[Endothelial dysfunction in thrombotic thrombocytopenic purpura: therapeutic perspectives]. / Dysfonction endothéliale au cours du Purpura Thrombotique Thrombocytopénique : un nouvel axe de prise en charge ?

Immune Thrombotic Thrombocytopenic Purpura (iTTP) is a rare but severe disease with a mortality rate of almost 100 % in the absence of adequate treatment. iTTP is caused by a severe deficiency in ADAMTS13 activity due to the production of inhibitory antibodies. Age has been shown to be a major prognostic factor. iTTP patients in the elderly (60yo and over) have more frequent organ involvement, especially heart and kidney failures compared with younger patients. They also have non-specific neurologic symptoms leading to a delayed diagnosis. Factors influencing this impaired survival among older patients remain unknown so far. Alteration of the functional capacity of involved organs could be part of the explanation as could be the consequences of vascular aging. In fact, severe ADAMTS13 deficiency is necessary but likely not sufficient for iTTP physiopathology. A second hit leading to endothelial activation is thought to play a central role in iTTP. Interestingly, the mechanisms involved in endothelial activation may share common features with those involved in vascular aging, potentially leading to endothelial dysfunction. It could thus be interesting to better investigate the causes of mid- and long-term mortality among older iTTP patients to confirm whether inflammation and endothelial activation really impact vascular aging and long-term mortality in those patients, in addition to their presumed role at iTTP acute phase. If so, further insights into the mechanisms involved could 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.

[Olmesartan therapy and enteropathy: About two cases and review of the literature]. / Traitement par olmésartan et entéropathie : à propos de deux cas et revue de la littérature.

INTRODUCTION: Olmesartan is an angiotensin II receptor blocker, used to treat arterial hypertension. Severe digestive manifestations have been associated with olmesartan, including sprue-like enteropathy and lymphocytic colitis. OBSERVATIONS: We report two cases of sprue-like enteropathy associated with olmesartan, leading to malabsorption syndrome related to villous atrophy. After olmesartan discontinuation, patients exhibited resolution of clinical digestive symptoms and disappearance of biochemical abnormalities. CONCLUSION: Our case reports underscore that accurate questioning is crucial in diagnostic approach, allowing to make the diagnosis of sprue-like enteropathy related to olmesartan in our patients. Interestingly, particular attention has recently been drawn to the fact that sprue-like disease may be a class effect of angiotensin II receptor blockers; further investigations are warranted to confirm these latter data.

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.

[Erythromelalgia: Diagnosis and therapeutic approach]. / L'érythromélalgie : approche diagnostique et thérapeutique actuelle.

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.

Assessment of endothelial damage and cardiac injury in a mouse model mimicking thrombotic thrombocytopenic purpura.

Essentials Endothelial injury is thought to be a key event in thrombotic thrombocytopenic purpura (TTP). Endothelial and cardiac damages were assessed in a model of TTP using ADAMTS-13 knockout mice. Damages of cardiac perfusion and function were associated with nitric oxide pathway alteration. Endothelial dysfunction constitutes a critical event in TTP development and cardiac injury. SUMMARY: Background Cardiac alterations represent a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). Endothelial injury remains poorly defined, but seems to be a key initiating event leading to the formation of platelet-rich thrombi in TTP patients. Objectives To assess the changes in endothelial function and the induced cardiac damage in a mouse model of TTP. Patients/methods We used an animal model in which TTP-like symptoms are triggered by injection of 2000 units kg-1 of recombinant von Willebrand factor in ADAMTS-13 knockout mice. Results These mice developed TTP-like symptoms, i.e. severe thrombocytopenia, schistocytosis, and anemia. On day 2, magnetic resonance imaging demonstrated a decrease in left ventricular perfusion associated with alteration of left ventricular ejection fraction, fractional shortening, and cardiac output, suggesting early systolic dysfunction. This was associated with decrease in endothelium-mediated relaxation responses to acetylcholine in mesenteric and coronary arteries, demonstrating severe early endothelial dysfunction. In parallel, we showed decreased cardiac expression of endothelial nitric oxide (NO) synthase and increased expression of antioxidant enzymes, suggesting alteration of the NO pathway. At this time, cardiac immunohistochemistry revealed an increase in the expression of VCAM-1 and E-selectin. Conclusion This study provides evidence that the heart is a sensitive target organ in TTP, and shows, for the first time, strong mesenteric and coronary endothelial dysfunction in an induced-TTP model. The mechanisms incriminated are the occurrence of a pro-oxidant state, and proadhesive and proinflammatory phenotypes. This previously largely unrecognized vascular dysfunction may represent an important contributor to the systemic organ failure occurring in TTP.

