Sarah Skeoch

Atherosclerosis in rheumatoid arthritis: is it all about inflammation?

Rheumatoid arthritis (RA) has long been associated with increased cardiovascular risk, but despite substantial improvements in disease management, mortality remains high. Atherosclerosis is more prevalent in RA than in the general population, and atherosclerotic lesions progress at a faster rate and might be more prone to rupture, causing clinical events. Cells and cytokines implicated in RA pathogenesis are also involved in the development and progression of atherosclerosis, which is generally recognized as an inflammatory condition. The two diseases also share genetic and environmental risk factors, which suggests that patients who develop RA might also be predisposed to developing cardiovascular disease. In RA, inflammation and atherosclerosis are closely linked. Inflammation mediates its effects on atherosclerosis both through modulation of traditional risk factors and by directly affecting the vessel wall. Treatments such as TNF inhibitors might have a beneficial effect on cardiovascular risk. However, whether this benefit is attributable to effective control of inflammation or whether targeting specific cytokines, implicated in atherosclerosis, provides additional risk reduction is unclear. Further knowledge of the predictors of cardiovascular risk, the effects of early control of inflammation and of drug-specific effects are likely to improve the recognition and management of cardiovascular risk in patients with RA.

Cell adhesion molecules as potential biomarkers of nephritis, damage and accelerated atherosclerosis in patients with SLE.

Objectives The aim of the current study was to compare levels of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin in lupus patients and controls and to investigate their association with clinical phenotype, disease activity and damage. Methods We compared levels of serum VCAM-1 and E-selectin in 178 female lupus patients and 69 age-and sex-matched controls. Using linear regression we also examined the association between these markers and disease activity, damage, renal and skin involvement as well as clinical and subclinical cardiovascular disease. Results E-selectin was increased in patients compared to controls (median (IQR) 10.5 (6.85, 13.9) vs 7.86 (5.39, 10.4) ng/ml; p < 0.001). E-selectin was also associated with overall damage and carotid plaque (β (95% confidence interval): 0.27 (0.029, 0.511) and 0.26 (0.148, 0.507)). Whilst there was no significant difference in VCAM-1 levels between groups overall, we found a significant association between VCAM-1 and with active renal disease (β (95% confidence interval): 1.10 (0.69, 1.51)). Conclusions E-selectin may act as a marker of cardiovascular risk in SLE, whilst VCAM-1 may have a role as a non-invasive biomarker for lupus nephritis activity.

Diagnostic yield of FDG-PET/CT in fever of unknown origin: a systematic review, meta-analysis, and Delphi exercise

AIM To perform a systematic review, meta-analysis and Delphi exercise to evaluate diagnostic yield of combined 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography and computed tomography (FDG-PET/CT) in fever of unknown origin (FUO). MATERIALS AND METHODS Four databases were searched for studies of FDG-PET/CT in FUO 1/1/2000-1/12/2015. Exclusions were non-English language, case reports, non-standard FDG radiotracer, and significant missing data. Quality was assessed by two authors independently using a standardised tool. Pooled diagnostic yield was calculated using a random-effects model. An iterative electronic and face-to-face Delphi exercise generated interspeciality consensus. RESULTS Pooled diagnostic yield was 56% (95% confidence interval [CI]: 50-61%, I2=61%) from 18 studies and 905 patients. Only five studies reported results of previous imaging, and subgroup analysis estimated diagnostic yield beyond conventional CT at 32% (95% CI: 22-44%; I2=66%). Consensus was established that FDG-PET/CT is increasingly available with an emerging role, but there is prevailing variability in practice. CONCLUSION There is insufficient evidence to support the value of FDG-PET/CT in investigative algorithms of FUO. A paradigm shift in research is needed, involving prospective studies recruiting at diagnosis of FUO, with updated case definitions and hard outcome measures. Although these studies will be a significant undertaking with multicentre collaboration, their completion is vital for balancing both radiation exposure and costs against the possible benefits of utilising FDG-PET/CT.

Imaging atherosclerosis in rheumatoid arthritis: evidence for increased prevalence, altered phenotype and a link between systemic and localised plaque inflammation.

In rheumatoid arthritis (RA), chronic inflammation is thought to drive increased cardiovascular risk through accelerated atherosclerosis. It may also lead to a more high-risk plaque phenotype. We sought to investigate carotid plaque phenotype in RA patients using Dynamic Contrast-Enhanced MRI (DCE-MRI) and Fludeoxyglucose Positron Emission Tomography(FDG-PET). In this pilot study, RA patients and age/sex-matched controls were evaluated for cardiovascular risk factors and carotid plaque on ultrasound. Subjects with plaque >2 mm thick underwent DCE-MRI, and a subgroup of patients had FDG-PET. Comparison of MRI findings between groups and correlation between clinical, serological markers and imaging findings was undertaken. 130 patients and 62 controls were recruited. Plaque was more prevalent in the RA group (53.1% vs 37.0%, p = 0.038) and was independently associated with IL6 levels (HR[95%CI]: 2.03 [1.26, 3.26] per quartile). DCE-MRI data were available in 15 patients and 5 controls. Higher prevalence of plaque calcification was noted in RA, despite similar plaque size (73.3% vs 20%, p = 0.04). FDG-PET detected plaque inflammation in 12/13 patients scanned and degree of inflammation correlated with hs-CRP (r = 0.58, p = 0.04). This study confirms increased prevalence of atherosclerosis in RA and provides data to support the hypothesis that patients have a high-risk plaque phenotype.

