Arthritis & Rheumatology最新文献

{"title":"Unraveling The Genetics of Shared Clinical and Serological Manifestations in Systemic Inflammatory Autoimmune Diseases","authors":"Matteo Bianchi, Sergey V. Kozyrev, Antonella Notarnicola, Johanna K. Sandling, Mats Pettersson, Dag Leonard, Christopher Sjöwall, Iva Gunnarsson, Solbritt Rantapää‐Dahlqvist, Anders A. Bengtsson, Andreas Jönsen, Elisabet Svenungsson, Helena Enocsson, Marika Kvarnström, Helena Forsblad‐d'Elia, Sara Magnusson Bucher, Katrine B. Norheim, Eva Baecklund, Roland Jonsson, Daniel Hammenfors, Per Eriksson, Thomas Mandl, Roald Omdal, Leonid Padyukov, Helena Andersson, Øyvind Molberg, Louise Pyndt Diederichsen, Ann‐Christine Syvänen, Marie Wahren‐Herlenius, Gunnel Nordmark, Ingrid E. Lundberg, Lars Rönnblom, Kerstin Lindblad‐Toh","doi":"10.1002/art.42988","DOIUrl":"https://doi.org/10.1002/art.42988","url":null,"abstract":"OBJECTIVESSystemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study aimed at elucidating the genetics underlying these common features.METHODSWe performed targeted DNA sequencing of coding and regulatory regions from ~1,900 immune‐related genes in a large SIAD cohort of 2,292 well‐characterized Scandinavian patients with SLE, pSS and myositis, as well as 1,252 controls. A gene‐based functionally‐weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by <jats:italic>in‐silico</jats:italic> functional analyses and <jats:italic>in‐vitro</jats:italic> reporter experiments.RESULTSCase‐control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case‐case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by ANA and anti‐dsDNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that <jats:italic>DUSP1</jats:italic> protective genetic variants lead to increased gene expression and potentially to anti‐inflammatory effects on the SIAD‐associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported downregulation of the MAPK signaling‐related gene <jats:italic>DUSP1</jats:italic> in other skin disorders.CONCLUSIONTogether, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"33 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236431","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":"TLR7/8 Activation in Immune Cells and Muscle by RNA‐Containing Immune Complexes: Role in Inflammation and the Pathogenesis of Myositis","authors":"Yin Wu, Aditee Deshpande, Nicholas Geraci, Petra Budde, Vera Sellers, Phanindra Velisetty, Chia‐Chi Sun, Fatima Strand, Carmina Bhavsar, Timothy B. Niewold, Mark A. Jensen, Irina Kalatskaya, Kavita Y. Sarin, David Fiorentino, Andrew T. Bender","doi":"10.1002/art.42989","DOIUrl":"https://doi.org/10.1002/art.42989","url":null,"abstract":"ObjectiveActivation of endosomal toll‐like receptors (TLRs) is one possible driver of inflammation in idiopathic inflammatory myopathies (IIM). We investigated the potential contribution of TLR7 and TLR8 to IIM pathogenesis.MethodsActivation of TLR7/8 in healthy donor peripheral blood mononuclear cells (PBMCs) by immune complexes from patients with IIM and lupus was tested. Autoantibody profiling of patient IgG samples was performed using a 1581‐antigen array. TLR7 and/or TLR8 activation by RNA molecules associated with autoantibodies was assessed. Gene expression in human myoblasts and satellite cells following treatment with supernatants from TLR7/8‐activated PBMCs was evaluated by NanoString. C57BL/6 mice were dosed intramuscularly with the TLR7/8 agonist R848 and single‐cell RNA‐sequencing was performed on the muscle to ascertain the cell types responding to TLR7/8 activation and the downstream effects.ResultsOverall, 69 patients with IIM were included with representation of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM) subsets. Immune complexes from patients with IIM, as well as autoantibody‐associated RNAs His‐tRNA, Y1, Y4 and U1, activated PBMCs to produce IFN‐α and IL‐6 via TLR7/8. Several canonical (Ro60, Ro52, HIST1H4A) and novel (IL‐36RN) autoreactivities correlated highly with TLR7/8 activation. Supernatants from TLR7/8‐activated PBMCs had a negative impact on human myoblasts and satellite cells. Endothelial cells were activated by R848 in mouse muscle <jats:italic>in vivo</jats:italic>, in addition to immune cells such as monocytes and macrophages.ConclusionOur results suggest that patients with IIM have autoantibodies in their blood causing TLR7/8 activation, which leads to inflammation in muscles with potential deleterious effects.