Search

Introduction La nouvelle pandemie mondiale (COVID19) causee par le coronavirus 2 du syndrome respiratoire aigu severe (SRAS-CoV-2) est responsable de nombreux deces dans le monde entier au cours des derniers mois. Au cours des formes graves, il a ete note une reponse inflammatoire exageree connue sous le nom de “orage cytokinique”. Ceci a souleve la question de la sensibilite et de la gravite de l’infection par le SRAS-CoV2 chez les patients presentant une hyperactivation genetique de l’immunite innee tels que la fievre mediterraneenne familiale (FMF). En outre, les patients avec FMF prennent de la colchicine au long cours, medicament qui a ete teste chez des patients infectes par le SRAS-CoV2 avec des resultats contradictoires [1] . Patients et methodes Etude menee sur l’infection par le SRAS-CoV2 chez les patients atteints de FMF suivis dans 2 sites du centre de reference national des maladies autoinflammatoires en region parisienne et inclus dans la JIR cohorte, une base de donnees europeenne multicentrique. Les patients adultes et pediatriques inclus repondaient aux criteres internationaux de FMF et avaient un diagnostic genetique confirme. Resultats Les patients identifies (n = 627) ont ete invites a repondre a un bref questionnaire soit en consultation, soit par telephone, soit par courrier electronique sur une possible infection par le SARS-CoV2 pendant la periode de mars a juin 2020 ; 342 patients ont repondu a l’enquete. Le diagnostic etait retenu si le patient presentait des symptomes cliniques avec PCR ou serologie positive ou scanner thoracique typique. Au total, 27 patients FMF (7,8 % des repondants ; sexe ratio 1/1) ont contracte le virus. Tous les 27 patients FMF-COVID+ sauf un prenaient de la colchicine quotidiennement depuis une periode mediane de 23 ans, la dose moyenne de colchicine etait de 1 mg/jour. Quatre recevaient en plus un inhibiteur de l’IL-1. Parmi les 27 patients FMF-COVID+, sept symptomatiques ont ete hospitalises (25 %) et six ont eu besoin d’oxygene ; trois (11 %) ont developpe un syndrome de detresse respiratoire aigue necessitant des soins intensifs pour une ventilation mecanique et une hemodialyse. Deux patients sont decedes (7 %) mais presentaient respectivement 3 et 4 comorbidites pour une infection grave par le SRAS-CoV2 ; le troisieme patient, âge de 40 ans, souffrait d’hypertension et d’obesite. Les patients âges de plus de 65 ans representaient 17 % de l’ensemble de la cohorte FMF-COVID + ; 75 % ont ete hospitalises et ont eu besoin d’oxygene ; l’un d’eux est decede. Trois patients FMF-COVID + avaient une amylose AA : 2 ont ete hospitalises et un est decede. Aucun traitement anti-viral supplementaire n’a ete administre. Les 5 survivants apres hospitalisation sont rentres chez eux. Aucun d’entre eux n’a presente de signes cliniques de crise de FMF lors de l’infection par le SRAS-CoV2. Discussion Le profil des patients FMF atteints d’une forme grave ou potentiellement mortelle par le SRAS-CoV2 etait le meme que celui de la population generale. Ainsi, seuls les patients FMF presentant des facteurs de risque connus (tels que âge avance, maladie renale chronique, hypertension, maladie vasculaire, obesite et dysfonctionnement pulmonaire) ont developpe une infection grave par le SARS-CoV2 [2] . Cette etude n’est pas en faveur d’un surrisque en soi de developper une infection severe a SRAS-CoV2 en presence d’une maladie autoinflammatoire monogenique touchant un inflammasome. Aucune conclusion formelle ne peut etre tiree sur l’effet preventif de la colchicinotherapie au long cours, bien que ce travail retrospectif porte sur une large cohorte de patients traites par colchicine depuis plusieurs annees. Il est difficile de conclure a l’efficacite du traitement par inhibiteur d’IL1 vis-a-vis l’infection par le SRAS-CoV-2 chez les patients FMF, mais 50 % des patients traites au long cours sont decedes mais avaient plusieurs comorbidites ; et des publications recentes semblent plaider en faveur de l’efficacite de l’anakinra dans l’infection grave par le SRAS-CoV-2 [3] . Conclusion La FMF ne semble pas constituer un facteur de risque de developper une forme severe d’infection par SARS-CoV2 chez les patients traites au long cours par de la colchicine quotidienne, par rapport a la population generale.

