Mechanism of neurodegeneration mediated by clonal inflammatory microglia.

Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and an increased risk of neurodegeneration. Surprisingly, we found pervasive PU.1+ microglia mutant clones across the brain of LCH and ECD patients with and without neurological symptoms, associated with microgliosis, reactive astrocytosis, and neuronal loss. The disease predominated in the grey nuclei of the rhombencephalon, a topography attributable to a local proliferative advantage of mutant microglia. Presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1+ clones (p= 0.0003). Genetic lineage tracing of PU.1+ clones suggest a resident macrophage lineage or a bone marrow precursor origin depending on patients. Finally, a CSF1R-inhibitor depleted mutant microglia and limited neuronal loss in mice suggesting an alternative to MAPK inhibitors. These studies characterize a progressive neurodegenerative disease, caused by clonal proliferation of inflammatory microglia (CPIM), with a decade(s)-long preclinical stage of incipient disease that represent a therapeutic window for prevention of neuronal death.

[Role of university hospital doctors specialized in internal medicine in health professions training and institutions in France: Survey of the National College of Teachers of Internal Medicine (CEMI)]. / Rôle des médecins hospitalo-universitaires de médecine interne dans la formation aux métiers de la santé et au sein des institutions en France : enquête du Collège National des Enseignants de Médecine Interne (CEMI).

RATIONALE: On the occasion of the General stage meeting of Internal Medicine, the National College of Internal Medicine Teachers (CEMI) conducted a survey on teaching activity among all French university hospital (HU) internal medicine specialists. METHOD: The survey was carried out in September 2023 by sending an email to 101 hospital practitioners university professors (PU-PH) and 18 hospital practitioners assistant professors (MCU-PH) of internal medicine in subsection 53-01 of the National council of universities (CNU), as well as to the 11 HU internists working in immunology (subsection 47-01) or therapeutics (subsection 48-04). RESULTS: Seventy-three HUs (56.1%) responded to the survey, including 65 PU-PH, 7 MCU-PH and 1 university hospital practitioner (PHU). Internal medicine HUs participate in faculty teaching: 80% are responsible for teaching, 30% are responsible for the year or cycle or lead committees and 40% have had or have an elected mandate at the faculty or at university. Internal medicine HU are involved in the teaching of semiology during the first cycle of medical studies, but also in pharmaceutical sciences, dentistry, midwifery and in paramedical training. They are very invested in the implementation of the second cycle reform and 80% are involved in the preparation of Objective Structured Clinical Examinations (ECOS), mainly as examiners (90%). They also participate in teaching using simulation (60%), teaching advanced practice nurses (IPA) (25%), and writing CEMI books (75%). For ECOS, 90% participate as examiners, 60% participate in teaching using simulation, 25% are involved in teaching advanced practice nurses (IPA), 75% participated in the writing of CEMI works. Eight (12%) internal medicine HUs co-facilitate training with patients and 26 (38%) participate in master's courses at the Faculty of Sciences. Finally, 94% are affiliated with a research unit and 48% supervise university theses students. CONCLUSION: Internal medicine universities teachers have a strong educational commitment, particularly in semiology and in the reform of the second cycle of medical studies with ECOS and simulation.

Risk of flare in patients with SLE in remission after hydroxychloroquine or chloroquine withdrawal.

