The usefulness of ultrasound in the diagnostics of Sjögren's syndrome.

Sjögren's syndrome is an autoimmune exocrinopathy which manifests itself with dryness of the eyes and the oral cavity. These symptoms comprise a so-called sicca syndrome (xerostomia and xerophthalmia). Two forms of this disease may be distinguished: primary Sjögren's syndrome which affects salivary glands and secondary Sjögren's syndrome with other autoimmune diseases present such as rheumatoid arthritis, systemic lupus erythematosus or systemic scleroderma. The diagnosis is based on the classification criteria established in 2002 by a group of American and European scientists (American-European Consensus Group), which involve the interview and physical examination as well as serological, histopathological and radiological tests. Most of these examinations show some limitations such as invasiveness, expensiveness or limited accessibility. The latest research suggests that ultrasound examination may appear promising in the diagnostics of the main salivary glands: submandibular and parotid glands. It is an accessible and relatively cheap examination with high sensitivity and specificity values which are comparable to those obtained via conventional means used in the diagnostics of this disease, i.e. biopsy of the minor salivary glands, sialography and scintigraphy, as well as superior to those obtained in sialometry and Schirmer's test. Additionally, ultrasonography correlates with the results of magnetic resonance imaging. Therefore, a number of authors claim that US examination should be included in the classification criteria of Sjögren's syndrome. The aim of this article is to present the diagnostic capacity of the US examination in Sjögren's syndrome using the current ultrasound classification systems based on the grey-scale, Doppler and contrast-enhanced examinations. The latest research confirms that the most valuable diagnostic criterion in Sjögren's syndrome is the heterogeneity of the glandular parenchyma. The outcome of the examination greatly depends on the examiner's experience.

According to the classification criteria from 2002, the basic examinations performed in the diagnostics of the Sjögren's syndrome (SS) constitute: interview, physical examination as well as serological, radiological and histopathological tests including Schirmer's test, sialometry, sialography, biopsy of the minor salivary glands and scintigraphy(. Supplementary examinations conducted in patients suffering from SS encompass: computed tomography, sialochemistry, magnetic resonance imaging and magnetic resonance sialography. All the listed methods show some limitations and therefore, other diagnostic solutions are sought for. Ultrasound examination (US) is a highly promising method.

The first attempts to use ultrasonography for the diagnosis of inflammatory changes of the salivary glands in the course of SS were made in the 1980s and their pioneers were Bradus et al.( Since then, we have observed an extraordinary technological progress in the field of ultrasonography, which resulted from, among others, the introduction of high frequency transducers (up to 18, and even 50 MHz), options of harmonic and cross-beam imaging as well as the perfection of Doppler technique, in particular the power Doppler, which is significant in rheumatic diseases. The recent publications attest to the improvement of the diagnostic value of ultrasonography. For instance, it allows for the visualization of the peripheral nerves with the diameter not greater than 1 mm( or capsular ligamentous complexes of the joints( as well as it enables to explore the pathogenesis of diseases, including the rheumatic ones(. Whereas in the first studies concerning SS diagnostics, US was secondary to the examinations considered basic at that time, such as sialography and biopsy of the salivary glands(, currently, it is postulated that US examination should be included in the diagnostic criteria of Sjögren's syndrome.

The first US examinations in the diagnostics of SS were performed in a limited number of patients(. Nevertheless, they showed that the most sensitive indicator of glandular involvement in SS was the heterogeneity of the parenchyma, which was confirmed in subsequent years(. Different authors proposed various methods with the aim to evaluate the parenchymal heterogeneity of the salivary glands. Some of them considered the parenchymal heterogeneity to be a single indicator of salivary gland involvement in SS. Others included additional elements such as echogenicity of the parenchyma (in relation to the echogenicity of the thyroid parenchyma or surrounding muscles), the volume of the salivary glands, their maximum dimensions, the visibility of the posterior boundary, the presence of the areas of increased or decreased echogenicity, linear thickening with or without the consequential shadowing and, finally, the presence of normal or pathological intraglandular/extraglandular lymph nodes with or without visible echogenic hilus(. Some authors evaluated solely the submandibular or parotid glands, others analyzed all salivary glands. Such diverse methods of the gland evaluation resulted in a multitude of classifications and a broad scope of obtained sensitivity and specificity values.

