The Heart and Lupus
IntroductionAt some stage in their disease, more than half of patients with lupus will develop a heart abnormality. It is, therefore, one of the more important clinical manifestations of lupus to detect although, of course, it need not necessarily be serious.
Lupus involvement of the heart may affect all its layers: the pericardium, myocardium and endocardium as well as the coronary arteries and broader cardiovascular system.
Involvement may be primary, due to inflammation of the cardiac tissue related directly to lupus, or secondary, due to damage to other organs such as the lungs and renal system. Additionally, symptoms may be due to co-morbid conditions such as coronary artery disease, reflux oesophagitis, pleurisy and costochondritis.
As in all areas of assessment in SLE, it is of upmost importance that attribution of a cardiac manifestation is accurate (i.e. is there active inflammation or not and is it lupus-related), to allow the most appropriate treatment to be initiated. Treatment should not be targeted at active inflammation alone if a manifestation is unrelated to SLE, and it should never be assumed that a new symptom in someone with SLE is always related to active inflammatory disease. Working stepwise through the layers of the heart this chapter will describe how they may be involved in lupus and what the clinical manifestations are.
PericarditisA manifestation of serositis, pericarditis is the most common heart abnormality encountered in lupus. Reports estimate that 6-45% of lupus patients will have some form of pericardial abnormality during their disease, with many suffering recurring episodes. Pericarditis classically presents as substernal chest pain, usually in the context of SLE activity in other systems. In some instances, this may progress to a symptomatic pericardial effusion, but asymptomatic small pericardial effusions are also common and are often incidental findings on an echocardiogram. Repeated episodes of pericardial inflammation can cause the pericardium to constrict, causing additional symptoms. An uncommon complication is for the pericardium to become infected by haematogenous spread of bacteria, termed purulent pericarditis, and is more common in an unwell, immunosuppressed patient.
• Sub-sternal pain: this may be aggravated by breathing, coughing, swallowing, twisting or bending forward. There is a range of severity and the symptoms may be intermittent.
• Breathlessness: this is caused by constriction of the ventricles by an inflamed, restricted pericardium or by an associated pericardial effusion.
Assessment should always include full history and examination for other active lupus manifestations, and for evidence of other causes of pericarditis (e.g. recent viral illness). If a diagnosis is suspected, it may be confirmed by detecting a friction rub on auscultation. Signs of a large pericardial effusion and/or cardiac tamponade should be sought if the patient is unwell.
Blood investigations should beconsidered if symptoms are severe or multisystem in nature, as pericarditis usually occurs in the context of more generalised disease activity. These include inflammatory markers and immunological assessment. It is worth noting that serositis (such as pericarditis) is one of the few disease manifestations that can cause an acute phase response in active lupus. Ordinarily, a high CRP in SLE should prompt thorough assessment for infection but can be observed in the context of active serositis.
Characteristic electrocardiographic changes may be present (tall T waves and elevated ST segments) in the acute stages and should be performed to exclude other cause of chest pain. An echocardiogram is useful for visualising and assessing pericardial effusions.
The course of uncomplicated pericarditis and incidental small pericardial effusions is usually benign, and often managed with symptomatic therapies. Symptoms of pericarditis usually respond well to non-steroidal anti-inflammatory drugs and/or short courses of oral prednisolone (less than 0.5mg/kg). Pericardiocentesis is usually reserved for patients with large, symptomatic pericardial effusions, cardiac tamponade, or in whom there is diagnostic uncertainty or concern over a purulent effusion. Further assessment of the patient and their lupus should occur, to assess overall disease control and the need for additional systemic therapies. Anti-malarial therapies may be effective at preventing recurring episodes of pericardial disease, but additional immunosuppression may also be required.
MyocarditisInflammation of the myocardium can range in severity from an incidental finding in patients with systemically active disease (up to 25% of some cohorts) to severe myocardial disease with evidence of global hypokinesis and symptomatic heart failure in less than 10% of patients. Acute myocarditis is usually associated with a generalised lupus flare, but rarely may be drug induced e.g. cyclophosphamide or anti malarials. Similar inflammation may also be found in skeletal muscles and myocarditis may be part of a generalised myositis, with reports suggesting that anti-RNP antibodies may be more prevalent in these patients. As in other manifestations of active SLE, immune complex deposition within the myocardium is thought to form part of the pathological process by activating the complement cascade.
