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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., (Copyright © 2024 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

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., Competing Interests: Déclaration de liens d'intérêts Les auteurs ne déclarent aucun lien d'intérêt concernant cet article., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Introduction: Before attending residency, 6th-year French medical students must validate a final examination including a practical clinical test in their faculty. However, the national ranking that determines their future specialty and region solely relies on a computerized knowledge test. Our goal was to investigate the association between the final faculty test and the national ranking test., Methods: In our faculty, the final examination includes a computerized theoretical test (similar to the national one) and a practical test: a standardized evaluation of semiology skills at the bedside and a standardized assessment of relational skills with role plays. The agreements between the national test and faculty computerized and practical tests were analyzed by intraclass correlation coefficients (ICC)., Results: Data from 1806 students who underwent the three examinations from 2017 to 2021 were analyzed. There was a good agreement between the ranks in the faculty and national computerized tests: ICC 0.83 (95% CI 0.81-0.85). By contrast, the agreement between the ranks in the faculty practical test and the national computerized test was poor: ICC 0.13 (95% CI 0.08-0.17). Results were stable over the years., Conclusion: The agreement between the ranking of the current national test and the clinical skills assessed by a specific faculty test is poor. This could relate to a true independence or to different levels of motivation to perform well. Indeed, the result of the national test is the most important one as it determines their career. Incorporating a clinical assessment into the national ranking test will motivate students to acquire clinical skills and value those who perform well this practical dimension., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis that frequently infiltrates the peri-kidney space ("hairy kidney" appearance), kidney pelvis and proximal ureters, leading to obstructive uropathy. Here, we analyzed the clinical characteristics, imaging findings and long-term kidney outcome of a large multicenter cohort comprising 195 consecutive patients with ECD. Retroperitoneal peri-kidney or peri-ureteral involvement was detected at diagnosis in 147 patients. Of them, 70 had hydronephrosis (bilateral in 47), and 16 with kidney atrophy (unilateral in 14). Kidney vascular peduncle infiltration was found in 60 patients, and kidney artery stenosis in 31. The estimated glomerular filtration rate (eGFR) at diagnosis was significantly lower in patients with than in those without peri-kidney involvement (median 74 vs. 98 mL/min/1.73 m 2 ). Ureteral stenting often failed to achieve kidney function recovery. A total of 181 patients received medical therapies: first-line treatments included interferon-α (61%), BRAF-inhibitors (17%), mTOR-inhibitors (7%), or other drugs (15%). These therapies were efficacious for ECD but rarely induced kidney function improvement (one-year eGFR increase over 25% in under 10% of patients). After a median of 43 months, 19% of patients died and 5% developed kidney failure. Among patients with peri-kidney involvement, 44% developed chronic kidney disease (CKD) 3-5 at five years vs. 5% of those without. Unadjusted predictors of advanced CKD and kidney failure/death were age over 50 years, hypertension, BRAFV600E mutation, and baseline eGFR. At multivariable analysis, cardiovascular comorbidities were associated with advanced CKD, and age over 50 years with kidney failure/death. Thus, kidney involvement is common in ECD and can lead to CKD or kidney failure despite effective medical therapies or urological procedures., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Some common clinical situations, such as splenomegaly or lymphocytosis, or less common, such as autoimmune hemolytic anemia, cold agglutinin disease, or cryoglobulinemia can lead to the diagnosis of splenic lymphoma. Splenic lymphoma is rare, mainly of non-hodgkinian origin, encompassing very different hematological entities in their clinical and biological presentation from an aggressive form such as hepato-splenic lymphoma to indolent B-cell lymphoma not requiring treatment such as marginal zone lymphoma, the most frequent form of splenic lymphoma. These entities can be challenging to diagnose and differentiate. This review presents different clinical and biological manifestations suspicious of splenic lymphoma and proposes a diagnosis work-up. We extended the strict definition of splenic lymphoma (lymphoma exclusively involving the spleen) to lymphoma thant can be revealed by a splenomegaly and we discuss the differential diagnosis of splenomegaly., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Histiocytoses constitute a heterogeneous group of rare disorders, characterised by infiltration of almost any organ by myeloid cells with diverse macrophage or dendritic cell phenotypes. Histiocytoses can start at any age. Diagnosis is based on histology in combination with appropriate clinical and radiological findings. The low incidence and broad spectrum of clinical manifestations often leads to diagnostic delay, especially for adults. In most cases, biopsy specimens infiltrated by histiocytes have somatic