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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.
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Sjögren disease (SjD) is widely recognized by the presence of B cell-dominated lymphocytic infiltration in the salivary glands (SGs). Contrary to what was originally presumed, however, SG hypofunction in SjD is not strongly correlated with the degree of SG lymphocytic infiltration in the SGs.
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OBJECTIVE: Vaginal dryness is an important factor influencing sexual function in women with primary Sjögren syndrome (pSS). Previous studies showed a higher degree of inflammation in vaginal biopsies from patients with pSS compared to non-pSS controls. However, the molecular pathways that drive this inflammation remain unclear. Therefore, the aim of this study was to investigate inflammatory pathway activity in the vaginal tissue of patients with pSS. METHODS: Vaginal biopsies of 8 premenopausal patients with pSS experiencing vaginal dryness and 7 age-matched non-pSS controls were included. Expression of genes involved in inflammation and tissue homeostasis was measured using NanoString technology and validated using TaqMan Real-Time PCR. Vaginal tissue sections were stained by immunohistochemistry for myxovirus resistance protein 1 (MxA) and CD123 (plasmacytoid dendritic cells [pDCs]). RESULTS: The most enriched pathway in vaginal biopsies from patients with pSS compared to non-pSS controls was the interferon (IFN) signaling pathway (P < 0.01). Pathway scores for Janus kinase and signal transducer and activator of transcription (JAK-STAT) and Notch signaling were also higher (P < 0.01 for both pathways). Conversely, transforming growth factor-ß signaling and angiogenesis pathway scores were lower in pSS (P = 0.02 and P = 0.04, respectively). Differences in IFN signaling between patients with pSS and non-pSS controls were confirmed by PCR and MxA tissue staining. No CD123+ pDCs were detected in vaginal biopsies. IFN-stimulated gene expression levels correlated positively with CD45+ cell numbers in vaginal biopsies and serum anti-SSA/Ro positivity. CONCLUSION: Upregulation of IFN signaling in vaginal tissue of women with pSS, along with its association with tissue pathology, suggests that IFNs contribute to inflammation of the vaginal wall and potentially also to clinical symptomatology (ie, vaginal dryness).
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Interferons , Transdução de Sinais , Síndrome de Sjogren , Vagina , Humanos , Feminino , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia , Vagina/patologia , Vagina/imunologia , Vagina/metabolismo , Adulto , Pessoa de Meia-Idade , Interferons/metabolismo , Proteínas de Resistência a Myxovirus/genética , Proteínas de Resistência a Myxovirus/metabolismo , Biópsia , Doenças Vaginais/metabolismo , Doenças Vaginais/patologia , Doenças Vaginais/imunologiaRESUMO
BACKGROUND: Rheumatoid factors (RF) are one of the hallmark autoantibodies characteristic of rheumatoid arthritis (RA), and are frequently observed in other diseases and in healthy individuals. RFs comprise multiple subtypes with different specificities towards the constant region of human IgG. Studies indicate that these patterns differ between naturally occurring RFs and RFs associated with disease. However, individual specificities characteristic of either have not been clearly defined. METHODS: In this study, we developed an extended set of engineered IgG-fragment crystallisable (Fc) targets with preferential RF binding to specific (conformational) epitopes, which was subsequently used for profiling of RF binding patterns in a compiled exploration cohort, consisting of sera from healthy donors with measurable RF and patients with RA, primary Sjögren's syndrome (pSS) and seropositive arthralgia. RESULTS: We identified an epitope that is strongly associated with RA, which was targeted by both IgM-RF and IgA-RF. We also identified an epitope that is preferentially targeted by healthy donor (IgM) RFs. IgM-RFs derived from healthy donors and patients with RA and pSS all target distinct regions on the IgG-Fc, whereas overall, the IgA-RF repertoire is largely restricted to pathology-associated specificities. Using monoclonal RFs with different specificities, we furthermore demonstrate that the capacity to activate complement or even inhibit IgG-mediated complement activation varies according to the epitopes to which RFs bind. CONCLUSIONS: Our results demonstrate both the need and feasibility to redefine 'RF' into pathological and physiological autoantibody subtypes.