International audience; Background: NLRP3-associated autoinflammatory diseases (NLRP3-AIDs) include conditions of various severities, due to germline or somatic mosaic NLRP3 mutations.Objective: To identify mosaic- versus germline-specific NLRP3 mutations' characteristics, we reinterpreted all the mutations reported in NLRP3-AIDs and performed an in-depth study of 3 novel patients.Methods: The pathogenicity of all reported mosaic/germline mutations was reassessed according to international recommendations and their location on the NLRP3 3-dimensional structure. Deep-targeted sequencing and NLRP3-inflammasome-activation assays were used to identify the disease-causing mutation in 3 patients.Results: We identified, in 3 patients, mosaic mutations affecting the same NLRP3 amino acid (Glu569). This residue belongs to 1 of the 2 mosaic mutational hot spots that face each other in the core of the NLRP3 ATPase domain. The review of the 90 NLRP3 mutations identified in 277 patients revealed that those hot spots account for 68.5% of patients (37 of 54) with mosaic mutations. Glu569 is affected in 22% of the patients (12 of 54) with mosaic mutations and in 0.4% of patients (1 of 223) with germline mutations. Only 8 of 90 mutations were found in mosaic and germinal states. All of the germline mutations were associated with a severe phenotype. These data suggest that mutations found only in mosaic state could be incompatible with life if present in germinal state. None of the 5 most frequent germline mutations was identified in mosaic state. Mutations found only in germinal state could, therefore, be asymptomatic in mosaic state.Conclusions: The phenotypic spectrum of NLRP3-AIDs appears to be related to the germinal/mosaic status and localization of the underlying mutations.

Background:Clinical manifestations are scarce in AA amyloidosis (AAA) and, contrary to other types of amyloidosis, involvement of the peripheral nervous system was rarely reported in AAA. However, the usual absence of hypertension despite chronic renal failure and the digestive involvement may be secondary to dysautonomia, but the autonomic nervous system has rarely been studied in AAA (1). Measure of the electrochemical skin conductance (ESC) is a simple and reproducible method to evaluate the function of eccrine sweat glands, which are innervated by small non-myelinated C fibers, and patients with AL and hereditary transthyretin amyloidoses show decreased ESC values (2,3).Objectives:To evaluate ESC values by Sudoscan in patients with AAA.Methods:Patients diagnosed as having AAA based on positive immunohistochemistry with an anti-serum amyloid A antibody followed at the national reference center for AAA in Tenon Hospital between July, 2017 and September, 2020, were routinely assessed for ESC with FDA approved Sudoscan (Impeto Medical, Paris, France). An ESC value above 60 microSiemens (µS) or 70 µS were considered normal for hands or feet, respectively. Categorical variables are reported as percentages and continuous variables are expressed as means±standard deviation. Correlations between age, body mass index (BMI), hemoglobin levels, C-reactive protein levels, estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (defined as 0 for dialysis patients) and ESC values were calculated using the nonparametric Spearman test. GraphPad Prism Version 7 software (GraphPad Software, San Diego, California, USA) was used for statistical analyses. A p-value Results:Overall, 32 patients (16 women) were included, with a mean age of 57.4±13.6 years and a mean BMI of 25.2±6.8 kg/m2. Six (19%) had diabetes mellitus, and 5 (16%) had a kidney transplantation. The main causes of AAA were: monogenic autoinflammatory diseases (n=11, 34%, including 9 patients with familial Mediterranean fever), chronic and/or recurrent infections (n=5, 16%), obesity (n=3, 9%) and undefined (n=3, 9%). The mean hands’ ESC values was normal at 65.5±21.1 µS, although 8 (25%) patients had ESC values below 60 µS, including 2 diabetic patients. In contrast, the mean feet’s ESC values was abnormal at 62.7±23.7 µS, including half of the patients with ESC values below 70 µS (2 diabetic patients). Eight patients had abnormal ESC values only for feet, and 1 had abnormal values only for hands. Apart from a significant correlation between feet and hands’ ESC values (pConclusion:To our knowledge, this is the first study to assess ESC in AAA. Feet’s ESC values were moderately impaired in half of the patients with AAA. Therefore, this study reinforces the previously reported alterations in the autonomic nervous system in patients with AAA that should probably be searched for in these patients. In addition, the identification of an alteration of the ESC values cannot allow to distinguish the type of amyloidosis.References:[1]Nussinovitch U, Volovitz B, Nussinovitch M, Lidar M, Feld O, Nussinovitch N, et al. Abnormal heart rate variability in AA amyloidosis of familial Mediterranean fever. Amyloid 2011;18:206–10.[2]Montcuquet A, Duchesne M, Roussellet O, Jaccard A, Magy L. Electrochemical skin conductance values suggest frequent subclinical autonomic involvement in patients with AL amyloidosis. Amyloid 2020;27:215–6.[3]Fortanier E, Delmont E, Verschueren A, Attarian S. Quantitative sudomotor test helps differentiate transthyretin familial amyloid polyneuropathy from chronic inflammatory demyelinating polyneuropathy. Clin Neurophysiol 2020;131:1129–33.Disclosure of Interests:None declared

