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Atopic Dermatitis treatment

Read time: 100 mins
Last updated:17th May 2022
Published:27th Jul 2021

Atopic dermatitis is a common inflammatory skin disease predominantly affecting children1. Learn about the current and upcoming treatment classes available to manage the condition and prevent acute flares.

  • Gain clarity regarding classical and targeted treatment options available to alleviate symptoms and prevent an atopic march
  • Look to current research and future possibility for treatments which can target specific pathways and inflammatory mediators
  • Understand the treatment algorithm, including when and how to use specific therapies for varying severities of atopic dermatitis

Treatment goals for atopic dermatitis

While atopic dermatitis may spontaneously resolve in patients, it is not curable. Many patients will experience chronic disease and so the aims of treatment are limited to2:

  1. Minimise the number of flares
  2. Reduce the duration and degree of any flares

Interestingly, when 3,846 dermatology patients across 13 countries were asked whether they had treatment-related issues, 63.4% of patients with atopic dermatitis said they did – more than any other skin disease assessed3.

80% of patients in an online survey were dissatisfied with their atopic dermatitis treatment4

The topical treatments for atopic dermatitis have changed little over the past 15 years, consisting of topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). The effectiveness of TCS has been demonstrated over the years, however, local and systemic adverse effects limit their use. This is of particular concern in children where a greater surface area to body weight ratio increases the potential for elevated exposure5.

Professor Michael Cork explains a significant unmet need in atopic dermatitis and considers the potential limitations of treatment in relation to the need for additional therapeutics to become available.

Table 1: Adverse effects associated with the use of topical corticosteroids (adapted from Zane et al.5).

Atopic_Derm_Table5_Diagnosis_1__F63D375F-AEA0-4642-9F9A0E4E0A0A090E.png

While many patients are satisfied with the efficacy of TCS treatment, concerns over their use are common. Steroid phobia, or corticophobia, has been observed in over 80% of patients and parents6,7, impacting treatment compliance and failure7. Interestingly, a study of steroid phobia among French dermatologists, paediatricians and pharmacists identified concerns among all groups, but particularly among pharmacists, which may lead to increased concerns among patients8. A separate study also observed concern among French pharmacists around the use of topical corticosteroids in patients with atopic dermatitis, with this lack of trust potentially helping to maintain the fear of corticosteroids among parents and patients9. A validated questionnaire (TOPICOP©) has now been developed enabling patients’ topical corticosteroid phobia to be assessed in everyday clinical practice, helping to identify patients requiring additional support and education10,11.

Two TCIs are currently available for patients who are inadequately responsive to, or intolerant of, TCS. However, TCIs are also associated with application site burning and stinging as well as a small increase in the incidence of herpes simplex infection12,5 although no increased risk of infection was observed versus TCS treatment in a 5-year study of pimecrolimus in mild-to-moderate atopic dermatitis13. Of greater concern has been the historical link between TCI and increased lymphoma risk. In 2006, a boxed warning was added to the tacrolimus and pimecrolimus labels. Recent epidemiologic data suggests that the incidence of lymphoma was no greater in TCI-treated patients than the general population. However, U.S. FDA deemed an association may still exist and kept the boxed warning in place5.

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Non-pharmacological management

Identification and avoidance of an individual’s trigger factors allows longer periods of remission or total clearance of symptoms. Numerous non-specific physical, chemical and biological factors can irritate the skin and elicit flares in patients with atopic dermatitis. Meanwhile, specific allergens can also promote skin lesions in sensitised patients18.

AD_Fig18__15061C6F-2019-4311-9CA5A89A300D0B1F.png

Figure 3: A selection of common non-specific (left) and specific (right) triggers seen in patients with atopic dermatitis (adapted from Wollenberg et al.18).

Environmental factors such as tobacco smoke and traffic exhaust have been shown to increase the risk of children developing atopic dermatitis and avoidance of them in young children has been introduced into the German S3 guidelines for the prevention of atopic diseases19.

