Erythroferrone Expression in Anemic Rheumatoid Arthritis Patients: Is It Disordered Iron Trafficking or Disease Activity?

Abstract

Purpose: Erythroferrone (ERFE) is well acknowledged for its inhibitory function on hepcidin synthesis in the liver during stress erythropoiesis, thereby ensuring sufficient iron supply to bone marrow erythroblasts. Hepcidin plays an indispensable role in the pathogenesis of anemia of chronic disease (ACD). Thus, ERFE was suggested to protect against ACD in various diseases. Rheumatoid arthritis (RA) is commonly involved with ACD and high hepcidin levels, with a further increase of the latter in active states. The present study is a case-control study that aimed to determine the pattern of ERFE expression in RA patients with concomitant ACD and study its relationship with hepcidin, erythropoietin (EPO) and disease activity. Patients and Methods: Fifty-five RA patients with ACD were categorized into active and inactive RA using the disease activity score (DAS28); 15 healthy subjects were included as control subjects. ERFE was measured for patients and control subjects using quantitative real-time polymerase chain reaction, in addition to testing for CBC, ESR, CRP, iron profile parameters and hepcidin. EPO was assessed for patients of both active and inactive RA groups. Results: ERFE and hepcidin showed the highest levels in active RA; ERFE values were similar in control subjects and inactive RA patients, while hepcidin was significantly higher in inactive RA than control subjects. Patients with high ERFE levels had higher RBC, Hct, MCV, hepcidin and EPO levels. Stepwise regression analysis has identified DAS28 and disease duration as the best predictors of ERFE values, whereas ERFE and hepcidin were independent predictors of disease activity. Conclusion:We introduce ERFE as a novel marker of RA activity. Although the inhibitory effect of ERFE on hepcidin is not evident, our results still indicate that ERFE may have a beneficial erythropoietic effect in the context of ACD in RA disease activity.

Prevalence of anemia in patients with rheumatoid arthritis and its association with dietary inflammatory index: A population-based study from NHANES 1999 to 2018

“…For example, the presence of anemia of chronic disease (ACD) in RA patients is a crucial confounding factor that needs consideration. [ 53 – 55 ] ACD, often linked to RA disease activity and inflammation, can suppress red blood cell production. Disease activity and medication history play a pivotal role in the context of anemia and could greatly affect our study’s outcomes.…”

Effect of Recombinant Human Erythroferrone Protein on Hepcidin Gene (Hamp1) Expression in HepG2 and HuH7 Cells

“…Nevertheless, serum levels of ERFE and EPO, along with erythropoietic activity and hepcidin, were higher in active rheumatoid arthritis patients who had anemia than in control patients. This would seem to indicate that ERFE and hepcidin may be independent predictors [ 24 ]. Moreover, there was a positive correlation between serum hepcidin concentrations and divalent metal ion transporter-1 (DMT1) and TfR1 in the liver, as well as in serum ERFE concentrations and TfR2 in the liver [ 25 ].…”

Iron metabolism and arthritis: Exploring connections and therapeutic avenues

“…[18] And, this treatment is believed to protect against ACD in various diseases, including RA. [19] Ferroptosis is a newly discovered form of programmed cell death characterized by uncontrolled iron-dependent lipid peroxidation. [7] Based on the systemic metabolic pathway of iron, divalent iron is stored in cells as the labile iron pool (LIP), where it is bound to low molecular weight compounds such as GSH.…”

“…[ 18 ] And, this treatment is believed to protect against ACD in various diseases, including RA. [ 19 ]…”