What is the role of azathioprine in treating autoimmune and inflammatory skin conditions in dermatology?

Azathioprine in Dermatology

Azathioprine serves as a critical steroid-sparing immunosuppressant for autoimmune bullous disorders and as monotherapy for severe atopic dermatitis, with mandatory pre-treatment TPMT testing to prevent life-threatening pancytopenia. 1

Mechanism of Action

Azathioprine functions through incorporation of 6-thioguanine nucleotides into DNA, suppressing cell-mediated hypersensitivity and T-cell effects. 1 The drug is metabolized to 6-mercaptopurine, which follows three competing pathways involving thiopurine methyltransferase (TPMT), xanthine oxidase, and hypoxanthine guanine phosphoribosyl transferase. 1, 2 Genetic polymorphisms in TPMT and NUDT15 directly predict myelosuppression risk, with approximately 0.3% of European/African ancestry patients having two loss-of-function TPMT alleles (poor metabolizers) and 10% having one allele (intermediate metabolizers). 2

Primary Dermatologic Indications

Licensed Uses

• Pemphigus vulgaris: Azathioprine functions primarily as a steroid-sparing agent, though the evidence base remains limited. 1
• Bullous pemphigoid: Moderate evidence supports its use as a steroid-sparing agent. 1
• Lupus-related cutaneous manifestations: The American College of Rheumatology recommends azathioprine for maintenance treatment of lupus nephritis, demonstrating superiority to cyclophosphamide following induction. 1
• Dermatomyositis: Effective as second-line therapy in moderate-to-severe refractory disease, with 57-75% of patients showing improvement; combination with methotrexate is superior to IV methotrexate alone (P = 0.025). 1

Unlicensed but Evidence-Based Uses

• Severe atopic dermatitis: The British Association of Dermatologists recommends azathioprine as monotherapy for severe, recalcitrant disease, supported by double-blind, placebo-controlled trials (Grade A evidence). 1 All but one patient in prospective pediatric studies showed clinical improvement with few adverse effects. 3
• Chronic actinic dermatitis: Strong evidence (Grade A) supports its use. 1
• Behçet's disease: Strong evidence (Grade A) particularly for preventing ocular complications and reducing extraocular manifestations. 1
• Vasculitis and psoriasis: Moderate evidence exists, though azathioprine is rarely used for psoriasis in current practice. 1

Critical Pre-Treatment Requirements

TPMT testing is mandatory before initiating azathioprine per NICE guidelines, as patients with very low or absent TPMT activity face high risk of life-threatening pancytopenia. 1 Approximately 2% of East Asian patients have two loss-of-function NUDT15 alleles, and 21% have one allele, requiring consideration of NUDT15 testing in this population. 2

Absolute Contraindications

• Concurrent allopurinol use (causes increased plasma concentrations leading to toxicity) 1, 2
• Pregnancy 1
• Breastfeeding 1
• Known hypersensitivity to azathioprine or 6-mercaptopurine 1
• Active malignancy 1

Dosing Considerations

Common Pitfall: Only 13% of dermatologists prescribe azathioprine according to body weight, despite this being optimal for efficacy and minimizing myelotoxicity. 4 Weight-based dosing combined with TPMT activity measurement optimizes outcomes. 4

Patients with reduced TPMT or NUDT15 activity require dose modification or alternative therapy when receiving usual doses, as they accumulate excessive cellular concentrations of active 6-TGNs. 2

Monitoring During Treatment

• Routine monitoring for azathioprine toxicity is required regardless of indication. 5
• Repeat TPMT assessment may be helpful: Three patients in one study showed significant changes in TPMT activity during treatment (two with mild decreases, one with enzyme inducibility from intermediate to normal range), which inversely correlated with clinical response. 3
• Measurement of thiopurine metabolites (6-thioguanine nucleotide and 6-methylmercaptopurine) during treatment was not clinically useful in pediatric studies. 3

Special Populations: Contraception in Behçet's Disease

For patients with Behçet's disease on azathioprine requiring contraception, the European League Against Rheumatism recommends that estrogen-containing contraceptives can be continued if: 1

• No history of thrombotic events (DVT, PE, stroke) 5
• Negative antiphospholipid antibodies 5

Alternative contraceptive options include: 5

• Levonorgestrel IUD (highly effective, avoids systemic estrogen)
• Progestin-only pills

Avoid depot medroxyprogesterone acetate (DMPA) due to potential thrombogenic effects. 5

The decision depends on thrombotic risk profile, not the azathioprine itself, as azathioprine does not interact pharmacologically with levonorgestrel or ethinyl estradiol. 5

Tolerability Profile

Most dermatologists report that azathioprine is well tolerated with a relatively good safety profile compared to other immunosuppressants like cyclophosphamide. 4, 6 Azathioprine is considered a slow-acting drug, and effects may persist after discontinuation. 2