SS Patients Research Articles

Interest of a New Method for Free Plasma Heme Related Species Dosages in Sickle Cell Disease and Beta Thalassemia

Introduction: Hemolytic anemia combines 3 components to various extents: extravascular hemolysis, intravascular hemolysis and dyserythropoiesis. Global hemolysis in excess to defense lines induces oxidative and inflammatory syndromes and vascular damages in various organs. Therefore, accurate hemolysis biomarkers are required for a better evaluation of hemolytic disorders, such as sickle cell disease (SCD) or thalassemia syndromes and to evaluate the efficacy of various therapies. Accordingly, we have developed a new spectrophotometric method to measure and calculate several hemolysis biomarkers in plasma or serum including Hemoglobin in various forms (HbO2, HbCO, MetHb), Heme or Hemin bound to albumin or to hemopexin, total bilirubin and total hemopexin. Patients and Method : Blood samples were collected at steady-state for 77 SCD adults (mean age 39.8 ± 10.2 yrs, M/F ratio 0.64) and 23 beta thalassemia patients (mean age 42.7 ± 16 yrs, M/F ratio 0.91); SCD patients (SS or Sb0-Thalassemia) were either treated with Hydroxycarbamide (HU: 27) or not (NT: 50). For comparison, plasma samples from healthy volunteers (HV) were also analyzed. Continuous variables were expressed as means ± SD or medians [interquartile range], depending on their normal or asymmetric distributions. Categorical variables were expressed as numbers (%). Univariate analyses were done using Student's t-test or Mann-Whitney non-parametric test, depending on the distribution. Correlation were analyzed using a spearman test. The dosage methodology is based on the light absorption spectrophotometry of plasma samples using an appropriate mathematical conversion of the signal, reference spectra of the different species and some chemical modifications of the iron redox and ligation states. Results: The levels of plasma Hb were statistically higher in homozygous SCD patients compared to beta-thalassemia patients (p=0.001) and healthy volunteers, with median of 6.3 [3.4-11], 2.6 [1-5.4] and 1.7 [0.5-3] µM respectively (Table 1). Interestingly levels of plasma heme were higher in beta thalassemia patient compared to SCD patients (p=0.0001) and HV, with a mean of 1.05 [0.05-3], 10.5 [3.5-24] and ≤ 0.2 µM level of detection respectively (Table 1). A significant negative correlation was found between heme and hemopexin levels in both diseases (p<0.0001; r=0.85). Among 77 SS or Sb0-Thalassemia patients, 29 were treated by HU without any difference for plasma Hb, plasma Heme and Hemopexin values compared to non-treated patients. Discussion and Conclusions: plasma Hb is a more accurate dosage for intra vascular hemolysis than other biomarkers which are not specific of intra vascular hemolysis and could be biased by other pathological conditions: LDH or ASAT can be increased in hepatic or muscular cytolysis, bilirubin is dependent on the heme oxygenase and glycuronyl transferase activities, and reticulocytes are dependent on erythropoiesis. Our results showed that the intra-vascular hemolysis is more pronounced in SCD compared to beta-thalassemia based on the plasma Hb levels. The elevated plasma heme concentration in beta thalassemia is a new finding that should be investigated in more details. It could reflect the ineffective erythropoiesis or heme export from erythroblasts or macrophages involving hemopexin scavenging. Disclosures Bencheikh: Hemanext: Research Funding. Bartolucci:HEMANEXT: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

The Effect of Rigid Red Blood Cells on Platelet Adhesion in Blood Flow and Implications in Sickle Cell Disease

Introduction: Sickle cell disease (SCD) occurs due to a mutation in the β-subunit of hemoglobin, causing stiffening of red blood cells (RBCs) and leading to RBC sickling and vaso-occlusive crises (VOC) in SCD patients. While sickled RBCs remain a hallmark of SCD, they are prone to lysis and represent a small fraction of the total RBCs present in patients at a given time. The remaining RBCs maintain a normal, discoid shape and are either healthy or stiff due to polymerization of the hemoglobin β-globin subunit. In healthy blood flow, RBCs form a core in the center of the vessel and the remaining cells, platelets and white blood cells (WBCs), marginate towards the endothelium. However, the increased stiffness of RBCs in SCD disrupts this neat segregation of blood cells to different areas of the blood vessel and can contribute to VOC, the root cause of many acute and chronic complications for SCD patients. Despite the presence of normally shaped, stiffened RBCs in SCD patients, the impact of these RBCs on other cell types in blood flow is currently not well understood. Our laboratory previously demonstrated that the presence of artificially rigidified RBCs leads to an expansion of the RBC core and significantly decreases WBC adhesion to an inflamed endothelium in vitro. Here, we examine the impact of stiffened RBCs on platelet adhesion to a damaged endothelium in vitro by first using a model system with artificially rigidified RBCs and second, utilizing SCD patient blood to further support our model and understand platelet-RBC interactions in SCD patients. Methods: In our model system, we artificially rigidified RBCs taken from healthy donors and reconstituted them into whole blood before perfusing the mixture over an activated, damaged endothelium using a parallel plate flow chamber. We quantified platelet adhesion to the endothelium in comparison to healthy, non-rigidified controls using fluorescent microscopy. To determine if our model findings translated to SCD, we recruited a cohort of hemoglobin SS and SC patients during routine visits and similarly perfused their whole blood over the same damaged endothelium and quantified platelet adhesion. Results and conclusions: The inclusion of artificially rigidified RBCs in otherwise healthy subject blood flow significantly increased platelet adhesion to a damaged endothelium with a maximum increase in platelet adhesion of six-fold over a healthy, non-rigid control in our model system. Both RBC rigidity and the percentage of RBCs that were artificially rigidified had a large impact on the increase in platelet adhesion. SCD platelet adhesion to the damaged endothelium model varied from donor to donor based on variables such as treatment method and disease severity. Overall, this work experimentally elucidates the biophysical impact of stiffened RBCs on platelet adhesion using both an artificial model utilizing healthy blood as well as SCD blood, which can help determine the mechanism of action causing VOC in SCD. Disclosures No relevant conflicts of interest to declare.

