FormalPara Key Summary Points

The prevalence of atopic dermatitis (AD) has seen an increase in the Asia–Pacific region.

Topical corticosteroids are still used as the first line of therapy for the treatment of AD.

Pimecrolimus (1%) is a topical calcineurin inhibitor which can used as an alternative to steroid therapy.

Although the safety and efficacy of pimecrolimus has been established through various clinical trials, its use is still restricted in many Asian countries.

Existing post-marketing surveys and meta-analyses did not find an increasing risk of cancer with the long-term use of pimecrolimus.

Based on the available evidence, the expert panel recommends pimecrolimus in infants between 3 months and 2 years of age in the Asian population.

Introduction

Atopic dermatitis (AD) is one of the most common chronic, multisystem inflammatory skin diseases in pediatric patients. It affects the quality of life (QoL) of not only the patients but also their care givers [1]. Almost 20% of the global pediatric population, which is estimated to be about 230 million, are affected by AD [2, 3]. In the Asia–Pacific region, the prevalence of AD in the pediatric population is between < 5 and 10.1% [2]. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase 3 has reported an increase in AD cases in the Asia–Pacific region [4].

AD is characterized by skin barrier and immune dysfunction, inflammation and an intense itch [5]. The majority of AD is mild to moderate, frequently affecting sensitive skin areas. The distribution and morphology of the lesions vary with age, and especially during infancy, sensitive skin areas, such as the face, neck and scalp, are affected. Studies have reported that genetic, epigenetic, environmental and cultural factors may lead to differences in the clinical manifestation and prevalence of AD between races [1]. AD is believed to exhibit a difference in etiology between Caucasians and Asian races. Evidence shows a predominantly higher number of interleukin 17 (IL-17)-producing cells in Asian patients with AD [6,7,8]. The occurrence of AD is often associated with the atopic march leading to comorbidities such as asthma and allergic rhinitis [9]. Apart from these comorbidities, AD also causes psychological disorders such as depression, anxiety and attention deficit hyperactivity disorder in the patients [10].

Early treatment of AD is essential to prevent worsening and the development of atopic comorbidities. The treatment paradigm for mild to moderate AD is based on emollients, topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). Topical corticosteroids (TCS) are generally used as the first line treatment for AD [11]. Long-term use of TCS may cause local side effects such as skin infections, impairment of the epidermal barrier function and skin atrophy. Also, “corticosteroid phobia” is increasingly recognized as a significant factor contributing to poor TCS treatment adherence [6, 12].

Pimecrolimus (PIM) 1% is a TCI that is indicated for the treatment of mild to moderate AD [13]. The safety and efficacy of PIM in infants has been established by many studies, including the 5-year PETITE study (Table 1) [14]. PIM (1%) is approved in Australia, New Zealand, Russia, Brazil, Israel, Canada and Europe for the treatment of AD in infants ≥ 3 months of age. Among the Asian countries, it is approved in India, Indonesia, the Philippines, Thailand and Taiwan [15].

Table 1 Overview of clinical studies evaluating the topical use of pimecrolimus in infants
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In many of the Asian countries, the use of PIM in infants is still restricted due to safety concerns, even though the safety of PIM has been demonstrated in several randomized clinical trials, multiple publications and registries. Hence, there is a high need to have consensus guidance on the use of PIM in infants between 3 months and 2 years of age in the Asian population. The aim of this article is to encourage the use of pimecrolimus in infants between 3 months and 2 years of age in the Asian population due to its safety profile. The expert panel also recommends that the labeling restrictions for this age group are no longer justified.

Compliance with Ethics

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Epidemiology of AD in the Asian population

Studies show that the occurrence of AD is higher in the Asian region. Approximately 88% of the pediatric patients in Asia have mild to moderate AD. The ISAAC Phase 3 study showed that prevalence was higher (> 10%) in Thailand, Malaysia and South Korea and lower (< 5%) in Hong Kong, Pakistan, India, Syria, Iran, Oman and Vietnam [2]. In Japan, the prevalence of AD is almost 10.2% in the pediatric population [22]. The prevalence of AD in China is > 12%, with an average onset age of 0.86 ± 3.87 years [23]. In Taiwan, a prevalence rate of 22.4% was found in infants < 1 year old [24] and 16.93% in children younger than 2 years [25]. There is a prevalence rate of 3.4% in the Philippines, with 24% of the patients being infants < 1 year [26]. Singapore has an AD prevalence rate of 20.6% in children [27]. In Malaysia, 13.8% of infants < 2 years suffer from AD [28]. A systemic review of studies done on AD between 1990 and 2010 showed an increasing trend of AD cases in the Asian region [29].

