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Clin Exp Med
Clin Exp Med
Clinical and Experimental Medicine
1591-8890
1591-9528
Springer International Publishing Cham

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10.1007/s10238-024-01486-x
Review
Ultrasound shear wave elastography for assessing minor salivary gland involvement in anti-centromere antibody-positive primary Sjögren’s syndrome: a retrospective study
Wang Xinyu 1
Wang Xujie 2
Wu Jian 1
Dong Fenglin 2
Chang Xin xinchang@suda.edu.cn

1
Wang Aju 13814875143@163.com

2
1 https://ror.org/051jg5p78 grid.429222.d 0000 0004 1798 0228 Departments of Rheumatology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu China
2 https://ror.org/051jg5p78 grid.429222.d 0000 0004 1798 0228 Departments of Ultrasound, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu China
17 9 2024
17 9 2024
2024
24 1 22118 7 2024
4 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
The aim of this study is to investigate salivary gland involvement in patients with anti-centromere antibody (ACA)-positive primary Sjögren’s syndrome (pSS). We retrospectively evaluated 134 patients with pSS. Patients were divided into four groups based on the results of ACA and SSA antibodies. We compared clinical manifestations, laboratory findings, salivary gland shear wave elastography, minor salivary gland biopsy results, and EULAR Sjögren’s syndrome disease activity index (ESSDAI) scores among the four groups. A total of 134 patients were classified as having pSS and divided into three groups based on serum ACA and anti-SSA antibody status: ACA + SSA + , ACA + SSA-, ACA-SSA + , and seronegative. The primary analysis focused on comparing the clinical and SWE findings between the ACA + SSA + and ACA + SSA- groups. In the double-positive group, SWE revealed fewer minor salivary glands along with higher mean (Emean) and maximum (Emax) values of Young’s moduli than those in the ACA-negative group. Patients in the positive group had increased occurrence of Raynaud’s phenomenon, liver involvement, and a higher incidence of malignancy (P < 0.05). ACA-positive pSS patients are a subgroup with different clinical manifestations and more pronounced involvement of the minor salivary glands. SWE findings revealed that ACA-positive patients exhibit significantly higher mean and maximum stiffness values compared to ACA-negative patients, indicating more extensive glandular fibrosis and involvement. These results underscore the utility of SWE as a valuable method for evaluating salivary gland pathology and supporting the stratification of pSS patients.

Keywords

Sjogren’s syndrome
Shear wave elastography
Anti-centromere antibody
Salivary gland
issue-copyright-statement© Springer Nature Switzerland AG 2024
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pmcIntroduction

Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disease characterized by dryness of the mouth and eyes, caused by lymphocytic infiltration of the exocrine glands and dysfunction in glandular secretion [1]. It is classified as primary or secondary SS based on the presence or absence of comorbidities with other connective tissue diseases. Previous studies have found significant differences in the clinical characteristics of patients with positive and negative anti-centromere antibodies (ACA) in pSS [2, 3]. ACA is associated with distinct clinical features, including a higher incidence of salivary gland involvement and an increased risk of fibrotic changes. However, the extent and nature of these fibrotic changes in ACA-positive pSS patients are still debated. This inconsistency underscores the need for further research into the pathophysiological mechanisms underlying ACA-positive pSS.

The ultrasound of salivary glands, a noninvasive method, plays an increasingly important role in assessing disease activity and prognosis in patients with pSS [4]. Shear wave elastography (SWE) is an imaging technique that uses acoustic radiation force pulses to generate shear waves, tracks the displacement and velocity of the waves as they propagate, and calculates tissue displacement using a speckle-tracking algorithm. This technique measures the propagation velocity of the shear waves to assess tissue stiffness [5, 6]. Previously, we conducted a study confirming that ultrasound SWE is useful for diagnosing and assessing conditions in patients with pSS [7].

In this study, we aimed to utilize SWE to evaluate minor salivary gland involvement in ACA-positive patients with pSS, particularly focusing on the detection of potential fibrotic changes. Our hypothesis is that SWE can provide a noninvasive assessment of glandular stiffness, thereby aiding in the diagnosis and stratification of disease severity in ACA-positive pSS patients. This study seeks to quantitatively assess the tissue stiffness of affected minor salivary glands in pSS patients, providing a basis for stratified evaluation and serving as an important method for future disease assessment.

Methods

Patients and data collection

Exactly 556 patients with SS who met the American College of Rheumatology/European League classification criteria [8] were enrolled in this study. All patients visited the First Affiliated Hospital of Soochow University between May 2019 and May 2023.

The inclusion criteria were patients with (1) primary SS, (2) complete clinical data, (3) who underwent salivary gland biopsy after providing informed consent, and (4) who underwent salivary gland ultrasonography after providing informed consent. The exclusion criteria were as follows: (1) secondary SS; (2) liver diseases such as viral hepatitis (hepatitis A, B, C, D, and E) and autoimmune liver disease; (3) history of head and neck radiation therapy; (4) malignant tumors of the salivary glands; (5) inflammation of the glands associated with acute infections; (6) IgG4-related diseases; (7) graft-versus-host disease; and (8) systemic sclerosis, excluded based on the 2013 ACR/EULAR classification criteria.

