Annals of the Rheumatic Diseases最新文献

{"title":"Radiographic structural damage in axial spondyloarthritis: is there a preferred way to quantify progression over time? Comparison of blinded versus unblinded mSASSS scoring.","authors":"Xenofon Baraliakos, Mikhail Protopopov, Valeria Rios Rodriguez, Murat Torgutalp, Ani Dilbaryan, Hildrun Haibel, Joachim Sieper, Juergen Braun, Martin Rudwaleit, Denis Poddubnyy","doi":"10.1016/j.ard.2025.03.017","DOIUrl":"https://doi.org/10.1016/j.ard.2025.03.017","url":null,"abstract":"<p><strong>Objectives: </strong>Structural progression in spine in axial spondyloarthritis (axSpA) is assessed by conventional radiographs and quantified by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Blinded mSASSS scoring might be associated with 'background noise,' and for assessing a slow-progressing disease such as axSpA, high sensitivity to change without loss of specificity is crucial. The aim of this study was to compare the sensitivity to change of blinded vs unblinded application of mSASSS for identification of a preferred way of assessing radiographic damage in axSpA over time.</p><p><strong>Methods: </strong>Cervical and lumbar radiographcs of axSpA patients participating in a national inception cohort (GErman SPondyloarthritis Inception Cohort) obtained at baseline and after 2 years were scored using the mSASSS by 5 experienced readers, 2 blinded and 3 unblinded to chronology. Mean scores were used for calculations.</p><p><strong>Results: </strong>Overall, 210 patients (37.3 years, 51% male, 79% human leukocyte antigen B27 positive) were included. The mean baseline mSASSS was 4.2 ± 8.3 vs 3.4±7.9 and mean mSASSS progression was 0.7 ± 2.3 vs 1.0 ± 1.9 for the blinded vs unblinded scoring method, respectively (P = .005). Progression of ≥2 mSASSS units was found in 30 (14.3%) vs 37 (17.6%) patients in blinded and unblinded scoring. In the shift analysis, mSASSS worsening was found in 35 (0.8%) vs 109 (2.2%) and improvement in 4 (0.1%) vs 2 (0.04%) of a total of 4.373 and 4914 vertebral edges in the blinded vs unblinded group, respectively. The majority of progression was found for the development of syndesmophytes in both groups.</p><p><strong>Conclusions: </strong>More mSASSS progression was detected using unblinded vs blinded scoring. Scoring spinal radiographs with known chronological order seems to be more sensitive to changes.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pulmonary arterial hypertension in adults with Still's disease: another pulmonary manifestation associated with HLA-DRB1*15.","authors":"Athénaïs Boucly, Stéphane Mitrovic, Maryvonnick Carmagnat, Laurent Savale, Xavier Jaïs, Jean-Luc Taupin, Estibaliz Lazaro, Emilie Berthoux, Nicolas Schleinitz, Maria-Rosa Ghigna, Joanna Kedra, Xavier Mariette, Céline Roussin, Pierre-Antoine Juge, Marc Humbert, Olivier Sitbon, David Montani, Bruno Fautrel","doi":"10.1016/j.ard.2025.04.016","DOIUrl":"https://doi.org/10.1016/j.ard.2025.04.016","url":null,"abstract":"<p><strong>Objectives: </strong>Inflammatory lung disease in Still's disease (SD) has recently been described. Among its manifestations, pulmonary arterial hypertension (PAH) is a rare and life-threatening event, with only a few case reports published. The objective was to report the largest adult cohort of PAH occurring in the context of SD.</p><p><strong>Methods: </strong>We identified 16 adult SD patients with PAH (PAH+) by a call for observations from the CRI-IMIDIATE (Club Rhumatismes & Inflammation - Immune-Mediated Inflammatory Disease Alliance for Translational and Clinical Research) network (https://cri-net.com/recherche/reseau-CRI-Imidiate/) and a search of the French pulmonary hypertension network registry. Patient characteristics and disease evolution were retrospectively compared with those of 111 SD controls without PAH (PAH-) followed in a reference centre.