Annals of the Rheumatic Diseases最新文献

Objectives: Systemic sclerosis (SSc) is an autoimmune disease that transitions from vasculopathy as an initiating pathogenic event to tissue fibrosis. The mechanisms of these transitions remain, however, poorly understood, mainly because complex multicellular human models of SSc vasculopathy are lacking. We aimed to develop a complex multicellular human model of SSc vasculopathy and use it to investigate the mechanisms underlying this process.

Methods: Blood vessel organoids (BVOs) were derived from induced pluripotent stem cells of patients with SSc and healthy controls. Organoids were exposed to serum from patients with SSc with clinically manifest microvasculopathy or healthy donors. Structural and molecular changes were evaluated using confocal imaging, transcriptomic (RNA sequencing), epigenetic (assay for transposase-accessible chromatin sequencing), and spatial proteomic (codetection by indexing) profiling. Serum immunoglobulin G (IgG) was selectively depleted or enriched to investigate antibody contributions. Therapeutic interventions included bosentan and the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT).

Results: SSc-derived BVOs exposed to SSc serum exhibited profound angiogenic defects, characterised by reduced vessel integrity, loss of endothelial-pericyte interactions, and induction of endothelial-to-mesenchymal transition (EndMT). Epigenetic and transcriptional profiling revealed upregulation of fibrosis-related genes and loss of endothelial markers. Spatial proteomic data confirmed EndMT at the protein level and demonstrated shifts in endothelial and pericyte subpopulation as well as alterations in their interactions reminiscent of those seen in tissues of patient with SSc. IgG depletion from SSc serum restored vascular structure, and transfer of SSc IgG to healthy serum phenocopied the pathological phenotype, implicating autoantibodies in endothelial injury. Both bosentan and DAPT partially reversed vascular abnormalities and downregulated EndMT markers.

Conclusions: This study establishes BVOs as a complex human model of SSc vasculopathy and demonstrates in a multiomic approach that they recapitulate disease-specific vascular dysfunction and its transition to fibrosis. We show that genetic susceptibility and pathogenic autoantibodies synergise in driving microvascular injury in SSc. Furthermore, we provide evidence that SSc BVOs are a promising platform for evaluating therapies that prevent the transition from vasculopathy to fibrosis, and present Notch/γ-secretase inhibition as a potential novel target in SSc vasculopathy.

Objectives: Systemic lupus erythematosus (SLE) frequently affects the central nervous system, leading to neuropsychiatric SLE (NPSLE). Major depressive disorder in SLE (SLE_MDD) is the most frequent manifestation of NPSLE and is believed to arise from an immune-mediated process. However, biomarkers for SLE_MDD remain lacking. The aim of this study was to identify candidate immunometabolic biomarkers associated with SLE_MDD.

Methods: We analysed deep flow cytometry immune phenotyping, gut microbiota profiling, and targeted mass spectrometry-based metabolomics from 99 patients from the LUPIL-2 study (NCT02955615). Biological signatures were identified using unsupervised principal component analysis and supervised decision tree classification. They were then validated in an independent cohort from the TRANSIMMUNOM study (NCT02466217).

Results: SLE_MDD patients exhibited a distinct immune profile with decreased naïve CD4⁺ T cells and naïve regulatory T cells (Tregs), alongside increased ICOS⁺ effector memory Tregs (94% classification accuracy). Gut microbiota diversity was reduced with depletion of Akkermansia muciniphila and enrichment of Faecalibacterium prausnitzii. Metabolomic analyses revealed disruptions in kynurenine and short-chain fatty acid pathways, including decreased butyrate levels. Integrative analyses demonstrated coordinated alterations linking Treg activation, microbial metabolites, and immune pathways, distinguishing SLE_MDD from SLE_non-MDD with up to 85% accuracy.

Conclusions: SLE_MDD is associated with an immunometabolic signature involving alterations in Treg phenotype, gut microbiota composition, and metabolic pathways. These findings provide a rationale for future immunoregulatory or microbiota-targeted therapeutic strategies in SLE_MDD.

Objectives: Dermatomyositis (DM) is characterised by systemic inflammation, debilitating muscle weakness, cutaneous lesions, and increased mortality. An upregulation of type I interferon (IFN)-stimulated genes is observed in patients with DM. However, it remains unclear whether type I IFNs cause muscle weakness in DM. This study aimed to investigate the role of IFN-α/β receptor signalling in muscle weakness induced by factors in DM serum.

