Diagnosing Sjogren’s syndrome, will ultrasound be the next "right assistant"?

*Only for medical professionals to read for reference.
Accurate diagnosis of Sjogren’s syndrome is a prerequisite for providing reliable prognostic evaluation and systematic treatment for patients, and it is also a major and difficult point in clinical work
.

The 2021 American Academy of Rheumatology (ACR) Annual Meeting (ACR 2021) just ended.
Under the leadership of Professor Alan Baer, ​​Professor Vatinee from the University of Pennsylvania, Professor Richard from the University of California, and Professor Divi from France jointly diagnosed Sjogren’s syndrome accurately.
The objective diagnosis was shared
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The medical profession and the 19 experts from the Youth Committee of the Chinese Medical Association Rheumatology Branch brought a two-day live interpretation of ACR 2021 very quickly, relatively comprehensively and in depth.
I hope to "connect with the international cutting-edge information" with colleagues in the rheumatology and immunology department.
, Combined with Chinese clinical practice"
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Sjogren’s syndrome is a relatively common autoimmune disease, but the onset is hidden.
The accurate diagnosis of Sjogren’s syndrome is a prerequisite for reliable prognostic evaluation and systematic treatment for patients, and it is also a major difficulty in clinical work
.

Professor Wang Xiaobing from the First Affiliated Hospital of Wenzhou Medical University took us into ACR 2021 and explained the difficult problem of accurate diagnosis of Sjogren’s syndrome
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The causes of dry eye and the first part of the canthus examination score were explained by Professor Vatinee Bunya of the University of Pennsylvania.
The main clinical symptoms of Sjogren’s syndrome are dry mouth and dry eyes, and dry eye is mainly manifested by decreased tear secretion and/or abnormal quality
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Inflammation plays a key role in pathophysiology.
In addition to causing pain and discomfort to the patient's eyes, dry eye can also affect visual function
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1.
Clinically, the optional eye examinations for dry eye include slit lamp examination and reactive dye staining.
Commonly used reactive dyes are fluorescein, lissamine green and rose red
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2.
For ocular surface examination, the order of the inspection items is very important, and attention should be paid not to drip local anesthetics, otherwise it may lead to erroneous results
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The examination mainly includes the following four aspects: 1.
Tear film rupture time measurement (TBUT): The TBUT test mainly reflects the function of the meibomian glands to secrete lipids.
When the meibomian glands are damaged, the lipid layer is also affected, and tear evaporation increases.
, Leading to a decrease in TBUT, normal TBUT> 8-10 seconds; 2.
Fluorescein staining: it can reflect punctate defects and epithelial erosions on the cornea, and can be divided into 1-3 grades according to the number of staining points; 3.
Lissamine Green staining: the staining of the cornea, which can be divided into 0-3 grades according to the number of green spots; 4.
Schirmer test
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3.
Corneal and conjunctival staining score (OSS) If the score is based on one eye, the central corneal staining has a score of 0-3, and the nasal and temporal conjunctiva next to the cornea also have a score of 0-3.
Add on both sides
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If you can see the fusion of stained spots on the cornea, or there is staining in the pupil area, or filamentous staining, you need to add one point to each
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So in summary, the total score for one eye is 12 points
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In the 2016 ACR/European Alliance against Rheumatism (EULAR) Sjogren’s syndrome classification standard, if an eye’s OSS score is ≥5, it accounts for one point in the overall assessment of Sjogren’s syndrome [1]
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Figure 1 An example of staining of the cornea and conjunctiva of the right eye of a patient.
The cornea of ​​the right eye of this patient has a large number of punctate stains.
The score is 3 points, and there is a point of epithelial erosion (1 point), pupil confluence (1 point), no filaments (0 points), the cornea is calculated as 5 points
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The nasal side and the temporal side of the patient are stained, one point each, and two points for the conjunctiva
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Therefore, the OSS score of the patient's right eye was finally 7 points
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How to do a labial gland biopsy? Teach you these four tricks! This section is lectured by Professor Richard Jordan from the University of California.
Salivary gland involvement is the main clinical manifestation of primary Sjogren’s syndrome.
A labial gland biopsy is of great significance for the diagnosis of Sjogren’s syndrome.
The premise is that a labial gland biopsy requires enough lips.
In order to carry out the next pathological evaluation, it is necessary to collect 8-10 labial glands from a total sample of 12-15 mm2 saliva tissue.
At the same time, skilled technology is also essential to control the quality of the specimen, the comfort of the patient, and the patient experience.

