Inflammatory markers in patients with rheumatoid arthritis (2023)

Table of Contents
Allergologia et Immunopathologia Abstract Background Methods Results Conclusions Introduction Section snippets Methods Results Discussion Conflict of interest Funding statement Confidentiality of data Right to privacy and informed consent Protection of human and animal subjects References (33) Clin Biochem Semin Arthritis Rheum Clin Biochem Am J Med Sci Pharmacol Ther Lancet New concepts in the treatment of rheumatoid arthritis Annu Rev Med High sensitivity C-reactive protein is associated with lower tibial cartilage volume but not lower patella cartilage volume in healthy women at mid-life Arthritis Res Ther Inflammation and rheumatoid arthritis J Physiol Biochem Increased levels of C-reactive protein in serum from blood donors before the onset of rheumatoid arthritis Arthritis Rheum Cytokine blockade as a new strategy to treat rheumatoid arthritis: inhibition of tumor necrosis factor Arch Intern Med Cytokines in the pathogenesis of rheumatoid arthritis Nat Rev Immunol Interleukin-10 Interleukin-16 and Interferon-γ in serum of patients with rheumatoid arthritis and correlation with disease activity Egypt J Hosp Med The American Rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis Arthritis Rheum Combined anti-tumor necrosis factor-α therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone Front Immunol Relationship between time-integrated C-reactive protein levels and radiologic progression in patients with rheumatoid arthritis Arthritis Rheum Cited by (41) Recommended articles (6) FAQs Videos
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Allergologia et Immunopathologia

Volume 43, Issue 1,

January–February 2015

, Pages 81-87

Abstract

Background

Autoimmune diseases such as rheumatoid arthritis (RA) are the consequence of a persistent imbalance between pro- and anti-inflammatory immune mechanisms, leading to chronic inflammation. The objective of this study was to determine whether the high sensitive C-reactive protein (hs-CRP) and cytokines are elevated in RA patients and to investigate the relationship between these markers and disease activity in RA, measured by disease activity score 28 (DAS28).

Methods

We studied 110 RA patients according to American College of Rheumatology revised criteria for RA, and 55 controls matched by age and sex. Serum levels of hs-CRP and cytokines interleukin (IL)-6, IL-10 and tumour necrosis factor-α (TNF-α) were estimated and correlated with the DAS28. Serum hs-CRP was assayed immunoturbidimetrically and cytokines were analysed by commercially available ELISA kit.

Results

We found that RA patients had significantly higher levels of serum hs-CRP (p<0.001), IL-6 (p<0.001), TNF-α (p<0.001), and IL-10 (p<0.01) as compared to healthy controls. hs-CRP, IL-6 and TNF-α correlated positively (p<0.001) and IL-10 correlated negatively (p<0.01) with DAS28.

Conclusions

These results demonstrate that RA patients have high levels of inflammatory markers, and these levels are correlated with the DAS28. These findings suggest a possible role of these markers in the pathogenesis of RA. Moreover, these biomarkers can be used as markers of disease activity in the diagnosis and treatment of RA.

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that is characterised by polyarthritis with often progressive joint damage and disability, immunological abnormalities, systemic inflammation, increased co-morbidity, and premature mortality. It affects 1% of the adult population worldwide and also occurs among one in a thousand children as juvenile RA. RA is much more common in women and affects women 2–3 times more frequently than men, and during pregnancy 70% of women suffering from RA experience remission, with flare-ups after birth.1 The aetiology of RA is not known, but it is classified as one of the autoimmune diseases.2 It is associated with reduced life expectancy and a major cause of chronic disability and handicap, and conditions become more dangerous with time. Many studies have shown that advance therapy including the use of early, aggressive therapy, and the introduction of anti-cytokines agent have improved patient's quality of life, eased clinical symptoms, retarded the progression of joint destruction, and delayed disability.3

