RMD Open

Objectives: Juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM) are systemic autoimmune rheumatic diseases (RMDs) with childhood-onset associated with increased risk of damage accumulation and cardiovascular disease (CVD) over the life course. Methods: Damage associated with JSLE and JDM has been assessed using validated outcome measures in a longitudinal single-centre cohort study with long-term follow-up, involving data collected both retrospectively and prospectively. Descriptive statistics, sensitivity and regression analyses have been used to evaluate predictors of damage and CVD-risk. Results: We assessed comparatively a JSLE cohort (n=76), with a mean age of 24.3 +/- 4.2 years and a JDM cohort (n=79) with a mean 20.1 +/-5.0 years (p<0.001), with matched duration of follow-up (10.0 +/- 4.2 vs. 11.0 +/- 5.1, respectively, p=0.68). Traditional CVD-risk factors, including hypertension (p=0.02), dyslipidaemia (p=0.0005), and higher total cholesterol (p=0.01) and LDL-cholesterol (p=0.02) levels at the last assessment were higher in JSLE vs. JDM. Over the disease course, 39 (51.3%) AYA with JSLE vs. 47 (59.4%) AYA with JDM accumulated damage (p=0.307), which was independently predicted by the body mass index in both cohorts (p=0.038 and p=0.026, respectively). The PDAY score was the only tool able to stratify AYA based on CVD-risk (median = 5 (4-13) points in JSLE vs. 0 (0-3) points in JDM, p=0.0001), as all the adult CVD-risk scores were very low in both cohorts. Conclusions: This is the first comparative evaluation of JSLE vs. JDM in adulthood, which highlighted increased damage burden and CVD-risk in JSLE that warrants further investigation.

BackgroundAntiphospholipid syndrome (APS) complicating pregnancy carries significant obstetric morbidity. Secondary APS, arising in the context of systemic autoimmune disease, may confer worse outcomes than primary APS due to additional inflammatory and immunological mechanisms. This study aimed to compare pregnancy outcomes between autoimmune rheumatic disease-associated secondary APS and primary APS managed at a quaternary care hospital in Chennai. MethodsA retrospective observational study analysed 82 pregnancies (secondary APS n=46; primary APS n=36) managed between January 2025 and March 2026. Outcomes including live birth rate, miscarriage, fetal death, preterm birth, pre-eclampsia, and intrauterine growth restriction (IUGR) were compared using chi-square test, Fisher exact test, and independent t-test. Multivariable logistic regression identified independent predictors of adverse outcomes. ResultsLive birth rate was significantly lower in secondary APS compared to primary APS (69.6% vs 86.1%; p=0.048). Triple antiphospholipid antibody positivity was more prevalent in secondary APS (47.8% vs 25.0%; p=0.032). On multivariable analysis, secondary APS (aOR 2.71; 95% CI 1.08-6.81; p=0.033), triple positivity (aOR 3.45; 95% CI 1.39-8.57; p=0.007), and lupus anticoagulant (aOR 2.62; 95% CI 1.01-6.76; p=0.047) independently predicted adverse outcomes. Hydroxychloroquine (aOR 0.39; p=0.038) and combination aspirin plus low-molecular-weight heparin (aOR 0.31; p=0.019) were independently protective. ConclusionSecondary APS is associated with significantly worse pregnancy outcomes than primary APS. Triple antiphospholipid positivity and lupus anticoagulant independently increase obstetric risk. Hydroxychloroquine and combination antithrombotic therapy significantly improve live birth rates. Early rheumatology referral and multidisciplinary obstetric management are essential.

Background: Rheumatoid arthritis is a chronic inflammatory disorder in which exercise is increasingly recognized as an important component of long-term management. Yet, most reviews in this field evaluate the effects of single exercise modalities, while bibliometric studies primarily identify publication trends and research hotspots without showing whether highly visible themes also represent coherent and comparatively mature evidence domains. Methods: We searched the Web of Science Core Collection for publications on exercise interventions in rheumatoid arthritis from 2016 to 2025. CiteSpace (6.4.1) and VOSviewer (1.6.20) were used to analyze publication growth, collaboration networks, keyword co-occurrence, thematic clusters, and burst terms. We then applied structured content coding in Excel 2021 to classify exercise modalities, outcome domains, and mechanistic topics, and integrated these findings into a visual evidence-distribution profile. Results: Publication output increased from 16 studies in 2016 to 37 in 2025. The United States led in productivity, Karolinska Institutet was the most prolific institution, and Kitas, Duda, and Metsios were among the most influential authors. Keyword analyses identified a shift from function- and disease-focused themes toward quality of life, risk factors, and comprehensive management. The integrated analysis revealed an uneven evidence structure: aerobic and resistance training accounted for the most concentrated and recurrently studied exercise-outcome domains, whereas mind-body and water-based interventions formed visible but methodologically heterogeneous clusters. Newer modalities, including blood flow restriction training and high-intensity interval training, showed growing prominence but limited depth of evidence. Conclusion:Exercise research in rheumatoid arthritis has evolved toward broader and more patient-centered management targets, but the field remains imbalanced across intervention types and outcome domains. This study demonstrates the value of combining bibliometric mapping with structured content analysis to distinguish thematic visibility from evidentiary coherence in heterogeneous intervention fields and may offer a transferable analytical framework for research evaluation beyond rheumatoid arthritis. Keywords: Rheumatoid Arthritis; Exercise Intervention; Bibliometrics; Content Analysis; Rehabilitation

