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

ObjectivesPathways 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.MethodsAmino 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.ResultsNo 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).ConclusionSelected 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

The Risk of Severe Infections Following Rituximab Administration in Patients With Autoimmune Kidney Diseases: Austrian ABCDE Registry Analysis.

OBJECTIVE: To characterize the incidence, type, and risk factors of severe infections (SI) in patients with autoimmune kidney diseases treated with rituximab (RTX). METHODS: We conducted a multicenter retrospective cohort study of adult patients with immune-related kidney diseases treated with at least one course of RTX between 2015 and 2019. As a part of the ABCDE Registry, detailed data on RTX application and SI were collected. SI were defined by Common Terminology Criteria for Adverse Events v5.0 as infectious complications grade 3 and above. Patients were dichotomized between "nephrotic" and "nephritic" indications. The primary outcome was the incidence of SI within 12 months after the first RTX application. RESULTS: A total of 144 patients were included. Twenty-five patients (17.4%) presented with SI, mostly within the first 3 months after RTX administration. Most patients in the nephritic group had ANCA-associated vasculitis, while membranous nephropathy was the leading entity in the nephrotic group. Respiratory infections were the leading SI (n= 10, 40%), followed by urinary tract (n=3, 12%) and gastrointestinal infections (n=2, 8%). On multivariable analysis, body mass index (BMI, 24.6 kg/m2versus 26.9 kg/m2, HR: 0.88; 95%CI: 0.79-0.99; p=0.039) and baseline creatinine (HR: 1.25; 95%CI: 1.04-1.49; p=0.017) were significantly associated with SI. All patients in the nephritic group (n=19; 100%) who experienced a SI received oral glucocorticoid (GC) treatment at the time of infection. Hypogammaglobulinemia was frequent (58.5%) but not associated with SI. CONCLUSIONS: After RTX administration, impaired kidney function and lower BMI are independent risk factors for SI. Patients with nephritic glomerular diseases having concomitant GC treatment might be at higher risk of developing SI

Challenges of defining renal response in ANCA-associated vasculitis: call to action?

Avoiding end-stage kidney disease in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has a high therapeutic priority. Although renal response is a crucial measure to capture clinically relevant changes, clinal trials have used various definitions and no well-studied key surrogate markers to predict renal outcome in AAV exist. Differences in clinical features and histopathologic and therapeutic approaches will influence the course of kidney function. Its assessment through traditional surrogates (i.e. serum creatinine, glomerular filtration rate, proteinuria, hematuria and disease activity scores) has limitations. Refinement of these markers and the incorporation of novel approaches such as the assessment of histopathological changes using cutting-edge molecular and machine learning mechanisms or new biomarkers could significantly improve prognostication. The timing is favourable since large datasets of trials conducted in AAV are available and provide a valuable resource to establish renal surrogate markers and, likely, aim to investigate optimized and tailored treatment approaches according to a renal response score. In this review we discuss important points missed in the assessment of kidney function in patients with AAV and point towards the importance of defining renal response and clinically important short- and long-term predictors of renal outcome

Challenges of defining renal response in ANCA-associated vasculitis: call to action?

Lay Summary This review focuses on kidney survival of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Impaired kidney function is a major contributor to morbidity and mortality. In this review we discuss current knowledge about recovery potential of the kidney, influences thereof and how future modern approaches may help to improve prediction. This will eventually include kidney biopsies, markers measured in blood and urine and baseline characteristics of patients. Avoiding end-stage kidney disease in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has a high therapeutic priority. Although renal response is a crucial measure to capture clinically relevant changes, clinal trials have used various definitions and no well-studied key surrogate markers to predict renal outcome in AAV exist. Differences in clinical features and histopathologic and therapeutic approaches will influence the course of kidney function. Its assessment through traditional surrogates (i.e. serum creatinine, glomerular filtration rate, proteinuria, hematuria and disease activity scores) has limitations. Refinement of these markers and the incorporation of novel approaches such as the assessment of histopathological changes using cutting-edge molecular and machine learning mechanisms or new biomarkers could significantly improve prognostication. The timing is favourable since large datasets of trials conducted in AAV are available and provide a valuable resource to establish renal surrogate markers and, likely, aim to investigate optimized and tailored treatment approaches according to a renal response score. In this review we discuss important points missed in the assessment of kidney function in patients with AAV and point towards the importance of defining renal response and clinically important short- and long-term predictors of renal outcome.Funding Agencies|Austrian Science Fund [J 4664-B]; Wellcome Trust; Health Research Board [203930/B/16/Z]; Health Service Executive, National Doctors Training and Planning; Health and Social Care, Research and Development Division, Northern Ireland</p

