We report an exploratory subgroup analysis of a Chinese phase 3 study to investigate the effect of baseline inflammation measured by magnetic resonance imaging (MRI) on ixekizumab efficacy in radiographic axial spondyloarthritis (r-axSpA). Adults with r-axSpA were randomized (1:1) to receive ixekizumab 80 mg every 4 weeks (IXEQ4W) or placebo for 16 weeks. Endpoints analyzed by baseline Spondyloarthritis Research Consortium of Canada (SPARCC) MRI spine or sacroiliac joint (SIJ) inflammation score (< 2 or ≥ 2; elevated inflammation defined as score ≥ 2) were: Assessment of SpondyloArthritis International Society 40 (ASAS40); Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI50); Ankylosing Spondylitis Disease Activity Score (ASDAS) < 2.1; ASDAS clinically important improvement (CII; change from baseline ≥ 1.1); Patient Global Assessment of Disease Activity (PtGA); spinal pain; nocturnal spinal pain; stiffness/inflammation; function; fatigue; Short Form-36 Physical Component Score (SF-36 PCS); European Quality of Life 5 Dimensions 5 Levels visual analog scale (EQ-5D-5L VAS). Overall, 145 patients were included. At Week 16, ASAS40 response rates were numerically improved with IXEQ4W versus placebo in the SPARCC MRI spine score < 2 subgroup (40.9

OBJECTIVE:To investigate whether MLKL crotonylation is associated with tubular autophagy-lysosome pathway homeostasis in lupus nephritis (LN) and to explore its relationship with RAB1A-mechanistic target of rapamycin (mTOR) signalling. METHODS:Crotonylome proteomics was performed in peripheral blood mononuclear cells from patients with LN, patients with systemic lupus erythematosus without nephritis and healthy controls. Renal biopsy tissues were evaluated for tubulointerstitial fibrosis and autophagy-lysosome pathway-related markers. Mechanistic studies were conducted in lipopolysaccharide-stimulated HK-2 cells. Autophagic flux was assessed using bafilomycin A1. The dependency of mTOR/autophagy changes on RAB1A was tested by siRNA-mediated knockdown. RESULTS:MLKL was identified as a differentially crotonylated protein in LN, with increased crotonylation at K95 and K219. Kidney tissues from patients with LN showed increased fibronectin and collagen III deposition compared with controls, whereas no significant difference was observed between class IV and class V LN. LC3 signal did not differ significantly between groups, whereas LAMP1 expression and LC3-LAMP1 co-localisation were reduced in LN. In HK-2 cells, crotonylation-deficient MLKL mutants were associated with increased LC3-II and reduced p62, whereas K219Q showed the opposite pattern. Autophagic flux assays using bafilomycin A1 showed that K219R-expressing cells had higher LC3-II levels than WT cells both before and after lysosomal inhibition, with comparable BafA1-induced LC3-II accumulation, consistent with increased autophagosome formation rather than impaired lysosomal degradation. HDAC1 knockdown increased MLKL crotonylation and was accompanied by mTOR activation. MLKL crotonylation enhanced RAB1A guanriphosphat osphate (GTP) binding without altering total RAB1A abundance. RAB1A knockdown in MLKL WT-expressing cells attenuated mTOR phosphorylation and partly reversed the autophagy-suppressive marker profile. Sodium crotonate induced an autophagy-suppressive marker profile that was partly reversed by rapamycin. CONCLUSION:MLKL crotonylation is associated with activation of the RAB1A-mTOR axis and altered tubular autophagy-lysosome pathway homeostasis in LN. These findings suggest that tubular injury-related changes in LN may not be fully reflected by glomerulus-based classification alone.

