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Background Hormonal exposure leads to an increased risk of venous thromboembolism (VTE) but the risk of VTE associated with assisted reproductive technology (ART) is not clearly determined. Methods We searched in PubMed, EMBASE, Web of Science, and the Cochrane Library databases and identified all relevant articles published up to February 1, 2021. The primary objective was to determine the frequency of VTE associated with ART. Secondary objectives were to determine (1) the risk of VTE associated with ART as compared to pregnancy without ART; (2) the risk of VTE associated with ovarian hyperstimulation syndrome (OHSS); and (3) to determine potential risk factors of VTE related to ART. Results Fourteen studies were included. The overall frequency of VTE associated with ART was 0.23% (95% confidence interval [CI]: 0.07–0.46). Women undergoing ART had a two- to threefold increased risk of VTE as compared to spontaneous pregnancy (relative risk [RR]: 2.66; 95% CI: 1.60–4.43). The overall frequency of VTE specifically related to OHSS was Conclusion Further large prospective studies on risk factors of VTE in women undergoing ART are needed in order to optimize thromboprophylaxis in this context.

Background There is an increased risk of arterial events including major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after venous thromboembolism (VTE). However, their risk factors remain little explored.Methods We aimed to determine the risk factors for MACE (acute coronary syndrome/stroke/cardiovascular death) and MALE (limb ischemia/critical limb ischemia/non-traumatic amputation/any limb revascularization) after VTE. Competing risk models (Fine-Gray) were used in a multicenter prospective cohort of 4,940 patients (mean age: 64.6 years and median follow-up: 64 months).Results MACE occurred in 17.3% of participants (2.35% per patient-years) and MALE in 1.7% (0.27% per patient-years). In multivariable analysis, the identified risk factors for MACE were the age of 50 to 65 years (vs. 65 years (vs. Conclusions Risk factors for MACE and MALE after VTE included some traditional cardiovascular risk factors, patient's comorbidities, and some characteristics of VTE.

Women with a previous venous thromboembolism (VTE) are at risk of recurrence during pregnancy.We aimed to assess the incidence rate of recurrent VTE during pregnancy, according to the period of pregnancy, and the clinical parameters associated with recurrence, in a prospective cohort of women of childbearing age after a first VTE.A total of 189 women aged 15-49 years with a first documented VTE were followed until a subsequent pregnancy of at least 20 weeks' gestation between 2000 and 2020. VTE recurrences during pregnancy were recorded, as were potential clinical risk factors for recurrence.Recurrent VTE occurred in six women during antepartum: five during the first trimester (incidence rate 106.4 per 1000 women-years) (95% confidence interval [CI] 46.3-226.0); none during the second trimester; and one during the third trimester (incidence rate 27.0 per 1000 women-years [95% CI 4.8-138.2]). During postpartum, recurrences occurred in 11 women (incidence rate 212.8 per 1000 women-years [95% CI 119.9-349.1]). These 17 recurrent VTEs presented as pulmonary embolism ± deep vein thrombosis (DVT) in five patients and isolated DVT in 12. Failure of thromboprophylaxis occurred in two cases (33.3%) antepartum and in 10 cases (90.9%) postpartum. In multivariable analysis, only obesity (defined on prepregnancy body mass index) was associated with recurrent VTE (odds ratio 3.34 [95% CI 1.11-10.05, p = .03]).This study confirms a high risk of recurrent VTE postpartum, despite thromboprophylaxis, in women with a previous VTE. Only obesity was associated with VTE recurrence during pregnancy, suggesting that low-dose anticoagulation might not be appropriate in obese pregnant women.

We evaluated the diagnostic performances of the French translation of a self-administered questionnaire designed by Diehl et al. looking for a history of pre-eclampsia. After a phone call, 206 women who gave birth at Brest University Hospital responded to the questionnaire online. Then, their responses were compared to their medical files. The sensitivity of the questionnaire was 95.2% and its specificity was 98.0%. This French questionnaire has then demonstrated its validity. It can now be used to explore the role of a pre-eclampsia history on various pathologies and, by this mean, to improve knowledge about women's health.

After first episodes of venous thromboembolism (VTE), patients are at increased risk of recurrent VTE and arterial thrombotic events (ATE) compared with the general population, two disorders that are influenced by anticoagulation. However, risk factors of these conditions occurring during and after anticoagulation are little described. Using cause-specific hazard regression models, we aimed to determine risk factors of the composite outcome recurrent VTE/ATE, and separately recurrent VTE or ATE, during and after anticoagulation in patients with first episodes of VTE from a prospective cohort. Hazard ratios (HRs) are given with 95% confidence intervals (CIs). A total of 2,011 patients treated for at least 3 months were included. A total of 647 patients had recurrent VTE/ATE (incidence: 4.69% per patient-years) during overall follow-up (median: 92 months). Of these events, 173 occurred during anticoagulation (incidence: 3.67% per patient-years). Among patients free of events at the end of anticoagulation, 801 had a post-anticoagulation follow-up ≥3 months; and 95 had recurrent VTE/ATE (incidence: 1.27% per patient-years). After adjustment for confounders, cancer-associated VTE (HR: 2.64, 95% CI: 1.70–4.11) and unprovoked VTE (HR: 1.95, 95% CI: 1.35–2.81) were the identified risk factors of recurrent VTE/ATE during anticoagulation (vs. transient risk factor–related VTE). Risk factors of recurrent VTE/ATE after anticoagulation included 50 to 65 years of age (vs.

