Predictors of subclinical systemic sclerosis primary heart involvement characterised by microvasculopathy and myocardial fibrosis.

OBJECTIVES: SSc primary heart involvement (SSc-pHI) is a significant cause of mortality. We aimed to characterize and identify predictors of subclinical SSc-pHI using cardiovascular MRI. METHODS: A total of 83 SSc patients with no history of cardiovascular disease or pulmonary arterial hypertension and 44 healthy controls (HCs) underwent 3 Tesla contrast-enhanced cardiovascular MRI, including T1 mapping and quantitative stress perfusion. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide were also measured. RESULTS: Cardiovascular MRI revealed a lower myocardial perfusion reserve in the SSc patients compared with HCs {median (interquartile range (IQR)] 1.9 (1.6-2.4) vs 3 (2-3.6), P < 0.001}. Late gadolinium enhancement, indicating focal fibrosis, was observed in 17/83 patients but in none of the HCs, with significantly higher extracellular volume (ECV), suggestive of diffuse fibrosis, in SSc vs HC [mean (s.d.) 31 (4) vs 25 (2), P < 0.001]. Presence of late gadolinium enhancement and higher ECV was associated with skin score [odds ratio (OR) = 1.115, P = 0.048; R2 = 0.353, P = 0.004], and ECV and myocardial perfusion reserve was associated with the presence of digital ulcers at multivariate analysis (R2 = 0.353, P < 0.001; R2 = 0.238, P = 0.011). High-sensitivity troponin I was significantly higher in patients with late gadolinium enhancement, and N-terminal pro-brain natriuretic peptide was associated with ECV (P < 0.05). CONCLUSION: Subclinical SSc-pHI is characterized by myocardial microvasculopathy, diffuse and focal myocardial fibrosis but preserved myocardial contractile function. This subclinical phenotype of SSc-pHI was associated with high-sensitivity troponin I, N-terminal pro-brain natriuretic peptide, SSc disease severity and complicated peripheral vasculopathy. These data provide information regarding the underlying pathophysiological processes and provide a basis for identifying individuals at risk of SSc-pHI.

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.

Incidental significant arrhythmia in scleroderma associates with cardiac magnetic resonance measure of fibrosis and hs-TnI and NT-proBNP.

OBJECTIVES: To screen for significant arrhythmias with an implantable loop recorder (ILR) in patients with SSc and no known cardiovascular disease, and identify associated disease phenotype, blood and cardiovascular magnetic resonance (CMR) biomarkers. METHODS: Twenty patients with SSc with no history of primary SSc heart disease, traditional cardiovascular disease, diabetes or maximum one traditional cardiovascular risk factor underwent clinical assessment, contrast-enhanced CMR and ILR insertion. RESULTS: ILR data were available for 19 patients: 63% female, mean (s.d.) age of 53 (12) years, 32% diffuse SSc. Eight patients had significant arrhythmias over 3 years: one complete heart block, two non-sustained ventricular tachycardia [all three dcSSc, two anti-topoisomerase antibodies (Scl70) positive, three interstitial lung disease and two previous digital ulceration] and five atrial arrhythmias of which four were with limited SSc. These required interventions with one permanent pacemaker implantation, four anti-arrhythmic pharmacotherapy, one anticoagulation.Patients with significant arrhythmia had higher baseline high-sensitivity troponin I and N-terminal pro-brain natriuretic peptide [mean difference (95% CI) 117 (-11, 245) and 92 (-30, 215) ng/l, respectively], and CMR-extracellular volume [mean (s.d.) 32 (2) vs 29 (4)%]. Late gadolinium enhancement was observed in five patients, only one with significant arrhythmia. CONCLUSION: This first ILR study identified potentially life-threatening arrhythmias in asymptomatic SSc patients attributable to a primary SSc heart disease. Disease phenotype, CMR-extracellular volume (indicating diffuse fibrosis) and cardiac biomarkers may identify at-risk patients that would benefit from ILR screening. Future studies can inform a risk model and provide insights into SSc-associated arrhythmia pathogenesis.

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.

Improvement in insulin resistance is greater when infliximab is added to methotrexate during intensive treatment of early rheumatoid arthritis-results from the IDEA study.

