What is azathioprine?

What is Azathioprine?

Azathioprine is an immunosuppressive prodrug that has been used since 1957, rapidly converting to its active metabolite 6-mercaptopurine, which inhibits purine and DNA synthesis primarily in immune cells. 1, 2

Mechanism of Action

• Azathioprine is converted to 6-mercaptopurine (6-MP), which then inhibits purine synthesis and subsequently DNA synthesis, particularly affecting immune cells. 1, 2
• The active metabolite 6-thioguanine nucleotides (6-TGN) gets incorporated into DNA/RNA structure, causing decreased purine metabolism that produces immunosuppressive effects. 3
• The drug suppresses cell-mediated hypersensitivity and causes variable alterations in antibody production, with greater suppression of delayed hypersensitivity and cellular cytotoxicity than antibody responses. 2
• Azathioprine is considered a slow-acting drug, often taking several months for full effect, and its effects may persist after discontinuation. 1, 2

Metabolism and Genetic Considerations

Critical genetic polymorphisms affect azathioprine safety: 1, 2

• 6-mercaptopurine undergoes three metabolic pathways: 1

  • Methylation to inactive 6-methyl mercaptopurine by thiopurine methyltransferase (TPMT)
  • Oxidation to inactive 6-thiouric acid by xanthine oxidase
  • Conversion to active 6-thioguanine nucleotides via HPRT

• TPMT deficiency creates life-threatening risk: 1, 2

  • Approximately 0.3% (1:300) of European/African ancestry patients have two loss-of-function TPMT alleles (homozygous deficient) with little or no TPMT activity
  • About 10% have one loss-of-function allele (heterozygous deficient) with intermediate activity
  • These patients accumulate excessive 6-TGN concentrations and face severe myelosuppression risk

• NUDT15 deficiency is another critical genetic factor: 2

  • Detected in <1% of European/African ancestry patients
  • Among East Asian patients: 2% have two loss-of-function alleles, 21% have one loss-of-function allele
  • Deficiency leads to accumulation of active metabolites and increased myelosuppression risk

Clinical Indications

Licensed indications include: 1

• Solid-organ transplant rejection prevention
• Systemic lupus erythematosus
• Dermatomyositis
• Pemphigus vulgaris

Unlicensed but evidence-supported dermatologic uses: 1

• Severe, recalcitrant atopic dermatitis (Grade A; level I evidence)
• Bullous pemphigoid (as steroid-sparing agent)
• Chronic actinic dermatitis (Grade A; level I evidence)
• Behçet's disease (Grade A; level I evidence)
• Severe, recalcitrant psoriasis (Grade C; level IV evidence)
• Pyoderma gangrenosum, pityriasis rubra pilaris, Wegener's granulomatosis, cutaneous vasculitis, lichen planus (anecdotal evidence)

Other medical uses: 1, 3

• Immune thrombocytopenia (ITP) with durable response rates of 51.2-64.2% in trials, though approximately half require ongoing therapy to maintain response
• Crohn's disease, Churg-Strauss syndrome, myasthenia gravis

Dosing

• Adults: 50 to 200 mg per day orally 1
• Children: 1.5 to 3 mg/kg per day 1
• Therapeutic effect typically delayed for weeks to 2-3 months 1
• Sometimes administered with danazol, though little data supports higher response for the combination 1

Major Adverse Effects

Common toxicities (15-28% of patients): 1

• Myelosuppression (dose-related)
• Nausea and vomiting
• Infection (9.9%)
• Liver function abnormalities
• Neutropenia and anemia
• Rash, pancreatitis, hypersensitivity reactions

Serious risks: 1, 2

• Life-threatening pancytopenia in TPMT or NUDT15 deficient patients
• Secondary malignancies (though risk smaller than originally feared)
• Infertility (with cyclophosphamide-like agents)

Critical Drug Interactions

Allopurinol interaction is potentially life-threatening: 1, 4

• Allopurinol inhibits xanthine oxidase, causing decreased metabolism of 6-MP to inactive metabolites
• This leads to increased generation of immunosuppressant 6-thioguanine nucleotides
• Results in significant myelosuppression risk
• Concurrent treatment with allopurinol should be avoided 1, 4

Pregnancy and Lactation

Azathioprine is one of the few ITP medications deemed "safe" in pregnancy, with no increased rate of fetal malformation. 1

However, important caveats exist: 1

• Generally contraindicated in pregnancy except where benefit outweighs risk (such as in allograft recipients)
• Safe during lactation according to ITP guidelines, but other guidelines note 6-MP is identified in colostrum and breast milk
• Women on azathioprine should be advised to bottle feed their babies per dermatology guidelines
• Adequate contraceptive precautions advised when either partner is taking azathioprine

Essential Monitoring Requirements

TPMT status must be assessed before initiating therapy: 1

• Very low or absent TPMT activity is an absolute contraindication due to high risk of life-threatening pancytopenia
• Patients displaying cytopenias should be tested for TPMT deficiency
• It is strongly recommended that azathioprine should not be used in patients whose TPMT status is unknown

Ongoing monitoring throughout treatment is essential: 1

• Continue monitoring blood counts throughout treatment
• Polymorphism in TPMT gene predicts hematological adverse reactions in 5-10% of patients
• Remaining adverse reactions may be mediated by immune mechanisms or other metabolic variables

Key Clinical Pitfalls

• Never combine with allopurinol - this creates a dangerous drug interaction mimicking TPMT deficiency 1, 4
• Always check TPMT status before starting - failure to do so risks life-threatening pancytopenia in deficient patients 1
• Consider NUDT15 testing in East Asian patients - 23% have deficiency variants 2
• Expect delayed onset - full therapeutic effect takes several months, not days or weeks 1, 2
• Hypersensitivity reactions can mimic disease relapse or sepsis - maintain high index of suspicion 5
• Approximately half of ITP responders require ongoing therapy - durable response does not always mean drug discontinuation is possible 1