Pub Date : 2024-12-19DOI: 10.1186/s13075-024-03450-2
Zijuan Fan, Wenzhu Song, Yan Ke, Ligan Jia, Songyan Li, Jiao Jiao Li, Yuqing Zhang, Jianhao Lin, Bin Wang
To use routine demographic and clinical data to develop an interpretable individual-level machine learning (ML) model to diagnose knee osteoarthritis (KOA) and to identify highly ranked features. In this retrospective, population-based cohort study, anonymized questionnaire data was retrieved from the Wu Chuan KOA Study, Inner Mongolia, China. After feature selections, participants were divided in a 7:3 ratio into training and test sets. Class balancing was applied to the training set for data augmentation. Four ML classifiers were compared by cross-validation within the training set and their performance was further analyzed with an unseen test set. Classifications were evaluated using sensitivity, specificity, positive predictive value, negative predictive value, accuracy, area under the curve(AUC), G-means, and F1 scores. The best model was explained using Shapley values to extract highly ranked features. A total of 1188 participants were investigated in this study, among whom 26.3% were diagnosed with KOA. Comparatively, XGBoost with Boruta exhibited the highest classification performance among the four models, with an AUC of 0.758, G-means of 0.800, and F1 scores of 0.703. The SHAP method reveals the top 17 features of KOA according to the importance ranking, and the average of the experience of joint pain was recognized as the most important features. Our study highlights the usefulness of machine learning in unveiling important factors that influence the diagnosis of KOA to guide new prevention strategies. Further work is needed to validate this approach.
{"title":"XGBoost-SHAP-based interpretable diagnostic framework for knee osteoarthritis: a population-based retrospective cohort study","authors":"Zijuan Fan, Wenzhu Song, Yan Ke, Ligan Jia, Songyan Li, Jiao Jiao Li, Yuqing Zhang, Jianhao Lin, Bin Wang","doi":"10.1186/s13075-024-03450-2","DOIUrl":"https://doi.org/10.1186/s13075-024-03450-2","url":null,"abstract":"To use routine demographic and clinical data to develop an interpretable individual-level machine learning (ML) model to diagnose knee osteoarthritis (KOA) and to identify highly ranked features. In this retrospective, population-based cohort study, anonymized questionnaire data was retrieved from the Wu Chuan KOA Study, Inner Mongolia, China. After feature selections, participants were divided in a 7:3 ratio into training and test sets. Class balancing was applied to the training set for data augmentation. Four ML classifiers were compared by cross-validation within the training set and their performance was further analyzed with an unseen test set. Classifications were evaluated using sensitivity, specificity, positive predictive value, negative predictive value, accuracy, area under the curve(AUC), G-means, and F1 scores. The best model was explained using Shapley values to extract highly ranked features. A total of 1188 participants were investigated in this study, among whom 26.3% were diagnosed with KOA. Comparatively, XGBoost with Boruta exhibited the highest classification performance among the four models, with an AUC of 0.758, G-means of 0.800, and F1 scores of 0.703. The SHAP method reveals the top 17 features of KOA according to the importance ranking, and the average of the experience of joint pain was recognized as the most important features. Our study highlights the usefulness of machine learning in unveiling important factors that influence the diagnosis of KOA to guide new prevention strategies. Further work is needed to validate this approach.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"77 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-18DOI: 10.1186/s13075-024-03424-4
Gilson Goncalves dos Santos, Juan Miguel Jiménez-Andrade, Enriqueta Muñoz-Islas, Mariana E. Candanedo-Quiroz, Andrea Gonzalez Cardenas, Bronwen Drummond, Peter Pham, Gwendalynn Stilson, Chao-Chin Hsu, Lauriane Delay, Juliana M. Navia-Pelaez, Julia Paes Lemes, Yury I. Miller, Tony L. Yaksh, Maripat Corr
In the murine K/BxN serum transfer rheumatoid arthritis (RA) model, tactile allodynia persists after resolution of inflammation in male and partially in female wild type (WT) mice, which is absent in Toll-like receptor (TLR)4 deficient animals. We assessed the role of TLR4 on allodynia, bone remodeling and afferent sprouting in this model of arthritis. K/BxN sera were injected into male and female mice with conditional or stable TLR4 deletion and controls. Paw swelling was scored and allodynia assessed by von Frey filaments. At day 28, synovial neural fibers were visualized with confocal microscopy and bone density assayed with microCT. Microglial activity and TLR4 dimerization in spinal cords were examined by immunofluorescence and flow cytometry. In the synovium, K/BxN injected WT male and female mice showed robust increases in calcitonin gene related-peptide (CGRP+), tyrosine hydroxylase (TH)+ and GAP43+ nerve fibers. Trabecular bone density by microCT was significantly decreased in K/BxN WT female but not in WT male mice. The number of osteoclasts increased in both sexes of WT mice, but not in Tlr4-/- K/BxN mice. We used conditional strains with Cre drivers for monocytes/osteoclasts (lysozyme M), microglia (Tmem119 and Cx3CR1), astrocytes (GFAP) and sensory neurons (advillin) for Tlr4f/f disruption. All strains developed similar arthritis scores after K/BxN serum injection with the exception being the Tlr4Tmem119 mice which showed a reduction. Both sexes of Tlr4Lyz2, Tlr4Tmem119 and Tlr4Cx3cr1 mice displayed a partial reversal of the chronic pain phenotype but not in Tlr4Avil, and Tlr4Gfap mice. WT K/BxN male mice showed increases in spinal Iba1, but not GFAP, compared to Tlr4-/- male mice. To determine whether spinal TLR4 was indeed activated in the K/BxN mice, flow cytometry of lumbar spinal cords of WT K/BxN male mice was performed and revealed that TLR4 in microglia cells (CD11b+ /TMEM119+) demonstrated dimerization (e.g. activation) and a characteristic increase in lipid rafts. These results demonstrated a complex chronic allodynia phenotype associated with TLR4 in microglia and monocytic cell lineages, and a parallel spinal TLR4 activation. However, TLR4 is dispensable for the development of peripheral nerve sprouting in this model.
