Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. PsA disease involves flares, which are associated with increased joint inflammation and tissue remodeling. There is a need for identifying biomarkers related to PsA disease activity and flares to improve the management of PsA patients and decrease flares. The tissue turnover imbalance that occurs during the inflammatory and fibro-proliferative processes during flares leads to an increased degradation and/or reorganization of the extracellular matrix (ECM), where increased proteolysis plays a key role. Hence, protease-mediated fragments of inflammatory and tissue-remodeling components could be used as markers reflecting flares in PsA patients. A broad panel of protease-mediated biomarkers reflecting inflammation and tissue remodeling was measured in serum and synovial fluid (SF) obtained from PsA patients experiencing flares (acutely swollen joint[s], PsA-flare). In serum, biomarker levels assessed in PsA-flare patients were compared to controls and in early-diagnosed PsA patients not experiencing flares (referred to as PsA without flare). Furthermore, the biomarker levels assessed in SF from PsA-flare patients were compared to the levels in SF of osteoarthritis (OA) patients. In serum, levels of the PRO-C3 and C3M, reflecting formation and degradation of the interstitial matrix, were found significantly elevated in PsA-flare compared to controls and PsA without flare. The remodeling marker of the basement membrane, PRO-C4, was significantly elevated in PsA-flare compared to PsA without flare. The inflammation and immune cell activity related markers, CRPM, VICM, and CPa9-HNE were significantly elevated in PsA-flare patients compared to controls and PsA without flare. In addition, VICM (AUC = 0.71), CPa9-HNE (AUC = 0.89), CRPM (AUC = 0.76), and PRO-C3 (AUC = 0.86) showed good discriminatory performance for separating PsA-flare from PsA without flare. In SF, the macrophage activity marker, VICM, was significantly elevated whereas the type II collagen formation marker, PRO-C2, was significantly reduced in the PsA-flare compared to OA. The combination of five serum markers reflecting type III and IV collagen degradation (C3M and C4M, respectively), type III and VI collagen formation (PRO-C3 and PRO-C6, respectively), and neutrophil activity (CPa9-HNE) showed an excellent discriminatory performance (AUC = 0.98) for separating PsA-flare from PsA without flares. The serum biomarker panel of C3M, C4M, PRO-C3, PRO-C6, and CPa9-HNE reflecting synovitis, enthesitis, and neutrophil activity may serve as novel tool for quantitatively monitoring flares in PsA patients.
{"title":"Investigating protease-mediated peptides of inflammation and tissue remodeling as biomarkers associated with flares in psoriatic arthritis","authors":"Solveig Skovlund Groen, Signe Holm Nielsen, Anne Christine Bay-Jensen, Mozhgan Rasti, Darshini Ganatra, Katerina Oikonomopoulou, Vinod Chandran","doi":"10.1186/s13075-024-03332-7","DOIUrl":"https://doi.org/10.1186/s13075-024-03332-7","url":null,"abstract":"Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. PsA disease involves flares, which are associated with increased joint inflammation and tissue remodeling. There is a need for identifying biomarkers related to PsA disease activity and flares to improve the management of PsA patients and decrease flares. The tissue turnover imbalance that occurs during the inflammatory and fibro-proliferative processes during flares leads to an increased degradation and/or reorganization of the extracellular matrix (ECM), where increased proteolysis plays a key role. Hence, protease-mediated fragments of inflammatory and tissue-remodeling components could be used as markers reflecting flares in PsA patients. A broad panel of protease-mediated biomarkers reflecting inflammation and tissue remodeling was measured in serum and synovial fluid (SF) obtained from PsA patients experiencing flares (acutely swollen joint[s], PsA-flare). In serum, biomarker levels assessed in PsA-flare patients were compared to controls and in early-diagnosed PsA patients not experiencing flares (referred to as PsA without flare). Furthermore, the biomarker levels assessed in SF from PsA-flare patients were compared to the levels in SF of osteoarthritis (OA) patients. In serum, levels of the PRO-C3 and C3M, reflecting formation and degradation of the interstitial matrix, were found significantly elevated in PsA-flare compared to controls and PsA without flare. The remodeling marker of the basement membrane, PRO-C4, was significantly elevated in PsA-flare compared to PsA without flare. The inflammation and immune cell activity related markers, CRPM, VICM, and CPa9-HNE were significantly elevated in PsA-flare patients compared to controls and PsA without flare. In addition, VICM (AUC = 0.71), CPa9-HNE (AUC = 0.89), CRPM (AUC = 0.76), and PRO-C3 (AUC = 0.86) showed good discriminatory performance for separating PsA-flare from PsA without flare. In SF, the macrophage activity marker, VICM, was significantly elevated whereas the type II collagen formation marker, PRO-C2, was significantly reduced in the PsA-flare compared to OA. The combination of five serum markers reflecting type III and IV collagen degradation (C3M and C4M, respectively), type III and VI collagen formation (PRO-C3 and PRO-C6, respectively), and neutrophil activity (CPa9-HNE) showed an excellent discriminatory performance (AUC = 0.98) for separating PsA-flare from PsA without flares. The serum biomarker panel of C3M, C4M, PRO-C3, PRO-C6, and CPa9-HNE reflecting synovitis, enthesitis, and neutrophil activity may serve as novel tool for quantitatively monitoring flares in PsA patients.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156594","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}
The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guideline has recently revised the hemodynamic definition of pulmonary arterial hypertension. However, there is currently limited research on the prognosis and treatment of system lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH) patients that have been reclassified by the new hemodynamic definition. This study aims to analyze the prognosis of newly reclassified SLE-PAH patients and provide recommendations for the management strategy. This retrospective study analyzed records of 236 SLE-PAH patients who visited Peking Union Medical College Hospital (PUMCH) from 2011 to 2023, among whom 22 patients were reclassified into mild SLE-PAH (mean pulmonary arterial pressure (mPAP) of 21–24 mmHg, pulmonary vascular resistance (PVR) of 2–3 WU, and PAWP ≤ 15 mmHg) according to the guidelines and 14 were defined as unclassified SLE-PAH patients (mPAP 21–24 mmHg and PVR ≤ 2 WU). The prognosis was compared among mild SLE-PAH, unclassified SLE-PH, and conventional SLE-PAH patients (mPAP ≥ 25 mmHg and PVR > 3WU). Besides, the effectiveness of pulmonary arterial hypertension (PAH)-specific therapy was evaluated in mild SLE-PAH patients. Those mild SLE-PAH patients had significantly longer progression-free time than the conventional SLE-PAH patients. Among the mild SLE-PAH patients, 4 did not receive PAH-specific therapy and had a similar prognosis as patients not receiving specific therapy. This study supports the revised hemodynamic definition of SLE-PAH in the 2022 ESC/ERS guideline. Those mild and unclassified SLE-PH patients had a better prognosis, demonstrating the possibility and significance of early diagnosis and intervention for SLE-PAH. This study also proposed a hypothesis that IIT against SLE might be sufficient for those reclassified SLE-PAH patients.
