Arthritis & Rheumatology最新文献

{"title":"Pharmacological Weight Loss in Gout Prevention: Emphasizing Dynamic Risk Assessment and Community Strategies.","authors":"Xueneng Yang,Ruijuan Li","doi":"10.1002/art.43330","DOIUrl":"https://doi.org/10.1002/art.43330","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"47 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701224","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":"Serum urate levels alter the spatial distribution of urate crystals in synovium and correlate with synovitis and pain in non-gout female patients with anteromedial knee osteoarthritis.","authors":"Hao Xu,Peng Wang,Haiyang Fu,Longxiao Zhang,Fenggang Xiang,Shuai Xiang","doi":"10.1002/art.43337","DOIUrl":"https://doi.org/10.1002/art.43337","url":null,"abstract":"OBJECTIVEThis study aimed to investigate alterations in the spatial distribution of urate crystals in the osteoarthritic synovium of patients with different levels of serum uric acid (SUA). Additionally, we examined the association between SUA levels and severity of synovitis and pain in anteromedial osteoarthritis (AMOA) of the knee.METHODSPatients who underwent knee arthroplasty due to AMOA were prospectively enrolled. Blood, synovial fluid, and synovium samples were collected and UA levels were quantified. The degree of synovitis was evaluated histologically, and the levels of inflammatory cytokines in the synovial fluid were measured. The spatial distribution of urate crystals in the synovium was determined using Gomori methenamine silver staining, and the pain subscale of the Western Ontario McMaster Universities Osteoarthritis Index was used to evaluate knee pain. The relationships between SUA, degree of synovitis, and knee pain were assessed using Spearman rank correlation and multivariable analyses.RESULTSThe pattern of urate crystal deposition in the osteoarthritic synovium was significantly altered in populations with different SUA levels. The capillary wall, sublining layer, and lining cells were sequentially affected. SUA level was the only risk factor for high-grade synovitis and severe pain in the multivariate analysis. SUA level was also positively correlated with UA level in the synovial fluid and synovium, Krenn histological score of the synovium, knee pain, and inflammatory cytokine level in the synovial fluid.CONCLUSIONSpatial urate crystal distribution in the synovium was altered when SUA levels were elevated. Elevated SUA levels were also associated with aggravated synovitis and pain.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"13 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701227","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":"Risk of serious infection in patients with rheumatoid arthritis-associated interstitial lung disease or bronchiectasis: A comparative cohort study.","authors":"Qianru Zhang,Ying Qi,Xiaosong Wang,Gregory C McDermott,Sung Hae Chang,Mark Chaballa,Vadim Khaychuk,Misti L Paudel,Jeffrey A Sparks","doi":"10.1002/art.43338","DOIUrl":"https://doi.org/10.1002/art.43338","url":null,"abstract":"OBJECTIVETo investigate the association between rheumatoid arthritis-associated lung disease (RA-LD) and serious infection risk.METHODSWe conducted a retrospective cohort study using the MGB Biobank (Boston, Massachusetts), comparing RA-LD to RA patients without lung disease (RA-no LD), matched by age, sex, and RA duration. RA-LD cases were verified by medical record review and chest imaging for clinically apparent RA-associated interstitial lung disease (RA-ILD) and/or RA-associated bronchiectasis (RA-BR). The primary outcome was serious infection. Incidence rates and propensity score-adjusted subdistribution hazard ratios (sdHR) were calculated using Fine and Gray models to account for competing risk of death.RESULTSAmong 221 RA-LD cases (151 RA-ILD and 70 RA-BR) and 980 RA-no LD comparators, RA-LD had a significantly higher serious infection risk compared to RA-no LD comparators (55.8 vs. 25.8 per 1,000 person-years, sdHR 1.60, 95%CI 1.20-2.12). The increased risk remained significant for RA-ILD cases (sdHR 1.79, 95%CI 1.33-2.41), but not for RA-BR (sdHR 1.19, 95%CI 0.72-1.97). Anatomic sites of infection that were more common in RA-LD included pulmonary, skin and soft tissue, and ear, nose and throat; RA-LD was associated with various pathogen types: virus, bacteria, fungus, and mycobacteria. Specific pathogens with higher frequency in RA-LD cases, particularly among RA-BR, included influenza virus, respiratory syncytial virus, Staphylococcus, Pseudomonas, and nontuberculous mycobacteria.CONCLUSIONRA-LD, particularly RA-ILD, is associated with a significant increased risk of serious infection across anatomic sites and diverse pathogen types. RA-BR is associated with increased pulmonary infections. Prospective studies and trials are needed to clarify optimal approaches to treat patients with RA-LD and reduce infection risk.