Susceptibility for lupus nephritis by low copy number of the FCGR3B gene is linked to increased levels of pathogenic autoantibodies

Low copy number (CN) of the FCGR3B gene reduces FCGR3B membrane expression on neutrophils and results in clearance of a smaller amount of immune complex. We investigated FCGR3B CN in relation to the clinical phenotype in a Caucasian SLE cohort (n = 107). FCGR3B CN was determined by three different qPCR parameter estimations (Ct-, Cy0, and cpD1) and confirmed by the FCGR2C/FCGR2A paralog ratio test. Clinical and serological data were then analyzed for their association with FCGR3B CN. Low FCGR3B CN (2). In multivariate analyses, LN was independently associated with anti-C1q-Ab levels (P = 0.03) and low FCGR3B CN (P = 0.09). We conclude that the susceptibility for LN in patients with low FCGR3B CN is linked to increased levels of pathogenic autoantibodies.Johannes C. Nossent, Andrea Becker-Merok, Maureen Rischmueller, and Sue Leste

Pulmonary involvement in primary Sjogren's syndrome, as measured by the ESSDAI

Objective: Systemic features influence disease prognosis and choice of treatment in primary Sjogren's syndrome (pSS). Our aim was to investigate the prevalence of pulmonary involvement in pSS patients and to classify patients according to the pulmonary domain of the EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI). Methods: This retrospective cohort study included consecutive pSS patients, fulfilling American-European Consensus Group/American College of Rheumatology classification criteria, who visited the Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, in 2015. Data on pulmonary complaints and pulmonary tests were obtained from electronic patient records. Pulmonary involvement was recorded if therapy was needed or follow-up was recommended, and when it was possibly or assumed to be related to pSS instead of coincidental factors. Results: Of the 262 included pSS patients, 88 (34%) had pulmonary complaints, mostly cough or dyspnoea on exertion. Pulmonary diagnostics were performed in 225 patients (86%). Pulmonary involvement was present and assumed to be related to pSS in 25 patients (10%) and possibly related to pSS in 14 (5%). Interstitial lung disease (ILD, n = 15), especially non-specific interstitial pneumonia (n = 7), was present most commonly. In total, 16 patients (6%) were scored as low (n = 4), moderate (n = 11), or high activity (n = 1) on the ESSDAI pulmonary domain. Conclusion: In this cross-sectional study in daily clinical practice, pulmonary involvement was present in 10-15% of pSS patients, of which ILD was most common. Of all pSS patients, 6% were scored as active on the pulmonary domain of the ESSDAI

Circulating Small Non-coding RNAs as Biomarkers for Recovery After Exhaustive or Repetitive Exercise

Circulating microRNAs have proven to be reliable biomarkers, due to their high stability, both in vivo in the circulation, and ex vivo during sample preparation and storage. Small nucleolar RNAs (snoRNAs) are a different type of small non-coding RNAs that can also be reliably measured in plasma, but have only been studied sporadically. In this study, we aimed to identify RNA-biomarkers that can distinguish between different exercise regimes and that entail clues about muscle repair and recovery after prolonged exhaustive endurance exercise. We compared plasma microRNA profiles between two cohorts of elite cyclists, subjected to two different types of exercise regimes, as well as a cohort of patients with peripheral artery disease (PAD) that were scheduled to undergo lower limb amputation, due to critical limb ischemia. In elite athletes, muscle tissue recovers quickly even after exhaustive exercise, whereas in PAD patients, recovery is completely impaired. Furthermore, we measured levels of a specific group of snoRNAs in the plasma of both elite cyclists and PAD patients. Using a multiplex qPCR screening, we detected a total of 179 microRNAs overall, of which, on average, 161 microRNAs were detected per sample. However, only 30 microRNAs were consistently expressed in all samples. Of these, two microRNAs, miR-29a-3p and miR193a-5p, that responded differently two different types of exercise, namely exhaustive exercise and non-exhaustive endurance exercise. Using individual rt/qPCR, we also identified a snoRNA, SNORD114.1, which was significantly upregulated in plasma in response to endurance exercise. Furthermore, two microRNAs, miR-29a-3p and miR-495-3p, were significantly differentially expressed in athletes compared to PAD patients, but only following exercise. We suggest that these two microRNAs could function as markers of impaired muscle repair and recovery. In conclusion, microRNAs miR-29a-3p and miR-193a-5p may help us distinguish between repeated exhaustive and non-exhaustive endurance exercise. MicroRNA miR-29a-3p, as well as miR-495-3p, may further mark impaired muscle recovery in patients with severe critical limb ischemia. Furthermore, we showed for the first time that a circulating snoRNA, SNORD114.1, is regulated in response to exercise and may be used as biomarker

