Background/Objectives: Behçet’s disease (BD) is a systemic vasculitis frequently affecting women of childbearing age. However, the relationship between systemic manifestations and pregnancy loss remains unclear. This study evaluated the association between pregnancy loss history and systemic clinical characteristics in women with BD. Methods: This retrospective cohort study included 114 women with BD followed in a rheumatology outpatient clinic between January 2021 and December 2025. In total, 196 pregnancies were recorded. Women without a pregnancy history were excluded. Pregnancy loss was defined as any spontaneous loss, including biochemical pregnancy, miscarriage, or fetal death, excluding elective terminations. Disease activity was assessed using the Krause score, and univariable logistic regression was performed. Results: Among 97 women with a pregnancy history, 25 (25.8%) had at least one pregnancy loss. Compared with women without pregnancy loss, those with pregnancy loss had longer disease duration and higher Krause scores. Gastrointestinal involvement (OR 6.31, 95% CI 1.87–23.28, p = 0.0035) and ocular involvement (OR 3.93, 95% CI 1.44–10.89, p = 0.0076) were significantly associated with pregnancy loss history. Higher Krause scores were also associated with greater odds of pregnancy loss history. Conclusions: In women with BD, pregnancy loss history was associated with systemic organ involvement and higher disease activity, particularly gastrointestinal and ocular involvement. These findings should be interpreted cautiously in light of the retrospective design and univariable analyses, and they suggest that pregnancy loss history may be associated with greater systemic disease burden.

OBJECTIVE:To characterize the clinical, immunologic, and proteomic changes associated with CD19 chimeric antigen receptor T cell therapy in patients with progressive systemic sclerosis (SSc). METHODS:Patients with progressive SSc received CD19 chimeric antigen receptor (CAR)-T cell therapy and were observed longitudinally for safety, clinical efficacy, immune reconstitution, and plasma proteomic changes. Clinical assessments included skin, pulmonary, vascular, patient-reported, and physician-reported outcomes. Plasma proteins were profiled at baseline and serial post-treatment time points using the SomaScan platform. Differential protein abundance and pathway-level changes were analyzed to explore treatment-associated molecular remodeling. RESULTS:CD19 CAR-T cell therapy was associated with manageable safety profiles and sustained clinical improvement across multiple SSc disease domains, including skin involvement and patient- and physician-assessed disease activity. Treatment induced rapid B cell depletion followed by immune reconstitution. Longitudinal proteomic profiling revealed coordinated changes in proteins and pathways related to inflammation, fibrosis, vascular remodeling, and immune regulation. At day 180, differential protein analysis identified treatment-associated shifts in multiple systemic sclerosis-relevant proteins, including down-regulation of proteins linked to profibrotic or inflammatory activity and up-regulation of proteins potentially associated with vascular repair or immune regulation. Pathway-level analyses further supported broad attenuation of inflammatory and fibrotic programs with relative enhancement of repair-associated biologic processes. CONCLUSION:Relma-cel therapy in patients with SSc led to early clinical improvement, supported by CAR-T cell expansion, B cell depletion, and a favorable safety profile. Proteomic alterations were associated with the observed clinical improvements and suggested broad remodeling of inflammatory and fibrotic pathways. Further studies with larger sample sizes are warranted.

