Novel Glycomimetics Protect against Glycated Low-Density Lipoprotein-Induced Vascular Calcification In Vitro via Attenuation of the RAGE/ERK/CREB Pathway.

Heparan sulphate (HS) can act as a co-receptor on the cell surface and alterations in this process underpin many pathological conditions. We have previously described the usefulness of mimics of HS (glycomimetics) in protection against ß-glycerophosphate-induced vascular calcification and in the restoration of the functional capacity of diabetic endothelial colony-forming cells in vitro. This study aims to investigate whether our novel glycomimetic compounds can attenuate glycated low-density lipoprotein (g-LDL)-induced calcification by inhibiting RAGE signalling within the context of critical limb ischemia (CLI). We used an established osteogenic in vitro vascular smooth muscle cell (VSMC) model. Osteoprotegerin (OPG), sclerostin and glycation levels were all significantly increased in CLI serum compared to healthy controls, while the vascular calcification marker osteocalcin (OCN) was down-regulated in CLI patients vs. controls. Incubation with both CLI serum and g-LDL (10 µg/mL) significantly increased VSMC calcification vs. controls after 21 days, with CLI serum-induced calcification apparent after only 10 days. Glycomimetics (C2 and C3) significantly inhibited g-LDL and CLI serum-induced mineralisation, as shown by a reduction in alizarin red (AR) staining and alkaline phosphatase (ALP) activity. Furthermore, secretion of the osteogenic marker OCN was significantly reduced in VSMCs incubated with CLI serum in the presence of glycomimetics. Phosphorylation of cyclic AMP response element-binding protein (CREB) was significantly increased in g-LDL-treated cells vs. untreated controls, which was attenuated with glycomimetics. Blocking CREB activation with a pharmacological inhibitor 666-15 replicated the protective effects of glycomimetics, evidenced by elevated AR staining. In silico molecular docking simulations revealed the binding affinity of the glycomimetics C2 and C3 with the V domain of RAGE. In conclusion, these findings demonstrate that novel glycomimetics, C2 and C3 have potent anti-calcification properties in vitro, inhibiting both g-LDL and CLI serum-induced VSMC mineralisation via the inhibition of LDLR, RAGE, CREB and subsequent expression of the downstream osteogenic markers, ALP and OCN.

Management and treatment of children, young people and adults with systemic lupus erythematosus: British Society for Rheumatology guideline scope.

The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of SLE that builds upon the existing treatment guideline for adults living with SLE published in 2017. This will incorporate advances in the assessment, diagnosis, monitoring, non-pharmacological and pharmacological management of SLE. General approaches to management as well as organ-specific treatment, including lupus nephritis and cutaneous lupus, will be covered. This will be the first guideline in SLE using a whole life course approach from childhood through adolescence and adulthood. The guideline will be developed with people with SLE as an important target audience in addition to healthcare professionals. It will include guidance related to emerging approved therapies and account for National Institute for Health and Care Excellence Technology Appraisals, National Health Service England clinical commissioning policies and national guidance relevant to SLE. The guideline will be developed using the methods and rigorous processes outlined in 'Creating Clinical Guidelines: Our Protocol' by the British Society for Rheumatology.

Incidence of giant cell arteritis is associated with COVID-19 prevalence: A population-level retrospective study.

Background: Following the first wave of the COVID-19 pandemic, it was observed that giant cell arteritis (GCA) diagnoses increased at the Royal National Hospital for Rheumatic Diseases (RNHRD) in Bath, UK. This finding may support the viral aetiology hypothesis of GCA. Better understanding of the causes of GCA may help improve diagnostic and treatment strategies leading to better outcomes for patients. Objectives: The study aims to estimate the local incidence of GCA during the early COVID-19 pandemic (2020-2021) and compare it to pre-pandemic (2015-2019) data. This study will also evaluate the temporal relationship between COVID-19 infections and GCA diagnoses. Methods: Annual incidence rates of GCA were calculated between 2015 and 2021. Local COVID-19 prevalence was estimated by measuring the number of hospital beds taken up by COVID-19 positive patients. Poisson statistics were used to compare the annual mean incidence of GCA between 2019 and 2020, and Granger causality tested the temporal relationship between COVID-19 prevalence and GCA incidence. Results: There were 60 (95% confidence interval [CI] 46-77) GCA diagnoses made in 2020 compared to 28 (CI 19-41) in 2019 (P = 0.016). Peaks in the number of COVID-19 inpatients correlated with peaks in GCA diagnoses. Granger causality testing found a statistically significant association between these peaks with a lag period of 40-45 days. Conclusion: The incidence of GCA in Bath was significantly increased in 2020 and 2021 compared to 2015-2019. The lag period between peaks was 40-45 days, suggesting that the COVID-19 virus may be a precipitating factor for GCA. More work is currently underway to interrogate the causal relationship between these two diseases.

