Major vault protein/lung resistance related protein: a novel biomarker for rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) can lead to joint destruction and early institution of effective treatment can preserve joint function. Biomarkers can establish early diagnosis and predict effect of treatment. Vault particles, large cytoplasmic ribonucleoprotein particles that participate in inflammation, might serve as biomarkers. The aim of this study was to assess the diagnostic and the prognostic value of major vault protein (MVP) and their antibodies in RA. METHODS: Serum samples from 159 RA patients, 26 early RA (ERA) patients, 21 patients with osteoarthritis (OA) and 30 healthy individuals were tested for MVP, anti-cyclic citrullinated peptide (anti-CCP) and C-reactive protein (CRP) using enzyme-linked immunosorbent assays (ELISA). Rheumatoid factor (RF) was tested by nephelometry, and anti-MVP antibodies were detected by anti-MVP peptide ELISA using an in-house protocol. RESULTS: MVP levels were higher in RA and ERA, compared to OA and healthy controls (p<0.00001). A combination of MVP with RF or anti-CCP showed an improved diagnostic accuracy compared to RF or anti-CCP alone in RA and ERA. MVP exhibited similar AUC levels to anti-CCP and RF in RA whereas in ERA, MVP exhibited the same or slightly higher AUC levels, compared to anti-CCP and RF, respectively. High MVP levels were associated with lack of response to treatment. Levels of anti-MVP peptide 2 antibodies were significantly higher in RA compared to healthy controls (t= 2.73, p=0.007). CONCLUSIONS: MVP and autoantibodies against MVP may have the potential to serve as diagnostic and prognostic biomarkers in RA.

Cardiac magnetic resonance predicts ventricular arrhythmias in scleroderma: the Scleroderma Arrhythmia Clinical Utility Study (SAnCtUS).

OBJECTIVES: Cardiac rhythm disturbances constitute the most frequent cardiovascular cause of death in SSc. However, electrocardiographic findings are not a part of risk stratification in SSc. We aimed to translate 24 h Holter findings into a tangible risk prediction score using cardiovascular magnetic resonance. METHODS: The Scleroderma Arrhythmia Clinical Utility Study (SAnCtUS) was a prospective multicentre study including 150 consecutive SSc patients from eight European centres, assessed with 24 h Holter and cardiovascular magnetic resonance, including ventricular function, oedema (T2 ratio) and late gadolinium enhancement (%LGE). Laboratory/clinical parameters were included in multivariable corrections. A combined endpoint of sustained ventricular tachycardia requiring hospitalization and sudden cardiac death at a median (interquartile range) follow-up of 1 (1.0-1.4) year was generated. RESULTS: Only T2 ratio and %LGE were significant predictors of ventricular rhythm disturbances, but not of supraventricular rhythm disturbances, after multivariable correction and adjustment for multiple comparisons. Using decision-tree analysis, we created the SAnCtUS score, a four-category scoring system based on T2 ratio and %LGE, for identifying SSc patients at high risk of experiencing ventricular rhythm disturbance at baseline. Increasing SAnCtUS scores were associated with a greater disease and arrhythmic burden. All cases of non-sustained ventricular tachycardia (n = 7) occurred in patients with the highest SAnCtUS score (=4). Having a score of 4 conveyed a higher risk of reaching the combined endpoint in multivariable Cox regression compared with scores 1/2/3 [hazard ratio (95% CI): 3.86 (1.14, 13.04), P = 0.029] independently of left ventricular ejection fraction and baseline ventricular tachycardia occurrence. CONCLUSION: T2 ratio and %LGE had the greatest utility as independent predictors of rhythm disturbances in SSc patients.

Is There a Brain/Heart Interaction in Rheumatoid Arthritis and Seronegative Spondyloartropathies? A Combined Brain/Heart Magnetic Resonance Imaging Reveals the Answer.