Inflammatory processes play a pivotal role in the pathogenesis of RA. Markers of inflammation such as C-reactive protein (CRP), interleukin (IL)-6, tumour necrosis factor (TNF)-α and anti-inflammatory marker IL-10 are highly expressed in synovium fluid and serum of arthritic patients and play an important role in the pathophysiology of RA. CRP is an acute-phase protein produced by hepatocytes, upon stimulation by the cytokines IL-1, IL-6 and TNF-α, during an acute-phase response.4, 5 CRP is a general marker of systemic inflammation and is elevated in patients with RA. Some studies reported a higher frequency of increased CRP concentrations in serum samples of RA patients before the onset of RA.6

In RA, several cytokines are involved in almost all aspects of articular inflammation and destruction.7 Increased levels of pro-inflammatory cytokines lead to the proliferation of synovial tissue, and thereby cause damage in the articular cartilage and bone destruction in the adjacent area. Anti-inflammatory cytokines can also be found in the affected joints, and it has been postulated that chronic synovitis may reflect an imbalance in pro- and anti-inflammatory cytokines production in RA. IL-6 is the most abundantly expressed cytokine in RA patients with biological activities that include regulation of immune response, inflammation, and haematopoiesis. IL-6 stimulates the secretion of immunoglobulin by plasmacytes, activates and promotes the proliferation of T and B cells (thus it is involved in the production of the rheumatoid factor), induces synthesis of acute-phase proteins such as CRP, fibrinogen, haptoglobin and serum amyloid-A, regulates the proliferation and differentiation of osteoclasts, and induces bone resorption.8

(Video) Reviewing inflammatory markers in joint pain and inflammatory arthropathies

TNF-α is one of the pivotal pro-inflammatory cytokines responsible for inflammation and joint destruction in RA. TNF-α and its two receptors (p55 and p75 TNFR) are readily detected in both synovial fluid and serum of patients with RA. The severity of this disease is correlated with the concentration of TNF-α in RA patients.9 TNF-α is a potent stimulator of mesenchymal cells, such as synovial fibroblasts, osteoclasts, and chondrocytes that release tissue-destroying matrix metalloproteinases. TNF-α also inhibits the production of tissue inhibitors of metalloproteinases by synovial fibroblasts. These dual actions are thought to lead to joint damage. Although, TNF-α and IL-6 have overlapping and synergic actions, some of the effects of these two cytokines are regulated by distinct mechanisms.10 IL-10 is a potent immunosuppressive and anti-inflammatory cytokine, produced as a part of the homeostatic response to infection and inflammation, and plays a critical role in limiting the duration and intensity of immune and inflammatory reactions. As an anti-inflammatory cytokine, IL-10 has been shown to inhibit the synthesis of pro-inflammatory cytokines.

In the present study, we have screened 110 RA cases attending the Rheumatology OPD of a tertiary care hospital in Delhi, India. Acute phase protein hs-CRP, pro-inflammatory markers IL-6 and TNF-α and anti-inflammatory marker IL-10 were estimated in the serum of RA patients to rule out the levels of these biomarkers during active RA and compared them with healthy controls, and then investigated the correlation between serum levels of these inflammatory markers with the disease activity score 28 (DAS28) in the patient group.

Section snippets

Methods

The present study was carried out on 110 RA patients, fulfilling the 1987 revised criteria of the American College of Rheumatology (formerly, the American Rheumatism Association).11 All cases were selected from the Rheumatology Department of a tertiary care hospital in Delhi, India, under the guidance of a specialist rheumatologist. All patients had active RA (>3 swollen and >3 tender joints). Some of them had evidence of erosive disease on X-rays of hands or feet. Disease activity in RA

Results

The demographic and clinical data of the study groups are shown in Table 1. The mean age of the 110 patients with RA was 46.71±7.12 years and the patient group was comprised of 30 males and 80 females. The mean value of morning stiffness was 85±41.75min. The mean disease duration of the patients was 58.3±19.88 months. The mean DAS28 of RA patients was 4.13±1.77. Fifteen of the 110 patients had a family history of RA or other types of arthritis, and 16 had a former fracture. RA is closely

Discussion

The results of our study confirm the observation of previous studies that the serum concentrations of inflammatory markers are elevated in the majority of patients with RA. RA is characterised by chronic inflammation and hypertrophy of the synovial membranes. Inflammation of the joints occurs in response to production of growth factors, cytokines, and chemokines by many different types of cells present in synovium and cartilage, in addition to infiltrating cells from the peripheral blood.12 In

Conflict of interest

None of the authors have a competing interest to disclose.

