Practical algorithm to inform clinical decision‐making in the topical treatment of atopic dermatitis

Atopic dermatitis is a chronic relapsing, inflammatory skin disorder associated with skin barrier dysfunction, the prevalence of which has increased dramatically in developing countries. In this article, we propose a treatment algorithm for patients with mild‐to‐moderate and severe atopic dermatitis flares in daily clinical practice. An international panel of 15 dermatology and allergy experts from eight countries was formed to develop a practical algorithm for the treatment of patients with atopic dermatitis, with a particular focus on topical therapies. In cases of mild‐to‐moderate atopic dermatitis involving sensitive skin areas, the topical calcineurin inhibitor pimecrolimus should be applied twice daily at the first signs of atopic dermatitis. For other body locations, patients should apply a topical calcineurin inhibitor, either pimecrolimus or tacrolimus, twice daily at the first signs of atopic dermatitis, such as pruritus, or twice weekly in previously affected skin areas. Emollients should be used regularly. Patients experiencing acute atopic dermatitis flares in sensitive skin areas should apply a topical corticosteroid twice daily or alternate once‐daily topical corticosteroid/topical calcineurin inhibitor until symptoms improve. Following improvement, topical corticosteroid therapy should be discontinued and patients switched to a topical calcineurin inhibitor. Maintenance therapy should include the use of pimecrolimus once daily for sensitive areas and tacrolimus for other body locations. This treatment algorithm can help guide clinical decision‐making in the treatment of atopic dermatitis.


| INTRODUC TI ON
Atopic dermatitis (AD) is a common chronic disease characterized by general skin dryness, eczematous lesions, and pruritus. 1 The worldwide prevalence of AD is estimated at 15-20% in children (aged 6-14 years) and 1-3% in adults; 2 however, there is substantial variation between countries, 3 and increases in the prevalence of AD have been observed over the past decade in developing countries. 4 In China, the prevalence of AD in children has increased from 3% in 2004 5 to 13% in 2016, 6 although variations between urban and rural areas have been observed. 5 In Turkey, the prevalence of AD in children was 5% in 1994, 10% in 2004, and 7% in 2014, 7 and data published from Ukraine in 2018 reported that the prevalence of AD in children aged between 8 and 9 years in the Poltava region was 5%. 8 In 2010, a 10% prevalence of AD was observed in children from rural and urban areas of Belarus. 9 In Russia, data published between 2006 and 2016 reported that the incidence of AD was 6.2-15.5%, and was region dependent. 10,11 In 2016, 72% of all patients with AD were children (0-17 years old); 41% of these cases were among children aged 0-4 years. 11 The prevalence of AD among children aged 15-17 years was 1.16%. 10,11 In a study of allergic diseases conducted in Russian adolescents, the prevalence of AD was shown to be up to 5-times greater than that reported in official statistics. 12 Alongside regional differences in the prevalence of AD, the progress and symptoms of AD can differ between races. Recent studies involving Asian, European American, and African American children and adults with AD have shown that AD is a complex disease characterized by different phenotypes related to age, chronicity of the disease, race, epidermal barrier, immunological status, and molecular endotypes. 13,14 Events that happen during the first 1000 days of life, including those that occur during gestation, may increase an individual's predisposition to developing AD. 15 The microbiome of the intestine and skin have been found to play an important role in AD; dysbiosis of both the gut and skin microbiome have recently been linked to alterations in immune responses, and can result in skin diseases, such as AD. 16,17 Frequent use of antimicrobials, as well as early use of antibiotics, has been associated with changes in the gut microbiome, which has also been associated with AD. [18][19][20][21][22] Infants with Staphylococcus epidermidis or Staphylococcus hominis colonization experience milder AD than those colonized by Staphylococcus aureus. 17,23 Furthermore, studies investigating S. aureus colonization have shown that certain strains of S. hominis can prevent S. aureus colonization on the skin of patients with AD. 17 The increasing prevalence of AD in some developing countries may be attributed to lifestyle changes, including a Western diet. 24 Furthermore, food allergy is an increasingly common precursor to AD, 25,26 and is predisposed by food avoidance during infancy and childhood. 27,28 Atopic dermatitis negatively impacts quality of life of patients and caregivers 29,30 and can predispose to mental health disorders, [31][32][33][34] highlighting that the prevention of AD progression must be considered through early and effective treatment. Proactive maintenance treatment, where therapies are applied in the absence of visible lesions, may also be required. Early diagnosis of AD is necessary for timely implementation of treatment and to prevent comorbid diseases by reducing contact with pro-inflammatory agents; 35,36 late diagnosis and subsequent undertreatment can lead to significant complications and further increases the burden of AD. 37 The general strategies adopted for treating AD should be adapted based on the patient's location, as geographical and genetic differences can lead to varying prevalence, presentation of symptoms, and availability of health care. 38 In this article we propose a treatment algorithm for the management of patients with mild-to-moderate AD and severe flares in daily clinical practice, with a particular focus on topical treatments.  [39][40][41][42][43][44][45][46] The treatment algorithm has flares in sensitive skin areas should apply a topical corticosteroid twice daily or alternate once-daily topical corticosteroid/topical calcineurin inhibitor until symptoms improve.

