Kevin Y Cunningham, Benjamin Hur, Vinod K Gupta, Matthew J Koster, Cornelia M Weyand, David Cuthbertson, Nader A Khalidi, Curry L Koening, Carol A Langford, Carol A McAlear, Paul A Monach, Larry W Moreland, Christian Pagnoux, Rennie L Rhee, Philip Seo, Peter A Merkel, Kenneth J Warrington, Jaeyun Sung
Objectives: This study aimed to identify plasma proteomic signatures that differentiate active and inactive giant cell arteritis (GCA) from non-disease controls. By comprehensively profiling the plasma proteome of both patients with GCA and controls, we aimed to identify plasma proteins that (1) distinguish patients from controls and (2) associate with disease activity in GCA.
Methods: Plasma samples were obtained from 30 patients with GCA in a multi-institutional, prospective longitudinal study: one captured during active disease and another while in clinical remission. Samples from 30 age-matched/sex-matched/race-matched non-disease controls were also collected. A high-throughput, aptamer-based proteomics assay, which examines over 7000 protein features, was used to generate plasma proteome profiles from study participants.
Results: After adjusting for potential confounders, we identified 537 proteins differentially abundant between active GCA and controls, and 781 between inactive GCA and controls. These proteins suggest distinct immune responses, metabolic pathways and potentially novel physiological processes involved in each disease state. Additionally, we found 16 proteins associated with disease activity in patients with active GCA. Random forest models trained on the plasma proteome profiles accurately differentiated active and inactive GCA groups from controls (95.0% and 98.3% in 10-fold cross-validation, respectively). However, plasma proteins alone provided limited ability to distinguish between active and inactive disease states within the same patients.
Conclusions: This comprehensive analysis of the plasma proteome in GCA suggests that blood protein signatures integrated with machine learning hold promise for discovering multiplex biomarkers for GCA.
{"title":"Plasma proteome profiling in giant cell arteritis.","authors":"Kevin Y Cunningham, Benjamin Hur, Vinod K Gupta, Matthew J Koster, Cornelia M Weyand, David Cuthbertson, Nader A Khalidi, Curry L Koening, Carol A Langford, Carol A McAlear, Paul A Monach, Larry W Moreland, Christian Pagnoux, Rennie L Rhee, Philip Seo, Peter A Merkel, Kenneth J Warrington, Jaeyun Sung","doi":"10.1136/ard-2024-225868","DOIUrl":"https://doi.org/10.1136/ard-2024-225868","url":null,"abstract":"<p><strong>Objectives: </strong>This study aimed to identify plasma proteomic signatures that differentiate active and inactive giant cell arteritis (GCA) from non-disease controls. By comprehensively profiling the plasma proteome of both patients with GCA and controls, we aimed to identify plasma proteins that (1) distinguish patients from controls and (2) associate with disease activity in GCA.</p><p><strong>Methods: </strong>Plasma samples were obtained from 30 patients with GCA in a multi-institutional, prospective longitudinal study: one captured during active disease and another while in clinical remission. Samples from 30 age-matched/sex-matched/race-matched non-disease controls were also collected. A high-throughput, aptamer-based proteomics assay, which examines over 7000 protein features, was used to generate plasma proteome profiles from study participants.</p><p><strong>Results: </strong>After adjusting for potential confounders, we identified 537 proteins differentially abundant between active GCA and controls, and 781 between inactive GCA and controls. These proteins suggest distinct immune responses, metabolic pathways and potentially novel physiological processes involved in each disease state. Additionally, we found 16 proteins associated with disease activity in patients with active GCA. Random forest models trained on the plasma proteome profiles accurately differentiated active and inactive GCA groups from controls (95.0% and 98.3% in 10-fold cross-validation, respectively). However, plasma proteins alone provided limited ability to distinguish between active and inactive disease states within the same patients.</p><p><strong>Conclusions: </strong>This comprehensive analysis of the plasma proteome in GCA suggests that blood protein signatures integrated with machine learning hold promise for discovering multiplex biomarkers for GCA.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995124","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}
Carlo Tur, Markus Eckstein, Joachim Velden, Simon Rauber, Christina Bergmann, Janina Auth, Laura Bucci, Giulia Corte, Melanie Hagen, Andreas Wirsching, Ricardo Grieshaber-Bouyer, Petra Reis, Nicolai Kittan, Jochen Wacker, Aleix Rius Rigau, Andreas Ramming, Maria-Antonietta D'Agostino, Arndt Hartmann, Fabian Müller, Andreas Mackensen, Aline Bozec, Georg Schett, Maria Gabriella Raimondo
Objectives: CD19-targeting chimeric antigen receptor (CAR) T-cell therapy can induce long-term drug-free remission in patients with autoimmune diseases (AIDs). The efficacy of CD19-CAR T-cell therapy is presumably based on deep tissue depletion of B cells; however, such effect has not been proven in humans in vivo.
Methods: Sequential ultrasound-guided inguinal lymph node biopsies were performed at baseline and after CD19-CAR T-cell therapy in patients with AIDs. Results were compared with lymph node biopsies from rituximab (RTX)-treated AID patients with absence of peripheral B cells. Conventional and immunohistochemistry staining were performed on lymph node tissue to assess architecture as well the number of B cells, follicular dendritic cells (FDCs), plasma cells, T cells and macrophages.
