Interactions between erythropoietin and iron metabolism in anaemia of chronic disorders

To the editor: Anaemia of chronic disorders (ACD) occurs frequently in the course of many chronic diseases such as rheumatoid arthritis (RA). The degree of the anaemia often correlates with RA disease activity (1). Its pathogenesis is not yet fully established. Recently, a number of studies focused on the role of an impaired erythropoietin (Epo) responsiveness to the anaemia in ACD. It is not unlikely that, in ACD in RA, Epo responsiveness to the anaemia and, perhaps, bone marrow epo sensitivity are decreased (2). Boyd and Lappin recently published a very interesting study concerning the role of Epo responsiveness in ACD in this journal (3). They compared serum Epo levels in 2 subsets of patients with ACD (RA and malignancy) with levels found in uncomplicated ir0.n deficiency (ID) and renal failure. It was clearly demonstrated that, in spite of similar haemoglobin (Hb) levels in the 4 groups, serum Epo levels were significantly lower in RA and malignancy than in ID. In renal failure Epo levels were lowest although a small overlap occurred with the RA group, confirming that, in ACD in RA, Epo responsiveness indeed is impaired. From their study it may be concluded that Epo response is adequate in ID and impaired in ACD. In ACD iron stores usually are increased, so it may be speculated that the Epo response is regulated by iron stores. However, we may assume that in the ID group no specific underlying disease was present, in contrast to the other groups. Possibly, Epo response is also determined by certain factors associated with disease activity. In 2 earlier studies it was shown that, among RA patients with ID, The Epo response to the anaemia was higher than in those with ACD (4, 5). Based on a possible inverse relationship between iron stores and Epo responsiveness to the anaemia we studied the effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L l), synthesised by Kontoghiorghes et al. (6) , on Hb and Epo levels (7). After 1 week of treatment we found a rise in both Hb and epo levels which were correlated positively. We also observed a positive correlation of ferritin decrease with the Hb and Epo rise. So, apparently, if iron stores decrease the Epo response to the anaemia increases, which is in support of the findings of Boyd and Lappin (3) although, as stated before, their ID group had no underlying disease. We found no decrease in RA activity, which could be anticipated after just 1 wk of treatment, so this could not explain the rise in Hb and Epo. Theoretically, a fall in serum Epo after a Hb rise is expected and it may thus be speculated that the Epo rise effectively contributed to the Hb increase. As Boyd and Lappin ( 3 ) suggested, clinical trials using recombinant human Epo (r-Hu-Epo) in patients with ACD examining the effects on Hb and iron stores are justified. Pincus et al. (8) showed that a Hb rise followed treatment with r-Hu-Epo in RA. However, the majority of their patients had concomitant ID while they were also being treated with iron, limiting the interpretation of the effects of r-Hu-Epo. We therefore studied the effects of r-Hu-Epo treatment in RA patients with ACD (determined by increased stainable bone marrow iron and exclusion of other causes of anaemia) on erythropoiesis and iron status. Five RA patients with ACD were treated with r-Hu-Epo (240 U/kg S.C. three times a week for 6 wk). They were compared with a control group consisting of 5 RA patients with ACD who only received conventional antirheumatic treatment. In all 10 patients antirheumatic treatment was kept unchanged throughout the study period. No differences in age, duration of RA or treatment modality existed between the 2 groups. All patients gave written informed consent. Table 1 shows that a significant Hb increase and ferritin decrease occurs, while CRP as a marker of RA activity remains unchanged. In the control group, no changes occurred in Hb, ferritin or CRP. Fig. 1 illustrates the inverse changes of Hb and ferritin. It also shows that 3 patients had iron deficiency afterwards (ferritin levels below 50 yg/l). The findings obtained confirm that a decrease in Epo responsiveness to the anaemia is one of the factors involved in the pathogenesis of ACD, as was