Objective To compare preconception disease-activity indices—systemic lupus erythematosus Disease Activity Score low disease activity (SLE-DAS LDA), lupus low disease activity state (LLDAS) and SLE-DAS remission—with Definitions of Remission in SLE (DORIS) remission in predicting adverse maternal and fetal outcomes among pregnant women with SLE.Methods This retrospective cohort study included 202 pregnancies in 196 women with SLE managed at Shenzhen People’s Hospital between January 2017 and December 2024. Preconception disease activity was categorised using SLE-DAS, LLDAS and DORIS remission criteria. Main outcomes were maternal flares and fetal outcomes, including spontaneous abortion, therapeutic abortion, total fetal loss, preterm delivery and small for gestational age (SGA). Predictive accuracies of indices were compared.Results Preconceptionally, 127 pregnancies (62.8%) met LLDAS, 131 (64.9%) met SLE-DAS LDA and 78 (38.6%) achieved DORIS remission. Compared with higher disease activity, SLE-DAS LDA was associated with fewer maternal flares (22.1% vs 45.1%) and therapeutic abortions (6.4% vs 15.7%). LLDAS was associated with lower rates of flare (21.3% vs 45.3%), therapeutic abortion (7.9% vs 17.3%), total fetal loss (19.7% vs 34.2%) and preterm delivery (22.0% vs 25.3%). SLE-DAS and DORIS remission performed similarly for maternal outcomes, while DORIS remission correlated more strongly with favourable fetal outcomes, including lower total fetal loss (15.4% vs 31.5%), preterm delivery (15.4% vs 28.2%) and SGA (9.0% vs 19.4%). Multivariable analyses confirmed that achieving these disease-activity states preconception independently protected against total fetal loss, maternal flare and therapeutic abortion. LLDAS was the best overall predictor, while SLE-DAS LDA was the most attainable and predictive for maternal complications.Conclusion SLE-DAS LDA effectively predicts maternal complication, while LLDAS better identifies fetal risk. Remission offers similar protection but is less attainable, suggesting LDA suffices for conception planning. Optimising preconception disease control remains essential and warrants multicentre validation.

BACKGROUND:Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammation and multi-organ involvement, yet its molecular mechanisms remain incompletely understood. While plasma proteomics provides valuable insights into disease-associated alterations, most studies focus on high-abundance proteins. Low-abundance plasma proteins, which often serve as critical regulators of immune signaling and inflammatory pathways, remain insufficiently characterized in RA. METHODS:Plasma samples from 27 RA patients and 10 healthy controls (HCs) were analyzed using the SomaScan P11K platform. Differential expression analysis, pathway enrichment, protein-protein interaction network construction, and drug repurposing analyses were performed. Enzyme-linked immunosorbent assay (ELISA) validation was conducted in independent cohorts. RESULTS:A total of 218 differentially expressed low-abundance proteins were identified. Neutrophil extracellular trap (NET) formation was the most significantly enriched KEGG pathway (p = 0.0057), with seven NET-associated proteins showing differential expression. Protein-protein interaction (PPI) analysis revealed functional integration with mitogen-activated protein kinase (MAPK) and chemokine signaling pathways. ELISA validation confirmed differential expression of NCF1, PPIF, and HDAC3. Drug repurposing analysis identified several candidate compounds, among which Delsemidine emerged as one of the top-ranked compounds in the exploratory analysis. CONCLUSIONS:This study systematically characterizes NET-associated molecular signatures in the low-abundance plasma proteome of RA and provides a hypothesis-generating basis for future validation of candidate biomarkers and related pathways.

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by immune cell dysfunction. The endomembrane system, consisting of the endoplasmic reticulum (ER) and Golgi apparatus (GA), plays a central role in protein synthesis and trafficking. However, the regulatory architecture of the ER-Golgi axis in RA immune cells remains incompletely understood.MethodsWe performed an integrative multi-omics analysis of peripheral blood mononuclear cells (PBMCs) from 96 RA patients and 90 healthy controls (HCs). Proteomic data were obtained from a previously published study from our research group, and transcriptomic data were retrieved from the GEO database (GSE17755). Protein-protein interaction (PPI) networks were constructed using STRING and Cytoscape. Kinase activity and related signaling molecules were identified based on the functional annotations of differentially expressed proteins and phosphoproteins. Upstream transcription factor (TF) regulatory networks were built through integration with hTFtarget. Drug candidates were screened using the DSigDB database.ResultsRA immune cells exhibited coordinated dysregulation of the ER-Golgi axis. Proteomics revealed downregulation of vesicular transport components (RAB1A, SEC16A) and upregulation of ER stress-related proteins (DNAJC3, SERPINH1). Phosphoproteomics identified 122 differentially phosphorylated sites, including novel hypophosphorylation of SEC16A (S1305/S1356) and decreased phosphorylation of PRKCD at T507, T295, and S664, suggesting altered PRKCD-related signaling in RA immune cells. PPI network analysis highlighted RPS3 as a dual hub linking translation and inflammatory signaling. Upstream regulatory analysis identified PML, STAT1, CBFB, and RAD21 as potential TFs, while AKT1-CK2-PRKD and TBK1-IKBKB constituted major kinase hubs. These findings indicate coordinated alterations in vesicular transport, ER stress-related processes, and inflammatory signaling in RA immune cells.ConclusionsThis integrative multi-omics analysis characterizes coordinated alterations of the ER-Golgi axis in RA immune cells and highlights candidate regulatory nodes, including SEC16A phosphorylation sites, RPS3, and major kinase hubs. As a hypothesis-generating study, these findings provide a systems-level framework for understanding how endomembrane dysregulation may be associated with sustained immune activation in RA.

