Original Article
Recombinant Erythropoietin for the Treatment of Anemia in Inflammatory Bowel Disease
N Engl J Med 1996; 334:619-624March 7, 1996
- Abstract
Background
Some patients with inflammatory bowel disease have anemia that is refractory to treatment with iron and vitamins. We examined whether administering iron and recombinant erythropoietin could raise hemoglobin levels in such patients.
Methods
Thirty-four patients with inflammatory bowel disease (15 with ulcerative colitis and 19 with Crohn's disease) and anemia refractory to iron therapy (hemoglobin concentrations below 10.0 g per deciliter [6.2 mmol per liter]) were randomly assigned in a prospective, double-blind, 12-week trial to receive either oral iron (100 mg per day) and subcutaneous erythropoietin (150 U per kilogram of body weight twice per week) (n = 17) or oral iron and placebo (n = 17). The primary measure of efficacy was an increase in hemoglobin levels of more than 1.0 g per deciliter (0.62 mmol per liter). Additional analyses were performed with other patients with inflammatory bowel disease.
Results
The severity of anemia was related to clinical disease activity as well as to in vitro monocyte secretion of interleukin-1β, a proinflammatory cytokine. Serum erythropoietin concentrations were increased in 52 randomly selected outpatients with inflammatory bowel disease and anemia, but the concentrations were inadequate in relation to the degree of anemia. Twelve weeks of therapy with recombinant erythropoietin and oral iron increased mean (±SE) hemoglobin concentrations from 8.81±0.27 g per deciliter (5.47±0.17 mmol per liter) to 10.52±0.41 g per deciliter (6.5±0.25 mmol per liter), whereas hemoglobin concentrations in the placebo group decreased from 8.69±0.11 g per deciliter (5.4±0.068 mmol per liter) to 7.84±0.33 g per deciliter (4.9±0.2 mmol per liter) (P<0.001). After 12 weeks, hemoglobin levels had increased by more than 1.0 g per deciliter in 82 percent of the patients in the erythropoietin group, as compared with 24 percent of those in the placebo group (P = 0.002). There were five treatment failures in the placebo group and two in the erythropoietin group (P = 0.18); treatment failure was defined as a decrease in hemoglobin levels of more than 2.0 g per deciliter (1.24 mmol per liter) to a value below 8.0 g per deciliter (4.96 mmol per liter) or any decrease to less than 6.5 g per deciliter (4.03 mmol per liter).
Conclusions
In patients with inflammatory bowel disease and anemia refractory to treatment with iron and vitamins, treatment with oral iron and recombinant erythropoietin can raise hemoglobin levels.
Media in This Article
Figure 3
Kaplan–Meier Analysis of Treatment Success.Figure 2
Relation of the Log Serum Erythropoietin Concentration to the Hematocrit.Article Activity
- Article
Some patients with inflammatory bowel disease have anemia that is refractory to treatment with iron and vitamins. A lack of erythropoietin may be important in the pathophysiology of anemia associated with inflammation,1,2 if deficiencies in iron, cobalamin, and folic acid have been ruled out.
Erythropoietin is the primary growth factor regulating the proliferation and maturation of erythroid precursor cells.3 Proinflammatory cytokines, including interleukin-1β, tumor necrosis factor α, and interferon γ, are produced in increased amounts by peripheral-blood monocytes and mononuclear cells of the intestinal lamina propria in patients with inflammatory bowel disease.4-7 Such cytokines can contribute to the development of anemia by inducing a relative deficiency of erythropoietin as well as a resistance to erythropoietin on the part of erythroid precursor cells in various in vitro and in vivo models.8-11 In these models, administering erythropoietin could reverse most of the suppression related to proinflammatory cytokines of cell maturation of the erythroid lineage.8-10 The use of recombinant erythropoietin (epoetin) to treat anemia in chronic rheumatoid arthritis as well as anemia associated with malignant disease has been suggested.8,11
We studied patients with inflammatory bowel disease who had chronic anemia refractory to oral iron therapy and evaluated treatment with erythropoietin in a double-blind, prospective, randomized trial.
Methods
The prevalence of anemia in patients with inflammatory bowel disease who were referred to the University of Hamburg was analyzed between January 1990 and December 1992 with regard to disease characteristics, the secretion of proinflammatory cytokines, and erythropoietin levels. Patients with “treatment-refractory anemia,” as assessed by their physicians, were selected. Sustained nonresponsiveness to iron was verified in a six-week preliminary phase. Eligible patients whose anemia was refractory to orally administered iron were randomly assigned to receive subcutaneous injections of recombinant erythropoietin or placebo during a 12-week trial. Written informed consent was obtained from each patient. The trial was reviewed by the ethics committee of the University of Hamburg.
