Pub Date : 2024-11-12DOI: 10.1186/s13075-024-03417-3
Jeonghyeon Moon, Keun-Hyung Cho, JooYeon Jhun, JeongWon Choi, Hyun-Sik Na, Jeong Su Lee, Seung Yoon Lee, Jun-Ki Min, Anan Shetty, Sung-Hwan Park, Seok Jung Kim, Mi-La Cho
Osteoarthritis (OA) is a degenerative joint disease caused by the breakdown of joint cartilage and adjacent bone. Joint injury, being overweight, differences in leg length, high levels of joint stress, abnormal joint or limb development, and inherited factors have been implicated in the etiology of OA. In addition to physical damage to the joint, a role for inflammatory processes has been identified as well. Small heterodimer partner-interacting leucine zipper protein (SMILE) regulates transcription and many cellular functions. Among the proteins activated by SMILE is the peroxisome proliferator-activated receptor (PPAR) γ, which mediates the activities of CD4 + T helper cells, including Th1, Th2, and Th17, as well as Treg cells. PPAR-γ binds to STAT3 to inhibit its transcription, thereby suppressing the expression of the NF-κB pathway, and in turn, the expression of the inflammatory cytokines interferon (IFN), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which are sub-signals of STAT3 and NF-κB. OA was induced in control C57BL/6 mice and in C57BL/6-derived SMILE-overexpressing transgenic (SMILE Tg) mice. The protein expression levels in the joint and spleen tissues were analyzed by immunohistochemistry and immunofluorescence images. In addition, flow cytometry was performed for detecting changes of the changes of immune cells. Less cartilage damage and significantly reduced levels of OA biomarkers (MMP13, TIMP3 and MCP-1) were observed in SMILE Tg mice. Immunohistochemistry performed to identify the signaling pathway involved in the link between SMILE expression and OA revealed decreased levels of IL-1β, IL-6, TNF-α, and phosphorylated AMPK in synovial tissues as well as a significant decrease in phosphorylated STAT3 in both cartilage and synovium. Changes in systemic immune cells were investigated via flow cytometry to analyze splenocytes isolated from control and SMILE Tg mice. SMILE Tg mice had elevated proportions of CD4 + IL-4 + cells (Th2) and CD4 + CD25 + Foxp3 + cells (Treg) and a notable decrease in CD4 + IL-17 + cells (Th17). Our results show that overexpressed SMILE attenuates the symptoms of OA, by increasing AMPK signaling and decreasing STAT3, thus reducing the levels of inflammatory immune cells.
{"title":"Small heterodimer partner-interacting leucine zipper protein suppresses pain and cartilage destruction in an osteoarthritis model by modulating the AMPK/STAT3 signaling pathway","authors":"Jeonghyeon Moon, Keun-Hyung Cho, JooYeon Jhun, JeongWon Choi, Hyun-Sik Na, Jeong Su Lee, Seung Yoon Lee, Jun-Ki Min, Anan Shetty, Sung-Hwan Park, Seok Jung Kim, Mi-La Cho","doi":"10.1186/s13075-024-03417-3","DOIUrl":"https://doi.org/10.1186/s13075-024-03417-3","url":null,"abstract":"Osteoarthritis (OA) is a degenerative joint disease caused by the breakdown of joint cartilage and adjacent bone. Joint injury, being overweight, differences in leg length, high levels of joint stress, abnormal joint or limb development, and inherited factors have been implicated in the etiology of OA. In addition to physical damage to the joint, a role for inflammatory processes has been identified as well. Small heterodimer partner-interacting leucine zipper protein (SMILE) regulates transcription and many cellular functions. Among the proteins activated by SMILE is the peroxisome proliferator-activated receptor (PPAR) γ, which mediates the activities of CD4 + T helper cells, including Th1, Th2, and Th17, as well as Treg cells. PPAR-γ binds to STAT3 to inhibit its transcription, thereby suppressing the expression of the NF-κB pathway, and in turn, the expression of the inflammatory cytokines interferon (IFN), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which are sub-signals of STAT3 and NF-κB. OA was induced in control C57BL/6 mice and in C57BL/6-derived SMILE-overexpressing transgenic (SMILE Tg) mice. The protein expression levels in the joint and spleen tissues were analyzed by immunohistochemistry and immunofluorescence images. In addition, flow cytometry was performed for detecting changes of the changes of immune cells. Less cartilage damage and significantly reduced levels of OA biomarkers (MMP13, TIMP3 and MCP-1) were observed in SMILE Tg mice. Immunohistochemistry performed to identify the signaling pathway involved in the link between SMILE expression and OA revealed decreased levels of IL-1β, IL-6, TNF-α, and phosphorylated AMPK in synovial tissues as well as a significant decrease in phosphorylated STAT3 in both cartilage and synovium. Changes in systemic immune cells were investigated via flow cytometry to analyze splenocytes isolated from control and SMILE Tg mice. SMILE Tg mice had elevated proportions of CD4 + IL-4 + cells (Th2) and CD4 + CD25 + Foxp3 + cells (Treg) and a notable decrease in CD4 + IL-17 + cells (Th17). Our results show that overexpressed SMILE attenuates the symptoms of OA, by increasing AMPK signaling and decreasing STAT3, thus reducing the levels of inflammatory immune cells.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"36 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599797","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}
Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection in patients undergoing immunosuppressive therapy, such as glucocorticoid (GC) medication, for systemic autoimmune diseases like systemic lupus erythematosus (SLE). Despite the confirmed effectiveness of PCP prophylaxis, its clinical administration, especially in conjunction with GC dosage, remains unclear. We aimed to describe the clinical practice of PCP prophylaxis in association with SLE in Japan, evaluate the relationship between GC dosage and PCP prophylaxis, and explore the practice patterns associated with PCP prophylaxis. This cross-sectional study used data from the Lupus Registry of Nationwide Institutions in Japan from 2016 to 2021 and included patients diagnosed with SLE. Using descriptive statistics, multivariate analysis, and decision tree analysis, we examined the prevalence of PCP prophylaxis and its association with the GC dosage. Out of 1,460 patients, 21% underwent PCP prophylaxis. The frequency of prophylaxis decreased with a decrease in GC dosage. After adjusting for confounders, logistic regression revealed the odds ratio of PCP prophylaxis increased with higher prednisolone (PSL) doses: 3.7 for 5 ≤ PSL < 7.5 mg, 5.2 for 7.5 ≤ PSL < 10 mg, 9.0 for 10 ≤ PSL < 20 mg, and 43.1 for PSL ≥ 20 mg, using PSL < 5 mg as the reference. Decision tree analysis indicated that a PSL dosage of < 11 mg/day and immunosuppressant use were key determinants of PCP prophylaxis. This study provides valuable insights into PCP prophylaxis practices in patients with SLE in Japan, underscoring the importance of GC dosage and concomitant immunosuppressant use.
