Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients.

BACKGROUND: A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome ('Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome'). OBJECTIVES: To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome. METHODS: One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow-up, were recorded. RESULTS: The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow-up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild-to-moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C-reactive protein levels and less frequent chondritis). The 5-year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis. CONCLUSIONS: VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.

[Peripheral neuropathies after bariatric surgery]. / Polyneuropathies après chirurgie bariatrique.

INTRODUCTION: Peripheral neuropathies sometimes complicate bariatric surgery. PATIENTS AND METHODS: We report the detailed clinical, electrophysiological, biological and histological characteristics of five patients who developed peripheral neuropathy after bariatric surgery. RESULTS: Three patients presented with small fiber neuropathy, one presented with axonal polyneuropathy, and one with demyelinating polyradiculoneuropathy. All patients had in common prominent neuropathic pain, massive weight loss, and multiple nutritional deficiencies. The pathophysiology of postbariatric surgery polyneuropathies is complex and involves nutritional, infectious and dysimmune mechanisms. CONCLUSION: The spectrum of peripheral neuropathies complicating bariatric surgery is wide, and includes pure small fiber neuropathy, axonal polyneuropathy, and demyelinating polyradiculoneuropathy. Treatment is mainly preventive, but sometimes surgical revision is needed.

[Bayesian statistic: an approach fitted to clinic]. / La statistique bayésienne : une approche des statistiques adaptée à la clinique.

Bayesian statistic has known a growing success though quite limited. This is surprising since Bayes' theorem on which this paradigm relies is frequently used by the clinicians. There is a direct link between the routine diagnostic test and the Bayesian statistic. This link is the Bayes' theorem which allows one to compute positive and negative predictive values of a test. The principle of this theorem is extended to simple statistical situations as an introduction to Bayesian statistic. The conceptual simplicity of Bayesian statistic should make for a greater acceptance in the biomedical world.

[Obesity and cancer]. / Obésité et cancer.

Obesity which is now well recognized as a public health problem increases the risk of developing cancers. Some systematic review and meta-analyses assessed the strength of associations between body mass index and common cancers such as breast, endometrial, colon and adenocarcinoma of oesophagus. The causal mechanisms remain unexplained. However, epidemiological data and animal models have provided some evidence that hormonal alteration linked to obesity, such as hyperinsulinism, high insulin-like growth factor (IGF-1) levels or biodisponibility, low adiponectin serum level and high oestradiol serum level resulting from an enhanced aromatase activity may have mitogenic and antiapoptotic effects. The inflammation associated with visceral adiposity is another factor which promotes cancer. To date, there are no convincing data that weight loss could improve the prognosis of treated neoplasia. However, a regular physical activity and a limited caloric intake are probably safe in healthy subject to prevent cancer and also in cancer survivors.

[Cardiac manifestations of pheochromocytoma]. / Manifestations cardiaques des phéochromocytomes.

Pheochromocytoma is a rare cause of secondary hypertension which may have protean clinical presentations. Noteworthy, it may be revealed or complicated by cardiovascular symptoms such as arrythmia, cardiomyopathy, acute coronary syndrome and cardiogenic shock. These cardiac manifestations of pheochromocytoma may delay diagnosis and must be known in order to provide the best chance at early detection. In some cases pheochromocytoma may be associated to a large apical dyskinesia of the left ventricule apex, tako-tsubo-like which is a reversible acute myocardiopathy. These acute cardiologic manifestations appear to be induced by a toxic effect of elevated catecholamine levels.

[Value of left atrial dilation in the diagnosis of silent myocardial ischemia in diabetes mellitus patients]. / Facteurs prédictifs de l'existence d'une ischémie myocardique silencieuse chez le patient diabétique. Intérêt de l'évaluation de la surface de l'oreillette gauche.

