Efficacy and safety of a facial serum and a mask containing salicylic acid and lipohydroxy acid in acne management: A randomized controlled trial

Inflammatory and non‐inflammatory acne lesions constitute a significant clinical challenge in acne subjects.


| INTRODUC TI ON
Acne vulgaris is a chronic skin disease characterized by inflammatory and non-inflammatory skin eruptions, including pustules, papules, and open and closed comedones. 1 From a pathogenetic perspective, the development of facial acne might be influenced by the regulatory activity of sebaceous glands and disturbances in the sebum composition. 2 Subjects with even mild acne can show defective skin barrier, decreased skin hydration and increased sebum secretion.
Pigmentary alterations, such as post-inflammatory erythema (PIE) and post-inflammatory hyperpigmentation (PIH), represent a clinical challenge; they are reported in more than 80% of all acne patients and could last up to 5 years. 3 Those alterations are developed simultaneously with acne, due to the inflammatory process stimulating excess melanogenesis and abnormal melanin deposition. 4,5 Although PIH is reported more often in patients with darker skin phototypes (Fitzpatrick III-VI) and PIE in lighter skin, both could be more distressing than active acne lesions and constitute a significant clinical challenge. 4 These chronic skin conditions have been reported to affect the health-related quality of life on multiple dimensions, including psychosocial consequences such as anxiety and depression. 6 Topical retinoids, benzoyl peroxide, azelaic acid, and combinations of topical agents are currently considered the first-line choice in the management of acne. 7,8 Combining retinoids with other topical agents, procedures and oral therapies is also recommended. 7 Although some of these agents could effectively prevent PIE and/ or PIH, 9 clinical studies addressing their use are limited and often biased by small sample sizes. Moreover, the question of combining various skin care products and cosmetics that may also stimulate hyperpigmentation is rarely addressed.
It was reported that lipohydroxy acid (LHA) formulation significantly decreased both the number and total size of microcomedones in 2 weeks in acne-prone subjects. 10 In previous reports, salicylic acid (SA) was shown to effectively treat acne vulgaris and PIH, 11 while serum containing diacid, glycolic acid, SA, LHA, citric acid and hydroxyethyl piperazine ethyl sulfonic acid (HEPES) significantly improved PIH and helped control sebum production. 12,13 Based on the above, this randomized controlled study aimed to evaluate the efficacy and safety of a facial serum and a mask containing multiple components, including SA and LHA, for improving the skin condition and acne management in adult acne in combination with sebum dysregulation.

| Study design and subjects
This randomized controlled study enrolled adults with inflammatory and non-inflammatory acne lesions as well as self-assessed sebum dysregulation in Shanghai, China, in July 2021.
Inclusion criteria were as follows: (1) 18-45 years of age; (2) ≥10 blackheads on the nose, as examined by the dermatologist; (3) ≥8 closed comedones (whiteheads), papules, pustules, and foci of PIE and PIH were counted by the dermatologist. The intensities of PIE and PIH were assessed by the visual analogue scale (VAS), ranging from 0 to 9 points, with 0 representing none and similar to the bare skin, and 9 points representing very dark and significant pigmentation. Skin tone evenness was also assessed by the VAS score, ranging from 0 to 9 points, with 0 representing even and healthy skin color, and 9 representing uneven and discolored appearance (brown and/or red foci).

| Instrumental assessment
The density of skin pores was assessed with the Dermascore® system (L'Oreal, Paris, France) with grades ranging from 0 to 7, with 0 representing absence of pores and 7 representing extreme presence ( Figure S1).
Sebum secretion of the forehead skin ( Figure S2A

| Participant-reported outcomes
A self-assessment questionnaire of product efficacy evaluation was filled out by each subject at T14d and T56d. Scores for each question were 1-5 points: 5, agreement; 4, relative agreement; 3, neutrality; 2, relative disagreement; and 1, disagreement. The proportion of subjects with 4 or 5 points for each question was calculated.

| Statistical analysis
Statistical analysis was performed with SPSS (version 25.0, IBM).
Continuous data with normal distribution were expressed as mean ± standard deviation (SD) and compared between the two groups by the Student's t test. Continuous data with non-normal distribution were expressed as median (interquartile range) and analyzed by non-parametric tests. Repeated measured continuous data were analyzed by ANOVA or the Wilcoxon rank-sum test. Categorical data were expressed as frequency and percentage, and analyzed by the Chi-square test or Fisher's exact test. Two-sided p < 0.05 was considered statistically significant.

| Study flowchart
A total of 154 subjects were screened, of whom 61 did not meet the eligibility criteria. Thus, 93 participants were enrolled and randomized, including 45 and 48 in the Serum + Mask and Serum groups, respectively. Four subjects in the Serum + Mask group and 6 in the Serum group voluntarily withdrew from the study without follow-up.
Finally, 41 and 42 subjects in the Serum + Mask and Serum groups were included in the analysis, respectively ( Figure 1).

| Baseline characteristics of the participants
Mean ages of the participants were 33.15 ± 7.00 and 32.95 ± 6.50 years in the Serum + Mask and Serum groups, respectively; 75.90% of the participants were women, and 21.68% had selfassessed sensitive skin. PIE intensities at baseline were 3.71 ± 0.20 and 3.76 ± 0.19 in the Serum + Mask and Serum groups, respectively.
PIH intensities at baseline were 4.20 ± 0.09 and 4.29 ± 0.14, respectively. As shown in Table 1, the skin condition at baseline was balanced between the two groups, without significant differences.

F I G U R E 2
Changes from baseline in investigator global assessment score of acne severity (A), skin pore density (B), and skin tone evenness (C) in both groups. *p < 0.05 versus baseline. ***p < 0.05 between the two groups.

