Search

Introduction Antiphospholipid syndrome (APS) is associated with greater atherothrombotic risk and endothelial dysfunction, suggesting that endothelial glycocalyx is impaired in this disease. Objectives The aim was to investigate the endothelial glycocalyx and the relationship between glycocalyx markers, endothelial dysfunction parameters and atherosclerotic markers in APS. Methods A total of 15 primary arterial APS patients and healthy controls were included in the study. Glycocalyx was assessed in both groups by sublingual sidestream dark field imaging and syndecan-1 plasma level. Endothelial function was evaluated by brachial artery flow-mediated dilatation (FMD) and early atherosclerosis by carotid intima media thickness (IMT). Thrombotic profile was also performed by measuring the plasma level of the tissue factor (TF). Results APS patients had significantly increased syndecan-1 plasma level 38.6 ± 5.0 pg/ml vs. 19.1 ± 3.5 pg/ml; p Conclusions This preliminary study supports, for the first time, that in APS patients endothelial glycocalyx is impaired, which could lead to thrombosis, endothelial dysfunction and early atherosclerosis.

Resume Introduction Dans notre etablissement, le service d’accueil et des urgences (SU) adulte, accueille chaque annee plus de 100,000 patients. Afin de fluidifier le parcours d’hospitalisation non programmee a partir des urgences, ont ete mises en place fin 2017 une unite d’hospitalisation d’attente de 20 lits et une gestion centralisee des lits (gestionnaire de lits, logiciel de gestion des lits, lits dedies). Le bilan d’une premiere annee de fonctionnement fait l’objet de ce travail. Patients et methodes Le nombre de passages au SU adulte continue a progresser (+ 3,5 % entre 2017 et 2018), avec un taux d’hospitalisation directe a partir du SU vers les secteurs d’hospitalisation conventionnelle d’environ 20 %, deux tiers en medecine et un tiers en chirurgie. En 2018, 3450 patients dont 54,6 % de plus de 75 ans ont ete admis dans cette unite d’attente, avec une duree moyenne de sejour de 1,3 ± 1,4 jours, 35,4 % restant moins de 24 heures, 29,3 % sortant a moins de 48 heures et 34,8 % plus de 48 heures, dont 5,2 % restes plus de 4 jours. Cent trente-deux patients (3,8 %) sont decedes, 805 (23,3 %) sont retournes a domicile, 220 (6,4 %) ont ete transferes dans un autre etablissement et 2287 (66,3 %) ont ete secondairement hospitalises dans un autre service de l’hopital, plus de 9 fois sur 10 dans un service de medecine (medecine interne 30 %, geriatrie 27,9 %, pneumologie 12,2 %). La filiere d’hospitalisation non programmee a partir du SU mise en place, permet une hospitalisation quotidienne en lits de court sejour de pres de 50 patients, avec le week-end une diminution nette du nombre de lits disponibles pour cette filiere. Les principales pathologies sont les infections respiratoires (14,2 %), les cardiopathies (9,7 %), les troubles metaboliques (3,9 %) et les infections de l’appareil urinaire (3,6 %). Conclusion Cette unite d’hospitalisation d’attente associee a une gestion centralisee donne satisfaction dans l’amelioration de la filiere du non programmee notamment pour la filiere medicale venant du service des urgences. La problematique du manque de lits d’aval le week-end et la gestion des periodes epidemiques restent un defi a relever.

Introduction: Immune thrombotic thrombocytopenic purpura (iTTP) is an immune-mediated deficiency in von Willebrand factor-cleaving protease ADAMTS13 allowing unrestrained adhesion of von Willebrand factor multimers to platelets and microthrombosis. Caplacizumab, an anti-von Willebrand factor humanized, bivalent single-domain nanobody preventing its binding to the platelet has been investigated and approved for use in the treatment of iTTP. Areas covered: The purpose of this article is to summarize the available clinical data on the efficacy and safety of caplacizumab in iTTP and to provide our opinion on the place of caplacizumab in current treatment regimens. Expert opinion: Caplacizumab is a new drug with a complementary mechanism of action with respect to the standard available therapeutics. It demonstrated efficacy in clinical trials through a faster platelet count normalization and protection of patients from exacerbations and refractoriness. Caplacizumab is well tolerated with minor bleeds as the most important side effect. The efficacy of caplacizumab now needs to be assessed in real-life but definitely, this drug opens hope for a significant improvement in iTTP prognosis at the very early, critical step of the disease.

Carpal tunnel syndrome is a common peripheral neuropathy, usually idiopathic or post-traumatic due to the compression of the median nerve. Numbness and paresthesias in the median nerve distribution are the most common symptoms associated with this condition. Persistent median artery is a rare anatomic variation, thrombosis of this additional artery can be responsible for an acute carpal tunnel syndrome, and patients frequently complain about coldness and acute hand swelling. These unusual features must lead clinicians to think of a vascular cause. The diagnosis can be easily confirmed by using ultrasound doppler, but CT-scan and MRI are sometimes helpful. We describe 2 cases of acute carpal tunnel syndrome due to thrombosed persistent median artery, including a case of thromboangiitis obliterans. These thrombosis might also be due to traumatic causes. No guidelines are currently available to help physicians for the management of carpal tunnel syndrome from thrombosed persistent median artery. Antiplatelet therapy, statin, anticoagulant might be helpful, and surgery has sometimes be reported as effective.

Background Gemcitabine is a broadly prescribed chemotherapy, the use of which can be limited by renal adverse events, including thrombotic microangiopathy (TMA). Methods This study evaluated the efficacy of eculizumab, a monoclonal antibody targeting the terminal complement pathway, in patients with gemcitabine-induced TMA (G-TMA). We conducted an observational, retrospective, multicenter study in 5 French centres, between 2011 and 2016. Results Twelve patients with a G-TMA treated by eculizumab were included. The main characteristics were acute renal failure (100%), including stage 3 acute kidney injury (AKI, 58%) and renal replacement therapy (17%), hypertension (92%) and diffuse oedema (83%). Eculizumab was started after a median of 15 days (range 4–44) following TMA diagnosis. A median of 4 injections of eculizumab was performed (range 2–22). Complete hematological remission was achieved in 10 patients (83%) and blood transfusion significantly decreased after only one injection of eculizumab (median of 3 packed red blood cells (range 0–10) before treatment vs 0 (range 0–1) after one injection, P 2 respectively in the eculizumab group and in the control group. Conclusions These results suggest that eculizumab is efficient on haemolysis and reduces transfusion requirement in G-TMA. Moreover, eculizumab may improve renal function recovery.

