Le syndrome des anti-synthétases (SAS) est une maladie auto-immune systémique associée à la présence d’anticorps anti-ARNt synthétase, essentiellement anti-Jo1, PL7 et PL12. Il peut être limité à un organe et touche le poumon dans environ 75 % des cas. L’atteinte pulmonaire et sa sévérité conditionnent le pronostic et le traitement. Le traitement est basé sur la corticothérapie à forte dose qui est efficace pour induire la rémission mais les rechutes surviennent dans environ 50 % en cas de monothérapie, et l’ajout d’un immunosuppresseur d’emblée a montré un bénéfice sur la survie et la réduction des rechutes. Les immunosuppresseurs les plus fréquemment utilisés sont l’azathioprine (AZA), le mycophénolate mofétil (MMF), le méthotrexate (MTX), le tacrolimus (TAC), le rituximab (RTX) et le cyclophosphamide (CYC). Les CAR-T (Chimeric Antigen Receptor T) cells et anticorps bispécifiques sont des traitements innovants prometteurs. Les anti-fibrosants peuvent être utilisés en cas de fibrose pulmonaire progressive. Cependant il n’y a pas de recommandation thérapeutique dédiée au SAS, les données étant essentiellement basées sur des études rétrospectives ou extrapolées à partir d’essais cliniques incluant des patients atteints de myopathie inflammatoire ou de pneumopathie interstitielle diffuse associée aux connectivites. Cette mise au point vise à synthétiser les données existantes d’efficacité et de tolérance des traitements dans le SAS, et à présenter un algorithme de traitement actualisé.

BACKGROUND AIMS:Systemic lupus erythematosus (SLE) is a rare and highly heterogeneous autoimmune disease in which standard treatment is based on corticosteroids and conventional or biological immunosuppressive drugs. In severe SLE patients (resistant to first- and second-line therapies), the 10-year mortality rate remains around 10-15%. Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has recently demonstrated sustained remission in this subset of SLE patients, but the number of treated patients remains low. The objective of this study was to assess the clinical practices (CPs) and various challenges in recruiting severe SLE patients eligible for CAR T-cell therapy. METHODS:A 1-year (February 2024 to February 2025) retrospective multicenter study was conducted across seven certified autoimmune disease reference centers. All adult SLE patients fulfilling the 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology criteria were screened for disease activity and severity according to the 2024 EBMT-International Society for Cell & Gene Therapy expert consensus. Eligibility for CAR T-cell or other non-cell and gene therapy trials and reasons for non-inclusion were analyzed. RESULTS:Among 1844 SLE patients screened over this 1-year retrospective study: 54 (2.9%) demonstrated severe disease criteria and, three (0.16 %) were ultimately treated by CAR- T while 49 were not selected for CAR T-cell trials because of either disease remission, lack of specific autoantibody, participation in other trials, physician/patient refusal or exclusion criteria at time of enrollment. CONCLUSIONS:Retrospective analysis of CPs showed that very few severe SLE patients were enrolled in the CAR T-cell trial despite eligibility criteria. Streamlined referral pathways, multidisciplinary coordination and improved physician education are needed to enhance access to advanced cell and gene therapies.

Anti-synthetase syndrome (ASS) is a systemic autoimmune disease associated with the presence of anti-aminoacyl tRNA synthetase antibodies, primarily anti-Jo1, PL7, and PL12. It may be limited to a single organ and involves the lungs in approximately 75% of cases. Pulmonary involvement and its severity determine both prognosis and treatment. Management relies on high-dose corticosteroid therapy, which is effective in inducing remission. Nevertheless, relapses occur in roughly 50% of cases with monotherapy by corticosteroid. The early addition of an immunosuppressant has demonstrated benefits in terms of survival and relapse reduction. The most commonly used immunosuppressants are azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), tacrolimus (TAC), rituximab (RTX), and cyclophosphamide (CYC). Chimeric Antigen Receptor T (CAR-T) cells and bispecific antibodies are promising innovative therapies. Antifibrotic drugs can be used in cases of progressive pulmonary fibrosis. However, there are currently no dedicated treatment guidelines for ASS, as available data are mainly derived from retrospective studies or extrapolated from clinical trials including patients with inflammatory myopathy or connective tissue disease-associated interstitial lung disease. This review aims to synthesize existing data on the efficacy and safety of treatments in ASS and to present an updated treatment algorithm.