Preliminary Phase and Randomization
Patients with confirmed diagnoses of Crohn's disease or ulcerative colitis who had refractory anemia were referred for possible erythropoietin treatment. Criteria for exclusion from the study were the use of immunosuppressive agents during the previous four months, arterial hypertension resistant to therapy, pregnancy or lactation, impaired renal function (serum creatinine levels above 1.2 mg per deciliter [106.1 μmol per liter]), obvious need for surgery (as indicated by the severity of disease and of complications), and anemia from other causes (abnormal erythrocyte morphology or severe iron deficiency [e.g., due to intestinal blood loss or associated with ferritin levels of <20 ng per milliliter in women and <30 ng per milliliter in men]). Vitamin deficiency was ruled out by examination of the erythroid morphology and assessment of serum levels of folic acid and cobalamin. A medically approved plan of contraception was required for all menstruating women. Patients with a history of anemia and hemoglobin levels below 10.0 g per deciliter (6.2 mmol per liter) were enrolled in a six-week preliminary phase in which they received oral iron (at least 100 mg per day). Patients were seen at least once a week.
Only the 34 patients (15 with ulcerative colitis and 19 with Crohn's disease) with hemoglobin levels of <10.0 g per deciliter (6.2 mmol per liter) throughout the preliminary phase were randomized. Seventeen received erythropoietin (150 U per kilogram of body weight administered subcutaneously twice a week [Erypo, Cilag, Sulzbach, Germany]), and 17 received placebo (Table 1Table 1
Base-Line Characteristics and Conditions of the 34 Patients.). Concomitant treatment with iron (100 mg per day [Ferrosanol-duodenal, Sanol, Monheim, Germany]) was required. Antiinflammatory treatment (with corticosteroids or aminosalicylates) was administered according to the severity and site of disease. Groups were similar in age, sex, duration of disease, disease manifestation, duration of present remission, antiinflammatory regimens, and previous treatment. The original trial design included a crossover into a second 12-week treatment period. However, because of a strong carryover effect (most of the patients in the erythropoietin group had already responded), the second period was dropped.Study Protocol
At the initial visit, a medical history was taken for each patient and a physical examination and stool examination for ova, parasites, and enteric pathogens were carried out. Blood was drawn for the assessment of electrolytes, protein, albumin, glucose, liver enzymes, amylase, creatinine, urea, erythropoietin, serum iron, ferritin, and in vitro monocyte secretion of interleukin-1β, and to determine the differential blood count. The physical examination and routine laboratory assessment were repeated weekly. After six weeks, the serum concentrations of erythropoietin, iron, and ferritin were assessed and the studies from the initial visit repeated.
Patients kept daily diaries in which they recorded the occurrence of specific symptoms used to calculate the Crohn's Disease Activity Index12,13 or the Clinical Colitis Activity Index.14 The Crohn's Disease Activity Index provides a calculated composite score that incorporates eight items: the number of liquid or very soft stools, the degree of general well-being, the degree of abdominal pain, the size of any abdominal mass, the hematocrit, body weight, extraintestinal manifestations, and the use of opiate-receptor–stimulating drugs for the control of diarrhea. Higher scores indicate more disease activity. Patients with a score below 150 are considered to be in clinical remission. Scores above 450 reflect severe active Crohn's disease. The Clinical Colitis Activity Index14 incorporates seven clinical items: the number of stools, whether there is blood in the stools, an investigator's global assessment of the patient's symptomatic state, increased body temperature due to colitis, the degree of abdominal pain, the presence of extraintestinal manifestations, and the erythrocyte sedimentation rate. Patients with a Clinical Colitis Activity Index of 4 or less (on a scale of 0 to 16) are considered to be in remission.14
Serum erythropoietin levels were measured in frozen serum samples (-80°C) by a commercial radioimmunoassay (Bio-Merieux, Nörtingen, Germany). The lower limit of sensitivity was 4 U per milliliter. The amount of immunoreactive erythropoietin determined by the radioimmunoassay correlates with biologic activity as assessed by the polycythemic-mouse bioassay.15,16
To assess the immunologic activity of the disease, peripheral-blood mononuclear cells were isolated by density-gradient centrifugation over Ficoll–Hypaque (Pharmacia, Freiburg, Germany),17 and monocytes were purified by substrate adherence.7,18 Viability was more than 96 percent, and the cell suspension contained more than 97 percent monocytes. Monocytes were cultured at a concentration of 50,000 cells per milliliter in the presence of pokeweed mitogen (1 percent vol/vol),7,18 and supernatants were collected after 24 hours. Concentrations of interleukin-1β were assessed with the use of a specific sandwich enzyme-linked immunosorbent assay (DPC/Biermann, Bad Nauheim, Germany).7,18 All samples were analyzed in triplicate.
End Points and Measures of Efficacy
The primary measure of efficacy was an increase in hemoglobin levels by more than 1.0 g per deciliter (0.62 mmol per liter). End points were the completion of the 12-week treatment protocol and treatment failure — defined as a drop in the hemoglobin level of more than 2.0 g per deciliter (1.24 mmol per liter) to a value below 8.0 g per deciliter (4.96 mmol per liter), or any drop in hemoglobin to less than 6.5 g per deciliter (4.03 mmol per liter); the latter also indicated the need for transfusion. Criteria for withdrawal from the study were severe reactions at the injection site, major surgery, hemoglobin levels of 14.0 g per deciliter (8.69 mmol per liter) or higher, signs of hemolysis, intestinal blood loss leading to hospital admission, gastrointestinal ulcer disease, and withdrawal of consent. If 12 weeks of treatment were not completed, patients underwent the 12-week study-termination examination early.
