Anti-mutated Citrullinated Vimentin Research Articles

Association of ERAP1 and ERAP2 gene polymorphisms and ERAP2 protein with the susceptibility and severity of rheumatoid arthritis in the Ukrainian population.

Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. Although RA is chiefly associated with HLA class II, nevertheless some HLA class I associations have also been observed. These molecules present antigenic peptides to CD8+ T lymphocytes and natural killer cells. HLA-I molecules bind their peptide cargo (8-10 amino acids long) in the endoplasmic reticulum. Peptides longer than 10 amino acids are trimmed by the endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 to fit the peptide binding groove of the HLA-I molecule. Here, we investigated the possible association of ERAP1 and ERAP2 polymorphisms with RA, and also any possible correlation between serum levels of the ERAP2 protein with disease severity. We used Real-Time PCR to genotype ERAP1 and ERAP2 and ELISA test to detect ERAP2 protein. We found significant associations of ERAP1 rs30187, rs27044, and rs26618, as well as ERAP2 rs2248374, with susceptibility to RA. ERAP1 rs26653 and ERAP2 rs2248374 were also associated with the Disease Activity Score (DAS28), and some polymorphisms were also associated with anti-citrullinated protein or anti-mutated citrullinated vimentin antibodies. RA patients secreted higher concentrations of ERAP2 than controls. Patients with mild disease activity (DAS28 < 3.2) released a concentration of ERAP2 four times lower than that of patients with severe disease activity (DAS28 > 5.1). We detected a higher level of ERAP2 in rheumatoid factor (RF)-positive patients than in RF-negative patients. ERAP2 concentration above 5.85 ng/mL indicated a severe phase of RA. Some ERAP1 and ERAP2 polymorphisms seem to be related to susceptibility to RA or the severity of the disease. The ERAP2 protein tested in serum could be a valuable biomarker of RA severity.

Evaluation of the clinical performance of anti-mutated citrullinated vimentin antibody and 14-3-3 eta testing in rheumatoid arthritis.

Early rheumatoid arthritis (RA) detection is crucial for improving patient prognosis. Anticyclic citrullinated peptide antibodies (anti-CCP) and rheumatoid factors (RF) support RA diagnosis but are undetectable in ∼20 % of cases. Recently, antibodies against mutated citrullinated vimentin (anti-MCV) and detection of 14-3-3 eta have emerged with implications for preclinical RA diagnosis and monitoring treatment. The objective of this study was to assess the clinical performance of anti-MCV antibodies and 14-3-3 eta in RA and to compare it to current RA criteria anti-CCP and RF markers, individually and in combination. A retrospective chart review of 326 subjects submitted for RA serology testing identified 134 RA positive and 192 RA negative disease control individuals. Fifty healthy controls specimens were also included. Performance of anti-MCV and 14-3-3 eta, alone and combined with CCP3.1 and RF, was assessed. Anti-MCV had a sensitivity of 71 % and a specificity of 92 %. 14-3-3 eta had a sensitivity of 43 % and a specificity of 90 %. In comparison, CCP3.1 and RF displayed a sensitivity of 79 % and 84 % and a specificity of 92 % and 61 %, respectively. ROC curve analysis demonstrated CCP3.1 and anti-MCV had superior diagnostic performance compared to RF and 14-3-3 eta. In our cohort, anti-MCV and 14-3-3 eta failed to identify seronegative RA patients. Different combinations of double antibody positivity increased specificity at the cost of lost sensitivity. Individually, 14-3-3 eta, anti-MCV and CCP3.1 assays had≥90 % specificity in diagnosed RA patients, with better sensitivities for anti-MCV and CCP3.1 than 14-3-3 eta. Overall diagnostic performance of anti-MCV was similar to CCP3.1 and RF, all of which outperformed 14-3-3 eta in our cohort.

Clinical significance of anti-mutated citrullinated vimentin antibodies in rheumatoid arthritis patients.

Anti-mutated citrullinated vimentin (MCV) antibodies have recently been recommended as a better arthritis diagnostic marker. To investigate the association between anti-MCV antibodies and the clinical, functional, and radiographic characteristics of rheumatoid arthritis (RA) patients. This case-control study was conducted on 40RApatients and 40healthy subjects. All patients were subjected to an assessment of disease using the 28-joint DAS (DAS28) and Clinical Disease Activity Index (CDAI), function by HAQ-DI, physical activity by International Physical Activity Questionnaire (IPAQ), fatigue by Functional Assessment of Chronic Illness Therapy (FACIT), serological tests as well as anti-MCV Abs measurement. A plain X-ray of both hands and wrists was done. The anti-MCV Abs level was significantly higher in RA patients than in healthy controls (P< 0.001). The anti-MCV Abs had a significant positive correlation with DAS, CDAI, HAQ, RF, Anti-CCP, and CRP (P= 0.006, 0.013, 0.005, < 0.001, < 0.001and 0.041respectively) and a significant negative correlation with FACIT (p= 0.007). Positive anti-MCV RA patients had significantly higher erosions, JSN, and a total sharp score. Anti-MCV Abs may contribute to poor physical activity and more fatigue in RA patients beyond their established role in disease activity and erosion.

