ABSTRACT
OBJECTIVES: To compare focus score (FS) and other histopathological features between paired labial and parotid salivary gland biopsies in a diagnostic cohort of suspected Sjögren's disease (SjD) patients. METHODS: Labial and parotid salivary gland biopsies were simultaneously obtained from patients with sicca complaints, suspected of having SjD. Biopsies were formalin fixed and paraffin embedded. Sections were stained with haematoxylin & eosin (H&E) and for CD3, CD20, CD45, cytokeratin, CD21, Bcl6, activation induced deaminase (AID), and IgA/IgG. FS and other histopathological features characteristic for SjD were analysed. RESULTS: Based on the expert opinion of three experienced rheumatologists, 36 patients were diagnosed as SjD and 63 as non-SjD sicca patients. When taking all patients together, absolute agreement of various histopathological features between labial and parotid biopsies was high and varied between 80% (FS) and 93% ((pre-)lymphoepithelial lesions (LELs)). More labial gland biopsies had a FS ≥ 1 compared with their parotid counterpart. Accordingly, the area of infiltrate was larger in labial gland biopsies. When considering only SjD patients, labial glands contained significantly less B-lymphocytes, GCs/mm2 and less severe LELs compared with parotid glands. CONCLUSION: Labial and parotid glands from SjD patients contain similar histopathological key features, and thus both glands can be used for diagnosis and classification of SjD. However, parotid salivary glands reveal more evident B-lymphocyte related features, while labial glands exhibit more inflammation, which may be partially unrelated to SjD.
ABSTRACT
OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of the labial salivary gland biopsy based on multiple histopathological features in patients with suspected primary Sjögren syndrome (pSS). METHODS: Patients from a diagnostic sicca cohort with clinically suspected pSS who underwent a labial gland biopsy were included. Patients were categorized as having pSS or non-Sjögren syndrome sicca (non-SS sicca) based on vignettes scored by an expert panel. Labial gland biopsies were analyzed for the presence of four histopathological features: focus score (FS) ≥1, prelymphoepithelial and lymphoepithelial lesions, immunoglobulin G plasma cell shift, and germinal centers. Sensitivity and specificity of histologic features were calculated, and the optimal cutoff value for the number of histopathological features needed to diagnose pSS was determined with receiver operating curve analysis. RESULTS: A total of 38 patients were categorized as having pSS and 65 as having non-SS sicca. In labial gland biopsies of patients with pSS, the prevalence of FS ≥1 was 82%, followed by 68% for pre-lymphoepithelial and lymphoepithelial lesions, 63% for plasma cell shift, and 24% for germinal centers. Although FS ≥1 showed the highest sensitivity for patients with pSS (82%), specificity was higher for the other three features (98%-100%). The presence of two or more (of four) histopathological features had almost comparable sensitivity to FS alone, but specificity increased with 12% to 100%. For fulfillment of American College of Rheumatology/EULAR criteria, specificity increased from 84% to 95% when an abnormal biopsy was defined by the presence of two or more histopathological features instead of FS ≥1 only. CONCLUSION: The diagnostic accuracy of the labial gland biopsy increases when other histopathological features besides FS are taken into account, by reducing the number of false-positive biopsies.
