Up to one-third of people living with psoriasis develop psoriatic arthritis (PsA), and the majority have active psoriasis prior to the development of arthritis. Clinical risk factors, such as nail involvement, in conjunction with novel blood biomarkers, could improve PsA risk monitoring and early diagnosis. The aim of the HIPPOCRATES Prospective Observational Study (HPOS-www.hpos.study) is to follow a cohort living with psoriasis and identify risk factors for the development of PsA. HPOS is a patient-driven online prospective European observational cohort. Adult participants with psoriasis but with no prior diagnosis of PsA are eligible. Participants are invited to provide consent and join the study online. They complete a semi-structured questionnaire to collect data on demographics, psoriasis, comorbidities, risk factors for PsA, and the Psoriasis Epidemiology Screening Tool screening questionnaire. Follow-up is conducted through a questionnaire every 6 months. The primary outcome is the new onset of PsA confirmed by a diagnosis from their doctor. The study will also collect peripheral blood samples from a subset of participants for biomarker identification. This study follows the principles of the Declaration of Helsinki. To date, ethical approval has been granted by independent ethical committees in 10 countries. Studying a cohort of individuals with psoriasis will allow us to identify risk factors for arthritis development and to develop a risk calculator. This can support focused efforts on screening, patient education, and even studies looking to delay or prevent the onset of arthritis. This study, run via remote online data collection, provides an efficient way to recruit a large cohort (25,000) across multiple countries. However, challenges have had to be addressed with some key changes in study design, ethical review, and recruitment strategies required for each individual country. HPOS, Clinicaltrials.gov ID: NCT05858528, IRAS number 325080; https://clinicaltrials.gov/study/NCT05858528?locStr=United%20Kingdom&country=United%20Kingdom&cond=Psoriasis&term=HPOS&aggFilters=status%3Anot%20rec&rank=1. The HIPPOCRATES prospective observational study (HPOS) The HPOS Study, part of the HIPPOCRATES project, aims to find out what signs or factors can show which people with psoriasis might later develop Psoriatic Arthritis (PsA). PsA is a type of inflammatory arthritis that is related to the skin condition psoriasis. It occurs in about 1–2% of the general population but can develop in up to 30% of people who already have skin or nail psoriasis. Diagnosing PsA early can be difficult because symptoms can be vague or inconsistent, which means treatment often starts only after joint damage has already happened. By learning more about how psoriasis develops into PsA, researchers hope to find new ways to treat the disease earlier—or even prevent or delay it. The HPOS Study is an observational study that uses online questionnaires. Adults (aged 18 or older) who have psoriasis but not PsA can take part. Participants fill out a questionnaire every six months for three years. These questionnaires collect information about age, psoriasis details, lifestyle and health factors, early joint symptoms (using the PEST questionnaire), daily function, treatment satisfaction, disease impact, fatigue, and mental health. If early signs of PsA appear, participants are advised to contact a doctor for assessment. The study plans to recruit 25,000 people across 14 European countries (including the UK, Ireland, France, Germany, and others) and expects that around 675 participants will develop PsA each year. A smaller group of 3,000 participants will also provide a small finger-prick blood sample, which will help researchers look for blood markers that might predict PsA development. HPOS is the first large-scale European study to track how psoriasis progresses to PsA. The findings could lead to a “risk calculator” that helps doctors identify people at high risk of developing PsA earlier.
Since the publication of the first European Society for the Study of Coeliac Disease (ESsCD) guidelines in 2019, substantial advances have been made in understanding the management and complex disease courses of coeliac disease (CeD) in adults. These 2025 updated guidelines aim to integrate new evidence, refine management strategies, and promote a personalised and multidisciplinary approach to care. The ESsCD convened a multidisciplinary panel of experts to revise the 2019 guidelines using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) framework. Evidence was appraised and graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Statements and recommendations were draughted within working groups and finalised through a structured Delphi consensus process. The updated guidelines are presented in two parts. Part 1, which has already been published, addresses the diagnostic approach to CeD in adults, whereas Part 2 focuses on disease management, structured follow-up, and the evaluation and treatment of persistent symptoms despite a gluten-free diet or refractory disease. New or expanded sections include guidance on the safe inclusion of oats, use of low-FODMAP diets in patients with persistent symptoms, management of exocrine pancreatic insufficiency, recognition of functional asplenia and related vaccination recommendations, and stratified bone-health screening. The guidelines also discuss nutritional and psychosocial support, digital models of care, and structured transition from paediatric to adult services. Updated therapeutic strategies for refractory CeD are provided, including immunosuppressive and novel pharmacologic options. These updated guidelines offer a comprehensive, evidence-based framework for the management and follow-up of adults with CeD. By integrating recent scientific advances with pragmatic, patient-centred recommendations, they seek to optimise clinical outcomes, quality of life, and long-term health in individuals with CeD.
