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BACKGROUND: Sjögren's disease is a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease. METHODS: This randomised, double-blind, placebo-controlled, phase 2b study, conducted at 71 sites in 23 countries, enrolled patients aged 18 years or older fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) 2016 criteria. In the dose-ranging cohort 1, patients with a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or higher were randomly assigned (1:1:1:1) to subcutaneous iscalimab 150 mg, 300 mg, 600 mg, or placebo. In the proof-of-concept cohort 2, patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher were randomly assigned (1:1) to iscalimab 600 mg or placebo. The sponsor, investigator, site personnel, and patients were masked to the treatment assignment. The primary objectives were to demonstrate a dose-response relationship of iscalimab based on the change in ESSDAI from baseline to week 24 in cohort 1 by Multiple Comparison Procedure-Modelling (MCP-Mod), and to assess the effect of iscalimab 600 mg on ESSPRI at week 24 in cohort 2. All the efficacy analyses included all patients who were randomly assigned, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03905525), and is complete. FINDINGS: Between Oct 1, 2019, and Feb 28, 2022, 460 patients were screened; 173 patients were assigned to cohort 1 (44 to iscalimab 150 mg, 43 to 300 mg, 43 to 600 mg, and 43 to placebo) and 100 to cohort 2 (50 to each group). In cohort 1, the MCP step showed a significant dose-response relationship for placebo-adjusted ESSDAI change from baseline in one of four models (Linlog model, one-sided p=0·0041). ESSDAI decreased from baseline to week 24 with all three doses of iscalimab; 150 mg and 600 mg doses showed statistically significant improvement (placebo-adjusted least squares [LS] mean difference -3·0 [95% CI -4·9 to -1·1]; p=0·0025 for 150 mg and -2·9 [-4·9 to -1·0]; p=0·0037 for 600 mg). In cohort 2, ESSPRI showed a trend towards improvement with iscalimab 600 mg (placebo-adjusted LS mean change from baseline -0·57 points [95% CI -1·30 to 0·15]; p=0·12). Serious adverse events were reported in nine patients in cohort 1 (one [2%] of 43 in the placebo group, one [2%] of 44 in the iscalimab 150 mg group, three [7%] of 42 in the 300 mg group, four [9%] of 44 in the 600 mg group) and four patients in cohort 2 (two [4%] of 50 in each group). No deaths occurred over the 24-week period. INTERPRETATION: The study met the primary objective of demonstrating a significant dose-response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials. FUNDING: Novartis Pharma.
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Relação Dose-Resposta a Droga , Síndrome de Sjogren , Humanos , Método Duplo-Cego , Feminino , Masculino , Pessoa de Meia-Idade , Síndrome de Sjogren/tratamento farmacológico , Injeções Subcutâneas , Adulto , Resultado do Tratamento , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Idoso , Índice de Gravidade de Doença , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêuticoRESUMO
OBJECTIVE: To investigate the proportion of low-density granulocytes (LDGs), circulating plasma neutrophil extracellular traps (NETs), and serum-induced NET formation in patients with incomplete systemic lupus erythematosus (iSLE) and systemic lupus erythematosus (SLE). METHODS: LDGs were measured cross-sectionally in 18 iSLE patients, 11 SLE patients and 14 healthy controls (HCs), whereas circulating NETs and serum-induced NET formation were assessed in 35 iSLE patients, 41 SLE patients and 16 HCs. LDGs (CD14lowCD15+) were measured in PBMCs using flow cytometry and circulating plasma NETs were measured using anti-myeloperoxidase-DNA, anti-citrullinated histone H3 and anti-elastase-DNA complex ELISAs. Serum-induced NET formation was assessed by incubating healthy neutrophils with serum from iSLE patients, SLE patients or HCs and visualizing NETs with fluorescence microscopy. RESULTS: Proportions of LDGs and circulating plasma NETs were similarly elevated in iSLE and SLE patients compared with those in HCs. Furthermore, patients under hydroxychloroquine (HCQ) treatment had lower proportions of LDGs than those without. Serum from iSLE and SLE patients similarly induced NET formation in healthy neutrophils. In iSLE patients, myeloperoxidase-DNA complexes were correlated with proportions of age-associated B-cells, memory B-cells and negatively with naïve B-cells, while we did not find associations between measures of NETs or serum-induced NET formation and interferon score or clinical parameters. CONCLUSION: These results show that neutrophil dysfunction, including higher proportions of LDGs, and increased NET formation, already occur in iSLE, similar to SLE, despite differences in disease manifestations. Thereby, neutrophil dysfunction may contribute to sustained exposure to autoantigens and autoreactivity in early stages of SLE.