</p><p><strong>Results: </strong>The profile of patients in the PAH+ and PAH- groups differed: 100% versus 69.4% female (P = .006), 75% versus 17.1% Black (P < .0001), more active SD both at diagnosis and throughout the disease course, and more likely to present macrophage activation syndrome (62.5% vs 14.4%, P < .0001) and exhibit eosinophilia during the disease course (68.7% vs 7.2%, P < .0001). For the 84 out of 127 patients with genetic typing, the HLA-DRB1*15 allele was more prevalent in PAH+ than PAH- patients (8/11 [72.7%] vs 22/73 [30.1%], P = .014). PAH+ patients more frequently received canakinumab and immunosuppressants than did PAH- patients and had higher frequency of drug reactions to interleukin 1 (IL-1) and/or IL-6 inhibitors (37.5% vs 7.2%, P = .002). Mortality was higher in PAH+ than PAH- patients (37.5% vs 0.9%, P < .0001), and all deaths were related to SD flare.</p><p><strong>Conclusions: </strong>These results reinforce the association between the HLA-DRB1*15 allele and severe forms of SD and raise the question of therapeutic optimisation in such patients.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to: Correspondence on 'Evaluating the limitations of random forest and SHAP in predicting treatment responses in systemic lupus erythematosus'.","authors":"Andrea R Daamen, Prathyusha Bachali, Peter E Lipsky","doi":"10.1016/j.ard.2025.04.017","DOIUrl":"https://doi.org/10.1016/j.ard.2025.04.017","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New IgG and IgA autoantibody specificities against DNA-binding and RNA-binding proteins discriminate systemic lupus erythematosus from health and non-lupus autoimmunity-could anti-LIN28A enhance precision in diagnostics?","authors":"Ioannis Parodis, Denis Lagutkin, Julius Lindblom, Helena Idborg, Lorenzo Beretta, Maria Orietta Borghi, Janique M Peyper, Guillermo Barturen, Per-Johan Jakobsson, Marta E Alarcón-Riquelme, Natalia Sherina, Dionysis Nikolopoulos","doi":"10.1016/j.ard.2025.04.003","DOIUrl":"https://doi.org/10.1016/j.ard.2025.04.003","url":null,"abstract":"<p><strong>Objectives: </strong>In response to the urgent unmet needs of heterogeneity, unpredictability, and diagnostic delay in systemic lupus erythematosus (SLE), we aimed to identify and validate new immunoglobulin (Ig)G and IgA autoantibody specificities.</p><p><strong>Methods: </strong>Using a KoRectly EXpressed technology-based microarrays (i-Ome Discovery; Sengenics), we screened for circulating IgG and IgA autoantibodies against 1609 proteins in 2 independent cohorts (discovery: NTC02890121; validation: NCT02890134) comprising patients with SLE (n = 199 and n = 30), primary Sjögren's disease (n = 115 and n = 31), and systemic sclerosis (n = 115 and n = 24), and healthy controls (HCs; n = 111 and n = 84), respectively.</p><p><strong>Results: </strong>We identified and validated 5 IgG (anti-Lin-28 homolog A [LIN28A], anti-HNRNPA2B1, anti-HMG20B, anti-HMGB2, and anti-alpha-globin transcription factor CP2 [TFCP2]) and 4 IgA (anti-LIN28A, anti-HMG20B, anti-SUB1, and anti-TFCP2) autoantibodies that demonstrated high specificity for SLE (0.91-0.94), along with consistent and robust positivity (0.22-0.69) in differentially abundant autoantibody (daAAb) analysis between SLE and comparator groups. IgG and IgA anti-LIN28A levels varied over a 14-month follow-up in the validation cohort of newly diagnosed patients with SLE and exhibited metrics that outperformed those of traditional autoantibody markers such as anti-double-stranded DNA. Clustering of patients with SLE based on autoantibody positivity (levels above the HC median plus 2 IQRs in the discovery cohort) status revealed 1 subgroup demonstrating seroreactivity against multiple antigens, 3 exhibiting varying reactivity, and 1 showing no reactivity. In pathway analysis, daAAb targets pointed to DNA-binding and RNA-binding and transcription functions.</p><p><strong>Conclusions: </strong>Novel autoantibodies validated in this study may enhance diagnostics and molecular characterisation in SLE. The prominent IgA seroreactivity implicates important roles of mucosal tissues in SLE autoimmunity, warranting further investigation.