The efficiency and safety of low‐dosage isotretinoin therapy for Chinese acne vulgaris patients

Acne vulgaris is one of the most common skin conditions in dermatology clinics. Accumulating evidence has implicated oral low‐dosage isotretinoin was an effective treatment for acne with fewer side effects. Currently, the data on low‐dosage isotretinoin use in Chinese is limited.


| INTRODUC TI ON
Acne vulgaris is a highly common dermatosis in dermatology clinics.Nodulocystic acne is sometimes severe and can lead to permanent scars.Oral isotretinoin is the most efficacious therapy for acne with the potential for long-term clearance; however, laboratory monitoring practices while prescribing isotretinoin vary among dermatologists. 1e conventional standard dose recommended for isotretinoin is 0.5-1 mg/kg/day for 4-6 months with a cumulative dose of 120 mg/ kg 2 .Unfortunately, its adverse effects are mainly dose-dependent; many Chinese patients cannot tolerate the side effects such as cheilitis under the dose of 0.5 or 1 mg/kg/day in our clinical practice.Many strategies have tried to limit the side effects, increase compliance, and without reducing the therapeutic effectiveness.
Since many studies have reported the effectiveness of low-dosage isotretinoin in acne treatment, [3][4][5] lower and more intermittent dosage regimens have been suggested to decrease the adverse effects.
The low-dosage regimens of isotretinoin such as daily dose, intermittent treatment, intermittent daily treatment, and gradual increase in daily dose have been used in various studies. 6Furthermore, a dietary supplement containing γ-linolenic acid, coenzyme Q10, vitamin C, vitamin E, beta-carotene, and Vitis Vitifera has been recognized as a valuable supplement in the treatment and prevention of dry skin related to the application of oral isotretinoin. 7is study aimed to analyze the low dose of isotretinoin (0.2-0.4 mg/kg/day) in a Chinese patient cohort, concentrating on the dosing profile, adverse effects, and outcomes of isotretinoin in acne vulgaris treatment.

| Participants
A retrospective review was performed of patients treated in the Shanghai General Hospital Dermatology Department between March 2018 and May 2020.Inclusion criteria were the following: (1) patients with the International Classification of Diseases (ICD) 9 or 10 code for acne (L70.0,706.1); (2) all these patients completed 1 course of isotretinoin with a cumulative dose of 120 mg/kg.Patients with metabolic disorders, liver diseases, and concomitant drug treatments increasing the blood lipids and interacting with isotretinoin such as contraceptives, antibiotics, and topical acne treatments were excluded from the study.Three hundred and eighty-eight patients were enrolled.Up to now, there is no universally agreed-upon grading system for acne; disease severity was evaluated using the Global Evaluation Acne (GEA) scale and categorized as mild (grade 2), moderate (grade 3), or severe (grades 4 and 5). 8Complete remission was defined as complete clearance of acne (residual erythema and hyperpigmentation are allowed).Demographic information was summarized in Table 1.This study was approved by the Human Ethics Committee of Shanghai General Hospital.

| Dosage of isotretinoin
The dose of isotretinoin (10 mg per capsule, Shanghai Pharmaceuticals Sine) was 0.2-0.4mg/kg/d.All patients completed a total cumulative dose of 120 mg/kg.

| Laboratory investigation
Laboratory investigations including serum total cholesterol, triglyceride level (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and low-density lipoprotein (LDL) were evaluated at the baseline, once a month for the first 3 months, and then once every 3 months till the therapy was finished.Routine complete blood cell counts were not monitored in this study because they were not recommended. 9Female patients were advised TA B L E 1 Basic demographics of patients and response to therapy.

Patients, n 388
Age, y, mean ± SD 25.9 ± 6. of contraception, and pregnancy tests were performed in suspected cases before treatment.Patients with preexisting hypothyroidism, hyperlipidemia, hematological diseases, liver dysfunction, and concomitant medication therapy elevating the blood lipids and interacting with isotretinoin were excluded from the clinical trial.

| Statistical analysis
GraphPad Prism9 software was used for statistical analysis.The chisquare test and one-way ANOVA test were used.Data are presented as mean ± standard deviation (SD).A value of p < 0.05 was considered significant.

| Clinical and demographic data
Three hundred and eighty-eight patients who completed the isotretinoin course were enrolled, with a mean age of 25.9 years (standard deviation of 6.5 years, range from 14 to 44 years) and female:male ratio of 1.7:1 (242 female and 146 male).The indication for isotretinoin therapy was severe (GEA scales 4 and 5) acne (80.2%), followed by moderate (GEA scale 3) acne (11.9%) and mild (GEA scale 2) acne (7.9%).On average, patients received 13.5 months of treatment.The relevant data are summarized in Table 1.