The study aimed to investigate the associations between impaired spirometry such as obstructive pattern and preserved ratio impaired spirometry (PRISm) and occurrent cardiovascular events and deaths in patients with acute myocardial infarction. Cohort study of 517 patients with age ≥40 years and ≥10 pack-years of smoking, hospitalized for myocardial infarction at eight sites in Sweden and the United Kingdom. The Vitalograph® COPD-6 device was used to assess the ratio of forced expiratory volume in 1 and 6 seconds (FEV1/FEV6) and FEV1 as a percentage of the predicted value (FEV1%pred). Obstructive pattern was defined as FEV1/FEV6 <0.7, PRISm as FEV1/FEV6 >0.7 and FEV1%pred <80, and normal findings as FEV1/FEV6 ≥0.7 and FEV1%pred ≥80. Follow-up data were obtained from national registers or follow-up visits. Multivariable Cox regression was used to analyze the associations of obstructive pattern and PRISm with the incidence of acute ischemic cardiovascular events or major adverse cardiovascular events (MACE), respectively, within one year. Obstructive pattern was found in 95 (18%), PRISm in 192 (37%) and normal spirometry in 230 (45%) patients. A cardiovascular event occurred in 21 (4%) and MACE in 28 (5%). Compared with normal spirometry, PRISm was independently associated with both new cardiovascular events (HR (95% CI) 3.44 (1.07-11.0)) and MACE (4.94 (1.63 to 15.0)), and obstructive pattern with MACE (3.87 (1.08-13.8)). Further adjustment for cardiac or COPD treatment did not substantially change the results. About half of patients with acute myocardial infarction and a ≥10 pack-year smoking history have abnormal spirometry findings. Both obstructive pattern and PRISm are independently associated with increased risk for MACE within one year. We suggest that spirometry should be considered as a routine assessment in patients with smoking history and recent myocardial infarction. Impaired spirometry such as obstructive pattern as in chronic obstructive pulmonary disease (COPD) and preserved ratio impaired spirometry (PRISm) are associated with increased risk of mortality in the general populationThe present study investigated the prevalence and associations of obstructive pattern and PRISm with and occurrent cardiovascular events and deaths in patients with acute myocardial infarction, in cohorts from Sweden and the United KingdomWe found that about half of patients with acute myocardial infarction and a ≥10 pack-year smoking history have abnormal spirometry findingsIn patients with acute myocardial infarction and a ≥10 pack-year smoking history, obstructive pattern and PRISm are both associated with increased one-year risk of occurrent acute ischemic cardiovascular events and cardiovascular deaths.
This study included patients diagnosed with Takayasu's arteritis (TAK) according to the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for TAK and compared the frequencies of items satisfied in the 2022 criteria between patients with young-onset TAK (YOTAK) and those with lateonset TAK (LOTAK). The medical records of 138 patients with TAK were retrospectively reviewed. YOTAK was arbitrarily defined as TAK diagnosed at 20-40 years of age, whereas LOTAK was defined as TAK classified at 41-60 years of age. The analyses were conducted by assessing and comparing the frequencies of items that fulfilled the 2022 criteria for TAK. The median age of the 138 patients diagnosed with TAK was 45.0 years, and 89.1% of the patients were female. Of the 138 patients, 47 and 91 were allocated to the YOTAK and LOTAK groups. Patients with LOTAK exhibited significantly higher frequencies of the items of vascular bruit (85.7% vs. 70.2%, OR 2.55 (95% CI 1.08-6.00), p=0.030), reduced pulse in upper extremities (73.6% vs. 42.6%, OR 3.77 (95% CI 1.79-7.92), p<0.001), and systolic blood pressure difference in arms (96.7% vs. 87.2%, OR 4.29 (95% CI 1.02-18.02), p=0.033) than those with YOTAK. Conversely, the involvement of the ascending aorta was significantly more frequently found in patients with YOTAK than those with LOTAK (19.1% vs. 7.7%, OR 0.35 (95% CI 0.12-0.99), p=0.046). Results of this study revealed that patients with LOTAK exhibited higher frequencies of vascular bruit, reduced brachial arterial pulse, and systolic blood pressure differences in arms, but a lower frequency of ascending aorta involvement than those with YOTAK.