Autoantibodies Serum Level and 10-Year Risk of Fractures Evaluated by FRAX® Tool in Rheumatoid Arthritis Patients.

FRAX® is a tool used for evaluation of risk of fracture in RA and non-RA patients and to identify those eligible for intervention. One of the limitations of FRAX in RA settings is that it does not consider factors known to contribute to osteoporosis such as autoantibodies. This study analysed the association of anti-mutated citrullinated vimentin antibody (anti-MCV), anti-cyclic citrullinated peptide antibody (anti-CCP), IgM rheumatoid factor (RF), IgA RF with 10-year risk of major osteoporosis and hip fracture. FRAX® tool was used to estimate 10-year risk of major osteoporosis fracture and hip fracture in 189 RA patients over 40 years of age. Anti-MCV, anti-CCP, IgM RF and IgA RF were tested using enzyme immunoassay and analysed at different levels. Results were adjusted for various confounders including disease activity. Fifty-one (26.9%) RA patients had high (≥20%) 10-year risk of major osteoporosis fracture and 67 (35.4%) had high (>3%) 10-year risk of hip fracture. Among all the tested autoantibodies, only IgM RF at elevated levels was associated with high 10-year risk of major osteoporosis fracture (adjusted OR = 4.1, 95% CI = 1.5-11.3, p = 0.006) and of hip fracture (adjusted OR = 17.4, 95% CI = 3.7-81.3, p < 0.0001). There was no agreement between FRAX and femoral neck (FN) BMD. None of the autoantibodies tested were associated with FN osteopenia or osteoporosis including IgM RF at high levels. Our study highlights the importance of quantitative measurement of autoantibodies in assessment of risk for fractures among RA patients. Our preliminary findings need to be assessed in prospective studies to determine the actual predictive value of high IgM RF levels among patients with RA.

VEXAS syndrome mimicking lupus-like disease.

Dear Editor, We report on an 81-year-old male Caucasian patient, who initially presented with oral ulcerations and disseminated erythematous papules on the upper back, chest, arms and legs with histopathological evidence of lymphocytic infiltration and small vessel vasculitis matching subacute lupus erythematous (Fig. 1A and B). His skin manifestations improved with topical CS and HCQ at standard dosages. However, a complete remission of the lesions could not be achieved. Therefore, repeated skin biopsies were performed, showing features of subacute eczema or Sweet Syndrome. Fourteen months later, the patient developed recurrent episodes of oral ulcerations, painful auricular and nasal erythematous swelling and arthritis in hands and feet (Fig. 1C and D). A hand MRI showed a moderate to severe wrist joint synovitis. Another 6 months later, he presented with clinical symptoms and laboratory findings of anaemia with increased, corpuscular volume (102.9 fl; normal range 81–98 fl), leukopoenia, lymphopenia, thrombocytopenia, increased levels of CRP, serum amyloid A and IL-6 as well as anti-mutated citrullinated vimentin (MCV) antibodies (Fig. 1G). Treatment with MTX was started at 15 mg/week and was well tolerated, leading to improvement of skin and joint symptoms. The patient experienced one episode of epilepsy with generalized convulsions. Cerebral MRI scan showed unspecific cerebral microangiopathy but no specific lesion. To rule out further foci of inflammation, an 18-fluorodeoxyglucose (18FDG)-PET/CT was performed, showing an enhanced FDG uptake typical for bone marrow activation (Fig. 1E and F), in accordance with a previous description [1]. Over the last 6 months, his skin and joints were well controlled by MTX. However, haematological and inflammatory parameters did not improve. As the patient fulfilled the major diagnostic traits of VEXAS [2], including male sex, increased corpuscular volume >100 fl and low platelets G/l, genetic testing was done. This patient was identified to carry the pathogenic variant c.121A>C, p. (Met41Leu) in exon 2 of UBA1 (NM_003334) (ACMG class 5) in mosaic state (68% of 93 reads), confirming the diagnosis of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome.

