-
1.
Association between Markers of Synovial Inflammation, Matrix Turnover and Symptoms in Knee Osteoarthritis: A Cross-Sectional Study.
Yang, X, Thudium, CS, Bay-Jensen, AC, Karsdal, MA, van Santen, J, Arden, NK, Perry, TA, Kluzek, S
Cells. 2021;(7)
Abstract
To investigate the association between markers of synovial inflammation and matrix turnover (MRI-based and serum biomarkers) and knee symptoms in established knee osteoarthritis (KOA). This cross-sectional study utilised data from a randomised, multicentre placebo-controlled trial (UK-VIDEO) of vitamin D therapy in symptomatic KOA. Data on serum biomarkers, type III collagen degradation (C3M), metabolite of C-reactive protein (CRPM) and cartilage oligomeric matrix protein (COMP), were available at baseline whilst contrast-enhanced (CE) MRI data were acquired in a subsample at baseline and annually. Knee symptoms were assessed using WOMAC at all visits. We examined the cross-sectional association between knee symptoms and three MRI-based and three serum markers of synovitis and matrix turnover, respectively. A total of 447 participants were included in the serum and 136 participants in the MRI analyses. MRI-defined medial perimeniscal synovitis was positively associated with knee pain and, suprapatellar and medial perimeniscal synovitis with knee function in multivariate analysis. We observed a statistically significant, negative association between a higher concentration of serum C3M and CRPM and knee pain, respectively. Furthermore, the highest CRPM quartile was negatively associated with knee function. Our findings suggest that, in established painful radiographic KOA, MRI-defined medial perimeniscal and suprapatellar synovitis were positively associated with knee symptoms. Serum-based C3M and CRPM markers were negatively associated with knee symptoms. Pain fluctuations are common in KOA and a better understanding of the relationship between markers of synovitis and matrix turnover and knee symptoms would facilitate a more accurate assessment of temporal changes in disease progression.
-
2.
Treatment Effects of Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial): A Double-Blinded, Placebo-Controlled, Single-Center, Randomized, Clinical Trial.
Meyer, MAS, Wiberg, S, Grand, J, Meyer, ASP, Obling, LER, Frydland, M, Thomsen, JH, Josiassen, J, Møller, JE, Kjaergaard, J, et al
Circulation. 2021;(19):1841-1851
-
-
Free full text
-
Abstract
BACKGROUND Patients experiencing out-of-hospital cardiac arrest who remain comatose after initial resuscitation are at high risk of morbidity and mortality attributable to the ensuing post-cardiac arrest syndrome. Systemic inflammation constitutes a major component of post-cardiac arrest syndrome, and IL-6 (interleukin-6) levels are associated with post-cardiac arrest syndrome severity. The IL-6 receptor antagonist tocilizumab could potentially dampen inflammation in post-cardiac arrest syndrome. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest of a presumed cardiac cause and thereby potentially mitigate organ injury. METHODS Eighty comatose patients with out-of-hospital cardiac arrest were randomly assigned 1:1 in a double-blinded placebo-controlled trial to a single infusion of tocilizumab or placebo in addition to standard of care including targeted temperature management. Blood samples were sequentially drawn during the initial 72 hours. The primary end point was the reduction in C-reactive protein response from baseline until 72 hours in patients treated with tocilizumab evaluated by mixed-model analysis for a treatment-by-time interaction. Secondary end points (main) were the marker of inflammation: leukocytes; the markers of myocardial injury: creatine kinase myocardial band, troponin T, and N-terminal pro B-type natriuretic peptide; and the marker of brain injury: neuron-specific enolase. These secondary end points were analyzed by mixed-model analysis. RESULTS The primary end point of reducing the C-reactive protein response by tocilizumab was achieved since there was a significant treatment-by-time interaction, P<0.0001, and a profound effect on C-reactive protein levels. Systemic inflammation was reduced by treatment with tocilizumab because both C-reactive protein and leukocyte levels were markedly reduced, tocilizumab versus placebo at 24 hours: -84% [-90%; -76%] and -34% [-46%; -19%], respectively, both P<0.001. Myocardial injury was also reduced, documented by reductions in creatine kinase myocardial band and troponin T; tocilizumab versus placebo at 12 hours: -36% [-54%; -11%] and -38% [-53%; -19%], respectively, both P<0.01. N-terminal pro B-type natriuretic peptide was similarly reduced by active treatment; tocilizumab versus placebo at 48 hours: -65% [-80%; -41%], P<0.001. There were no differences in survival or neurological outcome. CONCLUSIONS Treatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in comatose patients resuscitated from out-of-hospital cardiac arrest. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03863015.
