Amylose AA

AA amyloidosis remains one of the three main types of systemic amyloidosis with AL and ATTR. Its incidence has been however decreasing recently in Western countries. Chronic inflammatory diseases are currently the first cause of AA amyloidosis, including rheumatoid arthritis, spondyloarthritis and autoinflammatory diseases. Castleman's disease is a specific cause of AA amyloidosis that can be cured by surgery. A chronic inflammatory response is required to develop amyloidosis. Other genetic and environmental factors are also involved. The first clinical manifestation is a chronic glomerular nephropathy, which can be detected by urine examination and serum creatinine measure. Immunohistochemistry is mandatory to confirm the clinical diagnosis of AA amyloidosis and to avoid misdiagnosis. Long-term prognosis remains poor on chronic dialysis in case of clinical gut involvement. Current treatment is based on the control of the inflammatory response. Specific treatment aimed at inhibiting amyloid formation targeting serum amyloid P component and heparan sulphate are currently evaluated.L’amylose AA reste l’une des trois grandes variété d’amylose multisystémique, avec l’amylose AL et les formes héréditaires. Son incidence semble toutefois diminuer dans les pays occidentaux, où les maladies inflammatoires sont la principale cause d’amylose, au premier rang desquelles se tient la polyarthrite rhumatoïde, suivie par la spondylarthrite ankylosante et les syndromes auto-inflammatoires. Parmi les tumeurs, il faut signaler la maladie de Castleman, dont l’ablation chirurgicale permet parfois la résolution des symptômes de l’amylose. Une inflammation prolongée est un prérequis au développement d’une amylose AA; la protéine majoritaire des dépôts est un fragment de la protéine serum amyloid A (SAA), l’une des protéines de la réaction inflammatoire. Cependant, d’autres facteurs, notamment génétiques, sont impliqués dans la susceptibilité à la survenue de l’amylose AA. La néphropathie est la principale manifestation clinique de l’amylose de type AA. La recherche de protéinurie et la mesure de la créatinine plasmatique restent les éléments de dépistage de l’amylose au cours de toute maladie qui comporte une inflammation chronique. Le diagnostic précis de l’amylose AA nécessite de confronter l’ensemble des données cliniques et histologiques et notamment de l’immunohistochimie, afin de ne pas la confondre avec l’une des autres variétés. Une fois installée, l’amylose AA reste de mauvais pronostic en raison de l’insuffisance rénale terminale, qui est le terme ultime de la néphropathie, et de l’atteinte digestive qui s’accompagne de dénutrition profonde. Les traitements actuels sont ciblés sur la maîtrise de l’inflammation ; des médicaments inhibant l’interaction de la protéine AA aux composants communs de l’amylose (composant amyloïde P et héparane sulfate) sont en cours d’évaluation

Familial Mediterranean Fever in Heterozygotes: Are We Able to Accurately Diagnose the Disease in Very Young Children?

International audienceObjective: Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disease due to mutations in MEFV. Descriptions of disease manifestations among patients carrying a single mutated MEFV allele are becoming more frequent, although no data are available on the long-term outcome. We undertook this study to assess the accuracy of clinical diagnosis in children carrying a single mutated MEFV allele with symptoms of recurrent autoinflammatory disorder.Methods: We performed a retrospective single-center study of 33 patients with autoinflammatory disorders age <6 years at disease onset with 1 mutated MEFV allele. The phenotype of the patients was investigated in detail, and the clinical picture and outcome of 18 patients with an initial FMF diagnosis according to current clinical criteria were compared to those of 25 homozygous or compound heterozygous FMF patients.Results: No major differences in presenting signs or initial response to colchicine were observed between patient groups. During followup, heterozygotes had a milder disease course compared to homozygotes and were less prone than homozygotes to experience new clinical signs of FMF. At puberty, clinical signs of FMF completely disappeared in 5 of 18 heterozygotes, allowing them to discontinue colchicine without recurrence of symptoms or increases in inflammatory marker levels.Conclusion: Our data suggest that the clinical diagnosis of FMF in very young heterozygous children should be made with caution. At this young age they can present with an FMF-like disease-similar to that seen in patients carrying 2 mutated alleles-that is not necessarily predictive of life-long illness

How should we approach classification of autoinflammatory diseases?

International audienceThe notion of 'autoinflammatory' disease was introduced at the end of the 1990s, and, since then, this concept has rapidly evolved. As a result, multiple definitions of autoinflammatory disease, and classifications of conditions encompassed by these definitions, have been proposed; this succession highlights advances that have been made in understanding of the innate immune system, and especially the roles of IL-1β and the inflammasome in autoinflammtory conditions. However, the definitions and classifications that have been suggested to date face a number of structure and content issues. We therefore propose another, more clinically-oriented, definition: autoinflammatory diseases are diseases with clinical signs of inflammation, associated with elevated levels of acute-phase reactants, which are attributable to dysfunction of the innate immune system, genetically-determined or triggered by an endogenous factor. From this foundation, we propose a clinically-based classification of autoinflammatory diseases, and go on to discuss how immunological diseases as a whole, including autoimmune diseases, can be appropriately located within a continuum only if the classification process is multidimensional. For this purpose, we appeal to the philosophical concepts of family resemblance and signature

Dramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure

Background. Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder, for which systemic AA amyloidosis is the major complication revealed most of the time by renal abnormalities. Current treatment is daily colchicine that prevents both recurrent inflammatory attacks and amyloidosis deposition in most patients. However, some patients still develop amyloidosis and renal failure. Functional studies suggest that interleukin (IL)-1 is implicated in the inflammatory reaction in FMF and therefore, IL-1 inhibitors could be a new approach to treat FMF. The aim of this series study was to evaluate anakinra in patients with FMF complicated with amyloidosis and renal failure

The association of psychiatric comorbidities with emergency visits and hospitalisations in adult sickle‐cell patients: a cohort study

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Subclinical left ventricular systolic impairment in steady state young adult patients with sickle-cell anemia

International audienceChronic volume overload in sickle-cell anemia (SCA) is associated with left ventricular (LV) enlargement and hypertrophy. The effect of the disease on LV systolic function remains debated. The aim of our study was to investigate LV systolic function in SCA patients using 2D speckle-tracking imaging. We compared 30 steady state asymptomatic adult SCA patients (17 women, mean age 24.7 ± 5.1 years) with 30 age and sex-matched healthy subjects (17 women, mean age 25.0 ± 4.9 years). In addition to conventional echocardiographic parameters including LV ejection fraction (LVEF) and LV mass index (LVMi), global longitudinal strain (GLS) and strain rate (GLSR) were measured. GLS (-17.9 ± 2.0 vs. -19.7 ± 2.5 %, p = 0.004) and GLSR (-0.92 ± 0.09 vs. -1.07 ± 0.17 s(-1), p < 0.0001) values were lower in SCA patients while LVEF values (60.1 ± 3.8 vs. 61.7 ± 4.7 %, p = 0.30) were not different. LVMi was increased in SCA patients (100.7 ± 23.5 vs. 72.4 ± 15.2 g/m(2), p = 0.0001) and GLSR was significantly lower in the subgroup of patients with LV hypertrophy (-0.88 ± 0.09 vs. -0.96 ± 0.08 s(-1), p = 0.02). In SCA patients LVMi was correlated to GLS (r = 0.58, p = 0.001) and GLSR (r = 0.45, p = 0.015) pleading in favor of a pathological LV remodeling. Asymptomatic SCA patients exhibited a subclinical alteration of LV systolic function. Myocardial dysfunction appears to be linked to the degree of LV hypertrophy. 2D speckle-tracking imaging might be useful for long-term follow-up and to study the natural course of LV dysfunction in SCA patients

Left atrial volume is not an index of left ventricular diastolic dysfunction in patients with sickle cell anaemia

SummaryBackgroundLeft ventricular diastolic dysfunction (LVDD) is common in sickle cell anaemia (SCA). Left atrial (LA) size is widely used as an index of LVDD; however, LA enlargement in SCA might also be due to chronic volume overload.AimTo investigate whether LA size can be used to diagnose LVDD in SCA.MethodsOne hundred and twenty-seven adults with stable SCA underwent echocardiographic assessment. LA volume was measured by the area–length method and indexed to body surface area (LAVi). Left ventricular (LV) filling pressures were assessed using the ratio of early peak diastolic velocities of mitral inflow and septal annular mitral plane (E/e′). Using mitral inflow profile and E/e′, LV diastolic function was classified as normal or abnormal. LAVi>28mL/m2 was used as the threshold to define LA enlargement.ResultsThe mean age was 28.6±8.5years; there were 83 women. Mean LAVi was 48.3±11.1mL/m2 and 124 (98%) patients had LA dilatation. In multivariable analysis, age, haemoglobin concentration and LV end-diastolic volume index were independent determinants of LAVi (R2=0.51; P<0.0001). E/e′ was not linked to LAVi (P=0.43). Twenty patients had LVDD; when compared with patients without LVDD, they had a similar LAVi (52.2±14.7 and 47.5±10.2mL/m2, respectively; P=0.29). Receiver operating characteristics curve analysis showed that LAVi could not be used to diagnose LVDD (area under curve=0.58; P=0.36).ConclusionLA enlargement is common in SCA but appears not to be linked to LVDD. LAVi in this population is related to age, haemoglobin concentration and LV morphology

Spondyloarthritis associated with familial Mediterranean fever: successful treatment with anakinra

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The risk of familial Mediterranean fever in MEFV heterozygotes: a statistical approach.

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder due to MEFV mutations and one of the most frequent Mediterranean genetic diseases. The observation of many heterozygous patients in whom a second mutated allele was excluded led to the proposal that heterozygosity could be causal. However, heterozygosity might be coincidental in many patients due to the very high rate of mutations in Mediterranean populations.To better delineate the pathogenicity of heterozygosity in order to improve genetic counselling and disease management.Complementary statistical approaches were used: estimation of FMF prevalence at population levels, genotype comparison in siblings from 63 familial forms, and genotype study in 557 patients from four Mediterranean populations.At the population level, we did not observe any contribution of heterozygosity to disease prevalence. In affected siblings of patients carrying two MEFV mutations, 92% carry two mutated alleles, whereas 4% are heterozygous with typical FMF diagnosis. We demonstrated statistically that patients are more likely to be heterozygous than healthy individuals, as shown by the higher ratio heterozygous carriers/non carriers in patients (p<10(-7)-p<0.003). The risk for heterozygotes to develop FMF was estimated between 2.1 × 10(-3) and 5.8 × 10(-3) and the relative risk, as compared to non carriers, between 6.3 and 8.1.This is the first statistical demonstration that heterozygosity is not responsible for classical Mendelian FMF per se, but constitutes a susceptibility factor for clinically-similar multifactorial forms of the disease. We also provide a first estimate of the risk for heterozygotes to develop FMF