Will combining azathioprine with infliximab (chimeric monoclonal antibody against tumor necrosis factor-alpha) help maintain remission in an adult patient with a chronic inflammatory condition, such as Crohn's disease or rheumatoid arthritis, who has no antibodies against infliximab and adequate trough levels?

Azathioprine Continuation in Patients with Adequate Infliximab Levels and No Antibodies

In patients with therapeutic infliximab trough levels (>10 mg/L) and no anti-drug antibodies, azathioprine can be discontinued, as the primary benefit of combination therapy is optimizing infliximab pharmacokinetics—a goal already achieved in this clinical scenario. 1

Rationale for Azathioprine Withdrawal

The evidence demonstrates that azathioprine's primary mechanism in combination therapy is pharmacokinetic enhancement rather than independent therapeutic benefit:

• Combination therapy improves efficacy primarily by increasing infliximab serum concentrations and reducing immunogenicity. Among patients with similar infliximab trough levels, combination therapy with azathioprine was not significantly more effective than infliximab monotherapy for achieving corticosteroid-free remission. 1

• When infliximab levels are adequate (>10 mg/L) and antibodies are absent, the pharmacokinetic advantage of azathioprine is already achieved. The SONIC trial post-hoc analysis showed that within quartiles of similar infliximab concentrations, clinical remission rates did not differ significantly between combination therapy and monotherapy. 1

• Anti-drug antibodies were detected only in the lowest quartile of infliximab concentrations (35.9% with monotherapy vs 8.3% with combination therapy), indicating that patients with therapeutic levels and no antibodies have already overcome the primary risk that combination therapy addresses. 1

Evidence Supporting Withdrawal

Risk-Benefit Analysis

• Azathioprine withdrawal in patients with adequate infliximab levels may reduce serious adverse event risk without compromising efficacy. The primary concern with continuing azathioprine is the cumulative toxicity risk, including lymphoproliferative disorders, non-melanoma skin cancers, myeloid disorders, and urinary tract cancers. 2

• Hepatosplenic T-cell lymphoma (HSTCL), though rare, occurs almost exclusively in patients receiving combination therapy with azathioprine or 6-mercaptopurine. Most cases have been fatal and occurred predominantly in adolescent and young adult males with inflammatory bowel disease. 3

• The decision to continue combination therapy must weigh the possibility of higher HSTCL risk with combination therapy versus the observed increased risk of immunogenicity with monotherapy. 3 However, this consideration becomes less relevant when immunogenicity is already absent and drug levels are therapeutic.

Duration of Combination Therapy Matters

• Patients who received combination therapy for ≤811 days (approximately 27 months) had a 7.46-fold higher hazard ratio for infliximab failure after azathioprine withdrawal compared to those with longer exposure. 4

• If combination therapy duration has been <27 months, continuing azathioprine may be prudent even with adequate levels, as premature withdrawal increases relapse risk. 4

• Additional predictors of failure after azathioprine withdrawal include C-reactive protein >5 mg/L (HR=4.79) and platelet count >298×10⁹/L (HR=4.75), suggesting ongoing subclinical inflammation. 4

Clinical Algorithm for Decision-Making

Proceed with Azathioprine Withdrawal if ALL criteria are met:

• Infliximab trough levels >10 mg/L 1
• No detectable anti-infliximab antibodies 1
• Combination therapy duration >27 months 4
• C-reactive protein ≤5 mg/L 4
• Platelet count ≤298×10⁹/L 4
• Clinical remission maintained for ≥6 months 2

Continue Combination Therapy if ANY of the following:

• Combination therapy duration <27 months 4
• Evidence of subclinical inflammation (elevated CRP or platelets) 4
• History of rapid antibody formation or loss of response 2
• HLA-DQA1*05 genotype (higher risk of immunogenicity) 2

Guideline Perspectives on Maintenance Combination Therapy

The evidence for continuing combination therapy specifically for maintenance is equivocal:

• The AGA makes no recommendation for or against combination therapy versus anti-TNF monotherapy to maintain remission induced by combination therapy, citing conflicting data and low-quality evidence. 2

• The SONIC trial showed benefits of combination therapy persisting through week 50, but this was an induction trial with long-term follow-up, not a maintenance-specific study. 2

• A small open-label trial found that combination maintenance therapy with infliximab and azathioprine was not superior to infliximab alone in maintaining remission. 2

• The British Society of Gastroenterology notes that withdrawal of azathioprine in ulcerative colitis is associated with relapse risk, with 31% relapse in those continuing azathioprine versus 61% in placebo at 1 year. 2 However, this data predates therapeutic drug monitoring and applies to azathioprine monotherapy withdrawal, not combination therapy with adequate biologic levels.

Critical Caveats

• Shared decision-making should address the long-term risks of continuing azathioprine including elevated risk of lymphoproliferative disorders, non-melanoma skin cancers, myeloid disorders, and urinary tract cancers. 2

• Close monitoring after azathioprine withdrawal is essential: Check infliximab trough levels and antibodies at 3-6 months post-withdrawal to detect early immunogenicity. 2

• If antibodies develop or trough levels decline after withdrawal, consider reintroducing azathioprine or switching to methotrexate rather than dose escalation alone. 2