Cutaneous Manifestations of Systemic Lupus Erythematosus and Their Correlation With Cardiac Involvement

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by widespread immune dysregulation that affects multiple organ systems, including the skin and cardiovascular system. The crosstalk between different cell death pathways-such as apoptosis, necroptosis, and neutrophil extracellular trap (NETosis), plays a pivotal role in the pathogenesis of SLE, influencing both cutaneous and cardiac manifestations. Cutaneous lupus erythematosus (CLE) is one of the most common early signs of SLE, affecting up to 80% of patients. CLE presents in several forms, including acute, subacute, and chronic lesions, each with varying degrees of association with systemic disease. Cardiac involvement, although often underrecognized, significantly contributes to morbidity and mortality in SLE patients, manifesting as pericarditis, myocarditis, valvular disease, and accelerated atherosclerosis. Emerging research suggests that these cutaneous and cardiac manifestations may be connected through shared immune mechanisms, including immune complex deposition, endothelial dysfunction, and chronic inflammation driven by cytokines such as Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). The severity of skin involvement may correlate with an increased risk of cardiovascular events, underscoring the importance of early diagnosis and a multidisciplinary approach to treatment. This review explores the crosstalk among cell death pathways in SLE and examines how these pathways contribute to both cutaneous and cardiac manifestations. Furthermore, it highlights the clinical implications of this crosstalk and discusses potential therapeutic strategies aimed at modulating these cell death pathways to improve patient outcomes. Challenges and gaps in current research are also addressed, emphasizing the need for further investigation into these complex interactions.

Keywords: autoimmune disease and heart complications; biologics in lupus management; cardiac involvement in sle; cutaneous manifestations; immunosuppressive therapy in sle; lupus skin lesions; multidisciplinary care in sle; skin-cardiac correlation in lupus; systemic lupus erythematosus (sle).

Figure 1. Mechanism of SLE pathogenesis

The pathogenesis of SLE involves a complex interaction of factors, including genetic predisposition, epigenetic dysregulation, defective clearance of autoantigens, deposition of autoimmune complex, and dysbiosis of microbiota. Environmental risks such as ultraviolet light (UV) and infections accelerate the production of apoptotic debris and subsequently activate the autoinflammatory cascade in multiple ways. In addition, other mechanisms such as hormonal milieu and X chromosome abnormalities have been reported to contribute to the female susceptibility to SLE. CTLA4: Cytotoxic T-lymphocyte–associated antigen 4; PTPN22: Tyrosine-protein phosphatase non-receptor type 22; IRF5: Interferon Regulatory Factor 5; HLA: Human leukocyte antigens; BLK: B-lymphoid tyrosine kinase; STAT4: Signal transducer and activator of transcription 4; ITGAM: Integrin subunit alpha M; IFN: Interferon; NET: Neutrophil extracellular traps; RNA: Ribonucleic acid; SLE: Systemic lupus erythematosus; BANK: B-cell scaffold protein with ankyrin repeats Image credits: Aly Barakat

Figure 2. CAD pathophysiology in SLE.

The figure depicts the pathophysiological mechanisms involved in developing CAD in SLE. It demonstrates how the deposition of immune complexes triggers inflammatory processes within the vascular walls, contributing to endothelial damage. Additionally, cholesterol accumulation promotes atherosclerotic plaque formation, while impaired fibrinolysis hinders the breakdown of clots, increasing the risk of thrombosis. Dysfunction of the vascular endothelium further exacerbates vascular injury, and platelet hyperactivity enhances clot formation, leading to potential vascular occlusion. Together, these mechanisms contribute to the heightened risk of CAD in SLE patients. CAD: Coronary artery disease; SLE: Systemic lupus erythematosus Image credits: Raaj Pawan Kumar Lingamgunta

Figure 3. CVD in SLE etiology: Pathophysiological mechanisms contributing to CVD in SLE.

This diagram represents the various mechanisms contributing to cardiovascular disease development in patients with SLE. Inflammation, dyslipidemia, lipid oxidation, hypertension with renal involvement, and antiphospholipid antibodies are all known to contribute to CVD progression in SLE. Additionally, the increased prevalence of atherosclerotic plaques further exacerbates cardiovascular risk. The roles of Th2 cytokines, autoantibodies, corticosteroids, and other treatment modalities remain controversial. Together, these factors contribute to the elevated cardiovascular risk observed in SLE patients. CVD: Cardiovascular diseases; SLE: Systemic lupus erythematosus; Th2: T helper 2 Image Credits: Prashanthi Sarayu Gadde

Figure 4. CLE-related pathways to CVD

This diagram illustrates the potential mechanisms linking CLE to CVD. CLE contributes to an increased cardiovascular risk in combination with other multiple factors, including smoking, psychosocial stress, medications, vitamin D deficiency, and traditional cardiovascular risk factors. These risk factors lead to inflammation and atherosclerosis, both of which play critical roles in the development of cardiovascular disease in patients with CLE. The interconnection between inflammatory pathways and the progression of atherosclerosis highlights the complex interaction between CLE and CVD. CLE: Cutaneous lupus erythematosus; CVD: Cardiovascular disease Image Credits: Sunjida Mehnaz