Joint Bone Spine 78 (2011) 131–137ReviewRheumatoid anemiaCharles Masson ∗Service de rhumatologie, pôle ostéoarticulaire, 4...
132                                                           C. Masson / Joint Bone Spine 78 (2011) 131–137Table 1       ...
C. Masson / Joint Bone Spine 78 (2011) 131–137                                             133    In a multicenter cohort ...
134                                                    C. Masson / Joint Bone Spine 78 (2011) 131–137androgen exposure. Pa...
C. Masson / Joint Bone Spine 78 (2011) 131–137                                            135serum iron and CRP levels dro...
136                                                           C. Masson / Joint Bone Spine 78 (2011) 131–137Table 4       ...
C. Masson / Joint Bone Spine 78 (2011) 131–137                                                             137[13] Suomine...
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Rheumatoid anemia

  1. 1. Joint Bone Spine 78 (2011) 131–137ReviewRheumatoid anemiaCharles Masson ∗Service de rhumatologie, pôle ostéoarticulaire, 4, rue Larrey, CHU d’Angers, Angers 49933 cedex 9, Francea r t i c l e i n f o a b s t r a c tArticle history: Rheumatoid anemia is a typical example of anemia of chronic disease. It differs from other forms ofAccepted 19 May 2010 anemia, such as iron deficiency anemia or iatrogenic anemia. Rheumatoid anemia is normochromic,Available online 18 September 2010 normocytic or, less often, microcytic, aregenerative, and accompanied with thrombocytosis. Serum trans- ferrin levels are normal or low, transferrin saturation is decreased, serum ferritin levels are normal orKeywords: high, the soluble transferrin receptor (sTfR) is not increased (a distinguishing feature with iron deficiencyRheumatoid anemia anemia), and the sTfR/log ferritin ratio is lower than 1. This review discusses the prevalence and impactTransferrin of rheumatoid anemia based on a review of the literature. Iron metabolism, absorption, diffusion, storage,Transferrin receptorFerritin and use by the bone marrow are described using published data on transferrin, ferritin, and hepcidin.Hepcidin Hepcidin is now recognized as a key factor in rheumatoid anemia, in conjunction with the cytokineInterleukin-6 interleukin-6 (IL-6). Hepcidin is a hormone that lowers serum iron levels and regulates iron transportErythropoietin across membranes, preventing iron from exiting the enterocytes, macrophages, and hepatocytes. In addi- tion, hepcidin inhibits intestinal iron absorption and iron release from macrophages and hepatocytes. The action of hepcidin is mediated by binding to the iron exporter ferroportin. Hepcidin expression in the liver is dependent on the protein hemojuvelin. Inflammation leads to increased hepcidin production via IL-6, whereas iron deficiency and factors associated with increased erythropoiesis (hypoxia, bleeding, hemolysis, dyserythropoiesis) suppress the production of hepcidin. Data from oncology studies and the effects of recombinant human IL-6 support a causal link between IL-6 production and the development of anemia in patients with chronic disease. IL-6 diminishes the proportion of nucleated erythroid cells in the bone marrow and lowers the serum iron level, and these abnormalities can be corrected by admin- istering an IL-6 antagonist. IL-6 stimulates hepcidin gene transcription, most notably in the hepatocytes. Studies involving human hepatocyte exposure to a panel of cytokines showed that IL-6, but not TNF␣ or IL-1, induced the production of hepcidin mRNA. Recent data on hepcidin level variations in patients with rheumatoid arthritis are reviewed. Rheumatoid anemia is best corrected by ensuring optimal control of systemic disease activity. The role for iron supplementation (per os or intravenously) and erythropoi- etin in the treatment of rheumatoid anemia is discussed. Given the cascade of interactions linking IL-6, hepcidin, and anemia, IL-6 antagonists hold considerable promise for the management of rheumatoid anemia. © 2010 Société francaise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. ¸1. Introduction (IL-1), and interleukin-6 (IL-6). IL-6, in particular, exerts major effects on the iron-lowering hormone hepcidin [5]. Polymorphisms Anemia associated with rheumatoid arthritis (RA), known as in the TNFRSF1A and TNFRSF1B genes may affect the expression ofrheumatoid anemia, is a typical example of anemia of chronic dis- rheumatoid anemia [6].ease (Table 1) [1–2]. In the absence of effective treatment, anemia is Although anemia in a patient with RA is usually rheumatoidhighly prevalent among RA patients. The mechanisms involved in anemia, other causes exist, depending on the stage of the