Arthritis Research & Therapy

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.

ObjectivesMechanical cues are essential for maintaining cartilage function, yet how they integrate with molecular pathways dysregulated in osteoarthritis (OA) remains poorly defined in human tissue. Canonical Wnt signalling influences cartilage biology and cell-matrix interactions, but its role in integrin-dependent mechanoregulation in human cartilage is not fully understood. This study aimed to determine how Wnt activation affects chondrocyte responses to physiological mechanical loading, with a focus on 5{beta}1integrin and cytoskeletal organisation. MethodsHuman cartilage explants from non-OA and OA donors were subjected to short-term physiological cyclic compression. Canonical Wnt signalling was activated with CHIR99021, and integrin-mediated adhesion was modulated using the 5{beta}1 blocking peptide ATN-161 during loading. Chondrocyte responses were assessed by analysing mechanoresponsive and matrix-related gene expression, 5{beta}1 complex formation via proximity ligation assay and actin cytoskeletal organisation by confocal microscopy. ResultsOA chondrocytes exhibited a distinct integrin profile, characterised by increased ITGA5 and ITGB1 but reduced ITGA10 expression. In non-OA cartilage, canonical Wnt activation increased ITGB1 expression and 5{beta}1 integrin complex formation, while mechanical loading further enhanced ITGA5 and ITGB1 transcription under Wnt-activated conditions. Under control conditions, loading induced mechanoresponsive and anabolic gene expression in non-OA cartilage; these responses were attenuated following Wnt-activation and partially restored by 5{beta}1 blockade. Mechanical loading induced F-actin reorganization toward a more cortical distribution across cartilage zones, irrespective of disease status or treatment. Wnt activation did not result in distinct cytoskeletal phenotypes under load, and load-induced actin remodelling was comparable between groups. ConclusionThese findings identify 5{beta}1integrin as a key mediator linking canonical Wnt signalling to altered chondrocyte mechanoresponsiveness in human cartilage. While mechanical loading consistently induced cortical F-actin reorganization, Wnt-associated changes in load responsiveness arose primarily from integrin-dependent mechanisms rather than major alterations in actin organization. This study highlights the complexity of cartilage mechanoregulation and identifies integrin-mediated signaling as important contributors to canonical Wnt-driven alterations in load responsiveness relevant to OA.

Abstract: Objective This study aimed to systematically screen for potential candidate biomarkers and identify therapeutic targets associated with gouty arthritis (GA) through integrated analyses of single-cell and bulk RNA sequencing (RNA-seq) data. Methods The single-cell dataset GSE211783 and the bulk RNA-seq dataset GSE160170 were analyzed using a series of bioinformatic approaches, including cell clustering, differential expression analysis, immune cell infiltration assessment, protein-protein interaction network construction, gene set enrichment analysis, as well as drug sensitivity evaluation. To establish an animal model of GA, monosodium urate crystals were injected intra-articularly into experimental mice. Joint swelling was evaluated, and morphological changes in joint tissues were analyzed through hematoxylin-eosin staining. The presence of TREM1-positive cells was detected by immunohistochemistry and the level of TREM1 protein expression in joint tissues were assessed by Western blotting. Results We identified 102 differentially expressed genes (DEGs) and 14 signaling pathways associated with GA. The PPI network revealed 25 hub genes, of which 17 (including TREM1, TNF, PTGS2, and NLRP3) were highly expressed and 8 (including FCGR3B and CXCR6) showed low expression in the GA samples. These genes correlated significantly with the infiltration levels of macrophages. Among the hub genes, TREM1 was selected for further validation because it correlated significantly with all 14 differential pathways. In animal experiments, GA mice developed marked joint swelling and inflammatory tissue injury, along with a significant increase in TREM1-positive cells and TREM1 protein expression. Conclusion Integrative analysis of single-cell and bulk RNA-seq data identified 102 GA-related DEGs and 14 key pathways, from which 25 hub genes were screened. TREM1 is significantly upregulated in GA and may be linked to macrophage function, providing new insights into biomarker and therapeutic target discovery for GA.