OBJECTIVE: Previous studies have provided evidence that the discontinuation of hydroxychloroquine (HCQ), and chloroquine (CQ), in patients with systemic lupus erythematosus (SLE) is associated with an increased risk of disease flares, with limited information on the level of disease activity at the time of HCQ/CQ discontinuation. Here we aimed to describe the risk of SLE flare after withdrawal of HCQ or CQ in patients with SLE in remission. METHODS: Case-control study (1:2) comparing the evolution of patients with SLE after HCQ/CQ withdrawal for antimalarial retinopathy (cases) with patients with SLE matched for sex, antimalarial treatment duration and age at SLE diagnosis, whose antimalarial treatment was continued throughout the entire follow-up period (controls). To be included in the study, patients had to be in remission for at least one year according to the DORIS classification. The primary endpoint was the proportion of patient experiencing a flare according to the SELENA-SLEDAI Flare Index after a 36-month follow-up. RESULTS: We studied 48 cases and 96 controls. The proportion of patients experiencing a flare was significantly higher in the HCQ/CQ withdrawal group as compared to the maintenance group (15 [31.3%] patients versus 12 [12.5%]; OR 3.1 [95%CI 1.2-8.2], P=0.01). Withdrawal of HCQ/CQ was inferior with respect to occurrence of severe SLE flare (12 [25.0%] vs 11 [11.5%]; OR 2.5 [95%CI 0.9-6.9], P=0.053) and time to first flare (HR 6.3 [2.0-19.9], P<0.005). Elevated serum levels of anti-dsDNA antibodies were identified as a risk factor for SLE flare following HCQ/CQ discontinuation (HR 5.4 [1.5-18.7], P<0.01). CONCLUSION: Withdrawal of HCQ or CQ in patients with SLE in remission is associated with a 3-fold increased risk of relapse.

Long-term outcome and prognosis of mixed histiocytosis (Erdheim-Chester disease and Langerhans Cell Histiocytosis).

Background: Erdheim-Chester disease (ECD) is a rare histiocytosis that may overlap with Langerhans Cell Histiocytosis (LCH). This "mixed" entity is poorly characterized. We here investigated the clinical phenotype, outcome, and prognostic factors of a large cohort of patients with mixed ECD-LCH. Methods: This retrospective study was performed at two referral centers in France and Italy (Pitié-Salpêtrière Hospital, Paris; Meyer Children's Hospital, Florence). We included children and adults with ECD diagnosed in 2000-2022 who had biopsy-proven LCH, available data on clinical presentation, treatment and outcome, and a minimum follow-up of one year. Outcomes included differences in clinical presentation and survival between mixed ECD-LCH and isolated ECD; we also investigated response to treatments and predictors of survival in the mixed cohort. Survival was analyzed using the Kaplan-Maier method and differences in survival with the long-rank test. Cox regression models were used to evaluate the potential impact of age and gender on survival and to identify predictors of non-response and survival. Findings: Out of a cohort of 502 ECD patients, 69 (14%) had mixed ECD-LCH. Compared to isolated ECD, mixed ECD-LCH occurred more frequently in females (51 vs. 26%, p < 0.001) and in patients with multisystem disease (≥4 sites). Mixed ECD-LCH more frequently involved long bones (91 vs. 79%, p = 0.014), central nervous system (51 vs. 34%, p = 0.007), facial/orbit (52 vs. 38%, p = 0.031), lungs (43 vs. 28%, p = 0.009), hypothalamic/pituitary axis (51 vs. 26%, p < 0.001), skin (61 vs. 29%, p < 0.001), and lymph nodes (15 vs. 7%, p = 0.028); the BRAFV600E mutation was also more frequent in mixed ECD-LCH (81 vs. 59%, p < 0.001). Targeted treatments (BRAF and/or MEK inhibitors) induced response more frequently than conventional therapies (interferon-α, chemotherapy), either as first-line (77 vs. 29%, p < 0.001) or as any line (75 vs. 24%, p < 0.001). After a median follow-up of 71 months, 24 patients (35%) died. Survival probability was comparable between ECD alone and mixed ECD-LCH (log-rank p = 0.948). At multivariable analysis, age at diagnosis (HR 1.052, 95% CI 1.008-1.096), associated hematologic conditions (HR 3.030, 95% CI 1.040-8.827), and treatment failure (HR 9.736, 95% CI 2.919-32.481) were associated with an increased risk of death, while lytic bone lesions with a lower risk (HR 0.116, 95% CI 0.031-0.432). Interpretation: Mixed ECD-LCH is a multisystem disease driven by the BRAFV600E mutation and targeted treatments are effective. Age at diagnosis, bone lesion patterns, associated hematologic conditions, and treatment failure are the main predictors of death in mixed ECD-LCH. Funding: None.

Clinical phenotype of adult-onset systemic histiocytosis harboring BRAF in-frame deletions.

Not available.

Complete remission after a single bisphosphonate infusion in isolated bone Langerhans cell histiocytosis lesion: a case report and a narrative review of the literature.