In the first studies published in 1990s, the diagnostic value of ultrasonography was high: in the research of Kawamura et al.(, the sensitivity of the US was 88% and in the study of De Vita et al.( – 88.8% (specificity – 84.6%). The results obtained by other authors verified these data. Based on the literature, the sensitivity of the US examination in the diagnostics of the salivary gland involvement in SS, ranges between 43–90% and the specificity – 84–100%(. Such great discrepancies of the US results in the SS diagnostics obtained in the last 20 years may result from:

the modification of the criteria used in the clinical classifications;

the diversity of the analyzed ultrasound parameters of the salivary glands;

the technological development of the US apparatus, including the appearance of high frequency transducers and power Doppler technique.

Furthermore, different US sensitivity values were obtained for submandibular and parotid glands. The discrepancies may have resulted from various acoustic properties of the tissues surrounding these two glands, their different accessibility and dissimilar histopathological structures: serous structure of the parotid gland and mixed, seromucous structure of the submandibular gland(. For instance, in the early papers of 1990s, the authors reported certain problems in determining the parotid gland size due to poorly visible boundaries on the background of the surrounding tissues(. Pathological changes were more frequently detected in the submandibular glands, which corresponded to their function disorders (lesser accumulation of pertechnetium-99m as compared with the parotid glands in scintigraphy)(. In the autopsy examinations, other authors also confirmed the fact that submandibular gland was more frequently affected in SS(.

As has already been mentioned – in connection with the grey-scale examination – the heterogeneity of the salivary parenchyma seems to be the main diagnostic crite-rion(. The heterogeneity described in the literature means: hypoechoic areas, lines or spots or hypoechoic areas surrounded by hyperechoic lines and/or spots resembling a reticular or honeycomb image( (fig. 1). The highest values of sensitivity and specificity (90.0% and 95.1%) for this parameter were obtained by Milic et al. in 2010(. With the use of a 12-degree scale, they proved that this element of the US image, as a single parameter, allows for the diagnosis of the affected salivary glands. In the material of Wernicke et al.( the sensitivity and specificity of ultrasonography with the parenchymal heterogeneity observed in at least two main salivary glands, constituted 63.1% and 96.1% respectively. Salaffiet al.(, when assessing the glandular parenchyma according to a 16-degree scale, obtained slightly higher sensitivity (75.3%), but lower specificity (83.5%) values. The sig-nificance of the parenchymal heterogeneity of the salivary glands in the SS diagnostics was also confirmed in magnetic resonance imaging(.

Fig. 1

Parotid (A, B) and submandibular gland (C, D) ultrasound in patients with SS. The image presents hypoechoic areas resembling a honeycomb, hypoechoic areas, lines or spots surrounded by hyperechoic lines and spots resembling a reticular image, decreased echogenicity and indistinct glandular boundaries

What is more, several authors demonstrated that the diagnostic value of the parenchymal heterogeneity factor was dependent on the type of SS. The evident disturbance in the homogeneity of the parenchyma is typical of primary SS(. However, the average disturbance in parenchymal homogeneity does not exclude primary SS, particularly in the case of positive results of sialography and histopathological tests(. Discrete changes of parenchymal echogenicity, on the other hand, were observed in patients with “sicca syndrome”, secondary SS as well as in healthy persons(. The slight disturbance in the homogeneity of the parenchyma also resulted from a hematoma or occurred in unilateral bacterial infections of the salivary gland, in the course of a proliferative process (one should remember that the changes typical of SS are bilateral and affect both submandibular and parotid glands)(. Moreover, changes in the salivary glands require the differentiation from viral infections, HIV, chronic sialadenitis and sarcoidosis(. Finally, the parenchymal heterogeneity of the parotid glands was the only anomaly in the US image which enabled the differentiation between persons with primary SS and patients with sicca syndrome but without confirmed SS(. What is more, Kawamura and Ariji demonstrated that the degree of parenchymal heterogeneity correlates with advanced changes in sialography( and Shimizu et al.( proposed a scale of homogeneity disturbances (evident heterogeneity, heterogeneity of average degree and lack of heterogeneity) which correlates with the degree of function disorders of the glands in sialography.

