Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that is associated with autoantibody production and complement-fixing immune complex deposition. The immune system attack triggers an inflammatory process, resulting in tissue damage. SLE is the prototype of an autoimmune disease that can cause a wide spectrum of clinical presentations and is characterized by remissions and exacerbation. Periods of active illness are sometimes called flares. The course of the disease is unpredictable but can sometimes be triggered by environmental factors, such as ultraviolet light and certain drugs. Although the cause of SLE is not yet fully elucidated, there are known to be a variety of genes that make individuals susceptible to the disease and to its flares. SLE can affect skin, joints, kidneys, lungs, heart, blood vessels, liver, and the nervous system. The disease occurs nine times more often in women than in men, especially in the childbearing years between the ages of 15 and 45 years. The disease can also be found in pediatric and geriatric populations. The prevalence in the general population is approximately 1 in every 2000 persons, but it varies according to race, ethnicity, and socioeconomic background.

The American College of Rheumatology formulated a set of clinical and laboratory findings known as the classification criteria of SLE in 1985 and subsequently revised them in 1997 (Table 160.1). The classification criteria were designed for investigators recruiting SLE patients into clinical trials, but many clinicians also commonly use them in practice to establish a diagnosis in a given patient.

Table 160.1

The 1997 Revised Criteria for the Classification of Systemic Lupus Erythematosus

Criterion	Definition
1. Malar rash	Fixed malar erythema, flat or raised
2. Discoid rash	Erythematous raised patches with keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
3. Photosensitivity	Skin rash as an unusual reaction to sunlight, by patient history or physician observation
4. Oral ulcers	Oral or nasopharyngeal ulcers, usually painless, observed by physician
5. Arthritis	Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion
6. Serositis	a. Pleuritis (convincing history of pleuritic pain or rub heard by physician or evidence of pleural effusion) or b. Pericarditis (documented by electrocardiogram, rub, or evidence of pericardial effusion)
7. Renal disorder	a. Persistent proteinuria (> 0.5 g/day or > 3 +) or b. Cellular casts of any type
8. Neurologic disorder	a. Seizures (in the absence of other causes) or b. Psychosis (in the absence of other causes)
9. Hematologic disorder	a. Hemolytic anemia or b. Leukopenia (< 4000/μL on two or more occasions) or c. Lymphopenia (< 1500/μL on two or more occasions) or d. Thrombocytopenia (< 100,000/μL in the absence of offending drugs)
10. Immunologic disorder	a. Anti–double-stranded DNA or b. Anti-Sm or c. Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of immunoglobulin G or M anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test
11. Antinuclear antibody	An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any time and in the absence of drugs known to be associated with “drug-induced lupus syndrome”
For identifying patients in clinical studies, a person shall be said to have SLE if any 4 or more of the 11 criteria are present, either serially or simultaneously, during any interval of observation.

From Hochberg MG. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus [letter]. Arthritis Rheum 1997;40:1725.

Symptoms

SLE can cause a variety of symptoms ranging from mild to severe. Patients can present with constitutional symptoms and organ-specific symptoms. Constitutional symptoms include fever, weight loss, and fatigue, which are typically present at some time during the course of the disease in most SLE patients. Mucocutaneous manifestations are important, as shown by the fact that they account for 4 of the 11 classification criteria (see Table 160.1). Skin lesions can be burning, tender, or itching. Rashes such as the classic malar (butterfly) rash and discoid lesions are characteristic. Patients may experience photosensitivity after a period of sun exposure. Photosensitivity is clinically defined as an abnormal response to ultraviolet light. These responses are manifested as exaggerated sunburn reactions and are often associated with systemic symptoms including fever, weakness, fatigue, and joint pain. Photosensitivity seems to correlate strongly with the presence of Ro/SSA antibodies [1]. Oral ulcerations are common and may be painless or asymptomatic. They are commonly on the hard palate and usually indicate active disease. The location and often asymptomatic nature of lupus-related oral ulcerations help differentiate them from non-lupus ulcerations, including aphthous stomatitis, lichen planus, herpes simplex, and drug-related lesions such as thrush due to corticosteroids and mucositis due to methotrexate. Nasal ulcers can also be found during disease activity and are often painful.

Patients may note thin hair, alopecia, or bald spots. Diffuse alopecia is nonspecific and can be caused by many systemic illnesses as well as by drugs such as cyclophosphamide and steroids. Focal bald spots, known as alopecia areata, are almost always due to autoimmune reactions and are characteristic of SLE. Painful red eyes from episcleritis, scleritis, or uveitis can be seen in SLE patients. Visual loss can occur in SLE patients with retinitis, vasculitis, optic neuritis, or thrombosis due to the antiphospholipid antibody syndrome. Some SLE patients experience sicca symptoms of dry eyes and dry mouth due to secondary Sjögren syndrome.

