be used when there is evidence of cutaneous infection (e.g., cellulitis, impetigo).[50][81] A topical antibiotic should be considered first if the infection is limited.[113] [ ]

AAD guidelines conditionally recommend against the use of topical antimicrobials and topical antiseptics to treat uninfected atopic dermatitis in adults.[85] For patients with moderate to severe atopic dermatitis and clinical signs of secondary bacterial infection, bleach baths or the use of topical sodium hypochlorite may be suggested to reduce disease severity.[85]

Phototherapy (UV therapy)

UV phototherapy is frequently used in the management of moderate to severe generalized atopic dermatitis. It exerts beneficial effects through immunosuppressive, immunomodulating, and anti‐inflammatory actions.

Several forms of phototherapy are available for disease and symptom control, but comparative studies are limited, with low-certainty conclusions.[114] With respect to efficacy, the AAD does not differentiate between the different types of phototherapy; choice is informed by factors including availability, patient skin type, and patient use of photosensitizing medications. Narrow-band UVB is the most widely used form of phototherapy in the US.[81] AAD guidelines do not recommend psoralen plus UVA (PUVA) due to insufficient evidence.[81]

Patients are treated two to three times weekly until clearance is achieved, at which point spacing between treatments is progressively increased, and treatment is often stopped altogether. Most regimens require treatments for 10-14 weeks; this requires a substantial time commitment for patients and may not be feasible depending on the distance required to travel, as well as school, work or other responsibilities.[81]

Management of hand atopic dermatitis will include consideration of patch testing, optimization of topical therapy, and possibly the need for phototherapy. If hand atopic dermatitis does not improve with phototherapy, a systemic drug such as alitretinoin may be added.[115]

Phototherapy is rarely used in children. European guidelines advise that it can be used after assessment of skin type, but that frequent and/or protracted treatment cycles should be avoided.[50] In the UK, phototherapy should only be considered for children with severe atopic dermatitis when other management options have failed, or are inappropriate.[45]

A small proportion of patients will experience a flare in atopic dermatitis with both sunlight and phototherapy. Common phototherapy adverse effects include: actinic damage, local erythema and tenderness, pruritus, burning, and stinging.[81] Phototherapy should not be used in patients with a history of skin cancer or with an increased risk of skin cancer (including photodamaged skin and those on systemic immunosuppressants).[50] Topical calcineurin inhibitors should not be used concomitantly with phototherapy.[116]

Systemic therapy

The International Eczema Council advises starting systemic therapy if:[117]

The patient has moderate to severe atopic dermatitis that has not responded to topical therapy and phototherapy (disease severity measured using a score such as the Eczema Area and Severity Index [EASI])
Adequate education has been provided, including discussion of possible steroid phobia
Infection has been excluded and allergy has been considered including, if indicated, patch testing or referral to allergy services.

Systemic therapies must be used under the guidance of a specialist.[118] Include assessment of severity and quality of life, while considering the individual's general health status, psychological needs, and personal attitudes toward systemic therapies when deciding to start systemic medication.[117]

Systemic treatments can be divided into the following categories:

Biologics

US and European guidelines recommend dupilumab as a suitable first-line treatment option for most patients who require systemic treatment.[50][81]
Tralokinumab is an alternative to dupilumab.[50][81]

Oral Janus kinase (JAK) inhibitors

JAK inhibitors (e.g., upadacitinib, abrocitinib, baricitinib) are used in patients with moderate to severe atopic dermatitis who are refractory to (or unable to have) other systemic therapies.[81]

Conventional systemic treatments

Broad-acting immunosuppressant agents are used for atopic dermatitis with reported efficacy in moderate to severe disease.[117] Agents include cyclosporine, methotrexate, and azathioprine. Mycophenolate can be used in patients with refractory atopic dermatitis and those with adverse effects to initial systemic agents.

Choice of therapy is determined by onset and severity of symptoms (e.g., cyclosporine may be used in an acute, severe flare due to rapid onset of action and the patient may then be switched to another agent when disease has been controlled), sex (methotrexate may be avoided in women of childbearing age planning to conceive), comorbidities (cyclosporine is avoided in renal impairment, methotrexate is avoided if liver fibrosis is present or in renal impairment), and patient choice.

