Annals of the Rheumatic Diseases最新文献

Polymyalgia rheumatica (PMR) is one of the most common inflammatory rheumatic diseases in people aged ≥50 years and is characterised by neck pain, bilateral shoulder and hip girdle pain, and morning stiffness. It is closely interlinked with giant cell arteritis (GCA) (potentially considered the GCA-PMR spectrum) and rheumatoid arthritis and shares a common immunopathophysiology with both. Glucocorticoids (GCs) have been the standard of care for PMR for several decades (American College of Rheumatology/European Alliance of Associations for Rheumatology guidelines); however, >50% of patients cannot successfully taper GCs, and long-term treatment is associated with considerable GC-related adverse events. Immunohistological studies using biopsies from subacromial bursae have indicated that various cytokines and cells, including macrophages, interleukin-6 (IL-6), and fibroblast-like synoviocytes (FLS), play an integral role in the immunopathophysiology of PMR. Proinflammatory cytokines, including IL-1, IL-6, IL-17, and tumour necrosis factor-alpha, activate FLS which then secrete IL-6 that can further promote FLS proliferation. Activation of synoviocytes in bursae may result in bursitis which can lead to a high concentration of acute-phase reactants and systemic inflammation. IL-6 also plays a role in sleep disturbances, mood disorders, pain, and fatigue; it is often seen in PMR, via disruption of the hypothalamic-pituitary-adrenal axis, and actions on the peripheral and central pain pathways. Given the diverse roles of IL-6 in the immunopathophysiology of PMR, targeted molecular therapies such as IL-6 receptor inhibitors offer promising alternatives for disease management, distinct from the nonspecific immunosuppressive effects of GCs. In this review, we describe the immunopathophysiology of PMR and discuss unmet medical needs and therapeutic options for PMR.

Objectives: This study aims to identify and validate a transcriptomic signature capable of predicting the response to tumour necrosis factor inhibitors (TNFi) therapy in patients with rheumatoid arthritis (RA) before treatment initiation.

Methods: We performed a retrospective transcriptomic analysis using 2 public datasets, RNA-seq data from peripheral blood mononuclear cells (GSE138746) and microarray data from whole blood (GSE33377), to define a small-scale gene signature predictive of the response to TNFi treatment. Three external validations were then conducted, resulting in a total of 279 individuals, 169 responders, and 110 nonresponders.

Results: Initial RNA-seq analysis (GSE138746) revealed 53 genes differentially expressed between responders and nonresponders; however, none of these genes remained significant after P value adjustment with the Benjamini-Hochberg method. A small-scale genetic signature comprising the 18 most discriminatory genes was then developed, achieving a leave-one-out cross-validation predictive accuracy of 88.75%. We further refined this list to 7 genes (COMTD1, MRPL24, DNTTIP1, GLS2, GTPBP2, IL18R1, and KCNK17) that effectively predicted the response to TNFi treatment, with an area under the receiver operating characteristic curve (AUC) of 0.84 in the GSE33377 dataset. Internal validation of the GSE138746 dataset yielded an AUC = 0.89. Finally, external validation confirmed the robustness of the 7-gene model (AUC ≥ 0.85).

Conclusions: We identified a transcriptomic signature that aids the prediction of the response to TNFi treatment in patients with RA. These findings support its potential use as a precision medicine tool to improve therapeutic decision-making and reduce exposure to ineffective treatments in patients with RA.

Objectives: This study aims to assess statin usage and its association with incident major adverse cardiovascular (CV) events (MACE) in patients with rheumatoid arthritis (RA) treated with tofacitinib vs tumour necrosis factor inhibitors (TNFi) in ORAL Surveillance.

Methods: Patients with RA aged ≥50 years and ≥1 additional CV risk factor received tofacitinib 5 mg (N = 1455) or 10 mg twice a day (N = 1456) or TNFi (N = 1451). Statin treatment was assessed at baseline and during the study. Hazard ratios (HR) were evaluated for MACE in participants with a history of atherosclerotic cardiovascular disease (ASCVD) and in categories of predicted CV risk.

