07/12/11

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EXPERT ANALYSIS FROM ARCHIVES OF DERMATOLOGY

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Balancing Risks, Benefits is Everyone’s Job

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Although no link between isotretinoin therapy and inflammatory bowel disease has been proven, the absolute risk for these disorders in conjunction with treatment appears small.

"We would need to treat 2,977 patients with isotretinoin to observe 1 excess case of ulcerative colitis," Dr. Catalin Mihai Popescu and her colleagues wrote in a research review (Arch. Dermatol. 2011;147:724-9).

Dr. Popescu, of Colentina Hospital, Bucharest, Romania, and her colleagues reviewed three case-controlled studies that examined the relationship between isotretinoin treatment for acne and the development of irritable bowel disease (IBD) or ulcerative colitis.

"Because the incidence of IBD is very low, randomized controlled trials or prospective cohort studies cannot be performed owing to issues of cost and sample size," the authors wrote. "The most feasible, quickest, and cheapest approach that can provide the best evidence is a population-based case-control study."

The studies examined included two led by Dr. S.D. Crockett of the University of North Carolina, Chapel Hill: a review of 12 case reports and 1 case series (Am. J. Gastroenterol. 2009;104:2387-93) and a population-based case-control study (Am. J. Gastroenterol. 2010;105:1986-93). The third study, led by Dr. C.N. Bernstein of the University of Manitoba IBD Clinical and Research Centre, Winnipeg, was also a population-based case-control study (Am. J. Gastroenterol. 2009;104:2274-78).

In their review of case reports, Dr. Crockett and colleagues found 15 cases of IBD among isotretinoin users in seven countries over a 23-year period. Based on this finding, the authors suggested that 59 cases of IBD could occur each year in conjunction with isotretinoin treatment.

In the population-based case control study, Dr. Crockett and colleagues used data from a large insurance claims database of 87 U.S. health plans. The authors found no significant isotretinoin association among patients with diagnostic claims for IBD, Crohn’s disease, or ulcerative colitis. When the researchers considered any exposure to the drug, they found that only the risk for ulcerative colitis was significant (odds ratio, 4.36). Higher doses, dose escalation, and longer duration of isotretinoin treatment increased the risk for ulcerative colitis significantly (up to OR 5.63).

Dr. Bernstein and colleagues' case-control study found 1,960 cases of IBD diagnosed in a Manitoba health database during the period from 1995 to 2007. IBD and ulcerative colitis cases were matched with more than 19,419 controls. Patients with IBD were no more likely than matched controls to have used isotretinoin before diagnosis.

Dr. Popescu and her colleagues noted the quality of the studies was high, but their disparate findings make logical conclusions difficult. Dr. Popescu also suggested that antibiotics could be a possible link between acne treatment and IBD. Before taking isotretinoin, most patients with acne undergo protracted antibiotic treatment.

"A recent population-based case-control study showed that the hazard ratio for developing IBD for any exposure to a tetracycline antibiotic was 1.39," they wrote. Other antibiotics used for acne treatment were associated with higher risks for Crohn’s disease: HR 2.25 for doxycycline and Crohn’s disease, and 1.61 for tetracycline/oxytetracycline.

"The risk of ulcerative colitis, but not Crohn’s disease, seems to be increased in patients taking isotretinoin," the authors noted, "but further studies are needed to confirm or refute this finding. Although the absolute risk is very small ... dermatologists and their patients should be aware of it, and, if persistent bowel symptoms develop, isotretinoin administration should be discontinued and patients should be referred to a gastroenterologist."

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