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Artrite Reumatoide , Fator Reumatoide , Humanos , Autoanticorpos , Epitopos , Autoimunidade , Imunoglobulina G , Imunoglobulina M , Imunoglobulina ARESUMO
OBJECTIVES: To assess the usefulness of [18F]-fluorodeoxyglucose (FDG)-PET/CT (i) to discriminate between primary SS (pSS) patients with and without lymphomas and (ii) to evaluate systemic disease activity in pSS. METHODS: ACR-EULAR-positive pSS patients who underwent FDG-PET/CT were included. Scans were visually evaluated and quantitative analysis was performed by measuring standardized uptake values (SUV) of salivary and lacrimal glands and systemic regions. Receiver operating characteristic curve analyses were performed to find SUV cut-off values to discriminate between lymphoma and non-lymphoma. RESULTS: Of the 70 included patients, 26 were diagnosed with a pSS-associated lymphoma, mostly of the mucosa-associated lymphoid tissue type (23/26). Lymphoma patients showed higher FDG uptake in the parotid and submandibular glands, and more frequently showed presence of nodular lung lesions, compared with non-lymphoma patients. The accuracy of the maximum SUV (SUVmax) in the parotid and submandibular gland to predict lymphoma diagnosis was good, with optimal cut-off points of 3.1 and 2.9. After combining these three visual and quantitative findings (nodular lung lesions, parotid SUVmax > 3.1 and submandibular SUVmax > 2.9), sensitivity was 92% when at least one of the three features were present, and specificity was 91% in case at least two features were present. Furthermore, FDG-PET/CT was able to detect systemic manifestations in pSS patients, mostly involving lymph nodes, entheses and lungs. CONCLUSIONS: FDG-PET/CT can assist in excluding pSS-associated lymphomas in patients without PET abnormalities, possibly leading to a decrease of invasive biopsies in suspected lymphoma patients. Furthermore, FDG-PET/CT is able to detect systemic manifestations in pSS and can guide to the best biopsy location.
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Linfoma de Zona Marginal Tipo Células B , Síndrome de Sjogren , Humanos , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Linfoma de Zona Marginal Tipo Células B/diagnóstico por imagem , Compostos RadiofarmacêuticosRESUMO
OBJECTIVES: To perform a systematic review and meta-analysis to determine the power of salivary electrolytes for the diagnosis of Sjögren's disease (SjD). METHODS: A literature search was conducted (last search March 2023) using PubMed and Web of Science and completed with a manual search. Articles were screened for reports of human salivary ion concentrations, comparing SjD patients with healthy controls and/or sicca patients. Articles not using the SjD classification criteria or performing the classification as part of the experimental design were excluded. Forest plots were used to present the meta-analyses results for each ion, distinguishing between salivary type (unstimulated and stimulated whole saliva, submandibular/sublingual and parotid saliva). RESULTS: A total of 21 out of 722 articles were eligible for inclusion. For SjD patients a significant increase in salivary ion concentration was observed for sodium, chloride and calcium when comparing to healthy controls. Significant differences between SjD and sicca patients were noted for sodium, chloride, phosphate, calcium, phosphate, nitrite and nitrate. Stimulated whole saliva showed larger variability in results between studies in comparison to other types of saliva (unstimulated whole saliva, submandibular/sublingual saliva and parotid saliva). CONCLUSIONS: Despite differences in saliva type, salivary ion levels could be utilised for the screening for SjD. Making use of chloride in combination with sodium would be most promising for distinguishing SjD patients from healthy controls and adding phosphate to potentially make a distinguishment with sicca patients. Unstimulated whole saliva should be the first choice when testing salivary ion concentrations.
