• Predilection for females of childbearing age.
  
• Multisystem disease, often with a relapsing-remitting course.
  
• Photosensitive rash, polyarthritis, serositis, and fatigue are common manifestations of disease flares.
  
• Renal disease and central nervous system involvement are important causes of morbidity.
  
• Presence of antinuclear antibodies.
  
• Certain autoantibodies (anti-dsDNA and anti-Sm) have great specificity for the diagnosis of SLE, but lack sensitivity.
  
• Hypocomplementemia may occur during flares.

Systemic lupus erythematosus (SLE) is the prototypic autoimmune disease characterized by multisystem involvement and the production of an array of autoantibodies. Clinical features in individual patients are highly variable, ranging from skin and joint involvement to organ-threatening and life-threatening disease. SLE is typically associated with a waxing and waning clinical course, but some patients have continuous disease activity.

The prevalence of SLE varies across gender, race/ethnicity, and geographic regions. SLE demonstrates a striking female predominance with a peak incidence of disease during the reproductive years. In adults, the female to male ratio is 10–15:1. In the United States, the estimated prevalence is 100 per 100,000 white women and 400 per 100,000 black women. SLE is more common in blacks in the United States but is rare among blacks in Africa. Approximately 160,000 to 320,000 people in the United States are living with SLE.

Although the etiology of SLE remains unclear, genetic, hormonal, and environmental influences play a role in disease pathogenesis. It is postulated that an environmental exposure triggers the onset of disease in a genetically susceptible person. Evidence of a genetic component to SLE is derived from studies showing strong familial risk. The disease concordance rate of 24–58% for monozygotic twins in comparison to the concordance rate of 2–5% for dizygotic twins confirms this strong genetic component. Multiple genes have been associated with SLE, including the genes within the major histocompatibility complex and genes that encode components of the complement pathway, Fcγ receptors, protein tyrosine phosphatase non-receptor type 22 (PTPN22), programmed cell death 1 gene (PDCD1), and cytotoxic T lymphocyte associated antigen 4 (CTLA4). The reasons for female sex predilection remain murky. Some observational data suggest that sex hormones might contribute to disease onset. For example, data from the Nurses Health Study suggest that early age at menarche (relative risk 2.1), oral contraceptive use (relative risk 1.5), and use of postmenopausal hormones (relative risk 1.9) increases the risk of SLE. In addition, the risk of SLE in men with Klinefelter syndrome (47, XXY) is 14-fold higher than in healthy male controls. In contrast, large controlled trials have shown that combined oral contraceptives do not increase the risk of flares in women with stable SLE, and studies examining serum sex hormone levels in patients with lupus compared with patients in a control group have been inconclusive. Thus, whether hormonal factors or nonhormonal aspects of sex are most important in influencing disease risk remains to be determined.

Various environmental factors have been examined as potential triggers for the development of SLE. Smoking is a risk factor for SLE and has been associated with anti-dsDNA production in patients with SLE. Exposure to UV light exacerbates both cutaneous and internal organ manifestations of SLE, but there is no clear evidence to suggest that UV light triggers onset of the disease.

Several viruses have been investigated as possible triggering factors for SLE, although there is no conclusive evidence linking one pathogen to development of disease. The virus that has received the most attention in this regard is Epstein-Barr virus (EBV). Studies in pediatric and adult patients have demonstrated a higher seroprevalence of antibodies to EBV antigens and a higher EBV viral load in SLE patients versus controls. Molecular mimicry between EBV and self proteins is postulated to play a role in SLE pathogenesis.

There is increasing evidence that interferon α (IFNα) plays an important role in the pathogenesis of SLE. Approximately 50% of SLE patients overexpress IFNα inducible genes, and the degree of overexpression correlates with disease activity and severity. This pattern of gene expression is referred to as the “interferon α signature.” Studies have shown that plasmacytoid dendritic cells release IFNα after stimulation with immune complexes containing nucleic acid.

