Understanding Laboratory Tests and Results for Lupus (SLE)

Patients with suspected or confirmed Systemic Lupus Erythematosus (SLE) undergo laboratory tests for multiple reasons. Physicians and other health care professionals test patients periodically and will use the information derived from the tests in various ways.

Uses for laboratory tests

• To diagnose: Physicians want to know that medical history, physical examination and laboratory findings are consistent and that they confirm the diagnosis. Lupus symptoms often mimic those of other diseases and vice versa. Healthcare providers want to verify that what they see is lupus and not another disease.
• To determine prognosis: Physicians want to understand how a patient’s disease will progress. Laboratory tests are used to establish baseline at the time of diagnosis and to predict whether lupus is likely to improve or worsen.
• To monitor: Laboratory tests help assess the severity of the disease, the efficacy of treatment, medication-related side effects, especially those of blood counts, liver and kidneys.
• To guide therapy: Laboratory test results are used to help make treatment recommendations and to adjust for changing symptoms.

Standard laboratory tests for SLE

Antinuclear antibody (ANA) autoantibodies, or antibodies produced by the immune system that attack the body’s own cells, are a hallmark of lupus. ANA is a screening test, since almost all patients with lupus have a strongly positive test. ANA is measured in how strongly it is positive, usually measured as 0 to 4+ or as a titer (the number of times a blood sample can be diluted and still be positive). ANA of 0, 1+ or 2+, or titers less than 1:80 (diluted 80 times) are usually unimportant.

A positive ANA does not by itself diagnose lupus since about 10% of normal people and many people with other autoimmune diseases, such as thyroid disease, also have positive tests, but usually less strongly positive. Once positive, an ANA mostly stays positive, so need not be repeated.

Many laboratories also measure pattern or the way the test looks when viewed through a microscope. Different types of ANA patterns may indicate different characteristics of lupus. These include:

• Homogenous (the entire nucleus of cell is seen, like  a full moon)—a very common pattern, not specific for a particular specific illness, but usual in lupus.
• Peripheral or rim (only the outline of the nucleus is seen, like a halo)—not common, almost always indicates lupus
• Speckled (tiny dots throughout the nucleus)—a common pattern, not specific, but often indicating anti-Sm or anti-RNP antibodies (see below) found in lupus or mixed connective tissue disease
• Nucleolar/centromere (only two very bright dots in the nucleus)—an uncommon pattern most often associated with scleroderma, but also found in persons who are fully well.

Test results that identify and confirm diagnosis

Anti-double-stranded DNA (dsDNA)

Anti-double-stranded DNA (dsDNA), in high titer, is nearly specific to lupus. It is usually associated with a homogeneous or peripheral ANA pattern. The antibody is named for its ability to bind to the normal DNA in patients’ cells. Patients with this antibody who do not have SLE usually have a similar illness, such as rheumatoid arthritis. Sometimes the test is positive in otherwise well family members of lupus patients. About 80% of SLE patients with active, untreated disease have positive tests. Monitoring anti-dsDNA is important since levels usually vary with disease activity, high titers indicating active disease, low titers quiescent disease. Laboratories vary in how they report the test. Some  do so as 0-4+ (3+ and 4+ are high), others as numbers, which vary with the test. To know which is high you have to know the range used by the laboratory.

A diagnosis of lupus is based on symptoms, physical examination abnormalities, and laboratory tests; not all patients with SLE have anti-dsDNA. Anti-single-stranded DNA [ssDNA] is sometimes also measured. It is non-specific and gives no useful information to a physician. Patients who do not have anti-dsDNA usually have a related antibody, anti-Sm.

Anti-Sm

Anti-Sm (anti-Smith, named for the first patient known to have this antibody) is associated with a speckled ANA pattern and is the antibody seen in most patients who do not have anti-dsDNA. Some patients have both anti-dsDNA and anti-Sm. Anti-Sm antibody binds to a protein that is attached to DNA. Unlike anti-dsDNA, the Sm antibody does not change in titer during the flare or treatment so need not be monitored.

