Pub Date : 2024-12-19DOI: 10.1186/s13075-024-03454-y
Lu Liu, Karina de Leeuw, Harry van Goor, Berber Doornbos-van der Meer, Suzanne Arends, Johanna Westra
To investigate the levels of plasma neutrophil extracellular traps (NETs) and free thiols, the latter reflecting systemic oxidative stress (OS), and to explore the relationship between NETs and OS in quiescent systemic lupus erythematosus (SLE) patients with and without renal involvement. Plasma levels of NETs and free thiols were measured cross-sectionally in 100 SLE patients with low disease activity (SLEDAI < 5), of whom 73 patients had no renal involvement (non-LN) and 27 patients had lupus nephritis (LN). Additionally, 22 healthy controls (HCs) were included. NETs were measured using a myeloperoxidase-DNA complex ELISA and free thiols were measured using a thiol assay kit. NETs levels were significantly higher in both non-LN and LN patients compared to HCs (p < 0.001, p = 0.013), with no difference between the two patient groups (p = 0.799). Free thiol levels were not significantly different between groups. Interestingly, NETs were negatively correlated with free thiols in all 100 SLE patients (rho = -0.32) and non-LN patients (rho = -0.38), but not in LN patients. Levels of free thiols were significantly lower in subgroups of patients with estimated glomerular filtration rate (eGFR) < 60, serum creatinine (sCr) ≥ 90, C reactive protein (CRP) levels ≥ 5 and body mass index (BMI) ≥ 30. In multivariable regression, disease duration, NETs levels, and eGFR were independently associated with free thiol levels. Levels of NETs were increased in quiescent SLE patients. Although free thiol levels did not differ among the groups. The levels of NETs and free thiols were independently associated in SLE patients, suggesting a potential role of OS in NETs formation. Therefore, reducing OS might be an additional therapeutic target for SLE treatment.
{"title":"Neutrophil extracellular traps and oxidative stress in systemic lupus erythematosus patients with and without renal involvement","authors":"Lu Liu, Karina de Leeuw, Harry van Goor, Berber Doornbos-van der Meer, Suzanne Arends, Johanna Westra","doi":"10.1186/s13075-024-03454-y","DOIUrl":"https://doi.org/10.1186/s13075-024-03454-y","url":null,"abstract":"To investigate the levels of plasma neutrophil extracellular traps (NETs) and free thiols, the latter reflecting systemic oxidative stress (OS), and to explore the relationship between NETs and OS in quiescent systemic lupus erythematosus (SLE) patients with and without renal involvement. Plasma levels of NETs and free thiols were measured cross-sectionally in 100 SLE patients with low disease activity (SLEDAI < 5), of whom 73 patients had no renal involvement (non-LN) and 27 patients had lupus nephritis (LN). Additionally, 22 healthy controls (HCs) were included. NETs were measured using a myeloperoxidase-DNA complex ELISA and free thiols were measured using a thiol assay kit. NETs levels were significantly higher in both non-LN and LN patients compared to HCs (p < 0.001, p = 0.013), with no difference between the two patient groups (p = 0.799). Free thiol levels were not significantly different between groups. Interestingly, NETs were negatively correlated with free thiols in all 100 SLE patients (rho = -0.32) and non-LN patients (rho = -0.38), but not in LN patients. Levels of free thiols were significantly lower in subgroups of patients with estimated glomerular filtration rate (eGFR) < 60, serum creatinine (sCr) ≥ 90, C reactive protein (CRP) levels ≥ 5 and body mass index (BMI) ≥ 30. In multivariable regression, disease duration, NETs levels, and eGFR were independently associated with free thiol levels. Levels of NETs were increased in quiescent SLE patients. Although free thiol levels did not differ among the groups. The levels of NETs and free thiols were independently associated in SLE patients, suggesting a potential role of OS in NETs formation. Therefore, reducing OS might be an additional therapeutic target for SLE treatment.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"47 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849184","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}
Limb-girdle muscular dystrophy (LGMD) is usually confused with idiopathic inflammatory myopathy (IIM) in clinical practice. Our study aimed to establish convenient and reliable diagnostic models for distinguishing between LGMD and IIM. A total of 71 IIM patients, 24 LGMDR2 patients and 22 LGMDR1 patients diagnosed at our neuromuscular center were enrolled. Differences in clinical, laboratory and histopathological characteristics were comprehensively compared. A nomogram and a decision tree were developed to distinguish between LGMD and IIM patients. Compared to patients with LGMD, IIM patients exhibited a significantly older age of onset, a higher prevalence of cervical flexor weakness and a more commonly diffuse MHC-I expression on muscle pathology. The ratio of synchronous serum myoglobin (Mb, ng/ml) to creatine kinase (CK, U/L) before immunotherapy was significantly higher in IIM patients than in LGMD patients. Receiver operating characteristic analysis indicated a high differential diagnostic efficiency of synchronous Mb/CK with a cutoff value of 0.18. A nomogram prediction model and a decision tree were developed based on four independent indicators (age of onset, cervical flexor weakness, synchronous Mb/CK and diffuse MHC-I expression). Five-fold cross-validation and bootstrapping techniques substantiated the discriminate efficacy of the nomograph and decision tree. We developed two practical differential diagnosis models for LGMD and IIM based on the analysis of four accessible indicators, including the age of onset, cervical flexor weakness, the ratio of synchronous Mb/CK values and diffuse MHC-I expression. Further studies with larger samples are needed to refine the predictive efficiency of the differential diagnostic models.
