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Symptomatic Exacerbation of Crohn Disease after Treatment with High-Dose Interleukin-2
- Joseph A. Sparano, MD;
- Lawrence J. Brandt, MD;
- Janice P. Dutcher, MD;
- Jon S. Dubois, MD; and
- Michael B. Atkins, MD
- From Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York; New England Medical Center, Boston, Massachusetts. Requests for Reprints: Joseph A. Sparano, MD, Albert Einstein Cancer Center, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467. Acknowledgments: The authors thank Dr. Panna Mahadevia who assisted in reviewing the pathologic material. Grant Support: In part by a grant from the National Institutes of Health (CA P30CA1130) and an American Cancer Society Career Development Award (JAS, 92-274).
Abstract
Two patients treated with high-dose interleukin-2 (IL-2), who had a history of Crohn disease that was clinically quiescent for 4 and 9 years before therapy, developed symptomatic reactivation of Crohn disease requiring surgical intervention. At laparotomy, both patients had histologic evidence of active Crohn disease. One patient had previously received another cytokine, -interferon-, without disease reactivation, suggesting that this effect was specific for IL-2. The striking temporal relation between the administration of IL-2 and the symptomatic reactivation of previously quiescent Crohn disease suggests the need to carefully evaluate patients with a history of inflammatory bowel disease who are considered for IL-2 therapy and provides evidence supporting an important role for IL-2 in the pathogenesis of Crohn disease.
Treatment with interleukin-2 (IL-2) results in objective tumor regression in approximately 15% of patients with advanced renal cell carcinoma when administered in a high-dose schedule (which was associated with toxicity requiring intensive-care unit support) [1, 2] and was recently approved for this indication. Gastrointestinal toxicity complicating therapy includes nausea, vomiting, and diarrhea in most patients; colonic perforation or ischemia or both occur rarely [3, 4]. Of the more than 300 patients whom we have treated with IL-2, only 2 patients had a history of Crohn disease and both developed an apparent exacerbation of the disease during treatment with IL-2. Our report is the first to show that administration of IL-2 may produce a symptomatic exacerbation of Crohn disease and to suggest an important role for IL-2 in the pathogenesis of Crohn disease.
Patient 1
A 66-year-old man with advanced renal cell carcinoma that had progressed during a 1-month trial of -interferon therapy (6 106 IU given subcutaneously three times weekly) received IL-2 (Aldesleukin, Chiron Corporation, Emeryville, California) 18 106 IU/m2 per day, using a continuous intravenous infusion for 5 days. The patient had a history of Crohn disease for 13 years, complicated by an ileal-sigmoid fistula that occurred 9 years earlier. No symptoms related to Crohn disease or its treatments occurred in the 9 years before IL-2 therapy. On the fifth and last day of IL-2 treatment, abdominal distention developed. Roentgenographic examination of the abdomen showed dilated loops of large and small bowel, sigmoidoscopy showed a polypoid mass in the sigmoid, and barium enema showed a mass lesion in the sigmoid colon as well as fistulization to the ileum. After exploratory laparotomy, an inflammatory mass of the sigmoid was found with a large patent ileal-sigmoid fistula requiring en-bloc resection. Pathologic examination of the specimen showed findings consistent with active Crohn disease (Figure 1). The patient had no further symptoms of Crohn disease and died 1 year later from progressive renal cell carcinoma.
Patient 2
A 52-year-old man with metastatic renal cell carcinoma received IL-2 (6 105 IU/kg every 8 hours) on days 1 to 5 and 16 to 20. He had a 23-year history of Crohn disease and had required small-bowel resections 10 and 9 years earlier, as well as stricturoplasty of an ileal stricture 4 years earlier. No symptoms related to Crohn disease or related treatments occurred in the 4 years before IL-2 therapy. On day 20, after the 17th dose of IL-2 had been given, exploratory laparotomy was done emergently after signs of peritonitis developed. At laparotomy, we found a closed-loop obstruction involving a middle segment of the jejunum and found cloudy peritoneal fluid suggesting perforation. A small-bowel resection was done, and pathologic examination showed active granulomatous ileitis with surface ulcerations, rare granulomata, transmural inflammation, and areas of obstruction. These findings were consistent with active Crohn disease.
Discussion
Evidence suggesting altered immunity in the pathogenesis of Crohn disease includes the lymphocytic nature of the inflammatory infiltrate, the frequent association with extraintestinal complications, its responsiveness to a variety of immunosuppressive agents, and the recent report [5] of disease remission associated with the onset of the acquired immunodeficiency syndrome and its attendant immunosuppression.
Interleukin-2, a glycoprotein produced by activated T lymphocytes, has broad effects on host immunity that include enhancement of T- and B-cell function as well as stimulation of secondary cytokine production [6]. Intestinal mononuclear cells from patients with Crohn disease may be more sensitive to the immunoenhancing effects of IL-2 [7]. Furthermore, patients with active Crohn disease have elevated serum IL-2 and soluble IL-2-receptor concentrations (P < 0.05) Additionally, patients with active disease who respond to cyclosporin therapy are more likely to have decreases (P < 0.05) in serum IL-2 and soluble IL-2-receptor levels than are cyclosporin-refractory patients [8]. Although these observations do not prove a critical role for IL-2 in the pathogenesis of Crohn disease, they do provide an explanation for why exogenously administered IL-2 might produce a disease flare.
Interleukin-2 produces a capillary-leak syndrome characterized clinically by edema, weight gain, ascites, and pleural effusions [1, 2]. Furthermore, IL-2 enhances capillary permeability twofold in the intestine in an in vivo model [9]. Pretreatment with irradiation, cyclophosphamide, or corticosteroids in this model, however, eliminates vascular leakage, showing the importance of lymphocytes or lymphocyte-derived secondary cytokines in mediating this effect. Thus, the development of edema in a chronically strictured or fistulized segment of bowel may also have contributed to the onset of symptoms in our patients.
Our data provide some support for an important role for IL-2 in the pathogenesis of Crohn disease and suggest that Crohn disease should be considered a contraindication for IL-2 therapy.
- Copyright 2004 by the American College of Physicians
