Pub Date : 2025-09-29DOI: 10.1186/s13075-025-03645-1
Francesco Natalucci, Clément Triaille, Emilie Sapart, Stéphanie Dierckx, Cécile Van Mullem, Stéphanie De Montjoye, Tatiana Sokolova, Alexandra Avramovska, Patrick Durez
Despite an increasing number of targeted and biological disease-modifying anti-rheumatic drugs (ts or bDMARDs), a significant number of Rheumatoid Arthritis (RA) patients are refractory to multiple lines of treatments. The definition of Difficult-to-treat (D2T) RA patients has been proposed to harmonize research on this condition. While data on D2T in established RA are emerging, this is the first study to specifically address the evolution from early disease (ERA) to D2T-RA. To identify early clinical, laboratory, and radiographic predictors of progression from early rheumatoid arthritis to difficult-to-treat RA over a five-year follow-up. This was a retrospective monocentric cohort study of DMARD-naïve ERA patients (symptom duration ≤ 12 months), enrolled between 2010 and 2019. Patients were followed for 5 years with data collection at baseline, 6, 12, 36, and 60 months. The primary outcome was the development of D2T-RA, defined according to EULAR 2021 criteria. Baseline analyzed variables included clinical features, serology, radiographic damage, disease activity scores, patient-reported outcomes (PROs) and demographic features. Associations between baseline variables and D2T status were evaluated using univariate and multivariate logistic regression analyses. We included 391 ERA patients [M/F 109/282, median age 48.2 years IQR (21.26)]. After 5 years, forty-one patients (10.5%) matched the D2T definition. A higher baseline radiographic damage, seropositivity, and baseline disease activity characterized these patients. Only radiographic damage was confirmed as an independent factor for progression to D2T-RA in a multivariate analysis [OR = 2.38 CI (1.09–5.54); p = 0.03]. During the follow-up, disease activity was consistently higher in the D2T group. D2T patients were exposed to a higher dose of glucocorticoids and more commonly suffered from infections and osteoporosis. Baseline radiographic damage, seropositivity, and high disease activity represent the major risk factors for the evolution from ERA to D2T-RA. Disease activity indices were consistently higher in D2T patients all along the five-year follow-up. In addition, D2T patients received higher GC doses and more commonly developed disease and treatment-related comorbidities.
尽管越来越多的靶向和生物疾病改善抗风湿药物（ts或bDMARDs），但仍有相当数量的类风湿性关节炎（RA）患者对多种治疗方法难以耐受。难以治疗（D2T）类风湿性关节炎患者的定义已被提出，以协调对这种情况的研究。虽然D2T在已建立的RA中的数据正在出现，但这是第一个专门研究从早期疾病（ERA）到D2T-RA的演变的研究。在5年的随访中，确定从早期类风湿关节炎到难以治疗的类风湿性关节炎进展的早期临床、实验室和放射学预测因素。这是一项针对DMARD-naïve ERA患者（症状持续时间≤12个月）的回顾性单中心队列研究，纳入时间为2010年至2019年。患者随访5年，在基线、6个月、12个月、36个月和60个月收集数据。主要结果是D2T-RA的发展，根据EULAR 2021标准定义。基线分析的变量包括临床特征、血清学、放射学损害、疾病活动评分、患者报告的结果（PROs）和人口统计学特征。使用单变量和多变量逻辑回归分析评估基线变量与D2T状态之间的关联。我们纳入391例ERA患者[M/F 109/282，中位年龄48.2岁IQR(21.26)]。5年后，41名患者（10.5%）符合D2T定义。这些患者具有较高的基线放射学损伤、血清阳性和基线疾病活动性特征。在多变量分析中，仅影像学损伤被证实为进展为D2T-RA的独立因素[OR = 2.38 CI (1.09-5.54)；p = 0.03]。在随访期间，D2T组的疾病活动性始终较高。D2T患者暴露于更高剂量的糖皮质激素，更常见的是感染和骨质疏松症。基线放射学损害、血清阳性和高疾病活动性是ERA向D2T-RA演变的主要危险因素。在5年随访期间，D2T患者的疾病活动指数始终较高。此外，D2T患者接受了更高的GC剂量，更常见的疾病和治疗相关的合并症。
{"title":"Evolution from early to difficult-to-treat rheumatoid arthritis: incidence and risk factors in the ERA uclouvain Brussels cohort","authors":"Francesco Natalucci, Clément Triaille, Emilie Sapart, Stéphanie Dierckx, Cécile Van Mullem, Stéphanie De Montjoye, Tatiana Sokolova, Alexandra Avramovska, Patrick Durez","doi":"10.1186/s13075-025-03645-1","DOIUrl":"https://doi.org/10.1186/s13075-025-03645-1","url":null,"abstract":"Despite an increasing number of targeted and biological disease-modifying anti-rheumatic drugs (ts or bDMARDs), a significant number of Rheumatoid Arthritis (RA) patients are refractory to multiple lines of treatments. The definition of Difficult-to-treat (D2T) RA patients has been proposed to harmonize research on this condition. While data on D2T in established RA are emerging, this is the first study to specifically address the evolution from early disease (ERA) to D2T-RA. To identify early clinical, laboratory, and radiographic predictors of progression from early rheumatoid arthritis to difficult-to-treat RA over a five-year follow-up. This was a retrospective monocentric cohort study of DMARD-naïve ERA patients (symptom duration ≤ 12 months), enrolled between 2010 and 2019. Patients were followed for 5 years with data collection at baseline, 6, 12, 36, and 60 months. The primary outcome was the development of D2T-RA, defined according to EULAR 2021 criteria. Baseline analyzed variables included clinical features, serology, radiographic damage, disease activity scores, patient-reported outcomes (PROs) and demographic features. Associations between baseline variables and D2T status were evaluated using univariate and multivariate logistic regression analyses. We included 391 ERA patients [M/F 109/282, median age 48.2 years IQR (21.26)]. After 5 years, forty-one patients (10.5%) matched the D2T definition. A higher baseline radiographic damage, seropositivity, and baseline disease activity characterized these patients. Only radiographic damage was confirmed as an independent factor for progression to D2T-RA in a multivariate analysis [OR = 2.38 CI (1.09–5.54); p = 0.03]. During the follow-up, disease activity was consistently higher in the D2T group. D2T patients were exposed to a higher dose of glucocorticoids and more commonly suffered from infections and osteoporosis. Baseline radiographic damage, seropositivity, and high disease activity represent the major risk factors for the evolution from ERA to D2T-RA. Disease activity indices were consistently higher in D2T patients all along the five-year follow-up. In addition, D2T patients received higher GC doses and more commonly developed disease and treatment-related comorbidities.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"17 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188762","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}