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-TFAM antibodies link mitochondrial damage with antiphospholipid syndrome and thrombosis in SLE.","authors":"Eduardo Gómez-Bañuelos, Alessandra Ida Celia, Maria Isabel Trejo-Zambrano, Jesus Aureliano Robles-De Anda, Merlin Paz, Shruti Chaturvedi, Fabrizio Conti, Cristiano Alessandri, Eleni Tiniakou, Daniel W Goldman, Robert A Brodsky, Michelle Petri, Felipe Andrade","doi":"10.1016/j.ard.2025.04.015","DOIUrl":"https://doi.org/10.1016/j.ard.2025.04.015","url":null,"abstract":"<p><strong>Objectives: </strong>Mitochondria are a source of autoantigens and damage-associated molecular patterns (DAMPs) in systemic lupus erythematosus (SLE). Nucleoids carrying TFAM (transcription factor A, mitochondrial) and mitochondrial DNA (mtDNA) are important DAMPs in SLE. While mtDNA has been associated with anti-double-stranded (ds)DNA antibodies and type I interferon (IFN-I), the immunogenic role of TFAM in SLE pathogenesis is unknown. Here, we characterised the clinical and transcriptional phenotypes linked to anti-TFAM antibodies in SLE.</p><p><strong>Methods: </strong>Anti-TFAM antibodies were discovered in an exploratory sample of 22 SLE patients and 9 healthy controls. To define the prevalence, clinical significance, and associations with transcriptional profiles and IFN levels, anti-TFAM antibodies were detected using enzyme-linked immunosorbent assay (ELISA) in 98 healthy controls and 158 SLE patients. Sera from patients with dermatomyositis, rheumatoid arthritis, and primary antiphospholipid syndrome (PAPS) were also tested.</p><p><strong>Results: </strong>Anti-TFAM antibodies were discovered in patients with SLE while analysing neutrophil autoantigens and confirmed by ELISA and immunoblotting. One-third of SLE patients (48/158) were positive for anti-TFAM antibodies. Unlike anti-dsDNA antibodies, anti-TFAM antibodies were not associated with disease activity or the IFN signature. Instead, anti-TFAM antibodies were associated with thrombosis, antiphospholipid syndrome (APS) (odds ratio [OR], 2.9 and 5.4, respectively), thrombosis-associated transcriptional profiles, and elevated IFN-III. Anti-TFAM antibodies were also found in PAPS, supporting their role in APS but not SLE pathogenesis. Lupus anticoagulant increased the risk of thrombosis associated with anti-TFAM antibodies (OR, 8.71), indicating they are markers of independent prothrombotic pathways.</p><p><strong>Conclusions: </strong>Anti-TFAM antibodies identify a distinct clinical and transcriptional disease subset associated with mitochondrial damage, thrombosis, and APS in SLE.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating endogenous immune-mediated monocyte memory in rheumatoid arthritis.","authors":"Anna M Marzeda, Anja Schwenzer, Bogdan S Didov, Kieran Woolcock, Jean-Baptiste Richard, Libby K Jennings, Amélie M Julé, Nan Yang, Sarah Davidson, Steve Sansom, Adam P Cribbs, Calliope A Dendrou, Wyatt W Yue, Carl S Goodyear, Karim Raza, Kim S Midwood","doi":"10.1016/j.ard.2025.03.016","DOIUrl":"https://doi.org/10.1016/j.ard.2025.03.016","url":null,"abstract":"<p><strong>Objectives: </strong>Inflammation triggered by endogenous stimuli that signal cellular stress or tissue injury must be tightly controlled to balance robust protection from intrinsic danger while avoiding catastrophic destruction of healthy tissues. Here, we assess the contribution of innate memory to this balance.</p><p><strong>Methods: </strong>Memory evoked by the extracellular matrix protein tenascin-C, a damage-associated, toll-like receptor 4 (TLR4) agonist, was compared to that induced by the pathogenic TLR4 agonist lipopolysaccharide (LPS) by transcriptomic and epigenetic profiling of monocytes from healthy individuals or people wirh rheumatoid arthritis (RA), and tissue macrophages from the RA synovium.