Faculty Bibliography

Platelets, classically defined by their hemostatic function, are increasingly recognized as immune effectors that shape chronic inflammation and vascular pathology in immune-mediated inflammatory diseases. In conditions such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, immune activation skews platelet adhesion, secretion, and procoagulant activity, while persistent interferon signaling and immune complex engagement (via receptors such as FcγRIIA) amplify thromboinflammation. Platelets orchestrate leukocyte recruitment and endothelial activation through P-selectin/PSGL-1 (P-selectin glycoprotein ligand-1) interactions, CD40 ligand, interleukin-1β, and the release of extracellular vesicles carrying cytokines and RNAs. Platelet involvement manifests differently across immune-mediated inflammatory diseases. In systemic lupus erythematosus, they promote type I interferon priming, neutrophil extracellular trap formation, and endothelial dysfunction. In rheumatoid arthritis, they generate abundant synovial microparticles and systemic vascular changes. In psoriasis, they accumulate within skin lesions, enhance platelet-leukocyte aggregation and activate proatherogenic endothelial responses. These pathways promote, independent of traditional cardiovascular risk factors, atherothrombosis including myocardial infarction, stroke, and venous thromboembolism. Limited translational data suggest that hydroxychloroquine may attenuate platelet activation and improve endothelial function. P2Y₁₂ inhibition may blunt interferon-linked platelet RNA signatures and leukocyte-platelet interactions. However, some therapies targeting inflammation, such as Janus kinase inhibitors, may promote thrombosis, the mechanisms of which are not fully known. Advances in multiomics, single-cell and spatial profiling, and in vivo models are delineating targets for intervention and enabling biomarker-driven risk stratification. Collectively, platelets function as central translators between autoimmunity and atherothrombosis. Defining and modulating platelet-immune crosstalk holds the potential to reduce cardiovascular risk in rheumatologic populations.

OBJECTIVES/OBJECTIVE:Patients with rheumatoid arthritis (RA) have excess cardiovascular risk beyond traditional factors. We evaluated associations between plasma metabolites and incident major adverse cardiovascular events (MACE) in RA and compared findings with matched controls. METHODS:We studied 1,271 Mass General Brigham Biobank participants with RA, without known cardiovascular disease, and no statin use at blood draw. 1H-NMR metabolomics quantified 168 metabolites spanning lipoprotein particles and contents, fatty acids, amino acids, and glycolysis. Incident MACE (myocardial infarction, stroke, transient ischemic attack, or death) was identified using ICD codes. Multivariable Cox models with false discovery rate correction assessed associations. Findings were compared with a 1:2 matched non-RA control cohort. RESULTS:The mean age was 62 years, 80% were women, and 8% experienced incident MACE over a median follow-up of 7.8 years. Twenty-five plasma metabolites were significantly associated with MACE. Lower MACE risk was primarily associated with higher levels of small HDL particle concentration and lipid content, as well as circulating albumin and select amino acids. In contrast, higher MACE risk was strongly associated with triglyceride-rich and remnant-like lipoprotein measures. When compared with controls, several associations were unique to the RA patients, who demonstrated a distinct metabolomic risk profile, involving triglyceride-rich VLDL and HDL particles. CONCLUSION/CONCLUSIONS:In this first metabolomic study in RA, we identified a distinct cardiovascular risk profile. Higher levels of large HDL particles were associated with increased risk, whereas small HDL particles were associated with lower risk, with potential implications for inflammation-targeted and HDL-modifying therapies.

BACKGROUND/UNASSIGNED:Psoriasis is a chronic immune-mediated inflammatory disease associated with heightened cardiovascular risk. Platelets are increasingly implicated in this link through their capacity to amplify vascular inflammation and interact with leukocytes. Circulating leukocyte-platelet aggregates are elevated in psoriasis, although the biological significance of these aggregates remains incompletely understood. We investigated whether increased leukocyte-platelet aggregates is associated with alterations in the platelet transcriptomic profile in psoriasis. METHODS/UNASSIGNED:Leukocyte-platelet aggregate levels were compared between psoriasis patients (n = 42) and healthy controls (n = 29). Psoriasis patients were stratified by the cohort median lymphocyte-platelet aggregate (LyPA) or neutrophil-platelet aggregate (NPA) levels into high vs low aggregate groups. Platelet RNA sequencing was then performed to define transcriptomic differences in high-vs low-aggregate psoriasis. RESULTS/UNASSIGNED:= 0.04) compared with healthy controls (mean age 42; 55% male; 69% Caucasian). Platelet RNA sequencing revealed that psoriasis patients with high LyPA or high NPA had downregulation of platelet inflammatory pathways, including interferon, tumor necrosis factor (TNF), IL-8, and IL-6 signaling. CONCLUSION/UNASSIGNED:These findings identify inflammatory platelet transcriptomic alterations associated with elevated lymphocyte-platelet and neutrophil-platelet aggregates in psoriasis and motivate further work to define the functional consequences of leukocyte-platelet aggregates in psoriasis.