KEY POINTS:Platelet-activating factor receptor contributed to renal tubular epithelial cells G2/M arrest through suppressing mouse double minute 2-mediated p53 ubiquitin degradation in AKI-to-CKD transition. Phosphatidylethanolamine (18:0/18:1) served as a novel endogenous ligand of platelet-activating factor receptor, inducing the downstream signaling. WAY-639497, a small-molecule platelet-activating factor receptor antagonist identified by virtual screening, mitigated renal tubular epithelial cells G2/M arrest and AKI-to-CKD transition. BACKGROUND:AKI represents a critical clinical complication with a high propensity of progression to CKD, yet effective therapies remain limited. G protein-coupled receptors mediate diverse pathophysiological processes and are promising therapeutic targets. Here, we investigated the role of platelet-activating factor receptor (PTAFR), a lipophilic G protein-coupled receptor, in AKI-to-CKD transition. METHODS:A mouse model of ischemia-reperfusion injury (IRI)-induced AKI was built by bilateral renal artery clamping. The phenotypic role of PTAFR in renal tubular epithelial cells (RTECs) after AKI was investigated in tubule-specific PTAFR-deficiency mice. The functional and molecular mechanisms were determined by transcriptomic profiling, flow cytometry, coimmunoprecipitation, Western blotting, and immunofluorescence. Lipidomic analysis and biological experiments were used to identify the endogenous ligand of PTAFR. The translational potential of PTAFR was evaluated by structure-based high-throughput virtual screening of a small-molecule inhibitor in vivo and in vitro assays. RESULTS:The expression of PTAFR was upregulated in RTECs after AKI in vivo and in vitro . Tubule-specific depletion of PTAFR alleviated IRI-induced RTEC injury and kidney fibrosis after AKI. Mechanistically, PTAFR promoted RTECs G2/M arrest by suppressing mouse double minute 2-mediated p53 ubiquitin degradation. Phosphatidylethanolamine (18:0/18:1) was identified as a novel PTAFR endogenous ligand inducing RTECs G2/M arrest. Urinary phosphatidylethanolamine (18:0/18:1) was correlated with kidney dysfunction and was able to effectively distinguish patients with AKI from healthy controls. High-throughput virtual screening identified WAY-639497, a small-molecule PTAFR antagonist, that was able to mitigate IRI-induced RTEC injury and kidney fibrosis after AKI. CONCLUSIONS:PTAFR promoted tubular epithelial cell G2/M arrest by inhibiting mouse double minute 2-mediated p53 ubiquitin degradation and further contributed AKI-to-CKD transition.

Implant-associated infections (IAIs), particularly those caused by antibiotic-resistant pathogens and protected by biofilms, remain a formidable challenge in orthopedic surgery due to limited antibiotic efficacy and sustained local immunosuppression. Addressing this dual bottleneck, we report a multifunctional MoS₂@Fe₃O₄ heterostructure nanocomposite that enables ultrasound (US)-triggered piezocatalytic antibacterial therapy coupled with immune microenvironment remodeling. The nanoplatform integrates the piezoelectric polarization of MoS₂ and the Fenton-like catalytic activity of Fe₃O₄ to achieve efficient charge separation, interfacial polarization, and enhanced Fe³⁺/Fe²⁺ cycling, generating high levels of ROS (•OH, •O₂⁻, ¹O₂) under low-intensity US irradiation. These reactive species effectively disrupt MRSA biofilms, promote bacterial membrane rupture, and expose pathogen-associated antigens. Importantly, this treatment activates the cGAS–STING signaling axis in dendritic cells, enhances M1-type macrophage polarization, and triggers coordinated innate and adaptive immune responses. In a murine subcutaneous IAI model, MoS₂@Fe₃O₄ + US not only eradicated biofilm infections and reduced myeloid-derived suppressor cell (MDSC) infiltration, but also induced robust CD4⁺/CD8⁺ T cell activation and memory B/T cell formation, effectively preventing infection recurrence after implant replacement. This work presents a paradigm-shifting, non-antibiotic immunotherapeutic strategy that integrates catalytic disinfection, immune activation, and long-term protection in a single nanoplatform. By overcoming key limitations of current treatments, our approach offers substantial promise for improving clinical outcomes in IAIs and advancing the field of immune-interactive nanomedicine.

