Practical Recommendations for the Topical Treatment of Atopic Dermatitis in South and East Asia

As mentioned above, corticophobia can compromise effective treatment with TCS because patients may fail to use their prescribed treatment or discontinue treatment prematurely to minimize steroid exposure [51‐54]. While providing patients with accurate information regarding TCS may help alleviate concerns [55], TCI should also be considered in cases where patients (or parents/caregivers of pediatric patients) express concerns regarding TCS use [56]. Conversely, some patients may be reluctant to use a TCI due to perceived safety concerns, since both tacrolimus and pimecrolimus carry a black box warning for risk of malignancy (e.g., lymphoma) [57, 58]. However, no causal relationship has been established, and as safety data accumulate, systematic reviews have not found evidence of increased cancer risk [59, 60]. Indeed, the first Asian study to investigate the risk of malignancies with TCI in patients with AD found no association between pimecrolimus and tacrolimus use and overall development of malignancies [61]. Furthermore, a recent prospective, observational study of approximately 8000 children with AD who were treated with tacrolimus ointment for ≥ 6 weeks observed no incidence of lymphoma over a 10-year period [62]. The authors of the study concluded that there was no evidence to suggest that tacrolimus increased the long-term risk of cancer in children with AD [62]. A proactive approach by the clinician to openly discuss the content of the black box warning with the patient may help to reduce patient anxiety and subsequently help to improve TCI adherence [26, 63]. Nevertheless, misinformation and distrust of TCI and TCS persists in Asian populations [64].

In an observational study of the efficacy and safety of pimecrolimus 1% cream in patients with AD who were previously treated with TCS, patient satisfaction was higher with pimecrolimus than with TCS [65]. Approximately 60% of patients had no concerns about using pimecrolimus on sensitive skin compared with 10.1% for TCS [65]. In addition, more than 77% of patients felt that pimecrolimus improved their quality of life compared with less than 43% for TCS [65]. Similarly, in a 4-year follow-up study of children and adult patients with AD treated with 0.1% tacrolimus, 75% of patients and 76% of investigators expressed high satisfaction with the treatment [66]. In studies comparing tacrolimus 0.1% and TCS, efficacy results have favored tacrolimus although comparison of their impact on quality of life is less clear-cut [67, 68]. In a study comparing pimecrolimus 1% cream and tacrolimus 0.03% ointment in pediatric patients with AD, although efficacy was similar between treatments, a greater proportion of patients (or caregivers, in the case of pediatric patients unable to answer questions themselves) rated pimecrolimus as very good or excellent compared with tacrolimus for several aspects, including suitability for use on sensitive facial skin; non-sticky feel; ease of application; and ease of rub-in [69]. In the hot and humid climate of South and East Asia, the propensity to sweat from excessive heat is high and can be an aggravating factor for AD [70]. Therefore, certain product characteristics attributed to pimecrolimus, such as its non-sticky feel and ease of rub-in, should prove to be particularly beneficial. By contrast, ointments may be more occlusive and feel more greasy, especially when used in hot and humid conditions, trapping excess heat and sweat on the skin and potentially further exacerbating the risk of AD flares.

Sensitive skin areas, such as the face, neck, and skin flexures, are at particular risk of epidermal barrier impairment and skin atrophy with TCS treatment. Therefore, TCI are useful to treat patients with AD affecting these areas [14, 22]. In support of this approach, American and European guidelines for the treatment of AD recommend TCI, rather than TCS, as the preferred treatment for sensitive skin areas [25, 26].

The proactive treatment of sensitive skin areas involves long-term, low-dose intermittent topical anti-inflammatory therapy for previously affected areas with subclinical inflammation [71]. Patients experiencing frequent flares may require proactive anti-inflammatory treatment as an adjunct to continued use of emollients for maintenance treatment. Concerns regarding the side effects of TCS may be heightened if their prolonged use is required. In contrast, beneficial effects of TCI have been observed in long-term studies. Two early intervention studies of pimecrolimus (one in infants aged 3–23 months and one in children aged 2–17 years) have demonstrated a reduction in the incidence of flares with pimecrolimus compared with vehicle, as well as improved control of AD, over a period of 12 months [72, 73]. Furthermore, a 5-year study of ‘as needed’ treatment with pimecrolimus or TCS in infants with AD demonstrated that pimecrolimus had a similar efficacy to TCS and raised no safety concerns [74]. A non-comparative study of intermittent or continuous application of tacrolimus 0.1% ointment for up to 4 years (patients ≥ 2 years old) demonstrated sustained efficacy and a safety profile comparable with those reported for shorter studies [66]. Long-term proactive treatment of AD in children with either pimecrolimus 1% cream (16-week study [75]) or tacrolimus 0.03% ointment (40-week study [76] and two 12-month assessments [77, 78]) has been found to delay flares and prevent relapses. Therefore, patients requiring proactive anti-inflammatory treatment and those for whom prolonged TCS use is not desired, may benefit from a TCI.

The authors of a recent systematic review of long-term efficacy and safety of both TCS and TCI for pediatric use concluded that TCI should be the standard-of-care maintenance therapy, with low-to-mid potency TCS used intermittently to control flares [60]. Twice-weekly application of TCI (rather than daily application) and regular emollient use is recommended for long-term maintenance therapy [22].

Patients who have experienced steroid-induced side effects when using corticosteroids for other pathologies are also candidates for treatment with TCI [25, 56].

Preclinical studies have shown that, unlike TCS and tacrolimus [83, 84], pimecrolimus does not affect epidermal Langerhans cells, which have an important role in cutaneous immunological responses [85, 86]. These findings have also been confirmed in a clinical study [87]. Analysis of skin biopsies from patients treated with pimecrolimus or betamethasone valerate (BMV) showed that pimecrolimus depleted T cells at sites of inflammation via the induction of apoptosis, but spared Langerhans cells, whereas BMV application depleted both Langerhans cells and T cells [87]. Both treatments also depleted dendritic epidermal cells in this study [87]. Tacrolimus depletes inflammatory dendritic epidermal cells with greater selectivity than TCS but also affects the immunophenotype of Langerhans cells [83, 84]. Pimecrolimus therefore has a more favorable balance of anti-inflammatory versus immunosuppressive activity compared with tacrolimus and TCS [88].

The beneficial property of TCI in terms of its lower potential for trancutaneous resporption is a particularly important consideration in thin skin areas because it reduces systemic exposure to topically applied medication. A comparison of the TCI revealed that pimecrolimus permeates the skin to a lesser extent than tacrolimus due to its greater lipophilicity and higher binding affinity for skin proteins [89, 90]. When pimecrolimus was compared with tacrolimus, the permeation of pimecrolimus through human skin was consistently lower by factors of 9–10, and in comparison with TCS the permeation was lower by factors of 70–110 [89]. While pimecrolimus possesses comparatively low exposure, it should be noted that patients treated with the highest concentration of tacrolimus (0.1%) experience low systemic exposure [91], and both TCI can be considered to be appropriate agents for situations requiring low permeability.

Given the mechanistic differences described above, we recommend pimecrolimus as the first-choice TCI for sensitive skin areas in mild-to-moderate disease; studies providing clinical evidence to support its use in special situations, such as facial AD, are summarized in Table 2 [69, 74, 92‐95]. As pimecrolimus is not indicated for severe AD, we recommend tacrolimus for sensitive skin areas beyond moderate disease, as tacrolimus is recommended for use in moderate and severe disease; short-term treatment with TCS may also be appropriate, with a subsequent switch to a TCI when inflammation subsides. For AD in other parts of the body, the selection of a TCI can be determined by physician and patient preference.