Objective To assess the superiority of adipose tissue-derived stromal vascular fraction (AD-SVF) injection into the fingers vs placebo in reducing hand disability in systemic sclerosis (SSc) patients. Methods We performed a double-blind, multicentre, phase II trial from October 2015 to January 2018 in France. SSc patients with a Cochin Hand Function Scale (CHFS) ≥20/90 were randomized 1:1 to receive injection of AD-SVF or placebo. AD-SVF was obtained using the automated processing Celution 800/CRS system. The placebo was lactated Ringer’s solution. The primary efficacy end point was the change of the CHFS score from baseline to 3 months. Secondary efficacy endpoints included the CHFS score at 6 months, hand function, vasculopathy, hand pain, skin fibrosis, sensitivity of the finger pulps, Scleroderma Health Assessment Questionnaire, patients and physician satisfaction, and safety. Results Forty patients were randomized. The AD-SVF and placebo groups were comparable for age, sex ratio, disease duration, skin fibrosis of the hands and main cause of hand disability. After 3 months’ follow-up, hand function significantly improved in both groups with no between-group difference of CHFS (mean change of −9.2 [12.2] in the AD-SVF group vs −7.6 [13.2] in the placebo group). At 6 months, hand function improved in both groups. Conclusion This study showed an improvement of hand function in both groups over time, with no superiority of the AD-SVF. Considering the limits of this trial, studies on a larger population of patients with homogeneous phenotype and hand handicap should be encouraged to accurately assess the benefit of AD-SVF therapy. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT02558543. Registered on September 24, 2015.

Antiphospholipid syndrome (APS) is associated with thrombotic events (tAPS) and/or obstetrical morbidity (oAPS), with persisting antiphospholipid antibodies (aPL). Despite an update of aPL in 2006, several patients had typical clinical events without the classical biological criteria. The aim of our study was to evaluate the hypercoagulability state with both thrombin generation (TG) profiles and activated protein C resistance (aPCR) in different types of APS. Methods: We retrospectively included 41 patients with Sydney criteria classification (tAPS, oAPS) and no clinical manifestation of APS with persistent aPL (biological APS). A thrombin generation assay was performed with a Fluoroskan Ascent fluorometer in platelet-poor plasma (PPP). Activated protein C resistance was measured as a ratio: ETP+aPC/ETP-aPC × 100. Results: Thrombotic APS and oAPS had an increase of global thrombin generation (ETPcontrol = 808 nM.min (756–853) vs. 1265 nM.min (956–1741) and 1863 nM.min (1434–2080), respectively) (Peakcontrol = 78 nM (74–86) vs. 153 nM (109–215) and 254 nM.min (232–289), respectively). Biological APS had only a lag time increase (Tcontrol = 4.89 ± 1.65 min vs. 13.6 ± 3.9 min). An increased aPCR was observed in tAPS (52.7 ± 16.4%), oAPS (64.1 ± 14.6%) as compared to the control group (27.2 ± 13.8%). Conclusion: Our data suggest an increase of thrombin generation in thrombotic and obstetrical APS and no hypercoagulable states in patients with biological APS. The study of a prospective and a larger controlled cohort could determine the TGA useful for APS monitoring and could confirm an aPCR evaluation in PPP.

International audience; Objectives: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE.Methods: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders.Results: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83).Conclusions: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.

Summary Background Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases. Methods In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609. Findings Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66–6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46–0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55–3·19, p=0·53). Interpretation Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases. Funding None.

The anti–von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on postmarketing surveillance. We treated 90 iTTP patients with a compassionate frontline triplet regimen associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE, and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs 12.2% in historical patients (P = .01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs 44%, P < .01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36; P < .01), with fewer TPE sessions and lower plasma volumes (P < .01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 vs 22 days; P < .01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant nonmajor hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the 3 processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care.

Objective Adult-onset Still's disease (AOSD) is a rare inflammatory disease that may be life-threatening if complicated by cardiac problems. We performed a retrospective multicenter study to describe the manifestations, treatments and outcomes of cardiac involvement in AOSD. Methods We reviewed the medical databases of eight centers. All AOSD patients identified as fulfilling Yamagushi's or Fautrel's criteria were included in the study. Cardiac involvement, clinical manifestations, laboratory features, the course of the disease and treatments were evaluated. Results We included 96 AOSD patients in this study: 28 (29%) had documented cardiac involvement (AOSD + C group) and 68 (71%) had no cardiac involvement (control group). Cardiac complications were observed at diagnosis in 89% of cases. It were pericarditis (n = 17), tamponade (n = 5), myocarditis (n = 5) and non-infectious endocarditis (n = 1). Levels of leukocytes, neutrophils and C-reactive protein were significantly higher (p = 0.02, p = 0.02 and p = 0.002, respectively in the AOSD + C group than in the control group. Admission to intensive care, and the use of biotherapy were more frequent during follow-up in the AOSD + C group than the control group (p = 0.0001 and p = 0.03 respectively). Cardiac involvement was associated with refractory form in multivariate analyzed (p = 0.01). Corticosteroids were effective with or without methotrexate in 71% of patients but not in severe involvement as myocarditis or tamponade. Conclusion Cardiac complications are frequent, inaugural, can be life-threatening and predictive of a refractory course in patients with AOSD. Systematic cardiac screening should be proposed at diagnosis and biotherapy early use should be considered especially in myocarditis.

Introduction Our objective was to evaluate characteristics, treatment and outcome of vasculitis associated with myelodysplastic syndrome (MDS) and chronic myelomonicytic leukemia (CMML) Patients and Methods Retrospective descriptive analysis of MDS/CMML-related vasculitis and comparison with MDS/CMML patients without dysimmune features. Results Seventy patients with vasculitis and MDS/CMML were included, with median age of 71.5 [21–90] years and male/female ratio of 2.3. Vasculitis was diagnosed prior to MDS/CMML in 31 patients (44%), and after in 20 patients. In comparison with MDS/CMML without autoimmune/inflammatory features, vasculitis with MDS/MPN showed no difference in MDS/CMML subtypes distribution nor International Prognostic Scoring System and CMML-specific prognostic (IPSS/CPSS) scores. Vasculitis subtypes included Giant cell arteritis in 24 patients (34%), Behcet's-like syndrome in 11 patients (20%) and polyarteritis nodosa in 6 patients (9%). Glucocorticoids (GCs) were used as first-line therapy for MDS/CMML vasculitis in 64/70 patients (91%) and 41 (59%) received combined immunosuppressive therapies during the follow-up. After a median follow-up of 33.2 months [1–162], 31 patients (44%) achieved sustained remission. At least one relapse occurred in 43 patients (61%). Relapse rates were higher in patients treated with conventional Disease Modifying Anti-Rheumatic Drug (DMARDs) (odds ratio 4.86 [95% CI 1.38 - 17.10]), but did not differ for biologics (odds ratio 0.59 [95% CI 0.11–3.20]) and azacytidine (odds ratio 1.44 [95% CI 0.21–9.76]) than under glucocorticoids. Overall survival in MDS/CMML vasculitis was not significantly different from MDS/CMML patients without autoimmune/inflammatory features (p = 0.5), but acute leukemia progression rates were decreased (log rank Conclusion This study shows no correlation of vasculitis diagnoses with subtypes and severity of MDS/CMML, and no significant impact of vasculitis on overall survival. Whereas conventional DMARDs seem to be less effective, biologics or azacytidine therapy could be considered for even low-risk MDS/CMML vasculitis.

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.

