How does methotrexate affect the immune system?

Methotrexate's Effects on the Immune System

Methotrexate primarily affects the immune system through its immunosuppressive properties, inhibiting the JAK/STAT signaling pathway and reducing inflammatory cytokines, which can increase the risk of infections and reactivation of latent tuberculosis, hepatitis, and lymphoma, particularly Epstein-Barr virus-associated B-cell lymphoma. 1, 2

Primary Immunomodulatory Mechanisms

Methotrexate (MTX) exerts its immunosuppressive effects through several key mechanisms:

1. JAK/STAT Pathway Inhibition: Recent evidence suggests that MTX inhibits the JAK/STAT signaling pathway, which is central to both inflammatory and immune system regulation 2

2. T-Cell and Macrophage Effects:

   • Selectively affects T-cell function, particularly cycling CD8+ cells
   • Prevents macrophage activation by inhibiting T-cell function 3
   • Reduces proliferation of monocytes, macrophages, and synoviocytes 4

3. Cytokine Modulation:

   • Decreases production of pro-inflammatory cytokines including TNF-alpha
   • Reduces IL-6 concentration
   • Inhibits IL-8 activity and production 4

4. Neutrophil Function:

   • Suppresses neutrophil chemotaxis, potentially altering pathologic activity of neutrophils in inflammatory skin conditions 3
   • Decreases synthesis of B-4 leukotriene in neutrophils 4

Clinical Immunologic Consequences

The immunosuppressive effects of methotrexate lead to several important clinical considerations:

Infection Risk

• Increased susceptibility: MTX treatment may increase the risk of infection, particularly pneumonia, skin/soft tissue infections, and urinary tract infections 1
• Opportunistic infections: Risk of Pneumocystis carinii pneumonia and other opportunistic infections, which can be potentially fatal 5
• Timing of infections: Most infections occur within the first 18 months of treatment, with opportunistic infections typically developing within the first 12 weeks 1

Reactivation of Latent Infections

• Tuberculosis: Can reactivate latent TB, necessitating baseline TB testing (PPD, T-Spot, or QuantiFERON Gold) 1
• Viral hepatitis: May reactivate latent hepatitis B or C 1
• Lymphoma risk: Particularly Epstein-Barr virus-associated B-cell lymphoma 1

Vaccination Considerations

• Live vaccines: Generally contraindicated during MTX therapy due to risk of disseminated infection 5
• Vaccine efficacy: Immunization may be less effective when given during MTX therapy 5

Differential Effects Compared to Biologics

Interestingly, MTX has a different immunologic profile compared to biologics like adalimumab:

• Limited cytokine suppression: MTX induces only minor changes in cytokine responses, while biologics like adalimumab affect a wide range of cytokines important for immune defense against microorganisms 6

• Endothelial effects: MTX reduces expression of endothelial cell adhesive proteins and synthesis of chemotactic factors, inhibiting leukocyte migration to tissues 4

Monitoring Recommendations

Due to these immunologic effects, patients on MTX require careful monitoring:

• Regular laboratory monitoring: Complete blood count, liver function tests, and renal function tests should be performed every 3-6 months 1

• Infection vigilance: Maintain high suspicion for infections, particularly in the first 18 months of treatment 1

• Temporary discontinuation: MTX should be stopped temporarily during severe infection or when infection is not responding to standard treatment, but can be restarted when the infection has cleared 1

• Permanent discontinuation: Consider discontinuing MTX in patients who develop opportunistic infections 1

The understanding of MTX's immunologic effects continues to evolve, with recent evidence suggesting its DMARD activity is largely mediated through JAK/STAT pathway inhibition rather than solely through the folate pathway as previously thought 2.