Annals of the Rheumatic Diseases最新文献

Objectives: Around 30% of patients with rheumatoid arthritis (RA) lack rheumatoid factor and anti-citrullinated protein antibodies (ACPA) complicating diagnosis and potentially delaying treatment. We hypothesised that innate immune mechanisms might be more prominent in ACPA- RA.

Methods: We performed single-cell RNA sequencing of mononuclear cells from peripheral blood (PBMC) and synovial fluid (SFMC) of patients with ACPA- and ACPA+ RA (n = 4 per group: discovery cohort; n = 8 per group: validation cohort). Dendritic cells and proinflammatory cytokine production were analysed by flow cytometry on SFMC from patients with ACPA- RA, ACPA+ RA, and psoriatic arthritis. Interferon (IFN) levels in synovial fluid (SF) and serum were measured in these groups.

Results: Several macrophage subsets and cDC2 were enriched in ACPA- RA SF whereas the frequency of Tph and B cells was increased in ACPA+ RA SF. Type I IFN-stimulated genes were detected in SFMC, but not PBMC, of patients with ACPA- RA. A type I IFN signature was also observed in synovial tissue from two patients with ACPA- RA in an independent dataset. IFN levels were higher in SF than serum but IFN-α/β production did not differ between ACPA+ and ACPA- RA.

Conclusions: This study identifies a distinct innate cell composition and type I IFN gene response in synovial joints, but not in peripheral blood, of patients with ACPA- RA. Similar IFN levels across groups suggest the IFN signature may have been primed before the cells entered the joints. These findings provide a foundation for future research on type I IFN responses in ACPA- RA.

Objectives: To identify serum and salivary gland proteomic biomarkers in primary Sjögren's disease (SjD), evaluate their correlation with tissue inflammation, and relate findings to clinical, autoantibody, and genetic profiles.

Methods: Paired salivary gland extracts and serum samples from patients with SjD (n = 81) and sicca controls (n = 19), and serum from larger Swedish (SjD n = 456; controls n = 141) and Norwegian (SjD n = 233; controls n = 137) cohorts, were analysed using proximity extension assay technology. Patients were stratified by antinuclear antibodies (ANA), anti-Ro/SSA, anti-La/SSB autoantibodies, and extraglandular manifestations. Human leukocute antigen (HLA) alleles were integrated to assess genetic associations.

Results: Proteomic analysis revealed more pronounced alterations in the salivary gland extracts compared to serum. In serum, 27 proteins were associated with SjD in the Swedish discovery cohort, of which 16 proteins were validated in the Norwegian replication cohort. Several proteins including both described biomarkers C-X-C motif chemokine ligand (CXCL)10 and CXCL13 and more novel lysosome-associated membrane glycoprotein 3 and cytotoxic and regulatory T cell molecule correlated with extraglandular manifestations, particularly pulmonary involvement. Levels of the 16 validated proteins increased in a stepwise fashion across serological subgroups, from lowest in ANA negative to highest in anti-Ro/SSA and anti-La/SSB double-positive patients and were linked to risk alleles HLA-DRB1*03 and DRB1*15. A composite 'Sjögren protein score' based on the 16 validated proteins correlated with salivary gland focus score and successfully distinguished SjD from healthy controls (area under the curve 0.888; 89% specificity, 76% sensitivity).

Conclusions: We define a validated serum proteomic signature that reflects local glandular inflammation and correlates with genetic and serological features. The 'Sjögren protein score' holds promise as a noninvasive biomarker for the diagnosis of SjD.

Objectives: Despite expanding regulatory T (Treg) cells, low-dose interleukin-2 (IL-2) therapy shows variable clinical efficacy in systemic lupus erythematosus (SLE). Here, we investigated whether previously unrecognised effects of IL-2 on age-associated B cells (ABCs) explain this therapeutic heterogeneity.

Methods: Integrated transcriptomic analysis was used to identify the prevalent signalling pathways associated with lupus pathogenic ABCs. The effects of IL-2 on ABCs were examined. TLR7-driven lupus-prone mice were administered to assess the efficacy of IL-2 therapy. IL-2 responsiveness of ABC was further evaluated in patients with SLE through bioinformatic analysis.

Results: Transcriptomic and single-cell analyses revealed elevated IL-2 signalling in ABCs, with a more pronounced IL-2 signature in patients with SLE than in healthy controls. IL2RB, a subunit of the IL-2 receptor, was significantly enriched in ABCs and showed increased chromatin accessibility at its promoter. IL-2 promoted ABC survival and differentiation in a stage-dependent manner. Prior IL-2 administration to recipient mice promoted the persistence of adoptively transferred ABCs. In lupus-prone mice, IL-2 administration increased both ABC and Treg populations without ameliorating disease manifestations with ABC's promotion being more dependent on the disease condition. Additionally, ABCs showed elevated expression of IL-2 receptor correlating with ABC frequency in our cohorts, and activation of IL-2 signalling was further observed in B cells and ABCs from patients with SLE.

Conclusions: This study identified ABCs as a novel target of IL-2, expanding the understanding of IL-2's role in SLE beyond the traditional Treg-centric view and offering insights into the variable therapeutic efficacy of IL-2 in this context.

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.