OBJECTIVES: To determine the change in established biomarkers of cardiovascular (CV) risk, namely, total cholesterol/high-density lipoprotein cholesterol ratio (TC/HDL-C), N-terminal pro-brain natriuretic peptide (NT-proBNP) and insulin resistance (IR) in patients with early RA treated with two different treat-to-target strategies. METHODS: Fasting glucose, lipids, insulin and NT-proBNP were measured at baseline, weeks 26 and 78 in 79 DMARD-naïve RA patients, free of CV disease, as part of a double-blind randomized controlled trial of MTX with either infliximab (IFX) or methylprednisolone as induction therapy. Homeostasis model assessment-estimated IR (HOMA-IR) (glucose*insulin/405) was used to measure IR. Multiple imputation was employed, and linear regression analyses were adjusted for baseline values. RESULTS: Changes in DAS44-CRP did not differ between the treatment arms at weeks 26 and 78. Mean TC/HDL-C, HOMA-IR and NT-proBNP improved in both groups at weeks 26 and 78, although change in NT-proBNP was not statistically significant at week 78. Changes in TC/HDL-C and NT-proBNP were similar between treatment arms, but HOMA-IR values in the IFX + MTX arm were 42% lower than those treated with MTX + methylprednisolone at week 78 (P = 0.003); the difference remained significant after adjustment for baseline BMI, ACPA positivity, smoking status and intramuscular glucocorticoid use (P = 0.007). CONCLUSION: When implementing a treat-to-target approach, treatment of early RA was associated with improvement in TC/HDL-C, HOMA-IR and NT-proBNP, and a greater long-term improvement in HOMA-IR was seen in those treated with IFX. TRIAL REGISTRATION: EU Clinical Trials Register, http://www.clinicaltrialsregister.eu, Eudract-2005-005013-37; ISRTCNregisrty, http://www.isrctn.com, ISRCTN48638981.

Absence of Scleroderma pattern at nail fold capillaroscopy valuable in the exclusion of Scleroderma in unselected patients with Raynaud's Phenomenon.

BACKGROUND: To report the predictive value of nail-fold capillaroscopy (NFC) patterns of vasculopathy for systemic sclerosis (Scleroderma; SSc) in an unselected cohort of patients with Raynaud's phenomenon (RP). METHODS: Patients referred to a tertiary SSc clinic with RP were evaluated by light/video-NFC. Clinical diagnosis, details and serology were recorded. Primary RP was defined as RP with no features of connective tissue disease (CTD)/antibody. NFC patterns were determined: normal, non-specific, 'early', 'active' or 'late' SSc patterns. Fulfilment of the VEDOSS or 2013 ACR/EULAR criteria for SSc was determined following NFC assessment. RESULTS: Three hundred forty-seven patients were referred: mean (SD) age 47 (15.2) years. On clinical review, 54 (16 %) did not have RP, 69 (20 %) had primary RP, 52 (15 %) had SSc and 172 (50 %) had secondary RP. NFC SSc pattern was detected in 80 (23 %) patients; 37/52 with SSc, 30/172 with secondary RP, 9/69 with primary RP and 4/54 with no RP. For identifying patients who met either the VEDOSS or 2013 ACR/EULAR criteria for SSc, detection of a SSc NFC pattern had a sensitivity of 71 %, specificity 95 %, positive predictive value 84 % and negative predictive value 90 %. CONCLUSIONS: The absence of SSc NFC pattern in patients with RP or suspected CTD is very valuable in the exclusion of SSc.

Subclinical Systemic Sclerosis Primary Heart Involvement by Cardiovascular Magnetic Resonance Shows No Significant Interval Change.

OBJECTIVE: Subclinical systemic sclerosis (SSc) primary heart involvement is commonly described. Whether these findings progress over time is not clear. The study aimed to investigate cardiovascular magnetic resonance (CMR) interval change of subclinical SSc primary heart involvement. METHODS: Patients with SSc with no cardiovascular disease underwent two CMR scans that included T1 mapping and quantitative stress perfusion. The CMR change (mean difference) and association between CMR measures and clinical phenotype were assessed. The study had a prospective design. RESULTS: Thirty-one patients with SSc participated, with a median (interquartile range) follow-up of 33 (17-37) months (10 [32%] in the diffuse subset, 16 [52%] with interstitial lung disease [ILD], and 11 [29%] who were Scl-70+). Four of thirty-one patients had focal late gadolinium enhancement (LGE) at visit 1; one of four had an increase in LGE scar mass between visits. Two patients showed new focal LGE at visit 2. No change in other CMR indices was noted. The three patients with SSc with increased or new LGE at visit 2 had diffuse cutaneous SSc with ILD, and two were Scl-70+. A reduction in forced vital capacity and total lung capacity was associated with a reduction in left ventricular ejection fraction (ρ = 0.413, P = 0.021; ρ = 0.335, P = 0.07) and myocardial perfusion reserve (MPR) (ρ = 0.543, P = 0.007; ρ = 0.627, P = 0.002). An increase in the N-terminal pro-brain natriuretic peptide level was associated with a reduction in MPR (ρ = -0.448, P = 0.042). Patients on disease-modifying antirheumatic drugs (DMARDs) had an increase in native T1 (mean [SD] 1208 [65] vs. 1265 [56] milliseconds, P = 0.008). No other clinically meaningful CMR change in patients receiving DMARDs or vasodilators was noted. CONCLUSION: Serial CMR detects interval subclinical SSc primary heart involvement progression; however, this study suggests abnormalities remain largely stable with follow-up.