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Cálcio , Síndrome de Sjogren , Humanos , Cloretos/análise , Síndrome de Sjogren/diagnóstico , Saliva , Eletrólitos , Sódio/análise , FosfatosRESUMO
OBJECTIVES: To evaluate changes in major salivary gland functioning over time using salivary gland ultrasonography (SGUS), salivary flow measurements (sialometry), and patient-reported outcome measures (PROMs) in patients diagnosed with primary Sjögren's disease (SjD). METHODS: Consecutive outpatients from the ongoing prospective REgistry of Sjögren Syndrome LongiTudinal (RESULT) cohort, all fulfilling the ACR-EULAR classification criteria for SjD, were included. SGUS images assessed with the Hocevar and OMERACT scoring system, unstimulated and stimulated whole saliva (UWS/SWS), unstimulated and stimulated submandibular/sublingual saliva (uSMSLS/sSMSLS) and parotid saliva, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) general dryness, oral dryness, and Xerostomia Inventory were assessed at baseline (BL), 2-year (Y2) and 5-year (Y5) follow-up. RESULTS: In total, BL and Y2 data were available for 253 patients and 75 patients had already reached Y5. At group level, SGUS Hocevar (i.e., mean±SD: 22±10 at BL, 22±10 at Y2 and 23±10 at Y5), OMERACT scores, UWS, SWS and PROMs remained stable over time (all p>0.05). Slightly decreased uSMSLS (p=0.025) and sSMSLS (p=0.004) were observed at Y5. At individual patient level, a similar proportion showed an increase or decrease of ≥25% for Hocevar, UWS and SWS. At baseline, poor associations were observed between SGUS and PROMs and fair associations between sialometry and PROMs. Over time, changes in objective assessments did not correlate with changes in PROMs. CONCLUSIONS: Overall, major salivary gland functioning assessed with SGUS, sialometry and PROMs did not change significantly up to 5 years of follow-up in a standard-of-care cohort of SjD patients from daily clinical practice.
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Síndrome de Sjogren , Xerostomia , Humanos , Síndrome de Sjogren/diagnóstico por imagem , Glândulas Salivares/diagnóstico por imagem , Xerostomia/diagnóstico , Xerostomia/etiologia , Saliva , Ultrassonografia/métodos , Glândula Parótida/diagnóstico por imagemRESUMO
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.
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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 , UltrassonografiaRESUMO
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.
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Linfócitos Intraepiteliais , Síndrome de Sjogren , Humanos , Linfócitos Intraepiteliais/patologia , Hiperplasia/patologia , Glândulas Salivares/patologia , Linfócitos BRESUMO
According to a recent survey of patients with the autoimmune disease primary Sjögren's syndrome (pSS), dry eye symptoms are present in 95-98% of pSS patients. As one of the most disabling symptoms mentioned by pSS patients, dry eyes have demonstrable effects on quality of their life, leading to eye dryness, itching, and pain, with some patients describing as a recurrent sensation of sand or gravel in the eyes. The symptoms are matched only in prevalence by dry mouth and chronic fatigue. In contrast to the prevalence of dry eye symptoms in pSS and their burden on pSS patients, our comprehension of dry eye disease development is minimal; specifically how function of the tear-fluid producing gland the lacrimal gland (LG), manifests. The comparison becomes stronger again when we consider what we know about dysfunction of the salivary gland (SG) in pSS, for example the appreciation of the transcriptome of 'innately activated' B cells invading the SG, their complicity in formation of lymphoepithelial lesions, and the ability of the SG epithelium to actively contribute to the inflammatory milieu. The exploration of ultrasound imaging as an additional modality to garner information about SG dysfunction in pSS has opened many doors for non-invasive, repeatable imaging in pSS. Here we summarise SG histology and ultrasound phenotype briefly and then juxtapose this with available studies examining LG pathology and ultrasound, and our understanding of LG dysfunction in pSS.
