Abstract Background CD4+ T cell hyperactivation is a pivotal driver of systemic autoimmunity in systemic lupus erythematosus (SLE), yet the molecular regulators that set its activation threshold remain poorly defined. Methods PPP2R3C expression was measured by qRT‐PCR and Western blotting in CD4+ T cells from 45 SLE patients and 37 healthy controls, as well as in pristane‐induced lupus (PIL) mice. Jurkat cells with PPP2R3C knockdown or overexpression were generated by lentiviral transduction. Signaling mechanisms were dissected using transcriptome sequencing and calcium flux assays. In vivo, PPP2R3C was restored in PIL mice via T cell‐targeted Ark313 vector or systemic AAV9 delivery; disease progression was assessed at 24 and 48 weeks after pristane induction. Results We identified the protein phosphatase 2A regulatory subunit PPP2R3C as a critical and selective negative regulator of T cell receptor (TCR) signaling, which was downregulated in CD4+ T cells from SLE patients and pristane‐induced lupus (PIL) mice. Reduced PPP2R3C expression was also observed in the kidneys of both PIL mice and lupus nephritis patients. In PIL mice, this reduction was evident in podocytes, endothelial cells, and mesangial cells, indicating widespread downregulation across kidney resident cell populations. Mechanistically, PPP2R3C deficiency enhanced T cell activation, cytokine production, and calcium flux by potentiating PLCγ1 phosphorylation and subsequent TCR‐driven JNK/c‐Jun signaling, whereas its overexpression produced opposing effects. To assess therapeutic potential, we restored PPP2R3C expression in PIL mice using two complementary gene delivery strategies. T cell‐targeted reconstitution via the Ark313 vector potently suppressed T cell activation and autoantibody production at an early stage (24 weeks), culminating in markedly attenuated proteinuria and glomerular immune complex deposition by late‐stage disease (48 weeks). Systemic delivery of AAV9‐PPP2R3C provided comprehensive therapeutic effects, ameliorating renal pathology while also normalizing immune dysregulation in both the thymus and spleen across both time points. Conclusions Our findings identify PPP2R3C as an important contributor to SLE pathogenesis and support its restoration as a gene therapy approach worthy of further exploration for its ability to rebalance immunity and mitigate tissue injury in SLE. Key points PPP2R3C is selectively downregulated in SLE CD4+ T cells and correlates with disease activity. It restrains the PLCγ1‐JNK axis to limit T cell hyperactivation and cytokine production. Gene therapy restoring PPP2R3C suppresses autoimmunity and lupus nephritis in mice, and its reduction in kidney resident cells indicates a direct renoprotective effect, positioning PPP2R3C as a promising therapeutic target for SLE.

OBJECTIVES:Current PsA therapies, from conventional agents (e.g. MTX) to targeted biologics (e.g. TNF and IL-17 inhibitors), demonstrate distinct therapeutic profiles. Vunakizumab (SHR-1314) is a novel humanized mAb targeting IL-17A. The phase 2 trial evaluated the efficacy and safety of vunakizumab in patients with active PsA. METHODS:Patients aged 18-75 years with a confirmed diagnosis of active PsA were randomized (1:1:1) to receive either s.c. vunakizumab 120 mg (n = 38), vunakizumab 240 mg (n = 37) or placebo (n = 37) at weeks 0, 2, 4 and 8. At week 12, patients on placebo were switched to vunakizumab (1:1 re-randomized to 120 mg or 240 mg through week 20), while vunakizumab groups continued treatment. The primary endpoint was ACR 20% improvement (ACR20) response rate at week 12. RESULTS:At week 12, ACR20 response rates were higher in the vunakizumab 120 mg (47.4%) or 240 mg (59.5%) groups vs placebo group (21.6%; P = 0.02 and P = 0.001, respectively). In addition, improvements were sustained through 24 weeks and were noted in patients who switched from placebo after week 12. Treatment-emergent adverse events (TEAEs) incidence exhibited analogous frequencies between vunakizumab [73.7% (120 mg), 64.9% (240 mg)] and placebo (70.3%) during the 12-week core treatment period, and no severe TEAEs occurred. CONCLUSIONS:Vunakizumab demonstrated superior efficacy to placebo and was well tolerated with an acceptable safety profile in patients with active PsA. The findings support proceeding to a phase 3 study. TRIAL REGISTRATION:ClinicalTrials.gov, www. clinicaltrials.gov, NCT05055934.