In the absence of other causes, acute myocarditis should be suspected in a patient presenting with any or all of:
Myocarditis may be asymptomatic but should be considered in a patient with unexplained tachycardia, ECG abnormalities and/or cardiomegaly. It usually occurs in patients with generalised inflammatory lupus activity.
Patients with evidence of symptomatic myocarditis are usually best assessed in an acute setting, with rapid access to appropriate investigations. Initial clinical assessment should be targeted at evaluating cardiac function and for the presence of systemic inflammatory lupus activity, whilst also excluding non-lupus causes of myocardial disease. Clinical signs to elicit include evidence of congestive heart failure, a gallop rhythm and other heart murmurs. Evidence of a more generalised myositis may be present, such as myalgia and proximal myopathy. Assessment for co-morbid conditions presenting in a similar fashion should also be conducted. Initial investigations should include measurement of markers of cardiac damage (creatinine kinase and troponin), as well as blood investigations for SLE and co-morbid conditions, such as renal function. The ECG may reveal ST and T wave abnormalities and is important to exclude ischaemic heart disease. A chest x-ray is useful to assess for signs of heart failure and cardiomegaly. An echocardiogram is essential to assess systolic and diastolic function, and for areas of hypokinesia, whilst cardiac magnetic resonance imaging is increasingly utilised to differentiate active inflammatory change from previous involvement and fibrosis.
The approach to treatment, as in all other areas of lupus management, should be to distinguish active inflammatory myocardial disease from co-morbid conditions and/or past involvement with damage and fibrosis. Confirmation of active lupus myocarditis usually prompts initiation of potent immunosuppressive therapies, such as high-dose corticosteroids and cyclophosphamide or equivalent, depending on severity of disease and generalised disease activity. Medications for heart failure, when present, are also indicated.
EndocarditisLibman-Sachs endocarditis describes a sterile, verruocous or nodular valvular lesion in SLE that results from inflammation of the endocardium. These vegetations are usually found near the edge of the heart valves but can also occur between the atrial and ventricular chambers. They are often associated with valvular dysfunction, such as regurgitation, and constitutional symptoms such as anaemia and fever. In this context, distinguishing sterile lupus related endocarditis form subacute bacterial endocarditis is an important and challenging clinical problem. Interestingly, sterile valvular lesions in SLE do not always occur in the context of active lupus and may occur at any time. Thorough assessment of an unwell patient with SLE should always include auscultating for new murmurs, as this is the most common clinical finding.
Clinical symptoms of endocarditis:
• General malaise
Not all patients with endocarditis will be symptomatic, therefore intermittent auscultation of the heart for new murmurs may alert the physician to its presence. Mitral and aortic valves are most commonly involved. Complications of endocarditis include heart failure and embolization of vegetations to the brain or lung, for example. Libman-Sachs endocarditis may be complicated by super-added infection, as the endocardium will be predisposed to attack by blood borne organisms.
In an unwell or febrile patient, investigations should focus on excluding a non-sterile endocarditis initially. Cardiac auscultation should be carried out regularly and echocardiography is indicated if significant or changing murmurs are detected or if cardiac function is changing. Trans-oesophageal echocardiography is more sensitive than the trans-thoracic approach and may be indicated when the diagnosis is proving challenging. There is no indication for routine screening with echocardiography in the absence of symptoms or signs. Valvular lesions in SLE are more prevalent in patients with high titres of anti-phospholipid antibodies. Therefore, their presence should be tested for, if not already known.
Additional immunosuppressive therapy is not always indicated in isolated, uncomplicated endocarditis, and there are no studies to guide the decision. If there are other systemic manifestations, and no evidence of bacterial endocarditis, then steroids and immunosuppressive therapies may be necessary. For patients with asymptomatic valve thickening, low dose aspirin may be indicated. In non bacterial thrombotic endocarditis with systemic emboli, anticoagulation should be considered, especially in the presence of anti-phospholipid antibodies. Antibiotic prophylaxis may be recommended for selected patients with lupus undergoing procedures with an associated risk of bacteraemia e.g. dental treatment. Valve replacement surgery or valvoplasty may be necessary if severe mitral or aortic valvular insufficiency develops.
