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

Azathioprine in Dermatology

Azathioprine is a thiopurine immunosuppressant that serves as a cornerstone treatment for autoimmune and inflammatory skin diseases, functioning primarily as a steroid-sparing agent in bullous disorders and as monotherapy for severe atopic dermatitis. 1

Mechanism of Action

Azathioprine works through incorporation of 6-thioguanine nucleotides (6-TGN) into DNA, suppressing cell-mediated hypersensitivity and causing variable alterations in antibody production. 2 The drug is metabolized to 6-mercaptopurine, which then follows three competing pathways involving thiopurine methyltransferase (TPMT), xanthine oxidase, and hypoxanthine guanine phosphoribosyl transferase. 1 This metabolism is critical because genetic polymorphisms in TPMT directly predict myelosuppression risk—approximately 11% of the population has intermediate TPMT activity and 1 in 200-300 individuals has absent TPMT activity, making them susceptible to life-threatening pancytopenia. 1

Licensed Indications

The following conditions have regulatory approval for azathioprine treatment:

• Systemic lupus erythematosus: Azathioprine demonstrates superiority for maintenance compared with cyclophosphamide following induction in lupus nephritis. 1
• Dermatomyositis: Effective as a second-line agent in moderate-to-severe refractory disease, with 57-75% of patients showing improvement in case series. 1 A 6-month RCT demonstrated that combination MTX plus azathioprine was superior to intravenous MTX alone (P = 0.025). 1
• Pemphigus vulgaris: Used primarily as a steroid-sparing agent, though the evidence base is limited. 1

Unlicensed but Evidence-Based Indications

Strong Evidence (Grade A)

• Atopic dermatitis: Azathioprine has the strongest evidence as monotherapy for severe, recalcitrant atopic dermatitis, supported by double-blind, placebo-controlled trials. 1 Prospective pediatric data show clinical improvement in all but 1 of 12 children with severe disease. 3
• Chronic actinic dermatitis: Double-blind, placebo-controlled trials demonstrate benefit. 1
• Behçet's disease: Double-blind, placebo-controlled trials show efficacy, particularly for preventing ocular complications. 1, 4

Moderate Evidence

• Bullous pemphigoid: While evidence for adjunctive azathioprine is lacking, it continues to be used when oral prednisolone provides incomplete control, as dermatologists are familiar with its safety profile. 1
• Vasculitis: In Wegener's granulomatosis, an RCT demonstrated azathioprine is as effective as cyclophosphamide for maintaining remission following induction. 1 Limited evidence supports use in severe cutaneous leukocytoclastic vasculitis combined with corticosteroids. 1

Limited Evidence (Grade C)

• Psoriasis: May be effective as monotherapy for moderate-to-severe disease, though rarely used in current practice. 1 Recent retrospective data suggest potential combination with biologics like infliximab for long-term maintenance. 1
• Pyoderma gangrenosum, pityriasis rubra pilaris, lupus erythematosus, lichen planus: Evidence is anecdotal only. 1

Critical Safety Requirements

Mandatory Pre-Treatment Assessment

TPMT testing is absolutely required before initiating azathioprine—prescribing without knowing TPMT status is strongly contraindicated. 1 Patients with very low or absent TPMT activity face high risk of life-threatening pancytopenia and should not receive azathioprine. 1 Those with intermediate TPMT activity require dose modification. 2

Absolute Contraindications

• Concurrent allopurinol use: This combination causes severe myelosuppression by inhibiting xanthine oxidase, leading to excessive accumulation of active 6-TGN metabolites. 1
• Pregnancy: Contraindicated except where benefit outweighs risk (such as transplant recipients). 1
• Breastfeeding: 6-mercaptopurine is identified in breast milk; bottle feeding is mandatory. 1
• Known hypersensitivity to azathioprine or 6-mercaptopurine. 1
• Active malignancy: Treatment should not usually be initiated or continued in patients with known malignancy, though the risk is smaller than originally feared. 1

Contraception Considerations

For patients with Behçet's disease on azathioprine, estrogen-containing contraceptives can be continued if there is no history of thrombotic events (DVT, PE, stroke) and negative antiphospholipid antibodies. 4 Azathioprine does not interact pharmacologically with levonorgestrel or ethinyl estradiol. 4 Alternative options include levonorgestrel IUD or progestin-only pills; avoid depot medroxyprogesterone acetate due to thrombogenic effects. 4

Common Pitfalls

• Dosing by body weight: Only 13% of dermatologists prescribe according to body weight, yet this practice combined with TPMT testing optimizes efficacy and minimizes myelotoxicity. 5
• Delayed therapeutic effect: Azathioprine is a slow-acting drug with effects typically delayed for weeks to 2-3 months; effects may persist after discontinuation. 1, 2
• Monitoring throughout treatment: Adverse drug reactions occur in 15-28% of patients, and blood count monitoring must continue throughout treatment regardless of TPMT status, as many adverse reactions are unexplained by TPMT polymorphisms alone. 1
• NUDT15 deficiency: Among East Asian patients, 2% have two loss-of-function NUDT15 alleles and 21% have one, requiring dose modification or alternative therapy. 2

Clinical Practice Patterns

Survey data from UK dermatologists show the most commonly treated conditions are pemphigoid, pemphigus, and atopic eczema, with most clinicians finding azathioprine well-tolerated. 5 The drug is perceived as having benefits that outweigh risks compared to other immunosuppressants. 1