Subject(s)
Sjogren's Syndrome , Humans , Sjogren's Syndrome/diagnosis , Sjogren's Syndrome/pathology , Salivary Glands, Minor/pathology , Sensitivity and Specificity , Germinal Center , BiopsyABSTRACT
OBJECTIVE: Salivary glands of primary SS (pSS) patients characteristically harbour periductal infiltrates, in which lymphoepithelial lesions (LELs) can develop. LELs are composed of hyperplastic ductal epithelium with infiltrating lymphocytes and may assist in the challenging diagnostic process of pSS. As manual identification of LELs remains difficult, we aimed to identify LELs by using an objective digital image analysis (DIA) algorithm that detects intraepithelial lymphocytes. METHODS: A virtual triple-staining technique developed for this study was used to count intraepithelial lymphocytes in consecutive slides stained for CD3 (T-lymphocytes), high-molecular-weight cytokeratin (hmwCK) (striated ducts) and CD20 (B-lymphocytes) in labial and parotid gland biopsies in a diagnostic cohort of 109 sicca patients. Patients were classified as having pSS or non-SS according to the ACR-EULAR classification criteria. RESULTS: T-lymphocytes were detected in almost all analysed ducts of pSS and non-SS sicca patients, whereas intraepithelial B-lymphocytes were present in 59-68% of labial and parotid gland biopsies of pSS patients, against only 2-3% of patients classified as non-SS. Intraepithelial B-lymphocytes were found in almost all striated ducts with hyperplasia (LELs). Remarkably, â¼25% of analysed striated ducts without hyperplasia of pSS patients also contained B-lymphocytes (precursor-LELs). Furthermore, presence of intraepithelial B-lymphocytes was associated with clinical parameters of pSS (i.e. serology). CONCLUSION: The presence of intraepithelial B-lymphocytes in salivary gland biopsies of sicca patients is a clear indicator of pSS and can be used as an objective alternative to LEL scoring. Therefore, identification of B-lymphocyte-containing ducts should be added to the diagnostic histopathological work-up of patients suspected of pSS.
Subject(s)
Intraepithelial Lymphocytes , Sjogren's Syndrome , Humans , Intraepithelial Lymphocytes/pathology , Hyperplasia/pathology , Salivary Glands/pathology , B-LymphocytesABSTRACT
Patients with primary Sjogren's syndrome (pSS) are at risk of developing extranodal marginal zone lymphoma (ENMZL) of the mucosa-associated lymphoid tissue (MALT) in the parotid glands. Unlike recurrent genomic aberrations observed in MALT lymphoma, which were not associated with pSS (non-pSS), it is unknown which somatic aberrations underlie the development of pSS-associated MALT lymphomas. Whole-exome sequencing was performed on 17 pSS-associated MALT lymphomas. In total, 222 nonsynonymous somatic variants affecting 182 genes were identified across the 17 cases. The median number of variants was seven (range 2-78), including three cases with a relatively high mutational load (≥24/case). Out of 16 recurrently mutated genes, ID3, TBL1XR1, PAX5, IGLL5 and APC are known to be associated with lymphomagenesis. A total of 18 copy number alterations were detected in eight cases. MALT1 translocations were not detected. With respect to outcome, only two cases relapsed outside of the salivary glands. Both had a high mutational load, suggesting a more advanced stage of lymphoma. The low mutational load and lack of a clear lymphoma-related mutation profile suggests that localized pSS-associated MALT lymphomas are genomically more stable than non-pSS MALT lymphomas and most likely depend on a stimulatory micro-environment.
ABSTRACT
OBJECTIVE: The involvement of salivary glands in primary SS (pSS) can be assessed in different ways: histopathology, salivary flow and ultrasonography. To understand the relative value of these different approaches, it is crucial to understand the relationship between them. As we routinely perform these three modalities in the parotid gland for disease evaluation, our aim was to investigate the construct validity between these modalities in one and the same gland. METHODS: Consecutive sicca patients underwent a multidisciplinary diagnostic workup including parotid gland biopsy, collection of parotid gland-specific saliva and parotid gland ultrasonography. Patients who were classified as pSS according to the ACR-EULAR criteria were included. Construct validity was assessed using Spearman's correlation coefficients. RESULTS: The 41 included pSS patients completed a full workup within a mean time interval of 2.6 months. Correlations between histopathological features and stimulated parotid salivary flow were fair (ρ = -0.123 for focus score and ρ = -0.259 for percentage of CD45+ infiltrate). Likewise, poor correlations were observed between stimulated parotid salivary flow and parotid ultrasonography (ρ = -0.196). Moderate to good associations were found between the histopathological items focus score and the percentage of CD45+ infiltrate, with parotid US scores (total US score: ρ = 0.510 and ρ = 0.560; highest for homogeneity: ρ = 0.574 and ρ = 0.633). CONCLUSION: Although pSS-associated ultrasonographic findings did correlate with histopathological features, the three modalities that evaluate salivary gland involvement assess different (or at best partly related) constructs. Therefore histopathology, salivary flow and ultrasonography are complementary measurements and cannot directly replace each other in the workup of pSS.
