Search

PURPOSE To describe the posterior ophthalmic manifestations of catastrophic antiphospholipid syndrome. METHODS Retrospective case series of patients presenting with catastrophic antiphospholipid syndrome and posterior segment ocular manifestations. The main outcomes were the type of posterior segment manifestations at catastrophic antiphospholipid syndrome diagnosis, specifically retinal vascular occlusion, vasculitis, or choroidopathy, and the final best-corrected visual acuity. RESULTS This study included 23 patients (11 cases treated by the authors and 12 published case reports); 21 (91%) of them female. Their median age at diagnosis was 28 years (range, 16-79 years). Ophthalmologic manifestations were usually bilateral (n = 19, 83%) and involved vascular occlusive retinopathy (n = 17, 74%), choroidopathy (n = 11, 48%), or retinal vasculitis (n = 1, 4%). Final best-corrected visual acuity was not significantly worse than the best-corrected visual acuity at diagnosis (P = 0.16). Retinal vascular occlusions were associated with poorer final visual acuity than choroidopathy (P = 0.002). After a median follow-up of 14 months (range, 2-132 months), nearly half the patients (n = 11, 48%) had permanent vision loss including best-corrected visual acuity of

Histiocytoses are heterogeneous hematopoietic diseases characterized by the accumulation of CD68(+) cells with various admixed inflammatory infiltrates. The identification of the pivotal role of the mitogen-activated protein kinase (MAPK) pathway has opened new avenues of research and therapeutic approaches. We review the neurologic manifestations of 3 histiocytic disorders with frequent involvement of the brain and spine: Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman-Destombes disease (RDD). Central nervous system (CNS) manifestations occur in 10%-25% of LCH cases, with both tumorous or neurodegenerative forms. These subtypes differ by clinical and radiological presentation, pathogenesis, and prognosis. Tumorous or degenerative neurologic involvement occurs in 30%-40% of ECD patients and affects the hypothalamic-pituitary axis, meninges, and brain parenchyma. RDD lesions are typically tumorous with meningeal or parenchymal masses with strong contrast enhancement. Unlike LCH and ECD, neurodegenerative lesions or syndromes have not been described with RDD. Familiarity with principles of evaluation and treatment both shared among and distinct to each of these 3 diseases is critical for effective management. Refractory or disabling neurohistiocytic involvement should prompt the consideration for use of targeted kinase inhibitor therapies.

Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600–mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.

Erdheim-Chester disease (ECD) is characterized by the infiltration of tissues by foamy CD68+CD1a− histiocytes, with 1500 known cases since 1930. Mutations activating the MAPK pathway are found in more than 80% of patients with ECD, mainly the BRAFV600E activating mutation in 57% to 70% of cases, followed by MAP2K1 in close to 20%. The discovery of BRAF mutations and of other MAP kinase pathway alterations, as well as the co-occurrence of ECD with LCH in 15% of patients with ECD, led to the 2016 revision of the classification of histiocytoses in which LCH and ECD belong to the “L” group. Both conditions are considered inflammatory myeloid neoplasms. Ten percent of ECD cases are associated with myeloproliferative neoplasms and/or myelodysplastic syndromes. Some of the most striking signs of ECD are the long bone involvement (80%-95%), as well as the hairy kidney appearance on computed tomography scan (63%), the coated aorta (40%), and the right atrium pseudo-tumoral infiltration (36%). Central nervous system involvement is a strong prognostic factor and independent predictor of death. Interferon-α seems to be the best initial treatment of ECD. Since 2012, more than 200 patients worldwide with multisystem or refractory ECD have benefitted from highly effective therapy with BRAF and MEK inhibitors. Targeted therapies have an overall, robust, and reproducible efficacy in ECD, with no acquired resistance to date, but their use may be best reserved for the most severe manifestations of the disease, as they may be associated with serious adverse effects and as-yet-unknown long-term consequences.

Takayasu arteritis (TAK) is a large vessel vasculitis affecting young women of childbearing age. The outcome of pregnancies in TAK patients, factors associated with maternal and foetal complications and adverse outcomes were analysed.All pregnancies in women with a TAK diagnosis were retrospectively included from 20 French hospitals providing care for TAK, until August 2015.The study consisted of 43 pregnancies in 33 women, including 29 with a pre-existing TAK diagnosis and 4 diagnosed during pregnancy. Complications were observed in 20 pregnancies (47%), including 35% with arterial hypertension (n = 15), 9% with pre-eclampsia (n = 4), 2% with HELLP syndrome (n = 1) and 14% with intrauterine growth restriction (IUGR, n = 6, leading in one case to a medically indicated termination of pregnancy). There were 42 live births (98%) at a median term of 38 [27-42] weeks gestation including 9 before 37 weeks (21%). The median birth weight was 2940 [610-4310] grams. Five children (12%) required transfer to a neonatal intensive care unit. One premature boy (27 weeks gestation) died after 2 days. Treatment during pregnancy included steroids (n = 25/43; 58%), azathioprine (n = 9/43; 21%) and infliximab (n = 1/43; 2%). The risk of developing arterial hypertension during pregnancy was associated with previous chronic arterial hypertension and with an infra-diaphragmatic vasculitis injury (P = 0.01 and P = 0.04, respectively). No correlation was reported between TAK activity and any of the obstetrical complications described in the study.This study showed a high rate of adverse obstetrical complications without significant impact on live birth rates. Pregnancy did not appear to influence TAK disease activity. Key Points • We observed a high rate of adverse obstetrical complications in women with Takayasu arteritis; however, the rate of live births was high. Pregnancy did not appear to influence TA disease activity.

Langerhans cell histiocytosis (LCH) is a rare protean disease that usually affects children. Few data are available for management of adult-onset cases. A complete picture of the efficacy and safety of 2CdA (2-chlorodeoxyadenosine, cladribine) is lacking. We report a retrospective multicentre study of 23 adult LCH (a-LCH) patients who received single-agent 2CdA and a systematic literature review. All had previously received systemic therapy (vinblastine, n = 19). Response to 2CdA was evaluable in 22 cases. Overall response rate (ORR) was 91%. Complete response (CR) occurred in 11 cases (50%). Nine patients (39%) developed grade 3-4 neutropenia and/or severe infection. A literature review yielded 48 additional cases. A pooled analysis confirmed our findings (ORR: 88%, CR: 49%). CRs were rare with cumulative dose

Poster: "ESTI 2019 / P-0109 / Lung involvement in Destombes-Rosai-Dorfman disease: clinical and radiological features, and response to the MEK inhibitor cobimetinib " by: "Q. moyon, S. Boussouar , F. cohen aubart, P. maksud, N. Aladjidi, G. Prevot, J. donadieu, Z. amoura, P. A. Grenier, J. haroche; Paris/FR"