[Which place for direct oral anticoagulants in routine hospital medical practice?]. / Quelle place pour les anticoagulants oraux directs en pratique hospitalière quotidienne?

PURPOSE: More than one million patients received an oral anticoagulant treatment in France. This medication is the first aetiology of iatrogenic events. Recently, direct oral anticoagulant (DOA) provided efficacy and safety in the treatment of atrial fibrillation and venous thromboembolic events. Given the growing increase in the prescription of these molecules, with many advantages but also disadvantages, it seemed interesting to assess in routine hospital medical practice, the proportion of patients for which the initiation of AOD could be safe. METHODS: This prospective, observational study was conducted in the department of internal medicine from October 2012 and September 2013. All inpatients receiving oral anticoagulant treatment have been included. Demographic data, indication of anticoagulant treatment, contraindications and interactions have been reported. From these information, we have established the percentage of patients who could benefit from DOA safely and securely. RESULTS: Two hundred and ninety inpatients were included with a mean age of 76.3±15.2 years old. Atrial fibrillation and thromboembolic venous disease were the most prevalent indications of anticoagulant treatments (67.2% and 22.4% of cases respectively). Among all patients, 260 had an indication of DOA (89.7%), authorized by the French National health agency. Eighty percent had both indication and no contraindication for DOA. However, only 53.1% of patients neither had drug-drug interaction. Main contraindications were severe renal failure (clearance<30mL/min) in 10.7% of cases, and recent history of gastric ulcer in 15.3% of cases. The most frequent interactions with DOA were antiplatelet agent (14.5%) and amiodarone (11.6%). Almost two thirds of inpatients (65.1%) had at least one drug-drug interaction with VKA. CONCLUSION: These results, coming from "real life", provide that only 53.1% of inpatients under anticoagulants could receive DOA safely. Caution is warranted, and VKA still have a preponderant role among anticoagulant drugs.

New insights into systemic sclerosis related microcirculatory dysfunction by assessment of sublingual micr\ocirculation and vascular glycocalyx layer. Results from a preliminary study.

BACKGROUND: Initial morphological and functional markers of systemic sclerosis (SSc) are evidenced in microvascular structural damage. However, nailfold videocapillaroscopy (NVC) explores only morphological abnormalities. Sidestream Dark Field (SDF) imaging of sublingual microcirculation enables assessment of both morphological and functional capillary impairment and allows measurement of the glycocalyx layer, which is an indicator of endothelial dysfunction. OBJECTIVE: To describe and validate sublingual abnormalities assessed by SDF device in comparison with NVC findings and to measure the thickness of the glycocalyx layer. METHODS: From February to May 2014, 26 subjects (16 SSc patients and 10 healthy controls) underwent standardised NVC and SDF imaging of sublingual microcirculation. Glycocalyx thickness was also measured. RESULTS: Capillary density and percentage of perfused vessels were significantly reduced in patients with SSc (n = 13) compared to controls. Correlation between nailfold capillary density assessed by NVC and sublingual capillary density assessed by SDF was observed (r(2) = 0.59; P = 0.023). According to the NVC pattern, patients with "active" disease experienced greater reduction in capillary density than patients with "late" disease as suggested by the de Backer score (9.17 ± 0.81 vs 10.86 ± 1.19; P = 0.03). Additionally, the decrease in glycocalyx thickness was measured in SSc patients (n = 13) compared to controls (n = 10) (0.41 ± 0.03 versus 0.76 ± 0.29 P = 0.003). CONCLUSION: Our results suggest for the first time in SSc, that sublingual microcirculation and glycocalyx are impaired and that SDF imaging findings correlate with those of NVC. Nevertheless, further studies are required for the validation of our preliminary results.

[Renal sarcoidosis: a series of five patients]. / Sarcoïdose rénale: à propos d'une série de cinq patients.

INTRODUCTION: Renal involvement is uncommon in sarcoidosis, occurring in less than 5% of the patients. Diagnostic delay should be minimal to improve the outcome. METHODS: From 1996 to 2009, 78 patients were seen for sarcoidosis in the Department of Internal Medicine of Rouen University hospital. RESULTS: Five patients (6.4%) had renal involvement. Diagnosis of renal involvement and sarcoidosis were concomitant in two patients while in the three remaining patients, renal manifestations occurred during the course of sarcoidosis. The five patients with renal manifestations exhibited: isolated sarcoid granulomatous interstitial nephritis (n=2), sarcoid granulomatous interstitial nephritis and nephrocalcinosis (n=2), renal failure due to hypercalcemia (n=1). CONCLUSION: This series underlines that renal function tests should be performed systematically both during initial evaluation and the follow-up of patients with sarcoidosis.