Background Systemic Lupus Erythematosus (SLE) is a rare and highly heterogeneous autoimmune disease (AD), where standard treatment is based on corticosteroids and conventional or biological immunosuppressive drugs. In severe SLE patients, resistant to 1st and 2nd line therapies, the 10-year mortality remains around 10-15%. Autologous anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy has recently demonstrated sustained remission in this subset of SLE patients, but real-word treated cases remain low. Objective To assess Clinical Practices (CPs) and the various challenges in recruiting severe SLE patients eligible for CAR-T cell therapy. Methods A one year retrospective multicenter study (February 2024–February 2025) was conducted across seven certified AD reference centers. All adult SLE patients fulfilling the 2019 EULAR/ACR criteria were screened for disease activity and severity according to the 2024 EBMT-ISCT expert consensus. Eligibility for CAR-T or other non-cell and gene (CGT) therapy trials and reasons for non-inclusion were analyzed. Results Among 1,844 SLE patients, 54 (2.9%) demonstrated severe disease criteria. Of these, 49 patients were not selected for CAR-T trials, due to either disease remission, lack of specific autoantibody, participation in other trials, physician/patient refusal or exclusion criteria at enrollment and three (1.8%) were ultimately treated. Conclusions Retrospective analysis of CPs showed that very few severe SLE patients were enrolled for CAR-T trial despite eligibility criteria. Streamlined referral pathways, multidisciplinary coordination, and improved physician education are needed to enhance access to advanced CGT therapies. Keywords : CAR-T cell; SLE; Lupus; Cell and Gene therapy (CGT) Acknowledgements “This work was supported as part of the national plan for rare diseases by the French Ministry of Health, FAI2R”

PURPOSE:Paraneoplastic fever (PF) is an exclusion diagnosis that affects around 10% of patients in oncology, combining fever of unknown origin and the presence of cancer. There is no consensus or guidelines in the literature about the minimum criteria required for the diagnosis of (PF). The objective of this survey was to select clinical and paraclinical criteria to establish the diagnosis of PF. METHODS:After a review of the literature, 23 categories and 48 items were set up in an online survey. A two-round Delphi questionnaire survey was carried out from May to August 2021 with the participation of experts in several specialties in France and abroad. RESULTS:Thirty-seven and 33 experts responded in the first and second rounds respectively. Nine items obtained consensus. Among them, the need to rule out suspected infection by a directed bacteriological statement, an up-to-date imaging and doppler ultrasound of the lower limbs was highly consensual. No biological criteria were retained. Thirty-six propositions did not reach consensus and five were considered useless in this setting. CONCLUSION:The 9 selected criteria confirm the importance to eliminating differential fever aetiologies whereas no specific clinical or biological markers were retained. This survey constitute the first consensus of experts in this field.

Extubation failure leading to reintubation is associated with high mortality. In patients at high-risk of extubation failure, clinical practice guidelines recommend prophylactic non-invasive ventilation (NIV) over high-flow nasal oxygen (HFNO) immediately after extubation. However, the physiological effects supporting the beneficial effect of NIV have been poorly explored. We hypothesized that NIV may reduce patient inspiratory efforts to a greater extent than HFNO after extubation. In a prospective physiological study, patients at high-risk of extubation failure (> 65 years old or underlying cardiac or respiratory disease) were included to receive after planned extubation prophylactic NIV and HFNO in a randomized crossover order, followed by standard oxygen. Inspiratory efforts were assessed by calculation of the simplified esophageal pressure–time-product per minute (sPTPes in cmH2O s/min). Tidal volumes, distribution and homogeneity of ventilation were estimated using electrical impedance tomography. Twenty patients were retained in the analysis. Inspiratory efforts were lower with NIV than with HFNO (sPTPes 196 cm H2O s/min [116–234] vs. 220 [178–327], p < 0.001) whereas tidal volumes were larger with NIV than with HFNO (8.4 mL/kg of predicted body weight [6.7–9.9] vs. 6.9 [5.3–8.6], p = 0.005). There was a non-significant increase in dorsal region ventilation under NIV compared to HFNO. In patients at high-risk of extubation failure, prophylactic NIV significantly decreased inspiratory efforts with increased tidal volumes compared to HFNO. The clinical benefits of NIV to prevent reintubation in patients at high-risk may be mediated by these physiological effects. Trial registration Clinicaltrials.gov: ID NCT04036175), retrospectively registered 17 June 2019.

