Association of clinical, imaging and laboratory parameters with adverse effects of glucocorticoid therapy in patients with giant cell arteritis.

Background: Giant cell arteritis (GCA) is characterized by inflammation of large and medium vessels. First-line therapy for the treatment of GCA are glucocorticoids, which are effective while potential adverse effects should be considered, especially during long-term use. The aim was to investigate the incidence of glucocorticoids' adverse effects and potential predictors for them. Materials and methods: 138 GCA patients were retrospectively evaluated for newly developed glucocorticoid adverse effects in 2020. Potential predictors, defined as initial glucocorticoid pulse therapy, relapse of GCA and concomitant polymyalgia rheumatica as well as parameters of inflammation and endothelial dysfunction, including pulse-wave velocity and intima-media-thickness, were measured in 2012. Results: Potential new glucocorticoid adverse effects per patient was 1 (25th-75th 0-3) of which chronic kidney disease progression (29%), bone fractures (23.2%), cataracts (18.1%), dementia, and arterial hypertension (each at 12.3%) were most commonly recorded. Significant associations were found between occurrence of any relapse and new diabetes mellitus and between initial glucocorticoid pulse therapy and new dementia (all with p < 0.05). In multivariate regression analysis, any relapse was a predictor for developing diabetes mellitus (OR 9.23 [95% CI 1.33-64.05], p = 0.025). However, no correlations were observed between endothelial dysfunction or inflammatory parameters and development of new glucocorticoid adverse effects. Conclusion: GCA relapses may be associated for development of diabetes mellitus potentially by increasing glucocorticoid doses. Parameters of inflammation and endothelial dysfunction are not suited predictors for glucocorticoid adverse effects.

Successful long-term systemic sclerosis treatment by high-frequent low-dose B cell-depleting therapy.

OBJECTIVES: Systemic sclerosis (SSc) is a multiorgan disease with a 10-year mortality rate of up to 50 %. B cell-depleting therapy with rituximab (RTX) appears effective in SSc treatment, but data from randomized controlled trials (RCTs) are lacking, and the frequency and dosage of RTX in SSc have no consensus. We aimed to evaluate the long-term efficacy and safety of quarterly RTX administration in SSc. METHODS: This study retrospectively analyzed 40 patients with SSC treated with RTX twice within 14 days every 3 months from 2010 to 2020. The patients fulfilled the LeRoy and the American College of Rheumatology/European League Against Rheumatism Criteria for SSc. Modified Rodnan skin score (mRSS), lung function test results, and serum immunoglobulin (IgG, IgA, and IgM) concentrations were analyzed. RESULTS: A total of 40 patients with SSc received RTX over a median time of 3.9 years (range: 1-10 years). The median mRSS (baseline: 19, 24 months: 16, p < 0.001) demonstrated a significant improvement, and the predicted forced vital capacity was stable. No new or unexpected safety signals, especially regarding treatment-related infectious adverse events, were observed. Immunoglobulin concentrations were within normal range, and specific antibodies to pneumococcal polysaccharides were preserved despite long-term B cell-depleting therapy. None of the patients died during the observation period of up to 10 years. CONCLUSION: SSc was effectively and safely treated with low-dose RTX quarterly. RCTs are warranted to validate the advantage of continuous B cell depletion by quarterly low-dose RTX administration compared to other treatment intervals.

Cardiovascular diseases and their associations with lipid parameters and endothelial dysfunction in giant cell arteritis.

OBJECTIVES: Evaluation of endothelial dysfunction, lipid metabolism, prevalence and development of cardiovascular diseases in patients with giant cell arteritis (GCA). METHODS: 138 GCA patients and 100 controls were evaluated for prevalent cardiovascular diseases in 2012. Cholesterol, lipoproteins and triglycerides, intima-media thickness, arterial stiffness, asymmetric and symmetric dimethylarginine were also measured in 2012. Cardiovascular events, mortality and relapse were retrieved by chart review in 2020. RESULTS: Prevalent carotid and vertebral artery disease was higher in GCA patients than in controls (p<0.001). GCA patients had higher levels of total cholesterol, low-density lipoprotein (LDL), intermediate-density lipoprotein, high-density lipoprotein, apolipoprotein A1 and B, and augmentation index (all with p<0.05). Target LDL levels were less frequently achieved at study inclusion by GCA patients (p=0.001), who developed more frequently new cardiovascular events, also with a higher amount, during follow-up (all with p<0.001). Statin treatment in GCA patients was associated with lower levels of asymmetric dimethylarginine, monocytes and C reactive protein (all with p<0.05). Relapse was independently associated with higher risk of future cardiovascular events (OR 5.01 (95% CI 1.55 to 16.22), p=0.007). CONCLUSIONS: GCA patients are at a high risk of developing cardiovascular diseases. Of relevance, there was underuse of statins and a large proportion of these patients showed LDL cholesterol concentrations above the treatment targets for high-risk patients. These data underscore the need for improvement of preventive strategies to reduce cardiovascular risk in GCA patients.