mutations in genes activating the MAP kinase cell-signalling pathway. These mutations might also be present in blood cells and haematopoietic progenitors of patients with multisystem disease. A comprehensive range of investigations and molecular typing are essential to accurately predict prognosis, which can vary from spontaneous resolution to life-threatening disseminated disease. Targeted therapies with BRAF or MEK inhibitors have revolutionised salvage treatment. However, the type and duration of treatment are still debated, and the prevention of neurological sequelae remains a crucial issue., Competing Interests: Declaration of interests OA-W reports personal fees from Envisagenics, Pfizer Boulder, AIChemy, Janssen, Merck, H3 Biomedicine, Prelude Therapeutics, and Foundation Medicine, and grants from LOXO Oncology, during the conduct of the study. FC-A and JH are investigators (FC-A being the principal investigator) of an academic study on the efficacy of cobimetinib for treating histiocytoses (COBRAH, NCT 04007848). AI reports grants, research support, and travel funding from Carthera; grants from Transgene, Sanofi, Air Liquide, and Nutritheragene; personal fees from Novocure; and personal fees and travel funding from Leo Pharma, outside the submitted work. BJR received reimbursement for travel and lodging expenses from Eli Lilly and Company. JD reports grants from X4 Pharmaceuticals, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: In France, at the end of the sixth year of medical studies, students take a national ranking examination including progressive clinical case-based multiple-choice questions (MCQs). We aimed to evaluate the ability of these MCQs for testing higher-order thinking more than knowledge recall, and to identify their characteristics associated with success and discrimination., Methods: We analysed the 72 progressive clinical cases taken by the students in the years 2016-2019, through an online platform., Results: A total of 72 progressive clinical cases (18 for each of the 4 studied years), corresponding to 1059 questions, were analysed. Most of the clinical cases (n=43, 60%) had 15 questions. Clinical questions represented 89% of all questions, whereas basic sciences questions accounted for 9%. The most frequent medical subspecialties were internal medicine (n=90, 8%) and infectious diseases (n=88, 8%). The most frequent question types concerned therapeutics (26%), exams (19%), diagnosis (14%), and semiology (13%). Level 2 questions ("understand and apply") accounted for 59% of all questions according to the Bloom's taxonomy. The level of Bloom's taxonomy significantly changed over time with a decreasing number of level 1 questions ("remember") (P=0.04). We also analysed the results of the students among 853 questions of training ECNi. Success and discrimination significantly decreased when the number of correct answers increased (P<0.0001 both). The success, discrimination, mean score, and mean number of discrepancies did not differ according to the diagnosis, exam, imaging, semiology, or therapeutic type of questions., Conclusion: Progressive clinical case-based MCQs represent an innovative way to evaluate undergraduate students., (Copyright © 2020 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Script concordance tests (SCTs) have been developed to assess clinical reasoning in uncertain situations. Their reliability for the evaluation of undergraduate medical students has not been evaluated., Methods: Twenty internal medicine SCT cases were implemented in undergraduate students of two programs. The results obtained on the SCTs were compared to those obtained by the same students on clinical-based classical multiple-choice questions (MCQs)., Results: A total of 551/883 students (62%) answered the SCTs. The mean aggregate score (based on a total 20 points) was 11.54 (3.29). The success rate and mean score for each question did not differ depending on the modal response but the discrimination rate did. The results obtained by the students on the SCT test correlated with their scores on the MCQ tests. Among students, 446/517 (86%) considered the SCTs to be more difficult than classical MCQs, although the mean score did not differ between the SCT and MCQ tests., Conclusion: The use of SCTs is a feasible option for the evaluation of undergraduate students. The SCT scores correlated with those obtained on classical MCQ tests., (Copyright © 2020 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Infections are a frequent cause of cerebral vasculitis, important to diagnose because a specific treatment may be required. Infection-associated vasculitis can be caused by angiotropic pathogens (varicella zoster virus, syphilis, aspergillus). They can be associated with subarachnoidal meningitis (tuberculosis, pyogenic meningitis, cysticercosis). They can appear contiguously to sinuses or orbital infection (aspergillosis, mucormycosis). Finally, they also may be due to an immune mechanism in the context of chronic infections (hepatitis B virus, hepatitis C virus, human immunodeficiency virus). Cerebral vasculitis are severe conditions and their prognosis is directly linked to early recognition and diagnosis. Infectious causes must therefore be systematically considered ahead of cerebral vasculitis, and the appropriate investigations must be determined according to the patient's clinical context. We propose here an update on the infectious causes of cerebral vasculitis, their diagnosis modalities, and therapeutic options., (Copyright © 2020. Published by Elsevier Masson SAS.)

