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Serum connective tissue growth factor is a highly discriminatory biomarker for the diagnosis of rheumatoid arthritis.

ABSTRACT: BACKGROUND:Our previous proteomic study indicated that connective tissue growth factor (CTGF) may be a potential biomarker for rheumatoid arthritis (RA) diagnosis. The aim was to assess the performance of CTGF as a biomarker of RA. METHOD:Serum and synovial fluid CTGF was detected using a direct high sensitivity sandwich ELISA kit. Serum CTGF levels were tested for discriminatory capacity and optimal assay cutoffs determined in a training cohort of 98 cases of RA with 103 healthy controls. The assay performance was then validated in a further cohort of 572 patients (with RA (n?=?217), ankylosing spondylitis (n?=?92), gout (n?=?74), osteoarthritis (n?=?52), systemic lupus erythematosus (n?=?72), or primary Sjögren's syndrome (pSS) (n?=?65)). RESULTS:Significant elevation of synovial fluid CTGF concentration was found in RA patients, demonstrating excellent diagnostic ability to predict RA (area under the curve (AUC)?=?0.97). Similar results were found in serum CTGF detection. At the optimal cutoff value 88.66 pg/mL, the sensitivity, specificity, and the AUC was 0.86, 0.92, and 0.92, respectively, in the training cohort. Similar performance was observed in the validation cohort, with sensitivity, specificity, positive likelihood, and negative likelihood of 0.82, 0.91, 5.74, and 0.12, respectively. Stronger discriminatory capacity was seen with the combination of CTGF and anti-citrullinated protein antibody (ACPA) (AUC?=?0.96) than with either ACPA or rheumatoid factor (RF) alone (AUC?=?0.80 or 0.79, respectively). The discriminatory performance of serum CTGF was consistent across all inflammatory conditions tested (AUC >0.92 in all cases), with the sole exception of pSS. Serum CTGF did not vary with symptom duration or disease activity. CONCLUSIONS:Serum CTGF is a promising diagnostic biomarker for RA, with performance in the current study better than either ACPA or RF.

SUBMITTER: Yang X

PROVIDER: S-EPMC5700625 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Serum connective tissue growth factor is a highly discriminatory biomarker for the diagnosis of rheumatoid arthritis.

Yang Xinyu X Lin Ke K Ni Shanmin S Wang Jianmin J Tian Qingqing Q Chen Huaijun H Brown Matthew A MA Zheng Kaidi K Zhai Weitao W Sun Li L Jin Shengwei S Wang Jianguang J

Arthritis research & therapy 20171122 1

<h4>Background</h4>Our previous proteomic study indicated that connective tissue growth factor (CTGF) may be a potential biomarker for rheumatoid arthritis (RA) diagnosis. The aim was to assess the performance of CTGF as a biomarker of RA.<h4>Method</h4>Serum and synovial fluid CTGF was detected using a direct high sensitivity sandwich ELISA kit. Serum CTGF levels were tested for discriminatory capacity and optimal assay cutoffs determined in a training cohort of 98 cases of RA with 103 healthy ...[more]

PMID: 29166915

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Project description:BACKGROUND:Calprotectin (S100A8/S100A9 protein) is known as a damage-associated molecular pattern (DAMP) protein and reflects mainly neutrophil activation. Serum calprotectin levels might be a good alternative to acute-phase protein as a biomarker in inflammatory rheumatic diseases. The aim of this study is to investigate the association of serum calprotectin with disease activity and severity in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), and psoriatic arthritis (PsA). METHODS:Serum calprotectin was measured in patients with RA, axSpA, and PsA from the prospective Swiss Clinical Quality Management (SCQM) registry. Asymptomatic first-degree relatives of RA patients were used as healthy controls (HC). Outcomes included swollen joint count (SJC), Disease Activity Score (DAS), Health Assessment questionnaire (HAQ), joint radiographs, and ultrasound power Doppler (USPD) score for RA; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS) and coxitis for axSpA; and SJC and Disease Activity Index for PSoriatic Arthritis (DAPSA) for PsA. Comparison of outcomes by calprotectin quartile levels was performed using Kruskal-Wallis tests for continuous outcomes or trend tests for categorical outcomes. RESULTS:A total of 1729 subjects [RA?=?969, axSpA?=?451, PsA?=?237, and HC?=?72] were included. Median levels of serum calprotectin were higher in each disease group compared to HC (p?<?0.01). In RA patients, all clinical outcomes were statistically different between quartiles of serum calprotectin, indicating an association between calprotectin levels and higher disease activity (SJC, DAS, and USPD scores) and severity (joint radiographs and HAQ). In axSpA, an association between calprotectin levels and ASDAS score (p?<?0.01) and prevalence of coxitis (p?=?0.02) was observed. For PsA patients, SJC and DAPSA did not differ across calprotectin quartiles. CONCLUSIONS:This large study supports the association of serum calprotectin levels with disease activity in both RA and axSpA, but not in PsA.