Acute effects of exercise on pain symptoms, clinical inflammatory markers and inflammatory cytokines in people with rheumatoid arthritis: a systematic literature review.

Background: Exercise is advocated in the treatment of rheumatoid arthritis (RA). However, uncertainty around the acute effects of exercise on pain and inflammation may be stopping people with RA from exercising more regularly. Objectives: To determine the acute effects of exercise on pain symptoms, clinical inflammatory markers, and inflammatory cytokines in RA. Design: A systematic review of the literature. Data sources and methods: Five databases were searched (PubMed, Cochrane Library, CINAHL, Scopus and SPORTDiscus); inclusion criteria were studies with acute exercise, a definite diagnosis of RA and disease characteristics assessed by clinical function (i.e., disease activity score, health assessment questionnaire and self-reported pain), clinical markers associated with inflammation (i.e., c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)), and inflammatory cytokines (i.e., interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α)). Results: From a total of 1544 articles, initial screening and full text assessment left 11 studies meeting the inclusion criteria. A total of 274 people were included in the studies (RA = 186; control = 88). Acute bouts of aerobic, resistance, and combined aerobic and resistance exercise did not appear to exacerbate pain symptoms in people with RA. Conclusion: Post-exercise responses for pain, clinical inflammatory markers and inflammatory cytokines were not different between people with or without RA. Exercise prescription was variable between studies, which limited between-study comparisons. Therefore, future investigations in people with RA are warranted, which combine different exercise modes and intensities to examine acute effects on pain symptoms and inflammatory markers. Registration: The PROSPERO international prospective register of systematic reviews - CRD42018091155.

Effectiveness of SARS-CoV-2 vaccination in patients with rheumatoid arthritis (RA) on DMARDs: as determined by antibody and T cell responses.

OBJECTIVES: To assess antibody and T cell responses to SARS-CoV-2 vaccination in patients with rheumatoid arthritis (RA) on disease-modifying antirheumatic drugs (DMARDs). METHODS: This prospective study recruited 100 patients with RA on a variety of DMARDs for antibody and T cell analysis, pre-vaccination and 4 weeks post-vaccination. Positive antibody response was defined as sera IgG binding to ≥1 antigen. Those that remained seronegative after first vaccination were retested 4 weeks after second vaccination; and if still seronegative after vaccination three. A T cell response was defined an ELISpot count of ≥7 interferon (IFN)γ-positive cells when exposed to spike antigens. Type I IFN activity was determined using the luminex multiplex assay IFN score. RESULTS: After vaccine one, in patients without prior SARS-CoV-2 exposure, 37/83 (45%) developed vaccine-specific antibody responses, 44/83 (53%) vaccine-specific T cell responses and 64/83 (77%) developed either antibody or T cell responses. Reduced seroconversion was seen with abatacept, rituximab (RTX) and those on concomitant methotrexate (MTX) compared to 100% for healthy controls (p<0.001). Better seroconversion occurred with anti-tumour necrosis factor (TNF) versus RTX (p=0.012) and with age ≤50 (p=0.012). Pre-vaccine SARS-CoV-2 exposure was associated with higher quantitative seroconversion (≥3 antibodies) (p<0.001). In the subgroup of non-seroconverters, a second vaccination produced seroconversion in 54% (19/35), and after a third in 20% (2/10). IFN score analysis showed no change post-vaccine. CONCLUSION: Patients with RA on DMARDs have reduced vaccine responses, particularly on certain DMARDs, with improvement on subsequent vaccinations but with approximately 10% still seronegative after three doses.