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., (© 2021 by The American Society of Hematology.)

Introduction: Erdheim-Chester disease (ECD) is a rare multisystemic disease characterised by an infiltration of various organs by CD68 + CD1a - histiocytes. The clinical and radiological presentation is very variable., Case Report: We report the case of a 71-year-old woman with ECD which was revealed by neurological and cutaneous manifestations. The diagnosis was confirmed by skin biopsy and the BRAFV600E mutation was identified in skin tissue, leading to the use of combined therapy targeting the RAS-RAF-ERK-MEK pathway. This therapy allowed an improvement of cutaneous manifestations but neurological manifestations lead to death, underlying their notable severity., Conclusion: Our case report shows the persistent diagnostic difficulty of the ECD and the particular gravity of neurologic involvement., (Copyright © 2020 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

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., (© 2020 by The American Society of Hematology.)

Background: Cardiac sarcoidosis (CS) is a challenging diagnosis. Patients may progress to end-stage congestive heart failure and require cardiac transplantation without ever having been diagnosed. Characteristics and outcomes of patients with granulomas in the explanted hearts are unknown., Methods: All French heart transplantation centers were contacted to participate in the study. Each center searched through local databases for the cases of non-caseating granuloma in the explanted hearts between 2000 and 2017. Data before and after transplantation were recorded from medical charts. Survival of CS and all- cause heart transplantation patients were compared., Results: Fifteen patients (10 men, 5 women) received a diagnosis of CS based on pathologic data of the explanted heart and were recruited for the study. All patients were diagnosed as non-ischemic dilated or hypertrophic cardiomyopathy and presented congestive heart failure. Eight patients (53%) had ventricular rhythm disturbances, and 3 (20%) a complete heart block. Ten out of 13 patients (77%) had extracardiac radiological signs compatible with sarcoidosis on chest computed tomography (CT) scans. One patient died 3 months after transplantation from infectious complications. The 14 remaining patients were still alive at the end of the study (median follow-up of 28.8 months). One patient had a second heart transplantation 5 years later because of chronic allograft vasculopathy. One patient presented a relapse of CS confirmed by myocardial biopsies 9 years after transplantation, requiring an escalation of immunosuppressive therapy., Conclusion: CS may be undiagnosed before heart transplantation. In 77% of cases, sarcoidosis could have been detected before transplantation with non-invasive imaging techniques., (Copyright © 2019. Published by Elsevier B.V.)

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., (© 2020 by The American Society of Hematology.)