Evaluation of carotid plaque inflammation in patients with active rheumatoid arthritis using 18F-fluorodeoxyglucose PET-CT and MRI: a pilot study

BACKGROUND Rheumatoid arthritis is associated with a 50% increased risk in cardiovascular mortality. Inflammation is thought to accelerate atherosclerosis and might also lead to an inflammatory rupture-prone plaque phenotype. We tested the hypothesis that patients with active rheumatoid arthritis also have carotid plaque inflammation and that plaque inflammation correlates with clinical and serological markers of inflammation. METHODS Patients with active rheumatoid arthritis, defined as the Disease Activity Score in 28 joints (DAS28) score of more than 3·2, were recruited to a single centre study in the UK. Patients with carotid plaque on ultrasound underwent carotid MRI followed by (18)F-fluorodeoxyglucose ((18)F-FDG) PET-CT. Scans were co-registered and analysed by a physicist, masked to clinical information. The maximum standardised uptake values (SUV(max)) were measured in the plaque area. The association of SUV with DAS28, C-reactive protein, and CD4+CD28- T-cell frequency was tested with non-parametric statistics. Ethics approval and informed consent were obtained. FINDINGS Scans were done in 13 patients, nine of whom were women. Median age was 60 years (IQR 57-65), disease duration was 11 years (6-25), and DAS28 score was 4·52 (4·32-5·13). None had a history or symptoms of clinical cardiovascular disease or took statins. All plaques caused less than 70% stenosis, and tracer uptake in plaque was seen on PET in all 13 patients. Median SUV(max) was 2·18 (IQR 2·00-2·65), and all cases had an SUV(max) greater than 1·6 (the threshold for defining carotid plaque inflammation). There was a significant association with SUV(max) and C-reactive protein (r=0·58, p=0·04) and quartiles of CD4+CD28- T-cell frequency (p=0·045), but not with low-density lipoprotein concentrations (r=-0·49, p=0·09) or DAS28 score (r=0·38, p=0·20). No association was found with age (r=0·13, p=0·69) or sex (p=0·64). INTERPRETATION In this small pilot study, plaque inflammation was seen in all patients and correlated with C-reactive protein. Whether this finding represents simultaneous joint and plaque inflammation, which might improve on treatment of joint disease, remains to be determined. CD4+CD28- T-cells are known to predict cardiovascular events in patients with angina. Their association with plaque inflammation in this study suggests a possible role in cardiovascular risk prediction in rheumatoid arthritis. Larger studies are warranted to investigate these findings further. FUNDING North West England MRC Clinical Pharmacology and Therapeutics Clinical Research Fellowship, National Institute for Health Research, AstraZeneca-University of Manchester Strategic Alliance Fund.

Drug-Induced Interstitial Lung Disease: A Systematic Review

Background: Drug-induced interstitial lung disease (DIILD) occurs as a result of numerous agents, but the risk often only becomes apparent after the marketing authorisation of such agents. Methods: In this PRISMA-compliant systematic review, we aimed to evaluate and synthesise the current literature on DIILD. Results: Following a quality assessment, 156 full-text papers describing more than 6000 DIILD cases were included in the review. However, the majority of the papers were of low or very low quality in relation to the review question (78%). Thus, it was not possible to perform a meta-analysis, and descriptive review was undertaken instead. DIILD incidence rates varied between 4.1 and 12.4 cases/million/year. DIILD accounted for 3–5% of prevalent ILD cases. Cancer drugs, followed by rheumatology drugs, amiodarone and antibiotics, were the most common causes of DIILD. The radiopathological phenotype of DIILD varied between and within agents, and no typical radiological pattern specific to DIILD was identified. Mortality rates of over 50% were reported in some studies. Severity at presentation was the most reliable predictor of mortality. Glucocorticoids (GCs) were commonly used to treat DIILD, but no prospective studies examined their effect on outcome. Conclusions: Overall high-quality evidence in DIILD is lacking, and the current review will inform larger prospective studies to investigate the diagnosis and management of DIILD.

The Association of Baseline and Longitudinal Change in Endothelial Microparticle Count with Mortality in Chronic Kidney Disease.

