Biologic Markers in The Diagnosis and Assessment of Rheumatoid Arthritis - UpToDate

Biologic markers in the diagnosis and assessment of rheumatoid arthritis - UpToDate 11/10/17 15'48
Authors: Peter C Taylor, MA, PhD, FRCP, Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Section Editor: James R O'Dell, MD
Deputy Editor: Paul L Romain, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: May 05, 2017.
INTRODUCTION — Biologic markers, commonly termed "biomarkers," are biologic characteristics (eg, of blood or joint fluid) that can be
objectively measured and serve as indicators of normal or pathologic processes or as measures of the response to therapy. In patients with
rheumatoid arthritis (RA) the term is commonly applied to diagnostic or prognostic indicators, such as rheumatoid factor (RF), and to measures
used to assess disease activity, such as acute phase reactants. The US National Institutes of Health has defined a biological marker
(biomarker) as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic
processes, or pharmacologic responses to a therapeutic intervention" [1].
RA follows a variable disease course with regard to joint injury and functional outcomes, and early RA may be challenging to diagnose with
accuracy. Thus, early identification of patients with RA and, in particular, those likely to assume a more rapidly destructive form of disease can
help to target those patients most likely to benefit from early, aggressive intervention with disease-modifying agents. The response to therapy in
patients with RA is typically assessed using a combination of subjective reporting and physical and laboratory findings; no single biologic
measure has proven sufficient for the measurement of disease activity. These observations highlight the need for biologic markers in blood and
joint fluids that may serve as reliable objective indicators of prognosis, the response to therapy, and the degree of ongoing disease activity.
This topic will review markers that are widely used in clinical practice and others proposed for such use that may serve as aids in the diagnosis
of RA, for predicting prognosis, and for the assessment of disease activity. Genetic features of RA and clinical findings or associations that may
have prognostic or diagnostic implications, and the diagnosis and differential diagnosis of RA are presented separately, as are more detailed
discussions of RF and acute phase reactants. (See "HLA and other susceptibility genes in rheumatoid arthritis" and "Disease outcome and
functional capacity in rheumatoid arthritis" and "General principles of management of rheumatoid arthritis in adults", section on 'Prognosis' and
"Diagnosis and differential diagnosis of rheumatoid arthritis" and "Origin and utility of measurement of rheumatoid factors" and "Acute phase
reactants".)
DIAGNOSIS AND PROGNOSIS — The main clinically useful biologic markers for the diagnosis of rheumatoid arthritis (RA) are rheumatoid
factors (RF) and antibodies to citrullinated peptides (ACPA) (see 'Rheumatoid factors' below and 'Anti-citrullinated peptide antibodies' below).
The presence of RF or ACPA also predicts poorer functional and radiographic outcomes. However, neither of the tests is of sufficient specificity
alone to establish the diagnosis of RA, and prognosis varies widely within seropositive and seronegative patient populations, respectively.
Other commercially available biomarkers may provide additional useful information, but require further study. (See '14-3-3eta' below.)
Rheumatoid factors — RF are autoantibodies directed against the Fc portion of immunoglobulin G (IgG). They are found in 75 to 80 percent
of RA patients at some time during the course of their disease. High-titer IgM RF is relatively specific for the diagnosis of RA in the context of a
chronic polyarthritis and was, for decades, the sole serologic criterion widely used in the diagnosis of RA. However, it has little predictive value
in the general population because of the relatively low overall prevalence of RA. RF are briefly addressed here and discussed in more detail
separately. (See "Origin and utility of measurement of rheumatoid factors".)
Testing for IgM RF remains useful in clinical practice, despite the widespread availability of additional diagnostic tests, particularly ACPA. Both
RF and ACPA are among the criteria for RA [2]. A small proportion of patients eventually diagnosed with RA may be positive for RF, but not for
ACPA, especially in the early stages of their presentation; thus, measurement of both RF and ACPA, rather than ACPA alone, improves the
specificity and sensitivity of serologic testing for establishing a diagnosis of RA. (See "Diagnosis and differential diagnosis of rheumatoid
arthritis" and 'Anti-CCP antibodies' below and "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis", section on
'Autoantibodies' and "Origin and utility of measurement of rheumatoid factors".)
Moreover, high-titer RF appears to be a better predictor of a severe disease course, showing a stronger correlation with extraarticular
manifestations, such as interstitial lung disease and vasculitis, than appears to be the case with ACPA. The presence of RF also increases the
likelihood of a clinically significant response to rituximab after failure of tumor necrosis factor (TNF) inhibitor therapy [3]. (See "Epidemiology of,
risk factors for, and possible causes of rheumatoid arthritis", section on 'Autoantibodies' and "Origin and utility of measurement of rheumatoid
factors".)
https://www-uptodate-com.pbidi.unam.mx:2443/contents/biologic-mar…assessment-of-rheumatoid-arthritis?source=related_link#H56835572 Página 1 de 16
RF has only moderate specificity; it also may be present in conditions other than RA. As an example, some connective tissue diseases, such as
systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (SS), may be associated with the presence of RF. In addition, RF levels
may be elevated in patients with certain infections, such as malaria, rubella, hepatitis C, and those following vaccinations.
RF may have some prognostic value with regard to disease manifestations and activity, as well as the severity of joint erosions. Seropositive
RA (ie, RA associated with a positive RF test) is often associated with more aggressive joint disease and is more commonly complicated by
extraarticular manifestations than seronegative RA [4-10]. As examples:
● Rheumatoid nodules and vasculitis occur almost exclusively in seropositive patients [6-9,11]; these findings are associated with increased
mortality [12].
● Radiographic progression may be more rapid among patients with a positive RF at initial evaluation [13-15].
● A retrospective analysis of a case-control study of 135 women with early RA found that patients with persistently positive RF had more
erosions, nodules, extraarticular disease, functional disability, and disease activity than seronegative or intermittently seronegative
individuals over a mean period of six years of follow-up [16].
It has also been proposed that the rate of formation of new erosions among seropositive patients correlates with the RF titer [17]. This finding,
however, was not confirmed in an eight-year study of a community-based cohort of patients with recent-onset arthritis [18].
The presence of RF, particularly at high levels, may antedate the clinical development of RA [19]. These issues are discussed in detail
elsewhere. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis", section on 'Autoantibodies' and "Origin and
utility of measurement of rheumatoid factors", section on 'Healthy individuals'.)
Anti-citrullinated peptide antibodies — Testing for ACPA is useful in the diagnostic evaluation of patients for RA (see "Diagnosis and
differential diagnosis of rheumatoid arthritis"). The sensitivity of ACPA assays for RA varies from about 50 to 75 percent, depending upon the
assay and study population, while specificity of ACPA for RA is relatively high, usually over 90 percent [20-27]. Measurement of ACPA is useful
in the differential diagnosis of early polyarthritis, because of the relatively high specificity for RA of these antibodies [26,28]. (See
"Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes".)
