Sho Fukui, Masato Okada, Tomohiro Shinozaki, Takahiro Asano, Takehiro Nakai, Hiromichi Tamaki, Mitsumasa Kishimoto, Hiroshi Hasegawa, Takeaki Matsuda, Javier Marrugo, Sara K Tedeschi, Hyon Choi, Daniel H Solomon
Introduction: Despite the established cross-sectional association between alcohol intake and serum urate (SU), its longitudinal association remains unknown. This study aimed to determine whether changes in alcohol intake have a clinically relevant association with SU change.
Method: We conducted retrospective analyses using systematically collected annual medical examination data from October 2012 to October 2022 in a Japanese preventive medicine centre. The exposure was changes in alcohol intake between two consecutive visits. The association of SU changes with alcohol intake changes was estimated by mixed-effect linear regression with adjustment for relevant covariates.
Results: We analysed 63 486 participants (median age, 47.0 years; 55% women; 58.6% regular alcohol drinkers with a median of 1.4 drinks/day) with 370 572 visits. The median SU level was 5.3 mg/dL, and 506 (0.8%) participants had diagnoses of gout or hyperuricemia without medication use during the study period. Decreasing one daily alcohol intake had a clinically small association with SU changes (-0.019 (95% CI: -0.021 to -0.017) mg/dL). Beer had the largest association with SU (-0.036 (95% CI: -0.039 to -0.032) mg/dL for one beer decrease). Complete discontinuation of any alcohol from a mean of 0.8 drinks/day was associated with -0.056 mg/dL (95% CI: -0.068 to -0.043) decrease in SU; the association became larger in hyperuricemic participants (-0.110 mg/dL (95% CI: -0.154 to -0.066) for alcohol discontinuation from a mean of 1.0 drinks/day).
Conclusions: This study revealed changes in alcohol intake had small associations with SU change at the general Japanese population level. Complete discontinuation of alcohol in hyperuricemic participants had only modest improvement in SU.
导言:尽管酒精摄入量与血清尿酸盐(SU)之间的横向联系已经确立,但其纵向联系仍不清楚。本研究旨在确定酒精摄入量的变化是否与血清尿酸盐的变化有临床相关性:我们利用日本一家预防医学中心系统收集的 2012 年 10 月至 2022 年 10 月的年度体检数据进行了回顾性分析。研究对象是两次连续就诊之间酒精摄入量的变化。在对相关协变量进行调整后,通过混合效应线性回归估算了SU变化与酒精摄入量变化之间的关联:我们分析了 63 486 名参与者(年龄中位数为 47.0 岁;55% 为女性;58.6% 为经常饮酒者,饮酒中位数为 1.4 杯/天)的 370 572 次就诊情况。研究期间,SU 水平中位数为 5.3 mg/dL,506 人(0.8%)确诊为痛风或高尿酸血症,但未使用药物。每日酒精摄入量的减少与 SU 变化的临床联系较小(-0.019 (95% CI: -0.021 to -0.017) mg/dL)。啤酒与 SU 的关系最大(减少一瓶啤酒的摄入量为-0.036(95% CI:-0.039 至-0.032)毫克/分升)。从平均每天 0.8 杯开始完全停止饮酒与 SU 下降-0.056 毫克/分升(95% CI:-0.068 至 -0.043)有关;在高尿酸血症参与者中,这种关联变得更大(从平均每天 1.0 杯开始停止饮酒与 SU 下降-0.110 毫克/分升(95% CI:-0.154 至 -0.066)有关):这项研究表明,在日本普通人群中,酒精摄入量的变化与 SU 变化的关系不大。高尿酸血症患者完全戒酒对 SU 的改善不大。
{"title":"Changes in alcohol intake and serum urate changes: longitudinal analyses of annual medical examination database.","authors":"Sho Fukui, Masato Okada, Tomohiro Shinozaki, Takahiro Asano, Takehiro Nakai, Hiromichi Tamaki, Mitsumasa Kishimoto, Hiroshi Hasegawa, Takeaki Matsuda, Javier Marrugo, Sara K Tedeschi, Hyon Choi, Daniel H Solomon","doi":"10.1136/ard-2023-225389","DOIUrl":"10.1136/ard-2023-225389","url":null,"abstract":"<p><strong>Introduction: </strong>Despite the established cross-sectional association between alcohol intake and serum urate (SU), its longitudinal association remains unknown. This study aimed to determine whether changes in alcohol intake have a clinically relevant association with SU change.</p><p><strong>Method: </strong>We conducted retrospective analyses using systematically collected annual medical examination data from October 2012 to October 2022 in a Japanese preventive medicine centre. The exposure was changes in alcohol intake between two consecutive visits. The association of SU changes with alcohol intake changes was estimated by mixed-effect linear regression with adjustment for relevant covariates.</p><p><strong>Results: </strong>We analysed 63 486 participants (median age, 47.0 years; 55% women; 58.6% regular alcohol drinkers with a median of 1.4 drinks/day) with 370 572 visits. The median SU level was 5.3 mg/dL, and 506 (0.8%) participants had diagnoses of gout or hyperuricemia without medication use during the study period. Decreasing one daily alcohol intake had a clinically small association with SU changes (-0.019 (95% CI: -0.021 to -0.017) mg/dL). Beer had the largest association with SU (-0.036 (95% CI: -0.039 to -0.032) mg/dL for one beer decrease). Complete discontinuation of any alcohol from a mean of 0.8 drinks/day was associated with -0.056 mg/dL (95% CI: -0.068 to -0.043) decrease in SU; the association became larger in hyperuricemic participants (-0.110 mg/dL (95% CI: -0.154 to -0.066) for alcohol discontinuation from a mean of 1.0 drinks/day).