A 595 nm pulsed dye laser as an adjuvant intervention for post‐comedone extraction erythema and comedone reduction: A randomized, split‐face controlled trial

Comedone extraction provides greater satisfaction for acne treatment than conventional treatment alone; however, post‐comedone extraction erythema (PCEE) remains a concern for patients.


| Participants
The inclusion criteria were healthy acne participants aged between 12 and 25 years with mild to moderate acne severity according to the comprehensive acne severity scale (CASS) 11 (grades 2 and 3).The exclusion criteria were those with recent facial laser or light therapy within 3 months, use of systemic retinoids within 6 months, signs of androgen excess, and current medication intakes including over-thecounter acne products.The washout periods were 2 weeks for topical acne treatments, 4 weeks for oral antibiotics, and 12 weeks for contraceptive medication.

| Study procedures & assessments
Baseline demographic data included sex, age, history of topical and systemic medications, previous laser treatment, daily routine use of dermocosmetics (moisturizer, sunscreen, cosmetics, etc.), Fitzpatrick's skin type, and acne lesion counts (comedone, papules, pustules, and nodules).The participants were photographed by VISIA® (Canfield Scientific, Inc., Parsippany, NJ).CASS were evaluated from the recorded images all 3 visits by 3 independent pediatric dermatologists (S.W., T.T., and S.C.), blinded as to which side received treatment.The final CASS score was calculated as the mean from the three scores.
Comedone extraction was performed by a single physician (R.B.).After anti-septic application, the optimal pressure along the downward direction of the hair follicle was centrally applied by the comedone extractor.The optimal pressure was defined as minimal pressure needed to extract the entire comedone contents.To make minimally traumatized extractions in closed comedones, the uppermost surface was pierced by a 21G needle before performing the extraction. 5 obtain the sampling of selected lesions for comedone extraction, a mid-pupillary line was vertically drawn.On each side of the face, 3 prominently visible closed comedones nearest to the line of the midface below the forehead were selected.
All participants were blocked-randomized for the PDL-treated side and the control side in a split-face fashion.To identify the erythematous lesions caused by comedone extraction, a flexible, nonstretchable plastic facial mask was designed for each participant's face.After placing the mask on the face, the erythematous lesions caused by comedone extraction were circled and numbered.The location of medial and lateral canthus of the eyes, nasal ridge, and tip of the nose were marked on each individual plastic mask to allow the evaluation of erythematous lesions exactly on the same spots during the follow-up visits.
The PCEE was quantitatively measured by the erythema index (EI) by Mexameter® (MX18, Courage and Khazaka, Cologne, Germany) three times with the mean used for analysis.The mean EI on the same spots at every follow-up visit was evaluated for EI differences.
The PDL therapy (V-beam perfecta, Syneron Candela, MA, 595nm PDL) with parameters 10-ms pulse duration, 7-mm spot size, 8-J/ cm 2 fluence, and a cryogen cooling device was delivered to the randomized side in a painting pattern with 10% pulse overlapping for 1 pass by a single physician.The area of treatment was from the hairline to the jawline without eyelid involvement.An additional shot was repeated only at each selected comedone extraction site.
For the control group, an identical PDL treatment protocol was performed without the delivery of laser energy.
Participants were evaluated in 3 visits: day 0 (at baseline), day 14 ± 2, and day 28 ± 2. Baseline demographic data, TALC, acne severity, and EI were recorded.On the 2nd visit (day 14 ± 2) and the 3rd visit (day 28 ± 2), participants were assessed by the same physician for TALC, acne severity, and EI.History of menstruation in female subjects and mental tension/stress under examination within 1 week prior to the follow-up visits were additionally reviewed.Participant satisfaction was measured by a numeric rating scale (0-10 from dissatisfied to most satisfied) at the end of the study.The adverse effects caused by PDL were recorded on both follow-up visits.
The EI and TALC were compared between the PDL-treated side and the control side at baseline and each follow-up visit of the study in split-face fashion.All measurements were conducted by a single blinded investigator.Intention-to-treat analysis was the guiding principle for data assessment.

| Acne lesion counts and comprehensive acne severity scales
At baseline, there were no statistically significant differences in acne lesion counts in all subcategories of comedones, papules, pustules, and TALC, as well as CASS, between the PDL-treated and the control sides.Comedones were the most prominent acne lesions, while papules and pustules were slightly found among participants throughout the study.Nodular lesions were not observed during the study.
For the crude number, there were significantly fewer comedones (p = 0.001) and a lower TALC (p < 0.001) at day 14 on the PDL-treated side compared to the control side.Day 28 showed an increasing crude number of comedones and higher TALC compared to day 14.
Notwithstanding the difference in median acne counts from baseline, the PDL-treated side had a significantly lower number of comedones (Figure 2A) and TALC (Figure 2B) on day 14 and 28, while the control side failed to demonstrate similar results.The CASS revealed no significant difference between both sides, either at baseline or at follow-up visits (Figure 3).