Venous Thromboembolism (VTE) in Sickle Cell Disease (SCD) Is Associated with Neutrophilia

Introduction Venous thromboembolic events (VTE) are a frequent complication of patients with sickle cell disease (SCD). The estimated incidence of thrombosis is 25% and is associated with increased morbidity and mortality. Recent studies have implicated leukocytes and their subsets in development and propagation of VTE in malignancies and inflammatory diseases. However the role of leukocytes have not been elucidated in SCD. We conducted a retrospective study to precisely study the association of leukocytes and their subsets in VTE. Methods We accessed the medical records of patients with SCD who presented to University Hospitals Seidman Cancer Center from 2004 to 2018. Information collected included demographic characteristics, comorbidities, laboratory parameters as well as treatment details. Patient records were reviewed for VTE with radiographic confirmation. Cases were defined as patients with SCD with diagnosed VTE and controls were SCD patients without VTE. Cases and controls were matched for age, gender, red blood cell (RBC) genotype and treatment. We included twice as many controls as cases for the study. Inclusion criteria were age greater than 18 years and were followed up at the outpatient sickle cell clinic. Patients were excluded if they had infection, thrombophilia, neoplasm, pregnancy or arterial thrombosis. For cases, lab parameters at the time of the VTE were recorded. Since most patients with VTE were diagnosed during an admission, lab parameters for controls were also recorded during an admission for pain crises. For both cases and controls, steady state lab data 3 months prior to their admission was also recorded and compared. Data was analyzed using STATA SE 15 version. Mann-Whitney U test was used to analyze continuous variables and Fischer's exact test was used to analyze discrete variables. P-values less than 0.05 were considered significant. Results A total of 263 records were reviewed of which 97 patients were eligible for the study. There were 35 patients with VTE and 62 patients without VTE. Baseline characteristics are presented in Table 1. Compared to controls, patients with VTE had more comorbidities such as avascular necrosis (AVN; p = 0.0038), pulmonary hypertension or albuminuria (pHTN; p= 0.032), higher body mass index (BMI) (p = 0.038) and had more hospitalizations (p < 0.001). Due to small number of patients, the comorbidities were analyzed as a group across all genotypes. A complete list of comparison of comorbidities is summarized in Table 2. When compared to controls, patients with VTE as a group had higher total white blood cell count (WBC) and neutrophil count (p=0.0032 and p = 0.0006 respectively) at the time of event. When RBC genotype was taken into account, patients with SC and SS genotype had a significantly elevated neutrophil count whereas only patients with SS genotype had a higher WBC count compared to controls (Please refer to Table 3). When compared to controls, cases as a group also had WBC and neutrophil count 3 months prior to the event (p=0.025 and p=0.020 respectively). Patients with SS and SC patients had a significantly higher WBC count 3 months prior compared to their non VTE counterparts (Please refer to Table 4) No other comorbidity or lab parameter was found to be significantly different between cases and controls. A multivariate analysis could not be performed due to small study numbers. Conclusion Our study is the first to show that VTE in SCD was associated with higher neutrophil counts 3 months prior to the event suggesting that patients with baseline or steady state leukocytosis and neutrophilia are at increased risk of thrombosis. Larger studies are needed to confirm this association. In addition, patients with VTE also had higher incidence of comorbidities such as AVN, pHTN or albuminuria and increased hospitalizations. Given the small number of patient, a multivariate analysis was not possible. While the association between pHTN and VTE is well documented; the association of AVN and higher BMI with VTE described here is novel and needs further exploration with larger studies. Disclosures Little: Hemex Health, Inc.: Patents & Royalties; GBT: Research Funding.