PURPOSE OF REVIEW: To present the interaction between brain/heart and emphasize the role of combined brain/heart magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA) and other seronegative spondyloarthropathies (SNA). RECENT FINDINGS: Both traditional cardiovascular disease (CVD) risk factors and intrinsic RA/SNA features contribute to the increased CVD-related morbidity/mortality. CVD in RA usually occurs a decade earlier than age- and sex-matched controls, and RA patients are twice more likely to develop myocardial infarction irrespective of age, history of prior CVD, and traditional CVD risk factors. RA also increases risk of non-ischemic heart failure (HF), valvular disease, and myo-pericarditis. CVD in SNA affects more commonly patients with long-standing disease. Ascending aortitis, aortic/mitral insufficiency, conduction defects, and diastolic dysfunction are the commonest findings in ankylosing spondylitis (AS). CVD is also the leading cause of death in psoriatic arthritis (PsA), due to myopericarditis, diastolic dysfunction, and valvular disease. Brain damage, due to either ischemic or hemorrhagic stroke and silent vascular damage, such as white matter hyperenhancement (WMH), is increased in both RA/SNA and may lead to cognitive dysfunction, depression, and brain atrophy. Magnetic resonance imaging (MRI) is ideal for serial brain/heart evaluation of patients with systemic diseases. RA/SNA patients are at high risk for brain/heart damage at early age, irrespectively of classic risk factors. Until more data will be obtained, a combined brain/heart MRI evaluation can be proposed in RA/SNA with new onset of arrhythmia and/or HF, cognitive dysfunction and/or depression.

Current understanding and future perspectives of brain-heart-kidney axis in psoriatic arthritis.

Psoriatic arthritis (PsA) patients are at a higher risk of systemic inflammatory sequelae, leading to microalbuminuria, cardiovascular (CVD) and neuropsychiatric (NPD) disease. Our aim is to present the existing literature about the relationship between CVD, kidney and NPD in PsA. The literature evaluation of PsA revealed that chronic T-cell activation and increased levels of circulating immune complexes can cause glomerular injury leading to microalbuminuria, which predicts CVD and all-cause mortality in both diabetic and non-diabetic patients. Furthermore, it is a marker of preclinical brain damage and identifies patients at higher risk of NPD/CVD events. Among the currently used imaging modalities in PsA, magnetic resonance imaging (MRI) maintains a crucial role, because it is ideal for concurrent evaluation of brain/heart involvement and serial follow up assessment. There is increasing evidence regarding the relationship between kidneys, heart and brain in PsA. Although currently there are no official recommendations about a combined brain/heart MRI in PsA, it could be considered in PsA with microalbuminuria, arrhythmia, HF, cognitive dysfunction and/or depression.

Can cardiovascular magnetic resonance prompt early cardiovascular/rheumatic treatment in autoimmune rheumatic diseases? Current practice and future perspectives.

Life expectancy in autoimmune rheumatic diseases (ARDs) remains lower compared to the general population, due to various comoborbidities. Cardiovascular disease (CVD) represents the main contributor to premature mortality. Conventional and biologic disease-modifying antirheumatic drugs (DMARDs) have considerably improved long-term outcomes in ARDs not only by suppressing systemic inflammation but also by lowering CVD burden. Regarding atherosclerotic disease prevention, EULAR has recommended tight disease control accompanied by regular assessment of traditional CVD risk factors and lifestyle changes. However, this approach, although rational and evidence-based, does not account for important issues such as myocardial inflammation and the long asymptomatic period that usually proceeds clinical manifestations of CVD disease in ARDs before or after the diagnosis of systemic disease. Cardiovascular magnetic resonance (CMR) can offer reliable, reproducible and operator independent information regarding myocardial inflammation, ischemia and fibrosis. Some studies suggest a role for CMR in the risk stratification of ARDs and demonstrate that oedema/fibrosis visualisation with CMR may have the potential to inform cardiac and rheumatic treatment modification in ARDs with or without abnormal routine cardiac evaluation. In this review, we discuss how CMR findings could influence anti-rheumatic treatment decisions targeting optimal control of both systemic and myocardial inflammation irrespective of clinical manifestations of cardiac disease. CMR can provide a different approach that is very promising for risk stratification and treatment modification; however, further studies are needed before the inclusion of CMR in the routine evaluation and treatment of patients with ARDs.