Langerhans cell histiocytosis (LCH) is a rare disease with limited treatment options. We present a case involving a 57-year-old woman afflicted with an isolated LCH bone osteolytic lesion. A single bisphosphonate infusion significantly alleviated pain, and follow-up scans via CT, PET-CT, and MRI revealed a substantial recalcification of the lesion. Conducting an extensive literature review, we identified 46 cases documenting the efficacy of bisphosphonates in the context of LCH. These findings have raised interest in bisphosphonate infusion as a simple therapeutic alternative in similar situations, with benefits in terms of bone recalcification and pain control for individuals with LCH.

Phenotypes in antiphospholipid syndrome: A hierarchical cluster analysis based on two independent databases.

BACKGROUND: Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by thromboses at various sites and obstetric events associated with the persistent presence of antiphospholipid antibodies. The identification of clinical phenotypes in APS patients is a clinical need. In this study, we aimed to determine the clinical phenotypes of APS patients through an unsupervised analysis of two well-characterized cohorts of APS patients. PATIENTS AND METHODS: APS phenotypes were defined by an ascending hierarchical cluster analysis to identify preferential associations between 18 types of organ involvement and clinical characteristics. This analysis was performed on an initial multi-center cohort of 1000 patients, with validation in a replication cohort of 435 patients. RESULTS: The hierarchical analysis identified three APS phenotypes in both the initial and replication cohorts: an obstetric phenotype (n = 259 and n = 74 patients, respectively), a venous thrombosis phenotype, accounting for the largest number of patients (n = 461 and n = 297 patients, respectively), and a skin-central nervous system-heart phenotype (n = 280 and n = 64 patients, respectively). The clinical characteristics of the patients differed significantly between the three phenotypes, but there was no difference in antiphospholipid antibody profile between the groups. CONCLUSIONS: We identified three phenotypes of APS defined based on preferential associations of organ involvements and differences in presentation. These observations may help clinicians to detect organ involvement and to manage treatment.

Identification of new risk factors for hydroxychloroquine and chloroquine retinopathy in systemic lupus erythematosus patients.

BACKGROUND: Long-term hydroxychloroquine (HCQ) or chloroquine (CQ) intake causes retinal toxicity in 0.3-8 % of patients with rheumatic diseases. Numerous risk factors have been described, eg, daily dose by weight, treatment duration, chronic kidney disease, concurrent tamoxifen therapy and pre-existing retinal or macular disease. However, those factors cannot explain the entire risk of developing antimalarial retinopathy. OBJECTIVE: This study was undertaken to identify new risk factors associated with HCQ or CQ retinopathy (QRNP) in systemic lupus erythematosus (SLE) patients. METHODS: This case-control (1:2) study compared SLE patients with QRNP (cases) to those without (controls). Controls were matched for sex and known QRNP risk factors: HCQ and/or CQ treatment duration (±1 year) and age (±5 year) at SLE diagnosis. RESULTS: Forty-eight cases were compared to 96 SLE controls. Multivariable logistic-regression analysis retained the following as independent determinants significantly associated with QRNP: concomitant selective serotonin-reuptake inhibitor (SSRI) or serotonin- and norepinephrine-reuptake inhibitor (SNRI) intake (OR [95 % confidence interval] 6.6 [1.2 to 40.9]; p < 0.01); antiphospholipid syndrome (OR=8.9 [2.2 to 41.4] p < 0.01); blood hydroxychloroquine/desethylchloroquine concentration ([HCQ]/[DCQ]) ratio <7.2 (OR 8.4 [2.7 to 30.8]; p < 0.01) or skin phototype ≥4 (OR 5.5 [1.4 to 26.5]; p = 0.02), but not daily HCQ dose, blood [HCQ] or body mass index. CONCLUSION: The results of this case-control study identified blood [HCQ]/[DCQ] ratio, concurrent SSRI/SNRI therapy, skin phototype ≥4 and antiphospholipid syndrome as new risk factors for QRNP.

Prognostic value of hypermetabolic bone sarcoidosis observed by 18F-fluorodeoxyglucose positron emission tomography.