| ME THODS
Following improvement, topical corticosteroid therapy should be discontinued and patients switched to a topical calcineurin inhibitor. Maintenance therapy should include the use of pimecrolimus once daily for sensitive areas and tacrolimus for other body locations. This treatment algorithm can help guide clinical decision-making in the treatment of atopic dermatitis.

K E Y W O R D S
algorithm, atopic dermatitis, pimecrolimus, tacrolimus, therapeutics been adapted for use in the Middle East 47 and in Asia 48 by separate groups of experts from these regions.

| TRE ATMENT ALG ORITHM
The proposed algorithm for the treatment of AD is detailed in

| First-line treatment according to proposed algorithm: mild-to-moderate AD
The topical calcineurin inhibitors (TCI) pimecrolimus and tacrolimus are licensed for the treatment of AD. 4 4, 52-54 Tacrolimus 0.03% ointment is approved for the treatment of moderate-to-severe AD in patients aged 2-15 years, and tacrolimus 0.1% ointment for the treatment of patients aged 16 years or more. Pimecrolimus 1% cream is generally approved for mild-to-moderate AD in adults and children aged 2 years or more, but is also approved for use in infants aged 3 months or more in Australia, Brazil, Canada, India, Indonesia, Israel, New Zealand, the Philippines, Russia, and Thailand. [55][56][57][58][59][60][61][62][63][64][65] However, pimecrolimus is not available in some countries, including Japan. In the European atopic eczema (AD) guidelines, pimecrolimus is the preferred TCI for the treatment of facial lesions and children (according to overall recommendations), with tacrolimus recommended for long-term maintenance treatment. 44 In non-sensitive body locations, either pimecrolimus or tacrolimus are recommended for use ( Figure 1). Patients with mild-to-moderate AD aged 2-15 years treated with tacrolimus 0.03% ointment showed a significantly greater percent improvement in Eczema Area and Severity Index (EASI) scores compared with vehicle ointment (54.8% vs. 20.8%), alongside improvements in the total body surface area affected by AD and a lower itch score in the tacrolimus group. 66 Pimecrolimus 1% cream has been shown to reduce the number of AD flares and increase the median time to first AD flare when compared with a vehicle cream control (144 vs. 26 days, p < 0.001). 67 While both TCI are preferred over topical corticosteroid (TCS) for the treatment of sensitive skin areas, pimecrolimus is preferred over tacrolimus for use in sensitive areas. 68 Sensitive areas include the head, face (eyelids and perioral region), neck, axilla region, inguinal folds, and genital area. In direct head-to-head comparisons of topical pimecrolimus with tacrolimus, pimecrolimus demonstrated greater efficacy in reducing the signs and symptoms of AD in sensitive skin areas, specifically in the head and neck region (54% reduction in AD with pimecrolimus treatment vs. 35% with tacrolimus treatment; treatment difference not significant). 69 Alongside these results, local erythema was less common and was experienced for a shorter duration of time in patients being treated with pimecrolimus than with tacrolimus. 69 TCI do not impair the skin barrier and may even be able to restore barrier function in damaged skin. 70,71 Systemic exposure is lower for pimecrolimus than tacrolimus, making it more suitable for patients with extensive lesions and in children, as systemic absorption is minimized. 72,73 This difference in systemic absorption is due to pimecrolimus being more lipophilic with a greater binding affinity for skin proteins and lower skin permeability. 74,75 The use of pimecrolimus 1% cream was well tolerated and demonstrated marked improvements in treating patients with Netherton syndrome, even when applied to 50% of the total body surface area. 76 In contrast to tacrolimus, pimecrolimus systemic absorption in children with Netherton syndrome is very low after 4 weeks of treatment resulting in a significant improvement of the skin lesions. 