Results: Sequential lymph node biopsies were analysed from five patients with AID before and after CD19-CAR T-cell therapy and from five patients with AID after RTX treatment. In addition, non-lymphoid organ biopsies (colon, kidney and gallbladder) from three additional patients with AID after CD19-CAR T-cell therapy were analysed. CD19+ and CD20+ B cells were completely depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX treatment. Plasma cells, T cells and macrophages in the lymph nodes remained unchanged. Follicular structures were disrupted and FDCs were depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX. Non-lymphoid organs were completely depleted of B cells.
Discussion: This study demonstrates complete B-cell depletion in secondary lymphoid tissues of patients with AIDs following CD19-CAR T-cell therapy combined with standard lymphodepleting therapy.
目的:CD19靶向嵌合抗原受体(CAR)T细胞疗法可诱导自身免疫性疾病(AIDs)患者长期无药缓解。CD19-CAR T细胞疗法的疗效可能是基于B细胞的深层组织消耗;然而,这种效果尚未在人体体内得到证实:方法:在基线和 CD19-CAR T 细胞疗法后,对艾滋病患者进行超声引导下的腹股沟淋巴结活检。结果与利妥昔单抗(RTX)治疗后外周B细胞缺失的AID患者的淋巴结活检结果进行了比较。对淋巴结组织进行常规染色和免疫组化染色,以评估其结构以及B细胞、滤泡树突状细胞(FDC)、浆细胞、T细胞和巨噬细胞的数量:对 CD19-CAR T 细胞治疗前后的五名艾滋病患者以及 RTX 治疗后的五名艾滋病患者的连续淋巴结活检组织进行了分析。此外,还分析了另外三名 CD19-CAR T 细胞治疗后的 AID 患者的非淋巴器官活检组织(结肠、肾脏和胆囊)。CD19-CAR T细胞疗法后,淋巴结中的CD19+和CD20+ B细胞被完全清除,而RTX疗法后则没有。淋巴结中的浆细胞、T细胞和巨噬细胞保持不变。CD19-CAR T细胞治疗后,淋巴结中的滤泡结构被破坏,FDC被耗尽,而RTX治疗后则没有。非淋巴器官中的 B 细胞被完全耗尽:本研究表明,CD19-CAR T 细胞疗法与标准淋巴细胞清除疗法结合使用后,艾滋病患者继发性淋巴组织中的 B 细胞被完全清除。
{"title":"CD19-CAR T-cell therapy induces deep tissue depletion of B cells.","authors":"Carlo Tur, Markus Eckstein, Joachim Velden, Simon Rauber, Christina Bergmann, Janina Auth, Laura Bucci, Giulia Corte, Melanie Hagen, Andreas Wirsching, Ricardo Grieshaber-Bouyer, Petra Reis, Nicolai Kittan, Jochen Wacker, Aleix Rius Rigau, Andreas Ramming, Maria-Antonietta D'Agostino, Arndt Hartmann, Fabian Müller, Andreas Mackensen, Aline Bozec, Georg Schett, Maria Gabriella Raimondo","doi":"10.1136/ard-2024-226142","DOIUrl":"https://doi.org/10.1136/ard-2024-226142","url":null,"abstract":"<p><strong>Objectives: </strong>CD19-targeting chimeric antigen receptor (CAR) T-cell therapy can induce long-term drug-free remission in patients with autoimmune diseases (AIDs). The efficacy of CD19-CAR T-cell therapy is presumably based on deep tissue depletion of B cells; however, such effect has not been proven in humans in vivo.</p><p><strong>Methods: </strong>Sequential ultrasound-guided inguinal lymph node biopsies were performed at baseline and after CD19-CAR T-cell therapy in patients with AIDs. Results were compared with lymph node biopsies from rituximab (RTX)-treated AID patients with absence of peripheral B cells. Conventional and immunohistochemistry staining were performed on lymph node tissue to assess architecture as well the number of B cells, follicular dendritic cells (FDCs), plasma cells, T cells and macrophages.</p><p><strong>Results: </strong>Sequential lymph node biopsies were analysed from five patients with AID before and after CD19-CAR T-cell therapy and from five patients with AID after RTX treatment. In addition, non-lymphoid organ biopsies (colon, kidney and gallbladder) from three additional patients with AID after CD19-CAR T-cell therapy were analysed. CD19<sup>+</sup> and CD20<sup>+</sup> B cells were completely depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX treatment. Plasma cells, T cells and macrophages in the lymph nodes remained unchanged. Follicular structures were disrupted and FDCs were depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX. Non-lymphoid organs were completely depleted of B cells.</p><p><strong>Discussion: </strong>This study demonstrates complete B-cell depletion in secondary lymphoid tissues of patients with AIDs following CD19-CAR T-cell therapy combined with standard lymphodepleting therapy.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995123","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}
Augustin Latourte, Sarah Jaulerry, Alice Combier, Chahrazad Cherifi, Yohan Jouan, Thierry Grange, Julien Daligault, Hang-Korng Ea, Martine Cohen-Solal, Eric Hay, Pascal Richette
Objectives: Inflammatory mediators such as interleukin 6 (IL-6) are known to activate catabolic responses in chondrocytes during osteoarthritis (OA). This study aimed to investigate the role of a downstream target gene of IL-6, the serine protease inhibitor SerpinA3N, in the development of cartilage damage in OA.