Une femme, âgee de 73 ans, ancienne documentaliste, consultait a veille de Noel. Ses antecedents comportaient une constipation hronique, une hepatite virale guerie, une hypertension arterielle, ne insuffisance veineuse, un syndrome de Raynaud, une presyacousie, une depression severe avec beaucoup d’insomnies, un ancer du sein droit en remission et une keratoconjonctivite bilaerale recidivante. Son pere et sa sœur avaient deja fait plusieurs entatives de suicide. Un de ses fils, geriatre de profession, avait fait n burn-out et l’autre etait depressif. Elle avait rec u 20 ans auparavant une anticoagulation curative et ne corticotherapie generale pour une nevrite optique anterieure roite et des arthralgies etiquetees « maladie de Horton ». Elle avait te hospitalisee quelques mois apres cet episode pour une aggraation de la nevrite optique qui semblait d’allure inflammatoire. es lesions cutanees erythemato-papuleuses non prurigineuses

Summary Fever of unknown origin (FUO) are defined by a fever greater than 38.3 °C evolving during at least 3 weeks and without diagnosis despite appropriate explorations. This clinical entity is not so uncommon. More than 200 causes of FUO have been reported. Despite medical advances, they remain unexplained in 10 to 30% of cases after exhaustive work-up. So FUO is a challenging medical problem. Clinical evaluation remains the basis of the initial evaluation of the patient with FUO. Newer diagnostic modalities, including blood chemistry, immunological tests and molecular methods have important role in the assessment of these patients. We will discuss in this review terminology, common causes of FUO and technical innovation.

Early studies on prolonged fever date back to the 1960s. Fifty years later, prolonged unexplained fever remains a diagnostic challenge to the general internists. Although the aetiologies of prolonged fevers have not changed much in the general population, the distribution between the various causes is not the same anymore. A regular decrease in infectious and neoplastic causes is noticed whatever the age. Prolonged fevers related to inflammatory disorders and fevers that remain of unknown origin still represent approximately 30 to 50% of the cases. In the young adult population, as in the older patients, prolonged fevers can be attributed to four groups: infection, inflammation, neoplasic and other aetiologies (including drug-related fevers). In the young adult population, the management of prolonged fever presents some specific issues that are the purpose of this review coupled with our own experience. The prognosis of undiagnosed prolonged fever is usually favourable, as a life-threatening aetiology is exceptionally diagnosed during the follow-up if the initial management was complete and accurate.

Resume En dehors de la fievre mediterraneenne familiale Quatre maladies hereditaires se presentant sous forme d’acces inflammatoires intermittents ont ete reconnues et maintenant bien caracterisees dans leurs aspects cliniques et genetiques. Le chef de file de ce groupe reste la fievre mediterraneenne familiale (FMF), une maladie qui affecte des milliers de personnes originaires du Bassin mediterraneen. Mais la fievre mediterraneenne familiale n’est plus seule au sein des maladies inflammatoires recurrentes hereditaires. Trois autres entites clinico-genetiques maintenant bien definies Il s’agit de la fievre intermittente secondaire a des mutations du recepteur de type 1A du Tumor Necrosis Factor (TNF), de transmission genetique autosomique dominante, le syndrome d’hyperimmunoglobulinemie D, et une derniere entite regroupant le syndrome de Muckle-Wells, l’urticaire familiale au froid et le syndrome CINCA (Chronic Infantile Neurological Cutaneous and Articular) . En pratique Un diagnostic precis de ces affections est crucial, car leur prise en charge et leur traitement sont specifiques.

