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The 3 hot topics in the diagnosis and treatment of Sjogren syndrome can be read in one article

 Last Update: 2023-01-01
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Primary Sjogren syndrome (pSS) is a chronic systemic autoimmune disease characterized by dry mouth and eyes, while pSS can also affect other exocrine glands and organs
.
What needs to be improved in the identification, prevention and management of Sjogren's syndrome? This year's American College of Rheumatology (ACR) Annual Meeting invited two speakers to share in-depth views on lip biopsy, lung and kidney involvement
.
The Rheumatology and Immunology Channel of the medical community specially invited Professor Zhu Xiaoxia of Huashan Hospital affiliated to Fudan University to interpret
this topic through the "Youth Committee of the Rheumatology Society Take You to See ACR".

Introductory cognition: The principle of salivary glands in Sjogren's syndrome

pSS is characterized by activation of lymphocyte proliferation, gland involvement in the pathological process can be assessed by biopsy and imaging, and pSS salivary gland is characterized by focal lymphocytic sialadenitis (FLS), manifested
by lymphatic aggregation in the periductal or perivascular glands.
Among them, lymphatic aggregation is a dense aggregate containing at least 50 lymphocytes, which are usually located around ducts or blood vessels, and the surrounding tissue is mainly composed of
unaffected parenchymal tissue.
If the lesion score (FS) ≥ 1 cluster/4^mm2, the pathology is considered positive ^[1].

Figure 1.
Common sense cognition of lymphatic aggregation

in pathological sections of pSS salivary glands: 2 main modes of SS involvement

In the systemic manifestations of SS, lung and kidney are the two main organs affected, and about 10%-20% of patients with SS are affected by the lungs, while renal involvement is mainly
renal tubular acidosis.

Figure 2.
Pulmonary involvement of SS Manifestations When pulmonary involvement is suspected in patients with SS, there is a slight difference in the thinking of diagnosis and treatment with or without associated symptoms:

Figure 3.
Common diagnostic and therapeutic thinking for pulmonary involvement

In renal involvement of SS, the following findings are common:
• Manifestations of distal tubular acidosis (hypokalemia, hypobicarbonate, urine pH >5.
5, nephrolithiasis)
• Renal interstitial nephritis
• Proximal tubular acidosis and Fanconi syndrome • Nephrogenic diabetes insipidus
• Gitelman syndrome

• Glomerulonephritis
Mild IgG+, strong IgM+, κ and λ+, C3+ and C1q weak positive, electron microscopy, electron dense subepithelial deposition, cold globulin-related hints; Clinical manifestations are abnormal creatinine, abnormal urinalysis, and high disease activity, except for ANCA-associated vasculitis and SLE; Laboratory tests are common positive for rheumatoid factor, hypocomplementemia, and cryoglobulin; At present, low-temperature-related membranous proliferative diseases such as membranous nephropathy, focal segmental glomerulosclerosis and IgA nephropathy have been reported, and treatment is mainly
immunosuppressive.

• Chronic kidney disease

There is no increased risk of end-stage renal disease in patients with pSS, but the risk of CKD is significantly increased, suggesting the need for regular monitoring of the kidneys in patients with pSS
.

Figure 4.
Tubulointerstitial nephritis lymphocyte interstitial infiltrates

Advanced cognition: diagnosis of SS-associated lymphoma

Non-Hodgkin lymphoma is the most serious complication of pSS, occurring in about 5%-10% of pSS, and the risk of lymphoma in pSS patients is highest in autoimmune diseases, of which mucosa-associated lymphoid tissue lymphoma (MALT) is the most common and can occur in 75% of pSS-associated lymphoma cases, while the salivary gland is the main disease, and about 60% of lymphoma pSS patients occur in the large salivary gland
.

Common open biopsy and ultrasound-guided core needle biopsy (US-CNB) are similar in accuracy and safety to parotid gland localization and can be effective diagnostic modalities
.
In the setting of focal lesions or submandibular gland involvement, US-CNB may be superior to open biopsy, in which the puncture point is located between 1 cm anterior and 1 cm below the earlobe, and the surface depth of the biopsy needle (within 1–1.
5 cm of the gland's surface).

Overall, the rate of positive biopsy in patients with pSS is close to 70%.

Figure 5.
Schematic of SS needle biopsy

Lip gland (LSG) biopsy is the key diagnostic and differential basis for Sjogren's syndrome-associated lymphoma, and for suspected SS patients with negative anti-Ro/SSA antibodies, LSG biopsy is mandatory (at least 4-6 LSGs must be examined with a minimum surface area of 8^mm2).

Lip gland biopsy and anti-SSA antibody titers have been shown to be highly effective, improving sensitivity for differential diagnosis of pSS (eg, differentiating IgG4-related diseases from sarcoidosis), facilitating direct comparisons between imaging and histology, early diagnosis of pSS-associated lymphoma, and multiple biopsies of the same gland for study ^[2]
。
In addition, clinical manifestations, laboratory tests, histopathology and imaging factors can predict pSS-associated lymphoma, and 7 independent risk factors (salivary gland enlargement, lymph node lesions, Raynaud's phenomenon, anti-Ro/SSA and/or anti-La/SSB positive, rheumatoid factor positive, monoclonal gammopathy, low C4 complementemia) were summarized, and 2 independent risk factors were found, Patients with pSS with three to six independent risk factors and seven independent risk factors have a 3.
8 percent, 40 percent, and 100 percent likelihood of lymphoma, respectively ^[3-4], with the main predictors being salivary gland enlargement, mixed cryoglobulinemia, RF positivity, low C4, and purpura
.