| Erythema index (EI)
Baseline EI demonstrated no significant difference between both sides at the beginning of the study.On the follow-up visits, a significantly lower EI compared to baseline was observed on both sides on day 14 and 28.However, EI was significantly lower on the PDLtreated side compared to the control side on both follow-up visits (p < 0.001; Figure 2).
The mean difference in EI (Figure 2C) was an approximate threetime greater reduction from baseline on the treatment side compared to the control side and reached statistical significance on day 14 and 28.

| Gender and menstruation
Controlling for gender on the PDL-treated side, EI significantly decreased from baseline by day 14 and 28 in all males (p < 0.001 and p = 0.001) and females (p < 0.001 and p < 0.001).No difference was also found among females based on menstruation status (p = 0.81 on day 14 and p = 0.56 on day 28; Table 1).On the control side, females with menstruation did not show a significant EI reduction from baseline on day 28 (p = 0.49).
Results on TALC showed a significantly greater reduction from baseline among males (p = 0.02) and females without menstruation on day 14 (p = 0.002) only on the treatment side (Table 1).This result remained consistent in females without menstruation on day 28 on the treatment side.Adjusting for menstruation status, TALC significantly increased in females with menstruation only on the control side.On the treatment side, there was a numerical reduction in TALC among females independent to menstruation in the sample, but statistical significance was not reached.

| Mental tension/stress from examination
Participants without examination showed a statistically significant reduction in the EI from baseline to day 14 and 28 on both sides, but the reduction was nearly double on the treatment side (−37.4 vs. −70.6 on day 14 and −36.6 vs. −79.7 on day 28; Table 2).Among those completing an examination, only the treatment side demonstrated a significant EI reduction from baseline in both follow-up visits.No differences in EI reduction were observed on the treatment side based on examination stress.
For TALC, PDL demonstrated lower TALC from baseline compared to the control side regardless of the examination on day 14, but only those without an examination showed a similar result on day 28.On the control side, there was no significant TALC reduction on both follow-up visits, regardless of the examination.

| Participant satisfaction, safety, and adverse effects
More than 90% of the participants expressed satisfaction on PDL treatments, with a median score of 8 (IQR 7-9) in both follow-up visits.Neither complications nor adverse effects from PDL therapy were reported.