<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/art42989-toc-0001-m.png\"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"63 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236432","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":"IĸBζ is a central modulator of inflammatory arthritis pathogenesis","authors":"Gaurav Swarnkar, Musarrat Naaz, Dorothy Mims, Prashant Gupta, Timothy Peterson, Matthew J. Christopher, Srikanth Singamaneni, Gabriel Mbalaviele, Yousef Abu-Amer","doi":"10.1002/art.42990","DOIUrl":"https://doi.org/10.1002/art.42990","url":null,"abstract":"Current therapies targeting individual factors in inflammatory arthritis (IA) show variable efficacy, often requiring treatment using combinations of drugs and associated with undesirable side effects. NF-ĸB is critical for production and function of most inflammatory cytokines. However, given its essential role in physiologic processes, targeting NF-ĸB is precarious. Hence, identifying pathways downstream of NF-κB that selectively govern expression of inflammatory cytokines in IA would be advantageous. We have previously identified IĸBζ as a unique inflammatory signature of NF-ĸB that controls transcription of inflammatory cytokines only under pathologic conditions while sparing physiologic NF-ĸB signals.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"64 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246252","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":"Hypoxia Promotes the Expression of ADAM9 by Tubular Epithelial Cells which Enhances TGF-β1 Activation and Promotes Tissue Fibrosis in Lupus Nephritis","authors":"Masataka Umeda, Kohei Karino, Abhigyan Satyam, Nobuya Yoshida, Ryo Hisada, Rhea Bhargava, Theodoros Vichos, Ana Laura Kunzler, Takashi Igawa, Kunihiro Ichinose, Kenta Torigoe, Tomoya Nishino, Takahiro Maeda, Caroline A. Owen, Reza Abdi, Atsushi Kawakami, George C. Tsokos","doi":"10.1002/art.42987","DOIUrl":"https://doi.org/10.1002/art.42987","url":null,"abstract":"Enhanced expression of transforming growth factor-beta (TGF-β) in the kidneys of patients with lupus nephritis (LN) can lead to progressive fibrosis, resulting in end-organ damage. Disintegrin and metalloproteinases 9 (ADAM9) activate TGF-β1 by cleaving the latency-associated peptide (LAP). We hypothesized that ADAM9 in the kidney may accelerate fibrogenesis by activating TGF-β1.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"9 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236978","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":"Short-term risk of cardiovascular events in people newly diagnosed with gout","authors":"Edoardo Cipolletta, Georgina Nakafero, Pascal Richette, Anthony J. Avery, Mamas A. Mamas, Laila J. Tata, Abhishek Abhishek","doi":"10.1002/art.42986","DOIUrl":"https://doi.org/10.1002/art.42986","url":null,"abstract":"To investigate the temporal association between first diagnosis of gout and cardiovascular events in the short-term.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"7 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236976","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":"Understanding the role of type I IFN in cutaneous lupus and dermatomyositis: towards better therapeutics","authors":"Grace A. Hile, Victoria P Werth","doi":"10.1002/art.42983","DOIUrl":"https://doi.org/10.1002/art.42983","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"105 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174819","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":"Enhancing intracellular cholesterol efflux in chondrocytes alleviates osteoarthritis progression","authors":"Gyuseok Lee, Jiye Yang, Su-Jin Kim, Thanh-Tam Tran, Sun Young Lee, Ka Hyon Park, Seung-Hee Kwon, Ki-Ho Chung, Jeong-Tae Koh, Yun Hyun Huh, Jong-Keun Seon, Hyun Ah Kim, Jang-Soo Chun, Je-Hwang Ryu","doi":"10.1002/art.42984","DOIUrl":"https://doi.org/10.1002/art.42984","url":null,"abstract":"Osteoarthritis (OA) is the most common degenerative disease worldwide with no practical means of prevention and limited treatment options. Recently, our group unveiled a novel mechanism contributing to OA pathogenesis in association with abnormal cholesterol metabolism in chondrocytes. In this study, we aimed to establish a clinical link between lipid profiles and OA in humans, assess the effectiveness of cholesterol-lowering drugs in suppressing OA development in mice, and uncover the cholesterol-lowering mechanisms that effectively impede OA progression.