76 Pimecrolimus has a selective action on T lymphocytes, mast cells and basophils, and, unlike tacrolimus, has no action on Langerhans cells. [77][78][79] Skin burning is a common adverse event following TCI application; 80,81 within the clinic, this usually occurs in the first 3 days of treatment. Based on clinical experience, cooling the product in the refrigerator for 15-20 min before application may help to reduce the sensation of burning at the application site or, in adults, administrating oral acetylsalicylic acid 1 h prior to treatment for the first 3 days may help avoid or alleviate burning. 82,83 A shorter duration of warmth, stinging, and burning reactions was reported in patients treated with pimecrolimus compared with those treated with tacrolimus. Although the incidence of these specific application site reactions was similar between groups in this particular study, 69 the incidence of burning sensations experienced by patients treated with pimecrolimus in clinical trials has been found to be generally low (~7-10%), 84,85 whereas tacrolimus-treated patients may experience a high incidence (36-50%) of applicationsite burning. 81

| First-line treatment according to proposed algorithm: severe AD flares
For severe AD flares in sensitive skin areas, TCS can be used as initial treatment until an improvement in severity has been observed ( Figure 1). Alternatively, once-daily TCS/TCI can be used in alternate until an improvement in severity is observed (Figure 1). Following an improvement in severity, TCS use should be discontinued and switched to TCI. Although TCS are effective for the short-term treatment of AD, 85,87,88 long-term use is not recommended. Application to sensitive areas should be minimized due to potential side-effects, 89 particularly as the increased skin permeation of TCS, relative to pimecrolimus, increases the risks of side-effects. 74 Side-effects associated with TCS include local cutaneous events (e.g., impairment of epidermal barrier function, 70,90 skin atrophy, and acne) and systemic effects (e.g., hypothalamic-pituitary-adrenal axis suppression). 88,89 Awareness and fear of these side-effects, or corticophobia, is common in several European and Asian countries [91][92][93][94][95][96] and is associated with non-adherence to treatment. 95,97,98

| Management of AD in infants
Early treatment of AD during infancy and early childhood may reduce the progression of AD and prevent atopic march. 50 Emollients are an important part of treatment, and long-term use of emollients has demonstrated preventative effects in infants who are at risk of developing AD. 50,51 Topical calcineurin inhibitors are an effective treatment option in infants with mild-to-moderate AD, 55 p < 0.001) when compared with vehicle ointment in a 12-month study. 109 Following 16 weeks of maintenance treatment with pimecrolimus, the disease relapse rate was reduced in patients receiving once-and twice-daily applications (14.7% and 9.9%, respectively). 110 Furthermore, a 12-month efficacy study of pimecrolimus treatment at the early signs of AD, showed a significant reduction in the incidence of flares (67.6% vs. 30.4%, p < 0.001) and an improvement in the overall control of AD when treated with pimecrolimus compared with vehicle. 106 Long-term safety data for TCI, together with guideline recommendations, support the use of pimecrolimus as the preferred treatment option for sensitive skin areas. 44,111 Currently, there is no evidence that proactive treatment is superior to treatment started at the first signs and symptoms, usually itch, of a new AD flare. Proactive treatment with TCS may also be considered for patients with frequent flares, as there is evidence to indicate that using TCS plus emollients as maintenance therapy is more effective for preventing relapses compared with emollients alone. 41,112 Regular use of emollients in AD is recommended as epidermal barrier dysfunction can negatively affect skin hydration and increase transepidermal water loss. 113,114

