What is thiopurine medication?

What is Thiopurine Medication

Thiopurines are immunosuppressive antimetabolite drugs that include azathioprine, 6-mercaptopurine (6-MP), and thioguanine, primarily used to maintain remission in inflammatory bowel disease, treat acute lymphoblastic leukemia, and manage various autoimmune conditions including dermatological diseases. 1, 2, 3

Mechanism of Action

Thiopurines work through multiple pathways to achieve immunosuppression:

• Azathioprine is a prodrug that requires enzymatic and nonenzymatic conversion via glutathione to become 6-mercaptopurine 1
• The active metabolite 6-thioguanine nucleotides (6-TGN) incorporate into DNA instead of guanine nucleotides, inhibiting purine and protein synthesis in lymphocytes 1
• Additional mechanisms include blocking thiol groups through alkylation, inhibiting nucleic acid biosynthesis pathways, and altering lymphocyte function 4
• The drugs reduce lamina propria plasma cells and affect natural killer cell function 4

Clinical Applications

Primary Indications

• Inflammatory bowel disease (Crohn's disease and ulcerative colitis): maintenance of remission and steroid-sparing therapy 1
• Acute lymphoblastic leukemia: part of combination chemotherapy maintenance regimens 2
• Dermatological conditions: various inflammatory skin diseases requiring immunosuppression 1
• Solid organ transplantation: immunosuppression to prevent rejection 1

Important Limitation

Thiopurines are slow-acting drugs with clinical efficacy not expected until several weeks or months of treatment, making them inappropriate as monotherapy for acute relapsing disease 4

Dosing Guidelines

Standard Dosing

• Azathioprine: 2-2.5 mg/kg/day for patients with normal TPMT activity 1
• 6-Mercaptopurine: 1-1.5 mg/kg/day for patients with normal TPMT activity 1
• Start at full target dose immediately; gradual dose escalation does not improve safety or tolerance and delays achieving therapeutic levels 1

Dose Modifications Based on Genetics

• Homozygous TPMT or NUDT15 deficiency: reduce to 10% or less of standard dose, or avoid thiopurines entirely 2
• Heterozygous TPMT deficiency: 50% of standard dose (1 mg/kg azathioprine or 0.5 mg/kg mercaptopurine) 1
• Patients heterozygous for both TPMT and NUDT15 may require more substantial dose reductions 2

Special Populations

• Renal impairment: use lowest starting dose if creatinine clearance <50 mL/min; reduce to 75% if CLcr 10-50 mL/min and 50% if <10 mL/min 1, 2
• Hepatic impairment: use lowest starting dose and adjust based on tolerability 2
• Concomitant allopurinol use: reduce thiopurine dose to one-third to one-quarter of current dose 2

Required Pre-Treatment Testing

Before initiating thiopurines, mandatory baseline testing includes:

• TPMT activity or genotype testing to identify patients at risk for severe myelosuppression (strength of recommendation A, level of evidence 1+) 1, 5
• NUDT15 genotype testing, particularly for Asian patients who have higher frequency of NUDT15 variants 1, 2
• Complete blood count with differential to identify pre-existing cytopenias 1, 5
• Liver function tests including transaminases, as hepatotoxicity can occur 1, 5
• Renal function tests to guide dose adjustments 1, 5
• Screening for hepatitis B, hepatitis C, and HIV; consider HBV vaccination if naïve 1
• Varicella zoster virus (VZV) immunity with vaccination if low 1
• Pregnancy testing in women of childbearing age, as thiopurines are pregnancy category D 5

Monitoring Requirements

Initial Monitoring Phase

• FBC, U&E, and LFTs at weeks 2,4,8, and 12 after starting therapy 1
• Repeat bloods 2 weeks after all dose increases 1
• The manufacturer's recommendation of weekly FBCs for 8 weeks has no evidence of effectiveness 1

Ongoing Monitoring

• At least 3-monthly blood monitoring (FBC, U&E, LFTs) as toxicity can occur at any stage during therapy 1
• Thiopurine metabolite testing (6-TGN and 6-MMP levels) to detect non-adherence, inadequate dosing, or excessive methylation ("shunters") 1
• Cervical screening participation for women, as thiopurines increase risk of cervical dysplasia 1
• Annual skin cancer surveillance, particularly for Caucasian patients on long-term therapy 1

