Cyclosporin

Cyclosporin (CyA) is an inhibitor of calcineurin, preventing clonal expansion of T-cell subsets. It has a rapid onset of action and is effective in the management of severe UC which failed to improve from the intensive steroidal therapy. Several uncontrolled studies and a few controlled studies of intravenous cyclosporine in patients with severe UC are available. Lichtiger et al. reported on 20 patients, 9 randomized to placebo and 11 to CyA, in continuous infusion, in addition to steroids for up to 14 days. Nine out of 11 patients on CyA responded after a mean period of 7 days compared with none on placebo. Responders continued on oral CyA 8 mg/kg/day and, at 6 months, 5 out of 11 maintained remission [53].

When used as a monotherapy (continuous infusion of either CyA 4 mg/kg/day or methylpred-nisolone 40 mg/day), a response at 8 days was obtained in 9 out of 14 of CyA vs. 8 out of 15 of methylprednisolone. Responders were slowly switched to AZA maintenance. At 12 months, 7 out of 9 patients initially treated with CyA maintained remission compared with 3 out of 8 with steroids. [54].

In a further study, 30 patients were randomised to monotherapy with CyA 4 mg/kg/day i.v. or CyA i.v in combination with methylprednisolone 1 mg/kg/day. At 7 days, a complete remission was obtained in 10 out of 15 on CyA vs. 14 out of 15 on the combination therapy [55]. While 2 and 4 mg of the drug show the same efficacy, topical treatment is not effective [56, 57].

Intravenous CyA is rapidly effective as a salvage therapy for patients with refractory colitis, who would otherwise face colectomy, but its use is controversial because of toxicity and its high long-term failure rate. There is now a trend to use CyA earlier to improve outcome. To do so, early predictors of steroid failure are needed [58-59]. For its rapid onset of action, CyA can be considered as a "bridge" to maintenance therapy with immunomodulators and only rarely should be continued for more than 3-6 months.

In a recent Cochrane Review, it was concluded that there is limited evidence that CyA is more effective than standard treatment alone in preventing colectomy in severe UC, even if its beneficial effect cannot be excluded due to the small sample size [60]. The possible efficacy of CyA in these severe cases has to be weighed against possible side effects. Minor side effects occur in 31-51%, including tremor, paresthesias, malaise, headache, abnormal liver function, gingival hyperplasia, and hirsutism. Major complications are renal insufficiency (23%), infections (20%), seizures (3%), death (2%) and anaphylaxis (1%) [61].

The risk of seizures is increased in patients on intravenous CyA with serum cholesterol less than 120 mg/dl and serum magnesium less than 1.5 mg/dl. Oral therapy is an alternative in these circumstances [62]. Using prophylaxis against Pneumocystis carinii pneumonia is an individual decision dependent on nutritional state, concomitant immunomodulator therapy, and duration of therapy, but other opportunistic infections (for example, Aspergillus sp.) may be as common.

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