Pain, fatigue, and impaired health-related quality of life are common manifestations of rheumatoid arthritis. The aim of this study was to compare the effects of active conventional treatment with three different biological disease-modifying antirheumatic drugs (DMARDs) on patient-reported outcomes after 48 weeks, in patients with early rheumatoid arthritis using data from the NORD-STAR trial. NORD-STAR was an investigator-initiated open-label randomised controlled trial done at 29 rheumatology centres across Denmark, Finland, Iceland, Norway, Sweden, and the Netherlands. Newly diagnosed patients aged 18 years or older, with rheumatoid arthritis (according to the 2010 American College of Rheumatology-European Allience of Associations for Rheumatology classification criteria for rheumatoid arthritis), symptom duration less than 24 months and who were naïve to DMARDs were randomly assigned (1:1:1:1) to receive active conventional treatment, certolizumab pegol, abatacept, or tocilizumab. The patient-reported outcomes assessed at baseline and weeks 4, 8, 12, 16, 24, 32, 40, and 48 included pain, patient's global assessment of disease activity, Health Assessment Questionnaire Disability Index, Fatigue, Short Form-36 (reflecting health-related quality of life, morning stiffness, and patient's acceptable symptom state). Linear mixed regression and logistic regression analyses were adjusted for sex, country, baseline patient-reported outcomes values, anti-citrullinated protein antibody status, and treatment group. Proportions of patients reporting improvements greater than or equal to the minimal clinically important difference (MCID) were assessed. There was lived experience involvement in the design and implementation of the study. This trial was registered with ClinicalTrials.gov, NCT01491815, and EudraCT, 2011-004720-35. Between Dec 14, 2012, and Dec 11, 2018, 812 patients were enrolled and randomly assigned; after exclusion of 17 patients not receiving tocilizumab due to administrative issues, the intention-to-treat population consisted of 795 patients (200 [25%] received active conventional treatment, 203 [26%] received certolizumab pegol plus methotrexate, 204 [26%] received abatacept plus methotrexate, and 188 [24%] received tocilizumab plus methotrexate). 547 (69%) of 795 patients were female, 248 (31%) were male, the mean age was 54 years (SD 15). Between baseline and week 48 large and clinically relevant improvements in patient-reported outcomes were observed in all treatment groups. At 48 weeks the biological DMARD groups had larger improvements in pain, fatigue, physical component score, and bodily pain of SF-36 compared with the active conventional treatment group. For pain, improvement exceeding MCID was reported by 155 (76%) of 203 patients with certolizumab pegol plus methotrexate and 162 (79%) of 204 patients with abatacept plus methotrexate compared with 136 (68%) of 200 patients in the active conventional treatment group. In the group of patients with tocilizumab and methotrexate 132 (70%) of 188 patients reported pain improvement exceeding MCID. The absolute differences between the biological DMARD groups and the active conventional treatment group were otherwise generally marginal. All treatment groups showed substantial improvements in patient-reported outcomes over time. Biological DMARDs produced somewhat greater gains in pain, fatigue, and physical quality of life measures than conventional treatments, though overall differences between groups were small. The results highlight that early treatment and effective disease control in rheumatoid arthritis lead to strong patient-reported benefits regardless of therapy type. Stockholm County Council, Swedish Medical Research Council, Swedish Rheumatism Association, Academy of Finland, Finska Läkaresällskapet, South-Eastern Health Region Norway, HUS Institutional grant, Icelandic Society for Rheumatology, Interregional grant from all health regions in Norway, NordForsk, Regionernes Medicinpulje, The Research Fund of University Hospital Reykjavik, UCB, Bristol Myers Squibb.
Breast cancer is a leading cause of mortality and morbidity among females worldwide. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, we provided an updated comprehensive assessment of the epidemiological trends, disease burden, and risk factors associated with breast cancer globally, regionally, and nationally from 1990 to 2023. Breast cancer incidence, mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) were estimated by age and sex for 204 countries and territories from 1990 to 2023. Mortality estimates were generated using GBD Cause of Death Ensemble models, leveraging data from population-based cancer registration systems, vital registration systems, and verbal autopsies. Mortality-to-incidence ratios were calculated to derive both mortality and incidence estimates. Prevalence was calculated by combining incidence and modelled survival estimates. YLLs were established by multiplying age-specific deaths with the GBD standard life expectancy at the age of death. YLDs were estimated by applying disability weights to prevalence estimates. The sum of YLLs and YLDs equalled the number of DALYs. Breast cancer burden attributable to seven risk factors was examined through the comparative risk assessment framework. The GBD forecasting framework was used to forecast breast cancer incidence and mortality from 2024 to 2050. Age-standardised rates were calculated for each metric using the GBD 2023 world standard population. In 2023, there were an estimated 2·30 million (95% uncertainty interval [UI] 2·01 to 2·61) breast cancer incident cases, 764 000 deaths (672 000 to 854 000), and 24·1 million (21·3 to 27·5) DALYs among females globally. In the World Bank low-income group, where a low age-standardised incidence rate (ASIR) was estimated (44·2 per 100 000 person-years [31·2 to 58·4]), the age-standardised mortality rate (ASMR) was the highest (24·1 per 100 000 [16·8 to 31·9]). The highest ASIR was in the high-income group (75·7 per 100 000 [67·1 to 84·0]), and the lowest ASMR was in the upper-middle-income group (11·2 per 100 000 [10·2 to 12·3]). Between 1990 and 2023, the ASIR in the low-income group increased by 147·2% (38·1 to 271·7), compared with a 1·2% (-11·5 to 17·2) change in the high-income group. The ASMR decreased in the high-income group, changing by -29·9% (-33·6 to -25·9), but increased by 99·3% (12·5 to 202·9) in the low-income group. The increase in age-standardised DALY rates followed that of ASMRs. Risk factors such as dietary risks, tobacco use, and high fasting plasma glucose contributed to 28·3% (16·6 to 38·9) of breast cancer DALYs in 2023. The risk factors with a decrease in attributable DALYs between 1990 and 2023 were high alcohol use and tobacco. By 2050, the global incident cases of breast cancer among females were forecast to reach 3·56 million (2·29 to 4·83), with 1·37 million (0·841 to 2·02) deaths. The stable incidence and declining mortality rates of female breast cancer in high-income nations reflect success in screening, diagnosis, and treatment. In contrast, the concurrent rise in incidence and mortality in other regions signals health system deficits. Without effective interventions, many countries will fall short of the WHO Global Breast Cancer Initiative's ambitious target of achieving an annual reduction of 2·5% in age-standardised mortality rates by 2040. The mounting breast cancer burden, disproportionately affecting some of the world's most vulnerable populations, will further exacerbate health inequalities across the globe without decisive immediate action. Gates Foundation, St Jude Children's Research Hospital.