Apart from the heterogeneity of the parenchyma, a range of scoring systems for evaluating the salivary glands was proposed, which included other elements of the US image. However, the values of sensitivity and specificity obtained this way were not significantly better than those obtained in 2010 by Milic et al.(, i.e. 95.1% and 90.0% respectiv ely(. For example, in the study of Hocevar et al.(, who analyzed several variables in a 48-point scale, the sensitivity and specificity of the US examination constituted 58.8% and 98.7% respectively. The variables analyzed comprised: echogenicity, parenchymal homogeneity, presence of hypo- and hyperechoic areas and visibility of the posterior boundary of the gland. In 2009, Milic et al.( adopted a similar scoring system and obtained the sensitivity and specificity of 87.1% and 90.8% respectively. The system proposed by Ariji et al.(, on the other hand, which consisted in a quantitative evaluation of morphological changes in the salivary glands, occurred to be unfeasible in clinical practice (despite good results: sensitivity 89.9%, specificity 93.6%)(.

Another step in the US examination of the salivary glands was the introduction of Doppler technique to assess the vascularization of the parenchyma and pathological changes. The patients with confirmed SS, in whom heterogeneous parenchyma of the salivary glands was observed, presented increased vascularization. This contrasted the situation in the patients suffering from SS with normal, homogeneous image (with respect to the echogenicity) of the salivary glands as well as in healthy persons( (fig. 2). In addition, the spectrum analysis of blood flow in the external carotid artery and the facial artery, prior to and after the stimulation by lemon juice, demonstrated statistically significant differences between the flow parameters and increased vascularization within the parenchyma only in a group of patients suffering from mild SS. There were no statistically significant changes in the whole group of the SS patients(. Additionally, the abnormalities of flow parameters of the facial artery were strictly correlated with the degree of damage of the submandibular glands and thus decreased secretory function in the course of SS and the diminished vascularization. The decrease of the pulsatility and resistance of the facial artery as well as impaired blood flow in response to stimulation are probably caused by secreting strong vasodilators, which is manifested as intense glandular hyperemia in SS(. Further analysis of the flow parameters may prove useful in assessing the state of the disease, but the results are not significantly better than those obtained so far. Similar studies of the contrast enhancement with the use of SonoVue contrast agent, which were carried out by Giuseppetti et al.(, did not have the desired effects. The sensitivity and specificity constituted 87.5% and 85% respectively.

Fig. 2

Salivary glands in Doppler examination: A. normal salivary gland with appropriate vascularization; B, C. salivary gland in a patient suffering from SS with increased vascularization, heterogeneous echogenicity, with hypoechoic areas and hyperechoic linear echoes