dis-rheumatoid anemia include shortening of the erythrocyte lifespan, ease and treatments used. Among them, the most common isinadequate bone marrow erythropoiesis in response to the ane- iron deficiency anemia due to malabsorption or, more often, ironmia, and iron metabolism abnormalities [1–5]. The development loss (Table 2). Patients with RA may have folate deficiency ane-of rheumatoid anemia is related to the effects of the proinflam- mia (usually counteracted in patients taking the anti-folate agentmatory cytokines TNF␣, interferon gamma (IFN␥), interleukin-1 methotrexate); vitamin B12 deficiency anemia (although concomi- tant Biermer’s anemia is rare); hemolytic anemia; anemia related to myelodysplastic syndrome; or anemia induced by medications ∗ Tel.: +33 241 353 572; fax: +33 241 353 570. such as methotrexate, salazopyrine, or leflunomide, via various E-mail address: ChMasson@chu-angers.fr. mechanisms [7–8].1297-319X/$ – see front matter © 2010 Société francaise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. ¸doi:10.1016/j.jbspin.2010.05.017
  2. 2. 132 C. Masson / Joint Bone Spine 78 (2011) 131–137Table 1 2.2. The soluble transferrin receptor (sTfR)Causes of anemia of chronic disease other than rheumatoid arthritis. Acute, subacute, and chronic infections The sTfR level [11], which is not affected by inflammation, is Cancer, most notably of the kidney and pancreas increased in iron deficiency anemia but not in rheumatoid ane- Hematological malignancies: Hodgkin lymphoma, non-Hodgkin lymphoma, mia. A study of patients with rheumatoid anemia showed that myeloma, Waldenström’s macroglobulinemia Chronic renal failure, chronic hemodialysis sTfR elevation indicated concomitant iron deficiency [12]. How- Chronic inflammatory bowel disease ever, this study also found considerable overlap in sTfR values Systemic diseases other than rheumatoid arthritis including systemic lupus between patients with and without iron deficiency, making a single erythematosus, vasculitides, and adult-onset Still disease sTfR value difficult to interpret. 2.3. sTfR/log ferritin indexTable 2Causes of iron deficiency anemia. An sTfR/log ferritin index smaller than 1 suggests anemia related Drugs: Nonsteroidal antiinflammatory drugs, antiplatelet drugs, and to inflammation, whereas a value greater than 2 suggests iron glucocorticoids deficiency with or without anemia of inflammation. In a study of Esophagitis, gastric or duodenal ulcer, bowel lesions Gynecological disorders: menstruation, myoma, endometrial cancer 30 patients with rheumatoid anemia, bone marrow examination Digestive system disorders: tumors, inflammation, or systemic disease showed severe iron-store depletion in 18 patients, who received affecting the esophagus, stomach, duodenum, small bowel, colon, or oral iron supplementation [13]. The baseline sTfR, ferritin, and rectum sTfR/log ferritin values accurately classified the patients as having Malabsorption, celiac disease anemia of chronic disease or iron deficiency anemia (Table 3). Kidney disease Special situations Hemosiderosis (concomitant rheumatoid arthritis and hemosiderosis, which 2.4. Bone marrow iron stores is exceedingly rare) Heyde syndrome (angiodysplasia, aortic valve stenosis, and acquired von Bone marrow biopsy with Perls’ stain for iron is performed Willebrandt factor abnormalities) Rendu-Osler disease in selected clinical situations and in research projects, with the Factitious disorder (Lasthenie de Ferjol syndrome described by Jean Bernard consent of the patient. With Perls’ stain, iron in hemosiderin, mito- but never reported in rheumatoid arthritis) chondria, and Pappenheimer bodies is stained blue-green, whereasAmong patients with unexplained iron deficiency, about half have lesions identified neither ferritin nor hemoglobin is stained. The normal or increasedby endoscopic examination of the upper gastrointestinal tract and colon. When no iron stores seen in bone marrow macrophages in rheumatoidlesion is found, repeating both endoscopic examinations identifies a lesion in 6% of anemia contrast with the iron depletion of macrophages and ery-cases. throblasts in iron deficiency anemia. Presence of sideroblasts,When a tumor or other small bowel lesion is suspected, computed tomographyenteroclysis may be in order, followed by video capsule enteroscopy if no steno- which are erythroblasts containing iron granules, suggests primarysis is found, and finally by enteroscopy, which may be performed intraoperatively or secondary sideroblastic anemia.through an incision in the gut wall. 3. Prevalence and impact of rheumatoid anemia2. Diagnosing rheumatoid anemia Wilson et al. reviewed English-language articles on rheuma- toid