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BACKGROUND AND OBJECTIVE: Anemia of chronic disorders (ACD) is a mild to moderate anemia characterized by decreased serum iron, decreased total iron-binding capacity and increased iron stores that occurs in a wide variety of diseases including cancer, chronic infections and inflammatory disorders. The reason for this review is two-fold. First, systemic autoimmune diseases are frequently characterized by ACD. Second, advances in our knowledge of the pathophysiology of systemic autoimmune diseases as well as pathogenesis and treatment of ACD have so far been dealt with separately. Consequently, the approach to the evaluation of ACD in systemic autoimmune disorders has usually been either immunology- or hematology-oriented. The aim of this review is to integrate the pertinent information from both these fields in order to arrive at a more complete understanding of a problem common to hematologists and immunologists. INFORMATION SOURCES: The articles reviewed have been published in journals listed in the Science Citation Index and Medline. In addition, the authors have a vast experience in the field of hematology and are actively working in the field of systemic autoimmune disorders. STATE OF ART AND PERSPECTIVES: ACD is a parameter of disease activity in systemic autoimmune diseases. The severe inflammatory stimuli responsible for the pathophysiology of these disorders lead to several systemic changes (referred to as chronic active phase response) through which the organism tries to cope with chronic tissue injuries. These reactions are brought about by inflammation-associated cytokines, like IL-6, IL-1, TNF alpha, TGF beta that regulate hepatic synthesis of acute phase proteins. Many cytokines involved in chronic acute phase response, including IL-1, TNF alpha, TGF beta, have an inhibitory activity on erythroid colony formation in vitro. In addition, circulating TNF alpha is elevated in rheumatoid arthritis (RA), IL-1 beta serum levels are significantly increased in RA with ACD and RA patients treated in vivo with antibodies (Abs) to TNF alpha show disease improvement, including an increase in Hb values. Reduced erythropoietin (EPO) activity, usually the result of reduced production, plays a role in the pathogenesis of ACD observed in systemic autoimmune diseases. Both the production and the action of EPO may fall under the control of IL-1 and IFN-gamma. The most controversial and stimulating aspect of the pathogenesis of ACD in systemic autoimmune disorders is the role of iron metabolism and nitric oxide (NO), which contributes to the regulation of iron cellular metabolism. Both iron deficiency and iron overload may influence the proliferation of B and T lymphocytes and differentially affect T helper (TH)-1 and TH-2 lymphocytes. Furthermore, TH-1 cytokines stimulate and TH-2-type cytokines inhibit NO production. For these reasons, cell-mediated immunity may be expected to have influence on NO synthesis and on the mechanisms leading to iron accumulation in the reticuloendothelial system.