Lesley-Anne Bissell

Primary myocardial disease in scleroderma—a comprehensive review of the literature to inform the UK Systemic Sclerosis Study Group cardiac working group

Cardiac disease is prevalent in SSc and associated with a poor prognosis. Differentiating primary myocardial disease (SSc-cardiomyopathy) from ischaemic heart disease is difficult and the disease phenotype most at risk is unclear. A comprehensive literature review was performed to inform the UK Systemic Sclerosis Study Group for cardiac disease tasked with producing a best practice pathway for the management of cardiac disease in SSc. This review describes the prevalence of SSc-cardiomyopathy, its associated greater mortality and various manifestations (e.g. heart failure, arrhythmias and diastolic dysfunction). The limited evidence suggests SSc-cardiomyopathy is associated with other poor prognostic indicators, including diffuse cutaneous disease, positive SSc-specific serology, black ethnicity, older age at disease onset, tendon friction rubs, abnormal nail-fold capillaroscopy and worse quality-of-life scores. Differentiating SSc-cardiomyopathy from ischaemic heart disease requires well-planned studies. Non-invasive investigative techniques are improving the understanding of its pathophysiological basis.

Consensus best practice pathway of the UK Systemic Sclerosis Study group:management of cardiac disease in systemic sclerosis

Objective Cardiac disease in SSc can manifest in various ways and is associated with a poor prognosis. There is little evidence on how best to detect and manage cardiac disease in SSc. Our objective was to produce an expert consensus best practice pathway for the management of cardiac disease in SSc. Methods The UK Systemic Sclerosis Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including cardiac disease. A multidisciplinary task force was convened. The guidelines were partly informed by a comprehensive literature review. Results A best practice pathway for cardiac disease (with a focus on primary cardiac disease) in SSc is presented, including approaches for early detection and standard pharmacological and device therapies. Due to the benefits, shared care and a multidisciplinary approach are recommended. A future research agenda has been formulated in response to the relative lack of understanding of the natural history of primary cardiac disease that was highlighted by the initiative. Conclusion The physician should be alert to the possibility of cardiac disease in SSc; it is best managed within a multidisciplinary team including both rheumatologists and cardiologists. This pathway provides a reference for all physicians managing patients with SSc.

Abnormal left ventricular geometry is prevalent in asymptomatic patients with established rheumatoid arthritis compared with those with early disease and healthy controls

Background Rheumatoid arthritis (RA) is associated with increased incidence of cardiovascular disease (CVD) and heart failure (HF) compared to the general population. CMR studies in the general population demonstrate that increases in left ventricular (LV) mass and early LV structural changes are predictors of HF in asymptomatic patients. Previous studies have reported conflicting data on LV geometry in heterogeneously sampled RA populations. Objectives To investigate the influence of disease duration on LV geometry using CMR by assessing and comparing two distinct RA populations; a well-defined population of newly diagnosed, treatment-naive RA and an established disease group. Method Seventy-five patients underwent CMR at 3.0T (Philips Achieva TX). None had known CVD or diabetes. 30 were RA patients fulfilling 2010 ACR/EULAR classification criteria, with symptoms for less than 1 year, no therapy with disease modifying anti-rheumatic drugs, disease activity score (DAS28) ≥3.2 and at least one poor RA prognostic factor. They were age-matched with 30 RA patients with disease duration >5 yrs. 15 healthy controls were age-matched. Standard balanced steady state free precession cine images were acquired and LV dimensions calculated offline. Tissue-tagging for strain analysis was acquired using a spatial modulation of magnetization pulse sequence. Results Participant characteristics can be seen in Table 1. Age, sex, blood pressure and body size were not different between the 3 groups. The established RA group had excellent disease control with median (IQR) CRP 0.0 mg/L (5.3) and DAS28 2.0 (1.7). CMR measurements are in Table 2. LV systolic performance, using LVEF and Ecc, was normal and similar in all groups. LV geometry was similar between early RA patients and healthy controls (p-values for LVEDV, LV Mass and LV Mass/LVEDV being 0.19, 0.51 and 0.11 respectively). Indexed LV mass and LV mass/LVEDV were lower in the established RA group compared to the early RA group (Mean±SD, 33 g ± 8/m 2 vs. 43 ± 9 g/m 2 , p Conclusion We compare two distinct RA populations and demonstrate that ventricular systolic performance (LVEF and Ecc) in the RA population is similar to controls of similar age. Abnormal LV geometry (LV mass and LVmass/EDV) is prevalent in asymptomatic patients with established RA. LV remodelling appears to occur despite excellent disease control, with the caveat that this is cross-sectional disease activity. These insights suggest that ventricular remodelling occurs later in RA and that CMR is a sensitive tool to detect such changes. Additional longitudinal evaluation can inform on the impact of inflammation/disease activity over time.