Coronary Artery DiseaseEstablished SLE is associated with an increased risk of premature clinical and subclinical atherosclerosis. Overall, women with SLE have a greater than five fold increased risk of clinical coronary heart disease (CHD) events and notably, a 50-fold increased relative risk in younger patients. Although the absolute risk in younger patients remains small, many CHD risk factors are present at a younger age and are, therefore, potentially modifiable.
The excess cardiovascular (CV) risk in SLE includes increased risk of both CHD and stroke, and accelerated atherosclerosis is the key driver of this excessive CV mortality and morbidity. Studies have shown that the average age at the time of the first coronary event in women with SLE was 53 years, much younger than women without SLE. It is important to highlight that both classic and lupus related factors act to increase the CHD risk in patients with SLE, therefore, attention to both is required to modify this risk in the long term.
Classic CHD Risk Factors
Many traditional risk factors for CHD are over-represented in patients with SLE, such as hypertension, smoking, elevated lipid profile and sedentary lifestyle. Many studies have shown that the prevalence of these risk factors is higher than in control populations, and as such, their presence should be actively sought when managing long-term risk prevention. The metabolic syndrome (the collection of central obesity, hypertension, dyslipidaemia and insulin resistance) is also more prevalent in SLE cohorts and is often worsened by both lupus activity (such as renal disease) and the therapies used to manage lupus (such as steroids). As such, risk factors often change over time and patients should, therefore, be assessed periodically to re-assess this risk.
Lupus-related Risk Factors
Many studies, however, suggest that classic risk factors alone, whilst more common in SLE, do not fully explain the higher CVD risk observed in this population. Therefore, SLE can be considered as an ‘independent’ CHD risk factor. It is likely that multiple additional factors related to inflammatory disease burden, clinical phenotype and therapy all interact to enhance risk directly (such as endothelial inflammation in active disease) or indirectly (such as steroids aggravating traditional risk factors). However, this interaction remains incompletely understood.
Symptomatic coronary artery disease (CAD) is described in up to 45% of patients with lupus and may lead to acute myocardial infarction. It is, therefore, imperative to recognise cardiac-sounding chest pain in patients with SLE (see Table), and direct them for appropriate cardiac investigations if indicated. Symptomatic CAD is rarely due to inflammatory SLE activity or coronary vasculitis, so a standard approach to investigation and therapy is indicated. An awareness of the increased risk of CHD, particularly in younger patients, is therefore essential to ensure appropriate investigations are requested.
Perhaps more importantly in a chronic disease cohort is the assessment of CHD risk and the implementation of prevention strategies to reduce morbidity. Traditionally, prediction of CVD events using standard scoring systems based on the Framingham
risk score and QRISK was not possible as these risk equations significantly underestimated CVD risk in SLE. However, the QRISK3 algorithm, used in the UK since May 2017 to estimate 10 year risk of a major CVD event, now includes SLE as a risk factor and it is this version that should be used.
Prevention and treatment
Recognition of the increased risk of CHD in SLE is vital in reducing morbidity long term. Attention to modifiable risk factors is important in both a primary and secondary care setting e.g. hypertension, hyperlipidaemia, cigarette smoking, obesity, diabetes and sedentary lifestyles. Studies have indicated that glucocorticoids may lead to worsening of risk factors e.g. cholesterol, arterial blood pressure and body weight. Therefore, minimising exposure whilst controlling disease activity is a key approach in managing long term risk. The use of statins in managing CHD risk in SLE, especially in younger women of child-bearing age, can be challenging. Prior to initiating a statin for long-term risk prevention, lifestyle interventions should be tried and steroid dose should be minimised, as these alone may improve lipid profiles sufficiently. Where CHD risk indicates a statin, these should be prescribed, with an awareness of renal function and disease phenotype (e.g. concurrent myositis). Similarly, the use of prophylactic aspirin should be an individual decision based on risk and benefit. From a rheumatologist’s perspective, active lupus should be adequately managed in the long term, and steroid doses should be minimised and, ideally, withdrawn whenever possible. Many large observational studies have suggested that hydroxychloroquine has beneficial effects on CHD risk in lupus, in addition to its disease-modifying role, and should be considered if not already prescribed.
The Kellgren Centre for Rheumatology
Manchester Royal Infirmary
Honorary Senior Lecturer
Centre for Musculoskeletal Research
University of Manchester