OBJECTIVES:Orelabrutinib is an oral, highly selective, irreversible inhibitor of Bruton's tyrosine kinase (BTK). Preclinical mechanistic studies have demonstrated its therapeutic potential in systemic lupus erythematosus (SLE). METHODS:A multicentre, double-blind, randomised, placebo-controlled, parallel-group, phase Ib/IIa study was conducted in 11 centres in China. Patients diagnosed with SLE were randomised 1:1:1:1 to receive oral orelabrutinib at 50 mg, 80 mg, and 100 mg or placebo once daily for 12 weeks, respectively. This trial is registered with ClinicalTrials.gov, NCT04305197. RESULTS:Between July 9, 2020 and September 29, 2021, 60 patients were randomised, with 55 patients who completed 12 weeks of treatment. Adverse events (AEs) were mostly mild or moderate. In all evaluable patients, the SLE Response Index (SRI)-4 rates at week 12 were 50%, 62%, and 64% for orelabrutinib at 50 mg, 80 mg, and 100 mg, respectively, compared with 36% for placebo, indicating dose-dependent improvement. Among patients with baseline SLEDAI-2K > 8, significantly higher SRI-4 responses were noted with orelabrutinib at 50 mg (80%, p = 0·048), 80 mg (83%, p = 0·048), and 100 mg (100%, p = 0·029) compared to placebo (0%). SRI-6 responses at week 12 were 36%, 39%, and 21% for orelabrutinib at 50 mg, 80 mg, and 100 mg, respectively, compared with 7% for placebo. Reduced proteinuria, anti-dsDNA, IgG, and IgM and increased C4 were observed with orelabrutinib treatment. CONCLUSIONS:Orelabrutinib was well tolerated and potentially efficacious in patients with SLE.

OBJECTIVES:Lung ultrasound (LUS) assesses lung lesion severity in systemic autoimmune rheumatic disease-associated interstitial lung disease (SARD-ILD). The ultrasound manifestations of SARD-ILD include pleural line (PL) abnormalities and heterogeneous B-line (BL) distribution. We aimed to investigate the feasibility of a modified ultrasound scoring system based on refined grading of BL and PL features in patients with SARD-ILD, to determine whether BLs and PLs can effectively reflect ILD patterns across different lung compartments. METHODS:One hundred and ninety-five patients with nine SARD-ILDs underwent LUS-chest high-resolution computed tomography (HRCT) pairing was used to determine BLs and PLs diagnostic performance for ILD patterns characterization. BL and PL scores for both were refined to obtain the modified LUS score. Correlations with the Warrick score, ILD-GAP, and severity based on forced vital capacity (FVC) were analysed, and receiver operating characteristic (ROC) were calculated. RESULTS:Using HRCT as a criterion, BLs and PLs showed high concordance for diagnosing ground-glass opacity (kappa = 0.606) and reticular opacity (kappa = 0.743), respectively. Modified LUS scores were positively correlated with the Warrick score (r = 0.863; P < 0.001) and ILD-GAP (r = 0.613; P < 0.005). ROC analysis revealed optimal modified LUS score thresholds of 11.5 for identifying cases with high fibrosis burden (Warrick score >8), 18.5 for high mortality risk (ILD-GAP ≥2), and 9.5 for severe functional impairment (FVC% predicted <60%). CONCLUSION:BLs and PLs have different diagnostic significances for different ILD patterns. The modified LUS scoring system reliably assesses lesion severity and suggesting poor prognosis in SARD-ILD compared with computed tomography scan.

