Mortality risk factors in primary Sjögren syndrome:a real-world, retrospective, cohort study

BACKGROUND: What baseline predictors would be involved in mortality in people with primary Sjögren syndrome (SjS) remains uncertain. This study aimed to investigate the baseline characteristics collected at the time of diagnosis of SjS associated with mortality and to identify mortality risk factors for all-cause death and deaths related to systemic SjS activity measured by the ESSDAI score.METHODS: In this international, real-world, retrospective, cohort study, we retrospectively collected data from 27 countries on mortality and causes of death from the Big Data Sjögren Registry. Inclusion criteria consisted of fulfilling 2002/2016 SjS classification criteria, and exclusion criteria included chronic HCV/HIV infections and associated systemic autoimmune diseases. A statistical approach based on a directed acyclic graph was used, with all-cause and Sjögren-related mortality as primary endpoints. The key determinants that defined the disease phenotype at diagnosis (glandular, systemic, and immunological) were analysed as independent variables.FINDINGS: Between January 1st, 2014 and December 31, 2023, data from 11,372 patients with primary SjS (93.5% women, 78.4% classified as White, mean age at diagnosis of 51.1 years) included in the Registry were analysed. 876 (7.7%) deaths were recorded after a mean follow-up of 8.6 years (SD 7.12). Univariate analysis of prognostic factors for all-cause death identified eight Sjögren-related variables (ocular and oral tests, salivary biopsy, ESSDAI, ANA, anti-Ro, anti-La, and cryoglobulins). The multivariate CPH model adjusted for these variables and the epidemiological features showed that DAS-ESSDAI (high vs no high: HR = 1.68; 95% CI, 1.27-2.22) and cryoglobulins (positive vs negative: HR = 1.72; 95% CI, 1.22-2.42) were independent predictors of all-cause death. Of the 640 deaths with available information detailing the specific cause of death, 14% were due to systemic SjS. Univariate analysis of prognostic factors for Sjögren-cause death identified five Sjögren-related variables (oral tests, clinESSDAI, DAS-ESSDAI, ANA, and cryoglobulins). The multivariate competing risks CPH model adjusted for these variables and the epidemiological features showed that oral tests (abnormal vs normal results: HR = 1.38; 95% CI, 1.01-1.87), DAS-ESSDAI (high vs no high: HR = 1.55; 95% CI, 1.22-1.96) and cryoglobulins (positive vs negative: HR = 1.52; 95% CI, 1.16-2) were independent predictors of SjS-related death.INTERPRETATION: The key mortality risk factors at the time of SjS diagnosis were positive cryoglobulins and a high systemic activity scored using the ESSDAI, conferring a 2-times increased risk of all-cause and SjS-related death. ESSDAI measurement and cryoglobulin testing should be considered mandatory when an individual is diagnosed with SjS.FUNDING: Novartis.</p

Caracterización clínicoevolutiva de la afección neurológica del síndrome de Sjögren