Following an acute thrombotic thrombocytopenic purpura (TTP) episode, patients are at risk for relapse, and a careful long-term follow-up is needed. Adherence to the follow-up by patients implies a good understanding of the disease. However, TTP literacy in patients is currently unknown. To explore the TTP literacy in patients and identify factors associated with poor disease understanding, a questionnaire was developed focusing on patient's characteristics, knowledge about TTP and patients’ actions in an emergency. The questionnaire was presented to 120 TTP patients in remission from the French National Registry for Thrombotic Microangiopathies. TTP literacy was low in 24%, intermediate in 43% and high in 33% of the patients. Low TTP literacy was associated with older age and low education level. Among the knowledge gaps identified, few patients knew that plasma exchange in acute phase is mandatory and has to be done daily (39%), 47% of participants did not consider themselves at risk for relapse, and 30% of women did not know that pregnancy exposes them to a greater risk of relapse. Importantly, few patients responded about life-saving actions in an emergency. Hence, the design of educational material should pay special attention to the age and education level of the target population focusing on the events leading to TTP, the importance of the emergency treatment, controllable predisposing factors for TTP development and patient attitude in an emergency. ispartof: HemaSphere vol:4 issue:4 ispartof: location:United States status: published

Objective To report the long term mortality in Takayasu arteritis (TA) and to identify prognosis factors. Methods We analyzed the causes of death and the factors associated with mortality in a cohort of 318 patients [median age at diagnosis was 36 [25–47] years and 276 (86%) patients were women] fulfilling American College of Rheumatology and/or Ishikawa criteria of TA. A prognostic score for death and vascular complications was elaborated based on a multivariate model. Results Among 318 TA patients, 16 (5%) died after a median [IQR] follow-up of 6.1 [2.8–13.0] years. The median age at death was 38 [25–47] years with 88% of women. Main causes of death included mesenteric ischemia (n = 4, 25%) and aortic aneurysm rupture (n = 4, 25%). The mortality rate at 5 and 10 years was of 1.9% and 3.9%, respectively. Caucasians (p = 0.049) and smokers (p = 0.002) TA patients were more likely to die. There was an increased mortality in TA (SMR with 95% confidence interval, 2.73 [1.69–4.22]) as compared to age and sex matched healthy controls. We defined high risk patients for death and vascular complications according to the presence of two of the following factors (i.e a progressive clinical course, thoracic aorta involvement and/or retinopathy). In the high risk TA group, the 5-year incidence of death and vascular complication was 48.5% compared to 21.6% (p = 0.001) in those with low risk. Conclusion The overall mortality in our Takayasu cohort was 5% after a median follow-up of 6.1 years. We identified specific characteristics that distinguish TA patients at highest risk for death and vascular complications.

International audience; Objective: To compare the efficacy and safety of Disease-modifying antirheumatic drugs (DMARDs) and anti-TNF-α agents in patients with non-infectious non-anterior uveitis.Methods: Single center retrospective study including adult patients with non-infectious intermediate, posterior or pan-uveitis. Outcomes were compared between patients treated with DMARDs or anti-TNF-α agents. The primary outcome was treatment failure or occurrence of serious adverse events. Treatment failure was determined by ophthalmologic criteria.Results: Seventy-three patients were included, mostly female (52%). Among them, 39 were treated with DMARDs and 34 with anti-TNF-α agents. The main uveitis causes were idiopathic (30%), birdshot chorio-retinopathy (25%), sarcoidosis (16%) and Behçet's disease (14%). The primary outcome was observed in 56% of patients treated with anti-TNF-α agents versus 59% of patients treated with DMARDs (p = 0.82). Median time to observe the primary outcome was 16 months (anti-TNF-α group) versus 21 months (p = 0.52). There was no significant difference between the two groups in terms of treatment failure, corticosteroid sparing effect, visual acuity improvement or adverse events. Earlier control of ocular inflammation was achieved with anti-TNF-α agents than with DMARDs (p = 0.006). In relapsing patients, anti-TNF-α agents allowed better corticosteroid sparing (p = 0.06).Conclusion: DMARDs could still be used as first-line therapy for non-infectious non-anterior uveitis after corticosteroid therapy. However, anti-TNF-α agents could be proposed as an alternative in cases of severe inflammation or initial high level of steroid dependency.

Myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MDS/MPN) can be associated with giant cell arteritis (GCA). In this nationwide study by the "French Network of dysimmune disorders associated with hemopathies" (MINHEMON) the objective was to evaluate characteristics, treatment and outcome of GCA MDS-MDS/MPN.Retrospective analysis of patients that presented a MDS or MDS/MPN associated with GCA. Treatment efficiency, relapse-free and overall survival of GCA MDS-MDS/MPN were compared to GCA alone.Twenty-one patients with GCA MDS-MDS/MPN were included with median age 76 [42-92], M/F ratio 2.5, 8 MDS with multilineage dysplasia (38%), 4 chronic myelomonocytic leukemia (19%), at low or intermediate risk according to IPPS and IPSS-R. The prevalence of headaches, jaw claudication and anterior ischemic optic neuropathy was significantly lower in patients with GCA MDS-MDS/MPN compared to idiopathic GCA (14.3%, 0% and 0% versus 30%, 25%, and 25%, respectively; p .05). Other clinical and histology findings were similar. All GCA patients received steroid therapy as first-line treatment. Complete or partial response was observed in 14 GCA MDS-MDS/MPN patients (66.7%), of whom 6 (28.6%) received combined immunosuppressive therapies (versus 10% of idiopathic GCA; p = .07). Relapse incidence was similar in the two groups. Steroid dependence was more frequent among GCA MDS-MDS/MPN patients (12 (57%) versus 18 (22.5%); p .05). Relapse-free and steroid-free survivals were significantly decreased in GCA MDS-MDS/MPN patients (log rank 0.002 and 0.049 respectively), but not overall survival.Characteristics of GCA MDS-MDS/MPN seem different than idiopathic GCA, with a distinct clinical phenotype and poorer outcome with a higher risk of steroid dependence and relapse.

Low-molecular-weight heparins (LMWH) are to date the standard for 3-to-6-month treatment of cancer-associated thrombosis (CAT) as they are consistently recommended by international clinical practice guidelines. Despite the high risk of VTE recurrence and death in patients with cancer and the favorable benefit-risk profile of LMWH demonstrated in randomized-control studies, the implementation of treatment guidelines remains insufficient in the clinical practice. A systematic review of observational studies, registries and surveys reveals that approximately only 50% of patients with CAT are treated according to practice guidelines while both physicians and patients may be accountable for this situation. Based on the few available published data, we have observed differences between guidelines and clinical practice and we have identified factors influencing patient's management with the perspective to improve adherence to clinical practice guidelines in patients with CAT. Improving the implementation of clinical practice guidelines requires a better knowledge of physician and patient-related factors that influence therapeutic decisions. A global approach of patients with CAT is warranted to optimize the therapeutic management of cancer-associated VTE.