Project description:BackgroundThe etiology of rheumatoid arthritis (RA) remains poorly understood. Early and accurate diagnosis still difficult to achieve. Inflammatory related molecules released into the circulation such cytokines and exosome-derived microRNAs (exomiRNAs) could be good candidates for early diagnosis of autoimmune diseases. We sought to discover a serum biomarker panel for the early detection of RA based on exomiRNAs and inflammatory markers.MethodsA 179 miRNAs-microarray panel was analyzed in a pilot study (4 early RA and 4 controls). Validation of deregulated exomiRNAs was performed in a larger cohort (24 patients with early RA and 24 controls). miRNet software was used to predict exomiRNA gene-targets interactions. Potentially altered pathways were analyzed by Reactome pathway database search. STRING database was used to predict protein-protein interaction networks. Enzyme-linked immunosorbent assay was used to measure serum levels of sTWEAK and sCD163. Signature biomarker candidates were statistical analyzed.ResultsWe detected 11 differentially expressed exomiRNAs in early RA pilot study. Validation analysis revealed that 6/11 exomiRNAs showed strong agreement with the pilot microarray data (exomiR-144-3p, -25-3p, -15a-5p, -451a, -107 and -185-5p). sTWEAK and sCD163 biomarkers were significantly elevated in the serum of patients with early RA. Receiver operating characteristic (ROC) analysis showed that the best panel to diagnose early RA contained exomiR-451a, exomiR-25-3p and sTWEAK, and could correctly classify 95.6% of patients, with an area under the ROC curve of 0.983 and with 100% specificity and 85.7% sensitivity. The YWHAB gene was identified as a common target of the putative miRNA-regulated pathways.ConclusionA novel serum biomarker panel composed of exomiR-451a, exomiR-25-3p and serum levels of sTWEAK may have use in the early clinical diagnosis of RA. A new predicted exomiRNA-target gene YHWAB has been identified and may have a relevant role in the development of RA.

Project description:BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint stiffness, finally leading to tissue destruction. Connective tissue growth factor (CTGF) is a critical factor in RA progression, which promotes fibroblast-like synoviocyte (FLS) proliferation, pannus formation, and the damage of cartilage as well as bone. Resolvin D1 (RvD1) can promote inflammation resolution in acute inflammatory diseases, and recently, effects of RvD1 on chronic inflammatory diseases also attracted attention. This study aimed to examine the effect of RvD1 on pannus formation in RA and the underlying mechanism.MethodsSerum levels of RvD1 and CTGF were determined in RA patients and healthy persons by UPLC-MS/MS and ELISA respectively. The levels of CTGF and inflammatory factors were assessed by qRT-PCR and ELISA. MicroRNA expression profile was determined by miRNA microarray. The effects of CTGF, RvD1, and miR-146a-5p on angiogenesis were evaluated with tube formation and chick chorioallantoic membrane (CAM) assays. Collagen-induced arthritis (CIA) mice were constructed to detect the effects of RvD1 and miR146a-5p on RA. STAT3 activation was determined by Western blotting.ResultsRvD1 levels decreased while CTGF levels increased in RA patients' serum, and an inverse correlation of the concentrations of RvD1 and CTGF in the serum of RA patients was synchronously observed. In CIA mice, RvD1 suppressed angiopoiesis and decreased the expression of CTGF. Simultaneously, RvD1 significantly decreased CTGF and pro-inflammation cytokines levels in RA FLS. Furthermore, CTGF suppressed angiopoiesis and RvD1 inhibited the proliferation and migration of RA FLS and angiopoiesis. MiRNA microarray and qRT-PCR results showed that RvD1 upregulated miRNA-146a-5p. The transfection experiments demonstrated that miRNA-146a-5p could decrease inflammatory factors and CTGF levels. Moreover, miRNA-146a-5p decreased the proliferation of FLS and angiogenesis in vivo. MiRNA-146a-5p also suppressed angiogenesis and downregulated the expression of CTGF in CIA mice. Finally, Western blot results revealed that miRNA-146a-5p inhibited the activation of STAT3.ConclusionRvD1 is prone to alleviate RA progression through the upregulation of miRNA-146a-5p to suppress the expression of CTGF and inflammatory mediators, thereby decreasing pannus formation and cartilage damage.