First-line treatments of autoimmune systemic diseases (ARD) are based on the use of various types of immunosuppressive or immunomodulatory drugs, either alone or in association, according to standardized reference protocols. Prolonged use of these drugs in severe or refractory ARD is associated with high morbidity and increased mortality. Innovative cell therapies represent a new promising approach for patients with ARDs, with the recent clinical use of: a) mesenchymal stromal cells (MSCs), based on their immunomodulatory, antifibrotic and pro-angiogenic properties and b) Chimeric Antigen Receptors (CAR) T cell therapies T lymphocytes, where genetically modified expression of a chimeric antigen receptor (CAR-T cells). Therapeutic use of MSC or CAR-T cells, remains indications of exception in patients with severe ARDs resistant to prior standard therapies with new prerequisite and organisation of health-care pathways as compared to traditional drugs, not only for the Cell and Gene Therapy (CGT) product definition and delivery process, but also for the patient clinical management before and after administration of the CGT product. The aim of this workshop under the auspices of the French Speaking Society of Bone Marrow and Cell transplantation (SFGM-TC) working group on autoimmune diseases (MATHEC) is to describe: a) the prerequisite for French hospitals to set-up the specific health-care pathways for MSC or CART therapy in ARDs patients, in accordance with regulatory and safety needs to perform academic or industry sponsored clinical trials, and b) the care-pathway for ARD patients treated with CGT, highlighting the importance of working in tandem between the ARD and the CAR-T cell specialist all along the indication, procedures and follow-up of ARDs. Patient safety considerations are central to guidance on patient selection to be validated collectively at the multidisciplinary team meeting (MDTM) based on recent (less than 3 months) thorough patient evaluation. MSC and CAR-T procedural aspects and follow-up are then carried out within appropriately experienced and SFGM-TC accredited centres in close collaboration with the ADs specialist.