A total of 556 patients were initially screened. After applying the inclusion and exclusion criteria, 422 patients were excluded due to not meeting the inclusion criteria or meeting the exclusion criteria. Specifically, 98 patients were excluded due to secondary Sjögren’s syndrome, 19 patients were excluded due to liver diseases, 101 patients were excluded due to inflammation associated with acute infections, 1 patient were excluded due to IgG4-related disease, and 203 patients were excluded because they did not undergo salivary gland ultrasound examination or lacked relevant clinical data. Finally, 134 patients met the inclusion criteria and were included in the study.

The general conditions of the patients were recorded: gender, age at onset, age at pSS diagnosis, duration of disease; clinical manifestations: ocular and oral symptoms, dental caries, serologic tests (including antinuclear, anti-Ro/SSA, anti-La/SSB, and anti-attachment point antibodies, rheumatoid factor, erythrocyte sedimentation rate, immunoglobulin G, immunoglobulin A, immunoglobulin M, complement C3, complement C4, etc.), SWE, minor salivary gland biopsy and other extra-glandular manifestations such as cutaneous vasculitis, arthritis (joint pain, swelling, or inflammation), hematologic involvement (anemia, leukopenia, or thrombocytopenia), interstitial lung lesions (interstitial lung disease characterized by diffuse parenchymal abnormalities), renal involvement (including renal tubular acidosis, interstitial nephritis, or proteinuria), liver involvement (manifested as elevated liver enzymes), and neurologic involvement (manifested as peripheral neuropathy, cranial nerve involvement, or central nervous system complications).

This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Affiliated Hospital of Soochow University (2,020,105).

Ultrasound and SWE examination of the salivary gland

Lip gland examination: Two radiologists with 2 years of SWE imaging experience were randomized to perform the examination. Before the examination began, the examiners were trained and calibrated to standardize image acquisition. The intra-class correlation coefficients for intra-observer agreement were all > 0.80. A Supersonic Imagine Aixplorer diagnograph was used, and a linear probe SLH20-6 with a frequency of 6–20 MHz and an examination depth of 0.2 cm was selected. All patients were placed supine, with the lower lip divided into right and left portions and the midline of the teeth as the body marking. During examination, the patient gently pulled the lower lip to expose both sides. A disposable sterile probe cover was used to prevent contact between the mucosa and the probe and avoid cross-infection. The mucosa was examined, and the patient was subjected to routine ultrasonography to determine the number of labial glands in the probe (detection range: 27.3 × 8.7 mm2, 234.98 mm2). The measurements were taken five times. Statistical analysis involved calculating the average values of SWE, including Emin, Emean, Emax, and Eratio.

Examination of the submandibular and parotid glands: The patient was placed supine, with the head slightly tilted to the contralateral side to better expose the examination area. Ultrasonic examination of the parotid gland was performed in the longitudinal section in front of the ear screen and the transverse section below the earlobe. The patient’s head was tilted back, and the bilateral submandibular glands were examined along the long axis of the diameters of the diastema muscle and in the cross-sectional plane. The size and shape of the glands, internal echoes, and margins were observed, and the ultrasound scores of the submandibular and the parotid glands were scored based on the scoring method of 0 − 4 points as follows: 0 points, homogeneous echoes of the glands; 1 point, small hypoechoic areas in the glands with no echogenic bands; 2 points, multiple hypoechoic areas in the glands with diameters of < 2 mm, with hyperechoic bands; 3 points, multiple hyperechoic areas in the glands with diameters of 2 − 6 mm with hyperechoic bands; 3 points, multiple hyperechoic areas in the glands with diameters of 2 − 6 mm in diameter with hyperechoic bands; score 4, multiple hypoechoic areas within the gland, diameter > 6 mm or multiple calcified echoes.

Minor salivary gland biopsy

Minor salivary gland biopsies were performed by a rheumatologist. The subjects’ lips were routinely sterilized, and after local anesthesia with 2% lidocaine, an incision was made in the mucosa of the lower lip, and 3 − 5 lip glands were removed. After suturing the incision, gland specimens were fixed in 10% formalin, embedded, sectioned, stained with hematoxylin and eosin (HE), and observed under a microscope. The focus score (FS) was defined as the number of lymphocyte foci per 4 mm2; ≥ 50 lymphocyte aggregates were considered as one foci.

Statistical analysis

Statistical analyses were performed using the IBM SPSS Statistics version 25. The Wilcoxon rank-sum test was used to compare differences between two groups, while the Kruskal–Wallis test was employed for comparisons among multiple groups. Categorical variables were compared using the Chi-square test or Fisher’s exact test, as appropriate. Differences were considered statistically significant at P < 0.05.

