Cosmetic therapies for Chinese patients with acne taking concomitant or recent intake of oral isotretinoin: A retrospective study

The current standard recommendation is to initiate the cosmetic therapies after discontinuing taking oral isotretinoin for at least 6 months. However, this recommendation has been questioned in several recent publications, and it is difficult to operate in clinical practice as early initiation of effective treatment is desirable for patients with acne sequelae.


| INTRODUC TI ON
Acne is a common chronic inflammatory, debilitating disease that occurs in adolescents.The incidence in Chinese adolescents is as high as 87%. 1 Some patients continue to experience this issue in the adulthood, which has a great impact on their appearance and social life.Permanent scarring is the worst lifelong sequelae.Oral isotretinoin has been prescribed for serious acne such as nodulocystic acne and refractory acne of antibiotics since 1982.Patients with physical scarring and psychological impact are recommended to take oral isotretinoin as the first-line treatment since 2000 with expanded indication.When the inflammatory lesions are controlled by isotretinoin, the sequelae including postinflammatory erythema (PIE), hyperpigmentation (PIH), and atrophic scarring are followed.Cosmetic therapies including glycolic acid chemical peeling, intense pulsed light (IPL), fractional laser, and radiofrequency are effective for acne sequelae.But for nearly two decades, many practitioners believed that oral isotretinoin should be stopped for at least 6 months before applying the cosmetic therapies, although no previous scientific reports supported this theory.
In 2016, Indian scholar Mahadevappa and colleagues reported a large prospective study of 183 acne patients who took isotretinoin or discontinued medication for <6 months.They were applied with 503 treatments, including chemical stripping, laser, Microdermabrasion, and surgical treatment, followed up for 1 year, nearly 2 patients with keloids.This large sample of studies confirms that previous clinical observations have led to a skin treatment operation with isotretinoin, and the rate of scar formation has not increased significantly.The incidence of adverse reactions is <1%. 2 In 2017, the American Society of Dermatology Surgery ASDS published the first expert consensus on whether it is possible to give dermatological and surgical procedures during the administration of isotretinoin and within 6 months of discontinuation. 3In the same year, a similar consensus was published in Jama Dermatology, which reviewed the treatment of dermabrasion, chemical peeling, skin surgery, laser hair removal, and nonablative/ablative fractional laser.Many of the early case reports were related to mechanical dermabrasion, so the evidence-based recommendation level was only D, while manual microabrasion did not produce abnormal scars, so the level was B. The relationship between surgery and isotretinoin does not have sufficient medical evidence, so the recommended grade is D, but delays are not recommended for operations such as skin biopsy.Chemical peeling, laser hair removal, and fractional laser are safe, with a recommended level of B. 4 Based on this, the Indian Society of Dermatological Surgery published a guideline in 2018.Hair removal, fractional laser, pigmental Q-switch laser, radiofrequency microneedle, fractional radiofrequency, superficial chemical peeling, microdermabrasion, and skin biopsy are safe during the administration of isotretinoin, and the level of evidence-based medicine grades are B and C. 5 Since the skin types of the Indian population are similar to the Chinese, the guideline could be generalized to Chinese patients.Chinese scholar Jun Xia published a paper in 2018, using a randomized half-side self-control method to study the efficacy and safety of 1550 nm nonablative fractional laser combined with low-dose isotretinoin (10 mg/d) in the treatment of 18 patients with acne vulgaris.After three treatments and up to 9 months of follow-up, the study found that the non-inflammatory comedones, inflammatory papules, nodules on the combined treatment side were significantly better than the non-treated side, and the carbox atrophic scars on the treatment side were significantly improved.This indicates that low-dose isotretinoin combined with nonablative fractional laser for Chinese patients is safe and effective.Timely treatment during the active period can significantly accelerate the regression of lesions, and prevent and improve scars. 6is retrospective study aimed to investigate the safety of cosmetic interventions offered to acne patients, who recently took oral isotretinoin.