In an acute severe flare, cyclosporine or a short rescue course of an oral corticosteroid can be useful due to their rapid onset of action. The patient may be switched to another agent once disease is controlled. Systemic corticosteroids are not recommended for the long-term treatment of atopic dermatitis due to their adverse effects, although guidelines concede that clinicians might consider short courses in limited circumstances, such as when no other options are available, or as a bridge to other long-term therapies.[50][81]

Dupilumab

A fully human monoclonal antibody that blocks interleukin (IL)-4 and IL-13, critical cytokines that are thought to be involved in the atopic dermatitis pathway.[119]

Dupilumab is approved for the treatment of moderate to severe atopic dermatitis in adults and children ≥6 months of age whose disease is not adequately controlled with topical prescription therapies (or when those therapies are not advisable).[50][81]
The efficacy of dupilumab for moderate to severe atopic dermatitis is supported by data from large randomized trials.[120][121][122] Compared with standard of care, there is high-certainty evidence that dupilumab decreases Scoring of Atopic Dermatitis (SCORAD) value, EASI, and pruritus and improves quality of life in adult patients with atopic dermatitis.[123] Efficacy outcomes are similar in adolescents.
One Cochrane network analysis found that dupilumab is the most effective biologic treatment for atopic dermatitis.[124] [ ] Evidence for most standard systemic agents (e.g., azathioprine, methotrexate) was weak. Another network meta-analysis found that dupilumab has similar efficacy to higher-dose cyclosporine and that both are more effective for short-term (up to 16 weeks) treatment of adult patients with atopic dermatitis than methotrexate and azathioprine.[125]
Clinical response is seen in 4-6 weeks.[126] Results from one cohort study indicate that patient-reported benefits of rapid and sustained disease may be maintained for up to 12 months.[127]
Has an excellent safety track record in clinical trials and few major emergent safety concerns.[81] Adverse effects include ocular problems (particularly conjunctivitis), injection-site reactions, upper respiratory tract infections, arthralgia, and oral herpes.[128] For most patients, conjunctivitis is self-limited and can be managed conservatively.[81]
Can be used in combination with topical corticosteroids, topical calcineurin inhibitors, and UV light therapy.[50]
No laboratory monitoring is required before initiation or during treatment.[50][81]

Tralokinumab

A fully human monoclonal antibody that blocks IL-13.[50][81]

Approved for the treatment of moderate to severe atopic dermatitis in patients ages 12 years and older whose disease is not adequately controlled with topical prescription therapies (or when those therapies are not advisable).[50][81]
Clinical response seen in 4-8 weeks.[126]
In two 52-week, double-blind, placebo-controlled, phase 3 trials, adults with moderate to severe atopic dermatitis were randomized to subcutaneous tralokinumab or placebo. Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment. The majority of week 16 tralokinumab-responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication.[129] In another phase 3 trial, tralokinumab was associated with a significant reduction in atopic dermatitis severity in adolescents, compared with placebo.[130]
A further phase 3 double-blind, placebo-controlled study evaluated the efficacy and safety of tralokinumab in combination with topical corticosteroids as required in patients with moderate to severe atopic dermatitis.[131] Significant improvements were reported at week 16 in the treatment group versus placebo. Progressive and sustained improvements in atopic dermatitis signs, symptoms, and health-related quality of life were seen at 32 weeks.[132]
There are no head-to-head studies comparing tralokinumab with other systemic therapies.[81] In network meta-analysis, it was somewhat less effective than dupilumab at 16 weeks of treatment, with differences in change in EASI score within the minimal clinically important difference threshold.[133]
No major safety concerns have been identified in clinical trials. Conjunctivitis is a common adverse effect (though appears to be less of a problem than with dupilumab); for most patients it is self-limited and can be managed conservatively.[50][81] Other reported adverse effects include viral upper respiratory tract infections and injection-site reactions.[134]
No laboratory monitoring required before initiation or during treatment.[50][81]

JAK inhibitors

Target the JAK signaling pathway, which is used by cytokines to trigger inflammation. JAK inhibition has been reported to attenuate chronic itch and improve skin barrier function by regulating the expression of the skin barrier protein filaggrin.[50]