ObjectiveThis study aimed to develop and externally validate a clinical risk identification model for prevalent rheumatoid arthritis-associated interstitial lung disease (RA-ILD) using multicenter Chinese patient cohorts. We also evaluated the discriminative value of MUC5B polymorphisms (rs35705950 and rs868903) in a combined clinical-genetic model for this purpose.MethodsA multicenter, two-phase design was adopted. A total of 446 patients with rheumatoid arthritis (RA) from five medical centers were retrospectively enrolled in the discovery phase. Multivariate logistic regression was used to identify independent risk factors associated with RA-ILD and to construct a clinical risk identification model. A total of 238 patients with RA from three medical centers were then prospectively recruited for the validation phase and genotyped for MUC5B (rs35705950 and rs868903). External validation of the clinical model was performed first, followed by the construction of a combined clinical-genetic model. The model’s discrimination was assessed using receiver operating characteristic (ROC) curve analysis, and calibration was evaluated using the Hosmer–Lemeshow test.ResultsIn the discovery phase, smoking history (odds ratio [OR] = 2.00, P = 0.045), elevated rheumatoid factor (RF) (OR = 1.10 per 10 IU/mL, P = 0.037), a higher 28-joint disease activity score (DAS28) (OR = 1.20, P = 0.023), elevated serum carbohydrate antigen 19-9 (CA19-9) (OR = 3.70, P = 0.002), elevated lactate dehydrogenase (LDH) (OR = 1.13 per 10 U L, P < 0.001), and disease duration of ≥ 24 months (OR = 1.73, P = 0.029) were identified as independent risk factors for RA-ILD. Our clinical risk identification model yielded an area under the ROC curve (AUC) of 0.785 (95% confidence interval [CI]: 0.74–0.83). In the prospective validation cohort, we identified a novel association between MUC5B rs868903 and RA-ILD (OR = 2.58, P = 0.001), with both rs868903 and rs35705950 distinguishing patients with RA-ILD from those without ILD (P < 0.05).The combined model incorporating MUC5B genotypes achieved an AUC of 0.786, which did not differ significantly from that of the clinical model alone (P = 0.507). Although the genetic variants significantly improved continuous risk stratification (integrated discrimination improvement [IDI] = 0.020, P = 0.040; continuous net reclassification improvement [NRI] = 0.466, P < 0.001), categorical NRI at clinically relevant thresholds was non-significant.ConclusionsThis multicenter study validated a clinical risk identification model for RA-ILD. We identified a novel association between MUC5B rs868903 and RA-ILD in a Chinese cohort. Although the incorporation of genetic information improved continuous risk estimation, it provided limited incremental value at standard clinical decision-making thresholds, indicating that clinical indicators play a dominant role in RA-ILD risk identification. The resultant clinical model may have broad potential for routine clinical use.

To evaluate infection risks in rheumatoid arthritis (RA) patients with biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) as monotherapy or combined with conventional synthetic DMARDs (csDMARDs). A comprehensive literature search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from their inception to 31 October 2024 was conducted to identify randomized controlled trials (RCTs) assessing infection risks in RA patients receiving b/tsDMARDs. Primary outcome was serious infection incidence; secondary outcomes included any infection and specific events such as respiratory tract infections, gastroenteritis and herpes zoster. A frequentist network meta-analysis was performed to calculate odds ratios (ORs). A total of 127 RCTs involving 55,749 patients were included. b/tsDMARD monotherapy showed a similar risk of serious infections versus csDMARDs. Combining csDMARDs with adalimumab, infliximab, tofacitinib, or upadacitinib (though not with other b/tsDMARDs) was associated with a significantly increased risk of serious infections (OR 1.51, 95

