Pub Date : 2025-11-19DOI: 10.1016/S2665-9913(25)00283-8
Coziana Ciurtin, Junjie Peng, Ruby Taylor-Gotch, Hannah Peckham, Robert Wilson, Muthana Al Obaidi, Elizabeth C Jury
<p><strong>Background: </strong>Childhood-onset Sjögren's disease is a rare and under-investigated rheumatic condition. The natural course of childhood-onset Sjögren's disease in adulthood in not known. This study aimed to evaluate long-term disease trajectories and complications of childhood-onset Sjögren's disease and explore management strategies.</p><p><strong>Methods: </strong>This combined retrospective and prospective analysis of a childhood-onset Sjögren's disease cohort with long-term follow-up into adulthood was done in individuals aged 13-36 years with childhood-onset Sjögren's disease recruited from a single tertiary adolescent and young adult rheumatology service at University College London Hospital, UK. Participants were either approached consecutively during routine clinical appointments, or their data were collected retrospectively from the time of diagnosis to the time of transition to the service, and prospectively thereafter. We mapped the cohort onto clinical phenotypes defined by the Florida Scoring System at disease onset and stratified them based on the Newcastle Sjögren's Stratification Tool at last assessment. Disease activity, symptom severity, and damage trajectories were assessed using European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI), EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), and Sjögren's Syndrome Disease Damage Index (SSDDI), respectively. People with related lived experience were involved in the study design and implementation.</p><p><strong>Findings: </strong>Between March 1, 2020, and June 30, 2024, we identified 30 children and young people diagnosed with childhood-onset Sjögren's disease based on expert opinion. Mean age at onset was 12·7 years (SD 3·3). 28 (93%) of 30 individuals were female and two (7%) were male. The most common disease manifestations at onset were fatigue (22 [73%] of 30 individuals), arthralgia (21 [70%]), dryness (17 [57%]), glandular swelling (15 [50%]), and skin rashes (ten [30%]). Diagnostic delay of more than 3 years from symptoms onset increased the prevalence of reported dryness (nine [100%] of nine vs eight [38%] of 21; p=0·0014). Children and young people with childhood-onset Sjögren's disease had two distinct disease activity and symptom trajectories (high ESSDAI: mean 3·9 [SD 2·2] vs low ESSDAI: mean 0·8 [1·1]; p<0·0001 and high ESSPRI: mean 5·6 [2·7] vs low ESSPRI: mean 3·1 [1·0]; p=0·036), which could not be predicted by sex or age at onset, symptom duration, or duration of follow-up. Damage accrual did not differ based on activity and symptom trajectory (p=0·080 and p=1·0, respectively). At last review, the median ESSDAI score was 2·0 (IQR 2·0-8·0) and the ESSPRI score was 5·3 (3·0-7·0). Four (13%) of 30 patients developed lymphoma and 17 (57%) accumulated damage (SSDDI score ≥1).</p><p><strong>Interpretation: </strong>This preliminary evaluation of long-term outcomes of childhood-onset Sjögren's dis
{"title":"Clinical phenotypes, classification, and long-term outcomes of childhood-onset Sjögren's disease into adulthood: a single-centre cohort study.","authors":"Coziana Ciurtin, Junjie Peng, Ruby Taylor-Gotch, Hannah Peckham, Robert Wilson, Muthana Al Obaidi, Elizabeth C Jury","doi":"10.1016/S2665-9913(25)00283-8","DOIUrl":"https://doi.org/10.1016/S2665-9913(25)00283-8","url":null,"abstract":"<p><strong>Background: </strong>Childhood-onset Sjögren's disease is a rare and under-investigated rheumatic condition. The natural course of childhood-onset Sjögren's disease in adulthood in not known. This study aimed to evaluate long-term disease trajectories and complications of childhood-onset Sjögren's disease and explore management strategies.