Pericardial disease is common in patients with immune-mediated inflammatory diseases (IMIDs), especially in systemic lupus erythematosus. Pericardial disease may present as an asymptomatic pericardial effusion or acute and recurrent pericarditis, and may sometimes lead to complications (cardiac tamponade and constrictive pericarditis). Pathophysiology of pericarditis in IMIDs is likely related to the underlying immune dysregulation. Diagnosis of IMID-related pericarditis relies on general diagnostic criteria, supported by inflammatory biomarkers and non-invasive multimodality imaging. Initial management of IMID-related pericarditis overlaps with idiopathic pericarditis (nonsteroidal anti-inflammatory drugs and colchicine) together with treatment of the underlying IMID. Glucocorticoids are used in cases of poor response to first-line treatments. The use of immunosuppressive therapies is driven by the underlying IMID and systemic organ involvement beyond the pericardium. Multi-disciplinary care collaboration between cardiologists, radiologists, internists, and rheumatologists is pivotal to develop an appropriate, common treatment plan based on the individual features of each patient with IMIDs.

Inflammatory myocardial and pericardial syndromes (IMPS), including myocarditis, pericarditis, and overlapping myopericardial syndromes, constitute a heterogeneous group of immune-mediated cardiac disorders with clinical trajectories ranging from complete recovery to progressive heart failure and sudden death. This state-of-the-art review synthesizes current insights into immunopathogenesis, emphasizing the interplay among genetic susceptibility, environmental factors, and systemic inflammatory drivers, including rheumatological diseases. A pragmatic diagnostic framework is presented; it integrates targeted serological evaluation, genetic testing, multimodality imaging, and selective endomyocardial biopsy to enable precise etiologic classification. Therapeutic strategies are examined across the spectrum of disease severity, including guideline-directed medical therapy for heart failure, immunosuppression for autoimmune and fulminant phenotypes, and cytokine-directed biologics for recurrent pericarditis. Prognostic determinants, indications for advanced heart failure therapies, and emerging directions in precision immunology, molecular profiling, and AI-enabled risk stratification are discussed to guide future clinical and translational advances.

INTRODUCTION/BACKGROUND:Inflammatory bowel disease (IBD) is a chronic inflammatory condition affecting approximately 2.39 million individuals in the USA. IBD is associated with extraintestinal manifestations (EIMs), among which pericarditis is prominent, comprising 70% of cardiac EIMs. The onset of pericarditis in these patients is primarily attributed to IBD medication-related adverse effects and is predominantly documented through case reports. This highlights the need for an epidemiological study in a large, propensity-matched cohort, given the significant morbidity and mortality of pericarditis. METHODS:Using the National Institutes of Health's (NIH) All of Us Research Program, we conducted a cross-sectional study and propensity-matched 5,178 IBD cases to 15,534 controls (1:3). We compared demographics, clinical characteristics, prevalence of autoimmune diseases, and rates of pericarditis. Logistic regressions assessed the association between IBD and pericarditis, adjusting for confounders (p < 0.15), and a sensitivity analysis confirmed the association (p < 0.001). A Kaplan-Meier analysis compared the incidence of pericarditis in various IBD severity cohorts, including mild (n = 620) and moderate/severe (n = 1,908), stratified by IBD medication exposure. RESULTS:Pericarditis was significantly more prevalent in IBD cases (1.3% vs. 0.6%; absolute risk difference 0.7%, 95% confidence interval [CI]: 0.37%-1.03%), with significant associations in univariable (odds ratio [OR] 2.2, 95% CI: 1.6-3.0, p < 0.001) and multivariable (OR 1.9, 95% CI: 1.3-2.6, p < 0.001) analyses. IBD preceded pericarditis in 65% of cases. There was no difference in pericarditis-free survival between mild and moderate/severe cohorts (p = 0.90). CONCLUSION/CONCLUSIONS:This study uniquely provides evidence of a significant association between IBD and pericarditis, establishing pericarditis as a clinically significant EIM in a large, diverse US cohort, independent of disease severity. This highlights the need for heightened screening to enhance pericarditis management and patient outcomes.

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