Annals of the Rheumatic Diseases最新文献

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.

Objectives: The APEX study evaluated the effects of guselkumab, a fully human, dual-acting monoclonal antibody able to bind CD64 and selectively inhibit the interleukin (IL)-23p19 subunit, on clinical and radiographic outcomes in active psoriatic arthritis (PsA).

Methods: APEX (ongoing, phase 3b, double-blind, placebo-controlled) randomised (5:7:7) biologic-naïve adults with active PsA (≥3 tender, ≥3 swollen joints; C-reactive protein ≥0.3 mg/dL; ≥2 erosive joints) to subcutaneous guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, then every 8 weeks (Q8W); or placebo every 4 weeks. Primary (proportion of participants achieving ≥20% improvement in American College of Rheumatology response criteria [ACR20]) and major secondary (total PsA-modified van der Heijde-Sharp [vdH-S] score least squares mean [LSM] change from baseline) endpoints at week 24 were multiplicity-controlled for comparing each guselkumab group versus placebo.

Results: Among 1020 participants (Q4W: 273; Q8W: 371; placebo: 376), significantly greater proportions of participants receiving guselkumab Q4W (66.6%) and Q8W (68.3%) versus placebo (47.0%) achieved ACR20 at week 24 (both P < 0.001). Baseline mean total vdH-S scores were 26.7 to 27.7 across groups; guselkumab Q4W- and Q8W-treated participants exhibited significantly lower rates of radiographic progression versus placebo at week 24 (total vdH-S score LSM change: 0.55 and 0.54 vs 1.35; P = 0.002 and P < 0.001, respectively). Through week 24, 38.2%, 42.5%, and 37.3% of participants receiving guselkumab Q4W, Q8W, and placebo, respectively, had ≥1 adverse event, with no new safety signals.

Conclusions: Guselkumab, a fully human monoclonal antibody able to bind CD64 and simultaneously inhibit the IL-23p19 subunit, provided significantly higher rates of clinical improvement and significant inhibition of structural damage progression versus placebo, with no new safety signals, at week 24 in biologic-naïve participants with active and erosive PsA.

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.