Methods: In ex vivo experiments, flexor digitorum brevis muscles were isolated from healthy mice and incubated 24 hours with 10% healthy serum or serum from patients with DM (n = 9). To modulate IFN signalling, an antibody against the type I IFN receptor α/β subunit 1 (IFNAR1) or the Janus kinase-signal transducer and activator of transcription inhibitor ruxolitinib was used. RNA sequencing, followed by bioinformatics analysis, was conducted to identify differentially expressed genes and affected pathways related to IFN signalling.

Results: Incubation with serum from patients with DM, but not that from healthy controls, caused significant muscle weakness manifested by a reduction in muscle force. Bioinformatic analyses revealed downregulation of type I IFN-inducible genes with IFNAR1 antibody. Pathway analysis showed enrichment of several IFN-related pathways. Inhibition of type I IFN signalling with either an IFNAR1 antibody or ruxolitinib abolished DM serum-induced effects.

Conclusions: Factors in serum from patients with DM can activate the type I IFN signalling pathway in skeletal muscles, which constitutes an important causal factor for muscle weakness. Our data support a mechanistic model where blood-borne factors contribute to muscle disease phenotypes and underscore the therapeutic possibilities of pharmacological interventions targeting the IFNAR1 signalling pathway.

Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by dysregulation of the adaptive and innate immunity. This study aimed to identify transcriptomic differences in neutrophils from patients with SLE and healthy individuals, analyse ex vivo adaptation dynamics, and evaluate the impact of chimeric antigen receptor (CAR) T-cell therapy on neutrophil transcriptomic profiles.

Methods: Neutrophils were isolated via negative selection from 7 patients with SLE and 7 healthy individuals. RNA sequencing was performed to assess transcriptomic differences, ex vivo dynamics over 60 minutes, and responses to lipopolysaccharide (LPS) stimulation. In addition, longitudinal transcriptomic data from a patient with SLE undergoing KYV-101 anti-CD19 CAR T-cell therapy were evaluated.

Results: We identified 258 differentially expressed genes consistently distinguishing SLE from healthy neutrophils; they spanned multiple clusters, enriched in interferon-related and DNA damage repair genes (upregulated), and ribosomal protein genes (downregulated). Ex vivo adaptation revealed shared activation pathways, such as NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells) and apoptosis, in both groups. LPS stimulation highlighted overlapping inflammatory responses, demonstrating retained functional capacities in SLE neutrophils. Following CAR T-cell therapy of a patient with SLE, neutrophil transcriptomic profiles were realigned with healthy controls by 3 months posttreatment.

Conclusions: Neutrophils in SLE exhibit intrinsic, disease-specific transcriptomic alterations while sharing ex vivo adaptation dynamics with healthy individuals. The disease-specific alterations appear to be modifiable through targeted therapeutic intervention, as anti-CD19 CAR T-cell therapy resets neutrophil gene expression towards healthy patterns despite targeting B cells rather than neutrophils directly. These findings provide insights into SLE pathogenesis and highlight potential therapeutic strategies targeting both adaptive and innate immunity.

Objectives: Systemic sclerosis (SSc) is associated with increased mortality. Intensive therapies have emerged for severe or refractory cases, but carry significant risks. The Risk score for Early mortality to Stratify for Intensive SSc Therapy (RESIST) score was developed to predict early mortality (<5 years) in patients eligible for such treatments.

Methods: Using the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort, patients unsuitable for intensive therapy were excluded. Survival was analysed via Kaplan-Meier estimates. A multivariable Cox model with adaptive LASSO (Least Absolute Shrinkage and Selection Operator) selection was built, informed by expert opinion, univariable analyses, and literature. Model performance was evaluated using the concordance index, area under the curve (AUC) at 3 and 5 years, and calibration. Missing data were imputed, and pseudo external validation was performed on 6251 excluded patients.

Results: Of 22,059 EUSTAR patients, 4526 met the inclusion criteria; 138 died within 5 years. Deceased patients were more often male (28% vs 16%), older (53 vs 49 years), and had diffuse cutaneous SSc (dcSSc) (61% vs 35%) compared to survivors. The RESIST score included: male sex; dcSSc; age >55 years; elevated C-reactive protein; digital ulcers; modified Rodnan skin score >14; left ventricular ejection fraction <60%; and diffusing capacity of the lung for carbon monoxide <60%. This allowed patients with SSc to be discriminated into 3 groups with the following 5-year survival rates: low risk (99%, 95% CI: 98%-100%), intermediate risk (96%, 95% CI: 95%-97%), and high risk (82%, 95% CI: 78%-87%). The model showed good discrimination in both the development and validation cohorts (AUC: 0.79 [0.77-0.79] and 0.78 [0.77-0.79], respectively).

