Arthritis Research & Therapy

Osteoarthritis (OA), a degenerative joint disease, is associated with increased systemic inflammation, chronic pain, and cardiovascular dysfunction. Epidemiological evidence establishes that OA increases the risk of cardiovascular disease (CVD) threefold, yet the causal role of OAs contributions remains underexamined. We assessed cardiac function longitudinally following destabilization of the medial meniscus (DMM) surgery to induce osteoarthritis in mice. DMM-mice exhibited significant, sexually dimorphic alterations in echocardiographic parameters. Female DMM mice developed impaired relaxation with altered E/A ratios, increased E/e ratios, and prolonged intraventricular relaxation time with no change in ejection fraction, while male DMM mice showed progressive systolic dysfunction with decreasing ejection fraction, increased E/e ratio, and prolonged intraventricular contraction time. Transcriptomic profiles and biochemical analyses demonstrated divergent cellular responses involving fibrosis and oxidative stress in female mice, whereas autophagic and apoptotic responses were observed in male mice. Using a tumor necrosis factor 2 (TNFR2) agonist shown to reduce systemic inflammation, we investigated its potential therapeutic role in the context of OA-induced cardiovascular dysfunction. TNFR2 agonism proved to be effective both prophylactically and therapeutically for female diastolic dysfunction. While prophylactic and therapeutic administration delayed male systolic dysfunction, the efficacy declined over time. Our findings demonstrate evidence of a novel sexually dimorphic model of OA-induced CVD that recapitulates the sexually dimorphic pattern of patient phenotypes and a promising new therapeutic approach to CVD. Translational RelevanceOsteoarthritis patients have higher, often unrecognized, cardiovascular risk, yet preclinical models linking joint disease to cardiac dysfunction remain unexplored. Using a murine preclinical model of OA reveals the key findings. First, OA alone drives sex-specific cardiac phenotypes - females develop diastolic dysfunction, whereas males develop progressive systolic impairment. Second, selective TNFR2 agonism prevents and reverses OA-induced diastolic dysfunction in female mice and delays systolic decline in males. These findings suggest sex-dependent cardiac monitoring in OA patients and indicate that TNFR2-targeted therapy will likely be a sex-informed intervention to provide cardioprotective benefit. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/736778v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1f41661org.highwire.dtl.DTLVardef@1e94cb7org.highwire.dtl.DTLVardef@1abbac0org.highwire.dtl.DTLVardef@171cc86_HPS_FORMAT_FIGEXP M_FIG C_FIG

Background Pain frequently persists in rheumatoid arthritis (RA), despite effective control of inflammation. The mechanisms driving this residual pain remain poorly characterised in individual patients. Methods In 172 patients with established RA and clinically relevant pain (mean NRS 6.5/10) and 80 pain free controls, we combined indicators of inflammatory disease (CRP, joint counts, power Doppler ultrasound), centrally mediated pain (Widespread Pain Index, painDETECT), psychological distress (PHQ ADS) and quantitative sensory testing (QST). Latent profile analysis was applied without predefined thresholds. Results Four phenotypes were identified: a peripheral, low-inflammation/low-central phenotype (38%); a predominantly inflammatory phenotype (7%); and moderate (43%) and severe (12%) centrally mediated phenotypes. Centrally mediated phenotypes reported the highest pain (NRS 8.2), worst disease impact and lowest employment. DAS28 CRP was similar in both the inflammatory and severe centrally mediated phenotypes but for different reasons, swollen joints and CRP versus tender joints , and did not distinguish them. Conditioned pain modulation was impaired relative to controls (p<0.001) and most reduced in the severe centrally mediated phenotype. Psychological distress was the strongest independent predictor of pain severity (model R squared=0.33), whereas inflammatory markers were not. Principal components analysis identified swollen joint count (loading 0.63) and the tender swollen joint difference (loading 0.60) as accessible clinical markers of the inflammatory and centrally mediated phenotypes respectively. Conclusions A data driven approach identified four mechanism-based pain phenotypes in RA. This framework moves pain assessment beyond inflammation alone and provides a basis for testing analgesic strategies to target the predominant pain mechanism in individual patients.

