Anti-mutated Citrullinated Vimentin Antibodies Research Articles

Greater prevalence of seropositivity for anti-cyclic citrullinated peptide antibody in unaffected first-degree relatives in multicase rheumatoid arthritis-affected families

Background/AimsThis study determined the prevalence and determinants of seropositivity for rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibody, and anti-mutated citrullinated vimentin (anti-MCV) antibody in unaffected first-degree relatives (FDRs) of rheumatoid arthritis (RA) patients.MethodsA total of 337 subjects (135 with RA and 202 FDRs) were enrolled in this case-control study. Serum RF, anti-CCP antibody, and anti-MCV antibody were assayed. Subjects in multicase families (≥ 2 affected FDRs within the same family) were identified. Multivariate logistic regression analysis was used to identify risk factors associated with RA-related autoantibodies.ResultsSeropositivity for RF, anti-CCP antibody, or anti-MCV antibody was detected in 14.4%, 5.0%, or 13.4% of unaffected FDRs, respectively. Anti-CCP antibody seropositivity was more prevalent in FDRs in multicase families (17.8%) than in those not in multicase families (1.3%, p < 0.0001). Significant correlations between RA-associated autoantibodies were detected in the FDR group (between RF and anti-CCP antibody: r = 0.366, p < 0.0001; between RF and anti-MCV antibody: r = 0.343, p < 0.0001; and between anti-CCP antibody and anti-MCV antibody: r = 0.849, p < 0.0001). After adjustment for age and sex, anti-CCP antibody seropositivity in FDRs was significantly associated with being in a multicase family (odds ratio, 49.8; 95% confidence interval, 5.6 to 441.6).ConclusionsThe association between anti-CCP antibody seropositivity in unaffected FDRs and being in a multicase family suggests that genetic and/or environmental factors may increase the risk for RA development in unaffected FDRs.

Measurement of cell‐bound complement activation products enhances diagnostic performance in systemic lupus erythematosus

To determine the value of cell-bound complement activation products in combination with antinuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), and anti-mutated citrullinated vimentin antibody (anti-MCV) for the diagnosis of systemic lupus erythematosus (SLE). This was a multicenter cross-sectional study in which 593 subjects were enrolled (210 SLE patients, 178 patients with other rheumatic diseases, and 205 healthy subjects). Complement receptor 1 levels on erythrocytes (ECR1) together with complement C4d levels on erythrocytes (EC4d), platelets (PC4d), and B cells (BC4d) were determined using fluorescence-activated cell sorting. Serologic markers were measured by enzyme-linked immunosorbent assay. Statistical analyses were performed using area under the curve (AUC), logistic regression, and calculations of diagnostic sensitivity and specificity. Anti-dsDNA was an insensitive (30%) but specific (>95%) marker for SLE. Levels of EC4d, BC4d, and PC4d were several times higher, and levels of ECR1 lower, in SLE patients compared to patients with other rheumatic diseases and healthy subjects. Among 523 anti-dsDNA-negative subjects, multivariate logistic regression analysis revealed that SLE was associated with ANA positivity (≥20 units), anti-MCV negativity (≤70 units), and elevated levels of both EC4d and BC4d (AUC 0.918, P < 0.001). A positive index score corresponding to the weighted sum of these 4 markers correctly categorized 72% of SLE patients. Specificity in relation to patients with other rheumatic diseases and healthy controls was >90%. The combination of anti-dsDNA and index score positivity yielded 80% sensitivity for SLE and 87% specificity against other rheumatic diseases. An assay panel combining anti-dsDNA, ANA, anti-MCV, EC4d, and BC4d is sensitive and specific for the diagnosis of SLE.

Effects of TNF inhibitor on innate inflammatory and Th17 cytokines in stimulated whole blood from rheumatoid arthritis patients

