Cyclophosphamide vs rituximab for eradicating inhibitors in acquired hemophilia A: A randomized trial in 108 patients.

BACKGROUND: Acquired hemophilia A (AHA) is a rare autoimmune disorder due to autoantibodies against Factor VIII, with a high mortality risk. Treatments aim to control bleeding and eradicate antibodies by immunosuppression. International recommendations rely on registers and international expert panels. METHODS: CREHA, an open-label randomized trial, compared the efficacy and safety of cyclophosphamide and rituximab in association with steroids in patients with newly diagnosed AHA. Participants were treated with 1 mg/kg prednisone daily and randomly assigned to receive either 1.5-2 mg/kg/day cyclophosphamide orally for 6 weeks, or 375 mg/m2 rituximab once weekly for 4 weeks. The primary endpoint was complete remission over 18 months. Secondary endpoints included time to achieve complete remission, relapse occurrence, mortality, infections and bleeding, and severe adverse events. RESULTS: Recruitment was interrupted because of new treatment recommendations after 108 patients included (58 cyclophosphamide, 50 rituximab). After 18 months, 39 cyclophosphamide patients (67.2 %) and 31 rituximab patients (62.0 %) were in complete remission (OR 1.26; 95 % CI, 0.57 to 2.78). In the poor prognosis group (FVIII < 1 IU/dL, inhibitor titer > 20 BU mL-1), significantly more remissions were observed with cyclophosphamide (22 patients, 78.6 %) than with rituximab (12 patients, 48.0 %; p = 0.02). Relapse rates, deaths, severe infections, and bleeding were similar in the 2 groups. In patients with severe infection, cumulative doses of steroids were significantly higher than in patients without infection (p = 0.03). CONCLUSION: Cyclophosphamide and rituximab showed similar efficacy and safety. As first line, cyclophosphamide seems preferable, especially in poor prognosis patients, as administered orally and less expensive. FUNDING: French Ministry of Health. CLINICALTRIALS: gov number: NCT01808911.

[Acquired hemophilia and pregnancy: A necessarily multidisciplinary approach]. / Hémophilie acquise et grossesse : une approche forcément multidisciplinaire.

The occurrence of acquired hemophilia during pregnancy or postpartum is rare (2 to 10 % in series). It is generally suspected in the presence of haemorrhagic manifestations (especially subcutataneous or mucosal bleeding) associated with an isolated prolongation of the activated partial thromboplastin time (APTT). The diagnosis is confirmed by the association of a low level of factor VIII (FVIII) and the presence of an anti-FVIII inhibitor. Postpartum management is similar to that of other acquired haemophilias: correction of a severe haemorrhagic syndrome by "bypassing" agents, eradication of the inhibitor by corticosteroids alone or in combination with another immunosuppressive agent depending on the residual level of FVIII and the titer of the inhibitor. Management of the forms occurring during pregnancy is based on rare experiences or expert opinions. The management of childbirth is particularly delicate in terms of haemorrhage, especially if the anti-FVIII inhibitor is still present, and must be prepared in a multidisciplinary manner. Finally, as with any acquired hemophilia, a relapse is possible, especially in the year following remission. During a subsequent pregnancy, the risk of recurrence is possible but should not be a contraindication to a new pregnancy.

[Identification of factors associated with performance in objective structured clinical examination in Rouen medical school]. / Identification des facteurs associés à la réussite aux examens cliniques objectifs et structurés dans la faculté de médecine de Rouen.

CONTEXT: Objective structured clinical examination (OSCE) became a national exam at the end of medical studies in France. The aim of this study was to identify the predictive factors for success at OSCEs. METHODS: Aurvey query after the OSCEs was completed by fifth-year medicine students at Rouen Uuniversity.. Data on continuous variables were compared using the Mann-Whitney test. Data on quantitative variables were compared using the Spearman's correlation. RESULTS: Two hundred and thirty-nine students, i.e., 98.7 % of the students, responded to the query. The median (IQR 25-75) OSCE score was 13.6/20 (12.5-14.2). Students' personal factors significantly associated with a higher OSCE performance were female sex (median score of 13.7 versus 13.4; P=0.03) and good health during the clerkship (median score of 13.6 versus 12.6; P=0.02). A higher OSCE performance was associated with an increased number (≥6)  of medicine clerkships (median score of 13.8 versus 13.3; P=0.02) and a decreased number (<3) of surgery clerkships (median score of 13.7 versus 12.9; P=0.009). There was no correlation between the OSCE score and medical school performance (Spearman's correlation, r=0.24). CONCLUSION: Homogenization of student's clerkships, assistance to students with health problems seem to be teaching approaches to promote success at OSCEs.

Characterizing hospital pathways for the care of acquired hemophilia in France using comprehensive national health data.