Small fiber neuropathy (SFN) is still unknown. Characterised by neuropathic pain, it typically begins by burning feet, but could take many other expression. SFN affects the thinly myelinated Aδ and unmyelinated C-fibers, by an inherited or acquired mechanism, which could lead to paresthesia, thermoalgic disorder or autonomic dysfunction. Recent studies suggest the preponderant role of ion channels such as Nav1.7. Furthermore, erythromelalgia or burning mouth syndrome are now recognized as real SFN. Various aetiologies of SFN are described. It could be isolated or associated with diabetes, impaired glucose metabolism, vitamin deficiency, alcohol, auto-immune disease, sarcoidosis etc. Several mutations have recently been identified, like Nav1.7 channel leading to channelopathies. Diagnostic management is based primarily on clinical examination and demonstration of small fiber dysfunction. Laser evoked potentials, Sudoscan®, cutaneous biopsy are the main test, but had a difficult access. Treatment is based on multidisciplinary management, combining symptomatic treatment, psychological management and treatment of an associated etiology.

Introduction La lymphohistiocytose hemophagocytaire (LHH) est une maladie rare mais grave dont le pronostic est souvent fatal. Aucune prise en charge codifiee n’existe de maniere generale et selon le sous-type de LHH. L’objectif de l’etude etait de comparer les caracteristiques cliniques, biologiques et le profil evolutif des patients atteint de LHH en globalite et selon leur etiologie. Materiels et methodes Nous avons realise une etude observationnelle, retrospective, au CHU de Rouen entre 2010 et 2020 sur tous les patients dont le diagnostic de LHH etait pose formellement par un clinicien et/ou par un HScore ≥ 70 %. Resultats Au total 100 patients ont ete inclus. Ils avaient en moyenne 53,6 ans et un sex-ratio de 1,56 hommes pour 1 femme. Les etiologies etaient pour 45 % infectieuses, 37 % hematologiques, 9 % maladies auto-immunes/inflammatoires, 6 % cancer et 3 % autres. La presence d’une organomegalie, de cytopenies profondes, une elevation importante de la ferritine, des LDH et de la bilirubine totale semble etre significativement associees aux LHH hematologiques. Un taux de ferritine extremement eleve (> 15 000 ng/mL) semble significativement associe a la presence d’une hemopathie ou d’une MAI. Une elevation des PAL, quant a elle, orienterait plus vers une cause oncologique. La realisation d’une imagerie a permis d’orienter le diagnostic de la cause de LHH dans 47 % des cas notamment via la realisation d’un TDM TAP. Le myelogramme n’a ete identifie comme indispensable au diagnostic de LHH dans seulement 8 % des cas et sa realisation systematique semble donc discutable. Les facteurs pronostiques de transfert en reanimation etaient : un taux de GB Les facteurs pronostiques de deces identifies etaient : l’âge > 60 ans (HRa = 2,14 [1,10–4,17]), l’Hb Une analyse de survie comparative des patients traites ou non par etoposide n’a pas montre d’amelioration de la survie sous etoposide. Le deces etait plus important dans le sous-groupe infectieux traite par etoposide (p = 0,035). La mortalite sous etoposide semblait plus importante chez les patients ayant ≥ 2 defaillances d’organe vs 0 ou 1 defaillance toute cause confondue. Une introduction precoce avant l’apparition de multiples defaillances semble donc preferable. Notre etude n’a pas permis d’identifier d’amelioration du pronostic sous traitement specifique (corticoides et/ou immunoglobulines IV et/ou etoposide) non plus. Conclusion La LHH est peu connue et peu etudiee. Notre etude a permis de confirmer des facteurs pronostiques de deces. Nous n’avons pas demontre d’amelioration du pronostic sous etoposide ou traitement specifique. On constate une grande variabilite du profil evolutif selon l’etiologie de la LHH. Une etude de plus grande ampleur du profil evolutif selon les differentes etiologies de LHH et ajustee sur la gravite des patients serait pertinente afin de definir une meilleure strategie therapeutique chez les patients atteints de LHH pour qui il existe un reel manque de donnees.

Introduction La fibrose retroperitoneale (FRP) est une maladie rare caracterisee par la presence d’un tissu fibro-inflammatoire engainant les structures retroperitoneales. Elle peut etre idiopathique ou secondaire a diverses etiologies qui doivent etre exclues. Le pronostic de la FRPi est lie au risque de survenue d’une insuffisance renale chronique. Notre objectif etait de rapporter les donnees epidemiologiques de la cohorte rouennaise, et d’analyser les strategies diagnostiques et therapeutiques, le suivi et le pronostic chez ces patients. Patients et methodes Il s’agissait d’une etude retrospective monocentrique menee au CHU de Rouen. Les cas de FRP pris en charge dans les services de medecine interne, nephrologie et urologie entre 2010 et 2021 ont ete colliges. Le diagnostic de FRP reposait essentiellement sur l’imagerie. Les donnees epidemiologiques, clinico-biologiques, radiologiques, therapeutiques et de suivi ont ete recueillies de maniere retrospective. Une comparaison a ete realisee entre les formes idiopathique et secondaire. Resultats 56 patients ont ete inclus avec un âge moyen au diagnostic de 62,8 ± 12,6 ans, et un ratio hommes/femmes de 2,7. La FRP etait idiopathique pour 33 patients (59 %). Cinq FRP secondaires etaient liees a une MAG4 (22 %) et 8 secondaires (14 %) a une neoplasie. Une preuve histologique etait disponible pour 9 patients dont 8 ayant montre un tissus fibro-inflammatoire non specifique. Les symptomes inauguraux les plus frequents etaient des douleurs lombaires et/ou abdominales (75 %) et des symptomes systemiques (48 %). Un syndrome inflammatoire biologique etait souvent observe (89 %). Le taux de creatinine moyen au diagnostic etait de 189,5mcmol/L. Dans la population globale, 35 patients (63 %) ont recu un traitement par corticoides (82 % dans le groupe idiopathique vs 40 % dans le groupe secondaire, p = 0.002). Le recours a la pose d’une sonde double J a ete necessaire pour 35 patients (63 %), bilaterale pour 16 patients, sans difference entre les 2 groupes. Une rechute et une recidive ont ete observees chez 30 % et 16 % respectivement des patients traites par corticoides, sans difference significative entre les groupes idiopathique et secondaire. Au terme du suivi, 26 patients (47 %) etaient en remission (67 % vs 18 %, p = 0.001 entre les formes idiopathique et secondaire, respectivement). Un retrait des sondes double J a pu etre realise chez 14 patients (40 %), principalement chez les patients du groupe idiopathique (35 % vs 13 %, p = 0,11). Une insuffisance renale chronique etait notee chez 32 % des patients, et 7 % avec une atteinte terminale. Conclusion Les conduites diagnostiques et therapeutiques des FRP sont heterogenes et necessitent une prise en charge pluridisciplinaire. Les formes secondaires ont une evolution moins favorable. Les patients atteints de FRPi justifient un suivi a long terme du fait de recidive possible et du risque d’insuffisance renale chronique.