Recent studies point to important roles for IL-17 and Th17 cells in sustaining chronic inflammation and articular destruction in rheumatoid arthritis (RA). We investigated the effects of TNF inhibitor on innate inflammatory and Th17 cytokines production by ex vivo lipopolysaccharide (LPS)-stimulated whole blood in patients with RA and the associations of cytokine levels in whole blood cultures with autoantibodies and markers of disease activity. Whole blood cultures from 18 healthy volunteers and 19 RA patients on etanercept therapy were stimulated with LPS and the production of IL-6, TNF-α, IL-23, IL-17A and IL-21 was measured by ELISA. After stimulation with LPS, the interleukin (IL)-17A (p=0.020) and IL-21 (p=0.0001) secretions were significantly higher in patients with RA than in controls, while the TNF-α (p=0.002) was significantly lower at baseline. Etanercept significantly decreased IL-21 production (p=0.007), while IL-6 production (p=0.005) significantly increased after 6months of therapy. IL-21 significantly correlated with RF (r=0.917, p<0.01) and antimutated citrullinated vimentin antibodies (r=0.770, p<0.01) at baseline. Logistic regression analysis revealed that baseline IL-21 levels (p=0.004) were significant predictors of DAS28-ESR at 6months follow-up. Stimulation with LPS increased production of Th17 cytokines in whole blood cultures in patients with RA. Etanercept therapy decreased IL-21 secretion, while the capacity of whole blood cells to produce IL-6 increased. IL-21 production is strongly associated with the levels of autoantibodies. Our findings suggest that IL-21 production in LPS-stimulated whole blood cultures may be predictive of clinical response to etanercept treatment in patients with RA.

The diagnostic and monitoring value of serum anti-mutated citrullinated vimentin antibodies (anti-MCV) in juvenile rheumatoid arthritis

Background: JRA is currently diagnosed using the American College of Rheumatology (ACR) 1987 revised criteria that are primarily based on clinical parameters. The criteria may be insufficient for the diagnosis of early RA as they are based upon measurements of disease classification predominately featuring manifestations typical of later-stage disease. Measurement of serum anti-mutated citrullinated vimentin antibodies (MCV) has been shown to be a better marker for early adult RA, and it correlates well with the disease activity score (DAS). Objectives: The aim of this work is to evaluate the role of antimutated citrullinated vimentin antibodies (anti-MCV) in the diagnosis, and in monitoring disease activity in juvenile rheumatoid arthritis. Methods: The study included 40 children with JRA fulfilling the American College of Rheumatology criteria for diagnosis of JRA: 4 children with oligoarticular JRA, 12 with polyarticular JRA and 24 children with systemic onset JRA. Fifty healthy children, matching the patients in age and sex served as a control group. The studied children with JRA were subjected to laboratory tests including CBC, ESR, CRP, ANA and rheumatoid factor (RF). Serum samples from both patients and controls were assayed for anti-MCV levels using an ELISA technique. Results: The study showed high mean serum anti-MCV antibodies level in JRA patients when compared to controls (P= 0.00). In addition, there were no significant correlations between anti-MCV antibody levels and parameters of disease activity, namely, number of swollen joints, number of tender joints, ESR and CRP. The receiver operating characteristic (ROC) curve was drawn and it showed that the area under the curve (AUC) was (0.896). At a cutoff level > 17 u/mL, anti-MCV antibodies had diagnostic specificity of 88%, diagnostic sensitivity of 87.5%, negative and positive predictive values of 89.8% and 85.4%, respectively and diagnostic efficacy of 87.8%. We also reported 3/40 of JRA patients to be positive for RF and 2/40 of JRA patients to be positive for ANA. Conclusion: Measurement of serum anti MCV antibody level holds promise as a diagnostic tool in JRA. However, they failed to show a significant efficacy in determining disease activity. Keywords: Juvenile rheumatoid arthritis, MCV Egypt J Pediatr Allergy Immunol 2012;10(2):75-80

Evaluation of Anti-Mutated Citrullinated Vimentin Antibodies, Anti-Cyclic Citrullinated Peptide Antibodies and Rheumatoid Factor in Omani Patients with Rheumatoid Arthritis

Rheumatoid factor (RF) is currently used in the diagnosis of rheumatoid arthritis (RA). The discovery of anticitrullinated protein autoantibodies has led to the development of various new tests, such as anti-cyclic citrullinated peptide (anti-CCP) antibodies, and anti-mutated citrullinated vimentin (anti-MCV) antibodies, to diagnose RA. The aims of this study were to determine the sensitivity and specificity of anti-MCV antibodies in comparison with anti-CCP antibodies and RF in Omani Arab patients with RA and compare our findings with published values from different ethnic groups. The sensitivity of anti-MCV antibodies was 72% with 87% specificity. For anti-CCP antibodies the sensitivity was 52% and the specificity was 97%. The sensitivity of RF was 57% with 94% specificity. Anti-CCP antibodies have higher diagnostic specificity and positive predictive value than RF and anti-MCV antibodies. Anti-MCV antibodies have the highest sensitivity when compared to anti-CCP antibodies and RF. Anti-MCV antibodies do not appear to be very useful in the diagnosis of RA. However, long-term study is required to find out whether anti-MCV antibodies can be used as predictive test for incidence of RA.

