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خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده: مورد

Biologic markers in the assessment of rheumatoid arthritis

Biologic markers in the assessment of rheumatoid arthritis
Authors:
Bent Deleuran, DMSc
Stinne R Greisen, MD, PhD
Section Editor:
James R O'Dell, MD
Deputy Editor:
Philip Seo, MD, MHS
Literature review current through: May 2025. | This topic last updated: Jul 02, 2025.

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 National Institutes of Health in the United States has defined a 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" [1,2].

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 as well as others proposed for such use that may serve as aids in diagnosing RA, predicting prognosis, and assessing disease activity. Genetic features of RA and clinical findings or associations that may have prognostic or diagnostic implications, as well as 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".)

●(See "Disease outcome and functional capacity in rheumatoid arthritis".)

●(See "Overview of the management of rheumatoid arthritis in adults", section on 'Prognosis'.)

●(See "Diagnosis and differential diagnosis of rheumatoid arthritis".)

●(See "Rheumatoid factor: Biology and utility of measurement".)

●(See "Acute phase reactants".)

USE IN PROGNOSIS — 

The presence of rheumatoid factor (RF) or anti-citrullinated peptide antibodies (ACPA) also predicts poorer functional and radiographic outcomes. However, prognosis varies widely within seropositive and seronegative patient populations. It is important to remember that biomarkers are primarily predictive on a group level. No biomarker has yet been judged so specific that it can be used on an individual level.

Other commercially available biomarkers may provide additional useful information but require further study. (See '14-3-3eta' below.)

Rheumatoid factor — High-titer RF appears to be a 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]. Most TNF inhibitors used in the treatment of rheumatoid arthritis (RA) are monoclonal antibodies or receptor constructs with an Fc region (Fc-mAbs) that can be bound by RF. By contrast, certolizumab pegol is a Fab that lacks an Fc region. Binding of IgM-RF to Fc-mAbs enables the formation of large protein complexes, which are subsequently internalized and undergo lysosomal degradation by macrophages. In a post hoc analysis of the phase 4 EXXELERATE trial, which included biologic disease-modifying antirheumatic drug (bDMARD)-naïve patients with RA, certolizumab pegol-treated patients with the highest quartile RF levels in the study (>204 international units/mL) exhibited similar drug concentrations and clinical responses as patients with RA and lower RF levels. By contrast, patients with RA and high RF levels treated with adalimumab had lower drug concentrations and poorer clinical outcomes than adalimumab-treated patients with low RF levels [4]. (See "Rheumatoid factor: Biology and utility of measurement" and "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis".)

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 [5-11]. As examples:

●Rheumatoid nodules and vasculitis occur almost exclusively in seropositive patients [7-10,12]; these findings are associated with increased mortality [13].

●Radiographic progression may be more rapid among patients with a positive RF at initial evaluation [14-16].

●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 [17].

The presence of RF, particularly at high levels, may antedate the clinical development of RA [18]. These issues are discussed in detail elsewhere. (See "Rheumatoid factor: Biology and utility of measurement", section on 'Healthy individuals' and "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis".)

Anti-citrullinated peptide antibodies (ACPA) — Enzyme-linked immunosorbent assays (ELISA) for anti-cyclic citrullinated peptide (anti-CCP) antibodies 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.)

Importantly, a decrease in ACPA titers can be seen in patients treated effectively, particularly if treated early with nonbiologic or biologic DMARDs, but is less frequent and of a lesser magnitude than the decrease in immunoglobulin M (IgM) RF that may be seen in such patients [19].

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".)

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 — In an ELISA 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 or anti-CCP-3), have improved sensitivity and specificity compared with the original anti-CCP assays.

ACPA have been reported in other disease including several autoimmune rheumatic diseases (eg, systemic lupus erythematosus, psoriatic arthritis) [20-29], tuberculosis [30-32], and sometimes chronic lung disease [30-35].

