Table 8.

Key Learning Points

1.	Thiopurines are effective for maintenance of remission for CD and UC.
2.	An elaborate clinical workup is required for initiating and monitoring therapy with thiopurines.
3.	Screening for infections like HBV, HCV, VZV, and EBV is recommended.
4.	Daily doses of AZA, 6-MP and 6-TG are 2–3 mg/kg, 1–1.5 mg/kg, and 0.2–0.3 mg/kg respectively. Lower doses of AZA (< 2 mg/kg/day) are effective in Asians. Combination of low dose thiopurines and allopurinol can be used in patients who are hypermethylators with 6-MMPR: 6-TGN ratio > 11. Genetic testing for polymorphisms in TPMT and NUDT15 can guide about the starting dose and predict dose-dependent adverse effects.
5.	Combination of thiopurines with IFX is superior to either therapy alone in inducing remission in both UC and CD. Thiopurines decrease the formation of anti-drug antibodies and thereby improve the clinical efficacy of IFX. Evidence for combining AZA with adalimumab is not convincing. Concomitant use of thiopurines with vedolizumab and ustekinumab is not recommended at the moment.
6.	Thiopurines have a narrow therapeutic window, therefore monitoring of treatment is required for optimization of therapy and prevent adverse effects. 6-TGN and 6-MMPR are the 2 metabolites measured in clinical practice to guide therapy. Mean corpuscular volume may be considered a surrogate marker for thiopurine metabolites where drug metabolite levels are not available/affordable.
7.	Thiopurine use is associated with development of both idiosyncratic and dose-dependent adverse effects. Idiosyncratic adverse effects include fatigue, flu like illness, myalgias, gastrointestinal intolerance, headache, and pancreatitis whereas leucopenia, myelosuppression and hepatotoxicity are dose-dependent adverse effects.
8.	Thiopurines carry a risk of development of malignancy. Lymphoma (non-Hodgkin lymphoma, NHL) is the commonest malignancy, usually seen in elderly patients receiving thiopurines. The risk decreases gradually after withdrawal of therapy. Hepatosplenic T cell lymphoma is a peripheral T cell lymphoma that occurs in young males receiving combination therapy with thiopurines and anti-TNF agents for ≥ 2 years. Thiopurines increase the risk of development of primary EBV infection (especially in seronegative patients) which can progress to an aggressive and fatal lymphoma. Thiopurines should therefore be avoided in EBV seronegative patients. There is also an increased risk of nonmelanoma skin cancer and uterine cervical cancer.
9.	Pregnancy in patients with IBD should be planned when the disease is in clinical remission. Thiopurines can be continued during pregnancy and lactation.
10.	Thiopurine use in elderly (≥ 60 years) is associated with increased risk of adverse effects including infections and malignancies and therefore should be used with caution.
11.	Thiopurines can be continued in patients with IBD at risk for COVID-19.
12.	Vaccination with live (except MMR) and inactivated vaccines is recommended.

CD, Crohn’s disease; UC, ulcerative colitis; HBV, hepatitis B virus; HCV, hepatitis C virus; VZV, varicella zoster virus; EBV, Epstein-Barr virus; AZA, azathioprine; 6-MP, 6-mercaptopurine; 6-TG, 6-thioguanine; 6-MMPR, 6-methyl mercaptopurine ribonucleotides; 6-TGN, 6-thioguanine nucleotides; TPMT, thiopurine-S-methyltransferase; NUDT15, nucleoside diphosphate-linked moiety X-type motif 15; IFX, infliximab; TNF, tumor necrosis factor; IBD, inflammatory bowel disease; COVID-19, coronavirus disease 2019; MMR, measles mumps rubella.