Statistical Analysis
Normality was tested by the Shapiro–Wilk's W test.19 The Student t-test was used to evaluate differences in hemoglobin values between the treatment groups, and Welch's unpaired t-test was used to compare serum erythropoietin concentrations. Differences in levels of cytokine secretion between the groups were tested with the Mann–Whitney U test. Treatment success (during the preliminary phase and erythropoietin treatment) was evaluated with the use of Kaplan–Meier statistics in life-table analyses, and differences were tested for statistical significance with the log-rank test.20
Results
Patient Group
Clinical and laboratory data on all outpatients with inflammatory bowel disease were reviewed. Of 334 patients with Crohn's disease, 88 were anemic (26 percent), with hemoglobin levels of <10.0 g per deciliter. Patients with anemia had greater clinical disease activity than those who were not anemic (Crohn's Disease Activity Index, 207±27 vs. 137±22; P = 0.02). Findings in 342 patients with ulcerative colitis were similar: 126 were anemic (37 percent) and had greater disease activity than the patients without anemia (mean [±SE] Clinical Colitis Activity Index, 8.7±2.1 vs. 3.7±1.8; P = 0.04). Ninety-one patients (34 with Crohn's disease and 57 with ulcerative colitis) entered the preliminary phase designed to identify patients with anemia refractory to sustained iron therapy. Of the remaining patients with anemia, 64 were not classified by their physicians as having anemia that was difficult to treat, 15 were not willing to participate, and 44 were excluded for other reasons (31 had used immunosuppressive drugs within the previous four months, 5 needed surgical treatment, 3 had suspected iron deficiency, 2 had impaired renal function, 2 lacked an approved method of contraception, and 1 had arterial hypertension).
Hemoglobin Levels and Immunologic-Disease Activity
In vitro monocyte secretion of interleukin-1β was assessed in 22 patients with anemia who had been randomly selected during the preliminary phase. Secretion was related to hemoglobin levels (Figure 1Figure 1
Relation of in Vitro Monocyte Secretion of Interleukin-1β to Hemoglobin Concentrations in 22 Patients with Inflammatory Bowel Disease and in Healthy Volunteers.). If patients were arbitrarily grouped according to the severity of their anemia, monocytes from 11 patients with severe anemia (hemoglobin level, <9.0 g per deciliter [5.59 mmol per liter]) had higher levels of in vitro secretion of interleukin-1β (median, 132 pg per milliliter; range, 24 to 280) than those from 11 patients with mild anemia (hemoglobin level, 9.0 to 10.0 g per deciliter) (median interleukin-1β concentration, 62 pg per milliliter; range, 22 to 174; P = 0.012) (Figure 1). Monocytes from 10 healthy volunteers had a median secretion of interleukin-1β of 37.5 pg per milliliter (range, 0 to 87), which was lower than for the patients with anemia associated with inflammatory bowel disease (P = 0.007).Serum Erythropoietin Levels in Patients with Inflammatory Bowel Disease and Anemia
Serum erythropoietin levels were assessed in 52 randomly selected outpatients with inflammatory bowel disease (34 had Crohn's disease and 18 had ulcerative colitis). The 18 patients with anemia associated with inflammatory bowel disease had higher serum erythropoietin levels (40.4±7.17 U per milliliter) than the 34 patients with inflammatory bowel disease without anemia (21.1±1.3 U per milliliter; P = 0.002) or 24 normal controls (13.7±1.2 U per milliliter; P = 0.002).
In models designed to test whether serum erythropoietin concentrations were adequate in relation to the degree of anemia, a linear regression was calculated between the logarithms of serum erythropoietin concentrations and the corresponding hematocrits.21 The slope of the grade relates serum erythropoietin levels to the degree of anemia. We performed a linear regression analysis, including data on the 52 randomly selected patients with inflammatory bowel disease (with and without anemia) and, to permit definition of the normal response over a range of hematocrits, data on 24 healthy volunteers and 18 patients with anemia for reasons other than inflammation (e.g., blood loss following trauma or surgery) (Figure 2Figure 2
Relation of the Log Serum Erythropoietin Concentration to the Hematocrit.). The slope for the control population (log erythropoietin = 3.446 - 0.0522 × hematocrit;r = -0.88; P<0.001) was in the same range as has been described elsewhere.21 The slope for patients with inflammatory bowel disease (log erythropoietin = 2.233 - 0.0255 × hematocrit; r = -0.61; P = 0.007) was lower than for the controls without inflammatory bowel disease (P = 0.03). Although anemia in inflammatory bowel disease is associated with increased erythropoietin levels, these levels were not as high as in patients with anemia of equal severity from noninflammatory conditions.Erythropoietin Treatment of Patients with Anemia and Inflammatory Bowel Disease
Anemia refractory to the sustained iron treatment used during the preliminary selection phase of the study was more frequent (P = 0.007) in patients with Crohn's disease (19 of 34, 56 percent) than in those with ulcerative colitis (15 of 57, 26 percent). The base-line characteristics of the 34 patients who were randomized are shown in Table 1.