Anti-CCP and rheumatoid arthritis prognosis — ACPA-positive patients with early RA are at increased risk of progressive joint damage [11,16,36-38], and ACPA testing may predict erosive disease more effectively than RF [39,40]. The prediction of a more erosive outcome is strengthened when ACPA is positive and the patient is smoking at the same time. 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 [37]. The presence of ACPA was also predictive of more rapid radiographic progression in two studies of 183 and 279 Swedish patients with early RA [16,38] and in the BeSt (Behandelstrategieën voor Reumatoide Artritis [Treatment Strategies for Rheumatoid Arthritis]) trial of 508 Dutch patients [11].

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 [41]. 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 [42-44].

Anti-MCV antibodies — A commercial assay for anti-mutated citrullinated vimentin (anti-MCV) is available. Anti-MCV antibodies may be associated with more severe disease than anti-CCP antibodies and may be comparable to anti-CCP in predicting radiographic progression [45-47].

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 [46,48], and since vimentin is expressed and appears to be implicated in pathogenesis, it is a candidate biomarker [49]. Vimentin is a widely expressed intermediate filament. It becomes citrullinated through deamination, which occurs in macrophages undergoing apoptosis.

Although it is interesting from a pathogenic viewpoint, it has added little to our ability to predict outcome in clinical practice. As examples, the presence of antibodies to citrullinated fibrinogen, citrullinated vimentin (anti-Sa), citrullinated synthetic type I or type II collagen telopeptides, and alpha-enolase may have sensitivity and specificity similar to that of anti-CCP testing [46,50-56].

The 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 [45]. 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 [57]. 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 [58].

Other ACPA — 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 posttranslational modification of arginine [59-73].

Antibodies to other citrullinated proteins include antibodies to citrullinated fibrinogen, citrullinated vimentin (anti-Sa), citrullinated synthetic type I or type II collagen telopeptides, and alpha-enolase [46-48,50-56,74,75]. A commercial assay for anti-mutated citrullinated vimentin is also available. (See 'Anti-MCV antibodies' above.)

Anti-CarP — Anti-carbamylated protein (anti-CarP) antibodies are a class of autoantibodies identified in patients with RA. Carbamylation is a posttranslational modification where lysine residues are converted into homocitrulline. Anti-CarP antibodies target these modified proteins and have been detected in 30 to 45 percent of RA patients [76,77]. As for ACPA and IgM-RF, Anti-CarP can be detected in individuals before the clinical onset of RA. Being triple positive for IgM-RF, ACPA, and anti-CarP results in an increased risk of developing more severe disease outcome.

Anti-CarP antibodies are emerging as additional valuable biomarkers in RA, especially in diagnosing ACPA-negative patients or as a predicting tool in triple-positive RA patients.

Anti-collagen-II antibodies — Antibodies towards collagen-II are seen in 30 to 50 percent of patients with RA but have also been reported in many other arthritic diseases. High levels of anti-collagen-II antibodies only predict radiographic destruction in a low number of RA patients [78,79].

DISEASE ACTIVITY AND PROGNOSIS: ACUTE PHASE REACTANTS — 

The main clinically useful biologic markers (biomarkers) 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/hour with CRP ≤0.8 mg/dL or ESR ≤28 mm/hour with CRP >0.8 mg/dL) in approximately one-quarter of patients in a large practice-based registry, regardless of the level of disease activity [80].

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 [81-83]. 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) [15,16,84].

The rate at which erythrocytes fall through plasma, the ESR, depends largely upon the plasma concentration of fibrinogen [85]. 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 [15,16,86]. 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 [87]. 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 [DAS]) and DR4 and RF positivity [88].

Another study assessed progression of radiologic damage in 110 patients with early RA who had symptoms for less than one year [89]. A highly significant correlation between radiologic progression and cumulative CRP production was noted [89]. 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 DR4 (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 [90,91]. 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 initially testing 130 candidate biomarkers in feasibility studies, then selecting 25 for algorithm training [90]. Multi-biomarker statistical models outperformed individual biomarkers at estimating disease activity assessed by the DAS using a 28-joint count and CRP 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 [92-94]. 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 [92].

