Reviews of physiology, biochemistry and pharmacologyUndurti N Das
Inflammation and immune dysregulation are at the center of various diseases, including autoimmune diseases, especially rheumatoid arthritis (RA) and systemic lupus erythematosus (lupus). In general, corticosteroids, disease-modifying drugs, and monoclonal antibodies against IL-6 and TNF-α, JAK inhibitors, and various other immunomodulators are extensively used in the treatment of RA and lupus. It is known that EFA (essential fatty acid) metabolism, especially that of AA, is altered in RA and lupus. It is proposed that metabolism of AA and of other PUFAs may play a role in predicting disease progression, prognosis, and response to treatments offered. For this discussion, a better understanding of the interaction between corticosteroids and EFA metabolism is needed.Corticosterone acts on three classes of PLA2 (calcium-independent PLA2 [iPLA2], secretory PLA2 [sPLA2], and cytosolic PLA2 [cPLA2]) and COX-2 and LOX to produce radical changes in the plasma and tissue concentrations of anti-inflammatory LXA4, resolvins, protectins, and maresins and pro-inflammatory (PGE2), leukotrienes (LTs), interleukin-1β (IL-1β), and platelet-activating factor (PAF) that modulate the inflammatory process. Studies revealed that corticosteroids inhibit the activities of Δ6 and Δ5 desaturases and, thus, decrease the formation of ω-6 (GLA, DGLA, AA) and ω-3 (EPA and DHA) that would limit the formation of both pro- and anti-inflammatory eicosanoids. Our previous studies revealed that AA and its metabolite LXA4 have potent anti-inflammatory effects. These results suggest that corticosteroids act at various stages of PUFA metabolism, implying that measurement of plasma levels of LA, ALA, GLA, DGLA, AA, EPA, DHA, LXA4, LTs, and TXs and cytokines may aid in predicting and monitoring the efficacy and potential adverse actions of corticosteroids and immunomodulators.
Pakistan journal of pharmaceutical sciencesHui Chen, Guangjie Pan, Pingshan Yang, Jun Xie
BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease for which targeted therapies remain limited. The Notch signaling pathway has been implicated in T cell differentiation and autoimmune inflammation. OBJECTIVES: This study aimed to investigate the therapeutic effects of the Notch signaling antagonist DAPT on autoimmune arthritis in mice and to explore its underlying immunological mechanisms. METHODS: A collagen-induced arthritis (CIA) mouse model was established. DAPT (100 ng/kg) or PBS was administered intraperitoneally every other day from day 0 to day 36. Notch pathway activation in CD4+ T cells and synovial tissues was assessed by Western blot and immunohistochemistry. Arthritis severity was evaluated by clinical scoring, radiological examination and histopathology. Th1, Th17 and Treg cell frequencies and absolute numbers in spleen and lymph nodes (LNs) were analyzed by flow cytometry. Plasma cytokine levels were measured by multiplex assay. In-vitro Th17 differentiation assays were performed with DAPT or a Notch agonist. RESULTS: Compared with normal mice, CIA mice showed significant upregulation of NICD expression in CD4+ T cells and synovial tissues. DAPT treatment significantly reduced clinical arthritis scores, joint erosion and cartilage destruction. DAPT also decreased the frequencies and absolute numbers of Th1 and Th17 cells in the spleen and LNs, alongwith reduced plasma levels of IFN-γ and IL-17. In-vitro, DAPT suppressed Th17 differentiation, while Notch agonist enhanced it. Treg cells were not significantly altered by DAPT. CONCLUSION: The Notch signaling antagonist DAPT ameliorates autoimmune arthritis in mice by suppressing Th1 and Th17 immune responses, highlighting Notch signaling as a potential therapeutic target for RA.
The authors have informed the Pakistan Journal of Pharmaceutical Sciences (PJPS) of an error in Figure 5 of the published article. During the editorial revision process, an incorrect version of Figure 5 was inadvertently included in the final published version. The authors have confirmed that the extreme-right panel (panel D) should be removed and that the remaining panels constitute the corrected Figure 5. Accordingly, Figure 5 is corrected by removing panel D. No other part of the figure is modified. The caption of Figure 5 remains unchanged, and no other figures or content of the article require modification. This corrigendum records the correction to the published version of the article. The correction is limited to the removal of panel D from Figure 5.
OBJECTIVE: To identify culturally relevant functioning issues experienced by Indian adults with knee osteoarthritis (KOA) using the International Classification of Functioning, Disability and Health (ICF) framework. METHODS: A qualitative descriptive study using semi-structured focus group interviews was conducted with 38 ambulatory adults (35-85 years) diagnosed with knee osteoarthritis (KOA). Participants were recruited from physiotherapy outpatient departments and community settings using maximum variation sampling. Interviews were conducted in Gujarati, audio-recorded, transcribed verbatim, translated into English and analysed using reflexive thematic analysis. Meaningful concepts were systematically linked to ICF categories using established linking rules. Dual independent coding and consensus discussions ensured the analytic rigour. RESULTS: This study included 38 participants with KOA. Fifty-five meaningful second-level categories were identified. The most represented components were activities and participation (41.2%) and body functions (29.4%). Frequently mapped first-level categories included mobility (n = 22), neuromusculoskeletal and movement-related functions (n = 9), d6 domestic life (n = 10), community, social and civic life (n = 7) and products and technology (n = 9). Sixteen additional categories not represented in the existing ICF Core Set for OA emerged, particularly relating to culturally embedded activities such as floor sitting, squatting for toileting and religious participation. Environmental barriers, including inaccessible infrastructure and limited rehabilitation services, influenced disability experience. CONCLUSION: Functioning among Indian adults with KOA is influenced by culturally embedded participation demands and contextual barriers that are insufficiently captured in the existing ICF Core Set for osteoarthritis (OA). These findings provide preliminary empirical support for contextual validation of the ICF Core Set for OA and inform potential culturally responsive adaptation for KOA.
Pakistan journal of pharmaceutical sciencesYuan Gao, Lei Chi, Kun Gao, Yanning Liu, Mengdan Zhou
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, joint swelling, pain, cartilage destruction and bone erosion. Qingteng Waifu San is an external sinomenine-containing preparation, but its site-specific transdermal response requires disease-relevant evaluation. OBJECTIVES: To compare Zusanli (ST36)-site and adjacent non-acupoint transdermal application of Qingteng Waifu San in an ovalbumin/complete Freund's adjuvant-induced RA rabbit model and to evaluate formulation, neuropeptide, inflammatory, behavioural and histopathological outcomes. METHODS: Forty-eight New Zealand white rabbits were allocated into six groups (n=8 each): normal control, vehicle-only transdermal control, acupuncture, acupoint injection, ST36-site transdermal Qingteng Waifu San and adjacent non-acupoint transdermal Qingteng Waifu San. Gel appearance, pH, viscosity, spreadability, sinomenine content and high-performance liquid chromatography (HPLC) fingerprint similarity were assessed. Substance P (SP), calcitonin gene-related peptide (CGRP), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1 beta (IL-1beta) were measured by enzyme-linked immunosorbent assay (ELISA). SP and CGRP messenger RNA (mRNA) were analysed by real-time polymerase chain reaction (PCR). Arthritis score, paw volume, mechanical withdrawal threshold and histopathological scores were assessed. RESULTS: The vehicle-only group showed RA-related changes compared with normal controls. ST36-site Qingteng Waifu San reduced arthritis score, paw volume, serum cytokines and histopathological injury scores and improved mechanical withdrawal threshold compared with vehicle-only control. SP and CGRP levels were higher after ST36 application than after adjacent non-acupoint application, indicating site-dependent neurocutaneous modulation. CONCLUSION: ST36-site transdermal Qingteng Waifu San produced stronger neuropeptide modulation and more favourable RA-related outcome profiles than adjacent non-acupoint application.
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and joint destruction. Bone marrow mesenchymal stem cells (BMSCs) have shown therapeutic potential in RA, but the underlying mechanisms remain poorly understood. OBJECTIVES: To investigate the effects of BMSCs on human RA fibroblast-like synovial MH7A cells and complete Freund's adjuvant (CFA)-induced arthritis in rats and to explore the involvement of the JAK/STAT and TLR-4/NF-κB signaling pathways. METHODS: BMSCs were isolated and co-cultured with MH7A cells. CFA-induced arthritis rat models were established. MH7A cell viability, inflammatory cytokine levels, paw withdrawal thermal latency (PWTL), gait parameters and the expression of JAK/STAT and TLR-4/NF-κB pathway-related genes and proteins were assessed. RESULTS: In-vitro, BMSC co-culture significantly inhibited MH7A cell viability and reduced TNF-α, IL-6 and IL-8 levels. BMSC treatment also downregulated the expression of JAK2, p-JAK2, STAT3, p-STAT3, TLR4, P65 and p-P65 in MH7A cells. In-vivo, BMSC administration improved PWTL and gait parameters, reduced serum inflammatory cytokine levels and suppressed the expression of JAK/STAT and TLR-4/NF-κB pathway components in synovial tissues of CFA-induced arthritic rats. CONCLUSION: BMSCs alleviate RA by inhibiting inflammatory responses in vitro and in vivo and the underlying mechanism may involve blockade of the JAK/STAT and TLR-4/NF-κB signaling pathways.