Anti-mutated citrullinated vimentin antibodies in rheumatoid arthritis; diagnostic utility and association with deformities and disease activity

Rheumatoid arthritis (RA) is a chronic autoimmune disease with multiple morbidity burdens. Early diagnosis of RA is the main key in management and prevention of disease complications. Much research nowadays is looking for a serological marker with high accuracy in diagnosis of early RA cases. Our aim in this study was to evaluate the role of anti-mutated citrullinated vimentin (anti-MCV) antibodies in the early diagnosis of RA. In addition to compare its diagnostic sensitivity and specificity with anti-cyclic citrullinated peptide antibodies (anti-CCP) and RF antibodies in early versus established RA patients. This prospective cross-sectional study included 80 participants: 40 RA patients (20 early RA patients and 20 established RA patients), 20 patients with other rheumatic diseases (as a disease control group), and 20 apparently healthy participants as normal controls. All participants underwent history taking, clinical examination (general, articular assessment and calculation of disease activity score (DAS28-ESR)) for RA patients, radiological and laboratory investigations (RF, anti-CCP2 and anti-MCV antibodies measurements by ELISA technique). The results showed that the mean values of anti-CCP2 and anti-MCV were significantly increased in RA cases compared to the control groups (p=0.00 and p=0.01, respectively). Anti-MCV had sensitivity and specificity of 63% and 83%, respectively for diagnosing of early RA at area under curve of 0.80 compared to sensitivity and specificity 37% and 100%, respectively for anti-CCP2. Also, both (anti-CCP2 and anti-MCV) had positive significant correlations with ESR (p < 0.001 and p=0.02, respectively), CRP (p=0.01 and p=0.02, respectively) and DAS 28 (p < 0.001 for both). In conclusion, our data indicated that anti-MCV antibodies may represent a valuable marker for diagnosis of early RA cases.

Correlation between anti-mutated citrullinated vimentin and bone turnover markers (CTX-1 and P1NP) in patients with rheumatoid arthritis in remission and low-disease activity

IntroductionRheumatoid arthritis is associated with bone loss and the risk of osteoporotic fracture. Bone loss in this disease is mediated by inflammation and autoimmunity. Many studies have shown that anti-citrullinated protein antibody is capable of inducing bone loss through several mechanisms.This study aimed to determine the relationship between autoimmunity, represented by anti-mutated citrullinated vimentin (anti-MCV) in this study, and bone loss, represented by C-terminal cross-linking telopeptide of type I collagen (CTX-1), and N-terminal pro-peptide of type 1 procollagen (P1NP) in this study, in patients with rheumatoid arthritis in remission and low disease activity.Material and methodsThis study enrolled 38 rheumatoid arthritis patients with disease remission and low disease activity in Cipto Mangunkusumo Hospital between August and September 2019. We collected the patients’ demographic data, Disease Activity Score 28 (DAS28), and treatment history. All participants underwent blood work for anti-MCV, CTX-1, and P1NP.ResultsThirty-four of the subjects were women (89.5%), with the mean age of 40 ±7.6 years and the median disease duration of 36 months. Among the subjects, 26 patients (68.4%) were anti-MCV positive. There was no correlation between anti-MCV and CTX-1 levels (r = 0.101, p = 0.274). There was a moderate negative correlation between anti-MCV and P1NP (r = –0.449, p = 0.001). The mean difference of P1NP according to anti-MCV level also showed a significant difference (p = 0.019)ConclusionsThe anti-MCV levels are not directly correlated with CTX-1 levels, indicating heterogeneity in the disease course even after inflammation has ceased. The anti-MCV and P1NP levels are moderately correlated, indicating that bone formation is resumed during the suppression of autoimmunity.

Perioperative management of patient with late rheumatoid arthritis and post-bone tuberculosis with genu contracture undergoing tenotomy

Background: Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease that potentially attacks all parts of the human body. Despite the use of disease-modifying anti-rheumatic drugs (DMARDs), the rate of total knee arthroplasty (TKA) remains high. Critical complications such as infection, dislocation, and readmission following TKA are also reportedly high and therefore, appropriate management during perioperative period is critical. We reported the perioperative management of a patient with late RA and genu contracture underwent tenotomy. Case Presentation: A 22-year-old male was referred to Dr. Soetomo General Hospital with a chief complaint of pain in the right and left groin. He also complained of immobilization and stiffness in both knees. He had been diagnosed with bone tuberculosis in 2014 and underwent a total knee replacement of both knees in 2015 due to stiffness and inability to walk. Radiography examination indicated erosion and loss of joint spaces in the joints of the hip, fingers, and toes. Laboratory investigation showed positive anti-mutated citrullinated vimentin (anti-MCV), confirming RA. The patient underwent tenotomy surgery and was treated with methylprednisolone 4 mg peroral daily, chloroquine 250 mg peroral daily, and natrium diclofenac peroral to reduce pain. Tenotomy was performed. Considering the disease activity, conventional DMARDs (chloroquine 250 mg peroral and low dose steroid, methylprednisolone 1x4mg peroral) were prescribed. Conclusion: The case highlights the complexity of perioperative management of late RA and genu contracture underwent tenotomy that required multiple disciplines. Therefore, interdisciplinary collaborative team is critical to be able to achieve optimal results of the patient.

Tumor necrosis factor-alpha stimulated gene-6: A biomarker reflecting disease activity in rheumatoid arthritis.