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Síndromes do Olho Seco , Aparelho Lacrimal , Síndrome de Sjogren , Humanos , Aparelho Lacrimal/diagnóstico por imagem , Glândulas Salivares , Síndromes do Olho Seco/diagnóstico por imagem , Síndromes do Olho Seco/etiologia , UltrassonografiaRESUMO
In the last decade, many randomised controlled trials (RCTs) with biological DMARDs (bDMARDs) have been performed in patients with primary Sjögren's syndrome (pSS). Unfortunately, no bDMARD has yet been approved for systemic treatment of pSS. The heterogeneity of disease manifestations raises two essential questions: 1) which outcome measure is valid, reliable and responsive to demonstrate treatment efficacy and should be used as primary study endpoint? and 2) which pSS patients should be included in clinical trials? Both the selection of the primary study endpoint and the selection of patients are crucial and evolving issues in clinical trial design in pSS. This article summarises the history and comments the selection of primary study endpoints including the novel development of composite endpoints. Furthermore, this article gives an overview of inclusion criteria used for phase II and III trials, and illustrates by data-analysis based on two prospective observational cohorts that each additional selection criterion will (largely) decrease the number of eligible patients in daily clinical practice.
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Antirreumáticos , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/tratamento farmacológico , Antirreumáticos/uso terapêutico , Resultado do Tratamento , Avaliação de Resultados em Cuidados de Saúde , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: The peripheral lymphocyte compartment of patients with primary Sjögren's syndrome (pSS) differs strongly from healthy individuals. Whether this altered lymphocyte composition also changes abnormally during immune reactions, especially by novel CoV-2-vaccines, is unknown. METHODS: Peripheral blood mononuclear cells (PBMC) from 26 pSS patients and 6 healthy controls were compared before Coronavirus-2 (CoV-2) vaccination (Pfizer/BNT162b2, Moderna/mRNA-1273, AstraZeneca/AZD122 ChAdOx1 nCoV-19) and 7 days after secondary vaccination. Spike 1 (S1)-receptor binding domain (RBD)-specific IgG antibodies were measured in serum samples. Among PBMCs, B and T cell subpopulations were phenotypically analysed and RBD-specific B and plasma cells were evaluated. RESULTS: Immunisation induced CoV-2 specific serum antibodies in all pSS patients and healthy participants. When analysing pSS patients and controls together, frequencies of circulating IgG+ RBD-specific antibody-secreting cells (ASC) and anti-RBD serum titres correlated (r=0.42, p=0.022). Previously described alterations of peripheral B cells in pSS patients (e.g. reduced memory B cells, increased naive and transitional B cells and higher maturity of ASCs) remained stable during vaccination. The subset distribution of CD4+ and CD8+ T cells also stayed largely unchanged. However, frequencies of CD4+CXCR5-PD-1+ circulating peripheral helper T (cTPH)-like cells increased in pSS patients comparing pre- and post-vaccination (p=0.020), while circulating CD4+CXCR5+PD-1+ follicular helper T (cTFH)-like cells declined (p=0.024). CONCLUSIONS: An immune reaction induced by vaccination with the novel CoV-2 vaccines yields adequate antibody production and vaccine specific lymphocytes in pSS patients and controls. Aberrant lymphocyte subset distribution in pSS patients persisted after vaccination and no major changes were induced despite small changes in cTPH and cTFH cells.