</p><p><strong>Conclusions: </strong>This study revealed changes in alcohol intake had small associations with SU change at the general Japanese population level. Complete discontinuation of alcohol in hyperuricemic participants had only modest improvement in SU.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139989152","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}
Sharon Cowley, Patricia Harkins, Colm Kirby, Richard Conway, David J Kane
There is a growing appreciation that both giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are closely interrelated conditions that have significant overlap in aetiology, clinical characteristics and treatment regimens. Subclinical GCA in PMR is becoming increasingly recognised, and there is evolving evidence that this may be a more aggressive disease phenotype than PMR. Ultrasound (US) lends itself well as a screening tool for GCA in PMR; it is inexpensive, non-invasive, widely available, lacks ionising radiation, may be performed at the bedside and is recommended by EULAR as a first-line investigation for suspected GCA. There is insufficient evidence to currently recommend that all patients with PMR should have a US assessment for vascular involvement. However, as clinical and laboratory parameters alone do not accurately diagnose patients with subclinical GCA, we suggest that vascular US will be increasingly performed by rheumatologists in practice to identify these patients with PMR, preferably as part of larger prospective outcome studies.
{"title":"Should all patients with polymyalgia rheumatica have a vascular ultrasound assessment?","authors":"Sharon Cowley, Patricia Harkins, Colm Kirby, Richard Conway, David J Kane","doi":"10.1136/ard-2024-225650","DOIUrl":"10.1136/ard-2024-225650","url":null,"abstract":"<p><p>There is a growing appreciation that both giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are closely interrelated conditions that have significant overlap in aetiology, clinical characteristics and treatment regimens. Subclinical GCA in PMR is becoming increasingly recognised, and there is evolving evidence that this may be a more aggressive disease phenotype than PMR. Ultrasound (US) lends itself well as a screening tool for GCA in PMR; it is inexpensive, non-invasive, widely available, lacks ionising radiation, may be performed at the bedside and is recommended by EULAR as a first-line investigation for suspected GCA. There is insufficient evidence to currently recommend that all patients with PMR should have a US assessment for vascular involvement. However, as clinical and laboratory parameters alone do not accurately diagnose patients with subclinical GCA, we suggest that vascular US will be increasingly performed by rheumatologists in practice to identify these patients with PMR, preferably as part of larger prospective outcome studies.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326269","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}
Pregnancy can be an exciting time but for those living with rheumatic musculoskeletal diseases (RMDs), it can also be a time fraught with concern, including what effect pregnancy will have on the underlying RMD and what effect the RMD may have on the pregnancy and the baby, including the effects of medications. Generating an evidence base in pregnancy is challenging. Few interventional trials of medications in RMD pregnancies have ever been conducted, often for concerns of safety for both the mother and the child. Therefore, observational research remains important for informing clinical practice and helping women with RMDs make decisions regarding their health preconception and during pregnancy. The Annals of the Rheumatic Diseases (ARD) continues to publish important research on pregnancy in RMDs to increase the evidence base on this subject. Here we present an overview of papers published on this topic between January 2018 and December 2023. Our focus includes papers on pregnancy and RMD outcome, the effects of drug exposure, fetal outcomes as well as fertility.
