Annals of the Rheumatic Diseases最新文献

Objectives: Although genetic risk factors, such as HLA-DRB1 alleles, contribute to the pathogenesis of rheumatoid arthritis (RA), the concordance rate in monozygotic (MZ) twins is low, suggesting that other factors are involved in disease development. Further, the relative contribution of nongenetic elements in identical twins has not been characterised. Here, we aimed to characterise host and microbial biomarkers of RA by studying MZ twins discordant for disease using a multiomics approach.

Methods: Eight pairs of MZ twins discordant for RA (N = 16) were enrolled in the United States (US). The gut microbiome was assessed using shotgun metagenomic sequencing. Autoantibodies, cytokines, and plasma proteins were measured in both plasma and faeces. Levels of short-chain fatty acids (SCFAs) from serum and faeces were quantified using gas chromatography mass spectrometry (GC-MS). Metagenomic data from a UK twin registry (TwinsUK) (N = 14) were used to validate findings in the US population.

Results: Although microbiome diversity and composition did not differ between twins, we observed a significant decrease in the SCFA-producing bacteria Blautia faecis and significantly lower concentrations of faecal butyrate and propionate in affected RA twins in the US. TwinsUK showed a similar reduction in the SCFA-producers Gemmiger formicilis and Faecalicatena fissicatena, as well as bacterial SCFA metabolism pathways.

Conclusions: Multiomics biomarkers differentiate MZ twins discordant for RA. Faecal butyrate and propionate, as well as SCFA-producing bacteria, were decreased in affected twins. We found a similar decrease in SCFA-producing taxa in affected twins in a geographically distinct cohort in the UK. Our results suggest that, if further validated in larger cohorts, multiomics approaches may improve our understanding of RA pathogenesis and, potentially, contribute to more accurate diagnostics and coadjuvant therapies.

Objectives: The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is widely used to assess axial disease activity in psoriatic arthritis (PsA). However, 5 of its 6 questions reflect general disease activity rather than axial-specific symptoms. We aimed to evaluate the performance of BASDAI and its back pain subscore in assessing axial disease in PsA.

Methods: Patients with BASDAI scores were identified from a longitudinal PsA cohort initiated in 1978. Axial disease was defined radiographically. Trends in BASDAI and back pain scores were compared between patients with and without axial involvement. Associations of total BASDAI and back pain subscore with axial disease were assessed using univariable and multivariable linear mixed models in the entire cohort and stratified subgroups.

Results: Of 1059 patients, 449 (42.4%) had axial and 610 (57.6%) had peripheral disease only. The mean age was 44.4 years (SD 12.8), and 55.9% were male. No difference in the BASDAI and back pain trends was observed between the axial and peripheral disease groups. Axial involvement was not associated with total BASDAI scores (β = -0.14, 95% CI -0.05 to 0.33). However, it was associated with a small, yet significant increase in back pain subscore (0.30, 0.06-0.55). Both BASDAI and back pain scores were associated with active peripheral joints, enthesitis, dactylitis, age, Psoriasis Area and Severity Index, and inversely with male sex. These associations were consistent across axial and peripheral disease subgroups.

Conclusions: BASDAI and its back pain subscore are influenced by peripheral musculoskeletal and skin disease activity in PsA, limiting their utility for assessing axial activity.

Objectives: The objective of this paper is to examine whether patients with newly diagnosed rheumatoid arthritis (RA) can discontinue prednisolone after short-term bridging therapy.

Methods: Patients naïve to disease-modifying antirheumatic drugs with recent-onset RA in the ARCTIC (Aiming for Remission in rheumatoid arthritis: a randomised trial examining the benefit of ultrasound in a Clinical TIght Control regimen) trial were followed for 24 months, with initial methotrexate monotherapy and prednisolone bridging therapy (tapering doses from 15 mg to 0 over 7 weeks). We explored the proportion of patients successfully discontinuing prednisolone, defined as no prednisolone use after bridging therapy, and for at least 4 subsequent months. Discontinuation was assessed after cessation of bridging therapy at 2, 3, 6, 12, 20, and 24 months. Additionally, we examined how many patients used prednisolone continuously for ≥3 months.

