Thioguanine in Inflammatory Bowel Disease: Finding hidden treasures in old drugs

This thesis was dedicated to provide a comprehensive insight into the safe and efficacious utilization of thioguanine as an immunosuppressive treatment for inflammatory bowel diseases (IBD) encompassing Crohn’s disease and ulcerative colitis. Azathioprine and mercaptopurine have been used for decades in the maintenance treatment of IBD, but half of the patients discontinue therapy within two years due to side effects or insufficient efficacy. Thioguanine, traditionally used as a chemotherapeutic agent and also belonging to the thiopurine class, offers a more favorable metabolic profile and was proposed as a treatment option for IBD. We have found that thioguanine is an effective medication for IBD, with a corticosteroid-free remission rate of 45% after 12 months of treatment (Chapter 4). The clinical efficacy of thioguanine is quite comparable to azathioprine and mercaptopurine. The advantage of thioguanine appears to be its better tolerance and more favorable side effect profile, with 80% of patients tolerating the drug well, compared to less than 50% with azathioprine and/or mercaptopurine (Chapter 3). Relevant thioguanine-related side effects were observed in 13% of patients, with severe side effects occurring in 5% (myelotoxicity and hepatotoxicity each in 6%, infections in 10%, and portal hypertension in one patient). Moreover, among members of the Dutch National Crohn's and Colitis patient organization, 75% of patients reported satisfaction with the treatment, and 80% were satisfied with the quality of care (Chapter 5). Initially, there were concerns about the safety of thioguanine, particularly regarding the development of (histological) liver abnormalities (such as nodular regenerative hyperplasia, NRH). In multiple studies, we have shown that when thioguanine is adequately dosed (i.e., 0.2-0.3 mg/kg, maximum 25 mg per day), these liver abnormalities are found in only a small percentage of patients (2 out of 52 patients with liver biopsies, 3.8%; both asymptomatic) and are rarely clinically relevant (Chapter 7 and 8). Additionally, our cohort study of 117 pregnancies, resulting in 109 live births, suggests that thioguanine is safe for pregnant IBD patients, and maternal and fetal outcomes are comparable to those observed with azathioprine and mercaptopurine during pregnancy (Chapter 6).