Systemic lupus erythematosus (SLE) is a chronic, multi-organ autoimmune disease characterised by a highly heterogeneous presentation. Specific genetic variations predispose patients to the disease, and rare monogenic forms caused by single-gene variations have been identified in a small percentage of patients, often with early disease onset. In this study, we used exome sequencing in a large cohort of patient with juvenile-onset SLE to gain insight into the genetic basis of juvenile SLE (jSLE). Patients were selected if disease onset occurred before the age of 18. We performed exome sequencing on 263 individuals across 172 distinct families. The majority of cases were solo exomes (n = 118), while others included affected duos, trios, or multiplex families (n = 18 + 5 + 1), as well as classical trios with unaffected parents (n = 30). A molecular diagnosis consistent with the clinical presentation was established in 17 patients from unrelated families (10%). Among them, we identified pathogenic or likely pathogenic variants in genes previously associated with monogenic lupus, including a novel C1QA variant as well as other lupus-associated genes (COPA, ADAR, TLR7, IKZF3, RELA, PTPN11, SERPING1). Strikingly, exome sequencing also revealed variants in immunodeficiency-associated genes (IRAK4, USB1), autoinflammatory disorders (PSTPIP1) and unexpected candidates like ETV6, and MAN1B1 revealing previously unrecognised pathways in SLE development. Syndromic features and very early-onset (before the age of 5) were strongly associated with a higher diagnostic yield, reaching nearly 33% in these subgroups. This study expands our understanding of causes of lupus, highlighting its genetic heterogeneity. It also supports the systematic use of genetic testing in cases of juvenile lupus, especially those with very early onset or syndromic features, regardless of the clinical presentation. Given the range of unexpected molecular diagnoses identified in this study, pangenomic analysis such as exome or genome sequencing appears to be the most appropriate approach in these cases. This work was supported by: The Institut National de la Santé et de la Recherche Médicale (INSERM); Government grants managed by the Agence Nationale de la Recherche (ANR) as part of the "Investment for the Future" program: Institut Hospitalo-Universitaire Imagine (ANR-10-IAHU-01), Recherche Hospitalo-Universitaire (ANR-18-RHUS-0010); The Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH); The Fondation pour la Recherche Médicale (FRM: EQU202103012670, FDM202006011291); French and European grants managed by the ANR: ANR-14-CE14-0026 (Lumugène), ANR-21-CE17-0064 (SOCSIMMUNITY); The National Reference Center for Rheumatic, Autoimmune and Systemic Diseases in Children (RAISE).
Antibodies produced by B cells aid in the recognition and clearance of pathogens and are the cornerstone of vaccination strategies. Humans produce nine different antibody isotypes, and their effector functions differ according to the type of antigen and route of exposure. Phenotypic variation between isotype-switched B cell subsets is expected but not studied in detail. To obtain a molecular definition of isotype-defined cell identity, we performed proteomics and transcriptomics on isotype-defined populations of human naive and memory B cells (MBCs): CD27-IgM+IgD+, CD27+CD38lo/-IgM+IgD+, CD27+CD38lo/-IgM+IgD-, and IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4 MBCs (CD27+CD38lo/-Ig+). Combined proteome and transcriptome analysis revealed that mRNA and protein expression profiles separate isotype-defined B cell subsets according to their differentiation status. mRNA and protein expression levels correlated reasonably well for many genes. IgG4-switched B cells were most distinct from naive B cells in terms of mRNA as well as protein expression profiles. Besides a distinct expression profile of cytokine and Fc receptors, we identified a high expression of IgE-coding mRNA in IgG4-switched B cells. SDR16C5 was identified as uniquely upregulated in IgG4-switched B cells. Taken together, this study highlights the distinct phenotypic profile of IgG4-switched B cells.