Contains fulltext : 249882.pdf (Publisher’s version ) (Closed access) ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

ObjectivesTo compare the efficacy to prevent flares of maintenance versus withdrawal of 5 mg/day prednisone in systemic lupus erythematosus (SLE) patients with clinically quiescent disease.MethodsA monocentric, 12-month, superiority, open-label, randomised (1:1) controlled trial was conducted with 61 patients continuing 5 mg/day prednisone and 63 stopping it. Eligibility criteria were SLE patients who, during the year preceding the inclusion, had a clinically inactive disease and a stable SLE treatment including 5 mg/day prednisone. The primary endpoint was the proportion of patient experiencing a flare defined with the SELENA-SLEDAI flare index (SFI) at 52 weeks. Secondary endpoints included time to flare, flare severity according to SFI and British Isles Lupus Assessment Group (BILAG) index and increase in the Systemic Lupus International Collaborating Clinics (SLICC) damage index (SDI).ResultsProportion of patients experiencing a flare was significantly lower in the maintenance group as compared with the withdrawal group (4 patients vs 17; RR 0.2 (95% CI 0.1 to 0.7), p=0.003). Maintenance of 5 mg prednisone was superior with respect to time to first flare (HR 0.2; 95% CI 0.1 to 0.6, p=0.002), occurrence of mild/moderate flares using the SFI (3 patients vs 12; RR 0.2 (95% CI 0.1 to 0.8), p=0.012) and occurrence of moderate/severe flares using the BILAG index (1 patient vs 8; RR 0.1 (95% CI 0.1 to 0.9), p=0.013). SDI increase and adverse events were similar in the two treatment groups. Subgroup analyses of the primary endpoint by predefined baseline characteristics did not show evidence of a different clinical response.ConclusionMaintenance of long term 5 mg prednisone in SLE patients with inactive disease prevents relapse.Trial registration numberNCT02558517; Results

Erdheim–Chester disease is a rare histiocytosis characterized by iconic features associated with compatible histology. Most patients have somatic mutations in the MAP-kinase pathway gene, and the mutations occur in CD14+ monocytes. Differentiation of the myeloid lineage plays a central role in the pathogenesis of histiocytosis. Monocytes are myeloid-derived white blood cells, divided into three subsets, but only the CD14++CD16− “classical monocyte” can differentiate into dendritic cells and tissue macrophages. Since most mutations occur in CD14+ cells and since ECD patients have a particular monocytic phenotype resembling CMML, we studied the correlation between disease activity and monocytic subset distribution during the course of a severe vascular form of ECD requiring liver transplantation. During early follow-up, increased CD14++CD16− “classical monocyte” associated with decreased CD14lowCD16++ “non-classical monocyte” correlated with disease activity. Further studies are needed to confirm the use of monocyte as a marker of disease activity in patients with ECD.

International audience; Inorganic antigens may contribute to paediatric sarcoidosis. Thirty-six patients matched with 36 healthy controls as well as a group of 21 sickle-cell disease (SCD) controls answered an environmental questionnaire. Patients' indirect exposure to inorganic particles, through coresidents' occupations, was higher than in healthy and SCD controls (median score: 2.5 (0.5-7) vs 0.5 (0-2), p=0.003 and 1 (0-2), p=0.012, respectively), especially for construction, exposures to metal dust, talc, abrasive reagents and scouring products. Wood or fossil energies heating were also linked to paediatric sarcoidosis. This study supports a link between mineral environmental exposure due to adult coresident occupations and paediatric sarcoidosis.

Consider immune reconstitution syndrome in case of neurologic worsening during nivolumab treatment given for progressive multifocal leukoencephalopathy.

Neurosarcoidosis is a rare inflammatory neurological condition. We describe a challenging radiological presentation of neurosarcoidosis. The eclipse sign refers to hypo T1-weighted parenchymal or leptomeningeal images surrounded by circular gadolinium enhancement. The eclipse sign was identified in 3 out of 46 patients with histologically-proven neurosarcoidosis. The eclipse sign may correspond to necrotizing parenchymal or leptomeningeal granuloma. This sign expands the spectrum of radiological presentations of neurosarcoidosis.

PURPOSE Off-label use of vemurafenib (VMF) to treat BRAFV600E mutation–positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 ( P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAFV600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAFV600E clone. CONCLUSION VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.

Objectives Interstitial lung disease (ILD) is a common feature of mixed connective tissue disease. However, many patients do not meet the criteria for mixed connective tissue disease and thus may be diagnosed as interstitial pneumonia with autoimmune features. The aim of this study was to characterize ILD associated with anti-ribonucleoprotein (RNP) antibodies. Methods Chest computed tomography scans of patients with anti-RNP antibody who were seen between January 2011 and October 2015 were reviewed. The underlying disease was classified with international criteria using clinical and serological features. Results Among 544 patients with anti-RNP antibodies, 188 had a chest computed tomography scan, and 48 (26%) of them had radiological features of ILD. The presence of ILD was significantly associated with dyspnea, crackles, arthritis, Raynaud phenomenon, myositis, and sicca syndrome. The most frequent pattern was nonspecific interstitial pneumonia in 39 patients (81%). Among patients with ILD, 17 (35%) had a radiological pattern consisting of cysts and ground-glass attenuation not fulfilling the lymphoid interstitial pneumonia criteria. In 3 patients, cysts were related to fibrosis; in 14 patients, cysts corresponded to an original ILD pattern. Conclusions Interstitial lung disease was found in 26% of patients with anti-RNP antibodies independently of the underlying disease. Anti-RNP-associated ILD mainly corresponds to nonspecific interstitial pneumonia or an original pattern consisting of cysts and ground-glass attenuation.

