Azathioprine

Immunosuppressant for the treatment of autoimmune diseases and after transplantation

Azathioprine is a purine antagonist with immunosuppressive and cytostatic properties that has been used in transplant medicine and for the treatment of various autoimmune diseases since the 1960s. The active substance belongs to the group of antimetabolites and was originally developed as a prodrug of 6-mercaptopurine. In the UK and many countries, azathioprine is available under brand names such as Imuran and numerous generics. It is used as a tablet or infusion solution.

Azathioprine is one of the longest clinically used immunosuppressants and remains an indispensable medicine in rheumatology, gastroenterology, neurology, dermatology and transplant medicine despite newer biologics and targeted therapies. Its use requires careful monitoring of the blood count and liver function, as well as knowledge of genetic variants in its metabolism.

Mechanism of Action

Azathioprine is a prodrug that, after oral administration, is converted to 6-mercaptopurine (6-MP) by non-enzymatic reaction with glutathione and subsequent enzymatic degradation. 6-MP is then processed by several enzymes into the actual active metabolites. The central step is conversion by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to 6-thioguanine nucleotides (6-TGN). These metabolites are incorporated into the DNA and RNA of proliferating cells and inhibit purine synthesis and DNA replication.

Since T and B lymphocytes are highly dependent on de novo purine synthesis during the immune response (unlike most other body cells, which can fall back on salvage pathways), these cells are particularly strongly inhibited in their proliferation by azathioprine. Inhibition of cellular immune reactions and suppression of antibody production are the main therapeutic effects.

Another enzyme crucial for dosing is thiopurine S-methyltransferase (TPMT). TPMT inactivates 6-MP by methylation. Patients with low or absent TPMT activity (genetic polymorphism) accumulate high amounts of active 6-TGN and are at increased risk of severe myelosuppression. TPMT testing before starting therapy is therefore recommended.

Indications

• Transplant medicine: Prevention of rejection after kidney, liver, heart and other organ transplants, often in combination with ciclosporin and corticosteroids
• Chronic inflammatory bowel diseases: Crohn's disease and ulcerative colitis, particularly for maintenance of remission after steroid-induced remission or in steroid-dependent courses
• Rheumatoid arthritis: As a disease-modifying antirheumatic drug (DMARD) when other basic therapeutics are insufficient
• Systemic lupus erythematosus (SLE): Maintenance of remission and steroid-sparing therapy
• Autoimmune hepatitis: Standard therapy in combination with prednisolone for remission induction and maintenance
• Myasthenia gravis: Long-term immunosuppression to reduce the corticosteroid dose
• Vasculitides: Granulomatosis with polyangiitis (Wegener's) and other systemic vasculitides for maintenance of remission
• Dermatological diseases: Atopic dermatitis (severe), pemphigus, bullous pemphigoid
• Multiple sclerosis: Occasionally as a reserve agent in certain disease courses

Dosage and Administration

Transplant indication: Initially 3 to 5 mg/kg body weight (BW) daily; maintenance dose 1 to 3 mg/kg BW daily. Autoimmune diseases (adults): Starting dose 1 to 1.5 mg/kg BW daily; gradual increase to 2 to 3 mg/kg BW daily after 4 to 6 weeks if no intolerance occurs. The daily dose is given once or divided into two individual doses. Children: Weight-adapted dosing according to indication, generally 1 to 3 mg/kg BW daily.

Azathioprine should be taken after meals to reduce gastrointestinal intolerance. The onset of action is delayed and only occurs fully after 3 to 6 months; in chronic inflammatory bowel diseases sometimes only after 3 to 4 months. Regular blood count checks (every 1 to 4 weeks during the adjustment phase, then every 3 months) are mandatory.

Side Effects

Very common: Bone marrow depression with leukopenia, thrombocytopenia and anaemia; the risk depends strongly on TPMT activity. Gastrointestinal complaints (nausea, vomiting, diarrhoea) in the initial phase.

Common: Susceptibility to infections due to immunosuppression; bacterial, viral (CMV, EBV, varicella) and opportunistic infections (Pneumocystis jirovecii pneumonia with severe immunosuppression). Elevated liver values (transaminases, alkaline phosphatase), cholestatic hepatitis.

