How is it diagnosed?

Diagnosis

Because many lupus symptoms mimic other illnesses, are sometimes vague and may come and go, lupus can be difficult to diagnose. Diagnosis is usually made by a careful review of a person's entire medical history coupled with an analysis of the results obtained in routine laboratory tests and some specialized tests related to immune status.

Currently, there is no single laboratory test that can determine whether a person has lupus or not. To assist the physician in the diagnosis of lupus, the American College of Rheumatology (ACR) in 1982 issued a list of 11 symptoms or signs that help distinguish lupus from other diseases. A person should have four or more of these symptoms to suspect lupus. The symptoms do not all have to occur at the same time.

The Eleven Criteria Used for the Diagnosis of Lupus

Criterion	Definition
Malar Rash	Rash over the cheeks
Discoid Rash	Red raised patches
Photosensitivity	Reaction to sunlight, resulting in the development of or increase in skin rash
Oral Ulcers	Ulcers in the nose or mouth, usually painless
Arthritis	Nonerosive arthritis involving two or more peripheral joints (arthritis in which the bones around the joints do not become destroyed)
Serositis	Pleuritis or pericarditis (inflammation of the lining of the lung or heart)
Renal Disorder	Excessive protein in the urine (greater than 0.5 gm/day or 3+ on test sticks) and/or cellular casts (abnormal elements the urine, derived from red and/or white cells and/or kidney tubule cells)
Neurologic Disorder	Seizures (convulsions) and/or psychosis in the absence of drugs or metabolic disturbances which are known to cause such effects
Hematologic Disorder	Hemolytic anemia or leukopenia (white blood count below 4,000 cells per cubic millimeter) or lymphopenia (less than 1,500 lymphocytes per cubic millimeter) or thrombocytopenia (less than 100,000 platelets per cubic millimeter). The leukopenia and lymphopenia must be detected on two or more occasions. The thrombocytopenia must be detected in the absence of drugs known to induce it.
Antinuclear Antibody	Positive test for antinuclear antibodies (ANA) in the absence of drugs known to induce it.
Immunologic Disorder	Positive anti-double stranded anti-DNA test, positive anti-Sm test, positive antiphospholipid antibody such as anticardiolipin, or false positive syphilis test (VDRL).

Adapted from: Tan, E.M., et. al. The 1982 Revised Criteria for the Classification of SLE. Arth Rheum 25: 1271-1277.

Laboratory Tests

Symptoms, Signs and Tests

Because many symptoms of systemic lupus erythematosus (SLE) mimic those of other illnesses, lupus can be a difficult disease to diagnose. Diagnosis is usually made by a careful review of three factors:

the individual's entire medical history
an analysis of the results obtained in routine laboratory tests and
some specialized tests related to immune status.

To make a diagnosis of SLE, an individual must show clinical evidence of a multi-system disease (i.e. has shown abnormalities in several different organ systems). Typical symptoms or signs that might lead to suspicion of SLE are:

Skin:Butterfly rash across the cheeks; ulcers in the mouth; hair loss.

Joints:Pain; redness, swelling.

Kidney: Abnormal urinalysis suggesting kidney disease.

Lining membranes:Pleurisy (inflammation of the lining of the lung); pericarditis (inflammation of the heart lining); and/or peritonitis (inflammation around the abdomen). Taken together, these types of inflammation are known as polyserositis.

Blood:Hemolytic anemia (the red cells are destroyed by autoantibodies); leukopenia (low white blood cell count); thrombocytopenia (low number of platelets).

Lungs:Infiltrates (shadowy areas seen on a chest x-ray) that come and go

Nervous system:Convulsions (seizures); psychosis; nerve abnormalities that cause strange sensations or alter muscular control or strength.

If an individual has several of these symptoms, the physician will then usually order a series of tests to examine how well the individual's immune system is functioning. In general, physicians look for evidence of autoantibodies. Although there is no one test that can definitely say whether or not a person has lupus, there are many laboratory tests which aid the physician in making a lupus diagnosis.

Routine clinical tests which suggest that the person has an active systemic disease include:

sedimentation rate (ESR) and CRP (C-reactive protein) binding, both of which are frequently elevated in inflammation from any cause
serum protein electrophoresis which may reveal increased gammaglobulin and decreased albumin
routine blood counts which may reveal anemia and low platelet and white cell counts
routine chemistry panels which may reveal
- kidney involvement by increases in serum blood urea nitrogen and creatinine
- abnormalities of liver function tests
- increased muscle enzymes (such as CPK) if muscle involvement is present.