BackgroundTo explore the serum tumor necrosis factor‐alpha stimulated gene‐6 (TSG‐6) level and its association with disease activity in rheumatoid arthritis (RA) patients.MethodsWe recruited 176 RA patients, 178 non‐RA patients (lupus erythematosus, osteoarthritis, ulcerative colitis, ankylosing spondylitis and psoriasis) and 71 healthy subjects. Serum TSG‐6 levels were detected by enzyme‐linked immunosorbent assay (ELISA). RA patients were divided into inactive RA and active RA groups by disease activity score of 28 joints based on C‐reactive protein (DAS28‐CRP). The receiver operating characteristic (ROC) curve and Spearman's rank correlation test analyzed the correlation between TSG‐6 concentration and RA disease activity.ResultsTumor necrosis factor‐alpha stimulated gene‐6 levels in the RA group were increased (p < 0.01). TSG‐6 concentrations indicated an upward tendency with increased disease activity; The area under the curve (AUC) of TSG‐6 for diagnosing RA and assessing the severity of RA were 0.78 and 0.80, respectively; The combination of TSG‐6 and anti‐mutated citrullinated vimentin antibodies (anti‐MCV) (sensitivity:98.4%)improved the diagnostic accuracy of RA. Binary logistic regression analysis showed that TSG‐6 was an independent risk factor related to the severity of RA, and OR (95% CI) was 1.2 (1.003–1.453).ConclusionThe TSG‐6 levels in RA patients were elevated and related to disease activity. Therefore, TSG‐6 may serve as a new potential biomarker for evaluating RA disease activity.

Predictive value of anti-mutated citrullinated vimentin antibody on one-year radiographic progression in patients with rheumatoid arthritis

Objective: To investigate the value of baseline anti-mutated citrullinated vimentin (MCV) antibody for predicting one-year radiographic progression in patients with rheumatoid arthritis (RA). Methods: Consecutive RA patients were recruited from November 2014 to July 2018 at Department of Rheumatology, Sun Yat-sen Memorial Hospital, Clinical data were collected including disease activity score in 28 joints with four variables including C-reactive protein (CRP).Serum anti-MCV antibody at baseline was detected by enzyme-linked immunosorbent assay. X ray assessment of both hands/wrists was performed and assessed according to the Sharp/van der Heijde modified score (mTSS) at baseline and the 12th month. Univariate and multivariate logistic regression analyses were used to identify the risk factors for one-year radiographic progression. Results: Among 220 RA patients recruited, the positive rate of anti-MCV antibody at baseline was 77.7%. Compared with those with negative anti-MCV antibody, RA patients with positive anti-MCV antibody had higher disease activity score in 28 joints with four variables induding CRP [3.8 (2.4, 5.0) vs. 3.1 (2.1, 4.0), P=0.007], more physical dysfunction (21.6% vs. 8.2%, P=0.033) and higher radiographic indicators including mTSS [11 (2, 27) vs. 4 (1, 10), P=0.003], joint space narrowing [JSN, 4 (0, 14) vs. 2 (0, 6), P=0.024] and joint erosion[JE, 5 (1, 18)vs. 3 (0, 5), P=0.003]. After one-year follow-up, sixty-six RA patients (30.0%) developed radiographic progression, the percentage of whom was significantly higher in positive anti-MCV group than that in negative anti-MCV group (33.9% vs.16.3%, P=0.018). Multivariate logistic regression analysis suggested that positive anti-MCV antibody at baseline was an independent risk factor for one-year radiographic progression (OR=2.341, 95%CI 1.002-5.469). Conclusion: Positive anti-MCV antibody at baseline predicts one-year radiographic progression in RA patients. In the future, anti-MCV antibody can be used not only as a supplementary laboratory marker, but also in disease activity assessment and prognosis prediction for RA.

ANTI-CYCLIC CITRULLINATED PEPTIDE ANTIBODIES VERSUS ANTI-MUTATED CITRULLINATED VIMENTIN ANTIBODIES IN JUVENILE IDIOPATHIC ARTHRITIS

Background: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood and is of unknown etiology. Anti-cyclic citrullinated peptide antibodies (Anti CCP) and anti-mutated citrullinated vimentin antibodies (Anti MCV) may help in diagnosis of JIA. Objective: Measurement of anti CCP and anti MCV level in JIA patients, and healthy persons to assess its possible role in diagnosis. Patients and methods: This study included 70 patients with JIA, and 20 healthy volunteers with matched age and sex. We assessed serum anti CCP and anti MCV level in both groups by enzyme linked immunosorbent assay (ELISA). This study carried out over a period from July, 2019 to December, 2019. Results: Serum anti-CCP and anti-MCV level showed a statistical significant difference between control and patient groups. Conclusion: Anti-CCP as well as anti-MCV antibodies may be helpful in the diagnosis of JIA and should clearly be taken into consideration.

