Clinical study on the effects of the applied volume of moisturizer in patients with asteatosis

Abstract Asteatosis is characterized by decreased stratum corneum water content, and the basic treatment is to keep the skin moisturized. Poor application of moisturizers by patients may reduce treatment efficiency, so it is important to continue application as instructed by dermatologists. Application instructions based on the finger‐tip unit are useful for patients, but there is no clear evidence of its efficacy. We investigated the effects of the volume of the moisturizer (Hirudoid® Cream 0.3%) administrated with 1/3 finger‐tip unit and 1 finger‐tip unit equivalent doses per target lower leg of patients with asteatosis (twice daily, 28 days) on the overall dry skin scores, itch numerical rating scale scores, and skin physiological parameters (stratum corneum water content, transepidermal water loss, and skin pH). Sixty patients were randomized with a 1:1 allocation ratio into two groups: the 1/3 finger‐tip unit and 1 finger‐tip unit equivalent dose groups. The results showed that 43.3% of the patients in the 1 finger‐tip unit equivalent dose group, compared with 13.3% in the 1/3 finger‐tip unit equivalent dose group, presented zero overall dry skin scores 1 week later. As the overall dry skin scores improved, the stratum corneum water content also increased. In patients with moderate itching, the itch numerical rating scale scores of the 1 finger‐tip unit equivalent dose group decreased significantly compared with those of the 1/3 finger‐tip unit equivalent dose group. The results suggested that the application of 1 finger‐tip unit equivalent dose of the moisturizer twice daily in clinical practice could induce remission more quickly. With the 1/3 finger‐tip unit equivalent dose, prolonged treatment may be necessary to achieve the desired effect; therefore, application adherence is strictly required. In conclusion, the application of a 1 finger‐tip unit equivalent dose would be quite reasonable in clinical practice.

therapy), and environmental factors (such as low humidity and low temperature). [1][2][3] In patients with asteatosis, the skin becomes white, scaly, and cracked, and is often itchy. 1,2 Scratching destroys the skin barrier and leads to asteatotic eczema or nummular eczema. In elderly patients, in particular, age-related reduction of sweating and sebum secretion lead to asteatosis and asteatotic eczema, which are commonly seen in clinical practice. These conditions are accompanied by itching, which causes poor quality of life, including a reduction in daily activities, appetite loss, or sleep disorders. 3,4 In addition, asteatosis also worsens other skin diseases, such as atopic dermatitis and psoriasis. Thus, it is important to prevent asteatosis. 5 The cornerstone of treatment for asteatosis is to keep the skin moisturized. Moisturizers are categorized as emollients, such as white petrolatum, and humectants, such as heparinoid preparations and urea preparations. In the case of asteatotic eczema, moisturizers should be continued, with the addition of topical steroids.
Moisturizers are usually applied by patients themselves or by caregivers. Skin care instructions need to be followed during application, especially in terms of volume and frequency of treatment. In dermatology, the finger-tip unit (FTU) is often used as a guide for the application of topical drugs such as ointment or cream. 6 One FTU, which is approximately 0.5 g, is the volume of the drug expelled from a tube with a 5-mm diameter nozzle from the tip to the distal interphalangeal joint of the adult index finger. This volume covers the area of two adult hands, which is approximately 2% of the body surface area. Some reports suggest that application instructions based on the FTU are useful for moisturizers, 7 but clinical studies have not been conducted to examine whether the 1 FTU equivalent dose is optimal. Due to the lack of reliable evidence, it is difficult for healthcare professionals to instruct an appropriate volume of application of a moisturizer to patients and caregivers, often resulting in misunderstandings or poor adherence. 8,9 According to an internet survey of 322 Japanese doctors (including dermatologists, pediatricians, and internists) exploring application instructions for prescribed moisturizers in clinical practice, the doctors reported explaining the frequency and timing of application to their patients. Conversely, it was revealed that many doctors frequently do not provide instructions on the volume of application (Internet survey by Macromill Carenet, 30 April 2020, not published).
The Internet survey was conducted on 818 patients or their parents at the same time and revealed that half of the patients who received the instructions about the volume of the moisturizers did not apply a volume equivalent to 1 FTU (Internet survey by Macromill Carenet, 30 April 2020, not published).
In addition, in a study including 62 healthy volunteers, the applied volume that was deemed appropriate without any specific instruction was investigated using topical bases, and there was a large variation (0.2-2.4 FTU equivalent) in volumes applied. 10 Over half of the volunteers did not apply the volume corresponding to 1 FTU equivalent dose, and the applied volume was instead 0.3-0.4 FTU equivalent dose in the case of half. 10 These results suggested that failure to understand appropriate volume instructions among patients would result in lower than intended equivalent doses in clinical practice.

