Promoting optimal care for Sjogren's, a common, serious, systemic disease.
LAB TESTS THAT SUPPORT
A SJOGREN'S DIAGNOSIS
Key Concepts
There is no single test that can be used to monitor Sjogren's:​ rheumatologists must consider many systems in the body to assess how a patient is doing.
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No single test diagnoses Sjogren’s early and accurately. Sjogren’s is a clinical diagnosis that is supported by, but cannot be ruled out by, diagnostic tests.
Sjogren’s manifestations often overlap with other autoimmune rheumatic diseases (AIRDs) such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). These are often referred to as connective tissue diseases (CTDs). CTD is a broad term that can also describe non-rheumatic disease; AIRD is less confusing. Sjogren’s may co-occur with other AIRDs. Rheumatologists need to look at many factors to determine the correct diagnosis, or if more than one AIRD is present.
Autoantibody titers and inflammatory markers such as CRP and ESR do not correlate with overall disease activity or damage in Sjogren's.
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See the Myths About Sjogren's page to learn more about common that get in the way of diagnosis.
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Note: This page discusses laboratory tests in the context of diagnosis. There are many additional tests that are used for ongoing monitoring and care.
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Initial Sjogren's Labs
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ANA, SSA, SSB, CCP, RF, ESR, CRP (titers do not reflect disease severity)
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CBC with differential and platelets, serum potassium, LFTs
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UA, Random urine protein/Cr
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HIV, HEP C
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If SSA negative, minor salivary gland biopsy (MSGB), usually via rheumatology consult.
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Note: I consulted with several Sjogren’s experts when I developed this list of initial labs for PCPs. These tests may vary depending on the medical institution/ rheumatologist the PCP is working with.
Description Of Individual Labs Used For Diagnosis
The "lip biopsy" aka minor salivary gland biopsy (MSGB)
This is discussed on a separate page. The MSGB is an important part of the Sjogren's classification criteria.
SSA (anti-Ro antibodies) is the blood test that is most helpful in supporting a diagnosis of Sjogren’s. More formally, it is called anti-SSA, but referred to as SSA. It is present in 50-70% of Sjogren’s patients. SSA is also seen in other AIRDs, especially SLE, and sometimes in healthy people (5, 6, 9). SSA is one type of ANA.
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SSB (anti-La) - SSB, formally, anti-SSB, is usually (with exceptions) present only when SSA is present. For that reason, SSB is no longer used in the Sjogren's classification criteria.
Rheumatologists often like to see this test prior to referral because it may be associated with organ involvement and certain cardiac arrhythmias.
SSB is present in about 40% of Sjogren’s patients. Like SSA, SSB may be seen in other AIRD, especially SLE, and sometimes in healthy people (4, 5, 6, 9).
SSB and SSA are types of ANA, although about 10% of Sjogren's patients with SSA have a negative ANA test.
ANA (Anti-Nuclear Antibodies) - Positive in 50-80 % of Sjogren’s. ANA is positive in many other CTDs (5, 6, 9). Some healthy people carry ANA, although usually at lower titers such as 1:80 or 1:160 (6). Infections, liver disease, and other conditions may also be associated with a positive ANA test. Higher titers ae more likely to be associated with autoimmunity but may be caused by other conditions such as infections, malignancies (cancer) or certain medications.
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CCP (anti-citrullinated peptide, a subset of ACPA, anti-citrullinated protein antibodies) - Positive antibodies to CCP in the presence of erosive arthritis is suggestive of RA. However, these autoantibodies may be occasionally seen in Sjogren’s (3-10%) (5, 11), SLE, and other AIRDs. A rheumatologist’s expertise is needed for interpreting this test when a patient presents CCP/ACPA along with clinical signs of Sjogren’s.
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RF (Rheumatoid factor) - Positive in many AIRDs and in 60-70% of Sjogren’s patients. Also positive in many infections, and occasionally in healthy people (6).
