Annals of the Rheumatic Diseases最新文献

{"title":"Integrative exome sequencing and machine learning identify MICB and interferon pathway genes as contributors to SSc risk.","authors":"Shamika Ketkar, Hongzheng Dai, Lindsay Burrage, David Murdock, Brian Dawson, Marialbert Acosta-Herrera, Martin Kerick, Javier Martin, Kevin Wilhelm, Jennifer Kay Asmussen, Olivier Lichtarge, Regeneron Genetics Center, Shervin Assassi, Maureen D Mayes, Brendan H Lee","doi":"10.1016/j.ard.2025.05.009","DOIUrl":"https://doi.org/10.1016/j.ard.2025.05.009","url":null,"abstract":"<p><strong>Objectives: </strong>Systemic sclerosis (SSc) is a complex autoimmune disease with both known and unidentified genetic contributors. While genome-wide association studies (GWAS) have implicated multiple loci, many reside in noncoding regions. We aimed to identify novel protein-coding variants and pathogenic pathways using exome sequencing (ES) integrated with an Evolutionary Action-Machine Learning (EAML) framework, single-cell RNA sequencing (scRNA-seq), and expression quantitative trait locus (eQTL) analysis.</p><p><strong>Methods: </strong>GWAS was conducted in 2,559 SSc cases and 893 controls of Caucasian ancestry, with replication in 9,846 cases and 18,333 controls of European ancestry. EAML prioritized genes with high-impact missense variants predictive of disease. Public scRNA-seq data from SSc and control skin biopsies were analyzed to localize gene expression across cell types. Whole blood eQTL data were used to identify regulatory effects of risk variants.</p><p><strong>Results: </strong>A novel SSc risk locus at MICB (rs2516497, P = 3.66 × 10^-13) was identified and replicated. EAML highlighted 284 genes enriched in interferon signaling. scRNA-seq localized MICB and NOTCH4 to fibroblasts and endothelial cells, while HLA class II genes were enriched in macrophages and fibroblasts. eQTL analysis confirmed regulatory effects at MICB, NOTCH4, and other prioritized genes, linking SSc-associated variants to transcriptional dysregulation.</p><p><strong>Conclusions: </strong>This integrative genomic study identifies novel risk loci and mechanistic pathways in SSc, highlighting MICB, NOTCH4, and interferon-related genes. The findings provide insight into the cellular and regulatory architecture of SSc and support the utility of combining ES, machine learning, scRNA-seq, and eQTL data in complex disease genetics.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293246","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":"Corrigendum to 'Compendium of Skin Molecular Signatures Identifies Key Pathologic Features Associated with Fibrosis in Systemic Sclerosis' Ann Rheum Dis. 2019;78:817-825.","authors":"Su-Jin Moon, Jung Min Bae, Kyung-Su Park, Ilias Tagkopoulos, Ki-Jo Kim","doi":"10.1016/j.ard.2025.05.001","DOIUrl":"https://doi.org/10.1016/j.ard.2025.05.001","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246111","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 the correspondence by Wendling et al on 'ASAS consensus-based expert definition of difficult-to-manage, including treatment-refractory, axial spondyloarthritis'.","authors":"Denis Poddubnyy, Xenofon Baraliakos, Victoria Navarro-Compán, Désirée van der Heijde","doi":"10.1016/j.ard.2025.03.008","DOIUrl":"10.1016/j.ard.2025.03.008","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"e25-e27"},"PeriodicalIF":20.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958733","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":"Chasing the target: reports from the Advances in Targeted Therapies meeting, 2024.","authors":"Kevin L Winthrop, Joan Bathon, Andreas Kerschbaumer, John D Isaacs, Philip Mease, Jaque-Eric Gottenberg, Mary K Crow, Jonathan Kay, Leslie Crofford, Xenofon Baraliakos, Vivian Bykerk, Stefan Siebert, Margreet Kloppenburg, Daniel Aletaha, Iain B McInnes, Thomas Huizinga, Reinhard Voll, Ellen M Gravallese, Ferdinand C Breedveld, Ronald van Vollenhoven, Josef S Smolen","doi":"10.1016/j.ard.2025.02.009","DOIUrl":"10.1016/j.ard.2025.02.009","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;The Advances in Targeted Therapies annual meeting brings together experts within the field of rheumatology and immunology to highlight and discuss the latest scientific developments and needs in the field. The objective is to highlight unmet scientific needs in the field of rheumatology.