Silent myocarditis in systemic sclerosis detected by cardiovascular magnetic resonance using Lake Louise criteria.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by microvascular abnormalities, inflammation and fibrosis. We hypothesized that myocarditis may be diagnosed in asymptomatic SSc, undergoing routine cardio-vascular magnetic resonance (CMR) for fibrosis assessment, using the Lake Louise criteria: T2 ratio, early (EGE) and late gadolinium enhanced (LGE) images. METHODS: Eighty-two asymptomatic SSc, diagnosed according to American College of Rheumatology criteria, aged 43 ± 5 yrs., 62 with diffuse (dSSc) and 20 with localized (lSSc) systemic sclerosis were evaluated by CMR, performed at 1.5 T scanner, according to Lake Louise criteria. RESULTS: CMR documented normal biventricular function in all SSc. However, 7/62 (11.2%) with dSSc and 2/20 (10%) with lSSc, had CMR signs of myocarditis according to Lake Louise criteria, without any clinical cardiac symptom. In these 9 patients, T2 ratio, EGE ratio and LGE (positive in all 9 SSc) were 2.8 ± 0.5%, 8 ± 3% and 5 ± 3% of LV mass, respectively. No correlation between CMR and blood inflammatory indices (C-reactive protein and erythrocyte sedimentation rate), cardiac troponin T, disease characteristics or type of SSc was identified. A repeat CMR at 6 months, after treatment with prednisone and azathioprine, showed normalisation of the acute inflammation CMR indices. CONCLUSIONS: Silent myocarditis may be diagnosed using the Lake Louise paper criteria in SSc patients without cardiac symptoms, has no correlation with blood inflammatory indices, cardiac troponin or disease characteristics. CMR is a promising tool to diagnose silent myocarditis in SSc and monitor the response to immunosuppressive treatment.

Cardiovascular Magnetic Resonance Reveals Cardiac Pathophysiology in Autoimmune Rheumatic Diseases.

BACKGROUND/AIMS: The high incidence of cardiovascular disease (CVD) in patients with autoimmune rheumatic diseases (ARDs) is the main driver towards increased mortality in this patient group. Cardiovascular magnetic resonance (CMR) can non-invasively and robustly detect CVD in ARD patients at an early stage of development. The review summarises the diagnostic information provided by CMR in ARD patients. SUMMARY: CMR uses a strong magnetic field combined with radio-frequency pulses (pulse sequences) to generate images. Firstly, balanced steady-state free precession (bSSFP) can be used for evaluating cardiac anatomy, mass, wall motion, atrial/ventricular function. Secondly, T2-weighted imaging (T2-W) can be used for oedema detection, which appears as a high signal intensity area on STIR (short tau inversion recovery) images. T2 mapping is a newer T2-W technique that can provide more optimal identification of myocardial oedema. Lastly, late gadolinium enhanced (LGE) T1-W images, taken 15 min. after injection of contrast agent, allow the detection of myocardial replacement fibrosis, which appears as a bright area in a background of black myocardium. However, LGE has inherent disadvantages for the assessment of diffuse myocardial fibrosis. Therefore, T1 mapping and extracellular volume fraction (ECV) have been developed to quantify diffuse myocardial fibrosis. RESULTS: Although multicentre studies are still missing, the CMR parameters have been extensively applied for the identification of oedema/fibrosis and treatment decision making in ARDs. CONCLUSIONS: Tissue characterisation with CMR allows early and robust identification of CVD in ARD patients and contributes to personalized management in the patients.

Systemic and local interleukin-17 and linked cytokines associated with Sjögren's syndrome immunopathogenesis.

Recently recognized as a distinct CD4(+) T helper (Th) lineage, Th17 cells have been implicated in host responses to infections and in pathogenesis associated with autoimmune diseases. This cytokine is implicated in primary Sjögren's syndrome (pSS) immunopathology because of the increased levels of circulating interleukin (IL)-17 in pSS. Plasma and minor salivary glands (MSGs) from patients with pSS were therefore evaluated for CD4(+) T cells, T regulatory cells, IL-17, and supporting cytokines by immunohistochemistry, RT-PCR, and microbead assays. MSGs from pSS patients contain IL-17-expressing cells as a dominant population within inflammatory lesions. IL-17 protein expression progressively increased with higher biopsy focus scores (P < 0.0001), in parallel with detection by RT-PCR. Transforming growth factor-beta, IL-6 and IL-23, which are requisite promoters of Th17 differentiation, were found in abundance compared with the amounts in control tissues. Although transforming growth factor-beta is also a pivotal differentiation factor for immunosuppressive Foxp3(+) T regulatory cells (Tregs), an increase in Foxp3(+) Tregs was evident in biopsy specimens with mild and moderate inflammation but this increase was disproportionate to escalating pro-inflammatory Th17 populations in advanced disease. Furthermore, the Th17-centric cytokines IL-17, IL-6, IL-23, and IL-12 were significantly elevated in pSS plasma. These data identify a profusion of IL-17-generating cells and supporting cytokines within diseased pSS MSGs without a compensatory increase in immunomodulatory Tregs; this imbalance seems to foster a pathogenic milieu that may be causative and predictive of infiltrative injury and amenable to therapeutic intervention.

