Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
1.
Rheumatology (Oxford) ; 63(10): 2670-2677, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-38538884

RESUMO

OBJECTIVES: To compare focus score 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, and for CD3, CD20, CD45, cytokeratin, CD21, Bcl6, activation-induced deaminase (AID) and IgA/IgG. Focus score 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% (focus score) and 93% [(pre-)lymphoepithelial lesions (LELs)]. More labial gland biopsies had a focus score ≥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 fewer B-lymphocytes and germinal centres/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.


Assuntos
Glândula Parótida , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/patologia , Feminino , Pessoa de Meia-Idade , Glândula Parótida/patologia , Masculino , Biópsia , Adulto , Idoso , Glândulas Salivares Menores/patologia , Linfócitos B/patologia
2.
Rheumatology (Oxford) ; 62(1): 428-438, 2022 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-35412585

RESUMO

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, ∼25% 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.


Assuntos
Linfócitos Intraepiteliais , Síndrome de Sjogren , Humanos , Linfócitos Intraepiteliais/patologia , Hiperplasia/patologia , Glândulas Salivares/patologia , Linfócitos B
3.
Rheumatology (Oxford) ; 61(6): 2472-2482, 2022 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-34672336

RESUMO

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.


Assuntos
Glândula Parótida , Síndrome de Sjogren , Humanos , Glândula Parótida/diagnóstico por imagem , Glândula Parótida/patologia , Saliva , Glândulas Salivares/diagnóstico por imagem , Glândulas Salivares/patologia , Síndrome de Sjogren/diagnóstico por imagem , Síndrome de Sjogren/patologia , Ultrassonografia
4.
J Autoimmun ; 109: 102439, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32201227

RESUMO

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.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Epitélio/imunologia , Epitélio/metabolismo , Perfilação da Expressão Gênica , Receptores Fc/metabolismo , Síndrome de Sjogren/etiologia , Transcriptoma , Idoso , Biomarcadores , Suscetibilidade a Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Receptores Fc/genética , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Transdução de Sinais , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia
5.
Clin Exp Rheumatol ; 37 Suppl 118(3): 42-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31074726

RESUMO

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.


Assuntos
Linfócitos B/imunologia , Glândula Parótida , Glândulas Salivares Menores , Síndrome de Sjogren , Humanos , Glândula Parótida/imunologia , Glândula Parótida/patologia , Glândulas Salivares , Glândulas Salivares Menores/imunologia , Glândulas Salivares Menores/patologia , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia
6.
Rheumatology (Oxford) ; 57(5): 818-825, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29444331

RESUMO

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.


Assuntos
Consenso , Etnicidade , Glândula Parótida/patologia , Reumatologia/métodos , Síndrome de Sjogren/classificação , Biópsia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Países Baixos/epidemiologia , Estudos Prospectivos , Índice de Gravidade de Doença , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/etnologia , Fatores de Tempo
7.
Clin Exp Rheumatol ; 36 Suppl 112(3): 222-233, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30156550

RESUMO

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.


Assuntos
Tecido Linfoide/patologia , Glândulas Salivares/patologia , Síndrome de Sjogren/patologia , Antirreumáticos/uso terapêutico , Biomarcadores/análise , Biópsia , Técnicas de Apoio para a Decisão , Imuno-Histoquímica , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/imunologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/imunologia , Índice de Gravidade de Doença , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/imunologia , Resultado do Tratamento
8.
Ann Rheum Dis ; 76(10): 1781-1784, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28710097

RESUMO

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.


Assuntos
Centro Germinativo/patologia , Lábio/patologia , Linfoma de Zona Marginal Tipo Células B , Neoplasias Parotídeas , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/patologia , Adulto , Idoso , Biópsia , Estudos de Casos e Controles , Feminino , Centro Germinativo/química , Humanos , Antígenos Comuns de Leucócito/análise , Lábio/química , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Pessoa de Meia-Idade , Neoplasias Parotídeas/diagnóstico , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-bcl-6/análise
9.
Ann Rheum Dis ; 76(7): 1161-1168, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27965259

RESUMO

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.