-
3.
IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial.
Ridker, PM, Devalaraja, M, Baeres, FMM, Engelmann, MDM, Hovingh, GK, Ivkovic, M, Lo, L, Kling, D, Pergola, P, Raj, D, et al
Lancet (London, England). 2021;(10289):2060-2069
Abstract
BACKGROUND IL-6 has emerged as a pivotal factor in atherothrombosis. Yet, the safety and efficacy of IL-6 inhibition among individuals at high atherosclerotic risk but without a systemic inflammatory disorder is unknown. We therefore addressed whether ziltivekimab, a fully human monoclonal antibody directed against the IL-6 ligand, safely and effectively reduces biomarkers of inflammation and thrombosis among patients with high cardiovascular risk. We focused on individuals with elevated high-sensitivity CRP and chronic kidney disease, a group with substantial unmet clinical need in whom previous studies in inflammation inhibition have shown efficacy for cardiovascular event reduction. METHODS RESCUE is a randomised, double-blind, phase 2 trial done at 40 clinical sites in the USA. Inclusion criteria were age 18 years or older, moderate to severe chronic kidney disease, and high-sensitivity CRP of at least 2 mg/L. Participants were randomly allocated (1:1:1:1) to subcutaneous administration of placebo or ziltivekimab 7·5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks. The primary outcome was percentage change from baseline in high-sensitivity CRP after 12 weeks of treatment with ziltivekimab compared with placebo, with additional biomarker and safety data collected over 24 weeks of treatment. Primary analyses were done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. The trial is registered with ClinicalTrials.gov, NCT03926117. FINDINGS Between June 17, 2019, and Jan 14, 2020, 264 participants were enrolled into the trial, of whom 66 were randomly assigned to each of the four treatment groups. At 12 weeks after randomisation, median high-sensitivity CRP levels were reduced by 77% for the 7·5 mg group, 88% for the 15 mg group, and 92% for the 30 mg group compared with 4% for the placebo group. As such, the median pairwise differences in percentage change in high-sensitivity CRP between the ziltivekimab and placebo groups, after aligning for strata, were -66·2% for the 7·5 mg group, -77·7% for the 15 mg group, and -87·8% for the 30 mg group (all p<0·0001). Effects were stable over the 24-week treatment period. Dose-dependent reductions were also observed for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a). Ziltivekimab was well tolerated, did not affect the total cholesterol to HDL cholesterol ratio, and there were no serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia. INTERPRETATION Ziltivekimab markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis. On the basis of these data, a large-scale cardiovascular outcomes trial will investigate the effect of ziltivekimab in patients with chronic kidney disease, increased high-sensitivity CRP, and established cardiovascular disease. FUNDING Novo Nordisk.
-
4.
Markers of Myocardial Stress, Myocardial Injury, and Subclinical Inflammation and the Risk of Sudden Death.
Everett, BM, Moorthy, MV, Tikkanen, JT, Cook, NR, Albert, CM
Circulation. 2020;(12):1148-1158
-
-
Free full text
-
Abstract
BACKGROUND The majority of sudden cardiac deaths (SCDs) occur in low-risk populations often as the first manifestation of cardiovascular disease (CVD). Biomarkers are screening tools that may identify subclinical cardiovascular disease and those at elevated risk for SCD. We aimed to determine whether the total to high-density lipoprotein cholesterol ratio, high-sensitivity cardiac troponin I, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity C-reactive protein individually or in combination could identify individuals at higher SCD risk in large, free-living populations with and without cardiovascular disease. METHODS We performed a nested case-control study within 6 prospective cohort studies using 565 SCD cases matched to 1090 controls (1:2) by age, sex, ethnicity, smoking status, and presence of cardiovascular disease. RESULTS The median study follow-up time until SCD was 11.3 years. When examined as quartiles or continuous variables in conditional logistic regression models, each of the biomarkers was significantly and independently associated with SCD risk after mutually controlling for cardiac risk factors and other biomarkers. The mutually adjusted odds ratios for the top compared with the bottom quartile were 1.90 (95% CI, 1.30-2.76) for total to high-density lipoprotein cholesterol ratio, 2.59 (95% CI, 1.76-3.83) for high-sensitivity cardiac troponin I, 1.65 (95% CI, 1.12-2.44) for NT-proBNP, and 1.65 (95% CI, 1.13-2.41) for high-sensitivity C-reactive protein. A biomarker score that awarded 1 point when the concentration of any of those 4 biomarkers was in the top quartile (score range, 0-4) was strongly associated with SCD, with an adjusted odds ratio of 1.56 (95% CI, 1.37-1.77) per 1-unit increase in the score. CONCLUSIONS Widely available measures of lipids, subclinical myocardial injury, myocardial strain, and vascular inflammation show significant independent associations with SCD risk in apparently low-risk populations. In combination, these measures may have utility to identify individuals at risk for SCD.