Funding statement

No funding was received for this study.

Confidentiality of data

The authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study.

Right to privacy and informed consent

The authors have obtained the informed consent of the patients and/or subjects mentioned in the article. The author for correspondence is in possession of this document.

Protection of human and animal subjects

The authors declare that no experiments were

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      A case-control association study recruited 200 RA patients and 200 age- as well as gender- matched (p>0.05) controls, after written informed consent. A total of eight SNPs were selected on the basis of in silico analysis, which were subjected to genetic analysis using different techniques. LD was calculated and different haplotypes were constructed.

      Significant association of three SNPs i.e. rs1009977, rs4644, and rs74050921 along with elevated galectin-3 levels were observed with susceptibility towards RA. Further, high prevalence of TACGTAGC haplotype were observed in RA patients. In addition to the studied SNPs, eight novel variants were also identified in the CRD region of LGALS3. Genotype phenotype correlation indicated significant elevated galectin-3 levels among different genotypes in rs1009977 and rs74050921.

      The findings of the present study may indicate the role of galectin-3 and its variants in pathogenesis of RA.

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    FAQs

    What are the inflammatory markers for rheumatoid arthritis? ›

    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).

    Can you have RA without inflammation markers? ›

    People who don't test positive for the presence of RF and anti-CCP can still be diagnosed with rheumatoid arthritis based on their symptoms, a physical exam of their joints, and imaging tests (X-rays and ultrasounds) that can show patterns of cartilage and bone deterioration.

    How much CRP level is rheumatoid arthritis? ›

    In response, the body releases CRP into the bloodstream. Doctors measure CRP levels as part of the diagnosis and management of RA. While many factors influence a person's CRP levels, and there is no definitive normal range, CRP levels above 10 mg/l suggest substantial inflammation.

    What is a high CRP for rheumatoid arthritis? ›

    10.0 – 100.0. Moderately elevated, which signifies infection or an inflammatory condition such as rheumatoid arthritis (RA), Crohn's disease, or lupus. 100.0 – 500.0. Elevated, which signifies infection, inflammation of the blood vessels, or major trauma. 500.0 and above.

    What does it mean when your inflammatory markers are elevated? ›

    If you already have an inflammatory disease then rising inflammatory markers may suggest a flare up or a poor response to a treatment; a decreasing inflammatory marker can mean a good response to treatment.

    Which of the following biomarkers is the most specific for rheumatoid arthritis? ›

    Among these, anti-CCP antibodies are the most specific for rheumatoid arthritis, with 67% (95% confidence interval 62% to 72%) sensitivity and specificity of 95% (94% to 97%).

    What is the gold standard for diagnosing rheumatoid arthritis? ›

    Radiographic imaging: the 'gold standard' for assessment of disease progression in rheumatoid arthritis.

    How do you confirm rheumatoid arthritis? ›

    Your rheumatologist will order blood tests and imaging tests. The blood tests look for inflammation and blood proteins (antibodies) that are signs of rheumatoid arthritis. These may include: Erythrocyte sedimentation rate (ESR) or “sed rate” confirms inflammation in your joints.

    Can you have rheumatoid arthritis with a negative CCP? ›

    That means between about half of rheumatoid arthritis patients test negative for anti-CCP. Though there are exceptions, people who have symptoms characteristic of rheumatoid arthritis and who test positive for anti-CCP will almost certainly be diagnosed with the disease.

    What level of CRP indicates autoimmune disease? ›

    A CRP test result of 1.0 to 10.0 milligrams per deciliter (mg/dL) is generally considered a moderately elevated level. This result may indicate any of the following conditions: Systemic inflammation from conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or other autoimmune conditions.