OP0180 Risk of Developing Clinical Synovitis in ACPA Positive Patients with Non-Specific Musculoskeletal Symptoms

Background Rheumatoid Arthritis (RA) is associated with autoantibodies including ACPA which may be present years before clinical presentation. In the pre clinical phase, patients usually present with non specific musculoskeletal (MSK) symptoms. Objectives 1- To monitor the progression In ACPA positive patients with non specific MSK symptoms to clinical synovitis (CS). 2- To investigate if demographic, clinical, imaging, and serological measures can identify patients at high risk of developing RA at pre-clinical stage. Methods Patients were recruited from rheumatology clinics and primary care. Clinical assessment and investigations including magnetic resonance imaging (MRI) and ultrasound (US) were undertaken at baseline and 3-6 month intervals or at change of symptoms. The end point was the development of CS, defined as the presence of at least one tender and swollen joint. Healthy controls were recruited as a comparator group. Results A total of 122 patients without a diagnosis of inflammatory arthritis were studied. 22 patients were found to have CS at baseline and hence were excluded from analysis. 100 patients (73% females) with a mean age of 51 years (±11.8) had no CS at baseline and were followed up for a median duration of 38.5 weeks (range 1-234 weeks). 44 patients (44%) developed CS after a median duration of 26.5 weeks (1-170 weeks); 22 patients (22%) within 6 months and 33 (33%) within 12 months. Baseline early morning stiffness (EMS) was the only clinical parameter which demonstrated significant difference between the two groups; 59 minutes in those who progressed and 19 minutes in those who did not (P=0.001). The remaining baseline demographic, clinical, and serological parameters were not significantly different between the two groups. Baseline US of wrist and hands (controls =28, patients=98) showed a mean total power Doppler (PD) of 0.2 (SD 0.5) in the controls. In patients who did not progress, mean total PD score was 0.8 (SD 1.8) compared to 2.0 (SD 3.0) in those who progressed (p=0.003). A sub group of ACPA positive patients underwent MRI of a wrist and hand (n=33). Significant difference in flexor tenosynovitis mean score was demonstrated between groups (1.8 (SD 1.6) in patients who progressed vs. 0.7 (SD 1.1) in those with no progression, p=0.024). Conclusions A significant proportion of patients in this cohort progressed to clinical synovitis, the majority within 12 months of presentation. EMS was the only clinical parameter associated with progression. US and MRI may provide a useful tool in identifying patients who may progress to CS. Disclosure of Interest C. Rakieh: None Declared, J. Nam: None Declared, L. Hunt: None Declared, E. Villeneuve: None Declared, L.-A. Bissell: None Declared, S. Das: None Declared, P. Conaghan: None Declared, D. McGonagle: None Declared, R. Wakefield: None Declared, P. Emery Consultant for: Honoraria/Advisory Board: Abbot, Pfizer, Roche, Chugai, BMS, UCB, MSD

FRI0119 Improvement in some, but not all, surrogate measures of cardiovascular disease following intensive treatment of early rheumatoid arthritis

