Etiology and Pathogenesis

The cause of SLE involves a complex interplay of genetic, environmental, and immunologic factors. Several genes have been identified that confer susceptibility to SLE, including human leukocyte antigen haplotypes, complement component and receptor genes, cytokine polymorphisms, Fc receptors, and T-cell receptor polymorphisms. It is likely that a combination of these genes provides a genetic risk profile that allows the subsequent development of SLE under the appropriate conditions. Familial clustering has been reported, and the concordance rates among monozygotic and dizygotic twins are 25% and 2%, respectively

The immune dysregulation in SLE is multifactorial and includes abnormal clearance of apoptotic debris, B- and T-cell abnormalities, and autoantibody and immune complex formation. In SLE, the system of apoptotic particle removal is dysfunctional, allowing for the presentation of autoantigens to T cells. These T cells stimulate B cells to produce high-affinity autoantibodies that bind directly to cells in end organs, causing injury, or form immune complexes in the circulation that deposit in tissues and cause inflammation. Additionally, early classical complement deficiencies are associated with SLE; this association is probably secondary to delayed clearance of apoptotic debris and immune complexes.

Other factors have been hypothesized to play a role in the cause of SLE, including hormonal influences, Epstein-Barr virus and other infections, exposure to ultraviolet light, L-canavanine (a chemical in alfalfa sprouts), and silica dust inhalation. Although the precise cause of SLE is unknown, it is clear that genetic susceptibility, immunologic dysregulation, and environmental influences all contribute.

Clinical Presentation

SLE is rare in children younger than age 5 years and is uncommon before adolescence. In childhood, girls are affected approximately four times more often than boys. The presenting symptoms are widely variable. Constitutional signs and symptoms, including fever, fatigue, lymphadenopathy, hepatosplenomegaly, and weight loss, are commonly seen. The most frequently involved specific sites affected by SLE are the skin, joints, and kidneys. Symptoms often precede the diagnosis by several months and may be insidious or acute in onset. The American College of Rheumatology provides criteria which are used clinically to aid in the diagnosis of SLE (Table 29-1, Figure 29-1). The diagnosis of SLE is made if at least four of the criteria are present or have been present in the past without another diagnosis that explains the findings. The antinuclear antibody (ANA), one of the criteria for diagnosis of SLE, is not a useful general screening test for rheumatologic disease and should not be sent routinely in the absence of other criteria for SLE.

Table 29-1 American College of Rheumatology 1997 Revised Classification Criteria for Systemic Lupus Erythematosus

Adapted from Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40(9):1725, 1997.

Figure 29-1 Criteria used for the diagnosis of systemic lupus erythematosus.

Skin and Mucus Membrane Manifestations

There are four skin and mucocutaneous criteria: malar rash, discoid rash, oral or nasal ulcers, and photosensitivity. The malar rash, or classic “butterfly rash,” is typically maculopapular and photosensitive. Additionally, it classically extends across the nasal bridge, spares the nasolabial folds, and is nonscarring (Figure 29-2). Depending on the race of the child, it may be either hyper- or hypopigmented. A discoid rash is less common. These inflammatory lesions are coin shaped, raised, and erythematous. They are most commonly located on the face (especially the ears), scalp, and extremities. These lesions are scarring and lead to permanent alopecia when they occur on the scalp. The oral and nasal ulcers associated with SLE are usually painless; oral ulcers are classically located on the hard palate (see Figure 29-2). Other common skin manifestations include livedo reticularis (see Figure 29-2), alopecia, Raynaud’s phenomenon (see Figure 27-2), and digital ulcerations.

Figure 29-2 Skin and mucous membrane manifestations of systemic lupus erythematosus.

Morbidity and Mortality

Renal, neurologic, hematologic, and cardiovascular disease processes are the main sources of morbidity and mortality in patients with SLE. SLE is a lifelong illness that was considered uniformly fatal within 2 years as recently as the 1960s. The long-term survival of children with SLE has improved significantly over the years with earlier diagnosis, the use of immunosuppressant therapies early in the disease course, and better understanding of the appropriate management of end stage renal disease. Five-year survival rates are now near 100%, and 10-year survival rates are greater than 85%.

The morbidity and mortality attributed to renal disease is related to the histology of the lupus nephritis seen on the kidney biopsy (Figure 29-3). End-stage renal disease is most strongly associated with focal lupus nephritis (class III) and diffuse lupus nephritis (class IV). The most frequent cause of death for children with SLE is infection. Factors including leukopenia, hypocomplementemia, and immunosuppressive therapy contribute to an immunocompromised state that can result in death if a serious infection is not recognized.

Figure 29-3 Renal manifestations of systemic lupus erythematosus.

Over the long term, the renal disease, vasculitis, hypercoagulable state, lipid abnormalities, and steroid therapy can all contribute to life-limiting accelerated cardiovascular disease, including atherosclerosis, stroke, and myocardial infarction during adolescence and young adulthood.

Evaluation and Management

The diagnosis of SLE is established using the classification criteria, with consideration of important possibilities in the differential diagnosis based on the presenting signs and symptoms (see Table 29-1). In addition to the laboratory evaluation necessary to determine the criteria met by the patient, several other laboratory studies should be considered as part of the evaluation of a child with suspected SLE. Inflammatory markers (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) are helpful as a general screen of the degree of inflammation present. Classically, the ESR is markedly elevated, and the CRP is normal or mildly elevated in patients with SLE. Complement levels (C3, C4) are decreased when active nephritis is present. The partial thromboplastin time (PTT) is prolonged when the lupus anticoagulant is present. Despite the prolongation of the PTT in the laboratory, the lupus anticoagulant leads to a hypercoagulable state clinically as described above. A complete urinalysis should be performed in all SLE patients. If proteinuria is present, a first-morning urine protein to creatinine ratio and a 24-hour urine collection should follow. If proteinuria is significant (>1 g/24 h), then a renal biopsy is warranted before therapy initiation to stage the lupus nephritis and aid in treatment decision making. It is also recommended that children with a new diagnosis have a baseline electrocardiogram, echocardiogram, and chest radiograph.

Future Directions

Our improved understanding of the pathogenesis of SLE will lead to more precise, targeted therapies with more favorable adverse effect profiles in the coming years. Targets of particular interest for pharmacologic intervention include other B-cell surface markers, the antigen-presenting cell–T-cell interaction, components of the complement cascade, and cytokines known to be elevated in SLE. Continued progress in our understanding of the mechanism of disease and rigorous prospective evaluation of disease-modifying agents may indicate that a cure for SLE will soon be within reach.