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Indian J Dermatol
Indian J Dermatol
IJD
Indian J Dermatol
Indian Journal of Dermatology
0019-5154
1998-3611
Wolters Kluwer - Medknow India

IJD-69-301
10.4103/ijd.ijd_644_23
Original Article
Association between Isotretinoin Exposure and Inflammatory Bowel Disease: A Nationwide Case-Control Study in South Korea
Hyeong Jin H. *
Son Minkook 1*
Jeong Dayeon
Jang Ye J.
Kim Kwang H.
Kim Kwang J.
Park Eun J.
From the Department of Dermatology, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea
1 Department of Physiology, Dong-A University College of Medicine, Busan, Republic of Korea
Address for correspondence: Dr. Eun J. Park, 22 Gwanpyeong-ro 170beon-gil Dongan-gu, Anyang-si Gyeonggi-do, 431-796 South Korea. E-mail: anpark7770@hanmail.net
* These authors contributed equally to this work.

Jul-Aug 2024
19 8 2024
69 4 301305
6 2023
3 2024
Copyright: © 2024 Indian Journal of Dermatology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Context:

Isotretinoin is commonly prescribed for the treatment of acne. However, its association with inflammatory bowel disease (IBD) could not be confirmed due to inconsistencies in the literature. Furthermore, no related study has been conducted on an Asian population.

Aims:

The aim of this study was to investigate the association between isotretinoin and inflammatory bowel disease.

Methods and Material:

A nationwide, population-based, case-control study using the National Health Insurance Service database of South Korea was conducted. The case group comprised 107,434 patients with IBD, while the control group comprised 393,830 patients who were matched using a 1:4 propensity score. Data on isotretinoin exposure within the previous 5 years were extracted, and a multivariable-adjusted, conditional, logistic, regression analysis was performed.

Results:

After adjusting for age, sex, underlying disease, the Charlson co-morbidity index, and tetracycline use, a significant association between isotretinoin exposure and IBD was found, with an odds ratio of 1.20 (95% confidence interval, 1.10–1.30). Furthermore, the association appeared to become stronger with longer exposure, more of a cumulative dose, and a longer time since the first exposure. When analyzed separately for ulcerative colitis and Crohn’s disease, isotretinoin exposure was significantly associated with both diseases.

Conclusions:

Our study reveals a dose–response relationship between isotretinoin exposure and IBD risk in an Asian population. Healthcare professionals should be aware of the association and consider alternative medications for acne treatment, particularly in patients who are at a higher risk of developing IBD.

KEY WORDS:

Isotretinoin
inflammatory bowel disease
crohn’s disease
ulcerative colitis
==== Body
pmcIntroduction

Acne is a major cause of cosmetic stress, and isotretinoin is the most effective medication for reducing the size and sebum production levels of sebaceous glands, normalizing follicular keratinization, and inhibiting the growth of Propionibacterium acnes.[1] Despite its efficacy, isotretinoin has several side effects, ranging from mild effects, such as xerosis and cheilitis, to severe effects, such as teratogenicity. Current treatment guidelines for acne vulgaris restrict isotretinoin use for severe recalcitrant due to its potential for life-threatening congenital malformations and spontaneous abortions. However, in clinical practice, isotretinoin is often prescribed more extensively than recommended by treatment guidelines due to patients’ desire for quick and effective results.

Although most of the side effects of isotretinoin are short-term, a cumulative dose of 120–150 mg/kg is required for the manifestation of long-term effects, such as sebaceous gland shrinkage.[1] Therefore, the long-term side effects of isotretinoin, such as the increased risk of other chronic diseases, need to be studied. In recent years, inflammatory bowel disease (IBD) has been actively researched due to its potential association with isotretinoin use.

Fewer than 10 studies have been conducted on the correlation between isotretinoin use and the onset of IBD.[234] Lee et al.[2] published a meta-analysis of six retrospective studies in 2016 with the conclusion that there was no correlation between isotretinoin use and IBD. Since then, however, Wright et al.[3] and Kridin et al.[4] conducted retrospective cohort studies using healthcare data in 2020 and 2022, respectively. They concluded that isotretinoin exposure slightly increases the risk of IBD.