BACKGROUND: Accelerated atherothrombosis is a common feature in diabetes mellitus patients (DM), which can be related to abnormalities in vascular cell apoptosis and activation leading to the release of procoagulant microparticles (MPs). In DM patients, we hypothesized that circulating levels of biomarkers involved in atherothrombosis processes as well as cardiac and carotid echocardiography variables could be useful in the detection of silent myocardial diagnosed by myocardial perfusion imaging. METHODS AND RESULTS: We investigated, in 55 patients with diabetes (mean age 62+/-10 years) and 15 nondiabetics (46+/-14 years) patients the prevalence of silent myocardial ischemia (SMI) detected by a treadmill exercise or dipyridamole (99m)Tc-sestamibi stress test. Echocardiographic and -carotid variables were obtained using standardized methods. Biomarkers assessing endothelial apoptosis or activation (CD31+-MPs, CD62+-MPs, VCAM-1), inflammatory status (CD11a +/- MPs, MCP-1, CRP), platelet activation (GPIb+/-MPs, CD40-L, P-selectin, GPV) ventricular stretch (BNP) were measured in the plasma. SMI was diagnosed in 23/55 (42%) diabetics patients and in 3/15 (20%) nondiabetics patients. Enhanced inflammatory status and leukocyte damage (CD11a+-MPs) were evidenced in diabetic patients. Within the diabetic population, biomarkers levels of atherothrombosis were not significantly associated to the detection of SMI. In multivariable analyses adjusted for LV hypertophy, left atrial surface (LA) remained independent predictor of silent myocardial ischemia (OR 4.14; IC [1.7-16.13]; P=0.039). CONCLUSIONS: In diabetes mellitus patients, LA surface independently predicted silent myocardial ischemia after adjustment for established echocardiographic, and inflammatory risk factors. This simple measure of LA dilation could be helpful in the identification of diabetes mellitus patients at heightened cardiovascular risk.

Circulating procoagulant microparticles in obesity.

AIM: Obesity is a risk factor for cardiovascular diseases and venous thromboembolism. Circulating procoagulant microparticles (MP) have been described in various clinical situations associated with thrombosis and in diabetic patients. The aim of this preliminary study was to evaluate the presence of MP in obese patients without any other vascular risk factor in particular diabetes. METHODS: Fifty-eight obese women <50 year-old without other cardiovascular risk factors were recruited from a single out-patient nutrition clinic. They were compared to 45 age-matched healthy normal weight controls. Main outcome was MP levels in patients and controls. Relationships between MP concentrations and parameters reflecting insulin resistance in patients were also studied. RESULTS: Obese patients were 33.3 +/- 1.2 years old and had a mean BMI of 42.4 +/- 0.9 kg/m2. There vas a greater proportion of smokers in the obese group (34.5 vs 15.6%). Mean MP levels were markedly higher in obese patients compared to controls (10.6 +/- 0.5 vs 3.2 +/- 0.3 nMPSeq, P < 0.001). There was no difference in MP concentrations between smokers and non smokers. In the obese group, there was a negative correlation between MP and BMI (r = -0.265, P < 0.05) but no relationship could be established between MP concentrations and markers of insulin resistance. CONCLUSION: This increase in circulating MP levels reflects cell activation and could account for the increased risk of thrombotic complications in obesity. Further studies are ongoing to explore the relationships between MP levels and coagulation markers and to assess the effect of weight reduction.

Hematological response to short-term oral cyanocobalamin therapy for the treatment of cobalamin deficiencies in elderly patients.

OBJECTIVES: The aim of this trial was to demonstrate the efficacy of one month of oral cobalamin (vitamin B12) therapy in elderly patients with cobalamin deficiency related to food-cobalamin malabsorption (FCM). PATIENTS AND METHOD: Twenty elderly patients (mean age: 78+/-17 years) with established cobalamin deficiency related to FCM were included in an open-label, non-randomized, non-placebo trial. They were treated with a maximum of 1,000 microgram per day of oral crystalline cyanocobalamin for at least 1 month. Serum cobalamin levels (primary endpoint), blood count abnormalities and reticulocytes count (secondary endpoints) were determined at baseline and during the first month of treatment. RESULTS: 85% of the patients normalized their serum cobalamin levels with a mean increase of+167 pg/ml (p<0.001 compared with baseline). 100% of the patients corrected their initial macrocytosis and 25% their anemia; 100% of the patients had medullar regeneration with a mean increase of reticulocytes count of 32+/-11.3 x 106/l (p=0.03 compared with baseline). CONCLUSIONS: Our findings support the view that one month of oral crystalline cyanocobalamin is effective to correct serum vitamin B12 levels and to obtain hematological responses in elderly patients with cobalamin deficiency related to FCM.