Background: Systemic sclerosis (SSc) is a progressive autoimmune disease associated with high morbidity and mortality, although the Very Early Diagnosis of SSc (VEDOSS) framework extends the diagnostic window, subclinical injury may already be established at this stage. We aimed to characterize molecular alterations across the spectrum from the asymptomatic SSc-specific autoantibody-positive phase (SSAP) through VEDOSS to established SSc using integrated multi-omics profiling. Methods: In this cross-sectional multi-omics study within the Renji Scleroderma Longitudinal Cohort, peripheral blood mononuclear cell transcriptomic profiling and plasma proteomic analyses were performed in healthy controls, individuals with SSAP, VEDOSS, limited cutaneous SSc (lcSSc), and diffuse cutaneous SSc (dcSSc). Differential expression analysis, trend modelling, and functional enrichment analysis were used to evaluate stage-associated molecular features. Results: Both transcriptomic and proteomic analyses revealed a continuous molecular gradient from healthy controls to established SSc, positioning SSAP and VEDOSS as intermediate states. Immune dysregulation, particularly innate immune activation and type I interferon signaling, was detectable at the SSAP stage and progressively intensified with disease progression. Concurrently, proteins associated with vascular injury and extracellular matrix remodeling were upregulated from the earliest stages and sustained throughout disease evolution. Preliminary longitudinal observations were consistent with these findings, with individuals in the SSAP and VEDOSS groups showing a potential for clinical progression. Conclusions: SSc pathogenesis begins prior to clinical onset, with early immune activation, vascular perturbation, and profibrotic signaling already evident in the asymptomatic autoantibody-positive phase. This study provides a multi-omics characterization of early disease-associated changes and supports further investigation of their potential role in risk stratification and early disease recognition.

Dysregulation of the CARD11-BCL10-MALT1 (CBM) complex is associated with a group of inborn errors of immunity termed “CBM-opathies,” which encompass a spectrum of clinical manifestations including combined immunodeficiency, autoimmune inflammation, atopic disorders, and lymphoproliferation. In this study, we identified novel compound heterozygous variants in the CBM complex in a patient with a family history of immune dysfunction. The patient inherited the variants CARD11 p.K215N and MALT1 p.K543R/p.M732T from asymptomatic carrier parents. Phenotypically, the patient exhibited a developmental arrest of B lymphocytes at the transitional/naïve B cell stage, accompanied by activation of virus-response pathways. Impaired development of T follicular helper cells was linked to defective germinal center formation and agammaglobulinemia. Furthermore, the patient showed expansion of T peripheral helper cells and a deficiency in regulatory T cells, both associated with autoimmunity and colitis. In vitro studies confirmed an imbalance in Tph/Tfh cell differentiation. Single-cell RNA sequencing further revealed a deficiency in B cell development and an enriched population of pro-inflammatory CD3dimCD4−CD8−CD247+ T cells, functionally enriched in the MAPK signaling pathway. Mechanistically, the MALT1 K543R and M732T variants attenuated MALT1’s enzymatic activity and compromised its protein stability, while the CARD11K215N variant disrupted CARD11-mediated promotion of BCL10 filament formation. We demonstrated that these three variants act synergistically to impair NF-κB activation. Specifically, CARD11K215N cooperates with the co-pathogenic MALT1M732T and the modifier variant MALT1K543R to destabilize the functional integrity of the CBM complex, thereby driving the patient’s phenotype. In summary, our study provides new insights into the pathogenesis of autoimmune inflammatory disorders within the spectrum of CBM-opathies and reveals a potential role for the CBM complex in regulating the balance between T peripheral helper and T follicular helper cells. Identified three novel variants in the CBM complex in a patient with a family history of immune dysfunction. CARD11K215N/MALT1K543R/M732T variants impaired B cell development and CD4+T cell differentiation, especially T peripheral helper and T follicular helper cells, by destabilizing the functional integrity of CBM complex.

Background/Objectives: Systemic sclerosis (SSc) is an autoimmune fibrosing disorder in which cutaneous involvement is a major manifestation. We investigated whether shear wave elastography (SWE) can distinguish SSc from healthy controls and examined how SWE relates to clinical and histological indices of skin fibrosis. Methods: The study included 78 patients with SSc and 30 healthy controls (HCs). High-frequency ultrasound (HFUS) quantified skin thickness and SWE quantified stiffness at the fingers, dorsal hands, and forearms. Ultrasound findings were examined in relation to the modified Rodnan Skin Score (mRSS). In 15 patients with diffuse cutaneous SSc (dcSSc), matched forearm biopsies were additionally analyzed for dermal thickness and collagen content. Results: Relative to HCs, patients with dcSSc had greater epidermal and dermal thickness at all examined sites, while patients with lcSSc had greater dermal thickness only at the fingers. Associations between dermal thickness and mRSS varied by site (Spearman ρ, 0.47–0.66). SWE values were higher in SSc than in HCs. The AUCs for distinguishing SSc from HCs were 0.820 at the fingers, 0.734 at the dorsal hands, and 0.760 at the forearms. Within the dcSSc biopsy subgroup, SWE correlated with collagen volume fraction (ρ = 0.68, p = 0.0068) and histological dermal thickness (ρ = 0.63, p = 0.0142). Conclusions: SWE enables quantitative non-invasive characterization of skin stiffness in SSc. Matched forearm histology in a small dcSSc subgroup provides preliminary evidence that the imaging measurements converge with tissue-level measures. Validation in larger independent cohorts is needed.

