losartan-potassium and Arthritis--Rheumatoid

Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disorder that mainly affects the small joints of the hands and feet. Erythropoiesis-stimulating agents have been used to treat anemia, one of the extra-articular manifestations of RA. Although anemia is less of a problem now because of the reduction in inflammation due to disease-modifying antirheumatic drugs (DMARDs), it could still be an issue in countries where DMARDs are not yet accessible.. We assessed the clinical benefits and harms of erythropoiesis-stimulating agents for anemia in rheumatoid arthritis.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (issue 7 2012), Ovid MEDLINE and Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations (1948 to 7 August 2012), OVID EMBASE (1980 to 7 August 2012), LILACS (1982 to 7 August 2012), the Clinical Trials Search Portal of the World Health Organization, reference lists of the retrieved publications and review articles. We did not apply any language restrictions.. We included randomized controlled trials (RCTs) in patients aged 16 years or over, with a diagnosis of rheumatoid arthritis affected by anemia. We considered health-related quality of life, fatigue and safety as the primary outcomes.. Two authors independently performed trial selection, risk of bias assessment, and data extraction. We estimated difference in means with 95% confidence intervals (CIs) for continuous outcomes. We estimated risk ratios with 95% CIs for binary outcomes.. We included three RCTs with a total of 133 participants. All trials compared human recombinant erythropoietin (EPO), for different durations (8, 12 and 52 weeks), versus placebo. All RCTs assessed health-related quality of life. All trials had high or unclear risk of bias for most domains, and were sponsored by the pharmaceutical industry. Two trials administered EPO by a subcutaneous route while the other used an intravenous route.We decided not to pool results from trials, due to inconsistencies in the reporting of results.Health-related quality of life: subcutaneous EPO - one trial with 70 patients at 52 weeks showed a statistically significant difference in improvement of patient global assessment (median and interquartile range 3.5 (1.0 to 6.0) compared with placebo 4.5 (2.0 to 7.5) (P = 0.027) on a VAS scale (0 to 10)). The other shorter term trials (12 weeks with subcutaneous EPO and eight weeks with intravenous administration) did not find statistically significant differences between treatment and control groups in health-related quality of life outcomes.Change in hemoglobin: both trials of subcutaneous EPO showed a statistically significant difference in increasing hemoglobin levels; (i) at 52 weeks (one trial, 70 patients), intervention hemoglobin level (median 134, interquartile range 110 to 158 g/litre) compared with the placebo group level (median 112, interquartile range; 86 to 128 g/litre) (P = 0.0001); (ii) at 12 weeks (one trial, 24 patients) compared with placebo (difference in means 8.00, 95% CI 7.43 to 8.57). Intravenous EPO at eight weeks showed no statistically significant difference in increasing hematocrit level for EPO versus placebo (difference in means 4.69, 95% CI -0.17 to 9.55; P = 0.06).Information on withdrawals due to adverse events was not reported in two trials, and one trial found no serious adverse events leading to withdrawals. None of the trials reported withdrawals due to high blood pressure, or to lack of efficacy or to fatigue.. We found conflicting evidence for erythropoiesis-stimulating agents to increase quality of life and hemoglobin level by treating anemia in patients with rheumatoid arthritis. However, this conclusion is based on randomized controlled trials with a high risk of bias, and relies on trials assessing human recombinant erythropoietin (EPO). The safety profile of EPO is unclear. Future trials assessing erythropoiesis-stimulating agents for anemia in rheumatoid arthritis should be conducted by independent researchers and reported according to the CONSORT statements. Trials should be based on Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) and The Patient-Centered Outcomes Research Institute (PCORI) approaches for combining both clinician and patient perspectives.

Topics: Anemia; Arthritis, Rheumatoid; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobin A; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins

Topics: Anemia; Antibodies, Monoclonal, Humanized; Antimicrobial Cationic Peptides; Arthritis, Rheumatoid; Erythropoiesis; Erythropoietin; Hepcidins; Humans; Inflammation; Interleukin-6; Iron; Vitamin D; Vitamins

Anemia is a common comorbidity in individuals with rheumatoid arthritis (RA). In fact, anemia of the type characterized by low serum iron concentrations in conjunction with adequate iron stores is frequently associated with RA and has served as a model for anemia of chronic disease. A systematic search of the scientific literature published since January 1966 identified 19 articles that reported findings on either the prevalence of anemia in patients with RA or outcomes for patients with anemia and RA. Ten articles addressed the prevalence of anemia in patients with RA. Estimates of the prevalence of mild anemia ranged between 33% and 60%; however, the 2 studies that examined demographics in patients with RA did not identify subpopulations at particular risk for anemia. Twelve articles assessed the impact of the resolution of anemia on symptoms and quality of life (QOL) in patients with RA. For many of the parameters assessed-including swollen, painful, and tender joints, pain, muscle strength, and energy levels-a positive correlation was observed between improvement of symptoms and the resolution of anemia. In addition, 2 studies reported a significant improvement in QOL scores in patients with RA who experienced a response to treatment for anemia. These results suggest that (1) patients with RA who have anemia are likely to have more severe joint disease and (2) if the anemia is successfully treated, the joint disease will likely respond to treatment as well. Whether improvements in QOL and/or joint symptoms occur with improvement of anemia, independent of other signs of an overall response to RA therapy, remains to be determined.

Topics: Activities of Daily Living; Adult; Age Distribution; Anemia; Arthritis, Rheumatoid; Blood Transfusion; Child; Cost of Illness; Erythropoietin; Fatigue; Female; Hand Strength; Humans; Iron; Male; Outcome Assessment, Health Care; Pain; Prevalence; Quality of Life; Risk Factors; Severity of Illness Index; Sex Distribution

Recombinant human erythropoietin (rHuEPO) and intravenous (i.v.) iron administration may be useful tools to save blood in surgery. In the perioperative period, rHuEPO should be used in slightly anemic patients for whom an autologous predonation program is not recommended (or feasible). In such cases, i.v. iron is only given if there is a functional or real iron deficiency state. In the post-operative period, i.v. iron is administered in association with rHuEPO in an attempt to rapidly correct severe post-operative anemia. The same regimen is used for patients undergoing surgery for inflammatory bowel disease and rheumatoid arthritis. Finally, other particular categories of patients, such as those with reduced body weight (< 50 kg), candidates for surgery with increased blood needs (> 5 units), or those with a too-short period of time before surgery, also benefit from the administration of these two drugs.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anemia; Arthritis, Rheumatoid; Blood Loss, Surgical; Blood Transfusion, Autologous; Erythropoietin; Hemoglobins; Humans; Inflammatory Bowel Diseases; Infusions, Intravenous; Iron; Iron Deficiencies; Postoperative Care; Postoperative Complications; Preoperative Care; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Surgical Procedures, Operative; Time Factors

The correction of anemia in patients with chronic renal failure (CRF) has become the most important application of recombinant human erythropoietin (rHuEpo). The merits of rHuEpo therapy in patients with CRF are overt. Firstly, patients with CRF have an absolute deficiency in endogenous erythropoietin production and a relatively low maintenance dose of rHuEpo (often less than 100 IU/kg body weight per week) is effective in avoiding regular transfusions in the majority of the patients with CRF. Secondly, rHuEpo is able to avoid long-term complications of frequent transfusions (hemochromatosis, transfusion-transmissible diseases). Thirdly, patients with uremia notice a considerable improvement in quality of life (QOL) after initiation of rHuEpo. These advantages justify administration of this costly drug in CRF patients. The use of rHuEpo outside the setting of uremia do, however, not cover the complete spectrum of beneficial effects as compared to its use in (pre)dialysis patients. The aim of this overview is to provide some annotations on recently approved (cisplatin-induced anemia, preoperative anemia, zidovudine-related anemia) and possibly future (several types of malignancy and inflammation) indications for rHuEpo in non-uremic patients, leaving out the correction of anemia due to relatively uncommon disorders in the Dutch population (such as sickle cell anemia and thalassemia).

Topics: Anemia; Anti-HIV Agents; Arthritis, Rheumatoid; Blood Transfusion, Autologous; Chemotherapy, Adjuvant; Erythropoietin; Female; Humans; Male; Multiple Myeloma; Myelodysplastic Syndromes; Recombinant Proteins; Uremia; Zidovudine

Topics: Anemia; Arthritis, Rheumatoid; Bone Marrow; Chronic Disease; Cytokines; Erythropoietin; Ferritins; Humans

Topics: Anemia; Arthritis, Rheumatoid; Cytokines; Erythropoietin; Humans; Iron Metabolism Disorders; Polycythemia

In patients scheduled for major orthopedic surgery, the presence of anemia can preclude the donation of sufficient autologous blood (AB) to meet transfusion requirements. Although a number of studies have investigated the use of epoetin alfa (in conjunction with parenteral iron supplementation) to facilitate AB donation and reduce exposure to allogeneic blood in this patient population, the optimum treatment regimen and route of administration has yet to be defined. In rheumatoid arthritis (RA) patients with a low predonation hematocrit (Hct; < or = 39%), intravenous (i.v.) treatment with epoetin alfa 300 IU/kg twice weekly for 3 weeks was the optimum dosage for facilitation of AB donation and minimization of the decrease in Hct prior to elective orthopedic surgery. However, the subcutaneous (s.c.) route of epoetin alfa administration may allow lower dosages of epoetin alfa to be used. Indeed, epoetin alfa 100 IU/kg s.c. twice weekly for 3 weeks (in conjunction with a single i.v. bolus of 200 IU/ kg at the first s.c. dose) was as effective as 300 IU/kg i.v. administered according to the same schedule. The number of AB units collected, total red blood cell (RBC) volume donated, and peak proportion of reticulocytes were similar regardless of the route of administration. Both treatment groups were associated with a significant reduction in allogeneic blood exposure compared with historical controls. Findings consistent to all of these studies were that epoetin alfa was well tolerated, and that i.v. iron supplementation was necessary to maximize its beneficial effects.

Topics: Anemia; Arthritis, Rheumatoid; Blood Transfusion; Blood Transfusion, Autologous; Dose-Response Relationship, Drug; Double-Blind Method; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematocrit; Humans; Injections, Intravenous; Injections, Subcutaneous; Orthopedics; Premedication; Recombinant Proteins; Treatment Outcome

The anaemia of chronic disease is the second most common anaemia in the world and is an underproduction anaemia with relatively low erythropoietin (EPO) values for the degree of the anaemia. This anaemia occurs with inflammation, infection, or malignancy and a principle question has been whether it would respond to recombinant human EPO (r-HuEPO). Several studies are now available to answer this question. In one study 12 of 16 patients with rheumatoid arthritis receiving r-HuEPO increased their haematocrits 6 percentage points or more and 11 of 12 reached normal haematocrits. Investigations of the effect of r-HuEPO on the anaemia of AIDS showed that patients with EPO levels of 500 U/L or less had an increase in the mean haematocrit of 4.6 percentage points with a decrease in red cell transfusions from 5.3 to 3.2 units per patient. Quality of life indices significantly improved in responders. When 413 patients with anaemia due to a wide variety of malignancies were randomized to r-HuEPO treatment, 58% of those receiving chemotherapy increased their haematocrits by at least 6 points over 12 weeks. Quality of life parameters of responders also significantly improved. Anaemia in three patients with inflammatory bowel disease also responded in 8-14 weeks to r-HuEPO and two of the three reached normal haemoglobin levels. It is clear that r-HuEPO can correct the anaemia of chronic disease and can improve the quality of life of responders.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Arthritis, Rheumatoid; Erythropoietin; Humans; Inflammatory Bowel Diseases; Neoplasms; Recombinant Proteins

The anemia of chronic disease may be viewed simply as the anemia that accompanies chronic inflammatory, infectious, or neoplastic disorders. Because these conditions are very common, the anemia of chronic disease is one of the most frequent anemias encountered, and is only second in incidence to iron-deficiency anemia. The anemia of chronic disease is primarily an anemia due to underproduction of red cells, with low reticulocyte production, and is most often a normochromic, normocytic anemia. However, in 30% to 50% of patients, the red cells are hypochromic and microcytic and, most often, the serum iron, total iron-binding capacity, and transferrin saturation are reduced in the presence of adequate iron stores. Although the differential diagnosis includes other underproduction anemias, such as those caused by vitamin and mineral deficiencies, renal failure, endocrinopathies, and myelodysplasia, it generally is easily distinguished from these conditions. Nevertheless, an understanding of the pathogenesis of this condition, as well as a means of alleviating the anemia when the chronic disorder persists, has remained elusive. Recently, major advances have occurred toward understanding the pathogenesis of the anemia of chronic disease and its treatment, and these advances are reviewed.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Anemia, Hypochromic; Animals; Arthritis, Rheumatoid; Bone Marrow; Chronic Disease; Cytokines; Erythropoietin; Humans; Incidence; Neoplasms; Recombinant Proteins

Topics: Anemia, Hypochromic; Arthritis, Rheumatoid; Erythropoiesis; Erythropoietin; Ferritins; Hemosiderin; Humans; Transferrin; Vitamin B 12 Deficiency

Topics: Anemia; Arthritis, Rheumatoid; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins

The pathogenesis, diagnosis and treatment of the anaemia of chronic disorders (ACD) in rheumatoid arthritis (RA) were reviewed. Causes of anaemia other than ACD frequently present in RA. Decreased iron absorption was shown to be the result of active RA rather than a cause of ACD or iron deficiency. It has been hypothesized that bone marrow iron availability decreases due to decreased iron release by the mononuclear phagocyte system or that the anaemia in ACD is due to ineffective erythropoiesis; these remain controversial theories. Studies considering a decreased erythropoietin responsiveness have not produced consistent results. Erythroid colony growth is suppressed in vitro by interleukins and tumour necrosis factor but their role in vivo in ACD is unknown. The diagnosis of ACD is made by exclusion. Iron deficiency is detected by transferrin, ferritin, and cellular indices after adaptation of their normal values. Treatment of the anaemia consists merely of antirheumatic treatment. Iron administration is counterproductive since iron chelators or exogenous erythropoietin administration might increase erythropoiesis.

