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Abstract: The aim of this study was to evaluate the potential associations between Sjogren syndrome and outcomes of acute myocardial infarction (AMI) hospitalization. This population-based, retrospective observational study extracted data from the US Nationwide Inpatient Sample between 2005 and 2018. Adults aged 20 years or older hospitalized for AMI were eligible for inclusion. Propensity score matching was applied to balance the characteristics between the comparison groups (ie, with and without Sjogren syndrome). Associations between Sjogren syndrome and in-hospital outcomes were determined using univariate and multivariable logistic regression analyses. A total of 1,735,142 patients were included. After propensity score matching, 4740 patients remained for subsequent analyses (948 had Sjogren syndrome and 3792 did not). After adjustment, patients with Sjogren syndrome had significantly lower in-hospital mortality (adjusted OR: 0.52, 95% CI, 0.36-0.73, P < 0.001), prolonged length of stay (aOR: 0.83, 95% CI, 0.69-0.995, P = 0.044), cardiogenic shock (aOR: 0.58, 95% CI, 0.40-0.83, P = 0.004), cardiac dysrhythmias (aOR: 0.77, 95% CI, 0.66-0.90, P < 0.001), acute kidney injury (aOR: 0.56, 95% CI, 0.45-0.70, P < 0.001), or respiratory failure (aOR: 0.63, 95% CI, 0.48-0.81, P < 0.001) than those without Sjogren syndrome. The stratified analysis revealed that Sjogren syndrome was associated with decreased odds of in-hospital mortality in patients with non-ST elevation myocardial infarction or ST-elevation myocardial infarction. In conclusion, among patients admitted to US hospitals for AMI, the patients with Sjogren syndrome have a lowered probability of in-hospital mortality, certain morbidities, and prolonged length of stay. Further investigations should be conducted to establish a robust understanding of the associations observed., Competing Interests: The author reports no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Sjögren's disease is the autoimmune disease with the highest risk of lymphoma development. There is no consensus on the optimal way to manage Sjögren's disease complicated by lymphoma. We aimed to describe characteristics, therapeutic strategies, and outcomes of non-Hodgkin lymphoma associated with Sjögren's disease, and their effect on lymphoma and Sjögren's disease prognoses., Methods: We did a multicentre, retrospective, observational study including patients with Sjögren's disease according to the 2016 American College of Rheumatology-European League Against Rheumatism criteria who did not fulfil diagnostic criteria for other connective tissue diseases. We included patients with a lymphoma diagnosis made before Jan 1, 2020, from two expert centres in Paris (France); from the French, multicentre, prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome cohort; and via practitioners registered with the Club Rhumatismes et Inflammation. Using inverse probability of treatment weighting, the effect of lymphoma treatment was compared in relation to three endpoints: lymphoma progression-free survival, new Sjögren's disease systemic activity, and overall survival. Exploratory analyses also aimed to identify factors associated with lymphoma relapse, new Sjögren's disease systemic activity, and overall survival. People with lived experience were not involved in this research., Findings: 106 patients with Sjögren's disease who developed lymphoma were included in the study. The most frequent histological subtype was mucosa-associated lymphoid tissue lymphoma (68 [64%] of 106 patients), followed by other marginal zone subtypes (14 [13%] of 106 patients) and diffuse large B-cell lymphoma (14 [13%] of 106 patients). Among the 82 patients with marginal zone lymphoma (72 [88%] women and ten (12%) men; mean age at lymphoma diagnosis 57·5 years [SD 14·8]), multivariable analysis showed that pulmonary localisation was associated with mortality (hazard ratio [HR] 7·92 [95% CI 1·70-37·0]). A watch and wait approach was proposed in 19 (23%) of 82 patients with marginal zone lymphoma, 13 (16%) had first-line localised treatment (surgery or radiotherapy), and 50 (61%) had first-line systemic treatment. After a median follow-up of 7 years, 26 patients (32%) had lymphoma relapse, nine (11%) died, and 27 (33%) had new Sjögren's disease systemic activity. After inverse probability of treatment weighting, patients with systemic treatment at lymphoma diagnosis had a reduced risk of new Sjögren's disease activity (HR 0·43 [95% CI 0·21-0·90]). When comparing patients treated with a combination of chemotherapy and anti-CD20 therapy (n=32) with patients treated with monotherapy (n=18) as a first-line therapy for lymphoma, lymphoma-progression-free survival was improved in patients treated with combination therapy (HR 0·36 [95% CI 0·14-0·94]). The were no differences in new Sjögren's disease systemic activity or overall survival according to combination therapy or monotherapy., Interpretation: A systemic treatment strategy for Sjögren's disease-associated lymphoma, rather than localised treatment or a watch and wait strategy, reduces the risk of new Sjögren's disease systemic activity and combination therapy is associated with decreased risk of lymphoma relapse., Funding: None., Competing Interests: Declaration of interests VLG received consulting fees from Novartis; honoraria from Novartis and Bristol Myers Squibb; and travel fees from AstraZeneca and Novartis. MC received honoraria from Lilly and travel fees from Novartis, Janssen, UCB, and Pfizer. XM received consulting fees from AstraZeneca, Bristol Myers Squibb, Galapagos, GSK, Novartis, and Pfizer. RS received consulting fees from GSK, Bristol Myers Squibb, Boehringer, and Janssen; honoraria from GSK, Bristol Myers Squibb, Boehringer, Amgen, Pfizer, and Roche; and travel fees from Amgen and GSK. GN received honoraria from Novartis, Boehringer, AbbVie, and Galapagos SASU and travel fees from Amgen, AbbVie, and UCB. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Aim: This study aimed to evaluate the long-term survival, causes of death, and prognostic factors in Chinese patients with primary Sjögren syndrome (pSS)., Methods: We included patients with pSS registered in the Chinese Rheumatism Data Centre between May 2016 and December 2021, and collected baseline clinical, laboratory, and treatment data. Survival and standard mortality rates were calculated using general population mortality data. Factors related to mortality were identified using Cox proportional hazards regression., Results: Among the 8588 patients included, 274 died during a median follow-up of 4.0 years. The overall standardized mortality ratio was 1.61 (95% CI: 1.43-1.81). Overall survival rates were 98.2% at 5 years and 93.8% at 10 years. The predominant causes of death were comorbidities, including cardiovascular diseases, tumors, and infections, while the most frequent pSS-related causes of death were interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). Male sex, older age, ILD, PAH, and high EULAR Sjögren's syndrome disease activity index (ESSDAI), thrombocytopenia, anemia, high immunoglobulin A (IgA) level, and glucocorticoid treatment independently increased the mortality risk, while using hydroxychloroquine was a protective factor., Conclusion: Mortality rates have significantly increased in Chinese patients with pSS. Comorbidities, rather than pSS-related organ damage, were the main causes of death. All-cause mortality was associated with male sex, older age, ILD, PAH, high ESSDAI, thrombocytopenia, anemia, high IgA level, and glucocorticoid treatment, whereas hydroxychloroquine use might improve the long-term survival., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objectives: The association between immune-mediated thrombotic thrombocytopenic purpura (iTTP) and Sjögren disease (SjD) has been poorly investigated. This study presents the first retrospective cohort of iTTP-SjD aiming to identify risk factors for iTTP occurrence in SjD patients and examine their clinical course., Methods: Patients with iTTP-SjD were identified within the French TTP Registry based on American College of Rheumatology/European League Against Rheumatism 2016 criteria. A comparative analysis was conducted with two control groups comprising primary SjD (pSjD) patients from the French ASSESS cohort and idiopathic iTTP patients from the French TTP Registry. Demographic, clinical and biological data were retrospectively collected., Results: Thirty iTTP-SjD patients were included and compared with 65 pSjD and 45 idiopathic iTTP patients. The majority of iTTP-SjD patients (n=18) were diagnosed with SjD at the time of iTTP diagnosis. In comparison with the pSjD cohort, iTTP-SjD patients were diagnosed with SjD at a younger age (p=0.039) and showed a higher prevalence of anti-SjS-related antigen A antibody positivity and xerostomia (p=0.015, p=0.035, respectively). EULAR Sjogren's Syndrome Disease Activity Index showed similar activity levels between the two groups. iTTP-SjD patients were treated with plasma exchange (n=28), corticosteroids, rituximab (n=19) and caplacizumab (n=3). In comparison with the idiopathic iTTP cohort, mortality rates (log-rank tests, p=0.228), biological and clinical iTTP relapses (multivariate analysis, p=0.181) were comparable and short-term outcomes (survival at day 30, relapse) were favourable., Conclusion: iTTP can be a rare complication in patients with SjD. Further studies involving larger cohorts and long-term follow-up are warranted to confirm these findings and to explore the efficacy of immunomodulators and caplacizumab in iTTP-SjD patients., Competing Interests: Competing interests: GN received speaker fees from Novartis, Amgen, Galapagos and BMS. AV is a member of the French advisory boards for Sanofi and Takeda and received speaker fees from Sanofi, Octapharma, LFB-Biomédicaments and Takeda. XM received fees from BMS, Galapagos, GSK, Novartis and Pfizer. PC is a member of advisory boards and received speaker fees from Sanofi, Alexion, Octapharma and Takeda. IB received speaker fees from Galapagos. BSJ received speaker fees from Sanofi, Takeda and LFB-Biomédicaments. JL, LG and RB declare no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The role of nutritional status as a prognostic factor in patients with Sjögren's syndrome-associated interstitial lung disease (SjS-ILD) is currently unclear. This study aimed to predict the prognosis of patients with SjS-ILD through their nutritional status assessment. In this retrospective observational study, nutritional status was evaluated at the time of diagnosis using body mass index (BMI) and nutritional markers such as controlling nutritional status (CONUT), the Glasgow prognostic score (GPS), and prognostic nutrition index (PNI) for all participants. Receiver operating characteristic (ROC) analyses were performed using BMI and each nutritional marker data to compare the area under the ROC curve (AUC) and find the cutoff value using the maximum Youden index. Kaplan-Meier analysis and Cox proportional hazards regression analysis were performed to predict the prognosis of SjS-ILD patients. A total of 112 SjS-ILD patients were enrolled in the study, and 8.9% died during the follow-up period. The median time from diagnosis to follow-up period was 4.2 years. The AUC for PNI was the highest among nutritional markers and BMI, and PNI cutoff value was used to distinguish between the PNI < 47.7 and PNI ≥ 47.7 groups. A statistical difference was observed in the Kaplan-Meier analysis and log-rank test (p = 0.005). In multivariable analyses, PNI < 47.7 (hazard ratio 9.40, 95% confidence interval 1.54-57.21) is associated with increased mortality, suggesting the importance of early nutritional intervention for malnutrition in SjS-ILD patients., (© 2024. The Author(s).)

