The Relationship of Haemoglobin to Serum Erythropoietin Concentrations in the Anaemia of Rheumatoid Arthritis: The Effect of Oral Prednisolone

Kendall, R.; Wasti, Afshan Zeeshan; Harvey, Andrew; Hill, J. M.; Chapman, C.; Norfolk, D. R.; Pullar, T

doi:10.1093/rheumatology/32.3.204

Cited by 10 publications

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“…This might as well be explained by TNF effects not specifically directed toward erythropoietic cells but rather as a general down-regulation of proinflammatory cytokines downstream of TNF. Interestingly, similar effects were found after administration of oral prednisolone to patients suffering from rheumatoid arthritis and ACD (Kendall et al, 1993), supporting the notion that inhibition of production and action of mediators of inflammation can cause minor but significant increases in hemoglobin in ACD. Additionally, TNF blockade as well as oral prednisolone lead to a reduction of the EPO serum concentration (Davis et al, 1997;Kendall et al, 1993), ruling out that TNF negatively regulates EPO production.…”

Section: Schubert Et Alsupporting

confidence: 68%

TNF-Independent Development of Transient Anemia of Chronic Disease in a Mouse Model of Protracted Septic Peritonitis

Schubert

Echtenacher

Hofstädter

et al. 2003

Laboratory Investigation

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SUMMARY:TNF is considered one of the inflammatory cytokines and contributes mainly to the generation of anemia of chronic disease (ACD). In nude mice TNF has been reported to impair iron metabolism and erythropoiesis, leading to anemia with a low serum iron and preserved iron stores. In this work, we established a murine model for ACD based on sublethal cecal ligation and puncture (CLP) with ensuing protracted peritonitis. Starting on Day 3 after CLP, a severe protracted depression of erythropoiesis in the bone marrow was noted. Two weeks after CLP, we observed a moderate normochromic anemia, low serum iron concentration, and preserved iron stores consistent with transient ACD. To determine whether TNF contributes to the development of ACD in vivo, we neutralized TNF after CLP shortly before and during the phase of most severe bone marrow depression to prevent anemia. Additionally, we studied TNF-deficient mice undergoing CLP. Two weeks after CLP, we determined red blood count, hemoglobin concentration, hematocrit, serum iron concentration, and iron stores in spleens of wild-type mice, TNF-deficient mice, and mice after neutralization of TNF. Neutralization of TNF after CLP could not prevent mice from contracting anemia. Accordingly, TNF-deficient mice developed anemia to the same extent as wild-type mice. Serum iron concentration was lowered and iron stores were overloaded in both TNF-deficient and wild-type mice after CLP. Our results clearly demonstrate that TNF is not a mediator of ACD in our model with transient anemia induced by protracted septic peritonitis. (Lab Invest 2003, 83:1743-1750.A nemia commonly occurs in chronic infection, inflammation, and malignancy (Barrett-Connor, 1972;Zucker et al, 1974). This type of anemia is characterized by decreased plasma iron and ironbinding capacity, normal or elevated iron stores, modest decrease of red cell survival, and relative failure of bone marrow to increase red cell production. It was first described with infection (Cartwright, 1966); however, because of its association with other instances of chronic disease such as chronic inflammation and cancer, it is called anemia of chronic diseases (ACD). An understanding of the role that inflammatory cytokines play in most of the diseases underlying ACD has suggested that cytokines are important factors in the pathophysiology of ACD. Inflammatory cytokines such as TNF and IL-1 have effects on iron metabolism and red cell survival in vivo (Freireich et al, 1957;Johnson et al, 1989;Moldawer et al, 1989;Rogers et al, 1990). Inflammatory cytokines have also been implicated in the inappropriately low erythropoietin (EPO) levels in ACD patients (Miller et al, 1990). Supporting the idea that cytokines could contribute to ACD are data that suggest that TNF, IL-1, and IFN-␥ also exert direct inhibitory effects on hematopoiesis in vivo and in vitro (Means et al, 1992(Means et al, , 1994Means and Krantz, 1993;Salleri et al, 1996;Wang et al, 1995). In summary, our present knowledge of the role of cytokines in ACD is mainly bas...

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Section: Schubert Et Alsupporting

confidence: 68%

TNF-Independent Development of Transient Anemia of Chronic Disease in a Mouse Model of Protracted Septic Peritonitis

Schubert

Echtenacher

Hofstädter

et al. 2003

Laboratory Investigation

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“…Improvement in ACD following high-dose oral corticosteroid treatment in RA has been reported recently [47]. Interestingly, Hb showed signi®cant improvement as early as 4 days after prednisolone therapy was instituted and was accompanied by a fall in EPO levels, indicating a mechanism other than increased EPO production.…”

Section: Discussionmentioning

confidence: 61%

Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumour necrosis factor alpha blockade

Davis¹,

Charles²,

Potter³

et al. 1997

Rheumatology

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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.