SLE is characterized by the production of a variety of autoantibodies to nuclear antigens (antinuclear antibodies [ANA]), cytoplasmic antigens, cell surface antigens, and soluble antigens in the circulation such as IgG and phospholipids. Subtypes of ANAs can be useful for establishing a diagnosis, detecting certain disease manifestations, and sometimes in monitoring the course of the disease. Antibodies to surface antigens on red blood cells and platelets can lead to autoimmune hemolytic anemia and immune-mediated thrombocytopenia, respectively. In the majority of SLE patients, the presence of autoantibodies predates the development of symptoms or signs of SLE, and patients accrue different autoantibodies up until the time of diagnosis. One study utilizing the Department of Defense Serum Repository demonstrated that ANA, anti-Ro/SSA antibodies, anti-La/SSB antibodies, and antiphospholipid antibodies were the first to appear and did so at a mean of 3.4 years prior to the diagnosis of SLE. Antibodies to double-stranded DNA (anti-dsDNA) appeared next at a mean of 2.2 years prior to diagnosis, and anti-Smith (anti-Sm) and anti-ribonucleoprotein (anti-RNP) were the last to appear at 1 year before diagnosis. This study also showed that the autoantibody profile at the time of SLE diagnosis remained relatively constant in the years after diagnosis.

Symptoms and Signs

Constitutional

Constitutional symptoms, such as fever, fatigue, and weight changes, are common in SLE. Not infrequently, fatigue is out of proportion to other disease manifestations. In these instances, it is important to consider other factors such as deconditioning, stress, and sleep disturbance. Fever, usually low-grade, can occur in active SLE, particularly with serositis. Infection, however, is always a concern when fever develops in a lupus patient, especially in the setting of immunosuppressive therapy.

Mucocutaneous

Four of the 11 American College of Rheumatology (ACR) classification criteria describe mucocutaneous manifestations, and approximately 80–90% of SLE patients will have mucocutaneous involvement at some point during the course of the disease (Tables 21–1 and 21–2). Photosensitivity, defined by the ACR as “skin rash as a result of unusual reaction to sunlight, by patient history, or physician observation,” occurs frequently. Patients may be sensitive to UV-A, UV-B, or visible light. Photoprovocation testing has shown that greater than 90% of lupus patients have an abnormal skin reaction to UV or visible light. SLE patients also have reported symptoms after exposure to sunlight through car glass windows and to light from fluorescent tubes and photocopiers. The majority of skin reactions occur more than 1 week after sun exposure and last for weeks to months. In addition to skin eruptions, some SLE patients report an exacerbation of systemic symptoms such as fatigue and arthralgias after sun exposure. Polymorphous light eruption and photosensitizing medications are additional diagnostic considerations when evaluating a SLE patient with a photosensitive rash. In contrast to SLE photosensitivity, polymorphous light eruption is characterized by an intensely pruritic papular, non-scarring rash developing hours after sun exposure and resolving after a few days. Polymorphous light eruption may occur in patients with known SLE.

Patchy or diffuse alopecia and thin, friable hair occur during active SLE flares but may also occur as a side effect of certain medications that are commonly used to treat SLE. Hair re-growth begins 6–8 weeks after disease quiescence or discontinuation of the offending drug. Permanent alopecia can occur following the development of scarring discoid lesions.

Nasal or oral ulcers, which are typically painless, commonly develop in SLE patients. This is in contrast to aphthous stomatitis which is usually painful. Lupus oral ulcers have a gradual onset and can occur anywhere on the oral mucosa. Most lesions present as erythema, petechiae, or ulcerations. They typically occur on the hard palate, buccal mucosa, and vermillion border, and are unilateral or asymmetric. Discoid lupus erythematosus (DLE) can also occur in the oral cavity and can be very painful. Oral candidiasis and oral lichen planus can resemble the oral ulcers of SLE.

Cutaneous lupus lesions are categorized as “lupus specific” versus “lupus nonspecific” based on the presence or absence of interface dermatitis on histopathology. Acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE), and chronic cutaneous lupus erythematosus (CCLE) are all considered to be lupus specific lesions. ACLE lesions can be localized or generalized. The localized form produces the classic malar or “butterfly” rash, which is characterized by sharply demarcated erythema on the cheeks and bridge of the nose, sparing the nasolabial folds (Plate 35). Induration and scaling may occur. The malar rash of SLE is sometimes confused with that of acne rosacea, seborrheic dermatitis, and flushing syndromes. Unlike SLE, rosacea is characterized by the predominance of telangiectasias and pustules that may sting and burn. Heat and alcohol intake worsen the erythema of rosacea. Seborrheic dermatitis is manifested by scaly erythematous plaques that occur on the eyebrows and the lateral sides of the nose. In contrast to the malar rash of SLE, seborrheic dermatitis is commonly found within the nasolabial folds. If the diagnosis remains unclear after clinical examination, biopsy of the rash can be helpful to distinguish SLE from these other dermatologic entities.