Osteoarthritis (OA) drug development remains constrained by preclinical models that fail to recapitulate the multicellular interactions that regulate human joint inflammation and extracellular matrix degeneration in response to investigational drugs. Tanezumab, a humanized anti-nerve growth factor monoclonal antibody developed for non-opioid pain relief, advanced to late-stage clinical trials but was discontinued due to unresolved joint-localized safety concerns, including rapidly progressive OA. This study evaluated whether a human microfluidic joint-on-a-chip co-culture system could detect early biomarker responses to tanezumab exposure that were not apparent in conventional chondrocyte monoculture. Tanezumab was first tested in human chondrocyte monoculture under untreated and disease-like (i.e., IL-1{beta}-treated) conditions. Across a 20-analyte panel of inflammatory and matrix-remodeling biomarkers, statistically significant monoculture responses to tanezumab were limited to decreased IL-1{beta} from 335 to 132 pg/mL ([~]0.39-fold) and increased IL-8 from 575 to 675 pg/mL ([~]1.17-fold). Major OA-associated matrix-remodeling markers, including MMP-1, MMP-3, and MMP-13, remained largely unchanged, indicating that monoculture conditions are insufficiently sensitive to detect clinically predictive drug-related molecular changes. Tanezumab was then evaluated in co-cultures containing chondrocytes, osteoblasts, fibroblast-like cells, and macrophages under low-inflammation (i.e., M0 macrophage-based) and high-inflammation (i.e., M1 macrophage-based) conditions. In the M0-based co-culture, tanezumab increased MMP-1 from [~]4.20 x 104 to [~]6.20 x 104 pg/mL ([~]1.48-fold), MMP-3 from [~]8.00 x 104 to [~]1.20 x 105 pg/mL ([~]1.50-fold), and MCP-1 from 2.85 x 103 to 4.31 x 103 pg/mL ([~]1.51-fold). In contrast, the M1-based co-culture showed decreases in MMP-13 from [~]1.66 x 104 to [~]1.17 x 104 pg/mL ([~]0.70-fold) and IFN-{gamma} from [~]1.95 x 104 to [~]1.56 x 104 pg/mL ([~]0.80-fold), changes that may appear beneficial despite the drugs known clinical risks. Collectively, these findings show that low-inflammation multicellular co-culture revealed coordinated matrix remodeling and inflammatory responses to NGF blockade that were missed in monoculture and were partly obscured in highly stimulated disease-like conditions. This platform may provide a useful, human-relevant approach for safety signal assessment and early evaluation of OA therapeutics within a defined context of use focused on joint-specific, tissue-level drug-response testing.

Rheumatoid arthritis is a chronic inflammatory joint disease in which progressive destruction of cartilage and bone drives long-term disability. Current disease-modifying therapies target the immune and cytokine networks that sustain synovial inflammation, but none is directed at the chondrocyte, the resident cell responsible for maintaining cartilage matrix. Chondrocyte survival and matrix homeostasis depend on {beta}1-integrin-mediated adhesion to the extracellular matrix, and dysregulated integrin signalling has been implicated in cartilage injury. Here we test the hypothesis that allosteric modulation of {beta}1 integrin, rather than simple adhesion blockade, is chondroprotective. Using the monoclonal antibody JB1a, which binds an epitope in the hybrid domain of {beta}1 integrin and stabilises the receptor in a low-affinity conformation, we show that intra-articular administration produces both functional and structural amelioration of Freunds complete adjuvant (FCA)-induced arthritis in mice. JB1a abolished the FCA-induced increase in joint diameter and hyperalgesia and markedly reduced synovial inflammation, pannus formation and cartilage erosion, with no effect on the contralateral joint and no observed adverse effects. These changes were accompanied by a reduction in chondrocyte apoptosis in vivo. In primary human articular chondrocytes, JB1a abolished interleukin-1{beta} (IL-1{beta})-induced caspase 3/7 activation, reduced IL-8 secretion, and restored the sinusoidal oscillation of intracellular ATP that was otherwise abrogated by IL-1{beta}. In contrast, the adhesion-blocking, integrin-clustering antibody 6S6 activated caspase 3/7 and amplified IL-1{beta}-induced IL-8 secretion, indicating that the therapeutic effect is a property of the specific mode of receptor engagement rather than of adhesion blockade per se. These findings identify {beta}1-integrin conformational state as a determinant of chondrocyte energy homeostasis and survival, and nominate allosteric {beta}1-integrin modulation as a mechanistically distinct, chondrocyte-directed therapeutic strategy in inflammatory arthritis.