{"title":"Role of TLR4 activation and signaling in bone remodeling, and afferent sprouting in serum transfer arthritis","authors":"Gilson Goncalves dos Santos, Juan Miguel Jiménez-Andrade, Enriqueta Muñoz-Islas, Mariana E. Candanedo-Quiroz, Andrea Gonzalez Cardenas, Bronwen Drummond, Peter Pham, Gwendalynn Stilson, Chao-Chin Hsu, Lauriane Delay, Juliana M. Navia-Pelaez, Julia Paes Lemes, Yury I. Miller, Tony L. Yaksh, Maripat Corr","doi":"10.1186/s13075-024-03424-4","DOIUrl":"https://doi.org/10.1186/s13075-024-03424-4","url":null,"abstract":"In the murine K/BxN serum transfer rheumatoid arthritis (RA) model, tactile allodynia persists after resolution of inflammation in male and partially in female wild type (WT) mice, which is absent in Toll-like receptor (TLR)4 deficient animals. We assessed the role of TLR4 on allodynia, bone remodeling and afferent sprouting in this model of arthritis. K/BxN sera were injected into male and female mice with conditional or stable TLR4 deletion and controls. Paw swelling was scored and allodynia assessed by von Frey filaments. At day 28, synovial neural fibers were visualized with confocal microscopy and bone density assayed with microCT. Microglial activity and TLR4 dimerization in spinal cords were examined by immunofluorescence and flow cytometry. In the synovium, K/BxN injected WT male and female mice showed robust increases in calcitonin gene related-peptide (CGRP+), tyrosine hydroxylase (TH)+ and GAP43+ nerve fibers. Trabecular bone density by microCT was significantly decreased in K/BxN WT female but not in WT male mice. The number of osteoclasts increased in both sexes of WT mice, but not in Tlr4-/- K/BxN mice. We used conditional strains with Cre drivers for monocytes/osteoclasts (lysozyme M), microglia (Tmem119 and Cx3CR1), astrocytes (GFAP) and sensory neurons (advillin) for Tlr4f/f disruption. All strains developed similar arthritis scores after K/BxN serum injection with the exception being the Tlr4Tmem119 mice which showed a reduction. Both sexes of Tlr4Lyz2, Tlr4Tmem119 and Tlr4Cx3cr1 mice displayed a partial reversal of the chronic pain phenotype but not in Tlr4Avil, and Tlr4Gfap mice. WT K/BxN male mice showed increases in spinal Iba1, but not GFAP, compared to Tlr4-/- male mice. To determine whether spinal TLR4 was indeed activated in the K/BxN mice, flow cytometry of lumbar spinal cords of WT K/BxN male mice was performed and revealed that TLR4 in microglia cells (CD11b+ /TMEM119+) demonstrated dimerization (e.g. activation) and a characteristic increase in lipid rafts. These results demonstrated a complex chronic allodynia phenotype associated with TLR4 in microglia and monocytic cell lineages, and a parallel spinal TLR4 activation. However, TLR4 is dispensable for the development of peripheral nerve sprouting in this model.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"23 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142840776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-13DOI: 10.1186/s13075-024-03451-1
Maren Claus, Merle Freitag, Meike Ewald, Lea Rodon, Franca Deicher, Carsten Watzl, Philipp Kolb, Hanns-Martin Lorenz, Michael Schmitt, Wolfgang Merkt
The high potential of CD19.CAR-T cells to treat autoimmune diseases such as Systemic Sclerosis (SSc) supposedly relies on the disappearance of autoantibodies. Here we investigated effects of CAR-T cells on the innate immune system which is an important contributor to pathology in SSc. Longitudinal analysis of peripheral blood mononuclear cells from an Scl70 + SSc patient treated with CAR-T cells sampled over 18 months by 29-color spectral flow cytometry, in vitro experiments using sera from patient cohorts. In the patient treated with CAR-T cells, the substantial clinical improvement was paralleled by dynamic changes in innate lymphoid cells, namely Fcγ-receptor IIIA-expressing natural killer (NK) cells. NK cells adopted a more juvenile, less activated, and less differentiated phenotype. In parallel, the potency of serum to form Scl70-containing immune complexes that activate Fcγ-receptor IIIA decreased over time. These observations suggested a mechanistic link between reversal of adaptive autoimmunity and recovering Fcγ-receptor IIIA-expressing innate immune cells after CAR-T cell therapy via regressing immune complex activity. Experiments with sera from the non-CAR-T-treated SSc cohort confirmed that Scl70-containing immune complexes activate Fcγ-receptor IIIA-expressing NK cells in a dose-dependent manner, substantiating the relevance of this link between adaptive and innate immunity in SSc. This report describes for the first time the phenotypic recovery of innate Fcγ-receptor-expressing cells in an SSc patient treated with CAR-T cells. Decreasing autoantibody levels associated with a reduced ability to form functional immune complexes, the latter appearing to contribute to pathology in SSc via activation of Fcγ receptor IIIA + cells such as NK cells. Proposed mechanism of involvement of NK cells and soluble Immune Complexes (sICs) in disease progression during active autoimmunity in SSc (left) and resolution of fibrosis after deep B cell depletion by CD19.CAR-T cells and disappearance of autoantibodies (right).