PURPOSE: Acquired hemophilia (AH) is a rare, serious bleeding disorder most often associated with older age and life-threatening complications. The patient care pathway for AH is complex because of the different types of bleeding, the presence of comorbidities, and the heterogeneity of medical specialists who care for these patients. METHODS: This observational study used the French national PMSI (Programme de médicalisation des systèmes d'information) database to characterize patients with AH in real-life practice and analyze their hospital pathway. In total, 180 patients with AH were identified over a 5-year study period (January 2010 to December 2014), based on three criteria: bypassing agent use, International Classification of Diseases, 10th revision code allocation, and aged over 65 years. Comparison of the incidence rate of AH versus registry data validated the PMSI as an epidemiological database. RESULTS: Rituximab was prescribed more often (60/180; 33.3%) than expected following guidelines and was associated in half of cases to early infections (32/60; 53.3%), surgery procedures were frequently performed during the year before AH onset (29/159; 18.2%), which may suggest a triggering effect, extended hospital stays (median: 20 days) and mortality remaining high (66/180; 36.7%) that occurred mainly during the first month after AH diagnosis. Median costs and number of injections were comparable between recombinant activated factor VII and plasma-derived activated prothrombin complex concentrate. CONCLUSION: These findings could inform future medico-economic approaches in this AH population (duration of stays, bypassing agents, rituximab use, comorbidities, hospitalizations with infections).

Systematic screening for a proximal DVT in COVID-19 hospitalized patients: Results of a comparative study.

INTRODUCTION: The COVID-19 pandemic is associated with a high incidence of venous thromboembolism questioning the utility of a systematic screening for deep venous thrombosis (DVT) in hospitalised patients. METHODS: In this prospective bicentric controlled study, 4-point ultrasound using a pocket device was used to screen for DVT, in patients with SARS-CoV-2 infection and controls admitted for acute medical illness not related to COVID-19 hospitalised in general ward, in order to assess the utility of a routine screening and to estimate the prevalence of VTE among those patients. RESULTS: Between April and May 2020, 135 patients were screened, 69 in the COVID+ group and 66 in the control one. There was no significant difference in the rate of proximal DVT between the two groups (2.2% vs. 1.5%; P=0.52), despite the high rate of PE diagnosed among COVID-19 infected patients (10.1% vs. 1.5%, P=0.063). No isolated DVT was detected, 37.5% of PE was associated with DVT. Mortality (7.2% vs. 1.5%) was not different (P=0.21) between COVID-19 patients and controls. CONCLUSION: The systematic screening for proximal DVT was not found to be relevant among COVID-19 patients hospitalized in general ward despite the increase of VTE among this population. Further studies are needed to confirm the hypothesis of a local pulmonary thrombosis which may lead to new therapeutic targets.

Granulomatosis with polyangiitis and pregnancy: A case report and review of the literature.

The association of granulomatosis with polyangiitis and pregnancy is rare and therapeutic options are limited by the risk of teratogenicity and fetotoxicity. There is a paucity of published literature to guide clinical decision-making in these cases. We report the case of a 26-year-old woman with no medical history who presented at 21 weeks of gestation with a bilateral sudden loss of hearing and erosive rhinitis. The diagnosis of granulomatosis with polyangiitis was confirmed radiologically and biologically. Corticosteroids were not enough to stabilize the disease and she received intravenous immunoglobulins with remission. A successful delivery of a healthy male newborn was done at 36 weeks. A review of all published literature on granulomatosis with polyangiitis in pregnancy between 1970 and 2017 is presented. Trial registration: Not applicable.

New insights into antiphospholipid-related endothelial dysfunction by assessment of vascular glycocalyx layer: results from a preliminary cross-sectional study.

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 < 0.01 and a reduced glycocalyx thickness 0.26 ± 0.03 µm vs. 0.75 ± 0.07 µm; p < 0.01 compared with control. FMD was impaired in APS patients compared with control, 5.68% ± 0.42 vs. 8.29 ± 0.30, p < 0.01, respectively. IMT was significantly increased in APS patients compared with control, 0.52 ± 0.13 mm vs. 0.40 ± 0.06 mm, p < 0.01, respectively. Soluble TF, thiobarbituric acid-reactive substances levels were increased in the sera from APS patients compared with control. 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.

[Giant cell arteritis: Role of color-duplex ultrasound]. / Artérite gigantocellulaire : apport de l'écho-doppler.

Giant cell arteritis is the most common primary vasculitis of large-vessel occurring in subjects over 50 years of age. Many imaging techniques has been evaluated to improve the diagnosis of giant cell arteritis. Among these imaging techniques, ultrasound has shown good performances to detect inflammatory involvement of the temporal arteries as well as branches of the aorta. Several publications and recent EULAR recommendations have emhasized the place of this tool in the diagnosis of giant cell arteritis.