Background Patients with rheumatoid arthritis (RA) have an elevated risk of cardiovascular disease (CVD), predominantly ischaemic heart disease (IHD). Systemic inflammation is thought to be a key contributor to this risk and it is hoped early therapeutic suppression of inflammation will reduce cardiovascular (CV) events in the long term. Insulin resistance, associated with metabolic syndrome, N-terminal pro-brain natriuretic peptide (NT-proBNP) and atherogenic lipid profiles have been proposed as potential surrogate measures of atherosclerosis in RA. Each has been shown to correlate with systemic inflammation, but their utility in RA above measurement of the acute phase response remains unknown. Objectives To determine whether suppression of inflammation in early RA influences surrogate measures of atherosclerosis, including the homeostasis model assessment of insulin resistance (HOMA-IR), NT-proBNP and dyslipidaemia. Methods CRP, fasting glucose and lipids, and in a sub-group, NT-proBNP and fasting insulin, were measured at baseline and week 26 in DMARD naïve RA patients, with 3-12 months symptoms, recruited into the Infliximab as Induction therapy for Early rheumatoid Arthritis (IDEA) multicentre double-blind randomised controlled trial. Patients met the 1987 ACR criteria. Treatment was randomised to IFX +MTX or MTX with 250mg IV methylprednisolone as induction therapy. 120mg IM methylprednisolone was given if DAS>2.4 at 3 time points within the first 26 weeks. HOMA-IR was calculated at each time point. Descriptive statistics, Wilcoxon and paired t-test, and Spearman’s correlation were performed. Results Data from 112 patients (69% female, mean age 53 years, 55% RF and 70% anti-CCP positive) were analysed. At baseline, 9% were on a statin and 14% an anti-hypertensive agent. 4 patients had known IHD and were excluded from the subsequent analysis. The median (range) CRP was 13mg/l (0-30) with CRP normal (<5.0mg/l) in 33%. Baseline CRP negatively correlated with HDL (rho -2.78, p=0.024) and total cholesterol (TC) (rho -2.33, p=0.026). 15%, 30%, 39%, and 25% had at risk levels for HDL, LDL, TC and triglyceride (TG), respectively1. In the subgroup of 79 patients with data on NT-proBNP and fasting insulin, 17% and 38% of patients had raised levels of NT-proBNP and HOMA-IR, respectively. Comparing week 26 to baseline, there was a significant fall in CRP (p<0.001; normal levels in 64%) and HOMA-IR (p=0.008; abnormal in 19%), but not NT-proBNP (p=0.132; elevated in 17%). With respect to the dyslipidaemia, HDL and TC rose (p<0.001 and p<0.001 respectively), but there was no significant change in LDL or TG. 5%, 46%, 61%, and 20% had at risk levels for HDL, LDL, TC and TG, respectively. Conclusions In this study, suppression of inflammation was associated with improvement in insulin resistance and increased HDL, but no significant change in NT-proBNP, TG or LDL following 26 weeks intensive RA treatment. Further analyses of biomarkers at week 78 and drug specific effects are underway. Long term follow up is being performed to determine if those patients with persistently abnormal CV biomarkers develop subclinical or overt CVD in the future despite intensive early treatment for RA. References JAMA. 2001;285(19):2486-97 Disclosure of Interest L.-A. Bissell: None Declared, S. Mackie: None Declared, L. Kozera: None Declared, J. Nam: None Declared, A. Burska: None Declared, E. Hensor: None Declared, H. Keen: None Declared, E. Villeneuve: None Declared, H. Donica: None Declared, P. Conaghan: None Declared, J. Andrews: None Declared, P. Emery: None Declared, A. Morgan Grant/Research support from: Supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Limited. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Limited

European multicentre study validates enhanced liver fibrosis test as biomarker of fibrosis in systemic sclerosis