{"title":"Clinical practice pattern of Pneumocystis pneumonia prophylaxis in systemic lupus erythematosus: a cross-sectional study from lupus registry of nationwide institutions (LUNA)","authors":"Takahisa Onishi, Ken-ei Sada, Keigo Hayashi, Yoshia Miyawaki, Ryusuke Yoshimi, Yasuhiro Shimojima, Shigeru Ohno, Hiroshi Kajiyama, Kunihiro Ichinose, Shuzo Sato, Michio Fujiwara, Nobuyuki Yajima, Takashi Kida, Yusuke Matsuo, Keisuke Nishimura, Takashi Yamane","doi":"10.1186/s13075-024-03434-2","DOIUrl":"https://doi.org/10.1186/s13075-024-03434-2","url":null,"abstract":"Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection in patients undergoing immunosuppressive therapy, such as glucocorticoid (GC) medication, for systemic autoimmune diseases like systemic lupus erythematosus (SLE). Despite the confirmed effectiveness of PCP prophylaxis, its clinical administration, especially in conjunction with GC dosage, remains unclear. We aimed to describe the clinical practice of PCP prophylaxis in association with SLE in Japan, evaluate the relationship between GC dosage and PCP prophylaxis, and explore the practice patterns associated with PCP prophylaxis. This cross-sectional study used data from the Lupus Registry of Nationwide Institutions in Japan from 2016 to 2021 and included patients diagnosed with SLE. Using descriptive statistics, multivariate analysis, and decision tree analysis, we examined the prevalence of PCP prophylaxis and its association with the GC dosage. Out of 1,460 patients, 21% underwent PCP prophylaxis. The frequency of prophylaxis decreased with a decrease in GC dosage. After adjusting for confounders, logistic regression revealed the odds ratio of PCP prophylaxis increased with higher prednisolone (PSL) doses: 3.7 for 5 ≤ PSL < 7.5 mg, 5.2 for 7.5 ≤ PSL < 10 mg, 9.0 for 10 ≤ PSL < 20 mg, and 43.1 for PSL ≥ 20 mg, using PSL < 5 mg as the reference. Decision tree analysis indicated that a PSL dosage of < 11 mg/day and immunosuppressant use were key determinants of PCP prophylaxis. This study provides valuable insights into PCP prophylaxis practices in patients with SLE in Japan, underscoring the importance of GC dosage and concomitant immunosuppressant use.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"10 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599798","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 : 2024-11-12DOI: 10.1186/s13075-024-03430-6
Chongyang Feng, Lin Liu, Jinxue Zhang, Linxiao Wang, Ke Lv, Hongbo Li, Yong Ding
Osteoarthritis (OA) is the most common motor system disease in older people, characterized by a high incidence and significant social and economic burden. Women have a higher risk of OA, more severe clinical symptoms, and a higher rate of disabilities than men. However, the pathogenesis of OA remains unclear. Therefore, we screened for differentially expressed genes (DEGs) in OA patients of different sex and searched for new targets that may be involved in regulating the development of OA. The study compared the expression of DEGs in synovial fluid exosomes between male and female patients with OA through RNA sequencing combined with bioinformatics analysis using public data. To evaluate the screened DEGs, synovial tissue and fluid samples were obtained from patients with OA who underwent joint replacement surgery. SiRNA-mediated knockdown in vitro experiments were performed to investigate the role of glycoprotein membrane 6B (GPM6B). Meanwhile, GPM6B gene knockout mice were used to assess the in vivo pathological roles of GPM6B in OA. The results revealed that GPM6B is a potential target associated with OA. Immunofluorescence staining demonstrated that GPM6B was expressed in fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes in patients with OA. In vitro experiments confirmed that GPM6B knockdown can reduce the expression of inflammatory factors in primary FLS from patients with OA. Under inflammatory conditions, GPM6B knockdown can reduce the expression of matrix metalloproteinases as well as proliferation of FLS. In addition, using a destabilization of the medial meniscus-induced OA model, we revealed that GPM6B is associated with OA progression in mice. Thus, we provided evidence that GPM6B act as a new target associated with OA.