Pakistan journal of pharmaceutical sciencesJingjing Liu, Dan Pan, Weiguang Hou, Huiwu Zhang, Runan Pan, Qing Pan, Chengjie Tang
BACKGROUND: The TNF/TNFR superfamily and B7/CD28 costimulatory molecules are critical regulators of immune responses; however, their interplay in rheumatoid arthritis (RA) remains unclear. OBJECTIVES: To investigate whether the TNF/TNFR superfamily regulates B7/CD28 expression via the NF-κB pathway in RA and to evaluate its effects on synovial cell inflammation and apoptosis. METHODS: Peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocytes (FLS) were obtained from 40 patients with active rheumatoid arthritis (RA) (13 males, 27 females; mean age 42.3 ± 8.1 years, range 26-55; DAS28-ESR > 3.2) and 40 age- and sex-matched healthy controls (15 males, 25 females; mean age 41.8 ± 7.9 years, range 26-54) with no history of arthritis or autoimmune diseases; all participants provided written informed consent. A co-culture system of PBMCs and FLS was established and divided into three groups: control (healthy PBMCs + FLS), model (RA PBMCs + FLS) and inhibition (RA PBMCs + FLS treated with PDTC, an NF-κB inhibitor). After 48 hours, cell viability, apoptosis, inflammatory cytokines (TNF-α, IL-1β), COX-2, Bax, Bcl-2, TNF-R1/TNF-R2 mRNA and the expression of CD28 and CD80 on CD4+ and CD8+ T cells were assessed. RESULTS: Compared to controls, the model group exhibited increased FLS viability, reduced apoptosis, elevated levels of TNF-α, IL-1β, COX-2, Bcl-2 and TNF-R1/R2 mRNA, along with decreased Bax expression and lower CD28/CD80 expression on CD4+ T cells (all P < 0.05). NF-κB inhibition with PDTC significantly reduced FLS viability and increased apoptosis, downregulated IL-1β and COX-2 and restored CD28/CD80 expression on CD4+ T cells (P < 0.05), but did not alter TNF-α or TNFR mRNA levels. CONCLUSION: Inhibition of the NF-κB pathway attenuates RA-FLS inflammation and restores B7/CD28 expression on T cells; however, these effects were not directly mediated by changes in TNF/TNFR expression.
Archives of orthopaedic and trauma surgeryBinyamin Finkel, Hadar Gan-Or, Shaked Ankol, Mohamd Tawatha, Eyal Behrbalk
BACKGROUND: Whether coded rheumatoid arthritis (RA) among patients undergoing elective total hip arthroplasty (THA) is associated with excess short-term inpatient morbidity in contemporary U.S. practice remains uncertain. METHODS: We performed a retrospective cohort study using the National Inpatient Sample (2016-2021). Adults undergoing elective primary THA were identified using ICD-10-CM/PCS codes. The exposure cohort included admissions with coded RA in any diagnosis position. The comparator cohort included admissions with narrow primary hip osteoarthritis (OA) as the principal diagnosis and no RA. Propensity scores were estimated from demographic, socioeconomic, hospital, and comorbidity variables. Inverse probability of treatment weighting (IPTW) with survey weighting was used for the primary analysis, followed by doubly adjusted regression models that included age and all variables with persistent post-weighting imbalance greater than 0.10 (female sex, osteoporosis, chronic obstructive pulmonary disease, chronic anemia, depression, and race). Additional sensitivity analyses included stricter weight truncation, a restriction analysis, conventional multivariable modeling, and sex-stratified analyses addressing residual sex imbalance. RESULTS: A total of 274,582 admissions met eligibility criteria; 274,539 were included in the final analytic cohort after exclusion of 43 records with missing or invalid propensity-weight inputs. The analytic cohort included 7,264 RA admissions and 267,275 OA admissions. In the primary weighted analysis, RA was associated with higher odds of acute blood loss anemia (OR 1.30, 95% CI 1.23-1.38), red blood cell transfusion (OR 1.40, 95% CI 1.23-1.60), acute kidney injury (OR 1.47, 95% CI 1.26-1.71), non-home discharge (OR 1.27, 95% CI 1.19-1.36), and a composite hematologic/renal in-hospital complication (OR 1.31, 95% CI 1.24-1.39).RA was also associated with slightly longer length of stay (+ 0.14 days, 95% CI + 0.10 to + 0.19) and modestly higher total hospital charges (+$1,018, 95% CI +$89 to +$1,947). Findings were directionally consistent across sensitivity analyses, including stricter weight truncation, restriction to admissions with principal OA plus concomitant RA, and sex-stratified analyses. CONCLUSIONS: In this contemporary national THA cohort, coded RA was associated with a small but consistent increase in in-hospital complication and resource-utilization burden compared with OA. These findings should be interpreted as adjusted associations rather than causal effects, and the modest effect sizes should not be overstated. They may provide context for perioperative risk assessment and discharge planning among patients with coded RA undergoing elective THA.
International journal of biometeorologyMaria Chiara Maccarone, Gabriel Dias Rodrigues, Martin Offenbächer
Balneotherapy (BT) is widely used as a non-pharmacological intervention for osteoarthritis (OA); however, potential sex differences in treatment response remain poorly understood. This scoping review mapped randomized controlled trials (RCTs) of BT in OA to describe (i) how participants' sex was reported, (ii) whether sex-stratified or sex-by-treatment interaction analyses were performed and (iii) the sex-related findings of such analyses. Twenty-two publications, derived from 21 distinct RCTs, were included. Sex distribution was reported for 20 trials, including 2,211 participants (594 males and 1,617 females; 73.1% female). The greatest imbalance was observed in knee OA trials (497 males vs. 1,216 females). Overall, BT was associated with reduced pain, improved physical function and enhanced quality of life in predominantly female samples. However, only one trial formally tested sex as an effect modifier, reporting significant treatment × sex interactions for pain, stiffness, physical function and quality of life, and one further trial enrolled women only. No other trial, including those with a relatively balanced sex distribution, reported outcomes separately for women and men. Therefore, the available evidence is insufficient to establish whether sex modifies the clinical response to BT. Sex-related differences in thermoregulation, nociceptive processing and immune modulation provide a biologically plausible, but as yet untested, rationale for such effect modification. Future BT trials should report outcomes separately for women and men and include pre-specified, adequately powered sex-by-treatment interaction analyses.
BACKGROUND: Osteoarthritis (OA) is increasingly recognized as a chronic inflammatory disease, with dysregulated immune responses contributing to cartilage degeneration and disease progression. Immune dysregulation, including alterations in Th1-associated responses, may contribute to the chronic inflammatory environment observed in osteoarthritis. MSC-derived exosomes have been highlighted as potential cell-free therapeutic agents due to their potent immunomodulatory properties; however, their effects on Th1-associated immune responses in OA remain poorly understood. METHODS: Extracellular vesicles produced from MSCs were extracted and analyzed by scanning electron microscopy (SEM), dynamic light scattering, and Western blotting for CD9, CD81, and CD63. Healthy controls and OA patients' PBMCs were grown with and without MSC-derived extracellular vesicles. Flow cytometry was used to quantify Th1 cells. STAT1, IL-1β, IL-6, and TNFα expression was assessed by quantitative real-time PCR. ELISA measured cytokine secretion in culture supernatants. RESULTS: PBMCs were obtained from 10 patients with OA and 10 age- and sex-matched healthy controls. Treatment with the MSC-derived extracellular vesicle preparation (20 µg total protein-equivalent material per approximately 1 × 10⁶ PBMCs for 48 h) was associated with a significant reduction in CD4⁺IFN-γ⁺ Th1-cell frequency in both healthy controls and OA patients. In OA PBMCs, Th1-cell frequency decreased from 33.8% ± 7.7% at baseline to 26.9% ± 7.0% after treatment (P = 0.0080). STAT1 mRNA expression decreased from 2.21 ± 0.45 to 1.54 ± 0.27 relative expression units (P = 0.0028). Treatment was also associated with reduced IL-1β, IL-6, and TNF-α mRNA expression and decreased concentrations of these cytokines in culture supernatants. CONCLUSIONS: MSC-derived extracellular vesicles were associated with reduced Th1-associated responses, decreased STAT1 mRNA expression, and reduced inflammatory cytokine production in PBMCs from patients with OA. These findings provide preliminary in vitro evidence of an immunomodulatory effect; however, they do not establish a causal role for STAT1 or demonstrate therapeutic efficacy. Further studies with comprehensive EV characterization and pathway-specific mechanistic analyses are warranted.
European journal of nutritionLucas Pacoureau, François Barde, Chloé Marques, Amandine Gelot, Emmanuelle Correia, Francesca Romana Mancini, Yann Nguyen, Raphaèle Seror
OBJECTIVES: Environmental determinants of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) remain poorly understood. We investigated whether adherence to plant-based dietary patterns (overall (PDI), healthful (hPDI), and unhealthful (uPDI)) is associated with incident GCA and PMR in a large prospective cohort. METHODS: The E3N study follows 98,995 French women since 1990. Dietary intake was assessed in 1993 using a validated food frequency questionnaire. PDI, hPDI, and uPDI were constructed following the approach of Satija et al. Incident GCA and PMR cases were identified and validated through repeated questionnaires and medication reimbursement data. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regression models adjusted for age, energy intake, and key confounders. RESULTS: Among 60,187 eligible women, 602 incident cases were identified over a median of 17.6 years between dietary assessment and disease onset (142 GCA, 373 PMR, 87 undifferentiated). No association was observed between any plant-based diet index and overall GCA/PMR risk nor PMR risk separately. Higher adherence to the hPDI was inversely associated with GCA risk (HR tertile 3 vs. 1: 0.62 [0.39-0.97]; p-trend = 0.04). A non-linear pattern was observed for the overall PDI (HR tertile 2 vs. 1: 0.65 [0.43-0.98]). No association was found for the uPDI. CONCLUSION: Adherence to a healthful plant-based diet was inversely associated with GCA risk but not PMR, suggesting disease-specific environmental pathways. These findings provide the first prospective evidence linking dietary quality to GCA risk, supporting further investigation of dietary exposures in inflammatory rheumatic diseases.
