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Multiplex serum protein analysis reveals potential mechanisms and markers of response to hyperimmune caprine serum in systemic sclerosis.

ABSTRACT: Hyperimmune caprine serum (HICS) is a novel biological therapy with potential benefit for skin in established diffuse cutaneous systemic sclerosis. Here we report multiplex protein analysis of blood samples from a placebo-controlled phase II clinical trial and explore mechanisms of action and markers of response.Patients were treated with HICS (n?=?10) or placebo (n?=?10) over 26 weeks, with follow-up open-label treatment to 52 weeks in 14 patients. Serum or plasma samples at baseline, 26 and 52 weeks were analysed using multiplex or individual immunoassays for 41 proteins. Patterns of change were analysed by clustering using Netwalker 1.0, Pearson coefficient and significance analysis of microarrays (SAM) correction.Cluster analysis, SAM multiplex testing and paired comparison of individual analytes identified proteins that were upregulated or downregulated during treatment with HICS. There was upregulation of the hypothalamo-pituitary-adrenal axis after HICS treatment evidenced by increases in ?-MSH and ACTH in cases treated with HICS. Interestingly, significant increase in PIIINP was associated with HICS treatment and improved MRSS suggesting that this may be a marker of extracellular matrix turnover. Other relevant factors reduced in HICS-treated patients compared with controls, although not reaching statistical significance included COMP, CCL2, IL6, TIMP2, Fractalkine and TGF?1 levels.Our results suggest mechanisms of action for HICS, including upregulation of ?-MSH, that has been shown to be anti-fibrotic in preclinical models, and possible markers to be included in future trials targeting skin in diffuse cutaneous systemic sclerosis.Eudract, No. 2007-003122-24. ClinTrials.gov, No. NCT00769028 . Registered 7 October 2008.

SUBMITTER: Quillinan N

PROVIDER: S-EPMC5341430 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Multiplex serum protein analysis reveals potential mechanisms and markers of response to hyperimmune caprine serum in systemic sclerosis.

Quillinan Niamh N Clark Kristina E N KE Youl Bryan B Vernes Jeffrey J McIntosh Deirdre D Haq Syed S Denton Christopher P CP

Arthritis research & therapy 20170307 1

<h4>Background</h4>Hyperimmune caprine serum (HICS) is a novel biological therapy with potential benefit for skin in established diffuse cutaneous systemic sclerosis. Here we report multiplex protein analysis of blood samples from a placebo-controlled phase II clinical trial and explore mechanisms of action and markers of response.<h4>Methods</h4>Patients were treated with HICS (n = 10) or placebo (n = 10) over 26 weeks, with follow-up open-label treatment to 52 weeks in 14 patients. Serum or pl ...[more]

PMID: 28270187

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Project description:BackgroundThe study of molecular mechanisms characterizing disease progression may be relevant to get insights into systemic sclerosis (SSc) pathogenesis and to intercept patients at very early stage. We aimed at investigating the proteomic profile of preclinical systemic sclerosis (PreSSc) via a discovery/validation two-step approach.MethodsSOMAcan aptamer-based analysis was performed on a serum sample of 13 PreSSc (discovery cohort) according to 2001 LeRoy and Medsger criteria (characterized solely by Raynaud phenomenon plus a positive nailfold capillaroscopy and SSc-specific antibodies without any other sign of definite disease) and 8 healthy controls (HCs) age, gender, and ethnicity matched. Prospective data were available up to 4±0.6 years to determine the progression to definite SSc according to the EULAR/ACR 2013 classification criteria. In proteins with relative fluorescence units (RFU) > |1.5|-fold vs HCs values, univariate analysis was conducted via bootstrap aggregating models to determine the predicting accuracy (progression vs non-progression) of categorized baseline protein values. Gene Ontologies (GO terms) and Reactome terms of significant proteins at the adjusted 0.05 threshold were explored. Significant proteins from the discovery cohort were finally validated via ELISAs in an independent validation cohort of 50 PreSSc with clinical prospective data up to 5 years. Time-to-event analysis for interval-censored data was used to evaluate disease progression.ResultsIn the discovery cohort, 286 out of 1306 proteins analyzed via SomaScan, were differentially expressed versus HCs. Ten proteins were significantly associated with disease progression; analysis through GO and Reactome showed differentially enriched pathways involving angiogenesis, endothelial cell chemotaxis, and endothelial cell chemotaxis to fibroblast growth factor (FGF). In the validation cohort, endostatin (HR=10.23, CI95=2.2-47.59, p=0.003) was strongly associated with disease progression, as well as bFGF (HR=0.84, CI95=0.709-0.996, p=0.045) and PAF-AHβ (HR=0.372, CI95=0.171-0.809, p=0.013) CONCLUSIONS: A distinct protein profile characterized PreSSc from HCs and proteins associated with hypoxia, vasculopathy, and fibrosis regulation are linked with the progression from preclinical to definite SSc. These proteins, in particular endostatin, can be regarded both as markers of severity and molecules with pathogenetic significance as well as therapeutic targets.