Association of amino acids and parameters of bone metabolism with endothelial dysfunction and vasculopathic changes in limited systemic sclerosis.

Objectives: Pathways contributing to endothelial dysfunction in patients with limited cutaneous systemic sclerosis (lcSSc) are largely unknown. The aim of this study was to investigate potential associations of amino acids and parameters of bone metabolism with endothelial dysfunction and vasculopathy-related changes in patients with lcSSc and early-stage vasculopathy. Methods: Amino acids, calciotropic parameters, including 25-hydroxyvitamin D and parathyroid hormone (PTH), and bone turnover parameters, including osteocalcin and N-terminal peptide of procollagen-3 (P3NP), were measured in 38 lcSSc patients and 38 controls. Endothelial dysfunction was assessed by biochemical parameters, pulse-wave analysis, flow-mediated and nitroglycerine-mediated dilation. Additionally, vasculopathy-related and SSc-specific clinical changes including capillaroscopic, skin, renal, pulmonary, gastrointestinal and periodontal parameters were recorded. Results: No significant differences in amino acids, calciotropic and bone turnover parameters were observed between lcSSc patients and controls. In patients with lcSSc, several significant correlations were found between selected amino acids, parameters of endothelial dysfunction, vasculopathy-related and SSc-specific clinical changes (all with p < 0.05). In addition, significant correlations were observed between PTH and 25-hydroxyvitamin D with homoarginine, and between osteocalcin, PTH and P3NP with modified Rodnan skin score and selected periodontal parameters (all with p < 0.05). Vitamin D deficiency defined as 25-hydroxyvitamin D < 20 ng/ml was associated with the presence of puffy finger (p = 0.046) and early pattern (p = 0.040). Conclusion: Selected amino acids may affect endothelial function and may be associated to vasculopathy-related and clinical changes in lcSSc patients, while the association with parameters of bone metabolism seems to be minor.

Clinical characteristics of COVID-19 associated vasculopathic diseases.

Coronavirus disease 19 (COVID-19) has shown to be an infectious disease affecting not only of the respiratory system, but also cardiovascular system leading to different COVID-19-associated vasculopathies. Venous and arterial thromboembolic events have been frequently described among hospitalized patients with COVID-19 and inflammatory vasculopathic changes have also been observed. Several of the reported COVID-19 associated vasculopathies exhibit differences on epidemiology, clinical characteristics and outcome compared to non-COVID-19 types. This review focuses on the epidemiology, clinical, diagnostic and therapeutic characteristics as well as outcome data of COVID-19 associated thromboembolic events and inflammatory vasculopathies, elaborating similarities and differences with non-COVID-19 cohorts.

Pathophysiological Aspects of COVID-19-Associated Vasculopathic Diseases.

Since the beginning of coronavirus disease 2019 (COVID-19) pandemic, numerous data reported potential effects on the cardiovascular system due to infection by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which may lead to COVID-19-associated vasculopathies during the acute phase and measurable vascular changes in the convalescent phase. Infection by SARS-CoV-2 seems to have specific direct and indirect effects on the endothelium, immune and coagulation systems thus promoting endothelial dysfunction, immunothrombosis, and formation of neutrophil extracellular traps although the exact mechanisms still need to be elucidated. This review represents a recent update of pathophysiological pathways of the respective three major mechanisms contributing to COVID-19 vasculopathies and vascular changes and includes clinical implications and significance of outcome data.

Periodontal disease and its association to endothelial dysfunction and clinical changes in limited systemic sclerosis: A case-control study.