{"title":"Annals of the Rheumatic Diseases collection on pregnancy 2018-2023: observational data-driven knowledge.","authors":"Kate Duhig, Kimme L Hyrich","doi":"10.1136/ard-2023-224861","DOIUrl":"10.1136/ard-2023-224861","url":null,"abstract":"<p><p>Pregnancy can be an exciting time but for those living with rheumatic musculoskeletal diseases (RMDs), it can also be a time fraught with concern, including what effect pregnancy will have on the underlying RMD and what effect the RMD may have on the pregnancy and the baby, including the effects of medications. Generating an evidence base in pregnancy is challenging. Few interventional trials of medications in RMD pregnancies have ever been conducted, often for concerns of safety for both the mother and the child. Therefore, observational research remains important for informing clinical practice and helping women with RMDs make decisions regarding their health preconception and during pregnancy. The Annals of the Rheumatic Diseases (ARD) continues to publish important research on pregnancy in RMDs to increase the evidence base on this subject. Here we present an overview of papers published on this topic between January 2018 and December 2023. Our focus includes papers on pregnancy and RMD outcome, the effects of drug exposure, fetal outcomes as well as fertility.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139705902","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":"Kauko Vainio (1913-1989): pioneer of rheumaorthopaedic surgery.","authors":"Janis Timsans, Raine Tiihonen, Markku Kauppi","doi":"10.1136/ard-2024-225814","DOIUrl":"10.1136/ard-2024-225814","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140915741","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}
Norbert Bittner, Chenfu Shi, Danyun Zhao, James Ding, Lorraine Southam, Diane Swift, Peter Kreitmaier, Mauro Tutino, Odysseas Stergiou, Jackson T S Cheung, Georgia Katsoula, Jenny Hankinson, Jeremy Mark Wilkinson, Gisela Orozco, Eleftheria Zeggini
Objectives: Osteoarthritis is a complex disease with a huge public health burden. Genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated sequence variants, but the effector genes underpinning these signals remain largely elusive. Understanding chromosome organisation in three-dimensional (3D) space is essential for identifying long-range contacts between distant genomic features (e.g., between genes and regulatory elements), in a tissue-specific manner. Here, we generate the first whole genome chromosome conformation analysis (Hi-C) map of primary osteoarthritis chondrocytes and identify novel candidate effector genes for the disease.
Methods: Primary chondrocytes collected from 8 patients with knee osteoarthritis underwent Hi-C analysis to link chromosomal structure to genomic sequence. The identified loops were then combined with osteoarthritis GWAS results and epigenomic data from primary knee osteoarthritis chondrocytes to identify variants involved in gene regulation via enhancer-promoter interactions.