Obesity has been linked to increased rheumatoid arthritis (RA) risk, but the impact of longitudinal changes in obesity indices remains unclear. A clearer understanding of these dynamic patterns could enhance early identification and prevention strategies. This study aimed to examine the associations between longitudinal changes in body mass index (BMI), waist-to-hip ratio (WHR), and body roundness index (BRI) and the incidence of RA. We analyzed data from 68,061 UK Biobank participants (aged 40–73 years) with at least two obesity index measurements. Obesity change patterns were categorized as stable or transitional, and the annual average rate of change (AARC) was calculated. Cox regression and restricted cubic spline (RCS) models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Over a median follow-up of 4.06 years, 354 participants developed RA. Stable overweight (HR: 1.45; 95% CI: 1.12, 1.88), abdominal obesity (HR: 1.48; 95% CI: 1.12, 1.96) and high BRI (HR: 1.46; 95% CI: 1.12, 1.89) were related to an increased risk of RA. Additionally, the transition from non-abdominal obesity to abdominal obesity was connected to a 39% increase in RA risk (HR: 1.39; 95% CI: 1.00, 1.91). The RCS model showed a non-linear association between AARC in BMI and RA risk, with RA risk increasing when AARC exceeded 1.106 (P for non-linearity = 0.019). The findings suggest that specific dynamic changes in obesity indices are associated with an increased risk of RA, and that maintaining a normal body composition may contribute to risk reduction.
{"title":"Longitudinal patterns of obesity index changes and risk of incident rheumatoid arthritis: evidence from a population-based cohort","authors":"Xuanli Zhao, Xiaohui Sun, Fuhua Wu, Ke Huang, Xinzhe Jing, Meiqun Lv, Jing Zhu, Jiayu Li, Fangyuan Jing, Yingying Mao, Ding Ye","doi":"10.1186/s13075-025-03655-z","DOIUrl":"https://doi.org/10.1186/s13075-025-03655-z","url":null,"abstract":"Obesity has been linked to increased rheumatoid arthritis (RA) risk, but the impact of longitudinal changes in obesity indices remains unclear. A clearer understanding of these dynamic patterns could enhance early identification and prevention strategies. This study aimed to examine the associations between longitudinal changes in body mass index (BMI), waist-to-hip ratio (WHR), and body roundness index (BRI) and the incidence of RA. We analyzed data from 68,061 UK Biobank participants (aged 40–73 years) with at least two obesity index measurements. Obesity change patterns were categorized as stable or transitional, and the annual average rate of change (AARC) was calculated. Cox regression and restricted cubic spline (RCS) models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Over a median follow-up of 4.06 years, 354 participants developed RA. Stable overweight (HR: 1.45; 95% CI: 1.12, 1.88), abdominal obesity (HR: 1.48; 95% CI: 1.12, 1.96) and high BRI (HR: 1.46; 95% CI: 1.12, 1.89) were related to an increased risk of RA. Additionally, the transition from non-abdominal obesity to abdominal obesity was connected to a 39% increase in RA risk (HR: 1.39; 95% CI: 1.00, 1.91). The RCS model showed a non-linear association between AARC in BMI and RA risk, with RA risk increasing when AARC exceeded 1.106 (P for non-linearity = 0.019). The findings suggest that specific dynamic changes in obesity indices are associated with an increased risk of RA, and that maintaining a normal body composition may contribute to risk reduction.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"26 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188700","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 : 2025-09-29DOI: 10.1186/s13075-025-03652-2
Nora Vladimirova, Anna EF Hadsbjerg, Simon Krabbe, Adrian Ciurea, Kristýna Bubová, Monika Gregová, Michael J. Nissen, Burkhard Möller, Raphael Micheroli, Susanne J. Pedersen, Jakub Závada, Ziga Snoj, Karlo Pintaric, Bjorn Gudbjornsson, Ziga Rotar, Iris Eshed, Iwona Sudol-Szopinska, Kasper Gosvig, Torsten Diekhoff, Robert GW Lambert, Manouk de Hooge, Maurice Donzallaz, Alexander Bernatschek, Merete Lund Hetland, Lykke M Ørnbjerg, Mikkel Østergaard
Axial involvement in psoriatic arthritis (axPsA) is associated with more severe disease and increased pain, yet no consensus definition of axPsA exists. This study aims to describe the occurrence and characteristics of MRI and radiographic sacroiliac joint (SIJ) involvement in a European PsA cohort. Patients with a clinical diagnosis of PsA or of axial spondyloarthritis with psoriasis and available routine care SIJ MRIs were included from five European registries in the EuroSpA collaboration. SIJ MRIs and radiographs were centrally assessed for inflammatory and structural lesions, differential diagnoses, and globally evaluated for SpA-indicative findings. Among 581 PsA patients (mean age 45 years, 47% male), 31% exhibited SpA-indicative SIJ-MRI findings (MRI-axPsA). In MRI-axPsA patients, the most common lesions were bone marrow edema (BME) (69%), erosions (68%), and fat lesions (58%), generally present bilaterally. BME ≥ 1 cm, inflammation in an erosion cavity, capsulitis, fat lesions ≥ 1 cm, backfill, and ankylosis were observed almost exclusively in MRI-AxPsA patients. Differential diagnoses included osteitis condensans ilii (8%), probable strain-related BME (11%) and degenerative disease (16%). Among 259 patients with radiographs, 29% met the radiographic mNY criteria for ankylosing spondylitis and 38% had SpA-indicative MRI findings. Male sex, HLA-B27 positivity, elevated CRP and history of inflammatory back pain (but not current back pain) were independently associated with MRI-detected axial involvement. In this large European cohort, one-third of routine care PsA patients had axial involvement, based on global SIJ MRI assessment. The study supports incorporating MRI into the future definition of axPsA to enable early identification.