{"title":"The prognosis and management of reclassified systemic lupus erythematosus associated pulmonary arterial hypertension according to 2022 ESC/ERS guidelines","authors":"Yutong Li, Junyan Qian, Xingbei Dong, Jiuliang Zhao, Qian Wang, Yanhong Wang, Xiaofeng Zeng, Zhuang Tian, Mengtao Li","doi":"10.1186/s13075-024-03338-1","DOIUrl":"https://doi.org/10.1186/s13075-024-03338-1","url":null,"abstract":"The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guideline has recently revised the hemodynamic definition of pulmonary arterial hypertension. However, there is currently limited research on the prognosis and treatment of system lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH) patients that have been reclassified by the new hemodynamic definition. This study aims to analyze the prognosis of newly reclassified SLE-PAH patients and provide recommendations for the management strategy. This retrospective study analyzed records of 236 SLE-PAH patients who visited Peking Union Medical College Hospital (PUMCH) from 2011 to 2023, among whom 22 patients were reclassified into mild SLE-PAH (mean pulmonary arterial pressure (mPAP) of 21–24 mmHg, pulmonary vascular resistance (PVR) of 2–3 WU, and PAWP ≤ 15 mmHg) according to the guidelines and 14 were defined as unclassified SLE-PAH patients (mPAP 21–24 mmHg and PVR ≤ 2 WU). The prognosis was compared among mild SLE-PAH, unclassified SLE-PH, and conventional SLE-PAH patients (mPAP ≥ 25 mmHg and PVR > 3WU). Besides, the effectiveness of pulmonary arterial hypertension (PAH)-specific therapy was evaluated in mild SLE-PAH patients. Those mild SLE-PAH patients had significantly longer progression-free time than the conventional SLE-PAH patients. Among the mild SLE-PAH patients, 4 did not receive PAH-specific therapy and had a similar prognosis as patients not receiving specific therapy. This study supports the revised hemodynamic definition of SLE-PAH in the 2022 ESC/ERS guideline. Those mild and unclassified SLE-PH patients had a better prognosis, demonstrating the possibility and significance of early diagnosis and intervention for SLE-PAH. This study also proposed a hypothesis that IIT against SLE might be sufficient for those reclassified SLE-PAH patients.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156671","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 : 2024-05-27DOI: 10.1186/s13075-024-03339-0
Amir Haddad, Perach Chen Elkayam, Nili Stein, Ilan Feldhamer, Arnon Dov Cohen, Walid Saliba, Devy Zisman
Psoriatic arthritis (PsA) is a chronic, potentially debilitating inflammatory arthritis often associated with psoriasis. Understanding the epidemiology of PsA across diverse populations can provide valuable insights into its global burden and the role of genetic and environmental factors. This study aimed to estimate PsA’s temporal trends, prevalence, and incidence, while assessing variations in age, gender, and ethnicity in Israel from 2016 to 2022. Data were sourced from the Clalit Health Services (CHS) database, covering over half of the Israeli population. Algorithm-based definitions for PsA and psoriasis cases were used. Demographic factors, including age, gender, socioeconomic status (SES), ethnicity, urban/rural residence, BMI, and smoking status, were analyzed. Standardized prevalence and incidence rates were calculated. Logistic regression analyses examined associations of sociodemographic variables with PsA. In 2022, the prevalence of PsA was 0.221%, with an incidence rate of 13.54 per 100,000 population. This prevalence has tripled since 2006, reflecting a rising trend in PsA over time. Females exhibited a higher prevalence (1.15; 95%CI 1.09–1.21), and PsA was more common in Jewish individuals (1.58; 95%CI 1.45–1.71) those with higher SES (1.4; 95% CI 1.31, 1.5), and those with obesity (2.17; 95%CI 2.04–2.31). This comprehensive population-based study pointed to an increase prevalence of PsA, emphasizing the rising healthcare demands and economic burden faced by this patient population. Further research is essential to delve into the factors driving these trends.