anemia published between 1966 and 2001 then extended their The World Health Organization (WHO) defines anemia as a review to 2003 [3]. Thus, their review deals with the prebiother-hemoglobin level lower than 12 g/dl in women and 13 g/dl in men. apy era. They identified 10 studies of the prevalence of rheumatoid anemia and 12 of the impact of anemia resolution. At joint replace- ment surgery, 4.5% of patients had hemoglobin levels lower than2.1. Blood cell counts, serum transferrin, serum ferritin 8 g/dl. Moderate anemia (defined in a number of ways) was found in 33.3 to 59.1% of patients, the upper limit of normal being set at Rheumatoid anemia is usually mild to moderate, nor- 14 or 12 g/dl and the lower limit of normal at 9.5 or 10 g/dl. In twomochromic, normocytic or, less often, microcytic, and aregener- studies, the upper limit was defined according to gender, as 13 g/dlative (no increase in circulating reticulocytes). Thrombocytosis is for men and 11.5 g/dl for women; the prevalence of anemia in thesefairly common but may also occur in conjunction with iron defi- two studies was 27.0 and 33%, respectively, in men; and 26.7 andciency anemia [9]. Serum transferrin levels are normal or low, 41%, respectively, in women [3].transferrin saturation (computed as the ratio of serum iron over Of 111 patients with early RA and a mean follow-up of 6 years,total transferrin binding capacity) is low, and serum ferritin levels 25% had anemia during the first year [14]. By univariate analysis,are normal or high. Absolute iron deficiency is usually defined as a hemoglobin levels correlated negatively with erythropoietin levels.serum ferritin value lower than 16 ng/mL (or 12 ng/mL) [10]. How- By multivariate analysis, however, only the erythrocyte sedimenta-ever, the cutoff may be higher in RA, as the inflammatory process tion rate (ESR) and serum IL-6 were independently associated withis associated with serum ferritin elevation [2]. the hemoglobin level.Table 3Variations in blood iron status markers in rheumatoid anemia, iron deficiency anemia, and both. Biomarkers Rheumatoid anemia Iron deficiency Both Serum iron Low Low Low Serum transferrin Normal or low High-normal or high Normal or low Transferrin saturation Low Low Low Serum ferritin Normal or high Low Normal or low Serum soluble transferrin receptor Normal High Normal or highFindings suggestive of iron deficiency include a hypochromic erythrocyte count greater than 6 or 10%, a reticulocyte hemoglobin content lower than 28 ␮g, and high levelsof zinc protoporphyrin (a heme precursor that incorporates zinc when no iron is available).
  3. 3. C. Masson / Joint Bone Spine 78 (2011) 131–137 133 In a multicenter cohort of early RA patients (ERAS) initiated in cytosis), and the 25 to 30 mg of iron thus released from heme meets1986 in nine hospitals throughout the UK (1429 patients with RA the needs of the bone marrow for erythropoiesis. The marrow ery-of less than 2 years’ duration and no disease-modifying treatment; throblasts capture 28 mg of iron per day on average to producemedian age, 55 years, 66% of women, and 26% of patients with ero- hemoglobin. About 5 mg of iron is released or captured by cells insions), 230 (16%) patients had at least one hemoglobin level lower storage tissues.than 10 g/dl during the 10-year follow-up (compared to 32% withnodules, 10% with sicca syndrome, and 5% with lung involvement) 5. Role for transferrin[4]. The percentage of patients with anemia was 5% after 1 year,11% after 3 years, 13% after 5 years, 16% after 7 years, and 7% after 5.1. Structure10 years. In a prospectively acquired database of 2120 patients with RA Transferrin (beta1 globulin) is a plasma glycoprotein that is pro-who had 26,221 hemoglobin assays, the prevalence of anemia duced by the liver and has a half-life of 8 days. Transferrin has aas defined by the WHO was 30.4% in men and 32.0% in women molecular weight of 75 to 80 kDa, with a single protein chain of[15]. Anemia prevalence was three times higher in the RA patients 679 amino acids, two binding sites for trivalent iron (one at the N-than in the 7124 patients without inflammatory joint disease. terminus and the other at the C-terminus), and two glycan chains.Hemoglobin levels were lower than 10 g/dl in 3.4% of RA patients Transferrin may bind one or two iron atoms. Transferrin not boundand lower than 11 g/dl in 11.1%. Both serum CRP and the ESR to iron is known as apotransferrin. The plasma transferrin level inwere significantly associated with rheumatoid anemia. At baseline, adults is usually between 1.8 and 3.2 g/L. Although transferrin ishigher Health Assessment Questionnaire (HAQ) scores (indicating produced chiefly in the liver (16 