{"title":"Development of differential diagnostic models for distinguishing between limb-girdle muscular dystrophy and idiopathic inflammatory myopathy","authors":"Guangyu Wang, Lijun Fu, Lining Zhang, Kai Shao, Ying Hou, Tingjun Dai, Pengfei Lin, Chuanzhu Yan, Bing Zhao","doi":"10.1186/s13075-024-03458-8","DOIUrl":"https://doi.org/10.1186/s13075-024-03458-8","url":null,"abstract":"Limb-girdle muscular dystrophy (LGMD) is usually confused with idiopathic inflammatory myopathy (IIM) in clinical practice. Our study aimed to establish convenient and reliable diagnostic models for distinguishing between LGMD and IIM. A total of 71 IIM patients, 24 LGMDR2 patients and 22 LGMDR1 patients diagnosed at our neuromuscular center were enrolled. Differences in clinical, laboratory and histopathological characteristics were comprehensively compared. A nomogram and a decision tree were developed to distinguish between LGMD and IIM patients. Compared to patients with LGMD, IIM patients exhibited a significantly older age of onset, a higher prevalence of cervical flexor weakness and a more commonly diffuse MHC-I expression on muscle pathology. The ratio of synchronous serum myoglobin (Mb, ng/ml) to creatine kinase (CK, U/L) before immunotherapy was significantly higher in IIM patients than in LGMD patients. Receiver operating characteristic analysis indicated a high differential diagnostic efficiency of synchronous Mb/CK with a cutoff value of 0.18. A nomogram prediction model and a decision tree were developed based on four independent indicators (age of onset, cervical flexor weakness, synchronous Mb/CK and diffuse MHC-I expression). Five-fold cross-validation and bootstrapping techniques substantiated the discriminate efficacy of the nomograph and decision tree. We developed two practical differential diagnosis models for LGMD and IIM based on the analysis of four accessible indicators, including the age of onset, cervical flexor weakness, the ratio of synchronous Mb/CK values and diffuse MHC-I expression. Further studies with larger samples are needed to refine the predictive efficiency of the differential diagnostic models.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"24 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848847","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 : 2024-12-19DOI: 10.1186/s13075-024-03455-x
Khaled A. Elsaid, Ling X. Zhang, Thomas Zhao, Ava Marks, Derek Jenkins, Tannin A. Schmidt, Gregory D. Jay
Synovial macrophages (SMs) are important effectors of joint health and disease. A novel Cx3CR1 + TREM2 + SM population expressing the tight junction protein claudin-5, was recently discovered in synovial lining. Ablation of these SMs was associated with onset of arthritis. Proteoglycan 4 (PRG4) is a mucinous glycoprotein that fulfills lubricating and homeostatic roles in the joint. The aim of this work is to study the role of PRG4 in modulating synovitis in the context of SM homeostasis and assess the contribution of xanthine oxidase (XO)-hypoxia inducible factor alpha (HIF-1a) axis to this regulation. We used Prg4FrtloxP/FrtloxP;R26FlpoER/+, a novel transgenic mouse, where the Prg4Frt allele normally expresses the PRG4 protein and was designed to flank the first two exons of Prg4 with a flippase recognition target and “LOXP” sites. Inducing flippase activity with tamoxifen (TAM) inactivates the Frt allele and thus creates a conditional knockout state. We studied anti-inflammatory SMs and XO by quantitative immunohistochemistry, isolated RNA and studied immune pathway activations by multiplexed assays and isolated SMs and studied PRG4 signaling dysfunction in relation to glycolytic switching due to pro-inflammatory activation. Prg4 inactivated mice were treated with oral febuxostat, a specific XO inhibitor, and quantification of Cx3CR1 + TREM2 + SMs, XO immunostaining and synovitis assessment were conducted. Prg4 inactivation induced Cx3CR1 + TREM2 + SM loss (p < 0.001) and upregulated glycolysis and innate immune pathways in the synovium. In isolated SMs, Xdh (p < 0.01) and Hif1a (p < 0.05) were upregulated. Pro-inflammatory activation of SMs was evident by enhanced glycolytic flux and XO-generated reactive oxygen species (ROS). Febuxostat reduced glycolytic flux (p < 0.001) and HIF-1a levels (p < 0.0001) in SMs. Febuxostat also reduced systemic inflammation (p < 0.001), synovial hyperplasia (p < 0.001) and preserved Cx3CR1 + TREM2 + SMs (p < 0.0001) in synovia of Prg4 inactivated mice. PRG4 is a biologically significant modulator of synovial homeostasis via inhibition of XO expression and downstream HIF-1a activation. PRG4 signaling is anti-inflammatory and promotes synovial homeostasis in chronic synovitis, where direct XO inhibition is potentially therapeutic in chronic synovitis.