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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
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: Wide variety in salivary gland 18F-FDG-uptake is observed in the general population. A general consensus about the usefulness of 18F-FDG-PET/CT to detect salivary gland inflammatory conditions, such as in primary Sjögren's syndrome (pSS), is not yet clear. This study aimed to investigate whether there are differences in uptake of 18F-FDG in salivary glands among two autoimmune groups [pSS, giant cell arteritis (GCA)] and a non-autoimmune group (lung cancer). METHODS: PSS patients aged ≥50 years who underwent 18F-FDG-PET/CT were included and age-matched with GCA patients and a non-autoimmune control group (lung cancer patients). Scans were visually evaluated and quantitative analysis was performed by measuring standardised uptake values (SUV) within salivary glands and lacrimal glands. For GCA patients, arteries in the vicinity of the parotid and submandibular gland were assessed for positivity. RESULTS: PSS patients did not show increased 18F-FDG-uptake in the parotid or submandibular gland, compared to the other two groups. For the tubarial gland, significantly higher SUVmax was found in the pSS patient group. Interestingly, GCA patients had significantly higher SUVmax in the submandibular gland than the other two groups. Visual 18F-FDG-positivity of cranial arteries related to the parotid and submandibular glands was associated with significantly higher SUVmax in salivary glands of GCA patients. CONCLUSIONS: Although 18F-FDG-uptake was not increased in parotid and submandibular glands of pSS patients, increased 18F-FDG-uptake in tubarial glands of pSS patients might indicate a role for these glands in pSS. Furthermore, parotid and submandibular glands may be affected by local vasculitis in GCA.
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Arterite de Células Gigantes , Neoplasias Pulmonares , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico por imagem , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Arterite de Células Gigantes/diagnóstico por imagem , Glândulas Salivares/diagnóstico por imagem , Glândula Parótida/diagnóstico por imagem , Glândula SubmandibularRESUMO
OBJECTIVES: Ultrasound of the major salivary glands (SGUS) is widely used to assess the major salivary glands in Sjögren's disease (SjD). Little is known, however, regarding the diagnostic accuracy of SGUS to differentiate SjD from its mimics. This study aims to investigate the diagnostic accuracy of SGUS in differentiating SjD from other diseases with salivary gland involvement. METHODS: SGUS was performed in 20 consecutive patients with SjD and 20 consecutive patients with well-established systemic disease, i.e., with either sarcoidosis, amyloidosis, HIV infection or chronic HCV infection. Images were scored independently by two blinded observers using the Hocevar scoring system. Diagnostic accuracy to discriminate between the patient (sub-)groups was explored. RESULTS: The accuracy of SGUS to differentiate SjD from other systemic diseases was excellent (area under ROC curve of 0.91). The optimal cut-off value to define positive or negative ultrasound for SS was 15. Sensitivity, specificity, positive predictive value and negative predictive value were high, varying from 85-90%, and diagnostic odds ratio was 51. SGUS was positive in the vast majority of SjD patients (n=18), but also in 2 patients with HIV infection and one patient with sarcoidosis. SGUS score differed significantly between patients with SjD and other systemic diseases (median 27 vs. 10, p<0.001) as well as between SjD patients and patients with either sarcoidosis, amyloidosis, HIV or HCV infection (all p<0.05). CONCLUSIONS: This study indicates that SGUS has a potentially high diagnostic accuracy to discriminate SjD from systemic diseases which can also cause salivary gland involvement.