Hemoglobin levels in the 17 patients treated with erythropoietin increased from 8.81±0.27 g per deciliter (5.47±0.17 mmol per liter) to 10.52±0.41 g per deciliter (6.5±0.25 mmol per liter); hemoglobin concentrations in the 17 patients in the placebo group decreased from 8.69±0.11 g per deciliter (5.4±0.068 mmol per liter) to 7.84±0.33 g per deciliter (4.9±0.2 mmol per liter). Hemoglobin levels increased by 1.71±0.43 g per deciliter (1.06±0.27 mmol per liter) in the patients treated with erythropoietin, as compared with a decrease of 0.85±0.29 g per deciliter (0.53±0.18 mmol per liter) in the placebo group (P<0.001) (Table 2Table 2
Hemoglobin Levels.). A Kaplan–Meier analysis of treatment success is shown in Figure 3Figure 3Kaplan–Meier Analysis of Treatment Success.. Treatment with erythropoietin and iron was better than treatment with placebo and iron (rate of treatment success at day 84, 82 percent vs. 24 percent; P = 0.002). In the erythropoietin group, serum erythropoietin levels increased over the 12-week period by 22.4±8.1 U per milliliter, as compared with an increase of 7.1±7.4 U per milliliter in the placebo group (P = 0.17).During the trial, there were five treatment failures in the placebo group and two in the erythropoietin group (P = 0.18).
Predictors of Response to Erythropoietin
Age, sex, corticosteroid use, clinical activity, site of disease, and serum concentrations of erythropoietin, ferritin, and C-reactive protein did not predict the response to erythropoietin (data not shown). We investigated whether the proinflammatory activity of monocytes from patients with inflammatory bowel disease predicted the response to erythropoietin in vivo. Monocyte secretion of interleukin-1β correlated inversely (r = -0.62) with changes in hemoglobin levels during 12 weeks of erythropoietin treatment (P = 0.07). Both of the patients in the erythropoietin group who did not respond to treatment had high proinflammatory activity (monocyte-supernatant interleukin-1β concentrations, 137 and 187 pg per milliliter; normal range, 0 to 87).
Discussion
The development of anemia in patients with chronic disease caused by an impairment of iron use has been attributed in animal models8-10 and in people22 to a relative deficiency of erythropoietin. An enhanced production of proinflammatory mediators, including interleukin-1β, tumor necrosis factor α, and interferon γ, which may inhibit both the production of erythropoietin and the stimulatory effect of erythropoietin on the proliferation and maturation of erythroid precursors, may be an underlying pathophysiologic mechanism.23
We confirmed that serum erythropoietin levels in patients with a history of chronic anemia in inflammatory bowel disease, although higher than normal, are lower than in patients with anemia from noninflammatory disorders and are inadequate for the degree of anemia.1,2 A relative deficiency of erythropoietin, despite normal renal function, may contribute to the development of chronic anemia in patients with inflammatory bowel disease.
We also demonstrated an association between the degree of anemia in inflammatory bowel disease and both clinical disease activity and in vitro proinflammatory-cytokine (interleukin-1β) production by monocytes, which is increased during acute intestinal inflammation.4-7 We suggest the applicability of findings in animal models, which delineate clinical inflammation and proinflammatory-cytokine activity as key factors in the pathophysiology of anemia in chronic diseases, to the pathophysiology of iron-resistant anemia in inflammatory bowel disease.
We studied whether substitution treatment with recombinant erythropoietin may be beneficial for patients with anemia associated with inflammatory bowel disease and refractory to iron therapy. We found that subcutaneous administration of pharmacologic doses24 of erythropoietin twice a week, concomitantly with oral iron, increased hemoglobin concentrations in such patients, whereas there was a decrease in the placebo group, which received oral iron only.
Our analysis of the response to erythropoietin treatment and the proinflammatory activity of monocytes from patients with inflammatory bowel disease supports the initial hypothesis that proinflammatory cytokines may have a pivotal role in the development of anemia refractory to therapy in patients with inflammatory bowel disease: an inverse relation was seen between high proinflammatory activity (secretion of interleukin-1β by peripheral-blood monocytes) and the response to erythropoietin therapy. Moreover, both of the patients who failed to respond to erythropoietin were among those with high proinflammatory activity. It is possible that in some patients an impaired response to erythropoietin may be overcome by increasing the dosage.
Our results suggest that recombinant erythropoietin, in conjunction with oral iron, may be of use in patients with active inflammatory bowel disease and severe anemia refractory to iron therapy. It is important to determine whether the response to recombinant erythropoietin is dose-dependent. The possible role of proinflammatory mediators as modulators of the erythropoietin response should be characterized. Simultaneous assessment of total body iron and iron use should help determine the optimal dose and formulation of iron supplementation during erythropoietin treatment.
Presented in part at the 94th and the 95th annual meetings of the American Gastroenterological Association, Boston, May 16–18, 1993, and New Orleans, May 15–17, 1994.
Supported in part by a grant (DFG SCH 512/1-2) from the Deutsche Forschungsgemeinschaft (to Dr. Schreiber).
We are indebted to Dr. Dieter Begemann from Cilag (Germany) for assistance and advice, and to A. Bouchard, U. Panzer, and R. Reinking for determining levels of proinflammatory cytokines in supernatants of cultures of peripheral-blood monocytes.