{"title":"Proteoglycan 4 (Lubricin) and regulation of xanthine oxidase in synovial macrophage as a mechanism of controlling synovitis","authors":"Khaled A. Elsaid, Ling X. Zhang, Thomas Zhao, Ava Marks, Derek Jenkins, Tannin A. Schmidt, Gregory D. Jay","doi":"10.1186/s13075-024-03455-x","DOIUrl":"https://doi.org/10.1186/s13075-024-03455-x","url":null,"abstract":"Synovial macrophages (SMs) are important effectors of joint health and disease. A novel Cx3CR1 + TREM2 + SM population expressing the tight junction protein claudin-5, was recently discovered in synovial lining. Ablation of these SMs was associated with onset of arthritis. Proteoglycan 4 (PRG4) is a mucinous glycoprotein that fulfills lubricating and homeostatic roles in the joint. The aim of this work is to study the role of PRG4 in modulating synovitis in the context of SM homeostasis and assess the contribution of xanthine oxidase (XO)-hypoxia inducible factor alpha (HIF-1a) axis to this regulation. We used Prg4FrtloxP/FrtloxP;R26FlpoER/+, a novel transgenic mouse, where the Prg4Frt allele normally expresses the PRG4 protein and was designed to flank the first two exons of Prg4 with a flippase recognition target and “LOXP” sites. Inducing flippase activity with tamoxifen (TAM) inactivates the Frt allele and thus creates a conditional knockout state. We studied anti-inflammatory SMs and XO by quantitative immunohistochemistry, isolated RNA and studied immune pathway activations by multiplexed assays and isolated SMs and studied PRG4 signaling dysfunction in relation to glycolytic switching due to pro-inflammatory activation. Prg4 inactivated mice were treated with oral febuxostat, a specific XO inhibitor, and quantification of Cx3CR1 + TREM2 + SMs, XO immunostaining and synovitis assessment were conducted. Prg4 inactivation induced Cx3CR1 + TREM2 + SM loss (p < 0.001) and upregulated glycolysis and innate immune pathways in the synovium. In isolated SMs, Xdh (p < 0.01) and Hif1a (p < 0.05) were upregulated. Pro-inflammatory activation of SMs was evident by enhanced glycolytic flux and XO-generated reactive oxygen species (ROS). Febuxostat reduced glycolytic flux (p < 0.001) and HIF-1a levels (p < 0.0001) in SMs. Febuxostat also reduced systemic inflammation (p < 0.001), synovial hyperplasia (p < 0.001) and preserved Cx3CR1 + TREM2 + SMs (p < 0.0001) in synovia of Prg4 inactivated mice. PRG4 is a biologically significant modulator of synovial homeostasis via inhibition of XO expression and downstream HIF-1a activation. PRG4 signaling is anti-inflammatory and promotes synovial homeostasis in chronic synovitis, where direct XO inhibition is potentially therapeutic in chronic synovitis.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"7 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848848","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 : 2024-12-19DOI: 10.1186/s13075-024-03452-0
Tanu Dixit, Anuradha Vaidya, Selvan Ravindran
In an age where there is a remarkable upsurge in developing precision medicines, antibody-drug conjugates (ADCs) have emerged as a progressive therapeutic strategy. ADCs typically consist of monoclonal antibodies (mAb) conjugated to the cytotoxic payloads by utilizing a linker, combining the benefits of definitive target specificity of mAbs and potent killing impact of payload to achieve precise and efficient elimination of target cells. In addition to their well-established role in oncology, ADCs are currently demonstrating encouraging potential in addressing the unmet requirements in the treatment of autoimmune conditions such as rheumatoid arthritis (RA). Prevalent long-term autoimmune disease RA costs billions of dollars annually but still, there is a lack of precision-targeted therapeutics with minimal side effects. This review provides an overview of the RA pathogenesis, pre-existing therapies, and their limitations, the introduction of ADCs in RA treatment, the mechanism of ADCs, and a summary of ADCs in preclinical and clinical trials. Based on the literature we also propose a strategy in ADC synthesis, which may increase the efficiency in targeting multifactorial diseases like RA. We propose to utilize DMARDs (Disease-modifying anti-rheumatic drugs), the first-line treatment for RA, as a payload for ADC synthesis. DMARDs are the only class of medication that limits the disease progression, but their efficacy is limited due to off-target toxicities. Hence, utilizing them as payload will help to deliver them directly at the targeted site, reducing their off-target toxicity, which in turn will increase their efficiency in targeting disease. Also, as mAbs are not sufficient to achieve remission, they are given in combinations with DMARDs. Hence, synthesizing ADCs may reduce the multiple and higher dosages given to patients, which in turn may enhance patient compliance.
{"title":"Therapeutic potential of antibody-drug conjugates possessing bifunctional anti-inflammatory action in the pathogenies of rheumatoid arthritis","authors":"Tanu Dixit, Anuradha Vaidya, Selvan Ravindran","doi":"10.1186/s13075-024-03452-0","DOIUrl":"https://doi.org/10.1186/s13075-024-03452-0","url":null,"abstract":"In an age where there is a remarkable upsurge in developing precision medicines, antibody-drug conjugates (ADCs) have emerged as a progressive therapeutic strategy. ADCs typically consist of monoclonal antibodies (mAb) conjugated to the cytotoxic payloads by utilizing a linker, combining the benefits of definitive target specificity of mAbs and potent killing impact of payload to achieve precise and efficient elimination of target cells. In addition to their well-established role in oncology, ADCs are currently demonstrating encouraging potential in addressing the unmet requirements in the treatment of autoimmune conditions such as rheumatoid arthritis (RA). Prevalent long-term autoimmune disease RA costs billions of dollars annually but still, there is a lack of precision-targeted therapeutics with minimal side effects. This review provides an overview of the RA pathogenesis, pre-existing therapies, and their limitations, the introduction of ADCs in RA treatment, the mechanism of ADCs, and a summary of ADCs in preclinical and clinical trials. Based on the literature we also propose a strategy in ADC synthesis, which may increase the efficiency in targeting multifactorial diseases like RA. We propose to utilize DMARDs (Disease-modifying anti-rheumatic drugs), the first-line treatment for RA, as a payload for ADC synthesis. DMARDs are the only class of medication that limits the disease progression, but their efficacy is limited due to off-target toxicities. Hence, utilizing them as payload will help to deliver them directly at the targeted site, reducing their off-target toxicity, which in turn will increase their efficiency in targeting disease. Also, as mAbs are not sufficient to achieve remission, they are given in combinations with DMARDs. Hence, synthesizing ADCs may reduce the multiple and higher dosages given to patients, which in turn may enhance patient compliance.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"4 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848853","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 : 2024-12-19DOI: 10.1186/s13075-024-03448-w
Xun Hu, Inmaculada Xu Lou, Qilan Chen
Accumulated evidence supports the tendency of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis(AAV) to coexist with atherosclerosis (AS). However, the common etiology of these two diseases remains unclear. This study aims to explore the mechanisms underlying the concurrent occurrence of ANCA and AS. Microarray data of AAV and AS were examined in a comprehensive gene expression database. Weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis (GEO2R) were performed to identify common genes between AAV and AS. Based on the co-expressed genes, functional enrichment analysis, protein-protein interaction (PPI) network analysis, and identification of hub genes (HGs) were conducted. Subsequently, co-expression analysis of HGs was performed, and their expression and diagnostic value were validated. We further explored immune cell infiltration and analyzed the correlation between HGs and infiltrating immune cells. Finally, the reliability of the selected pathways was verified. The results of the common gene analysis suggest that immune and inflammatory responses may be common features in the pathophysiology of AAV and AS. Through the interaction of different analysis results, we confirmed five HGs (CYBB, FCER1G, TYROBP, IL10RA, CSF1R). The CytoHubba plugin and HG validation demonstrated the reliability of the selected five HGs. Co-expression network analysis revealed that these five HGs could influence monocyte migration. Analysis of immune cell infiltration showed that monocytes in ANCA and M0 macrophages in AS constituted a higher proportion of all infiltrating immune cells, with significant differences in infiltration. We also found significant positive correlations between CYBB, FCER1G, TYROBP, IL10RA, CSF1R, and monocytes/M0 macrophages in AAV, as well as between CYBB, FCER1G, TYROBP, IL10RA, CSF1R, and M0 macrophages in AS. These five HGs can promote monocyte differentiation into macrophages, leading to the concurrent occurrence of AAV and AS. Our study provides insights into the mechanisms underlying the coexistence of AAV and AS.