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 18 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., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Though several assessment tools for resident professional skills based on workplace direct observation have been validated, they remain scarcely used in France. The objective of this study was to evaluate the reliability and the validity of a workbook including several assessment forms for different components of the professional competency., Methods: Three assessment forms have been tested over a period of 6 months in a multicentric study including 12 French internal medicine departments: the French version of the mini-CEX, an interpersonal skills assessment form (OD&#95;CR) and the multisource feedback form (E&#95;360). Reliability has been assess using the intra-class correlation coefficient (ICC) and the Cronbach alpha coefficient. Arguments for validity have been provided looking at the ability of the forms to detect an increase in the scores over time and according to the level of experience of the resident., Results: Twenty-five residents have been included. The Cronbach alpha was of 0.90 (n=70) with the mini-CEX, 0.89 with the OD&#95;CR (n=62) and 0.77 with the E&#95;360 (n=86). ICC showed a wide variation according to the items of the mini-CEX and the OD-CR probably due to the poor number of observations performed by residents. The scores of most of the items of these two forms increased between M1 and M6. The scores of the E&#95;360 were high: 7.3±0.8 to 8.3±2.4 (maximum 9) and did not vary according to the level of experience., Conclusion: This study suggest that it would be difficult to ensure a sufficient reliability for professional skills assessment using these tools given our available current human and material resources. However, these assessment forms could be added to the resident portfolio as supports for the debriefing in order to document their progression during their formation., (Copyright © 2019 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Heart failure during systemic lupus erythematosus has various causes., Case Report: A 29-year-old female presented with a systemic lupus flare and a nephrotic syndrome, followed by cardiogenic shock requiring extra-corporeal membranous oxygenation. Ventricular dysfunction was related to massive myocardial infarction due to an anterior interventricular artery thrombosis and an underlying atheroma. The young age and the absence of chest pain were not suggestive of coronary artery disease initially. Coronary thrombosis was probably favored by the nephrotic syndrome, in which the arterial thrombotic risk is increased., Conclusion: Coronary artery disease should be systematically evoked in the presence of ventricular dysfunction in patients with systemic lupus, including when they are young and in the absence of chest pain. Nephrotic syndrome should be identified as a risk factor for arterial thrombosis., (Copyright © 2019 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Giant-cell arteritis (GCA) is a large vessel vasculitis. Data regarding mortality are controversial. We describe the mortality data of the French death certificates for the period of 2005 to 2014., Methods: Using multiple-cause-of-death (MCOD) analysis, we calculated age-adjusted mortality rates for GCA, examined differences in mortality rates according to age and gender and analyzed the underlying causes of death (UCD)., Results: We analyzed 4628 death certificates listing a diagnosis of GCA as UCD or non-underlying cause of death (NUCD). The mean age of death was 86 (±6.8) years. The overall age-standardized mortality rate among GCA patients was 7.2 per million population. Throughout the study period, the mean age of death was significantly increased (r = 0.17, p < .0001) in both genders. There was no significant difference with age repartition of death in the general population (p = .26). When GCA was listed as the UCD, most frequent associated diseases were cardiovascular (79%) and infectious diseases (35%). When GCA was reported as the NUCD, the listed UCD was a cardiovascular event in 40% of cases, neoplasm in 13%, neurodegenerative disorder in 11% and infectious disease in 10%. When GCA was the UCD or NUCD, an age-adjusted observed/expected ratio > 1 in GCA-associated mortality compared with the general population mortality was observed for tuberculosis, pneumonia and cardiovascular diseases., Conclusion: In this analysis of French death certificates mentioning GCA, we observed a stable standardized mortality rate between 2005 and 2014. The most frequent associated diseases were cardiovascular diseases and infections., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rosai-Dorfman disease (RDD) was first described by the French pathologist Paul Destombes in 1965. It frequently affects children or young adults and is characterized by the presence of large histiocytes with emperipolesis. More than 50 years after this first description, the pathogenesis of this rare disease is still poorly understood. The revised classification of histiocytoses published in 2016 identified various forms of RDD, from familial RDD to IgG4-associated RDD. Almost 90% of the patients with RDD have cervical lymph nodes involvement although all the organs may virtually be involved. Outcomes are typically favorable. Treatments may be necessary in case of compression or obstruction, and are not well codified. The main therapeutic strategies rely on surgery, radiotherapy, steroids, immunosuppressive drugs or interferon-alpha and cladribine., (Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

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., (© 2018 by The American Society of Hematology.)

