When should Azoran (Azathioprine) be stopped in patients with a history of autoimmune diseases or organ transplantation?

When to Stop Azoran (Azathioprine)

Azathioprine should only be stopped after a minimum of 2 years of continuous treatment with at least 12 consecutive months of completely normal liver tests, and ideally only after liver biopsy confirms complete histological remission with no interface hepatitis. 1, 2

Critical Prerequisites Before Considering Withdrawal

You must verify ALL of the following before even considering stopping azathioprine:

• Minimum treatment duration of 2 years total, regardless of when biochemical remission was achieved 1, 2
• At least 12 consecutive months of normal liver tests (AST, ALT, γ-globulin, and IgG all within normal range) 1, 2
• Liver biopsy showing complete histological remission is strongly recommended before withdrawal, as 55% of patients with normal blood tests still have active interface hepatitis on biopsy and will relapse after stopping 1, 2
• Average time to achieve biochemical normalization is 19 months, with histological resolution requiring an additional 3-8 months, so most patients need 22-27 months minimum 1

High-Risk Patients Who Should NEVER Stop Azathioprine

Continue azathioprine indefinitely (lifelong maintenance at 2 mg/kg/day) in these patients:

• Any patient who has relapsed even once after previous drug withdrawal 1, 2
• Younger patients with decades of life expectancy ahead 1
• Patients with cirrhosis or history of decompensation 1
• Patients positive for anti-LKM or anti-SLA antibodies (higher relapse risk) 1
• Patients who experienced severe disease at initial presentation 1
• Patients with corticosteroid-related side effects or intolerance 1

Expected Outcomes After Stopping (The Reality)

50-90% of patients relapse after stopping azathioprine, even with documented biochemical and histological remission. 2, 3 This is the single most important fact to communicate to patients.

• Only 25-36% achieve "sustained remission" (loosely defined as AST <3× upper limit of normal, not true remission) 1
• Most relapses occur within the first 12 months, but late relapses can occur even 7+ years after stopping 1, 3
• In one study, 50% of patients relapsed after a median of 7 years following withdrawal after 5 years of treatment 1
• 92% of patients who relapse will regain remission with retreatment, but this requires higher corticosteroid doses with additional side effects 1

Mandatory Monitoring Protocol After Withdrawal (If Attempted)

Lifelong monitoring is required even after successful withdrawal:

• Weeks 1-12 after stopping: Clinical assessment and liver tests (AST, ALT, bilirubin, γ-globulin, IgG) every 3 weeks 1, 2
• Months 4-12: Laboratory tests every 4-6 weeks 2, 3
• After first year: Continue monitoring every 3-6 months indefinitely for life 1, 3
• IgG elevation may precede AST/ALT rise in relapse, so monitor both 1
• Relapse is defined as AST >2× upper limit of normal; liver biopsy is usually not necessary to confirm relapse 2

Special Circumstances

Inflammatory Bowel Disease (Ulcerative Colitis/Crohn's Disease)

• Stopping thiopurines may be considered only after 5-10 years or more of clinical, endoscopic, AND histological remission 1
• Relapse rate is 37% after mean follow-up of 55 months in patients stopping after minimum 3 years with complete remission 1
• All patients stopping thiopurines should continue 5-ASA therapy if tolerated, as this reduces relapse rates 1
• Consider periodic fecal calprotectin monitoring after cessation to detect subclinical inflammation 1

Pregnancy

• Azathioprine has FDA Category D pregnancy rating and should be discontinued if possible during pregnancy 1
• However, the risk-benefit must be carefully weighed, as stopping may trigger severe relapse 1
• Postpartum exacerbation must be anticipated—resume standard therapy 2 weeks before anticipated delivery 1

Drug Toxicity Requiring Immediate Discontinuation

Stop azathioprine immediately if any of these occur:

• Severe leukopenia (WBC <4,000/mm³), thrombocytopenia (<150,000/mm³), or pancytopenia 4
• Severe hepatotoxicity or progressive liver dysfunction 4
• Development of malignancy (lymphoma, hepatosplenic T-cell lymphoma, or myelodysplastic syndrome) 4, 5
• Progressive multifocal leukoencephalopathy (PML) 4
• Intrahepatic cholestasis of pregnancy 4

Common Pitfalls to Avoid

• Do not stop azathioprine based solely on normal blood tests—55% of these patients still have active histological disease and will relapse 1, 2
• Do not assume remission is permanent—late relapses occur even after many years, requiring lifelong surveillance 1, 3
• Do not abruptly stop without establishing intensive monitoring—most relapses occur in the first year and require prompt detection 3
• Do not stop in patients with even one prior relapse—these patients require lifelong maintenance therapy 1, 2