Annals of the Rheumatic Diseases最新文献

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.

Objectives: Anticitrullinated protein antibodies (ACPAs) are associated with increased mortality in patients with rheumatoid arthritis (RA). Previous data suggest ACPAs might be associated with worse disease outcomes in patients without RA with coronary artery disease (CAD). Therefore, we investigated ACPA prevalence and its association with mortality in patients with CAD without RA. Furthermore, the role of systemic inflammation in the relation between ACPAs and mortality was investigated in RA.

Methods: The prevalence of ACPAs in patients with CAD without RA was investigated in 2 CAD cohorts (LUdwigshafen Risk and Cardiovascular Health n = 2189 patients and 656 controls; CLARIthromycin for patients with stable CORonary heart disease n = 959 patients) using a commercial enzyme-linked immunosorbent assay. Multivariable Cox proportional hazards models were performed to investigate the association between ACPAs and all-cause mortality. In 2 RA cohorts (Early Arthritis Clinic [EAC] n = 764; Better Anti-rheumatic Farmaco-therapy [BARFOT] n = 794), joint models were applied to investigate the role of C-reactive protein (CRP) on the association between ACPAs and (cardiovascular) mortality.

Results: Average follow-up time in the cohorts ranged between 8.2 and 11.8 years. In both CAD cohorts, ACPA prevalence was low (0.9% and 4.6%), and no association was found between seropositivity and all-cause mortality. In patients with RA, the association between ACPA positivity and all-cause mortality was no longer significant after adjustment for CRP. In contrast, CRP was significantly associated with all-cause and cardiovascular mortality in RA (indirect effect hazard ratio [95% CI]: EAC 1.24 [1.14-1.34], BARFOT 1.33 [1.24-1.42]).

Conclusions: ACPA prevalence is not increased in patients with CAD without RA. In RA, the association between ACPA positivity and increased (cardiovascular) mortality was primarily explained by CRP. This highlights the impact of chronic inflammation on cardiovascular outcomes in RA.

Objectives: Sjögren's disease (SjD) is clinically and biologically heterogeneous, and no immunomodulatory drug has yet demonstrated efficacy in phase 3 trials. We previously identified 4 transcriptomic endotypes in SjD patients using whole-blood RNA sequencing. We hypothesised that these endotypes may predict differential therapeutic responses.

Methods: We analysed clinical, biological, and transcriptomic data from 3 randomised controlled trials evaluating hydroxychloroquine-leflunomide (HCQ-LEF; n = 18; RepurpSS-I trial), rituximab (RTX; n = 56; TRACTISS trial), and abatacept (n = 117). Patients were assigned to the 4 endotypes using semisupervised uniform manifold approximation and projection combined with a support vector machine model. Demographics, disease activity, and therapeutic response, as defined by the Sjögren Tool for Assessing Response index, were compared across clusters in both pooled and individual trial analyses.

Results: Of 170 patients, 81, 24, 80, and 6 were classified into clusters 1 to 4, respectively. European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Patient Reported Index scores were comparable across clusters, while the EULAR Sjögren's Syndrome Disease Activity Index was significantly higher in clusters 3 and 4 vs clusters 1 and 2 (P = .003). In pooled analyses, patients in cluster 1 had significantly greater response rates with active treatment vs placebo (61.5% vs 32.6%: P = .016), with a similar trend in the RTX trial. In contrast, patients in cluster 3 benefitted from HCQ-LEF, whereas cluster 2 (healthy-like patients) showed no significant response to any therapy.

Conclusions: Transcriptomic stratification of SjD patients revealed differential responses to HCQ-LEF and RTX. Notably, healthy-like patients exhibited minimal treatment response, suggesting they may be unsuitable candidates for future therapeutic trials.

Objectives: To evaluate temporal trends in treatment efficacy and placebo responses in randomized controlled trials in axial spondyloarthritis (axSpA).

Methods: We conducted a systematic review of RCTs in MEDLINE up to July 2024 (PROSPERO: CRD42024563776). Eligible trials compared tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, infliximab, golimumab) or interleukin-17 inhibitors (bimekizumab, ixekizumab, secukinumab) versus placebo in axSpA. Two reviewers independently selected studies and extracted data. Primary outcomes were temporal trends in placebo response for Assessment of SpondyloArthritis International Society 20% and 40% response criteria (ASAS20/40), axSpA Disease Activity Score (ASDAS) Clinically Important Improvement, and ASDAS Inactive Disease (ASDAS-ID) at each trial's primary endpoint. Random-effects meta-regressions estimated annual changes in treatment effects (odds ratios) and in arm-specific response rates, adjusted for age, sex, radiographic status, region, route of administration, baseline Bath Ankylosing Spondylitis Disease Activity Index score, baseline C-reactive protein, and disease duration.

Results: Thirty-one RCTs (n = 6437) were included. Treatment effect declined over time for ASAS20 (-5% per year, P < .001) and ASAS40 (-3.7%, P = .04), driven by increased placebo response (ASAS20: +1% per year, P < .0001) and a decline in treatment response for ASAS40. In contrast, ASDAS-based treatment effects were stable, despite a small increase in placebo ASDAS-ID (+0.19% per year, P < .05).

Conclusions: ASAS20/40 treatment effects have declined over time in axSpA trials, consistent with a fading of reported effectiveness, whereas ASDAS-based endpoints remain stable, indicating greater robustness to placebo effects and temporal trends.