Etiology of AD in the Asian Population

Studies have shown that there are genetic factors which influence different features of AD [30]. Mutations in genes involved in skin barrier function (FLG, FLG-2, SPINK5) and innate/adaptive immunity (IL-4, IL-13, DEFB1) affect the severity and occurrence of AD in different ethnic groups [31]. Asian patients with AD have more IL-17-producing cells [6,7,8]. The interleukin 19 (IL-19) level was also higher in the Asian population with AD. IL-19 increases IL-17’s effect on keratinocytes, which play an important role in atopic skin inflammation [32]. There are also increased TH17 frequencies in blood and acute lesions in Japanese patients with AD [33]. A mutation in the filaggrin (FLG) gene (c.3321delA) that is unique to the Asian population is found in AD patients in China, Japan and Korea [22]. FLG-null mutations (c.3321delA, c.6950_6957del8, p.S1515X, p.S2706X, p.Q2417X, p.E2422X, p.G323X) were found in 80% of AD patients in Singapore [34]. FLG encodes a key epidermal barrier protein, and mutations in this gene disrupt the skin barrier [35]. This increases epidermal permeability to environmental pollutants and allergens that are responsible for triggering immunologic responses leading to AD development [36]. The differential expression of inflammatory cytokines causes lichenified, well-demarcated and scaly lesions in Asians [7, 37]. East Asians are also characterized by low skin maturation and a weak skin barrier, resulting in increased skin sensitivity [38].

There are variations in skin properties at the stratum corneum level across different ethnic groups [38]. Epidermal thickness is high in the Asian phenotype. In addition, demographic and socioeconomic factors, active and passive smoking, urbanization, diet, breastfeeding and time of solid food introduction, obesity and physical exercise, and environmental air pollutants are some of the conditions which affect the occurrence of AD (Fig. 1) [36].

Fig. 1
figure 1

Different causative factors of atopic dermatitis in the Asian population

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Importance of Early Treatment of AD in Infants

AD is a chronic, relapsing skin disease which requires continuous treatment and compliance to control the symptoms [39]. Most (60%) childhood AD is remitted by adulthood. However, children with already persistent disease, later onset, and/or more severe disease have increased persistence [40]. Early treatment at the first signs and symptoms in infants and children is necessary for long-term treatment of AD and to prevent comorbidity [41]. AD is the first step in the atopic march leading to allergic rhinitis, asthma and food allergy [9]. A systematic review of 66 studies confirmed a strong link between AD and food allergy [42]. AD increases skin permeability to allergens, bacteria and other bigger molecules due to the weakened skin barrier. This in turn increases sensitization due to increased IgE, leading to the atopic march [43]. A randomized study of 1091 infants (SAM study) with AD showed that IgE levels increased with AD severity [44]. Hence, early interventions to improve skin barrier function would subsequently prevent the atopic march.

Role of Pimecrolimus in the Management of AD in Infants

Pharmacokinetic Profile of Pimecrolimus

PIM has negligible systemic bioavailability and a low potential for systemic side effects. In a study with guinea pigs as a model, it was seen that PIM in the blood was < 0.8% of the dermal bioavailability [45]. Permeation through the skin is lower for PIM compared to TCSs by a factor of 70–110 and lower by a factor of 9 compared to tacrolimus [46]. The primary reason for the low systemic bioavailability is that PIM is a highly lipophilic molecule. It has to pass through the horny layer (stratum corneum), which is lipid rich, to enter the lower epidermal layer, which is lipophobic. The lipid-rich horny layer slows down the permeation of PIM, resulting in a concentration gradient [47].

