NK cell compartment in the peripheral blood and spleen in adult patients with primary immune thrombocytopenia.

Immune thrombocytopenic purpura (ITP) is a disease characterized by antibody-mediated platelet destruction. The T- and B-cell subsets have been extensively studied in primary ITP, but the NK cell compartment has been less thoroughly explored. We investigated the NK cell receptor repertoire and the functionality of NK cells in the peripheral blood and spleen in patients with primary ITP. An immunophenotypic analysis of peripheral blood lymphocytes from patients revealed that the numbers of CD19+ B lymphocytes, CD4+ and CD8+ T lymphocytes and CD3-CD56+ NK cells were within the normal range. No major alteration to the expression of distinct inhibitory or activating NK cell receptors was observed. The functionality of NK cells, as evaluated by their ability to degranulate in conditions of natural cytotoxicity or antibody-dependent cell cytotoxicity (ADCC), was preserved in these patients. By contrast, these stimuli induced lower levels of IFNγ production by the NK cells of ITP patients than by those of healthy controls. We then compared the splenic NK cell functions of ITP patients with those of cadaveric heart-beating donors (CHBD) as controls. The splenic NK cells of ITP patients tended to be less efficient in natural cytotoxicity conditions and more efficient in ADCC conditions than control splenic NK cells. Finally, we found that infusions of intravenous immunoglobulin led to the inhibition of NK cell activation through the modulation of the interface between target cells and NK cells.

Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects.

OBJECTIVES: The aim of this study was to investigate whether the quadrivalent human papillomavirus (HPV) vaccine Gardasil is associated with a change in the risk of autoimmune disorders (ADs) in young female subjects. DESIGN: Systematic case-control study of incident ADs associated with quadrivalent HPV vaccination in young women across France. PARTICIPANTS AND SETTING: A total of 113 specialised centres recruited (from December 2007 to April 2011) females aged 14-26 years with incident cases of six types of ADs: idiopathic thrombocytopenic purpura (ITP), central demyelination/multiple sclerosis (MS), Guillain-Barré syndrome, connective tissue disorders (systemic lupus erythematosus, rheumatoid arthritis/juvenile arthritis), type 1 diabetes mellitus and autoimmune thyroiditis. Control subjects matched to cases were recruited from general practice. ANALYSIS: Multivariate conditional logistic regression analysis; factors included age, geographical origin, smoking, alcohol consumption, use of oral contraceptive(s) or vaccine(s) other than Gardasil received within 24 months before the index date and personal/family history of ADs. RESULTS: Overall, 211 definite cases of ADs were matched to 875 controls. The adjusted odds ratio (OR) for any quadrivalent HPV vaccine use was 0.9 [95% confidence interval (CI) 0.5-1.5]. The individual ORs were 1.0 (95% CI 0.4-2.6) for ITP, 0.3 (95% CI 0.1-0.9) for MS, 0.8 (95% CI 0.3-2.4) for connective disorders and 1.2 (95% CI 0.4-3.6) for type 1 diabetes. No exposure to HPV vaccine was observed in cases with either Guillain-Barré syndrome or thyroiditis. CONCLUSIONS: No evidence of an increase in the risk of the studied ADs was observable following vaccination with Gardasil within the time periods studied. There was insufficient statistical power to allow conclusions to be drawn regarding individual ADs.

[Messages from the estates general on French internal medicine]. / Que retenir des états généraux de la médecine interne française ?

Internal medicine is a medical specialty that is often poorly understood by the general public and sometimes misidentified. In an era of increasing subspecialization and high technicality, it is characterized by a comprehensive approach centered on clinical evaluation. Unlike what is observed in most developed countries, where systemic autoimmune diseases are managed by organ specialists based on their mode of presentation, French internists are at the forefront for diagnosing and managing these diseases. Their multidisciplinary training gives them legitimacy to justify this role. Internists also play a crucial role in the management of patients requiring unplanned hospitalizations downstream from emergency departments and in connection with primary care. Internists primarily practice in a hospital setting, with a specific position in the French healthcare system aligned with the training frameworks of all medical specialties. To better define internal medicine, its role in care activities, as well as in education and research, internists organized a General Assembly of internal medicine that took place on September 28, 2023, in Paris. Structured around think tanks focusing on care, education, and research activities, the general assembly aimed to improve visibility on internal medicine and internists. This article recounts the discussions that animated this meeting and highlights the main ideas that emerged. These general assemblies constitute a foundational step and will be followed by a Consultation Conference in order to better identify and promote internal medicine and internists, regardless of their types and places of practice.

Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry.

OBJECTIVE: The risk of severe infection is a crucial factor in the assessment of the short-term risk:benefit ratio of biologic drugs in rheumatoid arthritis (RA). There is no increase in severe infections in RA patients treated with rituximab (RTX) in controlled trials, but this has not yet been assessed in daily practice. We undertook this study to investigate the occurrence of and risk factors for severe infections in off-trial patients using data from the AutoImmunity and Rituximab (AIR) registry. METHODS: The AIR registry was set up by the French Society of Rheumatology. The charts of patients with severe infections were reviewed. RESULTS: Of the enrolled patients, 1,303 had at least 1 followup visit at 3 months or later, with a mean ± SD followup period of 1.2 ± 0.8 years (1,629 patient-years). Eighty-two severe infections occurred in 78 patients (5.0 severe infections per 100 patient-years), half of them in the 3 months following the last RTX infusion. Multivariate analysis showed that chronic lung disease and/or cardiac insufficiency (odds ratio 3.0 [95% confidence interval 1.3-7.3], P = 0.01), extraarticular involvement (odds ratio 2.9 [95% confidence interval 1.3-6.7], P = 0.009), and low IgG level (<6 gm/liter) before initiation of RTX treatment (odds ratio 4.9 [95% confidence interval 1.6-15.2], P = 0.005) were significantly associated with increased risk of a severe infection. CONCLUSION: The rate of severe infections in current practice is similar to that reported in clinical trials. The risk factors for severe infections include chronic lung and/or cardiac disease, extraarticular involvement, and low IgG before RTX treatment. This suggests that serum IgG should be checked and the risk:benefit ratio of RTX discussed for patients found to have low levels of IgG.

Rituximab and immune thrombocytopenia in adults: The state of knowledge 20 years later.

Rituximab has been used for immune thrombocytopenia (ITP) for almost 20 years and is now considered a valid off-label second-line treatment. About 60% to 70% of patients with ITP show initial response to rituximab, but in half of these patients, the disease will eventually relapse. Therefore, in 30% of patients with persistent or chronic ITP, one course of rituximab at 375 mg/m2/week for 4 weeks or 2 fixed 1000-mg rituximab infusions allows for a sustained response rate at 5 years. Unfortunately, to date, no robust predictor of long-term sustained response has been found to assist the physician in deciding to treat with rituximab on an individual basis, and the choice of rituximab or another second-line treatment must be individualized and shared with the patient. Retreatment with rituximab has been found efficient, with a similar or higher magnitude and duration of response in most patients. Rituximab is usually well tolerated, with mainly mild and easily manageable infusion-related adverse events. Severe infections are uncommon, including in the long-term, and occur in patients with at least another contributing factor in more than two thirds. Several issues remain to be resolved. Indeed, head-to-head comparisons with other and new treatments in ITP and robust predictors of long-term response are urgently needed to better determine the position of rituximab in the therapeutic armamentarium for adult ITP. Additionally, the place of combination therapies, maintenance therapy with rituximab and rituximab in newly-diagnosed ITP deserve additional studies.

[Adult immune thrombocytopenia and thrombopoietin receptor agonist: Ten years later]. / Agonistes du récepteur de la thrombopoïétine et purpura thrombopénique immunologique de l'adulte : où en sommes-nous 10 ans après ?

Ten years after their licence in France, the use of the two thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, has deeply modified the landscape of immune thrombocytopenia (ITP) treatment. In this review, we summarise data on efficacy and safety of these treatments during ITP, as well as their use in clinical practice. Their place in therapeutic strategy, the recent description of persistant remission after discontinuation of TPO-RA, and future new thrombopoietic agents are also discussed. Their use has progressively increased and early use at a newly diagnosed stage of the disease is under evaluation. However physician have to keep in mind that thromboembolism rates appear to be higher with TPO-RA treatment in ITP patients at high risk of thrombosis, and that data from "real-life" studies with very long term follow up are not available. Finally, the cost of these treatments should also be evaluated in future therapeutic strategies comparisons.