Results

Clinical characteristics of pSS patients

Exactly 134 patients with pSS were included in this study, with 17 ACA-positive patients accounting for 14.5% of all patients. Among them, 11 patients were double-positive for both ACA and anti-SSA antibodies, while 6 were ACA-positive only. Patients in the ACA-only group showed a higher likelihood of Raynaud’s phenomenon (P = 0.026), while ACA-positive patients had higher rates of jaundice (P = 0.015). Additionally, ACA-positive patients showed an increased incidence of malignant tumors (therioma) compared to other groups (P = 0.006). Regarding clinical presentation, there was no statistically significant difference between the groups in terms of dryness of the mouth and eyes or multiple caries. Further details are shown in Table 1.Table 1 Extra-glandular manifestations in pSS

	ACA(-)SSA(-) (n = 19)	ACA( +)SSA(-) (n = 6)	ACA(-)SSA( +) (n = 98)	ACA( +)SSA( +) (n = 11)	P	
Fever, n (%)	2 (10.53)	0 (0.00)	10 (10.20)	3 (27.27)	0.359	
Dry, n (%)	14 (73.68)	5 (83.33)	84 (83.67)	10 (90.91)	0.637	
Fatigue, n (%)	4 (21.05)	0 (0.00)	7 (7.14)	1 (9.09)	0.216	
Dental caries, n (%)	5 (26.32)	2 (33.33)	33 (33.67)	3 (27.27)	0.949	
Joint involvement, n (%)	6 (31.59)	3 (50.00)	38 (38.78)	2 (18.18)	0.516	
Skin involvement, n (%)	5 (26.32)	2 (33.33)	27 (27.55)	2 (18.18)	0.907	
Rp, n (%)	1 (5.26)	3 (50.00)	9 (9.18)	2 (18.18)	0.026	
Sclerodactyly, n (%)	0 (0.00)	1 (16.67)	1 (1.02)	1 (9.09)	0.052	
Edema, n (%)	2 (1.49)	0 (0.00)	0 (0.00)	0 (0.00)	0.047	
Jaundice, n (%)	0 (0.00)	1 (16.67)	0 (0.00)	1 (9.09)	0.015	
Nausea, n (%)	0 (0.00)	1 (16.67)	2 (2.04)	0 (0.00)	0.248	
Kidney involvement, n (%)	3 (15.79)	0 (0.00)	1 (1.02)	1 (9.09)	0.020	
PAH, n (%)	1 (5.26)	0 (0.00)	5 (5.10)	1 (9.09)	0.848	
Pulmonary bullae, n (%)	0 (0.00)	0 (0.00)	4 (4.08)	1 (9.09)	0.591	
ILD, n (%)	1 (5.26)	2 (33.33)	13 (13.27)	2 (18.18)	0.258	
Lymphatic system involvement, n (%)	1 (5.26)	0 (0.00)	19 (19.39)	1 (9.09)	0.361	
Blood system involvement, n (%)	9 (47.37)	2 (33.33)	68 (69.39)	9 (81.82)	0.061	
Therioma, n (%)	1 (5.26)	1 (16.67)	2 (2.06)	3 (27.27)	0.006	
Osteoarthritis, n (%)	3 (15.79)	1 (16.67)	5 (5.15)	2 (18.18)	0.074	
RP: Raynaud’s phenomenon; PAH: pulmonary artery hypertension; ILD: interstitial lung disease

Patients in the ACA-positive groups had a later age of onset. Elevated serum levels of alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP) were observed particularly in the ACA-only group compared to others (P = 0.006, 0.009, and 0.002). Notably, abnormal liver function was more common among ACA-positive groups. The prevalence of anti-SSB antibody positivity rate is significantly lower in ACA-positive groups. Further details are presented in Table 2.Table 2 Demographics and clinical characteristics of pSS