The Doubled-Edged Sword of T1-Mapping in Systemic Sclerosis-A Comparison with Infectious Myocarditis Using Cardiovascular Magnetic Resonance.

AIMS: T1-mapping is considered a surrogate marker of acute myocardial inflammation. However, in diffuse cutaneous systemic sclerosis (dcSSc) this might be confounded by coexisting myocardial fibrosis. We hypothesized that T1-based indices should not by themselves be considered as indicators of myocardial inflammation in dcSSc patients. METHODS/RESULTS: A cohort of 59 dcSSc and 34 infectious myocarditis patients was prospectively evaluated using a 1.5-Tesla system for an indication of suspected myocardial inflammation and was compared with 31 healthy controls. Collectively, 33 (97%) and 57 (98%) of myocarditis and dcSSc patients respectively had ≥1 pathologic T2-based index. However, 33 (97%) and 45 (76%) of myocarditis and dcSSc patients respectively had ≥1 pathologic T2-based index. T2-signal ratio was significantly higher in myocarditis patients compared with dcSSc patients (2.5 (0.6) vs. 2.1 (0.4), p < 0.001). Early gadolinium enhancement, late gadolinium enhancement and T2-mapping did not differ significantly between groups. However, both native T1-mapping and extracellular volume fraction were significantly lower in myocarditis compared with dcSSc patients (1051.0 (1027.0, 1099.0) vs. 1120.0 (1065.0, 1170.0), p < 0.001 and 28.0 (26.0, 30.0) vs. 31.5 (30.0, 33.0), p < 0.001, respectively). The original Lake Louise criteria (LLc) were positive in 34 (100%) myocarditis and 40 (69%) dcSSc patients, while the updated LLc were positive in 32 (94%) and 44 (76%) patients, respectively. Both criteria had good agreement with greater but nonsignificant discordance in dcSSc patients. CONCLUSIONS: ~25% of dcSSc patients with suspected myocardial inflammation had no CMR evidence of acute inflammatory processes. T1-based indices should not be used by themselves as surrogates of acute myocardial inflammation in dcSSc patients.

Combined Brain/Heart Magnetic Resonance Imaging in Systemic Lupus Erythematosus.

Cardiovascular Disease (CVD) in Systemic Lupus Erythematosus (SLE) and Neuropsychiatric SLE (NPSLE) has an estimated prevalence of 50% and 40%, respectively and both constitute major causes of death among SLE patients. In this review, a combined brain/heart Magnetic Resonance Imaging (MRI) for SLE risk stratification has been proposed. The pathophysiologic background of NPSLE includes microangiopathy, macroscopic infarcts and accelerated atherosclerosis. Classic brain MRI findings demonstrate lesions suggestive of NPSLE in 50% of the NPSLE cases, while advanced MRI indices can detect pre-clinical lesions in the majority of them, but their clinical impact still remains unknown. Cardiac involvement in SLE includes myo-pericarditis, valvular disease/endocarditis, Heart Failure (HF), coronary macro-microvascular disease, vasculitis and pulmonary hypertension. Classic and advanced Cardiovascular Magnetic Resonance (CMR) indices allow function and tissue characterization for early diagnosis and treatment follow-up of CVD in SLE. Although currently, there are no clinical data supporting the combined use of brain/heart MRI in asymptomatic SLE, it may have a place in cases with clinical suspicion of brain/heart involvement, especially in patients at high risk for CVD/stroke such as SLE with antiphospholipid syndrome (SLE/APS), in whom concurrent cardiac and brain lesions have been identified. Furthermore, it may be of value in SLE with multi-organ involvement, NPSLE with concurrent cardiac involvement, and recent onset of arrhythmia and/or heart failure.

Combined Brain-Heart Magnetic Resonance Imaging in Autoimmune Rheumatic Disease Patients with Cardiac Symptoms: Hypothesis Generating Insights from a Cross-sectional Study.

