Systemic lupus erythematosus (SLE) is a chronic, potentially serious systemic autoimmune disease. It is characterized biochemically by the presence of autoantibodies; in particular, antibodies directed against nuclear antigens. SLE is a heterogeneous disease in that clinical manifestations can vary significantly from patient to patient, ranging from mild presentations to severe organ dysfunction. Morbidity and mortality rates have improved dramatically over the past few decades due to advances in therapy.

EPIDEMIOLOGY

SLE primarily affects women of childbearing age, including adolescents, with a female:male ratio of 4-5:1. Approximately 10% to 20% of SLE is diagnosed before adulthood. Female predominance is less pronounced, with younger age of onset. It is extraordinarily rare for SLE to present before the age of 5 years, and female:male ratio is essentially equal in this group. Children tend to have more severe disease as compared with adults, with increased rates of nephritis and long-term morbidity.

Overall prevalence rates in the United States are estimated at 40 to 150 per 100,000, with a trend toward increasing prevalence over time. Non-Caucasian populations are more significantly affected, with higher prevalence in Asians, Hispanics, and African-Americans. African-American and Hispanic groups also have higher morbidity and mortality as compared with Caucasian patients.

PATHOPHYSIOLOGY

The pathogenesis of SLE is complex and remains inadequately understood. Immune abnormalities have been described on multiple levels involving both the innate and adaptive immune systems. From the innate immune perspective, dysregulated apoptosis and clearance of cellular debris lead to improper antigen presentation and increased production of proinflammatory cytokines. Loss of self-tolerance allows the development of autoreactive T and B cells that mediate tissue damage.

Immune abnormalities in SLE are affected by genetic, hormonal, and environmental influences. Polymorphisms in many immune-related genes have been described in SLE patients, including STAT4, PTPN22, and IRF5. In most patients, variations in multiple genes are thought to contribute to the development of lupus. There are also rare cases of monogenic SLE developing in children. Examples include deficiencies in complement (especially C1q and C4) and mutations in TREX1, a gene encoding an exonuclease involved in DNA repair and apoptosis.

Hormonal influences are suggested by the strong female predominance in SLE. Flares of disease triggered by pregnancy or exogenous estrogen administration have been well described. However, the exact mechanisms by which sex hormones interact with the immune system are not known.

Environmental triggers, particularly viral infections, are also thought to affect SLE. One example is Epstein-Barr virus (EBV), which infects B cells leading to B cell activation and proliferation. In one study of pediatric SLE patients, more than 99% had prior seroconversion to EBV as compared to 70% in age-matched controls.

Drug-induced lupus can present in identical fashion to SLE; common triggers include hydralazine, procainamide, and minocycline. Anti-histone antibodies are often observed in these patients. Symptoms generally resolve with discontinuation of the triggering medication, but immunosuppressive medications are sometimes needed to speed this process.

INITIAL PRESENTATION

SLE is quite variable in its presentation, and symptoms may develop acutely or insidiously. The diagnosis of SLE may thus be made in both outpatient and inpatient settings. In pediatric patients in particular, new presentations may be severe and require hospitalization.

Classification criteria revised in 1997 by the American College of Rheumatology (ACR) for the study of SLE are commonly used for diagnosis (Table 153-1, Figure 153-1).¹ Although studies in adults show that fulfillment of 4 of 11 criteria have >95% sensitivity and specificity for the diagnosis of SLE, these criteria have not been adequately validated in the pediatric population. Clinical manifestations may evolve over time. It is important to remember that patients who do not yet meet ACR criteria may still have SLE and thus warrant treatment.

Additional symptoms not included in the ACR criteria but often described by patients include malaise, fever, alopecia, myalgias, weight loss, and Raynaud phenomenon.

DISEASE COURSE AND PROGNOSIS

SLE is a chronic disease with an often unpredictable remitting and relapsing course. In general, lupus that presents during childhood is more likely to have renal involvement, more severe onset, and require more aggressive therapy as compared to adult onset SLE.² After the first 1 to 2 years of disease, new organs tend not to be involved, with the exception of the central nervous system.

The long-term prognosis is primarily related to renal disease and central nervous system involvement, which are the main causes of morbidity. Risk factors for poor renal outcome include hypertension, impaired renal function at diagnosis, and specific renal biopsy findings such as diffuse proliferative lupus nephritis.^3,4

The 2-year mortality of SLE approached 100% in the early 1960s. With the use of immunosuppressive treatments and improved management of chronic renal failure, the 20-year survival rate is now >75%.⁵ These increased survival rates are accompanied by greater morbidity related to medication side effects and development of comorbid conditions. Children with lupus are at increased risk for accelerated atherosclerosis, cerebrovascular accident, and myocardial infarction as they age. Risk factors for cardiovascular disease include prolonged use of steroids, coronary vasculitis, obesity, hypertension, lupus nephritis, hyperlipidemia, lupus anticoagulant, and family history of cardiac disease.

Overwhelming infection is the most frequent cause of mortality among children with SLE, and those with active disease are at the greatest risk of developing an infection. Children with SLE are immunocompromised by the disease itself (i.e. neutropenia, lymphopenia, hypocomplementemia, functional asplenia) as well as by immunosuppressive medications used to treat the disease. These medications may also mask fever and other signs of infection, complicating the ability to distinguish between lupus flares and acute infection. Other major causes of mortality include renal failure, central nervous system disease, pulmonary hemorrhage, and myocardial infarction.

NEONATAL LUPUS

Neonatal lupus is a distinct, uncommon condition found in infants born to mothers with anti-SSA/Ro and/or anti-SSB/La antibodies. The mothers may or may not have other evidence of systemic autoimmune disease; many are asymptomatic. Transplacental passage of these autoantibodies can cause a range of symptoms in the infant including rash, congenital heart block, anemia or thrombocytopenia, and hepatitis. Congenital heart block is the most worrisome feature and can be detected as early as the second trimester (Figure 153-2). Congenital heart block associated with neonatal lupus is thought to occur when transplacental passage of maternal autoantibodies to the intracellular ribonucleoproteins Ro (SS-A) and La (SS-B) cross the placenta and injure the previously normal fetal heart. Even when detected early in pregnancy, studies have not shown benefit with immunosuppressive treatment. Complete heart block is not reversible and requires placement of a pacemaker after birth. These infants are also at risk of subsequent cardiomyopathy. In contrast, the other clinical manifestations generally resolve over several months as the maternal antibodies are cleared.