Risk Factors for Kidney Disease in Hb SC and Hb Sβ+-Thalassemia Sickle Cell Disease

Sickle cells disease (SCD) is an inherited red blood disorder that leads to acute and chronic organ complications. The kidneys are among the most commonly affected organ systems and chronic kidney disease (CKD) predicts increased morbidity and early mortality in SCD (PMID 1892333). Risk factors for CKD have been primarily investigated in patients with homozygous inheritance of the hemoglobin (Hb) S mutation but are not as well understood in other SCD variants, such as in those with Hb SC or Hb SB+-thalassemia. We investigated clinical, laboratory, and genetic predictors (α-thalassemia and the APOL1 G1 and G2 kidney disease risk variants) for CKD in a combined analysis of non-Hb SS patients from the University of Illinois at Chicago and the multi-center Walk-PHaSST cohort. Clinical and laboratory variables were obtained at the time of enrolment. Estimated glomerular filtration (eGFR) rate was calculated using the CKD-EPI formula and CKD stage was defined according to the KDIGO guidelines. Univariate analysis for the association of variables with eGFR, albuminuria, and CKD stage were conducted using the linear trend test and Cochran's test for linear trend. Variables with a P < 0.1 were entered into linear and ordinal logistic regression models adjusting for age and sex. Median and interquartile ranges (IQR) are provided. Two hundred and forty-seven patients were included in this analysis. The median age of this cohort was 39 years (IQR, 24 - 50 years), 62% were female, 16% were on hydroxyurea, and 72% were Hb SC genotype. Albuminuria data was available in 174 patients; microalbuminuria (albuminuria 30 - 300 mg/g creatinine) was present in 24% and macroalbuminuria (albuminuria > 300 mg/g creatinine) in 5% of patients. Patients with higher urine albumin concentration were older, had higher systolic blood pressures and LDH concentrations, and lower hemoglobin concentrations (P ≤ 0.03). On multivariate analysis, the urine albumin concentration was independently associated with a higher systolic blood pressure (log transformed β +3.08 ± 1.09; P = 0.005) and a lower hemoglobin concentration (β -0.17 ± 0.09; P = 0.05). Patients with lower eGFR were older, had higher body mass indexes and systolic blood pressures, lower hemoglobin concentrations, and were more frequently female (P ≤ 0.04). No variables were independently associated with eGFR on multivariate analysis after adjusting for age and sex. When applying the KDIGO CKD staging criteria, 67% were classified as not having CKD (urine albumin < 30mg/g creatinine and eGFR > 60 mL/min/1.73m2), 23% had stage 1 or 2 CKD (urine albumin ≥ 30mg/g creatinine and eGFR > 60 mL/min/1.73m2), and 10% had stage 3 or greater CKD (eGFR < 60 mL/min/1.73m2). Patients with increasing CKD stage were older, had higher systolic blood pressures and LDH concentrations, and lower hemoglobin concentrations (Table 1) (P ≤ 0.005). On multivariate analysis, incremental CKD stage was independently associated with lower hemoglobin (OR 0.91, 95%CI: 0.88 - 0.94; P = 0.002) and higher LDH (natural log OR 1.43, 95% CI: 1.27 - 1.61; P = 0.004) concentrations. We did not observe an association between coinheritance of α-thalassemia or the APOL1 G1/G2 risk variants with urine albumin concentration, eGFR, or CKD stage. In conclusion, we demonstrate that CKD is a common comorbidity that is observed in approximately one third of SCD patients with the Hb SC or Hb Sβ+-thalassemia genotypes. A lower hemoglobin concentration and higher systolic blood pressure were independently associated with greater urine albumin concentration. This may reflect anemia causing reduced oxygen delivery to the renal cortex and hypertension-mediated vascular and glomerular damage. The association of worsening CKD stage with lower hemoglobin and higher LDH concentrations, consistent with increased hemolysis, is similar to what has been observed in the Hb SS genotypes. The potential effects of hemolysis on kidney function in the Hb SC and Sβ+-thalassemia genotypes will need to be explored further. Disclosures Gladwin: Bayer Pharmaceuticals: Other: Co-investigator; United Therapeutics: Patents & Royalties: Co-inventor on an NIH government patent for the use of nitrite salts in cardiovascular diseases ; Globin Solutions, Inc: Patents & Royalties: Provisional patents for the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning. Gordeuk:Novartis: Consultancy, Honoraria, Research Funding; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; Emmaus: Consultancy, Honoraria; Modus Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Modus Therapeutics: Consultancy, Honoraria; Pfizer: Research Funding; Inctye: Research Funding; Inctye: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Ironwood: Research Funding; Ironwood: Research Funding; Imara: Research Funding; Imara: Research Funding. Saraf:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding.