Methods: RNA sequencing was performed in murine primary chondrocytes treated with IL-6, and identified target genes were confirmed in human and murine OA cartilage samples. Male cartilage-specific Serpina3n-deficient mice and control mice underwent meniscectomy (MNX) or sham surgery at 10 weeks of age. Intra-articular injections of SerpinA3N or sivelestat (an inhibitor of leucocyte elastase (LE), a substrate for SerpinA3N) were performed in wild-type mice after MNX. Joint damage was assessed 3-9 weeks after surgery by histology and micro-CT. The effect of sivelestat was assessed in cartilage explants exposed to macrophage-derived conditioned media.
Results: RNA sequencing revealed that SerpinA3N is a major target gene of IL-6 in chondrocytes. The expression of SerpinA3N is increased in OA cartilage. Conditional loss of SerpinA3N in chondrocytes aggravated OA in mice, while intra-articular injection of SerpinA3N limited joint damage. Chondrocytes did not produce serine proteases targeted by SerpinA3N. By contrast, macrophages produced LE on IL-6 stimulation. Sivelestat limited the cartilage catabolism induced by conditioned media derived from IL-6-stimulated macrophages. Additionally, an intra-articular injection of sivelestat is protected against OA in the MNX model.
Conclusions: SerpinA3N protects cartilage against catabolic factors produced by macrophages, including LE. SerpinA3N and LE represent new therapeutic targets to dampen cartilage damage in OA.
{"title":"SerpinA3N limits cartilage destruction in osteoarthritis by inhibiting macrophage-derived leucocyte elastase.","authors":"Augustin Latourte, Sarah Jaulerry, Alice Combier, Chahrazad Cherifi, Yohan Jouan, Thierry Grange, Julien Daligault, Hang-Korng Ea, Martine Cohen-Solal, Eric Hay, Pascal Richette","doi":"10.1136/ard-2024-225645","DOIUrl":"https://doi.org/10.1136/ard-2024-225645","url":null,"abstract":"<p><strong>Objectives: </strong>Inflammatory mediators such as interleukin 6 (IL-6) are known to activate catabolic responses in chondrocytes during osteoarthritis (OA). This study aimed to investigate the role of a downstream target gene of IL-6, the serine protease inhibitor SerpinA3N, in the development of cartilage damage in OA.</p><p><strong>Methods: </strong>RNA sequencing was performed in murine primary chondrocytes treated with IL-6, and identified target genes were confirmed in human and murine OA cartilage samples. Male cartilage-specific <i>Serpina3n</i>-deficient mice and control mice underwent meniscectomy (MNX) or sham surgery at 10 weeks of age. Intra-articular injections of SerpinA3N or sivelestat (an inhibitor of leucocyte elastase (LE), a substrate for SerpinA3N) were performed in wild-type mice after MNX. Joint damage was assessed 3-9 weeks after surgery by histology and micro-CT. The effect of sivelestat was assessed in cartilage explants exposed to macrophage-derived conditioned media.</p><p><strong>Results: </strong>RNA sequencing revealed that SerpinA3N is a major target gene of IL-6 in chondrocytes. The expression of SerpinA3N is increased in OA cartilage. Conditional loss of SerpinA3N in chondrocytes aggravated OA in mice, while intra-articular injection of SerpinA3N limited joint damage. Chondrocytes did not produce serine proteases targeted by SerpinA3N. By contrast, macrophages produced LE on IL-6 stimulation. Sivelestat limited the cartilage catabolism induced by conditioned media derived from IL-6-stimulated macrophages. Additionally, an intra-articular injection of sivelestat is protected against OA in the MNX model.</p><p><strong>Conclusions: </strong>SerpinA3N protects cartilage against catabolic factors produced by macrophages, including LE. SerpinA3N and LE represent new therapeutic targets to dampen cartilage damage in OA.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970470","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}
Tsz On Lam, Edric Chi Ching Ip, Wendy Wan Hang Lau, Agnes Wai Sze Chan, Christina Man Tung Cheung, Joshua Jing Xi Li, Joanna Ka Man Ng, Lai-Shan Tam
{"title":"Mutilating arthropathy with skin nodules.","authors":"Tsz On Lam, Edric Chi Ching Ip, Wendy Wan Hang Lau, Agnes Wai Sze Chan, Christina Man Tung Cheung, Joshua Jing Xi Li, Joanna Ka Man Ng, Lai-Shan Tam","doi":"10.1136/ard-2024-226186","DOIUrl":"https://doi.org/10.1136/ard-2024-226186","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905654","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}
Rheumatologists and rheumatology have had a prominent role in the conceptualisation of nociplastic pain since the prototypical nociplastic pain condition is fibromyalgia. Fibromyalgia had been previously known as fibrositis, until it became clear that this condition could be differentiatied from autoimmune disorders because of a lack of systemic inflammation and tissue damage. Nociplastic pain is now thought to be a third descriptor/mechanism of pain, in addition to nociceptive pain (pain due to peripheral damage or inflammation) and neuropathic pain. Nociplastic pain can occur in isolation, or as a co-morbidity with other mechanisms of pain, as commonly occurs in individuals with autoimmune disorders. We now know that the cardinal symptoms of nociplastic pain are widespread pain (or pain in areas not without evidence of inflammation/damage), accompanied by fatigue, sleep and memory issues. There is objective evidence of amplification/augmentation of pain, as well as of non-painful stimuli such as the brightness of lights and unpleasantness of sound or odors. Nociplastic pain states can be triggered by a variety of stressors such as trauma, infections and chronic stressors. Together these features suggest that the central nervous system (CNS) is playing a major role in causing and maintaining nociplastic pain, but these CNS factors may in some be driven by ongoing peripheral nociceptive input. The most effective drug therapies for nociplastic pain are non-opioid centrally acting analgesics such as tricyclics, serotonin-norepinephrine reuptake inhibitors and gabapentinoids. However the mainstay of therapy of nociplastic pain is the use of a variety of non-pharmacological integrative therapies, especially those which improve activity/exercise, sleep and address psychological co-morbidities.