Objectives: Age has a significant impact on systemic lupus erythematosus (SLE). However, data on very late-onset SLE (vlSLE) are scarce. We have compared the clinical and serological features of vlSLE patients with younger-onset patients., Methods: We assessed the clinical and laboratory data of all patients fulfilling SLE classification criteria evaluated at a university hospital from 1978 to 2023. Patients were divided into 4 groups according to age at diagnosis: juvenile SLE (jSLE <8 years); adult SLE (aSLE 18-49 years); late SLE (lSLE 50-59 years); vlSLE (≥60 years)., Results: 845 patients were enrolled. The jSLE, aSLE, lSLE, and vlSLE groups included 153, 630, 47, and 15 patients, respectively. The vlSLE group tended to have a lower female-to-male ratio (4:1; p=0.282), was mainly Caucasian (93.3%; p<0.001), and had the lowest survival time (20.3 years; p<0.001). vlSLE patients had the lowest prevalence of positive anti-dsDNA antibodies (26.7%; p=0.010) and low C3 levels (13.3%; p<0.001). Although arthritis was less common among vlSLE patients (73.3%; p=0.043), they more commonly developed Sjögren's syndrome (SS 33.3%; p<0.001) and rheumatoid arthritis (RA 13.3%; p<0.001). Infections and malignancy were the main causes of death., Conclusions: Compared with younger patients, in vlSLE, female predominance is less pronounced. Arthritis, anti-dsDNA antibodies and low C3 levels are less frequent. SS and RA are more common. Despite lower disease activity, vlSLE patients have the lowest survival rate. While uncommon, SLE should not be excluded as a possible diagnosis in the elderly.

Objectives: To clarify the impact of anti-U1RNP antibodies on the clinical features and prognosis of patients with SSc., Methods: We conducted a monocentric case-control, retrospective, longitudinal study. For each patient with SSc and anti-U1RNP antibodies (SSc-RNP + ), one patient with mixed connective tissue disease (MCTD) and 2 SSc patients without anti-U1RNP antibodies (SSc-RNP - ) were matched for age, sex, and date of inclusion., Results: Sixty-four SSc-RNP + patients were compared to 128 SSc-RNP - and 64 MCTD patients. Compared to SSc-RNP - , SSc-RNP + patients were more often of Afro-Caribbean origin (31.3% vs. 11%, p < 0.01), and more often had an overlap syndrome than SSc-RNP - patients (53.1 % vs. 22.7%, p < 0.0001), overlapping with Sjögren's syndrome (n = 23, 35.9%) and/or systemic lupus erythematosus (n = 19, 29.7%). SSc-RNP + patients were distinctly different from MCTD patients but less often had joint involvement (p < 0.01). SSc-RNP + patients more frequently developed interstitial lung disease (ILD) (73.4% vs. 55.5% vs. 31.3%, p < 0.05), pulmonary fibrosis (PF) (60.9% vs. 37.5% vs. 10.9%, p < 0.0001), SSc associated myopathy (29.7% vs. 6.3% vs. 7.8%, p < 0.0001), and kidney involvement (10.9% vs. 2.3% vs. 1.6%, p < 0.05). Over a 200-month follow-up period, SSc-RNP + patients had worse overall survival (p < 0.05), worse survival without PF occurrence (p < 0.01), ILD or PF progression (p < 0.01 and p < 0.0001)., Conclusions: In SSc patients, anti-U1RNP antibodies are associated with a higher incidence of overlap syndrome, a distinct clinical phenotype, and poorer survival compared to SSc-RNP - and MCTD patients. Our study suggests that SSc-RNP + patients should be separated from MCTD patients and may constitute an enriched population for progressive lung disease., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease that is manifested by the sensation of dry eyes and dry mouth. The higher incidence of non-Hodgkin lymphoma (NHL) among pSS has already been extensively researched. However, there are uncertanties whether the mortality risk in pSS patients and in pSS patients with NHL is increased. The purpose of this study was to describe the prevalence of NHL among pSS patients and to calculate their mortality risk. We retrospectively analysed data on 1367 patients treated in our rheumatology department under the ICD-10 code M35.0. The study finally recruited 155 patients who met the 2016 ACR/EULAR criteria for the diagnosis of pSS. Descriptive statistics was used in data analysis. We applied the indirect standardization by age to compare the incidence rate of NHL in our cohort to general population. Additionally, we compared the mortality in our study to the general population by calculating the standardized mortality ratio (SMR). The overall incidence rate of NHL was 440 per 100,000 patient-years. The SIR compared to the general population was 30.13 (95% CI 12.87-54.63). The overall mortality rate of pSS patients in our cohort was nearly identical to that of the general population (SMR = 0.98 [95% CI (0.47-1.69)]). This study confirms that there are significant differences in lymphoma prevalence, histology, and prognosis across the studied populations. Furthermore, this study found that patients with pSS have similar mortality risk as the general population, and no patient in our cohort died from NHL., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: Aim of the study was to determine the characteristics and prognosis, and to identify the risk factors for mortality in patients with primary Sjögren syndrome (pSS) with interstitial lung disease (pSS-ILD).A total of 1422 patients with SS were screened and 178 patients with pSS-ILD were recruited. The medical records and outcomes were retrospectively reviewed. Overall survival and case control study were performed to explore the predictors of death.Among 178 pSS-ILD patients, 87.1% were women. Mean age was 61.59 ± 11.69-year-old. Median disease duration was 72.0 (24.0, 156.0) months. Nonspecific interstitial pneumonia was the predominant high-resolution computed tomography pattern (44.9%). Impairment in diffusion capacity was the most common abnormality of pulmonary function test (75.8%) and the most severe consequence. Type 1 respiratory failure and hypoxia were observed in 15.0% and 30.0% patients, respectively. Mean survival time after confirmation of pSS-ILD diagnosis was 9.0 (6.8, 13.0) years. The 10-year survival rate for all patients with pSS-ILD was 81.7%. Forty-four (24.7%) of 178 patients died during the follow-up period. The most predominant cause of death was respiratory failure (n = 27). Twenty-seven patients died of ILD and formed study group. The 78 patients who survived formed control group. Age and smoking were risk factors for mortality in patients with pSS-ILD. In addition, severity of ILD, as reflected by high-resolution computed tomography, pulmonary function test, and arterial blood gas, was an independent risk factor. However, inflammation status (erythrocyte sedimentation rate, C-reactive protein) and anti-Sjögren syndrome-related antigen A and anti-Sjögren syndrome-related antigen B were not.ILD is a severe complication of pSS. Age, smoking, and severity of lung involvement are more critical for prognosis rather than inflammation status and autoantibodies., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: It remains debated whether patients with primary Sjögren's syndrome (pSS) are at greater risk of mortality. We aimed to determine the magnitude of all-cause mortality risk in patients with pSS compared with the general population through a systematic review and meta-analysis., Methods: We searched PubMed, EMBASE and Cochrane Library for studies published from inception to October 2020. Stata meta-analysis software was used to calculate the pooled risk estimates for mortality (standardized mortality ratio, SMR)., Results: Our search identified 2796 articles, of which 14 studies with 14 584 patients were eventually included for the analysis. A total of 902 deaths were observed. Overall, we found a 1.46-fold increased risk of death in pSS patients when compared with the general population [meta-standardized mortality ratio (SMR): 1.46, 95% CI: 1.10, 1.93]. Subgroup analyses showed that mortality risks were higher in European countries (meta-SMR: 1.55, 95% CI: 1.04, 2.33), in retrospective studies (meta-SMR: 1.50, 95% CI: 1.09, 2.05), in studies based on referral cohorts (meta-SMR: 1.55, 95% CI: 1.04, 2.30), in studies that enrolled >500 patients (meta-SMR: 1.70, 95% CI: 1.11, 2.61) and in studies with follow-up time longer than 8 years (meta-SMR: 1.55, 95% CI: 0.87, 2.77). Significantly greater mortality risk was found in patients with older age, male gender, vasculitis, interstitial lung disease, low complements, positive anti-La/SSB and cryoglobulinaemia., Conclusion: The existing data indicated ∼50% increase of mortality among patients with pSS compared with the general population. More attention should be paid to those patients with poor prognostic factors., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To analyse the prognosis and outcomes of SARS-CoV-2 infection in patients with primary SS., Methods: We searched for patients with primary SS presenting with SARS-CoV-2 infection (defined following and according to the European Centre for Disease Prevention and Control guidelines) among those included in the Big Data Sjögren Registry, an international, multicentre registry of patients diagnosed according to the 2002/2016 classification criteria., Results: A total of 51 patients were included in the study (46 women, mean age at diagnosis of infection of 60 years). According to the number of patients with primary SS evaluated in the Registry (n = 8211), the estimated frequency of SARS-CoV-2 infection was 0.62% (95% CI 0.44, 0.80). All but two presented with symptoms suggestive of COVID-19, including fever (82%), cough (57%), dyspnoea (39%), fatigue/myalgias (27%) and diarrhoea (24%), and the most frequent abnormalities included raised lactate dehydrogenase (LDH) (88%), CRP (81%) and D-dimer (82%) values, and lymphopenia (70%). Infection was managed at home in 26 (51%) cases and 25 (49%) required hospitalization (five required admission to ICU, four died). Compared with patients managed at home, those requiring hospitalization had higher odds of having lymphopenia as laboratory abnormality (adjusted OR 21.22, 95% CI 2.39, 524.09). Patients with comorbidities had an older age (adjusted OR 1.05, 95% CI 1.00, 1.11) and showed a risk for hospital admission six times higher than those without (adjusted OR 6.01, 95% CI 1.72, 23.51) in the multivariate analysis., Conclusion: Baseline comorbidities were a key risk factor for a more complicated COVID-19 in patients with primary SS, with higher rates of hospitalization and poor outcomes in comparison with patients without comorbidities., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Interstitial lung disease (ILD) is the most common lung manifestation in patients with Sjögren syndrome (SJS) and is associated with poor outcomes. This study aimed to investigate the long-term clinical course and prognostic factors in patients with SJS-ILD. Clinical data and high-resolution computed tomography (HRCT) images of 62 patients with primary SJS-ILD were retrospectively analyzed (biopsy-proven cases, n = 16). The mean patient age was 59.8 years; 83.9% of the patients were females, and 38.7% showed a usual interstitial pneumonia (UIP) pattern on HRCT. The median follow-up period was 61.5 months. During follow-up, 15 patients (24.2%) died, 7 (11.3%) experienced acute exacerbation (AE), and 27 (43.5%) progressed. The 1-, 3- and 5-year survival rates were 93.5%, 85.8%, and 81.1%, respectively. Age (hazard ratio [HR]: 1.158, P = 0.003), C-reactive protein (CRP) level (HR: 1.212, P = 0.045), FVC (HR: 0.902, P = 0.005), and a UIP pattern on HRCT (HR: 4.580, P = 0.029) were significant prognostic factors in multivariable Cox analysis. In conclusion, death, AE, and ILD progression occurred in 25%, 10%, and 50% of the patients with SJS-ILD, respectively. Older age, higher CRP level, lower FVC, and a UIP pattern on HRCT indicated poor prognosis.

