Approach Considerations
Some laboratory tests can be used to assess salivary and lacrimal involvement in Sjögren syndrome. However, no single test is sufficiently sensitive or specific in the diagnosis of Sjögren syndrome. The condition is properly diagnosed only when the results of various tests are simultaneously positive and when subjective symptoms and serologic abnormalities are present. [66]
Laboratory test results may indicate the following:
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Elevated erythrocyte sedimentation rate (ESR)
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Anemia
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Leukopenia
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Eosinophilia
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Hypergammaglobulinemia
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Presence of antinuclear antibodies (ANAs), especially anti-Ro and anti-La
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Presence of rheumatoid factor (RF)
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Presence of anti–alpha-fodrin antibody (reliable diagnostic marker of juvenile Sjögren syndrome)
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Creatinine clearance may be diminished in up to 50% of patients
Multiple autoantibodies are associated with Sjögren syndrome. [67] In a study in which atypical autoantibodies were evaluated in 82 patients with primary Sjögren syndrome, an immunologic overlap (defined by the presence of autoantibodies typical of other systemic autoimmune diseases) was evident in 20% of the patients. The clinical significance of these atypical autoantibodies varied widely. [68]
Patients with primary Sjögren syndrome may have positive test results for lupus anticoagulant and/or anticardiolipin antibodies, and some patients develop clinical events (ie, fetal wastage, arterial and/or venous thrombosis) associated with antiphospholipid syndrome. Anti ̶ salivary duct antibodies are present in most cases of secondary Sjögren syndrome.
Type II cryoglobulins are noted, particularly in patients with palpable and nonpalpable vasculitic purpura. Hepatitis C should be sought in these patients.
In some studies, patients with Sjögren syndrome have an increased frequency of autoimmune thyroid disease with hypothyroidism (10-15%). Lymphocytic i)nfiltration can be observed in the thyroid gland.
Elevations of serum immunoglobulin G4 (IgG4), found in IgG4-related plasmacytic disease (which can mimic the glandular infiltrations of Sjögren syndrome), are not seen in Sjögren syndrome. [69, 70]
Antibodies to carbonic anhydrase 11 can be seen in patients with Sjögren syndrome who have primary billiary cirrhosis. [63]
Schirmer test
The Schirmer test is probably the only test available in the emergency department (ED) that can be used to strongly support or refute suspicion of Sjögren syndrome. A test strip of number 41 Whatman filter paper is placed near the lower conjunctival sac to measure tear formation. Healthy persons wet 15 mm or more of the paper after 5 minutes. A positive test occurs when less than 5 mm of the strip is wet after 5 minutes. A Schirmer test is shown in the image below.
Photograph that demonstrates the Schirmer test, which is used to detect deficient tear production in patients with Sjögren syndrome. The filter paper strip is placed at the junction of the eyelid margins. After 5 minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. Persons older than 40 years may moisten between 10 mm and 15 mm. Patients with Sjögren syndrome have less moistening. Sjögren syndrome is most common in patients with rheumatoid arthritis but may also occur without associated disease and in systemic lupus erythematosus, polyarteritis, systemic sclerosis, lymphoma, and sarcoidosis. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Rheumatoid factor
RF is present in 52% of patients with primary Sjögren syndrome and in 98% of patients with the secondary disease, occurring even when rheumatoid arthritis is not present. Consider a diagnosis of rheumatoid arthritis if the patient has symmetrical polyarticular synovitis.
The presence of RF has been independently associated with elevated risk for lymphoma in patients with primary Sjögren syndrome. [71] However, loss of a previously positive RF finding can be observed in some patients with Sjögren syndrome who develop lymphoma.
Antinuclear antibodies
ANAs are typically present in patients with Sjögren syndrome. Consider the diagnosis of systemic lupus erythematosus (SLE) in patients with ANAs only if symptoms and signs typical of SLE are present.
Serum protein electrophoresis
Patients with Sjögren syndrome often have a polyclonal gammopathy. Loss of a previously detected polyclonal gammopathy can be observed in some patients with Sjögren syndrome who develop lymphoma. Development of a monoclonal gammopathy can also signal the development of a lymphoma.
Staining
Rose bengal is an aniline dye that stains epithelial surfaces with diminished mucin protection or with exposed epithelial cell membranes. Conjunctival staining can be detected with the naked eye. Slit-lamp examination is performed after rose bengal staining to detect abnormal uptake in the cornea.
Lissamine green staining works similarly but is less irritating to the eye. Fluorescein staining can be used to detect corneal damage.
Salivary testing
Sialometry is a good measure of the degree of decreased salivary flow and helps to establish xerostomia, but the findings do not narrow the differential diagnoses.