Ankylosing spondylitis (AS) is an immune-mediated spondyloarthropathy with unmet clinical needs. We conducted a superiority, phase 3, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of XKH004, a humanized monoclonal antibody targeting interleukin-17A/F in active AS. Of 489 screened patients with inadequate response to conventional therapy, 166 were excluded based on predefined criteria. The remaining 323 eligible patients were randomized 1:1 via a centralized interactive web-response system to receive subcutaneous XKH004 160 mg every 4 weeks or placebo until week 16. All patients completed a 52-week follow-up period, comprising 44 weeks of open-label XKH004 treatment followed by an 8-week safety follow-up. Participants and investigators were blinded to treatment allocation. Efficacy analyses utilized the Cochran–Mantel–Haenszel test. The primary endpoint was Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 16; secondary endpoints included ASAS20/50, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Ankylosing Spondylitis Quality of Life, and Ankylosing Spondylitis Disease Activity Score. At week 16, ASAS40 response was achieved by 45.4% with XKH004 (n = 161) vs 19.4% with placebo (n = 162; absolute difference, 95% confidence interval, 15.47–35.02; P < 0.001), with efficacy in the XKH004 group sustaining and further improving to 66.2% by week 52. Serious adverse events occurred in 1.2% and 2.5% of patients in the XKH004 and placebo groups, respectively. Overall, XKH004 was well tolerated and induced rapid, sustained improvements, supporting its potential as a novel therapeutic option for active AS. The trial was registered in the China Drug Experiment database (CTR20232310) and ClinicalTrials.gov (NCT07498634) and supported by the National Natural Science Foundation of China, National Key Research and Development Project, Shanghai Municipal Key Clinical Specialty, and Shanghai Science and Technology Development Funds.

AIM: To identify biomarkers and potential therapeutic targets related to angiogenesis and RNA modification in diabetic retinopathy (DR). METHODS: The Gene Expression Omnibus (GEO) datasets GSE12610, GSE87433, and GSE111465, which contain retinal samples from diabetic and normal mice, were analyzed to identify differentially expressed genes (DEGs). The DEGs were then intersected with angiogenesis- and RNA modification-related genes (A&RMRGs) obtained from GeneCards and other databases to identify differentially expressed A&RMRGs in DR. Hub genes were subsequently identified from the protein-protein interaction (PPI) network built on the enrichment results. Their diagnostic value was then estimated by receiver operating characteristic (ROC) analysis, and their expression levels were tested for associations with immune cell infiltration. Regulatory networks of hub genes were constructed using MicroRNA Target Prediction Database (miRDB), ChIPBase, and the Comparative Toxicogenomics Database (CTD). To validate the bioinformatic findings, hub gene transcript levels were quantified with reverse transcription quantitative polymerase chain reaction (RT-qPCR) in high-glucose-treated rat retinal microvascular endothelial cells (rRMECs). RESULTS: Forty-two A&RMRGs showed differential expression in the diabetic retina, with Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment implicating RNA modification and immune-inflammatory regulation, alongside Gene Set Enrichment Analysis (GSEA) evidence of activated RNA-silencing and fatty-acid-transport programs and suppressed neuronal and retinoid-cycle programs. Seven hub genes (Wdr3, Crebbp, Sdad1, Stat3, Gnl2, Nhp2, and Hsp90aa1) were selected, all of them were upregulated in DR. The DR retina showed higher levels of central memory CD8+ T cells and lower levels of monocytes, Tregs, and CD56bright natural killer (NK) cells. Monocyte infiltration was inversely associated with Stat3 expression (r=-0.604, P<0.001), and central memory CD8+ T cell levels were positively associated with Nhp2 expression (r=0.539, P=0.003). A total of 60 miRNAs, 43 transcription factors (TFs), and 47 drugs may regulate RNA modification of angiogenesis-associated genes in DR. Gnl2 [area under the ROC curve (AUC)=0.914, 95% confidence interval (CI): 0.810–1.000) and Stat3 (AUC=0.964, 95%CI: 0.892–1.000) showed high diagnostic value. Exposure of rRMECs to high glucose led to a marked rise in Stat3 expression and a fall in Sdad1, leaving the transcript levels of the remaining five hub genes unchanged. CONCLUSION: These findings identify Stat3 as a point of convergence between RNA modification, immune dysregulation, and angiogenesis, nominating the hub genes as candidate biomarkers and the associated drug–gene interactions as repurposing leads.

