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57

Acute Phase Reactants


and the Concept of
Inflammation
AMIT SAXENA BRUCE N. CRONSTEIN

KEY POINTS
Inflammation comprises a complex and highly variable set of
processes that represent a response to tissue damage from
infection or injury.
The acute phase response, a major accompaniment of
inflammation, is induced by inflammation-associated
cytokines and includes reorchestration of acute phase
protein synthesis by the liver.
The erythrocyte sedimentation rate (ESR), the most
commonly employed clinical measure of inflammation,
depends on numerous physical and chemical characteristics
of blood, many of which are not related to inflammation.
The quintessential acute phase protein, C-reactive protein
(CRP) not only offers biomarker utility in the clinic but also,
plays a role in host defense by recognition of biologic
substrates, activation of the complement pathway, and
binding to leukocytes.
Cytokines, chemokines, adhesion molecules, and other
products of activated inflammatory cells are secreted during
and play roles in the inflammatory response, but several
problems limit the clinical usefulness of their quantitation for
routine clinical purposes.
CRP and ESR may reflect disease activity and correlate with
disease prognosis in rheumatoid arthritis but generally are
not helpful for differential diagnosis.
Although CRP and ESR correlate with clinical activity in many
inflammatory rheumatic diseases, the absent or modest CRP
response seen in some patients with active systemic lupus
erythematosus remains unexplained.
CRP or ESR is elevated in more than 80% of patients with
polymyalgia rheumatica and in about 95% of patients with
giant cell arteritis; both are useful for disease follow-up, but
their imperfect correlation with disease activity indicates that
these measures cannot supplant sound clinical judgment.
Minor elevations of CRP, within the normal population
reference range, are associated with increased risk of
myocardial infarction but are nonspecific (especially in
patients with rheumatic disease). Minor CRP elevation
is associated with well-recognized risk factors for
cardiovascular disease, which may explain its predictive
value.

The inflammatory response is the bodys natural defense


against unchecked tissue damage from infection or injury.
It occurs during the acute phase of an inciting event and,
if the stimulus is not eliminated, in a chronic, healing stage.
When excessive or uncontrolled, these responses have the
potential to cause significant harm to the host through
818

processes such as autoimmune diseases, allergic reactions,


and septic shock.
The concept of inflammation itself has evolved over
thousands of years; Celsus first described the cardinal signs
of redness, swelling, heat, and pain in the 1st century ad.
The fifth sign, loss of function, is often attributed to Galens
work during the 2nd century.1 Since that time, countless
advances have been made in the understanding of inflammation, from histologic findings of inflammatory cells
within tissues, to the discovery of hematologic and soluble
mediators such as cytokines and complement. Also, the
molecular signaling pathways that drive both its protective
effects and the inappropriate injurious responses have been
recently elucidated.
With increasing insight into mechanisms of the inflammatory response has come an appreciation of its significant
complexity. Molecular and microscopic processes are different during acute and chronic stages, and diverse responses
are induced by various types of exogenous and endogenous
stimuli (e.g., bacteria, viruses, parasites, crystals, allergens,
ischemia). More recently, the role of the milieu of the
inflammatory response, especially at the level of the vascular endothelium, has taken on considerable importance.2
Furthermore, inherent redundancies of functions have been
noted, as have interactions between the mediators of inflammation that allow for a broad, effective response, but these
redundancies make it difficult to understand the pathways
of inflammation in a linear fashion. These intricacies have
resulted in a vague definition and on continued reliance on
the final downstream macroscopic cardinal signs to tie
together all of the ongoing processes. It is these same intricacies that have made evaluation of inflammation through
laboratory tests imprecise.
Basic hematologic abnormalities may give clues to the
presence of inflammation, but different patterns are often
associated with underlying causes and are not universally
found. Leukocytosis can be seen in infections, acute crystal
diseases, and some autoimmune disorders such as adult
Stills disease. Anemia is often associated with certain diseases that cause chronic inflammation, such as rheumatoid
arthritis (RA). Reactive thrombocytosis occurs secondary
to the release of cytokines after an inciting infectious or
inflammatory event, and the role of platelets and plateletderived mediators in stimulating inflammation has been
described at the molecular level.3
Laboratory tests most commonly used by physicians to
objectively obtain information about the extent of inflammation are those that measure the acute phase reaction. In
response to injury, local inflammatory cells secrete cytokines
that influence the liver to increase or decrease production
of various proteins. The erythrocyte sedimentation rate

CHAPTER 57

Acute Phase Reactants and the Concept of Inflammation

(ESR) has been the classic marker of inflammation, with


serum C-reactive protein (CRP) taking on an increasingly
prominent role. Other novel inflammatory markers have
been recognized but have not been found to be more clinically useful.
CRP elevations, especially minor ones, have been noted
in numerous conditions that traditionally have not been
considered inflammatory, most significantly involving the
cardiovascular system. This has shed light on subclinical
inflammation as a possible factor in the pathogenesis of a
great number of diseases.

ACUTE PHASE RESPONSE


Within minutes of tissue injury, activation of the innate
immune system induces cytokine production that results in
a multisystem acute phase response involving the liver, vascular system, bone marrow, and central nervous system.4,5
Many elements of the reaction can be regarded as part of
the innate response and are defensive or adaptive in nature.6
Mouse studies have shown that up to 7% of the regulatable
gene pool undergoes significant changes in expression
during inflammation, and that induction of liver acute
phase genes is mediated by the transcription factor signal
transducer and activator of transcription 3 (STAT3).7-9
Although the acute phase response can trigger numerous
neuroendocrine, hematopoietic, and metabolic effects, it is
the changes in plasma proteins synthesized by hepatocytes
that are monitored as signs of underlying inflammation
(Tables 57-1 and 57-2). An acute phase protein is one
whose plasma concentration changes from baseline by at
least 25% during inflammation; responses vary in terms of
concentration and kinetics (Figure 57-1).10 CRP and serum
amyloid A (SAA) levels increase more than 1000-fold
during acute infection, and peak at 2 to 3 days. Concentrations of other proteins peak at longer periods and can range
from a 50% increase in complement and ceruloplasmin, to
a several-fold amplification in haptoglobin, fibrinogen, 1proteinase inhibitor, and 1-acid glycoprotein. Other proteins are negative acute phase proteins whose concentrations
fall during the inflammatory response. These include antithrombin III, protein S, prealbumin, albumin, transferrin,
and apolipoprotein A-I.4,5
Hepatic stimulation of acute phase proteins is induced
by cytokines released by activated monocytes, macrophages,
neutrophils, natural killer (NK) cells, and endothelial cells
acting at the front lines of the inflammatory response. The
main cytokine influencing the liver is interleukin (IL)-6,
once called the hepatocyte-stimulating factor. It likely
mediates protein expression via the Janus-activated kinase
(JAK) and STAT3 pathways, as well as C/EBP family
members and Rel proteins (nuclear factor B [NFB]).9,11
During initial stages, IL-1 and tumor necrosis factor (TNF)
synergize with IL-6 and trigger further IL-6 production, but
their roles are limited.12 The soluble IL-6 receptor amplifies
IL-6 effects both locally and systemically. IL-6 also performs
a protective role during disease, inducing the expression of
an IL-1 receptor antagonist.13
Acute phase protein levels are not uniform in their
expression; this is likely related to the underlying pathophysiologic state and is regulated by different combinations
and interactions of cytokines.5 The roles of the acute phase

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Table 57-1 Human Acute Phase Proteins


Patients Whose Plasma Concentrations Increase
Complement System
C3
C4
C9
Factor B
C1 inhibitor
C4b-binding protein
Mannose-binding lectin
Coagulation and Fibrinolytic System
Fibrinogen
Plasminogen
Tissue plasminogen activator
Urokinase
Protein S
Vitronectin
Plasminogen-activator inhibitor 1
Antiproteases
-Protease inhibitor
-Antichymotrypsin
Pancreatic secretory trypsin inhibitor
Inter--trypsin inhibitors
Transport Proteins
Ceruloplasmin
Haptoglobin
Hemopexin
Participants in Inflammatory Responses
Secreted phospholipase A2
Lipopolysaccharide-binding protein
Interleukin-1receptor antagonist
Granulocyte colony-stimulating factor
Others
C-reactive protein
Serum amyloid A
-Acid glycoprotein
Fibronectin
Ferritin
Angiotensinogen
Proteins Whose Plasma Concentrations Decrease
Albumin
Transferrin
Transthyretin
-HS glycoprotein
Alpha-fetoprotein
Thyroxine-binding globulin
Insulin-like growth factor I
Factor XII
HS, Heremans-Schmid.
From Gabay C, Kushner I: Acte-phase proteins and other systemic
responses to inflammation, N Engl J Med 340:448454, 1999.

proteins themselves will be discussed throughout the chapter


but have been found to include direct involvement in host
defense by activation of the complement, proteinase inhibition, and antioxidant activity.14 However, some of the
described in vitro effects of proteins may not be relevant in
vivo.
Erythrocyte Sedimentation Rate
Although ESR is an indirect screen for elevated concentrations of acute phase proteins, it has been the most widely
used marker of inflammation for almost a century.

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|DIAGNOSTIC TESTS AND PROCEDURES IN RHEUMATIC DISEASES

Measurement of ESR is performed when blood is placed in


a vertical tube and the rate of fall of erythrocytes is measured. The ancient Greeks recognized increased red blood
cell (RBC) sedimentation as a way to detect bad bodily
humors, but our modern understanding and use of RBC
sedimentation as a test date back to the German scholar
Fahraeus in 1918.15 He determined that certain plasma proteins, especially fibrinogen, are able to lower the electrostatic charge on RBC surfaces so they can aggregate, form
rouleaux, and fall faster.
Several factors are involved in acceleration of ESR.
Asymmetric plasma proteins such as fibrinogen and, to a
lesser extent, alpha2, beta, and gamma globulins decrease
the negative charge of erythrocytes (zeta potential) that
prevents rouleaux formation. Red cell factors also play a role
in that changes in plasma ratios in anemic states also favor
rouleaux. However, microcytosis, polycythemia, and abnormally shaped RBCs (e.g., sickle cells, spherocytes) hinder
aggregation and lower the ESR.16 Conditions that elevate
fibrinogen, even if they are not necessarily considered
inflammatory, can raise ESR. These include pregnancy, diabetes, end-stage renal disease, and heart disease. Major
increases in the concentration of a single molecular species,
such as a monoclonal immunoglobulin in multiple myeloma,
also cause increased sedimentation.17 The ESR is elevated
in obesity, as is CRP, presumably as a result of IL-6 secretion
by adipocytes.18 Factors such as glucocorticoids, cryoglobulins, hypofibrinogenemia, and hyperviscosity have been
shown to lower the value.4 The physiochemical dynamics
that allows for sedimentation has been a continued source
of debate, with disparate models presented to explain
Table 57-2 Other Acute Phase Phenomena
Neuroendocrine Changes
Fever, somnolence, and anorexia
Increased secretion of corticotropin-releasing hormone,
corticotropin, and cortisol
Increased secretion of arginine vasopressin
Decreased production of insulin-like growth factor I
Increased adrenal secretion of catecholamines
Hematopoeitic Changes
Anemia of chronic disease
Leukocytosis
Thrombocytosis
Metabolic Changes
Loss of muscle and negative nitrogen balance
Decreased gluconeogenesis
Osteoporosis
Increased hepatic lipogenesis
Increased lipolysis in adipose tissue
Decreased lipoprotein lipase activity in muscle and adipose tissue
Cachexia
Hepatic Changes
Increased metallothionein, inducible nitric oxide synthase, heme
oxygenase, manganese superoxide dismutase, and tissue
inhibitor of metalloproteinase-1
Decreased phosphoenolpyruvate carboxykinase activity
Changes in Nonprotein Plasma Constituents
Hypozincemia, hypoferremia, and hypercupremia
Increased plasma retinol and glutathione concentrations
From Gabay C, Kushner I: Acte-phase proteins and other systemic responses
to inflammation, N Engl J Med 340:448454, 1999.