{"title":"From fibrositis to fibromyalgia to nociplastic pain: how rheumatology helped get us here and where do we go from here?","authors":"Daniel J Clauw","doi":"10.1136/ard-2023-225327","DOIUrl":"https://doi.org/10.1136/ard-2023-225327","url":null,"abstract":"<p><p>Rheumatologists and rheumatology have had a prominent role in the conceptualisation of nociplastic pain since the prototypical nociplastic pain condition is fibromyalgia. Fibromyalgia had been previously known as fibrositis, until it became clear that this condition could be differentiatied from autoimmune disorders because of a lack of systemic inflammation and tissue damage. Nociplastic pain is now thought to be a third descriptor/mechanism of pain, in addition to nociceptive pain (pain due to peripheral damage or inflammation) and neuropathic pain. Nociplastic pain can occur in isolation, or as a co-morbidity with other mechanisms of pain, as commonly occurs in individuals with autoimmune disorders. We now know that the cardinal symptoms of nociplastic pain are widespread pain (or pain in areas not without evidence of inflammation/damage), accompanied by fatigue, sleep and memory issues. There is objective evidence of amplification/augmentation of pain, as well as of non-painful stimuli such as the brightness of lights and unpleasantness of sound or odors. Nociplastic pain states can be triggered by a variety of stressors such as trauma, infections and chronic stressors. Together these features suggest that the central nervous system (CNS) is playing a major role in causing and maintaining nociplastic pain, but these CNS factors may in some be driven by ongoing peripheral nociceptive input. The most effective drug therapies for nociplastic pain are non-opioid centrally acting analgesics such as tricyclics, serotonin-norepinephrine reuptake inhibitors and gabapentinoids. However the mainstay of therapy of nociplastic pain is the use of a variety of non-pharmacological integrative therapies, especially those which improve activity/exercise, sleep and address psychological co-morbidities.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896615","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}
Robert G W Lambert, Xenofon Baraliakos, Stephanie A Bernard, John A Carrino, Torsten Diekhoff, Iris Eshed, Kay Geert A Hermann, Nele Herregods, Jacob Jaremko, Lennart Bo Jans, Anne Grethe Jurik, John M D O'Neill, Monique Reijnierse, Michael J Tuite, Walter P Maksymowych
Background: A range of sacroiliac joint (SIJ) MRI protocols are used in clinical practice but not all were specifically designed for diagnostic ascertainment. This can be confusing and no standard diagnostic SIJ MRI protocol is currently accepted worldwide.
Objective: To develop a standardised MRI image acquisition protocol (IAP) for diagnostic ascertainment of sacroiliitis.
Methods: 13 radiologist members of Assessment of SpondyloArthritis International Society (ASAS) and the SpondyloArthritis Research and Treatment Network (SPARTAN) plus two rheumatologists participated in a consensus exercise. A draft IAP was circulated with background information and online examples. Feedback on all issues was tabulated and recirculated. The remaining points of contention were resolved and the revised IAP was presented to the entire ASAS membership.
Results: A minimum four-sequence IAP is recommended for diagnostic ascertainment of sacroiliitis and its differential diagnoses meeting the following requirements. Three semicoronal sequences, parallel to the dorsal cortex of the S2 vertebral body, should include sequences sensitive for detection of (1) changes in fat signal and structural damage with T1-weighting; (2) active inflammation, being T2-weighted with fat suppression; (3) bone erosion optimally depicting the bone-cartilage interface of the articular surface and (4) a semiaxial sequence sensitive for detection of inflammation. The IAP was approved at the 2022 ASAS annual meeting with 91% of the membership in favour.
Conclusion: A standardised IAP for SIJ MRI for diagnostic ascertainment of sacroiliitis is recommended and should be composed of at least four sequences that include imaging in two planes and optimally visualise inflammation, structural damage and the bone-cartilage interface.