	ACA(-)SSA(-) (n = 19)	ACA( +)SSA(-) (n = 6)	ACA(-)SSA( +) (n = 98)	ACA( +)SSA( +) (n = 11)	P	
Female, N (%)	18 (94.74)	6 (100.00)	96 (97.96)	11 (100.00)	0.612	
Age (years)	50.00 (39.50,63.50)	53.50 (50.25,56.75)	46.50 (37.00,57.00)	58.00 (53.00,63.50)	0.035	
Age at pSS diagnosis (years)	49.00 (39.50,59.50)	52.50 (49.50,56.25)	42.00 (33.25,52.00)	57.00 (48.00,59.50)	0.015	
Disease duration (years)	2.00 (0.62,3.50)	2.50 (2.00,3.75)	4.50 (2.00,12.75)	5.00 (1.00,31.00)	0.085	
Hospitalization (days)	9.00 (6.00,11.00)	7.50 (5.50,8.75)	7.00 (5.00,9.00)	9.00 (7.00,10.50)	0.128	
WBC (10⁹/L)	5.46 (4.58,7.12)	4.83 (4.19,7.23)	4.62 (3.59,5.42)	5.92 (5.06,7.21)	0.010	
Lym (10⁹/L)	1.69 (1.38,2.03)	1.82 (1.40,2.07)	1.42 (1.07,1.83)	1.47 (1.16,1.93)	0.216	
Mono (10⁹/L)	0.42 (0.32,0.47)	0.41 (0.34,0.52)	0.33 (0.28,0.43)	0.42 (0.38,0.43)	0.185	
Neu (10⁹/L)	3.06 (2.56,5.82)	2.65 (2.34,4.00)	2.63 (1.95,3.22)	3.53 (2.75,5.38)	0.038	
Hb (g/L)	124.00 (120.00,135.50)	128.00 (123.50,131.75)	121.00 (113.25,129.00)	118.00 (106.00,120.00)	0.074	
Plt (10⁹/L)	198.00 (177.00,247.50)	165.50 (136.00,261.00)	188.50 (148.00,217.75)	158.00 (110.50,227.50)	0.532	
ESR (mm/h)	13.00 (5.00,22.50)	10.00 (7.75,19.00)	20.00 (8.00,35.00)	35.00 (20.00,49.00)	0.020	
CRP (mg/L)	1.95 (1.26,4.08)	1.12 (1.09,2.01)	1.50 (0.82,2.94)	3.09 (1.31,11.69)	0.199	
RF IU L, M (Q₁, Q₃)	20.00 (20.00,24.57)	20.10 (20.05,54.10)	48.30 (20.00,108.00)	54.75 (20.00,100.07)	0.075	
Fer, M (Q₁, Q₃)	85.29 (38.01,178.90)	102.01 (65.50,144.23)	91.56 (35.97,171.25)	177.69 (29.27,275.57)	0.761	
IgG g L, M (Q₁, Q₃)	14.80 (12.00,17.90)	12.10 (11.80,14.88)	16.90 (14.83,20.88)	18.50 (14.35,20.50)	0.016	
IgA g L, M (Q₁, Q₃)	3.63 (2.50,4.42)	2.62 (2.15,2.95)	2.87 (2.26,3.99)	3.43 (2.55,5.53)	0.438	
IgM g L, M (Q₁, Q₃)	1.21 (0.80,1.61)	1.20 (0.82,4.04)	1.17 (0.84,1.71)	1.40 (1.23,1.93)	0.587	
C3 mg L, M (Q₁, Q₃)	0.90 (0.82,0.98)	0.73 (0.65,0.99)	0.82 (0.70,0.93)	0.73 (0.65,0.99)	0.110	
C4 mg L, M (Q₁, Q₃)	0.20 (0.15,0.23)	0.24 (0.19,0.32)	0.16 (0.13,0.20)	0.17 (0.14,0.23)	0.031	
ALT, M (Q₁, Q₃)	18.60 (13.95,29.85)	50.55 (35.38,74.27)	14.65 (10.95,23.65)	24.50 (12.50,47.70)	0.006	
AST, M (Q₁, Q₃)	21.70 (18.20,24.90)	33.20 (24.35,41.00)	20.55 (17.07,25.00)	22.40 (16.45,47.25)	0.078	
GGT, M (Q₁, Q₃)	22.50 (15.00,37.60)	37.20 (31.33,58.98)	19.25 (15.00,31.53)	39.40 (21.50,139.00)	0.009	
ALP, M (Q₁, Q₃)	62.20 (53.05,86.90)	85.85 (69.30,111.70)	61.10 (47.47,72.65)	116.00 (70.70,155.20)	0.002	
TBiL, M (Q₁, Q₃)	11.70 (8.25,14.75)	12.00 (11.70,12.75)	10.95 (8.22,13.55)	12.30 (9.30,14.45)	0.611	
DBiL, M (Q₁, Q₃)	4.20 (2.70,4.45)	3.85 (3.42,4.42)	3.70 (2.70,4.57)	3.80 (2.45,4.75)	0.853	
IBiL, M (Q₁, Q₃)	7.40 (5.80,9.70)	8.35 (8.15,8.92)	6.80 (5.50,9.35)	7.20 (6.55,10.55)	0.614	
ALB, M (Q₁, Q₃)	40.40 (38.40,41.65)	42.00 (41.00,42.25)	39.85 (37.60,42.77)	39.20 (35.15,41.50)	0.496	
Cr, M (Q₁, Q₃)	51.20 (47.90,53.05)	62.55 (53.62,68.62)	55.60 (49.00,61.80)	50.80 (48.10,54.75)	0.137	
UA, M (Q₁, Q₃)	302.80 (272.55,362.55)	280.15 (227.45,366.15)	288.20 (251.53,371.20)	200.50 (170.10,304.65)	0.141	
ESSDAI, M (Q₁, Q₃)	4.00 (3.00,5.00)	6.00 (3.75,6.75)	6.00 (3.00,9.00)	5.00 (4.00,10.00)	0.232	
Anti-SSB( +), n (%)	2 (10.53)	0 (0.00)	75 (76.53)	3 (27.27)	 < 0.001	
pSS, primary Sjogren’s syndrome; WBC, white blood cell; Lym, lymphocytes; Mono, monocytes; Plt, platelets; RF, ESR, electrolyte sedimentation rate; AST, aspartate transaminase; ALT, alanine transaminase; GGT, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase;; anti-SSB, anti-Sjögren’s syndrome type B; ESSDAI, EULAR Sjögren’s syndrome disease activity index; GFR, glomerular filtration rate; CRP, C-reactive protein; Cr, creatinine

