were analyzed. Patients were defined to be exposed to thio- purines if they had used at least 50 mg azathioprine (AZA) and/or 6-mercaptopurine (6-MP) per day ...
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Risk of Nonmelanoma Skin Cancer in Patients With Inflammatory Bowel Disease Who Use Thiopurines Is Not Increased Dear Editor: We read with interest the article by Long et al1 in this journal, in which an increased risk for nonmelanoma skin cancer (NMSC) in patients with inflammatory bowel disease (IBD) was reported. This increased risk was associated with both recent and persistent thiopurine use as well as with recent and persistent biological use in patients with Crohn’s disease. The concerns for the development of NMSC in patients with IBD who use thiopurines are plausible, because in organ transplant patients its use is associated with an increased risk of malignancy, including non-Hodgkin’s lymphoma and skin cancer.2 Likewise, several studies have reported an increased risk of lymphoma in IBD patients who use thiopurines.3,4 The study by Long et al1 is the first to primarily investigate the association between thiopurine use and the development of NMSC in patients with IBD. In analogy to their study, we performed an identical study in a large Dutch database consisting of health claims and pathology reports to investigate whether we could confirm their findings in Europe. Data of 2887 patients with histologically confirmed IBD were analyzed. Patients were defined to be exposed to thiopurines if they had used at least 50 mg azathioprine (AZA) and/or 6-mercaptopurine (6-MP) per day during a period of 6 months. A total of 819 patients (28%) were defined as thiopurine users, and these were not different from nonusers with regard to type of IBD, gender, age, and extent of IBD. Eighty-six patients (3%) developed NMSC during 18,663 person-years of follow-up (incidence rate, 4.6 per 1000 personyears of follow-up). This was not significantly different between thiopurine users (4.4 per 1000 person-years) and nonusers (4.7 per 1000 person-years). By using Cox proportional hazard regression analysis, we found that increasing age and duration of IBD were associated with a higher risk of developing NMSC, whereas a diagnosis of ulcerative colitis, compared with Crohn’s disease, and female gender were associated with a decreased risk of NMSC (Table 1). Thiopurine use was not associated with an increased risk of developing NMSC, even after adjustment for confounders. We repeated these analyses for different definitions of user by extending the period of use, but this did not change our results (Supplementary Figure 1). Therefore, our results do not confirm the findings reported by Long et al.1 The contrasting outcomes might be related to different study designs. Although Long et al also used health claims data, they did not use pathology-confirmed end points of NMSC, which might lead to an overestimation of the incidence in their patients. The incidence rate for NMSC in IBD was 7.33 per 1000 person-years of follow-up in their study, compared with only 4.6 per 1000 person-years in our study. Besides overestimation, the difference in incidence rate might also be related to regional differences, including sun exposure, and differences in skin type. A final issue is the definition of exposure. To emulate clinical practice, we defined IBD patients as thiopurine users when they used at least 50 mg AZA or 6-MP per day during a period of 6 months. This is strikingly different from the definition used by Long et al, because they already defined patients as thio-
Table 1. Cox Proportional Hazard Analysis of Association Between Thiopurine Use and Development of NMSC
Thiopurine use Presence of ulcerative colitis Female gender Increasing age, y Duration of IBD, mo
Unadjusted HR (95% CI)
Adjusteda HR (95% CI)
0.94 (0.58–1.50) 1.08 (0.69–1.67)
0.85 (0.51–1.41) 0.62 (0.40–0.98)
0.45 (0.29–0.69) 1.06 (1.05–1.07) 1.01 (1.00–1.01)
0.47 (0.30–0.74) 1.06 (1.04–1.08) 1.00 (1.00–1.01)
HR, hazard ratio; 95% CI, 95% confidence interval. aAdjusted for all the covariates listed in the table.
purine users if patients had received at least 1 thiopurine prescription during the 90 days before NMSC diagnosis. By adopting the 6-month period of use in our study, we assured that patients had at least 2 prescriptions, which might not have been the case in the definition used by Long et al. On the basis of the results of this Dutch database analysis, the risk of developing NMSC in IBD patients who use thiopurines is less evident than reported in the study by Long et al.1 Therefore, it seems that thiopurines can safely be used in IBD patients with an indication for these drugs. To further elucidate the association between thiopurines and NMSC, a prospective randomized study stratified for geographic area with predefined end points should be designed.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at doi:10.1016/ j.cgh.2011.01.021. FIONA D. M. VAN SCHAIK MARTIJN G. H. VAN OIJEN Department of Gastroenterology and Hepatology University Medical Center Utrecht Utrecht, The Netherlands HUGO M. SMEETS Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht, The Netherlands and Agis Health Insurance Amersfoort, The Netherlands GEERT J. M. G. VAN DER HEIJDEN Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht, The Netherlands PETER D. SIERSEMA BAS OLDENBURG Department of Gastroenterology and Hepatology University Medical Center Utrecht Utrecht, The Netherlands
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1. Long MD, Herfarth HH, Pipkin CA, et al. Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2010;8:268 –274. 2. Kinlen LJ, Sheil AG, Peto J, et al. Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs. BMJ 1979;2:1461–1466. 3. Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009;374:1617–1625. 4. Kandiel A, Fraser AG, Korelitz BI, et al. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 2005;54:1121–1125.
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Acknowledgments The authors thank Mariel Casparie and Lucy Overbeek (PALGA, Utrecht, The Netherlands) for PALGA data collection and Henk Evers (Agis, Amersfoort) for data collection from the Agis database. Conflict of interest The authors disclose no conflicts. Funding The study was supported by a grant of Tramedico, Weesp, The Netherlands. doi:10.1016/j.cgh.2011.01.021
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Supplementary Figure 1. Hazard ratios (HR) and 95% confidence intervals (CI) for the development of non-melanoma skin cancer (NMSC) categorized in different durations of thiopurine use.
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