What is the difference between azathioprine and methotrexate for treating ulcerative colitis?

Azathioprine vs. Methotrexate for Ulcerative Colitis

Azathioprine is the preferred immunomodulator for ulcerative colitis, while methotrexate should be avoided as it has not demonstrated efficacy for either induction or maintenance of remission in UC. 1

Evidence-Based Recommendations

Azathioprine: First-Line Immunomodulator

Azathioprine (1.5-2.5 mg/kg/day) is the first-line immunomodulator of choice for steroid-dependent ulcerative colitis. 1 The 2020 AGA guidelines provide the most recent high-quality evidence:

• For maintenance of remission: Azathioprine is effective at preventing disease relapse (RR 0.61; 95% CI 0.49-0.77) compared to placebo or 5-ASA in patients with inactive UC 1
• For induction of remission: The AGA suggests against using azathioprine monotherapy for active disease due to its slow onset of action (typically 3-6 months), though it may be started alongside corticosteroids to facilitate later steroid withdrawal 1

Methotrexate: Not Recommended for UC

The AGA explicitly recommends against using methotrexate monotherapy for either induction or maintenance of remission in ulcerative colitis. 1 This represents a critical difference from Crohn's disease, where methotrexate has proven efficacy:

• No benefit demonstrated: Meta-analysis showed no significant difference between methotrexate and placebo for inducing remission (RR 1.31; 95% CI 0.89-1.94) or maintaining remission (RR 1.01; 95% CI 0.79-1.29) 1
• Quality of evidence: The evidence was rated as very low quality due to serious indirectness and imprecision 1
• The pivotal METEOR trial failed to demonstrate efficacy for methotrexate in UC 1

Clinical Algorithm for Immunomodulator Selection

When to Use Azathioprine:

• Steroid-dependent disease: Patients who relapse when steroids are reduced below 20 mg/day or within 6 weeks of stopping 1
• Frequent relapses: Patients relapsing more than once per year as steroids are withdrawn 1
• Maintenance after steroid-induced remission: To prevent relapse in patients who achieved remission with corticosteroids 1

When Methotrexate Might Be Considered (Limited Role):

• Only as salvage therapy: If azathioprine causes intolerance (not treatment failure), some retrospective data suggest methotrexate may have modest benefit 2, 3, 4
• However, this contradicts current AGA guidelines which recommend against methotrexate use 1
• Better alternative: Advance to biologic therapy (infliximab, vedolizumab, or ustekinumab) rather than trying methotrexate 5, 6

Monitoring Requirements

Azathioprine Monitoring:

• Complete blood count: Within 4 weeks of starting, then every 6-12 weeks thereafter to detect neutropenia 1
• Caveat: Profound neutropenia can develop rapidly despite monitoring 1
• TPMT testing: Not routinely required but may identify some patients at risk for neutropenia 1

Methotrexate Monitoring (if used despite guidelines):

• Complete blood count and liver function tests: Before starting, within 4 weeks, then monthly 1
• Folic acid supplementation: 5 mg two or three days apart from methotrexate to reduce gastrointestinal toxicity 1

Side Effect Profile Differences

Azathioprine:

• Bone marrow suppression: Most serious concern, requires regular monitoring 1, 7, 8
• Acute pancreatitis: Occurs in small percentage, requires immediate discontinuation 7, 8
• Hepatotoxicity: Mild and reversible with drug withdrawal 8
• Lymphoma risk: At best small, with decision analysis suggesting benefits outweigh risks 1

Methotrexate:

• Gastrointestinal toxicity: Nausea, vomiting, diarrhea, stomatitis (10-18% discontinue due to side effects) 1
• Hepatotoxicity: Mild histological abnormalities reported; withhold if AST doubles 1
• Pneumonitis: Rare but serious (2-3 cases per 100 patient-years) 1

Common Pitfalls to Avoid

• Do not use methotrexate as first-line therapy for UC - it lacks efficacy data and contradicts current guidelines 1
• Do not expect rapid response from azathioprine - onset of action takes 3-6 months, so it should not be used as monotherapy for active disease 1
• Do not substitute methotrexate when azathioprine fails - advance to biologic therapy instead 5
• Do not continue azathioprine indefinitely without monitoring - neutropenia can develop suddenly despite previous tolerance 1

When Azathioprine Fails

If azathioprine fails due to intolerance or lack of efficacy, advance directly to biologic therapy rather than trying methotrexate: 5, 6

• First-line biologics: Infliximab (preferably with continued azathioprine if tolerated) or vedolizumab monotherapy 5
• Alternative options: Ustekinumab or JAK inhibitors (tofacitinib, upadacitinib) 5
• Do not use methotrexate as a bridge therapy - this is not supported by evidence in UC 5