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"65 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701226","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":"Distinct Cancer Risk Profiles in Patients with Systemic Sclerosis with Autoantibody Stratification.","authors":"Arjun Mahajan,Maria Vazquez-Machado,Nikki Zangenah,Jeffrey A Sparks,Avery H LaChance","doi":"10.1002/art.43339","DOIUrl":"https://doi.org/10.1002/art.43339","url":null,"abstract":"BACKGROUND/PURPOSEPatients with systemic sclerosis (SSc) face increased cancer risk compared to the general population, yet current evidence on specific cancer patterns and their relationship to autoantibody status remains poorly characterized. This study seeks to evaluate cancer risk patterns in SSc patients and investigate associations between specific autoantibodies and cancer development.METHODSThis multi-center cohort study analyzed 5-year cancer incidences in 66,637 adults with SSc versus matched controls with seborrheic keratosis using electronic medical records from 128 healthcare organizations (from 2014-2024). Patients were stratified by autoantibody status (RNA polymerase III, anti-centromere, or anti-Scl-70) where available. Primary outcomes included 5-year incidences of hematologic and solid-organ cancers, with hazard ratios (HRs) calculated via Cox proportional hazards regression.RESULTSSSc patients demonstrated elevated 5-year all-type cancer risk (HR 1.17; 95% CI 1.11-1.23). Hematologic cancer risk was significantly increased (HR 1.68; 95% CI 1.50-1.88), particularly for multiple myeloma (HR 2.13; 95% CI 1.61-2.81) and myelodysplastic syndromes (HR 2.03; 95% CI 1.49-2.77). For solid organ cancers (HR 1.23; 95% CI 1.16-1.31), esophageal cancer showed the highest risk (HR 3.96; 95% CI 2.36-6.65), followed by lung cancer (HR 2.32; 95% CI 2.00-2.69). Among autoantibody subgroups, anti-Scl-70 positive patients showed increased overall cancer risk (HR 1.40; 95% CI 1.03-1.92), RNA Polymerase III positive patients had higher rates of hematologic cancers (HR 2.20; 95% CI 1.10-4.28), while anti-centromere positive patients demonstrated no increased cancer risks.CONCLUSIONSSc patients demonstrate significantly increased risks for both hematologic and solid organ cancers, with risk profiles varying by autoantibody status. These findings suggest the need for targeted cancer screening strategies in SSc and further research to confirm the generalizability of these findings.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"7 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701225","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":"Alu Overexpression Leads to an Increased Double-stranded RNA Signature in Dermatomyositis.","authors":"Rayan Najjar, Andrew Mammen, Tomas Mustelin","doi":"10.1002/art.43328","DOIUrl":"https://doi.org/10.1002/art.43328","url":null,"abstract":"<p><strong>Objective: </strong>Dermatomyositis is an autoimmune condition characterized by a high interferon signature of unknown etiology. Because coding sequences constitute <1.2% of our genomes, there is a need to explore the role of the non-coding genome in disease pathogenesis. Our genomes include roughly 1.2 million Alu elements occupying about 10% of the genome, which can form double-stranded (ds)RNA capable of triggering MDA5 leading to interferon production.</p><p><strong>Methods: </strong>We aligned muscle biopsy RNA sequencing data to the Telomere-to-Telomere reference genome and quantified short interspersed elements including Alus. Since Alus have a propensity to form dsRNA and are the major targets of both ADAR and MDA5, we quantified A-to-I RNA editing, which reflects dsRNA in vivo.</p><p><strong>Results: </strong>Dermatomyositis muscle (n=39) showed a global elevation in Alu expression (including inverted repeat Alus with high potential to form dsRNA), as well as an increased expression of unique Alu elements (n=557, q<0.05) compared to healthy controls (n=34), in a pattern not seen in other myositis types (n=81). The majority (75.3%) of these Alus originated from genomic regions outside genes. A cluster of the uniquely overexpressed Alus (n=167) correlated with interferon stimulated genes and markers of myositis activity. Additionally, we found a uniquely expanded Alu A-to-I editome in dermatomyositis, reflecting an increase in dsRNA. Edited Alus clustered on chromosome 19, which is known to have the highest concentration of dsRNA.