LETTERS TO THE EDITOR

nature publishing group

Isotretinoin and Risk of Inflammatory Bowel Disease Cong Dai, PhD1, Min Jiang, PhD1 and Ming-Jun Sun, PhD1 doi:10.1038/ajg.2014.184

To the Editor: We read with interest the article by Racine et al. (1) estimating the association between isotretinoin use and the risk for ulcerative colitis (UC) and Crohn’s disease (CD) by a large nationwide case–control study in France. The authors concluded that isotretinoin use was not associated with increased UC risk but was associated with a decreased CD risk, and it provides reassuring data for people using isotretinoin. However, the results of this study warrant further discussion. Isotretinoin is the gold-standard treatment for acne, and it is the only Food and Drug Administration (FDA)-approved medication for this indication (2). Now isotretinoin has received attention for

a potential association with inflammatory bowel disease (IBD) (3). However, evidence regarding this association is conflicting. Therefore, we conducted a meta-analysis of published studies to capture a global effect of isotretinoin and IBD. For the meta-analysis, we searched MEDLINE, PUBMED, and EMBASE from 1990 through February 2014 using the following terms: isotretinoin, IBD, UC, and CD. We selected large epidemiologic studies and excluded case reports. In addition, we used the rare disease assumption and considered odds ratios to be a close approximation of relative risks (RRs). We have found seven relevant studies. The pooled RRs among these studies were 0.94 (95% confidence interval (CI) = 0.73– 1.21) (IBD), 0.76 (95% CI = 0.50–1.16) (CD), and 1.41 (95% CI = 1.13–1.76) (UC) (Figures 1–3). Our meta-analysis result showed that isotretinoin use was not associated with an increased UC risk but was associated with an increased CD risk. It is different from the results of Antoine Racine’s study. There are many reasons to explain this discrepancy. For example, the definition and diagnosis of IBD, the delay between disease exposure and disease onset, smoking, acne itself, and other

treatments may confound the relationship between isotretinoin exposure and IBD risk. Therefore, we should be more careful to draw conclusions about isotretinoin exposure and IBD risk. In fact, the mechanism by which isotretinoin could induce IBD is unknown, but the medication’s ability to stimulate natural killer cells and apoptosis, regulate cytokines, inhibit neutrophil chemotaxis, differentiate B cells, and alter glycoprotein synthesis and epithelial tissue growth are all speculated mechanisms (4). It is also plausible that isotretinoin could help prevent IBD because of the ability of retinoic acid to enhance barrier function, inhibit proinflammatory Th-17 cells, and upregulate T-regulatory cells. Therefore, it is difficult to draw a definitive conclusion. In addition, future research should be exploring the relationship among isotretinoin, acne, and IBD. CONFLICT OF INTEREST

Guarantor of the article: Ming-Jun Sun, PhD. Specific author contributions: Cong Dai and Ming-Jun Sun had the original idea for the paper, formulated the protocol, and contributed to data abstraction

ES (95% Cl)

% Weight

Bernstein, et al. 2009

1.16 (0.73, 1.77)

14.10

Crockett, et al. 2010

1.68 (0.98, 2.88)

11.80

Etminan, et al. 2012

0.62 (0.42, 0.88)

16.16

Racine, et al. 2012

0.68 (0.41, 1.10)

12.80

Etminan, et al. 2013

0.99 (0.52, 1.90)

9.52

Racine, et al. 2014

0.74 (0.49, 1.13)

14.78

Alhusayen, et al. 2013

1.14 (0.92, 1.41)

20.84

Overall (I 2 = 62.7%, P = 0.013)

0.94 (0.73, 1.21)

100.00

Study ID

NOTE: Weights are from random effects analysis 0.35

1

2.86

Figure 1. Forest plot for the association between isotretinoin and inflammatory bowel disease. CI, confidence interval.

© 2014 by the American College of Gastroenterology

The American Journal of GASTROENTEROLOGY

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Letters to the Editor

Study ID

ES (95% Cl)

% Weight

Bernstein, et al. 2009

1.15 (0.61, 2.02)

17.88

Crockett, et al. 2010

0.68 (0.28, 1.68)

12.30

Racine, et al. 2012

0.40 (0.19, 0.85)

14.81

Etminan, et al. 2013

0.91 (0.37, 2.25)

12.19

Racine, et al. 2014

0.45 (0.24, 0.83)

17.41

Alhusayen, et al. 2013

1.17 (0.90, 1.52)

25.41

Overall (I 2 = 64.4%, P = 0.015)

0.76 (0.50, 1.16)

100.00

NOTE: Weights are from random effects analysis 0.19

1

5.26

Figure 2. Forest plot for the association between isotretinoin and Crohn’s disease. CI, confidence interval.

ES (95% Cl)

% Weight

Bernstein, et al. 2009

1.16 (0.56, 2.20)

10.46

Crockett, et al. 2010

4.36 (1.97, 9.66)

7.75

Racine, et al. 2012

1.29 (0.68, 2.44)

12.00

Etminan, et al. 2013

1.10 (0.44, 2.70)

5.95

Racine, et al. 2014

1.36 (0.76, 2.45)

14.29

Alhusayen, et al. 2013

1.31 (0.96, 1.80)

49.56

Overall (I 2 = 42.2%, P = 0.124)

1.41 (1.13, 1.76)

100.00

Study ID

0.104

1

9.66

Figure 3. Forest plot for the association between isotretinoin and ulcerative colitis. CI, confidence interval.

and analysis. All authors reviewed and approved the final draft of the paper. Financial support: None. Potential competing interests: None. REFERENCES 1. Racine A, Cuerq A, Bijon A et al. Isotretinoin and risk of inflammatory bowel disease: a French Nationwide Study. Am J Gastroenterol 2014;109:563–9. 2. Femia AN, Ann Vleugels R. Toward improved understanding of a potential association between isotretinoin and inflammatory bowel disease. J Invest Dermatol 2013;133: 866–8.

The American Journal of GASTROENTEROLOGY

3. Papageorgiou NP, Altman A, Shoenfeld Y. Inflammatory bowel disease: adverse effect of isotretinoin. Isr Med Assoc J 2009;11: 505–6. 4. Reddy D, Siegel CA, Sands BE et al. Possible association between isotretinoin and inflammatory bowel disease. Am J Gastroenterol 2006;101:1569–73.

Response to Dai et al. Antoine Racine, MD1,2, Marie-Christine Boutron-Ruault, MD2 and Franck Carbonnel, MD, PhD1,2 doi:10.1038/ajg.2014.236

1

Department of Gastroenterology, First Affiliated Hospital, China Medical University, Shenyang City, China. Correspondence: Ming-Jun Sun, Department of Gastroenterology, First Affiliated Hospital, China Medical University, No. 92 of Beier Road, Heping District, 110001 Shenyang City, Liaoning Province, China. E-mail: [email protected]

To the Editor: We appreciate the interesting analysis provided by Dai et al. (1) regarding our study (2).

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Isotretinoin and risk of inflammatory bowel disease.

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