LAB TESTS THAT SUPPORT

A SJOGREN'S DIAGNOSIS

Key Concepts

  1. No one 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.
     

  2. Sjogren’s manifestations often overlap with other connective tissue diseases (CTDs). In addition, Sjogren’s may co-occur with other CTDs. Rheumatologists need to look at many factors to determine the correct diagnosis, or if more than one CTD is present.
     

  3. Autoantibody titers and inflammatory markers such as CRP and ESR do not correlate with disease activity.

Initial Sjogren's Labs

  •  ANA, SSA, SSB, CCP, RF, ESR, CRP    (titers do not reflect disease severity)    

  •  CBC with diff and platelets, serum potassium, LFTs

  •  UA, Random urine protein/Cr

  •  HIV, HEP C       

  •  Minor salivary gland biopsy (MSGB)- if SSA  negative- Usually via rheumatology consult.

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

MSGB (“lip biopsy)-  see separate page.  MSGB is an important part of the Classification Criteria.

 

SSA (anti-Ro) is the blood test that is most helpful in supporting a diagnosis of Sjogren’s. It is present in 55-70% of Sjogren’s patients. SSA is also seen in other CTDs, especially lupus, and sometimes in healthy people (5, 6, 9).

SSB (anti-La)- Even though SSB is rarely present without SSA and no longer used in the 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 CTDs, especially lupus, and sometimes in healthy people (4, 5, 6, 9).

 

CCP (or ACPA) - Positive antibodies to CCPs in the presence of erosive arthritis is suggestive of RA.  However, these antibodies may be occasionally seen in Sjogren’s (3-10%) (5, 11), SLE and other CTDs. A rheumatologist’s expertise is needed for interpreting this test when a patient presents with ACPA along with clinical signs of Sjogren’s.

ANA (Anti-nuclear antibodies)-  Positive in 50-70 % of  Sjogren’s. ANA is positive in many other CTDs (5, 6, 9).  Some healthy people carry ANA, although often at lower titers (6). Infections, liver disease, and other conditions may also be associated with a positive ANA test. 

RF (Rheumatoid factor)- Positive in many CTDs, and 60-70% of Sjogren’s patients.  Also positive in many infections, and occasionally in healthy people (6). 

CRP and ESR- These classic markers of inflammation are often completely normal in Sjogren's, even though Sjogren's is a systemic inflammatory disease. There are many other markers of inflammation that do occur in Sjogren's, but it is not practical to measure them in most clinic settings.

A high CRP in Sjogren's should prompt an investigation for infection, other rheumatologic diseases, or other sources of inflammation. High ESR (“sed rate”) is fairly common in Sjogren’s. This is usually related to high antibody levels in the blood. ESR and CRP are not generally useful in assessing how active the disease is.

CBC with diff and platelets-  Cytopenias refer to low counts of various blood cell types. All together, 30-60 % of Sjogren's patients have one or more cytopenias (151, Ch. 6). Cytopenias are a systemic feature of Sjogren's. They are one of the twelve categories in the ESSDAI, a tool used by researchers to measure systemic activity. Cytopenias are usually mild and not associated with symptoms. Sometimes they are caused by medications. 
Cytopenias include low white blood cells (lymphopenia and neutropenia), low platelets (thrombocytopenia), and 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)

Serum Potassium-  Hypokalemia may indicate distal renal tubular acidosis, a kidney complication of Sjogren’s. (10)

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. UTI, irritable bladder and interstitial cystitis, however, are common due to chronic inflammation of the bladder wall (10, 11).

LFTs- May indicate liver and/or biliary tract disease. Liver enzymes are elevated in about 7%.(10, 13).

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.

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 SSA 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. SSA and SSB are members of the family of antibodies called anti-nuclear antibodies (ANAs). SSA is now used without SSB for Classification because patients who have SSB alone are unlikely to have Sjogren’s (4, 6). However, SSB positive/SSA 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 SSA. Some researchers and rheumatologists may include ANA, SSB, or RF along with SSA 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 SSA is a type of antinuclear antibody, it is logical to expect ANA to be positive every time SSA is positive. However, some patients will test positive for SSA 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... 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.”

 http://www.rheumatology.org/Portals/0/Files/Methodology%20of%20Testing%20Antinuclear%20Antibodies%20Position%20Statement.pdf

~ 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.”

https://www.hopkinslupus.org/lupus-tests/lupus-blood-tests/

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)

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)

"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 cytopenias 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)

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.

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).

PLEASE NOTE:  This page discusses laboratory tests in the context of diagnosis. There are many additional tests that are used for ongoing monitoring and care.   

Updated 3-20-21