Figure 6.
Pathology of lip gland biopsy: A is the salivary gland biopsy HE stained section obtained by pSS patients; the red outline in B is the gland tissue, which is used to calculate the number of lesions score (FS), and the area in the black line is divided by the entire gland surface area and multiplied by 4 to obtain the number of lymphatic aggregations per^4mm2; C is a salivary gland biopsy in a patient with pSS, with enlarged images showing gland fibrosis and gland parenchymal atrophy, and regional lymphocytic sialadenitis ^[5]
In addition to salivary gland enlargement that can occur at any time point in pSS, ultrasound and PET-CT of pSS-associated lymphoma are also prominent:
● Ultrasound is generally characterized by diffuse and severe inhomogeneity, with confluent low/anechoic zones; OMERACT scores are generally 3 (not 0 or 1);
6 or more ultrasound features significantly increase the likelihood of pSS-associated lymphoma ^[6-7]The
PET-CT manifestations of lymphoma in patients with pSS are in the lymph nodes and parotid ^gland18 High F-FDG uptake is most common (note: this can also be observed in the absence of lymphoma) ^[8].

Figure 8.
PET-CT observed focal condensation or nodular pulmonary lesions, SUV maximum ≥5.
6 at any point, and parotid SUV maximum ≥4.
7, all of which suspected pSS-associated lymphoma (SUV: standard uptake value).

summary

Lung involvement is common in SS, so screening for pulmonary involvement is recommended at initial presentation, regardless of abnormal pulmonary function tests, even if some patients are asymptomatic
.

In addition, screening for renal disease in SS patients is also necessary, and the most common manifestation of renal involvement is renal tubular acidosis, which can affect long-term health and should be treated
promptly.

Although glomerular disease is less common than tubulointerstitial lesions, it is necessary
to differentiate and even administer immunosuppressive therapy.

Expert profiles

Professor Zhu Xiaoxia

•Deputy Chief Physician, Department of Rheumatology and Immunology, Huashan Hospital, Fudan University;

•Member of Rheumatology Branch of Shanghai Medical Association;

• Member and Secretary of the Youth Committee of the Rheumatology Branch of the Chinese Medical Association;

• Member and Secretary of Gout Group, Rheumatology and Immunology Branch of Chinese Medical Doctor Association;

• Youth Committee of Immunotherapy Engineering Branch of Chinese Society of Biomedical Engineering Vice Chairman;

• Member and Secretary of the Gout Group of the Rheumatology and Immunology Professional Committee of the Cross-Strait Medical and Health Exchange Association;

• Member and Secretary of the Expert Committee on Hyperuric Acid and Gout of the Chinese Geriatrics Council;

• From October 2009 to April 2011, he studied abroad
at Harvard Medical School.

• Main achievements: He presided over a number of international, provincial and ministerial projects such as the National Natural Science Foundation of China, the special scientific research fund for doctoral disciplines in colleges and universities of the Ministry of Education, the appropriate technology promotion of Shanghai Shenkang Development Center, and published a number of SCI and core journal articles

References:

[1] Shiboski C H, Shiboski S C, Seror R, et al.
2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome: a consensus and data‐driven methodology involving three international patient cohorts[J].
Arthritis & rheumatology, 2017, 69(1): 35-45.

[2] Verstappen G M, Moerman R V, van Nimwegen J F, et al.
Serum immunoglobulin free light chains are sensitive biomarkers for monitoring disease activity and treatment response in primary Sjögren’s syndrome[J].
Rheumatology, 2018, 57(10): 1812-1821.

[3] Zandonella Callegher S, Giovannini I, Zenz S, et al.
Sjögren syndrome: looking forward to the future[J].
Therapeutic Advances in Musculoskeletal Disease, 2022, 14: 1759720X221100295.

[4] Brito Zerón P, Acar Denizli N, Ng W F, et al.
How immunological profle drives clinical phenotype of primary Sjögren’s syndrome at diagnosis: analysis of 10,500 patients (Sjögren Big Data Project)[J].
2018.

[5] Fisher B A, Jonsson R, Daniels T, et al.
Standardisation of labial salivary gland histopathology in clinical trials in primary Sjögren's syndrome[J].
Annals of the rheumatic diseases, 2017, 76(7): 1161-1168.

[6] Zabotti A, Zandonella Callegher S, Lorenzon M, et al.
Ultrasound-guided core needle biopsy compared with open biopsy: a new diagnostic approach to salivary gland enlargement in Sjögren’s syndrome? [J].
Rheumatology, 2021, 60(3): 1282-1290.

[7] Lorenzon M, Tulipano Di Franco F, Zabotti A, et al.
Sonographic features of lymphoma of the major salivary glands diagnosed with ultrasound-guided core needle biopsy in Sjögren's syndrome[J].
Clin Exp Rheumatol, 2021, 39(133): S175-S183.

[8] Keraen J, Blanc E, Besson F L, et al.
Usefulness of 18F‐Labeled Fluorodeoxyglucose–Positron Emission Tomography for the Diagnosis of Lymphoma in Primary Sjögren's Syndrome[J].
Arthritis & Rheumatology, 2019, 71(7): 1147-1157.

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