Department of Medicine, Section of Digestive Diseases, Yale University, New Haven, CT
The author declares that he has nothing to disclose.
Reprints: Ioannis Oikonomou, MD, 40 Temple Street, Suite 1A, New Haven, CT 06510 (e-mail: firstname.lastname@example.org).
Crohn’s disease can affect any part of the digestive tract. About one fourth of patients present with Crohn’s colitis and half of the patients present with ileocecal involvement.1 Our armamentarium of drugs for moderate to severe colonic Crohn’s disease includes corticosteroids, immunomodulators such as azathioprine, or methotrexate and anti-TNF agents. Cyclosporine has been used in specialized centers for the treatment of acute severe ulcerative colitis but has been rarely used for the management of Crohn’s disease. In this issue of Journal of Clinical Gastroenterology, Lazarev et al2 present a retrospective cohort study evaluating the use of cyclosporine in patients with Crohn’s colitis.
In ulcerative colitis, cyclosporine is used as a bridge therapy to thiopurines. In acute severe ulcerative colitis, the response rate to cyclosporine has been reported to be up to 85%.3 The long-term benefit of cyclosporine in ulcerative colitis in terms of avoidance of colectomy is questionable. A study of patients successfully treated with cyclosporine has shown that the probability of avoiding colectomy was 63% at 1 year that dropped to 12% at 7 years.4 The use of cyclosporine in ulcerative colitis has further been limited by its side-effect profile.5
What happens in Crohn’s colitis? Do patients with Crohn’s colitis respond in a similar manner to intravenous (IV) cyclosporine as patients with ulcerative colitis? The study by Lazarev and colleagues aims to give us an answer.
This was a retrospective chart review evaluating the role of IV cyclosporine in the management of patients with Crohn’s colitis or indeterminate colitis (IC) favoring Crohn’s disease. Primary endpoint was the colectomy rate during an inpatient admission for IV cyclosporine. Secondary endpoints were the colectomy-free survival at 6 and 12 months after the initial admission for IV cyclosporine. This was the largest reported cohort of patients with Crohn’s colitis treated with cyclosporine. Within a 12.5-year period, 41 patients with Crohn’s colitis and 7 patients with IC favoring Crohn’s disease who were treated with IV cyclosporine were identified. The median follow-up time was 12 months (range, 1 to 128 mo). The follow-up data on 2 patients were not available. Only 6 of 48 patients (12.5%) required colectomy during the initial hospitalization. The colectomy rate was higher in patients with IC favoring Crohn’s disease. Among 7 IC patients, 2 (28.6%) required colectomy. The long-term avoidance of colectomy was not as impressive. Similar to the data from ulcerative colitis trials, the colectomy rate increased significantly during follow-up.4 Almost half of the patients (52%) underwent colectomy during follow-up. The colectomy rate at 6 months was 28.2% and at 12 months 41.1%. Before the hospitalization, 85% of the patients had used immunomodulators and 69% had used an anti-TNF agent. Among multiple demographic and laboratory parameters as well as duration, location of disease, smoking status, prednisone, thiopurine and infliximab use, only anti-TNF use within 4 weeks before hospitalization predicted surgery with an odds ratio of 7.2. Three out of 6 patients who had colectomy were on anti-TNF agents recently, whereas there were no data available for 1 patient. Three patients received at least 1 subsequent course of IV cyclosporine after their hospitalization.
The study was performed in an institution with a strong tradition in the use of cyclosporine. Among 620 patients treated with cyclosporine 91 had Crohn’s disease. About half of these patients were eligible for the study. The relatively small number of subjects and the heterogenous population precludes drawing a definitive conclusion. Some of the patients might have been hospitalized only for IV cyclosporine treatment requiring inpatient monitoring, without having severe Crohn’s colitis. Only 48% of the patients were on prednisone before admission, which points toward less severe disease. Mild to moderate Crohn’s disease activity can bias the study toward a lower probability for colectomy, which is the primary endpoint. Interestingly, the colectomy rate in patients with IC favoring Crohn’s was much higher than in the rest of the subjects. That could be partially explained by the fact that the diagnosis of IC favoring Crohn’s might have been given after the surgery. The threshold for surgery might have been lower in patients with a preoperative diagnosis of IC or IC favoring ulcerative colitis. Initiation of thiopurines along with cyclosporine in thiopurine-naïve patients improves the colectomy-free survival in ulcerative colitis.4 Among the study subjects, 85% had used immunomodulators in the past. Unfortunately, data about the thiopurine use after the hospitalization was not available. Even if all patients had been on thiopurines after the hospitalization, an impressive long-term colectomy-free survival would not be expected, because it seems that many of the patients had either failed or did not tolerate thiopurines before the IV cyclosporine administration. One flaw of this retrospective study was the unavailability of the cyclosporine dosing that could help us assess potential difference in efficacy between 2 and 4 mg/kg/d.