</p><p><strong>Methods: </strong>This combined retrospective and prospective analysis of a childhood-onset Sjögren's disease cohort with long-term follow-up into adulthood was done in individuals aged 13-36 years with childhood-onset Sjögren's disease recruited from a single tertiary adolescent and young adult rheumatology service at University College London Hospital, UK. Participants were either approached consecutively during routine clinical appointments, or their data were collected retrospectively from the time of diagnosis to the time of transition to the service, and prospectively thereafter. We mapped the cohort onto clinical phenotypes defined by the Florida Scoring System at disease onset and stratified them based on the Newcastle Sjögren's Stratification Tool at last assessment. Disease activity, symptom severity, and damage trajectories were assessed using European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI), EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), and Sjögren's Syndrome Disease Damage Index (SSDDI), respectively. People with related lived experience were involved in the study design and implementation.</p><p><strong>Findings: </strong>Between March 1, 2020, and June 30, 2024, we identified 30 children and young people diagnosed with childhood-onset Sjögren's disease based on expert opinion. Mean age at onset was 12·7 years (SD 3·3). 28 (93%) of 30 individuals were female and two (7%) were male. The most common disease manifestations at onset were fatigue (22 [73%] of 30 individuals), arthralgia (21 [70%]), dryness (17 [57%]), glandular swelling (15 [50%]), and skin rashes (ten [30%]). Diagnostic delay of more than 3 years from symptoms onset increased the prevalence of reported dryness (nine [100%] of nine vs eight [38%] of 21; p=0·0014). Children and young people with childhood-onset Sjögren's disease had two distinct disease activity and symptom trajectories (high ESSDAI: mean 3·9 [SD 2·2] vs low ESSDAI: mean 0·8 [1·1]; p<0·0001 and high ESSPRI: mean 5·6 [2·7] vs low ESSPRI: mean 3·1 [1·0]; p=0·036), which could not be predicted by sex or age at onset, symptom duration, or duration of follow-up. Damage accrual did not differ based on activity and symptom trajectory (p=0·080 and p=1·0, respectively). At last review, the median ESSDAI score was 2·0 (IQR 2·0-8·0) and the ESSPRI score was 5·3 (3·0-7·0). Four (13%) of 30 patients developed lymphoma and 17 (57%) accumulated damage (SSDDI score ≥1).</p><p><strong>Interpretation: </strong>This preliminary evaluation of long-term outcomes of childhood-onset Sjögren's dis","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":" ","pages":""},"PeriodicalIF":16.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582679","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}
Pub Date : 2025-11-18DOI: 10.1016/S2665-9913(25)00250-4
Prof David J Beard DPhil , Loretta J Davies DPhil , Prof Jonathan A Cook PhD , Prof Graeme MacLennan MSc , Jemma Hudson PhD , Prof Andrew J Price FRCS , Prof Andrew J Carr FRCS , Matthew Little PhD , Jose Leal PhD , Prof Ray Fitzpatrick DPhil , Prof David W Murray FRCS , Prof Marion K Campbell PhD
<div><h3>Background</h3><div>The Total or Partial Knee Arthroplasty Trial (TOPKAT) aimed to evaluate the difference between total knee replacement (TKR) and partial (unicompartmental) replacement (PKR) for treatment of late-stage medial compartment knee osteoarthritis. As longevity is a key issue for joint replacement, extended follow-up periods are required to fully evaluate the long-term efficacy. In this analysis, we report the 10-year follow-up of the TOPKAT trial.</div></div><div><h3>Methods</h3><div>TOPKAT was a multicentre, randomised, pragmatic comparative effectiveness trial including an expertise component. Patients with medial compartment knee osteoarthritis were enrolled from 27 UK National Health Service (NHS) hospitals and randomly assigned (1:1) to receive PKR or TKR by surgeons who were either expert in and willing to perform both surgeries or by a surgeon with particular expertise in the allocated procedure. Neither surgeons, patients, nor follow-up assessors were masked to allocation, but the implant type was not highlighted at any stage. The primary long-term endpoint was the Oxford Knee Score (OKS) in the intention-to-treat population at 10 years. Cost effectiveness was also assessed. Individuals with relevant lived experience were involved in the study design. This trial is registered with ISRCTN03013488 and <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span>, <span><span>NCT01352247</span><svg><path></path></svg></span>, and is complete.