BACKGROUND: Autoimmune rheumatic diseases (ARDs) may affect both the heart and the brain. However, little is known about the interaction between these organs in ARD patients. We asked whether brain lesions are more frequent in ARD patients with cardiac symptoms compared with non-ARD patients with cardiovascular disease (CVD). METHODS: 57 ARD patients with mean age of 48 ± 13 years presenting with shortness of breath, chest pain, and/or palpitations, and 30 age-matched disease-controls with non-autoimmune CVD, were evaluated using combined brain-heart magnetic resonance imaging (MRI) in a 1.5T system. RESULTS: 52 (91%) ARD patients and 16 (53%) controls had white matter hyperintensities (p < 0.001) in at least one brain area (subcortical/deep/periventricular white matter, basal ganglia, pons, brainstem, or mesial temporal lobe). Only the frequency and number of subcortical and deep white matter lesions were significantly greater in ARD patients (p < 0.001 and 0.014, respectively). ARD vs. control status was the only independent predictor of having any brain lesion. Specifically for deep white matter lesions, each increase in ECV independently predicted a higher number of lesions [odds ratio (95% confidence interval): 1.16 (1.01-1.33), p = 0.031] in ordered logistic regression. Penalized logistic regression selected only ARD vs. control status as the most important feature for predicting whether brain lesions were present on brain MRI (odds ratio: 5.46, marginal false discovery rate = 0.011). CONCLUSIONS: Subclinical brain involvement was highly prevalent in this cohort of ARD patients and was mostly independent of the severity of cardiac involvement. However, further research is required to determine the clinical relevance of these findings.

Cardiovascular Magnetic Resonance Identifies High-Risk Systemic Sclerosis Patients with Normal Echocardiograms and Provides Incremental Prognostic Value.

BACKGROUND: Acute cardiac events are a significant contributor to mortality in systemic sclerosis (SSc). However, echocardiographic evaluation may be deceptively normal during an acute presentation. We hypothesized that in diffuse SSc patients presenting with acute cardiac events and a normal echocardiogram, cardiovascular magnetic resonance (CMR) would have incremental diagnostic/prognostic value. METHODS: 50 consecutive diffuse SSc patients with normal echocardiograms were evaluated using a 1.5T system. A total of 27 (63%) had experienced an acute cardiac event three to tendays before CMR evaluation (rhythm disturbances, angina pectoris, shortness of breath). Left/right ventricular (LV/RV) volumes and ejection fractions (EF), as well as LV mass, the T2-signal ratio, early/late gadolinium enhancement (EGE/LGE), native/post-contrast T1-mapping, T2-mapping and extracellular volume fraction (ECV) were compared between the event and no-event groups. RESULTS: No differences were identified in LV/RV volumes/EF/mass. In logistic regression analyses, independent predictors of belonging to the event group were EGE (odds ratio (95% CI): 1.55 (1.06-2.26), p = 0.024), LGE (1.81 (1.23-2.67), p = 0.003), T2 mapping (1.20 (1.06-1.36), p = 0.004) and native/post-contrast T1 mapping (1.17 (1.04-1.32), p = 0.007 and 0.86 (0.75-0.98), p = 0.025). At a median follow-up of ~1.2 years, 42% vs. 11% of the event/no-event group respectively reached a combined endpoint of event occurrence/recurrence or cardiovascular mortality. Of the independent predictors resulting from logistic regression analyses, only LGE (hazard ratio (95% CI): 1.20 (1.11-1.30), p < 0.001), T2-mapping (1.07 (1.01-1.14), p = 0.025) and native T1-mapping (1.08 (1.01-1.15), p = 0.017) independently predicted the combined endpoint. CONCLUSIONS: A normal echocardiogram does not preclude myocardial lesions in diffuse SSc patients, which can be detected by CMR especially in symptomatic patients.

CMR feature tracking in cardiac asymptomatic systemic sclerosis: Clinical implications.