BACKGROUND:Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheumatoid arthritis (RA). However, the immune-fibrotic mediators that bridge articular inflammation and pulmonary injury have not been fully defined. Natural products represent a promising source of multi-target therapeutics, but their therapeutic effects and mechanisms in RA-ILD remain largely unclear. PURPOSE:This study aimed to identify key immune-related secretory proteins involved in RA-ILD and to explore potential therapeutic compounds targeting the inflammatory-fibrotic axis. METHODS:We performed an integrated bioinformatic analysis using transcriptomic datasets from RA synovial tissues, RA peripheral blood mononuclear cells (PBMCs), and ILD lung tissues. RA-associated differentially expressed secretory proteins and ILD lung key genes were identified through differential expression analysis and weighted gene co-expression network analysis (WGCNA). Shared candidate genes were further prioritized using LASSO regression, support vector machine-recursive feature elimination (SVM-RFE), and external validation in an independent RA-ILD dataset. Protein-protein interaction (PPI) network analysis and functional enrichment were used to define a shared inflammatory program and guide compound prediction. Tanshinone IIA (TANIIA) was prioritized for experimental validation. Serum ELISA, collagen-induced arthritis (CIA) mouse studies, histology, flow cytometry, immunofluorescence, single-cell RNA sequencing analysis, macrophage-fibroblast co-culture, western blotting, and cellular thermal shift assay (CETSA) were used to validate molecular and pharmacological findings. RESULTS:SLAMF7 was identified as the sole hub gene converging RA-associated secretory proteins, ILD-related key genes, and RA-ILD differential expression signatures, exhibiting strong diagnostic performance and significantly elevated serum levels in RA-ILD patients. Network analysis identified a broader inflammatory hub-gene program enriched in TNF, chemokine, and IL-17 signaling pathways, with SLAMF7 linked to this network. TANIIA was prioritized as a candidate compound and showed favorable docking affinity to multiple hub-gene targets. In CIA mice, TANIIA alleviated arthritis, reduced circulating inflammatory and profibrotic mediators, downregulated SLAMF7 expression, and attenuated pulmonary fibrosis and macrophage infiltration. scRNA-seq revealed that SLAMF7 was enriched in pulmonary macrophages with a profibrotic transcriptional program. In vitro, recombinant SLAMF7 was sufficient to induce M2-like macrophage polarization accompanied by CREB/C/EBPβ activation, whereas TANIIA attenuated this response. CONCLUSION:SLAMF7 is a potential biomarker and mechanistically relevant mediator linking inflammation and fibrosis in RA-ILD. TANIIA exerts dual protective effects on joint and lung pathology by suppressing inflammatory responses and targeting the SLAMF7-associated macrophage-fibrosis axis.

