Annals of the Rheumatic Diseases最新文献

Objectives: Systemic lupus erythematosus (SLE) remains a deadly disease, yet our ability to predict adverse outcomes is poor. Mitochondria are organelles recognised by the immune system when released from cells, and antimitochondrial antibodies (AMA) can be detected in people with SLE. We assessed AMA as markers of nephritis, arterial vascular events (AVE), and other outcomes including mortality.

Methods: We studied sera and data from 1114 participants of the Systemic Lupus International Collaborating Clinics inception cohort. We measured antiwhole mitochondria (AwMA), antimitochondrial DNA (AmtDNA), and antimitochondrial RNA (AmtRNA) antibodies by direct Enzyme-Linked ImmunoSorbent Assays (ELISAs). Separate multivariable Cox proportional hazards regression models estimated associations of either baseline or most recent measures of AMA with the outcomes, adjusted for biological sex, age, medications, and other clinical factors. Interactions of AMA with biological sex were tested for each outcome.

Results: All AMA titres were elevated in SLE vs healthy individuals. Higher AMA levels were associated with a higher hazard of nephritis, with the strongest associations for most recent AmtDNA (adjusted hazard ratio [aHR] =1.61 for increase of 1 SD, 95% CI 1.43-1.82) and AmtRNA (aHR =1.59, 1.46-1.73). Higher baseline AwMA levels predicted early mortality (aHR =1.19, 1.02-1.40). Most recent AmtDNA (aHR =1.68, 1.28-2.19) was associated with higher mortality throughout the follow-up. For AVE, the impact of higher AmtRNA was stronger in females.

Conclusions: Baseline and most recent assessments of AMA levels may help identify individuals at higher risk of severe outcomes in SLE, including mortality. Integrating AMA into precision medicine strategies will allow deeper exploration of lupus heterogeneity.

Objectives: Patients with rheumatic diseases frequently turn to online sources for medical information. Large language models, such as ChatGPT, may offer an accessible alternative to conventional patient‑education resources; however, their reliability remains poorly explored. We conducted an exploratory, descriptive comparison to examine whether ChatGPT-4 might provide responses comparable to those of experts.

Methods: Seventy-six psoriatic arthritis (PsA) patients generated 32 questions (296 selections) grouped into 6 themes. Each question was answered by ChatGPT-4 and by 12 Italian PsA specialists (each drafted 2-3 answers). Fourteen clinicians, The 14 clinicians scored the accuracy and completeness of AI and human-generated answers, rated accuracy (1-5 Likert scale) and completeness (1-3). Interrater reliability was calculated, and mixed-effects ordinal logistic models were used to compare sources. In a separate arm, 67 PsA patients reviewed 16 randomly selected answer pairs and indicated their preference. Readability was assessed. No formal sample size calculation was performed; P values were descriptive and interpreted alongside effect sizes and 95% CIs.

Results: Patients most frequently sought information on prognosis/comorbidities (54/76, 71.1%), therapy strategy (48/76, 63.2%), and treatment risks (38/76, 50.0%). Accuracy appeared comparable between ChatGPT and experts, but ChatGPT scored lower in completeness. Accuracy was lower for pregnancy/fertility, with no clear relevant differences in other domains. ChatGPT answers were chosen 491/998 times (49.2%), clinician answers 343/998 times (34.4%), and no preference 164/998 times (16.4%, P < .001), with a relative preference for ChatGPT responses in prognosis and therapy. ChatGPT responses were, on average, more readable across indices.

Conclusions: In this exploratory study, ChatGPT-4 appeared able to generate accurate and readable responses to PsA-related questions and was often preferred by patients.

Objectives: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death. Systemic autoimmune and inflammatory diseases are associated with increased ASCVD risk, severity, and mortality. The inflammatory cytokine interleukin 9 (IL-9) has been linked to murine atherogenesis, raising fundamental questions about the populations in which and the mechanisms by which IL-9 drives ASCVD.

Methods: Circulating T helper subsets and coronary computed tomography angiography data were analysed in patients with psoriasis. Murine models of psoriatic atherogenesis (imiquimod-ApoE^-/-, IL-23-ApoE^-/-, and Card14^ΔE138-ApoE^-/-) were investigated using IL-9 blockade or global and endothelial-specific Il9r deletion. Primary human aortic endothelial cells were used to assess IL-9/STAT3-dependent endothelial responses.

Results: Here, we found that expansion of IL-9-producing T helper cells (Th9) was significantly associated with high-risk radiographic ASCVD in patients with the autoimmune disease psoriasis. Th9 cells were poised to migrate to coronary vessels and were identified in human atherosclerotic plaque from individuals with psoriasis. In vivo, murine inflammatory atherogenesis was prevented by IL-9 blockade and by IL-9 receptor (IL-9R) deletion in endothelial cells. In human arterial endothelial cells, IL-9R/STAT3 signalling promoted endothelial dysfunction via diverse mechanisms including adhesion, activation, angiogenesis, and release of leukocyte chemoattractants.

