Key points

Neonatal lupus and congenital heart block

Autoantibodies serve as a diagnostic tool for systemic lupus erythematosus (SLE) and other autoimmune diseases, but certain autoantibodies are thought to be directly pathogenic in some circumstances. For example, the presence of anti-Ro/SS-A autoantibodies is strongly associated with the risk of developing neonatal lupus erythematosus as a form of passively transferred autoimmunity from mother to child. Neonatal lupus is a congenital disorder in which the cardiac conduction system is often damaged by maternal anti-Ro/SS-A autoantibodies that cross the placenta. Infants with neonatal lupus sometimes develop complete heart block, which requires pacing for survival. Complete heart block in the fetus is associated with fetal myocarditis. Neonatal lupus can develop whenever a pregnant woman has circulating anti-Ro/SS-A antibodies, even if she does not have SLE. This possibility includes patients with Sjögren syndrome and even asymptomatic patients with anti-Ro/SS-A. Studies have estimated that between 60% and 90% of all cases of congenital heart block are secondary to maternal autoantibodies that are transferred to the fetus across the placenta.

Although anti-Ro/SS-A antibodies might be directly pathogenic to the fetus, adults with anti-Ro/SS-A are not prone to developing heart block. However, several recent studies have found evidence that the QTc interval is prolonged in adults with anti-Ro/SS-A and that certain ventricular arrhythmias may be more common in adults with these autoantibodies. One study found a statistically significant difference in QTc interval, with anti-Ro/SS-A being associated with a mean QTc of 445 milliseconds compared with 419 milliseconds in patients lacking the autoantibody. This finding suggests that anti-Ro/SS-A autoantibodies may contribute to a mild form of conduction disease in adults.

It is difficult to explain the discrepancy between neonatal and adult conduction disease. One hypothesis involves a contribution from an unknown fetal factor that enhances the effect of anti-Ro/SSA autoantibodies. In support of this, immune complexes directed against the fetal conduction system have been observed. However, only about 2% of fetuses develop congenital heart block in the presence of anti-Ro/SS-A antibodies. Furthermore, epidemiologic studies do not directly support the presence of a pathogenic fetal factor. If a mother with anti-Ro/SS-A autoantibodies has had prior offspring with complete heart block, the probability of future offspring developing complete heart block increases from 2% to 18%. However, monozygotic twins of mothers with circulating anti-Ro/SS-A antibodies discordantly develop congenital heart block, which implies that the pathogenesis of neonatal complete heart block is complex and that it does not simply depend on the presence of anti-Ro/SS-A and an unknown fetal factor. An alternative hypothesis is that certain autoantibodies are destructive only to the developing cardiac conduction system, possibly because of exposure of unique antigens in the fetus, but monozygotic twin discordance makes this possibility less likely. In addition, small differences within the uterine environment or in the developing immune system might contribute to discordant phenotypes in genetically identical neonates, but this has yet to be demonstrated.

Progression of incomplete heart block to irreversible complete heart block can sometimes be prevented by treatment with corticosteroids. Some case reports describe postnatal progression of heart block despite depletion of circulating autoantibodies. Given the severe, potentially life-threatening, complications of neonatal lupus, it is important to explain this risk to women of child-bearing age who are known to have anti-Ro/SSA antibodies. Maternal use of hydroxychloroquine may reduce the risk of recurrent neonatal lupus in subsequent pregnancies.

Neonatal lupus and congenital heart block

Autoantibodies serve as a diagnostic tool for systemic lupus erythematosus (SLE) and other autoimmune diseases, but certain autoantibodies are thought to be directly pathogenic in some circumstances. For example, the presence of anti-Ro/SS-A autoantibodies is strongly associated with the risk of developing neonatal lupus erythematosus as a form of passively transferred autoimmunity from mother to child. Neonatal lupus is a congenital disorder in which the cardiac conduction system is often damaged by maternal anti-Ro/SS-A autoantibodies that cross the placenta. Infants with neonatal lupus sometimes develop complete heart block, which requires pacing for survival. Complete heart block in the fetus is associated with fetal myocarditis. Neonatal lupus can develop whenever a pregnant woman has circulating anti-Ro/SS-A antibodies, even if she does not have SLE. This possibility includes patients with Sjögren syndrome and even asymptomatic patients with anti-Ro/SS-A. Studies have estimated that between 60% and 90% of all cases of congenital heart block are secondary to maternal autoantibodies that are transferred to the fetus across the placenta.