{"title":"Sacroiliac joint involvement in psoriatic arthritis – MRI, radiographic and clinical findings in 581 European routine care patients","authors":"Nora Vladimirova, Anna EF Hadsbjerg, Simon Krabbe, Adrian Ciurea, Kristýna Bubová, Monika Gregová, Michael J. Nissen, Burkhard Möller, Raphael Micheroli, Susanne J. Pedersen, Jakub Závada, Ziga Snoj, Karlo Pintaric, Bjorn Gudbjornsson, Ziga Rotar, Iris Eshed, Iwona Sudol-Szopinska, Kasper Gosvig, Torsten Diekhoff, Robert GW Lambert, Manouk de Hooge, Maurice Donzallaz, Alexander Bernatschek, Merete Lund Hetland, Lykke M Ørnbjerg, Mikkel Østergaard","doi":"10.1186/s13075-025-03652-2","DOIUrl":"https://doi.org/10.1186/s13075-025-03652-2","url":null,"abstract":"Axial involvement in psoriatic arthritis (axPsA) is associated with more severe disease and increased pain, yet no consensus definition of axPsA exists. This study aims to describe the occurrence and characteristics of MRI and radiographic sacroiliac joint (SIJ) involvement in a European PsA cohort. Patients with a clinical diagnosis of PsA or of axial spondyloarthritis with psoriasis and available routine care SIJ MRIs were included from five European registries in the EuroSpA collaboration. SIJ MRIs and radiographs were centrally assessed for inflammatory and structural lesions, differential diagnoses, and globally evaluated for SpA-indicative findings. Among 581 PsA patients (mean age 45 years, 47% male), 31% exhibited SpA-indicative SIJ-MRI findings (MRI-axPsA). In MRI-axPsA patients, the most common lesions were bone marrow edema (BME) (69%), erosions (68%), and fat lesions (58%), generally present bilaterally. BME ≥ 1 cm, inflammation in an erosion cavity, capsulitis, fat lesions ≥ 1 cm, backfill, and ankylosis were observed almost exclusively in MRI-AxPsA patients. Differential diagnoses included osteitis condensans ilii (8%), probable strain-related BME (11%) and degenerative disease (16%). Among 259 patients with radiographs, 29% met the radiographic mNY criteria for ankylosing spondylitis and 38% had SpA-indicative MRI findings. Male sex, HLA-B27 positivity, elevated CRP and history of inflammatory back pain (but not current back pain) were independently associated with MRI-detected axial involvement. In this large European cohort, one-third of routine care PsA patients had axial involvement, based on global SIJ MRI assessment. The study supports incorporating MRI into the future definition of axPsA to enable early identification. ","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"31 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188701","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 : 2025-09-29DOI: 10.1186/s13075-025-03656-y
Bo Broens, Conny J. van der Laken, Iris A. Simons, Tamara Dekker, Jan-Willem Duitman, Alexandre E. Voskuyl
Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is difficult to manage due to the heterogeneous disease course. There is a high need for new biomarkers to identify patients at high risk for ILD progression. Fibroblast activation protein (FAP) has gained interest as a biomarker to reflect fibrotic activity. As circulating FAP (cFAP) can be measured in blood, we aimed to investigate the value of cFAP in SSc-ILD. cFAP concentrations were determined in plasma samples of 210 patients with systemic sclerosis (SSc) using an enzyme-linked immunosorbent assay. We compared cFAP in baseline and repeated longitudinal samples between SSc patients with (n = 63) and without ILD (n = 147). Furthermore, we investigated the correlation between cFAP and ILD progression at follow-up. In an exploratory analysis, we also investigated if cFAP was associated with other disease-related clinical features and all-cause mortality. cFAP levels were not different between SSc patients with- and without ILD, both at baseline (median 91.5 and 97.7 ng/mL respectively; p = 0.80) or during follow-up. Furthermore, we found no association between cFAP at baseline and ILD progression at 1, 2 and 5 years of follow-up. Notably, cFAP levels were elevated at baseline in patients with higher skin scores (mRSS ≥ 10 compared to mRSS < 10; p = 0.01). Finally, we did not find an association between cFAP and all-cause mortality at 5 and 10 years of follow-up. In conclusion, cFAP does not seem useful as a biomarker in SSc-ILD. However, the association between cFAP and skin score deserves further investigation.
{"title":"Longitudinal assessment of circulating fibroblast activation protein in systemic sclerosis-associated interstitial lung disease","authors":"Bo Broens, Conny J. van der Laken, Iris A. Simons, Tamara Dekker, Jan-Willem Duitman, Alexandre E. Voskuyl","doi":"10.1186/s13075-025-03656-y","DOIUrl":"https://doi.org/10.1186/s13075-025-03656-y","url":null,"abstract":"Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is difficult to manage due to the heterogeneous disease course. There is a high need for new biomarkers to identify patients at high risk for ILD progression. Fibroblast activation protein (FAP) has gained interest as a biomarker to reflect fibrotic activity. As circulating FAP (cFAP) can be measured in blood, we aimed to investigate the value of cFAP in SSc-ILD. cFAP concentrations were determined in plasma samples of 210 patients with systemic sclerosis (SSc) using an enzyme-linked immunosorbent assay. We compared cFAP in baseline and repeated longitudinal samples between SSc patients with (n = 63) and without ILD (n = 147). Furthermore, we investigated the correlation between cFAP and ILD progression at follow-up. In an exploratory analysis, we also investigated if cFAP was associated with other disease-related clinical features and all-cause mortality. cFAP levels were not different between SSc patients with- and without ILD, both at baseline (median 91.5 and 97.7 ng/mL respectively; p = 0.80) or during follow-up. Furthermore, we found no association between cFAP at baseline and ILD progression at 1, 2 and 5 years of follow-up. Notably, cFAP levels were elevated at baseline in patients with higher skin scores (mRSS ≥ 10 compared to mRSS < 10; p = 0.01). Finally, we did not find an association between cFAP and all-cause mortality at 5 and 10 years of follow-up. In conclusion, cFAP does not seem useful as a biomarker in SSc-ILD. However, the association between cFAP and skin score deserves further investigation.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"1 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188702","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 : 2025-09-29DOI: 10.1186/s13075-025-03653-1
Ying Liu, YuJie Pang, Yang Liu, Na Zhang, LiangYu Mi, Yanan Gao, Wenqin Gao, Ke Xu