Conclusions: These findings suggest the Th9^high state may represent a novel psoriatic ASCVD endotype that could be targeted using precision approaches to prevent ASCVD in at-risk individuals.

Objectives: The activation of runt-related transcription factor 1 (RUNX1) in fibroblasts has been implicated in wound healing and fibrosis; however, the role of RUNX1 in the fibrotic progression of the autoimmune disease systemic sclerosis (SSc) remains known.

Methods: Leveraging gene expression, genome-wide DNA methylation, and single-cell resolution data of SSc skin and fibroblast, we analysed the impact of RUNX1 dysregulation in SSc dermal fibrosis. RUNX1 function was subsequently assessed using siRNA, pharmacologic inhibition, and CRISPR knockout in 2-dimensional and 3-dimensional fibroblast cultures.

Results: Analysis of gene expression in multiple cohorts demonstrated an association between the severity of dermal fibrosis and the expression levels of RUNX1 in the skin of patients with SSc. Epigenomic analyses of methylation identified hypomethylated 5-Cytosine-phosphate-Guanine-3 (CpG) sites proximal to the RUNX1 gene, implicating their potential role in the increased expression of RUNX1. Analysis of single-cell RNA-seq data from skin biopsies of individuals with SSc revealed that RUNX1 is higher in subpopulations of fibroblasts enriched in SSc, which are believed to contribute to fibrosis. RUNX1 CRISPR knockout resulted in reduced alpha smooth muscle actin expression. Inhibition of RUNX1 activity caused a reduction in fibroblast activation, contraction, extracellular matrix components, and proliferation rates, including a reduction in SFRP4, LUM, and COL1A1.

Conclusions: This study is the first to demonstrate a potential role for RUNX1 in the pathogenesis of SSc dermal fibrosis. RUNX1 is associated with more severe SSc fibrosis and is associated with a subpopulation of dermal fibroblasts implicated in fibrosis.

Objectives: Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE), yet the mechanisms linking neutrophil activation to early kidney damage remain elusive. We aimed to elucidate the role of neutrophils and neutrophil extracellular traps (NETs) in driving mesangial cell (MC) activation during LN progression.

Methods: Histology and flow cytometry were performed in NZB/W F₁ and C57/BL6 mice to evaluate neutrophil dynamics throughout LN development. Human LN kidney biopsies were analysed for NETs and neutrophil infiltration. In vitro, human MCs were stimulated with either NETs or purified citrullinated histone H3 (citH3), followed by assessment via enzyme-linked immunosorbent assay and RNA sequencing. Plasma levels of NET remnants (citH3-DNA complexes) were measured in patients with SLE and correlated with clinical parameters.

Results: In NZB/W F₁ mice, NETs progressively accumulated in mesangial regions before proteinuria onset and correlated nephritis severity and mesangial expansion. Similar NET deposition was observed in human LN biopsies. MCs internalised NETs in vitro, leading to enhanced proliferation. CitH3 induced Toll-like receptor 4 dependent MC activation, resulting in increased proinflammatory cytokines, type I interferon-stimulated genes, and collagen IV expression. Transcriptomic profiling of citH3-stimulated MCs revealed overlap with mesangial gene signatures in childhood-onset LN kidneys. Plasma citH3-DNA complex levels were elevated in patients with active LN and correlated with systemic lupus erythematosus disease activity index, hypocomplementemia, renal and musculoskeletal involvement.

Conclusions: NET-producing neutrophils infiltrate the kidney early in LN. NET-derived citH3 activates MC through Toll-like receptor 4, promoting inflammation and fibrosis, establishing a novel NET-MC axis that may represent a mechanistic driver and therapeutic target in LN.

Objectives: B cell depletion or B cell activating factor (BAFF) blockade has shown benefits in systemic lupus erythematosus (SLE). We compared ianalumab, a monoclonal antibody targeting BAFF receptor (BAFF-R)-expressing B cells to lyse B cells and block BAFF-R, with placebo for SLE treatment combined with standard therapies.

Methods: Patients with active SLE were randomised (1:1) to monthly subcutaneous ianalumab 300 mg or placebo. The primary outcome was a composite of SLE Responder Index (SRI)-4 at week 28 in patients successfully achieving corticosteroid (CS) tapering criteria. Patients subsequently received open-label (OL) ianalumab until week 48, followed by exploratory assessments at week 52 and off-treatment to week 68. Safety monitoring continued until B cell recovery. This report describes interim analyses conducted on the week 68 dataset.