OBJECTIVES:Previous studies have identified unique challenges for RA patients of different genders, which impact disease management. However, the association between disease activity and health-care-seeking behaviours in male and female RA patients remains underexplored. This study aimed to investigate this association, with a specific focus on the gender-specific effects of follow-up intervals on disease control. METHODS:A nationwide survey (July-September 2023) across 330 rheumatology centres in China included 13 278 female (83.85%) and 2557 male RA patients (16.15%) aged ≥18 years. Standardized questionnaires captured demographic and health-care-seeking behaviours. Disease activity was assessed using the Clinical Disease Activity Index (CDAI). RESULTS:Females had younger disease onset (45.84 vs 51.03 years, P < 0.001), longer disease duration (7.51 vs 5.64 years, P < 0.001), higher low disease activity/clinical remission rates (22.61% vs 15.33%, P < 0.001), and lower glucocorticoid use (39.5% vs 47.73%, P < 0.001). Despite similar self-reported regular follow-up rates (84.73% vs 83.14%), both genders experienced suboptimal visit intervals (>3 months: 61.30% vs 62.65%, P < 0.001). Prolonged follow-up intervals were independently associated with poor disease control (CDAI > 10) in the female subgroup, with longer intervals linked to higher odds of inadequate control at 6-month [odds ratio (OR) = 1.22, 95% CI: 1.09-1.37, P < 0.001] and 12-month intervals (OR = 1.43, 95% CI: 1.22-1.60, P < 0.001). Regular monitoring reduced high disease activity risk across genders (OR = 0.64, 95% CI: 0.56-0.74, P < 0.001). A generalized linear model showed no significant follow-up interval - gender interaction on disease activity (all P > 0.20). CONCLUSION:This large-scale study revealed gender-dimorphic patterns in RA progression and health-care engagement. Females tended to exhibit better treatment response, with a more pronounced interval-dependent disease control trend. No significant interval-gender interaction confirmed this was a descriptive trend, not a validated gender-specific difference. Our findings emphasize the need for strategies accounting for such gender-dimorphic trends to optimize care continuity and improve RA management.

OBJECTIVES:This study aimed to evaluate the efficacy and safety of mufemilast, a novel small-molecule selective phosphodiesterase 4 (PDE4) inhibitor, in patients with Behçet's syndrome (BS). METHODS:Patients diagnosed with BS according to the International Diagnostic (Classification) Criteria for Behçet's Disease 2013 and with active oral ulcers were eligible. Patients were randomly assigned to mufemilast (45 mg or 60 mg) or placebo, administered orally twice daily for 12 weeks. The primary endpoint was the area under the curve (AUC) for the number of oral ulcers from baseline to week 12. Safety was measured in all patients who received at least 1 dose of the study drug (ClinicalTrials: NCT04609397). RESULTS:Ninety patients were randomly assigned to the mufemilast 45 mg, 60 mg, or placebo groups (29, 31, and 30, respectively). The least-squares mean difference in AUC0-12 for oral ulcers between the 45 mg and 60 mg groups and the placebo was -104.8 (95% CI, -156.3 to -53.2; P < .001) and -142.5 (95% CI, -192.4 to -92.7; P < .001), respectively. The visual analogue pain scores and time to ulcer-free remission were significantly improved with mufemilast (P < .001). PDE4-related side effects were transient and resolved spontaneously, and discontinuation rates were low (7% for 45 mg, 7% for 60 mg, and 3% for placebo). No serious adverse events were reported related to the drug. CONCLUSIONS:Among patients with oral ulcers associated with BS, mufemilast significantly reduced the number of oral ulcers, improved pain scores, and induced significantly more ulcer-free remissions compared with placebo, with an acceptable safety profile.

