Annals of the Rheumatic Diseases最新文献

Objectives: Idiopathic inflammatory myopathies (IIM) are autoimmune disorders with distinct subtype features, but their molecular mechanisms remain unclear. This study integrated multiomics data to identify subtype-specific molecular signatures and evaluate their prognostic significance in a Han Chinese IIM cohort.

Methods: RNA sequencing, proteomics, and metabolomics were generated on muscle tissues from 203 patients with IIM (including 44 in a validation cohort) and 18 controls. Differential expression was analysed for exons, intron retentions (IRs), proteins, and metabolites, integrated via multiomics factor analysis (MOFA). Pathway enrichment, single-sample Gene Set Enrichment Analysis (ssGSEA), correlation with clinical features, receiver operating characteristic curve, and survival analyses were conducted.

Results: MOFA distinguished dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), and antisynthetase syndrome (ASyS) from controls, identifying 798, 748, and 297 subtype-specific features and pathways, respectively, which were further validated in an independent cohort. In DM, upregulated interferon (IFN) and cytokine pathways were prominent, with 11 IFN-related genes altered at exon, IR, and protein levels, alongside changes in related metabolites. IFNs and cytokine scores correlated with skin manifestations, perifascicular atrophy/necrosis, inflammation, and relapse risk. IMNM showed changes in myosin, actin, and troponin genes, with enrichment of cytoskeleton and extracellular matrix (ECM) pathways that were positively linked to muscle necrosis, regeneration, and inflammation. Protein-level of ECM-related pathways predicted a favourable prognosis. ASyS displayed distinct metabolic signatures (nucleosides, ketones, phosphatidylserine) and endothelial dysfunction, with key metabolism-regulated genes (FABP3, AKR1C2, AKR1C3) showing multiomics alterations associated with necrosis, inflammation, and prognosis.

Conclusions: This multiomics analysis elucidates distinct molecular mechanisms in IIM subtypes, identifying potential biomarkers for personalised prognosis and therapy.

Objectives: Novel biologic agents targeting the neonatal Fc receptor (FcRn) offer a promising strategy to prevent cardiac neonatal lupus (cardiac-NL) in pregnant patients with high-titre anti-SSA/Ro52 kD or 60 kD autoantibodies via dual effects: reducing serum immunoglobin G (IgG) levels and inhibiting placental transfer. This study was initiated to assess the feasibility of FcRn blockade as prophylactic therapy for recurrent cardiac-NL.

Methods: A 34-year-old pregnant patient with systemic lupus erythematosus and 3 prior consecutive pregnancies complicated by neonatal lupus (1 cutaneous, 1 fatal cardiac-NL at 20 weeks, 1 cardiac-NL delivered at 32 weeks and neonatal cutaneous NL), each despite hydroxychloroquine 400 mg daily, was treated with weekly subcutaneous infusions of 560 mg rozanolixizumab (humanised IgG4 monoclonal antibody against FcRn) from gestational weeks 14 to 28 (to cover the vulnerable period of fetal cardiac injury) through a compassionate use designation. The patient performed home fetal heart rhythm monitoring thrice daily with weekly echocardiograms.

Results: Maternal anti-SSA/Ro52 kD and 60 kD autoantibodies, total IgG, and subclasses IgG1, 2, 3 decreased by about 65% at gestational week 22, with a return to near baseline levels by week 34. The pregnancy was uncomplicated, resulting in a spontaneous vaginal delivery of a healthy neonate at 37 weeks. At delivery, cord blood and maternal IgG levels were normal, obviating the need for rescue intravenous immune globulin. The neonate had a normal echocardiogram and electrocardiogram but developed a rash consistent with neonatal lupus at 5 weeks of life. There were no serious adverse events.

Conclusions: The successful application of FcRn blockade to prevent recurrent cardiac-NL sets a precedent for a multicentre study.

Objectives: In 2016, rheumatologists and gout researchers developed a preliminary definition for gout remission. A subsequent qualitative study involving people with gout identified redundancies in the preliminary definition, prompting the development of a simplified definition consisting of no gout flares over 12 months, absence of subcutaneous tophi and serum urate <0.36 mmol/L (6 mg/dL) over 12 months. Here, we describe the evaluation and validation of the simplified definition and endorsement of this definition as the Gout, Hyperuricemia, and Crystal-Associated Disease Network (G-CAN) definition of clinical remission in gout.

Methods: After establishment of the simplified definition, this multiphase project involved consecutive steps: analysis of the definition across a range of gout clinical trial datasets and study populations, summary of evaluation and validation of this definition presented to G-CAN members, discussion of this definition by G-CAN members, voting and G-CAN Board endorsement.

Results: The simplified definition exhibited face validity, construct validity, predictive validity, feasibility, responsiveness, and discrimination across a range of gout clinical trial datasets. It also captured both inflammatory disease activity and urate burden in gout and reflected the patient perspective on gout remission. It was suggested by G-CAN members to consider the definition as one for 'clinical gout remission' since there is no domain evaluating complete crystal dissolution. In voting, this definition was supported by 98% of G-CAN members, and the G-CAN Board endorsed the definition.

Conclusions: The G-CAN definition is feasible and has high validity. We recommend that this definition is used when assessing clinical remission in gout.