Background Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which can lead to progressive disability and damage to multiple organs. Obesity is associated with higher disease activity in RA and inadequate long-term outcomes, so better understanding of mechanisms linking adiposity to immune dysregulation might help to refine optimal treatments. Monocytes are important contributors to immune activation in RA through antigen presentation and costimulatory signaling. We hypothesized that adiposity enhances monocyte costimulatory programming in RA, thereby promoting adaptive immune activation. Methods Single-cell RNA sequencing was performed using the 10x Genomics Flex platform on purified circulating monocytes from 31 donors (16 RA participants fulfilling 2010 ACR/EULAR classification criteria and 15 non-RA controls) generating transcriptomic profiles for approximately 135,599 monocytes. Donor-level pathway enrichment scores were calculated for predefined immune activation pathways including antigen processing and presentation, interferon signaling, and regulation of T-cell costimulation. Analyses were performed at the donor level to avoid cell-level pseudoreplication. Associations with disease status and body mass index were evaluated using factorial linear models and Spearman correlation analyses. Results Single-cell transcriptomic profiling identified classical, intermediate-like, non-classical, and interferon-responsive monocyte populations. RA was associated with enrichment of antigen processing and presentation programs in circulating monocytes (p=0.0106), indicating a primed antigen-presenting state. In contrast, regulation of T-cell costimulation pathway enrichment did not differ by RA status alone. However, within RA participants, higher BMI was associated with increased enrichment of monocyte T-cell costimulatory pathways (Spearman {rho}=0.56, p=0.0248), unlike in non-RA controls. Gene-level analyses demonstrated strong baseline expression of CD86, while ICOSLG and TNFSF4 transcripts were expressed at low levels overall, consistent with inducible costimulatory signaling programs. Conclusions These findings support a model in which metabolic dysregulation amplifies monocyte-mediated immune activation and may contribute to worsened disease outcomes in RA.

ObjectivesPatients with osteoarthritis (OA) affecting multiple joints have poorer health outcomes than those without, yet most research examines isolated joints, leaving a gap in multi-joint disease. This study aimed to describe radiographically defined hip (rHOA) and knee OA (rKOA) within UK Biobank (UKB), exploring interrelationships across joints, and associations with joint pain, obesity, race and deprivation. MethodsAutomated machine learning was applied to left and right hip and knee dual-energy X-ray absorptiometry scans. Radiographic OA (rOA) was defined as custom grades [&ge;]2. Joint pain was assessed through self-reported questionnaires. Descriptive statistics summarised the population characteristics. Logistic regression models examined bilateral and cross-joint associations, as well as associations with joint pain. Adjustments were made for age, sex, race, height, weight and deprivation. Other models examined the associations between body size and OA. ResultsAmong 59,475 individuals (mean age 65 years; 52.8% female), rHOA prevalence was 4,098 (6.9%)) and 4,841 (8.1%) for the right and left joints, respectively. The corresponding estimates for rKOA were 3,750 (6.3%) and 4,220 (7.1%). Overall, increasing grades of rOA and number of joints affected were more strongly associated with joint pain. Regarding joint-interrelationships, bilateral associations were stronger at the knee, whereas cross-joint associations (hip-knee) were weaker. Associations with BMI and height differed between the hip and knee. ConclusionsRadiographic hip and knee OA exhibit distinct patterns of interrelationship, associations with symptoms and risk factors, suggesting heterogeneity in disease process and the need for joint-specific treatment. Key MessagesO_ST_ABSWhat is already known on this topic?C_ST_ABSO_LIOsteoarthritis (OA) commonly affects the hip and knee and is associated with pain and disability, with recognised risk factors such as age, obesity and deprivation. C_LIO_LIIncreasing interest in multi-joint OA challenges the traditional concept of lower-limb OA as a monoarthritis, but most research examines joints in isolation. C_LIO_LIGenetic evidence suggests that hip and knee OA may differ in underlying mechanisms, yet population-scale comparisons are limited. C_LI What this study adds?O_LIAmong 59,574 individuals, this study identifies that radiographic OA captures structurally and clinically relevant disease with increasing severity and greater number of joints affected, positively associated with chronic joint pain. C_LIO_LIRadiographic hip and knee OA demonstrated strong bilateral but weaker cross-joint associations, indicating preferential within-joint symmetry. C_LIO_LIRisk factors differed by anatomical site with BMI and weight strongly associated with knee OA and weakly associated with hip OA. Height showed the opposite associations. C_LI How this study might affect research, practice or policy?O_LIThese findings support that hip and knee OA may partially represent different disease processes rather than a single condition. C_LIO_LIClinical practice should consider cumulative joint involvement and joint-specific risk factors. C_LIO_LIFuture research should consider the development of more targeted treatment to prevent multi-joint progression. C_LI