</div></div><div><h3>Findings</h3><div>Between Jan 18, 2010, and Sept 30, 2013, of 962 patients assessed for eligibility, 528 patients (306 [58%] male, 222 [42%] female, mean age 65 years [SD 8·7]) were randomly assigned (PKR n=264; TKR n=264). Follow-up primary outcome response rate for eligible patients (excluding those who had died or withdrew) at 10 years was 326 (73%) of 444. Both operations provided good outcome. The between-group estimates ruled out any individually clinically meaningful differences in mean OKS scores (mean difference 0·27, 95% CI −1·59 to 2·13) or cumulatively over 10 years in the area under the curve analysis (mean difference 0·45, 95% CI −0·98 to 1·88). At 10 years, by treatment received, complications were 53 (22%) of 245 for PKR and 74 (27%) of 270 for TKR, reoperations (including revision) were 21 (9%) for PKR and 23 (9%) for TKR, and revision rates were 15 (6%) for PKR and 11 (4%) for TKR. By treatment allocated, for PKR and TKR respectively, complication occurred in 55 (21%) of 263 and 72 (29%) of 252, reoperations in 20 (8%) and 24 (10%), with revisions in 13 (5%) and 13 (5%) patients. PKR was more cost-effective compared with TKR, being associated with increased health benefits (mean difference in quality-adjusted life years of 0·322, 95% CI −0·069 to 0·712) and lower health-care costs (mean difference in cost −£731, 95% CI −1352 to −110).</div></div><div><h3>Interpretation</h3><div>10-year results comparing TKR and PKR show similar clinical
背景：全或部分膝关节置换术试验（TOPKAT）旨在评估全膝关节置换术（TKR）和部分（单室）置换术（PKR）治疗晚期内侧间室膝关节骨关节炎的差异。由于寿命是关节置换术的关键问题，需要延长随访期以充分评估长期疗效。在本分析中，我们报告了TOPKAT试验的10年随访。方法：TOPKAT是一项多中心、随机、实用的比较有效性试验，包括专家成分。从27家英国国民健康服务（NHS）医院招募了患有内侧室膝关节骨性关节炎的患者，并随机分配（1:1）接受PKR或TKR，由专家和愿意进行这两种手术的外科医生或由在分配手术中具有特殊专业知识的外科医生进行。外科医生、患者和随访评估人员都没有被隐瞒，但植入物类型在任何阶段都没有被突出显示。主要的长期终点是10年意向治疗人群的牛津膝关节评分（OKS）。还评估了成本效益。有相关生活经验的个人参与了研究设计。该试验已注册ISRCTN03013488和ClinicalTrials.gov, NCT01352247，并且已经完成。结果：2010年1月18日至2013年9月30日，962例入选患者中，528例患者（306例[58%]男性，222例[42%]女性，平均年龄65岁[SD 8.7]）被随机分配（PKR n=264, TKR n=264）。随访10年时，符合条件的患者（不包括死亡或退出治疗的患者）的主要结局缓解率为326(73%)/ 444。两种手术均取得了良好的效果。组间估计排除了平均OKS评分（平均差值0.27,95% CI - 0.59至2.13）或曲线下分析区域10年累积的任何个体临床意义差异（平均差值0.45,95% CI - 0.98至1.88）。10年，通过接受治疗，PKR患者245例中有53例（22%）出现并发症，TKR患者270例中有74例（27%）出现并发症，再手术（包括翻修）PKR患者21例（9%），TKR患者23例（9%），PKR患者翻修率为15例（6%），TKR患者翻修率为11例（4%）。根据分配的治疗方案，263例PKR和TKR患者中分别有55例（21%）和72例（29%）出现并发症，20例（8%）和24例（10%）患者再次手术，13例（5%）和13例（5%）患者进行翻修。与TKR相比，PKR更具成本效益，与增加的健康效益（质量调整生命年的平均差异为0.322,95% CI为- 0.069至0.712）和更低的医疗保健成本（成本平均差异为- 731英镑，95% CI为-1352至-110）相关。解释：比较TKR和PKR的10年结果显示，临床结果、再手术率和翻修率相似，但成本效益更有利于PKR。资助：国家卫生和保健研究所卫生技术评估方案。
{"title":"Assessing clinical and cost effectiveness of total versus partial knee replacement (TOPKAT): 10-year follow-up of a multicentre, randomised controlled trial","authors":"Prof David J Beard DPhil , Loretta J Davies DPhil , Prof Jonathan A Cook PhD , Prof Graeme MacLennan MSc , Jemma Hudson PhD , Prof Andrew J Price FRCS , Prof Andrew J Carr FRCS , Matthew Little PhD , Jose Leal PhD , Prof Ray Fitzpatrick DPhil , Prof David W Murray FRCS , Prof Marion K Campbell PhD","doi":"10.1016/S2665-9913(25)00250-4","DOIUrl":"10.1016/S2665-9913(25)00250-4","url":null,"abstract":"<div><h3>Background</h3><div>The Total or Partial Knee Arthroplasty Trial (TOPKAT) aimed to evaluate the difference between total knee replacement (TKR) and partial (unicompartmental) replacement (PKR) for treatment of late-stage medial compartment knee osteoarthritis. As longevity is a key issue for joint replacement, extended follow-up periods are required to fully evaluate the long-term efficacy. In this analysis, we report the 10-year follow-up of the TOPKAT trial.