-
5.
Effect of Gum Arabic (Acacia senegal) on C-reactive protein level among sickle cell anemia patients.
Kaddam, LA, Kaddam, AS
BMC research notes. 2020;(1):162
Abstract
OBJECTIVES Inflammation is ongoing process among sickle cell anemia even during steady state. C reactive protein (CRP) is cardinal marker that utilized widely as inflammatory indicator. Gum Arabic (GA) is gummy exudates from Acacia senegal tree. Fermentation by colonic bacteria increases serum butyrate concentrations, so considered as prebiotic agent. Gum Arabic (GA) has anti-inflammatory activity through butyrate. Earlier we proved that regular intake of GA increased fetal hemoglobin and anti-oxidant capacity most likely through raised level of butyrate, which would ameliorate symptoms of sickle cell anemia. Best of our knowledge this is the first study conducted to investigate GA intake on inflammatory markers among sickle patients. RESULTS This was a retrospective study conducted on stored samples from trial of Gum Arabic and sickle cell anemia. Quantitative CRP was measured by Mindray BS 200 before and after Gum Arabic consumption for 12 weeks. Daily intake of GA significantly decreased C reactive protein level (P.V = 001) (95% CI 0.943-3.098). No correlation between CRP and age, fetal hemoglobin, hemolysis markers and white blood cells. Our findings revealed novel effect of GA as anti-inflammatory agent could be consumed as natural dietary supplement to modulate disease severity and downregulate inflammatory process. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02467257. Registered 3rd June 2015.
-
6.
Effects of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) on Atherogenic Lipid/Lipoprotein, Apolipoprotein, and Inflammatory Parameters in Patients With Elevated High-Sensitivity C-Reactive Protein (from the ANCHOR Study).
Miller, M, Ballantyne, CM, Bays, HE, Granowitz, C, Doyle, RT, Juliano, RA, Philip, S
The American journal of cardiology. 2019;(5):696-701
Abstract
Icosapent ethyl is pure prescription eicosapentaenoic acid approved at 4 g/day as an adjunct to diet to reduce triglycerides (TG) in adults with TG ≥500 mg/dl. Elevated high-sensitivity C-reactive protein (hsCRP) is associated with increased cardiovascular risk. The 12-week ANCHOR study randomized 702 statin-treated patients at increased cardiovascular risk with TG 200 to 499 mg/dl despite low-density lipoprotein cholesterol (LDL-C) control (40 to 99 mg/dl). This post hoc analysis assessed 246 ANCHOR patients with baseline hsCRP ≥ 2.0 mg/L randomized to icosapent ethyl 4 g/day (n = 126; approved dose) or placebo (n = 120). Without increasing LDL-C, icosapent ethyl significantly reduced median TG (-20%; p < 0.0001), non-high-density lipoprotein cholesterol (-12.3%; p < 0.0001), total cholesterol (-11.1%; p < 0.0001), high-density lipoprotein cholesterol (-5.2%; p = 0.0042), very LDL-C (-21.0%; p < 0.0001), very low-density lipoprotein TG (-22.9%; p < 0.0001), remnant lipoprotein cholesterol (-23.0%; p = 0.0125), apolipoprotein B (-7.4%; p = 0.0021), apolipoprotein C-III (-16%; p < 0.0001), oxidized LDL (-13.7%; p = 0.0020), lipoprotein-associated phospholipase A2 (-19.6%; p < 0.0001), and hsCRP (-17.9%; p = 0.0213) versus placebo, while interleukin-6 and intercellular adhesion molecule-1 were not significantly changed. Eicosapentaenoic acid increased with icosapent ethyl 4 g/day +637% in plasma and +632% in red blood cells versus placebo (both p < 0.0001). Icosapent ethyl exhibited a safety profile similar to placebo. In conclusion, in statin-treated patients with hsCRP ≥ 2.0 mg/L and TG 200 to 499 mg/dl at baseline, icosapent ethyl 4 g/day significantly and safely reduced TG and other atherogenic and inflammatory parameters without increasing LDL-C versus placebo.