Background: Hereditary angioedema (HAE) is characterized by unpredictable and potentially life-threatening attacks of cutaneous and submucosal swelling. Over the past decade, new agents, based on a better understanding of the underlying biologic mechanisms of HAE, have changed the face of long-term prophylaxis (LTP). Objective: The objective was to describe current practices and unmet needs with regard to LTP for HAE in expert centers in France. Methods: The study was conducted in France in 2020. Based on their experience with patients with HAE who had visited their center at least once in the past 3 years, physicians from 25 centers who are expert in the management of HAE were requested to fill in a questionnaire that encapsulated their active patient list, criteria for prescribing LTP, and medications used. They were asked about potential unmet needs with currently available therapies. They were asked to express their expectations with regard to the future of HAE management. Results: Analysis was restricted to 20 centers that had an active patient file and agreed to participate. There were 714 patients with C1 inhibitor (C1-INH) deficiency, of whom 423 (59.2%) were treated with LTP. Altered quality of life triggered the decision to start LTP, as did the frequency and severity of attacks. Ongoing LTP included androgens (28.4%), progestins (25.8%), lanadelumab (25.3%), tranexamic acid (14.2%), intravenous C1-INHs (5.6%), and recombinant C1-INH (0.7%). Twenty-nine percent of the patents with LTP were considered to still have unmet needs. Physicians' concerns varied among therapies: poor tolerability for androgens and progestins, a lack of efficacy for tranexamic acid and progestins, dosage form, and high costs for C1-INHs and lanadelumab. Physicians' expectations encompassed more-efficacious and better-tolerated medications, easier treatment administration for the sake of improved quality of life of patients, and less-expensive therapies. Conclusion: Despite the recent enrichment of the therapeutic armamentarium for LTP, physicians still expressed unmet needs with currently available therapies.

Objective To describe the main features at diagnosis and evolution over time of patients with localized granulomatosis with polyangiitis (L-GPA) compared with those of systemic GPA (S-GPA). Methods EULAR definitions of L-GPA, i.e. upper and/or lower respiratory tract involvement, and S-GPA were applied to patients from the French Vasculitis Study Group Registry. L-GPA and S-GPA patients’ characteristics at diagnosis and long-term outcomes were analysed and compared. Results Among the 795 Registry patients, 79 (10%) had L-GPA. Their main clinical manifestations were rhinitis, lung nodules, sinusitis and otitis. L-GPA vs S-GPA patients at diagnosis, respectively, were younger, more frequently had saddle nose deformity or subglottic stenosis and were less often PR3-ANCA–positive. L-GPA vs S-GPA induction therapy less frequently included CYC but more often a combination of MTX and glucocorticoids; 64% of MTX-treated patients experienced disease progression within 18 months post-diagnosis. L- and S-GPA patients’ estimated relapse-free–survival probabilities, relapse rates and refractory disease rates at each time point were comparable, but L-GPA patients had more frequent ENT and lung relapses, and higher overall survival rates (P Conclusions The relapse risks of L-GPA and S-GPA were similar, but relapse patterns differed and L-GPA overall survival rate was higher. About one-quarter of L-GPA patients developed S-GPA over time, but without end-stage organ involvement.

Data on long-term venous thromboembolism (VTE) recurrence risk according to gender are conflicting.To evaluate long-term VTE recurrence risk after a first VTE in men and women under 50 years old.Since May 2000, 875 consecutive patients (315 men, 560 women) with a first symptomatic VTE under 50 years old were enrolled in a French prospective multicentre cohort study and were followed up as long as possible. The primary outcome was symptomatic recurrent VTE during follow-up.At baseline, men were older and had more comorbidities than women. First VTE was mainly unprovoked in men (80.6%) and hormone-related in women (84.3%). During a median follow-up of 7.0 years (inter-quartile range, 5.0-11.0), recurrent VTE occurred in 97 men (30.8%) and in 72 women (12.9%) (annual incidence rates of recurrent VTE of 4.8% versus 1.8%-person-years, P0.001). However, there was no difference according to gender in subgroups of patients with a first unprovoked VTE (5.8% versus 3.8%-person-years, P = 0.09). In women, duration of hormonal treatment before first VTE did not influence recurrence risk. In multivariable analysis, unprovoked VTE and family history of VTE were independently associated with recurrence (hazard ratio of 2.50 (95% confidence interval, 1.61 to 3.85) and 1.52 (1.11 to 2.09) respectively).Number of women with unprovoked VTE was low.In patients with a first VTE under 50 years old, a first unprovoked episode and a family history of VTE, but not gender, were associated with a high risk of long-term recurrence.

IntroductionAntiphospholipid syndrome (APS) is an autoimmune disease characterised by thrombosis (arterial, venous or small vessel) or obstetrical events and persistent antiphospholipid antibodies (aPL), according to the Sydney classification criteria. Many studies have performed cluster analyses among patients with primary APS and associated autoimmune disease, but none has focused solely on primary APS. We aimed to perform a cluster analysis among patients with primary APS and asymptomatic aPL carriers without any autoimmune disease, to assess prognostic value.MethodsIn this multicentre French cohort study, we included all patients with persistent APS antibodies (Sydney criteria) measured between January 2012 and January 2019. We excluded all patients with systemic lupus erythematosus or other systemic autoimmune diseases. We performed hierarchical cluster analysis on the factor analysis of mixed data coordinates results with baseline patient characteristics to generate clusters.ResultsWe identified four clusters: cluster 1, comprising ‘asymptomatic aPL carriers’, with low risk of events during follow-up; cluster 2, the ‘male thrombotic phenotype’, with older patients and more venous thromboembolic events; cluster 3, the ‘female obstetrical phenotype’, with obstetrical and thrombotic events; and cluster 4, ‘high-risk APS’, which included younger patients with more frequent triple positivity, antinuclear antibodies, non-criteria manifestations and arterial events. Regarding survival analyses, asymptomatic aPL carriers relapsed less frequently than the others, but no other differences in terms of relapse rates or deaths were found between clusters.ConclusionsWe identified four clusters among patients with primary APS, one of which was ‘high-risk APS’. Clustering-based treatment strategies should be explored in future prospective studies.