    What CRP level is dangerously high? ›

    Generally, “a CRP reading greater than 10 mg/L is considered dangerous,” says Daniel Boyer, MD, researcher at the Farr Institute in West Des Moines, Iowa. “It is likely caused by a severe bacterial infection and indicates acute inflammation that requires further tests to determine the cause of the inflammation.”

    Is CRP 40 high? ›

    On the other hand viral infection without bacterial involvement is very improbable if CRP is > 40 mg/l. Our results suggest that high CRP values rule out viral infection as a sole aetiology of infection; bacterial infection and antibiotic treatment should be considered in these cases.

    What does a CRP of 70 mean? ›

    CRP levels above 10.0 mg/dl — called marked elevation — will typically indicate an underlying inflammatory issue. The hs-CRP test results indicate a person's risk of developing cardiovascular disease, with the following ranges: less than 2 mg/l indicates a lower risk. greater than 2 mg/l indicates a higher risk.

    Is a CRP of 17 high? ›

    Generally, a CRP level under 10 milligrams per liter (mg/L) is considered normal. If the level of CRP in your blood is higher than that, it may mean your body is having an inflammatory reaction to something.

    What is the normal range for rheumatoid factor? ›

    Value, normal less than 15 IU/mL. Titer, normal less than 1:80 (1 to 80)

    How do you reduce inflammatory markers? ›

    Follow these six tips for reducing inflammation in your body:
    1. Load up on anti-inflammatory foods. ...
    2. Cut back or eliminate inflammatory foods. ...
    3. Control blood sugar. ...
    4. Make time to exercise. ...
    5. Lose weight. ...
    6. Manage stress.
    15 Jan 2020

    What are the 5 classic signs of inflammation? ›

    Based on visual observation, the ancients characterised inflammation by five cardinal signs, namely redness (rubor), swelling (tumour), heat (calor; only applicable to the body' extremities), pain (dolor) and loss of function (functio laesa).

    Is ESR always elevated in rheumatoid arthritis? ›

    The degree of elevation of these acute phase reactants varies with the severity of inflammation and synovitis. As an example, an ESR of 50 to 80 is not uncommon in patients with severely active RA. By comparison, an ESR of 20 to 30 can be observed with only a few mildly to moderately active joints.

    What is the lead marker for detection of rheumatoid arthritis? ›

    RF is the first well-known RA immunologic marker. It is observed in 80-85% of patients with RA. Elevated serum level of RF has been associated with increased disease activity, radiographic progression, and the presence of extraarticular manifestations. The sensitivity of RF is 50-90%, and specificity is 50-95%.

    What is positive rheumatoid factor? ›

    A positive rheumatoid factor test result indicates that a high level of rheumatoid factor was detected in your blood. A higher level of rheumatoid factor in your blood is closely associated with autoimmune disease, particularly rheumatoid arthritis.

    Is there a blood test for rheumatoid arthritis? ›

    Blood tests

    No blood test can definitively prove or rule out a diagnosis of rheumatoid arthritis, but several tests can show indications of the condition. Some of the main blood tests used include: erythrocyte sedimentation rate (ESR) – which can help assess levels of inflammation in the body.

    Can you have rheumatoid arthritis without rheumatoid factor? ›

    Does Seronegative Rheumatoid Arthritis Exist? The quick answer is yes, seronegative rheumatoid arthritis does exist. A seronegative test for rheumatoid arthritis means that a person tests negative for rheumatoid factor (RF) and cyclic citrullinated peptides (CCP).

    Which of the following tests is most specific to the diagnosis of rheumatoid arthritis? ›

    Anti-Citrullinated Protein Antibody Test (Anti-CCP or ACPA)

    This test is 97 percent specific for RA if the disease is present, according to the Hospital for Special Surgery.

    What are 3 symptoms of rheumatoid arthritis? ›

    Signs and symptoms of RA include:
    • Pain or aching in more than one joint.
    • Stiffness in more than one joint.
    • Tenderness and swelling in more than one joint.
    • The same symptoms on both sides of the body (such as in both hands or both knees)
    • Weight loss.
    • Fever.
    • Fatigue or tiredness.
    • Weakness.