Conclusions: The RESIST score reliably predicts early mortality in patients with SSc eligible for intensive therapies and may guide treatment decisions by identifying those at high risk of death.

Objectives: This study aims to assess the risks of primary and second primary keratinocyte cancers (KCs) in patients with rheumatoid arthritis (RA) and in relation to treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic disease-modifying antirheumatic drugs.

Methods: Nationwide cohort study of patients treated with Janus kinase inhibitors (JAKi), tumour necrosis factor inhibitor (TNFi), or non-TNFi bDMARDs, using data from the Swedish Rheumatology Quality Register linked to other registers including the National Cancer Register, 2012 through 2023. Adjusted hazard ratios (HRs) were estimated via Cox regression using TNFi as reference.

Results: We identified 21,756 unique patients with RA. Based on 155 incident KC with JAKi, 458 with non-TNFi and 766 with TNFi, the HR for JAKi vs TNFi was 1.39 (1.16-1.68), corresponding to 1 extra KC case per every 244 patients per year. For non-TNFi vs TNFi, the HR was 0.96 (0.86-1.08). By subtype, the HR for JAKi vs TNFi was 1.41 (1.13-1.75) for basal cell carcinoma and 1.49 (1.09-2.05) for squamous cell carcinoma (SCC). For abatacept vs etanercept, the HR for SCC was 1.48 (1.11-1.97). The HR for a second primary KC was 1.31 (0.94-1.82) for JAKi and 0.94 (0.75-1.17) for non-TNFi bDMARD vs TNFi.

Conclusions: Patients treated with JAKi have an elevated risk of KC compared with patients treated with TNFi. Although the class of non-TNFi bDMARDs is not associated with increased KC risk, we repeated a drug-specific signal of increased risk for SCC with abatacept.

Objectives: No app-based nonpharmacological intervention has yet demonstrated to meaningfully improve disease activity, functional status, and disease-specific quality of life in axial spondyloarthritis (axSpA). We evaluated Axia, a CE-marked smartphone application designed for axSpA, that combines personalised exercise therapy, patient education, and disease management, supported by gamification for long-term adherence.

Methods: To evaluate its clinical efficacy, a 12-week monocentric randomised controlled interventional trial was conducted involving 200 patients with axSpA with stable pharmacotherapy. Patients were randomised (1:1) to either using Axia (intervention group [IG]) or standard of care (control group [CG]).

Results: A total of 186 participants (mean age 50.61 years, 66% females, 56% with radiographic axSpA, mean Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] 5.17, and 58% received biologicals or Janus kinase inhibitors) completed the study (95 in the IG and 91 in the CG). Compared to CG, participants in the IG demonstrated significant improvements in BASDAI (analysis of covariance [ANCOVA]-estimated group difference: -1.508, P < .001), Bath Ankylosing Spondylitis Functional Index (-1.139; P < .001), and Ankylosing Spondylitis Quality of Life questionnaire (-2.297; P < .001), all exceeding minimal clinically important difference thresholds. A significantly higher proportion of patients in the IG achieved an Assessment of Spondyloarthritis International Society (ASAS)20 response compared to the CG (51% vs 9%; P < .001), and the ASAS40 response rate was also higher (23% vs 3%; P < .001). No concerning safety signals were observed.

Conclusions: These findings support the potential of Axia as a safe and effective nonpharmacological intervention to further improve the state of care of patients with axSpA in addition to conventional anti-inflammatory pharmacotherapy.

Objectives: Calcium pyrophosphate deposition (CPPD) disease is a common form of arthritis affecting older individuals. This disease is characterised by high levels of pyrophosphate in articular cartilage, resulting in calcium pyrophosphate crystal formation in humans and inflammatory and degenerative arthritis. A loss-of-function mutation in the TNFRSF11B locus (also known as CCAL1), which encodes osteoprotegerin (OPG) causes familial CPPD. OPG acts as a decoy receptor for RANKL, thereby inhibiting osteoclast differentiation and activity. CPPD currently lacks any animal models. The goal of this study was to develop a murine model of early CPPD by incorporating the TNFRSF11B gene mutation in mice and determining its effects on bones, joints and CPPD biomarkers.

Methods: We used CRISPR/Cas9 editing to generate mice carrying the TNFRSF11B mutation (Opg^mt). Joint and bone phenotypes, bone remodelling biomarkers and key CPPD biomarkers were assessed in wild type (WT; Opg^wt/wt), Opg^wt/mt and Opg^mt/mt mice at 6 and 12 months of age.