OBJECTIVE:This multicenter study aimed to analytically compare the performance of automated quantitative assays-chemiluminescence immunoassay (CLIA) and multiplexed bead immunoassay (MBI)-for detecting anti-Ro/La antibodies in Chinese patients with primary Sjögren's syndrome (pSS), compared to line immunoassay (LIA) that is most commonly used in China. METHODS:Based on the Chinese Sjögren's Syndrome Collaborative Research Group, serum samples from 434 patients with pSS and 100 healthy controls were analyzed using LIA, CLIA, and MBI. Sensitivity, specificity, and qualitative agreement were assessed. Receiver operating characteristic (ROC) analysis was carried out to compare the analytical accuracy among assays in detecting anti-Ro/La antibodies, and the DeLong test was used to compare areas under curves (AUCs). RESULTS:High specificity (95% to 100%) was observed in these assays, and LIA demonstrated the highest sensitivity for anti-Ro60 (92.6%) and anti-Ro52 (89.2%). CLIA and MBI exhibited comparable sensitivity to LIA for anti-La (50.9% vs. 50.2% vs. 48.2%). Qualitative agreement among assays was good for anti-Ro60 (κ: 0.84-0.93) and moderate for anti-La (κ: 0.74-0.86). MBI achieved the highest AUC values for anti-Ro60 (0.980), anti-Ro52 (0.970), and anti-La (0.935), outperforming CLIA and LIA (p  < 0.05). CONCLUSION:Automated assays (CLIA and MBI) demonstrate high specificity and analytical accuracy for anti-Ro/La antibody detection in pSS. MBI achieved the highest accuracy, whereas LIA showed superior sensitivity for anti-Ro60/52 detection. CLIA provided reliable specificity but failed to detect anti-Ro52 in this study. Collectively, these findings indicate that CLIA and MBI may represent reliable alternatives to LIA, although validation in disease-controlled cohorts is required before clinical implementation.

Inflammatory cytokine overproduction is critically involved in immune dysregulation and tissue damage, but the role of interleukin-18 (IL-18), a cytokine associated with inflammasome activation, in modulating the T-cell response and autoimmune pathogenesis remains largely unclear. In this study, we detected high expression levels of the IL-18 receptor α chain (IL-18Rα) in murine and human Th17 cells. In culture, IL-18 markedly promoted Th17 cell differentiation with increased GM-CSF production, a phenotype of pathogenic Th17 (pTh17) cells. Transcriptomic profiling via RNA sequencing revealed that IL-18-induced pTh17 cells presented increased glycolytic flux and proinflammatory signatures. Mechanistically, IL-18 promoted Stat3 phosphorylation, which stabilized Bhlhe40 mRNA to potentiate Bhlhe40-dependent glycolysis and cytokine production. In patients with primary Sjögren’s syndrome (pSS) and systemic lupus erythematosus (SLE), IL-18 levels in plasma and inflamed tissues were significantly increased and positively correlated with disease activity. Moreover, the expression levels of IL-18 were markedly increased in the salivary glands of experimental Sjögren’s syndrome (ESS) model mice and the renal tissues of lupus model mice. Furthermore, adoptive transfer of IL-18-induced pTh17 cells profoundly exacerbated disease severity and tissue damage in recipient IL-17-deficient mice, whereas IL-18 neutralization with a monoclonal antibody effectively suppressed the pTh17 cell response and ameliorated tissue pathology in both ESS and lupus mice. Together, our findings reveal a novel function of IL-18 in driving the pTh17 cell response during autoimmune development, indicating that IL-18 blockade may serve as a promising therapeutic strategy for the treatment of autoimmune diseases.