Various strategies to avoid allergens have been proposed although with varying levels of evidence. While smooth clothing and avoidance of irritating fabrics and fibres are essential to avoid primary skin irritation other options include18:

  • Mite-proof bedding and pyjamas
  • Pollen avoidance
  • Avoidance of relevant contact allergens e.g. fragrances, preservatives, emulsifiers
  • Primary prevention of food allergy-associated adverse events with exclusive breast milk feeding until 4 months of age
  • Observe a therapeutic diet eliminating those foods that elicited clinical early or late reactions upon controlled oral provocation tests

Emollients and skin care

Management of dry skin is critical to help maintain barrier function. The effective use of bathing and emollients are frequently recommended as an essential component of atopic dermatitis therapy18.

Cleansing and bathing

Cleansing the skin is essential to carefully remove dead skin and eliminate bacterial contaminants. However, it must be performed gently, and quickly to avoid irritation and epidermal dehydration. The use of bath oils, non-soap-based and acidic-cleansers as well as the addition of antiseptics have all been suggested to help manage atopic dermatitis18,20.

Emollients

Emollients represent the mainstay of atopic dermatitis management and typically contain a humectant to promote stratum corneum hydration, and an occludent to reduce evaporation.

It has been demonstrated that long-term emollient therapy improves xerosis associated with atopic dermatitis and the daily use of emollients from birth may significantly reduce the incidence of atopic dermatitis in a high-risk population. However, long-term follow-up data is required to confirm this18. Importantly, the use of emollients has been shown to be steroid sparing, reducing the side effect risks commonly associated with their prolonged use. A short-term steroid sparing effect has been observed in children and adults with mild-to-moderate atopic dermatitis following emollient use21,22,23, while long-term maintenance of stable disease has been achievable through regular use of emollients following induction of remission with TCS24,25.

Some caution should be exercised over the use of certain emollients in young children as some ingredients may cause irritation or under-desirable side effects. Urea can be used as a humectant but has been shown to cause irritation and kidney dysfunction in infants and should be avoided, while in toddlers, a lower concentration should be used than in adults. Meanwhile propylene glycol can irritate the skin of children aged below 2 years and so should not be used18. Concerns have also been raised about emollients containing intact proteins. While the use of colloidal oat meal has been shown to improve clinical outcomes in atopic dermatitis26, there are fears that it may increase the risk of skin sensitisation and allergy in at risk patients and so should be avoided in children below two years of age18.

Finally, it is worth considering that the sole use of emollients without sufficient topical anti-inflammatory therapy increases the risk of disseminated bacterial and viral infection – a risk that is already elevated in those with atopic dermatitis27.

Phototherapy

Patients with atopic dermatitis frequently observe an improvement in their symptoms during summer due to the increased sun exposure. During the course of the summer holidays, 74% of patients with mild-to-moderate atopic dermatitis saw complete resolution in one study. Interestingly, more patients saw complete resolution on seaside holidays (91%) than mountain holidays (11%)28. While UV exposure does not completely explain this difference, it supports the positive effects of UV radiation on atopic dermatitis18.

Table 2: Phototherapy options (adapted from Schäfer et al.18). UVA, ultraviolet A; UVB, ultraviolet B; NB-UVB, narrowband UVB; BB-UVB, broadband UVB; UVAB, combination of UVA and UVB; PUVA, psoralen plus UVA; UV, ultraviolet.

Atopic_Derm_Table8_Diagnosis_1__CE42D52C-7070-452C-9C5E1BEA55F34599.png


In Europe, NB-UVB has been used for patients with chronic, moderate forms of atopic dermatitis and is preferred to BB-UVB, while more severe cases have been treated with UVA118. Interestingly, a small number of patients with atopic dermatitis do not tolerate NB-UVB but respond well to BB-UVB29.

Mechanism of action

Ultraviolet radiation has been observed to produce a number of biological effects within the skin that may explain its ability to treat atopic dermatitis.

AD_Fig20.1__F1EFC9E4-398E-4B31-A57B1FAD7FBFD745.png

Figure 4: Proposed mechanisms of action for phototherapy in atopic dermatitis (adapted from Schäfer et al.18).

Phototherapy and pruritus

Use of narrowband UVB and UVA1 has been shown to be the most effective forms of UV therapy in multiple RCTs, including in the reduction of itch intensity. There is no anti-itch specific data for UV therapy though18.