Cardiovascular events are the second leading cause of death in France. The assessment of overall cardiovascular risk using a personalized assessment with weighting risk factors can predict the risk of cardiovascular events in ten years. The validated treatments to reduce cardiovascular mortality in primary prevention are few. The use of statins in primary prevention is discussed. We report in this review the updated conclusions from clinical trials regarding the treatment with statins in primary prevention.

Vaccine-induced immune thrombotic thrombocytopenia is a rare syndrome following the ChAdOx1 nCov-19 or Ad26.COV2.S vaccine. Reported patients developed mainly venous thrombosis. We describe a case of a young healthy women suffering from acute ischemic stroke due to large vessel occlusion without cerebral venous thrombosis 8 days after vaccination and its consequences on recanalization strategy. Considering the thrombocytopenia, intravenous thrombolysis was contraindicated. She underwent mechanical thrombectomy with complete recanalization and dramatically improved clinically. Positive detection of anti-PF4-heparin-antibodies confirmed vaccine-induced immune thrombotic thrombocytopenia diagnosis. In case of acute ischemic stroke after recent ChAdOx1 nCov-19 or Ad26.COV2.S vaccine, platelet count should be systematically checked before giving thrombolysis, and direct mechanical thrombectomy should be proposed in patients with large vessel occlusion.

Background: Because of the wide variation in the course of Takayasu arteritis (TA), predicting outcome is challenging. We assess long-term outcome and prognosis factors for vascular complications in patients with TA. Methods: A retrospective multicenter study of characteristics and outcomes of 318 patients with TA fulfilling American College of Rheumatology and Ishikawa criteria was analyzed. Factors associated with event-free survival, relapse-free survival, and incidences of vascular complications were assessed. Risk factors for vascular complications were identified in a multivariable model. Results: The median age at TA diagnosis was 36 [25–47] years, and 276 patients (86.8%) were women. After a median follow-up of 6.1 years, relapses were observed in 43%, vascular complications in 38%, and death in 5%. Progressive clinical course was observed in 45%, carotidodynia in 10%, and retinopathy in 4%. The 5- and 10-year event-free survival, relapse-free survival, and complication-free survival were 48.2% (42.2; 54.9) and 36.4% (30.3; 43.9), 58.6% (52.7; 65.1) and 47.7% (41.2; 55.1), and 69.9% (64.3; 76.0) and 53.7% (46.8; 61.7), respectively. Progressive disease course ( P =0.018) and carotidynia ( P =0.036) were independently associated with event-free survival. Male sex ( P =0.048), elevated C-reactive protein ( P =0.013), and carotidynia ( P =0.003) were associated with relapse-free survival. Progressive disease course ( P =0.017), thoracic aorta involvement ( P =0.009), and retinopathy ( P =0.002) were associated with complication-free survival. Conclusions: This nationwide study shows that 50% of patients with TA will relapse and experience a vascular complication ≤10 years from diagnosis. We identified specific characteristics that identified those at highest risk for subsequent vascular complications.

Erythromelalgia is a rare intermittent vascular acrosyndrome characterized by the combination of recurrent burning pain, warmth and redness of the extremities. It is considered in its primary form as an autosomal dominant neuropathy related to mutations of SCN9A, the encoding gene of a voltage-gated sodium channel subtype Nav1.7. Secondary erythromelalgia is associated with myeloproliferative disorders, drugs (bromocriptine, calcium channel blockers), or clinical conditions such as rheumatic diseases or viral infection. Primary familial erythromelalgia include genetics and sporadic forms associated with small fibers neuropathy. Aspirin is a useful treatment of erythromelagia associated with myeloproliferative disorders. Treatment of primary erythromelalgia is difficult, individualized, with sodium channel blockers such as lidocaine, carbamazepine and mexiletine.

Thrombotic thrombocytopenic purpura (TTP) has a devastating prognosis without adapted management. Sources of misdiagnosis need to be identified to avoid delayed treatment. We studied 84 patients with a final diagnosis of severe (

Introduction Le purpura thrombotique thrombocytopenique (PTT) est defini par l’association d’une anemie hemolytique mecanique, d’une thrombopenie profonde, de souffrances viscerales et d’un deficit fonctionnel severe en ADAMTS13. L’etude des mecanismes de ce deficit a pu identifier deux causes principales : une forme congenitale due a l’existence de mutations du gene ADAMTS13 et une forme acquise auto-immune secondaire a la presence d’auto-anticorps diriges contre la protease. Cependant, chez 20 a 25 %, les IgG anti-ADAMTS13 ne sont pas detectables, suggerant un autre mecanisme. L’objectif principal de ce travail est donc de caracteriser les patients PTT acquis a IgG negatif a la phase inaugurale et d’en analyser le profil evolutif. Patients et methodes Tous les patients atteints d’un PTT acquis sans auto-anticorps a la phase inaugurale inclus de maniere prospective entre janvier 2000 et decembre 2019 dans le registre francais des microangiopathies thrombotiques ont ete analyses dans l’etude. L’ensemble des donnees demographiques, cliniques et biologiques, les traitements recus, l’evolution du PTT, et la reponse au Rituximab ont ete analyses. Resultats 273 patients PTT acquis sans auto-anticorps a la phase inaugurale ont ete inclus, representant 20 % des PTT du registre national avec pres de 70 % de formes non idiopathiques. L’atteinte cerebrale reste une atteinte d’organe frequente (52 %), alors que l’atteinte renale touche 70 % des patients et predomine dans les formes non-idiopathiques de la maladie (81 % vs 46 %, p Conclusion L’analyse du registre national du CNR-MAT nous a permis d’etablir des caracteristiques demographiques, epidemiologiques et clinico-biologiques des formes acquises de PTT sans auto-anticorps, nous permettant de decrire deux entites : les PTT idiopathiques ou associees a des maladies auto-immunes a considerer comme une forme auto-immune et les PTT non idiopathiques ayant des caracteristiques distinctes, suggerant d’autres mecanismes aboutissant a un deficit severe en ADAMTS 13 transitoire. Un groupe controle appariee permettrait de mieux preciser nos premiers resultats, et une approche mecanistique pour comprendre la physiopathologie de ces formes serait utile.

Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was 50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management. ispartof: BLOOD vol:136 issue:3 pages:353-361 ispartof: location:United States status: published

Resume Propos Le syndrome des antiphospholipides (SAPL) est un syndrome clinicobiologique associant une atteinte vasculaire et la persistance d’anticorps antiphospholipides (aPL). Les patients avec des manifestations cliniques evocatrices de SAPL mais sans aPL sont consideres comme « SAPL seronegatif » (SNAPS). Le but de cette etude etait d’evaluer l’interet de la recherche d’anticorps antiphosphatidylethanolamine (aPE) chez les patients ayant une suspicion de SNAPS. Methodes Il s’agit d’une etude retrospective sur tous les patients ayant eu une suspicion de SNAPS. La recherche d’aPE a ete realisee par une methode Elisa « maison ». Cette methode a ete comparee avec un Elisa de screening global d’aPL. Resultats Au total, 228 patients ont ete repertories pour une recherche de SNAPS. La recherche d’aPE a ete effectuee dans 58,3 % des cas pour un evenement thrombotique. Parmi ces patients, 23 avaient une recherche d’aPE positive et persistante dans le temps (10 %). Quinze patients avaient eu un accident thrombotique, 6 avaient eu une complication obstetricale et 2 un evenement combine. Le test de screening des aPL n’etait positif que dans 11 de ces 23 patients (47,8 %). Conclusion Ces donnees sont en faveur de l’implication des aPE dans le SNAPS. Elles suggerent qu’il semble interessant de rechercher les aPL non conventionnels pour ameliorer le diagnostic de SNAPS.