OBJECTIVES: Periodontal disease occurs frequently in patients with limited cutaneous systemic sclerosis (lcSSc) while data about underlying pathways contributing to periodontal changes are scarce. The aim of this study was to evaluate periodontal disease and to investigate its association with endothelial dysfunction and clinical changes in patients with lcSSc. METHODS: In 38 lcSSc patients and 38 controls, periodontal status was evaluated by disease-specific questionnaire, dental examination including bleeding on probing (BOP), pocket depth, and plaque index, and dental panoramic radiograph. Periodontopathogen bacteria were collected subgingivally using paper points and interleukin-1 (IL-1) gene polymorphisms were evaluated using buccal swabs. Endothelial dysfunction was measured by flow-mediated dilatation, pulse-wave velocity and biochemical analysis, including arginine metabolites and endothelial microparticles. Additionally, lcSSc-specific clinical changes and parameters were recorded. RESULTS: Periodontitis was present in 31 patients with lcSSc (81.6%) and in 27 controls (71.1%) (p = .280). LcSSc patients had a lower teeth number (p = .039) and Eikenella corrodens was to a higher degree detectable in patients with lcSSc (p = .041) while the remaining periodontal parameters revealed no differences between both cohorts. Significant correlations between parameters of arterial stiffness, EUSTAR index, number of teeth and BOP were observed (all p < .05). Detection of Prevotella intermedia was associated with selected IL-1 gene polymorphisms (p = .032) and Porphyromonas gingivalis was associated with severe periodontitis (p = .041). CONCLUSION: Periodontal disease may occur frequently in patients with lcSSc and may be associated with arterial stiffness and with SSc activity.

Association of immunological parameters with aortic dilatation in giant cell arteritis: a cross-sectional study.

Aortic dilatation (AD) occurs in up to 30% of patients with giant cell arteritis (GCA). Reliable biomarkers for AD development, however, are still absent. The aim of this exploratory study was to evaluate whether immunological parameters are associated with the occurrence of AD in GCA. Cross-sectional study on 20 GCA patients with AD, 20 GCA patients without AD, and 20 non-GCA controls without AD measuring leukocytes, neutrophils, lymphocytes, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum amyloid A (SAA), interferon (IFN)-α, IFN-γ, IFN-γ-induced protein 10 (IP-10), interleukin (IL) 5, IL-8, IL-10, IL-17A, IL-18, IL-1 receptor antagonist, tumor necrosis factor (TNF)-α, platelet-derived growth factor (PDGF), L-selectin, P-selectin, and soluble intercellular adhesion molecule 1 (sICAM-1). AD was measured by aortic contrast-enhanced computed tomography and defined by enlargement of the aorta above population-based aortic diameters adjusted by age, gender, and body surface area. No significant differences were observed between GCA patients with AD and GCA patients without AD concerning levels of leukocytes, neutrophils, lymphocytes, CRP, ESR, SAA, IL-8, IL-18, PDGF, IP-10, selectins, and sICAM-1. Values of IFN-α, IFN-γ, IL-5, IL-10, IL-17A, IL-1 receptor antagonist, and TNF-α were all below the detection limits in more than 70% of subjects. Lymphocytes and CRP revealed positive correlations with the diameter of the thoracic descending aorta. Immunological parameters were not useful to conclude on the presence of AD in GCA. Further studies are required to test if CRP and lymphocytes may be useful to predict future development of AD in GCA.

Lipoprotein(a) and Pulmonary Embolism Severity-A Retrospective Data Analysis.

AIM: We aimed to investigate a correlation between PE severity and Lp(a) levels. METHODS: We performed a retrospective data analysis from our medical records of PE patients admitted to the University Hospital Graz, Austria. Patients with an Lp(a) reading within a 1-year interval before and after PE diagnosis were included. In accordance with the 2019 ESC guidelines for the diagnosis and management of acute PE, severity assessment was carried out classifying patients into four groups: low risk (LR), intermediate low risk (IML), intermediate high risk (IMH) and high risk (HR). The study period of interest was between January 1, 2002 and August 1, 2020. RESULTS: We analyzed 811 patients with PE, of whom 323 (40%) had low-risk PE, 343 (42%) had intermediate-low-risk PE, 64 (8%) had intermediate-high-risk PE, and 81 (10%) had high-risk PE, respectively. We did not observe an association between PE severity and Lp(a) concentrations. In detail, median Lp(a) concentrations were 17 mg/dL [25-75th percentile: 10-37] in low-risk PE patients, 16 mg/dL [10-37] in intermediate-low-risk PE patients, 15mg/dL [10-48] in intermediate-high-risk PE patients, and 13mg/dL [10-27] in high-risk PE patients, respectively (Kruskal-Wallis p = 0.658, p for linear trend = 0.358). CONCLUSION: The current findings suggest no correlation between PE severity and Lp(a) levels.

