When should azathioprine, small molecules, or biologics (e.g. infliximab, adalimumab) be added to a treatment regimen for a patient with ulcerative colitis (UC) who experiences yearly relapses while on mesalamine?

When to Escalate from Mesalamine to Advanced Therapy in Ulcerative Colitis

If a patient with ulcerative colitis experiences yearly relapses despite mesalamine therapy, you should escalate to azathioprine/immunomodulators or directly to biologics (infliximab or vedolizumab) now, rather than continuing to cycle through repeated courses of corticosteroids. 1

The Evidence-Based Threshold for Escalation

Patients who relapse more than once per year on mesalamine maintenance therapy meet the criteria for immunomodulator or biologic therapy. 1 The British Society of Gastroenterology explicitly states that lifelong maintenance therapy is recommended for all patients, especially those with left-sided or extensive disease, and those with distal disease who relapse more than once a year. 1

Traditional Step-Up Approach: Azathioprine First

• Azathioprine 1.5-2.5 mg/kg/day or mercaptopurine 0.75-1.25 mg/kg/day are appropriate for patients who relapse more than once per year as steroids are withdrawn. 1
• This approach has been the traditional standard, with evidence showing azathioprine combined with sulfasalazine is more effective than sulfasalazine alone in maintaining remission (23.5% vs 55.6% relapse rate at 1 year). 2
• However, azathioprine monotherapy shows comparable relapse rates to sulfasalazine in some studies, with a trend toward earlier treatment failure. 3

Modern Accelerated Approach: Direct to Biologics

The contemporary evidence strongly supports bypassing azathioprine and proceeding directly to biologic therapy in patients with moderate-to-severe disease or frequent relapses. 1, 4

When to Choose Direct Biologic Escalation:

• Moderate-to-severe disease activity (not just mild symptoms during relapses) 1
• Extensive colitis (beyond just proctitis) 1
• Corticosteroid-dependent disease (requiring steroids to control each relapse) 1
• Young age (younger patients have higher relapse rates and may benefit from earlier aggressive therapy) 1

Specific Treatment Algorithm After Mesalamine Failure

Step 1: Assess Disease Severity and Extent

• If the patient has proctitis only with yearly relapses, consider adding corticosteroid suppositories or oral 5-ASA dose optimization (up to 4-4.8 g daily) before escalating to immunomodulators/biologics. 1
• If the patient has left-sided or extensive colitis with yearly relapses, proceed directly to Step 2. 1

Step 2: Choose Between Azathioprine or Direct Biologic Therapy

Option A: Azathioprine (Traditional Approach)

• Appropriate for patients with mild-moderate disease who are not corticosteroid-dependent 1
• Dose: 1.5-2.5 mg/kg/day 1
• Monitor FBC within 4 weeks and every 6-12 weeks thereafter 1
• Response takes 2-4 weeks to manifest 5

Option B: Direct to Biologics (Preferred Modern Approach)

• First-line biologic choice: Infliximab 5 mg/kg combined with azathioprine 4
  • Achieves 39.7% corticosteroid-free remission at 16 weeks 4
  • Combination therapy significantly more effective than monotherapy (61.5% vs 42.2% in corticosteroid-free remission at 52 weeks) 1
• Alternative first-line: Vedolizumab monotherapy if combination therapy not feasible 4
  • Lower infectious complications than TNF antagonists 4
  • Particularly effective after anti-TNF failure (36.1% remission at 52 weeks) 4
• Avoid adalimumab as first-line after azathioprine failure due to inferior efficacy compared to infliximab and vedolizumab 4

Step 3: Special Considerations for Acute Severe Presentations

If the patient presents with acute severe ulcerative colitis (>6 bloody stools/day plus systemic toxicity):

• Admit to hospital immediately 1
• Start IV methylprednisolone 40-60 mg/day 1
• Assess response by day 3 1
• If no response by day 3-7, use rescue therapy with IV infliximab or ciclosporin 1
• After responding to IV steroids during ASUC, maintenance with infliximab plus azathioprine is superior to azathioprine alone (46.7% vs 81.5% treatment failure at 52 weeks) 1

Critical Decision Points and Common Pitfalls

Pitfall #1: Continuing 5-ASA After Starting Biologics

Stop mesalamine once biologic therapy is initiated. 1, 4 There is no additional benefit for maintaining remission in moderate-to-severe disease, and continuation provides no added value. 1

Pitfall #2: Using Methotrexate Instead of Azathioprine

Do not substitute methotrexate for azathioprine in ulcerative colitis. 4 Methotrexate is not recommended for either induction or maintenance of remission in UC. 4

Pitfall #3: Stopping Azathioprine When Starting Infliximab

Continue azathioprine when starting infliximab unless there are specific safety concerns or intolerance. 4 The combination is significantly more effective than either agent alone. 4

Pitfall #4: Delaying Surgery Discussion

Discuss surgery as an option when advancing through multiple therapeutic agents. 4 There is generally a reduction in response to each successive immunosuppressive or biologic drug, and up to 10% of patients requiring colectomy have only distal colitis. 4

Risk Stratification for Treatment Selection

High-Risk Features Favoring Direct Biologic Therapy:

• Extensive colitis (beyond splenic flexure) 1
• Young age at diagnosis 1
• Severe endoscopic activity (Mayo endoscopic subscore ≥2) 1
• Elevated inflammatory markers (CRP >30 mg/L) 1
• Previous hospitalization for UC 1
• Corticosteroid requirement for each relapse 1

Lower-Risk Features Where Azathioprine May Be Appropriate:

• Distal colitis only 1
• Older age 1
• Mild endoscopic activity 1
• No corticosteroid dependency 1

Monitoring After Escalation

• On azathioprine: Check FBC within 4 weeks and every 6-12 weeks thereafter 1
• On biologics: Consider therapeutic drug monitoring to optimize dosing and prevent loss of response 1
• After any escalation: Reassess disease extent within the first year to confirm diagnosis and predict disease course 6

The Bottom Line

For a patient experiencing yearly relapses on mesalamine, the threshold for escalation has been crossed. 1 The choice between azathioprine and direct biologic therapy depends on disease severity, extent, and corticosteroid dependency. Modern evidence increasingly favors early biologic therapy, particularly infliximab combined with azathioprine, for patients with moderate-to-severe or extensive disease. 1, 4 Traditional azathioprine monotherapy remains an option for milder disease without corticosteroid dependency, but recognize that response rates are modest and many patients will ultimately require biologic therapy. 2, 3