Objectives To validate enhanced liver fibrosis (ELF) test and its components-amino-terminal propeptide of procollagen type III (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and HA-as biomarkers of fibrosis in SSc in an independent, international, multicentre cohort. Methods Two hundred and fifty-four SSc patients from six Rheumatology Centres were included. Sera were collected and stored according to EUSTAR biobanking recommendations and analysed through automated high throughput diagnostics. Statistical analysis was performed with SPSS software. Results Two hundred and forty-seven SSc patients (mean age 55.7 ± 13.9 years, 202 F) were analysed. ELF score, TIMP-1 and PIIINP levels were higher in males (P = 0.0197, P = 0.0107, P = 0.0108 respectively) and in dcSSc (P = 0.001, P = 0.0008, P < 0.0001 respectively). ELF score and the single markers significantly correlated with modified Rodnan skin score (r = 0.37, P < 0.0001), disease activity and severity (P < 0.0001 for all markers, except for HA P = 0.0001) and inversely with forced vital capacity, (FVC) % (TIMP-1, r = -0.21, P = 0.0012; PIIINP, r = -0.26, P = 0.0001), TLC% (ELF score, r = -0.20, P = 0.0036; TIMP-1, r = -0.32, P < 0.0001; PIIINP, r = -0.28, P < 0.0001), diffusion capacity of the lung for carbon monoxide (DLCO) % (P < 0.0001 for all markers, except for HA P = 0.0115). Multivariate analysis indicated that age (P < 0.001), modified Rodnan skin score (P < 0.001) and DLCO% (P = 0.005) were independently associated with ELF score. Conclusion Between the first and this validation studies, the value of the ELF score as independent marker of skin and lung involvement in SSc is confirmed in 457 patients. A longitudinal study is on-going to identify an SSc specific algorithm with predictive value for skin and lung progression.

Cardiovascular outcomes of patients with rheumatoid arthritis prescribed disease modifying anti-rheumatic drugs: a review

ABSTRACT Introduction: Rheumatoid arthritis (RA) is associated with a heightened risk of cardiovascular disease (CVD), with both traditional CV risk factors and inflammation contributing to this risk. Areas covered: This review highlights the burden of CVD in RA and associated traditional CV risk factors, including the complexity of dyslipidemia in RA and the so-called ‘lipid paradox.’ Furthermore, the recognized RA-disease-specific factors associated with higher risk of CVD and the role of systemic inflammation in the pathogenesis of CVD in RA will be addressed. With the advent of biologic and targeted synthetic therapies in the treatment of RA, the effect of conventional and newer generation disease modifying anti-rheumatic therapies (DMARDs) on CV risk and associated risk factors will also be discussed. Expert opinion: Identifying the RA phenotype at greatest risk of CVD, understanding the interplay of increased traditional risk factors, common inflammatory processes and RA-specific factors, and personalized use of DMARDs according to disease phenotype and comorbidity to reduce this risk are key areas for future research.

AB0047 Expression of ifn type i responsive genes in a cardiovascular disease continuum of rheumatoid arthritis

Background Rheumatoid Arthritis (RA) patients have a prominent increase in cardiovascular disease (CVD) not fully explained by traditional risk factors1. Interferons type 1 (IFN-I) have been associated with premature CVD in SLE2 and are implicated in several aspects of atherosclerosis and acute coronary syndromes3. A subpopulation of RA patients also display a peripheral blood IFN-I signature from 25% to 65%4, associated with clinical response to biologics5. The IFN-I signature association with CVD in RA remains unclear. Objectives To analyse expression of interferon type 1 response genes (ISGs) along a cardiac MRI (CMR) phenotyped CVD continuum in patients with RA. Methods PBMC samples from 94 RA patients and 21 healthy controls (HC) were obtained. RA patients were stratified based on CMR into: RA CMRneg (no CVD-RA, n=13), RA CMRpos (subclinical CVD-RA, n=54), and RA with clinical CVD (defined as history of cerebrovascular disease or ischaemic heart disease) (RA-CVD n=25). qPCR of ISGs was performed using TaqMan Gene Expression Assays on Biomark (Fluidigm) with compatible reagents. Factor analysis of Ct values from 51 genes was used to create scores by calculating median dCt for genes loaded by each factor. Results RA cohort median(IQR) age 63 (13.3)yrs, 69% female, disease duration 148.7 (215.3)mths; HC age 43 (16.5)y, 62% female. Three IFN-I factors (IFN Score 1, 2,3) were present in the dataset and were composed of 19, 21 and 7 genes respectively. The Jonckheere Tepstra test showed significant increases in expression of Score 2 across the 4 groups(p=0.002), consistent with a continuum, and multiplicity-corrected post-hoc analysis identified differences between HC and subclinical CVD (p=0.034), HC and RA-CVD (p=0.004); as well as between no CVD-RA and subclinical CVD-RA (p=0.034); and subclinical CVD-RA with RA-CVD (p=0.029). Scores 1 and 3 did not show consistent directional trends across all studied groups. In no CVD-RA expression of Score 1 and 2 positively correlated with CRP (rho=0.744, p=0.002 and rho=659, p=0.010 recspectively). Score 1 with Low-Density Lipoproteins (rho=0.527, p=0.044), Framingham 10y risk (rho=0.595, p=0.019) and Score 3 with Pulse Wave Velocity (rho=0.584, p=0.022). In subclinical CVD-RA score 3 expression negatively correlated with Left Ventricular mass (rho=−0.381, p=0.005), in RA-CVD score 3 expression positively correlated with Glucose (rho=0.724, p=0.042, Triglycerydes (rho=0.821, p=0.023) and Total Cholesterol/High-Density Lipoprotein ratio (rho=0.505, p=0.039).Abstract AB0047 – Figure 1 Conclusions An IFN-I score (Score 2) emerged as a possible factor characterising progression along a CVD continuum in RA patients, from no CVD to subclinical and clinical CVD; also distinguishing between HC and RA with subclinical and clinical CVD. IFN –I is involved in metabolic disturbancies associated with CVD development in RA. These results warrant further evaluation to confirm the findings in a larger cohort. References [1] Kaplan MJ. Curr. Opin. Rheumatol2006;18(3):289–297. [2] Somers EC, et al. PloS one2012;7(5):e37000. [3] de Winther MPJ. Arterioscler. Thromb. Vasc. Biol2016;36(2):217–218. [4] Rodríguez-Carrio J, et al. Front Immunol2018;8. [5] Thurlings RM, et al. Arthritis Rheum2010;62:3607–3614. Disclosure of Interest None declared

