The purpose of present paper is to critically address the recent advances on diagnostic procedures of Sjögren's syndrome, taking into account the attained local and systemic features of the disease.
A comprehensive review of the available literature regarding to the diagnostic approaches to Sjögren's syndrome was conducted. Eligible studies were identified by searching the electronic literature PubMed, Medline, Embase, and ScienceDirect databases for relevant reports (last search update January 2012) combining the MESH heading term "Sjögren's syndrome", with the words "diagnosis, diagnostic procedures, salivary gland function, ocular tests, histopathology, salivary gland imaging, serology". The authors checked the references of the selected articles to identify additional eligible publications and contacted the authors, if necessary.
Presented article addresses the established diagnostic criteria for Sjögren's syndrome and critically evaluates the most commonly used diagnostic procedures, presenting data from author's own clinical experience. Diagnostic criteria for Sjögren's syndrome are required both by healthcare professionals and patients, namely in order to provide a rational basis for the assessment of the symptoms, establish an individual disease prognosis, and orientate the therapeutic intervention.
Sjögren's syndrome is quite a common autoimmune disease of which the diagnosis and treatment are not easily established. Due to its systemic involvement, it can exhibit a wide range of clinical manifestations that contribute to confusion and delay in diagnosis. The use of proper diagnostic modalities will help to reduce the time to diagnosis and preserve the health and quality of life of patients with Sjögren's syndrome.
Sjögren's syndrome (SS) is quite a common autoimmune disease evidenced by broad
organ-specific and systemic manifestations. The most prevalent symptoms are
diminished lacrymal and salivary gland function, xerostomia and keratoconjunctivitis
sicca [
The purpose of present paper is to critically address the recent advances and own clinical opinion on diagnostic procedures of Sjögren's syndrome, taking into account the attained local and systemic features of the disease.
A comprehensive review of the available literature between 1970 and 2012, regarding to the diagnostic approaches to SS was conducted. Eligible studies were identified by searching the electronic literature PubMed, Medline, Embase, and ScienceDirect databases for relevant reports (last search update January 2012), combining the MESH heading term "Sjögren's syndrome", with the words "diagnosis, diagnostic procedures, salivary gland function, ocular tests, histopathology, salivary gland imaging, serology". The authors checked the references of the selected articles to identify additional eligible publications and contacted the authors, if necessary. Present article addresses the established diagnostic criteria for SS and critically evaluates the most commonly used diagnostic procedures. However, it is not possible to comprehensively discuss every subject, because that would require a text too extensive for a single article. When appropriate, references are cited.
The early and accurate establishment of a correct diagnosis of SS can assist on the prevention and timely treatment of many complications associated with the disease's natural course.
Although minor salivary gland biopsy has been traditionally considered "the gold
standard" for the diagnosis of SS, newer criteria have emerged to assist on this
disease identification. In 1993, the Preliminary European Classification criteria
for SS were proposed and have been widely used, both in research and in clinical
practice [
Revised international classification criteria for Sjögren's syndrome, by the American-European Consensus Group Criteria, 2002
Daily, persistent troublesome dry eyes for more than 3 months Recurrent sensation of sand or gravel in the eyes Use of tear substitutes more than 3 times per day |
Daily feeling of dry mouth for more than 3 months Recurrent or persistent swollen salivary glands, as an adult Need to drink liquids to aid swallowing dry food |
Schrimer's I test, performed without anesthesia (< 5 mm in 5 minutes) Rose Bengal score or other ocular dye score (> 4, according to van Bijstervald's scoring system) |
In minor salivary glands – biopsied from normal-appearing mucosa – focal lymphocytic sialoadenitis, evaluated by an expert histopathologist, with a focus score > 1 (defined as the number of lymphocytic foci containing more than 50 lymphocytes, adjacent to normal-appearing mucous acini, per 4 mm2 of glandular tissue |
Unstimulated whole salivary flow (< 1.5 ml in 15 minutes) Parotid sialography showing the presence of diffuse sialectasias Salivary scintigraphy showing delayed uptake, reduced concentration, and/or delayed excretion of tracer |
Antibodies to Ro (SSA) or La (SSB), or both, in the serum |
|
An alternative classification for diagnosing SS was proposed by a Japanese expert
group. This has been initially published in the late 1970's, and revised in 1999
[
Revised Japanese Criteria for Sjögren's syndrome, 1999
Focus score ≥ 1 (periductal lymphoid cell infiltration ≥ 50) in a 4 mm2 minor salivary gland biopsy Focus score ≥ 1 (periductal lymphoid cell infiltration ≥ 50) in a 4 mm2 lacrimal gland biopsy |
Abnormal findings in sialography ≥ Stage I (diffuse punctate shadows of less than 1mm) Decreased salivary secretion (flow rate ≤ 10 ml/10 min according to the chewing gum test or ≤ 2 g/2 min according to the Saxon test) and decreased salivary function according to salivary gland scintigraphy |
Schirmer's test ≤ 5 mm/5 min and Rose Bengal test ≥ 3 according to the van Bijsterveld score Schirmer's test ≤ 5 mm/5 min and positive fluorescein staining test |
Anti-Ro/SS-A antibody Anti-La/SS-B antibody |
Following, the major signs, symptoms and tests commonly used for the diagnosis of SS are presented and critically appraised.