Background Patients with systemic lupus erythematosus (SLE) with inadequate responses to standard therapies have unmet therapeutic needs. The immunomodulatory, proangiogenic, and antifibrotic properties of mesenchymal stromal cells support their use in treating patients with SLE. We aimed to assess the safety of a single intravenous infusion of allogeneic umbilical cord-derived mesenchymal stromal cells in patients with severe SLE. Methods This prospective, single-centre, open-label, dose-escalation, Bayesian phase 1 study was done at the SaintLouis University Hospital (Paris, France). Eligible patients were aged 18-70 years, were diagnosed with SLE according to American College of Rheumatology criteria with positive antinuclear antibodies, had a baseline Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score of 6 or more, and had disease that was refractory to first and second line SLE therapies. Patients were to receive a single intravenous infusion of 1 x 106, 2 x 106, or 4 x 106 umbilical cord-derived mesenchymal stromal cells per kg (manufactured from a single umbilical cord) in cohorts of five patients per dose, starting at 2 x 106 cells per kg. The primary endpoint was the rate of treatment-related severe adverse events (grade >= 3) in the first 10 days after infusion of umbilical cord-derived mesenchymal stromal cells. People with lived experience were involved in study design, patient enrolment, and dissemination of the study findings. This study is registered with ClinicalTrials.gov, NCT03562065, and the EU Clinical Trials Register, EudraCT2017-001400-29. Findings From May 14, 2019, to March 6, 2023, 29 patients were screened for eligibility, eight of whom were enrolled in the study. Enrolment was terminated early after inclusion of eight patients and no patients received the 1 x 106 dose of umbilical cord-derived mesenchymal stromal cells. Seven (88%) of eight participants were cisgender women and one (13%) was a cisgender man. The median age was 35 years (range 26-57) and the median SLE disease duration was 12 years (5-19). All patients received at least 2 x 106 cells per kg (range 2 x 106 to 4 x 106). No severe adverse events and three infusion-related adverse events (two grade 1 and one grade 2) occurred in two patients in the first 10 days after infusion. After 124 months (range 12-13) of follow-up, no treatment-related severe adverse events and three non-treatment-related severe adverse events occurred in one patient after relapse. Interpretation Our results suggest that a single infusion of 2 x 106 cells per kg or 4 x 106 cells per kg of allogeneic umbilical cord-derived mesenchymal stromal cells was safe in patients with severe SLE. Placebo-controlled trials are needed to confirm clinical efficacy and the role of B-cell modifications in clinical benefit. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Dans une démarche visant à uniformiser les procédures d’allogreffe et d’autogreffe de cellules hématopoïétiques, la Société francophone de greffe de moelle et thérapie cellulaire (SFGM-TC) a organisé les treizièmes ateliers d’harmonisation des pratiques en septembre 2022 à Lille. L’objectif de cet atelier est de mettre à jour les protocoles de mobilisation et conditionnement pour les greffes de cellules souches hématopoïétiques autologues dans les maladies auto-immunes, et de préciser les contre-indications à la greffe, les critères de choix du conditionnement, les modalités d’arrêt des traitements avant mobilisation et les surveillances spécifiques à mettre en œuvre selon le type de maladie auto-immune.

Introduction Nous rapportons un cas de vascularite cérébrale liée à une méningite à éosinophiles avec hyperéosinophilie sanguine chez un patient asthmatique et la discussion entre deux diagnostics différentiels rares. Observation Un patient âgé de 63 ans est hospitalisé pour des crises d’épilepsie focales brachio-faciales gauches. Il présente une parésie du membre supérieur gauche. Ses antécédents comprennent un asthme diagnostiqué un an auparavant. Le bilan biologique montre une hyperéosinophilie sanguine jusqu’à 2,5G/L, une méningite avec 69 éléments/mm3 dont 38 % d’éosinophiles et une protéinorachie supérieure à 6g/L. L’IRM cérébrale initiale révèle des plages en hypersignal FLAIR pariétales et pariéto-occipitales droites, avec des lésions ischémiques punctiformes corticales associées à un aspect d’hémosidérose et de leptoméningite dans ces mêmes régions. L’évolution clinique est péjorative avec sur quelques semaines une détérioration cognitive et des troubles de la vigilance. L’IRM cérébrale à un mois montre une majoration globale des lésions méningées et parenchymateuses. Le bilan paraclinique a permis d’éliminer une cause dysimmune, infectieuse ou tumorale notamment une hémopathie maligne. La biopsie durale n’a pas été contributive. Le diagnostic retenu est une vascularite secondaire à un syndrome hyperéosinophilique idiopathique. Une corticothérapie à fortes doses est suivie d’une normalisation rapide du taux d’éosinophiles sanguins, d’une diminution de l’activité radiologique et d’une amélioration clinique partielle. Discussion La co-occurrence d’une vascularite cérébrale et d’une hyperéosinophilie sanguine chez un patient asthmatique nous fait d’abord suspecter une granulomatose éosinophilique avec polyangéite. Cependant, l’absence d’élévation de la CRP, la négativité des ANCA et l’absence d’autre signe systémique nous orientent vers le diagnostic rare de vascularite cérébrale compliquant un syndrome hyperéosinophilie idiopathique. Conclusion Cette observation fait discuter deux entités syndromiques rares, pourvoyeuses de vascularites cérébrales graves, importantes à différencier pour proposer une thérapeutique adaptée.

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 13th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures in September 2022 in Lille, France. The aim of this workshop is to update the mobilization and conditioning protocols for autologous hematopoietic stem cell transplantation for autoimmune diseases, and to specify contraindications for transplant, conditioning regimen selection, immunosuppressive treatment discontinuation before mobilization and disease-specific surveillance.