[Challenges and potential solutions in first-line treatments for immune thrombocytopenia in adults]. / Traitements de première ligne au cours du purpura thrombopénique immunologique de l'adulte : état des lieux et perspectives.

The first line treatment of immune thrombocytopenic purpura (ITP) is well established and based on short course of corticosteroids associated with intravenous immunoglobulins (IVIg) for the most severe forms. Predniso(lo)ne is the corticosteroid agent usually given but dexamethasone appears as an alternative. Some guidelines recommend to use dexamethasone as first line when a rapid increase of platelet count is required. Dexamethasone could be used rather than IVIg for moderate to severe but non life-threatening bleeding manifestations. Other therapeutic options such as anti FcRn monoclonal antibodies or recombinant FcγR currently in development for ITP could be an option in the future. In newly diagnosed ITP, we unfortunately lack robust predictive risk factors of severity and chronic outcome. Identifying such factors could be helpful for considering the early use of some treatments which are commonly used as second or third line.

[Association between psychiatric comorbidities and hospital length of stay in post-emergency internal medicine patients]. / Association des comorbidités psychiatriques avec la durée de séjour des patients en médecine interne d'aval des urgences.

INTRODUCTION: Patients with psychiatric disorders suffer from a higher rate of somatic disorders than those without psychiatric disorder, often inappropriately managed. Our study aimed to describe patients with psychiatric comorbidity in post-emergency internal medicine units and to compare their length of hospital stay to patients without psychiatric disease. METHODS: This French cross sectional study used the data warehouse of the greater Paris hospitals. It included, all patients hospitalized through the emergency department in 9 internal medicine departments during the year 2017. Psychiatric disorders and the burden of somatic disorders (Charlson score) were determined through diagnostic coding. Charlson score and hospital length of stay were compared between patients with and without psychiatric comorbidity. RESULTS: In total, 8981 hospital stays (8001 patients) were included, 1867 (21%) with psychiatric comorbidity. After adjusting for age, gender, hospital and main diagnosis, the Charlson score was on average 0.68 higher in the psychiatric comorbidity group (P<0.001) and the length of hospital stay was 30% higher after further adjustment on the Charlson score (P<0.001). These differences were consistent for each main diagnosis. CONCLUSION: Patients with psychiatric comorbidity are frequent in post-emergency internal medicine wards. They experience longer hospital stays, only partly related with a higher burden of somatic disorders. Special attention should be paid to this vulnerable population.

[Immune thrombocytopenic purpura: pathophysiology and treatment]. / Purpura thrombopénique immunologique: physiopathologie et traitement.

Immune thrombopenic purpura (ITP) is an autoimmune disease characterized by a peripheral destruction of platelets. B lymphocytes play a key role but pathophysiology is more complex, involving humoral and cellular immunity associated with an inappropriate platelet production. The treatment of ITP is still based on uncontrolled studies. Prednisone and intravenous immunoglobulins remain the first line treatments. Splenectomy remains the best "curative" treatment for adults with chronic ITP. However, most patients are reluctant to undergo surgery and new treatments give promising results. Among them, rituximab and thrombopoietin receptor agonists could replace splenectomy in near future.

[Hemophagocytic lymphohistiocytosis with granulomatosis and diffuse T-cell infiltration associated with disseminated Nocardiosis and pulmonary infection due to Streptomyces spp]. / Syndrome d'activation macrophagique associé à une granulomatose et une infiltration lymphocytaire T CD4 diffuse révélant une nocardiose disséminée et une infection pulmonaire à Streptomyces spp.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome frequently secondary to infectious disease, especially in immuno-compromised patients. We report a HLH secondary to disseminated nocardiosis and Streptomyces spp pulmonary infection. CASE REPORT: A 69-years-old women had recent subcutaneous nodules of the forearms and loins associated with peripheral neuropathy and pulmonary nodule of the right upper lobe. Cutaneous biopsy revealed granuloma. Cutaneous lesions worsened and the patient developed a HLH with probable cardiac and neurological involvement, associated with cutaneous granulomatosis and diffuse polyclonal lymphocyte proliferation. Nocardia PCR was positive in cutaneous biopsy. Pulmonary samples revealed Streptomyces in culture and Nocardia in PCR. The evolution under antibiotic treatment was favorable. CONCLUSION: Recent diagnosis of HLH without obvious etiology should lead to etiological investigation, including the search for infections with slow-growing bacteria such as Nocardia or Streptomyces spp.