30,100
30,000
700
Plasma concentration
(% change)

820

C-reactive protein

600
500

Serum amyloid A

400
300

Haptoglobin

200
100

Fibrinogen

C3

0
Albumin
0
Inflammatory
stimulus

Transferrin
7

14

21

Days

Figure 57-1 Typical plasma acute phase protein changes after a moderate inflammatory stimulus. Several patterns of response are seen:
major acute phase protein, increase 100-fold (e.g., C-reactive protein,
serum amyloid A); moderate acute phase protein, increase twofold to
fourfold (e.g., fibrinogen, haptoglobin); minor acute phase protein,
increase 50% to 100% (e.g., complement C3); and negative acute phase
protein, decrease (e.g., albumin, transferrin). (Adapted from Gitlin JD,
Colten HR: Molecular biology of the acute-phase plasma proteins. In Pick E,
Landy M, editors: Lymphokines, vol 14, San Diego, 1987, Academic Press,
pp 123153.)

how proteins on cell surfaces interact to cause RBC


aggregation.19
Although novel and rapid tests for ESR have proved
promising, the International Committee for Standardization in Hematology continues to recommend the Westergren technique of testing anticoagulated blood.20,21 The
usual accepted upper limits of normal are 15mm/hr for
males and 20mm/hr for females; however, the ESR increases
with age and varies by race, calling the reliability of the test
into question. A simple formula for calculating the upper
limit of normal ESR at any age has been used regularly: In
men, age in years divided by 2; in women, 10 plus age in
years divided by 2. Despite the ability to control for age,
other limitations of the test have been noted and are listed
in Table 57-3. The relative virtues of CRP determination
have diminished some of the importance of ESR, but it
remains an easy, inexpensive test with a wealth of background literature. Therefore the sedimentation rate will
continue to play a prominent role in clinical practice.
C-Reactive Protein
C-reactive protein is an acute phase protein whose serum
concentration reflects ongoing inflammation better than
other tests in most, but not all, diseases.22 CRP was identified in 1930, when sera obtained from patients with Streptococcus pneumonia infection were found to contain a
protein that could bind to the C polysaccharide of the
bacterial cell wall. This protein circulates as a 115-kD pentamer of noncovalently linked 23-kD subunits, which has

CHAPTER 57

Acute Phase Reactants and the Concept of Inflammation

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Table 57-3 Comparison of Erythrocyte Sedimentation Rate and C-Reactive Protein


Erythrocyte Sedimentation Rate

C-Reactive Protein

Advantages

Much clinical information in the literature


May reflect overall health status

Disadvantages

Affected by age and gender


Affected by red blood cell morphology
Affected by anemia and polycythemia
Reflects levels of many plasma proteins, not
all of which are acute phase proteins
Responds slowly to inflammatory stimuli
Requires fresh sample
May be affected by drugs

Rapid response to inflammatory stimuli


Wide range of clinically relevant values are detectable
Unaffected by age and gender
Reflects value of a single acute phase protein
Can be measured on stored sera
Quantitation is precise and reproducible
None

been highly conserved over hundreds of millions of years of


evolution. In contrast to immunoglobulins and complement
components, CRP deficiency in humans has not been
described. Genome-wide associated studies performed
recently have shown that at least seven distinct loci are
involved in the basal expression of CRP,23-25 which is upregulated upon stimulation by the transcription factors C/EBP
and Rel.26 It is present in trace concentrations in the plasma
of all humans (roughly 1mg/L, with higher concentrations
in women and the elderly). Plasma C-reactive protein is
synthesized by hepatocytes, although other sites of local
production and possibly minimal secretion have been
suggested.
The precise function of CRP is unknown and may be
varied, but it exhibits important recognition and activation
capabilities, and it binds to numerous ligands.27 CRP recognizes phosphocholine, phospholipids, fibronectin, chromatin, and histones, all of which are exposed at sites of tissue
damage and by apoptotic cells; CRP may target them for
clearance.28 C-reactive protein bridges the gap between
innate and adaptive immunity by activating the classical
complement pathway and interacting with cells of the
immune system through binding of Fc receptors.29,30 CRP
induces inflammatory cytokines, tissue factors, and shedding
of the IL-6 receptor, all of which result in a complementdependent increase in tissue damage.28 Other CRP functions are anti-inflammatory, including promoting the
noninflammatory clearance of apoptotic cells and preventing neutrophil adhesion to the endothelium.31,32 Thus CRP
may play many pathophysiologic roles during the course of
the inflammatory process.14,33
After an acute inflammatory stimulus, CRP concentration increases rapidly and peaks at 2 to 3 days at levels that

reflect the extent of tissue injury. If the stimulus has been


removed, serum CRP levels drop rapidly, with a half-life of
roughly 19 hours.34 Persistent elevations in CRP are seen in
chronic inflammatory states such as active RA, pulmonary
tuberculosis, or extensive malignant disease.
Immunoassays and laser nephelometry are used at modest
cost to quantify serum CRP levels. Most healthy adults have
levels less than 0.3mg/dL. The significance of minor elevations in CRP is being debated and will be discussed subsequently. However, usual methods of CRP determination are
less precise at concentrations in the range of 0.3 to 1mg/
dL, so high-sensitivity (hs)CRP methods are used to accurately measure these levels. Generally, concentrations
greater than 1mg/dL reflect clinically significant inflammatory disease.35,36 Concentrations of 1 to 10mg/dL can be
considered to represent moderate increases, and concentrations greater than 10mg/dL show marked increases. Most
patients with extremely high levels (e.g., >15mg/dL) have
bacterial infection; one study found that in patients with
CRP concentrations greater than 50mg/dL, infection was
present in 88% of subjects.37 Clinical conditions associated
with varying degrees of elevation of CRP are listed in Table
57-4, and the range of CRP concentrations in many rheumatologic diseases is shown in Figure 57-2.
Several limitations associated with the use of C-reactive
protein measurement must be acknowledged. No uniformity
in reporting concentrations has been noted between laboratories, and values can be conveyed in mg/L, g/mL, or mg/
dL. Similar to ESR, population studies show a skewed,
rather than Gaussian, distribution, leaving parametric statistical tests inappropriate for interpretation of CRP data.
Population differences in CRP levels in the United States
have been reported between sexes and among racial groups.

Table 57-4 Conditions Associated with Elevated C-Reactive Protein Levels


Normal or Minor Elevation (<1mg/dL)

Moderate Elevation (1-10mg/dL)

Marked Elevation (>10mg/dL)

Vigorous exercise
Common cold
Pregnancy
Gingivitis
Seizures
Depression
Insulin resistance and diabetes
Several genetic polymorphisms
Obesity

Myocardial infarction
Malignancies
Pancreatitis
Mucosal infection (bronchitis, cystitis)
Most connective tissue diseases
Rheumatoid arthritis

Acute bacterial infection (80%-85%)


Major trauma
Systemic vasculitis

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Serum CRP Levels (mg/dL)
0.1

0.2

0.5

1.0

2.0

5.0

10

20

50

100

Normal
Osteoarthritis
Rheumatoid
arthritis
Gout
Lupus without
serositis
Lupus with
serositis
Spondylitis
Vasculitis
Adult Stills
Figure 57-2 Range of C-reactive protein (CRP) levels in rheumatic disease. Authors estimates of expected levels of CRP (mg/dL) in certain rheumatic
diseases.

This is presumably also prevalent as an issue in practice in


other populations globally. Elevation of C-reactive protein
in the elderly may represent age-related disorders whose
pathogenesis may involve low-grade inflammation, complicating the issue of what levels are considered normal.38

was higher than 95% after 6 years for individuals whose


median SAA was less than 10mg/L, but 40% if median
SAA remained above 10mg/L.52 However, reliable testing
for acute phase SAA is not yet widely available, and data
about levels expected in disease are limited.

Serum Amyloid A

Other Acute Phase Proteins

Serum amyloid A (SAA) consists of a circulating family of


proteins produced by hepatocytes, adipocytes, macrophages,
and fibroblast-like synoviocytes. Although some types are
expressed constitutively, the hepatic production of SAA is
responsible for an acute phase increase in plasma
concentrationup to 1000-fold within 2 days of the inflammatory stimulus.39 SAA is the fibrillar component of amyloid
deposits in secondary amyloidosis and is tightly associated
with high-density lipoprotein (HDL).40
The function of SAA has not been fully defined, although
it is generally considered proinflammatory; it likely acts in
part through Toll-like receptor (TLR)2 activation of the
NFB pathway and binding to the G proteincoupled
formyl peptide receptor like-1 (FPRL1).39 These actions
induce a variety of cytokines, act as a chemotactic for leukocytes, and stimulate angiogenesis, tissue factor, and matrix
metalloproteinase expression.41-44 SAA may have a direct
role in immunity, acting as an opsonin for gram-negative
bacteria and showing antiviral properties in vitro.45,46 It also
has a well-identified role in cholesterol export from cells
during inflammatory conditions.47,48
Numerous clinical associations with SAA have been
described. Studies have shown correlation with disease
activity in a number of inflammatory disorders, possibly
more so than with ESR and CRP.49 Serum concentrations
of SAA secreted by adipocytes correlate with body mass
index and may provide a link between obesity and its
comorbidities.50 The normal level of SAA in healthy adults
is less than 10mg/L, with a median value of 3mg/L in a
European population.51 The test could be useful in those at
risk for secondary amyloidosis, whose probability of survival

Measurement of other acute phase proteins has been of


limited value clinically, because their responses to tissue
injury are often slower, and the magnitude of concentration
change is smaller than with CRP and SAA. Serum ferritin
is moderately increased, triggered by cytokines such as IL-1,
IL-6, IL-18, and TNF. Levels are frequently high in adultonset Stills disease and systemic lupus erythematosus (SLE),
and they correlate with disease activity.53,54 Hepcidin, a
liver-derived antimicrobial peptide and regulator of iron
homeostasis, is induced by inflammation, and by IL-6 in
particular.55 Its levels rise in parallel with ferritin, and it is
important in the development of anemia of chronic disease,
acting as a negative regulator of iron absorption and macrophage iron release teleologically, to deprive microbes of
iron.56 Transferrin, which binds and transports iron, is a
negative acute phase protein.
The prohormone of calcitonin, procalcitonin, is produced by many cell types during severe infection and has
been used as a marker to distinguish bacterial infection from
other types of inflammatory processes, with some caveats.57
Apolipoprotein a-I, the principal protein constituent of
HDL, is another negative acute phase protein. In chronic
inflammatory diseases such as RA and SLE, decreased levels
may contribute to increased risk of thrombotic events.58,59
Serum albumin and prealbumin (transthyretin) are also
negative acute phase proteins, although their measurement
has not been shown to be more helpful in diagnosis or
prognosis than standard tests.60 Serum complement fractions become depressed when the system is activated in
certain autoimmune disorders but otherwise rise during the
acute phase response.

CHAPTER 57

Acute Phase Reactants and the Concept of Inflammation

Table 57-5 Products of Inflammatory,


Endothelial, and Resident Target Tissue
Cells/Matrix
Cytokines and Related Molecules
Cytokines:
IL-1
IL-6
IL-12
Interferon-
Tumor necrosis factor
Granulocyte-macrophage
colony-stimulating factor
IL-1 receptor antagonist

Products of Inflammatory
and Endothelial Cells
Calprotectin
von Willebrand factor
Soluble adhesion
molecules (e.g., sVCAM
and sE-selectin)
Hyaluronic acid
Collagen and aggrecan
degradation products
Osteocalcin

IL, interleukin.

Cytokines
Although not acute phase proteins in the classic sense,
cytokines display the most striking acute phase behavior of
any circulating proteins. IL-6 responds dramatically to tissue
injury, with concentration changes that are faster and
greater than those of CRP or SAA. Acute inflammation and
chronic inflammation have been associated with increases
in IL-6, and serum levels of this cytokine have been correlated with the severity and course of disease in RA, juvenile arthritis, ankylosing spondylitis, and polymyalgia
rheumatica (PMR).61,62 It is also more sensitive than ESR
for detecting disease activity in giant cell arteritis (GCA).63
IL-6 levels may be useful in monitoring inflammation if
hepatocytes are damaged to the point of not being able to
synthesize acute phase proteins.4 The importance of cytokines such as TNF and IL-1 has been inferred by the successful reduction of inflammation by their therapeutic
inhibitors. Certain diseases, such as the TNF receptor
associated periodic syndrome (TRAPS) and the auto
inflammatory syndromes that involve mutations of the
inflammasome controlling IL-1, point to the importance of
these cytokines.
Increased levels of several other cytokines and circulating cytokine receptors have been associated with inflammation or disease activity as well (Table 57-5).63,64 Different
patterns of cytokine responses have been reported in different diseases, suggesting that cytokine determinations are
potentially useful clinically.65,66 However, their quantitation
presents several problems related to their short plasma halflives, the presence of blocking factors and natural inhibitors, and other technical considerations.67 At present, high
costs, limited availability, and absence of standardization
discourage measurement of plasma cytokines and their
receptors in clinical practice.

