Chan Beals

Intensification of Statin Therapy Results in a Rapid Reduction in Atherosclerotic Inflammation Results of a Multicenter Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography Feasibility Study

OBJECTIVES The study sought to test whether high-dose statin treatment would result in greater reductions in plaque inflammation than low-dose statins, using fluorodeoxyglucose-positron emission tomography/computed tomographic imaging (FDG-PET/CT). BACKGROUND Intensification of statin therapy reduces major cardiovascular events. METHODS Adults with risk factors or with established atherosclerosis, who were not taking high-dose statins (n = 83), were randomized to atorvastatin 10 versus 80 mg in a double-blind, multicenter trial. FDG-PET/CT imaging of the ascending thoracic aorta and carotid arteries was performed at baseline, 4, and 12 weeks after randomization and target-to-background ratio (TBR) of FDG uptake within the artery wall was assessed while blinded to time points and treatment. RESULTS Sixty-seven subjects completed the study, providing imaging data for analysis. At 12 weeks, inflammation (TBR) in the index vessel was significantly reduced from baseline with atorvastatin 80 mg (% reduction [95% confidence interval]: 14.42% [8.7% to 19.8%]; p < 0.001), but not atorvastatin 10 mg (% reduction: 4.2% [-2.3% to 10.4%]; p > 0.1). Atorvastatin 80 mg resulted in significant additional relative reductions in TBR versus atorvastatin 10 mg (10.6% [2.2% to 18.3%]; p = 0.01) at week 12. Reductions from baseline in TBR were seen as early as 4 weeks after randomization with atorvastatin 10 mg (6.4% reduction, p < 0.05) and 80 mg (12.5% reduction, p < 0.001). Changes in TBR did not correlate with lipid profile changes. CONCLUSIONS Statin therapy produced significant rapid dose-dependent reductions in FDG uptake that may represent changes in atherosclerotic plaque inflammation. FDG-PET imaging may be useful in detecting early treatment effects in patients at risk or with established atherosclerosis.

Bone marrow lesions and joint effusion are strongly and independently associated with weight-bearing pain in knee osteoarthritis: data from the osteoarthritis initiative

OBJECTIVE It is widely believed that there are multiple sources of pain at a tissue level in osteoarthritis (OA). Magnetic Resonance Images (MRIs) provide a wealth of anatomic information and may allow identification of specific features associated with pain. We hypothesized that in knees with OA, bone marrow lesions (BMLs), synovitis, and effusion would be associated with weight-bearing and (less so with) non-weight-bearing pain independently. METHODS In a cross-sectional study of persons with symptomatic knee OA using univariate and multivariate logistic regressions with maximal BML, effusion, and synovitis defined by Boston Leeds Osteoarthritis Knee Score as predictors, and knee pain using weight-bearing and non-weight-bearing Western Ontario and McMaster University OA Index pain questions as the outcome, we tested the association between MRI findings and knee symptoms. RESULTS 160 participants, mean age 61 (+/-9.9), mean body mass index (BMI) 30.3 (+/-4.7) and 50% female, stronger associations were seen with weight-bearing compared with non-weight-bearing knee pain with adjusted risk ratios (RRs) of weight-bearing knee pain, for increasing maximal BML scores of 1.0 (referent) (maximal BML=0), 1.2, 1.9, and 2.0 (P for trend=0.006). For effusion scores, adjusted RRs of knee pain were 1.0, 1.7, 2.0, and 2.6 (P for trend=0.0004); and for synovitis scores, adjusted ORs were 1.0, 1.4, 1.5, and 1.9 (P for trend=0.22). CONCLUSION Cross-sectionally, maximal BML and effusion scores are independently associated with weight-bearing and less so with non-weight-bearing knee pain, supporting the idea that pain in OA is multifactorial. These MRI features should be considered as possible new treatment targets in knee OA.

Change in cartilage morphometry: a sample of the progression cohort of the Osteoarthritis Initiative