Objective: To evaluate the efficacy and safety of Xeligekimab (GR1501), a fully human monoclonal antibody against interleukin-17A, in Chinese patients with active axial spondyloarthritis (axSpA) who did not respond or were intolerant to nonsteroidal anti-inflammatory drugs (NSAIDs). Methods: This phase II, randomized, double-blind, placebo-controlled, multicenter study enrolled 160 patients with active axSpA. Participants were randomized equally to receive placebo or Xeligekimab at 100 mg, 200 mg, or 300 mg subcutaneously every two weeks for 16 weeks, followed by an 8-week follow-up. The primary endpoint was the Assessment of SpondyloArthritis International Society 20 (ASAS20) response at week 16. Secondary endpoints included ASAS40, ASDAS-CRP, BASDAI, BASFI, and patient-reported outcomes. Safety and immunogenicity were evaluated throughout the study. Results: At week 16, ASAS20 response rates were 52.5% with placebo and 77.5%, 75.0%, and 72.5% with Xeligekimab 100 mg, 200 mg, and 300 mg, respectively. The 100 mg and 200 mg groups showed significant improvement versus placebo (P < 0.05). Benefits in ASAS40, ASDAS-CRP, and BASDAI were maintained through week 24. Xeligekimab was generally well tolerated, and the overall incidence of adverse events was comparable to placebo. No treatment-emergent anti-drug antibodies were detected. Conclusion: Xeligekimab at 100 mg and 200 mg achieved meaningful clinical improvement with good tolerability in patients with active axSpA, supporting further clinical evaluation of this therapy.

OBJECTIVES:This study aimed to investigate the gender-specific factors influencing health-related quality of life (HRQoL) among rheumatoid arthritis (RA) patients within biopsychosocial framework and the interacting effects of these factors. METHODS:A prospective multi-centre cross-sectional study was conducted. Binary logistic regression and subsequent stratified analyses were used to analyse the determinants of HRQoL among RA patients and how they interacted. RESULTS:Female patients (83.85%) exhibited earlier onset (45.68 vs. 50.85 years), longer disease duration (60.00 vs. 36.00 months), lower Clinical Disease Activity Index (CDAI) (19.00 vs. 22.00), and less glucocorticoid use (39.55% vs. 47.75%). Multivariable analysis suggested that better HRQoL was linked to urban residence and higher education. Worse HRQoL was related to older age at onset, higher financial burden, glucocorticoid use, elevated CDAI, irregular follow up, longer follow-up intervals, comorbidities, anxiety/depressive symptoms, poor sleep satisfaction, and fatigue. Stratified analysis revealed significant interactions among CDAI and financial burden, anxiety/depressive symptoms and sleep satisfaction. CONCLUSIONS:These findings highlight the biopsychosocial factors affecting HRQoL, emphasising the need for gender-specific strategies and targeted interventions focusing on financial burden, anxiety/depressive symptoms and sleep satisfaction in RA patients with moderate-to-high disease activity.