{"title":"Development of international consensus on a standardised image acquisition protocol for diagnostic evaluation of the sacroiliac joints by MRI: an ASAS-SPARTAN collaboration.","authors":"Robert G W Lambert, Xenofon Baraliakos, Stephanie A Bernard, John A Carrino, Torsten Diekhoff, Iris Eshed, Kay Geert A Hermann, Nele Herregods, Jacob Jaremko, Lennart Bo Jans, Anne Grethe Jurik, John M D O'Neill, Monique Reijnierse, Michael J Tuite, Walter P Maksymowych","doi":"10.1136/ard-2024-225882","DOIUrl":"https://doi.org/10.1136/ard-2024-225882","url":null,"abstract":"<p><strong>Background: </strong>A range of sacroiliac joint (SIJ) MRI protocols are used in clinical practice but not all were specifically designed for diagnostic ascertainment. This can be confusing and no standard diagnostic SIJ MRI protocol is currently accepted worldwide.</p><p><strong>Objective: </strong>To develop a standardised MRI image acquisition protocol (IAP) for diagnostic ascertainment of sacroiliitis.</p><p><strong>Methods: </strong>13 radiologist members of Assessment of SpondyloArthritis International Society (ASAS) and the SpondyloArthritis Research and Treatment Network (SPARTAN) plus two rheumatologists participated in a consensus exercise. A draft IAP was circulated with background information and online examples. Feedback on all issues was tabulated and recirculated. The remaining points of contention were resolved and the revised IAP was presented to the entire ASAS membership.</p><p><strong>Results: </strong>A minimum four-sequence IAP is recommended for diagnostic ascertainment of sacroiliitis and its differential diagnoses meeting the following requirements. Three semicoronal sequences, parallel to the dorsal cortex of the S2 vertebral body, should include sequences sensitive for detection of (1) changes in fat signal and structural damage with T1-weighting; (2) active inflammation, being T2-weighted with fat suppression; (3) bone erosion optimally depicting the bone-cartilage interface of the articular surface and (4) a semiaxial sequence sensitive for detection of inflammation. The IAP was approved at the 2022 ASAS annual meeting with 91% of the membership in favour.</p><p><strong>Conclusion: </strong>A standardised IAP for SIJ MRI for diagnostic ascertainment of sacroiliitis is recommended and should be composed of at least four sequences that include imaging in two planes and optimally visualise inflammation, structural damage and the bone-cartilage interface.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896614","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}
Ann-Kathrin Eiers, Sabine Vettorazzi, Jan P Tuckermann
For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding of GCs binding to nuclear receptors, mainly the glucocorticoid receptor (GR) and their molecular mechanisms has changed dramatically. Initially, in the late 1950s, GCs were considered important regulators of energy metabolism. By the 1970s/1980s, they were characterised as ligands for hormone-inducible transcription factors that regulate many aspects of cell biology and physiology. More recently, their impact on cellular metabolism has been rediscovered. Our understanding of cell-type-specific GC actions and the crosstalk between various immune and stromal cells in arthritis models has evolved by investigating conditional GR mutant mice using the Cre/LoxP system. A major achievement in studying the complex, cell-type-specific interplay is the recent advent of omics technologies at single-cell resolution, which will provide further unprecedented insights into the cell types and factors mediating GC responses. Alongside gene-encoded factors, anti-inflammatory metabolites that participate in resolving inflammation by GCs during arthritis are just being uncovered. The translation of this knowledge into therapeutic concepts will help tackle inflammatory diseases and reduce side effects. In this review, we describe major milestones in preclinical research that led to our current understanding of GC and GR action 75 years after the first use of GCs in arthritis.
{"title":"Journey through discovery of 75 years glucocorticoids: evolution of our knowledge of glucocorticoid receptor mechanisms in rheumatic diseases.","authors":"Ann-Kathrin Eiers, Sabine Vettorazzi, Jan P Tuckermann","doi":"10.1136/ard-2023-225371","DOIUrl":"https://doi.org/10.1136/ard-2023-225371","url":null,"abstract":"<p><p>For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding of GCs binding to nuclear receptors, mainly the glucocorticoid receptor (GR) and their molecular mechanisms has changed dramatically. Initially, in the late 1950s, GCs were considered important regulators of energy metabolism. By the 1970s/1980s, they were characterised as ligands for hormone-inducible transcription factors that regulate many aspects of cell biology and physiology. More recently, their impact on cellular metabolism has been rediscovered. Our understanding of cell-type-specific GC actions and the crosstalk between various immune and stromal cells in arthritis models has evolved by investigating conditional GR mutant mice using the Cre/LoxP system. A major achievement in studying the complex, cell-type-specific interplay is the recent advent of omics technologies at single-cell resolution, which will provide further unprecedented insights into the cell types and factors mediating GC responses. Alongside gene-encoded factors, anti-inflammatory metabolites that participate in resolving inflammation by GCs during arthritis are just being uncovered. The translation of this knowledge into therapeutic concepts will help tackle inflammatory diseases and reduce side effects. In this review, we describe major milestones in preclinical research that led to our current understanding of GC and GR action 75 years after the first use of GCs in arthritis.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896616","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}
Objective: Helicobacter pylori infection has been reported to aggravate rheumatoid arthritis (RA), but the relevant mechanism remains unclear. This study aimed to investigate the underlying pathogenic mechanism of H. pylori infection in the progression of RA.
Methods: The Disease Activity Score (DAS-28) and serum anticitrullinated protein antibody (ACPA) levels were compared between H. pylori-negative and H. pylori-positive patients with RA. MH7A cells were stimulated with polyclonal ACPA purified from the peripheral blood of patients with RA. The citrullination levels were assessed by western blot in GES-1 cells and sera. ChIP, luciferase reporter assays, mass spectrometry and ELISA were applied to explore the molecular mechanism of H. pylori infection in RA progression.