骨关节炎（OA）是老年人最常见的运动系统疾病，具有发病率高、社会和经济负担重的特点。与男性相比，女性患 OA 的风险更高，临床症状更严重，致残率也更高。然而，OA 的发病机制仍不清楚。因此，我们筛选了不同性别 OA 患者的差异表达基因（DEGs），并寻找可能参与调控 OA 发病的新靶点。本研究通过RNA测序结合生物信息学分析，利用公开数据比较了男性和女性OA患者滑膜液外泌体中DEGs的表达情况。为了评估筛选出的 DEGs，研究人员从接受关节置换手术的 OA 患者身上采集了滑膜组织和滑膜液样本。通过 SiRNA 介导的体外敲除实验研究糖蛋白膜 6B（GPM6B）的作用。同时，利用 GPM6B 基因敲除小鼠评估 GPM6B 在 OA 中的体内病理作用。结果显示，GPM6B是与OA相关的潜在靶点。免疫荧光染色显示，GPM6B 在 OA 患者的成纤维细胞样滑膜细胞（FLS）和巨噬细胞样滑膜细胞中均有表达。体外实验证实，敲除 GPM6B 可减少 OA 患者原代 FLS 中炎症因子的表达。在炎症条件下，GPM6B 基因敲除可减少基质金属蛋白酶的表达以及 FLS 的增殖。此外，我们利用内侧半月板失稳诱导的 OA 模型，发现 GPM6B 与小鼠 OA 的进展有关。因此，我们为 GPM6B 成为与 OA 相关的新靶点提供了证据。
{"title":"Investigation of GPM6B as a novel therapeutic target in Osteoarthritis","authors":"Chongyang Feng, Lin Liu, Jinxue Zhang, Linxiao Wang, Ke Lv, Hongbo Li, Yong Ding","doi":"10.1186/s13075-024-03430-6","DOIUrl":"https://doi.org/10.1186/s13075-024-03430-6","url":null,"abstract":"Osteoarthritis (OA) is the most common motor system disease in older people, characterized by a high incidence and significant social and economic burden. Women have a higher risk of OA, more severe clinical symptoms, and a higher rate of disabilities than men. However, the pathogenesis of OA remains unclear. Therefore, we screened for differentially expressed genes (DEGs) in OA patients of different sex and searched for new targets that may be involved in regulating the development of OA. The study compared the expression of DEGs in synovial fluid exosomes between male and female patients with OA through RNA sequencing combined with bioinformatics analysis using public data. To evaluate the screened DEGs, synovial tissue and fluid samples were obtained from patients with OA who underwent joint replacement surgery. SiRNA-mediated knockdown in vitro experiments were performed to investigate the role of glycoprotein membrane 6B (GPM6B). Meanwhile, GPM6B gene knockout mice were used to assess the in vivo pathological roles of GPM6B in OA. The results revealed that GPM6B is a potential target associated with OA. Immunofluorescence staining demonstrated that GPM6B was expressed in fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes in patients with OA. In vitro experiments confirmed that GPM6B knockdown can reduce the expression of inflammatory factors in primary FLS from patients with OA. Under inflammatory conditions, GPM6B knockdown can reduce the expression of matrix metalloproteinases as well as proliferation of FLS. In addition, using a destabilization of the medial meniscus-induced OA model, we revealed that GPM6B is associated with OA progression in mice. Thus, we provided evidence that GPM6B act as a new target associated with OA.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"41 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599751","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 : 2024-11-11DOI: 10.1186/s13075-024-03421-7
A. Clare Sparling, James M. Ward, Kakali Sarkar, Adam Schiffenbauer, Payam Noroozi Farhadi, Michael A. Smith, Saifur Rahman, Kamelia Zerrouki, Frederick W. Miller, Jian-Liang Li, Kerry A. Casey, Lisa G. Rider
Serum protein abundance was assessed in adult and juvenile dermatomyositis (DM and JDM) patients to determine differentially regulated proteins, altered pathways, and candidate disease activity biomarkers. Serum protein expression from 17 active adult DM and JDM patients each was compared to matched, healthy control subjects by a multiplex immunoassay. Pathway analysis and protein clustering of the differentially regulated proteins were examined to assess underlying mechanisms. Candidate disease activity biomarkers were identified by correlating protein expression with disease activity measures. Seventy-eight of 172 proteins were differentially expressed in the sera of DM and JDM patients compared to healthy controls. Forty-eight proteins were differentially expressed in DM, 32 proteins in JDM, and 14 proteins in both DM and JDM. Twelve additional differentially expressed proteins were identified after combining the DM and JDM cohorts. C-X-C motif chemokine ligand 10 (CXCL10) was the most strongly upregulated protein in both DM and JDM sera. Other highly upregulated proteins in DM included S100 calcium binding protein A12 (S100A12), CXCL9, and nicotinamide phosphoribosyltransferase (NAMPT), while highly upregulated proteins in JDM included matrix metallopeptidase 3 (MMP3), growth differentiation factor 15 (GDF15), and von Willebrand factor (vWF). Pathway analysis indicated that phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), and toll-like receptor 7 (TLR7) signaling were activated in DM and JDM. Additional pathways specific to DM or JDM were identified. A protein cluster associated with neutrophils and mononuclear leukocytes and a cluster of interferon-associated proteins were observed in both DM and JDM. Twenty-two proteins in DM and 24 proteins in JDM sera correlated with global, muscle, and/or skin disease activity. Seven proteins correlated with disease activity measures in both DM and JDM sera. IL-1 receptor like 1 (IL1RL1) emerged as a candidate global disease activity biomarker in DM and JDM. Coordinate analysis of protein expression in DM and JDM patient sera by a multiplex immunoassay validated previous gene expression studies and identified novel dysregulated proteins, altered signaling pathways, and candidate disease activity biomarkers. These findings may further inform the assessment of DM and JDM patients and aid in the identification of potential therapeutic targets.