mg/kg/day), other production sitesgreater impairment) correlated with lower hemoglobin levels, and include the macrophages, lymphoid organs and, to a lesser degree,an at least 1-g increase in hemoglobin after 22 weeks was indepen- lymphocytes.dently associated with HAQ score improvement. To bind to plasma transferrin, iron must first be oxidized to fer- In 2495 patients included in three placebo-controlled trials of ric (trivalent) iron, a reaction catalyzed by hephaestin, a proteininfliximab (with methotrexate), anemia was independently asso- that shares 50% homology with ceruloplasmin (copper-dependentciated with physical disability as assessed using the HAQ score at oxidases).baseline (n = 2471) and after 22 weeks (n = 2458), [16]. The WHOdefinition of anemia was met in 37% of patients overall, 39% of 5.2. Total iron binding capacitywomen, and 32% of men. Of 10,397 patients entered in the COR-RONA registry between October 2001 and February 2007, 16.7% Total iron binding capacity (␮m/L) is obtained by multiplyingof patients met the WHO definition of anemia, and anemia was the plasma transferrin level (g/L) by 25 to account for conversionassociated with RA severity and with several comorbidities [17]. from micromoles to moles (106 ), the molecular mass of transfer- rin, and the ability of each transferrin molecule to bind two iron atoms. Total iron binding capacity is normally 45 to 80 micromol/L.4. Iron Massive hemolysis releases large amounts of iron that exceed the binding capacity of transferrin.4.1. Iron: ubiquitous, rare, indispensable, dangerous 5.3. Transferrin saturation Iron, one of the most abundant metal on Earth, is found in thehuman body in a small amount of about 4 to 5 g. Iron is absorbed by Transferrin saturation, measured as a percentage, is the ratio ofthe duodenum, used in the bone marrow, and stored in the liver and serum iron (␮mol/L) over the total iron binding capacity (␮mol/L).spleen. It continuously cycles within the body from the storage sites Usual values are 20–40% in males and 15–35% in females. Valuesto the marrow or various intracellular compartments and back. Iron greater than 45% indicate iron overload. Transferrin saturation isis stored in soluble form in ferritin and sequestered in insoluble decreased in both iron deficiency anemia and anemia of chronic dis-form within cells in lactoferrin and hemosiderin. The human body ease. Serum iron levels fluctuate across the 24-hour cycle, whereashas no mechanism for eliminating excess iron. transferrin levels do not. Serum iron is low in iron deficiency anemia Iron is required for the growth of infectious agents [18]. One and anemia of chronic disease and also diminishes during men-of the defense mechanisms against infections consists in activat- struation. Serum iron determination serves to compute transferrining the metabolic pathways that increase intracellular iron, which saturation and should be performed in the fasting state, 24–48 hdecreases serum iron. There is less iron available for erythrocyte after stopping any iron supplements (or 8 days after a blood trans-production (200 billion/day), and anemia of chronic disease devel- fusion or intravenous iron administration).ops. During the acute-phase reaction, which is often chronic in 5.4. Variations in transferrin levelsRA, the proinflammatory cytokines affect iron metabolism, mostnotably plasma iron levels and the production of transferrin, fer- Plasma transferrin levels decrease in the event of systemicritin, and hepcidin. inflammation. In patients with iron deficiency, serum iron levels are initially maintained within the normal range via the use of4.2. Cycle available iron stores. Subsequently, increased amounts of trans- ferrin are produced and, finally, serum iron levels decrease and A large portion of the iron in the body is associated with hypochromic anemia develops. Thus, transferrin levels are highhemoglobin in the circulating erythrocytes (about 2.5 g). The in patients with iron deficiency [11–13]. Other causes of transfer-inevitable iron losses of about 1–2 mg/day due to epithelial cell rin elevation include increased estrogen impregnation (e.g., duringshedding (intestine and skin) are counterbalanced by the intestinal pregnancy, hormone replacement therapy, or oral contraception,absorption of dietary iron by mature enterocytes at the tips of the although low and ultra-low dose pills have a smaller effect), useduodenal villi. About 1–2 mg/d of iron are absorbed each day for of thiazide diuretics, and severe hypogonadism in males. Transfer-a mean iron intake of 13–18 mg/d. The macrophages continuously rin levels decrease in patients with inflammatory diseases such asphagocytize and catabolize senescent erythrocytes (erythrophago- RA, cancer, infection, malnutrition, protein wasting, or exogenous