| Novel topical therapies for AD
Crisaborole ointment is a topical phosphodiesterase-4 inhibitor used for the treatment of mild-to-moderate AD, 115 which is currently approved in a limited number of countries. A pooled analysis of clinical data showed that crisaborole 2% ointment significantly reduced the severity of pruritus compared with treatment with vehicle. 115 Safety analyses showed crisaborole 2% ointment to be well tolerated, with the most commonly reported treatment-related adverse events being application site pain, pruritus, and dermatitis. 115 Microbiome-targeting treatments are being developed due to the promising results of a phase 1/2 trial investigating treatment with topical Roseomonas mucosa. In this study, significant decreases in AD severity, TCS requirements, and S. aureus burden were observed following treatment with R. mucosa in patients with AD. 116 Janus kinase (JAK), a family of tyrosine kinases, has been implicated in AD, with inhibition of JAK resulting in sustained anti-pruritic effects. 117 F I G U R E 1 Algorithm for the topical treatment of atopic dermatitis in children, adolescents, and adults. a These areas include the head, face (eyelids and perioral region), neck, axilla region, inguinal folds, and genital area. In these areas, a cream is preferred to an ointment. b Pimecrolimus 1% cream for all ages; tacrolimus 0.1% ointment for adults; tacrolimus 0.03% ointment for children. Pimecrolimus is indicated for mild-to-moderate AD and tacrolimus is indicated for moderate-to-severe AD. 55,124c Not included in the Summary of Product Characteristics for pimecrolimus. Abbreviations: AD, atopic dermatitis; TCI, topical calcineurin inhibitor; TCS, topical corticosteroid [Color figure can be viewed at wileyonlinelibrary.com] In a recent phase 2 trial in patients with AD, treatment with ruxolitinib cream, a potent JAK1/JAK2 inhibitor, significantly improved EASI score versus vehicle cream at week 4 (71.6% improvement vs. 15.5%, p < 0.001). 118 Treatment with topical ruxolitinib also significantly improved the Investigators Global Assessment (IGA) score and pruritus compared with vehicle at week 4. 118 Another JAK inhibitor, delgocitinib, has been approved in Japan for topical use in patients with AD. 119 In both phase 2 and phase 3 trials in Japanese patients with AD, delgocitinib demonstrated significantly reduced modified EASI scores versus vehicle ointment after 4 weeks. 120,121 Tapinarof is a topical aryl hydrocarbon receptor agonist that has been investigated in patients with AD. 122 In a recent study, the rate of treatment success (minimum 2-grade IGA score improvement) with tapinarof cream at week 12 was shown to range from 34% to 53% (dose dependent) and was significantly higher than that with vehicle treatment (24%). 122 It should be noted that some of these novel treatments are costly, which may limit their use. The treatments recommended in the proposed algorithm ( Figure 1) are economical 123 and effective for the management of AD.

| CON CLUS IONS
The proposed treatment algorithm should help guide physicians in clinical practice when treating patients with mild-to-moderate AD and those with severe flares. According to the algorithm, pimecrolimus is the preferred TCI for application on sensitive skin areas due to its efficacy, tolerability, and selectivity profile compared with tacroli-