Resume Propos. – Le Traps ou Tumor necrosis factor Receptor Associated Periodic fever Syndrome, que l’on peut traduire par fievre intermittente secondaire a des mutations du recepteur de type 1A du TNF (ou recepteur de 55 kDa) appartient au groupe des fievres hereditaires recurrentes ou syndromes auto-inflammatoires hereditaires. Actualites et points forts. – Le diagnostic de Traps doit etre evoque en presence des signes cliniques suivants et d’une histoire familiale, et cela quelle que soit la population d’origine. Les acces inflammatoires du Traps sont caracterises par leur duree de quelques jours a 3 semaines, la presence de douleurs abdominales, de myalgies, de lesions cutanees diverses, dont une variete de pseudoerysipele, accompagnes de fievre. L’inflammation serique est constante pendant les acces et la maladie peut se compliquer d’amylose AA. Le diagnostic de Traps repose sur l’association de signes cliniques a une mutation du recepteur de type 1A du TNF, qui peut etre cherchee a partir de l’ADN sanguin. Le traitement n’est pas bien codifie, la colchicine semble inefficace, les corticosteroides peuvent diminuer l’intensite et la duree des acces. Perspectives et projets . – La place des molecules anti-TNF dans le traitement de cette affection doit etre evaluee avec plus de recul. Les mecanismes de la maladie ne sont pas completement elucides. Il existe dans certaines familles un relatif deficit en recepteur soluble circulant, par defaut de clivage a la membrane cellulaire. Ce mecanisme ne rend pas compte de ce qui est observe pour d’autres mutations.

Resume Introduction Le tumor necrosis factor receptor associated periodic fever syndrome (TRAPS), que l’on peut traduire par fievre intermittente secondaire a des mutations du recepteur de type 1A du TNF, appartient au groupe des fievres recurrentes ou syndromes auto-inflammatoires hereditaires. Nous rapportons deux nouvelles observations de patients presentant un TRAPS, qui ont l’interet de suggerer que le phenotype de la maladie pourrait varier en fonction de la mutation responsable. Observations Le premier patient, porteur d’une mutation du gene TNFRSF 1A C30S, presentait des manifestations cliniques digestives « pseudochirurgicales », l’obligeant a interrompre son activite professionnelle durant les acces douloureux ; de plus, le TRAPS etait corticodependant (> 20 mg/j) et necessitait la mise en route d’un traitement anti-TNF-α par etanercept. Chez la seconde patiente, ayant une mutation R92Q, les manifestations cliniques etaient moderees et l’evolution favorable sous prednisone. Conclusion Ainsi, le phenotype des patients presentant la mutation R92Q semble moins severe. En revanche, les patients ayant une mutation portant sur les cysteines pourraient etre plus a risque d’evoluer vers l’amylose. Ces donnees suggerent que le suivi de ces derniers patients devrait etre plus etroit.

Familial Mediterranean fever (FMF) is an autosomal recessively inherited disease affecting patients of the Mediterranean basin. FMF is characterized by recurrent episodes of fever accompanied with topical signs of inflammation. Some patients can develop a renal amyloidosis associated (AA) amyloidosis. The administration of colchicine is an effective preventive treatment of both the attacks and amyloidosis. The FMF gene (MEFV) was cloned and missense mutations were found to be responsible for the disease. We investigated a large series of 303 unselected and unrelated patients of various ethnic backgrounds with a clinical suspicion of FMF to confirm or invalidate the diagnosis of FMF and to determine the spectrum of MEFV mutations. Molecular analysis focused on all the most frequent mutations identified so far, and an exhaustive analysis of exon 10, containing the mutational hotspot, was performed through DNA sequencing. Sixty-two percent of Sephardic, North African Arabs, Armenian and Turkish patients were either homozygous or compound heterozygous for MEFV mutations. In other populations surrounding the Mediterranean Sea such as Greek, Italian, Portuguese, Kurdish and Lebanese populations, mutations were also found. In general, patients without Mediterranean origin had no mutations in the MEFV gene. Two new mis-sense mutations were identified in exon 10 of the MEFV gene: the S675N in an Italian patient and the M680L in a French patient without any known at-risk ethnic ancestry.

Resume Nous rapportons les observations de deux malades traites par heparine de bas poids moleculaire pour une thrombose veineuse profonde, chez qui est survenue une hemorragie fatale. Plusieurs facteurs de risque d'hemorragie ont pu etre releves: la presence d'une maladie sous-jacente grave (cancer dans un cas, obesite et insuffisance cardiaque dans l'autre), l'âge superieur a 80 ans, l'aggravation d'une insuffisance renale preexistante dans les deux cas, une intervention chirurgicale recente dans un cas. L'activite anti-Xa etait elevee, au-dessus des valeurs recommandees dans les deux cas. La surveillance biologique des traitements par heparine de bas poids moleculaire dans les thromboses veineuses est discutee.

