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ObjectiveRegulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential.AimWe aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases.MethodsWe performed a prospective, open-label, phase I–IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet’s disease, granulomatosis with polyangiitis, Takayasu’s disease, Crohn’s disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation.Resultsld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed.ConclusionThe dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases.Trial registration numberNCT01988506.

Sugiyama et al. recently described in “Latent class analysis of 216 patients with adult-onset Still’s disease,” baseline characteristics, laboratory tests, treatment, relapse, and death of adult-onset Still’s disease (AOSD) patients from a Japanese hospital. They identified two subgroups: Class 1 ( n =155) with a younger age and typical symptoms of AOSD and Class 2 ( n =61) with older patients and fewer typical symptoms of AOSD. In 2022, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, an established X-linked disease associated with a somatic mutation in UBA1 , is considered as a differential diagnosis for AOSD particularly in elderly. These patients from Class 2 could benefit from more explorations for mild myelodysplasia and VEXAS.

Autoimmune disorders (ADs) are encountered in 10 to 20% of patients with myelodysplastic syndromes (MDS). Available data suggest that ADs concern more often younger patients with higher risk IPSS. MDS subtypes associated with ADs are mainly MDS with single lineage dysplasia (MDS-SLD) and MDS with excess blasts (MDS-EB). Various types of ADs have been described in association with MDS, ranging from limited clinical manifestations to systemic diseases affecting multiple organs. Defined clinical entities as vasculitis, connective tissue diseases, inflammatory arthritis, and neutrophilic diseases are frequently reported; however, unclassified or isolated organ impairment can be seen. In general, ADs do not seem to confer worse survival, although certain ADs may be associated with adverse outcomes (i.e., vasculitis) or progression of MDS (Sweet syndrome). While steroids and immunosuppressive treatment (IST) remain the backbone of first-line treatment, increasing evidence suggests that MDS-specific therapy as hypomethylating agents, based on their immunomodulatory effect, may be effective in treating these complications and for sparing steroids.

Cross-reactive immune responses between endemic human coronaviruses and SARS-CoV-2 have been proposed as a potential factor mitigating COVID-19 severity. Because parents may have more frequent exposure to seasonal respiratory viruses through contact with children, we investigated whether parental status was associated with improved survival among adults hospitalized with COVID-19. We conducted a retrospective cohort study using the Assistance Publique-Hôpitaux de Paris (AP-HP) Clinical Data Warehouse. We included all adults (≥18 years) hospitalized with RT-PCR-confirmed SARS-CoV-2 infection between January 29, 2020 and March 1, 2022. The primary endpoint was 90-day mortality after admission, analyzed as a time-to-event outcome using Cox proportional hazards models adjusted for demographics, comorbidities, admission period (pandemic wave), and baseline biological variables. Parental status was extracted from electronic health record text reports. We tested for interaction between age and parental status. Among 30,386 patients, 22,713 (75%) were classified as having children. Compared with patients without children, those with children were older and had more comorbidities. In the overall adjusted analysis, parental status was not associated with 90-day survival (HR = 1.00, 95%CI 0.94-1.07; p = 0.91). The association between parental status and survival was significantly modified by age (pinteraction = 0.002), with an association with lower mortality observed in younger adults that attenuated toward the null in older age groups. After stratification by age (<65 vs ≥ 65 years), having children was associated with improved 90-day survival in patients <65 years (Hazard Ratio (HR)=0.83, 95%CI 0.72-0.95; p = 0.009), whereas no significant association was observed in patients ≥65 years (HR = 1.07, 95%CI 0.99-1.15; p = 0.09). In this large EHR-based cohort of adults hospitalized with COVID-19, parenthood was associated with lower 90-day mortality among patients younger than 65 years. These findings are observational and may reflect unmeasured confounding; further studies are needed to clarify underlying mechanisms.