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Vacinas contra COVID-19 , COVID-19 , Síndrome de Sjogren , Humanos , Anticorpos Antivirais , Formação de Anticorpos , Vacina BNT162 , ChAdOx1 nCoV-19 , COVID-19/prevenção & controle , Imunoglobulina G , Leucócitos Mononucleares , Receptor de Morte Celular Programada 1 , SARS-CoV-2 , Linfócitos T Auxiliares-Indutores , Vacinação/efeitos adversos , Vacinas contra COVID-19/efeitos adversosRESUMO
In patients with primary Sjögren's syndrome (pSS), inflamed salivary gland (SG) tissue may contain lymphoepithelial lesions (LELs). LELs are histopathological phenomena whereby B cells are present in hyperplastic ductal epithelium of the SG. Despite the potential role of LELs in pSS pathogenesis, studies on their formation, detection, and prevalence in benign lesions (not complicated with lymphoma) are scarce. Recent evidence however shows that LELs are present in approximately half of the patients with pSS, both in minor and major SGs. Migration of a small number of B cells into the epithelium appears to be a critical initial step in LEL formation. These intra-epithelial B cells are proliferative, exhibit an innate-like phenotype, and may be linked to MALT lymphoma development. Alongside intra-epithelial B cells, the hyperplastic epithelial partner in LELs also engages in the local immune reaction. Epithelial cells are a source of cytokines and chemokines, with CXCL10 in particular playing a potential role in LEL formation. Importantly, LELs also have a negative impact on the maintenance of SG homeostasis by SG progenitor cell (SGPC) populations, likely due to dysregulation of SGPC lineage commitment or induction of plasticity. In conclusion, LEL formation mirrors a perfect storm of B and epithelial cell interaction culminating in increased risk of B cell derailment and SGPC dysregulation in pSS patients. We therefore argue that attenuation of LEL formation is an important treatment goal to preserve SG function and prevent B cell derailment in pSS.
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Linfoma de Zona Marginal Tipo Células B , Síndrome de Sjogren , Humanos , Glândulas Salivares , Linfócitos B , Linfoma de Zona Marginal Tipo Células B/etiologia , Células EpiteliaisRESUMO
OBJECTIVES: Fatigue is a major complaint in primary Sjögren's syndrome (pSS). To acquire a better understanding of fatigue in pSS, we investigated objective measures of performance decline (performance fatigability). Furthermore, we evaluated the relationship of self-reported fatigue with performance fatigability and factors modulating perceptions of fatigability (perceived fatigability). METHODS: Thirty-nine pSS patients and 27 healthy controls were included. To assess performance fatigability, force decline was measured during a sustained (124s) maximal voluntary contraction (MVC) with the index finger abductor muscle, and voluntary muscle activation was indexed using peripheral nerve stimulation. Self-reported fatigue was quantified using the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS). Pain, depression, and anxiety assessed using questionnaires and inflammatory biomarkers measured in blood were used as factors relating to perceived fatigability. RESULTS: Voluntary muscle activation was reduced in pSS (p=0.030), but force decline during the sustained MVC did not differ between groups. Self-reported fatigue was significantly higher in pSS than in controls (FSS: 4.4 vs. 2.6, p<0.001). Multivariable linear regression showed that both performance fatigability (force decline) and perceived fatigability (pain and depression) were associated with the MFIS physical domain in pSS (total explained variance of 47%). Negative associations with fatigue were observed for two interferon-associated proteins: MxA and CXCL10. CONCLUSIONS: This study demonstrates that performance fatigability in pSS was compromised by a reduced capacity of the central nervous system to drive the muscle. Furthermore, self-reported fatigue is a multifactorial symptom associated with both performance fatigability and perceived fatigability in patients with pSS.
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Depressão , Síndrome de Sjogren , Humanos , Depressão/diagnóstico , Depressão/etiologia , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Fadiga/diagnóstico , Fadiga/etiologia , Dor , Desempenho Físico FuncionalRESUMO
Ultrasound is a promising diagnostic method when it comes to assessing the involvement of major salivary glands in patients with primary Sjögren's syndrome (pSS). A matter of debate is whether ultrasound of the major salivary glands (SGUS) can replace a salivary gland biopsy in the diagnosis or classification of pSS. The intra- and inter-observer reliability of SGUS was found to be good, especially when focusing on hypoechogenic areas and homogeneity, and comparable to the reliability of histopathologic characteristics of salivary gland biopsies of pSS patients. However, replacing salivary gland biopsy by SGUS led to substantial decrease of the accuracy of the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria with clinical diagnosis as the gold standard. When SGUS was added as an additional item to the criteria, the accuracy of the criteria remained high, offering at the same time the clinicians a wider array of tools to assess patients. Combination of SGUS and anti-SSA antibodies was shown to be highly predictive of the classification of a patient suspected of pSS, making routine salivary gland biopsy debatable.