Background: Rheumatoid arthritis (RA) has a preclinical period characterised by elevations in serum autoantibodies. Identifying the timing and magnitude of autoantibody trajectory changes may inform screening strategies and preventative interventions. Methods: Using a Bayesian multivariate segmented regression, we jointly modelled longitudinal autoantibody trajectories from two Department of Defense Serum Repository cohorts (Sample A: 209 matched case-control pairs, 1566 samples, six biomarkers; Sample B: 309 cases with two matched controls each, 2758 samples, eight biomarkers). Change-points and magnitudes of change were estimated simultaneously under a multivariate likelihood with an unstructured residual correlation matrix. Results: In Sample A, five of six biomarkers exhibited pre-diagnostic trajectory shifts with 95% highest posterior density intervals excluding zero. RF-IgM demonstrated the earliest change-point at 8.10 years before diagnosis (95% HPDI: -10.47, -5.73), followed by ACPA-IgG at 7.43 years (95% HPDI: -9.33, -5.76). In Sample B, only the four IgG isotypes showed pre-diagnostic shifts, with anti-CCP3 (IgG) earliest at 7.00 years (95% HPDI: -8.48, -5.29). A composite metric integrating timing and magnitude reordered rankings. Conclusions: This Bayesian framework enables simultaneous estimation of change-points and magnitudes across correlated autoantibodies while fully characterising uncertainty, offering a complementary approach to prior divergence-based methods for understanding preclinical RA autoimmunity.

BackgroundRheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease characterized by a heterogeneous clinical course with periods of remission and flare. Although biologic DMARDs (bDMARDs) have revolutionized RA treatment by enabling sustained disease control, their long-term use is associated with adverse effects and high costs, making dose tapering an attractive but clinically challenging strategy. The lack of reliable biomarkers to predict flare risk limits safe implementation of treatment de-escalation. This study aimed to identify novel circulating protein biomarkers associated with flare risk in RA patients undergoing bDMARDs tapering, useful to enable biomarker-guided treatment optimization strategies. MethodsA discovery proteomic analysis using mass spectrometry was performed on baseline serum samples from a subset of the OPTIBIO clinical trial (n=44), followed by validation in the full cohort (n=194) using ELISA. Functional pathway analysis explored biological processes associated with candidate biomarkers. In parallel, anti-cytokine autoantibodies were profiled using multiplex immunoassays. Logistic and Cox regression models were used to assess associations with flare risk. Predictive models integrating biomarkers and clinical variables were evaluated using receiver operating characteristic (ROC) analysis, sensitivity and specificity metrics, and decision curve analysis to assess clinical utility. ResultsMass spectrometry identified 806 proteins, of which 87 were differentially expressed at baseline between patients who flared and those who maintained remission during follow-up within the intervention (tapering) arm. Functional enrichment analysis highlighted immune-regulatory and innate immune pathways. Among the candidates, V-set immunoglobulin-domain-containing 4 (VSIG4) was validated as a biomarker associated with increased flare risk. Anti-interferon-{gamma} (anti-IFN{gamma}) autoantibodies were also associated with flare. A combined model including VSIG4, anti-IFN{gamma}, and the clinical variable DAS28-CRP improved predictive performance compared with clinical variables alone (AUC 0.76 vs 0.66), achieving significantly higher sensitivity. Decision curve analysis demonstrated higher net benefit of the combined model, indicating improved clinical decision-making. In a secondary analysis focused on patients with prolonged remission, representing the most suitable candidates for safe treatment tapering, the model performance further improved (AUC 0.84). ConclusionIntegration of novel serum proteomic and autoantibody biomarkers with clinical parameters improves prediction of flare during biologic tapering in RA and provides clinically relevant benefit for patient stratification. These findings support further development of biomarker-driven approaches for personalized treatment optimization strategies.