{"title":"Integrated bioinformatic analysis of the shared molecular mechanisms between ANCA-associated vasculitis and atherosclerosis","authors":"Xun Hu, Inmaculada Xu Lou, Qilan Chen","doi":"10.1186/s13075-024-03448-w","DOIUrl":"https://doi.org/10.1186/s13075-024-03448-w","url":null,"abstract":"Accumulated evidence supports the tendency of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis(AAV) to coexist with atherosclerosis (AS). However, the common etiology of these two diseases remains unclear. This study aims to explore the mechanisms underlying the concurrent occurrence of ANCA and AS. Microarray data of AAV and AS were examined in a comprehensive gene expression database. Weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis (GEO2R) were performed to identify common genes between AAV and AS. Based on the co-expressed genes, functional enrichment analysis, protein-protein interaction (PPI) network analysis, and identification of hub genes (HGs) were conducted. Subsequently, co-expression analysis of HGs was performed, and their expression and diagnostic value were validated. We further explored immune cell infiltration and analyzed the correlation between HGs and infiltrating immune cells. Finally, the reliability of the selected pathways was verified. The results of the common gene analysis suggest that immune and inflammatory responses may be common features in the pathophysiology of AAV and AS. Through the interaction of different analysis results, we confirmed five HGs (CYBB, FCER1G, TYROBP, IL10RA, CSF1R). The CytoHubba plugin and HG validation demonstrated the reliability of the selected five HGs. Co-expression network analysis revealed that these five HGs could influence monocyte migration. Analysis of immune cell infiltration showed that monocytes in ANCA and M0 macrophages in AS constituted a higher proportion of all infiltrating immune cells, with significant differences in infiltration. We also found significant positive correlations between CYBB, FCER1G, TYROBP, IL10RA, CSF1R, and monocytes/M0 macrophages in AAV, as well as between CYBB, FCER1G, TYROBP, IL10RA, CSF1R, and M0 macrophages in AS. These five HGs can promote monocyte differentiation into macrophages, leading to the concurrent occurrence of AAV and AS. Our study provides insights into the mechanisms underlying the coexistence of AAV and AS.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"47 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849180","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 investigated poor prognostic factors for the relapse of interstitial lung disease (ILD) in patients with microscopic polyangiitis (MPA) after remission induction therapy. We enrolled patients diagnosed with MPA complicated by ILD according to the Chapel Hill Consensus definition from 2001 to 2023 in multiple institutions in the REVEAL cohort. All patients who were treated with immunosuppressive therapy were followed up, and those who relapsed with ILD were extracted in this study. We explored the risk factors for predicting ILD relapse in patients with MPA-ILD by comparing the demographic, clinical, laboratory, and radiological findings and treatments between the relapsed and non-relapsed groups on admission. Of 243 patients with MPA, 134 (55.1%) with MPA-ILD were enrolled. Among them, 28 (20.9%) relapsed during a mean follow-up of 4.2 years. The initial serum Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) levels and the prevalence of usual interstitial pneumonia (UIP) pattern were significantly higher in the relapsed group. The biomarkers were also risk factors for relapse in multivariate Cox regression analysis. The best cut-off values of KL-6, SP-D for predicting ILD relapse were 430 U/mL and 89.5 ng/mL, respectively. We created prediction models based on the best cut-off values for KL-6, SP-D, and the presence of the UIP pattern (KSU model). The 10-year relapse rate was significantly different among patients with MPA-ILD stratified by the number of risk factors based on the KSU model. A higher relapse rate was associated with higher all-cause mortality. The initial serum high KL-6 and SP-D levels and the prevalence of the UIP pattern were associated with ILD relapse in patients with MPA-ILD. Our multicentre cohort study indicated that the KSU model, which consists of KL-6 ≥ 430 U/mL, SP-D ≥ 89.5 ng/mL, and the presence of the UIP pattern, is a useful predictor of ILD relapse in patients with MPA after immunosuppressive therapy.