[spa] Los artículos que se han incluido en esta Tesis Doctoral se centran en el estudio y caracterización de la afección neurológica que presentan los pacientes con Síndrome de Sjögren (SS) primario, incluyendo la evaluación tanto de la afección del sistema nervioso central como del sistema nervioso periférico en una cohorte de pacientes que ha sido estudiada de forma estandarizada y prospectiva en el Servicio de Enfermedades Autoinmunes del Hospital Clínic de Barcelona desde principios de los años 90. En los artículos se han analizado también aspectos específicos que pudieran influir en la prevalencia y expresión de la afección neurológica en el SS primario, como los factores de riesgo vascular, los criterios clasificatorios aplicados o el perfil inmunológico. - El primer artículo describe las principales características de la afección del Sistema Nervioso Central en el paciente con SS primario, las lesiones de sustancia blanca cerebral. Se ha analizado su posible asociación con la expresión sistémica del Síndrome de Sjögren, el perfil inmunológico y los factores de riesgo vascular. - El segundo artículo analiza la prevalencia de los diferentes tipos de neuropatía periférica en pacientes con SS primario, describiendo su etiología, características, respuesta terapéutica y pronóstico. - El tercer artículo describe las características de los pacientes con un diagnóstico clínico bien establecido de SS primario, a los que se aplicaron los criterios clasificatorios de 2002. Se evaluó la influencia de los dos principales grupos de criterios (2002 frente a 1993) buscando diferencias en la prevalencia y características de las principales manifestaciones clínicas (tales como los distintos tipos de afección neurológica) e inmunológicas. - El cuarto artículo analiza como la determinación de anticuerpos contra el antígeno Ro52 influye en la clasificación y la caracterización clínica de los pacientes con sospecha de SS primario, incluyendo la afección del sistema nervioso. - El artículo I del Suplemento analiza la prevalencia y la importancia clínica de los factores de riesgo cardiovascular en el SS primario, centrándose en la posible asociación con las características inmunológicas y dentro de estas últimas la afección neurológica incluyendo sistema nervioso central, sistema nervioso periférico y pares craneales.[eng] The articles included in this thesis focuses on the study and characterization of the neurological condition presenting patients with primary Sjögren's syndrome (SS), including the assessment of both the condition of the central nervous system and peripheral nervous system in a cohort of patients that has been studied, standardized and prospectively in the Department of Autoimmune Diseases Hospital Clínic of Barcelona since the early 90s. Articles were also analyzed specific aspects that may influence the prevalence and expression of neurological disease in primary SS, such as vascular risk factors, the classification criteria applied or immunological profile. • The first article describes the main features of the condition of the central nervous system in patients with primary SS, the cerebral white matter lesions. We analyzed the possible association with systemic expression of Sjögren's syndrome, the immune profile and vascular risk factors. • The second article discusses the prevalence of different types of peripheral neuropathy in patients with primary SS, describing their causes, characteristics, treatment response and prognosis. • The third article describes the characteristics of patients with a clinical diagnosis of primary SS well established, to which the 2002 classification criteria were applied. The influence of the two main groups of criteria (2002 versus 1993) looking for differences in the prevalence and characteristics of the major clinical manifestations (such as different types of neurological disease) and immunological was evaluated. • The fourth article discusses the determination of antibodies to Ro52 antigen affect the classification and clinical characterization of patients with suspected primary SS, including the condition of the nervous system. • The Article I of the Supplement discusses the prevalence and clinical significance of cardiovascular risk factors in primary SS, focusing on the possible association with the immunological characteristics and within the latter the neurological disease including central nervous system, nervous system peripheral and cranial nerves

Caracterización clínicoevolutiva de la afección neurológica del síndrome de Sjögren