Anti-RNP

Anti-RNP (anti-U1 ribonucleoprotein) is a non-specific antibody, associated with a speckled pattern that occurs in many patients with SLE and other rheumatic diseases. When present in high titer—again, check how the laboratory reports its values to interpret the test--without other autoantibodies anti-RNP suggests a specific lupus-like disease, called mixed connective tissue disease (MCTD), characterized by lupus, scleroderma, and dermatomyositis-like symptoms, that include:

• Puffy hands or other scleroderma-like features
• Raynaud’s phenomenon (fingers and toes have poor circulation and become numb and pale in response to cold temperatures or stress)
• Pulmonary hypertension (high blood pressure that affects the arteries in the lungs and the right side of the heart
• Rashes
• Muscle inflammation and weakness
• MCTD patients, unlike those with SLE, have low risk for developing kidney disease

Anti-Ro/SSA and anti-La/SSB

Anti-Ro/SSA and anti-La/SSB antibodies identify other molecules in the nucleus. Two different groups of researchers found these antibodies almost simultaneously. One named them anti-Ro and anti-La for the first letters of the names of the patients in whom they were found; the[MDL1]  other group named the antibodies SSA and SSB for Sjogrens syndrome A and B, since they are very characteristic of this illness.

These autoantibodies are associated with a speckled ANA. For technical reasons based on the size of the antigens (molecules to which the autoantibodies react), anti-Ro/SSA is subdivided into 60kd (kilodalton, the size of the molecule) and 52kd components, and La/SSB is 48kd, in doctors’ shorthand, 60, 52, and 48. Distinguishing among them is useful in some special circumstances.

Patients with these antibodies:

• May develop Sjogren’s syndrome, a related autoimmune disorder characterized by dry eyes, dry mouth and arthritis.
• Are more likely to suffer from sun-sensitive rashes.
• May have infants who develop neonatal lupus, a transient and generally benign rash and sometimes blood count abnormalities that lasts a few weeks, is not serious, and usually needs no treatment. This affects a minority of pregnant women or up to 20%, depending on some details.

Less than 2% of infants of antibody-positive women develop a serious heart condition (less than 2%), that must be treated. The heart condition occurs mostly in children of women who are strongly positive for all three 60, 52, and 48kd antibodies. For this reason fetuses of pregnant women with this antibody profile are closely monitored, usually with fetal electro- or echocardiograms, neither of which requires needles or other invasive procedure.

Antiphospholipid antibodies

Antiphospholipid antibodies (aPL) occur in about one-third of lupus patients; about 10% of lupus patients may have antiphospholipid syndrome (APS), which is characterized by recurring blood clots, pregnancy complications, and other features. Laboratory tests that identify aPL are:

• Lupus anticoagulant (LAC), a test for blood clotting (sometimes referred to by the specific test done, such as aPTT or dRVVT)
• Anticardiolipin (aCL), which has three subcomponents, lgG, lgA, lgM
• Anti-beta2glycoprotein 1 (aB2GP1), which has the same three subcomponents

The LAC is the most important of these antibodies.  Of the subcomponents of aCL and aB2GP1, IgG is the most important. As with other autoantibodies, strongly positive tests are much more important than are weakly positive ones. LAC may be reported as a ratio (1:3 is positive, 1:5 or 1:6 is strong positive) or as seconds need to form a clot, compared to normal done that day (if the normal is 28 seconds, 35 seconds and higher would be unequivocally positive and 60 seconds very strongly positive). For aCL and aB2GP1, using the standard international units, normal is usually16 or 20, equivocal 21-40, positive 41-80, and high positive >80.  Because a number of infections and injuries can cause transiently positive antibodies, diagnosis of antiphospholipid syndrome (APS) usually requires that the antibody be present for at least 12 weeks.

If aPL are found and the patient has no blood clots and is not pregnant, usually no treatment is necessary, though individual circumstances may suggest use of aspirin or hydroxychloroquine and sometimes other medications if risk of blood clot is high, for instance before a long airplane flight or surgery. If a patient has a blood clot or other signs of APS, anticoagulation (blood thinning) may be necessary, potentially life-long.

