The efficacy of topical 0.1% adapalene gel for use in the treatment of childhood acanthosis nigricans: a pilot study.

AIMS: To assess the degree of improvement of neck hyperpigmentation in childhood acanthosis nigricans (AN) after treatment with topical 0.1% adapalene gel and the assessment of localized tissue tolerance to the gel. SUBJECTS AND METHODS: A split comparison study of the hyperpigmentation on the neck was conducted in patients diagnosed with childhood AN. Patients were treated with topical 0.1% adapalene gel for a period of 4 weeks. The skin color of their neck was evaluated at baseline, 2 weeks and 4 weeks using a skin color chart. Skin color ratio (the skin on their necks compared with the skin on their backs) was calculated for all subjects. The investigator's global evaluation (IGE) scale and the parent's global evaluation (PGE) scale were used to assess the efficacy of the patients' treatment at the end of the 4(th) week.
RESULTS: The mean skin color ratio of therapeutic side was significantly decreased from the baseline scores, at weeks 2 and 4, respectively (30.1%, 18.3%, and 12.9%, P < 0.001), with marked skin improvement at 60.7% ± 28.5%. The percentage of changes of skin color ratio was consistent with the efficacy evaluations as performed by the IGE and PGE scales. Treatment-related cutaneous irritation was minimal, predominantly in the first 2 weeks of treatment and was shown to be well-tolerated at week 4 following a modification of the treatment regimen.
CONCLUSIONS: The study has shown the efficacy of topical 0.1% adapalene gel in the treatment of AN, specifically, in regards to the skin darkening with minimal cutaneous irritation.

What was known?

Childhood acanthosis nigricans (AN) is often associated with childhood obesity and insulin resistance. Retinoids have been reported to be successful in the treatment of AN.

Introduction

Acanthosis nigricans (AN) is a dermatosis typically characterized by areas of thickened, brownish-black, hyperkeratotic plaques. The posterior neck fold is the most common location of these plaques.[1] However, it may also involve the eyelids, lips, mucosal surfaces, the dorsal areas of the hands, and the flexural areas in the groin. It is often associated with childhood obesity and insulin resistance which can predispose early diagnoses of related disorders that include type 2 diabetes and other endocrinological diseases as well as malignancy.[2] Epidermal keratinocytes and dermal fibroblasts stimulated by growth factors are considered to be important in the pathogenesis of AN. Concomitant with an increasing prevalence of childhood obesity in Thailand,[34] AN has also shown to be increasing. This is associated with psychological consequences, especially, compounding problems with low self-esteem already experienced with the problems of obesity. The improvement of the skin lesions is often the patients’ primary concern.

To date, no randomized, controlled trial exists for any treatments for AN. Retinoids have been reported to be successful in the treatment of AN. Topical 0.1% tretinoin has shown an improvement of AN within 2 weeks of treatment.[5] Another patient had shown resolution of AN after the application of 0.1% tretinoin gel, twice a day for 2 weeks.[6] Common treatment-related adverse events include erythema, scaling, skin dryness, and resulting irritation as experienced with stinging and burning sensations.

Adapalene, a 3rd generation topical retinoid, is commonly used in the treatment of mild to moderate acne vulgaris.[7] Adapalene affects the cellular keratinization and the inflammatory process. The anti-inflammatory activity is due to inhibition of lipooxygenase and the oxidative metabolism of arachidonic acid.[8] This anti-inflammatory effect may be the reason for a decreased risk of irritation as shown with adapalene use. Adapalene has a very low percutaneous absorption.[8] Erythema, dryness, peeling, and burning are the most frequently encountered side effects. Thus, adapalene may be beneficial in the improvement of skin lesions associated with AN with minimal adverse cutaneous reactions.

This study's aim is to assess the degree of improvement of the neck darkening in childhood AN after treatment with topical 0.1% adapalene gel and to assess its localized tissue tolerance.

Subjects and Methods

Study design

The study was designed as a split comparison study of the hyperpigmentation on the neck of the patients with a 4-week trial of topical 0.1% adapalene gel. The efficacy and local tissue tolerance of topical 0.1% adapalene gel were compared with placebo gel. The participants were given two unlabelled packs of topical agents; adapalene gel and a placebo. They were informed to perform daily application of adapalene gel on the target side of their neck and the placebo on the opposite side for a period of 4 weeks. Patients were not allowed to use any other treatments and were instructed to contact the investigators if they experience any problems during the study period. Body weights (kg) and heights (cm) were recorded along with a calculated body mass index (BMI, kg/m2) for every patient. Efficacy and safety evaluations were performed at the baseline, at week 2 and at week 4 by a physician as an evaluation done in the blind. The study had been reviewed and approved by the appropriate institutional review boards and the ethics committee of HRH Princess Maha Chakri Sirindhorn Medical Center. All patients and their parents had signed and presented their letters of consent before engaging in this study.