Comparison of SWE of minor salivary glands

The comparison of shear wave elastography (SWE) of minor salivary glands revealed significant differences between the ACA-positive and ACA-negative groups. The average number of labial glands per unit area under the right lower lip, left lower lip, and middle part of the lower lip significantly reduced in the ACA-positive group (P = 0.002, 0.004, and 0.022, respectively). Additionally, the mean Young’s modulus (Emean) and max (Emax) were significantly higher in the ACA-positive group than in the ACA-negative group (P = 0.003 and 0.002, respectively). However, there was no significant difference in the minimum Young’s modulus (Emin) between the two groups (P > 0.05) (Table 3) (Fig. 1).Table 3 Comparison of SWE and FS results of labial glands in patients with pSS in the ACA-positive and ACA-negative groups

	ACA (-)SSA( +) (n = 98)	ACA ( +)SSA( +) (n = 11)	P	
Number of labial glands (Right), M (Q₁, Q₃)	2.00 (2.00, 3.00)	1.00 (1.00, 2.00)	0.002	
Number of labial glands (Left), M (Q₁, Q₃)	3.00 (2.00, 3.00)	2.00 (1.00, 2.00)	0.004	
Number of labial glands (Middle), M (Q₁, Q₃)	3.00 (2.00, 4.00)	2.00 (1.25, 3.00)	0.022	
Average number of labial glands, M (Q₁, Q₃)	2.67 (2.00, 3.67)	1.33 (1.33, 2.00)	0.002	
E (Right), M (Q₁, Q₃)	11.65 (9.40, 16.00)	12.80 (11.40, 19.55)	0.095	
E (Left), M (Q₁, Q₃)	11.05 (9.22, 14.88)	15.10 (11.55, 19.45)	0.047	
Emax, M (Q₁, Q₃)	15.75 (11.83, 18.10)	20.60 (17.60, 23.70)	0.002	
Emin, M (Q₁, Q₃)	9.60 (7.53, 11.45)	11.90 (9.80, 13.40)	0.083	
Emean, M (Q₁, Q₃)	12.39 (10.47, 14.65)	16.05 (14.14, 18.00)	0.003	
FS, M (Q₁, Q₃)	2.00 (1.00,3.00)	2.00 (2.00,3.00)	0.334	
FS ≥ 1, n (%)	79 (80.61)	11 (100.00)	0.235	
FS: focus score; ACA: anti-centromere antibody; Emin: minimum elastic modulus; Emax: maximum elastic modulus; Emean: mean elastic modulus; Eratio: elastic modulus ratio

Fig. 1 SWE of the minor salivary glands in patients with pSS. a Gray-scale ultrasound image showing the structure of the minor salivary glands with an arrow indicating the hypoechoic area, suggesting glandular involvement. b SWE color-coded image demonstrating the tissue stiffness distribution within the minor salivary glands. Abbreviations: SWE, shear wave elastography; pSS, primary Sjogren’s syndrome

Comparison of ultrasound scores of the major salivary glands

There were no significant differences in the ultrasound scores of the parotid and submandibular glands between the ACA-positive and ACA-negative groups (P > 0.05) (Table 4) (Fig. 2).Table 4 Ultrasound scores of the major salivary glands

	ACA (-)SSA( +) (n = 98)	ACA ( +)SSA( +) (n = 11)	P	
PG, n (%)			0.866	
0	6 (6.12)	1 (9.09)		
1	14 (14.29)	1 (9.09)		
2	10 (10.20)	1 (9.09)		
3	63 (64.29)	7 (63.64)		
4	5 (5.10)	1 (9.09)		
SMG, n (%)			0.791	
0	6 (6.12)	0 (0.00)		
1	7 (7.14)	1 (9.09)		
2	29 (29.59)	2 (18.18)		
3	53 (54.08)	8 (72.73)		
4	3 (3.06)	0 (0.00)		
PG: parotid gland; SMG: submaxillary gland

Fig. 2 Longitudinal ultrasound images of the minor salivary glands in patients with primary Sjögren’s syndrome (pSS). c and d Gray-scale longitudinal images showing the typical glandular structure of the minor salivary glands without significant abnormalities. e Composite image including gray-scale and Doppler ultrasound showing minimal vascular flow within the gland, indicating no significant inflammatory changes. f Longitudinal gray-scale image demonstrating reduced echogenicity of the gland, suggesting possible glandular involvement

Discussion

In this study, we utilized SWE to evaluate minor salivary gland involvement in ACA-positive patients with pSS. Our findings revealed that the overall positivity rate for ACA in patients with pSS was 14.5%, and patients in the ACA-positive group had significantly fewer minor salivary glands and higher mean and maximum Young’s moduli than those in the ACA-negative group.