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The 24th annual Advances in Targeted Therapies meeting convened with more than 100 international clinicians and scientific researchers in rheumatology, immunology, and other specialities relating to all aspects of immune-mediated inflammatory diseases. During the meeting, we held 5 rheumatologic disease-specific discussion sections consisting of experts in each field. These groups included rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), osteoarthritis (OA), and systemic lupus erythematosus (SLE). In each group, experts were asked to identify the top 2 to 3 most important overarching and disease-specific scientific unmet needs to be addressed in the next 5 years.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The overarching themes across disciplines included the need for precision medicine, improved classification of disease states, and the further identification of targets and associated therapies, including the potential role of chimeric antigen receptor (CAR) T cell therapies. Within RA, the group highlighted the lack of precision medicine and the need for better biomarkers. Further, the lack of targeted therapies against fibroblasts in RA was discussed, with the potential impact of targeting fibroblasts early in the disease as an unmet need. For PsA, there is a continued need for a better definition of disease endotypes and for the categorisation of those with complex and difficult-to-treat (D2T) diseases. The development of bispecific molecules and combination therapeutic approaches remain a high priority. For axSpA, the disease-modifying characteristics of nonsteroid anti-inflammatory drugs need further evaluation, as does the treatment of residual pain and fatigue frequently in the disease. In OA, new therapeutic targets remain an unmet need, and the discussion group prioritised potential experimental strategies that could lead to innovative therapeutic targets. Elucidating the specific signalling and target cells responsible for, or inhibiting, repair will be essential for developing targeted therapies. SLE experts emphasised the need to identify the most predictive biological contributions to disease progression in patients with early clinical precursors of SLE. The role of CAR T cell therapy must be further investigated, along with ancillary biologic studies (eg, immune system profiling) that provide critical insights into disease pathogenesis. Further, there is a need to determine the relationship of patient-relevant symptoms to the pathophysiology of SLE and identify new therapeutic targets for these symptoms.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;There remain many u","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"927-936"},"PeriodicalIF":20.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967281","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":"Rapid clinical and transcriptomic response to anifrolumab in refractory anti-TIF1γ-positive juvenile dermatomyositis.","authors":"Clément Triaille, Maryam Piram, Benjamin Ellezam, Karine Leveille, Catherine Maari, Amandine Remy, Khampoun Sayasith, Elie Haddad, Marie-Paule Morin","doi":"10.1016/j.ard.2025.02.002","DOIUrl":"10.1016/j.ard.2025.02.002","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1052-1054"},"PeriodicalIF":20.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961975","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":"Certolizumab pegol to prevent adverse pregnancy outcomes in patients with antiphospholipid syndrome and lupus anticoagulant (IMPACT): results of a prospective, single-arm, open-label, phase 2 trial.","authors":"D Ware Branch, Mimi Y Kim, Marta M Guerra, Joseph Worden, Carl A Laskin, Maria T DeSancho, Inna V Landres, Jason S Knight, Haley S Slosberg, Margaret Minett, Jane E Salmon","doi":"10.1016/j.ard.2025.02.012","DOIUrl":"10.1016/j.ard.2025.02.012","url":null,"abstract":"<p><strong>Objectives: </strong>The aim of this study was to evaluate whether certolizumab pegol, a tumour necrosis factor α inhibitor with little or no transport across the placenta, added to standard treatment with low molecular weight heparin plus low dose aspirin, reduces rates of adverse pregnancy outcome (APO) in high-risk pregnancies with antiphospholipid syndrome (APS).</p><p><strong>Methods: </strong>We assessed treatment with certolizumab in pregnant patients with APS and lupus anticoagulant, administered gestational weeks 8 through 28, in addition to standard treatment. The primary APO was a composite of fetal death ≥10 weeks' gestation or pre-eclampsia with severe features or placental insufficiency requiring delivery <34 weeks' gestation. Target sample size was 45 with expected APO rate of 20% with certolizumab versus 40% in historical controls from a prospectively observed population of similarly managed APS pregnancies.