Purpose: To report the significance of extraglandular ocular involvement and long-term systemic morbidity and mortality in primary Sjögren's Syndrome (SS)., Methods: This retrospective, longitudinal cohort study included consecutive patients with primary SS evaluated at a tertiary referral center. An electronic chart review was performed and all available data were extracted from clinic visits between October 1999 and March 2019. The primary outcome measures included occurrence of extraglandular ocular manifestations of SS, serological markers, prevalence of malignancy, and incidence of death., Results: One hundred and twenty-six SS patients with minimum 3 years of follow-up (median 9.6, range 3.0-15.9 years, total of 1,235 patient-years) were included. Of those, 10 patients with inflammatory keratolysis or scleritis had 2.3 times greater likelihood of death compared to the rest of the cohort (OR = 2.3, 95% confidence interval [CI] 0.5 to 4.0, p = 0.01) due to SS related complications. The lifetime prevalence of any malignancy in the entire cohort was 15.5%. The most common hematologic malignancy was non-Hodgkin's lymphoma (4.8%) and the most common solid malignancy was breast cancer (6.0%). Men SS patients were more likely to have a history of or concurrent malignancy compared to women (30.0% versus 13.7%, p = 0.16) and double the mortality (OR = 2.1, 95% CI 0.09 to 1.4, p = 0.04), independent of malignancy., Conclusions: SS patients with serious ocular manifestations, particularly men, may be at greater risk for mortality due to SS complications. The eye seems to be the barometer of systemic disease activity., Competing Interests: The authors have declared that no competing interests exist. Dr. Akpek is an unpaid member of the Sjögren’s Foundation.

Aim: To describe changes in the 2001-2014 mortality of 6 autoimmune systemic diseases (AISDs), namely Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc), Idiopathic Inflammatory Myopathies (IIM), Sjögren's Syndrome (SS), Mixed Connective Tissue Disease (MCTD) and ANCA-associated vasculitis (AAV) at the country-, continent-, and world-levels., Methods: Mortality data were retrieved from the World Health Organization (WHO) mortality database for each disease, based on ICD-10 codes. We computed age-standardized mortality rate (ASMR) as the estimated number of deaths per million inhabitants and its 95% confidence interval (95%CI). The association between gender, geographical areas and disease-specific mortality was analyzed using multivariate Poisson regression. The 2001-2014 temporal trends were analyzed using Jointpoint software., Results: In 2014, the worldwide ASMR for SLE was 2.68 (95%CI: 2.62-2.75) deaths/millions inhabitants, 1.46 (1.42-1.51) for SSc, 0.47 (0.44-0.49) for IIM, 0.17 (0.15-0.18) for SS, 0.11 (0.10-0.13) for MCTD and 0.53 (0.50-0.56) for AAV, with ASMRs generally lower in Europe than in North America, Latin America and Asia. Between 2001 and 2014, the worldwide ASMR decreased significantly for SSc (-0.71%/year), IIM (-1.65%/year) and AAV (-1.01%/year; p < .001 for all) and increased for SS (+1.53%/year, p = .01). The worldwide ASMR of SLE decreased significantly between 2001 and 2003 (-6.37%, p < .05) before increasing slightly between 2004 and 2014 (+0.58%, p < .01)., Conclusions: We observed a strong heterogeneity of standardized mortality rates across all countries analyzed for 6 autoimmune diseases. Those results further highlight the impact of world-wide inequities and major gaps in access to care and strategies for diagnosis and management of rare diseases, a crucial finding for world-wide physicians, patient associations and policy makers., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: This study was conducted to determine long-term survival rates and the factors associated with mortality in Turkish primary Sjögren syndrome (pSS) patients., Methods: All patients diagnosed with pSS between 2004 and 2014 were included in this study. By January 2019, all subjects still living by the end of the study, as well as any death, were identified. Survival rates and standard mortality rates (SMRs) using general population mortality data were calculated. Mortality-related factors were determined by univariate and multivariate analysis., Results: During follow-up, 33 cases of 372 pSS patients resulted in death (8.9%). Of those patients, they were typically older at disease onset, at recruitment, and had shorter follow-up times (p < 0.001 for all). The overall SMR of all pSS patients compared with the general population was 2.11 (95% confidence interval (CI) 1.39-2.83). Male pSS patients had a higher SMR than that of general male patients. Overall survival rates were 97.8% at five years, 90.2% at 10 years, and 87.1% at 15 years in patients with pSS. The survival rate of pSS patients was significantly lower than the general Turkish population (p = 0.011). Multivariate Cox regression analysis showed that older age at disease onset and the presence of interstitial lung disease (ILD) were independent risk factors for mortality., Conclusions: Based on these data, mortality rates of Turkish pSS patients are higher compared with the general population. Survival significantly decreased in the pSS patients with ILD, especially in older male patients at disease onset. Male gender and malignancy may also be associated with a worse prognosis in pSS patients.Key Point• Mortality in Sjögren's syndrome.

Objective: Interstitial lung disease (ILD) is a condition characterized by a higher mortality rate in primary Sjögren's syndrome (pSS). However, factors influencing the outcome of patients with pSS-associated ILD remain unclear. The aim of the present study was to evaluate predictive factors associated with a worse prognosis in pSS-ILD., Methods: This retrospective study included 99 consecutive patients with pSS-ILD. Clinical characteristics, laboratory findings, and pulmonary function tests at the time of diagnosis were analyzed. Chest HRCT images were reviewed by two experienced chest radiologists. Prognostic factors were assessed by univariate and multivariate analyses, using Cox proportional hazards regression model., Results: Median age was 68 years (73% women). In the total patient population, the 5- and 10-year survival rates were 89.8% and 79.0%, respectively. Univariate analysis revealed a significant association between prognosis and age, serum Krebs von den Lungen-6 (KL-6) levels, and %FVC. None of the chest HRCT findings were related to patient outcomes. Based on multivariate analyses adjusted by age and gender, lower levels of %FVC and higher levels of KL-6 were significantly associated with poor outcomes. Using optimal cutoff levels, according to receiver operating characteristic curve analyses, KL-6 > 800 U/mL were significantly associated with worse prognosis (HR: 2.91, 95% CI: 1.04-8.10). Patients with elevated serum KL-6 levels (>800 U/mL) showed a higher mortality rate than those without elevated serum KL-6 levels (p = 0.02)., Conclusions: Lower %FVC and higher serum KL-6 levels are predictive factors for poor outcome in patients with pSS-ILD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Competing Interests: Competing interests: RS received consulting fees from Roche (<10.000€). Other authors declared any competing interest in link with the present study.

