What is azathioprine used for?

What is Azathioprine Used For?

Azathioprine is an immunosuppressive medication primarily used to treat autoimmune and inflammatory conditions, with licensed indications including systemic lupus erythematosus, dermatomyositis, and pemphigus vulgaris, plus extensive off-label use in conditions like severe atopic dermatitis, inflammatory bowel disease, and organ transplant rejection. 1, 2

Mechanism of Action

Azathioprine functions as a purine analog prodrug that is metabolized to 6-mercaptopurine (6-MP), which ultimately converts to 6-thioguanine nucleotides (6-TGNs) that incorporate into DNA, inhibiting purine synthesis and preferentially affecting rapidly dividing cells like activated B and T lymphocytes. 1, 2 This mechanism provides both immunosuppressive and cytotoxic properties, with therapeutic effects that are delayed (typically 2-3 months) and may persist after discontinuation. 1, 2

Licensed (FDA-Approved) Indications

Dermatologic Conditions

• Systemic lupus erythematosus: Effective for maintenance therapy, particularly after cyclophosphamide induction in lupus nephritis 1, 3
• Dermatomyositis: Functions as a second-line steroid-sparing agent, with 57-75% of patients showing improvement 1
• Pemphigus vulgaris: Used primarily as a steroid-sparing agent in combination therapy 1

Non-Dermatologic Licensed Uses

• Rheumatoid arthritis: FDA-approved for severe cases 2, 4
• Organ transplant rejection prophylaxis: Original indication, particularly for renal transplants 1, 2

Major Unlicensed (Off-Label) Indications

Dermatologic Conditions with Strong Evidence

Severe atopic dermatitis: This represents one of the strongest off-label indications, with Grade A, Level I evidence from double-blind, placebo-controlled trials showing 37% improvement versus 20% with placebo. 1 The American Academy of Dermatology recommends azathioprine as a systemic agent for refractory atopic dermatitis, with typical dosing of 1-3 mg/kg/day. 1

Bullous pemphigoid: Used as a steroid-sparing agent, though evidence is less robust than for pemphigus vulgaris 1

Behçet's disease: Grade A, Level I evidence from double-blind trials demonstrates efficacy, particularly for preventing ocular complications 1, 5

Chronic actinic dermatitis: Grade A, Level I evidence supports use 1

Dermatologic Conditions with Limited Evidence

• Psoriasis: Grade C, Level IV evidence as monotherapy; rarely used in current practice but may be combined with biologics like infliximab 1
• Pyoderma gangrenosum: Anecdotal evidence only (Grade C, Level IV) 1
• Pityriasis rubra pilaris: Limited evidence 1
• Lichen planus: Anecdotal evidence 1

Vasculitis and Systemic Conditions

Wegener's granulomatosis (Granulomatosis with polyangiitis): Randomized controlled trials demonstrate azathioprine is as effective as cyclophosphamide for maintaining remission after induction therapy 1

Cutaneous vasculitis: May be combined with corticosteroids for severe leucocytoclastic vasculitis unresponsive to first-line therapy like dapsone 1

Polymyositis: Similar efficacy to dermatomyositis, with 57-75% improvement rates 1

Non-Dermatologic Off-Label Uses

• Inflammatory bowel disease (Crohn's disease, ulcerative colitis) 4
• Myasthenia gravis 4
• Churg-Strauss syndrome 4
• Chronic immune thrombocytopenia (ITP): Complete response rates of 45-64% with durable remissions in approximately 40% of patients after discontinuation 6

Critical Safety Considerations

Mandatory Pre-Treatment Testing

TPMT (Thiopurine Methyltransferase) testing is strongly recommended before initiating azathioprine. 1 Approximately 11% of the population has low TPMT activity (heterozygous deficient), and 0.3% (1 in 300) have undetectable TPMT activity (homozygous deficient), placing them at high risk for life-threatening pancytopenia. 1, 2 Very low or absent TPMT activity is an absolute contraindication to azathioprine use. 1

NUDT15 deficiency should also be considered, particularly in patients of East Asian ancestry, where 2% have two loss-of-function alleles and 21% have one loss-of-function allele. 2

Absolute Contraindications

• Concurrent allopurinol use: This combination causes severe myelosuppression by inhibiting xanthine oxidase, leading to accumulation of toxic metabolites; if combination is unavoidable, reduce azathioprine dose to 25% of standard 1
• Pregnancy: Contraindicated except where benefit outweighs risk (such as organ transplant recipients) 1
• Breastfeeding: 6-mercaptopurine is present in breast milk; bottle feeding is advised 1
• Known hypersensitivity to azathioprine or 6-mercaptopurine 1
• Active malignancy: Relative contraindication due to concerns about increased cancer risk 1

Common Adverse Effects

Adverse reactions occur in 15-28% of patients and include: 1

• Gastrointestinal symptoms: Nausea, vomiting, bloating, anorexia (most common, often dose-limiting) 1
• Myelosuppression: Requires ongoing blood count monitoring throughout treatment 1
• Hepatotoxicity: Transaminase elevations up to 3x normal 6
• Pancreatitis: Rare but serious 1
• Hypersensitivity reactions: Including rash and angioedema 7
• Anagen effluvium: May be an early sign of toxicity 4

Dosing and Administration

Standard dosing: 1-3 mg/kg/day orally, with graduated dosing preferred to minimize side effects 1 For patients with intermediate TPMT activity, dose reduction is necessary; for those with absent TPMT activity, alternative therapy is required. 2

Onset of action: Delayed, typically requiring 2-3 months or longer for full clinical benefit 1, 2

Asian populations: May require lower doses (<1.5 mg/kg/day) due to higher prevalence of ITPA polymorphisms 8

Special Populations

Pregnancy: Azathioprine is one of the few immunosuppressants considered relatively safe in pregnancy for conditions like ITP, with no increased fetal malformation rate, though it remains contraindicated for most dermatologic indications unless benefit clearly outweighs risk. 6

Pediatric use: Effective in juvenile dermatomyositis and severe atopic dermatitis, with similar efficacy to adults 1

Common Clinical Pitfalls

• Premature discontinuation: The most common error is stopping azathioprine before 3-6 months, as therapeutic response is delayed 6
• Failure to check TPMT status: Initiating therapy without TPMT testing risks life-threatening pancytopenia 1
• Combining with phototherapy: Concomitant UVA exposure increases DNA damage risk and potential photocarcinogenicity 1
• Overlooking drug interactions: Beyond allopurinol, multiple medications can interact with azathioprine metabolism 1
• Inadequate monitoring: Blood counts must be monitored throughout treatment, not just initially 1