Bleeding complications and antithrombotic treatment in 264 pregnancies in antiphospholipid syndrome.

Purpose The purpose of this study was to evaluate the safety of antithrombotic treatments prescribed during pregnancy in patients with antiphospholipid syndrome (APS). Methods This international, multicenter study included two cohorts of patients: a retrospective French cohort and a prospective US cohort (PROMISSE study). Inclusion criteria were (1) APS (Sydney criteria), (2) live pregnancy at 12 weeks of gestation (WG) with (3) follow-up data until six weeks post-partum. According to APS standard of care, patients were treated with aspirin and/or low-molecular weight heparin (LMWH) at prophylactic (pure obstetric APS) or therapeutic doses (history of thrombosis). Major bleeding was defined as abnormal blood loss during the pregnancy and/or post-partum period requiring intervention for hemostasis or transfusion, or during the peripartum period greater than 500 mL and/or requiring surgery or transfusion. Other bleeding events were classified as minor. Results Two hundred and sixty-four pregnancies (87 prospectively collected) in 204 patients were included (46% with history of thrombosis, 23% with associated systemic lupus). During pregnancy, treatment included LMWH ( n = 253; 96%) or low-dose aspirin ( n = 223; 84%), and 215 (81%) patients received both therapies. The live birth rate was 89% and 82% in the retrospective and prospective cohorts, respectively. Adverse pregnancy outcomes occurred in 28% of the retrospective cohort and in 40% of the prospective cohort. No maternal death was observed in either cohort. A combined total of 45 hemorrhagic events (25%) occurred in the retrospective cohort, but major bleeding was reported in only six pregnancies (3%). Neither heparin nor aspirin alone nor combined therapy increased the risk of hemorrhage. We also did not observe an increased rate of bleeding in the case of a short interval between last LMWH (less than 24 hours) or aspirin (less than five days) doses and delivery. Only emergency Caesarean section was significantly associated with an increased risk of bleeding (odds ratio (OR) 5.03 (1.41-17.96); p=.016). In the prospective cohort, only one minor bleeding event was reported (vaginal bleeding). Conclusion Our findings support the safety of antithrombotic therapy with aspirin and/or LMWH during pregnancy in high-risk women with APS, and highlight the need for better treatments to improve pregnancy outcomes in APS. PROMISSE Study ClinicalTrials.gov identifier: NCT00198068.

[Type 3 Gaucher disease, also an adult disease?] / Maladie de Gaucher de type 3, une maladie également de l'adulte ?

INTRODUCTION: Gaucher disease is a genetic lysosomal storage disorder due to a glucocerebrosidase deficiency. Type 3, including neurological impairment, may have a specific phenotype in the context of the D409H mutation. OBSERVATION: We report the case of a 22-year-old woman who presented with Gaucher disease. Enzyme replacement therapy by imiglucerase was followed by rapid clinical and biological improvement. However, communication difficulties, which were initially attributed to the language barrier, revealed neurological impairment. After complementary assessment, the diagnosis of type 3 Gaucher disease was suspected. Gene analysis of the glucocerebrosidase showed a homozygous D409H mutation. CONCLUSION: This mutation results in calcified heart valves, corneal opacities, alteration of oculomotricity and hydrocephalus. The mild manifestation at onset and the late neurological involvement in the medical history make the diagnosis more difficult. This particular clinical phenotype deserves to be known in adult medicine departments.

Diagnosis of primary antibody and complement deficiencies in young adults after a first invasive bacterial infection.