Results: Of 230 patients, 227 started prednisolone bridging therapy and were included for analyses. At baseline, mean (SD) age was 52 (13.7) years, mean (SD) disease activity score was 3.47 (1.17), 62% patients were female, and 82% patients were anticitrullinated peptide antibody positive. After 7 weeks, 84% (191/227) had discontinued prednisolone, 89% (203/227) had discontinued at 3 months, and 95% (216/227) within 24 months. Five percent (11/227) used prednisolone at every visit. The median number of days (IQR) of prednisolone use during 2 years was 55 (48-90). Among those who discontinued after 7 weeks, 80% (152/191) did not restart prednisolone. Continuous use for at least 3 months was observed in 22%.

Conclusions: In newly diagnosed patients with RA using bridging therapy when starting methotrexate, over 80% successfully discontinued prednisolone. This supports that tapering to discontinuation is achievable in most patients after short-term bridging with prednisolone, in line with current European Alliance of Associations for Rheumatology recommendations.

Objectives: Neutrophil extracellular traps (NETs) are increasingly recognised for their role in primary antiphospholipid syndrome (PAPS) pathogenesis. Herein, we examined underlying mechanisms driving NET formation and the thrombogenic effects of NETs in patients with PAPS, along with potential inhibitors.

Methods: We examined NET release in PAPS, asymptomatic antiphospholipid autoantibodies (aPLs) carriers, and healthy controls (HCs) as well as NET-bound proteins by immunofluorescence, immunoblotting, quantitative polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA). We assessed platelet-neutrophil aggregates by flow cytometry (CD61/CD66b staining) and autophagy using LC3B immunofluorescence and immunoblotting. Immunofluorescence was performed in paraffin-embedded kidney, skin ulcer, and endoarterial thrombus tissues from patients with PAPS. Suppression of NET release via CD40-CD40L inhibition was tested in in vitro and venous thrombosis mouse models.

Results: Neutrophils from patients with PAPS exhibited increased NET release compared with asymptomatic aPL carriers and HCs. NETs from patients with PAPS expressed tissue factor (TF) that induced thrombin generation in platelet-poor plasma from HCs. aPL induced in vitro intracellular TF expression in HC neutrophils. TF-expressing NETs were abundant in the kidney, skin ulcer, and endoarterial thrombus tissues from patients with PAPS, and colocalised with fibrinogen. NET release in PAPS neutrophils was driven by aPL-mediated platelet activation, subsequent platelet-neutrophil interaction, and autophagy induction. CD40-CD40L blockade reduced platelet activation, autophagy, and NET formation in patients with PAPS. In a mouse model, inhibition of CD40-CD40L reduced neutrophil-platelet aggregates and myeloperoxidase (MPO)-DNA complexes in mouse peripheral blood, and the presence of NETs in the formed thrombi.

Conclusions: Targeting the platelet-neutrophil/autophagy/TF-expressing NETs axis by CD40-CD40L inhibition attenuates thromboinflammation in PAPS and should be explored as a potential therapeutic target.

Objectives: Interstitial lung disease (ILD) carries significant morbidity and mortality risk in systemic sclerosis (SSc). We aimed to estimate the incidence of new-onset SSc-ILD and the associated risk factors, as well as its impact on the prognosis.

Methods: Patients classified as having SSc, with the absence of ILD signs on high-resolution computed tomography (HRCT) at baseline and having at least 1 follow-up visit with available HRCT data, were selected. SSc-ILD incidence was calculated as a rate per 100 person-years. Predictors of new-onset ILD and risk factors for ILD progression and mortality were chosen according to the literature and expert opinion. Risk factors for new-onset ILD, as well as its prognostic impact on ILD progression and mortality, were tested by generalised logistic estimating equation and Cox regression models, respectively.

Results: Among 5331 patients with SSc with negative baseline HRCT, the incidence of new-onset ILD was 3.83 cases per 100 person-years. Notably, there was a continuous detection of new ILD onset up to 10 years from baseline. Risk factors for new-onset ILD included New York Heart Association stage ≥2, muscle weakness, high inflammatory markers, and SSc-specific autoantibodies, but not disease duration. Despite a lower risk of ILD progression compared with prevalent ILD diagnosed at baseline, incident ILD still carried an increased risk for mortality, which was almost double when compared with ILD-negative cases.

Conclusions: Patients with SSc should be considered for regular screening following a negative baseline HRCT, in particular when carrying high-risk features for new ILD onset, given its incidence and prognostic implications.