ACUTE PHASE REACTANTS IN THE


MANAGEMENT OF RHEUMATIC
DISEASES
Measurement of ESR and CRP has no role in the diagnosis
of any particular disease, including RA, osteoarthritis, SLE,
PMR, GCA, or other inflammatory arthropathies. However,
these measurements can be clinically helpful in three ways:

823

(1) in evaluating the extent or severity of inflammation, (2)


in monitoring changes in disease activity over time, and (3)
in assessing prognosis.
Rheumatoid Arthritis
ESR and CRP cannot be used in the diagnosis of RA because
45% of patients may have normal serum levels at presentation,68 although these values represent part of the diagnostic
syndrome or classification criteria sets. These tests are more
appropriately applied in RA for monitoring disease activity
and response to therapy. Although ESR traditionally has
been more widely used for these purposes, many studies have
suggested that CRP levels correlate better with disease
activity.69 Some recent reports state that CRP levels may
overestimate disease response compared with ESR; others
claim that differences between the two are minimal.69-71 The
existence of patients with depressed CRP concentrations
caused by carrying low-CRPassociated genetic variants
must be taken into account when this test is used universally.72 Matrix metalloproteinase (MMP)-3, pro-MMP-3,
and soluble E-selectin have also been proposed as markers
for RA disease activity; their measurements correlate with
CRP levels but do not provide more information than is
provided by standard tests.73-75
CRP levels average 2 to 3mg/dL in adult RA patients
with moderate disease activity.76 However, variation is considerable: At least 5% to 10% of patients have values in the
normal range, whereas a few patients with severe disease
activity have levels greater than 10mg/dL. ESR values have
been found to remain stable over the years.77 ESR and CRP
have long been used to follow the response to therapy; in
general, effective disease-modifying antirheumatic drug
therapy decreases CRP by about 40%. Inhibition of joint
damage by these agents usually is accompanied by marked
improvement in acute phase reactants. Progression of joint
damage can occur while the patient is on therapy, however,
despite decreases in ESR and CRP.78 Even more striking
improvement has been seen with biologic agents introduced
since the 1990s, providing objective laboratory support for
the encouraging clinical responses observed. In early reports
of anti-TNF therapy, CRP and SAA levels declined by 75%
and 85% in about 1 week.79 Treatment with abatacept, the
T cell CD80/CD86:CD28 co-stimulation modulator,
resulted in significant decreases in CRP at both 90 and 360
days of therapy.80 In one study, failure to suppress CRP levels
2 weeks after initiation of infliximab therapy identified most
patients who would prove to be clinical nonresponders after
12 weeks.81 In contrast to traditional disease-modifying
antirheumatic drugs, TNF inhibitors have been found to
inhibit joint damage even while clinical activity, reflected
by CRP levels, remains high.82 Tocilizumab, a human IL-6
receptor antibody, improves RA by inhibiting effects of the
cytokine. However, owing to its mechanism of action,
inflammatory markers such as ESR and CRP drop to negative values, so that tracking them may not reflect the actual
effect of the drug; care must be taken when monitoring
disease activity during tocilizumab therapy.83,84
ESR and CRP also have value as prognostic indicators
in RA. Elevated acute phase reactant levels are associated
with early synovitis and erosions as detected by magnetic
resonance imaging, with inflammatory cellular infiltrates in

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|DIAGNOSTIC TESTS AND PROCEDURES IN RHEUMATIC DISEASES

synovium, and with osteoclastic activation and reduced


bone mineral density.85-87 CRP predicts radiographic progression, as do ESR and the matrix metalloproteinases
MMP-3 and MMP-1.73,74,88-90 Finally, and perhaps most
important, acute phase reactants correlate with work disability on long-term follow-up and predict progression to
major joint replacement.91,92 As in the normal population,
CRP levels are associated with death from cardiovascular
disease.93 In RA patients who developed heart failure, ESR
was higher during the 6-month period immediately preceding the onset of heart failure than earlier in their course.94
Serum or synovial fluid levels of many other tissue products (see Table 57-5) have been correlated with clinical
measures of disease activity, severity, and radiographic
damage.
Systemic Lupus Erythematosus
Although serum levels of CRP often parallel disease activity
in autoimmune disorders, it has been recognized that SLE
is an exception.95 Although marked CRP responses are seen
in subsets of patients, such as those with serositis or chronic
synovitis, many (such as patients with nephritis) show mild
or no elevation during periods of activity.96-98 Serum levels
of SAA are also relatively low in comparison with those of
RA patients.99 In contrast, ESR correlates with disease
activity and accrued tissue damage in SLE.100 Fibrinogen
levels increased over time in patients, regardless of disease
activity.101 Data are insufficient to evaluate the potential use
of some of the other newer markers described previously, but
many SLE patients with normal CRP levels show elevated
IL-6 concentrations.102 Therefore a deficiency in IL-6 does
not explain the muted CRP response in SLE.
Although the concomitant decrease in SAA may point
against it, several investigations have raised the possibility
that low CRP levels may be related to the pathogenesis of
SLE: (1) An association has been noted between SLE and
a genetic polymorphism associated with low CRP levels, (2)
it has been observed that low CRP levels may contribute to
defective clearance of autoantigens during apoptosis, and
(3) the therapeutic efficacy of CRP has been reported in
mouse models of SLE.96,103-106 Recent studies have also raised
the possibility that type I interferon (IFN), which has been
shown to be expressed significantly in SLE, may inhibit
CRP expression.107,108
Substantial CRP elevation in SLE patients is more likely
to result from superimposed infection than from activation
of lupus. CRP levels greater than 6mg/dL in these patients
should serve as an impetus to exclude the possibility of
infection, just as they should in other diseases.10 Such levels
should not be regarded as proof of infection, however; as
indicated earlier, marked CRP elevation related to active
SLE can be seen in the absence of infection.
Carotid plaque and intima-media wall thickness, correlates of atherosclerotic vascular disease, have been found in
association with minor CRP elevation in women with SLE,
as they have in patients with RA.109,110
Polymyalgia Rheumatica and Giant Cell Arteritis
The diagnosis of PMR or GCA is supported by an elevated
ESR, often greater than 100mm/hr. However, such

elevation is no longer regarded as a sine qua non of these


disorders; continuing reports suggest that 10% to 20% of
patients with PMR can have normal ESRs, depending on
which value is taken as the limit of normal. Such patients
tend to have fewer systemic symptoms and less severe, less
frequent anemia.111 They have the same frequency of positive temporal artery biopsy results, however, as patients with
elevated ESR.112,113
Only about 5% of patients with GCA had ESR values
less than 40mm/hr; these patients had fewer visual and
systemic symptoms than patients with high ESR values.114
In contrast to these findings, ESR and CRP were found to
be significantly lower in patients with ocular involvement,
most commonly in the range of 70mm/hr to 100mm/hr.
Patients with ESR greater than 100mm/hr had decreased
incidence of visual ischemic events.115-117
In PMR and GCA, CRP and ESR have been regarded
in the past as equally valuable in assessing disease activity.
However, recent reports suggest that CRP is more sensitive
for both conditions and should be included routinely in the
diagnostic workup.113,118,119 The report that IL-6 is more
sensitive than ESR for indicating disease activity in GCA
is of particular interest.120 Subsets of patients with PMR who
have been noted to have persistently elevated levels of CRP
and IL-6 despite corticosteroid treatment have been shown
to have a higher risk of relapse.121 A polymorphism at the
IL-6 gene promoter has characterized these PMR patients
with persistently elevated levels of the cytokine.122 Clinical
manifestations of disease, even in the presence of a normal
ESR or CRP level, should not be ignored. Extreme elevation of the ESR in the absence of symptoms of PMR or
GCA should raise suspicion of other disorders, such as infection, malignancy, or renal disease.
Numerous markers of endothelial perturbation, although
not acute phase reactants in the strict sense, are elevated in
plasma in various inflammatory disorders of vessels, particularly PMR, GCA, and other vasculitides.123 These molecules
include von Willebrand factor, thrombomodulin, some
vasoactive prostanoids, and a variety of adhesion molecules,
such as vascular cell adhesion molecule-1.
Adult-Onset Stills Disease
Markedly elevated concentrations of ferritin, disproportionately high compared with those of other acute phase reactants, have long been noted in adult-onset Stills disease but
are not specific.124 Only a low percentagecommonly less
than 20%of ferritin is glycosylated in adult-onset Stills
diseasea criterion included in recently proposed classification criteria for this condition.125,126 Extremely elevated ferritin levels have been found in macrophage activation
syndrome, and 40% of individuals with this condition meet
the criteria for adult-onset Stills disease, suggesting to some
that the two disorders are not distinct entities.127-129 Concentrations of serum IL-18 were extremely elevated in
patients with active adult-onset Stills disease compared
with those of patients with other connective tissue diseases
or of healthy individuals and were correlated with serum
ferritin values and disease severity.130 The cytokine profile
in the sera of patients suggests a type 1 T helper cell (Th1)
response, with significantly higher levels of TNF, IL-6, and
IL-8, in addition to IL-18.131 The role of IL-1 has been

CHAPTER 57

Acute Phase Reactants and the Concept of Inflammation

inferred from significant improvement in disease activity by


the IL-1 receptor antagonist, anakinra.132,133 It has been
suggested that interferon- may be responsible for the
hyperferritinemia of adult-onset Stills disease.124 CRP levels
are usually markedly elevated in this disease.
Ankylosing Spondylitis
Ankylosing spondylitis ordinarily does not lead to a substantial increase in ESR or CRP. Median ESR and CRP levels
are 13mm/hr and 1.6mg/dL, respectively, in patients with
only spinal involvement, and 21mm/hr and 2.5mg/dL in
patients with peripheral involvement or associated inflammatory bowel disease.134 Treatment with infliximab led to
an average decrease of 75% in CRP concentration after 12
weeks. Patients with lower CRP levels showed little
improvement, however, raising the possibility that patients
with higher CRP values show better responses to anti-TNF
treatment than do patients with lower CRP levels.135-137
High-sensitivity CRP may better correlate with clinical
disease activity compared with standard CRP testing.138 It
has been reported that levels of IL-8, IL-17, and IL-23 are
elevated in the serum of patients with active ankylosing
spondylitis, and polymorphisms in the IL-23 receptor gene
are associated with the disease.139-141
Osteoarthritis
Minor CRP elevations of 0.3 to 1.0mg/dL have been
reported in patients with osteoarthritis, particularly those
with progressive joint damage.142 However, no evidence
supports this association independent of body mass index
(BMI), because obesity is a common accompaniment of
osteoarthritis.143 Although local inflammation likely plays a
role in the pathogenesis of osteoarthritis, systemic inflammation likely does not. However, CRP levels are higher in
patients with erosive osteoarthritis of the hand than in
those with nonerosive osteoarthritis.144
Other Rheumatic Diseases
Acute phase markers are elevated in numerous rheumatic
diseases as the inflammatory cascade commences. Elevated
ESR and CRP can be found in systemic vasculitides, crystal
arthropathies, psoriatic and reactive arthritides, and infectious joint diseases.145-148 Monitoring for elevated SAA
levels has been proposed as a tool for diagnosis and medication adjustment in familial Mediterranean fever.149 CRP is
often normal in patients with primary Sjgrens syndrome,
and those with elevated responses do not differ clinically
from patients with normal levels.150 Oligoarticular-onset
juvenile idiopathic arthritis is classically considered as not
associated with elevated inflammatory markers, although
they are present in patients most at risk for developing
systemic disease.151

PRACTICAL USE OF ACUTE


PHASE REACTANTS
When surveyed in the 1990s, rheumatologists were found
to use the ESR more than twice as frequently as they did

825

CRP levels,152 although ESR reflects many complex, poorly


understood changes in the physical and chemical characteristics of blood not associated with inflammation. As indicated earlier, the reference normal values for ESR are
unclear. It is well established that mean ESR values increase
substantially with age and differ between men and women.
Difficulties associated with interpretation of the ESR and
an increasingly positive clinical experience with CRP
suggest that rheumatologists may benefit from relying more
on CRP than ESR testing.153 No single ideal test can be used
to evaluate the acute phase response, however. The relative
virtues of these tests in following patients with RA have
been discussed.70,154
Discrepancies between ESR and CRP may result from
effects of blood constituents that are not related to inflammation, but that can influence the ESR, as was discussed
earlier. In addition, patterns of acute phase protein changes
differ in different conditions.5 ESR may be markedly elevated in many patients with active SLE, whereas CRP is
normal. Undoubtedly, numerous other clinical situations
exist in which similar discrepancies occur. Although falsely
high ESR has many noninflammatory physicochemical
causes (some known, and many unknown), CRP values
greater than 1mg/dL almost invariably reflect a clinically
significant inflammatory process. In light of these considerations, many authors believe that several tests, rather than
a single test, should be performed and interpreted in their
clinical context. It has been suggested that ESR, which is
associated with anemia and immunoglobulin levels, may
reflect general severity in RA, whereas CRP is a better
test of active inflammation per se.155

C-REACTIVE PROTEIN AND HEALTH:


ASSOCIATIONS WITH
NONRHEUMATOLOGIC CONDITIONS
Although most ostensibly healthy individuals have CRP
concentrations of 0.3mg/dL or less, some have concentrations greater than 1mg/dL. Such minor CRP elevation has
long been attributed to trivial tissue injury or to minimal
inflammatory processes, such as gingivitis. However, recent
data indicate that CRP concentrations between 0.3 and
1mg/dL have clinical relevance. This has led to an explosion of published literature measuring CRP levels in cardiac,
neurologic, neoplastic, pulmonary, and even psychiatric
disease.156-160 The foundation of these investigations is the
well-established notion that when a high-sensitivity CRP
assay is used, serum CRP levels greater than 0.3mg/dL
indicate increased relative risk of atherogenesis and future
myocardial infarction.161 The statistical strength of this
association has been shown to be as robust as, but not more
robust than, established risk factors such as hypertension,
diabetes, and hypercholesterolemia.162-164 The primary
unanswered questions remain: Why does CRP predict myocardial infarction? Is it a pathogenic mediator itself?
The observation that CRP is associated with many noninflammatory conditions, such as low levels of physical
activity, low intake of fruits and vegetables, a variety of
other unhealthy diets, smoking, hypertension, obesity,
sleep deprivation, and low alcohol intake, indicates
that classic inflammation does not invariably underlie a

