Primary prevention aims to modify atherogenesis, a process governed by a complex interplay of inflammation, tissue remodeling, and cellular transdifferentiation, which can make attempts at delineating the cell type a challenge. Lipoprotein-associated phospholipase A2 (Lp-PLA2), degrades platelet-activating factor and oxidized low-density lipoprotein (ox-LDL). Most of the circulating Lp-PLA2 is produced by macrophages within the vascular wall, but whether statins can reduce Lp-PLA2 is still inconclusive. Colchicine may attenuate Lp-PLA2 production by inhibiting leukocyte adhesion and infiltration, providing a mechanistic rationale for combination therapy with statins to reduce major adverse cardiovascular events. However, both agents are substrates and inhibitors of cytochrome p – 450 (CYP) 3A4 and P-glycoprotein, and their combined use may substantially increase the risk of musculoskeletal toxicity, including life-threatening rhabdomyolysis and neuromyopathy.

Accurate characterization of coronary atherosclerosis in rheumatic disease requires assessment beyond luminal stenosis alone. Defining plaque burden, composition, and lesion-specific functional significance represents a critical step in cardiovascular risk stratification and is optimally achieved within dedicated cardio-rheumatology clinics using advanced imaging modalities. Figure 1 illustrates contemporary coronary plaque analysis integrating anatomic plaque quantification, compositional assessment, and CT-derived fractional flow reserve, highlighting how noncalcified plaque burden may contribute to functional impairment even in the absence of severe stenosis.

Inflammation-driven vascular pathology may further escape detection by traditional calcification-based metrics. Figure 2 demonstrates perivascular adipose tissue attenuation as a marker of coronary inflammation, illustrating that vascular changes in autoimmune diseases such as systemic lupus erythematosus may reflect active inflammatory remodeling rather than conventional atherosclerotic calcification. Together, these imaging approaches underscore the limitations of relying solely on calcium scoring in autoimmune populations and support inflammation-sensitive, multimodal assessment strategies.

Prepregnancy counseling in rheumatic disease should include delineation of current functional and structural cardiovascular status and appropriate adjustment of medications. Pulmonary hypertension screening is standard for prepregnancy planning in systemic sclerosis; there may be value in additional screening with cardiac magnetic resonance (CMR) imaging. When imaging is required during pregnancy, gadolinium-based contrast agents are contraindicated, and cardiovascular magnetic resonance protocols should rely on noncontrast techniques, including cine imaging and precontrast parametric mapping, when clinically indicated. The role of standardized cardiac imaging in cardio-rheumatology clinics for women of childbearing potential is not currently incorporated into guidelines.

Promotion of health education, such as dietary goals for body weight control, tobacco cessation, stress management, and regular exercise, is appropriate for atherosclerotic cardiovascular disease (ASCVD) risk modification in all patients regardless of sex or childbearing potential. However, medication additions have important considerations in rheumatic disease. For example, blood pressure management may benefit from agents also used to treat Raynaud’s phenomenon, such as calcium channel blockers or angiotensin receptor blockers. ^, Other agents, such as angiotensin converting enzyme (ACE)-inhibitors, may be avoided in patients at high risk for renal crisis, since prophylactic use is associated with worse outcomes. In patients with rheumatic disease, one should assess for underlying myopathy before statin addition and renal insufficiency before colchicine addition. Medication screening is especially critical in women of childbearing potential ( Figure 4 ). Medications including ACE inhibitors and angiotensin receptor blockers are contraindicated for use in pregnancy, particularly during the second and third trimesters.

Medication review in cardio-rheumatology clinic.

Mild myalgia may affect 5% to 10% of statin users; however, the documentation of a baseline creatinine kinase (CK) before the addition of a statin can be helpful as a myopathy screen. If CK is noted to be significantly elevated while a patient is on a statin, autoimmune necrotizing myopathy should be considered, and an anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase should be checked. If the anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase is positive, statin-associated cardiomyopathy should be considered, and a CMR image should be obtained to assess for subacute cardiac toxicity. When CMR imaging is required in women who are pregnant or may be pregnant, gadolinium-based contrast agents are contraindicated, and noncontrast protocols should be used when clinically indicated.

Colchicine is taken up by leukocytes and, due to its ability to bind to tubulin, interferes with microtubular function and the expression of cytokines and interleukins, which impedes the ability of neutrophils to marginate, express superoxide, release neutrophil extracellular traps, and interact with platelets. Colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo in a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction, but did not reduce the incidence of the composite primary outcome (death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization). ^, The 0.5-mg colchicine tablet is not available in some countries, including the United States, where only 0.6-mg tablets are available. About 90% of ASCVD patients, in the absence of advanced renal or liver disease, can tolerate colchicine, gastrointestinal tract adverse effects can be problematic. ^, Notably, colchicine-induced rhabdomyolysis can occur and is a consideration in patients with elevated CK on this drug, ^, which further illustrates the consideration of baseline CK and aldolase laboratories before drug initiation, especially if used in addition to statin primary prevention therapy. While colchicine can be used during pregnancy, its role for CVD prevention in this situation is not established. On the other hand, women of childbearing potential should be on an effective contraception while on statins, and its use is not recommended during pregnancy. The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in autoimmune disease patients with ASCVD is also uncertain and controversial due to potential pleiotropic immunomodulatory effects; however, it is a consideration in patients requiring lipid lowering with autoimmune necrotizing myopathy. ^,, The use of PCSK9 inhibitors (medications like alirocumab and evolocumab) during pregnancy should be avoided due to potential risks of fetal malformations involving multiple systems.