Objectives: Childhood-onset systemic lupus erythematosus (cSLE) is a severe autoimmune disease with significant morbidity and enhanced type I interferon (IFN-I) signalling, potentially contributing to its aggressive clinical course. This study aimed to deliver the most comprehensive multiomic characterisation of IFN-I signalling in cSLE, defining its heterogeneity at transcriptomic, proteomic, and cellular levels, and linking these profiles to detailed clinical trajectories.

Methods: We profiled 74 young females with cSLE and 20 matched controls using RNA-sequencing of peripheral blood mononuclear cells, single molecule array (SIMOA) for IFNα quantification, IFN-I luciferase reporter cells, spectral flow cytometry, and Olink proteomics (validated by enzyme-linked immunosorbent assay, (ELISA)). Clinical data were assessed in endotype groups based on IFN-I readouts with longitudinal trajectory analysis, and clustering reproducibility was tested in independent validation cohorts.

Results: Gene expression analysis revealed significantly upregulated genes in cSLE with strong IFN-I pathway enrichment. Patients clustered into IFN-high (65%) and IFN-low (35%) groups, independent of disease activity. IFN-high patients showed elevated IFNα, reporter cell activity, reduced lymphocyte counts, and greater in vitro response to anifrolumab. LAMP3 emerged as a stable and reproducible biomarker of IFN-high status. T cells and plasmacytoid dendritic cells were most sensitive to IFN-I ex vivo, with distinct functional marker profiles. Integrated transcriptomic, proteomic, and cellular data defined 6 IFN-driven endotypes with unique immune signatures and clinical phenotypes. Endotypes differed in IFN-I activity, organ damage, flare burden, and corticosteroid exposure with divergent longitudinal trajectories.

Conclusions: Multilevel IFN profiling revealed an important biomarker of IFN-high patients for potential use in clinical practice, immune lineage-specific responses, and clinically meaningful endotypes, supporting systems immunology approaches and biomarker-guided personalised treatment strategies.

Objectives: B-cell activating factor (BAFF) of the Tumors Necrosis Factor (TNF) family is involved in the pathogenesis of Sjögren's disease (SjD). A functional variant (BAFF variant [BAFF-var]) of the BAFF gene (TNFSF13B), leading to increased levels of BAFF, has been described. The aim of this study was to investigate the association between BAFF-var and clinical phenotype and risk of SjD.

Methods: A case-control study including cases from Paris Saclay and the Assessment of Systemic Signs and Evolution in Sjögren's syndrome (ASSESS) cohort and controls (blood donors from Etablissement Français du Sang [EFS]) was conducted. Genetic association analyses included only patients with European ancestry assessed by a principal component analysis using 24 ancestry-informative markers.

Results: We included 770 cases (420 from Paris Saclay and 350 from ASSESS) and 786 controls from EFS. Among them, 666 cases and 721 controls were found of European ancestry. We found that BAFF-var was significantly associated with higher soluble BAFF (sBAFF) level (1392.7 vs 1107.0 pg/mL, P < .001), and with increased occurrence of lymphoma (13% in patients with SjD with BAFF-var vs 5.8% in patients with SjD with BAFF-WT (wild-type), P = .013). BAFF-var remained independently associated with lymphoma after adjustment for rheumatoid factor, sex, and cumulative European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (odds ratio [OR] 2.60, 95% CI: 1.14-5.47). By comparison with ancestry-matched controls, BAFF-var was also associated with SjD itself with a minor allele frequency of 0.061 in cases and 0.035 in controls (OR = 1.77, P = .0017).

Conclusions: We found an association between BAFF-var and sBAFF levels, occurrence of lymphoma as well as occurrence of SjD itself. This variant could be a new biomarker for lymphoma risk in SjD.

Objectives: Most mammalian tissues have limited regenerative capacity. It has been speculated that the brain might regulate tissue regeneration, while this concept has yet to be experimentally addressed. Using cartilage, a tissue with limited regenerative capacity as an example, we investigated this hypothesis.

Methods: We employed magnetic resonance imaging, polysynaptic retrograde tracing, chemogenetic/optogenetic manipulations, and single-cell RNA sequencing to characterise a functional brain-cartilage neural circuit regulating cartilage regeneration in human and mouse models.

