Eleni Pagkopoulou

Despite continuously evolving medical advances, CVD risk in Rheumatoid Arthritis (RA) remains paradoxically high to date. Carotid intima-media thickness (cIMT) is a widely used surrogate marker for atherosclerosis. However, issues related to operator-dependent assessment, availability and cost of carotid ultrasound are barriers to its wide implementation as an aid to cardiovascular risk assessment in RA. We aimed to develop a computational artificial intelligence (AI) model for cIMT prediction in RA. The recently proposed DERGA algorithm (Data Ensemble Refinement Greedy Algorithm) was employed in a database of datasets from 101 patients with RA, utilizing information on a wide range of clinical and laboratory variables, classical cardiovascular risk factors, disease-related parameters, and vascular assessments obtained with nailfold videocapillaroscopy (NVC). A total of 13,917,800 models were designed and trained. Among the four evaluated regression metaheuristic algorithms, the best predictive performance was achieved by the DERGA–Extra Trees model. The optimal model utilized only 8 of the 52 available input variables, while maintaining excellent predictive accuracy. Eventually, the 8 most important parameters predicting cIMT, listed from the most influential to the least influential, were white blood count, age, high density lipoprotein cholesterol, capillary density, systolic blood pressure, microhemorrhages, inhibitors of the renin-angiotensin-aldosterone, and methotrexate. A very strong positive linear correlation was observed between predicted and actual (measured) cIMT values ( R = 0.9843), supporting the high predictive capability of the proposed computational intelligence model. Pending external validation in larger cohorts, the findings of the present study should be considered preliminary. Nevertheless, they provide further evidencesupporting the potential utility of AI applications for the assessment of subclinical vascular involvement in RA. While the role of NVC as an indicator of cardiovascular health is beginning to unfold, these findings underscore its promise as an adjunctive modality to facilitate more effective CVD risk stratification in RA.

Adverse cardiovascular events and increased mortality are associated with cardiac autonomic nervous system dysfunction in the early stages of the systemic sclerosis (SSc), even prior to the development of cardiac fibrosis. The objective of the study was to evaluate the impact of a three-month exercise training regimen and a subsequent comparable period of detraining on the activity of the cardiac autonomic nervous system in patients with SSc. A total of forty patients with SSc were randomized to either the control group (Group COΝ) or the exercise training group (Group ET). Cardiopulmonary exercise testing was performed at baseline, three months later, and six months later to assess peak oxygen uptake (VO₂peak). They also had 24 h electrocardiogram monitoring for heart rate variability (HRV) and heart rate turbulence analysis. The following time-domain indices were evaluated in the context of HRV analysis: the standard deviation of NN intervals (SDNN), the root mean square of successive RR interval differences (rMSSD), and the percentage of successive RR intervals that differ by more than 50 ms (pNN50). Additionally, regarding the frequency-domain indicators, the low-frequency (LF) and high-frequency (HF) components, as well as the LF/HF ratio, were evaluated. Independent t-tests and Chi-square tests were used for baseline comparisons, while two-way repeated measures ANOVA with Bonferroni post hoc tests assessed changes over time and between groups. Linear and multiple regression analyses were conducted to explore relationships among variables and identify predictors of HRV indices and VO₂peak. Group ET implemented a three-month mixed-type exercise training program, while Group COΝ received standard care. Group ET improved indices of vagal activity [rMSSD by 32.6% (p = 0.017), pNN50 by 57.1% (p = 0.01) and HF by 20.1% (p = 0.01)] and sympathovagal activity [SDNN by 15.5% (p = 0.002) and LF/HF by 12.03% (p = 0.004)] after three months. Exercising patients also increased their VO₂peak by 20.8% (p = 0.001). A robust positive correlation was observed between ΔVO₂peak and ΔSDNN (r = 0.754, p < 0.001). After three months, there was no statistically significant difference in the VO₂peak or any HRV index in the group COΝ. Compared to the baseline values, there was no statistically significant difference in group ET at 6 months, whereas the control group exhibited a decline. In summary, a three-month mixed-type exercise training program can enhance the cardiorespiratory efficiency and cardiac autonomic nervous system function of patients with SSc, as well as alleviate the deterioration that arises following the detraining period.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by widespread immune dysregulation and the production of autoantibodies targeting nuclear, cytoplasmic, and cell surface antigens. These autoantibodies are central to disease pathogenesis, contribute to immune complex formation and organ damage, and serve as essential diagnostic and prognostic markers. Their detection supports disease classification, guides clinical decision-making, and offers insight into disease activity and therapeutic response. Traditional markers such as anti-nuclear antibodies (ANA), anti-dsDNA, and anti-Sm antibodies remain diagnostic cornerstones, but growing attention is given to anti-C1q, anti-nucleosome antibodies (ANuA), anti-ribosomal P, antiphospholipid, and anti-cytokine antibodies due to their associations with specific disease phenotypes and activity. These markers may reflect disease activity, specific organ involvement, or predict flares. The mechanisms underlying their persistence include B cell tolerance failure and long-lived plasma cell activity. The aim of this review is to summarize current knowledge on the major autoantibodies in SLE, appraise available detection methods, highlight their clinical utility and limitations and present evidence on the association between antibodies and disease phenotypes.