BackgroundExcessive accumulation of fibrillar collagen causes pathological scarring and fibrosis. A promising anti-fibrotic strategy targets the extracellular assembly of collagen fibrils rather than intracellular synthesis pathways. We previously developed a chimeric monoclonal antibody targeting the C-terminal telopeptide of the 2(I) chain of human collagen I that effectively disrupts fibrillogenesis. This study details the engineering of a humanized antibody variant optimized for therapeutic application, augmented with a collagen-binding peptide (CBP) to enhance targeted retention in fibrotic tissues. MethodsA humanized ACA was engineered by in silico homology modeling, complementarity-determining region grafting, and sequence optimization to eliminate chemical liabilities. Variants were expressed in mammalian cells and evaluated for binding kinetics and specificity. To improve spatial localization, the CBP was fused to the antibody. The lead variant was assessed for in vitro cytotoxicity, matrix retention, and in vivo efficacy using a rabbit model of post-traumatic knee arthrofibrosis. ResultsThe humanized ACA variants maintained high specificity and affinity for the 2Ct target domain. Fusing the CBP to the C-terminus of the light chain (C-cbpACA) successfully enhanced matrix retention without compromising target engagement or causing cellular toxicity. In the rabbit arthrofibrosis model, intra-articular C-cbpACA delivery significantly reduced flexion contracture and decreased total collagen deposition in the joint capsule compared to untreated controls. ConclusionWe successfully engineered a clinically viable, humanized, and matrix-targeted anti-fibrotic antibody that specifically inhibited extracellular collagen assembly and exhibited enhanced localization within fibrotic tissues. This construct represents a promising therapeutic strategy for mitigating pathological scarring and improving post-traumatic functional outcomes.

Introduction Knee pain is a highly prevalent condition in the general population and is more common than knee osteoarthritis. Population-based evidence linking metabolic dysfunction to knee pain remains limited, and data on sex-specific effects are scarce. Therefore, we examined sex-specific associations between metabolic dysregulation and knee pain in a population-based cohort. Method We analyzed data from a population-based cohort of 1,512 adults (mean age 37.2 years at baseline), of whom 250 completed follow-up after a mean of 9.4 years. Metabolic dysfunction was assessed using a continuous MetS severity score (cMetS) derived from waist circumference, triglycerides, HDL cholesterol, fasting glucose, and systolic blood pressure. Knee pain at follow-up was defined using a combined measure based on a standardized question and a body manikin. Logistic regression models were used to examine associations between baseline cMetS and knee pain, including interaction analyses by sex. Results At follow-up, 28.5% of participants reported knee pain. Higher baseline cMetS was associated with increased odds of knee pain in males (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.17-1.69) but not in females (OR 0.94, 95% CI 0.84-1.07), with evidence of interaction by sex (interaction P < 0.001). Findings were consistent across sensitivity analyses. Conclusions These results indicate that metabolic dysfunction is associated with knee pain in males but not in females, suggesting sex-specific mechanisms linking metabolic dysfunction and knee pain.

ObjectiveEnhanced glycolysis is a metabolic hallmark of chondrocytes in osteoarthritis (OA); however, the roles of the glycolytic rate-limiting enzyme hexokinase 2 (HK2) in cartilage remain poorly understood. MethodsPharmacological approach (3-bromopyruvate (3-BrPA) treatment) and mice model involving HK2 knockout in Col2a1-expressing chondrocytes are utilized to access the impact of HK2 blockage on cartilage ex vivo and in vivo. The in vivo effects of HK2 inhibition on OA progression were evaluated using a destabilization of the medial meniscus (DMM)-induced OA mouse model, through both intra-articular 3-BrPA administration and chondrocyte HK2 deletion. Additionally, we analyzed published single-cell RNA sequencing (scRNA-seq) datasets from human articular cartilage and integrated these with bulk RNA-seq data from HK2-deficient chondrocytes to characterize HK2 expression features across conditions. ResultsBoth pharmacological inhibition and genetic deletion of HK2 impair cartilage formation ex vivo. Bulk RNA-seq analysis and ex vivo studies demonstrated a promoted ossification-like process due to HK2 ablation in chondrocytes. Through pseudotime analysis of published single-cell RNA sequencing (scRNA-seq) datasets from human articular cartilages, we further identified that HK2 is differentially expressed across conditions, with a feature of a relatively high expression level at terminal stages of chondrocyte differentiation in the context of OA. We next confirmed HK2 deficiency in chondrocytes significantly exacerbated OA progression but having no impact on skeletal development in mice. ConclusionsHK2 plays a critical role in maintaining cartilage health, likely through the regulation of calcification, thereby highlighting the potential risks associated with targeting glycolytic enzymes as a therapeutic strategy for OA.