{"title":"Poor prognostic factors for relapse of interstitial lung disease in microscopic polyangiitis: the Japanese multicentre REVEAL cohort study","authors":"Shogo Matsuda, Takuya Kotani, Ayana Okazaki, Daisuke Nishioka, Yuichi Masuda, Mayu Shiomi, Ryu Watanabe, Tomoki Taniguchi, Atsushi Manabe, Keiichiro Kadoba, Tsuneyasu Yoshida, Ryosuke Hiwa, Wataru Yamamoto, Motomu Hashimoto, Tohru Takeuchi","doi":"10.1186/s13075-024-03453-z","DOIUrl":"https://doi.org/10.1186/s13075-024-03453-z","url":null,"abstract":"This study investigated poor prognostic factors for the relapse of interstitial lung disease (ILD) in patients with microscopic polyangiitis (MPA) after remission induction therapy. We enrolled patients diagnosed with MPA complicated by ILD according to the Chapel Hill Consensus definition from 2001 to 2023 in multiple institutions in the REVEAL cohort. All patients who were treated with immunosuppressive therapy were followed up, and those who relapsed with ILD were extracted in this study. We explored the risk factors for predicting ILD relapse in patients with MPA-ILD by comparing the demographic, clinical, laboratory, and radiological findings and treatments between the relapsed and non-relapsed groups on admission. Of 243 patients with MPA, 134 (55.1%) with MPA-ILD were enrolled. Among them, 28 (20.9%) relapsed during a mean follow-up of 4.2 years. The initial serum Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) levels and the prevalence of usual interstitial pneumonia (UIP) pattern were significantly higher in the relapsed group. The biomarkers were also risk factors for relapse in multivariate Cox regression analysis. The best cut-off values of KL-6, SP-D for predicting ILD relapse were 430 U/mL and 89.5 ng/mL, respectively. We created prediction models based on the best cut-off values for KL-6, SP-D, and the presence of the UIP pattern (KSU model). The 10-year relapse rate was significantly different among patients with MPA-ILD stratified by the number of risk factors based on the KSU model. A higher relapse rate was associated with higher all-cause mortality. The initial serum high KL-6 and SP-D levels and the prevalence of the UIP pattern were associated with ILD relapse in patients with MPA-ILD. Our multicentre cohort study indicated that the KSU model, which consists of KL-6 ≥ 430 U/mL, SP-D ≥ 89.5 ng/mL, and the presence of the UIP pattern, is a useful predictor of ILD relapse in patients with MPA after immunosuppressive therapy.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"24 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849183","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}
Minor salivary gland (MSG) biopsy is a critical but invasive method for the classification of primary Sjögren’s disease (pSjD). Here we aimed to identify salivary proteins as potential biomarkers and to establish a non-invasive prediction model for pSjD. Liquid chromatography-tandem mass spectrometry was conducted on whole saliva samples from patients with pSjD and non-Sjögren control subjects (non-pSjD). Proteins involved in immune processes were upregulated in the pSjD group, such as complement C3 (C3), complement factor B (CFB), clusterin (CLU), calreticulin (CALR), and neutrophil elastase (NE), which were further confirmed by ELISA. Multivariate logistic regression analyses were performed to identify markers that differentiated pSjD from non-pSjD; receiver operating characteristic (ROC) curves were constructed. A diagnostic model based on the combination of salivary biomarkers (CFB, CLU, and NE), serum autoantibodies (anti-SSA /Ro60 and anti-SSA/Ro52), and Schirmer’s test was evaluated in 186 patients (derivation cohort) with replication in 72 patients (validation cohort). In multivariate analyses, CFB, CLU, and NE were independent predictors of pSS. A model based on the combination of salivary biomarkers (CFB, CLU, and NE), serum autoantibodies (anti-SSA and anti-Ro52), and Schirmer’s test achieved significant discrimination of pSS. In the derivation cohort, the area under curve (AUC) of the ROC was 0.930 (95% CI 0.877–0.965, P < 0.001), with a sensitivity and specificity of 84.85% and 92.45%, respectively. Notably, similar results were obtained in a validation cohort. The 6-biomarker panel could provide a novel non-invasive tool for the classification of pSjD.
小唾液腺（MSG）活检是原发性Sjögren病（pSjD）分类的一种关键但有创的方法。本研究旨在鉴定唾液蛋白作为潜在的生物标志物，并建立pSjD的非侵入性预测模型。采用液相色谱-串联质谱法对pSjD患者和non-Sjögren对照组（非pSjD）的全唾液样本进行分析。pSjD组参与免疫过程的蛋白如补体C3 （C3）、补体因子B （CFB）、聚簇蛋白（CLU）、钙网蛋白（CALR）和中性粒细胞弹性酶（NE）上调，ELISA进一步证实了这一点。进行多变量logistic回归分析，以确定区分pSjD与非pSjD的标记；构建受试者工作特征（ROC）曲线。基于唾液生物标志物（CFB、CLU和NE）、血清自身抗体（抗ssa /Ro60和抗ssa /Ro52）和Schirmer试验的诊断模型在186例患者（衍生队列）中进行了评估，并在72例患者（验证队列）中进行了复制。在多变量分析中，CFB、CLU和NE是pSS的独立预测因子。基于唾液生物标志物（CFB、CLU和NE）、血清自身抗体（抗ssa和抗ro52）和Schirmer检验联合建立的模型对pSS有显著的鉴别效果。衍生队列的ROC曲线下面积（AUC）为0.930 (95% CI 0.877 ~ 0.965, P < 0.001)，敏感性为84.85%，特异性为92.45%。值得注意的是，在验证队列中获得了类似的结果。6-生物标志物面板可为pSjD的分类提供一种新的无创工具。