ObjectiveAntiphospholipid syndrome (APS) is defined by the association of thromboembolic and/or obstetrical clinical manifestations and the presence of antiphospholipid antibodies. The objective of our study was to evaluate the impact of the triple-positive profile in a cohort of 204 APS patients.MethodsWe conducted a retrospective study, including patients with primary or secondary APS, meeting the Sydney criteria with at least one thrombotic and/or obstetrical complication. Clinical characteristics and the risk of relapse (defined by the occurrence of a new thrombotic event and/or a new adverse obstetrical event) between triple-positive and non-triple-positive APS patients were compared.Results204 patients were included in our study, 68 were triple-positive and 136 were single or double positive. 122 patients (59.8%) had primary APS. 67 patients (32.8%) had obstetrical APS, with a higher rate among triple-positive patients (45.6% vs 26.5%, p=0.010), and 170 patients (83.3%) had thrombotic APS, without difference between triple-positive and others. Thrombotic events were more often venous (56.4%) than arterial (37.7%). Triple-positive patients had more placental complications than others (17.6% vs 2.9%, p=0.001) and more non-criteria events (48.5% vs 25.7%, p=0.002). Among non-criteria events, there was a higher frequency of Sneddon syndrome in triple-positive patients (7.4% vs 0.7%, p=0.028). The relapse rate was higher in triple-positive patients than in others (63.2% vs 39,7%, p=0002). In multivariate analysis, the triple-positive profile was associated with a higher risk of relapse (HR 1.63; 95% CI 1.04 to 2.55; p=0.031).ConclusionThe triple-positivity is associated with a higher risk of relapse and obstetrical complications.

Increase in prevalence of maternal obesity worldwide raises concern among health professionals. Our purpose was to evaluate the impact of maternal obesity and of excessive gestational weight gain (GWG) on the course of singleton pregnancies in a French maternity ward.3599 consecutive women who delivered from April 2013 to May 2015 at Brest University Hospital were included in HPP-IPF cohort study, a study designed to evaluate clinical and biological determinants of postpartum hemorrhage (PPH). Maternal obesity was defined by a pre-pregnancy Body Mass Index (BMI) ≥ 30 kg/mOut of the 3162 women analyzed for this report, 583 (18.4%) were overweight, 400 (12.7%) were obese and 36.6% had excessive GWG. In multivariable analysis, after adjustment for confounding factors, obese women were at increased risk of GDM (OR 5.83, 95%CI 4.37-7.79), PPH (OR 1.69, 95%CI 1.19-2.41), C-section (OR 2.50, 95%CI 1.92-3.26) and macrosomia (OR 1.90, 95%CI 1.31-2.76). Similarly, women with excessive GWG were at increased risk of GDM (OR 1.55, 95%CI 1.17-2.06), C-section (OR 1.46, 95%CI 1.16-1.83) and macrosomia (OR 2.09, 95%CI 1.50-2.91).Maternal obesity and excessive GWG are independent risk factors for GDM, C-section and macrosomia in singleton pregnancies. Further studies are needed to evaluate if a lifestyle intervention aiming at avoiding excessive GWG could improve clinical outcomes in pregnant women.

ObjectiveTo investigate whether antineutrophil cytoplasm antibody (ANCA)-negative and myeloperoxidase (MPO)-ANCA–positive granulomatosis with polyangiitis (GPA) differ from proteinase-3 (PR3)-ANCA–positive GPA.MethodsDiagnostic characteristics and outcomes of newly diagnosed French Vasculitis Study Group Registry patients with ANCA-negative, MPO-ANCA–positive or PR3-ANCA–positive GPA satisfying American College of Rheumatology criteria and/or Chapel Hill Conference Consensus Nomenclature were compared.ResultsAmong 727 GPA, 62 (8.5%) were ANCA-negative, 119 (16.4%) MPO-ANCA–positive and 546 (75.1%) PR3-ANCA–positive. ANCA-negative patients had significantly (pConclusionsBased on this large cohort, ANCA-negative versus ANCA-positive patients more frequently had limited disease but similar RFS and OS. MPO-ANCA–positive patients had similar RFS but lower OS due to their older age. PR3-ANCA–positive GPA patients’ RFS was lower than those of the two other subsets combined but that difference did not persist when comparing only PR3 versus MPO-ANCA–positive patients.

ObjectiveA new adult-onset autoinflammatory syndrome has been described, named VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic). We aimed to compare the clinical characteristics, the laboratory features and the outcomes between idiopathic-relapsing polychondritis (I-RP) and VEXAS-relapsing polychondritis (VEXAS-RP).MethodsPatients from French retrospective multicentre cohort of RP were separated into two groups: a VEXAS-RP and an I-RP.ResultsCompared with patients with I-RP (n=40), patients with VEXAS-RP (n=55) were men (96% vs 30%, pConclusionWe report the largest cohort of VEXAS-RP, characterised by high prevalence of male sex, fever, skin lesion, ocular involvement, pulmonary infiltration, heart involvement, older age and MDS association.

Objectives To describe the effectiveness and safety of biologics for the treatment of relapsing and/or refractory polyarteritis nodosa (PAN). Methods A retrospective European collaborative study was conducted in patients with PAN who received biologics for relapsing and/or refractory disease. Results Forty-two patients with PAN received a total of 53 biologic courses, including TNF-α blockers in 15 cases, rituximab (RTX) in 18 cases, tocilizumab (TCZ) in 10 cases and other biologics in 10 cases. TNF-α blockers and TCZ were mainly used for refractory diseases whereas RTX was mainly initiated for relapsing disease. After a median follow-up of 29 (8–50) months, remission, partial response, treatment failure and treatment discontinuation due to severe adverse events occurred in, respectively, 40%, 13%, 40% and 7% of patients receiving TNF-α blockers, 50%, none, 30% and 20% of TCZ recipients, and 33%, 11%, 56% and none of the RTX recipients. No remission was noted in patients treated with other biologics. Severe adverse events were observed in 14 (28%) patients without significant differences between the three biologics, leading to early biologics discontinuation in only three cases. Conclusion These results suggest that TCZ may be effective in relapsing and/or refractory PAN. Our data warrant further study to confirm these findings.

