Systemic Lupus Erythematosus (SLE)

At a Glance

Systemic lupus erythematosus (SLE) is an autoimmune multisystem disease that is characterized by the presence of several autoantibodies, formation of immune complexes (ICs), and inflammation in several organs.

SLE symptoms may develop slowly over months or years, or they may appear suddenly. They are widely based on the involvement of several organ systems. The most frequent symptoms are persistent fatigue, arthritis-like pain in one or more joints (but no or little joint damage), muscle pain, fever, skin rashes, sensitivity to ultraviolet light, hair loss, and inflammation and damage to organs and tissues (i.e., kidneys, lungs, heart, central nervous system, and blood vessels).

Nearly all SLE patients have mild to extreme fatigue. Even mild fatigue affects the ability to participate in daily activities and exercise. Increased fatigue can predict a symptom flare.

Joint pain, one of the most common symptoms, is often accompanied by redness and swelling. It occurs in about 90% of patients. The most frequently affected joints are fingers, wrists, elbows, knees, and ankles, often simultaneously on both sides of the body. The pain is rarely uniform; it improves during the day and then recurs. Morning stiffness may also be reported. The severity of the pain ranges from mild to severe.

Low-grade fever occurs in 90% of patients. It is usually caused by the inflammatory process of the disease, not by infection. It can flare up during an acute lupus crisis.

Skin inflammation and skin lesions can be seen in about 75% of patients. About half of these lesions are photosensitive (i.e., they worsen if exposed to sunlight). Typical findings in the skin include a butterfly-shaped rash across the cheeks and bridge of the nose and discoid lesions (coin-shaped, round, raised scaly formations that can lead to scarring). Inflammation of blood vessels in the skin causes red welts, small reddish spots on the skin or nail beds, and ulcers on mucous membranes. Some patients have only skin symptoms (discoid lupus). Hair loss is a frequent finding in SLE. Alopecia can be permanent because of follicle damage caused by skin lesions or transient if it occurs without skin rashes.

Nervous system disorders can develop as part of the disease. They include seizures, nerve paralysis, severe depression, psychosis, and stroke. The most common symptom is headaches, although others, such as thought and memory disturbances, personality changes, and numbness or weakness in arms and legs, can be present as well.

SLE also affects the heart and blood vessels. The inflammatory process can cause pericarditis, development of vegetations on heart valves (Libman-Sachs endocarditis), and vasculitis. Pericarditis can mimic a heart attack, as it presents with severe, sudden pain in the center of the left side of the chest that may spread to the neck, back, shoulders, or arms. Some patients with SLE develop Raynaud’s phenomenon. In affected individuals, cold or stress can cause spasms in the impaired blood vessels, resulting in pain in the fingers and toes. The affected skin feels numb, tingly, and cold to the touch.

Swelling of hands and feet indicates renal involvement, which can lead to nephritis.

SLE can cause inflammation of the pleural membranes of the lung and accumulation of fluid in the pleural space. This can lead to chest pain, shortness of breath, and cough and can be confused with pulmonary embolism and pneumonia.

About 50% of SLA patients have signs of hemolytic anemia, leukopenia, and thrombocytopenia. Although clotting problems in SLE typically lead to bleeding and bruising, some patients who develop antiphospholipid antibodies show evidence of thrombosis. Women with these antibodies can have a higher incidence of spontaneous miscarriages.

Other symptoms include dryness of the eyes and mouth (sicca syndrome), swollen lymph nodes, menstrual irregularities, sleep disorders like restless legs syndrome and sleep apnea, loss of appetite, nausea, and weight loss.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

There is no single test that can confirm or rule out SLE. Therefore, it is necessary to conduct a battery of tests to diagnose and monitor progression of the disease. Overall, there are three goals in laboratory testing:

confirm a diagnosis with clinical signs and symptoms suggestive of the disease, particularly in differentiating SLE from other rheumatologic diseases and determining the extent of the organ involvement

monitor the effectiveness of therapy

distinguish lupus subsets that have specific clinical implications

Testing for Autoantibodies

Antinuclear antibodies (ANAs) is a good screening test for SLA, since high levels of ANAs can be found in more than 98% of patients with SLA. However, there are other conditions that can cause high levels of ANA, so this test cannot be used in isolation for the diagnosis of SLE. An ANA titer of 1:40 or higher is considered positive. An ANA titer of less than 1:40 is useful for ruling out SLE in children (sensitivity of 98%). A repeated negative result makes a diagnosis of SLE unlikely but not impossible. The ANA titer does not correlate with the severity of the disease. The pattern of the ANA (homogenous (diffuse), speckled, peripheral (rim)) is generally not helpful, except for the peripheral pattern seen almost exclusively in SLE.

There are several ANA subtypes that can be found in SLE patients. These are anti-double stranded DNA (anti-ds DNA), anti-Smith (Anti-Sm), anti-Ro (also called anti-SSA), anti-La (also called anti-SSB), and anti-histone antibodies.

Anti-ds DNA antibodies can be found in 70% of SLE patients and are characteristic of active disease. High levels often indicate kidney involvement. Anti-ds DNA levels tend to fluctuate over time in correlation with disease activity and are good for monitoring SLA patients for signs of disease exacerbation.

Anti-ds DNA antibodies are usually found only in SLE and are present in 30-40% of patients. They are highly diagnostic of SLA but do not typically correlate with disease activity or clinical manifestations. Although many lupus patients may not have this antibody, its presence almost always indicates SLE.

