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Treatment of choice for acute severe steroid-refractory ulcerative colitis is cyclosporine
Article first published online: 11 FEB 2008
Copyright © 2008 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 15, Issue 1, pages 141–142, January 2009
How to Cite
Lichtiger, S. (2009), Treatment of choice for acute severe steroid-refractory ulcerative colitis is cyclosporine. Inflamm Bowel Dis, 15: 141–142. doi: 10.1002/ibd.20363
- Issue published online: 5 DEC 2008
- Article first published online: 11 FEB 2008
- Manuscript Accepted: 9 NOV 2007
- Manuscript Received: 28 MAR 2007
July 1985: Armed with a decade of experience in the transplant literature, cyclosporine (CSA) was an effective and rapidly acting immunosuppressant, interfering with both the induction and amplification of inflammation. Its mechanism of action was thought to be inactivation of calcineurin, which subsequently prevented the transcription of mRNA encoding for interleukin-2, thereby interfering with mucosal inflammation. We postulated that patients with severe ulcerative colitis (UC) would benefit from parenteral administration, and that blood levels would be more reliable when the drug was given by continuous infusion. Replete with literature on the renal toxicity of CSA in transplant patients, we postulated that toxicity would be different in patients who had normal renal function.
1986–1989: Patients with severe UC who had failed intensive steroid therapy were studied in an open, uncontrolled manner. Our initial dose of CSA was 4 mg/kg/day infused continuously; blood levels were easily maintained, response was a mean of 5.8 days, and 73% of patients avoided colectomy. There were no serious adverse events and we continued CSA orally at 8 mg/kg/day. Our outpatient management evolved by observation, but we recognized that CSA is an induction rather than a maintenance medication.
1991–1992: In conjunction with the University of Chicago, we initiated a double-blind, placebo-controlled trial in patients who had failed intravenous steroid therapy.1 Our intent was to study a total of 50 patients; however, after studying 20 patients a study monitor as well as 2 independent reviewers found a significant difference in the response rates of each group and the study was terminated. In all, 82% responded to CSA, 0% responded to placebo, and of the 9 placebo patients who did not respond initially, 55% did well when crossed over to open-label CSA. No patient developed nephrotoxity; however, a single patient had a grand mal seizure.
Subsequent to our initial studies, there have been 4 controlled trials of CSA's effect on patients with severe UC. Although each study had individual differences, they all reproduced our acute response rate of ≈80%. D'Haens et al2 studied 30 patients who were randomized to either CSA or methylprednisone. After 8 days, 64% of patients who received CSA and 53% who received steroids were in clinical remission. Those considered responders were then continued on oral CSA and Immuran. At 1 year, 78% of the CSA-treated group were in remission as opposed to 37% who were initially treated with steroids. Svavoni et al3 randomized patients with severe disease to monotherapy with CSA, versus a group treated with both steroids and CSA. At 2 weeks, 93% of patients on both therapies were in clinical remission, whereas 67% of those treated with CSA alone were in clinical remission. Van Assche et al4 reproduced a similar response rate of 83% in patients receiving intravenous CSA for severe UC, both in patients receiving 2 mg/kg/day and in patients who received 4 mg/kg/day. Moskovitz et al5 again reproduced the 83% response rate to parenteral CSA, and in my own series of 156 patients the short-term response was 81%. Review of the large uncontrolled data again reproduced responses between 70%–80%. Of these open trials6–9 the preferred dosage administered was 4 mg/kg/day, and similar to the aforementioned controlled trials the response was rapid, and maintenance of remission long-term was improved by addition of 6-MP or Immuran. In fact, there has never been a series reported where there is less than a 60% response rate to parenteral CSA.
As mentioned in the historical introduction, the initial toxicity data of CSA was determined in patients who had undergone either renal or hepatic transplantation.10 We assumed that their inherent renal disease contributed to the associated toxicity, and that patients with IBD and normal renal function would respond differently. Since the renal insult is caused by vasoconstriction of the afferent arteriole, and is reversible within 2 weeks after the drugs discontinuation, we reasoned that healthy patients would manifest a lower degree of renal damage. Initially, we minimized toxicity by patient selection, and too-frequent CSA, BUN, and creatinine levels. We had little toxicity in our open, controlled, and personal series. Sandborn and colleagues11 reviewed the adverse effects in 27 studies, and although the incidence of paresthesias and hypertrichosis were high, renal insufficiency occurred in only 6% of patients. Renal toxicity is related to dosage, and may be reversed by dose adjustment. Renal biopsies were not done; therefore, subclinical renal disease could not be fully evaluated. We did have a single patient who developed renal failure eventually leading to her death. In ≈400 patients treated at Mount Sinai we have had a single patient with disseminated cytomegalovirus (CMV). There are case reports of pneumocystis pneumonia; therefore, Septra prophylaxis is advised. Seizures are directly related to serum magnesium and cholesterol, and should be averted by repletion of Mg, as well as nutritional supplementation.
Although surgery is curative of the inflammation of UC, it is not curative of symptoms of diarrhea, incontinence, nocturnal leakage, and in the majority of patients does not obviate the need for medication. In several surgical series that follow patients a minimum of 5 years, up to 60% of patients are still having greater than 8 bowel movements daily, 55% incontinence, and 50% nocturnal leakage. Significant pouchitis is reported in 8%–30% of patients and the long-term concern with fertility must be considered. An irritable pouch syndrome, as well as studies that document poor quality of life after surgery, leave ileal-pouch anal anastomosis (IPAA) with unresolved questions.
Well, if that is the case, why are we even questioning its use in severe UC? Have we enough evidence-based medicine to initiate a different agent? If all of these studies are indeed entering steroid failures in the setting of severe disease, the only other alternative is surgery. Is the potential toxicity overstated? Is the long-term 45%–50% remission surprising, given the severity of their disease? And is CSA's failure in maintaining a long-term response really a reflection of the need for a better maintenance regimen?
The argument that CSA should not be initiated because the long-term remission rate is low has been based on conflicting studies. Cohen et al12 reported that 70% of patients treated with CSA were in clinical remission at year 5. In my personal series of 156 patients, 49% of patients retained their colons, with a mean follow-up of 12.6 years. More recently, Moskovitz et al5 reported that by life table analysis only 12% of patients retained their colon at 8 years. However, these long-term studies do not reflect the ability of CSA to induce remission and they reflect the fact that we need better maintenance agents. By definition, these are a sicker subgroup of patients who, in our trial, had no response to placebo. Are we to reason that patients who receive a course of IV steroids have early colectomy because they also have long-term remission rates of 55%? Of course not! Rather, we have to study new maintenance agents that will allow us to improve the long-term remission. CSA is an induction agent, with universal 80% success in avoiding early colectomy. To date, we have little else to offer, and like all medications its toxicity can be minimized by careful monitoring. The issue is not its long-term efficacy, as that is not its purpose. Development of better maintenance agents will address that issue. Thus, it is Cyclo and not Psychosporine.
- 12Intravenous cyclosporin in ulcerative colitis; a five year experience. Am J Gastroenterol. 1999; 94; 1587–1592., , ,Direct Link: