Definition and scope
Inflammatory and autoimmune diseases are immune-mediated inflammatory diseases (IMIDs) that include rheumatoid arthritis (RA), psoriatic arthritis, spondyloarthropathies, systemic lupus erythematosus (SLE), systemic sclerosis, vasculitides, mixed connective-tissue disease, myositis, Sjögren syndrome, gout and antiphospholipid syndrome (APS). Collectively, these disorders are associated with excess cardiovascular disease (CVD), although the cardiovascular phenotype varies substantially between diseases.
Cardiovascular involvement extends beyond conventional atherosclerotic coronary artery disease. It may include:
Accelerated atherosclerosis and premature myocardial infarction
Coronary microvascular dysfunction
Myocarditis and pericarditis
Coronary or large-vessel arteritis
Pulmonary arterial vasculopathy and pulmonary hypertension
Arterial and venous thrombosis
Valvular heart disease
Cardiac dysrhythmias
Arterial stiffness and endothelial dysfunction
The increased cardiovascular burden is particularly important because it may occur at a younger age, may not be fully captured by conventional risk scores and may be the first clinically important manifestation of an otherwise unrecognized inflammatory disease.
Epidemiology and disease-specific patterns
Patients with inflammatory rheumatic disease have a higher cardiovascular risk than the general population. This excess risk has been documented across a broad range of conditions, including gout, vasculitis, systemic sclerosis, myositis, mixed connective-tissue disease, Sjögren syndrome, SLE and APS. Some patient groups have a two- to three-fold greater prevalence of asymptomatic atherosclerotic cardiovascular disease (ASCVD) than the general population.
The evidence for premature atherosclerosis is particularly strong in RA and SLE. Ankylosing spondylitis, psoriatic arthritis, antineutrophil cytoplasmic antibody-associated vasculitis, Takayasu arteritis, giant-cell arteritis and APS may also be associated with premature atherosclerotic disease.
In a large UK clinical database, autoimmune disease was associated with 23.3 cardiovascular events per 1000 patient-years, compared with 15.0 per 1000 patient-years in age-matched controls without autoimmune disease. The greatest risks were reported with systemic sclerosis, Addison disease, SLE and type 1 diabetes. Traditional factors such as smoking, family history of premature coronary disease, hypertension and hypercholesterolaemia did not fully explain the excess coronary risk.
Rheumatoid arthritis
RA is associated with increased carotid intima–media thickness, early plaque formation and coronary microvascular dysfunction. Women with RA were reported to have approximately twice the myocardial infarction risk of age-matched controls. Cardiovascular events occur earlier, and approximately half of premature deaths in RA may be directly attributable to CVD. Excess mortality becomes apparent approximately 7–10 years after diagnosis and is associated with persistent disease activity, rheumatoid factor and anti-cyclic citrullinated peptide antibodies.
RA is also accompanied by a higher prevalence of conventional cardiovascular risk factors. Smoking and insulin resistance are associated with both RA and cardiovascular risk. Dyslipidaemia may be difficult to interpret during active disease: inflammatory cytokines can lower LDL and HDL concentrations while increasing the atherogenic index, a pattern described as the “lipid paradox.” High-dose glucocorticoids may worsen dyslipidaemia.
Systemic lupus erythematosus and antiphospholipid syndrome
SLE may affect the cardiovascular system through several pathways, including:
Coronary arteritis
Accelerated atherosclerosis
Coronary microvascular dysfunction
Pericarditis
Myocarditis
Valvular disease
APS and Behçet disease can cause both arterial and venous thrombosis. In SLE, renal artery involvement may contribute to difficult-to-control hypertension. The cardiovascular consequences of these disorders therefore reflect both inflammatory vascular injury and disease-specific thrombotic mechanisms.
Systemic sclerosis
Systemic sclerosis predominantly affects the microvasculature and may produce pulmonary arterial vasculopathy and pulmonary arterial hypertension. The guidance cited in the source material advises avoiding beta-blockers in systemic sclerosis.
Vasculitides
The vascular distribution varies according to the vasculitic disorder:
ANCA-associated vasculitides preferentially affect arterioles.
Large-vessel vasculitides involve the aorta and its major branches.
Takayasu arteritis may cause renal artery stenosis, severe hypertension and occlusive disease.
Takayasu arteritis and giant-cell arteritis may produce subclavian, axillary or iliac obstruction, with limb claudication.
Cardiovascular specialists should consider an underlying inflammatory disease in young patients with otherwise unexplained angina, myocardial infarction or stroke.
Pathophysiology
Systemic inflammation and atherogenesis
Persistent systemic inflammation promotes premature atherogenesis through endothelial activation and injury. Inflammatory disease may accelerate plaque development, amplify the effects of conventional cardiovascular risk factors and alter plaque composition in ways that increase the likelihood of rupture.
Patients with IMIDs more commonly demonstrate endothelial dysfunction and increased aortic stiffness than the general population. Treatment of the underlying inflammatory disease does not invariably reverse these abnormalities. The inflammatory milieu may produce higher-risk plaques without necessarily causing a proportionate increase in total plaque burden.
Thus, cardiovascular risk may arise from two complementary processes:
More rapid development of atherosclerosis
Formation of plaques with greater propensity to destabilisation and rupture
Endothelial dysfunction
The normal endothelium is quiescent, antithrombotic and antiadhesive, while regulating vasodilatation and vascular permeability. Chronic inflammation, as observed in RA and SLE, can cause endothelial injury, increase endothelial apoptosis and impair vasodilator function.
Proinflammatory mediators implicated in vascular injury include:
Tumour necrosis factor-α
Interleukin-1
Type I interferons, including interferon-α
Interleukin-6
These mediators promote endothelial activation, leukocyte adhesion, endothelial permeability and vascular injury. Chronic toll-like receptor activation, impaired endothelial repair and increased endothelial-cell apoptosis may further sustain vascular dysfunction.
Immune and thrombo-inflammatory mechanisms
Additional mechanisms include the effects of:
Antiphospholipid antibodies
CD4+CD28− cytotoxic T cells
Th17/T-regulatory-cell imbalance
Complement deficiency or excessive complement activation
Genetic polymorphisms
Potential contributions from clonal haematopoiesis
The inflammatory pathways involved in RA overlap with those implicated in atherosclerosis. Interleukin-1, interleukin-6, tumour necrosis factor and downstream Janus kinase–signal transducer and activator of transcription signalling contribute to both joint inflammation and coronary atherogenesis. Their downstream effects include leukocyte adhesion, endothelial dysfunction, tissue-factor production, matrix-metalloproteinase activity, plaque destabilisation and thrombus formation.
Interaction with conventional risk factors
Inflammation does not replace conventional risk factors; rather, it may intensify their vascular effects. Smoking, hypertension, dyslipidaemia, insulin resistance and family history remain clinically relevant, but their presence alone does not account for the full cardiovascular burden of autoimmune disease.
Drug-related effects may also contribute. Glucocorticoids and ciclosporin can promote vascular dysfunction, while high-dose glucocorticoids may worsen dyslipidaemia.
Clinical presentation
Atherosclerotic presentations
Cardiovascular presentation may include:
Premature angina
Myocardial infarction
Ischaemic heart failure
Ischaemic stroke
Peripheral arterial disease
Sudden cardiac death
Patients with IMIDs who sustain myocardial infarction may have worse subsequent heart-failure and mortality outcomes than age-matched individuals without inflammatory disease.
Microvascular and inflammatory cardiac disease
Cardiovascular disease may also present with:
Angina despite limited obstructive epicardial disease, reflecting coronary microvascular dysfunction
Pericarditic chest pain
Myocarditis or inflammatory cardiomyopathy
Cardiac dysrhythmias
Valvular disease
Pulmonary hypertension related to systemic sclerosis or pulmonary arterial vasculopathy
SLE is notable for its broad cardiac phenotype, which may include coronary arteritis, atherosclerosis, microvascular dysfunction, pericarditis, myocarditis and valvular disease.
Thrombotic and vascular presentations
APS and Behçet disease may present with arterial or venous thrombosis. Large-vessel vasculitis may cause limb claudication, renovascular hypertension or other manifestations of aortic and branch-vessel obstruction.
Evaluation and physical examination
Clinical assessment
Evaluation should integrate the inflammatory disease history with conventional cardiovascular risk assessment. Important features include:
Disease type, duration and activity
Persistent inflammatory activity
Rheumatoid factor and anti-cyclic citrullinated peptide antibody status in RA
Previous arterial or venous thrombotic events
Smoking and family history of premature coronary disease
Hypertension, dyslipidaemia and insulin resistance
Exposure to glucocorticoids, ciclosporin and other potentially adverse therapies
Symptoms suggesting angina, heart failure, arrhythmia, pericarditis or vascular obstruction
Young patients with unexplained angina, myocardial infarction or stroke should be assessed for an underlying inflammatory disease.
Physical examination
The source material does not provide a detailed disease-specific physical-examination protocol. Examination should nevertheless be directed toward the cardiovascular manifestations described, including evidence of:
Hypertension
Heart failure
Pericardial or myocardial disease
Valvular disease
Arrhythmia
Limb ischaemia or claudication
Large-vessel obstruction
Pulmonary hypertension
Blood-pressure assessment is particularly important in SLE, Takayasu arteritis and patients with possible renal artery involvement.
Cardiovascular diagnostics
Risk assessment
No validated IMID-specific cardiovascular risk score is available in the source material. Generic risk scores are therefore recommended, particularly QRISK3 in patients without RA or SLE. Risk scores may underestimate risk because they do not fully incorporate inflammatory disease activity, disease duration, vascular phenotype or treatment-related factors.
Regular screening and monitoring of modifiable cardiovascular risk factors are recommended across the IMID spectrum.
Detection of subclinical atherosclerosis
Carotid artery plaque may be considered during cardiovascular risk evaluation. Identification of carotid plaque can assist in detecting asymptomatic ASCVD in patients whose risk may otherwise be underestimated.
Coronary computed tomography can aid cardiovascular risk assessment in IMIDs. Novel CT-derived measures, including perivascular fat attenuation index and pericoronary adipose-tissue density, may provide information about vascular inflammation and are considered promising approaches in this population.
Coronary microvascular disease
Coronary microvascular dysfunction has been reported in RA and has prognostic importance. Patients with anginal symptoms and no clear explanation from epicardial coronary disease may therefore require assessment for microvascular disease, although the source material does not specify a particular diagnostic protocol.
ECG, echocardiography and cardiac magnetic resonance
The supplied material does not provide detailed ECG criteria, echocardiographic parameters or cardiac magnetic resonance protocols for cardiovascular risk assessment in IMIDs. It does, however, identify dysrhythmias, myocarditis, pericarditis, valvular disease, pulmonary hypertension and ventricular dysfunction as relevant cardiovascular manifestations requiring appropriate cardiac investigation.
Biomarkers and laboratory findings
The source material does not provide a defined biomarker panel or diagnostic thresholds for cardiovascular risk in inflammatory and autoimmune disease.
Relevant disease-associated laboratory information includes:
Rheumatoid factor and anti-cyclic citrullinated peptide antibodies, which are associated with excess cardiovascular mortality in RA
Antiphospholipid antibodies, which may contribute to thrombotic vascular disease
Inflammatory cytokine pathways involving tumour necrosis factor, interleukin-1, interleukin-6 and type I interferons
Lipid abnormalities in active RA, where LDL and HDL may be depressed despite a higher atherogenic index
Dyslipidaemia potentially aggravated by high-dose glucocorticoids
Lipid interpretation in active inflammatory disease should therefore be contextualised within disease activity and treatment exposure rather than considered in isolation.
Treatment and management
Multidisciplinary care
Optimal care requires cooperation between cardiologists and rheumatologists. Early recognition of immune-mediated cardiovascular disease, control of inflammation and systematic management of cardiovascular risk factors are central components of care.
Control of inflammatory disease
Adequate inflammatory disease control is recommended to reduce cardiovascular risk. Glucocorticoid exposure should be minimised where clinically feasible because glucocorticoids may worsen dyslipidaemia and contribute to vascular dysfunction.
The source material notes that some antirheumatic therapies reduce cardiovascular disease in patients with rheumatic disease and in some patients with atherosclerotic coronary disease without rheumatologic disorders. It does not provide sufficient treatment-specific regimens or doses for individual antirheumatic agents.
Lipid management
Lipid-lowering treatment should be used according to general-population approaches in patients with inflammatory rheumatic disease and chronic coronary syndrome. Chronic inflammatory disorders are considered ASCVD risk enhancers that may favour initiation of statin therapy in individuals with borderline ASCVD risk.
Lipid assessment should account for the lipid paradox of active RA, in which low LDL and HDL concentrations may coexist with increased atherogenic risk.
Blood-pressure management
Antihypertensive treatment should be provided according to general-population principles in patients with inflammatory rheumatic disease and chronic coronary syndrome. Blood-pressure reduction is associated with favourable cardiovascular outcomes regardless of whether coronary artery disease is present.
Specific considerations identified in the source material include:
In SLE, a blood-pressure target greater than 130/80 mm Hg should be achieved.
Diuretics should be avoided in gout.
Beta-blockers should be avoided in systemic sclerosis.
Renal artery stenosis should be considered in Takayasu arteritis when hypertension is difficult to control.
The source material does not provide individual antihypertensive drug doses.
Antithrombotic management
APS and Behçet disease may cause both arterial and venous thrombosis. The supplied material establishes the thrombotic association but does not specify antiplatelet or anticoagulant regimens, doses or duration.
Colchicine and anti-inflammatory cardiovascular therapy
Colchicine has received approval for treatment of coronary atherosclerosis and is identified as a rheumatology medication with cardiovascular applications. The source material does not provide a dose or a detailed prescribing strategy.
Anti-inflammatory therapies directed against interleukin-1, interleukin-6 and other inflammatory pathways are discussed as therapeutically relevant in cardiovascular disease. However, no general dosing recommendations for these agents are provided for IMID-associated cardiovascular risk.
Guideline recommendations
The guidance summarised in the source material supports the following principles:
Screen regularly for cardiovascular risk. Modifiable risk factors should be assessed and managed in gout, vasculitis, systemic sclerosis, mixed connective-tissue disease, myositis, Sjögren syndrome, SLE and APS.
Use generic cardiovascular risk tools when necessary. No validated IMID-specific risk score is available; QRISK3 is particularly recommended in patients without RA or SLE.
Recognise that conventional scores may be incomplete. Inflammatory disease, disease activity and disease-specific vascular complications may not be adequately represented.
Treat lipids and blood pressure as in the general population. This applies particularly to patients with inflammatory rheumatic disease and chronic coronary syndrome.
Achieve adequate inflammatory control. Persistent inflammation contributes to endothelial dysfunction, arterial stiffness and plaque instability.
Minimise glucocorticoids. Their potential adverse effects include worsening dyslipidaemia and vascular dysfunction.
Apply disease-specific cautions. Diuretics should be avoided in gout, beta-blockers in systemic sclerosis, and blood pressure greater than 130/80 mm Hg should be achieved in SLE.
Consider subclinical ASCVD assessment. Carotid plaque detection and coronary CT may assist cardiovascular risk evaluation.
Use coordinated cardiorheumatology care. Collaboration between specialties is recommended to improve recognition, prevention and longitudinal management.
Prognosis and follow-up
Inflammatory and autoimmune disease is associated with premature cardiovascular morbidity and mortality. Outcomes may be worse after myocardial infarction, with higher risks of heart failure and death than in age-matched individuals without IMIDs. In RA, excess cardiovascular mortality may become evident 7–10 years after diagnosis, particularly with persistent disease activity and seropositivity.
Follow-up should therefore be longitudinal and should include:
Periodic cardiovascular risk assessment
Reassessment of smoking, blood pressure, lipid status and insulin resistance
Monitoring of inflammatory disease activity
Review and minimisation of glucocorticoid exposure
Evaluation for new angina, myocardial infarction, stroke, heart failure, arrhythmia or vascular obstruction
Consideration of carotid plaque assessment or coronary CT when risk estimation is uncertain
Ongoing communication between cardiology and rheumatology
The source material does not define a universal follow-up interval or a disease-specific surveillance schedule. The intensity of follow-up should reflect the inflammatory disorder, its activity, prior cardiovascular disease, thrombotic history and evidence of subclinical vascular involvement.