ObjectiveRecently, alternatives to animal testing, such as new approach methodologies, are being developed in the orthopedic research field; animal models still provide valuable insights into the pathogenesis of knee osteoarthritis (OA). However, commonly used models develop OA much more rapidly and severely than those observed in human patients. We aimed to develop a novel murine model that closely mimics the slow progression of human OA with posterior Cruciate ligament (PCL) rupture. Design12-week-old C57BL/6 mice were induced to PCL-rupture (PCL-R) by manually applying an external tibial posterior translation force. We analyzed joint kinematics, histological observations, and bone structure to confirm the absence of concurrent injury on day 0. Then, joint stability and the pathophysiological progression of knee OA were analyzed at 8, 16, and 34 weeks post-PCL-R. The destabilized medial meniscus (DMM) model was also analyzed to compare the OA progression. ResultsNon-invasive PCL-R intervention induced the complete rupture in the central region of PCL without concurrent injury. The PCL-R group showed larger posterior tibial deviation than the INTACT (P=0.008). Regarding the range of motion in the PCL-R group, there was no limitation in range of motion on day 0, but extension limitations occurred at weeks 16 and 34 weeks. Histologically, articular cartilage degeneration in PCL-R was milder than DMM. In the subchondral bone, micro-CT reconstruction images indicated that, compared with the INTACT group, the DMM group observed progressive subchondral bone formation from 16 weeks post-surgery. In contrast, the PCLR group maintained the subchondral bone structure even at 34 weeks. ConclusionsPCL-R model induced mild abnormal mechanical stress depending on posterior instability, and cartilage degeneration occurred more slowly in this model than in DMM models.

BackgroundCalcific aortic valve disease (CAVD) is the most common valvular heart disease in developed countries, yet no pharmacological therapy is available to slow or halt its progression. CAVD is driven by progressive calcification of aortic valve leaflets, in which myeloid cells play a central role. While macrophages have been implicated in CAVD pathogenesis, the contribution of their precursors, monocytes, remains poorly understood. We hypothesized that circulating monocytes acquire a pro-calcific and pro-inflammatory phenotype contributing to valve remodelling and CAVD progression. MethodsWe profiled circulating CD14+ monocytes from healthy volunteers (Vol), patients with CAVD, and without CAVD (NCAVD). Peripheral blood mononuclear cells (PBMCs) were isolated, and monocyte subpopulations were phenotyped by flow cytometry. Transcriptome profiling by RNA sequencing identified disease-associated gene signatures, which were validated by RT-qPCR. The CD14+ monocyte secretome was analysed using multiplex assays. Functional ability of CAVD-derived CD14+ monocytes to induce myofibroblastic transdifferentiation (MT) and osteoblastic differentiation (OD) of human valvular interstitial cells (VICS) was evaluated by immunocytochemistry and quantitative o-cresolphthalein complexone assays. ResultsIn PBMCs, CAVD monocytes displayed a subpopulation shift, with an increased proportion of CD14CD16- classical monocytes and a reduced CD14CD16 non-classical monocyte levels. In CD14+ monocytes, transcriptomic analysis revealed upregulation of inflammation-related (PDK4) and calcification-related (ATP2B1) genes, alongside downregulation of immunomodulatory genes (DDR1, IKBKE). Secretome analysis showed reduced production of immunomodulatory and anti-osteoblastogenic cytokines (IL-4, CCL3) while promoting gene expression of factors promoting MT and OD in VICS. These alterations were associated with a marked monocyte-induced increase in SMA and OPN expression in VICS and a two-fold increase in calcification. ConclusionWe demonstrate for the first time that circulating monocytes from patients with CAVD exhibit enhanced pro-inflammatory and pro-calcific properties that may contribute to CAVD progression. Additionally, we identify dysregulated gene sets within these monocytes that represent potential novel therapeutic targets for CAVD.

BackgroundJuvenile idiopathic arthritis (JIA) shows recognised sex differences, but their impact on treatment and early outcomes remains uncertain. This study assesses sex-specific patterns in onset, phenotype, treatment timing, and short- and medium-term outcomes in JIA. MethodsData were drawn from the Childhood Arthritis Prospective Study (CAPS), a UK multicentre inception cohort of 1,789 children presenting with a new episode of arthritis. Demographics, subtype distribution, clinical features, and 6- and 12-month outcomes were stratified by sex. Cox, Kaplan-Meier, and linear regression models assessed associations between sex and treatment initiation and 12-month outcomes. ResultsThe cohort was predominantly female (64.3%), with a median age at symptom onset of 6.8 years. Girls were younger than boys at onset (6.1 vs 7.8 years, p<0.0001) and diagnosis (7.0 vs 9.1 years, p<0.0001) and demonstrated a distinct bimodal age distribution. Diagnostic delay was short and comparable (median 4.4 months, p=0.8932). At diagnosis, girls had slightly higher active joint counts (p=0.0080, while inflammatory markers were similar except in psoriatic JIA, where females had higher ESR and CRP. After adjustment, sex was not associated with time to methotrexate (HR 0.89, 95% CI 0.74-1.06) or biologic initiation (HR 0.91, 95% CI 0.72-1.16). Outcomes at 6- and 12-month were largely comparable, with only ESR showing a modest male-favoured improvement at 12 months (p=0.0480). ConclusionsSex shaped age at onset and subtype distribution but did not independently influence treatment timing or early outcomes, underscoring the value of sex-aware analyses while confirming broadly comparable short-term trajectories in JIA. Evidence before this studyRecent evidence on sex effects in JIA is genuinely mixed: several cohorts have reported that girls, despite more severe onset, show greater resolution of objective inflammation, while a newer, large network analysis found females had poorer outcomes across composite disease activity and pain, pointing to potential inequities or phenotype-driven differences. In parallel, boys, especially in enthesitis-related arthritis (ERA), often exhibit more persistent activity and risk of damage. Overall, the picture is controversial: sex appears to shape biology, trajectory, and patient-reported burden in different ways across subtypes and settings, reinforcing the need for sex-stratified analyses, careful adjustment for confounders, and precision approaches that integrate biomarkers, subtype, and social context in JIA care. Added value of this studyThe study establishes that, although sex is closely linked to JIA subtype distribution and baseline clinical features, it does not independently determine the timing of methotrexate or biologic initiation within a UK inception cohort. By analysing one of Europes largest prospective multicentre datasets, it provides strong evidence that treatment decisions appear to be guided by disease characteristics rather than demographic bias. Within the context of the UK National Health Service (NHS), where universal access to paediatric rheumatology care is a core principle, this study provides important epidemiological evidence on sex and equity in JIA. Although clear sex differences were observed in age at onset, subtype distribution, and certain diagnostic features, these did not translate into disparities in treatment timing or medium-term disease burden. The absence of sex-based differences in 6 and 12-month outcomes, despite variation in baseline presentation, suggests that the NHS model of coordinated, guideline-driven care may help buffer against inequities that might otherwise emerge in systems with variable access. These findings reinforce the value of population-based cohorts in evaluating equity within healthcare delivery and highlight that, in this setting, sex does not appear to drive differential treatment or short-term clinical trajectories. Implications of all the available evidence.This study underscores sex as an important biological variable in JIA. Although treatment initiation was equitable and disease-driven, baseline phenotype differences and isolated effects on 12-month outcomes highlight how sex interacts with JIA subtype and initial disease burden. Prior work shows that females often present earlier with higher inflammatory burden, while males are more frequently affected by ERA, a subtype linked to treatment resistance and poorer long-term outcomes. Yet published findings remain inconsistent, with some cohorts reporting better resolution of inflammation in females and others suggesting poorer outcomes. Our findings suggest that coordinated and guideline-driven care may minimise sex-related disparities in JIA, even when underlying biological or phenotypic differences exist. The comparable medium-term trajectories observed across sexes support equitable paediatric rheumatology care in the UK and highlight the need to continue monitoring for structural or access-related inequities beyond clinical measures.

