“Anemia is the most common extra-articular manifestation of

rheumatoid arthritis, estimated to occur in 30% to 60% of patients.”

VII Anemia&
Rheumatoid
Arthritis
Key Points

• Anemia is common in rheumatoid arthritis

(RA) and may constitute an important clinical
problem for many patients.
• The two primary types of anemia in patients
with RA are anemia of chronic disease and iron
deficiency anemia.
• Erythropoietin therapy in combination with iron
supplementation corrects anemia in most
patients with RA, and may improve RA outcomes
and quality of life.
• Erythropoietin is useful in facilitating autologous
blood donation prior to elective surgery for
patients with RA and in reducing transfusion
requirements.
46
RA: A Chronic Inflammatory Disease
Rheumatoid arthritis (RA) is a chronic
inflammatory disease that affects an esti-
mated 2.1 million Americans.1 Although
patients who meet diagnostic criteria for
RA for less than 6 months may enjoy a
spontaneous remission,2,3 patients with
persistent inflammation over a year or
longer generally have a chronic progres-
sive disease.4-6 Most patients with RA
experience joint destruction, radiograph-
ic damage, functional declines, work dis-
ability after 10 years of disease,7,8 and
premature death by 10 to 15 years.4,9
RA remains a source of significant
morbidity in the United States, estimated
to involve costs of 1% of the gross
domestic product,10,11 much of which are
indirect costs secondary to work disabili-
ty.12 The goal of therapy is to control
inflammation in order to prevent long-
term joint damage.13-16 The variables that
best identify and predict severe out-
comes, including work disability, high
costs, and premature mortality, are poor
functional status, comorbidities, old age,
and low socioeconomic status, and, to a
lesser degree, high radiographic scores
and rheumatoid factor titer.6
Anemia Common in RA
Anemia is the most common extra-
articular manifestation of RA, estimated
to occur in 30% to 60% of patients.17-19
Patients with RA who are anemic have
evidence of more severe disease, with
more involved joints and higher levels of
functional disability and pain.19-21
Although any type of anemia may be
seen in patients with RA, the two prima-
ry types of anemia in RA appear to be
iron deficiency anemia and anemia of
chronic disease. In their retrospective
Anemia: A Hidden Epidemic
review of 225 patients with RA, Peeters
and colleagues identified 64% as anemic.
Of the group classified as anemic, 77%
were found to have anemia of chronic
disease and 23% to have iron deficiency
anemia.19
Differential diagnosis may be difficult,
as serum iron levels are low in both
types of anemia, and bone marrow stain-
ing for iron stores may be required.
However, serum ferritin testing usually
distinguishes between iron deficiency
and anemia of chronic disease. Patients
with serum ferritin levels >50 µg/mL are
likely to have anemia of chronic disease,
while those with a lower value of serum
ferritin are likely to be iron deficient.22-24
The most common causes of iron defi-
ciency anemia in RA are blood loss
through menstrual bleeding and/or gas-
trointestinal bleeding secondary to nons-
teroidal anti-inflammatory drugs. Anemia
of chronic disease is an “inflammatory
anemia,” and its features in RA are simi-
lar to those seen in inflammatory bowel
disease, HIV, aging, and cancer.
Impact of Inflammatory Cytokines
Development of anemia of chronic
disease in patients with RA appears to
be related to inflammatory cytokines,
which cause joint inflammation and
interfere with normal red blood cell for-
mation and destruction.25-28
Patients with RA make erythropoietin
in response to the inflammatory anemia,
as expected. However, the response is
blunted in these patients, with both inad-
equate production of erythropoietin and
inadequate bone marrow responses com-
pared to people with similar levels of
anemia and no inflammation.17,18,20,29,30
Animal studies suggest that increased
VII. Anemia & Rheumatoid Arthritis
levels of the inflammatory cytokines inter-
leukin-1 (IL-1) and tumor necrosis factor-∝
(TNF-∝) inhibit erythropoietin production
and interfere with erythroid colony-form-
ing units in the bone marrow.28,31,32
RA Patients
10,000
3,000
1,000
EP 300
mU/ml
100
30
10
3 3
3 5 7 9 11 13
Hemoglobin g/dL
Figure 7-1. Patients with RA exhibit a blunted erythropoietin response compared to patients
without RA. Adapted and reprinted with permission from Brit J Hematol.17
Treatment of Anemia in RA
Antirheumatic Drugs
The first principle of treating anemia
in RA is to reduce inflammation to as
low a level as possible with disease-
modifying antirheumatic drugs
(DMARDs),13-16 using methotrexate as an
anchor drug in combination with addi-
tional DMARDs and biologic agents,
including leflunomide, etanercept,
infliximab, and anakinra.33 Treatment of
patients with RA with infliximab (an
anti–TNF-∝ agent) and anakinra
(an IL-1 receptor antagonist) led to
improvement in anemia not seen in
patients treated with placebo,34
although improvement of clinical fea-
tures of RA was not correlated signifi-
47
cantly with improvement of anemia.
Iron Supplementation
Iron supplementation is of great
importance in patients who have iron
Patients without RA
10,000
3,000
1,000
300
100
30
10
15 3 5 7 9 11 13 15
Hemoglobin g/dL
deficiency. Furthermore, iron deficiency
may occur concomitantly with anemia of
chronic disease.28,35 Iron repletion is
almost always required as an adjunctive
treatment to erythropoietin therapy, as
erythroid production is increased.36-39
Erythropoietin Therapy
Erythropoietin therapy is effective in
correcting anemia of chronic disease in
patients with RA.37,40,41 However, the
doses of erythropoietin required are
higher than those needed by patients
with anemia from noninflammatory caus-
es, such as renal failure.
In most early studies, the increase in
Hb levels was not accompanied by
improvement of functional status, as
measured by capacity to perform activ-
48
ities of daily living and pain scores on
patient questionnaires.42-44 As in the
studies noted above, patients who
were treated with epoetin generally
required high doses of iron to maintain
erythrocyte production. When the ery-
thropoietin was discontinued, the Hb
level declined.
More recent studies have indicated
that treatment of patients with RA with
epoetin does lead to functional improve-
ment. Peeters and colleagues noted that
patients with RA who were treated with
epoetin experienced improvement in
joint tenderness and swelling, in addition
to improvement in Hct.40,41 Another report
noted improvement in Nottingham
Health Profile scores for energy in
patients treated with epoetin.20 Kaltwasser
and colleagues found that combined
Anemia: A Hidden Epidemic
treatment with epoetin and intravenous
iron in patients with RA with anemia of
chronic disease led to increased Hb lev-
els, decreased disease activity, and
improved quality of life (decreased
fatigue and increased vitality and muscle
strength).37 The beneficial effects of ane-
mia treatment with epoetin appear to
extend to children with juvenile RA,
improving both quality of life and
growth rates in children who are still in
their growing phase.45
Treatment with epoetin may also facil-
itate autologous blood donation by
patients with RA prior to total hip or
knee arthroplasty.21,46-48 This therapy has
also been shown to reduce transfusion
requirements in patients with RA who
undergo elective joint replacement
surgery.33,48,49
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