Autoantibodies against a novel citrullinated fibrinogen peptide related to smoking status, disease activity and therapeutic response to methotrexate in cuban patients with early rheumatoid arthritis

Treatment recommendations of early rheumatoid arthritis (RA) suggest differential management of patients on the basis of prognostic factors. In this study we aimed to investigate the relationship between autoantibodies against a novel citrullinated fibrinogen peptide (anti-CFP), smoking status, clinical activity and therapeutic response in Cuban patients with early RA, receiving treatment with methotrexate in comparison to rheumatoid factor (RF), anti-cyclic citrullinated peptide of second generation (anti-CCP2) and anti-mutated citrullinated vimentin (anti-MCV). A 6-month prospective observational study was performed in 60 early RA patients at baseline and 6months after receiving methotrexate. Baseline and outcome measures included disease activity score of 28 joints (DAS 28), simplified disease activity index (SDAI), anti-CFP antibodies, RF, anti-CCP2 and anti-MCV. Therapeutic response was determined using 20/50/70 American College of Rheumatology (ACR) response rates. DAS28 (p < 0.0001), SDAI (p < 0.0001) as well as titres of anti-CFP (p = 0.0481), anti-CCP2 (p = 0.0082), RF IgM (p = 0.0187) and RF IgA (p = 0.0252) decreased under therapy. Multivariate analyses showed association of final anti-CFP values with sex and smoking status (p = 0.0296). It is of note that anti-CFP antibodies were one of predictors for DAS 28 (p = 0.0072) SDAI (p < 0.0001) and ACR response (p = 0.0003) in multivariate models. Anti-CFP antibodies decrease in correspondence with clinical improvement after 6-month therapy and are associated with sex and smoking status. Moreover, baseline anti-CFP antibodies, using in combination with sex, smoking status and autoantibodies (anti-CCP2, anti-MCV or RF) seems to have clinical relevance for predicting clinical activity and therapeutic response.

Abatacept induced long-term non-progressive reduction in gamma-globulins and autoantibodies: dissociation from disease activity control.

To evaluate long-term effects on gamma-globulins and autoantibodies of abatacept (ABA) versus tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients. Eighteen RA patients undergoing abatacept (ABA-RA) and 18 age/sex-matched patients treated with TNFi (TNFi-RA) were compared regarding clinical data, total gamma-globulins (TGG), specific subtypes (IgG, IgM, IgA), free light chains (FLC), IgM/IgG rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP3), and anti-mutated citrullinated vimentin (anti-MCV), assessed before and every 6months, up to 24months. previous abatacept/rituximab or low TGG (< 0.7g/dL). At baseline, female sex (78 vs. 78%), age (55 vs. 53years), DAS28 (5.73 vs. 5.67), TGG (1.4 vs. 1.35g/dL), IgG (1168 vs. 1079mg/dL), IgM (107 vs. 113mg/dL), IgA (333 vs. 322mg/dL), kappa (342 vs. 249mg/dL), lambda (170 vs. 150mg/dL), IgM-RF (76 vs. 53UI), IgG-RF (63 vs. 25UI), anti-CCP3 (216 vs. 189UI), and anti-MCV (202 vs. 102UI) were comparable in ABA-RA and TNFi-RA (p > 0.05). Similar disease activity improvement was observed in both groups. In ABA-RA, significant decreases (p < 0.05) were observed in TGG (1.4 vs. 1.05g/dL), IgG (1168 vs. 997), IgA (333 vs. 278mg/dL), kappa (342 vs. 257mg/dL), lambda (170 vs. 144mg/dL), IgM-RF (76 vs. 37UI), IgG-RF (65 vs. 24UI), anti-CCP3 (216 vs. 183UI), and anti-MCV (202 vs. 60UI) at 6months, without further decreases. In contrast, TNFi-RA showed no decrease in any of such parameters. ABA-RA also had more often transient IgG levels under the lower limit of normality (66.7% vs. 33.3%, p = 0.046). No severe infection occurred. DAS28, ESR, and CRP correlated significantly to gamma-globulins and FLC at baseline (p < 0.05), but these correlations were longitudinally lost in ABA-RA, but not in TNFi-RA. ABA, but not TNFi, induces a safe, persistent, long-term, and non-progressive reduction in gamma-globulins and autoantibodies, including anti-MCV. This pattern is dissociated from disease activity control.Key Points• ABA induces a long-term and non-progressive reduction in gamma-globulins and FLC, which occurs regardless of disease activity control.• ABA-induced reduction in gamma-globulins and FLC promotes a dissociation of such parameters and disease activity.• The same pattern of reduction is observed in autoantibodies: IgM-RF, IgG-RF, anti-CCP3, and anti-MCV.• Low transient IgG can be observed in RA patients treated with ABA, but does not correlate to infection.