Implementable Deep Learning for Multi-sequence Proton MRI Lung Segmentation: A Multi-center, Multi-vendor, and Multi-disease Study.

BACKGROUND: Recently, deep learning via convolutional neural networks (CNNs) has largely superseded conventional methods for proton (1 H)-MRI lung segmentation. However, previous deep learning studies have utilized single-center data and limited acquisition parameters. PURPOSE: Develop a generalizable CNN for lung segmentation in 1 H-MRI, robust to pathology, acquisition protocol, vendor, and center. STUDY TYPE: Retrospective. POPULATION: A total of 809 1 H-MRI scans from 258 participants with various pulmonary pathologies (median age (range): 57 (6-85); 42% females) and 31 healthy participants (median age (range): 34 (23-76); 34% females) that were split into training (593 scans (74%); 157 participants (55%)), testing (50 scans (6%); 50 participants (17%)) and external validation (164 scans (20%); 82 participants (28%)) sets. FIELD STRENGTH/SEQUENCE: 1.5-T and 3-T/3D spoiled-gradient recalled and ultrashort echo-time 1 H-MRI. ASSESSMENT: 2D and 3D CNNs, trained on single-center, multi-sequence data, and the conventional spatial fuzzy c-means (SFCM) method were compared to manually delineated expert segmentations. Each method was validated on external data originating from several centers. Dice similarity coefficient (DSC), average boundary Hausdorff distance (Average HD), and relative error (XOR) metrics to assess segmentation performance. STATISTICAL TESTS: Kruskal-Wallis tests assessed significances of differences between acquisitions in the testing set. Friedman tests with post hoc multiple comparisons assessed differences between the 2D CNN, 3D CNN, and SFCM. Bland-Altman analyses assessed agreement with manually derived lung volumes. A P value of <0.05 was considered statistically significant. RESULTS: The 3D CNN significantly outperformed its 2D analog and SFCM, yielding a median (range) DSC of 0.961 (0.880-0.987), Average HD of 1.63 mm (0.65-5.45) and XOR of 0.079 (0.025-0.240) on the testing set and a DSC of 0.973 (0.866-0.987), Average HD of 1.11 mm (0.47-8.13) and XOR of 0.054 (0.026-0.255) on external validation data. DATA CONCLUSION: The 3D CNN generated accurate 1 H-MRI lung segmentations on a heterogenous dataset, demonstrating robustness to disease pathology, sequence, vendor, and center. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 1.

Imaging biomarkers of lung ventilation in interstitial lung disease from 129Xe and oxygen enhanced 1H MRI.

PURPOSE: To compare imaging biomarkers from hyperpolarised 129Xe ventilation MRI and dynamic oxygen-enhanced MRI (OE-MRI) with standard pulmonary function tests (PFT) in interstitial lung disease (ILD) patients. To evaluate if biomarkers can separate ILD subtypes and detect early signs of disease resolution or progression. STUDY TYPE: Prospective longitudinal. POPULATION: Forty-one ILD (fourteen idiopathic pulmonary fibrosis (IPF), eleven hypersensitivity pneumonitis (HP), eleven drug-induced ILD (DI-ILD), five connective tissue disease related-ILD (CTD-ILD)) patients and ten healthy volunteers imaged at visit 1. Thirty-four ILD patients completed visit 2 (eleven IPF, eight HP, ten DIILD, five CTD-ILD) after 6 or 26 weeks. FIELD STRENGTH/SEQUENCE: MRI was performed at 1.5 T, including inversion recovery T1 mapping, dynamic MRI acquisition with varying oxygen levels, and hyperpolarised 129Xe ventilation MRI. Subjects underwent standard spirometry and gas transfer testing. ASSESSMENT: Five 1H MRI and two 129Xe MRI ventilation metrics were compared with spirometry and gas transfer measurements. STATISTICAL TEST: To evaluate differences at visit 1 among subgroups: ANOVA or Kruskal-Wallis rank tests with correction for multiple comparisons. To assess the relationships between imaging biomarkers, PFT, age and gender, at visit 1 and for the change between visit 1 and 2: Pearson correlations and multilinear regression models. RESULTS: The global PFT tests could not distinguish ILD subtypes. Percentage ventilated volumes were lower in ILD patients than in HVs when measured with 129Xe MRI (HV 97.4 ± 2.6, CTD-ILD: 91.0 ± 4.8 p = 0.017, DI-ILD 90.1 ± 7.4 p = 0.003, HP 92.6 ± 4.0 p = 0.013, IPF 88.1 ± 6.5 p < 0.001), but not with OE-MRI. 129Xe reported more heterogeneous ventilation in DI-ILD and IPF than in HV, and OE-MRI reported more heterogeneous ventilation in DI-ILD and IPF than in HP or CTD-ILD. The longitudinal changes reported by the imaging biomarkers did not correlate with the PFT changes between visits. DATA CONCLUSION: Neither 129Xe ventilation nor OE-MRI biomarkers investigated in this study were able to differentiate between ILD subtypes, suggesting that ventilation-only biomarkers are not indicated for this task. Limited but progressive loss of ventilated volume as measured by 129Xe-MRI may be present as the biomarker of focal disease progresses. OE-MRI biomarkers are feasible in ILD patients and do not correlate strongly with PFT. Both OE-MRI and 129Xe MRI revealed more spatially heterogeneous ventilation in DI-ILD and IPF.