  4. 4. 134 C. Masson / Joint Bone Spine 78 (2011) 131–137androgen exposure. Patients with hemochromatosis may have low 7.3. Numberstransferrin levels. The total amount of ferritin in the body is 1 g in men and 0.4 g in women. The normal plasma ferritin range is 30–300 ␮g/L in men6. Membrane transferrin receptor and 20–200 ␮g/L in women. Intracellular ferritin contains about 0.5 g of readily available iron. Plasma ferritin is best assayed after6.1. The membrane receptor several days without iron supplementation. As mentioned above, plasma ferritin values lower than 12–16 ng/L are diagnostic for The transferrin receptor is a membrane-spanning glycoprotein iron deficiency. In the event of anemia, plasma ferritin consistentlycomposed of 760 amino acids with two monomers bound together returns to normal after recovery of normal erythrocyte counts.by two disulfide bonds to produce a 190 kDa molecule. All cells inthe body except mature erythrocytes express the transferrin recep-tor on their surface membrane, but 80% of the receptor molecules 8. Crucial role for hepcidin in conjunction with IL-6 inin adults are located on the bone marrow erythroblast precursors. rheumatoid anemiaIron deficiency promptly induces a sharp increase in transferrinreceptor production. 8.1. Characteristics of hepcidin6.2. The soluble transferrin receptor Hepcidin, a circulating peptide with a key role in iron home- ostasis, links iron metabolism to inflammation [18,21,22]. Hepcidin The sTfR is the monomeric form of the transferrin membrane can be viewed as a type II acute-phase protein. Prohepcidin, an 84-receptor. The sTfR level is a marker for erythropoietic activity and amino acid prepropeptide, is cleaved by the proprotein convertasetissue iron deficiency. The plasma sTfR level is proportional to the furin, which releases hepcidin, a mature peptide containing only 20amount of transferrin at the surface of hematopoietic cells and to 25 amino acids with eight cysteine residues linked by four disul-increases in proportion to the severity of iron deficiency. Systemic fide bonds, leading to a highly convoluted conformation. Hepcidininflammation does not affect sTfR levels [19]. is produced in the liver, as well as in the macrophages, kidney cells, and adipocytes. It is eliminated through the urine. Hepcidin lowers serum iron levels by acting as a gatekeeper6.3. Bone marrow function for transmembrane iron transport. More specifically, hepcidin prevents iron from exiting cells, most notably enterocytes, The iron used in the bone marrow for erythropoiesis is macrophages, and hepatocytes, thereby decreasing iron levelstransferred from the macrophages to the erythroblasts via their in the bloodstream. Thus, hepcidin inhibits both intestinal irontransferrin membrane receptors. Only iron bound to transferrin absorption and the release of iron stored in macrophages and hep-can be used by the erythroblasts. Thus, marrow erythropoietic pre- atocytes [10].cursors acquire iron as iron-transferrin complexes via the large Hepcidin acts by binding to ferroportin, a protein that exportsnumber of transferrin receptors at their surface. The iron is then ferric iron from cells. Ferroportin is expressed at the basolateralexported to the cytosol, and most of it enters the mitochondria, pole of enterocytes. Hepcidin causes the internalization, ubiquiti-where it is inserted into protoporphyrin IX to form heme. The heme nation, and lysosomal degradation of ferroportin.thus formed is exported to the cytosol, where it becomes associated Hepcidin expression in the liver is dependent on the proteinwith globin chains. hemojuvelin, which is one of the repulsive guidance molecules. Hemojuvelin is a coreceptor of bone morphogenetic proteins and7. Ferritin activates hepcidin gene transcription via a Smad4-dependent path- way. Hemojuvelin is required for basal hepcidin expression.7.1. Structure In iron deficiency and other situations associated with increased erythropoiesis (hypoxia, bleeding, hemolysis, and dyserythro- Ferritin is a glycoprotein macromolecule (450 kDa) found chiefly poiesis), hepcidin synthesis is suppressed. On the opposite,within cells. It is ubiquitous and highly conserved during evolu- inflammation upregulates hepcidin production via IL-6.tion. Ferritin is an alpha2 globulin composed of 24 subunits, whichare either heart-type (H) or liver-type (L), allowing many combina- 8.2. Interleukin-6 and anemiations that produce different isoforms [18]. Glycosylated ferritin hasa longer half-life than nonglycosylated ferritin and contributes 60 IL-6, a 21 kDa polypeptide composed of 212 amino