Sepsis is a dysregulated host response to infection resulting in life-threatening organ failure. Although immune dysregulation is central to the sepsis definition, immunomodulation trials enrol participants based on clinical severity, not the extent of dysregulation, which could contribute to treatment heterogeneity. A pragmatic way to quantify immune dysregulation could improve prognostication, help to evaluate treatment responses, and identify individuals most likely to benefit from immunomodulation. We aimed to construct a parsimonious machine-learning tool that defines and quantifies immune dysregulation, thereby supporting biologically informed immunomodulation. In this multicohort analysis and reanalysis of a randomised controlled trial, the primary objective was to derive and validate a categorical and continuous immune dysregulation score that is independent of clinical presentation or outcome. We measured 35 plasma biomarkers reflecting key host response domains in individuals with community-acquired pneumonia (CAP) across different care settings (emergency department, general ward, and intensive care unit) and disease severities using data from three independent cohorts. We applied unsupervised trajectory inference analysis to identify an immune dysregulation gradient captured as discrete immune dysregulation stages (Dysregulated Immune Profile [DIP]) and a continuous score (cDIP; 0-1). We developed two parsimonious machine-learning models to predict the DIP stages and cDIP scores based on 35 biomarkers, and validated their ability to capture immune dysregulation and predict clinical outcomes in five independent cohorts. On the basis of our hypothesis that only individuals with severe immune dysregulation benefit from immunomodulation, we carried out a post-hoc analysis of a randomised trial evaluating hydrocortisone in severe CAP (CAPE COD trial, NCT02517489), assessing treatment effects across DIP stages and the cDIP continuum, and how hydrocortisone influenced dysregulation trajectories over time. We organised 398 participants with CAP along a continuum of immune dysregulation from mild to severe on the basis of 35 plasma biomarkers, yielding three dysregulation stages (DIP1-3) and a continuous score (cDIP). Clinical severity proved to be an inadequate proxy for immune dysregulation. A three-biomarker machine-learning framework (procalcitonin, soluble TREM-1, and IL-6) accurately predicted the degree of dysregulation derived from 35 biomarkers (DIP stage accuracy 91·2%; cDIP root mean square error 0·056). Although the framework was not designed for outcome prediction, increased immune dysregulation-reflected in DIP and cDIP-was associated with a gradual rise in mortality (cDIP odds ratio [OR] 1·26 [95% CI 1·13-1·40] per 10% increase, p<0·0001) and secondary infections (OR 1·50 [1·22-1·93] per 10% increase, p=0·0005), independent of clinical severity. The three-biomarker tool was validated in five external cohorts of varying infections, severities, and care settings (n=1191). Reanalysis of the CAPE COD trial showed that hydrocortisone conferred a survival benefit only in participants classified as severely dysregulated by our model (30-day mortality: DIP3 OR 0·25 [0·05-0·85], p=0·042; cDIP ≥0·63 OR 0·21 [0·10-0·72], p=0·011), accompanied by faster immune recovery (time × treatment interaction, p<0·0001). No such effect modification was observed when stratifying participants by clinical severity. We have provided a publicly available three-biomarker framework to determine the extent of host response dysregulation with potential value for precision-guided immunomodulatory therapy. EU Horizon 2020.
Chronic inflammation is closely associated with the most common and socially significant prostate conditions, including benign prostatic hyperplasia (BPH), prostate cancer (PCa), and prostatitis syndromes. NIH-category IV prostatitis (histologic prostatitis, HP) is defined as asymptomatic chronic inflammation of the prostate. The presence of lymphoid follicles, referred to as tertiary lymphoid structures (TLSs), along with benign lympho-epithelial lesions (BLELs), is among the key histological indicators of immune inflammation and can be assessed relatively easily. This study aimed to quantitatively assess TLSs and BLELs, as well as their relationship with the severity of HP. We investigated TLSs and BLELs in 110 prostatic specimens, including inflammatory and normal tissues, within the context of common prostate pathologies such as BPH and PCa. HP was graded as low-grade (LG) or high-grade (HG) based on the severity of inflammation. TLSs were observed in 51 out of 110 cases (46.4%), while BLELs were identified in 78 cases (70.44%). Both TLSs and BLELs co-occurred in 45 cases (40.9%). Statistical analysis revealed a significant correlation between the presence of TLSs, BLELs (individually or combined), and HG-HP (p < 0.001). This study is the first to quantitatively evaluate the immunopathologic patterns in the inflamed human prostate by analyzing the presence and co-occurrence of TLSs and BLELs. Their formation, likely triggered by antigenic stimuli and external factors, indicates a chronic inflammatory microenvironment. The strong association between TLSs, BLELs, and HG-HP underscores their potential role in HP aggressiveness. These findings suggest that TLSs and BLELs may be crucial contributors to the pathophysiology and morphogenesis of NIH-category IV prostatitis. Furthermore, TLS/BLEL formation may represent a hallmark of tissue autoimmunity, reflecting the immune or autoimmune phase of this prostatitis subtype.
