Effect of recombinant human erythropoietin on anaemia and disease activity in patients with rheumatoid arthritis and anaemia of chronic disease: a randomised placebo controlled double blind 52 weeks clinical trial. Enterally dosed recombinant human erythropoietin does not stimulate erythropoiesis in neonates. Follow-up of very low birth weight infants after erythropoietin treatment to prevent anemia of prematurity. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Availability of iron and degree of inflammation modifies the response to recombinant human erythropoietin when treating anemia of chronic disease in patients with rheumatoid arthritis. Effects of early human recombinant erythropoietin therapy on the transfusion in healthy preterm infants. [Early erythropoietin use for the prevention of anemia in infant premature]. A program for improving energy conservation behaviors in adults with rheumatoid arthritis. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. Effects of altering dietary essential fatty acids on requirements for non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis: a double blind placebo controlled study. Changes in thrombopoiesis and platelet reactivity in extremely low birth weight infants undergoing erythropoietin therapy for treatment of anaemia of prematurity.
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. Human fetuses and neonates ingest erythropoietin (Epo) when they swallow amniotic fluid, colostrum, and human milk. This study was designed to determine whether enterally dosed recombinant Epo (rEpo) stimulates erythropoiesis in preterm neonates.
                Preterm infants (<1500 g birth weight) were randomly assigned to receive feedings supplemented with either rEpo (1000 U/kg per day) or placebo for 14 days (n=36). Reticulocyte counts, serum Epo concentrations, hematocrit, and zinc protoporphyrin to heme ratios were measured at baseline and after 7 and 14 days of study drug administration. Transfusion guidelines were followed. Transfusion requirements, medications, feeding tolerance, and clinical diagnoses were documented.
                Enteral rEpo was well tolerated. There were no differences in erythropoietic indexes based on treatment group. Serum Epo concentrations were not different in the treatment versus placebo group, nor were transfusion requirements.
                Enterally dosed rEpo (1000 U/kg/day) does not significantly influence erythropoiesis or iron utilization when given for a 2-week period, nor does it elevate the serum Epo concentration in preterm or term infants. Oral administration of rEpo is not an effective substitute for parenteral administration. Treatment with recombinant human erythropoietin (rHuEPO) stimulates erythropoiesis and reduces the need for transfusions in hospitalized preterm infants. The aim of our study was to follow very low birth weight infants after the initial 6 weeks of rHuEPO treatment.
                We randomly assigned 97 very low birth weight infants with a gestational age of 31 weeks or less and birth weight of 1500 gm or less to receive rHuEPO, 300 units/kg per week (erythropoietin (EPO) 300, n = 33), rHuEPO, 750 units/kg per week (EPO 750; n = 28), or no treatment (control, n = 36). The rHuEPO was administered from the first week of life for 6 weeks. After EPO therapy was discontinued, 75 neonates were followed weekly until discharge and at 3, 6, and 12 months of age.
                Mean numbers (+/- SD) of packed erythrocyte transfusions per patient from the time rHuEPO therapy was discontinued until discharge were 0.38 +/- 0.64 (EPO 300), 0.23 +/- 0.52 (EPO 750), 0.9 +/- 1.1 (control) (p < 0.05 in both EPO groups vs control). Mean reticulocyte counts at the sixth week were 6% +/- 2.2% (EPO 300), 6.9% +/- 2.2% (EPO 750), and 3.1% +/- 2.6% (control) in the three groups (p < 0.01 in both EPO groups vs control), and at the eighth week were 4.7% +/- 2.8% (EPO 300), 5.4% +/- 2.7% (EPO 750), and 2.6% +/- 2.2% (control) (p < 0.01 in both EPO groups vs control). Serum ferritin levels were significantly higher at the sixth week, and the percentage of hemoglobin F was significantly lower at 6, 8, and 10 weeks in the control group versus EPO groups. At 3, 6, and 12 months of age, there were no differences in reticulocytes, ferritin, HbF, and growth among groups.
                Preterm infants who received rHuEPO had a normal pattern of erythropoiesis after the drug was discontinued. These data provide strong evidence that the anemia of prematurity is the result of a transient developmental abnormality in EPO production. 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. 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. Early recombinant erythropoietin therapy and iron therapy would decrease the need for red blood cells transfusions and prevents anemia of prematurity.
                Fifty-eight preterm infants in newborn services at Ghaem Medical Center randomly were assigned, among them 18 patients were excluded. A total of 40 preterm infants with gestational age 28-34 weeks, birth weight 1000-1750 g followed the study: 20 infants in treatment group and 20 infants in control group were randomized to treatment (rhu EPO, 500u per kg, per week, 2 times weekly, subcutaneous) and control (no treatment). Therapy was initiated 4 days after birth and continued throughout the 4 weeks. All infants on enteral feeds received supplements: iron 3 mg/kg/d, vitamins and folat. Complete blood cells and reticulocyte counts were measured weekly. Transfusions and phlebotomy data were recorded. Statistical significance was determined by chi-square test, student t test and Mann-Whitney. A P value of < 0.05 was considered statistically significant.
                The reticulocyte counts were higher in treated infants during the study (p: 0.009). Final hematocrits were higher in treated infants (p: 0.02).The volume of packed red blood cells transfusions mililiter per infant significantly reduced (p: 0.05), the average number of transfusion per infant was also lower for treated infant than control [2 (10 % )vs 8 (40%) respectively]. No adverse effects of EPO or supplemental iron occurred.