Patients may present with pleuritic chest pain related to serositis or pulmonary embolism. In addition, SLE patients have a very high incidence of premature atherosclerosis, and myocardial infarctions and strokes are not uncommon in young women with SLE. The authors have seen such events in a number of women in their late teens and 20s.

Epigastric pain in SLE patients can be due to nonsteroidal anti-inflammatory drugs, but the differential diagnosis must include pancreatitis, a life-threatening complication of SLE or of drugs used to treat it, such as azathioprine.

Patients presenting with dependent edema must be evaluated for lupus nephritis, which can cause the nephrotic syndrome. In the case of unilateral leg swelling, deep venous thrombosis needs to be ruled out. The hypercoagulable state in SLE patients is often associated with the antiphospholipid antibody syndrome. Antiphospholipid antibodies, including the lupus anticoagulant, are seen in approximately one fourth of SLE patients. Many remain asymptomatic, but the antibodies are associated with a number of clinical manifestations, including deep venous thrombosis and pulmonary embolism, arterial clots, recurrent spontaneous abortions, and strokes.

Articular symptoms are almost universal in SLE patients. Typical joint involvement in SLE affects the small joints of the hands as well as the wrists, feet, and knees. The joint symptoms are inflammatory in nature; therefore, they tend to be worse in the morning and are often accompanied by generalized stiffness. Patients generally experience significant joint pain out of proportion to objective physical findings. In patients who have received high doses of corticosteroids, avascular necrosis (osteonecrosis) needs to be in the differential diagnosis of severe joint pain, especially in the hips, knees, and shoulders. Raynaud phenomenon is an additional risk factor for this complication in SLE.

Raynaud phenomenon occurs in at least a third of SLE patients and may be the presenting manifestation. Raynaud phenomenon is caused by episodic vasospasm and ischemia of the extremities in response to cold or emotional stimuli. Typical color change is triphasic from white to blue to red, but many patients do not go through all three phases. Instead, they may just have periods of blanching followed by a return to normal color. In severe cases, digital ulcers may occur and can lead to shortening of the distal phalanx.

Neurologic symptoms, including headaches, numbness, tingling, and weakness, can vary from mild to severe. Strokes are found at an increased incidence in SLE because of both the accelerated atherosclerosis mentioned before and the hypercoagulable state due to associated antiphospholipid antibodies. SLE can also affect the spinal cord with rapidly progressive transverse myelitis, a consideration in any patient with lower extremity neurologic symptoms plus bladder or bowel incontinence.

Proximal muscle weakness involving the upper arms and thighs can be seen in SLE patients as a result of concomitant inflammatory muscle disease. SLE patients are also at risk for steroid myopathy, which is typically much worse in the proximal lower extremities. Patients with myopathy generally present with significant muscle weakness rather than with muscle pain. They have difficulty in using their arms for over-the-shoulder tasks and difficulty in getting up from a chair or a low position as well as using stairs.

Physical Examination

A thorough physical examination is important in evaluating SLE patients, given the nature of their multisystem involvement (Table 160.2). Articular manifestations can present as painful, nonerosive symmetric synovitis. Patients who have had repeated bouts of arthritis in their hands can also develop Jaccoud arthropathy, which is clinically characterized by reversible joint deformities including swan-neck changes, thumb subluxations, ulnar deviation, and boutonnière and hallux valgus deformities along with an absence of articular erosions on plain radiographs (Fig. 160.1). In general, its prevalence is around 5% to 10%.

Table 160.2

Organ Involvement in Systemic Lupus Erythematosus

Mucocutaneous	Facial rashes including malar or butterfly rash, discoid rash, alopecia, photosensitivity, oral ulcerations
Musculoskeletal	Joint pain with or without swelling, morning stiffness, Jaccoud arthropathy, muscle weakness, muscle aches and pain, osteonecrosis
Serosal	Pleuritis, pericarditis, peritonitis
Cardiovascular	Myocarditis, sterile endocarditis Premature atherosclerosis Raynaud phenomenon, digital ulcers
Pulmonary	Pulmonary hypertension, interstitial lung disease, diffuse alveolar hemorrhage, shrinking lung syndrome, pulmonary embolism
Hematologic	Leukopenia, anemia, thrombocytopenia
Renal	Nephritis, nephrotic syndrome
Neuropsychiatric	Headaches, seizures, stroke, peripheral neuropathy, cranial neuropathy, transverse myelitis, psychosis, cognitive dysfunction