Objective Familial Mediterranean fever (FMF) is an autosomal-recessive disorder characterized by recurrent attacks of fever, with abdominal, thoracic, or articular pain. FMF is particularly common in Mediterranean populations, while other populations are rarely affected. MEFV gene analysis provides the only objective diagnostic criterion for FMF. However, the spectrum of MEFV mutations, which was first established in classically affected populations, remains insufficiently studied in other populations. The purpose of this study was to assess involvement of MEFV in the phenotype of western European Caucasian patients with a clinical diagnosis of FMF. Methods Mutation analysis was performed in 208 Caucasian patients from western Europe, by screening for the most common MEFV mutations in exons 2, 3, 5, and 10, and by sequencing the promoter region and the whole MEFV coding sequence in 21 of these patients. Results None of the patients carried 2 mutated alleles. Only 2 patients carried 1 mutated allele. Conclusion FMF-like syndromes in western European Caucasian populations cannot be explained by MEFV mutations. These results should be helpful in avoiding laborious and costly MEFV molecular analyses that, at the population level, seem to be of poor diagnostic value in the case of western European Caucasian patients, and rather should prompt a search for other causes in those patients.

Background Colchicine is the standard treatment of FMF, preventing attacks and inflammatory complications in more than 90% of cases. Some patients, especially those carrying 2 M694V mutations in MEFV gene, may require doses higher than recommended overcoming disease manifestations. True resistance to colchicine may be exceptional but is still not defined on a consensus basis. IL 1 targeting drugs are effective but are expensive alternative treatments requiring rigorous indications in FMF. Objectives To survey when and how physicians consider resistance to colchicine in FMF patients and to report how they handle this situation in their practise. Methods We performed a retrospective chart review of patients identified through reference centers and networks of inflammatory diseases expert physicians. We asked them to report their patients with a clinical diagnosis of FMF and at least one pathogenic MEFV mutation, in whom they considered resistance to colchicine. Patients with concomitant SPA or Crohn9s disease were excluded. We collected their clinical data, genotypes, and more detailed information on colchicine treatment dose adjustment and compliance. Finally we tried to analyse the reason(s) to consider their patients as resistant to treatment and we collected the alternative attitudes treatments used. Results We identified 42 patients from 7 to 86 years old (mean age (±SD): 28,2 ± 22.1 years old) recruited from 10 centers. Thirty six of them could be fully analysed and consisted of 14 males and 22 females with a clinical diagnosis of FMF and, in whom 15 were children before 16 years. Sephardim Jews were the most represented. (n=23, 64%). All patients carried pathogenic mutations in the exon 10 of the MEFV gene except one girl and a woman with a complex allele including MEFV deletion. The mean (±SD) maximal dose of colchicine given in adult patients was 1.8± 0.65 mg, and it was 1.7 ± 0.6 mg (0.1 ± 0.01 mg/kg) in paediatric patients. The level of CRP in between attacks was evaluated in 40 patients and reached a mean of 35,8 mg/L. Fourty percent of patients declared to be fully observant to colchicine treatment. The main reasons to consider resistance to colchicine treatment were: >6 attacks/year (44%), >4 attacks in the last 6 months (20%), persistent inflammation (41%) and other reasons (44%). Twenty percent of patients were intolerant to an increase of colchicine dose. Concomitant treatments to overcome FMF symptoms were essentially NSAIDS, steroids, and analgesics. Sixty five percent of these patients are currently treated with IL-1 targeted drugs including anakinra (48%) and canakinumab (17%). Conclusions Our study has confirmed that resistance to colchicine treatment is rare (0–10% of patients, per investigating center) and more likely observed in patients carrying severe MEFV genotypes. In most cases the mean reasons to consider resistance to treatment were severe clinical symptoms and persistent subclinical inflammation, however low compliance to high doses of colchicine seems to play a major role. Patient9s education and additional behavioural approaches preventing disease flares could probably reduce the use of biologics. Disclosure of Interest A. Corsia: None declared, S. Georgin-Lavialle: None declared, G. Grateau Consultant for: Novartis, SOBI, V. Hentgen Consultant for: Novartis, SOBI, A. Faye: None declared, P. Quartier Consultant for: Novartis, SOBI, Speakers bureau: Novartis, SOBI, I. Kone-Paut Grant/research support from: Novartis, SOBI, Consultant for: Novartis, SOBI