What is already known about this topic?:Human papillomavirus (HPV) is a globally prevalent sexually transmitted infection, with multiple genotypes strongly associated with cancers and other diseases. While extensive epidemiological data exist for HPV in females, studies on HPV genotype distribution in males, particularly those with confirmed HPV exposure, remain limited. What is added by this report?:This study provides a comprehensive analysis of HPV genotype distribution and its association with clinical outcomes in males with confirmed HPV exposure. The results demonstrate that low-risk HPV genotypes predominate in this population, with certain diseases showing unique HPV genotype associations. Additionally, older males exhibited a greater tendency toward multiple genotype co-infections. What are the implications for public health practice?:This study underscores the importance of including males in HPV vaccination programs. Expanding vaccination coverage to males, combined with early screening and targeted public health education, can effectively reduce HPV transmission between sexes and decrease the overall burden of HPV-related diseases.

Chromosomal structural variations (CSVs) that comprise multiple gene mutations are important determinants for multiple diseases. However, the relationship between CSVs, rheumatoid arthritis (RA), and lung cancer is not well understood. In this study, we analyzed CSV associations and differences between RA and RA with lung cancer (RA LC) using genome sequencing, with RA-associated interstitial lung disease (RA ILD) as a disease control. First, we analyzed the CSVs of each individual. Then, we identified common CSVs within each disease group and finally analyzed specific CSVs between different diseases. Gene Ontology/KEGG terms, canonical pathways, and feature gene sets were used for the functional annotation and analysis of CSV-related pathways. Cell size regulation and axon guidance were mutated in all disease groups. Protein deubiquitination was mutated in RA LC, while the negative regulation of extractable stroma and protein catabolism was mutated in RA ILD. Characterization of clinical data also revealed correlations with these specific pathways. This study identifies common and specific CSVs and associated pathways for RA, LC, and ILD, uncovering key genetic factors that provide new insights into their diagnosis and treatment.

OBJECTIVE:Dotinurad is a selective urate reabsorption inhibitor that reduces serum urate levels. We compared the efficacy and safety of dotinurad with febuxostat in Chinese patients with gout. METHODS:This phase 3, multicenter, randomized, double-blind, parallel-group study randomly allocated (1:1) eligible patients with gout to receive oral dotinurad or febuxostat. The primary end point was the responder rate (proportion of patients achieving serum urate levels ≤6.0 mg/dL) at week 24 in the full analysis set (FAS) to demonstrate superiority of dotinurad 4 mg/day to febuxostat 40 mg/day. The secondary end points included the responder rate at week 12 to show the noninferiority of dotinurad 2 mg/day to febuxostat 40 mg/day. Treatment-emergent adverse events (TEAEs) were also recorded. RESULTS:A total of 451 patients were randomized, and 441 were included in the FAS. Baseline characteristics were well balanced between treatment groups. The responder rate at week 24 was significantly higher for dotinurad 4 mg/day versus febuxostat 40 mg/day (73.6% vs 38.1%; adjusted difference 35.9% [95% confidence interval (CI) 27.4%-44.4%]; P < 0.0001), and at week 12, dotinurad 2 mg/day was noninferior to febuxostat 40 mg/day (55.5% vs 50.5%; adjusted difference 5.2% [95% CI -3.7% to 14.2%]). Incidences of TEAEs in the dotinurad and febuxostat groups were similar. CONCLUSION:Dotinurad 4 mg/day was superior to febuxostat 40 mg/day in achieving serum urate levels ≤6.0 mg/dL at week 24 and was well tolerated in Chinese patients with gout.

Systemic lupus erythematosus (SLE) has been associated with gut microbiota in some studies. There is no clear evidence that cytokines act as mediators. We first assessed the differences in gut microbiota between SLE patients and healthy controls using 16S rDNA sequencing. Subsequently, we used the summary statistics of gut microbiota, cytokines, and SLE from large genome-wide association studies. To explore the causal relationships between gut microbiota and SLE and identify potential mediating cytokines, we performed bidirectional Mendelian randomization analyses. Finally, the levels of potentially mediating cytokines were determined by ELISA. Fecal 16S rDNA sequencing showed that there was gut microbiota disorder in SLE patients. Based on two-sample analysis, seven gut microbiota taxa were causally associated with SLE. SLE influenced the relative abundance of two gut microbiota taxa in our large-scale MR study. Mediation analyses revealed that the causal relationship between genus Lachnospiraceae UCG001 and SLE was exclusively mediated by fibroblast growth factor 19 (FGF19) levels and the causal relationship between order Lactobacillales and SLE was exclusively mediated by tumor necrosis factor receptor superfamily member 9 (TNFRSF9) levels. Elevated levels of FGF19 affected the association between the reduced relative abundance of the genus Coprobacter and SLE, mediating by a proportion of 10.64

