POS0724 GENDER DIFFERENCES IN THROMBOTIC PRIMARY ANTIPHOSPHOLIPID SYNDROME IN A LARGE COHORT OF PATIENTS FROM FOUR EUROPEAN CENTERS

Background:Autoimmune diseases occur more frequently in females and their course and severity can be affected by gender. Antiphospholipid syndrome (APS) is a systemic autoimmune disorder in which antiphospholipid antibodies (aPL) exert a pathogenic role resulting in vascular thrombosis and/or pregnancy morbidities. Data about gender differences in thrombotic APS (t-APS) are still scarce1,2.Objectives:To evaluate the differences in frequency, disease expression and severity between females and males affected by primary t-APS.Methods:Retrospective study enrolling subjects with a formal diagnosis of primary APS (Miyakis 2006) with vascular thrombosis at onset. Women who presented with obstetric events as first aPL-related manifestation were excluded. All the patients were followed from 1967 to 2019 in four European centers: three French centers and one Italian center.Results:The study included 433 patients (68% females, 32% males). Median age at t-APS onset [31 (24-46) vs 41 (29-53) years, p<0.001] and at diagnosis [34 (27-50) vs 46 (34-57) years, p<0.001] was significantly lower in females.The most common presenting manifestations were venous thrombosis (60%) followed by arterial events (37%) and catastrophic APS (3%). Venous events were more frequent in women as compared to men (64% vs 51% p:0.012 OR:1.7 [1.1-2.5]). Sites of venous thrombosis included: limbs (35%), pulmonary (17%), cerebral (3%), portal and inferior cava (2%) and retinal (1%) veins, without gender differences. The arterial events were more frequent among men (43% vs 34% p:0.053). Strokes (27%) and myocardial infarctions (4%) were the most frequent manifestations, followed by thrombosis of limbs (2%), retina (2%) and abdominal organs (1%). Noteworthy, only men presented with visceral ischemia.During the follow-up, new thrombosis occurred in 41% of patients (179/433). 33% out of them had at least two episodes and these occurred especially among males (22% vs 10% p:0.001 OR:2.5 [1.3-4.8]). New events were mostly of the same type, but ⅓ of patients presented a switch from venous to arterial side and viceversa, with no gender differences.Complete aPL profile was available in 357 subjects: 33% had single aPL positivity, 24% double positivity and 43% triple positivity, with no differences between women and men. About 80% of the patients had a concomitant risk factor (RF) for thrombosis. Established cardiovascular RFs were more represented among men as shown in table 1. In women, estrogenic exposure was the main RFs, present in almost 40% of them.Table 1.MALESn= 137FEMALESn= 296POR [IC 95%]Traditional cardiovascular RFs, n (%)Smoke66 (48)81 (27)<0.0012.5 [1.6-3.8]Arterial hypertension59 (43)75 (25)<0.0012.2 [1.5-3.4]Dyslipidemia52 (38)72 (24)0.0041.9 [1.2-2.9]Diabetes16 (12)15 (5)0.0142.5 [1.8-5.1]Obesity13 (10)38 (13)nsOther thrombophilic factors, n (%)Estrogenic stimuli*0116 (39)-Trauma / surgery / immobilization21 (15)32 (11)nsCongenital thrombophilia9/94 (10)33/204 (16)nsData were compared using contingency tables, p value was calculated with Chi-Squared or Fisher exact test. *= hormonal therapy, pregnancy, post-partumConclusion:This gender-oriented analysis of patients with primary t-APS showed that women had the first vascular event at a younger age and mostly on the venous side, while men presented mainly with arterial events, later in life and suffered from more recurrent events. No differences were observed in the distribution of the aPL profile. The different frequency of arterial and venous events in the two groups could be attributed mainly to the presence of additional RFs rather than to biological gender-specific issues. However, it should be underlined that some RFs, such as the use of estrogens or classic cardiovascular RFs, are exclusive or more represented in one gender rather than the other, making it difficult to assess the link of causality between gender and manifestations of t-APS.References:[1]JF de Carvalho. Rheumatol Int. 2011.[2]LJ Jara. Lupus. 2005.Disclosure of Interests:None declare

Monitoring of drying kinetics evolution and hygrothermal properties of new earth-based materials using climatic chamber simulation