Topics: Absorption; Anemia; Arthritis, Rheumatoid; Cell Survival; Diagnosis, Differential; Erythrocytes; Erythropoiesis; Erythropoietin; Ferritins; Hemolysis; Humans; Iron; Lactoferrin; Phagocytes; Stem Cells

We reviewed studies on the role of erythropoietin (Epo) in the anaemia of chronic disease (ACD) in rheumatoid arthritis (RA). A relatively impaired Epo response to the anaemia was found in a number of studies although in others serum Epo level was the same as in other types of anaemia. Some arguments are found in favor of a reduced bone marrow-Epo sensitivity although these reflect results mainly from in vitro experiments. It is not yet established whether bone marrow macrophage Epo production is impaired in ACD. In two cases Epo administration to RA patients resulted in increased erythropoiesis. It was concluded that impaired Epo production or reduced bone marrow Epo sensitivity might be associated with ACD but it is not certain whether these factors are causally linked with ACD or side phenomena of RA disease activity. Future Epo treatment in RA and ACD will possibly solve this question.

Topics: Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Humans

Topics: Acquired Immunodeficiency Syndrome; Anemia; Arthritis, Rheumatoid; Blood Transfusion, Autologous; Erythropoietin; Humans; Hypertension; Inflammation; Iron; Kidney Failure, Chronic; Recombinant Proteins; Vascular Resistance

Recombinant human erythropoietin (rHuEpo) has now been in clinical trials for over four years. rHuEpo has been shown to be nearly uniformly effective in correcting the anaemia of patients on haemodialysis or patients with progressive chronic renal failure not yet on dialysis. rHuEpo has been shown to be effective in increasing the ability of individuals to donate blood for self-use and to increase the haematocrit in patients with rheumatoid arthritis. Preliminary results indicate that rHuEpo will decrease transfusion requirements of patients with the acquired immune deficiency syndrome who are anaemic. Trials in patients with anaemia associated with cancer or myelodysplastic syndromes are in early stages. rHuEpo will have a major impact as a therapeutic agent, particularly in patients with renal disease.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Arthritis, Rheumatoid; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Authors have reviewed recent literature on erythropoietin. They report new information regarding synthesis, modulation, changes during several diseases and the possibility for a clinical use of erythropoietin for the correction of many anaemias. Finally the Authors report some personal observations about the physiopathology of erythropoietin. They have studied the circadian rhythm, action of aging and the prostaglandin system, and plasma levels of E. in patients with anaemia of active rheumatoid arthritis.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anemia; Arthritis, Rheumatoid; Circadian Rhythm; Erythropoietin; Female; Humans; Male; Middle Aged; Prostaglandins; Random Allocation

Topics: Anemia; Arthritis, Rheumatoid; Chronic Disease; Diagnosis, Differential; Erythropoiesis; Erythropoietin; Humans; Iron; Neoplasms

Topics: Absorption; Anemia; Anemia, Hypochromic; Arthritis, Rheumatoid; Bone Marrow; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Iron; Iron-Dextran Complex; Synovial Membrane; Synovitis

Pure red cell aplasia is a selective aplasia of the marrow erythroid cells. Unlike aplastic anemia, the marrow has a normal cellularity and the patients generally have normal leukocyte and platelet blood counts. The congenital form of the disease occurs in the firlst 1 1/2 years of life and is often responsive to corticosteroids. The acquired form may be secondary to infections, drugs, chemicals, or hemolytic anemia (aplastic crisis). In these cases it is often acute and self-limited with cessation of the infection or drug ingestion. It may also be secondary to systemic lupus erythematosus, rheumatoid arthritis, acute severe renal failure, severe nutritional deficiency, or diverse neoplasms, and may remit with treatment of the primary condition. When a thymoma is present, it should be resected since a remission is produced in 29 per cent of these patients. The remaining patients have an acquired primary form of the disease that tends to be chronic and in some cases may have an immune pathogenesis. A cytotoxic immunoglobulin inhibitor of the marrow erythroid cells or erythropoietin has been described and these patients may respond to prednisone and/or to cytotoxic immunosuppressive drugs such as cyclophosphamide and 6-mercaptopurine. Pure red cell aplasia appears to be more common than the literature has revealed and has stimulated much investigation into an immune pathogenesis for marrow failure.

Topics: Acute Kidney Injury; Anemia, Aplastic; Antilymphocyte Serum; Arthritis, Rheumatoid; Blood Cell Count; Blood Transfusion; Cyclophosphamide; Deficiency Diseases; Erythropoietin; Humans; Immune System Diseases; Infections; Lupus Erythematosus, Systemic; Mercaptopurine; Prednisone; Remission, Spontaneous; Splenectomy; Thymoma; Thymus Neoplasms

Topics: Anemia; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Arthritis, Rheumatoid; Bone Marrow; Chronic Disease; Copper; Disease Models, Animal; Endotoxins; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Freund's Adjuvant; Hematocrit; Humans; Infections; Iron; Mononuclear Phagocyte System; Neoplasms; Porphyrins; Protein Binding; Rats; Transferrin

Preoperative epoetin-alpha administration is said to have a limited effect in patients with chronic inflammatory diseases such as rheumatoid arthritis (RA), due to lower iron availability. We studied the effects of preoperative epoetin-alpha treatment in orthopedic surgery patients in a daily life setting in which iron supplementation was assured, and compared the effects in RA and non-RA patients.. In an open, naturalistic, randomized controlled trial, 695 orthopedic surgery patients with preoperative hemoglobin (Hb) values of 10-13 g/dL, either with RA (113) or without RA (582), received either preoperative epoetin-alpha treatment added to standard care, or standard care alone. Hb values and transfusions were evaluated from entry into the study until 4-6 weeks after surgery.. Both in RA and non-RA patients, perioperative Hb values were significantly higher and transfusion requirements were significantly lower in epoetin-alpha treated patients than in control patients (p < 0.001). In RA patients, the outcomes regarding Hb values were not significantly or relevantly different from non-RA patients.. Just as with orthopedic patients in general, RA patients benefit from preoperative epoetin-alpha treatment in combination with iron supplementation. We postulate that iron supplementation during epoetin-alpha therapy in RA patients is important for optimal efficacy.

Topics: Aged; Arthritis, Rheumatoid; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Blood Loss, Surgical; Blood Transfusion; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Iron; Male; Middle Aged; Postoperative Complications; Premedication; Recombinant Proteins; Spinal Diseases; Treatment Outcome

Anemia of chronic disease (ACD) is a frequent complication of chronic inflammation in rheumatoid arthritis (RA). Recombinant human erythropoietin (rHuEpo) has been shown to be effective in correcting ACD, although with a variable rate of nonresponders. The first aim of this trial was to improve the response to rHuEpo by parenteral iron supplementation in cases of iron-deficient erythropoiesis (IDE). An additional goal was the evaluation of the zinc protoporphyrin content of erythrocytes (ZnPP), the soluble transferrin receptor (sTrfR) serum concentration, and the hemoglobin (Hb) content of reticulocytes (CHr) in stimulated erythropoiesis as diagnostic and prognostic parameters. Thirty RA patients with ACD were treated with subcutaneous 150 IU rHuEpo/kg body weight twice weekly. Intravenous iron supplementation (200 mg iron sucrose once weekly) was added in cases of IDE (n=23), which was defined by the presence of two of three criteria: saturation of transferrin (TrfS) < or =15%, hypochromic erythrocytes (HypoE) > or =10%, and a serum ferritin (Fn) concentration < or =50 microg/l. All 28 completers met the treatment goal, with an increase of the median Hb concentration from 10.3 g/dl to 13.3 g/dl. Epo treatment and iron supplementation was safe and well tolerated in all patients. Monitoring of Fn, TrfS, and HypoE every other week allowed a successful correction of anemia. Retrospective analysis of the evaluable parameters (CHr, sTrfR, and ZnPP) revealed no additional benefit for predicting or monitoring IDE in this setting, although the one or other may be advantageous in other therapeutic situations.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Biomarkers; Chronic Disease; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Iron Deficiencies; Male; Middle Aged; Protoporphyrins; Receptors, Transferrin; Recombinant Proteins; Reticulocytes

During recent years, it was shown, that treatment with recombinant human erythropoietin (rHuEPO) stimulates erythropoiesis in patients both with renal and nonrenal anaemia. Additionally in patients with chronic renal failure treated with rHuEPO a significant, however only transient, influence on function of endocrine glands was also found. The present study aimed to asses for the first time the influence of rHuEPO on function of endocrine organs in anaemic patients with rheumatoid arthritis and normal renal function. Twenty two woman with rheumatoid arthritis and concomitant anaemia (Ht < or = 30%) were enrolled into the study. In 13 of them rHuEPO was used during 4 months (5000 IU 2 times per week s.c.). The rest 9 woman with similar degree of anaemia did not receive rHuEPO therapy. In woman of both groups intensive clinical and biochemical monitoring during 4 months period was performed. Blood samples were withdrawn before and after 4 months of rHuEPO therapy or clinical observation only. In these blood samples plasma concentrations of somatotropin (HGH), insulin (IRI), aldosterone (ALD), atrial natriuretic peptide (ANP), 25-hydroxycholecalciferol (25OHD3), intact parathyroid hormone (iPTH) and plasma renin activity (PRA) were estimated. After 4 months of rHuEPO therapy significant increase of plasma IRI, ANP concentrations and significant decrease of PRA and plasma ALD, HGH concentrations were found. Therapy with rHuEPO does not influence significantly plasma iPTH and 25OHD3 concentration. During 4 months of clinical observation in patients not treated with rHuEPO, plasma concentrations of HGH, IRI, ALD, ANP, 25OHD3, iPTH and plasma renin activity (PRA) did not change significantly. Results obtained in this study suggest, that rHuEPO therapy does influence the function of endocrine organs also in patients with rheumatoid arthritis with normal renal function.

Topics: Adult; Aged; Aldosterone; Anemia; Arthritis, Rheumatoid; Atrial Natriuretic Factor; Endocrine Glands; Erythropoietin; Female; Hormones; Humans; Insulin; Middle Aged; Parathyroid Hormone; Recombinant Proteins; Renin

The effect of recombinant human erythropoietin on autologous blood donation was investigated in 73 rheumatoid arthritis patients who underwent hip or knee arthroplasty. Autologous blood donation of 400 mL was successful with recombinant human erythropoietin (12,000 U per week), and no homologous blood was required. The mean period of blood collection was 33.8 days. Mean hemoglobin levels were 9.7 g/dL before treatment, 10.7 g/dL before surgery, and 10.2 g/dL after surgery. This study confirmed recombinant human erythropoietin is effective for enabling preoperative blood donation in rheumatoid arthritis patients.

