What are the guidelines for combining azathioprine and Tumor Necrosis Factor-alpha (TNF-alpha) inhibitors, such as infliximab (infliximab) and adalimumab (adalimumab), for treating moderate to severe Inflammatory Bowel Disease (IBD) according to the European Crohn's and Colitis Organisation (ECCO), American Gastroenterological Association (AGA), and Canadian guidelines?

Combination Therapy of Azathioprine and TNF-α Inhibitors in IBD: ECCO, AGA, and Canadian Guidelines

Crohn's Disease: Strong Evidence for Combination Therapy

For moderate to severe Crohn's disease, combination therapy with TNF-α inhibitors (infliximab or adalimumab) plus azathioprine is superior to either monotherapy and should be the preferred initial approach in biologic-naïve patients. 1

Induction of Remission

• AGA (2013) provides a strong recommendation for using anti-TNF drugs in combination with thiopurines over thiopurine monotherapy to induce remission in patients with moderately severe CD, based on high-quality evidence from the SONIC and GETAID trials. 1

• AGA (2013) provides a weak recommendation for using anti-TNF drugs in combination with thiopurines over anti-TNF monotherapy to induce remission, based on moderate-quality evidence. 1

  • The SONIC trial demonstrated that combination infliximab plus azathioprine achieved 56.8% corticosteroid-free remission versus 44.4% with infliximab alone (p=0.02) and 30.0% with azathioprine alone (p<0.001). 1
  • Combination therapy significantly reduced anti-TNF antibody formation (0.9% vs 14.6%) and increased median infliximab trough levels (3.5 mg/mL vs 1.6 mg/mL). 1

• Canadian guidelines (2019) provide a conditional recommendation for combining anti-TNF therapy with a thiopurine over monotherapy to induce complete remission, based on low-quality evidence. 1

  • The Canadian guidelines extrapolate evidence from infliximab to adalimumab, though direct RCT evidence for adalimumab combination therapy is lacking. 1

• Canadian guidelines (2019) make no recommendation for or against combining anti-TNF therapy with methotrexate over monotherapy to induce complete remission, due to insufficient evidence. 1

Maintenance of Remission

• AGA (2013) strongly recommends using anti-TNF drugs over no anti-TNF drugs to maintain corticosteroid- or anti-TNF-induced remission in CD, based on high-quality evidence. 1

• Maintenance anti-TNF therapy is not associated with increased overall rates of serious infection or lymphoma risk. 1

Important Caveats for Crohn's Disease

• The benefit of combination therapy versus infliximab alone remains uncertain in patients who previously failed thiopurine therapy. 1

• Although combination therapy increases efficacy, it does not increase serious infection rates over 12 months in clinical trials. 1

Ulcerative Colitis: Conditional Support for Combination Therapy

For moderate to severe ulcerative colitis, combination therapy with TNF-α inhibitors plus immunomodulators is conditionally recommended over monotherapy, though the evidence is less robust than in Crohn's disease. 1

AGA Guidelines for UC

• AGA (2024) conditionally suggests using infliximab in combination with an immunomodulator over infliximab or immunomodulator alone, based on moderate certainty evidence. 1

• AGA (2024) conditionally suggests using adalimumab or golimumab in combination with an immunomodulator over monotherapy, based on low certainty evidence. 1

• AGA (2024) makes no recommendation for or against using non-TNF antagonist biologics (vedolizumab, ustekinumab) in combination with immunomodulators, identifying this as a knowledge gap. 1

• AGA (2020) conditionally suggests combining TNF-α antagonists, vedolizumab, or ustekinumab with thiopurines or methotrexate over biologic monotherapy, based on low-quality evidence. 1

• AGA (2020) conditionally suggests combining TNF-α antagonists, vedolizumab, or ustekinumab with thiopurines or methotrexate over thiopurine monotherapy, based on low-quality evidence. 1

Evidence Base for UC

• The UC-SUCCESS trial demonstrated that combination infliximab plus azathioprine achieved corticosteroid-free remission in 39.7% of patients at week 16 versus 22.1% with infliximab alone (RR 1.78; 95% CI 1.08-1.94). 1, 2