Source Information
From the Department of Medicine, University of Hamburg, Hamburg, Germany (S.S., S.H., M.S., A.R.); the Fourth Department of Medicine, Charité, Humboldt University, Berlin, Germany (S.S., S.N., J.B., H.L.); and the Fourth Medical Department, University of Vienna, Vienna, Austria (C.G.).
Address reprint requests to Dr. Schreiber at the Charité University Hospital, Fourth Department of Medicine, Schumannstrasse 20/21, 10117 Berlin, Germany.
- References
References
1
Johannsen H ,Jelkmann W ,Wiedemann G ,Otte M ,Wagner T . Erythropoietin/haemoglobulin relationship in leukaemia and ulcerative colitis. Eur J Haematol 1989;43:201-206
CrossRef | Web of Science | Medline2
Horina JH ,Petritsch W ,Schmid CR , et al. Treatment of anemia in inflammatory bowel disease with recombinant human erythropoietin: results in three patients. Gastroenterology 1993;104:1828-1831
Web of Science | Medline3
Eschbach JW ,Adamson JW . Guidelines for recombinant human erythropoietin therapy. Am J Kidney Dis 1989;14:Suppl 1:2-8
Web of Science | Medline4
Mahida YR ,Wu K ,Jewell DP . Enhanced production of interleukin 1-β by mononuclear cells isolated from mucosa with active ulcerative colitis of Crohn's disease. Gut 1989;30:835-838
CrossRef | Web of Science | Medline5
Ligumsky M ,Simon PL ,Karmeli F ,Rachmilewitz D . Role of interleukin 1 in inflammatory bowel disease -- enhanced production during active disease. Gut 1990;31:686-689
CrossRef | Web of Science | Medline6
MacDonald TT ,Hutchings P ,Choy MY ,Murch S ,Cooke A . Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine. Clin Exp Immunol 1990;81:301-305
CrossRef | Web of Science | Medline7
Reinecker H-C ,Steffen M ,Witthoeft T , et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol 1993;94:174-181
CrossRef | Web of Science | Medline8
Means RT Jr ,Krantz SB . Inhibition of human erythroid colony-forming units by gamma interferon can be corrected by recombinant human erythropoietin. Blood 1991;78:2564-2567
Web of Science | Medline9
Faquin WC ,Schneider TJ ,Goldberg MA . Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood 1992;79:1987-1994
Web of Science | Medline10
Smith MA ,Knight SM ,Maddison PJ ,Smith JG . Anaemia of chronic disease in rheumatoid arthritis: effect of the blunted response to erythropoietin and of interleukin 1 production by marrow macrophages. Ann Rheum Dis 1992;51:753-757
CrossRef | Web of Science | Medline11
Henry DH . Changing patterns of care in the management of anemia. Semin Oncol 1992;19:Suppl 8:3-7
Web of Science | Medline12
Best WR ,Becktel JM ,Singleton JW ,Kern F Jr . Development of a Crohn's disease activity index: National Cooperative Crohn's Disease Study. Gastroenterology 1976;70:439-444
Web of Science | Medline13
Best WR ,Becktel JM ,Singleton JW . Rederived values of the eight coefficients of the Crohn's Disease Activity Index (CDAI). Gastroenterology 1979;77:843-846
Web of Science | Medline14
Rachmilewitz D . Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ 1989;298:82-86
CrossRef | Web of Science | Medline15
Schlageter MH ,Toubert ME ,Podgorniak MP ,Najean Y . Radioimmunoassay of erythropoietin: analytical performance and clinical use in hematology. Clin Chem 1990;36:1731-1735
Web of Science | Medline16
Cotes PM . Immunoreactive erythropoietin in serum. I. Evidence for the validity of the assay method and the physiological relevance of estimates. Br J Haematol 1982;50:427-438
CrossRef | Web of Science | Medline17
Boyum A . Isolation of mononuclear cells and granulocytes from human blood: isolation of mononuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl 1968;97:77-89
Medline18
Schreiber S ,Heinig T ,Panzer U , et al. Impaired response of activated mononuclear phagocytes to interleukin 4 in inflammatory bowel disease. Gastroenterology 1995;108:21-33
CrossRef | Web of Science | Medline19
Shapiro SS ,Wilk MB ,Chen HJ . Comparative study of various tests of normality. J Am Stat Assoc 1968;63:1343-1372
CrossRef | Web of Science20
Sachs L. Angewandte Statistik. 7th ed. Heidelberg, Germany: Springer-Verlag, 1992.