{"title":"Neutrophil and mononuclear leukocyte pathways and upstream regulators revealed by serum proteomics of adult and juvenile dermatomyositis","authors":"A. Clare Sparling, James M. Ward, Kakali Sarkar, Adam Schiffenbauer, Payam Noroozi Farhadi, Michael A. Smith, Saifur Rahman, Kamelia Zerrouki, Frederick W. Miller, Jian-Liang Li, Kerry A. Casey, Lisa G. Rider","doi":"10.1186/s13075-024-03421-7","DOIUrl":"https://doi.org/10.1186/s13075-024-03421-7","url":null,"abstract":"Serum protein abundance was assessed in adult and juvenile dermatomyositis (DM and JDM) patients to determine differentially regulated proteins, altered pathways, and candidate disease activity biomarkers. Serum protein expression from 17 active adult DM and JDM patients each was compared to matched, healthy control subjects by a multiplex immunoassay. Pathway analysis and protein clustering of the differentially regulated proteins were examined to assess underlying mechanisms. Candidate disease activity biomarkers were identified by correlating protein expression with disease activity measures. Seventy-eight of 172 proteins were differentially expressed in the sera of DM and JDM patients compared to healthy controls. Forty-eight proteins were differentially expressed in DM, 32 proteins in JDM, and 14 proteins in both DM and JDM. Twelve additional differentially expressed proteins were identified after combining the DM and JDM cohorts. C-X-C motif chemokine ligand 10 (CXCL10) was the most strongly upregulated protein in both DM and JDM sera. Other highly upregulated proteins in DM included S100 calcium binding protein A12 (S100A12), CXCL9, and nicotinamide phosphoribosyltransferase (NAMPT), while highly upregulated proteins in JDM included matrix metallopeptidase 3 (MMP3), growth differentiation factor 15 (GDF15), and von Willebrand factor (vWF). Pathway analysis indicated that phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), and toll-like receptor 7 (TLR7) signaling were activated in DM and JDM. Additional pathways specific to DM or JDM were identified. A protein cluster associated with neutrophils and mononuclear leukocytes and a cluster of interferon-associated proteins were observed in both DM and JDM. Twenty-two proteins in DM and 24 proteins in JDM sera correlated with global, muscle, and/or skin disease activity. Seven proteins correlated with disease activity measures in both DM and JDM sera. IL-1 receptor like 1 (IL1RL1) emerged as a candidate global disease activity biomarker in DM and JDM. Coordinate analysis of protein expression in DM and JDM patient sera by a multiplex immunoassay validated previous gene expression studies and identified novel dysregulated proteins, altered signaling pathways, and candidate disease activity biomarkers. These findings may further inform the assessment of DM and JDM patients and aid in the identification of potential therapeutic targets.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"215 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598318","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 : 2024-11-11DOI: 10.1186/s13075-024-03428-0
Yu Katayama, Yoshia Miyawaki, Kenta Shidahara, Shoichi Nawachi, Yosuke Asano, Eri Katsuyama, Takayuki Katsuyama, Mariko Takano-Narazaki, Yoshinori Matsumoto, Nao Oguro, Nobuyuki Yajima, Yuichi Ishikawa, Natsuki Sakurai, Chiharu Hidekawa, Ryusuke Yoshimi, Shigeru Ohno, Takanori Ichikawa, Dai Kishida, Yasuhiro Shimojima, Ken-ei Sada, Jun Wada, David H. Thom, Noriaki Kurita
Patient trust plays a central role in the patient-physician relationship. This study aimed to determine whether the number of outpatient visits with a covering rheumatologist is associated with patient trust in their usual rheumatologist. Japanese adults with systemic lupus erythematosus (SLE) who met the 1997 revised classification criteria of the American College of Rheumatology and had outpatient visits with a covering rheumatologist in the past year were included. We used the 11-item Japanese version of the modified Trust in Physician Scale (range 0–100) to assess patient trust. A general linear model with cluster-robust variance estimation was used to evaluate the association between the number of outpatient visits with covering rheumatologists and the patient’s trust in their usual rheumatologist. Of the 515 enrolled participants, 421 patients with SLE were included in our analyses. Patients were divided into groups according to the number of outpatient visits with a covering rheumatologist in the past year as follows: no visits (59.9%; reference group), one to three visits (24.2%; low-frequency group), and four or more visits (15.9%; high-frequency group). The median Trust in Physician Scale score was 81.8 (interquartile range: 72.7–93.2). Both the low-frequency group (mean difference: -3.03; 95% confidence interval [CI] -5.93 to -0.80) and high-frequency group (mean difference: -4.17; 95% CI -7.77 to -0.58) exhibited lower trust in their usual rheumatologist. This study revealed that the number of outpatient visits with a covering rheumatologist was associated with lower trust in a patient’s usual rheumatologist.
{"title":"Association between discontinuity of care and patient trust in the usual rheumatologist among patients with systemic lupus erythematosus: a cross-sectional study","authors":"Yu Katayama, Yoshia Miyawaki, Kenta Shidahara, Shoichi Nawachi, Yosuke Asano, Eri Katsuyama, Takayuki Katsuyama, Mariko Takano-Narazaki, Yoshinori Matsumoto, Nao Oguro, Nobuyuki Yajima, Yuichi Ishikawa, Natsuki Sakurai, Chiharu Hidekawa, Ryusuke Yoshimi, Shigeru Ohno, Takanori Ichikawa, Dai Kishida, Yasuhiro Shimojima, Ken-ei Sada, Jun Wada, David H. Thom, Noriaki Kurita","doi":"10.1186/s13075-024-03428-0","DOIUrl":"https://doi.org/10.1186/s13075-024-03428-0","url":null,"abstract":"Patient trust plays a central role in the patient-physician relationship. This study aimed to determine whether the number of outpatient visits with a covering rheumatologist is associated with patient trust in their usual rheumatologist. Japanese adults with systemic lupus erythematosus (SLE) who met the 1997 revised classification criteria of the American College of Rheumatology and had outpatient visits with a covering rheumatologist in the past year were included. We used the 11-item Japanese version of the modified Trust in Physician Scale (range 0–100) to assess patient trust. A general linear model with cluster-robust variance estimation was used to evaluate the association between the number of outpatient visits with covering rheumatologists and the patient’s trust in their usual rheumatologist. Of the 515 enrolled participants, 421 patients with SLE were included in our analyses. Patients were divided into groups according to the number of outpatient visits with a covering rheumatologist in the past year as follows: no visits (59.9%; reference group), one to three visits (24.2%; low-frequency group), and four or more visits (15.9%; high-frequency group). The median Trust in Physician Scale score was 81.8 (interquartile range: 72.7–93.2). Both the low-frequency group (mean difference: -3.03; 95% confidence interval [CI] -5.93 to -0.80) and high-frequency group (mean difference: -4.17; 95% CI -7.77 to -0.58) exhibited lower trust in their usual rheumatologist. This study revealed that the number of outpatient visits with a covering rheumatologist was associated with lower trust in a patient’s usual rheumatologist.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"45 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598319","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}