| Patients
The study was prospective, interventional, and unblinded in nature.
During January 2013 to July 2017, a total of 511 patients with acne vulgaris, postinflammatory changes, and acne scars from the Department of Dermatology, Peking University Shenzhen Hospital were enrolled in the study.There were 202 males and 309 females, aged 13-42 years, with an average age of 23.6 ± 3.2 years.The disease course was from 0.6 to 18 years and an average duration of 3.4 ± 1.8 years.Skin type is Fitzpatrick II-V type.A total of 414 patients were taking oral isotretinoin during treatment, and 97 patients were discontinued for <6 months.The duration of medication was 2 weeks to 19 months, and the average duration was 5.6 ± 2.5 months.Among these patients, 62 patients (12.13%) were Fitzpatric skin type II, 224 patients (43.84%) were type III, 173 patients (33.86%) were type IV, and 52 patients (10.18%) were type V.All patients were administrated with oral isotretinoin (Chinese medicine standard H20113060, Chongqing Huabang Pharmaceutical Co., Ltd.), 10-30 mg/d, or the withdrawal time was <6 months from the last treatment.The cumulative dose range is 1.5-120 mg/kg (90-9600 mg).Exclusion criteria included patients with any hypertrophic scars or keloids, photosensitivity, pregnancy or lactation, current anticoagulative medication, and pigmentation after recent exposure to the sun or solarium.This study was approved by the Institutional Review Board of the Peking University Shenzhen Hospital.All patients signed an informed consent and a photo agreement.

| Intervention
Glycolic Acid Peeling: A total of 477 sessions of 20% glycolic acid (Winona, Kunming Beitaini Biotechnology Co., Ltd.) were performed on 137 patients as a starting concentration of treatment.All treatments were performed by a trained dermatologist.According Nonablative Fractional Laser: The treatments were performed using a dual-wavelength 1440 nm/1320 nm nonablative fractional laser device (Affirm, Cynosure).A total of 61 sessions were performed on 32 patients.The patented CAP composite vertex technology divides a beam of laser into 1000 diffracted tiny beams that act on both the epidermis and superficial dermis to remodel and regenerate collagen through fractional photothermolysis.All treatments were performed by a trained dermatologist.Topical anesthesia was applied for 60-90 min after cleansing the face.According to the patient's skin and lesion type, different parameters were selected, such as 10 and 14 mm laser spots, 1000 MTZ/cm 2 microthermal treatment zones (MTZ) density, 3 ms pulse duration, 2.0-2.8J/cm 2 pulse energy for 1440 nm laser and 5.0-6.8J/cm 2 for 1320 nm laser, and 4-to 8-week session interval.
Fractional Bipolar Radiofrequency: The treatment device was designed for deep dermal delivery of bipolar radiofrequency energy powered by a system (eMatrix™; Syneron Medical Ltd).The handheld applicator of the device was equipped with a disposable singleuse treatment tip, which consisted of eight parallel rows and columns of bipolar gold-coated electrode pins.A total of 101 sessions were performed on 48 patients using program C (85-95 mj/pin).Patients with acne scars received four treatments in 8-12 weeks intervals.
All treatments were performed by a trained dermatologist.Topical anesthesia was applied for 60-90 min before treatments.Treatment parameters were based on the depth of scars and the patient's skin type.Care was taken to keep skin dry during procedure, and a double-or three-pass treatment was performed with at most 5%-10% overlap.
Ablative Fractional CO 2 Laser: The treatments were performed using an ablative CO 2 laser system (CO2RE Syneron USA), with a wavelength of 10 600 nm, and maximum output power of 60 W. All treatments were performed by a trained dermatologist.Topical anesthesia was applied for 60-90 min before treatments.The treatment pulse energy was ranged from 50 to 80 mj/cm 2 with a spot size of 9 mm × 9 mm and density of 15%-40%.The treatment parameters were modified depending on the individual scar characteristics (depth, width, and type).Several treatment sessions [2][3][4] were taken at an interval of 3-6 months.
Patients were advised to avoid sun exposure and to use a highfactor, broad-spectrum sun cream (SPF ≥ 30, PA ≥ +++) during the study period.After the treatment, the skin recovery and the occurrence of complications were observed, and the therapeutic effect was evaluated.