Topics: Aged; Arthritis, Rheumatoid; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Blood Transfusion, Autologous; Erythropoietin; Female; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins

To investigate whether treatment of anemia of chronic disease (ACD) in patients with rheumatoid arthritis (RA) with recombinant human erythropoietin (rHu-Epo) in combination with intravenous (i.v.) iron influences health related quality of life (HRQoL) and clinical outcome including disease activity.. Thirty patients with ACD and RA were treated with 150 IU/kg rHu-Epo twice weekly for 12 weeks. As well, in case of functional iron deficiency 200 mg of iron-sucrose per week was given intravenously. Vitality and fatigue as dimensions of HRQoL were evaluated by the vitality subscale of the Short Form-36 (SF-36-VT) and the Multidimensional Assessment of Fatigue (MAF). Muscle strength was measured by the Muscle Strength Index.. All 28 patients completing the study responded to treatment; 23/28 patients developed functional iron deficiency and received i.v. iron (mean absolute dose 710 +/- 560 mg). Average hemoglobin concentration increased from 10.7 +/- 1.1 to 13.2 +/- 1.0 g/dl after a mean treatment period of 8.7 +/- 2.3 weeks. Muscle strength increased from 43.5 +/- 11.2 to 49.1 +/- 12.9 and SF-36-VT from 28.2% +/- 14.3% to 47.1% +/- 20.8%. while fatigue decreased (MAF from 34.7 +/- 9.3 to 25.0 +/- 11.3). Among the disease activity variables the number of swollen/tender joints, erythrocyte sedimentation rate, Disease Activity Score, and RA Disease Activity Index improved significantly during treatment.. Treatment of ACD in RA patients with rHu-Epo and i.v. iron is safe and effective in correction of anemia, increases muscle strength. improves vitality, and lowers fatigue. In addition we observed a reduction of disease activity.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Disability Evaluation; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Health Status; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Quality of Life; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Treatment with recombinant human erythropoietin (r-hu-Epo) in patients with rheumatoid arthritis (RA) and anaemia of chronic disease (ACD) resulted in improvement of both anaemia and disease activity. Utilities represent a generic and comprehensive quality of life measure, capable of integrating domain-specific information into one overall value which a patient assigns to his state of health. Therefore, the effect of r-hu-Epo on quality of life was studied by measuring utilities, derived from the rating scale and standard gamble, in a 52-week placebo-controlled randomised double-blind study with r-hu-Epo in 70 patients with active RA and ACD. Furthermore, the relation between anaemia as assessed by haemoglobin levels (Hb), disease activity as assessed with the Disease Activity Score (DAS), and utilities was investigated. Compared to the placebo group, significant improvement of Hb (P < 0.001), DAS (P = 0.01) and rating scale utilities (P = 0.002), but not of standard gamble utilities, was observed in the Epo group. Rating scale utilities correlated strongly with DAS (r = -0.47, P < 0.01), Hb (r = 0.37, P < 0.01) and changes in both DAS (r = -0.74, P < 0.01) and Hb (r = 0.44, P < 0.01). Both DAS and Hb contributed significantly to the variance in rating scale utilities (21% and 3% respectively) and to changes in rating scale utilities (43% and 3% respectively). Standard gamble utilities correlated less well with clinical disease variables than rating scale utilities did. These results indicate, that r-hu-Epo improves utility-derived health-related quality of life, most probably by improving both disease activity and anaemia. Utilities, particularly rating scale utilities, correlated well with conventional disease activity variables and proved sensitive to change. Utilities may be a useful tool for investigating quality of life in RA-patients.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Confidence Intervals; Double-Blind Method; Erythropoietin; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Quality of Life; Recombinant Proteins; Regression Analysis; Severity of Illness Index; Treatment Outcome

The aim of this study was to determine the conditions under which a sufficient preoperative amount of autologous blood could be obtained with administration of rHuEPO (recombinant human erythropoietin) in anaemic patients with rheumatoid arthritis (RA). Thirty-one patients (29 female, two male) with RA who were unable to donate any autologous blood owing to a haemoglobin level of less than 11 g/dl were recruited for this study. Their mean age at the time of operation was 59.3 years. The study protocol for preoperative autologous blood donations started 2.7 weeks before surgery. All patients received 6000 IU rHuEPO intravenously three times a week, supplemented with 40 mg intravenous saccharated ferric oxide at each rHuEPO administration. The protocol also included the provision that 200 g of blood at the first and third donations and 400 g of blood at the second donation were collected. The patients who were able or unable to donate 800 g of blood by this protocol were regarded as having a good or poor response, respectively, to rHuEPO. Patients with a poor response to rHuEPO showed greater clinical symptoms (morning stiffness, the number of swollen joints, Ritchie index) and higher laboratory inflammation parameters (ESR, CRP, platelets, IL-6, TNFalpha, IL-1beta) than patients with a good response to rHuEPO. The poor-response group showed a significant decrease in the progression of inflammation compared with the good-response group. Before treatment with rHuEPO, anaemia in the poor-response group was the same as that in the good-response group, except for impairment of UIBC (unsaturated iron-binding capacity). The poor-response group had a higher blood loss than the good-response group. In conclusion, anaemic RA patients should be considered as candidates for aggressive blood conservation interventions that depend on erythropoietin-modulated erythropoiesis. However, it is important to determine this approach under good control of inflammation.

Topics: Aged; Anemia; Arthritis, Rheumatoid; Arthroplasty; Biomarkers; Blood Cell Count; Blood Sedimentation; Blood Transfusion, Autologous; C-Reactive Protein; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Infusions, Intravenous; Interleukin-1; Interleukin-6; Male; Middle Aged; Preoperative Care; Recombinant Proteins; Retrospective Studies; Treatment Outcome; Tumor Necrosis Factor-alpha

Intravenous (i.v.) Recombinant erythropoietin (Epoetin alfa) is effective in allowing autologous blood donation in patients unable to donate because of anemia. We undertook this open pilot study in order to asses whether a low subcutaneous (s.c.) dose of Epoetin alfa would prove as effective and well tolerated as the higher i.v. dose. Such a move would also decrease costs.. A total Epoetin alfa s.c. dose of 800 IU/kg was compared with a total i.v. dose of 1,800 IU/kg. Twenty-two rheumatoid arthritis patients, unable to donate because of hemoglobin (Hb) < 11 g/dl, received 300 IU/kg of IV Epoetin alfa twice weekly for 3 weeks (11 patients), or 100 IU/kg of s.c. Epoetin alfa twice weekly for 3 weeks plus an i.v. bolus of 200 IU/kg of Epoetin alfa at the first visit (11 patients). At each visit, all patients received 100 mg of i.v. iron saccharate and when the hematocrit (hct) > or = 34%, 350 ml of autologous blood (AB) were collected.. No significant differences were observed between the 2 groups of treated patients in terms of units of AB collected (2.6 +/- 0.6 vs. 2.5 +/- 0.5 units for i.v. and s.c. groups, respectively), ml of RBC produced during the study period (291 +/- 99 vs. 337 +/- 65 ml for the i.v. and s.c. groups, respectively), or in the degree of reduced exposure to allogeneic blood in comparison with the control group.. Lower dose of Epoetin alfa (reduced by 56%), supplemented by i.v. iron, is as effective and well tolerated as higher doses administered i.v., supplemented by i.v. iron.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Blood Donors; Erythropoietin; Female; Hip Prosthesis; Humans; Injections, Intravenous; Injections, Subcutaneous; Knee Prosthesis; Male; Middle Aged; Pilot Projects; Recombinant Proteins

Forty-six patients with rheumatoid arthritis (RA) and documented anemia of chronic disease (Hb < 100/110 g/l) were randomized to receive either human recombinant erythropoietin (r-HuEPO, n = 36, 300 U/kg body weight) or placebo (n = 10) for 12 weeks in a multicenter study. An adequate response was defined as elevation of Hb > or = 120 g/l. Relevant clinical and laboratory assessments were made to evaluate efficacy and secure safety. A significant elevation in Hb from week 10 onwards was noted in twenty-six patients (five drop-outs) out of nine patients receiving placebo (one drop-out) (12 +/- 1.2 g/l vs 4 +/- 0.5 g/l; Hb elevation from 95 g/l to 107 g/l vs 93 g/l to 97 g/l, P < 0.05). Only 14.6%, however, were considered responders according to preset criteria. In the responders a lower initial CRP, a significant reduction in ESR but not in CRP was seen compared to the remaining r-HuEPO group. A significant elevation of energy level was noted in the r-HuEPO group; otherwise, no differences in clinical variables were seen. No serious adverse effects were noted. When analyzing patients receiving oral iron in combination with r-HuEPO and adding five additional, openly selected patients receiving both adequate iron supplementation and r-HuEPO, there was a significant weekly elevation of Hb from week 8 onwards in favor of combination therapy over the ones only receiving r-HuEPO (18 +/- 1.1 g/l vs 7 +/- 1.1 g/l, P < 0.05). The initial six responders had now reached ten of whom seven belonged to the combination therapy group. Response to r-HuEPO in RA patients appears to be dependent on availability of iron and on the degree of inflammation. If r-HuEPO treatment is considered, iron deficiency should always be corrected and strenuous efforts should have been made to control the disease itself.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Female; Humans; Inflammation; Iron; Male; Middle Aged; Recombinant Proteins

We studied whether orthopedic surgical patients with rheumatoid arthritis (RA) can generate an erythropoietic response to either endogenous erythropoietin or to recombinant human erythropoietin (EPO) therapy to the same extent as patients without rheumatoid arthritis (non-RA). Seventy patients (10 RA, 60 non-RA) were entered into clinical trials of aggressive autologous blood donation before elective orthopedic surgery at one institution, randomized to receive EPO (600 U/kg, iv, 6 times over 3 weeks) or placebo. RA patients given EPO had red blood cell (RBC) production that was enhanced by 624 +/- 137 ml (mean +/- SD) as compared with 271 +/- 174 ml (p = 0.02) for RA patients given placebo treatment. Preoperative RBC volume expansion in 10 RA patients was 5.9 +/- 3.7 ml/kg as compared with 7.4 +/- 3.9 ml/kg for 60 non-RA patients (p = 0.13). RA patients can benefit to the same extent as non-RA patients from aggressive blood conservation programs that incorporate erythropoietin-modulated erythropoiesis.

Topics: Arthritis, Rheumatoid; Blood Transfusion, Autologous; Body Weight; Bone Marrow; Erythrocyte Volume; Erythropoiesis; Erythropoietin; Ferritins; Hematocrit; Humans; Iron; Middle Aged; Recombinant Proteins; Treatment Outcome

Anaemia of chronic disease (ACD) is a common feature of active rheumatoid arthritis (RA). Inflammatory cytokines, particularly tumour necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1) and interleukin-6 (IL-6), are thought to contribute to the pathogenesis of ACD, possibly by inhibiting erythropoietin (EPO) production. In this study, we examined the in vivo effects of TNF-alpha blockade with a chimeric monoclonal antibody, cA2, on erythropoiesis in RA patients with ACD. Administration of cA2 led to a dose-dependent increase in haemoglobin levels compared to placebo and these changes were accompanied by a reduction in both EPO and IL-6 levels. The data support the notion that TNF-alpha is important in the causation of ACD, but suggest a mechanism independent of EPO suppression. Instead, TNF-alpha may act directly on bone marrow red cell precursors.

Topics: Anemia; Antibodies, Monoclonal; Arthritis, Rheumatoid; C-Reactive Protein; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Female; Hemoglobins; Humans; Interleukin-6; Male; Recombinant Fusion Proteins; Tumor Necrosis Factor-alpha

In patients scheduled for major orthopedic surgery, the presence of anemia can preclude the donation of sufficient autologous blood (AB) to meet transfusion requirements. Although a number of studies have investigated the use of epoetin alfa (in conjunction with parenteral iron supplementation) to facilitate AB donation and reduce exposure to allogeneic blood in this patient population, the optimum treatment regimen and route of administration has yet to be defined. In rheumatoid arthritis (RA) patients with a low predonation hematocrit (Hct; < or = 39%), intravenous (i.v.) treatment with epoetin alfa 300 IU/kg twice weekly for 3 weeks was the optimum dosage for facilitation of AB donation and minimization of the decrease in Hct prior to elective orthopedic surgery. However, the subcutaneous (s.c.) route of epoetin alfa administration may allow lower dosages of epoetin alfa to be used. Indeed, epoetin alfa 100 IU/kg s.c. twice weekly for 3 weeks (in conjunction with a single i.v. bolus of 200 IU/ kg at the first s.c. dose) was as effective as 300 IU/kg i.v. administered according to the same schedule. The number of AB units collected, total red blood cell (RBC) volume donated, and peak proportion of reticulocytes were similar regardless of the route of administration. Both treatment groups were associated with a significant reduction in allogeneic blood exposure compared with historical controls. Findings consistent to all of these studies were that epoetin alfa was well tolerated, and that i.v. iron supplementation was necessary to maximize its beneficial effects.