{"title":"Immunological effects of CD19.CAR-T cell therapy in systemic sclerosis: an extended case study","authors":"Maren Claus, Merle Freitag, Meike Ewald, Lea Rodon, Franca Deicher, Carsten Watzl, Philipp Kolb, Hanns-Martin Lorenz, Michael Schmitt, Wolfgang Merkt","doi":"10.1186/s13075-024-03451-1","DOIUrl":"https://doi.org/10.1186/s13075-024-03451-1","url":null,"abstract":"The high potential of CD19.CAR-T cells to treat autoimmune diseases such as Systemic Sclerosis (SSc) supposedly relies on the disappearance of autoantibodies. Here we investigated effects of CAR-T cells on the innate immune system which is an important contributor to pathology in SSc. Longitudinal analysis of peripheral blood mononuclear cells from an Scl70 + SSc patient treated with CAR-T cells sampled over 18 months by 29-color spectral flow cytometry, in vitro experiments using sera from patient cohorts. In the patient treated with CAR-T cells, the substantial clinical improvement was paralleled by dynamic changes in innate lymphoid cells, namely Fcγ-receptor IIIA-expressing natural killer (NK) cells. NK cells adopted a more juvenile, less activated, and less differentiated phenotype. In parallel, the potency of serum to form Scl70-containing immune complexes that activate Fcγ-receptor IIIA decreased over time. These observations suggested a mechanistic link between reversal of adaptive autoimmunity and recovering Fcγ-receptor IIIA-expressing innate immune cells after CAR-T cell therapy via regressing immune complex activity. Experiments with sera from the non-CAR-T-treated SSc cohort confirmed that Scl70-containing immune complexes activate Fcγ-receptor IIIA-expressing NK cells in a dose-dependent manner, substantiating the relevance of this link between adaptive and innate immunity in SSc. This report describes for the first time the phenotypic recovery of innate Fcγ-receptor-expressing cells in an SSc patient treated with CAR-T cells. Decreasing autoantibody levels associated with a reduced ability to form functional immune complexes, the latter appearing to contribute to pathology in SSc via activation of Fcγ receptor IIIA + cells such as NK cells. Proposed mechanism of involvement of NK cells and soluble Immune Complexes (sICs) in disease progression during active autoimmunity in SSc (left) and resolution of fibrosis after deep B cell depletion by CD19.CAR-T cells and disappearance of autoantibodies (right).","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"24 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-11DOI: 10.1186/s13075-024-03444-0
Michael Gernert, Tobias Müller, Lukas Schweiker, Marc Schmalzing, Matthias Fröhlich, Lea-Kristin Nagler, Patrick-Pascal Strunz, Hannah Labinsky, Eva Christina Schwaneck
Clonal T cell populations are frequently detected in patients with rheumatic diseases. The relevance of this finding is often uncertain, as the clinical spectrum can range from being asymptomatic to T cell leukemia. Former studies suggested that certain anti-rheumatic drugs might influence the course of the clonal T cell populations. A prospective long-term follow up study was performed including patients with rheumatic diseases and clonal T cell populations. Clinical features, adverse events, especially infections and cytopenias, and immunosuppressive medication were assessed. T cell populations were characterized by polymerase chain reaction, flow cytometry and stimulated cell cultures. 28 Patients with rheumatoid arthritis, spondyloarthritis, or giant cell arteritis were prospectively followed for up to 7.6 years. Severe infections or cytopenias (10.7% autoimmune neutropenias) were rare. The clonal T cell populations mostly persisted over time, the tumor burden decreased in the long-term. The cytokine secretion in stimulated T cell cultures did not differ in the subgroup of RA patients with versus without clonal T cells. Clonal T cell populations in patients with rheumatic diseases are common, but are rarely harmful. Feared neutropenia, infections or progression into T cell leukemia could not be detected in the long-term in our cohort.
{"title":"Clonal T cell populations scarcely impair patients with rheumatic diseases: a prospective long-term follow up study","authors":"Michael Gernert, Tobias Müller, Lukas Schweiker, Marc Schmalzing, Matthias Fröhlich, Lea-Kristin Nagler, Patrick-Pascal Strunz, Hannah Labinsky, Eva Christina Schwaneck","doi":"10.1186/s13075-024-03444-0","DOIUrl":"https://doi.org/10.1186/s13075-024-03444-0","url":null,"abstract":"Clonal T cell populations are frequently detected in patients with rheumatic diseases. The relevance of this finding is often uncertain, as the clinical spectrum can range from being asymptomatic to T cell leukemia. Former studies suggested that certain anti-rheumatic drugs might influence the course of the clonal T cell populations. A prospective long-term follow up study was performed including patients with rheumatic diseases and clonal T cell populations. Clinical features, adverse events, especially infections and cytopenias, and immunosuppressive medication were assessed. T cell populations were characterized by polymerase chain reaction, flow cytometry and stimulated cell cultures. 28 Patients with rheumatoid arthritis, spondyloarthritis, or giant cell arteritis were prospectively followed for up to 7.6 years. Severe infections or cytopenias (10.7% autoimmune neutropenias) were rare. The clonal T cell populations mostly persisted over time, the tumor burden decreased in the long-term. The cytokine secretion in stimulated T cell cultures did not differ in the subgroup of RA patients with versus without clonal T cells. Clonal T cell populations in patients with rheumatic diseases are common, but are rarely harmful. Feared neutropenia, infections or progression into T cell leukemia could not be detected in the long-term in our cohort.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"19 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-05DOI: 10.1186/s13075-024-03449-9
Ronja Ramien, Tatjana Rudi, Rieke Alten, Andreas Krause, Matthias Schneider, Martin Schaefer, Anja Strangfeld, Yvette Meissner
To investigate the association between the development of incident interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and the disease activity of RA with its various components, especially C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). We analysed data from RA patients, observed in the German biologics register RABBIT between 2001 and 2021. In a nested case-control study, patients with a reported incident ILD diagnosis during follow-up were matched 1:5 to patients without ILD. Matching criteria were sex, age, RA duration, date of enrolment and observation time. Defined by a directed acyclic graph (DAG), we adjusted the conditional logistic regression models for rheumatoid factor, smoking, chronic obstructive pulmonary disease and tuberculosis/chronic viral infections to investigate the impact of disease activity/systemic inflammation. Mean and categorized values were analysed within 12 months prior to ILD and during the entire observation time. Additionally, two sensitivity analyses were performed, using validated ILD cases only and considering ILD cases with an observation time of more than 12 months. We identified 139 RA patients with incident ILD and matched them to 686 controls. In 94 cases the diagnosis could be validated, and 98 cases had a follow-up of > 12 months. The averaged DAS28 composite score (including ESR or CRP) was not associated with developing RA-ILD (odds ratios 1.16 [95% confidence interval: 0.97–1.40] and 1.06 [0.86–1.29], respectively). However, single measures of inflammation, log ESR (1.86 [1.35–2.57]) and log CRP (1.55 [1.21–1.97]), were significantly associated with an increased RA-ILD risk. A higher risk for ILD was also revealed for persistently high inflammation. Other DAS28 components showed no significant associations with RA-ILD. These results were consistent for values over the entire observation time of a patient and within 12 months prior to the ILD. Sensitivity analyses confirmed these findings. Higher levels of systemic inflammation, as indicated by ESR and CRP, but not joint counts or patient’s global assessment, were significantly associated with the occurrence of incident ILD in patients with RA. As possible predictor for the development of RA-ILD, systemic inflammation should be monitored closely and independently of joint count results.