Subject(s)
Parotid Gland , Sjogren's Syndrome , Humans , Parotid Gland/diagnostic imaging , Parotid Gland/pathology , Saliva , Salivary Glands/diagnostic imaging , Salivary Glands/pathology , Sjogren's Syndrome/diagnostic imaging , Sjogren's Syndrome/pathology , UltrasonographyABSTRACT
Background: While all salivary glands (SGs) can be involved in primary Sjögren's syndrome (pSS), their respective role in pathogenesis remains unclear. Our objective was to assess immunopathway activation in paired parotid and labial gland tissue from biopsy-positive and biopsy-negative pSS and non-SS sicca patients. Methods: Paraffin-embedded, paired parotid and labial salivary gland tissue and peripheral blood mononuclear cells were obtained from 39 pSS and 20 non-SS sicca patients. RNA was extracted, complementary DNA libraries were prepared and sequenced. For analysis of differentially expressed genes (DEGs), patients were subdivided based on fulfillment of ACR-EULAR criteria and histopathology. Results: With principal component analysis, only biopsy-positive pSS could be separated from non-SS sicca patients based on SG gene expression. When comparing the transcriptome of biopsy-positive pSS and biopsy-negative non-SS sicca patients, 1235 and 624 DEGs (FDR<0.05, log2FC<-1 or >1) were identified for parotid and labial glands, respectively. The number of DEGs between biopsy-negative pSS and non-SS sicca patients was scarce. Overall, transcript expression levels correlated strongly between parotid and labial glands (R2 = 0.86, p-value<0.0001). Gene signatures present in both glands of biopsy-positive pSS patients included IFN-α signaling, IL-12/IL-18 signaling, CD3/CD28 T-cell activation, CD40 signaling in B-cells, DN2 B-cells, and FcRL4+ B-cells. Signature scores varied considerably amongst pSS patients. Conclusion: Transcriptomes of paired major and minor SGs in pSS were overall comparable, although significant inter-individual heterogeneity in immunopathway activation existed. The SG transcriptome of biopsy-negative pSS was indistinguishable from non-SS sicca patients. Different patterns of SG immunopathway activation in pSS argue for personalized treatment approaches.
Subject(s)
Salivary Glands, Minor/metabolism , Salivary Glands/metabolism , Sjogren's Syndrome/etiology , Transcriptome , Autoimmunity , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Biomarkers , Biopsy , Disease Susceptibility , Female , Gene Expression Profiling/methods , Gene Expression Regulation , Humans , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Male , Models, Biological , Salivary Glands/pathology , Salivary Glands, Minor/pathology , Sjogren's Syndrome/diagnosis , Sjogren's Syndrome/metabolismABSTRACT
OBJECTIVE: Patients with SjÓ§gren's syndrome (SS) have an increased risk of developing malignant B cell lymphomas, particularly mucosa-associated lymphoid tissue (MALT)-type lymphomas. We have previously shown that a predominant proportion of patients with SS-associated salivary gland MALT lymphoma express somatically hypermutated IgM with strong amino acid sequence homology with stereotypic rheumatoid factors (RFs). The present study was undertaken in a larger cohort of patients with SS-associated MALT lymphoma to more firmly assess the frequency of RF reactivity and the significance of somatic IGV-region mutations for RF reactivity. METHODS: B cell antigen receptors (BCRs) of 16 patients with SS-associated salivary gland MALT lymphoma were analyzed. Soluble recombinant IgM was produced of 12 MALT lymphoma samples, including 1 MALT lymphoma sample that expressed an IgM antibody fitting in a novel IGHV3-30-encoded stereotypic IGHV subset. For 4 of the 12 IgM antibodies from MALT lymphoma samples, the somatically mutated IGHV and IGKV gene sequences were reverted to germline configurations. Their RF activity and binding affinity were determined by enzyme-linked immunosorbent assay and surface plasmon resonance, respectively. RESULTS: Nine (75%) of the 12 IgM antibodies identified in patients with SS-associated salivary gland MALT lymphoma displayed strong monoreactive RF activity. Reversion of the IGHV and IGKV mutations to germline configuration resulted in RF affinities for IgG that were significantly lower for 3 of the 4 somatically mutated IgM antibodies. In stereotypic IGHV3-7/IGKV3-15-encoded RFs, a recurrent replacement mutation in the IGKV3-15-third complementarity-determining region was found to play a pivotal role in the affinity for IgG-Fc. CONCLUSION: A majority of patients with SS-associated salivary gland MALT lymphoma express somatically mutated BCRs that are selected for monoreactive, high-affinity binding of IgG-Fc. These data underscore the notion that soluble IgG, most likely in immune complexes in inflamed tissues, is the principal autoantigen in the pathogenesis of a variety of B cell lymphomas, particularly SS-associated MALT lymphomas.