| Efficacy
The majority (90.2%, n = 350) of patients showed complete remission, and the difference in severity of acne was not significant (p = 0.82).The daily dose was 21.3 ± 6.0 mg, and the cumulative dose was 7400 ± 2107 mg.The time between the isotretinoin start date and clear date between the mild and moderate groups was not significantly different (74 ± 24 vs. 84 ± 24 days).However, it took more time to resolve for the severe acne group than mild and moderate groups (112 ± 25 vs. 74 ± 24 and 84 ± 24 days, p < 0.05, respectively).
Follow-up 1 year after completion of the isotretinoin course, 3/27 (11.1%) patients in the mild group, 4/43 (9.3%) patients in the moderate group, and 30/280 (10.7%) patients in the severe group reported relapse, but the difference among the three groups was not significant (p = 0.96).

| Patients-reported side-effects
There was no pregnancy in 242 female patients.Isotretinoin was generally well-tolerated, and cheilitis and dry skin were the most common documented side effects (83.2%, n = 323).Fifteen patients (3.87%) reported photosensitivity, and three patients (0.77%) reported sticky skin.No other side effects were reported.
At any time of course, the maximum cholesterol level was 341.5 mg/dL, the maximum triglyceride level was 381.9 mg/dL, the maximum AST level was 124.9 IU/L (2.6-fold the upper limit of normal), the maximum ALT level was 178.6 IU/L (3.6-fold the upper limit of normal), and the maximum LDL level was 237.8 mg/d.According to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 grading system, no grade 3 or higher laboratory abnormalities were noted.The time from the initiation of treatment to the detection of laboratory abnormalities was detected.In detail, the mean time between the start of treatment and the detection of abnormalities for each test was: hypercholesterolemia at 37 days, hypertriglyceridemia at 45 days, LDL elevation at 71 days, ALT elevation at 67 days, and AST elevation at 73 days (Table 2).No patients discontinued isotretinoin therapy due to elevations.

| DISCUSS ION
It is well known that the conventional recommended dose of isotretinoin is 0.5 to 1 mg/kg per day with a target cumulative dose of 120-140 mg/kg.However, a higher incidence of side effects has been shown with such a daily dosage.Recent reports, studies, and consensus statements suggest optimizing the use of isotretinoin in acne. 6,10It has been recommended that a low daily dose (0.1-0.3 mg/ kg) for more than 6 months be effective with fewer side effects. 6rrent data on low-dosage isotretinoin use in China is limited.
Our retrospective study demonstrated the overall effectiveness and safety of low-dosage isotretinoin in Chinese acne vulgaris patients.
Consistent with previous studies, we showed that the majority of patients (90.2%, n = 350) achieved complete remission with low-dosage isotretinoin (0.2-0.4 mg/kg/d).Despite having a longer duration of treatment (13.5 months) than that in most other published studies, 6,10,11 our patients showed good compliance and satisfaction due to few side effects.Furthermore, our data showed an overall recurrence rate of 10.6% (37/350) 1 year after completion of the isotretinoin course, which is lower than the previous study. 12It may be related to the length of treatment time after acne clearance.In this study, the average time between the start of isotretinoin and acne clearance was 92 ± 31 days, while the average duration of treatment was 13.5 months, which may be a benefit for the low recurrence.
In addition, Patrick Tran et al. 13 reported that the average time to relapse was 460 days, some recurrent cases might be missed in our study due to the relatively short follow-up time.
Adverse effects were of major concern to clinicians during isotretinoin treatment.Skin and different mucosal dryness as well as cheilitis are the most common side effects. 14Other common side effects include headache, mood change, temporary hair loss, photosensitivity, nausea, blurred vision, dizziness, etc.As expected, the most common adverse effect recorded in our study was cheilitis and dry skin (83.2%), followed by photosensitivity (3.87%) and sticky skin (0.77%).No patients discontinued isotretinoin therapy due to it.
Furthermore, laboratory data regarding liver function and lipid abnormalities demonstrated clinically insignificant as no values above grade 2 were detected in this study, convincing that the low-dose regimen is safe and well-tolerated again.6][17] Lab investigation could be per-

ACK N OWLED G M ENTS
This study was supported by Innovative Research Team of Highlevel Local Universities in Shanghai.

CO N FLI C T O F I NTER E S T S TATEM ENT
None.

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 on request from the corresponding author.The data are not publicly available due to privacy or ethical restrictions.

E TH I C S S TATEM ENT
The study was approved by the Human Ethics Committee of Shanghai Jiaotong University.

formed after 2
months of treatment in healthy patients with normal baseline liver function and lipid panel tests.No further testing may be required if the findings are normal.Nevertheless, we have to acknowledge that there were some limitations in the present study.Firstly, this is a retrospective study with inevitable limitations such as missing data and incomplete umentation.Secondly, there are statistical limitations due to the low number of patients compared to previous studies.Lastly, relapse rates may be underestimated since the duration of follow-up after therapy cessation was not long enough.In summary, our study reaffirms the efficacy and safety of oral isotretinoin with low mean daily doses in Chinese acne vulgaris patients.Laboratory investigation could be performed after 2 months of treatment in healthy patients, and no further examination is required if the findings are normal.AUTH O R CO NTR I B UTI O N S Yiting Li: Design, Data analysis, Writing-original draft.Yibin Zeng: Data analysis, Validation.Zile Chen: Data Curation.Shu Nie: Data Curation.Zhouwei Wu: Design, Writing-review & editing.All authors contributed to the article and approved the submitted version.