A feasibility study of telemedicine for paediatric sickle cell patients living in a rural medically underserved area

Introduction Sickle cell disease (SCD) is the most common inherited haematological disease, with potentially devastating complications. Improvements in therapies have increased the life span of patients with SCD, but this is contingent on receiving timely evidence-based medical care, including regular evaluations with haematologists, disease-specific education and psychosocial care. Our objective was to evaluate the feasibility of utilizing telemedicine for the provision of subspecialty paediatric SCD care in a rural medically underserved area. Methods This was a cross-sectional, observational, feasibility study. All patients 0–21 years old with SCD seen at Riley Hospital for Children Comprehensive Pediatric Sickle Cell Clinic who lived within 30 miles of the spoke telemedicine facility were eligible for recruitment. The Telehealth Satisfaction Scale (TeSS) was adapted for the SCD population and administered at each visit. Results Ten SCD patients, ranging in age from 10 months to 18 years old, initiated telemedicine visits during this timeframe. Some 60% were lost to follow-up or did not attend >50% of scheduled visits prior to beginning telemedicine visits. Following initiation of telemedicine, all Hb SS patients were started and/or maintained on hydroxyurea. Nine out of 10 patients who participated during this timeframe had a 100% follow-up rate. All who participated rated the comfort and ease of using the telehealth system as good or excellent and would do a telemedicine visit again. Discussion This study provides critical information to determine the feasibility and acceptability of a telemedicine intervention to aid in SCD care. To our knowledge, this is the first study to examine the effectiveness of telemedicine to deliver comprehensive paediatric SCD care. Future research with a larger sample size is needed to confirm findings of our study, including expansion of telemedicine sites to include more urban areas.

Allogenic hematopoietic stem cell transplantation in sickle cell disease.

Discussing the currently available HSCT options for Hb SS patients highlighting advantages and disadvantages of each modality in the light of recently published data. When MSD is available, myeloablative regimen is the preferred approach for otherwise healthy children whereas the nonmyeloablative (NMA) regimen is of choice for adults as well as children with SCD-associated morbidities. Mixed chimerism is common especially with NMA conditioning and is usually enough for cure. Alternative donor HSCT outcomes are progressively improving especially with posttransplant cyclophosphamide for GVHD prophylaxis. Recent studies comparing HSCT and chronic transfusion in Hb SS patients increasingly come in favor of HSCT arm. Advances in HSCT field led to donor pool expansion and better tolerated regimens. It is easier now to tailor a personalized transplantation plan for almost every patient. A successful management plan should be sufficiently comprehensive addressing patients' and families' social and psychological concerns to ensure compliance and improve outcome.

1728P - Epidemiology of synovial sarcoma in EU28 countries

BackgroundSynovial sarcoma (SS) is a rare and aggressive soft tissue sarcoma which primarily affects the extremities of arms and legs. It also occurs in head and neck, trunk, lungs and pleura. Brennan et al. (2016) reported a SS incidence rate of 1.4 per million in 2009 in England. There are no other population-based studies providing the burden of SS in Europe (EU). In addition, the age- and gender- specific distribution of SS patient population have not been published. The objective of this study was to estimate the incidence, prevalence and mortality of SS in 2019 for the EU28 countries. MethodsData from the United States (US) Surveillance, Epidemiology, and End Results (SEER) 18 Registries, Nov. 2018 (2000-2016) was analyzed using SEER*Stat software (v8.3.5) to calculate the incidence, prevalence and mortality of SS (overall, and by age groups and gender) for 2019. The estimated age-standardized incidence rate of SS, based on this SEER analysis in the US, was similar to that reported by Brennan et al. (2016). These rates were applied to the overall, and age- and gender-specific 2019 EU28 population to estimate the burden of SS in EU28. ResultsIn the EU28 countries in 2019, there will be an estimated 993 incident cases of SS, 3,550 prevalent patients and 520 deaths. Most (74%) of the prevalent patients with SS will be 20-64 years old, and only 17% will be 65 years and older. Approximately 40% of patients newly diagnosed with SS will be of ages 20-44 years, and 32% of ages 45-64 years. There will be a low occurrence (<10%) of SS in the pediatric population ages 0-19 years, but more frequent in males for this age group. The incidence and prevalence of SS will not vary between males and females. However, the estimated mortality among adults will be higher in males than females. Accounting for the differences in incidence, among the pediatric SS patients, the mortality in females will be higher than males. 73% of the SS mortality in 2019 will be observed in 20-64 year old patients. ConclusionsSS is a rare disease. Life expectancy of patients with SS is lower than the general population in EU28 due to high mortality in the 20-64 year age group. SS also occurs among children. Population-based studies are needed to better characterize SS patient population for improving patient care and survival in EU28. Legal entity responsible for the studyThe authors. FundingGlaxoSmithKline. DisclosureN. Joseph: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. S. St. Laurent: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. S. Zheng: Full / Part-time employment: GlaxoSmithKline. H. Stirnadel-Farrant: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. C. Dharmani: Full / Part-time employment: GlaxoSmithKline.

Serum phosphatidylserine-specific phospholipase A1 as a novel biomarker for monitoring systemic lupus erythematosus disease activity.