Although anti-Ro/SS-A antibodies might be directly pathogenic to the fetus, adults with anti-Ro/SS-A are not prone to developing heart block. However, several recent studies have found evidence that the QTc interval is prolonged in adults with anti-Ro/SS-A and that certain ventricular arrhythmias may be more common in adults with these autoantibodies. One study found a statistically significant difference in QTc interval, with anti-Ro/SS-A being associated with a mean QTc of 445 milliseconds compared with 419 milliseconds in patients lacking the autoantibody. This finding suggests that anti-Ro/SS-A autoantibodies may contribute to a mild form of conduction disease in adults.

It is difficult to explain the discrepancy between neonatal and adult conduction disease. One hypothesis involves a contribution from an unknown fetal factor that enhances the effect of anti-Ro/SSA autoantibodies. In support of this, immune complexes directed against the fetal conduction system have been observed. However, only about 2% of fetuses develop congenital heart block in the presence of anti-Ro/SS-A antibodies. Furthermore, epidemiologic studies do not directly support the presence of a pathogenic fetal factor. If a mother with anti-Ro/SS-A autoantibodies has had prior offspring with complete heart block, the probability of future offspring developing complete heart block increases from 2% to 18%. However, monozygotic twins of mothers with circulating anti-Ro/SS-A antibodies discordantly develop congenital heart block, which implies that the pathogenesis of neonatal complete heart block is complex and that it does not simply depend on the presence of anti-Ro/SS-A and an unknown fetal factor. An alternative hypothesis is that certain autoantibodies are destructive only to the developing cardiac conduction system, possibly because of exposure of unique antigens in the fetus, but monozygotic twin discordance makes this possibility less likely. In addition, small differences within the uterine environment or in the developing immune system might contribute to discordant phenotypes in genetically identical neonates, but this has yet to be demonstrated.

Progression of incomplete heart block to irreversible complete heart block can sometimes be prevented by treatment with corticosteroids. Some case reports describe postnatal progression of heart block despite depletion of circulating autoantibodies. Given the severe, potentially life-threatening, complications of neonatal lupus, it is important to explain this risk to women of child-bearing age who are known to have anti-Ro/SSA antibodies. Maternal use of hydroxychloroquine may reduce the risk of recurrent neonatal lupus in subsequent pregnancies.

Pericarditis

Pericarditis is the most common cardiac manifestation of SLE. Approximately 25% of all patients with SLE develop symptomatic pericarditis at some point during the course of the disease, most often along with associated pleuritis. However, autopsy studies reveal a higher rate of subclinical pericarditis. It is rare for pericarditis to be the only symptom at presentation.

Patients with lupus pericarditis typically present with tachycardia, substernal or precordial chest discomfort, dyspnea, and positional pain. Some patients may have a friction rub on examination. All of these signs and symptoms are typical of pericarditis in general. Echocardiographic findings (pericardial effusion and thickened pericardium) and electrocardiogram changes (PR depression and diffuse ST segment elevation) are also similar to other forms of pericarditis.

The conventional wisdom is that tamponade and constrictive pericarditis are rare in SLE. Constrictive pericarditis has only been reported in SLE in a few patients. Tamponade is uncommon compared with the overall frequency of pericarditis in patients with lupus. For example, one large study of 1300 patients found tamponade in less than 1% of patients. However, other retrospective studies have found between that 13% and 22% of patients with symptomatic pericarditis had evidence of tamponade, suggesting that it might be more common than previously appreciated. Tamponade has also been reported as the initial, presenting manifestation of SLE. Severe pericarditis and tamponade might be more likely to occur in patients when the diagnosis or treatment are delayed, which could explain the differences in the prevalence of tamponade in various patient populations.