Background: Chronic kidney disease (CKD) is associated with a unique milieu of vascular pathology, and effective biomarkers of active vascular damage are lacking. A candidate biomarker is the quantification of circulating endothelial microparticles (EMPs). This study observed baseline and longitudinal EMP change (δEMP) and established the association of these with all-cause mortality and cardiovascular events in CKD. Method: An observational study in adults with CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). EMPs were quantified by flow cytometry of platelet poor plasma in 2 samples 12 months apart and categorised as EMP if AnnexinV+/CD31+/CD42b- EMPs were compared between primary renal diagnoses, and correlations between EMP/δEMP and other parameters made. Adjusted hazard ratios (HRs) for time to all-cause mortality and cardiovascular events were calculated for log-transformed EMP and δEMP using a Cox proportional hazard model. Results: There were 123 patients (age 63 ± 11 years, systolic blood pressure 135 ± 18 mm Hg, eGFR 32 ± 16 mL/min/1.73 m2). The median baseline EMP count was 144/μL (range 10-714/μL). EMPs were numerically the highest in autosomal dominant polycystic kidney disease (253 [41-610]). An increase in urine protein:creatinine ratio was associated with an increase in EMP (co-efficient 0.21, p = 0.02). The adjusted HR for all-cause mortality for EMP was 8.20 (1.67-40.2, p = 0.01) and for δEMP was 2.69 (0.04-165, p = 0.64). There was no association between EMP or δEMP and cardiovascular events. Conclusion: Although EMP count was a significant marker of mortality risk, longitudinal change was not. This may reflect disease-specific EMP behaviour and the limitation of EMP as a generalised biomarker in CKD.

SAT0657 Can vascular inflammation in ra be detected using contrast enhanced mri? preliminary results

Background In rheumatoid arthritis (RA) vascular inflammation may contribute to excess cardiovascular (CV) risk. Contrast enhanced MRI has been used to detect vascular inflammation in Takayasus arteritis. In RA, its utility has not been studied but it may provide a method of identifying and monitoring vascular inflammation and effects of therapy. Objectives We sought to compare carotid artery wall enhancement on contrast enhanced MRI in RA patients and controls and evaluate association with circulating markers of inflammation, endothelial activation and CV risk factors. Methods Patients and age/sex matched controls underwent clinical and serological assessment (details in Table 1) and a screening carotid ultrasound. Those with wall thickening>2mm had a carotid MRI. T1-weighted images were acquired before and after gadopentate injection on a 3T scanner. Increase in mean signal intensity (SI) in the carotid vessel wall normalised to adjacent skeletal muscle provided a global enhancement metric (WEG). Histograms of distribution of SIs on pre-and post- contrast images were generated and bimodal Gaussian distributions fitted to explore patterns of enhancement within the wall. MRI measurements were compared between groups and association with serological markers tested using non-parametric statistics. Results 27 patients and 10 controls underwent MR imaging. Key characteristics are seen in Table 1. There was no difference in WEG between groups and no association with serological markers. However a bimodal distribution of SI in vessel wall was observed (Figure 1) and in exploratory analysis these two components were analysed separately. For the low-signal component enhancement (WElow) correlated with ESR, I-CAM, e-selectin (r=0.39,p=0.03;r=0.44,p=0.01;r=0.37,p=0.04). There was a trend towards correlation with CRP (r=0.30,0.08) and towards higher values in patients (median 0.20 (0.15, 0.33) vs 0.14 (0.11, 0.22),p=0.051). Enhancement in the high-signal component (WEhigh) was not associated with serological markers or RA status.Table 1. Key characteristics (median (IQR) or frequency (%) where*) Cases Controls P value Age (yrs) 61.0 (56.5, 64.6) 55.4 (54.0, 57.0) 0.07 Female* 22 (81) 5 (50) 0.06 LDL (mmol/L) 2.7 (2.25, 3.23) 3.80 (3.24, 4.53) 0.08 Glucose (mmol/L) 4.8 (4.6, 5.0) 5.8 (5.3, 6.0) 0.01 Hs-CRP (mg/l) 3.34 (2.04, 5.75) 0.81 (0.39, 4.58) 0.047 ESR (mm/hr) 18 (10, 35) 7 (5, 10) 0.01 ICAM (ng/ml) 161.5 (134.8, 213.4) 151.3 (106.9, 220.8) 0.51 V-CAM1 (ng/ml) 398 (352, 473) 376 (353, 390) 0.52 E-selectin (ng/ml) 7.55 (5.79, 21.1) 4.71 (3.01, 7.76) 0.11 WEG 0.23 (0.23, 0.28) 0.25 (0.18, 0.27) 0.62 WElow 0.20 (0.15, 0.33) 0.14 (0.11, 0.22) 0.05 WEhigh 0.32 (0.22, 0.50) 0.33 (0.29, 0.38) 0.73 Conclusions Simple global SI measurement on MRI did not suggest vascular inflammation in RA. However, the bimodal SI distribution may represent different wall components e.g. intima and adventitia. The differential enhancement, and association of WElow with inflammation, endothelial activation and RA status, warrants further investigation. Disclosure of Interest None declared