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Amiloidose , Infecções por HIV , Hepatite C , Sarcoidose , Síndrome de Sjogren , Humanos , Glândulas Salivares/diagnóstico por imagem , Síndrome de Sjogren/diagnóstico por imagem , Ultrassonografia/métodos , Sarcoidose/diagnóstico por imagemRESUMO
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: To develop a composite responder index in primary Sjögren's syndrome (pSS): the Sjögren's Tool for Assessing Response (STAR). METHODS: To develop STAR, the NECESSITY (New clinical endpoints in primary Sjögren's syndrome: an interventional trial based on stratifying patients) consortium used data-driven methods based on nine randomised controlled trials (RCTs) and consensus techniques involving 78 experts and 20 patients. Based on reanalysis of rituximab trials and the literature, the Delphi panel identified a core set of domains with their respective outcome measures. STAR options combining these domains were proposed to the panel for selection and improvement. For each STAR option, sensitivity to change was estimated by the C-index in nine RCTs. Delphi rounds were run for selecting STAR. For the options remaining before the final vote, a meta-analysis of the RCTs was performed. RESULTS: The Delphi panel identified five core domains (systemic activity, patient symptoms, lachrymal gland function, salivary gland function and biological parameters), and 227 STAR options combining these domains were selected to be tested for sensitivity to change. After two Delphi rounds, a meta-analysis of the 20 remaining options was performed. The candidate STAR was then selected by a final vote based on metrological properties and clinical relevance. CONCLUSION: The candidate STAR is a composite responder index that includes all main disease features in a single tool and is designed for use as a primary endpoint in pSS RCTs. The rigorous and consensual development process ensures its face and content validity. The candidate STAR showed good sensitivity to change and will be prospectively validated by the NECESSITY consortium in a dedicated RCT.
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Síndrome de Sjogren , Consenso , Humanos , Avaliação de Resultados em Cuidados de Saúde , Rituximab/uso terapêutico , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/tratamento farmacológicoRESUMO
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
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
OBJECTIVES: To investigate, in daily clinical practice, TNF-α inhibitor serum trough levels in patients experiencing an increase in axial spondyloarthritis (ax-SpA) related symptoms. Secondly, to explore if these serum trough levels are associated with disease activity (DA) and/or change in DA. METHODS: Patients from the GLAS cohort treated with TNF-α inhibitors who had a serum trough level measurement during follow-up because of an increase in ax-SpA related symptoms between June 2015 and June 2018 were included. Serum trough levels were stratified in a therapeutic and below therapeutic range, based on published reference values of Sanquin in 2019. DA was assessed by ASDAS and BASDAI and change in DA (i.e. ΔASDAS or BASDAI compared to the visit before increasing symptoms). RESULTS: 31 patients had a serum trough level measurement because of increasing symptoms. These patients had a median treatment duration of 4.8 years (IQR 0.9-8.6). 22 (71%) had active disease according to ASDAS (score ≥2.1) and 15 (47%) had therapeutic drug levels. The increase in DA was significantly larger in patients with below therapeutic drug levels compared to patients with therapeutic levels (ΔASDAS: 0.94±0.81 vs. -0.07±1.26, p<0.05; ΔBASDAI: 1.72±1.73 vs. -0.53±1.8, p<0.005). No significant differences were found in absolute DA scores between patients with or without therapeutic drug levels. CONCLUSIONS: In this observational study in daily clinical practice, approximately half of ax-SpA patients who experienced an increase in symptoms had below therapeutic TNF-α inhibitor serum trough levels. Change in DA and not absolute DA scores was significantly associated with drug levels.
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Espondiloartrite Axial , Espondilartrite , Humanos , Índice de Gravidade de Doença , Espondilartrite/diagnóstico , Espondilartrite/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Fator de Necrose Tumoral alfaRESUMO
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
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.
Assuntos
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
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.
Assuntos
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
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.
Assuntos
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).