Generalized ACLE consists of maculopapular erythematosus lesions involving any area of the body in a photosensitive distribution. The dorsa of the hands and the extensor surfaces of the fingers are commonly involved. The erythema is typically found between the interphalangeal joints, which is in distinction to the Gottron papules of dermatomyositis, which occur over the joint. ACLE lesions heal without scarring, although post-inflammatory hyperpigmentation can be observed.

The rash of SCLE may be papulosquamous or annular and is believed to be the most photosensitive of all the lupus rashes. The scaly, erythematous papules are frequently located on the torso and limbs and spare the face. Neither scarring nor atrophy are present. Patients with such lesions often have anti-SSA/Ro antibody. Compared with other forms of cutaneous lupus, SCLE is more often induced by medications such as hydrochlorothiazide and terbinafine.

Discoid lupus is the most common subtype of CCLE. The term “discoid” refers to the disc shaped appearance of the lesions. Such lesions are raised, erythematous plaques with adherent scale occurring most commonly on the scalp, face, and neck (Plates 36, 37, and 38). There is usually an erythematous ring around the lesions, which denotes the active component (Plate 36). Over time, discoid lesions can lead to scarring and skin atrophy, resulting in permanent alopecia and disfigurement (Plates 37 and 38). DLE can also occur in the oral mucosa. Squamous cell carcinoma has been reported as a late sequela of DLE; thus, surveillance of known lesions and biopsy of changing or suspicions lesions is important.

Other subtypes of CCLE include hypertrophic lupus erythematosus and lupus panniculitis. Lupus panniculitis is a lobular panniculitis that has a predilection for the scalp, face, arms, buttocks, and thighs. When a cutaneous discoid lesion overlies the panniculitis, the entity is referred to as lupus profundus. Lupus panniculitis typically presents as a deep, firm nodule that can lead to cutaneous atrophy and rarely ulceration. Biopsy is often necessary to secure the diagnosis because there are reports of T cell lymphoma mimicking panniculitis. However, biopsy should be performed carefully because the lesions have tendency to break down. Lupus panniculitis is one of the few panniculitides that can occur above the waist.

Lupus nonspecific skin findings, such as bullous lesions, periungal erythema, chilblain lupus, and livedo reticularis, can also develop in SLE patients. Bullous lupus erythematosus is a rare cutaneous manifestation that presents as blistering skin lesions. SLE may also be associated with other bullous disorders such as bullous pemphigoid and dermatitis herpetiformis. The physical examination finding of periungal erythema represents dilatation of the capillaries at the base of the nail. These capillaries can be visualized at the bedside with a dermatoscope or ophthalmoscope. Other disorders associated with periungal erythema include scleroderma and mixed connective tissue disease. Unlike scleroderma and mixed connective tissue disease, SLE is not associated with capillary drop-out. Chilblain lupus is characterized by the presence of erythematous or violaceous macules or plaques (or both) on acral surfaces that worsen after exposure to a cold, humid weather. Livedo reticularis is characterized by an erythematous to violaceous reticular or net-like pattern of the skin. It is also highly associated with the antiphospholipid antibody syndrome.

Lymphadenopathy

Lymphadenopathy is a common feature of SLE and can be localized or diffuse. The lymph nodes are soft and nontender, and the cervical and axillary chains are most frequently involved. Biopsy reveals reactive hyperplasia. A change in the pattern of a patient’s lymphadenopathy or unusually enlarging or hard lymph nodes should prompt an evaluation for lymphoma, which has an increased incidence in SLE.

Musculoskeletal

Arthritis and arthralgias are noted in up to 95% of SLE patients at some time during the course of the illness and frequently involve the wrists and small joints of the hands. Swan-neck deformities and ligamental laxity are often noted. Unlike the joint findings in rheumatoid arthritis and mixed connective tissue disease, bony erosions rarely occur in SLE, and the swan-neck deformities are usually reducible (Jaccoud-like arthropathy).

Lupus Nephritis

Renal involvement is common in SLE and is a significant cause of morbidity and mortality. It is estimated that up to 90% of SLE patients have pathologic evidence of nephritis on biopsy, but clinically significant nephritis develops in only 50% of people with SLE. Lupus nephritis typically develops in the first 36 months of the disease, although there are exceptions. Immune complex glomerulonephritis is the most common form of SLE renal involvement, but tubulointerstitial disease and vascular disease may also be present. The clinical presentation of lupus nephritis is highly variable, ranging from asymptomatic hematuria or proteinuria (or both) to frank nephrotic syndrome to rapidly progressive glomerulonephritis with loss of renal function.