BALTIMORE — A new understanding of the “anemia of inflammation” may help point the way to new treatments in the future, but in the meantime it illustrates why iron supplementation does not raise hemoglobin levels in patients with rheumatoid arthritis and other inflammatory diseases, Dr. Joan Bathon said at a conference on rheumatic diseases sponsored by the Johns Hopkins University.
Formerly known as “anemia of chronic diseases” because it is commonly seen in inflammatory diseases such as rheumatoid arthritis (RA) as well as in chronic infections and some cancers, the condition is now known by the term “anemia of inflammation,” which better reflects its etiology. It is not the result of bleeding, hemolysis, nutritional deficit (vitamin B12, folate, iron), or a marrow disorder, said Dr. Bathon, professor of medicine at Johns Hopkins, Baltimore.
Lacking an understanding of the underlying etiology, health care providers will often give these patients iron supplementation. However, “we know that iron treatment does not really alleviate this anemia,” she said.
Anemia is extremely common among RA patients. In a study comparing 2,120 consecutive RA patients (contributing 26,221 hemoglobin determinations) with 3,843 patients who had noninflammatory rheumatic disorders (7,251 hemoglobin determinations) seen between 1974 and 2004 in a clinical practice setting, the prevalence of chronic anemia was 35.3% when a hemoglobin cutoff of less than 12 g/dL was used.
Hemoglobin levels were consistently lower among the RA patients than among those with noninflammatory conditions, by a mean of 0.8 g/dL.
Those data, reported at the 2005 American College of Rheumatology meeting by Dr. Frederick Wolfe of the National Data Bank for Rheumatic Diseases, Wichita, Kan., suggest that “more than one-third of patients with RA are anemic, if you use a broad definition,” according to Dr. Bathon.
That study also found that among the RA patients, lower hemoglobin was associated with high disease activity; C-reactive protein levels were strongly predictive of anemia; and quality of life was reduced by 5.5% among the patients with anemia after adjustment for age and gender.
In general, patients with anemia of inflammation have decreased total circulating iron levels and binding capacity, yet their total body iron (ferritin) stores are increased.
At the same time, erythropoietin production is blunted, as is the response to endogenous erythropoietin. Red blood cell survival is modestly decreased. “Exogenous iron and/or exogenous erythropoietin do not fully resolve the anemia,” she said.
Although iron is essential for oxygen transport and other vital functions, it also generates free radicals that can lead to oxidative damage, manifesting in conditions such as atherosclerosis, diabetes, or cancer.
But humans can't eliminate excess iron. Therefore, uptake from the gastrointestinal tract is tightly regulated and efficiently recycled. “No matter how much you give orally, there's only a limited amount the body can pick up,” Dr. Bathon explained.
Recently, a small peptide hormone called hepcidin was identified as the principal regulator of systemic iron homeostasis. Synthesized in the liver, hepcidin inhibits the intestinal absorption of iron and suppresses release of iron from macrophage and hepatocyte stores.
Measurement of hepcidin levels is now being investigated as a possible diagnostic tool for various iron disorders. In one study, a novel urine hepcidin assay using mass spectrometry was able to discriminate among patients with secondary iron overload, iron-deficient anemia, and hereditary hemochromatosis (Blood 2005;106:3268–70).
Hepcidin production would be expected to be increased in RA patients, but that hasn't been studied, Dr. Bathon said.
Other data suggest that interleukin-6—but not interleukin-1 (IL-1) or tumor necrosis factor-α (TNF-α)—promotes anemia of inflammation by synthesizing hepcidin (J. Clin. Invest. 2004;113:1271–6), and some investigators have suggested that an antibody directed against IL-6 might therefore offer potential treatment for inflammation-induced anemia (Ann. Rheum. Dis. 2000;59 [Suppl. 1]:i21–7).
But, even though TNF-α and IL-1 don't induce hepcidin in some models, it's not clear whether the process is entirely mediated by IL-6.
In fact, treatment of RA patients with TNF-α blockers often does improve their anemia. It's not yet clear which treatment would be a better method—inhibition of IL-6 or TNF—for resolving anemia inflammation, Dr. Bathon said.
The role of erythropoietin for treating anemia of inflammation is also currently unclear. Although the response to exogenous erythropoietin tends to be blunted in RA patients in proportion to the severity of their inflammation, data from a few small studies do suggest that the treatment may nonetheless be beneficial by lessening their anemia.
One such study, involving 17 patients who received a total 32 weeks of treatment, showed an overall excellent hematologic response without toxicity but with no meaningful change in rheumatologic clinical status (Am. J. Med. 1990;89:161–8).