What is the role of cyclosporine (CsA) in treating severe, refractory ulcerative colitis (UC)?

Cyclosporine in Ulcerative Colitis

Cyclosporine is an effective rescue therapy for acute severe ulcerative colitis that fails to respond to intravenous corticosteroids by day 3, with equivalent short-term efficacy to infliximab in preventing colectomy, but should be used as a bridge to thiopurine maintenance therapy rather than long-term treatment. 1

Indications and Patient Selection

Use cyclosporine specifically for patients with acute severe UC (≥6 bloody bowel movements daily plus systemic toxicity) who remain refractory to IV corticosteroids after 3 days of treatment. 1 This represents approximately 20-30% of hospitalized patients with severe UC who fail initial steroid therapy. 2

Optimal Candidates

• Thiopurine-naïve patients are the best candidates, as successful transition to azathioprine or 6-mercaptopurine significantly reduces long-term colectomy rates. 3, 1
• Patients who have already failed adequate thiopurine therapy are less suitable candidates and should preferentially receive infliximab instead. 3, 1
• Cyclosporine monotherapy (without concomitant steroids) is particularly useful for patients with steroid-related complications such as psychosis, severe osteoporosis, or poorly controlled diabetes. 3

Absolute Contraindications

Do not use cyclosporine if toxic megacolon, severe hemorrhage, or perforation is present—these require immediate subtotal colectomy. 1

Dosing and Administration

Use intravenous cyclosporine at 2 mg/kg/day, which has equivalent efficacy to 4 mg/kg/day with significantly fewer adverse events. 1, 4 The higher dose provides no additional clinical benefit but trends toward increased hypertension (23.7% vs 8.6%). 4

Target Levels and Monitoring

• Target cyclosporine trough levels of 100-200 ng/mL (mean levels around 237 ng/mL at 2 mg/kg). 3, 4
• Monitor blood pressure, complete blood count, renal function, and cyclosporine levels at 0,1, and 2 weeks, then monthly. 3
• Check cholesterol and magnesium before starting—levels below 3.0 mmol/L and 0.50 mmol/L respectively increase seizure risk. 3

Expected Response Timeline

Clinical response typically occurs within 4-9 days, with 84-86% of patients responding by day 8. 4, 5 If no improvement occurs by day 4-7 of cyclosporine therapy, proceed to colectomy rather than continuing medical therapy. 3

Bridging Strategy: The Critical Component

Cyclosporine should rarely be continued beyond 3-6 months and must serve as a bridge to thiopurine therapy. 3 This bridging strategy is what determines long-term success.

Transition Protocol

• Start azathioprine or 6-mercaptopurine while the patient is still receiving cyclosporine. 6
• Taper corticosteroids concurrently as the thiopurine is introduced. 6
• Successful transition to thiopurine maintenance is the single most important factor preventing future colectomy. 3

Long-Term Outcomes

While short-term response rates are impressive (76-86%), long-term colectomy rates remain substantial: 5, 2

• 28.3% require colectomy at 3 months 3
• 42-58% require colectomy within 1 year 3, 7
• 58-88% require colectomy over 7 years 3

Patients who successfully transition to thiopurine maintenance have significantly lower long-term colectomy rates. 3

Cyclosporine vs. Infliximab: Equivalent Options

The 2017 European consensus found no significant difference between cyclosporine and infliximab regarding quality of life, colectomy rates, mortality, or serious infections in 270 patients with acute severe steroid-refractory UC. 3 Both are acceptable first-line rescue options. 1

When to Choose Cyclosporine Over Infliximab

• Patient has already failed thiopurines and you plan to bridge to advanced biologics 1
• Infliximab is unavailable, contraindicated, or in resource-limited settings 6
• Patient has contraindications to anti-TNF therapy
• Lower upfront cost is a consideration (though total treatment costs may be higher long-term) 3

When to Choose Infliximab Over Cyclosporine

• Patient has already failed or is intolerant to thiopurines, as cyclosporine's efficacy depends on successful transition to thiopurine maintenance 3, 1
• Less intensive monitoring is preferred
• Continuation as maintenance therapy is planned

Critical Safety Considerations

Common Adverse Events (31-51% of patients)

Minor side effects include tremor, paresthesias, malaise, headache, abnormal liver function, gingival hyperplasia, and hirsutism. 3

Major Complications (0-17% of patients)

• Renal impairment
• Opportunistic infections (including Pneumocystis carinii pneumonia, Aspergillus)
• Neurotoxicity and seizures
• One death from P. carinii pneumonia was reported in a series of 21 patients 5

Mandatory Precautions

• Administer low-molecular-weight heparin for thromboprophylaxis in all patients. 3, 1
• Correct electrolyte abnormalities, particularly hypokalemia and hypomagnesemia. 1
• Consider Pneumocystis prophylaxis based on nutritional state, concomitant immunosuppression, and duration of therapy. 3
• Ensure joint care by gastroenterologist and colorectal surgeon throughout treatment. 3

Sequential Rescue Therapy: Generally Avoid

Only attempt one rescue therapy (either cyclosporine or infliximab) before proceeding to colectomy. 3 Sequential rescue therapy (using cyclosporine after infliximab failure or vice versa) has been studied in 314 patients with concerning results: 3

• Short-term response: 62.4%
• Colectomy at 3 months: 28.3%
• Colectomy at 12 months: 42.3%
• Serious infections: 6.7%
• Mortality: 1%

The European consensus states that no recommendation for or against sequential therapy can be made based on available data, though it may be considered in highly selected cases at specialist centers after careful multidisciplinary discussion. 3 The risk of cumulative immunosuppression and sepsis increases substantially with sequential therapy. 6

Role in Outpatient/Moderate-to-Severe UC: None

Cyclosporine has no role in outpatient management of moderate-to-severe UC. 1 For outpatients unresponsive to aminosalicylates and corticosteroids, use advanced therapies (anti-TNF agents, vedolizumab, JAK inhibitors, or anti-integrins) instead. 1

Predictors of Poor Response

Higher baseline Lichtiger scores (14.2 vs 12.3) and lower hemoglobin levels (10.1 vs 11.8 g/dL) predict colectomy within 1 year. 7 Active smoking is inversely correlated with clinical response (odds ratio 0.06). 4