Subjects

The subjects who participated in our study had to be 12 years of age or older with a diagnosis of AN. The exclusion criteria included infectious skin diseases, other serious medical disorders, diagnosis of diabetes mellitus, other recent diseases involving the neck, and any patients having received other therapies for up to 4 weeks prior to enrollment.

Efficacy and local tissue tolerance assessments

The skin color at the neck and interscapular areas (assumed as the baseline normal skin color) of all subjects was ranked according to Felix von Luschan's Skin Color chart [Figure 1][9] skin colors were ranged from 1 to 36, by one blinded investigator and were calculated as skin color ratio (skin color ratio = [(skin color at the neck on visit - skin color at the interscapular area)/skin color at the interscapular area] × 100) for each visit. The efficacy of the treatment was determined by the percentage of change of the skin color ratio (week 0 vs. week 4). The investigator's global evaluation (IGE) and parent's global evaluation (PGE) were also used to evaluate the overall success rate. IGE and PGE scales were evaluated on a scale ranging from 0 to 6 [0; clear (100% improvement)], [1; almost cleared (90-99% improvement)], [2; marked improvement (75-89% improvement)], [3; moderate improvement (50-74% improvement)], [4; mild improvement (≤50% improvement)], [5; no change], and [6; worsening].

Figure 1

Felix von Luschan skin color chart

Local tissue tolerance evaluation was conducted at all study visits with an assessment of any cutaneous irritation. At each visit, the investigator graded the degrees of erythema, dryness, peeling, burning, and itching using a scale of 0 to 4 (0; none, 1; slight, 2; mild, 3; moderate, and 4; severe).

Statistical analysis

Data were analyzed by using SPSS version 19 (IBM, New York). A repeated measure of the analysis of variance was used to compare the skin color ratios between the baseline and at weeks 2 and 4. A difference was considered statistically significant when the P < 0.05. An independent sample t-test was used to assess the correlation between the skin color change ratios, the patients’ age, body weight, body weight changes during the study, and the BMI.

Results

A total of 16 patients with AN were enrolled in the study. The mean age of the subjects was 13.4 ± 1.4 years of age. Most of the patients were female (62.5%). Mean body weight, BMI, and body weight changes during the study were 74.9 ± 13.8 kg, 28.6 ± 4.6 kg/m2, and 0.23 ± 1.2 kg, respectively. Obesity was the most common predisposing factor in the patients with AN, 100% and 75% of the patients had BMIs over the 85th and 95th percentile ranks for their ages, respectively. The mean skin color ratio at the target side at week 0, 2, and 4 was 30.1% ± 9.7%, 18.3% ± 10.6%, and 12.9% ± 11.2%, respectively, while the mean skin color ratio on the opposite side at week 0, 2, and 4 was 30.1% ± 9.7%, 29.4% ± 10.9%, and 28.9% ± 11.1%, respectively.

After 4 weeks, topical 0.1% adapalene gel had shown to be significantly superior to the placebo. The success rate was observed at the 2nd week of treatment and continuously increased throughout the course of the study, with a statistically significant difference percentage of change [Table 1]. The average percentage change of the skin color ratio between baseline and at the end of the 4th week on the target side and the opposite side was 60.7% ± 28.5% and 6.6% ± 10.9%, respectively. No correlation among the percentage of change of the skin color ratio to age, body weight, body weight changes during the study, or BMI (P > 0.1) was found.

Table 1

Repeated measures of ANOVA analysis compared between skin color ratios of therapeutic side at weeks 0, 2, and 4

The percentage of change of skin color ratio was consistent with the efficacy evaluations as performed by the IGE and PGE scales. Overall, 56.2% of the assessors reported that IGE and PGE scales at week 4 had shown more than 50% improvement [Table 2]. Representative photograph of the patient showed the skin color improvement [Figure 2].