Lupus enteritis (LE) is a serious manifestation of systemic lupus erythematosus (SLE), yet optimal treatment strategies remain unclear. This study aimed to compare the efficacy of rituximab (RTX) plus glucocorticoids versus glucocorticoids combined with conventional immunosuppressants in patients with moderate-to-severe LE. We retrospectively analyzed 36 patients with SLE-related intestinal involvement treated at our center between January 2015 and August 2024; sixteen received RTX plus glucocorticoids, and twenty received glucocorticoids with conventional immunosuppressants. Baseline characteristics, clinical features, abdominal CT findings, laboratory parameters (including serum and fecal IgA, IL-6, TNF-α, and IL-10), and disease activity scores (SLEDAI-2 K and BILAG-2004) were assessed. For fecal IgA analysis, age- and sex-matched healthy controls without relevant diseases or recent antibiotic/microbiota-modulating use were included. Treatment response and safety outcomes were compared over 6 months. Both patient groups exhibited comparable baseline characteristics. Both treatment strategies led to significant improvements in clinical symptoms and imaging abnormalities—including bowel wall thickening, mesenteric effusion, comb sign, or target sign—with no significant differences observed between the groups. After six months of treatment, the median SLEDAI-2 K score in the rituximab (RTX) group decreased from 15 to 0 (p < 0.001), and the BILAG-2004 score decreased from 31.5 to 0 (p < 0.001). IL-6 levels in the RTX group also significantly declined from 26.57 ± 7.94 pg/mL to 4.15 ± 2.10 pg/mL (p < 0.01), with a greater reduction compared to the control group. Fecal IgA levels were higher in lupus enteritis patients than in healthy controls and decreased in both groups following treatment. Baseline IL-6 correlated with SLEDAI-2 K and BILAG-2004 scores, whereas fecal IgA was elevated in patients with mesenteric effusion but not associated with overall disease activity. At 6 months, remission was achieved in 93.8% of RTX-treated patients and 85% of controls (p = 0.418), with comparable safety profiles. Both RTX plus glucocorticoids and conventional immunosuppressants plus glucocorticoids are effective in inducing clinical and radiologic remission in LE. RTX may lead to faster improvement in certain serologic and inflammatory biomarkers. Larger studies with longer follow-up and stratification by systemic involvement are warranted to optimize individualized treatment strategies.
{"title":"Low-dose rituximab in lupus enteritis: a comparative study on its efficacy in modulating mucosal immunity and reducing inflammation","authors":"Ying Liu, YuJie Pang, Yang Liu, Na Zhang, LiangYu Mi, Yanan Gao, Wenqin Gao, Ke Xu","doi":"10.1186/s13075-025-03653-1","DOIUrl":"https://doi.org/10.1186/s13075-025-03653-1","url":null,"abstract":"Lupus enteritis (LE) is a serious manifestation of systemic lupus erythematosus (SLE), yet optimal treatment strategies remain unclear. This study aimed to compare the efficacy of rituximab (RTX) plus glucocorticoids versus glucocorticoids combined with conventional immunosuppressants in patients with moderate-to-severe LE. We retrospectively analyzed 36 patients with SLE-related intestinal involvement treated at our center between January 2015 and August 2024; sixteen received RTX plus glucocorticoids, and twenty received glucocorticoids with conventional immunosuppressants. Baseline characteristics, clinical features, abdominal CT findings, laboratory parameters (including serum and fecal IgA, IL-6, TNF-α, and IL-10), and disease activity scores (SLEDAI-2 K and BILAG-2004) were assessed. For fecal IgA analysis, age- and sex-matched healthy controls without relevant diseases or recent antibiotic/microbiota-modulating use were included. Treatment response and safety outcomes were compared over 6 months. Both patient groups exhibited comparable baseline characteristics. Both treatment strategies led to significant improvements in clinical symptoms and imaging abnormalities—including bowel wall thickening, mesenteric effusion, comb sign, or target sign—with no significant differences observed between the groups. After six months of treatment, the median SLEDAI-2 K score in the rituximab (RTX) group decreased from 15 to 0 (p < 0.001), and the BILAG-2004 score decreased from 31.5 to 0 (p < 0.001). IL-6 levels in the RTX group also significantly declined from 26.57 ± 7.94 pg/mL to 4.15 ± 2.10 pg/mL (p < 0.01), with a greater reduction compared to the control group. Fecal IgA levels were higher in lupus enteritis patients than in healthy controls and decreased in both groups following treatment. Baseline IL-6 correlated with SLEDAI-2 K and BILAG-2004 scores, whereas fecal IgA was elevated in patients with mesenteric effusion but not associated with overall disease activity. At 6 months, remission was achieved in 93.8% of RTX-treated patients and 85% of controls (p = 0.418), with comparable safety profiles. Both RTX plus glucocorticoids and conventional immunosuppressants plus glucocorticoids are effective in inducing clinical and radiologic remission in LE. RTX may lead to faster improvement in certain serologic and inflammatory biomarkers. Larger studies with longer follow-up and stratification by systemic involvement are warranted to optimize individualized treatment strategies.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"54 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188763","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 : 2025-09-26DOI: 10.1186/s13075-025-03646-0
Chao Li, Congqiang Hao, Kechong Zhou, Peng Zhang, Quan Sun, Zhengxi Li
Knee osteoarthritis (KOA), a degenerative joint disease marked by chronic pain, is associated with systemic inflammation that may extend to neurocognitive dysfunction. While chronic low-grade inflammation in KOA has been implicated in mild cognitive impairment (MCI), a prodromal stage of dementia, the mediating role of inflammation in brain functional reorganization remains unclear. This study integrated neuroimaging, inflammatory biomarkers, and machine learning to investigate inflammation-mediated brain functional alterations in 63 KOA patients with/without MCI. Serum levels of pro-inflammatory cytokines (IL-6, TNF-α) and resting-state fMRI data were analyzed using voxel-wise Regional Homogeneity (ReHo) and Amplitude of Low-Frequency Fluctuation (ALFF). Comparisons across healthy controls, KOA-MCI, and KOA-non-MCI groups identified MCI-linked functional alterations in the medial prefrontal cortex (mPFC), precuneus, and superior temporal gyrus. Mediation analysis revealed that mPFC ReHo significantly mediated the relationship between elevated IL-6 and cognitive decline. Machine learning models incorporating ReHo features from mPFC demonstrated robust classification of MCI status (AUC: 0.87), validated in an external dataset. Our findings suggest that IL-6-driven mPFC dysfunction is a potential pathway linking KOA-related inflammation to MCI, while highlighting the combined utility of ReHo/ALFF metrics in mPFC, precuneus, and temporal regions as potential neuroimaging biomarkers. This multimodal approach advances understanding of neuroinflammatory mechanisms in osteoarthritis and provides a framework for early detection of cognitive vulnerability in KOA populations.
{"title":"Inflammation-mediated regional brain alterations associated with mild cognitive impairment in knee osteoarthritis","authors":"Chao Li, Congqiang Hao, Kechong Zhou, Peng Zhang, Quan Sun, Zhengxi Li","doi":"10.1186/s13075-025-03646-0","DOIUrl":"https://doi.org/10.1186/s13075-025-03646-0","url":null,"abstract":"Knee osteoarthritis (KOA), a degenerative joint disease marked by chronic pain, is associated with systemic inflammation that may extend to neurocognitive dysfunction. While chronic low-grade inflammation in KOA has been implicated in mild cognitive impairment (MCI), a prodromal stage of dementia, the mediating role of inflammation in brain functional reorganization remains unclear. This study integrated neuroimaging, inflammatory biomarkers, and machine learning to investigate inflammation-mediated brain functional alterations in 63 KOA patients with/without MCI. Serum levels of pro-inflammatory cytokines (IL-6, TNF-α) and resting-state fMRI data were analyzed using voxel-wise Regional Homogeneity (ReHo) and Amplitude of Low-Frequency Fluctuation (ALFF). Comparisons across healthy controls, KOA-MCI, and KOA-non-MCI groups identified MCI-linked functional alterations in the medial prefrontal cortex (mPFC), precuneus, and superior temporal gyrus. Mediation analysis revealed that mPFC ReHo significantly mediated the relationship between elevated IL-6 and cognitive decline. Machine learning models incorporating ReHo features from mPFC demonstrated robust classification of MCI status (AUC: 0.87), validated in an external dataset. Our findings suggest that IL-6-driven mPFC dysfunction is a potential pathway linking KOA-related inflammation to MCI, while highlighting the combined utility of ReHo/ALFF metrics in mPFC, precuneus, and temporal regions as potential neuroimaging biomarkers. This multimodal approach advances understanding of neuroinflammatory mechanisms in osteoarthritis and provides a framework for early detection of cognitive vulnerability in KOA populations.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"53 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141562","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}
Rheumatoid arthritis (RA) is an aggressive, systemic autoimmune disease in which overactivated macrophages play a critical role in its pathogenesis. This study aimed to explore the potential role of glycolytic reprogramming in the production of proinflammatory cytokines by macrophages in RA. The Seahorse assay was conducted on RA or healthy control (HC) serum-treated human monocyte-derived macrophages (HMDMs) to evaluate glycolysis levels. RNA sequencing was performed to identify activated signaling pathways and key molecules in HMDMs stimulated by RA serum. The proinflammatory cytokines and hypoxia-inducible factor 1α (HIF-1α) were verified by Western blotting and quantitative polymerase chain reaction (qPCR). We found that HMDMs stimulated with RA serum showed higher aerobic glycolysis levels than those treated with HC serum, along with higher expression of glycolysis-related genes, including hexokinase2 (HK2), pyruvate kinase L/R (PKLR), and phosphoglycerate kinase 1 (PGK1). Furthermore, RA serum-treated macrophages exhibited a higher level of interleukin-1 beta (IL-1β), and the expression of IL-1β positively correlated with HK2. Inhibition of glycolysis by 3-bromopyruvate (3BrPA) or HK2 knockdown significantly suppressed IL-1β production in macrophages. The HIF-1α-associated signaling pathways and HIF-1α protein levels were also elevated in RA serum-treated macrophages. Inhibition of glycolysis by 3BrPA or knockdown of HK2 reduced HIF-1α. Inhibiting HIF-1α can suppress IL-1β production of RA serum-treated macrophages, and vice versa. TNF-α and IL-1β enhanced HIF-1α and IL-1β expression in macrophages, an effect attenuated by glycolysis inhibition. Blocking TNF-α and IL-1β in RA serum diminished both glycolysis and IL-1β production. Our findings demonstrate that RA serum triggers aerobic glycolysis in macrophages, which promotes HIF-1α to drive IL-1β production. Notably, IL-1β within RA serum amplifies its own expression via this glycolysis-HIF-1α axis, establishing a pathogenic positive feedback loop in RA.
{"title":"The Glycolysis-HIF-1α axis induces IL-1β of macrophages in rheumatoid arthritis","authors":"Yimeng Jia, Rongli Li, Linfang Huang, Xunyao Wu, Lidan Zhao, Huaxia Yang, Xin You, Yunyun Fei","doi":"10.1186/s13075-025-03647-z","DOIUrl":"https://doi.org/10.1186/s13075-025-03647-z","url":null,"abstract":"Rheumatoid arthritis (RA) is an aggressive, systemic autoimmune disease in which overactivated macrophages play a critical role in its pathogenesis. This study aimed to explore the potential role of glycolytic reprogramming in the production of proinflammatory cytokines by macrophages in RA. The Seahorse assay was conducted on RA or healthy control (HC) serum-treated human monocyte-derived macrophages (HMDMs) to evaluate glycolysis levels. RNA sequencing was performed to identify activated signaling pathways and key molecules in HMDMs stimulated by RA serum. The proinflammatory cytokines and hypoxia-inducible factor 1α (HIF-1α) were verified by Western blotting and quantitative polymerase chain reaction (qPCR). We found that HMDMs stimulated with RA serum showed higher aerobic glycolysis levels than those treated with HC serum, along with higher expression of glycolysis-related genes, including hexokinase2 (HK2), pyruvate kinase L/R (PKLR), and phosphoglycerate kinase 1 (PGK1). Furthermore, RA serum-treated macrophages exhibited a higher level of interleukin-1 beta (IL-1β), and the expression of IL-1β positively correlated with HK2. Inhibition of glycolysis by 3-bromopyruvate (3BrPA) or HK2 knockdown significantly suppressed IL-1β production in macrophages. The HIF-1α-associated signaling pathways and HIF-1α protein levels were also elevated in RA serum-treated macrophages. Inhibition of glycolysis by 3BrPA or knockdown of HK2 reduced HIF-1α. Inhibiting HIF-1α can suppress IL-1β production of RA serum-treated macrophages, and vice versa. TNF-α and IL-1β enhanced HIF-1α and IL-1β expression in macrophages, an effect attenuated by glycolysis inhibition. Blocking TNF-α and IL-1β in RA serum diminished both glycolysis and IL-1β production. Our findings demonstrate that RA serum triggers aerobic glycolysis in macrophages, which promotes HIF-1α to drive IL-1β production. Notably, IL-1β within RA serum amplifies its own expression via this glycolysis-HIF-1α axis, establishing a pathogenic positive feedback loop in RA.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"4 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141201","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}
Subchondral bone changes, which include bone marrow lesion (BML), subchondral bone attrition (SBA) and subchondral bone cyst (SBC) by magnetic resonance imaging (MRI) analysis, are reportedly implicated for knee pain in knee osteoarthritis (OA). However, the relationship between these subchondral bone changes and OA knee pain and the effect of articular cartilage lesion on the pain remain elusive. Elderly subjects (1,145 subjects, 72.9 years old on average) in the Bunkyo Health Study, 71.5% of whom had knee OA with ≥ Kellgren-Lawrence grade 2, were enrolled. Knee pain in daily life over the past few days was measured using Visual Analogue Scale (VAS) in the Japanese Knee Osteoarthritis Measure. The subjects without or with pain were defined if they indicated a pain VAS score of 0 or a pain VAS score of ≥ 1. The association was examined between knee pain and MRI-detected OA structural changes which were determined according to the Whole Organ Magnetic Resonance Imaging Score. While 62.2% of the subjects were free from knee pain, 37.8% of the subjects had knee pain. Knee pain was not related with cartilage lesion without subchondral bone changes (odds ratio [OR]: 1.10 [95% confidence interval [CI]: 0.83–1.46]) or BML alone (OR: 1.32 [95% CI: 0.95–1.83]). However, knee pain was significantly associated with BML coexistent with SBA (OR: 2.22 [95% CI: 1.25–3.97]), SBC (OR: 1.79 [95% CI: 1.28–2.51]), or both SBA and SBC (OR: 2.18 [95% CI: 1.35–3.53]). Similar positive relationships between knee pain and coexisted subchondral bone changes were obtained regardless of the presence or absence of cartilage lesion present above the BML region. When BML was not coexistent with either SBA or SBC regardless of cartilage lesion above the subchondral bone changes, BML was not associated with knee pain (OR: 1.26 [95% CI: 0.90–1.77]) or (OR: 2.16 [95% CI: 0.89–5.23]). BML coexistent with SBA and/or SBC, but not BML without the coexistence, was associated with knee pain in the elderly with knee OA regardless of the presence or absence of cartilage lesion.
{"title":"Bone marrow lesion coexisted with subchondral bone attrition and/or subchondral bone cyst is associated with knee pain in knee osteoarthritis regardless of cartilage lesion: the Bunkyo health study","authors":"Jun Tomura, Haruka Kaneko, Arepati Adili, Takako Aoki, Lizu Liu, Yoshifumi Negishi, Keiichi Yoshida, Keiji Kobayashi, Suguru Wakana, Shinnosuke Hada, Jun Shiozawa, Yuichiro Machiyama, Takuya Yamamura, Takahiro Sasahara, Kengo Sugitani, Mitsuaki Kubota, Yuki Someya, Yoshifumi Tamura, Shuko Nojiri, Takako Negishi-Koga, Yasunori Okada, Muneaki Ishijima","doi":"10.1186/s13075-025-03644-2","DOIUrl":"https://doi.org/10.1186/s13075-025-03644-2","url":null,"abstract":"Subchondral bone changes, which include bone marrow lesion (BML), subchondral bone attrition (SBA) and subchondral bone cyst (SBC) by magnetic resonance imaging (MRI) analysis, are reportedly implicated for knee pain in knee osteoarthritis (OA). However, the relationship between these subchondral bone changes and OA knee pain and the effect of articular cartilage lesion on the pain remain elusive. Elderly subjects (1,145 subjects, 72.9 years old on average) in the Bunkyo Health Study, 71.5% of whom had knee OA with ≥ Kellgren-Lawrence grade 2, were enrolled. Knee pain in daily life over the past few days was measured using Visual Analogue Scale (VAS) in the Japanese Knee Osteoarthritis Measure. The subjects without or with pain were defined if they indicated a pain VAS score of 0 or a pain VAS score of ≥ 1. The association was examined between knee pain and MRI-detected OA structural changes which were determined according to the Whole Organ Magnetic Resonance Imaging Score. While 62.2% of the subjects were free from knee pain, 37.8% of the subjects had knee pain. Knee pain was not related with cartilage lesion without subchondral bone changes (odds ratio [OR]: 1.10 [95% confidence interval [CI]: 0.83–1.46]) or BML alone (OR: 1.32 [95% CI: 0.95–1.83]). However, knee pain was significantly associated with BML coexistent with SBA (OR: 2.22 [95% CI: 1.25–3.97]), SBC (OR: 1.79 [95% CI: 1.28–2.51]), or both SBA and SBC (OR: 2.18 [95% CI: 1.35–3.53]). Similar positive relationships between knee pain and coexisted subchondral bone changes were obtained regardless of the presence or absence of cartilage lesion present above the BML region. When BML was not coexistent with either SBA or SBC regardless of cartilage lesion above the subchondral bone changes, BML was not associated with knee pain (OR: 1.26 [95% CI: 0.90–1.77]) or (OR: 2.16 [95% CI: 0.89–5.23]). BML coexistent with SBA and/or SBC, but not BML without the coexistence, was associated with knee pain in the elderly with knee OA regardless of the presence or absence of cartilage lesion.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"42 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141565","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 : 2025-09-25DOI: 10.1186/s13075-025-03657-x
Tahzeeb Fatima, Yuan Zhang, Georgios K. Vasileiadis, Araz Rawshani, Ronald van Vollenhoven, Jon Lampa, Bjorn Gudbjornsson, Espen A. Haavardsholm, Dan Nordström, Gerdur Gröndal, Kim Hørslev-Petersen, Kristina Lend, Marte S. Heiberg, Merete Lund Hetland, Michael Nurmohamed, Mikkel Østergaard, Till Uhlig, Tuulikki Sokka-Isler, Anna Rudin, Cristina Maglio
<p><b>Correction: Arthritis Res Ther 27</b>,<b> 156 (2025)</b></p><p><b>https://doi.org/10.1186/s13075-025-03533-8</b></p><p>Following publication of the original article [1], the authors reported a typesetting error. Table footnote for Tables 1 and 2 were misplace in the main text.</p><p><i>Table 1 footnote was place on page 7 under the section “</i><b><i>Characteristics of the study participants</i></b><i>” as follows</i>:</p><p>Continuous variables are expressed as mean ± standard deviation, while categorical variables are expressed as number and percentages. Student t-test was used to compare continuous variables while Chi-square test was used to compare categorical variables between responders and non-responders. <i>p</i>-values are provided for a comparison between these two groups with a <i>p</i> ≤ 0.05 indicating significance.</p><p>BMI: body mass index, RF: rheumatoid factor, ACPA: anti-citrullinated peptide antibody, ESR: Erythrocyte sedimentation rate, CRP: C-reactive protein, SJC28: Swollen joint count (out of 28), TJC28: Tender joint count (out of 28), DAS28-ESR: Disease activity score of 28 joints (ESR-based), DAS28-CRP: Disease activity score using 28 joint counts (CRP-based), CDAI: Clinical Disease Activity Index.</p><p><i>The above statement has been move accordingly under Table 1 as footnote.</i></p><p><i>Table 2 footnote was place on page 11 before the section “</i><b><i>Discussion</i></b><i>” as follows</i>:</p><p>For clinical variables only, the best random forest model encompassed 500 trees with mtry 1 and min-n 10, while the best XGB encompassed 500 trees, with maximum tree depth 11, mtry 1, min-n 6, learn rate 4.2e-3, loss reduction 0 and sample size 1. For clinical & metabolites, the best random forest model encompassed 947 trees with mtry 2 and min-n 6, while the best XGB model encompassed 1057 trees, with maximum tree depth 2, mtry 15, min-n 3, learn rate 0.002, loss reduction 0, and sample size 0.8. ROC-AUC: area under the receiver operating characteristic curve, SVM: support vector machine XG-boost: extreme gradient boosting.</p><p><i>The above statement has been move accordingly under Table 2 as footnote.</i></p><p>The original article [1] has been updated.</p><ol data-track-component="outbound reference" data-track-context="references section"><li data-counter="1."><p>Fatima T, Zhang Y, Vasileiadis GK, et al. Disease activity and treatment response in early rheumatoid arthritis: an exploratory metabolomic profiling in the NORD-STAR cohort. Arthritis Res Ther. 2025;27:156. https://doi.org/10.1186/s13075-025-03616-6.</p><p>Article PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-download-medium" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></p><h3>Authors and Affiliations</h3><ol><li><p>Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Aca
{"title":"Correction: Disease activity and treatment response in early rheumatoid arthritis: an exploratory metabolomic profiling in the NORD-STAR cohort","authors":"Tahzeeb Fatima, Yuan Zhang, Georgios K. Vasileiadis, Araz Rawshani, Ronald van Vollenhoven, Jon Lampa, Bjorn Gudbjornsson, Espen A. Haavardsholm, Dan Nordström, Gerdur Gröndal, Kim Hørslev-Petersen, Kristina Lend, Marte S. Heiberg, Merete Lund Hetland, Michael Nurmohamed, Mikkel Østergaard, Till Uhlig, Tuulikki Sokka-Isler, Anna Rudin, Cristina Maglio","doi":"10.1186/s13075-025-03657-x","DOIUrl":"https://doi.org/10.1186/s13075-025-03657-x","url":null,"abstract":"<p><b>Correction: Arthritis Res Ther 27</b>,<b> 156 (2025)</b></p><p><b>https://doi.org/10.1186/s13075-025-03533-8</b></p><p>Following publication of the original article [1], the authors reported a typesetting error. Table footnote for Tables 1 and 2 were misplace in the main text.</p><p><i>Table 1 footnote was place on page 7 under the section “</i><b><i>Characteristics of the study participants</i></b><i>” as follows</i>:</p><p>Continuous variables are expressed as mean ± standard deviation, while categorical variables are expressed as number and percentages. Student t-test was used to compare continuous variables while Chi-square test was used to compare categorical variables between responders and non-responders. <i>p</i>-values are provided for a comparison between these two groups with a <i>p</i> ≤ 0.05 indicating significance.</p><p>BMI: body mass index, RF: rheumatoid factor, ACPA: anti-citrullinated peptide antibody, ESR: Erythrocyte sedimentation rate, CRP: C-reactive protein, SJC28: Swollen joint count (out of 28), TJC28: Tender joint count (out of 28), DAS28-ESR: Disease activity score of 28 joints (ESR-based), DAS28-CRP: Disease activity score using 28 joint counts (CRP-based), CDAI: Clinical Disease Activity Index.</p><p><i>The above statement has been move accordingly under Table 1 as footnote.</i></p><p><i>Table 2 footnote was place on page 11 before the section “</i><b><i>Discussion</i></b><i>” as follows</i>:</p><p>For clinical variables only, the best random forest model encompassed 500 trees with mtry 1 and min-n 10, while the best XGB encompassed 500 trees, with maximum tree depth 11, mtry 1, min-n 6, learn rate 4.2e-3, loss reduction 0 and sample size 1. For clinical & metabolites, the best random forest model encompassed 947 trees with mtry 2 and min-n 6, while the best XGB model encompassed 1057 trees, with maximum tree depth 2, mtry 15, min-n 3, learn rate 0.002, loss reduction 0, and sample size 0.8. ROC-AUC: area under the receiver operating characteristic curve, SVM: support vector machine XG-boost: extreme gradient boosting.</p><p><i>The above statement has been move accordingly under Table 2 as footnote.</i></p><p>The original article [1] has been updated.</p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Fatima T, Zhang Y, Vasileiadis GK, et al. Disease activity and treatment response in early rheumatoid arthritis: an exploratory metabolomic profiling in the NORD-STAR cohort. Arthritis Res Ther. 2025;27:156. https://doi.org/10.1186/s13075-025-03616-6.</p><p>Article PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><h3>Authors and Affiliations</h3><ol><li><p>Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Aca","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"28 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133660","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 : 2025-09-25DOI: 10.1186/s13075-025-03636-2
Helen Willcockson, Antonietta Greco, Agnese Fragassi, Roberto Palomba, Kihyun Kwon, Huseyin Ozkan, Samuel T. Bartlett, Richard F. Loeser, Paolo Decuzzi, Lara Longobardi
Fetuin-A is a glycoprotein with high affinity for calcium-phosphates, with a role in cartilage and bone metabolism, and an anti-inflammatory role in injury. Studies have shown decreasing serum fetuin-A levels in patients with severe osteoarthritis (OA), and lower amounts of fetuin-A in OA sclerotic osteoblasts. Therefore, decreasing fetuin-A during OA might be responsible for increased inflammation, cartilage mineralization and subchondral bone thickness. To assess the therapeutic potential of fetuin-A in post-traumatic OA (PTOA), we used micrometric hyaluronic-acid particles (µHA) to achieve a sustained intra-articular release of fetuin-A into diseased joint knees and followed PTOA progression over time. Because OA progression may lead to muscle degeneration, we also assessed muscle strength. Shape-defined hyaluronic-acid microparticles were fabricated and associated with fetuin-A, generating a fetuin-A µHA complex (Fet-µHA). After physicochemical characterization and biocompatibility studies on chondrocytes, the release profile of fetuin-A from Fet-µHA was established. The therapeutic efficacy of Fet-µHA on PTOA was assessed using the destabilization of the medial meniscus (DMM) model. We intra-articularly injected Fet-µHA (20 mg/kg, every 3wks), empty-µHA, or saline into DMM knees of C57BL/6 J mice, following OA outcomes at early and severe PTOA (4 weeks and 12 weeks post-DMM). Outcomes included cartilage structure (ACS score, H&E), matrix loss (Safranin-O score), articular cartilage (AC) thinning, osteophyte development, bone histomorphometry, synovial hyperplasia and maximal tetanic force. All group analyses were performed with ordinary two-way ANOVA (cell viability) or one-way ANOVA (in vivo studies), followed by Tukey’s post-hoc test for multiple comparisons (statistical significance at P < 0.05). The in vitro studies confirmed the biocompatibility of Fet-µHA and established a release profile up to 45 days. In vivo intra-articular administration of the Fet-µHA into DMM knees was beneficial for OA cartilage,bone damage and synovial hyperplasia. Furthermore, Fet-µHA treatment led to a significative improvement of tetanic max contraction force at the severe stage. This pre-clinical study not only opens new perspectives for the potential use of fetuin-A in OA treatment but confirms µHA as a promising drug carrier in OA.
{"title":"Sustained release of exogeneous fetuin-A from Hyaluronic acid microplates decreases joint degeneration, synovial hyperplasia and muscle damage in a murine post-traumatic osteoarthritis model","authors":"Helen Willcockson, Antonietta Greco, Agnese Fragassi, Roberto Palomba, Kihyun Kwon, Huseyin Ozkan, Samuel T. Bartlett, Richard F. Loeser, Paolo Decuzzi, Lara Longobardi","doi":"10.1186/s13075-025-03636-2","DOIUrl":"https://doi.org/10.1186/s13075-025-03636-2","url":null,"abstract":"Fetuin-A is a glycoprotein with high affinity for calcium-phosphates, with a role in cartilage and bone metabolism, and an anti-inflammatory role in injury. Studies have shown decreasing serum fetuin-A levels in patients with severe osteoarthritis (OA), and lower amounts of fetuin-A in OA sclerotic osteoblasts. Therefore, decreasing fetuin-A during OA might be responsible for increased inflammation, cartilage mineralization and subchondral bone thickness. To assess the therapeutic potential of fetuin-A in post-traumatic OA (PTOA), we used micrometric hyaluronic-acid particles (µHA) to achieve a sustained intra-articular release of fetuin-A into diseased joint knees and followed PTOA progression over time. Because OA progression may lead to muscle degeneration, we also assessed muscle strength. Shape-defined hyaluronic-acid microparticles were fabricated and associated with fetuin-A, generating a fetuin-A µHA complex (Fet-µHA). After physicochemical characterization and biocompatibility studies on chondrocytes, the release profile of fetuin-A from Fet-µHA was established. The therapeutic efficacy of Fet-µHA on PTOA was assessed using the destabilization of the medial meniscus (DMM) model. We intra-articularly injected Fet-µHA (20 mg/kg, every 3wks), empty-µHA, or saline into DMM knees of C57BL/6 J mice, following OA outcomes at early and severe PTOA (4 weeks and 12 weeks post-DMM). Outcomes included cartilage structure (ACS score, H&E), matrix loss (Safranin-O score), articular cartilage (AC) thinning, osteophyte development, bone histomorphometry, synovial hyperplasia and maximal tetanic force. All group analyses were performed with ordinary two-way ANOVA (cell viability) or one-way ANOVA (in vivo studies), followed by Tukey’s post-hoc test for multiple comparisons (statistical significance at P < 0.05). The in vitro studies confirmed the biocompatibility of Fet-µHA and established a release profile up to 45 days. In vivo intra-articular administration of the Fet-µHA into DMM knees was beneficial for OA cartilage,bone damage and synovial hyperplasia. Furthermore, Fet-µHA treatment led to a significative improvement of tetanic max contraction force at the severe stage. This pre-clinical study not only opens new perspectives for the potential use of fetuin-A in OA treatment but confirms µHA as a promising drug carrier in OA.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"6 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133662","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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