Cyclophosphamide for interstitial lung disease-associated acute respiratory failure:mortality, clinical response and radiological characteristics

BACKGROUND: Treatment for interstitial lung disease (ILD) patients with acute respiratory failure (ARF) is challenging, and literature to guide such treatment is scarce. The reported in-hospital mortality rates of ILD patients with ARF are high (62–66%). Cyclophosphamide is considered a second-line treatment in steroid-refractory ILD-associated ARF. The first aim of this study was to evaluate the in-hospital mortality in patients with ILD-associated ARF treated with cyclophosphamide. The second aim was to compare computed tomographic (CT) patterns and physiological and ventilator parameters between survivors and non-survivors. METHODS: Retrospective analysis of patients with ILD-associated ARF treated with cyclophosphamide between February 2016 and October 2017. Patients were categorized into three subgroups: connective tissue disease (CTD)-associated ILD, other ILD or vasculitis. In-hospital mortality was evaluated in the whole cohort and in these subgroups. Clinical response was determined using physiological and ventilator parameters: Sequential Organ Failure Assessment Score (SOFA), PaO2/FiO2 (P/F) ratio and dynamic compliance (Cdyn) before and after cyclophosphamide treatment. The following CT features were quantified: ground-glass opacification (GGO) proportion, reticulation proportion, overall extent of parenchymal disease and fibrosis coarseness score. RESULTS: Fifteen patients were included. The overall in-hospital mortality rate was 40%. In-hospital mortality rates for CTD-associated ILD, other ILD and vasculitis were 20, 57, and 33%, respectively. The GGO proportion (71% vs 45%) was higher in non-survivors. There were no significant differences in the SOFA score, P/F ratio or Cdyn between survivors and non-survivors. However, in survivors the P/F ratio increased from 129 to 220 mmHg and Cdyn from 75 to 92 mL/cmH2O 3 days after cyclophosphamide treatment. In non-survivors the P/F ratio hardly changed (113–114 mmHg) and Cdyn even decreased (27–20 mL/cmH2O). CONCLUSION: In this study, we found a mortality rate of 40% in patients treated with cyclophosphamide for ILD-associated ARF. Connective tissue disease-associated ILD and vasculitis were associated with a lower risk of death. In non-survivors, the CT GGO proportion was significantly higher. The P/F ratio and Cdyn in survivors increased after 3 days of cyclophosphamide treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12890-021-01615-2

Precision Medicine for More Oxygen (P4O2)-Study Design and First Results of the Long COVID-19 Extension