Topics: Anemia; Arthritis, Rheumatoid; Blood Transfusion; Blood Transfusion, Autologous; Dose-Response Relationship, Drug; Double-Blind Method; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematocrit; Humans; Injections, Intravenous; Injections, Subcutaneous; Orthopedics; Premedication; Recombinant Proteins; Treatment Outcome

To study whether recombinant human erythropoietin (r-hu-Epo) improves anaemia and reduces disease activity in patients with rheumatoid arthritis and anaemia of chronic disease (ACD).. A 52 week placebo controlled randomised double blind trial with r-hu-Epo was performed in 70 patients with active rheumatoid arthritis and ACD. Thirty four patients were treated with 240 U kg-1 r-hu-Epo subcutaneously, initially three doses weekly, while 36 patients received placebo.. A significant increase of haemoglobin from a median of 112 to 135 g litre-1 occurred in the Epo group within six weeks and could be sustained with reduced doses (median 240 U kg-1 once weekly). Sustained benefit compared to placebo was also apparent by six weeks for disease activity, as indicated by the Paulus 20% response rate. Of patients in the Epo group, 32% eventually showed a Paulus 20% response, compared to 8% of the placebo group (P = 0.016). Significant differences in favour of the Epo group were also observed in the secondary disease activity measures Ritchie index, number of swollen joints, pain score, ESR, and patients' global assessment of disease activity. C reactive protein concentrations did not change significantly.. Treatment of ACD in rheumatoid arthritis with r-hu-Epo is effective in restoring normal haemoglobin levels and also exerts a beneficial effect on disease activity.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Double-Blind Method; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Blood Sedimentation; Erythropoietin; Humans; Middle Aged; Recombinant Proteins; Treatment Outcome

In order to evaluate the effect of recombinant human erythropoietin (rHuEPO) on autologous blood transfusion in patients with rheumatoid arthritis (RA), we performed a phase II clinical trial in 65 RA patients undergoing elective surgery. rHuEPO was administered subcutaneously once a week and after observing erythropoiesis, autologous blood was collected. Fifty-seven of the 58 patients who completed treatment responded to rHuEPO and could donate more than 400 ml of autologous blood. Among them, 23 out of 28 patients undergoing total hip arthroplasty, 27 out of 28 undergoing total knee arthroplasty and 1 out of 1 undergoing spinal surgery did not need homologous blood transfusion perioperatively. During rHuEPO treatment, no significant changes of clinical parameters of RA activity were observed. Two patients discontinued the treatment because of mild and transient side effects. These results indicate that subcutaneous rHuEPO is safe and effective in eliminate the need for homologous blood transfusion, even in anemic RA patients undergoing elective orthopedic surgery.

Topics: Adult; Aged; Arthritis, Rheumatoid; Blood Transfusion, Autologous; Erythropoietin; Female; Humans; Japan; Joint Prosthesis; Male; Middle Aged; Recombinant Proteins

Mean (+/- SD) serum erythropoietin (EPO) levels were 18.6 +/- 5.6 mU/ml in 180 normal Japanese subjects. Serum EPO levels were elevated with a negative correlation on a log scale (r = -0.864, P < 0.005) to hematocrit (Ht) values in anemic patients not associated with rheumatoid arthritis (RA) or chronic renal failure (CRF). Serum EPO levels in patients with RA (31.6 +/- 16.4 mU/ml) were relatively lower than those in normal subjects and anemic patients without RA or CRF when matched for comparative Ht values. Seven anemic patients with RA were treated by daily subcutaneous (sc) injection of recombinant EPO (rEPO, 500-1,000 U/day) for 4 weeks. The patients had initial Ht values of 25.1% or less and maintained stable clinical status. The treatment with rEPO raised serum EPO levels (53.8 +/- 15.2 mU/ml, P < 0.05), which resulted in an increase in Ht values (more than 3%) in 6 out of 7 patients with RA. The mean (+/- SD) Ht values at the end of the treatment with rEPO (500-1,000 U/day) were greater than those before the treatment in the 7 patients with RA (28.5 +/- 4.6 vs. 22.7 +/- 2.5%, P < 0.05). These findings suggest that chronic anemia associated with RA may be corrected by daily sc injection of a small dose of rEPO.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Arthritis, Rheumatoid; Child; Child, Preschool; Chronic Disease; Erythropoietin; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Radioimmunoassay; Recombinant Proteins; Time Factors

Topics: Anemia; Arthritis, Rheumatoid; Erythropoietin; Ferritins; Hematocrit; Hemoglobins; Humans; Iron; Recombinant Proteins; Time Factors

To administer recombinant erythropoietin to patients with rheumatoid arthritis who had significant anemia, while monitoring hematologic and rheumatologic clinical responses as well as potential toxicity.. Seventeen patients with rheumatoid arthritis from five rheumatology care settings were studied. The patients had initial hematocrits of 34% or less and stable clinical status, and were not being treated with second-line drugs or corticosteroids. An 8-week randomized double-blind study involving various dosages of recombinant erythropoietin, as well as placebo, was followed by a 24-week open-label study in which dosage could be titrated to achieve a normal hematocrit.. In the 8-week randomized study, four of 13 patients who received injections of recombinant erythropoietin showed a hematologic response, arbitrarily defined as at least a 6-unit increase in hematocrit. None of four placebo-treated patients showed a meaningful hematologic response. All 11 patients who completed the subsequent 24-week open-label study reached a normal hematocrit level at some time during the study, and 10 of 11 showed an increase of hematocrit 6 units or greater. At least one adjustment, i.e., an increase, decrease, or omission of the erythropoietin dosage, was required in all patients to maintain the hematocrit at a target range of 35% for women or 40% for men. Meaningful changes were not seen in patients' capacity to perform activities of daily living or pain levels during either the 8-week randomized study or the 24-week open-label study. No adverse effects were associated with recombinant erythropoietin therapy.. Patients with rheumatoid arthritis showed excellent hematologic responses to recombinant erythropoietin, without toxicity, during careful monitoring for appropriate dosage adjustment, although a meaningful change in rheumatologic clinical status was not seen.

Topics: Activities of Daily Living; Adult; Aged; Anemia; Arthritis, Rheumatoid; Double-Blind Method; Erythropoietin; Female; Ferritins; Hematocrit; Humans; Male; Middle Aged; Monitoring, Physiologic; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Recombinant Proteins

Anaemia affects quality of life and radiographic outcome in rheumatoid arthritis (RA). In a cross-sectional study with 779 patients, we assessed the prognostic potential of the major haematopoietic regulators, hepcidin and erythropoietin, comparing their serum concentrations with respect to different anaemia types, inflammatory activity, anti-cytokine-specific treatment effects and iron deficiency (ID) indices. The results showed that clinical disease activity was more closely associated with haemoglobin levels than with anti-tumour necrosis factor-alpha or interleukin 6 receptor effects. In ID, hepcidin was suppressed, independently of inflammation. Erythropoietin levels were inappropriately low in relation to the degree of anaemia, but, in contrast to low haemoglobin, not directly associated with joint damage progression. Hepcidin and erythropoietin levels are intimately connected with inflammation and ID. Interventional studies on these important targets are already in progress.

Topics: Adult; Anemia, Iron-Deficiency; Arthritis, Rheumatoid; Cross-Sectional Studies; Disease Progression; Erythropoietin; Female; Hemoglobins; Hepcidins; Humans; Inflammation; Joints; Male; Middle Aged

Topics: Allergy and Immunology; Animals; Arthritis, Rheumatoid; Disease Models, Animal; Erythropoietin; History, 20th Century; Humans; Immunity, Innate; Tumor Necrosis Factor-alpha

Topics: Aged; Anemia; Arthritis, Rheumatoid; Disease Progression; Disseminated Intravascular Coagulation; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

rHuEPO (recombinant human erythropoietin) is a haemopoietic growth factor and a primary regulator of erythropoiesis that is used for the treatment of chronic anaemia associated with RA (rheumatoid arthritis). Erythropoietin also appears to modulate a broad array of cellular processes, including progenitor stem-cell development, cellular integrity, angiogenesis and oxidative damage. These diverse activities suggest the exciting possibility of multiple roles for rHuEPO therapy in a variety of disorders other than RA, including cerebral ischaemia, myocardial infarction, chronic congestive heart failure and cancer. Thus it appears that rHuEPO may be a pleiotropic agent, capable of influencing tissue remodelling independently of its established erythropoietic role. Whereas these effects may be largely beneficial, dose-related side effects could have implications for the safe therapeutic use of rHuEPO and its illegal use as a performance-enhancing agent in endurance sports.

Topics: 3T3 Cells; Anemia; Animals; Arthritis, Rheumatoid; Erythropoietin; Extracellular Matrix; Humans; Inflammation; Mice; Nitric Oxide; Recombinant Proteins

Macrophage inflammatory protein-1alpha (MIP-1alpha) is an interesting chemokine because in addition to its variety proinflammatory activities including chemotaxis and immunomodulation, it is a potent inhibitor of hematopoetic stem cell proliferation. Inhibition of erythroid progenitor cells due to MIP-1alpha or other cytokines can play a role in the pathogenesis of anemia which is one of the most common extra-articular features of active rheumatoid arthritis (RA). In 84 patients with RA, serological and immunological parameters were assessed to detect inflammatory mechanisms and anemia in relation to the serum concentrations of MIP-1alpha. All patients fulfilled the ACR criteria for the diagnosis of a definite or classic RA. We used a quantitative enzyme immuno assay for the detection of MIP-1alpha as well as for the measurement of the acute phase protein serum amyloid A (SAA), the erythropoiesis inducer erythropoietin (EPO) and the transferrin receptor (TfR). The immune activation marker neopterin was measured radioimmunologically. Half of the patients with RA were anemic with hemoglobin values below 12 g/dl. MIP-1alpha was found to be elevated significantly in serum of patients with active rheumatoid arthritis and in patients with anemia. Most of the anemic patients with markedly elevated acute phase reactions had an anemia with chronic diseases and not a functional iron deficiency alone. TfR correlated with EPO. The results show that enhanced expression of MIP-1alpha is indicative of systemic inflammation in RA. Moreover, besides the regulation of inflammatory processes, this chemokine may influence the pathogenesis of anemia in RA patients.

Topics: Acute-Phase Proteins; Adult; Aged; Anemia; Arthritis, Rheumatoid; Chemokine CCL3; Chemokine CCL4; Erythropoietin; Female; Ferritins; Hemoglobinometry; Humans; Macrophage Inflammatory Proteins; Male; Middle Aged; Receptors, Transferrin; Reference Values; Serum Amyloid A Protein

Erythropoietin (EPO), a haemopoietic growth factor and a primary regulator of erythropoiesis, is widely used to treat anaemia in various chronic complications of rheumatoid arthritis (RA). Fibroblast-like cells, found in the pannus tissue of joints, are thought to contribute to the inflammatory pathology of RA. Thus for the current study we investigated the effects of recombinant human EPO (rHuEPO) on NO metabolism, using an interleukin-1beta (IL-1beta)-stimulated Swiss 3T3 fibroblast monolayer as a model for fibroblast activity in RA. The results show that, over 3 days, both alone and in combination with the pro-inflammatory cytokine IL-1beta (10 ng/ml), rHuEPO (25 micro-units/ml) induced significant production of nitrite in cell culture supernatants. This is an indicator of NO production by nitric oxide synthase (NOS), which is a well-documented mediator of metalloproteinase-mediated tissue remodelling in RA. It therefore appears that, through modulation of NOS-dependent NO production, rHuEPO may influence remodelling of connective tissue in RA, independently of its established erythropoietic role.

Topics: 3T3 Cells; Animals; Arthritis, Rheumatoid; Disease Models, Animal; Erythropoietin; Fibroblasts; Humans; Interleukin-1; Mice; Nitric Oxide; Nitrites; Recombinant Proteins; Synovial Membrane; Time Factors

This case report examines the hospital course and functional recovery of a geriatric patient with severe anaemia undergoing rehabilitation following total hip replacement. It serves to highlight the need for further study of the impact of anaemia on recovery in the rehabilitation setting as well as the importance of developing clinical guidelines for the appropriate medical management of anaemia in this patient population.. Single case report.. The course of recovery during rehabilitation in a geriatric patient with severe post-operative anaemia was notably different from other geriatric patients undergoing rehabilitation following total hip replacement. The patient demonstrated a markedly reduced tolerance for therapies and prolonged length of stay, but did not experience cardiopulmonary complications during intensive rehabilitation. Her hematocrit responded nicely to treatment with human recombinant erythropoietin. Despite a prolonged recovery period, the patient ultimately progressed well and achieved a good functional outcome.. The impact of anaemia on functional recovery in the acute inpatient rehabilitation setting as well as the theoretical risk of increased morbidity and mortality during prescribed therapeutic exercise has not been closely examined in the literature. Further study is indicated to examine the implications for anaemia on functional recovery and cardiopulmonary complications during rehabilitation. General guidelines should be developed for the management of anaemia in the rehabilitation setting.