OBJECTIVES: Sarcoidosis is a multisystemic granulomatosis diagnosed mainly in young adults.18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) is useful in sarcoidosis cases to search for a biopsiable site or assess disease activity.18F-FDG PET-CT can reveal bone hypermetabolism in sarcoidosis patients, even in the absence of osteoarticular symptoms. The aim of this study was to describe metabolic bone involvement in sarcoidosis patients and to evaluate its prognostic impact. METHODS: This was an observational, comparative, retrospective, monocentric study. Inclusion criteria were a confirmed diagnosis of sarcoidosis according to the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) criteria and at least one 18F-FDG PET-CT scan during follow-up. Metabolic bone involvement of sarcoidosis was defined as focal bone hypermetabolism with no argument for a differential diagnosis of bone 18F-FDG uptake. Patients with and without bone involvement were compared. RESULTS: Among the 175 included patients, 32 (18%) had metabolic bone involvement of sarcoidosis. The metabolic bone involvement was mainly axial and mostly without bone abnormalities on CT. Metabolic bone involvement was associated with intrathoracic and extrathoracic lymph node involvement and with a higher number of organs involved. Patients with metabolic bone involvement more frequently received corticosteroids, methotrexate and tumor necrosis factor (TNF)-α inhibitors and a higher number of treatments. Relapse of sarcoidosis occurred sooner in patients with metabolic bone involvement. CONCLUSION: These results suggest that metabolic bone involvement is associated with more diffuse and more severe sarcoidosis.

Epidemiology and geographic clustering of Erdheim-Chester disease in Italy and France.

This geoepidemiological study, performed in Italy and France, shows that Erdheim-Chester disease is increasingly diagnosed and cases cluster in specific geographic areas, namely southern Italy and central France. Disease frequency inversely correlates with the Human Development Index.

[Cardiac sarcoidosis revealed by recurrent ventricular tachycardia]. / Tachycardie ventriculaire récidivante révélant une sarcoïdose cardiaque.

Sarcoidosis is an inflammatory disease whose diagnosis is suggested by clinical and paraclinical signs and confirmed by histological evidence showing granulomatosis without caseous necrosis. The clinical presentation is sometimes misleading and the diagnosis difficult to confirm. We report here the case of a young woman with cardiac sarcoidosis of difficult diagnosis, revealed by a myocardial infarction with normal coronary angiography and recurrent ventricular tachycardia. Multimodal imaging, combined with left ventricular endomyocardial biopsies guided by electrophysiological analysis and endocavitary mapping, finally confirmed the diagnosis, and allowed effective medical treatment.

Impaired metabolism predicts coronary artery calcification in women with systemic lupus erythematosus.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) exhibit a high risk for cardiovascular diseases (CVD) which is not fully explained by the classical Framingham risk factors. SLE is characterized by major metabolic alterations which can contribute to the elevated prevalence of CVD. METHODS: A comprehensive analysis of the circulating metabolome and lipidome was conducted in a large cohort of 211 women with SLE who underwent a multi-detector computed tomography scan for quantification of coronary artery calcium (CAC), a robust predictor of coronary heart disease (CHD). FINDINGS: Beyond traditional risk factors, including age and hypertension, disease activity and duration were independent risk factors for developing CAC in women with SLE. The presence of coronary calcium was associated with major alterations of circulating lipidome dominated by an elevated abundance of ceramides with very long chain fatty acids. Alterations in multiple metabolic pathways, including purine, arginine and proline metabolism, and microbiota-derived metabolites, were also associated with CAC in women with SLE. Logistic regression with bootstrapping of lipidomic and metabolomic variables were used to develop prognostic scores. Strikingly, combining metabolic and lipidomic variables with clinical and biological parameters markedly improved the prediction (area under the curve: 0.887, p < 0.001) of the presence of coronary calcium in women with SLE. INTERPRETATION: The present study uncovers the contribution of disturbed metabolism to the presence of coronary artery calcium and the associated risk of CHD in SLE. Identification of novel lipid and metabolite biomarkers may help stratifying patients for reducing CVD morbidity and mortality in SLE. FUNDING: INSERM and Sorbonne Université.

Sinonasal and ear manifestations of Erdheim-Chester disease.