Introduction: The revision of the French medical studies' third cycle ought to be competency-based. In internal medicine, theoretical and practical knowledge will be assessed online with e-learning and e-portfolio. In parallel, a reflection about clinical skills assessment forms is currently ongoing. In this context, our aim was to assess the reproducibility and validity of two assessment forms based on direct clinical observation., Method: A prospective and multicentric study has been conducted from November 2015 to October 2016 aiming at evaluating the French translations of the MINI-Clinical Examination Exercice (MINI-CEX) and the Standardized Patient Satisfaction Questionnaire (SPSQ). Included residents have been assessed 2 times over a period of 6 months by the same binoma of judges., Results: Nineteen residents have been included. The inter-judge reproducibility was satisfactory for the MINI-CEX: intraclass coefficients (ICC) between 0.4 and 0.8 and moderate for the SPSQ: ICC between 0.2 and 0.7 with a good internal coherence for both questionnaires (Cronbach between 0.92 and 0.94). Significant differences between the distributions of the scores given by the judges and a significant inter-center variability have been found., Conclusion: If the absolute value of the scores should not be taken into account in the evaluation process given its high variability, it could be of interest for the follow-up of the progression in the competencies. These forms could support the residents' debriefing based on the general trends given by the scores., (Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Introduction: Sarcoidosis 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., Observation: We 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., Conclusion: Sarcoidosis 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., (Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

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 JAK2 V617F and CALR mutations) coexisting with those characteristic of histiocytosis (such as BRAF V600E 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., (© 2017 by The American Society of Hematology.)

Langerhans cell histiocytosis (LCH) and the non-LCH neoplasm Erdheim-Chester disease (ECD) are heterogeneous neoplastic disorders marked by infiltration of pathologic macrophage-, dendritic cell-, or monocyte-derived cells in tissues driven by recurrent mutations activating MAPK signaling. Although recent data indicate that at least a proportion of LCH and ECD patients have detectable activating kinase mutations in circulating hematopoietic cells and bone marrow-based hematopoietic progenitors, functional evidence of the cell of origin of histiocytosis from actual patient materials has long been elusive. Here, we provide evidence for mutations in MAPK signaling intermediates in CD34 + cells from patients with ECD and LCH/ECD, including detection of shared origin of LCH and acute myelomonocytic leukemia driven by TET2 -mutant CD34 + cell progenitors in one patient. We also demonstrate functional self-renewal capacity for CD34 + cells to drive the development of histiocytosis in xenotransplantation assays in vivo. These data indicate that the cell of origin of at least a proportion of patients with systemic histiocytoses resides in hematopoietic progenitor cells prior to committed monocyte/macrophage or dendritic cell differentiation and provide the first example of a patient-derived xenotransplantation model for a human histiocytic neoplasm., (© 2017 by The American Society of Hematology.)