Easy-BILAG: a new tool for simplified recording of SLE disease activity using BILAG-2004 index.

OBJECTIVE: BILAG-2004 index is a comprehensive disease activity instrument for SLE but administrative burden and potential frequency of errors limits its use in routine practice. We aimed to develop a tool for more accurate, time-efficient scoring of BILAG-2004 index with full fidelity to the existing instrument. METHODS: Frequency of BILAG-2004 items was collated from a BILAG-biologics registry (BILAG-BR) dataset. Easy-BILAG prototypes were developed to address known issues affecting speed and accuracy. After expert verification, accuracy and usability of the finalized Easy-BILAG was validated against standard format BILAG-2004 in a workbook exercise of 10 case vignettes. Thirty-three professionals ranging in expertise from 14 UK centres completed the validation exercise. RESULTS: Easy-BILAG incorporates all items present in ≥5% BILAG-BR records, plus full constitutional and renal domains into a rapid single page assessment. An embedded glossary and colour-coding assists domain scoring. A second page captures rarer manifestations when needed. In the validation exercise, Easy-BILAG yielded higher median scoring accuracy (96.7%) than standard BILAG-2004 documentation (87.8%, P = 0.001), with better inter-rater agreement. Easy-BILAG was completed faster (59.5 min) than the standard format (80.0 min, P = 0.04) for 10 cases. An advantage in accuracy was observed with Easy-BILAG use among general hospital rheumatologists (91.3 vs 75.0, P = 0.02), leading to equivalent accuracy as tertiary centre rheumatologists. Clinicians rated Easy-BILAG as intuitive, convenient, and well adapted for routine practice. CONCLUSION: Easy-BILAG facilitates more rapid and accurate scoring of BILAG-2004 across all clinical settings, which could improve patient care and biologics prescribing. Easy-BILAG should be adopted wherever BILAG-2004 assessment is required.

Increased number of cases of giant cell arteritis and higher rates of ophthalmic involvement during the era of COVID-19.

OBJECTIVES: Our centre offers a fast-track assessment service for patients with suspected GCA and this service continued to operate during the coronavirus disease 2019 (COVID-19) pandemic. During and immediately following the peak of the COVID-19 pandemic in the UK we observed an increase in the number of patients diagnosed with GCA as well as an increased number of patients with visual complications. Our aim was to investigate this further. METHODS: The electronic medical records of all patients referred for GCA fast-track assessment from January 2019 were reviewed. A complete list of patients undergoing temporal artery ultrasound and temporal artery biopsy for investigation of GCA dating back to 2015 was also available. RESULTS: In the 12 week period between April and June 2020, 24 patients were diagnosed with GCA. Six (25%) had associated visual impairment. In contrast, during 2019, 28 new diagnoses of GCA were made in total and just 10% of patients suffered visual involvement. The number of patients diagnosed with GCA in April-June 2020 was nearly 5-fold that of the same time period the previous year. GCA diagnoses between April and June 2020 were supported by imaging (temporal artery ultrasound or CT-PET) in 72% of cases. We noted a higher proportion of male patients and a lower median age but no clear difference in the duration of symptoms prior to assessment. CONCLUSIONS: The reasons behind our observations remain unclear. However, our findings support the viral aetiopathogenesis hypothesis for GCA and demonstrate the importance of maintaining access to urgent rheumatology services during periods of healthcare disruption.

