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.

[Correlation between Objective structured clinical examinations (OSCE) and knowledge examination scores and analysis of factors associated with better OSCE success in fourth and fifth year medicine students at Dijon university hospital]. / Corrélation entre les notes obtenues aux ECOS et aux épreuves de connaissances et analyse des facteurs associés à une meilleure réussite aux ECOS chez les étudiants de DFASM1 et 2 au CHU de Dijon.

RATIONALE: Objective structured clinical examinations (OSCEs) were introduced to evaluate students not only on their knowledge, but also on their clinical skills and attitudes. The objectives were to study the correlation between OSCE scores and scores obtained to traditional knowledge examinations and to analyse factors associated with better OSCE performance in DFASM1 and 2 students at Dijon university hospital. METHODS: This was a prospective observational study conducted among all fourth and fifth year medical students in Dijon. The scores on the OSCE elective tests (2022) and the average score on the knowledge tests (2021-2022) were collected and their correlation measured. A questionnaire asked students about their demographic characteristics, their investment in formative and practicum OSCEs, their level of empathy (Jefferson questionnaire) and their personality traits (NEO-Pi-R). RESULTS: Of 549 students, 513 completed all tests. Scores on OSCE and faculty knowledge tests were correlated (r=0.39, P<0.001). Of these, 111 (20%) students responded to the questionnaire, and 97 were analized. We did not observe any significant difference between students who performed better on OSCEs than on knowledge tests and those who did not, regarding their age, their investment in formative tests, their personality traits or their level of empathy. CONCLUSION: Our results underline the need to optimize the evaluation of empathy and clinical skills in OSCE tests, using new tools, in order to better discriminate between students on these skills.

[Refeeding syndrome]. / Syndrome de renutrition inappropriée.

Refeeding syndrome (RS) is a rare but severe condition that is poorly understood, often under-diagnosed and can lead to death. It occurs within 5 days after refeeding in patients after prolonged fasting or in a context of undernutrition. As a consequence of the abrupt transition from catabolism to anabolism, RS is defined as a decrease in plasma levels of phosphorus, potassium and/or magnesium, whether or not associated with organ dysfunction resulting from a decrease in one of the electrolytes or a thiamine deficiency, after refeeding. The clinical symptoms are varied and non-specific and are related to hydro electrolyte disorders, sodium-hydroxide retention or failure of one or more organs. Patient management should be appropriate with regular clinical examination and careful biological monitoring, including hydro electrolyte monitoring. The correction of hydroelectrolytic disorders and systematic thiamine supplementation are essential during refeeding, that must be done carefully and very progressively, whatever its form (oral, enteral or parenteral). The severity of the refeeding syndrome indicates that its prevention and screening are the corners of its management in at-risk patients.

[Management of multirefractory immune thrombocytopenia]. / Prise en charge du purpura thrombopénique immunologique multiréfractaire.

Multirefractory immune thrombocytopenia (ITP) is defined by the absence of response to TPO receptor agonists, rituximab and splenectomy (or contraindicated or refused) and the need of treatment. The approach to multirefractory ITP must be systematic and firstly involves reconsidering the diagnosis. Inherited thrombocytopenia, lymphoid hemopathies and myelodysplastic syndrome are the main causes to be mentioned. Multirefractory ITP is often associated with secondary ITP with signs of clinical or biological autoimmunity, monoclonal gammopathy of undetermined significance and a poor response to corticosteroids. Therapeutic management is complex and is based on the combination of treatments. New treatments are being developed.

[Immune thrombocytopenia: From pathogenesis to treatment]. / Thrombopénie immunologique : de la physiopathologie aux traitements.

Immune thrombocytopenia (ITP) is a rare autoimmune disease due to an immune peripheral destruction of platelets and an inappropriate platelet production. The pathogenesis of ITP is now better understood: it involves a humoral immune response which dependents on the stimulation of B cells by specific T cells called T follicular helper cells, leading to their differentiation into plasma cells that produce antiplatelet antibodies thus promoting the phagocytosis of platelets mainly by splenic macrophages. The deciphering of ITP pathogenesis has led to a better understanding of the inefficiency of treatments such as rituximab, although it has not provided yet the determination of biological predictive factor of response to treatments. Moreover, new therapeutic perspectives have been opened in the last few years with the development of molecules targeting Fcγ receptor signalling such as Syk inhibitor, or molecules increasing the clearance of pathogenic autoantibodies such as inhibitors of the neonatal Fc receptor (FcRn).

[Transthyretin cardiac amyloidosis]. / L'amylose cardiaque à transthyrétine.