Topics: Activities of Daily Living; Aged; Anemia; Arthritis, Rheumatoid; Arthroplasty, Replacement, Hip; Erythropoietin; Female; Geriatric Assessment; Hematocrit; Humans; Postoperative Care; Practice Guidelines as Topic; Recovery of Function; Severity of Illness Index

To elucidate the characteristics of anemia of chronic disease(ACD) in rheumatoid arthritis(RA), and the role of TNF alpha, IFN-gamma and Epo in the pathogenesis of ACD.. Serum TNF alpha and IFN-gamma levels in RA patients and serum Epo levels in RA with ACD were measured by ELISA. Serum iron status profile in RA patients were also detected. The effects of TNF alpha and IFN-gamma on cobalt-induced erythropoietin production in human hepatic cancer cells(HepG2) were examined. The effect of TNF alpha and IFN-gamma erythroid colony formation (CFU-E and BFU-E) of normal bone marrow cells, and the effect of serum from RA patients and Epo on CFU-E yields of RA bone marrow cells.. Serum TNF alpha or IFN-gamma in RA and RA with ACD patients were higher than those in normal controls, and were inversely correlated with hemoglobin, and serum iron levels. Serum Epo levels in ACD patients were lower than those in iron-deficiency anemia patients with comparable hemoglobin level. TNF alpha and IFN-gamma could specifically inhibit cobalt-induced Epo production in HepG2 cells, and suppressed normal bone marrow BFU-E and CFU-E growth in a dose-dependent manner. Bone marrow CFU-E yields of RA patients were also suppressed by their own serum. The inhibitory effects of TNF alpha, IFN-gamma or serum from RA patients on erythroid colony formation could be corrected by the addition of rhEpo.. It suggested that there were hematopoietic inhibiting factors in the serum of RA patients. TNF alpha or IFN-gamma was involved in the pathogenesis of anemia in RA patients. Administration of rhEpo might be beneficial for anemia of RA patients.

Topics: Adolescent; Adult; Aged; Anemia; Arthritis, Rheumatoid; Erythropoietin; Female; Humans; Interferon-gamma; Iron; Male; Middle Aged; Tumor Necrosis Factor-alpha

Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) play an important role in decreased erythropoiesis in patients with anemia of chronic disease (ACD) and rheumatoid arthritis (RA). Modulation of quantities of bone marrow erythroid progenitors during chronic inflammation may be one of the pathogenetic mechanisms leading to ACD. We studied bone marrow from patients with ACD with RA by investigating, first, local production of inflammatory cytokines in the bone marrow, and second, the relative fraction of late erythroid progenitors (erythropoietin and transferrin receptor positive cells; EpoR+ TrfR+) in bone marrow. In addition, the effects of TNF-alpha on EpoR+ TrfR+ cells were studied in vitro.. Levels of IL-6 and TNF-alpha were measured by EL ELISA in supernatant of bone marrow and peripheral blood cultures from 14 patients with RA and ACD and 14 patients with RA without anemia. The numbers of EpoR+ TrfR+ cells in bone marrow samples of both groups were assessed by 2 color fluorescence flow cytometry.. Levels of IL-6 and TNF-alpha were significantly higher in the supernatant of bone marrow cultures of patients with ACD compared to controls. No significant differences in the fraction of EpoR+ TrfR+ cells in samples was observed between the 2 groups of patients. Incubation of the samples with TNF-alpha did not result in modulation of the number of EpoR+ TrfR+ cells.. Local production of proinflammatory cytokines in the bone marrow may be associated with the development of ACD in RA.

Topics: Adolescent; Adult; Aged; Anemia; Arthritis, Rheumatoid; Bone Marrow; Cells, Cultured; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Erythroblasts; Erythropoietin; Female; Flow Cytometry; Humans; Interleukin-6; Male; Middle Aged; Receptors, Transferrin; Tumor Necrosis Factor-alpha

Topics: Anemia; Arthritis, Rheumatoid; Blood Donors; Blood Transfusion, Autologous; Erythropoietin; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematocrit; Humans; Recombinant Proteins

To investigate the existence of circulating autoantibodies to erythropoietin (EPO) in sera from patients with systemic lupus erythematosus (SLE), and to correlate their presence with anemia and clinical activity.. Ninety-two consecutive patients with SLE, 80 patients with rheumatoid arthritis, and 42 normal individuals were studied. The patients with SLE were categorized into 3 groups according to hemoglobin (Hgb) level: group A (45 patients with Hgb > 12 gm/dl), group B (26 patients with Hgb 10.1-12 gm/dl), and group C (21 patients with Hgb < or = 10 gm/dl). In all patients with SLE, the disease activity was evaluated using the European Consensus Lupus Activity Measurement scale. Antibodies to EPO were detected using an enzyme-linked immunosorbent assay and purified recombinant human EPO as antigen. The specificity of the method was evaluated with homologous and cross-reactive inhibition assays.. Antibodies to EPO were found in 15.2% of the SLE patient sera. The distribution of these antibodies among the 3 groups of SLE patients was as follows: 8.8% (4 of 45) from group A, 15.4% (4 of 26) from group B, and 28.6% (6 of 21) from group C. The prevalence of antibodies to EPO in patients with severe anemia (group C) was statistically significantly higher compared with patients without anemia (chi(2) = 4.31, P < 0.05). Patients with antibodies to EPO had higher disease activity scores (P < 0.005) and lower levels of the C4 component of complement (P < 0.05) compared with patients without antibodies to EPO.. In this study, the presence of antibodies to EPO in the sera of SLE patients is demonstrated for the first time. The presence of these antibodies is associated with severe anemia and active disease.

Topics: Adolescent; Adult; Aged; Anemia; Arthritis, Rheumatoid; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Recombinant Proteins; Sensitivity and Specificity

Topics: Anemia; Arthritis, Rheumatoid; Coma; Critical Care; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Middle Aged; Recombinant Proteins; Respiratory Insufficiency

To investigate the effects of desferrioxamine (DFO) infusion on chronic disease anemia (CDA) of rheumatoid arthritis (RA) by evaluating interleukin-6 (IL-6) and erythropoietin (EPO) production.. Five patients with RA and CDA (group I) were treated with DFO, 500 mg daily, through a continuous 10-h subcutaneous infusion 5 days a week for 4 weeks. One month after withdrawal, DFO was resumed in all five group I patients (group II) with an increase to 1 g daily following the previous treatment schedule. Clinical and laboratory parameters were evaluated weekly during the two study periods. Serum EPO was measured by radioimmunoassay. IL-6 was detected by the enzyme-linked immunoabsorbent assay method.. No significant variations in hematological parameters, IL-6 or EPO levels were observed in group I patients. After 1 week of DFO 1 g daily, reticulocyte counts and EPO improved significantly. Hemoglobin and hematocrit rose significantly after 3 weeks of 1 g daily DFO therapy. Four weeks after DFO withdrawal, EPO, reticulocyte counts, hemoglobin and hematocrit returned to baseline levels. A significant improvement in the clinical parameters of disease activity was observed, particularly in group II patients.. DFO improves CDA in RA patients. The beneficial effects on erythropoiesis seem to be related to improved EPO responsiveness to the anemia.

Topics: Anemia; Arthritis, Rheumatoid; Chronic Disease; Deferoxamine; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Ferritins; Follow-Up Studies; Humans; Infusions, Parenteral; Interleukin-6; Iron; Male; Middle Aged; Siderophores; Treatment Outcome

Serum levels of the transferrin receptor (TfR) were monitored in 12 anemic patients with rheumatoid arthritis (RA) undergoing treatment with recombinant human erythropoietin (rHuEPO) for a 24-week period. Measurement of TfR was performed using an enzyme immunoassay. Compared to a mean pretreatment level of 4.2 mg/l (range 2.1-6.1 mg/l), there was an increase in the mean TfR concentrations from 2 weeks of treatment onwards to a maximum of 7.7 mg/l (range 2.1-12.3 mg/l) at 12 weeks (p < 0.01). Nine of the 12 patients responded to rHuEPO with an increase in blood hemoglobin concentration of 15 g/l or more. An increase in TfR levels was documented not only in the responders but also in the 3 nonresponders. We conclude that in anemic RA patients exogenous erythropoietin induces a swift and sustained increase in the serum concentration of TfR, which probably reflects increased expression of TfR on erythroblasts. This sustained elevation of TfR seems to occur even in patients who do not have an increase in their hemoglobin level.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Erythropoietin; Female; Ferritins; Hemoglobin A; Humans; Male; Middle Aged; Receptors, Transferrin; Recombinant Proteins

Anaemia of chronic disease (ACD) is a common extra-articular manifestation of rheumatoid arthritis (RA). Tumour necrosis factor alpha (TNF alpha) plays an important role in the development of ACD. The objective of the present study was to assess inhibition of in vitro colony-forming unit erythrocyte (CFUe) and blast-forming unit erythrocyte (BFUe) growth by TNF alpha and to examine whether this suppression could be counteracted by adding increasing concentrations of recombinant human erythropoietin (EPO) (r-h-EPO) to bone marrow cultures of RA patients with ACD and without anaemia (controls). Bone marrow cells of RA patients with ACD and control patients were cultured. The cultures were incubated with increasing concentrations of r-h-EPO (0.25; 0.5; 1; 2 U/ml), each in combination with increasing quantities of TFN alpha (0; 50; 100; 200; 400 U/ml). CFUe and BFUe were assessed after 7 and 14 days, respectively. Dose-dependent inhibition of BFUe and CFUe by increasing concentrations of TNF alpha was observed in ACD and controls. Regarding CFUe (ACD patients) incubated with 0.25 U/ml EPO, 50 U/ml TNF alpha caused 28% suppression compared to cultures without TNF alpha. Increasing the concentration of r-h-EPO from 0.25 U/ml to 2 U/ml completely restored the number of CFUe. A similar pattern was observed in BFUe growth in both groups. These data demonstrated the suppressive effects of TNF alpha on erythropoiesis in vitro and that the suppressed erythropoiesis could be partly corrected by the addition of excess r-h-EPO to the cultures. No significant differences were observed between ACD and control RA patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anemia; Arthritis, Rheumatoid; Bone Marrow Cells; Colony-Forming Units Assay; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; In Vitro Techniques; Recombinant Proteins; Tumor Necrosis Factor-alpha

In rheumatoid arthritis (RA) patients undergoing orthopedic surgery, anemia is the major factor in the use of allogeneic blood.. To determine whether recombinant human erythropoietin (rHuEPO) could allow preoperative autologous blood procurement and reduce allogeneic blood exposure, 11 RA patients who were unable preoperatively to deposit blood for autologous use because of their anemia (baseline hematocrit < 34% [0.34]) and who were scheduled for primary total hip replacement or total knee replacement were treated intravenously with 300 U per kg of rHuEPO in combination with intravenous iron saccharate (100 mg), given twice weekly for 3 weeks. The transfusion treatment was compared with that in 12 control patients with comparable baseline hematologic values who underwent the same operation.. Control patients could not preoperatively deposit any blood for autologous use, while all but one of the rHuEPO-treated patients deposited 2 or more units (mean, 2.6 +/- 0.6; range, 2-4) (p < 0.001). The control group received more allogeneic units (2.6 +/- 1.6 vs. 0.8 +/- 0.8) (p = 0.009). Moreover, 50 percent of the rHuEPO-treated patients, as compared with 8 percent of controls, completely avoided allogeneic transfusion.. Recombinant human erythropoietin is safe and effective in stimulating erythropoiesis, allowing preoperative donation of blood for autologous use, and reducing exposure to allogeneic blood for RA patients who are unable preoperatively to deposit blood because of anemia.

