Azathioprine: Uses, Dosage, Side Effects and Interactions

Azathioprine is a cornerstone immunosuppressive medication, widely used across several medical fields. Its unique mechanism and well-established clinical applications make it a valuable therapeutic option, but like all potent drugs, its use requires careful consideration of dosing, monitoring, and potential adverse effects. In this article, we'll explore azathioprine's main uses, recommended dosages, side effects, and key drug interactions, drawing on the latest clinical research.

Uses of Azathioprine

Azathioprine has a broad range of medical applications, primarily due to its immunosuppressive and anti-inflammatory effects. It is particularly valued in the management of chronic autoimmune and inflammatory conditions, as well as in organ transplantation.

Indication	Purpose	Patient Population	Evidence/Source
Organ Transplant	Prevent rejection	Transplant recipients	1 10
Crohn's Disease	Induce/maintain remission	Adults	2 3 7 8 13
Ulcerative Colitis	Steroid-sparing, maintain remission	Adults	8
Dermatological Diseases	Treat severe skin conditions	Adults, children	5 6 15
Neuromyelitis Optica	Prevent relapses	Adults	4
Connective Tissue Disease-Associated ILD	Disease stabilization	Adults	14
Autoimmune Diseases (e.g., SLE, RA)	Immunosuppression	Predominantly women	9

Table 1: Major Clinical Uses of Azathioprine

Transplantation

Azathioprine is a mainstay in post-transplant immunosuppression, reducing the risk of acute rejection by dampening the immune response against the transplanted organ. It's typically part of a multi-drug regimen, often combined with corticosteroids and calcineurin inhibitors. High-dose regimens, when carefully monitored, can further reduce rejection rates without significantly increasing myelotoxicity if metabolite levels are tracked 10.

Inflammatory Bowel Diseases (IBD)

• Crohn's Disease: Azathioprine is used to induce and maintain remission, and to reduce dependence on corticosteroids ("steroid-sparing"). Evidence supports its efficacy over placebo, with higher response rates at increased doses, though onset of effect can be slow 2 3 7 13.
• Ulcerative Colitis: Similar to Crohn’s, azathioprine helps maintain remission and reduce steroid use. Low-dose regimens can be effective and may have a better safety profile in some populations 8.

Dermatological Disorders

Azathioprine is effective for severe, refractory skin diseases such as immunobullous disorders, photodermatoses, and severe atopic eczema unresponsive to topical therapies. TPMT-guided dosing has improved its safety profile in dermatology 5 6 15.

Neurological and Pulmonary Disorders

• Neuromyelitis Optica Spectrum Disorder (NMOSD): Used as a first-line agent to prevent relapses. While effective, newer biologics like tocilizumab may offer superior relapse prevention 4.
• Connective Tissue Disease-Associated Interstitial Lung Disease: Used for disease stabilization, though tolerance issues lead some patients to discontinue therapy 14.

Other Autoimmune Diseases

Azathioprine is employed in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and other autoimmune conditions, particularly in patients requiring long-term immunosuppression or steroid-sparing strategies 9.

Dosage of Azathioprine

Dosing azathioprine is both science and art, balancing effectiveness with safety. Doses are individualized based on indication, patient weight, and, increasingly, genetic and enzyme activity testing.

Indication	Typical Dose (mg/kg/day)	Key Considerations	Source(s)
Transplantation	1–5	Often with monitoring	9 10
IBD (Crohn’s/UC)	1–2.5	Start low, titrate up	2 3 8
Dermatology	1–2.5 (adults); 1–2.5 (peds)	TPMT-based dosing	5 6 15
NMOSD	2–3	Monotherapy or combo	4
Atopic Eczema	1.0 (TPMT heterozygotes), 2.5 (normal TPMT)	TPMT testing	6 15

Table 2: Typical Dosing Strategies for Azathioprine

Individualized Dosing

• Weight-based dosing: Most regimens start at 1–2.5 mg/kg/day, with some transplantation protocols using up to 5 mg/kg/day under close monitoring 9 10.
• TPMT Testing: Thiopurine methyltransferase (TPMT) activity is now routinely measured before starting azathioprine, as low TPMT activity increases risk of myelotoxicity. Heterozygotes may require lower starting doses (e.g., 1 mg/kg/day) 6 8 15.
• Loading Dose: In Crohn’s disease, intravenous loading can hasten clinical response, though this is not standard practice in all settings 7.

Dose Adjustments and Monitoring

• Titration: Doses are often titrated upwards, starting low to minimize side effects such as gastrointestinal upset.
• Therapeutic Drug Monitoring: Measuring azathioprine metabolites (6-thioguanine nucleotides) can optimize efficacy and safety, especially in transplant recipients 10.
• Renal and Hepatic Impairment: Dose adjustments may be needed; careful monitoring is essential.

Special Populations

• Pediatrics: Dosing is weight-based, with lower starting doses for those with reduced TPMT activity 15.
• Pregnancy: Azathioprine can be continued if necessary, as data do not show a high risk of teratogenicity, but risks and benefits must be weighed carefully 9.

Side Effects of Azathioprine

As with all immunosuppressants, azathioprine carries a risk of side effects, some of which can be serious. Understanding, anticipating, and monitoring for adverse effects is crucial to safe use.

