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Background In ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload. Case presentation An 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15. Conclusions This case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias.

IntroductionAntiphospholipid syndrome (APS) is an autoimmune disease characterised by thrombosis (arterial, venous or small vessel) or obstetrical events and persistent antiphospholipid antibodies (aPL), according to the Sydney classification criteria. Many studies have performed cluster analyses among patients with primary APS and associated autoimmune disease, but none has focused solely on primary APS. We aimed to perform a cluster analysis among patients with primary APS and asymptomatic aPL carriers without any autoimmune disease, to assess prognostic value.MethodsIn this multicentre French cohort study, we included all patients with persistent APS antibodies (Sydney criteria) measured between January 2012 and January 2019. We excluded all patients with systemic lupus erythematosus or other systemic autoimmune diseases. We performed hierarchical cluster analysis on the factor analysis of mixed data coordinates results with baseline patient characteristics to generate clusters.ResultsWe identified four clusters: cluster 1, comprising ‘asymptomatic aPL carriers’, with low risk of events during follow-up; cluster 2, the ‘male thrombotic phenotype’, with older patients and more venous thromboembolic events; cluster 3, the ‘female obstetrical phenotype’, with obstetrical and thrombotic events; and cluster 4, ‘high-risk APS’, which included younger patients with more frequent triple positivity, antinuclear antibodies, non-criteria manifestations and arterial events. Regarding survival analyses, asymptomatic aPL carriers relapsed less frequently than the others, but no other differences in terms of relapse rates or deaths were found between clusters.ConclusionsWe identified four clusters among patients with primary APS, one of which was ‘high-risk APS’. Clustering-based treatment strategies should be explored in future prospective studies.

ObjectiveAntiphospholipid syndrome (APS) is defined by the association of thromboembolic and/or obstetrical clinical manifestations and the presence of antiphospholipid antibodies. The objective of our study was to evaluate the impact of the triple-positive profile in a cohort of 204 APS patients.MethodsWe conducted a retrospective study, including patients with primary or secondary APS, meeting the Sydney criteria with at least one thrombotic and/or obstetrical complication. Clinical characteristics and the risk of relapse (defined by the occurrence of a new thrombotic event and/or a new adverse obstetrical event) between triple-positive and non-triple-positive APS patients were compared.Results204 patients were included in our study, 68 were triple-positive and 136 were single or double positive. 122 patients (59.8%) had primary APS. 67 patients (32.8%) had obstetrical APS, with a higher rate among triple-positive patients (45.6% vs 26.5%, p=0.010), and 170 patients (83.3%) had thrombotic APS, without difference between triple-positive and others. Thrombotic events were more often venous (56.4%) than arterial (37.7%). Triple-positive patients had more placental complications than others (17.6% vs 2.9%, p=0.001) and more non-criteria events (48.5% vs 25.7%, p=0.002). Among non-criteria events, there was a higher frequency of Sneddon syndrome in triple-positive patients (7.4% vs 0.7%, p=0.028). The relapse rate was higher in triple-positive patients than in others (63.2% vs 39,7%, p=0002). In multivariate analysis, the triple-positive profile was associated with a higher risk of relapse (HR 1.63; 95% CI 1.04 to 2.55; p=0.031).ConclusionThe triple-positivity is associated with a higher risk of relapse and obstetrical complications.

There is currently no evidence of the possible benefit of plasma cell-targeting therapies (PCTT) in immunoglobulin A (IgA) monoclonal gammopathy (MG) associated with IgA vasculitis (IgAV). We report the outcome of different PCTT regimens in a cohort of MG-IgAV.We used a French network to retrospectively describe the outcome of MG-IgAV patients treated with PCTT.Five patients were included (mean age 65 years). All patients had severe baseline presentation including extensive necrotic purpura (n = 5), gastrointestinal involvement (n = 2), peripheral neuropathies (n = 2), and glomerulonephritis (n = 1). Two patients had IgA indolent multiple myeloma and three had IgA "MG of undetermined significance." Monotypic IgA deposition in the skin vessels wall was highlighted using an immunofluorescence assay. Cases of vasculitis in three patients (n = 3) were refractory to multiple line therapies, including cyclophosphamide (n = 3) or rituximab. Finally, PCTT including bortezomib plus cyclophosphamide and dexamethasone, bortezomib plus melphalan and prednisone, or bortezomib plus lenalidomide and dexamethasone were proposed, allowing complete remission in 4/5 patients without major adverse drug events.This study suggests that the MG-IgAV phenotype might be distinctive of usual IgAV (severe and refractory to conventional immunosuppressive regimens) and supports the benefit of PCTT. This study sheds new light on the overall biology of IgAV, strengthening the pathogenic role of the monoclonal IgA component in IgAV.