To compare the diagnostic accuracy of 3D versus 2D contrast-enhanced vessel-wall (CE-VW) MRI of extracranial and intracranial arteries in the diagnosis of GCA. This prospective two-center study was approved by a national research ethics board and enrolled participants from December 2014 to October 2017. A protocol including both a 2D and a 3D CE-VW MRI at 3 T was performed in all patients. Two neuroradiologists, blinded to clinical data, individually analyzed separately and in random order 2D and 3D sequences in the axial plane only or with reformatting. The primary judgment criterion was the presence of GCA-related inflammatory changes of extracranial arteries. Secondary judgment criteria included inflammatory changes of intracranial arteries and the presence of artifacts. A McNemar’s test was used to compare 2D to 3D CE-VW MRIs. Seventy-nine participants were included in the study (42 men and 37 women, mean age 75 (± 9.5 years)). Fifty-one had a final diagnosis of GCA. Reformatted 3D CE-VW was significantly more sensitive than axial-only 3D CE-VW or 2D CE-VW when showing inflammatory change of extracranial arteries: 41/51(80%) versus 37/51 (73%) (p = 0.046) and 35/50 (70%) (p = 0.03). Reformatted 3D CE-VW was significantly more specific than 2D CE-VW: 27/27 (100%) versus 22/26 (85%) (p = 0.04). 3D CE-VW showed higher sensitivity than 2D CE-VW when detecting inflammatory changes of intracranial arteries: 10/51(20%) versus 4/50(8%), p = 0.01. Interobserver agreement was excellent for both 2D and 3D CE-VW MRI: κ = 0.84 and 0.82 respectively. 3D CE-VW MRI supported more accurate diagnoses of GCA than 2D CE-VW. • 3D contrast-enhanced vessel-wall magnetic resonance imaging is a high accuracy, non-invasive diagnostic tool used to diagnose giant cell arteritis. • 3D contrast-enhanced vessel-wall imaging is feasible for clinicians to complete within a relatively short time, allowing immediate assessment of extra and intracranial arteries. • 3D contrast-enhanced vessel-wall magnetic resonance imaging might be considered a diagnostic tool when intracranial manifestation of GCA is suspected.

Age at onset of large-vessel vasculitis (LVV) is commonly used to distinguish giant cell arteritis (GCA) and Takayasu arteritis (TA). However, LVV between age 50 and 60 years may be difficult to classify.We conducted a retrospective study including LVV aged between 50 and 60 years at onset (LVVWe included 183 LVV

International audience

Introduction Le purpura thrombotique thrombocytopenique (PTT) est defini par l’association d’une anemie hemolytique mecanique, d’une thrombopenie profonde, de souffrances viscerales et d’un deficit fonctionnel severe en ADAMTS13. L’etude des mecanismes de ce deficit a pu identifier deux causes principales : une forme congenitale due a l’existence de mutations du gene ADAMTS13 et une forme acquise auto-immune secondaire a la presence d’auto-anticorps diriges contre la protease. Cependant, chez 20 a 25 %, les IgG anti-ADAMTS13 ne sont pas detectables, suggerant un autre mecanisme. L’objectif principal de ce travail est donc de caracteriser les patients PTT acquis a IgG negatif a la phase inaugurale et d’en analyser le profil evolutif. Patients et methodes Tous les patients atteints d’un PTT acquis sans auto-anticorps a la phase inaugurale inclus de maniere prospective entre janvier 2000 et decembre 2019 dans le registre francais des microangiopathies thrombotiques ont ete analyses dans l’etude. L’ensemble des donnees demographiques, cliniques et biologiques, les traitements recus, l’evolution du PTT, et la reponse au Rituximab ont ete analyses. Resultats 273 patients PTT acquis sans auto-anticorps a la phase inaugurale ont ete inclus, representant 20 % des PTT du registre national avec pres de 70 % de formes non idiopathiques. L’atteinte cerebrale reste une atteinte d’organe frequente (52 %), mais l’atteinte renale touche 70 % des patients et predomine dans les formes non-idiopathiques de la maladie (81 % vs 46 %, p Conclusion L’analyse du registre national du CNR-MAT nous a permis d’etablir des caracteristiques demographiques, epidemiologiques et clinico-biologiques des formes acquises de PTT sans auto-anticorps, nous permettant de decrire deux entites : les PTT idiopathiques ou associees a des maladies auto-immunes a considerer comme une forme auto-immune et les PTT non idiopathiques ayant des caracteristiques distinctes, suggerant d’autres mecanismes aboutissant a un deficit severe en ADAMTS 13 transitoire. Un groupe controle appariee permettrait de mieux preciser nos premiers resultats, et une approche mecanistique pour comprendre la physiopathologie de ces formes serait utile.

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] and at diagnosis [34 (27-50) vs 46 (34-57) years, p] 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)2.5 [1.6-3.8]Arterial hypertension59 (43)75 (25)2.2 [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 declared

The standard four-rituximab infusions treatment in acquired thrombotic thrombocytopenic purpura (TTP) remains empirical. Peripheral B cell depletion is correlated with the decrease in serum concentrations of anti-ADAMTS13 and associated with clinical response. To assess the efficacy of a rituximab regimen based on B cell depletion, 24 TTP patients were enrolled in this prospective multicentre single arm phase II study and then compared to patients from a previous study. Patients with a suboptimal response to a plasma exchange-based regimen received two infusions of rituximab 375 mg/m2 within 4 days, and a third dose at day +15 of the first infusion if peripheral B cells were still detectable. Primary endpoint was the assessment of the time required to platelet count recovery from the first plasma exchange. Three patients died after the first rituximab administration. In the remaining patients, the B cell-driven treatment hastened remission and ADAMTS13 activity recovery as a result of rapid anti-ADAMTS13 depletion in a similar manner to the standard four-rituximab infusions schedule. The 1-year relapse-free survival was also comparable between both groups. A rituximab regimen based on B cell depletion is feasible and provides comparable results than with the four-rituximab infusions schedule. This regimen could represent a new standard in TTP. This trial was registered at www.clinicaltrials.gov (NCT00907751). This article is protected by copyright. All rights reserved.

