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Standardisation of labial salivary gland histopathology in clinical trials in primary Sjogren's syndrome.

ABSTRACT: Labial salivary gland (LSG) biopsy is used in the classification of primary Sjögren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0-10 scale) and comments. Criteria for agreement were a mean score ?6/10 and 75% of respondents scoring ?6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus.

SUBMITTER: Fisher BA

PROVIDER: S-EPMC5530351 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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Standardisation of labial salivary gland histopathology in clinical trials in primary Sjögren's syndrome.

Fisher Benjamin A BA Jonsson Roland R Daniels Troy T Bombardieri Michele M Brown Rachel M RM Morgan Peter P Bombardieri Stefano S Ng Wan-Fai WF Tzioufas Athanasios G AG Vitali Claudio C Shirlaw Pepe P Haacke Erlin E Costa Sebastian S Bootsma Hendrika H Devauchelle-Pensec Valerie V Radstake Timothy R TR Mariette Xavier X Richards Andrea A Stack Rebecca R Bowman Simon J SJ Barone Francesca F

Annals of the rheumatic diseases 20161213 7

Labial salivary gland (LSG) biopsy is used in the classification of primary Sjögren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of ...[more]

PMID: 27965259

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Project description:ObjectiveA major characteristic of the autoimmune disease primary Sjögren's syndrome (SS) is salivary gland (SG) hypofunction. The inability of resident SG stem cells (SGSCs) to maintain homeostasis and saliva production has never been explained and limits our comprehension of mechanisms underlying primary SS. The present study was undertaken to investigate the role of salivary gland stem cells in hyposalivation in primary SS.MethodsSGSCs were isolated from parotid biopsy samples from controls and patients classified as having primary SS or incomplete primary SS, according to the American College of Rheumatology/European League Against Rheumatism criteria. Self-renewal and differentiation assays were used to determine SGSC regenerative potential, RNA was extracted for sequencing analysis, single telomere length analysis was conducted to determine telomere length, and frozen tissue samples were used for immunohistochemical analysis.ResultsSGSCs isolated from primary SS parotid gland biopsy samples were regeneratively inferior to healthy control specimens. We demonstrated that SGSCs from samples from patients with primary SS are not only lower in number and less able to differentiate, but are likely to be senescent, as revealed by telomere length analysis, RNA sequencing, and immunostaining. We further found that SGSCs exposed to primary SS-associated proinflammatory cytokines we induced to proliferate, express senescence-associated genes, and subsequently differentiate into intercalated duct cells. We also localized p16+ senescent cells to the intercalated ducts in primary SS SG tissue, suggesting a block in SGSC differentiation into acinar cells.ConclusionThis study represents the first characterization of SGSCs in primary SS, and also the first demonstration of a linkage between an autoimmune disease and a parenchymal premature-aging phenotype. The knowledge garnered in this study indicates that disease-modifying antirheumatic drugs used to treat primary SS are not likely to restore saliva production, and should be supplemented with fresh SGSCs to recover saliva production.

Project description:Objective: Salivary gland ultrasound (SGUS) is emerging as a valid tool in the management of primary Sjögren's syndrome (pSS). This study aimed to investigate whether pSS patients with normal-appearing or pathological SGUS findings showed different clinical, laboratory, and pathologic pSS-related features, and to compare the results by using two different SGUS scores. Methods: Consecutive pSS patients, according to the ACR-EULAR classification criteria, were evaluated. Salivary glands were scored using the early 1992 score by De Vita et al. and the latest 2019 OMERACT score, both being semiquantitative 0-3 scoring systems focused on ultrasonographic parenchymal inhomogeneity (grades 0 and 1, normal-appearing; grades 2 and 3, pathological). The patients were then divided into two groups: "SGUS normal-appearing" if all the salivary glands had normal-appearing parenchyma (grade 0 or 1), or "SGUS pathological" if the grade was 2 or 3 in at least one salivary gland. The associations between SGUS and pSS-related clinical, laboratory, and pathological features were then investigated in the two groups. Results: One hundred pSS patients were evaluated, the mean age (±SD) was 60.9 ± 12.0 years, and mean disease duration was 11.7 ± 7.2 years. Twenty-nine out of 100 (29%) patients were in the "SGUS normal-appearing" group and 71/100 (71%) were in the "SGUS pathological" group. A normal-appearing SGUS was significantly associated with the absence of anti-La/SSB antibodies (p < 0.001) and normal unstimulated salivary flow rate (p = 0.02) by both univariate and multivariate analyses. By univariate analysis, a normal-appearing SGUS was significantly associated also with the absence of rheumatoid factor (p = 0.002) and of serum monoclonal component (p = 0.003), ESSDAI < 5 (p = 0.03), and with a negative lip biopsy (p = 0.029). No associations were found with other items, including anti-Ro/SSA (p = 0.145), Schirmer's test (p = 0.793), ESSPRI (p = 0.47), and demographic data. No differences in these results were observed by using the two SGUS scoring systems. Conclusion: The SGUS allowed the identification of different phenotypes of pSS, and different SGUS scores focused on salivary gland inhomogeneity may be effective to this end.

Project description:Primary Sjögren's syndrome is a multisystem autoimmune disease characterized by hypofunction of salivary and lacrimal glands and possible multi-organ system manifestations. Over the past 15 years, three sets of diagnostic criteria have been proposed, but none has included salivary gland ultrasonography. However, recent studies support its role in the diagnosis and prognostic evaluation of patients with Sjögren's syndrome. This study aimed to determine the value of salivary gland ultrasonography in the diagnosis and prognosis of Sjögren's syndrome by relating ultrasonography severity scores to clinical and laboratory data.Seventy patients who fulfilled the 2002 American-European Consensus Group diagnostic criteria for primary Sjögren's syndrome were selected from 84 patients receiving care in specialized outpatient clinics at our institution from November 2013 to May 2016. Their serology, European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI), salivary flow rate, immunoglobulin G, and salivary and serum beta-2 microglobulin levels were measured. Salivary gland ultrasonography was performed by an experienced radiologist, using scores of 1-4 to classify salivary gland impairment.Salivary gland ultrasonography scores of 1 or 2 were associated with an ESSDAI < 5. Ultrasonography scores of 3 or 4 were associated with an ESSDAI ≥5 (p = 0.064), a positive antinuclear antibody test (p = 0.006), positive anti-Ro/SSA antibodies (p = 0.003), positive anti-La/SSB antibodies (p = 0.077), positive rheumatoid factor (p = 0.034), and immunoglobulin G levels > 1600 mg/dL (p = 0.077). Salivary flow rate was lower in patients with scores 3 or 4 (p = 0.001).This study provides further evidence that salivary gland ultrasonography can be used not only for diagnosis but also for prognostic evaluation of primary Sjögren's syndrome. These findings confirm what has been reported in the literature. However, further analyses involving larger matched samples are required to support this finding and include salivary gland ultrasonography as part of the diagnostic criteria for Sjögren's syndrome.

Dataset Information

Standardisation of labial salivary gland histopathology in clinical trials in primary Sjogren's syndrome.

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Standardisation of labial salivary gland histopathology in clinical trials in primary Sjögren's syndrome.

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