[Pseudo-Sjogren's syndrome and bulimia]. / Pseudosyndrome de Gougerot-Sjögren et boulimie.

INTRODUCTION: Bilateral parotid enlargement are presenting features of some metabolic and systemic disease but also of chronic emesis. CASE RECORD: A 24-year old woman consulted during three years many physicians asking for the treatment of a painless parotid swelling confusing with a Sjogren's syndrome. After an initial denial, the weight history, alteration of tooth wear and hypokaliemia conducted to admit a self inducing vomiting with bulimia nervosa. CONCLUSION: Gender, young age, weight history, tooth alteration and electrolytic disorders are the main diagnostic tool of this dissimulated etiology of parotid swelling.

[Is subclinical hypothyroidism a cardiovascular risk factor?]. / L'hypothyroïdie fruste est-elle un facteur de risque cardiovasculaire?

OBJECTIVES: Subclinical hypothyroidism defined by the presence of elevated TSH levels but normal free T4 level is a common situation. Its consequences on health are yet on debate and the interest of a precocious treatment remains surrounded by controversy. KEY POINTS: The relationship between subclinical hypothyroidism and cardiovascular disease has been evaluated by several cross-sectional and longitudinal studies. Subclinical hypothyroidism has direct but subtle effects on the heart function, on the peripheral vascular resistance, and is associated with a mild elevation of LDL-cholesterol levels; all abnormalities may be partly reversed by a thyroxine supplementation. Data of the literature give insufficient evidence as to whether subclinical hypothyroidism is an independent cardiovascular risk factor. However treatment of subjects with TSH levels up or near to 10 mU/l would probably be beneficial in the prevention of cardiovascular disease. FUTURE PROSPECTS: Based on observational and interventional studies there are some arguments on the benefit of euthyroidism restoration only in patients with TSH levels superior to 10 mU/l.

[Impact of systemic disease on the pituitary gland]. / Répercussions hypophysaires des maladies systémiques.

Systemic diseases located in hypothalamo-pituitary region can slowly induce pituitary deficiency, diabetes insipidus and morphological abnormalities. The aim of this study is to review recent clinical data about diagnosis of these rare diseases, with a focus on granulomatous diseases: histiocytosis and sarcoidosis. Recent clinical studies on histiocytosis have improved our knowledge about endocrine expression of the disease in children and in adults as well. Diabetes insipidus is the most frequent condition, described mainly in children. GH deficiency is the most frequent pituitary deficit in children and adult patients. During neurosarcoidosis, diabetes insipidus is the most frequent condition and gonadotropic deficiency is the most frequent deficit but GH has not been systematically studied. MRI allows visualisation of some lesions and is very useful to follow the disease course. Diagnosis of these diseases is made by clinical evaluation of all the sites and by pathological analysis of biopsies of peripheral lesions. While pituitary hormone replacement therapy does not seem to raise specific problems in these diseases, etiological treatments are not yet available and indications for antimitotic or immunomodulatory treatment are sometimes discussed.

[Cobalamin deficiencies in adults: update of etiologies, clinical manifestations and treatment]. / Carences en vitamine B12 chez l'adulte: étiologies, manifestations cliniques et traitement.

PURPOSE: Update of the adult cobalamin deficiencies. CURRENT KNOWLEDGE AND KEY POINTS: More precise definitions establish the true cobalamin deficiencies and determine their real epidemiology. The current clinical data suggest the concept of food-cobalamin malabsorption as the leading etiology of cobalamin deficiency. The new features of cobalamin deficiency include neurological, gynecological and vascular manifestations. Current treatment modalities include nasal, sublingual and oral cobalamin administration. PROSPECTS AND PROJECTS: Studies are in the way to establish the relevance of the new clinical manifestations and to validate the usefulness of oral cobalamin therapy.

[The significance of circulating microparticles in physiology, inflammatory and thrombotic diseases]. / Les microparticules circulantes: rôles physiologiques et implications dans les maladies inflammatoires et thrombotiques.