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 [95]. However, post hoc analysis of data from the AMPLE ("abatacept versus adalimumab comparison in biologic-naïve RA subjects with background methotrexate") trial has been interpreted as indicating that the MBDA score cannot reliably be used to guide decision making in RA management, particularly for patients who receive abatacept or adalimumab as a first biologic agent [96]. Furthermore, as interleukin 6 (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 [97]. Based on this, MBDA has therefore not gained widespread use as a predictive parameter of RA.

INVESTIGATIONAL AND 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 [98]

●Anti-RA33 antibodies [15,99-101]

●Gal 0 glycoforms [102-107]

●Antibodies to alpha-enolase [108]

●Antibodies to glucose phosphate isomerase (GPI) [109]

●Antibodies to ferritin [110]

●Antibodies to the enzyme peptidyl-arginine deiminase 4 (PADI4) [111]

Other immune changes investigated as potential biomarkers in RA include enhanced expression of CD40 ligand (CD154) on activated T cells [112] and markers of complement activation, including the concentration of covalently linked C1q-C4 complement components [113].

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 DR (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 [114]

●Interleukin 10 (IL-10) promoter genotype polymorphisms and RA severity but not susceptibility [115]

●Sulfoxidation status and risk of disease persistence among patients with early RA [116]

In established RA, a longitudinal genomic analysis using serial ribonucleic acid (RNA) sequencing of RA blood samples revealed that preinflammatory mesenchymal cells and B cells are present one to two weeks before clinical flare of the arthritis, suggesting that activation of the flare in synovitis takes place outside the joint [117].

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 [118]. 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' below), other products of the synovium may be markers of disease activity and have prognostic implications. These include serum hyaluronan [119-123] and MMP, including MMP-1 and MMP-3 [124,125]. Elevated serum levels of immunoglobulin soluble receptor (Fc gamma RIIIa) in RA are thought to be due to synovial macrophages and/or natural killer cells [126].

●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 [127,128]; the aggrecan content of synovial fluid [129,130]; a putative marker of cartilage aggrecan synthesis, epitope 846, located on the chondroitin sulphate-rich area of the aggrecan molecule [128]; measurement of crosslinked c-terminal peptides from type II collagen (CTX-II) in urine [131,132]; and a peptide derived from the helical portion of type II collagen (HELIX-II) that may be detected in the urine [133].

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 [134].

●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 measured in synovial fluid [135]; measurement of pyridinoline crosslinks, a marker of bone degradation, that may be detected in urine [136]; measurement of crosslinked carboxyterminal telopeptides of type I collagen (ICTP), a larger serum marker for bone collagen degradation [131,137-139]; 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]) [140].

●Vascular markers – Serum vascular endothelial factor (VEGF) concentrations are elevated in RA patients compared with healthy controls and with patients with osteoarthritis [141-143], and elevated levels in patients with early RA correlate with the degree of radiographically assessed joint damage over the subsequent year [142].

●Plasma proteins – In a proteomic approach, 163 plasma proteins were evaluated in 44 patients with RA to determine which were associated with disease activity [144]. 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 alpha (TGF-alpha), and chemokine C-X-C motif ligand 13 (CXCL13). High serum levels of CXCL13 have been shown to predict long-term radiographic progression and lower response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) [145].

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 [146]. 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 [147].

An assay for serum 14-3-3eta is commercially available but is not widely used, as serum 14-3-3eta cannot predict clinical remission in a treat-to-target setup of RA [148].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Erythrocyte sedimentation rate (The Basics)")

SUMMARY

●Definitions – 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.)

●Use in diagnosis – The main clinically useful biomarkers for the diagnosis of RA are RF and anti-citrullinated peptide antibodies (ACPA).

●Assessing prognosis – 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 factor' above and 'Anti-CCP antibodies' above and '14-3-3eta' above.)

●Assessing disease activity – The main clinically useful biomarkers 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.)

●Investigational biomarkers – Biomarkers that remain investigational include (see 'Investigational and 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 peptide (anti-CCP) antibodies 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 10 (IL-10) promoter genotype, and sulfoxidation 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)

•Serum 14-3-3eta, an isoform of the 14-3-3 family of intracellular chaperonin proteins, which has been proposed as an additional useful diagnostic marker (see '14-3-3eta' above)

ACKNOWLEDGMENTS — 

The editorial staff at UpToDate acknowledge Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS, and Peter Taylor, MA, PhD, FRCP, who contributed to an earlier version of this topic review.