To assess the utility of serum levels of phosphatidylserine-specific phospholipase A1 (PS-PLA1 ), a lipase involved in the production of lysophosphatidylserine with multi-immunomodulatory effects, in systemic lupus erythematosus (SLE). Serum PS-PLA1 was measured in 161 patients with SLE (including 54 untreated patients), 80 disease controls (35 active rheumatoid arthritis [RA], 23 Sjögren's syndrome [SS], and 22 systemic sclerosis [SSc]), and 237 healthy controls. Serum PS-PLA1 was significantly higher in SLE patients than in healthy controls, RA and SS patients. Although PS-PLA1 was significantly elevated in SSc and SS patients compared with healthy controls, PS-PLA1 was significantly higher in untreated SLE patients than in treated SLE patients and disease control patients. Receiver operating characteristic analysis revealed that a cut-off value of 18.2ng/mL distinguished untreated SLE from disease control, with sensitivity and specificity of 71.4% and 57.5%, respectively. PS-PLA1 was significantly correlated with SLE Disease Activity Index (SLEDAI) and immunoglobulin G (IgG), and inversely correlated with white blood cell counts, lymphocyte counts, total complement hemolytic activity (CH50), complements C3, and C4 in SLE patients overall. Stepwise multiple regression identified SLEDAI, CH50, and IgG as significant parameters. In SLEDAI-based disease activity groups, PS-PLA1 was significantly higher in SLE patients with high disease activity than in those with low disease activity. PS-PLA1 decreased significantly in parallel with SLEDAI in 35 SLE patients whose paired serum samples were available pre- and post-treatment. Serum PS-PLA1 is associated with disease activity of SLE, indicating its possible use as a biomarker for monitoring SLE disease activity.

Aberrant MUC1 accumulation in salivary glands of Sjögren's syndrome patients is reversed by TUDCA in vitro.

Xerostomia in SS patients has been associated with low quality and quantity of salivary mucins, which are fundamental for the hydration and protection of the oral mucosa. The aim of this study was to evaluate if cytokines induce aberrant mucin expression and whether tauroursodeoxycholic acid (TUDCA) is able to counteract such an anomaly. Labial salivary glands from 16 SS patients and 15 control subjects, as well as 3D acini or human submandibular gland cells stimulated with TNF-α or IFN-γ and co-incubated with TUDCA, were analysed. mRNA and protein levels of Mucin 1 (MUC1) and MUC7 were determined by RT-qPCR and western blot, respectively. Co-immunoprecipitation and immunofluorescence assays for mucins and GRP78 [an endoplasmic reticulum (ER)-resident protein] were also performed. mRNA levels of RelA/p65 (nuclear factor-κB subunit), TNF-α, IL-1β, IL-6, SEL1L and EDEM1 were determined by RT-qPCR, and RelA/p65 localization was evaluated by immunofluorescence. MUC1 is overexpressed and accumulated in the ER of labial salivary gland from SS patients, while MUC7 accumulates throughout the cytoplasm of acinar cells; however, MUC1, but not MUC7, co-precipitated with GRP78. TUDCA diminished the overexpression and aberrant accumulation of MUC1 induced by TNF-α and IFN-γ, as well as the nuclear translocation of RelA/p65, together with the expression of inflammatory and ER stress markers in 3D acini. Chronic inflammation alters the secretory process of MUC1, inducing ER stress and affecting the quality of saliva in SS patients. TUDCA showed anti-inflammatory properties decreasing aberrant MUC1 accumulation. Further studies are necessary to evaluate the potential therapeutic effect of TUDCA in restoring glandular homeostasis in SS patients.

Psychological status and disease activity were major predictors of body image disturbances in patients with Sjögren’s syndrome

ABSTRACTSjögren’s syndrome (SS) often leads to disease-related body defects and functional impairments, which may result in the body image disturbances (BID) of patients. The aim of this study was to investigate the severity and predictors of BID among SS patients. Two hundred and thirty-one SS patients [mean (IQR) age: 51 (42–58); females: 94.4%] and 224 age and sex-matched healthy controls were included in this cross-sectional study. Questionnaires were applied: body image disturbance questionnaire (BIDQ), the hospital anxiety and depression scale (HADS), fatigue severity scale (FSS), the 10-cm pain Visual Analog Scale (VAS), the oral health impact profile-14 (OHIP-14), the ocular surface disease index (OSDI), the social support rate scale (SSRS). Independent sample t-test, Mann–Whitney U-test, Chi-square test, spearman rank correlation, and stepwise linear regression were performed by SPSS version 20.0 to analyze these data. In 231 SS patients, the mean of the overall BIDQ score was 1.80 ± 1.21, and SS patients had significantly higher scores in each domain of BIDQ compared with healthy controls (p < 0.05). The stepwise multiple linear regression analysis revealed that high BIDQ score was predicted by severe anxiety (β = 0.081; p < 0.001), high disease activity (β = 0.038; p < 0.001) and poor oral health (β = 0.017; p = 0.007) in SS patients. Patients with SS suffer from severe BID and it is necessary for rheumatologists to pay more attention to SS patients’ body image disturbance, especially those with high disease activity, severe anxiety, and poor oral health to improve patients’ quality of life.