Neuropsychiatric manifestations, such as cognitive impairment, are relatively prevalent in systemic sclerosis (SSc) patients. This study aimed to investigate the resting state (RS) functional alternations of SSc patients and the potential influenced factors. Forty-four SSc patients (mean age, 46.3 ± 11.4 years; 40 females) and 19 age and sex comparable healthy volunteers (mean age, 42.6 ± 11.3 years; 16 females) were recruited and underwent RS functional MR imaging (fMRI) and neuropsychological assessments. Functional segregation analysis was performed to calculate the amplitude of low frequency fluctuation (ALFF) and regional homogeneity (ReHo). Functional integration analysis was conducted using group independent component analysis to calculate intra-network and inter-network functional connectivity (FC). The fMRI measurements were compared between SSc patients and healthy volunteers using voxel-based pairwise two-sample t-tests. The correlations between clinical characteristics and fMRI measurements were also analyzed. Compared to healthy volunteers, SSc patients exhibited significantly decreased ALFF and increased ReHo (all P < 0.01, FWE corrected). SSc patients predominantly showed decreased intra-network and inter-network FC in the auditory network, visual network, default mode network, frontoparietal network and attention network (intra-network FC: P < 0.01, uncorrected, cluster size > 30; inter-network FC: P < 0.05, FDR correction). Furthermore, clinical characteristics including disease duration (r value ranged from − 0.31 to 0.36), elevated erythrocyte sedimentation rate (r = 0.35), Montreal Cognitive Assessment score (r = 0.43), and Hamilton Depression Scale score (r = -0.40) were significantly associated with fMRI measurements (all P < 0.05). Spontaneous activity and functional connectivity alternations can be seen in SSc patients, which are partially associated with neuropsychiatric manifestations and tend to aggravate with disease duration.
{"title":"Brain functional alternation in patients with systemic sclerosis: a resting-state functional magnetic resonance imaging study","authors":"Xinyu Tong, Huilin He, Shihan Xu, Rui Shen, Zihan Ning, Xiaofeng Zeng, Qian Wang, Dong Xu, Zuo-Xiang He, Xihai Zhao","doi":"10.1186/s13075-024-03433-3","DOIUrl":"https://doi.org/10.1186/s13075-024-03433-3","url":null,"abstract":"Neuropsychiatric manifestations, such as cognitive impairment, are relatively prevalent in systemic sclerosis (SSc) patients. This study aimed to investigate the resting state (RS) functional alternations of SSc patients and the potential influenced factors. Forty-four SSc patients (mean age, 46.3 ± 11.4 years; 40 females) and 19 age and sex comparable healthy volunteers (mean age, 42.6 ± 11.3 years; 16 females) were recruited and underwent RS functional MR imaging (fMRI) and neuropsychological assessments. Functional segregation analysis was performed to calculate the amplitude of low frequency fluctuation (ALFF) and regional homogeneity (ReHo). Functional integration analysis was conducted using group independent component analysis to calculate intra-network and inter-network functional connectivity (FC). The fMRI measurements were compared between SSc patients and healthy volunteers using voxel-based pairwise two-sample t-tests. The correlations between clinical characteristics and fMRI measurements were also analyzed. Compared to healthy volunteers, SSc patients exhibited significantly decreased ALFF and increased ReHo (all P < 0.01, FWE corrected). SSc patients predominantly showed decreased intra-network and inter-network FC in the auditory network, visual network, default mode network, frontoparietal network and attention network (intra-network FC: P < 0.01, uncorrected, cluster size > 30; inter-network FC: P < 0.05, FDR correction). Furthermore, clinical characteristics including disease duration (r value ranged from − 0.31 to 0.36), elevated erythrocyte sedimentation rate (r = 0.35), Montreal Cognitive Assessment score (r = 0.43), and Hamilton Depression Scale score (r = -0.40) were significantly associated with fMRI measurements (all P < 0.05). Spontaneous activity and functional connectivity alternations can be seen in SSc patients, which are partially associated with neuropsychiatric manifestations and tend to aggravate with disease duration.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"9 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596913","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}
Our objective was to ascertain the most recent prevalence and trends of hyperuricemia among adolescents, stratified by sex and race/ethnicity subgroups, as well as to investigate potential risk factors associated with hyperuricemia in US adolescents. Data were obtained from adolescents aged 12–17 years in the 1999–2018 NHANES cycles. Hyperuricemia for adolescents was defined as ≥ 5.5 mg/dL. The prevalence of hyperuricemia, along with 95% confidence intervals (CIs), was calculated for each four-year survey cycle, stratified by sex, race/ethnicity, body mass index (BMI), poverty income ratio (PIR), and parental education levels. Linear regression and logistic regression analyses were conducted independently to evaluate the linear trends in mean serum urate levels and the prevalence of hyperuricemia across the four-year cycles. Utilizing NHANES data from 2011 to 2018, we identified factors associated with mean serum urate levels and hyperuricemia through the application of linear regression and Poisson regression analyses. A total of 11 264 participants were included in the analysis. In 2015–2018, the overall hyperuricemia prevalence was 32.78%, 50.7% in males, and 13.51% in females. No significant trends were identified in the prevalence of hyperuricemia from 1999 to 2002 to 2015–2018. Between 2011 and 2018, hyperuricemia was significantly more prevalent among males compared to females (prevalence ratio [PR], 3.50 [95% CI, 2.83–4.33]), non-Hispanic Asians compared to non-Hispanic Whites (PR, 1.26 [95% CI, 1.04–1.53]), and individuals with overweight (PR, 1.63 [95% CI, 1.32–2.01]) or obesity (PR, 2.45 [95% CI, 2.08–2.88]) compared to those of normal weight. There was a stronger correlation between obesity and hyperuricemia among females (PR, 4.77 [95% CI, 3.08–7.39]) than in males (PR, 2.06 [95% CI, 1.82–2.34]). Furthermore, non-Hispanic Black adolescents with obesity exhibited higher PRs (PR, 3.40 [95% CI, 2.54–4.55]) for hyperuricemia in comparison to other ethnic groups. This study has updated recent trends in hyperuricemia by sex and race/ethnicity among US adolescents. Our results suggest that hyperuricemia has a significant association with greater obesity in US adolescents, and the degree of correlation varies by sex and race/ethnicity.