OBJECTIVES: Screening for primary immunodeficiencies (PIDs) in adults is recommended after two severe bacterial infections. We aimed to evaluate if screening should be performed after the first invasive infection in young adults. METHODS: Eligible patients were retrospectively identified using hospital discharge and bacteriology databases in three centres during a 3-year period. Eighteen to 40-year-old patients were included if they had experienced an invasive infection with encapsulated bacteria commonly encountered in PIDs (Streptococcus pneumoniae (SP), Neisseria meningitidis (NM), Neisseria gonorrhoeae (NG), Haemophilus influenzae (HI), or group A Streptococcus (GAS)). They were excluded in case of general or local predisposing factors. Immunological explorations and PIDs diagnoses were retrieved from medical records. Serum complement and IgG/A/M testings were systematically proposed at the time of study to patients with previously incomplete PID screening. RESULTS: The study population comprised 38 patients. Thirty-six had experienced a first invasive episode and a PID was diagnosed in seven (19%): two cases of common variable immunodeficiency revealed by SP bacteraemia, one case of idiopathic primary hypogammaglobulinaemia, and two cases of complement (C6 and C7) deficiency revealed by NM meningitis, one case of IgG2/IgG4 subclasses deficiency revealed by GAS bacteraemia, and one case of specific polysaccharide antibody deficiency revealed by HI meningitis. Two patients had previously experienced an invasive infection before the study period: in both cases, a complement deficiency was diagnosed after a second NM meningitis and a second NG bacteraemia, respectively. CONCLUSION: PID screening should be considered after a first unexplained invasive encapsulated-bacterial infection in young adults.

Role of B cells in the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is an orphan disease characterized by progressive fibrosis of the skin and internal organs. Aside from vasculopathy and fibrotic processes, its pathogenesis involves an aberrant activation of immune cells, among which B cells seem to play a significant role. Indeed, B cell homeostasis is disturbed during SSc: the memory subset is activated and displays an increased susceptibility to apoptosis, which is responsible for their decreased number. This chronic loss of B cells enhances bone marrow production of the naïve subset that accounts for their increased number in peripheral blood. This permanent activation state can be explained mainly by two mechanisms: a dysregulation of B cell receptor (BCR) signaling, and an overproduction of B cell survival signals, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). These disturbances of B cell homeostasis induce several functional anomalies that participate in the inflammatory and fibrotic events observed during SSc: autoantibody production (some being directly pathogenic); secretion of pro-inflammatory and pro-fibrotic cytokines (interleukin-6); direct cooperation with other SSc-involved cells [fibroblasts, through transforming growth factor-ß (TGF-ß) signaling, and T cells]. These data justify the evaluation of anti-B cell strategies as therapeutic options for SSc, such as B cell depletion or blockage of B cell survival signaling.

[Tolerance of bevacizumab therapy in systemic sclerosis-associated pulmonary arterial hypertension: A case report]. / Tolérance du bévacizumab au cours de l'hypertension artérielle pulmonaire associée à la sclérodermie systémique : à propos d'une observation.

INTRODUCTION: No data is available regarding the safety of bevacizumab, an anti-vascular endothelial growth factor-A (VEGF-A) antibody, in patients with pulmonary arterial hypertension (PAH), a condition in which VEGF seems to play a significant and probably protective role. CASE REPORT: We report a patient with a history of systemic sclerosis-associated PAH, stable under bosentan therapy. She was diagnosed with metastatic cervical epidermoid carcinoma and treated by two successive cytotoxic chemotherapy regimens. As these treatments failed to control disease progression, she was started on anti-angiogenic therapy: 3 infusions of bevacizumab 15 mg/kg were administered. Over the course of this treatment, no change in the clinical status or echocardiography parameters was noted. CONCLUSION: This observation suggests that, under careful clinical and echocardiographic follow-up, bevacizumab therapy can be well tolerated in case of stable and moderate PAH. Decision of treatment should be taken cautiously, as the possibility of PAH worsening is not excluded.

[Acute arterial thrombosis in a context of hyperhomocysteinemia: Case report and literature review]. / Thrombose artérielle aiguë dans un contexte d'hyperhomocystéinémie : à propos d'un cas et revue de la littérature.

INTRODUCTION: Hyperhomocysteinemia is a biological marker that could be identified in the venous thrombotic events and rarely during acute arterial thrombotic events. The consequences can be serious. Effective diagnostic strategy is needed to optimize the management. CASE REPORT: Following bariatric surgery, a 40-year-old patient was admitted with an acute encephalopathy associated with peripheral lower limb arterial ischemia. The diagnostic work-up identified a major hyperhomocysteinemia whose causes were several. Surgical treatment and anticoagulation was associated with vitamins and trace elements supplementation. Correcting deficiencies allowed delirium and hyperhomocysteinemia improvement. Once treatment established, the patient did not present a recurrent thrombotic episode. CONCLUSION: Major hyperhomocysteinemia seems to be associated with an increased risk of acute arterial thrombosis. This marker might be considered in nutritional deficiency situations with appropriate support on the vascular, metabolic and nutrition level.