Evaluation of a patient self-stratification methodology to identify those in need of shielding during COVID-19.

The logistical challenges of rapidly and accurately identifying those patients who needed to shield during the COVID-19 pandemic were unprecedented. We report our experiences of meeting this challenge for >9,000 patients with rheumatic and musculoskeletal disease at our centre, incorporating an element of guided patient self-stratification. Our results indicate that patients are able to stratify their own risk accurately using the BSR COVID-19 risk stratification guidance.

How consistently do physicians diagnose and manage drug-induced interstitial lung disease? Two surveys of European ILD specialist physicians.

INTRODUCTION: Currently there are no general guidelines for diagnosis or management of suspected drug-induced (DI) interstitial lung disease (ILD). The objective was to survey a sample of current European practice in the diagnosis and management of DI-ILD, in the context of the prescribing information approved by regulatory authorities for 28 licenced drugs with a recognised risk of DI-ILD. METHODS: Consultant physicians working in specialist ILD centres across Europe were emailed two surveys via a website link. Initially, opinion was sought regarding various diagnostic and management options based on seven clinical ILD case vignettes and five general questions regarding DI-ILD. The second survey involved 29 statements regarding the diagnosis and management of DI-ILD, derived from the results of the first survey. Consensus agreement was defined as 75% or greater. RESULTS: When making a diagnosis of DI-ILD, the favoured investigations used (other than computed tomography) included pulmonary function tests, bronchoscopy and blood tests. The preferred method used to decide when to stop treatment was a pulmonary function test. In the second survey, the majority of the statements were accepted by the 33 respondents, with only four of 29 statements not achieving consensus when the responses "agree" and "strongly agree" were combined as one answer. CONCLUSION: The two surveys provide guidance for clinicians regarding an approach to the diagnosis and management of DI-ILD in which the current evidence base is severely lacking, as demonstrated by the limited information provided by the manufacturers of the drugs associated with a high risk of DI-ILD that we reviewed.

The clinicoserological spectrum of inflammatory myopathy in the context of systemic sclerosis and systemic lupus erythematosus.

The autoimmune rheumatic diseases (ARDs) are characterised by a pathological triad composed of autoimmunity/inflammation, microangiopathy and aberrant tissue remodelling. Disease terms such as idiopathic inflammatory myopathy (IIM), scleroderma/systemic sclerosis (SSc), and systemic lupus erythematosus (SLE) are helpful clinically but disguise the considerable overlap that exists within these 'distinct' disorders. This is perhaps best demonstrated by inflammatory myopathy, which can be present in SSc or SLE, but can itself be absent in clinically amyopathic IIM. Archetypal clinical manifestations of ARD (such as Raynaud's phenomenon) are frequently present, albeit with varying prominence, within each of these diseases. This is certainly the case for inflammatory myositis, which has long been recognised as an important clinical feature of both SSc and SLE. Progress in elucidating the clinicoserological spectrum of autoimmune rheumatic diseases has identified autoantibody specificities that are strongly associated with 'overlap' disease and the presence of inflammatory myositis in SSc and SLE. In this review, we shall describe the prevalence, burden, prognostic value and management considerations of IIM in the context of both SSc and SLE. A major emphasis on the value of autoantibodies shall highlight the value of these tools in predicting the future occurrence of inflammatory myositis in both SSc and SLE. Where applicable, unmet research needs shall be highlighted. The review emphasises the importance of myopathy as a common feature across all the ARDs, and highlights specific antibody specificities that are strongly associated with myopathy in the context of SLE and SSc.

Progression of subclinical and clinical cardiovascular disease in a UK SLE cohort: the role of classic and SLE-related factors.