Transthyretin (TTR) cardiac amyloidosis results from the dissociation of the tetrameric, liver-synthetized transport protein, either because of a mutation (hereditary CA), or spontaneously due to ageing (wild type CA). Monomers self-associate into amyloid fibrils within the myocardium, causing heart failure, arrhythmias and conduction defects. This overlooked disease must be recognized in case of unexplained increased thickness of the myocardium, particularly in subjects of African descent, in patients with heart failure and preserved ejection fraction, and in those with aortic stenosis. Some extra-cardiac symptoms must also be considered as red flags: carpal tunnel syndrome, lumbar canal stenosis, recent deafness, peripheral neuropathy, or dysautonomia. Medical assessment includes an electrocardiogram, biological assessment including troponin, natriuretic peptide and monoclonal protein assay, echocardiography with 2-D strain study, MRI and bone scintigraphy. Once the diagnosis established, cardiologic management must avoid beta-blockers and other rate-slowing drugs, which are deleterious in restrictive cardiomyopathy, and restrain the use of renin-angiotensin system inhibitors, of little use and often poorly tolerated. Congestion must be treated with diuretics. Anticoagulants are often necessary due to the risk of arrhythmias and stroke. Pacemaker or defibrillator implantation should be determined in patients with high risk of sudden death. Until now, etiologic treatments were liver and/or heart transplantation in some rare cases. Tafamidis, a TTR stabilizer has recently been approved, and new therapeutic approaches targeting TTR at the transcriptional level are under investigation.

Endovascular stenting for chronic femoro-iliac venous obstructive disease: Clinical efficacy and short-term outcomes.

PURPOSE: To report the clinical efficacy and mid-term outcomes of endovascular treatment in patients with chronic, symptomatic, post-thrombotic femoro-iliac venous obstruction. MATERIALS AND METHODS: Forty-two patients with post-thrombotic syndrome (PTS) presenting with femoro-iliac venous obstructive lesions treated in our institution by endovascular approach between March 2012 and October 2017 were retrospectively included. There were 27 women and 15 men with a mean age of 47.3±17 (SD) years (range: 22-86 years). Procedure included first venous recanalization, then pre-dilatation and self-expandable metallic stenting of the narrowed or occluded iliac and/or femoral veins. Severity of PTS and quality of life were assessed at baseline and 3 months after the intervention respectively, using Villalta score and Chronic Venous Insufficiency Questionnaire (CIVIQ-20) scale. Imaging follow-up evaluation of stent patency was based on the results of duplex Doppler ultrasound and computed tomography. RESULTS: Immediate technical success was achieved in 41/42 (97.6%) patients, without any major complications. Primary patency, primary assisted patency and secondary patency at the end of the median imaging follow-up of 18.1 months (IQR, 9.7-34.4) were achieved in 29/42 (66.7%) patients, 33/42 (78.6%) patients and 37/42 (88.1%) patients, respectively. Median Villalta and CIVIQ-20 scores decreased from 14 (IQR, 10-19) and 57 (IQR, 39-72) at baseline, respectively, to 5 (IQR, 2-9) and 30 (IQR, 24-50) 3 months after the procedure, respectively (P<0.0001), showing significant decrease in the severity of PTS and improvement in the quality of life. The multiple linear regression model showed that both baseline Villalta and CIVIQ-20 scores ([95% CI: -7.80-3.79; P<0.0001] and [95% CI: 0.07-0.20; P<0.0001], respectively), age (95% CI: 0.04-0.19; P=0.002) and stenting expanse (95% CI: 0.97-5.65; P=0.006) were independent variables related to Villalta gain. Baseline Villalta (95% CI: 0.89-2.23; P<0.0001) was the single independent variable related to CIVIQ-20 gain. CONCLUSION: This study confirms the high clinical efficacy and favorable mid-term outcomes of endovascular stenting in patients with chronic symptomatic femoro-iliac venous obstructive lesions.

Fcγ receptor expression on splenic macrophages in adult immune thrombocytopenia.

Splenic macrophages play a key role in immune thrombocytopenia (ITP) pathogenesis by clearing opsonized platelets. Fcγ receptors (FcγR) participate in this phenomenon, but their expression on splenic macrophages and their modulation by treatment have scarcely been studied in human ITP. We aimed to compare the phenotype and function of splenic macrophages between six controls and 24 ITP patients and between ITP patients according to the treatments they received prior to splenectomy. CD86, human leucocyte antigen D-related (HLA-DR) and FcγR expression were measured by flow cytometry on splenic macrophages. The major FcγR polymorphisms were determined and splenic macrophage function was assessed by a phagocytosis assay. The expression of the activation markers CD86 and HLA-DR was higher on splenic macrophages during ITP compared to controls. While the expression of FcγR was not different between ITP and controls, the phagocytic function of splenic macrophages was reduced in ITP patients treated with intravenous immunoglobulin (IVIg) within the 2 weeks prior to splenectomy. The FCGR3A (158V/F) polymorphism, known to increase the affinity of FcγRIII to IgG, was over-represented in ITP patients. Thus, these are the first results arguing for the fact that the therapeutic use of IVIg during human chronic ITP does not modulate FcγR expression on splenic macrophages but decreases their phagocytic capabilities.