Subject(s)
Immunoglobulin G/immunology , Lymphoma, B-Cell, Marginal Zone/genetics , Mutation/immunology , Rheumatoid Factor/immunology , Sjogren's Syndrome/genetics , Humans , Lymphoma, B-Cell, Marginal Zone/immunology , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, B-Cell/immunology , Salivary Glands/immunologyABSTRACT
In primary Sjögren's syndrome (pSS), FcRL4+ B cells are present in inflamed salivary gland tissue, within or in close proximity to ductal epithelium. FcRL4 is also expressed by nearly all pSS-related mucosa-associated lymphoid tissue (MALT) B cell lymphomas, linking FcRL4 expression to lymphomagenesis. Whether glandular FcRL4+ B cells are pathogenic, how these cells originate, and how they functionally differ from FcRL4- B cells in pSS is unclear. This study aimed to investigate the phenotype and function of FcRL4+ B cells in the periphery and parotid gland tissue of patients with pSS. First, circulating FcRL4+ B cells from 44 pSS and 54 non-SS-sicca patients were analyzed by flow cytometry. Additionally, RNA sequencing of FcRL4+ B cells sorted from parotid gland cell suspensions of 6 pSS patients was performed. B cells were sorted from cell suspensions as mini bulk (5 cells/well) based on the following definitions: CD19+CD27-FcRL4- ('naive'), CD19+CD27+FcRL4- ('memory'), and CD19+FcRL4+ B cells. We found that, although FcRL4+ B cells were not enriched in blood in pSS compared with non-SS sicca patients, these cells generally exhibited a pro-inflammatory phenotype. Genes coding for CD11c (ITGAX), T-bet (TBX21), TACI (TNFRSF13B), Src tyrosine kinases and NF-κB pathway-related genes were, among others, significantly upregulated in glandular FcRL4+ B cells versus FcRL4- B cells. Pathway analysis showed upregulation of B cell activation, cell cycle and metabolic pathways. Thus, FcRL4+ B cells in pSS exhibit many characteristics of chronically activated, pro-inflammatory B cells and their gene expression profile suggests increased risk of lymphomagenesis. We postulate that these cells contribute significantly to the epithelial damage seen in the glandular tissue and that FcRL4+ B cells are an important treatment target in pSS.