Results: We identified 345 genetic variants residing within chromatin loop anchors that are associated with 77 osteoarthritis GWAS signals. Ten of these variants reside directly in enhancer regions of 10 newly described active enhancer-promoter loops, identified with multiomics analysis of publicly available chromatin immunoprecipitation sequencing (ChIP-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) data from primary knee chondrocyte cells, pointing to two new candidate effector genes SPRY4 and PAPPA (pregnancy-associated plasma protein A) as well as further support for the gene SLC44A2 known to be involved in osteoarthritis. For example, PAPPA is directly associated with the turnover of insulin-like growth factor 1 (IGF-1) proteins, and IGF-1 is an important factor in the repair of damaged chondrocytes.
Conclusions: We have constructed the first Hi-C map of primary human chondrocytes and have made it available as a resource for the scientific community. By integrating 3D genomics with large-scale genetic association and epigenetic data, we identify novel candidate effector genes for osteoarthritis, which enhance our understanding of disease and can serve as putative high-value novel drug targets.
{"title":"Primary osteoarthritis chondrocyte map of chromatin conformation reveals novel candidate effector genes.","authors":"Norbert Bittner, Chenfu Shi, Danyun Zhao, James Ding, Lorraine Southam, Diane Swift, Peter Kreitmaier, Mauro Tutino, Odysseas Stergiou, Jackson T S Cheung, Georgia Katsoula, Jenny Hankinson, Jeremy Mark Wilkinson, Gisela Orozco, Eleftheria Zeggini","doi":"10.1136/ard-2023-224945","DOIUrl":"10.1136/ard-2023-224945","url":null,"abstract":"<p><strong>Objectives: </strong>Osteoarthritis is a complex disease with a huge public health burden. Genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated sequence variants, but the effector genes underpinning these signals remain largely elusive. Understanding chromosome organisation in three-dimensional (3D) space is essential for identifying long-range contacts between distant genomic features (e.g., between genes and regulatory elements), in a tissue-specific manner. Here, we generate the first whole genome chromosome conformation analysis (Hi-C) map of primary osteoarthritis chondrocytes and identify novel candidate effector genes for the disease.</p><p><strong>Methods: </strong>Primary chondrocytes collected from 8 patients with knee osteoarthritis underwent Hi-C analysis to link chromosomal structure to genomic sequence. The identified loops were then combined with osteoarthritis GWAS results and epigenomic data from primary knee osteoarthritis chondrocytes to identify variants involved in gene regulation via enhancer-promoter interactions.</p><p><strong>Results: </strong>We identified 345 genetic variants residing within chromatin loop anchors that are associated with 77 osteoarthritis GWAS signals. Ten of these variants reside directly in enhancer regions of 10 newly described active enhancer-promoter loops, identified with multiomics analysis of publicly available chromatin immunoprecipitation sequencing (ChIP-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) data from primary knee chondrocyte cells, pointing to two new candidate effector genes <i>SPRY4</i> and <i>PAPPA (pregnancy-associated plasma protein A)</i> as well as further support for the gene <i>SLC44A2</i> known to be involved in osteoarthritis. For example, PAPPA is directly associated with the turnover of insulin-like growth factor 1 (IGF-1) proteins, and IGF-1 is an important factor in the repair of damaged chondrocytes.</p><p><strong>Conclusions: </strong>We have constructed the first Hi-C map of primary human chondrocytes and have made it available as a resource for the scientific community. By integrating 3D genomics with large-scale genetic association and epigenetic data, we identify novel candidate effector genes for osteoarthritis, which enhance our understanding of disease and can serve as putative high-value novel drug targets.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118562","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}
Erica Moore, Sushma Bharrhan, Deepak A Rao, Fernando Macian, Chaim Putterman
Objective: Diffuse central nervous system manifestations, referred to as neuropsychiatric lupus (NPSLE), are observed in 20-40% of lupus patients and involve complex mechanisms that have not yet been adequately elucidated. In murine NPSLE models, choroid plexus (ChP)-infiltrating T cells have not been fully evaluated as drivers of neuropsychiatric disease.
Method: Droplet-based single-cell transcriptomic analysis (single-cell RNA sequencing) and immune T-cell receptor profiling were performed on ChP tissue from MRL/lpr mice, an NPSLE mouse model, at an 'early' and 'late' disease state, to investigate the infiltrating immune cells that accumulate with NPSLE disease progression.
