Alemtuzumab-induced immune-mediated thrombotic thrombocytopenic purpura: A newly described drug-related autoimmune disease.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disease that may result from drug exposure. We report a case of iTTP occurring in a 39-year-old patient, 45 months following introduction of the anti-CD52 lymphoid cell depleting monoclonal antibody alemtuzumab, to treat a relapsing-remitting multiple sclerosis. Treatment consisted in plasma exchange, corticosteroids and caplacizumab, allowing clinical remission 3 months after the diagnosis, attested by the absence of thrombocytopenia and recovery of ADAMTS-13 activity. As other autoimmune disorders, iTTP may occur following alemtuzumab. This diagnosis should be suspected in patients with features of thrombotic microangiopathy following this treatment.

[Peripheral neuropathies during systemic diseases: Part II (vasculitis)]. / Neuropathies périphériques au cours des maladies de système : partie II (vascularites).

Primary systemic vasculitides, mainly of the small and medium-sized vessels, are frequently associated with peripheral neuropathies. When the disease is already known, the appearance of a neuropathy should suggest a specific injury, especially when associated with other systemic manifestations. Conversely, when neuropathy is inaugural, close collaboration between neurologists and internists is necessary to reach a diagnosis. A standardized electro-clinical investigation specifying the topography, the evolution and the mechanism of the nerve damage enables the positive diagnosis of the neuropathy. Several elements orient the etiological diagnosis and allow to eliminate the main differential diagnosis: non systemic vasculitic neuropathy. The existence of associated systemic manifestations (glomerular or vascular nephropathy, interstitial lung disease, intra-alveolar hemorrhage, ENT involvement…), biological markers (ANCA, cryoglobulinemia, rheumatoid factor), and invasive examinations allowing histological analysis (neuromuscular biopsy) are all useful tools for.

[Peripheral neuropathies during systemic diseases: Part I (connective tissue diseases and granulomatosis)]. / Neuropathies périphériques au cours des maladies de système : partie I (connectivites et granulomatoses).

Systemic diseases (connective disease, granulomatosis) may be associated with peripheral neuropathies. The diagnosis can be complex when the neuropathy is the presenting manifestation of the disease, requiring close collaboration between neurologists and internists. Conversely, when the systemic disease is already known, the main question remaining is its imputability in the neuropathy. Regardless of the situation, the positive diagnosis of neuropathy is based on a systematic and rigorous electro-clinical investigation, specifying the topography, the evolution and the mechanism of the nerve damage. Certain imaging examinations, such as nerve and/or plexus MRI, or other more invasive examinations (skin biopsy, neuromuscular biopsy) enable to specify the topography and the mechanism of the injury. The imputability of the neuropathy in the course of a known systemic disease is based mainly on its electro-clinical pattern, on which the alternatives diagnoses depend. In the case of an inaugural neuropathy, a set of arguments orients the diagnosis, including the underlying terrain (young subject), possible associated systemic manifestations (inflammatory arthralgias, polyadenopathy), results of first-line laboratory tests (lymphopenia, hyper-gammaglobulinemia, hypocomplementemia), autoantibodies (antinuclear, anti-native DNA, anti-SSA/B) and sometimes invasive examinations (neuromuscular biopsy).

Postgraduate oncology educational shifts during the COVID-19 pandemic: results of faculty and medical student surveys.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disrupted clinical practice, research and teaching. During peaks, virtual courses were implemented but these changes are poorly described, especially for oncology postgraduate students and faculty teachers. PATIENTS AND METHODS: We administered two surveys from June 2021 to October 2021 to students and faculty teachers (250 and 80 responses, respectively) who registered at Gustave Roussy School of Cancer Sciences (Université Paris-Saclay) during 3 consecutive university years (October 2018 to October 2021), where a major shift to e-learning was associated with COVID-19 pandemic. RESULTS: Most students were female (53%), attending physicians (50%), aged 30-39 years (54%) and 2020-2021 (66.4%) was the main year of training. Most faculty teachers were male (58%), aged 40-50 years (44%) and had participated in training for at least 3 years (83%). More than half of the students received 100% virtual training [55% versus 45% face-to-face/mixed teaching modalities; online (84%) versus remote teaching (16%)]. Only 34% of students declared >80% 'active listening' and only 16% of teachers considered e-learning to be more suitable (compared with face-to-face) for postgraduate education. Virtual teaching decreased student-teacher interactions as compared with mixed/face-to-face (lessons were sufficiently interactive for 54% students if virtual only teaching versus for 71% if other teaching modalities; P = 0.009). Teachers stated that virtual learning did not lead to any improvements in terms of attendance (68%), interaction (74%) and quality of teaching (68%). However, most faculty (76%) acknowledged that partial e-learning training should be maintained outside the pandemic, if it represents ≤50% of the whole teaching (teachers: 79% versus student: 66%; P = 0.04). CONCLUSIONS: COVID-19 accelerated the transition toward novel practices. Students and faculty teachers agreed on the need for future mixed (≤50% e-learning) teaching modalities. Adequate formation and the use of codified best newer virtual practices are required.