Pulmonary arterial hypertension (PAH) is a severe complication and leading cause of mortality in patients with primary Sjogren's syndrome (pSS). This study was to investigate the overall survival rates and the utility of red blood cell distribution width (RDW) as a potential prognostic factor of pSS-PAH. This cohort study retrospectively enrolled 55 patients with pSS-PAH who were followed up at the Department of Rheumatology of Peking Union Medical College Hospital (PUMCH) between August 2007 and May 2017. The patients were stratified according to the level of RDW (≤ 15.0 and > 15.0%). Baseline demographics, laboratory results, pulmonary function conditions, hemodynamic assessments, and treatment regimens were analyzed. Cox proportional hazards regression analysis was used to identify whether RDW level is a factor related to adverse outcome. A total of 55 patients were recruited, with an average age of 38.9 ± 9.3 years. Fifty-four were female (98.2%), and the average duration at the time of PAH diagnosis was 25.5 ± 33.2 months. Higher RDW levels were found in patients who deceased in follow-up (13.8 ± 2.6 vs 16.5 ± 1.6%, p = 0.003) and with higher NYHA classes (13.8 ± 1.8 vs 16.5 ± 2.9%, p < 0.001). Patients with RDW > 15% had a significantly worse overall survival than patients with RDW ≤ 15% (3-year survival rate 59.5 vs. 88.7% log-rank p = 0.015). Cox regression analysis identified RDW > 15% as a prognostic factor for adverse outcome (HR 1.786, 95% CI 1.137-2.803, p = 0.012). RDW can serve as a potential negative prognostic factor of pSS-PAH.

Objective: To assess the prevalence and causes of hepatobiliary involvement (HBI) in systemic sclerosis (SSc), to investigate the clinical characteristics and prognosis of SSc patients with HBI (SSc-HBI) and without HBI (SSc-non-HBI), and to compare both groups according to the cutaneous SSc subsets., Methods: In all, 1572 SSc patients were collected in the RESCLE registry up to January 2015, and all hepatobiliary disturbances were recorded. We investigated the HBI-related characteristics and survival from the entire SSc cohort and according to the following cutaneous subsets: diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma (ssSSc)., Results: Out of 1572, 118 (7.5%) patients had HBI. Primary biliary cholangitis (PBC) was largely the main cause (n = 67, 4.3%), followed by autoimmune hepatitis (n = 19, 1.2%), and anti-mitochondrial negative PBC (n = 6, 0.4%). Other causes of HBI were as follows: secondary liver diseases (n = 11, 0.7%), SSc-related HBI (n = 7, 0.4%), nodular regenerative hyperplasia (n = 3, 0.2%), liver cirrhosis (n = 3, 0.2%), and HBI of unknown origin (n = 2, 0.1%). In multivariate analysis, HBI was independently associated to lesser risk of dcSSc (5.1% vs. 24.4%), and higher frequency of calcinosis (26% vs. 18%), left ventricular diastolic dysfunction (46% vs. 27%), sicca syndrome (51% vs. 29%), and anti-centromere antibodies (ACA, 73% vs. 44%). According to the cutaneous subsets, HBI was associated (1) in lcSSc, to longer time from SSc onset to diagnosis (10.8 ± 12.5 vs. 7.2 ± 9.3 years), sicca syndrome (54% vs. 33%), and ACA (80% vs. 56%); (2) in ssSSc, to sicca syndrome (44% vs. 19%), and (3) in dcSSc, no associations were found. HBI was the cause of death in 2.3% patients but the cumulative survival according to the presence or absence of HBI showed no differences., Conclusions: HBI prevalence in SSc is 7.5% and dcSSc is the least involved subset. PBC is the main cause of HBI. Patients with SSc-HBI exhibited specific clinical and immunologic profile. Survival is similar for SSc patients with HBI., (Copyright © 2017 Elsevier Inc. All rights reserved.)

To determine the prevalence of pulmonary complications in primary Sjögren syndrome (pSS), and to identify the risk factors and the prognosis associated with pulmonary involvement in pSS patients.A total of 1341 hospitalized patients (853 with pSS and 488 with secondary Sjögren syndrome [sSS]) were retrospectively reviewed. Of these, 165 hospitalized patients with pSS-associated interstitial lung disease (ILD) were analyzed and recruited as a study group. Eighty-four pSS patients without organ damage were included as a control group.One hundred and sixty-five patients (19.34%) from the pSS group and 126 patients (25.82%) from the sSS group presented with lung involvement. Of the 165 pSS patients with lung complications, 151 (91.5%) were women. The mean age was 61.25 ± 9.79 years, and the median disease duration was 84 (24-156) months. Non-specific interstitial pneumonia (NSIP; 39.1%) was the predominant pattern on high-resolution computed tomography (HRCT). The total HRCT score was 9.71 ± 4.77. Impairment in diffusion capacity was the most common (74.3%) and severe complication (predicted value of TLCO was 57.5 ± 21.2%). The 5-year survival rate for all patients with pSS-ILD was 88.5%. Age, disease duration, rheumatoid factor (RF), and C-reactive protein (CRP) were significantly higher than in controls, whereas anti-SSA was less common. Age, RF, and CRP were independent predictors of ILD after adjustment for confounders.Lung involvement is a common and severe complication of Sjögren syndrome. Age and disease activity are correlated with pulmonary involvement in pSS patients.

Objectives: To analyse the clinical features and outcomes of patients presenting with life-threatening systemic disease in a large cohort of Spanish patients with primary Sjögren's syndrome (SS)., Methods: The GEAS-SS multicentre registry was formed in 2005 with the aim of collecting a large series of Spanish patients with primary SS, and included more than 20 Spanish reference centres with substantial experience in the management of SS patients. By January 2018, the database included 1580 consecutive patients fulfilling the 2002 classification criteria for primary SS. Severe, life-threatening systemic disease was defined as an activity level scored as "high" in at least one ESSDAI domain., Results: Among 1580 patients, 208 (13%) were classified as presenting a severe, potentially life-threatening systemic disease: 193 presented one ESSDAI domain classified as high, 14 presented two high scored domains and only one presented three high activity domains. The ESSDAI domains involved consisted of lymphadenopathy in 78 (37%) cases, CNS in 28 (13%), PNS in 25 (12%), pulmonary in 25 (12%), renal in 21 (10%), cutaneous in 19 (9%), articular in 18 (9%), haematological in 7 (3%) and muscular in 4 (2%). Patients with severe systemic disease were more frequently men (p=0.001) and had a higher frequency of anaemia (p<0.001), lymphopenia (p<0.001), rheumatoid factor (p=0.021), low C3 levels (p=0.015), low C4 levels (p<0.001) and cryoglobulins (p<0.001). From a therapeutic point of view, systemic patients received more frequently glucocorticoids (p<0.001), immunosuppressants (p<0.001), intravenous immunoglobulins (p=0.008) and rituximab (p<0.001). We found an overall mortality rate of 20% in severe systemic patients, a rate that reached to 33% in patients presenting two or more high systemic involvements; these patients had a higher frequency of low C4 levels (p=0.012) and cryoglobulins (p=0.001) in comparison with those with a single severe organ involved., Conclusions: 13% of patients with primary SS develop a potentially life-threatening systemic disease (mainly lymphoma, but also severe internal organ involvements including nervous system, the lungs and the kidneys). This subset of patients requires intensive therapeutic management with a mortality rate of nearly 20% of cases.