Results: We found that fractional anisotropy and amplitude of low-frequency fluctuations values of the paraventricular nucleus (PVN) are elevated, and correlate with Western Ontario and McMaster Universities Arthritis Index scores and synovial fluid norepinephrine (NE) concentrations in patients with osteoarthritis. We further demonstrate the existence of a functional trans-neuronal circuit to regulate cartilage regeneration, which originates from PVN^CRH neurons to sympathetic nerves in the synovium of joint. Inhibition of the circuit is sufficient to strongly promote the production of stable mature articular cartilage instead of fibrocartilage. This process fosters the regeneration of articular cartilage by inhibiting the pathways mediated by NE/articular cartilage via the β2-adrenergic receptor (ADRB2) in Proteoglycan 4⁺ cells. Furthermore, treatment with an ADRB2 inverse agonist prevented cartilage degradation in human articular cartilage explants.

Conclusions: Our findings unveil a brain-cartilage circuit that regulates cartilage regeneration, providing valuable insights into the inherent limitations of tissue regeneration and suggesting a promising treatment strategy for enhancing cartilage regeneration.

Objectives: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with pronounced clinical heterogeneity and symptom burden. Despite growing knowledge of SLE biology, sensitive noninvasive biomarkers for monitoring disease activity remain lacking. This study aimed to characterise the breath metabolome in SLE and to explore associations between volatile organic compounds (VOCs) and clinical features, including disease activity and fatigue.

Methods: Exhaled breath was collected from 30 SLE patients and 30 matched healthy controls using the ReCIVA Breath Sampler and analysed by thermal desorption gas chromatography-mass spectrometry. VOCs were identified using high-resolution libraries and classified by confidence levels. Associations with clinical and patient-reported outcomes were evaluated, including disease activity indices, fatigue scores, Definition Of Remission In SLE remission, and Lupus Low Disease Activity State.

Results: Of 1433 detected VOCs, 539 exhibited levels over background and were considered breath-derived. Distinct breathomic signatures discriminated patients from controls and stratified patients by SLE activity and fatigue burden. Five VOC clusters were identified. Methyl acetate was inversely associated with disease activity and fatigue, suggesting a role in immune homeostasis. A cluster of branched alkenes and alcohols was associated with active disease and greater fatigue, aligning with oxidative stress and lipid peroxidation. Nitrogen-containing heterocycles displayed U-shaped patterns across disease states, potentially reflecting varying intestinal permeability.

Conclusions: This is the first study to characterise the breath metabolome in SLE. VOC signatures reflected immunometabolic perturbations, oxidative stress, and gut barrier integrity. Breathomics may provide a noninvasive means to monitor disease activity and symptom burden in SLE.

Objectives: We aimed to characterise the dynamic transcriptional changes associated with treatment responses in lupus nephritis (LN) through longitudinal single-cell RNA sequencing analysis of peripheral blood mononuclear cells (PBMCs) during standard-of-care induction therapy.

Methods: We leveraged the Korean Unlimited multi-Dimensional Omics research in Systemic lupus erythematosus cohort, comprising patients with biopsy-proven active proliferative LN. Single-cell RNA sequencing of PBMCs was conducted at baseline and subsequently at 3, 6, and 12 months following initiation of therapy (n = 10). For validation purposes, bulk RNA sequencing of monocytes was performed in an independent patient group at baseline and at 3 months (n = 13). Renal response was classified as complete response or nonresponse at 12 months according to predefined criteria.

Results: In single-cell RNA sequencing analysis of patients with LN, the myeloid cell population-particularly classical and intermediate monocytes-demonstrated the highest number of differentially expressed genes following induction therapy. Weighted gene coexpression network analysis identified distinct gene modules closely associated with treatment responses. Complete responders exhibited progressive suppression of type I interferon (IFN-I) signalling, whereas nonresponders maintained persistent IFN-I-driven gene expression characterised by sustained inflammatory features. Bulk RNA sequencing of monocytes from an independent group of patients with LN confirmed that 6 IFN-I-responsive genes (IRF7, ISG15, LY6E, IFI44, IFI44L, and IFI6) were significantly downregulated by 3 months in complete responders, but not in nonresponders. This gene signature correlated with both proteinuria and disease activity scores.

Conclusions: This study demonstrates that persistent IFN-I-driven gene expression in monocytes characterises treatment resistance in LN. Our findings suggest that early transcriptional profiling may enable timely identification of nonresponders and warrant further investigation in larger, independent cohorts.