Diagnostic value of anti-fibrinogen citrullinated peptide in rheumatoid arthritis

ObjectiveTo determinate the diagnostic value of an antibody against a citrullinated fibrinogen peptide in Cuban patients with rheumatoid arthritis, using an enzyme immunoassay. Materials and methodsA citrullinated peptide of fibrinogen designed by informatics prediction was synthesised and used in an enzyme immunoassay. The participants were 81 patients with early disease, 81 patients with established disease, 58 patients with other rheumatic and inflammatory diseases, and 43 healthy individuals. Anti-citrullinated fibrinogen peptide, anti-mutated citrullinated vimentin, anti second generation citrullinated peptides and rheumatoid factor antibodies were determined by enzyme-linked immunosorbent assay. ResultsDetermination of anti-citrullinated peptide of fibrinogen antibodies by the designed enzyme immunoassay showed the best diagnostic value in early rheumatoid arthritis patients, with the highest value sensitivity (84%), negative predictive value (85%), Youden index (0.73%) and area under the receiver operating curve (0.9192). Specificity (89%) and positive predictive value (88%) were higher than rheumatoid factor, similar to anti-mutated citrullinated vimentin, but lower than second generation anti-citrullinated peptides assay. The positivity of C-reactive protein was associated with the presence of anti-citrullinated fibrinogen peptide antibodies and the titres of these antibodies correlated with clinical activity in early disease. ConclusionsThe immunoassay designed with a citrullinated fibrinogen peptide has a high diagnostic value and can identify patients with greater clinical activity in early rheumatoid arthritis.

Serum cytokine profile in early and established rheumatoid arthritis

Background:An important characteristic of immune pathology in rheumatoid arthritis (RA) is a B-cell tolerance defect, associated with autoantibodies production, and antigen-specific activation of Th-1 CD4+ T lymphocytes with an excess production of pro-inflammatory cytokines compared to anti-inflammatory ones. Pro-inflammatory cytokines contribute to the development of local inflammatory effects, induce bone destruction and pannus formation, and contribute to the development of autoimmune abnormalities and systemic manifestations. Anti-inflammatory cytokines are able to reduce the rate of joint destruction. There is evidence of the involvement of Th2 cytokines in the development of early RA. These facts suggest the need for a thorough investigation into the balance between the Th1 and Th2 types of immune response at different stages of the disease.Aim:To assess the importance of сytokine profiling in the evaluation of immune abnormalities in RA.Materials and methods:In this descriptive, controlled, retrospective study, we examined 118 patients with RA and 33 healthy donors as a control group. Serum IgM rheumatoid factor (RF) and C-reactive protein (CRP) levels were measured by immunonephelometry; anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-mutated citrullinated vimentin antibodies (anti-MCV) were determined by an enzyme immunoassay, cytokines levels with "xMAP" technique.Results:Serum cytokine levels vary depending on RA duration. The cytokine profile in early RA, unlike that in established RA with a duration of more than 6 months, is characterized by higher levels of pro-inflammatory (MIP-1α), Th1 (IFN-γ), and Th17 (IL-17) cytokines, colony-stimulating factors (IL-7, G-CSF), and chemokines (IL-8, IP-10) (p &lt; 0.05 for all parameters). In established RA, the levels of pro-inflammatory (IL-1β, -6, -15, TNF-α), anti-inflammatory (IL-1ra, IL-10, IL-13, IL-5), Th1 (IL-2, IL-12), Th2 (IL-9) cytokines and colony-stimulating factors (G-CSF, GM-CSF) correlate with the concentrations of IgM RF and antibodies to citrullinated proteins (antiCCP, anti-MCV) (all p &lt; 0.05). There was also а correlation between CRP and pro-inflammatory (IL-1β, IL-6, TNF-α), Th1 (IL-12), Th2 (IL-5, IL-9) cytokine levels and between DAS28 and pro-inflammatory cytokine (IL-6) and colony-stimulating factor (G-CSF) levels (all p &lt; 0.05).Conclusion:In RA, cytokines, chemokines and colony-stimulating factors mirror the inflammatory activity of the disease. Changes in blood concentrations of cytokines enable to get an insight into the complex interplay of numerous mediators of innate and acquired immunity

Predicting factors for disappearance of anti-mutated citrullinated vimentin antibodies in sera of patients with rheumatoid arthritis

