Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective

Abstract

The use of thiopurines in inflammatory bowel disease (IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor (anti-TNF) agents, and maintenance of remission and post-operative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.

Keywords: Azathioprine; Crohn’s disease; Inflammatory bowel disease; Mercaptopurine; Thiopurines; Ulcerative colitis.

Figure 1

Chemical structures of azathioprine and mercaptopurine. AZA: Azathioprine; 6-MP: 6-mercaptopurine.

Figure 2

Metabolic pathway for azathioprine and mercaptopurine. AZA: Azathioprine; 6-MP: 6-mercaptopurine; 6-TU: Thiouric acid; 6-MMP: 6-methylmercaptopurine; 6-TIMP: 6-thioinosine-monophosphate; 6-MMPR: Methyl-mercaptopurine ribonucleotide; 6-TGN: Thioguanine nucleotide; XO: Xanthine oxidase; TPMT: Thiopurine methyltransferase; HPRT: Hypoxanthine phosphoribosyl transferase; IMPDH: Inosine monophosphate dehydrogenase; GMPS: Guanosine monophosphate synthetase.