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Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico por imagem , Reprodutibilidade dos Testes , Glândulas Salivares/diagnóstico por imagem , Glândulas Salivares/patologia , Ultrassonografia , BiópsiaRESUMO
OBJECTIVES: To explore Patient Acceptable Symptom State (PASS) in a standard of care cohort of patients with primary Sjögren's syndrome (pSS) and to compare patient characteristics including EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) between PASS and non-PASS groups. METHODS: All pSS patients fulfilling ACR/EULAR classification criteria from the Registry of Sjögren's Syndrome LongiTudinal (RESULT) cohort, who had available PASS data at baseline were included. Patient-reported outcomes included the PASS question: "Considering all the different ways your disease is affecting you, if you were to stay in this state for the next few months, do you consider your current state satisfactory?"; yes: PASS / no: non-PASS. RESULTS: Of the 278 included pSS patients, 199 (72%) had an acceptable symptom state according to the PASS question, and median ESSPRI was 6 (IQR 4-7). In the PASS group, 118 (59%) patients had an unacceptable symptom state according to ESSPRI (score ≥5). In multivariable regression analyses, ESSPRI and disease duration were independently associated with presence of PASS. The accuracy of ESSPRI to predict PASS was fair (AUC of 0.78). The cut-off point of ESSPRI for presence of PASS with the highest Youden's index was 7.2 (sensitivity 85%, specificity 56%), followed by 5.2 (sensitivity 48%, specificity 90%). CONCLUSIONS: The majority of pSS patients reported being in an acceptable symptom state according to the PASS question, despite high ESSPRI scores. In our standard of care cohort, the optimal cut-off point of ESSPRI to predict PASS is different when focusing on sensitivity (±7) or specificity (±5).
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Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/complicações , Índice de Gravidade de DoençaRESUMO
Animal models of autoimmunity and human genetic association studies indicate that the dysregulation of B-cell receptor (BCR) signaling is an important driver of autoimmunity. We previously showed that in circulating B cells from primary Sjögren's syndrome (pSS) patients with high systemic disease activity, protein expression of the BCR signaling molecule Bruton's tyrosine kinase (BTK) was increased and correlated with T-cell infiltration in the target organ. We hypothesized that these alterations could be driven by increased B-cell activating factor (BAFF) levels in pSS. Here, we investigated whether altered BCR signaling was already present at diagnosis and distinguished pSS from non-SS sicca patients. Using (phospho-)flow cytometry, we quantified the phosphorylation of BCR signaling molecules, and investigated BTK and BAFF receptor (BAFFR) expression in circulating B cell subsets in an inception cohort of non-SS sicca and pSS patients, as well as healthy controls (HCs). We found that both BTK protein levels and BCR signaling activity were comparable among groups. Interestingly, BAFFR expression was significantly downregulated in pSS, but not in non-SS sicca patients, compared with HCs, and correlated with pSS-associated alterations in B cell subsets. These data indicate reduced BAFFR expression as a possible sign of early B cell involvement and a diagnostic marker for pSS.