Results: Male and female mice carrying Opg^mt displayed osteopenia and high bone remodelling markers at 6 and 12 months of age. This phenotype was concurrent with increased osteoclast numbers and activity. Female Opg^mt/mt mice also displayed significant osteoarthritis features by 12 months of age, including articular cartilage loss in the lateral compartment of the knee based on Mankin structural damage scores. Additionally, biomarkers pathognomonic of CPPD disease, such as pyrophosphate, transforming growth factor (TGF)-β1 levels and ENPP1 activity, were significantly elevated in the joints of both 6- and 12-month-old female mice with OPG^mt.

Conclusions: Mice carrying Opg^mt display bone and joint phenotypes characteristic of early-stage CPPD disease in humans. Opg^mt mice represent a novel preclinical model of early CPPD, ideal for exploring potential therapies targeting the disease prior to the development of major joint damage.

Objectives: This study aims to provide an update of the European Alliance of Associations for Rheumatology (EULAR) rheumatoid arthritis (RA) management recommendations addressing the most recent insights.

Methods: An International Task Force was formed with a wide expertise and solicited 2 systemic literature research activities on the safety and efficacy of disease-modifying antirheumatic drugs (DMARDs). New evidence was discussed, considering the update from 2022. A voting process was applied to each item. Levels of evidence and strengths of recommendation were assigned, and participants voted on the levels of agreement.

Results: The task force agreed on 5 overarching principles and reduced the number of recommendations to 9 concerning use of conventional synthetic DMARDs (methotrexate [MTX], leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b)DMARDs (tumour necrosis factor inhibitors [adalimumab, certolizumab pegol, etanercept, golimumab, infliximab], abatacept, rituximab, tocilizumab, sarilumab, including biosimilars) and targeted synthetic [ts]DMARDs (namely the Janus kinase inhibitors [JAKi] tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target), and tapering following clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were considered. Initially, MTX ideally in combination with short-term GCs is recommended; upon insufficient response after 3 to 6 months, a bDMARD should be added; after careful consideration of risks, including MACEs, malignancies and/or thrombo-embolic events, JAKi may also be considered. If the first bDMARD (or JAKi) fails, any other bDMARD (from another or the same class) or JAKi (considering risks) is recommended. With sustained remission, DMARDs may be tapered, but caution is required as stopping often leads to a flare. Levels of evidence and levels of agreement were high for most recommendations.

Conclusions: These updated EULAR recommendations provide consensus on RA management based on currently available evidence regarding efficacy, safety, and cost.

Objectives: Tenosynovitis is a key imaging feature in the preclinical phase of rheumatoid arthritis. Prior studies suggest that presence of magnetic resonance imaging (MRI) tenosynovitis may better predict future clinical arthritis than MRI synovitis. We hypothesised that the volume of subclinical inflammation within tendon sheaths may explain this association in anti-cyclic citrullinated peptide (anti-CCP) positive at-risk individuals. This study sought to assess whether MRI-derived tenosynovitis (TSV) and joint synovitis (SV) volumes predict inflammatory arthritis (IA) in anti-CCP-positive individuals without clinical synovitis, beyond clinical/serological markers.

Methods: We included 223 anti-CCP-positive individuals with musculoskeletal symptoms without clinical synovitis. All underwent baseline contrast-enhanced MRI of the hand and wrist. TSV and SV were quantified via manual segmentation and three-dimensional (3D) reconstruction (OsiriX-MD). IA progression was defined as ≥1 clinically swollen joint. Cox regression and receiver operating characteristic (ROC) analyses were performed.

Results: Of 223 participants, 67 (30%) developed IA over a median 13.3-month follow-up. Inter-reader agreement for volumetric scoring was excellent (intraclass correlation coefficient > 0.90 across all regions). Baseline tenosynovitis (34.5%) was associated with progression (P < .001). TSV was higher in progressors than non-progressors (1607 vs 705 mm³, P = .003), remained predictive after adjusting for SV (P = .008), and outperformed SV in ROC analysis (area under curve (AUC) = 0.697 vs 0.582). In multivariable analysis, TSV (P < .001) and tender joint count (P = .014) independently predicted progression beyond clinical and serological markers. Higher total inflammation volume correlated with shorter time to progression (P = .008).

Conclusions: MRI-derived TSV independently predicts IA and outperforms SV. Quantitative TSV assessment may enhance risk stratification and support preventive strategies in at-risk individuals.