Objective We developed a patient- and joint-specific explant co-culture system to model active psoriatic arthritis (PsA) and capture donor-specific tissue responses to therapeutic interventions. Methods Based on convergent joint pathology between end-stage osteoarthritis (OA) and PsA, OA cartilage-bone and synovium tissues from arthroplasty patients were exposed to synovial fluid (SF) obtained from PsA and OA patients. Histological outcomes (synovitis, proteoglycan distribution), curated gene expression, soluble mediators, and proteinase activity were assessed over 7-21-days. Model responses to dexamethasone (DEX) and the anti-tumor necrosis factor antibody adalimumab (ADA) were evaluated. Results PsA SF induced distinct inflammatory and tissue remodeling responses compared to OA SF and control conditions, including altered cartilage proteoglycan distribution, increased synovitis, and tissue-specific transcriptional changes. Multivariate analyses identified distinct osteochondral and synovial transcriptional responses to PsA SF, characterized by reduced osteochondral COL2A1 expression and increased synovial expression of inflammatory and matrix-remodeling genes, including MMP1 and CXCL8. DEX and ADA elicited donor-specific responses across histological, transcriptional, and protein readouts. Among multivariable model outputs, histologic synovitis scores emerged as the most clinically aligned parameter, demonstrating associations with baseline PsA donor disease activity, active joint counts, pain, high-sensitivity C-reactive protein (hsCRP), and radiographic scores. Synovitis score changes to DEX and ADA treatments also aligned with corresponding PsA SF donor clinical improvements to corticosteroid and TNF-modifying therapies. Conclusion This osteochondral-synovial explant co-culture model captured donor-specific inflammatory and treatment-responsive features of PsA SF-induced pathology, thereby providing a clinically relevant ex vivo platform for studying patient-specific therapeutic responses in PsA.

ObjectiveTo develop and apply a preclinical functional imaging assay for visualizing and analyzing activated synovial fibroblasts (SFs) at single-cell resolution using high-content imaging. MethodsA multiparametric functional imaging assay was developed to simultaneously interrogate six key cellular processes in cultured SFs from non-inflammatory control (NIC), osteoarthritis (OA) and rheumatoid arthritis (RA) patients. Two complementary fluorescent panels -- comprising LipidTOX, MitoSOX, TMRM, EdU Click-iT, CYTO-ID, and Sir-Lysosome -- collectively captured autophagy dynamics, mitochondrial health, lipid metabolism, and cellular proliferation within a single imaging workflow. Automated image acquisition and quantitative feature extraction via CellProfiler yielded approximately 1,200 morphological and intensity-based features per cell, enabling high-dimensional, unbiased phenotypic profiling at the individual cell level. ResultsApplication of this assay revealed marked heterogeneity in basal cellular functions among SFs stratified by disease state, and robustly differentiated between NIC, OA and RA SFs. Stimulation with inflammatory cytokines (TNF-, IL-1{beta}, IFN{gamma}) and toll-like receptor ligands (LPS, poly I:C) elicited distinct, stimulus-dependent phenotypic responses across disease groups. Multiparametric analysis and feature importance ranking identified IL-1{beta} as a key driver of enhanced autophagic activity, accompanied by significant remodeling of lipid metabolic profiles. ConclusionWe developed a scalable, sensitive approach for dissecting functional heterogeneity in primary SF cultures, revealing previously unappreciated complexity in SF biology across disease states. Our approach provides a robust framework for high-throughput drug screening and identification of candidate therapeutics selectively targeting pathogenic fibroblast functions in inflammatory arthritis.

Background: Psoriatic arthritis (PsA) is an inflammatory condition involving joints, tendon-bone entheses and synovium that can develop in individuals with psoriasis. Early, accurate clinical diagnosis remains difficult. Extracellular vesicles (EVs) carry proteins and miRNAs that Methods: PubMed and Embase were searched from inception through May 21st, 2026, and human studies examining EV-associated protein or miRNA biomarkers in PsA and related psoriatic or inflammatory diseases were included, with risk of bias assessed using a modified Newcastle-Ottawa Scale and diagnostic accuracy summarized using HSROC/BRMA models when data were sufficient. Results: Seven studies met the inclusion criteria, including 119 individuals with PsA (weighted mean age: 49.8 years; 43.7% female), 205 individuals with non-PsA psoriasis (weighted mean age: 46.4 years; female %: NA), 55 controls (weighted mean age: 44.5 years; 38.2% female), and 50 individuals with other inflammatory joint disorders (weighted mean age: 58.0 years; 58.0% female). EV-associated protein markers demonstrated heterogeneous findings related to immune, vascular, inflammatory, and osteoimmunological signaling. Only 4.2% (4/95) of miRNAs were consistently identified across studies comparing PsA with non-PsA psoriasis, with lower overlap (1.5%, 1/67) in studies comparing PsA with controls. ROC meta-analysis suggested preliminary diagnostic potential, particularly for distinguishing PsA from non-PsA psoriasis, although evidence was constrained by small study numbers. Conclusions: EV-associated proteins and miRNAs are potential biomarker candidates for PsA, reflecting inflammatory, vascular, and osteoimmunological processes underlying disease pathophysiology. However, current evidence remains preliminary and limited by small cohorts, methodological heterogeneity, and inconsistent reporting across studies.