However, these studies were all conducted in Western countries (US, Canada, France, and Germany), and no study has been conducted in an Asian country. As IBD has different prevalence rates among different ethnic groups,[5] the results might be different on an Asian population. Therefore, this study was carried out to determine the correlation between isotretinoin exposure and the onset of IBD using a Korean database.

Subjects and Methods

Data sources

For this case-control study, the researchers used the National Health Insurance Service (NHIS) database of South Korea, which covers almost the entire population of the country (around 51 million individuals or 97%). The NHIS database contains various types of insurance claims, demographic data, and diagnoses based on the International Classification of Disease, 10th revision (ICD-10). This study was approved by the institutional review board of Hallym University Sacred Heart Hospital (IRB no. 2019-07-020) and informed consent from the participants was not required because the NHIS database was de-identified in compliance with the Personal Data Protection Act’s guidelines.

Study design

This was a case-control study of patients who were diagnosed with IBD between January 2016 and December 2020, identified by ICD-10 diagnostic codes (K500, K501, K508, K509, K510, K512, K513, K515, K518, and K519). The control group consisted of patients who had not been diagnosed with IBD during the same period and were enrolled after a 1:4 propensity score matching with the IBD group based on index date, age, and sex. A total of 107,434 patients were included in the IBD case group, and 393,830 individuals were included in the control group [Figure 1]. Information was obtained regarding co-morbidities based on the Charlson co-morbidity index (CCI) as well as that for underlying diseases such as hypertension (I10-I15), diabetes (E10-E14), dyslipidemia (E78), and acne (L70, L730) based on ICD-10 codes. Additionally, data on exposure to tetracycline antibiotics prior to the index date were extracted.

Figure 1 Schematic illustration for the study design

Exposure to isotretinoin

The “index date” was defined as the date of first diagnosis of IBD listed in the database. As the main exposure of interest in this study was isotretinoin, patients’ isotretinoin medication histories were collected for a period of 5 years prior to the index date. Additionally, information on the cumulative duration of exposure (in days and tablets) as well as the time having elapsed since the first exposure was extracted.

Statistical analysis

To minimize the effects of confounding variables, we conducted a 1:4 propensity score matching between the IBD and control groups in this case-control study. After matching, the baseline characteristics were reported as the mean and standard deviation for continuous variables and as number and percentage (%) for categorical variables. The difference between the IBD and matched control groups was analyzed using Student’s t-test and Chi-squared test. To determine the association between isotretinoin exposure and IBD, a conditional logistic regression analysis was conducted and the odds ratio (OR) and 95% confidence intervals (CI) were calculated. Furthermore, a multi-variable-adjusted logistic model was used to estimate the adjusted OR by considering several confounding factors such as age, sex, underlying disease, CCI, and tetracycline antibiotics use.[6] All data analyses were performed using SAS software version 9.4 (SAS institute, Cary, NC), and P values less than 0.05 were considered to be statistically significant.

Results

Baseline characteristics of the study population

Table 1 presents the baseline characteristics of the study population. The mean age of the groups was 49.9 ± 18.6 years. The proportion of male patients in the IBD group was 53.6%, while that of female patients was 46.4%. A similar distribution existed in the control group. The prevalences of hypertension, diabetes, and dyslipidemia were significantly higher in the IBD group than in the control group (all P values < 0.0001). The prevalence of acne was lower in the IBD group than in the control group (4.2% vs. 31.8%, respectively; P value < 0.0001). The proportion of CCI greater than 3 was higher in the IBD group than in the control group, and tetracycline antibiotic use was higher in the control group than in the IBD group.