Neuropathies périphériques associées aux syndromes lymphoprolifératifs : spectre clinique et démarche diagnostique.

Lymphoproliferative syndromes (multiple myeloma, Waldenström's disease, chronic lymphocytic leukemia, lymphomas) may be associated with peripheral neuropathies. The mechanism can be dysimmune, associated or not with monoclonal gammopathies; paraneoplastic; infiltrative; or more commonly, iatrogenic or due to vitamin deficiency. The diagnosis can be complex, especially when the neuropathy is the presenting manifestation, requiring a close cooperation between internists and neurologists. The positive diagnosis of the neuropathy is based on a systematic electro-clinical investigation, which specifies the topography and the mechanism of the nerve damage, sometimes reinforced by imaging examinations, in particular, nerve and/or plexus MRI. The imputability of the neuropathy to a lymphoproliferative syndrome is based on a set of arguments including the clinical context (B signs, tumour syndrome), first-line laboratory tests (hemogram, protein electrophoresis, viral serologies, complement), auto-antibodies discussed according to the neuropathy (anti-MAG, anti-gangliosides) and sometimes more invasive examinations (bone marrow or neuro-muscular biopsies).

Anti-Ma2 antibody encephalitis associated with Sjogren's syndrome.

INTRODUCTION: Onconeuronal antibodies directed against intracellular antigens are strongly associated with paraneoplastic syndromes and their detection in the absence of cancer is unusual. We herein report a case of anti-Ma2 encephalitis associated with Sjogren's syndrome (SS). CASE REPORT: An 81-year-old woman followed for a cutaneous lupus with vasculitis associated with SS presented a flare of her disease with neurological worsening including walking difficulty, hypersialorrhea and dysphagia. A paraneoplastic origin of the symptoms was suspected and anti-Ma2 antibodies were positive in serum. The search for an underlying neoplasia was negative. The diagnosis of anti-Ma2 encephalitis secondary to a SS was made. In the literature, the association of anti-Ma2 encephalitis and SS has been previously reported twice. Cases of patients with other onconeuronal antibodies associated with SS have been also reported. Anti-Ma2 encephalitis is a rare condition with a wide spectrum of symptoms associated with a cancer in more than 90% of the cases. Anti-Ma2 encephalitis has also been described after the use of immune check points inhibitors underscoring the role of autoimmunity in its pathogenesis. CONCLUSION: Anti-Ma2 encephalitis is essentially associated with neoplasia but can occur in Sjogren's syndrome.

Progressive clinical case-based multiple-choice questions: An innovative way to evaluate and rank undergraduate medical students.

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.

Factors associated with tuberculosis-associated haemophagocytic syndrome: a multicentre case-control study.

SETTING: Tuberculosis (TB) is a potential trigger of haemophagocytic syndrome (HS) but little is known about the features of TB-associated HS.OBJECTIVE: To assess the risk factors associated with HS in patients with TB.DESIGN: We performed a multicentre case-control study assessing the medical records of adult patients diagnosed with proven TB with (TB/HS+) or without (TB/HS-) associated HS.RESULTS: Twenty-one patients with TB/HS+ (24% women, median age, 37 years [IQR 30-48]) were included in the study. Eleven patients (52%) were infected with human immunodeficiency virus and seven patients (33%) were immunocompromised due to other reasons. TB was disseminated in 17 patients (81%). Compared with 50 control TB patients (TB/HS-), patients with TB/HS+ were more likely to be immunocompromised (86% vs. 18%; P < 0.001) and to present with disseminated TB (80% vs. 12%; P < 0.001). The outcome was poorer in patients with TB/HS+, with a higher admission rate to intensive care (71% vs. 0%; P < 0.001) and a higher risk of death (38% vs. 7%; P = 0.005).CONCLUSION: TB/HS+ occurred more likely in immunocompromised patients and severely impaired the prognosis of TB. Further studies are needed to devise therapeutic strategies for patients with TB/HS+.

