Isotretinoin is not associated with inflammatory bowel disease even when compared with topical antibiotics and topical retinoids

To the Editor: We read with great interest the commentary of Lin et al1Lin C.Y. Yao C.A. Antibiotics used to treat acne may be associated with inflammatory bowel disease: response to Kridin et al.'s "Isotretinoin and the risk of inflammatory bowel disease and irritable bowel syndrome: a large-scale global study".J Am Acad Dermatol. 2024; 90: e135-e136Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar about our paper entitled: "Isotretinoin and the risk of inflammatory bowel disease and irritable bowel syndrome: a large-scale global study."2Kridin K. Ludwig R.J. Isotretinoin and the risk of inflammatory bowel disease and irritable bowel syndrome: a large-scale global study.J Am Acad Dermatol. 2023; 88: 824-830https://doi.org/10.1016/J.JAAD.2022.12.015Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Throughout the last decades, the dermatologic community has struggled with considerable controversy regarding the risk of inflammatory bowel disease (IBD) among patients treated with isotretinoin. Previous observational studies yielded inconsistent observations.3Alhusayen R.O. Juurlink D.N. Mamdani M.M. Morrow R.L. Shear N.H. Dormuth C.R. Isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study.J Invest Dermatol. 2013; 133: 907-912https://doi.org/10.1038/JID.2012.387Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Lin et al1Lin C.Y. Yao C.A. Antibiotics used to treat acne may be associated with inflammatory bowel disease: response to Kridin et al.'s "Isotretinoin and the risk of inflammatory bowel disease and irritable bowel syndrome: a large-scale global study".J Am Acad Dermatol. 2024; 90: e135-e136Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar assumed that patients with acne managed by oral antibiotics do not embody a good reference (unexposed) group that enables to elucidate the true risk of IBD under isotretinoin. Their concern stems from several reports linking acne-related systemic antibiotics, such as macrolides and tetracyclines, with the development of IBD.4Faye A.S. Allin K.H. Iversen A.T. et al.Antibiotic use as a risk factor for inflammatory bowel disease across the ages: a population-based cohort study.Gut. 2023; 72: 663-670https://doi.org/10.1136/GUTJNL-2022-327845Crossref PubMed Scopus (0) Google Scholar,5Margolis D.J. Fanelli M. Hoffstad O. Lewis J.D. Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease.Am J Gastroenterol. 2010; 105: 2610-2616https://doi.org/10.1038/AJG.2010.303Crossref PubMed Scopus (0) Google Scholar Lin et al1Lin C.Y. Yao C.A. Antibiotics used to treat acne may be associated with inflammatory bowel disease: response to Kridin et al.'s "Isotretinoin and the risk of inflammatory bowel disease and irritable bowel syndrome: a large-scale global study".J Am Acad Dermatol. 2024; 90: e135-e136Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar proposed that this reference group might bias our results because it tends to underestimate the true relative risk of IBD associated with isotretinoin, given that patients prescribed antibiotics have a higher baseline inherent risk of IBD (baseline risk confounding). To mitigate the probability of such a bias, we extended our analyses and compared the risk of IBD among isotretinoin initiators relative to the following 2 new reference groups: (i) patients with acne treated with topical tretinoin and (ii) patients with acne treated with topical benzoyl peroxide (Table I). Patients in both of these groups had lack of any prior or subsequent exposure to isotretinoin and the following oral antibiotics: doxycycline, minocycline, tetracycline, roxithromycin, and azithromycin. A comprehensive propensity score matching was conducted to optimize intergroup comparability as delineated in our original publication.2Kridin K. Ludwig R.J. Isotretinoin and the risk of inflammatory bowel disease and irritable bowel syndrome: a large-scale global study.J Am Acad Dermatol. 