| Study design
This study was performed as a single-center, randomized, singleblind (evaluator-blind), dose-comparison study with parallel-dose groups. The patients were randomized with a 1:1 allocation ratio by permuted block method with age (<65 years or ≥65 years) as a stratification factor. The study design is shown in Figure 1.
A fixed volume of the study drug was assigned to each treatment group, whereby approximately 0.5 g (1/3 FTU equivalent dose) was applied in one treatment group, and 1.5 g (1 FTU equivalent dose) was applied in the other group, twice daily for 28 days. The study drug was applied over the entire surface of the target lower leg of each patient in the morning and evening. The patients visited the clinic at week 0, which was the commencement of treatment, week 1, week 2, week 3, and week 4. Their overall dry skin (ODS) scores, itch NRS scores, and physiological functions of the skin were observed. Hirudoid ® Cream 0.3% (Maruho) was selected as the moisturizer.
The investigators instructed each patient to apply approximately 0.5 g (1/3 FTU equivalent dose) or 1.5 g (1 FTU equivalent dose) of moisturizer with the measuring spoon supplied by Maruho, and to spread the drug evenly on the target lower leg gently using his/ her hand. Moreover, the appropriate volume was ensured in each application by weighing the tube before and after use. The frequency of applications was checked in a patient's diary with every visit. Instructions to the patients were repeated as required. Patients were also instructed not to apply the moisturizer on the morning of the visit to the clinic. When eczema was observed on the target lower leg, topical steroids could be added as a rescue treatment, at the doctor's discretion.

| Inclusion and exclusion criteria
Patients with asteatosis, with an ODS score of 3 and no sign of eczema in at least one lower leg on the first day of the treatment, and who were at least 20 years of age were enrolled in this study.
The following patients were excluded from the study: (i) patients with a history or presence of serious allergic reactions (shock, anaphylactoid reactions) or hypersensitivity to topical medication; (ii) patients with skin diseases (except asteatosis) on the target lower leg or a bleeding hematological disease (hemophilia, thrombocytopenia, and purpura); (iii) patients who used any topical medicine (including non-prescription drugs or cosmetics) on the target lower leg within 14 days before treatment initiation; (iv) patients who used an antihistaminic drug within 14 days before treatment initiation; and (v) patients who used oral corticosteroids within 90 days before treatment initiation.

| Overall dry skin scores
The dermatologist evaluated the severity of dry skin on the target lower leg using the 5-point ODS scores: 0, absent; 1, faint scaling, faint roughness, and dull appearance; 2, small scales in combination with a few larger scales, slight roughness, and whitish appearance; 3, small and larger scales uniformly distributed, definite roughness, possible slight redness, and a few superficial cracks; and 4, dominated by large scales, advanced roughness, redness present, eczematous changes, and cracks. 11 Representative images of the skin for each ODS score are shown in Figure 2.