BackgroundRenal biopsy is the cornerstone of systemic lupus erythematosus (SLE) nephritis and antiphospholipid syndrome (APS) nephropathy management. However, transcutaneous renal biopsy (TCRB) is hampered by the antithrombotic treatment frequently prescribed for those diseases. Transjugular renal biopsy (TJRB) offers an attractive alternative for patients at increased risk of bleeding. The primary objective of the study was to describe the safety profile and diagnostic performance of TJRB in SLE and APS patients.MethodsAll SLE and/or APS patients who underwent a renal biopsy in our department (between January 2004 and October 2016) were retrospectively reviewed. Major complications were death, haemostasis nephrectomy, renal artery embolization, red blood cell transfusion, sepsis and vascular thrombosis; macroscopic haematuria, symptomatic perirenal/retroperitoneal bleeding and renal arteriovenous fistula without artery embolization were considered as minor complications.ResultsTwo hundred and fifty-six TJRBs—119 without antithrombotics (untreated), 69 under aspirin and 68 on anticoagulants and 54 TCRBs without antithrombotics—were analysed. Their major and minor complication rates, respectively, did not differ significantly for the four groups: 0 and 8% for untreated TJRBs, 1 and 6% for aspirin-treated, 6 and 10% for anticoagulant-treated and 2 and 2% for TCRBs. The number of glomeruli sampled and the biopsy contribution to establishing a histological diagnosis was similar for the four groups.ConclusionsTJRBs obtained from SLE and APS patients taking antithrombotics had diagnostic yields and safety profiles similar to those of untreated TCRBs. Thus, TJRB should be considered for SLE and APS patients at risk of bleeding.

International audience; OBJECTIVES:Infliximab is increasingly used to treat neurosarcoidosis. We aimed to determine the efficacy and tolerance of an infliximab biosimilar for treating neurosarcoidosis.METHODS:We conducted a retrospective single-center study to describe the efficacy, safety and immunogenicity of an infliximab biosimilar in neurosarcoidosis patients. We compared the survival time without relapse while receiving the biosimilar or previous originator-infliximab treatment.RESULTS:Twenty patients with histologically documented neurosarcoidosis were treated with an infliximab biosimilar (initiation of treatment in 12 and switch from the originator drug in 8) between February 2016 and August 2018. All patients presenting with neurological involvement of one or more areas, including meningeal (n = 15), cerebral (n = 10), spinal cord (n = 9), and/or cranial nerves (n = 5); epilepsy (n = 3); and/or intracranial hypertension (n = 3) were enrolled. Eighteen patients received glucocorticoids during infliximab treatment, and 16 had methotrexate or azathioprine concomitant treatment. The median duration of follow-up was 25 months (19-28). Six patients relapsed during biosimilar treatment. Relapse rates and time-to-relapse did not differ between the infliximab originator previously received and biosimilar treatment groups (p = 0.40 and 0.51, respectively). Nine patients experienced 11 adverse events with the infliximab biosimilar, including infections (n = 5), urticaria (n = 4), headache (n = 1), and diarrhea (n = 1). All side effects were grade 2 or less using the WHO classification.CONCLUSIONS:In this retrospective study, the infliximab biosimilar was efficacious and safe for treating neurosarcoidosis.

ObjectivePeritoneal or mesenteric tumours may correspond to several tumour types or tumour-like conditions, some of them being represented by histiocytosis. This rare condition often poses diagnostic difficulties that can lead to important time delay in targeted therapies. Our aim was to describe main features of histiocytoses with mesenteric localisation that can improve the diagnostic process.DesignWe performed a retrospective study on 22 patients, whose peritoneal/mesenteric biopsies were infiltrated by histiocytes.ResultsAbdominal pain was the revealing symptom in 10 cases, and 19 patients underwent surgical biopsies. The diagnosis of histiocytosis was proposed by initial pathologists in 41% of patients. The other initial diagnoses were inflammation (n=7), sclerosing mesenteritis (n=4) and liposarcoma (n=1). The CD163/CD68+CD1a- histiocytes infiltrated subserosa and/or deeper adipose tissues in 16 and 14 cases, respectively. A BRAFV600E mutation was detected within the biopsies in 11 cases, and two others were MAP2K1 mutated. The final diagnosis was histiocytosis in 18 patients, 15 of whom had Erdheim-Chester disease. The median diagnostic delay of histiocytosis was 9 months. Patients treated with BRAF or MEK inhibitors showed a partial response or a stable disease. One patient died soon after surgery, and five died by the progression of the disease.ConclusionDiagnosis of masses arising in the mesentery should be carefully explored as one of the possibilities in histiocytosis. This diagnosis is frequently missed on mesenteric biopsies. Molecular biology for detecting the mutations in BRAF or in genes of the MAP kinase pathway is a critical diagnostic tool.

AIM To describe MRI features, including diffusion-weighted imaging (DWI), magnetic resonance spectroscopy (MRS), and perfusion-weighted imaging (PWI), of intra-axial tumour-like presentations of four different subtypes of histiocytosis. MATERIAL AND METHODS The brain MRI findings of 23 patients with histologically proven histiocytosis were reviewed retrospectively (11 Langerhans cell histiocytosis [LCH], eight Erdheim–Chester disease [ECD], one overlap form LCH/ECD, two Rosai–Dorfman disease [RDD], and one haemophagocytic lymphohistiocytosis [HLH]) with single or multiple enhancing intraparenchymal brain lesions. RESULTS Histiocytic brain mass lesions show some similar MRI features including Supra and/or infratentorial and/or paraventricular subcortical well-delineated masses, linear ependymal enhancement along the ventricles and brain stem lesions. Masses always present with mixed hyper- and hypointense signal on T2-weighted imaging (WI). Their enhancement is often homogeneous. Apparent diffusion coefficient (ADC) values are often normal or elevated. CONCLUSION The presence of multiple periventricular and subcortical enhancing lesions with mixed signal intensity on T2WI and normal or high ADC values should lead radiologists to consider the diagnosis of histiocytic lesions and search for associated systemic lesions.

Patients with autoimmune encephalitis (AE) are likely to exhibit an acute onset of severe psychiatric features, including psychosis and/or catatonia. Based on the high prevalence of catatonia in AE and our clinical experience, we hypothesized that catatonia might be a marker of severity requiring more aggressive treatment approaches.To reach a sufficient number of cases with brain-autoimmune conditions, we pooled two samples (N = 58): the first from the French National Network of Rare Psychiatric diseases and the second from the largest Italian neuro-pediatrics center for encephalopathies. Autoimmune conditions were diagnosed using a multidisciplinary approach and numerous paraclinical investigations. We retrospectively compared patients with and without catatonia for psychiatric and non-psychiatric clinical features, biological and imaging assessments, type of immunotherapy used and outcomes.The sample included 25 patients (43%) with catatonia and 33 (57%) without catatonia. Forty-two patients (72.4%) had a definite AE (including 27 anti-NMDA receptor encephalitis) and 16 (27.6%) suspected autoimmune encephalitis. Patients with catatonia showed significantly more psychotic features [18 (72%) vs 9 (27.3%), p 0.001)] and more movement disorders [25 (100%) vs 20 (60.6%), p 0.001] than patients without catatonia. First line (corticoids, immunoglobulin and plasma exchanges) and second line (e.g., rituximab) therapies were more effective in patients with catatonia, with 24 (96%) vs 22 (66.7%) (p = 0.006) and 17 (68%) vs 9 (27.3%) (p = 0.002), respectively. However, those with catatonia received more combinations of first and second line treatments and had more relapses during outcomes.Despite its exploratory design, the study supports the idea that autoimmune catatonia may be a marker of severity and morbidity in terms of initial presentation and relapses, requiring the need for early and aggressive treatment.

SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis, characterized by sustained NF-κ B activity, TNF-α signaling, associated with decreased gene expression of NF-κ B inhibitors. We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1α and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology. Funding: The study was supported by the Institut National de la Sante et de la Recherche Medicale (INSERM), by the “URGENCE COVID-19” fundraising campaign of Institut Pasteur, by the Atip-Avenir, Emergence ville de Paris program and fond de dotation Janssen Horizon and by government grants managed by the Agence National de la Recherche as part of the “Investment for the Future” program (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01, Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010, Laboratoire d’Excellence ‘‘Milieu Interieur”, grant ANR-10-LABX-69-01), the Centre de Reference Deficits Immunitaires Hereditaires (CEREDIH), the Agence National de la Recherche (ANR-flash Covid19 “AIROCovid” to FRL and “CoVarImm” to DD and JDS), and by the FASTFoundation (French Friends of Sheba Tel Hashomer Hospital). The LabTech Single-Cell@Imagine is supported by the Paris Region and the “Investissements d’avenir” program through the 2019 ATF funding – Sesame Filieres PIA (Grant N°3877871).CdC is the recipient of a CIFRE-PhD (Sanofi). L.B. was a recipient of an Imagine institute PhD international program supported by the Fondation Bettencourt Schueller. L.B. was also supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) and is part of the Universite de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its“Investments for the Future” program. S.M. was a recipient of an INSERM and Institut Imagine post-doctorat program supported by the Fondation pour la Recherche Medicale (FRMN°SPF20170938825). NS was a recipient of the Pasteur-Roux-Cantarini Fellowship. VGP obtained an Imagine international PhD fellowship program supported by the Fondation Bettencourt Schueller. BPP is the recipient of an ANRS post-doctoral fellowship. Conflict of Interest: DD, FRL, JT and MMM are listed as inventors on a patent application related to this technology (European Patent Application no. EP21305197, entitled “Methods of predicting multisystem inflammatory syndrome (MIS-C) with severe myocarditis in subjects suffering from a SARS-CoV-2 infection”). Ethical Approval: The study was approved by the Ethics Committee (Comite de Protection des Personnes Ouest IV, n° DC-2017-2987).

Patients with interstitial lung disease have been considered at high risk of complications of COVID-19 because of their underlying lung disease and use of immunosuppressive agents.1 However, data on COVID-19 in patients with sarcoidosis are scarce.2–4 Several reasons for an increased risk of severe forms of COVID-19 among sarcoidosis patients have been hypothesised: the involvement of the lung in almost 90% of patients with COVID-19, some of whom have reduced pulmonary function and comorbidities such as diabetes or hypertension, which are largely associated with the use of glucocorticosteroids for treating sarcoidosis; and the use of immunosuppressive agents in a subset of these patients.5 Recently, Gyorfi et al 6 described the case of a patient with sarcoidosis who experienced a symptomatic SARS-CoV-2 infection with spontaneous clinical improvement, and a virological relapse after steroids treatment. This case illustrated the fact that immunosuppression with glucocorticoids may induce relapse of COVID-19 in patients with sarcoidosis. However, we lack data on the outcomes of patients with sarcoidosis affected by COVID-19. We retrospectively collected data for all patients with sarcoidosis and SARS-CoV-2 infection seen among 15 French centres between 1 March and 20 May 2020. The inclusion criteria were a sarcoidosis diagnosis based on the American Thoracic Society/European Respiratory Society/World Association for Sarcoidosis and other granulomatous diseases …

(1) Background: Pediatric sarcoidosis is a rare and mostly severe disease. Very few pediatric series with a prolonged follow-up are reported. We aimed to evaluate the evolution of pediatric sarcoidosis in adulthood. (2) Material and methods: Patients over 18-years-old with a pediatric-onset sarcoidosis (&le, 15-year-old) who completed at least a three-year follow-up in French expert centers were included. Clinical information at presentation and outcome in adulthood were studied. (3) Results: A total of 52 patients were included (34 prospectively in childhood and 18 retrospectively in adulthood), with a mean age of 12 (&plusmn, 2.7) at diagnosis. The median duration time of follow-up was 11.5 years (range 3&ndash, 44.5). Relapses mostly occurred during treatment decrease (84.5%), others within the three years after treatment interruption (9.1%), and rarely when the disease was stable for more than three years (6.4%). Sarcoidosis was severe in 11 (21.2%) in adulthood. Patients received a high corticosteroid cumulative dose (median 17,900 mg) for a median duration of five years (range 0&ndash, 32), resulting in mostly mild (18, 35.3%) and rarely severe (2, 3.8%) adverse events. (4) Conclusions: Pediatric-onset sarcoidosis needed a long-term treatment in almost half of the patients. Around one fifth of pediatric-onset sarcoidosis patients had severe sarcoidosis consequences in adulthood.

BackgroundIdentification of prognostic factors in COVID-19 remains a global challenge. The role of smoking is still controversial.ObjectiveTo evaluate the rate of daily smokers in patients with COVID-19.MethodsCOVID-19 in-and outpatients from a large French university hospital were systematically interviewed for their smoking status, use of e-cigarette and nicotinic substitutes. The rates of daily smokers in in-and outpatients were compared to those in the 2019 French general population, after standardization for sex and age.ResultsThe inpatient group was composed of 340 patients, median age 66 years: 203 men (59.7%) and 137 women (40.3%), median age for both 66 years, with a daily smokers rate of 4.1 % CI95% [2.3–6.9] (5.4% of men, 2.2% of women). The outpatient group was composed of 139 patients, median age 44 years: 62 men (44.6%, median age 43 years), and 77 women (55.4%, median age 44 years). The daily smoker rate was 6.1 % CI 95% [2.7 - 11.6] (5.1% of men, 6.8% of women). In the 2019 French population, the daily smoker rate was 24.0% (27.5% of men, 20.7% of women). Among inpatients, daily smokers represented 2.2% and 3.4% of the 45 dead patients and of the 29 patients transferred to ICU, respectively.The rate of daily smokers was significantly lower in COVID-19 patients, as compared to that in the French general population after standardization by age and sex, with Standardized Incidence Ratios of 0.24 [0.12-0.48] for outpatients and 0.24 [0.14-0.40] for inpatients.ConclusionDaily smokers rate in patients with symptomatic COVID-19 is lower as compared to the general population