Le traitement de première intention des maladies auto-immunes systémiques repose sur l’utilisation de différents types de médicaments immunosuppresseurs ou immunomodulateurs, utilisés seuls ou en association, selon des schémas standardisés dits de référence. Leur utilisation prolongée, lorsque la maladie auto-immune est réfractaire aux traitements de référence, est associée à une morbidité et une mortalité élevées. Plus récemment, l’utilisation de médicaments de thérapies innovantes, dont l’effet thérapeutique est médié par des cellules génétiquement modifiées ou non, constitue une approche prometteuse pour le traitement des maladies auto-immunes, notamment : a) les cellules stromales mésenchymateuses aux propriétés immunomodulatrices, antifibrosantes et pro-angiogéniques et b), les lymphocytes T génétiquement modifiés pour exprimer un récepteur chimérique à l’antigène (CAR-T cells) permettant de cibler et d’éliminer des lymphocytes B autoréactifs, et de rétablir la tolérance dans les organes affectés. L’utilisation des thérapies cellulaires innovantes, cellules stromales mésenchymateuses ou CAR-T, dans des indications d’exception chez des patients atteints de maladies auto-immunes systémiques sévères résistantes aux traitements classiques soulève des questions essentielles par rapport aux médicaments traditionnels, dans la définition des circuits de production et de délivrance, mais aussi dans la prise en charge clinique et le suivi des patients traités. Le présent atelier avait pour but : a) d’identifier les prérequis permettant aux hôpitaux français de s’organiser efficacement pour répondre aux sollicitations de promoteurs d’essais cliniques visant à évaluer l’utilisation des cellules stromales mésenchymateuses ou des CAR-T cells dans les maladies auto-immunes et b) de détailler chaque étape du parcours de soins des patients traités par médicaments de thérapies innovantes pour leur maladie auto-immune, en soulignant le rôle fondamental d’un binôme spécialiste de la maladie et spécialiste en thérapie cellulaire innovante. Les considérations relatives à la sécurité des patients sont primordiales pour la sélection des patients, qui doit être validée collectivement en réunion de concertation pluridisciplinaire, sur la base d’une évaluation détaillée clinique et paraclinique récente (moins de trois mois) du patient. La procédure de traitement par cellules stromales mésenchymateuses et CAR-Tcells et le suivi des patients sont effectués dans des centres accrédités par la SFGM-TC, en étroite collaboration avec les spécialistes des maladies auto-immunes considérées.

BACKGROUND:Polyclonal hypergammaglobulinaemia (PH) represents a classic diagnosis problem in internal medicine. However, there is no consensus threshold for PH. The aim of this study was to define a threshold for PH.METHODS:We conducted a retrospective multicentric study using laboratory biological databases between 1 January 2016 and 31 December 2016 in two university hospitals and one non-university hospital. All patients 18 years old or over and with at least one serum protein electrophoresis (SPE) available in 2016 were included. Exclusion criteria were monoclonal, biclonal, or oligoclonal spikes or, in case of hypogammaglobulinaemia, proven free light chain gammopathy. The main endpoint was to define the threshold values for PH in this population. Another objective was to define the 95th percentile of the distribution.RESULTS:20 766 SPEs were included in this cohort. The PH threshold on 95th percentile was 18.9 g/L. The threshold varied according to geographical areas.CONCLUSIONS:This is the first study to scientifically define a PH threshold. The main limitation is that our threshold is only biological. The study was not designed to associate this threshold with a clinically active disease. In conclusion, while the 19 g/L cut-off seems the most relevant threshold, but it will need to be validated by prospective studies.