Enzyme-linked immunosorbent assays (ELISA) for antibodies against cyclic citrullinated peptides (CCP) are the most commonly used assays
for ACPA (see 'Anti-CCP antibodies' below). Another ACPA assay that is commercially available detects antibodies against mutated citrullinated
vimentin (MCV). (See 'Anti-MCV antibodies' below.)
A decrease in ACPA titers can be seen in patients treated effectively, particularly if treated early with nonbiologic or biologic disease-modifying
antirheumatic drugs (DMARDs), but is less frequent and of a lesser magnitude than the decrease in IgM RF that may be seen in such patients
[29].
As with RF, ACPA may be present prior to the appearance of symptoms of RA. This phenomenon is discussed separately (see "Epidemiology
of, risk factors for, and possible causes of rheumatoid arthritis", section on 'Autoantibodies'). The relationships of ACPA to cigarette smoking
and to the shared epitope are also discussed elsewhere. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis",
section on 'Cigarette smoking' and "Pathogenesis of rheumatoid arthritis", section on 'Citrullinated proteins and peptides'.)
Anti-CCP antibodies
Anti-CCP assay — In an ELISA assay for ACPA, arginine residues are replaced by citrulline in a mixture of CCP, increasing the
sensitivity of the assay for ACPA. These anti-CCP assays have become the principal commercially available assay kits for the detection of
ACPA.
The newer-generation assays, including the second-generation anti-CCP antibody assays (anti-CCP2), have improved sensitivity and
specificity compared with the original anti-CCP assays [21,26,28,30-32]. The best data regarding test performance characteristics of ACPA
come from a 2010 systematic review and meta-analyses of 151 studies [28]. Sensitivity of ACPA in was 67 percent, and the specificity was 96
percent.
This analysis included the following findings:
● There was substantial heterogeneity in test performance, which resulted from differences in study design, stage of disease, and type of
ACPA used in a given study. Cross-sectional and case-control studies of patients with established RA overestimated sensitivity.
● In the cohort studies of patients with RA for less than two years, the sensitivity of anti-CCP2 and RF were nearly the same (58 versus 56
percent), but specificity was significantly higher for anti-CCP2 (96 versus 86 percent).
● There was insufficient evidence to determine whether the combination of anti-CCP2 and RF provides greater benefit than the use of anti-
CCP2 alone.
Positive anti-CCP in other diseases — Although ACPA testing is more specific than RF for RA [21,28], positive results can occur in
other diseases, including several autoimmune rheumatic diseases, tuberculosis, and sometimes chronic lung disease [27,33-37]. As examples:
● Anti-CCP antibodies have been reported in SLE and primary SS, usually in association with deforming or erosive arthritis [38-43]. As
examples, 17 percent of a cohort of 335 patients with SLE were anti-CCP-positive in one study [39], and, in another, 10 percent of 155
consecutive patients with primary SS were anti-CCP-positive [42]. However, in such cases, some experts suggest that such patients
should be reclassified as SLE-RA and primary SS/RA overlap syndromes, respectively [43].
● ACPA have also been found in 8 to 16 percent of patients with psoriatic arthritis; they are most frequently found in patients with erosive
and/or polyarticular disease, but may be present in patients with severe psoriasis in the absence of arthritis [44-47].
● An increased prevalence of anti-CCP antibodies has been noted in patients with active tuberculosis (TB). The rate in different studies has
ranged from as high as 32 to 39 percent [33,34] to as low as 7 percent [35]. Many patients with TB and anti-CCP also have antibodies to a
cyclic peptide that contains an unmodified arginine residue [34]. This suggests that binding of the antibodies from patients with TB is
determined by portions of the CCP other than the citrulline moiety.
● In contrast to RF, anti-CCP antibodies are rarely present in the serum of patients with hepatitis C virus (HCV) infections.
● In a study of 257 patients with alpha 1-antitrypsin deficiency (AATD) and 113 patients with chronic obstructive pulmonary disease, anti-
CCP antibodies were detected in 3 and 5 percent of patients, respectively [37]. In the patients with AATD, there was no difference in the
presence of anti-CCP antibodies between cigarette smokers and nonsmokers.
Anti-CCP and RA prognosis — ACPA-positive patients with early RA are at increased risk of progressive joint damage [10,15,22,48,49],
and ACPA testing may predict erosive disease more effectively than RF [21,50]. This was illustrated in a series of 145 such patients in which
there was more radiographically apparent damage after five years of observation in those with detectable ACPA compared with those who were
RF-positive [48]. The presence of ACPA was also predictive of more rapid radiographic progression in two studies of 183 and 279 Swedish
patients with early RA [15,49] and in the BeSt (Behandelstrategieën voor Reumatoide Artritis [Treatment Strategies for Rheumatoid Arthritis])
trial of 508 Dutch patients [10].
Positive ACPA testing also appears to predict an increased risk for radiographic progression in patients with early oligo- or polyarthritis who are
IgM-RF-negative. This was demonstrated in a prospective study that included 178 such patients [51]. Radiographic progression (more than 5
units by Sharp score) was more frequent in the ACPA-positive patients than in those with a negative test result (40 versus 5 percent). The anti-
CCP test for ACPA correctly predicted whether or not there would be worsening radiographic damage in 83 percent. Similar findings have been
noted in other studies [52-54].
Anti-MCV antibodies — Testing for anti-MCV antibodies has very similar results to anti-CCP antibody testing [55]. Anti-MCV antibodies
recognize a naturally occurring isoform of citrullinated vimentin, which can be found in patients with RA and in which arginine residues are
replaced by glycine [56,57]; and since vimentin is expressed and appears to be implicated in pathogenesis, it is a candidate biomarker [58].
Vimentin is a widely expressed intermediate filament. It becomes citrullinated through deimination, which occurs in macrophages undergoing
apoptosis. (See "Investigational biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Autoantibodies'.)
The diagnostic and prognostic value of anti-MCV antibodies in RA was analyzed in a 2010 systematic review of 14 studies, most of which used
a commercially available assay, finding similar performance to anti-CCP antibody testing [55]. A report subsequent to the systematic review,
which evaluated a longitudinal cohort of 238 patients with RA over 10 years, found that anti-MCV predicted joint damage and did so comparably
with anti-CCP [59]. The odds ratios (OR) for radiographic progression were increased in the presence of either anti-MCV or anti-CCP (OR 7.3,
95% CI 3.2-16.5, and OR 5.7, 95% CI 2.6-12.5, respectively). Additionally, the odds of progression increased not only based on the presence
or absence of anti-MCV antibodies but also with increasing levels of anti-MCV antibodies. Similar observations were previously made in this
cohort with anti-CCP antibodies [60].
In patients with undiagnosed early inflammatory arthritis or established RA, the diagnostic and prognostic value of adding anti-MCV antibody
testing to anti-CCP and RF testing, or substituting anti-MCV for other tests, remains uncertain. Further study is required to more clearly define
its role in routine clinical practice.
Other anti-citrullinated peptide antibodies — Prior to the widespread use of anti-CCP antibody measurements and the measurement of
anti-MCV antibodies, a number of antibodies were identified in the sera of patients with RA that led to the recognition of citrullinated peptides as
important antigenic targets in patients with RA. Testing for these antibodies is not widely available, and they are mainly of historical interest,
including antikeratin and antiperinuclear antibodies, which recognize epidermal filaggrin, an intermediate filament-associated protein for which a