ACA is a serum marker antibody for systemic sclerosis and is also expressed in other autoimmune diseases such as systemic lupus erythematosus, biliary cirrhosis, rheumatoid arthritis, and pSS [9]. In pSS, patients who test positive for ACA are considered a distinct subgroup, with an incidence of approximately 3.7% − 27%, as reported previously [10]. Previous studies have suggested that salivary gland involvement is more severe in ACA-positive patients and that the presence of antibodies significantly correlates with significant deterioration of exocrine gland function [2].

SWE, a noninvasive tool to quantify the degree of glandular elasticity and fibrosis, is widely used in the assessment of pSS owing to its safety, simplicity, and low dependence on the subjective judgment of the operator [11]. Various studies have confirmed that the elastic moduli of the bilateral parotid and submandibular glands in patients with pSS are higher than those in healthy controls, indicating a more significant increase in the stiffness of the affected glands in pSS [12–14]. The results of the present study showed that the average number of labial glands in patients with pSS decreased in the left, right, and middle lower lips, with typical hypoechoic and hyperechoic glandular structures. However, compared to the ACA-negative group, patients in the ACA-positive group had fewer glands, and their mean and maximum elastic modulus values were significantly higher, suggesting higher glandular stiffness. However, there was no significant difference in FS between the two groups. Nakamura et al. evaluated this for the first time using the quantitative analysis method of Azan Mallory staining and found that the degree of salivary gland fibrosis was more severe in ACA-positive patients than in the negative group [15]. Therefore, the pathological role of salivary gland fibrosis in pSS may be underestimated if only the FS is evaluated.

We found that patients with ACA-positive pSS had an older age of onset and diagnosis and were more likely to have clinical symptoms, such as Raynaud’s phenomenon, and yellowing of the skin and sclera, whereas oral and ocular dryness and joint involvement did not differ significantly from those in the negative group, in line with the results reported in the literature [3]. There are three pairs of major salivary glands distributed in the oral and maxillofacial regions, namely the parotid, submandibular, and sublingual glands, as well as minor salivary glands, such as the labial and lingual glands, which are located throughout the submucosa. The saliva secreted by the parotid and submandibular glands is predominantly plasma, whereas the saliva secreted by the sublingual and minor salivary glands is predominantly mucus. The parotid and submandibular glands were similarly involved in both groups, which may explain the presence of significant dry mouth symptoms in patients with similar reductions in plasma salivary secretion. The current assessment of oral dryness symptoms in patients with pSS is highly subjective, and the salivary flow rate mainly assesses the total amount of plasma saliva. Therefore, further exploration of more detailed methods of grading and evaluating oral symptoms may help determine treatment choices and prognosis in cases with different salivary gland involvement.

Among the patients with pSS included in this study, the proportion with liver involvement was also higher in the ACA-positive group, suggesting the need to consider the possibility of coexisting autoimmune liver diseases in follow-up patients. Additionally, antibody-positive patients had a significantly higher risk of developing malignant tumors, which should be considered.

Regarding the antibody phenotype, the anti-SSB antibody positivity rates of ACA-positive pSS patients were lower than those of negative patients, consistent with the findings of previous studies [15–18]. Therefore, patients with apparent dryness symptoms whose antibody tests are anti-Ro/SSA positive, anti-SSB negative, and ACA positive need further relevant examinations such as salivary gland biopsy and ultrasound to prevent missed diagnosis.

This study had several limitations. First, the sample size was relatively small. Second, the study was retrospective and most patients had a long history of the disease at the time of enrollment, which prevented a comprehensive assessment of their clinical presentation at disease onset. There was also potential recall bias due to the reliance on patient-reported disease duration, which could affect the accuracy of the findings. Additionally, the lack of clinical evaluation tools for pSS limited the scope of this study.

In conclusion, we found that patients with ACA-positive pSS were a subgroup with different clinical presentations: They were older at onset and diagnosis, with more severe involvement of the minor salivary glands. Anti-SSA antibody positivity was associated with lower anti-SSB antibody positivity and clinical manifestations, such as Raynaud’s phenomenon and sclerosis of the fingertips. Recent advancements in SWE technology, including enhanced imaging resolution and improved precision in quantitative analysis, have made it a more reliable tool for assessing glandular fibrosis and elasticity changes. SWE is widely utilized in evaluating salivary gland involvement in pSS patients, offering objective, quantitative data on glandular stiffness and minimizing operator dependency. This technology quantitatively assesses the tissue stiffness of the affected salivary glands, providing a solid foundation for stratifying pSS patients and serving as a crucial method for disease assessment. In future clinical practice, SWE could be integrated with other imaging techniques, such as magnetic resonance imaging (MRI), to enable multimodal assessments. This combined approach offers comprehensive insights into glandular structure, stiffness, blood flow, and function, leading to a more precise depiction of glandular pathology. Further exploration of detailed methods for grading and evaluating oral symptoms is essential for individualized evaluation of salivary gland involvement, potentially guiding treatment choices and improving prognosis.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Xujie Wang, Xin Chang, Ajun Wang, Fenglin Dong and Jian Wu. The first draft of the manuscript was written by Xinyu Wang, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by the youth talent support program of Suzhou Municipal Health Commission (No. GSWS2020018, Dr Chang).