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CRP and ESR - These classic markers of inflammation are often completely normal in Sjogren's, even though Sjogren's is a systemic inflammatory disease. Inflammation can be detected by other inflammatory markers in Sjogren's but these are not standard tests that are readily available in the clinic setting.
Practical Tips
ESR and CRP are not generally useful to assess how active or severe Sjogren's is.
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A high CRP in Sjogren's should prompt an investigation for infection, other rheumatologic diseases, or other sources of inflammation. However, CRP may be elevated in patients with vasculitis, a systemic manifestation which occurs in about 10% of Sjogren's patients.
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A high ESR (“sed rate”) is usually related to high antibody levels in the blood, not overall inflammation or disease activity (151, p. 121).
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CBC with diff and platelets - Cytopenia refer to low counts of various blood cell types. All together, 30-60% of Sjogren's patients have one or more cytopenia (151, Ch. 6). Cytopenia is a systemic feature of Sjogren's.
Any patient with cytopenia has systemic disease. It is one of the 12 major categories of the twelve categories in the ESSDAI, a research tool used to measure systemic activity.
Most cytopenia is mild and asymptomatic. Cytopenia can sometimes be caused by medications.
TYPES OF CYTOPENIA
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Low white blood cells (lymphopenia and neutropenia)
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Low platelets (thrombocytopenia)
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Low red blood cells (anemia)
This type of anemia is called anemia of chronic disease. It is not the same as iron deficiency anemia, although the two may occur together. Severe thrombocytopenia or autoimmune hemolytic anemia are uncommon, but do require management by a hematologist when they occur (10).
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Serum Potassium - Hypokalemia may indicate distal renal tubular acidosis, a kidney complication of Sjogren’s (10).
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UA, random urine protein and creatinine - Mild proteinuria is common in Sjogren’s, but usually occurs without symptoms. About 5% of Sjogren’s patients have clinically significant kidney disease. Many more will have mild distal renal tubular acidosis. Urinary tract infections, irritable bladder and interstitial cystitis, however, are common due to chronic inflammation of the bladder wall (10, 11).
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LFTs - May indicate liver and/or biliary tract disease. Liver enzymes are elevated in about 7%.(10, 13).
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HIV/ Hepatitis C - These infections often have symptoms that overlap with Sjogren’s, such as sicca and flu-like fatigue. It is important to rule these out early on.
What about the ENA panel?
"The ANA test evaluates the presence or absence of autoantibodies, while the ENA panel aims to determine to what proteins in the cell nucleus the autoantibodies recognize. If an ANA test is negative, then the person is extremely unlikely to test positive for a specific antinuclear antibody (which is what the ENA panel tests). In Sjogren's, SS-A sometimes occurs without a positive ANA."
FAQ About Autoantibody Tests
How do autoantibodies help diagnose Sjogren’s and other CTDs?
In many patients with CTDs, autoantibodies help clinicians distinguish between diseases that have overlapping manifestations. The relationship between autoantibodies and various diseases can be complicated. Many autoantibodies, including SSA, are associated with a number of diseases.
What role do antigen-antibody complexes have in the disease process?
Sjogren’s is considered to be an autoimmune disease. Antigen-antibody complexes have been found in damaged salivary and tear glands. However, the role that autoantibodies play in the disease process is not 100% clear. Many Sjogren’s patients do not carry SS-A or other known autoantibodies in the blood. Yet these “seronegative” patients also show tissue damage in MSGB specimens. It is possible that more than one disease process causes clinical Sjogren’s. It is increasingly thought that autoantibodies serve as useful biomarkers, but do not actually mediate the changes that lead to disease (166).
There appear to be subtypes of Sjogren’s patients with different types of biomarkers and possibly different underlying disease processes. Researchers are trying to uncover the complex immunologic, genetic, and cell biology changes that cause Sjogren’s.
What exactly are “Sjogren’s antibodies”?
SSA (anti-Ro) and SSB (anti-La) have been traditionally called Sjogren’s antibodies. This can be confusing because they may also be seen in other autoimmune rheumatic diseases. SS-A and SS-B are members of the family of antibodies called anti-nuclear antibodies (ANAs). SS-A is now used without SSB for Classification because patients who have SS-B alone are unlikely to have Sjogren’s (4, 6). However, SS-B positive/SS-A negative Sjogren's does occur on occasion, and may represent a subtype of the disease.
