What are the guidelines for using Imuran (azathioprine) in patients with a history of autoimmune diseases or immunocompromised status?

Azathioprine (Imuran) Guidelines for Autoimmune Diseases and Immunocompromised Patients

Critical Pre-Treatment Requirements

Before prescribing azathioprine to any patient with autoimmune disease or immunocompromised status, TPMT (thiopurine methyltransferase) testing is mandatory, as 11% of the population has low TPMT activity predisposing to severe myelosuppression, and 1 in 200-300 individuals have undetectable TPMT activity leading to life-threatening pancytopenia. 1

Absolute Contraindications

• Very low or absent TPMT activity - this is an absolute contraindication due to high risk of life-threatening pancytopenia 1, 2
• Concurrent allopurinol use - causes severe myelosuppression through xanthine oxidase inhibition and must be avoided 1
• Severe pretreatment cytopenia - white blood cell counts below 2.5 × 10⁹/L or platelet counts below 50 × 10⁹/L 1
• Pregnancy (FDA Category D) - contraindicated except when benefit outweighs risk in allograft recipients 1
• Breastfeeding - 6-mercaptopurine identified in breast milk; bottle feeding required 1

Mandatory Baseline Testing

Before initiating therapy, obtain: 1

• Complete blood count (CBC)
• Liver function tests (transaminases, alkaline phosphatase, bilirubin)
• Renal function (urea and electrolytes)
• TPMT activity (or genotype if activity unavailable)
• Hepatitis B and C serology
• HIV serology in high-risk groups
• Varicella zoster virus (VZV) serology if no history of chickenpox

Dosing Protocols for Autoimmune Diseases

Standard Combination Therapy (Preferred)

For autoimmune hepatitis and most autoimmune conditions, combination therapy with prednisone 30mg/day (tapering to 10mg/day maintenance) plus azathioprine 50mg/day (USA) or 1-2mg/kg/day (Europe) provides equivalent efficacy to prednisone alone but with significantly fewer steroid-related side effects (10% vs 44%). 3, 1

Dose Escalation Strategy

• Start at 1.5-2.5 mg/kg/day with gradual escalation over 2-3 weeks to minimize gastrointestinal side effects, particularly nausea which occurs in 10-20% of patients 4, 1
• For patients with normal TPMT activity, target maintenance dose is 2 mg/kg/day 1, 3
• For patients with intermediate TPMT activity (heterozygous deficient), reduce dose to 30-70% of standard dosing 2

Specific Indications in Dermatology

Licensed indications include: 1

• Systemic lupus erythematosus
• Dermatomyositis
• Pemphigus vulgaris

Unlicensed but evidence-supported indications: 1

• Bullous pemphigoid and pemphigus vulgaris (steroid-sparing agent)
• Severe, recalcitrant atopic dermatitis (Grade A; level I evidence)
• Chronic actinic dermatitis (Grade A; level I evidence from double-blind placebo-controlled trials)
• Behçet's disease (Grade A; level I evidence)

Monitoring Requirements During Treatment

Initial Phase (First 3 Months)

• CBC every 1-2 weeks initially, then monthly once stable to detect myelosuppression occurring in approximately 7% of patients 4, 1
• Liver function tests monthly 1
• Monitor for hypersensitivity reaction (fever, arthralgia, rash) requiring immediate discontinuation 4

Maintenance Phase

• CBC every 3-6 months to detect late-onset myelosuppression 5, 3
• Liver function tests every 3-6 months 5
• Yearly dermatologic screening for skin cancer in long-term users due to increased malignancy risk 5

Critical Warning Signs Requiring Urgent Medical Attention

Patients must be counseled to seek immediate care for: 1

• High fever or severe flu-like illness
• Unexplained bruising or bleeding
• New-onset jaundice

Special Considerations for Immunocompromised Patients

Infection Risk Management

While azathioprine increases susceptibility to infections, particularly VZV (chickenpox/shingles), the risk is lower with monotherapy compared to multi-drug immunosuppression in transplant recipients. 1

For VZV exposure in patients on azathioprine: 1

• Consider temporary withdrawal of azathioprine
• Prompt oral antivirals (aciclovir, valaciclovir, or famciclovir) for all patients
• Intravenous antiviral therapy for disseminated or ophthalmic VZV

Vaccination Requirements

• Pneumococcal vaccine and yearly influenza vaccination are recommended 1
• Patients have subnormal responses to vaccines due to immunosuppression 2

Drug Interactions in Immunocompromised Patients

Increased risk of haematological toxicity occurs with concurrent use of: 1

• Other immunosuppressants (cyclophosphamide, methotrexate, ciclosporin, anti-TNF agents, biologics)
• Myelotoxic drugs (co-trimoxazole, trimethoprim, clozapine)
• Aminosalicylates (cause in vitro TPMT inhibition; use cautious dosing and increased monitoring)
• Ribavirin (severe pancytopenia reported with nadir at 3-6 weeks)

Long-Term Management and Withdrawal

Maintenance Strategy After Remission

The preferred long-term approach is steroid-free azathioprine monotherapy at 2 mg/kg/day indefinitely, minimizing steroid-related side effects while maintaining remission. 5, 3, 6

Criteria for Considering Withdrawal

Withdrawal should only be attempted after: 5

• Complete biochemical and clinical remission maintained for at least 1-2 years
• Normalized serum aminotransferases, bilirubin, and immunoglobulin levels
• Resolution of symptoms
• Normal hepatic tissue or inactive cirrhosis (in autoimmune hepatitis)

Tapering Protocol

When tapering is appropriate, reduce azathioprine dose by 0.5 mg/kg increments at 3-month intervals, with laboratory monitoring (transaminases, inflammatory markers, disease-specific antibodies) every 3 weeks during tapering and for at least 3 months after withdrawal. 5

Patients Requiring Indefinite Therapy

Long-term maintenance therapy is mandatory for: 5

• Patients with cirrhosis or history of decompensated liver disease
• Those with multiple previous relapses after treatment withdrawal (50% relapse rate even after 5 years of stable therapy)
• Patients with predictors of relapse (LKM or SLA antibody positivity in autoimmune hepatitis)
• Patients who cannot tolerate corticosteroids

Common Pitfalls and Management

Gastrointestinal Side Effects

For nausea (occurring in 12% of patients): 1

• Use divided daily doses
• Take azathioprine after food
• Temporary dose reduction
• Co-prescription of antiemetics
• If severe, switch to 6-mercaptopurine which reduces gastrointestinal side-effects

Distinguishing Hypersensitivity from Common Side Effects

Nausea associated with fever, myalgia, or arthralgia suggests hypersensitivity reaction requiring immediate discontinuation, not simple dose-related gastrointestinal intolerance. 1

Hepatotoxicity Patterns

Two patterns occur: 1

• Acute drug-induced liver injury (cholestatic or hepatocellular)
• Rare but life-threatening hepatic veno-occlusive disease

If hepatic veno-occlusive disease is clinically suspected, azathioprine must be permanently withdrawn. 2

Alternative Agents for Intolerance

Mycophenolate mofetil (2 g/day) is the second-line steroid-sparing agent for patients intolerant to azathioprine. 4, 3