BACKGROUND: Impaired myocardial deformation has been sporadically described in cardiac asymptomatic systemic sclerosis (SSc). We aimed to study myocardial deformation indices in cardiac asymptomatic SSc patients using cardiac magnetic resonance feature tracking (CMR-FT) and correlate these findings to the phenotypic and autoimmune background. METHODS: Fifty-four cardiac asymptomatic SSc patients (44 females, 56±13 years), with normal routine cardiac assessment and CMR evaluation, including cine and late gadolinium enhancement (LGE) images, were included. SSc patients were compared to 21 sex- and age- matched healthy controls (17 females; 54±19 years). For CMR-FT analysis, a mid-ventricular slice for LV peak systolic radial and circumferential strain and a 4-chamber view for LV/RV peak systolic longitudinal strain were used. RESULTS: Twenty-four patients had diffuse cutaneous SSc and 30 limited cutaneous SSc. Thirteen patients had digital ulcers. Median disease duration was 3.6 years. LV ejection fraction was higher in SSc patients compared to controls (62±6% vs. 59±5%, p = 0.01). Four patients had no LGE examination; in the remaining patients LGE was absent in 74%, while 18% had RV insertion fibrosis and 8% evidence of subendocardial infarction. LV longitudinal strain differed in those with insertion fibrosis (-18.0%) and infarction (-16.7%) compared to no fibrosis (-20.3%, p = 0.04). Patients with SSc had lower RV longitudinal strain and strain rate compared to controls (p<0.001 and p = 0.01, respectively). All other strain and strain rate measurements were non-significant between patients and controls. CONCLUSIONS: In cardiac asymptomatic SSc patients with normal routine functional indices, CMR-FT identifies subclinical presence of insertion fibrosis and/or myocardial infarction by impaired LV longitudinal strain. RV derived longitudinal indices were impaired in the patient group. CMR FT indices did not correlate to the patients' phenotypic and autoimmune features.

Cardiovascular magnetic resonance imaging pattern in patients with autoimmune rheumatic diseases and ventricular tachycardia with preserved ejection fraction.

BACKGROUND: Ventricular tachycardia/fibrillation (VT/VF) may occur in autoimmune rheumatic diseases (ARDs). We hypothesized that cardiovascular magnetic resonance (CMR) can identify arrhythmogenic substrates in ARD patients. PATIENTS - METHODS: Using a 1.5 T system, we evaluated 61 consecutive patients with various types of ARDs and normal left ventricular ejection fraction (LVEF) on echocardiography. A comparison of patients with recent VT/VF and those that never experienced VT/VF was performed. CMR parameters included left and right ventricular (LV and RV) end-systolic and end-diastolic volumes (ESV and EDV), T2 signal ratio of myocardium over skeletal muscle, early/late gadolinium enhancement (EGE and LGE), T1/T2-mapping and extracellular volume fraction (ECV). RESULTS: 21 (34%) patients had a history of recent, electrocardiographically identified, VT/VF. No demographic or functional CMR variables differed significantly between groups. The same was the case for T2 signal ratio and EGE/LGE. Median native T1 mapping values were significantly higher in patients with VT/VF compared to those without [1135.0 (1076.0, 1201.0) vs. 1050.0 (1025.0, 1078.0), p < 0.001], as was the case for mean T2 mapping [60.4 (6.6) vs. 55.0 (7.9), p = 0.009] and median ECV values [32.0 (30.0, 32.0) vs. 29.0 (28.0, 31.5), p = 0.001]. After multivariate corrections for age, LVEDV, LVEF, RVEDV, RVEF, T2 signal ratio, EGE and LGE, these remained significant predictors of having experienced VT/VF in the past. CONCLUSIONS: T1/T2-mapping and ECV offer incremental value as identifiers of arrhythmogenic substrates in ARD patients, beyond traditionally used indices. They can thus guide implantable cardiac defibrillator (ICD) implantation in ARD patients presenting with VT/VF and normal LVEF.

Multicenter Cross-sectional Study of Patients with Rheumatoid Arthritis in Greece: Results from a cohort of 2.491 patients.

AIM OF THE STUDY: To evaluate the current disease characteristics, treatment and comorbidities of rheumatoid arthritis (RA) in Greece. METHODS: Multicenter, cross-sectional study with a 9-month recruitment period between 2015 and 2016. Demographics, disease characteristics, treatment and comorbidities were collected via a web-based platform. RESULTS: 2.491 RA patients were recruited: 96% from tertiary referral centers, 79% were females with a mean age of 63.1 years and disease duration of 9.9 years. Fifty-two percent were rheumatoid factor and/or anti-CCP positive, while 41% had erosive disease. Regarding treatment, 82% were on conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs), 42% on biologic DMARDs (TNFi: 22%, non-TNFi: 20%) and 40% on corticosteroids (mean daily dose: 5.2 mg). Despite therapy, 36% of patients had moderate and 12% high disease activity. The most frequent comorbidities were hypertension (42%), hyperlipidemia (33%), osteoporosis (29%), diabetes mellitus (15%) and depression (12%). Latent tuberculosis infection (positive tuberculin skin test or interferon gamma release assay) was diagnosed in 13 and 15.3% of patients, respectively. Regarding chronic viral infections, 6.2% had history of herpes zoster while 2% and 0.7% had chronic hepatitis B and C virus infection, respectively. A history of serious infection was documented in 9.6%. Only 36% and 52% of the participants had ever been vaccinated against pneumococcus and influenza virus, respectively. CONCLUSION: This is one of the largest epidemiologic studies providing valuable data regarding the current RA characteristics in Greece. Half of patients were seropositive but despite therapy, half displayed residual disease activity, while preventive vaccination was limited.

