Thiopurines and the Risk of Cancer in Patients With Inflammatory Bowel Disease and Reference Individuals Without Inflammatory Bowel Disease - A Danish Nationwide Cohort Study (1996-2018)

Mads Damsgaard Wewer; Gasper Letnar; Klaus Kaae Andersen; Mikkel Malham; Vibeke Wewer; Jakob Benedict Seidelin; Flemming Bendtsen; Johan Burisch

doi:10.1016/j.cgh.2024.08.006

Thiopurines and the Risk of Cancer in Patients With Inflammatory Bowel Disease and Reference Individuals Without Inflammatory Bowel Disease - A Danish Nationwide Cohort Study (1996-2018)

Clin Gastroenterol Hepatol. 2024 Aug 28:S1542-3565(24)00772-9. doi: 10.1016/j.cgh.2024.08.006. Online ahead of print.

Authors

Mads Damsgaard Wewer¹, Gasper Letnar², Klaus Kaae Andersen², Mikkel Malham³, Vibeke Wewer⁴, Jakob Benedict Seidelin⁵, Flemming Bendtsen⁶, Johan Burisch⁶

Affiliations

¹ Gastro Unit, Medical Division, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, Hvidovre, Denmark. Electronic address: mads.damsgaard.wewer.02@regionh.dk.
² Omicron ApS, Copenhagen, Denmark.
³ Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, Hvidovre, Denmark; The Department of Paediatrics and Adolescent Medicine, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
⁴ Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, Hvidovre, Denmark; The Department of Paediatrics and Adolescent Medicine, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
⁶ Gastro Unit, Medical Division, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, Hvidovre, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

PMID: 39209201
DOI: 10.1016/j.cgh.2024.08.006

Abstract

Background & aims: Thiopurine therapy is a cornerstone in the treatment of inflammatory bowel disease (IBD). We aimed to assess the effect of thiopurines on cancer risk in IBD according to drug exposure and age.

Methods: Danish national registers were used to identify incident IBD patients, exposure to drugs, and status of cancers, in 1996 to 2018. Cox regressions were used to compare cancer risks in IBD and non-IBD individuals and to assess IBD patients' cumulative drug exposure and the association to first cancer, excluding non-melanoma skin cancer.

Results: We followed 43,419 patients with IBD for a median of 8.2 years (interquartile range, 3.7-14.2 years) after IBD diagnosis. Cancer was reported in 3128 (7.2%) patients with IBD. The risk of cancer was increased in patients with IBD in all age categories compared with non-IBD individuals (<50 years: adjusted hazard ratio [aHR], 1.59; 95% confidence interval [CI], 1.43-1.77; 50-65 years: aHR, 1.31; 95% CI, 1.19-1.44; and >65 years: aHR, 1.14; 95% CI, 1.05-1.24). Monotherapy (aHR, 1.36; 95% CI, 1.17-1.57) and combination therapy (aHR, 2.49; 95% CI, 1.64-3.78) were associated with an increased risk of cancer compared to unexposed patients with IBD. Among elderly patients (>65 years), the aHR was 2.79 (95% CI, 1.24-6.28) in those receiving combination therapy. In patients discontinuing thiopurines, aHRs returned to the level of unexposed (aHR, 0.89; 95% CI, 0.78-1.01). The aHR was positively associated with cumulative thiopurine exposure and in patients with >5 years of exposure, reaching an aHR of 1.36 (95% CI, 1.15-1.61).

Conclusions: Thiopurines were associated with increased hazard of cancer, especially when used in combination therapy in the elderly. The hazard increased by 36% when patients were exposed to thiopurines for more than 5 years. Reassuringly, the hazard returned to baseline after discontinuation of thiopurines.

Keywords: Crohn’s Disease; Epidemiology; Malignancy; Ulcerative Colitis.