Rheumatologists and cardiologists must carefully assess the risks and benefits of nonsteroidal anti-inflammatories, corticosteroids, and Janus kinase inhibitors in patients with ASCVD, and the use of biomarkers such as high-sensitivity C-reactive protein, Lp(a), and CAC screening may help refine risk stratification. Similarly, the adverse cardiac effects of hydroxychloroquine (HCQ) used for rheumatic disease deserve mention when patients are seen in cardio-rheumatology clinics. While HCQ is safe during pregnancy, physicians should be mindful of its potential cardiac adverse effects and consider an electrocardiogram for QTc monitoring on patients receiving HCQ for the treatment of systemic autoimmune disease. Cardiomyopathy has been documented in patients with chronic HCQ toxicity and is thought to arise from lysosomal dysfunction and accumulation of toxic phospholipids within cardiomyocytes. Characteristics of cardiac biopsy findings include enlarged and vacuolated cells on light microscopy as well as the presence of myelinoid and curvilinear bodies on transmission electron microscopy. Peripartum cardiomyopathy assessments are aided by incorporating tissue-based analyses, with optimal management in cardio-rheumatology clinics.

Immune mechanisms play an important role in the development, progression, and vulnerability of atherosclerotic lesions. There is marked heterogeneity of immune cells in atherosclerotic plaques as well as in peripheral blood mononuclear cells in subjects with atherosclerosis. Immune responses to foam cells may be variable, but ultimately foam cells and macrophages die to give rise to cholesterol-rich necrotic cores that can rupture to stimulate thrombus formation. Thus, while environmental exposures and genetic susceptibility are important in the evolution of atherosclerosis, a well-recognized heterogeneity in inflammation within the atherosclerotic lesions is appreciated. Unfortunately, the progressive vasculopathy of atherosclerosis is not symptomatic until damage restricts perfusion. Hypoxia further contributes to an additional inflammatory response and is critical for vascular calcification. Risk for ASCVD shows considerable heterogeneity. While atherosclerotic intimal calcification is traditionally associated with increasing age, male sex, smoking, hypertension, dyslipidemia, and diabetes mellitus, systemic and local vascular inflammation in rheumatic diseases can also accelerate atherosclerosis. ^, Chronic inflammation promotes endothelial dysfunction and leukocyte transmigration, driving oxidation of apoB-containing lipoproteins and their subsequent uptake by activated macrophages. Calcification occurs very early in atherosclerosis and is detectable by computed tomography when it accumulates in the vasculature, and provides direct evidence of coronary artery disease. The presence and severity of coronary artery calcification are associated with increased risk of mortality independently of age and comorbidities in rheumatic disease. ^, Accordingly, CT-derived fractional flow reserve and CAC screening for subclinical atherosclerosis can refine cardiovascular risk stratification and further inform treatment decisions. ^, The role of statin therapy to modify inflammation on new coronary plaque formation and impact the calcification of prevalent noncalcified lesions is suggested in rheumatoid arthritis. Statins seem to promote a type of “beneficial” atherosclerotic calcification through suppressing atherosclerotic lesion expansion and impacting vulnerability to plaque rupture. However, the underlying biological mechanisms remain incompletely understood, and more research is required to clarify the underlying mechanisms of the stabilizing effect of statins on calcific plaques in both the general population and those with rheumatic diseases.

Advances in atheroma transcriptomic analysis identified that lesions from clinically symptomatic patients had higher fractions of proinflammatory M1 macrophages and pericytes, but lower fractions of classical and modulated smooth muscle cells compared with asymptomatic patients, particularly women. Of interest, the presence of diabetes or statin treatment did not affect the cell fraction distribution. Pericytes are multipotent cells wrapping microvascular capillaries, which are essential for vessel stabilization and immune cell trafficking across the vessel wall. The pericyte shares a common basement membrane and partially surrounds the endothelial cell, playing a fundamental role in maintaining local and tissue homeostasis and contributing to calcification. Pericytes share some properties and markers with multipotent mesenchymal stem cells and smooth muscle cells, and can transdifferentiate into other cells of the mesenchymal lineage (such as myocytes, osteocytes, chondrocytes, and adipocytes) and neural cells, making precise characterization and in vivo tracking challenging. Nonetheless, advances in tissue diagnostics offer the potential to uncover mechanisms of vascular pathology in rheumatic disease.

Placental analysis in rheumatic disease offers an additional opportunity for understanding significant vascular pathology, ^, especially related to maternal vascular infarction and calcification. Such insights may help improve outcomes for subsequent pregnancies and identify a high-risk group for postpartum screening. For instance, preeclampsia, when associated with placental maternal vascular malperfusion, was associated with higher odds of screening as high-risk for lifetime CVD at 6 months postpartum than women without these lesions; a finding relevant to rheumatology, given a significantly higher burden of preeclampsia among women with rheumatic disease. Thus, in addition to standardized imaging in cardio-rheumatology clinics, tissue analysis, including placental tissue, may help risk stratification.