Table 1 Baseline characteristics for study population after propensity score matching

Baseline characteristics	Inflammatory bowel disease group (n=107,434)	Control group (n=393,830)	P	
Age, mean±SD	49.9±18.6	49.9±18.6	1.00	
Sex, n (%)			1.00	
 Male	57,607 (53.6)	211,093 (53.6)		
 Female	49,827 (46.4)	182,737 (46.4)		
Underlying disease, n (%)				
 Hypertension	35,566 (33.1)	110,837 (28.1)	<0.0001	
 Diabetes	30,328 (28.2)	88,139 (22.4)	<0.0001	
 Dyslipidemia	59,179 (55.1)	171,379 (43.5)	<0.0001	
 Acne	4,504 (4.2)	125,282 (31.8)	<0.0001	
Charlson comorbidity index, n (%)			<0.0001	
 0	11,829 (11.0)	75,908 (19.3)		
 1	22,784 (21.2)	102,574 (26.0)		
 2	22,509 (21.0)	79,428 (20.2)		
 ≥3	50,312 (46.8)	135,920 (34.5)		
Tetracycline antibiotics use	17,343 (16.1)	83,894 (21.3)	<0.0001	
Isotretinoin exposure	708 (0.7)	14,625 (3.7)	<0.0001	
Cumulative duration of exposure (days)			<0.0001	
 Never	106,726 (99.3)	379,205 (96.3)		
 <30 days*	315 (0.3)	6,746 (1.7)		
 ≥30 days	393 (0.4)	7,879 (2.0)		
Cumulative dose of exposure (tablets)			<0.0001	
 Never	106,726 (99.3)	379,205 (96.3)		
 <56 tablets*	334 (0.3)	6,938 (1.8)		
 ≥56 tablets	374 (0.4)	7,686 (1.9)		
Time since first exposure (days)			<0.0001	
 Never	106,726 (99.3)	379,205 (96.3)		
 <1,096 days*	320 (0.3)	7,346 (1.9)		
 ≥1,096 days	388 (0.4)	7,279 (1.8)		
SD: Standard deviation. *Median value for exposure variables

Exposure to isotretinoin according to the study group

Details on the exposure to isotretinoin in the study group are presented in Table 1. Over a 5-year period, 708 (0.7%) patients in the IBD group and 14,625 (3.7%) individuals in the control group were exposed to isotretinoin. The median cumulative duration and dose of exposure was 30 days and 56 tablets, respectively, while the median time since first exposure was 1096 days.

Association between isotretinoin exposure and inflammatory bowel disease

The OR and 95% CI between isotretinoin exposure and IBD are described in Table 2. The adjusted OR between isotretinoin exposure and IBD was 1.20 (P < 0.0001). There were more significant associations in those with longer exposure, a larger cumulative dose, and a longer time since the first exposure (OR 1.25, 1.23, 1.35, respectively; all P value < 0.0001). Furthermore, after the outcome variable was divided into ulcerative colitis and Crohn’s disease, isotretinoin exposure showed significant associations with individual diseases of IBD (OR 1.19 for ulcerative colitis, P = 0.002, and OR 1.18 for Crohn’s disease; P = 0.003).

Table 2 The odds ratio and 95% confidence interval between isotretinoin exposure and inflammatory bowel disease

Exposure variable	Adjusted OR (95% CI)*	P	
Isotretinoin exposure			
 No	1 (reference)		
 Yes	1.20 (1.10-1.30)	<0.0001	
Cumulative duration of exposure (days)			
 Never	1 (reference)		
 <30 days	1.14 (1.01-1.28)	0.03	
 ≥30 days	1.25 (1.12-1.39)	<0.0001	
Cumulative dose of exposure (tablets)			
 Never	1 (reference)		
 <56 tablets	1.16 (1.03-1.30)	0.01	
 ≥56 tablets	1.23 (1.11-1.38)	<0.0001	
Time since first exposure (days)			
 Never	1 (reference)		
 <1,096 days	1.05 (0.93-1.18)	0.40	
 ≥1,096 days	1.35 (1.21-1.51)	<0.0001	
Outcome variable classification			
 Ulcerative colitis	1.19 (1.06-1.33)	0.002	
 Crohn’s disease	1.18 (1.06-1.33)	0.003	
OR: Odds ratio, CI: Confidence interval, CCI: Charlson comorbidity index. *Adjusted for age, sex, underlying disease, CCI, and antibiotic use

In addition, a sub-group analysis was performed by dividing the patients into two groups according to age (aged ≥60 years and aged <60 years) and sex [Figure 2]. Results revealed that isotretinoin exposure was significantly correlated to IBD in the <60 years age group and regardless of sex.