{"title":"Prevalence of and trends in hyperuricemia by race and ethnicity among US adolescents, 1999–2018","authors":"Kaifeng Guo, Yali Han, Shuang Liu, Hang Sun, Xiaojing Lin, Shaoling Yang, Yining Gao, Haibing Chen","doi":"10.1186/s13075-024-03427-1","DOIUrl":"https://doi.org/10.1186/s13075-024-03427-1","url":null,"abstract":"Our objective was to ascertain the most recent prevalence and trends of hyperuricemia among adolescents, stratified by sex and race/ethnicity subgroups, as well as to investigate potential risk factors associated with hyperuricemia in US adolescents. Data were obtained from adolescents aged 12–17 years in the 1999–2018 NHANES cycles. Hyperuricemia for adolescents was defined as ≥ 5.5 mg/dL. The prevalence of hyperuricemia, along with 95% confidence intervals (CIs), was calculated for each four-year survey cycle, stratified by sex, race/ethnicity, body mass index (BMI), poverty income ratio (PIR), and parental education levels. Linear regression and logistic regression analyses were conducted independently to evaluate the linear trends in mean serum urate levels and the prevalence of hyperuricemia across the four-year cycles. Utilizing NHANES data from 2011 to 2018, we identified factors associated with mean serum urate levels and hyperuricemia through the application of linear regression and Poisson regression analyses. A total of 11 264 participants were included in the analysis. In 2015–2018, the overall hyperuricemia prevalence was 32.78%, 50.7% in males, and 13.51% in females. No significant trends were identified in the prevalence of hyperuricemia from 1999 to 2002 to 2015–2018. Between 2011 and 2018, hyperuricemia was significantly more prevalent among males compared to females (prevalence ratio [PR], 3.50 [95% CI, 2.83–4.33]), non-Hispanic Asians compared to non-Hispanic Whites (PR, 1.26 [95% CI, 1.04–1.53]), and individuals with overweight (PR, 1.63 [95% CI, 1.32–2.01]) or obesity (PR, 2.45 [95% CI, 2.08–2.88]) compared to those of normal weight. There was a stronger correlation between obesity and hyperuricemia among females (PR, 4.77 [95% CI, 3.08–7.39]) than in males (PR, 2.06 [95% CI, 1.82–2.34]). Furthermore, non-Hispanic Black adolescents with obesity exhibited higher PRs (PR, 3.40 [95% CI, 2.54–4.55]) for hyperuricemia in comparison to other ethnic groups. This study has updated recent trends in hyperuricemia by sex and race/ethnicity among US adolescents. Our results suggest that hyperuricemia has a significant association with greater obesity in US adolescents, and the degree of correlation varies by sex and race/ethnicity.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"23 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596912","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 : 2024-11-08DOI: 10.1186/s13075-024-03431-5
Bernardo D’Onofrio, Ludovico De Stefano, Emanuele Bozzalla Cassione, Valentina Morandi, Francesca Cuzzocrea, Garifallia Sakellariou, Antonio Manzo, Carlomaurizio Montecucco, Serena Bugatti
To investigate the frequency of difficult-to-treat (D2T) rheumatoid arthritis (RA) in patients early escalated to biologic/targeted synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) after failure of treat-to-target with methotrexate (MTX). From a prospective cohort of early RA, all patients with their first access in the years 2005–2018, and eventually starting a b/tsDMARD before the end of 2022, were included and followed-up until April 2024. Study outcomes included drug survival on each consecutive b/tsDMARDs, development of D2T (according to the EULAR definition and subsequent modifications), and its predictors. Of a total cohort of 722 early RA patients treated with initial MTX and followed-up for at least 3 years from diagnosis, 155 (21.5%) had started a b/tsDMARD after a median of 19 months. In more than 70% of the cases, RA was uncontrolled despite optimal doses of MTX of ≥ 15 mg/day. The retention rates of the first and the second b/tsDMARD were approximatively 70% after 1 year but dropped to 40% after 5 years. After a median (IQR) follow up of 72.6 (34.5-134.2) months, 45 patients (29%) fulfilled the EULAR D2T criteria. At multivariable analysis, higher number of swollen joints and worse pain scores were confirmed as predictors of D2T. Furthermore, in this early RA cohort, shorter disease duration at the start of treatment with b/tsDMARDs, together with negativity for autoantibodies, were also independent predictors of D2T. Early implementation of treatment after failure of treat-to-target with MTX may not prevent the development of D2T in RA. Patients showing early refractoriness to conventional drugs and those lacking autoantibodies are at higher risk of multiple treatment failures.