{"title":"Impact of systemic inflammation and disease activity on the incidence of interstitial lung disease in patients with rheumatoid arthritis – a nested case-control study within the German biologics register RABBIT","authors":"Ronja Ramien, Tatjana Rudi, Rieke Alten, Andreas Krause, Matthias Schneider, Martin Schaefer, Anja Strangfeld, Yvette Meissner","doi":"10.1186/s13075-024-03449-9","DOIUrl":"https://doi.org/10.1186/s13075-024-03449-9","url":null,"abstract":"To investigate the association between the development of incident interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and the disease activity of RA with its various components, especially C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). We analysed data from RA patients, observed in the German biologics register RABBIT between 2001 and 2021. In a nested case-control study, patients with a reported incident ILD diagnosis during follow-up were matched 1:5 to patients without ILD. Matching criteria were sex, age, RA duration, date of enrolment and observation time. Defined by a directed acyclic graph (DAG), we adjusted the conditional logistic regression models for rheumatoid factor, smoking, chronic obstructive pulmonary disease and tuberculosis/chronic viral infections to investigate the impact of disease activity/systemic inflammation. Mean and categorized values were analysed within 12 months prior to ILD and during the entire observation time. Additionally, two sensitivity analyses were performed, using validated ILD cases only and considering ILD cases with an observation time of more than 12 months. We identified 139 RA patients with incident ILD and matched them to 686 controls. In 94 cases the diagnosis could be validated, and 98 cases had a follow-up of > 12 months. The averaged DAS28 composite score (including ESR or CRP) was not associated with developing RA-ILD (odds ratios 1.16 [95% confidence interval: 0.97–1.40] and 1.06 [0.86–1.29], respectively). However, single measures of inflammation, log ESR (1.86 [1.35–2.57]) and log CRP (1.55 [1.21–1.97]), were significantly associated with an increased RA-ILD risk. A higher risk for ILD was also revealed for persistently high inflammation. Other DAS28 components showed no significant associations with RA-ILD. These results were consistent for values over the entire observation time of a patient and within 12 months prior to the ILD. Sensitivity analyses confirmed these findings. Higher levels of systemic inflammation, as indicated by ESR and CRP, but not joint counts or patient’s global assessment, were significantly associated with the occurrence of incident ILD in patients with RA. As possible predictor for the development of RA-ILD, systemic inflammation should be monitored closely and independently of joint count results.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"1 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-03DOI: 10.1186/s13075-024-03443-1
Paloma Palm von Alten Blaskowitz, Anna-Maria Liphardt, Claudia Bouzas, Birte Coppers, Pascal Petit, Nicolas Vuillerme, Vanessa Bundle, Sebastian Rudolf, Johannes Knitza, Maria Gabriella Raimondo, Hannah Labinsky, Lukas Hatscher, Andreas Wirsching, Daniela Bohr, Elizabeth Araujo, Andreas Ramming, Alina Ramming, Georg Schett, Harriet Morf
Spondyloarthritides (SpAs) are a group of common rheumatic diseases that often cause limited mobility and lower back pain. Physiotherapy is an integral part of treatment, but access to physiotherapy limits treatment success. Digital health applications (DHAs) enable home-based physiotherapy and could significantly improve access for SpAs patients. The aim is to investigate the clinical effects of the DHA ViViRA compared with those of standard physiotherapy. SpAs patients with chronic back pain were enrolled in a randomized controlled trial. The intervention group received ViViRA DHA, whereas the control group received standard physiotherapy. Pain (verbal rating scale, PAIN-Detect), quality of life (SF-36) and mobility (BASMI) were assessed at baseline and after 12 weeks as the primary outcomes. Data from 59 participants (71.2% female, mean age 45.2 years) were analyzed. The intervention group showed a significant improvement in mobility (average BASMI score: baseline: 1.1 [range 0.7–1.5]; follow-up: 1.0 [range 0.5–1.4]; p = 0.05), whereas the control group showed a significant decrease in mobility (baseline: 1.5 [range 1.1–1.9]; follow-up: 1.8 [range 1.4–2.2]; p = 0.00). The intervention group demonstrated lower pain intensity (VRS pain level at week 3.5 ± 2.8) than did the control group (VRS pain level at week 4.5 ± 2) after 12 weeks. Our results highlight the efficacy of DHAs such as ViViRA in the treatment of lower back pain in SpAs patients. Compared with the current gold standard, physiotherapy, DHA use results in superior outcomes. However, further larger studies are needed to confirm these promising results. The study is registered in the German clinical trial registry (DRKS) under the following ID: DRKS00031254.