Importance: As the pandemic of COVID-19 is still under progression, identification of prognostic factors remains a global challenge. The role of smoking has been suggested among the disease risk factors, although it is highly controversial. Objective: To evaluate whether the rate of daily smokers in patients with COVID-19 was different to that in the French population. Participants: COVID-19-infected in- and outpatients in a large French university hospital between February 28, 2020 and March 30, 2020 for outpatients and from March 23, till April 9, 2020 for inpatients. Design: We systematically interviewed the patients on their smoking status, use of e-cigarette and nicotinic substitutes. The rate of daily smokers in inpatients and outpatients were compared to those in the 2018 French general population, after standardization for sex and age. Results: The inpatient group was composed of 340 patients, median age 66 years: 203 men (59.7%, median age 66 years) and 137 women (40.3%, median age 66 years),with a rate of daily smokers of 4.1% CI95% [2.3 – 6.9] (5.4% of men and 2.2% of women). The outpatient group was composed of 139 patients, median age 44 years: 62 men (44.6%, median age 43 years, and 77 women (55.4 %, median age 44 years). The daily smokers’ rate was 6.1 % CI95% [2.7 - 11.6] (5.1% of men and 6.8 % of women). In the French population, the daily smokers’ rate was 25.4% (28.2% of men and 22.9% of women). The rate of daily smokers was significantly lower in COVID-19 patients, as compared to that in the French general population after standardization by age and sex, with Standardized Incidence Ratios of 0.23 [0.11 - 0.45] for outpatients and 0.23 [0.14 - 0.39] for inpatients. These ratios did not significantly differ between the two groups (P=0.94). Conclusions and relevance: This cross sectional study in both COVID-19 out- and inpatients shows that daily smokers rate in patients with symptomatic COVID-19 is lower as compared to the general population.

Sarcoidosis is a rare disease of unknown cause with wide heterogeneity in clinical features and outcomes. We aimed to explore sarcoidosis phenotypes and their clinical relevance with particular attention to extrapulmonary subgroups.The Epidemiology of Sarcoidosis (EpiSarc) study is a French retrospective multicentre study. Sarcoidosis patients were identified through national hospitalisation records using appropriate codes from 11 hospital centres between 2013 and 2016 according to a standardised protocol. Medical charts were reviewed. The phenotypes of sarcoidosis were defined using a hierarchical cluster analysis.A total of 1237 patients were included (562 men and 675 women). The mean age at sarcoidosis diagnosis was 43.5±13 years. Hierarchical cluster analysis identified five distinct phenotypes according to organ involvement and disease type and symptoms: 1) erythema nodosum, joint involvement and hilar lymph nodes (n=180); 2) eye, neurological, digestive and kidney involvement (n=137); 3) pulmonary involvement with fibrosis and heart involvement (n=630); 4) lupus pernio and a high percentage of severe involvement (n=41); and 5) hepatosplenic, peripheral lymph node and bone involvement (n=249). Phenotype 1 was associated with being European/Caucasian and female and with non-manual work, phenotype 2 with being European/Caucasian, and phenotypes 3 and 5 with being non-European/Caucasian. The labour worker proportion was significantly lower in phenotype 5 than in the other phenotypes.This multicentre study confirms the existence of distinct phenotypes of sarcoidosis, with a non-random distribution of organ involvement. These phenotypes differ according to sex, geographical origin and socioprofessional category.

BackgroundCurrent data suggest that COVID-19 is less frequent in children, with a milder course. However, over the past weeks, an increase in the number of children presenting to hospitals in the greater Paris region with a phenotype resembling Kawasaki disease (KD) has led to an alert by the French national health authorities.MethodsMulticentre compilation of patients with KD in Paris region since April 2020, associated with the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (‘Kawa-COVID-19’). A historical cohort of ‘classical’ KD served as a comparator.ResultsSixteen patients were included (sex ratio=1, median age 10 years IQR (4·7 to 12.5)). SARS-CoV-2 was detected in 12 cases (69%), while a further three cases had documented recent contact with a quantitative PCR-positive individual (19%). Cardiac involvement included myocarditis in 44% (n=7). Factors prognostic for the development of severe disease (ie, requiring intensive care, n=7) were age over 5 years and ferritinaemia >1400 µg/L. Only five patients (31%) were successfully treated with a single intravenous immunoglobulin (IVIg) infusion, while 10 patients (62%) required a second line of treatment. The Kawa-COVID-19 cohort differed from a comparator group of ‘classical’ KD by older age at onset 10 vs 2 years (pConclusionKawa-COVID-19 likely represents a new systemic inflammatory syndrome temporally associated with SARS-CoV-2 infection in children. Further prospective international studies are necessary to confirm these findings and better understand the pathophysiology of Kawa-COVID-19.Trial registration numberNCT02377245

International audience

ObjectiveCNS involvement in Erdheim-Chester disease (ECD) leads to substantial morbidity and mortality. To assess CNS manifestations in a French cohort of 253 patients with ECD, we determined clinical characteristics and outcomes, including those under targeted therapies.MethodsThis was a retrospective longitudinal study. CNS manifestations were determined by clinical examination and brain or spine MRI. Targeted therapy efficacy was assessed using global assessment from a physician and a radiologist. The study was approved by the ethics committee Comité de Protection des Personnes Ile de France III.ResultsNinety-seven of 253 patients (38%) with ECD had CNS involvement. CNS involvement was significantly associated with a younger age at diagnosis (mean 55.5 years) and at symptom onset (mean 50.5 years), as well as with the presence of the BRAFV600E mutation (in 77% of cases), xanthelasma (34%), and diabetes insipidus (36%). Median survival among patients with CNS involvement was significantly lower than that of patients with ECD without CNS involvement (124 months vs 146 months, p = 0.03). Seventy-four CNS MRIs were centrally reviewed, which showed 3 patterns: tumoral in 66%, pseudo-degenerative in 50%, and vascular in 18%. Targeted therapy (BRAF or MEK inhibitors) was associated with improved symptoms in 43% of patients and MRI improvement in 45%.ConclusionsCNS manifestations are typically associated with poor prognosis in patients with ECD. Three distinct patterns can be recognized: tumoral, pseudodegenerative, and vascular.Classification of evidenceThis study provides Class III evidence that targeted therapy leads to clinical or imaging improvement in almost 50% of patients.

