Thiopurines

Thiopurines are older immune calming medicines used in Crohn’s disease and ulcerative colitis. The main drugs are azathioprine and 6‑mercaptopurine. They do not work quickly, but they can help keep remission once inflammation is controlled. Because side effects can be serious, long term use always involves careful blood test monitoring and regular safety checks.

Key Takeaways

• Thiopurines in IBD mainly mean azathioprine and 6‑mercaptopurine (6‑MP), used mostly for long term maintenance, not quick flare control.

• They are often started after steroids or with biologics to help keep inflammation quiet and reduce steroid use. (journals.lww.com)

• Before starting, many teams check TPMT and NUDT15 activity plus baseline blood counts and liver tests to lower the risk of severe toxicity. (news.mayocliniclabs.com)

• Ongoing care usually includes regular blood work and sometimes thiopurine metabolite levels to balance benefit and side effects. (pharmaceutical-journal.com)

• Important risks include bone marrow suppression, liver injury, pancreatitis, and a small increased risk of certain cancers and infections, especially with long term use. (pmc.ncbi.nlm.nih.gov)

• Decisions about use in pregnancy, combination with biologics, and long term continuation are individualized and should involve an IBD specialist. (pubmed.ncbi.nlm.nih.gov)

What are thiopurines?

Thiopurines are immune suppressing medicines that interfere with how certain white blood cells grow and divide. In IBD the main thiopurines are:

• Azathioprine (AZA)

• 6‑mercaptopurine (6‑MP)

Azathioprine is converted in the body into 6‑MP, so they act in similar ways.

In Crohn’s disease and ulcerative colitis, thiopurines are used to maintain remission and to reduce the need for repeated courses of steroids. They are not strong enough or fast enough to act as primary rescue treatment for moderate to severe flares. (journals.lww.com)

Thiopurines may be used:

• As maintenance treatment after remission with steroids

• As “steroid sparing” therapy in people who keep needing steroids

• Together with anti‑TNF biologics, such as infliximab or adalimumab, to reduce antibody formation and help the biologic work longer (journals.lww.com)

How quickly do thiopurines work?

Thiopurines have a slow onset.

• Early benefit may appear after about 8 to 12 weeks.

• Full effect can take up to 3 to 6 months in some people. (journals.lww.com)

Because of this slow effect, they are usually started while another treatment is controlling the flare, for example a steroid course or a biologic.

Typical dosing

Doses are usually based on body weight and on how fast the body breaks down thiopurines:

• Azathioprine: about 2.0 to 2.5 mg per kg per day

• 6‑MP: about 1.0 to 1.5 mg per kg per day (pharmaceutical-journal.com)

Some clinicians start at a lower dose and increase slowly to improve tolerance. Tablets are often taken once daily with food. If nausea occurs, splitting the dose or taking it in the evening can sometimes help.

Pre‑treatment safety checks

Before starting a thiopurine, teams usually check:

• Complete blood count (CBC)

• Liver tests

• Kidney function

• Sometimes pancreatic enzymes (amylase, lipase) (pmc.ncbi.nlm.nih.gov)

TPMT and NUDT15 testing

Two enzymes, TPMT (thiopurine methyltransferase) and NUDT15, strongly affect thiopurine breakdown.

• People with very low activity of either enzyme can build up high drug levels and develop dangerous bone marrow suppression.

• In many centers, blood or genetic tests for TPMT and NUDT15 are done before starting azathioprine or 6‑MP. (news.mayocliniclabs.com)

Typical approach:

• Normal activity: standard weight‑based dose, with routine lab monitoring

• Intermediate activity: start at a reduced dose and monitor more often

• Very low or absent activity: thiopurines are often avoided or used only at tiny doses with extremely close monitoring, if at all

Even with normal TPMT and NUDT15, blood counts can still drop, so enzyme testing never replaces regular lab checks.

Monitoring over time

Regular monitoring is central to safe thiopurine use.

Lab schedule

Exact schedules vary by clinic, but a common pattern is:

Blood tests are also repeated 2 weeks after any dose change or if new symptoms appear.