    How is inflammatory arthritis diagnosed? ›

    How is inflammatory arthritis diagnosed? Diagnosis is clinical, based on the presence of joint pain, early morning stiffness (>1 hour), and soft, often warm swelling around joints.

    How fast does rheumatoid arthritis progress? ›

    Clinical History. The typical case of rheumatoid arthritis begins insidiously, with the slow development of signs and symptoms over weeks to months. Often the patient first notices stiffness in one or more joints, usually accompanied by pain on movement and by tenderness in the joint.

    How common is seronegative rheumatoid arthritis? ›

    (An estimated 20% of RA patients are seronegative.) Although, either test (RF or anti-CCP) can still come back as positive when RA is not present. This is when your rheumatologist may order X-rays and perform physical exams to assess your joints and identify the signs of RA.

    Can your rheumatoid factor change? ›

    Your rheumatoid arthritis markers may change over time from negative to positive, since many people with seronegative rheumatoid arthritis begin to develop RF or ACPA antibodies. “It happens, but it's not that common,” says Dr.

    How accurate is the CCP test? ›

    With a specificity of about 96% and a positive likelihood ratio of about 14, anti-CCP assists with the diagnosis of RA. It is present in only a quarter to half of patients before or at diagnosis, so a negative result does not rule out RA. It can also predict aggressive joint erosion.

    Is CRP high in autoimmune disease? ›

    With autoimmune disease, the body is treating healthy cells like invaders. That reaction causes inflammation, so high CRP levels tick one box for an autoimmune diagnosis.

    Can CRP be high without infection? ›

    It is important to note that several conditions can be associated with marked elevations of CRP levels, with infection being most common (particularly at extreme elevations). We could not distinguish between conditions based on the CRP level, but above 350 mg/L the cause was almost always infection.

    What does CRP 50 mean? ›

    Clinical Significance. Very high levels of CRP, greater than 50 mg/dL, are associated with bacterial infections about 90% of the time. In multiple studies, CRP has been used as a prognostic factor in acute and chronic infections, including hepatitis C, dengue, and malaria.

    What does CRP 100 mean? ›

    A high CRP level may be moderately or dangerously elevated. The C-reactive protein level between 10mg/L and 100mg/L is considered moderately high, and that above 100mg/L is considered dangerously high. The higher the CRP level, the higher is the risk of cardiovascular conditions.

    What kind of inflammation causes high CRP? ›

    C-reactive protein exhibits elevated expression during inflammatory conditions such as rheumatoid arthritis, some cardiovascular diseases, and infection (6). As an acute-phase protein, the plasma concentration of CRP deviates by at least 25% during inflammatory disorders (7).

    Can high CRP cause fatigue? ›

    Furthermore, in anti-neutrophil cytoplasmic antibody-associated vasculitis, fatigue was associated with increased levels of C-reactive protein (CRP) [9].

    How do you read CRP results? ›

    The report might indicate that the level is high, low, or normal. Although “normal” CRP levels vary from lab to lab, it is generally accepted that a value of 0.8-1.0 mg/dL (or 8-10 mg/L) or lower is normal. Most healthy adults have CRP levels lower than 0.3 mg/dL.

    How quickly does CRP decrease? ›

    After the bacterial trigger for inflammation is eliminated, CRP levels decrease quickly, with a half-life of about 19 hours.

    How long does it take for CRP to return to normal? ›

    The serum CRP level in a “healthy” person is usually less than 5 mg/L; this will begin to rise four to eight hours after tissue is damaged, peak within 24 – 72 hours, and return to normal two to three days after the pathological process has ceased.

    What blood test shows rheumatoid arthritis? ›

    No blood test can definitively prove or rule out a diagnosis of rheumatoid arthritis, but several tests can show indications of the condition. Some of the main blood tests used include: erythrocyte sedimentation rate (ESR) – which can help assess levels of inflammation in the body.

    What is the gold standard for diagnosing rheumatoid arthritis? ›

    Radiographic imaging: the 'gold standard' for assessment of disease progression in rheumatoid arthritis.

