Annals of the Rheumatic Diseases最新文献

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.

Background: Interstitial lung disease (ILD) is a frequent manifestation of connective tissue diseases (CTDs) and is associated with high morbidity and mortality. Clinical practice guidelines to standardise screening, diagnosis, treatment and follow-up for CTD-ILD are of high importance for optimised patient care.

Methods: A European Respiratory Society and European Alliance of Associations for Rheumatology task force committee, composed of pulmonologists, rheumatologists, pathologists, radiologists, methodologists and patient representatives, developed recommendations based on PICO (Patients, Intervention, Comparison, Outcomes) questions with grading of the evidence according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology and complementary narrative questions agreed on by both societies. For both PICO and narrative questions, the Evidence to Decision framework was used to formulate the recommendations.

Results: The task force committee concluded with recommendations for 25 PICO and 28 narrative questions, regarding ILD in the context of systemic sclerosis, rheumatoid arthritis (RA), idiopathic inflammatory myopathies, Sjögren disease (SjD), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). In four narrative questions, regarding screening and assessment of risk for ILD progression in MCTD, SjD and SLE and one PICO question regarding pirfenidone in CTD-ILD other than RA-ILD, the task force had insufficient evidence to support recommendations. Screening, diagnostic, monitoring and treatment algorithms were developed based on the recommendations and usual clinical practice.

Conclusions: We provide practical guidance by evidence-based recommendations to clinicians for each of the CTDs. In many cases there is low certainty or absence of evidence and we encourage further research to fill these gaps.

Objectives: We aimed to characterise the synovial pathology of refractory rheumatoid arthritis (RA) by comparing two hypothesised clinical phenotypes-persistent inflammatory refractory RA (PIRRA) and noninflammatory refractory RA (NIRRA)-against nonrefractory RA (NORRA).

Methods: We conducted a prospective, observational cohort study at two academic rheumatology centres. Adult patients with established RA and active disease (Clinical Disease Activity Index >10) underwent ultrasound-guided synovial tissue biopsies in accordance with European Alliance of Associations for Rheumatology-Outcome Measures in Rheumatology guidelines. Based on the Physician Global Assessment (>2/10) and C-reactive protein (>5 mg/L) thresholds, biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs)-inadequate responders patients were classified as PIRRA or NIRRA, whereas b/tsDMARD-naïve were designated NORRA. Histopathological assessments included the Krenn Synovitis Score (KSS) and immunohistochemistry pathotype evaluation (lympho-myeloid, diffuse-myeloid, pauci-immune/fibroid).

Results: Of the 93 biopsied patients, 43 were PIRRA, 21 NIRRA, and 29 NORRA. NIRRA had lower KSS (P = .012), lymphoid aggregates (P < .001) and predominantly pauci-immune/fibroid pathotype (n = 21/43, 47.6%), whereas PIRRA displayed more lympho- and diffuse-myeloid pathotypes, coupled with higher inflammatory markers and ultrasound-power Doppler scores. The relative risk of having pauci-immune fibroid synovitis for NIRRA was 1.6 (95% CI 1.2 to 2.9, P = .006), indicating a statistically significant increase in risk compared to PIRRA. Despite having similar overall disease activity scores, NIRRA patients reported significantly greater pain (P = .005) and higher opioid use (P = .015) than PIRRA, and worse health-related quality of life than PIRRA or NORRA, underscoring noninflammatory mechanisms.

Conclusions: Our findings demonstrate distinct synovial and clinical phenotypes in refractory RA. Although PIRRA appears driven by active synovial inflammation and immune cell infiltration, NIRRA involves predominantly pauci-immune/fibroid histology with significant noninflammatory contributors to disease burden.

Objectives: To evaluate the likelihood of joint inflammation recurrence in previously affected joints during the disease course of psoriatic arthritis, and to identify joint-specific predictors associated with recurrence risk using real-world data.

Methods: Patients with PsA followed at the Tel Aviv Medical Center Rheumatology Institute were included. At each visit, the 68-swollen joint count (SJC68) was assessed. The association between baseline joint swelling and recurrence was analysed using mixed-effects logistic regression, adjusting for joint location and for follow-up visit. An interaction analysis was conducted to determine the association of each joint location.

Results: A total of 492 patients were included, with a median of 6 (IQR 4-9) follow-up visits. Of these, 44% were male, with a mean age at baseline of 48 y/o (SD 15), and a mean disease duration of 1 year (1.9). At baseline, 420 (85%) patients had at least 1 swollen joint, with a median SJC68 of 2 (1-5). Among the 33,456 joints assessed, 1402 were swollen at baseline (4.2%), and 514 (36.7%) of them recurred during follow-up. Mixed-effect logistic regression showed that baseline swelling predicted future swelling (odds ratio 2.88, 95% CI 2.61-3.18) with variation by joint location. This association was not modified by sex, age, or disease duration.

Conclusions: This study identified a strong association between baseline joint swelling and subsequent swelling episodes in patients with PsA. This association varied by joint and remained significant when limited to the most frequently swollen joints.

Objectives: The objective of this study was to update the 2019 European Alliance of Associations for Rheumatology (EULAR)/ European Renal Association/European Dialysis Transplantation Association (ERA-EDTA) recommendations for the management of systemic lupus erythematosus (SLE) with kidney involvement, taking into consideration emerging evidence and recent developments in the field.

Methods: We recruited an international Task Force of experts and followed the EULAR standard operating procedures. We performed systematic literature research (period January 2019 to March 2024), followed by the modified Delphi method, to form questions, elicit expert opinions, and reach consensus. The new evidence was examined, taking into consideration previous updates.

Results: The Task Force agreed on 4 overarching principles and 13 recommendations, which were also evaluated for their feasibility and impact on clinical care. These concern the use of kidney biopsy for diagnosis; targets of therapy and treatment milestones; immunomodulatory therapy with antimalarials, glucocorticoids, immunosuppressives (mycophenolate, cyclophosphamide, and calcineurin inhibitors), and biologics (belimumab, obinutuzumab, and rituximab); nonimmune therapy (kidney protection, vaccinations, cardiovascular, and bone protection); family planning; and management of kidney failure. Guidance on single-agent or early combination immune therapy, glucocorticoid tapering and withdrawal, duration of immune therapy, and treatment of refractory disease is provided.

Conclusions: The updated EULAR recommendations provide evidence- and expert-based consensus on the management of SLE with kidney involvement, adjusted for severity, and taking into consideration long-term efficacy, safety, cost, and local availability of drugs.