</p><p><strong>Results: </strong>Fifty-one patients were enrolled, and 9 had primary APO (17.6%; 95% CI, 8.4%-30.9%). Excluding 6 patients who had a pregnancy loss <10 weeks' gestation or fetal loss due to genetic abnormalities, primary APO occurred in 9 of the 45 patients (20%; 95% CI, 9.6%-34.6%), meeting predetermined criteria for efficacy of certolizumab and significantly lower than rates in historical controls. Median gestational age at delivery in certolizumab-treated patients was 36.5 weeks and was after 30 weeks in those who met the primary outcome of pre-eclampsia. Neonatal survival to hospital discharge was 93%. There were no serious infections and no new cases or severe flares of lupus.</p><p><strong>Conclusions: </strong>Certolizumab appears effective in preventing placenta-mediated adverse outcomes in high-risk patients with APS.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":"84 6","pages":"1011-1022"},"PeriodicalIF":20.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246113","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":"Responsiveness of systemic lupus erythematosus subjects to iberdomide based on molecular endotypes.","authors":"Prathyusha Bachali, Andrea Daamen, Shimon Korish, Yanhua Hu, Peter Schafer, Amrie Grammer, Peter E Lipsky","doi":"10.1016/j.ard.2025.01.044","DOIUrl":"10.1016/j.ard.2025.01.044","url":null,"abstract":"<p><strong>Objectives: </strong>Iberdomide is a cereblon E3-ligase modulator that promotes proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) and was shown to be efficacious among subjects with generalised systemic lupus erythematosus (SLE). This study sought to identify baseline gene expression profiles of SLE subjects responsive to iberdomide and analyse the impact of this agent on gene expression.</p><p><strong>Methods: </strong>Whole blood samples obtained from 276 female SLE subjects in the phase 2b iberdomide trial (NCT03161483) were assessed by RNA sequencing followed by gene set variation analysis (GSVA) using 32 informative gene modules. Unsupervised K-means clustering categorised subjects according to molecular endotypes at baseline. Each endotype was compared for treatment related gene expression changes.</p><p><strong>Results: </strong>K-means clustering of GSVA scores from whole blood yielded 5 patient subsets (endotypes A-E) with increases in molecular abnormalities indicative of enhanced immune activity. Significant clinical responses to iberdomide, determined using the SLE Responder Index 4, were confined to endotypes C and E. The most important treatment related gene modules in responders in endotype E were Treg cells, B cells, and interferon, whereas unfolded proteins, oxidative phosphorylation and anergic/activated T cells were associated with responsiveness in endotype C.</p><p><strong>Conclusions: </strong>Molecular profiles of SLE subjects identified pharmacodynamic effects of iberdomide that occurred in all endotypes as well as changes in specific gene modules altered in endotypes associated with a significant clinical response. Thus, gene expression-based molecular profiling may be useful to enrich clinical trials for treatment-responsive subjects and also monitor the pharmacodynamic impact of therapy.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1001-1010"},"PeriodicalIF":20.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530935","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":"Genome-wide association study in chondrocalcinosis reveals ENPP1 as a candidate therapeutic target in calcium pyrophosphate deposition disease.","authors":"Riku Takei, Ann Rosenthal, Tristan Pascart, Richard J Reynolds, Tuhina Neogi, Robert Terkeltaub, Sara K Tedeschi, Tony R Merriman","doi":"10.1016/j.ard.2025.04.002","DOIUrl":"10.1016/j.ard.2025.04.002","url":null,"abstract":"<p><strong>Objectives: </strong>The genetic basis of calcium pyrophosphate deposition (CPPD) disease is unknown. This limits the development of therapeutic strategies. We aimed to analyse a genome-wide association study (GWAS) on a large administrative database to identify new candidate causal genes for CPPD disease.