These kinds of abnormalities alert the doctor to the presence of a systemic disease with multiple organ involvement.

Commonly used blood tests in the diagnosis of SLE are:

Anti-nuclear antibody test (ANA) to determine if autoantibodies to cell nuclei are present in the blood
Anti-DNA antibody test to determine if there are antibodies to the genetic material in the cell
Anti-Sm antibody test to determine if there are antibodies to Sm, which is a ribonucleoprotein found in the cell nucleus
Serum (blood) complement test to examine the total level of a group of proteins which can be consumed in immune reactions
Complement proteins C3 and C4 test to examine specific levels

The Antinuclear Antibody (ANA or FANA) Test

Positive ANA

The immunofluorescent antinuclear antibody (ANA or FANA) test is positive in almost all individuals with systemic lupus (97 percent), and is the most sensitive diagnostic test currently available for confirming the diagnosis of systemic lupus when accompanied by typical clinical findings. When three or more typical clinical features are present, such as skin, joint, kidney, pleural, pericardial, hematological, or central nervous system findings as described above, a positive ANA test confirms the diagnosis of systemic lupus.

However, a positive ANA test, by itself, is not proof of lupus since the test may also be positive in:

1: other connective tissue diseases, such as:

scleroderma
Sjogren's syndrome
rheumatoid arthritis
thyroid disease
liver disease
juvenile arthritis

2: individuals being treated with certain drugs, including:

procainamide
hydralazine
isoniazid
chlorpromazine

3: viral illnesses, such as:

infectious mononucleosis

4: other chronic infectious diseases, such as:

hepatitis
lepromatous leprosy
subacute bacterial endocarditis
malaria

5: other autoimmune diseases, including:

thyroiditis
multiple sclerosis

6: as many as 30-40 percent of asymptomatic first-degree relatives of people with lupus (siblings, parents, and children).

Weakly positive ANA

The test can even be weakly positive in about 20 percent of healthy individuals. While a few of these healthy people may eventually develop lupus symptoms, the majority will never develop any signs of lupus or related conditions. The chances of a person having a positive ANA test increases as he or she ages.

Negative ANA

A negative ANA test is strong evidence against lupus as the cause of a person's illness, although there are very infrequent instances where SLE is present without detectable antinuclear antibodies. ANA-negative lupus can be found in people who have anti-Ro (SSA) or antiphospholipid antibodies.

ANA Titers and Patterns

ANA laboratory reports include a titer (pronounced TY-tur) and a pattern.

The titer indicates how many times the lab technician had to dilute plasma from the blood to get a sample free of the antinuclear antibodies.
- For example, a titer of 1:640 shows a greater concentration of anti-nuclear antibodies than a titer of 1:320 or 1:160.

The apparent great difference between various titers can be misleading.
- Since each dilution involves doubling the amount of test fluid, it is not surprising that titer numbers increase rather rapidly.
- In actuality, the difference between a 1:160 titer and a 1:320 titer is only a single dilution. This does not necessarily represent a major difference in disease activity.
- ANA titers go up and down during the course of the disease, and a high or low titer does not necessarily mean the disease is more or less active.
- Therefore, it is not always possible to determine the activity of the disease from the ANA titer.
- A titer above 1:80 is usually considered positive.
- Some laboratories may interpret different titer levels as positive, so one cannot compare titers from different laboratories.

The pattern of the ANA test can sometimes be helpful in determining which autoimmune disease is present and which treatment program is appropriate.
- The homogeneous, or smooth pattern is found in a variety of connective tissue diseases, as well as in people taking particular drugs, such as certain antiarrhythmics, anticonvulsants or antihypertensives.
- This homogenous pattern is also the one most commonly seen in healthy individuals who have positive ANA tests.
- The speckled pattern is found in SLE and other connective tissue diseases
- The peripheral, or rim pattern is found almost exclusively in SLE.
- The nucleolar pattern, with a few large spots, is found primarily in people who have scleroderma.