Purpose Data on long-term treatment with low-molecular-weight heparins (LMWH) in cancer patients treated for venous thromboembolism are scarce. Study objectives were to document the long-term clinical use of LMWH and patient perception in this setting. Methods Adult cancer patients receiving antineoplastic treatment or palliative care and LMWH for cancer associated venous thromboembolism (CAT) were eligible to participate in this prospective observational study. Main outcome was adherence to clinical practice guidelines based on recommended LMWH treatment doses for at least 3 months in the absence of severe renal insufficiency. Patients' perception of the treatment was assessed in an ancillary study using the Perception Anticoagulant Treatment Questionnaire (PACT-Q). Results Among 409 included cancer patients aged 65 ± 12.1 years, overall adherence to practice guidelines as defined in the protocol was 55.3% (226 patients). However, 98.0% of patients received a prescription for 3 months or more and mean LMWH treatment duration for VTE was 6.27 ± 0.15 months which meets guidelines recommendations. Main patients' expectations scored on a 1–5 scale were blood clots prevention (mean 3.94 ± 0.75), symptom relief (mean 3.98 ± 1.04) and ease of use (mean 4.22 ± 0.9). LMWH treatment appeared convenient (global score 79.7 ± 17.1 on a 0 to 100 scale) and 69.1% of patients were satisfied or very satisfied. Conclusion Despite incomplete strict adherence to guidelines, treatment duration with LMWH was adequate showing substantial progress in the management of CAT patients. Patients expectations were high while treatment was perceived convenient with a high degree of satisfaction.

Thrombotic thrombocytopenic purpura is a thrombotic microangiopathy related to a severe deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13; activity10%). We aimed to investigate the association between mechanisms for ADAMTS13 deficiency and the epidemiology and pathophysiology of thrombotic thrombocytopenic purpura at initial presentation.Between Jan 1, 1999, and Dec 31, 2013, we did a cross-sectional analysis of the French national registry for thrombotic microangiopathy to identify all patients with adult-onset thrombotic microangiopathy (first episode after age 18 years) who had severe ADAMTS13 deficiency at presentation. ADAMTS13 activity, anti-ADAMTS13 IgG, and ADAMTS13 gene mutations were investigated by a central laboratory. We collected patients' clinical data for correlation with their ADAMTS13 phenotype and genotype. We used logistic regression analysis to identify variables significantly associated with idiopathic thrombotic thrombocytopenic purpura, as measured by estimated odds ratios (ORs) and 95% CIs. This study is registered with ClinicalTrials.gov, number NCT00426686.We enrolled 939 patients with adult-onset thrombotic thrombocytopenic purpura, of whom 772 (82%) patients had available data and samples at presentation and comprised the cohort of interest. The prevalence of thrombotic thrombocytopenic purpura in France was 13 cases per million people. At presentation, 378 (49%) patients had idiopathic thrombotic thrombocytopenic purpura, whereas 394 (51%) patients had disease associated with miscellaneous clinical situations (infections, autoimmunity, pregnancy, cancer, organ transplantation, and drugs). Pathophysiologically, three distinct forms of thrombotic thrombocytopenic purpura were observed: 585 (75%) patients had autoimmune disease with anti-ADAMTS13 IgG, 166 (22%) patients had acquired disease of unknown cause and 21 (3%) patients had inherited disease (Upshaw-Schulman syndrome) with mutations of the ADAMTS13 gene. Idiopathic thrombotic thrombocytopenic purpura were mainly autoimmune (345 [91%] cases), whereas non-idiopathic diseases were heterogeneous, including a high rate of unexplained mechanisms for ADAMTS13 deficiency (133 [34%] cases). Obstetrical thrombotic thrombocytopenic purpura cases (n=62) were specifically remarkable because of the high rate of patients with Upshaw-Schulman syndrome (21 [34%] patients).Our study shows that thrombotic thrombocytopenic purpura is a heterogeneous syndrome, and that features of the disease at presentation are strongly associated with the mechanisms of ADAMTS13 deficiency. In addition to mechanistic insight, our findings could have implications for the initial therapeutic management of patients with this disorder.Assistance Publique-Hôpitaux de Paris.

Introduction Le caplacizumab, un nanocorps anti-facteur Willebrand, s’est revele efficace dans le purpura thrombotique thrombocytopenique autoimmun (PTTi) dans deux essais cliniques. Il a beneficie d’une autorisation de mise sur le marche pour les patients atteints d’un PTTi au diagnostic. A ce jour, aucune donnee de vraie vie (hors protocole therapeutique) n’est disponible. L’objectif de ce travail est de d’evaluer l’efficacite et la tolerance du caplacizumab chez des patients atteints de PTTi non selectionnes. Materiels et methodes En France, le caplacizumab a beneficie d’une autorisation temporaire d’utilisation depuis septembre 2018. Nous avons traite selon un schema consensuel au plan national 90 patients avec un diagnostic clinique de PTTi en 15 mois a partir de 27 centres nationaux. Le traitement a consiste en une « triplette » associant des le diagnostic (en premiere ligne) des echanges plasmatiques (EP), une immunosuppression par corticoides et rituximab, et du caplacizumab. L’evolution des patients a ete comparee a celle de 180 patients historiques apparies en termes de severite et traites selon le schema historique, par EP et corticoides au diagnostic, et rituximab en cas de reponse defavorable au traitement standard. Le critere principal de jugement etait un critere composite associant la mortalite et la survenue d’une forme refractaire de PTT. Resultats Le pourcentage de patients dans le groupe « triplette » avec le critere de jugement principal composite etait de 2,2 % contre 12,2 % chez les patients historiques (p = 0,01). Par consequent, les patients traites avec le schema triplette etaient 6,2 fois moins susceptibles d’avoir un deces lie a un PTTi ou a un PTTi refractaire que les patients de la cohorte historique (IC a 95 %, 1,4 a 26,3, p = 0,013). Le taux de mortalite etait de facon inattendu extremement faible (6,7 % ; n = 12) dans la cohorte historique, ne permettant pas d’atteindre une difference siginificative sur la mortalite entre les 2 groupes. (p = 0,09). Pourtant un seul patient âge (83 ans) est decede dans le groupe triplette d’une embolie pulmonaire. Une diminution significative des exacerbations a ete notee dans la groupe triplette par rapport a la cohorte historique (3,4 % vs 44 %, p 0,25 μg/l) ou un score de mortalite eleve (atteinte cerebrale clinique, âge > 60 ans et LDH > 10 N) que chez ceux sans ces atteintes d’organe. Des evenements indesirables lies au caplacizumab sont survenus chez 46 patients (51 %), dont 13 evenements hemorragiques majeurs ou non majeurs mais cliniquement pertinents. Onze patients (12 %) ont eu un evenement thromboembolique veineux (une EP n = 5 ; une TVP n = 4 et une thrombose liee au catheter veineux central n = 4) sans difference entre les deux groupes (p = 0,79). Aucun d’entre eux n’avait recu de thromboprophylaxie meme lorsque la numeration plaquettaire etait superieure a 50,103/mm3. La duree totale de traitement par caplacizumab a ete de 33 jours consecutifs (29–37). Une activite ADAMTS13 detectable (activite ≥ 20 %) a ete le plus souvent observee aux semaines 2 ou 3 apres le dernier EP. Une analyse medico-economique reposant uniquement sur les couts lies a la prise en charge en aigue de la maladie montre un cout 3 fois plus eleve de la prise en charge par la triplette. Conclusion Dans cette premiere etude de « vraie vie », nous montrons qu’une « triplette », associant des EP, un traitement immunosuppresseur par corticoides et rituximab, et du caplacizumab en premiere ligne previent les evolutions defavorables de la maladie et diminue tres significativement la charge de soin. Le caplacizumab, par son action immediate, protege les patients jusqu’a l’amelioration de l’activite ADAMTS13 par le rituximab. En gommant le pronostic historiquement pejoratif des atteintes cardiaque et cerebrale, il ameliore pour la premiere fois en plus de 20 ans le devenir des patients.