Objective: The performance characteristics of hyaline articular cartilage measurement on magnetic resonance imaging (MRI) need to be accurately delineated before widespread application of this technology. Our objective was to assess the rate of natural disease progression of cartilage morphometry measures from baseline to 1 year in knees with osteoarthritis (OA) from a subset of participants from the Osteoarthritis Initiative (OAI). Methods: Subjects included for this exploratory analysis are a subset of the approximately 4700 participants in the OAI Study. Bilateral radiographs and 3T MRI (Siemans Trio) of the knees and clinical data were obtained at baseline and annually in all participants. 160 subjects from the OAI Progression subcohort all of whom had both frequent symptoms and, in the same knee, radiographic OA based on a screening reading done at the OAI clinics were eligible for this exploratory analysis. One knee from each subject was selected for analysis. 150 participants were included. Using sagittal 3D DESSwe (double echo, steady-state sequence with water excitation) MR images from the baseline and 12 follow-up month visit, a segmentation algorithm was applied to the cartilage plates of the index knee to compute the cartilage volume, normalised cartilage volume (volume normalised to bone surface interface area), and percentage denuded area (total cartilage bone interface area denuded of cartilage). Results: Summary statistics of the changes (absolute and percentage) from baseline at 1 year and the standardised response mean (SRM), ie, mean change divided by the SD change were calculated. On average the subjects were 60.9 years of age and obese, with a mean body mass index of 30.3 kg/m2. The SRMs for cartilage volume of various locations are: central medial tibia −0.096; central medial femur −0.394; and patella −0.198. The SRMs for normalised cartilage volume of the various locations are central medial tibia −0.044, central medial femur −0.338 and patella −0.193. The majority of participants had a denuded area at baseline in the central medial femur (62%) and central medial tibia (60%). In general, the SRMs were small. Conclusions : These descriptive results of cartilage morphometry and its change at the 1-year time point from the first substantive MRI data release from the OAI Progression subcohort indicate that the annualised rates of change are small with the central medial femur showing the greatest consistent change.

Comparison of radiographic joint space width with magnetic resonance imaging cartilage morphometry: analysis of longitudinal data from the Osteoarthritis Initiative.

Magnetic resonance imaging (MRI) and radiography are established imaging modalities for the assessment of knee osteoarthritis (OA). The objective of our study was to compare the responsiveness of radiographic joint space width (JSW) with MRI‐derived measures of cartilage morphometry for OA progression in participants from the Osteoarthritis Initiative (OAI).

Test–retest repeatability of MR elastography for noninvasive liver fibrosis assessment in hepatitis C

To conduct a rigorous evaluation of the repeatability of liver stiffness assessed by MR elastography (MRE) in healthy and hepatitis‐C‐infected subjects.

Prednisone affects inflammation, glucose tolerance, and bone turnover within hours of treatment in healthy individuals

OBJECTIVE Use of glucocorticoids for anti-inflammatory efficacy is limited by their side effects. This study examined, in the same individuals, prednisones acute, dose-dependent effects on inflammation as well as biomarkers of glucose regulation and bone homeostasis. DESIGN In this randomized, double-blind, parallel-design trial of healthy adults demonstrating cutaneous allergen-induced hypersensitivity, patients received placebo or prednisone 10, 25 or 60 mg daily for 7 days. METHODS Effects on peripheral white blood cell (WBC) count, ex vivo whole blood lipopolysaccharide (LPS)-stimulated TNF-α release and response to cutaneous allergen challenge were assessed concurrently with biomarkers for glucose tolerance and bone turnover. RESULTS Differential peripheral WBC counts changed significantly within hours of prednisone administration. Ex vivo, LPS-stimulated TNF-α was significantly reduced by all prednisone doses on days 1 and 7. The late phase cutaneous allergen reaction was significantly reduced with prednisone 60 mg vs placebo on days 1 and 7. Oral glucose tolerance tests revealed significant increases in glycaemic excursion on days 1 and 7, whereas increases in insulin and C-peptide excursions were more notable on day 7 with all doses of prednisone. The bone formation markers osteocalcin, and procollagen I N- and C-terminal peptides decreased significantly on days 1 and 7 vs placebo. CONCLUSIONS In healthy young adults after single doses as low as 10 mg, prednisone treatment has significant effects on glucose tolerance and bone formation markers within hours of treatment, in parallel with anti-inflammatory effects.

Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination

Aging is associated with hyporesponse to vaccination, whose mechanisms remain unclear. In this study hepatitis B virus (HBV)-naive older adults received three vaccines, including one against HBV. Here we show, using transcriptional and cytometric profiling of whole blood collected before vaccination, that heightened expression of genes that augment B-cell responses and higher memory B-cell frequencies correlate with stronger responses to HBV vaccine. In contrast, higher levels of inflammatory response transcripts and increased frequencies of pro-inflammatory innate cells correlate with weaker responses to this vaccine. Increased numbers of erythrocytes and the haem-induced response also correlate with poor response to the HBV vaccine. A transcriptomics-based pre-vaccination predictor of response to HBV vaccine is built and validated in distinct sets of older adults. This moderately accurate (area under the curve≈65%) but robust signature is supported by flow cytometry and cytokine profiling. This study is the first that identifies baseline predictors and mechanisms of response to the HBV vaccine.