{"title":"Impact of the digital health application ViViRA on spinal mobility, physical function, quality of life and pain perception in spondyloarthritides patients: a randomized controlled trial","authors":"Paloma Palm von Alten Blaskowitz, Anna-Maria Liphardt, Claudia Bouzas, Birte Coppers, Pascal Petit, Nicolas Vuillerme, Vanessa Bundle, Sebastian Rudolf, Johannes Knitza, Maria Gabriella Raimondo, Hannah Labinsky, Lukas Hatscher, Andreas Wirsching, Daniela Bohr, Elizabeth Araujo, Andreas Ramming, Alina Ramming, Georg Schett, Harriet Morf","doi":"10.1186/s13075-024-03443-1","DOIUrl":"https://doi.org/10.1186/s13075-024-03443-1","url":null,"abstract":"Spondyloarthritides (SpAs) are a group of common rheumatic diseases that often cause limited mobility and lower back pain. Physiotherapy is an integral part of treatment, but access to physiotherapy limits treatment success. Digital health applications (DHAs) enable home-based physiotherapy and could significantly improve access for SpAs patients. The aim is to investigate the clinical effects of the DHA ViViRA compared with those of standard physiotherapy. SpAs patients with chronic back pain were enrolled in a randomized controlled trial. The intervention group received ViViRA DHA, whereas the control group received standard physiotherapy. Pain (verbal rating scale, PAIN-Detect), quality of life (SF-36) and mobility (BASMI) were assessed at baseline and after 12 weeks as the primary outcomes. Data from 59 participants (71.2% female, mean age 45.2 years) were analyzed. The intervention group showed a significant improvement in mobility (average BASMI score: baseline: 1.1 [range 0.7–1.5]; follow-up: 1.0 [range 0.5–1.4]; p = 0.05), whereas the control group showed a significant decrease in mobility (baseline: 1.5 [range 1.1–1.9]; follow-up: 1.8 [range 1.4–2.2]; p = 0.00). The intervention group demonstrated lower pain intensity (VRS pain level at week 3.5 ± 2.8) than did the control group (VRS pain level at week 4.5 ± 2) after 12 weeks. Our results highlight the efficacy of DHAs such as ViViRA in the treatment of lower back pain in SpAs patients. Compared with the current gold standard, physiotherapy, DHA use results in superior outcomes. However, further larger studies are needed to confirm these promising results. The study is registered in the German clinical trial registry (DRKS) under the following ID: DRKS00031254.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"136 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-02DOI: 10.1186/s13075-024-03446-y
Antonella Notarnicola, Charlotta Preger, Susanna L. Lundström, Nuria Renard, Edvard Wigren, Eveline Van Gompel, Angeles S. Galindo-Feria, Helena Persson, Maryam Fathi, Johan Grunewald, Per-Johan Jakobsson, Susanne Gräslund, Ingrid E. Lundberg, Cátia Fernandes-Cerqueira
<p><b>Correction</b><b>: </b><b>Arthritis Res Ther 24, 62 (2022)</b></p><p><b>https://doi.org/10.1186/s13075-022-02745-6</b></p><br/><p>Following publication of the original article [1], we have recently received a comment by PubPeer that has found a mistake in our Figure 1 D. The western blot image uploaded for patient P16 was by mistake the same as for patient P15. It was only when putting together the image that the error occurred and all calculations, results and conclusions are thus unchanged. We have now updated figure 1 in the publication with the correct image.</p><p>Incorrect figure 1.</p><figure><picture><source srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13075-024-03446-y/MediaObjects/13075_2024_3446_Figa_HTML.png?as=webp" type="image/webp"/><img alt="figure a" aria-describedby="Figa" height="740" loading="lazy" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13075-024-03446-y/MediaObjects/13075_2024_3446_Figa_HTML.png" width="685"/></picture></figure><p>Correct figure 1.</p><figure><picture><source srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13075-024-03446-y/MediaObjects/13075_2024_3446_Figb_HTML.png?as=webp" type="image/webp"/><img alt="figure b" aria-describedby="Figb" height="738" loading="lazy" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13075-024-03446-y/MediaObjects/13075_2024_3446_Figb_HTML.png" width="685"/></picture></figure><ol data-track-component="outbound reference" data-track-context="references section"><li data-counter="1."><p>Notarnicola A, Preger C, Lundström SL, et al. Longitudinal assessment of reactivity and affinity profile of anti-Jo1 autoantibodies to distinct HisRS domains and a splice variant in a cohort of patients with myositis and anti-synthetase syndrome. Arthritis Res Ther. 2022;24:62. https://doi.org/10.1186/s13075-022-02745-6.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-download-medium" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></p><span>Author notes</span><ol><li><p>Antonella Notarnicola, Charlotta Preger, Ingrid E. Lundberg and Cátia Fernandes-Cerqueira contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, 171 64, Solna, Stockholm, Sweden</p><p>Antonella Notarnicola, Charlotta Preger, Nuria Renard, Edvard Wigren, Eveline Van Gompel, Angeles S. Galindo-Feria, Per-Johan Jakobsson, Susanne Gräslund, Ingrid E. Lundberg & Cátia Fernandes-Cerqueira</p></li><li><p>Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden</p><p>Antonella Notarnicola, Charlotta Preger, Nuria Renard, Edvard Wigren, Eveline Van Gompel, Angeles S. Galindo-Feria, Johan Grunewald