A 1-year study in five infants (5.7–11.9 months of age) who had moderate to severe AD treated with PIM (1%) showed very low levels of the drug (0–1.94 ng/ml) in the blood [48]. The distribution of blood levels of PIM was found to be similar in all age groups (3–23 months) for 1133 patients treated up to 2 years during the clinical development of PIM [49]. In a three-week multicenter study with 22 infants below 2 years of age with AD (10–92% of the body surface area affected at baseline), treatment with PIM (1%) did not show accumulation of the drug in the blood. The concentration of the drug remained below 0.5 ng/ml in 71% of the patients [17]. A study of 17 Japanese infants treated with PIM 1% b.i.d. for 3 weeks showed blood concentrations of < 0.5 ng/mL. Further, the concentration of PIM in blood did not increase with increasing treated body surface area [50]. A randomized study of 49 adolescents and adults treated with PIM b.i.d. or q.i.d. did not show a dose-dependent increase in PIM in blood over a period of 3 weeks [51].

Efficacy of Pimecrolimus in Infants

A 6-month, open-label, multicenter study in 947 patients (≥ 3 months of age) with mild to severe AD treated with PIM (1%) showed that an improvement occurred within 1 week of treatment [52]. A 1-year, double-blind, controlled study was done in 251 infants (3–23 months of age) with PIM (1%). Treatment with PIM significantly modified the disease course in infants by reducing the incidence of flares and improving overall control of AD [19]. In a study conducted by Kaufmann et al., it was concluded that the mean Eczema Area and Severity Index (EASI) score decreased by 71.5% in the PIM group but increased by 19.4% in the vehicle group at the end of week 4. Patients who received PIM cream for 3 months showed a significant improvement in EASI score [16]. A 5-year study (PETITE study) with 2439 AD infants showed that PIM has similar efficacy in the treatment of AD to those of low- and mid-potency TCS [14]. PIM showed sustained long-term efficacy (12 months) in infants, with a high proportion of patients achieving treatment success (IGA 0 or 1) [19]. In a study with 713 AD patients, fewer of the patients using PIM required a TCS as rescue medication compared to the control (34.8% vs. 63.7%) [19]. PIM (1%) was also shown to achieve no to mild pruritus in 69.9% infants during a 6-week double-blind study in 186 infants with mild/moderate AD [20]. According to some studies in children, PIM is preferred over tacrolimus in sensitive skin areas because of its non-greasy appearance. This is of particular importance in countries with a hot and humid climate.

Safety of Pimecrolimus in Infants

PIM is safe and well tolerated for short- and long-term use. Patients treated with PIM had a lower susceptibility to bacterial and viral skin infections compared to TCS [53]. Topical treatment with PIM did not affect the density and function of epidermal Langerhans cells, contrary to topical corticosteroids and tacrolimus [54]. PIM is associated with initial burning (6.8–7.4% of pediatric patients; 6.8–10.4% of adults) at the application site, which is comparable to TCS (7.4% in the pediatric population; 3.1% in adults) and contrary to tacrolimus (47% of adults with tacrolimus 0.1%; 36–37% of the pediatric population and adults with tacrolimus 0.03%) [55]. However, this burning sensation is transient. The most common adverse events associated with the use of PIM in infants are nasopharyngitis, pyrexia, diarrhea, upper respiratory tract infection and cough, which are common childhood disorders (Table 2).

Table 2 Common adverse events (≥ 10% incidence) in infants treated with pimecrolimus (PIM) 1%
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A 6-month, open-label, multicenter study in 947 patients showed that PIM (1%) was well tolerated, and no clinically unexpected adverse events were reported [52]. According to US post-marketing surveillance, tacrolimus was associated with Hodgkin lymphoma (HL) and cutaneous T-cell lymphoma (CTCL), which were found in 11 patients (95% CI) [58]. According to worldwide post-marketing surveillance, HL and CTCL were found in 19 patients and 61 patients receiving PIM treatments, respectively [58, 59]. There is no increased risk of cancer [e.g., lymphoma or non-melanoma skin carcinoma (NMSC) or melanoma skin carcinoma (MSC)] associated with exposure to TCI or TCS [60]. However, one study demonstrated an increased risk of lymphoma with high-potency TCS (high-potency TCS are mainly used to treat severe AD, and severe AD may have acted as a confounding factor here) [60]. In a nested case–control study of 293,253 patients with AD, it was found that the use of TCI such as PIM or tacrolimus did not pose an increased risk of lymphoma [61]. A systematic literature review done by Legendre et al. also did not find any significant relation between use of TCI and risk of cancer [60]. In a recent meta-analysis of 110 studies (including 52 randomized controlled trials), the odds ratio (OR) of any type of cancer risk associated with the use of TCI such as PIM or tacrolimus was compared with the control (no TCI). The study included almost 3.4 million patients. The absolute risk of any cancer upon TCI exposure was similar to that of the control (absolute risk 4.70 per 1000 with TCI vs. 4.56 per 1000 without), suggesting that TCI is safe [62]. There was no impact of topical PIM use on T and B cell function or vaccination response [14].

