What are the potential side effects of azathioprine in a patient with a history of autoimmune or inflammatory skin conditions and possible impaired liver function?

Side Effects of Azathioprine

Azathioprine causes myelosuppression (particularly leukopenia followed by thrombocytopenia), gastrointestinal disturbances, hepatotoxicity, and carries increased risk of malignancy with long-term use, requiring close monitoring especially in patients with impaired liver function. 1

Hematologic Toxicity (Most Critical)

Bone marrow suppression is the most serious and common adverse effect:

• Leukopenia occurs most frequently and earliest, affecting >50% of renal transplant recipients and 28% of rheumatoid arthritis patients to any degree 2
• Severe leukopenia (<2500 cells/mm³) develops in 16% of transplant patients and 5.3% of rheumatoid arthritis patients 2
• Thrombocytopenia typically follows leukopenia as bone marrow suppression progresses 3
• Patients with platelet counts <50 × 10⁹/L or neutrophil counts <1.0 × 10⁹/L require immediate drug withdrawal and hematology consultation 1, 3
• Macrocytic anemia commonly occurs and can serve as a marker of drug compliance 4

Genetic Risk Factors for Severe Myelosuppression

• Patients with absent TPMT activity (0.3% of population) are at risk for life-threatening bone marrow failure 1, 2
• Patients with intermediate TPMT activity (10% of population) require dose reduction to 1.0-1.5 mg/kg daily 4
• However, 73% of patients who develop severe myelosuppression have normal TPMT activity, making regular monitoring essential regardless of TPMT status 4
• NUDT15 deficiency affects 2% of East Asian patients (homozygous) and 21% (heterozygous), increasing myelosuppression risk 2

Hepatotoxicity (Critical in Patients with Liver Dysfunction)

Liver toxicity manifests as elevated alkaline phosphatase, bilirubin, and transaminases:

• Hepatotoxicity occurs in <1% of rheumatoid arthritis patients but is more common in transplant recipients 2
• Most hepatotoxicity occurs within 6 months of transplantation and is generally reversible after drug interruption 2
• Rare but life-threatening hepatic veno-occlusive disease can occur with chronic administration 2
• Cholestatic hepatitis has been reported 1
• Patients with pre-existing liver dysfunction require more frequent monitoring 4

Gastrointestinal Side Effects

GI disturbances are common and often manageable:

• Nausea and vomiting occur in approximately 12% of rheumatoid arthritis patients, typically within the first few months 2
• Taking the drug in divided doses and/or after meals reduces GI disturbance frequency 1, 2
• Severe vomiting with abdominal pain may indicate hypersensitivity pancreatitis—this requires urgent medical attention and serum amylase testing 1
• Diarrhea and steatorrhea can occur 2

Malignancy Risk (Long-Term Concern)

Prolonged azathioprine use increases cancer risk:

• Lymphoproliferative disease occurs at 0.5% in transplant recipients 2
• Other neoplasms occur at 2.8% in transplant recipients 2
• Risk of photocarcinogenesis escalates with increasing duration of thiopurine treatment—strict photoprotection is essential 1
• Hepatosplenic T-cell lymphoma is a rare but serious complication 2

Hypersensitivity Reactions

Idiosyncratic reactions can mimic flu-like illness:

• Symptoms include fever, rash, malaise, and myalgias 1, 5
• Patients may initially mistake hypersensitivity symptoms for influenza 1
• Sweet's Syndrome (acute febrile neutrophilic dermatosis) has been reported 2

Infection Risk

Immunosuppression increases susceptibility to infections:

• Infection incidence in renal transplantation is 30-60 times higher than in rheumatoid arthritis patients 2
• Patients without prior chickenpox exposure require immediate zoster immune globulin if exposed to varicella or shingles 1
• Live vaccines are contraindicated 1

Other Side Effects

• Skin rashes and alopecia occur with variable frequency 2
• Reversible interstitial pneumonitis has been reported 2
• Arthralgias and fever can occur 2
• Negative nitrogen balance may develop 2

Special Population Considerations

Elderly Patients

• Elderly patients have significantly higher incidence of all categories of side effects 1
• Increased risk of drug interactions due to polypharmacy 1
• Doses should be at the lower end of the recommended range with additional haematological monitoring 1

Patients with Cirrhosis

• Cirrhotic patients have higher frequency of drug-related complications (25% vs 8%) 1
• Baseline cytopenia from cirrhosis complicates interpretation but requires close monitoring 1, 4
• Cytopenia in cirrhosis may be due to hypersplenism rather than azathioprine toxicity 1

Pregnancy

• Azathioprine has FDA Category D pregnancy rating 1
• Teratogenicity demonstrated in animal studies, though increased birth defects not consistently reported in humans 1
• Preconceptional counseling advised; discontinuation of azathioprine and use of prednisone alone recommended during pregnancy 1
• Major risk is prematurity; fetal loss up to 19%, perinatal mortality 4%, maternal mortality 3% 1

Critical Drug Interactions

Life-Threatening Interactions

• Allopurinol and febuxostat cause severe, life-threatening myelotoxicity—concomitant use should be avoided 1, 5
• If co-prescription is necessary, substantial dose reduction (to 25% of usual dose) and strict monitoring required 1

Other Significant Interactions

• Warfarin resistance occurs rapidly, requiring at least 2.5-fold increase in warfarin dose with careful coagulation monitoring 1
• Aminosalicylates (sulfasalazine) inhibit TPMT in vitro; increased FBC monitoring advised when co-prescribed 1
• Ribavirin causes severe pancytopenia 1
• Myelosuppressive drugs (co-trimoxazole, trimethoprim, clozapine, penicillamine) increase haematological toxicity risk 1
• ACE inhibitors have been reported to induce severe leucopenia 1

Monitoring Requirements to Detect Side Effects Early

• Weekly CBC and LFTs for first 4 weeks, then monthly until maintenance dose achieved, then every 3 months 4
• Return to weekly monitoring after any dose increase 4
• Patients must report immediately: unexplained bruising, sore throat, high fever, jaundice, or sudden abdominal pain 1, 4