{"title":"Timely escalation to second-line therapies after failure of methotrexate in patients with early rheumatoid arthritis does not reduce the risk of becoming difficult-to-treat","authors":"Bernardo D’Onofrio, Ludovico De Stefano, Emanuele Bozzalla Cassione, Valentina Morandi, Francesca Cuzzocrea, Garifallia Sakellariou, Antonio Manzo, Carlomaurizio Montecucco, Serena Bugatti","doi":"10.1186/s13075-024-03431-5","DOIUrl":"https://doi.org/10.1186/s13075-024-03431-5","url":null,"abstract":"To investigate the frequency of difficult-to-treat (D2T) rheumatoid arthritis (RA) in patients early escalated to biologic/targeted synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) after failure of treat-to-target with methotrexate (MTX). From a prospective cohort of early RA, all patients with their first access in the years 2005–2018, and eventually starting a b/tsDMARD before the end of 2022, were included and followed-up until April 2024. Study outcomes included drug survival on each consecutive b/tsDMARDs, development of D2T (according to the EULAR definition and subsequent modifications), and its predictors. Of a total cohort of 722 early RA patients treated with initial MTX and followed-up for at least 3 years from diagnosis, 155 (21.5%) had started a b/tsDMARD after a median of 19 months. In more than 70% of the cases, RA was uncontrolled despite optimal doses of MTX of ≥ 15 mg/day. The retention rates of the first and the second b/tsDMARD were approximatively 70% after 1 year but dropped to 40% after 5 years. After a median (IQR) follow up of 72.6 (34.5-134.2) months, 45 patients (29%) fulfilled the EULAR D2T criteria. At multivariable analysis, higher number of swollen joints and worse pain scores were confirmed as predictors of D2T. Furthermore, in this early RA cohort, shorter disease duration at the start of treatment with b/tsDMARDs, together with negativity for autoantibodies, were also independent predictors of D2T. Early implementation of treatment after failure of treat-to-target with MTX may not prevent the development of D2T in RA. Patients showing early refractoriness to conventional drugs and those lacking autoantibodies are at higher risk of multiple treatment failures.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596950","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 : 2024-11-07DOI: 10.1186/s13075-024-03413-7
Lian Gui, Xiaoyu Zuo, Junmei Feng, Mingbang Wang, Zena Chen, Yuhan Sun, Jun Qi, Zhuanggui Chen, Janak L. Pathak, Yanli Zhang, Chunping Cui, Pingping Zhang, Xinghua Guo, Qing Lv, Xi Zhang, Yan Zhang, Jieruo Gu, Zhiming Lin
Systemic lupus erythematosus (SLE) is linked to host gut dysbiosis. Here we performed faecal gut microbiome sequencing to investigate SLE-pathogenic gut microbes and their potential mechanisms. There were 134 healthy controls (HCs) and 114 SLE cases for 16 S ribosomal RNA (rRNA) sequencing and 97 HCs and 124 SLE cases for shotgun metagenomics. Faecal microbial changes and associations with clinical phenotypes were evaluated, and SLE-associated microbial genera were identified in amplicon analysis. Next, metagenomic sequencing was applied for accurate identification of microbial species and discovery of their metabolic pathways and immunogenic peptides both relevant to SLE. Finally, contribution of specific taxa to disease development was confirmed by oral gavage into lupus-prone MRL/lpr mice. SLE patients had gut microbiota richness reduction and composition alteration, particularly lupus nephritis and active patients. Proteobacteria/Bacteroidetes (P/B) ratio was remarkably up-regulated, and Escherichia was identified as the dominantly expanded genus in SLE, followed by metagenomics accurately located Escherichia coli and Escherichia unclassified species. Significant associations primarily appeared among Escherichia coli, metabolic pathways of purine nucleotide salvage or peptidoglycan maturation and SLE disease activity index (SLEDAI), and between multiple epitopes from Escherichia coli and disease activity or renal involvement phenotype. Finally, gavage with faecal Escherichia revealed that it upregulated lupus-associated serum traits and aggravated glomerular lesions in MRL/lpr mice. We characterize a novel SLE exacerbating Escherichia outgrowth and suggest its contribution to SLE procession may be partially associated with metabolite changes and cross-reactivity of gut microbiota-associated epitopes and host autoantigens. The findings could provide a deeper insight into gut Escherichia in the procession of SLE.
{"title":"Outgrowth of Escherichia is susceptible to aggravation of systemic lupus erythematosus","authors":"Lian Gui, Xiaoyu Zuo, Junmei Feng, Mingbang Wang, Zena Chen, Yuhan Sun, Jun Qi, Zhuanggui Chen, Janak L. Pathak, Yanli Zhang, Chunping Cui, Pingping Zhang, Xinghua Guo, Qing Lv, Xi Zhang, Yan Zhang, Jieruo Gu, Zhiming Lin","doi":"10.1186/s13075-024-03413-7","DOIUrl":"https://doi.org/10.1186/s13075-024-03413-7","url":null,"abstract":"Systemic lupus erythematosus (SLE) is linked to host gut dysbiosis. Here we performed faecal gut microbiome sequencing to investigate SLE-pathogenic gut microbes and their potential mechanisms. There were 134 healthy controls (HCs) and 114 SLE cases for 16 S ribosomal RNA (rRNA) sequencing and 97 HCs and 124 SLE cases for shotgun metagenomics. Faecal microbial changes and associations with clinical phenotypes were evaluated, and SLE-associated microbial genera were identified in amplicon analysis. Next, metagenomic sequencing was applied for accurate identification of microbial species and discovery of their metabolic pathways and immunogenic peptides both relevant to SLE. Finally, contribution of specific taxa to disease development was confirmed by oral gavage into lupus-prone MRL/lpr mice. SLE patients had gut microbiota richness reduction and composition alteration, particularly lupus nephritis and active patients. Proteobacteria/Bacteroidetes (P/B) ratio was remarkably up-regulated, and Escherichia was identified as the dominantly expanded genus in SLE, followed by metagenomics accurately located Escherichia coli and Escherichia unclassified species. Significant associations primarily appeared among Escherichia coli, metabolic pathways of purine nucleotide salvage or peptidoglycan maturation and SLE disease activity index (SLEDAI), and between multiple epitopes from Escherichia coli and disease activity or renal involvement phenotype. Finally, gavage with faecal Escherichia revealed that it upregulated lupus-associated serum traits and aggravated glomerular lesions in MRL/lpr mice. We characterize a novel SLE exacerbating Escherichia outgrowth and suggest its contribution to SLE procession may be partially associated with metabolite changes and cross-reactivity of gut microbiota-associated epitopes and host autoantigens. The findings could provide a deeper insight into gut Escherichia in the procession of SLE.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"28 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594642","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 : 2024-11-06DOI: 10.1186/s13075-024-03425-3
Molly Klimak, Amanda Cimino, Kristin L Lenz, Luke E Springer, Kelsey H Collins, Natalia S Harasymowicz, Nathan Xu, Christine T N Pham, Farshid Guilak
Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by increased levels of inflammation that primarily manifests in the joints. Macrophages act as key drivers for the progression of RA, contributing to the perpetuation of chronic inflammation and dysregulation of pro-inflammatory cytokines such as interleukin 1 (IL-1). The goal of this study was to develop a macrophage-based cell therapy for biologic drug delivery in an autoregulated manner.
Methods: For proof-of-concept, we developed "smart" macrophages to mitigate the effects of IL-1 by delivering its inhibitor, IL-1 receptor antagonist (IL-1Ra). Bone marrow-derived macrophages were lentivirally transduced with a synthetic gene circuit that uses an NF-κB inducible promoter upstream of either the Il1rn or firefly luciferase transgenes. Two types of joint like cells were utilized to examine therapeutic protection in vitro, miPSCs derived cartilage and isolated primary mouse synovial fibroblasts while the K/BxN mouse model of RA was utilized to examine in vivo therapeutic protection.
Results: These engineered macrophages were able to repeatably produce therapeutic levels of IL-1Ra that could successfully mitigate inflammatory activation in co-culture with both tissue-engineered cartilage constructs and synovial fibroblasts. Following injection in vivo, macrophages homed to sites of inflammation and mitigated disease severity in the K/BxN mouse model of RA.
Conclusion: These findings demonstrate the successful development of engineered macrophages that possess the ability for controlled, autoregulated production of IL-1 based on inflammatory signaling such as via the NF-κB pathway to mitigate the effects of this cytokine for applications in RA or other inflammatory diseases. This system provides proof of concept for applications in other immune cell types as self-regulating delivery systems for therapeutic applications in a range of diseases.
背景：类风湿性关节炎（RA）是一种全身性自身免疫性疾病，其特点是炎症程度加剧，主要表现在关节部位。巨噬细胞是导致类风湿性关节炎恶化的关键因素，会导致慢性炎症的持续存在以及白细胞介素 1（IL-1）等促炎细胞因子的失调。本研究的目标是开发一种基于巨噬细胞的细胞疗法，以自动调节的方式进行生物给药：为了验证概念，我们开发了 "智能 "巨噬细胞，通过递送 IL-1 抑制剂 IL-1 受体拮抗剂（IL-1Ra）来减轻 IL-1 的影响。我们用合成基因回路慢病毒转导骨髓来源的巨噬细胞，该基因回路使用了Il1rn或萤火虫荧光素酶转基因上游的NF-κB诱导启动子。利用两种类型的关节样细胞（miPSCs 衍生软骨和分离的小鼠滑膜原代成纤维细胞）来检测体外治疗保护，同时利用 K/BxN RA 小鼠模型来检测体内治疗保护：结果：这些工程巨噬细胞能重复产生治疗水平的IL-1Ra，在与组织工程软骨构建物和滑膜成纤维细胞共培养时，能成功缓解炎症激活。在体内注射后，巨噬细胞会聚集到炎症部位，减轻K/BxN小鼠RA模型的疾病严重程度：这些研究结果表明，我们成功地开发出了工程巨噬细胞，这种巨噬细胞能够根据炎症信号（如通过 NF-κB 通路）控制 IL-1 的自动调节产生，从而减轻这种细胞因子对 RA 或其他炎症性疾病的影响。该系统为在其他免疫细胞类型中应用自我调节递送系统提供了概念验证，可用于一系列疾病的治疗。
{"title":"Engineered self-regulating macrophages for targeted anti-inflammatory drug delivery.","authors":"Molly Klimak, Amanda Cimino, Kristin L Lenz, Luke E Springer, Kelsey H Collins, Natalia S Harasymowicz, Nathan Xu, Christine T N Pham, Farshid Guilak","doi":"10.1186/s13075-024-03425-3","DOIUrl":"10.1186/s13075-024-03425-3","url":null,"abstract":"<p><strong>Background: </strong>Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by increased levels of inflammation that primarily manifests in the joints. Macrophages act as key drivers for the progression of RA, contributing to the perpetuation of chronic inflammation and dysregulation of pro-inflammatory cytokines such as interleukin 1 (IL-1). The goal of this study was to develop a macrophage-based cell therapy for biologic drug delivery in an autoregulated manner.</p><p><strong>Methods: </strong>For proof-of-concept, we developed \"smart\" macrophages to mitigate the effects of IL-1 by delivering its inhibitor, IL-1 receptor antagonist (IL-1Ra). Bone marrow-derived macrophages were lentivirally transduced with a synthetic gene circuit that uses an NF-κB inducible promoter upstream of either the Il1rn or firefly luciferase transgenes. Two types of joint like cells were utilized to examine therapeutic protection in vitro, miPSCs derived cartilage and isolated primary mouse synovial fibroblasts while the K/BxN mouse model of RA was utilized to examine in vivo therapeutic protection.</p><p><strong>Results: </strong>These engineered macrophages were able to repeatably produce therapeutic levels of IL-1Ra that could successfully mitigate inflammatory activation in co-culture with both tissue-engineered cartilage constructs and synovial fibroblasts. Following injection in vivo, macrophages homed to sites of inflammation and mitigated disease severity in the K/BxN mouse model of RA.</p><p><strong>Conclusion: </strong>These findings demonstrate the successful development of engineered macrophages that possess the ability for controlled, autoregulated production of IL-1 based on inflammatory signaling such as via the NF-κB pathway to mitigate the effects of this cytokine for applications in RA or other inflammatory diseases. This system provides proof of concept for applications in other immune cell types as self-regulating delivery systems for therapeutic applications in a range of diseases.</p>","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"26 1","pages":"190"},"PeriodicalIF":4.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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