Results: Among participants with a history of ASCVD or high CV risk, 53.0% and 26.9%, respectively, used a statin at baseline. Baseline statin use was similar in tofacitinib and TNFi-treated participants. In participants with or without statins, low-density lipoprotein and high-density lipoprotein increased from baseline and to a larger extent with tofacitinib than with TNFi. Occurrence of MACE in participants with a history of ASCVD and no use of statins at any time was higher with tofacitinib vs TNFi (HR 4.07 [95% CI 1.20-13.82]). In participants with a history of ASCVD and use of statins at baseline or at any time, there was no difference in incident MACE with tofacitinib vs TNFi (HR 1.17 [95% CI 0.46-3.00]).

Conclusions: This post hoc analysis of ORAL Surveillance emphasises the gap in the CV preventive care of patients with RA. Among patients with a history of ASCVD, use of statins may mitigate the previously reported MACE risk observed to accompany tofacitinib use vs TNFi. This trial was registered with NCT number NCT02092467.

Objectives: This study aimed to develop evidence-based points to consider (PtC) and consensus definitions of difficult-to-manage (D2M) and treatment-refractory (TR) psoriatic arthritis (PsA).

Methods: A multidisciplinary international European Alliance of Associations for Rheumatology (EULAR) task force (TF) of 27 members, including rheumatologists, dermatologists, health practitioners, and patient partners, was established, and the EULAR standardised operating procedures, including a systematic literature review and a consensus process, were followed.

Results: The TF formulated 4 overarching principles addressing the proportion of patients with PsA with an unsatisfactory treatment response despite the best standard of care, and for which the causes are likely multifactorial. Six PtC highlight criterion relevant for subsequent definitions including failure to achieve or maintain response to ≥2 biological/targeted synthetic disease-modifying antirheumatic drugs with ≥2 different mechanisms of action; management of signs and symptoms perceived as problematic by the rheumatologist and/or the patient, and evidence of persistent disease activity in the presence of extramusculoskeletal manifestations and/or comorbidities and/or objective evidence of inflammatory activity. Finally, the following 2 definitions were developed: (1) D2M PsA, an umbrella term including drivers such as inflammation, comorbidities, psychosocial or other factors, incorporating (2) TR PsA, defined by persistent disease activity and objective evidence of active inflammation.

Conclusions: EULAR proposes 2 consensus definitions to identify a D2M PsA population, including a TR subgroup. These definitions should now be tested in research studies to understand disease pathogenesis and improve care for people living with PsA.

Objectives: Early trials of CD19-chimeric antigen receptor (CAR) T cell therapy in systemic lupus erythematosus (SLE) show promise, but the molecular mechanisms underlying its disease-modifying effects remain unclear. We aimed to compare biological profiles and alterations following CD19-CAR T cell versus standard pharmacotherapy in SLE.

Methods: Pseudo-bulk gene expression derived from single-cell RNA sequencing of peripheral blood mononuclear cells from 7 SLE patients before and after CD19-CAR T cell therapy was compared with whole-blood transcriptome data from 30 SLE patients in remission on standard pharmacotherapy and 31 SLE patients before and 6 months after treatment with rituximab, belimumab, or cyclophosphamide. Pathway analysis was conducted using Functional Analysis of Individual Microarray Expression and gene set enrichment analysis.

Results: CD19-CAR T cell-induced remission was characterised by marked suppression of complement activation, type I interferon, DNA damage response (DDR), and cell death pathways compared with remission following conventional pharmacotherapy, alongside an upregulation of lipid metabolism pathways. Compared with rituximab and belimumab, CD19-CAR T cell therapy induced greater downregulation of type I/II interferon, DDR, and chemokine pathways. Compared with cyclophosphamide, CD19-CAR T cell therapy induced greater suppression of interferon, mitochondrial, and mammalian target of rapamycin signalling pathways.

Conclusions: CD19-CAR T cell therapy induces substantial suppression of key immunological pathways involved in SLE, including complement activation and type I interferon responses, accompanied by a metabolic reprogramming. Molecular profiles of remission after CD19-CAR T cell therapy differ from those induced by conventional SLE pharmacotherapy, suggesting more profound CD19-CAR T cell-induced biological alterations.

Objectives: Pulmonary fibrosis can result from autoimmune, inflammatory, or idiopathic conditions, including systemic sclerosis-associated interstitial lung disease (SSc-ILD). Previous studies have implicated myofibroblasts and SPP1^hi macrophages as drivers of fibrosis in lungs, as well as other tissues. Single-cell RNA-sequencing has delineated fibroblast and macrophage transcriptomes but provides limited insight into the transcriptional control of profibrotic gene programmes.