Los artículos que se han incluido en esta Tesis Doctoral se centran en el estudio y caracterización de la afección neurológica que presentan los pacientes con Síndrome de Sjögren (SS) primario, incluyendo la evaluación tanto de la afección del sistema nervioso central como del sistema nervioso periférico en una cohorte de pacientes que ha sido estudiada de forma estandarizada y prospectiva en el Servicio de Enfermedades Autoinmunes del Hospital Clínic de Barcelona desde principios de los años 90. En los artículos se han analizado también aspectos específicos que pudieran influir en la prevalencia y expresión de la afección neurológica en el SS primario, como los factores de riesgo vascular, los criterios clasificatorios aplicados o el perfil inmunológico. - El primer artículo describe las principales características de la afección del Sistema Nervioso Central en el paciente con SS primario, las lesiones de sustancia blanca cerebral. Se ha analizado su posible asociación con la expresión sistémica del Síndrome de Sjögren, el perfil inmunológico y los factores de riesgo vascular. - El segundo artículo analiza la prevalencia de los diferentes tipos de neuropatía periférica en pacientes con SS primario, describiendo su etiología, características, respuesta terapéutica y pronóstico. - El tercer artículo describe las características de los pacientes con un diagnóstico clínico bien establecido de SS primario, a los que se aplicaron los criterios clasificatorios de 2002. Se evaluó la influencia de los dos principales grupos de criterios (2002 frente a 1993) buscando diferencias en la prevalencia y características de las principales manifestaciones clínicas (tales como los distintos tipos de afección neurológica) e inmunológicas. - El cuarto artículo analiza como la determinación de anticuerpos contra el antígeno Ro52 influye en la clasificación y la caracterización clínica de los pacientes con sospecha de SS primario, incluyendo la afección del sistema nervioso. - El artículo I del Suplemento analiza la prevalencia y la importancia clínica de los factores de riesgo cardiovascular en el SS primario, centrándose en la posible asociación con las características inmunológicas y dentro de estas últimas la afección neurológica incluyendo sistema nervioso central, sistema nervioso periférico y pares craneales.The articles included in this thesis focuses on the study and characterization of the neurological condition presenting patients with primary Sjögren's syndrome (SS), including the assessment of both the condition of the central nervous system and peripheral nervous system in a cohort of patients that has been studied, standardized and prospectively in the Department of Autoimmune Diseases Hospital Clínic of Barcelona since the early 90s. Articles were also analyzed specific aspects that may influence the prevalence and expression of neurological disease in primary SS, such as vascular risk factors, the classification criteria applied or immunological profile. • The first article describes the main features of the condition of the central nervous system in patients with primary SS, the cerebral white matter lesions. We analyzed the possible association with systemic expression of Sjögren's syndrome, the immune profile and vascular risk factors. • The second article discusses the prevalence of different types of peripheral neuropathy in patients with primary SS, describing their causes, characteristics, treatment response and prognosis. • The third article describes the characteristics of patients with a clinical diagnosis of primary SS well established, to which the 2002 classification criteria were applied. The influence of the two main groups of criteria (2002 versus 1993) looking for differences in the prevalence and characteristics of the major clinical manifestations (such as different types of neurological disease) and immunological was evaluated. • The fourth article discusses the determination of antibodies to Ro52 antigen affect the classification and clinical characterization of patients with suspected primary SS, including the condition of the nervous system. • The Article I of the Supplement discusses the prevalence and clinical significance of cardiovascular risk factors in primary SS, focusing on the possible association with the immunological characteristics and within the latter the neurological disease including central nervous system, nervous system peripheral and cranial nerves

Characterization and risk estimate of cancer in patients with primary Sjögren syndrome

Abstract Background The purpose of this study is to characterize the risk of cancer in a large cohort of patients with primary Sjögren syndrome (SjS). Methods We had analyzed the development of cancer in 1300 consecutive patients fulfilling the 2002 SjS classification criteria. The baseline clinical and immunological characteristics and systemic activity (ESSDAI scores) were assessed at diagnosis as predictors of cancer using Cox proportional hazards regression analysis adjusted for age at diagnosis and gender. The sex-and age-specific standardized incidence ratios (SIR) of cancer were estimated from 2012 Spanish mortality data. Results After a mean follow-up of 91 months, 127 (9.8%) patients developed 133 cancers. The most frequent type of cancer was B-cell lymphoma (including 27 MALT and 19 non-MALT B-cell lymphomas). Systemic activity at diagnosis of primary SjS correlated with the risk of hematological neoplasia and cryoglobulins with a high risk of either B-cell or non-B-cell lymphoma subtypes. Patients with cytopenias had a high risk of non-MALT B-cell and non-B-cell cancer, while those with low C3 levels had a high risk of MALT lymphomas and those with monoclonal gammopathy and low C4 levels had a high risk of non-MALT lymphomas. The estimated SIR for solid cancer was 1.13 and 11.02 for hematological cancer. SIRs for specific cancers were 36.17 for multiple myeloma and immunoproliferative diseases, 19.41 for Hodgkin lymphoma, 6.04 for other non-Hodgkin lymphomas, 5.17 for thyroid cancer, 4.81 for cancers of the lip and oral cavity, and 2.53 for stomach cancer. Conclusions One third of cancers developed by patients with primary SjS are B-cell lymphomas. The prognostic factors identified at SjS diagnosis differed according to the subtype of B-cell lymphoma developed. Primary SjS is also associated with the development of some non-hematological cancers (thyroid, oral cavity, and stomach)

Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial

Background: Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. Methods: In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027. Findings: Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of -2·7 percentage points (95% CI -7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41-0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47-0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. Interpretation: Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19

Additional file 2: Figure S1. of Characterization and risk estimate of cancer in patients with primary Sjögren syndrome

Frequency of the main WHO subtypes of hematological cancer and the corresponding predictive factors identified at SjS diagnosis. (TIF 182 kb