It was recently established that patients who developed VTE are at increased risk of major adverse cardiovascular events (MACE) compared with the general population. However, whether the anticoagulation used for VTE influences the risk of MACE remains undescribed.Does the anticoagulant treatment for VTE affect the risk of subsequent MACE?This study included patients from a large prospective cohort who received only one family of anticoagulant treatment after the acute phase of VTE, including vitamin K antagonist (VKAs) and direct oral anticoagulants (DOACs). MACE included nonfatal acute coronary syndrome, nonfatal stroke, and all-cause death. The secondary outcome, MACE-2, included cardiovascular death instead of all-cause death. Cox proportional and Fine-Gray models served to study the relationship between anticoagulation characteristics and the risk of outcomes.A total of 3,790 patients (47.2% male; mean age, 60.48 years) were included. A total of 1,228 patients (32.4%) were treated for 0 to 3 months (median in overall population, 6 months). Compared with these patients, those treated for 3 to 12 months (hazard ratio [HR], 0.64; 95% CI, 0.54-0.76) or12 months (HR, 0.47, 95% CI, 0.39-0.56) had a significant reduced risk of MACE following adjustment for confounders. Findings were similar for MACE-2 (sub-HR for 3-12 months, 0.61 [95% CI, 0.47-0.79]; sub-HR12 months, 0.52 [95% CI, 0.39-0.68]). After adjustment for confounders, there was a reduced risk of MACE (HR, 0.53; 95% CI, 0.39-0.71) and MACE-2 (sub-HR, 0.48; 95% CI, 0.29-0.77) in patients treated with DOACs (vs VKAs).Treatment of VTE for3 months is associated with a reduced risk of MACE, as is treatment with DOACs vs VKAs. These findings, which may influence the choice of anticoagulation strategies for VTE, need confirmation by randomized clinical trials.

We aimed to validate and to refine current recurrent venous thromboembolism (VTE) risk classification.We performed aDuring a 4.8-year median follow-up after anticoagulation discontinuation, symptomatic recurrent VTE occurred in 230 patients (12.2%). Based on the ISTH classification, patients with unprovoked VTE or VTE with minor or major persistent risk factors had a 2-fold increased recurrence risk compared with those with VTE and major transient risk factors. Recurrence risk was not increased in patients with minor transient factors (hazard ratio (HR) 1.31, 95% CI 0.84-2.06). Individual risk factors analysis identified hormone-related VTE (pregnancy: HR 0.26, 95% CI 0.08-0.82; oestrogens: HR 0.25, 95% CI 0.14-0.47) and amyotrophic lateral sclerosis (HR 5.84, 95% CI 1.82-18.70). After reclassification of these factors as major transient for the former and major persistent for the latter, the modified ISTH classification allowed us to accurately discriminate between patients at low risk of recurrence (Among patients who stopped anticoagulation after a first VTE, a refined ISTH classification based on recurrence risk intensity of individual factors allowed discrimination between patients at low recurrence risk, including hormonal exposure in women, and patients at high recurrence risk.

We describe a possible systemic vasculitis involving electively large veins. The patient presented with severe febrile lower limb pain. Diagnosis was made by color Doppler ultrasound (CDU) and confirmed by anatomopathological examination of the long saphenous vein, but not by examination of the temporal artery which was normal. CDU found a unilateral halo sign of one temporal artery and a major wall swelling of the lower limb proximal deep veins. The etiology of this possible vasculitis is still unknown. It could be an unusual clinical presentation of giant cell arteritis with vein involvement but without proven arterial involvement. To confirm this hypothesis, it would be interesting to look systematically for lower limb vein thickening with CDU in patients newly diagnosed with giant cell arteritis who have lower limb pain.

This study aimed at determining if first trimester serum biomarkers could predict adverse pregnancy outcomes associated with villitis (VUE) and chronic intervillositis of unknown etiology (CIUE).Between January 2013 and June 2018, we selected from pathology department files placentas with VUE or CIUE associated with VUE and control placentas with available first trimester Down syndrome screening results. First trimester PAPP-A and βhCG levels were recorded. Placental growth factor (PlGF) levels were measured in patients with an available first trimester serum sample. Histological findings in placentas, course of pregnancies and newborns' characteristics were compared between cases and controls.78 cases and 75 controls were included. In cases, there were 21,8% intrauterine growth restriction (IUGR), 30,8% small for gestational age (SGA). Compared to controls, placentas from cases were smaller (425 g [IQR 370-480] vs 460 g [IQR 390-523], p = 0,03), showed more maternal vascular malperfusion features (79,5% vs 22,7%, p 0,0001) and more fetal vascular malperfusion features (33,3% vs 12%, p = 0,002). Cases had lower PlGF (29,74 pg/ml [IQR 19,74-36,17] vs 36,37 pg/ml [IQR 27,36-49,13], p = 0,007) and βhCG levels (0,74 MoM [IQR 0,53-1,12] vs 1,00 MoM [IQR 0,72-1,53], p = 0,002) than controls. These differences resulted from lower PlGF levels in VUE patients compared to CIUE associated with VUE patients and controls (28,35 vs 34,05 and 36,37 pg/ml, p = 0,01) and from lower βhCG levels in CIUE associated with VUE patients compared to VUE patients and controls (0,65 vs 0,86 and 1, p = 0,005).Low first trimester PlGF levels in cases, especially in VUE patients, suggest that reduced angiogenesis is involved in adverse pregnancy outcomes related to VUE.