CXCL13 as biomarker for histological involvement in Sjögren's syndrome.

SS is an autoimmune condition characterized by systemic B-cell activation, autoantibody production and ectopic germinal centres' formation within the salivary gland (SG). The extent of SG infiltrate has been proposed as a biomarker of disease severity. Plasma levels of CXCL13 correlate with germinal centres' activity in animal models and disease severity in SS, suggesting its potential use as a surrogate serum marker to monitor local B-cell activation. The aim of this study was to evaluate the potential role of CXCL13 as a biomarker of SG pathology in two independent SS cohorts. 109 patients with SS were recruited at Sapienza University of Rome (Italy) (n = 60), or at Queen Elizabeth Hospital in Birmingham and Barts Health NHS Trust in London (n = 49). Both sera and matched minor SG biopsy were available. Sicca (n = 57) and healthy subjects' (n = 19) sera were used as control. CXCL13 serum level was higher in SS patients compared with controls. Correlations between its serum levels and a series of histomorphological parameters, including size of the aggregates and the presence germinal centres', were observed. Our data foster the use of CXCL13 to monitor the extent of local pathology in SS and its validation in longitudinal clinical studies.

Disease activity and patient reported outcome measures in Sjögren's - what are the best tools to evaluate?

In primary SS (pSS), clinical features in SS can be divided into two facets: the patient perceived manifestations such as dryness, pain and fatigue, and the systemic manifestations. In the past decades, with efforts made by an international collaboration, consensual clinical indexes were developed for assessing both facets: one patient reported outcome, the EULAR SS Patients Reported Index (ESSPRI), and one activity index for systemic manifestations, the EULAR SS Disease Activity Index (ESSDAI). In addition, objective measures were developed to quantify the importance and consequence of ocular and oral dryness, few being specific of pSS. Work is ongoing to develop indexes combining all these approaches. Recent changes in the assessment of pSS patients, and the emergence of new targeted therapies, have put a greater emphasis on the design of clinical trials in pSS, and led for the first time to a positive randomized clinical trial.

Vaspin, resistin, retinol-binding protein-4, interleukin-1α and interleukin-6 in patient with nonalcoholic fatty liver diseas

Background and rational. Data on newer adipokines and interleukins in patients with nonalcoholic fatty liver disease (NAFLD) are inconclusive. The primary aim of this study was the evaluation of serum vaspin, resistin, retinol-binding protein (RBP)-4, inter-leukin (IL)-1α and IL-6 levels in NAFLD patients compared to matched controls, and their association with disease severity.Material and methods. Twenty-nine consecutively enrolled NAFLD patients with histologically confirmed nonalcoholic simple steatosis (SS; n = 15) or steatohepatitis (NASH; n = 14) and 25 matched controls without NAFLD were recruited. Serum vaspin, resistin, RBP-4, IL-1α and IL-6 and biochemical tests were measured.Results. Serum vaspin levels were lower and IL-6 levels higher in NASH patients than controls, but similar between controls and SS patients, or NASH and SS patients (vaspin, controls: 728.5 ± 39.3; SS: 634.6 ± 63.7; NASH: 531.5 ± 52.0 pg/mL; p for trend 0.028; IL-6, controls: 1.5 ± 0.2; SS: 2.5 ± 0.6; NASH: 3.0 ± 0.6 pg/mL; p for trend 0.032). However, after adjustment for body mass index or waist circumference, both vaspin and IL-6 did not remain significantly different between groups. Resistin, RBP-4 and IL-1α were not statistically different between groups. None of the selected adipokines or interleukins could independently differentiate NAFLD from SS, or patients with more severe from less severe histological lesions.Conclusion. Lower circulating vaspin, but higher IL-6 levels were observed in NASH patients than controls, whereas resistin, RBP-4 and IL-1α levels were similar between groups. However, these differences did not remain robust after adjustment for body mass index or waist circumference.

Reduced acetylation of histones H3 in peripheral blood mononuclear cells of patients with Primary Sjögren’s syndrome

Abstract Sjögren’s syndrome (SS) is an autoimmune disease characterized by an exocrine glands epithelium injury with dense lymphocytic infiltrates, mainly composed of activated T and B cells, involvement of the peripheral nervous, pulmonary, blood, kidney, skin, and joint. Present at the interface of genetic and environmental risk factors, histone acetylation is suspected to play a key role in SS. To clarify this point, we investigated the expression of histone deacetylases (HDACs1–10) and histone acetyltransferase (HAT-p300 CREEBP PCAF) by real time PCR in peripheral blood mononuclear cells (PBMCs) from SS patients. Elisa measured HDACs\HATs and histone H3/ H4 acetylation activity. Flow Cytometry and western blot verified histone acetylation level. The expression of HDACs1-10, p300, CREEBP and PCAF in PBMCs from SS patients was decreased in mRNA comparison with healthy controls (HCs). Total histone acetylation was reduced in PBMCs from SS patients, while no difference was observed in histone deacetylation. The extent of total histone H3, but not H4, acetylation in PBMCs from SS patients was decreased compared to that in HCs. An altered balance between HDAC and HAT activity was found in SS PBMCs. As a consequence, part of the pathogenic mechanisms in SS may be linked to epigenetic modifications, thus opening new therapeutic perspectives in SS.