Objective We aimed to investigate whether anakinra, an interleukin-1receptor inhibitor, could improve outcome in moderate COVID-19 patients. Methods In this controlled, open-label trial, we enrolled adults with COVID-19 requiring oxygen. We randomly assigned patients to receive intravenous anakinra plus optimized standard of care (oSOC) vs. oSOC alone. The primary outcome was treatment success at day 14 defined as patient alive and not requiring mechanical ventilation or extracorporeal membrane oxygenation. Results Between 27th April and 6th October 2020, we enrolled 71 patients (240 patients planned to been enrolled): 37 were assigned to the anakinra group and 34 to oSOC group. The study ended prematurely by recommendation of the data and safety monitoring board due to safety concerns. On day 14, the proportion of treatment success was significantly lower in the anakinra group 70% (n = 26) vs. 91% (n = 31) in the oSOC group: risk difference—21 percentage points (95% CI, -39 to -2), odds ratio 0.23 (95% CI, 0.06 to 0.91), p = 0.027. After a 28-day follow-up, 9 patients in the anakinra group and 3 in the oSOC group had died. Overall survival at day 28 was 75% (95% CI, 62% to 91%) in the anakinra group versus 91% (95% CI, 82% to 100%) (p = 0.06) in the oSOC group. Serious adverse events occurred in 19 (51%) patients in the anakinra group and 18 (53%) in the oSOC group (p = 0·89). Conclusion This trial did not show efficacy of anakinra in patients with COVID-19. Furthermore, contrary to our hypothesis, we found that anakinra was inferior to oSOC in patients with moderate COVID-19 pneumonia.

Objectives Immunoglobulin A vasculitis (IgAV) is a small-vessel vasculitis most frequently benign in children while more severe in adults. We aimed to study the impact of age on presentation and outcome of adult IgAV. Methods We conducted a nationwide retrospective study including 260 IgAV patients. Patients were divided into four quartiles according to the age at IgAV diagnosis: Results Mean age at diagnosis was 50.1 (18) years and 63% were male. IgAV diagnosed in the lowest quartile of age was associated with more frequent joint (P 6 months, clinical response and relapse rates were similar between the four groups. Median follow-up was of 17.2 months (9.1–38.3 months). Renal failure at the end of follow-up was significantly more frequent in the highest quartile of age (P = 0.02), but the occurrence of end-stage renal disease was similar in all groups. Last, overall and IgAV-related deaths were associated with increase in age. Conclusion Aging negatively impacts the severity and outcome of IgAV in adults. Younger patients have more frequent joint and gastrointestinal involvement, while old patients display more frequent severe purpura and glomerulonephritis.

Objective To assess the effectiveness of corticosteroids among older adults with coronavirus disease 2019 (COVID-19) pneumonia requiring oxygen. Methods We used routine care data from 36 hospitals in France and Luxembourg to assess the effectiveness of corticosteroids with at least 0.4 mg/kg/day equivalent prednisone (treatment group) versus standard of care (control group). Participants were adults aged 80 years or older with PCR-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or CT scan images typical of COVID-19 pneumonia, requiring oxygen ≥3 L/min, and with an inflammatory syndrome (C-reactive protein ≥40 mg/L). The primary outcome was overall survival at day 14. In our main analysis, characteristics of patients at baseline (i.e. time when patients met all inclusion criteria) were balanced by using propensity-score inverse probability of treatment weighting. Results Among the 267 patients included in the analysis, 98 were assigned to the treatment group. Their median age was 86 years (interquartile range 83–90 years) and 95% had a SARS-CoV-2 PCR-confirmed diagnosis. In total, 43/98 (43.9%) patients in the treatment group and 84/166 (50.6%) in the control group died before day 14 (weighted hazard ratio 0.67, 95% CI 0.46–0.99). The treatment and control groups did not differ significantly for the proportion of patients discharged to home/rehabilitation at day 14 (weighted relative risk 1.12, 95% CI 0.68–1.82). Twenty-two (16.7%) patients receiving corticosteroids developed adverse events, but only 11 (6.4%) from the control group. Conclusions Corticosteroids were associated with a significant increase in the overall survival at day 14 of patients aged 80 years and older hospitalized for severe COVID-19.