Background: Janus kinase (JAK) inhibitors constitute a novel class of oral biologic disease-modifying antirheumatic drugs for patients with rheumatoid arthritis (RA). However, their use has been associated with increased risk of major cardiovascular events. We investigated whether treatment with JAK inhibitors exerts significant alterations in the micro- and microvasculature in RA patients. Methods: Thirteen patients with RA initiating treatment with JAK inhibitors were prospectively studied. Eventually, data from 11 patients who completed the study were analyzed. Procedures were performed at baseline and 3 months after treatment. Nailfold videocapillaroscopy was applied to detect alterations of the dermal capillary network. Participants underwent 24 h ambulatory blood pressure monitoring (Mobil-O-Graph device) for the assessment of blood pressure (both brachial and aortic) and markers of large artery stiffening [pulse wave velocity (PWV), augmentation index] throughout the whole 24 h and the respective day- and nighttime periods. Carotid intima–media thickness was assessed with ultrasound. Results: Three-month treatment with JAK inhibitors was not associated with any differences in brachial and aortic blood pressure, arterial stiffness, and carotid atherosclerosis, with the only exception of nighttime PWV, which was significantly elevated at follow-up. However, three-month treatment with JAK inhibitors induced significant microvascular alterations and increased the total number of capillaroscopic abnormalities. Conclusions: Three-month treatment with JAK inhibitors may exert significant effects on microcirculation as assessed with nailfold videocapillaroscopy, whereas macrovascular structure and function appears largely unaffected. Further research toward this direction may add substantial information to the available literature regarding cardiovascular aspects of JAK inhibitors in RA.

Background: Vascular dysfunction and its concomitant multi-organ involvement, including cardiac involvement, affects prognosis in systemic sclerosis (SSc) patients. Regular exercise has demonstrated to be able to improve vascular function in SSc. However, the effects of an exercise program on the heart and specifically in right ventricular (RV) morphology and function in SSc have yet to be explored. The study aimed to examine whether a 3-month combined exercise program can affect RV morphology and function in SSc patients. Methods: Twenty-eight SSc patients were randomly allocated to either the exercise training (ET) or the control (CON) group. Baseline and follow-up assessments consisted of a cardiopulmonary exercise test along with both a conventional and a two-dimensional speckle tracking echocardiography (2DSTE) focused on RV morphology and function. Following the baseline assessments, Group ET participated in a supervised combined exercise program for 12 weeks, while group CON received their usual care. Results: The ET group demonstrated increases in peak oxygen consumption by 25.1% (p < 0.001), global RV free wall longitudinal systolic strain by 6.69% (p < 0.03), RV free wall longitudinal systolic strain of the basal segment by 13.5% (p < 0.001), and global RV four-chamber longitudinal systolic strain by 6.76% (p < 0.03) following the exercise program. No differences were observed in group CON. Conclusions: Combined exercise improved cardiorespiratory efficiency and indices of RV systolic function, as assessed by the 2DSTE, in SSc patients.