major determinant of antibody binding is the presence of citrulline, formed by a post-translational modification of arginine [61-75].
Antibodies to other citrullinated proteins include antibodies to citrullinated fibrinogen, citrullinated vimentin (anti-Sa), citrullinated synthetic type I
or type II collagen telopeptides, and to alpha-enolase [56,57,76-85]. A commercial assay for anti-mutated citrullinated vimentin is also available.
(See 'Anti-MCV antibodies' above.)
14-3-3eta — Serum 14-3-3eta, an isoform of the 14-3-3 family of intracellular chaperonin proteins, may be helpful diagnostically in RA, as some
data suggest that it may have similar sensitivity and specificity to RF and ACPA in distinguishing patients with RA from osteoarthritis, other
autoimmune disorders, and healthy controls [86]. However, in a cohort of patients with arthralgia, preselected for ACPA and/or RF positivity, the
added predictive value of 14-3-3eta could not be established [87].
An assay for serum 14-3-3eta is commercially available, but is not widely used; further study is needed to justify a role for the assay in routine
clinical practice.
DISEASE ACTIVITY AND PROGNOSIS — The main clinically useful biologic markers in patients with rheumatoid arthritis (RA) that aid in
assessing disease activity and predicting functional and radiographic outcomes include acute phase reactants, particularly the erythrocyte
sedimentation rate (ESR) and C-reactive protein (CRP) (see 'Erythrocyte sedimentation rate' below and 'C-reactive protein' below).
Measurements of combinations of multiple acute phase proteins and other markers of the immune response in RA have also been used for this
purpose. (See 'Multi-protein biomarker algorithms' below.)
In patients with RA, the ESR and CRP generally tend to both be elevated or not in the same patients, but one study found that results for the
two tests were discordant (ESR >28 mm/hr with CRP ≤0.8 mg/dL or ESR ≤28 mm/hr with CRP >0.8 mg/dL) in about one-quarter of patients in a
large practice-based registry, regardless of the level of disease activity [88].
The acute phase response, including the ESR and CRP, is discussed in more detail separately. (See "Acute phase reactants".)
Erythrocyte sedimentation rate — The ESR level tends to correlate with disease activity in RA as well as disease severity and may be useful
for monitoring the therapeutic response [89-91]. Moreover, despite some shortcomings, an elevated ESR in patients with early RA is predictive
of greater radiographic joint damage in subsequent years despite treatment with conventional disease-modifying antirheumatic drugs
(DMARDs) [14,15,92].
The rate at which erythrocytes fall through plasma, the ESR, depends largely upon the plasma concentration of fibrinogen [93]. However, the
ESR can be greatly influenced by the size, shape, and number of red cells, as well as by other plasma constituents such as immunoglobulins.
Thus, results may be imprecise and sometimes misleading. (See "Acute phase reactants", section on 'Erythrocyte sedimentation rate'.)
C-reactive protein — Assessment of the CRP has been advocated as an objective measure of disease activity in RA. Radiologic damage, as
assessed by erosion counts in RA, is significantly more likely to progress when CRP and ESR are elevated, irrespective of the presence or
absence of rheumatoid factor (RF) and irrespective of therapeutic intervention [14,15,94]. Unlike the ESR, CRP can be measured using stored
serum samples, is independent of the hemoglobin concentration, and can be performed in automated serum analyzers.
Elevations of both ESR and CRP are stronger indications of radiologic progression than CRP alone [95]. In one study of 147 patients, for
example, absence or progression of radiographic joint damage after two years was correctly predicted in 83 percent of the patients using a
combination of disease activity at presentation (assessed by ESR, CRP, or disease activity score) and DR4 and RF positivity [96].
Another study assessed progression of radiologic damage in 110 patients with early RA who had symptoms for less than one year [97]. A highly
significant correlation between radiologic progression and cumulative CRP production was noted [97]. However, a wide variation in the
relationship between the degree of radiographic change and cumulative CRP was noted between patients, particularly those with low CRP
levels. This interindividual variability could not be accounted for by human leukocyte antigen (HLA)-DR4, positive RF, sex, or age, and limits the
value of serial measurements of acute phase proteins in predicting radiologic progression.
Multi-protein biomarker algorithms — A multi-biomarker disease activity (MBDA) test for RA has been developed that may provide a useful
adjunct to clinical assessment and the use of single laboratory tests [98,99]. The combined use of multiple markers may provide advantages
over the use of single markers for predicting disease activity and progression and for identifying patients with subclinical disease, although the
cost-effectiveness and optimal role for this test in routine clinical practice remains to be established.
The commercially available MBDA test for RA (Vectra DA) was developed by initial testing of 130 candidate biomarkers in feasibility studies,
then selecting 25 for algorithm training [98]. Multi-biomarker statistical models outperformed individual biomarkers at estimating disease activity
assessed by the disease activity score (DAS) using a 28 joint count and C-reactive protein level (DAS28-CRP). The final MBDA algorithm used
12 biomarkers to generate an MBDA score between 1 and 100.
Post hoc analyses of data from several clinical trials in patients with early RA showed that the MBDA score at baseline was a strong
independent predictor of radiographic progression at one year [100-102]. High MBDA scores were better predictors of such progression than
the DAS. As an example, in a study of 163 patients with RA in the Leiden Early Arthritis Cohort, at a total of 271 visits, patients with a high
MBDA score were 2.3 times more likely (95% CI 1.1-3.7) to have joint damage progression during the subsequent year [100].
Whether MBDA has a useful role in informing a clinical management decision has been more controversial. In an analysis of patients with RA
from the Swedish Pharmacotherapy (Swefot) trial with an inadequate response to methotrexate (MTX), those patients with greater MBDA score
reduction were more likely to respond to triple therapy (MTX plus sulfasalazine plus hydroxychloroquine) than to MTX plus infliximab [103].
However, post hoc analysis of data from the AMPLE ("abatacept versus adalimumab comparison in biologic-naive RA subjects with background
methotrexate") trial has been interpreted as indicating that the MBDA score cannot reliably be used to guide decisionmaking in RA
management, particularly for patients who receive abatacept or adalimumab as a first biologic agent [104]. Furthermore, as interleukin (IL)-6 is
a contributor to the MBDA score, caution must be exercised when interpreting MBDA response following use of IL-6R inhibitors, given that
blood IL-6 rises after treatment and therefore lowers the magnitude of response observed for the MBDA score compared with the DAS28-CRP
[105].
OTHER BIOMARKERS — A number of other potential markers have been the subject of investigation in rheumatoid arthritis (RA). Broadly
defined, these include:
● Immunologic or serologic abnormalities, in addition to rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) (see
'Immune abnormalities and autoantibodies' below)
● Genetic factors (see 'Genetic factors' below)
● Acute phase reactants, induced as part of the inflammatory response, in addition to the erythrocyte sedimentation rate (ESR) and C-
reactive protein (CRP)
● Macromolecules specific for joint associated tissues that are released or excreted as part of degenerative and reparative processes
Immune abnormalities and autoantibodies — A number of antibodies have been the subject of study in RA in addition to RF and ACPA, but
most are not available for routine clinical use and none has proven useful in routine clinical practice. Those of particular interest include:
● Anti-p68 (BiP) antibodies [106]

