1. Rheumatoid anemia is a common form of anemia seen in patients with rheumatoid arthritis. It is typically a mild to moderate normocytic anemia. 2. The anemia is caused by chronic inflammation which increases levels of hepcidin, an iron-regulatory hormone. Hepcidin inhibits iron absorption and transport, leading to low iron availability. 3. Studies have found the prevalence of rheumatoid anemia to be between 30-60% in patients with rheumatoid arthritis depending on how anemia is defined. Having rheumatoid anemia is associated with worse disease outcomes and impairment.

1. Joint Bone Spine 78 (2011) 131–137
Review
Rheumatoid anemia
Charles Masson ∗
Service de rhumatologie, pôle ostéoarticulaire, 4, rue Larrey, CHU d’Angers, Angers 49933 cedex 9, France
a r t i c l e i n f o a b s t r a c t
Article history: Rheumatoid anemia is a typical example of anemia of chronic disease. It differs from other forms of
Accepted 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 or
Keywords: high, the soluble transferrin receptor (sTfR) is not increased (a distinguishing feature with iron deficiency
Rheumatoid anemia anemia), and the sTfR/log ferritin ratio is lower than 1. This review discusses the prevalence and impact
Transferrin
of rheumatoid anemia based on a review of the literature. Iron metabolism, absorption, diffusion, storage,
Transferrin receptor
Ferritin
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 cytokine
Interleukin-6 interleukin-6 (IL-6). Hepcidin is a hormone that lowers serum iron levels and regulates iron transport
Erythropoietin 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 of
rheumatoid 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 rheumatoid
highly 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 is
inadequate bone marrow erythropoiesis in response to the ane- iron deficiency anemia due to malabsorption or, more often, iron
mia, 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 agent
matory 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. 132 C. Masson / Joint Bone Spine 78 (2011) 131–137
Table 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 index
Table 2
Causes 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, whereas
Among patients with unexplained iron deficiency, about half have lesions identified neither ferritin nor hemoglobin is stained. The normal or increased
by endoscopic examination of the upper gastrointestinal tract and colon. When no iron stores seen in bone marrow macrophages in rheumatoid
lesion 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 tomography
enteroclysis may be in order, followed by video capsule enteroscopy if no steno-
which are erythroblasts containing iron granules, suggests primary
sis 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 anemia
2. 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 than
2.1. 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 two
mochromic, normocytic or, less often, microcytic, and aregener- studies, the upper limit was defined according to gender, as 13 g/dl
ative (no increase in circulating reticulocytes). Thrombocytosis is for men and 11.5 g/dl for women; the prevalence of anemia in these
fairly common but may also occur in conjunction with iron defi- two studies was 27.0 and 33%, respectively, in men; and 26.7 and
ciency 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 with
is associated with serum ferritin elevation [2]. the hemoglobin level.
Table 3
Variations 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 high
Findings suggestive of iron deficiency include a hypochromic erythrocyte count greater than 6 or 10%, a reticulocyte hemoglobin content lower than 28 ␮g, and high levels
of zinc protoporphyrin (a heme precursor that incorporates zinc when no iron is available).

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 meets
1986 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 produce
median age, 55 years, 66% of women, and 26% of patients with ero- hemoglobin. About 5 mg of iron is released or captured by cells in
sions), 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% with
nodules, 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. Structure
10 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 a
as 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 bound
and lower than 11 g/dl in 11.1%. Both serum CRP and the ESR to iron is known as apotransferrin. The plasma transferrin level in
were significantly associated with rheumatoid anemia. At baseline, adults is usually between 1.8 and 3.2 g/L. Although transferrin is
higher Health Assessment Questionnaire (HAQ) scores (indicating produced chiefly in the liver (16 mg/kg/day), other production sites
greater 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 protein
infliximab (with methotrexate), anemia was independently asso- that shares 50% homology with ceruloplasmin (copper-dependent
ciated with physical disability as assessed using the HAQ score at oxidases).
baseline (n = 2471) and after 22 weeks (n = 2458), [16]. The WHO
definition of anemia was met in 37% of patients overall, 39% of 5.2. Total iron binding capacity
women, 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 multiplying
of patients met the WHO definition of anemia, and anemia was the plasma transferrin level (g/L) by 25 to account for conversion
associated 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 the
human body in a small amount of about 4 to 5 g. Iron is absorbed by
Transferrin saturation, measured as a percentage, is the ratio of
the 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. Values
to the marrow or various intracellular compartments and back. Iron
greater than 45% indicate iron overload. Transferrin saturation is
is 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, whereas
has 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 transferrin
ing the metabolic pathways that increase intracellular iron, which
saturation and should be performed in the fasting state, 24–48 h
decreases 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 levels
RA, the proinflammatory cytokines affect iron metabolism, most
notably plasma iron levels and the production of transferrin, fer-
Plasma transferrin levels decrease in the event of systemic
ritin, and hepcidin.
inflammation. In patients with iron deficiency, serum iron levels
are initially maintained within the normal range via the use of
4.2. 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 high
hemoglobin 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., during
shedding (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), use
duodenal 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 as
phagocytize and catabolize senescent erythrocytes (erythrophago- RA, cancer, infection, malnutrition, protein wasting, or exogenous