Evidence from systematic reviews demonstrates that JAK inhibitors are effective for treating atopic dermatitis, significantly reducing EASI and pruritus scores, and improving quality of life.[135][136]
Abrocitinib and upadacitinib are selective JAK1 inhibitors that are approved as a second-line treatment for adults with moderate to severe atopic dermatitis who have not responded to other systemic therapies (or when use of those therapies is inadvisable).[50][81] In phase 3 studies, upadacitinib used both as monotherapy and in combination with topical corticosteroids met all primary and secondary endpoints at week 16.[137][138] Data from long-term follow-up suggested that upadacitinib was effective at 52 weeks with no new adverse effects.[139] In phase 3 double-blind, placebo-controlled RCTs, monotherapy with abrocitinib was effective and well-tolerated in adults with moderate to severe atopic dermatitis.[140][141][142]
Baricitinib, a JAK1/2 inhibitor, is an alternative second-line systemic treatment for adults and children ages ≥2 years with moderate to severe atopic dermatitis and is approved for use in Europe but not the US.[81][136] No head-to-head clinical trials have been done; however, network meta-analysis suggests baricitinib is less efficacious than upadacitinib and abrocitinib.[133]
Adverse events associated with JAK inhibitors include an increased risk of serious and opportunistic infections (including herpes zoster), cardiac events, cancer, blood clots, and death. The European Medicines Agency advises that JAK inhibitors should only be used in the following patient groups when there are no suitable alternatives: those ages 65 years and older; those at increased risk of major cardiovascular problems (such as heart attack or stroke); those who smoke or who have a long past smoking history; and those at increased risk of cancer. Cautious use is also recommended in patients with other known risk factors for venous thromboembolism.[143] The FDA has issued similar recommendations.[144] Because of potential safety concerns, it is recommended that these medications be started at lower doses, particularly in older adults, a population considered to be at higher risk for adverse events.[50]
Shingles vaccination is recommended before initiating a JAK inhibitor, particularly in older patients. Any other required live vaccines should also be administered prior to commencing treatment.[81]
Regular monitoring of laboratory tests is required.[81]

Cyclosporine

Works by inhibiting calcineurin, a phosphatase necessary for the activation and proliferation of T cells.

Very effective for atopic dermatitis in both children and adults, with a better tolerability in children.[50]
Due to its rapid onset of action, short courses of cyclosporine (2 weeks) may be beneficial in controlling particularly treatment-resistant disease, and allow for the introduction of maintenance regimens.
May be more effective for short-term (up to 16 weeks) treatment of adult patients with atopic dermatitis than methotrexate and azathioprine.[125]
Long-term efficacy reported in children and adults.[145][146][147]
Not effective topically (due to its high molecular weight), but oral cyclosporine can be combined with topical corticosteroids and/or calcineurin inhibitors when needed. Should not be combined with UV light therapy due to increased risk of skin cancer.[50]
Associated with increased risk of hypertension and renal dysfunction.[19][64][148] US guidelines advise that it is not suitable for long-term use, as the potential for renal damage increases with cumulative dose. Treatment should be limited to no more than 12 months (and preferably less) and regular monitoring with blood pressure checks and laboratory tests is required.[50][81]
Licensed for adult atopic dermatitis in some countries, but use is off-label in the US.[50][81]

Methotrexate

A folic acid antagonist with anti-inflammatory effects, approved for use in psoriasis, rheumatoid arthritis, and mycosis fungoides. Although its exact action in atopic dermatitis is not fully understood, inhibition of the JAK/signal transducers and activators of transcription (STAT) pathway has been proposed.[50]