21
Cazzola M ,Bequin Y . New tools for clinical evaluation of erythron function in man. Br J Haematol 1992;80:278-284
CrossRef | Web of Science | Medline22
Erslev AJ ,Caro J ,Miller O ,Silver R . Plasma erythropoietin in health and disease. Ann Clin Lab Sci 1980;10:250-257
Web of Science | Medline23
Fuchs D ,Hausen A ,Reibnegger G , et al. Immune activation and the anaemia associated with chronic inflammatory disorders. Eur J Haematol 1991;46:65-70
CrossRef | Web of Science | Medline24
Macdougall IC ,Roberts DE ,Neubert P ,Dharmasena AD ,Coles GA ,Williams JD . Pharmacokinetics of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Lancet 1989;1:425-427
CrossRef | Web of Science | Medline
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1
2011. Hematopoietic Growth Factors in Transfusion Medicine. , 474-491.
CrossRef2
Pantelis Oustamanolakis, Ioannis E. Koutroubakis, Elias A. Kouroumalis. (2011) Diagnosing anemia in inflammatory bowel disease: Beyond the established markers. Journal of Crohn's and Colitis 5:5, 381-391
CrossRef3
Thomas W. Lee, Michael R. Kolber, Richard N. Fedorak, Sander Veldhuyzen van Zanten. (2011) Iron replacement therapy in inflammatory bowel disease patients with iron deficiency anemia: A systematic review and meta-analysis. Journal of Crohn's and Colitis
CrossRef4
Jonathan O. Cullis. (2011) Diagnosis and management of anaemia of chronic disease: current status. British Journal of Haematology 154:3, 289-300
CrossRef5
Konstantinos H. Katsanos, Athina Tatsioni, Dimitra Natsi, Dimitrios Sigounas, Dimitrios K. Christodoulou, Epameinondas V. Tsianos. (2011) Recombinant human erythropoietin in patients with inflammatory bowel disease and refractory anemia: A 15-year single center experience. Journal of Crohn's and Colitis
CrossRef6
David T. Rubin, Parvez Mulani, Jingdong Chao, Paul F. Pollack, Arielle G. Bensimon, Andrew P. Yu, Subrata Ghosh. (2011) Effect of adalimumab on clinical laboratory parameters in patients with Crohn's disease: Results from the CHARM trial. Inflammatory Bowel Diseasesn/a-n/a
CrossRef7
L. T. Goodnough, E. Nemeth, T. Ganz. (2010) Detection, evaluation, and management of iron-restricted erythropoiesis. Blood 116:23, 4754-4761
CrossRef8
Jürgen Stein, Franz Hartmann, Axel U. Dignass. (2010) Diagnosis and management of iron deficiency anemia in patients with IBD. Nature Reviews Gastroenterology & Hepatology
CrossRef9
Javier P. Gisbert, Fernando Bermejo, Ramón Pajares, Jose-Lázaro Pérez-Calle, María Rodríguez, Alicia Algaba, Noemí Mancenido, Felipe de la Morena, Jose Antonio Carneros, Adrián G. McNicholl, Yago González-Lama, José Maté. (2009) Oral and intravenous iron treatment in inflammatory bowel disease: Hematological response and quality of life improvement. Inflammatory Bowel Diseases 15:10, 1485-1491
CrossRef10
Stefanie Kulnigg, Lena Teischinger, Clemens Dejaco, Thomas Waldhör, Christoph Gasche. (2009) Rapid Recurrence of IBD-Associated Anemia and Iron Deficiency After Intravenous Iron Sucrose and Erythropoietin Treatment. The American Journal of Gastroenterology 104:6, 1460-1467
CrossRef11
Amosy E. M'Koma, Paul E. Wise, David A. Schwartz, Roberta L. Muldoon, Alan J. Herline. (2009) Prevalence and Outcome of Anemia After Restorative Proctocolectomy. Diseases of the Colon & Rectum 52:4, 726-739
CrossRef12
John W. Adamson. (2008) Renal Disease and Anemia in the Elderly. Seminars in Hematology 45:4, 235-241
CrossRef13
Stefanie Kulnigg, Simeon Stoinov, Vladimir Simanenkov, Larisa V. Dudar, Waldemar Karnafel, Luis Chaires Garcia, Alicia M. Sambuelli, Geert D'Haens, Christoph Gasche. (2008) A Novel Intravenous Iron Formulation for Treatment of Anemia in Inflammatory Bowel Disease: The Ferric Carboxymaltose (FERINJECT ® ) Randomized Controlled Trial. The American Journal of Gastroenterology 103:5, 1182-1192
CrossRef14
Michael Auerbach, Lawrence Tim Goodnough, Dan Picard, Alice Maniatis. (2008) The role of intravenous iron in anemia management and transfusion avoidance. Transfusion 48:5, 988-1000
CrossRef15
Javier P Gisbert, Fernando Gomollón. (2008) Common Misconceptions in the Diagnosis and Management of Anemia in Inflammatory Bowel Disease. The American Journal of Gastroenterology 103:5, 1299-1307
CrossRef16