Topical anti-inflammatory treatment

Topical anti-inflammatory treatments currently consist of topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). Their effective use requires18:

  1. Sufficient strength/potency
  2. Sufficient dosage
  3. Correct application

 

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Targeted treatment options for atopic dermatitis

Non-steroidal topical anti-inflammatory treatment

The limited range of topical treatments for atopic dermatitis has led to great interest in novel targeted non-steroidal anti-inflammatory therapies based on a growing understanding of AD pathophysiology. Recently, phosphodiesterase-4 (PDE4) has become a desirable target for therapy due to its role in the inflammatory cascade of atopic dermatitis36.

Phosphodiesterase-4 (PDE4) inhibitors

Currently, a number of PDE4 inhibitors are under investigation for the management of atopic dermatitis due to their ability to reduce the production of proinflammatory cytokines37.

PDE4 inhibitors utilise a unique mechanism, differing from that of TCSs and TCIs, that affects a wide range of cytokines in atopic dermatitis36,38

The first to reach the market was crisaborole, a small lipophilic, boron-based molecule added to a topical vehicle that has been approved by the FDA for the treatment of mild-to-moderate atopic dermatitis in patients two years and older in the USA18. Crisaborole was also approved for use by the European medicines Agency (EMA) for the treatment of mild-to-moderate atopic dermatitis in adults and paediatric patients in 2020. However, in early 2022, marketing authorisastion was revoked and crisaborole therapy was not launched in the region.39. Despite this, crisaborole maintains FDA approval and is widely used in the United States 18.

The clinical trials that led to crisaborole’s FDA approval included AD-301 and AD-302, two phase 3, vehicle-controlled, double blind studies40. These trials enrolled 1527 patients, aged two years and over, with mild-to-moderate atopic dermatitis. The studies compared the study drug with a vehicle control twice daily for 28 days with a primary endpoint of clear or almost clear and a 2-grade or more improvement on the Investigator’s Static Global Assessment40. A post-hoc analysis pooling data from these two phase III trials saw significantly more patients report early improvement in pruritus with crisaborole than with vehicle (56.6% vs. 39.5%; p<0.001)41.

Crisaborole is the first topical PDE-4 inhibitor indicated for the treatment of mild-to-moderate AD. It is a safe and efficacious second-line option for the treatment of mild-to-moderate AD in patients 2 years of age and older42.

Other PDE4 inhibitors are also under development for atopic dermatitis, including topical therapies such as roflumilast, apremilast, GW842470X, E6005, AN2898 and OPA-15406 and the oral therapy roflumilast (all of which have currently completed Phase II studies and some Phase III trials)38.

More on current recommendations for the use of PDE4 inhibitors in the treatment of atopic dermatitis

Mechanism of action

Phosphodiesterase 4 regulates inflammatory cytokine production through the degradation of cyclic adenosine monophosphate (cAMP). In patients with atopic dermatitis, increased PDE4 activity leads to reduced cAMP levels and increased inflammation43. Selective inhibition of PDE4 prevents cAMP degrading to AMP. Increased levels of cAMP consequently suppress NF-kB which leads to the suppression of IFN-y and reduced inflammation36.

AD_Fig22.1__ED3F7C51-F311-4751-AAC9F07F122292E3.png

Figure 6: PDE4 inhibitor-mediated downregulation of proinflammatory cytokines (adapted from Ahluwalia et al.44).
AC adenylyl cyclase; CREB cAMP response element-binding protein; IL interleukin; NFAT nuclear factor of activated T-cells; NFjB nuclear factor kappa-light-chain-enhancer of activated B cells; PKA protein kinase A.

Discover more about the mechanism of action of PDE4 inhibitors with Professor Mike Cork

Systemic therapy

A variety of systemic treatments have been used for the treatment of severe atopic dermatitis, many of which are off label. Below we discuss the treatments licensed for this indication.

Oral glucocorticoids

Many European countries continue to use oral glucocorticoids for the management of atopic dermatitis18. However, systemic corticosteroids are not anti-pruritic and their prolonged use in atopic dermatitis is not recommended due to their safety profile20.