Sjögren disease (SjD) causes salivary hypofunction and ocular dryness. To investigate mechanisms of autoimmunity and salivation, we profiled unstimulated whole saliva from SjD patients and demographically matched controls by 4D-DIA proteomics and untargeted LC–MS/MS metabolomics. Unstimulated whole saliva from patients meeting the 2016 ACR–EULAR criteria for SjD and demographically matched controls was profiled by 4D-DIA proteomics and untargeted LC–MS/MS metabolomics. An independent validation cohort (newly diagnosed SjD, n = 24; controls, n = 24) underwent ELISA for salivary ZG16B, a subset provided labial minor salivary gland (LSG) tissue for immunofluorescence (IF). Proteomics identified 2032 differentially expressed proteins (1355 up; 677 down). Gene Ontology indicated downregulation of epithelial differentiation, structural maintenance, and epithelial tube formation, while KEGG highlighted enrichment of protein catabolism, immune regulation, and protein processing pathways. ZG16B was significantly reduced in SjD. Metabolomics detected 702 differential metabolites (307 up; 385 down); upregulated pathways involved protein digestion/absorption and multiple amino-acid metabolisms, whereas downregulated pathways mapped to aerobic respiration, suggesting reduced energy production. In validation, salivary ZG16B levels were markedly lower in newly diagnosed SjD than controls, and IF showed absent or sparse ZG16B-positive acinar cells in SjD LSG. Salivary ZG16B correlated positively with tear and salivary flow rates and inversely with focus score (FS). Integrated proteo-metabolomic analysis reveals concurrent epithelial injury, immune activation, and compromised energy metabolism in SjD salivary glands. ZG16B downregulation is associated with exocrine dysfunction, supporting ZG16B as a promising noninvasive biomarker for SjD.

Nomenclature for the disease widely known as Sjögren syndrome has proven unsatisfactory. Patients have perceived ‘syndrome’ as indicative of a vague collection of symptoms, prompting the Sjögren’s Foundation to abandon the term. Furthermore, the traditional distinction between ‘primary’ and ‘secondary’ forms fails to account for the complex interplay between overlapping autoimmune diseases. Following a bibliometric analysis, systematic literature review and a Delphi consensus process with equal involvement of professional and patient representatives, five recommendations are now issued. First, the term ‘Sjögren disease’ should replace ‘Sjögren syndrome’. Second, the acronym ‘SjD’ should be used as an abbreviation for ‘Sjögren disease’. Third, the descriptor ‘associated’ should be used in lieu of ‘secondary’ for Sjögren disease occurring in association with a second systemic autoimmune disease for which classification criteria are fulfilled. Fourth, Sjögren disease is the preferred terminology in common parlance and in clinical diagnosis, without differentiation as to primary and associated forms. Fifth, the differentiation between primary and associated Sjögren is recommended for scientific studies to define a homogeneous population. In conclusion, the consensus endorses ‘Sjögren disease’ as the official nomenclature to acknowledge the distinct pathogenesis of this disorder and to improve clarity in both clinical practice and research. In this Consensus Statement, an international group of experts and patient representatives validates and endorses the transition from the term ‘Sjögren syndrome’ to ‘Sjögren disease’, and issue several additional recommendations regarding the nomenclature of this disorder.

Xeligekimab is a novel immunoglobulin G4 (IgG4) monoclonal antibody targeting interleukin-17A (IL-17A). In a phase III trial in patients with plaque psoriasis, xeligekimab showed efficacy and safety consistent with other IL-17A inhibitors, supporting its potential application in the treatment of spondyloarthritis. This phase III trial aimed to investigate the efficacy and safety of xeligekimab in patients with radiographic axial spondyloarthritis (r-axSpA). This was a phase III study conducted at multiple centers in China. Eligible patients were randomly assigned (1:1:1) to receive xeligekimab 100 mg, xeligekimab 200 mg, or placebo. Randomization was stratified by medication history (biologic-experienced vs. biologic-naïve) and weight (≥ 70 kg vs. < 70 kg). The primary endpoint was the proportion of patients achieving an Assessment of SpondyloArthritis International Society 20 (ASAS20) response at week 16. A key secondary endpoint was the ASAS40 response rate at the same time point. A total of 465 patients were recruited. A significantly higher proportion of patients receiving xeligekimab 200 mg (n = 114 (74.0

Autoimmune pathologies arise from dysregulated immune activation, yet conserved molecular programs across autoimmune contexts remain incompletely characterized. Here, we analyzed integrative single-cell RNA sequencing data of over 1.3 million cells from 239 samples spanning six autoimmune diseases, revealing disease-specific and cell type-specific transcriptional programs. Systematic immune profiling identified 41 functionally annotated gene clusters (GCs) with cross-disease activation. We identified a cytotoxic CD8 + T cell-enriched gene cluster (GC40) that drives enhanced cytotoxic function and clonal expansion across four autoimmune diseases. In parallel, we identified a secretory granule lumen-associated GC08 that is highly expressed in CD14 + monocytes and promotes plasma cell activation through upregulation of TNFSF13B secretion. Furthermore, we leveraged a disease classifier to discriminate autoimmune disease types and healthy states. Our study provides both a resource and a predictive framework at the single-cell level, supporting future targeted therapies for autoimmune diseases.