The Muckle-Wells syndrome is a rare autosomal dominant disorder belonging to the group of hereditary fever syndromes. The chronic infantile neurological cutaneous and articular (CINCA) syndrome is a systemic inflammatory disorder of unknown etiology with neonatal onset. They are considered as two different entities. We report the case of a 36-year-old man suffering since birth from a nonpruritic generalized urticaria, with inflammatory flares, joint manifestations and progressive deafness requiring a bilateral hearing aid. An initial diagnosis of Muckle-Wells syndrome was made. However, the patient had an unusual clinical presentation with slightly dysmorphic facial appearance, clubbing of the fingers, mild mental retardation and papilledema. After a genetic advice, a diagnosis of CINCA syndrome was made. Search for mutations in the CIAS1 gene revealed a new mutation in a heterozygous state. This case report really raises the question of a link between these two inflammatory diseases. Further studies are needed to confirm the involvement of mutations of the CIAS1 gene in CINCA syndrome.

CNS involvement is rare in systemic amyloidoses due to transthyretin (TTR) mutation and manifests as a combination of dementia, seizures, and myelopathy. The authors report two French siblings who experienced recurrent subarachnoid hemorrhages as the main clinical feature. Brain specimens showed that the leptomeningeal vessels walls were thickened by amyloid deposits, and sequencing of the TTR exons showed a heterozygous single base-pair transition from G to A (codon 53), resulting in a glycine for glutamic acid substitution (G53E).

International audience; Background: Identification of modifier genes and characterization of their effects represent major challenges in human genetics. SAA1 is one of the few modifiers identified in humans: this gene influences the risk of renal amyloidosis (RA) in patients with familial Mediterranean fever (FMF), a Mendelian autoinflammatory disorder associated with mutations in MEFV. Indeed, the SAA1 alpha homozygous genotype and the p.Met694Val homozygous genotype at the MEFV locus are two main risk factors for RA.Methodology/principal findings: HERE, WE INVESTIGATED ARMENIAN FMF PATIENTS AND CONTROLS FROM TWO NEIGHBORING COUNTRIES: Armenia, where RA is frequent (24%), and Karabakh, where RA is rare (2.5%). Sequencing of MEFV revealed similar frequencies of p.Met694Val homozygotes in the two groups of patients. However, a major deficit of SAA1 alpha homozygotes was found among Karabakhian patients (4%) as compared to Armenian patients (24%) (p = 5.10(-5)). Most importantly, we observed deviations from Hardy-Weinberg equilibrium (HWE) in the two groups of patients, and unexpectedly, in opposite directions, whereas, in the two control populations, genotype distributions at this locus were similar and complied with (HWE).Conclusions/significance: The excess of SAA1alpha homozygotes among Armenian patients could be explained by the recruitment of patients with severe phenotypes. In contrast, a population-based study revealed that the deficit of alpha/alpha among Karabakhian patients would result from a negative selection against carriers of this genotype. This study, which provides new insights into the role of SAA1 in the pathophysiology of FMF, represents the first example of deviations from HWE and selection involving the modifier gene of a Mendelian disorder.