Results: We found 19 unique clusters of stromal and infiltrating cells present in the ChP of NPSLE mice. Higher resolution of the T-cell clusters uncovered multiple T-cell subsets, with increased exhaustion and hypoxia expression profiles. Clonal analysis revealed that the clonal CD8+T cell CDR3 sequence, ASGDALGGYEQY, matched that of a published T-cell receptor sequence with specificity for myelin basic protein. Stromal fibroblasts are likely drivers of T-cell recruitment by upregulating the VCAM signalling pathway. Systemic blockade of VLA-4, the cognate ligand of VCAM, resulted in significant resolution of the ChP immune cell infiltration and attenuation of the depressive phenotype.
Conclusion: Our analysis details the dynamic transcriptomic changes associated with murine NPSLE disease progression, and highlights its potential use in identifying prospective lupus brain therapeutic targets.
{"title":"Characterisation of choroid plexus-infiltrating T cells reveals novel therapeutic targets in murine neuropsychiatric lupus.","authors":"Erica Moore, Sushma Bharrhan, Deepak A Rao, Fernando Macian, Chaim Putterman","doi":"10.1136/ard-2023-224689","DOIUrl":"10.1136/ard-2023-224689","url":null,"abstract":"<p><strong>Objective: </strong>Diffuse central nervous system manifestations, referred to as neuropsychiatric lupus (NPSLE), are observed in 20-40% of lupus patients and involve complex mechanisms that have not yet been adequately elucidated. In murine NPSLE models, choroid plexus (ChP)-infiltrating T cells have not been fully evaluated as drivers of neuropsychiatric disease.</p><p><strong>Method: </strong>Droplet-based single-cell transcriptomic analysis (single-cell RNA sequencing) and immune T-cell receptor profiling were performed on ChP tissue from MRL/lpr mice, an NPSLE mouse model, at an 'early' and 'late' disease state, to investigate the infiltrating immune cells that accumulate with NPSLE disease progression.</p><p><strong>Results: </strong>We found 19 unique clusters of stromal and infiltrating cells present in the ChP of NPSLE mice. Higher resolution of the T-cell clusters uncovered multiple T-cell subsets, with increased exhaustion and hypoxia expression profiles. Clonal analysis revealed that the clonal CD8+T cell CDR3 sequence, ASGDALGGYEQY, matched that of a published T-cell receptor sequence with specificity for myelin basic protein. Stromal fibroblasts are likely drivers of T-cell recruitment by upregulating the VCAM signalling pathway. Systemic blockade of VLA-4, the cognate ligand of VCAM, resulted in significant resolution of the ChP immune cell infiltration and attenuation of the depressive phenotype.</p><p><strong>Conclusion: </strong>Our analysis details the dynamic transcriptomic changes associated with murine NPSLE disease progression, and highlights its potential use in identifying prospective lupus brain therapeutic targets.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292498","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}
Sarthak Gupta, Eiko Yamada, Hiroyuki Nakamura, Paola Perez, Thomas Jf Pranzatelli, Kalie Dominick, Shyh-Ing Jang, Mehdi Abed, Daniel Martin, Peter Burbelo, ChangYu Zheng, Ben French, Ilias Alevizos, Zohreh Khavandgar, Margaret Beach, Eileen Pelayo, Brian Walitt, Sarfaraz Hasni, Mariana J Kaplan, Mayank Tandon, Maria Teresa Magone, David E Kleiner, John A Chiorini, Alan Baer, Blake M Warner
Objectives: Inflammatory cytokines that signal through the Janus kinases-signal transducer and activator of transcription (JAK-STAT) pathway, especially interferons (IFNs), are implicated in Sjögren's disease (SjD). Although inhibition of JAKs is effective in other autoimmune diseases, a systematic investigation of IFN-JAK-STAT signalling and the effect of JAK inhibitor (JAKi) therapy in SjD-affected human tissues has not been fully investigated.
