Is continuing off-label infliximab (infliximab) 800mg IV every 4 weeks, along with azathioprine, medically indicated for a patient with left-sided ulcerative colitis (UC) and gastroesophageal reflux disease (GERD), who has a history of treatment with mesalamine and adalimumab, and is currently in clinical and endoscopic remission with normal colonoscopy results and a Mayo grade of 0?

Continuation of Off-Label Infliximab with Azathioprine in Remission

For a patient with left-sided ulcerative colitis who has achieved complete clinical and endoscopic remission (Mayo 0) on infliximab 800mg IV every 4 weeks plus azathioprine, continuing this regimen is medically indicated, though consideration should be given to de-escalating to standard dosing intervals and potentially withdrawing azathioprine given the long-term malignancy risks. 1

Current Treatment Status Assessment

Your patient represents an optimal treatment outcome:

• Complete endoscopic remission (Mayo 0) indicates mucosal healing, which is the therapeutic target that reduces long-term complications including dysplasia and colorectal cancer risk 2
• Clinical remission on current therapy demonstrates treatment efficacy 3
• The combination of infliximab plus azathioprine has proven superior to monotherapy, with remission rates of 40% versus 22% for infliximab alone in moderate-to-severe UC 2, 4

Dosing Considerations for Maintenance

Off-Label Dosing Analysis

The current regimen (800mg every 4 weeks) is substantially higher than standard dosing:

• Standard FDA-approved dosing is 5 mg/kg (approximately 400mg for an 80kg patient) every 8 weeks for maintenance 3
• The 10 mg/kg dose showed no superiority over 5 mg/kg in randomized trials (ACT 1: 35% vs 34% remission at week 54) 1, 3
• British Society of Gastroenterology 2025 guidelines state that superiority of 10 mg/kg over 5 mg/kg was not demonstrated in clinical trials, though dose escalation may be appropriate for suboptimal response guided by therapeutic drug monitoring 1

Recommendation for Dose Optimization

Given complete remission, de-escalation to standard dosing (5 mg/kg every 8 weeks) should be strongly considered 1:

• Therapeutic drug monitoring demonstrates that targeting trough concentrations of 3-7 μg/mL results in more efficient drug use 5
• In the TAXIT trial, 93% of patients with trough levels >7 μg/mL successfully achieved target levels after dose reduction, resulting in 28% cost reduction without loss of efficacy 5
• Concentration-based dosing after optimization was associated with fewer flares (7% vs 17%) compared to clinical-based dosing 5

Combination Therapy Rationale

Benefits of Continuing Azathioprine

Combination therapy with infliximab plus azathioprine is superior to monotherapy and should generally be continued 1, 2:

• The UC SUCCESS trial demonstrated significantly higher week 16 remission rates with combination therapy (40%) versus infliximab alone (22%) 2, 4
• Combination therapy is an independent predictor of sustained clinical response (HR 3.98,95% CI 1.73-9.14) in long-term follow-up studies 6
• Azathioprine reduces immunogenicity to infliximab, which is particularly relevant given your patient's prior adalimumab failure suggesting potential immunogenicity issues 2, 4
• The 2016 consensus on acute severe UC states that combination infliximab-thiopurine therapy is more efficacious than monotherapy in the absence of contraindications 1

Risks of Continuing Azathioprine

The 2025 BSG guidelines emphasize that shared decision-making should address long-term azathioprine risks 1:

• Elevated risk of lymphoproliferative disorders 1
• Non-melanoma skin cancers 1
• Myeloid disorders and urinary tract cancers 1
• Historical data show that azathioprine withdrawal in patients with prolonged remission (>6 months) results in 31% relapse at 1 year versus 61% with placebo 1

Algorithmic Approach to Management

Step 1: Obtain Therapeutic Drug Monitoring

• Measure infliximab trough concentration before next infusion 1, 5
• Target trough level: 3-7 μg/mL for maintenance of remission 5
• If trough >7 μg/mL: Consider dose reduction to standard 5 mg/kg every 8 weeks 5
• If trough 3-7 μg/mL: Maintain current clinical remission but consider interval extension 5

Step 2: Assess Duration of Remission

• If remission >6 months on current therapy: Patient is candidate for potential treatment optimization 1
• If remission <6 months: Continue current regimen and reassess 1

Step 3: Shared Decision-Making on Azathioprine

Discuss with patient:

• Benefits: Reduced relapse risk (31% vs 61% at 1 year with withdrawal), reduced immunogenicity 1, 6
• Risks: Malignancy risk with long-term use (lymphoproliferative, skin cancers, myeloid disorders) 1
• Alternative approach: Some data suggest azathioprine plus 5-ASA maintenance after IFX induction can maintain remission in 68% at 1 year and 59% at 2 years, though this is lower quality evidence from resource-limited settings 7

Step 4: Consider De-escalation Strategy

For patients in deep remission, a stepwise de-escalation approach is reasonable 1, 5:

1. First, reduce infliximab to standard dosing (5 mg/kg every 8 weeks) with TDM guidance 5
2. Monitor for 6-12 months with clinical assessment and biomarkers (CRP) 5
3. If sustained remission continues, consider azathioprine withdrawal with close monitoring 1
4. Never withdraw both agents simultaneously - sequential withdrawal reduces relapse risk 1

Common Pitfalls to Avoid

• Do not abruptly discontinue therapy in complete remission without TDM guidance - this increases relapse risk 1, 5
• Do not continue supra-therapeutic dosing indefinitely without reassessing need - this increases cost and potential toxicity without proven benefit 5
• Do not withdraw azathioprine as first step if patient has history of immunogenicity to prior anti-TNF (adalimumab failure) - maintain combination therapy longer in this scenario 2, 4
• Do not ignore malignancy surveillance - patients on long-term azathioprine require skin cancer screening and age-appropriate cancer surveillance 1

Medical Necessity Conclusion

Yes, continuing anti-TNF therapy is medically indicated for maintaining complete remission 1, 3. The 2025 BSG guidelines provide strong recommendations that patients responding to infliximab induction should continue anti-TNF therapy to maintain complete remission 1. The 2020 AGA guidelines similarly provide strong recommendations for continued anti-TNF therapy in responders 1, 2.

However, the specific off-label dosing (800mg every 4 weeks) is not medically necessary given achievement of complete remission 1, 3, 5. Standard dosing with TDM optimization represents better evidence-based practice and more efficient resource utilization while maintaining efficacy 5.