[Chronic fatigue syndrome: A new disorder?] / Le syndrome de fatigue chronique : une nouvelle maladie ?

More than 30 years after its individualization, chronic fatigue syndrome (CFS) remains a debilitating condition for the patient and a confusing one to the physicians, both because of diagnostic difficulties and poorly codified management. Despite the numerous work carried out, its pathophysiology remains unclear, but a multifactorial origin is suggested with triggering (infections) and maintenance (psychological) factors as well as the persistence of inflammatory (low grade inflammation, microglial activation…), immunologic (decrease of NK cells, abnormal cytokine production, reactivity to a variety of allergens, role of estrogens…) and muscular (mitochondrial dysfunction and failure of bioenergetic performance) abnormalities at the origin of multiple dysfunctions (endocrine, neuromuscular, cardiovascular, digestive…). The complexity of the problem and the sometimes contradictory results of available studies performed so far are at the origin of different pathophysiological and diagnostic concepts. Based on a rigorous analysis of scientific data, the new American concept of Systemic Disease Exertion Intolerance proposed in 2015 simplifies the diagnostic approach and breaks with the past and terminologies (CFS and myalgic encephalomyelitis). It is still too early to distinguish a new disease, but this initiative is a strong signal to intensify the recognition and management of patients with CFS and stimulate research.

Antiviral therapy of primary cytomegalovirus infection with vascular thrombosis in immunocompetent adults.

BACKGROUND: Vascular thromboembolism (VTE) complicating cytomegalovirus (CMV) primary infection is increasingly reported in immunocompetent adults. No guideline is, however, currently available for the management of these infections and particularly for the antiviral therapy indication. METHODS: We performed a literature review of VTE complicating CMV primary infection in immunocompetent adults using PubMed. RESULTS: Sixty-nine case patients of VTE complicating CMV primary infection were reported. The main sites of venous thrombosis were the splanchnic veins (30 patients) or those of the lower limbs (18 patients). One-third of patients presented with pulmonary embolism (25 patients). Forty-nine patients (76%) had at least one VTE risk factor, inherited or acquired thrombophilia for 37 patients (58%), and another risk factor for 27 patients (42%). Only 11 patients received an antiviral therapy. A positive outcome was observed in all patients. CONCLUSION: We suggest that antiviral therapy should be considered for patients presenting with severe VTE, VTE with a negative outcome despite anticoagulation, severe organ involvement, or for patients managed in the intensive care unit.

[Pseudo-adult Still's disease, anasarca, thrombotic thrombocytopenic purpura and dysautonomia: An atypical presentation of multicentric Castleman's disease. Discussion of TAFRO syndrome]. / Pseudo-maladie de Still, anasarque, microangiopathie thrombotique et dysautonomie : présentation atypique d'une maladie de Castleman multicentrique. Discussion du syndrome TAFRO.

INTRODUCTION: Multicentric Castleman's disease can mimic adult-onset Still disease. It is exceptionally associated with anasarca, thrombotic microangiopathy and dysautonomia. CASE REPORT: We report a 32-year-old woman with an association of oligoanuria, anasarca, thrombotic microangiopathy with features compatible with adult-onset Still disease. The outcome was initially favorable with corticosteroids, immunoglobulins and plasmapheresis but with the persistence of relapses marked by severe autonomic syndrome and necessity of high dose corticosteroids. The diagnosis of mixed type Castleman's disease, HHV8 and HIV negative, was obtained four years after the onset of symptoms by a lymph node biopsy. The outcome was favorable after tocilizumab and corticosteroids but tocilizumab had to be switched to anakinra to ensure a proper and long-lasting control of the disease. CONCLUSION: Our patient partially fits the description of TAFRO syndrome (Thrombocytopenia, Anasarca, myeloFibrosis, Renal dysfunction, Organomegaly), a MCM rare variant, recently described in Japanese patients.