4. 134 C. Masson / Joint Bone Spine 78 (2011) 131–137
androgen exposure. Patients with hemochromatosis may have low 7.3. Numbers
transferrin 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 men
6. 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 after
6.1. 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 consistently
composed 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 in
the 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 in
in adults are located on the bone marrow erythroblast precursors. rheumatoid anemia
Iron deficiency promptly induces a sharp increase in transferrin
receptor production. 8.1. Characteristics of hepcidin
6.2. 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 convertase
tissue iron deficiency. The plasma sTfR level is proportional to the furin, which releases hepcidin, a mature peptide containing only 20
amount 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. Hepcidin
inflammation 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 gatekeeper
6.3. 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 levels
transferred from the macrophages to the erythroblasts via their in the bloodstream. Thus, hepcidin inhibits both intestinal iron
transferrin 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 exports
number of transferrin receptors at their surface. The iron is then ferric iron from cells. Ferroportin is expressed at the basolateral
exported 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 protein
with globin chains. hemojuvelin, which is one of the repulsive guidance molecules.
Hemojuvelin is a coreceptor of bone morphogenetic proteins and
7. 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, which
are either heart-type (H) or liver-type (L), allowing many combina-
8.2. Interleukin-6 and anemia
tions that produce different isoforms [18]. Glycosylated ferritin has
a longer half-life than nonglycosylated ferritin and contributes 60 IL-6, a 21 kDa polypeptide composed of 212 amino acids
to 80% of total ferritin. Apoferritin has an accessible central cavity
arranged in four alpha chains, is a versatile proinflammatory
that contains a core of ferric hydroxyphosphate microcrystals. Each
cytokine produced by numerous cell types. IL-6 is closely involved
ferritin 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 correlates
7.2. 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 types
ease [20]. Iron bound to ferritin is not toxic. Plasma ferritin (whose of anemia were reported. Dilution anemia related to the plasma
origin 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, anemia
up 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 transferrin
free iron. Nonglycosylated ferritin comes from parenchymal cells. on hepatocyte transferrin receptors, which induced a rapid drop
Elevation 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. C. Masson / Joint Bone Spine 78 (2011) 131–137 135
serum iron and CRP levels drop within 12 h. In nonhuman primates, 9.2. Role for erythropoietin
IL-6 diminishes the proportion of nucleated erythroid cells in the
bone marrow and decreases serum iron levels. These effects can be Erythropoietin is a 30.4 kDa glycoprotein composed of 165
corrected 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 was
increased during inflammation, via IL-6. IL-6 rapidly increases the cloned in 1983. The first clinical studies were started in 1986. The
production of hepcidin [23]. When human hepatocytes are exposed introduction of erythropoietin therapy has virtually eliminated the
to 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 inhibit
of hepcidin. In vitro, human hepatoma cells exposed to IL-6 pro- the production of erythropoietin mRNA to some extent, leading
duce 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 in
expression 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 production
In healthy human volunteers, IL-6 infusion increases the release of of suppressor of cytokine signaling/cytokine inducible SH2 protein
hepcidin 7.5-fold, increases urinary IL-6 excretion as early as the (SOCS/CIS). The result is resistance to the effects of erythropoietin
third hour, and decreases the serum iron level. [34].
9.3. Early hematopoiesis
8.4. 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␥, and
nificantly higher in 72 patients with RA than in 28 patients with TGF␤ synergistically activate human CD34 + cell apoptosis via the
systemic lupus erythematosus (SLE) and 33 healthy controls [28]. Fas/Fas-ligand system. TNF␣ can induce cellular senescence, thus
In 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-matched
prohepcidin levels varied widely. Another study found that serum controls, all of whom underwent bone marrow biopsy, the RA
prohepcidin was significantly lower in 30 patients with pure iron patients had fewer erythroid progenitors and precursors than did
deficiency than in 30 RA patients with non-iron-deficient anemia the controls [33]. In addition, the RA patients exhibited apoptotic
or 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. These
nificantly higher in 19 patients with rheumatoid anemia than in 12 abnormalities were more marked in the RA patients with anemia
patients with iron deficiency anemia or 14 healthy controls [30]. of chronic disease and high circulating levels of proinflammatory
Serum hepcidin levels showed a positive correlation with RA activ- cytokines. In 12 patients who underwent a second bone marrow
ity 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 of
anemia 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 this
model, the IL-6 antagonist tocilizumab reversed the anemia via an 9.4. Role for the bone marrow transferrin receptor
effect on hepcidin [32].
A question of considerable interest is whether serum or urinary The iron metabolism of erythroblasts in bone marrow biopsies
hepcidin 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 vitro
ment 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-labeled
9. 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 the
the production of erythropoietin, by decreasing the amount of iron group of RA patients with anemia of chronic disease, iron uptake
available for erythropoiesis, and by exerting direct toxic effects on by erythroblast transferrin was increased, although the number of
early-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, in
9.1. 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. The
apoptotic Fas/Fas-ligand system inhibits the proliferation of burst- 10. Treatment of rheumatoid anemia
forming 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 arthritis
tem, 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 ensure
erythroblasts. systemic disease control by administering synthetic or biologic

6. 136 C. Masson / Joint Bone Spine 78 (2011) 131–137
Table 4 ommendations for erythropoietin use in patients with rheumatoid
Iron Refractory Iron Deficiency Anemia (IRIDA): a distinctive form of iron deficiency
anemia. Recommendations are available for three other causes
anemia 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 of
disease-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 mean
pooled 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-blind
ciated 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 be
in those without anemia. For instance, in the TOWARD trial of refractory to erythropoietin, even in high doses, in up to 80% of
tocilizumab 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 patients
placebo arm [40]. Hemoglobin levels increased as early as the sec- with erythropoietin levels lower than 500 mU/ml or even
ond 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 iron
10.2. 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 thrombosis
ate 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 the
Standard 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 disease
10.3. Iron supplementation
control.
Oral iron supplementation is required in patients with docu-
mented iron deficiency (independently from rheumatoid anemia). Conflict of interest statement
Prevention of digestive toxicity is crucial [43]. For instance, in
patients 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 entity
is iron-refractory iron deficiency anemia. This is a genetic disease References
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