Faculty Bibliography

Targeted and biologic therapies are increasingly being used for treatment of dermatological conditions. Certain agents are associated with cardiometabolic toxicities, including major adverse cardiovascular events and altered lipid profiles, necessitating baseline and on-treatment monitoring. Close cardiometabolic monitoring is needed throughout treatment with co-management by cardiology, endocrinology, rheumatology, oncology, and primary care for symptomatic or high-risk patients. Conversely, some therapies may reduce systemic inflammation and atherogenic factors, possibly conferring reduced risk of cardiometabolic events. Randomized, controlled trials in dermatological populations are needed to corroborate these observations. In part II of this two-part continuing medical education series, we describe cardiometabolic effects of targeted and biologic therapies, including immune checkpoint inhibitors, antitumor monoclonal antibodies, intravenous immunoglobulins, Janus kinase inhibitors, tumor necrosis factor inhibitors, interleukin inhibitors, and apremilast. In addition, we outline recent advances in pathophysiology and supplement with practical recommendations for baseline assessment and monitoring in dermatological patients.

Systemic treatments for common dermatological conditions, including psoriasis, hair loss, and onychomycosis, may be associated with cardiometabolic toxicities or protective effects. Increased awareness of associations between these dermatological treatments and cardiovascular and metabolic health (termed collectively cardiometabolic health) is needed for proactive management of patients with increased risk of cardiovascular diseases. Preventive medications may be indicated with certain treatments. Multidisciplinary efforts between dermatologists, cardiologists, endocrinologists, rheumatologists, oncologists, and primary care physicians may help reduce the risk of major adverse cardiovascular events. In Part I of this two-part continuing medical education series, we provide updates regarding the potential impact on development or worsening of cardiometabolic diseases from traditional systemic treatments, including retinoids/rexinoids, anthracyclines, antifungals, oral minoxidil, methotrexate, ultraviolet phototherapy, and colchicine. We also describe mechanisms of actions impacting cardiometabolic diseases, as well as provide practical recommendations for workup and monitoring in dermatological patients.

Alopecia areata (AA) is a common autoimmune condition that affects approximately 2% of the global population. Although it most commonly presents with the abrupt onset of well-circumscribed, non-scarring alopecic patches on the scalp, the nails and other hair-bearing areas are also frequently affected. Clinical evaluation should document disease extent and employ trichoscopy to identify characteristic signs of the condition (e.g., black-dot hairs, exclamation point hairs). The Severity of Alopecia Tool (SALT) is standard for quantifying severity, and newer instruments like the Alopecia Areata Severity Scale (AASc) incorporate extra-scalp involvement and psychosocial burden. Moreover, machine learning approaches and validated patient-reported outcome measures, such as the Alopecia Areata Patient Priority Outcomes (AAPPO), have emerged that can standardize assessment and longitudinal tracking. AA prognosis is influenced by several factors, including age, disease subtype, extent and duration of hair loss, and family history. Pathogenesis is heterogeneous, multifactorial, and includes the collapse of immune privilege with cytotoxic CD8+ T cell inflammation. Genetic and pharmacologic data support a key role for the JAK/STAT pathway and demonstrate that Th2-related inflammation is involved in select patients. The quality-of-life impact of AA and associated comorbidities are substantial.

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.