OBJECTIVES: We aimed to describe the rate and determinants of carotid plaque progression and the onset of clinical cardiovascular disease (CVD) in a UK SLE cohort. METHODS: Female patients with SLE of white British ancestry were recruited from clinics in the North-West of England and had a baseline clinical and CVD risk assessment including measurement of carotid intima-media thickness (CIMT) and plaque using B-mode Doppler ultrasound. Patients were followed up (>3.5 years after baseline visit) and had a repeat carotid Doppler to assess progression of plaque and CIMT. Clinical CVD events between visits were also noted. RESULTS: Of 200 patients with a baseline scan, 124 (62%) patients had a second assessment at a median (IQR) of 5.8 (5.2-6.3) years follow-up. New plaque developed in 32 (26%) (4.5% per annum) patients and plaque progression was observed in 52 (41%) patients. Factors associated with plaque progression were older age (OR 1.13; 95% CI 1.06 to 1.20), anticardiolipin (OR 3.36; 1.27 to 10.40) and anti-Ro (OR 0.31; 0.11 to 0.86) antibodies. CVD events occurred in 7.2% over 5.8 years compared with 1.0% predicted using the Framingham risk score (p<0.001). Higher triglycerides (OR 3.6; 1.23 to 10.56), cyclophosphamide exposure 'ever' (OR 16.7; 1.46 to 63.5) and baseline Systemic Lupus International Collaborating Clinics damage index score (OR 9.62; 1.46 to 123) independently predicted future CVD events. CONCLUSION: Accelerated atherosclerosis remains a major challenge in SLE disease management. A more comprehensive approach to CVD risk management taking into account disease factors such as severity and anticardiolipin antibody status may be necessary to improve CVD outcomes in this high-risk population.

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.

Clinicians approaches to management of background treatment in patients with SLE in clinical remission: results of an international observational survey.

BACKGROUND: The definition of remission in systemic lupus erythematosus (SLE) remains unclear, especially how background treatment should be interpreted. OBJECTIVE: To determine preferences of clinicians in treatment of patients in clinical remission from SLE and to assess how previous severity, duration of remission and serology influence changes in treatment. METHODS: We undertook an internet-based survey of clinicians managing patients with SLE. Case scenarios were constructed to reflect different remission states, previous organ involvement, serological abnormalities, duration of remission and current treatment (hydroxychloroquine (HCQ), steroids and/or immunosuppressive (ISS) agents). RESULTS: 130 clinicians from 30 countries were surveyed. The median (range) duration of practice and number of patients with SLE seen each month was 13 (2-42) years and 30 (2-200), respectively. Management decisions in all scenarios varied with greater caution in treatment reduction with shorter duration of remission, extent of serological abnormalities and previous disease severity. Even with mild disease, normal serology and a 5-year clinical remission, 113 (86.9%) clinicians continue to prescribe HCQ. Persistent abnormal serology in any scenario led to a reluctance to reduce or discontinue medications. Prescribing in remission, particularly of steroids and HCQ, varied significantly according to geographical location. CONCLUSIONS: Clinicians preferences in withdrawing or reducing treatment in patients with SLE in clinical remission vary considerably. Serological abnormalities, previous disease severity and duration of remission all influence the decision to reduce treatment. It is unusual for clinicians to stop HCQ even after prolonged periods of clinical remission. Any definition(s) of remission needs to take into consideration such evidence on how maintenance treatments are managed.

Evaluation of non-contrast MRI biomarkers in lupus nephritis.

OBJECTIVES: To investigate the association of novel non-contrast MRI biomarkers with standard measurements of renal function and renal disease activity in lupus. METHODS: A pilot study of lupus nephritis (LN) and lupus non-nephritis (LNN) patients, and healthy volunteers (HV), was undertaken. Multi-modal renal MRI was performed including sequences for arterial spin labelling (ASL) measuring blood flow, diffusion tensor imaging (DTI), measuring microstructural disruption, and effective transverse relaxation time (T2*) which is a biomarker of micro-haemorrhage. MRI measurements were compared with urinary protein creatinine ratio (uPCR) and estimated glomerular filtration rate (eGFR) measurements in the whole study population, then differences in imaging measurements between the groups were explored. RESULTS: 21 patients (6 LN, 8 LNN and 7 HV) completed the study, although ASL data were not available in 4 subjects. In the whole cohort, eGFR correlated significantly with the apparent diffusion coefficient measurement from DTI in the medulla (r=0.47, p=0.03). uPCR correlated strongly with the fractional anisotropy (FA) DTI measurement in the cortex and moderately with T2* measurements (rho=-0.71, p<0.001 and rho=-0.53, p=0.013, respectively). Delayed blood flow to the medulla was found in LN subjects and there was a trend towards lower FA values in the cortex, suggesting micro-structural disruption (p=0.04 and p=0.07, respectively). CONCLUSIONS: This preliminary study demonstrates that non-contrast renal MRI biomarkers are associated with standard measures of disease activity in lupus. The potential utility of these non-invasive biomarkers warrants further investigation, as there is an unmet need for reliable biomarkers of disease activity in lupus nephritis.

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.

Evaluation of carotid plaque inflammation in patients with active rheumatoid arthritis using (18)F-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.

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.