● Anti-RA33 antibodies [14,107-109]
● Gal 0 glycoforms [110-115]
● Antibodies to alpha-enolase [116]
● Antibodies to glucose phosphate isomerase (GPI) [117]
● Antibodies to ferritin [118]
● Antibodies to the enzyme peptidyl-arginine deiminase 4 (PADI4) [119]
Other immune changes investigated as potential biomarkers in RA include enhanced expression of CD40 ligand (CD154) on activated T cells
[120] and markers of complement activation, including the concentration of covalently linked C1q-C4 complement components [121].
Genetic factors — Important associations have been noted between certain genetic polymorphisms and the susceptibility to and severity of
RA. Of particular interest has been the association with certain human leukocyte antigen (HLA)-DR alleles (particularly HLA-DR4) encoding a
conserved amino acid sequence in the third hypervariable region of the DRB1 chain, termed the shared epitope. These associations and their
role in RA pathogenesis are discussed separately; genetic testing has yet to play a role in diagnosis or treatment of RA. (See "HLA and other
susceptibility genes in rheumatoid arthritis".)
In addition to the shared epitope, other reported genetic associations include:
● Matrix metalloproteinase (MMP) genotype polymorphisms and RA disease severity [122]

● IL-10 promotor genotype polymorphisms and RA severity, but not susceptibility [123]
● Sulphoxidation status and risk of disease persistence among patients with early RA [124]
Other acute phase markers — IL-6 increases during the acute phase response, and IL-6-targeted biologics are effective in treating RA.
However, IL-6 levels have not been found to correlate with radiographic progression in RA, despite their close relationship to the acute phase
response in RA patients [125]. Measurement of IL-6 levels in blood or synovial fluid is not useful in routine clinical practice, although interest in
further research remains.
Tissue-specific markers — A number of biochemical markers of joint damage have been described in RA. These molecules may be synthetic
or degradative, their presence in body fluids arising as a consequence of metabolism of the tissue of origin. They are predominantly derived
from a single tissue such as cartilage, bone, or synovium and can be detected principally by immunoassay of joint fluid, serum, or urine.
Appropriate assays are not routinely available, and joint fluids are not readily available (apart from knee joints), in comparison with serum or
urine. There is, as yet, limited information regarding the usefulness of tissue-specific markers as measures of disease activity or response to
therapy in RA. However, some markers may be of prognostic value.
These include:
● Synovium-specific markers – In addition to 14-3-3eta, which is markedly enriched in synovial fluid compared with the serum (see '14-3-
3eta' above), other products of the synovium may be markers of disease activity and have prognostic implications. These include serum
hyaluronan [126-130] and MMP, including MMP-1 and MMP-3 [131,132]. Elevated serum levels of immunoglobulin soluble receptor (Fc
gamma RIIIa) in RA are thought to be due to synovial macrophages and/or NK cells [133].
● Cartilage-specific markers – Markers of cartilage metabolism may have some prognostic value in patients with RA. Studies have focused
upon elevated serum levels of cartilage oligomeric matrix protein (COMP), a member of the thrombospondin protein family, in early RA
[134,135]; the aggrecan content of synovial fluid [136,137]; a putative marker of cartilage aggrecan synthesis, epitope 846, located on the
chondroitin sulphate rich area of the aggrecan molecule [135]; measurement of crosslinked c-terminal peptides from type II collagen (CTX-
II) in urine [138,139]; and a peptide derived from the helical portion of type II collagen (HELIX-II) that may be detected in the urine [140].
The combination of cartilage and synovial biomarkers including both MMP-3 and CTX-II levels may have a better ability to predict
radiographic progression than either alone [141].
● Bone-specific markers – As with cartilage, several bone-specific markers may be useful in patients with RA as markers of disease
activity, prognosis, or both. These include bone sialoprotein, an osteoblast-derived protein preferentially expressed in juxtaarticular bone
that may be measure in synovial fluid [142]; measurement of pyridinoline cross-links, a marker of bone degradation, that may be detected
in urine [143]; measurement of cross-linked carboxyterminal telopeptides of type I collagen (ICTP), a larger serum marker for bone
collagen degradation [138,144-146]; and the initial ratio of serum levels of an inhibitor of osteoclast differentiation (osteoprotegerin) and a
stimulatory protein (Receptor Activator of Nuclear factor Kappa B ligand [RANKL]) [147].
● Vascular markers – Serum vascular endothelial factor (VEGF) concentrations are elevated in RA patients compared with healthy controls
and with patients with osteoarthritis [148-150], and elevated levels in patients with early RA correlate with the degree of radiographically
assessed joint damage over the subsequent year [149].
● Plasma proteins – In a proteomic approach, 163 plasma proteins were evaluated in 44 patients with RA to determine which were
associated with disease activity [151]. Plasma proteins whose concentrations were correlated with disease activity included IL-6,
oncostatin M, IL-2, macrophage colony-stimulating factor (M-CSF), tumor necrosis factor (TNF receptor superfamily member 9), C-C motif
chemokine 23 (CCL23), transforming growth factor (TGF)-alpha, and chemokine C-X-C motif ligand 13 (CXCL13).
SUMMARY
● Biologic markers, commonly termed "biomarkers," are biologic characteristics (eg, of blood or joint fluid) that can be objectively measured
and serve as indicators of normal or pathologic processes or as measures of the response to therapy. In patients with rheumatoid arthritis
(RA) the term is commonly applied to diagnostic or prognostic indicators, such as rheumatoid factor (RF), and to measures used to assess
disease activity, such as acute phase reactants. (See 'Introduction' above.)
● The main clinically useful biologic markers for the diagnosis of RA are RF and antibodies to citrullinated peptides (ACPA). The presence of
RF or ACPA also predicts poorer functional and radiographic outcomes, but neither is of sufficient specificity alone to establish the
diagnosis of RA, and prognosis varies widely within seropositive and seronegative patient populations, respectively. Other commercially
available biomarkers may provide additional useful information but require further study. (See 'Rheumatoid factors' above and 'Anti-CCP
antibodies' above and '14-3-3eta' above.)
● The main clinically useful biologic markers in patients with RA that aid in assessing disease activity and predicting functional and
radiographic outcomes include acute phase reactants, particularly the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).
Measurements of combinations of multiple acute phase proteins and other markers of the immune response in RA have also been used for
this purpose. (See 'Erythrocyte sedimentation rate' above and 'C-reactive protein' above and 'Multi-protein biomarker algorithms' above.)
● Biologic markers that remain investigational include (see 'Other biomarkers' above):
• Immunologic (or serologic) abnormalities, including various ACPA that were under study prior to the development and widespread
availability of anti-cyclic citrullinated peptides (CCP) and anti-mutated citrullinated vimentin (MCV) antibody assays, such as
antiperinuclear factor, antikeratin antibodies, and anti-Sa antibodies; other autoantibodies; and other immunologic markers (see
'Immune abnormalities and autoantibodies' above)
• Genetic factors that may influence the development and severity of RA, including the human leukocyte antigen (HLA) class II shared
epitope, matrix metalloproteinase (MMP) genotype, interleukin (IL)-10 promoter genotype, and sulphoxidation status (see 'Genetic
