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To the Editor:

We thank Dr. Jolobe for his interest in our study and his question regarding the interchangeability of RBC-Hgb, MCH, and MCV in the diagnosis of iron deficiency in rheumatoid arthritis patients with anemia. RBC-Hgb and MCH are representative of the Hgb content (in fmoles) of mature erythrocytes (1 fmole = 16.11 pg). In our study, both parameters were measured with a Sysmex-XE 2100 automated hematology analyzer and were found to correlate (R = 0.85, P < 0.001) (n = 105). However, the parameters are not fully identical. MCH is calculated based on whole blood intra- and extracellular Hgb concentrations (assessed by Hgb photometry) divided by erythrocyte concentrations (measured by impedance counting). In contrast, RBC-Hgb content is measured as RBC Hgb equivalents on a different channel of the instrument and is a direct measure of mature erythrocyte intracellular Hgb content (by means of a fluorescent optical count) (1, 2). As a consequence, in hemolytic samples, the MCH count might be falsely elevated since this assessment also includes the determination of extracellular Hgb. In our study, we did not find laboratory evidence of in vivo or ex vivo hemolysis in any of the patients.

ROC analysis was performed, and in comparisons between patients with IDA, patients with anemia of chronic disease, and the 2 anemia groups combined, we observed a slightly better test performance for RBC-Hgb compared to MCH and MCV in diagnosing iron deficiency in our rheumatoid arthritis study population (Figure 1). The area under the ROC curve (AUC) for RBC-Hgb was 0.78 (P = 0.05, SE 0.12) in the analysis of combined IDA/ACD patients (n = 9) versus the ACD patients (n = 8). The AUC for the same patients was 0.69 (P = 0.18, SE 0.13) for MCH and 0.76 (P = 0.07, SE 0.13) for MCV. For the IDA and IDA/ACD patients (n = 19) versus patients with ACD and other forms of anemia (n = 21) the AUC values for RBC-Hgb, MCH, and MCV were 0.80 (P = 0.001, SE 0.07), 0.69 (P = 0.04, SE 0.09), and 0.73 (P = 0.01, SE 0.08), respectively.

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Figure 1. Receiver operator characteristic analysis of hepcidin and hemoglobin content parameters as diagnostic tests for iron deficiency in rheumatoid arthritis patients with specific categories of anemia. Area under the curve (AUC) values are shown. IDA = iron deficiency anemia; ACD = anemia of chronic disease; Ret-Hgb = reticulocyte hemoglobin content; RBC-Hgb = erythrocyte (red blood cell) hemoglobin content; MCH = mean corpuscular hemoglobin; MCV= mean corpuscular volume.

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Identification of iron deficiency in rheumatoid arthritis patients with anemia and inflammation is a challenge. In our study, the test performances of serum hepcidin and Hgb content parameters (reticulocyte Hgb content [Ret-Hgb], measured as reticulocyte Hgb equivalents and RBC-Hgb) were better than those of MCV and MCH in the detection of iron deficiency. Yet, the differences among RBC-Hgb, MCH, and MCV in our study were small, and for that reason in the absence of hemolysis, RBC-Hgb and MCH might be interchangeable. However, our data do not corroborate Dr. Jolobe's suggestion that MCH might be a better indicator than MCV in the identification of IDA in these patients.

Furthermore, we would like to mention additional features that may support the preferred use of Hgb content parameters (as opposed to MCH and MCV) in the management of iron deficiency in this patient population. The difference between Ret-Hgb and RBC-Hgb, expressed as ΔHgb, provides information on the current iron availability and short-term iron incorporation for erythropoiesis owing to the long life span of mature erythrocytes compared to reticulocytes (3). As a consequence, in the presence of absolute iron deficiency, iron supplementation is expected to substantially raise the Ret-Hgb and ΔHgb within several days (4–6), while no effect, or only limited effect, is expected in the pure functional iron deficiency of the inflammatory state (patients with ACD). The combined use of Ret-Hgb and RBC-Hgb might thus prove an indicator of the effectiveness of oral iron supplementation in these patients, and as such, these parameters are promising additional markers for the management of anemia in patients with rheumatoid arthritis; we are currently investigating this hypothesis.

We agree with Dr. Jolobe that laboratories lacking the facilities to assess Hgb content parameters could use MCH (or MCV) in addition to serum hepcidin to diagnose iron deficiency in patients with anemia and chronic inflammation. However, our findings, and the findings of others, suggest that Hgb content parameters can provide added value in the management of patients with rheumatoid arthritis; more studies are needed to confirm this.

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    De Mast Q, van Dongen-Lases EC, Swinkels DW, Nieman AE, Roestenberg M, Druilhe P, et al. Mild increases in serum hepcidin and interleukin-6 concentrations impair iron incorporation in haemoglobin during an experimental human malaria infection. Br J Haematol 2009; 145: 65764.
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Susanne van Santen MD*, Annelies E. van Ede MD, PhD*, Dorine W. Swinkels MD, PhD*, * Radboud University Medical Centre, Nijmegen, The Netherlands.