更正：Arthritis Res Ther 24,62 (2022)https://doi.org/10.1186/s13075-022-02745-6Following原文b[1]发表后，我们最近收到PubPeer的评论，发现我们的图1 d中存在错误。患者P16上传的western blot图像与患者P15错误相同。只有在将图像组合在一起时才会出现错误，因此所有的计算、结果和结论都不会改变。我们现在用正确的图像更新了出版物中的图1。错误的图1。正确的图1。notannicola A, Preger C, Lundström SL，等。在肌炎和抗合成酶综合征患者队列中，抗jo1自身抗体对不同HisRS结构域和剪接变异体的反应性和亲和力的纵向评估关节炎杂志，2022;24:62。https://doi.org/10.1186/s13075-022-02745-6.Article CAS PubMed PubMed Central谷歌学者下载参考作者说明antonella Notarnicola， Charlotta Preger, Ingrid E. Lundberg和Cátia Fernandes-Cerqueira对这项工作也做出了同样的贡献。作者与单位：卡罗林斯卡医学院附属卡罗林斯卡大学医院内科风湿病科，1764年，斯德哥尔摩索尔纳，瑞典antonella Notarnicola， Charlotta Preger, Nuria Renard, edward Wigren, Eveline Van Gompel, Angeles S. Galindo-Feria, Per-Johan Jakobsson, Susanne Gräslund, Ingrid E. Lundberg &；Cátia瑞典斯德哥尔摩卡罗林斯卡医学院分子医学中心antonella Notarnicola， Charlotta Preger, Nuria Renard, edward Wigren, Eveline Van Gompel, Angeles S. Galindo-Feria, Johan Grunewald, Per-Johan Jakobsson, Susanne Gräslund, Ingrid E. Lundberg &；Cátia fernandes - cerqueira结构基因组学联盟，多伦多，加拿大Susanne GräslundDivision，卡罗林斯卡医学院医学生物化学与生物物理系，Solnavägen 9, 171 77，瑞典斯德哥尔摩；susanna L. LundströmLaboratory，组织同源性-疾病，骨骼生物学与工程研究中心，比利时鲁汶，鲁汶；meveline Van gompell生命科学实验室，药物发现与开发，瑞典斯德哥尔摩；helena persson化学、生物技术与健康工程科学学院；瑞典斯德哥尔摩皇家理工学院（KTH）呼吸医学和过敏科，J7:30，瑞典斯德哥尔摩卡罗林斯卡医学院附属卡罗林斯卡大学医院生物临床部，SE-171 76Johan grunewald4 cell, 14 Rue de La Beaune, 93100，蒙特勒伊FranceCatia Fernandes-CerqueiraAuthorsAntonella NotarnicolaView publicationsYou作者也可以搜索PubMed的作者在谷歌ScholarCharlotta PregerView publicationsYou作者也可以搜索PubMed的作者在谷歌ScholarSusanna l . LundstromView publicationsYou作者也可以搜索PubMed的作者在谷歌ScholarNuria RenardView publicationsYou作者也可以搜索PubMed的作者在谷歌ScholarEdvard WigrenView publicationsYou作者也可以搜索在PubMed谷歌ScholarEveline Van GompelView作者出版物您也可以在PubMed谷歌ScholarAngeles S. galindoferiview作者出版物中搜索此作者您也可以在PubMed谷歌ScholarHelena personsonview作者出版物中搜索此作者您也可以在PubMed谷歌ScholarMaryam FathiView作者出版物中搜索此作者您也可以在PubMed谷歌ScholarJohan GrunewaldView作者出版物中搜索此作者您也可以搜索PubMed的作者在谷歌ScholarPer-Johan JakobssonView publicationsYou作者也可以搜索PubMed的作者在谷歌ScholarSusanne GraslundView publicationsYou作者也可以搜索PubMed的作者在谷歌ScholarIngrid大肠LundbergView publicationsYou作者也可以搜索PubMed的作者在谷歌ScholarCatia Fernandes-CerqueiraView publicationsYou作者也可以搜索PubMed的作者在谷歌ScholarCorresponding authorCorrespondence安东内拉·Notarnicola·拉斯泰利。开放获取本文遵循知识共享署名4.0国际许可协议，该协议允许以任何媒介或格式使用、共享、改编、分发和复制，只要您适当地注明原作者和来源，提供知识共享许可协议的链接，并注明是否进行了更改。本文中的图像或其他第三方材料包含在文章的知识共享许可协议中，除非在材料的署名中另有说明。如果材料未包含在文章的知识共享许可中，并且您的预期用途不被法律法规允许或超过允许的用途，您将需要直接获得版权所有者的许可。要查看本许可的副本，请访问http://creativecommons.org/licenses/by/4.0/。 知识共享公共领域免责条款（http://creativecommons.org/publicdomain/zero/1.0/）适用于本文中提供的数据，除非在数据的署名中另有说明。转载和许可引用本文：otarnicola， A., Preger， C., Lundström， S.L.等。更正：在肌炎和抗合成酶综合征患者队列中，对抗jo1自身抗体对不同HisRS结构域和剪接变异体的反应性和亲和力进行纵向评估。关节炎杂志26,206（2024）。https://doi.org/10.1186/s13075-024-03446-yDownload citationpublishing: 02 December 2024DOI: https://doi.org/10.1186/s13075-024-03446-yShare这篇文章任何你分享以下链接的人都可以阅读到这篇文章：获取可共享链接对不起，这篇文章目前没有可共享的链接。复制到剪贴板由施普林格自然共享内容倡议提供
{"title":"Correction: Longitudinal assessment of reactivity and affinity profile of anti-Jo1 autoantibodies to distinct HisRS domains and a splice variant in a cohort of patients with myositis and anti-synthetase syndrome","authors":"Antonella Notarnicola, Charlotta Preger, Susanna L. Lundström, Nuria Renard, Edvard Wigren, Eveline Van Gompel, Angeles S. Galindo-Feria, Helena Persson, Maryam Fathi, Johan Grunewald, Per-Johan Jakobsson, Susanne Gräslund, Ingrid E. Lundberg, Cátia Fernandes-Cerqueira","doi":"10.1186/s13075-024-03446-y","DOIUrl":"https://doi.org/10.1186/s13075-024-03446-y","url":null,"abstract":"<p><b>Correction</b><b>: </b><b>Arthritis Res Ther 24, 62 (2022)</b></p><p><b>https://doi.org/10.1186/s13075-022-02745-6</b></p><br/><p>Following publication of the original article [1], we have recently received a comment by PubPeer that has found a mistake in our Figure 1 D. The western blot image uploaded for patient P16 was by mistake the same as for patient P15. It was only when putting together the image that the error occurred and all calculations, results and conclusions are thus unchanged. We have now updated figure 1 in the publication with the correct image.</p><p>Incorrect figure 1.</p><figure><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13075-024-03446-y/MediaObjects/13075_2024_3446_Figa_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure a\" aria-describedby=\"Figa\" height=\"740\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13075-024-03446-y/MediaObjects/13075_2024_3446_Figa_HTML.png\" width=\"685\"/></picture></figure><p>Correct figure 1.</p><figure><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13075-024-03446-y/MediaObjects/13075_2024_3446_Figb_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure b\" aria-describedby=\"Figb\" height=\"738\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13075-024-03446-y/MediaObjects/13075_2024_3446_Figb_HTML.png\" width=\"685\"/></picture></figure><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Notarnicola A, Preger C, Lundström SL, et al. Longitudinal assessment of reactivity and affinity profile of anti-Jo1 autoantibodies to distinct HisRS domains and a splice variant in a cohort of patients with myositis and anti-synthetase syndrome. Arthritis Res Ther. 2022;24:62. https://doi.org/10.1186/s13075-022-02745-6.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><span>Author notes</span><ol><li><p>Antonella Notarnicola, Charlotta Preger, Ingrid E. Lundberg and Cátia Fernandes-Cerqueira contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, 171 64, Solna, Stockholm, Sweden</p><p>Antonella Notarnicola, Charlotta Preger, Nuria Renard, Edvard Wigren, Eveline Van Gompel, Angeles S. Galindo-Feria, Per-Johan Jakobsson, Susanne Gräslund, Ingrid E. Lundberg & Cátia Fernandes-Cerqueira</p></li><li><p>Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden</p><p>Antonella Notarnicola, Charlotta Preger, Nuria Renard, Edvard Wigren, Eveline Van Gompel, Angeles S. Galindo-Feria, Johan Grunewald","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"205 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study investigates the causal role of metabolites mediating immune cells in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) through a Mendelian randomization (MR) study. The two-sample and two-step MR methods