Objectives: We aimed to determine the predicting factors for disappearance of anti-mutated citrullinated vimentin antibody (anti-MCV Ab) in sera from rheumatoid arthritis (RA) patients.Methods: In 2013, 95 RA patients whose Disease Activity Score with erythrocyte sedimentation rate were moderate to severe (DAS28-ESR ≥3.2) at baseline were enrolled. Titers of anti-MCV Ab and anti-cyclic citrullinated peptide (anti-CCP) Ab for 2013 and 2014 were measured. The association of anti-MCV disappearance with disease activity, treatment, interstitial lung disease (ILD), and serum markers of ILD were retrospectively examined. Predicting factors of anti-MCV disappearance were determined by multivariable analysis.Results: While anti-CCP positivity rate did not change during the year, anti-MCV Ab changed from positive to negative in 18 patients (=19.0%). Continuous biological disease-modifying anti-rheumatic drug use, prednisolone dose (≥5.0 mg daily), and low KL-6 level (<191 U/mL) were determined as predicting factors of anti-MCV disappearance by multivariable analysis. In our cohort, anti-MCV Ab disappearance was not linked to clinical and radiological improvement.Conclusion: Different from anti-CCP Ab, anti-MCV Ab in sera from RA patients can disappear in a year. Some predicting factors for such negative seroconversion were found, whereas clinical significance of anti-MCV Ab disappearance was undetermined.

Meta-analysis: compared with anti-CCP and rheumatoid factor, could anti-MCV be the next biomarker in the rheumatoid arthritis classification criteria?

Background Previous reviews of the diagnosis for rheumatoid arthritis (RA) have not compared anti-mutated citrullinated vimentin (MCV) with anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) in respect of sensitivity, specificity and the area under the curve (AUC) against disease controls for differential diagnosis. This meta-analysis aims to evaluate the value of anti-MCV in the diagnosis for RA, the combined sensitivity of anti-MCV and anti-CCP, and certain clinical characteristics related to the performance of anti-MCV. Methods Medline, Embase, Cochrane Library and Web of Science were searched for articles published up to 25 August 2018. A total of 33 studies including 6044 RA patients and 5094 healthy or disease controls achieved inclusive criteria. QUADAS-2 was applied to evaluate the quality of the included studies. The bivariate random effects model was employed in primary data synthesis to evaluate the diagnostic performance. Results The sensitivity of anti-MCV, anti-CCP and RF in RA diagnosis against a disease control group was 0.71, 0.71, 0.77, with the specificity of 0.89, 0.95, 0.73, and the AUC of the SROC of 0.89, 0.95, 0.82, respectively. The predesign of the primary study and diagnostic criteria were statistically significant as sources of heterogeneity. Anti-MCV and anti-CCP tests demonstrated a sensitivity of 0.77 when performed in parallel, with a sensitivity of 0.60 when performed in series; whereas, the combination of anti-MCV and RF presented a sensitivity of 0.64 when used in series. Conclusions Anti-MCV demonstrates comparable diagnostic value to anti-CCP and RF, thus it can be an effective diagnostic marker for RA and may be written into the next authoritative criteria.

Relationship between Helicobacter pylori cytotoxin-associated gene A protein with clinical outcomes in patients with rheumatoid arthritis

IntroductionThe Helicobacter pylori(H. pylori) infection leads to intensification of symptoms and calenture of autoimmune diseases. This study aimed to evaluate the relationship between H. pylori infection and clinical outcomes in rheumatoid arthritis (RA) patients. MethodologyThis study was performed on 100 RA patients. Blood samples were collected for measuring Anti-H. pylori IgG antibodies and cytotoxin-associated gene A (CagA) protein. Fresh fecal samples were also collected and the fecal H. pylori antigen was extracted. Clinical condition as well as severity and type of RA symptoms in both groups of H. pylori positive and H. pylori negative were also compared. ResultsSerum levels of rheumatoid factor (RF), ESR, CRP, anti-cyclic citrullinated peptide (Anti−CCP), and anti-mutated citrullinated vimentin (Anti-MCV) were significantly higher in H. pylori positive patients than in H. pylori negative patients (P < 0.05). Serum RF, ESR, CRP and Anti-MCV levels were significantly higher in CagA positive patients than in CagA negative patients (P < 0.05). There were no significant differences in DAS-28 scores between H. pylori positive and H. pylori negative patients (P = 0.064) as well as between patients with positive and negative fecal H. pylori antigen (P = 0.237). However, DAS-28 score was significantly higher in CagA positive patients than in CagA negative patients (P < 0.001). Furthermore, mean VAS score was significantly higher in H. pylori positive patients (P = 0.031) and CagA positive patients (P = 0.004); however, there were no significant differences in VAS scores between patients with positive and negative fecal H. pylori antigen (P = 0.310). ConclusionFollow-up and examination of RA patients in terms of infection with serum and fecal H. pylori organism and CagA seems necessary that will contribute to better and further control and treatment of the patients.