European journal of histochemistry : EJHZhendong Liu, Ruizhou Liu, Hongwei Yue, Peilai Liu, Rui Wang
Sinensetin (SIN) is a natural flavonoid with potential anti‑inflammatory effects. This study investigated whether SIN ameliorates osteoarthritis (OA) and explored its underlying mechanisms. In vitro, SIN (0.05-1 μg/mL) protected human OA chondrocytes from IL‑1β‑induced viability loss. Transcriptome sequencing and molecular docking identified SERPINA3 as a candidate target of SIN. SIN reduced the expression of NLRP3, GSDMD, and ASC, inhibited pyroptotic morphology, decreased TUNEL‑positive cells and LDH release, and lowered IL‑1β and IL‑18 secretion in IL‑1β‑treated chondrocytes. Knockdown of SERPINA3 reversed these effects, suggesting that SIN acts through SERPINA3 to inhibit the NLRP3 inflammasome. In a rat DMM‑induced OA model, SIN (20 mg/kg/day for 6 weeks) alleviated pain, reduced OARSI scores, improved cartilage matrix staining (Safranin O, Masson's trichrome), attenuated synovial hyperplasia and posterior capsule adhesions, and decreased plasma IL‑1β and IL‑18 levels. Western blot of rat cartilage confirmed that SIN suppressed GSDMD and NLRP3 expression. These results indicate that SIN ameliorates OA progression by inhibiting SERPINA3‑mediated NF‑κB/NLRP3‑driven chondrocyte pyroptosis. SIN may be a potential therapeutic candidate for OA.
The Journal of international medical researchJosé R Galindo-Donaire, Adriana E Vázquez-Hernández, Gabriela Hernández-Molina
Depression is a major and under-recognized comorbidity in Sjögren's disease, contributing to disease burden and impaired quality of life. This narrative review summarizes current evidence regarding the prevalence, pathophysiological mechanisms, clinical impact, assessment, and treatment of depression in patients with Sjögren's disease. Reported prevalence rates range widely from 3.2% to 78.6%, largely owing to methodological heterogeneity, although meta-analytic data demonstrate a significantly increased risk of depression in patients with Sjögren's disease than in healthy controls. Etiology is multifactorial, involving chronic pain, fatigue, dryness, psychosocial stressors, and immune-mediated mechanisms. Elevated inflammatory cytokines, altered serotonergic pathways, antibodies, gut dysbiosis, and neuroimaging abnormalities are the potential underlying links to depression. Furthermore, depression is associated with greater symptom burden, autonomic dysfunction, sleep disturbances, fatigue, reduced health-related quality of life, and impaired functional status. Patient-reported outcomes often correlate more closely with depression than with systemic disease activity. Although several screening instruments are available, their validation in patients with Sjögren's disease remains limited. Management requires a multidisciplinary approach integrating psychological interventions, lifestyle modification, and pharmacologic treatment. Selective serotonin reuptake inhibitors and other agents with low anticholinergic burden are preferred. Optimization of systemic disease control may provide additional benefits. Early recognition and comprehensive management of depression are essential to improve outcomes in patients with Sjögren's disease.
BACKGROUND: With the exponential growth of systematic reviews and meta-analyses on RA pharmacotherapy, a comprehensive and up-to-date assessment of methodological quality is urgently needed to gauge the credibility of this evidence base. OBJECTIVE: This protocol describes a meta-epidemiological study that will systematically appraise the methodological quality of published systematic reviews and meta-analyses of RA pharmacotherapy (csDMARDs, bDMARDs, and tsDMARDs) using the AMSTAR 2 instrument and explore study-level factors associated with methodological quality. METHODS: We will systematically search PubMed, Embase, the Cochrane Library and three Chinese databases-China National Knowledge Infrastructure (CNKI), Wanfang Data and China Science and Technology Journal Database-from inception to June 1, 2026. Two independent reviewers will screen studies, extract data and assess methodological quality using the AMSTAR 2 instrument; an overall rating (high, moderate, low, critically low) will be derived for each review. Binary logistic regression comparing "Adequate" (High/Moderate) versus "Inadequate" (Low/Critically Low) reviews will be used for the primary analysis, with ordinal logistic regression fitted as a pre-specified exploratory analysis; pre-specified sensitivity and robustness analyses (including penalized and Bayesian estimation for sparse categories) will test the stability of findings. RESULTS: The results will provide a descriptive overview of the methodological quality landscape, highlighting common strengths and critical weaknesses across published RA meta-analyses. The regression analysis will quantify the relationship between specific study characteristics and methodological quality. CONCLUSION: This study will provide a comprehensive, cross-drug-class AMSTAR 2-based methodological assessment of the RA pharmacotherapy evidence-synthesis field, complementing prior appraisals limited to specific complementary or single-agent interventions. The findings will offer clinicians and guideline developers a graded framework for judging evidence credibility and will provide empirical, actionable guidance for researchers to enhance the design, conduct, and reporting of future systematic reviews in RA.
Journal of visualized experiments : JoVEMinjie Wang, Yifei Xu, Yuwen Zhang, Kangjing Wei, Haojing Wang, Yi Zhang, Hao Xu, Liqun Yang, Huashun Cui
Osteoarthritis is a chronic degenerative joint disease that commonly affects the knee and causes pain, swelling, stiffness, and functional limitation. Synovial inflammation and changes in periarticular muscles contribute to disease initiation and progression. Clinical evidence suggests that electroacupuncture may alleviate local inflammation and modulate cartilage metabolism. In this study, knee osteoarthritis was induced in mice by surgical destabilization of the medial meniscus. Outcomes were assessed using a multimodal protocol comprising the rotarod test, ultrasound, infrared thermography, magnetic resonance imaging, and histological staining. Joint cavity volume and skin temperature were monitored longitudinally, and endpoint magnetic resonance imaging and Safranin O-Fast Green staining were used to assess periarticular muscle signal changes and cartilage pathology. Electroacupuncture was associated with improved motor performance, reduced joint swelling, higher local skin temperature, less pronounced periarticular muscle signal changes on magnetic resonance images, and lower cartilage degeneration scores. These findings support the use of this multimodal protocol to assess electroacupuncture-associated outcomes in a preclinical mouse model.
Arthritis research & therapyAnton Ahlsved, Anders Lundquist, Kristina Lejon, Solbritt Rantapää-Dahlqvist, Mikael Brink
OBJECTIVE: Autoimmune processes in rheumatoid arthritis (RA) begin years before clinical symptom onset. This study aimed to analyse inflammation-related proteins in individuals during the pre-symptomatic phase, in relation to healthy controls and patients with early RA, and their relationship to seroconversion. METHODS: Plasma samples collected prior to symptom onset from individuals who later developed RA (n = 419), healthy population controls (n = 49), and patients with early RA at diagnosis (n = 68) were obtained from a biobank. All samples were analysed for 92 inflammation-related proteins using a proximity extension assay and for anti-CCP2 antibodies and rheumatoid factor. After quality control 77 proteins remained. To identify differentially expressed proteins and enriched pathways, statistical analyses including logistic regression, generalized additive models, and network enrichment analysis was applied. RESULTS: Four proteins (MMP10, IL6, CCL19, and IL10RB) showed a higher concentration in pre-symptomatic individuals compared to controls (p < 0.05). Twelve proteins were associated with seropositivity in the pre-symptomatic phase and network enrichment analysis of these revealed associated pathways related to the complement system and cytokine activity. Three proteins (CXCL10, CCL7, and CDCP1) were consistently associated with seroconversion and showed increasing trends approaching symptom onset in individuals who seroconverted, but not in individuals who remained seronegative. Proteins associated with early seroconversion were associated with T-cell activity, whereas many of the proteins associated with late seroconversion were associated with bone remodelling, mineral metabolism, and collagen degradation. CONCLUSION: Proteomic alterations are detectable years before RA onset and linked to autoantibody development. Seroconverters differ from those who remain seronegative even in the pre-symptomatic period, supporting the notion that seropositive and seronegative RA represent biologically distinct entities from the earliest stages of the pathogenesis.