Project description:ObjectiveTo assess the utility of circulating adhesion molecule levels as a prognostic indicator of disease progression in systemic sclerosis (SSc) patients with early onset disease.MethodsNinety-two Japanese patients with early onset SSc presenting with diffuse skin sclerosis and/or interstitial lung disease were registered in a multicentre, observational study. Concentrations of intercellular adhesion molecule (ICAM) -1, E-selectin, L-selectin, and P-selectin in serum samples from all patients were measured by enzyme-linked immunosorbent asssay (ELISA). In 39 patients, adhesion molecule levels were measured each year for four years. The ability of baseline adhesion molecule levels to predict subsequent progression and severity in clinical and laboratory features were evaluated statistically.ResultsAt their first visit, serum levels of ICAM-1, E-selection, P-selectin were significantly elevated and serum L-selectin levels were significantly reduced in patients with SSc compared with healthy controls. Overall, serum ICAM-1 levels at each time point were significantly inversely associated with the %vital capacity (VC) of the same time and subsequent years by univariate analysis. The initial serum ICAM-1 levels were significantly inversely associated with the %VC at the fourth year by multiple regression analysis. The initial serum P-selectin levels were significantly associated with the health assessment questionnaire disability index (HAQ-DI) at the fourth year by multiple regression analysis. Initial adhesion molecule levels were not significantly associated with other clinical features including skin thickness score. Baseline adhesion molecule levels were not significantly associated with subsequent rate of change of clinical parameters.ConclusionIn patients with SSc, serum levels of ICAM-1 and P-selectin may serve as prognostic indicators of respiratory dysfunction and physical disability, respectively. Further longitudinal studies of larger populations are needed to confirm these findings.

Project description:BACKGROUND:Systemic sclerosis (SSc) is characterized by excessive fibrosis throughout the body. This leads to the release of extracellular matrix (ECM) fragments into circulation, where they may be quantified as biomarkers. The objectives were to investigate levels of ECM turnover biomarkers and the diagnostic power of these. METHODS:Diffuse SSc patients (n = 40) fulfilling the ACR/EULAR 2013 classification criteria and asymptomatic controls were included. Patients were divided into early (<2 years of symptoms; n = 20) and late (>10 years of symptoms; n = 20) diffuse SSc. Biomarkers of type I (C1M), III (C3A, C3M), IV (C4M), V (C5M) and VI (C6M) collagen degradation and type I (PRO-C1), II (PRO-C2), III (PRO-C3), IV (PRO-C4), V (PRO-C5) and VI (PRO-C6) collagen formation were measured in serum. Repeated measures ANOVA was used to test for differences in biomarker levels and the area under the receiver operating characteristic curve (AUC) was used to investigate the ability of the biomarkers to separate groups. RESULTS:In early diffuse SSc, formation biomarkers of type III, IV, V and VI collagen were significantly increased compared to asymptomatic controls (p<0.0001). Moreover, in early diffuse SSc formation biomarkers of type III, V and VI collagen were significantly increased compared to late diffuse SSc (p = 0.0006, 0.003 and 0.004, respectively). Type I (p<0.0001), III (C3M: p = 0.001, and C3A: p = 0.02), IV (p<0.0001) and VI (p<0.0001) collagen degradation biomarkers significantly increased in early diffuse SSc compared to controls. C4M, C6M, PRO-C4, PRO-C5 and PRO-C6 had an AUC of >0.85 when assessing asymptomatic controls vs. diffuse SSc. Biomarkers of type VI collagen (PRO-C6 and C6M) turnover had the best separation with an AUC's of >0.90. CONCLUSION:Formation biomarkers of ECM turnover were shown to be significantly different between asymptomatic controls and diffuse SSc. This pilot study suggest that serological biomarkers of the ECM turnover is potentially applicable in SSc.

Project description:To investigate the miRNA signature in the serum of systemic sclerosis (SSc) patients. The levels of 758 miRNAs were evaluated in the serum of 26 SSc patients as compared to 9 healthy controls by using an Openarray platform. Patients fulfilling the ACR/EULAR 2013 classification criteria were classified in relation to the extent of skin fibrosis as limited cutaneous (lcSSc) or diffuse cutaneous SSc (dcSSc); patients fulfilling the classification criteria without skin fibrosis will be referred to as non-cutaneous SSc (ncSSc). MicroRNAs (miRNAs) are regulatory molecules, which have been addressed as potential biomarkers and therapeutic targets in rheumatic diseases. Here, we investigated the miRNA signature in the serum of systemic sclerosis (SSc) patients and we further assessed their expression in early stages of the disease.The levels of 758 miRNAs were evaluated in the serum of 26 SSc patients as compared to 9 healthy controls by using an Openarray platform. Three miRNAs were examined in an additional cohort of 107 SSc patients and 24 healthy donors by single qPCR. MiR-483-5p expression was further analysed in the serum of patients with localized scleroderma (LoS) (n=22), systemic lupus erythematosus (SLE) (n=33) and primary Sjögren’s syndrome (pSS) (n=23). The function of miR-483-5p was examined by transfecting miR-483-5p into primary human dermal fibroblasts and pulmonary endothelial cells.30 miRNAs were significantly increased in patients with SSc. Of these, miR-483-5p showed reproducibly higher levels in an independent SSc cohort and was also elevated in patients with preclinical-SSc symptoms (early SSc). Notably, miR-483-5p was not differentially expressed in patients with SLE or pSS, whereas it was up-regulated in LoS, indicating that this miRNA could be involved in the development of skin fibrosis. Consistently, miR-483-5p overexpression in fibroblasts and endothelial cells modulated the expression of fibrosis-related genes.Our findings showed that miR-483-5p is up-regulated in the serum of SSc patients, from the early stages of the disease onwards, and indicated its potential function as a fine regulator of fibrosis in SSc.

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Multiplex serum protein analysis reveals potential mechanisms and markers of response to hyperimmune caprine serum in systemic sclerosis.

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Multiplex serum protein analysis reveals potential mechanisms and markers of response to hyperimmune caprine serum in systemic sclerosis.

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