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INTRODUCTION This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. METHODS AD polygenic risk scores (PRS) were tested for association with DS‐related traits. RESULTS The AD risk PRS was associated with disease status in several cohorts of sporadic late‐ and early‐onset and familial late‐onset AD, but not in familial early‐onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRSAPOE, p = 2.84 × 10−4; PRS excluding APOE, PRSnonAPOE, p = 1.60 × 10−2). PRSAPOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS. DISCUSSION These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits. Highlights Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults.

ObjectivesAdult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD.MethodsIn this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study.ResultsTen patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria.ConclusionsOur results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD.Trial registration numberNCT02398435.

INTRODUCTION Neuroinflammation, a key player in Alzheimer's disease (AD) pathogenesis, may be differentially involved in young‐onset (YOAD) compared to late‐onset (LOAD) AD. METHODS Using proximity extension assay technology, we examined 737 inflammatory markers in the CSF of 26 healthy controls (63.9 ± 8.7; 12♀), 57 patients with YOAD (60.8 ± 4.9 y/o; 40♀), and 33 with LOAD (76.6 ± 4.5 y/o; 18♀). We also assessed biomarkers of AD pathology (Aβ42, p‐tau181, t‐tau) and neurodegeneration (neurofilament light‐chain [NfL]). RESULTS Compared to controls, SCRN1 and MMP10 were increased in LOAD and YOAD, but 16 markers showed YOAD‐specific increases. Forty‐six markers were significantly associated with NfL. P‐tau181 and t‐tau mediated the association between inflammatory markers and NfL in YOAD. In LOAD we could not identify a direct or indirect relationship between neuroinflammation and neurodegeneration. DISCUSSION Using a proteomics approach, we observed an exacerbation of neuroinflammatory changes and a differential contribution of neuroinflammation to AD pathology and neurodegeneration in YOAD compared to LOAD. Highlights Olink's Proximity Extension Assay was used to compare the inflammatory profile of 26 healthy controls and 90 Alzheimer's disease (AD) patients. AD patients were further stratified into young‐onset (YOAD, n = 57) and late‐onset (LOAD, n = 33) AD. Cerebrospinal fluid (CSF) levels of MMP10 and SCRN1 were increased in both YOAD and LOAD, but 16 proteins were only increased in YOAD. Tau mediated the association between inflammatory markers and neurodegeneration in YOAD. Neuroinflammation may be differentially involved in the pathogenesis of YOAD compared to LOAD.

ObjectiveTo evaluate the efficacy and safety of tocilizumab, an interleukin-6 receptor antibody, in patients with adult-onset Still’s disease.MethodsIn this double-blind, randomised, placebo-controlled phase III trial, 27 patients with adult-onset Still’s disease refractory to glucocorticoids were randomised to tocilizumab at a dose of 8 mg/kg or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients received open-label tocilizumab for 40 weeks subsequently. The primary outcome was American College of Rheumatology (ACR) 50 response at week 4. The secondary outcomes included ACR 20/50/70, systemic feature score, glucocorticoid dose and adverse events at each point.ResultsIn the full analysis set, ACR50 response at week 4 was achieved in 61.5% (95% CI 31.6 to 86.1) in the tocilizumab group and 30.8% (95% CI 9.1 to 61.4) in the placebo group (p=0.24). The least squares means for change in systemic feature score at week 12 were –4.1 in the tocilizumab group and –2.3 in the placebo group (p=0.003). The dose of glucocorticoids at week 12 decreased by 46.2% in the tocilizumab group and 21.0% in the placebo group (p=0.017). At week 52, the rates of ACR20, ACR50 and ACR70 were 84.6%, 84.6% and 61.5%, respectively, in both groups. Serious adverse events in all participants who received one dose of tocilizumab were infections, aseptic necrosis in the hips, exacerbation of adult-onset Still’s disease, drug eruption and anaphylactic shock.ConclusionThe study suggests that tocilizumab is effective in adult-onset Still’s disease, although the primary endpoint was not met and solid conclusion was not drawn.

Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD) are considered the same disease, but a common approach for diagnosis and management is still missing.MethodsIn May 2022, EULAR and PReS endorsed a proposal for a joint task force (TF) to develop recommendations for the diagnosis and management of sJIA and AOSD. The TF agreed during a first meeting to address four topics: similarity between sJIA and AOSD, diagnostic biomarkers, therapeutic targets and strategies and complications including macrophage activation syndrome (MAS). Systematic literature reviews were conducted accordingly.ResultsThe TF based their recommendations on four overarching principles, highlighting notably that sJIA and AOSD are one disease, to be designated by one name, Still’s disease.Fourteen specific recommendations were issued. Two therapeutic targets were defined: clinically inactive disease (CID) and remission, that is, CID maintained for at least 6 months. The optimal therapeutic strategy relies on early use of interleukin (IL-1 or IL-6 inhibitors associated to short duration glucocorticoid (GC). MAS treatment should rely on high-dose GCs, IL-1 inhibitors, ciclosporin and interferon-γ inhibitors. A specific concern rose recently with cases of severe lung disease in children with Still’s disease, for which T cell directed immunosuppressant are suggested. The recommendations emphasised the key role of expert centres for difficult-to-treat patients. All overarching principles and recommendations were agreed by over 80% of the TF experts with a high level of agreement.ConclusionThese recommendations are the first consensus for the diagnosis and management of children and adults with Still’s disease.