</div></div><div><h3>Methods</h3><div>TOPKAT was a multicentre, randomised, pragmatic comparative effectiveness trial including an expertise component. Patients with medial compartment knee osteoarthritis were enrolled from 27 UK National Health Service (NHS) hospitals and randomly assigned (1:1) to receive PKR or TKR by surgeons who were either expert in and willing to perform both surgeries or by a surgeon with particular expertise in the allocated procedure. Neither surgeons, patients, nor follow-up assessors were masked to allocation, but the implant type was not highlighted at any stage. The primary long-term endpoint was the Oxford Knee Score (OKS) in the intention-to-treat population at 10 years. Cost effectiveness was also assessed. Individuals with relevant lived experience were involved in the study design. This trial is registered with ISRCTN03013488 and <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span>, <span><span>NCT01352247</span><svg><path></path></svg></span>, and is complete.</div></div><div><h3>Findings</h3><div>Between Jan 18, 2010, and Sept 30, 2013, of 962 patients assessed for eligibility, 528 patients (306 [58%] male, 222 [42%] female, mean age 65 years [SD 8·7]) were randomly assigned (PKR n=264; TKR n=264). Follow-up primary outcome response rate for eligible patients (excluding those who had died or withdrew) at 10 years was 326 (73%) of 444. Both operations provided good outcome. The between-group estimates ruled out any individually clinically meaningful differences in mean OKS scores (mean difference 0·27, 95% CI −1·59 to 2·13) or cumulatively over 10 years in the area under the curve analysis (mean difference 0·45, 95% CI −0·98 to 1·88). At 10 years, by treatment received, complications were 53 (22%) of 245 for PKR and 74 (27%) of 270 for TKR, reoperations (including revision) were 21 (9%) for PKR and 23 (9%) for TKR, and revision rates were 15 (6%) for PKR and 11 (4%) for TKR. By treatment allocated, for PKR and TKR respectively, complication occurred in 55 (21%) of 263 and 72 (29%) of 252, reoperations in 20 (8%) and 24 (10%), with revisions in 13 (5%) and 13 (5%) patients. PKR was more cost-effective compared with TKR, being associated with increased health benefits (mean difference in quality-adjusted life years of 0·322, 95% CI −0·069 to 0·712) and lower health-care costs (mean difference in cost −£731, 95% CI −1352 to −110).</div></div><div><h3>Interpretation</h3><div>10-year results comparing TKR and PKR show similar clinical ","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"8 2","pages":"Pages e116-e126"},"PeriodicalIF":16.4,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145574819","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}
Pub Date : 2025-11-18DOI: 10.1016/S2665-9913(25)00319-4
Audai H Abudayeh , Iakiv V Fishchenko
{"title":"An imaging crisis in axial spondyloarthritis","authors":"Audai H Abudayeh , Iakiv V Fishchenko","doi":"10.1016/S2665-9913(25)00319-4","DOIUrl":"10.1016/S2665-9913(25)00319-4","url":null,"abstract":"","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"8 1","pages":"Page e7"},"PeriodicalIF":16.4,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145574869","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}
Pub Date : 2025-11-17DOI: 10.1016/S2665-9913(25)00317-0
The Lancet Rheumatology
{"title":"The stark reality of living with arthritis in the UK","authors":"The Lancet Rheumatology","doi":"10.1016/S2665-9913(25)00317-0","DOIUrl":"10.1016/S2665-9913(25)00317-0","url":null,"abstract":"","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"7 12","pages":"Page e825"},"PeriodicalIF":16.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145532710","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}
Pub Date : 2025-11-12DOI: 10.1016/S2665-9913(25)00259-0