BackgroundBiologics and Janus kinase (JAK) inhibitors carry specific risks for Ankylosing Spondylitis patients at risk of tuberculosis infection or those with contraindications such as a history of cancer, there is an urgent need to explore safe and effective alternative treatment options. AimsTo evaluate the efficacy and safety of Iguratimod combined with Yunke injection in the treatment of ankylosing spondylitis at risk of tuberculosis infection or those with a history of cancer. Study DesignRetrospective cohort study. MethodsA retrospective study was conducted on 48 patients with ankylosing spondylitis who had received treatment over the past 3 years and had a history of tuberculosis infection or malignancy. Their treatment regimens and therapeutic outcomes were analyzed, with particular attention to the progression of tuberculosis and malignancy. ResultsThere was 30 patients receiving Iguratimod combined with Yunke injection treatment, and non-steroidal anti-inflammatory drugs (NSAIDs) were added when pain was severe,referred to as the observation group; 18 patients took Iguratimod and NSAIDs, referred to as the contral group. After treatment of 24 months, both groups showed significant improvements in Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Functional Index (BASFI), modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), Erythrocyte Sedimentation Rate (ESR), and C-Reactive Protein (CRP), and overall levels could achieve low disease activity. However, the improvement of observation groupin was better than that in the control group, P<0.05. Moreover, the use of NSAIDs in the observation group was significantly less than that in the control group, P<0.001. ConclusionThis study shows that Iguratimod combined with Yunke injection has good efficacy in patients with ankylosing spondylitis who cannot use biologics or JAK inhibitors, not only alleviating pain and morning stiffness but also slowing radiographic progression and reducing the dose of NSAIDs. The combination has a synergistic effect and does not increase adverse reactions. This therapy provides a novel option for patients with specific ankylosing spondylitis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes joint destruction along with extra-articular morbidity and early mortality. Abatacept (CTLA-4 Ig), a blocker of lymphocyte co-stimulation, has become a well-accepted biologic treatment with proven efficacy in established-RA and for preventing disease onset in predisposed individuals. To investigate the immunologic implications of abatacept treatment, we conducted a prospective, open-label trial with multi-omic single-cell analyses of lymphocytes and BCR repertoire profiling at predefined intervals. Treatment-induced low-disease activity correlated with coordinated depletion of circulating peripheral helper cells (Tph), late-activated naive cells (late-aNAV), and of CD27-IgD- (Double negative, DN) Zeb2+CD11c+ T-box transcription factor 21 (Tbet+) DN2 unconventional memory B cells, implicated in the tertiary lymphoid structures responsible for the propagation of pathologic autoimmune responses and joint destruction. Among B-cell subsets, DN2 had the greatest representation of molecular machinery for antigen-uptake, processing, and presentation. Among memory B-cell subsets, DN2 had the lowest representation of somatically generated N-glycosylation sites and somatic hypermutation. Yet abatacept induced DN2 cells to express elevated CXCR4 levels, which normalized upon drug withdrawal, suggesting that abatacept treatment may cause these cells to traffic out of pathologic synovial infiltrates. In conclusion, we have documented that abatacept affects the circulating immune cellular drivers of disease activity, Tph, late-aNAV and DN2. Therapeutic depletion of these pathologic lymphocyte subsets is associated with clinical benefits that can persist after therapy cessation. Hence, levels of these subsets may serve as surrogates for the overall burden of disease and potential response to abatacept therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/26348386v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@b44131org.highwire.dtl.DTLVardef@241f4eorg.highwire.dtl.DTLVardef@18361f6org.highwire.dtl.DTLVardef@9470b7_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryMulti-omics analyses showed costimulatory blockade depletes trafficking DN2 B cells and Tph cells that correlates with rheumatoid disease response.