2023; 88: 824-830https://doi.org/10.1016/J.JAAD.2022.12.015Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The index date was assigned when the intervention of interest (isotretinoin, tritinoin, and benzoyl peroxide) was first administered.Table ILifetime risk of Crohn's disease and ulcerative colitis among patients with acne treated with isotretinoin relative to those treated with topical tretinoin and topical benzoyl peroxideNo. of eligible participants∗Patients who had the investigated outcome before the initiation of the drugs were excluded from the analysis.No. of outcomesRisk, %No. of eligible participants∗Patients who had the investigated outcome before the initiation of the drugs were excluded from the analysis.No. of outcomesRisk, %Risk difference (95% CI), %Hazard ratio (95% CI)P valueIsotretinoin (N = 79,401)Topical tretinoin (N = 79,401)Crohn's disease79,1491510.1979,9601230.160.04 (–0.01 to 0.08)1.14 (0.90-1.45).271Ulcerative colitis79,2161620.2179,0711380.180.03 (–0.01 to –0.07)1.09 (0.87-1.38).424Isotretinoin (N = 82,960)Topical benzoyl peroxide (N = 82,960)Crohn's disease82,6961520.1882,5341510.180.00 (–0.04 to 0.04)1.10 (0.88-1.38).394Ulcerative colitis82,7681640.2082,6231880.23–0.03 (–0.07 to 0.02)0.97 (0.75-1.19).752∗ Patients who had the investigated outcome before the initiation of the drugs were excluded from the analysis. Open table in a new tab Table I demonstrates the risk of Crohn`s disease and ulcerative colitis among patients with acne initiating isotretinoin relative to the 2 aforementioned reference groups. Compared with topical tretinoin, isotretinoin was not associated with an elevated risk of Crohn's disease (hazard ratio [HR], 1.14; 95% CI, 0.90-1.45; P = .271) or ulcerative colitis (HR, 1.09; 95% CI, 0.87-1.38; P = .424). Correspondingly, isotretinoin did not confer an elevated risk of Crohn's disease (HR, 1.10; 95% CI, 0.88-1.38; P = .394) or ulcerative colitis (HR, 0.97; 95% CI, 0.75-1.19; P = .752) when compared with topical benzoyl peroxide. These findings refute the assertion made by Lin et al1Lin C.Y. Yao C.A. Antibiotics used to treat acne may be associated with inflammatory bowel disease: response to Kridin et al.'s "Isotretinoin and the risk of inflammatory bowel disease and irritable bowel syndrome: a large-scale global study".J Am Acad Dermatol. 2024; 90: e135-e136Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar regarding a confounding that originate from designating patients with acne starting oral antibiotics as a control group. It is noteworthy that these patients were initially selected as a comparator group because we sought to recruit controls with disease severity similar to those undergoing isotretinoin therapy. This reference group ensures a more accurate matching in terms of acne severity. In clinical practice, a common decision is whether to start isotretinoin or an oral antibiotic for acne. Therefore, with respect to clinical decision-making, we would want to know the relative risk of IBD between these 2 therapeutic options. In conclusion, isotretinoin did not impose an increased lifetime risk of IBD relative to 3 different reference therapies (oral antibiotics, topical antibiotics, and topical retinoids). This lends further weight to our conclusion regarding the lack of association between isotretinoin and the potential to trigger IBD. None disclosed. Antibiotics used to treat acne may be associated with inflammatory bowel disease: Response to Kridin et al "Isotretinoin and the risk of inflammatory bowel disease and irritable bowel syndrome: A large-scale global study"Journal of the American Academy of DermatologyVol. 90Issue 4PreviewTo the Editor: We have read the article that reports a large-scale cohort study on the risk of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) in patients treated with isotretinoin. However, we think that the conclusion of this study is biased by a major confounding factor: the use of oral antibiotics, such as macrolides and tetracyclines, which may also increase the risk of IBD. Several observational studies have shown that exposure to these antibiotics is associated with higher odds ratios (ORs), hazard ratios (HRs), and incidence rate ratios (IRRs) of developing IBD compared to nonusers. Full-Text PDF