Lyme arthritis, a manifestation of Lyme disease, is triggered by the spirochetal bacterium Borrelia burgdorferi (Bb), which is transmitted through the bite of the Ixodes tick. Although multiple studies have been conducted on the complex host immune response in Lyme arthritis, the spatial gene expression environment in the joint tissue remains unexplored. Here, we applied spatial transcriptomics to ankle joints of C3H mice infected with Bb, profiling tissues at peak inflammation (two weeks post infection) and after antibiotics (four weeks post-infection) during inflammation resolution. Analysis revealed spatially restricted signatures: pro-inflammatory responses dominated synovial and fibroblast populations two weeks post-infection, with elevated levels of Vimentin and I-Ek gene - and Vimentin protein - expression localized to these regions. By four weeks post-infection during the inflammation resolution phase, levels of Vimentin and I-Ek related gene and protein expression were reduced. Further, we noted an increase in the CD54+ and CD106+ double-positive population in infected mice joints compared to the vehicle treated controls. Notably, fibroblasts and synoviocytes in the medial joint regions adopted immune-like phenotypes during peak inflammation, while the same cell types in the exterior humeroradial joint displayed a more infection-resilient phenotype. These spatially resolved maps demonstrate that joint microenvironments play a crucial role in pathogenesis, offering unique insights into Lyme arthritis pathology.

BackgroundADP-ribosylation factor-like protein 15 (ARL15) is a rheumatoid arthritis (RA) susceptibility gene identified through GWAS. Previous studies suggested a role for ARL15 in synovial fibroblast (SF) pathogenicity, but its contribution to inflammatory arthritis remains unclear. We investigated the inflammatory role of ARL15 and its therapeutic potential in RA. MethodsARL15 was overexpressed in MH7A cells followed by bulk RNA sequencing and pathway enrichment analyses. Therapeutic relevance was evaluated in collagen-induced arthritis (CIA) mouse model using anti-ARL15 monoclonal antibodies, ARL15-targeting siRNA, or isoquinoline. Arthritis scores, histopathology, micro-CT and serum cytokines were assessed. Publicly available single-cell RNA sequencing (scRNA-seq) datasets were analyzed to determine ARL15 expression in RASF subsets. ResultsARL15 overexpression induced a pro-inflammatory transcriptional program characterized by upregulation of IL1A, IL1B, IL6, IL8, CXCL1, CXCL10, and CCL20. Gene set enrichment analysis revealed activation of IL6-JAK-STAT, TNF, interferon-response, and KRAS signaling pathways, with suppression of oxidative phosphorylation, lipid metabolism, and mTORC1 signaling. In CIA mice, ARL15 inhibition significantly reduced arthritis severity, inflammatory infiltrates, and joint destruction while preserving cartilage and bone integrity. Serum TNF-, IL-6, and IL-1{beta} levels were markedly decreased following ARL15 blockade. Combination monoclonal antibody treatment demonstrated the greatest therapeutic benefit. scRNA-seq analysis showed broad ARL15 expression across RA fibroblast populations, with enrichment in inflammatory lining and SF subsets. ConclusionsARL15 is a pro-inflammatory regulator of SF activation and arthritis progression. Integrated transcriptomic, single-cell, and in vivo analyses identify ARL15 as a therapeutic target for RA and support further translational development of ARL15 based therapies.