Pedro Santos Moreno MD MSc , Rodrigo García Salinas MD , Carlo Vinicio Caballero Uribe MD , María Lorena Brance PhD , Nicolas M Marín Zúcaro MD , Prof Dina Arrieta Vega MD MSc , Adriana Beltrán MD MSc , Sonia Cabrera MD PhD , Rosa Chacon Diaz MD , Inés Corbacho MD , Oscar Jair Felipe Diaz MD , Rocio Gamboa MD MSc , Prof Carla Gobbi MD , Generoso Guerra Bautista MD , Adriana María Kakehasi MD PhD , Fernanda Linhares MD , Prof Yimy F Medina MD MSc , Pablo Monge Zeledón MD , Alicia Ramagli MD , Lilith Stange MD , Prof Enrique Roberto Soriano MD MSc
The Pan American League of Associations for Rheumatology has developed evidence-based recommendations for the pharmacological management of rheumatoid arthritis in Latin America. A panel of rheumatoid arthritis experts from Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Mexico, Panama, Peru, Uruguay, and Venezuela formulated clinically relevant questions in the population, intervention, comparator, outcome format. Systematic literature reviews were done following the Grading of Recommendations Assessment, Development and Evaluation method. Recommendations were formulated based on evidence quality and expert consensus, which required at least 70% agreement among the voting members to be included in the guidelines. Ten recommendations and a treatment algorithm were developed. Key topics include early initiation of conventional synthetic disease-modifying antirheumatic drugs (DMARDs), particularly methotrexate, parenteral methotrexate for intolerance, cautious glucocorticoid use, switching mechanisms of action after unsuccessful biological or targeted synthetic DMARD treatment, tapering in remission, and guidance for rheumatoid arthritis-associated interstitial lung disease and vasculitis. Special attention is given to cost-effectiveness and accessibility considering the socioeconomic characteristics of Latin America. These recommendations aim to support clinicians in Latin America by providing a practical, evidence-based, and contextually relevant framework that addresses the unique challenges faced in the region.
{"title":"Pan American League of Associations for Rheumatology recommendations for the management of rheumatoid arthritis","authors":"Pedro Santos Moreno MD MSc , Rodrigo García Salinas MD , Carlo Vinicio Caballero Uribe MD , María Lorena Brance PhD , Nicolas M Marín Zúcaro MD , Prof Dina Arrieta Vega MD MSc , Adriana Beltrán MD MSc , Sonia Cabrera MD PhD , Rosa Chacon Diaz MD , Inés Corbacho MD , Oscar Jair Felipe Diaz MD , Rocio Gamboa MD MSc , Prof Carla Gobbi MD , Generoso Guerra Bautista MD , Adriana María Kakehasi MD PhD , Fernanda Linhares MD , Prof Yimy F Medina MD MSc , Pablo Monge Zeledón MD , Alicia Ramagli MD , Lilith Stange MD , Prof Enrique Roberto Soriano MD MSc","doi":"10.1016/S2665-9913(25)00259-0","DOIUrl":"10.1016/S2665-9913(25)00259-0","url":null,"abstract":"<div><div>The Pan American League of Associations for Rheumatology has developed evidence-based recommendations for the pharmacological management of rheumatoid arthritis in Latin America. A panel of rheumatoid arthritis experts from Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Mexico, Panama, Peru, Uruguay, and Venezuela formulated clinically relevant questions in the population, intervention, comparator, outcome format. Systematic literature reviews were done following the Grading of Recommendations Assessment, Development and Evaluation method. Recommendations were formulated based on evidence quality and expert consensus, which required at least 70% agreement among the voting members to be included in the guidelines. Ten recommendations and a treatment algorithm were developed. Key topics include early initiation of conventional synthetic disease-modifying antirheumatic drugs (DMARDs), particularly methotrexate, parenteral methotrexate for intolerance, cautious glucocorticoid use, switching mechanisms of action after unsuccessful biological or targeted synthetic DMARD treatment, tapering in remission, and guidance for rheumatoid arthritis-associated interstitial lung disease and vasculitis. Special attention is given to cost-effectiveness and accessibility considering the socioeconomic characteristics of Latin America. These recommendations aim to support clinicians in Latin America by providing a practical, evidence-based, and contextually relevant framework that addresses the unique challenges faced in the region.</div></div>","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"8 1","pages":"Pages e53-e65"},"PeriodicalIF":16.4,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530926","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}