were used for the current analysis: (1) causal effects of immune cells on RA and AS; (2) mediation effects of metabolites. Inverse variance weighted (IVW) is the main method to analyze causality, and MR results are verified by several sensitive analyses. This study first identified the immune cells and metabolites that are causally associated with RA and AS, respectively. Subsequent mediation analyses revealed that of the 61 metabolic factors that were causally associated with RA, 6 were identified as mediators of the relationship between immune cells and RA, including 4-cholesten-3-one levels (mediation ratio: 8.91%), N-lactoyl isoleucine levels (13%), 3- phosphoglycerate to glycerate ratio (12.9%, 2.31%, respectively), Gamma-glutamyl histidine levels (9.54%), and Citrulline to phosphate ratio (15.6%). Among the 52 metabolic factors that were causally associated with AS, 2 were identified as mediators of the relationship between immune cells and AS, including salicylate levels (10.4%) and Glucose to N-palmitoyl-sphingosine (d18:1 to 16:0) ratio (8.72%). These results performed well in sensitivity analysis. Genetic predictions show causal relationships between immune cells and autoimmune diseases, and that these causal relationships can be mediated by certain metabolites as mediators.
本研究通过孟德尔随机化（MR）研究，探讨代谢物介导免疫细胞在类风湿关节炎（RA）和强直性脊柱炎（AS）中的因果作用。目前的分析采用两样本两步MR方法：(1)免疫细胞对RA和AS的因果效应；(2)代谢物的中介作用。反方差加权（IVW）是分析因果关系的主要方法，MR结果通过几个敏感分析来验证。本研究首次确定了分别与RA和AS有因果关系的免疫细胞和代谢物。随后的中介分析显示，在61个与RA有因果关系的代谢因子中，有6个被确定为免疫细胞与RA之间关系的中介因子，包括4-胆甾醇-3- 1水平（中介比例为8.91%）、n-乳酰异亮氨酸水平（中介比例为13%）、3-磷酸甘油酸与甘油酸比率（中介比例分别为12.9%、2.31%）、γ -谷氨酰组氨酸水平（中介比例分别为9.54%）和瓜氨酸与磷酸盐比率（中介比例为15.6%）。在与AS有因果关系的52个代谢因子中，有2个被确定为免疫细胞与AS之间关系的介质，包括水杨酸水平（10.4%）和葡萄糖与n -棕榈酰鞘氨醇（d18:1 to 16:0）比（8.72%）。这些结果在敏感性分析中表现良好。遗传预测表明免疫细胞和自身免疫性疾病之间存在因果关系，这些因果关系可以通过某些代谢物作为介质来介导。
{"title":"Genetically predicted metabolite mediates the causal relationship between immune cells and autoimmune diseases","authors":"Jinpeng Wei, Jian Li, Tianyang Li, Tao Xu, Yingchi Zhang, Shuhan Yang, Hua Wu, Haihu Hao","doi":"10.1186/s13075-024-03445-z","DOIUrl":"https://doi.org/10.1186/s13075-024-03445-z","url":null,"abstract":"This study investigates the causal role of metabolites mediating immune cells in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) through a Mendelian randomization (MR) study. The two-sample and two-step MR methods were used for the current analysis: (1) causal effects of immune cells on RA and AS; (2) mediation effects of metabolites. Inverse variance weighted (IVW) is the main method to analyze causality, and MR results are verified by several sensitive analyses. This study first identified the immune cells and metabolites that are causally associated with RA and AS, respectively. Subsequent mediation analyses revealed that of the 61 metabolic factors that were causally associated with RA, 6 were identified as mediators of the relationship between immune cells and RA, including 4-cholesten-3-one levels (mediation ratio: 8.91%), N-lactoyl isoleucine levels (13%), 3- phosphoglycerate to glycerate ratio (12.9%, 2.31%, respectively), Gamma-glutamyl histidine levels (9.54%), and Citrulline to phosphate ratio (15.6%). Among the 52 metabolic factors that were causally associated with AS, 2 were identified as mediators of the relationship between immune cells and AS, including salicylate levels (10.4%) and Glucose to N-palmitoyl-sphingosine (d18:1 to 16:0) ratio (8.72%). These results performed well in sensitivity analysis. Genetic predictions show causal relationships between immune cells and autoimmune diseases, and that these causal relationships can be mediated by certain metabolites as mediators.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"16 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1186/s13075-024-03436-0
Orsolya I. Gaal, Megan Leask, Valentin Nica, Georgiana Cabău, Medeea Badii, Ioana Hotea, Dennis M de Graaf, Zhenhua Zhang, Yang Li, Cristina Pamfil, Simona Rednic, Tony R. Merriman, Tania O. Crișan, Leo A.B. Joosten
Gout is caused by the response of the innate immune system to monosodium urate (MSU) crystals. A recent gout GWAS identified a signal of genetic association at a locus encompassing IL1RN-IL1F10. Colocalisation analysis using Genotype Tissue Expression Database (GTEx) eQTL data showed that the signal overlaps with genetic control of IL1RN/IL1F10 gene expression. We assess the functional implications of IL1RN rs9973741, the lead gout-associated variant. We conducted functional validation of IL1RN rs9973741 in patients with gout and controls. The transcription level of IL1RN/IL1F10 was investigated in unstimulated or MSU-crystal co-stimulated PBMCs. Ex vivo functional assays were performed in PBMCs stimulated with C16 + MSU crystals or LPS for 24 h. Cytokine levels were assessed by ELISA. In unstimulated PBMCs, no association of IL1RN rs9973741 (gout risk allele G) to IL1RN expression was observed while IL-1F10 was hindered by low expression at both transcriptional and protein levels. However, G allele carriers showed lower IL1RN expression in PBMCs stimulated with C16/MSU crystal and lower concentrations of circulating IL-1Ra in both controls and gout patients. PBMCs depicted less spontaneous IL-1Ra release in GG homozygous controls and lower IL-1Ra production in response to C16 + MSU crystal costimulation in patients with gout. The G allele was associated with elevated IL-1β cytokine production in response to C16 + MSU crystal stimulation in controls. The gout risk allele G associates with lower circulating IL-1Ra, lower IL-1Ra production in PBMC assays and elevated IL-1β production in PBMCs challenged with C16 + MSU crystals but not in unchallenged cells. Our data indicate that the genetic signal that associates with gout at IL1RN-IL1F10 region functions to alter expression of IL-1Ra when stimulated by MSU crystals.