Methods: Human minor salivary glands (MSGs) and peripheral blood mononuclear cells (PBMCs) were investigated using bulk or single-cell (sc) RNA sequencing (RNAseq), immunofluorescence (IF) microscopy and flow cytometry. Ex vivo culture assays on PBMCs and primary salivary gland epithelial cell (pSGEC) lines were performed to model changes in target tissues before and after JAKi.
Results: RNAseq and IF showed activated JAK-STAT pathway in SjD MSGs. Elevated IFN-stimulated gene (ISGs) expression associated with clinical variables (eg, focus scores, anti-SSA positivity). scRNAseq of MSGs exhibited cell type-specific upregulation of JAK-STAT and ISGs; PBMCs showed similar trends, including markedly upregulated ISGs in monocytes. Ex vivo studies showed elevated basal pSTAT levels in SjD MSGs and PBMCs that were corrected with JAKi. SjD-derived pSGECs exhibited higher basal ISG expressions and exaggerated responses to IFN-β, which were normalised by JAKi without cytotoxicity.
Conclusions: SjD patients' tissues exhibit increased expression of ISGs and activation of the JAK-STAT pathway in a cell type-dependent manner. JAKi normalises this aberrant signalling at the tissue level and in PBMCs, suggesting a putative viable therapy for SjD, targeting both glandular and extraglandular symptoms. Predicated on these data, a phase Ib/IIa randomised controlled trial to treat SjD with tofacitinib was initiated.
{"title":"Inhibition of JAK-STAT pathway corrects salivary gland inflammation and interferon driven immune activation in Sjögren's disease.","authors":"Sarthak Gupta, Eiko Yamada, Hiroyuki Nakamura, Paola Perez, Thomas Jf Pranzatelli, Kalie Dominick, Shyh-Ing Jang, Mehdi Abed, Daniel Martin, Peter Burbelo, ChangYu Zheng, Ben French, Ilias Alevizos, Zohreh Khavandgar, Margaret Beach, Eileen Pelayo, Brian Walitt, Sarfaraz Hasni, Mariana J Kaplan, Mayank Tandon, Maria Teresa Magone, David E Kleiner, John A Chiorini, Alan Baer, Blake M Warner","doi":"10.1136/ard-2023-224842","DOIUrl":"10.1136/ard-2023-224842","url":null,"abstract":"<p><strong>Objectives: </strong>Inflammatory cytokines that signal through the Janus kinases-signal transducer and activator of transcription (JAK-STAT) pathway, especially interferons (IFNs), are implicated in Sjögren's disease (SjD). Although inhibition of JAKs is effective in other autoimmune diseases, a systematic investigation of IFN-JAK-STAT signalling and the effect of JAK inhibitor (JAKi) therapy in SjD-affected human tissues has not been fully investigated.</p><p><strong>Methods: </strong>Human minor salivary glands (MSGs) and peripheral blood mononuclear cells (PBMCs) were investigated using bulk or single-cell (sc) RNA sequencing (RNAseq), immunofluorescence (IF) microscopy and flow cytometry. Ex vivo culture assays on PBMCs and primary salivary gland epithelial cell (pSGEC) lines were performed to model changes in target tissues before and after JAKi.</p><p><strong>Results: </strong>RNAseq and IF showed activated JAK-STAT pathway in SjD MSGs. Elevated IFN-stimulated gene (ISGs) expression associated with clinical variables (eg, focus scores, anti-SSA positivity). scRNAseq of MSGs exhibited cell type-specific upregulation of JAK-STAT and ISGs; PBMCs showed similar trends, including markedly upregulated ISGs in monocytes. Ex vivo studies showed elevated basal pSTAT levels in SjD MSGs and PBMCs that were corrected with JAKi. SjD-derived pSGECs exhibited higher basal ISG expressions and exaggerated responses to IFN-β, which were normalised by JAKi without cytotoxicity.</p><p><strong>Conclusions: </strong>SjD patients' tissues exhibit increased expression of ISGs and activation of the JAK-STAT pathway in a cell type-dependent manner. JAKi normalises this aberrant signalling at the tissue level and in PBMCs, suggesting a putative viable therapy for SjD, targeting both glandular and extraglandular symptoms. Predicated on these data, a phase Ib/IIa randomised controlled trial to treat SjD with tofacitinib was initiated.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288084","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}
Karolina Gente, Manuel Feisst, Dorothea Marx, Karel D Klika, Petros Christopoulos, Jürgen Graf, Julia Will, Thomas Luft, Jessica C Hassel, Carsten Müller-Tidow, Rui A Carvalho, Hanns-Martin Lorenz, M Margarida Souto-Carneiro
Objectives: A timely diagnosis is imperative for curing cancer. However, in patients with rheumatic musculoskeletal diseases (RMDs) or paraneoplastic syndromes, misleading symptoms frequently delay cancer diagnosis. As metabolic remodelling characterises both cancer and RMD, we analysed if a metabolic signature can indicate paraneoplasia (PN) or reveal concomitant cancer in patients with RMD.