Objectives Pediatric catatonia is a rare and life-threatening syndrome. Around 20% of juvenile catatonia is associated with organic condition (Consoli et al., 2012). Autoimmune conditions represent a diagnostic and therapeutic challenge since specific antibodies can be missed. To facilitate decision making, we recently formulated a causality assessment score (CAUS) using a stepwise approach and an immunosuppressive therapeutic challenge (Ferrafiat et al., 2016). Our objectives were to validate retrospectively CAUS and to define its threshold for an accurate distinction between organic catatonia and non-organic catatonia, and specifically between autoimmune catatonia and non-organic catatonia. Method To obtain a sufficient number of cases with organic catatonia, we pooled two samples ( N = 104) – one from a child psychiatry center, the other from neuro-pediatrics center – expert in catatonia and autoimmune conditions. Organic conditions were diagnosed using a multidisciplinary approach and numerous paraclinical investigations. Given the binary classification needs, we used receiver operating characteristic (ROC) analysis (Peacock and Peacock, 2010) to calculate the best classification threshold. Results The cohort included 67 cases of non-organic catatonia and 37 cases of organic catatonia. ROC analysis showed that the CAUS performance in discriminating both organic catatonia vs. non-organic catatonia, and autoimmune catatonia vs. non-organic catatonia was excellent (Area Under the Curve = 0.99). In both analyses, for a CAUS threshold ≥ 5, accuracy equaled to 0.96. Conclusion Regarding juvenile catatonia, the use of the CAUS score algorithm combining a therapeutic challenge and a threshold ≥ 5 may help to diagnose and treat autoimmune conditions even without formal identification of auto-antibodies.

Objective— Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by the infiltration of multiple tissues with lipid-laden histiocytes. Cardiovascular involvement is frequent in ECD and leads to a severe prognosis. The objective of this study was to determine whether an alteration of lipid metabolism participates in the lipid accumulation in histiocytes and the cardiovascular involvement in ECD. Approach and Results— An analysis of plasma lipid levels indicated that male ECD patients carrying the BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) mutation exhibited hypoalphalipoproteinemia, as demonstrated by low plasma HDL-C (high-density lipoprotein cholesterol) levels. Capacity of sera from male BRAF V600E ECD patients to mediate free cholesterol efflux from human macrophages was reduced compared with control individuals. Cardiovascular involvement was detected in 84% of the ECD patients, and we reported that the presence of the BRAF V600E mutation and hypoalphalipoproteinemia is an independent determinant of aortic infiltration in ECD. Phenotyping of blood CD14 + cells, the precursors of histiocytes, enabled the identification of a specific inflammatory signature associated with aortic infiltration which was partially affected by the HDL phenotype. Finally, the treatment with vemurafenib, an inhibitor of the BRAF V600E mutation, restored the defective sera cholesterol efflux capacity and reduced the aortic infiltration. Conclusions— Our findings indicate that hypoalphalipoproteinemia in male ECD patients carrying the BRAF V600E mutation favors the formation of lipid-laden histiocytes. In addition, we identified the BRAF status and the HDL phenotype as independent determinants of the aortic involvement in ECD with a potential role of HDL in modulating the infiltration of blood CD14 + cells into the aorta.

Background Bullous systemic lupus erythematosus (BSLE) is a rare blistering condition associated with systemic lupus erythematosus (SLE). Patients and Methods We conducted a multi-center retrospective study in order to describe the clinical, immunological, and histological presentations and outcomes of BSLE. The skin biopsies were centrally reviewed, and sera obtained during a flare of BSLE were analyzed for identification of circulating anti-basement membrane zone antibodies. Results Ten patients (all women, median age at SLE diagnosis of 22 years) were included, as well as 118 cases from a systematic review of the literature. Lupus nephritis was associated in 50% of the cases. BSLE presented as tensed bullae on normal or erythematous skin, predominantly localized on the trunk, arms, head and neck. Urticarial lesions were associated in 31% of the cases, and mucous membrane involvement was seen in 51%. Histological analyses displayed sub-epidermal detachment, dermal infiltration of polynuclear neutrophils, alignment of these cells at the basal membrane zone and leukocytoclasis. The direct immunofluorescence was polymorphic, showing linear and/or granular deposits of IgG, IgA, IgM and/or C3. Anti-type VII collagen antibodies were detected in 69% of cases. Dapsone was efficacious in 90% of cases. Conclusion BSLE is an autoimmune neutrophilic blistering disease associated with SLE; it is not a cutaneous manifestation of lupus but may be associated with active extra-cutaneous manifestations of SLE. Dapsone is the first-choice option.

Rosai-Dorfman disease (RDD) was first described by the French pathologist Paul Destombes in 1965. It frequently affects children or young adults and is characterized by the presence of large histiocytes with emperipolesis. More than 50 years after this first description, the pathogenesis of this rare disease is still poorly understood. The revised classification of histiocytoses published in 2016 identified various forms of RDD, from familial RDD to IgG4-associated RDD. Almost 90% of the patients with RDD have cervical lymph nodes involvement although all the organs may virtually be involved. Outcomes are typically favorable. Treatments may be necessary in case of compression or obstruction, and are not well codified. The main therapeutic strategies rely on surgery, radiotherapy, steroids, immunosuppressive drugs or interferon-alpha and cladribine.

Background: Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytic disorder that almost exclusively affects adults. Reports of pediatric-onset ECD are only anecdotal. Additionally, a comprehensive clinical and molecular characterization of pediatric ECD is lacking. Methods: All prevalent and incident cases followed at three ECD referral centers in Italy and France were considered eligible when they had: a) an age Results: Ten patients were included (4 boys and 6 girls); their median age at diagnosis was 4.5 years (IQR 3-9). Bone pain, diabetes insipidus, and exophthalmos were the predominant clinical manifestations at onset. The most commonly involved sites were the hypothalamic/pituitary axis (8/10, 80%), the maxillary/facial structures (8/10, 80%), the bone (6/10, 60%), and the central nervous system (CNS; 7/10, 70%). Other less frequent localizations included the skin (3/10, 30%), the retroperitoneum (2/10, 20%), the lymph nodes (2/10, 20%), the large vessels (1/10, 10%), the heart (1/10, 10%), and the lung (1/10, 10%). The median number of involved sites was four (IQR 4-4). Four patients (of whom three were younger than nine years) had clinical or pathological features consistent with mixed histiocytosis (ECD-LCH). Molecular analysis of tissue biopsies revealed the BRAF V600E mutation in 6 patients (60%). As compared with adult series, the retroperitoneum, the heart, the lungs, and the skin seemed to be less frequently involved. Conversely, hypothalamic/pituitary and maxillary/facial involvement were apparently more frequent in our pediatric cohort. Treatments were heterogeneous. First-line regimens mainly consisted of chemotherapy deriving from LCH-based regimens: six out of the eight treated patients received chemotherapy, but only two of them achieved a transient response. Interferon-alpha was used in five patients (as first-line treatment in two and as a rescue treatment in three), with a partial response in two. Four patients with the BRAF V600E mutation received the BRAF inhibitor vemurafenib at some point (partial responses were obtained in all, in one case requiring a combination with cobimetinib). All patients were alive at last follow up (median 94 months, IQR 12-108). Chronic sequelae included end-stage kidney disease in one patient, growth retardation in two, and endocrine abnormalities in seven. Conclusions: The clinical phenotype of ECD differs between children and adults. The hypothalamic/pituitary axis and the maxillary/facial area are frequently involved in pediatric cases, whereas other localizations typically seen in adults (i.e., retroperitoneum, heart, lung, and skin) are rarer. An overlap with LCH is frequent, especially in younger patients. As for LCH, targeted treatments can be highly effective in children carrying the BRAF V600Emutation. Disclosures No relevant conflicts of interest to declare.

Neurological localizations of sarcoidosis are heterogeneous and may affect virtually every part of the central or peripheral nervous system. They are often the inaugural manifestation of sarcoidosis. The diagnosis may be difficult due to the lack of extra-neurological localization. Diagnosis may be discussed in the presence of an inflammatory neurological disease, in particular in case of suggestive radiological or biological pattern. Cerebrospinal fluid analysis shows lymphocytic pleiocytosis, often with low glucose level. The diagnosis relies on a clinical, biological and radiological presentation consistent with neurosarcoidosis, the presence of non-caseating granuloma and exclusion of differential diagnoses. Screening for other localizations of sarcoidosis, in particular cardiac disease may be obtained during neurosarcoidosis. The treatment of neurosarcoidosis relies on corticosteroids although immunosuppressive drugs are usually added because of the chronic course of this condition and to limit the side effects of steroids. Treatments and follow-up may be prolonged because of the high rate of relapses.

Sarcoidosis is a granulomatous disorder of unknown cause characterized by non-caseating granuloma in young adults. Cardiac involvement is rare and range from 2 to 75% depending on diagnostic criteria. Cardiac involvement in sarcoidosis may be asymptomatic or may manifest as rhythm/conduction troubles or congestive heart failure. The diagnosis and treatment of cardiac sarcoidosis may be challenging. However, advances have come in recent years from the use of cardiac MRI and 18FDG-TEP scanner, as well as from the stratification of the risk of ventricular tachycardia/fibrillation. Due to the rarity of the disease, there is no reliable prospective large study to guide therapeutic strategy for cardiac sarcoidosis. Corticosteroids are probably efficacious, in particular in case of atrio-ventricular block or moderate heart failure. Immunosuppressive drugs have not been largely studied but methotrexate could be helpful. In refractory forms, TNF-α antagonists have been used with success.

In a compatible clinico-radiological setting, the diagnosis of Erdheim-Chester disease (ECD) involves the analysis of histiocytes in tissue biopsies: they are typically foamy and CD68+ CD1a, whereas in Langerhans cell histiocytosis (LCH) they are CD68+ CD1a+. Overlap forms of histiocytoses are frequent. Technetium bone scintigraphy showing nearly constant tracer uptake by the long bones is highly suggestive of ECD and a 'hairy kidney' appearance on abdominal CT scan is observed in more than half ECD cases. CNS involvement is a strong prognostic factor and an independent predictor of death in cases of ECD. Optimal initial therapy for ECD appears to be administration of IFN-α (and/or pegylated IFN-α) and prolonged treatment significantly improves survival; however, tolerance may be poor. Best alternative therapies are anakinra, mainly effective for mild forms of the disease, infliximab, and sirolimus. Cases of ECD present with strong systemic immune activation, involving IFN-α, IL-1/IL1-RA, IL-6, IL-12, and MCP-1, consistent with the systemic immune Th-1-oriented disturbance associated with the disease. Between 57 and 75 % of ECD patients carry the BRAFV600E mutation, an activating mutation of the proto-oncogene BRAF. More than 50 cases harboring BRAF mutation and with severe multisystemic and refractory ECD (sometimes associated with LCH) have been treated worldwide with vemurafenib, a BRAF inhibitor that proved to be very beneficial. Other recurrent mutations of the MAPK (NRAS, MAP2K1) and PIK3 pathways (PIK3CA) have been found among ECD patients. As recurrent mutations in the MAPK pathway are found in ECD and LCH on a background of chronic inflammation, we believe that both conditions should be redefined as an inflammatory myeloid neoplasia.

Background: Remission and relapses prevention are the main objectives of the treatment of Systemic Lupus Erythematosus (SLE). Interferon alpha (IFNα) is a key cytokine in SLE, but its usefulness for the definition of remission and for the prediction of flare has not been validated in clinical practice. Objectives: To study the association between serum IFNα level, remission and risk of relapse. Methods: 502 SLE patients were assessed for serum IFNα level using a biological functional assay(1). Remission was defined by the absence of clinical manifestation of lupus activity (clinical SELENA-SLEDAI = 0) and a prednisone intake ≤ 5 mg/day(2). Patients in remission were subsequently followed for one year. The SELENA-SLEDAI Flare Index was used to identify SLE flare. Uni- and multivariable analyses were performed to define disease parameters associated with serum IFNα positivity in patients in remission at baseline. Survival curve analysis, log-rank tests and Hazard Ratios (HR) were calculated to evaluate the risk of flare depending on IFNα, dsDNA Abs and C3 levels at baseline. Results: 345 samples were obtained from patients in remission. 28.6% of the patients in clinical remission on treatment (requiring clinical SELENA-SLEDAI = 0, positive anti-dsDNA antibodies and/or C3 decrease and prednisone intake 1 – 5 mg/day) had an abnormal serum IFNα level, compared to 6.5% of the patients in complete remission on treatment (requiring clinical SELENA-SLEDAI = 0, no anti-dsDNA antibodies nor C3 decrease and prednisone intake 1 – 5 mg/day). In patients in remission, high serum IFNα levels at baseline were associated in multivariable analysis with the positivity of anti-dsDNA Abs (HR 3.4 [95%CI 1.6-7.2], p=0.0001) and anti-RNP Abs (HR 3.2 [95%CI 1.5-6.8], p=0.0002). In patients in remission, high serum IFNα level at baseline was a significant and independent risk factor of lupus flare (HR=4.8 [95%CI 2.3-9.7], p Conclusion: A large number of SLE patients in remission display abnormal levels of serum IFNα. Abnormal levels of serum IFNα in patients in remission were significantly associated with positive anti-dsDNA and anti-RNP Abs and were an independent predictive biomarker of lupus flare in the following year. Adding serum IFNα to the routine laboratory assessments perform in patient in remission could help clinicians to identify a subgroup of SLE patient clinically in remission but serologically active and at higher risk of relapse. References: [1] Mathian A, et al. Monitoring disease activity in systemic lupus erythematosus with single-molecule array digital ELISA quantification of serum interferon-α. Arthritis Rheumatol Hoboken NJ.2018Dec3; [2] Vollenhoven R, et al. A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS). Ann Rheum Dis. 2017Mar1;76(3):554–61. Disclosure of Interests: None declared