Rheumatology internationalIrini Flouri, Antonios Bertsias, Konstantina Zoupidou, Christos Koutsianas, George Fragoulis, Dimitrios Nezis-Katsifis, Elena Sambatakaki, Nestor Avgoustidis, …
Herein we report for baricitinib drug retention, predictors thereof and clinical responses in rheumatoid arthritis (RA) patients with a special focus in comorbidities. Prospective, multicenter, observational study of RA patients starting baricitinib because of active disease. Patients were followed every 3 months for 12 months. The primary endpoint was baricitinib retention at 12 months; predictors for survival and clinical responses at 6 months were secondary endpoints. Retention rate was estimated by Kaplan-Meier (K-M) while predictors of discontinuation by Cox regression. We recruited 135 patients, 93.3% females, mean (standard deviation-SD) age 56.1 (10.1) years, median (interquartile range) disease duration 57 (90) months. 18.5% started baricitinib as first line targeted therapy. 35.9% (28/88) and 44.1% (26/59) achieved DAS28 remission/low disease activity (LDA) at 6 and 12 months respectively. Baricitinib retention at 12 months was 68.9%. K-M analysis showed that hypertension (p=0.049), latent tuberculosis infection (LTBi) (p=0.007) and depression (p=0.005) were associated to lower retention, while multivariate analysis showed that depression [Hazard ratio (HR) 2.715, p=0.007] and LTBi (HR 2.519, p=0.020) predicted baricitinib discontinuation. Analysis for patients on therapy for at least 6 months showed that together with hypertension (HR 2.477, p=0.022) and LTBi (HR 3.761, p=0.023), higher DAS28 at 6 months (HR 1.434, p=0.024) predicted baricitinib discontinuation at 12 months. In established RA, 68.9% of the patients remained on baricitinib at 12 months and had an improvement of disease activity. Mostly comorbidities contributed to baricitinib persistence, supporting their importance as factors to be addressed to optimize RA clinical care.
Persistent pain remains a major unmet need in rheumatoid arthritis (RA), even in patients with adequately controlled inflammatory disease. Cannabinoids have been proposed as potential modulators of pain and inflammation, but their clinical role in RA remains uncertain. To map and critically appraise the available clinical evidence on cannabinoid-related interventions or exposures for pain management in adults with RA. PubMed/MEDLINE, Scopus, the Directory of Open Access Journals, and the Cochrane Central Register of Controlled Trials were searched for studies published from January 1, 1990, to September 10, 2026. Randomized controlled trials and observational studies evaluating cannabinoid-related interventions or exposures in adults with confirmed RA and reporting pain-related outcomes were eligible. Risk of bias was assessed using Cochrane RoB 2 for randomized trials and ROBINS-I for observational studies. Of 593 records identified, three studies met the eligibility criteria: one randomized placebo-controlled trial and two observational studies. In the randomized trial of 58 patients, nabiximols reduced pain on movement by 0.95 points (p = 0.044), pain at rest by 1.04 points (p = 0.018), and improved sleep quality by 1.17 points (p = 0.027); DAS28 decreased by 0.76 points (p = 0.002), while no serious adverse events were reported. Observational studies suggested possible symptomatic benefit but were limited by heterogeneous cannabinoid exposure and serious to critical risk of bias. Current clinical evidence remains insufficient to establish the efficacy or long-term safety of cannabinoids for RA-related pain. Larger, rigorously designed trials using standardized cannabinoid formulations and pain-relevant outcomes are needed.
Journal of medical systemsTim Wilhelmi, Vanessa Bartsch, Marius Platt, Asarnusch Rashid, Johannes Hornig, Martin Krusche, Axel J Hueber, Daniel Fink, Alexander Pfeil, Gabriel Dischereit…
Patients with rheumatic diseases have persistent information needs that are not fully addressed in routine care. We developed and evaluated guideline-grounded, large language model (LLM) chatbots to support patient self-management and education in rheumatology.Ten disease-specific chatbots based on German guidelines were co-developed and deployed through 13 rheumatology centres and six patient organisations. Chatbot users rated responses and completed a questionnaire. User questions, feedback, and response characteristics were analysed using category-based coding and a six-dimensional LLM-as-a-judge assessment, with LLM-based ratings compared with rheumatologist ratings in random subsets.Between September 2025 and January 2026, 6291 questions were recorded. Thirteen question categories were identified, most commonly disease-specific questions (50.2%), medication and monitoring (37.3%) and diagnostics (28.2%). The chatbots were unable to answer in 263 interactions (4.2%). Of 2671 responses rated by users, 2481 (92.9%) received a positive rating. Insufficient detail was the most common reason for negative ratings (125/190, 65.8%). Among 602 questionnaire respondents, 84.6% reported that the chatbot was easy to use, 84.1% that answers were easy to understand, and 80.2% that it was a useful addition to patient education. In the LLM-based evaluation, 95.3% of answers were rated as completely safe and 79.1% as completely correct. Guideline adherence was assessed separately, with 45.0% rated as fully adherent; agreement with physician assessment was weak.Guideline-grounded chatbots received predominantly positive user feedback in real-world use, while LLM-based evaluation suggested that most responses were safe and correct. User questions and feedback may help guide iterative improvements to source content and patient education materials. Further studies are needed to evaluate educational effectiveness and independently validate response quality and clinical safety.
This study evaluates associations between genetically predicted circulating levels of 91 inflammatory cytokines and juvenile idiopathic arthritis (JIA) susceptibility. Summary statistics for 91 circulating inflammatory cytokines were obtained from a meta-analysis of 11 cohorts comprising 14,824 participants of European ancestry. JIA summary statistics were obtained from FinnGen Release 9 and included 788 cases and 172,834 controls of European ancestry. The primary estimator was the inverse-variance weighted (IVW) random-effects model. MR-Egger, weighted median, simple mode, and weighted mode analyses were used as complementary estimators. Sensitivity analyses included the MR-Egger intercept, Mendelian Randomization Pleiotropy RESidual Sum and Outlier, Cochran's Q, MR-Steiger, and leave-one-out tests. The C-C motif chemokine ligand 19 (CCL19) analysis used 19 independent single-nucleotide polymorphism instruments. At the nominal threshold of P < .05, IVW estimates indicated associations of CCL19 (odds ratio [OR], 2.48), fibroblast growth factor 19 (OR, 0.78), and monocyte chemotactic protein 3 (OR, 0.79) with JIA. After Bonferroni correction for 91 tests (threshold P < 5.49 × 10-4), only CCL19 remained significant (IVW P = 8.93 × 10-8; adjusted P = 8.12 × 10-6). The direction of the CCL19 estimate was consistent across Mendelian randomization methods, although significant heterogeneity and attenuation after outlier correction using Mendelian Randomization Pleiotropy RESidual Sum and Outlier indicated uncertainty in its magnitude. Higher genetically predicted CCL19 levels were associated with greater JIA susceptibility in participants of European ancestry. These findings reflect genetically predicted associations rather than established causal effects and do not support clinical prediction or intervention. Independent genetic, experimental, and clinical validation is required before CCL19 can be considered a biomarker or therapeutic target.
International journal of molecular medicineHan Gong, Hao Shen, Feng Zhang, Wei Wang, Sheng Zhou, Lei Wang, Yu Sun
Osteoarthritis (OA) progression is driven by chronic synovitis. However, the spatially organized macrophage subsets that sustain unresolved inflammation through evasion of apoptosis remain poorly characterized. The present study investigated the functional subsets and spatial niches of synovial macrophages that regulate apoptotic pathways in OA pathogenesis. Spatial transcriptomics, single‑cell RNA sequencing and in vitro apoptotic models were integrated to characterize macrophage interactions in the OA synovium. The anti‑apoptotic role of SPP1+ macrophages was evaluated using adeno‑associated virus‑mediated macrophage‑targeted SPP1 knockdown and CCL3 neutralization in a mouse OA model. In addition, an in silico virtual knockout model was employed to delineate SPP1‑mediated apoptotic regulatory networks and prioritize candidate compounds for future validation. Spatial multi‑omics revealed a TGF‑β‑enriched niche in which SPP1+ macrophages expand adjacent to senescent synovial fibroblasts. Distinct from their reported pro‑fibrotic roles, SPP1+ macrophages directly suppressed apoptosis of inflammatory macrophages via the SPP1‑CD44 signaling axis, while recruiting additional myeloid cells through CCL3 secretion. In vivo, targeting SPP1 or neutralizing CCL3 effectively restored macrophage apoptosis, attenuated synovitis and cartilage degeneration. In silico myeloid specific SPP1 knockout delineated apoptotic pathway perturbations. In conclusion, TGF‑β‑induced SPP1+ macrophages establish an anti‑apoptotic inflammatory niche in OA synovium by directly inhibiting the apoptosis of inflammatory macrophages via SPP1 signaling and promoting myeloid recruitment. This spatially defined anti‑apoptotic circuit provides critical insight into persistent synovitis.
Nature communicationsWeiqiang Lin, Xinyi Xiao, Di Tian, Yun Gong, Lei Huang, Woong-Ki Kim, Md Ariful Islam, Guihua Pan, Binghao Zou, Zhe Luo, Qing Tian, William Sherman, Fernando S…
Although increasing evidence implicates subchondral bone alterations in osteoarthritis, the spatial organization of subchondral bone remodeling remains unclear. Applying spatial transcriptomics to human subchondral bone, we identify a spatially conserved osteogenic core-halo architecture that displays transcriptional reprogramming in sclerotic microenvironments. Spatial dependency and a customized cell-cell communication framework reveal disrupted osteoblast-osteoclast spatial coupling, enhanced osteoblast-mesenchymal interactions, and identify FN1-SDC2 and COL1A1-DDR2 as candidate stromal-osteogenic signaling axes that may contribute to aberrant bone remodeling. Additionally, we present the in situ transcriptional landscape of osteocytes and reveal its potential regulatory role in aberrant bone remodeling. We further delineate a continuum of spatial ecotypes exhibiting distinct enrichment, spatial topology reorganization, and inter-ecotype communication rewiring across pathological states. Metabolic flux inference additionally reveals substrate-limited, stressed states across multiple ecotypes in sclerotic microenvironments. Collectively, our findings provide critical insights into aberrant subchondral bone remodeling in osteoarthritis and offer a valuable framework for future mechanistic studies and therapeutic exploration.