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.

[IgA-mediated auto-immune haemolytic anaemia revealing a hepatitis C virus infection]. / Anémie hémolytique auto-immune à Coombs IgA révélant une infection par le virus de l'hépatite C.

INTRODUCTION: Confirmation of autoimmune hemolytic anaemia usually relies on the detection of erythrocyte membrane-bound autoantibodies using a direct antiglobulin test. In the rare case of IgA autoantibodies-mediated autoimmune hemolytic anemia, the direct antiglobulin test can be negative, because routinely used polyspecific direct antiglobulin test reagents contain only anti-IgG and anticomplement antibodies. EXEGESIS: We report the case of a 41-year-old woman presenting a severe autoimmune hemolytic anaemia caused by the presence of warm autoantibodies of IgA type that revealed a chronic hepatitis C virus infection. CONCLUSION: A negative direct antiglobulin test does not completely rule out the diagnosis of autoimmune hemolytic anaemia especially in the rare case of IgA mediated immune hemolysis. The diagnosis strategy of autoimmune hemolytic anaemia associated with negative direct antiglobulin test and the potential links between autoimmune hemolytic anaemia and HCV are discussed.

Risk factors for bleeding, including platelet count threshold, in newly diagnosed immune thrombocytopenia adults.

Essentials Risk factors of bleeding in adult immune thrombocytopenia are not known. This multicenter study assessed risk factors of bleeding at immune thrombocytopenia onset. Platelet count thresholds associated with bleeding were < 20 × 109 L-1 and < 10 × 109 L-1 . Exposure to anticoagulants was a major risk factor of severe bleeding. SUMMARY: Background The aim of this cross-sectional study was to assess risk factors for bleeding in immune thrombocytopenia (ITP) adults, including the determination of platelet count thresholds. Methods We selected all newly diagnosed ITP adults included in the Cytopénies Auto-immunes Registre Midi-PyrénéEN (CARMEN) register and at the French referral center for autoimmune cytopenias. The frequencies of any bleeding, mucosal bleeding and severe bleeding (gastrointestinal, intracranial, or macroscopic hematuria) at ITP onset were assessed. Platelet count thresholds were assessed by the use of receiver operating characteristic curves. All potential risk factors were included in logistic regression models. Results Among the 302 patients, the frequencies of any, mucosal and severe bleeding were 57.9%, 30.1%, and 6.6%, respectively. The best discriminant threshold of platelet count for any bleeding was 20 × 109 L-1 . In multivariate analysis, factors associated with any bleeding were platelet count (< 10 × 109 L-1 versus ≥ 20 × 109 L-1 , odds ratio [OR] 48.2, 95% confidence interval [CI] 20.0-116.3; between 10 × 109 L-1 and 19 × 109 L-1 versus ≥ 20 × 109 L-1 , OR 5.2, 95% CI 2.3-11.6), female sex (OR 2.6, 95% CI 1.3-5.0), and exposure to non-steroidal anti-inflammatory drugs (NSAIDs) (OR 4.8, 95% CI 1.1-20.7). A low platelet count was also the main risk factor for mucosal bleeding. Exposure to anticoagulant drugs was associated with severe bleeding (OR 4.3, 95% CI 1.3-14.1). Conclusions Platelet counts of < 20 × 109 L-1 and < 10 × 109 L-1 were thresholds for major increased risks of any and mucosal bleeding. Platelet count, female sex and exposure to NSAIDs should be considered for assessment of the risk of any bleeding. Exposure to anticoagulant drugs was a major risk factor for severe bleeding.

[Thrombosis during thrombopoietin receptor agonist treatment for immune thrombocytopenia. A French multicentric observational study]. / Thromboses sous agonistes du récepteur de la thrombopoïétine au cours du purpura thrombopénique immunologique. Étude rétrospective multicentrique en France.