Objective: Clonal hyperexpansion of CD4 T cells is a characteristic feature of rheumatoid arthritis (RA). Equally large T cell clones also arise in physiological ageing or latent viral infection and adopt a replicative senescence programme - a tolerance mechanism that limits immune activation by innate-like reprogramming and proliferative arrest. We aimed to characterise the senescence programme of hyperexpanded CD4 T cell clones in RA and to define their clinical associations. Methods: Hyperexpanded T cell clones were characterised by single-cell RNA and T cell receptor profiling of peripheral T cells from RA patients and healthy donors. Flow cytometric validation was performed in two cross-sectional cohorts (n=15, n=45), paired blood and synovial fluid (n=20) or synovial tissue (n=18) sampling, and a non-interventional study of co-stimulatory blockade with abatacept (n=6). Results: Hyperexpanded CD4 T cell clones exhibited a CCR7-CD27- phenotype and accumulated in RA joints. Their frequency correlated with disease activity and their surface profile was modulated by abatacept, suggesting susceptibility to therapeutic intervention. At the molecular level, hyperexpanded clones converged on a phenotype consistent with replicative senescence, characterised by natural killer (NK) cell-reminiscent cytotoxic reprogramming, loss of co-stimulatory molecules, and reduced translational activity. However, compared with healthy donor counterparts, hyperexpanded RA CD4 T cell clones showed reduced senescence-associated cytotoxic and NK cell markers, and increased IL-7 receptor signalling, indicating attenuated senescence and preserved capacity for homeostatic proliferation. Conclusion: We propose that replicative senescence insufficiently constrains hyperexpanded clones in RA, resulting in sustained antigen reactivity in autoreactive clones and perpetuation of chronic inflammation.

Rheumatoid arthritis (RA) remains incompletely understood, limiting targeted prevention. In this work, genome-wide association study meta-analyses were performed for RA and seropositive RA, comprising approximately one million participants of European ancestry. Eight and six novel genomic risk loci were defined for RA and seropositive RA, and candidate causal genes were identified, highlighting relevant biological pathways, including established immune pathways and estrogen metabolism. Novel disease-specific polygenic risk scores (PRSs) were constructed, enhancing predictive performance over clinical risk factors (incremental C-statistics of 2.7 and 5.1 for RA and seropositive RA, respectively). In parallel, integrating metabolomic data into high-dimensional models enhanced risk stratification over models based on clinical risk factors and genomics, particularly for seropositive RA, where the hazard ratio of the highest decile increased from 4.869 to 5.697. These findings expand the understanding of genetic factors underlying RA and support the value of including PRSs in risk assessment, while suggesting metabolomic integration may further enhance risk stratification, particularly for seropositive RA.

Objectives: To investigate the biological and clinical relevance of knee alignment in osteoarthritis by integrating population-scale imaging, genome-wide association, and functional genetic analyses. Methods: Femorotibial angle was derived from dual-energy X-ray absorptiometry scans in UK Biobank using machine-learning methods. Associations with knee and hip osteoarthritis outcomes were assessed. A genome-wide association study of mean femorotibial angle was performed, followed by fine-mapping and pathway enrichment analyses. Mendelian randomization was used to explore potential causal relationships. Results: Varus alignment was strongly and progressively associated with knee pain, knee osteoarthritis, and total knee replacement (HR 3.42 [95% CI 2.92, 4.02]), with no association observed for hip osteoarthritis. GWAS identified 20 independent loci associated with femorotibial angle, enriched for pathways related to skeletal development, cartilage biology, and endochondral ossification. Post-GWAS analyses demonstrated regulatory effects across fetal and adult joint tissues, supporting life course influences on alignment. Genetic correlation analyses showed shared architecture between femorotibial angle and knee osteoarthritis. Causal analyses suggested that genetic liability to osteoarthritis reduces femorotibial angle ({beta} -0.11 [-0.16, -0.06]), while evidence for an overall causal effect of femorotibial angle on osteoarthritis risk was limited (OR 0.93 [0.79, 1.10]). Conclusions: Knee alignment and susceptibility to knee osteoarthritis are partially genetically determined. At the population level, these genetic determinants support a causal effect of osteoarthritis on knee alignment, whereas evidence for a causal effect of alignment on knee osteoarthritis was limited. Furthermore, this study identifies novel genetic loci linking knee alignment with pathways involved in skeletal development and cartilage biology relevant to osteoarthritis.