826

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|DIAGNOSTIC TESTS AND PROCEDURES IN RHEUMATIC DISEASES

CRP response.165 Many of these CRP-associated conditions


are known to be risk factors for cardiovascular disease, confounding the situation and suggesting that CRP predicts
myocardial infarction because of its association with these
risk factors. In addition, elevated CRP may not reflect
inflammation, but rather a response to the presence of
distressed, metabolically disturbed cells.165 This reverse
causation offers a potential explanation of the laboratory
result, because atherosclerosis might trigger an elevation
in CRP.
Nevertheless, CRP has been known for many years to
bind to low-density lipoprotein (LDL) and to activate
complementa potentially proinflammatory response; it
has also been detected in atherosclerotic plaques.29,166-168
These observations have raised the possibility that CRP
may play a direct causal role in coronary heart disease.
Proatherogenic effects secondary to CRP injections given
to mice, however, may have been caused by contaminants
in commercial CRP preparations, not by CRP itself.169
Because statin drugs lower CRP and LDL, some consider
their effects to provide indirect evidence of a causal role of
CRP. In the recently published JUPITER trial, patients with
normal LDL and elevated CRP were prescribed rosuvastatin
20mg daily or placebo and were followed prospectively.
Those in the treatment arm had significant reductions in
major cardiovascular events.170 However, whether the
effects of the study can be solely dependent on CRP reduction remains unclear; alternative explanations have been
put forth, including the question of the importance of lowering LDL even among patients with normal levels.171
Whether to target CRP levels in cardiovascular disease is
an ongoing topic of intense debate.
Because no CRP inhibitor drugs are available to
directly measure the effect of lowering the protein, recent
studies have centered on observing patients with genetic
variations that result in different baseline levels of CRP. To
date, results have been conflicting with regard to the role
that genetically determined CRP levels play in coronary
heart disease. However, additional, more robust analyses are
ongoing.172-176
Epidemiologic studies describing an association of CRP
levels with morbidity and mortality in many chronic diseases and even in normal aging have become a cottage
industry. It is important to remember that these are observational population studies. Although such associations
may have broad and intriguing implications, particularly at
a societal level, they reflect probabilities; this limits their
clinical value when they are applied to the individual
patient.
Selected References
2. Biedermann B: Vascular endothelium: checkpoint for inflammation
and immunity, News Physiol Sci 16:8488, 2001.
3. Gawaz M, Langer H, May A: Platelets in inflammation and atherogenesis, J Clin Invest 115:33783384, 2005.
4. Dayer E, Dayer JM, Roux-Lombard P: Primer: the practical use of
biologic markers of rheumatic and systemic inflammatory diseases,
Nat Clin Pract Rheum 3:512520, 2007.
5. Gabay C, Kushner I: Acute-phase proteins and other systemic
responses to inflammation, N Engl J Med 340:448454, 1999.
6. Yoo JY, Desiderio S: Innate and acquired immunity intersect in a
global view of the acute-phase response, Proc Natl Acad Sci U S A
100:11571162, 2003.

8. Alonzi T, Maritano D, Gorgoni B, et al: Essential role of STAT3 in


the control of the acute-phase response as revealed by inducible gene
activation in the liver, Mol Cell Biol 21:16211632, 2001.
10. Morley JJ, Kushner I: Serum C-reactive protein levels in disease, Ann
N Y Acad Sci 389:406418, 1982.
12. Xing Z, Gauldie J, Cox G, et al: IL-6 is an anti-inflammatory cytokine
required for controlling local or systemic acute inflammatory
responses, J Clin Invest 101:311320, 1998.
13. Jones SA, Horiuchi S, Topley N, et al: The soluble interleukin 6
receptor: mechanisms of production and implications in disease,
FASEB J 15:4358, 2001.
14. Volanakis JE: Human C-reactive protein: expression, structure, and
function, Mol Immunol 38:189197, 2001.
17. Sox HC Jr, Liang MH: The erythrocyte sedimentation rate: guidelines for rational use, Ann Intern Med 104:515523, 1986.
18. Bastard JP, Maachi M, Van Nhieu JT, et al: Adipose tissue IL-6
content correlates with resistance to insulin activation of glucose
uptake both in vivo and in vitro, J Clin Endocrinol Metab 87:2084
2089, 2002.
20. Cha CH, Park CJ, Cha YJ, et al: Erythrocyte sedimentation rate
measurements by TEST 1 better reflect inflammation than do those
by the Westergren method in patients with malignancy, autoimmune
disease, or infection, Am J Clin Pathol 131:189194, 2009.
22. Pepys MB, Hirschfield GM: C-reactive protein: a critical update,
J Clin Invest 111:18051812, 2003.
23. Ridker PM, Pare G, Parker A, et al: Loci related to metabolicsyndrome pathways including LEPR, HNF1A, IL6R, and GCKR
associate with plasma C-reactive protein: the Womens Genome
Health Study, Am J Hum Genet 82:11851192, 2008.
26. Cha-Molstad H, Young DP, Kushner I, Samold D: The interaction of
C-rel with C/EBPbeta enhances C/EBPbeta binding to the C-reactive
protein gene promoter, Mol Immunol 44:29332942, 2007.
28. Griselli M, Herbert J, Hutchinson WL, et al: C-reactive protein and
complement are important mediators of tissue damage in acute myocardial infarction, J Exp Med 190:17331740, 1999.
29. Marnell L, Mold C, Du Clos TW: C-reactive protein: an activator of
innate immunity and a modulator of adaptive immunity, Immunol Res
30:261277, 2004.
31. Gershov D: C-reactive protein binds to apoptotic cells, protects the
cells from assembly of the terminal complement components, and
sustains an anti-inflammatory innate immune response: implications
for systemic autoimmunity, J Exp Med 192:13531364, 2000.
32. Zouki C, Beauchamp M, Baron C, Filep JG: Prevention of in vitro
neutrophil adhesion to endothelial cells through shedding of
L-selectin by C-reactive protein and peptides derived from C-reactive
protein, J Clin Invest 100:522529, 1997.
34. Vigushin DM, Pepys MB, Hawkins PN: Metabolic and scintigraphic
studies of radioiodinated human C-reactive protein in health and
disease, J Clin Invest 91:13511357, 1993.
35. Morley JJ, Kushner I: Serum C-reactive protein levels in disease, Ann
N Y Acad Sci 389:406418, 1982.
36. Macy EM, Hayes TE, Tracy RP: Variability in the measurement of
C-reactive protein in healthy subjects: implications for reference
intervals and epidemiological applications, Clin Chem 43:5258,
1997.
37. Vanderschueren S, Deeren D, Knockaert DC, et al: Extremely
elevated C-reactive protein, Eur J Intern Med 17:430433,
2006.
38. Woloshin S, Schwartz LM: Distribution of C-reactive protein
values in the United States, N Engl J Med 352:16111613,
2005.
39. Cheng N, He R, Tian J, et al: Cutting edge: TLR2 is a functional
receptor for acute-phase serum amyloid A, J Immunol 181:2226,
2008.
40. Malle E, De Beer FC: Human serum amyloid A (SAA) protein: a
prominent acute-phase reactant for clinical practice, Eur J Clin Invest
26:427435, 1996.
41. He R, Shepard LW, Chen J, et al: Serum amyloid A is an endogenous
ligand that differentially induces IL-12 and IL-23, J Immunol
177:40724079, 2006.
42. Mullan RH, Bresnihan B, Golden-Mason L, et al: Acute-phase
serum amyloid A stimulation of angiogenesis, leukocyte recruitment,
and matrix degradation in rheumatoid arthritis through an NFkappaB-dependent signal transduction, Arthritis Rheum 54:105114,
2006.

CHAPTER 57

Acute Phase Reactants and the Concept of Inflammation

45. Shah C, Hari-Dass R, Raynes JG: Serum amyloid A is an innate


immune opsonin for gram-negative bacteria, Blood 108:17511757,
2006.
46. Lavie M, Voisset C, Vu-Dac N, et al: Serum amyloid A has antiviral
activity against hepatitis C virus by inhibiting virus entry in a cell
culture system, Hepatology 44:16261634, 2006.
47. Tam SP, Flexman A, Hulme J, et al: Promoting export of macrophage
cholesterol: the physiological role of a major acute-phase protein,
serum amyloid A 2.1, J Lipid Res 43:14101420, 2002.
50. Yang RZ, Lee MJ, Hu H, et al: Acute-phase serum amyloid A: an
inflammatory adipokine and potential link between obesity and its
metabolic complications, PLos Med 3:884894, 2006.
52. Gilmore JD, Lovat LB, Persey MR, et al: Amyloid load and clinical
outcome in AA amyloidosis in relation to circulating concentration
of serum amyloid A protein, Lancet 358:2429, 2001.
53. Efthimiou P, Paik PK, Bielory L: Diagnosis and management of adult
onset Stills disease, Ann Rheum Dis 65:564572, 2006.
54. Nishiya K, Hashimoto K: Elevation of serum ferritin levels as a
marker for active systemic lupus erythematosus, Clin Exp Rheumatol
15:3944, 1997.
55. Nemeth E, Valore EV, Territo M, et al: Hepcidin, a putative mediator
of anemia of inflammation, is a type II acute-phase protein, Blood
101:24612463, 2003.
57. Delvaux I, Andr M, Colombier M, et al: Can procalcitonin measurement help in differentiating between bacterial infection and
other kinds of inflammatory processes? Ann Rheum Dis 62:337340,
2003.
58. Lahita RG, Rivkin E, Cavanagh I, Romano P: Low levels of total
cholesterol, high-density lipoprotein, and apolipoprotein A1 in association with anticardiolipin antibodies in patients with systemic
lupus erythematosus, Arthritis Rheum 36:15661574, 1993.
59. Park YB, Lee SK, Lee WK, et al: Lipid profiles in untreated patients
with rheumatoid arthritis, J Rheumatol 26:17011704, 1999.
60. Johnson AM, Merlini G, Sheldon J, Ichihara K: Clinical indications
for plasma proteins assays: transthyretin (prealbumin) in inflammation and malnutritionInternational Federation of Clinical Chemistry and Laboratory Medicine (IFCC), IFCC Scientific Division
Committee on Plasma Proteins (C-PP), Clin Chem Lab Med 45:419
426, 2007.
61. Tutuncu ZN, Bilgie A, Kennedy LG, et al: Interleukin-6, acute phase
reactants and clinical status in ankylosing spondylitis, Ann Rheum
Dis 53:425426, 1994.
62. Uddhammar A, Sundqvist KG, Ellis B, et al: Cytokines and adhesion
molecules in patients with polymyalgia rheumatica, Br J Rheumatol
37:766769, 1998.
63. Luqmani R, Sheeran T, Robinson M, et al: Systemic cytokine measurements: their role in monitoring the response to therapy in
patients with rheumatoid arthritis, Clin Exp Rheumatol 12:503508,
1994.
64. Pountain G, Hazleman B, Cawston TE: Circulating levels of IL-1beta,
IL-6 and soluble IL-2 receptor in polymyalgia rheumatica and giant
cell arteritis and rheumatoid arthritis, Br J Rheumatol 37:797798,
1998. [Letter].
65. Gabay C, Cakir N, Moral F, et al: Circulating levels of tumor necrosis
factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with
disease activity, J Rheumatol 24:303308, 1997.
66. Gabay C, Gay-Croisier F, Roux-Lombard P, et al: Elevated serum
levels of interleukin-1 receptor antagonist in polymyositis/
dermatomyositis: a biologic marker of disease activity with a possible
role in the lack of acute-phase protein response, Arthritis Rheum
37:17441751, 1994.
68. Sokka T, Pincus T: Erythrocyte sedimentation rate, C-reactive
protein, or rheumatoid factor is normal at presentation in 35-45% of
patients with rheumatoid arthritis seen between 1980 and 2004:
analysis from Finland and the United States, J Rheumatol 36:1387
1390, 2009.
69. Matsui T, Kuga Y, Kaneko A, et al: Disease Activity Score 28
(DAS28) using C-reactive protein underestimates disease activity
and overestimates EULAR response criteria compared with DAS28
using erythrocyte sedimentation rate in a large observational cohort
of rheumatoid arthritis patients in Japan, Ann Rheum Dis 66:1221
1226, 2007.
72. Rhodes B, Merriman ME, Harrison A, et al: A genetic association
study of serum acute-phase C-reactive protein levels in rheumatoid