Pre-Treatment Whole Blood Gene Expression Is Associated with 14-Week Response Assessed by Dynamic Contrast Enhanced Magnetic Resonance Imaging in Infliximab-Treated Rheumatoid Arthritis Patients

Approximately 30% of rheumatoid arthritis patients achieve inadequate response to anti-TNF biologics. Attempts to identify molecular biomarkers predicting response have met with mixed success. This may be attributable, in part, to the variable and subjective disease assessment endpoints with large placebo effects typically used to classify patient response. Sixty-one patients with active RA despite methotrexate treatment, and with MRI-documented synovitis, were randomized to receive infliximab or placebo. Blood was collected at baseline and genome-wide transcription in whole blood was measured using microarrays. The primary endpoint in this study was determined by measuring the transfer rate constant (Ktrans) of a gadolinium-based contrast agent from plasma to synovium using MRI. Secondary endpoints included repeated clinical assessments with DAS28(CRP), and assessments of osteitis and synovitis by the RAMRIS method. Infliximab showed greater decrease from baseline in DCE-MRI Ktrans of wrist and MCP at all visits compared with placebo (P<0.001). Statistical analysis was performed to identify genes associated with treatment-specific 14-week change in Ktrans. The 256 genes identified were used to derive a gene signature score by averaging their log expression within each patient. The resulting score correlated with improvement of Ktrans in infliximab-treated patients and with deterioration of Ktrans in placebo-treated subjects. Poor responders showed high expression of activated B-cell genes whereas good responders exhibited a gene expression pattern consistent with mobilization of neutrophils and monocytes and high levels of reticulated platelets. This gene signature was significantly associated with clinical response in two previously published whole blood gene expression studies using anti-TNF therapies. These data provide support for the hypothesis that anti-TNF inadequate responders comprise a distinct molecular subtype of RA characterized by differences in pre-treatment blood mRNA expression. They also highlight the importance of placebo controls and robust, objective endpoints in biomarker discovery. Trial Registration: ClinicalTrials.gov NCT01313520

Region of interest analysis: by selecting regions with denuded areas can we detect greater amounts of change?

INTRODUCTION Based on recent analyses, the measures of short-term responsiveness of magnetic resonance imaging (MRI) derived cartilage morphometry may not be as large as earlier studies had suggested. We examined if by selecting regions of interest with denuded cartilage, the remaining cartilage within this region of interest was susceptible to greater rates of cartilage loss. METHODS Subjects included for this analysis are a subset of the approximately 4700 participants in the Osteoarthritis Initiative (OAI) Study. Bilateral radiographs and 3T MRI (Siemens Trio) of the knees and clinical data are obtained at baseline and annually in all participants. Hundred and fifty subjects from the OAI progression subcohort all of whom had both frequent symptoms and, in the same knee, radiographic osteoarthritis (ROA defined as definite tibio-femoral osteophytes on X-ray) based on a screening reading done at the OAI clinics. One knee from each subject was selected for analysis. Using sagittal 3D DESSwe MR images from the baseline and 12-month follow-up visit, a segmentation algorithm was applied to the cartilage plates of the index knee to compute the cartilage volume, normalized cartilage volume (volume normalized to bone surface interface area), and percent denuded area (Total Cartilage Bone Interface area denuded of cartilage). Summary statistics of the changes (absolute and percentage) from baseline at 1 year and the standardized response mean (SRM), i.e., mean change divided by the standard deviation (SD) of that change were calculated. Analyses are stratified into three groups according to baseline assessment of denuded area: those with no denuded area in the region of interest at baseline, and then two groups (intermediate denuded area (<or=median) and severe (>or=median) denuded area) of equal sample size. RESULTS On average the subjects were 60.9 years of age and obese with a mean body mass index (BMI) of 30.3 kg/m(2). For the combined central medial femur and tibia the mean volume change for the whole sample was -48.2 (SD 159.8) mm(3), which gives an SRM of -0.30. In the subsample of knees with no denuded area the SRM was -0.25, in the knees with intermediate denuded area the SRM was -0.30, and in knees with severe denuded area the SRM was -1.00. For normalized volume of the central medial femur in the subsample of knees with no denuded area the SRM was -0.22, in the knees with intermediate denuded area the SRM was -0.26, and in knees with severe denuded area (n=23) the SRM was -0.71. The magnitude of the SRMs was generally smaller in participants with no denuded area. In contrast, the SRMs in participants with denuded area were larger. CONCLUSION By selecting participants with the presence of cartilage regions with denuded area the ability to demonstrate change in cartilage loss in that specific location is markedly improved compared to persons without a full thickness lesion in that cartilage plate. This option for screening during recruitment in clinical trials could facilitate the detection of participants at greater risk of subsequent cartilage loss.

The effects of simvastatin treatment on plasma lipid-related biomarkers in men with dyslipidaemia

Background: Lipidomic biomarkers will facilitate the development of novel anti-atherosclerotic therapies. Objective: To evaluate the responses of circulating biomarkers to simvastatin treatment. Methods: A randomized, cross-over study in men with mixed dyslipidaemia was used to compare effects of simvastatin 40 mg/day with placebo. Results: Plasma concentrations of nine fatty acids (FA; of 33 evaluated) were reduced significantly by simvastatin. No changes in the rates of FA synthesis or in hepatic lipase or lipoprotein lipase activities were apparent. Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels increased. Conclusion: We identified lipidomic biomarkers of simvastatin treatment effect that are consistent with statin inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase. Trial registration: ClinicalTrials.gov identifier: NCT00935259.