Introduction/objectives Systemic sclerosis (SSc) is characterized by generalized vasculopathy affecting mainly small vessels while macrovascular involvement is less investigated. The aim of this study was to examine associations between asymmetric dimethylarginine (ADMA) — a biomarker of atherosclerosis — and assessments of macrovascular endothelial function in patients with SSc. Methods This was a cross-sectional study including consecutive SSc patients attending the Scleroderma Outpatient Clinic. ADMA measurement in serum samples was based on an enzyme immunoassay technique. Participants underwent blood pressure measurement according to 2018 ESC/ESH Guidelines, applanation tonometry for the evaluation of arterial stiffness, and carotid ultrasound for the measurement of the intima-media thickness (cIMT). Results Eighty-one Caucasians (82.3% female) SSc individuals with mean age 55.44 ± 13.4 years were included in this analysis. The correlation analysis of ADMA levels (unadjusted and adjusted values) with functional and morphological parameters of atherosclerosis revealed no statistically significant associations. Subgroup analysis based on disease duration (≤ 4 years), immunologic profile (SCL-70 and ACA antibodies), disease type (limited, diffuse), and inflammatory status (erythrocyte sedimentation rate [ESR] > 25 mm/h and C-reactive protein [CRP] > 5 mg/L) showed no associations, except from a significant positive correlation between ADMA levels and cΙΜΤ_mean (r = 0.370, p = 0.044) in individuals with early SSc. Conclusions The results of the study suggest that ADMA may be related with accelerated atherosclerosis in early stages of the disease. However, the lack of association between other morphological and functional parameters of endothelial dysfunction may suggest that other regulators of nitric oxide metabolism may contribute to macrovascular injury in SSc in various phases of the disease. Key Points • ADMA is a biomarker of atherosclerosis and has been linked with microvascular complications of SSc. •ADMA was not correlated with morphological and functional parameters of atherosclerosis in the population of the study. •The demonstrated association between ADMA and cIMT in patients with early SSc may suggest a role of NO/ADMA pathway in the initiation of macrovascular injury in SSc.

Rheumatoid arthritis (RA) is a systemic inflammatory disease treated with conventional and biologic disease-modifying drugs. Methotrexate is the anchor drug for the treatment of RA and is also frequently used for various autoimmune diseases. Adverse events are common and generally easy to manage, involving mainly the gastrointestinal tract and the liver function. However, neurotoxicity is very uncommon in adults with rheumatic diseases. B cell depletion with rituximab is another therapy approach particularly in patients with refractory RA. Whistle leukoencephalopathy – namely progressive multifocal leukoencephalopathy—is an infrequent but well-described side effect of rituximab. In contrast, central nervous system toxicity due to methotrexate is extremely rare especially in RA individuals under oral or subcutaneous low dose on weekly basis. We present a challenging case of a RA patient on treatment with methotrexate and rituximab presenting with leukoencephalopathy. The patient was diagnosed with methotrexate-induced leukoencephalopathy which reversed after treatment discontinuation. We comment on the symptoms and diagnostic workout and we review the available literature on this issue based on recommendations for narrative reviews.