Neurological localizations of sarcoidosis are heterogeneous and may affect virtually every part of the central or peripheral nervous system. They are often the inaugural manifestation of sarcoidosis. The diagnosis may be difficult due to the lack of extra-neurological localization. Diagnosis may be discussed in the presence of an inflammatory neurological disease, in particular in case of suggestive radiological or biological pattern. Cerebrospinal fluid analysis shows lymphocytic pleiocytosis, often with low glucose level. The diagnosis relies on a clinical, biological and radiological presentation consistent with neurosarcoidosis, the presence of non-caseating granuloma and exclusion of differential diagnoses. Screening for other localizations of sarcoidosis, in particular cardiac disease may be obtained during neurosarcoidosis. The treatment of neurosarcoidosis relies on corticosteroids although immunosuppressive drugs are usually added because of the chronic course of this condition and to limit the side effects of steroids. Treatments and follow-up may be prolonged because of the high rate of relapses., (Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Sarcoidosis is a granulomatous disorder of unknown cause characterized by non-caseating granuloma in young adults. Cardiac involvement is rare and range from 2 to 75% depending on diagnostic criteria. Cardiac involvement in sarcoidosis may be asymptomatic or may manifest as rhythm/conduction troubles or congestive heart failure. The diagnosis and treatment of cardiac sarcoidosis may be challenging. However, advances have come in recent years from the use of cardiac MRI and 18 FDG-TEP scanner, as well as from the stratification of the risk of ventricular tachycardia/fibrillation. Due to the rarity of the disease, there is no reliable prospective large study to guide therapeutic strategy for cardiac sarcoidosis. Corticosteroids are probably efficacious, in particular in case of atrio-ventricular block or moderate heart failure. Immunosuppressive drugs have not been largely studied but methotrexate could be helpful. In refractory forms, TNF-α antagonists have been used with success., (Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Introduction: Shrinking lung syndrome (SLS) is a rare respiratory manifestation of systemic lupus erythematosus (SLE), characterized by dyspnea, chest pain, elevated hemidiaphragm and a restrictive pattern on pulmonary function tests. Here, we report 15 new observations of SLS during SLE and provide a systematic literature review. We studied the clinical, biological, functional and morphologic characteristics, the treatments used and their efficacy., Methods: The inclusion criteria were all patients with SLE defined by the American College of Rheumatology criteria Hochberg (1997) , associated with a restrictive pattern on pulmonary function tests. The exclusion criteria were all differential diagnoses of restrictive patterns, including obesity and pulmonary fibrosis. The patients were recruited from local databases through chest physicians, rheumatologists and internists. The data for the literature review were extracted from the Medline database using "shrinking lung syndrome" and "lupus" as key words., Results: All 15 new cases were women with a median age at SLS onset of 27years old (range 17-67years). All of them complained of dyspnea and all but one of chest pain. The antibodies were similar to those found in SLE, although the anti-SS-A was positive in 10 of 13 cases. Thoracic imaging showed elevated hemidiaphragm (12/15) and/or basal atelectasia (8/15). All of the patients had an isolated restrictive pattern on PFT, with a median decrease >50% of lung volume. All of the patients were treated, using corticosteroids (11/15), immunosuppressive drugs (8/15), beta-mimetics (2/15), physiotherapy (3/15) and/or colchicine (1/15). Improvement was described in 9 of 12 patients and stability in 3 of 12. We extracted 155 cases of SLE-associated SLS from the Medline database. The clinical, biological and functional parameters were similar to our cases. Clinical improvement was described in 48 of 52 cases (94%) and PFT improvement in 36 of 47 cases. Worsening occurred in 4 cases., Conclusion: SLS is a rare SLE manifestation. Pain and parietal inflammation seem to play important pathogenic roles. Steroids and antalgics are the most commonly used therapies with good responses. There is no proof of efficacy with immunosuppressive drugs for this entity. Rituximab can be discussed after failure of corticosteroids, as well as antalgics, theophylline and beta-mimetics., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Relapsing polychondritis (RP) is a very rare autoimmune disease characterised by a relapsing inflammation of the cartilaginous tissues (joints, ears, nose, intervertebral discs, larynx, trachea and cartilaginous bronchi), which may progress to long-lasting atrophy and/or deformity of the cartilages. Non-cartilaginous tissues may also be affected, such as the eyes, heart, aorta, inner ear and skin. RP has a long and unpredictable course. Because no randomised therapeutic trials are available, the treatment of RP remains mainly empirical. Minor forms of the disease can be treated with non-steroidal anti-inflammatory drugs, whereas more severe forms are treated with systemic corticosteroids. Life-threatening diseases and corticosteroid-dependent or resistant diseases are an indication for immunosuppressant therapy such as methotrexate, azathioprine, mycophenolate mofetil and cyclophosphamide. Biologics could be given as second-line treatment in patients with an active disease despite the use of steroids and immunosuppressive drugs. Although the biologics represent new potential treatment for RP, very scarce information is available to draw any firm conclusion on their use in RP., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Nitrofurantoin is a commonly used drug which can have liver and pulmonary adverse effects. Among hepatic nitrofurantoin-induced adverse effects, autoimmune hepatitis is a rare complication which must not be mistaken as a toxic hepatitis., Case Report: We report an 86-year-old woman who presented with acute hepatitis after a 3-month course of nitrofurantoin administration for urinary tract infections. She reported a previous hepatitis after treatment by nitrofurantoin twenty years before. Biological analysis showed polyclonal hypergammaglobulinemia, positive test for antinuclear antibodies and smooth muscle antibodies. Finally, liver histology showed lymphocytic infiltration, marked necrotic and inflammatory activity consistent with the diagnosis of autoimmune hepatitis. Nitrofurantoin was discontinued. Outcome of autoimmune hepatitis was good with corticosteroids and azathioprine but two months later, the patient died from a refractory global heart failure., Conclusion: Nitrofurantoin-induced autoimmune hepatitis is a severe condition which must be systematically discussed in patients taking nitrofurantoin who present with acute hepatitis. Hypergammaglobulinemia is an easily obtained blood marker, which can suggest this diagnosis. Treatment relies on nitrofurantoin eviction, corticosteroids and sometimes azathioprine. Outcome is usually favorable., (Copyright © 2015 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Erdheim-Chester disease (ECD) is a rare histiocytic disorder that is challenging to diagnose and treat. We performed molecular analysis of BRAF in the largest cohort of ECD patients studied to date followed by N/KRAS, PIK3CA, and AKT1 mutational analysis in BRAF wild-type patients. Forty-six of 80 (57.5%) of patients were BRAFV600E-mutant. NRAS mutations were detected in 3 of 17 ECD BRAFV600E wild-type patients. PIK3CA mutations (p.E542K, p.E545K, p.A1046T, and p.H1047R) were detected in 7 of 55 patients, 4 of whom also had BRAF mutations. Mutant NRAS was present in peripheral blood CD14(+) cells, but not lymphoid cells, from an NRASQ61R mutant patient. Our results underscore the central role of RAS-RAF-MEK-ERK activation in ECD and identify an important role of activation of RAS-PI3K-AKT signaling in ECD. These results provide a rationale for targeting mutant RAS or PI3K/AKT/mTOR signaling in the subset of ECD patients with NRAS or PIK3CA mutations., (© 2014 by The American Society of Hematology.)

