Faculty Bibliography

Background/Purpose: Critically ill patients with COVID-19 infection have a profound hypercoagulable state and can often develop thromboses in many different vascular beds. Given the presence of anti-phospholipid antibodies among COVID-19 patients reported previously, we hypothesized that poor outcomes and thrombosis could also be promoted by autoimmunity. In this retrospective case control analysis, we aimed to evaluate associations between aPL titers, clinical outcomes and mortality in hospitalized patients admitted with COVID-19 infection.
Method(s): We analyzed 138 electronic medical records of patients who were admitted to NYU Langone Hospital -Long Island between the months of March-April 2020 with findings of COVID-19 positivity via PCR and who had aPL titers determined. Patients with elevated titers of beta-2-Glycoprotein IgG, IgM, IgA and/or cardiolipin IgG, IgM, IgA were compared to those who were not elevated. Patients with positive lupus anticoagulant titers only were excluded due to prevalent use of anti-coagulation during this time. COVID-19 positive patients with aPL titers were assessed for clinical events (including DVT, PE, MI, CVA, extremity ischemia, skin ulcerations, visceral thrombosis and ocular and line occlusions) and mortality. The control group included patients that were negative for aPL antibody titers. Associations between Anti-Phospholipid (aPL) titer positivity and clinical events was assessed by Chi-square analysis using Fisher's exact test.
Result(s): The predominant aPL species that was noted in COVID-19 patients was anti-cardiolipin IgM. Of those patients with elevated antibody titers, cardiolipin IgM, IgG, IgA, and beta2GPI antibodies were prevalent at rates of 98.9%, 26.7%, 19.2%, and 16.5%, respectively. Multiple aPL isotypes were detected in several patients. There was a positive association between aPL positivity and elevations in IL-6, CRP, D-dimer, and LDH (P< 0.05). There was an increased incidence of clinical events in patients with COVID-19 and positive aPL titers (52/83 or 62%) compared to those who were aPL negative (32/55 or 58% ), however this association was not statistically significant. No significant association was detected between positive aPL titers and gender, age, or self-identified ethnicity. An increased incidence of ARDS and a rising serum creatinine was noted in the aPL positive group (P = 0.03 and P= 0.05 respectively). A significant increase in mortality was identified for the aPL positive group (P=0.01).
Conclusion(s): These findings suggest that aPL titers may provide insight into disease prognosis and outcome in hospitalized patients with COVID-19. Despite lack of significant association with discrete thrombotic events, association of aPL positivity with rising serum creatinine and ARDS suggest that aPL may contribute to end organ dysfunction through enhanced microthrombosis, resulting in increased mortality. (Figure Presented)

OBJECTIVE:Pulmonary disease is a potentially serious yet underdiagnosed complication of Sjögren's syndrome, the second most common autoimmune rheumatic disease. Approximately 16% of patients with Sjögren's demonstrate pulmonary involvement with higher mortality and lower quality of life. Clinical practice guidelines for pulmonary manifestations of Sjögren's were developed by the Sjögren's Foundation after identifying a critical need for early diagnosis and improved quality and consistency of care. METHODS:A rigorous and transparent methodology was followed according to American College of Rheumatology (ACR) guidelines. The Pulmonary Topic Review Group (TRG) developed clinical questions in the PICO (Patient, Intervention, Comparison, Outcome) format and selected literature search parameters. Each article was reviewed by a minimum of two TRG members for eligibility and assessment of quality of evidence and strength of recommendation. Guidelines were then drafted based on available evidence, expert opinion, and clinical importance. Draft recommendations with a clinical rationale and data extraction tables were submitted to a Consensus Expert Panel (CEP) for consideration and approval, with at least 75% agreement required for individual recommendations to be included in the final version. RESULTS:The literature search revealed 1,192 articles, of which 150 qualified for consideration in guideline development. Of the original 85 PICO questions posed by the TRG, 51 recommendations were generated. These were then reviewed by the CEP and 51 recommendations were finalized, with a mean agreement of 97.71% (range 79-100%). The recommendations span topics of evaluating Sjögren's patients for pulmonary manifestations and assessing, managing and treating upper and lower airway disease, interstitial lung disease, and lymphoproliferative disease. CONCLUSION/CONCLUSIONS:Clinical practice guidelines for pulmonary manifestations in Sjögren's will improve early identification, evaluation, and uniformity of care by primary care physicians, rheumatologists and pulmonologists. Additionally, opportunities for future research are identified.

INTRODUCTION AND AIMS/OBJECTIVE:Oxytocin (OT) is a neuropeptide hormone secreted by the posterior pituitary gland. Deficits in OT action have been observed in patients with behavioral and mood disorders, some of which correlate with an increased risk of cardiovascular disease (CVD). Recent research has revealed a wider systemic role that OT plays in inflammatory modulation and development of atherosclerotic plaques. This study investigated the role that OT plays in cholesterol transport and foam cell formation in LPS-stimulated THP-1 human macrophages. METHODS:THP-1 differentiated macrophages were treated with media, LPS (100 ng/ml), LPS + OT (10 pM), or LPS + OT (100 pM). Changes in gene expression and protein levels of cholesterol transporters were analyzed by real time quantitative PCR (RT-qPCR) and Western blot, while ox-LDL uptake and cholesterol efflux capacity were evaluated with fluorometric assays. RESULTS:RT-qPCR analysis revealed a significant increase in ABCG1 gene expression upon OT + LPS treatment, compared to LPS alone (p = 0.0081), with Western blotting supporting the increase in expression of the ABCG1 protein. Analysis of ox-LDL uptake showed a significantly lower fluorescent value in LPS + OT (100pM) -treated cells when compared to LPS alone (p < 0.0001). While not statistically significant (p = 0.06), cholesterol efflux capacity increased with LPS + OT treatment. CONCLUSION/CONCLUSIONS:We demonstrate here that OT can attenuate LPS-mediated lipid accumulation in THP-1 macrophages. These findings support the hypothesis that OT could be used to reduce pro-inflammatory and potentially atherogenic changes observed in patients with heightened CVD risk. This study suggests further exploration of OT effects on monocyte and macrophage cholesterol handling in vivo.