Discussion

AD requires long-term adherence to therapeutic management. Several factors such as the patient’s age, attitude to treatment options, and site of AD lesions should be taken into consideration before selecting an appropriate treatment regime. Poor treatment adherence is seen in the case of TCS due their side effects and steroid phobia [6]. The European consensus has also recommended the use of PIM for infants ≥ 3 months of age [53]. The NICE guidelines (National Institute for Health and Care Excellence) recommends the use of TCI for moderate to severe AD [63]. Experts in South and South-East Asia also recommend the use of PIM in infants ≥ 3 months of age [15, 53].

Although some Asian countries have approved the use of PIM in infants ≥ 3 months, its use is still restricted in many countries due to the black box warning issued by the FDA [64]. However, there is a lack of scientific evidence suggesting a direct link between the use of TCI and an increased risk of malignancy [65]. In China, the guidelines recommend the use of PIM (1%) in children with mild to moderate AD [66]. In India, TCI (PIM 1% and tacrolimus 0.03%) are recommended as first-line therapies for the treatment of mild to moderate AD, with PIM 1% being preferred in children less than 2 years of age and on the face, flexures and genitalia [67]. The Korean Atopic Dermatitis Association (KADA) has recommended the use of tacrolimus (0.03%) and PIM (1%) in children older than 2 years for the management of AD, but they also mention that both of them can be safely used in children younger than 2 years, even in infants [40]. The Taiwanese Dermatological Association (TDA) and the Taiwan Academy of Pediatric Allergy, Asthma and Immunology (TAPAAI) recommend the use of TCI in children requiring long-term topical treatment, or the frequent use of mild TCS for AD in face and sensitive areas [68, 69].

The PETITE study, which was a pivotal study of PIM in pediatric patients with AD [14], used a unique real-world design in which TCS were used according to their label. The caregivers of infants randomized to treatment with PIM had ready access to short-term TCS as a rescue medication if AD flares could not be controlled with PIM. The PETITE study showed that the long-term usage of PIM is safe in infants and there is no drug accumulation in the blood [53]. The use of PIM is also economically viable, as there are longer symptom-free periods, reducing hospital visit costs.

Consensus Statement

The Asian Expert Panel concluded that the treatment of AD should be initiated as early as infancy, based on the clinical evidence. The authors recommend that regulatory authorities in Asian countries should remove the current boxed warnings (due to the lack of long-term safety data and the potential risk of the development of malignancies), as this will allow AD patients to have access to effective medications with comprehensively established safety profiles. Based on a review of the available evidence, the Asian experts suggest that labeling restrictions of PIM in infants aged 3 months and above are no longer justified, and it is an effective and safe treatment for long-term management of AD in infants.

Conclusion

Early treatment of AD is essential to prevent worsening, the development of atopic comorbidities and, most importantly, decrease the significant burden of AD on the entire family and society. The use of PIM has advantages such as a reduced risk for flares, a mean EASI reduction, long-term disease control and early treatment success. Post-marketing surveys have shown that there is no increased risk of cancer (e.g., lymphoma or non-melanoma skin carcinoma) associated with exposure to TCI or TCS. Many Asian countries have already approved the use of pimecrolimus for the treatment of AD in infants. Based on the available evidence, the expert panel recommends pimecrolimus in infants between 3 months and 2 years of age in the Asian population.