Methods: Metabolic alterations in the sera of rheumatoid arthritis (RA) patients with (n=56) or without (n=52) a history of invasive cancer were quantified by nuclear magnetic resonance analysis. Metabolites indicative of cancer were determined by multivariable regression analyses. Two independent RA and spondyloarthritis (SpA) cohorts with or without a history of invasive cancer were used for blinded validation. Samples from patients with active cancer or cancer treatment, pulmonary and lymphoid type cancers, paraneoplastic syndromes, non-invasive (NI) precancerous lesions and non-melanoma skin cancer and systemic lupus erythematosus and samples prior to the development of malignancy were used to test the model performance.
Results: Based on the concentrations of acetate, creatine, glycine, formate and the lipid ratio L1/L6, a diagnostic model yielded a high sensitivity and specificity for cancer diagnosis with AUC=0.995 in the model cohort, AUC=0.940 in the blinded RA validation cohort and AUC=0.928 in the mixed RA/SpA cohort. It was equally capable of identifying cancer in patients with PN. The model was insensitive to common demographic or clinical confounders or the presence of NI malignancy like non-melanoma skin cancer.
Conclusions: This new set of metabolic markers reliably predicts the presence of cancer in arthritis or PN patients with high sensitivity and specificity and has the potential to facilitate a rapid and correct diagnosis of malignancy.
目标:及时诊断是治愈癌症的当务之急。然而,在患有风湿性肌肉骨骼疾病(RMD)或副肿瘤综合征的患者中,误导性症状经常会延误癌症诊断。由于代谢重塑是癌症和 RMD 的共同特征,我们分析了代谢特征是否能指示副肿瘤症(PN)或揭示 RMD 患者是否同时患有癌症:通过核磁共振分析,对有或没有侵袭性癌症病史的类风湿性关节炎(RA)患者(56 人)血清中的代谢变化进行量化。通过多变量回归分析确定了指示癌症的代谢物。有无浸润性癌症病史的两个独立 RA 和脊柱关节炎(SpA)队列被用于盲法验证。来自活动性癌症或癌症治疗、肺癌和淋巴型癌症、副肿瘤综合征、非侵袭性(NI)癌前病变、非黑色素瘤皮肤癌和系统性红斑狼疮患者的样本以及恶性肿瘤发生前的样本被用来测试模型的性能:根据醋酸盐、肌酸、甘氨酸、甲酸盐和脂质比率L1/L6的浓度,诊断模型对癌症诊断具有很高的灵敏度和特异性,在模型队列中的AUC=0.995,在盲法RA验证队列中的AUC=0.940,在RA/SpA混合队列中的AUC=0.928。该模型同样能够识别 PN 患者的癌症。该模型对常见的人口统计学或临床混杂因素或非黑素瘤皮肤癌等NI恶性肿瘤的存在不敏感:这组新的代谢标记物能可靠地预测关节炎或白血病患者是否罹患癌症,具有很高的灵敏度和特异性,有望促进恶性肿瘤的快速、正确诊断。
{"title":"Altered serum metabolome as an indicator of paraneoplasia or concomitant cancer in patients with rheumatic disease.","authors":"Karolina Gente, Manuel Feisst, Dorothea Marx, Karel D Klika, Petros Christopoulos, Jürgen Graf, Julia Will, Thomas Luft, Jessica C Hassel, Carsten Müller-Tidow, Rui A Carvalho, Hanns-Martin Lorenz, M Margarida Souto-Carneiro","doi":"10.1136/ard-2023-224839","DOIUrl":"10.1136/ard-2023-224839","url":null,"abstract":"<p><strong>Objectives: </strong>A timely diagnosis is imperative for curing cancer. However, in patients with rheumatic musculoskeletal diseases (RMDs) or paraneoplastic syndromes, misleading symptoms frequently delay cancer diagnosis. As metabolic remodelling characterises both cancer and RMD, we analysed if a metabolic signature can indicate paraneoplasia (PN) or reveal concomitant cancer in patients with RMD.