Critical Appraisal of Large Vitamin D Randomized Controlled Trials

As a consequence of epidemiological studies showing significant associations of vitamin D deficiency with a variety of adverse extra-skeletal clinical outcomes including cardiovascular diseases, cancer, and mortality, large vitamin D randomized controlled trials (RCTs) have been designed and conducted over the last few years. The vast majority of these trials did not restrict their study populations to individuals with vitamin D deficiency, and some even allowed moderate vitamin D supplementation in the placebo groups. In these RCTs, there were no significant effects on the primary outcomes, including cancer, cardiovascular events, and mortality, but explorative outcome analyses and meta-analyses revealed indications for potential benefits such as reductions in cancer mortality or acute respiratory infections. Importantly, data from RCTs with relatively high doses of vitamin D supplementation did, by the vast majority, not show significant safety issues, except for trials in critically or severely ill patients or in those using very high intermittent vitamin D doses. The recent large vitamin D RCTs did not challenge the beneficial effects of vitamin D regarding rickets and osteomalacia, that therefore continue to provide the scientific basis for nutritional vitamin D guidelines and recommendations. There remains a great need to evaluate the effects of vitamin D treatment in populations with vitamin D deficiency or certain characteristics suggesting a high sensitivity to treatment. Outcomes and limitations of recently published large vitamin D RCTs must inform the design of future vitamin D or nutrition trials that should use more personalized approaches

Myocardial infarction with non-obstructive coronary arteries in a patient double-seropositive for anti-glomerular basement membrane and anti-neutrophil cytoplasmic antibodies: A case report

Peer reviewed: TrueWe report a case of a patient double-seropositive for anti-glomerular basement membrane (anti-GBM) and anti-neutrophil cytoplasmic antibodies (ANCA) who reported retrosternal chest pain during a regular hemodialysis session associated with ST-segment depression in electrocardiogram and an increase of serum high-sensitivity troponin T. Urgent coronary angiography excluded obstructive coronary artery disease, suggesting the diagnosis of ischemia with non-obstructive coronary arteries. This case illustrates an unusual presentation of cardiovascular involvement in a patient with double-positive ANCA/anti-GBM disease, emphasizing the possible relevance of coronary microvascular dysfunction and the need for close cardiovascular follow-up in this patient population

COVID-19 outcomes in patients with a history of immune-mediated glomerular diseases

IntroductionPatients with immune-mediated glomerular diseases are considered at high risk for severe COVID-19 outcomes. However, conclusive evidence for this patient population is scarce.MethodsWe created a global registry and retrospectively collected clinical data of patients with COVID-19 and a previously diagnosed immune-mediated glomerular disease to characterize specific risk factors for severe COVID-19 outcomes.ResultsFifty-nine patients with a history of immune-mediated glomerular diseases were diagnosed with COVID-19 between 01.03.2020 and 31.08.2021. Over a mean follow-up period of 24.79 ± 18.89 days, ten patients (16.9%) developed acute kidney injury. Overall, 44.1% of patients were managed in an outpatient setting and therefore considered as having “non-severe” COVID-19, while 55.9% of patients had severe COVID-19 requiring hospitalization including worse outcomes. Comparing both groups, patients with severe COVID-19 were significantly older (53.55 ± 17.91 versus 39.77 ± 14.95 years, p = .003), had lower serum albumin levels at presentation (3.00 ± 0.80 g/dL versus 3.99 ± 0.68 g/dL, p = .016) and had a higher risk of developing acute kidney injury (27% versus 4%, p = .018). Male sex (p &lt;.001) and ongoing intake of corticosteroids at presentation (p = .047) were also significantly associated with severe COVID-19 outcomes, while the overall use of ongoing immunosuppressive agents and glomerular disease remission status showed no significant association with the severity of COVID-19 (p = .430 and p = .326, respectively).ConclusionOlder age, male sex, ongoing intake of corticosteroids and lower serum albumin levels at presentation were identified as risk factors for severe COVID-19 outcomes in patients with a history of various immune-mediated glomerular diseases

Risk factors for serious infections in ANCA-associated vasculitis.

Peer reviewed: TrueAcknowledgements: We thank all the patients who participated in the RAVE trial. Balazs Odler is a postdoctoral research fellow at the University of Cambridge supported by the Austrian Science Fund (FWF). David Jayne is supported by the NIHR Cambridge Biomedical Research Centre.Funder: NIHR Cambridge Biomedical Research CentreOBJECTIVES: Severe infections contribute to morbidity and mortality in antineutrophil cytoplasm antibody-associated vasculitis (AAV). This study aimed to identify risk factors associated with severe infections in participants of the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial. METHODS: Data on 197 patients recruited into the RAVE trial were analysed. Participants received either rituximab (RTX) or cyclophosphamide (CYC), followed by azathioprine (AZA). Clinical and laboratory data of patients with and without severe infections (≥grade 3, according to the Common Terminology Criteria for Adverse Events version 3.0) were compared. Risk factors for severe infections were investigated using Cox-regression models. RESULTS: Eighteen of 22 (82%) severe infections occurred within 6 months after trial entry, most commonly respiratory tract infections (15/22, 68%). At baseline, lower absolute numbers of CD19+ cells were observed in patients with severe infections either receiving RTX or CYC/AZA at baseline, while CD5+B and CD3+T cells did not differ between groups. In Cox-regression analysis, higher baseline serum immunoglobulin M levels were associated with the risk of severe infections, whereby a higher baseline total CD19+B cell number and prophylaxis against Pneumocystis jirovecii with trimethoprim-sulfamethoxazole (TMP/SMX) with decreased risk of severe infections. Use of TMP/SMX was associated with lower risk of severe infections in both groups, receiving either RTX or CYC/AZA. CONCLUSIONS: The use of low-dose TMP/SMX is associated with reduced risk of severe infections in patients with AAV treated with either RTX or CYC/AZA. Reduced B cell subpopulations at start of treatment might be a useful correlate of reduced immunocompetence