INTRODUCTION The antiphospholipid syndrome (APS) (1) is defined by the development of vascular thrombosis, or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL). Antinuclear antibodies (ANA) can be detected in primary APS patients without any clinical systemic autoimmune disease. The presence of ANA antibodies could confer a specific phenotype in primary APS. OBJECTIVE To evaluate the characteristics of APS patients with antinuclear antibodies without other autoimmune disease (ANA positive APS patients) in comparison with primary APS without ANA or secondary APS patients with associated systemic lupus erythematosus (SLE). METHODS Clinical and biologic data from 195 APS were retrospectively collected and patients were classified as primary APS with positive ANA (ANA-positive APS), primary APS without any ANA (ANA-negative APS), and SLE-associated APS (SLE-APS). RESULTS Fourty patients (21%) were classified into ANA-positive APS group, 77 (39%) in ANA-negative APS and 78 (40%) in SLE-APS. In ANA-positive APS patients, 20 patients (51%) had arterial thrombosis, 14 (41%) had veinous thrombosis and 19% had obstetrical complications. There was no difference between the three groups for the frequency of thrombotic manifestations and obstetrical complications. ANA-positive APS patients had more non-criteria manifestations than ANA-negative APS (48% versus 25%; P≤0.01). ANA-positive APS had more triple aPL positivity (59% versus 18%; P