Mitochondria have long been known to be involved in the regulation of innate immune response. We questioned whether cultured skin fibroblasts of patients suffering from mitochondrial diseases are valuable biological resources for the study of interferon signaling. Expression of interferon-stimulated genes was measured in control cells supplemented with interferon and in cultured fibroblasts of patients carrying pathogenic variants in mitochondrial disease-causing genes. Control fibroblasts showed a strong expression of interferon-stimulated genes in response to interferon, but only 43% of patients' fibroblasts displayed increased interferon stimulated genes scores. Cytosolic mitochondrial DNA and RNA were quantified by immunofluorescence and confocal microscopy. No correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA release could be established. We found that cultured skin fibroblasts represent a valuable biological resource for the investigation of interferon signaling, but that abnormal interferon signaling is not always observed in patients with mitochondrial diseases. At variance to gene silencing in control fibroblasts, the lack of correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA leakage in patients' fibroblasts questions the relevance of cellular models as illustrators of pathological situations in humans.
We aimed to assess the impact of socioeconomic status (SES) on risk of Sjögren's disease (SjD) compared with non-Sjögren's Sicca and population controls, and on the clinical features of SjD. A single-centre UK cohort provided participants with SjD (European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) 2016, n=256) and non-Sjögren's Sicca (anti-Sjögren's syndrome type A (SSA)/Ro negative, n=175). Health Survey for England 2019 provided local population controls (n=972). English Indices of Multiple Deprivation (IMD) 2019 quintiles at recruitment and highest educational attainment defined SES.Adjusted logistic regression models evaluated associations between SES and diagnosis. Linear models assessed the impact of IMD on disease variables. Population controls were matched with age, sex and ethnicity to compare SES distributions. Across IMD and educational attainment, participants with SjD had lower SES status compared to Sicca (p=0.008 and p=0.018). Odds of SjD (vs Sicca) were highest in most deprived IMD quintile 1 and reduced by 74% in quintile 2 (OR 0.26 (0.12, 0.58), p<0.001).Immunoglobulin G and A levels were inversely associated with IMD. In SjD, each unit increase in IMD reduced IgG by 6.03% (-9.84%, -2.05%; p=0.003) and IgA by 6.46% (-10.87%, -1.60%; p=0.010).When compared with population controls, IMD was not a risk factor for SjD (p=0.257) whereas Sicca was associated with lower deprivation (p=0.003). Those with a degree level qualification had the highest odds of diagnosis (SjD or Sicca). Low SES is associated with increased risk of SjD compared to Sicca and with higher immunoglobulin levels. The Sicca cohort may be less deprived than the general population. The role of environmental factors in modulating salivary gland pathology requires further exploration.
M. Barel, M. Balbo, M. Le Romancer and R. Frade, "Activation of Epstein-Barr Virus/C3d Receptor (gp140, CR2, CD21) on Human Cell Surface Triggers pp60src and Akt-GSK3 Activities Upstream and Downstream to PI 3-Kinase, Respectively," European Journal of Immunology 33, no. 9 (2003): 2557-2566, https://doi.org/10.1002/eji.200324059. This Expression of Concern is for the above article, published online on 18 August 2003 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editors-in-Chief, Matteo Iannacone and Nadja Bakocevic, and Wiley-VCH GmbH, Weinheim. The Expression of Concern has been issued after duplicated bands were identified between the anti‑nucleolin panels presented in Figures 1A2 and 3C2. Due to the time elapsed since publication, the authors were unable to provide supporting raw data. While the journal considers it unlikely that the conclusions of the article are affected, this Expression of Concern is published to inform readers of the issue.
Nowadays, especially in laboratories with high testing capacity, the widespread use of automated treponemal tests has increased the importance of algorithms used for syphilis serodiagnosis. In suspected syphilis cases, choosing the best algorithm is important from the aspect of diagnosis, treatment initiation, and treatment follow-up. In this study, we aimed to compare the diagnostic performance of traditional, reverse, and European Center for Disease Prevention and Control (ECDC) algorithms according to the clinical diagnosis of syphilis using rapid plasma reagin (RPR), chemiluminescence immunoassay (CLIA), and Treponema pallidum hemagglutination (TPHA) tests. Between March 2023 and July 2023, a total of 297 patients from various units of our hospital, suspected of having syphilis, were included in the study. All samples were analyzed using RPR, CLIA, and TPHA tests, and three different algorithms were examined separately. Clinical diagnosis was considered the gold standard. A total of 105 patients have been diagnosed with syphilis. When the patients' clinical diagnosis were used as a reference, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the traditional algorithm were found to be 41.9%, 100%, 100% and 75.9%, respectively, and all these parameters were found to be 100% for the reverse and ECDC algorithms. Moderate agreement (kappa value 0.483, p < 0.001) was found between the traditional and reverse algorithms. Very good agreement (kappa value 1.0, p < 0.001) was found between ECDC and the reverse algorithm. In diagnosing suspected syphilis cases, the reverse algorithm and ECDC algorithms utilizing treponemal tests as the initial step were found to be superior to the traditional algorithm. Our study demonstrates that treponemal antibody tests are superior when employed as the initial step in diagnosing syphilis in patients with latent syphilis among suspected cases. Nontreponemal tests should be used solely to evaluate disease activity and response to therapy.
