What is the role of thiopurines (such as azathioprine or mercaptopurine) in the treatment of ulcerative colitis?

Thiopurines in Ulcerative Colitis

Thiopurines (azathioprine and mercaptopurine) should be reserved for maintenance therapy in specific UC scenarios: steroid-dependent patients, those with frequent relapses despite optimal mesalamine, and as bridging therapy after calcineurin inhibitors or anti-TNF induction—but they should NOT be used as monotherapy for inducing remission in active disease. 1

Primary Indications for Thiopurines

Thiopurines are recommended for three specific clinical situations 1:

• Steroid-dependent UC patients who cannot taper corticosteroids below 10-20 mg/day without relapsing 1
• Patients with frequent or early relapses on optimal-dose mesalamine (≥2 g/day) or those intolerant to mesalamine 1
• Bridging therapy after rescue agents: patients responding to ciclosporin, tacrolimus, or infliximab who need transition to maintenance therapy 1

Efficacy Evidence

Maintenance of Remission (Primary Role)

Thiopurines demonstrate clear benefit for maintaining remission 1:

• Meta-analysis shows 32% relative risk reduction for maintaining remission compared to placebo (RR 0.68,95% CI 0.54-0.86) 1
• Updated 2024 analysis confirms efficacy with RR 0.61 (95% CI 0.49-0.77) for preventing relapse 1
• Long-term data from Oxford series: 58% overall remission rate, increasing to 87% in patients treated >6 months; 62% remained in remission at 5 years 1
• Median time to relapse after stopping: 18 months 1

Induction of Remission (Limited Role)

Thiopurines should NOT be used as monotherapy for inducing remission 1:

• Evidence quality is very low due to inability to distinguish whether remission was induced by concurrent corticosteroids versus thiopurines 1
• Slow onset of action (2-6 months) makes them unsuitable for active disease 1
• One recent 2024 RCT showed benefit (14/29 vs 3/30 achieved steroid-free remission), but patients received concurrent corticosteroids for 8 weeks 1

Critical Clinical Scenarios

After Calcineurin Inhibitor Rescue

Thiopurines are essential after ciclosporin or tacrolimus response to prevent colectomy 1:

• Without maintenance therapy, colectomy rates reach 36-69% within 12 months 1
• Start thiopurines while patient is still on calcineurin inhibitor, acting as a "bridge" until therapeutic effects achieved 1
• Retrospective data shows thiopurines reduce colectomy risk after ciclosporin induction 1

With Anti-TNF Therapy

Combination therapy with anti-TNF is appropriate, but thiopurine monotherapy is an alternative 1:

• Continuing anti-TNF with or without thiopurines is preferred for maintaining remission 1
• Thiopurine maintenance alone is a lower-tier alternative option 1

Safety Monitoring Requirements

Mandatory monitoring protocol 1:

• Before starting: TPMT genotype/phenotype testing (though therapy can begin before results available) 1
• Weeks 1-4: Weekly complete blood count and liver function tests 1
• Weeks 5-8: Fortnightly monitoring 1
• Ongoing: Every 3 months indefinitely 1

Common Adverse Effects 1

• Bone marrow suppression: 2-10.5% incidence, most frequently within 2-4 months but can occur anytime 1
• Acute pancreatitis: Occurred in 3/115 patients in meta-analysis 1
• Hepatotoxicity: 5-10% develop transient transaminase elevation; median onset 1.5-3 months 1
• Lymphoma risk: Including hepatosplenic T-cell lymphoma (rare but serious) 1

Practical Dosing Considerations

Low-dose azathioprine (50 mg/day or 0.6-1.2 mg/kg/day) is effective and safer in Asian populations 2:

• 88% maintained remission at 6 months 2
• Lower bone marrow suppression rates compared to standard dosing 2

Mercaptopurine switching strategy: For azathioprine-intolerant patients, 83-85% can tolerate mercaptopurine 3:

• Typical starting dose: 20 mg/day, titrate to 30 mg/day 3
• Effective for avoiding colectomy in AZA-intolerant patients 3

Duration of Therapy

Stopping thiopurines carries significant relapse risk 1:

• 36% relapse rate by 3 years after discontinuation 1
• Higher risk with extensive UC, biological disease activity at cessation, or short treatment duration 1
• Many patients may require lifelong therapy when properly indicated 4

Common Pitfalls to Avoid

• Do not use thiopurines as monotherapy for active moderate-severe UC expecting rapid remission—they require 2-6 months for effect 1
• Do not assume normal TPMT excludes myelotoxicity risk—monitoring remains mandatory regardless of genotype 1
• Do not coprescribe with 5-ASA expecting synergism—existing evidence does not support superior efficacy of combination over thiopurine monotherapy 4
• Do not discontinue prematurely—therapeutic benefit increases substantially after 6 months of therapy 1