Red urine and a red herring - diagnosing rare diseases in the light of the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has occupied the time and resources of health care professionals for more than 1 year. The risk of missed diagnoses has been discussed in the medical literature, mainly for common diseases such as cancer and cardiovascular events. However, rare diseases also need appropriate attention in times of a pandemic. CASE REPORT: We report a 34-year-old woman with fever, pinprick sensation in her chest and thoracic spine, and dizziness after receiving the first dose of ChAdOx1 nCoV-19 vaccination. The patient's condition worsened with abdominal pain, red urine, and hyponatremia, needing intensive care admission. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) was diagnosed. Vaccine-induced thrombocytopenia and thrombosis were ruled out. Acute hepatic porphyria was finally diagnosed, and the patient recovered completely after treatment with hemin. CONCLUSION: Currently, the focus of physicians is on COVID-19 and associated medical problems, such as vaccine side effects. However, it is important to be vigilant for other uncommon medical emergencies in medically exceptional situations that may shift our perception.

Evaluation of Endothelial Dysfunction and Inflammatory Vasculopathy After SARS-CoV-2 Infection-A Cross-Sectional Study.

Background: Rising data suggest that COVID-19 affects vascular endothelium while the underlying mechanisms promoting COVID-19-associated endothelial dysfunction and inflammatory vasculopathy are largely unknown. The aim was to evaluate the contribution of COVID-19 to persisting vascular injury and to identify parameters linked to COVID-19-associated endothelial dysfunction and inflammatory vasculopathy. Methods: In a cross-sectional design, flow-mediated dilation (FMD), nitroglycerine-related dilation (NMD), pulse-wave velocity (PWV), augmentation index, intima-media thickness (IMT), compounds of the arginine and kynurenine metabolism, homocysteine, von Willebrand factor (vWF), endothelial microparticles (EMP), antiendothelial cell antibodies, inflammatory, and immunological parameters, as well as nailfold capillary morphology were measured in post-COVID-19 patients, patients with atherosclerotic cardiovascular diseases (ASCVD) and healthy controls without prior or recent SARS-CoV-2 infection. Results: Post-COVID-19 patients had higher values of PWV, augmentation index, IMT, asymmetric and symmetric dimethylarginine, vWF, homocysteine, CD31+/CD42b- EMP, C-reactive protein, erythrocyte sedimentation rate, interleukin-6, and ß-2-glycoprotein antibodies as well as lower levels of homoarginine and tryptophan compared to healthy controls (all with p < 0.05). A higher total number of pathologically altered inflammatory conditions and higher rates of capillary ramifications, loss, caliber variability, elongations and bushy capillaries with an overall higher microangiopathy evolution score were also observed in post-COVID-19 patients (all with p < 0.05). Most parameters of endothelial dysfunction and inflammation were comparably altered in post-COVID-19 patients and patients with ASCVD, including FMD and NMD. Conclusion: COVID-19 may affect arterial stiffness, capillary morphology, EMP and selected parameters of arginine, kynurenine and homocysteine metabolism as well as of inflammation contributing to COVID-19-associated endothelial dysfunction and inflammatory vasculopathy.

Lower Lean Mass Is Associated with Greater Arterial Stiffness in Patients with Lower Extremity Artery Disease.

BACKGROUND: Arterial stiffness is independently associated with lower extremity artery disease (LEAD). Although obesity is already known as an independent cardiovascular risk factor, it was found that, paradoxically, in patients diagnosed with cardiovascular disease, an increase in body mass index (BMI) was associated with a decrease in mortality. However, the underlying mechanism of this paradoxical association remain uncertain. In this study, we firstly hypothesize that arterial stiffness correlates with body mass; secondly, the underlying mechanism of the association for patients with LEAD is individual body composition, in particular, lean mass. METHODS: The present study was performed as a single-center, prospective, observational analysis. A total of 412 patients with current or previously diagnosed LEAD (Rutherford Classification 2-4) were included, the cfPWV and AIx were measured as indices of arterial stiffness, and a body composition assessment was performed. RESULTS: In male patients, there was a significantly negative correlation between the AIx and lean mass coefficient (p = 0.004, 95% CI: -0.28 (-0.48-0.09)). CONCLUSION: For patients with peripheral arterial disease, our data show that lower lean mass in male patients is associated with increased arterial stiffness as measured by the AIx. Therefore, progressive resistance training may be beneficial for the reduction in arterial stiffness in PAD patients in secondary prevention.