Christoph Gasche, Arnold Berstad, Ragnar Befrits, Christoph Beglinger, Axel Dignass, Kari Erichsen, Fernando Gomollon, Henrik Hjortswang, Ioannis Koutroubakis, Stefanie Kulnigg, Bas Oldenburg, David Rampton, Oliver Schroeder, Jürgen Stein, Simon Travis, Gert Van Assche. (2007) Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases. Inflammatory Bowel Diseases 13:12, 1545-1553
CrossRef17
Konstantinos Katsanos, Etienne Cavalier, Marc Ferrante, Valérie Van Hauwaert, Liesbet Henckaerts, Fabian Schnitzler, Afroditi Katsaraki, Maja Noman, Séverine Vermeire, Epameinondas V. Tsianos, Paul Rutgeerts, Jean-Paul Chapelle, Gert Van Assche. (2007) Intravenous iron therapy restores functional iron deficiency induced by infliximab. Journal of Crohn's and Colitis 1:2, 97-105
CrossRef18
A. Vécsei, W.-D. Huber. (2007) Anämie bei chronisch-entzündlichen Darmerkrankungen in der Pädiatrie. Monatsschrift Kinderheilkunde 155:12, 1143-1149
CrossRef19
Lawrence Tim Goodnough. (2007) Erythropoietin and iron-restricted erythropoiesis. Experimental Hematology 35:4, 167-172
CrossRef20
S. KULNIGG, C. GASCHE. (2006) Systematic review: managing anaemia in Crohn's disease. Alimentary Pharmacology and Therapeutics 24:11-12, 1507-1523
CrossRef21
Lawrence Tim Goodnough. (2006) The Relevance of Iron in Erythropoietin-Stimulated Erythropoiesis. Seminars in Hematology 43, S3-S8
CrossRef22
Christoph Gasche, Stefanie Kulnigg. (2006) Intravenous Iron in Inflammatory Bowel Disease. Seminars in Hematology 43, S18-S22
CrossRef23
CHARLES J DISKIN, THOMAS J STOKES, LINDA M DANSBY, LAUTREC RADCLIFF, THOMAS B CARTER. (2006) Can acidosis and hyperphosphataemia result in increased erythropoietin dosing in haemodialysis patients?. Nephrology 11:5, 394-399
CrossRef24
Richard Eisenstaedt, Brenda W.J.H. Penninx, Richard C. Woodman. (2006) Anemia in the elderly: Current understanding and emerging concepts. Blood Reviews 20:4, 213-226
CrossRef25
Sripathi R. Kethu. (2006) Extraintestinal Manifestations of Inflammatory Bowel Diseases. Journal of Clinical Gastroenterology 40:6, 467-475
CrossRef26
H. Lochs, C. Dejong, F. Hammarqvist, X. Hebuterne, M. Leon-Sanz, T. Schütz, W. van Gemert, A. van Gossum, L. Valentini, H. Lübke, S. Bischoff, N. Engelmann, P. Thul. (2006) ESPEN Guidelines on Enteral Nutrition: Gastroenterology. Clinical Nutrition 25:2, 260-274
CrossRef27
Ioannis E. Koutroubakis, Konstantinos Karmiris, Sokratis Makreas, Costas Xidakis, Maria Niniraki, Elias A. Kouroumalis. (2006) Effectiveness of darbepoetin-alfa in combination with intravenous iron sucrose in patients with inflammatory bowel disease and refractory anaemia: a pilot study. European Journal of Gastroenterology & Hepatology 18:4, 421-425
CrossRef28
Christopher W Wells, Sarah Lewis, J Roger Barton, Sally Corbett. (2006) Effects of changes in hemoglobin level on quality of life and cognitive function in inflammatory bowel disease patients. Inflammatory Bowel Diseases 12:2, 123-130
CrossRef29
A. D. SILVA, E. TSIRONI, R. M. FEAKINS, D. S. RAMPTON. (2005) Efficacy and tolerability of oral iron therapy in inflammatory bowel disease: a prospective, comparative trial. Alimentary Pharmacology and Therapeutics 22:11-12, 1097-1105
CrossRef30
Oliver Schroder, Oliver Mickisch, Ursula Seidler, Andreas de Weerth, Axel U. Dignass, Hans Herfarth, Max Reinshagen, Stefan Schreiber, Ulrich Junge, Marc Schrott, Jurgen Stein. (2005) Intravenous Iron Sucrose versus Oral Iron Supplementation for the Treatment of Iron Deficiency Anemia in Patients with Inflammatory Bowel Disease-A Randomized, Controlled, Open-Label, Multicenter Study. The American Journal of Gastroenterology 100:11, 2503-2509
CrossRef31
William B. Ershler, Shan Sheng, Julie McKelvey, Andrew S. Artz, Neelima Denduluri, Josephine Tecson, Dennis D. Taub, Larry J. Brant, Luigi Ferrucci, Dan L. Longo. (2005) Serum Erythropoietin and Aging: A Longitudinal Analysis. Journal of the American Geriatrics Society 53:8, 1360-1365
CrossRef32
David Michael Wood, Alison H Thomson, Matthew Lawes, Alison Linda Jones, Paul Ivor Dargan. (2005) Hepatocellular Damage Following Therapeutic Intravenous Iron Sucrose Infusion in a Child. Therapeutic Drug Monitoring 27:4, 405-408
CrossRef33
S. Nikolaus, S. Schreiber, U. R. Fölsch. (2005) Pharmakotherapie chronisch entzündlicher Darmerkrankungen. Der Internist 46:5, 586-591
CrossRef34
John F. Randolph, Janet M. Scarlett, Tracy Stokol, Kathryn M. Saunders, James N. MacLeod. (2004) Expression, bioactivity, and clinical assessment of recombinant feline erythropoietin. American Journal of Veterinary Research 65:10, 1355-1366