ABSTRACT Importance: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE), due to both traditional CVD risk factors and SLE specific factors. Although statins are first-line therapy for primary prevention of CVD in the general population, it is unclear whether statins protect against first time cardiovascular events (CVEs) in patients with SLE. Objective: Determine whether statins are protective in primary prevention of CVEs among patients with SLE. Design, setting, and participants: This cohort study is a retrospective analysis of a well-characterized, prospective cohort of patients with SLE with patient follow-up beginning in 2013. Main outcome and measures: CVEs were defined as the occurrence of myocardial infarction, thrombotic stroke, onset of angina, or coronary bypass procedure. Statin use in the prior year was quantified based on standardized defined daily doses (DDD). Rates of occurrence were compared using pooled logistic regression. A multivariable model was performed to adjust for possible confounders. Results: The analysis was based on 8708 person-years of follow-up from 1396 cohort participants: 1283 (92%) were women, 567 (41%) Black, and 665 (48%) White. Patients were stratified by use of statin within the last year: none, < standard DDD, or [&ge;] standard DDD. The rate of events per 1000 person-years was respectively 5.3, 8.5, and 8.0 (p=0.31) within these 3 groups, suggesting potential lack of protective effect of statin treatment. The rates of CVEs among statin versus non-statin users remained the same after adjusting for and stratifying by total cholesterol level (p=0.18). Significantly higher rates of CVEs occurred among those with body mass index (BMI) 25-30 kg/m^2 (p=0.0066) and those prescribed [&ge;] 10 mg/day of prednisone (p=0.0003). Multivariable analysis also suggested a potential lack of protective effect of statins against CVEs (OR 1.48; 95% CI, 0.79-2.75; p=0.21883) and diabetes mellitus was found to be independently associated with an increased risk for development of CVEs (OR 4.48; 95% CI 1.99-10.08; p=0.00029). Conclusion and Relevance: Among patients with SLE, statin use may not be protective in primary prevention of CVEs, regardless of statin exposure. Prednisone use, history of diabetes mellitus, and elevated BMI were drivers of increased cardiovascular risk in univariate analysis. Diabetes mellitus persisted as an independent risk factor for CVEs in a multivariable model. Our work reinforces findings from clinical trials which have shown no reduction in subclinical measures of atherosclerosis with statin use among patients with SLE, as well as a mechanistic substudy which demonstrated that statins are ineffective in normalizing the pro-atherogenic changes induced by SLE.

1.Cancer-induced bone pain (CIBP) occurs in a majority of patients when primary or metastatic cancer develops within the bone. This pain has a significant impact on quality of life, yet there are limited effective treatment options available. Nerve sprouting is a complex mechanism that has been implicated in CIBP. Netrin-1 is a neuronal guidance molecule that is produced by numerous cell types, including cancer cells. In this study we aimed to determine whether netrin-1 inhibition (with NP137 - a humanized IGg1 monoclonal antibody) could ameliorate nerve sprouting, and nociception by extension, in three models of CIBP - osteosarcoma, metastatic breast cancer, and metastatic prostate cancer. Sustained administration of NP137 failed to produce an anti-nociceptive effect in these models, but a delayed onset was observed in the osteosarcoma model. NP137 did not produce a disease-modifying effect, as micro-computed tomography did not reveal reduced bone destruction in the NP137-treated groups. Additionally, there was no nerve fibre density reduction in any of the groups at the late-stage of the disease, suggesting that nerve sprouting occurs in early- to mid-stage CIBP development. Investigation of NP137 exposure indicated that serum levels of NP137 were comparable between the sham and cancer groups. Our study indicates that netrin-1 may play a role in early-stage CIBP development, but inhibition of this mechanism does not produce robust anti-nociception.

BackgroundOsteoarthritis cartilage contains heterogeneous chondrocyte states, but molecular programs linked to state transitions within human cartilage remain incompletely resolved using public single-cell data. MethodsA retrospective reanalysis was conducted of a public human knee cartilage single-cell RNA sequencing dataset (GSE255460) including 8 osteoarthritis donors and 3 non-osteoarthritis donors (19 samples). Cells underwent sample-wise quality control and doublet removal, followed by batch-corrected clustering, chondrocyte subclustering with marker-based annotation, and trajectory inference using Slingshot. Regulatory chondrocytes were prioritized for osteoarthritis versus control differential expression, with downstream Gene Ontology/KEGG enrichment (Benjamini-Hochberg false discovery rate <0.05) and protein-protein interaction network hub screening. ResultsAfter quality control, 27,036 cells were retained. Chondrocytes formed multiple transcriptional states with branching-like continuous relationships, and regulatory chondrocytes localized near the main manifold and adjacent to multiple inferred branches, consistent with a transition-adjacent state. In regulatory chondrocytes, osteoarthritis versus control differential expression was enriched for collagen-containing extracellular matrix and extracellular matrix organization, endoplasmic reticulum lumen-associated secretory/proteostasis processes, cell-matrix adhesion (including focal adhesion), and transforming growth factor beta/SMAD-related signaling. Protein-protein interaction analysis of regulatory-chondrocyte differential genes identified five high-connectivity hub genes: COL5A1, COL5A2, COL6A1, COL1A2, and COL3A1. ConclusionThis public-dataset reanalysis supports a transition-adjacent regulatory chondrocyte program in osteoarthritis characterized by coordinated extracellular matrix remodeling with concurrent secretory/proteostasis and adhesion-transforming growth factor beta signatures, nominating collagen-network hubs as candidates for downstream validation.