Methods: To determine the chromatin accessibility dynamics and transcription factors driving profibrotic gene programmes in human pulmonary fibrosis, we performed multiomic single-nucleus assay for transposase-accessible (ATAC)/RNA-sequencing on explanted SSc-ILD and control lungs. Using the neural network tool ChromBPNet, we analysed pseudobulk fibroblast and macrophage populations to infer transcription factor binding dynamics at single base-pair resolution. Hierarchical causal modelling for single-cell multiomics data (HALO), a novel algorithm developed to derive low-dimensional representations of sparse multiomics data, revealed transcription factor-regulatory element-gene networks.

Results: ChromBPNet inferred increased transcription factor binding to profibrotic genes, including CTHRC1 and ADAM12 in fibroblasts, and SPP1 and CCL18 in macrophages. SSc-ILD fibroblasts showed increased binding and enhancer activity by AP-1, RUNX, and EGR transcription factors to profibrotic genes, whereas macrophages displayed enhanced binding and activity of AP-1 and basic helix-loop-helix (bHLH)-ZIP transcription factors in genes regulating the SPP1^hi phenotype. HALO confirmed AP-1, RUNX, and EGR activity controlling profibrotic gene programmes.

Conclusions: These data provide comprehensive insights into the complexity of transcriptional control of SSc-ILD gene expression programmes and define specific AP-1, RUNX, and EGR enhancers in key myofibroblast marker genes CTHRC1 and ADAM12, and a bHLH-ZIP enhancer in SPP1^hi macrophages.

Advances in the understanding of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis have influenced both treatment strategies and approaches to disease monitoring. While conventional therapies remain the foundation of care, introducing targeted biologics, complement pathway inhibitors, and emerging cellular treatments have broadened therapeutic options to minimise adverse effects, reduce glucocorticoid requirements, and enhance disease control. Nevertheless, many patients still face frequent relapses, progressive tissue damage, and chronic impairments in quality of life. Existing definitions of remission underestimate ongoing disease activity and impact, and interpretation of residual symptoms can be challenging, especially in the absence of overt inflammation. There is a growing interest in personalised management to address these limitations, using biomarkers to better predict relapse risk, differentiate between active disease and residual damage, and guide treatment intensity. Effective long-term care now requires suppression of disease activity and careful management of treatment-related complications, comorbidity risks, and patient-experienced outcomes. Optimising care in ANCA-associated vasculitis will depend on integrating therapeutic innovation with a sustained focus on outcomes that matter most to patients, including durable remission, functional recovery, and improved day-to-day well-being.

Objectives: Systemic sclerosis (SSc) is an autoimmune-driven fibrotic disease, characterised by excessive extracellular matrix (ECM) deposition and fibroblast activation. Our study aimed to identify novel fibroblast subpopulations in SSc and determine their functional role.

Methods: We performed single-cell RNA sequencing on cultured dermal fibroblasts from healthy donors and patients with diffuse cutaneous SSc, verified selected, specific genes at the protein level and used siRNA knockdown experiments to provide evidence for a functional role of these proteins.

Results: SSc fibroblasts revealed high heterogeneity and in specific activated subsets strong upregulation of CD9 and four and a half LIM domain 1 (FHL1), previously described as a muscle-related protein. Overexpression of FHL1 and CD9 was also detected in fibroblast subsets in patient skin. CD9 was associated with the regulation of FHL1 expression. Downmodulation of FHL1 in primary skin fibroblasts correlated with downregulation of the vestigial-like family member 3 (VGLL3) gene, which is known to be expressed in myofibroblasts in a stiff and fibrotic environment and to upregulate collagen synthesis. Further, VGLL3 was confirmed to be upregulated in SSc donor skin.

Conclusions: Our study identified novel fibroblast subsets in SSc, characterised by CD9 and/or FHL1 upregulation. The data indicate a functional role of FHL1 in fibroblasts and its involvement in the regulation of ECM production and provide a new mechanistic link to VGLL3 regulation. Our findings suggest new avenues for therapeutic exploration targeting the perpetuating fibroblast activation by the fibrotic environment.