BACKGROUND: In multicellular organisms, apoptosis and subsequent microparticle shedding play a key role in homeostasis. Having long been considered as << cellular dust >>, microparticles released in biological fluids upon cell activation or apoptosis appear as multifunctional bioeffectors involved in the modulation of key functions including immunity, inflammation, hemostasis and thrombosis, angiogenesis. MP constitute reliable markers of vascular damage, accessible to biological detection whilst the cells they originate from remain sequestered in tissues or are promptly submitted to phagocytosis. RECENT FINDINGS: MP modulate biological functions of target cells through the transfer of cytoplasmic content, lipids and membrane receptors. The pharmacological modulation of circulating levels of microparticles could be of particular interest in thrombotic or inflammatory diseases, cancer or hemophilia. CONCLUSION: MP can now be viewed not only as a hallmark of cell damage but also as a true biological tool.

[Cellular mechanisms of thyroid hormone action]. / Mécanismes d'action cellulaire des hormones thyroïdiennes.

KEY POINTS: Thyroid hormones affect cardiac myocytes as well as the smooth muscle and endothelial cells of the vascular wall. Free 3,53'-L-triiodothyronine (FT3) and its specific nuclear receptor modulate the transcription of various proteins, principally those involved in the myocyte contractile apparatus (myosin heavy chains), and the regulation of intracellular calcium flux (sarcoplasmic reticulum Ca2+ATPase). Thyroid hormones also have non-genomic effects that work rapidly, complement the effects described above, and are related to alterations in the properties of many channels and membrane receptors, especially in the sinoatrial mode. Thyroid hormones also affect the smooth muscle and endothelial cells of the vascular walls and reduce systemic vascular resistance. These effects on cardiac and vascular cells globally explain the cardiac manifestations (especially the inotropic and chronotropic effects) observed during dysthyroidism, particularly in hyperthyroidism where they are often in the forefront (positive inotropic and chronotropic effects).

[Cardiac consequences of clinical dysthyroidism. Pathophysiological, clinical, and epidemiologic data]. / Répercussions cardiaques des dysthyroïdies avérées. Données physiopathologiques, cliniques et épidémiologiques.

KEY POINTS: Thyroid hormones affect the vascular system, including the diastolic and systolic functioning of the heart. Resting heart rate increases early in hyperthyroidism (cardiac contractility expands due to improved ventricular loading and decreased systemic vascular resistance). Paradoxically, these hemodynamic alterations progressively reduce cardiac performance on effort (changes in diastolic, then systolic functioning) and finally at rest (modification in ventricular loading following tachycardia or atrial fibrillation), especially in cases of underlying heart disease (in the elderly). Hypothyroidism has an inverse hemodynamic effect and is less noisy, usually limited to relative bradycardia. The morbidity and mortality associated with hypothyroidism are apparently related to the atherogenic and prothrombotic vascular modifications that follow thyroid hormone deficiency, whereas heart failure and particularly atrial fibrillation and its thromboembolic complications are the primary consequences of hyperthyroidism. In both cases, return to normal thyroid levels corrects the cardiac abnormalities caused by the dysthyroidism. Dysthyroidism (hypo- or hyperthyroidism) occurs in 10 to 20% of the patients treated with amiodarone for arrhythmia. Because of its potential seriousness, some clinical or laboratory tests are necessary before initiating treatment, and specific clinical surveillance should be scheduled, including laboratory tests.

[Cardiac consequences of subclinical dysthyroidism. Experimental, clinical, and epidemiologic data]. / Répercussions cardiaques des dysthyroïdies frustes. Données expérimentales, cliniques et épidémiologiques.

KEY POINTS: Although the cardiovascular consequences of clinical or "overt" dysthyroidism are well known and treatment relatively well established, subclinical dysthyroidism remains a controversial topic, both regarding its cardiovascular effects and the best methods for its management. Subclinical hyperthyroidism is frequent among the elderly, usually associated with multinodular goiter. Although several epidemiologic studies have demonstrated that subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation and high cardiovascular mortality, solid practical data on which management can be based are not currently available. The risks related to subclinical hypothyroidism appear essentially vascular but a conclusive assessment must await further epidemiologic surveys.

[Statins and cerebral and cardiovascular risk in elderly people]. / Statines et risque cérébro- et cardiovasculaire chez les personnes âgées.