To evaluate comparative effectiveness of methotrexate (MTX), calcineurin inhibitors (CNI), Janus kinase inhibitors (JAKi), and biologics for the first-line therapies in adult-onset Still’s disease (AOSD) in real-world settings. Two AOSD cohorts were retrospectively analysed. First, effectiveness of first-line biological versus non-biologic modulator was validated using overlap weighting of propensity scores in the Shanghai AOSD cohort. To compare AOSD treatment strategies (MTX, CNI, JAKi, biologics), we pooled data from the Shanghai and Erlangen cohorts, emulated a target trial, and applied doubly robust weighted regression to adjust for demographic and clinical confounders. The primary outcome was sustained event-free remission over 12 and 72 weeks. 124 AOSD patients were analyzed, 96 from the Shanghai and 28 from Erlangen cohort. In overlap-weighted analyses of Shanghai cohort, biologic was associated with higher sustained event-free remission and event-free state than non-biologic immune modulators (P = 0.0065 and P = 0.0096). In the pooled analysis, biologics were linked to higher likelihood of event-free state and sustained event-free remission at weeks 12 and 72 (all P < 0.05). Pairwise comparisons confirmed the advantage of biologics over CNI (sustained event-free remission at week 72 OR 0.11, p = 0.001), with significant benefits over MTX (OR 0.12, p = 0.002) and JAKi (OR 0.14, p = 0.008) emerging at week 72 for sustained event-free remission, and more frequent glucocorticoid discontinuation than MTX and CNI (both p < 0.05). First-line biological treatment is associated with improved sustained event-free remission compared to non-biologic treatments, such as MTX, CNI and JAKi and associated with more favorable long-term outcomes in AOSD.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial infiltration of polarized M1 macrophages that secrete pro-inflammatory cytokines (TNF-α/IL-1/IL-6) and activate JAK-STAT/NF-κB pathways. These events disrupt the osteoblast-osteoclast balance to induce cartilage degradation and bone erosion. Current disease-modifying antirheumatic drugs (DMARDs), including tofacitinib, show limited efficacy due to systemic toxicity, poor bone-targeting capacity, and inability to restore bone homeostasis. To overcome these limitations, we developed a multifunctional nanoplatform (MBGN-Tofa@PDA-FA) based on magnesium-doped mesoporous bioactive glass nanoparticles (Mg-MBGNs) to codeliver the JAK inhibitor tofacitinib and osteoimmunomodulatory Mg2+/Ca2+ ions, aiming to overcome the severe systemic toxicity of free drugs. This system suppresses inflammation by polarizing macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype (M1-to-M2 repolarization), and synergistically promotes osteoblast differentiation. Polydopamine (PDA) coating improves colloidal stability and enables photoacoustic imaging (PAI), while folic acid (FA) modification ensures selective uptake by folate receptor-overexpressing macrophages. By integrating imaging with targeted therapeutic delivery, this platform provides both real-time monitoring and enhanced treatment efficacy. Collectively, our strategy establishes a promising precision theranostic approach for RA by uniting targeted immunomodulation, bone regeneration, and treatment evaluation. Furthermore, in vivo evaluations demonstrated the excellent biodistribution and biosafety profile of this nanoplatform, reinforcing its strong potential for clinical translation.

Anti-MDA5 antibody-positive dermatomyositis (DM) is characterized by the presence of anti-MDA5 antibodies. We aimed to assess longitudinal changes of anti-MDA5 antibody levels and long-term outcomes in 6-month survivors of anti-MDA5 + DM with interstitial lung disease (ILD). Anti-MDA5 antibody titers were measured using enzyme-linked immunosorbent assay upon newly diagnosed anti-MDA5 + DM-ILD patients. Patients with follow-up beyond 6 months and at least two anti-MDA5 antibody measurements were subsequently subjected to group-based trajectory analysis by utilizing latent class mixture model. Seroconversion was defined as a change from positive to negative for anti-MDA5 antibodies. Outcome measurements include low disease activity (LDA) status and remission. In 6-month survivors, two anti-MDA5 antibody trajectories were identified: “fast seroconvertors” and “slow seroconvertors”. The median time to anti-MDA5 seroconversion for fast seroconvertors was 9 (IQR: 5–15) months, whereas slow seroconvertors did not achieve 50