Background: IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder that can affect virtually every organ. Although arterial involvements have been reported, no studies have examined the occurrence of arterial or venous thrombotic events in these patients. Objectives: To explore the frequency, the characteristics, and risk factors of arterial and venous thrombotic events in IgG4-related disease patients. Methods: An observational, descriptive, retrospective study was conducted from a multicentric national case registry for IgG4-RD. Patients fulfilled the Comprehensive Diagnostic Criteria (CDC) for IgG4-RD, and all patients with arterial or venous thrombotic events confirmed by imaging during follow-up were analyzed. Clinical, radiological, biological, histological and therapeutic characteristics were retrospectively collected using a standardized online data sheet. Results obtained in patients with thrombosis were compared to those without thrombosis. Results: One hundred eighty-nine patients with IgG4-RD (135 men/54 women, median age 61 years) were included. During a 12-months median follow-up, one or more arterial thrombotic events occurred in 10 patients and venous thrombotic events in 16 (5.3 and 8.5 events/100 patient-years, respectively). Arterial complications (coronary artery disease n=5, lower limb peripheral arterial disease n=2, mesenteric ischemia, transient ischemic attack, and carotid thrombosis: n=1) occurred on average 30 months [0-140] after the first symptoms of IgG4-RD. They were inaugural in 2 patients without any cardiovascular risk factor, and associated with IgG4-RD arterial involvement in 3 (coronary aneurysms n=2, leg arteritis n=1). Among patients with arterial thrombosis, 60% had systemic involvement (≥3 organs involved), 89% elevated serum IgG4 (> 3N in 56%), and 57% CRP >10 mg/l. Only 5/10 were treated with steroids at the time of arterial complication, and 4 had never been exposed to steroid therapy. Renal involvement was associated with the occurrence of an arterial thrombotic event (p = 0.03). Venous thromboembolic complications (deep venous thrombosis (DVT) n=12, pulmonary embolism n=4) occurred on average 24 months [0-164] after the first symptoms of IgG4-RD, but were inaugural in 6 patients. Usual venous thrombosis risk factors were found in only 3/16. Seven patients had retroperitoneal fibrosis (RPF), 2 had mediastinal fibrosis, 60% had localized IgG4-RD (≤2 organs involved), serum IgG4 level was normal in 67% and CRP Conclusion: Arterial and venous thrombotic complications are common in IgG4-RD patients. While arterial events are associated with mulitorgan involvement and elevated serum IgG4, venous thrombotic complications appear to affect more likely patients with compressive localized forms of the disease, such as RPF. Mechanisms responsible for this over-risk and clinical benefit of a preventive platelet antiaggregant or anticoagulant treatment in high risk of thrombosis subgroups remain to be evaluated. Disclosure of Interests: None declared

Background Glucocorticoids (GCs) are a mainstay of treatment for patients with SLE but are associated with significant adverse effects. Some SLE patients are maintained for a long-term under a low dose of prednisone to prevent relapse. There is no scientific data to sustain this therapeutic strategy. Objectives We hypothesized that maintaining a daily dose of 5 mg prednisone in patients with an inactive SLE for at least a year would prevent the risk of relapse. Methods The CORTICOLUP study (NCT02558517) was a prospective randomized, open-labeled, controlled, monocentric study sought to compare maintenance vs withdrawing of low-dose of prednisone (5mg) to reduce SLE flares, conducted from January 2014 to March 2017. Inclusion criteria were SLE patients who during the year preceding the inclusion had 1/an inactive SLE defined by a SLEDAI-2K score ≤ 4, a BILAG-2004 index C, D or E in all systems and a PGA =0 and 2/a stable SLE treatment including prednisone 5 mg daily. The primary end point was the number of patients with flares during 12 months of follow-up defined by the revised-SELENA SLEDAI Flare Index (rSFI). Secondary outcomes were occurrence of a BILAG scores A or B ≥1, clinical SLEDAI-2k >0, PGA ≥0.5 and increase of the SLICC damage index (SDI). All patients were included in the intention-to-treat analysis. Results A total of 124 patients (61 in the maintenance group and 63 in the withdrawal group) were included. No patients were lost to follow up. At baseline There were no significant differences between the maintenance and the withdrawal group with respect to: duration of SLE [mean (±standard deviation) duration of 11.8 (±0.9) versus 13.1 (±1.0) years], duration of remission [55.7 (±5.8) vs 67.5 (±6.8) months], HCQ treatment [98.2% vs 100.0%], immunosuppressive drugs [27.9% vs 25.4%], previous renal involvement [34.4% vs 41.3%], low C3 [16.4% vs 15.9%], positive Farr test [47.5% vs 46.0%], and SDI [mean index of 0.5 (±0.1) vs 0.7 (±0.2)]. There were significantly more flares in the withdrawal group compared to the maintenance group (17 flares versus 4, p=0.0034 using the Fisher’s exact test). Mild or moderate flares were more frequent in the withdrawal group compared to the maintenance group (12 vs 3, p=0.029). The occurrence of severe flare was not significantly different between the two groups (5 vs 1, p = 0.208). More than two-thirds of the flares in the withdrawal group occurred within the first six months. Within the withdrawal group, using forest plot analysis, no significant association was found between the occurrence of a flare and age, sex, duration of SLE, duration of SLE remission, duration of GCs treatment, immunosuppressants and serological SLE activity at randomization. Four patients in the withdrawal group and none in the maintenance group experienced damage: 2 osteoporosis bone fractures, 1 hydroxychloroquine retinopathy and 1 cataract. Conclusion Withdrawal of low dose of steroids in patients with inactive SLE and stable therapeutic regimen for more than a year is associated with a high risk of relapse. Disclosure of Interests None declared