factors' above)
• Other measures of the acute-phase response (eg, IL-6), elicited as part of the inflammatory process, in addition to measurement of
the ESR and CRP (see 'Other acute phase markers' above)
• Macromolecules specific for joint-associated tissues, such as cartilage, bone, and synovium, that are released into the circulation or
excreted in the urine as part of degenerative and reparative processes (see 'Tissue-specific markers' above)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Biomarkers Definitions Working Group.. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin
Pharmacol Ther 2001; 69:89.
2. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European
League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62:2569.
3. Quartuccio L, Fabris M, Salvin S, et al. Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a lower number
of anti-TNF agents failed are associated with response to rituximab in rheumatoid arthritis. Rheumatology (Oxford) 2009; 48:1557.
4. Egeland T, Munthe E. The role of the laboratory in rheumatology. Rheumatoid factors. Clin Rheum Dis 1983; 9:135.
5. Jacoby RK, Jayson MI, Cosh JA. Onset, early stages, and prognosis of rheumatoid arthritis: a clinical study of 100 patients with 11-year
follow-up. Br Med J 1973; 2:96.
6. Masi AT, Maldonado-Cocco JA, Kaplan SB, et al. Prospective study of the early course of rheumatoid arthritis in young adults:
comparison of patients with and without rheumatoid factor positivity at entry and identification of variables correlating with outcome.
Semin Arthritis Rheum 1976; 4:299.
7. Aho K, Steiner G, Kurki P, et al. Anti-RA 33 as a marker antibody of rheumatoid arthritis in a Finnish population. Clin Exp Rheumatol
1993; 11:645.
8. Alarcón GS, Koopman WJ, Acton RT, Barger BO. Seronegative rheumatoid arthritis. A distinct immunogenetic disease? Arthritis Rheum
1982; 25:502.
9. Westedt ML, Herbrink P, Molenaar JL, et al. Rheumatoid factors in rheumatoid arthritis and vasculitis. Rheumatol Int 1985; 5:209.
10. de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Verpoort KN, et al. Progression of joint damage in early rheumatoid arthritis: association
with HLA-DRB1, rheumatoid factor, and anti-citrullinated protein antibodies in relation to different treatment strategies. Arthritis Rheum
2008; 58:1293.
11. SHARP JT, CALKINS E, COHEN AS, et al. OBSERVATIONS ON THE CLINICAL, CHEMICAL, AND SEROLOGICAL MANIFESTATIONS
OF RHEUMATOID ARTHRITIS, BASED ON THE COURSE OF 154 CASES. Medicine (Baltimore) 1964; 43:41.
12. Erhardt CC, Mumford PA, Venables PJ, Maini RN. Factors predicting a poor life prognosis in rheumatoid arthritis: an eight year
prospective study. Ann Rheum Dis 1989; 48:7.
13. Listing J, Rau R, Müller B, et al. HLA-DRB1 genes, rheumatoid factor, and elevated C-reactive protein: independent risk factors of
radiographic progression in early rheumatoid arthritis. Berlin Collaborating Rheumatological Study Group. J Rheumatol 2000; 27:2100.
14. Combe B, Dougados M, Goupille P, et al. Prognostic factors for radiographic damage in early rheumatoid arthritis: a multiparameter
prospective study. Arthritis Rheum 2001; 44:1736.
15. Lindqvist E, Eberhardt K, Bendtzen K, et al. Prognostic laboratory markers of joint damage in rheumatoid arthritis. Ann Rheum Dis 2005;
64:196.
64:196.
16. van Zeben D, Hazes JM, Zwinderman AH, et al. Clinical significance of rheumatoid factors in early rheumatoid arthritis: results of a follow
up study. Ann Rheum Dis 1992; 51:1029.
17. SIEVERS K. THE RHEUMATOID FACTOR IN DEFINITE RHEUMATOID ARTHRITIS. AN ANALYSIS OF 1279 ADULT PATIENTS, WITH
A FOLLOW-UP STUDY. Acta Rheumatol Scand Suppl 1965; :SUPPL 9:1.
18. Aho K, Tuomi T, Palosuo T, et al. Is seropositive rheumatoid arthritis becoming less severe? Clin Exp Rheumatol 1989; 7:287.
19. Nielsen SF, Bojesen SE, Schnohr P, Nordestgaard BG. Elevated rheumatoid factor and long term risk of rheumatoid arthritis: a
prospective cohort study. BMJ 2012; 345:e5244.
20. Schellekens GA, de Jong BA, van den Hoogen FH, et al. Citrulline is an essential constituent of antigenic determinants recognized by
rheumatoid arthritis-specific autoantibodies. J Clin Invest 1998; 101:273.
21. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid
factor for rheumatoid arthritis. Ann Intern Med 2007; 146:797.
22. Bas S, Genevay S, Meyer O, Gabay C. Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and
prognosis of rheumatoid arthritis. Rheumatology (Oxford) 2003; 42:677.
23. Zeng X, Ai M, Tian X, et al. Diagnostic value of anti-cyclic citrullinated Peptide antibody in patients with rheumatoid arthritis. J Rheumatol
2003; 30:1451.
24. Lee DM, Schur PH. Clinical utility of the anti-CCP assay in patients with rheumatic diseases. Ann Rheum Dis 2003; 62:870.
25. van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, et al. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid
arthritis in patients with undifferentiated arthritis: a prospective cohort study. Arthritis Rheum 2004; 50:709.
26. Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a
systematic literature review. Ann Rheum Dis 2006; 65:845.
27. Fabien N, Olsson NO, Goetz J, et al. Prevalence of autoantibodies to cyclic citrullinated peptide in patients with rheumatic diseases other
than rheumatoid arthritis: a French multicenter study. Clin Rev Allergy Immunol 2008; 34:40.
28. Whiting PF, Smidt N, Sterne JA, et al. Systematic review: accuracy of anti-citrullinated Peptide antibodies for diagnosing rheumatoid
arthritis. Ann Intern Med 2010; 152:456.
29. Bobbio-Pallavicini F, Caporali R, Bugatti S, Montecucco C. What can we learn from treatment-induced changes in rheumatoid factor and
anti-citrullinated Peptide antibodies? J Rheumatol 2008; 35:1903.
30. Nijenhuis S, Zendman AJ, Vossenaar ER, et al. Autoantibodies to citrullinated proteins in rheumatoid arthritis: clinical performance and
biochemical aspects of an RA-specific marker. Clin Chim Acta 2004; 350:17.
31. Zendman AJ, van Venrooij WJ, Pruijn GJ. Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology
(Oxford) 2006; 45:20.
32. Pruijn GJ, Wiik A, van Venrooij WJ. The use of citrullinated peptides and proteins for the diagnosis of rheumatoid arthritis. Arthritis Res
Ther 2010; 12:203.
33. Elkayam O, Segal R, Lidgi M, Caspi D. Positive anti-cyclic citrullinated proteins and rheumatoid factor during active lung tuberculosis. Ann
Rheum Dis 2006; 65:1110.
34. Kakumanu P, Yamagata H, Sobel ES, et al. Patients with pulmonary tuberculosis are frequently positive for anti-cyclic citrullinated peptide
antibodies, but their sera also react with unmodified arginine-containing peptide. Arthritis Rheum 2008; 58:1576.
35. Mori S, Naito H, Ohtani S, et al. Diagnostic utility of anti-cyclic citrullinated peptide antibodies for rheumatoid arthritis in patients with
active lung tuberculosis. Clin Rheumatol 2009; 28:277.
36. Matsui T, Shimada K, Ozawa N, et al. Diagnostic utility of anti-cyclic citrullinated peptide antibodies for very early rheumatoid arthritis. J
Rheumatol 2006; 33:2390.
37. Wood AM, de Pablo P, Buckley CD, et al. Smoke exposure as a determinant of autoantibody titre in α₁-antitrypsin deficiency and COPD.
Eur Respir J 2011; 37:32.
38. Qing YF, Zhang QB, Zhou JG, et al. The detecting and clinical value of anti-cyclic citrullinated peptide antibodies in patients with systemic
lupus erythematosus. Lupus 2009; 18:713.
39. Kakumanu P, Sobel ES, Narain S, et al. Citrulline dependence of anti-cyclic citrullinated peptide antibodies in systemic lupus
erythematosus as a marker of deforming/erosive arthritis. J Rheumatol 2009; 36:2682.
40. Gottenberg JE, Mignot S, Nicaise-Rolland P, et al. Prevalence of anti-cyclic citrullinated peptide and anti-keratin antibodies in patients with
primary Sjögren's syndrome. Ann Rheum Dis 2005; 64:114.
41. Mohammed K, Pope J, Le Riche N, et al. Association of severe inflammatory polyarthritis in primary Sjögren's syndrome: clinical,
serologic, and HLA analysis. J Rheumatol 2009; 36:1937.

