What is the approach to treating steroid refractory and steroid dependent ulcerative colitis?

Management of Steroid Refractory and Steroid Dependent Ulcerative Colitis

For patients with steroid-dependent or steroid-refractory ulcerative colitis, immunomodulators (thiopurines), anti-TNF agents (preferably combined with thiopurines), or vedolizumab should be used as the next line of therapy to achieve remission and improve outcomes. 1

Definitions

Steroid-Refractory UC

• Active disease despite adequate dose and duration of prednisolone (>20 mg/day for >2 weeks) 1
• Requires prompt escalation of therapy to prevent complications and colectomy

Steroid-Dependent UC

• Relapse occurs when steroid dose is reduced below 20 mg/day
• Or relapse within 6 weeks of stopping steroids 1

Treatment Algorithm for Steroid-Refractory UC

1. First-line rescue therapy options:

   • Infliximab (5 mg/kg IV at weeks 0,2, and 6, then every 8 weeks) 1, 2
   • Cyclosporine (2 mg/kg/day IV, then transition to oral) 1
   • Tacrolimus (adjusted to trough levels 10-15 ng/ml) 1

2. If response to rescue therapy:

   • Transition to maintenance therapy with immunomodulators
   • For cyclosporine responders: introduce azathioprine/mercaptopurine while on cyclosporine, then taper cyclosporine over 3 months 3
   • For infliximab responders: continue infliximab with or without thiopurines 1

3. If no response to rescue therapy within 5-7 days:

   • Consider colectomy 1, 4

Treatment Algorithm for Steroid-Dependent UC

1. First-line therapy:

   • Azathioprine (1.5-2.5 mg/kg/day) or mercaptopurine (0.75-1.25 mg/kg/day) 1
   • Monitor FBC within 4 weeks of starting therapy and every 6-12 weeks thereafter 1

2. If thiopurine failure or intolerance:

   • Anti-TNF therapy (infliximab, adalimumab, or golimumab) 1
   • Consider combination therapy with anti-TNF plus azathioprine (especially for infliximab) 1
   • Vedolizumab 1
   • Methotrexate (25 mg IM weekly for 16 weeks, then 15 mg weekly) 1

3. For anti-TNF failure:

   • Switch to alternative anti-TNF agent 1
   • Vedolizumab 1
   • Consider tofacitinib for steroid-resistant cases 5

Efficacy of Treatments

Thiopurines

• 53% of patients achieve steroid-free clinical and endoscopic remission after 6 months with azathioprine vs. 21% with 5-ASA 1
• Long-term steroid-free remission rates with azathioprine at 12,24, and 36 months: 55%, 52%, and 45%, respectively 1, 6

Anti-TNF Agents

• Infliximab: 21.5% of steroid users achieve steroid-free remission by week 30 vs. 7.2% with placebo 1
• Adalimumab: 13.3% steroid-free remission at week 52 vs. 5.7% with placebo 1
• Golimumab: 34.4% steroid-free remission by week 54 vs. 20.7% with placebo 1
• Combination therapy (infliximab + azathioprine): 39.7% achieve corticosteroid-free remission at week 16 vs. 22.1% with infliximab alone 1

Monitoring and Follow-up

• Regular monitoring of blood counts for patients on thiopurines (FBC within 4 weeks of starting therapy and every 6-12 weeks thereafter) 1
• Endoscopic assessment of mucosal healing
• Monitoring for opportunistic infections in patients on immunosuppressive therapy
• Consider colectomy for patients with persistent symptoms despite optimal medical therapy 1

Important Considerations

• Long-term corticosteroid use is undesirable due to significant side effects 1
• Combination therapy with anti-TNF and thiopurines appears more effective than monotherapy but carries increased risk of infections and malignancies 1, 2
• In resource-limited settings, maintenance with azathioprine and 5-ASA after infliximab induction may be a cost-effective strategy 7
• Surgery should be considered in patients not responding to intensive medical therapy 1
• Smoking cessation is crucial for maintaining remission 8

Pitfalls to Avoid

• Delaying escalation of therapy in steroid-refractory cases can lead to increased morbidity and mortality
• Prolonged steroid use without implementing steroid-sparing strategies
• Failure to monitor for drug toxicity, especially neutropenia with thiopurines
• Not considering surgery as a therapeutic option in appropriate cases
• Inadequate prophylaxis against opportunistic infections in patients on multiple immunosuppressants