INTRODUCTION: The rationale for the treatment of hypercholesterolemia in the elderly is less clear than in middle-aged patients because of several conceptual, epidemiological, economical facts, a higher prevalence of polypathology and a weaker relation between hypercholesterolemia and cardiovascular risk when age increases. CURRENT KNOWLEDGE AND KEY POINTS: However, cardiovascular events-stroke and myocardial infarction occur mainly in people aged more than 65 years. The data of recent randomised clinical trials have demonstrated that the use of statins in the elderly remained associated to a reduced all-cause mortality, cardiovascular mortality and stroke. Statins were effective in elderly with average LDL-cholesterol in primary and secondary prevention trials. The drug tolerance was as good as in middle-aged patients. However, convincing data concerning subjects over 80 are lacking. CONCLUSION: On the basis of disponible data it may be considered that statins are useful in older persons with a serum LDL cholesterol level above 1.3 g/l and or a high cardiovascular risk, with or without cardiovascular disease, when their life expectancy is consequent.

[Hodgkin's disease manifesting as paraneoplastic limbic encephalitis]. / Encéphalite limbique révélatrice d'une maladie de Hodgkin.

INTRODUCTION: Malignancy is a possible cause of unexplained encephalitis. EXEGESIS: We describe a 59-years-old woman with limbic encephalitis, not explained by other causes, preceding diagnosis of Hodgkin's disease. Successful treatment of Hodgkin's disease was effective against neurological disturbance. CONCLUSION: This case provides evidence that Hodgkin's disease can be uncovered by paraneoplastic limbic encephalitis.

[Auto-immune-like disease post-bone marrow transplantation]. / Les manifestations d'allure auto-immune après allogreffe de moelle osseuse.

INTRODUCTION: Bone marrow transplantation (BMT) is based on destruction of the patient's bone marrow with rescue of haematopoietic stem cells from a donor. Chronic graft-vs-host disease (GVH) is the major complication post-BMT and mimics some autoimmune diseases, such as scleroderma, sicca syndrome, primary biliary cirrhosis and an increased prevalence of various autoantibodies. Other autoimmune-like manifestations have been reported as case reports or short series. The most common are myasthenia gravis, polymyositis, autoimmune cytopenias and Graves' disease or autoimmune hypothyroidism. CURRENT KNOWLEDGE AND KEY POINTS: These diseases occur mainly in association with chronic GVH. The pathophysiology of chronic GVH and other autoimmune-like diseases post-BMT remains poorly understood. Different mechanisms have been postulated. Most of the autoimmune events (either chronic GVH or more specific diseases) seem to be related to a poor or inadequate immunologic recovery post-BMT with an imbalance between autoregulatory and autoreactive lymphocytes. Microchimerism and molecular mimicry have been recently evocated. A minority of cases (autoimmune thyroid disorders) is attributed to the direct transfer of autoreactive cells from donor to patient (adoptive immunity). FUTURE PERSPECTIVES: Despite physiopathologic uncertainty, these autoimmune-like disorders post-BMT are an interesting model for primary autoimmune diseases.

[Do hematopoietic growth factors have a role in the treatment of drug-induced agranulocytosis?]. / Les facteurs de croissance hématopoïétique ont-ils une place dans le traitement des agranulocytoses médicamenteuses?

PURPOSE: Our study was aimed at determining the role of hematopoietic growth factor in drug-induced agranulocytosis. METHODS: Fifty-five cases of drug-induced agranulocytosis were reviewed and subdivided retrospectively into a G-CSF group (n = 15) and an untreated group (n = 40). Mortality and hematological recovery (number of days required for neutrophil counts to exceed 1.5 x 10(9)/L) were studied in the two groups. RESULTS: The mean granulocyte count was 0.09 x 10(9)/L. All patients presented infection. In the G-CSF group, no mortality (0% versus 5%, P = 0.85) and a shorter recovery time (8.1 versus 9.5 days P = 0.39) were observed. No significant difference between the two groups was observed in either the duration of antibiotic therapy (9.3 days in the G-CSF group versus 10.1 days in the untreated group, P = 0.51) or duration of hospitalization (10 days in the treated group versus 11 days in the G-CSF group, P = 0.46). CONCLUSION: Our results as well as a literature review indicate that G-CSF could decrease the time to hematological recovery and perhaps reduce mortality. However, the exact role of hematopoietic growth factors requires further investigations.