Erdheim-Chester disease is a rare and orphan disease. Despite having been overlooked previously, numerous new cases have been diagnosed more recently. The number of Erdheim-Chester disease cases reported has increased substantially: more than 300 new cases have been published in the past 10 years. This situation is mainly a result of the generally better awareness among pathologists, radiologists, and clinicians of various aspects of this rare disease. The field has been particularly active in the last few years, with evidence of the efficacy of interferon-α, the description of a systemic pro-inflammatory cytokine signature, and most recently, reports of the dramatic efficacy of BRAF inhibition in severe, BRAF(V600E) mutation-associated cases of Erdheim-Chester disease. Also, BRAF mutations have been found in more than half of the patients with Erdheim-Chester disease who were tested. Detailed elucidation of the pathogenesis of the disease is likely to lead to the development of better targeted and more effective therapies., (Copyright © 2014 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis. Diagnosis of ECD is based on the identification in tissue biopsy of histiocytes, which are typically foamy and immunostain for CD68+ CD1a-. Central nervous system involvement is a major prognostic factor in ECD. Interferon alpha may be the best first-line therapy and significantly improves survival of ECD. The BRAFV600E mutation is found in more than 50% of cases. Vemurafenib has been used for a small number of patients harbouring this mutation; inhibition of BRAF activation by vemurafenib was highly beneficial in these cases of severe multisystemic and refractory ECD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAFV600E gain-of-function mutations have been observed in 57% of cases of Langerhans cell histiocytosis (LCH) and 54% of cases of Erdheim-Chester disease (ECD), but not in other types of histiocytoses. Targeted therapy with an inhibitor of mutated BRAF (vemurafenib) improves survival of patients with melanoma. Here, we report vemurafenib treatment of 3 patients with multisystemic and refractory ECD carrying the BRAFV600E mutation; 2 also had skin or lymph node LCH involvement. The patients were assessed clinically, biologically (CRP values), histologically (skin biopsy), and morphologically (positron emission tomography [PET], computed tomography and magnetic resonance imaging). For all patients, vemurafenib treatment led to substantial and rapid clinical and biologic improvement, and the tumor response was confirmed by PET, computed tomography, and/or magnetic resonance imaging 1 month after treatment initiation. For the first patient treated, the PET response increased between months 1 and 4 of treatment. The treatment remained effective after 4 months of follow-up although persistent disease activity was still observed. Treatment with vemurafenib, a newly approved BRAF inhibitor, should be considered for patients with severe and refractory BRAFV600E histiocytoses, particularly when the disease is life-threatening.

Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAF mutations have been observed in Langerhans cell histiocytosis (LCH). We investigated the frequency of BRAF mutations in several types of histiocytoses. Histology from 127 patients with histiocytoses were reviewed. Detection of BRAF(V600) mutations was performed by pyrosequencing of DNA extracted from paraffin embedded samples. Diagnoses of Erdheim-Chester disease (ECD), LCH, Rosai-Dorfman disease, juvenile xanthogranuloma, histiocytic sarcoma, xanthoma disseminatum, interdigitating dendritic cell sarcoma, and necrobiotic xanthogranuloma were performed in 46, 39, 23, 12, 3, 2, 1, and 1 patients, respectively. BRAF status was obtained in 93 cases. BRAF(V600E) mutations were detected in 13 of 24 (54%) ECD, 11 of 29 (38%) LCH, and none of the other histiocytoses. Four patients with ECD died of disease. The high frequency of BRAF(V600E) in LCH and ECD suggests a common origin of these diseases. Treatment with vemurafenib should be investigated in patients with malignant BRAF(V600E) histiocytosis.

Background: Diagnosis of acute pericarditis remains difficult in clinical practice., Objectives: The purpose of this study was to evaluate the clinical and biological features of patients presenting with acute pericarditis, and to determine the incidence and significance of troponin I (cTnI) elevation in that context., Patients and Methods: We retrospectively included 55 patients with acute idiopathic pericarditis. We analyzed clinical presentation, ECG recordings, biologic results, echocardiography findings and cTnI level., Results: Fifty-five consecutive patients (41 men, 54+/-18 years) with idiopathic acute pericarditis were included. There was a typical chest pain in 90% of cases, whereas fever and pericardial friction rub were present in 25 and 18%, respectively. ST-segment elevation was observed in 58% of the patients. A rise of cTnI and C-reactive protein was detectable in 27 and 78% of cases respectively. The following characteristics were more frequently associated with a positive cTnI test: younger patients, recent infection and higher length-of-stay. Pericardial effusion was observed in 58% of patients. Cardiac tamponade and ventricular tachycardia both occurred in 3 patients (5%). After a mean follow-up of 33 months, recurrent pericarditis occurred in 13% of patients. A similar rate of complications was found in patients with a positive or a negative cTnI., Conclusion: Clinical spectra of acute pericarditis have changed and some classic assumptions and descriptions, perpetuated in some publications, are outdated. Clinical presentation implies a 45-55 year-old man, with a chest pain and ST-segment elevation, without fever or pericardial friction rub, and a positive cTnI test in 27% of cases. Therefore, misinterpretation as other disease, especially acute myocardial infarction, is common and diagnosis of acute pericarditis remains often retrospective. In our series, a cTnI rise did not appear as a negative prognostic marker.

Purpose: Recent end point trials of lipid-lowering drugs have shown that patients at very high-risk for coronary disease benefit from treatments that lowers low density lipoprotein cholesterol (LDL cholesterol) plasma levels< or =70 mg/dl and that patients with at least 2 risk factors benefit from LDL cholesterol levels< or =100 mg/dl. Epidemiologic studies have shown that the concentration of high density lipoprotein cholesterol (HDL cholesterol) is a strong, independent, inverse predictor of coronary disease risk. Innovative pharmacological approaches to raise low HDL cholesterol levels are currently of considerable interest, especially for patients with type 2 diabetes or metabolic syndrome., Results: Rosuvastatin has shown superior efficacy in lowering LDL cholesterol, although evidence of clinical benefit is actually lacking. Ezetimibe is a lipid-lowering drug that inhibits absorption of dietary and biliary cholesterol. Its co-administration with statin has given very interesting results. Niacin is the most effective of currently available options for raising HDL cholesterol, although tolerability can be an issue, with serious side effects such as loss of glucose control and liver toxicity. Flushing may occur in 80% of treated patients. Two CETP inhibitors have shown therapeutical efficacy to raise HDL cholesterol, but clinical benefit remains uncertain.

The association of idiopathic thrombocytopenic purpura and Graves' disease is rare. Hence, little is known about the outcomes of these two diseases when associated. We report two cases of idiopathic thrombocytopenic purpura associated with Graves' disease, in which the two diseases had distinct outcomes. Thus, the hypothesis of cross-reaction between antithyroid antibodies and platelet epitopes, which has been proposed to explain the association, seems unlikely.