INTRODUCTION: Thrombopoietin-receptor agonists (TPO-RA) are marketed for immune thrombocytopenia (ITP). They have been associated to thrombosis occurrence in randomized controlled trials. However, the characteristics of these thromboses in the real-life practice as well as their management are poorly known. The objectives of this study were to determine the risk factors, circumstances and management of thrombosis occurring during exposure to TPO-RA in ITP. METHODS: We carried out a multicentre retrospective study in France. Moreover, all cases reported to the French pharmacovigilance system were also analyzed. RESULTS: Overall, 41 thrombosis (13 arterial) in 36 ITP patients (14 males and 22 females, mean age: 59 years) were recorded between January 2009 and October 2015. Twenty patients were treated with romiplostim, 15 with eltrombopag and 1 was treated by both medications. Thirty-three (92%) of the patients had another risk factor for thrombosis. Ten (28%) had an history of thrombosis and 13 (36%) received immunoglobulin in the month preceding the thrombotic event. Three had antiphospholipid antibodies; congenital low-risk thrombophilia was found in 4 cases; 18 patients (50%) were splenectomized. Median platelet count at the time of thrombosis was 172G/l (1-1049G/l). In 22 patients (56%), a good prognosis was associated with the thrombosis and was not linked with TPO-RA withdrawal. Bleeding events occurred in 14% of the patients treated with antiplatelet or anticoagulant drug, including 5% serious events (1 death of intracranial haemorrhage, 1 death of haemorrhagic shock). CONCLUSIONS: The thrombotic risk may be carefully assessed before starting TPO-RA in ITP patients. The impact of antiphospholipid antibodies and of congenital thrombophilia remains to be defined. Thrombosis evolution seems independent of TPO-RA management. Bleeding manifestations seem rare. Poor prognosis was mainly due to ischemic sequelae.

[Burkitt's lymphoma in a patient with systemic lupus erythematosus treated with immunosuppressive drugs. A case report]. / Lymphome de Burkitt au cours d'un lupus systémique traité par immunosuppresseurs. A propos d'un cas.

INTRODUCTION: Neoplasia and lymphoproliferative disorders are sometimes reported in patients with systemic lupus erythematosus (SLE). However, the pathophysiological link between lymphoma and SLE is still a matter of debate. We report a new case of Burkitt's lymphoma occurring in a patient treated with immunosuppressive drugs for SLE. CASE REPORT: A 38-year-old woman with SLE treated for 10 years with immunosuppressive drugs was admitted for the rapid onset of multiple neuritis with cranial nerves palsy, without extra-neurological involvement. The cerebrospinal fluid was normal. A bone marrow biopsy revealed Burkitt's lymphoma. CONCLUSION: This is the third case reported of Burkitt's lymphoma occurring in SLE. Here we discuss the data of the literature and the possible pathophysiological links between Burkitt's lymphoma and SLE.

[Calciphylaxis: a rare differential diagnosis of systemic vasculitis]. / La calciphylaxie: un diagnostic différentiel rare de vascularite systémique à ne pas méconnaître.

INTRODUCTION: Calciphylaxis is a rare phenomenon of medium- and small-vessel calcifications leading to cutaneous necrosis mimicking vasculitis. CASE REPORT: A 75 year-old-woman with chronic renal insufficiency was admitted for extensive cutaneous necrosis of the limb. Diagnosis of vasculitis was made, but inspite of corticosteroid therapy, the condition of the patient was worsening. After cutaneous biopsy, the diagnosis of calciphylaxis was established. CONCLUSION: Calciphylaxis must be suspected in cases of cutaneous necrosis occurring in a patient with chronic renal failure. Treatment requires rapid normalization of phosphocalcic balance. It is a condition with high mortality.

[Hepatosplenic localization of cat scratch disease: two cases in immunocompetent adult patients]. / Atteinte hépatosplénique de la maladie des griffes du chat : à propos de deux observations chez l'immunocompétent.

INTRODUCTION: Cat-Scratch Disease (CSD) is a well-recognized benign cause of localized lymphadenopathy, which often recovers spontaneously. However systemic clinical presentations are described in immunodeficient adults (bacillary angiomatosis, bacillary splenitis) and are less common in immunocompetent ones. EXEGESIS: We report two cases of disseminated CSD in immunocompetent patients, presenting hepatosplenic nodules, associated in the second case with an endocarditis. CONCLUSION: Bartonella serology must be achieved in case of hepatosplenic nodules with fever. Treatment of disseminated CSD in immunocompetent adults is still empirical and recovery can occur without antibiotherapy when endocarditis is not associated.