| Assessments
Digital images (D40; Nikon) or VISIA analysis images (Canfield) were taken under the same photographic conditions before each treatment and at 4-week, 12-week, 24-week, and 1-year follow-up visits.Standard photographs of the patients were evaluated by three professional dermatologists who were not involved in the treatments.
The side effects include pain, crusting time, dislocation time, duration of flushing, duration of pigmentation after inflammation, secondary atrophic scars, hypertrophic scars, and keloids.Double-blinded investigators, who did not participate in the patient treatment, were unaware of the time point at which the photographs were taken except for the baseline image for comparison.
A five-point scoring method was used to evaluate the improvement of acne lesions including comedones, papules, nodules, pustules and cysts, postinflammatory erythema, and pigmentation after acne inflammation by comparing standardized photos before and after treatment: one point for the degree of improvement <10%, two points for the improvement between 11% and 25%, three points for the improvement between 26% and 50%, four points for the improvement between 51% and 75%, and five points for the improvement ≥75%.The clinical efficacy of acne scars was assessed by the ECCA score 7 according to the shape, traits, and intensity of acne.
The weighting method was illustrated in Table 1.

| Statistical analysis
Data were analyzed by Stata 13 analysis software.T-test, chi-square test, and a non-parametric test (Kruskal-Wallis H-test and Mann-Whitney U-test) were used, and the difference was statistically significant at p < 0.05.

| RE SULTS
A total of 1352 sessions were performed on all 511 patients.The detailed data are shown in Table 1.
There are 137 patients with active acne lesions, and they were all treated with glycolic acid.Among them, 118 patients were treated with isotretinoin (medication group) and 19 patients discontinued the medicine within 6 months (withdrawal group).After 1-7 sessions TA B L E 1 Treatment procedures and treatment sessions.

| Adverse reactions
Two sets of adverse events were documented (Table 2).The common set of adverse events were transient erythema, pigmentation, acnelike rush, and scab.The secondary hypertrophic scar and keloid were not noted.However, 80.32% cases did not have any adverse events.
Of the procedures carried out in glycolic peel, 197 cases had erythema, 104 had different degrees of scab, which all resolved in 1 week.Then, 18 cases had temporary acne-like rush, two cases stopped the treatment because of exacerbation.No case developed hypertrophic scars and keloid (Figure 1).
A total of 588 IPL-assisted acne therapies had no serious adverse in <3 months with topical hydroquinone (Figure 3).
Fractional ablative CO 2 laser resurfacing was done in 69 cases.
Among them, 25 cases developed postinflammatory hyperpigmentation, which resolved with sunscreen by 6 months.Only four cases persist for more than 6 months, but their hyperpigmentation all faded away in 8 months.None developed keloid or delayed wound healing.Interestingly, two cases with acne hypertrophic scar on the jaw line, who was on isotretinoin, did not develop keloid when fractional CO 2 laser was used to treat scar on the face (Figure 4).

| DISCUSS ION
The pharmacology of isotretinoin is thought to cause degeneration of the hair follicle sebaceous gland, which is the site of stem cells 8 required to rebuild the epidermis and hair follicles after deep trauma.
Thus, it is considered that isotretinoin affects wound healing.Some TA B L E 2 Adverse events.

