Is azathioprine needed in combination with infliximab (chimeric monoclonal antibody against tumor necrosis factor-alpha) or adalimumab (human monoclonal antibody against tumor necrosis factor-alpha)?

Combination Therapy with Azathioprine and Anti-TNF Agents

For infliximab, combination therapy with azathioprine is conditionally recommended to improve pharmacokinetic parameters and reduce immunogenicity, though the evidence for improved clinical outcomes is stronger than for adalimumab, where the benefit is less certain. 1

Infliximab with Azathioprine

Evidence for Combination Therapy

• The SONIC trial demonstrated that infliximab plus azathioprine achieved superior corticosteroid-free remission (56.8%) compared to infliximab monotherapy (44.4%, P=0.02) at 26 weeks. 1

• Mucosal healing rates were significantly higher with combination therapy, and patients were substantially less likely to develop anti-drug antibodies (0.9% vs 14.6%). 1

• Median serum infliximab trough levels were nearly double with combination therapy (3.5 mg/mL vs 1.6 mg/mL, P<0.001). 1

• The Canadian Association of Gastroenterology provides a conditional recommendation (low-quality evidence) for combining infliximab with a thiopurine when starting anti-TNF therapy. 1

Mechanism of Benefit

• Post-hoc analysis reveals that azathioprine improves efficacy primarily by enhancing infliximab pharmacokinetics rather than through synergistic therapeutic effects. 2

• Among patients with similar serum infliximab concentrations, combination therapy was not significantly more effective than monotherapy, indicating the benefit operates through improved drug levels. 2

• Anti-drug antibodies were detected in 35.9% of monotherapy patients versus only 8.3% of combination therapy patients in the lowest quartile of infliximab levels. 2

Adalimumab with Azathioprine

Mixed Evidence

• For adalimumab, the evidence is substantially weaker and more contradictory than for infliximab. 1

• One meta-analysis showed adalimumab monotherapy was inferior to combination therapy (OR 0.78,95% CI 0.64-0.96, P=0.02) for symptomatic remission. 1

• However, a more recent pooled analysis of 4 RCTs found no advantage with adalimumab plus immunosuppressant over adalimumab alone for symptomatic remission. 1

• An open-label RCT found no difference in symptomatic remission rates between adalimumab plus azathioprine (68.1%) and adalimumab monotherapy (71.8%, P=0.63). 1

• Endoscopic improvement was significantly higher with combination therapy at 6 months (84.2% vs 63.8%, P=0.019) but not at 12 months (79.6% vs 69.8%, P=0.36). 1

Critical Safety Considerations

Hepatosplenic T-Cell Lymphoma Risk

• Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare and fatal malignancy, have been reported almost exclusively in patients receiving TNF-blockers combined with azathioprine or 6-mercaptopurine. 3

• The majority of HSTCL cases occurred in adolescent and young adult males with Crohn's disease or ulcerative colitis. 3

• The Canadian pediatric guidelines specifically recommend AGAINST combining infliximab or adalimumab with thiopurines in males (conditional recommendation, low to very low-quality evidence). 1

• In male patients requiring combination therapy, methotrexate is suggested in preference to thiopurines. 1

Other Malignancy Risks

• Combination therapy with thiopurines increases lymphoma risk 2-3 fold compared to TNF-antagonist monotherapy. 1

• The overall lymphoma rate with infliximab is approximately 4-fold higher than the general population (0.10 cases per 100 patient-years). 3

• Melanoma, Merkel cell carcinoma, and cervical cancer have been reported with TNF-blocker therapy, requiring periodic screening. 3

Infection Risk

• Combination treatment is associated with increased risk of opportunistic infections compared to monotherapy. 4

Practical Clinical Algorithm

When to Use Combination Therapy

For adult patients (especially females) starting infliximab:

• Combine with azathioprine (2-2.5 mg/kg/day) to optimize pharmacokinetics and reduce immunogenicity. 1
• Consider TPMT testing before initiating azathioprine. 1

For adult patients starting adalimumab:

• The decision is less clear-cut given conflicting evidence. 1
• Consider combination therapy if endoscopic healing is a priority endpoint at 6 months. 1
• Monotherapy may be reasonable given the lack of consistent clinical remission benefit. 1

For male patients (particularly adolescents and young adults):

• Avoid thiopurine combination therapy due to HSTCL risk. 1, 3
• If combination therapy is deemed necessary, use methotrexate instead of azathioprine. 1

Duration of Combination Therapy

• Most immunogenicity develops early in treatment, suggesting combination therapy may only be needed for the first 12 months. 4

• Lower doses of immunosuppressives may be equally effective at reducing immunogenicity while potentially decreasing toxicity. 4

• No significant differences in anti-TNF levels or clinical response were found between standard azathioprine doses (2-2.5 mg/kg/day) and reduced doses (<2 mg/kg/day). 5

Monitoring Strategy

• Evaluate symptomatic response to anti-TNF induction therapy between 8-12 weeks. 1

• Consider therapeutic drug monitoring to guide dose optimization, particularly in patients with suboptimal response. 1

• Monitor for infections and perform periodic skin examinations given malignancy risks. 3

Alternative to Combination Therapy

• Therapeutic drug monitoring with dose adjustment may provide similar benefits to combination therapy without the added immunosuppressant risks. 1

• This approach is particularly relevant for newer biologics like vedolizumab and ustekinumab, which are less immunogenic than infliximab. 1

• Real-world data shows combination therapy decreases treatment failure for both CD (aHR 0.77,95% CI 0.66-0.90) and UC (aHR 0.72,95% CI 0.62-0.84). 6