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1.
The important technical steps in the labial gland biopsy process Figure 2 Labial gland biopsy step 11.
After the initial incision, assist the eversion of the lip.
The labial glands can be easily seen in the edge of the incision, because the labial glands are distributed under the epithelial mucosa In the lamina propria, there are nerve bundles and muscle bundles underneath, so the incision position should not be too deep
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Figure 3 Labial gland biopsy step 22.
Through the initial incision of the epithelium, press the fingers to make the gland prominent in the mucosa, insert the closed scissors into the epithelial lamina propria (LP) while holding the epithelium, spread the scissors in the lamina propria and place it Pull apart, the best section area of ​​the gland is 12-15mm2, minimize the blunt dissection of the submucosa, and remove the gland with the least operation
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Figure 4 Labial gland biopsy step 33.
The excised small salivary glands are best placed on paper.
Use a ruler to measure the size of the glands, and then put the glands and the paper into formalin soak
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Figure 5 Labial gland biopsy step 44, 6 days after surgery, it can be seen that the labial gland biopsy incision has healed well (arrow direction) [2]
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2.
Pathological section of labial gland biopsy Figure 6 shows the pathological section of labial gland biopsy.
The circled upper right corner is a single labial gland, and the lower left is the estimated area of ​​the labial gland.
It can also be calculated directly by computer
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The lower right is the image of lymphocyte infiltration foci.
The next step can be the labial gland focal index (FS) calculation
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Figure 6 How is the ultrasound diagnosis of Sjogren’s syndrome made by biopsy of the labial gland? The content of this part is explained by Professor Divi Cornec, who is very skilled in ultrasound diagnosis of Sjogren’s syndrome
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This time he gave us a wonderful sharing on the role of salivary gland ultrasound (SGUS) in the diagnosis and classification of Sjogren’s syndrome
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In the past 20 years, international guidelines have been updating the definition of salivary gland involvement in Sjogren’s syndrome.
In the latest 2016 ACR/EULAR standard, salivary gland involvement is defined as a decrease in salivary flow rate (UWS) (≤0.
1 ml/min)
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SGUS is also an important method to reflect damage to the salivary glands
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The parts of SGUS mainly include parotid gland and submandibular gland.
For parotid gland, cross-section and longitudinal section can be taken to observe the changes of salivary gland morphology
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In 2013, Professor Divi and his team published the results of a study on the use of ultrasound to diagnose Sjogren’s syndrome, and proposed the DIApSS cohort for the first time
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The study compared pSS patients and non-pSS patients in groups, and found that there was no significant difference in the size of the gland surface and the blood flow of the glands between the two groups, so the size of the gland surface and the blood flow did not have the diagnosis.
The value of levy
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Subsequently, Professor Divi and his team established a simplified homogeneity score commonly used in clinical practice, which was graded according to the uniformity of echo within the gland and the size of small nodules (Figure 7)
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Figure 7 Simplified homogeneity scoring standard Professor Divi tried to apply the scoring standard to score patients with Sjogren's syndrome to test the sensitivity and specificity of the score
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When the SGUS score is ≥2, the specificity of the patient is higher (95.
0%) and the sensitivity is lower (62.
8%)
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After stratified analysis of the cohort of patients according to the length of the disease, it was found that in patients with a disease course of less than 5 years, the specificity of the score was high (95.
3%), while the sensitivity was still low (65.
8%).
The SGUS score can be considered for early stage The disease has good diagnostic ability
.