Pub Date : 2025-11-03DOI: 10.1016/S2665-9913(25)00249-8
Davide Martorana , Augusto Vaglio
{"title":"New clues on the pathogenesis of IgG4-related disease come from genomics","authors":"Davide Martorana , Augusto Vaglio","doi":"10.1016/S2665-9913(25)00249-8","DOIUrl":"10.1016/S2665-9913(25)00249-8","url":null,"abstract":"","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"8 1","pages":"Pages e2-e3"},"PeriodicalIF":16.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460439","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}
<div><h3>Background</h3><div>IgG4-related disease is a rare autoimmune disorder characterised by tissue infiltration of IgG4-positive plasma cells, storiform fibrosis, elevated serum IgG4 concentrations, and increased risk of tumour complications. Previous genetic studies have implicated <em>FCGR2B</em> and <em>HLA</em> loci in susceptibility to IgG4-related disease; however, most relied on microarray-based genotyping and imputation, which have limited resolution in highly polymorphic and structurally complex regions. This study aimed to investigate genetic susceptibility to IgG4-related disease using comprehensive genomic variant analysis, including low-frequency and structural variants not readily captured by microarrays.</div></div><div><h3>Methods</h3><div>We conducted a genome-wide association study using whole-genome sequencing data in a two-set, subtype-stratified case–control design in the Japanese population. Set 1 included samples (cases) from patients with IgG4-related disease from 50 hospitals across Japan participating in the Japanese IgG4-related disease Working Consortium (recruited between Oct 27, 2008, and March 3, 2016) and previously sequenced Japanese population control samples. Set 2 included samples (cases) from patients with IgG4-related disease from eight hospitals of the Consortium (recruited between Aug 12, 2021, and Dec 20, 2023) and previously sequenced healthy individuals residing in the Tokyo metropolitan area (controls). No specific inclusion or exclusion criteria were applied to either cases and controls. We used whole-genome sequencing at depths of 15× or 30× using HiSeqX and NovaSeq platforms (Illumina; San Diego, CA, USA) to enable the inclusion of previously uncaptured single nucleotide polymorphisms and direct analysis of HLA amino acid residues. We investigated complement component 4 copy number variations using short-read sequencing data and established read-depth-based typing methods. People with lived experience of IgG4-related disease were not involved in the study.</div></div><div><h3>Findings</h3><div>This whole-genome sequencing study comprised of 2 sets. Set 1 included 646 patient samples (172 [26·6%] were female, 474 [73·4%] were male, and the mean age was 64·4 years [SD 11·4]) and 2254 population controls (1348 [59·8%] were female and 906 [40·2%] were male). Set 2 included 223 patient samples (78 [35·0%] were female, 145 [65·0%] were male, and the mean age was 63·5 years [10·9]) and 405 population controls (65 [16·0%] were female and 340 [84·0%] were male). All individuals were of Hondo Japanese ancestry. The average IgG4 concentration at diagnosis was 653·1 mg/dL (SD 596·3) in Set 1 and 543·5 mg/dL (603·5) in Set 2. We validated the <em>FCGR2B</em> (p=9·8 × 10<sup>–11</sup>) region as the susceptibility locus for IgG4-related disease. <em>PTCH1</em> (p=3·8 × 10<sup>−8</sup>) and long non-coding RNA <em>LOC102724227</em> were found to be specific susceptibility loci for Mikulicz's disease. We also c