Adverse events Frequency Percentage
No side effects 1008 80.32 has been recommended to avoid skin-related treatments for at least 6 months from discontinuing the medicine.Based on the relevant literature in dermatology, surgeons from other professions also adhere to this recommendation.
However, a number of zoological studies do not support this conclusion.The dose of isotretinoin was from 1.0 to 10 mg/kg/d, and no significant effect on wound healing after trauma was observed.
1][12][13][14][15] The conclusions drawn from animal experiments are not consistent with early clinical case reports.Isotretinoin requires a certain cumulative measurement for the acne treatment.Different skin treatments have different degree of skin damage, so the author revisited the previous clinical case reports and recently published papers.The dermabrasion and isotretinoin were first applied in 1985, and an atypical keloid was reported. 16In four case reports of dermabrasion, [16][17][18][19] one case of argon laser 20 and one case of pulsed dye laser, 21  Only one case report has been retrieved at present, which suggested that the high concentration chemical peeling could lead to pathological scars during isotretinoin treatment. 23In another prospective cohort study, oral isotretinoin (20 mg/d) combined with 20% salicylic acid peeling was effective and safe compared to the medication monotherapy, and no keloid formation was observed. 246][27][28][29][30] Some abstract reported of more than 100 acne patients taking isotretinoin, receiving Q-switch azurite 755 nm laser and Q-switched Nd: YAG to the patient's reaction and intolerance, the time of procedure duration varied from 1 to 6 min.The treatment interval was 2 to 4 weeks.Intense Pulsed Light (IPL): 225 patients received a total of 588 IPL treatments between levels 1-5, according to individual needs using an intense pulsed light treatment platform (M22; Lumenis).All treatments were performed by a trained dermatologist.Treatment sessions consisted of single or double passes with optical filters 560, 590, and 640 nm, double or triple pulses, 3-5 ms pulse duration, 10-40 ms pulse delay, 14 to 26 J/cm 2 pulse energy, and 4to 6-week session interval.
outcome.A few experienced local scab which fallen off in 10 days (eight cases), or a flare of acne which was treated with topical medicine (12 cases; Figure 2).Pain is the most common complain of the fractional procedure including nonablative laser, radiofrequency, and ablative laser, but all the participants tolerated and finished the procedure.Two cases treated with nonablative fractional laser developed blister, which then become scab in 3 days and fallen off in 7 days.One of them developed pigmentation in 3 months.In the fractional RF series, four cases had a flare of acne faded without any interventions.One case had a transient hyperpigmentation in the treated area and resolved believe that isotretinoin promotes the development of pathological scars such as keloids.The possible mechanism is to inhibit the synthesis of collagenase, which leads to the accumulation of excess collagen in the process of scar remodeling and the formation of keloids. 9Because of the potential risk of pathological scars or skin irritation, the historical practice for patients receiving isotretinoin F I G U R E 1 A 27-year-old female, skin type II, before treatment (A) and after four sessions glycolic acid treatment (B).F I G U R E 2 A 23-year-old female with severe acne, skin type III, treated with IPL after taking isotretinoin for 2 months.Taking isotretinoin for 1 months (A) and before IPL treatment (B), one session after treatment (C), four sessions after treatment (D).
the patients developed hypertrophic scar or keloid.Khatri et al. reported that a 19-year-old boy was given a non-exfoliating 1540 nm dot laser, an exfoliative 2940 nm dot laser, and a fully exfoliated 2940 nm holmium laser after 4 months of isotretinoin (80 mg/d).After 6 months, skin biopsy revealed the thickening of the epidermis and dermal papilla layer were normal after nonablative fractional laser and ablative fractional laser treatment.However, the epidermal layer was flat after full-ablative laser treatment, and collagen accumulation in the dermis was similar to the pathological manifestation of scar.22