[Adequacy of antibiotic therapy for urinary tract infection in a Medical Department from the university hospital of Lille: A retrospective cohort study]. / Évaluation de la qualité de l'antibiothérapie des infections urinaires dans le service de médecine polyvalente post-urgence du CHRU de Lille: une étude de cohorte rétrospective.

INTRODUCTION: The main objective of the study was to assess the adequacy of antibiotic therapy for urinary tract infections (UTI) in a French hospital medical department. The secondary objective was to identify factors associated with inadequacy of the antibiotic therapy. METHODS: A retrospective single centre cohort study was performed in the Post-Emergency Medicine Department (PEMD) of the university hospital of Lille. All patients presenting with an UTI from May 2012 to April 2014 were included. Adequacy of antibiotic therapy was assessed with reference to local guidelines. Factors associated with inadequacy of antibiotic prescription were determined using a multivariate logistic regression model. RESULTS: Two hundred and twenty-eight patients were included. The antibiotic prescription was fully adequate in 173 patients (76%) with appropriate use of a single or a combination antibiotic therapy in 96%, appropriate drug in 80%, appropriate dosage in 89% and appropriate route of administration in 95%. The risk for antibiotic inadequacy was significantly higher in patients with cystitis than in those with pyelonephritis (OR 12.01; 95% CI 4.17-34.65), when antibiotics were prescribed in the Emergency Department (OR 6.84; 95% CI 2.29-20.47) or before hospital admission (OR 382.46; 95% CI 19.61≥999.99) compared to when antibiotics were first administered in the PEMD, and in patients with severe UTI (OR 19.55; 95% CI 2.79-137.01). CONCLUSION: Adequacy of antibiotic therapy for UTI is relatively high in our study, reflecting the effective dissemination of antibiotic guidelines. However, antibiotic therapy is still inappropriate in cystitis, severe UTI and in case of prescription before the admission in the PEMD.

[Pharmacovigilance center --internal medicine interactions: A useful diagnostic tool]. / Interactions pharmacovigilance--service de médecine interne: une aide précieuse au diagnostic.

PURPOSE: Patients hospitalized in internal medicine often have unexplained clinical symptoms for which a drug origin can be considered. The prevalence of patients hospitalized for iatrogenic is estimated between 4-22%. We wanted to evaluate the diagnostic value of the regional center of pharmacovigilance to identify or confirm an iatrogenic disease in the department of internal medicine of Lille and characterize factors associated with drug-related side effect. METHODS: This is a single-center prospective diagnostic study. We included all subsequent requests from the department of internal medicine with the Nord-Pas-de-Calais regional pharmacovigilance center between 2010 and 2012. The opinion of the regional pharmacovigilance centre was held on the record of the adverse drug reaction in the national pharmacovigilance database and analyzed according to the conclusion of iatrogenic used by clinicians in internal medicine (reference diagnosis) with a follow-up to June 2013. The variables relating to the patient, medication and adverse events were analyzed by binary logistic regression. RESULTS: We analyzed 160 contacts: 118 concordant cases, 38 false-positives (drug-related side effect retained by the regional pharmacovigilance center only), 4 false negatives. Registration in the national pharmacovigilance database had a sensitivity of 96% (95% CI [0.92 to 0.99]), a specificity of 46% (95% CI [0.38 to 0.53]), a value positive predictive of 69% (95% CI [0.62 to 0.76]), a negative predictive value of 89% (95% CI [0.84 to 0.94]) and a negative likelihood ratio of 0.1. False-positive had chronological and semiological accountabilities questionable (adjusted RR=2.1, 95% CI [1.2 to 2.8]). CONCLUSION: In our study, the regional pharmacovigilance center confirms the clinician's suspicion of drug-related side effects and helps to exclude drug-induced with a high negative predictive value.

Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder associated with abnormal angiogenesis and disabling epistaxis. Tranexamic acid (TA) has been widely used in the treatment of these severe bleeds but with no properly designed trial. OBJECTIVES: To demonstrate the efficacy of TA in epistaxis in HHT patients and to explore its safety of use. PATIENTS/METHODS: A randomized, placebo-controlled, double-blind, cross-over trial was conducted. Participants were randomized to receive TA (3 g a day) then placebo or the opposite sequence. The main analysis compared intra-individual mean duration of epistaxis under TA vs. placebo on a log scale. The primary outcome was the mean duration of epistaxis per month, assessed with specific grids to be completed by participants. The number of epistaxis episodes was recorded as a secondary outcome. RESULTS: A total of 118 randomized patients contributed to the statistical analysis. The mean duration of epistaxis per month was significantly shorter with TA than placebo (0.19 on the log scale; SD = 0.07; P = 0.005), corresponding to a decrease of 17.3% (15.7 min) in the duration of epistaxis per month (CI 95%, 5.5-27.6). The median number of epistaxis episodes per month was 22.1 episodes in the placebo arm vs. 23.3 episodes in the TA arm. No thrombophlebitis was observed. CONCLUSIONS: In the ATERO study, we demonstrated a significant decrease in the duration of epistaxis in HHT patients taking TA. No safety issues were recorded in our cohort of patients.

Gastrointestinal mucosal abnormalities using videocapsule endoscopy in systemic sclerosis.

BACKGROUND: To date, there are no large studies on videocapsule endoscopy in systemic sclerosis (SSc). Consequently, the prevalence and features of gastrointestinal mucosal abnormalities in SSc have not been determined. AIMS: To determine both prevalence and characteristics of gastrointestinal mucosal abnormalities in unselected patients with SSc, using videocapsule endoscopy. To predict which SSc patients are at risk of developing potentially bleeding gastrointestinal vascular mucosal abnormalities. METHODS: Videocapsule endoscopy was performed on 50 patients with SSc. RESULTS: Prevalence of gastrointestinal mucosal abnormalities was 52%. Potentially bleeding vascular mucosal lesions were predominant, including: watermelon stomach (34.6%), gastric and/or small intestinal telangiectasia (26.9%) and gastric and/or small intestinal angiodysplasia (38.5%). SSc patients with gastrointestinal vascular mucosal lesions more often exhibited: limited cutaneous SSc (P = 0.06), digital ulcers (P = 0.05), higher score of nailfold videocapillaroscopy (P = 0.0009), anaemia (P = 0.02), lower levels of ferritin (P < 0.0001) and anti-centromere antibody. CONCLUSIONS: Our study identifies a high frequency of gastrointestinal mucosal abnormalities in SSc, with a marked predominance of vascular mucosal damage. Furthermore, our study shows a strong correlation between gastrointestinal vascular mucosal lesions and presence of severe extra-digestive vasculopathy (digital ulcers and higher nailfold videocapillaroscopy scores). This latter supports the theory that SSc-related diffuse vasculopathy is responsible for both cutaneous and digestive vascular lesions. Therefore, we suggest that nailfold videocapillaroscopy may be a helpful test for managing SSc patients. In fact, nailfold videocapillaroscopy score should be calculated routinely, as it may result in identification of SSc patients at higher risk of developing potentially bleeding gastrointestinal vascular mucosal lesions.

The hand in systemic diseases other than rheumatoid arthritis.

This review outlines the skin, vascular and musculoskeletal symptoms affecting the hand during systemic inflammatory diseases other than rheumatoid arthritis. Skin lesions are diagnosed clinically and their symptomatology is documented through an extensive series of photographs. These conditions may require specific care before a surgical procedure can be performed. Vascular lesions are also diagnosed clinically and their symptomatology is described in detail. It is important to recognize that acrocyanosis is always benign. The surgeon should be able to distinguish between primary, but benign Raynaud's disease and secondary Raynaud's syndrome, which has a high risk of finger necrosis. Current preventative and curative treatments for finger necrosis are described. The clinical, radiological, progressive and therapeutic features of musculoskeletal lesions are reviewed, namely those associated with psoriatic arthritis, systemic sclerosis and lupus.