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the First Affiliated Hospital of Soochow University (2020105).

Informed consent

Not applicable.

The work is attributed to Departments of Rheumatology, The First Affiliated Hospital of Soochow University.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Fox RI Sjögren’s syndrome Lancet 2005 366 9482 321 331 10.1016/S0140-6736(05)66990-5 16039337
Fox RI. Sjögren’s syndrome. Lancet. 2005;366(9482):321–31.16039337
2. Baer AN Medrano L McAdams-DeMarco M Gniadek TJ Association of anticentromere antibodies with more severe exocrine glandular dysfunction in Sjögren’s syndrome: analysis of the Sjögren’s international collaborative clinical alliance cohort Arthritis Care Res (Hoboken) 2016 68 10 1554 1559 10.1002/acr.22859 26867144
Baer AN, Medrano L, McAdams-DeMarco M, Gniadek TJ. Association of anticentromere antibodies with more severe exocrine glandular dysfunction in Sjögren’s syndrome: analysis of the Sjögren’s international collaborative clinical alliance cohort. Arthritis Care Res (Hoboken). 2016;68(10):1554–9.26867144
3. Tsukamoto M Suzuki K Takeuchi T Clinical and immunological features of anti-centromere antibody-positive primary Sjögren’s syndrome Rheumatol Ther 2018 5 2 499 505 10.1007/s40744-018-0126-2 30255483
Tsukamoto M, Suzuki K, Takeuchi T. Clinical and immunological features of anti-centromere antibody-positive primary Sjögren’s syndrome. Rheumatol Ther. 2018;5(2):499–505.30255483
4. Baldini C Zabotti A Filipovic N Vukicevic A Luciano N Ferro F Lorenzon M De Vita S Imaging in primary Sjögren’s syndrome: the ‘obsolete and the new’ Clin Exp Rheumatol 2018 36 Suppl 112 215 221 30156542
Baldini C, Zabotti A, Filipovic N, Vukicevic A, Luciano N, Ferro F, Lorenzon M, De Vita S. Imaging in primary Sjögren’s syndrome: the ‘obsolete and the new.’ Clin Exp Rheumatol. 2018;36(Suppl 112):215–21.30156542
5. Vachutka J Sedlackova Z Furst T Herman M Herman J Salzman R Dolezal L Evaluation of the effect of tissue compression on the results of shear wave elastography measurements Ultrason Imaging 2018 40 6 380 393 10.1177/0161734618793837 30101677
Vachutka J, Sedlackova Z, Furst T, Herman M, Herman J, Salzman R, Dolezal L. Evaluation of the effect of tissue compression on the results of shear wave elastography measurements. Ultrason Imaging. 2018;40(6):380–93.30101677
6. Taljanovic MS Gimber LH Becker GW Latt LD Klauser AS Melville DM Gao L Witte RS Shear-wave elastography: basic physics and musculoskeletal applications Radiographics 2017 37 3 855 870 10.1148/rg.2017160116 28493799
Taljanovic MS, Gimber LH, Becker GW, Latt LD, Klauser AS, Melville DM, Gao L, Witte RS. Shear-wave elastography: basic physics and musculoskeletal applications. Radiographics. 2017;37(3):855–70.28493799
7. Wang X Wang A Zhan X Xu L Chang X Dong F Value of conventional ultrasound and shear wave elastography in assessing disease activity and prognosis in female patients with Sjögren’s syndrome Clin Exp Rheumatol 2022 40 12 2350 2356 36305348
Wang X, Wang A, Zhan X, Xu L, Chang X, Dong F. Value of conventional ultrasound and shear wave elastography in assessing disease activity and prognosis in female patients with Sjögren’s syndrome. Clin Exp Rheumatol. 2022;40(12):2350–6.36305348
8. Shiboski CH Shiboski SC Seror R Criswell LA Labetoulle M Lietman TM Rasmussen A Scofield H Vitali C Bowman SJ 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 Ann Rheum Dis 2017 76 1 9 16 10.1136/annrheumdis-2016-210571 27789466
Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, Rasmussen A, Scofield H, Vitali C, Bowman SJ, 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. Ann Rheum Dis. 2017;76(1):9–16.27789466
9. Fritzler MJ Rattner JB Luft LM Edworthy SM Casiano CA Peebles C Mahler M Historical perspectives on the discovery and elucidation of autoantibodies to centromere proteins (CENP) and the emerging importance of antibodies to CENP-F Autoimmun Rev 2011 10 4 194 200 10.1016/j.autrev.2010.09.025 20933614
Fritzler MJ, Rattner JB, Luft LM, Edworthy SM, Casiano CA, Peebles C, Mahler M. Historical perspectives on the discovery and elucidation of autoantibodies to centromere proteins (CENP) and the emerging importance of antibodies to CENP-F. Autoimmun Rev. 2011;10(4):194–200.20933614