Finally, numerous studies have been devoted to the analysis of the size of the salivary glands in the course of SS. According to the data included in the references, the salivary gland volume in healthy persons does not depend on age, body surface or weight(. In the course of SS, a change in the size of the salivary glands is observed, but there is no uniform opinion concerning this issue. Milic et al.( demonstrated that the patients with dryness symptoms show the enlargement of parotid glands, evident parenchymal heterogeneity and increased echogenicity of the submandibular glands more frequently than the healthy persons of the control group. Another study( reports the decrease in the size of the glands in the patients with SS as compared with the control group. Moreover, the salivary glands with heterogeneous echostructure were smaller than those with homogeneous echostructure. Other reports indicate that the patients with primary or secondary SS undergo the reduction of the volume of the submandibular gland while the parotid gland remains unchanged(. The mean volume of the submandibular gland in the females suffering from SS was lower than in the control group by 33% and 40% in the case of primary and secondary SS respectively. In the males with primary SS, however, the volume was 28% lower (there are no data concerning secondary SS due to a limited number of patients). The literature data indicate that while evaluating the size of the glands in a group of women with primary and secondary SS, the sensitivity and specificity of the US examination constituted 48% and 93% respectively and the positive and negative predictive values were 77% and 80%(.

The place of the US examination in early SS diagnostics is also controversial. The changes of the salivary gland size and echogenicity of the parenchyma prove that the patients with SS develop atrophic changes(. In a group of patients with primary SS, a normal US presentation of the salivary gland was observed in the persons suffering from this disease for about 4.2 years. The disturbance in the echostructure of the salivary glands could be detected after 7.8 years from the appearance of the symptoms. In the patients with secondary SS, however, heterogeneous echostructure of the salivary glands was observed somewhat later – after 8.6 years from the onset of the disease(. This indicates that in early stages of SS, the features of salivary gland involvement may not be visible during the US examination.

On the other hand, Hocevar et al.( presented different conclusions concerning the possibility to detect changes in early SS by means of ultrasound. Based on the SS diagnostic scale that they had created, the authors noticed certain US features which indicated the possibility of the development of the disease in persons who had not been diagnosed with SS on the basis of the classification criteria from 2002. The first group comprised females with xerostomia confirmed in the unstimulated salivary production test, positive scintigraphy and eye test. No anti-Ro and anti-La antibodies as well as no pathological changes were detected in the material obtained during salivary gland biopsy of the lower lip. In the second group, the patients reported their subjective and objective symptoms of ocular dryness, the histopathological presentation was characteristic (focus score of 2.9), but SS was not confirmed in other diagnostic tests(.

It is generally believed that ultrasound is a sensitive and specific examination in the diagnostics of primary SS as opposed to secondary SS in which the glands are affected to a lesser degree(. Nevertheless, there is no unanimity concerning this problem, which is proven by the aforementioned studies as well as the research of Wernicke et al.(, in which identical US images of the salivary glands were obtained in both primary and secondary SS. It was noticed, however, that in patients whose US image of the salivary glands indicated primary SS, the course of the disease was longer, the rheumatoid factor concentration (RF) was higher, the results of scintigraphy were anomalous and the biopsy was positive(. Milic et al.( obtained similar results of the US compatibility with histopathological evaluation of the minor salivary glands, scintigraphy and concentration measurements of the anti-nuclear antibodies (ANA). Additionally, leukopenia and/or thrombocytopenia were diagnosed. No correlations between current RF value, anti-Ro/SS-A, anti-La/SS-B and US were observed(. Niemelä et al., on the other hand, did not confirm the correlation between the histopathological evaluation of the material obtained from the lip and US examination. It was not verified that there exists a connection between abnormal changes in the parenchyma of the salivary glands visible in the US examination and the dryness of the eyes and lips, articular symptoms (arthralgia, inflammation), Raynaud's phenomenon, pulmonary fibrosis or neurological disorders(. Nevertheless, a high correlation was observed between the concentrations of ANA and anti-Ro/SS-A and/or anti-La/SS-B antibodies, which was noticed in 97% of the subjects with parenchymal heterogeneity of the salivary glands visible in the US examination. Such a correlation was confirmed by other researchers(, apart from Milic et al.( who did not observe any relationship between parenchymal heterogeneity and the occurrence of immunological disorders. Niemelä et al.( did not demonstrate any relation between US examination and lacrimal or salivary secretion tests, age, the course of the disease as well as hypergammaglobulinemia.