Objectives: Venous thromboembolism (VTE), following Janus kinase inhibitors treatment (JAKi), is poorly understood in rheumatoid arthritis (RA). We investigated whether JAKi augmented immune cell-driven clotting or immunothrombosis in RA.

Methods: Peripheral blood leukocytes (PBLs) isolated from patients with RA and healthy controls were treated with various JAKi classes, before stimulation with Toll-like receptor (TLR)-4 (lipopolysaccharide [LPS]) or TLR3 (polyinosinic-polycytidylic acid-poly (I:C)) agonists. Conditioned supernatants were used in plasma turbidity assays to evaluate clot formation and lysis dynamics, while bulk RNA sequencing, enzyme-linked immunosorbent assay, and bead-based immunoassays were used to explore immunothrombosis mechanisms.

Results: Turbidity analyses showed that conditioned media from PBLs treated with LPS and tofacitinib significantly accelerated clot formation when compared to LPS alone, and this effect was tissue factor pathway dependent and accompanied by elevations in immunothrombotic cytokines, including tumour necrosis factor α, interleukin (IL)-1β, and IL-6. PBLs from patients with active RA exhibited significantly greater immunothrombotic potential compared to those with low disease activity, despite comparable baseline cytokine levels. RNA sequencing analysis revealed significant pathway enrichment in tofacitinib/LPS-treated PBLs, including activation of Nuclear Factor (NF)-κB pathways, increased tissue factor expression, and reduced levels of anticoagulant factors such as protein S. Pharmacological inhibition assays with 5 JAK therapies suggested that JAK1/tyrosine kinase 2-dependent effect underscored increased thrombosis but selective JAK3 inhibition did not reproduce the prothrombotic effects. Finally, patients with RA with JAK-associated pulmonary embolism showed interstitial changes compatible with immunothrombosis in 4/6 (67%).

Conclusions: Immunothrombosis offers a novel explanation for JAKi-associated VTE in RA.

Objectives: This study aims to evaluate the evolution of subchondral sacroiliac joint (SIJ) sclerosis from pregnancy to 12 months postpartum, and to explore preceding and concomitant magnetic resonance imaging (MRI) features, potentially indicating osteitis condensans ilii (OCI).

Methods: One hundred three first-time mothers were recruited for serial SIJ MRIs. MRI scans were performed at pregnancy weeks 20 and 32, and at 3, 6, and 12 months postpartum. Three readers independently evaluated subchondral sclerosis, bone marrow oedema (BME), fat lesions, and erosions. Sclerosis evolution and associations with BME, fat lesions, erosions, and pain were analysed.

Results: The prevalence of iliac subchondral sclerosis increased gradually from 20% at pregnancy week 20% to 46% at 12 months postpartum, predominantly located in the upper-middle and anterior joint portions with depth expanding from a mean of 6.5 to 7.5 mm. BME and fat lesions were frequent with BME peaking at 3 months postpartum and fat lesions later in the postpartum period. Expanding depth of sclerosis at 12 months postpartum was associated with increasing prevalence of BME and fat lesions, but not with pain. At 12 months postpartum, BME and fat lesions meeting Assessment of SpondyloArthritis International Society thresholds were significantly more frequent with sclerosis ≥8 mm (50/40%) compared to sclerosis <8 mm (15/7%).

Conclusions: Increasing depth of subchondral SIJ sclerosis during and after pregnancy was associated with BME peaking in the early and fat lesion in the late postpartum period suggesting that BME may precede the development of sclerosis and fat lesions. Sclerosis depth ≥8 mm, frequently accompanied by high-level BME and fat lesion, may serve as an MRI surrogate biomarker of radiographic OCI.

Objectives: This study aims to conduct a systematic literature review (SLR) to summarise associations between health literacy and inflammatory arthritis (IA) outcomes, to inform management.

Methods: Inclusion criteria were adults with IA; studies assessing health literacy or interventions targeting health literacy; observational and qualitative studies, randomised controlled trials. Searches were performed using MeSH headings for health literacy and IA. Data were extracted on demographics, health literacy assessment and relevant outcomes, grouped into themes using vote-counting.

Results: Of 3087 identified articles, 29 were included. The total number of participants across all studies was 16,402, comprising mostly females, with a mean age of 46 to 70 years. Ethnicity was reported in 13 studies; most participants were Caucasian. The most frequently reported IA was rheumatoid arthritis. Health literacy measures included: Test of Functional Health Literacy in Adults (n = 13); Single Item Literacy Screener (n = 10); Rapid Estimate of Adult Literacy in Medicine (n = 6); Health Literacy Questionnaire (n = 2). Six main associations were identified with low health literacy: higher disease activity; more disability; more mental health symptoms (including depression and anxiety); higher healthcare use; lower medication adherence; lower use of internet, telehealth and technology.

Conclusions: In people with IA, low health literacy is generally associated with worse outcomes including higher disease activity, mental health symptoms and disability, higher healthcare use, lower medication adherence, and lower use of technology. This is the first SLR to synthesise associations between health literacy and outcomes in IA. Our findings should inform policy and resource allocation and improve the quality of care for patients with IA and low health literacy.