International audience; Bradykinin mediated angioedema (BK-AE) can be associated either with C1Inhibitor deficiency (hereditary and acquired forms), either with normal C1Inh (hereditary form and drug induced AE as angiotensin converting enzyme inhibitors…). In case of high clinical suspicion of BK-AE, C1Inh exploration must be done at first: C1Inh function and antigenemy as well as C4 concentration. C1Inh deficiency is significant if the tests are below 50 % of the normal values and controlled a second time. In case of C1Inh deficiency, you have to identify hereditary from acquired forms. C1q and anti-C1Inh antibody tests are useful for acquired BK-AE. SERPING1 gene screening must be done if a hereditary angioedema is suspected, even if there is no family context (de novo mutation 15 %). If a hereditary BK-AE with normal C1Inh is suspected, F12 and PLG gene screening is suitable.

International audience; OBJECTIVES: Prosthetic vascular graft infection (PVGI) is a very severe disease. We aimed to determine the factors associated with treatment failure. METHODS: Patients admitted to two University Hospitals with PVGI were included in this retrospective study. PVGI was classified as possible, probable or proven according to an original set of diagnostic criteria. We defined treatment failure if one of the following events occurred within the first year after PVGI diagnosis: death and infection recurrence due to the same or another pathogen. RESULTS: One hundred and twelve patients were diagnosed with possible (n = 26), probable (n = 22) and proven (n = 64) PVGI. Bacterial documentation was obtained for 81% of patients. The most frequently identified pathogen was Staphylococcus aureus (n = 39). Surgery was performed in 96 patients (86%). Antibiotics were administered for more than 6 weeks in 41% of patients. Treatment failure occurred in 30 patients (27.5%). The factors associated with a lower probability of treatment failure were total removal of the infected graft (OR = 0.2, 95% CI [0.1-0.6]), rifampicin administration (OR = 0.3 [0.1-0.9]) and possible PVGI according to the GRIP criteria (OR = 0.3 [0.1-0.9]). CONCLUSIONS: Treatment failure occurred in 27.5% of patients with PVGI. Total removal of the infected graft and rifampicin administration were associated with better outcomes.

INTRODUCTION The antiphospholipid syndrome (APS) (1) is defined by the development of vascular thrombosis, or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL). Antinuclear antibodies (ANA) can be detected in primary APS patients without any clinical systemic autoimmune disease. The presence of ANA antibodies could confer a specific phenotype in primary APS. OBJECTIVE To evaluate the characteristics of APS patients with antinuclear antibodies without other autoimmune disease (ANA positive APS patients) in comparison with primary APS without ANA or secondary APS patients with associated systemic lupus erythematosus (SLE). METHODS Clinical and biologic data from 195 APS were retrospectively collected and patients were classified as primary APS with positive ANA (ANA-positive APS), primary APS without any ANA (ANA-negative APS), and SLE-associated APS (SLE-APS). RESULTS Fourty patients (21%) were classified into ANA-positive APS group, 77 (39%) in ANA-negative APS and 78 (40%) in SLE-APS. In ANA-positive APS patients, 20 patients (51%) had arterial thrombosis, 14 (41%) had veinous thrombosis and 19% had obstetrical complications. There was no difference between the three groups for the frequency of thrombotic manifestations and obstetrical complications. ANA-positive APS patients had more non-criteria manifestations than ANA-negative APS (48% versus 25%; P≤0.01). ANA-positive APS had more triple aPL positivity (59% versus 18%; P

BackgroundWe aimed to validate and to refine current recurrent venous thromboembolism (VTE) risk classification.MethodsWe performed apost hocanalysis of a multicentre cohort including 1881 patients with a first symptomatic VTE prospectively followed after anticoagulation discontinuation. The primary objective was to validate the International Society of Thrombosis and Haemostasis (ISTH) risk classification in predicting recurrence risk. The secondary objective was to evaluate a refined ISTH classification based on the recurrence risk estimate for each individual risk factor.ResultsDuring a 4.8-year median follow-up after anticoagulation discontinuation, symptomatic recurrent VTE occurred in 230 patients (12.2%). Based on the ISTH classification, patients with unprovoked VTE or VTE with minor or major persistent risk factors had a 2-fold increased recurrence risk compared with those with VTE and major transient risk factors. Recurrence risk was not increased in patients with minor transient factors (hazard ratio (HR) 1.31, 95% CI 0.84–2.06). Individual risk factors analysis identified hormone-related VTE (pregnancy: HR 0.26, 95% CI 0.08–0.82; oestrogens: HR 0.25, 95% CI 0.14–0.47) and amyotrophic lateral sclerosis (HR 5.84, 95% CI 1.82–18.70). After reclassification of these factors as major transient for the former and major persistent for the latter, the modified ISTH classification allowed us to accurately discriminate between patients at low risk of recurrence (i.e.with major transient risk factors) and those at high risk of recurrence (i.e.without major transient risk factors).ConclusionsAmong patients who stopped anticoagulation after a first VTE, a refined ISTH classification based on recurrence risk intensity of individual factors allowed discrimination between patients at low recurrence risk, including hormonal exposure in women, and patients at high recurrence risk.