[Routine screening of splenic or portal vein thrombosis after splenectomy]. / Dépistage systématique d'une thrombose veineuse splénique ou portale après splénectomie.

BACKGROUND: Portal and/or splenic vein thrombosis (PSVT) is common after splenectomy. It can be a life-threatening complication, with a risk of bowel ischemia and portal hypertension. An early diagnosis allows an effective medical treatment and prevents life-threatening complications. There is no consensus regarding the benefit of systematic screening of patients after splenectomy for PSVT. We started in January 2012 a routine screening of PSVT after elective splenectomy. The aim of this study was to assess this policy. METHODS: Since January 2012, all patients undergoing an elective splenectomy had an abdominal CT-scan on postoperative-day 7. Demographic data, pathology, type of surgery, platelet counts before and after surgery, outcome, results of medical imaging, and management of PSVT and its results were recorded. RESULTS: Over 3 years, 52 patients underwent an elective splenectomy. All of them had a CT-scan at postoperative-day 7. A PSVT was found in 11 patients (21.2 %). They were all asymptomatic. Lymphoma and splenomegaly were the main factors associated with PSVT in the univariate analysis. All patients with PSVT were treated with anticoagulation and no complication of PSVT occurred. The follow-up CT confirmed the efficacy of anticoagulation therapy in all patients. CONCLUSIONS: Routine screening of PSVT after elective splenectomy is warranted because it allows to start anticoagulant therapy and avoid further life-threatening complications. The incidence of PSVT is particularly high among patients operated on for lymphoma or with splenomegaly.

Is there still a place for "old therapies" in the management of immune thrombocytopenia?

New molecules such as rituximab or thrombopoietin receptor agonists (romiplostim and eltrombopag) have changed the management of immune thrombocytopenia. Therefore, old drugs which are less expensive and with a well-known benefit/risk ratio are being underused. We aim to define the place of dapsone, danazol, hydroxychloroquine and vinca-alkaloids at the era of targeted therapy in immune thrombocytopenia. With a response rate around 30% to 50%, dapsone is an interesting second-line therapy to be used just after corticosteroids. Patients with positive antinuclear antibodies can benefit from hydroxychloroquine with a 50% response rate. Because of its side effects, mostly virilization, danazol will be preferentially used in the elderly. Vinca-alkaloids could be temporarily used in patients that do not respond to intravenous immunoglobulins or to limit their use to avoid shortage periods.

[Diagnosis of an increased serum level of ferritin]. / Démarche diagnostique devant une hyperferritinémie.

The discovery of a hyperferritinemia is most of the time fortuitous. The diagnostic approach aims at looking for the responsible etiology and at verifying if an iron hepatic overload is present or not. Three diagnostic steps are proposed. The clinical elements and a few straightforward biological tests are sufficient at first to identify one of the four main causes: alcoholism, inflammatory syndrome, cytolysis, and metabolic syndrome. None of these causes is associated with a significant iron hepatic overload. If the transferring saturation coefficient is raised (>50%) a hereditary hemochromatosis should be discussed. Secondly, less common disorders will be discussed. Among these, only the chronic hematological disorders either acquired or congenital are at risk of iron hepatic overload. Thirdly, if a doubt persists in the etiologic research, and the serum ferritin level is very high or continues to rise, it is essential to verify that there is no iron hepatic overload. For that purpose, the MRI with study of the iron overload is the main test, which will guide the therapeutic attitude. Identification of more than a single etiology occurs in more than 40% of the cases.

Severe cardiomyopathy revealing antineutrophil cytoplasmic antibodies-negative eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of systemic vasculitis in which cardiac involvement is frequent and severe, and accounts for half of EGPA-related deaths. ANCA-positive EGPA differs from ANCA-negative EGPA in that the former is significantly associated with renal involvement, peripheral neuropathy and biopsy proven vasculitis, whereas the latter is associated with cardiac involvement. Herein, we report a case of EGPA with myocarditis in a woman, who was successfully treated with steroids and cyclophosphamide. This report highlights the importance of diagnosing cardiac involvement in EGPA early, especially in ANCA-negative patients.

The reversed halo sign: pathognomonic pattern of pulmonary mucormycosis in leukemic patients with neutropenia?