Background The long-term efficacy of canakinumab and changes in the daily lives of patients (and their caregivers) have not been thoroughly evaluated since its first use in France in 2007 and its approval for CAPS in 2010. Objectives A multicentre retrospective, observational study set up to assess the “real life” use of canakinumab in all French CAPS patients ever treated since 2007, to describe their clinical course on a long-term, and to analyse changes in their (and their caregiver9s) quality of lives. Methods We targeted the 70-80 patients ever treated for CAPS in France, at least once and even during a clinical trial. Investigators were known experts in the field of CAPS in France who accepted to take part in the study. Data were collected through questionnaires by phone interviews and medical chart reviews, at treatment initiation, 6 months, 12 months and at the last medical visit. They included: clinical data, canakinumab use in real life conditions, impact on patients9 (and caregivers9) quality of life, and care consumption. The significance limit was set at 5% for all of the statistical tests. Results 68 CAPS patients, >90% of the target number, were enrolled (23 children, 45 adults). Sixteen patients (24%) had FCAS, 43 (63%) had MWS and 9 (13%) had NOMID-CINCA. The median duration of treatment was 5 years (from July 2007 to July 2014). >95% of patients remained on treatment. Doses were not modified in nearly half cases (31/68). For 37 patients, dosage adjustments (more often increase) were required (102 in total), especially in younger patients and those with the most severe phenotypes. The global activity of the disease, skin disorders and most of the symptoms were significantly better after canakinumab treatment (p Conclusions ENVOL study showed real-life results similar to those obtained during the phase III clinical trials with canakinumab, reinforcing its sustained activity. The maintenance of more than 95% of patients on therapy confirmed its major benefit to CAPS patients, which was demonstrated herein by the positive impact of canakinumab in patients (and their caregivers) social, emotional, educational and professional lives. Disclosure of Interest I. Kone-Paut Grant/research support from: SOBI, Novartis, Roche, Consultant for: SOBI, Novartis, Pfizer, Abbvie, Chugai, Speakers bureau: Novartis, SOBI, P. Quartier Grant/research support from: Abbvie, Novartis, Pfizer, Consultant for: Abbvie, Novartis, Servier, SOBI, Speakers bureau: Abbvie, Chugai Roche, Medimmune, Novartis, Sobi, O. Fain Consultant for: Shire et CSL Behring, G. Grateau Grant/research support from: Abbvie, Novartis, Pfizer, Consultant for: Abbvie, Novartis, Servier, SOBI, Speakers bureau: Abbvie, Chugai Roche, Medimmune, Novartis, Sobi, P. Pillet: None declared, V. Despert: None declared, K. STANKOVIC STOJANOVIC: None declared, S. quere Employee of: Novartis employee, L. willemins Employee of: Novartis employee, O. Reigneau Employee of: novartis employee, E. Hachulla Consultant for: Novartis, SOBI

Resume L'amelioration de la prise en charge de patients atteints de mucoviscidose a permis un allongement de l'esperance de vie favorisant l'emergence de nouvelles complications ; parmi celles-ci, l'amylose renale secondaire a rarement ete rapportee. Observations Deux adultes mucoviscidosiques, âges de 25 et 22 ans, ont developpe une amylose renale secondaire. Ils etaient infectes depuis plusieurs annees par Pseudomonas aeruginosa. L'un des deux patients est decede d'insuffisance renale terminale en 2 ans. Conclusion L'insuffisance renale severe par amylose secondaire peut devenir le facteur essentiel du pronostic de la mucoviscidose de l'adulte.

Hereditary periodic fever syndromes are a group of diseases characterized by intermittent bouts of clinical inflammation with focal organ involvement, mainly of the abdomen, musculoskeletal system and skin. The most frequent is familial Mediterranean fever, which affects patients of Mediterranean descent all over the world. Three other types have recently been characterized clinically and genetically. A thorough diagnosis is warranted, as clinical and therapeutic management is specific for each of these diseases. The underlying mechanisms of these inflammatory diseases appear to be specific for each type, involving so far unknown proteins, and have already opened new avenues in our understanding of the inflammatory response.

The diagnosis of familial Mediterranean fever (FMF) has until recently been based on clinical signs alone. Discovery of the MEFV gene has enabled a molecular approach to diagnosis, which is already well established for diagnosing typical clinical forms of FMF. We evaluated the utility of this molecular approach in a large series of patients with various clinical presentations and ethnic origins. We looked for mutations in the MEFV gene in 303 unselected consecutive patients with a variable (from high to low) clinical suspicion of FMF. Two mutations were found in 133 patients (44%). In 22 patients (7%), the clinical diagnosis of FMF was unlikely according to the Tel Hashomer clinical criteria. Our results suggest that the spectrum of FMF-associated signs is broader than previously believed. Wider indications for genotyping should lead to more frequent diagnosis of FMF.

Other mechanisms may be involved: graft anoxia, haeIntroduction mostatic disorders or lipid metabolism, arterial trauma during transplant surgery (clamping and suturing of Along with infectious complications, cardiovascular renal artery) or pre-existing atherosclerotic patches in disease is the predominant cause of morbidity and graft arteries (especially in coronary arteries). mortality in renal transplant recipients [1,2]. The Most attempts at preventing graft arterial disease reasons for this association of arterial disease with have failed. One notable exception has been the prorenal transplantation are complex and have not been tective efficacy of pravastatin (an inhibitor of hydroxyfully elucidated, which makes prevention difficult. methylglutaryl coenzyme A reductase) against To progress in this field, it is essential to make a coronary disease after cardiac transplantation, through clear distinction between the arterial disease affecting a decrease in plasma cholesterol and/or in the cytotoxthe graft itself and the discrete involvement of host icity of natural killer cells [6 ]. Nonetheless, it would arteries, the mechanisms and consequences of these be premature to extend this relative success to the two pathologies being probably different. prevention of allovasculopathy involving arteries other than the coronaries. An essential feature of graft arterial disease is that Arterial disease of the graft it only affects graft arteries and spares the host arteries.