CrossRef35
M. Soncini, O. Triossi, P. Leo, G. Magni, . (2004) Inflammatory bowel disease and hospital treatment in Italy: the RING multi-centre study. Alimentary Pharmacology and Therapeutics 19:1, 63-68
CrossRef36
Seau-Tak Cheung, Robert N Allan. (2003) Mistaken identity. European Journal of Gastroenterology & Hepatology 15:11, 1245-1247
CrossRef37
Brian R. Jacobs, Kim Lyons, Richard J. Brilli. (2003) Erythropoietin therapy in children with bronchiolitis and anemia*. Pediatric Critical Care Medicine 4:1, 44-48
CrossRef38
R. Caprilli, A. Viscido, D. Guagnozzi. (2002) Biological agents in the treatment of Crohn's disease. Alimentary Pharmacology and Therapeutics 16:9, 1579-1590
CrossRef39
Petar Mamula, David A. Piccoli, Susan N. Peck, Jonathan E. Markowitz, Robert N. Baldassano. (2002) Total Dose Intravenous Infusion of Iron Dextran for Iron-Deficiency Anemia in Children With Inflammatory Bowel Disease. Journal of Pediatric Gastroenterology and Nutrition 34:3, 286-290
CrossRef40
Marco A Coccia, Keegan Cooke, Gregory Stoney, Jeanne Pistillo, Juan Del Castillo, Diane Duryea, John E Tarpley, Graham Molineux. (2001) Novel erythropoiesis stimulating protein (darbepoetin alfa) alleviates anemia associated with chronic inflammatory disease in a rodent model. Experimental Hematology 29:10, 1201-1209
CrossRef41
Onyekachi Ifudu, Antoinette Fowler. (2001) Hepatitis B Virus Infection and the Response to Erythropoietin in End-Stage Renal Disease. ASAIO Journal 47:5, 569-572
CrossRef42
B. Oldenburg, J. C. Koningsberger, G. P. Van Berge Henegouwen, B. S. Van Asbeck, J. J. M. Marx. (2001) Iron and inflammatory bowel disease. Alimentary Pharmacology and Therapeutics 15:4, 429-438
CrossRef43
Andreas N. Kapsoritakis, Michael I. Koukourakis, Aekaterini Sfiridaki, Spiros P. Potamianos, Maria G. Kosmadaki, Ioannis E. Koutroubakis, Elias A. Kouroumalis. (2001) Mean platelet volume: a useful marker of inflammatory bowel disease activity. The American Journal of Gastroenterology 96:3, 776-781
CrossRef44
Lauren B. Gerson, George Triadafilopoulos. (2000) Palliative care in inflammatory bowel disease: An evidence-based approach. Inflammatory Bowel Diseases 6:3, 228-243
CrossRef45
Oldenburg, van Berge Henegouwen, Rennick, van Asbeck, Koningsberger. (2000) Iron supplementation affects the production of pro-inflammatory cytokines in IL-10 deficient mice. European Journal of Clinical Investigation 30:6, 505-510
CrossRef46
John Schumacher, John F. Edwards, Noah D. Cohen. (2000) Chronic Idiopathic Inflammatory Bowel Diseases of the Horse. Journal of Veterinary Internal Medicine 14:3, 258-265
CrossRef47
Patrizia Cotroneo, Bianca Maria Ricerca, Lucia Todaro, Dario Pitocco, Andrea Manto, Valeria Ruotolo, Sergio Storti, Patrizia Damiani, Salvatore Caputo, Giovanni Ghirlanda. (2000) Blunted erythropoietin response to anemia in patients with Type 1 diabetes. Diabetes/Metabolism Research and Reviews 16:3, 172-176
CrossRef48
Christoph Gasche. (2000) Anemia in IBD: The overlooked villain. Inflammatory Bowel Diseases 6:2, 142-150
CrossRef49
Jerry L Spivak. (2000) The blood in systemic disorders. The Lancet 355:9216, 1707-1712
CrossRef50
MICHAEL N. SAWKA, VICTOR A. CONVERTINO, E. RANDY EICHNER, SUZANNE M. SCHNIEDER, ANDREW J. YOUNG. (2000) Blood volume: importance and adaptations to exercise training, environmental stresses, and trauma/sickness. Medicine & Science in Sports & Exercise 32:2, 332
CrossRef51
Gavin C. Harewood, Edward V. Loftus, Ayalew Tefferi, William J. Tremaine, William J. Sandborn. (1999) Concurrent inflammatory bowel disease and myelodysplastic syndromes. Inflammatory Bowel Diseases 5:2, 98-103
CrossRef52
EUGENE D. WEINBERG. (1999) Iron therapy and cancer. Kidney International 55:Suppl. 69, 131-134
CrossRef53
Stefan Schreiber, Susanne Wedel. (1998) Diagnosis and treatment of anemia in inflammatory bowel disease. Inflammatory Bowel Diseases 3:3, 204-216
CrossRef54
WOLFGANG JELKMANN. (1998) Proinflammatory Cytokines Lowering Erythropoietin Production. Journal of Interferon & Cytokine Research 18:8, 555-559
CrossRef55
(1996) Recombinant Erythropoietin for Anemia in Inflammatory Bowel Disease. New England Journal of Medicine 335:10, 751-752
Full Text56
Lacombe, Catherine, . (1996) Resistance to Erythropoietin. New England Journal of Medicine 334:10, 660-662
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