According to the literature data, patients suffering from SS belong to the risk group for lymphoproliferative diseases. In the 1990s, Kawamura et al.( suspected a proliferative disease in the submandibular gland on the basis of the US findings. This was later confirmed by a histopathological specimen evaluation. During the checkup, 5% of patients with SS were diagnosed with B-cell lymphoma which is frequently localized in the parotid gland(. Other researchers estimated that lymphoma develops in 6% of patients suffering from SS. In such a case, the risk of incidence is 44 times greater when compared with the healthy population. These observations prove that patients with SS require regular US checkups in order to detect the transformation into lymphoma as early as possible.

Conclusion

Due to the technological development in the field of ultrasonography in the recent years, the diagnostic value of this examination has undergone a considerable improvement(. Salaffiet al.( demonstrated that ultrasonography is more sensitive than sialography and scintigraphy (75.3%, 72.7% and 70.1% respectively) which, however, does not apply to the specificity of these methods. The specificity values were comparable (83.4%, 84.9% and 82.3%). The ratio of the sensitivity and specificity of LR 4.58 confirmed that the US examination is a single diagnostic method which allows for establishing the diagnosis of SS in patients with high concentration of anti-Ro and/or anti-La( antibodies. In their multivariate research, Yonetsu et al.( confirmed that ultrasonography and sialography equally differentiate the healthy gland from the one affected by SS. Out of six examinations performed in SS diagnostics (sialography, US examination, Saxon's test, Schirmer's test, anti-SS-A and anti-SS-B antibodies), sialography and US examination were the methods which best correlated with the clinical diagnosis of SS. Makula et al.( suggest that ultrasound examination should constitute an alternative for sialography. Moreover, in the case of patients with primary SS, advanced clinical symptoms and changes in immunological tests (anti-Ro/SS-A and/or anti-La/SS-B), it is suggested that ultrasound be used as a method alternative to biopsy(. According to the literature, there is a very high correlation between quantitative results of imaging examinations (MR and US) and gradation of pathological changes of the salivary glands in SS as well as accurate prediction of the disease(.

The bilateral, advanced morphological changes in the salivary glands are detected during US examination in the majority of patients with conformed primary SS, in comparison to patients with secondary SS, persons with sicca symptoms without confirmed SS and healthy persons(. The prevalent image presents the parenchymal heterogeneity which may be accompanied by other abnormal parameters of the salivary glands such as volume alteration, focal lesions and indistinct posterior wall of the gland(. The parenchymal heterogeneity remains the most accurate criterion. It is typical of primary SS and allows for its differentiation from sicca syndrome without SS(.

Nevertheless, ultrasonography is not flawless. The adoption of the heterogeneity as a single criterion in the evaluation of the affected salivary glands may lead to the overdiagnosis of SS. The parenchymal echogenicity disturbances are not always easy to recognize or to question(. Therefore, the heterogeneity factor is diagnostically valuable, but only in combination with other elements of the US image, other diagnostic criteria of the salivary glands and, to a large extent, with the examiner's experience(. Numerous authors recommend the quantitative US evaluation of the morphological changes in the salivary glands as a means to diagnose and observe primary SS.

The clinical symptoms of Sjögren's syndrome are well defined, but there is no diagnostic method which could confirm the clinical suspicion of SS. The methods of choice constitute histopathological test of the material obtained from the salivary gland by collecting the sample form the lower lip as well as sialography. These, however, are invasive procedures. Ultrasound and scintigraphy are complementary methods with current preference towards the US examination(. On the basis of the obtained US sensitivity and specificity values, the authors of numerous quoted studies assert that AECG classification (American-European Consensus Group) should be supplemented with US examination as the V criterion of Sjögren's syndrome diagnostics and the alternative to sialography and scintigraphy(. Due to good indicators of sensitivity and specificity, high correlation with biopsy results, accessibility, non-invasive character, repeatability and low cost, it seems that the US examination has a chance to become the main imaging technique in SS diagnostics.