</p><p><strong>Results: </strong>Tenascin-C reprograms monocyte response to subsequent threats, inducing concomitantly suppressed and enhanced responses to rechallenge. Comparative analysis of tenascin-C and LPS revealed common and distinct gene expression signatures, effects controlled transcriptionally and associated with stimulus-specific epigenetic mediators. Altered responses following rechallenge after priming with tenascin-C were not limited to subsequent TLR4 activation but were evident in response to various pathogenic and endogenous stimuli detected by different receptors. In healthy monocytes primed with tenascin-C, rechallenge with stimuli found at high levels in the joints of people with RA resulted in trained responses that were not induced by LPS, including genes associated with chronic inflammation, tissue destruction, altered metabolism, and poor treatment response in RA. The expression of a large subset of these genes was elevated in monocytes from people with RA in the absence of any stimulation and in RA synovial macrophage populations associated with disease flare. Moreover, higher levels of permissive complexes within key epigenetic nodes and increased bivalent modification creating poised loci within endogenously trained genes were observed in RA cells.</p><p><strong>Conclusions: </strong>These data highlight how innate reprogramming during 'sterile' inflammatory diseases contributes to chronicity, uncovering pathways unique to endogenous immune triggers that could provide disease-specific points of intervention without engendering global immune suppression.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced B cell and complement cascade gene signatures in patients with neuropsychiatric systemic lupus erythematosus.","authors":"Dionysis Nikolopoulos, George Sentis, Iasonas Kitsios, Panagiotis Garantziotis, Noemin Kapsala, Antigone Pieta, Sofia Flouda, Theodora Manolakou, Myrto Nikoloudaki, Aggelos Banos, Katerina Chavatza, Ioannis Parodis, Anastasia Filia, George Bertsias, Antonis Fanouriakis, Dimitrios T Boumpas","doi":"10.1016/j.ard.2025.04.006","DOIUrl":"https://doi.org/10.1016/j.ard.2025.04.006","url":null,"abstract":"<p><strong>Objectives: </strong>The management of neuropsychiatric systemic lupus erythematosus (NPSLE) remains challenging because of clinical heterogeneity and the complexity of pathophysiologic mechanisms involved. We sought to determine the molecular signature of NPSLE and its endotypes towards novel biomarkers and targeted therapies.</p><p><strong>Methods: </strong>Whole-blood RNA sequencing from 308 patients with systemic lupus erythematosus (119 with NPSLE, 189 non-NPSLE) and 72-matched healthy controls (HCs) were performed. Supervised pathway enrichment analysis and unsupervised weighted gene coexpression network analysis were applied to distinguish clinically and molecularly defined NPSLE endotypes.</p><p><strong>Results: </strong>Compared with HCs, patients with NPSLE demonstrated dysregulation of adaptive immune responses along with upregulation of interleukin (IL)-1, IL-6, IL-17, and IL-12/IL-23 signalling pathways. The comparison between NPSLE and non-NPSLE groups revealed a robust upregulation of complement cascade, DNA damage response, adaptive immunity, and IL-1 and IL-6 signalling. Furthermore, active NPSLE exhibited a strong autophagy signature. The B cell and complement cascade signatures exhibited a gradual upregulation across the non-NPSLE, inactive NPSLE, and active NPSLE subgroups. Within NPSLE, diffuse syndromes correlated positively with the oxidative phosphorylation module, while antiphospholipid antibody-positive NPSLE was not associated with specific signatures by unsupervised analysis. NPSLE endotypes such as cognitive dysfunction, seizures, psychosis, and optic neuritis were associated with distinct transcriptomic signatures namely IL-6 signalling and leukocyte migration, DNA damage response, inflammation, and type-I interferon, respectively.</p><p><strong>Conclusions: </strong>The clinical heterogeneity of NPSLE appears to be associated with molecular diversity, with certain endotypes or syndromes exhibiting distinct gene signatures. Upregulation of adaptive immune response and complement cascade suggests that complement inhibitors and B cell-targeted therapies could be further explored in NPSLE.