To calculate the prevalence of sinonasal and ear involvement in an Erdheim-Chester disease (ECD) population, to describe the different ear, nose and throat (ENT) manifestations and to study the association between ENT involvement, other organ involvement, and BRAF mutations. We led a retrospective monocentric study in the national referral center for ECD. One hundred and sixty-two patients with ECD and ENT data were included between January 1, 1980 and December 31, 2020. Ear and nose clinical and radiological findings were noted. We described and studied the prevalence of ENT involvement in ECD population. The association between sinonasal and ear involvement, other organ involvement, and BRAF mutations was calculated. The prevalence of ENT manifestations is around 45%. No clinical rhinologic or otologic signs were specific to ECD. Sinus imaging was abnormal in 70% of cases. A bilateral maxillary sinus frame osteosclerosis was highly specific of ECD. Associations were found between the sinus MRI imaging type and BRAF status, central nervous system involvement, cerebellum involvement and xanthelasma. Sinonasal or ear involvement is frequent in ECD and has specific imaging features for sinuses. Trial registration: #2011-A00447-34.

Increased neopterin in cerebrospinal fluid in active adult neurohistiocytosis.

Diagnosis of neuro-histiocytosis is challenging and relies on clinical presentation, imaging, and cerebrospinal fluid (CSF) analysis to exclude differential diagnoses. Brain biopsy remains the gold standard for accurate diagnosis, but it is rarely performed because of the risk of the procedure and the low rentability in neurodegenerative presentation. Therefore, there is an unmet need to identify a specific biomarker for diagnosing neurohistiocytosis in adults. Because microglia (brain macrophages) is involved in the pathogenesis of neurohistiocytosis and produces neopterin secondary to aggression, the purpose of our study was to evaluate the value of the CSF neopterin levels for the diagnosis of active neurohistiocytosis. Of the 21 adult patients with histiocytosis, four patients had clinical symptoms compatible with neurohistiocytosis. In the two patients with a confirmed diagnosis of neurohistiocytosis, CSF neopterin levels were elevated as well as IL-6 and IL-10 levels. In contrast, the two other patients in whom the diagnosis of neurohistiocytosis was infirmed and all other patients with histiocytosis without active neurological disease involvement had normal CSF neopterin levels. In summary, increased CSF neopterin concentration represented a valuable tool for diagnosing active neuro-histiocytosis in adults with histiocytic neoplasms in this preliminary study.

PU.1 is a useful nuclear marker to distinguish between histiocytosis and histiocyte-rich tumours.

AIMS: The aim was to test the expression of PU.1 on different types of histiocytoses and to test the utility of PU.1 in confirming or excluding a histiocytic origin in tumour samples with suspicion of histiocytosis. METHODS AND RESULTS: We analysed 66 biopsies of nonmalignant histiocytoses represented by Langerhans-cell histiocytosis (n = 13), Erdheim-Chester disease (ECD) (n = 19), Rosai-Dorfman disease (RDD) (n = 14), mixed ECD-RDD (n = 3), ALK-positive histiocytosis (n = 6), and juvenile xanthogranuloma (n = 11). All cases were positive for PU.1 in reactive and neoplastic histiocytes. In addition, 39 cases of tumours with high-grade cytological atypia were referred to our center as suspicion of malignant histiocytosis/histiocytic sarcoma and only 18 were confirmed. Indeed, more than half of these tumours (21/39) were either undifferentiated malignant tumours with a stroma rich in histiocytes, diffuse large B-cell lymphoma, or high-grade dedifferentiated liposarcoma. PU.1 was useful to distinguish between the negativity of large atypical nuclei and the positivity of stromal reactive histiocytes. CONCLUSION: PU.1 is expressed by all types of histiocytosis. It distinguishes histiocytosis from histiocyte-rich tumours with an easy interpretation due to its sharp nuclear staining. Its negativity in lesional/tumour cells in histiocyte-like lesions is useful to eliminate a histiocytosis.

Molecular and clinicopathologic characterization of pediatric histiocytoses.

The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAFV600E . Most BRAFWT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAFV600E -mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5). Wild-type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ-risk involvement and neurodegeneration. MAP-kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild-type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP-kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.