Randomized controlled trials (RCTs) variously report that methotrexate is less effective than or similarly effective to azathioprine.[149][150] One RCT compared the safety and efficacy of methotrexate and cyclosporine in children ages 2-16 years with severe atopic dermatitis. Both treatments proved effective, but methotrexate induced more sustained disease control after discontinuation, whereas cyclosporine resulted in a more rapid treatment response.[151]
There is inconsistency between studies regarding methods, dosing, and duration of methotrexate therapy.[145] Onset of action takes several weeks and peak efficacy is seen after months (although speed of treatment effect onset depends on the dosing regimen).[50] Oral and subcutaneous delivery are considered equivalent options of administration. For patients in whom oral methotrexate is ineffective or poorly tolerated, a trial of subcutaneous administration is an alternative; subcutaneous delivery increases bioavailability and tolerability, as well as adherence, compared with oral treatment.[50][152]
Use in atopic dermatitis is off-label.[50][81]
Adverse effects include nausea, elevated liver enzymes, and occasionally pancytopenia or hepatic or pulmonary toxicity.[153][154][155] Regular monitoring of laboratory tests is required.[81]
Affects fertility and is teratogenic; women of childbearing potential should use effective contraception. The same recommendation is made for men treated with methotrexate who live with a woman of childbearing potential.[50]
Combination with topical corticosteroids, topical calcineurin inhibitors, or narrow-band UV phototherapy is well established and considered safe. Concomitant use of cyclosporine is a relative contraindication.[50]

Azathioprine

A purine analog that antagonizes purine metabolism, inhibiting synthesis of DNA.

Efficacy and safety have been demonstrated for short- and long-term use (24 weeks).[145][156]
Assess thiopurine methyltransferase (TPMT) activity before initiating therapy, and reduce the dose in patients with reduced TPMT activity. Consider TPMT testing in patients with abnormal complete blood counts that persist despite dose reduction of azathioprine.
Adverse effects include gastrointestinal disturbances and abnormalities in liver enzymes and blood counts (e.g., lymphocytopenia). Regular monitoring of laboratory tests is required.[81]
Can be combined with topical corticosteroids and/or calcineurin inhibitors. However, because of a potentially increased risk of skin cancer, it should not be combined with UV light therapy.[50]
Not licensed for the treatment of atopic dermatitis in children but has proven beneficial in several retrospective pediatric case series.[50]
Main disadvantage is that it reaches its maximum treatment effect only after 3-4 months.[50]
Its use in refractory moderate to severe atopic dermatitis is off-label; however, survey data suggest that it is widely used.[157]

Mycophenolate

An immunosuppressant that blocks the purine biosynthesis pathway of cells.

Used off-label in the treatment of both adult and pediatric patients with treatment-refractory moderate to severe atopic dermatitis.[50][81]
Evidence supporting its use for atopic dermatitis is limited and mainly based upon small, observational studies; no randomized trials have evaluated its efficacy as first-line treatment for severe disease. One systematic review of patients with severe atopic dermatitis (n=140; average number of failed agents 3.5) reported partial or full remission in 77% of patients.[158] In case series, the efficacy and safety of mycophenolate in children have been investigated; the drug has shown a positive treatment response with minimal adverse effects and appears to be better tolerated than azathioprine.[50][159]
Can be combined with topical corticosteroids and/or calcineurin inhibitors when needed.[50]
Adverse effects include headaches, gastrointestinal complaints, fatigue, and infections. Hematologic adverse effects include anemia, leukopenia, neutropenia, and thrombocytopenia, albeit rarely.[50] Prolonged treatment (≥1 year) is associated with increased risk of herpes infections.[158]
Regular monitoring of laboratory tests is required.[50][81]

Therapies with no evidence

No objective evidence exists to support the effectiveness of antihistamines in treating atopic dermatitis.[81] Clinical studies have failed to demonstrate a clear benefit or have attributed a decrease in pruritus to sedative effects at high doses.[160][161]

Short courses of sedating antihistamines may be helpful for flares of acute atopic dermatitis associated with severe itching, particularly if sleep is disturbed.[45] However, routine prescribing of antihistamines for management of atopic dermatitis symptoms is not recommended.[45][50][81]

One Cochrane review reported a lack of evidence to determine the possible benefits and harms of leukotriene receptor antagonists for atopic dermatitis.[162] There was no evidence of difference between montelukast and placebo with respect to disease severity, pruritus improvement, and topical corticosteroid use.

Written action plans

Parents and guardians of children with atopic dermatitis may benefit from a written set of instructions on skin care, bathing regimens, and other strategies that assist in the effective management of their child’s skin disorder.

The written treatment plan should not serve as a substitute for education while in the clinic.[163] Many parents are grateful to have instructions that can be used as a reference when they return home to implement the care and guidance provided by their physician.[164][165]

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