Low-dose cyclosporine did not improve symptoms in Crohn disease
ACP J Club. 1994 Nov-Dec;121:69. doi:10.7326/ACPJC-1994-121-3-069
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Feagan BG, McDonald JW, Rochon J, et al. Low-dose cyclosporine for the treatment of Crohn's disease. N Engl J Med. 1994 Jun 30;330:1846-51.
To evaluate the long-term effectiveness and safety of low-dose cyclosporine in improving symptoms in patients with Crohn disease.
Randomized, double-blind, placebo-controlled trial with 18-month follow-up.
7 university-affiliated hospitals in Canada.
305 patients (mean age 33 y, 50% men) with active Crohn disease in the previous 2 years. Exclusion criteria were previous neoplasia, serious medical problems, creatinine clearance < 78 µmol/min, continuous use of anti-inflammatory drugs, hypertension, or diabetes mellitus. No patients were lost to follow-up.
151 patients were allocated to oral cyclosporine at an initial daily dose of 2.5 mg/kg body weight with a dose increase to 5 mg after 1 week. Thereafter, the dose was increased to a maximal daily dose of 15 mg/kg in order to attain a whole-blood trough concentration of 200 ng/mL. 154 patients were allocated to placebo capsules. All patients continued to receive their usual therapy for Crohn disease.
Main outcome measures
Clinically important worsening of Crohn disease, defined as a 100-point increase in the Crohn's Disease Activity Index; use of prednisone and 5-aminosalicylates mean quality-of-life score; and the need for surgery.
91 patients (60%) receiving cyclosporine had worsening of disease compared with 80 patients (52%) receiving placebo (P = 0.10) (Table). The mean time to the worsening of the disease was 338 days in the cyclosporine group and 492 days in the placebo group. No differences were shown for overall mean scores on the Crohn's Disease Activity Index (P = 0.31), mean quality-of-life scores (P = 0.49), and the use of prednisone and 5-aminosalicylates. Similar numbers of patients in the cyclosporine and placebo groups had surgery (25 vs 24). The most common adverse effects in the cyclosporine group were paresthesias, headaches, and hypertrichosis.
The addition of low-dose cyclosporine to usual treatment for Crohn disease did not improve symptoms or reduce the need for other forms of therapy.
Sources of funding: Sandoz Pharma, Quebec, Canada, and Medical Research Council of Canada.
For article reprint: Dr. B.G. Feagan, 6 OF 11 University Hospital, 339 Windermere Road, London, Ontario, N6A 5A5, Canada. FAX 519-663-2917.
Table. Low-dose cyclosporine vs placebo in active Crohn disease*
|Outcome at 18 mo||Low-dose cyclosporine||Placebo||RRI (95% CI)||NNH|
|Worsening of disease||60%||52%||16% (-5 to 42)||Not significant|
*Abbreviations defined in Glossary; RRI, NNH, and CI calculated from data in article.
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