BackgroundChildren with juvenile idiopathic arthritis (JIA) are reported to exhibit increased rates of symptoms affecting emotional regulation and behavior. However, underlying biological mechanisms remain unclear. Neuroinflammation in the central nervous system (CNS) can be triggered by peripheral immune effects and may contribute to these observations. In this study, we aimed to investigate if neurobiological alterations are present in systemic JIA (sJIA), and if CNS neuroinflammation occurs during arthritis, and to explore the potential mechanisms involved. MethodsPlasma samples from patients with active sJIA (n = 16) and sex- and age-matched healthy controls (HCs, n = 16), together with paired samples from the same sJIA patients during inactive disease (n = 12), were analyzed using Olink proteomics to determine the peripheral neurobiological and inflammation protein profiles. Clinical data was retrieved from the Swedish Pediatric Rheumatology Register and medical charts. CNS Neuroinflammatory responses and underlying mechanisms were further explored through in vivo and in vitro experiments. FindingsActive sJIA patients exhibited altered neurobiological protein profiles compared with HCs. These alterations correlated with higher scores of pain and life impact in patients, suggesting that the altered profiles may reflect neurofunctional changes in the patients. Notably, the neurobiological protein profile remained altered even during the inactive phase of the disease. In chronic arthritic mice, microglial activation and impaired neurogenesis were observed in hippocampus, with no significant cortical changes. RNA-seq analysis implicated mitochondrial dysfunction and oxidative stress in mediating neuroinflammation during chronic arthritis in mice. Heme oxygenase 2 (HMOX2) was identified as a peripheral biomarker indicating hippocampal microglia activation. Combined neurobiological and inflammation profiling in sJIA patients implicated Interleukin-6 (IL-6) and Interleukin-18 (IL-18) as key drivers of hippocampal microglia activation during arthritis. InterpretationChronic arthritis is associated with neuroinflammation and altered neurobiological protein profiles in sJIA. HMOX2 emerges as a promising plasma biomarker of CNS changes. IL-6 and especially IL-18 are indicated as key drivers of neuroinflammatory processes. These findings offer insights for clinical monitoring and targeted therapies. FundingThis study was funded by grants from the Swedish Research Council and The Swedish Rheumatism Association. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSChildren with juvenile idiopathic arthritis (JIA) have increased rates of emotional and behavioral disturbances compared with healthy peers. Systemic inflammation and chronic arthritis are suspected to affect the central nervous system, but biological mechanisms in systemic JIA (sJIA) are poorly understood. Added value of this studyIn this study, we demonstrate patients with sJIA have a distinct plasma neurobiological protein profile compared with healthy controls, which correlate with higher pain and life impact scores. In chronic arthritic mice, hippocampal microglial activation, impaired neurogenesis, and mitochondrial dysfunction with oxidative stress are presented. By combining patient and mouse data, we identify heme oxygenase 2 (HMOX2) as a candidate plasma biomarker of hippocampal neuroinflammation and implicate IL-6, and especially IL-18, as key mediators linking chronic arthritis to neurobiological changes. Implications of all the available evidenceThis study provides molecular evidence that neurobiological alterations in sJIA patients and supports incorporating neurobiological and neuropsychiatric monitoring into the clinical follow-up of children with sJIA. We highlight the mechanistic targets and measurable biomarkers (e.g. HMOX2) for future studies and trials aiming to modulate neuroinflammation in chronic arthritis. This study may inform the development of personalized treatment strategies, including IL-18-directed therapies, for patients at risk of neurological or psychosocial complications.

Background: immune dysregulation underlies cardiovascular risk excess in systemic autoimmune diseases, such as rheumatoid arthritis (RA) and Sjogren disease (SjD). However, exact mediators are unknown. Regulatory autoantibodies targeting G protein coupled receptors, including CXCR3, have emerged as modulators of immune and vascular homeostasis, but their role in autoimmunity remains ill defined. Our aim was to evaluate antiCXCR3 levels in systemic autoimmunity and their potential value as biomarkers. Methods: antiCXCR3 IgG serum levels were quantified in early RA (n=84), clinically suspect arthralgia (n=12), and controls (n=65). Established RA (n=103) and SjD (n=44) were recruited for validation. Atherosclerosis was assessed by carotid ultrasound. Cytokines were measured by multiplex immunoassays. Cardiometabolic related proteins were evaluated using high-throughput targeted proteomics. Publicly available datasets were used for validation. Results: antiCXCR3 antibodies were significantly reduced in early RA and arthralgia compared with controls, independently of disease activity, autoantibodies, or systemic inflammation. This finding was confirmed in validation cohorts. AntiCXCR3 were negatively associated with good therapeutic outcomes upon csDMARD at 6 and 12 months. Lower anti-CXCR3 levels were independently associated with atherosclerosis occurrence and extent across conditions. Incorporating antiCXCR3 into mSCORE improved risk stratification. AntiCXCR3 were related to proteomic signatures linked to immune activation and to apoptosis, chemotaxis, and cell adhesion in an atherosclerosis dependent manner. Transcriptomic analyses indicated compartment specific CXCR3 dysregulation. Conclusion: reduced antiCXCR3 antibodies represent a shared hallmark bridging systemic autoimmunity and atherosclerosis burden, shaping our understanding on the regulatory role of antibodies at the vascular immune interface. Clinical translation of anti-CXCR3 antibodies hold promise to improve risk stratification.