Symptoms from the eyes (item I) and from the oral cavity (item II) are highly
regarded in the American-European Consensus Group Criteria for SS diagnosis. In
these criteria, by responding affirmatively to at least one of the three predefined
questions for the function of each exocrine gland, two items are readily checked
positive. This means that 2 out of 4 items, half of the requirements for the SS
criteria, are based on a subjective analysis difficult to translate into
quantifiable data. Nonetheless, it is routinely found that specific groups of
patients (for instance, children and adolescents, or individuals experiencing
chronic discomfort and distress) quite often deny having symptoms, nevertheless
objective tests for dysfunction of the assayed exocrine glands (item II and III)
give abnormal results [
The authors converge into a position more close to the one of the Japanese expert group, stating that the symptomatology should not be included into the classification criteria for SS diagnosis, but should be highly regarded in the complex treatment of SS.
The Schirmer test for the eye quantitatively measures tear formation via placement of
filter paper in the lower conjunctival sac [
In STI, the strip is placed in the lower fornix between the medial and lateral third
of the eyelid of the unanaesthetised eye. After 5 minutes, the amount of wetting is
measured from the extrafornical position of the strip [
STI test (A) and test results (B) revealing a significant reduction in lachrymal secretion.
Alternatively, positive ocular surface Rose Bengal or other ocular dye score, (i.e.,
fluorescein vital staining, lissamine green, etc.) can also be conducted. These
tests are most commonly used for the evaluation of ocular surface epithelial damage,
since these vital stains mark cells, on the surface of the eye, that are not fully
coated by the mucin layer of tear fluid and/or are damaged. The Rose Bengal score, a
quantified version of the original Rose Bengal test, is commonly used to quantify
the degree of staining [
The tear break up time (BUT) test aims to measure the quality of the tear fluid
[
Laser scanning confocal microscopy (LSCM) has been recently used as an efficient,
noninvasive,
According to the reported criteria for SS diagnosis, the Revised International Classification Criteria substantiates that of the various tests that can be performed, only one single abnormal result is sufficient for the objective evidence of lachrymal gland involvement. On the contrary, the Japanese expert group agreed on that at least two objective tests for determining lachrymal gland involvement should be conducted and report abnormal results. While the authors converge to the need of test validation, and thus the requirement of at least two abnormal test results to claim the affection of lachrymal glands, it is clear that the STI test has the great advantage that can be easily conducted within the dental office while other ocular tests require the assistance of a certified ophthalmologist.
Minor salivary gland biopsy remains a highly used diagnostic procedure for the salivary component of SS. This is usually performed on the internal face of the lower lip on normal-appearing mucosa. Under local anaesthesia an incision of around 1.5 to 2 cm is made between midline and the commissure, through the mucosa with penetration of the epithelium. With this procedure, usually 5 or more minor salivary glands are excised. The biopsy contributes towards the diagnosis of SS if the histopathological examination reveals a mononuclear infiltration with periductal or perivascular distribution. The inflammatory infiltrate is quantified and a cluster of ≥ 50 lymphocytes is termed a focus. The numbers of focus in an area of 4 mm2 of tissue surface render the focus score. A focus score ≥ 1, as according to both the Revised International Classification Criteria and the Japanese expert criteria, are considered positive for SS diagnosis.
As an example, salivary gland tissue from a patient with Sjögren's syndrome, with a
focus score greater than 4, is shown in
Labial salivary gland biopsy consistent with Sjögren's syndrome, showing multiple lymphocytic foci (black arrow) and intact acinar units (white arrow) (hematoxylin and eosin stain, original magnification x100).
Minor salivary gland lip biopsy results, nonetheless reporting a useful diagnostic
value in SS, should be carefully addressed in the overall diagnostic procedure due
to inconsistencies of sensitivity and specificity. A false negative result range
from around 20 to 40% and also positive biopsy results have been found up to 10% of
healthy individuals [
In a different approach, and apart from the diagnostic value, the performance of
lymphoid organization in the form of germinal centre-like lesions in labial salivary
gland biopsies, taken at SS diagnosis, was proposed as a highly predictive marker
for non-Hodgkin's lymphoma development - associated with a high risk of mortality in
pSS-affected individuals [
Alternative biopsy techniques have also been proposed on the assessment of pSS
diagnosis. In one study, parotid biopsy was shown to have a diagnostic potential
comparable with that of a labial biopsy and could further be associated with less
morbidity [
Sialometry aims to measure the saliva flow function, and can be conducted with whole
saliva, saliva obtained from a specific gland, both with or without stimulation.