Results: The DAS-28 and ACPA levels of patients with RA in the H. pylori-positive group were significantly higher than those in the H. pylori-negative group. Polyclonal ACPA derived from H. pylori-positive patients promoted cell proliferation and induced secretion of IL-6 and IL-8. For the first time, we found that H. pylori infection induces cellular protein citrullination by upregulating protein arginine deiminase type 4 (PAD4). Furthermore, we confirmed a direct functional binding of hypoxia-inducible factor 1α on the PADI4 gene promoter. We demonstrated that PAD4 interacts with and citrullinates keratin 1 (K1), and serum and synovial fluid levels of anti-Cit-K1 antibody were markedly increased in H. pylori-infected patients with RA.
Conclusion: Our findings reveal a novel mechanism by which H. pylori infection contributes to RA progression. Therapeutic interventions targeting H. pylori may be a viable strategy for the management of RA.
目的:有报道称幽门螺杆菌感染会加重类风湿性关节炎(RA),但相关机制仍不清楚。本研究旨在探讨幽门螺杆菌感染导致 RA 病变进展的潜在致病机制:方法:比较幽门螺杆菌阴性和幽门螺杆菌阳性 RA 患者的疾病活动评分(DAS-28)和血清抗瓜氨酸蛋白抗体(ACPA)水平。用从 RA 患者外周血中纯化的多克隆 ACPA 刺激 MH7A 细胞。在 GES-1 细胞和血清中通过 Western 印迹评估瓜氨酸化水平。应用 ChIP、荧光素酶报告实验、质谱法和 ELISA 等方法探讨幽门螺杆菌感染导致 RA 病变的分子机制:结果:幽门螺杆菌阳性组RA患者的DAS-28和ACPA水平明显高于幽门螺杆菌阴性组。来自幽门螺杆菌阳性患者的多克隆ACPA能促进细胞增殖并诱导IL-6和IL-8的分泌。我们首次发现幽门螺杆菌感染会通过上调精氨酸脱氨酶 4 型(PAD4)诱导细胞蛋白瓜氨酸化。此外,我们还证实了低氧诱导因子 1α 与 PADI4 基因启动子的直接功能性结合。我们证明了 PAD4 与角蛋白 1(K1)相互作用并使其瓜氨酸化,幽门螺杆菌感染的 RA 患者血清和滑膜液中抗 Cit-K1 抗体水平明显升高:我们的研究结果揭示了幽门螺杆菌感染导致RA进展的新机制。针对幽门螺杆菌的治疗干预可能是治疗 RA 的可行策略。
{"title":"<i>Helicobacter pylori</i> upregulates PAD4 expression via stabilising HIF-1α to exacerbate rheumatoid arthritis.","authors":"Hui Wu, Hanmei Yuan, Jin Zhang, Taojun He, Yilin Deng, Ying Chen, Yunqi Zhang, Weisan Chen, Chao Wu","doi":"10.1136/ard-2023-225306","DOIUrl":"https://doi.org/10.1136/ard-2023-225306","url":null,"abstract":"<p><strong>Objective: </strong><i>Helicobacter pylori</i> infection has been reported to aggravate rheumatoid arthritis (RA), but the relevant mechanism remains unclear. This study aimed to investigate the underlying pathogenic mechanism of <i>H. pylori</i> infection in the progression of RA.</p><p><strong>Methods: </strong>The Disease Activity Score (DAS-28) and serum anticitrullinated protein antibody (ACPA) levels were compared between <i>H. pylori</i>-negative and <i>H. pylori</i>-positive patients with RA. MH7A cells were stimulated with polyclonal ACPA purified from the peripheral blood of patients with RA. The citrullination levels were assessed by western blot in GES-1 cells and sera. ChIP, luciferase reporter assays, mass spectrometry and ELISA were applied to explore the molecular mechanism of <i>H. pylori</i> infection in RA progression.</p><p><strong>Results: </strong>The DAS-28 and ACPA levels of patients with RA in the <i>H. pylori</i>-positive group were significantly higher than those in the <i>H. pylori</i>-negative group. Polyclonal ACPA derived from <i>H. pylori</i>-positive patients promoted cell proliferation and induced secretion of IL-6 and IL-8. For the first time, we found that <i>H. pylori</i> infection induces cellular protein citrullination by upregulating protein arginine deiminase type 4 (PAD4). Furthermore, we confirmed a direct functional binding of hypoxia-inducible factor 1α on the <i>PADI4</i> gene promoter. We demonstrated that PAD4 interacts with and citrullinates keratin 1 (K1), and serum and synovial fluid levels of anti-Cit-K1 antibody were markedly increased in <i>H. pylori</i>-infected patients with RA.</p><p><strong>Conclusion: </strong>Our findings reveal a novel mechanism by which <i>H. pylori</i> infection contributes to RA progression. Therapeutic interventions targeting <i>H. pylori</i> may be a viable strategy for the management of RA.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896613","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}
Fanlei Hu, Xin Li, Kai Liu, Yanpeng Li, Yang Xie, Chaonan Wei, Shuyan Liu, Jing Song, Ping Wang, Lianjie Shi, Chun Li, Jing Li, Liling Xu, Jimeng Xue, Xi Zheng, Mingxin Bai, Xiangyu Fang, Xu Jin, Lulu Cao, Pei Hao, Jing He, Jun Wang, Chiyu Zhang, Zhanguo Li
Objectives: Viruses have been considered as important participants in the development of rheumatoid arthritis (RA). However, the profile of enteric virome and its role in RA remains elusive. This study aimed to investigate the atlas and involvement of virome in RA pathogenesis.