acidsto 80% of total ferritin. Apoferritin has an accessible central cavity arranged in four alpha chains, is a versatile proinflammatorythat contains a core of ferric hydroxyphosphate microcrystals. Each cytokine produced by numerous cell types. IL-6 is closely involvedferritin molecule can store up to 4500 atoms of iron. in the development of anemia of chronic disease. Thus, in patients with advanced ovarian cancer, the severity of anemia correlates7.2. Function with the degree of IL-6 elevation. The IL-6 level, together with cancer stage, predicts the severity of anemia of chronic disease in Ferritin, which stores iron in an accessible form, is a key patients with ovarian cancer [10].molecule that limits iron-induced oxidizing stress in health and dis- In therapeutic trials of human recombinant IL-6, two typesease [20]. Iron bound to ferritin is not toxic. Plasma ferritin (whose of anemia were reported. Dilution anemia related to the plasmaorigin is unclear) contains fairly small amounts of iron, similar to volume increase developed rapidly, in a dose-dependent manner,hepatosplenic isoferritin; has a short half-life; and is rapidly taken and resolved upon treatment discontinuation. In contrast, anemiaup by the liver. Nevertheless, plasma ferritin is a source of readily related to iron dysregulation set in more slowly, over several weeks,available iron. The ferritin content of cells is regulated by the pool of as a result of IL-6 induced mobilization of iron bound to transferrinfree iron. Nonglycosylated ferritin comes from parenchymal cells. on hepatocyte transferrin receptors, which induced a rapid dropElevation of plasma levels of nonglycosylated ferritin indicates cell in serum iron levels. Within 24–48 h, IL-6 downregulates transfer-lysis. rin expression and upregulates ferritin expression, whereas both
  5. 5. C. Masson / Joint Bone Spine 78 (2011) 131–137 135serum iron and CRP levels drop within 12 h. In nonhuman primates, 9.2. Role for erythropoietinIL-6 diminishes the proportion of nucleated erythroid cells in thebone marrow and decreases serum iron levels. These effects can be Erythropoietin is a 30.4 kDa glycoprotein composed of 165corrected by administering an IL-6 antagonist [18–27]. amino acids. Erythropoietin inhibits erythroid progenitor apopto- sis and induces clonal proliferation of normoblasts. In adults, the kidneys produce 90 to 95% of the erythropoietin found in the blood-8.3. Interleukin-6 and hepcidin stream. The remainder is produced by the liver. Hypoxia activates erythropoietin production. Hepcidin gene transcription, most notably in the hepatocytes, is Erythropoietin was first purified in 1977 and the gene wasincreased during inflammation, via IL-6. IL-6 rapidly increases the cloned in 1983. The first clinical studies were started in 1986. Theproduction of hepcidin [23]. When human hepatocytes are exposed introduction of erythropoietin therapy has virtually eliminated theto a cytokine panel, only IL-6 upregulates the production of hep- need for blood transfusions in chronic hemodialysis patients.cidin mRNA. Neither TNF␣ nor IL-1 affects the hepatic synthesis In RA, the high proinflammatory cytokine levels usually inhibitof hepcidin. In vitro, human hepatoma cells exposed to IL-6 pro- the production of erythropoietin mRNA to some extent, leadingduce hepcidin. In wild-type mice, turpentine exposure to activate to a decrease in endogenous serum erythropoietin [10]. How-the inflammatory response markedly upregulates hepatic hepcidin ever, this pathogenic mechanism is not consistently present inexpression and decreases serum iron levels, whereas IL-6 knockout rheumatoid anemia [33]. Another mechanism of interest is erythro-mice have subnormal hepcidin levels and high serum iron levels. poietin signaling pathway alteration due to increased productionIn healthy human volunteers, IL-6 infusion increases the release of of suppressor of cytokine signaling/cytokine inducible SH2 proteinhepcidin 7.5-fold, increases urinary IL-6 excretion as early as the (SOCS/CIS). The result is resistance to the effects of erythropoietinthird hour, and decreases the serum iron level. [34]. 