Gout is a common inflammatory disease closely associated with hyperuricemia, and its global prevalence is increasing, highlighting the need for safer and more effective therapeutic strategies. Recently, microbiome-based therapeutics have emerged as promising alternatives, and the development of functionally validated NGP and their advanced forms, post-NGP strains, is gaining increasing attention. In this study, microbiome-derived bacterial strains were screened based on their in vitro uric acid (UA)-reducing capacity and hypoxanthine utilization. Among the tested strains, Mitsuokella jalaludinii exhibited the most pronounced uric acid reduction and growth enhancement in response to purine substrates compared to conventional lactic acid bacteria. This strain reduced uric acid levels by approximately 30% after 48 h (p < 0.001) and showed significantly increased growth in purine-enriched minimal medium (p < 0.01). WGS further confirmed its strain-level novelty, leading to its designation as PMC73, and revealed the presence of genetic features associated with purine metabolism and UA regulation. In a MSU-induced RAW 264.7 macrophage model, PMC73 significantly reduced UA levels (p < 0.001) and modulated immune responses by increasing anti-inflammatory cytokines while decreasing pro-inflammatory cytokines. These effects were associated with suppression of the NLRP3-caspase-1, along with downregulation of URAT1 and XOD, indicating coordinated regulation of uric acid production, reabsorption, and inflammatory pathways. Based on safety evaluation, including d-lactate production, cytotoxicity assays and oral toxicity assessment in a mouse model, demonstrated that PMC73 exhibited no pathogenic or toxic properties. Therefore, PMC73 represents a promising microbiome-based candidate with relevance to gout-associated hyperuricemia, warranting further in vivo and clinical investigations.
Journal of cellular biochemistryXiaodong Mao, Guoliang Che, Mimi Zhang, Xiao Tan, Zhengzhi Liu
Chondrocyte senescence is a central driver of osteoarthritis (OA) pathogenesis. While bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) exhibit therapeutic potential, their key functional components remain unclear. We therefore investigated whether Exportin-7 (XPO7), a protein enriched in BMSCs-Exos, alleviates OA by ameliorating chondrocyte senescence-associated changes and explores the underlying mechanism. Using an IL-1β-induced in vitro OA model in rat chondrocytes, we treated cells with exosomes from BMSCs with modulated XPO7 overexpression or knockdown; KDM2B was overexpressed in chondrocytes. Senescence, apoptosis, viability, senescence-associated secretory phenotype (SASP) markers, and extracellular matrix (ECM) metabolism were evaluated. We found that BMSCs-Exos significantly mitigated IL-1β-induced chondrocyte senescence-like changes, apoptosis, SASP (p16, p21, p53, IL-1β, IL-6, TNF-α), and ECM degradation, as evidenced by the reversal of IL-1β-induced suppression of anabolic genes SOX9, COL2, ACAN and elevated catabolic gene MMP13. These protective effects were enhanced by XPO7 overexpression and diminished by its knockdown. Co-immunoprecipitation and immunofluorescence further showed that XPO7 physically interacted with and negatively regulated the histone demethylase KDM2B, and overexpressing KDM2B abolished the protective effects of XPO7-enriched exosomes. In an in vivo rat OA model induced by anterior cruciate ligament transection (ACLT), systemic administration of BMSCs-Exos overexpressing XPO7 attenuated cartilage destruction and improved mechanical allodynia (increased paw withdrawal threshold). These therapeutic benefits were significantly reversed by concurrent intra-articular injection with a KDM2B overexpressing plasmid. Collectively, BMSCs-Exos deliver XPO7, which negatively regulates KDM2B to attenuate chondrocyte senescence-associated phenotypes and OA progression. The XPO7-KDM2B axis may represent a promising therapeutic target for OA intervention.
Pharmacoepidemiology and drug safetyStephen J Balevic, Timothy Beukelman, Thomas Phillips, Colleen Correll, Ann McMahon, CARRA Registry Investigators
OBJECTIVE: To compare the clinical characteristics and outcomes of children with juvenile idiopathic arthritis (JIA) treated with biologic drugs in traditional clinical trials with the real-world data (RWD) in the CARRA Registry. METHODS: This was a retrospective observational study. We reviewed data from 3192 children in the CARRA Registry with JIA exposed to adalimumab or canakinumab, 2 historical trials of polyarticular JIA participants exposed to adalimumab (n = 171 and 32), and 1 trial for canakinumab in systemic JIA (n = 43). We made matched and unmatched comparisons of demographic information and the ACR-Pedi response rate based on trial eligibility criteria. RESULTS: Very few children in the CARRA Registry would have been eligible for the historical clinical trials: < 10% for adalimumab and < 5% for canakinumab. There was a longer duration of follow-up and a wider range of body size in the CARRA Registry compared with the historical clinical trials. When matched on trial inclusion, the ACR-Pedi response rates broadly aligned with those observed in the trials for adalimumab, whereas the sample size for canakinumab limited comparisons for the response rate. CONCLUSION: Children encountered in clinical practice had wider ranges of body size and less severe disease at drug initiation. These results underscore that registration trials may be enriched for patients with more severe disease and are not fully representative of the broader JIA population who use these drugs after marketing. Real-world evidence generated from observational data may play an increasingly important role in regulatory decision making, along with the continued need for controlled clinical trials.
The Lancet. RheumatologyChristoffer Søvsø Våben, Andreas Wiggers Nielsen, Maria Sandovici, Søren Geill Kjær, Ib Tønder Hansen, Jesper Blegvad-Nissen, Berit Dalsgaard Nielsen, Christia…
BACKGROUND: Diagnosing polymyalgia rheumatica is challenging, and musculoskeletal ultrasound is primarily used in diagnostically difficult situations. Previous musculoskeletal ultrasound studies in patients with polymyalgia rheumatica used case-control designs or non-representative cohorts, reducing assessment of diagnostic accuracy. This study aimed to assess the diagnostic accuracy of musculoskeletal ultrasound in two independent cohorts of patients with suspected polymyalgia rheumatica. METHODS: This multicentre, diagnostic accuracy study included consecutive, glucocorticoid-naive patients with suspected polymyalgia rheumatica, referred for rheumatology evaluation at the University Medical Center Groningen, the Netherlands (retrospective cohort), between April 30, 2019, and Feb 13, 2024, and at Aarhus University Hospital, Silkeborg Regional Hospital, and Horsens Regional Hospital, Denmark (prospective cohort), between Sept 14, 2020, and June 30, 2022. The Aarhus cohort included patients older than 50 years with proximal muscle or joint pain and excluded patients with cranial symptoms suggestive of giant cell arteritis, cancer within the past 5 years, or pre-existing inflammatory rheumatic disease. No explicit referral criteria were applied in the Groningen cohort. Participants underwent protocolised clinical examination and musculoskeletal ultrasound. The reference standard was clinical diagnosis after 6 months (Groningen) or 12 months (Aarhus) of follow-up. Musculoskeletal ultrasound assessment included subacromial-subdeltoid bursitis, biceps tenosynovitis, and hip synovitis in both cohorts, plus glenohumeral synovitis and trochanteric bursitis in the Groningen cohort. A polymyalgia rheumatica ultrasound lesion count was calculated based on six (Aarhus) and ten (Groningen) sites. Diagnostic performance of individual and combined lesions was assessed using sensitivity, specificity, likelihood ratios, and receiver operating characteristic (ROC) analysis. There was no lived experience involvement in the study design or conduct. The Aarhus cohort study is registered with ClinicalTrials.gov, NCT04519580. FINDINGS: The Groningen cohort included 92 patients patients with suspected polymyalgia rheumatica (41 [45%] male, 51 [55%] female, mean age 69 years [SD 9]), of whom 58 (63%) were diagnosed with polymyalgia rheumatica after 6-month follow-up. The Aarhus cohort included 93 patients (53 [57%] male, 40 [43%] female, mean age 71 years [SD 8]), 66 (71%) of whom had a diagnosis of polymyalgia rheumatica at 12 months. No single musculoskeletal ultrasound finding was pathognomonic for polymyalgia rheumatica. The combination of musculoskeletal ultrasound findings with the highest sensitivity was the presence of at least one inflammatory lesion (Groningen: 10-site polymyalgia rheumatica ultrasound lesion count 93% [95% CI 83-98]; Aarhus: 6-site polymyalgia rheumatica ultrasound lesion count 92% [83-98]). The combination with highest specificity was the presence of at least one inflammatory lesion in both the shoulder and hip girdles (Groningen: 85% [95% CI 69-95]; Aarhus: 93% [76-99]). ROC analysis showed an area under the curve of 0·779 (95% CI 0·675-0·883) for the 10-site count in Groningen and 0·769 (0·664-0·875) for the 6-site count in Aarhus. Musculoskeletal ultrasound performed better in distinguishing polymyalgia rheumatica from non-inflammatory conditions than from other inflammatory rheumatic diseases. INTERPRETATION: Absence of shoulder and hip lesions on musculoskeletal ultrasound makes a polymyalgia rheumatica diagnosis unlikely. However, their presence requires careful clinical evaluation, as similar findings occur in other inflammatory rheumatic diseases. These findings support the use of musculoskeletal ultrasound as a potential adjunct to clinical assessment when evaluating patients with suspected polymyalgia rheumatica. FUNDING: FOREUM, Danish Rheumatism Association, Independent Research Fund Denmark, Ketty and Ejvind Lyngsbæks Foundation, Frimodt-Heineke's Foundation, Aase and Ejnar Danielsen's Foundation, AP Møller Foundation, Health Research Foundation of Central Denmark Region, and Regional Hospital Central Jutland Research Foundation.
PloS oneJiayin Pang, Yu Li, Zhichao Qi, Wenbin Yang
Osteoarthritis and osteoporosis frequently coexist in older adults, but shared molecular programs remain unclear. We developed a disease-first multilayer public-data integration framework to identify shared protein candidates while preserving disease-specific structure before cross-disease comparison. Public bulk transcriptomic datasets from osteoarthritis synovium and cartilage and osteoporosis-related monocytes, femoral bone, and osteogenic stromal compartments were analyzed independently within each disease. Disease-level signatures were generated using differential expression analysis, robust rank aggregation, functional enrichment, and weighted gene co-expression network analysis. A shared axis was defined by concordant dysregulation, shared biological processes, and criteria-positive coexpression-module correspondences, with module matching subsequently calibrated against a size-preserving null model. Candidate genes were mapped to proteins and prioritized by integrating interaction topology, signaling priors, protein annotation, tissue support, disease-association and genetic evidence, local CARNIVAL virtual knockout, and single-cell contextual perturbation analysis. Both diseases showed reproducible signatures enriched in antigen presentation, cytokine regulation, extracellular matrix organization, osteoclast differentiation, ossification, and bone remodeling. Cross-disease comparison yielded 234 criteria-positive module pairs; 53 retained pair-specific support at empirical FDR < 0.05, whereas the total number of criteria-positive pairs did not exceed the global null expectation. Protein-level integration prioritized HLA-DRB1, HSP90AA1, CTSK, RPL7, PRG4, HLA-DRA, CLEC3B, TIMP1, SPP1, and APOE. Local virtual knockout assigned the highest model-derived CARNIVAL scores to HLA-DRB1 and HSP90AA1. Across the evaluated network configurations, HLA-DRB1 exceeded the prespecified score threshold in all four evaluable configurations, whereas HSP90AA1 exceeded it in four of six, indicating greater configuration stability for HLA-DRB1. Primary matched-null calibration of 39 evaluable candidate-compartment pairs retained nine pairs at global FDR < 0.05. External quality-control sensitivity analysis retained 125,090 of 161,470 cells and identified 10 globally FDR-supported pairs. Although only two of the nine primary pairs remained supported in the same compartment, five of the six primary supported genes retained evidence in at least one compartment. Recalculation using the quality-controlled cell-context evidence retained all primary top 10 proteins, with HLA-DRB1 and HSP90AA1 remaining the two highest-ranked candidates. Composition-aware bulk sensitivity analysis retained the direction of 36 of 40 candidate-cohort effects, while matched transcriptional-program adjustment retained 24 of 27 effects and showed greater attenuation of MHC-II candidates than of ribosomal or protein-folding candidates. These findings support a shared osteoimmune-matrix-remodeling protein axis linking osteoarthritis and osteoporosis and provide candidates for future experimental validation.
RMD openMarina Jiménez-Martínez, Tineke A De Jong, Miranda Houtman, Johanna F Semmelink, Noam Zelcer, Marleen G H van de Sande, Wendy Dankers, Lisa G M van Baarsen
OBJECTIVE: Cellular ageing of the immune system has been suggested to play a role in the pathogenesis of rheumatoid arthritis (RA). RA onset is preceded by a preclinical phase of systemic autoimmunity without overt tissue inflammation, allowing the investigation of predisease cellular dysfunction in at-risk individuals. Lymph nodes (LNs) are crucial for (auto)antibody development, with LN fibroblasts playing a key role in regulating immune homeostasis. Here, we investigated age-associated alterations in LN fibroblast differentiation capacity during the at-risk and established stages of RA. METHODS: Primary LN fibroblasts were isolated from inguinal LN core biopsies obtained from healthy controls, at-risk individuals and patients with RA. Adipogenic differentiation assays served as a functional readout of cellular plasticity and bulk RNA sequencing was used to evaluate ageing-related transcriptional changes. RESULTS: LN fibroblasts from at-risk individuals and patients with RA exhibited reduced adipogenic capacity, reflected by fewer lipid droplet-positive cells on differentiation. Transcriptomic analysis revealed downregulation of cell cycle, DNA repair and differentiation pathways. These fibroblasts also failed to upregulate the cell cycle switch G0S2 on stimulation. CONCLUSION: Together, these findings indicate a disrupted coordination between cell cycle processes and differentiation in at-risk and RA LN fibroblasts, consistent with features of cellular ageing. Notably, these alterations were already present in at-risk individuals prior to clinical disease onset, suggesting that reduced fibroblast fitness may contribute to impaired LN tissue homeostasis in disease-prone individuals.
Physiotherapy research international : the journal for researchers and clinicians in physical therapyBruno Ruocco Verengue, Lisa C Carlesso, Barbara Greco Miura, Aron Charles Barbosa da Silva, Patrícia Gabrielle Dos Santos, Almir Vieira Dibai-Filho, Cid André …
BACKGROUND AND PURPOSE: Exercise therapy is a core treatment for knee osteoarthritis (KOA), but the effects of different exercise modalities on endogenous pain modulation remain unclear. This trial will compare a cycling-based aerobic exercise program with a resistance and neuromuscular exercise program on exercise-induced hypoalgesia (EIH) in people with KOA and altered baseline EIH. METHODS: This randomized, two-arm, controlled, single-blind trial will include 90 participants aged 40-75 years with symptomatic KOA, knee pain intensity of at least 3 points on the Numerical Pain Rating Scale, and altered baseline EIH. Participants will be randomized 1:1 to the Cycling-Based Aerobic Exercise Group (CAEG) or the Resistance and Neuromuscular Exercise Group (RNEG). Both groups will receive 30 supervised sessions over 10 weeks. The primary treatment effect will be the adjusted mean between-group difference in within-session change in pressure pain threshold at the most symptomatic knee, averaged across weeks 1, 4, 7, and 10. Secondary outcomes include EIH at other sites, conditioned pain modulation, pain, self-efficacy, function, performance, strength, global perceived effect, adherence, and enjoyment. RESULTS: This trial will evaluate whether the two exercise programs differ in their capacity to elicit EIH in KOA. DISCUSSION: This trial may clarify whether different exercise modalities produce distinct effects on acute endogenous pain modulation in KOA and may support a more precise exercise prescription for pain management. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NTC07302204.
Physiotherapy research international : the journal for researchers and clinicians in physical therapyPatrícia Gabrielle Dos Santos, Richard Eloin Liebano, Bruno Ruocco Verengue, Aron Charles Barbosa da Silva, Barbara Greco Miura, Carlos Eduardo Girasol, Almir …
BACKGROUND AND PURPOSE: Therapeutic exercise is central to knee osteoarthritis (KOA) management, but movement-evoked pain may limit adherence and outcomes. High-frequency transcutaneous electrical nerve stimulation may reduce pain during movement and enhance exercise-related outcomes. This study evaluated whether high-frequency transcutaneous electrical nerve stimulation applied during an exercise therapy program provides additional benefits over sham stimulation in individuals with KOA. METHODS: In this randomized, sham-controlled superiority trial with intended participant blinding and blinded outcome assessment, 96 individuals with KOA were randomized to exercise therapy plus active high-frequency transcutaneous electrical nerve stimulation or exercise therapy plus sham transcutaneous electrical nerve stimulation. The primary outcome was the Knee Injury and Osteoarthritis Outcome Score Pain subscale. Secondary outcomes included the remaining Knee Injury and Osteoarthritis Outcome Score subscales, pain intensity, pain-related self-efficacy, patient-specific function, disability, quadriceps isometric strength, and physical function. Outcomes were assessed at baseline, post-intervention, and 1 month follow-up. Linear mixed models were used for analysis. RESULTS: Active high-frequency transcutaneous electrical nerve stimulation did not provide additional benefit over sham stimulation for the Knee Injury and Osteoarthritis Outcome Score Pain subscale at post-intervention (adjusted mean difference, 1.05 points; 95% CI, -5.19 to 7.29) or at 1 month follow-up (0.40 points; 95% CI, -5.91 to 6.71). These confidence intervals did not reach the predefined 10-point minimal clinically important difference. No statistically significant between-group differences were observed for any secondary outcome. No adverse effects were reported. DISCUSSION: Adding high-frequency transcutaneous electrical nerve stimulation to a structured exercise therapy program did not confer additional benefits over sham stimulation in individuals with KOA. These findings should be interpreted in light of the absence of formal blinding assessment, the short follow-up, and the absence of an exercise-only group. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov on December 14, 2023, under the identifier NCT06184451.
International journal of rheumatic diseasesAbinaya Suresh, Shobana Ramaswamy, Santhi Silambanan, Mahesh Kumar Kuppusamy
BACKGROUND: Yoga, a holistic mind-body practice used to improve physical function and psychological well-being in chronic inflammatory conditions such as rheumatoid arthritis (RA). This systematic review and meta-analysis aimed to assess the effectiveness of yoga in reducing psychological function and inflammation in individuals with RA. METHODS: A thorough literature search was performed in MEDLINE (via PubMed) for studies published between January 1994 and June 2025. Randomized controlled trials (RCT) investigating the impact of yoga on RA were selected. Data extraction was carried out independently by two reviewers. The outcomes evaluated included both subjective and objective indicators of Disease Activity Score (DAS), Health assessment questionnaire (HAQ-DI) and inflammatory markers. RESULT: Eight RCT involving 651 participants were eligible for this study. Yoga interventions significantly improved psychological outcomes, with reductions in DAS 28 (SMD = -0.44; 95% CI = [-0.56 to -0.31]; p < 0.0001) compared to the control group. However, no significant changes were found in HAQ-DI (SMD = -0.23; 95% CI = [-0.81 to 0.36]; p = 0.30). Regarding inflammatory biomarkers, yoga significantly reduced serum Interleukin-6 (IL-6) levels (SMD = -0.65; 95% CI = [-1.17 to -0.13]; p = 0.03), while changes in Tumor Necrosis Factor-alpha (TNF-α) were not statistically significant (SMD = -0.71; 95% CI = [-1.74 to 0.33]; p = 0.10). CONCLUSION: This meta-analysis indicates that yoga significantly improves mental health by reducing stress, anxiety, depression & lowers inflammation through reduced IL-6 levels. However, its effect on physical health and TNF-α was not consistent, suggesting more research is needed. Further large-scale studies are needed to validate and standardize its use.
Journal of extracellular vesiclesStefanie Kurth, Edveena Hanser, Simone Häner-Massimi, Stavros Giaglis, Florian Geier, Dominik Burri, Katarzyna Buczak, Ute Heider, Stefan Wild, Yves P Acklin, …
Extracellular vesicles (EVs) are emerging as key mediators of disease-associated intercellular communication and as promising biomarker sources across many disease conditions, including joint disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA). Molecular profiling of synovial tissue has uncovered disease-driving cellular states, but tissue biopsies are invasive and not routinely available. EVs in synovial fluid may offer a minimally invasive and complementary window into joint pathobiology. However, the molecular complexity of synovial fluid and the heterogeneity of EV populations have hindered the analysis of defined disease-relevant EV subsets. To address this challenge, we developed a refined size-exclusion chromatography-ultrafiltration (SEC-UF) workflow coupled to magnetic bead-based immunocapture for targeted enrichment of cell type-associated EV subpopulations from arthritic synovial fluid. As proof-of-concept, we targeted a stromal-associated EV population using CD90/THY1, a surface marker expressed by discrete synovial fibroblasts subsets implicated in arthritis pathobiology. In vitro validation using synovial fibroblast-derived EVs confirmed surface-accessible CD90 and demonstrated selective immunocapture of defined EV subpopulations. Application to patient-derived synovial fluid showed that SEC-UF pre-enrichment improves the robustness of CD90+ EV recovery from this complex biofluid. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) profiling established broad EV-associated proteome coverage in synovial fluid (SF)-EV preparations and identified multiple proteins reflecting the inflamed arthritic synovial environment. Fraction-resolved proteomics enabled comparison of the CD90-immunocaptured SF-EV subset with the non-captured CD90-/CD90low SF-EV pool. Differential proteomics and surfaceome-informed cell-of-origin analysis supported enrichment of stromal-associated surface markers in the CD90+ fraction, whereas the non-captured SF-EV pool retained broader immune-associated and residual stromal EV inputs. Together, this fit-for-purpose workflow provides a strategy to resolve EV heterogeneity patient synovial fluid and supports future biomarker-oriented studies of defined subpopulations in arthritic diseases.
Rhode Island medical journal (2013)Mohamad Y Fares, Tarishi Parmar, Peter Boufadel, Mohammad Daher, Jonathan Berg, Adam Z Khan, Brian W Hill, John G Horneff, Joseph A Abboud
OBJECTIVES: Chatbots have been increasingly recognized as modern tools that provide patients with reliable health-related information. This study aimed to evaluate and compare ChatGPT-3.5 and GPT-4's ability to answer glenohumeral osteoarthritis-related questions. METHODS: Fifteen questions were derived from the 2020 AAOS Clinical Practice Guidelines for the Surgical Management of Glenohumeral Joint Osteoarthritis. Questions were categorized into three groups: risk factors, implant/intraoperative considerations, and pain/functional outcomes. ChatGPT-3.5 and GPT-4 were prompted with these questions, and responses were evaluated by four fellowship-trained shoulder and elbow surgeons. Each response was rated on a scale (scores:1-5) based on relevance, accuracy, clarity, completeness, and evidence-based support. Data was analyzed descriptively and statistically to compare the scores between ChatGPT-3.5 and GPT-4. RESULTS: Average score for ChatGPT-3.5 was 19.7/25, with "Risk Factor" prompts achieving the highest mean score. GPT-4 averaged 18.7/25, with "Functional Outcomes" prompts scoring highest. However, there were no statistically significant differences between different prompt themes for GPT-3.5 and GPT-4. "Clarity" category received the highest score for GPT-3.5, while "Relevance" was highest for GPT-4. Both models scored lowest on "Evidence-based" prompts. On the Flesch- Kincaid scale, GPT-3.5 responses had a significantly higher score of 18.3 compared to GPT-4's 15.4, indicating a more difficult reading level in GPT-3.5's responses. CONCLUSION: Both ChatGPT-3.5 and GPT-4 performed adequately in providing well-informed medical responses to patient queries about glenohumeral osteoarthritis. Future chatbot versions should focus on providing evidence-based content through systematic and reliable reviews of literature, in an accessible readable manner.
PloS oneLeila Solouki, Soodeh Shahsavari, Hamid Sharini, Amir Hossein Hashemian, Volker Johann Schmid, Samira Jafari, Saleh Rouhi, Behzad Mahaki
BACKGROUND: Fibromyalgia (FM) is a multifaceted chronic pain disorder presenting with pain throughout the musculoskeletal system, alongside chronic fatigue,sleep disturbances, and cognitive impairments. Current diagnostic criteria primarily rely on symptom questionnaires, with no specific laboratory markers or definitive tests, making diagnosis subjective and often delayed. Moreover, the overlap with other central pain syndromes further complicates accurate diagnosis. Neuroimaging studies, particularly functional magnetic resonance imaging (fMRI), have shown promise in elucidating brain abnormalities underlying FM. However, translating these findings into reliable diagnostic tools remains challenging, especially given small sample sizes. Therefore, this study aims to enhance the diagnostic accuracy of FM based on fMRI data by developing an intelligent model. This model employs machine learning algorithms designed to perform effectively with limited dataset sizes and incorporates features extracted through graph theory methods. We analyzed fMRI data from 32 FM patients and 30 healthy controls. Graph theory metrics were extracted from 13 regions of the emotion regulation network. A genetic algorithm was employed to select the most effective features, which were then used to train multiple machine learning classifiers-including Support Vector Machine (SVM) with polynomial and Radial Basis Function (RBF) kernels, Random Forest, Gradient Boosting Machine, Adaptive Boosting, and SVM with Mixture Kernels-within a cross-validation framework to ensure robustness. RESULT: The genetic algorithm selected 84 features as inputs for machine learning algorithms. The polynomial SVM achieved the highest overall accuracy, whereas the SVM with mixture kernels demonstrated superior sensitivity and AUC. Sensitivity and AUC were prioritized as the main criteria for model selection due to their clinical relevance in reducing false negatives. CONCLUSION: The study identified the SVM with Mixture Kernels as the most effective model for distinguishing FM patients from healthy controls. This approach demonstrates promising potential for enhancing diagnostic accuracy and supporting psychological and psychiatric interventions.
Science (New York, N.Y.)Su-Jin Kim, Hyo-Eun Kim, Ki-Ho Chung, Gyuseok Lee, Ka Hyon Park, Young-Gwon Kim, Mangeun Kim, Weon-Young Choi, Soo-Chang Joo, Hae Jin Kee, Seung-Hee Kwon, Jong…
Osteoarthritis (OA) is a degenerative joint disease, the progression of which is accelerated by systemic metabolic stress. Here, we identified a neuroendocrine pathway through which hypertension accelerates OA pathogenesis in joints predisposed by mechanical injury or aging. Nationwide cohort analyses and hypertensive mouse models demonstrated that elevated blood pressure exacerbates OA pathogenesis. OA-primed chondrocytes up-regulated arginine vasopressin (AVP) receptor 1A (AVPR1A), rendering them responsive to hypertension-associated circulating AVP. AVP-AVPR1A signaling enhanced catabolic signaling while suppressing anabolic regulators, thereby promoting cartilage catabolism. Genetic deletion or pharmacological inhibition of AVPR1A protected against hypertension-driven OA acceleration. Transcriptomic profiling and gene-silencing analyses identified NR4A3 as the principal downstream transcriptional mediator. Collectively, these findings establish the AVP-AVPR1A axis as a mechanistic link between systemic hypertensive stress and joint degeneration.
Immunity, inflammation and diseaseQianqian Chen, Yuhan Li, Yiming Chen, Yuhua Su, Xiaodong Wang, Chunxiao Guan
BACKGROUND: Sjögren's disease (SD) is a chronic systemic autoimmune disorder that can affect multiple organ systems. Interstitial lung disease (ILD) is a clinically significant pulmonary manifestation of SD and is associated with impaired quality of life and increased mortality. Interferon-γ (IFN-γ), a major effector cytokine of Th1 immunity, has been implicated in immune dysregulation and chronic inflammation; however, its contribution to SD-associated ILD (SD-ILD) and its relationship with fibrotic remodeling remain incompletely understood. MATERIALS AND METHODS: This pathway-oriented narrative review synthesized evidence identified through a structured and iterative search of PubMed, Embase, and Web of Science, updated through August 2026. Priority was given to direct evidence from SD-ILD. When disease-specific evidence was limited, mechanistic findings from SD without characterized ILD, related connective tissue disease-associated ILDs, fibrotic lung diseases, and experimental models were considered and interpreted as indirect or extrapolated evidence. RESULTS: Available evidence supports a conceptual network in which IFN-γ may function as a potential signaling node interacting with JAK/STAT, PI3K/AKT, NF-κB, MAPK, WNT/β-catenin, and IDO-kynurenine-AhR pathways. These pathways may contribute at different levels to immune-cell activation, inflammatory amplification, immunometabolic regulation, epithelial injury, fibroblast activation, and fibrotic remodeling. Evidence is strongest for the biological relevance of IFN-γ-JAK/STAT signaling, whereas support for PI3K/AKT, NF-κB, and MAPK is more indirect, and the relevance of WNT/β-catenin and particularly IDO-Kyn-AhR to SD-ILD remains less well established. DISCUSSION: The proposed IFN-γ-associated network should be regarded as a conceptual mechanistic framework rather than a fully validated signaling hierarchy in SD-ILD. Distinguishing direct disease-specific evidence from mechanistic extrapolation highlights important knowledge gaps and provides a rationale for future investigation of pathway-informed biomarkers and stage-specific therapeutic strategies. Prospective SD-ILD studies integrating longitudinal clinical data with spatial and single-cell approaches are needed to validate these relationships and clarify their translational relevance.
International journal of rheumatic diseasesJing Liang, Xiangyu Wei, Chen Shang, Siqi Shao, Wenting Hao, Yile Ren
AIM: Rheumatoid arthritis (RA) is a chronic autoimmune disease with intestinal dysbiosis implicated through the gut-joint axis. This study aimed to delineate fecal microbiome and metabolomic signatures in RA and identify biomarkers associated with disease activity. METHOD: Twenty-eight RA patients and 19 healthy controls were included in this cross-sectional study. Gut microbiota was characterized by 16S rRNA sequencing with operational taxonomic unit (OTU) and amplicon sequence variant (ASV) analysis. Fecal metabolites were profiled using untargeted metabolomics. Correlations between microbiota, metabolites, and disease activity indices were assessed. RESULTS: RA patients showed altered alpha diversity and distinct microbial composition versus healthy controls. Eight differential genera and three species were identified based on the combined OTU and ASV analyses. Allisonella was enriched in RA and positively correlated with disease activity, whereas Bifidobacterium adolescentis showed a negative correlation trend with autoantibody/inflammatory markers. Metabolomic analysis revealed 31 and 36 altered metabolites in both ion modes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment indicated dysregulation of unsaturated fatty acid biosynthesis and tryptophan metabolism. Microbiota-metabolite pairs correlated with disease activity. CONCLUSION: RA is characterized by distinct gut microbiota and fecal metabolite alterations associated with disease activity. Specific microbial taxa and metabolic pathways may serve as biomarkers, lending further support to the gut-joint axis in RA pathogenesis.
Physiotherapy research international : the journal for researchers and clinicians in physical therapyLili Yu, Cong Chen, Guancong Zhang, Qiuchen Huang, Miao Ye, Yukiko Makihara, Yusuke Nishida
BACKGROUND: Intramuscular fat infiltration (IMFI) is considered to be closely associated with knee osteoarthritis (KOA); however, its overall association, muscle-specific involvement, and clinical relevance remain unclear. OBJECTIVE: To quantify the association between IMFI and KOA, identify affected muscle groups, and evaluate prognostic value. METHODS: We searched PubMed, Web of Science, Scopus, and Embase up to December 2025 for observational studies. Two reviewers independently screened, extracted data, and assessed bias (NOS/JBI). Pooled standardized mean differences (SMDs) were calculated using random-effects models, with subgroup and sensitivity analyses. RESULTS: Seventeen studies were included. IMFI was significantly higher in KOA patients than controls (SMD = 0.63, 95% CI 0.41-0.85, I2 = 84.7%). Anatomically, the anterior thigh muscles (rectus femoris, vastus lateralis, vastus medialis) demonstrated a significant pooled effect (SMD = 0.96, 95% CI 0.66-1.25, I2 = 3.2%) and showed the strongest pooled association, whereas posterior, medial, and composite measures did not demonstrate significant associations. At the individual muscle level, a single study reported a notable association for the semimembranosus (SMD = 1.25, 95% CI 0.57-1.93); however, this finding is based on limited evidence and requires confirmation in future studies. Subgroup by imaging modality: CT demonstrated a significant association (SMD = 0.59, 95% CI 0.28-0.90), while MRI and ultrasound did not show significant associations. Elevated IMFI was also associated with reduced muscle strength, higher KOA incidence, structural progression, and increased knee replacement risk. CONCLUSION: A moderate positive association exists between IMFI and KOA, with notable muscle-specific heterogeneity. Anterior thigh muscles show the strongest pooled association, whereas individual muscle findings require further confirmation. These findings suggest that IMFI may represent a promising potential marker warranting further prospective investigation for risk stratification, though causality and its role in modifying disease progression remain to be established.
Cell biology internationalJiawei Shen, Zelin Zhou, Yu Hang Yiu, Zhifei Xie, Na Liu, Shawn He
Osteoarthritis (OA) is a multifactorial whole joint disease characterized by cartilage degeneration, subchondral bone remodeling, synovial inflammation, and progressive functional impairment. Increasing evidence suggests that OA is not simply a wear and tear disorder, but a mechanobiological disease in which abnormal mechanical stress interacts with inflammatory and metabolic pathways to drive joint degeneration. This review summarizes recent advances in the mechanobiology of OA, focusing on the interplay between mechanical stress, inflammation, and joint remodeling. We discuss the major mechanosensing and mechanotransduction mechanisms in chondrocytes, including primary cilia, integrins, the cytoskeleton, the LINC complex, and mechanosensitive ion channels such as TRPV4, TRPM7, and PIEZO channels. We further examine how these pathways regulate extracellular matrix homeostasis, chondrocyte fate, and the transition from anabolic maintenance to catabolic degeneration, as well as how altered joint loading affects subchondral bone remodeling through osteocyte responses, the RANK/RANKL/OPG axis, and Wnt/β-catenin signaling. Particular attention is given to the crosstalk between mechanotransduction and inflammatory signaling, including NF-κB, MAPK, and macrophage polarization pathways, which together amplify structural damage under pathological loading. Finally, we highlight emerging therapeutic strategies based on biomechanical modulation and mechano-inflammatory targeting. A better understanding of these integrated mechanisms may provide new insight into OA pathogenesis and support the development of disease-modifying therapies.
Immunity, inflammation and diseaseLina Leng, Quanyi Tang, Ying Li, Jinfeng Zhang, Yaorong Han, Xiaoli Li
BACKGROUND: The prognostic nutritional index (PNI) is a composite marker reflecting the nutritional and inflammatory status. Its association with disease activity in rheumatoid arthritis (RA) remains incompletely understood. This study aimed to investigate the relationship between PNI and RA disease activity. METHODS: A total of 984 RA patients were enrolled and stratified into three groups according to PNI tertiles. Univariate analysis and linear regression models were performed to evaluate the association between PNI and disease activity scores (DAS28-ESR/DAS28-CRP). A two stage (segmented) linear regression model was used to identify potential inflection points in the relationship. RESULTS: Univariate analysis showed that PNI was significantly negatively correlated with both DAS28-ESR (β = -0.043, p < 0.001) and DAS28-CRP (β = -0.045, p < 0.001). After adjusting for demographic characteristics, inflammatory markers, and therapeutic drugs, this negative correlation remained significant in the fully adjusted model (DAS28-ESR: β = -0.034, p < 0.001; DAS28-CRP: β = -0.044, p < 0.001). Segmented regression identified a non-linear relationship with an inflection point at approximately 45.0. Below this threshold, the negative association was markedly stronger (DAS28-ESR: β = -0.073; DAS28-CRP: β = -0.069). Above the inflection point, the association weakened and became non-significant for DAS28-ESR (β = -0.012, p > 0.05), while for DAS28-CRP it remained significant but attenuated (β = -0.020, p < 0.05). CONCLUSION: PNI is independently negatively associated with RA disease activity, with a notably stronger effect when PNI is below 45. PNI may serve as a simple and effective biomarker for assessing inflammation and nutritional status in RA patients, and may help identify patients with greater nutritional-inflammatory burden.