Figure 2 Subgroup analysis of the association between isotretinoin exposure and inflammatory bowel disease. OR: Odds ratio, CI: Confidence interval

Discussion

Numerous studies have investigated the relationship between isotretinoin exposure and the risk of IBD. In 2001, Reniers et al.[7] reported a case of isotretinoin-induced inflammatory bowel disease in an adolescent. Since then, several retrospective studies have supported the existence of an association between isotretinoin and IBD, while other studies have opposed it. In 2016, Lee et al.[2] published a meta-analysis and concluded that isotretinoin exposure is not associated with an increased risk of IBD. In 2020, Wright et al.[3] conducted a retrospective cohort study and reported an OR of 1.87 for a 6-month incidence of IBD after isotretinoin exposure; however, there was no statistical significance when isotretinoin was used for a longer duration. In 2022, Kridin et al.[4] conducted a retrospective cohort study on a slight and transient increase in the risk of ulcerative colitis (odds ratio 1.93 for 6 months) but not in Crohn’s disease.

However, these studies were all limited to Western countries (US, 4; Canada, 2; France, 1; and Germany, 1). Although the prevalence of IBD in Asian countries is increasing due to the westernization of diets, it is still lower than that in Western countries.[5] Therefore, studies conducted among Asian populations may have different implications.

Our study revealed a statistically significant association between prior isotretinoin exposure and IBD. Unlike most prior studies, our research involved the analysis of a dose–response relationship between IBD with isotretinoin exposure. Our analysis revealed higher odds ratios for longer exposure (over 30 days), higher cumulative dose (over 56 tablets), and longer time since first exposure (over 3 years since first exposure). Our study also comprised an analysis of the long-term effects of isotretinoin over a 5-year period. The risks for ulcerative colitis and Crohn’s disease were investigated individually, but almost no difference between them was found (OR 1.19 and 1.18, respectively). Furthermore, our sub-group analysis indicated a significant association between isotretinoin exposure and IBD regardless of sex.

The mechanism by which isotretinoin exposure leads to IBD is unclear; however, several theories have been suggested. One possible mechanism is the prevention of epithelial cell growth which can, in turn, impact the bowel epithelium and lead to a loss of integrity of the intestinal barrier and subsequent inflammation.[8] Another proposed mechanism suggests that disturbances in epithelial cell maturation can lead to inflammation, alterations in glycoprotein metabolism, and the induction of killer T-cell activity.[9] More research is needed to fully clarify the relationship between isotretinoin and IBD.

Our study has a few limitations. First, it is a case-control study for which the NHIS database was utilized. Due to the low prevalence of IBD, it is challenging to conduct prospective studies. Hence, as with other studies, it was conducted retrospectively. Because of the nature of a retrospective observational study, it was impossible to establish a cause-and-effect relationship between isotretinoin exposure and IBD. This calls for additional studies including randomized controlled trials. Second, the NHIS database may have lacked accuracy due to discrepancies between the insurance database and real patient data. There may also have been a selection bias in the study population as the NHIS database covers only those with insurance. However, considering the high enrolment rate of 97% among Koreans, this is deemed to be a minor concern. Third, certain hidden confounding factors may not have been adjusted for due to limitations in the study design. These include smoking, diet patterns, and obesity, all of which are risk factors for IBD and may have been confounding factors.[10] Last, since isotretinoin prescription requires monitoring, more frequent hospital visits may have led to an increased diagnosis of sub-clinical to mild IBD for those with short-term prescriptions.

In conclusion, prior isotretinoin exposure could increase the risk of IBD in the Asian population, highlighting a dose–response relationship. Physicians should be aware of this whenever isotretinoin is prescribed, especially for patients who are at high risk for IBD. In these cases, alternative medications should be considered.

Financial support and sponsorship

This study was supported by 2021 Dong Wha Research fund.

Conflicts of interest

There are no conflicts of interest.
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