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has led to the death of almost 7 million people, however, with a cumulative incidence of 0.76 billion, most people survive COVID-19. Several studies indicate that the acute phase of COVID-19 may be followed by persistent symptoms including fatigue, dyspnea, headache, musculoskeletal symptoms, and pulmonary functional-and radiological abnormalities. However, the impact of COVID-19 on long-term health outcomes remains to be elucidated. Aims: The Precision Medicine for more Oxygen (P4O2) consortium COVID-19 extension aims to identify long COVID patients that are at risk for developing chronic lung disease and furthermore, to identify treatable traits and innovative personalized therapeutic strategies for prevention and treatment. This study aims to describe the study design and first results of the P4O2 COVID-19 cohort. Methods: The P4O2 COVID-19 study is a prospective multicenter cohort study that includes nested personalized counseling intervention trial. Patients, aged 40-65 years, were recruited from outpatient post-COVID clinics from five hospitals in The Netherlands. During study visits at 3-6 and 12-18 months post-COVID-19, data from medical records, pulmonary function tests, chest computed tomography scans and biological samples were collected and questionnaires were administered. Furthermore, exposome data was collected at the patient's home and state-of-the-art imaging techniques as well as multi-omics analyses will be performed on collected data. Results: 95 long COVID patients were enrolled between May 2021 and September 2022. The current study showed persistence of clinical symptoms and signs of pulmonary function test/radiological abnormalities in post-COVID patients at 3-6 months post-COVID. The most commonly reported symptoms included respiratory symptoms (78.9%), neurological symptoms (68.4%) and fatigue (67.4%). Female sex and infection with the Delta, compared with the Beta, SARS-CoV-2 variant were significantly associated with more persisting symptom categories. Conclusions: The P4O2 COVID-19 study contributes to our understanding of the long-term health impacts of COVID-19. Furthermore, P4O2 COVID-19 can lead to the identification of different phenotypes of long COVID patients, for example those that are at risk for developing chronic lung disease. Understanding the mechanisms behind the different phenotypes and identifying these patients at an early stage can help to develop and optimize prevention and treatment strategies

How does SARS-CoV-2 targets the elderly patients? A review on potential mechanisms increasing disease severity

Importance: Among COVID-19 cases, especially the (frail) elderly show a high number of severe infections, hospital admissions, complications, and death. The highest mortality is found between 80 and 89 years old. Why do these patients have a higher risk of severe COVID-19? In this narrative review we address potential mechanisms regarding viral transmission, physical reserve and the immune system, increasing the severity of this infection in elderly patients. Observations: First, the spread of COVID-19 may be enhanced in elderly patients. Viral shedding may be increased, and early identification may be complicated due to atypical disease presentation and limited testing capacity. Applying hygiene and quarantine measures, especially in patients with cognitive disorders including dementia, can be challenging. Additionally, elderly patients have a decreased cardiorespiratory reserve and are more likely to have co-morbidity including atherosclerosis, rendering them more susceptible to complications. The aging innate and adaptive immune system is weakened, while there is a pro-inflammatory tendency. The effects of SARS-CoV-2 on the immune system on cytokine production and T-cells, further seem to aggravate this pro-inflammatory tendency, especially in patients with cardiovascular comorbidity, increasing disease severity. Conclusions and relevance: The combination of all factors mentio

Mortality in systemic lupus erythematosus in the United Kingdom 1999-2012

OBJECTIVES: To estimate the mortality associated with SLE during the period 1999-2012 by age, gender and region; and to ascertain the cause of death for people with SLE. METHODS: A retrospective cohort study using the UK Clinical Practice Research Datalink. Incident SLE cases diagnosed between 1999 and 2012 were matched by age, sex and practice to four controls. Age-, gender- and region-specific mortality rates were calculated per 1000 person-years and compared with control mortality rates using mortality rate ratios (MRRs). For individuals with linked Office of National Statistics data, cause of death was summarized by International Classification of Disease-10 chapter heading. RESULTS: Of 2740 incident cases, 227 died, giving a mortality rate of 15.84/1000 person-years (95% CI 13.91, 18.04). This was 67% higher than in controls (MRR 1.67, 95% CI 1.43, 1.94, P < 0.001). Men with SLE had higher rates of mortality than females with SLE. Compared with controls, the mortality rate for males with SLE was 1.80 times that of male controls (95% CI 1.32, 2.45, P < 0.001); for females the mortality rate was 1.64 times higher (95% CI 1.37, 1.96, P < 0.001). The age-specific mortality rates increased significantly with age; however, the MRR diminished from 3.81 (95% CI 1.43, 10.14) in those aged <40 years to 0.82 (95% CI 0.36, 1.83) in those 90 years. There was no significant difference in mortality between regions. Circulatory system disease and malignancy were the most frequent causes of death in both cases and controls. CONCLUSION: There remains an increased mortality for people with SLE compared with matched controls, particularly at younger ages