Objective: The onset of juvenile idiopathic arthritis (JIA) in the early years ([&le;]5 years) may negatively impact movement skill (encompassing related concepts of gross motor skills, fundamental movement skills, and functional ability) development. Few studies have explored the perceptions and needs of parents and physiotherapists towards children's difficulty with these movement skills, essential to identify potential areas for added support. The objective of this study is to understand the perceptions of physiotherapists and parents towards movement skills of children with JIA. Methods: Seventeen parents and 24 physiotherapists completed an online questionnaire consisting of multiple choice and open-ended questions about the movement skills of young children with JIA. Demographic and multiple choice questions were quantitively analysed using descriptive statistics. Open-ended responses were analyzed using qualitative conventional content analysis. Results: About half (47%) of parents perceived their children to have movement difficulties, and 75% of physiotherapists described the movement skills of children with JIA as worse than other children of the same age. Our qualitative analysis revealed three general themes including: functional task difficulties; clinical variability in movement skills; and psychosocial components of movement skill difficulties. Conclusion: This study provides an analysis of perceptions of physiotherapists and parents towards the movement skills of young children with JIA. A significant proportion of parents and physiotherapists identify movement difficulties among children with JIA that impact daily life. Future interventions co-designed with both parents and care providers targeting movement skills are needed.

BackgroundPain is one of the most prevalent and distressing symptoms in juvenile idiopathic arthritis (JIA) and often persists despite treatment. Damage-associated molecular patterns (DAMPs), such as high mobility group box 1 (HMGB1) and S100A8/A9, have been implicated in inflammatory activation and nociceptive sensitization, but their associations with pain are not fully characterized in JIA. MethodsPlasma and paired synovial fluid (SF) samples were obtained from patients with oligoarticular and polyarticular JIA from the Juvenile Arthritis Biobank (JABBA). A discovery cohort (n = 79) was used to investigate associations between biomarkers and pain, and these associations were subsequently examined in a validation cohort (n = 38). Levels of HMGB1, S100A8/A9, IL-6, IL-8, C2C, and TRAP5b were measured using ELISA. Associations between biomarkers and patient-reported pain scores were assessed using multivariable linear regression analyses. ResultsPlasma and SF levels of most biomarkers did not show significant correlations, except for TRAP5b, which demonstrated a moderate correlation. In the discovery cohort, as multivariable linear regression analyses, both CRP and SF HMGB1 ({beta} = 1.14, 95% CI: 0.21-2.08; {beta} = 1.54, 95% CI: 0.06-3.01 respectively in fully adjusted model) were independently associated with higher pain scores. SF S100A8/A9 ({beta} = 1.00, 95% CI: 0.10-1.89) was additionally associated with pain in fully adjusted models. Sensitivity analyses confirmed the robustness of these findings. These associations were further supported in the validation cohort. ConclusionsPain in JIA is associated with both systemic CRP and local alarmin markers, with SF HMGB1 showing a particularly robust association. These findings highlight the importance of local joint HMGB1 in pain mechanisms and suggest a potential role for DAMP-mediated pathways in persistent pain in JIA.

Abstract Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with complex and incompletely understood molecular mechanisms. Understanding circulating proteins associated with RA may improve understanding of disease biology and clarify its pathological links with cardiometabolic comorbidities. Methods A proteome-wide two-sample Mendelian randomisation (MR) drug target analysis was conducted using plasma proteins measured in 54,219 participants from the UK Biobank Pharma Proteomics Project as exposures and RA and cardiometabolic diseases as the outcomes. Summary statistics for RA included 53,663 cases and 1,070,200 controls. Colocalisation analysis was performed to confirm shared single causal variants and prioritise RA proteins supported by both MR and colocalisation. The prioritised proteins were then evaluated in the Accelerating Medicines Partnership RA Phase II synovial single-cell dataset for cell-type expression patterns. Druggability was then assessed followed by analysis of genetic overlap between RA-associated proteins and cardiometabolic diseases. Results 37 plasma proteins had a causal effect on RA risk, supported by combined evidence from MR and conditional colocalisation. In synovial tissue, TPPP3, RARRES2, AKAP12, and GGT5 were predominantly expressed in stromal and endothelial cell clusters. Druggability assessment identified IFNGR2, IL6R, CD40, and FCGR2B as Tier 1 targets. However, several biologically relevant proteins, including RARRES2, AKAP12, TPPP3, and SNX2, had limited available druggability data. Genetic overlap analysis demonstrated shared protein signals between RA and cardiovascular diseases, including overlap of RARRES2 and TPPP3 with coronary artery disease (CAD) and FCGR2B with atrial fibrillation (AF). To approximate the therapeutic effect of target inhibition, the direction of effect estimates for proteins showing overlap between RA-CAD and RA-AF was reversed. Conclusion This study identified circulating proteins involved in RA pathogenesis and reveals shared mechanisms between RA and cardiovascular diseases. While some proteins showed clear translational potential targets, several prioritised proteins had limited available druggability information and could not be confidently classified. Addressing these gaps may help identify new targets relevant to RA management. Future work should also use phenome-wide MR studies to evaluate potential on-target adverse effects of protein inhibition across RA-CAD and RA-AF.