Older age is associated with increased mortality in immune thrombotic thrombocytopenic purpura (iTTP). Yet, data are scarce regarding iTTP occurring among older patients. To assess clinical features and long-term impact of iTTP on mortality in older patients (>60 years old), characteristics and prognoses of adult iTTP patients enrolled in the French Reference Center for Thrombotic Microangiopathies registry between 2000 and 2016 were described according to age (/=60 years old). Long-term mortality of iTTP older survivors was compared with that of non-iTTP geriatric subjects. Comparing, respectively, older iTTP patients (N = 71) with younger patients (N = 340), time from hospital admission to diagnosis was longer (P < .0001); at diagnosis, delirium (P = .034), behavior impairment (P = .045), renal involvement (P < .0001), and elevated troponin level (P = .025) were more important whereas cytopenias were less profound (platelet count, 22 x 103/mm3 [9-57] vs 13 x 103/mm3 [9-21], respectively [P = .002]; hemoglobin level, 9 g/dL [8-11] vs 8 g/dL [7-10], respectively [P = .0007]). Short- and mid-term mortalities were higher (P < .0001) and increased for every 10 years of age range. Age >/=60 years, cardiac involvement, increased plasma creatinine level, and total plasma exchange volume were independently associated with 1-month mortality. Compared with a non-iTTP geriatric population, older survivors showed an increased long-term mortality (hazard ratio = 3.44; P < .001). In conclusion, older iTTP patients have atypical neurological presentation delaying the diagnosis. Age negatively impacts short-term but also long-term mortality.

International audience; Antiphospholipid antibodies (aPL) promote endothelial dysfunction, inflammation and pro-coagulant state. We investigated the effect of hydroxychloroquine (HCQ) on prothrombotic state and endothelial function in mice and in human aortic endothelial cells (HAEC). Human aPL were injected to C57BL/6 mice treated or not with HCQ. Vascular endothelial function and eNOS were assessed in isolated mesenteric arteries. Thrombosis was assessed both in vitro by measuring thrombin generation time (TGT) and tissue factor (TF) expression and in vivo by the measurement of the time to occlusion in carotid and the total thrombosis area in mesenteric arteries. TGT, TF, and VCAM1 expression were evaluated in HAEC. aPL increased VCAM-1 expression and reduced endothelium dependent relaxation to acetylcho-line. In parallel, aPL shortened the time to occlusion and extended thrombus area in mice. This was associated with an overexpression of TF and an increased TGT in mice and in HAEC. HCQ reduced clot formation as well as TGT, and improved endothelial-dependent relaxations. Finally, HCQ increased the p-eNOS/eNOS ratio. This study provides new evidence that HCQ improves procoagulant status and vascular function in APS by modulating eNOS, leading to an improvement in the production of NO.

Preemptive rituximab infusions prevent relapses in immune thrombotic thrombocytopenic purpura (iTTP) by maintaining normal ADAMTS13 activity. However, the long-term outcome of these patients and the potential adverse events of this strategy need to be determined. We report the long-term outcome of 92 patients with iTTP in clinical remission who received preemptive rituximab after identification of severe ADAMTS13 deficiency (activity 1 iTTP episode, and the median cumulative relapse incidence before preemptive rituximab was 0.33 episode per year (interquartile range [IQR], 0.23-0.66). After preemptive rituximab, the median cumulative relapse incidence in the whole population decreased to 0 episodes per year (IQR, 0-1.32; P < .001). After preemptive rituximab, ADAMTS13 activity recovery was sustained in 34 patients (37%) during a follow-up of 31.5 months (IQR, 18-65), and severe ADAMTS13 deficiency recurred in 45 patients (49%) after the initial improvement. ADAMTS13 activity usually improved with additional courses of preemptive rituximab. In 13 patients (14%), ADAMTS13 activity remained undetectable after the first rituximab course, but retreatment was efficient in 6 of 10 cases. In total, 14 patients (15%) clinically relapsed, and 19 patients (20.7%) experienced benign adverse effects. Preemptive rituximab treatment was associated with a change in ADAMTS13 conformation in respondent patients. Finally, in the group of 23 historical patients with iTTP and persistently undetectable ADAMTS13 activity, 74% clinically relapsed after a 7-year follow-up (IQR, 5-11). In conclusion, persistently undetectable ADAMTS13 activity in iTTP during remission is associated with a higher relapse rate. Preemptive rituximab reduces clinical relapses by maintaining a detectable ADAMTS13 activity with an advantageous risk-benefit balance. ispartof: Blood vol:132 issue:20 pages:2143-2153 ispartof: location:United States status: published

Biotherapies appear as potential drugs for the treatment of inflammatory noninfectious uveitis. In this report, we show that tocilizumab, an anti-IL-6 agent, greatly improved two patients with birdshot chorioretinopathy refractory to conventional immunosuppressive drugs, interferon α2a, and anti-TNFα agents. After a follow-up of 22 months, patients exhibited an improvement of both visual acuity and macular edema. A corticosteroid-sparing effect was achieved in both cases.

Summary Non-vitamin K antagonist oral anticoagulants (NOACs) – dabigatran, rivaroxaban, apixaban and edoxaban – are well established in terms of preventing stroke or systemic embolism in patients with non-valvular atrial fibrillation and high thromboembolism risk. When prescribed incorrectly, NOACs are associated with an increased risk of ischaemic events and bleeding. Current NOAC labels explicitly address dose adjustments according to age, body weight, renal function and concomitant treatment with P-glycoprotein inhibitors. The required dose adjustments vary significantly from molecule to molecule, thereby creating a complex dose adjustment environment. Furthermore, recommendations support assessment of individual risk using thromboembolic and bleeding risk scores. Evidence-based medicine also provides data about specific patient profiles. In particular, some patients who are at higher risk of bleeding, such as patients on polymedication, are often at higher risk of stroke. More and more patients are being treated with NOACs. The question of appropriate dosing has become important, as studies are starting to show that reduced doses are being prescribed at very high rates. Although these data have not been evaluated in light of individual risk assessments, in everyday practice, physicians are often more concerned about drug-related bleeding than about the spontaneous evolution of the disease (stroke/systemic embolism), leading to high rates of prescription of inadequately low doses. Recent results have shown that only certain risk criteria justify dose reduction. Thus, the right dose needs to be prescribed for the right patient in order to obtain, in real-life practice, the benefits of NOACs that have been demonstrated in randomized clinical trials.