Assuntos
Centro Germinativo/patologia , Linfócitos/patologia , Glândulas Salivares Menores/patologia , Sialadenite/patologia , Síndrome de Sjogren/patologia , Biópsia , Técnica Delphi , Humanos , Leucócitos/patologia , Lábio , Padrões de Referência
10.
J Autoimmun ; 81: 90-98, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28390747

RESUMO

Fc receptor-like protein 4 (FcRL4) is normally expressed on a small subset of mucosa-associated B-cells, as well as on mucosa-associated lymphoid tissue (MALT) lymphoma B-cells. Primary Sjögren's syndrome (pSS) patients have an increased risk of developing MALT lymphomas, preferentially in the parotid glands. For this reason we studied here by immunohistochemistry and mRNA analysis whether FcRL4 expressing B-cells are present in salivary gland tissue (labial and parotid) of pSS patients (n = 54) and non-pSS sicca patients (n = 16) and whether parotid gland MALT lymphomas in pSS patients (n = 49) also express this receptor. We also studied the effect of treatment (rituximab and abatacept) on the presence of FcRL4+ B-cells, and whether numbers in labial gland biopsies at time of diagnosis of pSS can predict whether patients are at risk for MALT lymphoma development. We demonstrate that FcRL4+ cells are present in salivary gland tissue of pSS patients where they are closely associated with ductal epithelial cells forming lymphoepithelial lesions. The glandular FcRL4+ cells are highly proliferative, genuine PAX5+ B-cells. These FcRL4+ B-cells are far more frequent in parotid gland than in labial gland tissue (p = 0.003). We further show that expression of FcRL4 is present in pSS-related parotid MALT lymphomas. The FcRL4 mRNA expression level in parotid MALT lymphoma is increased compared to parotid gland tissue of pSS patients without lymphoma (p = 0.017). However, numbers of FcRL4+ B-cells in labial gland biopsies taken at the time of pSS diagnosis, are not predictive for later development of MALT lymphoma. Reduction of parotid gland FcRL4+ B-cells by rituximab, but not abatacept is accompanied by restoration of the glandular epithelium, illustrating the crosstalk between these B-cells with the ductal cells. In conclusion, intraepithelial FcRL4+ B-cells are present in the salivary glands of pSS patients. These cells are likely involved in the epithelial changes seen in pSS. Their enrichment in parotid glands may explain why MALT lymphomas in pSS patients preferentially develop at this specific location.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Receptores Fc/metabolismo , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Adulto , Idoso , Antígenos CD20/metabolismo , Biópsia , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Imunofenotipagem , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/imunologia , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/imunologia , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Receptores Fc/genética , Rituximab/uso terapêutico , Saliva/citologia , Saliva/imunologia , Glândulas Salivares/patologia , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/genética
11.
Clin Exp Rheumatol ; 35(2): 317-320, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27908305

RESUMO

OBJECTIVES: The aim of this study was to assess the histopathological changes in parotid gland tissue of primary Sjögren's syndrome (pSS) patients treated with abatacept. METHODS: In all 15 pSS patients included in the open-label Active Sjögren Abatacept Pilot (ASAP, 8 abatacept infusions) study parotid gland biopsies were taken before treatment and at 24 weeks of follow up. Biopsies were analysed for pSS-related histopathological features and placed in context of clini- cal responsiveness as assessed with EULAR Sjögren's syndrome disease activity index (ESSDAI). RESULTS: Abatacept treatment resulted in a decrease of germinal centres (GCs)/ mm2 (p=0.173). Number of GCs/mm2 at baseline was associated with response in the glandular domain of ESSDAI (Spearman ρ=0.644, p=0.009). Abatacept treatment did not reduce focus score, lymphoepithelial lesions, area of lymphocytic infiltrate, amount of CD21+ networks of follicular dendritic cells, and numbers of CD3+ T-cells or CD20+ B- cells. Number of IgM plasma cells/mm2 increased (p=0.041), while numbers of IgA and IgG plasma cells/mm2 were unaffected during abatacept treatment. CONCLUSIONS: Abatacept affects formation of GCs of pSS patients in parotid glands, which is dependent on co-stimulation of activated follicular-helper-T-cells. Herewith, local formation of (autoreactive) memory B-cells is inhibited. Presence of GCs at baseline predicts responsiveness to abatacept in the ESSDAI glandular domain.


Assuntos
Abatacepte/uso terapêutico , Centro Germinativo/efeitos dos fármacos , Imunossupressores/uso terapêutico , Glândula Parótida/efeitos dos fármacos , Síndrome de Sjogren/tratamento farmacológico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Biópsia , Centro Germinativo/imunologia , Centro Germinativo/patologia , Humanos , Imuno-Histoquímica , Memória Imunológica/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Glândula Parótida/imunologia , Glândula Parótida/patologia , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Tempo , Resultado do Tratamento
12.
Ann Rheum Dis ; 75(11): 1933-1938, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26757748

