Thiopurines

Azathioprine and 6‑mercaptopurine are older immune‑modifying medicines used to keep Crohn’s disease and ulcerative colitis quiet after a flare. They work slowly, so they are not used to start remission. Before starting, most teams check enzyme genes that affect drug breakdown and set up regular blood tests. These medicines can be used alone or with some biologics and require sun protection and long‑term safety monitoring. (journals.lww.com)

Key takeaways

• Azathioprine and 6‑MP are for maintenance and steroid‑sparing, not for quick induction. Expect benefit after about 8 to 12 weeks. (journals.lww.com)

• Test TPMT and consider NUDT15 before starting; dosing depends on results. (gastro.org)

• Check blood counts and liver enzymes often at first, then every 3 months long term. (pmc.ncbi.nlm.nih.gov)

• Important risks include bone marrow suppression, pancreatitis early on, and higher rates of non‑melanoma skin cancer and rare lymphomas. Sun protection and skin checks matter. (academic.oup.com)

• Avoid febuxostat with thiopurines. If allopurinol is used to optimize metabolism, thiopurine dose must be cut to about one‑quarter to one‑third. (drugs.com)

How thiopurines work and when they are used

• What they are: Azathioprine (AZA) is converted in the body to 6‑mercaptopurine (6‑MP). Both lead to active 6‑thioguanine nucleotides that calm the immune system in the gut. (pubmed.ncbi.nlm.nih.gov)

• Role in IBD: They help maintain remission and reduce steroid use in Crohn’s disease and ulcerative colitis. They are not effective to induce rapid remission. (journals.lww.com)

• Combination therapy: Adding a thiopurine to infliximab can improve control and reduce anti‑drug antibodies, especially early in treatment. Trials in Crohn’s (SONIC) and in ulcerative colitis (UC‑SUCCESS) support this approach. (pmc.ncbi.nlm.nih.gov)

Dosing, onset, and practical use

• Typical doses

• Azathioprine: about 1.5 to 2.5 mg per kg daily.

• 6‑mercaptopurine: about 0.75 to 1.5 mg per kg daily. (journals.lww.com)

• Onset: Improvement is gradual and often appears after 8 to 12 weeks. Plan a bridge with steroids or a fast‑acting therapy if needed. (journals.lww.com)

• Pregnancy and lactation: Continuing thiopurines during pregnancy and breastfeeding is generally considered low risk and helps prevent relapse. Avoid starting for the first time during pregnancy when possible. Use shared decision making. (academic.oup.com)

Before starting: testing, screening, and vaccines

• Pharmacogenetics: Check thiopurine methyltransferase (TPMT) activity or genotype, and consider NUDT15, to guide dosing and avoid severe myelosuppression. Poor metabolizers may need major dose reductions or an alternate drug. (gastro.org)

• Infection prevention: Review hepatitis B immunity and vaccinate if non‑immune. Live vaccines are generally avoided once immunosuppression begins. Document influenza and pneumococcal vaccines. (academic.oup.com)

• EBV: In young adults, especially males, consider Epstein‑Barr virus IgG testing because primary EBV infection while on a thiopurine can trigger serious lymphoproliferative illness. (academic.oup.com)

Monitoring and follow‑up

• Lab schedule: Check complete blood count and liver enzymes at weeks 2, 4, 8, and 12, then at least every 3 months while on therapy and 2 weeks after any dose increase. (pmc.ncbi.nlm.nih.gov)

• Metabolites: If there is poor response or side effects, measure 6‑TGN and 6‑MMP. Targets often used are 6‑TGN 235–450 pmol/8×10^8 RBC, and 6‑MMP >5700 pmol suggests hepatotoxicity or “shunting.” (pmc.ncbi.nlm.nih.gov)

• Hyper‑methylators: For patients with high 6‑MMP and low 6‑TGN, switch to low‑dose thiopurine plus allopurinol 100 mg daily and cut the thiopurine dose to about 25 to 33%. Monitor closely. (pmc.ncbi.nlm.nih.gov)

Side effects and safety

• Common: Nausea, fatigue, mild liver enzyme rise, and flu‑like symptoms. Many improve with dose split or switching AZA↔6‑MP. (pmc.ncbi.nlm.nih.gov)

• Pancreatitis: Usually occurs within the first 3 to 4 weeks and is dose‑independent. It affects roughly 3% to 7% of users and resolves after stopping the drug. Do not re‑challenge. Smoking increases risk. (academic.oup.com)

• Bone marrow suppression: Can occur even with normal TPMT. This is why regular blood counts are essential. (pmc.ncbi.nlm.nih.gov)

• Cancers

• Lymphoma: Relative risk about 4 to 5 times higher during current use, with risk returning toward baseline after stopping. Absolute risk is still low and rises with age. (pubmed.ncbi.nlm.nih.gov)

• Non‑melanoma skin cancer: Risk is about twofold with ongoing exposure. Use sun protection and schedule skin exams. (academic.oup.com)

• Hepatosplenic T‑cell lymphoma: Very rare, seen mostly in young men, especially with long‑term thiopurines and anti‑TNF together. (pubmed.ncbi.nlm.nih.gov)

Drug interactions and special cautions

• Xanthine oxidase inhibitors

• Allopurinol can be used deliberately with a reduced thiopurine dose to fix unfavorable metabolism, as above.

• Febuxostat is contraindicated with azathioprine or 6‑MP because of life‑threatening toxicity. (pmc.ncbi.nlm.nih.gov)

• With infliximab: Combination can improve outcomes. If combination is chosen, many centers reassess after about 6 to 12 months and consider simplifying therapy, balancing benefit and risk. Evidence suggests at least 9 months of combination in UC before stopping AZA. Decisions are individualized. (pubmed.ncbi.nlm.nih.gov)

Quick reference

Sources for table: ACG guidelines, BSG monitoring guidance. (journals.lww.com)

FAQs

Are thiopurines still used now that newer biologics exist

Yes. They remain options for maintenance, especially after steroid response, and as partners with some anti‑TNF biologics. Many teams favor newer agents if safety concerns or higher disease risk are present. (journals.lww.com)

How long should combination therapy with infliximab and a thiopurine last

There is no single rule. Data in UC suggest at least 9 months before considering stopping AZA. In Crohn’s, practice varies; teams reassess once stable remission is achieved. (academic.oup.com)

What sun‑safety steps are recommended

Use daily sunscreen, protective clothing, and yearly skin exams. Risk of non‑melanoma skin cancer is higher with thiopurines and falls after stopping. (academic.oup.com)

Are thiopurines safe in pregnancy and breastfeeding

Most guidelines consider them low risk to continue if already effective. Breastfeeding is also acceptable. Discuss timing and plans with the care team. (academic.oup.com)

When should thiopurines be avoided

Avoid in patients with very low TPMT or NUDT15 activity, those with prior severe pancreatitis from a thiopurine, and those taking febuxostat. Caution is advised in EBV‑seronegative young adults. (cpicpgx.org)