Topics: Adult; Arthritis, Rheumatoid; Blood Donors; Blood Transfusion, Autologous; Bone Marrow; Bone Marrow Cells; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Humans; Iron; Male; Middle Aged; Recombinant Proteins; Reticulocytes

1. Serum levels of erythropoietin and the immune parameters tumour necrosis factor-alpha, soluble interleukin-2 receptor, interleukin-2, interleukin-6 and interferon-gamma were measured in patients with rheumatoid arthritis. 2. Out of 69 patients, 44 had anaemia with serum haemoglobin concentrations of 10.8 (SD 1.2) g/dl. In these patients erythropoietin levels were significantly higher than in non-anaemic patients [51.97 (SD 23.9) versus 26.06 (SD 11.9) m-units/ml; P < 0.0001; control patients: 18.1 (SD 13.8) m-units/ml]. Mean soluble interleukin-2 receptor activity was elevated in all patients with rheumatoid arthritis [1324 (SD 715) units/ml; control patients: 480 (SD 75) units/ml; P < 0.001] and was significantly higher in the anaemic group than in the non-anaemic group [1562 (SD 662) versus 696 (SD 402) units/ml; P < 0.0001]. The serum activity of soluble interleukin-2 receptor showed an inverse correlation with haemoglobin (r = 0.79; P < 0.0001) and a positive correlation with erythropoietin (r = 0.70, P < 0.0001). 3. Elevated serum tumour necrosis factor-alpha levels were found in 19 anaemic patients [20.6 (SD 9.1) pg/ml]. Concentrations of tumour necrosis factor-alpha in serum showed an inverse correlation with haemoglobin (r = 0.57, P < 0.001) and a positive correlation with erythropoietin (r = 0.46, P < 0.05). Interleukin-6 was detected in seven anaemic patients [21 (SD 14) pg/ml] and interleukin-2 activity in three anaemic patients (12, 16 and 14 units/ml, respectively). Interferon-gamma was not detected in any of the patients investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Cytokines; Erythropoietin; Female; Humans; Interferon-gamma; Interleukin-2; Interleukin-6; Iron; Male; Middle Aged; Receptors, Interleukin-2; Tumor Necrosis Factor-alpha

We investigated whether determination of serum transferrin receptor (TfR) is useful for detecting iron-deficiency in patients with chronic inflammatory diseases and for differentiating between iron-deficiency anaemia and anaemia of inflammation. Using an immunofluorometric assay, serum TfR was measured in 34 anaemic patients. Of these patients, 23 had a chronic rheumatic disease, 13 with both inflammation and iron-deficiency and 10 with anaemia of inflammation only; the other 11 patients had iron-deficiency anaemia and no evidence of inflammation. Serum TfR concentrations were lower in patients with anaemia of inflammation (2.6 +/- 0.2 mg/l, mean +/- S.E.M.) than in patients with iron-deficiency anaemia (6.7 +/- 1.1 mg/l, P < 0.01) or those with both inflammation and iron deficiency (5.8 +/- 1.0 mg/l, P < 0.01). Among patients with inflammatory disease, correlations between TfR and ferritin concentrations (r = -0.62, P < 0.05) and TfR and erythropoietin concentrations (r = 0.69, P < 0.001) were observed in iron-deficient subjects only. TfR, though not superior to serum ferritin, can help to distinguish between anaemia of inflammation and iron-deficiency anaemia and to identify iron-deficiency in subjects with chronic inflammation.

Topics: Adult; Anemia, Hypochromic; Arthritis, Rheumatoid; Diagnosis, Differential; Erythrocyte Indices; Erythropoietin; Female; Ferritins; Fluoroimmunoassay; Humans; Male; Receptors, Transferrin

12 anemic and 10 non-anemic patients with rheumatoid arthritis were treated with recombinant human erythropoietin (rHuEPO) before arthroplasty. The patients received 400-800 units/kg of rHuEPO subcutaneously once a week. Autologous blood was collected after the hemoglobin concentration was increased by 5 percent or more. All but one of the patients responded to the treatment. They were given 1-3 units of autologous blood, and underwent the operation without homologous blood transfusion. The mean duration of the treatment was 1 month. In 1 patient with severe anemia, additional transfusion with 2 units of blood was necessary during the operation. In all patients, there was a tendency for the hemoglobin response ratio to rHuEPO to correlate negatively with the initial CRP levels. The treatment did not affect the patients' clinical rheumatologic condition and there were no adverse effects. These results demonstrated that the treatment with subcutaneous rHuEPO is both effective and non-toxic and can therefore eliminate the need for homologous blood transfusion in anemic patients undergoing arthroplasty for rheumatoid arthritis.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Blood Transfusion, Autologous; Combined Modality Therapy; Erythropoietin; Female; Hemoglobins; Hip Joint; Hip Prosthesis; Humans; Injections, Subcutaneous; Knee Joint; Knee Prosthesis; Male; Middle Aged; Preoperative Care; Recombinant Proteins

The value of s-Transferrin Receptor (s-TfR) measurements in recognizing simultaneous iron deficiency in anaemia of chronic disease was examined in 35 anaemic patients with active rheumatoid arthritis. Based on a quantification of stainable bone marrow (marrow iron grade 0-4) and serum ferritin concentrations (levels < 60 micrograms l-1) compatible with iron deficiency) the anaemia was found to be aggravated by iron deficiency in 19/35 or 54% of the patients. There was no significant difference between the mean s-TfR concentrations in patients with adequate iron in comparison to patients with iron depletion [2.9 (1.6) mg l-1 v. 2.7 (1.4) mg l-1; t = 0.273; p = 0.786; Student's t-test]. Mean s-TfR levels in both patients with adequate iron and depleted iron stores were within the normal range, but tended to be higher than in normal individuals [mean (SD): 1.54 (0.43) mg l-1]. In patients with no stainable marrow iron (MIG 0; N = 15) a significant inverse correlation was found between s-TfR concentrations and s-ferritin levels (r = 0.57; p < 0.05). 5/15 patients with MIG = 0 exhibited significantly raised concentrations of s-TfR values > 3.05 mg l-1 (the highest normal value of the normal range). Increases of s-TfR levels were consistently moderate, and never exceeded a level of 7 mg l-1, which is markedly lower than concentrations measured in patients with iron deficiency anaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Anemia; Anemia, Hypochromic; Arthritis, Rheumatoid; Bone Marrow; Erythropoietin; Female; Ferritins; Humans; Iron; Male; Middle Aged; Receptors, Transferrin

The importance of autologous blood donation for elective surgery is recognized, and the method is being used at many hospitals. Not all patients are able to deposit a sufficient amount of blood before surgery because they cannot recover rapidly enough from phlebotomy-induced anemia. The ability to donate sufficient blood for autologous use was studied in patients who are particularly susceptible to phlebotomy-induced anemia.. Of 840 patients who donated blood for autologous use in elective surgery from November 1987 through May 1993, 20 with rheumatoid arthritis, 24 with iron deficiency anemia, and 37 aged 65 years and above with normocytic anemia were compared with 24 nonanemic elderly patients who donated a total of 1000 mL of blood for autologous use. Patients received iron sulfate orally and donated blood once a week until operation.. The amount of blood collected before surgery per control patient was more than that in others. Consequently, there was a tendency to allogeneic blood transfusion in patients with rheumatoid arthritis or elderly patients. The ferritin levels in controls and in patients with iron deficiency anemia during the donation period were almost within the normal range in spite of iron supplementation, which implied a good utilization of iron sulfate for erythropoiesis. On the other hand, the rise in ferritin levels in the elderly and in patients with rheumatoid arthritis suggested inappropriate iron availability for erythropoiesis and resulted in an increase in iron storage. Since an adequate endogenous erythropoietin response to phlebotomy-induced anemia was not observed in these patients, impaired erythropoietin production was considered one of the reasons for anemia.. Patients with iron deficiency anemia are able to continue donating blood for autologous use so long as they have sufficient iron supplementation. However, the elderly or those with rheumatoid arthritis occasionally fail to donate a sufficient volume of blood before surgery as a result of phlebotomy-induced anemia, which is caused in turn by impaired erythropoietin production.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Hypochromic; Arthritis, Rheumatoid; Blood Donors; Blood Transfusion, Autologous; Bloodletting; Erythropoietin; Female; Humans; Iron; Male; Middle Aged; Time Factors

Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Arthritis, Rheumatoid; Biomarkers; Cyclosporine; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Hematocrit; Humans; Middle Aged

Topics: Acquired Immunodeficiency Syndrome; Anemia; Arthritis, Rheumatoid; Autoimmune Diseases; Blood Donors; Erythropoietin; Hematologic Diseases; Humans; Kidney Failure, Chronic; Neoplasms; Recombinant Proteins

The effect of recombinant human erythropoietin (rHuEPO) on haem biosynthesis in peripheral red blood cells was evaluated in 12 patients with RA and anaemia (mean haemoglobin concentration 102 g/l, range 90-109 g/l). Before treatment, the serum concentrations of erythropoietin (EPO) were low (mean 13 pmol/l, range 5-32 pmol/l), the activities of haem-synthesizing enzymes within the reference intervals and the erythrocyte protoporphyrin (E-PROTO) concentrations clearly higher than normal. Nine patients responded with an increase in the haemoglobin level of 15 g/l or more. rHuEPO induced a rise in the mean haem synthase (HAEM-S) activity from a baseline of 12.1 to a maximum of 26.8 pmol/h per 10(6) reticulocytes after 20 weeks of treatment (P < 0.002). The mean E-PROTO concentration also rose and reached its maximum at 8 weeks of treatment. We conclude that correction of anaemia in patients with RA using rHuEPO is associated with an activation of HAEM-S, commonly regarded as the rate-limiting enzyme of haem synthesis in erythroid cells. Functional iron deficiency probably explains the simultaneous rise in E-PROTO concentration.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Erythrocytes; Erythropoietin; Female; Heme; Hemoglobins; Humans; Male; Middle Aged; Protoporphyrins

We performed a 24-week open clinical study in which 12 patients with rheumatoid arthritis (RA) and anemia (mean hemoglobin (Hb) value 102 g/l, range 90-109 g/l) were treated with recombinant human erythropoietin (rHuEPO). rHuEPO was given as a subcutaneous injection twice weekly with an initial dose of 300 U/kg/week. Nine of the 11 patients who completed the study responded with an increase in Hb value of 15 g/l or more within 3 to 17 weeks. Three months after treatment the Hb levels were significantly lower than the highest Hb levels (p < 0.0001). There was an inverse correlation between the response rate and the mean serum concentrations of C-reactive protein and serum amyloid A protein (p < 0.001 and p < 0.003, respectively). We conclude that rHuEPO can correct anemia in patients with RA, but the response seems to be adversely influenced by the inflammatory activity of the disease.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Injections, Subcutaneous; Male; Middle Aged; Recombinant Proteins

Topics: Anemia; Arthritis, Rheumatoid; Erythropoietin; Humans; Interleukin-6; Recombinant Proteins

Previous studies of the erythropoietin response to anaemia in RA have yielded conflicting findings. Some have found the response to be impaired and others have found a normal response. We have compared erythropoietin (EPO) levels measured by radioimmunoassay, in 54 anaemic rheumatoid patients and 55 patients with iron deficiency anaemia but no inflammatory disease. The erythropoietin response in the rheumatoid patients was impaired compared with the control group (P < 0.025) but only seven rheumatoid patients showed a response which fell below the 95% confidence intervals predicted for the control group. Rheumatoid patients who fell within the highest quartile for serum ferritin concentrations (i.e. those most likely to have anaemia of chronic disease) had significantly lower EPO levels compared with the control group (P < 0.01). EPO levels in rheumatoid patients within the lowest quartile for ferritin (i.e. those with iron deficiency anaemia) were not significantly different from the control group (P = 0.670). The difference in EPO response between the RA patients in the upper and lower quartile for ferritin approached but did not achieve significance (P = 0.056). In a second study 15 anaemic RA patients were given a 5-day course of oral prednisolone 1.5 mgkg-1. Hemoglobin did not rise significantly until day 4 but EPO levels fell by day 1 (P < 0.005) and remained lower than pretreatment values throughout the study. Thus, in RA patients, anaemia of chronic disease is associated with inappropriately low EPO concentrations but this does not appear to be the major cause of the anaemia and Hb response to prednisolone does not depend upon an increase in EPO concentration.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Anemia, Hypochromic; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Male; Middle Aged; Prednisolone; Radioimmunoassay; Time Factors

Topics: Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Humans

A consistent elevated level of erythropoietin was found in eight patients with R.A., who continuously for 10 years had a low hemoglobin (< 8 mmol/l) compared with nine patients with R.A., who had a normal hemoglobin (> or = 8 mmol/l) (p = 0.017). A significant inverse correlation between erythropoietin and hemoglobin (r = -0.61) was found in the low-hemoglobin group, but not in the normal-hemoglobin group. Erythropoietin was not found to be correlated to clinical variables.

Topics: Adult; Analysis of Variance; Arthritis, Rheumatoid; Blood Sedimentation; Erythropoietin; Female; Hemoglobins; Humans; Middle Aged; Reference Values; Regression Analysis

Topics: Acquired Immunodeficiency Syndrome; Arthritis, Rheumatoid; Erythropoietin; Forecasting; Humans; Neoplasms; Postoperative Care

Ten rheumatoid arthritis (RA) patients with anemia of chronic disorders (ACD) were treated with recombinant human erythropoietin (r-Hu-Epo) using a dose of 250 U/kg s.c. 3 times a week for 6 weeks, in order to evaluate its effects on the anemia, iron stores, and serum-soluble transferrin receptor (sTfR) levels. All patients showed a rise in hemoglobin (Hb). Median Hb increased from 5.9 (5.5-7.0) at baseline to 6.7 (5.8-7.8) at 3 weeks and to 7.2 (5.9-8.5) mmol/l at 6 weeks during treatment. Ferritin levels decreased significantly during the 6 weeks, and five patients were iron deficient after 6 weeks of treatment. TfR levels increased significantly at 3 and 6 weeks during treatment. These preliminary findings may indicate that r-Hu-Epo is effective in improving ACD in RA. The sTfR rise may be explained by an increase in erythroid precursor cell mass or increased TfR expression and a decrease in tissue iron stores, although direct effects of Epo on TfR regulation cannot be excluded. Large double-blind studies with r-Hu-Epo in patients with RA and ACD are warranted.