This viewpoint aims to explore whether precondition trials could be applied in systemic sclerosis (SSc)-the systemic autoimmune rheumatic disease (SARD) associated with the highest mortality and substantial morbidity. In contrast to type 1 diabetes and rheumatoid arthritis (RA), where predisease states have been more clearly defined, a consensus definition for pre-SSc is still lacking. A consensus framework for patients with signs and symptoms also common to other SARDs/connective tissue diseases, but that potentially identify a patient at a pre-SSc stage, needs to be collectively drafted. Such a framework would provide the basis for earlier recognition, risk stratification, and ultimately, timely intervention in pre-SSc. Considering the paradigm shift already achieved in type 1 diabetes and RA, a similar strategy targeting patients at risk of SSc could foster the development of innovative approaches to SSc management-preventing the onset of key SSc-related signs and symptoms, promoting long-term remission, and reducing SSc-related morbidity and mortality.

Rheumatology research increasingly relies on diverse real-world data sources to complement insights from randomised controlled trials. Real-world evidence or observational data derived from disease or treatment registries, administrative claims datasets, electronic health records, and distributed data networks can enable large-scale analyses of treatment effectiveness, safety, and healthcare utilisation that can improve patient care and outcomes. This review provides a structured overview of the key real-world data sources currently used in rheumatology, highlighting their strengths, limitations, and opportunities. While no single dataset is without limitations, aligning the right source to the right clinical research question requires careful attention to data provenance, data quality, generalisability, and reproducibility. We outline 10 key considerations to guide both healthcare professionals and researchers who work with observational data to critically appraise real-world studies and design robust, fit-for-purpose research. With the increasing use of artificial intelligence and machine learning being applied to health data, the review provides timely guidance on data considerations to reduce potential training and algorithmic biases. Recognising the trade-offs of different data sources and applying rigorous, transparent methods are essential to generate evidence that not only withstands scientific scrutiny but also meaningfully advances patient care and rheumatology research.

Objectives: Methotrexate is recommended in current guidelines as a first-choice glucocorticoid (GC)-sparing agent for patients with polymyalgia rheumatica (PMR) prone to relapses or prolonged GC use. Previous randomised controlled trials (RCTs) have reported conflicting results but used low doses of methotrexate (7.5-10 mg/wk). More evidence on higher doses (25 mg/wk) is needed.

Methods: In this 52-week blinded, placebo-controlled RCT, patients with recently diagnosed PMR (per 2012 European League Against Rheumatism/American College of Rheumatology criteria) and <8 weeks of GC use were randomised 1:1 to methotrexate 25 mg/wk or placebo, alongside a 24-week GC-tapering protocol. The primary outcome was GC-free remission (Polymyalgia Rheumatica-Activity Score <10 and no GC use) at week 52, tested with a 1-sided Cochran-Mantel-Haenszel test stratified by sex and inflammatory markers.

Results: Sixty-four patients were recruited, of whom 58 were included in the final analysis. GC-free remission at 52 weeks was achieved in 80% of patients in the methotrexate group vs 46% in the placebo group (risk difference 34%, 1-sided 95% CI: 14%, 1-sided P = .0042).

Conclusions: This small but high-quality RCT demonstrated that methotrexate 25 mg/wk significantly increases the likelihood of achieving GC-free remission at 52 weeks in newly diagnosed PMR. These findings show a benefit of early introduction of methotrexate in PMR. Further research is needed to determine the optimal timing of methotrexate initiation.

Objectives: Each autoantibody associated with systemic sclerosis (SSc) is linked to distinct clinical features, suggesting underlying molecular heterogeneity. Although studies have characterised molecular signatures in anticentromere (ACA), antitopoisomerase I (ATA), and anti-RNA polymerase III (ARA) antibodies in patients who are SSc-positive, less frequent autoantibody groups remain unexplored. Our study employed multiomics analysis to identify shared and unique molecular profiles across SSc-associated autoantibody subgroups.

Methods: We enrolled 166 patients with SSc stratified by antibody status (ACA = 55, ATA = 58, ARA = 24, anti-U1 ribonucleoprotein [U1RNP] = 12, anti-U3 ribonucleoprotein [U3RNP] = 8, anti-Ku [Ku] = 4, and anti-Th/To [Th/To] = 5). We performed multiomics profiling, including plasma proteomics, peripheral blood mononuclear cells (PBMCs) transcriptomics, immune cell phenotyping, and plasma metabolomics to identify shared and distinct features across groups.

Results: All SSc subsets demonstrated common pathogenic features, including endothelial injury, extracellular matrix deposition identified by plasma proteomics, upregulated type I interferon (IFN) signalling revealed by transcriptomic analysis, and decreased regulatory B cells observed by immune cell profiling. Meanwhile, each autoantibody subgroup exhibited unique disease mechanisms, such as calcinosis in ACA-positive patients, metabolic oxidative stress in ATA-positive patients, activation of oncogenic signalling in ARA-positive patients, enhanced chromatin remodelling activity in U1RNP-positive patients, muscle involvement in U3RNP/Ku groups, and unique metabolic signalling related to pulmonary hypertension in Th/To-positive cases.

Conclusions: Our study addresses a critical gap by providing a comprehensive multiomics characterisation of both common and rare SSc-associated autoantibody groups, revealing shared and distinct molecular signatures that correlate with clinical features. Our findings highlight the potential for autoantibody-based stratification to guide precision management of SSc, paving the way for biomarker-driven approaches in SSc care.