Degree of Immunosuppression: Azathioprine vs Corticosteroids
Systemic corticosteroids at doses ≥20 mg for >2 weeks cause more immunosuppression than azathioprine at standard doses, with corticosteroids conferring an 85% increased risk of infections compared to azathioprine's more modest risk profile. 1
Comparative Immunosuppression Classification
The most recent ECCO guidelines (2021) provide a clear framework for comparing these agents:
Corticosteroids
- Moderate-severe immunosuppression occurs with systemic steroids at doses ≥20 mg for >2 weeks 1
- Relative risk for infections is 1.85 at doses ≥20 mg compared to 1.10 for doses <5 mg/day 1
- Morbidity and mortality attributable to corticosteroid treatment is significantly higher, particularly at 1 mg/kg dosing 1
- Corticosteroids cause immunosuppression primarily through CD4+ T-lymphocyte sequestration and cytokine transcription inhibition 2
Azathioprine
- Moderate-severe immunosuppression only at doses >3 mg/kg/day 1
- Standard doses ≤3 mg/kg/day are classified as low-degree immunosuppression 1
- Azathioprine monotherapy does not cause marked increases in infection susceptibility 3
- The immunosuppressive effect is primarily through lymphocyte suppression via purine synthesis inhibition 2
Infection Risk Profile Differences
Specific Infection Patterns
- Corticosteroids are specifically associated with increased fungal infections (particularly Candida) 1
- Azathioprine is more associated with viral infections (particularly varicella zoster virus) 1, 3
- The combination of azathioprine plus steroids presents the greatest infection risk, with odds ratios increasing from 2.9 (single agent) to 14.5 (combination therapy) 1
Clinical Context Matters
When these agents are combined, the infection risk amplifies dramatically rather than simply adding together 1. This is particularly relevant in elderly patients with bullous pemphigoid, where combination therapy shows significantly higher mortality 1, 3.
Dose-Dependent Considerations
A critical pitfall is assuming all doses are equivalent:
- Low-dose corticosteroids (<5 mg/day) have minimal immunosuppressive effects (RR 1.10) 1
- High-dose corticosteroids (≥20 mg for >2 weeks) cause substantial immunosuppression (RR 1.85) 1
- Azathioprine at ≤3 mg/kg/day is considered low immunosuppression, while >3 mg/kg/day reaches moderate-severe levels 1
Practical Clinical Algorithm
For determining which agent causes more immunosuppression:
If comparing high-dose steroids (≥20 mg) to standard azathioprine (≤3 mg/kg/day): Steroids cause significantly more immunosuppression 1
If comparing low-dose steroids (<5 mg) to any dose azathioprine: Azathioprine causes more immunosuppression 1
If comparing high-dose azathioprine (>3 mg/kg/day) to high-dose steroids (≥20 mg): Both cause moderate-severe immunosuppression, but steroids have higher infection risk (RR 1.85) 1
Important Caveats
Duration matters critically for steroids: The threshold of >2 weeks at ≥20 mg is what defines moderate-severe immunosuppression 1. Shorter courses may not reach this level.
Topical steroids are different: Oral budesonide up to 6 mg/day for long-term maintenance did not result in higher infection rates compared to placebo 1, demonstrating that route and systemic absorption matter significantly.
Combination therapy is not additive—it's multiplicative: The infection risk with azathioprine plus steroids is far greater than either agent alone, with the combination presenting the greatest risk among all IBD therapies 1.