Since SGUS has good diagnostic ability, can SGUS replace labial gland biopsy? Professor Divi made an attempt.
He added SGUS instead of labial gland biopsy to the 2012 ambulatory electrocardiogram (AECG) standard, and got a surprising result—the consistency between SGUS and labial gland biopsy is poor
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For the consistency deviation between the two standards, the Cohen'κ value is 0.
474
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Combining SGUS with the original AECG standard, the score specificity can reach 96.
1%, and the sensitivity is 87.
0%
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Similarly, Professor Divi tried to include SGUS in the 2016 ACR/EULAR standard.
Related studies have shown that with the doctor’s diagnosis of pSS as the reference standard, its sensitivity increased from 87.
4% to 91.
1% (absolute increase of 3.
7%), and specificity It decreased slightly, but remained above 90% (95.
4% without SGUS vs 93.
8% with SGUS)
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It is worth noting that patients who meet the revised criteria are either SSA positive or ultrasound score positive
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Through the follow-up of 49 patients with salivary gland ultrasound examinations at intervals of one year, it was found that the salivary gland ultrasound scores were relatively stable.
This conclusion has also been verified in other cohort studies
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Through research, it is found that because the ultrasound scores of the glands on both sides are highly correlated, only one side can be checked when performing related examinations for diagnosis
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However, if abnormalities (lymph nodes, lymph nodes, etc.
) are found around the glands, it is recommended to do both side ultrasound examinations and evaluations at this time
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Can the reliability of the SGUS score stand the test? Ultrasound has a wide range of scoring systems, so choosing which score is the most suitable for diagnosis has become a difficult problem for clinicians.
In order to solve this problem, the US-pSS working group came into being! The first task established by the working group was to review and analyze all the previous literature on ultrasound evaluation and diagnosis of pSS, and found that the scoring systems of each ultrasound are actually very similar, with sensitivity between 60% and 80%, and specificity.
High, generally above 90%, but there is still no consensus on an ultrasound evaluation system that can be used as a clinical diagnosis [3]
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Therefore, the second task of the US-pSS working group is to establish a reliable consensus score.
The first step of this task is to collect still images in ultrasound, and the second step is to record dynamic images
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This study established the indicators that need to be used in ultrasound diagnosis, such as the internal homogeneity and hypoechoic nodules mentioned above, which are of great clinical significance
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The US-pSS working group conducted further research on the DIApSS cohort study.
They brought SGUS into the 2016 ACR/EULAR scoring standard.
After integrating the data, they found that the sensitivity was significantly improved (from 92% to 95.
6%) and specificity Similar, so the combined effect of the two is better
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And the weight of ultrasound is similar to the item of saliva flow rate used in the 2016 ACR/EULAR scoring standard (assignment of 1 point)
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Figure 8 The development of new classification standards based on SGUS The reliability of SGUS scores has also been verified by the OMERACT working group, and the OMERACT working group has also formulated the SGUS standardized operation process, which is conducive to the further promotion of SGUS
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Can SGUS replace labial gland biopsy? There is no conclusion yet.
Finally, Professor Divi concluded that salivary gland ultrasound should be included in the future pSS consensus classification criteria, because SGUS has good diagnostic performance in the early stage of pSS; and SGUS is simple to operate and can be repeated measurements; in addition, SGUS Having items that are independent of other classification criteria and being included in the diagnosis of Sjogren’s syndrome is conducive to operation
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There has been a heated discussion about whether SGUS can replace labial gland biopsy, but there is no conclusion yet.
Professor Divi gave an example to express his thoughts: If the patient's antibody and ultrasound results are negative, then the patient will undergo a labial gland biopsy.
The necessity is not great
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Professor Wang Xiaobing also shared his own experience: in the clinic, when the patient’s antibody and ultrasound results are negative, if the patient is still highly suspected of Sjogren’s syndrome, it is still necessary to perform a labial gland biopsy for screening, and the labial gland biopsy is The detection and prediction of lymphoma also has important clinical significance
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Expert profile Wang Xiaobing, deputy chief physician, doctor, associate professor, and doctoral supervisor of the Department of Rheumatology and Immunology, the First Affiliated Hospital of Wenzhou Medical University
.

Member of the Youth Committee of the Chinese Association of Rheumatology, Member of the Professional Committee of Rheumatology and Immune Rehabilitation of the Chinese Association of Rehabilitation Medicine, Secretary of the Rheumatology Committee of the Zhejiang Medical Association and Deputy Chairman of the Youth Committee, Youth Member of the Internal Medicine Branch of the Zhejiang Medical Association, Wenzhou Medical Association Member of the Rheumatology Committee and a visiting scholar at the University of Queensland, Australia
.

Presided over the National Natural Science Foundation of China and other topics, the first/corresponding author has published more than 10 SCI papers
.

References: [1]ABSTRACT SUPPLEMENT 2010 ANNUAL SCIENTIFIC MEETING.
November 6–11, 2010 Atlanta, Georgia.
AMERICAN COLLEGE OF RHEUMATOLOGY[2]American College of Rheumatology Classification Criteria for Syndrome: A Data-Driven, Expert Consensus Approach in the International Collaborative Clinical Alliance Cohort.
Vol.
64, No.
4, April 2012, pp 475–487 DOI 10.
1002/acr.
21591 © 2012, American College of Rheumatology.
[3]Is salivary gland ultrasonography a useful tool in Sj?gren's syndrome? Robert, I, FoxDOI: 10.
1093/rheumatology/kev409.
2016.
[4] Incorporation of salivary gland ultrasonography into the ACR-EULAR criteria for primary Sjgren's syndrome.
Jolien F.
van Nimwegen, Esther Mossel, Konstantina Delli, DOI: 10.
1002/acr .
240172019.