827

arthritis: implications for clinical interpretation, PLoS Med


7:e1000341, 2010.
74. Posthumus MD, Limburg PC, Westra J, et al: Serum matrix metalloproteinase 3 levels in comparison to C-reactive protein in periods
with and without progression of radiological damage in patients
with early rheumatoid arthritis, Clin Exp Rheumatol 21:465472,
2003.
75. Kuuliala A, Eberhardt K, Takala A, et al: Circulating soluble
E-selectin in early rheumatoid arthritis: a prospective five year study,
Ann Rheum Dis 61:242246, 2002.
76. Aletaha D, Smolen JS: The rheumatoid arthritis patient in the clinic:
comparing more than 1300 consecutive DMARD courses, Rheumatology (Oxford) 41:13671374, 2002.
77. Wolfe F, Pincus T: The level of inflammation in rheumatoid arthritis
is determined early and remains stable over the longterm course of
the illness, J Rheumatol 28:18171824, 2001.
78. Sanmarti R, Gomez A, Ercilla G, et al: Radiological progression
in early rheumatoid arthritis after DMARDS: a one-year follow-up
study in a clinical setting, Rheumatology (Oxford) 42:10441049,
2003.
79. Charles P, Elliott MJ, Davis D, et al: Regulation of cytokines,
cytokine inhibitors, and acute-phase proteins following anti-TNF
alpha therapy in rheumatoid arthritis, J Immunol 163:15211528,
1999.
80. Weisman MH, Durez P, Hallegua D, et al: Reduction of inflammatory
biomarker response by abatacept in treatment of rheumatoid arthritis,
J Rheumatol 33:21622166, 2006.
81. Buch MH, Seto Y, Bingham SJ, et al: C-reactive protein as a predictor
of infliximab treatment outcome in patients with rheumatoid arthritis: defining subtypes of nonresponse and subsequent response to
etanercept, Arthritis Rheum 52:4248, 2005.
82. Smolen JS, Van Der Heijde DM, St Clair EW, et al: Predictors
of joint damage in patients with early rheumatoid arthritis treated
with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial, Arthritis Rheum 54:702710,
2006.
83. Genovese MC, McKay JD, Nasonov EL, et al: Interluekin-6 receptor
inhibition with tocilizumab reduces disease activity in rheumatoid
arthritis with inadequate response to disease-modifying antirheumatic drugs. The Tocilizumab in Combination With Traditional
Disease-Modifying Antirheumatic Drug Therapy Study, Arthritis
Rheum 58:29682980, 2008.
86. Fujinami M, Sato K, Kashiwazaki S, et al: Comparable histological
appearance of synovitis in seropositive and seronegative rheumatoid
arthritis, Clin Exp Rheumatol 15:1117, 1997.
87. Gough A, Sambrook P, Devlin J, et al: Osteoclastic activation is the
principal mechanism leading to secondary osteoporosis in rheumatoid arthritis, J Rheumatol 25:12821289, 1998.
90. Combe B, Dougados M, Goupille P, et al: Prognostic factors for
radiographic damage in early rheumatoid arthritis: a multiparameter
prospective study, Arthritis Rheum 44:17361743, 2001.
92. Poole CD, Conway P, Reynolds A, Currie CJ: The association
between C-reactive protein and the likelihood of progression to joint
replacement in people with rheumatoid arthritis: a retrospective
observational study, BMC Musculoskelet Disord 9:146, 2008.
93. Goodson NJ, Symmons DP, Scott DG, et al: Baseline levels of
C-reactive protein and prediction of death from cardiovascular
disease in patients with inflammatory polyarthritis: a ten-year followup study of a primary care-based inception cohort, Arthritis Rheum
52:22932299, 2005.
94. Maradit-Kremers H, Nicola PJ, Crowson CS, et al: Raised erythrocyte
sedimentation rate signals heart failure in patients with rheumatoid
arthritis, Ann Rheum Dis 66:7680, 2007.
96. Gaitonde S, Samols D, Kushner I: C-reactive protein and
systemic lupus erythematosus, Arthritis Care Res 59:18141820,
2008.
98. Moutsopoulos HM, Mavridis AK, Acritidis NC, et al: High C-reactive
protein response in lupus polyarthritis, Clin Exp Rheumatol 1:5355,
1983.
99. Maury CP, Teppo AM, Wegelius O: Relationship between urinary
sialylated saccharides, serum amyloid A protein and C-reactive
protein in rheumatoid arthritis and systemic lupus erythematosus,
Ann Rheum Dis 41:268271, 1982.
100. Vila LM, Alarcon GS, McGwin G Jr, et al: Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXIX. Elevation of

828

PART 7

|DIAGNOSTIC TESTS AND PROCEDURES IN RHEUMATIC DISEASES

erythrocyte sedimentation rate is associated with disease activity and


damage accrual, J Rheumatol 32:21502155, 2005.
101. Ames PR, Alves J, Pap AF, et al: Fibrinogen in systemic lupus erythematosus: more than an acute phase reactant? J Rheumatol
27:11901195, 2000.
102. Gabay C, Roux-Lombard P, de Moerloose P, et al: Absence of correlation between interleukin 6 and C-reactive protein blood levels in
systemic lupus erythematosus compared with rheumatoid arthritis, J
Rheumatol 20:815821, 1993.
103. Russell AI, Cunninghame Graham DS, Shepherd C, et al: Polymorphism at the C-reactive protein locus influences gene expression and
predisposes to systemic lupus erythematosus, Hum Mol Genet 13:137
147, 2004.
106. Marnell L, Mold C, Du Clos TW: C-reactive protein: ligands,
receptors and role in inflammation, Clin Immunol 117:104111,
2005.
108. Kalabay L, Nemesanszky E, Csepregi A, et al: Paradoxical alteration
of acute phase protein levels in patients with chronic hepatitis C
treated with IFN-alpha 2b, Int Immunol 16:5154, 2004.
109. Selzer F, Sutton-Tyrrell K, Fitzgerald SG, et al: Comparison of risk
factors for vascular disease in the carotid artery and aorta in women
with systemic lupus erythematosus, Arthritis Rheum 50:151159,
2004.
111. Gonzalez-Gay MA, Rodriguez-Valverde V, Blanco R, et al: Polymyalgia rheumatica without significantly increased erythrocyte sedimentation rate: a more benign syndrome, Arch Intern Med 157:317320,
1997.
113. Cantini F, Salvarani C, Olivieri I, et al: Erythrocyte sedimentation
rate and C-reactive protein in the evaluation of disease activity and
severity in polymyalgia rheumatica: a prospective follow-up study,
Semin Arthritis Rheum 30:1724, 2000.
114. Salvarani C, Hunder GG: Giant cell arteritis with low erythrocyte
sedimentation rate: frequency of occurrence in a population-based
study, Arthritis Rheum 45:140145, 2001.
115. Salvarani C, Cimino L, Macchioni P, et al: Risk factors for visual loss
in an Italian population-based cohort of patients with giant cell
arteritis, Arthritis Rheum 53:293299, 2005.
120. Weyand CM, Fulbright JW, Hunder GG, et al: Treatment of giant
cell arteritis: interleukin-6 as a biologic marker of disease activity,
Arthritis Rheum 43:10411048, 2000.
121. Salvarani C, Cantini F, Niccoli L, et al: Acute-phase reactants and
the risk of relapse/recurrence in polymyalgia rheumatica: a prospective followup study, Arthritis Rheum Arthritis Care Res 53:3338, 2005.
122. Boiardi L, Casali B, Farnetti E, et al: Relationship between interleukin 6 promotor polymorphism at position-174, IL-6 serum levels, and
the risk of relapse/recurrence in polymyalgia rheumatica, J Rheumatol
33:703708, 2006.
123. Pearson JD: Markers of endothelial perturbation and damage, Br J
Rheumatol 32:651652, 1993.
125. Fautrel B, Le Moel G, Saint-Marcoux B, et al: Diagnostic value of
ferritin and glycosylated ferritin in adult onset Stills disease, J Rheumatol 28:322329, 2001.
126. Fautrel B, Zing E, Golmard JL, et al: Proposal for a new set of classification criteria for adult-onset Still disease, Medicine (Baltimore)
81:194200, 2002.
129. Grom AA: Natural killer cell dysfunction: a common pathway in
systemic-onset juvenile rheumatoid arthritis, macrophage activation
syndrome, and hemophagocytic lymphohistiocytosis? Arthritis Rheum
50:689698, 2004.
130. Kawashima M, Yamamura M, Taniai M, et al: Levels of interleukin-18
and its binding inhibitors in the blood circulation of patients with
adult-onset Stills disease, Arthritis Rheum 44:550560, 2001.
131. Chen DY, Lan JL, Fin FJ, Tsieh TY: Proinflammatory cytokine profiles
in sera and pathological tissues of patients with active untreated adult
onset Stills disease, J Rheumatol 31:21892198, 2004.
132. Fitzgerald AA, LeClercq SA, Yan A, et al: Rapid responses to
anakinra in patients with refractory adult-onset Stills disease, Arthritis Rheum 52:17941803, 2005.
134. Spoorenberg A, van der Heijde D, de Klerk E, et al: Relative value
of erythrocyte sedimentation rate and C-reactive protein in assessment of disease activity in ankylosing spondylitis, J Rheumatol
26:980984, 1999.
135. Braun J, Brandt J, Listing J, et al: Treatment of active ankylosing
spondylitis with infliximab: a randomized controlled multicentre
trial, Lancet 359:11871193, 2002.

136. Stone MA, Payne U, Pacheco-Tena C, et al: Cytokine correlates of


clinical response patterns to infliximab treatment of ankylosing spondylitis, Ann Rheum Dis 63:8487, 2004.
138. Poddubnyy DA, Rudwaleit M, Listing J, et al: Comparison of a high
sensitivity and standard C reactive protein measurement in patients
with ankylosing spondylitis and non-radiographic axial spondyloarthropathies, Ann Rheum Dis 69:13381341, 2010.
139. Sonel B, Tutkak H, Duzgun N: Serum levels of IL-1 beta, TNF-alpha,
IL-8, and acute phase proteins in seronegative spondyloarthropathies,
Joint Bone Spine 69:463467, 2002.
140. Wang X, Lin Z, Wei Q, et al: Expression of IL-23 and IL-17 and effect
of IL-23 on IL-17 production in ankylosing spondylitis, Rheumatol Int
29:13431347, 2009.
142. Spector TD, Hart DJ, Nandra D, et al: Low-level increases in serum
C-reactive protein are present in early osteoarthritis of the knee and
predict progressive disease, Arthritis Rheum 40:723727, 1997.
143. Kerkhof HJM, Bierma-Zeinstra SMA, Castano-Betancourt MC, et al:
Serum C reactive protein levels and genetic variation in the CRP
gene are not associated with the prevalence, incidence or progression
of osteoarthritis independent of body mass index, Ann Rheum Dis
69:19761982, 2010.
144. Punzi L, Ramonda R, Oliviero F, et al: Value of C reactive protein in
the assessment of erosive osteoarthritis, Osteoarthritis Cartilage
10:595601, 2002.
145. Hind CRK, Winearls CG, Pepys MB: Correlation of disease-activity
in systemic vasculitis with serum C-reactive protein measurementa
prospective study of 38 patients, Eur J Clin Invest 15:8994, 1985.
147. Laurent MR, Panayi GS, Shepherd P: Circulating immunecomplexes, serum immunoglobulins, and acute phase proteins in
psoriasis and psoriatic-arthritis, Ann Rheum Dis 40:6669, 1981.
149. Berkun Y, Padeh S, Reichman B, et al: A single testing of serum
amyloid A levels as a tool for diagnosis and treatment dilemmas in
familial Mediterranean fever, Semin Arthritis Rheum 37:182188,
2007.
150. Moutsopoulos HM, Elkon KB, Mavridis AK, et al: Serum C-reactive
protein in primary Sjgrens syndrome, Clin Exp Rheumatol 1:5758,
1983.
151. Guillaume S, Prieur AM, Coste J, Job-Deslandre C: Long term
outcome and prognosis in oligoarticular-onset juvenile idiopathic
arthritis, Arthritis Rheum 43:18581865, 2000.
152. Donald F, Ward MM: Evaluative laboratory testing practices of
United States rheumatologists, Arthritis Rheum 41:P725P729,
1998.
154. Paulus HE, Brahn E: Is erythrocyte sedimentation rate the preferable
measure of the acute phase response in rheumatoid arthritis? J Rheumatol 31:838840, 2004.
156. Pepys MB, Hirschfield GM, Tennent GA, et al: Targeting C-reactive
protein for the treatment of cardiovascular disease, Nature 440:1217
1221, 2006.
158. Heikkila K, Ebrahim S, Lawlor DA: A systematic review of the
association between circulating concentrations of C reactive protein
and cancer, J Epidemiol Commun Health 61:824832, 2007.
159. De Torres JP, Pinto-Pata V, Casanova C: C-reactive protein levels
and survival in patients with moderate to very severe COPD, Chest
133:13361343, 2008.
161. Danesh J, Wheeler JG, Hirschfield GM, et al: C-reactive protein and
other circulating markers of inflammation in the prediction of coronary heart disease, N Engl J Med 350:13871397, 2004.
162. Ridker PM: C-reactive protein and the prediction of cardiovascular
events among those at intermediate risk: moving an inflammatory
hypothesis toward consensus, J Am Coll Cardiol 49:21292138, 2007.
165. Kushner I, Rzewnicki D, Samols D: What does minor elevation of
C-reactive protein signify? Am J Med 119:e117e128, 2006.
166. De Beer FC, Soutar AK, Baltz ML, et al: Low density and very low
density lipoproteins are selectively bound by aggregated C-reactive
protein, J Exp Med 156:230242, 1982.
167. Pepys MD, Rowe IF, Baltz ML: C-reactive protein: binding to lipids
and lipoproteins, Int Rev Exp Pathol 27:83111, 1985.
169. Lowe GD, Pepys MB: C-reactive protein and cardiovascular disease:
weighing the evidence, Curr Atheroscler Rep 8:421428, 2006.
170. Ridker PM, Danielson E, Francisco AH, et al: Rosuvastatin to
prevent vascular events in men and women with elevated C-reactive
protein, N Engl J Med 359:21952207, 2008.
171. Genser B, Grammer TB, Stojakovic T, et al: Effect of HMG CoA
reductase inhibitors on low density lipoprotein cholesterol and