Introduction Le syndrome des anti-phospholipides (SAPL) est une maladie systemique auto-immune qui se caracterise par la survenue de thromboses vasculaires, de complications obstetricales et la presence persistante d’anticorps antiphospholipides (APL). Les criteres cliniques de la classification de Sydney ne prennent en compte que les thromboses arterielles et veineuses ainsi que certains evenements obstetricaux [1] . Cependant, plusieurs autres manifestations, appelees manifestations non-criteria peuvent etre associees a ces criteres cliniques dans le SAPL. Meme si ces manifestations non-criteria ne sont pas specifiques d’un SAPL primaire, certaines etudes suggerent que leur presence pourrait etre associee avec un risque eleve de thrombose et constituer un profil a « haut risque » de SAPL [2] , [3] . Dans cette etude retrospective, nous avons voulu: – ecrire les manifestations non-critera des patients atteints d’un SAPL primaire et leurs prevalences; – determiner la valeur pronostique des manifestations non-criteria. Patients et methodes Tous les patients diagnostiques d’un SAPL primaire (criteres de Sydney) entre janvier 2012 et janvier 2019 ont ete inclus dans cette etude francaise multicentrique retrospective. Resultats Cent soixante-quatre patients avec un SAPL primaire ont ete inclus dans l’etude, pour un âge median de 51 ans [39.5; 66] et une majorite de femmes (n = 99, 60 %). Parmi eux, quarante-sept patients (29 %) ont presente au moins une manifestation non-criteria pendant le suivi: cytopenies auto-immunes (n = 17; 36 %), endocardite de Libman Sachs (n = 5; 11 %), nephropathie associee au SAPL (n = 4; 9 %), livedo reticularis (n = 8; 17 %) et des manifestations neurologiques (n = 14; 30 %). Par rapport au SAPL primaire sans manifestation non-criteria (n = 117), les SAPL primaires avec manifestations non-criteria avaient moins souvent un profil de SAPL mixte (26 % vs 52 %; p = 0.019), plus d’evenements thrombotiques arteriels (56 % vs 35 %; p = 0.027), and plus de pre-eclampsies (14 % vs 3 %; p = 0.02). La prevalence de la triple positivite etait significativement augmentee chez les patients avec des manifestations non-criteria (48 % vs 20 %; p = 0.001). Les patients porteurs d’un SAPL primaire avec des manifestations non-criteria (n = 47) ont recu significativement plus de traitements additionnels associes aux anti-vitamine K et/ou antiagregants que ceux sans manifestation non-criteria. Le syndrome catastrophique des antiphospholipides (CAPS), bien que rare, avait tendance a etre plus frequent chez les patients avec un SAPL primaire avec manifestations non-criteria (5.1 % vs aucun; p = 0.074). Les patients porteur d’un SAPL primaire avec manifestations non-criteria presentaient des taux de rechute significativement superieurs (59 % vs 34 %; p = 0.018), mais les hazard ratios (HR) de rechute n’etaient pas significativement differents entre les deux groupes (HR at 1.34 [0.67; 2.68]; p = 0.2) Discussion Les principaux resultats de cette etude sont que: – les patients porteurs d’un SAPL primaire avec des manifestations non-criteria ont des phenotypes thrombotiques et obstetricaux differents, avec une prevalence augmentee de manifestations severes comme un profil de SAPL mixte, des thromboses arterielles et des pre-eclampsies; – le statut triple positif est augmente chez les SAPL primaire avec manifestations non-criteria – les porteurs d’un SAPL primaire avec manifestations non-criteria ont un pronostic plus defavorable, comme le suggerent le taux plus eleve de rechutes et le besoin de traitements additionnels. La definition et la stratification des profils de risque des patients porteurs d’un SAPL primaire sont d’interet majeur, puisque la prise en charge du SAPL est encore basee sur le phenotype obstetrical ou thrombotique du patient. Les manifestations non criteria pourraient aider a affiner la stratification du profil de risque du patient. D’autre part, l’interet de traitements additionnels, notamment dans le SAPL obstetrical a ete etudie, avec des resultats prometteurs sur l’usage de corticosteroides a faible doses, d’hydroxychloroquine ou d’echanges plasmatiques [3] . L’utilisation de traitement additionnels, notamment de l’hydroxychloroquine, comme illustre dans notre cohorte, devrait etre mieux etudiee chez les patients avec des manifestations non-criteria. Conclusion La presence de manifestations non-criteria chez les patients avec SAPL primaire est importante a prendre compte, etant donne qu’elle est associee a un profil clinico-biologique particulier, un risque de rechute augmente et un plus grand besoin de traitements additionnels. De nouvelles etudes prospectives sont necessaires pour mieux stratifier le pronostic et la prise en charge de ces patients.

Resume Introduction La maladie de Gaucher (MG) est une maladie genetique lysosomale, due a un deficit d’activite de la beta-glucocerebrosidase, caracterisee par des atteintes hematologiques, viscerales et osseuses. L’objectif principal de notre etude etait de decrire le parcours diagnostique de patients atteints de MG de type 1 et le role du medecin interniste. Methodes Etude retrospective multicentrique incluant des patients atteints de MG de type 1, menee au sein de 16 centres, entre 2009 et 2011. Resultats Cinquante-cinq patients atteints d’une MG de type 1 ont ete inclus, suivis par un interniste ou un hematologue. Ils etaient initialement hospitalises dans 8 services de specialite differents. Le diagnostic a ete etabli par un myelogramme chez 22 patients (40 %), par un dosage enzymatique de la glucocerebrosidase chez 15 patients (27 %), par une biopsie medullaire chez 9 patients (16 %). Le recours au dosage enzymatique etait plus frequent apres 1990. Le delai entre la date de premiere hospitalisation pour symptomes en lien avec la MG et le diagnostic definitif etait inferieur a 1 an pour 38 patients (81 %). Les suspicions de MG etaient majoritairement adressees a un medecin interniste. Conclusion La maladie semble mieux reconnue et diagnostiquee plus rapidement depuis 1990 malgre la multiplicite des parcours, dans lesquels le role du medecin interniste parait important.