Approximately 10% to 15% of patients with ulcerative colitis (UC) have a severe attack requiring hospitalization at some time point during the course of the disease. 1 Standard treatment of severe exacerbations of UC generally consists of intravenous glucocorticosteroids, but this approach fails to induce improvement in up to 40% of patients. Colectomy is then often necessary. 2 Besides glucocorticosteroids, cyclosporin A (CSA) is the only medication that has affected the outcome of severe acute UC. CSA is a potent immunosuppressor used in the prevention of organ graft rejection. It is a fungal metabolite, which acts as a calcineurin inhibitor, reducing the production of interleukin-2 and, hence, interfering with T lymphocyte function.
Lichtiger and colleagues performed the first double-blind, placebo-controlled trial demonstrating the efficacy of intravenous CSA in hospitalized patients. Nine of 11 patients (82%) in the CSA group improved and avoided colectomy, versus none in the placebo-group. 3 Since then, CSA has become standard therapy for steroid-refractory UC. In a controlled trial by D'Haens and colleagues it was even shown that therapy with CSA alone (without glucocorticosteroids) was as effective as glucocorticosteroids. 4 The goal of the current analysis was to study the efficacy and side effects in all patients treated with CSA at a single center.
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Severe attacks of UC are most frequently treated with IV glucocorticosteroids, although CSA mono-therapy has also been effective. Several papers have reported success with CSA, reflected as 56% to 100% of patients avoiding colectomy. (Table 4) 11–25 Our short-term success rate of 84% is consistent with other published data. After a mean follow-up of more than 2 years and with the majority of patients on maintenance immunomodulators, 62.7% (54/86) of our patients have avoided colectomy so far. Within this group, up to date, only 15 patients (27.7%) have developed a relapse of their UC. Overall, 39/86 patients (45%) have remained in remission without relapse. The life-table predicts that after 3 years, 55% of all treated patients will maintain their colon and, of these patients, 50% will develop a relapse.
Table 4. Short- and Long-Term Results of CSA IV in the Treatment of Severe Ulcerative Colitis Based on Literature Data
|Study||Start Dose mg/kg/d||Blood Cone. ng/ml||Number Patients||Short–Term Response||Long–Term Response (Mean Follow–up Period)|
|Cohen13||4||360 ±126||42||85.7%||61.9% (5.5 years)|
|Carbonnel16||3.21 ±0.95||279 ± 96||32||62.5%||31.3% (190d)|
|Gurudu17||4||550||7||85.7%|| 0.0% (1 year)|
|Van Gossum19||4||–||29||69.0%||44.8% (12m)|
Several minor and major complications have been reported with the use of CSA. Minor complications such as tremor, paresthesia, headache, hypertrichosis, and gingival hyperplasia are common and certainly impair the quality of life of the patients. The incidence of these side effects was lower in the current series than in other papers, but the retrospective character of the study may explain this; many minor side effects may not have been recorded in the medical charts.
Since a number of adverse events may be related to the dose of CSA, 5 we recently performed a comparative trial with CSA doses of 2 and 4 mg/kg/d. The results of this trial suggest that both doses are equally effective, although patients treated with 4 mg/kg had a more rapid response than with 2 mg/kg. 6 It can therefore be recommended to use doses of 2 or 3 mg/kg/d, especially in patients carrying a high risk of adverse events.
Several complications originated from IV lines, including 1 case of pneumothorax and several documented cases of catheter sepsis. This type of complications could be avoided by using oral instead of IV loading doses of CSA, as it was done by Actis and colleagues. They obtained identical results with both routes of administration. The study was unblinded and included only a small number of patients not responding to oral steroids. 7 These data need confirmation before oral CSA can be used as an alternative for IV CSA.
One patient in our study had anaphylactic shock caused by the solvent of CSA. When switched to oral CSA, complete remission of his colitis was achieved.
The most concerning issue of the current series is mortality. Three patients (3.5%) died of opportunistic infections. These patients were deeply immunosuppressed, having received high doses of IV glucocorticosteroids for more than 7 days before starting IV CSA, followed by oral glucocorticosteroids, oral CSA, and azathioprine. We believe that the risk of opportunistic infections can be reduced by using the lowest effective dose of CSA, tapering glucocorticosteroids as soon as possible, and adding prophylactic treatment of Pneumocystis pneumonia with trimethoprim-sulfamethoxazole. This strategy is now routinely being used in patients treated with CSA in our department, and no further mortality has occurred since. It is even questionable if IV CSA has to be switched to oral CSA. Preliminary Greek data suggest maintenance success with steroids, azathioprine, and 5-ASA comparable with steroids, oral CSA, and 5-ASA during 6 months after successful induction therapy with IV CSA + IV steroids. 8 This was evaluated in a small group of patients and larger studies are needed before we can recommend that oral CSA can be replaced by azathioprine. We do not believe, however, that CSA can be advocated as a long-term maintenance option, given the significant toxicity profile.
Cohen and colleagues showed a significantly better quality of life in patients responding to CSA than patients after a colectomy. 9 Another element to be aware of is that patients who keep their colon have an enhanced risk of developing dysplasia or cancer in the colon.
Our study reveals a number of pros and cons of CSA therapy for severe UC. The better quality of life without colectomy has to be balanced against the risk of minor and major toxicity and even mortality. We believe, however, that with better knowledge of the potential risks, maximal prevention of opportunistic infections, earlier initiation of IV CSA in patients not responding to IV glucocorticosteroids (as reported by Travis et al 10) and probably also lower doses of CSA, the mortality risk will further be reduced. At this moment we suggest to start with IV CSA 2 mg/kg to continue IV steroids and to start azathioprine/6MP from the moment a clinical response is observed. During the treatment period with triple immunosuppression, all patients should receive trimethoprim-sulfamethoxazole to prevent Pneumocystis pneumonia. If there is no clinical response after a maximum of 1 to 2 weeks, colectomy should be performed. For patients relapsing after CSA withdrawal, a second IV treatment with CSA can be considered.