OBJECTIVES:This study aimed to compare the efficacy and safety of subcutaneous MTX (SC MTX) and oral MTX (OR MTX) in treating Chinese patients with active RA. METHODS:This study included patients with active RA in China. All patients were randomly assigned to receive SC MTX or OR MTX. The primary end point was Disease Activity Score-28 for erythrocyte sedimentation rate (DAS28-ESR) after 12 weeks of treatment. RESULTS:DAS28-ESR scores of the SC MTX and OR MTX groups significantly decreased compared with baseline at week 12. The least squares mean (±S.E.) of the change in DAS28-ESR scores were -1.972 ± 0.1448 and -1.800 ± 0.1438 in the SC MTX and OR MTX groups. The intergroup difference was -0.173 ± 0.2041, indicating that the SC MTX group was not inferior to the OR MTX group. With respect to the secondary endpoints of ACR20/50/70, DAS28-CRP and the proportion of patients in disease remission by DAS28(CRP) but not with DAS28(ESR), SC MTX was numerically better than OR MTX during the first 8 weeks but not all by week 12. The safety profile of SC MTX is similar to that of OR MTX in general, and the incidence, occurrences and preferred term types of drug-related TEAE of gastrointestinal system disorders were lower. CONCLUSIONS:SC MTX had similar overall therapeutic effects compared with OR MTX and was generally well tolerated. Some efficacy results showed greater improvement during the first 8 weeks of SC MTX vs OR MTX but not by week 12. TRIAL REGISTRATION:https://www.chictr.org.cn, identifier ChiCTR2200066425.

This study is a prospective cohort study aimed at evaluating the impact of personalized rehabilitation guidance delivered through the WeChat Official Accounts Platform on functional recovery and quality of life in patients with knee osteoarthritis (KOA). Ninety patients diagnosed with KOA who underwent joint replacement surgery were recruited from two orthopedic wards. Patients from Orthopedic Ward 1 were assigned to the observation group, and patients from Orthopedic Ward 2 were assigned to the control group. The control group received traditional rehabilitation guidance, while the observation group received personalized rehabilitation guidance through the WeChat Official Accounts Platform in addition to traditional guidance. Key observation indicators included the 36-item Short Form Health Survey (SF-36), Numerical Rating Scale (NRS). The observation group demonstrated significantly higher SF-36 and Lysholm Knee Scoring Scale scores and lower NRS scores. These findings indicate that the personalized rehabilitation model effectively improves clinical outcomes in KOA patients. Personalized care plans delivered through the WeChat Official Accounts Platform significantly improve the quality of life, alleviate pain, and enhance knee joint function in KOA patients. This innovative, accessible, and cost-effective approach shows great promise for widespread application in home-based rehabilitation, addressing healthcare disparities and improving outcomes for patients. ClinicalTrials.gov Identifier: NCT06754241.

OBJECTIVE:The impact of primary Sjögren's syndrome (pSS) on adverse pregnancy outcomes remains a debated issue. Research suggests that newborns of mothers with pSS may be at a higher risk of developing heart conditions. This study aimed to examine the relationship between maternal pSS and the risk of cardiac disorders in neonates. METHODS:A multicentre, retrospective cohort study was conducted with pSS patients treated between January 2015 and May 2024. Data on demographics, comorbidities, disease activity, pregnancy outcomes and treatments were collected. Associations between adverse pregnancy outcomes and preconception characteristics were analysed. RESULTS:Among 169 newborns from pSS mothers, 49 had heart diseases, while 120 did not. Newborns with cardiac conditions had higher rates of premature birth (P = 0.002), lower birth weight (P = 0.012) and increased risk of neonatal asphyxia (P = 0.009), brain injury (P < 0.001) and neonatal infections (P < 0.001). Mothers who delivered babies with heart conditions had more umbilical cord abnormalities (P = 0.002) and threatened preterm labor (P = 0.008). Lower C3 and C4 levels (P = 0.022, P = 0.033) and use of glucocorticosteroids (P = 0.005) and ciclosporin A (P = 0.036) were linked to neonatal heart diseases. High EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scores increased the risk of heart disease in newborns [OR 1.503, 95% CI (1.148, 1.966), P = 0.003]. CONCLUSION:Maternal pSS, especially with high disease activity, elevates the risk of neonatal heart disease, highlighting the need for careful monitoring during pregnancy.