• The UC-SUCCESS trial was terminated prematurely before planned enrollment, limiting the strength of evidence. 1

• No RCTs have compared combination therapy of non-infliximab TNF-α antagonists (adalimumab, golimumab) with thiopurines versus biologic monotherapy in UC. 1

• The AGA extrapolates evidence from infliximab to other biologics based on pharmacokinetic principles: immunomodulators increase trough concentrations and decrease immunogenicity. 1

Canadian (Toronto) Guidelines for UC

• Canadian guidelines (2015) strongly recommend combining anti-TNF therapy with a thiopurine or methotrexate rather than monotherapy when starting anti-TNF therapy to induce complete remission, based on moderate-quality evidence for azathioprine and very low-quality evidence for methotrexate. 1

• The Canadian guidelines note that combination therapy is particularly important in patients with unfavorable pharmacokinetics: more severe disease, higher inflammatory burden, low albumin, or higher body mass index. 1

Patient Selection Considerations for UC

• Patients with less severe disease who place higher value on lower risk of adverse events with biologic monotherapy may reasonably choose monotherapy over combination therapy. 1

De-escalation of Combination Therapy

• AGA (2024) makes no recommendation in favor of withdrawing immunomodulators or continuing combination therapy in UC patients in corticosteroid-free remission for at least 6 months on combination TNF antagonist and immunomodulator therapy, identifying this as a knowledge gap. 1

• AGA (2024) conditionally suggests against withdrawal of TNF antagonists in patients in remission on combination therapy, based on very low certainty evidence. 1

• Very low-quality evidence from a retrospective French study suggests that continuing combination infliximab and azathioprine is superior to de-escalating to infliximab monotherapy in UC patients in remission. 1

Safety Considerations Across All Guidelines

• Combination therapy with anti-TNF agents and thiopurines may increase the risk of serious infections and lymphomas, particularly hepatosplenic T-cell lymphoma, though absolute rates remain low. 1, 3

• The increased risk of malignancy, particularly lymphoma and melanoma, requires careful consideration when applying combination therapy. 3

• Combination therapy was not associated with increased serious infections over 12 months in the SONIC trial for CD. 1

• Patients should be screened for latent tuberculosis, hepatitis B, and updated on vaccinations prior to initiating anti-TNF therapy. 4

Practical Algorithm for Combination Therapy Decision-Making

For Crohn's Disease (Biologic-Naïve Patients):

1. Start combination infliximab or adalimumab plus azathioprine as first-line therapy for moderate to severe disease. 1
2. Use standard induction dosing: infliximab 5 mg/kg IV at weeks 0,2, and 6. 5
3. Assess response at weeks 8-12. 5
4. Continue combination therapy for maintenance if remission achieved. 1

For Ulcerative Colitis (Biologic-Naïve Patients):

1. Consider combination infliximab plus azathioprine for moderate to severe disease, particularly in patients with unfavorable pharmacokinetics (severe disease, low albumin, high BMI). 1
2. For adalimumab or golimumab, combination therapy is conditionally suggested but evidence is weaker. 1
3. Patients with less severe disease may opt for monotherapy after shared decision-making. 1

For Patients with Prior Thiopurine Failure:

• The benefit of adding thiopurines to anti-TNF therapy is uncertain in CD patients who previously failed thiopurines. 1
• Consider anti-TNF monotherapy or alternative immunomodulator (methotrexate) in this scenario. 1

Key Differences Between Guidelines

• AGA provides stronger evidence-based recommendations for CD (strong recommendation, high-quality evidence) compared to UC (conditional recommendation, moderate to low-quality evidence). 1

• Canadian guidelines are more cautious, providing only conditional recommendations for combination therapy in both CD and UC. 1

• ECCO guidelines (referenced in Praxis summaries) align with AGA in recommending combination therapy, particularly for infliximab. 2, 5

• All guidelines agree that methotrexate evidence is weaker than azathioprine evidence for combination therapy. 1