CHAPTER 57

Acute Phase Reactants and the Concept of Inflammation

C-reactive protein: systemic review and meta-analysis, Int J Clin


Pharmacol Ther 46:497510, 2008.
172. Lawlor DA, Harbord RM, Timpson NJ, et al: The association of
C-reactive protein and CRP genotype with coronary heart disease:
findings from five studies with 4,610 cases amongst 18,637 participants, PLoS One 3:e3011, 2008.
173. Zacho J, Tybjaerg-Hansen A, Jensen JS, et al: Genetically elevated
C-reactive protein and ischemic vascular disease, N Engl J Med
359:18971908, 2008.

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174. Lange LA, Carlson CS, Hindorff LA, et al: Association of polymorphisms in the CRP gene with circulating C-reactive protein levels
and cardiovascular events, JAMA 296:27032711, 2006.
Full references for this chapter can be found on www.expertconsult.com.

CHAPTER 57

Acute Phase Reactants and the Concept of Inflammation

References
1. Van den Tweel J, Taylor C: A brief history of pathology, Virchows
Archiv 457:310, 2010.
2. Biedermann B: Vascular endothelium: checkpoint for inflammation
and immunity, News Physiol Sci 16:8488, 2001.
3. Gawaz M, Langer H, May A: Platelets in inflammation and atherogenesis, J Clin Invest 115:33783384, 2005.
4. Dayer E, Dayer JM, Roux-Lombard P: Primer: the practical use of
biologic markers of rheumatic and systemic inflammatory diseases,
Nat Clin Pract Rheum 3:512520, 2007.
5. Gabay C, Kushner I: Acute-phase proteins and other systemic
responses to inflammation, N Engl J Med 340:448454, 1999.
6. Yoo JY, Desiderio S: Innate and acquired immunity intersect in a
global view of the acute-phase response, Proc Natl Acad Sci U S A
100:11571162, 2003.
7. Desiderio S, Yoo JY: A genome-wide analysis of the acute-phase
response and its regulation by Stat3beta, Ann N Y Acad Sci 987:280
284, 2003.
8. Alonzi T, Maritano D, Gorgoni B, et al: Essential role of STAT3 in
the control of the acute-phase response as revealed by inducible gene
activation in the liver, Mol Cell Biol 21:16211632, 2001.
9. Quinton LJ, Jones MR, Robson BE, Mizgerd JP: Mechanisms of the
hepatic acute-phase response during bacterial pneumonia, Infect
Immun 77:24172426, 2009.
10. Morley JJ, Kushner I: Serum C-reactive protein levels in disease, Ann
N Y Acad Sci 389:406418, 1982.
11. Heinrich PC, Castell JV, Andus T: Interleukin-6 and the acute phase
response, Biochem J 265:621636, 1990.
12. Xing Z, Gauldie J, Cox G, et al: IL-6 is an anti-inflammatory cytokine
required for controlling local or systemic acute inflammatory
responses, J Clin Invest 101:311320, 1998.
13. Jones SA, Horiuchi S, Topley N, et al: The soluble interleukin 6
receptor: mechanisms of production and implications in disease,
FASEB J 15:4358, 2001.
14. Volanakis JE: Human C-reactive protein: expression, structure, and
function, Mol Immunol 38:189197, 2001.
15. Bedell SE, Bush BT: Erythrocyte sedimentation rate: from folklore to
facts, Am J Med 78(6 Pt 1):10011009, 1985.
16. Vajpayee N, Graham SS, Bem S: Basic examination of blood and
bone marrow. In McPherson RA, Pincus MR, editors: Henrys clinical
diagnosis and management by laboratory methods, ed 21, Philadelphia,
2007, Saunders Elsevier, pp 465466.
17. Sox HC Jr, Liang MH: The erythrocyte sedimentation rate: guidelines for rational use, Ann Intern Med 104:515523, 1986.
18. Bastard JP, Maachi M, Van Nhieu JT, et al: Adipose tissue IL-6
content correlates with resistance to insulin activation of glucose
uptake both in vivo and in vitro, J Clin Endocrinol Metab 87:2084
2089, 2002.
19. Neu B, Meiselman HJ: Red blood cell aggregation. In Baskurt OK,
Meiselman HJ, editors: Handbook of hemorheology and hemodynamics,
ed 1, Amsterdam, 2007, IOS Press, pp 114115.
20. Cha CH, Park CJ, Cha YJ, et al: Erythrocyte sedimentation rate
measurements by TEST 1 better reflect inflammation than do those
by the Westergren method in patients with malignancy, autoimmune
disease, or infection, Am J Clin Pathol 131:189194, 2009.
21. International Council for Standardization in Haematology (Expert
Panel on Blood Rheology): ICSH recommendations for measurement
of erythrocyte sedimentation rate [published erratum appears in J Clin
Pathol 46:488, 1993], J Clin Pathol 46:198203, 1993.
22. Pepys MB, Hirschfield GM: C-reactive protein: a critical update,
J Clin Invest 111:18051812, 2003.
23. Ridker PM, Pare G, Parker A, et al: Loci related to metabolicsyndrome pathways including LEPR, HNF1A, IL6R, and GCKR
associated with plasma C-reactive protein: the Womens Genome
Health Study, Am J Hum Genet 82:11851192, 2008.
24. Reiner AP, Barber MJ, Guan Y, et al: Polymorphisms of the
HNF1a gene encoding hepatocyte nuclear factor-1 alpha are
associated with C-reactive protein, Am J Hum Genet 82:11931201,
2008.
25. Kathiresan S, Larson MG, Vasan RS, et al: Contribution of clinical
correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level, Circulation
113:14151423, 2006.
26. Cha-Molstad H, Young DP, Kushner I, Samold D: The interaction of
C-rel with C/EBPbeta enhances C/EBPbeta binding to the C-reactive
protein gene promoter, Mol Immunol 44:29332942, 2007.

829.e1

27. Black S, Kushner I, Samols D: C-reactive protein, J Biol Chem


279:48487484900, 2004.
28. Griselli M, Herbert J, Hutchinson WL, et al: C-reactive protein and
complement are important mediators of tissue damage in acute myocardial infarction, J Exp Med 190:17331740, 1999.
29. Marnell L, Mold C, Du Clos TW: C-reactive protein: an activator of
innate immunity and a modulator of adaptive immunity, Immunol Res
30:261277, 2004.
30. Du Clos TW, Mold C: C-reactive protein: an activator of innate
immunity and a modulator of adaptive immunity, Immunol Res
30:261277, 2004.
31. Gershov D: C-reactive protein binds to apoptotic cells, protects the
cells from assembly of the terminal complement components, and
sustains an anti-inflammatory innate immune response: implications
for systemic autoimmunity, J Exp Med 192:13531364, 2000.
32. Zouki C, Beauchamp M, Baron C, Filep JG: Prevention of in vitro
neutrophil adhesion to endothelial cells through shedding of
L-selectin by C-reactive protein and peptides derived from C-reactive
protein, J Clin Invest 100:522529, 1997.
33. Mortensen RF: C-reactive protein, inflammation, and innate immunity, Immunol Res 24:163176, 2001.
34. Vigushin DM, Pepys MB, Hawkins PN: Metabolic and scintigraphic
studies of radioiodinated human C-reactive protein in health and
disease, J Clin Invest 91:13511357, 1993.
35. Morley JJ, Kushner I: Serum C-reactive protein levels in disease, Ann
N Y Acad Sci 389:406418, 1982.
36. Macy EM, Hayes TE, Tracy RP: Variability in the measurement of
C-reactive protein in healthy subjects: implications for reference
intervals and epidemiological applications, Clin Chem 43:5258,
1997.
37. Vanderschueren S, Deeren D, Knockaert DC, et al: Extremely elevated C-reactive protein, Eur J Intern Med 17:430433, 2006.
38. Woloshin S, Schwartz LM: Distribution of C-reactive protein values
in the United States, N Engl J Med 352:16111613, 2005.
39. Cheng N, He R, Tian J, et al: Cutting edge: TLR2 is a functional
receptor for acute-phase serum amyloid A, J Immunol 181:2226,
2008.
40. Malle E, De Beer FC: Human serum amyloid A (SAA) protein: a
prominent acute-phase reactant for clinical practice, Eur J Clin Invest
26:427435, 1996.
41. He R, Shepard LW, Chen J, et al: Serum amyloid A is an endogenous
ligand that differentially induces IL-12 and IL-23, J Immunol
177:40724079, 2006.
42. Mullan RH, Bresnihan B, Golden-Mason L, et al: Acute-phase serum
amyloid A stimulation of angiogenesis, leukocyte recruitment, and
matrix degradation in rheumatoid arthritis through an NF-kappaBdependent signal transduction, Arthritis Rheum 54:105114, 2006.
43. Lee MS, Yoo SA, Cho CS, et al: Serum amyloid A binding to formyl
peptide receptor-like 1 induces synovial hyperplasia and angiogenesis, J Immunol 177:55855594, 2006.
44. Cai H, Song CJ, Endoh I, et al: Serum amyloid A induces monocyte
tissue factor, J Immunol 178:18521860, 2007.
45. Shah C, Hari-Dass R, Raynes JG: Serum amyloid A is an innate
immune opsonin for gram-negative bacteria, Blood 108:17511757,
2006.
46. Lavie M, Voisset C, Vu-Dac N, et al: Serum amyloid A has antiviral
activity against hepatitis C virus by inhibiting virus entry in a cell
culture system, Hepatology 44:16261634, 2006.
47. Tam SP, Flexman A, Hulme J, et al: Promoting export of macrophage
cholesterol: the physiological role of a major acute-phase protein,
serum amyloid A 2.1, J Lipid Res 43:14101420, 2002.
48. Manley PN, Ancsin JB, Kisilevsky R: Rapid recycling of cholesterol:
the joint biologic role of C-reactive protein and serum amyloid A,
Med Hypotheses 66:784792, 2006.
49. Cunnane G, Grehan S, Geoghegan S, et al: Serum amyloid A in the
assessment of early inflammatory arthritis, J Rheumatol 27:5863,
2000.
50. Yang RZ, Lee MJ, Hu H, et al: Acute-phase serum amyloid A: an
inflammatory adipokine and potential link between obesity and its
metabolic complications, PLos Med 3:884894, 2006.
51. Wilkins J, Gallimore JR, Tennent GA, et al: Rapid automated
enzyme immunoassay of serum amyloid A, Clin Chem 40(7 Pt
1):12841290, 1994.
52. Gilmore JD, Lovat LB, Persey MR, et al: Amyloid load and clinical
outcome in AA amyloidosis in relation to circulating concentration
of serum amyloid A protein, Lancet 358:2429, 2001.