Whole saliva tests are generally easier and more conveniently performed. For a
diagnosis of hyposalivation, the unstimulated whole saliva flow rate (UWSFR) has
been proposed as the test of choice, as it may be reduced, even if the stimulated
whole saliva is unaffected [
Stimulated saliva assessment can be complicated in patients who do not tolerate the stimulus of salivation and, moreover, due to the wide variety of used stimulus (i.e., citric acid, gum, paraffin etc.) there is a generalized lack of agreement for normal values. A flow rate inferior to 10 ml/10 minutes, in the chewing gum test, is considered positive in the Japanese criteria. Alternatively, these criteria refer to the Saxon test, in which a 10 x 10 gauze sponge should be weighted and used for saliva collection by vigorous chewing for 2 minutes. The amount of saliva produced is determined by subtracting the original weight from the weight obtained after chewing. In the Japanese criteria, a value inferior to 2 g/2 minutes is considered positive.
Collection of the stimulated parotid saliva, and subsequent assessment of the flow
rate, can be conducted with the requirement of special suction cups placed over the
Stensen duct. Stimulated saliva is usually collected for 3 minutes and values
inferior to 0.5 mL/min are considered abnormal [
The lower lip mucosa is dried for 5 min expecting the small saliva drops to occur.
The width of the drop less than 1mm is considered to show hipofunction. This test is
easy to perform, but still needs more investigation to be included in SS
classification criteria instead of lower lip biopsy [
Several authors also highlight to the variation found in sensitivity and specificity
(ranging from around 45 to 82%, and from 60 to 92%, respectively) of sialometry in
SS diagnosis [
Nonetheless, it is the authors' inkling that salivary flow should be routinely performed, not only as part of SS diagnosis, but also as part of patient monitoring.
This study requires the radiographic imaging of a salivary gland (usually the parotid), following the retrograde injection of a contrast medium through the excretory duct. The medium is distributed through the duct system, allowing the analysis of the architecture and configuration of the glandular ducts' organization. In SS-affected patients it can be verified a dilatation and twisting of the ducts, with an uneven distribution of the contrast medium, broadly originating the appearance of a branching pattern of the ducts. A positive result in the sialographic study is part of both the Revised International Classification criteria and Japanese criteria for the SS diagnosis.
Sialography may be technically challenging, time-consuming, painful and risky. In
fact it is contraindicated in severe gland dysfunction due to the risk of
indefinitely retaining the contrast medium [
A sialography of a SS-affected patient (Stage 3) 5 minutes following the injection of
the contrast medium is reported in
Sialographic imaging of the parotid gland (Stage 3, according the Rubin and Holt classification). A = frontal view; B = lateral view. Note the dilated main duct and the sparse overall branching pattern of the ducts.
The scintigraphy is a non-invasive method to evaluate the function of salivary glands by addressing the uptake and secretion of a radioactive labelled substance (sodium pertechnate of 99mTc). Additionally, an abnormal salivary gland scintigraphy result is accepted by the American - European consensus group as a criterion for the diagnosis of Sjögren's syndrome. Normally, a rapid uptake and increased concentration of the radioactive probe is attained in the salivary glands (it can normally be seen within 10 minutes following intravenous administration). After 20-30 minutes, the substance is rapidly secreted into the mouth. Salivary flow may be stimulated with the use of a sialogogue (e.g., diluted lemon juice) administered to the dorsal tongue. Time-activity curves are calculated using manually drawn oval regions-of-interest around both the parotid and the submandibular glands. In Sjögren's syndrome, lower concentration and less secretion into the mouth are seen. The test reports a high sensitivity but a low specificity in SS diagnosis.
Scintigraphy data results are expressed as quantitative values, which are transformed
to semi qualitative indices. But generally in practice qualitative and
observer-dependent classification is used to present the results and to search for
clinical correlations. Schall's categorical classification is usually considered the
standard method for salivary scintigraphy interpretation, though subjective and with
limited capacity to discriminate borderline results [
However, this technique needs special equipment and staff that can only be found in reference clinical centers. Further, it may be unacceptable for the patient due to risk of radiation damage and high cost.
A scintigraphic study of the salivary glands of an SS-affected patient is shown in
Scintigraphic study of the salivary glands (class IV, according to the Schall's classification). The right parotid gland is encircled in red, the left parotid gland is encircled in green, the right submandibular gland is encircled in blue and the left submandibular gland is encircled in yellow. Time-activity curves are presented on the right and each colour corresponds to the previously encircled glands, respectively. Note the severe functional affection with a significant reduction in the uptake of the radioactive probe and absence of the discharge phase, even after the stimulation with a sialogogue (red line at 9 minutes).