Topics: Aged; Anemia; Arthritis, Rheumatoid; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Male; Middle Aged; Receptors, Transferrin; Recombinant Proteins

Erythroid alterations were studied in 136 patients with rheumatoid arthritis (RA). Anemia was present in 75 cases. A definite diagnosis was determined in 65. The most frequent anemia was that of chronic disease (ACD) (43 cases); 14 patients with ACD presented with moderate to severe anemia. Prevalence of deficiencies were also high (15 cases had iron deficiency anemia, IDA). Serum erythropoietin levels were different in patients with RA compared with a healthy control group (p < 0.00001). Serum erythropoietin was increased in ACD (49 +/- 28.8 U/l) with respect to both RA (38.6 +/- 12.7 U/l, p = 0.0036) and controls (18.2 +/- 7.6 U/l, p < 0.00001). Although hemoglobin (Hb) was similar in ACD and IDA, serum erythropoietin in ACD was lower than in IDA (p = 0.01). There was a negative relationship between Hb and serum erythropoietin in ACD (r = -0.42, p = 0.005). In conclusion, almost 50% of patients with RA have anemia and ACD is the most frequent. As serum erythropoietin in ACD is blunted, patients with moderate to severe ACD are possible candidates for erythropoietin treatment.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Female; Folic Acid Deficiency; Humans; Male; Middle Aged; Prevalence; Prospective Studies; Vitamin B 12 Deficiency

Topics: Arthritis, Rheumatoid; Down-Regulation; Erythropoietin; Humans; Iron

Topics: Arthritis, Rheumatoid; Erythropoietin; Humans; Kidney Diseases; Quality of Life

Eleven patients with chronic inflammatory arthritides and haemoglobin concentrations less than 105 g/l with symptoms from their anaemia were treated with a dose of 250 IU/kg/week of recombinant human erythropoietin for six weeks. The treatment was given as subcutaneous injections five days a week. All patients had active inflammatory disease. Nine patients responded to treatment with an increase in haemoglobin of more than 15 g/l. The mean (SD) haemoglobin concentration increased from 93.0 (8.0) g/l before treatment to 115.0 (12.0) g/l after six weeks. There was no correlation between the initial serum concentration of erythropoietin and the response. It was concluded that anaemia in chronic inflammatory arthritides responds to treatment with subcutaneous injections of recombinant human erythropoietin.

Topics: Administration, Cutaneous; Adult; Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Female; Humans; Male; Middle Aged

Anaemia in rheumatoid arthritis (RA) is a common and debilitating complication. The most common causes of this anaemia are iron deficiency and anaemia of chronic disease. Investigations have suggested that interleukin 1 (IL-1) or tumour necrosis factor (TNF), or both, from monocytes associated with chronic inflammation are responsible for the anaemia of chronic disease. On bone marrow examination anaemia of chronic disease is characterised by the diversion of iron from the erythropoietic compartment into marrow macrophages. This phenomenon is termed failure of iron utilisation. In this study, CFU-E (colony forming unit erythroid; late red cell precursors) and BFU-E (burst forming unit erythroid; early red cell precursors) stem cells were cultured from 10 normal marrow samples and 12 marrow samples from patients with RA with iron deficiency anaemia and 10 samples from patients with RA with failure of iron utilisation. All patients with RA were anaemic (haemoglobin less than 100 g/l), Potential accessory or inhibitory cells of erythropoiesis (CD4, CD8, or CD14 positive cells) were removed before culture. Control marrow samples were studied in a similar manner. Normal marrow samples yielded 377 (17) CFU-E and 133 (6) BFU-E (mean (SD)) colonies for each 2 x 10(5) light density cells plated. CD4 ablation caused reductions of 62 and 100% in CFU-E and BFU-E colonies respectively. CD14 removal resulted in considerable but lesser reductions of 46% for CFU-E and 25% for BFU-E. In both groups of patients with RA, CFU-E colony numbers were significantly lower than those seen in normal control subjects, 293 (17) for patients with iron deficiency anaemia and 242 (35) for patients with failure of iron utilisation. BFU-E colony numbers were 102 (13) and 108 (20) respectively. In patients with RA, CD4 removal caused a significantly greater loss of CFU-E colonies compared with normal control subjects. Cytolysis of CD14 positive cells caused a reduction in CFU-E colonies in the two RA groups which was similar to that seen in normal subjects. In conclusion, patients with RA seem to have fewer CFU-E progenitors but essentially normal numbers of BFU-E stem cells. Our data suggest a stimulatory role for marrow CD4 and CD14 cells in erythropoiesis in patients with RA. Monocytes-macrophages (CD14 positive) are known to be producers of IL-1 or TNF, or both, however, the predicted increase in the CFU-E colonies on removal of CD14 cells is not seen. Therefore, if IL-1 or TNF, or bot

Topics: Anemia; Arthritis, Rheumatoid; Bone Marrow; Cells, Cultured; Chronic Disease; Erythropoiesis; Erythropoietin; Humans; Interleukin-1; Macrophages

Topics: Adult; Anemia; Arthritis, Rheumatoid; Bone Marrow; Erythropoietin; Humans; Macrophages; Middle Aged; Reference Values

In this study we determined the serum erythropoietin (Epo) levels of 97 anaemic rheumatoid (RD) patients (Hb less than 11 g/dl) of whom 44 had serum ferritin greater than 60 micrograms/l (anaemia of chronic disorders; ACD), 26 had ferritin 20-60 micrograms/l and 27 had ferritin less than 20 micrograms/l. These results were compared with the Epo levels of 36 iron deficient controls (Hb less than 11 g/dl), 33 non-anaemic RD patients and 33 normals. The serum Epo levels of anaemic subjects were significantly higher (P less than 0.05) than those of non-anaemic patients. Despite similar Hb, the Epo results (geometric mean (confidence limits] of the ACD group (38 (32,45) mU/ml) and of RD patients with ferritin of 20-60 micrograms/l (39 (33,46)mU/ml) were significantly lower (P less than 0.05) than those of iron deficient controls (65 (52,80)mU/ml). When the Hb fell to 10 g/dl or less, the serum Epo of 13 RD patients with ferritin less than 20 micrograms/l was 65 (47,89)mU/ml, significantly lower (P less than 0.05) than that of 17 iron deficient controls (104 (78,136)mU/ml). These results justify clinical trials of recombinant human Epo in RD patients with ACD.

Topics: Adult; Anemia; Arthritis, Rheumatoid; C-Reactive Protein; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Male; Middle Aged; Reference Values

Topics: Anemia; Arthritis, Rheumatoid; Erythropoietin; Humans; Recombinant Proteins

Topics: Anemia; Arthritis, Rheumatoid; Erythropoietin; Humans; Recombinant Proteins

We treated 5 patients with rheumatoid arthritis (RA) with anemia of chronic disease with recombinant human erythropoietin (rHuEPO) for 11 weeks. An increase in hematocrit (Hct) greater than 5 was seen in 4 patients after 4 weeks of therapy. The 5th patient had a significant rise in Hct when the dosage of rHuEPO was increased to 150 units/kg from the 4th to 7th week. The subcutaneous administration of rHuEPO dose, reduced by one third with respect to initial dose, maintained an effective Hct value in all the 5 patients during the last 4 weeks of therapy. There was no change in disease activity. In one patient Hct normalization completely resolved symptoms of angina pectoris and permitted hip replacement surgery in another. No side effects occurred during rHuEPO therapy. We conclude that HuEPO is an effective, safe and well tolerated therapy for RA patients with severe anemia of chronic disease.

Topics: Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Female; Hematocrit; Humans; Injections, Subcutaneous; Male; Middle Aged; Recombinant Proteins

Serum erythropoietin (S-EPO) levels were measured in 50 patients with anaemia of chronic disorders (ACD), classified into three groups according to their aetiology: inflammatory (n = 20), infectious (n = 15) and neoplastic (n = 15). The inflammatory group showed a higher mean S-EPO level (mean value +/- SEM, 69 +/- 11 mU ml-1) than the neoplastic (43 +/- 5 mU ml-1; P less than 0.05) and infectious groups (27 +/- 4 mU ml-1; P less than 0.01). The S-EPO level in the inflammatory group also differed from that of 32 healthy controls (36 +/- 3 mU ml-1; P less than 0.05). Fourteen patients with added iron deficiency (12 subjects from the inflammatory group) showed the highest S-EPO concentration (72 +/- 17 mU ml-1). Conversely, S-EPO levels were lower in febrile subjects (12 patients with infection and five with malignancy) than in non-febrile patients (28 +/- 4 mU ml-1 vs. 55 +/- 7 mU ml-1; P less than 0.01). In the infectious group, the logarithm of S-EPO correlated directly with the haemoglobin and haematocrit values. We conclude that differences in S-EPO concentration in ACD may be further related to the patient's iron stores and temperature. A decrease in EPO production may contribute to the pathogenesis of ACD secondary to infection.

Topics: Anemia; Anemia, Hypochromic; Arthritis, Rheumatoid; Bacterial Infections; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Male; Middle Aged; Neoplasms

Topics: Anemia; Arthritis, Rheumatoid; Erythropoietin; Humans

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins

Topics: Anemia; Animals; Arthritis, Rheumatoid; Chronic Disease; Erythrocyte Aging; Erythropoietin; Female; Folic Acid Deficiency; Humans; Lupus Erythematosus, Systemic; Male; Recombinant Proteins; Vitamin B 12 Deficiency

Erythropoietin (Epo) receptors have been delineated using radioiodinated recombinant erythropoietin (rEpo) and highly purified murine and human erythroid colony-forming units (CFU-e). The murine CFU-e had 950 receptors/cell. One-third had a Kd of 0.09 nM while two-thirds had a Kd of 0.57 nM. Human CFU-e had 1,050 receptors/cell. Two hundred had a Kd of 0.10 nM and 850 had a Kd of 0.57 nM. 125I-rEpo was rapidly internalized and degraded by the CFU-e. Cross-linking of 125I-rEpo to human Epo receptors demonstrated two proteins of 100 and 90 kDa and proteolytic peptide mapping of each protein showed identical fragments indicating that they are very similar. rEpo was also used to treat patients with the anemia of rheumatoid arthritis, and one case is presented in which the patient's hematocrit rose from 32.5% to 44% in eight weeks. When the rEpo was discontinued, the hematocrit fell back to 33%.

Topics: Aged; Anemia; Animals; Arthritis, Rheumatoid; Cross-Linking Reagents; Culture Techniques; Erythroid Precursor Cells; Erythropoietin; Humans; Male; Mice; Receptors, Cell Surface; Receptors, Erythropoietin; Recombinant Proteins

Serum erythropoietin (EPO) was measured by radioimmunoassay in 67 patients with rheumatoid arthritis (RA). Twenty of these patients judged to have iron deficiency anemia, based on reduced serum ferritin levels, had higher serum EPO levels than did the 24 other anemic patients with normal or elevated serum ferritin levels. A significant negative correlation between serum EPO and hemoglobin concentrations was noted in the former group, but not in the latter. Human recombinant erythropoietin (r-EPO) was administered to 6 anemic patients with RA, resulting in improvement of anemia in 4 patients, 2 of whom showed no change in RA activity. These findings suggest a suppressed serum EPO response ot anemia and the effectiveness of r-EPO in treating anemia associated with RA.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Arthritis, Rheumatoid; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins

Thirty six patients with rheumatoid arthritis (RA) (25 with anaemia) were studied to establish the role of iron, vitamin B12, and folic acid deficiency, erythropoietin responsiveness, and iron absorption in the diagnosis and pathogenesis of anaemia in RA. Iron deficiency, assessed by stainable bone marrow iron content, occurred in 13/25 (52%), vitamin B12 deficiency in 7/24 (29%), and folic acid deficiency in 5/24 (21%) of the anaemic patients. Only 8/25 (32%) had just one type of anaemia. The iron deficiency of anaemia of chronic disease (ACD) was distinguished by ferritin concentration, which was higher in that group. Mean cell volume (MCV) and mean cell haemoglobin (MCH) were lower in both anaemic groups, but most pronounced in iron deficient patients. Folic acid, and especially vitamin B12 deficiency, masked iron deficiency by increasing the MCV and MCH. Iron absorption tended to be highest in iron deficiency and lowest in ACD, suggesting that decreased iron absorption is not a cause of ACD in RA. No specific causes were found for vitamin B12 or folic acid deficiency. Haemoglobin concentration was negatively correlated with erythrocyte sedimentation rate in the group with ACD. Erythropoietin response was lower in ACD than in iron deficient patients. It was concluded that generally more than one type of anaemia is present simultaneously in anaemic patients with RA. The diagnosis of each type may be masked by another. Studies on pathogenesis of the anaemia are difficult as deficiencies generally coexist with ACD. Disease activity and, possibly, erythropoietin responsiveness are major factors in ACD pathogenesis.