Six cases of chronic renal failure related to granulomatous renal sarcoidosis are reported and compared with data in the literature. The particular features of sarcoidosis granulomatous interstitial nephritis should be emphasised because presentation may be misleading. Renal failure usually presents with a rapidly progressive course, either isolated or associated with mild proteinuria and sterile leukocyturia, while extrarenal localisations may be absent. Diagnosis should be suspected on the basis of elevated or paradoxically normal serum calcium concentrations, due to increased plasma concentrations of calcitriol, while immunoreactive circulating parathormone concentrations are depressed. Calcitriol as well as angiotensin-converting enzyme could represent unregulated secretion products from granulomatous tissue and their plasma concentrations may roughly reflect activity of the disease. Early corticosteroid treatment dramatically improves renal function but long-term renal prognosis may be oblitered due to progressive chronic renal failure related to fibrosis scarring.

The prevalence of a recently described restriction fragment length polymorphism (RFLP) using Msp 1 for the serum amyloid P gene was determined in 3 groups of patients (patients with reactive amyloidosis, with rheumatoid arthritis without amyloidosis, and controls). No association was found between RFLP and reactive amyloidosis.

Variants of Alport's syndrome include mainly those associated with hereditary macrothrombocytopenia (and occasionally leukocyte inclusions) or with esophageal, tracheobronchial and genital leiomyomatosis. Within Alport's syndrome there appears to be no justification for differentiating those with nephritis and deafness from those with nephritis alone. However, in indirect immunofluorescence studies using the mouse monoclonal antibody, MCA-P1, which recognizes the glomerular basement membrane (GBM), reduced or absent binding was found in 20 of 42 cases of hereditary nephritis. Most of these showed typical ultrastructural GMB changes. These results suggest that there is probably a subset of patients characterized by typical GBM lesions and an absence, inaccessibility or abnormality of the GBM antigen recognized by MCA-P1.

Primary hyperoxaluria leading to calcium oxalate urinary stones and renal deposits occurs rarely in adults. We report three cases in whom end-stage renal failure was precipitated by urological surgery. In contrast, in one case renal stones were destroyed by extracorporeal shock-wave lithotripsy and renal function was not significantly altered. This emphasises the need for early diagnosis. This may not be easy in adult patients: urolithiasis may not be severe, radiological nephrocalcinosis may be lacking, and renal failure may develop late in life.

Results 16 patients (12H, 4F) with a median age of 41 years [2961] were included. Patients were Sefarad Jews (n=9), Turkish (n=2) and Arabic (n=5). Seven of them had a familial history of FMF, none had a familial history of auto-immune diseases. Their FMF was symptomatic during childhood except for two patients; most of them had colchicine. They displayed various type of vasculitis such as: HSP (n=7), PAN (n=4; two of them with viral B hepatitis), Granulomatosis with Polyangitis (GPA) (n=1), Microscopic Polyangitis (MPA) (n=1) and unclassified (n=3). Their vasculitis was diagnosed at a median age of 32 [5-43]. For one patient the diagnosis of vasculitis was made before the diagnosis of FMF. Patients with PAN mostly displayed weight loss, fever, myalgia, abdominal pain, arthralgia, with evidence of vasculitis of small or medium-sized blood vessels on a skin biopsy (n=3) or renal arterial aneurysms on an angiography (n=1). MEFV sequencing showed: homozygous M694V/M694V mutations (n=2), homozygous E148Q/E148Q mutation (n=1) and double heterozygous M694V/V726A mutation (n=1). The patient with GPA displayed an intra-alveolar hemorrhage with ORL involvement. He had a M694V/ M694V mutation and was the only patient which FMF was diagnosed after the vasculitis. All of 5 patients with HSP displayed a M694V/M694V MEFV mutation. The patient with MPA displayed erythema nodosum, arthro-myalgia, neuropathy, constrictive pericarditis, and cutaneous vasculitis. He displayed a M694V/E148Q MEFV mutation.