BACKGROUND: Pulmonary mucormycosis (PM) is a life-threatening fungal infection with an increasing incidence among patients with acute leukemia. In some immunocompromised hosts, the reversed halo sign (RHS) has been described on the pulmonary computed tomographic (CT) scan of patients with mucormycosis. METHODS: This study reports a single-center experience with PM exclusively in patients with acute leukemia. Clinical records, laboratory results, and CT scans were retrospectively analyzed to evaluate the clinical usefulness of the RHS for the early identification and treatment of PM, with regard to outcomes in these patients. RESULTS: Between 2003 and 2012, 16 cases of proven PM were diagnosed among 752 consecutive patients receiving chemotherapy for acute myeloblastic or lymphoblastic leukemia. At the time PM was diagnosed, all patients but one were neutropenic. The study of sequential thoracic CT scans showed that during the first week of the disease, the RHS was observed in 15 of 16 patients (94%). Initially, other radiologic findings (multiple nodules and pleural effusion) were less frequent, but appeared later in the course of the disease (6% and 12% before vs 64% and 55% after the first week). After the diagnosis of PM, median overall survival was 25 weeks (range, 3-193 weeks), and 6 patients (38%) died before day 90. CONCLUSIONS: In the particular setting of neutropenic leukemia patients with pulmonary infection, the presence of the RHS on CT was a strong indicator of PM. It could allow the early initiation of appropriate therapy and thus improve the outcome.

Pathogenesis of giant cell arteritis: new insight into the implication of CD161+ T cells.

Giant cell arteritis (GCA) is a granulomatous large-vessel vasculitis that usually affects the aorta and/or its major branches, especially the branches of the carotid arteries. Histo-pathological lesions are observed in all layers of the artery leading to segmental and focal panarteritis with a polymorphic cell infiltrate that includes T cells, macrophages and multinucleated giant cells, a fragmented internal elastic lamina and intimal hyperplasia. The pathophysiology of GCA is complex and not fully understood. In this review, we discuss the immunological aspects of GCA pathogenesis with a particular emphasis on T cell responses. Upon dendritic cell activation in the adventitia, CD4 T cells co-expressing CD161 are recruited in the arterial wall and polarised into Th1 and Th17 cells that produce IFN-γ and IL-17, respectively. These cytokines activate macrophages, giant cells and vascular smooth muscle cells, thus inducing vascular remodelling which leads to the ischaemic manifestations of GCA. Macrophages infiltrating the adventitia produce IL-1ß and IL-6, which are responsible for the general symptoms encountered in GCA.

[Isolated tracheobronchial involvement by atrophic polychondritis: role of PET scanning]. / Atteinte trachéobronchique isolée de la polychondrite atrophiante: intérêt du TEP-scanner.

INTRODUCTION: Atrophic polychondritis is a rare and serious disease characterised by multifocal inflammatory lesions of cartilage. The diagnosis, though urgent, is difficult when there is isolated tracheal involvement. CASE REPORT: We report the case of a woman of 55 with recent, non-infectious febrile episodes accompanied by a steroid sensitive inflammatory syndrome. Auscultation, lung function tests and a thoracic CT scan suggested tracheobronchomalacia. Atrophic polychondritis was suspected without being confirmed on the basis of histological or biological tests; particularly as no other cartilaginous involvement was discovered. Laryngeal and tracheal hypermetabolism on a PET scan, performed in the absence of corticosteroid treatment, was also in favour of this diagnosis. One month after resumption of steroid treatment at increased dosage, this examination was normal. Secondarily, after careful reduction of steroids, the patient developed nasal chondritis, confirming the diagnosis of atrophic polychondritis. CONCLUSION: The PET scanner could be useful in the diagnosis of atrophic polychondritis in its isolated tracheobronchial form. Its place in the follow-up of this disease remains to be evaluated and should take account of the irradiation dose of this examination.

Haemolytic-uraemic syndrome during severe lupus nephritis: efficacy of plasma exchange.

Systemic lupus erythematosus (SLE) has been described as a cause of thrombotic microangiopathy, especially thrombotic thrombocytopenic purpura (TTP). Haemolytic-uraemic syndrome (HUS) is less frequent in SLE. We report a case of such an association during an episode of severe lupus nephritis in a young woman, who was successfully treated with steroids, cyclophosphamide and especially plasma exchange with plasma replacement. This report highlights the importance of recognising atypical HUS in SLE patients by looking for schistocytes in case of haemolytic anemia with a negative antiglobulin test, in order to begin plasma exchange.

Scalp vein thrombosis mimicking giant cell arteritis relapse.

Scalp vein thrombosis is an unusual complication during giant cell arteritis. Revealed by headache, it can be misdiagnosed as a disease relapse. An ultrasound scan should rapidly be performed to make the diagnosis, avoiding inappropriate treatment escalation.