Project description:BackgroundDifferential diagnosis among psoriatic arthritis (PsA) and seronegative rheumatoid arthritis (Abneg RA) can be challenging particularly in the clinical setting of peripheral phenotype and autoantibodies seronegativity. The aim of the study was to identify synovial tissue (ST) biomarkers differentially expressed in PsA and Abneg RA and test their predictive value of therapeutic response.MethodsThirty-four PsA patients [12 DMARD naive and 22 non-responder to methotrexate (MTX-IR)] with peripheral joint involvement and 55 Abneg RA (27 DMARD naive and 28 MTX-IR) underwent US-guided ST biopsy and immunohistochemistry (IHC) for CD68+, CD3+, CD20+, CD21+, CD117+, and CD138+ cells. After study entry, each DMARD-naive patient started MTX therapy and was followed in an outpatient setting for at least 6 months to define the achievement of Minimal Disease Activity (PsA) and DAS remission (Abneg RA) status respectively. Each IR-MTX patient was treated according to EULAR recommendations.ResultsAt study entry, IHC analysis revealed that PsA patients had comparable levels of lining and sublining CD68+ and sublining CD21+, CD20+, and CD3+ cells than Abneg RA, despite the therapeutic regimen. Moreover, regardless of the therapeutic scheme, PsA patients showed higher IHC score of CD117+ cells (p = 0.0004 and p = 0.0005 for naive and MTX-IR patients respectively) compared to Abneg RA patients. Conversely, Abneg RA patients showed higher IHC score of CD138+ cells, irrespective to the therapeutic scheme (p = 0.04 and p = 0.002 for naive and MTX-IR patients respectively). Analyzing the response rate to the therapeutic scheme, naive PsA patients reaching MDA status at 6 months follow-up, showed, at the study entry, lower IHC score of CD3+ cells compared to PsA patients not reaching this outcome (p = 0.02); conversely, naive Abneg RA patients reaching DAS remission status at 6 months follow-up, showed, at the study entry, lower IHC score of sublining CD68+ cells compared to Abneg RA patients not reaching this outcome (p < 0.001).ConclusionsCD117+ and CD138+ cells are differentially distributed among PsA and Abneg RA. Histological analysis of ST may help to solve the clinical overlap between the two diseases and provides prognostic data about the therapy success.