Additional testing for treating lupus

Complement level: C3, C4, and CH50

The complement system is a series of more than 15 proteins that assemble in domino fashion to destroy bacteria and viruses invading the body. The signal that initiates the domino cascade (called “activating” complement) is that an antibody meets an antigen (the bacterium or virus). Because lupus autoantibodies give the same signal and activate complement, measurement of complement can be used to monitor lupus. Because they give sufficient information, It usually suffices to measure only two of the complement proteins, called C3 and C4. CH50 measures all the complement proteins at once and occasionally gives additional information, but is a much more complicated test to do. In special circumstances other complement components can be measured.

Low C3 and C4 levels, below 60 for C3 and 15 for C4 (in the usual American measure), occur in active lupus, especially in the setting of kidney disease or immune breakdown of blood cells (autoimmune hemolytic anemia, AIHA). Some types of lupus, such as brain disease, do not cause low complement levels.

Low complement levels are not specific for lupus and may be seen in other immune illnesses and severe infections. About 10% of lupus patients are born with abnormal complement components, especially C4, so their tests are always abnormal. Appropriately interpreted, in context, C3 and C4 levels indicate the activity of the disease. In most patients, recovery from flare is indicated by return of complement levels to normal. In an apparently well patient who usually has a normal complement level a decrease may signal an impending flare and so a need for close follow-up.

Autoantibody panels

Several commercial laboratories have begun to sell panel tests that combine several of the above tests and sometimes add additional tests, such as complement bound to red blood cells, that they say give better information, more conveniently, than do standard tests. As of this writing there is no proof that these tests are beneficial. False positives are common. Since many tests do not need to be checked repeatedly, the cost of monitoring patients according to the panels is likely greater than that of selecting patient-specific tests, as most physicians now do.

Tests used to monitor lupus and general health

The tests below help to monitor disease activity and guide treatment. If the results are abnormal, further evaluation is likely needed to see if the disease or the treatment is causing problems.

Complete Blood Count (CBC)

CBC provides information about the red blood cell (RBC), white blood cell (WBC), and platelet counts, and health of RBCs, all of which may be abnormal in lupus and may need treatment. Common issues are:

• Low RBC (hematocrit, hemoglobin).  A normal hematocrit is 35-40%, hemoglobin 11.5-15.0. Low counts indicate anemia; common causes of anemia indicate active lupus, AIHA, bleeding, drug toxicity, and sometimes genetic abnormalities like thalassemia or sickle cell disease.
• Low WBC (leukopenia). Almost all untreated SLE patients have leukopenia—it is a clue to diagnosis. A normal count is 4,500-10,000. WBC protect against infection.  Abnormally low WBC can be due to lupus, drug toxicity, and certain infections. A mildly low count is not important except for the information it gives, but if it is below 2,000 the patient is at risk for infection.
• Low platelets (thrombocytopenia). This is also common in lupus. A normal count is 150,000-300,000.  Causes of low platelets can be lupus, medication, and other illnesses. Counts between 30,000 and 100,000 serve as an alert. Counts below 30,000 indicate that the patient is at risk for hemorrhage and should be treated.

Erythrocyte Sedimentation Rate (ESR)

ESR is an indirect indicator of inflammation. A high ESR, if there are no other reasons for it to be high, such as infection, suggests that lupus is active; a low test is reassuring. The test is simple and cheap but non-specific and subject to inaccuracy. Normal values are for women younger than 50 years old: 0-20 mm/hr, or >50 years: 0-30 mm/hr; for men <50, 0-15 mm/hr; >50 years: 0-20 mm/hr.

C-Reactive Protein (CRP)

CRP, like the ESR, is an indirect indication of inflammation, but is more specific in the detection of disease activity, since it is not affected by as many variables. Levels may be high in obese persons and in infection. A normal value is <1.0.

Confusingly, cardiologists use a measure called high-sensitivity CRP (hsCRP) to predict risk of heart disease. hsCRP is the same test, done differently, and performed in normal people without SLE or other illness. It is roughly 10 times more sensitive than is the standard CRP; its normal is <0.1. A result of 0.8, which might be abnormal in a normal person, is not of concern in one known to have SLE.

Complete metabolic panel (CMP) or biochemical profile (BCP)

There are several names for this panel, which looks at liver, kidney, endocrine, and other functions. Within the panel:

• Glucose is a measure for diabetes
• Sodium (Na), potassium (K), and chloride (Cl), creatinine (Cr) and blood urea nitrogen (BUN) levels measure mostly kidney function but other things as well
• Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (alkP), and bilirubin measure liver function.
• Lactic dehydrogenase (LDH) measures liver function and is often high in forms of illness in which damage to tissues occurs.

Urine with microscopy

Because lupus patients are prone to kidney disease, urine tests are ordered on a regular basis. Urine tests are evaluated for:

• pH—to determine if the urine is acidic (normal) or alkaline (suggests infection or problems in the way the kidney functions).
• Protein—the level should be 0 or trace. If protein is present, it may indicate kidney disease
• Protein/creatinine ratio—this is an add-on test to quantify the protein if the above is abnormal
• WBC—only a low number are normally present; a high WBC count in urine may indicate a urinary infection
• Blood—more than a very small number of RBC or a positive test for hemoglobin may indicate bladder or kidney disease or kidney stones (unless a woman has her menstrual period)
• Casts—uncommon, but suggesting more severe kidney disease
• Bacteria—indicative of infection if the specimen was properly collected

X-rays, ultrasounds, CT scans, MRI scans, angiograms, PET scans, BMD studies

It is beyond the scope of this article to discuss these tests in detail. Brief outlines follow:

• X-rays can see joints and bones and air in tissue, such as lungs and intestines. In lupus they are mostly used to check for pneumonia (chest) or bone damage due to osteoporosis or osteonecrosis. Sometimes a dye (contrast material) is given by injection or by mouth to get better detail. X-rays can be harmful to a fetus.
• Ultrasounds bounce echoes off tissues to see their structure. They are used to look at joints, the heart, fetuses inside a mother, the abdomen, and other organs. They are safe in pregnancy.
• CT (computerized tomography) scans are very powerful X-rays that show fine details of bones and joints and allow some visualization of soft tissues. CT scans are particularly used in the lung to look for infection, blood clot, or scar; the brain for stroke, injury, or tumor; the abdomen for tumor or abscess; and the extremities for bone abnormalities. They use X-rays and can be harmful to a fetus.
• MRI (magnetic resonance imaging) scans use magnetic fields rather than X-rays to show fine detail of every part of the body, particularly the brain and soft tissues of the extremities but other organs as well. They are safe to use in pregnancy. Special rules govern their use in people with metal implants, such as heart pacemakers or artificial joints.
• Angiograms are images of blood vessels obtained by injecting or swallowing a dye to show fine detail of blood vessels. They can be done by X-ray, CT, MRI, or ultrasound, depending on the specific situation and need.
• PET (positron emission tomography) measures local areas of high metabolic activity (how busy an organ is) by administering a radioactive substance then taking a picture to see how much the organ “lights up”. It is usually used to search for tumor or infection and sometimes for inflamed blood vessels or other tissue.
• BMD (bone mineral density) is used to measure how strong bones are, usually for osteoporosis.

In Summary

Ms. Richey ended her presentation by using case scenarios to demonstrate the many ways in which lab tests can be used in combination with other pertinent information to make a diagnosis of lupus. It is important to note that:

• Healthcare professionals will take into consideration the whole person when diagnosing and treating lupus. Diagnosis and treatment are based on physical examination, lab tests and other imaging studies.
• Each person’s lupus is unique, and that no two lupus patients are the same.
• Lab tests can help complete the puzzle of diagnosis, treatment and monitoring of the disease.
• Each lab test provides information about different components of lupus.
• Lab tests can also help doctors better understand the different characteristics of a patient’s lupus.
• Patients should communicate with their doctors and be sure to ask about their lab test results in order to gain a clearer picture of their disease.

Learn more information about the SLE Workshop at HSS, a free support and education group held monthly for people with lupus and their families and friends.

Updated: 7/18/2019

Authors

Monica Richey, MSN, ANP-BC/GNP
Nurse Coordinator, Mary Kirkland Center for Lupus Care
Nurse Coordinator, Cardiovascular Disease Prevention Program

Michael D. Lockshin, MD
Attending Rheumatologist, Hospital for Special Surgery
Director, Barbara Volcker Center for Women and Rheumatic Disease