9.3. Early hematopoiesis8.4. Hepcidin and rheumatoid arthritis TNF␣ and TGF␤ inhibit the proliferation of murine progeni- In a cross-sectional study, serum prohepcidin levels were sig- tors and self-renewal of pluripotent stem cells. TNF␣, IFN␥, andnificantly higher in 72 patients with RA than in 28 patients with TGF␤ synergistically activate human CD34 + cell apoptosis via thesystemic lupus erythematosus (SLE) and 33 healthy controls [28]. Fas/Fas-ligand system. TNF␣ can induce cellular senescence, thusIn the controls, serum prohepcidin levels correlated with serum IL- further contributing to inhibit growth.6, TNF␣, and ferritin levels. In both patients and controls, serum In a study comparing 40 RA patients to 24 age- and sex-matchedprohepcidin levels varied widely. Another study found that serum controls, all of whom underwent bone marrow biopsy, the RAprohepcidin was significantly lower in 30 patients with pure iron patients had fewer erythroid progenitors and precursors than diddeficiency than in 30 RA patients with non-iron-deficient anemia the controls [33]. In addition, the RA patients exhibited apoptoticor 20 healthy controls [29]. Furthermore, the sTfR level was higher depletion of CD34 + /CD71 + and CD36 + /glycoA + erythroid cells,in the group with iron deficiency. Serum hepcidin levels were sig- probably in relation to increased local TNF␣ production. Thesenificantly higher in 19 patients with rheumatoid anemia than in 12 abnormalities were more marked in the RA patients with anemiapatients with iron deficiency anemia or 14 healthy controls [30]. of chronic disease and high circulating levels of proinflammatorySerum hepcidin levels showed a positive correlation with RA activ- cytokines. In 12 patients who underwent a second bone marrowity and a negative correlation with the hemoglobin level. biopsy after infliximab perfusions according to the recommended In a nonhuman primate model of collagen-induced arthritis, regimen, counts of CD34 + /CD71 + and CD36 + /glycoA + cells and ofanemia correlated with serum IL-6 levels (which correlated with BFU-E were increased compared to the pretreatment biopsy.serum CRP levels) but not with serum TNF␣ levels [31]. In thismodel, the IL-6 antagonist tocilizumab reversed the anemia via an 9.4. Role for the bone marrow transferrin receptoreffect on hepcidin [32]. A question of considerable interest is whether serum or urinary The iron metabolism of erythroblasts in bone marrow biopsieshepcidin assays might readily distinguish between rheumatoid from 29 patients with RA and anemia, six patients with iron defi-anemia and iron deficiency anemia, thus providing valuable treat- ciency anemia, and nine healthy volunteers was studied in vitroment guidance. [35]. High purity erythroblast fractions were obtained from 35 of the 44 bone marrow biopsies. Transferrin receptor expression at the erythroblast surface was assessed using iodine 135-labeled9. Erythropoiesis and rheumatoid anemia transferrin and iron uptake using iron 59-labeled transferrin. The RA patients were classified as having rheumatoid anemia or iron Cytokines affect erythropoiesis in three ways: by diminishing deficiency anemia based on the bone marrow iron content. In thethe production of erythropoietin, by decreasing the amount of iron group of RA patients with anemia of chronic disease, iron uptakeavailable for erythropoiesis, and by exerting direct toxic effects on by erythroblast transferrin was increased, although the number ofearly-stage erythropoietic cells. transferrin receptors on the erythroblast surface was not, suggest- ing greater efficiency of iron uptake compensating for the decrease in serum iron. In the patients with iron deficiency anemia, in9.1. Erythropoiesis contrast, both iron uptake and the number of surface transferrin receptors were increased, and serum sTfR was elevated. TNF␣ and IFN␥ inhibit erythroid colony formation in vitro. Theapoptotic Fas/Fas-ligand system inhibits the proliferation of burst- 10. Treatment of rheumatoid anemiaforming unit-erythroid (BFU-E) and colony-forming unit-erythroid(CFU-E) progenitors. Some of the ligands of the Fas/Fas-ligand sys- 10.1. Treatment of rheumatoid arthritistem, produced by mature erythroblasts and inflammatory cells,exert a negative feedback effect on the development of less mature The best means of correcting rheumatoid anemia is to ensureerythroblasts. systemic disease control by administering synthetic or biologic
  6. 6. 136 C. Masson / Joint Bone Spine 78 (2011) 131–137Table 4 ommendations for erythropoietin use in patients with rheumatoidIron Refractory Iron Deficiency Anemia (IRIDA): a distinctive form of iron deficiency anemia. Recommendations are available for three other causesanemia due to a genetic abnormality [18]. of anemia of chronic disease (cancer, chronic kidney failure, and Cause: inactivating mutations in the gene for matriptase-2, a protein involved chronic bowel disease) [34]. The goal of erythropoietin therapy is in hepcidin regulation usually to increase the hemoglobin level to 11 or 12 g/dl. With cur- High hepcidin levels Low serum iron and normal-to-low serum ferritin rently available drugs for RA, hemoglobin levels lower than 11 g/dl Microcytic hypochromic anemia are uncommon. No