    What are the normal ranges for rheumatoid factor? ›

    Value, normal less than 15 IU/mL. Titer, normal less than 1:80 (1 to 80)

    What is a high level of rheumatoid factor? ›

    What are the normal ranges for rheumatoid factor? The "normal" range (or negative test result) for rheumatoid factor is less than 14 IU/ml. Any result with values 14 IU/ml or above is considered abnormally high, elevated, or positive.

    How do you confirm rheumatoid arthritis? ›

    Your rheumatologist will order blood tests and imaging tests. The blood tests look for inflammation and blood proteins (antibodies) that are signs of rheumatoid arthritis. These may include: Erythrocyte sedimentation rate (ESR) or “sed rate” confirms inflammation in your joints.

    How do I read my rheumatoid arthritis results? ›

    A level above 20 suggests the possibility of RA. As with rheumatoid factor, some people with positive anti-CCP antibody will not have RA, but this test is somewhat more specific for RA than the rheumatoid factor. The higher the levels of anti-CCP antibody, the more likely it is to suggest RA.

    How do rheumatologists diagnose rheumatoid arthritis? ›

    The diagnosis of rheumatoid arthritis can't be established with just one test. Instead, rheumatologists rely on a combination of your medical history, a physical exam, laboratory tests, and sometimes imaging tests to pinpoint the disease.

    Can you have rheumatoid arthritis without rheumatoid factor? ›

    Does Seronegative Rheumatoid Arthritis Exist? The quick answer is yes, seronegative rheumatoid arthritis does exist. A seronegative test for rheumatoid arthritis means that a person tests negative for rheumatoid factor (RF) and cyclic citrullinated peptides (CCP).

    Which of the following tests is most specific to the diagnosis of rheumatoid arthritis? ›

    Anti-Citrullinated Protein Antibody Test (Anti-CCP or ACPA)

    This test is 97 percent specific for RA if the disease is present, according to the Hospital for Special Surgery.

    What does it mean to have rheumatoid arthritis without rheumatoid factor? ›

    Rheumatoid factors are proteins produced by your immune system that can attack healthy tissue in your body. High levels of rheumatoid factor in the blood are most often associated with autoimmune diseases, such as rheumatoid arthritis and Sjogren's syndrome.

    Is a rheumatoid factor of 25 high? ›

    The normal range of rheumatoid factor levels is usually between < 14 and < 20 IU/mL. A level above these values is considered a positive result and may indicate rheumatoid arthritis or other disorders [9, 10, 11].

    Is rheumatoid factor 10 normal? ›

    Most medical centers consider the normal range of rheumatoid factor to be up to 10 IU/mL or 20 IU/mL, says rheumatologist Steffan Schulz, MD, assistant professor of clinical medicine with Penn Medicine in Philadelphia.

    Can your rheumatoid factor change? ›

    Your rheumatoid arthritis markers may change over time from negative to positive, since many people with seronegative rheumatoid arthritis begin to develop RF or ACPA antibodies. “It happens, but it's not that common,” says Dr.

    Can rheumatoid factor decrease? ›

    RF may appear up to several years before the onset of clinical RA. With effective treatment, RF titers can decrease, which is especially typical for B cell–directed therapy with rituximab.

    What does a rheumatoid factor of 60 mean? ›

    As with rheumatoid factor, values >20 are normally considered positive; however, most RA patients will have strongly positive results (i.e., >60 units). Abnormally high values are associated with, but not diagnostic of RA. Reference ranges may vary but are often <0.6-0.8 mg/dl.

    What are the 4 stages of rheumatoid arthritis? ›

    The four stages of rheumatoid arthritis are known as synovitis, pannus, fibrous ankylosis, and bony ankylosis.
    • Stage I: Synovitis. During stage I, you may start having mild symptoms, including joint pain and joint stiffness. ...
    • Stage II: Pannus. ...
    • Stage III: Fibrous Ankylosis. ...
    • Stage IV: Bony Ankylosis.
    12 Oct 2021

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