Subject(s)
B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Epithelium/immunology , Epithelium/metabolism , Gene Expression Profiling , Receptors, Fc/metabolism , Sjogren's Syndrome/etiology , Transcriptome , Aged , Biomarkers , Disease Susceptibility , Female , Gene Expression Regulation , Humans , Immunohistochemistry , Immunophenotyping , Male , Middle Aged , Receptors, Fc/genetics , Salivary Glands/immunology , Salivary Glands/metabolism , Signal Transduction , Sjogren's Syndrome/metabolism , Sjogren's Syndrome/pathologySubject(s)
Sjogren's Syndrome , Biopsy , Germinal Center , Humans , Proto-Oncogene Proteins c-bcl-6/genetics , Salivary GlandsABSTRACT
BACKGROUND: Several small open-label studies have suggested efficacy of abatacept-a co-stimulation inhibitor-in patients with primary Sjögren's syndrome. These promising results warranted further evaluation. We therefore aimed to further assess the safety and efficacy of abatacept compared with placebo in patients with primary Sjögren's syndrome. METHODS: We did a single-centre, randomised, double-blind, placebo-controlled, phase 3 trial at the University Medical Center Groningen (Groningen, Netherlands). We included patients with primary Sjögren's syndrome fulfilling the American-European Consensus Group criteria, aged 18 years or older, with positive salivary gland biopsies, time from diagnosis of 7 years or less, and a European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or more. Independent pharmacists randomly allocated patients (1:1) to either the abatacept group or placebo group using a computer-generated sequence stratified by previous use of disease-modifying anti-rheumatic drugs. Patients received at-home subcutaneous injections of abatacept (125 mg) or placebo once a week for 24 weeks. The primary outcome was the between-group difference in ESSDAI score at week 24. Efficacy was analysed in patients who received at least one drug dose and for whom post-baseline data were collected. Safety was analysed in all patients who received at least one drug dose. FINDINGS: Between Aug 14, 2014, and Aug 23, 2018, 580 patients were reviewed for eligibility, of which 80 patients were randomly assigned to receive study treatment. Efficacy was analysed in 40 patients receiving abatacept and 39 patients receiving placebo (one patient in this group was lost to follow-up). The primary outcome did not significantly differ between the treatment groups. The adjusted mean difference in ESSDAI score at week 24 between the abatacept group and placebo group was -1·3 (95% CI -4·1 to 1·6). No deaths or treatment-related serious adverse events occurred. In 38 (95%) of 40 patients in the abatacept group, 103 adverse events occurred, including one serious adverse event and 46 infections. In 38 (95%) of 40 patients in the placebo group, 87 adverse events occurred, including four serious adverse events and 49 infections. INTERPRETATION: On the basis of this trial, we cannot recommend abatacept treatment as standard of care to reduce systemic disease activity in patients with primary Sjögren's syndrome. Further studies should evaluate whether patients with specific clinical manifestations and biological characteristics might benefit from abatacept treatment. FUNDING: Bristol-Myers Squibb.
ABSTRACT
OBJECTIVES: Lymphoepithelial lesions (LELs) in salivary glands are associated with primary Sjögren's syndrome (pSS). LELs are composed of hyperplastic epithelium infiltrated with lymphocytes. The objective of this study was obtaining insight in the relative roles of intraepithelial B- and T-lymphocytes in the formation of LELs in salivary glands of pSS patients. METHODS: Parotid and labial salivary gland biopsies of pSS patients (n=15), non-SS sicca patients (n=5) and non-sicca controls (n=5) were analysed. Serial sections were stained with H & E and for cytokeratin, CD20 and CD3. Striated ducts with lymphocytes, but without hyperplasia, and striated ducts with LELs were identified in H & E and cytokeratin stained sections. LELs were classified in successive stages of severity based on the amount of hyperplasia (stage1-3). Numbers of B- and T-lymphocytes within striated ducts and LELs were counted in CD20 and CD3 stained sections. RESULTS: Lymphocyte-containing striated ducts of both salivary glands of all pSS and control patients harboured T-lymphocytes, scattered throughout the ductal epithelium. In contrast, B-lymphocytes were exclusively found in a small fraction (21%) of striated ducts without hyperplasia and in nearly all striated ducts with LELs of pSS patients, but not in controls. In striated ducts with LELs B-lymphocytes were mostly located in the areas of proliferating epithelium. Numbers of B-lymphocytes and B/T-ratios increased significantly with higher severity of LELs. This was even more pronounced in the parotid than in the labial gland. CONCLUSIONS: We conclude there is an association between presence of intraepithelial B-lymphocytes and the formation of LELs in salivary glands of pSS patients.