Objectives To describe the clinical and pathological features of biopsy-proven cutaneous vasculitis (CV) associated with SLE, focusing on diagnosis classification and impact on overall SLE activity. Methods Retrospective multicentric cohort study including SLE patients with biopsy-proven CV identified by (i) data from pathology departments of three university hospitals and (ii) a national call for cases. SLE was defined according to 1997 revised ACR and/or 2019 ACR/EULAR criteria. CV diagnosis was confirmed histologically and classified by using the dermatological addendum of the Chapel Hill classification. SLE activity and flare severity at the time of CV diagnosis were assessed independently of vasculitis items with the SELENA-SLEDAI and SELENA-SLEDAI Flare Index. Results Overall, 39 patients were included; 35 (90%) were female. Cutaneous manifestations included mostly palpable purpura (n = 21; 54%) and urticarial lesions (n = 18; 46%); lower limbs were the most common location (n = 33; 85%). Eleven (28%) patients exhibited extracutaneous vasculitis. A higher prevalence of Sjogren's syndrome (51%) was found compared with SLE patients without CV from the French referral centre group (12%, P < 0.0001) and the Swiss SLE Cohort (11%, P < 0.0001). CV was mostly classified as urticarial vasculitis (n = 14, 36%) and cryoglobulinaemia (n = 13, 33%). Only 2 (5%) patients had no other cause than SLE to explain the CV. Sixty-one percent of patients had inactive SLE. Conclusion SLE-related vasculitis seems very rare and other causes of vasculitis should be ruled out before considering this diagnosis. Moreover, in more than half of patients, CV was not associated with another sign of active SLE.

BACKGROUND: Sleep deprivation alters respiratory muscle performance and may precipitate respiratory failure. This study aimed to assess sleep in subjects admitted to ICU for acute hypoxemic respiratory failure and its role in the risk of intubation. METHODS: This was a prospective observational single-center cohort study including subjects admitted to ICU for de novo acute hypoxemic respiratory failure defined as breathing frequency ≥ 25 breaths/min or clinical signs of respiratory distress and PaO2/FIO2 < 300 mm Hg while receiving high-flow nasal oxygen. Subjects with altered consciousness, central nervous or psychiatric disorders, continuous sedation or neuroleptic medication, or were uncooperative were excluded. Sleep was assessed by complete polysomnography (PSG) the night following ICU admission. The main outcome was to assess sleep among subjects with acute hypoxemic respiratory failure and to compare sleep between subjects who eventually required intubation to those who did not. RESULTS: Over a 24-month inclusion period, 34 subjects had complete PSG, among whom 5 (15%) required intubation in the ICU. Total sleep time was 4.2 h in median (interquartile range 2.9–6.8); deep-sleep duration was 70 min (34–127), and rapid eye movement (REM) sleep duration was 9 min (0–28). Among them, 13 subjects (38%) had no REM sleep. Total sleep time and duration of deep and REM sleep stages did not differ between subjects who required intubation and those successfully treated with high-flow nasal oxygen. CONCLUSIONS: Whereas total sleep time remained relatively preserved in critically ill subjects with acute hypoxemic respiratory failure, REM sleep time was uncommon or completely absent in a large number of subjects. Sleep did not differ between subjects who required intubation and those who did not. However, given a trend toward an increased risk of intubation in subjects with a complete absence of REM sleep, further studies are needed to better explore the impact of REM sleep on the risk of intubation.

Data on venous thromboembolic events (VTEs) in patients receiving immune checkpoint inhibitors (ICIs) are scarce and conflicting. This study investigated the risk of reporting VTEs associated with ICIs in comparison with all other anticancer drugs. The World Health Organization pharmacovigilance database (VigiBase), comprising >30 million individual case safety reports, was queried. All reports on patients with cancer, involving at least one anticancer drug as a suspect or interacting drug and registered from January 1, 2008, to May 31, 2021, were included. The association between ICIs and the risk of reporting VTEs was estimated using the reporting odds ratio (ROR) as a measure of disproportionality with all other anticancer drugs as comparators. RORs were estimated as crude and adjusted RORs for age, sex, and other medications (excluding anticancer drugs) associated with risk of VTEs. Among 1,196 patients experiencing VTEs after ICI treatment, the median age was 65 years and 57.6% were men. Anti-PD-1 agents (62.5%) were the most frequently reported. ICIs were not associated with higher reporting of VTEs when compared with other anticancer drugs (crude ROR 0.63, 95% confidence interval (CI) 0.60 to 0.67 and adjusted ROR 0.70, 95% CI 0.65-0.74). No signal of disproportionate reporting was found when considering each class of ICIs. In conclusion, ICIs were not associated with higher reporting of VTEs, in comparison with all other anticancer drugs in a large-scale pharmacovigilance database. Owing to the limitations inherent to pharmacovigilance studies, prospective studies, including an adequate comparison group, are needed to assess the risk of VTEs in ICI-treated patients.

