The links of hepcidin and erythropoietin in the interplay of inflammation and iron deficiency in a large observational study of rheumatoid arthritis

Abstract

Summary 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.

Role of Hepcidin in Anemia of Chronic Disease in Rheumatoid Arthritis

“…19 Our PCA analysis revealed that regarding the factor 1, explaining approximately 1/3 of total variance, variables that had significant loadings were all markers of anemia, markers of iron metabolism (IRON, TFsat, and sTFr), and erythropoiesis (EPO and HEP). Anemic state in chronic disease is influenced by the complex interaction between inflammation, erythropoiesis, and iron metabolism 15 33 34 35 however, it is not clear to what extend anemia is merely a marker of disease severity and progression or a causative factor that specifically impacts on the underlying inflammatory process by the progression of joint destruction. 15 34 Inflammation-induced cytokines activate HEP production (IL-6) and increased levels of HEP induce a state of “functional iron deficiency” 33 however as the disease progresses low, IRON levels may actually exert inhibitory effects on HEP production.…”

“…Anemic state in chronic disease is influenced by the complex interaction between inflammation, erythropoiesis, and iron metabolism 15 33 34 35 however, it is not clear to what extend anemia is merely a marker of disease severity and progression or a causative factor that specifically impacts on the underlying inflammatory process by the progression of joint destruction. 15 34 Inflammation-induced cytokines activate HEP production (IL-6) and increased levels of HEP induce a state of “functional iron deficiency” 33 however as the disease progresses low, IRON levels may actually exert inhibitory effects on HEP production. 15 On the other end of the spectrum low IRON availability further activates erythropoiesis, while EPO may act regulatory effects on HEP.…”

“… 15 34 Inflammation-induced cytokines activate HEP production (IL-6) and increased levels of HEP induce a state of “functional iron deficiency” 33 however as the disease progresses low, IRON levels may actually exert inhibitory effects on HEP production. 15 On the other end of the spectrum low IRON availability further activates erythropoiesis, while EPO may act regulatory effects on HEP. 15 This loop of inflammation-induced erythropoiesis-iron availability-anemia is depicted in factor 1 of our PCA analysis.…”

“…In addition, all patients underwent a complete physical examination to evaluate articular and extraarticular manifestations of the disease. Blood samples were collected in the morning, after an overnight fast and serum was separated by centrifugation at 1500 g for 15…”

“…9,14 In this complex interplay of anemia, inflammation, and iron metabolism, HEP (along with EPO) is considered a mediator of hematopoiesis, but its production is also influenced by markers of inflammation such as interleukin-6 (IL-6) and tumor necrosis factor alpha. 15 Typically, HEP binds to cell membrane-localized ferroportin and initiates the internalization and degradation of ferroportin that results in rapid iron sequestration into specialized storage cells and iron retention in the duodenal epithelium. 16 Thus, the aim of the present cross-sectional observational study was to assess the relationships of HEP with markers of anemia, iron metabolism, inflammation, and erythropoiesis.…”