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"58 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171365","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":"Emapalumab Treatment in Patients With Rheumatologic Disease-Associated Hemophagocytic Lymphohistiocytosis in the United States: A Retrospective Medical Chart Review Study.","authors":"Shanmuganathan Chandrakasan, Carl E Allen, Deepika Bhatla, John Carter, May Chien, Robert Cooper, Lauren Draper, Olive S Eckstein, Rabi Hanna, J Allyson Hays, Michelle L Hermiston, Ashley P Hinson, Patricia M Hobday, Michael S Isakoff, Michael B Jordan, Jennifer W Leiding, Renee Modica, Taizo A Nakano, Abiola Oladapo, Sachit A Patel, Priti Pednekar, Mona Riskalla, Susmita N Sarangi, Prakash Satwani, Anand Tandra, Kelly J Walkovich, John D Yee, Adi Zoref-Lorenz, Edward M Behrens","doi":"10.1002/art.42985","DOIUrl":"10.1002/art.42985","url":null,"abstract":"<p><strong>Objective: </strong>Rheumatologic disease-associated hemophagocytic lymphohistiocytosis (HLH), a rare, life-threatening, systemic hyperinflammatory syndrome, occurs as a complication of underlying rheumatologic disease. Real-world evidence is lacking on emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon-γ, approved for treating patients with primary HLH.</p><p><strong>Methods: </strong>REAL-HLH, a retrospective medical chart review study conducted across 33 US hospitals, assessed real-world treatment patterns and outcomes in patients with HLH treated with one or more dose of emapalumab between November 20, 2018, and October 31, 2021. Data are presented for the subset of patients with rheumatologic disease-associated HLH.</p><p><strong>Results: </strong>Fifteen of 105 patients (14.3%) had rheumatologic disease-associated HLH. Of these, nine (60.0%) had systemic juvenile idiopathic arthritis, and one (6.7%) had adult-onset Still disease. Median (range) age at HLH diagnosis was 5 (0.9-39) years. Most patients (9 of 15; 60.0%) initiated emapalumab in an intensive care unit. Emapalumab was most frequently initiated for treating refractory or recurrent (10 of 15; 66.7%) disease. Most patients received HLH-related therapies before (10 of 15; 66.7%) and concurrently with (15 of 15; 100.0%) emapalumab. Emapalumab-containing regimens stabilized or achieved physician-determined normalization of most laboratory parameters, including absolute neutrophil count and absolute lymphocyte count (13 of 14; 92.9%), chemokine ligand 9 (9 of 11; 81.8%), and platelets and alanine transaminase (11 of 14; 78.6%), and reduced glucocorticoid dose by 80%. Overall survival and 12-month survival probability from emapalumab initiation were 86.7%.</p><p><strong>Conclusion: </strong>Emapalumab-containing regimens stabilized or normalized most key laboratory parameters, reduced glucocorticoid dose, and were associated with low disease-related mortality, thereby demonstrating potential benefits in patients with rheumatologic disease-associated HLH.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152665","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":"Do Existing MRI Definitions of Knee Osteoarthritis Identify Knees That Will Develop Clinically Significant Disease Over Up To 11 Years of Follow-Up?","authors":"Alison H Chang, Frank W Roemer, Ali Guermazi, Orit Almagor, Jungwha Julia Lee, Joan S Chmiel, Lutfiyya N Muhammad, Jing Song, Leena Sharma","doi":"10.1002/art.42982","DOIUrl":"10.1002/art.42982","url":null,"abstract":"<p><strong>Objective: </strong>In individuals without radiographic knee osteoarthritis (OA), we investigated whether magnetic resonance imaging (MRI)-defined knee OA at baseline was associated with incident radiographic and symptomatic disease during up to 11 years of follow-up.