Pericardial fluid from patients with lupus pericarditis typically reveals inflammatory exudate with neutrophil predominance. Pericardial biopsy is not required to establish a diagnosis, but histopathology often reveals mononuclear cells, fibrinous material, and immune complex deposition. Autoantibodies can sometimes be detected in the pericardial fluid, although this is not diagnostically useful.

Whether to check antinuclear antibody (ANA) in patients with a first episode of pericarditis depends on the clinical situation. A positive ANA test is nonspecific and occurs frequently in patients who do not have SLE. Positive results are often confusing for patients and have poor predictive value when ordered inappropriately. As a general rule, it is reasonable to check ANA in patients who have additional signs or symptoms of lupus or in those who have had recurrent, unexplained bouts of idiopathic pericarditis. The clinical context is important to consider. For example, patients with idiopathic pericarditis are more likely to have had a recent viral infection, whereas the presence of leukopenia and/or lymphopenia, Raynaud, or a malar rash suggests the possibility of SLE.

Mild pericarditis can be treated with nonsteroidal antiinflammatory drugs, but most patients with lupus pericarditis require corticosteroids in addition to optimization of disease-modifying antirheumatic drug (DMARD) therapy. Selection of an appropriate DMARD depends on the severity of disease and whether the patient has additional organ-threatening disease. For example, a patient with tamponade and/or class IV nephritis requires high-dose corticosteroids in addition to cyclophosphamide or mycophenolate mofetil, whereas patients with mild- to-moderate disease may respond to a slow steroid taper combined with hydroxychloroquine, methotrexate, or azathioprine. Biologic DMARD therapies such as rituximab or belimumab have not been definitively shown to treat lupus pericarditis, although there is likely to be a role for these therapies in some patients.

Myocarditis and cardiomyopathy

Clinically apparent lupus myocarditis is rare. As with pericarditis, autopsy studies have revealed subclinical myocarditis in a higher percentage of patients. Autoimmune myocarditis with deposition of immune complexes has been shown at autopsy and by endomyocardial biopsy. Pathology typically reveals mononuclear cell infiltrates, perivascular inflammation or arteriopathy, and necrosis of the cardiomyocytes. The primary lesion is thought to be perivascular inflammation. Patients with lupus myocarditis can present with symptoms of heart failure including resting tachycardia and dyspnea, but they also sometimes present with chest discomfort, fever, and/or myopericarditis. Global hypokinesis on echocardiogram in patients without evidence of coronary artery disease (CAD) supports the diagnosis. Cardiac magnetic resonance imaging (MRI) shows delayed gadolinium enhancement in lupus myocarditis, although it cannot always distinguish among the various forms of myocarditis. Biopsy is typically low yield and not required for the diagnosis, although it can be helpful in some patients. Treatment with high-dose methylprednisolone is typically required, as is optimization of DMARD therapy.

Advances in human genetics research have led to the identification of specific genes and mutations that appear to contribute to pathogenesis of SLE. For example, mutations in the DNA exonuclease Trex1 have been associated with SLE in approximately 2% to 3% of patients. Mice lacking Trex1 develop a lupus-like disease with severe, fatal myocarditis. This mouse model may continue to yield important insights into the pathogenesis of myocarditis in patients with SLE. In addition to myocarditis, some patients with SLE develop cardiomyopathy, which can be directly caused by the SLE. However, cardiomyopathy in SLE can also be secondary to CAD, which is common in patients with SLE. Cardiomyopathy secondary to hydroxychloroquine has also been reported, although this is rare at doses typically prescribed for SLE. The most common cause for cardiomyopathy in patients with SLE is likely coexisting hypertension and/or CAD. Cardiomyopathy secondary to small vessel disease and thrombosis of the microcirculation have also been described.

Sometimes it is difficult to determine whether cardiomyopathy is secondary to lupus myocarditis or another underlying process. In addition to cardiac MRI, another useful diagnostic approach is to perform an echocardiographic or nuclear medicine evaluation for reversibility after a period of treatment with high-dose corticosteroids. However, patients with lupus with cardiomyopathy almost always require additional cardiac work-up to exclude other underlying causes, including an evaluation for underlying CAD.