Tumor Necrosis Factor Blockade Differentially Affects Innate Inflammatory and Th17 Cytokines in Rheumatoid Arthritis

To evaluate the effect of a tumor necrosis factor-α (TNF-α) inhibitor (etanercept) on innate inflammatory and Th17 cytokines in patients with rheumatoid arthritis (RA). Serum samples were collected from 40 patients with active RA refractory to conventional disease-modifying antirheumatic drugs who initiated therapy with etanercept plus methotrexate (MTX). Treatment response was assessed at Week 24 according to the European League Against Rheumatism response criteria. Serum levels of interleukin 6 (IL-6), TNF-α, IL-32, IL-23, IL-17A, IL-21, and IL-22 were measured in patients with RA and 25 healthy controls. Patients with RA had increased levels of IL-6 (p < 0.001), IL-32 (p < 0.001), IL-23 (p < 0.001), and a trend toward increased IL-21 in the sera compared to controls. At 24 weeks' posttreatment, followup serum samples of etanercept responders had decreased levels of IL-6 (p < 0.001) and increased IL-21 (p < 0.05) and IL-32 (p < 0.001), while there were no differences in cytokine levels in non-responders. Serum IL-6 levels were positively correlated with levels of erythrocyte sedimentation rate (r = 0.458, p < 0.01), C-reactive protein (r = 0.593, p < 0.01), and 28-joint Disease Activity Score (r = 0.432, p < 0.01) at baseline. Serum IL-21 levels were positively correlated with levels of rheumatoid factor (r = 0.513, r = 0.633, both p < 0.01) and antimutated citrullinated vimentin antibodies (r = 0.515, p < 0.01; r = 0.428, p < 0.05) at baseline and after 24 weeks of treatment with etanercept. Multiple inflammatory pathways contribute to persistent chronic inflammation in RA. In contrast to nonresponders, etanercept therapy modulated serum cytokine levels and caused a marked decrease of IL-6 levels in responders. IL-21 might be involved in the regulation of autoantibody production in RA.

PADI4 polymorphisms and related haplotype in rheumatoid arthritis patients

ObjectiveTo investigate whether peptidyl arginine deiminase type IV gene (PADI4) polymorphisms contribute to rheumatoid arthritis (RA) susceptibility in Egyptians, whether they influence disease severity and activity, and whether they affect anti-mutated citrullinated vimentin antibodies (anti-MCV) level. MethodsThree PADI4 single nucleotide polymorphisms (SNPs) (PADI4-92, PADI4-96, and PADI4-102) were screened in 275 RA patients and 275 unaffected controls by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method. Serum anti-MCV levels were measured by enzyme-linked immunosorbent assay (ELISA). ResultsThere were significant associations between RA susceptibility with the minor alleles of PADI4-92 and PADI4-102 [odds ratio (OD) and 95% confidence interval (CI) for the minor alleles of PADI4-92 and PADI4-102: 1.48 (1.17–1.88) and 2.05 (1.61–2.61) respectively] but not with PADI4-96 [OD and 95% CI for the C allele: 1.09 (0.86–1.39)]. PADI4 haplotypes 2 (GCC) and 3 (GCT) were also associated with RA susceptibility while PADI4 haplotypes 1 (CTC) may be protective against developing of this disease. A significant association was detected between PADI4 haplotypes and RA severity. ConclusionsThe PADI4 SNPs and haplotypes were associated with RA susceptibility, although no relation was observed between the PADI4 haplotypes and anti-MCV levels.

Anti-mutated citrullinated vimentin (anti-MCV) and anti-65 kDa heat shock protein (anti-hsp65): New biomarkers in ankylosing spondylitis