ObjectiveFungal infections are uncommon but potentially life-threatening complications in adult-onset Still’s disease (AOSD). The immunological features of AOSD patients with fungal infections remain poorly defined, and this study aimed to characterize immune activation profiles in this population.MethodsWe retrospectively analyzed 277 patients diagnosed with AOSD, among whom 35 (12.6%) developed fungal infections. Clinical features and immunological parameters, including neutrophil CD64 (nCD64), myeloid-derived suppressor cells (MDSCs), activated T cells, and serum cytokine profiles, were compared between patients with and without fungal infections.ResultsCompared to non-infected AOSD patients, those with fungal infections had a higher frequency of splenomegaly (60.0% vs. 33.5%, p = 0.0024), pulmonary infiltrates (57.1% vs. 20.2%, p < 0.001), and pericarditis (42.9% vs. 20.7%, p = 0.0038). Immunologically, the infection group showed significantly elevated levels of nCD64 (45.39 vs. 11.16, p < 0.05) and enhanced CD8+ T cell activation, particularly CD8+CD38+ T cells (81.54% vs. 66.89%, p < 0.05). Serum soluble IL-2R levels were also higher in infection patients (1884.18 vs. 1259.13 U/mL, p < 0.05). Cytokines such as IL-8, and IL-10 were markedly elevated during infection episodes. Additionally, ferritin elevation remained independently associated with fungal infection after adjusting for disease activity, MAS, and glucocorticoid exposure.ConclusionsAOSD patients with fungal infections exhibit distinct immune activation patterns involving neutrophils and CD8+ T cells, reflecting dynamic immune changes during infection episodes. These immunological features may support integrated immune assessment and inform therapeutic considerations under immunosuppressive treatment.

Macrophage activation syndrome (MAS) represents a severe and potentially life-threatening complication of adult-onset Still’s disease (AOSD), necessitating the identification of sensitive and specific biomarkers for early diagnosis. Our study found significantly elevated CD64 mRNA expression in neutrophils of AOSD patients compared to healthy controls (p = 0.029). The neutrophil CD64 index (nCD64 index) positively correlated with key clinical manifestations, including splenomegaly, sore throat, pulmonary infiltrates, and pericarditis. Effective treatments led to a rapid and significant decrease in the nCD64 index (p < 0.001). Logistic regression showed that an elevated nCD64 index is a risk factor for MAS (OR = 1.073, p = 0.003). ROC curve analysis indicated that the nCD64 index reliably distinguished AOSD patients with MAS (AUC = 0.877; cutoff = 32.09; p < 0.001) and combined utilization of nCD64 index, ferritin, and sIL-2R demonstrated a strong predictive value. Correlations with hospitalization length (r = 0.382, p < 0.001) and maximum glucocorticoid dose (r = 0.326, p = 0.003) were also observed. Kaplan-Meier analysis revealed a significantly higher cumulative incidence of MAS in patients with an nCD64 index > 32.09 (p < 0.001). These findings suggest the nCD64 index is a promising biomarker for early identifying AOSD patients at risk of MAS, aiding in timely diagnosis and management.

Damage-associated molecular patterns (DAMPs)-induced sterile inflammation is considered as a typical feature of acute kidney injury (AKI). Plasma membrane rupture in renal tubular epithelial cells (RTECs) is the major cause of DAMP release and nerve injury-induced protein 1 (NINJ1) has recently emerged as an executor of plasma membrane rupture, while its role in AKI pathophysiology remains largely unknown. Here, we show upregulated NINJ1 expression and oligomerization in renal tubules among human biopsies and mouse models as well as in cultured RTECs after AKI, accompanied by plasma membrane rupture, increased DAMP release and inflammatory response. Furthermore, knockdown of NINJ1 or inhibition of its oligomerization effectively prevents plasma membrane rupture in RTECs, thereby alleviating DAMP-induced inflammatory response and renal tubular injury. Mechanistically, the ETS transcription factor (ELK1) is identified as a novel transcription factor for NINJ1 during AKI, especially ELK1 phosphorylation at Ser383 significantly enhances its transcriptional activity. Importantly, genetic silencing of NINJ1 or pharmacological inhibition of Ser383-phosphorylated ELK1 can protect against AKI and improve AKI prognosis. Collectively, these findings highlight the ELK1-NINJ1 axis as a pivotal regulator of plasma membrane rupture in RTECs upon AKI, suggesting that it may serve as a potential target for AKI treatment and prognosis improvement.