Background/UNASSIGNED:There is increasing recognition of a prothrombotic state in COVID-19. Post-mortem examination can provide important mechanistic insights. Methods/UNASSIGNED:We present a COVID-19 autopsy series including findings in lungs, heart, kidneys, liver, and bone, from a New York academic medical center. Findings/UNASSIGNED: = 2). Platelet-rich peri‑tubular fibrin microthrombi were a prominent renal feature. Acute tubular necrosis, and red blood cell and granular casts were seen in multiple cases. Significant glomerular pathology was notably absent. Numerous platelet-fibrin microthrombi were identified in hepatic sinusoids. All lungs exhibited diffuse alveolar damage (DAD) with a spectrum of exudative and proliferative phases including hyaline membranes, and pneumocyte hyperplasia, with viral inclusions in epithelial cells and macrophages. Three cases had superimposed acute bronchopneumonia, focally necrotizing. Interpretation/UNASSIGNED:In this series of seven COVID-19 autopsies, thrombosis was a prominent feature in multiple organs, in some cases despite full anticoagulation and regardless of timing of the disease course, suggesting that thrombosis plays a role very early in the disease process. The finding of megakaryocytes and platelet-rich thrombi in the lungs, heart and kidneys suggests a role in thrombosis. Funding/UNASSIGNED:None.

OBJECTIVES/OBJECTIVE:To evaluate the systemic phenotype associated with the presence of isolated anti-La/SSB antibodies in a large international registry of patients with primary Sjögren's syndrome (pSS) fulfilling the 2002 classification criteria. METHODS:The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. Baseline clinical information from leading centres on clinical research in SS of the 5 continents was collected. Combination patterns of anti-Ro/SSA-La/SSB antibodies at the time of diagnosis defined the following four immunological phenotypes: double positive (combined Ro/SSA and La/SSB,) isolated anti-Ro/SSA, isolated anti-La/SSB, and immunonegative. RESULTS:The cohort included 12,084 patients (11,293 females, mean 52.4 years) with recorded ESSDAI scores available. Among them, 279 (2.3%) had isolated anti-La/SSB antibodies. The mean total ESSDAI score at diagnosis of patients with pSS carrying isolated anti-La/SSB was 6.0, and 80.4% of patients had systemic activity (global ESSDAI score ≥1) at diagnosis. The domains with the highest frequency of active patients were the biological (42.8%), glandular (36.8%) and articular (31.2%) domains. Patients with isolated anti-La/SSB showed a higher frequency of active patients in all ESSDAI domains but two (articular and peripheral nerve) in comparison with immune-negative patients, and even a higher absolute frequency in six clinical ESSDAI domains in comparison with patients with isolated anti-Ro/SSA. In addition, patients with isolated anti-La/SSB showed a higher frequency of active patients in two ESSDAI domains (pulmonary and glandular) with respect to the most active immunological subset (double-positive antibodies). Meanwhile, systemic activity detected in patients with isolated anti-La/SSB was overwhelmingly low. Even in ESSDAI domains where patients with isolated anti-La/SSB had the highest frequencies of systemic activity (lymphadenopathy and muscular), the percentage of patients with moderate or high activity was lower in comparison with the combined Ro/SSA and La/SSB group. CONCLUSIONS:Patients carrying isolated La/SSB antibodies represent a very small subset of patients with a systemic SS phenotype characterised by a significant frequency of active patients in most clinical ESSDAI domains but with a relative low frequency of the highest severe organ-specific involvements. Primary SS still remains the best clinical diagnosis for this subset of patients.

Adenosine is an endogenous nucleoside with a short half-life that regulates many physiological functions involving the heart and cardiovascular system. Among the cardioprotective properties of adenosine are its ability to improve cholesterol homeostasis, impact platelet aggregation and inhibit the inflammatory response. Through modulation of forward and reverse cholesterol transport pathways, adenosine can improve cholesterol balance and thereby protect macrophages from lipid overload and foam cell transformation. The function of adenosine is controlled through four G-protein coupled receptors: A₁, A_2A, A_2B and A₃. Of these four, it is the A_2A receptor that is in a large part responsible for the anti-inflammatory effects of adenosine as well as defense against excess cholesterol accumulation. A_2A receptor agonists are the focus of efforts by the pharmaceutical industry to develop new cardiovascular therapies, and pharmacological actions of the atheroprotective and anti-inflammatory drug methotrexate are mediated via release of adenosine and activation of the A_2A receptor. Also relevant are anti-platelet agents that decrease platelet activation and adhesion and reduce thrombotic occlusion of atherosclerotic arteries by antagonizing adenosine diphosphate-mediated effects on the P2Y12 receptor. The purpose of this review is to discuss the effects of adenosine on cell types found in the arterial wall that are involved in atherosclerosis, to describe use of adenosine and its receptor ligands to limit excess cholesterol accumulation and to explore clinically applied anti-platelet effects. Its impact on electrophysiology and use as a clinical treatment for myocardial preservation during infarct will also be covered. Results of cell culture studies, animal experiments and human clinical trials are presented. Finally, we highlight future directions of research in the application of adenosine as an approach to improving outcomes in persons with cardiovascular disease.