Aim: To retrospectively investigate the features of renal involvements in patients with primary Sjögren's syndrome (pSS) with biopsy results., Methods: A total of 2096 pSS inpatients at Peking Union Medical College Hospital in China from 2005 to 2015 were identified. Patients with biopsy-proven renal involvement (SS-renal) and matched controls (SS-only) were recruited. The clinical and pathologic features as well as treatments and outcomes were systematically analyzed., Results: One hundred and three pSS nephritis (inpatients had biopsy-proven renal involvement. Tubulointerstitial 53, 51.5%) was the prominent pathologic pattern with glomerulonephritis (GN) present in 50 (48.5%) of the renal lesions. The patterns of GN lesions included membranous nephropathy (37, 35.9%), mesangial proliferative glomerulonephritis (six, 5.8%) or immunoglobulin A nephropathy (three, 2.9%), minimal change disease (four, 3.9%) and focal segmental glomerulosclerosis (three, 2.9%). Compared to SS-only patients, SS-renal patients had fewer dry eyes and positive objective xerostomia (P < 0.05). They presented with a significantly lower incidence of interstitial lung disease (ILD), leukocytopenia and elevated immunoglobulin G levels (P < 0.05). They received a larger initial dosage of corticosteroid and had a higher mortality rate (P < 0.05)., Conclusion: This Chinese SS-renal population with biopsy results has diverse pathologic patterns and distinct clinical features. They are characterized with prominent renal-associated and mild SS-associated features. They received more vigorous treatment but had poorer prognosis., (© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objectives: The objective of this study was to investigate the epidemiological features of primary Sjögren's syndrome (pSS) in Korea at a national level, including the incidence, mortality, and causes of death., Methods: We used a national, population-based registry database called the Rare Intractable Disease Registration Program from the Health Insurance Review and Assessment Service to obtain pSS patient data for the period between 2010 and 2014. pSS was diagnosed by a physician based on uniform criteria. We also used data from Statistics Korea to confirm the mortality and causes of death., Results: Between 2010 and 2014, the total number of patients newly diagnosed with pSS was 5891, resulting in an annual incidence of 2.34 per 100,000 individuals. The female-to-male ratio was 14.5:1. A total of 114 pSS patients died during the study period. The overall survival rate of pSS patients was 99.0%, and the 1-year, 2-year, and 5-year survival rates were 98.7%, 98.1%, and 97.1%, respectively, and the standardized mortality ratio (SMR) was 1.47 (2.14 for males and 1.35 for females). The most common causes of death were respiratory disease (n = 25; 21.9%) followed by circulatory diseases (n = 21; 18.4%), musculoskeletal connective tissue diseases (n = 21; 18.4%), and cancer (n=19; 16.7%)., Conclusions: The national incidence of pSS in Korea presented in this study was lower in comparison with reports from other countries. However, the mortality rate was significantly higher than the corresponding values in the age- and gender-matched general population. The higher mortality in pSS patients is attributable to respiratory diseases and lung cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Pulmonary arterial hypertension (PAH) is a major cause of death in connective tissue disease patients. This study investigated the clinical characteristics and survival of CTD-PAH in Chinese patients., Methods: This cohort study enrolled 190 consecutive PAH patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), or primary Sjögren's syndrome (pSS) who visited our referral center between May 2006 and December 2014. Baseline demographics, clinical features, laboratory results, and hemodynamic assessments were analyzed. Cox proportional hazards regression analysis was used to identify independent factors associated with increased risk of mortality., Results: The PAH patients were more likely to have SLE (58.4%) as the underlying CTD than SSc (26.3%) or pSS (15.3%). Mean age was 37.8±10.4years, and patients with SLE were youngest at the time of PAH diagnosis. The most prevalent autoantibody was anti-U1RNP antibody (55.8%). The three groups did not differ significantly regarding World Health Organization functional class or hemodynamic results. The overall 1-, 3-, and 5-year survival rates were 87.1%, 79.1%, and 62.9%, respectively. The 3-year survival rate of 81.3% for those with SLE-PAH was significantly better than that for patients with SSc-PAH (63.6%, P<0.05). Independent predictors of mortality were 6-minute walk distance (6MWD) ≤380m (HR 3.222, 95% CI 1.485-6.987, P=0.003) and underlying CTD (HR 1.684; 95CI% 1.082-2.622, P=0.021)., Conclusion: Independent predictors of mortality for CTD-PAH were 6MWD <380m and SSc as the underlying CTD. Increased awareness of pSS-PAH is needed because of its worse prognosis compared to SLE-PAH., (Copyright © 2016. Published by Elsevier B.V.)

Objective: To estimate the incidence and mortality rates, and their evolution over time, of physician-diagnosed primary Sjögren syndrome (pSS) in residents of Olmsted County, Minnesota., Patients and Methods: Medical records of patients with a diagnosis or suspicion of SS in Olmsted County from January 1, 2006, through December 31, 2015, were reviewed to identify incident cases of pSS (defined by physician diagnosis). These cases were combined with those from a 1976 through 2005 incident cohort (n=111) from the same population. Incidence rates were age and sex adjusted to the 2010 US white population. Survival rates were compared with the expected rates in the population of Minnesota., Results: With 61 incident cases of pSS diagnosed in Olmsted County from 2006 through 2015, the total cohort included 172 patients with incident pSS from 1976 through 2015. Of the 172 patients, 151 (88%) were women and 161 (94%) were white, with a mean ± SD age at diagnosis of 58.3±16.7 years. The average age- and sex-adjusted annual incidence for 2006 through 2015 was 5.9 per 100,000 population (95% CI, 4.4-7.4 per 100,000 population), and the overall incidence for the entire period was 5.8 per 100,000 (95% CI, 4.9-6.6 per 100,000). The incidence increased with calendar time over the 40-year period (P=.005). There was no difference in mortality in the pSS cohort compared with expected (standardized mortality ratio, 1.15; 95% CI, 0.86-1.50)., Conclusion: The average annual incidence of pSS in this population-based cohort was 5.8 per 100,000, with a progressive increase over the 40 years of the study. Overall survival of patients with pSS was not different from that of the general population., (Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the fulfilment of classification criteria for cryoglobulinaemic vasculitis (CV) at diagnosis in a large cohort of patients with primary SS and their correlation with poor outcomes., Methods: We included 515 consecutive patients tested for serum cryoglobulins who fulfilled the 2002 classification criteria for primary SS. CV classification criteria and serum cryoglobulins at diagnosis were assessed as predictors of death and lymphoma using Cox proportional-hazards regression analysis adjusted for age and gender., Results: Positive serum cryoglobulins were detected in 65 (12%) patients, of whom 21 (32%) fulfilled CV classification criteria. Compared with patients positive for cryoglobulins who did not fulfil CV criteria, patients with CV had a higher frequency of type II cryoglobulinaemia (86% vs 43%, P = 0.04), a higher mean cryocrit level (6.58% vs 1.25%, P < 0.001) and a higher cumulated mean EULAR-SS disease activity index score (35.3 vs 16.2, P < 0.001). After a mean follow-up of 110 months, 45 (9%) patients developed B-cell lymphoma and 33 (6%) died. Compared with patients without cryoglobulins, patients with cryoglobulins who fulfilled [hazard ratio (HR) = 7.47, 95% CI: 3.38, 16.53] and did not fulfil (HR = 2.56, 95% CI: 1.03, 6.35) CV criteria both showed a higher risk of B-cell lymphoma in the univariate analysis, but not in the multivariate models. Compared with patients without cryoglobulins, patients with CV had a higher risk of death in both the univariate (HR = 11.68, 95% CI: 4.44, 30.74) and multivariate (HR = 4.36, 95% CI: 1.32, 14.47) models., Conclusion: Patients with primary SS who fulfilled criteria for cryoglobulinaemic vasculitis at diagnosis are at higher risk of death., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In 9-20% of cases, Sjögren's syndrome is associated with various respiratory symptoms. The most typical manifestations are chronic interstitial lung disease (ILD) and tracheobronchial disease. The most common manifestation of ILD is nonspecific interstitial pneumonia in its fibrosing variant. Other types of ILD, such as organising pneumonia, usual interstitial pneumonia and lymphocytic interstitial pneumonitis, are rare. Their radiological presentation is less distinctive, and definitive diagnosis may require the use of transbronchial or surgical lung biopsy. Corticosteroid therapy is the mainstay of ILD treatment in Sjögren's syndrome, but the use of other immunosuppressive drugs needs to be determined. ILD is a significant cause of death in Sjögren's syndrome. Tracheobronchial disease is common in Sjögren's syndrome, characterised by diffuse lymphocytic infiltration of the airway. It is sometimes responsible for a crippling chronic cough. It can also present in the form of bronchial hyperresponsiveness, bronchiectasis, bronchiolitis or recurrent respiratory infections. The management of these manifestations may require treatment for dryness and/or inflammation of the airways. Airway disease has little effect on respiratory function and is rarely the cause of death in Sjögren's syndrome patients. Rare respiratory complications such as amyloidosis, lymphoma or pulmonary hypertension should not be disregarded in Sjögren's syndrome patients., (Copyright ©ERS 2016.)

Objectives: There is conflicting evidence regarding prognosis in patients with primary SS (pSS). The aim of this study was to estimate the rate, risk factors and causes of mortality in patients with pSS through a systematic review and meta-analysis., Methods: Through a systematic review of multiple databases through October 2014, we identified cohort studies reporting relative risk (compared with standardized population), risk factors and causes of mortality in patients with pSS. We estimated summary risk ratios (RRs) with 95% CIs using random effects model., Results: We identified 10 studies with 7888 patients (91% females) with pSS, of whom 682 patients died over a median average follow-up of 9 years. The pooled standardized mortality ratio in patients with pSS was 1.38 (95% CI 0.94, 2.01). Leading causes of mortality were cardiovascular diseases, solid-organ and lymphoid malignancies and infections; however, it is unclear whether these observed causes were overrepresented in patients with pSS as compared with the general population. Risk factors associated with increased mortality were advanced age at diagnosis [RR 1.09 (95% CI 1.07, 1.12)], male sex [RR 2.18 (95% CI 1.45, 3.27)], parotid enlargement [RR 1.81 (95% CI 1.02, 3.21)], abnormal parotid scintigraphy [RR 2.96 (95% CI 1.36, 6.45)], extraglandular involvement [RR 1.77 (95% CI 1.06, 2.95)], vasculitis [RR 7.27 (95% CI 2.70, 19.57)], anti-SSB positivity [RR 1.45 (95% CI 1.03, 2.04)], low C3 [RR 2.14 (95% CI 1.38, 3.32)] and C4 [RR 3.08 (95% CI 2.14, 4.42)] and cryoglobulinaemia [RR 2.62 (95% CI 1.77, 3.90)]., Conclusion: pSS is not associated with an increase in all-cause mortality as compared with the general population. However, a subset of patients with extraglandular involvement, vasculitis, hypocomplementaemia and cryoglobulinaemia may be at increased risk of mortality and require close follow-up., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To score systemic activity at diagnosis and correlate baseline activity with survival in a large cohort of patients with primary Sjögren syndrome (SS)., Patients and Methods: We include 1045 consecutive patients who fulfilled the 2002 classification criteria for primary SS. The clinical and immunological characteristics and level of activity (EULAR-SS Disease Activity Index (ESSDAI) scores) were assessed at diagnosis as predictors of death using Cox proportional hazards regression analysis adjusted for age at diagnosis. The risk of death was calculated at diagnosis according to four different predictive models., Results: After a mean follow-up of 117 months, 115 (11%) patients died. The adjusted standardised mortality ratio for the total cohort was 4.66 (95% CI 3.85 to 5.60), and survival rates at 5, 10, 20 and 30 years were 96%, 90%, 81% and 60%, respectively. The main baseline factors associated with overall mortality in the multivariate analysis were male gender, cryoglobulins and low C4 levels. Baseline activity in the constitutional, pulmonary and biological domains was associated with a higher risk of death. High activity in at least one ESSDAI domain (HR 2.14), a baseline ESSDAI score ≥14 (HR 1.85) and more than one laboratory predictive marker (lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4 and/or cryoglobulins) (HR 2.82) were associated with overall mortality; these HRs increased threefold to 10-fold when the analysis was restricted to mortality associated with systemic disease., Conclusions: Patients with primary SS, who present at diagnosis with high systemic activity (ESSDAI ≥14) and/or predictive immunological markers (especially those with more than one), are at higher risk of death., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The incidence of Sjögren syndrome (SS) in primary biliary cirrhosis (PBC) patients is high. The influence of SS on the clinical outcomes of PBC patients, however, remains unclear. Our study retrospectively collected data on PBC-only patients and PBC patients with concomitant SS (PBC-SS) to compare the clinical differences of long-term outcomes between them.A total of 183 patients were diagnosed with PBC from January 1999 to December 2014 at our hospital. Of these, the authors excluded patients with diabetes, hypertension, advanced liver cirrhosis at initial diagnosis of PBC (Child-Turcotte-Pugh classification score of ≥7) and other liver diseases (ie, alcoholic liver disease, alpha-antitrypsin deficiency, viral hepatitis, and primary sclerosing cholangitis), and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Of the remaining 125 patients, 77 (61.6%) were PBC-only and 48 (38.4%) were PBC-SS patients.The mean follow-up duration was 8.76 years. During the observation period, the incidence of interstitial lung disease was higher in the PBC-SS group than in the PBC-only group (P = 0.005). The occurrence of spontaneous bacterial peritonitis was significantly different in PBC-SS patients than in PBC-only patients (P = 0.002). The overall survival was lower in PBC-SS patients than in PBC-only patients (P = 0.033). Although the incidence of hepatocellular carcinoma, end-stage renal disease, variceal bleeding, and hypothyroidism were all higher in the PBC-SS group than in the PBC-only group, the differences were not significant.Our study suggests that PBC-SS patients have a higher risk of developing interstitial lung disease and spontaneous bacterial peritonitis and have a poor prognosis. Aggressive surveillance of thyroid and pulmonary functions should therefore be performed in these patients.