</p><p><strong>Methods: </strong>Metabolic alterations in the sera of rheumatoid arthritis (RA) patients with (n=56) or without (n=52) a history of invasive cancer were quantified by nuclear magnetic resonance analysis. Metabolites indicative of cancer were determined by multivariable regression analyses. Two independent RA and spondyloarthritis (SpA) cohorts with or without a history of invasive cancer were used for blinded validation. Samples from patients with active cancer or cancer treatment, pulmonary and lymphoid type cancers, paraneoplastic syndromes, non-invasive (NI) precancerous lesions and non-melanoma skin cancer and systemic lupus erythematosus and samples prior to the development of malignancy were used to test the model performance.</p><p><strong>Results: </strong>Based on the concentrations of acetate, creatine, glycine, formate and the lipid ratio L1/L6, a diagnostic model yielded a high sensitivity and specificity for cancer diagnosis with AUC=0.995 in the model cohort, AUC=0.940 in the blinded RA validation cohort and AUC=0.928 in the mixed RA/SpA cohort. It was equally capable of identifying cancer in patients with PN. The model was insensitive to common demographic or clinical confounders or the presence of NI malignancy like non-melanoma skin cancer.</p><p><strong>Conclusions: </strong>This new set of metabolic markers reliably predicts the presence of cancer in arthritis or PN patients with high sensitivity and specificity and has the potential to facilitate a rapid and correct diagnosis of malignancy.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334519","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}
Laura C M Schenning, Rosanne Ottevanger, Koen D Quint, Sander W Tas
{"title":"An ulcerating skin tumour in a patient with rheumatoid arthritis.","authors":"Laura C M Schenning, Rosanne Ottevanger, Koen D Quint, Sander W Tas","doi":"10.1136/ard-2023-225436","DOIUrl":"10.1136/ard-2023-225436","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691062","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}
Ana-Luisa Stefanski, Hector Rincon-Arevalo, Iris Dressler-Steinbach, Nadja Nomovi, Alma Mackert, Arman Aue, Jacob Ritter, Annika Wiedemann, Franziska Szelinski, Eva Schrezenmeier, Anja A Kühl, Andreia C Lino, Wolfgang Henrich, Thomas Dörner
{"title":"Dysregulation of immune checkpoint molecules as a characteristic of autoimmune congenital heart block.","authors":"Ana-Luisa Stefanski, Hector Rincon-Arevalo, Iris Dressler-Steinbach, Nadja Nomovi, Alma Mackert, Arman Aue, Jacob Ritter, Annika Wiedemann, Franziska Szelinski, Eva Schrezenmeier, Anja A Kühl, Andreia C Lino, Wolfgang Henrich, Thomas Dörner","doi":"10.1136/ard-2024-226176","DOIUrl":"https://doi.org/10.1136/ard-2024-226176","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598325","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}