829.e2

PART 7

|DIAGNOSTIC TESTS AND PROCEDURES IN RHEUMATIC DISEASES

53. Efthimiou P, Paik PK, Bielory L: Diagnosis and management of adult


onset Stills disease, Ann Rheum Dis 65:564572, 2006.
54. Nishiya K, Hashimoto K: Elevation of serum ferritin levels as a
marker for active systemic lupus erythematosus, Clin Exp Rheumatol
15:3944, 1997.
55. Nemeth E, Valore EV, Territo M, et al: Hepcidin, a putative mediator
of anemia of inflammation, is a type II acute-phase protein, Blood
101:24612463, 2003.
56. Andrews NC: Anemia of inflammation: the cytokine-hepcidin link,
J Clin Invest 113:12511253, 2004.
57. Delvaux I, Andr M, Colombier M, et al: Can procalcitonin measurement help in differentiating between bacterial infection and
other kinds of inflammatory processes? Ann Rheum Dis 62:337340,
2003.
58. Lahita RG, Rivkin E, Cavanagh I, Romano P: Low levels of total
cholesterol, high-density lipoprotein, and apolipoprotein A1 in association with anticardiolipin antibodies in patients with systemic
lupus erythematosus, Arthritis Rheum 36:15661574, 1993.
59. Park YB, Lee SK, Lee WK, et al: Lipid profiles in untreated patients
with rheumatoid arthritis, J Rheumatol 26:17011704, 1999.
60. Johnson AM, Merlini G, Sheldon J, Ichihara K: Clinical indications
for plasma proteins assays: transthyretin (prealbumin) in inflammation and malnutritionInternational Federation of Clinical Chemistry and Laboratory Medicine (IFCC), IFCC Scientific Division
Committee on Plasma Proteins (C-PP), Clin Chem Lab Med 45:419
426, 2007.
61. Tutuncu ZN, Bilgie A, Kennedy LG, et al: Interleukin-6, acute phase
reactants and clinical status in anklyosing spondylitis, Ann Rheum
Dis 53:425426, 1994.
62. Uddhammar A, Sundqvist KG, Ellis B, et al: Cytokines and adhesion
molecules in patients with polymyalgia rheumatica, Br J Rheumatol
37:766769, 1998.
63. Luqmani R, Sheeran T, Robinson M, et al: Systemic cytokine measurements: their role in monitoring the response to therapy in
patients with rheumatoid arthritis, Clin Exp Rheumatol 12:503508,
1994.
64. Pountain G, Hazleman B, Cawston TE: Circulating levels of IL-1beta,
IL-6 and soluble IL-2 receptor in polymyalgia rheumatica and giant
cell arteritis and rheumatoid arthritis, Br J Rheumatol 37:797798,
1998. [Letter].
65. Gabay C, Cakir N, Moral F, et al: Circulating levels of tumor necrosis
factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with
disease activity, J Rheumatol 24:303308, 1997.
66. Gabay C, Gay-Croisier F, Roux-Lombard P, et al: Elevated serum
levels of interleukin-1 receptor antagonist in polymyositis/
dermatomyositis: a biologic marker of disease activity with a possible
role in the lack of acute-phase protein response, Arthritis Rheum
37:17441751, 1994.
67. Barnes A: Measurement of serum cytokines, Lancet 352:324325,
1998. [Letter].
68. Sokka T, Pincus T: Erythrocyte sedimentation rate, C-reactive
protein, or rheumatoid factor is normal at presentation in 35-45% of
patients with rheumatoid arthritis seen between 1980 and 2004:
analysis from Finland and the United States, J Rheumatol 36:1387
1390, 2009.
69. Matsui T, Kuga Y, Kaneko A, et al: Disease Activity Score 28
(DAS28) using C-reactive protein underestimates disease activity
and overestimates EULAR response criteria compared with DAS28
using erythrocyte sedimentation rate in a large observational cohort
of rheumatoid arthritis patients in Japan, Ann Rheum Dis 66:1221
1226, 2007.
70. Crowson CS, Rahman MU, Metteson EL: Which measure of inflammation to use? A comparison of erythrocyte sedimentation rate and
C-reactive protein measurements from randomized clinical trials of
Golimumab in rheumatoid arthritis, J Rheumatol 36:16061610,
2009.
71. Wells G, Becker JC, Teng J, et al: Validation of the 28-joint Disease
Activity Score (DAS28) and European League Against Rheumatism
response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the
DAS28 based on erythrocyte sedimentation rate, Ann Rheum Dis
68:954960, 2009.
72. Rhodes B, Merriman ME, Harrison A, et al: A genetic association
study of serum acute-phase C-reactive protein levels in rheumatoid

arthritis: implications for clinical interpretation, PLoS Med


7:e1000341, 2010.
73. Green MJ, Gough AK, Devlin J, et al: Serum MMP-3 and MMP-1
and progression of joint damage in early rheumatoid arthritis, Rheumatology (Oxf) 42:8388, 2003.
74. Posthumus MD, Limburg PC, Westra J, et al: Serum matrix metalloproteinase 3 levels in comparison to C-reactive protein in periods
with and without progression of radiological damage in patients with
early rheumatoid arthritis, Clin Exp Rheumatol 21:465472, 2003.
75. Kuuliala A, Eberhardt K, Takala A, et al: Circulating soluble
E-selectin in early rheumatoid arthritis: a prospective five year study,
Ann Rheum Dis 61:242246, 2002.
76. Aletaha D, Smolen JS: The rheumatoid arthritis patient in the clinic:
comparing more than 1300 consecutive DMARD courses, Rheumatology (Oxf) 41:13671374, 2002.
77. Wolfe F, Pincus T: The level of inflammation in rheumatoid arthritis
is determined early and remains stable over the longterm course of
the illness, J Rheumatol 28:18171824, 2001.
78. Sanmarti R, Gomez A, Ercilla G, et al: Radiological progression in
early rheumatoid arthritis after DMARDS: a one-year follow-up study
in a clinical setting, Rheumatology (Oxf) 42:10441049, 2003.
79. Charles P, Elliott MJ, Davis D, et al: Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF alpha
therapy in rheumatoid arthritis, J Immunol 163:15211528, 1999.
80. Weisman MH, Durez P, Hallegua D, et al: Reduction of inflammatory
biomarker response by abatacept in treatment of rheumatoid arthritis,
J Rheumatol 33:21622166, 2006.
81. Buch MH, Seto Y, Bingham SJ, et al: C-reactive protein as a predictor
of infliximab treatment outcome in patients with rheumatoid arthritis: defining subtypes of nonresponse and subsequent response to
etanercept, Arthritis Rheum 52:4248, 2005.
82. Smolen JS, Van Der Heijde DM, St Clair EW, et al: Predictors of
joint damage in patients with early rheumatoid arthritis treated with
high-dose methotrexate with or without concomitant infliximab:
results from the ASPIRE trial, Arthritis Rheum 54:702710, 2006.
83. Genovese MC, McKay JD, Nasonov EL, et al: Interluekin-6 receptor
inhibition with tocilizumab reduces disease activity in rheumatoid
arthritis with inadequate response to disease-modifying antirheumatic drugs. The Tocilizumab in Combination With Traditional
Disease-Modifying Antirheumatic Drug Therapy Study, Arthritis
Rheum 58:29682980, 2008.
84. Funahashi K, Koyano S, Miura T, et al: Efficacy of tocilizumab and
evaluation of clinical remission as determined by CDAI and MMP-3
level, Mod Rheumatol 19:507512, 2009.
85. Graudal N, Tarp U, Jurik AG, et al: Inflammatory patterns in rheumatoid arthritis estimated by the number of swollen and tender
joints, the erythrocyte sedimentation rate, and hemoglobin: longterm
course and association to radiographic progression, J Rheumatol
27:4757, 2000.
86. Fujinami M, Sato K, Kashiwazaki S, et al: Comparable histological
appearance of synovitis in seropositive and seronegative rheumatoid
arthritis, Clin Exp Rheumatol 15:1117, 1997.
87. Gough A, Sambrook P, Devlin J, et al: Osteoclastic activation is the
principal mechanism leading to secondary osteoporosis in rheumatoid arthritis, J Rheumatol 25:12821289, 1998.
88. Machold KP, Stamm TA, Nell VP, et al: Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiological progression over the first years of disease,
Rheumatology (Oxf) 46:342349, 2007.
89. Symmons DP, Silman AJ: Aspects of early arthritis: what determines
the evolution of early undifferentiated arthritis and rheumatoid
arthritis? An update from the Norfolk Arthritis Register, Arthritis Res
Ther 8:214, 2006.
90. Combe B, Dougados M, Goupille P, et al: Prognostic factors for
radiographic damage in early rheumatoid arthritis: a multiparameter
prospective study, Arthritis Rheum 44:17361743, 2001.
91. Wolfe F, Sharp JT: Radiographic outcome of recent-onset rheumatoid
arthritis: a 19 year study of radiographic progression, Arthritis Rheum
41:15711582, 1998.
92. Poole CD, Conway P, Reynolds A, Currie CJ: The association
between C-reactive protein and the likelihood of progression to joint
replacement in people with rheumatoid arthritis: a retrospective
observational study, BMC Musculoskelet Disord 9:146, 2008.
93. Goodson NJ, Symmons DP, Scott DG, et al: Baseline levels of
C-reactive protein and prediction of death from cardiovascular

CHAPTER 57

Acute Phase Reactants and the Concept of Inflammation

disease in patients with inflammatory polyarthritis: a ten-year followup study of a primary care-based inception cohort, Arthritis Rheum
52:22932299, 2005.
94. Maradit-Kremers H, Nicola PJ, Crowson CS, et al: Raised erythrocyte
sedimentation rate signals heart failure in patients with rheumatoid
arthritis, Ann Rheum Dis 66:7680, 2007.
95. Honig S, Gorevic P, Weissmann G: C-reactive protein in systemic
lupus erythematosus, Arthritis Rheum 20:10651070, 1977.
96. Gaitonde S, Samols D, Kushner I: C-reactive protein and systemic
lupus erythematosus, Arthritis Care Res 59:18141820, 2008.
97. ter Borg EJ, Horst G, Limburg PC, et al: C-reactive protein levels
during disease exacerbations and infections in systemic lupus erythematosus: a prospective longitudinal study, J Rheumatol 17:16421648,
1990.
98. Moutsopoulos HM, Mavridis AK, Acritidis NC, et al: High C-reactive
protein response in lupus polyarthritis, Clin Exp Rheumatol 1:5355,
1983.
99. Maury CP, Teppo AM, Wegelius O: Relationship between urinary
sialylated saccharides, serum amyloid A protein and C-reactive
protein in rheumatoid arthritis and systemic lupus erythematosus,
Ann Rheum Dis 41:268271, 1982.
100. Vila LM, Alarcon GS, McGwin G Jr, et al: Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXIX. Elevation of
erythrocyte sedimentation rate is associated with disease activity and
damage accrual, J Rheumatol 32:21502155, 2005.
101. Ames PR, Alves J, Pap AF, et al: Fibrinogen in systemic lupus erythematosus: more than an acute phase reactant? J Rheumatol
27:11901195, 2000.
102. Gabay C, Roux-Lombard P, de Moerloose P, et al: Absence of correlation between interleukin 6 and C-reactive protein blood levels in
systemic lupus erythematosus compared with rheumatoid arthritis,
J Rheumatol 20:815821, 1993.
103. Russell AI, Cunninghame Graham DS, Shepherd C, et al: Polymorphism at the C-reactive protein locus influences gene expression and
predisposes to systemic lupus erythematosus, Hum Mol Genet 13:137
147, 2004.
104. Jonsen A, Gunnarsson I, Gullstrand B, et al: Association between
SLE nephritis and polymorphic variants of the CRP and Fc gamma
RIIIa genes, Rheumatology (Oxford) 46:14171421, 2007.
105. Vogt B, Fuhrnrohr B, Muller R, et al: CRP and the disposal of dying
cells: consequences for systemic lupus erythematosus and rheumatoid
arthritis, Autoimmunity 40:295298, 2007.
106. Marnell L, Mold C, Du Clos TW: C-reactive protein: ligands,
receptors and role in inflammation, Clin Immunol 117:104111,
2005.
107. Ito N, Kawata S, Tamura S, et al: Induction of interleukin-6 by
interferon alpha and its abrogation by a serine protease inhibitor in
patients with chronic hepatitis C, Hepatology 23:669675, 1996.
108. Kalabay L, Nemesanszky E, Csepregi A, et al: Paradoxical alteration
of acute phase protein levels in patients with chronic hepatitis C
treated with IFN-alpha 2b, Int Immunol 16:5154, 2004.
109. Selzer F, Sutton-Tyrrell K, Fitzgerald SG, et al: Comparison of risk
factors for vascular disease in the carotid artery and aorta in women
with systemic lupus erythematosus, Arthritis Rheum 50:151159,
2004.
110. Pahor A, Hojs R, Gorenjak M, et al: Accelerated atherosclerosis in
pre-menopausal female patients with rheumatoid arthritis, Rheumatol
Int 27:119123, 2006.
111. Gonzalez-Gay MA, Rodriguez-Valverde V, Blanco R, et al: Polymyalgia rheumatica without significantly increased erythrocyte sedimentation rate: a more benign syndrome, Arch Intern Med 157:317320,
1997.
112. Proven A, Gabriel SE, OFallon WM, et al: Polymyalgia rheumatica
with low erythrocyte sedimentation rate at diagnosis, J Rheumatol
26:13331337, 1999.
113. Cantini F, Salvarani C, Olivieri I, et al: Erythrocyte sedimentation
rate and C-reactive protein in the evaluation of disease activity and
severity in polymyalgia rheumatica: a prospective follow-up study,
Semin Arthritis Rheum 30:1724, 2000.
114. Salvarani C, Hunder GG: Giant cell arteritis with low erythrocyte
sedimentation rate: frequency of occurrence in a population-based
study, Arthritis Rheum 45:140145, 2001.
115. Salvarani C, Cimino L, Macchioni P, et al: Risk factors for visual loss
in an Italian population-based cohort of patients with giant cell
arteritis, Arthritis Rheum 53:293299, 2005.