Objective Our study aimed toconstruct a web-based calculator to predict high risk patients of interstitial lung disease (ILD) in systemic lupus erythematosus (SLE). Methods This retrospective study comprised training and test cohorts, including 581 and 86 patients, respectively. Univariate, least absolute shrinkage and selection operator (LASSO), random forest (RF), eXtreme Gradient Boosting (XGBoost), and logistic regression (LR) analyses were performed. A Venn diagram was used to investigate critical features. Receiver operating characteristic (ROC) analysis and decision curve analysis were used to evaluate the model’s performance. Risk stratification was performed using the best ROC cut-off value. The web-based calculator was established using Streamlit software. Results Characteristics such as Raynaud’s phenomenon, pulmonary artery systolic pressure, serositis, anti-U1RNP antibodies, anti-Ro52 antibodies, C-reactive protein, age, and disease course were associated with SLE complicated by ILD (SLE-ILD). LR-Venn, RF-Venn, XGBoost-Venn, LASSO-logic, RF, and XGBoost models were constructed. In training cohort, the XGBoost model demonstrated the highest area under the ROC curve (AUC, 0.890; cut-off value, 0.197; sensitivity, 0.793; specificity, 0.836) and provideda netbenefitin decision curve analysis (odds ratio [OR] for SLE-ILD [high- vs. low-risk], 19.6). The model was validated in the test cohort (AUC, 0.866; sensitivity, 0.722; specificity, 0.897; OR, 22.7). Furthermore, an XGBoost model-based web calculator was developed. Conclusion Our web calculator (https://st-xgboost-app-kcv9qm.streamlit.app/) greatly improved risk prediction for SLE-ILD and was implemented effectively.

HPK1 (Hematopoietic Progenitor Kinase 1) is a member of the MAP4K family, which is a group of kinases that catalyze the phosphorylation of serine or threonine residues in proteins. HPK1 is mainly expressed in hematopoietic and immune cells. Loss of HPK1 kinase function increases cytokine secretion, enhances T cell signaling, viral clearance, and tumor growth inhibition. Therefore, HPK1 is considered as a promising target for tumor immunotherapy. Currently, there are several small molecule inhibitors targeting HPK1 in clinical trials, which only inhibit the kinase activity of HPK1, and cannot completely block its downstream signal transduction, and have low selectivity and poor safety. Therefore, we developed a proteolysis targeting chimera (PROTAC) drug, HDM2006, that specifically targets HPK1 while inhibiting HPK1 kinase activity and deleting its skeletal function, and has better efficacy and safety than small molecule inhibitors. The robust monotherapy and combined with anti-mPD-1 efficacy of HDM2006 makes it a IO drug and also a new option for patients with advanced tumors. TR-FRET assay were utilized to assess the target binding activity and ternary complex formation activity. Western blot was utilized to investigate the degradation activity of HDM2006 in human T lymphoma Jurkat cells. The effect of HDM2006 on the secretion of IL-2 and IFN-γ by human Pan-T cells was detected by ELISA. In vivo anti-tumor efficacy of HDM2006 monotherapy and combined with anti-mPD-1 was evaluated in murine colorectal cancer MC38 cell allograft models. Oral-bioavailability and repeat-dose GLP toxicity studies were profiled in rats and cynomolgus monkeys. HDM2006 bound to human HPK1 and E3 ubiquitin ligase CRBN, and formed a ternary complex. Meanwhile, HDM2006 targeted and degraded HPK1 in Jurkat cells, with a DC50 of 20.68 nM and a Dmax of 96.36% (24 h). HDM2006 did not degrade other CRBN substrates, avoiding IMiDs off-target effect. HDM2006 can stimulate hPBMCs to secrete IL-2 and IFN-γ, the maximum activation fold can be more than 9.3-41.6 folds. Furthermore, immune activation upon HPK1 degradation was observed even in immune-suppressed environments (PGE2, adenosine, and T cell exhaustion). In vivo, HDM2006 showed efficacy in mouse colorectal cancer model in mono and in combination with anti-mPD-1, and TGI was similar to the small-molecule inhibitor at very low dose. In addition, the results of GLP toxicity studies in rats and cynomolgus monkeys indicated that HDM2006 has a large safety margin, and the NOAEL dose exposure was approximately 435.9-fold and 21.4-fold of the optimal effective dose exposure. HDM2006 is a novel, potent, highly selective and orally active PROTAC targeting HPK1. Preclinical studies have confirmed that HDM2006 has excellent profile for druggability, safety, and efficacy. HDM2006 has entered the clinical Phase 1 trial. Liubin Guo, Zhimin Zhang, Xi Yang, Rongyao Zhu, Zhiping Zhang, Sirui Liu, Hao Pan, Zhao Dong, Chunhua Jiang, Dongzhou Liu. HDM2006, A novel and potent HPK1 PROTAC, enhances immune cell activation and induces robust tumor growth inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5632.