Saliva from patients with Sjögren syndrome has elevated levels of sodium, chloride, lactoferrin, and IgA, but these findings are not specific.
Sedimentation rate
The ESR is elevated in 80% of patients with Sjögren syndrome, but the finding is nonspecific.
Protein profiling
Protein profiling (tear proteomics) has revealed reproducible patterns in patients with primary Sjögren syndrome and appears to hold promise as a diagnostic test for this disorder. [72]
Additional test considerations
Other test results to consider are as follows:
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High total protein level or a low albumin level - Should prompt the clinician to perform serum protein electrophoresis
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High alkaline phosphatase level - Should prompt consideration of primary biliary cirrhosis
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Elevated transaminase levels - Consider the possibility of chronic active hepatitis, which can be associated with sicca symptoms, or hepatitis C, which can cause mild salivary gland enlargement; however, mild (< 2-fold) increases in transaminase levels have been observed in 22% of patients with Sjögren syndrome [73]
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Low bicarbonate level - Consider evaluating patients with a low bicarbonate level for type I (distal) renal tubular acidosis; less commonly, patients can also develop proximal renal tubular acidosis with Fanconi syndrome
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Hypokalemia - This condition, which is occasionally severe enough to lead to periodic paralysis, can be observed in patients with type I renal tubular acidosis; however, it can also be observed in patients who have Sjögren syndrome without renal tubular acidosis [49]
SSA and SSB
Antibodies against SSA/Ro are found in approximately 50% of patients with the disease (75% of patients with primary Sjögren syndrome and 15% of patients with secondary Sjögren syndrome). Thus, the absence of anti-SSA/Ro antibodies does not eliminate the diagnosis of primary or secondary Sjögren syndrome.
Anti-Ro is a polyclonal antibody directed against nuclear and nucleolar RNA binding protein of 60KD or cytoplasmic protein of 52KD (E3 ubiquitin ligase). Patients can have a negative ANA and a positive Ro antibody test if they only have anti-Ro against cytoplasmic protein of 52KD.
Anti-La is an oligoclonal antibody that is predominantly directed against nuclear 47KD RNA binding protein.
Antibodies against SSA/Ro are present in 50% of patients with SLE and are sometimes found in healthy individuals. Thus, the presence of antibody against SSA/Ro cannot by itself be used to establish a diagnosis of Sjögren syndrome.
Antibodies against SSB/La are present in 40-50% of patients with primary Sjögren syndrome and in 15% of patients with SLE. Finding antibodies against SSB/La in patients without antibodies against SSA/Ro is unusual, but this combination has occurred in patients with primary biliary cirrhosis and autoimmune hepatitis.
Titers of anti-SSA/Ro and anti-SSB/La antibodies do not reflect disease activity. Current enzyme-linked immunosorbent assay (ELISA) tests for these antibodies are more sensitive than previous tests. Thus, the specificity is lower.
Antibodies against SSA/Ro are also associated with the annular erythematous lesions of subacute cutaneous lupus. They are also found in the mothers of newborns with neonatal lupus syndromes and congenital heart block, and some of these mothers have or will develop Sjögren syndrome.
Complete Blood Count
In patients with Sjögren syndrome, the complete blood count (CBC) is most often within the reference range, but anemia of chronic disease may be present. Pernicious anemia may be associated with the atrophic gastritis.
An abnormal white blood cell (WBC) count, especially with an abnormal differential count, should prompt concerns for a lymphoreticular malignancy. In addition, although a low platelet or WBC count can occur in persons with primary Sjögren syndrome, the finding should also prompt consideration for coexisting SLE.
A mild, normochromic, normocytic anemia is present in 50% of patients. Leukopenia occurs in up to 42% of patients.
Sialography and Scintigraphy
In sialography, radiopaque material is injected into the salivary glands. Sialography is useful to exclude the presence of obstructions or strictures, but the diffuse sialectasis of Sjögren syndrome is seen in various other diseases and is therefore not specific.
Oil-based contrast medium may not be adequately cleared in patients with Sjögren syndrome and, consequently, may damage adjacent tissues and lead to a chronic granulomatous reaction. Performing this procedure with oil-based contrast should be avoided, especially during episodes of acute swelling.
With salivary scintigraphy, the uptake and secretion of sodium pertechnetate technetium-99m (99m Tc) is a gauge of the salivary flow rates and can provide an objective measurement of salivary gland dysfunction. However, the finding of low flow rates is not specific to Sjögren syndrome.