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders, representing high risk of progression to acute myeloid leukaemia, and frequently associated to somatic mutations, notably in the epigenetic regulator TET2 . Natural Killer (NK) cells play a role in the anti-leukemic immune response via their cytolytic activity. Here we show that patients with MDS clones harbouring mutations in the TET2 gene are characterised by phenotypic defects in their circulating NK cells. Remarkably, NK cells and MDS clones from the same patient share the TET2 genotype, and the NK cells are characterised by increased methylation of genomic DNA and reduced expression of Killer Immunoglobulin-like receptors (KIR), perforin, and TNF-α. In vitro inhibition of TET2 in NK cells of healthy donors reduces their cytotoxicity, supporting its critical role in NK cell function. Conversely, NK cells from patients treated with azacytidine (#NCT02985190; https://clinicaltrials.gov/ ) show increased KIR and cytolytic protein expression, and IFN-γ production. Altogether, our findings show that, in addition to their oncogenic consequences in the myeloid cell subsets, TET2 mutations contribute to repressing NK-cell function in MDS patients. Myelodysplastic syndromes are characterised by clonal haematopoiesis, with the affected cells often harbouring mutations in the TET2 gene, an important regulator of DNA methylation state. Here authors show that the same mutations are also found in NK cells, perturbing their DNA methylation pattern and cytolytic function.

The aim of this study was to assess the prevalence of cardiovascular risk factors in TAK, to describe the use of aspirin and statins and the risk factors associated with vascular ischemic complications and relapses. We conducted a retrospective study on TAK patients diagnosed between 2010 and 2018. Demographic, clinical, laboratory data and treatments were evaluated at diagnosis and during the follow-up. We included fifty-two TAK patients with median age 37.5 years [range 16–53] and 43 (83%) women. At diagnosis, cardiovascular risk factors were present in 32 (62%) patients: hypertension (n = 20, 38%), hyperlipidemia (n = 8, 15%), tobacco use (n = 16, 31%). During the median 4-year follow-up [range 0.1–17 years], 17 (33%) patients had at least one ischemic event and 15 (29%) patients needed endovascular procedure. Whereas TAK patients with cardiovascular risk factors were more frequently on statins and anti-hypertensive drugs, they have higher rates of cumulative ischemic complications (5 (24%) versus 21 (67%); p  = 0.004), but similar rates of aspirin-treated patients. Patients who have developed vascular ischemic events were more frequently smokers (53% versus 20%; p  = 0.03). The vascular complication-free survival was not significantly different in TAK patients with or without statins or aspirin at diagnosis. During the follow-up, 27 (52%) patients had at least one relapse, and the relapse-free survival was not significantly different in patients treated with statins or aspirin. Cardiovascular risk factors in TAK have to be strictly controlled since these risk factors could be associated with increased risk of ischemic complications.

Relapsing polychondritis is a rare inflammatory disease characterized by recurrent inflammation of cartilaginous structures, mainly of the ears, nose and respiratory tract, with a broad spectrum of accompanying systemic features. Despite its rarity, prompt recognition and accurate diagnosis of relapsing polychondritis is crucial for appropriate management and optimal outcomes. Our understanding of relapsing polychondritis has changed markedly in the past couple of years with the identification of three distinct patient clusters that have different clinical manifestations and prognostic outcomes. With the progress of pangenomic sequencing and the discovery of new somatic and monogenic autoinflammatory diseases, new differential diagnoses have emerged, notably the vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome, autoinflammatory diseases and immune checkpoint inhibitor-related adverse events. In this Review, we present a detailed update of the newly identified clusters and highlight red flags that should raise suspicion of these alternative diagnoses. The identification of these different clusters and mimickers has a direct impact on the management, follow-up and prognosis of patients with relapsing polychondritis and autoinflammatory syndromes.Relapsing polychondritis, a rare inflammatory disorder that affects cartilaginous structures, presents challenges in diagnosis owing to overlapping symptoms with other conditions. This Review provides a clinical update on relapsing polychondritis, emphasizing the importance of distinguishing this disease from similar conditions.

