What are the treatment options for moderate to severe inflammatory bowel disease using Azathioprine and Tofacitinib (Xeljanz)?

Treatment Options for Moderate to Severe Inflammatory Bowel Disease: Azathioprine and Tofacitinib

Direct Recommendation

For moderate to severe ulcerative colitis, azathioprine should NOT be used for induction of remission but may be considered for maintenance therapy, while tofacitinib is indicated only after failure of or intolerance to TNF-α antagonists. 1, 2

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Azathioprine in Inflammatory Bowel Disease

Role and Positioning

Azathioprine is not recommended for induction of remission in moderate to severe ulcerative colitis but has a role in maintenance therapy and steroid-dependent disease. 1

Specific Indications:

• Maintenance of remission: Azathioprine monotherapy (1.5-2.5 mg/kg/day) is suggested over no treatment for maintaining remission in UC patients already in remission 1
• Steroid-dependent Crohn's disease: First-line agent at 1.5-2.5 mg/kg/day for patients who relapse when steroids are reduced below 20 mg/day or within 6 weeks of stopping steroids 1
• Frequent relapsers: Appropriate for CD patients who relapse more than once per year as steroids are withdrawn 1

Combination Therapy:

• Superior to monotherapy: Combining azathioprine with TNF-α antagonists (particularly infliximab) is more effective than either agent alone for induction of remission in UC 1
• The UC-SUCCESS trial demonstrated combination infliximab plus azathioprine achieved higher corticosteroid-free remission rates (RR 1.78) compared to infliximab monotherapy 1

Monitoring Requirements:

• Complete blood count: Check within 4 weeks of starting therapy, then every 6-12 weeks to detect neutropenia 1
• Risk stratification: Azathioprine at doses ≤3 mg/kg/day is considered low-degree immunosuppression; higher doses constitute moderate-severe immunosuppression 1
• Profound neutropenia and sepsis can develop rapidly despite monitoring 1

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Tofacitinib in Inflammatory Bowel Disease

FDA-Approved Indication and Restrictions

Tofacitinib is FDA-approved for moderately to severely active ulcerative colitis in adults who have inadequate response or intolerance to one or more TNF blockers. 2

Critical FDA Restrictions:

• Second-line therapy only: Updated FDA recommendations (July 26,2019) specify tofacitinib should be used only after failure of or intolerance to TNF-α antagonists 1
• Not for biologic-naïve patients: The AGA recommends tofacitinib be used in biologic-naïve patients only within clinical or registry studies 1
• Contraindicated with immunosuppressants: Use in combination with biological therapies or potent immunosuppressants such as azathioprine and cyclosporine is not recommended 2

Dosing and Clinical Response

Induction Dosing:

• 10 mg twice daily orally for induction of remission 3
• Clinical response typically evident within 8 weeks of therapy 3

Maintenance Dosing:

• 5 mg twice daily after achieving clinical response 3

Efficacy Profile

• Rapid symptom improvement: Greatest benefits in bowel symptoms, particularly loose bowel movements and rectal bleeding, with improvements seen at 4 and 8 weeks 4
• Quality of life: Significant improvements in all Inflammatory Bowel Disease Questionnaire items compared to placebo 4
• TNF-experienced patients: Treatment benefits numerically higher in TNF-experienced versus TNF-naïve patients 4

Positioning After Infliximab Failure

In patients with prior infliximab exposure, particularly those with primary non-response, tofacitinib or ustekinumab are preferred over vedolizumab or adalimumab for induction of remission. 1

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Safety Considerations

Azathioprine Risks:

• Bone marrow suppression: Neutropenia requiring drug discontinuation 5
• Acute pancreatitis: Rare but serious adverse effect 5
• Immunosuppression: Moderate-severe at standard doses (>3 mg/kg/day), increasing infection risk 1

Tofacitinib Black Box Warnings:

Major Cardiovascular Events (MACE):

• Increased risk in high-risk patients: Patients ≥50 years with ≥1 cardiovascular risk factor have higher rates of cardiovascular death, MI, and stroke compared to TNF blockers 2
• Current/past smokers: Additional increased risk 2
• Discontinue immediately: After myocardial infarction or stroke 2

Thrombosis:

• Pulmonary embolism, DVT, arterial thrombosis: Serious events, some fatal, in patients ≥50 years with ≥1 cardiovascular risk factor 2
• Avoid in at-risk patients and discontinue promptly if thrombosis symptoms develop 2

Infections:

• Herpes zoster: Increased risk requiring vaccination where feasible before starting therapy 3
• Tuberculosis reactivation: Baseline testing and management of latent TB required 3
• Hepatitis B: Baseline evaluation and management necessary 3

Malignancy:

• Lymphomas and other malignancies: Observed with Janus kinase inhibitors 2
• Avoid in patients with previous malignancy 3

Contraindications and Cautions for Tofacitinib:

• Elderly patients 3
• Cardiovascular comorbidity or uncontrolled cardiac risk factors 3
• Previous thrombotic episodes or high VTE risk 3
• Pregnancy and lactation: Maternal exposure should be avoided during pre-conception, pregnancy, and lactation 3

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Treatment Algorithm

For Moderate to Severe Ulcerative Colitis:

1. First-line biologic therapy: Infliximab or vedolizumab preferred over adalimumab in biologic-naïve patients 1, 6

2. Consider combination therapy: TNF-α antagonists with azathioprine more effective than monotherapy, particularly in patients with unfavorable pharmacokinetics (severe disease, high inflammatory burden, low albumin, high BMI) 1

3. After TNF-α antagonist failure: Tofacitinib or ustekinumab preferred, especially with primary non-response to infliximab 1

4. Maintenance strategy:

   • Continue biologic ± immunomodulator 1
   • Azathioprine monotherapy acceptable if already in remission 1
   • Discontinue 5-ASA in patients on biologics/immunomodulators after 5-ASA failure 1

For Crohn's Disease:

1. Steroid-dependent disease: Azathioprine 1.5-2.5 mg/kg/day as first-line steroid-sparing agent 1

2. Frequent relapsers: Immunomodulation with azathioprine for patients relapsing >1 time per year during steroid withdrawal 1

3. Refractory disease: Reserve infliximab for patients refractory to or intolerant of steroids, mesalazine, azathioprine/mercaptopurine, and methotrexate where surgery inappropriate 1

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Key Clinical Pitfalls

• Do not use azathioprine for induction: Onset of action too slow for acute moderate-severe UC 1
• Do not use tofacitinib first-line: FDA restricts use to post-TNF-α antagonist failure 1, 2
• Do not combine tofacitinib with azathioprine: Explicitly contraindicated due to excessive immunosuppression risk 2
• Screen cardiovascular risk before tofacitinib: Age ≥50 years plus any CV risk factor substantially increases MACE and thrombosis risk 2, 3
• Monitor azathioprine closely: Neutropenia can develop rapidly despite regular monitoring 1
• Vaccinate before tofacitinib: Complete adult vaccinations, including herpes zoster, where feasible 3