RESUMO

OBJECTIVES: The aims of this study were (1) to assess the effect of rituximab (RTX; anti-CD20) treatment in patients with primary Sjögren's syndrome (pSS) based on sequential parotid biopsies obtained in a placebo-controlled, randomised clinical trial, and (2) to assess the prognostic value of the histological characteristics of parotid gland tissue with regard to responsiveness to RTX treatment. METHODS: In a double-blinded, placebo-controlled trial, sequential parotid gland biopsies were taken from 20 RTX-treated and 10 placebo-treated patients with pSS, at baseline and 12 weeks after treatment. The relative amount of lymphocytic infiltrate (stained for CD45), absolute number of T cells and B cells per mm2 parenchyma (stained for CD3 and CD20, respectively), focus score, number of germinal centres and of lymphoepithelial lesions per mm2 in parotid gland parenchyma were assessed. Histopathological data were compared between clinical responders (decrease in European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) score of ≥3 at 12 weeks compared with baseline) and non-responders (change in ESSDAI<3) to RTX treatment. RESULTS: In RTX-treated patients, a significant reduction in the number of CD20+ B cells/mm2 parenchyma was observed, while no such reduction was observed in placebo-treated patients. The number of CD3+ T cells/mm2 in parenchyma did not change in either group. Furthermore, the number and the severity of lymphoepithelial lesions/mm2 and number of germinal centres/mm2 was significantly reduced in RTX-treated patients, but did not change in placebo-treated patients. When comparing the pretreatment characteristics of clinical responders with non-responders, the median number of CD20+ B cells/mm2 parenchyma at baseline was significantly higher in responders (1871 vs 353 cells/mm2, p<0.05). Other histopathological baseline characteristics were not predictive for response to RTX treatment. CONCLUSIONS: RTX treatment in pSS leads to a major reduction of lymphocytic infiltration and to fewer B cells, germinal centres and lymphoepithelial lesions in parotid gland parenchyma. A high pretreatment number of CD20+ B cells/mm2 parotid gland parenchyma predicts better responsiveness of patients with pSS to RTX treatment. Pretreatment parotid gland histopathological characteristics could therefore contribute to a more personalised treatment approach to pSS.


Assuntos
Fatores Imunológicos/uso terapêutico , Glândula Parótida/patologia , Rituximab/uso terapêutico , Síndrome de Sjogren/patologia , Adulto , Linfócitos B/metabolismo , Biópsia , Contagem de Células , Método Duplo-Cego , Feminino , Humanos , Masculino , Glândula Parótida/citologia , Medicina de Precisão , Índice de Gravidade de Doença , Síndrome de Sjogren/tratamento farmacológico , Linfócitos T/metabolismo , Resultado do Tratamento
15.
Arthritis Rheumatol ; 76(3): 421-428, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37791984

RESUMO

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.


Assuntos
Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/patologia , Glândulas Salivares Menores/patologia , Sensibilidade e Especificidade , Centro Germinativo , Biópsia
18.
Ann Rheum Dis ; 71(11): 1881-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22615459

RESUMO

OBJECTIVES: To assess the persistence of immunoglobulin-producing cell populations in the parotid salivary glands of patients with primary Sjögren's syndrome (pSS) after B cell depletion therapy with rituximab. METHODS: Thirteen patients with pSS and four control patients were included in this study. Patients with pSS were treated with rituximab or placebo. Sequence analysis was carried out on IgA- and IgG-encoding transcripts extracted from parotid salivary gland biopsy specimens taken before treatment and at 12-16 and 36-52 weeks after treatment. RESULTS: At baseline, many clonally related sequences were seen in patients with pSS. The number of clonal expansions was significantly higher in patients with pSS than in control patients. Clonal expansions were composed of IgA- and/or IgG-expressing cells. Rituximab did not significantly alter the degree of clonal expansions. Groups of clonally related cells had members which were shared between biopsy specimens taken before and after treatment. Mutation frequencies of immunoglobulin sequences from clonally related cells in patients with pSS were higher after treatment. CONCLUSIONS: Rituximab treatment does not alter the characteristic features of increased clonal expansions seen in the parotid salivary glands of patients with pSS. The presence of clonally related immunoglobulin-producing cells before and after rituximab treatment strongly suggests that immunoglobulin-producing cells persist in salivary glands of patients with pSS despite B cell depletion. The presence of mixed isotype expression within groups of clonally related cells indicates local class switching in salivary glands of patients with pSS. Persistent immunoglobulin-producing cells may underlie disease relapse after treatment.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Células Produtoras de Anticorpos/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Glândula Parótida/efeitos dos fármacos , Síndrome de Sjogren/tratamento farmacológico , Adolescente , Adulto , Idoso , Células Produtoras de Anticorpos/imunologia , Células Produtoras de Anticorpos/patologia , Linfócitos B/imunologia , Linfócitos B/patologia , Células Clonais , Feminino , Humanos , Imunoglobulina A/metabolismo , Imunoglobulina G/metabolismo , Depleção Linfocítica/métodos , Pessoa de Meia-Idade , Glândula Parótida/imunologia , Glândula Parótida/patologia , Rituximab , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia , Adulto Jovem
19.
Cancers (Basel) ; 14(4)2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35205758

RESUMO

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.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA