Intravenous Iron and Erythropoietin for Anemia Associated with Crohn Disease

The cause of Crohn disease is still unclear, and therapeutic interventions for this condition are therefore designed to alleviate symptoms and improve quality of life [1]. Along with diarrhea and abdominal pain, anemia is an important symptom of Croh... show more

The cause of Crohn disease is still unclear, and therapeutic interventions for this condition are therefore designed to alleviate symptoms and improve quality of life [1]. Along with diarrhea and abdominal pain, anemia is an important symptom of Crohn disease. It occurs in about one third of patients; in approximately 15% of patients, it is severe (hemoglobin concentration 10.5 g/dL [to convert g/dL to g/L, multiply by 10]). It is associated with a decrease in quality of life and an increase in rates of hospitalization and death [2, 3], which suggests that it should be effectively treated. Anemia in patients with Crohn disease results primarily from iron deficiency due to chronic intestinal blood loss [4]. Furthermore, intestinal inflammation is mediated by overproduction of cytokines (including interferon-, interleukin-1, or tumor necrosis factor-) [5, 6], which may contribute to the generation of the anemia of chronic disease [7], accompanied by inadequate erythropoietin production [4]. Since it was first used in chronic renal failure [8], recombinant human erythropoietin has been shown to be effective for treating the anemia that accompanies several chronic diseases [9]. After it was used successfully in three selected cases of anemia associated with inflammatory bowel disease [10], recombinant human erythropoietin was studied in a controlled trial of patients with anemia refractory to oral iron treatment [11]. The therapeutic effectiveness of erythropoietin, however, was limited by concomitant iron deficiency. Because erythropoietin therapy is costly, its therapeutic potency should be maximized. Our primary objective was to test the efficacy of intravenous iron alone and supplemented with erythropoietin for the treatment of anemia associated with Crohn disease. A second objective was to investigate the effect of the treatment of anemia on quality of life. Methods Patients Forty patients with Crohn disease and severe anemia (hemoglobin concentration 10.5 g/dL) were randomly assigned to receive erythropoietin or placebo after giving informed consent. All patients had been unresponsive to oral iron therapy (100 mg/d) for at least 2 months (n = 14) or had been unable to tolerate oral iron therapy because of gastrointestinal side effects (n = 26). Patients who were younger than 18 years of age; who were unable to comply with the protocol; who needed surgery; or who had recently had myelosuppressive or immunosuppressive therapy, cancer, hemolysis, deficiencies in folic acid or cobalamin, creatinine concentrations greater than 2 mg/dL (152 mol/L), hypertension, thrombosis, or iron overload were excluded. The protocol was approved by the local ethics committee of our faculty. Study Design Blinded Phase Patients were randomly assigned to receive erythropoietin or placebo in a 1:1 ratio using the minimization method described by White and Freedman [12]. This method was used to balance the two study groups for the following prognostic variables: hemoglobin concentration (group boundary, 9.0 g/dL), Crohn's disease activity index (group boundary, 200 points), and sex. Individual allocations to treatment group were done at a central location in a blinded manner. All patients received iron saccharate as an intravenous infusion for 16 weeks. During the first 8 weeks, all patients received either erythropoietin or placebo in a double-blind manner. A response was defined as an increase in hemoglobin concentration of 2 g/dL or more within 8 weeks. Treatment was stopped early in patients who reached a hemoglobin concentration greater than 14.0 g/dL before the end of the blinded phase. Open Phase During the second 8 weeks of the study (the open-label phase), the erythropoietin dose was increased in nonresponders in the erythropoietin group and erythropoietin therapy was started in nonresponders in the placebo group. All patients continued to receive intravenous iron saccharate. Laboratory data on hemoglobin concentration (normal value, 14 to 18 g/dL for men, 12 to 16 g/dL for women), reticulocyte count (normal, 0.5% to 2.0%), transferrin level (normal, 2.00 to 3.80 g/L), transferrin saturation (normal, 16% to 45%), ferritin level (normal, 55 to 440 g/L), and C-reactive protein level (normal, < 0.5 mg/dL) were obtained every second week. The Crohn's disease activity index (a composite of 8 items: number of liquid or very soft stools, abdominal pain, general well-being, extraintestinal manifestations, use of opiates, abdominal mass, hematocrit, and body weight [range, 0 to >500 points (no upper limit), with 200 points indicating active disease]) [13] was also assessed every second week. Serum concentrations of erythropoietin (normal value, 5 to 29 mU/mL) were analyzed at study entry by using radioimmunoassay (Incstar, Stillwater, Minnesota) [14]. Quality of life was determined at study entry, after the blinded phase, and at the end of the open phase by using a previously validated questionnaire that contained nine items (feeling of well-being, mood, level of activity, pain, nausea, appetite, physical ability, social activities, and anxiety [range, 9 to 45 points, 45 indicating lowest quality of life]) [15]. Medication Ten milliliters of iron saccharate, corresponding to 200 mg Fe3+ (Ferrum Hausmann, Vifor AG, St. Gallen, Switzerland), diluted in 250 mL of 0.9% sodium chloride solution, was given intravenously to all patients throughout the trial. Infusions were given twice weekly during the first 2 weeks and once weekly thereafter until the end of the trial. To avoid iron overload, iron supplementation was withheld when transferrin saturation exceeded 50% and was restarted when saturation decreased to less than 30%. In the blinded phase, 150 IU of erythropoietin per kg of body weight (Erypo, Janssen & Cilag Pharma, Vienna, Austria) or placebo were injected subcutaneously three times a week by each participant. The drug and the placebo were similar in appearance and were supplied in vials that contained a w show less