{"title":"A non-invasive model for diagnosis of primary Sjogren’s disease based on salivary biomarkers, serum autoantibodies, and Schirmer’s test","authors":"Xinwei Zhang, Zhangdi Liao, Yangchun Chen, Huiqin Lu, Aodi Wang, Yingying Shi, Qi Zhang, Ying Wang, Yan Li, Jingying Lan, Chubing Chen, Chaoqiong Deng, Wuwei Zhuang, Lingyu Liu, Hongyan Qian, Shiju Chen, Zhibin Li, Guixiu Shi, Yuan Liu","doi":"10.1186/s13075-024-03459-7","DOIUrl":"https://doi.org/10.1186/s13075-024-03459-7","url":null,"abstract":"Minor salivary gland (MSG) biopsy is a critical but invasive method for the classification of primary Sjögren’s disease (pSjD). Here we aimed to identify salivary proteins as potential biomarkers and to establish a non-invasive prediction model for pSjD. Liquid chromatography-tandem mass spectrometry was conducted on whole saliva samples from patients with pSjD and non-Sjögren control subjects (non-pSjD). Proteins involved in immune processes were upregulated in the pSjD group, such as complement C3 (C3), complement factor B (CFB), clusterin (CLU), calreticulin (CALR), and neutrophil elastase (NE), which were further confirmed by ELISA. Multivariate logistic regression analyses were performed to identify markers that differentiated pSjD from non-pSjD; receiver operating characteristic (ROC) curves were constructed. A diagnostic model based on the combination of salivary biomarkers (CFB, CLU, and NE), serum autoantibodies (anti-SSA /Ro60 and anti-SSA/Ro52), and Schirmer’s test was evaluated in 186 patients (derivation cohort) with replication in 72 patients (validation cohort). In multivariate analyses, CFB, CLU, and NE were independent predictors of pSS. A model based on the combination of salivary biomarkers (CFB, CLU, and NE), serum autoantibodies (anti-SSA and anti-Ro52), and Schirmer’s test achieved significant discrimination of pSS. In the derivation cohort, the area under curve (AUC) of the ROC was 0.930 (95% CI 0.877–0.965, P < 0.001), with a sensitivity and specificity of 84.85% and 92.45%, respectively. Notably, similar results were obtained in a validation cohort. The 6-biomarker panel could provide a novel non-invasive tool for the classification of pSjD.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"4 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848846","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 : 2024-12-19DOI: 10.1186/s13075-024-03442-2
Dafna D. Gladman, Peter Nash, Philip J. Mease, Oliver FitzGerald, Stephanie Duench, Mary Jane Cadatal, Karim R. Masri
Data on treatment switching directly from tumor necrosis factor inhibitors to tofacitinib in psoriatic arthritis (PsA) are limited. This post hoc analysis assessed efficacy and safety outcomes in patients with PsA who directly switched to tofacitinib in a long-term extension (LTE) study after receiving adalimumab (ADA) in a Phase 3 study, compared with those who continued to receive tofacitinib. Patients with active PsA received tofacitinib 5 mg twice daily (BID) or ADA 40 mg once every 2 weeks in a 12-month, randomized, double-blind study (OPAL Broaden) and then continued or switched to tofacitinib 5 mg BID and maintained this dose in an open-label LTE study (OPAL Balance). Efficacy was assessed 3 months before the last visit and at the last visit in the Phase 3 study, and at month 3 (or month 6 for select outcomes) in the LTE study and included rates of ≥ 20/50/70% improvement in American College of Rheumatology response criteria, Psoriasis Area and Severity Index ≥ 75% improvement, Health Assessment Questionnaire-Disability Index (HAQ-DI) response (decrease from baseline ≥ 0.35 for patients with baseline HAQ-DI ≥ 0.35), Psoriatic Arthritis Disease Activity Score ≤ 3.2, and minimal disease activity; and change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue score. Safety was assessed at months 3 and 12 in both studies via incidence rates (patients with first events/100 patient-years). Overall, 180 patients were included (ADA→tofacitinib 5 mg BID: n = 91; continuing tofacitinib 5 mg BID: n = 89). At Phase 3 baseline, patients in the ADA→tofacitinib 5 mg BID group tended to be younger and have less active disease compared with those continuing tofacitinib. Efficacy was similar between groups in the Phase 3 study, and was maintained to month 3 or 6 in the LTE study. Treatment-emergent adverse events (AEs), serious AEs, and serious infections were generally similar in the Phase 3 and LTE studies, and between groups within each study. Tofacitinib efficacy and safety were similar in patients with PsA who directly switched from ADA to tofacitinib and those who continued tofacitinib, suggesting that patients can be directly switched from ADA to tofacitinib without any washout period. NCT01877668; NCT01976364
银屑病关节炎（PsA）直接从肿瘤坏死因子抑制剂转为托法替尼治疗的数据有限。这项事后分析评估了PsA患者在接受阿达木单抗（ADA）后，与继续接受托法替尼的患者相比，在长期延长（LTE）研究中直接切换到托法替尼的疗效和安全性结果。在一项为期12个月的随机双盲研究（OPAL拓宽）中，活动性PsA患者接受托法替尼5 mg每日2次（BID）或ADA 40 mg每2周1次（每2周1次），然后在一项开放标签LTE研究（OPAL Balance）中继续或切换到托法替尼5 mg BID，并维持该剂量。在3期研究的最后一次访问前3个月和最后一次访问时以及LTE研究的第3个月（或选择结果的第6个月）评估疗效，包括美国风湿病学会反应标准≥20/50/70%的改善率，银屑病面积和严重程度指数≥75%的改善率，健康评估问卷-残疾指数（HAQ-DI）反应（基线HAQ-DI≥0.35的患者从基线≥0.35下降）。银屑病关节炎疾病活动性评分≤3.2，且疾病活动性最小；慢性疾病治疗功能评估-疲劳评分与基线的变化。两项研究在第3个月和第12个月通过发病率（首次事件患者/100患者-年）评估安全性。总共纳入180例患者(ADA→tofacitinib 5 mg BID: n = 91；继续服用法替尼5mg BID: n = 89)。在3期基线时，与继续使用托法替尼的患者相比，ADA→托法替尼5mg BID组患者更年轻，活动性疾病更少。在3期研究中，两组之间的疗效相似，在LTE研究中维持到第3个月或第6个月。在3期和LTE研究中，以及每个研究的组之间，治疗出现的不良事件（ae）、严重ae和严重感染通常相似。在PsA患者中，直接从ADA切换到托法替尼和继续使用托法替尼的患者，托法替尼的疗效和安全性相似，提示患者可以直接从ADA切换到托法替尼，无需任何洗脱期。NCT01877668;NCT01976364
{"title":"Efficacy and safety of tofacitinib in an open-label, long-term extension study in patients with psoriatic arthritis who received adalimumab or tofacitinib in a Phase 3 randomized controlled study: a post hoc analysis","authors":"Dafna D. Gladman, Peter Nash, Philip J. Mease, Oliver FitzGerald, Stephanie Duench, Mary Jane Cadatal, Karim R. Masri","doi":"10.1186/s13075-024-03442-2","DOIUrl":"https://doi.org/10.1186/s13075-024-03442-2","url":null,"abstract":"Data on treatment switching directly from tumor necrosis factor inhibitors to tofacitinib in psoriatic arthritis (PsA) are limited. This post hoc analysis assessed efficacy and safety outcomes in patients with PsA who directly switched to tofacitinib in a long-term extension (LTE) study after receiving adalimumab (ADA) in a Phase 3 study, compared with those who continued to receive tofacitinib. Patients with active