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel IgG and IgA autoantibodies validated in two independent cohorts are associated with disease activity and determine organ manifestations in systemic lupus erythematosus: implications for anti-LIN28A, anti-HMGN5, anti-IRF5, and anti-TGIF1.","authors":"Julius Lindblom, Denis Lagutkin, Natalia Sherina, Helena Idborg, Lorenzo Beretta, Maria Orietta Borghi, Janique M Peyper, Guillermo Barturen, Per-Johan Jakobsson, Marta E Alarcón-Riquelme, Dionysis Nikolopoulos, Ioannis Parodis","doi":"10.1016/j.ard.2025.04.008","DOIUrl":"https://doi.org/10.1016/j.ard.2025.04.008","url":null,"abstract":"<p><strong>Objectives: </strong>This study aimed to identify and validate novel autoantibodies that reflect global and organ-specific disease activity in systemic lupus erythematosus (SLE).</p><p><strong>Methods: </strong>Plasma samples were screened for IgG and IgA seroreactivity against 1609 protein autoantigens using a microarray (i-Ome Discovery; Sengenics). We determined differentially abundant autoantibodies (daAAbs) in patients with SLE vs healthy controls within a discovery (n = 196 vs n = 110; NTC02890121) and an independent validation cohort (n = 30 vs n = 83; NCT02890134) from the European PRECISESADS project. Validated daAAbs were analysed in relation to global and organ-specific disease activity using linear and logistic regression, along with daAAb target pathway enrichment analysis.</p><p><strong>Results: </strong>We validated 89 IgG and 66 IgA daAAbs. IgG anti-LIN28A, IgG anti-HMGN5, and both isotypes for anti-IRF5 and anti-TGIF1 were associated with a SLE disease activity index 2000 score of ≥10, negatively associated with lupus low disease activity state, and highly prevalent in subgroups with active disease across organ manifestations. IgG anti-LIN28A levels exceeded the cutoff for positivity in 53% of patients with central nervous system (CNS) involvement, a prevalence higher than that observed for anti-double-stranded DNA (20%) and 47% of patients with renal activity. A cluster of IgG and IgA daAAbs against RNA-binding proteins, including anti-LIN28A, was linked to CNS involvement. IgA anti-FOSL2 was elevated uniquely in patients with musculoskeletal activity. Enriched pathways involving DNA binding and repair showed considerable overlap across manifestations.</p><p><strong>Conclusions: </strong>Novel IgG and IgA autoantibodies, including IgG anti-LIN28A, IgG anti-HMGN5, IgG and IgA anti-IRF5, and IgG and IgA anti-TGIF1 were associated with SLE disease activity and highly abundant across organ manifestations.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time-independent disease state identification defines distinct trajectories determined by localised vs systemic inflammation in patients with early rheumatoid arthritis.","authors":"Nils Steinz, Tjardo D Maarseveen, Erik B van den Akker, Andrew P Cope, John D Isaacs, Aaron R Winkler, Tom W J Huizinga, Yann Abraham, Rachel Knevel","doi":"10.1016/j.ard.2025.04.011","DOIUrl":"https://doi.org/10.1016/j.ard.2025.04.011","url":null,"abstract":"<p><strong>Objectives: </strong>Patients with rheumatoid arthritis (RA) display different trajectories towards improvement of disease. We aimed to disentangle the heterogeneity of RA disease trajectories from the first clinical visit onwards using graph-based pseudotime analysis.</p><p><strong>Methods: </strong>We studied early patients with RA over 1.5 years in 2 data sets: Leiden (Netherlands), n = 1237, with 5017 visits, and Towards a Cure for Early Rheumatoid Arthritis (TACERA) (United Kingdom), n = 243, with 750 visits. We created a pipeline for time-independent clustering of clinical and haematologic features to identify disease states. Sequence analyses of these states defined the trajectories. We studied the predictability of the trajectories with baseline features.