BACKGROUND:Individuals with rheumatoid arthritis (RA) are at a significantly increased risk of developing lung cancer (LC), with a 30%-40% higher incidence compared to the general population. Although a link between the two conditions has been established, the molecular mechanisms and genetic factors remain not fully elucidated. This study aims to uncover the potential associations between LC and RA through an integrative approach of transcriptomics and genomics analysis. METHODS:We collected whole-genome expression data from patients with LC, RA, and healthy controls. Next-generation sequencing (NGS) was applied to analyze genomic variations in blood samples from RA patients, including those with comorbid LC and interstitial lung disease (ILD). Using bioinformatics tools, we identified differentially expressed genes (DEGs) and conducted an integrative analysis of pathways shared and specific to LC and RA. RESULTS:The transcriptome analysis identified 1,051 DEGs common to both LC and RA, with distinct regulatory patterns. Among these, 441 genes were commonly upregulated, 345 were downregulated, and 265 exhibited opposite regulation between the two diseases. After integrating significant genomic mutation data, an additional 92 upregulated, 90 downregulated, and 41 oppositely regulated key genes were identified. Functional and enrichment analyses of these key genes revealed shared alterations in immune-related pathways, particularly the upregulation of viral response and immune signaling pathways, and the downregulation of T-cell receptor (TCR) signaling, T cell activation, and non-coding RNA metabolism. Furthermore, lymphocyte and leukocyte migration, as well as the positive regulation of programmed cell death, showed opposite regulation patterns between the two diseases. Laboratory tests also revealed changes in lymphocytes. CONCLUSION:This study delineates potential common mechanisms between LC and RA, suggesting that an enhanced viral response, attenuated TCR signaling, and reduced T cell activation in the peripheral system may represent shared pathological mechanisms, potentially contributing to the increased LC risk in RA patients. Conversely regulated DEGs may serve as novel biomarkers for pulmonary diseases. The changes in immune-related pathways and their potential association with lymphocyte activity provide new perspectives for understanding the relationship between LC and RA.

Patient-reported outcomes (PROs) help to understand rheumatoid arthritis (RA) from patients’ perspective and play an important role in RA management. This study aims to describe the PRO changes over 6 months among patients with RA in China and explore the relationships between PROs and RA disease activity. This multicenter prospective cohort study enrolled patients with RA aged ≥ 18 years. At enrollment, patients were dichotomized into remission/low disease activity (LDA) and moderate-to-high disease activity (MDA/HDA) based on Disease Activity Score-28 with C-Reactive Protein (DAS28-CRP). Only patients with MDA/HDA (DAS28-CRP ≥ 3.2) were followed for 6 months. PROs included pain, fatigue, morning stiffness, Patients’ Global Assessment (PtGA), disability, work productivity, and activity impairment. Disease activity measures included DAS28-CRP, DAS28-Erythrocyte Sedimentation Rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI). A total of 872 patients were enrolled: 520 patients in remission/LDA and 352 in MDA/HDA. In MDA/HDA patients, pain decreased significantly from enrollment at month 1 (p < 0.0001), month 3 (p < 0.0001), and month 6 (p = 0.0094). Fatigue improved significantly at month 3 (p = 0.0073). Other PROs, including morning stiffness, PtGA, disability, work productivity, and activity impairment, also improved. Patients who achieved remission/LDA had significant faster decline in pain, fatigue, PtGA, and work productivity compared to those who did not. Pain was positively correlated with disease activity measures at months 1, 3, and 6, while fatigue was positively associated with disease activity measures at months 3 and 6 only. Morning stiffness, PtGA, and disability correlated with disease activity at months 1 and 3. Patients with RA with MDA/HDA in China experienced significant improvement in pain and fatigue over 6 months. Improvement in DAS28-CRP was associated with faster improvement in certain PROs. While disease activity correlated with some PROs, they did not fully capture patient experience, highlighting the importance of PROs in RA management.