This study focuses on the drying kinetics of cob and light-earth layers comprising a hybrid walling system. Volumetric water content sensors are immersed and placed at different positions on the walls of a building to measure the drying kinetics. In addition, an experimental analysis of the effect of temperature, relative humidity (RH), and wind velocity variations on thermal conductivity in a climatic chamber under winter and summer conditions was conducted. The analysis of samples in laboratory aims to investigate the hygrothermal properties of cob and light-earth materials, and their dependency on the aforementioned parameters. The in situ drying kinetics of both materials involves water content reduction and stabilization; however, in the laboratory, although the water content of materials decreases, the drying is incomplete. Which may be due to the limited wind speed. The hydrothermal properties show that open porosity affects water vapor permeability and modifies the RH of cob and light-earth. At 23 °C, when the relative humidity (RH) range was 10–30%, the absorbed water vapor of cob and light earth was 0–2%. However, when the RH is 40–90%, the absorbed water vapor of light earth (2–9%) exceeds that of cob (0.5–2%). Moreover, the response to relative humidity (RH) with regard to the mixing law of components and samples differs. The resistance factor to water vapor diffusion values for cob and light-earth are 12.9 and 8.2, respectively. In this study, the thermal conductivity measurements under summer and winter conditions provide the relationship between the thermal conductivity, density, and water content of cob and light-earth materials

Earth construction: Field variabilities and laboratory reproducibility

Building construction is a major polluting sector. As a result, there is increasing global interest in the development of sustainable building materials with low environmental impact. Earth-based materials are among the materials of interest and building with earth-based materials has thus received a particular renewal of attention. Previous research has focused on the physical characteristics and durability of these materials. The aim of this study is to assess the variability of materials made in-situ and their reproducibility in the laboratory using an automatic normal Proctor machine with different compaction energies. Both cob and light earth were investigated. Cylindrical and prismatic specimens were produced on-site and in the laboratory: cob was made of silt, silty clay, sandy silt, and flax straw; and a separate layer of light earth was made of elastic silt and reed fibres. An experimental program was designed to evaluate the properties of the materials in terms of their water content, density, porosity, compressive strength, and thermal conductivity. The results revealed that the in-situ densities could be reproduced in the laboratory with compaction energies of 0.6 MJ/m3 and 0.2 MJ/m3 for cob and light earth, respectively. These compaction energies will allow the research to produce laboratory specimens that were representative of the materials implemented on-site. Regarding the compressive strength, the values obtained in the laboratory were higher than those of the in-situ specimens. Correction factors of 0.88 and 0.67 for cob and light earth. These values should be applied to calibrate the laboratory results in relation to in-situ. Concerning the thermal conductivity, the values obtained in the laboratory were similar for cob and higher for light earth. A correction factor of 0.87 should be applied to calibrate the laboratory results to those obtained in-situ

Stiripentol in D ravet syndrome: Results of a retrospective U . S . study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100157/1/epi12303.pd

THU0275 SEVERE PREECLAMPSIA RELATED TO ANTIPHOSPHOLIPID SYNDROME: AN EUROPEAN STUDY OF 40 WOMEN

Background:One of the 3 features of obstetrical antiphospholipid syndrome (APS) is severe preeclampsia (PE). Its time of occurrence, the associated risk of thromboses and systemic lupus erythematosus (SLE) have not been reported yet.Objectives:We analyzed severe PE in a series of women with APS.Methods:We retrospectively collected data of female patients from 5 French internal medicine and 1 Italian rheumatology units. Inclusion criteria were: a severe PE/eclampsia(1), that occurred before 34 weeks of gestation (WG) in patients who met the APS classification criteria(2).Results:40 patients were enrolled (Table 1). Because of known APS/positive aPL/previous obstetrical complications, 23(57.5%) patients were treated during the index PE: 4 with low dose aspirin (LDA), 4 with low molecular weight heparin (LMWH), and 15 with a combination of both. 7 patients were also treated with hydroxychloroquine, 8 with corticosteroids and 3 with immunosuppressants. 17(42.5%) patients received no treatment. 24(60%) live births were observed. During a follow-up period of 3 years, 26(65%) patients had at least 1 new pregnancy, with a total of 38 pregnancies which resulted in 33(86.8%) live births. 57.5% pregnancies who resulted in live births occurred without any maternal or fetal complications. All 26 patients who had at least 1 pregnancy after index PE were treated with LDA; LMWH was given at prophylactic and therapeutic dosage in 13(50%) patients, respectively. No patient experienced 3 consecutive miscarriages.Table 1.40 APS patients with severe PEOverall features (n, %)Patients40 (100)Age at PE, (median, IQR)30.5 (27-33)PE term, WG (median, IQR)25.5 (23-29) Live births24 (60) Birth term, WG (median, IQR)25.5 (23.7-30.3) Associated SLE12 (30)Maternal complications (n, %)25 (62.5) HELLP18 (45) E6 (15) CAPS3 (7.5) Placental abruptions3 (7.5)Fetal complications (n, %)31 (77.5) IUGR18 (45) IUFD11 (2.5) Preterm delivery22 (55)Obstetrical history (n, %) Primiparous21 (52.5) Index PE before APS12 (30)Thrombosis (n, %) Thrombosis before PE index14 (35.0) Thrombosis after PE index2 (5.0)Abs at APS diagnosis (n, %) aPL triple positivity21 (52.5) IgG/IgM anti-cardiolipin34 (85.0) IgG/IgM anti-β2GPI25 (62.5) LAC33 (82.5)Legend to Table 1:PE: preeclampsia; APS: antiphospholipid syndrome; IQR: interquartile range; WG: weeks of gestation; SLE: systemic lupus erythematosus; HELLP: Hemolysis, elevated liver enzymes, low platelet; E: eclampsia; CAPS: catastrophic APS; IUGR: intrauterine growth restriction; IUFD: intrauterine fetal death; CHB: congenital atrioventricular block; aPL: antiphospholipid antibodies; LAC: lupus anticoagulant.Conclusion:Among the APS criteria, "3 consecutive miscarriages criterion" was not found. The majority of patients also experienced thrombosis and SLE before the index PE.References:[1]Diagnosis and Management of preeclampsia and eclampsia. International Journal of Gynecology &Obestetrics 2002;77:67-75.[2]Miyakis S, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295e 306.Disclosure of Interests:Maddalena Larosa: None declared, Nathalie Morel: None declared, Meriem BELHOCINE: None declared, Amelia Ruffatti: None declared, Nicolas Martin Silva: None declared, Romain Paul: None declared, Luc Mouthon: None declared, Michel DREYFUS: None declared, Jean-Charles PIETTE: None declared, Odile Souchaud-Debouverie: None declared, Catherine Deneux-Tharaux: None declared, Vassilis Tsatsaris: None declared, Emmanuelle Pannier: None declared, Gaêlle Guettrot Imbert: None declared, Véronique LE GUERN Grant/research support from: UCB for GR2 study (to our institution), Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS, Nathalie Costedoat-Chalumeau Grant/research support from: UCB to my institutio

