The continuous rediscovery and the benefit–risk ratio of thioguanine, a comprehensive review

Abstract

Introduction: In the 1950s, thioguanine (TG), a thiopurine-derivative together with azathioprine (AZA) and mercaptopurine (MP), were developed for the treatment of childhood leukemia. Over the years, the use of TG was also explored for other, mainly immune-mediated and inflammatory, diseases such as in the field of dermatology and rheumatology (e.g. psoriasis, systemic lupus erythematosus (SLE)) and gastroenterology and hepatology (e.g. inflammatory bowel diseases (IBD), autoimmune hepatitis).Areas covered: This review provides a comprehensive overview of all the clinical uses of TG and describes its mechanism of action, pharmacokinetic/pharmacodynamic features, and toxicity. Expert opinion: Thioguanine has shown beneficial clinical effects in hematological (particularly leukemia) and several immune-inflammatory diseases including psoriasis, SLE, polycythemia vera, Churg-Strauss syndrome, IBD, collagenous sprue, refractory celiac disease, and autoimmune hepatitis. Thioguanine is not effective in treating solid-cancers. At relatively low dosages, i.e. 0.2-0.3mg/kg/day or 20 mg/day, TG has a favorable risk-benefit ratio and is a safe and effective drug in the long-term treatment of amongst other IBD patients. Thioguanine toxicity, especially myelotoxicity, and hepatotoxicity, including nodular regenerative hyperplasia (NRH) of the liver, is limited when dosed adequately. The occurrence of NRH appears dose-dependent and has been especially described during high dose TG above 40 mg/day.

A comparative analysis of tioguanine versus low‐dose thiopurines combined with allopurinol in inflammatory bowel disease patients

“…Physicians should be aware that LDTA strategy carries the risk of developing myelotoxicity, due to skewing towards 6‐TGN 3 . Previous studies showed 4% myelotoxicity in LDTA treatment after conventional thiopurines (n = 221) while this is not clearly identified for tioguanine therapy (0.2‐0.3 mg/kg) 10,26 . In our study, we observed myelotoxicity in 5.7% (n = 5) of patients starting LDTA, compared to 3.2% (n = 3) of patients starting tioguanine.…”

“…Tioguanine is metabolised in fewer steps towards the effective 6‐TGN metabolite, bypassing multiple intermediate metabolites which are associated with the majority of adverse events 3 . However, the use of tioguanine in IBD was initially discouraged when high doses of tioguanine (>40 mg/day) were associated with the development of nodular regenerative hyperplasia of the liver (NRH) 8‐10 . Recent studies with reduced dosing (0.2‐0.3 mg/kg) have shown no increased risk for NRH in patients using tioguanine when compared to thiopurine‐naïve IBD patients and demonstrated a favourable safety profile 11,12 .…”

Coronavirus Disease 2019 in Autoimmune Hepatitis: A Lesson From Immunosuppressed Patients

“…Whether it would be sensible to stop thiopurines and increase steroids in patients with COVID-19 treated with immunosuppression is difficult to be ascertained, and more evidence is needed. One should consider that it is highly likely that the immunosuppressive effect of thiopurines would not immediately cease after drug withdrawal, thanks to their mechanism of action, (15) while this is probably not true for steroids, as suggested by the early relapse occurred in case number 9. Moreover, there is well-established literature showing that patients with AIH in stable control of their disease are at high risk of relapse when they suddenly reduce/stop their immunosuppression; therefore, empirical change of immunosuppressive medications should be considered with caution, (3,16) before more evidence is available.…”

Efficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom

“…Having considered these potential risks, the benefits of TG remain important in the treatment of patients with IBD [22]. For this reason, a few centres continue to use TG but only at a lowered dose (10-40 mg/day).…”