[Immune-related adverse events after immune checkpoints inhibitors in 2019: An update]. / Toxicités immunologiques induites par les inhibiteurs de checkpoint en 2019 : mise au point.

Use of checkpoint inhibitors to treat cancer was one of the most important revolution these last years and an increasing number of new types of tumors is currently under investigation with these new treatments. However, immune-related adverse events associated with these agents frequently affect various organs, mimicking auto-immune or inflammatory diseases. Some of these effects can be severe, often requiring hospitalization and specialized treatment (immunosuppression). Most known agents are ipilimumab (anti-CTLA-4 antibody) nivolumab and pembrolizumab (anti-PD-1 antibodies). New molecules are now approved or in development as anti-PD-L1 antibodies, anti-LAG-3 or anti-TIM-3 antibodies, increasing the probability and new description of immune-related adverse events. With his experience in auto-immune diseases, the immunologist/internal medicine specialist has an important role in the management of these toxicities. The goal of this review is to focus on the incidence, diagnostic assessment and recommended management of the most relevant immune-related adverse events.

[Cervical spinal sarcoidosis mimicking compressive cervical myelopathy: Poor prognosis after surgery]. / Sarcoïdose médullaire mimant une myélopathie cervico-arthrosique : mauvais pronostic après chirurgie.

INTRODUCTION: Cervical spinal sarcoidosis can mimic compressive cervical myelopathy leading to potentially harmful surgical procedures before the diagnosis can be made. METHODS: Retrospective description of 3 patients and review of the literature. RESULTS: Twenty-seven patients (16 men/11 women), median age 58 years [range 29-74] were described. Neurosurgical procedures consisted of laminectomy (n=10), laminoplasty (n=15) and anterior discectomy (n=2). Immediately after surgery, 17 patients (63%) worsened or remained disabled. Among the 10 patients who improved, 9 worsened secondarily. The analysis of preoperative MRI showed T2 hypersignal lesions and contrast enhancement in all patients. Neurological symptoms were inaugural in 25/27 patients, and systemic involvement of the sarcoidosis was found after surgery in 15/27 patients. After surgery, all patients received corticosteroids, along with immunosuppressive therapy in 8 cases/27. After a follow-up of 24 [16-72] months; 13 patients were stabilized or worsened, 7 were partially improved. Three died of other cause. Only 5 recovered without sequelae. CONCLUSION: In patients with compressive cervical myelopathy, leptomeningeal contrast enhancement, a T2-weighted hypersignal exceeding the compression level on MRI, and the presence of extraneurological symptoms should point to inflammatory disease. These rare manifestations may be the first symptoms of sarcoidosis and should be recognized to avoid harmful surgical procedures and to provide appropriate medical treatment.

Haematological immune-related adverse events with immune checkpoint inhibitors, how to manage?

Immune checkpoint inhibitors (ICIs) are changing the treatments of many patients with cancer. These immunotherapies are generally better tolerated than chemotherapy, and their adverse events are immune-related mimicking autoimmune or inflammatory conditions. Although these immune-related adverse events mainly affect the skin, endocrine glands, digestive tract, joints, liver or lungs, all the organs can be theoretically affected, and the haematopoietic system is not spared. This review of the literature will focus on the haematological immune-related adverse events (Haem-irAEs). By reviewing the largest clinical trials of ICIs, we estimate the frequency of Haem-irAEs at 3.6% for all grades and 0.7% for grades III-IV. Frequency of Haem-irAEs of all grades was found to be higher with anti-programmed cell death 1 (4.1%) or anti-programmed cell death ligand 1 (4.7%) than with anti-cytotoxic T-lymphocyte-associated protein 4 (0.5%) (p < 0.0001). From the 63 cases with Haem-irAEs reported in the literature, the mean time to the onset was found to be 10 weeks after ICI initiation, and the large range for occurrence (1-84 weeks) and the regular incidence suggest that Haem-irAEs could occur at any time after ICI therapy. Among the 63 reported cases with Haem-irAEs, the distribution was immune thrombocytopenia (n = 18, 29%), pancytopenia or immune aplastic anaemia (n = 12, 19%), neutropenia (n = 11, 17%), haemolytic anaemia (n = 10, 16%), cytokine release syndrome with haemophagocytic syndrome (n = 7, 11%) and other Haem-irAEs including bicytopenia or pure red cell aplasia (n = 5, 8%). Haem-irAEs are generally highly severe adverse reactions with a mortality rate of Haem-irAEs reported to be 14% (9 deaths among the 63 cases reported). The more severe and life-threatening Haem-irAEs were both cytokine release syndrome with haemophagocytic syndrome and pancytopenia or aplastic anaemia. Haem-irAEs induced by ICIs are potentially life-threatening. By discussing their pathophysiological aspects and clinical picture, we propose in this review clinical guidelines for management.