| DISCUSS ION
According to our study results, PDL effectively improved PCEE and TALC in adolescents and young adults who had mild to moderate acne severity without serious complications.Similarly, many studies have also documented positive outcomes of PDL in erythema reduction in acne patients. 10,13In contrast, Leheta showed that PDL had no difference in post-acne erythema (PAE) reduction compared to other acne treatments. 13This was possibly due to the use of a different erythema measurement tool with a 4-point semiquantitative scale and a different methodology.A recent randomized split-face study also yielded a trend of PAE improvement by PDL without statistical difference compared to baseline. 10The erythema reduction could be explained by the extended theory of selective photothermolysis. 3Oxyhemoglobin acts as chromophores to absorb the PDL energy. 14With an adequate pulse width and energy fluence, the releasing energy from chromophores leads to vascular apoptosis. 3,14PCEE without PDL therapy also decreases over time, as in the normal wound healing process.It will progress into the remodeling stage with vascular apoptosis at 2 weeks after comedone extraction. 15Notwithstanding the normal wound healing process, PDL has a great impact on rapid erythema reduction without significant complications.Therefore, PDL can be recommended as an adjunctive or optional treatment for PCEE.
Regarding menstruation, hormonal variations account for vascularization and dilatation of blood vessels. 16A recent study demonstrated that many erythematous dermatoses, such as acne, rosacea, and cutaneous lupus erythematosus, flared under ovulatory effects. 17This mechanism might explain why PCEE had no significant change on the control side at week 4 in females with menstruation.
However, PDL was effective in PCEE reduction, regardless of gender and menstrual status.
Stress can affect skin conditions via the brain-skin axis. 18der mental or emotional stress, the corticotropin-releasing hormone (CRH) from the hypothalamus and the adrenocorticotropic hormone (ACTH) from the pituitary gland play crucial roles in the activation of skin stress responses. 19Cytokines and hormones including substance P, cutaneous CRH, histamine, nitric oxide, and vascular endothelial growth factor released from stress induces vascular permeability and dilatation as well as inflammation. 18Eventually, these processes can lead to erythema. 18,19This potential hypothesis was observed in our study by the failure to reduce PCEE on the control side at week 4 in participants with Previous studies showed that PDL could stimulate the expression of TGF-β1 through heat shock protein 20 up to 15 times in normal skin. 12Many studies showed that TGF-β1 plays a central role in the inhibition of microcomedone formation and the resolution of inflammatory acne. 12,20TGF-β1-induced keratinocyte proliferation suppression in pilosebaceous units, 12 as well as mild photodynamic effects on Cutibacterium acnes, 20,21 and the interference of the sebaceous gland function 21 leads to the prevention of comedone formation.Furthermore, following the potent immunosuppressive properties and inhibitory effects of proinflammatory cytokines, TGF-β1 could diminish the existence of inflammatory papules. 12,20r study results were clinically and theoretically concordant with this mechanism.PDL resulted in a reduction of both comedones and total acne lesions, which was comparable to many previous reports. 8,9,11,14We note that the small number of papules and pustules in our participants was insufficient to evaluate clinical differences in these types of acne.Orringer had previously reported that PDL did not lower the number of acne lesions. 22This study was comprised of a larger number of severe acne patients that had cystic lesions and used PDL treatment parameters different from our study.
When considering menstrual effects, the altered hormonal levels of androgen, estrogen, and progesterone are responsible for higher sebum production, which induce pilosebaceous blockage, C. acnes disequilibrium, and inflammation and subsequently leads to acne flares. 17In our study, PDL could not suppress menstruation-related acne.This was possibly due to the mechanism of menstruation-related acne, which is mainly associated with hormonal effects rather than pro-inflammatory cytokine formation. 23However, without menstrual influences, PDL could effectively improve TALC.
Examination stress has proven to be associated with acne in many studies. 24As mentioned earlier, the central and cutaneous peripheral CRH play a role via the brain-skin axis. 18,19The activation of CRH, ACTH, α-melanocyte stimulating hormones, and peroxisome proliferator-activated receptorγ results in abnormal sebum production, while cutaneous pro-inflammatory cytokines, including interleukin-6, −11, and tumor necrosis factorα, are also released. 25sults from our study supported the connection between high stress and increased acne formation.
Although a reduction of 13 comedones and 13 on the TALC starting on week 2 should sufficiently provide a clinical difference in mild to moderate acne patients, CASS showed no statistical difference.
Strengths of this study included the reduction in performance bias by the blinded investigator and CASS assessors.In addition, menstruation issues and examination stress were taken into consideration.However, our study results may not be generalizable to moderate-to-severe acne patients.Additionally, our PDL parameters were not generalized to all skin types, and the subgroup analysis was calculated from a small population.Future studies with larger samples including multicenter or multiethnic study, and a longer follow-up period might overcome these limitations.TA B L E 2 Difference of erythema index and total acne counts before and after PDL therapy, regarding mental tension/stress from examination.Representing p-value between the PDL-treated and control group.

STATA version 15 .
1 was used for statistical analysis.Categorical variables were presented by count and percentage.Comparisons were made by either Chi-square test or McNemar's test for independent or dependent variables, respectively.Continuous variables were presented as either mean and SD or median and IQR depending on data distribution.Comparisons were done by paired t-test or Wilcoxon matched-pairs signed-rank test.The 3-group comparison was performed by ANOVA test or Kruskal-Wallis test.The p < 0.05 was considered statistically significant.3 | RE SULTS 3.1 | Demographic data Forty-six participants were recruited into the study with 35 meeting eligibility criteria including mild-to-moderate acne (Figure 1).Median age was 19.4 years (range 12.9-24.2years), and 75% were females with Fitzpatrick's skin type III in all cases.The PDL-treated side was blocked-randomized almost equally between the left (17) and the right (18) sides of the face.Dermocosmetic use was reported by more than half of the participants with moisturizers and sunscreen as predominant products.The median number of laser pulses was 260 (range 233-290) shots on the treatment side of the face.All participants completed the study without dropout or loss during follow-up.

F I G U R E 2
The difference from the baseline in acne lesion counts and erythema index.(A) Median difference from the baseline in comedone counts.(B) Median difference from the baseline in total acne lesion counts.(C) Mean difference from the baseline in EI.

F I G U R E 3 a
Comparison of the PDLtreated side (3 circles) and the control by VISIA®.TA B L E 1 Difference of erythema index and total acne counts before and after PDL therapy regarding gender and menstruation.Representing p-value within the group compared to the baseline.b Representing p-value between female with and without menstruation group.c Representing p-value among male group, female with and without menstruation group.examination; nevertheless, PDL could lead to PCEE reduction, regardless of stress.

a
Representing p-value within the group compared to the baseline.b