</p><p><strong>Results: </strong>Clustering identified 8 disease states with localised inflammation (joints) and systemic inflammation (erythrocyte sedimentation rate [ESR] or leucocytes) as the main discriminating factors. The disease state sequences consisted of 4 trajectories, which we independently replicated in TACERA: A, high ESR; B, rapid progression from many inflamed joints towards remission; C, high leucocytes; and D, many inflamed joints with poor prognosis. Systemic vs local inflammation patterns showed moderate predictability at baseline (sensitivity of 71% and precision of 0.73 for trajectory A, although lower precision of 0.52 for trajectory B), while other trajectories were less predictable. Trajectories C and D had strong resemblance with B at baseline but deteriorated into less favourable trajectories. Patients in trajectory A were more often female and on average older. The trajectories were not explained by time till disease-modifying antirheumatic drug, baseline disease activity, or symptom duration. The suboptimal trajectories coincided with worse patient-reported outcomes, even when the inflammation was mainly systemic.</p><p><strong>Conclusions: </strong>We identified 4 distinct trajectories in early RA, differentiating RA into localised vs systemic inflammation. Our results highlight potential differences in disease pathology and opportunities for further targeted treatment. Inevitably, patterns without linkage to our selected features could not be detected.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epitopes targeted by autoantibodies in presymptomatic individuals predict early rheumatoid arthritis.","authors":"Yibo He, Outi Sareila, Linda Johansson, Monica Leu Agelii, Lei Cheng, Anders Lundquist, Erik Lönnblom, Gerdur Gröndal, Bjorn Gudbjornsson, Kim Hørslev-Petersen, Jon Lampa, Kristina Lend, Merete Lund Hetland, Dan Nordström, Michael Nurmohamed, Anna Rudin, Till Uhlig, Mikkel Østergaard, Inger Gjertsson, Solbritt Rantapää-Dahlqvist, Rikard Holmdahl","doi":"10.1016/j.ard.2025.04.013","DOIUrl":"https://doi.org/10.1016/j.ard.2025.04.013","url":null,"abstract":"<p><strong>Objectives: </strong>To determine anticitrullinated protein antibody (ACPA) responses to novel peptides predicting the clinical outcomes of treatment-naïve early rheumatoid arthritis (RA) in the presymptomatic stage.</p><p><strong>Methods: </strong>We analysed monoclonal ACPAs derived from RA patients, including a characterised protective ACPA (clone E4), along with plasma samples collected from 520 presymptomatic individuals, of whom 244 were also sampled at diagnosis of RA, and 530 population controls in Sweden. The validation cohort (The Nordic Rheumatic Diseases Strategy Trials and Registries, NORD-STAR) consisted of 690 treatment-naïve early RA patients. Responses to citrullinated or native alpha-enolase (ENO1) or peptidylarginine deiminase 4 (PAD4) peptides were analysed by bead-based multiplex flow immunoassay. Clinical outcomes included C-reactive protein (CRP) and the 28-joint disease activity score (DAS28) with its components: tender joint count (TJC), swollen joint count (SJC), and erythrocyte sedimentation rate (ESR).</p><p><strong>Results: </strong>Monoclonal ACPAs displayed distinct binding patterns to ENO1 and PAD4 peptides. A time-dependent increase of ACPA response to citrullinated peptides was observed in the presymptomatic stage towards onset. In the presymptomatic (0.2-5 years before onset) and early RA stage, ACPA responses to several ENO1 and PAD4 peptides were associated with less severe RA, assessed as lower levels of CRP and DAS28 and its components. In early RA, the association was more pronounced in rheumatoid factor (RF)-negative patients based on lower SJC. In presymptomatic individuals, ACPA responses widely predicted lower disease activity in early RA and were more pronounced in 5 selected peptides.</p><p><strong>Conclusions: </strong>Antibody responses to certain citrullinated epitopes are associated with lower disease activity in treatment-naïve early RA and appear years before symptom onset of RA.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}