{"title":"Gout-associated SNP at the IL1RN-IL1F10 region is associated with altered cytokine production in PBMCs of patients with gout and controls","authors":"Orsolya I. Gaal, Megan Leask, Valentin Nica, Georgiana Cabău, Medeea Badii, Ioana Hotea, Dennis M de Graaf, Zhenhua Zhang, Yang Li, Cristina Pamfil, Simona Rednic, Tony R. Merriman, Tania O. Crișan, Leo A.B. Joosten","doi":"10.1186/s13075-024-03436-0","DOIUrl":"https://doi.org/10.1186/s13075-024-03436-0","url":null,"abstract":"Gout is caused by the response of the innate immune system to monosodium urate (MSU) crystals. A recent gout GWAS identified a signal of genetic association at a locus encompassing IL1RN-IL1F10. Colocalisation analysis using Genotype Tissue Expression Database (GTEx) eQTL data showed that the signal overlaps with genetic control of IL1RN/IL1F10 gene expression. We assess the functional implications of IL1RN rs9973741, the lead gout-associated variant. We conducted functional validation of IL1RN rs9973741 in patients with gout and controls. The transcription level of IL1RN/IL1F10 was investigated in unstimulated or MSU-crystal co-stimulated PBMCs. Ex vivo functional assays were performed in PBMCs stimulated with C16 + MSU crystals or LPS for 24 h. Cytokine levels were assessed by ELISA. In unstimulated PBMCs, no association of IL1RN rs9973741 (gout risk allele G) to IL1RN expression was observed while IL-1F10 was hindered by low expression at both transcriptional and protein levels. However, G allele carriers showed lower IL1RN expression in PBMCs stimulated with C16/MSU crystal and lower concentrations of circulating IL-1Ra in both controls and gout patients. PBMCs depicted less spontaneous IL-1Ra release in GG homozygous controls and lower IL-1Ra production in response to C16 + MSU crystal costimulation in patients with gout. The G allele was associated with elevated IL-1β cytokine production in response to C16 + MSU crystal stimulation in controls. The gout risk allele G associates with lower circulating IL-1Ra, lower IL-1Ra production in PBMC assays and elevated IL-1β production in PBMCs challenged with C16 + MSU crystals but not in unchallenged cells. Our data indicate that the genetic signal that associates with gout at IL1RN-IL1F10 region functions to alter expression of IL-1Ra when stimulated by MSU crystals.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"170 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1186/s13075-024-03437-z
Xin Chen, Lingjiang Zhu, Jieying Xu, Qi Cheng, Yuanji Dong, Yifan Xie, Li Hua, Yan Du
Previously, we reported that serum Semaphorin 5 A (Sema5A) levels were increased in systemic lupus erythematosus (SLE) patients compared with healthy controls (HC), and elevated Sema5A correlated with disease activity and lupus nephritis in SLE patients. In this study, we aimed to further understand the role of Sema5A in promoting Th17 cells differentiation in SLE. Sema5A, interferon gamma (IFN-γ), interleukin 4 (IL-4), interleukin 17 A (IL-17 A) and interleukin 10 (IL-10) were measured by Enzyme Linked Immunosorbent Assay (ELISA). RNA and protein were isolated from peripheral blood mononuclear cells (PBMCs) in SLE patients and HC. Expression of PlexinA1 and PlexinB3 were measured by quantitative RT-PCR (qRT-PCR) and Western Blot. Th cell subsets were detected by flow cytometry. Treatment with recombinant human Sema5A (rhSema5A) and small interfering RNA (siRNA) were employed to examine the in vitro effect of Sema5A in CD4+T cell differentiation in SLE patients. IL-17 A elevated in SLE patients and positively correlated with Sema5A. PlexinA1 was upregulated and mainly expressed in CD4+ T cells of SLE; Sema5A treatment induced the differentiation of Th17 cells, while did not affect the Th1 and Th2 skewing. These effects were associated with an upregulation of the transcription factor RORγt by Th17 cells, but not T-bet or GATA3 in Th1 and Th2 cells, respectively. Knock down PlexinA1 regulates IL-17 A production by CD4+T cells. Functional assays showed that Sema5A-PlexinA1 axis promoted Th17 cells differentiation via PI3K/Akt/mTOR signaling. These findings demonstrated that Sema5A-PlexinA1 axis acts as a key mediator on Th17 differentiation, suggesting that Sema5A might be a novel therapeutic target in SLE.
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