42. Atzeni F, Sarzi-Puttini P, Lama N, et al. Anti-cyclic citrullinated peptide antibodies in primary Sjögren syndrome may be associated with
non-erosive synovitis. Arthritis Res Ther 2008; 10:R51.
43. Chan MT, Owen P, Dunphy J, et al. Associations of erosive arthritis with anti-cyclic citrullinated peptide antibodies and MHC Class II
alleles in systemic lupus erythematosus. J Rheumatol 2008; 35:77.
44. Bogliolo L, Alpini C, Caporali R, et al. Antibodies to cyclic citrullinated peptides in psoriatic arthritis. J Rheumatol 2005; 32:511.
45. Vander Cruyssen B, Hoffman IE, Zmierczak H, et al. Anti-citrullinated peptide antibodies may occur in patients with psoriatic arthritis. Ann
Rheum Dis 2005; 64:1145.
46. Alenius GM, Berglin E, Rantapää Dahlqvist S. Antibodies against cyclic citrullinated peptide (CCP) in psoriatic patients with or without
joint inflammation. Ann Rheum Dis 2006; 65:398.
47. Böckelmann R, Gollnick H, Bonnekoh B. Anti-cyclic citrullinated peptide antibodies in psoriasis patients without arthritis. Arthritis Rheum
2006; 54:1701.
48. Meyer O, Labarre C, Dougados M, et al. Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five
year radiographic damage. Ann Rheum Dis 2003; 62:120.
49. Rönnelid J, Wick MC, Lampa J, et al. Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in
early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression. Ann Rheum Dis 2005;
64:1744.
50. Finckh A, Liang MH. Anti-cyclic citrullinated peptide antibodies in the diagnosis of rheumatoid arthritis: bayes clears the haze. Ann Intern
Med 2007; 146:816.
51. Jansen LM, van Schaardenburg D, van der Horst-Bruinsma I, et al. The predictive value of anti-cyclic citrullinated peptide antibodies in
early arthritis. J Rheumatol 2003; 30:1691.
52. van der Helm-van Mil AH, Verpoort KN, Breedveld FC, et al. Antibodies to citrullinated proteins and differences in clinical progression of
rheumatoid arthritis. Arthritis Res Ther 2005; 7:R949.
53. Quinn MA, Gough AK, Green MJ, et al. Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis
and predict radiological and functional outcome. Rheumatology (Oxford) 2006; 45:478.
54. Bukhari M, Thomson W, Naseem H, et al. The performance of anti-cyclic citrullinated peptide antibodies in predicting the severity of
radiologic damage in inflammatory polyarthritis: results from the Norfolk Arthritis Register. Arthritis Rheum 2007; 56:2929.
55. Luime JJ, Colin EM, Hazes JM, Lubberts E. Does anti-mutated citrullinated vimentin have additional value as a serological marker in the
diagnostic and prognostic investigation of patients with rheumatoid arthritis? A systematic review. Ann Rheum Dis 2010; 69:337.
56. Bang H, Egerer K, Gauliard A, et al. Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis
Rheum 2007; 56:2503.
57. Vossenaar ER, Després N, Lapointe E, et al. Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin. Arthritis Res
Ther 2004; 6:R142.
58. Harre U, Georgess D, Bang H, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated
vimentin. J Clin Invest 2012; 122:1791.
59. Syversen SW, Goll GL, van der Heijde D, et al. Prediction of radiographic progression in rheumatoid arthritis and the role of antibodies
against mutated citrullinated vimentin: results from a 10-year prospective study. Ann Rheum Dis 2010; 69:345.
60. Syversen SW, Gaarder PI, Goll GL, et al. High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict
radiographic progression in patients with rheumatoid arthritis: results from a 10-year longitudinal study. Ann Rheum Dis 2008; 67:212.
61. Young BJ, Mallya RK, Leslie RD, et al. Anti-keratin antibodies in rheumatoid arthritis. Br Med J 1979; 2:97.
62. NIENHUIS RL, MANDEMA E. A NEW SERUM FACTOR IN PATIENTS WITH RHEUMATOID ARTHRITIS; THE ANTIPERINUCLEAR
FACTOR. Ann Rheum Dis 1964; 23:302.
63. Sebbag M, Simon M, Vincent C, et al. The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid
arthritis-specific autoantibodies. J Clin Invest 1995; 95:2672.
64. Palosuo T, Lukka M, Alenius H, et al. Purification of filaggrin from human epidermis and measurement of antifilaggrin autoantibodies in
sera from patients with rheumatoid arthritis by an enzyme-linked immunosorbent assay. Int Arch Allergy Immunol 1998; 115:294.
65. Hoet R, van Venroijj WJ. The antiperinuclear factor (APF) and antikeratin antibodies (AKA) in rheumatoid arthritis. In: Rheumatoid Arthritis
, Smolen JS, Kalden JR, Maini RN (Eds), Springer-Verlag, Berlin 1992. p.299.
66. Vivino FB, Maul GG. Histologic and electron microscopic characterization of the antiperinuclear factor antigen. Arthritis Rheum 1990;
33:960.
67. Janssens X, Veys EM, Verbruggen G, Declercq L. The diagnostic significance of the antiperinuclear factor for rheumatoid arthritis. J
Rheumatol 1988; 15:1346.
68. Hoet RM, Boerbooms AM, Arends M, et al. Antiperinuclear factor, a marker autoantibody for rheumatoid arthritis: colocalisation of the
perinuclear factor and profilaggrin. Ann Rheum Dis 1991; 50:611.
69. Gomès-Daudrix V, Sebbag M, Girbal E, et al. Immunoblotting detection of so-called 'antikeratin antibodies': a new assay for the diagnosis
of rheumatoid arthritis. Ann Rheum Dis 1994; 53:735.
70. von Essen R, Kurki P, Isomäki H, et al. Prospect for an additional laboratory criterion for rheumatoid arthritis. Scand J Rheumatol 1993;
22:267.
71. Kurki P, von Essen R, Kaarela K, et al. Antibody to stratum corneum (antikeratin antibody) and antiperinuclear factor: markers for
progressive rheumatoid arthritis. Scand J Rheumatol 1997; 26:346.
72. Paimela L, Palosuo T, Aho K, et al. Association of autoantibodies to filaggrin with an active disease in early rheumatoid arthritis. Ann
Rheum Dis 2001; 60:32.
73. Kurki P, Aho K, Palosuo T, Heliövaara M. Immunopathology of rheumatoid arthritis. Antikeratin antibodies precede the clinical disease.
Arthritis Rheum 1992; 35:914.
74. Aho K, von Essen R, Kurki P, et al. Antikeratin antibody and antiperinuclear factor as markers for subclinical rheumatoid disease process.
J Rheumatol 1993; 20:1278.
75. Aho K, Palosuo T, Heliövaara M, et al. Antifilaggrin antibodies within "normal" range predict rheumatoid arthritis in a linear fashion. J
Rheumatol 2000; 27:2743.
76. Nielen MM, van der Horst AR, van Schaardenburg D, et al. Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and
prognostic value in early arthritis. Ann Rheum Dis 2005; 64:1199.
77. Vander Cruyssen B, Cantaert T, Nogueira L, et al. Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four
other anti-citrullinated protein assays. Arthritis Res Ther 2006; 8:R122.
78. Dejaco C, Klotz W, Larcher H, et al. Diagnostic value of antibodies against a modified citrullinated vimentin in rheumatoid arthritis. Arthritis
Res Ther 2006; 8:R119.
79. Koivula MK, Heliövaara M, Ramberg J, et al. Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinated
peptides predict synergistically the development of seropositive rheumatoid arthritis. Ann Rheum Dis 2007; 66:1450.
80. Lundberg K, Kinloch A, Fisher BA, et al. Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-
react with bacterial enolase. Arthritis Rheum 2008; 58:3009.
81. Nicaise Roland P, Grootenboer Mignot S, Bruns A, et al. Antibodies to mutated citrullinated vimentin for diagnosing rheumatoid arthritis in
anti-CCP-negative patients and for monitoring infliximab therapy. Arthritis Res Ther 2008; 10:R142.
82. Snir O, Widhe M, von Spee C, et al. Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis:
association with HLA-DRB1 alleles. Ann Rheum Dis 2009; 68:736.