ObjectiveTo compare characteristics, pregnancies and treatments during pregnancies of seronegative and seropositive antiphospholipid syndrome (APS), to analyse factors associated with obstetrical outcome.Patients and methodsInclusion criteria were: (1) thrombotic and/or obstetrical APS (Sydney criteria); (2) absence of conventional antiphospholipid antibodies (APL); (3) at least one persistent non-conventional APL among IgA anticardiolipin antibodies, IgA anti-B2GPI, anti-vimentin G/M, anti-annexin V G/M, anti-phosphatidylethanolamine G/M and anti-phosphatidylserine/prothrombin G/M antibodies. The exclusion criteria were: (1) systemic lupus erythematosus ( SLE) or SLE-like disease; and (2) other connective tissue disease.ResultsA total of 187 women (mean 33±5 years) with seronegative APS were included from 14 centres in Austria, Spain, Italy, Slovenia and France and compared with 285 patients with seropositive APS. Seronegative APS has more obstetrical rather than thrombotic phenotypes, with only 6% of venous thrombosis in comparison to seropositive APS. Cumulative incidence of adverse obstetrical events was similar in seronegative and seropositive APS patients, although higher rates of intrauterine deaths (15% vs 5%; p=0.03), of preeclampsia (7% vs 16%, p=0.048) and lower live birth term (36±3 vs 38±3 weeks of gestation; p=0.04) were noted in seropositive APS. The cumulative incidence of adverse obstetrical events was significantly improved in treated versus untreated seronegative APS (log rankConclusionSeveral non-criteria APL can be detected in patients with clinical APS features without any conventional APL, with various rates. The detection of non-criteria APL and thus the diagnosis of seronegative APS could discuss the therapeutic management similar to seropositive APS, but well-designed controlled studies are necessary.

International audience; Objectives: We aimed at describing placental abruption in our county and at evaluating factors associated with poor fetal outcome.Study design: In this case-control study, women with placental abruption were identified from two databases of Brest University Hospital between January 2013 and December 2018.Main outcome measures: Placental histological findings, course of pregnancies, maternal and fetal characteristics were described and compared between cases (placental abruption with stillbirth or neonatal death) and controls.Results: We identified 135 placental abruption, of whom 24.4% were complicated with stillbirth and 6.5% with neonatal death. Forty percent of women were smokers and 14.1% had a history of vasculoplacental disorder. Pregnancies were complicated with 42.2% of pre-eclampsia and 43% of intrauterine growth restriction. Cases were associated with more autoimmune diseases in mother (20.0% versus 3.2%, P = 0.003), more aspirin or heparin use during pregnancy (20.0% versus 6.3%, P = 0.03), less pre-eclampsia (25.0% versus 49.5%, P = 0.01) and more deliveries ≤ 34 weeks of gestation (80.0% versus 43.2%, P = 0.0001) than controls. Placentas from cases showed more placental indentation ≥ 30% (42.5% versus 5.3%, P < 0.0001) and less histological chronic inflammation, especially less chronic chorioamniotitis (2.5% versus 24.2%, P = 0.002) than controls. In multivariate analysis, factors negatively associated with poor fetal outcome were placental histological chronic inflammation (P = 0.01) and macroscopic infarcts (P = 0.01).Conclusions: Poor fetal outcome is negatively associated with certain placental histological chronic lesions, but not with pre-eclampsia, what suggests various pathophysiological processes among placental abruption.

International audience

International audience; Scleromyxedema is a rare skin and systemic mucinosis that is usually associated with monoclonal gammopathy (MG). In this French, multicenter, retrospective study of 33 patients, we investigated the clinical and therapeutic features of MG-associated scleromyxedema. Skin molecular signatures were analyzed using a transcriptomic approach. Skin symptoms included papular eruptions (100%), sclerodermoid features (91%), and leonine facies (39%). MG involved an IgG isotype in all patients, with a predominant λ light chain (73%). Associated hematologic malignancies were diagnosed in 4/33 patients (12%) (smoldering myeloma, n=2; chronic lymphoid leukemia, n=1; and refractory cytopenia with multilineage dysplasia n=1). Carpal tunnel syndrome (33%), arthralgia (25%) and dermato-neuro syndrome (DNS) (18%) were the most common systemic complications. One patient with mucinous cardiopathy died of acute heart failure. Intravenous immunoglobulin (HDIVig) treatment alone or in combination with steroids appeared to be quite effective in nonsevere cases (clinical complete response achieved in 13/31 patients). Plasma cell-directed therapies using lenalidomide and/or bortezomib with dexamethasone and HDIVig led to a significant improvement in severe cases (HDIVig-refractory or cases with central nervous system or cardiac involvement). The emergency treatment of DNS with combined plasmapheresis, HDIVig, and high-dose corticosteroids induced the complete remission of neurological symptoms in 4/5 patients. Quantitative reverse transcriptase-PCR (RT-PCR) analysis of 6 scleromyxedema skin samples showed significantly higher profibrotic pathway levels (transforming growth factor β (TGFβ) and collagen-1) than in healthy skin. Prospective studies targeting plasma cell clones and/or fibrotic pathways are warranted for long-term scleromyxedema management.

International audience; Patients with type 1 Gaucher disease (GD1) present thrombocytopenia, anemia, organomegaly, and bone complications. Most experts consider that the less aggressive forms do not require specific treatment. However, little is known about the disease course of these forms. The objective of this cross-sectional retrospective study was to compare the clinical, radiological, and laboratory characteristics of patients with less severe GD1 at diagnosis and at the last evaluation to identify features that might lead to potential complications. Non-splenectomized and never-treated patients (19 women and 17 men) were identified in the French Gaucher Disease Registry (FGDR). Their median age was 36.6 years (2.4–75.1), and their median follow-up was 7.8 years (0.4–32.4). Moreover, 38.7% were heterozygous for the GBA1 N370S variant, and 22.6% for the GBA1 L444P variant. From diagnosis to the last evaluation, GD1 did not worsen in 75% of these patients. Some parameters improved (fatigue and hemoglobin concentration), whereas platelet count and chitotriosidase level remained stable. In one patient (2.7%), Lewy body dementia was diagnosed at 46 years of age. Bone lesion onset was late and usually a single event in most patients. This analysis highlights the genotypic heterogeneity of this subgroup, in which disease could remain stable and even improve spontaneously. It also draws attention to the possible risk of Lewy body disease and late onset of bone complications, even if isolated, to be confirmed in larger series and with longer follow-up.

