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.

[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.

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.

[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).

[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.

[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.

[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.

[Smoking and the thyroid]. / Thyroïde et tabac des relations complexes.

The effects of smoking on the thyroid gland have been studied for years. The consequences of smoking on thyroid function and size are however still controversial. It is accepted that an increase in serum thyiocyanate, a potent inhibitor of iodine transport, may contribute to the development of thyroid dysfunction, particularly in geographical areas with borderline iodine deficiency. In the general population, smoking is associated with normal thyroid hormone levels, with a tendency to lower TSH levels and enlargement of thyroid size. There is an increased risk of developing over thyroid disease. The relationship between smoking and relapse of Graves' disease and the incidence and severity of Graves' ophthalmopathy are constantly reported. Smoking also has a potent nodular goitrigenic effect in low iodine areas. Despite the fact that smoking decrease both thyroid secretion and thyroid hormone action, hypothyroidism does not appear to be more frequent. Smoking does however increase the metabolic effects of hypothyroidism. Active and passive smoking have proven deleterious effects on the fetal thyroid. Paradoxically, there is evidence of reduced risk for thyroid cancer in smokers.

[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.

[Autoimmune peripheral neuropathies with anti-MAG antibodies and hematological disorders. Five cases]. / Neuropathies périphériques auto-immunes à anticorps anti-MAG et hémopathies. A propos de 5 observations.

OBJECTIVE: The aim of this study was to report our experience with autoimmune neuropathies associated with hematological disorders and to describe their etiological and clinical polymorphism. PATIENTS AND METHODS: A retrospective study was conducted in five patients with autoimmune peripheral neuropathies with anti-MAG (myelin-associated glycoprotein) antibodies. RESULTS: Autoimmune neuropathies were associated with Waldenström's macroglobulinemia (n=2), Hodgkin disease (n=1), chronic lymphocytic leukemia (n=1) and idiopathic polyclonal B lymphoproliferation (n=1). Most of the patients had a sensorial polyneuropathy, predominant in the legs, exhibiting slow progress. Our patients showed a disappointing response to chemotherapy with stabilization or short response.

[Capillary hyperpermeability syndrome of the face]. / Syndrome d'hyperperméabilité capillaire de la face.

BACKGROUND: Capillary leak syndrome is a rare disorder, with various clinical features, characterized by episodes of diffuse edema. CASE REPORT: We report the case of a 83 year-old woman with capillary leak syndrome of the face characterized by recurrent episodes of edamata. We found a follicular non-Hodgkin's lymphoma and high levels of plasma interleukin (IL) 2 and IL 6. Regression of edema and remission of hematology disease have been obtained with corticoids and chloraminophene. DISCUSSION: This case illustrates that capillary leak syndrome may present as an edema of the face and may be in some cases considered as a paraneoplastic syndrome. The role of cytokines seems important. This case suggests that corticoids may be useful in the management of neoplasm induced capillary leak syndrome.

[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.