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Topic 7503 Version 34.0

References

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20 : The detecting and clinical value of anti-cyclic citrullinated peptide antibodies in patients with systemic lupus erythematosus.

21 : Citrulline dependence of anti-cyclic citrullinated peptide antibodies in systemic lupus erythematosus as a marker of deforming/erosive arthritis.

22 : Prevalence of anti-cyclic citrullinated peptide and anti-keratin antibodies in patients with primary Sjögren's syndrome.

23 : Association of severe inflammatory polyarthritis in primary Sjögren's syndrome: clinical, serologic, and HLA analysis.

24 : Anti-cyclic citrullinated peptide antibodies in primary Sjögren syndrome may be associated with non-erosive synovitis.

25 : Associations of erosive arthritis with anti-cyclic citrullinated peptide antibodies and MHC Class II alleles in systemic lupus erythematosus.

26 : Antibodies to cyclic citrullinated peptides in psoriatic arthritis.

27 : Anti-citrullinated peptide antibodies may occur in patients with psoriatic arthritis.

28 : Antibodies against cyclic citrullinated peptide (CCP) in psoriatic patients with or without joint inflammation.

29 : Anti-cyclic citrullinated peptide antibodies in psoriasis patients without arthritis.

30 : Positive anti-cyclic citrullinated proteins and rheumatoid factor during active lung tuberculosis.

31 : Patients with pulmonary tuberculosis are frequently positive for anti-cyclic citrullinated peptide antibodies, but their sera also react with unmodified arginine-containing peptide.

32 : Diagnostic utility of anti-cyclic citrullinated peptide antibodies for rheumatoid arthritis in patients with active lung tuberculosis.

33 : Prevalence of autoantibodies to cyclic citrullinated peptide in patients with rheumatic diseases other than rheumatoid arthritis: a French multicenter study.

34 : Diagnostic utility of anti-cyclic citrullinated peptide antibodies for very early rheumatoid arthritis.

35 : Smoke exposure as a determinant of autoantibody titre inα₁-antitrypsin deficiency and COPD.

36 : Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis.

37 : Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage.

38 : 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.

39 : Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis.

40 : Anti-cyclic citrullinated peptide antibodies in the diagnosis of rheumatoid arthritis: bayes clears the haze.

41 : The predictive value of anti-cyclic citrullinated peptide antibodies in early arthritis.

42 : Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis.

43 : Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radiological and functional outcome.

44 : The performance of anti-cyclic citrullinated peptide antibodies in predicting the severity of radiologic damage in inflammatory polyarthritis: results from the Norfolk Arthritis Register.

45 : 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.

46 : Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis.

47 : 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.

48 : Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin.

49 : Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin.

50 : Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis.

51 : Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four other anti-citrullinated protein assays.

52 : Diagnostic value of antibodies against a modified citrullinated vimentin in rheumatoid arthritis.

53 : Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinated peptides predict synergistically the development of seropositive rheumatoid arthritis.

54 : Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase.

55 : Antibodies to mutated citrullinated vimentin for diagnosing rheumatoid arthritis in anti-CCP-negative patients and for monitoring infliximab therapy.

56 : Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles.

57 : Prediction of radiographic progression in rheumatoid arthritis and the role of antibodies against mutated citrullinated vimentin: results from a 10-year prospective study.

58 : 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.

59 : Anti-keratin antibodies in rheumatoid arthritis.

60 : A NEW SERUM FACTOR IN PATIENTS WITH RHEUMATOID ARTHRITIS; THE ANTIPERINUCLEAR FACTOR.

61 : The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies.

62 : Purification of filaggrin from human epidermis and measurement of antifilaggrin autoantibodies in sera from patients with rheumatoid arthritis by an enzyme-linked immunosorbent assay.

63 : Purification of filaggrin from human epidermis and measurement of antifilaggrin autoantibodies in sera from patients with rheumatoid arthritis by an enzyme-linked immunosorbent assay.