Results: Sixty-seven patients were randomised and received blinded treatments until week 28. The primary composite endpoint was more frequently achieved with ianalumab vs placebo: 15/34 (44.1%) vs 3/33 (9.1%), with responses sustained to week 52 and replicated by placebo transitioned to OL ianalumab: 15/33 (45.5%) and 13/32 (40.6%). Positive treatment effects were consistently observed across other lupus disease activity outcomes (SRI-6, Definition of Remission in SLE, Lupus Low Disease Activity State, flare reduction, and CS use) at week 28, with clinical benefits until weeks 52 and 68. Ianalumab was not associated with increased serious adverse events or serious infections. Nonserious local injection site reactions occurred more frequently with ianalumab.

Conclusions: At week 28, reduced disease activity was observed in patients with SLE receiving ianalumab plus standard therapies compared with those receiving standard therapies alone, with sustained benefits with further treatment until 1 year, which was well tolerated.

Objectives: Gout is a prevalent condition characterised by high serum urate levels, leading to crystal deposition in the joints. Although many studies have explored the mechanisms underlying gout flares, the dynamics of tophus formation remain unknown. This study provides the first transcriptomic profile of the tophaceous gout joint and investigates immune-stromal cell interactions in the pathogenesis of tophus formation.

Methods: Single-cell transcriptomic profiling was conducted on 44,221 synovial tissue cells from patients with intercritical gout (without tophi) and tophaceous gout. Spatial transcriptomics showed gene expression patterns in the corona and fibrovascular zones of tophi. Gene expression pattern comparisons, pseudotime, and differential gene enrichment analyses were conducted on stage-specific macrophage subsets. Immunofluorescence and flow cytometry on the tophi samples validated the transcription results and visualised the spatial localisation of the macrophage-fibroblast subpopulation. Differential causal inference combined with Mendelian randomisation elucidated gene regulatory networks and their causal relationships with gout pathology.

Results: We identified SPP1⁺/MMP9^+/CHI3L1⁺ macrophages within the corona zone exclusive to tophaceous gout, exhibiting extracellular matrix regulation genes, enhanced integrin-mediated interactions with stromal cells and transitional potential towards osteoclast differentiation. Notably, coexpression of the fibroblast marker S100A4 and COL6A2 in these macrophages suggested a fibroblast-like phenotype. Distinct CD4⁺ T-cell transcriptional profiles between disease states indicated a phenotypic shift from inflammatory to immune-regulatory subsets during tophus development.

Conclusions: This study reveals a novel macrophage population (SPP1⁺/MMP9^+/CHI3L1⁺) with dual immunomodulatory and matrix-remodelling capabilities, exclusively present in tophus tissues but absent in intercritical gout synovium or flare-associated synovial fluid. It may play a role in the pathogenesis of fibrosis and bone erosion in gout.

Objectives: Hypervascularisation is a dominant feature of the inflamed synovium in rheumatoid arthritis (RA). As RA synovial fibroblasts (RASFs) are key cells of synovial pathophysiology and are located adjacent to the aberrant endothelial cells (ECs), we hypothesised that this interaction might be responsible for the pathological hypervascularisation.

Methods: In the severe combined immunodeficiency (SCID) mouse model for RA, RASF-mediated helix-like vessel (HLV) formation was described and modulated by canstatin, an antiangiogenic collagen IV fragment that blocks the angiopoietin (ANGPT)/Tie2 pathway in EC. ANGPT2/CD31 and CXCL2 immunofluorescence on implants and human synovium was performed. RASF were stimulated with interleukin (IL)-1β once or repetitively and immunoassays, real-time polymerase chain reaction and RNA sequencing were performed. Two-dimensional (2D) tube formation and 3-dimensional spheroid-based assays using human umbilical vein ECs and fluorescent-stained RASF with/without canstatin, IL-11 and CXCL2 were evaluated.

Results: In SCID mice, RASF-specific HLV formation started early and increased until day 30. The number of HLV was significantly reduced by canstatin. Compared to osteoarthritis synovium, ANGPT2 was significantly upregulated in RA vessels. Repetitive RASF stimulation significantly decreased IL-6, IL-11 and CXCL-2 compared to RASF stimulated once with IL-1β. When RASF was stimulated once, CXCL2 and IL-11 were significantly reduced along with 2D tube formation, while repetitive stimulation significantly attenuated hypervascularisation. RNAseq revealed underlying pathways leading to altered tube formation.

Conclusions: We showed that RASF affect vascularisation in vitro and in vivo. The results support the idea that canstatin is able to alter the RASF pathological HLV formation. In the SCID mouse model, this was regulated on a molecular level mediated by ANGPT2 in a vascular endothelial growth factor A-independent manner, contributing significantly to one of the central aspects of RA pathophysiology.