{"title":"Epidemiological trends in psoriatic arthritis: a comprehensive population-based study","authors":"Amir Haddad, Perach Chen Elkayam, Nili Stein, Ilan Feldhamer, Arnon Dov Cohen, Walid Saliba, Devy Zisman","doi":"10.1186/s13075-024-03339-0","DOIUrl":"https://doi.org/10.1186/s13075-024-03339-0","url":null,"abstract":"Psoriatic arthritis (PsA) is a chronic, potentially debilitating inflammatory arthritis often associated with psoriasis. Understanding the epidemiology of PsA across diverse populations can provide valuable insights into its global burden and the role of genetic and environmental factors. This study aimed to estimate PsA’s temporal trends, prevalence, and incidence, while assessing variations in age, gender, and ethnicity in Israel from 2016 to 2022. Data were sourced from the Clalit Health Services (CHS) database, covering over half of the Israeli population. Algorithm-based definitions for PsA and psoriasis cases were used. Demographic factors, including age, gender, socioeconomic status (SES), ethnicity, urban/rural residence, BMI, and smoking status, were analyzed. Standardized prevalence and incidence rates were calculated. Logistic regression analyses examined associations of sociodemographic variables with PsA. In 2022, the prevalence of PsA was 0.221%, with an incidence rate of 13.54 per 100,000 population. This prevalence has tripled since 2006, reflecting a rising trend in PsA over time. Females exhibited a higher prevalence (1.15; 95%CI 1.09–1.21), and PsA was more common in Jewish individuals (1.58; 95%CI 1.45–1.71) those with higher SES (1.4; 95% CI 1.31, 1.5), and those with obesity (2.17; 95%CI 2.04–2.31). This comprehensive population-based study pointed to an increase prevalence of PsA, emphasizing the rising healthcare demands and economic burden faced by this patient population. Further research is essential to delve into the factors driving these trends.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156631","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 : 2024-05-24DOI: 10.1186/s13075-024-03342-5
Miya Marco, Mylène Jansen, Goran van der Weiden, Eli Reich, Yonathan H Maatuf, Simon C Mastbergen, Mona Dvir-Ginzberg
Background: Previously, fragments from Sirtuin 1 (SIRT1) were identified in preclinical and clinical samples to display an increase in serum levels for N-terminal (NT) SIRT1 vs. C-terminal (CT) SIRT1, indicative of early signs of OA. Here we tested NT/CT SIRT1 levels as well as a novel formulated sandwich assay to simultaneously detect both domains of SIRT1 in a manner that may inform us about the levels of full-length SIRT1 in the circulation (flSIRT1) of clinical cohorts undergoing knee joint distraction (KJD).
Methods: We employed an indirect ELISA assay to test NT- and CT-SIRT1 levels and calculated their ratio. Further, to test flSIRT1 we utilized novel antibodies (Ab), which were validated for site specificity and used in a sandwich ELISA method, wherein the CT-reactive served as capture Ab, and its NT-reactive served as primary detection Ab. This method was employed in human serum samples derived from a two-year longitudinal study of KJD patients. Two-year clinical and structural outcomes were correlated with serum levels of flSIRT1 compared to baseline.
Results: Assessing the cohort, exhibited a significant increase of NT/CT SIRT1 serum levels with increased osteophytes and PIIANP/CTX-II at baseline, while a contradictory increase in NT/CT SIRT1 was associated with less denuded bone, post-KJD. On the other hand, flSIRT1 exhibited an upward trend in serum level, accompanied by reduced denuded bone for 2-year adjusted values. Moreover, 2 year-adjusted flSIRT1 levels displayed a steeper linear regression for cartilage and bone-related structural improvement than those observed for NT/CT SIRT1.
Conclusions: Our data support that increased flSIRT1 serum levels are a potential molecular endotype for cartilage-related structural improvement post-KJD, while NT/CT SIRT1 appears to correlate with osteophyte and PIIANP/CTX-II reduction at baseline, to potentially indicate baseline OA severity.
{"title":"Two-year post-distraction cartilage-related structural improvement is accompanied by increased serum full-length SIRT1.","authors":"Miya Marco, Mylène Jansen, Goran van der Weiden, Eli Reich, Yonathan H Maatuf, Simon C Mastbergen, Mona Dvir-Ginzberg","doi":"10.1186/s13075-024-03342-5","DOIUrl":"10.1186/s13075-024-03342-5","url":null,"abstract":"<p><strong>Background: </strong>Previously, fragments from Sirtuin 1 (SIRT1) were identified in preclinical and clinical samples to display an increase in serum levels for N-terminal (NT) SIRT1 vs. C-terminal (CT) SIRT1, indicative of early signs of OA. Here we tested NT/CT SIRT1 levels as well as a novel formulated sandwich assay to simultaneously detect both domains of SIRT1 in a manner that may inform us about the levels of full-length SIRT1 in the circulation (flSIRT1) of clinical cohorts undergoing knee joint distraction (KJD).</p><p><strong>Methods: </strong>We employed an indirect ELISA assay to test NT- and CT-SIRT1 levels and calculated their ratio. Further, to test flSIRT1 we utilized novel antibodies (Ab), which were validated for site specificity and used in a sandwich ELISA method, wherein the CT-reactive served as capture Ab, and its NT-reactive served as primary detection Ab. This method was employed in human serum samples derived from a two-year longitudinal study of KJD patients. Two-year clinical and structural outcomes were correlated with serum levels of flSIRT1 compared to baseline.</p><p><strong>Results: </strong>Assessing the cohort, exhibited a significant increase of NT/CT SIRT1 serum levels with increased osteophytes and PIIANP/CTX-II at baseline, while a contradictory increase in NT/CT SIRT1 was associated with less denuded bone, post-KJD. On the other hand, flSIRT1 exhibited an upward trend in serum level, accompanied by reduced denuded bone for 2-year adjusted values. Moreover, 2 year-adjusted flSIRT1 levels displayed a steeper linear regression for cartilage and bone-related structural improvement than those observed for NT/CT SIRT1.</p><p><strong>Conclusions: </strong>Our data support that increased flSIRT1 serum levels are a potential molecular endotype for cartilage-related structural improvement post-KJD, while NT/CT SIRT1 appears to correlate with osteophyte and PIIANP/CTX-II reduction at baseline, to potentially indicate baseline OA severity.</p>","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11127335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092568","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}
Pub Date : 2024-05-24DOI: 10.1186/s13075-024-03313-w
Victoria Navarro-Compán, Atul Deodhar, Rachid Bahiri, Andrew G Bushmakin, Joseph C Cappelleri, Jihane Rammaoui
Background: Tofacitinib is an oral Janus kinase inhibitor for treatment of ankylosing spondylitis (AS). Time to improvement in core domains of AS was estimated in tofacitinib-treated patients with AS.