83. Innala L, Kokkonen H, Eriksson C, et al. Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24
months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides. J Rheumatol 2008; 35:1002.
84. Hayem G, Chazerain P, Combe B, et al. Anti-Sa antibody is an accurate diagnostic and prognostic marker in adult rheumatoid arthritis. J
Rheumatol 1999; 26:7.
85. López-Longo FJ, Rodríguez-Mahou M, Sánchez-Ramón S, et al. Anti-cyclic citrullinated peptide versus anti-Sa antibodies in diagnosis of
rheumatoid arthritis in an outpatient clinic for connective tissue disease and spondyloarthritis. J Rheumatol 2006; 33:1476.
86. Maksymowych WP, Naides SJ, Bykerk V, et al. Serum 14-3-3η is a novel marker that complements current serological measurements to
enhance detection of patients with rheumatoid arthritis. J Rheumatol 2014; 41:2104.
87. van Beers-Tas MH, Marotta A, Boers M, et al. A prospective cohort study of 14-3-3η in ACPA and/or RF-positive patients with arthralgia.
Arthritis Res Ther 2016; 18:76.
88. Kay J, Morgacheva O, Messing SP, et al. Clinical disease activity and acute phase reactant levels are discordant among patients with
active rheumatoid arthritis: acute phase reactant levels contribute separately to predicting outcome at one year. Arthritis Res Ther 2014;
16:R40.
89. Lane SK, Gravel JW Jr. Clinical utility of common serum rheumatologic tests. Am Fam Physician 2002; 65:1073.
90. Donald F, Ward MM. Evaluative laboratory testing practices of United States rheumatologists. Arthritis Rheum 1998; 41:725.
91. Nam J, Villeneuve E, Emery P. The role of biomarkers in the management of patients with rheumatoid arthritis. Curr Rheumatol Rep 2009;
https://www-uptodate-com.pbidi.unam.mx:2443/contents/biologic-ma…assessment-of-rheumatoid-arthritis?source=related_link#H56835572 Página 10 de 16
11:371.
92. Dixey J, Solymossy C, Young A, Early RA Study. Is it possible to predict radiological damage in early rheumatoid arthritis (RA)? A report
on the occurrence, progression, and prognostic factors of radiological erosions over the first 3 years in 866 patients from the Early RA
Study (ERAS). J Rheumatol Suppl 2004; 69:48.
93. Bedell SE, Bush BT. Erythrocyte sedimentation rate. From folklore to facts. Am J Med 1985; 78:1001.
94. Amos RS, Constable TJ, Crockson RA, et al. Rheumatoid arthritis: relation of serum C-reactive protein and erythrocyte sedimentation
rates to radiographic changes. Br Med J 1977; 1:195.
95. Davis MJ, Dawes PT, Fowler PD, et al. Comparison and evaluation of a disease activity index for use in patients with rheumatoid arthritis.
Br J Rheumatol 1990; 29:111.
96. van der Heijde DM, van Riel PL, van Leeuwen MA, et al. Prognostic factors for radiographic damage and physical disability in early
rheumatoid arthritis. A prospective follow-up study of 147 patients. Br J Rheumatol 1992; 31:519.
97. van Leeuwen MA, van Rijswijk MH, van der Heijde DM, et al. The acute-phase response in relation to radiographic progression in early
rheumatoid arthritis: a prospective study during the first three years of the disease. Br J Rheumatol 1993; 32 Suppl 3:9.
98. Centola M, Cavet G, Shen Y, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One 2013;
8:e60635.
99. Curtis JR, van der Helm-van Mil AH, Knevel R, et al. Validation of a novel multibiomarker test to assess rheumatoid arthritis disease
activity. Arthritis Care Res (Hoboken) 2012; 64:1794.
100. van der Helm-van Mil AH, Knevel R, Cavet G, et al. An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing
radiographic progression. Rheumatology (Oxford) 2013; 52:839.
101. Markusse IM, Dirven L, van den Broek M, et al. A multibiomarker disease activity score for rheumatoid arthritis predicts radiographic joint
damage in the BeSt study. J Rheumatol 2014; 41:2114.
102. Hambardzumyan K, Bolce R, Saevarsdottir S, et al. Pretreatment multi-biomarker disease activity score and radiographic progression in
early RA: results from the SWEFOT trial. Ann Rheum Dis 2015; 74:1102.
103. Hambardzumyan K, Saevarsdottir S, Forslind K, et al. A Multi-Biomarker Disease Activity Score and the Choice of Second-Line Therapy
in Early Rheumatoid Arthritis After Methotrexate Failure. Arthritis Rheumatol 2017; 69:953.
104. Fleischmann R, Connolly SE, Maldonado MA, Schiff M. Brief Report: Estimating Disease Activity Using Multi-Biomarker Disease Activity
Scores in Rheumatoid Arthritis Patients Treated With Abatacept or Adalimumab. Arthritis Rheumatol 2016; 68:2083.
105. Reiss WG, Devenport JN, Low JM, et al. Interpreting the multi-biomarker disease activity score in the context of tocilizumab treatment for
patients with rheumatoid arthritis. Rheumatol Int 2016; 36:295.
106. Bläss S, Union A, Raymackers J, et al. The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis.
107. Hassfeld W, Steiner G, Graninger W, et al. Autoantibody to the nuclear antigen RA33: a marker for early rheumatoid arthritis. Br J
Rheumatol 1993; 32:199.
108. Hassfeld W, Steiner G, Studnicka-Benke A, et al. Autoimmune response to the spliceosome. An immunologic link between rheumatoid
arthritis, mixed connective tissue disease, and systemic lupus erythematosus. Arthritis Rheum 1995; 38:777.
109. Isenberg DA, Steiner G, Smolen JS. Clinical utility and serological connections of anti-RA33 antibodies in systemic lupus erythematosus.
J Rheumatol 1994; 21:1260.
110. Parekh RB, Dwek RA, Sutton BJ, et al. Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation
pattern of total serum IgG. Nature 1985; 316:452.
111. Rook GA, Steele J, Brealey R, et al. Changes in IgG glycoform levels are associated with remission of arthritis during pregnancy. J
Autoimmun 1991; 4:779.
112. Malhotra R, Wormald MR, Rudd PM, et al. Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via
the mannose-binding protein. Nat Med 1995; 1:237.
113. Graudal NA, Madsen HO, Tarp U, et al. The association of variant mannose-binding lectin genotypes with radiographic outcome in
rheumatoid arthritis. Arthritis Rheum 2000; 43:515.
114. Ip WK, Lau YL, Chan SY, et al. Mannose-binding lectin and rheumatoid arthritis in southern Chinese. Arthritis Rheum 2000; 43:1679.
115. Young A, Sumar N, Bodman K, et al. Agalactosyl IgG: an aid to differential diagnosis in early synovitis. Arthritis Rheum 1991; 34:1425.
116. Saulot V, Vittecoq O, Charlionet R, et al. Presence of autoantibodies to the glycolytic enzyme alpha-enolase in sera from patients with
early rheumatoid arthritis. Arthritis Rheum 2002; 46:1196.
117. van Gaalen FA, Toes RE, Ditzel HJ, et al. Association of autoantibodies to glucose-6-phosphate isomerase with extraarticular
complications in rheumatoid arthritis. Arthritis Rheum 2004; 50:395.
118. Mewar D, Moore DJ, Young-Min S, et al. Antiferritin antibodies discovered by phage display expression cloning are associated with
radiographic damage in rheumatoid arthritis. Arthritis Rheum 2005; 52:3868.
119. Zhao J, Zhao Y, He J, et al. Prevalence and significance of anti-peptidylarginine deiminase 4 antibodies in rheumatoid arthritis. J
Rheumatol 2008; 35:969.
120. Berner B, Wolf G, Hummel KM, et al. Increased expression of CD40 ligand (CD154) on CD4+ T cells as a marker of disease activity in
rheumatoid arthritis. Ann Rheum Dis 2000; 59:190.
121. Wouters D, Voskuyl AE, Molenaar ET, et al. Evaluation of classical complement pathway activation in rheumatoid arthritis: measurement
of C1q-C4 complexes as novel activation products. Arthritis Rheum 2006; 54:1143.