Major Adverse Effects

Myelosuppression

• Most consistent dose-related toxicity, manifesting as anemia, leukopenia, or thrombocytopenia 2
• Profound leucopenia occurs in approximately 3% of patients and can develop suddenly between blood tests 1
• Patients with TPMT deficiency have odds ratio of 4.3 for leukopenia if heterozygous and 20.8 if homozygous 1
• Most leukopenia occurs within 8 weeks, but can happen after many months of therapy 1
• If white cells <3.5×10⁹/L or neutrophils <2×10⁹/L: withhold thiopurine until counts normalize 1
• If neutrophils <1×10⁹/L: warn patients to present for antibiotics ± G-CSF if febrile 1

Hepatotoxicity

• Occurs in approximately 4% of patients 1
• Two patterns: acute idiosyncratic drug-induced liver injury (cholestatic or hepatocellular) and nodular regenerative hyperplasia 1
• Mild LFT derangement is common and may not require therapy alteration 1
• Associated with high 6-MMP levels in patients with skewed metabolism toward methylation 1
• Stop thiopurine if transaminases exceed twice upper limit of normal 1

Pancreatitis

• Occurs in approximately 4% of patients, more common in Crohn's disease and with concurrent prednisolone 1
• Do not rechallenge with azathioprine or mercaptopurine, even at low dose, due to high recurrence risk 1

Gastrointestinal Intolerance

• Flu-like symptoms (myalgia, headache, diarrhea) affect up to 20%, characteristically occurring after 2-3 weeks 1
• Nausea and vomiting in approximately 8% of patients 1
• Management: try switching from azathioprine to mercaptopurine, split dosing, or consider low-dose thiopurine (25-33% standard dose) with allopurinol 100 mg 1

Malignancy Risk

Non-melanoma skin cancer:

• Adjusted odds ratio of 4.3 for NMSC with thiopurine use >1 year in IBD patients 1
• Odds ratio of 5.0 overall, and 12.4 in Caucasian patients for non-melanoma skin cancer 6
• Mechanism involves UVA photosensitivity: 6-thioguanine has maximum absorbance at 340 nm, generating reactive oxygen species when exposed to UVA radiation 1
• Rigorous photoprotection is essential for all patients on long-term thiopurine therapy 1

Lymphoproliferative disorders:

• Higher absolute risk in elderly patients (>65 years) compared to those <50 years 1
• Evidence is contradictory regarding overall lymphoma risk in IBD patients 1
• If increased, the absolute risk appears small in short-to-medium term use 1

Age-related considerations:

• Elderly patients (>65 years) have higher absolute risk of thiopurine-related malignancies compared to younger patients 1
• Prudence about new initiation in elderly is important, but routine discontinuation based solely on age is not appropriate 1

Common Pitfalls and How to Avoid Them

Failure to Test TPMT/NUDT15

Pitfall: Starting thiopurines without genetic testing leads to severe myelosuppression in deficient patients 1, 5

Solution: Always test TPMT before initiation (strength A, level 1+); test NUDT15 especially in Asian populations 1, 2

Inadequate Photoprotection Counseling

Pitfall: Not educating patients about UV exposure risks leads to increased skin cancer 1

Solution: Emphasize rigorous photoprotection for all patients, particularly Caucasians on long-term therapy; arrange regular dermatology surveillance 1

Inappropriate Dose Escalation

Pitfall: Starting at low doses and gradually increasing delays therapeutic effect without improving safety 1

Solution: Start at full target dose immediately (2-2.5 mg/kg azathioprine or 1-1.5 mg/kg mercaptopurine) for patients with normal TPMT 1

Missing "Shunters"

Pitfall: Patients with preferential methylation have poor response and hepatotoxicity risk 1

Solution: Measure thiopurine metabolites (6-TGN and 6-MMP) to identify shunters; consider low-dose thiopurine with allopurinol 100 mg 1

Rechallenge After Pancreatitis

Pitfall: Attempting to restart thiopurines after pancreatitis leads to high recurrence rate 1

Solution: Never rechallenge with azathioprine or mercaptopurine after pancreatitis, even at low doses 1

Overlooking Renal/Hepatic Impairment

Pitfall: Standard dosing in impaired patients leads to toxicity 1, 2

Solution: Use lowest starting dose and adjust based on organ function and metabolite levels 1, 2

Inadequate Monitoring Frequency

Pitfall: Relying only on 3-monthly monitoring misses sudden cytopenias 1

Solution: Monitor at weeks 2,4,8, and 12 initially, then at least 3-monthly; educate patients to report infections immediately 1