CAD

During the second half of the twentieth century, CAD became an increasingly appreciated manifestation of SLE. CAD is the most common cause of death in patients with late-onset or long-standing SLE. In addition to CAD, there are also reports of other forms of coronary inflammation and thrombosis in patients with SLE. These reports include examples of vasospasm, coronary arteritis, and embolization into coronary arteries. However, these phenomena are less common. Atherosclerosis remains the most prevalent and significant mortality risk in older adult patients with SLE.

Thrombosis and inflammation were once thought to be distinct, but over the last few decades it has become increasingly clear that these processes are linked. Several studies have described an association between antiphospholipid antibodies and development of CAD, whereas others have failed to show an association. One group found that anticardiolipin antibody levels predicted atherosclerosis independently of other risk factors.

The risk of fatal myocardial infarction increases with time from diagnosis with SLE, but one of the most striking features of CAD in patients with lupus is the development of premature CAD. Even children with SLE have been noted to develop premature atherosclerosis, including 1 case of myocardial infarction in a 5-year-old patient. Young women with SLE are at greater risk of developing myocardial infarction at an early age, even when controlling for other risk factors. However, not all patients with lupus seem to have similar susceptibility to developing premature atherosclerosis. There is no reliable method for predicting the patients who are at the greatest risk, but it is reasonable to assume that patients with traditional risk factors like hypertension, a history of smoking, a family history of CAD, and hyperlipidemia have higher risk. Markers of inflammation predict cardiovascular risk, and therefore systemic inflammation is likely to be driving premature atherosclerosis. It is not known whether improved control of systemic inflammation could have an impact on the frequency of cardiovascular events in patients with SLE.

Treatment with corticosteroids increases the risk of developing CAD by contributing to hyperlipidemia, hypertension, weight gain, and the development of steroid-induced diabetes mellitus. However, high-density lipoprotein levels are lower in patients with lupus even in the absence of corticosteroid therapy. Petri and colleagues found that an increase in prednisone of 10 mg per day results in an average increase of 2.5 kg in weight, a 1.1 mm Hg increase in blood pressure, and a 7.5 mg/dL increase in total cholesterol. Longer duration of corticosteroid therapy increases the risk of developing subclinical cardiovascular disease and independently predicts risk of cardiovascular events. Another study found that patients on 30 mg of prednisone daily have a 60% greater 2-year risk of cardiovascular events compared with patients with lupus with the same risk factors and disease activity but not taking corticosteroids. This finding further underscores the importance of minimizing corticosteroid dose whenever possible.

Patients with SLE are more likely to have subclinical CAD. When young patients with lupus complain of chest pain, myocardial infarction ought to remain in the differential diagnosis even when it would be easily dismissed in patients lacking more traditional risk factors. Because of the increased risk of atherosclerosis in patients with lupus, a reasonable preventative approach is to have a lower threshold for initiation of statin therapy, a lower target low-density lipoprotein, and lower blood pressure goal (130/80 mm Hg). Patients with chronic, systemic inflammation are increasingly being classified as having a CAD risk equivalent, much like patients with diabetes mellitus. Hydroxychloroquine is associated with favorable effects on lipids and blood glucose, and so it might reduce the risk of cardiovascular events. The reduction in cardiovascular disease activity by lipid-lowering therapy seen in patients who do not have SLE (including those with rheumatoid arthritis or multiple sclerosis) has not been realized in patients with SLE. In a placebo-controlled study where 200 adults with SLE were randomized to receive atorvastatin or placebo, no differences were observed in coronary artery calcium, carotid intima media thickness, carotid plaque, SLE disease activity, or endothelial cell activation.

As with SLE, rheumatoid arthritis (RA) causes premature atherosclerosis, leading to increased mortality caused by myocardial infarction. Autopsies of patients with RA revealed that their atherosclerotic plaques were more likely to contain a thin, inflamed fibrous cap that is especially prone to rupture and myocardial infarction. Although this issue still needs additional investigation, a recent study suggested that carotid atherosclerotic plaques in patients with lupus seem to be more vulnerable based on echolucency. Because inflammation promotes plaque rupture, it puts these patients at greater risk.