Recurrent miscarriage (RM) and vasculoplacental disorders, such as preeclampsia (PE), affect women of childbearing age worldwide. Vascular endothelial dysfunction and immunological impairment are associated with both RM and PE. To date, there is no effective or optimal therapeutic approach for these conditions. Notably, aspirin use is only partially effective in the prevention of PE. Hydroxychloroquine (HCQ) has demonstrated beneficial effects on disease flares, pregnancy outcomes and cardiovascular impairment in systemic erythaematosus lupus (SLE) through its immunomodulatory, vasculoprotective and antithrombotic properties. Here, in the context of the underlying physiological dysregulation associated with PE and RM, the beneficial properties and potential therapeutic efficacy of HCQ are reviewed in anticipation of the results of current and future trials. Two related trials addressing RM in the absence of maternal autoimmune disease are ongoing. Other trials addressing pregnancy outcomes in the presence of maternal autoimmune disease are forthcoming. In this review, we hypothesise that the immunological and endothelial effects of HCQ may be beneficial in the context of PE and RM, regardless of the maternal autoimmune status.

Background Venous thromboembolism (VTE) can be the first manifestation of cancer; however, the current incidence of malignancy in unselected patients with first unprovoked VTE needs to be confirmed. Material and methods Between March 1st, 2013 and February 28th, 2015 we included and followed-up all patients living in the Brest district, France, who were seen in hospitals or the community for a first symptomatic unprovoked VTE event. The primary study outcome was the one-year incidence of cancer. Results 526 patients, mean age 66.6 ± 18.1 years, 246 (46.8%) men, were included in the study. In the year following VTE, 26 patients were diagnosed with cancer, corresponding to a one-year cumulative incidence of cancer of 5.06% (95% CI 3.47–7.35). Age ≥60, smoking and pulmonary embolism were significantly associated with cancer diagnosis in multivariate analysis. Fifty percent of cancers were patent at the time of VTE diagnosis, mostly detected on CTPA (Computed Tomographic Pulmonary Angiography) performed for pulmonary embolism assessment. After excluding patients with patent cancer at VTE diagnosis, the one-year incidence of cancer was 2.65% (95% CI: 1.55–4.52); in multivariate analysis, only current smoking was independently associated with a significant 5.4-fold increased risk for cancer diagnosis (HR 5.40; 95% CI 1.31–22.27). No cancer was diagnosed in patients aged 50 years or younger. Conclusion The one-year incidence of cancer after a first unprovoked VTE was 5.06%. Half of the cancers were diagnosed during the diagnosis procedure for pulmonary embolism using CTPA.

Introduction Les angioedemes bradykiniques (AEB) sous antagonistes des recepteurs de l’angiotensine II (ARAII) sont rares et peuvent mimer les angioedemes histaminiques (AEHi) qui sont plus frequents ce qui mene alors a tort a l’arret du medicament. L’objectif de cette etude etait alors d’evaluer les caracteristiques cliniques, therapeutiques et d’evolution d’une cohorte de patients suspects d’AEB secondaires aux ARAII. Materiel et methodes Cette etude multicentrique nationale, observationnelle et retrospective a inclus les cas consecutifs d’angioedemes acquis apparus chez des patients sous ARAII et suivi dans un centre de Reference associe sur les angioedemes a kinines (CReAk). Discussion Cinquante-cinq patients adresses dans les services specialises pour AE sous ARAII ont ete inclus. Le diagnostic final etait un AEB dans 30 (55 %) cas et un AEHi dans 25 (45 %) cas a la fin du suivi. Les caracteristiques cliniques des AE n’etaient pas significativement differentes dans les deux groupes. Le concentre de C1 inhibiteur etait significativement plus utilise dans le groupe AEB que AEHi, soit respectivement 30 % et 4% (p

Introduction La sclerodermie systemique (SSc) est une maladie auto-immune polyfactorielle. Parmi ses facteurs de risque, on peut noter une predisposition genetique et des facteurs environnementaux. Les cas de SSc lies a l’exposition a la silice microcristalline peuvent etre reconnus en Maladie Professionnelle (MP) au titre du tableau 25 A-3 du Regime General et 22 A-3 du Regime Agricole. Les expositions aux solvants peuvent egalement amener a une reconnaissance de MP hors-tableaux. D’autres expositions ont ete mises en causes : produits chimiques contenus dans les vernis, peintures, fumees de soudure, pesticides, teintures pour cheveux et metaux lourds. Patients et methodes Les patients en HDJ de Medecine Interne pour bilan de SSc sont vus pour un interrogatoire professionnel et environnemental par un medecin du Centre Regional de Pathologie Professionnelle et Environnementale (CRPPE) de Brest depuis le 06/12/2018. Les objectifs sont : – d’identifier des expositions professionnelles potentiellement en lien avec la SSc et, le cas echeant, d’initier des demarches en vue d’une reconnaissance en MP ; – d’identifier des expositions environnementales potentiellement en lien avec la SSc ; – de realiser des propositions d’amenagement de poste afin de favoriser le maintien dans l’emploi ; – eventuellement, de proposer une demande de Reconnaissance de Qualite de Travailleur Handicape (RQTH). Resultats 17 patients ont ete vus depuis la mise en place de cette consultation. Des expositions professionnelles imputables a la survenue de la SSc ont ete mises en evidence chez 8 d’entre eux. Ces expositions etaient fortement imputables chez 5 patients : silice microcristalline et solvants. L’imputabilite etait incertaine chez les 3 autres : pesticides et fumees de soudure. Une demande de reconnaissance de MP a ete conseillee pour 3 patients. Des expositions aux vibrations du systeme main-bras ont ete retrouvees chez 4 patients. Des expositions environnementales ont ete retrouvees chez 4 patients : silice microcristalline dans le cadre de taille de pierre de loisir, pesticides, solvants, resines, teintures pour cheveux. Cette consultation a abouti a des propositions d’amenagement de poste pour 3 patients et a une demande de RQTH pour 3 patients. Conclusion Les perspectives suite a la mise en place de cette consultation sont : – la description des expositions professionnelles et environnementales des patients brestois atteints de SSc et des profils cliniques et auto-immuns associes ; – la redaction de supports pour favoriser leur maintien dans l’emploi ; – l’extension de ce type de consultation a d’autres types de maladies auto-immunes (ex : polyarthrite rhumatoide, lupus systemique).