Topics: Aged; Anemia; Anemia, Hypochromic; Arthritis, Rheumatoid; Bone Marrow; Chronic Disease; Erythropoietin; Female; Folic Acid Deficiency; Humans; Iron Deficiencies; Male; Middle Aged; Vitamin B 12 Deficiency

Topics: Anemia; Arthritis, Rheumatoid; Erythropoietin; Humans; Recombinant Proteins

Immunoreactive serum erythropoietin concentrations were measured in 35 patients with anaemia associated with active rheumatoid arthritis. Based on an evaluation of stainable iron in the bone marrow (marrow iron grade 0-4) and serum ferritin concentrations (concentrations less than or equal to 60 micrograms/l compatible with iron deficiency) the anaemia was found to be complicated by iron deficiency in 19/35 (54%) of the patients. The mean serum erythropoietin level (57.6 (SD) 27.3) U/l) was sufficiently raised for the degree of anaemia irrespective of the size of the marrow iron stores. Thus the data do not support the contention that suppressed secretion of erythropoietin is involved in the pathogenesis of anaemia of chronic disorders. There was a significant inverse correlation between the haemoglobin concentration and log serum erythropoietin in the patients with rheumatoid arthritis. In the patients with adequate iron stores, but not in the iron depleted patients, there was a tendency for serum erythropoietin concentrations to correlate positively both with C reactive protein and erythrocyte sedimentation rate. Red cell distribution width (mean (SD) 16.3 (1.8)%) was above normal (11.5-14.5%) both in the iron replete and the iron depleted patients, and the mean red cell distribution width values did not differ significantly among the two subpopulations. The plasma lactoferrin concentration (mean (SD) 137.6 (109.9) micrograms/l) was normal and did not differ significantly between the iron deficient patients and those with adequate iron.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythrocyte Indices; Erythrocyte Volume; Erythrocytes; Erythropoietin; Female; Ferritins; Humans; Iron; Male; Middle Aged

A sensitive radioimmunoassay (RIA) for the detection of erythropoietin (EPO) was developed using anti-recombinant EPO antibody with high affinity. The sensitivity was 100 amol/tube (5 mIU/ml) and it was possible to detect a serum EPO level between 5 and 200 mIU/ml. This method enabled us to measure native EPO as well as recombinant EPO. With this method we determined serum EPO levels in healthy individuals and patients with chronic renal disease, rheumatoid arthritis and iron deficiency anemia. Values in patients with chronic renal disease were lower than those in healthy individuals, while values in patients with rheumatoid arthritis, or iron deficiency anemia were significantly higher than those in healthy individuals.

Topics: Anemia, Hypochromic; Arthritis, Rheumatoid; Erythropoietin; Evaluation Studies as Topic; Female; Humans; Kidney Failure, Chronic; Male; Radioimmunoassay; Recombinant Proteins; Reference Values

Two anemic patients with rheumatoid arthritis were treated with recombinant human erythropoietin (EPO) for 5 months. Both patients showed significant increases in hematocrit, red cell volumes, and marrow erythroid and megakaryocyte progenitor cells. No significant toxic effects from EPO were observed. These data indicate that EPO may be effective in overcoming the pathogenetic factors that limit erythropoiesis in rheumatoid arthritis.

Topics: Adult; Anemia; Arthritis, Rheumatoid; Blood Cell Count; Bone Marrow; Colony-Forming Units Assay; Erythropoietin; Female; Hematocrit; Humans; Middle Aged; Recombinant Proteins; Vitamin B 12

Serum immunoreactive erythropoietin (EP) levels were measured in 116 patients with rheumatoid arthritis (RA) and 20 control patients with iron deficiency anemia. Serum EP levels were significantly higher in the 46 anemic RA patients than in the 70 nonanemic RA patients (mean +/- SD 31.0 +/- 19.8 mU/ml versus 16.8 +/- 12.4 mU/ml; P less than 0.0001). Furthermore, although a significant inverse correlation between the serum EP level and the hemoglobin value was present in the anemic RA patients (r = -0.57, P less than 0.0001), the regression coefficient describing the relationship between serum EP and hemoglobin was significantly lower for the anemic RA patients than for patients with iron deficiency anemia (F = 6.01, P less than 0.025).

Topics: Anemia; Arthritis, Rheumatoid; Erythropoietin; Female; Hemoglobins; Humans; Male; Radioimmunoassay; Regression Analysis

Erythropoietin titers when related to the hematocrit percentage and measured by bioassay in 33 normal volunteers and in 61 patients with anemias not complicated by renal or chronic disease were found to overlap with titers measured by radioimmunoassay in 20 normals and 28 patients with similar anemias. Erythropoietin titers measured by radioimmunoassay in 34 patients with rheumatoid arthritis, 25 patients with sickle cell anemia (58 separate samples), and 28 patients with erythroid hypoplasia caused by hematologic malignancies were compared with those in the control group of patients with uncomplicated anemias and found not to differ significantly from titers in this group. Erythropoietin titers measured by bioassay in 12 patients with aplastic anemia also fell within the range of those in the control group. Consequently, erythropoietin titers in these anemias appear to be determined primarily by the degree of anemia and not by any specific effect of these illnesses on the production of erythropoietin.

Topics: Anemia; Anemia, Aplastic; Anemia, Sickle Cell; Arthritis, Rheumatoid; Biological Assay; Erythropoietin; Female; Hematologic Diseases; Humans; Male; Radioimmunoassay; Red-Cell Aplasia, Pure

Serum erythropoietin (s-Epo) was measured with a sensitive radioimmunoassay method in 58 patients with classical rheumatoid arthritis (n = 41) or seronegative spondyloarthropathies (n = 17). Epo was significantly (P less than 0.001) increased and on an average two times higher than in a healthy population. A correlation was found between Hb and s-Epo (r = -0.46, P less than 0.005), indicating that these patients respond to anaemia with an increase in s-Epo. In order to investigate if inflammation has a direct influence on s-Epo levels a short period of corticosteroid treatment was given to rapidly decrease inflammatory activity. No increase in s-Epo was seen after 1 week. Furthermore, there was a correlation between s-Epo and ESR in all patients (r = 0.59, P less than 0.01). These results indicate that s-Epo is directed by the Hb level, which in turn is influenced by the inflammatory activity: a higher inflammatory activity gives a lower Hb and an increase in s-Epo. In comparison to previously published figures for the relation between Hb and s-Epo these patients seem to have an ordinary Epo response. We conclude that the anaemia of patients with chronic inflammatory joint disease is not caused by a diminished Epo production.

Topics: Adult; Aged; Anemia; Anti-Inflammatory Agents; Arthritis; Arthritis, Rheumatoid; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Radioimmunoassay

The relationship of serum immunoreactive erythropoietin to haemoglobin concentration was defined for 54 patients with rheumatoid arthritis (RA) and 41 patients with anaemia of varying aetiology (excluding pregnancy and renal insufficiency), not associated with RA. Significant inverse correlations between the logarithm of serum immunoreactive erythropoietin and the haemoglobin concentration were noted for the anaemic patients in both groups. The regression line for the RA patients had a similar slope, but a significantly lower y-intercept as compared to that for the non-RA patients. Erythropoietin levels were also significantly lower for the group of RA patients than for the group of non-RA patients when matched for comparable haemoglobin concentrations. These studies suggest that the erythropoietin response to anaemia in RA is intact but blunted relative to that for anaemia of other aetiologies. Lower levels of serum erythropoietin in anaemic RA patients may contribute to the pathogenesis of their anaemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Anemia, Hypochromic; Arthritis, Rheumatoid; Child; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged

The normal response to anemic or hypoxic hypoxia is synthesis and release of erythropoietin in accord with the concept that erythropoietin production is controlled by a renal oxygen sensor. In this study, erythropoietin production, as predicted, was abrogated in patients with renal impairment (55 cases), but normal in nonuremic individuals. Specifically, patients with rheumatoid arthritis (34 cases), sickle cell anemia (25 cases), aregenerative anemia (27 cases), and aplastic anemia (13 cases) had erythropoietin titers overlapping with those observed in simple anemia (61 cases) at corresponding hematocrits. The response of polycythemic laboratory animals to hypoxia is more difficult to fit within the concept of an oxygen sensor responsive both to anemic and hypoxic hypoxia. If the polycythemia was induced by hypertransfusion, erythropoietin production in response to hypoxia was, as predicted, less than that observed in normal animals. If, however the polycythemia was induced by previous exposure to hypoxia, the animals responded to hypoxia as though they were not polycythemic. An explanation for this challenging observation may provide a clue as to the operation of the oxygen sensor.

Topics: Anemia; Animals; Arthritis, Rheumatoid; Erythropoietin; Feedback; Humans; Hypoxia; Kidney; Kidney Diseases; Mice; Oxygen; Polycythemia

Topics: Adult; Aged; Arthritis, Rheumatoid; Bone Marrow; Erythroblasts; Erythrocytes; Erythropoietin; Female; Heme; Humans; Male; Middle Aged

Iron status and erythropoietin (Ep) level in serum and urine were determined in 30 patients with anaemia in rheumatoid arthritis. The anaemia in these patients was mild and fulfilled the criteria for anaemia of chronic disorders. The iron status of these patients differed from the iron status in patients with sideropenic anaemia. Serum Ep, level, measured indirectly by the polycythaemic mouse bioassay, was either not detected or when detected it did not correspond to the degree of anaemia. The data suggest that the failure to produce sufficient amount of Ep, among other causes, could be important in the pathogenesis of anaemia in rheumatoid arthritis.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Erythropoietin; Female; Hemoglobins; Humans; Iron; Male; Middle Aged

Topics: Anemia, Hypochromic; Arthritis, Rheumatoid; Erythropoietin; Female; Humans; Male; Polycythemia; Polycythemia Vera; Uremia

A major factor in the anemia of infection, inflammation, and malignancy is a relative failure of the bone marrow to increase erythropoiesis in response to a shortened red cell survival. The possible causes for this diminished marrow response are: (a) a reduced production of erythropoietin, or, (b) impaired bone marrow response to erythropoietin. In this report studies were performed on 6 normals, 13 patients with anemia from infection or inflammation, and 18 patients with anemia caused by advanced malignancy. Serum erythropoietin activity was measured using the posthypoxic, polycythemic mouse assay. Assessment of bone marrow response to erythropoietin was made by measuring (59)Fe-heme synthesis in bone marrow suspensions cultured for 3 days with and without the addition of erythropoietin. The results showed that marrow heme synthesis was increased in erythropoietin-treated cultures as compared with saline control cultures by 66+/-8% (mean +/-SE) in normals, 101+/-10% in patients with infection or inflammation, and 31+/-5% in malignancy. Serum erythropoietin levels were consistently diminished relative to expected levels for the degree of anemia in the infection-inflammatory group, but not in malignancy. In these patients, plasma inhibitors to the biological activity of erythropoietin were not detected in vitro. These studies suggest that another factor to consider in the anemia of malignancy is a decreased bone marrow response to erythropoietin. In the anemia of infection-inflammation, marrow response to erythropoietin is normal, but serum levels of erythropoietin are decreased relative to the degree of anemia.

Topics: Aged; Anemia; Animals; Arthritis, Rheumatoid; Biological Assay; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Female; Heme; Humans; Infections; Iron Radioisotopes; Male; Mice; Middle Aged; Neoplasms; Rats

Topics: Anemia; Arthritis, Rheumatoid; Blood Proteins; Bone Marrow; Bone Marrow Cells; Chronic Disease; Erythropoietin; gamma-Globulins; Hematocrit; Humans; Infections; Iron; Neoplasms; Protein Biosynthesis; Serum Albumin; Transferrin; Vitamin B 12

Topics: Anemia; Anemia, Hypochromic; Arthritis, Rheumatoid; Erythropoietin; Hematocrit; Humans; Neutralization Tests