A High Frequency of HIV-Specific Circulating Follicular Helper T Cells Is Associated with Preserved Memory B Cell Responses in HIV Controllers.

Follicular helper T cells (Tfh) play an essential role in the affinity maturation of the antibody response by providing help to B cells. To determine whether this CD4+ T cell subset may contribute to the spontaneous control of HIV infection, we analyzed the phenotype and function of circulating Tfh (cTfh) in patients from the ANRS CO21 CODEX cohort who naturally controlled HIV-1 replication to undetectable levels and compared them to treated patients with similarly low viral loads. HIV-specific cTfh (Tet+), detected by Gag-major histocompatibility complex class II (MHC-II) tetramer labeling in the CD45RA- CXCR5+ CD4+ T cell population, proved more frequent in the controller group (P = 0.002). The frequency of PD-1 expression in Tet+ cTfh was increased in both groups (median, >75%) compared to total cTfh (<30%), but the intensity of PD-1 expression per cell remained higher in the treated patient group (P = 0.02), pointing to the persistence of abnormal immune activation in treated patients. The function of cTfh, analyzed by the capacity to promote IgG secretion in cocultures with autologous memory B cells, did not show major differences between groups in terms of total IgG production but proved significantly more efficient in the controller group when measuring HIV-specific IgG production. The frequency of Tet+ cTfh correlated with HIV-specific IgG production (R = 0.71 for Gag-specific and R = 0.79 for Env-specific IgG, respectively). Taken together, our findings indicate that key cTfh-B cell interactions are preserved in controlled HIV infection, resulting in potent memory B cell responses that may play an underappreciated role in HIV control.IMPORTANCE The rare patients who spontaneously control HIV replication in the absence of therapy provide a unique model to identify determinants of an effective anti-HIV immune response. HIV controllers show signs of particularly efficient antiviral T cell responses, while their humoral response was until recently considered to play only a minor role in viral control. However, emerging evidence suggests that HIV controllers maintain a significant but "silent" antiviral memory B cell population that can be reactivated upon antigenic stimulation. We report that cTfh help likely contributes to the persistence of controller memory B cell responses, as the frequency of HIV-specific cTfh correlated with the induction of HIV-specific antibodies in functional assays. These findings suggest that T follicular help may contribute to HIV control and highlight the need for inducing such help in HIV vaccine strategies that aim at eliciting persistent B cell responses.

[The Script Concordance Test: A multimodal teaching tool]. / Le test de concordance de script : un outil pédagogique multimodal.

In recent years, there has been a major interest in assessing learners during their medical education. The core of medical competence is the clinical reasoning that should be acquired by all medical actors. Its assessment includes the ability to integrate and apply different types of knowledge, weigh critical evidence and think about the process used to have a diagnosis. French faculties of medicine will have to include it in the training and evaluation of students during 2017. It should therefore be part of the new docimological modalities of the computerized "Épreuves Classantes Nationales" from 2020 onwards. In this article, we did a specific review of the literature concerning the theoretical foundations, methodology and use of Script Concordance Test (SCT) in the field of health. To do so, we used the PubMed, EMBASE and PsycINFO databases and selected articles in English and French language using the following keywords alone or in combination: script, concordance, script concordance test, medical studies, validity, fidelity, psychometric properties. We have found 62 articles that matched our search. Built on a well-targeted methodology, the SCT is a reliable and valid pedagogical tool. It can discriminate the levels of practice between medical students, residents and medical doctors, evaluate the progression and skills of clinical reasoning. It can be administered online, in multicentric centers, at a national or international level. There are, however, limitations that teachers must take into account.