Search

Resume Introduction La nitrofurantoine peut entrainer des effets indesirables hepatiques et pulmonaires. Parmi les atteintes hepatiques, l’hepatite auto-immune induite par la nitrofurantoine est une complication rare a ne pas confondre avec l’hepatite toxique. Observation Vingt ans apres un premier episode d’hepatite aigue lors d’un traitement par nitrofurantoine, une patiente de 86 ans presentait une hepatite aigue apres reintroduction de cet antibiotique. Le diagnostic d’hepatite auto-immune declenchee par la nitrofurantoine a pu etre porte sur l’anamnese, la biologie (hypergammaglobulinemie polyclonale importante, presence d’anticorps anti-nucleaires, et d’anticorps anti-muscle lisse) et l’histologie hepatique (infiltrat lymphocytaire et activite necrotico-inflammatoire importante). L’evolution de l’hepatite auto-immune etait favorable sous corticoides et azathioprine associes a l’arret de la nitrofurantoine. Apres 2 mois de traitement, la patiente decedait d’un episode d’insuffisance cardiaque globale refractaire. Conclusion L’hepatite auto-immune induite par la nitrofurantoine est une complication grave qu’il faut evoquer systematiquement lors d’une hepatite aigue chez un patient prenant de la nitrofurantoine. La presence d’une hypergammaglobulinemie polyclonale oriente le diagnostic. Il faut alors rechercher les auto-anticorps (anti-nucleaires et anti-muscle lisse) et proposer une biopsie hepatique. Le traitement est celui des hepatites auto-immunes, avec habituellement une evolution favorable et peu de rechutes apres arret de la nitrofurantoine.

Cardiac neonatal lupus syndrome is due to anti-SSA or SSB antibodies and mainly includes congenital heart block (CHB) and dilated cardiomyopathy (DCM). Its optimal management is still debated. We report a large series of autoimmune high degree CHB.Inclusion criteria in this retrospective study were fetuses or neonates with high-degree CHB associated with maternal anti-SSA/SSB antibodies.214 CHB were included: 202 detected in utero at a median term of 23 weeks' gestation (WG) [range 16 to 39 WG] and 12 neonatal cases diagnosed at a median age of 0 days [range birth to 8 days]. The 214 cases of CHB included 202 (94.4%) third-degree CHB, 8 (3.7%) second-degree CHB, and 4 (1.9%) intermittent CHB. In multivariate analysis, the factors associated with feto-neonatal deaths (15.7%) were hydrops (p0.001; hazard ratio [HR] 12.4 [95% confidence interval (95%CI) 4.7-32.7]) and prematurity (p=0.002; HR 17.1 [95%CI 2.8-103.1]). During a median follow-up of 7 years [birth to 36 years], 148 of 187 children born alive (79.1%) had a pacemaker, 35 (18.8%, one missing data) had DCM, and 22 (11.8%) died. In multivariate analysis, factors associated with child death were in utero DCM (p=0.0157; HR 6.37 [95%CI: 1.25-32.44]), postnatal DCM (p0.0001; HR 227.58[95%CI: 24.33-2128.46]) and pacemaker implantation (p=0.0035; HR 0.11[95%CI: 0.02-0.51]). The use of fluorinated steroids was neither associated with survival nor with regression of 2nd degree CHB.In this second largest series of CHB, we confirm some of the previous results. We were unable to find data supporting the routine use of in utero fluorinated steroids.

Background:The understanding of Erdheim-Chester Disease (ECD) pathogenesis has been greatly improved these past few years with the discovery of activating MAPK pathway mutations in most of ECD patients. However, the inflammatory phenotype of ECD remains widely unknown.Objectives:We aimed to explore the inflammatory phenotype of Erdheim-Chester disease (ECD) using mass cytometry.Methods:We analyzed peripheral blood mononuclear cells from 13 ECD patients and 11 healthy donors (HD) using mass cytometry with 29 metal-conjugated antibodies.Results:Compared to HD, untreated ECD patients had increased proportion of classical monocytes (90.8 [87.1-96.5] vs 81.6 [76.2-87.5] %, p=0.02) and decreased proportion of non-classical monocytes (4.7 [3.4-9.7] vs 11.8 [6.6-17.2] %, p=0.047). Untreated ECD patients had more circulating Th17 cells compared to HD (3.3 [3-5.3] vs 1.3 [0.4-2.3] %, p=0.015) and ECD patients treated with BRAF or MEK inhibitors (3.3 (3-5.3] vs 1.9 [0.6-2.4] %, p=0.005). Moreover Treg cells were lower in ECD patients than HD, with an increased Th17/Treg ratio (1.37 [0.74-1.9] vs 0.34 [0.19-0.43], p=0.0004). There was no difference regarding Th1 cells, Th2 cells, B cells, NK cells and circulating dendritic cells.Conclusion:ECD monocyte profile seems similar to what have been described in CMML. Inflammation observed in ECD may be driven through Th17 cells, and might be targeted with specific treatment.Disclosure of Interests:None declared

7560 Background: Erdheim–Chester disease (ECD), an inflammatory myeloid neoplasm from the L group, is an histiocytosis associated with multisystem infiltration. Around 1500 cases have been reported worldwide since 1930. In 15% of cases, ECD is associated with another histiocytosis corresponding to mixed histiocytosis. Before 2004, 60% of patients died within 3 years after diagnosis. The targetable BRAFV600Emutation is present in as much as 70% of all ECD cases. Targeted therapies (BRAF inhibitors in April 2012, followed by MEK inhibitors after 2015) have revolutionized the therapeutic options and prognosis of refractory ECD and mixed histiocytosis. Methods: This retrospective study was conducted between April 2012 and December 2019 on 117 ECD patients who received targeted therapies in the French National Referral Center for Histiocytosis at Pitié-Salpêtrière Hospital in Paris, France. 28 patients (pts) (24%) had a mixed histiocytosis. Results: 43 (36.7%) pts were female and 95/116 exploitable pts (81.9%) had a BRAF V600E mutation. 12 (10.3%) pts had a co-ocurring hemopathy (myeloproliferative neoplasm or myelodysplastic syndrom). Age at diagnosis was 57.2 yr (+/- 13.8). The main sites of involvement were: vascular (“coated aorta”) in 85 pts (73%), heart in 83 pts (71%), xanthelasma in 30 pts (26%), central nervous system in 56 pts (48%) and peri-renal (“hairy kidney”) in 84 pts (72%). 34 pts (29%) had previously received corticosteroids, and 63 pts (54%) interferon alpha regimen (mainly PEG interferon). 86 (74%) pts received the BRAF inhibitor vemurafenib, and 42 (36%) pts the MEK inhibitor cobimetinib (some patients receiving both). 25 pts died during follow-up. The median survival of patients with targeted therapies in december 2019 was undefined, whereas the patients with no targeted therapies had a median survival of 133 months (HR 0.64 (0.42-0.99); p = 0.04). Among the 117 pts, only 2 had a progression of VAF of mutations within genes frequently mutated in myeloid neoplasms. The most serious adverse events were cutaneous (squamous cell carcinoma, basocellular carcinoma, DRESS) and acute pancreatitis with BRAF inhibitors, whereas chorioretinitis and left ventricular dysfunction were seen with MEK inhibitors. None of the patients receiving targeted therapies progressed. Conclusions: Targeted therapies (BRAF and/or MEK inhibitors) were found dramatically efficacious in 117 patients with severe and refractory ECD and mixed histiocytosis, improving survival of patients.

We read with interest the letter by Campochiaro et al 1 that reported the efficacy of a combination regimen including anakinra and targeted therapy for the treatment of Erdheim-Chester disease (ECD), a rare multisystem inflammatory histiocytosis. Based on the involvement of inflammatory cytokines, including tumour necrosis factor-alpha and interleukin-1, in the pathophysiology and the clinical manifestations of ECD, previous reports demonstrated a variable efficacy with a good tolerance of daily subcutaneous anakinra and infliximab for the treatment of ECD.2 3 Among 262 patients with ECD who have been seen at our institution until 2019, 31 (12%) (including 12 described in a previous analysis2) were treated with 100 mg (n=27) or 200 mg (n=4) daily of anakinra, with a mean duration of 29 months (range, 1–132). Patients were followed on a regular basis and evaluated as previously described.4 The clinical and molecular details are provided in table 1. Patients treated with anakinra had more osseous and less central nervous system (CNS) involvements. The patients were treated with anakinra alone or in combination with steroids in two patients, and interferon-alpha in one patient. In the …

Introduction: Although the clinical expression of sarcoidosis in each organ has been well described, there are few data on the associations among the various disorders. Methods: 1237 patients (45% men, mean age=43.5±13 yrs) were recruited through the French Medical Information Systems Program (PMSI) databases from January 2013 to December 2016. Medical records were reviewed by a panel of experts to validate inclusion criteria (sarcoidosis with histological documentation and at least one extra-pulmonary disease, or Lofgren9s syndrome) and determine patient characteristics. Results: Cluster analysis identified 5 phenotypes. Cluster 1 (n=180) associating erythema nodosum and joint involvement, characterized by female sex (F:M ratio=2.4), being more European (51%) and less manual workers (30%). This phenotype was the less treated (corticotherapy (53% of cases), anti-TNF alfa (4%)). Cluster 2 (n=137) associating nervous system involvement and uveitis, characterized by being mainly European (62.5%), men (F:M=1.3) and manual workers (44%). Cluster 3 (n=630) identified a preferential association of pulmonary lesions, sometimes fibrosing, with cardiac lesions associated mainly with a 1.1 F:M ratio, being manual workers (46%) and non-European (58%). Cluster 4 (n=41) marked by the presence of lupus pernio occurring more in non-Europeans (80%). This was the most commonly treated phenotype (corticotherapy (88%), anti-TNF alfa (41%)). Cluster 5 (n=249) associating hepato-splenic involvement with extra-mediastinal lymphadenopathy, characterized by being mainly non-European (62.5%), women (F:M=1.1) and manual workers (35%). Conclusion: We identified 5 clinical phenotypes of sarcoidosis with distinct demographic features and outcomes.

International audience; Background: Episodic Angioedema with eosinophilia (EAE, Gleich's syndrome) is a rare disorder consisting of recurrent episodes of angioedema, hypereosinophilia and frequent elevated serum Immunoglobin M.Methods: We conducted a retrospective multicenter nationwide study regarding the clinical spectrum and therapeutic management of patients with EAE in France.Results: Thirty patients were included with a median age at diagnosis of 41 years [5-84]. The median duration of each crisis was 5.5 days [1-90] with swelling affecting mainly the face and the upper limbs. Total serum IgM levels were increased in 20 patients (67%). Abnormal T-cell immunophenotypes were detected in 12 patients (40%) among which 5 (17%) showed evidence of clonal TCR γ gene rearrangement. Median follow-up duration was 53 months [31-99]. The presence of an abnormal T-cell population was the sole factor associated with a shorter time to flare (hazard ratio 4.15 [CI 95% 1.18-14.66; p=0.02). At last follow-up, 3 patients (10%) were able to withdraw all treatments and 11 (37%) were in clinical and biological remission with less than 10 mg of daily prednisone.Conclusion: EAE is a heterogeneous condition that encompasses several disease forms. Although patients usually respond well to glucocorticoids, those with evidence of abnormal T-cell phenotype have a shorter time to flare.

Context - Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by tissue infiltration of CD68 (+), CD1a (-) histiocytes in various organs. It has been classified as a myeloid neoplasia since the discovery of the RAS-RAF-MEK-ERK pathway alterations. Angiogenesis displays an important role in neoplastic and inflammatory process. Vascular Endothelial Growth Factor (VEGF) is a major proangiogenic factor. VEGF is expressed by many tumor cells, and was found to be expressed by Langerhans histiocytic cells. Mechanisms of cardiovascular involvement in ECD are still not clear, however we hypothesize that VEGF may contribute to the development of lesions of ECD. We further hypothesize that VEGF serum level could help distinguish different profiles of patients and study their response to treatment. Patients and Methods - We conducted a retrospective study in patients with ECD seen in the French National Reference Center for Histiocytoses of the Pitié-Salpêtrière Hospital. These patients had histologically confirmed ECD and were included in the study if they had at least one determination of serum VEGF. Serum VEGF level was assessed by ELISA and considered high when above a concentration of 500pg/mL. Evaluation of cardiac and vascular involvements was based on cardiac magnetic-resonance imaging and CT-angiography of the aorta as often as possible, and replaced by other imaging modalities when they were contraindicated. Results - We screened 254 patients of whom 231 had had at least one determination of VEGF serum level. Serums VEGF were high in 122 out of 231 patients (52.8%). Patients with a high serum VEGF level had more frequently a vascular involvement of ECD (68.8% vs 48.6%, p=0.001), especially signs of a "coated aorta" (47.5% vs 33%, p=0.025). Cardiac involvement was also more prevalent in patients with high serum VEGF level (59% vs 41.2%, p=0.007). Notably, coronary arteries were twice as frequently affected (28.7% vs 14.7%, p=0.010). BRAF status was not significantly different between patients with high or low levels of VEGF. VEGF level were not correlated to the presence of an inflammatory syndrome (evaluated on CRP elevation). At first determination, median serum VEGF among patients with high levels was 850pg/mL (SD 682.22). Under treatment, we observed a decrease of the serum VEGF level. Among 68 patients with a serum VEGF level determination at 12 months, the concentration of VEGF decreased significantly (mean difference 305.4, p Conclusion - Cardiovascular involvement is frequent and prognostically relevant in ECD. Evaluation of ECD clinical course and response to treatment is still challenging, and repeated imaging is often necessary. VEGF serum level could help distinguish patients with cardiovascular profile and contribute to follow up under treatment. Comprehension of the role of VEGF and the possible impact of anti-VEGF treatment will benefit from a study of VEGF and VEGF-receptor expression in lesions of ECD patients. Disclosures No relevant conflicts of interest to declare.

Background: Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis, characterized by the infiltration of tissues by foamy CD68+CD1a- histiocytes, with 1500 known-cases since 90 years. Mutations activating the MAPK pathway are found in more than 80% of ECD patients, mainly the BRAFV600E in 57 to 70%. Central nervous system (CNS) involvement during ECD lead to significant morbidity and mortality. We assessed CNS manifestations in a French cohort of 253 ECD patients. Since 2012, close to 200 patients worldwide with multi-systemic and refractory ECD (e.g. heart and/or CNS involvements) have benefited from BRAF and MEK inhibitors, which have proven highly beneficial. Methods: CNS manifestations were determined by clinical examination and brain and/or spine magnetic resonance imaging (MRI). Targeted therapy efficacy was assessed using physician and radiologist global assessment. Results: Ninety-seven (38%) among the 253 of the whole cohort of ECD patients had CNS involvement. CNS involvement was significantly associated with a younger age at diagnosis (mean 55.5 years) and at symptoms onset (mean 50.5 years), and also 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 in ECD patients without CNS involvement (124 months versus 146 months, p=0.03). Seventy-four CNS MRI were centrally reviewed, corresponding to 3 patterns: tumoral in 66%, degenerative in 50%, and vascular in 18%. Targeted therapy (BRAF and/or MEK inhibitors) was associated with improvement of symptoms in 43% of patients, and MRI improvement in 45%. Conclusions: CNS manifestations are typically associated with a poor prognosis in ECD. Three distinct patterns may be recognized: tumoral, degenerative, and vascular. Targeted therapy leads to clinical and/or imaging improvement in almost 50% of patients. OffLabel Disclosure: Targeted therapies such as BRAF inhibitor (vemurafenib) and MEK inhibitor (cobimetinib) are used in severe histiocytosis in EU but are off label

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

Background Renal biopsy is the cornerstone of Lupus nephritis (LN) management. However, transcutaneous renal biopsy (TCRB) is hampered by the antithrombotic treatment frequently prescribed in Systemic Lupus Erythematosus (SLE) and Antiphospholipid Antibody Syndrome (APS). Transjugular renal biopsy (TJRB) offers an attractive alternative for patients at increased risk of bleeding. Objectives The primary objective of the study was to describe the safety and the diagnostic performance of TJRB in SLE and APS. Methods A retrospective review of SLE and/or APS patients who consecutively underwent a renal biopsy in our department between January 2004 and October 2016 was performed. Biopsies were divided into four groups: TCRB, TJRB with aspirin treatment (aspirin TJRB), TJRB with anticoagulant treatment (anticoagulant TJRB), and TJRB without anti-thrombotic drug (no-antithrombotic TJRB). Major complications were defined as decease, haemostasis nephrectomy, renal artery embolization, blood transfusion, sepsis and vascular thrombosis. Minor complications were defined as gross haematuria, renal hematoma and arterio-venous fistula. Results Fifty-four TCRB and 256 TJRB were analysed – 69 aspirin TJRB, 68 anticoagulant TJRB and 119 no-antithrombotic TJRB. Major complications rate was 1.9% for TCRB and 2.0% for TJRB (p=1). One patient in the TJRB group suffering from catastrophic antiphospholipid syndrome (CAPS) died suddenly 6 weeks after the biopsy. No patient died of bleeding complication. One patient in the anticoagulant TJRB group required a renal artery embolization and blood transfusion. Four other patients required blood transfusion (1 in the TCRB group, 1 in the aspirin TJRB group and 2 in the anticoagulant TJRB group). Minor complications rate was 1.9% for TCRB and 7.8% for TJRB (p=0.2). Among the 256 TJRB, the rate of complication (major or minor) was higher for patients with glomerular filtration rate CKD-EPI 30 mL/min (16/232 [7%], p 140/90 mmHg, APS or positive antiphospholipid biology without APS, Prothrombin Time 1.2, platelets The number of glomeruli sampled and the performance of the biopsy to establish a histologic diagnostic were similar in the 4 groups. Conclusions TJRB provides diagnostic yield and safety similar to those of TCRB. It should be considered as a first intention procedure for SLE and APS patients at risk of bleeding. Disclosure of Interest None declared

Background Coronary artery disease (CAD) is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE) patients.1 Whether SLE is a cardiovascular risk factor per se remains controversial. Objectives This study was conducted to determine the clinical and angiographic characteristics of SLE patients with CAD and to compare them to those of control non-SLE patients with CAD. Methods All SLE patients who underwent a coronary angiography procedure in our tertiary centre between 2005 and 2016 were enrolled in the study. Those without significant atherosclerosis (stenosis >50%) were excluded. Each SLE patient was matched by sex and age at catheterization with seven non-SLE controls with significant CAD. Angiographic characteristics were reviewed by two independent cardiologists. Results Among the 73 SLE patients who underwent coronary angiography, 28 patients had at least one significant coronary atherosclerotic lesion. The SLE patients were predominantly female (75%, median age of 55.7 years) with a long-standing disease duration (median SLE duration of 20.5 years). Ten patients (35%) had renal involvement, and 9 patients (32%) had antiphospholipid syndrome. The patients with SLE had fewer cardiovascular risk factors (1.6 vs 2.1, p=0.01) than the controls, including lower body mass index (23.8 kg/m² vs 24.98 kg/m², p=0.03), less frequent family history of coronary artery disease (3.5% vs 18%, p=0.049) and less diabetes (7% vs 22%, p=0.07) than controls. However, SLE patients were more likely to have chronic kidney failure (35% vs 20%, p=0.07) and to need hemodialysis (17% vs 2%, p=0.001). The SLE patients more often had multivessel disease (50%). Conclusions While they have fewer cardiovascular risk factors, patients with SLE experience more severe CAD than non-SLE patients, suggesting that SLE, associated conditions or the treatments themselves play key roles in the development of atherosclerosis.2 References [1] Lee YH, Choi SJ, Ji JD, Song GG. Overall and cause-specific mortality in systemic lupus erythematosus: an updated meta-analysis. Lupus2016Jun;25(7):727–734. [2] Schoenfeld SR, Kasturi S, Costenbader KH. The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review. Semin Arthritis Rheum2013Aug;43(1):77–95. Disclosure of Interest None declared

International audience; Neurodegenerative (ND) complications in Langerhans cell histiocytosis (LCH) are a late-onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH (cND-LCH) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1·9%) were diagnosed with a cND-LCH. The 10-year cumulative incidence of cND-LCH was 4·1%. cND-LCH typically affected patients previously treated for a multisystem, risk organ-negative LCH, represented in 69·4% of cND-LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent (P < 0·001) in cND-LCH patients compared to those without cND-LCH (respectively 86·1% vs. 12·2%, 75·0% vs. 34·2%, and 63·9% vs. 28·4%). The 'cND susceptible patients' (n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10-year cND risk of 7·8% vs. 0% for patients who did not meet these criteria. Finally, BRAFV 600E status added important information among these cND susceptible patients, with the 10-year cND risk of 33·1% if a BRAFV 600E mutation was present compared to 2·9% if it was absent (P = 0·002).

International audience; ObjectivesTakayasu arteritis (TA) is a giant cell arteritis usually affecting young women and characterized by inflammatory and ischemic signs of large vessel involvement, including extracranial cerebral arteries. The impact of stroke on TA prognosis has not been well evaluated.MethodsWe performed a retrospective multicenter review of patients with definite TA who experienced at least one stroke and compared the findings to 17 matched patients with TA diagnosis without neurological involvement.ResultsSeventeen patients (15 women, median age at stroke diagnosis 44 years) receiving a diagnosis of TA and stroke between 2002 and 2016 in our institution were included, from a cohort of 126 patients suffering from TA (13.5%). At diagnosis, patients from both groups had comparable cardiovascular risk factors. The first cerebrovascular event was ischemic stroke (n = 15) or transient ischemic attack (n = 2). In eight patients, stroke occurred after the TA diagnosis was made. In four patients, stroke occurred after carotid surgery. At the end of follow-up, 59% of patients had a neurological impairment, 35% had a recurrence of stroke, and 24% suffered from epilepsy.ConclusionsStroke is a major cause of disability in TA patients. Internal carotid surgery may be performed with caution because of the risk of stroke after the procedure.

Rosai-Dorfman-Destombes disease (RDD) is a rare non–Langerhans cell histiocytosis characterized by accumulation of activated histiocytes within affected tissues. RDD, which now belongs to the R group of the 2016 revised histiocytosis classification, is a widely heterogeneous entity with a range of clinical phenotypes occurring in isolation or in association with autoimmune or malignant diseases. Recent studies have found NRAS, KRAS, MAP2K1, and ARAF mutations in lesional tissues, raising the possibility of a clonal origin in some forms of RDD. More than 1000 reports have been published in the English literature; however, there is a lack of consensus regarding approach for the clinical management of RDD. Although in most cases RDD can be observed or treated with local therapies, some patients with refractory or multifocal disease experience morbidity and mortality. Here we provide the first consensus multidisciplinary recommendations for the diagnosis and management of RDD. These recommendations were discussed at the 32nd Histiocyte Society Meeting by an international group of academic clinicians and pathologists with expertise in RDD. We include guidelines for clinical, laboratory, pathologic, and radiographic evaluation of patients with RDD together with treatment recommendations based on clinical experience and review of the literature.

Rosai-Dorfman Disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare, nonmalignant histiocytic proliferation of unknown etiology. According to the new classification, it belongs to the R group of histiocytoses.[1][1] The clinical course of this disease is quite

Objective Patients with autoimmune or inflammatory disease (AID) are susceptible to immune-related adverse events (irAEs) when treated with immune check-point inhibitors (ICIs). We decided to analyse the safety and effectiveness of anti-PD-1 antibodies in AID patients and look for an association between the presence of pre-existing AID and the clinical outcome. Methods In a prospective study of the REISAMIC registry of grade ≥2 irAEs occurring in ICI-treated patients, we studied the associations between pre-existing AID on one hand and irAE-free survival, overall survival and best objective response rate on the other. Results We identified 45 patients with 53 AIDs in REISAMIC. The cancer diagnoses included melanoma (n = 36), non–small-cell lung cancer (n = 6) and others (n = 3). The most frequent pre-existing AIDs were vitiligo (n = 17), psoriasis (n = 12), thyroiditis (n = 7), Sjogren syndrome (n = 4) and rheumatoid arthritis (n = 2). Twenty patients (44.4%) presented with at least one irAE: eleven of these were associated with a pre-existing AID (‘AID flare’). Treatment with anti-PD-1 antibodies was maintained in 15 of the 20 patients with an irAE. The IrAE-free survival time was significantly shorter in AID patients (median: 5.4 months) than in AID-free patients (median: 13 months, p = 2.1 × 10−4). The AID and AID-free groups did not differ significantly with regard to the overall survival time and objective response rate (p = 0.38 and 0.098, respectively). Conclusion In patients treated with anti-PD-1 antibody, pre-existing AID was associated with a significantly increased risk of irAEs. Our results indicate that cancer treatments with anti-PD-1 antibodies are just as effective in AID patients as they are in AID-free patients.

International audience

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterised by long bones and various other organs’ involvements.1 Tissues are infiltrated by CD68+ CD1a− foamy histiocytes.2 Therapeutic options are pegylated interferon-α,3 cladribine,4 mTOR inhibitors5 and anakinra in mild forms of ECD.6 7 Conversely, targeted BRAF or MEK inhibitor therapies are used for refractory or life-threatening ECD manifestations.8 9 All these therapies have frequent side effects. Interferon-α leads to fatigue, cytopenias and autoimmune diseases. Anakinra needs subcutaneous daily injections, with frequent local intolerance. Targeted therapies cause skin cancers, QT allongement, rhabdomyolysis and haemorrhage,10 and we lack long-term safety data with these drugs. Moreover, targeted therapies are not available in all countries. Thus, there is an unmet need for improving treatments in many patients with ECD, particularly in countries where access to targeted therapies is complicated or impossible. Although our comprehension of this disease has recently moved from inflammatory to clonal myeloproliferative disease,11 the accumulation of pathological histiocytes leads to an increase of several cytokines in blood and affected tissues. Cytokine/chemokine network has been described in ECD lesions, and most of these factors are regulated by tumour necrosis factor alpha (TNF-α), which is also expressed in ECD lesions and serous fluids like pericardial effusion12–14 and has been implicated in ECD pathogenesis in in vitro models.15 Two ECD patients with cardiovascular involvement were successfully treated with infliximab, a TNF-α monoclonal chimeric antibody, achieving an improvement of symptoms, cardiac involvement and function.14 We aim to determine the efficacy of infliximab in a larger series of patients with ECD. We retrospectively reviewed …

Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis, characterized by the infiltration of tissues by foamy CD68(+)CD1a(-) histiocytes. (99)Technetium bone scintigraphy revealing almost constant tracer uptake by the long bones is highly suggestive of ECD, and a 'hairy kidney' appearance on abdominal computed tomography scan is observed in about half of all ECD cases. CNS involvement is a strong prognostic factor and independent predictor of death. IFN-α seems to be the best initial treatment for ECD. More than half of all ECD patients carry the BRAF(V600E) mutation. More than 30 patients worldwide harboring this mutation and displaying multisystemic, refractory ECD have been treated with vemurafenib, a BRAF inhibitor, which has proven highly beneficial. Other recurrent mutations of the MAPK and PIK3 pathways (NRAS, PIK3CA) have recently been described. These mutations should lead to a new classification of histiocytic disorders such that Langerhans cell histiocytosis and ECD are classified as inflammatory myeloid neoplasms.

Resume Propos L’objectif de ce travail etait de proposer des recommandations relatives aux modalites de depistage et de prise en charge des facteurs de risque cardiovasculaire au cours du lupus systemique. Methodes Trente-neuf experts internistes, rhumatologues ou nephrologues francais, membres du reseau des centres de reference et de competence du lupus systemique ont pris part a un vote visant a retenir ou non des recommandations preparees par un groupe de travail a partir d’une revue de la litterature. Resultats Les experts ont souligne que les facteurs de risque cardiovasculaires modifiables doivent etre recherches au moins annuellement au cours du lupus systemique. La prescription d’une statine en prevention primaire depend du taux de LDL-cholesterol et du nombre de facteurs de risque cardiovasculaires, en considerant le lupus systemique comme un facteur de risque cardiovasculaire supplementaire. En prevention secondaire, les experts s’accordent a proposer une cible de LDL-cholesterol Conclusions Ces recommandations vont permettre d’ameliorer et d’homogeneiser la pratique des differents medecins francais impliques dans la prise en charge du lupus systemique. L’actualisation de ces recommandations pourra etre ulterieurement envisagee, en fonction des nouvelles donnees publiees.

Background Vinblastine is the standard treatment for children with Langerhans cell histiocytosis (LCH). Whether this treatment could be extended to adults with LCH is questionable. This retrospective multicenter study included 35 adult patients (median age 33 years; 23 men; 80% with multisystem LCH) who were treated with vinblastine + steroids as a first-line chemotherapy and followed for a median time of 83 months. The objectives were to determine the overall response rate (based on the Histiocyte Society criteria), disease reactivation rate, toxicity, permanent consequences, and survival rate corresponding to this treatment. The lung involvement outcome was based on serial lung function tests. The distribution of right-censored end points was estimated by the Kaplan-Meier method. Univariate Cox model with time-fixed and time-varying covariates was used for the predictive analysis of reactivation in the responders. Univariate analyses of risk factors for neurotoxicity were based on nonparametric Wilcoxon rank sum tests and exact Fisher tests. Results The median duration of the first course of vinblastine was 7.6 months, with a median cumulative dose of 160 mg [IQR 120–212]. Seventy percent of the patients were responders at the end of this treatment. Subsequently, LCH reactivation occurred with a 5-year cumulative incidence of 40%. During the study, 27 reactivations were observed in 17 patients, and half of these episodes were retreated with vinblastine. At the end of the last vinblastine treatment, 70% of the patients were responders. None of the patients with impaired lung function improved. No grade 3–4 peripheral neuropathy was observed. At the final vinblastine treatment, permanent LCH consequences, primarily pituitary stalk involvement, were present in 15 (43%) patients, and all were present at the time of vinblastine initiation. The 10-year survival rate was 86.2% (95CI, 71.8–100%), and the 2 patients who died from LCH had risk organ localizations. Conclusions Vinblastine is an effective and well-tolerated first-line treatment for adult LCH except in patients with lung involvement and impaired lung function. However, a significant portion of patients experienced LCH reactivation during long-term follow up. As in childhood LCH, the presence of risk organ involvement has a negative impact on patient prognosis.

Multiple mononeuropathy (MM) occurs rarely during systemic lupus erythematosus (SLE) but may lead to major disability. The aim of this study was to investigate the clinic-pathological presentations of MM during SLE, as well as long-term outcomes. We conducted a multicentric retrospective study that included patients receiving a diagnosis of MM during SLE. Ten patients were included (8 women and 2 men, median age at MM diagnosis: 40.4 years). SLE was diagnosed before MM in 9/10 patients (median time 8.2 years). When MM occurred, the SLEDAI score was ≥6 for 6/9 patients. Presenting symptoms consisted of sensory deficits (n = 10), neuropathic pain (n = 9), and/or motor deficits (n = 9), sometimes symmetrical, affecting the lower limbs (10/10) and occasionally the upper limbs (5/10). All patients presented with uni- or bilateral damage of the common fibular nerve, with less frequent involvement of the tibial nerve. Serum cryoglobulinemia was positive in 5/9 patients. Electrophysiological studies confirmed the non-symmetrical involvement of multiple nerve trunks in all patients. Neuromuscular biopsy (performed in five patients) showed histological signs of vasculitis in two patients and perivascular lymphocytic inflammatory infiltrates in two others. All patients were treated with glucocorticosteroids combined with cyclophosphamide (n = 6), rituximab (n = 3), or mycophenolate-mofetil (n = 1). The median follow-up was 5 years. Two patients relapsed during follow-up. All patients had motor and/or sensory sequelae upon follow-up. MM associated with SLE is frequently caused by a vasculitis mechanism. Patients improve with steroids and immunosuppressive drugs. Long-term outcomes include frequent clinical sequelae and possible relapses.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis that most commonly affects adults and is driven by a high frequency of mutations in BRAF, MAP2K1, and kinases promoting MAPK signaling. Because of the relative rarity of ECD, key clinical features of the disease may not be well defined. Across a multi-institutional cohort of 189 patients with ECD and ECD overlapping with Langerhans cell histiocytosis (so-called mixed histiocytosis [MH]), we identified an unexpected and heretofore undescribed frequent occurrence of myeloid neoplasms among patients with ECD and MH. Some 10.1% (19/189) of patients with ECD have an overlapping myeloid neoplasm, most commonly occurring as a myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), or mixed MDS/MPN overlap syndrome (including chronic myelomonocytic leukemia). Consistent with this, molecular analysis frequently detected hallmark driver mutations of myeloid neoplasms (such as JAK2V617F and CALR mutations) coexisting with those characteristic of histiocytosis (such as BRAFV600E and MAP2K1 mutations). Histiocytosis patients diagnosed with a concomitant myeloid malignancy were significantly older at diagnosis and more commonly presented with MH than those without a myeloid malignancy. In some cases, the presence of distinct kinase mutations in the histiocytosis and myeloid neoplasm resulted in discordant and adverse responses to kinase-directed targeted therapies. These data highlight the clinical importance of evaluating adults with histiocytosis for a concomitant myeloid neoplasm.

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10−54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10−40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10−10, OR = 1.28; and rs128738, p = 4.60 × 10−9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.

Erdheim-Chester disease (ECD) was first described as “lipoid granulomatose” by Jakob Erdheim and William Chester in 1930 [1]. This non-Langerhans histiocytosis of unknown origin is rare, with less than 1000 cases as of December 2015 [2–5]. ECD, morphologically and immunohistochemically, appears to be a member of the juvenile xanthogranuloma (JXG) family that involves the long bones in a bilateral fashion. ECD can be distinguished from Langerhans cell histiocytosis (LCH) by the characteristic xanthogranuloma immunostaining, which is factor XIIIa + /CD68 + /CD163 + /fascin + and S100 − /CD1a − /Langerin − /Birbeck granules − [6].

International audience; IntroductionSarcoidosis is a systemic granulomatous disorder of unknown cause. Apparition or flare of previously diagnosed sarcoidosis following hematopoietic stem cell transplantation (HSCT) has rarely been reported.ObservationWe report a 62-year-old woman who presented a radiological flare of sarcoidosis post-autologous stem cell transplantation for a POEMS syndrome. Imaging findings and lymph node histology, which revealed non-caseating granuloma, were consistent with the sarcoidosis diagnosis. The patient was asymptomatic and was kept free of treatment.ConclusionSarcoidosis must be considered ahead of compatible clinicoradiological presentation occurring after HSCT. Sarcoidosis can mimic metastatic cancer or lymphatic relapse. Tissue biopsies and exclusion of differential diagnosis of granuloma diseases are warranted to confirm sarcoidosis diagnosis.; IntroductionLa sarcoïdose est une affection granulomateuse multisystémique d’étiologie inconnue. L’apparition ou la majoration d’une granulomatose après transplantation de cellules souches hématopoïétiques (TCSH) a rarement été rapportée dans la littérature.ObservationNous rapportons le cas d’une patiente de 62 ans, ayant présenté une poussée de sarcoïdose dans les suites d’une autogreffe de cellules souches hématopoïétiques (CSH) réalisée dans le cadre d’un POEMS syndrome. La poussée de sarcoïdose a été mise en évidence par les examens d’imagerie et confirmée par l’obtention d’une histologie ganglionnaire ayant révélé la présence de granulomes épithélioïdes et gigantocellulaires non nécrotiques. La patiente était asymptomatique et ne nécessitait pas de traitement.ConclusionLe diagnostic de granulomatose doit être envisagé dans les suites d’une TCSH devant une présentation clinicoradiologique compatible. La confirmation reste histologique. Les diagnostics différentiels de granulomatose doivent être éliminés. Chez un malade ayant une sarcoïdose devant bénéficier d’une TCSH, le risque d’aggravation de la sarcoïdose devra être considéré.

International audience; Giant-cell arteritis (GCA) is a large-vessel vasculitis usually affecting individuals over 50 years old; half of cases are associated with polymyalgia rheumatica [1]. The aorta and its large arterial branches are typically involved, particularly the branches of the external carotids, leading to headache, jaw claudication, scalp tenderness and temporal artery thickening [2]. GCA affects the aorta and its large branches in up to 83% of cases, leading to aneurysms or arterial stenosis [3].Internal carotids and vertebral arteries are less commonly involved and may be responsible for ischemic cerebrovascular events in cases of stenosis or occlusion. Strokes in GCA patients occur frequently in the first year after diagnosis and may sometimes be the initial symptom of GCA. The impact of stroke on mortality in GCA patients has not been well evaluated.

International audience; Background: Monoclonal gammopathy-associated systemic capillary-leak syndrome, also known as Clarkson disease, is a rare condition characterized by recurrent life-threatening episodes of capillary hyperpermeability in the context of a monoclonal gammopathy. This study was conducted to better describe the clinical characteristics, natural history, and long-term outcome of monoclonal gammopathy-associated systemic capillary-leak syndrome.Methods: We conducted a cohort analysis of all patients included in the European Clarkson disease (EurêClark) registry between January 1997 and March 2016. From diagnosis to last follow-up, studied outcomes (eg, the frequency and severity of attacks, death, and evolution toward multiple myeloma) and the type of preventive treatments administered were monitored every 6 months.Results: Sixty-nine patients (M/F sex ratio 1:1; mean ± SD age at disease onset 52 ± 12 years) were included in the study. All patients had monoclonal gammopathy of immunoglobulin G type, with kappa light chains in 47 (68%). Median (interquartile range) follow-up duration was 5.1 (2.5-9.7) years. Twenty-four patients (35%) died after 3.3 (0.9-8) years. Fifty-seven (86%) patients received at least one preventive treatment, including intravenous immunoglobulins (IVIg) n = 48 (73.8%), theophylline n = 22 (33.8%), terbutaline n = 22 (33.8%), and thalidomide n = 5 (7.7%). In the 65 patients with follow-up, 5- and 10-year survival rates were 78% (n = 35) and 69% (n = 17), respectively. Multivariate analysis found preventive treatment with IVIg (hazard ratio 0.27; 95% confidence interval, 0.10-0.70; P = .007) and terbutaline (hazard ratio 0.35; 95% confidence interval, 0.13-0.96; P = .041) to be independent predictors of mortality.Conclusions: We describe the largest cohort to date of patients with well-defined monoclonal gammopathy-associated systemic capillary-leak syndrome. Preventive treatment with IVIg was the strongest factor associated with survival, suggesting the use of IVIg as the first line in prevention therapy.

Langerhans cell histiocytosis (LCH) is a rare multisystemic disease. LCH is characterized by proliferation of myeloid progenitors with altered differentiation program and similar phenotypic features to epidermal dendritic cells termed Langerhans cell. LCH cells express CD1a+ and langerin and exhibit BRAF V600E mutation in ∼50% of cases. Neurological involvement or neuro-LCH is observed in 5 to 10% of cases. Three subtypes of neuro-LCH are individualized. The tumor type, accounting for 45% of neuro-LCH, affect mainly young adults. Tumor neuro-LCH is characterized by space occupying lesion(s) with contrast enhancement on MRI. Clinical symptoms are due to tumor brain location(s). Pathological examination of tumor neuro-LCH lesions reveals typical features of LCH. Treatment relies on surgical resection with/without chemotherapy. Degenerative neuro-LCH, accounting for 45% of cases, is usually revealed, mostly in children, by: (i) a cerebellar syndrome, (ii) a pyramidal syndrome, (iii) a pseubulbar palsy, and/or (iv) cognitive disorders. On MRI, several signs may coexist: (i) cortex atrophy, (ii) white matter T2 hyperintensities, and (iii) deep gray matter T1 hyperintensities. Pathological analysis of degenerative neuro-LCH lesions have been rarely performed and have never detected CD1a+ histiocytes but unspecific lesions (i.e. gliosis, neuronal loss and/or demyelination). Treatment of degenerative neuro-LCH patients is poorly standardized and poorly efficient. Functional rehabilitation and socio-educational care of these young patients are crucial. The mixed subtype of neuro-LCH combines clinico-radio-pathological characteristics of the first two first forms in the same patient, and represents 10% of neuro-HL. Neuro-HL, therefore, includes three very distinct entities with epidemiological, clinical, radiological and histological specific features requiring specific medical management.

International audience

7019 Background: Erdheim–Chester disease (ECD), an inflammatory myeloid neoplasm, is an histiocytosis associated with multisystem infiltration. Cardiovascular involvement in ECD is under-diagnosed and associated with poor outcome. The targetable BRAFV600Emutation is present in up to 70% of all ECD. Methods: Retrospective study of 205 patients (pts) with ECD who had cardiac imaging (195 MRI, 10 CT when MRI was contraindicated). We identified the types of lesions (infiltration, tumor, and effusion), localization (pericardial, myocardial, valvular) and consequences on cardiac function (coronary stenosis, atrial wall dyskinesia, diastolic and systolic functions). Results: 141 (68.8%) pts were male. 30 (14.6%) had mixed histiocytosis (mainly ECD + langerhans cell histiocytosis). BRAF mutation ( BRAFm) was found in 112 (54.6%) cases, while 59 pts (28.8%) were Wild Type (WT) and 34 pts (7.6%) had unknown BRAF status. Among the 205 cardiac imaging, 101 (49.3%) were abnormal. Cardiac involvement was found in 93 pts (49%). Among these, 72 had an impairment of the right ventricular atrioventricular sulcus (74%), 65 of the right atrium (RA) enclosure (69%). Alteration of Tricuspid Annular Plane Systolic Excursion was found in 15% and correlated with the size of the tumor. Pericardial involvement (effusion, thickening or contrast enhancement) was found in 59 pts (29%). Among BRAFm pts, 75 (67%) had a heart abnormality while 37 (33%) had normal imaging; Among WT pts 14 (23.7%) showed heart abnormality, whereas 45 (76.3%) had normal imaging (RR 2.8 (CI: 1.8-4.5); p = 1.8*10-7). A RA tumor was present in 51 (45.5%) BRAFm but only 6 (10.2%) WT pts respectively (RR 4.5 (CI : 2.0-9.8); p = 7*10-6). BRAFm was also associated with aortic infiltration (RR 1.76 (CI: 1.2–2.5)) and pericardial involvement (RR 2.12 (CI: 1.1–3.9), p = 0.0017). Conclusions: Cardiac infiltration is frequent in ECD (49.3%), especially RA tumor. BRAFm is associated with RA, aortic and pericardial involvements.

Objective To evaluate the usefulness of 2-[18F]-fluoro-2-deoxy-d-glucose–positron emission tomography/computed tomography (FDG-PET/CT) in IgG4-related disease (IgG4-RD) for the staging of the disease and the followup under treatment. Methods All patients included in the French IgG4-RD registry who underwent ≥1 FDG-PET/CT scan were included in the study. Clinical, biologic, pathologic, radiologic, and FDG-PET/CT qualitative and quantitative findings were retrospectively collected and analyzed. Results Twenty-one patients were included in the study and 46 FDG-PET/CT examinations were evaluated. At either diagnosis or relapse, all evaluated patients presented abnormal 18F-FDG uptake in typical IgG4-RD localizations. In most cases, FDG-PET/CT was more sensitive than conventional imaging to detect organ involvement, especially in arteries, salivary glands, and lymph nodes. In few cases (small-sized lesions and brain or kidney contiguous lesions), false-negative results were noted. Evaluation before and after treatment showed in most cases a good correlation of FDG-PET/CT results with treatment response and disease activity. Conclusion This large retrospective study shows that FDG-PET/CT imaging is useful for the staging of IgG4-RD. Moreover, FDG-PET/CT is useful to assess the response to treatment during followup.

Introduction La maladie d’Erdheim-Chester (MEC) est une histiocytose du groupe L dont le diagnostic repose sur l’imagerie et une histologie compatible. La maladie touche l’adulte et se manifeste classiquement par une atteinte osseuse et perirenale. L’histologie montre un infiltrat inflammatoire renfermant des histiocytes spumeux au sein d’un amas de fibrose. Les histiocytes sont Cd68 + , Cd1a − et PS100 − . L’atteinte vasculaire est decrite dans la maladie avec des stenoses etagees pouvant toucher tous les vaisseaux dont l’aorte. Parmi les facteurs de risque d’atteintes vasculaires, on note la presence de la mutation BRAF V600 E presente chez plus de la moitie des patients atteints de MEC. Nous rapportons le cas d’un patient presentant un tableau initial de stenoses arterielles multiples qui permet le diagnostic de MEC. Observation Un patient de 71 ans a ete adresse en medecine interne pour exploration de douleurs insomniantes des membres inferieurs. Les antecedents sont marques par une coxarthrose, une fracture du col femoral et une hypertrophie prostatique. L’etat general du patient est conserve et la seule anomalie clinique est une plaie du troisieme orteil du membre inferieur droit. Le bilan biologique montre une hemoglobine a 14,6 g/dL, plaquettes 563 G/L ( La proteine C reactive (CRP) est a 45 mg/L ( L’angioscanner montre une gaine de fibrose periaortique englobant l’aorte descendante, une stenose significative du tronc cœliaque et une stenose des arteres renales droites et gauches. Il existe egalement une thrombose de l’artere poplitee droite a sa naissance sur 5 cm et une thrombose de l’artere tibiale anterieure droite. Il existe une thrombose de l’artere femorale superficielle gauche. Les coupes abdominales revelent egalement une infiltration de la graisse perirenale. L’echographie cardiaque en preoperatoire objective une fraction d’ejection du ventricule gauche (FEVG) a 30 % de la theorique et la presence d’un epanchement pericardique sans signe de tamponnade. La coronarographie revele une stenose serree (70–90 %) de l’interventriculaire anterieure et de la premiere diagonale necessitant la pose de stents. Devant la presence de stenoses arterielles etagees et d’infiltrat perirenal, les diagnostics de lymphome et d’histiocytose sont evoques. Le PET-scan et la scintigraphie osseuse objectivent une hyperfixation metaphyso-diaphysaire des plateaux tibiaux compatibles avec une maladie d’Erdheim-Chester. La biopsie du perirein identifie un infiltrat inflammatoire comprenant de la fibrose, des histiocytes spumeux avec un marquage Cd68 + , Cd1a − et Ps100 − compatible avec une maladie d’Erdheim Chester. La recherche de la mutation BRAF V600 E est positive. Le patient a eu un pontage arteriel femoropoplite droit et a recu un traitement par Interferon pegyle puis Cobimetinib a la reception de la mutation BRAF. Le myelogramme realise du fait de la thrombocytose a confirme une thrombocytemie essentielle (TE) associee a une mutation JAK2 + Discussion La MEC a une presentation polymorphe pouvant aller de douleurs osseuses a la presence de xanthelasma ou d’orbitopathie. La presence d’epaississement de l’aorte (« coated-aorta ») est un signe evocateur de la maladie et son association a des « reins chevelus » doit amener a la realisation d’une imagerie des os longs. L’atteinte vasculaire de la maladie a ete associee a la presence de la mutation BRAF et a l’existence d’une hypo-alphalipoprotidemie. La meilleure comprehension de l’implication de mutations activatrices sur la voie des MAPK kinases, notamment BRAF, dans les histiocytoses du groupe L a revolutionne le pronostic de la maladie avec l’avenement des therapies ciblees par Vemurafenib et Cobimetinib. La presence d’une TE associee a la MEC n’est pas fortuite et renforce le concept de « neoplasie myeloide » inflammatoire. Conclusion La presence de stenoses arterielles multiples incluant les arteres cardiaques peut reveler une maladie d’Erdheim-Chester.

Introduction L’histiocytose langerhansienne (HCL) est une pathologie essentiellement pediatrique au pronostic tres variable. La mutation somatique BRAF (V600E), identifiee dans 38 a 64 % des cas, est associee aux formes severes et chimioresistantes. Dans plusieurs centres europeens, les enfants atteints d’HCL refractaire mutee BRAF (V600E) sont traites par vemurafenib (VMU), therapie ciblee anti-BRAF. Les effets indesirables cutanes (EIC) du VMU sont connus chez l’adulte, mais n’ont pas ete etudies chez l’enfant. Les objectifs de cette etude etaient d’evaluer, chez les enfants traites par VMU pour HCL, la frequence des EIC, leur severite et leur impact sur la poursuite du VMU. Materiel et methodes Etude retrospective sur la cohorte europeenne d’enfants traites par VMU en monotherapie pour HCL refractaire mutee BRAF V600E entre octobre 2013 et janvier 2018. Resultats Trente-huit enfants inclus : âge median 2,2 ans [0,2–20,4], sex-ratio 0,65, duree mediane de traitement 183,5 jours [20–759], dose mediane de VMU 21 mg/kg/j [12,9–41,4]. Trente enfants (78,9 %) presentaient au moins un EIC : rash folliculaire (39,5 %) ( Fig. 1 ), photosensibilite (28,9 %), xerose (26,3 %), keratose pilaire (23,7 %) et panniculite neutrophilique (15,8 %) ( Fig. 2 ). Trois enfants (7,8 %) presentaient un angiœdeme. La majorite des EIC etaient de grade 1 (65,8 %) ou 2 (26,8 %). On observait 3,7 % de grade 3, aucun grade 4 ou 5. Un seul EIC (1,2 %) entrainait l’arret definitif du VMU (phototoxicite et angiœdeme recidivant, reintroduction non contre-indiquee mais refusee par la patiente). Une reduction de dose etait necessaire dans 10,9 % des cas, un arret temporaire dans 6,0 % des cas. Aucune tumeur cutanee, toxidermie severe ni syndrome main pied n’etait observe. Discussion Comme chez l’adulte, les EIC etaient frequents, rarement severes, avec un impact limite sur la poursuite du traitement. La frequence de chaque type d’EIC observee etait comparable a celle decrite chez l’adulte. Les angiœdemes, observes ici dans 7,8 % des cas, ne sont pas decrits chez l’adulte. Les autres particularites sont l’absence de syndrome main pied, de toxidermie severe et de tumeur cutanee induite. Ces dernieres sont liees a une activation paradoxale de la voie MAPK dans les cellules NRAS mutees. Les mutations NRAS cutanees, UV induites, sont probablement rares chez les enfants en bas âge, ce qui pourrait expliquer l’absence de tumeur cutanee induite chez l’enfant. Les limites de cette etude sont le caractere retrospectif, l’absence de groupe controle et un effectif peu important. Conclusion Comme chez l’adulte, les EIC sont frequents mais rarement graves avec un impact limite sur la poursuite du traitement. Aucune tumeur cutanee induite n’etait observee dans cette etude. Un suivi dermatologique mensuel reste indispensable pour gerer les EIC et depister des possibles tumeurs cutanees paradoxales.

Introduction Le syndrome de Gleich ou angioedeme avec hypereosinophilie est une entite rare associant des crises recurrentes d’angioedeme avec hypereosinophilie concomitante et elevation frequente d’immunoglobulines M seriques polyclonales. Patients et methodes Nous avons conduit une etude retrospective nationale multicentrique afin d’evaluer le spectre clinique et la prise en charge therapeutique des angiœdemes avec hypereosinophilie. Resultats Trente patients ont ete inclus avec un âge median au diagnostic de 41 ans [5–84]. La duree mediane de chaque crise d’angiœdeme etait de 5,5 jours [1–90] avec atteinte principale du visage et des membres superieurs. Le taux seriques d’immunoglobuline M etait eleve pour 20 patients (67 %). Un phenotype lymphocytaire T aberrant etait detecte chez 12 patients (40 %) avec mise en evidence d’un rearrangement clonal du TCR γ chez 5 de ces patients (17 %). Le suivi median etait de 53 mois [31-99]. Tous les patients ont recu une corticotherapie initialement efficace, mais 15 patients ont rechute apres cette premiere ligne (50 %) justifiant une deuxieme ou troisieme ligne de traitement par interferon-α (n = 8,27 %), mepolizumab (n = 2,7 %), ciclosporine A (n = 5,17 %), methotrexate (n = 4,13 %) ou hydroxycarbamide (n = 2,7 %). La presence d’un phenotype lymphocytaire aberrant etait le seul facteur associe aux rechutes (hazard ratio 4,15 [IC 95 % 1,18–14,66] ;p = 0,02). Lors du dernier suivi, 3 patients (10 %) etaient sevres de tout traitement et 11 patients (37 %) etaient en remission clinique et biologique sous moins de 10 mg d’equivalent prednisone par jour. Conclusion Le syndrome de Gleich ou angiœdeme avec hypereosinophilie est une entite heterogene au sein des syndromes hypereosinophiliques. Bien que les patients presentent une bonne reponse a la corticotherapie, les patients porteurs d’un phenotype lymphocytaire T aberrant ont un risque de rechute augmente.

Rationale: In patients with Erdheim-Chester disease (ECD), accumulation of foamy histiocytes leads to multi-systemic disease with various organs involvement. The fact that BRAFV600E mutation is found in as much as 70% of ECD tissues, led to the reclassification of ECD as a myeloid neoplasm and has already greatly improved therapy for adults with histiocytoses. Despite these advances, there is still a need to further improve therapy for ECD patients as targeted therapies may cause morbidity and late treatment effects from such regimens and as patients almost systematically relapse when these therapies are stopped. In 2015, Galatica et al reported an increased expression of PD-L1 in 4/4 ECD cases tested all of which were BRAFV600E mutated. We thus decided to analyze a larger case series of patients as this could represent rationale for addition of immune check-point inhibitors in treatment of multisystemic and/or refractory histiocytoses. Patients and Methods: We included 36 ECD patients for which BRAF status was determined. Biopsy samples were re-read in all cases. The density of inflammatory cells (lymphocytes and plasma cells) other than histiocytes was evaluated as mild (+), moderate (++), or marked (+++). Immunostaining was performed to detect PD-L1 (QR1Clone) in histiocytes and PD-1 (NAT105 clone) in lymphocytes. PD-L1 was assessed as percentage of positive histiocytes. The positivity of PD-L1 was defined as ≥ 5%. PD-1 immunostaining was evaluated as mild (+), moderate (++), or marked (+++). Results: Overall, BRAFV600E was present in 19 patients (52.8%), MAP2K1 in 2 (5.5%) and NRAS in 1 (2.8 %). PD-L1 was positive in 15 patients (41.7%), PD-1 in 23 (63.8%) and both were found in 13 (36.1%). The intensity of inflammation in 21 patients (58.3%) was mild, moderate in 9 (25%) and high in 6 (16.7%). Among the 23 PD-1 positive cases, 15 (65.2%) were mild and 8 (34.8%) moderate. We found a strong association between PD-L1 positivity and intensity of inflammation: 13 PD-L1 positive patients were moderate/marked, vs 2 PD-L1 positive being mild; only 2 PD-L1 negative patients were moderate/marked, vs 19 PD-L1 negative being mild (p Conclusions: We found a negative association between PD-L1 positivity and BRAFV600E mutation. Eleven patients only (30.5%) of ECD patients were PD-L1 and PD-1 negative. The recent success of immune checkpoint blockade therapy in some cancer types combined with the expression of immune checkpoint antigens in ECD samples suggests that such therapies should be investigated for refractory ECD. Disclosures No relevant conflicts of interest to declare.

Purpose Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAFV600E mutation occurs frequently, but clinical significance remains to be determined. Patients and Methods BRAFV600E mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. Results Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAFV600E mutation. Patients with BRAFV600E manifested more severe disease than did those with wild-type BRAF. Patients with BRAFV600E comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAFV600E mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAFV600E more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). Conclusion In children with LCH, BRAFV600E mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.

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 BRAF

International audience; Langerhans cell histiocytosis (LCH) is a rare multisystemic disease. LCH is characterized by proliferation of myeloid progenitors with altered differentiation program and similar phenotypic features to epidermal dendritic cells termed Langerhans cell. LCH cells express CD1a+ and langerin and exhibit BRAF V600E mutation in ∼ 50% of cases. Neurological involvement or neuro-LCH is observed in 5 to 10% of cases. Three subtypes of neuro-LCH are individualized. The tumor type, accounting for 45% of neuro-LCH, affect mainly young adults. Tumor neuro-LCH is characterized by space occupying lesion(s) with contrast enhancement on MRI. Clinical symptoms are due to tumor brain location(s). Pathological examination of tumor neuro-LCH lesions reveals typical features of LCH. Treatment relies on surgical resection with/without chemotherapy. Degenerative neuro-LCH, accounting for 45% of cases, is usually revealed, mostly in children, by: (i) a cerebellar syndrome, (ii) a pyramidal syndrome, (iii) a pseubulbar palsy, and/or (iv) cognitive disorders. On MRI, several signs may coexist: (i) cortex atrophy, (ii) white matter T2 hyperintensities, and (iii) deep gray matter T1 hyperintensities. Pathological analysis of degenerative neuro-LCH lesions have been rarely performed and have never detected CD1a+ histiocytes but unspecific lesions (i.e. gliosis, neuronal loss and/or demyelination). Treatment of degenerative neuro-LCH patients is poorly standardized and poorly efficient. Functional rehabilitation and socio-educational care of these young patients are crucial. The mixed subtype of neuro-LCH combines clinico-radio-pathological characteristics of the first two first forms in the same patient, and represents 10% of neuro-HL. Neuro-HL, therefore, includes three very distinct entities with epidemiological, clinical, radiological and histological specific features requiring specific medical management.; L’histiocytose langerhansienne (HL) est une maladie multisystémique rare. L’HL est correspond à une prolifération de cellules myéloïdes progénitrices au programme de différenciation altéré et au phénotype proche de celui des cellules dendritiques épidermiques, les cellules de Langerhans. Les cellules de l’HL sont caractérisées par l’expression de CD1a et de la langerin et par la présence (∼ 50 %) de mutation du gène BRAF. L’atteinte neurologique ou neuro-HL est observée dans 5 à 10 % des cas. Trois formes de neuro-HL sont individualisées. La forme tumorale, représentant 45 % des neuro-HL, touche l’adulte jeune. Elle se caractérise un ou (des processus) expansif(s) intracrânien(s) prenant le contraste à l’IRM. Les manifestations neurologiques sont en rapport avec la (ou les) localisation(s) lésionnelle(s). L’analyse histologique des lésions neurologiques retrouve les caractéristiques de l’HL. Le traitement repose sur la chirurgie et/ou la chimiothérapie. La forme dégénérative, représentant 45 % des cas, se manifeste, principalement chez l’enfant, par un syndrome cérébello-spasmodique, un syndrome pseudobulbaire et/ou des troubles neuropsychologiques. À l’IRM cérébrale, on observe dans la forme complète : (i) une atrophie corticale, (ii) des hypersignaux T2 de la substance blanche et (iii) des hypersignaux T1 de la substance grise profonde. Les analyses histologiques des lésions cérébrales, bien que rares, n’ont jamais mis en évidence d’histiocytes CD1a+ caractéristiques de la maladie mais des lésions aspécifiques de gliose, de perte neuronale, et/ou de démyélinisation. Le traitement est peu codifié et d’efficacité modeste. La rééducation fonctionnelle et la prise en charge socio-éducative, de ces jeunes patients, sont cruciales. La forme mixte combine les caractéristiques clinicoradiopathologiques des deux premières formes chez le même patient, et représente 10 % des neuro-HL. Les neuro-HL regroupent donc trois entités très distinctes sur le plan épidémiologique, clinique, radiologique et histologique nécessitant des prises en charge spécifiques.

International audience; Pulmonary hyalinizing granuloma (PHG) is a rare disease characterized by single or multiple benign lung nodules mimicking lung neoplasma. Histologic analysis reveals homogenous hyaline lamellae, usually surrounded by collection of plasma cells, lymphocytes and histiocytes in a perivascular distribution. The clinical and radiological findings have been described in small series, but the long-term outcomes have rarely been reported. The objectives were to describe the clinical, radiological and outcomes of PHG in new cases and through a literature review. Patients with PHG were found by a multicenter search among French departments of internal medicine, pulmonology and anatomo-pathology. Review of the literature was made through the National Library of Medicine’s MEDLINE database using keywords “hyalinizing granuloma.” Five news cases and 135 cases of the literature were found. There were 82 men and 57 women, mean age at the diagnosis 44.6 years (15–83). Patients were frequently asymptomatic (n = 39, 27.4 %). The nodule was unique in 37 cases (28.9 %) and multiple in 91 cases (71.1 %). 18FDG PET scan revealed hypermetabolism of the nodule in 9/15 cases (60 %). A systemic disease was associated in 65 cases (mainly mediastinal and retroperitoneal fibrosis, autoimmune, tumoral or infectious disease or thromboembolism). The outcomes were evaluated in 73 patients when follow-up was available: 14 patients had a surgical resection of the nodule. Forty-five patients did not receive any immunosuppressive drug. Among these patients, 2 improved, 29 were stable and 14 worsened. Corticosteroids were used as a monotherapy in 19 patients and led to radiological improvement in 8 cases, stabilization in 8 cases and worsening in 3 cases. Five patients were treated with corticosteroids and at least one immunosuppressive drug and 4 patients improved. PHG is a rare benign disease, mimicking lung neoplasma, frequently associated with systemic diseases.

Rosai–Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim–Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously. In a minority of cases, systemic disease can occur and can be life threatening. Juvenile myelomonocytic leukemia (JMML), as well as germline mutations in NF1 and NF2, have been reported in children with JXG. Recent whole-exome sequencing of JXG cases did not show the BRAF-V600E mutation, although 1 patient had PI3KCD mutation. ECD is an adult histiocytosis characterized by symmetrical long bone involvement, cardiovascular infiltration, a hairy kidney, and retroperitoneal fibrosis. Central nervous system involvement is a poor prognostic factor. Interferon-α is the standard as front-line therapy, although cladribine and anakinra can be effective in a few refractory cases. More than one-half of ECD patients carry the BRAF-V600E mutation. Currently, >40 patients worldwide with multisystemic, refractory BRAF-V600E+ ECD have been treated with vemurafenib, a BRAF inhibitor, which was found to be highly effective. Other recurrent mutations of the MAP kinase and PI3K pathways have been described in ECD. These discoveries may redefine ECD, JXG, and LCH as inflammatory myeloid neoplasms, which may lead to new targeted therapies.

While our knowledge of the pathogenesis of Takayasu's arteritis (TA) has considerably improved during the last decade, the exact pathogenic sequence remains to be elucidated. It is now hypothesised that an unknown stimulus triggers the expression of the 65 kDa Heat-shock protein in the aortic tissue which, in turn, induces the Major Histocompatibility Class I Chain-Related A (MICA) on vascular cells. The γδ T cells and NK cells expressing NKG2D receptors recognize MICA on vascular smooth muscle cells and release perforin, resulting in acute vascular inflammation. Pro-inflammatory cytokines are released and increase the recruitment of mononuclear cells within the vascular wall. T cells infiltrate and recognize one or a few antigens presented by a shared epitope, which is associated with specific major Histocompatibility Complex alleles on the dendritic cells, these latter being activated through Toll-like receptors. Th1 lymphocytes drive the formation of giant cells through the production of interferon-γ, and activate macrophages with release of VEGF resulting in increased neovascularisation and PDGF, resulting in smooth muscle migration and intimal proliferation. Th17 cells induced by the IL-23 microenvironnement also contribute to vascular lesions through activation of infiltrating neutrophils. Although still controversial, dendritic cells may cooperate with B lymphocytes and trigger the production of anti-endothelial cell auto-antibodies resulting in complement-dependent cytotoxicity against endothelial cells. In a near future, novel drugs specifically designed to target some of the pathogenic mechanisms described above could be expanding the physician's therapeutic arsenal in Takayasu's arteritis.

Objective To assess the factors influencing the efficacy of 2 injections of a pandemic 2009 influenza A (H1N1) vaccine in patients with systemic lupus erythematosus (SLE). Methods We conducted a single-center, observational prospective study of 111 patients who were vaccinated with a monovalent, inactivated, nonadjuvanted, split-virus vaccine during December 2009 and January 2010 and received a second dose of vaccine 3 weeks later. The antibody response was evaluated using the hemagglutination inhibition assay according to the guidelines recommended for the pandemic vaccine, consisting of 3 immunogenicity criteria (i.e., a seroprotection rate of 70%, a seroconversion rate of 40%, and a geometric mean ratio [GMR] of 2.5). Results The 3 immunogenicity criteria were met on day 42 (seroprotection rate 80.0% [95% confidence interval (95% CI) 72.5–87.5%], seroconversion rate 71.8% [95% CI 63.4–80.2%], and GMR 10.3 [95% CI 2.9–14.2]), while only 2 criteria were met on day 21 (seroprotection rate 66.7% [95% CI 57.9–75.4%], seroconversion rate 60.4% [95% CI 51.3–69.5%], and GMR 8.5 [95% CI 3.2–12.0]). The vaccine was well tolerated. Disease activity, assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index, the British Isles Lupus Assessment Group score, and the Systemic Lupus Activity Questionnaire, did not increase. In the multivariate analysis, vaccination failure was significantly associated with immunosuppressive treatment or a lymphocyte count of ≤1.0 × 109/liter. The second injection significantly increased the immunogenicity in these subgroups, but not high enough to fulfill the seroprotection criterion in patients receiving immunosuppressive treatment. Conclusion Our findings indicate that the efficacy of the vaccine was impaired in patients who were receiving immunosuppressive drugs or who had lymphopenia. A second injection increased vaccine immunogenicity without reaching all efficacy criteria for a pandemic vaccine in patients receiving an immunosuppressive agent. These results open possibilities for improving anti-influenza vaccination in SLE.

The DEFI study has collected clinical data and biological specimens from kindreds with CVID. Patients with demonstrated parental consanguinity (cCVID group) were compared to patients without parental consanguinity (ncCVID). A total of 24 of the 436 patients with CVID had consanguineous parents. Age at first symptoms and age at diagnosis were comparable in the two groups. Some complications were more frequent in cCVID patients: splenomegaly (62.5% vs. 29%; p = 0.001), granulomatous disease (29% vs. 12%; p = 0.02), and bronchiectasis (58% vs. 29%; p = 0.003). A high incidence of opportunistic infections was also observed in this population (29% vs. 5%; p < 0.001). Distribution of B-cell subsets were similar in the two groups. Naive CD4+ T cells were decreased in cCVID patients (15% vs. 28%; p < 0.001), while activated CD4 + CD95+ (88% vs. 74%; p = 0.002) and CD8 + HLA-DR + T cells (47% vs. 31%; p < 0.001) were increased in these patients when compared to ncCVID patients. Parental consanguinity is associated with an increased risk of developing severe clinical complications in patients with CVID. Most of these patients presented with severe T-cell abnormalities and should be considered with a diagnosis of late-onset combined immune deficiency (LOCID). Systematic investigation for parental consanguinity in patients with CVID provides useful information for specific clinical care and genetic screening.

OBJECTIVE: The aim of this work was to describe chorea during systemic lupus erythematosus or antiphospholipid antibodies and its long-term outcome. METHODS: We retrospectively analyzed clinical features, laboratory findings, imaging characteristics, and outcome in a series of 32 patients. RESULTS: Most patients were women (28 of 32), and mean age at onset of chorea was 20.6 (9-62) years. Chorea was inaugural for 28 patients. Improvement was observed with various treatments. During follow-up (12.2 ± 11.3 years), severe manifestations of systemic lupus erythematosus were rare. Antiphospholipid antibodies were repeatedly positive for 90% of the patients. Twelve patients developed arterial thrombosis. Prophylactic treatment with antithrombotic therapy might reduce the risk of further thrombosis (8% versus 57%; P = 0.01). Cardiac valvulopathy occurred in 22 patients during follow-up. Chorea relapsed in 8 cases. CONCLUSIONS: Chorea had a good outcome in itself. This long-term follow-up shows, for the first time, that these patients have substantial risk for further arterial thrombosis.