Introduction Citrullination as well as anti-citrullinated protein/peptide antibodies (ACPA) have been implicated in the pathogenesis of rheumatoid arthritis (RA). While ACPAs are specific and sensitive markers for RA, there have been hardly any reports regarding ACPAs in ankylosing spondylitis (AS). The possible role of antibodies to Mycobacterial 65 kDa heat shock protein (hsp65) has not been characterized in AS. As new laboratory biomarkers of AS are needed, we investigated the prevalence of anti-mutated citrullinated vimentin (MCV) and anti-hsp65 antibodies in AS. Methods Altogether 43 AS and 44 healthy controls were included in the study. Anti-MCV and anti-hsp65 were determined in sera by commercial and in-house ELISA, respectively. Serum autoantibody levels were correlated with ESR, CRP, HLA-B27 status, smoking habits, pain intensity, BASDAI, BASFI and BASMI indices. Results Patients with AS had significantly higher serum anti-MCV levels (17.3 U/mL, range: 8.3–31.5 U/mL) in comparison to healthy subjects (8.9 U/mL, range: 5.4–13.3 U/mL) ( p < 0.01). Sixteen of the 43 AS patients (37%) and none of the 44 healthy controls (0%) were anti-MCV positive using the cut-off value recommended by the manufacturer (> 20 U/mL). The mean anti-hsp65 concentration in AS sera was 124.8 AU/mL (range: 27.2–1000 AU/mL), while controls exerted significantly lower anti-hsp65 levels (mean: 51.8 AU/mL; range: 22.5–88.5 AU/mL) ( p < 0.001). Correlation analysis revealed that both anti-MCV positivity ( r = 0.613; p = 0.012) and absolute serum anti-MCV levels ( r = 0.553; p = 0.021) correlated with anti-hsp65 levels. Anti-MCV positivity also correlated with ESR ( r = 0.437; p = 0.03). Conclusions Anti-MCV and anti-hsp65 may be novel biomarkers in AS.

Smoke exposure as a determinant of autoantibody titre in 1-antitrypsin deficiency and COPD

Liberation of elastin peptides from damaged lung may be a mechanism of autoimmune lung disease. Citrullination, and anti-citrullinated protein antibody formation occurs in smokers, but the role of smoking in autoantibody generation relevant to pulmonary disease is unclear. Anti-elastin, anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) antibodies were measured in 257 subjects with α₁-antitrypsin deficiency (AATD), 113 subjects with usual chronic obstructive pulmonary disease (COPD) and 22 healthy nonsmokers. Levels were compared between groups, against phenotypic features and against smoke exposure. Anti-elastin antibodies were higher in controls relative to AATD (p = 0.008) and usual COPD (p < 0.00001), and in AATD relative to usual COPD (p < 0.00001). Anti-elastin levels showed a threshold at 10 pack-yrs, being higher in those who had smoked less (p = 0.004). No relationships between antibody levels and clinical phenotype were seen after adjustment for smoke exposure. Anti-CCP antibodies were higher in usual COPD than AATD (p = 0.002) but the relationship to smoke exposure was less clear. Smoke exposure is the main determinant of anti-elastin antibody levels, which fall after 10 pack-yrs. Local antibody complexes may be a better measure of elastin directed autoimmunity than circulating levels.

Meta-analysis: diagnostic value of serum anti-mutated citrullinated vimentin antibodies in patients with rheumatoid arthritis

Conventional tests are not always helpful in making a diagnosis of rheumatoid arthritis (RA). This study aimed to comprehensively and quantitatively summarize the evidence on the accuracy of anti-mutated citrullinated vimentin (MCV) assay in the diagnosis of RA. A comprehensive meta-review of data on the accuracy of MCV concentrations in the diagnosis of RA were carried out from 16 published studies. Furthermore, receiver operating characteristic curves were used to summarize the overall test performance. The summary estimates for MCV in the diagnosis of RA were: sensitivity 0.77 [95% confidence interval (CI) 0.75-0.78], specificity 0.89 (95% CI 0.87-0.90), positive likelihood ratio (LR+) 7.24 (95% CI 5.60-9.36), negative likelihood ratio (LR-) 0.28 (95% CI 0.23-0.34) and diagnostic odds ratio 29.66 (95% CI 21.09-41.71). The area under the summary receiver operating characteristic curves was 0.92. Data from meta-analysis suggest the accuracy of MCV assay in the diagnosis of RA is high, but ultimately clinician must consider the results of MCV tests combing with other conventional examinations and the clinical feature.

The Anti-mutated Citrullinated Vimentin Response Classifies Patients with Rheumatoid Arthritis into Broad and Narrow Responders

Autoantibodies against citrullinated peptide antigens (ACPA) are routinely determined to diagnose rheumatoid arthritis (RA) and are predictive of a more severe course of the disease. We here set out to address an involvement of ACPA in the pathogenesis of RA and investigated the recognition pattern of antibodies against 2 citrullinated antigens in more detail. The sera of 77 patients fulfilling the American College of Rheumatology criteria for RA were analyzed for subclass titers of anti-mutated citrullinated vimentin (MCV) and anticyclic citrullinated peptide (CCP) antibodies by combining subclass specific detection antibodies with commercially available CCP and MCV ELISA plates. Cross-reactivities between anti-MCV and anti-CCP antibodies were detected using a sequential ELISA system. IgG1, IgG3, and IgG4 titers among anti-MCV and anti-CCP antibodies correlated significantly. Cross-reactivity of MCV-specific antibodies against CCP could be detected in 8 of 16 patients' sera; however, cross-binding of MCV-specific IgG4 was weaker compared to total IgG. The inherent capacity of IgG4 to exchange F(ab) arms provides insight into the anti-MCV antibody diversity and suggests a classification of ACPA positive patients into broad and narrow responders.