PsA received tofacitinib 5 mg twice daily (BID) or ADA 40 mg once every 2 weeks in a 12-month, randomized, double-blind study (OPAL Broaden) and then continued or switched to tofacitinib 5 mg BID and maintained this dose in an open-label LTE study (OPAL Balance). Efficacy was assessed 3 months before the last visit and at the last visit in the Phase 3 study, and at month 3 (or month 6 for select outcomes) in the LTE study and included rates of ≥ 20/50/70% improvement in American College of Rheumatology response criteria, Psoriasis Area and Severity Index ≥ 75% improvement, Health Assessment Questionnaire-Disability Index (HAQ-DI) response (decrease from baseline ≥ 0.35 for patients with baseline HAQ-DI ≥ 0.35), Psoriatic Arthritis Disease Activity Score ≤ 3.2, and minimal disease activity; and change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue score. Safety was assessed at months 3 and 12 in both studies via incidence rates (patients with first events/100 patient-years). Overall, 180 patients were included (ADA→tofacitinib 5 mg BID: n = 91; continuing tofacitinib 5 mg BID: n = 89). At Phase 3 baseline, patients in the ADA→tofacitinib 5 mg BID group tended to be younger and have less active disease compared with those continuing tofacitinib. Efficacy was similar between groups in the Phase 3 study, and was maintained to month 3 or 6 in the LTE study. Treatment-emergent adverse events (AEs), serious AEs, and serious infections were generally similar in the Phase 3 and LTE studies, and between groups within each study. Tofacitinib efficacy and safety were similar in patients with PsA who directly switched from ADA to tofacitinib and those who continued tofacitinib, suggesting that patients can be directly switched from ADA to tofacitinib without any washout period. NCT01877668; NCT01976364","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"115 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849186","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 : 2024-12-19DOI: 10.1186/s13075-024-03447-x
Bo Broens, Esther J. Nossent, Lilian J. Meijboom, Gerben J. C. Zwezerijnen, Julia Spierings, Jeska K. de Vries-Bouwstra, Jacob M. van Laar, Conny J. van der Laken, Alexandre E. Voskuyl
This study aimed to assess the quantitative uptake of 18F-FDG PET-CT in the lungs of patients with early severe diffuse cutaneous systemic sclerosis (SSc) with and without interstitial lung disease (ILD), compared to controls. In patients with SSc-ILD, 18F-FDG uptake was correlated to high-resolution computed tomography (HRCT) and pulmonary function test (PFT) parameters. A prospective, cross-sectional study was conducted, involving 15 patients with SSc-ILD, 5 patients with SSc without ILD, and 7 controls without SSc. 18F-FDG PET-CT scans were performed following standardized protocols, and quantitative analysis of tracer uptake was conducted in predefined lung regions. In addition, HRCT scans were evaluated for ILD-related radiologic abnormalities. Between-group differences were compared with non-parametric tests, while correlations with PFT parameters were analyzed using Spearman correlation coefficients. 18F-FDG uptake was mainly increased in the dorsobasal lung fields of patients with SSc-ILD compared to SSc without ILD and controls (p = 0.03 and p < 0.001, respectively). 18F-FDG uptake was higher in SSc patients with extensive ILD (≥ 20% vs < 20%, p = 0.04) and correlated with lower DLCO% (R = -0.59, p = 0.02). Ground-glass opacities, with or without reticulation, corresponded to increased 18F-FDG uptake. 18F-FDG PET-CT can detect metabolic activity in the lungs of patients with early severe diffuse cutaneous SSc and ILD, correlating with higher ILD extent (≥ 20%) and lower DLCO%. These results suggest the potential utility of 18F-FDG PET-CT in the early detection of ILD (progression) and aiding in risk stratification.
本研究旨在评估伴有或不伴有间质性肺疾病（ILD）的早期严重弥漫性皮肤系统性硬化症（SSc）患者肺部18F-FDG PET-CT的定量摄取，与对照组相比。在SSc-ILD患者中，18F-FDG摄取与高分辨率计算机断层扫描（HRCT）和肺功能测试（PFT）参数相关。进行了一项前瞻性横断面研究，包括15例SSc-ILD患者，5例SSc无ILD患者和7例无SSc对照。按照标准化方案进行18F-FDG PET-CT扫描，并在预定义的肺区域进行示踪剂摄取的定量分析。此外，HRCT扫描评估ild相关放射学异常。用非参数检验比较组间差异，用Spearman相关系数分析与PFT参数的相关性。与无ILD的SSc和对照组相比，SSc-ILD患者肺背基底野的18F-FDG摄取主要增加（p = 0.03和p < 0.001）。SSc合并广泛ILD患者的18F-FDG摄取较高（≥20% vs < 20%, p = 0.04），并与较低的DLCO%相关（R = -0.59, p = 0.02）。毛玻璃混浊，不论有无网状，都与18F-FDG摄取增加有关。18F-FDG PET-CT可检测早期严重弥漫性皮肤SSc和ILD患者肺部代谢活性，与ILD程度高（≥20%）和DLCO%低相关。这些结果表明18F-FDG PET-CT在早期发现ILD（进展）和帮助风险分层方面的潜在效用。
{"title":"Quantitative 18F-FDG PET-CT can assess presence and extent of interstitial lung disease in early severe diffuse cutaneous systemic sclerosis","authors":"Bo Broens, Esther J. Nossent, Lilian J. Meijboom, Gerben J. C. Zwezerijnen, Julia Spierings, Jeska K. de Vries-Bouwstra, Jacob M. van Laar, Conny J. van der Laken, Alexandre E. Voskuyl","doi":"10.1186/s13075-024-03447-x","DOIUrl":"https://doi.org/10.1186/s13075-024-03447-x","url":null,"abstract":"This study aimed to assess the quantitative uptake of 18F-FDG PET-CT in the lungs of patients with early severe diffuse cutaneous systemic sclerosis (SSc) with and without interstitial lung disease (ILD), compared to controls. In patients with SSc-ILD, 18F-FDG uptake was correlated to high-resolution computed tomography (HRCT) and pulmonary function test (PFT) parameters. A prospective, cross-sectional study was conducted, involving 15 patients with SSc-ILD, 5 patients with SSc without ILD, and 7 controls without SSc. 18F-FDG PET-CT scans were performed following standardized protocols, and quantitative analysis of tracer uptake was conducted in predefined lung regions. In addition, HRCT scans were evaluated for ILD-related radiologic abnormalities. Between-group differences were compared with non-parametric tests, while correlations with PFT parameters were analyzed using Spearman correlation coefficients. 