Project description:BackgroundChemerin has a potential role in perpetuating inflammation in autoimmune diseases. Nevertheless, to date, there is no conclusive information on whether high chemerin levels increase the severity of rheumatoid arthritis (RA). Therefore, this study evaluated whether serum chemerin is a biomarker of disease activity in RA patients.MethodsStudy design: cross-sectional. The assessment included clinical and laboratory characteristics, body mass index (BMI) and fat mass. The severity of the disease activity was identified according to the DAS28-CRP index as follows: A) RA with a DAS28-CRP≤2.9 (remission/mild activity) and B) RA with a DAS28-CRP>2.9 (moderate/severe activity). Serum chemerin concentrations were measured by ELISA, and ≥103 ng/mL was considered a high level. Logistic regression analysis was applied to determine whether high chemerin levels were associated with disease activity in RA after adjusting for confounders. Multiple regression analysis was performed to identify variables associated with chemerin levels.ResultsOf 210 RA patients, 89 (42%) subjects had moderate/severe disease activity and had higher serum chemerin levels than patients with low disease activity or remission (86 ± 34 vs 73± 27; p = 0.003). Serum chemerin correlated with the number of swollen joints (r = 0.15; p = 0.03), DAS28-CRP (r = 0.22; p = 0.002), and C-reactive protein levels (r = 0.14; p = 0.04), but no correlation was observed with BMI and fat mass. In the adjusted logistic regression analysis, high chemerin levels (≥103 ng/mL) were associated with an increased risk of moderate/severe disease activity (OR: 2.76, 95% CI 1.35-5.62; p = 0.005). In the multiple regression analysis, after adjusting for potential confounders, serum chemerin levels were associated with higher DAS28-CRP (p = 0.002).ConclusionsHigher chemerin levels increased the risk of moderate and severe disease activity in RA. These results support the role of chemerin as a marker of inflammation in RA. Follow-up studies will identify if maintaining low chemerin levels can be used as a therapeutic target.

Project description:ObjectiveAssociations between rheumatoid arthritis (RA) and effect of treatment at the tissue levels are poorly understood. We investigated the scope of released extracellular matrix (ECM) metabolites as a consequence of tissue remodelling in patients treated with methotrexate (MTX) and tocilizumab (TCZ) compared to placebo.MethodsTissue metabolites from 387 RA patients treated with either TCZ (8 mg/kg) or MTX monotherapy (7.5-20 mg/kg) were measured at baseline and 8 weeks sera by validated ELISA assays. The levels of collagen biomarkers (C1M, C2M, C3M and C4M) together with C-reactive protein (CRP) and CRP metabolite (CRPM) were investigated. Baseline levels of biomarkers have been compared with 72 age- and gender-matched healthy controls. Comparison between treatment and response groups were done by ANCOVA, Spearman's correlation and logistic regression adjusted for age, gender, BMI and disease duration.ResultsC1M and C3M were significantly (P < 0.05) inhibited by TCZ and C3M by MTX (P < 0.01) compared to placebo. C1M and C3M inhibition with TCZ was respectively 23% and 16% greater than that of MTX (P < 0.01 and P < 0.0001). C4M was inhibited by TCZ and MTX, but the effect of TCZ was 22% greater than MTX (P < 0.0001). TCZ and MTX had minimal effect on C2M levels. MTX had no effect on CRP and CRPM, whereas TCZ reduced their levels to 69% and 27% from baseline. Investigated biomarkers revealed a significant (P < 0.05) difference in biomarker profiles of MTX ACR50 treatment responders and non-responders. Change to week 8 in levels of C3M, C4M, CRP and CRPM in MTX patients correlated significantly (rho = 0.41 to 0.18, P < 0.0001 to 0.039) with change in disease activity (DAS28) at weeks 8, 16 and 24, whereas only CRP in TCZ patients (rho = 0.32 to 0.21, P < 0.0001 to 0.01).ConclusionPatients receiving TCZ treatment for 8 weeks had higher suppression of tissue remodelling and inflammatory biomarkers over patients treated with MTX. Measured biomarkers enabled for a discrimination of biomarker profiles of ACR50 treatment responding patients and identification of those who benefit at the early time point. Week 8 change in levels of C3M, C4M, CRP and CRPM significantly predicted clinical response to treatment and correlated with DAS28 at all time points.Trial registrationClinicalTrials.gov, NCT00109408 . Date of registration: July 2005. Name of the registry: A Study to Assess the Safety and Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis.

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Serum connective tissue growth factor is a highly discriminatory biomarker for the diagnosis of rheumatoid arthritis.

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Serum connective tissue growth factor is a highly discriminatory biomarker for the diagnosis of rheumatoid arthritis.

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