What is the role of Azathioprine (immunosuppressive agent) in treating patients with severe or systemic Sjogren's syndrome, particularly those who have failed first-line therapies?

Azathioprine in Sjögren's Syndrome

Azathioprine should be considered as a first-line steroid-sparing maintenance agent specifically for Sjögren's patients with symptomatic moderate-to-severe interstitial lung disease (ILD), but it has no established role in treating sicca symptoms or uncomplicated systemic disease. 1

Primary Indication: Sjögren's-Associated ILD

For Sjögren's patients with symptomatic ILD showing moderate-to-severe impairment on pulmonary function testing, imaging, or gas exchange, azathioprine should be considered when long-term steroid use is contemplated and steroid-sparing immunosuppressive therapy is required. 1

Treatment Algorithm for Sjögren's-ILD:

• Initial therapy: Systemic corticosteroids (0.5-1.0 mg/kg prednisone) for moderate-to-severe symptomatic ILD 1
• Maintenance therapy: Azathioprine or mycophenolate mofetil (MMF) as first-line steroid-sparing agents 1
• Second-line options: If azathioprine or MMF are insufficient or not tolerated, consider rituximab, calcineurin inhibitors (cyclosporine or tacrolimus) 1

The 2024 ACR/CHEST guidelines rank mycophenolate as the preferred first-line agent over azathioprine based on head-to-head voting, though both are conditionally recommended options. 1

Critical Safety Requirements

Mandatory Pre-Treatment Testing:

Testing for thiopurine methyltransferase (TPMT) activity or genotype before initiating azathioprine is strongly recommended (HIGH strength, STRONG recommendation) to reduce the risk of severe, life-threatening leukopenia due to complete lack of TPMT activity. 1, 2, 3

• Approximately 0.3% (1:300) of patients of European or African ancestry have two loss-of-function TPMT alleles (homozygous deficient) with little or no TPMT activity 3
• Approximately 10% have one loss-of-function allele (heterozygous deficient) with intermediate TPMT activity 3
• Among East Asian patients, NUDT15 deficiency testing should also be considered (2% have two loss-of-function alleles, 21% have one) 3

Known Toxicities to Monitor:

Patients and providers must be aware of potential risks including drug-induced pneumonitis, GI upset, hepatotoxicity, bone marrow suppression, rash, and hypersensitivity syndrome. 1

• Weekly CBC monitoring for the first month after starting azathioprine 2
• Monthly CBC monitoring once stable on therapy 2
• Immediate discontinuation if severe leukopenia develops or TPMT deficiency is confirmed 2

Where Azathioprine Does NOT Work

No Role in Uncomplicated Sjögren's:

A double-blind, placebo-controlled trial demonstrated that low-dose azathioprine (1 mg/kg/day) does not function as a disease-modifying agent in patients with uncomplicated primary Sjögren's syndrome. 4

• No significant change in disease activity when measured clinically, serologically, or histologically 4
• Six of 25 patients (all receiving active drug) withdrew due to side effects 4

Limited Evidence for Systemic Manifestations:

Traditional disease-modifying antirheumatic drugs, including azathioprine, show limited efficacy in primary Sjögren's overall and as disease-modifying agents for general systemic manifestations. 5, 6, 7

Contraindication in Rapidly Progressive ILD

For Sjögren's patients with rapidly progressive ILD (RP-ILD), azathioprine is conditionally recommended AGAINST as first-line treatment. 1

• Preferred first-line agents for RP-ILD include pulse IV methylprednisolone, rituximab, cyclophosphamide, IVIG, mycophenolate, calcineurin inhibitors, and JAK inhibitors 1
• Upfront combination therapy is recommended over monotherapy for RP-ILD 1

Common Pitfalls to Avoid

1. Never start azathioprine without TPMT testing - this is a HIGH strength, STRONG recommendation to prevent life-threatening leukopenia 1, 2, 3

2. Do not use azathioprine for sicca symptoms or mild systemic disease - it has no proven benefit and exposes patients to unnecessary toxicity 4

3. Do not miss drug-induced pneumonitis - azathioprine itself can cause pneumonitis in Sjögren's-ILD patients, creating diagnostic confusion 1

4. Avoid concurrent xanthine oxidase inhibitors - inhibition of xanthine oxidase may cause increased plasma concentrations of azathioprine or its metabolites leading to toxicity 3

5. Switch to mycophenolate if severe leukopenia develops - this is the recommended alternative steroid-sparing agent 2

Practical Implementation

When azathioprine is appropriate (Sjögren's-ILD requiring steroid-sparing therapy):

• Check TPMT (and NUDT15 in East Asian patients) before prescribing 1, 2, 3
• Baseline CBC with differential before starting therapy 2
• Standard dosing: typically 1-2 mg/kg/day, adjusted based on TPMT status 3
• Close monitoring: Weekly CBC for first month, then monthly 2
• Serial PFTs every 3-6 months to assess ILD response, especially in first 1-2 years 1
• Consider switching to mycophenolate if intolerance develops or inadequate response 2