</p><p><strong>Conclusion: </strong>We hypothesize that overexpressed Alus in dermatomyositis form endogenous dsRNA that exceed the capacity of RNA editing enzymes and trigger dsRNA sensors leading to interferon production.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681696","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":"Longitudinal Analysis of Somatic Mosaicism and Clonal Hematopoiesis in Cryopyrin-Associated Periodic Syndrome.","authors":"Kentaro Kato,Yoshitaka Honda,Takashi Kamatani,Kosaku Murakami,Masaki Shimizu,Toshihiko Komai,Hiroko Kanda,Junko Yasumura,Taiki Ando,Yuichi Yamasaki,Syuji Takei,Hidenori Ohnishi,Tomoyo Matsubara,Takumi Takizawa,Toshinao Kawai,Hiroaki Umebayashi,Shigeo Nishimata,Hisashi Kawashima,Naoto Tamura,Junichi Hosokawa,Naotomo Kambe,Hiroki Kitamoto,Makoto Okabe,Shuji Yamamoto,Yoichi Kurosawa,Utako Kaneko,Yosuke Nakamura,Takayuki Miyamoto,Hiroshi Nihira,Hirofumi Shibata,Takayuki Tanaka,Eitaro Hiejima,Keishi Fujio,Ayako Nakajima,Mai Yamagishi,Yoshitaka Shirasaki,Megumu K Saito,Satoshi Okada,Seishi Ogawa,Junko Takita,Osamu Ohara,Ryuta Nishikomori,Takahiro Yasumi,Kazushi Izawa","doi":"10.1002/art.43329","DOIUrl":"https://doi.org/10.1002/art.43329","url":null,"abstract":"OBJECTIVECryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory disease caused by gain-of-function mutations in NLRP3. Although somatic NLRP3 mosaicism is increasingly recognized, it remains unclear how variant allele frequency (VAF) changes over time and whether disease onset age reflects differences in somatic mutation dynamics. This study aimed to analyze the longitudinal VAF trends and their correlation with clonal hematopoiesis (CH) in patients with CAPS mosaicism.METHODSWe analyzed NLRP3 VAF in blood and various tissues, including dried umbilical cord (DUC) using digital PCR and deep amplicon sequencing. Whole-exome and single-cell genome sequencing were performed to evaluate CH-related mutations.RESULTSWe included 15 patients with VAFs of 4.3% to 34.9%. In the 12 early-onset cases, VAFs were generally consistent across various tissues and did not increase over time, including the DUC. Conversely, in the three late-onset cases, VAFs were particularly high in myeloid cells. Notably, in one late-onset case, no mutations were detected in DUC. After disease onset, VAFs exhibited 2.9%-to-10.6% and 6.2%-to-16.4% increase in the whole blood and neutrophils over 6.4 and 4.4 years, respectively, showing a clonal expansion of NLRP3-mutant cells. Single-cell genome sequencing revealed frequent co-occurrence of NLRP3 and TET2 mutations in the same cells, with a gradual increase in both VAFs over 3 years, in one late-onset case.CONCLUSIONIn early-onset cases, the VAFs were comparable across various tissues and did not increase over time. Mutations in late-onset cases were enriched in myeloid cells, and VAFs were increased, suggesting a link to CH.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"115 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677852","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":"Association of Abatacept with Lower Mortality Risk Compared to Rituximab in Rheumatoid Arthritis-Associated Interstitial Lung Disease: An Emulated Target Trial.","authors":"Po-Cheng Shih,Shiow-Ing Wang,Qing-Wen Wang,James Cheng Chung Wei","doi":"10.1002/art.43332","DOIUrl":"https://doi.org/10.1002/art.43332","url":null,"abstract":"BACKGROUNDThe optimal treatment strategy for rheumatoid arthritis-associated interstitial lung disease (RA-ILD) remains uncertain, and direct comparative data between biologics is limited. This study aimed to evaluate the effectiveness and safety of abatacept compared with rituximab in patients with RA-ILD.METHODSAn emulated target trial was designed using the TriNetX US Collaborative Network database, including patients with RA-ILD, diagnosed between 2007 and 2024. Propensity score matching (PSM) was used to balance baseline characteristics between the two treatment groups (abatacept and rituximab). The primary outcome was all-cause mortality, while secondary outcomes included respiratory events, medical utilization, and infection-related adverse events. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated to use Cox proportional hazards models.RESULTS1,615 patients per group were identified after matching for analysis. Abatacept was associated with a significantly lower risk of all-cause mortality compared with rituximab (HR 0.689, 95% CI 0.581-0.818) and a reduced risk of mechanical ventilation (HR 0.698, 95% CI 0.521-0.934). The subgroup analyses yielded consistent findings. Sensitivity analyses excluding patients with concomitant connective tissue diseases also demonstrated consistent results (mortality, HR 0.679, 95% CI 0.570-0.810), reinforcing the robustness of the findings.CONCLUSIONAbatacept was associated with a lower risk of mortality compared with rituximab in patients with RA-ILD. Because clinicians may preferentially reserve abatacept for less aggressive RA-ILD, residual confounding by indication cannot be excluded; thus, the association should not be interpreted as proof of causality. Prospective randomized trials are needed to confirm whether abatacept confers a true survival advantage.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"110 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677974","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":"Differences in IgG Sialylation Distinguish Asymptomatic from Symptomatic Anti-Nuclear Antibody Positive Individuals.","authors":"Carolina Muñoz-Grajales,Carmen C Ucciferri,Sindhu R Johnson,Zahi Touma,Zareen Ahmad,Dennisse Bonilla,Linda T Hiraki,Arthur Bookman,Joan E Wither","doi":"10.1002/art.43323","DOIUrl":"https://doi.org/10.1002/art.43323","url":null,"abstract":"OBJECTIVEThe transition from asymptomatic anti-nuclear antibody (ANA) positivity to systemic autoimmune rheumatic disease (SARD) is associated with increased production of pro-inflamamtory factors such as TNF-α. Here we investigate whether the relative absence of inflammation in asymptomatic ANA+ individuals (ANA+NS) results from a lack of circulating immune complexes (ICs) or from changes in the characteristics of the IgG auto-Abs produced.METHODSFlow cytometry was used to characterize circulating microparticles (MPs) in 18 healthy controls (ANA-HC), 31 ANA+NS and 51 symptomatic ANA+ patients. Differences in the ability of the total MPs, purified IgG-coated MPs, or aggregated IgG to elicit inflammation were investigated by co-culture with ANA-HC monocytes or monocyte derived dendritic cells (moDC), measuring cytokines in the supernatants. IgG sialylation was quantified by ELISA or lectin blotting using Sambucus Nigra Agglutinin, a sialic acid-binding lectin.RESULTSAll ANA+ individuals had higher numbers of total and IgG-coated MPs than ANA-HC. IgG sialylation was significantly reduced in SARD compared to ANA+NS and ANA-HC, and in ANA+NS who clinically progressed in the next 2 years compared to those who did not. moDC stimulated with IgG-coated MPs or aggregated IgG from SLE patients produced significantly more TNF-α than those from ANA+NS. The levels of TNF-α produced in culture supernatants and serum demonstrated a negative correlation with IgG sialylation.CONCLUSIONSThe absence of pro-inflammatory factors in ANA+NS does not result from a lack of circulating ICs, but instead may reflect differences in the extent of IgG sialylation in the ICs from ANA+NS as compared to SARD.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"29 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677975","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":"Late-Onset Spondylarthritis Presenting as Glucocorticoid-Resistant Polymyalgia Rheumatica: A hitherto underappreciated entity where TNF or IL-17 Blockade may have a Therapeutic Role.","authors":"Kerem Abacar,Gabriele De Marco,Jake Weddell,Katya Meridor,Tom Macleod,Andrew Scarsbrook,Kulveer Mankia,Edward Vital,Andrew Barr,Colin Pease,Helena Marzo-Ortega,Sarah L Mackie,Dennis McGonagle","doi":"10.1002/art.43320","DOIUrl":"https://doi.org/10.1002/art.43320","url":null,"abstract":"BACKGROUNDPolymyalgia rheumatica (PMR) is an age-related inflammatory disease with shoulder-hip girdle involvement. Magnetic resonance imaging (MRI) reveals extracapsular/entheseal soft tissue involvements in both PMR and spondyloarthritis (SpA) with sacroiliac joint and peri-entheseal spinal bone marrow oedema (BMO) being characteristic of SpA. Therefore, some shared anatomical topography might be expected to result in similar clinical features. Herein we describe the clinical and imaging features of SpA initially diagnosed as PMR.METHODSPatients followed at Leeds Teaching Hospitals NHS Trust with a diagnosis of psoriatic arthritis (PsA), or axial SpA (axSpA) were screened to