<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}
<div><h3>Background</h3><div>Prospective data on pregnancies in systemic sclerosis are scarce. We aimed to examine the frequency of adverse pregnancy outcomes and maternal disease progression in systemic sclerosis, as well as the factors that predict these events.</div></div><div><h3>Methods</h3><div>In this analysis, we studied pregnant women with systemic sclerosis (American College of Rheumatology–European League Against Rheumatism 2013 classification) or with Very Early Diagnosis of Systemic Sclerosis (VEDOSS criteria) included in the GR2 French prospective study. Frequency of composite adverse pregnancy outcomes (preterm birth at 34 weeks or less, placental insufficiency complications, small for gestational age, or fetal or neonatal death) and maternal disease course were the primary objectives. The secondary objectives were to assess other complications related to pregnancy (including delivery outcomes and postpartum complications) and compare these results with outcomes for age-matched controls from the French perinatal survey (ENP) 2016 (ie, general population), and to identify predictive factors associated with composite adverse pregnancy outcomes and maternal disease course using univariate analysis.</div></div><div><h3>Findings</h3><div>Between May 1, 2014, and Dec 27, 2020, we included 58 pregnancies (in 52 women), with 53 (91·4%) resulting in livebirths. Of the 53 ongoing pregnancies beyond 22 weeks of gestation, 14 (26·4%) had a composite adverse pregnancy outcome, including two (3·8%) preterm deliveries at 34 weeks of gestation or less, 12 (22·6%) placental insufficiency complications (pre-eclampsia or fetal growth restriction), and six (11·3%) small for gestational age. Among the 53 pregnancies, six (11·3%) severe postpartum haemorrhage events occurred. When compared with the 2016 ENP survey results, pre-eclampsia (seven [13·2%] of 53 <em>vs</em> 16 [3·0%] of 530, p=0·0010, preterm birth before 37 weeks of gestation (seven [13·2%] of 53 <em>vs</em> 31 [5·8%] of 530, p=0·047), birthweight of less than 2500 g (11 [21·1%] of 52 <em>vs</em> 23 [4·3%] of 530, p<0·0001), and severe postpartum haemorrhage (six [11·3%] of 53 <em>vs</em> seven [1·4%] of 516, p=0·0001) were more frequent than in the general population. No factors were significantly associated with the composite adverse pregnancy outcome in univariate analysis. Systemic sclerosis or VEDOSS worsened in 23 (39·7%) of 58 pregnancies, mainly during the postpartum period. In the univariate analysis, diffuse cutaneous systemic sclerosis (odds ratio 3·7 [95% CI 1·1–12·4]) and previous cutaneous vascular involvement (3·7 [1·2–11·5]) were associated with maternal disease progression, whereas the presence of anticentromere antibodies was inversely associated with stable disease (0·2 [0·1–0·8]).</div></div><div><h3>Interpretation</h3><div>Despite 53 (91·4%) of 58 livebirths, systemic sclerosis pregnancies were associated with higher rates of adverse pregnancy outcomes and severe pos
{"title":"Fetal and maternal outcome in the pregnancies of patients with systemic sclerosis and very early diagnosis of systemic sclerosis in France: a prospective study","authors":"Anne Murarasu MD , Lauren Beaudeau MD , Veronique Le Guern MD , Gaelle Guettrot-Imbert MD , Claire Cazalets MD , Cécile Durant MD , Cécile Yelnik PhD , Céline Lartigau Roussin MD , Marie-Charlotte Besse MD , Emilie Berthoux MD , Emmanuel Chatelus MD , Eric Hachulla PhD , Estibaliz Lazaro PhD , Francois Maurier MD , Gaëlle Leroux MD , Gregory Pugnet PhD , Isabelle Durieu PhD , Loic Raffray PhD , Maelle Le Besnerais MD , Mélanie Roriz MD , Cécile YELNIK","doi":"10.1016/S2665-9913(25)00185-7","DOIUrl":"10.1016/S2665-9913(25)00185-7","url":null,"abstract":"<div><h3>Background</h3><div>Prospective data on pregnancies in systemic sclerosis are scarce. We aimed to examine the frequency of adverse pregnancy outcomes and maternal disease progression in systemic sclerosis, as well as the factors that predict these events.</div></div><div><h3>Methods</h3><div>In this analysis, we studied pregnant women with systemic sclerosis (American College of Rheumatology–European League Against Rheumatism 2013 classification) or with Very Early Diagnosis of Systemic Sclerosis (VEDOSS criteria) included in the GR2 French prospective study. Frequency of composite adverse pregnancy outcomes (preterm birth at 34 weeks or less, placental insufficiency complications, small for gestational age, or fetal or neonatal death) and maternal disease course were the primary objectives. The secondary objectives were to assess other complications related to pregnancy (including delivery outcomes and postpartum complications) and compare these results with outcomes for age-matched controls from the French perinatal survey (ENP) 2016 (ie, general population), and to identify predictive factors associated with composite adverse pregnancy outcomes and maternal disease course using univariate analysis.