T lymphocytes in Sjögren's syndrome: contributors to and regulators of pathophysiology.

Sjögren's syndrome is a chronic autoimmune disorder characterized by lymphocytic infiltration and malfunction of the exocrine glands, resulting in dry mouth and eyes. This multigenic and multifunctional disease can present as primary Sjögren's syndrome or secondary to an underlying connective tissue disease. Immune activation subsequent to activation or apoptosis of glandular epithelial cells in genetically predisposed individuals may expose autoantigens, which engage self-perpetuating T cell dependent autoimmune sequelae. The cellular and molecular context of this immune response may drive proinflammatory (Th1 and Th17) and restrain inhibitory (Treg) pathways. Inability to suppress the immune response results in persistent tissue damage and compromised function of salivary and lacrimal glands. Defining the contributions of participating T cells may unravel strategies for therapeutic intervention.

Myocardial perfusion in peripheral Raynaud's phenomenon. Evaluation using stress cardiovascular magnetic resonance.

BACKGROUND: Peripheral Raynaud's phenomenon (RP) is either primary (PRP), without any coexisting disease or secondary (SRP), due to connective tissue diseases (CTD). We hypothesized that adenosine stress cardiovascular magnetic resonance (CMR) can assess myocardial perfusion in a population of PRP and SRP. PATIENTS-METHODS: Twenty CTDs, aged 30.6±7.5yrs., 16F/4M, including 9 systemic sclerosis (SSc), 4 systemic lupus erythematosus (SLE), 3 mixed connective tissue disease (MCTD), 2 polymyositis (PM) and 2 rheumatoid arthritis (RA), with SRP, under treatment with calcium blockers, were evaluated by stress CMR and compared with age-sex matched PRP and controls. All RP patients were under treatment with calcium blockers. Stress perfusion CMR was performed by 1.5T system using 140mg/kg/min adenosine for 4min and 0.05mmol/kg Gd-DTPA for first-pass perfusion. A rest perfusion was performed with the same protocol. Late gadolinium enhanced (LGE) images were acquired after another dose of Gd-DTPA. RESULTS: In both PRP, SRP, the myocardial perfusion reserve index (MPRI) was significantly reduced compared with the controls (1.7±0.6 vs 3.5±0.4, p<0.001 and 0.7±0.2 vs 3.5±0.4, p<0.001, respectively). Furthermore, in SRP, MPRI was significantly reduced, compared with PRP (0.7±0.2 vs 1.7±0.6, p<0.001). Subendo-cardial LGE=8.2±1.7 of LV mass was revealed in 1 SLE, 1MCTD and 2 SSc, but in none of PR patients. CONCLUSIONS: MPRI reduction is common in both PRP and SRP, but it is more severe in SRP, even if RP patients are under treatment with calcium blockers. Occult fibrosis may coexist with the reduced MPRI in SRP but not in PRP.

Cardiovascular magnetic resonance imaging pattern at the time of diagnosis of treatment naïve patients with connective tissue diseases.