Introduction Microvascular dysfunction is the key element in the pathogenesis of systemic sclerosis (SSc), whereas the contribution of large and medium size vessel abnormalities is yet to be established. The aim of the present study is to assess the association between micro- and macrovascular function by utilizing a broad spectrum of assessments of vascular performance. Methods We included consecutive, consenting SSc patients who underwent nailfold video capillaroscopy (NVC) for microcirculation evaluation. Peripheral and central systolic and diastolic blood pressure, carotid intima-media thickness (cIMT), aortic augmentation index (AIx) corrected for a heart rate of 75 beats per minute (AIx-75), and carotid-femoral pulse wave velocity (PWV) were also performed to assess macrovascular function. Cardiovascular risk disease (CVD) algorithms were also calculated and included in the analysis. Results A total of 81 patients (6 males) were studied with mean age 55.44 ± 13.40 years. Reduced capillary density was inversely correlated with arterial stiffness (Alx-75) and augmentation pressure (r = − 0.262, p = 0.018, and r = − 0.249, p = 0.025 respectively). Alx was significantly lower in the early compared to late pattern (28.24 ± 11.75 vs 35.63 ± 10.47, p = 0.036). A significant trend was found among NVC patterns with Alx-75 values being higher with the progression of microangiopathy towards the “late” group (26.36 ± 10.90 vs 30.81 ± 11.59 vs 35.21 ± 7.90, p = 0.027 for trend). Similarly, Framingham risk score and Atherosclerotic Cardiovascular Disease score were progressively higher across the worsening NVC patterns (4.10 ± 4.13 vs 2.99 ± 2.72 vs 6.36 ± 5.65, p = 0.023, and 6.99 ± 7.18 vs 5.63 ± 4.41 vs 12.09 ± 9.90, p = 0.019, respectively, for trends). Finally, QRISK3 (10-year cardiovascular disease risk) and ASCVD (Atherosclerotic Cardiovascular Disease) scores were inversely correlated with the number of capillaries (r = − 0.231, p = 0.048, and r = − 0.260, p = 0.038 respectively). Conclusion These data suggest that CVD risk scores and macrovascular parameters are strongly correlated with microvasculopathy in patients with SSc. Key Points • Microangiopathy is the hallmark of SSc, but the relationship between subclinical atherosclerosis and small vessel disease remains unknown. • Arterial stiffening and CVD risk scores are positively associated with the degree of progression of peripheral microvasculopathy assessed with NVC. • The results of the study suggest an association between NVC abnormalities and higher CVD risk in SSc patients.

Pulmonary arterial hypertension (PAH) represents one of the most devastating complications in connective tissue diseases (CTDs). The aim of this study was to investigate the presence of peripheral microangiopathy in patients with PAH associated with CTDs (CTD-PAH) by exploring nailfold videocapillaroscopic (NVC) changes and identify possible associations of NVC characteristics with markers of disease severity. Α cross-sectional study was performed in 18 CTD-PAH patients [13 PAH due to systemic sclerosis (SSc-PAH) and 5 with other types of CTD-PAH], 14 patients with SSc without PAH (SSc-non-PAH) and 20 healthy controls. NVC quantitative and qualitative parameters were evaluated using Optilia Digital Capillaroscope. To ensure inter-observer repeatability, capillaroscopic images were reviewed by two independent investigators. When compared to healthy controls, patients with CTD-PAH (77.8% women, mean age 65.9 years) presented reduced capillary density (6.5 ± 1.6 loops/mm vs. 9.7 ± 0.7 loops/mm, p < 0.001) and increased capillary loop width (23.3 ± 10.1 μm vs. 11.2 ± 2.5 μm, p < 0.001). SSc-PAH patients presented lower capillary density in comparison with other CTD-PAH patients and SSc-non-PAH subjects and abnormal and disorganized capillaries compared to controls. Patients with other CTD-PAH had also reduced capillary density and increased loop diameter compared to controls. A significant linear correlation was identified between capillary density and estimated glomerular filtration rate in the total CTD-PAH population (r = 0.63, p = 0.007). In SSc-PAH group, capillary loop diameter was positively correlated to cardiac index (r = 0.61, p = 0.02). Significant NVC microvascular changes were detected in patients with various types of CTD-PAH, suggesting an impaired peripheral microcirculation parallel to pulmonary vasculopathy.