OBJECTIVES:Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), characterised by kidney inflammation, tubular injury, and interstitial fibrosis. However, the spatial organisation of these heterogeneous cell populations and their regulatory mechanisms in LN remain poorly understood. The objective of this study was to investigate the regulatory mechanisms underlying region-specific kidney lesions and tubular damage in LN. METHODS:We performed single-cell multiome and spatial transcriptomic analyses on kidney biopsy samples from patients with LN and controls, integrating data from the largest East Asian SLE genome-wide association studies (GWAS) (208,370 samples) to date. Validation experiments were performed using multiplex immunohistochemistry (mIHC), in vitro lentiviral-mediated transcription factor overexpression, and functional stimulation assays. RESULTS:We identified VCAM1-expressing proximal tubule (PT_VCAM1) cells as components of an LN-specific inflammatory niche (niche 5) localised in the kidney cortex. Both in silico and in vitro experiments demonstrated that interactions between PT_VCAM1 cells and myofibroblasts, as well as immune cells in niche 5, promote their epithelial-mesenchymal transition. Trajectory analysis suggested that PT_VCAM1 cells originate from a failed-repair pathway in proximal tubule cells, regulated by transcriptional networks involving BACH2. Integrative GWAS analysis further linked SLE-associated risk single-nucleotide polymorphisms to cis-regulatory elements specific to PT_VCAM1 cells, including single-nucleotide polymorphisms within the distal enhancer of the BMP2K locus, which establishes a BACH2 motif. CONCLUSIONS:Collectively, our findings characterise PT_VCAM1 cells as injury-responsive cell states that contribute to the inflammatory and fibrotic niche in LN, linking genetic predisposition to cellular injury and disease progression.

Background: Promoting coronavirus disease 2019 (COVID-19) vaccination is crucial among older adults, particularly those geriatric. This study aimed to analyze the association between chronic conditions, multimorbidity, and vaccination status in adults aged >= 80 years old to provide recommendations for vaccine-preventable diseases. Methods: A cross-sectional study was conducted in Beijing from April 5, 2023, to May 5, 2023, including participants aged >= 80 years old who did not receive the booster COVID-19 vaccination. Data on vaccination status, COVID-19 infection history, nine underlying conditions, and disease-control status were collected via cluster sampling through door-to-door interviews and telephone surveys using questionnaires. A multiple logistic regression model adjusted for age, sex, location, COVID-19 infection history, and education level were used to analyze the association between underlying conditions and vaccination status. Results: In total, 51,834 participants were included of whom 41,209 (76.6 %) were unvaccinated. Underlying diseases (92.3 %) and multimorbidities (65.7 %) were prevalent among the participants. Hypertension (74.6 %), cardiovascular disease (48.5 %), and diabetes (42.0 %) were the most prevalent conditions. Participants diagnosed with underlying conditions were significantly associated with being unvaccinated (Odds ratio [95 % confidential interval] OR [95 %CI]: 2.21 [2.05-2.37]). Furthermore, the proportion of unvaccinated individuals increased with both the number and severity of underlying conditions. Conclusions: The number and severity of underlying conditions were associated with unvaccinated status. To promote vaccination for geriatrics, standardized vaccination guidelines for individuals with underlying conditions should be developed. Additionally, family doctors play an essential role in vaccination assessment and recommendations during disease diagnosis and treatment.