Among Sjogren's researchers and experts, the term “seropositive” usually refers to patients who are positive for SS-A. Some researchers and rheumatologists may include ANA, SS-B, or RF along with SS-A in their definition of seropositivity. Many primary care providers equate seropositive with positive RF. This can be very confusing!
Why are some people SS-A positive and ANA negative?
Because SS-A is a type of antinuclear antibody, it is logical to expect ANA to be positive every time SS-A is positive. However, some patients will test positive for SS-A and negative for ANA. This is usually a problem with the test itself, especially if the laboratory uses the less sensitive solid phase ANA.
Not All ANA Tests Are The Same
The cheap "qualitative", solid phase ANA is used by the vast majority of labs.
It only contains 8-10 autoantigens, while the IFA identifies over 100 and is, therefore, more sensitive.
The ACR has actually come out with a position paper about it:
“The ACR supports the immunofluorescence antinuclear antibody (ANA) test using Human Epithelial type 2 (HEp-2) substrate, as the gold standard for ANA testing.”
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~ Personal Communication from, Donald E. Thomas, Jr., M.D., FACP, FACR, RhMSUS, CCD, Author of "The Lupus Encyclopedia"
What are ANA staining patterns?
“The pattern of the ANA test can give information about the type of autoimmune disease present and the appropriate treatment program. A homogenous (diffuse) pattern appears as total nuclear fluorescence and is common in people with systemic lupus. A peripheral pattern indicates that fluorescence occurs at the edges of the nucleus in a shaggy appearance; this pattern is almost exclusive to systemic lupus. A speckled pattern is also found in lupus. Another pattern, known as a nucleolar pattern, is common in people with scleroderma.”
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Sjogren’s more typically has a speckled pattern, although this is not specific to Sjogren’s.
Do titers of ANA and SSA correlate with disease severity or activity? Should these tests be used to follow the disease?
No and no! With rare exceptions, there is no need to repeat these tests for diagnosis once a positive SSA is obtained. Sometimes SSA and ANA may be repeated by a rheumatologist for reasons other than diagnosis. Titers of SSA and or ANA going up and down do not reflect disease severity. (6)
SS-A, SS-B, and ANA are used for diagnosis, not for monitoring. See this article to learn why repeated tests are not generally recommended.
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No single test can tell you "how sick you are".
At this time, there is no test that measures overall disease activity in Sjogren’s. ESSDAI and ESSPRI are research tools for measuring disease activity, although they are rarely used in the clinic setting.(10)
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"In a patient who has Sjögren’s syndrome with SSA (Ro) and/or SSB (La) antibodies, the levels of these antibodies do not correlate with disease activity. In fact, these levels remain fairly constant in a given patient." ~ Alan Baer, MD, October 2012 The Moisture Seekers
Other tests that can support a Sjogren's diagnosis
There are many other tests that can help point to a Sjogren’s diagnosis. Laboratory markers, such as cytopenia and hypergammaglobulinemia (elevated IgG) are common in Sjogren’s. Rheumatologists often consider these as part of the big clinical picture that suggests a Sjogren’s diagnosis. (3)
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There are tests that help determine risk for organ system involvement or lymphoma. This will be discussed in more detail in other sections.
New Diagnostic Tests
New biomarkers are being investigated, including PSP (parotid secretory protein), CA-6 (carbonic anhydrase VI) various tear proteins (9, 15) and others. At this time these tests do not appear to be more sensitive in diagnosing Sjogren’s. These tests and others are in the early stages of investigation.
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Salivary Gland Ultrasound may eventually replace MSGB, which is invasive and has been shown to produce false positive and false negative results. However, the focus score and presence of germinal centers in MSGB may correlate with disease characteristics, making the test useful for uncovering certain high risk populations (3, 14, 16).
Updated 08-31-2023