Long-term risk: Increased risk of malignancies, particularly non-Hodgkin lymphomas and skin tumours (squamous cell carcinomas), with long-term use. The risk increases with the duration and intensity of immunosuppression. Regular oncological preventive examinations (skin inspection, lymph node monitoring) are recommended. Photosensitisation with increased UV-related skin cancer risk is known; consistent sun protection is important.

Rare: Pancreatitis (particularly in Crohn's disease patients), interstitial pneumonitis, alopecia (hair loss), severe hypersensitivity reactions (fever, exanthema, myalgias, hypotension).

Drug Interactions

Allopurinol (and febuxostat): The most important interaction. Allopurinol inhibits xanthine oxidase, an enzyme that breaks down 6-MP. If taken simultaneously, the levels of toxic metabolites rise fourfold; life-threatening myelosuppression may result. The azathioprine dose must be reduced to a quarter of the initial dose and the blood count monitored closely.

Other immunosuppressants (ciclosporin, methotrexate, mycophenolate mofetil): Additive immunosuppression with increased infection and malignancy risk; combination only under strict indication and monitoring.

Live vaccines: Contraindicated with azathioprine; the attenuated pathogen can cause serious disease in immunosuppressed patients. Inactivated vaccines can be administered, but the vaccination success may be reduced.

ACE inhibitors: Increased risk of severe anaemia and leukopenia in combination.

Warfarin: Azathioprine can weaken the anticoagulant effect of warfarin; INR monitoring is recommended.

Ribavirin, mesalazine, sulfasalazine: Inhibition of TPMT can lead to elevated 6-TGN levels and thus increased toxicity.

Special Notes

TPMT testing: Before starting therapy, TPMT enzyme activity or genotype should be determined. Patients with absent TPMT activity (homozygous genotypes, approx. 0.3% of the population) should not receive azathioprine or only with extreme caution and significantly reduced dose. Patients with intermediate activity require a dose reduction.

Pregnancy: Azathioprine is classified as teratogenic in pregnancy but is used in certain indications (e.g. after transplantation, SLE) when the benefit outweighs the risk. Pregnancies under azathioprine should be closely monitored by specialists. Breastfeeding is not recommended while taking azathioprine.

Vaccinations: All necessary vaccinations should be completed as far as possible before starting azathioprine therapy. Live vaccines are contraindicated.

Skin protection: Due to the increased risk of skin cancer, consistent UV protection (sunscreen with high sun protection factor, protective clothing, avoidance of sunbeds) is important throughout the entire duration of therapy.

Frequently Asked Questions

How long does it take for azathioprine to work?

Azathioprine only develops its full immunosuppressive effect after 3 to 6 months of regular intake. In chronic inflammatory bowel diseases, a significant improvement may not occur until 4 to 6 months. In the initial phase, bridging corticosteroids are therefore often used.

What is the difference between azathioprine and 6-mercaptopurine?

Azathioprine is a prodrug that is converted to 6-mercaptopurine (6-MP) in the body. 6-MP itself is also available as a medicine (mainly in paediatric oncology). The difference lies in bioavailability and stability; azathioprine has a slightly better and more even absorption.

Can you drink alcohol while taking azathioprine?

Alcohol is not strictly forbidden with azathioprine therapy, but it should be noted that both alcohol and azathioprine can have hepatotoxic effects. In the presence of liver problems or elevated liver values, alcohol should be avoided. In general, very moderate or no alcohol consumption is recommended.

Is azathioprine a chemotherapy drug?

Azathioprine belongs to the same class of substances as some cytostatics (antimetabolites) and inhibits cell division. However, in the low doses used in immunosuppression, it is not classified as a chemotherapy drug in the oncological sense; the mechanism of action is the same, but the target and dosage differ fundamentally from tumour therapy.

References

• Summary of Product Characteristics Imuran (Aspen Pharma), as of 2024
• German Society for Gastroenterology (DGVS): Guidelines for Crohn's Disease and Ulcerative Colitis, 2022
• European Medicines Agency (EMA): Azathioprine EPAR
• Tiede I et al.: CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. Journal of Clinical Investigation, 2003
• Federal Institute for Drugs and Medical Devices (BfArM): Product monograph azathioprine