MR imaging (MRI), MR sialography and US are noninvasive methodologies that allow the
imaging of salivary glands in their physiological state without artefacts induced by
intraductal contrast media or biopsy procedures. Further, these imaging modalities
allow a reduction in the inconveniences and risk of complications to the patient
[
MR imaging was shown to provide a reliable imaging procedure to evaluate glandular
alterations. It allows multiplanar evaluation and processes a high contrast tissue
resolution. Characteristically, in SS, MRI reveals an inhomogeneous internal pattern
on both T1 and T2 sequences, with multiple hypo- and hyper-intense nodules of
different sizes [
MR sialography has largely replaced conventional sialography in the latter years and
can produce sialographic images similar to those of conventional sialography without
the use of contrast media or radiation. The underlying principles are set on the use
of a protocol that uses a heavily T2-weighted, fat-suppressed pulse sequence and
rapid acquisition with relaxation enhancement [
Salivary ultrasonography (US) is a noninvasive and low cost imaging technique that
has been recently used in the diagnosis and staging of SS. US is more effective on
the parotid gland and less helpful in the assessment of other salivary glands.
Moreover, it is a technique highly operator-dependent [
An US of the parotid and submandibular glands is shown in
Gray-scale (A) and a power Doppler (B) US images showing advanced-stage Sjögren's syndrome in salivary glands. The gland has an inhomogeneous structure with multiple small, oval, hypoechoic areas (arrowheads) and increased blood flow. The position of the US probe is shown in the inset diagram. A = imaging of the right parotid gland; B = imaging of the left submandibular gland.
The authors come together to the relevance of the available noninvasive imaging modalities in the assessment of salivary gland involvement in SS, despite the acknowledgement that comparative large-scale multicenter studies should be conducted to confirm the relation between diagnostic value and cost-effectiveness in SS.
Sialochemistry involves the analysis of salivary composition, both including organic
and inorganic constituents, by means of different biochemical, electrophoretic and
immunological analytical methods. They aim to address the injuries submitted to
salivary glands regarding secretion content. Various parameters have been evaluated
and the salivary protein profile of SS is a mixture of increased inflammatory
proteins and decreased acinar proteins when compared to healthy controls [
Patients affected by SS usually present a wide range of serologic and laboratory
findings, ranging from cytopenias (e.g., anaemia, leukopenia, thrombocytopenia),
hypergammaglobulinemias (usually of the IgG class, and more rarely of the IgA and
IgM classes), high erythrocyte sedimentation rate and C-protein levels, and
autoantibodies [
Positive autoantibodies are one the attained classification criteria for SS in both
the Revised International Classification and the Japanese Revised criteria, being
the only analytical data included. The 1993 European Criteria include the presence
of one or more of ANAs, rheumatoid factor (RF), Ro/SS-A, and/or La/SS-B, while the
2002 Criteria include only anti-Ro/SS-A and/or anti-La/SS-B antibodies. ANAs are the
most frequently detected auto-antibodies in pSS and are closely associated with
various extraglandular and analytical SS features [
Despite the relevance of ANAs and RF, the most widely used biomarkers of SS are still
serum IgG autoantibodies against two nuclear proteins, Ro-52/SSA and La/SSB. In
clinical setting, these antibodies are measured in serum for diagnostic purpose. IgG
anti-La/SSB antibodies represent the major serum antibody class, whereas IgA and IgM
are rarely detected. IgG antibodies, rarely IgA, are also detected in saliva from
patients with SS. As for anti-Ro/SSA, IgG remains to be the main class while IgA and
IgM classes have not been identified [
Several studies have also found that patient with hypocomplementemia and
cryoglobulins at diagnosis were shown to possess a higher risk of developing
vasculitis and B-cell lymphoma during follow-up, and that the presence of these
markers reported to be a key prognostic value in patient survival [
Sjögren's syndrome is a common autoimmune disease of which the diagnosis and treatment are frequently delayed. Due to its systemic involvement, it can exhibit a wide range of clinical manifestations that contribute to confusion and delay in diagnosis. An increased awareness of SS and its many and varied manifestations encourages a more expansive approach to diagnosing this disease. The use of recently refined criteria for diagnosis can assist in identifying patients with SS early. Particularly, due to the fact that there is no simple and validated test for SS diagnosis and the need for an easy, low-cost and straightforward test for the assessment of the oral component of SS, is still highly demanded. The use of all available diagnostic modalities will help to reduce the time to diagnosis and preserve the health and quality of life of patients with SS.
The authors declare that they have no conflict of interests.