Methods: Faecal samples from 30 pairs of RA and healthy siblings that minimise genetic interferences were collected for metagenomic sequencing. The α and β diversity of the virome and the virome-bacteriome interaction were analysed. The differential bacteriophages were identified, and their correlations with clinical and immunological features of RA were analysed. The potential involvement of these differential bacteriophages in RA pathogenesis was further investigated by auxiliary metabolic gene annotation and molecular mimicry study. The responses of CD4+ T cells and B cells to the mimotopes derived from the differential bacteriophages were systemically studied.
Results: The composition of the enteric bacteriophageome was distorted in RA. The differentially presented bacteriophages correlated with the immunological features of RA, including anti-CCP autoantibody and HLA-DR shared epitope. Intriguingly, the glycerolipid and purine metabolic genes were highly active in the bacteriophages from RA. Moreover, peptides of RA-enriched phages, in particular Prevotella phage and Oscillibacter phage could provoke the autoimmune responses in CD4+ T cells and plasma cells via molecular mimicry of the disease-associated autoantigen epitopes, especially those of Bip.
Conclusions: This study provides new insights into enteric bacteriophageome in RA development. In particular, the aberrant bacteriophages demonstrated autoimmunity-provoking potential that would promote the occurrence of the disease.
目的:病毒一直被认为是类风湿性关节炎(RA)发病的重要参与者。然而,肠道病毒组的概况及其在 RA 中的作用仍然难以捉摸。本研究旨在调查类风湿关节炎发病机制中病毒组的图谱和参与情况:方法:收集 30 对 RA 和健康兄弟姐妹的粪便样本进行元基因组测序,以尽量减少遗传干扰。分析了病毒组的α和β多样性以及病毒组与细菌组之间的相互作用。鉴定了不同的噬菌体,并分析了它们与 RA 临床和免疫学特征的相关性。通过辅助代谢基因注释和分子模拟研究,进一步研究了这些差异噬菌体在RA发病机制中的潜在参与。系统研究了CD4+ T细胞和B细胞对来自差异噬菌体的模拟物的反应:结果:肠道噬菌体组的组成在RA中发生了扭曲。结果:RA患者肠道噬菌体组的组成发生了扭曲,不同的噬菌体与RA的免疫学特征相关,包括抗CCP自身抗体和HLA-DR共享表位。耐人寻味的是,RA噬菌体中的甘油脂和嘌呤代谢基因高度活跃。此外,富含RA的噬菌体,特别是普雷沃特氏菌噬菌体和奥希氏菌噬菌体的肽可通过分子模拟疾病相关的自身抗原表位,尤其是Bip的表位,激发CD4+ T细胞和浆细胞的自身免疫反应:这项研究为了解肠道噬菌体在 RA 发病过程中的作用提供了新的视角。结论:这项研究为了解肠道噬菌体组在 RA 发病过程中的作用提供了新的视角,尤其是噬菌体的异常表现出了诱发自身免疫的潜力,这将促进疾病的发生。
{"title":"Rheumatoid arthritis patients harbour aberrant enteric bacteriophages with autoimmunity-provoking potential: a paired sibling study.","authors":"Fanlei Hu, Xin Li, Kai Liu, Yanpeng Li, Yang Xie, Chaonan Wei, Shuyan Liu, Jing Song, Ping Wang, Lianjie Shi, Chun Li, Jing Li, Liling Xu, Jimeng Xue, Xi Zheng, Mingxin Bai, Xiangyu Fang, Xu Jin, Lulu Cao, Pei Hao, Jing He, Jun Wang, Chiyu Zhang, Zhanguo Li","doi":"10.1136/ard-2024-225564","DOIUrl":"https://doi.org/10.1136/ard-2024-225564","url":null,"abstract":"<p><strong>Objectives: </strong>Viruses have been considered as important participants in the development of rheumatoid arthritis (RA). However, the profile of enteric virome and its role in RA remains elusive. This study aimed to investigate the atlas and involvement of virome in RA pathogenesis.</p><p><strong>Methods: </strong>Faecal samples from 30 pairs of RA and healthy siblings that minimise genetic interferences were collected for metagenomic sequencing. The α and β diversity of the virome and the virome-bacteriome interaction were analysed. The differential bacteriophages were identified, and their correlations with clinical and immunological features of RA were analysed. The potential involvement of these differential bacteriophages in RA pathogenesis was further investigated by auxiliary metabolic gene annotation and molecular mimicry study. The responses of CD4<sup>+</sup> T cells and B cells to the mimotopes derived from the differential bacteriophages were systemically studied.</p><p><strong>Results: </strong>The composition of the enteric bacteriophageome was distorted in RA. The differentially presented bacteriophages correlated with the immunological features of RA, including anti-CCP autoantibody and HLA-DR shared epitope. Intriguingly, the glycerolipid and purine metabolic genes were highly active in the bacteriophages from RA. Moreover, peptides of RA-enriched phages, in particular <i>Prevotella</i> phage and <i>Oscillibacter</i> phage could provoke the autoimmune responses in CD4<sup>+</sup> T cells and plasma cells via molecular mimicry of the disease-associated autoantigen epitopes, especially those of Bip.</p><p><strong>Conclusions: </strong>This study provides new insights into enteric bacteriophageome in RA development. In particular, the aberrant bacteriophages demonstrated autoimmunity-provoking potential that would promote the occurrence of the disease.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858891","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}
Kristina Lend, Jon Lampa, Leonid Padyukov, Merete Lund Hetland, Marte Schrumpf Heiberg, Dan C Nordström, Michael T Nurmohamed, Anna Rudin, Mikkel Østergaard, Espen A Haavardsholm, Kim Hørslev-Petersen, Till Uhlig, Tuulikki Sokka-Isler, Bjorn Gudbjornsson, Gerdur Grondal, Giulia Frazzei, Jeroen Christiaans, Gertjan Wolbink, Theo Rispens, Jos W R Twisk, Ronald F van Vollenhoven
Objectives: To investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional treatment (ACT).