64 : Histologic and electron microscopic characterization of the antiperinuclear factor antigen.

65 : The diagnostic significance of the antiperinuclear factor for rheumatoid arthritis.

66 : Antiperinuclear factor, a marker autoantibody for rheumatoid arthritis: colocalisation of the perinuclear factor and profilaggrin.

67 : Immunoblotting detection of so-called 'antikeratin antibodies': a new assay for the diagnosis of rheumatoid arthritis.

68 : Prospect for an additional laboratory criterion for rheumatoid arthritis.

69 : Antibody to stratum corneum (antikeratin antibody) and antiperinuclear factor: markers for progressive rheumatoid arthritis.

70 : Association of autoantibodies to filaggrin with an active disease in early rheumatoid arthritis.

71 : Immunopathology of rheumatoid arthritis. Antikeratin antibodies precede the clinical disease.

72 : Antikeratin antibody and antiperinuclear factor as markers for subclinical rheumatoid disease process.

73 : Antifilaggrin antibodies within "normal" range predict rheumatoid arthritis in a linear fashion.

74 : Anti-Sa antibody is an accurate diagnostic and prognostic marker in adult rheumatoid arthritis.

75 : Anti-cyclic citrullinated peptide versus anti-Sa antibodies in diagnosis of rheumatoid arthritis in an outpatient clinic for connective tissue disease and spondyloarthritis.

76 : Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage.

77 : The role of Anti-PAD4, Anti-CarP, and Anti-RA33 antibodies combined with RF and ACPA in predicting abatacept response in rheumatoid arthritis.

78 : Autoantibodies to type II collagen: occurrence in rheumatoid arthritis, other arthritides, autoimmune connective tissue diseases, and chronic inflammatory syndromes.

79 : Anti-type II collagen antibodies are associated with early radiographic destruction in rheumatoid arthritis.

80 : 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.

81 : Clinical utility of common serum rheumatologic tests.

82 : Evaluative laboratory testing practices of United States rheumatologists.

83 : The role of biomarkers in the management of patients with rheumatoid arthritis.

84 : 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).

85 : Erythrocyte sedimentation rate. From folklore to facts.

86 : Rheumatoid arthritis: relation of serum C-reactive protein and erythrocyte sedimentation rates to radiographic changes.

87 : Comparison and evaluation of a disease activity index for use in patients with rheumatoid arthritis.

88 : Prognostic factors for radiographic damage and physical disability in early rheumatoid arthritis. A prospective follow-up study of 147 patients.

89 : The acute-phase response in relation to radiographic progression in early rheumatoid arthritis: a prospective study during the first three years of the disease.

90 : Development of a multi-biomarker disease activity test for rheumatoid arthritis.

91 : Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity.

92 : An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing radiographic progression.

93 : A multibiomarker disease activity score for rheumatoid arthritis predicts radiographic joint damage in the BeSt study.

94 : Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial.

95 : A Multi-Biomarker Disease Activity Score and the Choice of Second-Line Therapy in Early Rheumatoid Arthritis After Methotrexate Failure.

96 : Brief Report: Estimating Disease Activity Using Multi-Biomarker Disease Activity Scores in Rheumatoid Arthritis Patients Treated With Abatacept or Adalimumab.

97 : Interpreting the multi-biomarker disease activity score in the context of tocilizumab treatment for patients with rheumatoid arthritis.

98 : The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis.

99 : Autoantibody to the nuclear antigen RA33: a marker for early rheumatoid arthritis.

100 : Autoimmune response to the spliceosome. An immunologic link between rheumatoid arthritis, mixed connective tissue disease, and systemic lupus erythematosus.

101 : Clinical utility and serological connections of anti-RA33 antibodies in systemic lupus erythematosus.

102 : Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG.

103 : Changes in IgG glycoform levels are associated with remission of arthritis during pregnancy.

104 : Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein.

105 : The association of variant mannose-binding lectin genotypes with radiographic outcome in rheumatoid arthritis.

106 : Mannose-binding lectin and rheumatoid arthritis in southern Chinese.