Subject(s)
B-Lymphocytes/immunology , Parotid Gland , Salivary Glands, Minor , Sjogren's Syndrome , Humans , Parotid Gland/immunology , Parotid Gland/pathology , Salivary Glands , Salivary Glands, Minor/immunology , Salivary Glands, Minor/pathology , Sjogren's Syndrome/immunology , Sjogren's Syndrome/pathologyABSTRACT
Giant cell arteritis (GCA) can be classified into Cranial(C)-GCA and Large Vessel(LV)-GCA. Based on analysis of temporal arteries, GCA is postulated to be T-cell-mediated. Recently, a disturbed B-cell homeostasis was documented in newly diagnosed GCA patients. In the current study, we assessed the presence of B-cells and their level of ectopic organization in the aorta of LV-GCA patients. Aorta tissue samples of 9 histologically-proven LV-GCA patients and 22 age- and sex-matched atherosclerosis patients who underwent aortic aneurysm surgery were studied by immunohistochemistry. Sections were stained for B-cells, T-cells, follicular dendritic cells, high endothelial venules, germinal center B-cells, proliferating B-cells, macrophages, and plasma cells. Aortas of LV-GCA patients showed massive infiltration of B-cells, which clearly outnumbered T-cells, as opposed to C-GCA patients where, as previously reported, T-cells outnumber B-cells. B-cells were mainly found in the adventitia of the vessel wall and were organized into artery tertiary lymphoid organs. These tertiary lymphoid organs had germinal centers, proliferating B-cells and plasma cell niches. In conclusion, we found massive and organized B-cell infiltrates in the aorta of LV-GCA patients, which is in line with the previously documented decrease of circulating B-cells in active GCA. Our data indicate a role for B-cells in the pathogenesis of GCA and thus evoke further investigation into the factors determining the tissue tropism and organization of B-cells in GCA.
Subject(s)
Aorta/pathology , Atherosclerosis/pathology , B-Lymphocytes/pathology , Giant Cell Arteritis/pathology , Temporal Arteries/pathology , Tertiary Lymphoid Structures/physiopathology , Adventitia/pathology , Aged , Aortic Aneurysm/surgery , B-Lymphocytes/metabolism , Cell Proliferation , Female , Germinal Center/pathology , Humans , Immunohistochemistry , Male , Middle Aged , Plasma Cells/pathology , Retrospective Studies , T-Lymphocytes/pathologySubject(s)
Sjogren's Syndrome , Double-Blind Method , Humans , Rituximab , Salivary Glands , UltrasonographySubject(s)
Lymphoma, Non-Hodgkin , Lymphoma , Sjogren's Syndrome , Biopsy , Germinal Center , Humans , Risk Factors , Salivary Glands, MinorABSTRACT
The formation of lymphomononuclear cell infiltrates organising as periductal infiltrates in the salivary glands of patients with primary Sjögren's syndrome (pSS) is one of the hallmarks of the disease. Historically, the clinical role of salivary gland histopathology, most commonly performed on labial salivary gland biopsies, has been confined to the clinical classification and diagnosis of pSS whereby according to the ACR-EULAR a positive histopathology finding is a requirement for the diagnosis of pSS in the absence of anti-Ro/SSA antibodies. In recent years, further understanding of the heterogeneity of the immune cell infiltration and organisation within the salivary glands of pSS patients and its correlation with clinical manifestations of the disease has led to propose salivary gland histopathology as a novel tool able to identify patients at higher risk of developing more severe extraglandular manifestations and lymphoma. Furthermore, recent clinical developments in ongoing randomised clinical trials with novel biologics in pSS have focused on salivary glands histopathology to inform on patients stratification based on target validation, proof of drug efficacy and mechanisms of response/resistance to therapy. However, lack of standardisation of methodology and analysis has hindered the reproducibility of data from different groups and no definitive evidence in support of the use of salivary glands histopathology to inform clinical management of patients with pSS has been provided. In this review, we summarise recent evidence highlighting the promises and pitfalls of salivary glands histopathology in pSS emphasising the need for an international consensus on standardisation of methodology with validation in large prospective multicentre initiatives.