Methods: Patients with treatment-naïve early rheumatoid arthritis were randomised in the NORD-STAR trial to ACT, certolizumab pegol, abatacept or tocilizumab, all with methotrexate. Centralised laboratory analyses for ACPA, RF and SE were performed. Clinical Disease Activity Index remission was analysed longitudinally with logistic generalised estimating equations. Differences in treatment effect across RF, ACPA and SE subgroups were assessed with interaction terms at 24 and 48 weeks, adjusted for sex, country, age, body mass index, Disease Activity Score of 28 joints based on C-reactive protein and smoking.
Results: In total, 778 patients were included. At 24 weeks, abatacept treatment showed a better response than ACT in the RF and/or ACPA-positive subgroups, but this effect was not significantly different from the negative subgroups. By 48 weeks, abatacept treatment showed better response regardless of RF/ACPA status. No differences were found across RF, ACPA, SE allele, valine at amino acid position 11 or valine-arginine-alanine haplotype subgroups for any biological treatment at 48 weeks.
Conclusions: Based on this randomised controlled trial, abatacept treatment was associated with a better response than ACT in the RF and/or ACPA-positive subgroup at 24 weeks, but this was no longer seen at 48 weeks; adding SE allele-related genetic markers did not strengthen the association. Moreover, ACPA, RF and SE allele-related genotypes were not, alone or in combination, associated with clinical responses of importance sufficiently strongly to warrant implementation in clinical practice.
{"title":"Association of rheumatoid factor, anti-citrullinated protein antibodies and shared epitope with clinical response to initial treatment in patients with early rheumatoid arthritis: data from a randomised controlled trial.","authors":"Kristina Lend, Jon Lampa, Leonid Padyukov, Merete Lund Hetland, Marte Schrumpf Heiberg, Dan C Nordström, Michael T Nurmohamed, Anna Rudin, Mikkel Østergaard, Espen A Haavardsholm, Kim Hørslev-Petersen, Till Uhlig, Tuulikki Sokka-Isler, Bjorn Gudbjornsson, Gerdur Grondal, Giulia Frazzei, Jeroen Christiaans, Gertjan Wolbink, Theo Rispens, Jos W R Twisk, Ronald F van Vollenhoven","doi":"10.1136/ard-2024-226024","DOIUrl":"https://doi.org/10.1136/ard-2024-226024","url":null,"abstract":"<p><strong>Objectives: </strong>To investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional treatment (ACT).</p><p><strong>Methods: </strong>Patients with treatment-naïve early rheumatoid arthritis were randomised in the NORD-STAR trial to ACT, certolizumab pegol, abatacept or tocilizumab, all with methotrexate. Centralised laboratory analyses for ACPA, RF and SE were performed. Clinical Disease Activity Index remission was analysed longitudinally with logistic generalised estimating equations. Differences in treatment effect across RF, ACPA and SE subgroups were assessed with interaction terms at 24 and 48 weeks, adjusted for sex, country, age, body mass index, Disease Activity Score of 28 joints based on C-reactive protein and smoking.</p><p><strong>Results: </strong>In total, 778 patients were included. At 24 weeks, abatacept treatment showed a better response than ACT in the RF and/or ACPA-positive subgroups, but this effect was not significantly different from the negative subgroups. By 48 weeks, abatacept treatment showed better response regardless of RF/ACPA status. No differences were found across RF, ACPA, SE allele, valine at amino acid position 11 or valine-arginine-alanine haplotype subgroups for any biological treatment at 48 weeks.</p><p><strong>Conclusions: </strong>Based on this randomised controlled trial, abatacept treatment was associated with a better response than ACT in the RF and/or ACPA-positive subgroup at 24 weeks, but this was no longer seen at 48 weeks; adding SE allele-related genetic markers did not strengthen the association. Moreover, ACPA, RF and SE allele-related genotypes were not, alone or in combination, associated with clinical responses of importance sufficiently strongly to warrant implementation in clinical practice.</p><p><strong>Trial registration number: </strong>EudraCT 2011-004720-35; ClinicalTrials.gov NCT01491815.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854585","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}