Pulmonary involvement in a mouse model of Sjögren’s syndrome induced by activation of the STING pathway

Abstract Sjögren’s Syndrome (SS) is a chronic autoimmune disorder characterized by an increased type 1 interferon gene signature, autoantibody production, and salivary gland inflammation. Engagement of Stimulator of interferon genes (STING) induces type 1 interferon production. Gain of function mutations in TMEM173, encoding STING, results in a severe vasculopathy affecting the skin and lungs. We have previously reported that activation of the STING pathway in mice, using a STING agonist DMXAA, causes an SS-like disease characterized by sialoadenitis and salivary gland dysfunction. Considering that lungs are affected in 9–20% of SS patients, this study was undertaken to investigate lung involvement in DMXAA treated mice. Female C57BL/6 mice injected with DMXAA rapidly upregulated expression of IFNβ, IFNγ, and Mx1 in the lungs at 4 hours. This was followed by an increase in type 1 innate lymphoid cells on day 8. Histopathologic analysis showed the presence of peri-bronchial inflammatory infiltrates on day 35, which persisted until day 57. The lung inflammation was associated with an increased expression of multiple pro-inflammatory genes including CCl20, CXCl10, CXCl9, and IL17α. In addition, there was an increased frequency of lymphatic endothelial cells, suggestive of lymphangiogenesis. Although STING expression was seen in bronchial epithelium and alveolar cells in the lung, bone marrow chimeras between STING KO and wild type mice suggest that STING expression in myeloid cells was critical for lung inflammation. Our results show that systemic activation of the STING pathway might play an essential role in lung inflammation in SS patients.

Contribution of STAT3 and RAD23B in Primary Sézary Cells to Histone Deacetylase Inhibitor FK228 Resistance

FK228 (romidepsin) and suberoylanilide hydroxamic acid (vorinostat) are histone deacetylase inhibitors (HDACi) approved by the US Food and Drug Administration for cutaneous T-cell lymphoma (CTCL), including the leukemic subtype Sézary syndrome. This study investigates RAD23B and STAT3 gene perturbations in a large cohort of primary Sézary cells and the effect of FK228 treatment on tyrosine phosphorylation of STAT3 (pYSTAT3) and RAD23B expression. We report RAD23B copy number variation in 10% (12/119, P ≤ 0.01) of SS patients, associated with reduced mRNA expression (P= 0.04). RAD23B knockdown in a CTCL cell line led to a reduction in FK228-induced apoptosis. Histone deacetylase inhibitor treatment significantly reduced pYSTAT3 in primary Sézary cells and was partially mediated by RAD23B. A distinct pattern of RAD23B-pYSTAT3 co-expression in primary Sézary cells was detected. Critically, Sézary cells harboring the common STAT3 Y640F variant were less sensitive to FK228-induced apoptosis and exogenous expression of STAT3 Y640F, and D661Y conferred partial resistance to STAT3 transcriptional inhibition by FK228 (P ≤ 0.0024). These findings suggest that RAD23B and STAT3 gene perturbations could reduce sensitivity to histone deacetylase inhibitors in SS patients.

Increased risk of thyroid disease in patients with Sjogren's syndrome: a systematic review and meta-analysis.

BackgroundSjogren’s syndrome (SS) is a chronic autoimmune epithelitis characterized by disruption of epithelial cells, ensuing lymphoplasmocytic infiltration of exocrine glands, and subsequent dryness of the mouth and eyes. Individuals with SS are more likely to have the thyroid disease. However, this association remains controversial. This meta-analysis aimed to evaluate the risk of thyroid disease in patients with SS.MethodsWe performed this systematic review by searching both English and Chinese literature databases. Random- or fixed-effects models were used to summarize the association between thyroid disease and SS. The results were subjected to meta-analysis with odds ratios (ORs) and corresponding 95% confidence intervals (CIs).ResultsThe eight articles in this meta-analysis included 988 SS cases and 2,884 controls. Overall, the risk of thyroid disease in patients with SS was significantly increased compared with controls (OR, 3.29; 95% CI [2.08–5.21]). The risk of autoimmune thyroid disease (AITD) and non-AITD were also higher in patients with SS than in controls (OR, 3.48; 95% CI [1.59–7.63]; and OR, 2.90; 95% CI [1.51–5.57], respectively).ConclusionsTo the best of our knowledge, this systematic review is the first to demonstrate that the risk of thyroid disease was increased in SS compared to controls, suggesting that SS patients should be screened for thyroid disease.