Subject(s)
Lymphoid Tissue/pathology , Salivary Glands/pathology , Sjogren's Syndrome/pathology , Antirheumatic Agents/therapeutic use , Biomarkers/analysis , Biopsy , Decision Support Techniques , Immunohistochemistry , Lymphoid Tissue/drug effects , Lymphoid Tissue/immunology , Predictive Value of Tests , Reproducibility of Results , Risk Assessment , Risk Factors , Salivary Glands/drug effects , Salivary Glands/immunology , Severity of Illness Index , Sjogren's Syndrome/drug therapy , Sjogren's Syndrome/immunology , Treatment OutcomeSubject(s)
Sjogren's Syndrome , Biomarkers , Humans , Lymphoid Tissue , T-Lymphocytes, Helper-InducerABSTRACT
Objectives: To validate the ACR-EULAR classification criteria for primary SS (pSS), and compare them to the American-European Consensus Group (AECG) and ACR criteria in a Dutch prospective diagnostic cohort. Methods: Consecutive patients (n = 129) referred for suspicion of pSS underwent a multidisciplinary evaluation, including a labial and/or parotid gland biopsy. Patients with an incomplete work-up (n = 8) or associated systemic auto-immune disease (n = 7) were excluded. The ACR-EULAR classification was compared with expert classification, AECG and ACR classification. Additionally, the accuracy of individual ACR-EULAR items in discriminating pSS from non-pSS was evaluated. The validity of criteria sets was described separately using parotid or labial gland biopsy results for classification. Results: Of the 114 evaluated patients, the expert panel classified 34 (30%) as pSS and 80 (70%) as non-pSS. Using labial gland biopsy results, ACR-EULAR classification showed 87% absolute agreement (κ = 0.73) with expert classification, with a sensitivity of 97% and specificity of 83%. Using the parotid gland biopsy results, the ACR-EULAR criteria performed excellently as well. Focus score, anti-SSA titre and ocular staining score showed good to excellent accuracy, whereas unstimulated whole saliva and Schirmer's test had poor accuracy. The ACR-EULAR and AECG criteria had equal validity. Compared with ACR classification, ACR-EULAR classification showed higher sensitivity but lower specificity. Conclusion: The ACR-EULAR criteria showed good agreement with expert classification, but some patients may be misclassified as pSS. Unstimulated whole saliva and Schirmer's test showed poor discriminative value. The ACR-EULAR criteria performed equally to the AECG criteria, and had higher sensitivity but lower specificity than the ACR criteria.
Subject(s)
Consensus , Ethnicity , Parotid Gland/pathology , Rheumatology/methods , Sjogren's Syndrome/classification , Biopsy , Female , Follow-Up Studies , Humans , Incidence , Male , Netherlands/epidemiology , Prospective Studies , Severity of Illness Index , Sjogren's Syndrome/diagnosis , Sjogren's Syndrome/ethnology , Time FactorsSubject(s)
Lymphoma, B-Cell, Marginal Zone , Sjogren's Syndrome , Biopsy , Germinal Center , Humans , Salivary GlandsABSTRACT
OBJECTIVE: Patients with primary Sjögren's syndrome (pSS) have an increased risk of developing non-Hodgkin's lymphoma (NHL), particularly parotid gland mucosa-associated lymphoid tissue (MALT) lymphomas. Presence of germinal centres (GCs) in labial gland biopsies has been suggested as predictive factor for NHL. We assessed whether presence of GCs is increased in labial gland biopsies from patients with pSS who developed parotid MALT lymphoma, the dominant NHL-subtype in pSS, compared with patients with pSS who did not develop lymphoma. METHODS: Eleven labial gland biopsies from patients with pSS that were taken prior to parotid MALT lymphoma development were compared with biopsies of 22 matched pSS controls (1:2) who did not develop lymphoma. Biopsies were evaluated for GCs (H&E and Bcl6). RESULTS: Labial gland biopsies of pSS MALT lymphoma patients, revealed GCs in 2/11 (18%) H&E sections and 3/11 (27%) Bcl6 stained sections. In controls, GCs were present in 4/22 (18%) of H&E sections and 5/22 (23%) of Bcl6 stained sections. CONCLUSION: Presence of GCs in labial gland biopsies does not differ between patients with pSS that develop parotid MALT lymphoma and patients with pSS who do not develop lymphoma. The presence of GCs in labial gland biopsies is therefore not a predictive factor for pSS-associated parotid MALT lymphomas.