| Itch numerical rating scales scores
The patients evaluated the severity of average itching in the previous 24 h using the NRS scores between 0 (no itching) and 10 (the worst itching they ever experienced). 12,13

| Physiological functions in the skin
The SCWC, TEWL, and skin pH were measured at one site (3 cm × 3 cm in area) of the target lower leg. The SCWC was measured using a Corneometer CM825 device (Courage + Khazaka Electronic). The mean value of five independent measurements at F I G U R E 1 Study design. The patients were subjected to a permuted block randomization process for equal allocation between the two dose groups. If the patients showed eczema after the start of treatment, the rescue treatment (topical administration of steroids) could be added under the direction of the doctor. The study treatment was continued if the overall dry skin score was 0. FTU, finger-tip unit F I G U R E 2 Representative images for each overall dry skin (ODS) score. Each picture shows an ODS score of 0, 1, 2, and 3. Patients with an ODS score of 3 were enrolled in this study; images up to an ODS score of 3 are shown a single site was used for the evaluation. The TEWL was measured using a portable VapoMeter device (Delfin Technologies; Keystone Scientific). The mean value of three measurements at a single site was used for the evaluation. Skin pH was measured using a Skin-pH-Meter PH905 (Courage + Khazaka Electronic). The mean value of three measurements at a single site was used for the evaluation.

| Adverse events
Information on adverse events (AE) experienced by the patients during the study period was collected for the safety analysis. AE included all unfavorable or unintended symptoms, diseases, and aggravation of present diseases.

| Statistical analysis
Adjustment for multiplicity in the test was not performed. All tests were performed as two-sided tests at a 5% significance level. The two-sided 95% confidence interval (CI) was also calculated. Results are shown as the mean ± standard deviation (SD).
The ODS and itch NRS scores were compared between the treatment groups at each evaluation time point and compared with those of week 0 in each treatment group. The differences between the treatment groups were compared using the Wilcoxon rank-sum test, and the differences in each treatment group were compared using the Wilcoxon signed-rank test.
The SCWC, TEWL, and skin pH were compared in each treatment group with those of week 0 using the paired t-test. The changes in the SCWC and TEWL were compared between the treatment groups at each evaluation time point using the two-sample t-test.
The correlation between the ODS scores and SCWC was calculated using Pearson's correlation coefficient.

| Study population, baseline demographics, and clinical characteristics
Sixty patients were enrolled in this study ( Figure 3). Four patients  Table 1. There were no differences in the characteristics between the two groups. The mean age ± SD of the patients was 45.5 ± 10.8 and 47.7 ± 9.2 years for the 1/3 FTU and 1 FTU equivalent dose groups, respectively.
Regarding complications, one patient in the 1/3 FTU equivalent dose group had diabetes mellitus, eight and four patients had allergic rhinitis in the 1/3 FTU and 1 FTU equivalent dose groups, respectively, and six and four patients in the 1/3 FTU and 1 FTU equivalent dose groups had allergic conjunctivitis, respectively. Table 1, all patients (60/60, 100%) lacked experience in receiving skin care instructions and knowledge of the FTU, and 88.3% of the patients (53/60) had no history of treatment for asteatosis.

| Application adherence
The rates of application adherence of the 1/3 FTU and the 1 FTU equivalent dose groups were 99.3% (range, 88.5-100.0%) and 99.7%

| Changes in itch NRS scores
Changes in the itch NRS scores are shown in Figure 5. Almost all pa- was somewhat higher than that of the 1/3 FTU equivalent dose group (2.6) in week 0, but it decreased to comparable scores (1.4 and 1.2, respectively) in week 1, followed by similar profiles in weeks 2, 3, and 4.
We classified and analyzed cases according to the degree of mild and moderate itch, regarding the itch NRS scores of 3 or less as mild and 4 or more as moderate. 12,13 In the patients with mild itch, no difference in the changes in itch NRS scores was observed between the two groups ( Figure 6a). Conversely, in the patients with moderate itch, the changes in itch NRS scores of the 1 FTU equivalent dose group were significantly lower than those of the 1/3 FTU equivalent dose group (p < 0.05, Figure 6b).

