Pub Date : 2025-10-22DOI: 10.1186/s13075-025-03667-9
Maximilian T Löffler, Gabby B Joseph, John A Lynch, Nancy E Lane, Valentina Pedoia, Sharmila Majumdar, Michael Nevitt, Charles McCulloch, Thomas M Link
{"title":"Association between constant and intermittent knee pain and T2 values and cartilage thickness: data from the osteoarthritis initiative.","authors":"Maximilian T Löffler, Gabby B Joseph, John A Lynch, Nancy E Lane, Valentina Pedoia, Sharmila Majumdar, Michael Nevitt, Charles McCulloch, Thomas M Link","doi":"10.1186/s13075-025-03667-9","DOIUrl":"10.1186/s13075-025-03667-9","url":null,"abstract":"","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"27 1","pages":"196"},"PeriodicalIF":4.6,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12542445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342631","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 : 2025-10-21DOI: 10.1186/s13075-025-03663-z
Johan Karlsson Wallman, Elisabeth Mogard, Jonas Sagard, Kristofer Andréasson, Jan Marsal, Fatih Inci, Mats Geijer, Tor Olofsson, Elisabet Lindqvist
Background: In axial spondyloarthritis (axSpA), 5-10% of patients have comorbid inflammatory bowel disease (IBD). Beyond that, 50-60% display histologic inflammation in ileum/colon biopsies, and fecal calprotectin (F-calprotectin) is elevated in relation to healthy controls. Prior studies have shown such, often subclinical, gut inflammation in axSpA to be associated with more active disease, as measured by clinical indices as well as magnetic resonance imaging - both known risk factors for structural spinal damage development. In light of this, in the current study we aimed to examine whether gut inflammation, assessed by F-calprotectin, is associated with more structural spinal damage in axSpA.
Methods: Patients with well-characterized non-radiographic or radiographic axSpA (nr-axSpA/r-axSpA; n = 76/152), according to ASAS or modified New York criteria, enrolled in a population-based cohort study in southern Sweden, were assessed for structural spinal damage (modified Stoke ankylosing spondylitis spinal score [mSASSS]) and gut inflammation (F-calprotectin). mSASSS values were compared between patients with normal (< 50 mg/kg), moderately elevated (50-149 mg/kg) or distinctly elevated (≥ 150 mg/kg) F-calprotectin, reflecting no/some/evident gut inflammation, respectively (one-way ANOVA). Moreover, logistic regression was applied to explore if elevated F-calprotectin (≥ 50 mg/kg) was associated with mSASSS values above the median, adjusted for sex, symptom duration, HLA-B27 status, smoking, CRP, NSAID and anti-TNF therapy. Analyses limited to r-axSpA were also performed.
Results: In both axSpA patients overall and separately in r-axSpA, mSASSS distributions differed significantly between subjects with normal/moderately/distinctly elevated F-calprotectin, with more damage observed in those with higher F-calprotectin levels. Furthermore, elevated F-calprotectin (≥ 50 mg/kg) was associated with mSASSS values above the median, in both the entire axSpA group (adjusted odds ratio [OR] 2.2 [95%CI 1.1-4.2]); and in r-axSpA alone (adjusted OR 2.9 [1.2-7.1]).
Conclusion: In the current study, the presence of gut inflammation, assessed by F-calprotectin, was cross-sectionally associated with more structural damage in the spine in patients with axSpA, even after adjustments for known risk factors for spinal damage. Prospective studies are, however, needed to investigate whether gut inflammation may be a predictor of spinal radiographic progression in axSpA.
{"title":"Gut inflammation is associated with structural spinal damage in axial spondyloarthritis - results from the observational SPARTAKUS cohort.","authors":"Johan Karlsson Wallman, Elisabeth Mogard, Jonas Sagard, Kristofer Andréasson, Jan Marsal, Fatih Inci, Mats Geijer, Tor Olofsson, Elisabet Lindqvist","doi":"10.1186/s13075-025-03663-z","DOIUrl":"10.1186/s13075-025-03663-z","url":null,"abstract":"<p><strong>Background: </strong>In axial spondyloarthritis (axSpA), 5-10% of patients have comorbid inflammatory bowel disease (IBD). Beyond that, 50-60% display histologic inflammation in ileum/colon biopsies, and fecal calprotectin (F-calprotectin) is elevated in relation to healthy controls. Prior studies have shown such, often subclinical, gut inflammation in axSpA to be associated with more active disease, as measured by clinical indices as well as magnetic resonance imaging - both known risk factors for structural spinal damage development. In light of this, in the current study we aimed to examine whether gut inflammation, assessed by F-calprotectin, is associated with more structural spinal damage in axSpA.</p><p><strong>Methods: </strong>Patients with well-characterized non-radiographic or radiographic axSpA (nr-axSpA/r-axSpA; n = 76/152), according to ASAS or modified New York criteria, enrolled in a population-based cohort study in southern Sweden, were assessed for structural spinal damage (modified Stoke ankylosing spondylitis spinal score [mSASSS]) and gut inflammation (F-calprotectin). mSASSS values were compared between patients with normal (< 50 mg/kg), moderately elevated (50-149 mg/kg) or distinctly elevated (≥ 150 mg/kg) F-calprotectin, reflecting no/some/evident gut inflammation, respectively (one-way ANOVA). Moreover, logistic regression was applied to explore if elevated F-calprotectin (≥ 50 mg/kg) was associated with mSASSS values above the median, adjusted for sex, symptom duration, HLA-B27 status, smoking, CRP, NSAID and anti-TNF therapy. Analyses limited to r-axSpA were also performed.</p><p><strong>Results: </strong>In both axSpA patients overall and separately in r-axSpA, mSASSS distributions differed significantly between subjects with normal/moderately/distinctly elevated F-calprotectin, with more damage observed in those with higher F-calprotectin levels. Furthermore, elevated F-calprotectin (≥ 50 mg/kg) was associated with mSASSS values above the median, in both the entire axSpA group (adjusted odds ratio [OR] 2.2 [95%CI 1.1-4.2]); and in r-axSpA alone (adjusted OR 2.9 [1.2-7.1]).</p><p><strong>Conclusion: </strong>In the current study, the presence of gut inflammation, assessed by F-calprotectin, was cross-sectionally associated with more structural damage in the spine in patients with axSpA, even after adjustments for known risk factors for spinal damage. Prospective studies are, however, needed to investigate whether gut inflammation may be a predictor of spinal radiographic progression in axSpA.</p>","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"27 1","pages":"195"},"PeriodicalIF":4.6,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12539032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342570","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 : 2025-10-17DOI: 10.1186/s13075-025-03649-x
Espen Riskedal, Astanand Jugessur, Silje Watterdal Syversen, Cathrine Lund Hadley, Jennifer R. Harris, Maria Dahl Mjaavatten, Joe Sexton, Janis Neumann, Gina Hetland Brinkmann, Guro Løvik Goll, Grethe-Elisabeth Stenvik, Håkon Bøås, Arne Søraas, Karl Trygve Kalleberg, Siri Lillegraven, Espen A. Haavardsholm
Rheumatoid arthritis (RA), particularly seronegative disease, is difficult to diagnose early, which can delay treatment initiation. This study aims to develop a binary DNA methylation (DNAm)-based algorithm to diagnose RA. Three datasets (discovery, training, holdout) were constructed from DNAm profiles from 1366 persons (treatment-naïve RA, other inflammatory/autoimmune diseases, healthy individuals). DNAm features that differentiate RA from other inflammatory/autoimmune diseases and healthy individuals were identified using the discovery set. Our classification algorithm was developed using machine learning techniques in the training set. Its diagnostic performance, with and without serological status, was evaluated in the holdout set containing RA cases (15 seropositive, 6 seronegative) and controls (14 other arthritides, 11 healthy individuals). Our algorithm included 391 DNAm features. Combined with serological status, it classified RA from controls in the holdout set with the following performance: sensitivity 0.90 [95% CI: 0.70–0.99], specificity 0.88 [95% CI: 0.69–0.97], and AUC 0.96 [95% CI: 0.91–1.00]. Its performance in classifying patients with seronegative RA versus those with other arthritides was: sensitivity 0.83 [95% CI: 0.36–1.00], specificity 0.79 [95% CI: 0.49–0.95], and AUC 0.81 [95% CI: 0.61–1.00]. The present DNAm-based classification algorithm may be clinically useful for the early diagnosis of RA, especially in seronegative patients, which currently often poses a diagnostic challenge.
{"title":"A DNA methylation-based algorithm for diagnosing rheumatoid arthritis","authors":"Espen Riskedal, Astanand Jugessur, Silje Watterdal Syversen, Cathrine Lund Hadley, Jennifer R. Harris, Maria Dahl Mjaavatten, Joe Sexton, Janis Neumann, Gina Hetland Brinkmann, Guro Løvik Goll, Grethe-Elisabeth Stenvik, Håkon Bøås, Arne Søraas, Karl Trygve Kalleberg, Siri Lillegraven, Espen A. Haavardsholm","doi":"10.1186/s13075-025-03649-x","DOIUrl":"https://doi.org/10.1186/s13075-025-03649-x","url":null,"abstract":"Rheumatoid arthritis (RA), particularly seronegative disease, is difficult to diagnose early, which can delay treatment initiation. This study aims to develop a binary DNA methylation (DNAm)-based algorithm to diagnose RA. Three datasets (discovery, training, holdout) were constructed from DNAm profiles from 1366 persons (treatment-naïve RA, other inflammatory/autoimmune diseases, healthy individuals). DNAm features that differentiate RA from other inflammatory/autoimmune diseases and healthy individuals were identified using the discovery set. Our classification algorithm was developed using machine learning techniques in the training set. Its diagnostic performance, with and without serological status, was evaluated in the holdout set containing RA cases (15 seropositive, 6 seronegative) and controls (14 other arthritides, 11 healthy individuals). Our algorithm included 391 DNAm features. Combined with serological status, it classified RA from controls in the holdout set with the following performance: sensitivity 0.90 [95% CI: 0.70–0.99], specificity 0.88 [95% CI: 0.69–0.97], and AUC 0.96 [95% CI: 0.91–1.00]. Its performance in classifying patients with seronegative RA versus those with other arthritides was: sensitivity 0.83 [95% CI: 0.36–1.00], specificity 0.79 [95% CI: 0.49–0.95], and AUC 0.81 [95% CI: 0.61–1.00]. The present DNAm-based classification algorithm may be clinically useful for the early diagnosis of RA, especially in seronegative patients, which currently often poses a diagnostic challenge.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"97 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311541","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 efficacy of rituximab (RTX) for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD) has not been fully established. This study compared the efficacy and safety of RTX and intravenous cyclophosphamide (CY) for SSc-ILD. This retrospective study compared the efficacy and safety of RTX (20 patients) and CY (30 patients) after adjusting for the stabilised inverse probability of treatment weighting based on propensity scores. The efficacy endpoints were the absolute changes in forced vital capacity (FVC) and serum Krebs von den Lungen-6 (KL-6) levels from baseline to 6 and 12 months after treatment. The incidence of progression based on the definition of progressive pulmonary fibrosis was also recorded. The safety endpoint was the frequency of adverse events. The clinical characteristics of the two groups were well-balanced after adjusting for confounders (i.e., FVC, nintedanib use, and newly diagnosed cases). From baseline to 6 and 12 months after the start of treatment, the median FVC increased by 50 and 60 ml in the RTX group and 40 and 15 ml in the CY group, respectively, with no difference after adjustment. The changes in serum KL-6 levels and the incidences of progression were identical in both groups after adjustment. The overall adverse events were similar in both groups after adjustment. RTX demonstrated comparable safety and efficacy as CY in patients with SSc-ILD. Thus, RTX may be an alternative to CY for the treatment of SSc-ILD.
利妥昔单抗（RTX）治疗系统性硬化症相关间质性肺疾病（SSc-ILD）的疗效尚未完全确定。本研究比较了RTX和静脉注射环磷酰胺（CY）治疗SSc-ILD的疗效和安全性。本回顾性研究比较了RTX（20例患者）和CY（30例患者）在调整基于倾向评分的治疗加权的稳定逆概率后的疗效和安全性。疗效终点是治疗后6个月和12个月的强迫肺活量（FVC）和血清Krebs von den Lungen-6 （KL-6）水平的绝对变化。根据进行性肺纤维化的定义，还记录了进展的发生率。安全性终点是不良事件发生的频率。在调整混杂因素（即FVC、尼达尼布使用和新诊断病例）后，两组的临床特征很好地平衡。从基线到治疗开始后6个月和12个月，RTX组的中位FVC分别增加了50和60 ml， CY组增加了40和15 ml，调整后无差异。调整后两组血清KL-6水平变化及进展发生率相同。调整后两组总体不良事件相似。RTX在SSc-ILD患者中的安全性和有效性与CY相当。因此，RTX可能是治疗SSc-ILD的替代方法。
{"title":"Efficacy and safety of rituximab versus intravenous cyclophosphamide for systemic sclerosis-associated interstitial lung disease: a retrospective cohort study","authors":"Rioko Hiura, Masahiro Ayano, Ayumi Uchino, Junki Hiura, Naoyasu Ueda, Atsushi Tanaka, Seiji Yoshizawa, Shotaro Kawano, Fumiaki Sagawa, Shun-Ichiro Ota, Akie Hirata, Sho Fujimoto, Naoya Nishimura, Ayako Takaki-Kuwahara, Yasutaka Kimoto, Koichi Akashi, Hiroaki Niiro","doi":"10.1186/s13075-025-03654-0","DOIUrl":"https://doi.org/10.1186/s13075-025-03654-0","url":null,"abstract":"The efficacy of rituximab (RTX) for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD) has not been fully established. This study compared the efficacy and safety of RTX and intravenous cyclophosphamide (CY) for SSc-ILD. This retrospective study compared the efficacy and safety of RTX (20 patients) and CY (30 patients) after adjusting for the stabilised inverse probability of treatment weighting based on propensity scores. The efficacy endpoints were the absolute changes in forced vital capacity (FVC) and serum Krebs von den Lungen-6 (KL-6) levels from baseline to 6 and 12 months after treatment. The incidence of progression based on the definition of progressive pulmonary fibrosis was also recorded. The safety endpoint was the frequency of adverse events. The clinical characteristics of the two groups were well-balanced after adjusting for confounders (i.e., FVC, nintedanib use, and newly diagnosed cases). From baseline to 6 and 12 months after the start of treatment, the median FVC increased by 50 and 60 ml in the RTX group and 40 and 15 ml in the CY group, respectively, with no difference after adjustment. The changes in serum KL-6 levels and the incidences of progression were identical in both groups after adjustment. The overall adverse events were similar in both groups after adjustment. RTX demonstrated comparable safety and efficacy as CY in patients with SSc-ILD. Thus, RTX may be an alternative to CY for the treatment of SSc-ILD.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"27 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311540","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}
β2-adrenergic receptor (β2-AR) is widely expressed on immune cells, including T cells and it has a non-canonical signaling pathway, which is β2-AR-β-arrestin 2 (β-Arr2)-extracellular signal-regulated kinase 1/2 (ERK1/2). Our previous studies have shown that the β2-AR agonist terbutaline (Terb) can activate β2-AR and significantly inhibit helper T (Th) 17 cell function in collagen-induced arthritis (CIA). However, the effects of β2-AR on regulatory T (Treg) cells in CIA have not been consistently determined. The aim of our research was to explore whether β2-AR-β-Arr2-ERK1/2 signaling in Treg cells regulates inflammatory responses and signs in CIA. DBA1/J mice were used to prepare CIA model by intradermal injection of collagen type II (CII). Inducible Treg (iTreg) cells were induced from CD4+ T cells that were isolated from the spleens of normal or CIA mice and treated with Terb, β-Arr2 gene silence or overexpression or the ERK1/2 inhibitor U0126 in vitro. β2-AR and β-Arr2 expression, pERK1/2 level, interleukin (IL)-10 and transforming growth factor (TGF)-β production and the suppression of effector T (Teff) cell proliferation mediated by nature Treg (nTreg) cells were determined. β-Arr2-overexpressed Treg cells were intravenously injected into the tail base of CIA mice. Arthritic symptoms were assessed by clinical arthritis scores. Frequencies of Th17 and Treg cells, cytokine production and osteoclast and osteoblast-specific gene expression were estimated. The increased β-Arr2 expression and pERK1/2 level induced by Terb in CIA iTregs were reduced by β-Arr2 gene silence. The increased TGF-β and IL-10 production in iTreg cells by Terb and the suppression of Teff cell proliferation mediated by Terb-treated nTregs from CIA mice were downregulated by β-Arr2 gene silence or U0126 and further enhanced by β-Arr2 gene overexpression. Adoptive transfer of β-Arr2-overexpressed Treg cells into CIA mice reduced limb inflammation, osteoclast-specific gene expression in joints and Th17 cell cytokine production in joints and serum but increased osteoblast-specific gene expression in joints and Treg cell cytokine production in joints and serum. β2-AR/β-Arr2/ERK signaling in Treg cells contributes to alleviation of inflammatory responses and symptoms in CIA.
{"title":"Treg cells mitigate inflammatory responses and symptoms via β2-AR/β-Arr2/ERK signaling in an experimental rheumatoid arthritis","authors":"Yan Liu, Xiao-Qin Wang, Jian-Hua Lu, Hui-Wei Huang, Yi-Hua Qiu, Yu-Ping Peng","doi":"10.1186/s13075-025-03659-9","DOIUrl":"https://doi.org/10.1186/s13075-025-03659-9","url":null,"abstract":"β2-adrenergic receptor (β2-AR) is widely expressed on immune cells, including T cells and it has a non-canonical signaling pathway, which is β2-AR-β-arrestin 2 (β-Arr2)-extracellular signal-regulated kinase 1/2 (ERK1/2). Our previous studies have shown that the β2-AR agonist terbutaline (Terb) can activate β2-AR and significantly inhibit helper T (Th) 17 cell function in collagen-induced arthritis (CIA). However, the effects of β2-AR on regulatory T (Treg) cells in CIA have not been consistently determined. The aim of our research was to explore whether β2-AR-β-Arr2-ERK1/2 signaling in Treg cells regulates inflammatory responses and signs in CIA. DBA1/J mice were used to prepare CIA model by intradermal injection of collagen type II (CII). Inducible Treg (iTreg) cells were induced from CD4+ T cells that were isolated from the spleens of normal or CIA mice and treated with Terb, β-Arr2 gene silence or overexpression or the ERK1/2 inhibitor U0126 in vitro. β2-AR and β-Arr2 expression, pERK1/2 level, interleukin (IL)-10 and transforming growth factor (TGF)-β production and the suppression of effector T (Teff) cell proliferation mediated by nature Treg (nTreg) cells were determined. β-Arr2-overexpressed Treg cells were intravenously injected into the tail base of CIA mice. Arthritic symptoms were assessed by clinical arthritis scores. Frequencies of Th17 and Treg cells, cytokine production and osteoclast and osteoblast-specific gene expression were estimated. The increased β-Arr2 expression and pERK1/2 level induced by Terb in CIA iTregs were reduced by β-Arr2 gene silence. The increased TGF-β and IL-10 production in iTreg cells by Terb and the suppression of Teff cell proliferation mediated by Terb-treated nTregs from CIA mice were downregulated by β-Arr2 gene silence or U0126 and further enhanced by β-Arr2 gene overexpression. Adoptive transfer of β-Arr2-overexpressed Treg cells into CIA mice reduced limb inflammation, osteoclast-specific gene expression in joints and Th17 cell cytokine production in joints and serum but increased osteoblast-specific gene expression in joints and Treg cell cytokine production in joints and serum. β2-AR/β-Arr2/ERK signaling in Treg cells contributes to alleviation of inflammatory responses and symptoms in CIA.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"6 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311539","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 : 2025-10-15DOI: 10.1186/s13075-025-03651-3
Blair N. Irish, Christine T. Chambers, Justine Dol, Jennifer A. Parker, Adam M. Huber, Yvonne N. Brandelli, Devyn Nichols, Jennifer Brause
Juvenile idiopathic arthritis (JIA) is a chronic inflammatory condition often marked by pain in childhood. JIA pain has a variable course and often lacks any visible signs. As such, youth with JIA can experience negative judgement from others in response to their pain (i.e., pain-related stigma). Theoretical models indicate that pain-related stigma experiences contribute to affective, behavioural, and cognitive reactions from youth in the moment (i.e., situational) and over time (i.e., enduring) that ultimately influence their health. Caregivers also play a crucial role in supporting their children’s health. While caregivers may protect their children from the potential negative impacts of pain-related stigma, caregivers can also be affected by their children’s stigma experiences. Thus, this qualitative study aimed to explore both the situational and enduring reactions of youth with JIA and their caregivers to pain-related stigma. It also examined similarities and differences in their reactions to identify potentially protective reactions and areas where additional support may be needed. Ten youth aged 15–19 years with JIA and 12 caregivers participated. Youth and caregivers completed separate semi-structured interviews. During interviews, participants were asked about the youth’s experiences of pain-related stigma and how these experiences affected their situational and enduring cognitive, affective, and behavioural reactions. Interview transcripts were analyzed using reflexive thematic analysis. Themes generated between groups were triangulated to assess for convergence and divergence. A matrix analysis was subsequently used to develop meta-themes capturing overlapping concepts. Separate themes for each group were developed. The matrix analysis resulted in five meta-themes that capture the overlapping situational and enduring reactions of youth and caregivers to pain-related stigma: (1) addressing stigma and increasing perceived credibility; (2) responding to individual needs; (3) fear and avoidance due to anticipatory stigma; (4) long-term impacts on mental health and well-being; and (5) education and advocacy. Pain-related stigma can impact youth with JIA and their caregivers in various ways, with some reactions being protective of their health and well-being. Strategies to support youth with JIA and their caregivers with navigating pain-related stigma experiences are necessary to promote positive health outcomes.
{"title":"“I’m in pain, and I’m not faking it”: A qualitative exploration of the reactions of youth with juvenile idiopathic arthritis and their caregivers to pain-related stigma","authors":"Blair N. Irish, Christine T. Chambers, Justine Dol, Jennifer A. Parker, Adam M. Huber, Yvonne N. Brandelli, Devyn Nichols, Jennifer Brause","doi":"10.1186/s13075-025-03651-3","DOIUrl":"https://doi.org/10.1186/s13075-025-03651-3","url":null,"abstract":"Juvenile idiopathic arthritis (JIA) is a chronic inflammatory condition often marked by pain in childhood. JIA pain has a variable course and often lacks any visible signs. As such, youth with JIA can experience negative judgement from others in response to their pain (i.e., pain-related stigma). Theoretical models indicate that pain-related stigma experiences contribute to affective, behavioural, and cognitive reactions from youth in the moment (i.e., situational) and over time (i.e., enduring) that ultimately influence their health. Caregivers also play a crucial role in supporting their children’s health. While caregivers may protect their children from the potential negative impacts of pain-related stigma, caregivers can also be affected by their children’s stigma experiences. Thus, this qualitative study aimed to explore both the situational and enduring reactions of youth with JIA and their caregivers to pain-related stigma. It also examined similarities and differences in their reactions to identify potentially protective reactions and areas where additional support may be needed. Ten youth aged 15–19 years with JIA and 12 caregivers participated. Youth and caregivers completed separate semi-structured interviews. During interviews, participants were asked about the youth’s experiences of pain-related stigma and how these experiences affected their situational and enduring cognitive, affective, and behavioural reactions. Interview transcripts were analyzed using reflexive thematic analysis. Themes generated between groups were triangulated to assess for convergence and divergence. A matrix analysis was subsequently used to develop meta-themes capturing overlapping concepts. Separate themes for each group were developed. The matrix analysis resulted in five meta-themes that capture the overlapping situational and enduring reactions of youth and caregivers to pain-related stigma: (1) addressing stigma and increasing perceived credibility; (2) responding to individual needs; (3) fear and avoidance due to anticipatory stigma; (4) long-term impacts on mental health and well-being; and (5) education and advocacy. Pain-related stigma can impact youth with JIA and their caregivers in various ways, with some reactions being protective of their health and well-being. Strategies to support youth with JIA and their caregivers with navigating pain-related stigma experiences are necessary to promote positive health outcomes.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"97 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145289386","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 : 2025-10-14DOI: 10.1186/s13075-025-03640-6
Jeonghwan Lee, Ji Hyoun Kim, Chi-Hoon Choi, In Ah Choi
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that often affects the central nervous system (CNS), leading to structural and functional brain alterations. Although neuroimaging studies have reported significant cortical and white matter changes in SLE, findings remain inconsistent, particularly regarding disease duration and organ damage. This study aimed to comprehensively investigate multimodal brain alterations in SLE using structural and functional neuroimaging. This cross-sectional study included 30 SLE patients without overt neuropsychiatric manifestations and 34 age-matched healthy controls (HCs). Neuroimaging data were acquired using a 3 T magnetic resonance imaging (MRI) scanner. Structural analyses included cortical and subcortical volume measurements via FreeSurfer (30 SLE, 34 HC) and white matter connectometry based on diffusion tensor imaging (DTI) using DSI Studio (29 SLE, 28 HC). Interhemispheric functional connectivity was assessed using resting-state fMRI in the CONN toolbox (27 per group). Clinical assessments included the SLEDAI-2 K, SLICC Damage Index, and SLICC Frailty Index, along with neurocognitive tests that assessed working memory, psychomotor speed, and executive function. Statistical analyses involved ANCOVA adjusted for age and intracranial volume, along with correlation analyses to explore associations between neuroimaging findings and clinical or neurocognitive measures. SLE patients exhibited significantly reduced volumes in the right occipital lobe (F = 11.274, η2 = 0.153, corrected p = .008) and left thalamus (F = 10.502, η2 = 0.140, corrected p = .028). DTI revealed reduced fractional anisotropy (FA) in the corpus callosum, right cingulum, and brainstem. FA values negatively correlated with disease duration, especially in the left and right inferior fronto-occipital fasciculi and the left cingulum. Patients with organ damage exhibited further FA reductions in the brainstem and left cingulum. FA decreases were also associated with poorer cognitive performance. While global interhemispheric functional connectivity was preserved, patients with moderate disease activity showed reduced connectivity in the frontal operculum and insula. Even in the absence of overt neuropsychiatric symptoms, SLE patients demonstrated structural brain changes—specifically reduced occipital and thalamic volumes and widespread white matter disruptions—associated with disease duration, organ damage, and neurocognitive dysfunction. Functional interhemispheric connectivity was globally preserved but impaired in the moderate activity subgroup.
{"title":"Multimodal brain structural and functional analysis in systemic lupus erythematosus patients without overt neuropsychiatric manifestations: associations with disease duration, organ damage, and neurocognitive function","authors":"Jeonghwan Lee, Ji Hyoun Kim, Chi-Hoon Choi, In Ah Choi","doi":"10.1186/s13075-025-03640-6","DOIUrl":"https://doi.org/10.1186/s13075-025-03640-6","url":null,"abstract":"Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that often affects the central nervous system (CNS), leading to structural and functional brain alterations. Although neuroimaging studies have reported significant cortical and white matter changes in SLE, findings remain inconsistent, particularly regarding disease duration and organ damage. This study aimed to comprehensively investigate multimodal brain alterations in SLE using structural and functional neuroimaging. This cross-sectional study included 30 SLE patients without overt neuropsychiatric manifestations and 34 age-matched healthy controls (HCs). Neuroimaging data were acquired using a 3 T magnetic resonance imaging (MRI) scanner. Structural analyses included cortical and subcortical volume measurements via FreeSurfer (30 SLE, 34 HC) and white matter connectometry based on diffusion tensor imaging (DTI) using DSI Studio (29 SLE, 28 HC). Interhemispheric functional connectivity was assessed using resting-state fMRI in the CONN toolbox (27 per group). Clinical assessments included the SLEDAI-2 K, SLICC Damage Index, and SLICC Frailty Index, along with neurocognitive tests that assessed working memory, psychomotor speed, and executive function. Statistical analyses involved ANCOVA adjusted for age and intracranial volume, along with correlation analyses to explore associations between neuroimaging findings and clinical or neurocognitive measures. SLE patients exhibited significantly reduced volumes in the right occipital lobe (F = 11.274, η2 = 0.153, corrected p = .008) and left thalamus (F = 10.502, η2 = 0.140, corrected p = .028). DTI revealed reduced fractional anisotropy (FA) in the corpus callosum, right cingulum, and brainstem. FA values negatively correlated with disease duration, especially in the left and right inferior fronto-occipital fasciculi and the left cingulum. Patients with organ damage exhibited further FA reductions in the brainstem and left cingulum. FA decreases were also associated with poorer cognitive performance. While global interhemispheric functional connectivity was preserved, patients with moderate disease activity showed reduced connectivity in the frontal operculum and insula. Even in the absence of overt neuropsychiatric symptoms, SLE patients demonstrated structural brain changes—specifically reduced occipital and thalamic volumes and widespread white matter disruptions—associated with disease duration, organ damage, and neurocognitive dysfunction. Functional interhemispheric connectivity was globally preserved but impaired in the moderate activity subgroup.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"96 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283527","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 : 2025-10-08DOI: 10.1186/s13075-025-03639-z
Chenghua Weng, Enzhuo Liu, Hui Zheng, Zhenke Wen, Yiting Ji, Gang Wang, Lei Zhang, Rongfang Hu, Lei Shen, Zhichun Liu
Anti-melanoma differentiation-associated protein 5 antibody positive dermatomyositis (MDA5+ DM) is an autoimmune disease related to rapidly progressive interstitial lung disease (RPILD) with high mortality. However, the pathogenesis of MDA5+ DM with RPILD remains unclear. We aimed to explore the peripheral immune landscape of MDA5+ DM with RPILD using single-cell RNA sequencing (scRNA-seq). We performed scRNA-seq of peripheral blood mononuclear cells (PBMCs) from MDA5+ DM with RPILD (n = 4), MDA5+ DM with ILD (non-RPILD, n = 3), and healthy controls (HCs, n = 3). The proportion of CD14+ monocytes increased, but the proportion of natural killer cells, CD4+ T cells and CD8+ T cells decreased in MDA5+ DM with RPILD compared with HCs. Obvious antiviral response was the main feature of MDA5+ DM with RPILD, and the expression of several interferon-stimulated genes (ISGs) related to RIG-I pathway increased, including IRF7, DDX60, IFI27 and IFI6. However, this antiviral response was not significant in MDA5+ DM with ILD. In addition, multiple immune pathways were downregulated in MDA5+ DM with RPILD, including antigen processing and presentation, translation initiation, mRNA splicing, and activation of T and B cells. Cell communication analysis revealed that multiple signaling pathways, including MHC-I and MHC-II, were attenuated in MDA5+ DM with RPILD. Notably, MHC-II signaling was absent in CD4+ naïve T cells from MDA5+ DM with RPILD. This study demonstrates that antiviral response plays an important role in the pathogenesis of MDA5+ DM with RPILD, as well as changes in downstream immune pathways, providing potential therapeutic targets for future treatment.
{"title":"Single-cell sequencing reveals distinct peripheral immune responses in anti-MDA5 antibody positive dermatomyositis with rapidly progressive interstitial lung disease","authors":"Chenghua Weng, Enzhuo Liu, Hui Zheng, Zhenke Wen, Yiting Ji, Gang Wang, Lei Zhang, Rongfang Hu, Lei Shen, Zhichun Liu","doi":"10.1186/s13075-025-03639-z","DOIUrl":"https://doi.org/10.1186/s13075-025-03639-z","url":null,"abstract":"Anti-melanoma differentiation-associated protein 5 antibody positive dermatomyositis (MDA5+ DM) is an autoimmune disease related to rapidly progressive interstitial lung disease (RPILD) with high mortality. However, the pathogenesis of MDA5+ DM with RPILD remains unclear. We aimed to explore the peripheral immune landscape of MDA5+ DM with RPILD using single-cell RNA sequencing (scRNA-seq). We performed scRNA-seq of peripheral blood mononuclear cells (PBMCs) from MDA5+ DM with RPILD (n = 4), MDA5+ DM with ILD (non-RPILD, n = 3), and healthy controls (HCs, n = 3). The proportion of CD14+ monocytes increased, but the proportion of natural killer cells, CD4+ T cells and CD8+ T cells decreased in MDA5+ DM with RPILD compared with HCs. Obvious antiviral response was the main feature of MDA5+ DM with RPILD, and the expression of several interferon-stimulated genes (ISGs) related to RIG-I pathway increased, including IRF7, DDX60, IFI27 and IFI6. However, this antiviral response was not significant in MDA5+ DM with ILD. In addition, multiple immune pathways were downregulated in MDA5+ DM with RPILD, including antigen processing and presentation, translation initiation, mRNA splicing, and activation of T and B cells. Cell communication analysis revealed that multiple signaling pathways, including MHC-I and MHC-II, were attenuated in MDA5+ DM with RPILD. Notably, MHC-II signaling was absent in CD4+ naïve T cells from MDA5+ DM with RPILD. This study demonstrates that antiviral response plays an important role in the pathogenesis of MDA5+ DM with RPILD, as well as changes in downstream immune pathways, providing potential therapeutic targets for future treatment.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"57 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241875","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 : 2025-10-02DOI: 10.1186/s13075-025-03650-4
Lisa Lindner, Anja Weiß, Andreas Reich, Christine Baumann, Frank Behrens, Xenofon Baraliakos, Anne C. Regierer
In psoriatic arthritis (PsA), growing evidence indicates sex-specific differences regarding clinical manifestation and treatment outcomes. Research has highlighted that females may be less likely to achieve treatment targets and are more prone to discontinuing therapy, though data on sex-specific adverse events is limited. This analysis investigates sex differences in treatment outcomes, persistence, discontinuation reasons, and adverse events during first-line b/tsDMARD therapy. In this analysis bionaïve patients with PsA from the RABBIT-SpA register were included at the start of their first b/tsDMARD. Therapy persistence was estimated using the Cox-regression adjusted for age. Descriptive analyses were used to examine and compare sex–specific differences on reasons for therapy discontinuation. A total of 457 female patients and 343 male patients were included. Females exhibited more severe joint involvement and poorer patient-reported parameters, such as higher disease activity, more pain, and greater functional limitations. In contrast, males showed more pronounced skin involvement and a higher prevalence of nail psoriasis. Females had lower treatment persistence rates, both in the overall analysis of all first-line b/tsDMARDs and in subgroup analyses restricted to TNFi and IL17i therapies. At 12 months, 52% of females and 68% of males remained on their initial b/tsDMARD therapy. Notable sex differences were also observed in the reasons for therapy discontinuation: males more frequently discontinued due to lack of efficacy or remission, while females more often stopped treatment due to adverse events. Our safety analysis indicated that although female patients experienced a greater number of overall adverse events, males reported serious adverse events at twice the rate. Our findings underscore the need for sex-specific treatment strategies and more comprehensive research into biological and sociocultural factors influencing therapy persistence and reasons for discontinuation in real-world settings. Tailored treatment strategies are needed with regard to biologic therapy to overcome worse therapeutic outcomes in female patients with PsA. Not applicable.
{"title":"Real-world sex differences in treatment persistence and reasons for discontinuation in psoriatic arthritis patients: results from the German RABBIT-SpA register","authors":"Lisa Lindner, Anja Weiß, Andreas Reich, Christine Baumann, Frank Behrens, Xenofon Baraliakos, Anne C. Regierer","doi":"10.1186/s13075-025-03650-4","DOIUrl":"https://doi.org/10.1186/s13075-025-03650-4","url":null,"abstract":"In psoriatic arthritis (PsA), growing evidence indicates sex-specific differences regarding clinical manifestation and treatment outcomes. Research has highlighted that females may be less likely to achieve treatment targets and are more prone to discontinuing therapy, though data on sex-specific adverse events is limited. This analysis investigates sex differences in treatment outcomes, persistence, discontinuation reasons, and adverse events during first-line b/tsDMARD therapy. In this analysis bionaïve patients with PsA from the RABBIT-SpA register were included at the start of their first b/tsDMARD. Therapy persistence was estimated using the Cox-regression adjusted for age. Descriptive analyses were used to examine and compare sex–specific differences on reasons for therapy discontinuation. A total of 457 female patients and 343 male patients were included. Females exhibited more severe joint involvement and poorer patient-reported parameters, such as higher disease activity, more pain, and greater functional limitations. In contrast, males showed more pronounced skin involvement and a higher prevalence of nail psoriasis. Females had lower treatment persistence rates, both in the overall analysis of all first-line b/tsDMARDs and in subgroup analyses restricted to TNFi and IL17i therapies. At 12 months, 52% of females and 68% of males remained on their initial b/tsDMARD therapy. Notable sex differences were also observed in the reasons for therapy discontinuation: males more frequently discontinued due to lack of efficacy or remission, while females more often stopped treatment due to adverse events. Our safety analysis indicated that although female patients experienced a greater number of overall adverse events, males reported serious adverse events at twice the rate. Our findings underscore the need for sex-specific treatment strategies and more comprehensive research into biological and sociocultural factors influencing therapy persistence and reasons for discontinuation in real-world settings. Tailored treatment strategies are needed with regard to biologic therapy to overcome worse therapeutic outcomes in female patients with PsA. Not applicable.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"2 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203259","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 : 2025-09-30DOI: 10.1186/s13075-025-03635-3
Camilla SA Davan-Wetton, Natalya Khodeneva, Christopher P. Denton, David J. Abraham, Mauro Perretti, Trinidad Montero-Melendez
Conditions like fibrosis, rheumatoid arthritis or cancer, once seen as distinct diseases, are now recognized to share strikingly common pathogenic mechanisms. The key to this convergence lies in the fibroblast, a pivotal driver of disease progression, tissue injury and chronicity. Despite this central pathogenic role and growing recognition as a therapeutic target, effective treatments targeting fibroblasts remain elusive, leaving a critical gap in disease intervention. Here we present a novel approach to target fibrosis using the melanocortin compound BMS-470539 to treat in vitro cultured human dermal fibroblasts obtained from healthy volunteers and systemic sclerosis patients and measuring various markers of senescence and fibroblast activation combining microscopy, DNA sequencing, cell migration and RNA sequencing and PCR techniques. We also used the in vivo bleomycin induced skin fibrosis in mice to determine pre-clinical efficacy of BMS-470539. BMS-470539 induced a ‘senescence-like’ state in human dermal fibroblasts from systemic sclerosis patients, characterised by proliferation arrest, lack of pro-inflammatory secretome and inability to induce secondary senescence. This senescence-like activity (accompanied by β-galactosidase activity, lipofuscin accumulation and other markers) resulted in the downregulation of fibrosis markers including ⍺-smooth muscle actin, migration, CCL2 and genes related to TGFβ and fibroblast activation. In vivo, the compound reduced skin thickness on the bleomycin-induced skin fibrosis murine model when administered intraperitoneally, and importantly, this senescence-like activity did not cause signs of fibrosis when administered intradermally. Here, we introduce a novel strategy to disarm pathogenic fibroblasts in the context of skin fibrosis using a therapeutic pro-senescence-like approach using the unconventional melanocortin compound BMS-470539, to reset fibroblast behaviour and disrupt disease progression. This work also emphasizes the translational potential of how understanding shared pathogenic mechanisms across diseases may lead to new therapeutic opportunities to manage multiple diseases like arthritis and fibrosis.
{"title":"The senescence-like activity of BMS-470539 is associated with anti-fibrotic actions in models of dermal fibrosis","authors":"Camilla SA Davan-Wetton, Natalya Khodeneva, Christopher P. Denton, David J. Abraham, Mauro Perretti, Trinidad Montero-Melendez","doi":"10.1186/s13075-025-03635-3","DOIUrl":"https://doi.org/10.1186/s13075-025-03635-3","url":null,"abstract":"Conditions like fibrosis, rheumatoid arthritis or cancer, once seen as distinct diseases, are now recognized to share strikingly common pathogenic mechanisms. The key to this convergence lies in the fibroblast, a pivotal driver of disease progression, tissue injury and chronicity. Despite this central pathogenic role and growing recognition as a therapeutic target, effective treatments targeting fibroblasts remain elusive, leaving a critical gap in disease intervention. Here we present a novel approach to target fibrosis using the melanocortin compound BMS-470539 to treat in vitro cultured human dermal fibroblasts obtained from healthy volunteers and systemic sclerosis patients and measuring various markers of senescence and fibroblast activation combining microscopy, DNA sequencing, cell migration and RNA sequencing and PCR techniques. We also used the in vivo bleomycin induced skin fibrosis in mice to determine pre-clinical efficacy of BMS-470539. BMS-470539 induced a ‘senescence-like’ state in human dermal fibroblasts from systemic sclerosis patients, characterised by proliferation arrest, lack of pro-inflammatory secretome and inability to induce secondary senescence. This senescence-like activity (accompanied by β-galactosidase activity, lipofuscin accumulation and other markers) resulted in the downregulation of fibrosis markers including ⍺-smooth muscle actin, migration, CCL2 and genes related to TGFβ and fibroblast activation. In vivo, the compound reduced skin thickness on the bleomycin-induced skin fibrosis murine model when administered intraperitoneally, and importantly, this senescence-like activity did not cause signs of fibrosis when administered intradermally. Here, we introduce a novel strategy to disarm pathogenic fibroblasts in the context of skin fibrosis using a therapeutic pro-senescence-like approach using the unconventional melanocortin compound BMS-470539, to reset fibroblast behaviour and disrupt disease progression. This work also emphasizes the translational potential of how understanding shared pathogenic mechanisms across diseases may lead to new therapeutic opportunities to manage multiple diseases like arthritis and fibrosis.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"20 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188699","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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