What is the usage and dosing of Azatioprine (Imuran) in treating autoimmune diseases and organ transplantation?

Azathioprine Usage and Dosing in Autoimmune Diseases and Organ Transplantation

Azathioprine is a cornerstone immunosuppressive agent used at 1-3 mg/kg/day for organ transplantation and 1-2.5 mg/kg/day for autoimmune diseases, with mandatory TPMT testing before initiation to prevent life-threatening myelosuppression. 1

Pre-Treatment Assessment

Before initiating azathioprine, specific testing is essential:

• Measure TPMT (thiopurine methyltransferase) activity in all patients - this is a strength A recommendation with level 1+ evidence 2, 1
• Consider NUDT15 genotyping, particularly in Asian patients, as genetic variants significantly increase myelosuppression risk 1, 3
• Obtain baseline complete blood count, liver function tests, and renal function 1
• Screen for hepatitis B, hepatitis C, HIV, and varicella zoster virus immunity 1
• Patients with homozygous TPMT or NUDT15 deficiency (up to 0.25% of population) should NOT receive azathioprine due to risk of severe cytopenias 2, 3

Dosing by Indication

Organ Transplantation

Initial dosing for transplant recipients is 3-5 mg/kg daily beginning at the time of transplant, with maintenance reduction to 1-3 mg/kg daily 3. The drug is typically given as a single daily dose on the day of transplantation, though in some cases it may be started 1-3 days before the procedure 3.

Autoimmune Hepatitis

For autoimmune hepatitis, the recommended first-line regimen is prednisolone 30 mg/day (reducing to 10 mg/day over 4 weeks) plus azathioprine 1 mg/kg/day 2. The azathioprine dose should be initiated at 50 mg/day and increased to 1-2 mg/kg based on tolerance and response 2.

• Azathioprine can be started when bilirubin is below 6 mg/dL (100 μmol/L), ideally two weeks after initiating steroids 2
• For non-responding patients, increase azathioprine to 2 mg/kg/day combined with higher-dose steroids or methylprednisolone 2
• Treatment should continue for at least 2 years and for at least 12 months after transaminase normalization 2
• The indefinite azathioprine strategy involves increasing azathioprine to 2 mg/kg daily while tapering prednisone by 2.5 mg monthly until complete withdrawal, maintaining 87% of patients in remission 2

Rheumatoid Arthritis

Initial dose is 1.0 mg/kg (50-100 mg) given as a single daily dose or twice-daily 3. If no serious toxicity occurs and initial response is unsatisfactory after 6-8 weeks, increase by 0.5 mg/kg increments at 4-week intervals up to a maximum of 2.5 mg/kg per day 3.

• Therapeutic response typically occurs after 6-8 weeks; an adequate trial requires minimum 12 weeks 3
• Patients not improved after 12 weeks are considered refractory 3

Immune Thrombocytopenia (ITP)

Azathioprine is administered at 50-200 mg per day in adults as a third-line agent 2. The drug takes several months for full effect, with durable response rates of 51-64% reported, though approximately half of responders require ongoing therapy 2.

Dermatological Conditions

For conditions like pemphigus vulgaris and atopic eczema, azathioprine is used at 1-2.5 mg/kg/day, often as a steroid-sparing agent 2. The therapeutic effect is typically delayed for weeks to 2-3 months 2.

Dose Modifications for Genetic Deficiency

For patients with heterozygous TPMT or NUDT15 deficiency, start at 50% of standard dose (1-1.5 mg/kg/day) 1, 3. Patients heterozygous for both TPMT and NUDT15 deficiency require more substantial reductions 3.

Dose Adjustments for Organ Dysfunction

In renal impairment:

• Use 75% of usual dose for creatinine clearance 10-50 mL/min 1
• Use 50% of usual dose for creatinine clearance <10 mL/min 1
• Oliguric patients, especially those with tubular necrosis post-transplant, require lower doses due to delayed drug clearance 3

In hepatic impairment, use lower doses and monitor more frequently 1, as hepatic insufficiency attenuates pharmacologic activity 4.

Monitoring Protocol

Monitor CBC and liver function tests weekly for the first 4 weeks, then every 3 months throughout therapy 2, 1. Return to weekly monitoring if dose is increased 1. More frequent monitoring is required for patients with intermediate TPMT activity, higher doses, or hepatic/renal impairment 1.

If severe cytopenias develop, test for TPMT deficiency and consider early drug discontinuation 3. Early discontinuation should be considered in patients with abnormal CBC results that do not respond to dose reduction 3.

Special Populations

Pregnancy and Lactation: Azathioprine is FDA category D but considered relatively safe in pregnancy based on extensive experience in autoimmune hepatitis, inflammatory bowel disease, and transplantation 2. It is one of the few ITP medications deemed safe in pregnancy with no increased rate of fetal malformation 2. Very little azathioprine is excreted in breast milk, though breastfeeding decisions should be individualized 2.

Elderly patients should receive doses at the lower end of the range (1 mg/kg/day) 1.

Common Adverse Effects and Management

The most common adverse effects include:

• Nausea and gastrointestinal symptoms - administer with food 3
• Myelosuppression (leukopenia, anemia, neutropenia) - occurs in 7-15% 2
• Infection risk (9.9%) 2
• Liver function abnormalities 2
• Withdrawal arthralgia (63% with indefinite azathioprine strategy) 2
• Lymphopenia (57%) 2
• Diverse malignancies (8% in long-term use) 2

Dose reduction or discontinuation may be necessary for severe hematologic toxicity, even if this risks rejection or disease flare 3.

Critical Pitfalls to Avoid

• Never initiate azathioprine without TPMT testing - homozygous deficiency can cause life-threatening myelosuppression 2, 1
• Do not increase doses to toxic levels in transplant patients solely to prevent threatened rejection 3
• Avoid abrupt discontinuation in autoimmune hepatitis - relapse occurs in 50-90% of patients after withdrawal 2
• Do not expect immediate response - therapeutic effects take weeks to months 2, 1
• Monitor for secondary malignancies with long-term use 2