Myasthenia gravis (MG) is a chronic autoimmune disease mediated by autoantibodies targeting the neuromuscular junction and leading to muscle weakness. Although there are autoantibodies of different specificities, most MG patients have autoantibodies directed against the nicotinic acetylcholine receptor (AChR), in particular against the extracellular domain of the α1 subunit (αECD), containing the main immunogenic region (MIR). Here, we demonstrate an original approach to selectively deplete plasma cells secreting autoantibodies targeting αECD. An antibody-mediated cytotoxicity-engager (ACE) consisting of an anti-hCD38-antibody conjugated to hAChR αECD (αECD) was used to deplete hAChR αECD-specific cells selectively in vivo. The reduction of pathogenic cells was accompanied by lower antibody titers, a reduction of MG disease score, protection of grip strength, and maintenance of body weight. Notably, antibody-secreting cells that are nonspecific for hAChR αECD were not affected. The resulting amelioration of MG pathology in ACE-treated animals highlights the decisive role of αECD-antibodies in the pathogenesis of MG and the clinical relevance of the novel therapeutic strategy.
There is emerging evidence for the ANCA Renal Risk Score (ARRS) and ANCA Kidney Risk Score (AKRiS) as simple and effective measures to predict risk of end-stage kidney disease (ESKD) in glomerulonephritis (GN) secondary to ANCA-associated vasculitis (AAV). We sought to externally validate these scores on an Aotearoa New Zealand (AoNZ) cohort. Using a biopsy database, cases of pauci-immune GN in the three metropolitan Auckland districts between 1 January 2008 and31 December 2018 were retrospectively identified and histopathological data extracted. Hospital electronic records were screened to obtain relevant clinical information. Cox proportional hazards model was used to estimate survival distributions and perform receiver operating characteristic curve analysis. One hundred twenty-one patients had sufficient data for risk score calculation. The cohort was predominantly male (60%) and of European ethnicity (71%). Māori and Pacific Peoples comprised 12% of the cohort. The vast majority (82%) of patients received cyclophosphamide induction. Ethnicity was associated with AKRiS score (p = 0.015) with Pacific Peoples being over-represented in the high risk AKRiS category. Both ARRS and AKRiS were significantly associated with ESKD (p < 0.001), with ordinal increases in probability of ESKD with risk category (apart from very high risk AKRiS group). Harrell's C-index for ARRS was 0.78 (95% CI: 0.705-0.862), and for AKRiS was 0.83 (95% CI: 0.753-0.896), without a significant increase with inclusion of ethnicity in the models. Brier scores were 0.131 for ARRS and 0.119 for AKRiS. In a cohort of AoNZ AAV GN patients, both ARRS and AKRiS performed well in predicting the risk of ESKD.
Nectin and nectin-like proteins are cell adhesion molecules belonging to the immunoglobulin superfamily that also play a crucial role in the process of immune modulation by interacting with immune receptors like TIGIT, DNAM-1, CD96 and PVRIG. Nectin-4 is a tumour-specific antigen that interacts exclusively with the inhibitory immune receptor TIGIT, resulting in inhibition of NK-cell cytotoxicity and facilitating the process of immune evasion by the cancer cells in the tumour microenvironment. Therefore, deciphering the molecular and structural mechanisms underlying this novel interaction can provide insights for the development of targeted immunotherapeutic interventions. In this study, using structure-guided mutagenesis studies, a novel TIGIT mutant is engineered exhibiting enhanced interaction affinity towards nectin-4 and reduced binding to other TIGIT ligands, such as PVR and nectin-2, which, in contrast to nectin-4, are predominantly expressed on healthy cells. Surface plasmon resonance-based biophysical studies were done to characterize and compare the interaction kinetics of the wild-type (WT) and the engineered mutant TIGIT ectodomains with their ligands. We have shown how a single point mutation of an amino acid residue located in the centre of the F strand of TIGIT dictates its interaction affinity with its ligand. These findings can provide a framework for the development of small-sized non-antibody therapeutics specifically targeted towards nectin-4 overexpressing cancer cells with minimal off-target effects on healthy cells.