Anti-mutant citrullinated vimentin antibody in the diagnosis of rheumatoid arthritis

Objective This study aimed to assess the diagnostic value of anti-mutated citrullinated vimentin (MCV) antibodies in rheumatoid arthritis (RA) and its correlation with disease progression, extra-articular manifestations and overlap syndrome. Methods Retrospective Studies. Clinical data of 837 patients in PekingUnionMedicalCollegeHospitalfrom June to August 2017 were collected, including the result of anti-MCV, anti-cyclic citrullinated peptide (anti-CCP) antibodies, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR) and High-sensitivity-C-reactive protein (CRP). According to the 1987 American College of Rheumatology classification criteria for rheumatoid arthritis, there were 323 patients diagnosed with RA, including 59 males and 264 females with the average age of 51 years. According to whether the RA patients have overlap syndrome with other autoimmune disease (AID) or have extra-articular manifestations, 258 cases were categorized into RA group, including 47 males and 211 females with the average age of 50 years; 14 cases were categorized into the group of overlap syndrome, including 1 male and 13 females with the average age of 36 years; 51 cases were categorized into the group of extra-articular manifestations, including 11 males and 40 females with the average age of 59 years.According to 2010 rheumatoid arthritis classification criteria for destruction in joints, the radiographic changes were divided into 4 stages.There were 203 casesenrolled in our study, 88 caseswere fitted into early stage group (stage I)including 21 males and 67 females with the average age of 48 years; 115 caseswere fitted into progressive stage group, which compromisedstageⅡ (interim stage), stage Ⅲ (severe stage) and stage Ⅳ (final stage) cases, including 19 males and 96 females with the average age of 53 years. Mann-Whitney U test, χ2 test,Receiver operating characteristic (ROC) curves and Spearmancorrelation coefficientwere used in Statistical analysis. Results Ⅰ Amongdiagnosed RA patients, 199 (61.6%) cases were positive for anti-MCV, anti-CCP and RFsimultaneously, 42 (13%) cases were positive for anti-MCV, which was higher than anti-CCP positive (1 cases, 0.3%) or RF positive (7cases, 2.2%). The difference was statistically significant(P<0.001, P<0.001). Ⅱ ROC was calculated and MCV=35.95 U/ml was used as best-fit cut-off value. The AUC for anti-MCV was 0.867, while the sensitivity was 80.5% and specificity was 80.9%. Ⅲ The detection levels of anti-MCV (682.8 (106.4-1000.0)), anti-CCP (407 (4.0-1536.0)) and RF (82.8 (21.1-244.9)) in the group of progressive stage were higher than those in the group of early stage (114.5 (28.5-1000.0), 62.5 (5.0-1020.7), 50.1 (6.7-127.1)), which showed a significant difference (P<0.05, P<0.05, P<0.05). The anti-MCV, anti-CCP and RF were positively related to the degree of joint destruction (r=0.229, P<0.05; r=0.187, P<0.05; r=0.167, P<0.05); anti-MCV and anti-CCP were positively related to extra-articular manifestation (r=0.152, P<0.05; r=0.136, P<0.05). Conclusion Anti-MCV antibodies are more sensitive in patients with RA, and have complementary diagnostic value for anti-CCP and RF-negative patients; high levels of anti-MCV and anti-CCP in RA patients are associated with RA progression and extra-articular involvement. Key words: Arthritis, rheumatoid; Autoantibodies; Peptides, cyclic; Vimentin

Autoantibody and metalloproteinase activity in early arthritis

ObjectivesThe aim of the study was to evaluate the frequency of anti-mutated citrullinated vimentin antibodies (a-Sa), anti-citrullinated α-enolase peptide 1 antibodies (a-CEP-1), anti-filaggrin antibodies (AFAs), heterogeneous nuclear ribonucleoprotein compies/anti-RA33-antibodies (a-hnRNP/RA33), anti-carbamylated protein antibodies (a-CarP), and metalloproteinase (MMPs) activity in patients with early inflammatory arthritis (EIA).MethodsSeventy-four patients with EIA: 51 diagnosed with RA (rheumatoid arthritis) and 23 with UA (undifferentiated arthritis), and 20 healthy volunteers were enrolled to the study. Inflammatory markers, rheumatoid factor (RF), and antibodies mentioned above were assessed in all patients.ResultsIn the EIA group, we observed significantly higher concentration of a-CEP-1 (65.8 ± 111.6 RU/mL) than in controls (2.0 ± 0.0 RU/mL). In RF(+) RA patients, we observed higher concentration of a-Sa and a-CEP-1 than in other groups. A-Sa were positive in 69% of RF(+) RA, 37% of RF(−) RA, 26% of UA patients and in 10% of controls. A–CEP-1 were positive in 77% of RF(+) RA patients, in 56% of RF(−) RA patients, in 8.7% of UA patients, but they were negative in controls. In patients with RF(+) RA, positive a-CarP were present statistically significantly more often than in RF (−) RA patients. No statistically significant difference in frequency of a-hnRNP/RA33 and AFA between RF(+) RA, RF(−) RA, and UA was observed.ConclusionsOur results suggest that a-CEP-1 may help in differentiation between RF(−) RA and UA. a-CEP-1 and a-Sa may be useful while diagnosing EIA. a-CarP may be used in differentiation of RA RF(−) and UA. However, a follow-up study is needed to evaluate the prognostic value of analyzed antibodies.