Only 1 double-blind placebo-controlled study using high-dose oral cyclosporine (median 7.6 mg/kg/d) in patients with Crohn’s disease has shown beneficial but not impressive results after 12 weeks of treatment.6 That study used a nonvalidated clinical scale. By using the Crohn’s Disease Activity Index, there was no statistical difference between high-dose cyclosporine and placebo. None of 3 other studies found any statistically significant difference in response or remission with low-dose oral cyclosporine treatment (5 mg/kg/d) used by itself or in combination with corticosteroids compared with placebo.7–9 A Cochrane meta-analysis has confirmed that the use of low-dose oral cyclosporine is not effective in terms of induction of remission in patients with Crohn’s disease.10 Data on high-dose IV cyclosporine use for induction of remission are scant. Few retrospective cohorts with small numbers of patients have shown that IV cyclosporine has a temporary efficacy that is reversible upon its discontinuation.11–13 Better efficacy has been shown in patients with fistulizing Crohn’s disease with a response rate of up to 88% but significant relapse rate after drug discontinuation.12,14 Unfortunately, the toxicity and side effects of cyclosporine such as nephrotoxicity, hypertension, nausea/vomiting, infections, paresthesias, hypertrichosis, headaches, and tremors limit its use. A mortality rate of about 1.8% associated with its use in inflammatory bowel disease has dampened the enthusiasm in its use.5 The side effects can be minimized by the use of lower-dose cyclosporine such as 2 mg/kg/d, electrolyte replenishment, antibiotic prophylaxis, and limited concomitant immunosuppressive use.
In summary, this is an interesting study that shows potential benefit of treatment of colonic Crohn’s disease with IV cyclosporine. At least in the short term, patients with Crohn’s colitis can avoid colectomy. A randomized placebo-controlled study with IV cyclosporine in patients with severe colonic Crohn’s disease might be able to support the justification of its use. Nevertheless, the question remains about the long-term colectomy-free survival. The cyclosporine toxicity should be taken into consideration and an extensive discussion with the patient about the ultimate goal of treatment should take place. With limited segmental colonic Crohn’s disease refractory to anti-TNF agents, a surgical approach might be preferable. Patients with severe extensive Crohn’s colitis, naïve to thiopurines might be potential candidates for cyclosporine use. Larger, prospective studies might be able to delineate the role of cyclosporine in Crohn’s disease.
1. Lapidus A, Bernell O, Hellers G, et al. Incidence of Crohn’s disease in Stockholm County 1955-1989. Gut. 1997;41:480–486
2. Lazarev M, Present D, Lichtiger S, et al. The effect of intravenous cyclosporin on rates of colonic surgery in hospitalized patients with severe Crohn’s colitis. J Clin Gastroenterol. 2012;46:764–767
3. Cheifetz AS, Stern J, Garud S, et al. Cyclosporine is safe and effective in patients with severe ulcerative colitis. J Clin Gastroenterol. 2011;45:107–112
4. Moskovitz DN, Van Assche G, Maenhout B, et al. Incidence of colectomy during long-term follow-up after cyclosporine-induced remission of severe ulcerative colitis. Clin Gastroenterol Hepatol. 2006;4:760–765
5. Sternthal MB, Murphy SJ, George J, et al. Adverse events associated with the use of cyclosporine in patients with inflammatory bowel disease. Am J Gastroenterol. 2008;103:937–943
6. Brynskov J, Freund L, Rasmussen SN, et al. A placebo-controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn’s disease. N Engl J Med. 1989;321:845–850
7. Feagan BG, McDonald JW, Rochon J, et al. Low-dose cyclosporine for the treatment of Crohn’s disease. The Canadian Crohn’s Relapse Prevention Trial Investigators. N Engl J Med. 1994;330:1846–1851
8. Stange EF, Modigliani R, Peña AS, et al. European trial of cyclosporine in chronic active Crohn’s disease: a 12-month study. The European Study Group. Gastroenterology. 1995;109:774–782
9. Jewell D, Lennard-Jones J, Lowes J, et al. Oral cyclosporin for chronic active Crohn’s disease: a multicentre controlled trial. Eur J Gastroenterol Hepatol. 1994:499–505
10. McDonald JW, Feagan BG, Jewell D, et al. Cyclosporine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2005:CD000297
11. Mahdi G, Israel DM, Hassall E. Cyclosporine and 6-mercaptopurine for active, refractory Crohn’s colitis in children. Am J Gastroenterol. 1996;91:1355–1359
12. Egan LJ, Sandborn WJ, Tremaine WJ. Clinical outcome following treatment of refractory inflammatory and fistulizing Crohn’s disease with intravenous cyclosporine. Am J Gastroenterol. 1998;93:442–448
13. Santos JV, Baudet JA, Casellas FJ, et al. Intravenous cyclosporine for steroid-refractory attacks of Crohn’s disease. Short- and long-term results. J Clin Gastroenterol. 1995;20:207–210
14. Present DH, Lichtiger S. Efficacy of cyclosporine in treatment of fistula of Crohn’s disease. Dig Dis Sci. 1994;39:374–380