Objectives: To identify the causes and risk factors for hospitalisation in primary Sjögren's syndrome (pSS)., Methods: We included 170 pSS patients who regularly attended our Institution (2000-2013) and retrospectively collected demographic, clinical (glandular and extraglandular features) and serological (anti-Ro/SSA, anti-La/SSB, RF, low C3 or C4 and immunoglobulin levels) data. If they were hospitalised, a rheumatologist determined the primary cause. We registered the length of hospitalisation, need for Intensive Care Unit (ICU) admission, number of hospitalisations and death. The Disease Damage Index (SSDDI) (excluding the oral and ocular items) and the Charlson comorbidity Index were assessed. We used a logistic regression analysis and multiple imputation method for missing data., Results: Fifty-five (32%) patients were hospitalised, representing 111 hospitalisations (28 patients had ≥1 hospital admission). The hospitalisation incidence density rate was 6.49/100 patient / years. The median length of hospital stay was 9 days (IQR 6-15), there were 7 ICU admissions and 6 deaths. The main causes of admissions were disease activity (33.3%) and infection (32.4%). At the multivariate analysis, the variables associated with hospitalisation were hepatic involvement (OR=5.4; 95% CI 1.61-18.15; p=0.006), vasculitis (OR=3.8; 95% CI 1.11-13.09; p=0.03), the SSDDI (OR=1.3; 95% CI 1.01-1.66; p=0.03) and the use of antimalarials (OR=0.08; 95% CI 0.02-0.22; p<0.001)., Conclusions: The major causes for hospitalisation were disease activity and infection. Patients with hepatic involvement, vasculitis and more damage accrual had the highest risk for being hospitalised, while the use of antimalarials was protective.

Few studies are available on the risk of ischemic stroke after a diagnosis of primary Sjögren's syndrome (PSS). This study investigated whether PSS increased the risk of ischemic stroke in a large, nationwide cohort. Data for 4,276 patients who were newly diagnosed with PSS from 2000 to 2006 and who did not have a stroke prior to diagnosis of PSS were obtained from the Registry of Catastrophic Illness in Taiwan. For each PSS patient, data for ten controls (matched by age, gender, comorbidities, and enrollment date) without systemic autoimmune disease or previous stroke were obtained from the Longitudinal Health Insurance 2000 database. All study subjects were followed up from the date of enrollment until they developed ischemic stroke, died, or until the end of 2006, whichever was earliest. To investigate if PSS was an independent factor in determining the risk of developing ischemic stroke, a Cox regression model was used with adjustment for age, gender, and comorbid disorders. Among 4,276 PSS patients and 42,760 controls, 669 subjects (51 PSS patients and 618 controls) developed ischemic stroke during the mean 3.7-year follow-up period (interquartile range 2.2-5.2 years). Patients with PSS and controls had a similar incidence of ischemic stroke occurrence (3.17/1,000 vs. 3.90/1,000 person years). Multivariate analysis adjusted for baseline covariates indicated that PSS did not increase the risk of ischemic stroke (adjusted hazard ratio: 0.84, 95 % confidence interval: 0.63-1.12, P = 0.244). PSS is not associated with an increased risk of ischemic stroke subsequent to diagnosis.

In recent years considerable progress has been made in our understanding of the immunopathology of primary Sjögren's syndrome. Several genetic and environmental risk factors as well as cellular and molecular pathways have been identified, providing multiple targets for therapeutic strategies. Establishment of disease activity scores allows careful monitoring of therapeutic strategies and has set the stage for definition of clinical response criteria. Early detection of autoimmune symptoms before the onset of primary Sjögren's syndrome might trigger early intervention strategies to prevent immunopathology. New studies that indicated a strong association between lymphoid neogenesis and development of lymphoma and extra-glandular manifestations indicate that future therapeutic strategies should perhaps be directed at patients at risk for more severe disease. Several challenges remain, such as dissecting the causes and consequences of several types of IFN signatures or elucidating how viral triggering of the immune system is involved and could be targeted. The biggest challenge may be prevention of dryness since the causes of dryness remain elusive and could include non-immunological ones. In the coming years it will become clear to what extent novel drugs can prevent immunopathology and clinical symptoms like dryness and fatigue.

The objective of this study was to evaluate the 25-year outcome of patients with primary Sjögren's syndrome (pSS). One hundred and fifty-two patients diagnosed with pSS (American-European classification criteria) were retrospectively and descriptively analysed (1986-2011). Of all 152 patients, 55.9% were alive, 18.4% had died and 25.7% discontinued follow-up (mostly due to old age). Malignancy affected 28.3% and non-Hodgkin's lymphoma (NHL) affected 10.5%. The adjusted risk for development of NHL was an odds ratio (OR) of 10.5 (95% confidence interval [CI]: 3.05-36.42) in patients with vasculitis (p<0.001), and OR 3.4 (95% CI 1.05-11.2) in the presence of glandular complications (parotid swelling, lymphadenopathy) (p < 0.041). Seventy-five patients (49.3%) developed other autoimmune diseases (autoimmune thyroid disease [15.8%], pulmonary fibrosis [7.2%] and vasculitis [10.5%]). Although the course of pSS is relatively benign, over 25 years patients experience more clinical complications than previously described. In addition, vasculitis and glandular manifestations were significant predictors for NHL.

Background: Lung involvement is one of the major systemic manifestations of primary Sjögren's syndrome (pSS). This study aims to demonstrate the correlation between high-resolution computed tomography (HRCT), pulmonary function test (PFT) results, and outcome in these patients., Methods: Forty-four pSS patients were enrolled and their PFT results and HRCT findings/scores were retrospectively investigated., Results: All patients had reduced carbon monoxide-diffusing capacity (DLCO; <75% of the predicted value); <60% of the predicted value of peak expiratory flow (PEF), of forced vital capacity (FVC), and of forced expiratory volume in the 1st second (FEV1) were noted in 15 (34.1%) patients, 13 (29.5%) patients, and 12 (27.3%) patients, respectively. HRCT scores had a negative correlation with DLCO (r = -0.376, p = 0.012), but not with other PFT results. Twelve patients (27.3%) expired during a mean follow-up of 3.7 years; 11 (91.7%) patients died of respiratory failure in the lung-involved patients, of which three were present with pneumonia. The expired patients had lower predicted values of FEV1 (63.1 ± 19.4% vs. 79.0 ± 22.7%, p = 0.017), FVC (58.7 ± 20.4% vs. 77.1 ± 17.5%, p = 0.005), and PEF (54.3 ± 20.5% vs. 72.0 ± 24.8%, p = 0.035), and higher HRCT scores (9.2 ± 5.7 vs. 5.2 ± 3.5, p = 0.033) than those patients who survived. Patients with FEV1, FVC, PEF < 60% of the predicted value, or high HRCT score (13-18) presented shorter median overall survival (p = 0.005, p < 0.001, p = 0.021, p < 0.001, respectively). Multivariate analysis adjusted for PFT results showed that HRCT ≥13 was an independent risk factor for mortality (p = 0.007)., Conclusion: The clinical outcome of pSS patients with lung involvement in Taiwan is not very favorable. Although HRCT score was poorly correlated with PFT, high HRCT score was significantly associated with higher mortality., (Copyright © 2013. Published by Elsevier B.V.)