Table 2

IGE score and PGE scales observation of therapeutic side at week 4

Figure 2

Comparative photograph between application of topical 0.1% adapalene and placebo at week 4. The photograph shows an improvement in the neck darkening and skin thickening

Local tissue tolerance

Overall, topical 0.1% adapalene gel was well-tolerated. A total of eight patients (50.0%) experienced cutaneous irritation at week 2 and the incidence decreased to four patients (25%) at week 4 [Table 3] and it was scored as a mild reaction by the end of study on therapeutic side [Figure 3]. There was no cutaneous irritation on the neck applying the placebo. Treatment-related cutaneous irritation was minimal, with signs of slight skin dryness, peeling, erythema, and burning sensation. The highest irritation scores were recorded during the 1st week and subsequently declined throughout the treatment. There was no discontinuation related to cutaneous irritation. One patient had experienced erythema and a burning sensation. The patient was instructed to change the application regimen of the topical 0.1% adapalene to every other day. As a result, the cutaneous irritation gradually improved.

Table 3

Overall treatment-related cutaneous irritation of therapeutic side

Figure 3

Cutaneous irritation grading scales in the patients (erythema, dryness, peeling, burning, and itching)-0: None, 1: Slight, 2: Mild, 3: Moderate, and 4: Severe

Discussion

This pilot study has shown the efficacy of topical 0.1% adapalene gel which confirms that topical retinoid can be useful in the treatment of AN. Our finding was consistent with the results of previous studies.[56] The postulate mechanism of the therapeutic effect was to modify the epidermal keratinization.[8] The histopathology of AN after retinoid application has also shown nearly complete reversion to the normal state.[10] According to reports of the early effectiveness of retinoids, and also the restrictions of the study of topical 0.1% adapalene in children,[5610] we designed the study's duration as ending at 4 weeks. As the result of the study, rapid improvement was observed at the 2nd week of treatment and increased continuously throughout the course of the study. Nevertheless, AN was not cured, and relapses of AN could be found after stopping the treatment and further treatments were required to maintain the overall improved status.[1011] The extended duration of treatments and the safety of topical 0.1% adapalene use in children should be studied further.

In addition to topical therapy, multiple case reports suggested that AN can be improved with treatment of its underlying condition.[121314] Herein, we found that obesity was the major predisposing factor in the development of AN. Therefore, body weight change could be a factor that could possibly affect the results of treatment. Accordingly, in obese patients, AN could be improved with weight reduction.[1314] In our study, there has not been any statistically significant correlation among the percentage of change in the skin color ratio with age, body weight, and body weight changes during the study, and/or BMI. A combination of treatment and weight control could possibly be beneficial for obese patients. However, the treatments should be directed to the underlying causes.

Currently, a wide range of techniques are available to aid physicians in the assessment of skin color among which visual assessment remains the gold standard.[15] Moreover, there were also reports given to the roles of photographs and skin color scale charts used to assess the skin color.[151617] As each patient had different skin colors and skin tones in their neck at the start of treatment, to obtain a comparable proportion, we calculated the patients; skin to skin color ratio and the percentage of the intensity of the color on their necks as compared with their normal skin color. The skin color ratio before and after treatments were then compared to assess the treatment outcomes and to perform statistical comparisons. Other than the differences in their skin color, there may have been thickening of the skin with intensification of the skin markings which should be considered in the evaluation method.

Although there have been reported systemic side effect of retinoids.[18] Over the past decade, no systemic side effects on long-term treatment with topical retinoid have been observed. Furthermore, with appropriate use, there was minimal percutaneous absorption of tretinoin into the circulation.[19] The frequent adverse effect of topical retinoids is skin irritation. The other side effect associated with topical retinoid therapy is photosensitization, which commonly occurs at the beginning of the therapy. Irritation of the skin was the major factor that affected adherence to treatment regimens. In our study, the reports of skin irritation were mild for most of the patients, occurring during the first 2 weeks, and improving by the end of the treatments, with modification to application every other day instead of a daily application to minimize early irritation. Although adverse effect of topical retinoid was skin irritation, several comparative studies had shown that topical adapalene has shown a better cutaneous safety profile than other formulations of tretinoin.[2021] Cutaneous safety, tolerability, and compliance with topical 0.1% adapalene gel therapy was of particular importance in the overall effectiveness of AN treatment.

In conclusion, this study has shown the efficacy of topical 0.1% adapalene gel in the treatment of AN, specifically regarding the skin darkening, and it has been generally well-tolerated. Additional studies with higher numbers of subjects are recommended to help confirm these results.

What is new?

The study has shown the efficacy of topical adapalene in the treatment of childhood acanthosis nigricans.