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116. Gonzalez-Gay MA, Lopez-Diaz MJ, Barros S, et al: Giant cell arteritis: laboratory tests at the time of diagnosis in a series of 240 patients,
Medicine (Baltimore) 84:277290, 2005.
117. Lopez-Diaz MJ, Llorca J, Gonzalez-Juanatey C, et al: The erythrocyte
sedimentation rate is associated with the development of visual complications in biopsy-proven giant cell arteritis, Semin Arthritis Rheum
38:116123, 2008.
118. Larrosa M, Gratacos J, Sala M: Polymyalgia rheumatica with low
erythrocyte sedimentation rate at diagnosis, J Rheumatol 27:1815
1816, 2000.
119. Liozon E, Jauberteau-Marchan MO, Ly K, et al: Giant cell arteritis
with a low erythrocyte sedimentation rate: comments on the article
by Salvarani and Hunder, Arthritis Rheum 47:692693, author reply
693-694, 2002.
120. Weyand CM, Fulbright JW, Hunder GG, et al: Treatment of giant
cell arteritis: interleukin-6 as a biologic marker of disease activity,
Arthritis Rheum 43:10411048, 2000.
121. Salvarani C, Cantini F, Niccoli L, et al: Acute-phase reactants and
the risk of relapse/recurrence in polymyalgia rheumatica: a prospective followup study, Arthritis Rheum Arthritis Care Res 53:3338,
2005.
122. Boiardi L, Casali B, Farnetti E, et al: Relationship between interleukin 6 promotor polymorphism at position-174, IL-6 serum levels, and
the risk of relapse/recurrence in polymyalgia rheumatica, J Rheumatol
33:703708, 2006.
123. Pearson JD: Markers of endothelial perturbation and damage, Br J
Rheumatol 32:651652, 1993.
124. Stam TC, Swaak AJ, Kruit WH, et al: Regulation of ferritin: a specific
role for interferon-alpha (IFN-alpha)? The acute-phase response in
patients treated with INF-alpha-2b, Eur J Clin Invest 32(Suppl 1):79
83, 2002.
125. Fautrel B, Le Moel G, Saint-Marcoux B, et al: Diagnostic value of
ferritin and glycosylated ferritin in adult onset Stills disease, J Rheumatol 28:322329, 2001.
126. Fautrel B, Zing E, Golmard JL, et al: Proposal for a new set of classification criteria for adult-onset Still disease, Medicine (Baltimore)
81:194200, 2002.
127. Emmenegger U, Frey U, Reimers A, et al: Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes, Am J Hematol 68:410, 2001.
128. Emmenegger U, Reimers A, Frey U, et al: Reactive macrophage
activation syndrome: a simple screening strategy and its potential in
early treatment initiation, Swiss Med Wkly 132:230236, 2002.
129. Grom AA: Natural killer cell dysfunction: a common pathway in
systemic-onset juvenile rheumatoid arthritis, macrophage activation
syndrome, and hemophagocytic lymphohistiocytosis? Arthritis Rheum
50:689698, 2004.
130. Kawashima M, Yamamura M, Taniai M, et al: Levels of interleukin-18
and its binding inhibitors in the blood circulation of patients with
adult-onset Stills disease, Arthritis Rheum 44:550560, 2001.
131. Chen DY, Lan JL, Fin FJ, Tsieh TY: Proinflammatory cytokine profiles
in sera and pathological tissues of patients with active untreated adult
onset Stills disease, J Rheumatol 31:21892198, 2004.
132. Fitzgerald AA, LeClercq SA, Yan A, et al: Rapid responses to
anakinra in patients with refractory adult-onset Stills disease, Arthritis Rheum 52:17941803, 2005.
133. Lequerre T, Quartier P, Rosellini D, et al: Interleukin-1 receptor
antagonist (anakinra) treatment in patients with systemic-onset
juvenile idiopathic arthritis or adult onset Still disease: preliminary
experience in France, Ann Rheum Dis 67:302308, 2008.
134. Spoorenberg A, van der Heijde D, de Klerk E, et al: Relative value
of erythrocyte sedimentation rate and C-reactive protein in assessment of disease activity in ankylosing spondylitis, J Rheumatol
26:980984, 1999.
135. Braun J, Brandt J, Listing J, et al: Treatment of active ankylosing
spondylitis with infliximab: a randomized controlled multicentre
trial, Lancet 359:11871193, 2002.
136. Stone MA, Payne U, Pacheco-Tena C, et al: Cytokine correlates of
clinical response patterns to infliximab treatment of ankylosing spondylitis, Ann Rheum Dis 63:8487, 2004.
137. De Vries MK, van Eijk IC, van der Horst-Bruinsma IE, et al: Erythrocyte sedimentation rate, C-reactive protein level, and serum
amyloid A protein for patient selection and monitoring of anti-tumor
necrosis factor treatment in ankylosing spondylitis, Arthritis Rheum
Arthritis Care Res 61:14841490, 2009.

829.e4

PART 7

|DIAGNOSTIC TESTS AND PROCEDURES IN RHEUMATIC DISEASES

138. Poddubnyy DA, Rudwaleit M, Listing J, et al: Comparison of a high


sensitivity and standard C reactive protein measurement in patients
with ankylosing spondylitis and non-radiographic axial spondyloarthropathies, Ann Rheum Dis 69:13381341, 2010.
139. Sonel B, Tutkak H, Duzgun N: Serum levels of IL-1 beta, TNF-alpha,
IL-8, and acute phase proteins in seronegative spondyloarthropathies,
Joint Bone Spine 69:463467, 2002.
140. Wang X, Lin Z, Wei Q, et al: Expression of IL-23 and IL-17 and effect
of IL-23 on IL-17 production in ankylosing spondylitis, Rheumatol Int
29:13431347, 2009.
141. Karaderi T, Harvey D, Farrar C, et al: Association between the interleukin 23 receptor and ankylosing spondylitis is confirmed by a new
UK case control study and meta-analysis of published series, Rheumatology (Oxford) 48:386389, 2009.
142. Spector TD, Hart DJ, Nandra D, et al: Low-level increases in serum
C-reactive protein are present in early osteoarthritis of the knee and
predict progressive disease, Arthritis Rheum 40:723727, 1997.
143. Kerkhof HJM, Bierma-Zeinstra SMA, Castano-Betancourt MC, et al:
Serum C reactive protein levels and genetic variation in the CRP
gene are not associated with the prevalence, incidence or progression
of osteoarthritis independent of body mass index, Ann Rheum Dis
69:19761982, 2010.
144. Punzi L, Ramonda R, Oliviero F, et al: Value of C reactive protein in
the assessment of erosive osteoarthritis, Osteoarthritis Cartilage
10:595601, 2002.
145. Hind CRK, Winearls CG, Pepys MB: Correlation of disease-activity
in systemic vasculitis with serum C-reactive protein measurementa
prospective study of 38 patients, Eur J Clin Invest 15:8994, 1985.
146. Roseff R, Wohlgethan JR, Sipe JD, Canoso JJ: The acute phase
response in gout, J Rheumatol 14:974977, 1987.
147. Laurent MR, Panayi GS, Shepherd P: Circulating immunecomplexes, serum immunoglobulins, and acute phase proteins in
psoriasis and psoriatic-arthritis, Ann Rheum Dis 40:6669, 1981.
148. Nashel DJ, Petrone DL, Ulmer CC, Sliwinski AJ: C-reactive
proteina marker for disease-activity in ankylosing spondylitis and
Reiters-syndrome, J Rheumatol 13:364367, 1986.
149. Berkun Y, Padeh S, Reichman B, et al: A single testing of serum
amyloid A levels as a tool for diagnosis and treatment dilemmas in
familial Mediterranean fever, Semin Arthritis Rheum 37:182188,
2007.
150. Moutsopoulos HM, Elkon KB, Mavridis AK, et al: Serum C-reactive
protein in primary Sjgrens syndrome, Clin Exp Rheumatol 1:5758,
1983.
151. Guillaume S, Prieur AM, Coste J, Job-Deslandre C: Long term
outcome and prognosis in oligoarticular-onset juvenile idiopathic
arthritis, Arthritis Rheum 43:18581865, 2000.
152. Donald F, Ward MM: Evaluative laboratory testing practices of
United States rheumatologists, Arthritis Rheum 41:P725P729, 1998.
153. Giacomello A, Quaratino CP, Zoppini A: Erythrocyte sedimentation
rate within rheumatic disease clinics, J Rheumatol 24:22632265,
1997 [Letter].
154. Paulus HE, Brahn E: Is erythrocyte sedimentation rate the preferable
measure of the acute phase response in rheumatoid arthritis? J Rheumatol 31:838840, 2004.
155. Wolfe F: Comparative usefulness of C-reactive protein and erythrocyte sedimentation rate in patients with rheumatoid arthritis, J Rheumatol 24:14771485, 1997.
156. Pepys MB, Hirschfield GM, Tennent GA, et al: Targeting C-reactive
protein for the treatment of cardiovascular disease, Nature 440:1217
1221, 2006.

157. Locascio JJ, Fukumoto H, Yap L, et al: Plasma amyloid beta-protein


and C-reactive protein in relation to the rate of progression of
Alzheimer disease, Arch Neurol 65:776785, 2008.
158. Heikkila K, Ebrahim S, Lawlor DA: A systematic review of the
association between circulating concentrations of C reactive protein
and cancer, J Epidemiol Commun Health 61:824832, 2007.
159. De Torres JP, Pinto-Pata V, Casanova C: C-reactive protein levels
and survival in patients with moderate to very severe COPD, Chest
133:13361343, 2008.
160. Ford DE, Erlinger TP: Depression and C-reactive protein in US
adults: data from the Third National Health and Nutrition Examination Survey, Arch Intern Med 164:10101014, 2004.
161. Danesh J, Wheeler JG, Hirschfield GM, et al: C-reactive protein and
other circulating markers of inflammation in the prediction of coronary heart disease, N Engl J Med 350:13871397, 2004.
162. Ridker PM: C-reactive protein and the prediction of cardiovascular
events among those at intermediate risk: moving an inflammatory
hypothesis toward consensus, J Am Coll Cardiol 49:21292138,
2007.
163. Lloyd-Jones DM, Liu K, Tian L, et al: Narrative review: assessment
of C-reactive protein in risk prediction for cardiovascular disease,
Ann Intern Med 145:3542, 2006.
164. Schunkert H, Samani NJ: Elevated C-reactive protein in
atherosclerosischicken or egg? N Engl J Med 359:19531955,
2008.
165. Kushner I, Rzewnicki D, Samols D: What does minor elevation of
C-reactive protein signify? Am J Med 119:e117e128, 2006.
166. De Beer FC, Soutar AK, Baltz ML, et al: Low density and very low
density lipoproteins are selectively bound by aggregated C-reactive
protein, J Exp Med 156:230242, 1982.
167. Pepys MD, Rowe IF, Baltz ML: C-reactive protein: binding to lipids
and lipoproteins, Int Rev Exp Pathol 27:83111, 1985.
168. Casas JP, Shah T, Hingorani AD, et al: C-reactive protein and coronary heart disease: a critical review, J Intern Med 264:295314, 2008.
169. Lowe GD, Pepys MB: C-reactive protein and cardiovascular disease:
weighing the evidence, Curr Atheroscler Rep 8:421428, 2006.
170. Ridker PM, Danielson E, Francisco AH, et al: Rosuvastatin to
prevent vascular events in men and women with elevated C-reactive
protein, N Engl J Med 359:21952207, 2008.
171. Genser B, Grammer TB, Stojakovic T, et al: Effect of HMG CoA
reductase inhibitors on low density lipoprotein cholesterol and
C-reactive protein: systemic review and meta-analysis, Int J Clin
Pharmacol Ther 46:497510, 2008.
172. Lawlor DA, Harbord RM, Timpson NJ, et al: The association of
C-reactive protein and CRP genotype with coronary heart disease:
findings from five studies with 4,610 cases amongst 18,637 participants, PLoS One 3:e3011, 2008.
173. Zacho J, Tybjaerg-Hansen A, Jensen JS, et al: Genetically elevated
C-reactive protein and ischemic vascular disease, N Engl J Med
359:18971908, 2008.
174. Lange LA, Carlson CS, Hindorff LA, et al: Association of polymorphisms in the CRP gene with circulating C-reactive protein levels
and cardiovascular events, JAMA 296:27032711, 2006.
175. CRP CHD Genetics Collaboration: Collaborative pooled analysis of
data on C-reactive protein gene variants and coronary disease:
judging causality by Mendelian randomization, Eur J Epidemiol
23:531540, 2008.
176. Hingorani AD, Shah T, Casas JP, et al: C-reactive protein and coronary heart disease: predictive test or therapeutic target? Clin Chem
55:239255, 2009.