Side Effect	Frequency/Severity	Risk Factors	Source(s)
Myelosuppression	Common; sometimes severe	Low TPMT, drug interactions	6 8 11 13 15 17
Hepatotoxicity	Occasional	Dose-dependent	11 13
Gastrointestinal Upset	Common, mild-moderate	Dose-related	13 15
Hypersensitivity	Uncommon, potentially severe	Idiosyncratic	6 11 13
Increased Infection	Moderate	Immunosuppression	3 13 15
Skin Cancer (SCC)	Increased risk (OTRs)	Sun exposure, long-term use	12
Others (pancreatitis, macrocytosis)	Rare	Unknown	3 11 13

Table 3: Common and Serious Side Effects of Azathioprine

Hematological Toxicity

• Leukopenia (low white cell count): The most significant dose-limiting toxicity. Risk is heightened in patients with low TPMT activity or those on interacting drugs (e.g., allopurinol) 6 8 11 13 15 17.
• Anemia and Thrombocytopenia: Can occur, especially with higher doses or concurrent myelotoxic drugs 11 17.
• Macrocytosis: Often benign, but warrants monitoring 11 15.

Hepatotoxicity

• Elevated liver enzymes: Occurs in a small percentage of patients; typically reversible with dose reduction or discontinuation 11 13.
• Cholestatic hepatitis: Rare but possible.

Gastrointestinal Effects

• Nausea, vomiting, abdominal pain: Common, usually transient or dose-related 13 15.
• Pancreatitis: Rare but can be severe and requires immediate cessation 3 13.

Hypersensitivity and Systemic Reactions

• Fever, rash, malaise: May signal a hypersensitivity reaction; azathioprine should be stopped if this occurs 6 11 13.

Infection Risk

• Opportunistic infections: Increased due to immunosuppression; risk is higher when combined with other immunosuppressants 3 13 15.

Malignancy

• Skin cancers (especially squamous cell carcinoma): Long-term use, particularly in organ transplant recipients, increases risk. Regular skin monitoring and sun protection are advised 12.
• Other cancers: Evidence is less robust for other malignancies.

Pediatric Considerations

• Adverse effects in children mirror those in adults, with myelosuppression the most significant concern. Regular monitoring is advised 15.

Discontinuation Rates and Monitoring

• 15–22% of patients may discontinue due to side effects, most of which are reversible 13 14.
• Regular blood counts and liver function tests are essential, especially in the first few months or after dose changes 6 13 15.

Interactions of Azathioprine

Azathioprine’s metabolism is influenced by numerous medications, and drug interactions can significantly impact safety.

Interacting Drug/Class	Effect on Azathioprine	Clinical Consequence	Source(s)
Allopurinol	Inhibits metabolism	Severe myelosuppression	11 17
Aminosalicylates (e.g., mesalazine)	Inhibit TPMT	↑ Myelosuppression risk	16
Other immunosuppressants	Additive effect	↑ Infection, toxicity	3 4 10 14
Warfarin	Reduced effect	↑ Thrombotic risk	5
ACE inhibitors, cotrimoxazole	↑ Myelosuppression	Cytopenias	5

Table 4: Key Drug Interactions with Azathioprine

Allopurinol and Xanthine Oxidase Inhibitors

• Mechanism: Allopurinol blocks xanthine oxidase, a key enzyme in azathioprine metabolism, leading to accumulation of active metabolites.
• Clinical Impact: Risk of severe, sometimes life-threatening myelosuppression. The azathioprine dose should be reduced by at least two-thirds (often to 25% of original) if co-administered, and close hematological monitoring is essential 11 17.

Aminosalicylates (5-ASA, mesalazine, sulfasalazine)

• Mechanism: These drugs can inhibit TPMT, leading to increased active metabolites and risk of myelotoxicity.
• Clinical Impact: Caution is needed when using azathioprine with these agents, particularly in IBD; monitor blood counts closely 16.

Other Immunosuppressants and Biologics

• Combined Use: Frequently used together in transplantation and autoimmune diseases.
• Risks: Additive suppression of immune function increases infection and malignancy risk. Vigilant monitoring and dose adjustments may be needed 3 4 10 14.

Other Drug Interactions

• Warfarin: Azathioprine can reduce warfarin efficacy, increasing risk of thrombosis 5.
• ACE inhibitors, cotrimoxazole: May increase risk of hematological toxicity; monitor for cytopenias 5.

Conclusion

Azathioprine remains a versatile and effective immunosuppressant across a spectrum of diseases, from organ transplantation to chronic autoimmune and dermatological disorders. However, its use is tempered by a significant side effect profile and important drug interactions. Careful patient selection, dose individualization (using TPMT testing), and vigilant monitoring are essential to maximize benefits and minimize harms.

Key Takeaways:

• Wide-ranging uses: Azathioprine is effective in transplantation, IBD, dermatological, neurological, and other autoimmune conditions.
• Individualized dosing: Doses are tailored to indication, weight, and TPMT activity, with careful titration and monitoring.
• Significant side effects: Myelosuppression, hepatotoxicity, infection risk, and malignancy (notably skin cancer) are main concerns; most adverse effects are reversible with prompt management.
• Critical drug interactions: Allopurinol and aminosalicylates require dose adjustments and close monitoring due to increased toxicity risk.
• Safe use requires: Regular blood monitoring, patient education, and a multidisciplinary approach for optimal outcomes.

With thoughtful application and ongoing research, azathioprine continues to have a prominent role in the management of immune-mediated diseases.