The aim of this retrospective, single-centre study was to investigate the clinical and laboratory features and disease outcomes of 547 patients diagnosed with primary Sjögren's syndrome (pSS) between 1975 and 2010. The patients were followed up for 11.4±6.2 years. We evaluated the clinical and laboratory features, and assessed their influence on the time of diagnosis, survival, and mortality ratios, and compared them within subgroups defined by gender, glandular and extraglandular manifestations (EGMs), associated diseases, and immunoserological abnormalities. The most frequent EGMs were polyarthritis, Raynaud's phenomenon, and vasculitis among our patients; the most common associated disease was thyroiditis. During the follow-up period, 51 patients died; the median survival time was 33.71 years. Our results revealed a negative effect of cryoglobulinemia on survival ratios; additionally, the presence of vasculitis and lymphoproliferative diseases at the time of diagnosis increased the risk of mortality. The development of vasculitis was the most powerful predictor of mortality. Mortality in the group of patients with extraglandular symptoms was two- to threefold higher than in the glandular group. Attention is drawn to the importance of close monitoring and targeted diagnostic approaches in those pSS subgroups with obviously increased mortality risk.

Objective: To estimate the prevalence and investigate the clinical features and the outcome of clinically significant renal involvement in a large cohort of patients with primary Sjögren's syndrome (SS)., Methods: Among 715 patients who met the American-European Consensus Group criteria for primary SS, those with clinically significant renal involvement were identified and their clinical and immunologic features were recorded. The prognosis in patients with primary SS with renal involvement was assessed by the clinical appearance of any of the following major outcomes: death, hemodialysis, chronic renal failure (CRF), and lymphoma. Kaplan-Meier analysis was applied to compare death rates between patients without and those with renal involvement., Results: Thirty-five patients with primary SS (4.9%) had clinically significant renal involvement, representing a total followup time after renal diagnosis of 252.2 person-years. Thirteen patients (37.1%) had interstitial nephritis alone, 17 patients (48.6%) had glomerulonephritis (GN) alone, and 5 patients (14.3%) had both entities. Nine patients died (25.7%), 11 developed CRF (including 4 requiring chronic hemodialysis) (31.4%), and 9 developed lymphoma (25.7%). The overall 5-year survival rate was 85%. Kaplan-Meier analysis showed statistically significant reduced survival for patients with primary SS with renal involvement compared to those without renal involvement (P < 0.0001 by log rank test), with GN patients displaying increased mortality. Eight of 9 reported deaths (89%) and 8 of 9 lymphomas (89%) were observed among patients with GN., Conclusion: The long-term prognosis varies for patients with primary SS who have clinically significant renal involvement. Patients with interstitial nephritis display a favorable prognosis, while patients with GN are at high risk of developing lymphoma and have poor survival., (Copyright © 2013 by the American College of Rheumatology.)

The objective of this prospective cross-sectional case-control study was to examine the prevalence of dryness symptoms and its impact on quality of life (QoL) among very long-term survivors after hematopoietic SCT (HSCT) in comparison with their respective sibling donors. Forty-four allogeneic HSCT recipients with a long-term survival (median: 17.5; range: 11-26 years) were included. Their respective, HLA-identical sibling donors served as controls. Clinical examinations included saliva flow rates (SFR) and the Schirmer's test. The presence of sicca symptoms of mouth, eyes and skin were inquired. The social functioning (SF)-36 questionnaire was applied. Recipients had lower (P<0.01) unstimulated and stimulated mean SFR than donors. Schirmer's test results <5 mm was found in 45% of the recipients in comparison with 27% of the donors (P = 0.07). Xerostomia (34 vs 4 subjects), xerophtalmia (23 vs 3) and dry skin (32 vs 12) were reported more often by the recipients than donors (P<0.001). Sicca symptoms and their objective findings correlated with QoL. The mean SF-36 scores of the donors were significantly higher than those of the recipients for physical component summary. In conclusion, sicca symptoms are common amongst long-term survivors of HSCT and affect remarkably the QoL.

Objective: The aim of the present study was to describe the prevalence of clinical pulmonary manifestations in primary SS (pSS), and based on registry data, to assess quality of life (QoL) and mortality in these patients., Methods: Patients with pSS consecutively included in the Norwegian systemic CTD and vasculitis registry (NOSVAR) were investigated for pulmonary manifestations when presenting with clinical pulmonary symptoms. Pulmonary involvement was defined as typical abnormalities identified with high-resolution CT (HRCT) and/or pulmonary function tests (PFTs)., Results: Among patients referred from our primary area, Oslo (n = 117), lung involvement was found in 26 patients (22%). In our total cohort (n = 216), 59 patients (27%) were affected. A higher rate of pulmonary complications and trends towards longer disease duration and higher age indicated a selection of more complicated cases referred from outside our primary area. Abnormal HRCTs were found in 50 patients (23%) and PFTs in 34 patients (16%). The Medical Outcomes Study 36-Item Short-Form Health Survey Physical Functioning subscore, was significantly reduced in patients with lung involvement (P = 0.03). Furthermore, a 4-fold increased risk of dying after 10 years of disease among patients with lung involvement (n = 10, 17%) compared with those without lung involvement (n = 7, 4.5%) (P = 0.002) was found., Conclusion: We found a high population-based prevalence of clinical pulmonary involvement (22%) among patients with pSS. Moreover, patients with lung involvement had reduced QoL represented by the subscale Physical Functioning, and mortality was increased.

Objectives: To determine mortality and long-term survival factors in patients with systemic autoimmune diseases (SAD) admitted to the intensive care unit (ICU)., Methods: Retrospective observational study including all consecutive patients with a diagnosis of any systemic autoimmune disease admitted to the medical ICU in a tertiary hospital between 1999 and 2007. Factors associated with reduced survival were identified by means of log rank test and backward stepwise Cox regression., Results: Thirty-seven patients (26 females) were included with median age being 44.3 years (interquartilic range [IQR]: 31.3). Sixteen (43.2%) patients had systemic lupus erythematosus, 9 (24.3%) had systemic vasculitis, 4 (10.8%) had systemic sclerosis and 4 (10.8%) had primary antiphospholipid syndrome. The main reason for ICU admission was autoimmune disease flare-up in 20 (54.0%) patients, followed by infections in 12 (32.4%). Median APACHE II at admission was 17 (IQR 7). At the end of follow-up, 15 (40.5%) patients died, 10 (27%) during hospitalisation (7 in the ICU) and 5 after hospital discharge. Factors associated with reduced long-term survival were: APACHE II score ≥18 (HR 6.02, 95% CI 1.76-20.62), age <45 years (HR 6.54, 95% CI 1.84-23.29), presence of any previous chronic disease (HR 18.20, 95% CI 3.72-88.96), and increase of corticosteroid therapy during ICU stay (HR 22.87, 95% CI 4.31-121.30)., Conclusions: The long-term survival of patients with systemic autoimmune diseases admitted to the ICU was related with age, higher APACHE II score, previous chronic diseases, and an increase in corticosteroids dose when comparing with previous ICU admissions.

Sjögren syndrome (SS) has been associated with the development of non-Hodgkin lymphoma (NHL). From a cohort of 584 SS patients followed in our department from 1980 to 2010, we retrospectively analyzed 53 consecutive NHL cases. Considerations included histologic type, clinical manifestation and NHL staging, treatment, response rate and overall survival (OS), event-free survival (EFS), and standardized mortality ratio (SMR).Mucosa-associated lymphoid tissue (MALT) lymphomas constituted the majority (59%) of NHL subtypes, followed by nodal marginal zone lymphomas (NMZLs) (15%) and diffuse large B-cell lymphomas (DLBCLs) (15%). Six lymphoma patients died during the median follow-up of 40.8 months. The corresponding age/sex-adjusted SMR of SS with and without NHLs versus the general population was 3.25 (95% confidence interval [CI] 1.32-6.76) and 1.08 (95% CI, 0.79-1.45), respectively. A "watch and wait" policy was adopted for 9 patients with asymptomatic localized salivary MALT lymphomas. Eight patients with limited-stage MALT lymphomas and extraglandular manifestations were treated with rituximab. Ten MALT lymphoma patients with disseminated disease received chemotherapy with or without rituximab. The 3-year OS and EFS in patients with MALT lymphomas was 97% and 78%, respectively. Rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) was the chosen therapeutic intervention for patients with DLBCLs. A successful outcome was recorded for this group, with 100% OS and EFS at 3 years. Patients with NMZLs had a less favorable outcome, with a 3-year OS of 80% and EFS of 53%. Our results describe the course and prognosis of SS-associated NHL and highlight the need for a risk-stratified treatment approach.

Background: The aim of this paper was to study the evolution of primary Sjögren's syndrome (pSS) immunological profile, its impact on pSS activity and long-term evolution in a bicentric cohort of French patients with pSS (n = 445, mean age 53.6 ± 14 years, mean follow-up 76.1 ± 51 months)., Methods: This is a retrospective cohort study., Results: Two hundred twelve patients were Sjögren's syndrome A (SSA) positive, and 131 were both SSA and Sjögren's syndrome B (SSB) positive. Sixty-eight patients (15%) had cryoglobulinemia. Active systemic profile (i.e., hypergammaglobulinemia, rheumatoid factor (RF), and anti-Sjögren's syndrome A (anti-SSA), anti-Sjögren's syndrome B (anti-SSB) positivity), associated with multisystemic involvement, leads to an increased utilization of corticosteroid and hydroxychloroquine. Multivariate analysis pointed out independent statistical association between hypergammaglobulinemia, anti-SSA, anti-SSB, and RF. Cryoglobulinemia is associated with multi-systemic involvement, lymphoma, and pSS-related death., Conclusion: The subset of patients with active immunological profile is characterized by systemic complications leading to immunosuppressive drug utilization and polyclonal B-cell activation profile.