There is growing recognition of early-onset gastrointestinal (GI) malignancies in young adults < 50 years of age. While much of the literature has emphasized colorectal cancer, these also include esophageal, gastric, liver, pancreatic, and biliary tract malignancies. Various factors, including lifestyle, hereditary, and environmental elements, have been proposed to explain the rising incidence of GI malignancies in the younger population. This review aims to provide an overview of the recent literature, including global trends and information regarding genetic and environmental risk factors.

Objective To compare the clinical symptomatology in patients with Early‐Onset Schizophrenia (EOS, N = 176), especially the subgroup Very Early Onset Schizophrenia (VEOS) and Adult Onset Schizophrenia (AOS, N = 551). Method In a large French multicentric sample, 727 stable schizophrenia patients, classified by age at onset of the disorder, were assessed using standardized and extensive clinical and neuropsychological batteries: AOS with onset ≥ 18 years and EOS with onset < 18 years (including 22 VEOS < 13 years). Results The importance of better diagnosing EOS group, and in particularly VEOS, appeared in a longer DUP Duration of Untreated Psychosis (respectively, 2.6 years ± 4.1 and 8.1 years ± 5.7 vs. 1.0 years ± 2.5), more severe symptomatology (PANSS Positive And Negative Syndrome Scale scores), and lower educational level than the AOS group. In addition, the VEOS subgroup had a more frequent childhood history of learning disabilities and lower prevalence of right‐handedness quotient than the AOS. Conclusion The study demonstrates the existence of an increased gradient of clinical severity from AOS to VEOS. In order to improve the prognosis of the early forms of schizophrenia and to reduce the DUP, clinicians need to pay attention to the prodromal manifestations of the disease. To describe schizophrenia from childhood to adulthood is complex and patients with early‐onset schizophrenia (EOS) remain undiagnosed or misclassified, especially the subgroup with very early‐onset schizophrenia (VEOS). In patients with VEOS, the DUP which exceeds 8 years, almost eight times higher than in patients with AOS, objective the problem of early diagnosis and the need to develop diagnostic programs and management cares.

Background Adult-onset Still’s disease (AOSD) is a systemic inflammatory disease characterized by neutrophilia and NLRP3 inflammasome and macrophage activation. We investigated the role of neutrophil extracellular traps (NETs) in the pathogenesis of AOSD, and explored the effect of NETs on activating NLRP3 inflammasome and proinflammatory macrophages. Methods The sera of 73 AOSD patients and 40 healthy controls were used to detect the level of cell-free DNA and NET-DNA complexes. NET formation ex vivo was analyzed using immunofluorescence and flow plates. The activation of NLRP3 inflammasome in THP-1 cells and proinflammatory macrophages stimulated with DNA purified from NETs was measured using RT-PCR, ELISA, Western blotting and flow cytometry. Results The levels of cell-free DNA and NET-DNA complexes were significantly increased in the circulation of patients with AOSD compared with healthy controls, and freshly isolated neutrophils from patients with AOSD were predisposed to high levels of spontaneous NET release. Interestingly, enhanced NET release was abrogated with NADPH oxidase inhibitors and a mitochondrial scavenger. Furthermore, DNA purified from AOSD NETs activated NLRP3 inflammasomes. NET DNA from AOSD also exerted a potent capacity to accelerate the activation of CD68 + CD86 + macrophages and increased the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Finally, the copy number of mitochondrial DNA (mtDNA) in NETs and plasma was significantly increased in AOSD patients, suggesting that mtDNA may be involved in the activation of NLRP3 and inflammatory macrophages. Conclusions These findings implicate accelerated NET formation in AOSD pathogenesis through activation of NLRP3 and proinflammatory macrophages, and identify a novel link between neutrophils and macrophages by NET formation in AOSD.

INTRODUCTION Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller‐scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD. METHODS Z‐score cognitive‐domain composites for 311 amyloid‐positive sporadic EOAD and 314 amyloid‐positive LOAD participants were calculated from baseline data from age‐appropriate control cohorts. Z‐score composites were compared between AD groups for each domain. RESULTS After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory. DISCUSSION Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non‐amnestic impairments in younger patients to ensure proper identification and intervention using disease‐modifying treatments. Highlights Both early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) participants displayed widespread cognitive impairments relative to their same‐aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv‐PPA), and frontal‐variant AD.

ObjectivesDrug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Still’s disease with atypical lung disease. We sought to characterise features of patients with Still’s disease with DRESS compared with drug-tolerant Still’s controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort.MethodsIn a case/control study, we collected a multicentre series of patients with Still’s disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still’s controls (n=65). We retrospectively analysed clinical data from all Still’s subjects and typed 94/131 for HLA. European Still’s-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still’s cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still’s-DRESS cases (n=64) compared with drug-tolerant Still’s controls (n=30). KD subjects (n=19) were similarly studied.ResultsStill’s-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still’s-DRESS (64%) versus drug-tolerant Still’s (3%; p=1.2×10−14). We found striking enrichment for HLA-DRB1*15 haplotypes in Still’s-DRESS cases versus INCHARGE Still’s controls (p=7.5×10-13) and versus self-identified, ancestry-matched Still’s controls (p=6.3×10−10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions.ConclusionsDRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.