Cyclosporine was effective for corticosteroid-resistant ulcerative colitis
ACP J Club. 1994 Nov-Dec;121:68. doi:10.7326/ACPJC-1994-121-3-068
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Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994 Jun 30;330:1841-5.
To evaluate the effectiveness and safety of intravenous cyclosporine therapy in improving symptoms in patients with severe ulcerative colitis refractory to steroid therapy.
Randomized, double-blind, placebo-controlled trial with a maximum 14-day follow-up.
2 university hospitals.
20 patients (mean age 39 y, 55% women) hospitalized with severe ulcerative colitis, with no response to intravenous corticosteroids after ≥ 7 days. Exclusion criteria were bacterial or parasitic pathogens in stools, Clostridium difficile toxin, septicemia, perforation of the bowel, active fungal or viral infection, uncontrolled hypertension, mercaptopurine or azathioprine therapy in the previous 2 weeks, elevated serum concentrations of hepatic enzymes, hyperbilirubinemia, renal dysfunction, or a serum cholesterol concentration < 3.1 mmol/L. Follow-up was complete.
11 patients were allocated to continuous intravenous cyclosporine, 4 mg/kg body weight per day, and 9 patients were allocated to an identical-appearing intravenous solution of cremaphor and alcohol.
Main outcome measure
Clinical activity score (a score of 0 indicated no symptoms and a score of 21 indicated severe symptoms) that was determined daily after reviewing the patient's experience with daily diarrhea, nocturnal diarrhea, visible blood in the stool, fecal incontinence, abdominal pain or cramping, general well-being, abdominal tenderness, and the need for antidiarrheal drugs.
9 patients (82%) receiving cyclosporine had an improvement in the clinical activity score within a mean of 7 days compared with 0 patients receiving placebo (P < 0.001). The mean clinical activity score decreased from 13 to 6 in patients receiving cyclosporine and from 14 to 13 in patients receiving placebo. The most frequently noted adverse effects in patients receiving cyclosporine were paresthesias (36%) and hypertension (36%).
Intravenous cyclosporine therapy decreased symptoms in patients with severe ulcerative colitis refractory to steroid therapy.
Source of funding: Not stated.
For article reprint: Dr. S. Lichtiger, 1185 Park Avenue, New York, NY 10128, USA. FAX 212-996-0779.
Cyclosporine, which selectively blocks the activation of T-helper and cytotoxic lymphocytes, has revolutionized organ transplantation and is used to treat several autoimmune disorders. This drug is now being explored as therapy for inflammatory bowel disease. Two well-designed and well-executed double-blind, controlled trials are reported here. An editorial in the same journal is recommended to readers (1).
The study by Lichtiger and colleagues is a continuation of their previously published work suggesting an important role for cyclosporine in the treatment of severe ulcerative colitis refractory to steroid therapy. In this study, the response to intravenous infusion of cyclosporine, 4 mg/kg per day, was rapid and impressive. The response was assessed using a clinical activity score. Patients in the placebo group who were switched to cyclosporine also had important improvement in symptoms. Although not documented in this study, endoscopic and histologic improvement in these patients has been reported by these authors.
On the other hand, Feagan and colleagues, in a well-designed study, have shown the lack of effectiveness of cyclosporine at a low oral dose in patients with Crohn disease. The size of the population enrolled in the study was adequate for statistical analysis and the outcome measures were based on well-accepted parameters used in similar studies. Patients were followed for a period of 18 months, which seems to be adequate to evaluate effectiveness of therapy in a chronic disorder such as Crohn disease. Cyclosporine did not improve symptoms or reduce the requirement for other medications. Interestingly, no relation existed among cyclosporine dose, blood levels, or clinical outcome.
What can clinicians conclude from these studies and what will be the role of cyclosporine in inflammatory bowel disease? Intravenous cyclosporine appears to be effective in the treatment of acute ulcerative colitis. Further studies are needed to establish the value of cyclosporine at a lower dose (2 mg/kg), to assess use of this drug as the initial treatment (rather than use in patients who are unresponsive to corticosteroids), and to provide endoscopic and histologic follow-up for a larger number of patients. If these studies show efficacy, cyclosporine will be the first drug since steroids to be introduced in the last 4 decades for treatment of acute ulcerative colitis.
As for the role of cyclosporine in Crohn disease, the jury is still out. Cyclosporine most likely will not be of wide use in this disease. 1 controlled trial (2) using higher doses of cyclosporine showed a beneficial effect; however, the toxicity associated with higher doses cannot be ignored. The reason for the lack of responsiveness in Crohn disease and especially the worsening of symptoms in most patients treated with cyclosporine, as documented in this study, deserve further investigation, possibly in the laboratory rather than in the clinic. The good news in Crohn disease treatment is, however, the documented effectiveness of other immunosuppressive medications, such as azathioprine and mercaptopurine. Newer delivery systems and a whole new generation of 5-aminosalicylate derivatives could offer new horizons for the treatment of Crohn disease.
As with all other immunosuppressive drugs, the adverse effects of cyclosporine need to be considered. Short-term side effects are well known. More worrisome, though, are the long-term effects of cyclosporine in patients with inflammatory bowel disease. Unfortunately, both ulcerative colitis and Crohn disease may predispose the colon to develop malignancy. What will be the effect of short-term and long-term use of cyclosporine on organs that are already predisposed to develop malignancy? Although cyclosporine has been used in other autoimmune disorders and in transplantation, none of these disorders has the inherent tendency to predispose patients to develop malignancies as does ulcerative colitis. Cyclosporine (or other immunosuppressive drugs) in association with allograft transplantation is thought to be an independent risk factor for some malignancies, but increased cancer of the colon has not been shown. The question of when to use cyclosporine as a primary therapy in inflammatory bowel disease probably will remain unanswered until we have a sufficient number of years of follow-up on a larger number of patients.
Joseph J. Nidiry, MD
Harvard University College of MedicineWashington, D.C., USA