Objective: To clarify the mortality rates, causes of death, and contributing clinical factors in Japanese patients with systemic sclerosis (SSc)., Methods: A cohort of 405 patients with SSc, who attended our institution during the period 1973 to 2008, was retrospectively analyzed until the end of 2009. Clinical data were obtained from medical records or autopsy reports., Results: The 405 patients with SSc consisted of 310 (76.5%) survivors, 86 (21.2%) who died, and 9 who were lost to followup. Diffuse cutaneous SSc and involvement of organs other than the gastrointestinal tract were more frequent in patients who died, and were associated with a worse prognosis according to Kaplan-Meier analysis. Female sex, limited cutaneous SSc, anticentromere antibody (ACA), and overlap with Sjögren's syndrome (SS) were factors favoring a better prognosis, while overlap with myositis contributed to a poor prognosis. The overall 10-year survival rate was 88%. The patients with SSc had a significantly higher mortality than the general population (standardized mortality ratio 2.76), but the patients with ACA or overlapping SS did not. The most common causes of death were unknown ones including sudden death, followed by malignancy and infection. In patients with pulmonary arterial hypertension, sudden death was the most common cause of mortality., Conclusion: The overall mortality rate of patients with SSc was higher than that of the general population, probably because of poor prognostic factors including organ involvement. These factors should be carefully monitored during followup.

Objective: To estimate the incidence and mortality of treated primary Sjögren's syndrome (pSS) by sex and age group in Taiwan., Methods: We used claims data of the Bureau of National Health Insurance (NHI) of Taiwan from 2005 to 2007 for analysis. According to the NHI, pSS is classified as one of the financially catastrophic illnesses and patients with pSS could be exempted from copayment of all medical costs. To obtain a catastrophic illness certificate (CIC) for pSS, patients are required to meet the criteria of the American-European Consensus Group for pSS, and are reviewed by a committee. Patients approved for receipt of a CIC for pSS for the first time were defined as incident cases of treated pSS., Results: A total of 3352 incident cases occurred between 2005 and 2007. The estimated mean annual incidence was 6.0 per 100,000 inhabitants (95% CI 5.8-6.2) for both sexes, 11.0 (95% CI 10.6-11.4) for women and 1.1 (95% CI 1.0-1.2) for men, with a female/male ratio of 9.9 (95% CI 8.8-11.1). Incidence increased with age, peaking at age 55-64 years in women and 65-74 years in men. The mortality rate was 33.4 per 1000 case person-years for men and 11.4 for women, with a male/female rate ratio of 2.9 (95% CI 1.7-5.3)., Conclusion: The incidence of treated pSS in women is 10 times that in men. Nevertheless, pSS mortality in men is 3 times that in women.

Objective: To analyze the prevalence of neutropenia in a large cohort of patients with primary Sjögren's syndrome (SS) and its association with clinical and immunological disease expression and adverse outcomes., Methods: The study cohort included 300 patients diagnosed with primary SS in our department between 1984 and 2002. The outcomes measured after the first laboratory evidence of neutropenia (<2.5 x 10(9)/L) were first hospital admission caused by infection, development of systemic manifestations, neoplasia, and death., Results: Ninety-nine (33%) patients had neutropenia during the follow-up, which was related to neoplasia or drugs in 9 (3%) patients and was considered idiopathic in the remaining 90 (30%). Patients with neutropenia had a lower mean age at diagnosis of SS (51.9 versus 59.4 years, P < 0.001) and a higher prevalence of anti-Ro/La antibodies (53% versus 22%, P < 0.001), rheumatoid factor (49% versus 32%, P = 0.009), and low C4 levels (17% versus 8%, P = 0.044) than those without neutropenia. Patients with neutropenia had a higher incidence of hospital admission caused by infection (24% versus 9%, P = 0.002), especially those with neutropenia <1 x 10(9)/L (50% versus 9%, P = 0.002), and a higher rate of admission (log rank = 0.0023) in comparison with those without neutropenia. Agranulocytosis was found in 7 (2%) patients, predominantly related to neoplasia (5 cases). One (1%) of the 90 patients with SS-related neutropenia developed large granular lymphocyte T-cell leukemia., Conclusion: Neutropenia should be considered a relevant hematologic finding of primary SS, due both to its elevated prevalence and to its clinical significance (close association with anti-Ro/La antibodies, coexistence with other cytopenias, and development of severe infections).

Sjögren's syndrome (SS) is a chronic autoimmune disease that involves primarily the exocrine glands and results in their functional impairment. The disease may occur alone (primary SS, pSS) or in association with other autoimmune diseases, such as rheumatoid arthritis (secondary SS, sSS). Although the clinical manifestations of pSS patients are mainly those of an autoimmune exocrinopathy, 40% to 50% of patients develop extraglandular disease, which may be manifested either by epithelial lymphocytic invasion of lung, liver, or kidney (resulting in interstitial nephritis) or by skin vasculitis, peripheral neuropathy, glomerulonephritis, and low C4 levels, conditions which represent an immune-complex mediated disease. Patients belonging to the latter category, inferring a high risk for development of non-Hodgkin's lymphoma, by default have a worse prognosis with higher mortality rates. In this review, the role of several factors involved in mortality of pSS, as well as markers predictive for lymphoma development are discussed.

The natural history of primary Sjögren's syndrome has been little studied. Some studies agree that, although it is not a benign disease, it is characterized by a steady evolution of the predominant symptoms (sicca and general manifestations). However, there are 2 main exceptions to this chronic course: the development of vasculitic manifestations, and the high incidence of lymphomas, both processes being related to the excess of mortality in patients with primary Sjögren's syndrome. Recent studies have prospectively analyzed the outcome of this disease in a large series of patients and identified those factors present at diagnosis prospectively associated with an adverse outcome. The main prognostic factors identified are severe involvement of the exocrine glands, vasculitis, hypocomplementemia and cryoglobulins at diagnosis. These features identify a specific subset of patients diagnosed with primary Sjögren's syndrome in whom a closer follow-up, and probably an earlier and more robust therapeutic management, should be mandatory.

Twelve years ago we reported that lymphocytic alveolitis [or bronchoalveolar lavage (BAL) lymphocytosis] correlates with clinical pulmonary involvement in primary Sjogren's syndrome (pSS). Our thesis was based on subtle clinical and functional evidence of interstitial lung disease (ILD) in pSS patients with "high lymphocytic alveolitis" (>15% lymphocytes in BAL). This report is a follow-up study of these patients. Basic clinical and functional re-evaluation of the 22 patients with pSS, studied in 1991, emphasized the differences between those with alveolitis and those without alveolitis. There was no significant functional decline. There were, however, two statistically significant differences between the two groups: (1) only patients with BAL lymphocytosis had to be treated with steroids (5/12 vs. 0/10, P < 0.05) and (2) only patients with BAL lymphocytosis had died in the mean time (6/12 vs. 0/10, P < 0.01). The causes of death were various. On only two occasions were they related to respiratory infections while there were no deaths from respiratory failure secondary to ILD. BAL lymphocytosis appears to be a surprisingly serious index of dismal prognosis in patients with pSS. We offer no unifying pathophysiologic mechanism for it and, therefore, all we propose is that BAL is performed early, in as many patients with pSS as possible. These patients should then be followed up systematically, in order to evaluate if BAL lymphocytosis has any pathophysiologic importance in the development of clinically serious pSS, which is serious enough to lead to death.

Objective: This study was undertaken to analyze standardized mortality ratios (SMRs) and causes and predictors of death in primary Sjögren's syndrome (SS) diagnosed according to 3 different classification criteria sets (the Copenhagen criteria, the European criteria, and the American-European consensus criteria (AECC)., Methods: A linked registry study using information from the Malmö Primary SS Registry combined with the Swedish Cause-of-Death Registry was performed, and SMRs were calculated. Kaplan-Meier survival curves and log rank tests were used to compare survival probability between subgroups of patients with primary SS. Cox regression analysis was used to study the predictive value of various laboratory findings at the time of diagnosis., Results: Four hundred eighty-four patients with a median followup of 7 years (range 1 month to 17 years 11 months) were included. The SMR for those fulfilling the AECC (n = 265) was 1.17 (95% confidence interval [95% CI] 0.81-1.63). Thirty-four deaths occurred in this group of patients. Excess mortality was found only for lymphoproliferative malignancy (cause-specific SMR 7.89 [95% CI 2.89-17.18]), corresponding to 2.53 excess deaths per 1,000 person-years at risk. In those not fulfilling the AECC (n = 219), 14 deaths occurred, the SMR was 0.71 (95% CI 0.39-1.20), and no excess mortality due to any specific cause was found. Hypocomplementemia, defined as C3 and/or C4 values in the lowest quartile of the SS patients' values at the time of diagnosis, was a significant predictor of death, mainly due to lymphoproliferative malignancy., Conclusion: No increased all-cause mortality could be detected for patients with primary SS compared with the general population. When subgroups of primary SS were compared, excess mortality due to lymphoproliferative malignancy was found in patients fulfilling the AECC, the strongest predictor for unfavorable outcome being low C3 and/or C4 levels at the time of diagnosis.