They should only be used short-term, preferably in combination with topical corticosteroids, to manage acute flares of severe, widespread disease. Given the risk of adverse effects, oral glucocorticoids should be tapered and replaced with an alternative immunosuppressant2. The use of systemic steroids in children should be undertaken with even greater caution than that with adults18.

The mechanism of action for oral glucocorticoids is consistent with that for topical corticosteroids, but experienced at a broader, systemic level.

Ciclosporin A

Ciclosporin A is an oral calcineurin inhibitor that promotes immunosuppression. In many European countries, it is a first-line treatment for adult patients with chronic severe atopic dermatitis who require systemic treatment.

While effective, treatment should not exceed two years and patients should be monitored for severe adverse effects. Common adverse effects include nephrotoxicity and hypertension with renal effects more likely if the daily dose exceeds 5 mg/kg, serum creatinine levels are elevated, or the patient is elderly18.

Ciclosporin A has a similar mechanism of action to the topical calcineurin inhibitors except it interacts with cyclophilin rather than macrophilin-1233.

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Treating mild-to-moderate atopic dermatitis

Early treatment of atopic dermatitis is key to optimal treatment outcome in treating skin disease and may also delay or prevent the atopic march. There is limited data available regarding the specific clinical and economic burden of mild-to-moderate atopic dermatitis, however a possible link has been proposed between disease burden and disease severity68. Therefore, optimal management of mild-to-moderate presentation of this condition is essential.

Classical and targeted treatments each have a role to play in the treatment of mild-to-moderate manifestation of atopic dermatitis. Research continues to establish the most effective treatments that might be or become available to reduce symptoms and allow clinicians and patients to establish effective management.

A systematic review and meta-analysis of the application of topical phosphodiesterase 4 (PDE4) inhibitors in mild-to-moderate atopic dermatitis was conducted in 2019. The results indicated favourable efficacy and safety of PDE4 inhibitors, especially crisaborole and AN289869.

PDE4 inhibitor research continues into their use, particularly in children. Professor Michael Cork explains more, with reference to new technology to evaluate the effect that both PDE4 inhibitors and topical corticosteroids are having on the skin.

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Treating moderate-to-severe atopic dermatitis

There is a clear need for the continued development of targeted therapies, including biologics, which can address specific cytokine pathways implicated in atopic dermatitis. Biologics include those targeting Th2, Th22, TH17/IL-23 and IgE.

Guidelines recommend the anti-inflammatory biologic dupilumab, which targets IL-4 and IL-13, for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy, and the treatment of severe atopic dermatitis in children 6 to 11 years old who are candidates for systemic therapy71. Licensed for use in the U.S. and Europe, dupilumab has been shown to hold significant efficacy in improving signs and symptoms of atopic dermatitis, with an acceptable safety profile46,47,49,72,73.

Tralokinumab, which selectively targets IL-13, a key driver of peripheral inflammation, has been demonstrated to be efficacious in the treatment of atopic dermatitis in large phase 3 studies, and has recently been approved by the FDA and EMA for use in adults eligible for systemic therapy50,52.

Oral JAK inhibitors have recently been approved for use in Europe and the United States, and when combined with topical agents, offer the most promising targeted treatment for moderate-to-severe AD, especially for people who have a suboptimal response to dupilumab60. Of note is abrocitinib, approved in early 2022 with outstanding efficacy and no serious safety concerns62. Short-term head-to-head studies of upadacitinib and abrocitinib vs dupilumab suggest a more rapid onset of efficacy and itch relief, and equivalent or better efficacy compared with dupilumab in EASI90, IGA0, or IGA1 end points65,74. However, as these treatments have only been recently approved, official guidelines have not yet been adapted to consider this emerging evidence.

Emerging topical and systemic therapies are being developed to primarily target the type 2 immune pathway. Topical treatments being investigated include ruxolitinib and delgocitinib (JAK inhibitors), tapinarof (an aryl hydrocarbon receptor agonist), and creams aimed at correcting microbial dysbiosis75. In addition to monoclonal antibodies targeting IL-4 and IL-13 (dupilumab and tralokinumab) other biologics targeting IL-13, IL-31, IL-33, OX40, and thymic stromal lymphopoietin are currently being tested in clinical trials75.

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References

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