Diagnosis of large vessel vasculitis (LVV) and evaluation of its inflammatory activity can be challenging. Our aim was to investigate the value of hybrid positron-emission tomography/magnetic resonance imaging (PET/MRI) in LVV. All consecutive patients with LVV from the Department of Internal Medicine who underwent PET/MRI were included. Three PET/MRI patterns were defined: (i) “inflammatory,” with positive PET (>liver uptake) and abnormal MRI (stenosis and/or wall thickening); (ii) “fibrous”, negative PET (≤liver uptake) and abnormal MRI; and (iii) “normal”. Thirteen patients (10 female; median age: 67-years [range: 23–87]) underwent 18 PET/MRI scans. PET/MRI was performed at diagnosis (n = 4), at relapse (n = 7), or during remission (n = 7). Among the 18 scans, eight (44%) showed an inflammatory pattern and three (17%) a fibrous pattern; the other seven were normal. The distribution of the three patterns did not differ between patients with Takayasu arteritis (TA, n = 10 scans) and those with giant cell arteritis (GCA, n = 8 scans). PET/MRI findings were normal in 2/10 (20%) TA scans vs. 5/8 (62%) GCA scans (p = 0.3). Median SUV max was 4.7 [2.1–8.6] vs. 2 [1.8–2.6] in patients with active disease vs. remission, respectively (p = 0.003). PET/MRI is a new hybrid imaging modality allowing comprehensive and multimodal analysis of vascular wall inflammation and the vascular lumen. This technique offers promising perspectives for the diagnosis and monitoring of LVV.

Transfusion-related acute lung injury (TRALI), defined as the onset of acute respiratory distress after blood transfusion, is a rare complication which is a leading cause of transfusion related-mortality. In this retrospective study, we report the French nationwide experience of intravenous immunoglobulin (IVIG)-related TRALI, with a literature review and analysis of management and outcome of this rare condition. With the pharmacovigilance services, we conducted a retrospective multicenter study in the French network of intensive care units with TRALI concomitant to IVIG use and pooled with data from a literature review. Overall, 17 cases have been included in this case-series, our case report, seven personal cases and nine cases from the literature review. The median age was 55 years [2–79] with 10/17 (59%) male subjects. The underlying diseases motivating IVIG infusion were neurologic diseases in 35% of cases (Guillain Barre syndrome = 2, peripheral neuropathy = 2, neurolupus = 1, myasthenia = 1), multiple myeloma with hypogammaglobulinemia (n = 2; 12%), primary hypogammaglobulinemia (n = 2; 12%), autoimmune cytopenias (n = 2; 12%), graft versus host cutaneous disease after allogeneic hematopoietic stem cell transplantation for acute myeloid leukaemia (n = 1), anti-HLA antibodies after lung transplant (n = 1), cancer-associated thrombotic thrombocytopenic purpura-haemolytic uremic syndrome (n = 1), Kawasaki disease (n = 1) and in experimental essay (n = 1). TRALI symptoms begin either after the start or during the infusion (n = 7; 41%), or after the infusion (n = 10; 59%, 10 min to 24 h). Besides respiratory distress, it was also noted shock (33%), fever (18 %), cough (18%), nausea/vomiting (18 %), chills (12%) and agitation (12%). The X-ray showed mainly bilateral alveolar opacities (n = 15; 88%). Mechanical ventilation was needed in nine cases (53%), with median 1-day duration [1–4]. Four patients (24%) died during hospitalisation in the intensive care unit. Given the increasing use of intravenous immunoglobulins, TRALI must now be discussed in cases of respiratory distress occurring during or immediately following the infusion even if this side effect remains rare.Key Points• TRALI must now be discussed in cases of respiratory distress occurring during or immediately following an infusion of intravenous immunoglobulins.