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.

[Mechanisms of pharmacokinetic drug-drug interactions]. / Mécanismes des interactions médicamenteuses d'origine pharmacocinétique.

Pharmacokinetic drug-drug interactions occur when a drug alters the disposition (absorption, distribution, elimination) of a coadministered agent. Pharmacokinetic interactions may result in the increase or the decrease of plasma drug concentrations. These modifications are variable in intensity but can lead to contraindications of the association. The mechanisms of pharmacokinetic interactions involve drug metabolizing enzymes, drug transporters and orphan nuclear receptors that regulate at the transcriptional level the expression of enzymes and transporters. The increase of drug plasma concentrations is generally related to the inhibition of enzymes and/or drug transport. The decrease of drug concentrations reflects the activation of orphan nuclear receptors by inducers that lead to the increase of the expression of enzymes and drug transporters. Inhibition of drug metabolism or transport is quite immediate (24-48h) while induction is a slower process (7-10 days). Complex situations may be observed with drugs that are both inducers and inhibitors (rifampin, ritonavir). They can cause the decrease and the increase of the exposure of the combined agent depending on the duration of the association.

[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.

[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.

Increased reverse triiodothyronine is associated with shorter survival in independently-living elderly: the Alsanut study.

OBJECTIVE: Increased reverse tritiodothyronine (T(3)) used to be described as a part of euthyroid sick syndrome (ESS). It was demonstrated to be associated with increased mortality in acutely ill patients. It can also be found with low or normal T(3) in non-severely ill subjects but its significance remains unclear. PATIENTS AND DESIGN: The Alsanut study included a representative sample of 440 independently-living subjects aged 65 or over constituted between January 1988 and September 1989. Past and current medical history and nutritional data were collected at inclusion. Baseline thyroid hormone (TSH, FT(4), FT(3) and rT(3)) serum levels were measured. Life status was determined on 1 December 2005. RESULTS: Of the 374 elderly subjects included in the final analysis, 52 had abnormal TSH (43 with hyperthyroidism, nine with hypothyroidism) and 80.7% had died by 1 December 2005. There was no statistical difference in survival between subjects according to thyroid function (P=0.54). Of the 322 elderly subjects with normal TSH, mortality rate was 81.1%. ESS was found in 3.4%, whereas 8.1% of the participants displayed elevated rT(3) with normal FT(3). Time to death was strongly related to rT(3) (P<0.0001) and FT(3) (P<0.0001) in a univariate analysis. After adjusting for other confounding variables, rT(3) was the only thyroid hormone associated with shorter survival (P=0.014). CONCLUSIONS: RT(3) was the only thyroid hormone associated with shorter survival in a representative population of independently-living elderly. In these subjects, isolated elevated rT(3) might be an equivalent of ESS, reflecting declining health.

[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.

[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.

[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.

[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.

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.

Current hematological findings in cobalamin deficiency. A study of 201 consecutive patients with documented cobalamin deficiency.

With the introduction of automated assays for measuring serum cobalamin levels over the last decades, the hematological manifestations related to cobalamin deficiency have been changed from the description reported in 'old' studies or textbooks. We studied the hematological manifestations or abnormalities in 201 patients (median age: 67 +/- 6 years) with well-documented cobalamin deficiency (mean serum vitamin B12 levels 125 +/- 47 pg/ml) extracted from an observational cohort study (1995-2003). Assessment included clinical features, blood count and morphological review. Hematological abnormalities were reported in at least two-third of the patients: anemia (37%), leukopenia (13.9%), thrombopenia (9.9%), macrocytosis (54%) and hypegmented neutrophils (32%). The mean hemoglobin level was 10.3 +/- 0.4 g/dl and the mean erythrocyte cell volume 98.9 +/- 25.6 fl. Approximately 10% of the patients have life-threatening hematological manifestations with documented symptomatic pancytopenia (5%), 'pseudo' thrombotic microangiopathy (Moschkowitz; 2.5%), severe anemia (defined as Hb levels <6 g/dl; 2.5%) and hemolytic anemia (1.5%). Correction of the hematological abnormalities was achieved in at least two-thirds of the patients, equally well in patients treated with either intramuscular or oral crystalline cyanocobalamin. This study, based on real data from a single institution with a large number of consecutive patients with well-documented cobalamin deficiency, confirms several 'older' findings that were previously reported before the 1990s in several studies and in textbooks.

[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.