Immune checkpoint inhibitors (ICIs) have become the standard of care for several types of cancer due to their superiority in terms of survival benefits in first- and second-line treatments compared to conventional therapies, and they present a better safety profile (lower absolute number of grade 1–5 adverse events), especially if used in monotherapy. However, the pattern of ICI-related adverse events is totally different, as they are characterized by the development of specific immune-related adverse events (irAEs) that are unique in terms of the organs involved, onset patterns, and severity. The decision to resume ICI treatment after its interruption due to irAEs is challenged by the need for tumor control versus the risk of occurrence of the same or different irAEs. Studies that specifically assess this point remain scarce, heterogenous and mostly based on small samples of patients or focused only on the recurrence rate of the same irAE after ICI resumption. Moreover, patients with grade ≥3 irAEs were excluded from many of these studies. Herein, we provide a narrative review on the field of safety of ICI resumption after interruption due to irAE(s).

Immune checkpoint inhibitor (ICI)-related cytopenias have been poorly described. This study aimed to further characterize ICI-related cytopenias, using the French pharmacovigilance database. All grade ≥ 2 hematological adverse drug reactions involving at least one ICI coded as suspected or interacting drug according to the World Health Organization criteria and reported up to 31 March 2022, were extracted from the French pharmacovigilance database. Patients were included if they experienced ICI-related grade ≥ 2 cytopenia. We included 68 patients (75 ICI-related cytopenias). Sixty-three percent were male, and the median age was 63.0 years. Seven patients (10.3%) had a previous history of autoimmune disease. Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) were the most frequently reported (50.7% and 25.3%, respectively). The median time to onset of ICI-related cytopenias was 2 months. Nearly half were grade ≥ 4, and three patients died from bleeding complications of refractory ITP and from thromboembolic disease with active AIHA. Out of 61 evaluable responses, complete or partial remission was observed after conventional treatment in 72.1% of ICI-related cytopenias. Among the 10 patients with ICI resumption after grade ≥ 2 ICI-related cytopenia, three relapsed. ICI-related cytopenias are rare but potentially life-threatening. Further studies are needed to identify risk factors of ICI-related cytopenias.

BACKGROUND: Whereas high-flow nasal cannula (HFNC) oxygen therapy is increasingly used in patients with exacerbation of COPD, the effectiveness of β2 agonist nebulization through HFNC has been poorly assessed. We hypothesized that salbutamol vibrating-mesh nebulization through HFNC improves pulmonary function tests in subjects with COPD. METHODS: We conducted a physiological crossover study including subjects admitted to the ICU for severe exacerbation of COPD. After subject improvement allowing a 3-h washout period without bronchodilator, pulmonary function tests were performed while breathing through HFNC alone and after salbutamol vibrating-mesh nebulization through HFNC. The primary end point consisted in the changes in FEV1 before and after salbutamol nebulization. Secondary end points included the changes in FVC, peak expiratory flow (PEF), airway resistance, and clinical parameters. RESULTS: Among the 15 subjects included, mean (SD) FEV1 significantly increased after salbutamol nebulization from 931 mL (383) to 1,019 (432), mean difference +87 mL (95% CI 30–145) (P = .006). Similarly, FVC and PEF significantly increased, +174 mL (95% CI 66–282) (P = .004) and +0.3 L/min (95% CI 0–0.6) (P = .037), respectively. Airway resistances and breathing frequency did not significantly differ, whereas heart rate significantly increased after nebulization. CONCLUSIONS: In subjects with severe exacerbation of COPD, salbutamol vibrating-mesh nebulization through HFNC induced a significant bronchodilator effect with volume and flow improvement.