</p><p><strong>Methods: </strong>Osteoarthritis Initiative participants without tibiofemoral radiographic knee OA at baseline were assessed for MRI-based tibiofemoral cartilage damage, osteophyte presence, bone marrow lesions, and meniscal damage/extrusion. We defined MRI knee OA using alternative, reported definitions (Def A and Def B). Kellgren-Lawrence (KL) grade, joint space narrowing (JSN), and frequent knee symptoms (Sx) were assessed at baseline, 1-, 2-, 3-, 4-, 6-, 8-, and 10/11-year follow-up visits. Incident tibiofemoral radiographic knee OA (outcome) was defined as (1) KL ≥2, (2) KL ≥2 and JSN, or (3) KL ≥2 and Sx. Adjusted Cox proportional hazards regression models examined associations of baseline MRI-defined knee OA (Def A and Def B) with incident outcomes during up to 11 years of follow-up.</p><p><strong>Results: </strong>Among 1,621 participants (mean age ± SD 58.8 ± 9.0 years, mean body mass index ± SD 27.2 ± 4.5 kg/m², 59.5% women), 17% had MRI-defined knee OA by Def A and 24% by Def B. Baseline MRI-defined knee OA was associated with incident KL ≥2 (odds ratio 2.94 [95% confidence interval (95% CI) 2.34-3.68] for Def A and 2.44 [95% CI 1.97-3.03] for Def B). However, a substantial proportion of individuals with baseline MRI-defined knee OA did not develop incident KL ≥2 during follow-up (59% for Def A and 64% for Def B). Findings were similar for the other two outcomes.</p><p><strong>Conclusion: </strong>Current MRI definitions of knee OA do not adequately identify knees that will develop radiographic and symptomatic disease.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124303","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":"Diversity and Epitope Spreading of Anti-RNA Polymerase III Antibodies in Systemic Sclerosis: A Potential Biomarker for Skin and Lung Involvement.","authors":"Hirohito Kotani, Kazuki M Matsuda, Kei Yamaguchi, Chihiro Ono, Emi Kogo, Koji Ogawa, Yuki Kobayashi, Teruyoshi Hisamoto, Ruriko Kawanabe, Ai Kuzumi, Takemichi Fukasawa, Asako Yoshizaki-Ogawa, Naoki Goshima, Shinichi Sato, Ayumi Yoshizaki","doi":"10.1002/art.42975","DOIUrl":"10.1002/art.42975","url":null,"abstract":"<p><strong>Objective: </strong>Epitope spreading (ES), involving autoantibodies, plays a crucial role in the development and persistence of autoimmune reactions in various autoimmune diseases. This study aimed to investigate the relationship between ES of anti-RNA polymerase III (RNAP III) antibodies (ARAs) and the clinical manifestations of systemic sclerosis (SSc).</p><p><strong>Methods: </strong>We investigated whether intermolecular ES occurs in the subunits of the RNAP III complex and whether intramolecular ES targets the major antigen, RNA polymerase III subunit A (RPC1), in patients with SSc. To achieve this, we synthesized 17 full-length subunit proteins of the RNAP III complex and 5 truncated forms of RPC1 in vitro using a wheat germ cell-free translation system. Subsequently, we prepared antigen-binding plates and measured autoantibodies in the serum of patients with SSc.</p><p><strong>Results: </strong>Autoantibodies against different RNAP III complex subunits were found in patients who were ARA-positive with SSc. The intermolecular ES indicators significantly correlated with the modified Rodnan skin thickness score (mRSS) and surfactant protein-D, a biomarker of interstitial lung disease. However, the extent of disease on high-resolution computed tomography or pulmonary function tests did not show any significant correlation. Intramolecular ES indicator against RPC1 were significantly correlated with mRSS and renal crisis. Furthermore, longitudinal assessment of ES in RNAP III complex subunits correlated with mRSS and exhibited potential as a disease activity biomarker.</p><p><strong>Conclusion: </strong>Our findings indicate a correlation between ES levels and the severity of skin sclerosis or the risk of other complications in SSc. This study suggests that measuring ES in SSc serves as a novel biomarker for disease activity.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102476","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}