BACKGROUND-AIM: Cardiac involvement at diagnosis of connective tissue disease (CTD) has been described by echocardiography. We hypothesized that cardio-vascular magnetic resonance (CMR) detects occult lesions at CTD diagnosis. PATIENTS-METHODS: CMR was performed early after diagnosis in 78 treatment-naïve CTDs (aged 43±11, 59F/19M) without cardiac involvement [5 Takayasu arteritis (TA), 4 Churg Strauss syndrome (CSS), 5 Wegener granulomatosis (WG), 16 systemic lupus erythematosus (SLE), 12 rheumatoid arthritis (RA), 8 mixed connective tissue diseases (MCTD), 12 ankylosing spondylitis (AS), 3 polymyalgia rheumatica (PMR), 8 systemic sclerosis (SSc) and 5 dermatomyositis (DM)]. Acute and chronic lesions were assessed by T2>2 with positive LGE and T2<2 with positive LGE, respectively. RESULTS: In 3/5 TA, 3/4 CSS, 4/5 WG, 10/16 SLE, 9/12 RA, 6/8 MCTD, 4/12 AS, 1/3 PMR, 2/8 SSc and 2/5 DM, the T2 ratio was higher compared to normal (2.78±0.25 vs 1.5±0.2, p<0.01). Myocarditis was identified in 1 TA, 1 SLE, 1 RA, 1 SSc and 2 DM patients; diffuse, subendocardial fibrosis in 1 CSS and 1 RA patient, while subendocardial myocardial infarction in 3 SLE, 1 MCTD, 1 PMR and 2 RA patients. CMR re-evaluation after 6 and 12months of rheumatic and cardiac treatment, available in 28/52 CTDs with increased T2 ratio, showed significant improvement in T2 ratio (p<0.001), non-significant change in LGE extent and normalisation of those with impaired LV function. CONCLUSIONS: Occult CMR lesions, including oedema, myocarditis, diffuse subendocardial fibrosis and myocardial infarction are not unusual in treatment naïve CTDs and may be reversed with appropriate treatment.

Pseudo-infarction pattern in diffuse systemic sclerosis. Evaluation using cardiovascular magnetic resonance.

BACKGROUND: Diffuse systemic sclerosis (dSSc) is characterized by vascular lesions and fibrosis. Cardiac involvement, although silent, accounts for 36% of deaths. We hypothesized that cardiovascular magnetic resonance (CMR) can clarify the pathophysiology of Q waves in dSSc patients. PATIENTS-METHODS: 105 dSSc, aged 48±2years, with atypical symptoms and normal routine assessment, were evaluated by ECG and CMR using a 1.5 T system. Biventricular function was assessed by steady-state free-precession sequence (SSFP). To identify fibrosis, late gadolinium enhanced areas (LGE) were evaluated 15min after injection of 0.2mmol/kg gadolinium-DTPA and expressed as % of LV mass. RESULTS: Q waves in V1-V5 (Group A), II, III, AVF (Group B) and I, AVL, II, III, AVF, V1-V5 (Group C) were found in 25/105, 8/105 and 5/105 dSSc, respectively. In 25 dSSc with Q in V1-V6, patchy intramyocardial LGE was detected in 24/25 and involved 8±2% of LV mass. LGE involved the intraventricular septum (IVS) in 11/24 and the lateral wall (LAT) in 5/24 dSSc. Only in 1/25 dSSc, an anterior, transmural LGE, due to LAD occlusion, was identified. In 8 dSSc with Q in II, III, AVF, patchy intramyocardial LGE was detected in the inferior wall and involved 5±2% of LV mass. In 5 dSSc with Q in V1-V5, II, III, AVF, patchy intramyocardial LGE was detected in anterior and inferolateral wall and involved 9±2% of LV mass. CONCLUSION: CMR unveiled that the pattern of myocardial fibrosis in dSSc with Q waves is due to the systemic disease and not to CAD.

Cardiovascular magnetic resonance in rheumatology: Current status and recommendations for use.

Targeted therapies in connective tissue diseases (CTDs) have led to improvements of disease-associated outcomes, but life expectancy remains lower compared to general population due to emerging co-morbidities, particularly due to excess cardiovascular risk. Cardiovascular magnetic resonance (CMR) is a noninvasive imaging technique which can provide detailed information about multiple cardiovascular pathologies without using ionizing radiation. CMR is considered the reference standard for quantitative evaluation of left and right ventricular volumes, mass and function, cardiac tissue characterization and assessment of thoracic vessels; it may also be used for the quantitative assessment of myocardial blood flow with high spatial resolution and for the evaluation of the proximal coronary arteries. These applications are of particular interest in CTDs, because of the potential of serious and variable involvement of the cardiovascular system during their course. The International Consensus Group on CMR in Rheumatology was formed in January 2012 aiming to achieve consensus among CMR and rheumatology experts in developing initial recommendations on the current state-of-the-art use of CMR in CTDs. The present report outlines the recommendations of the participating CMR and rheumatology experts with regards to: (a) indications for use of CMR in rheumatoid arthritis, the spondyloarthropathies, systemic lupus erythematosus, vasculitis of small, medium and large vessels, myositis, sarcoidosis (SRC), and scleroderma (SSc); (b) CMR protocols, terminology for reporting CMR and diagnostic CMR criteria for assessment and quantification of cardiovascular involvement in CTDs; and (c) a research agenda for the further development of this evolving field.