Methods: This post hoc analysis used phase 3 trial data from patients with AS receiving tofacitinib 5 mg twice daily or placebo to week (W)16; all patients received open-label tofacitinib W16-48.
Outcomes: nocturnal pain; total back pain; fatigue, spinal pain, peripheral joint pain/swelling, enthesitis, and morning stiffness (Bath AS Disease Activity Index [BASDAI] questions 1-6); BASDAI total score; AS Disease Activity Score (ASDAS). Median time to improvement events was estimated using non-parametric Kaplan-Meier models. Improvement events were defined as initial (first post-baseline observation) and continued (sustained for 2 consecutive visits) ≥ 30% and ≥ 50% improvement in back/nocturnal pain or BASDAI questions/total scores, or ASDAS improvement ≥ 1.1 and ≥ 2.0 points.
Results: 269 patients (tofacitinib: n = 133; placebo-to-tofacitinib: n = 136) were assessed. Median time to improvement was shorter, and more patients experienced improvements with tofacitinib vs. placebo-to-tofacitinib; differences observed from W2 (first post-baseline assessment). Median time to initial (continued) ≥ 30% pain improvement was 4 (4-8) weeks for tofacitinib vs. 24 (24) weeks for placebo-to-tofacitinib (8 [8] weeks post-switch). Median time to initial (continued) ≥ 50% improvement of pain, peripheral joint pain/swelling and enthesitis, morning stiffness, BASDAI total score, and fatigue was 8-24 (12-40) weeks with tofacitinib vs. 24-32 weeks (32 weeks-not estimable [NE]) with placebo-to-tofacitinib. Median time to initial (continued) ASDAS improvement ≥ 1.1 points was 4 (8) weeks for tofacitinib vs. 24 (24) weeks for placebo-to-tofacitinib, and NE for improvement ≥ 2.0 points with either treatment.
Conclusions: Improvements in AS core domains occurred more rapidly with tofacitinib vs. placebo-to-tofacitinib. Half of tofacitinib-treated patients with AS will likely experience improvements ≥ 30% in pain and ≥ 1.1 points in ASDAS during month (M)1, ≥ 50% improvement in nocturnal pain and enthesitis by M2, and in morning stiffness by M3. Results show that initiating tofacitinib as soon as possible is associated with quicker improvements in AS core domains vs. delaying treatment.
Trial registration: ClinicalTrials.gov, NCT03502616, 11 April 2018.
{"title":"Time to improvement of pain, morning stiffness, fatigue, and disease activity in patients with ankylosing spondylitis treated with tofacitinib: a post hoc analysis.","authors":"Victoria Navarro-Compán, Atul Deodhar, Rachid Bahiri, Andrew G Bushmakin, Joseph C Cappelleri, Jihane Rammaoui","doi":"10.1186/s13075-024-03313-w","DOIUrl":"10.1186/s13075-024-03313-w","url":null,"abstract":"<p><strong>Background: </strong>Tofacitinib is an oral Janus kinase inhibitor for treatment of ankylosing spondylitis (AS). Time to improvement in core domains of AS was estimated in tofacitinib-treated patients with AS.</p><p><strong>Methods: </strong>This post hoc analysis used phase 3 trial data from patients with AS receiving tofacitinib 5 mg twice daily or placebo to week (W)16; all patients received open-label tofacitinib W16-48.</p><p><strong>Outcomes: </strong>nocturnal pain; total back pain; fatigue, spinal pain, peripheral joint pain/swelling, enthesitis, and morning stiffness (Bath AS Disease Activity Index [BASDAI] questions 1-6); BASDAI total score; AS Disease Activity Score (ASDAS). Median time to improvement events was estimated using non-parametric Kaplan-Meier models. Improvement events were defined as initial (first post-baseline observation) and continued (sustained for 2 consecutive visits) ≥ 30% and ≥ 50% improvement in back/nocturnal pain or BASDAI questions/total scores, or ASDAS improvement ≥ 1.1 and ≥ 2.0 points.</p><p><strong>Results: </strong>269 patients (tofacitinib: n = 133; placebo-to-tofacitinib: n = 136) were assessed. Median time to improvement was shorter, and more patients experienced improvements with tofacitinib vs. placebo-to-tofacitinib; differences observed from W2 (first post-baseline assessment). Median time to initial (continued) ≥ 30% pain improvement was 4 (4-8) weeks for tofacitinib vs. 24 (24) weeks for placebo-to-tofacitinib (8 [8] weeks post-switch). Median time to initial (continued) ≥ 50% improvement of pain, peripheral joint pain/swelling and enthesitis, morning stiffness, BASDAI total score, and fatigue was 8-24 (12-40) weeks with tofacitinib vs. 24-32 weeks (32 weeks-not estimable [NE]) with placebo-to-tofacitinib. Median time to initial (continued) ASDAS improvement ≥ 1.1 points was 4 (8) weeks for tofacitinib vs. 24 (24) weeks for placebo-to-tofacitinib, and NE for improvement ≥ 2.0 points with either treatment.</p><p><strong>Conclusions: </strong>Improvements in AS core domains occurred more rapidly with tofacitinib vs. placebo-to-tofacitinib. Half of tofacitinib-treated patients with AS will likely experience improvements ≥ 30% in pain and ≥ 1.1 points in ASDAS during month (M)1, ≥ 50% improvement in nocturnal pain and enthesitis by M2, and in morning stiffness by M3. Results show that initiating tofacitinib as soon as possible is associated with quicker improvements in AS core domains vs. delaying treatment.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT03502616, 11 April 2018.</p>","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11127290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092552","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}
Pub Date : 2024-05-23DOI: 10.1186/s13075-024-03336-3
Zehu Chen, Xuegang Li, Honglei Shi, Yiying Huang, Jing Liu
Epidemiological observational studies have elucidated a correlation between rheumatoid arthritis (RA) and bronchiectasis. However, the causal nature of this association remains ambiguous. To clarify this potential causal linkage, we conducted a two-sample Mendelian randomization (MR) analysis to explore the bidirectional causality between RA and bronchiectasis. Summary statistics for RA and bronchiectasis were obtained from the IEU OpenGWAS database We employed various methods, including inverse variance weighting (IVW), MR-Egger, weighted median, weighted mode, and simple mode, to explore potential causal links between RA and bronchiectasis. Additionally, a series of sensitivity studies, such as Cochran’s Q test, MR Egger intercept test, and leave-one-out analysis, were conducted to assess the MR analysis’s accuracy further. In the forward MR analysis, the primary analysis indicated that a genetic predisposition to RA correlated with an increased risk of bronchiectasis in European populations (IVW odds ratio (OR): 1.28, 95% confidence interval (CI): 1.20–1.37, p = 1.18E-13). Comparable results were noted in the East Asian subjects (IVW OR: 1.55, 95% CI: 1.30–1.34, p = 8.33E-07). The OR estimates from the other four methods were consistent with those obtained from the IVW method. Sensitivity analysis detected no evidence of horizontal pleiotropy or heterogeneity. Conversely, in the reverse MR analysis, we found no evidence to support a genetic causality between bronchiectasis and RA in either European or East Asian populations. This study indicates that genetic predisposition to RA correlates with a heightened risk of bronchiectasis in both European and East Asian populations. These results imply that routine screening for bronchiectasis in RA patients could be beneficial, and effective management of RA may contribute to a reduced risk of bronchiectasis. Future research should aim to clarify the underlying mechanisms linking these two conditions.
流行病学观察研究阐明了类风湿性关节炎（RA）与支气管扩张之间的相关性。然而，这种关联的因果关系仍不明确。为了澄清这种潜在的因果联系，我们进行了双样本孟德尔随机化（MR）分析，以探讨 RA 与支气管扩张之间的双向因果关系。我们采用了多种方法，包括反方差加权（IVW）、MR-Egger、加权中位数、加权模式和简单模式，来探讨 RA 和支气管扩张之间的潜在因果联系。此外，还进行了一系列敏感性研究，如科克兰Q检验、MR-Egger截距检验和leave-one-out分析，以进一步评估MR分析的准确性。在前瞻性 MR 分析中，主要分析表明，在欧洲人群中，RA 遗传易感性与支气管扩张症风险的增加相关（IVW 比值比 (OR): 1.28, 95% 置信区间 (CI): 1.20-1.37, p = 1.18E-13）。东亚受试者的结果与此相当（IVW OR：1.55，95% CI：1.30-1.34，p = 8.33E-07）。其他四种方法得出的 OR 估计值与 IVW 方法得出的结果一致。敏感性分析没有发现水平多向性或异质性的证据。相反，在反向 MR 分析中，我们没有发现任何证据支持欧洲或东亚人群中支气管扩张症与 RA 之间的遗传因果关系。本研究表明，在欧洲和东亚人群中，RA 的遗传易感性与支气管扩张症的高风险相关。这些结果表明，对 RA 患者进行支气管扩张症的常规筛查可能是有益的，对 RA 的有效管理可能有助于降低支气管扩张症的风险。未来的研究应致力于阐明这两种疾病之间的内在联系。
{"title":"Causal relationship between rheumatoid arthritis and bronchiectasis: a bidirectional mendelian randomization study","authors":"Zehu Chen, Xuegang Li, Honglei Shi, Yiying Huang, Jing Liu","doi":"10.1186/s13075-024-03336-3","DOIUrl":"https://doi.org/10.1186/s13075-024-03336-3","url":null,"abstract":"Epidemiological observational studies have elucidated a correlation between rheumatoid arthritis (RA) and bronchiectasis. However, the causal nature of this association remains ambiguous. To clarify this potential causal linkage, we conducted a two-sample Mendelian randomization (MR) analysis to explore the bidirectional causality between RA and bronchiectasis. Summary statistics for RA and bronchiectasis were obtained from the IEU OpenGWAS database We employed various methods, including inverse variance weighting (IVW), MR-Egger, weighted median, weighted mode, and simple mode, to explore potential causal links between RA and bronchiectasis. Additionally, a series of sensitivity studies, such as Cochran’s Q test, MR Egger intercept test, and leave-one-out analysis, were conducted to assess the MR analysis’s accuracy further. In the forward MR analysis, the primary analysis indicated that a genetic predisposition to RA correlated with an increased risk of bronchiectasis in European populations (IVW odds ratio (OR): 1.28, 95% confidence interval (CI): 1.20–1.37, p = 1.18E-13). Comparable results were noted in the East Asian subjects (IVW OR: 1.55, 95% CI: 1.30–1.34, p = 8.33E-07). The OR estimates from the other four methods were consistent with those obtained from the IVW method. Sensitivity analysis detected no evidence of horizontal pleiotropy or heterogeneity. Conversely, in the reverse MR analysis, we found no evidence to support a genetic causality between bronchiectasis and RA in either European or East Asian populations. This study indicates that genetic predisposition to RA correlates with a heightened risk of bronchiectasis in both European and East Asian populations. These results imply that routine screening for bronchiectasis in RA patients could be beneficial, and effective management of RA may contribute to a reduced risk of bronchiectasis. Future research should aim to clarify the underlying mechanisms linking these two conditions.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085524","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 : 2024-05-23DOI: 10.1186/s13075-024-03343-4
Hongyan Qian, Chaoqiong Deng, Shiju Chen, Xinwei Zhang, Yan He, Jingying Lan, Aodi Wang, Guixiu Shi, Yuan Liu
Fibroblast-like synoviocytes (FLSs) play a central role in RA pathogenesis and are the main cellular component in the inflamed synovium of patients with rheumatoid arthritis (RA). FLSs are emerging as promising new therapeutic targets in RA. However, fibroblasts perform many essential functions that are required for sustaining tissue homeostasis. Direct targeting of general fibroblast markers on FLSs is challenging because fibroblasts in other tissues might be altered and side effects such as reduced wound healing or fibrosis can occur. To date, no FLS-specific targeted therapies have been applied in the clinical management of RA. With the help of high-throughput technologies such as scRNA-seq in recent years, several specific pathogenic FLS subsets in RA have been identified. Understanding the characteristics of these pathogenic FLS clusters and the mechanisms that drive their differentiation can provide new insights into the development of novel FLS-targeting strategies for RA. Here, we discuss the pathogenic FLS subsets in RA that have been elucidated in recent years and potential strategies for targeting pathogenic FLSs.
{"title":"Targeting pathogenic fibroblast-like synoviocyte subsets in rheumatoid arthritis","authors":"Hongyan Qian, Chaoqiong Deng, Shiju Chen, Xinwei Zhang, Yan He, Jingying Lan, Aodi Wang, Guixiu Shi, Yuan Liu","doi":"10.1186/s13075-024-03343-4","DOIUrl":"https://doi.org/10.1186/s13075-024-03343-4","url":null,"abstract":"Fibroblast-like synoviocytes (FLSs) play a central role in RA pathogenesis and are the main cellular component in the inflamed synovium of patients with rheumatoid arthritis (RA). FLSs are emerging as promising new therapeutic targets in RA. However, fibroblasts perform many essential functions that are required for sustaining tissue homeostasis. Direct targeting of general fibroblast markers on FLSs is challenging because fibroblasts in other tissues might be altered and side effects such as reduced wound healing or fibrosis can occur. To date, no FLS-specific targeted therapies have been applied in the clinical management of RA. With the help of high-throughput technologies such as scRNA-seq in recent years, several specific pathogenic FLS subsets in RA have been identified. Understanding the characteristics of these pathogenic FLS clusters and the mechanisms that drive their differentiation can provide new insights into the development of novel FLS-targeting strategies for RA. Here, we discuss the pathogenic FLS subsets in RA that have been elucidated in recent years and potential strategies for targeting pathogenic FLSs.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085552","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 : 2024-05-22DOI: 10.1186/s13075-024-03324-7
Phillip Lee, Lorraine Green, Bartosz Marzec, Fiona Meldrum, Francesco Del Galdo, Begonya Alcacer-Pitarch
To perform a detailed morphological analysis of the inorganic portion of two different clinical presentations of calcium-based deposits retrieved from subjects with SSc and identify a chemical dissolution of these deposits suitable for clinical use. Chemical analysis using Fourier Transform IR spectroscopy (‘FTIR’), Raman microscopy, Powder X-Ray Diffraction (‘PXRD’), and Transmission Electron Microscopy (‘TEM’) was undertaken of two distinct types of calcinosis deposits: paste and stone. Calcinosis sample titration with ethylenediaminetetraacetic acid (‘EDTA’) assessed the concentration at which the EDTA dissolved the calcinosis deposits in vitro. FTIR spectra of the samples displayed peaks characteristic of hydroxyapatite, where signals attributable to the phosphate and carbonate ions were all identified. Polymorph characterization using Raman spectra were identical to a hydroxyapatite reference while the PXRD and electron diffraction patterns conclusively identified the mineral present as hydroxyapatite. TEM analysis showed differences of morphology between the samples. Rounded particles from stone samples were up to a few micron in size, while needle-like crystals from paste samples reached up to 0.5 µm in length. Calcium phosphate deposits were effectively dissolved with 3% aqueous solutions of EDTA, in vitro. Complete dissolution of both types of deposit was achieved in approximately 30 min using a molar ratio of EDTA/HAp of ≈ 300. Stone and paste calcium-based deposits both comprise hydroxyapatite, but the constituent crystals vary in size and morphology. Hydroxyapatite is the only crystalline polymorph present in the SSc-related calcinosis deposits. Hydroxyapatite can be dissolved in vitro using a dosage of EDTA considered safe for clinical application. Further research is required to establish the optimal medium to develop the medical product, determine the protocol for clinical application, and to assess the effectiveness of EDTA for local treatment of dystrophic calcinosis.
{"title":"Dystrophic calcinosis: structural and morphological composition, and evaluation of ethylenediaminetetraacetic acid (‘EDTA’) for potential local treatment","authors":"Phillip Lee, Lorraine Green, Bartosz Marzec, Fiona Meldrum, Francesco Del Galdo, Begonya Alcacer-Pitarch","doi":"10.1186/s13075-024-03324-7","DOIUrl":"https://doi.org/10.1186/s13075-024-03324-7","url":null,"abstract":"To perform a detailed morphological analysis of the inorganic portion of two different clinical presentations of calcium-based deposits retrieved from subjects with SSc and identify a chemical dissolution of these deposits suitable for clinical use. Chemical analysis using Fourier Transform IR spectroscopy (‘FTIR’), Raman microscopy, Powder X-Ray Diffraction (‘PXRD’), and Transmission Electron Microscopy (‘TEM’) was undertaken of two distinct types of calcinosis deposits: paste and stone. Calcinosis sample titration with ethylenediaminetetraacetic acid (‘EDTA’) assessed the concentration at which the EDTA dissolved the calcinosis deposits in vitro. FTIR spectra of the samples displayed peaks characteristic of hydroxyapatite, where signals attributable to the phosphate and carbonate ions were all identified. Polymorph characterization using Raman spectra were identical to a hydroxyapatite reference while the PXRD and electron diffraction patterns conclusively identified the mineral present as hydroxyapatite. TEM analysis showed differences of morphology between the samples. Rounded particles from stone samples were up to a few micron in size, while needle-like crystals from paste samples reached up to 0.5 µm in length. Calcium phosphate deposits were effectively dissolved with 3% aqueous solutions of EDTA, in vitro. Complete dissolution of both types of deposit was achieved in approximately 30 min using a molar ratio of EDTA/HAp of ≈ 300. Stone and paste calcium-based deposits both comprise hydroxyapatite, but the constituent crystals vary in size and morphology. Hydroxyapatite is the only crystalline polymorph present in the SSc-related calcinosis deposits. Hydroxyapatite can be dissolved in vitro using a dosage of EDTA considered safe for clinical application. Further research is required to establish the optimal medium to develop the medical product, determine the protocol for clinical application, and to assess the effectiveness of EDTA for local treatment of dystrophic calcinosis.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079373","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 : 2024-05-14DOI: 10.1186/s13075-024-03340-7
Xiaochan Chen, Linjiang Zhu, Huaxiang Wu
The purpose of this study was to investigate the role of macrophage polarization in the pathogenesis of primary Sjogren’s syndrome (pSS). Peripheral venous blood samples were collected from 30 patients with pSS and 30 healthy controls. Minor salivary gland samples were abtainted from 10 of these patients and 10 non-pSS controls whose minor salivary gland didn’t fulfill the classification criteria for pSS. Enzyme-linked immuno sorbent assay was used to examine the serum concentration of M1/M2 macrophage related cytokines (TNF-a, IL-6, IL-23, IL-4, IL-10 and TGF-β). Flow cytometry was used to examine the numbers of CD86+ M1 macrophages and CD206+ M2 macrophages in peripheral blood mononuclear cells (PBMCs). Immunofluorescence was used to test the infiltration of macrophages in minor salivary glands. This study observed a significant increase in pSS patients both in the numbers of M1 macrophages in peripheral blood and serum levels of M1-related pro-inflammatory cytokines (IL-6, IL-23 and TNF-α). Conversely, M2 macrophages were downregulated in the peripheral blood of pSS patients. Similarly, in the minor salivary glands of pSS patients, the expression of M1 macrophages was increased, and that of M2 macrophages was decreased. Furthermore, a significantly positive correlation was found between the proportions of M1 macrophages in PBMCs and serum levels of IgG and RF. This study reveals the presence of an significant imbalance in M1/M2 macrophages in pSS patients. The M1 polarization of macrophages may play an central role in the pathogenesis of pSS.
{"title":"The role of M1/M2 macrophage polarization in primary Sjogren’s syndrome","authors":"Xiaochan Chen, Linjiang Zhu, Huaxiang Wu","doi":"10.1186/s13075-024-03340-7","DOIUrl":"https://doi.org/10.1186/s13075-024-03340-7","url":null,"abstract":"The purpose of this study was to investigate the role of macrophage polarization in the pathogenesis of primary Sjogren’s syndrome (pSS). Peripheral venous blood samples were collected from 30 patients with pSS and 30 healthy controls. Minor salivary gland samples were abtainted from 10 of these patients and 10 non-pSS controls whose minor salivary gland didn’t fulfill the classification criteria for pSS. Enzyme-linked immuno sorbent assay was used to examine the serum concentration of M1/M2 macrophage related cytokines (TNF-a, IL-6, IL-23, IL-4, IL-10 and TGF-β). Flow cytometry was used to examine the numbers of CD86+ M1 macrophages and CD206+ M2 macrophages in peripheral blood mononuclear cells (PBMCs). Immunofluorescence was used to test the infiltration of macrophages in minor salivary glands. This study observed a significant increase in pSS patients both in the numbers of M1 macrophages in peripheral blood and serum levels of M1-related pro-inflammatory cytokines (IL-6, IL-23 and TNF-α). Conversely, M2 macrophages were downregulated in the peripheral blood of pSS patients. Similarly, in the minor salivary glands of pSS patients, the expression of M1 macrophages was increased, and that of M2 macrophages was decreased. Furthermore, a significantly positive correlation was found between the proportions of M1 macrophages in PBMCs and serum levels of IgG and RF. This study reveals the presence of an significant imbalance in M1/M2 macrophages in pSS patients. The M1 polarization of macrophages may play an central role in the pathogenesis of pSS.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140919572","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 : 2024-05-13DOI: 10.1186/s13075-024-03327-4
Frank Qingyun Wang, Li Shao, Xiao Dang, Yong-Fei Wang, Shuxiong Chen, Zhongyi Liu, Yujing Mao, Yuping Jiang, Fei Hou, Xianghua Guo, Jian Li, Lili Zhang, Yuting Sang, Xuan Zhao, Ruirui Ma, Kai Zhang, Yanfang Zhang, Jing Yang, Xiwu Wen, Jiong Liu, Wei Wei, Chuanpeng Zhang, Weiyang Li, Xiao Qin, Yao Lei, Hong Feng, Xingtian Yang, Chun Hing She, Caicai Zhang, Huidong Su, Xinxin Chen, Jing Yang, Yu Lung Lau, Qingjun Wu, Bo Ban, Qin Song, Wanling Yang
This study aims to elucidate the transcriptomic signatures and dysregulated pathways in patients with Systemic Lupus Erythematosus (SLE), with a particular focus on those persisting during disease remission. We conducted bulk RNA-sequencing of peripheral blood mononuclear cells (PBMCs) from a well-defined cohort comprising 26 remission patients meeting the Low Lupus Disease Activity State (LLDAS) criteria, 76 patients experiencing disease flares, and 15 healthy controls. To elucidate immune signature changes associated with varying disease states, we performed extensive analyses, including the identification of differentially expressed genes and pathways, as well as the construction of protein-protein interaction networks. Several transcriptomic features recovered during remission compared to the active disease state, including down-regulation of plasma and cell cycle signatures, as well as up-regulation of lymphocytes. However, specific innate immune response signatures, such as the interferon (IFN) signature, and gene modules involved in chromatin structure modification, persisted across different disease states. Drug repurposing analysis revealed certain drug classes that can target these persistent signatures, potentially preventing disease relapse. Our comprehensive transcriptomic study revealed gene expression signatures for SLE in both active and remission states. The discovery of gene expression modules persisting in the remission stage may shed light on the underlying mechanisms of vulnerability to relapse in these patients, providing valuable insights for their treatment.
{"title":"Unraveling transcriptomic signatures and dysregulated pathways in systemic lupus erythematosus across disease states","authors":"Frank Qingyun Wang, Li Shao, Xiao Dang, Yong-Fei Wang, Shuxiong Chen, Zhongyi Liu, Yujing Mao, Yuping Jiang, Fei Hou, Xianghua Guo, Jian Li, Lili Zhang, Yuting Sang, Xuan Zhao, Ruirui Ma, Kai Zhang, Yanfang Zhang, Jing Yang, Xiwu Wen, Jiong Liu, Wei Wei, Chuanpeng Zhang, Weiyang Li, Xiao Qin, Yao Lei, Hong Feng, Xingtian Yang, Chun Hing She, Caicai Zhang, Huidong Su, Xinxin Chen, Jing Yang, Yu Lung Lau, Qingjun Wu, Bo Ban, Qin Song, Wanling Yang","doi":"10.1186/s13075-024-03327-4","DOIUrl":"https://doi.org/10.1186/s13075-024-03327-4","url":null,"abstract":"This study aims to elucidate the transcriptomic signatures and dysregulated pathways in patients with Systemic Lupus Erythematosus (SLE), with a particular focus on those persisting during disease remission. We conducted bulk RNA-sequencing of peripheral blood mononuclear cells (PBMCs) from a well-defined cohort comprising 26 remission patients meeting the Low Lupus Disease Activity State (LLDAS) criteria, 76 patients experiencing disease flares, and 15 healthy controls. To elucidate immune signature changes associated with varying disease states, we performed extensive analyses, including the identification of differentially expressed genes and pathways, as well as the construction of protein-protein interaction networks. Several transcriptomic features recovered during remission compared to the active disease state, including down-regulation of plasma and cell cycle signatures, as well as up-regulation of lymphocytes. However, specific innate immune response signatures, such as the interferon (IFN) signature, and gene modules involved in chromatin structure modification, persisted across different disease states. Drug repurposing analysis revealed certain drug classes that can target these persistent signatures, potentially preventing disease relapse. Our comprehensive transcriptomic study revealed gene expression signatures for SLE in both active and remission states. The discovery of gene expression modules persisting in the remission stage may shed light on the underlying mechanisms of vulnerability to relapse in these patients, providing valuable insights for their treatment.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140914928","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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