                The combination of early rhu EPO and iron as administered in the present study stimulated erythropoiesis and decreased red blood cells transfusion in premature infants who were 1000-1750 g at birth. The enrollments of the larger and healthier preterm infants, who are at lower risk for transfusion, are limitation of the present study. Anemia is common among very low birth weight newborns and requires frequent blood transfusions. Erythropoietin was been reported to be useful in the prevention of this anemia.
                To assess the benefits of early (before the third week of life) Human recombinant Erythropoietin (r-EPO) administration to reduce the requirement of blood transfusions in very low birth weight newborns.
                Sixty newborns under 1500 g of birthweight were randomly assigned to receive r-EPO (n = 29) or placebo (n = 31) three times per week, during four weeks. Packed red cell volume and reticulocyte counts were measured weekly. Serum erythropoietin was measured prior to eighth dose. Transfusion requirements were recorded.
                r-EPO reduced transfusions from 1.41 +/- 1.1 to 0.69 +/- 1 transfusions/newborns (p < 0.001). At the fourth week of treatment, reticulocyte count was 14.8 +/- 7 and 6.4 +/- 4.9% in the active treatment group and placebo group respectively (p < 0.001).
                r-EPO reduces the requirement of transfusions in low birth weight infants. This paper presents the design and evaluation of an occupational therapy program developed at the National Institutes of Health for teaching energy conservation and joint protection to adults with rheumatoid arthritis. An existing model for educational diagnosis in health education was used to identify program, behavioral, and educational objectives for the new program. The use of this model resulted in measurable objectives, which were used as outcome measures in the randomized research evaluation of the new program. The dependent variables measured were activity-of-daily-living status, psychosocial adjustment to illness, knowledge, disease activity, pain, and fatigue. None were significantly different after the intervention. The independent variables measured included components of balancing rest and physical activity. After 3 months, a greater percentage of the subjects receiving the workbook-based occupational therapy program than those receiving traditional occupational therapy demonstrated an application of the behaviors the intervention was designed to change. Effective new therapies are needed for rheumatoid arthritis. Current therapies target the products of activated macrophages; however, T cells also have an important role in rheumatoid arthritis. A fusion protein--cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig)--is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis. CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells, blocking the engagement of CD28 on T cells and preventing T-cell activation. A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis.
                We randomly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig per kilogram of body weight (105 patients), 10 mg of CTLA4Ig per kilogram (115 patients), or placebo (119 patients) for six months. All patients also received methotrexate therapy during the study. The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology (ACR), which define the response according to its extent: 20 percent (ACR 20), 50 percent (ACR 50), or 70 percent (ACR 70). Additional end points included measures of the health-related quality of life.
                Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo (60 percent vs. 35 percent, P<0.001). Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group. The group given 10 mg of CTLA4Ig per kilogram had clinically meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey. CTLA4Ig was well tolerated, with an overall safety profile similar to that of placebo.
                In patients with active rheumatoid arthritis who were receiving methotrexate, treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life. CTLA4Ig is a promising new therapy for rheumatoid arthritis.
                Copyright 2003 Massachusetts Medical Society In rheumatoid arthritis (RA) benefit from non-steroidal anti-inflammatory drugs (NSAIDs) is mediated through inhibition of the cyclo-oxygenase enzyme, thereby decreasing production of the 2 series prostaglandins (PGs). The lipoxygenase enzyme is intact, however, allowing leucotriene (LT) production, e.g., LTB4 (an inflammatory mediator). Treatment with evening primrose oil (EPO) which contains gamma-linolenic acid (GLA) leads to production of the 1 series PGs, e.g., PGE1, which has less inflammatory effects. Also LT production is inhibited. Eicosapentaenoic acid (EPA, fish oil) treatment provides a substrate for PGs and LTs, which are also less inflammatory. In this study 16 patients with RA were given 540 mg GLA/day (EPO), 15 patients 240 mg EPA and 450 mg GLA/day (EPO/fish oil), and 18 patients an inert oil (placebo). The aim of this study was to determine if EPO or EPO/fish oil could replace NSAID treatment in RA. The initial 12 month treatment period was followed by three months of placebo for all groups. Results at 12 months showed a significant subjective improvement for EPO and EPO/fish oil compared with placebo. In addition, by 12 months the patients receiving EPO and EPO/fish oil had significantly reduced their NSAIDs. After 3 months of placebo those receiving active treatment had relapsed. Despite the decrease in NSAIDs, measures of disease activity did not worsen. It is suggested that EPO and EPO/fish oil produce a subjective improvement and allow some patients to reduce or stop treatment with NSAIDs. There is, however, no evidence that they act as disease modifying agents. Erythropoietin (Epo) is frequently administered to premature infants to stimulate erythropoiesis. There is evidence from studies in animals and healthy adults that Epo also interacts with thrombopoiesis and platelet function. This study investigates the effect of Epo therapy on platelet reactivity, peripheral platelet counts and thiazole orange-positive (TO+) platelets in extremely low birth weight (ELBW) infants. In a randomised-controlled trial, ELBW infants with a birth weight < or =800 g and a gestational age < or =32 weeks were either randomised to a group receiving Epo during the first weeks of life or to a control group. Our results show that thrombin receptor-activating peptide (TRAP-6) -induced expression of P-selectin increased significantly during the first two weeks of Epo treatment. With the exception of week five, the number of TO+ platelets was significantly higher during the first eight weeks in Epo-treated infants compared to controls. The increase of TO+ platelets was not paralleled by an increase in total platelet count. We can conclude that Epo therapy has a short-lasting effect on platelet reactivity toTRAP-6 in ELBW infants during the first two weeks of life. Furthermore, Epo therapy is associated with an increase in the number of TO+ platelets compared to controls.
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.