identify those initially diagnosed with PMR from 2002 to 2024. Only those patients who retrospectively fulfilled the 2012 EULAR/ACR classification criteria or the Bird criteria for PMR were included. Clinical data relevant to initial PMR diagnosis, imaging features, follow-up and treatment data were collected, as well as radiographic or MRI features that established the final diagnosis.RESULTSThirty-one patients [median age in years (IQR): 62 (58-69); 17 females and 14 males] presenting with typical PMR shoulder/hip girdle pain were subsequently classified as SpA-spectrum disorders. The SpA diagnosis was made in 12 patients within three months of presentation, and in 19 patients during the remaining follow-up period [median (IQR): 3 (1-4) years]. Four of 27 tested patients were HLA-B27 positive. BMO on MRI was detected in the spine and/or sacroiliac joints in 20 of 25 imaged patients (80%) (sacroiliac joint: 17 patients [68%], spine: 15 patients [60%]). Clinical resolution with CRP normalisation occurred in 21 of 31 patients following initial glucocorticoid (GC) therapy, but 7 of these 21 initial responders experienced disease flares or CRP elevations. Therapy-wise, disease-modifying antirheumatic drugs (DMARDs) were used in 21 of 31 cases: 8 received conventional DMARDs, and 11 received biologic agents (eight anti-TNFs, three IL-17 inhibitors), while the remaining 10 patients were treated with 10 mg/day or less GC therapy.CONCLUSIONLate-onset SpA with PMR clinical presentations is characterised by failure to respond to or taper GC therapy and is often identified by SpA-specific osteitis patterns on MRI. We propose that a PMR-SpA overlap may account for biological therapy efficacy in steroid-refractory PMR.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"14 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677978","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":"Clinical manifestations of VEXAS syndrome across a broad spectrum of UBA1 mutation burden","authors":"Meghan Anderson, Defne Ercelen, Ashley Richardson, Jung Kim, Rebecca I. Torene, Maria Sirenko, Jeremy S. Haley, Adam Cook, Wesley Hill, James Dove, Kyle Retterer, Eitan Carroll, David J. Carey, Samira Asgari, Douglas R. Stewart, David B. Beck","doi":"10.1002/art.43327","DOIUrl":"https://doi.org/10.1002/art.43327","url":null,"abstract":"ObjectiveVEXAS is a progressive systemic autoinflammatory disorder caused by somatic variants in <jats:italic>UBA1</jats:italic> in blood. Previous analyses have shown discordant disease penetrance. In this study, we examine the associations between demographic features and <jats:italic>UBA1</jats:italic> variant allele frequency (VAF) with disease manifestations.MethodsWhole exome sequencing data from 192,584 participants from Geisinger MyCode Community Health Initiative and Mount Sinai Bio<jats:italic>Me</jats:italic> Biobank were analyzed for disease‐causing variants in <jats:italic>UBA1</jats:italic>. Clinical manifestations were analyzed across individuals with <jats:italic>UBA1</jats:italic>‐variant.ResultsNine <jats:italic>UBA1</jats:italic> variants (VAF range 2.9%‐79%), in 23 participants (69.6% male) were identified. Cases with high VAF (&gt;20%) developed macrocytic anemia more often (87.5%) than patients with low VAF (≤ 20%) variants (27%; p=0.009). Specifically at the time of genetic testing, 87.5% of high VAF cases had macrocytic anemia, compared to 13.3% of low VAF cases (p=0.001). However, there was no significant difference in the development of anemia or thrombocytopenia (p=0.53). In two high VAF cases, macrocytosis developed more than 5 years prior to time of sample collection, followed by anemia approximately at the time of sample collection. In one low VAF case with other inflammatory symptoms, macrocytic anemia did not develop until 5 years after sample collection.ConclusionVEXAS syndrome disease severity and penetrance increase at higher VAFs. Low VAF cases demonstrate incomplete penetrance and those with disease tend to be milder. Females are enriched in lower VAFs and have milder symptoms suggesting a protective role against disease severity. Low VAF cases, especially ≤ 10%, can be initially asymptomatic and later develop disease.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" mimetype=\"image/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic/art43327-toc-0001-m.png\"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"26 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669636","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}