Positive findings on either sialography or scintigraphy fulfill a criterion for objective evidence of Sjögren syndrome by the American-European Consensus Group. [3]
Biopsy
Minor salivary gland biopsy [74] currently is the best single test to establish a diagnosis of Sjögren syndrome. In this procedure, an incision is made on the inner lip, and some minor salivary glands are removed for examination. In patients with a possible diagnosis of this disease but with severe extraglandular symptoms, a lip biopsy is often performed to firmly establish the diagnosis of Sjögren syndrome. Obtaining the biopsy sample from below normal-appearing mucosa is important in order to avoid false-positive results. At least 4 salivary gland lobules should be obtained for analysis.
While this is the most definitive test, performing it is not absolutely necessary from a clinical standpoint. Patients with Sjögren syndrome are essentially treated symptomatically and are observed for the development of other rheumatic disorders or lymphoma. This can be initiated without performing a biopsy. If, however, the diagnosis is in doubt or if a definitive diagnosis is needed, then this is the best test.
Salivary gland biopsy can also help to detect pseudolymphoma or lymphoma, as well as the noncaseating granulomas of sarcoidosis.
One study showed that not all patients undergoing lip biopsy derived diagnostic benefit from this procedure and that clinical symptoms and serology did not predict a positive lip biopsy. [75]
In another study, however, a significant correlation was found between positive findings in minor salivary gland biopsy and the Schirmer test, the rose bengal test, xerostomia, and parotid swelling. The investigators utilized biopsy specimens from the lower lip of 360 patients. [76]
Histologic Findings
Although pathologists use different classification systems, the characteristic findings of minor salivary gland biopsy in a person with Sjögren syndrome include the following (see the image below) [77] :
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The biopsy shows focal aggregates of at least 50 lymphocytes, and, to a lesser extent, plasma cells and macrophages
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More than 1 focal aggregate is seen per 4 mm 2
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T cells, predominantly CD4 + cells, are present, unlike the predominance of CD8 + T cells seen in the salivary gland biopsy samples from patients with DILS associated with HIV disease
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Normal acini are replaced by lymphocytes
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Focal aggregates are seen in almost all glands
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Ten percent of the lymphocytes are CD5 + B cells that produce IgM and IgG antibodies, often with a monoclonal or oligoclonal pattern
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Large foci are present, possibly showing germinal centers
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Epimyoepithelial islands are uncommon in the minor salivary gland but can be seen in the major salivary glands
Photomicrograph of a lip biopsy specimen showing two lymphocytic foci adjacent to normal-appearing mucinous acini typical of minor salivary gland abnormalities in Sjögren syndrome. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
A score of greater than 1 focus per 4 mm2 has a specificity of 83.5-95% and a sensitivity of 63-81.8% in the diagnosis of Sjögren syndrome. The focus score may be associated with keratoconjunctivitis sicca, the presence of autoantibodies, and, less commonly, xerostomia.
Lymphocytic infiltrates are also seen in other organs. Findings from a gastric mucosal biopsy may show lymphocytic infiltrates with atrophic gastritis. A kidney biopsy may show interstitial lymphocytic infiltration. Lung biopsy can reveal infiltrating CD4+ T cells of a lymphocytic interstitial pneumonitis. Salivary gland biopsy can help to detect pseudolymphoma or lymphoma, as well as the noncaseating granulomas of sarcoidosis.
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Marked bilateral parotid gland enlargement in a patient with primary Sjögren syndrome. Sicca syndrome is a common clinical finding. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
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Clinical photograph and photomicrograph of a 48-year-old man with Sjögren syndrome with a large left parotid mass. On biopsy, B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type was identified. Microscopic section of parotid biopsy, stained with immunoperoxidase for kappa light chains (brown-stained cells), showed monoclonal population of B cells, confirming the diagnosis. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
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Photograph that demonstrates the Schirmer test, which is used to detect deficient tear production in patients with Sjögren syndrome. The filter paper strip is placed at the junction of the eyelid margins. After 5 minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. Persons older than 40 years may moisten between 10 mm and 15 mm. Patients with Sjögren syndrome have less moistening. Sjögren syndrome is most common in patients with rheumatoid arthritis but may also occur without associated disease and in systemic lupus erythematosus, polyarteritis, systemic sclerosis, lymphoma, and sarcoidosis. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
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Dryness of the mouth and tongue due to lack of salivary secretion is characteristic of xerostomia associated with Sjögren syndrome. Mouth dryness may produce a deep red tongue, as shown here, and dental caries are common. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
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Photomicrograph of a lip biopsy specimen showing two lymphocytic foci adjacent to normal-appearing mucinous acini typical of minor salivary gland abnormalities in Sjögren syndrome. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
