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.