response to oral iron supplementation In one study, 30 patients with rheumatoid anemia were given Response to intravenous iron supplementation recombinant human erythropoietin, 150 IU/kg twice a week for 12 weeks [45]. Patients with functional iron deficiency (22 ofdisease-modifying antirheumatic drugs (methotrexate [36], TNF␣ the 28 patients who completed the study) also received intra-antagonists [37], rituximab, abatacept, and tocilizumab [38–42]). A venous iron, 200 mg/week. After a mean of 9 weeks, the meanpooled analysis of data from three randomized clinical trials com- hemoglobin level increased from 10.7 g/dl to 13.2 g/dl. Other bene-paring infliximab to placebo, with methotrexate, in RA patients fits included decreased disease activity, improved muscle strength,showed that the infliximab-methotrexate combination was asso- and decreased fatigue. Similarly, a placebo-controlled double-blindciated with a greater than 1-g increase in serum hemoglobin levels randomized study in 70 patients with RA and anemia of chronic dis-in 40% of patients and produced normal hemoglobin level in 43% ease (hemoglobin < 11.7 g/dl) showed that erythropoietin therapy[37]. improved quality of life and increased the mean hemoglobin level In trials of tocilizumab in RA, hemoglobin levels showed fairly by 2.2 g/dl at week 52 (versus no change in the placebo group).substantial increases in patients with anemia and smaller increases However, published data suggest that rheumatoid anemia may bein those without anemia. For instance, in the TOWARD trial of refractory to erythropoietin, even in high doses, in up to 80% oftocilizumab 8 mg/kg/month in RA, the hemoglobin level in patients patients [10].with anemia increased by 1.7 g/dl, compared to 0.2 g/dl in the Erythropoietin therapy might be best reserved for RA patientsplacebo arm [40]. Hemoglobin levels increased as early as the sec- with erythropoietin levels lower than 500 mU/ml or evenond week of tocilizumab therapy. 100 mU/ml [34]. In patients scheduled for elective surgery, ery- thropoietin therapy and perhaps intravenous iron supplementation may deserve consideration based on the hemoglobin level and iron10.2. Blood transfusions status [3]. The inflammation that characterizes RA is associated with a risk Transfusions of red blood cell packs are very rarely appropri- of vascular events. Thus, the risk of hypertension and thrombosisate for the treatment of rheumatoid anemia. Transfusions may be with erythropoietin therapy must be weighed against the poten-needed in patients requiring surgery (e.g., hip or knee replacement). tial benefits. The cardiovascular risk may be greatest when theStandard precautions must be followed scrupulously. hemoglobin level increases by more than 1 g every 2 weeks. The best treatment strategy for rheumatoid anemia is effective disease10.3. Iron supplementation control. Oral iron supplementation is required in patients with docu-mented iron deficiency (independently from rheumatoid anemia). Conflict of interest statementPrevention of digestive toxicity is crucial [43]. For instance, inpatients scheduled for surgery, intravenous colloidal iron (100 to The author declares no conflicts of interest.200 mg) once weekly for a few weeks, may deserve consideration,depending on the serum ferritin level. A recently described entityis iron-refractory iron deficiency anemia. This is a genetic disease Referenceswith iron deficiency and no response to oral iron supplementation [1] Gomollon F, Gisbert JP. Anemia and inflammatory bowel diseases. World J(Table 4) [18]. Gastroenterol 2009;15:4659–65. Classically, oral iron supplementation for rheumatoid anemia [2] Masson CJ. L’anémie rhumatoïde. Rev Rhum Mal Osteoartic 1992;59(6was believed to carry a risk of RA flares [2]. No flares occurred in a bis):30–6S. [3] Wilson A, Yu HT, Goodnough LT, Nissenson AR. Prevalence and outcome ofstudy of a small number of RA patients given intravenous iron [44]. anemia in rheumatoid arthritis: a systematic review of the literature. Am J Med 2004;116(Suppl. 7A):50S–7S.10.4. Erythropoietin [4] Young A, Koduri G. Extra-articular manifestations and complications of rheumatoid arthritis. Best Pract Res Clin Rheumatol 2007;21:907–27. [5] Means RT. Hepcidin and anemia. Blood Rev 2004;18:219–25. In patients with persistent anemia despite specific RA treat- [6] Glossop JR, Dawes PT, Hassell AB, et al. Anemia in rheumatoid arthritis: associ-ment, erythropoietin therapy (Table 5) may be considered if the ation with polymorphism in the tumor necrosis factor receptor I and II genes. J Rheumatol 2005;32:1673–8.serum erythropoietin levels are low given the degree of anemia. 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