F I G U R E 3 Changes from baseline in the number of closed comedones on the face (A) and open comedones on the nose (B) in both
groups. *p < 0.05 versus baseline. ***p < 0.05 between the two groups.

| Advantages of study mask in addition to the serum
A difference in efficacy was noted at some points between the two groups. Particularly, at T56d, acne severity in the Serum + Mask group was significantly improved compared with baseline (p = 0.002), and the improvement was significantly more pronounced than that of the Serum group (−0.39 ± 0.08 vs. −0.12 ± 0.09, p = 0.026) (Figure 2A). In addition, the number of closed comedones on the face was improved in the Serum + Mask group compared with the Serum group at this time point (−6.56 ± 0.39 vs. −5.19 ± 0.44, p = 0.022; Figure 3A). The improvement of skin tone evenness from baseline was faster in the Serum + Mask group than in the Serum group, starting at 1 and 8 weeks post-treatment, respectively ( Figure 2C). At T56d, the improvement in PIH intensity was significantly more pronounced in the Serum + Mask group than in the Serum group ( Figure 5B).

| Participant-reported outcomes
At weeks 2 and 8, more than 88% of the subjects thought that the study products were enjoyable to use, and the skin felt more comfortable ( Table 2). From week 2 to week 8, the proportion of subjects who were willing to continue using the serum and mask increased (both ≥98% at week 8) (Table 3). No burning sensation, tingling sensation, allergy, and other adverse reactions or skin discomfort were observed during the study in either group.

| DISCUSS ION
This randomized controlled study evaluated the efficacy, safety, including cosmetic products. 18,19 A previous randomized, placebocontrolled study reported its effectiveness for facial skin aesthetics and well-being. 20 Our results indicate that the study serum was highly effective against both inflammatory and non-inflammatory acne lesions, which was consistent with previous reports.
Topical agents used for facial acne treatment usually have a comparatively rapid onset of action. Some of the previous trials showed that combinations of stearic acid/glycolic acid/SA/LHA/ citric acid/HEPES and clindamycin/benzoyl peroxide usually show improvement within 2-4 weeks. 13,21 Improvement in PIH symptoms, however, requires a longer treatment period (up to 8 weeks) in the trials of serum containing HEPES 12 and 30% SA. 11 In this study, PIE and PIH intensities, as well as skin pore density and sebum secretion were significantly different from baseline after 2 weeks of treatment, but the most promising results were observed during the later visits. SA reduces melanin levels and tyrosinase activity in normal epidermal melanocytes and inhibits melanocyte melanogenesis and melanin transport, and, thus, improves skin pigmentation. 22 This study found that the addition of a mask accelerated the effects of treatment without compromising safety. When exposure was prolonged by combining the serum with a mask, the improvements of closed comedones on the face, acne severity, PIH intensity, and skin tone evenness were more pronounced than using the serum alone. Both the serum and mask contained SA, which may enhance the efficacy of dissolving oil and dredging pores. Bamboo activated carbon base, used in the mask, can strengthen oil adsorption on skin surface. 23 As a result, adding the mask could improve acne severity (−0.39 ± 0.08 vs. −0.12 ± 0.09, p = 0.026) and closed comedones on the face (−6.56 ± 0.39 vs. −5.19 ± 0.44, p = 0.022) more significantly than simply using serum. Furthermore, the study mask contained nicotinamide, which has been shown to improve PIH intensity and skin tone evenness. 24 High-molecular-weight sodium hyaluronate, another component in the study mask, showed remarkable efficacy in anti-inflammation and could improve the anti-inflammatory properties of carnosine. 25 In contrast to a previous study of SA, 11 no adverse reactions, including burning sensation, exfoliation, and acne outbreak, were reported in the present study, suggesting that the study product could be safely used for a long period. Skin hydration in both groups was significantly improved compared with baseline, while TEWL was similar to baseline. In addition, sebum secretion was significantly improved from baseline in both groups. Consequently, the two products tested had excellent safety profiles due to their ability to moisturize and control sebum secretion while not compromising skin barrier function. It is noteworthy that acne-prone subjects usually require daily skin care to maintain a balance of skin hydration and sebum contents, and the study serum and mask were appropriate for long-term daily use.
Although to achieve statistical significance the number of participants should most likely be higher, about one fifth of all subjects had sensitive skin, and more than 90% of subjects felt more comfortable during the final visit. There was a high degree of satisfaction with both products after 8 weeks, with 98% and 100% of the subjects willing to continue using the mask and serum.
This study had some limitations. First, the Global Evaluation Acne (GEA) scale was not applied for the assessment of acne severity, as the subjects had mild-to-moderate acne that only required daily skin care rather than comprehensive treatment. Second, this study was not designed to be split-face controlled, as half-face use of the mask may cause issues with compliance and impair self-assessment by the subjects.
In conclusion, using the study serum for 8 weeks improved the skin condition by regulating skin barrier function and achieving a balance of skin hydration and sebum secretion, removing acne and TA B L E 2 Self-assessment. Niu, Andrew Steel, and Hequn (Tracy) Wang carried out the data collection and data analysis and revised the paper. All authors reviewed the results and approved the final version of the manuscript.

ACK N OWLED G M ENTS
This study was funded by L'Oreal.

CO N FLI C T O F I NTER E S T S TATEM ENT
No conflict of interest was reported by the authors.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

E TH I C S S TATEM ENT
This study was approved by Shanghai Ethics Committee for Clinical Research (Review No.: SECCR/2021-94) and registered in http:// www.chictr.org.cn/index.aspx (Registration ID: ChiCTR2200061221).
All subjects provided signed informed consent before enrollment.

PH OTO CO N S ENT S TATEM ENT
All subjects provided signed informed consent.