CHAPLE disease (Complement Hyperactivation, Angiopathic Thrombosis, and Protein-Losing Enteropathy [PLE]) is a rare, life-threatening disorder caused by biallelic mutations in the CD55 gene, which encodes decay-accelerating factor, a key regulator of the complement system. The disease typically manifests in early childhood with hypoalbuminemic edema, gastrointestinal symptoms, recurrent infections, and failure to thrive, alongside an elevated thrombotic risk due to complement-mediated endothelial injury and coagulation activation. Given these pathogenetic mechanisms, complement-targeted therapies have emerged as a rational approach to disease management. Eculizumab, a monoclonal antibody against complement component C5, initially demonstrated clinical benefit when administered on a compassionate-use basis. Building upon this success, pozelimab, a next-generation subcutaneous anti-C5 monoclonal antibody, was evaluated in CHAPLE patients and subsequently received U.S. FDA approval for this indication. Pozelimab effectively inhibits terminal complement activation, leading to sustained remission of PLE, obviating the need for albumin replacement, reducing hospitalization rates, improving symptom control and nutritional status, and ultimately enhancing overall quality of life. This review highlights the evolving role of pozelimab in CHAPLE disease by discussing its mechanistic basis, emerging clinical evidence, and implications for patient-centered care. CHAPLE disease is a very rare and serious condition that starts in early childhood. It is caused by mutations in a gene called CD55, which normally helps control the body’s immune system, especially a part called the complement system. When this system is not controlled properly, it attacks the body’s own blood vessels, lymphatic vessels, and organs.Children with CHAPLE often have swelling from low protein levels, stomach problems (like pain, vomiting, and diarrhea), frequent infections, and poor growth. They are also at high risk of dangerous blood clots.The main problem in CHAPLE is damage to lymphatic vessels in the intestines and abnormal clotting caused by overactive immune responses. This leads to loss of protein from the intestines and other serious complications.Treatments that target the overactive complement system have shown promise. One such drug, eculizumab, helped patients with this condition. A newer medicine called pozelimab, administered by subcutaneous injection, has now been approved by the FDA. It works by blocking part of the immune system that causes the damage.Pozelimab has helped CHAPLE patients by stopping protein loss, improving growth and nutrition, and enhancing overall quality of life. This review explains how pozelimab works, what the latest research shows, and how it transforms CHAPLE care.
Meningitis remains the leading infectious cause of neurological disabilities globally, disproportionately affecting children younger than 5 years and populations in the African meningitis belt. Whereas previous global estimates focused on ten pathogen categories, this study presents the most comprehensive analysis to date, assessing the meningitis burden attributable to 17 causative pathogens based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 framework. GBD is a systematic, scientific effort aimed at quantifying the comparative magnitude of health loss caused by diseases, injuries, and risk factors across age groups, sexes, and geographical locations over time. We estimated meningitis mortality using the Cause of Death Ensemble model (CODEm) and morbidity using DisMod-MR 2.1, incorporating data from vital registration, verbal autopsy, surveillance, hospital data, and systematic reviews. Aetiology-specific estimates were generated with pathogen-linked case-fatality ratios and splined binomial regression models. Risk factor attribution was based on established risk-outcome pairs and population attributable fractions. In 2023, there were 259 000 (95% uncertainty interval 202 000-335 000) global deaths and 2·54 million (2·20-2·93) incident cases of meningitis. Children younger than 5 years accounted for more than a third of deaths (86 600 [53 300-149 000]). Streptococcus pneumoniae, Neisseria meningitidis, non-polio enteroviruses, and other viruses were the leading causes of death, while non-polio enteroviruses caused the most cases. The four WHO-defined preventable meningitis pathogens of interest (S pneumoniae, N meningitidis, Haemophilus influenzae, and Group B streptococcus) contributed to 98 700 deaths (77 000-127 000) and 594 000 cases (514 000-686 000). Low birthweight, short gestation, and household air pollution were the top risk factors for meningitis-related mortality. Although mortality and incidence have declined significantly since 1990, progress is insufficient to meet WHO 2030 targets. Despite marked progress in reducing bacterial meningitis via global vaccination campaigns, a substantial meningitis burden persists, attributable both to common pathogens such as S pneumoniae and N meningitidis and to emerging non-bacterial pathogens such as Candida spp and drug-resistant fungi. Achieving WHO goals will require sustained investment in surveillance, vaccination, maternal screening, and health-system strengthening, especially in high-burden settings. Gates Foundation, Wellcome Trust, and UK Department of Health and Social Care.
Neonates are particularly susceptible to infections because of a reduced ability to fight bacterial pathogens while simultaneously exhibiting enhanced inflammatory damage. Neonatal neutrophilic cells (NNC) are a heterogeneous population of innate immune cells, which differ substantially from adults. They display functional deficits in pro-inflammatory responses and include a suppressive subpopulation known as myeloid-derived suppressor cells (MDSC). It remains unclear whether pro- or anti-inflammatory properties of NNC predominate immediately after birth. This study aimed to clarify the role of neutrophilic cells in neonatal murine sepsis. We established a neonatal mouse model of E. coli-sepsis and depleted NNC using an anti-Ly6G antibody to assess mortality, bacterial load, cytokine responses, and immune cell composition. A dose of 30,000 CFU E. coli resulted in a 67% survival rate in neonatal mice with litters of 5-6 pups, while mortality increased in larger litters. NNC-depletion significantly increased mortality and systemic inflammation during neonatal sepsis, whereas bacterial load was only minimally affected. Other immune cell populations remained unchanged. E. coli sepsis induced pronounced neutrophil infiltration into organs of adults, whereas neonates exhibit reduced numbers of NNC in affected organs. Overall, our findings suggest that NNC-mediated control of inflammation may protect neonates from lethal sepsis.