To explore SLE staging markers, we analyzed eccDNA in plasma using circular sequencing, comparing healthy controls (HC), active SLE (ASLE), and inactive SLE (ISLE) patients. We found higher eccDNA levels and lower GC content in ASLE and ISLE compared to healthy controls, with a negative correlation between GC content and anti-daDNA, C3, and C4 levels in SLE and HC samples. Differential expression of exon-derived eccGenes in ASLE and ISLE suggests their role in SLE development, with KEGG analysis showing enrichment in SLE-related pathways for these differentially expressed genes. By protein-protein interactions network analysis we found 9 exon-derived eccGenes that were significantly differentially expressed and scored high in both ISLE-HC and ASLE-ISLE as diagnostic criteria for differentiating different disease stages of SLE. In conclusion, the present study reveals that eccDNA length GC content as well as chromosomal distribution in ASLE, ISLE and HC suggests that with eccDNA is associated with the creation of SLE, suggesting GC count of eccDNA as a diagnostic marker for systemic lupus erythematosus. Significant changes in the abundance of eccDNA-related genes from exons such as SOS1, GAD2, BCL11B, PPT1, and GCNT3 were observed in ISLE as compared to ASLE and HC groups and were significantly correlated with SLEDAI-2K. This suggests that these exon-derived eccGenes may play a role in the development and progression of the disease. Consequently, the abundance levels of these exon-derived eccGenes could potentially assist in distinguishing different stages of SLE, beyond a confirmed diagnosis, thus serving as possible biomarkers for the condition.

Background and objectives: Interstitial lung disease (ILD) is the main cause of morbidity and mortality in patients with connective tissue disease (CTD). Therefore, effective biomarkers for diagnosis and predicting progression of CTD-ILD could be significant. Galectin-9 (Gal-9) has been reported to be associated with autoimmune diseases. Here, this study aims to investigate the role of circulating Gal-9 in the diagnosis and progression monitoring in patients with CTD-ILD. Methods: A total of 128 patients with CTD-ILD, 101 patients with CTD and 52 healthy controls were enrolled in this study. Serum Gal-9 levels were measured by enzyme-linked immunosorbent assay, and its correlation with clinical indices in patients with CTD-ILD were assessed using Spearman’s analysis. Receiver operating characteristic (ROC) analysis was applied to measure the diagnostic accuracy of Gal-9 in patients with CTD-ILD. Kaplan-Meier analysis was performed to assess the progression of ILD in patients with CTD-ILD with high and low baseline levels of serum Gal-9. Results: Serum Gal-9 levels were significantly higher in CTD-ILD patients than either CTD patients or healthy controls (median 18.3 ng/mL vs. 9.3 ng/mL vs. 7.6 ng/mL). Serum Gal-9 levels showed a significantly positive correlation with serum inflammatory indexes and Krebs von den Lungen-6 (KL-6), as well as lung computed tomography scores and reduced pulmonary function in patients with CTD-ILD (all p < 0.05). Additionally, serum Gal-9 exhibited moderate diagnostic ability to identify the presence of ILD in patients with CTD. Intriguingly, longitudinal study revealed a significant reduction in serum Gal-9 levels after treatment in patients with CTD-ILD (35.0 ng/mL vs. 17.3 ng/mL, p = 0.0012). Furthermore, patients with CTD-ILD with a baseline serum Gal-9 level of ≥ 10.45 ng/mL experienced a higher percentage of ILD progression than those with a level of < 10.45 ng/mL over a two-year follow-up (36.4% vs. 0.0%). Conclusions: Serum Gal-9 could serve as a potential circulating indicator for both the presence and severity of ILD, and it may also have prognostic significance in predicting ILD progression in patients with CTD.