F I G U R E 3
A 25-year-old female, skin type III, treated with nonablative fractional laser, before treatment (A) and three sessions after treatment (B).F I G U R E 4 A 30-year-old female, skin type III, treated with ablative fractional laser, before treatment (A) and two sessions after treatment (B).532 nm/1064 nm laser for the treatment of pigmented diseases, in the course of a 7-year follow-up, no abnormal wound healing or scar formation was observed.[29][30][31]Moradi et al.32 treated 148 acne patients with at least 4 months oral isotretinoin (1 mg/kg/d) with three low-energy pulsed dye lasers, five times a week with Er: YAG laser, and found scar formation or other side effects.We found dermabrasion had higher risk of developing scar when combined with isotretinoin.This may due to its nature of reaching the deeper layer of the dermis.Recent literature on dermabrasion showed the use of isotretinoin with less invasive and topical treatment may be safe when the withdrawal time is insufficient.In a prospective study, seven patients received 10-40 mg of isotretinoin daily for 1-6 months, and manual (no manual engine) microdermabrasion was used to treat facial focal scars.No surgically associated scar formation was found after 180 days of follow-up.33Picosse et al.conducted a prospective study of 10 patients with facial acne scars, who took isotretinoin and received a full-thickness deep chemical peeling and manual sandpaper dermabrasion for 1-3 months.Their facial skin was completely re-epithelialized, no hypertrophic scars or keloids occurred, and depressed acne scars were improved after 6 months of follow-up.Only one Fitzpatrick V-type skin patient developed postinflammatory hyperpigmentation.34There are currently only eight papers on the relationship between fractional lasers and isotretinoin.Most prospective cohort studies excluded the use of isotretinoin or insufficient withdrawal time in their study design.Three of these studies were randomized controlled trials,[35][36][37] two for nonablative 1550 nm fractional laser and one for ablative fractional CO 2 lasers to treat patients with acne scars who were taking isotretinoin compared with patients in the untreated group.Kim et al. used a case-control analysis of 110 patients with acne scars who underwent ablative CO 2 laser treatment during oral administration of isotretinoin (dosage 10-60 mg/d) or within 3 months of discontinuation.At 6 months, the epidermis is normally re-epithelialized without hypertrophic scar or keloid formation.38The other four articles were case reports of nonablative 1550 nm fractional laser and ablative fractional CO 2 lasers used to treat acne scars, small sweat gland cystadenoma, sebaceous gland hyperplasia and other abnormal scar formation.31,[39][40][41]Lilia et al. used a retrospective cross-sectional study to analyze the relationship between isotretinoin and hypertrophic scars and keloids, and no correlation was found.42Our results suggested similar findings.Many acne patients need to continue taking isotretinoin to achieve the recommended cumulative dose after inflammatory rash control.Clinically, patients are required for early dermatological cosmetic treatment to improve postinflammatory erythema, pigmentation, and scars.The dose of isotretinoin used in this study was 0.2-0.5 mg/kg/d, which did not exceed the clinically recommended dose.After more than 4 years of retrospective investigation, 511 patients, as many as 1352 treatments, only three patients with acne scars treated with ablative CO 2 laser treatment showed postinflammatory hyperpigmentation for more than 6 months but gradually subsided within 12 months.No patients had delayed response to wound healing, and no patients developed hypertrophic scars or keloids.Interestingly, we found that patients taking isotretinoin combined with cosmetic therapies performed better than patients who did not take the drug, and patients were more satisfied.The results suggest that there is no need to delay skin procedures during isotretinoin treatment.Early treatment can significantly improve the appearance of the patient's skin, their satisfaction, and even quality of life.Although retrospective studies have limitations such as selection bias, information bias, and confounding bias.But they could provide important clinical clues for further prospective studies and even multicenter, randomized, controlled, double-blind studies.

Cases Sessions Total sessions Average sessions
(average 3.48 ± 1.35 sessions), 83 patients (60.58%) achieved five points regarding recovery, 42 patients (30.66%) achieved four points regarding significant effect, eight patients (5.84%) achieved three points regarding getting better, four patients (2.92%) achieved two points regarding poor efficacy, and none achieved one point regarding no efficacy or getting worse.The total effective rate was 91.24%.The effective rate was 94.07%(111/118) in the medication group and 73.68% (14/19) in the discontinuation group.There was a statistically significant difference between the two groups (p < 0.05).A total of 225 patients underwent 588 sessions of intense pulsed light therapy.Of these, 186 patients were treated with isotretinoin (medication group) and 39 patients were discontinued within 6 months (withdrawal group).The medication group started the treatment within 12 weeks after taking the drug for 4 weeks.ment was 233.33 ± 48.20 for the medication group (57 cases), and 230.00 ± 46.22 for the withdrawal group (12 cases).There was no statistical difference between the two groups.After 1-4 sessions (average 2.60 ± 0.71 sessions), the average ECCA score decreased from 232.75 ± 47.55 to 147.46 ± 35.13, with a statistical difference (p < 0.01).