| Physiological functions in the skin
The physiological parameters are summarized in Table 2. No differences in baseline characteristics for each parameter were observed between the groups. F I G U R E 3 Subject disposition. The investigator decided to discontinue participation in four patients because they did not visit the clinic. FTU, finger-tip unit Significant differences in the measured values of males and females were observed in the TEWL (males: 9.06 ± 1.33; females: 7.52 ± 1.59; p < 0.001) and skin pH (males: 4.636 ± 1.303; females: 5.690 ± 1.751; p < 0.016), but no differences in the SCWC were The TEWL decreased significantly in weeks 2, 3, and 4 in both groups compared with that in week 0 (p < 0.001) but reached a plateau in weeks 3 and 4 in both groups (Table 2). There was no difference between the changes in either group (Figure 8). The skin pH was slightly acidic at week 4 compared with week 0 in both groups (Table 2). There was no significant difference between the groups.

| Relationship between skin symptoms and physiological functions
The ODS scores decreased significantly, and the SCWC increased

| Safety
Three AE of itching were observed in three patients in the 1 FTU equivalent dose group, and none of these were serious events. All patients continued the study and recovered without any medical treatment.

| DISCUSS ION
Asteatosis is a disease resulting from a decrease in the water content of the epidermal stratum corneum and may induce inflammatory cascades that trigger itch. 1,14 Patients with asteatosis often experience symptoms of itching. 1,2 Scratching the skin damages the barrier function and results in the worsening of symptoms. Therefore, early moisturizing care of the affected region would be very important in patients with asteatosis to prevent the progression of symptoms. 1,14 Unlike oral medications, the treatment effects of topical medication greatly depend on the adherence and understanding of each patient, which tend to decline in clinical practice. [15][16][17] Moisturizers are known to exert a more beneficial effect when applied twice daily rather than once daily. 18 guidelines for the management of atopic dermatitis 2018" in Japan state that moisturizers should be applied twice daily. 20 As for the volume of moisturizer to be applied, some reports recommended applying a 1 FTU equivalent dose, 7 but the recommended volume has not been supported by clinical studies. Therefore, we focused our study on the evaluation of outcomes based on the applied volume of moisturizers.
We investigated whether the treatment outcomes with the application of moisturizer twice daily were different between the 1 FTU equivalent dose (~ 1.5 g/target lower leg) and 1/3 FTU equivalent dose (~0.5 g/target lower leg) in patients with moderate to severe asteatosis. The 1/3 FTU equivalent dose was selected as "a usual dose in clinical practice" because it was considered appropriate by patients who had not received any dosage instructions from their treating clinician. 10 The results after twice daily treatment with the moisturizer showed that the dry symptoms of the skin in the 1 FTU equivalent dose group improved earlier than in the 1/3 FTU equivalent dose  20,21 In this study, however, the treatment effect of a 2 FTU equivalent dose was not considered as this is considered to be an excessive amount for application, and it will not remain on the skin because a portion of the coating drug attaches to clothes in daily life.
The improvement in skin symptoms was also supported by an increase in SCWC. Compared with the quick improvement of the ODS scores and the SCWC, the TEWL began to decrease at week 2 or later, suggesting that the improvement of the skin barrier function requires more time. Furthermore, we found the pH of the skin to be slightly acidic at week 4. Of note, the restoration of the skin barrier function has been reported to be hampered in alkaline conditions. [22][23][24][25] This study had some limitations. First, we used only a heparinoid preparation (Hirudoid ® Cream 0.3%) as a moisturizer, and the effects of other moisturizers need to be investigated further. Second, the number of elderly patients was small.
In conclusion, we investigated the effects of two different applied volumes (1/3 FTU and 1 FTU equivalent doses) of the moisturizer. Among patients assigned to the 1 FTU equivalent dose group, the ODS scores improved significantly in week 1, and more patients had zero scores compared with those assigned to the 1/3 FTU equivalent dose group. The results suggest that the application of 1 FTU equivalent dose of the moisturizer twice a day in clinical practice could induce remission more quickly. With 1/3 FTU equivalent dose, prolonged treatment may be necessary until the desired treatment effect is achieved, and high adherence to the treatment is strictly required. Therefore, the 1 FTU equivalent dose would be quite reasonable for application instruction in clinical practice.

ACK N OWLED G M ENTS
The authors would like to thank the members of Shinanokai, Shinanozaka Clinic (Tokyo, Japan) and the patients who participated in this study.