10. Fayyaz A Kurien BT Scofield RH Autoantibodies in Sjögren’s syndrome Rheum Dis Clin North Am 2016 42 3 419 434 10.1016/j.rdc.2016.03.002 27431345
Fayyaz A, Kurien BT, Scofield RH. Autoantibodies in Sjögren’s syndrome. Rheum Dis Clin North Am. 2016;42(3):419–34.27431345
11. Mo YQ Hao SY Li QH Liang JJ Luo Y Lan YQ Zhong JL Wang JW Zhang XP Huang WK Ultrasonography predicts the results of labial salivary gland biopsy in patients with suspected Sjögren’s syndrome a matrix risk model Ther Adv Musculoskelet Dis 2021 13 1759720x211010592 10.1177/1759720X211010592 33995602
Mo YQ, Hao SY, Li QH, Liang JJ, Luo Y, Lan YQ, Zhong JL, Wang JW, Zhang XP, Huang WK, et al. Ultrasonography predicts the results of labial salivary gland biopsy in patients with suspected Sjögren’s syndrome a matrix risk model. Ther Adv Musculoskelet Dis. 2021;13:1759720x211010592.33995602
12. Świecka M Paluch Ł Pietruski P Maślińska M Zakrzewski J Kwiatkowska B Shear wave elastography as a potential additional diagnostic tool in primary Sjögren’s syndrome: an observational study Rheumatol Int 2022 42 9 1579 1587 10.1007/s00296-022-05120-5 35507104
Świecka M, Paluch Ł, Pietruski P, Maślińska M, Zakrzewski J, Kwiatkowska B. Shear wave elastography as a potential additional diagnostic tool in primary Sjögren’s syndrome: an observational study. Rheumatol Int. 2022;42(9):1579–87.35507104
13. Samier-Guérin A Saraux A Gestin S Cornec D Marhadour T Devauchelle-Pensec V Bressollette L Nonent M Jousse-Joulin S Can ARFI elastometry of the salivary glands contribute to the diagnosis of Sjögren’s syndrome? Joint Bone Spine 2016 83 3 301 306 10.1016/j.jbspin.2015.11.002 26678002
Samier-Guérin A, Saraux A, Gestin S, Cornec D, Marhadour T, Devauchelle-Pensec V, Bressollette L, Nonent M, Jousse-Joulin S. Can ARFI elastometry of the salivary glands contribute to the diagnosis of Sjögren’s syndrome? Joint Bone Spine. 2016;83(3):301–6.26678002
14. Ma H Liu L Sun X Liu M Liu Z The diagnostic value of shear-wave elastography in the salivary glands of patients with primary Sjögren syndrome Int J Rheum Dis 2023 26 7 1314 1320 10.1111/1756-185X.14734 37218589
Ma H, Liu L, Sun X, Liu M, Liu Z. The diagnostic value of shear-wave elastography in the salivary glands of patients with primary Sjögren syndrome. Int J Rheum Dis. 2023;26(7):1314–20.37218589
15. Nakamura H Kawakami A Hayashi T Iwamoto N Okada A Tamai M Yamasaki S Ida H Eguchi K Anti-centromere antibody-seropositive Sjögren’s syndrome differs from conventional subgroup in clinical and pathological study BMC Musculoskelet Disord 2010 11 140 10.1186/1471-2474-11-140 20591195
Nakamura H, Kawakami A, Hayashi T, Iwamoto N, Okada A, Tamai M, Yamasaki S, Ida H, Eguchi K. Anti-centromere antibody-seropositive Sjögren’s syndrome differs from conventional subgroup in clinical and pathological study. BMC Musculoskelet Disord. 2010;11:140.20591195
16. Salliot C Gottenberg JE Bengoufa D Desmoulins F Miceli-Richard C Mariette X Anticentromere antibodies identify patients with Sjögren’s syndrome and autoimmune overlap syndrome J Rheumatol 2007 34 11 2253 2258 17937465
Salliot C, Gottenberg JE, Bengoufa D, Desmoulins F, Miceli-Richard C, Mariette X. Anticentromere antibodies identify patients with Sjögren’s syndrome and autoimmune overlap syndrome. J Rheumatol. 2007;34(11):2253–8.17937465
17. Li Y Bookman AAM Comparison of effect on sicca symptoms of anticentromere antibody-positive Sjögren syndrome and primary sjögren syndrome alone J Rheumatol 2020 47 6 876 880 10.3899/jrheum.190462 31615914
Li Y, Bookman AAM. Comparison of effect on sicca symptoms of anticentromere antibody-positive Sjögren syndrome and primary sjögren syndrome alone. J Rheumatol. 2020;47(6):876–80.31615914
18. Katano K Kawano M Koni I Sugai S Muro Y Clinical and laboratory features of anticentromere antibody positive primary Sjögren’s syndrome J Rheumatol 2001 28 10 2238 2244 11669163
Katano K, Kawano M, Koni I, Sugai S, Muro Y. Clinical and laboratory features of anticentromere antibody positive primary Sjögren’s syndrome. J Rheumatol. 2001;28(10):2238–44.11669163