122. Constantin A, Lauwers-Cancès V, Navaux F, et al. Stromelysin 1 (matrix metalloproteinase 3) and HLA-DRB1 gene polymorphisms:
Association with severity and progression of rheumatoid arthritis in a prospective study. Arthritis Rheum 2002; 46:1754.
123. Lard LR, van Gaalen FA, Schonkeren JJ, et al. Association of the -2849 interleukin-10 promoter polymorphism with autoantibody
production and joint destruction in rheumatoid arthritis. Arthritis Rheum 2003; 48:1841.
124. Emery P, Bradley H, Arthur V, et al. Genetic factors influencing the outcome of early arthritis--the role of sulphoxidation status. Br J
Rheumatol 1992; 31:449.
125. van Leeuwen MA, Westra J, Limburg PC, et al. Clinical significance of interleukin-6 measurement in early rheumatoid arthritis: relation
with laboratory and clinical variables and radiological progression in a three year prospective study. Ann Rheum Dis 1995; 54:674.
126. Engström-Laurent A, Hällgren R. Circulating hyaluronate in rheumatoid arthritis: relationship to inflammatory activity and the effect of
corticosteroid therapy. Ann Rheum Dis 1985; 44:83.
127. Poole AR, Witter J, Roberts N, et al. Inflammation and cartilage metabolism in rheumatoid arthritis. Studies of the blood markers
hyaluronic acid, orosomucoid, and keratan sulfate. Arthritis Rheum 1990; 33:790.
128. Dahl IM, Husby G. Hyaluronic acid production in vitro by synovial lining cells from normal and rheumatoid joints. Ann Rheum Dis 1985;
44:647.
129. Paimela L, Heiskanen A, Kurki P, et al. Serum hyaluronate level as a predictor of radiologic progression in early rheumatoid arthritis.
130. Manicourt DH, Poilvache P, Nzeusseu A, et al. Serum levels of hyaluronan, antigenic keratan sulfate, matrix metalloproteinase 3, and
tissue inhibitor of metalloproteinases 1 change predictably in rheumatoid arthritis patients who have begun activity after a night of bed
rest. Arthritis Rheum 1999; 42:1861.
131. Yamanaka H, Matsuda Y, Tanaka M, et al. Serum matrix metalloproteinase 3 as a predictor of the degree of joint destruction during the six
months after measurement, in patients with early rheumatoid arthritis. Arthritis Rheum 2000; 43:852.
132. Green MJ, Gough AK, Devlin J, et al. Serum MMP-3 and MMP-1 and progression of joint damage in early rheumatoid arthritis.
Rheumatology (Oxford) 2003; 42:83.
133. Masuda M, Morimoto T, De Haas M, et al. Increase of soluble FcgRIIIa derived from natural killer cells and macrophages in plasma from
patients with rheumatoid arthritis. J Rheumatol 2003; 30:1911.
134. Forslind K, Eberhardt K, Jonsson A, Saxne T. Increased serum concentrations of cartilage oligomeric matrix protein. A prognostic marker
in early rheumatoid arthritis. Br J Rheumatol 1992; 31:593.
135. Månsson B, Carey D, Alini M, et al. Cartilage and bone metabolism in rheumatoid arthritis. Differences between rapid and slow
progression of disease identified by serum markers of cartilage metabolism. J Clin Invest 1995; 95:1071.
136. Månsson B, Geborek P, Saxne T. Cartilage and bone macromolecules in knee joint synovial fluid in rheumatoid arthritis: relation to
development of knee or hip joint destruction. Ann Rheum Dis 1997; 56:91.
137. Saxne T, Heinegård D. Synovial fluid analysis of two groups of proteoglycan epitopes distinguishes early and late cartilage lesions.
138. Garnero P, Landewé R, Boers M, et al. Association of baseline levels of markers of bone and cartilage degradation with long-term
progression of joint damage in patients with early rheumatoid arthritis: the COBRA study. Arthritis Rheum 2002; 46:2847.
139. Landewé R, Geusens P, Boers M, et al. Markers for type II collagen breakdown predict the effect of disease-modifying treatment on long-
term radiographic progression in patients with rheumatoid arthritis. Arthritis Rheum 2004; 50:1390.
140. Charni N, Juillet F, Garnero P. Urinary type II collagen helical peptide (HELIX-II) as a new biochemical marker of cartilage degradation in
patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 2005; 52:1081.
141. Young-Min S, Cawston T, Marshall N, et al. Biomarkers predict radiographic progression in early rheumatoid arthritis and perform well
compared with traditional markers. Arthritis Rheum 2007; 56:3236.
142. Saxne T, Zunino L, Heinegård D. Increased release of bone sialoprotein into synovial fluid reflects tissue destruction in rheumatoid
arthritis. Arthritis Rheum 1995; 38:82.
143. Kollerup G, Hansen M, Hørslev-Petersen K. Urinary hydroxypyridinium cross-links of collagen in rheumatoid arthritis. Relation to disease
activity and effects of methylprednisolone. Br J Rheumatol 1994; 33:816.
144. Paimela L, Leirisalo-Repo M, Risteli L, et al. Type I collagen degradation product in serum of patients with early rheumatoid arthritis:
relationship to disease activity and radiological progression in a 3-year follow-up. Br J Rheumatol 1994; 33:1012.
145. Aman S, Risteli J, Luukkainen R, et al. The value of synovial fluid analysis in the assessment of knee joint destruction in arthritis in a three
year follow up study. Ann Rheum Dis 1999; 58:559.
146. Hakala M, Risteli J, Aman S, et al. Combination drug strategy in recent-onset rheumatoid arthritis suppresses collagen I degradation and
is associated with retardation of radiological progression. Scand J Rheumatol 2008; 37:90.
147. Geusens PP, Landewé RB, Garnero P, et al. The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later
joint destruction. Arthritis Rheum 2006; 54:1772.
148. Harada M, Mitsuyama K, Yoshida H, et al. Vascular endothelial growth factor in patients with rheumatoid arthritis. Scand J Rheumatol
1998; 27:377.
149. Ballara S, Taylor PC, Reusch P, et al. Raised serum vascular endothelial growth factor levels are associated with destructive change in
inflammatory arthritis. Arthritis Rheum 2001; 44:2055.
150. Nagashima M, Wauke K, Hirano D, et al. Effects of combinations of anti-rheumatic drugs on the production of vascular endothelial growth
factor and basic fibroblast growth factor in cultured synoviocytes and patients with rheumatoid arthritis. Rheumatology (Oxford) 2000;
39:1255.
151. Rioja I, Hughes FJ, Sharp CH, et al. Potential novel biomarkers of disease activity in rheumatoid arthritis patients: CXCL13, CCL23,
transforming growth factor alpha, tumor necrosis factor receptor superfamily member 9, and macrophage colony-stimulating factor.
Topic 7503 Version 16.0

Biologic Markers in The Diagnosis and Assessment of Rheumatoid Arthritis - UpToDate

Uploaded by

Copyright:

Available Formats

Biologic Markers in The Diagnosis and Assessment of Rheumatoid Arthritis - UpToDate

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Biologic Markers in The Diagnosis and Assessment of Rheumatoid Arthritis - UpToDate

Uploaded by

Copyright:

Available Formats

What are some biomarkers that are useful for diagnosing rheumatoid arthritis?

What biomarkers can help predict prognosis in rheumatoid arthritis patients?

Biologic markers in the diagnosis and assessment of rheumatoid arthritis - UpToDate 11/10/17 15'48

This analysis included the following findings:

● Anti-p68 (BiP) antibodies [106]

In addition to the shared epitope, other reported genetic associations include:

● Matrix metalloproteinase (MMP) genotype polymorphisms and RA disease severity [122]

Use of UpToDate is subject to the Subscription and License Agreement.

serologic, and HLA analysis. J Rheumatol 2009; 36:1937.

Topic 7503 Version 16.0

You might also like