18F-FDG uptake was mainly increased in the dorsobasal lung fields of patients with SSc-ILD compared to SSc without ILD and controls (p = 0.03 and p < 0.001, respectively). 18F-FDG uptake was higher in SSc patients with extensive ILD (≥ 20% vs < 20%, p = 0.04) and correlated with lower DLCO% (R = -0.59, p = 0.02). Ground-glass opacities, with or without reticulation, corresponded to increased 18F-FDG uptake. 18F-FDG PET-CT can detect metabolic activity in the lungs of patients with early severe diffuse cutaneous SSc and ILD, correlating with higher ILD extent (≥ 20%) and lower DLCO%. These results suggest the potential utility of 18F-FDG PET-CT in the early detection of ILD (progression) and aiding in risk stratification.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849185","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}
Neutropenia is more common in patients with systemic lupus erythematosus (SLE) and is a major cause of life-threatening infections. The increased apoptosis of neutrophils is likely to be an essential cause of neutropenia in SLE. However, the detailed mechanisms of increased neutrophil apoptosis in SLE remain unknown. This study focused on the role of Krüppel-like factor 2 (KLF2) in the regulation of neutrophil apoptosis and its association with SLE disease activity. The levels of KLF2 in neutrophils from SLE patients and healthy controls (HCs) were detected by RT-PCR and western blot. The relationship between the levels of KLF2 and the apoptosis levels of neutrophils in SLE patients was analyzed. The KLF2 inhibitor Geranylgeranyl pyrophosphate (GGPP) and the KLF2 inducer geranylgeranyl transferase inhibitor (GGTI-298) were used to incubate with neutrophils to investigate the role of KLF2 in the regulation of neutrophil apoptosis. To clarify whether serum from SLE patients affects neutrophil KLF2 expression and apoptosis, sera from SLE patients were collected and used to incubate with neutrophils from HCs, followed by the detection of KLF2 levels and apoptosis levels of neutrophils. Additionally, the correlation between KLF2 levels and SLE disease activity index (SLEDAI) was analyzed. The expression of KLF2 in neutrophils of SLE patients was significantly suppressed, and the decreased KLF2 was associated with the upregulation of neutrophil apoptosis. Moreover, newly diagnosed SLE patients, SLE patients with higher serum IgG and positive anti-Smith antibodies had lower KLF2 expression. Furthermore, we demonstrated that modulating the expression of KLF2 can regulate the apoptosis of neutrophils. The levels of KLF2 in neutrophils were associated with the SLEDAI. In addition, we found that serum from SLE patients could induce apoptosis in neutrophils by down-regulating the expression of KLF2. KLF2 controls the apoptosis of neutrophils and is associated with SLEDAI, which suggests that KLF2 in neutrophils may be involved in the occurrence and development of SLE.
{"title":"KLF2 controls the apoptosis of neutrophils and is associated with disease activity of systemic lupus erythematosus","authors":"Hongshuai Zhao, Zaichuan Lin, Peiwen Zhang, Jiayue Rao, Shumin Xu, Qing Luo, Junming Li","doi":"10.1186/s13075-024-03461-z","DOIUrl":"https://doi.org/10.1186/s13075-024-03461-z","url":null,"abstract":"Neutropenia is more common in patients with systemic lupus erythematosus (SLE) and is a major cause of life-threatening infections. The increased apoptosis of neutrophils is likely to be an essential cause of neutropenia in SLE. However, the detailed mechanisms of increased neutrophil apoptosis in SLE remain unknown. This study focused on the role of Krüppel-like factor 2 (KLF2) in the regulation of neutrophil apoptosis and its association with SLE disease activity. The levels of KLF2 in neutrophils from SLE patients and healthy controls (HCs) were detected by RT-PCR and western blot. The relationship between the levels of KLF2 and the apoptosis levels of neutrophils in SLE patients was analyzed. The KLF2 inhibitor Geranylgeranyl pyrophosphate (GGPP) and the KLF2 inducer geranylgeranyl transferase inhibitor (GGTI-298) were used to incubate with neutrophils to investigate the role of KLF2 in the regulation of neutrophil apoptosis. To clarify whether serum from SLE patients affects neutrophil KLF2 expression and apoptosis, sera from SLE patients were collected and used to incubate with neutrophils from HCs, followed by the detection of KLF2 levels and apoptosis levels of neutrophils. Additionally, the correlation between KLF2 levels and SLE disease activity index (SLEDAI) was analyzed. The expression of KLF2 in neutrophils of SLE patients was significantly suppressed, and the decreased KLF2 was associated with the upregulation of neutrophil apoptosis. Moreover, newly diagnosed SLE patients, SLE patients with higher serum IgG and positive anti-Smith antibodies had lower KLF2 expression. Furthermore, we demonstrated that modulating the expression of KLF2 can regulate the apoptosis of neutrophils. The levels of KLF2 in neutrophils were associated with the SLEDAI. In addition, we found that serum from SLE patients could induce apoptosis in neutrophils by down-regulating the expression of KLF2. KLF2 controls the apoptosis of neutrophils and is associated with SLEDAI, which suggests that KLF2 in neutrophils may be involved in the occurrence and development of SLE.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"12 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849181","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}
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