SAT0507 Implantable loop recorder can screen for incidental significant arrhythmias in scleroderma, with cardiac mri ecv and troponin biomarker, useful for risk stratification

Background Cardiac involvement and in particular conduction abnormalities represent a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). No studies assessed the value of implantable loop recorder (ILR) for early detection of arrhythmias in asymptomatic patients with SSc; or whether cardiac magnetic resonance (CMR) features associate with arrhythmias. Objectives To assess the prevalence of conduction abnormalities over a 3 year period using an ILR (REVEAL) and evaluate relationship with disease phenotype, cardiac biomarkers and CMR in SSc patients. Methods 20 patients(pts) with ACR/EULAR criteria for SSc, with no history of cardiovascular (CV) disease and ≤1 CV risk factor had 3T CMR with late gadolinium enhancement (LGE) and T1 mapping for ECV quantification. An ILR was then inserted, for 3 years follow-up. ILR data were downloaded every 3 months. Serum cardiac biomarkers were also measured at the initial visit. Results 19 pts had available ILR data; 12 (63%) females, median (SD) age 53(,12 6 (32%) diffuse SSc(dcSSc), 6 (32%) ACA+, 4 (21%) Scl70+, 8 (42%)history of interstitial lung disease (ILD) and 7 (36%) history of digital ulcers (DU). 14/19 had any ILR abnormalities, 8/14 significant arrhythmias: 1 complete heart block; 2 non-sustained ventricular tachycardia (NSVT), and 5 atrial arrhythmias (1 atrial flutter, 1 AF, 1 SVT, 1 AF and SVT and 1 AF followed by atrial flutter and SVT). Of these 8 pts, 4 had dcSSc, 2 Scl70+, 4 ACA+, 3 with ILD and 3 DU history. All 3 patients with severe arrhythmias (NSVT/CHB) were dcSSc, 2 Scl70+, 2 males. Management comprised 1 permanent pacemaker implantation, 3 antiarrhythmic treatment, 1 anticoagulation.15 pts had CMR. The 8 pts with significant arrhythmia appeared to have higher ECV, LV mass, and LVEF%(table 1). LGE was observed in 1(NSVT), of a total of 5/15 with LGE. HsTnI was considerably higher in those with significant arrhythmias[(mean diff.(95% CI)117 (-10, 245)].NTproBNP [(mean diff.(95% CI) 92 (-30, 214)] also appeared greater in those with significant arrhythmias. There was no difference in CK levels between the two groups. CMR baseline ILR significant arrhythmias, all yearsn=6Mean(SD) ILR no significant arrhythmiasn=9Mean(SD) Mean difference [95% CI] ECV% 32(,2 n=5 29(,4 n=9 2 [-2,6] LVEDV/BSA (ml/m2) 84(16 83(20 1 [-21, 22] LVEF% 62(4 59(5 2 [3–8] LV mass/BSA(g/m2) 46(7 44(14 2 [-10, 15] LVSV/BSA(ml/m2) 51(8 49(11 2 [-9, 13] LVESV/BSA(ml/m2) 33(9 34(10 −2[−13, 9] Distensibility(10–3mmHg-1) 5 (4) 4 (2) 0.4 [-3, 4] Torsion o 12(,6 n=5 14(,5 n=8 −2[−8, 5] LGE N 1/5 N 4/9 Conclusions This pilot study demonstrates the ability of ILR to detect life-threatening arrhythmia in asymptomatic SSc pt. The data suggest CMR ECV(but not LGE) and cardiac biomarkers, in particular hsTnI (indicating subclinical myocardial injury) may be able to identify at risk pts that would benefit from ILR screening. Future studies can inform a risk model, and provide insight into the pathogenesis of SSc associated arrhythmias. Disclosure of Interest None declared

