👤 Sagar Paudel

Cardiovascular (CV) disease risk is increased in rheumatoid arthritis (RA) and is the leading cause of mortality. Improved CV risk stratification tools in RA could enhance use of preventative care and improve outcomes. We previously studied biomarkers of CV disease - adiponectin, hsCRP, Lp(a), osteoprotegerin (OPG), high-sensitivity cardiac troponin T (hsTnT), serum amyloid A (SAA), YKL-40, soluble TNF receptor1 (sTNFR1) -- that were associated with CV risk. In the current study, these biomarkers were tested in an unrelated external cohort of RA patients followed at a single academic medical center without a history of CV events. CV events were identified through Medicare and Medicaid administrative data or through medical record review of self-reported events.Biomarkers were assessed at cohort entry among a nested cohort of cases and controls, matched 1:1 on sex and age. Analyses were conducted using conditional logistic regression. We examined whether the candidate biomarkers added to clinical CV risk factors improved model prediction, using the area under the curve (AUC) as well as the net reclassification index (NRI). From a cohort of 1,345 eligible patients with RA, we identified 123 patients with confirmed CV events. Cases and matched controls were typical of RA: median age 63 years, 77% women, RA disease duration 11 years, 72% seropositive, 85% used a biologic or conventional disease modifying anti-rheumatic drug, 58% non-steroidal anti-inflammatory drugs, and 30% oral glucocorticoids. From the candidate biomarkers, LASSO regression selected hsTnT and sTNFR1 as associated with CV events. The AUC for models that included only clinical risk factors was 0.758 (95% CI 0.689-0.829); after adding hsTnT and sTNFR1, the AUC increased to 0.802 (95% CI 0.718-0.998). The NRI of the model with biomarkers was 16.3%, with improvement only observed in patients who did not have CV events during follow-up. Adding selected biomarkers to clinical risk factors enhances the discrimination of models predicting CV events among patients with RA. These risk models require prospective testing to see if they have value in clinical practice decision-making regarding preventative care. Show less

During acute infectious and inflammatory conditions, a large number of neutrophils are in high demand as they are consumed in peripheral organs. The hematopoietic system rapidly responds to the demand by turning from steady state to emergency granulopoiesis to expedite neutrophil generation in the bone marrow (BM). How the hematopoietic system integrates pathogenic and inflammatory stress signals into the molecular cues of emergency granulopoiesis has been the subject of investigations. Recent studies in the field have highlighted emerging concepts, including the direct sensing of pathogens by BM resident or sentinel hematopoietic stem and progenitor cells (HSPCs), the crosstalk of HSPCs, endothelial cells, and stromal cells to convert signals to granulopoiesis, and the identification of novel inflammatory molecules, such as C/EBP-β, ROS, IL-27, IFN-γ, CXCL1 with direct effects on HSPCs. In this review, we will provide a detailed account of emerging concepts while reassessing well-established cellular and molecular players of emergency granulopoiesis. While providing our views on the discrepant results and theories, we will postulate an updated model of granulopoiesis in the context of health and disease. Show less