Cardiovascular outcomes in systemic sclerosis with abnormal cardiovascular MRI and serum cardiac biomarkers.

OBJECTIVES: To explore the prognostic value of subclinical cardiovascular (CV) imaging measures and serum cardiac biomarkers in systemic sclerosis (SSc) for the development of CV outcomes of primary heart involvement (pHI). METHODS: Patients with SSc with no clinical SSc-pHI and no history of heart disease underwent cardiovascular magnetic resonance (CMR) imaging, and measurement of serum high-sensitivity-troponin I (hs-TnI) and N-terminal-pro-brain natriuretic peptide (NT-proBNP). Follow-up clinical and CV outcome data were recorded. CV outcomes were defined as myocarditis, arrhythmia and/or echocardiographic functional impairment including systolic dysfunction and/or diastolic dysfunction. RESULTS: Seventy-four patients with a median (IQR) age of 57 (49, 63) years, 32% diffuse cutaneous SSc, 39% interstitial lung disease, 30% Scl70+ were followed up for median (IQR) 22 (15, 54) months. Ten patients developed CV outcomes, comprising one patient with myocarditis and systolic dysfunction and nine arrhythmias: three non-sustained ventricular tachycardia and six supraventricular arrhythmias. The probability of CV outcomes was considerably higher in those with NT-proBNP >125 pg/mL versus normal NT-proBNP (X2=4.47, p=0.035). Trend for poorer time-to-event was noted in those with higher extracellular volume (ECV; indicating diffuse fibrosis) and hs-TnI levels versus those with normal values (X2=2.659, p=0.103; X2=2.530, p=0.112, respectively). In a predictive model, NT-proBNP >125 pg/mL associated with CV outcomes (OR=5.335, p=0.040), with a trend observed for ECV >29% (OR=4.347, p=0.073). CONCLUSION: These data indicate standard serum cardiac biomarkers (notably NT-proBNP) and CMR indices of myocardial fibrosis associate with adverse CV outcomes in SSc. This forms the basis to develop a prognostic model in larger, longitudinal studies.

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

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.

Carotid artery volumetric measures associate with clinical ten-year cardiovascular (CV) risk scores and individual traditional CV risk factors in rheumatoid arthritis; a carotid-MRI feasibility study.

BACKGROUND: Common carotid artery intima-media thickness (CIMT), as measured by ultrasound, has utility in stratification of the accelerated cardiovascular risk seen in rheumatoid arthritis (RA); however, the technique has limitations. Carotid magnetic resonance imaging (MRI) is emerging as a useful research tool in the general population, but has yet to be applied in RA populations. Our objectives were to describe the utility of carotid artery MRI (carotid-MRI) in patients with RA in comparison to healthy controls and to describe the association with RA disease phenotype. METHODS: Sixty-four patients with RA and no history of cardiovascular (CV) disease/diabetes mellitus were assessed for RA and CV profile, including homeostasis model assessment-estimated insulin resistance (HOMA-IR) and N-terminal pro-brain natriuretic peptide (NT-proBNP). All underwent carotid-MRI (3 T), and were compared to 24 healthy controls. Univariable analysis (UVA) and multivariable linear regression models (MVA) were used to determine associations between disease phenotype and carotid-MRI measures. RESULTS: There were no significant differences in carotid arterial wall measurements between patients with RA and controls. Wall and luminal volume correlated with 10-year CV risk scores (adjusted as per 2017 European League Against Rheumatism (EULAR) guidance); rho = 0.33 (p = 0.012) and rho = 0.35 (p = 0.008), respectively, for Joint British Societies-2 risk score. In UVA, carotid-MRI volumetric measures predominantly were associated with traditional CV risk factors including age, ever-smoking and HOMA-IR (p < 0.05). Lower body mass index was associated with wall maximum thickness (r = - 0.25 p = 0.026). In MVA, age was independently associated with wall volume (B 1.13 (95% CI 0.32, 1.93), p = 0.007) and luminal volume (B 3.69 (95% CI 0.55, 6.83, p = 0.022), and RA disease duration was associated with luminal volume (B 3.88 (95% CI 0.80, 6.97), p = 0.015). CONCLUSIONS: This study demonstrates the utility of carotid-MRI in RA, reporting an association between three-dimensional measures in particular and CV risk scores, individual traditional CV risk factors and RA disease duration. Carotid-MRI in RA is a promising research tool in the investigation of CVD.