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Receptor do Fator Ativador de Células B , Subpopulações de Linfócitos B , Receptores de Antígenos de Linfócitos B , Síndrome de Sjogren , Tirosina Quinase da Agamaglobulinemia/metabolismo , Receptor do Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/metabolismo , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Humanos , Receptores de Antígenos de Linfócitos B/metabolismo , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/metabolismoRESUMO
A histologic hallmark of primary SS (pSS) is lymphocytic infiltration of the salivary and lacrimal glands, in particular by CD4+ T and B cells. In the early stages of the disease, infiltrates are dominated by CD4+ T cells, while B cell accumulation occurs at later stages. Activated T cells contribute to pathogenesis by producing pro-inflammatory cytokines and by inducing B cell activation, which results in the establishment of a positive feedback loop. In the inflamed glandular tissues, many different CD4+ effector subsets are present, including IFN-γ-producing Th1 cells, IL-17-producing Th17 cells and IL-21-producing T follicular helper cells. In blood from pSS patients, frequently observed abnormalities of the T cell compartment are CD4+ T cell lymphopenia and enrichment of circulating follicular helper T (Tfh) cells. Tfh cells are critical mediators of T cell-dependent B cell hyperactivity and these cells can be targeted by immunotherapy. Inhibition of T cell activation, preferably early in the disease process, can mitigate B cell activity and may be a promising treatment approach in this disease.
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Patients with primary Sjögren's syndrome (SS) suffer widely from lack of saliva production. Here we investigate potential mechanisms underpinning changes in SS patient saliva composition. Sodium concentration was significantly higher in all saliva samples collected: unstimulated submandibular/sublingual (SmSl) saliva (p<0.0001), stimulated SmSl saliva (p=0.002) and stimulated parotid (PG) (p<0.0001) saliva, compared to non-SS sicca controls. Chloride, phosphate and potassium ion concentrations, α-amylase activity and total protein content correlations were less consistently changed between SS and non-SS saliva types. Stimulated PG salivary sodium levels correlated with the degree of CD45+ lymphocytic cell infiltrate in the parotid glands (r=0.69, p<0.001), and even more strongly so with infiltrating CD20+ B cells (r=0.73, p<0.0001). CD3+ T cells were only moderately correlated with salivary sodium (r=0.23, p=0.015). In non-SS control or focus score (FS) negative SS PG tissue, the epithelial sodium channel (ENaC), responsible for sodium transport out of saliva, was localised to the apical membrane of luminal striated duct cells. In PG tissue from FS+ SS patients, apical ENaC expression appeared absent. We hypothesise that B cell-related proinflammatory cytokines in SS salivary glands may dysregulate sodium transport channels in SS.
Assuntos
Canais Epiteliais de Sódio , Síndrome de Sjogren , Humanos , Glândula Parótida , Saliva , SódioRESUMO
OBJECTIVES: Primary Sjögren's syndrome (pSS) is a rare disease in paediatric patients. Presenting symptoms differ from those in adult patients. The aim of this study was to evaluate presenting symptoms, classification criteria and clinical assessments, including salivary gland ultrasonography (SGUS), at disease onset in paediatric and adult patients with pSS. METHODS: Data of 23 paediatric- and 33 adult-onset patients with pSS were obtained from our standardised multidisciplinary REpSULT and RESULT cohorts, respectively. Clinical, patient-reported, serological, functional, biopsy and SGUS parameters were compared. RESULTS: In paediatric-onset pSS (pedSS) patients, recurrent parotid gland swelling (91% vs. 49%, p<0.001) and fever (30% vs. 3%, p=0.006) were more often present than in adult-onset patients. In contrast, sicca symptoms of mouth (52% vs. 79%, p=0.046) and eyes (26% vs. 73%, p<0.001) were less common in pedSS patients. In paediatric patients, the entry criteria of the ACR/EULAR classification were most often met due to activity in the glandular domain of the ESSDAI. When applying the ACR/EULAR classification criteria, only 78% of pedSS fulfilled these criteria compared to 100% of adult patients. Abnormal glandular function tests had a greater contribution to fulfilling the criteria in adults, while the biopsy had a greater contribution in paediatric patients. Anti-SSA/Ro serology had similar contribution for both cohorts. SGUS Hocevar score was significantly higher in paediatric compared to adult patients (median 25 vs. 18, p=0.004). CONCLUSION: PedSS has a different presentation than adult-onset pSS. Recurrent parotid gland swelling in paediatric patients should alert clinicians to the potential presence of pSS.