Because the ANA is positive in so many conditions, the results of the ANA test have to be interpreted in light of the person's medical history, as well as his or her clinical symptoms. Thus, a positive ANA alone is never enough to diagnose lupus.On the other hand, a negative ANA argues against lupus but does not rule out the disease completely.

A Positive ANA Does Not Equate to Having a Disease

The ANA should be looked at as a screening test. If it is positive in a person who is not feeling well and who has other symptoms or signs of lupus, the physician will probably want to conduct further tests for lupus.

If the ANA is positive in a person who is feeling well and in whom there are no other signs of lupus, it can be ignored. If there is any doubt, a consultation with a rheumatologist should clarify the situation.

Other Autoantibodies

In those individuals with a positive ANA, additional tests can be done for certain particular antibodies that may better establish a diagnosis of SLE. The knowledge of which particular antibody is responsible for the positive ANA test can sometimes be helpful in determining which autoimmune disease is present.

Antibodies to DNA (the protein that makes up the body's genetic code) are found primarily in SLE.
Antibodies to histones (DNA packaging proteins) are usually found in people with drug-induced lupus (DIL), but may also be found in those with SLE.
Antibodies to the Sm antigen are found almost exclusively in lupus, and often help to confirm the diagnosis of SLE.
Antibodies to RNP (ribonucleoprotein) are found in a number of connective tissue diseases. When present in very high levels, RNP antibodies are suggestive of mixed connective tissue disease (MCTD), a condition with symptoms like those of SLE, polymyositis, and scleroderma.
Antibodies to Ro/SS-A are found in people with either lupus or Sjogren's syndrome, and are almost always found in babies who are born with neonatal lupus.
Antibodies to Jo-1 are associated with polymyositis.
Antibodies to PM-Scl are associated with certain cases of polymyositis that also have features of scleroderma.
Antibodies to Scl-70 are found in people with a generalized form of scleroderma.
Antibodies to the centromere (a structure involved in cell division) are found in people with a limited form of scleroderma which tends to have a chronic course.

Complement

Laboratory tests which measure complement levels in the blood may also be helpful to the physician in making a diagnosis of SLE.

Complement is a blood protein that destroys bacteria and also influences inflammation.
Complement proteins are identified by the letter "C" and a number.
The most common complement tests are C3, C4, and CH50.

If the total blood complement level is low, or the C3 or C4 complement values are low and the person also has a positive ANA, some weight is added to the diagnosis of lupus. Low C3 and C4 complement levels in individuals with a positive ANA may signify the presence of active disease, especially kidney disease.

Biopsy

Sometimes examination of a tissue sample (biopsy) can be helpful in making a diagnosis. The biopsy is one of the best ways to evaluate an organ or tissue. The procedure involves removal of a small sliver of tissue, which is then examined under a microscope.

The doctor can use the biopsy to identify the amount of inflammation and damage to the tissue.
Further tests can be performed on the specimen to determine whether the problem is due to lupus or is caused by some other factor such as infection or medication.
Almost any tissue can be biopsied. The most common sites biopsied in lupus are the skin and kidney.
The results of the biopsy, like any other laboratory test, should be examined in combination with the individual's medical history and clinical findings.

Tests to Assess Disease Activity

When a person diagnosed with lupus develops new or recurring symptoms, laboratory testing of blood or urine can help determine if the symptoms are due to an increase in lupus activity.

Disease activity correlates with a rise in:

CRP (C-reactive protein) binding
ESR, or sedimentation rate
Anti-DNA
Liver and kidney function tests (AST, ALT, BUN, creatinine)
CPK (muscle enzyme)
Urine protein or cellular casts

Disease activity also correlates with a fall in:

CBC or complete blood count (white blood cell count, hemoglobin, platelets)
Complement components
Serum albumin

Putting It All Together

The interpretation of all these tests, and their relationship to symptoms, can be difficult. When a person has many symptoms and signs of lupus and has positive tests for lupus, it is easier for physicians to make a correct diagnosis and begin treatment. However it is more common for an individual to report vague, seemingly unrelated symptoms of achy joints, fever, fatigue, or pain, and to have negative or borderline test results.

Fortunately, with growing awareness of SLE, an increasing number of physicians will consider the possibility of lupus in the diagnosis. While these tests are useful only when their strengths and limitations are understood, in the hands of skilled physicians these are important tools that assist in diagnosing lupus.