</p><p><strong>Methods: </strong>We used publicly available GWAS summary statistics for Phecode-defined chondrocalcinosis and crystal arthropathy from the Veterans Affairs Million Veteran Program in people of African (AFR) and European (EUR) ancestry. Included were 3004 (536 AFR and 2468 EUR) cases for chondrocalcinosis and 3766 (700 AFR and 3066 EUR) cases for crystal arthropathy (operationally interpreted as calcium crystal arthropathy). Our primary analysis was in chondrocalcinosis, with secondary analysis in crystal arthropathy. We tested for colocalisation of chondrocalcinosis genetic association signals with genetic control of gene expression.</p><p><strong>Results: </strong>There were 2 genome-wide significant loci for chondrocalcinosis in both AFR and EUR cases, both on chromosome 6 (signals within the ENPP1 and RNF144B genes). Findings were supported by analysis of the crystal arthropathy cohort. Colocalisation analysis of chondrocalcinosis genetic association signals with genetic control of gene expression and alternative splicing further supported ENPP1 and RNF144B as candidate casual genes. At ENPP1, the allele that increases the risk for chondrocalcinosis was associated with increased ENPP1 expression.</p><p><strong>Conclusions: </strong>ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (NPP1) that produces adenosine monophosphate (AMP) and inorganic pyrophosphate which, together with calcium ions, leads to the formation of calcium pyrophosphate crystals. Selective NPP1 inhibitors developed for infectious disease and cancer could be tested as treatment for CPPD disease.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":"84 6","pages":"1023-1032"},"PeriodicalIF":20.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12248263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correspondence on 'The Assessment of SpondyloArthritis International Society (ASAS) consensus-based expert definition of difficult-to-manage, including treatment-refractory, axial spondyloarthritis' by Poddubnyy D, et al.","authors":"Daniel Wendling, Olivier Fakih, Frank Verhoeven, Clément Prati","doi":"10.1016/j.ard.2025.02.022","DOIUrl":"10.1016/j.ard.2025.02.022","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"e23-e24"},"PeriodicalIF":20.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708146","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":"Increased healthcare utilisation in the 5 years preceding systemic lupus erythematosus diagnosis: a Danish nationwide cohort study.","authors":"Sofie Geday, Anders Prior, Henrik Schou Pedersen, Annette de Thurah, Esben Næser, Anne Troldborg","doi":"10.1016/j.ard.2025.02.001","DOIUrl":"10.1016/j.ard.2025.02.001","url":null,"abstract":"<p><strong>Objectives: </strong>This study aimed to analyse healthcare utilisation patterns in the 5 years preceding a diagnosis of systemic lupus erythematosus (SLE) in Denmark compared to matched healthy individuals. Understanding these patterns could support earlier diagnosis and reduce diagnostic delay.</p><p><strong>Methods: </strong>A nationwide, registry-based cohort study was conducted using data from the Danish national healthcare registries between 2006 and 2021. Healthcare utilisation, including general practitioner (GP) visits, specialist consultations, prescriptions, blood tests, diagnostic imaging, and hospital admissions, was examined. Incidence rate ratios were calculated using negative binomial regression models adjusted for demographic and clinical covariates.</p><p><strong>Results: </strong>We included 2022 individuals diagnosed with SLE and 20,019 matched reference individuals. 83.8% of patients were female, with an average age of 47.1 years. Even at baseline, patients with SLE exhibited significantly higher healthcare utilisation compared to references for all outcomes which continued throughout the 5-year follow-up. Patients with SLE had approximately 12 annual GP contacts until 1.5 year before diagnosis, where the contact rate increased substantially. Reference individuals consistently had about 4 contacts per year. The incidence rate ratio was approximately 3 during the 5 to 1.5 years preceding diagnosis, increasing to 5.20 (95% confidence interval 4.95-5.46) in the last 6 months before diagnosis.</p><p><strong>Conclusions: </strong>Increased healthcare utilisation years before SLE diagnosis suggests that early symptoms are present and prompt medical attention long before formal diagnosis. These findings highlight the potential for earlier identification of SLE, underscoring the need for improved diagnostic strategies to reduce delays and enhance patient outcomes.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"992-1000"},"PeriodicalIF":20.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498080","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}