-
7.
Pentraxin 3 Detects Clinically Significant Fibrosis in Patients with Chronic Viral Hepatitis C.
Gorka-Dynysiewicz, J, Pazgan-Simon, M, Zuwala-Jagiello, J
BioMed research international. 2019;:2639248
Abstract
Pentraxin 3 (PTX3) plays a pathogenic role in experimental models of chronic liver injury and contributes to the progression of fibrosis. The detection of advanced fibrosis (METAVIR F≥3) is important to identify patients who are in urgent need of antiviral treatments versus those whose treatment could be deferred (F≥2). The aim was to assess the diagnostic value of PTX3 as a potential biomarker for clinically significant and advanced fibrosis. PTX3 associations with biochemical and histological parameters of inflammatory activity and fibrosis were investigated in 138 patients with chronic viral hepatitis C (HCV) before antiviral treatment. METAVIR histological scores of activity and fibrosis were obtained. PTX3 was measured by enzyme-linked immunosorbent assay. The diagnostic accuracy of serum PTX3 levels was compared to that of other fibrosis markers, including transforming growth factor-β 1 (TGF-β 1), hyaluronic acid (HA), aspartate transaminase to platelet ratio index (APRI), fibrosis score based on four factors (FIB4), gamma-glutamyltranspeptidase to platelet ratio (GPR), and the liver stiffness measurement (LSM) by transient elastography (FibroScan®). In HCV patients the PTX3 level increased in parallel with the METAVIR histological score of activity, being independently associated with the METAVIR fibrosis score (P < 0.001). Using the receiver operating characteristics analysis, the best marker for detecting F≥2 and F≥3 was PTX3 with AUC = 0.802 and AUC = 0.867, respectively. The area under the curve of PTX3 for predicting significant fibrosis (F≥2) was significantly greater than those for the GPR ratio (AUC = 0.648) and FIB-4 score (AUC = 0.770) and similar to that for APRI index (AUC = 0.831). PTX3 provided clinically relevant diagnostic accuracy as a single marker of significant fibrosis.
-
8.
C-reactive protein and blood pressure variability in type 2 hypertensive diabetic patients.
Schein, ASO, Bock, PM, Massierer, D, Gus, M, Schaan, BD
Blood pressure monitoring. 2019;(2):52-58
Abstract
OBJECTIVE Increased blood pressure (BP) variability and inflammation are included among the factors recognized as potential predictors of cardiovascular events in type 2 diabetes and hypertension. This study aimed to evaluate whether C-reactive protein (CRP) is associated with increased BP variability in diabetic-hypertensive patients. PATIENTS AND METHODS We carried out a cross-sectional study with 285 diabetic-hypertensive patients, evaluating laboratory characteristics and 24-h ambulatory BP monitoring. SD, coefficient of variation (CV%), time-rate index of 24-h systolic BP (SBP), and 24-h BP patterns were evaluated. Pearson's χ-test, Student's t-test, and the Mann-Whitney test were used to compare the groups. Groups were defined by CRP of up to 3 mg/l (low) and more than 3 mg/l (high). RESULTS The age of the patients was 59 (54-62) years; 101 (35%) were men. There was an increase in office SBP [137 (127-148) vs. 145 (130-157) mmHg] and DBP [79 (73-86) vs. 82 (76-91) mmHg] in the high CRP group. Blood pressure variability indexes were not different among groups [SD: 11.2 (9-15) vs. 12.2 (10-15) mmHg; CV%: 8.6 (7-11) vs. 9.4 (7-12); time rate: 0.55±0.12 vs.12.2 (10-15) mmHg/min]. In addition, BMI (29.3±3.8 vs. 30.9±3.6 kg/m), total cholesterol [166 (148-190) vs. 177 (156-210) mg/dl], and HbA1c [7.5% (6.6-8.9) vs.8.3% (7.1-9.9)] were higher in the high CRP group. CONCLUSION In patients with diabetes and hypertension, higher CRP levels are linked to cardiometabolic derangements, although they are not associated with increased BP variability.
-
9.
Oxidative Stress Biomarkers of Brain Damage: Hyperacute Plasma F2-Isoprostane Predicts Infarct Growth in Stroke.