SNP variations in IL10, TNF\u03b1 and TNFAIP3 genes in patients with dry eye syndrome and Sjogren\u2019s syndrome

BackgroundCytokines are known to be key players in dry eye syndrome (DES) and Sjogren’s syndrome (SS) pathogenesis. In this study we compared single nucleotide polymorphism (SNP) variations in genes encoding cytokine levels among SS and DES patients in Israel.MethodsWe recruited 180 subjects, 82 with SS and 98 with DES. Using a candidate gene approach and allele-specific PCR technique for genotyping, proportions of risk alleles in Tumor Necrosis Factor α (TNFα) (rs1800629), IinterLeukin-10 (IL-10) (rs1800896) and TNFAIP3 (rs2230926) SNPs were compared between study groups.ResultsAllelic distribution was found very similar to Caucasian (CEU – Utah residents with Northern and Western European roots) population distributions in these SNPs. While none of the SNPs’ variants were significantly associated with SS or DES in a recessive model, in an additive model the TNFα G risk allele was found higher among SS patients compared to DES (Homozygote-G: 84.2% vs. 70.8%; Heterozygote: 26.9% vs. 11.2%, respectively, p = 0.02). After adjustment for age, gender and ethnicity, these variants weren’t associated with SS. Genetic scoring reveals that SS patients are more likely to present variants of all three SNPs than DES subjects.ConclusionsThis is the first study evaluating these SNP variations among both patients with DES and patients with SS. We found the allelic distribution in each SNP to be very similar to that found in healthy Caucasian populations presented in the HapMap project. We found the TNFα allele significantly associated with DES for homozygotes, and associated with SS for heterozygotes in the additive model.

Aspirin Triggered Resolvin D1 reduces inflammation and restores saliva secretion in a Sjögren's syndrome mouse model.

SS is characterized by chronic inflammation of the salivary glands leading to loss of secretory function, thereby suggesting specialized pro-resolving mediators targeting inflammation to be a viable option for treating SS. Previous studies demonstrated that aspirin-triggered resolvin D1 (AT-RvD1) prevents chronic inflammation and enhances saliva secretion in a SS-like mouse model when applied before disease onset. However, this therapy cannot be used in SS patients given that diagnosis occurs post-disease onset and no reliable screening methods exist. Therefore, we examined whether treatment with AT-RvD1 reduces SS-like features in a mouse model post-disease onset. Tail vein injections were performed in a SS-like mouse model both with and without AT-RvD1 post-disease onset for 8 weeks, with salivary gland function and inflammatory status subsequently determined. Treatment of a SS-like mouse model with AT-RvD1 post-disease onset restores saliva secretion in both females and males. Moreover, although AT-RvD1 treatment does not reduce the overall submandibular gland lymphocytic infiltration, it does reduce the number of T helper 17 cells within the infiltrates in both sexes. Finally, AT-RvD1 reduces SS-associated pro-inflammatory cytokine gene and protein expression levels in submandibular glands from female but not male mice. AT-RvD1 treatment administered post-disease onset reduces T helper 17 cells and successfully restores salivary gland function in a SS mouse model with variable effects noted by sex, thus warranting further examination of both the causes for the sex differences and the mechanisms responsible for the observed treatment effect.

Le Fort III in Syndromic Craniosynostosis: Cost Comparison of Distraction Osteogenesis Versus Single-Stage Internal Fixation Techniques.

In syndromic craniosynostosis, the Le Fort III osteotomy is used to correct dental/skeletal imbalance, improve exorbitism, and increase the airway. The purpose of this study is to perform a cost comparison between the standard technique of single-stage rigid internal fixation and distraction osteogenesis (DO) in the Le Fort III osteotomy in this patient population. Hospital cost accounting databases were queried for patients undergoing single-stage advancement (SS) or DO from 2007 to 2016. Nominal cost data were adjusted using the Bank of Canada Consumer Price Index. Reported costs represented the full length of stay for all utilization per patient. Demographic information and cost data for single-stage osteotomy and DO were compared. Total costs for single-stage (n = 8) were higher than distraction (n = 6; mean $CAD57 825 vs $38 268, P < .05). Intensive care unit (ICU) costs for single-stage were significantly higher than distraction (mean, $17 746 vs $5585, P < .005). Distraction cases had higher operating room (OR) costs than single stage, but the difference was not significant (mean, $12 540 vs $9696). Length of stay was significantly longer for SS patients (mean, 11 days vs 7 days, P < .05). This single-institution retrospective cost analysis indicates standard SS rigid internal fixation Le Fort III is more costly than DO. Despite higher OR costs, prolonged ICU and hospital stay was the primary reason behind this difference. This information may be of benefit when advocating for new technology perceived as high cost.