The Role of Anti-Mutated Citrullinated Vimentin Antibodies in the Diagnosis of Early Rheumatoid Arthritis

Anti-mutated citrullinated vimentin (MCV) antibodies have been reported as a fairly sensitive serological marker of rheumatoid arthritis (RA). We evaluated the diagnostic value of anti-MCV in a large cohort of Chinese patients with early RA. One hundred seventy patients with early RA (<1 yr duration), 66 with other rheumatic diseases, 10 with infectious diseases, and 60 healthy individuals were included in our study. Serum anti-MCV and second-generation anti-cyclic citrullinated peptide antibodies (anti-CCP2) were measured by ELISA, and rheumatoid factor (RF) was measured by rate nephelometry. The associated clinical data of patients with early RA were also evaluated. Then disease activity was scored by the formula for Disease Activity Score (DAS)28, and the degree of radiological changes was assessed by Sharp score. The prevalence of serum anti-MCV in patients with early RA (78.2%, 133/170) was significantly higher than that of other rheumatologic patients and patients with infectious diseases. It was 12% (3/25) in systemic lupus erythematosus, 9.5% (2/21) in primary Sjögren's syndrome, 10% (1/10) in systemic sclerosis, 20% (2/10) in ankylosing spondylitis, 12.5% (1/8) in viral hepatitis type B, and 0% (0/2) in tuberculosis. Anti-MCV was not found in the serum of healthy subjects. The sensitivities of anti-MCV, anti-CCP2, and RF tests for early RA were 78.2%, 61.8%, and 72.4%, respectively, and the specificities were 93.4%, 96.3%, and 80.1%. The combination of anti-MCV and anti-CCP2 positivity showed a very high specificity (97.8%) and positive predictive value (97.1%), but a low sensitivity (58.8%). The sensitivity reached 81.2% when the union of anti-MCV and anti-CCP2 positivities was used as one combined criterion. Statistically, anti-MCV had significant correlation with anti-CCP2 (r=0.587, p=0.01, 2-tailed) and RF (r=0.389, p=0.01, 2-tailed). In addition, it had an interesting correlation with radiological assessment (r=0.349, p=0.05, 2-tailed). The anti-MCV had no significant correlation with other factors, such as erythrocyte sedimentation rate, C-reactive protein, antikeratin antibody, antiperinuclear factor, global visual analog scale score for joint pain, IgA, IgG, IgM, C3, C4, hidden rheumatoid factor for IgA (HRFIgA), HRFIgG, and DAS28. Anti-MCV is a novel diagnostic marker for early RA. It may be more useful if the anti-CCP2 assay is performed concomitantly to diagnose patients with early RA.

Value of anti-mutated citrullinated vimentin antibodies in diagnosing rheumatoid arthritis

We assessed the diagnostic value of anti-mutated citrullinated vimentin antibodies (anti-MCV) and compared it with those of anti-cyclic citrullinated peptide antibodies (anti-CCP), IgA (ARF), IgM (MRF) and IgG (GRF) rheumatoid factors for rheumatoid arthritis (RA). Serum samples of 170 RA patients, with early and established RA, and 309 controls were tested for anti-MCV, anti-CCP, ARF, MRF and GRF using commercially available ELISA kits. Cut off of different tests was determined with ROC curves. The sensitivity and the specificity of anti-MCV were 74.1 and 79%, respectively. Sixty-five of 309 (21%) controls were anti-MCV positive. Sensitivity and specificity of anti-CCP were 72.4 and 96.1%, respectively. Only 12 of 309 (3.9%) controls were anti-CCP positive. Sensitivity of ARF, MRF and GRF were 64.1, 65.9 and 68.2%, respectively. Their specificity was 79.6, 74.4 and 68.9%, respectively. No significant association was observed between the antibodies tested and extrarticular manifestations. Anti-MCV shows comparable sensitivity but lower specificity than that of anti-CCP. They do not appear to be very useful in the diagnosis of RA.