107 : Agalactosyl IgG: an aid to differential diagnosis in early synovitis.

108 : Presence of autoantibodies to the glycolytic enzyme alpha-enolase in sera from patients with early rheumatoid arthritis.

109 : Association of autoantibodies to glucose-6-phosphate isomerase with extraarticular complications in rheumatoid arthritis.

110 : Antiferritin antibodies discovered by phage display expression cloning are associated with radiographic damage in rheumatoid arthritis.

111 : Prevalence and significance of anti-peptidylarginine deiminase 4 antibodies in rheumatoid arthritis.

112 : Increased expression of CD40 ligand (CD154) on CD4+ T cells as a marker of disease activity in rheumatoid arthritis.

113 : Evaluation of classical complement pathway activation in rheumatoid arthritis: measurement of C1q-C4 complexes as novel activation products.

114 : Stromelysin 1 (matrix metalloproteinase 3) and HLA-DRB1 gene polymorphisms: Association with severity and progression of rheumatoid arthritis in a prospective study.

115 : Association of the -2849 interleukin-10 promoter polymorphism with autoantibody production and joint destruction in rheumatoid arthritis.

116 : Genetic factors influencing the outcome of early arthritis--the role of sulphoxidation status.

117 : RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares.

118 : 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.

119 : Circulating hyaluronate in rheumatoid arthritis: relationship to inflammatory activity and the effect of corticosteroid therapy.

120 : Inflammation and cartilage metabolism in rheumatoid arthritis. Studies of the blood markers hyaluronic acid, orosomucoid, and keratan sulfate.

121 : Hyaluronic acid production in vitro by synovial lining cells from normal and rheumatoid joints.

122 : Serum hyaluronate level as a predictor of radiologic progression in early rheumatoid arthritis.

123 : 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.

124 : 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.

125 : Serum MMP-3 and MMP-1 and progression of joint damage in early rheumatoid arthritis.

126 : Increase of soluble FcgRIIIa derived from natural killer cells and macrophages in plasma from patients with rheumatoid arthritis.

127 : Increased serum concentrations of cartilage oligomeric matrix protein. A prognostic marker in early rheumatoid arthritis.

128 : Cartilage and bone metabolism in rheumatoid arthritis. Differences between rapid and slow progression of disease identified by serum markers of cartilage metabolism.

129 : Cartilage and bone macromolecules in knee joint synovial fluid in rheumatoid arthritis: relation to development of knee or hip joint destruction.

130 : Synovial fluid analysis of two groups of proteoglycan epitopes distinguishes early and late cartilage lesions.

131 : 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.

132 : Markers for type II collagen breakdown predict the effect of disease-modifying treatment on long-term radiographic progression in patients with rheumatoid arthritis.

133 : Urinary type II collagen helical peptide (HELIX-II) as a new biochemical marker of cartilage degradation in patients with osteoarthritis and rheumatoid arthritis.

134 : Biomarkers predict radiographic progression in early rheumatoid arthritis and perform well compared with traditional markers.

135 : Increased release of bone sialoprotein into synovial fluid reflects tissue destruction in rheumatoid arthritis.

136 : Urinary hydroxypyridinium cross-links of collagen in rheumatoid arthritis. Relation to disease activity and effects of methylprednisolone.

137 : 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.

138 : The value of synovial fluid analysis in the assessment of knee joint destruction in arthritis in a three year follow up study.

139 : Combination drug strategy in recent-onset rheumatoid arthritis suppresses collagen I degradation and is associated with retardation of radiological progression.

140 : The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction.

141 : Vascular endothelial growth factor in patients with rheumatoid arthritis.

142 : Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis.

143 : 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.

144 : 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.

145 : CXCL13 predicts long-term radiographic status in early rheumatoid arthritis.

146 : Serum 14-3-3ηis a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis.

147 : A prospective cohort study of 14-3-3ηin ACPA and/or RF-positive patients with arthralgia.

148 : Serum 14-3-3ηas predictor of clinical remission and progression of structural damage in early rheumatoid arthritis following a treat-to-target strategy in a randomized controlled trial.

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