Anti-Ro antibodies characterize several lupus subtypes, but they are not lupus-specific, as they are often found in patients with Sjogren’s syndrome. They are found in subacute cutaneous SLE, which is characterized by sun-sensitive rashes that do not result in scarring. They are also associated with neonatal lupus syndrome, in which maternal antibodies cross the placenta and cause photosensitive rashes and congenital heart block in affected babies. Therefore, all SLE female patients of child-bearing age should be screened for this antibody. Anti-La antibodies are usually associated with anti-Ro and linked with decreased risk for nephritis.

Anti-histone antibodies are found in 60% of all patients with SLA and in 90% of patients with drug-induced lupus.

Antiphospholipid antibodies increase the risk of thrombosis and are linked with miscarriages and other pregnancy complications, strokes, heart attacks, and blood clots in almost any part of the body. Antiphospholipid syndrome (APS) is characterized by the presence of these autoantibodies and a history of venous or arterial thrombosis or frequent miscarriage. This syndrome often occurs in SLE but can also develop independently. These antibodies cause the false VDRL test for syphilis, which is often seen in SLE.

Phospholipid antibodies can be detected by lupus anticoagulant (LA) testing and anticardiolipin antibody testing. L is a nonspecific clotting inhibitor. If an initial sensitive low phospholipid-based activated prothrombin time and/or dilute Russell venom viper test is prolonged, then mixing studies with normal plasma and correction studies with excess phospholipid confirm the existence of LA. Anticardiolipin testing is performed by the enzyme-linked immunosorbent assay. High titers of IgG anticardiolipin (>50 IU) indicate high risk of thrombosis.

SLE patients can develop other autoantibodies, including antibodies to ribonucleoprotein (RNP), antibodies to SR proteins, anti-erythrocyte antibodies, anti-platelet antibodies, anti-neuronal antibodies, and anti-ribosomal antibodies. Anti-neuronal antibodies should be tested in the CSF fluid. None of these antibodies are specific for SLA.

Additional Tests

Although the following tests are not specific of SLE, they can contribute to the diagnosis, assess the severity of the disease, and monitor the effects of treatment.

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are nonspecific markers of inflammation and are not usually elevated in SLE.

CBC can show signs of hemolytic anemia, leykopenia, and thrombocytopenia.

Urine testing (urinalysis and microscopy) is helpful in assessing kidney involvement. Presence of red cells and protein indicates active kidney inflammation in the absence of bladder and kidney infection.

In active lupus, liver enzymes ALT and AST can be elevated but will return to normal after treatment. In case of kidney involvement and reduction of kidney function, BUN and creatinine will be above normal values. Muscle enzymes (CPK) can be high because of muscle inflammation.

Other helpful tests include C3 and C4 complement component (elevated levels may be predictive for glomerulonephritis in SLE), rheumatoid factor (may be positive or negative), serum protein electrophoresis (show increased gamma globulins), cryoglobulins (frequently positive), and direct Comb’s test (frequently positive).

Follow-up Tests

In SLE patients with skin rashes, direct immunofluorescent testing performed on the skin biopsy often shows the presence of antibodies (IgG, IgM, and IgA), C3 complement, and/or fibrinogen deposited at the junction of dermis and epidermis (positive “lupus band test”). A confluent stain with all five proteins implies a greater than 99% probability of having SLE; if four proteins are present, a 95% probability; three proteins, an 86% probability; and two proteins, a 60% probability, provided that IgG is one of the proteins. These antibodies can also be found on uninvolved skin (sun-exposed and non-sun-exposed) and are much more likely to be present with active SLE then with inactive disease. The biopsy will not differentiate between systemic and discoid lupus, but it can rule out other diseases.

If chemistry testing indicates kidney involvement, kidney biopsy may be performed to determine the presence of lupus nephritis. It is not absolutely accurate, but it helps determine treatment. Electron microscopy may be especially important in obtaining critical information on the degree of kidney damage.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

A positive ANA result does not necessarily mean a patient has SLE, as most ANA-positive individuals do not have SLE. This finding is present in other connective tissue diseases, such as Sjogren’s syndrome, scleroderma, rheumatoid arthritis, and juvenile rheumatoid arthritis, as well as in fibromyalgia. ANA can also be found in healthy individuals. In these instances, the ANA titers are lower and have a different immunofluorescent pattern.

The prevalence of SLE in the population affects the rates of positive ANA tests. Populations with a low prevalence of the disease, such as primary care patients, have higher false-positive ANA rates at 1:40 dilution. Therefore, ANA titers should be obtained only in patients who meet specific clinical criteria. When ANA titers are measured, laboratories should report ANA levels at both 1:40 and 1:60 dilutions and should include the percentage of normal persons who are positive at each dilution. Data shows that 32% of the general population had ANA tests positive at 1:40 dilution and 5% at a 1:60 dilution.

Certain medications, such as hydralazine, isoniazid, procainamide, chlorpromazine, and some anticonvulsants, can cause a false-positive ANA test.

What Lab Results Are Absolutely Confirmatory?

There are no confirmatory laboratory results for SLE.

Although laboratory results are key in establishing the presence of 4 of the 11 diagnostic criteria of SLA–evidence of kidney disease (elevated BUN and creatinine, presence of red cells and proteins in urine), blood disorders (hemolytic anemia, leukopenia, thrombocytopenia), immunologic abnormalities (anti-DNA antibodies, lupus anticoagulant or falsely-positive test for syphilis), and presence of antinuclear antibodies–they are not usually sufficient to make the diagnosis of SLE.