{"title":"IgG4-related disease in the Japanese population: a whole-genome sequencing study","authors":"Yuxun Oswald Zhang MPH , Takeshi Iwasaki MD PhD , Takahisa Kawaguchi PhD , Prof Hiroki Takahashi MD PhD , Shuji Kawaguchi PhD , Atsushi Kanno MD PhD , Izumi Yamaguchi PhD , Prof Kensuke Kubota MD PhD , Hiroaki Dobashi MD PhD , Prof Masao Nagasaki PhD , Motohisa Yamamoto MD PhD , Meiko Takahashi PhD , Masakazu Shimizu PhD , Tsukasa Ikeura MD PhD , Prof Shoko Matsui MD PhD , Masatoshi Kanda MD PhD , Koki Nakamura MD , Kensuke Yokoyama MD PhD , Atsushi Azumi MD PhD , Prof Yasufumi Masaki MD PhD , Yukitaka Yamashita","doi":"10.1016/S2665-9913(25)00195-X","DOIUrl":"10.1016/S2665-9913(25)00195-X","url":null,"abstract":"<div><h3>Background</h3><div>IgG4-related disease is a rare autoimmune disorder characterised by tissue infiltration of IgG4-positive plasma cells, storiform fibrosis, elevated serum IgG4 concentrations, and increased risk of tumour complications. Previous genetic studies have implicated <em>FCGR2B</em> and <em>HLA</em> loci in susceptibility to IgG4-related disease; however, most relied on microarray-based genotyping and imputation, which have limited resolution in highly polymorphic and structurally complex regions. This study aimed to investigate genetic susceptibility to IgG4-related disease using comprehensive genomic variant analysis, including low-frequency and structural variants not readily captured by microarrays.</div></div><div><h3>Methods</h3><div>We conducted a genome-wide association study using whole-genome sequencing data in a two-set, subtype-stratified case–control design in the Japanese population. Set 1 included samples (cases) from patients with IgG4-related disease from 50 hospitals across Japan participating in the Japanese IgG4-related disease Working Consortium (recruited between Oct 27, 2008, and March 3, 2016) and previously sequenced Japanese population control samples. Set 2 included samples (cases) from patients with IgG4-related disease from eight hospitals of the Consortium (recruited between Aug 12, 2021, and Dec 20, 2023) and previously sequenced healthy individuals residing in the Tokyo metropolitan area (controls). No specific inclusion or exclusion criteria were applied to either cases and controls. We used whole-genome sequencing at depths of 15× or 30× using HiSeqX and NovaSeq platforms (Illumina; San Diego, CA, USA) to enable the inclusion of previously uncaptured single nucleotide polymorphisms and direct analysis of HLA amino acid residues. We investigated complement component 4 copy number variations using short-read sequencing data and established read-depth-based typing methods. People with lived experience of IgG4-related disease were not involved in the study.</div></div><div><h3>Findings</h3><div>This whole-genome sequencing study comprised of 2 sets. Set 1 included 646 patient samples (172 [26·6%] were female, 474 [73·4%] were male, and the mean age was 64·4 years [SD 11·4]) and 2254 population controls (1348 [59·8%] were female and 906 [40·2%] were male). Set 2 included 223 patient samples (78 [35·0%] were female, 145 [65·0%] were male, and the mean age was 63·5 years [10·9]) and 405 population controls (65 [16·0%] were female and 340 [84·0%] were male). All individuals were of Hondo Japanese ancestry. The average IgG4 concentration at diagnosis was 653·1 mg/dL (SD 596·3) in Set 1 and 543·5 mg/dL (603·5) in Set 2. We validated the <em>FCGR2B</em> (p=9·8 × 10<sup>–11</sup>) region as the susceptibility locus for IgG4-related disease. <em>PTCH1</em> (p=3·8 × 10<sup>−8</sup>) and long non-coding RNA <em>LOC102724227</em> were found to be specific susceptibility loci for Mikulicz's disease. We also c","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"8 1","pages":"Pages e11-e22"},"PeriodicalIF":16.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460423","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}
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