Background. A substantial minority (~20%) of patients fail to achieve meaningful pain reduction following surgery intended to relieve pain. Risk is elevated in patients with nociplastic pain features, but available self-report measures were not designed for pre-surgical screening. We aimed to develop a brief, data- driven screener for poor analgesic response to surgery. Methods. Participants were recruited from tertiary orthopedic and chronic pelvic pain clinics. Total hip arthroplasty participants had Kellgren-Lawrence grades III-IV with hip pain greater than or equal to 1 year; hysterectomy participants had chronic pelvic pain greater than or equal to 6 months. The primary outcome was a 50% reduction in worst pain at six months. Items were selected via elastic net regression with k-fold cross-validation from 68 candidates. Results. Of 428 participants (81% female; mean age 51), 35% failed to achieve a 50% pain reduction. The resulting 11-item screener - the GenerAlized sensory sensitivity for sUrGical rEsponsiveness (GAUGE) - comprises pain across seven body regions and four symptom items measuring interoception (nausea, numbness/tingling) and exteroception (sensitivity to sound, sensitivity to odors). GAUGE outperformed the Central Sensitization Inventory, Fibromyalgia Survey Criteria, and PainDETECT for predicting surgical non-response (RR 1.535, 95% CI 1.342-1.55; AUC 0.738; sensitivity 0.741, specificity 0.635) and for predicting Patient Global Impression of Change. In an independent validation cohort of 54 total knee arthroplasty patients, GAUGE outperformed the Fibromyalgia Survey Criteria in predicting pain severity at six-months. Conclusions. GAUGE is a data-driven, theoretically grounded screener for poor analgesic response to surgery, with potential utility for pre-surgical counseling and clinical trial enrichment.

BackgroundDespite advances in therapy, optimal management of juvenile idiopathic arthritis (JIA) remains challenging. The ability to predict disease progression in JIA can improve personalized treatment decisions, but few reliable clinical predictors have been identified. We developed machine learning approaches to predict disease trajectories in children with JIA. MethodsUsing data from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry (years 2015-2024), we developed machine learning models to predict attainment of inactive disease in children with non-systemic JIA. We applied Dynamic Bayesian Networks (DBN) to model temporal dependencies and causal relationships, and Convolutional Neural Networks (CNN) to capture complex non-linear patterns. Model input included demographic factors, longitudinal clinical factors, and medication use in the preceding 12 months. FindingsA total of 8,093 participants were included. When tested on an independent test cohort, both DBN (AUC:0.76; precision:0.73; recall:0.83; F1-score:0.78; accuracy:0.71) and CNN (AUC:0.76; precision:0.71; recall:0.63; F1-score:0.67; accuracy:0.70) models achieved comparable performance in predicting inactive disease. Disease activity levels in the preceding 12 months, presence of enthesitis and uveitis were the strongest predictors. Causal relationships captured in the DBN model revealed suboptimal care patterns, likely shaped by insurance constraints and a predominantly reactive approach to JIA management. InterpretationOur study demonstrates that machine learning approaches can predict disease trajectories in JIA with good discriminative performance. Unlike prior studies that predict outcomes at single timepoints, our models are the first to predict inactive disease longitudinally. However, suboptimal care patterns in retrospective data limit models capacity to learn treatment-outcome relationships, underscoring critical opportunities to improve JIA care and the need for prospective comparative studies to better inform prediction models. FundingPatient-Centered Outcomes Research Institute (PCORI) Award (ME-2022C2-25573-IC). RESEARCH IN CONTEXT Evidence before this studyNumerous studies have sought to identify clinical predictors of JIA progression and outcomes. However, few reliable predictors have emerged and existing prediction models demonstrate limited performance. As a result, our ability to personalize treatment decisions based on individual risk of severe disease course remains limited. Added value of this studyWe developed novel machine learning models that predict individualized disease trajectories in children with polyarticular and oligoarticular JIA using data from their preceding 12-month clinical course. These models demonstrated strong discriminative performance and outperformed previously published machine learning approaches in JIA. Unlike prior studies limited to single time-point predictions, our models are the first to predict inactive disease longitudinally, enabling a patient-specific projection of disease progression over time. Importantly, our findings also bright to light patterns of suboptimal care, likely driven by insurance constraints and a reactive treatment paradigm, underscoring critical opportunities to improve JIA management. Implications of all the available evidenceOur models have the potential to support clinical decision-making by enabling early identification of children with JIA at risk for unfavorable disease trajectories. In addition, the suboptimal care patterns and systems-level barriers identified through our analyses highlight priority areas for quality improvement initiatives and policy interventions to reduce gaps in JIA care delivery.