Background: Group A streptococcal (GAS) pharyngitis drives substantial antibiotic prescribing in children. The 10-day standard burdens adherence and prolongs exposure, increasing selective pressure for resistance. Yet, whether shorter courses achieve comparable outcomes remains unresolved. Purpose: To address how the duration of oral antibiotics affects clinical outcomes in children and adolescents with suspected or confirmed GAS pharyngitis. Data Sources: MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL from inception to July 2025. Reviewers also searched reference lists of eligible trials and relevant systematic reviews. Study Selection: Randomized trials enrolling children and adolescents [&le;]18 years with suspected or confirmed GAS pharyngitis comparing different durations of oral antibiotics, or oral antibiotics against placebo or no treatment. Data Extraction: Paired reviewers independently screened records, extracted data, and assessed risk of bias. Data Synthesis: We performed random-effects dose-response meta-analyses with restricted cubic splines and rated the certainty of evidence using GRADE. Forty-five trials enrolling 22,636 participants met eligibility criteria. Across outcomes, low to moderate certainty evidence suggests that 3, 5, and 10 days of antibiotic treatment may produce little to no difference. Moderate certainty evidence supports similar effects of 5 and 10 days on clinical cure, relapse, and adverse events. Evidence comparing 3 and 10 days carries lower certainty. Serious adverse events were rare: no deaths, 4 cases of acute rheumatic fever, and 4 cases of post-streptococcal glomerulonephritis among 776, 8,818, and 9,096 participants, respectively, making clinically important differences across treatment durations unlikely. Limitations: Evidence on 3-day courses came almost exclusively from trials of azithromycin, limiting inference about shorter penicillin regimens. Findings apply most directly to high-income settings. Conclusion: These findings challenge the long-standing 10-day standard for pediatric GAS pharyngitis and show that 5 days of oral antibiotics are likely as effective and safe as 10 days.

Psoriatic disease (PsD) is associated with metabolic dysfunction-associated steatotic liver disease (MASLD), but the hepatic effects of biologic therapies are unclear. We evaluated paired liver MRI and multi-modal immunoprofiling in PsD patients initiating new systemic therapy. COLIPSO is a prospective cohort of adults with moderate-to-severe psoriasis or psoriatic arthritis (PsA) starting a new conventional synthetic or biologic disease-modifying antirheumatic drug (DMARD). Liver MRI was performed at baseline and ~6 months. A subset of participants with PsA underwent peripheral blood flow cytometry and single-cell RNA sequencing (scRNAseq). Primary outcomes were within-subject change in quantitative MRI measures of liver disease activity and fat content (iron-corrected T1 [cT1] and proton density fat fraction [PDFF]). Bayesian models were used. Thirty-five participants (mean age 50 +/- 13 years; 61% male) were followed for ~29 weeks. Baseline disease activity was moderate (mean DAPSA 29) and 40% had MASLD. IL 17 inhibitors (IL-17i) improved PDFF (-1.58 +/- 1.61%) and cT1(-43.6 +/- 52.7ms), whereas TNFi showed little change. Compared with csDMARD, IL 17i improved PDFF (probability of direction [pd] 89%) and cT1 (pd 93%), which was not seen with TNFi. Flow cytometry (n=17) linked baseline gamma delta T-cell and ThGM-CSF T-cell abundance with cT1 and PDFF. scRNAseq highlighted baseline transcriptomic signatures in MAIT cells associated with cT1 and PDFF. Naive T-cell RNA signatures at baseline were associated with MRI improvements. In PsD, only IL-17i were associated with improved liver disease in addition to improving clinical PsD outcomes. T-cell subtypes bridging innate and adaptive immunity were associated with liver disease features.

Nociplastic pain represents a major burden across immune-mediated inflammatory diseases (IMIDs). It is hypothesised, but not yet demonstrated, that peripheral inflammation promotes nociplastic pain by bottom-up sensitisation of the central nervous system (CNS). In rheumatoid arthritis (RA), a prototypic IMID, we used ultra-high field (7T) brain resting-state functional MRI to evaluate whether peripherally targeted anti-inflammatory therapies alter a biomarker of bottom-up CNS sensitisation: inferior parietal lobule (IPL)--insula connectivity. In discovery and replication cohorts, JAK-STAT pathway inhibitors significantly shifted IPL--insula connectivity toward a normalised pattern. This effect was not seen with placebo or anti-TNF therapy. Moreover, after performing an agnostic whole-brain multivariate analysis of functional connectivity change related to JAK-STAT inhibition, the posterior cingulate cortex (PCC) was identified; like the IPL, a major hub of the default mode network (DMN). We then probed the DMN with transcranial magnetic stimulation in an independent RA cohort. Active, but not sham, stimulation altered DMN connectivity and reduced peripheral blood monocyte pSTAT3 function, a surrogate of immune inactivation, suggesting a bi-directional brain-immune circuit. Together, these findings provide the first human experimental evidence that peripheral JAK-STAT pathways contribute to nociplastic pain in IMIDs.

Introduction Complement and coagulation are tightly interconnected systems that contribute to immunothrombosis and can drive inflammatory or thrombotic diseases. Leveraging this relationship and crosstalk we developed a method to functionally evaluate complement-induced coagulation activity using thromboelastometry (thermoelastometry of complement-driven immunothrombosis; TCDI). Methods To study the complement-dependent activation of coagulation, platelet-poor plasma (PPP) from patients was mixed with healthy blood in the presence or absence of the compstatin-based C3 inhibitor Cp40. PPP from healthy controls (n=10), or from patients with antiphospholipid syndrome (APS; n=6), severe COVID-19 (n=13), rheumatoid arthritis (RA; n=7), or synovial fluid (SF) from RA patients, were analyzed for their capacity to induce complement activation in healthy blood. Whole blood coagulation was analyzed by thromboelastometry and complement-driven immunothrombosis was quantified as clotting time (CT) prolongation following Cp40 treatment, expressed as fractional difference percentage (FD%). In parallel, C3a generation was measured by ELISA to monitor the C3 inhibitory activity of Cp40. Results Plasma from patients with APS and COVID-19 induced significant CT prolongation following C3 inhibition by Cp40 and increased FD% values compared with controls, indicating active complement-driven immunothrombosis. Higher TCDI levels were associated with mortality in severe COVID-19. In RA, TCDI positivity was detected in synovial fluid (SF) rather than peripheral plasma. Moreover, TCDI-positive samples treated with Cp40 exhibited significant inhibition of C3a generation, which strongly correlated with FD% values (r=0.67, p=0.0005). Conclusion The TCDI assay may provide a rapid, real-time evaluation of immunothrombotic activity in inflammatory and thrombotic disorders, which could inform timely medical prevention.

BackgroundExtracellular matrix (ECM) remodeling is increasingly recognized as an important component of neuroinflammatory pathology in multiple sclerosis (MS), yet the mechanisms by which CNS cells sense and respond to alterations in their mechanical environment and the spatial across which mechanical changes can influence cellular behavior remain poorly understood. Piezo1 is a mechanosensitive ion channel that regulates cellular responses to mechanical stimuli and has recently emerged as a potential modulator of neuroinflammation. MethodsExperimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 wildtype mice using myelin oligodendrocyte glycoprotein (MOG):35-55. Immunohistochemical analyses were performed in spinal cord gray matter (GM), normal-appearing white matter (NAWM), and white matter lesion (LES) regions to assess ECM remodeling, total Piezo1 expression, and astrocyte-specific Piezo1 expression during acute and chronic EAE stages. Correlations with clinical EAE severity were determined. In parallel, mixed primary murine glial cultures were exposed to substrates of different stiffness and analyzed by transcriptomic profiling to investigate mechanobiological responses in vitro. ResultsECM-associated proteins, including glial fibrillary acidic protein (GFAP), fibronectin-1 and matrix metalloproteinase-3 (MMP3), were regionally upregulated during EAE, indicating widespread tissue remodeling beyond focal inflammatory lesions. Total Piezo1 expression was increased within lesions and transiently elevated in GM, whereas astrocyte-specific Piezo1 remained persistently upregulated during both acute and chronic EAE. Astrocytic Piezo1 expression correlated closely with ECM remodeling and clinical EAE severity, particularly in GM and NAWM. Notably, both total and astrocyte-specific Piezo1 showed stronger associations with clinical disability than classical inflammatory markers. Transcriptomic analysis revealed pronounced stiffness-dependent responses in glial cells, including alterations in extracellular matrix organization, cytokine signaling, cell adhesion, and proliferative pathways. ConclusionsOur findings identify astrocytic Piezo1 as a prominent component of neuroinflammatory tissue remodeling during EAE. The close association of Piezo1 with ECM alterations, clinical disease severity, and stiffness-dependent glial responses supports a link between neuroinflammation and mechanosensory signaling. These results highlight mechanosensation as a potentially important contributor to CNS pathology and establish Piezo1 alteration as a candidate biomarker for neuroinflammatory disease.