What is the role of cyclosporine (CsA) in treating severe, acute ulcerative colitis (UC) that is refractory to conventional therapies, including intravenous (IV) corticosteroids?

Cyclosporine in Ulcerative Colitis

For patients with acute severe ulcerative colitis who fail to respond to intravenous corticosteroids by day 3, cyclosporine at 2 mg/kg/day IV is an effective rescue therapy that can avoid colectomy in 76-85% of patients in the short term, with equivalent efficacy to infliximab. 1

When to Use Cyclosporine

Assessment Timeline

• Evaluate response to IV steroids on day 3 of treatment with methylprednisolone 60 mg/24h or hydrocortisone 100 mg four times daily 1, 2
• Failure indicators at day 3 include: >8 bowel movements/day, or 3-8 bowel movements/day with CRP >45 mg/L, mucosal islands or colonic dilatation on imaging, or deep ulceration on sigmoidoscopy 2, 3
• Do not extend IV steroid therapy beyond 7-10 days as this provides no additional benefit and increases surgical morbidity and mortality 1, 2, 3

Cyclosporine as First-Line Alternative

• Cyclosporine 2 mg/kg/day IV can be used as monotherapy (without steroids) in patients who should avoid corticosteroids, including those with steroid psychosis, severe osteoporosis, or poorly controlled diabetes 1
• This approach is supported by an RCT showing 4 mg/kg/day IV cyclosporine was as effective as IV methylprednisolone 40 mg/day for acute severe UC 1, 4

Dosing and Administration

Standard Dosing Protocol

• Use 2 mg/kg/day IV cyclosporine as the standard dose 1
• An RCT demonstrated that 2 mg/kg/day and 4 mg/kg/day had equivalent response rates (83% vs 82% at day 8) with similar colectomy rates (9% vs 13%), but the lower dose has a superior safety profile 1
• Adjust dose based on serum concentration monitoring 1

Expected Response Timeline

• Median time to response is 4 days, allowing timely identification of non-responders for colectomy 1
• Clinical response typically occurs within 3.5 days (range 1-7 days) 5
• If no improvement after 4-7 days of cyclosporine, proceed to colectomy 1

Efficacy Outcomes

Short-Term Results

• 76-85% of steroid-refractory patients respond to IV cyclosporine and avoid immediate colectomy 1
• In the CONSTRUCT trial of 135 steroid-refractory patients, colectomy rates were 25% in-hospital, 30% at 3 months, and 45% at 12 months 1

Long-Term Results

• Long-term colectomy-free survival is approximately 58-70% at 5 years 6, 7
• Successful transition to oral thiopurine (azathioprine or 6-mercaptopurine) after initial cyclosporine response is a critical factor in preventing future colectomy 1
• Patients who are thiopurine-naïve at baseline and successfully transition to thiopurine therapy have significantly better long-term outcomes 1
• In one series, 80% of initial cyclosporine responders who also received 6-MP/azathioprine avoided colectomy, versus only 55% of those not receiving thiopurines 6

Comparison with Infliximab

• Cyclosporine and infliximab have equivalent efficacy for steroid-refractory acute severe UC 1
• Two head-to-head RCTs showed no significant difference in short-term colectomy risk (RR 1.00,95% CI 0.72-1.40) 1
• Long-term follow-up (median 4.5 years) showed similar colectomy-free survival: 61.5% with cyclosporine vs 65.1% with infliximab (p=0.97) 1

Safety Monitoring and Adverse Events

Critical Monitoring Requirements

• Monitor serum cyclosporine levels: target trough levels (C0) should not exceed 100 ng/mL, and 2-hour post-dose levels (C2) should not exceed 700 ng/mL 5
• Monitor renal function with serum creatinine and consider inulin clearance for more precise assessment 4
• Provide Pneumocystis jirovecii prophylaxis (typically trimethoprim-sulfamethoxazole) during cyclosporine therapy 5, 6

Adverse Event Profile

• Mortality rate is 3-4% with cyclosporine therapy, which has limited its widespread acceptance 1
• Common reversible side effects include: mild transient renal impairment, hypertension, opportunistic infections (CMV, esophageal candidiasis), and neurological symptoms 5, 6
• All serious complications are reversible with drug discontinuation and result in complete recovery 6
• The narrow therapeutic index requires intensive monitoring, particularly at higher doses 7

Critical Pitfalls to Avoid

Sequential Therapy Concerns

• Do not attempt sequential rescue therapy (cyclosporine after infliximab failure, or vice versa) as this increases adverse events without clear benefit 3
• Only one attempt at rescue therapy should be considered before proceeding to colectomy 3

Surgical Consultation

• Involve colorectal surgery from day of admission for all patients with acute severe UC 1, 3
• This multidisciplinary approach is essential as delayed colectomy increases morbidity and mortality 1, 3

Infection Screening

• Screen for C. difficile, CMV, and other enteric pathogens before initiating cyclosporine 1, 3
• If C. difficile is detected, administer oral vancomycin 500 mg every 6 hours while continuing immunosuppressive therapy 1, 3

Medication Withdrawal

• Discontinue anticholinergics, antidiarrheals, NSAIDs, and opioids as these may precipitate toxic megacolon 1, 2, 3

Supportive Care During Cyclosporine Therapy

• Provide IV fluid and electrolyte replacement with potassium supplementation of at least 60 mmol/day 2, 3
• Administer low-molecular-weight heparin for thromboprophylaxis 1, 2, 3
• Maintain hemoglobin above 8-10 g/dL with blood transfusion if needed 1, 3
• Correct electrolyte abnormalities and anemia 1, 2

Transition to Maintenance Therapy

• After initial response to IV cyclosporine, transition to oral cyclosporine (8 mg/kg/day) combined with azathioprine or 6-mercaptopurine 6
• Continue oral cyclosporine for approximately 3-6 months while establishing thiopurine therapy 6
• The combination of cyclosporine bridging to thiopurine maintenance is critical for long-term colectomy-free survival 1, 6