Thiopurine metabolite testing

Some centers measure thiopurine metabolites in the blood:

• 6‑TGN (6‑thioguanine nucleotides): linked to treatment effect

• 6‑MMP (6‑methylmercaptopurine): linked to liver irritation

Metabolite testing helps when:

• Symptoms continue despite an apparently adequate dose

• Side effects suggest high or imbalanced metabolite levels

• There is concern about missed doses

Metabolite levels can guide dose adjustment or switching strategies. (pharmaceutical-journal.com)

Side effects and long term risks

Common early side effects

Some people experience:

• Nausea or poor appetite

• Fatigue or mild flu‑like feelings

• Joint or muscle aches

• Mild hair thinning

These often improve with dose adjustment or timing changes.

A small percentage, roughly 3 to 5 percent, develop acute pancreatitis within the first weeks. This causes upper abdominal pain, often with vomiting, and usually resolves once the drug is stopped. Re‑starting a thiopurine after pancreatitis is generally avoided. (aafp.org)

Bone marrow and liver effects

Thiopurines can suppress the bone marrow, leading to:

• Low white blood cells

• Sometimes low platelets or anemia

This can increase infection and bleeding risk, which is why CBC monitoring is so important. (pharmaceutical-journal.com)

Liver side effects include:

• Rising liver enzymes on blood tests

• Less often, a cholestatic picture with itching and jaundice

• Very rarely, more serious chronic liver changes

High 6‑MMP levels are linked to some liver problems, which metabolite testing can help uncover. (pharmaceutical-journal.com)

Infection and cancer risk

Because thiopurines suppress the immune system, they modestly increase the risk of infections, especially when combined with steroids or biologics.

Large studies show:

• A small absolute increase in lymphoma risk during current thiopurine use

• A higher risk when thiopurines are used together with anti‑TNF biologics

• A higher rate of non‑melanoma skin cancers, especially in fair‑skinned people and with many years of use (pubmed.ncbi.nlm.nih.gov)

Most people never develop these cancers, but the risks shape how long thiopurines are used and how closely skin and lymph nodes are watched. Good sun protection and, for many, regular skin checks are advised.

Vaccines, pregnancy, and special situations

Because thiopurines lower immune function, inactivated vaccines such as influenza, COVID‑19, pneumonia, HPV, and hepatitis B are usually encouraged. Live vaccines are often given before starting long term immunosuppression, if needed. Details appear in the Infection Prevention & Vaccination articles.

For pregnancy, multiple studies in IBD suggest that continuing azathioprine or 6‑MP does not increase major birth defects or miscarriage, though some data show a small increase in preterm birth. (pubmed.ncbi.nlm.nih.gov)

Recent safety alerts describe rare cases of intrahepatic cholestasis of pregnancy linked to thiopurines, where pregnant people developed severe itching and high bile acids that improved when the drug was stopped. (fda.gov)

Choices about starting, continuing, or stopping thiopurines around conception or pregnancy are individualized and ideally involve both an IBD specialist and obstetric team.

Practical long term tips

For people using thiopurines long term, common practices include:

• Keeping a consistent daily routine for taking the medicine

• Attending all scheduled blood test appointments

• Using sun protection and avoiding tanning beds

• Telling the care team about new medicines, especially allopurinol or febuxostat, which can greatly increase thiopurine levels and require major dose changes

• Seeking urgent care for high fever, severe sore throat, easy bruising, yellowing of the skin or eyes, very dark urine, or severe upper abdominal pain

Any decision to start, adjust, combine, or stop thiopurines should be made together with the medical team, weighing benefits for IBD control against long term safety.

FAQs

How long can someone safely stay on a thiopurine?

Many people stay on azathioprine or 6‑MP for years, especially if the medicine is well tolerated and the disease is well controlled. Because some risks, such as certain cancers and skin damage, rise with age and duration, teams often re‑evaluate the need for ongoing therapy at regular intervals.

What is the difference between azathioprine and 6‑MP?

Azathioprine is a prodrug that the body converts into 6‑MP. Dosing numbers differ, but the end effect is similar. Some people who feel nausea or headaches on azathioprine do better after switching to 6‑MP, but serious reactions like pancreatitis or bone marrow suppression usually occur with both.

What if TPMT or NUDT15 activity is low?

People with intermediate TPMT or NUDT15 activity can sometimes take thiopurines at lower doses with very close monitoring. Those with very low or absent activity have a high risk of life threatening bone marrow suppression at standard doses, so thiopurines are often avoided and other medicines are chosen instead. (cpicpgx.org)