Lorenzano, S, Rost, NS, Khan, M, Li, H, Lima, FO, Maas, MB, Green, RE, Thankachan, TK, Dipietro, AJ, Arai, K, et al
Stroke. 2018;(3):630-637
-
-
Free full text
-
Abstract
BACKGROUND AND PURPOSE Oxidative stress is an early response to cerebral ischemia and is likely to play an important role in the pathogenesis of cerebral ischemic injury. We sought to evaluate whether hyperacute plasma concentrations of biomarkers of oxidative stress, inflammation, and tissue damage predict infarct growth (IG). METHODS We prospectively measured plasma F2-isoprostane (F2-isoP), urinary 8-oxo-7,8-dihydro-2'-deoxyguoanosine, plasma oxygen radical absorbance capacity assay, high sensitivity C reactive protein, and matrix metalloproteinase 2 and 9 in consecutive patients with acute ischemic stroke presenting within 9 hours of symptom onset. Patients with baseline diffusion-weighted magnetic resonance imaging and follow-up diffusion-weighted imaging or computed tomographic scan were included to evaluate the final infarct volume. Baseline diffusion-weighted imaging volume and final infarct volume were analyzed using semiautomated volumetric method. IG volume was defined as the difference between final infarct volume and baseline diffusion-weighted imaging volume. RESULTS A total of 220 acute ischemic stroke subjects were included in the final analysis. One hundred seventy of these had IG. Baseline F2-isoP significantly correlated with IG volume (Spearman ρ=0.20; P=0.005) and final infarct volume (Spearman ρ=0.19; P=0.009). In a multivariate binary logistic regression model, baseline F2-isoP emerged as an independent predictor of the occurrence of IG (odds ratio, 2.57; 95% confidence interval, 1.37-4.83; P=0.007). In a multivariate linear regression model, baseline F2-isoP was independently associated with IG volume (B, 0.38; 95% confidence interval, 0.04-0.72; P=0.03). CONCLUSIONS Elevated hyperacute plasma F2-isoP concentrations independently predict the occurrence of IG and IG volume in patients with acute ischemic stroke. If validated in future studies, measuring plasma F2-isoP might be helpful in the acute setting to stratify patients with acute ischemic stroke for relative severity of ischemic injury and expected progression.
-
10.
Particulate metal exposures induce plasma metabolome changes in a commuter panel study.
Ladva, CN, Golan, R, Liang, D, Greenwald, R, Walker, DI, Uppal, K, Raysoni, AU, Tran, V, Yu, T, Flanders, WD, et al
PloS one. 2018;(9):e0203468
Abstract
INTRODUCTION Advances in liquid chromatography-mass spectrometry (LC-MS) have enabled high-resolution metabolomics (HRM) to emerge as a sensitive tool for measuring environmental exposures and corresponding biological response. Using measurements collected as part of a large, panel-based study of car commuters, the current analysis examines in-vehicle air pollution concentrations, targeted inflammatory biomarker levels, and metabolomic profiles to trace potential metabolic perturbations associated with on-road traffic exposures. METHODS A 60-person panel of adults participated in a crossover study, where each participant conducted a highway commute and randomized to either a side-street commute or clinic exposure session. In addition to in-vehicle exposure characterizations, participants contributed pre- and post-exposure dried blood spots for 2-hr changes in targeted proinflammatory and vascular injury biomarkers and 10-hr changes in the plasma metabolome. Samples were analyzed on a Thermo QExactive MS system in positive and negative electrospray ionization (ESI) mode. Data were processed and analyzed in R using apLCMS, xMSanalyzer, and limma. Features associated with environmental exposures or biological endpoints were identified with a linear mixed effects model and annotated through human metabolic pathway analysis in mummichog. RESULTS HRM detected 10-hr perturbations in 110 features associated with in-vehicle, particulate metal exposures (Al, Pb, and Fe) which reflect changes in arachidonic acid, leukotriene, and tryptophan metabolism. Two-hour changes in proinflammatory biomarkers hs-CRP, IL-6, IL-8, and IL-1β were also associated with 10-hr changes in the plasma metabolome, suggesting diverse amino acid, leukotriene, and antioxidant metabolism effects. A putatively identified metabolite, 20-OH-LTB4, decreased after in-vehicle exposure to particulate metals, suggesting a subclinical immune response. CONCLUSIONS Acute exposures to traffic-related air pollutants are associated with broad inflammatory response, including several traditional markers of inflammation.