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“…On the other hand, only 2/34 patients with anemia of chronic disease had a RAI value > 17 (5.9%), as did 18/34 non-diabetic patients with iron deficiency anemia (52.9%, p < 0.001). This overlapping is substantially smaller to that observed, when comparing serum Epo levels in these two groups of anemic patients [29]. Therefore, in the absence of renal failure and in otherwise unclear cases of hypochromic and microcytic anemia, the detection of a RAI value < 15 may not support the diagnosis of iron deficiency anemia, whereas a RAI value > 17 may discourage the diagnosis of anemia of chronic disease.…”

Section: Differential Diagnosis Of Iron-deficiency Anemia Versus Anemmentioning

confidence: 63%

Quantification of the Erythropoietic Response to Anemia and Determination of the Hb × log(Epo) Component as an Independent Parameter, Indicating the Response to Hypoxic Stress

Symeonidis¹,

Kouraklis-Symeonidis²,

Labropoulou³

et al. 2016

JBiSE

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Serum erythropoietin (Epo) levels are influenced by the integrity of renal function, the severity and etiology of anemia, the percentage of hemoglobin F and other factors. We aimed to create a parametric expression for the response to anemic/hypoxic stress and we evaluated serum Epo levels in 1096 subjects with normal renal function, of whom 837 were anemic (Hb < 12 g/dl), 204 were non anemic (Hb 12 -16.5 g/dl), and 55 were erythremic (Hb > 16.5 g/dl). Hb ranged between 3.6 and 23.8 g/dl and the corresponding Epo between <3.4 and 2670 mIU/ml. Between log-Epo and Hb the correlation coefficient r was −0.706. The function linking Hb and log-Epo was determined as log(Epo) = 3.05 -0.131 × Hb. Investigating various mathematic models, which could parametrically express the "response to anemia/hypoxia", we found that the Hb × log(Epo) product was a stable parameter and fitted a normal distribution. Arbitrarily defining as normal range about one SD between the mean (12 -21) we found that only 224 patients (20.8%) exhibited a Response to Anemia Index (RAI) beyond these limits. Below the lower limit there were 106 patients, diagnosed with polycythemia vera (12/38, 31.6%) anemia of chronic disease (10/34, 29.4%), megaloblastic anemia (17/56, 30.4%) and β-thalassemia trait (11/41, 26.8%).Forty-eight patients (45.3%) were diabetic. Above the defined upper normal RAI limit there were 118 patients, mainly diagnosed with secondary erythrocytosis (24/34, 70.6%), aplastic anemia (8/20, 40%), hemolytic anemia (3/14, 21.4%) and myelodysplastic syndromes (46/326, 14.1%). RAI was a rather constant parameter for each individual, with minimal variation in different evaluations, when Epo was esti-How to cite this paper: Symeonidis, A., Kouraklis-Symeonidis, A., Labropoulou, V., Lazaris, V., Katsaouni, P., Verigou, E., Spiridonidis, T., Tzouvara, E., Tiniakou, M., Apostolopoulos, D. and Leotsinidis, M. (2016) Quantification of the Erythropoietic Response to Anemia and Determination of the Hb × log(Epo) Component as an Independent Parameter, Indicating the Response to Hypoxic Stress. J. Biomedical Science and Engineering, 9, 460-477. http://dx.A. Symeonidis et al. 461mated in the absence of inflammatory conditions. We have validated the superiority of RAI for the prediction of response to Epo in a cohort of 669 patients, who received Epo treatment. It is concluded that RAI is a reliable parameter describing the response to hypoxic/anemic stress.

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The Relationship of Haemoglobin to Serum Erythropoietin Concentrations in the Anaemia of Rheumatoid Arthritis: The Effect of Oral Prednisolone

Cited by 10 publications

References 0 publications

TNF-Independent Development of Transient Anemia of Chronic Disease in a Mouse Model of Protracted Septic Peritonitis

TNF-Independent Development of Transient Anemia of Chronic Disease in a Mouse Model of Protracted Septic Peritonitis

Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumour necrosis factor alpha blockade

Quantification of the Erythropoietic Response to Anemia and Determination of the Hb × log(Epo) Component as an Independent Parameter, Indicating the Response to Hypoxic Stress

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The Relationship of Haemoglobin to Serum Erythropoietin Concentrations in the Anaemia of Rheumatoid Arthritis: The Effect of Oral Prednisolone

Cited by 10 publications

References 0 publications

TNF-Independent Development of Transient Anemia of Chronic Disease in a Mouse Model of Protracted Septic Peritonitis

TNF-Independent Development of Transient Anemia of Chronic Disease in a Mouse Model of Protracted Septic Peritonitis

Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumour necrosis factor alpha blockade

Quantification of the Erythropoietic Response to Anemia and Determination of the Hb &#215; log(Epo) Component as an Independent Parameter, Indicating the Response to Hypoxic Stress

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Quantification of the Erythropoietic Response to Anemia and Determination of the Hb × log(Epo) Component as an Independent Parameter, Indicating the Response to Hypoxic Stress