Observation: A patient with a prosthetic superior vena cava graft had complications of thrombosis and infection. The blood cultures were positive for Peptostreptococcus micros and Prevotella denticola. The latter are known to exist in oral cavities. Clinical and radiological examinations of the oral cavity revealed the presence of oral infectious foci. Commentary: Superior vena cava prosthetic graft infections of oral origin have not previously been described in the literature. The highlighting of oral infectious foci, their eradication, and the follow-up of patients who had been subject to a vascular graft procedures are essential elements in preventing any associated lesions.

Background: Polyarteritis nodosa (PAN) is a rare systemic necrotizing vasculitis of medium- and small-sized arteries, not associated with antineutrophil cytoplasmic antibodies (ANCA). Conventional treatments include glucocorticoids (GCs) for non-severe disease and a combination of GCs and immunosuppressive agents for severe disease. Nevertheless, some patients have refractory and/or relapsing disease. Objectives: We examined the use of off-label biological therapy for relapsing/refractory PAN. Methods: This retrospective European collaborative study included patients with PAN meeting ACR criteria and/or Chapel Hill Consensus Conference 2012 definitions. Treatment efficacy and safety are recorded. Remission was defined as the absence of vasculitis manifestations (BVAS = 0) with a prednisone dose ≤5 mg/day. Partial response was defined as a BVAS = 0 with a prednisone dose between 6 and 10 mg/day. Results: Fifty-one patients (24 men, 27 women; median age 51 years) were included. Eighteen (35%) patients received TNF-alpha blockers, 16 (31%) received rituximab (RTX), 9 (18%) tocilizumab (TCZ), and 8 (16%) other biologics (including alemtuzumab in 3, anakinra in 2, interferon-alpha in 2 and abatacept in one). Previous treatments were: GCs in all cases, including methylprednisolone infusions (72%) and oral GCs (92%), cyclophosphamide (61%), azathioprine (53%), methotrexate (45%) and mycophenolate mofetil (47%). At inclusion, median BVAS was 5 (range 0-18), including 5 (2-12) in the TNF-alpha blockers group, 5 (2-12) in the RTX group and 4 (0-6) in the TCZ group. After median follow-up of 34.4 months (IQR 21.5-59.5), remissions, partial responses and treatment failure, respectively, were noted in 41%, 6% and 53% for TNF-alpha blockers recipients, 25%, 12% and 63% for RTX recipients, and 57%, 0% and 43% for TCZ recipients. No remission was noted in patients treated with anakinra, alemtuzumab and abatacept. Median BVAS dropped to 3 at 6 months, 0 at 12 months and 0 at last follow-up in the TNF-alpha blockers group, to 3.5, 0 and 2 in the RTX group, respectively, and 0, 0 and 0 in the TCZ group. A GC-sparing effect seemed more important with TNF-alpha blockers and TCZ. Median GCs dose decreased from the baseline 15 mg/day to 10 at 6 months, 5 at 12 months and 5 at last follow-up in the TNF-alpha blockers group, from 15 mg/day to 10 at 6 months, 5 at 12 months and 10 at last follow-up in the RTX group, and from 15 mg/day to 7 at 6 months, 5 at 12 months and 5 at last follow-up in the TCZ group. Four (22%) patients stopped TNF-alpha blockers because of allergic reaction in one and refractory disease in 3. Six (38%) stopped RTX because of refractory disease. Finally, 4 (44%) stopped TCZ because of adverse events in 2 (testicular abscess and worsening renal failure) and refractory disease in 2. Conclusion: The results of this study suggest that TNF-alpha blockers and TCZ may achieve higher rates of remission and GC-sparing in relapsing and/or refractory PAN than other biologics. Our data warrant further study to confirm or not these findings. Disclosure of Interests: Alice Canzian: None declared, Omer Karadag: None declared, Anne Contis: None declared, Francois Maurier: None declared, Silvia Sartorelli: None declared, Laure Denis: None declared, Sebastien Sanges: None declared, Claire De Moreuil: None declared, Cecile-Audrey Durel: None declared, Stephane Durupt: None declared, Marie Jachiet: None declared, Diane Rouzaud: None declared, Carlo Salvarani: None declared, Franco Schiavon: None declared, Lorenzo Dagna Consultant for: Prof Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Sanofi-Genzyme, and SOBI., Fabrice Bonnet: None declared, David Jayne Grant/research support from: David Jayne has received research grants from Chemocentryx, GSK, Roche/Genentech and Sanofi-Genzyme. He has received consultancy fees from Astra-Zeneca, Boehringer-Ingelheim, Chemocentryx, Chugai, GSK, Infla-RX, Insmed and Takeda, Loic Guillevin: None declared, Benjamin Terrier: None declared