Characteristics and outcomes of SARS-CoV-2 breakthrough infections among double-vaccinated and triple-vaccinated patients with inflammatory rheumatic diseases.

OBJECTIVE: To analyse the clinical profile of SARS-CoV-2 breakthrough infections in at least double-vaccinated patients with inflammatory rheumatic diseases (IRDs). METHODS: Data from the physician-reported German COVID-19-IRD registry collected between February 2021 and July 2022 were analysed. SARS-CoV-2 cases were stratified according to patients' vaccination status as being not vaccinated, double-vaccinated or triple-vaccinated prior to SARS-CoV-2 infection and descriptively compared. Independent associations between demographic and disease features and outcome of breakthrough infections were estimated by multivariable logistic regression. RESULTS: In total, 2314 cases were included in the analysis (unvaccinated n=923, double-vaccinated n=551, triple-vaccinated n=803, quadruple-vaccinated n=37). SARS-CoV-2 infections occurred after a median of 151 (range 14-347) days in patients being double-vaccinated, and after 88 (range 14-270) days in those with a third vaccination. Hospitalisation was required in 15% of unvaccinated, 8% of double-vaccinated and 3% of triple-vaccinated/quadruple-vaccinated patients (p<0.001). Mortality was 2% in unvaccinated, 1.8% in the double-vaccinated and 0.6% in triple-vaccinated patients. Compared with unvaccinated patients, double-vaccinated (OR 0.43, 95% CI 0.29 to 0.62) and triple-vaccinated (OR 0.13, 95% CI 0.08 to 0.21) patients showed a significant lower risk of COVID-19-related hospitalisation. Using multivariable analysis, the third vaccination was significantly associated with a lower risk for COVID-19-related death (OR 0.26; 95% CI 0.01 to 0.73). CONCLUSIONS: Our cross-sectional data of COVID-19 infections in patients with IRD showed a significant reduction of hospitalisation due to infection in double-vaccinated or triple-vaccinated patients compared with those without vaccination and even a significant reduction of COVID-19-related deaths in triple-vaccinated patients. These data strongly support the beneficial effect of COVID-19 vaccination in patients with IRD. TRIAL REGISTRATION NUMBER: EuDRACT 2020-001958-21.

Endothelial/lymphocyte activation leads to prominent CD4+ T cell infiltration in the gastric mucosa of patients with systemic sclerosis.

OBJECTIVE: Although gastrointestinal tract dysfunction is a common feature in patients with systemic sclerosis (SSc; scleroderma), few studies have addressed the pathogenetic mechanisms of gastrointestinal tract involvement in SSc. We previously showed that severe fibrosis and increased expression of profibrotic cytokines are important hallmarks in the gastric wall of patients with SSc. The aim of the present study was to investigate whether immune and/or microvascular abnormalities may account for tissue damage in gastric wall specimens obtained from patients with SSc. METHODS: Gastric biopsy samples from 27 patients with SSc and 15 healthy control subjects were analyzed by immunohistochemistry for CD45/leukocyte common antigen, CD3/T cells, CD4/T helper cells, CD8/cytotoxic T cells, CD20/B cells, CD14/monocytes, CD68/macrophages, cell adhesion molecules CD11a/lymphocyte function-associated antigen 1 (LFA-1), CD49d/very late activation antigen 4 (VLA-4), CD54/intercellular adhesion molecule 1 (ICAM-1), CD106/vascular cell adhesion molecule 1 (VCAM-1), CD31/platelet endothelial cell adhesion molecule 1, and vascular endothelial growth factor (VEGF). RESULTS: T cell infiltration was a prominent finding in gastric specimens from patients with SSc. The CD4+/CD8+ T cell ratio was significantly increased in SSc specimens compared with controls. T cells were found in both lymphocyte aggregates and diffuse infiltrates and strongly expressed the activation markers VLA-4, LFA-1, and ICAM-1. Endothelial cells showed corresponding surface activation with strong expression of VCAM-1 and ICAM-1. Mature B cells were frequently observed arranged in aggregates and rarely were seen in a diffuse pattern. Most lymphocyte aggregates lacked monocyte/macrophages. No difference in microvascular density was observed between SSc specimens and controls. Both SSc and control specimens showed weak or no expression of VEGF. CONCLUSION: Our findings provide the first evidence that endothelial/lymphocyte activation leading to prominent CD4+ T cell infiltration may play a key pathogenetic role within the gastric wall of patients with SSc and may represent an important therapeutic target.

A potential important role of skeletal muscle in human counterregulation of hypoglycemia.

CONTEXT: During hypoglycemia, systemic glucose uptake (SGU) decreases and endogenous glucose release (EGR) increases. Skeletal muscle appears to be primarily responsible for the reduced SGU and may be important for the increased EGR by providing lactate for gluconeogenesis (GN). OBJECTIVE: The objective of the study was to test the hypothesis that reduced muscle glucose uptake and increased muscle lactate release both make major contributions to glucose counterregulation using systemic isotopic techniques in combination with forearm net balance measurements. SETTING: The study was conducted at the University of Giessen Clinical Research Center. PARTICIPANTS: Nine healthy volunteers participated in the study. INTERVENTION: A 2-h hyperinsulinemic euglycemic clamp (blood glucose approximately 4.4 mm) was followed by a 90-min hypoglycemic clamp (blood glucose approximately 2.6 mm). RESULTS: Compared with the euglycemic clamp, SGU decreased (21.0 +/- 2.0 vs. 29.6 +/- 1.8 micromol.kg body weight(-1).min(-1); P < 0.001), whereas EGR (11.2 +/- 1.7 vs. 4.9 +/- 1.3 micromol.kg body weight(-1) .min(-1); P < 0.003), arterial lactate concentrations (1051 +/- 162 vs. 907 +/- 115 microm; P < 0.02), systemic lactate release (23.5 +/- 0.9 vs. 17.1 +/- 0.9 micromol.kg body weight(-1).min(-1); P < 0.001), and lactate GN (4.50 +/- 0.60 vs. 2.74 +/- 0.30 micromol.kg body weight(-1).min(-1); P < 0.02) increased during hypoglycemia; the proportion of lactate used for GN remained unchanged (38 +/- 4 vs. 32 +/- 3%; P = 0.27). Whole-body muscle glucose uptake decreased approximately 50% during hypoglycemia (6.4 +/- 1.9 vs. 13.6 +/- 2.9 micromol.kg body weight(-1).min(-1); P < 0.001), which accounted for approximately 85% of the reduction of SGU. Whole-body muscle lactate release increased 6.6 +/- 1.6 micromol.kg body weight(-1). min(-1) (P < 0.01), which could have accounted for all the increase in systemic lactate release and, considering the proportion of lactate used for GN, contributed 1.4 +/- 0.4 micromol.kg body weight(-1).min(-1) (approximately 25%) to the increase in EGR. CONCLUSIONS: Reduced muscle glucose uptake and increased muscle lactate release both make major contributions to glucose counterregulation in humans.