Identification of distinct subgroups of Sj\uf6gren\u27s disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts

\ua9 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: Sj\uf6gren\u27s disease is a heterogenous autoimmune disease with a wide range of symptoms—including dryness, fatigue, and pain—in addition to systemic manifestations and an increased risk of lymphoma. We aimed to identify distinct subgroups of the disease, using cluster analysis based on subjective symptoms and clinical and biological manifestations, and to compare the prognoses of patients in these subgroups. Methods: This study included patients with Sj\uf6gren\u27s disease from two independent cohorts in France: the cross-sectional Paris-Saclay cohort and the prospective Assessment of Systemic Signs and Evolution of Sj\uf6gren\u27s Syndrome (ASSESS) cohort. We first used an unsupervised multiple correspondence analysis to identify clusters within the Paris-Saclay cohort using 26 variables comprising patient-reported symptoms and clinical and biological manifestations. Next, we validated these clusters using patients from the ASSESS cohort. Changes in disease activity (measured by the European Alliance of Associations for Rheumatology [EULAR] Sj\uf6gren\u27s Syndrome Disease Activity Index [ESSDAI]), patient-acceptable symptom state (measured by the EULAR Sj\uf6gren\u27s Syndrome Patient Reported Index [ESSPRI]), and lymphoma incidence during follow-up were compared between clusters. Finally, we compared our clusters with the symptom-based subgroups previously described by Tarn and colleagues. Findings: 534 patients from the Paris-Saclay cohort (502 [94%] women, 32 [6%] men, median age 54 years [IQR 43–64]), recruited between 1999 and 2022, and 395 patients from the ASSESS cohort (370 [94%] women, 25 [6%] men, median age 53 years [43–63]), recruited between 2006 and 2009, were included in this study. In both cohorts, hierarchical cluster analysis revealed three distinct subgroups of patients: those with B-cell active disease and low symptom burden (BALS), those with high systemic disease activity (HSA), and those with low systemic disease activity and high symptom burden (LSAHS). During follow-up in the ASSESS cohort, disease activity and symptom states worsened for patients in the BALS cluster (67 [36%] of 186 patients with ESSPRI score &lt;5 at month 60 vs 92 [49%] of 186 at inclusion; p&lt;0\ub70001). Lymphomas occurred in patients in the BALS cluster (five [3%] of 186 patients; diagnosed a median of 70 months [IQR 42–104] after inclusion) and the HSA cluster (six [4%] of 158 patients; diagnosed 23 months [13–83] after inclusion). All patients from the Paris-Saclay cohort with a history of lymphoma were in the BALS and HSA clusters. This unsupervised clustering classification based on symptoms and clinical and biological manifestations did not correlate with a previous classification based on symptoms only. Interpretation: On the basis of symptoms and clinical and biological manifestations, we identified three distinct subgroups of patients with Sj\uf6gren\u27s disease with different prognoses. Our results suggest that these subgroups represent different heterogeneous pathophysiological disease mechanisms, stages of disease, or both. These findings could be of interest when stratifying patients in future therapeutic trials. Funding: Fondation pour la Recherche M\ue9dicale, French Ministry of Health, French Society of Rheumatology, Innovative Medicines Initiative 2 Joint Undertaking, Medical Research Council UK, and Foundation for Research in Rheumatology

SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms