Publications by authors named "Julien Haroche"

180 Publications

Catastrophic antiphospholipid syndrome and posterior ocular involvement: case series of 11 patients and literature review.

Retina 2021 Apr 2. Epub 2021 Apr 2.

AP-HP, Cochin Hospital, Internal Medicine department, Centre de référence maladies auto-immunes et systémiques rares de l'Ile de France, Paris, France. Université Paris-Descartes, Paris, France. AP-HP, Cochin Hospital, Ophthalmology Department, Paris, France. Centre Hospitalier Saint Joseph Saint Luc, Internal medicine department, Lyon, France. Foch Hospital, Internal Medicine department, Suresnes, France. AP-HP, Henri Mondor Hospital, Internal Medicine department, Creteil, France. AP-HP, La Pitié-Salpêtrière Hospital, Internal Medicine department, Centre de référence maladies auto-immunes et systémiques rares de l'Ile de France, Paris, France. Normandie Université, UNIROUEN, Inserm U1096, Rouen university hospital, department of internal medicine, vascular and thrombosis unit, 76000 Rouen, France. Univ. Lille ; INSERM U1167 ; CHU Lille, Internal Medicine department, Centre National de Référence Maladies Systémiques et Auto-Immunes Rares, European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases (ReCONNECT), F-59000 Lille, France Department of Internal Medicine, CHU de Saint-Etienne, France. Université Paris Descartes-Sorbonne Paris Cité, Paris, France ; INSERM U 1153, Center for Epidemiology and Statistics, Sorbonne Paris Cité (CRESS), Paris, France.

Purpose: To describe the posterior ophthalmic manifestations of catastrophic antiphospholipid syndrome (CAPS).

Methods: Retrospective case series of patients presenting with CAPS and posterior segment ocular manifestations. The main outcomes were the type of posterior segment manifestations at CAPS diagnosis, specifically retinal vascular occlusion, vasculitis, or choroidopathy, and the final best corrected visual acuity (BCVA).

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). Ophthalmologic manifestations were usually bilateral (n = 19, 83%) and involved vascular occlusive retinopathy (n = 17, 74%), choroidopathy (n=11, 48%), and/or retinal vasculitis (n = 1, 4%). Final BCVA was not significantly worse than BCVA 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 [2-132], nearly half the patients (n = 11, 48%) had permanent vision loss including BCVA < 20/400 for 4 patients.

Conclusion: Posterior ophthalmic manifestations of CAPS were mainly bilateral retinal vascular occlusion, which had the worst visual prognosis, followed by choroidopathy and retinal vasculitis. Permanent visual loss was common.
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http://dx.doi.org/10.1097/IAE.0000000000003185DOI Listing
April 2021

The Contribution of MicroRNAs to the Inflammatory and Neoplastic Characteristics of Erdheim-Chester Disease.

Cancers (Basel) 2020 Nov 3;12(11). Epub 2020 Nov 3.

Department of Molecular Biology, Faculty of Natural Sciences, Ariel University, Ariel 40700, Israel.

The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p, -15b-5p, -21-5p, -107, -221-3p, -320e, -630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH.
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http://dx.doi.org/10.3390/cancers12113240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693724PMC
November 2020

Factors associated with implantable cardioverter defibrillators appropriate therapy in cardiac sarcoidosis: a meta-analysis.

Sarcoidosis Vasc Diffuse Lung Dis 2020 15;37(1):17-23. Epub 2020 Mar 15.

Sorbonne Université, INSERM UMRS-1135, CIMI, Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares, Hôpital Pitié-Salpêtrière, 75013-Paris, France.

Background: Patients with cardiac sarcoidosis (CS) are at increased risk of atrioventricular blocks, ventricular arrhythmias, and sudden cardiac death. Objectives We aimed to investigate the characteristics associated with appropriate therapy in implantable cardiac defibrillator (ICD) -implanted CS patients.

Methods: We performed a PubMed and Web of Science search for studies reporting patients with CS who underwent an ICD implantation. The primary criterion was an appropriate therapy.

Results: We screened 705 studies, of which 5 were included in the final analysis. We conducted a meta-analysis including 464 patients (mean age 55 years, 282 males (60%)). The mean follow-up was 3.5 years. Among the 464 patients, 180 received an appropriate therapy (39%). Patients who received an appropriate therapy were younger (-3.33, 95% confidence interval (CI) -6.42 to -0.23, p=0.004), were more likely to be male (OR 2.06, 95% CI 1.37-3.09, p=0.0005), had a lower left ventricular ejection fraction (LVEF) (-10.5, 95% CI -18.23 to -2.78, p=0.008), had a higher rate of complete heart block (OR 2.19, 95% CI 1.20 to 3.99, p=0.01), and more frequently had ventricular pacing (OR 6.44 95% CI 2.57 to 16.16, p<0.0001).

Conclusions: Appropriate ICD therapy during CS is associated with young age, male sex, low LVEF, history of complete heart block, and ventricular pacing. .
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http://dx.doi.org/10.36141/svdld.v37i1.8271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569536PMC
November 2020

Clinical phenotypes of extrapulmonary sarcoidosis: an analysis of a French, multi-ethnic, multicentre cohort.

Eur Respir J 2021 Apr 1;57(4). Epub 2021 Apr 1.

Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares, Lupus et Syndrome des Anticorps Antiphospholipides, Centre National de Référence Histiocytoses, Sorbonne Université, Assistance Publique Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Paris, France

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.
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http://dx.doi.org/10.1183/13993003.01160-2020DOI Listing
April 2021

High frequency of clonal hematopoiesis in Erdheim-Chester disease.

Blood 2021 Jan;137(4):485-492

Service de Médecine Interne 2, Centre National de Référence Histiocytoses, and.

Erdheim-Chester disease (ECD) is a clonal hematopoietic disorder characterized by the accumulation of foamy histiocytes within organs (in particular, frequent retroperitoneal involvement) and a high frequency of BRAFV600E mutations. Although ECD is not commonly recognized to have overt peripheral blood (PB) or bone marrow (BM) disease, we recently identified that ECD patients have a high frequency of a concomitant myeloid malignancy. We thus conducted a systematic clinical and molecular analysis of the BM from 120 ECD patients. Surprisingly, 42.5% of ECD patients (51 of 120) had clonal hematopoiesis whereas 15.8% of patients (19 of 120) developed an overt hematologic malignancy (nearly all of which were a myeloid neoplasm). The most frequently mutated genes in BM were TET2, ASXL1, DNMT3A, and NRAS. ECD patients with clonal hematopoiesis were more likely to be older (P < .0001), have retroperitoneal involvement (P = .02), and harbor a BRAFV600E mutation (P = .049) than those without clonal hematopoiesis. The presence of the TET2 mutation was associated with a BRAFV600E mutation in tissue ECD lesions (P = .0006) and TET2-mutant ECD patients were more likely to have vascular involvement than TET2 wild-type ECD patients. Clonal hematopoiesis mutations in ECD were detected in cells derived from CD34+CD38- BM progenitors and PB monocytes but less frequently present in PB B and T lymphocytes. These data identify a heretofore unrecognized high frequency of clonal hematopoiesis in ECD patients, reaffirm the development of additional high risk of myeloid neoplasms in ECD, and provide evidence of a BM-based precursor cell of origin for many patients with ECD.
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http://dx.doi.org/10.1182/blood.2020005101DOI Listing
January 2021

Patients with both Langerhans cell histiocytosis and Crohn's disease highlight a common role of interleukin-23.

Acta Paediatr 2021 04 8;110(4):1315-1321. Epub 2020 Oct 8.

Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Aim: To present the first case series of patients with Langerhans cell histiocytosis (LCH) also affected by Crohn's disease (CD), both of which are granulomatous diseases, and in LCH investigate the role of interleukin (IL)-23, which is a well-described disease mediator in CD.

Methods: A case series of three patients with LCH and CD were described; a cohort of LCH patients (n = 55) as well as controls (n = 55) were analysed for circulating IL-23 levels; and the relation between the percentage of LCH cells in lesions and circulating IL-23 levels was analysed in seven LCH patients.

Results: Differential diagnostic challenges for these two granulomatous diseases were highlighted in the case series, and it took up to 3 years to diagnose CD. Elevated IL-23 levels were found in LCH patients. The amount of lesional LCH cells correlated with the levels of circulating IL-23.

Conclusion: Both CD and LCH should be considered in patients with inflammatory gastrointestinal involvement. The IL-23 pathway is a common immunological trait between these two granulomatous diseases.
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http://dx.doi.org/10.1111/apa.15590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984331PMC
April 2021

Central nervous system involvement in Erdheim-Chester disease: An observational cohort study.

Neurology 2020 11 4;95(20):e2746-e2754. Epub 2020 Sep 4.

From Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares et Histiocytoses (F.C.A., Z.A., J.H.), Service de Neuroradiologie (D.G., B.L.-Y.), Service d'Anatomopathologie (F.C.), Service de Médecine Nucléaire (P.M.), Service de Neuropathologie (D.S.), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université; Service de Neurologie 2-Mazarin (A.I., K.H.-Z.), Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle Épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Sorbonne Université, Paris; Département de Pathologie (J.-F.E.), EA4340, Université Versailles-Saint Quentin, Assistance Publique Hôpitaux de Paris, Hôpital Ambroise Paré, Boulogne; and Service d'Hématologie Pédiatrique, Centre de Référence National Histiocytoses (J.D.), Hôpital Trousseau, Sorbonne Université, Paris, France.

Objective: CNS 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.

Methods: This 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.

Results: Ninety-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 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, = 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%.

Conclusions: CNS manifestations are typically associated with poor prognosis in patients with ECD. Three distinct patterns can be recognized: tumoral, pseudodegenerative, and vascular.

Classification Of Evidence: This study provides Class III evidence that targeted therapy leads to clinical or imaging improvement in almost 50% of patients.
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http://dx.doi.org/10.1212/WNL.0000000000010748DOI Listing
November 2020

Child-Adult Transition in Sarcoidosis: A Series of 52 Patients.

J Clin Med 2020 Jul 3;9(7). Epub 2020 Jul 3.

AP-HP Pediatric Pulmonology Department and Reference Center for Rare Lung Diseases (RespiRare), Armand Trousseau Hospital, 75012 Paris, France.

(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 (≤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 (±2.7) at diagnosis. The median duration time of follow-up was 11.5 years (range 3-44.5). 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 0-32), 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.
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http://dx.doi.org/10.3390/jcm9072097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408766PMC
July 2020

Psychiatric autoimmune conditions in children and adolescents: Is catatonia a severity marker?

Prog Neuropsychopharmacol Biol Psychiatry 2021 Jan 1;104:110028. Epub 2020 Jul 1.

Department of Child and Adolescent Psychiatry, Sorbonne Université, Hôpital Pitié-Salpêtrière, AP-HP, 47-83 Boulevard de l'Hôpital, 75013 Paris, France; GRC 15 PSYDEV. Troubles psychiatriques et développement. Sorbonne Université, Paris, France.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110028DOI Listing
January 2021

Erdheim-Chester disease: a rapidly evolving disease model.

Leukemia 2020 11 26;34(11):2840-2857. Epub 2020 Jun 26.

Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Firenze, and Nephrology and Dialysis Unit, Meyer Children's Hospital, Firenze, Italy.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis with a putative neoplastic and inflammatory nature. The disease is driven by mutations in proto-oncogenes such as BRAF and MEK, while immune-mediated mechanisms contribute to disease development and progression. The clinical presentation of ECD is highly heterogeneous, ranging from smouldering unifocal forms to multiorgan life-threatening disease. Almost any organ can be involved, but the most common lesions include long-bone involvement, retroperitoneal fibrosis, interstitial lung disease, pericardial and myocardial infiltration, CNS, retro-orbital, and large-vessel involvement. These manifestations may mimic those of neoplastic and systemic immune-mediated diseases. Overlap with these conditions represents an emerging challenge for the clinician. A variety of treatments are efficacious for ECD, targeting both the MAPK-pathway and the immune-mediated pathomechanisms. The traditional approach is based on immunomodulatory agents (interferon-α), but recent alternatives-including anti-cytokine therapies (IL1- and TNFα-blockers) and immunosuppressants (mTOR-inhibitors)-showed promising results. However, since the detection of MAPK pathway activation in most patients and the dramatic efficacy of BRAF and MEK inhibitors, these targeted treatments represent the first-line approach in patients with severe disease forms. High rates of radiologic responses do not often mean clinical remission, especially for CNS involvement, which often results in chronic disability. This review will outline the main clinical features of ECD, with emphasis on the emerging challenges in pathogenesis and management, and on the role of recent targeted approaches.
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http://dx.doi.org/10.1038/s41375-020-0944-4DOI Listing
November 2020

Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort.

Ann Rheum Dis 2020 08 11;79(8):999-1006. Epub 2020 Jun 11.

General Paediatrics, Department of Infectious Disease and Internal Medicine, Reference centre for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Paris, France, Robert Debré University Hospital, AP-HP, Paris, France

Background: Current 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.

Methods: Multicentre 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.

Results: Sixteen 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 (p<0.0001), lower platelet count (188 vs 383 G/L (p<0.0001)), a higher rate of myocarditis 7/16 vs 3/220 (p=0.0001) and resistance to first IVIg treatment 10/16 vs 45/220 (p=0.004).

Conclusion: Kawa-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. NCT02377245.
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http://dx.doi.org/10.1136/annrheumdis-2020-217960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299653PMC
August 2020

Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine.

Ann Rheum Dis 2020 06 24;79(6):837-839. Epub 2020 Apr 24.

Sorbonne Université, Assistance Publique - Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.

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http://dx.doi.org/10.1136/annrheumdis-2020-217566DOI Listing
June 2020

Analysis of risk factors for complications and adverse obstetrical outcomes in women with Takayasu arteritis: a French retrospective study and literature review.

Clin Rheumatol 2020 Sep 23;39(9):2707-2713. Epub 2020 Mar 23.

Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne, Hôpital Avicenne, Université Paris 13, 93000, Bobigny, France.

Objective: 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.

Methods: All pregnancies in women with a TAK diagnosis were retrospectively included from 20 French hospitals providing care for TAK, until August 2015.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1007/s10067-020-05024-4DOI Listing
September 2020

Long-term efficacy and safety of 2CdA (cladribine) in extra-pulmonary adult-onset Langerhans cell histiocytosis: analysis of 23 cases from the French Histiocytosis Group and systematic literature review.

Br J Haematol 2020 06 19;189(5):869-878. Epub 2020 Mar 19.

Service de Pneumologie, Assistance Publique-Hôpitaux de Paris, Centre National de Référence des Histiocytoses, Hôpital Saint-Louis, Paris, France.

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 <50 mg/m . Disease progression rates were 20% and 30% at two and five years, respectively. Partial response (PR) to 2CdA was predictive of disease progression. Among eight re-treated patients, five went into CR, two in PR, and one died. Single-agent 2CdA is effective in reactivated a-LCH, including at intermediate doses. Toxicity, significant but acceptable, warrants infectious prophylaxis. Complete responders may enter prolonged remission. Further studies are needed to determine 2CdA sequencing with other agents (vinblastine, cytarabine).
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http://dx.doi.org/10.1111/bjh.16449DOI Listing
June 2020

Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era.

Blood 2020 05;135(22):1929-1945

Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY.

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.
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http://dx.doi.org/10.1182/blood.2019003507DOI Listing
May 2020

Erdheim-Chester disease.

Blood 2020 04;135(16):1311-1318

Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne 2, Maladies Auto-Imunes et Systémiques, Centre National de Référence des Histiocytoses, Hôpital Pitié-Salpêtrière, Paris, France.

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.
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http://dx.doi.org/10.1182/blood.2019002766DOI Listing
April 2020

Response to: 'Efficacy and improved tolerability of combination therapy with interleukin-1 blockade and MAPK pathway inhibitors for the treatment of Erdheim-Chester disease' by Campochiaro .

Ann Rheum Dis 2020 Jan 20. Epub 2020 Jan 20.

Sorbonne Université, Assistance Publique Hôpitaux de Paris, Service de Médecine Interne 2, Hôpital de la Pitié-Salpêtrière, Centre National de Référence Lupus Systémique et Histiocytoses, Paris, France.

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http://dx.doi.org/10.1136/annrheumdis-2019-216755DOI Listing
January 2020

Withdrawal of low-dose prednisone in SLE patients with a clinically quiescent disease for more than 1 year: a randomised clinical trial.

Ann Rheum Dis 2020 03 18;79(3):339-346. Epub 2019 Dec 18.

Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France

Objectives: To 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.

Methods: A 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).

Results: Proportion 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.

Conclusion: Maintenance of long term 5 mg prednisone in SLE patients with inactive disease prevents relapse.

Trial Registration Number: NCT02558517; Results.
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http://dx.doi.org/10.1136/annrheumdis-2019-216303DOI Listing
March 2020

Erdheim-Chester Disease: a Concise Review.

Curr Rheumatol Rep 2019 12 5;21(12):66. Epub 2019 Dec 5.

Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne 2, Centre National de Référence des Histiocytoses, Hôpital Pitié-Salpêtrière, 47-83, boulevard de l'Hôpital, 75651, Paris Cedex 13, France.

Purpose Of Review: This report provides an overview of the current knowledge of molecular characterization, clinical description, and treatment of Erdheim-Chester disease (ECD), a multi-systemic adult histiocytosis of the L group.

Recent Findings: The recent identification of several MAPK mutations in histiocytes of ECD lesions. Leading to targeted therapies. The discovery of the BRAF mutation in ECD lesions followed by several other kinase mutations in the MAPK pathway has revolutionized our understanding of the disease pathogenesis and led to trials with targeted therapies that demonstrated robust efficacy.
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http://dx.doi.org/10.1007/s11926-019-0865-2DOI Listing
December 2019

Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms.

Nat Med 2019 12 25;25(12):1839-1842. Epub 2019 Nov 25.

Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.
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http://dx.doi.org/10.1038/s41591-019-0653-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898787PMC
December 2019

Coronary artery disease in systemic lupus: A case-controlled angiographic study.

Autoimmun Rev 2020 Jan 14;19(1):102427. Epub 2019 Nov 14.

Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares, Hôpital Pitié-Salpêtrière, INSERM UMRS-1135, 75013 Paris, France.

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http://dx.doi.org/10.1016/j.autrev.2019.102427DOI Listing
January 2020

The eclipse sign as a radiological presentation of neurosarcoidosis.

Int J Neurosci 2020 May 1;130(5):435-437. Epub 2019 Dec 1.

Service de Médecine Interne 2, Institut e3m, Hôpital de la Pitié-Salpêtrière, Centre National de Référence Maladies Systémiques Rares, Lupus, Syndrome des anticorps antiphospholipides, Sorbonne Université, Assistance Publique Hôpitaux de Paris, Paris, France.

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.
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http://dx.doi.org/10.1080/00207454.2019.1688807DOI Listing
May 2020

Lung Involvement in Destombes-Rosai-Dorfman Disease: Clinical and Radiological Features and Response to the MEK Inhibitor Cobimetinib.

Chest 2020 02 24;157(2):323-333. Epub 2019 Oct 24.

Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares et Histiocytoses, Sorbonne Université, Assistance Publique Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Paris, France. Electronic address:

Background: Destombes-Rosai-Dorfman disease (RDD) is a rare multisystemic histiocytosis. Pulmonary involvement during RDD has been poorly described. The goal of this study was to examine the clinical presentations, radiological features, and outcomes of 15 patients with RDD and lung involvement.

Methods: The cases of RDD with lung involvement were extracted from the French National Histiocytosis registry. Efficacy of the MEK inhibitor cobimetinib in treating lung disease was evaluated with an fluorodeoxyglucose PET scanner and chest CT scans.

Results: Fifteen patients (six women; median age, 40 years at RDD diagnosis) were included. All patients had evidence of systemic disease with extrapulmonary localizations of the disease (lymphadenopathy [n = 12], skin [n = 9], bones [n = 6], retroperitoneal involvement [n = 3], sinuses [n = 3], parotid gland [n = 2], submandibular gland [n = 1], and breast [n = 1]). Presenting symptoms were dominated by dyspnea and dry cough in seven patients. Restrictive physiology was observed in two of five patients. BAL showed lymphocytosis in one of five cases. Eight patients received corticosteroids, all but one with variable immunosuppressive or immunomodulatory therapies. Two patients received cobimetinib for severe lung disease, with dramatic pulmonary metabolic and tumoral responses. Two patients died during follow-up: one of hemoptysis, and the other of an unrelated cerebral tumor.

Conclusions: Pulmonary involvement in RDD is rare, proteiform, and sometimes severe. The MEK inhibitor cobimetinib can lead to dramatic responses.
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http://dx.doi.org/10.1016/j.chest.2019.09.036DOI Listing
February 2020

Ultrasensitive serum interferon-α quantification during SLE remission identifies patients at risk for relapse.

Ann Rheum Dis 2019 12 30;78(12):1669-1676. Epub 2019 Sep 30.

Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.

Objectives: Maintenance of remission has become central in the management of systemic lupus erythematosus (SLE). The importance of interferon-alpha (IFN-α) in the pathogenesis of SLE notwithstanding, its expression in remission has been poorly studied as yet. To study its expression in remission and its prognostic value in the prediction of a disease relapse, serum IFN-α levels were determined using an ultrasensitive single-molecule array digital immunoassay which enables the measurement of cytokines at physiological concentrations.

Methods: A total of 254 SLE patients in remission, according to the Definition of Remission in SLE classification, were included in the study. Serum IFN-α concentrations were determined at baseline and patients were followed up for 1 year. Lupus flares were defined according to the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index Flare Index, whereas the Kaplan-Meier analysis and Cox regression analysis were used to estimate the time to relapse and to identify baseline factors associated with time to relapse, respectively.

Results: Of all patients in remission, 26% displayed abnormally high IFN-α serum levels that were associated with the presence of antibodies specific for ribonucleoprotein (RNP), double stranded (ds)DNA and Ro/SSA60, as well as young age. Importantly, elevated-baseline IFN-α serum levels and remission duration were associated in an independent fashion, with shorter time to relapse, while low serum levels of complement component 3 and anti-dsDNA Abs were not.

Conclusion: Direct serum IFN-α assessment with highly sensitive digital immunoassay permits clinicians to identify a subgroup of SLE patients, clinically in remission, but at higher risk of relapse.
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http://dx.doi.org/10.1136/annrheumdis-2019-215571DOI Listing
December 2019

Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study.

J Clin Oncol 2019 11 12;37(31):2857-2865. Epub 2019 Sep 12.

Trousseau Hospital, Paris, France.

Purpose: Off-label use of vemurafenib (VMF) to treat 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 ( < .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 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; < .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 clone.

Conclusion: VMF seemed safe and effective in children with refractory -positive LCH. Additional studies are needed to find effective maintenance therapy approaches.
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http://dx.doi.org/10.1200/JCO.19.00456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823889PMC
November 2019