Faculty Bibliography

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.

OBJECTIVE:Mycophenolate (MPA) and cyclosporin A (CsA) are two immunosuppressive agents currently used for the treatment of autoimmune diseases. However, reports regarding their effects on inflammation and lipid handling are controversial. Here, we compare the effect of these two drugs on the expression of proteins involved in cholesterol handling and lipid accumulation in a macrophage cell system utilizing M0, M1 and M2 human macrophages and in murine bone marrow-derived macrophages (BMDM). METHODS:. RESULTS:In M0 macrophages, MPA increased expression of ABCA1 and CXCL16 in a concentration-dependent manner. In M1 THP-1 macrophages, MPA caused a significant increase of 27-hydroxylase mRNA and CD36 and SR-A1 receptor mRNAs. Exposure of M2 macrophages to MPA also stimulated expression of 27-hydroxylase, while downregulating all evaluated scavenger receptors. In contrast, CsA had no impact on cholesterol efflux in M0 and M1 macrophages, but significantly augmented expression of ABCA1 and 27-hydroxylase in M2 macrophages. CsA significantly increased expression of the LOX1 receptor in naïve macrophages, downregulated expression of CD36 and SR-A1 in the M1 subpopulation and upregulated expression of all evaluated scavenger receptors. However, CsA enhanced foam cell transformation in M0 and M2 macrophages, while MPA had no effect on foam cell formation unless used at a high concentration in the M2 subtype. CONCLUSIONS:Our results clearly underline the importance of further evaluation of the effects of these drugs when used in atherosclerosis-prone patients with autoimmune or renal disease.

Background andObjectives: Atherosclerotic cardiovascular disease (CVD) remains a major cause of morbidity and mortality in persons with systemic lupus erythematosus (SLE, lupus). Atherosclerosis, which involves interplay between cholesterol metabolism and cellular inflammatory pathways, is primarily treated with statins since statins have lipid-lowering and anti-inflammatory properties. The Lupus Atherosclerosis Prevention Study (LAPS) was designed to investigate the efficacy of statins against CVD in SLE patients. LAPS demonstrated that 2 years of atorvastatin administration did not reduce atherosclerosis progression in lupus patients. In this LAPs substudy, we use cultured macrophages to explore the atherogenic properties of plasma from LAPS subjects to explain the mechanistic rationale for the inability of statins to reduce CVD in lupus. Materials and Methods: THP-1 differentiated macrophages were treated for 18 h with 10% SLE patient plasma obtained pre- and post-atorvastatin therapy or placebo. Gene expression of the following cholesterol transport genes was measured by qRT-PCR. For efflux-ATP binding cassette transporter (ABC)A1 and ABCG1, 27-hydroxylase, peroxisome proliferator-activated receptor (PPAR)γ, and liver X receptor (LXR)α; and for influx-cluster of differentiation 36 (CD36) and scavenger receptor (ScR)A1. Results: Macrophages exposed to plasma from both statin-treated and placebo-treated groups showed a significant decrease in cholesterol efflux proteins ATP binding cassette (ABC) transporters A1 and ABCG1, an increase in 27-hydroxylase, an increase in the LDL receptor and a decrease in intracellular free cholesterol. No change in influx receptors ScRA1 and CD36, nor nuclear proteins LXRα and PPARγ was observed. Conclusions: Statins do not normalize pro-atherogenic changes induced by lupus and these changes continue to worsen over time. This study provides mechanistic insight into LAPS findings by demonstrating that statins are overall ineffective in altering the balance of cholesterol transport gene expression in human macrophages. Furthermore, our study suggests that statins as a CVD treatment may not be useful in attenuating lipid overload in the SLE environment.

Background: Primary Sjogren's syndrome (pSS) is a systemic progressive autoimmune disease characterised by formation of lymphoid structures and germinal centres within glandular tissue. Iscalimab (CFZ533) is a novel monoclonal antibody that potently and selectively blocks CD40, a co-stimulatory pathway receptor important for germinal centre reactions and B cell activation. Iscalimab showed clinical efficacy in a Proof of Concept randomised controlled trial at a dose of 10 mg/kg intravenously (IV), whereas subcutaneous (SC) dosing at 3 mg/kg was associated with unexpectedly low plasma concentrations and reduced efficacy, likely due to efficient pre-systemic target-mediated clearance.
Objective(s): To test IV versus SC loading doses of iscalimab followed by SC maintenance dosing, as a means of achieving target drug exposure and clinical efficacy.
Method(s): Patients with clinically active pSS [EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) >=6] were randomised to receive either 600 mg SC iscalimab weekly on 4 occasions, followed by 300 mg SC weekly until week 12, or a single IV dose of 10 mg/kg iscalimab on study Day 1, followed by 300 mg SC weekly until week 12. Subjects and investigator staff remained blinded to study treatment allocation until first dosing.
Result(s): Twenty-five patients were randomised; 13 in the SC loading and 12 in the IV loading arms. Baseline characteristics were similar to the previous phase IIa cohorts with mean ESSDAI scores of 12.7 (SD 6.1) and 10.4 (5.9) in the SC and IV loading arms respectively. In Arm 1 (SC) and Arm 2 (IV), the mean trough plasma concentrations were 169mug/mL (SD 64.1, CV 38%) and 135mug/mL (SD 70.9, CV 53%) on Day 85, respectively. Both values were well above levels previously reported to be sufficient for suppression of germinal centre development and T dependent antigen responses in cynomolgus monkeys. Consistent with this finding, clinically important improvements were seen in both arms with a mean decrease in ESSDAI scores of -5.5 (+/- SD: 5.5) and -7.6 (+/- 7.1) points from baseline to Day 85 in the SC and IV dosing arms. Improvements were also seen in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) scores: -1.67 (+/- 1.8) and -1.17 (+/- 2.3), respectively. Other secondary efficacy outcomes showed similar patterns of improvement. Treatment with iscalimab was associated with a reduction in the germinal centre-related serum biomarker CXCL13 in both groups. Overall, iscalimab was safe and well-tolerated with no new safety signal emerging. One subject experienced three SAEs (hemarthrosis, worsening of right knee pain and swelling requiring arthroscopy) in the safety followup period, all unrelated to study drug.
Conclusion(s): These results further support the safety and efficacy of iscalimab in pSS and the suitability of SC dosing for future development