</div></div><div><h3>Findings</h3><div>Between May 1, 2014, and Dec 27, 2020, we included 58 pregnancies (in 52 women), with 53 (91·4%) resulting in livebirths. Of the 53 ongoing pregnancies beyond 22 weeks of gestation, 14 (26·4%) had a composite adverse pregnancy outcome, including two (3·8%) preterm deliveries at 34 weeks of gestation or less, 12 (22·6%) placental insufficiency complications (pre-eclampsia or fetal growth restriction), and six (11·3%) small for gestational age. Among the 53 pregnancies, six (11·3%) severe postpartum haemorrhage events occurred. When compared with the 2016 ENP survey results, pre-eclampsia (seven [13·2%] of 53 <em>vs</em> 16 [3·0%] of 530, p=0·0010, preterm birth before 37 weeks of gestation (seven [13·2%] of 53 <em>vs</em> 31 [5·8%] of 530, p=0·047), birthweight of less than 2500 g (11 [21·1%] of 52 <em>vs</em> 23 [4·3%] of 530, p<0·0001), and severe postpartum haemorrhage (six [11·3%] of 53 <em>vs</em> seven [1·4%] of 516, p=0·0001) were more frequent than in the general population. No factors were significantly associated with the composite adverse pregnancy outcome in univariate analysis. Systemic sclerosis or VEDOSS worsened in 23 (39·7%) of 58 pregnancies, mainly during the postpartum period. In the univariate analysis, diffuse cutaneous systemic sclerosis (odds ratio 3·7 [95% CI 1·1–12·4]) and previous cutaneous vascular involvement (3·7 [1·2–11·5]) were associated with maternal disease progression, whereas the presence of anticentromere antibodies was inversely associated with stable disease (0·2 [0·1–0·8]).</div></div><div><h3>Interpretation</h3><div>Despite 53 (91·4%) of 58 livebirths, systemic sclerosis pregnancies were associated with higher rates of adverse pregnancy outcomes and severe pos","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"8 1","pages":"Pages e33-e41"},"PeriodicalIF":16.4,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145423180","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 : 2025-10-24DOI: 10.1016/S2665-9913(25)00291-7
{"title":"Correction to Lancet Rheumatol 2025; published online Oct 15. https://doi.org/10.1016/S2665-9913(25)00248-6","authors":"","doi":"10.1016/S2665-9913(25)00291-7","DOIUrl":"10.1016/S2665-9913(25)00291-7","url":null,"abstract":"","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"7 12","pages":"Page e837"},"PeriodicalIF":16.4,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145532194","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 : 2025-10-23DOI: 10.1016/S2665-9913(25)00311-X
Heather Van Epps
{"title":"The Nobel celebrates tolerance","authors":"Heather Van Epps","doi":"10.1016/S2665-9913(25)00311-X","DOIUrl":"10.1016/S2665-9913(25)00311-X","url":null,"abstract":"","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"7 12","pages":"Page e839"},"PeriodicalIF":16.4,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145532680","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 : 2025-10-20DOI: 10.1016/S2665-9913(25)00253-X
Ufuk Ilgen
{"title":"MRI in rheumatoid arthritis and at-risk populations: the importance of context","authors":"Ufuk Ilgen","doi":"10.1016/S2665-9913(25)00253-X","DOIUrl":"10.1016/S2665-9913(25)00253-X","url":null,"abstract":"","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"7 11","pages":"Pages e758-e759"},"PeriodicalIF":16.4,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145327039","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 : 2025-10-20DOI: 10.1016/S2665-9913(25)00254-1
Dennis A Ton , Nikolet K den Hollander , Hanna W van Steenbergen , Annette H M van der Helm-van Mil
{"title":"MRI in rheumatoid arthritis and at-risk populations: the importance of context – Authors' reply","authors":"Dennis A Ton , Nikolet K den Hollander , Hanna W van Steenbergen , Annette H M van der Helm-van Mil","doi":"10.1016/S2665-9913(25)00254-1","DOIUrl":"10.1016/S2665-9913(25)00254-1","url":null,"abstract":"","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"7 11","pages":"Pages e759-e760"},"PeriodicalIF":16.4,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145327040","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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