Patient 1

A 66-year-old man with advanced renal cell carcinoma that had progressed during a 1-month trial of -interferon therapy (6 x 10⁶ IU given subcutaneously three times weekly) received IL-2 (Aldesleukin, Chiron Corporation, Emeryville, California) 18 x 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.

View larger version (191K): [in this window] [in a new window]   Figure 1. Sigmoid colon. Photoµgraph of the sigmoid colon showing a deep-fissure ulcer (long arrows) lined by granulation tissue (short open arrow) (original magnification, x 10).

Patient 2

A 52-year-old man with metastatic renal cell carcinoma received IL-2 (6 x 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

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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.