FRI0239 Complementary Value of ELF Test and NT-proBNP in Reflecting Fibrosis and Vasculopathy in Systemic Sclerosis

Background The ELF test and its components (PIIINP, TIMP-1 and HA) have been shown to correlate with skin, lung and overall fibrosis and not with any vascular manifestation of Systemic Sclerosis (SSc)1. On the contrary, NT-proBNP has been suggested to be useful for stratification of SSc patients, especially to identify those at risk of pulmonary hypertension2. Objectives Aims of this study were: a) to validate ELF score and its single analytes on an independent cohort of scleroderma patients; b) to evaluate whether NT-proBNP could provide additional value to the development of an SSc-specific algorithm. Methods 250 sera from SSc patients from a single UK centre were analysed employing a high-throughput in vitro diagnostic of a routine NHS pathology lab to measure ELF score, its analytes and NT-proBNP levels. All patients fulfilled 2013 ACR/EULAR classification criteria for SSc. Clinical, laboratory and instrumental data were collected at time of sampling. Statistical analysis was performed using SPSS. P<0.05 was considered statistically significant. Results Multivariate analysis of ELF score (including the variables found statistically significant in univariate analysis) identified age, mRSS and DLCO% as independently associated with ELF score (p<0.0001 for all), confirming results previously published on an independent Italian cohort. As previously shown, ELF score and single analytes were not associated with heart and vascular manifestations of the disease. On the contrary NT-proBNP significantly correlated with heart severity (p<0.0001) and peripheral vasculopathy (p=0.005). Its levels were higher in patients with current digital ulcers (p=0.001), digital pitting scars (p=0.01), telangiectasias (p=0.01), systemic arterial hypertension (p=0.004), pulmonary artery hypertension (PAH) (p=0.01), diastolic dysfuction (p=0.002), reduced ejection fraction (p=0.0002), arrhythmias (p<0.0001) and dyspnoea (p=0.003) compared to those without the manifestation. Multivariate analysis identified presence of arrhythmias (p<0.0001), age (p<0.0001), PAH (p<0.001) and DLCO% (p=0.006) as independently associated with NT-proBNP. All the biomarkers significantly correlated with total Medsgers severity scale and EScSGactivity index (p<0.0001). Conclusions Our findings validate the value of ELF score in a second independent cohort of 250 SSc sera and suggest that NT-proBNP has a complementary value correlating with other aspects of the disease such as PAH and heart severity. Longitudinal multicentres studies are warranted to determine the sensitivity to change and the predictive value of these biomarkers in SSc patients and to build up a new combined scleroderma specific algorithm including markers of fibrosis and vasculopathy. References Abignano G et al. Ann Rheum Dis 2014 Avouac J et al. Arthritis Care Res 2015 Disclosure of Interest None declared