[Pre-hospitalization unit: A simple organization and a place for internists to improve the non-scheduled hospitalization stream from emergencies]. / Unité d'attente d'hospitalisation : une organisation simple et une place pour les internistes pour améliorer la filière d'hospitalisation non programmée à partir des urgences.

INTRODUCTION: The adult emergency department at Rouen University hospital (CHU) welcomes over 100.000 patients per year. In order to streamline unscheduled hospital admissions from the emergency room (ER), a 20-bed pre-hospitalization unit and a centralized bed management system (bed manager, bed manager software, dedicated beds) have been put into place. PATIENTS AND METHODS: Emergency admissions have increased by (+3.5% between 2017 and 2018) with 20% direct hospitalization from the ER to other conventional units (2/3 in medicine, 1/3 in surgery). In 2018, 3450 patients, of which 54% aged over 75 years have been admitted in the pre-hospitalization unit with an average length of stay of 1.3±1.4 days: 35.4% stayed less than 24hours and 34.8% more than 48hours of which 5.2% stated more than 4 days, 132 patients (3.8%) died, 805 patients (23.3%) were discharged at home, 220 (6.4%) transferred to another facility, and 2287 (66.3%) were secondarily hospitalized in another hospital unit: more than 9 times out of 10 in a medicine unit (internal medicine 30%, geriatrics 27.9%, respiratory medicine 12.2%). This unscheduled emergency hospitalization allowed a daily hospitalization of 50 short stay inpatients beds. It has to be noted that the number of available inpatient beds clearly decreases during the week-ends. The main pathologies were respiratory infections (14.2%), heart diseases (9.7%), metabolic disorders (3.9%), and urinary tract infections (13.6%). CONCLUSION: This pre-hospitalization unit associated with a centralized bed management system has clearly improved the unscheduled hospital admissions, in particular concerning the emergency medical sector. The lack of inpatient beds at the week-end and the management of epidemic periods still remain a challenge that has to be taken up.

[Stretching and chylothorax]. / Stretching et chylothorax.

INTRODUCTION: Chylothorax is a rare cause of pleural effusion. The most common causes are iatrogenic or medical. We report an unusual and rare cause of bilateral chylothorax. CASE REPORT: A 73-year-old woman with no past history was admitted to the emergency department for sudden onset of dyspnoea. Chest X-ray and thoracic CT scan revealed large bilateral pleural effusions. Analysis of the fluid revealed a chylothorax. The patient was treated by chest tube drainage and a fat free (medium chain triglyceride) diet. This led to drying up of the effusions and rapid discharge. Complementary imaging examinations with chest-abdomen-pelvis CT, PET CT and pelvic MRI did not reveal any underlying cause. The final diagnosis was bilateral traumatic chylothorax caused by tearing of the thoracic duct during stretching exercises. CONCLUSION: Following a literature review, similar cases with the same clinical presentation were found. Combined treatment with thoracic drainage and medium chain triglyceride diet was effective in drying up the effusions. Our diagnosis was a diagnosis of exclusion. It is important to exclude a medical cause by thorough investigation.

[Acute carpal tunnel syndrome caused by a thrombosis of a persistent median artery: 2 case reports]. / Canal carpien aigu : penser à la thrombose de l'artère persistante du nerf médian !

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.

[Which place of antiphosphatidylethanolamine antibodies research in seronegative antiphospholipid syndrome suspicion?] / Quelle place pour la recherche des anticorps antiphosphatidyléthanolamine dans la suspicion du syndrome des antiphospholipides séronégatif ?

PURPOSE: Antiphospholipid syndrome (APS) is a clinico-biological syndrome, which associates vascular injury and persisting antiphospholipid antibodies (aPL). Patients with clinical symptoms of APS but without aPL are defined as "seronegative APS" (SNAPS). The aim of this study was to evaluate antiphosphatidylethanolamine antibody (aPE) investigation in patients with SNAPS suspicion. METHODS: This retrospective study was conducted in patients with SNAPS suspicion. A homemade enzyme-linked immunosorbent assay (ELISA) was used to search for aPE. The results of this homemade method were compared with those from a global screening ELISA. RESULTS: Two hundred twenty-eight patients with SNAPS suspicion were included. Among them, 58.3% had a thrombotic event. The homemade ELISA found positive persisting aPE in 23 patients (10%): 15 with a thrombotic event, 6 with obstetrical morbidity and 2 with a combined event. The global screening ELISA was positive in only 11 of these 23 patients (47.8%). CONCLUSION: These results suggest the implication of aPE in SNAPS.

Tocilizumab for the treatment of birdshot uveitis that failed interferon alpha and anti-tumor necrosis factor-alpha therapy: two cases report and literature review.

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.

[Statins in primary prevention of cardiovascular disease]. / Statines en prévention primaire des événements cardiovasculaires.

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.

[Small fiber neuropathy]. / La neuropathie des petites fibres.

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.