ObjectivesThe inositol phosphatase SHIP2 plays a crucial role in skeletal development and chondrocyte differentiation, and mutations in INPPL1 (encoding SHIP2) cause opsismodysplasia, a chondrodysplasia with marked cartilage abnormalities. We investigated whether SHIP2 contributes to structural joint remodeling in osteoarthritis (OA). MethodsA cartilage-specific conditional knockout of SHIP2 was generated using Ship2fl/fl mice crossed with AggrecanCreERT2 mice. OA was induced at 9 weeks of age via destabilization of the medial meniscus (DMM). Sham surgery served as control. Mice were sacrificed 12 weeks post-surgery. Histological evaluation of articular cartilage, synovium, osteophytes, and subchondral bone was performed. Chondrocyte hypertrophy was assessed by type X collagen (COLX) staining, and SHIP1 was evaluated as a potential compensatory mechanism. ResultsDMM surgery induced OA-like changes in all genotypes, including cartilage damage, synovial inflammation, osteophyte formation, and subchondral bone thickening. However, Ship2cCART-KO mice showed no differences in OA-related parameters compared to control littermates. COLX expression increased following DMM surgery, independent of SHIP2 deletion. SHIP1 protein levels were not elevated in SHIP2-deficient mice. ConclusionThese findings indicate that SHIP2, while essential for cartilage development, does not act as a structural disease modifier in post-traumatic OA, suggesting that within this context, SHIP2 is not required for maintaining adult articular cartilage structure and is unlikely to represent a major therapeutic target for modifying structural disease progression.

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

ObjectiveInvestigate how Ca2+/calmodulin dependent protein kinase kinase 2 (CaMKK2) orchestrates a catabolic shift in chondrocytes during early osteoarthritis (OA). MethodsCartilage, osteochondral plugs and chondrocytes were collected from patients undergoing total hip arthroplasty or non-OA donors. SOX9 levels were assessed via immunoblotting or immunohistochemistry (IHC). Sox9 levels were also assessed by IHC in knee joints from wild-type (WT) and Camkk2-/- mice that underwent sham or destabilization of medial meniscus (DMM), with or without STO-609 (0.033 mg/kg) treatment. Co-immunoprecipitation followed by mass spectrometry was performed to identify CaMKK2 interacting proteins in chondrocytes. Kinase assays were analyzed by immunoblotting and phosphosites identified by mass spectrometry. Proteasome function was assessed in murine and human chondrocytes lacking or expressing kinase-active or kinase-inactive CaMKK2. ResultsInhibition or loss of CaMKK2 increased SOX9, whereas the expression of kinase-active, not inactive, CaMKK2 reduced Sox9 in human and mouse OA cartilage. Proteomic analysis of CaMKK2 immunoprecipitates revealed the presence of ubiquitin E3 ligase Ubr4 and the 19S proteasome regulatory particle (RP). CaMKK2 kinase activity was dispensable for its interactions with Ubr4, 19S RP, and Sox9-ubiquitin conjugates, and kinase-inactive CaMKK2 attenuated Sox9 degradation in chondrocytes. Further, CaMKK2 phosphorylated the 19S RP ATPase Psmc5 on Ser136, and an intact kinase increased proteasome activity in chondrocytes. ConclusionsOur findings identify CaMKK2 as a dual-function regulator of chondrocyte UPS with a scaffolding role to assemble UPSUbr4-19S RP around polyubiquitinated proteins such as Sox9, and a catalytic role to enhance proteasome function, potentially through Psmc5 phosphorylation, thereby linking chondrocyte inflammatory signaling to Sox9 degradation and cartilage degeneration.

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.

In this large multi-center cohort of children evaluated for Lyme disease in a Lyme-endemic emergency department, we assessed the diagnostic accuracy of clinician suspicion and subsequent clinical decision-making for children presenting with monoarthritis. Among 1,582 children with monoarthritis evaluated for Lyme disease, 623 (39%) had Lyme arthritis and 32 (2%) had septic arthritis. Overall, 313 (20%) had an invasive joint procedure (arthrocentesis or arthroscopy), 194 (12%) received parenteral antibiotics, and 376 (24%) were hospitalized. Clinician suspicion had moderate discriminative ability for Lyme disease (area under the receiver operating characteristics curve: 0.75, 95% confidence interval: 0.72-0.77). Children with higher clinician suspicion were less likely to receive parenteral antibiotics or to be hospitalized, although invasive procedure rates were similar. Our findings highlight the challenge of clinically distinguishing Lyme from septic arthritis. Better diagnostic tools are needed to improve timely diagnosis and minimize invasive testing among children with monoarthritis in Lyme-endemic regions.

BackgroundPain with movement is common in adults with knee osteoarthritis (OA), but the effect of movement-evoked pain on gait is not well understood. This relationship is vital to understand as gait mechanics are associated with OA initiation and progression. Our current understanding of acute changes in pain and gait stems from extended bouts of walking, however these bouts likely dont represent real-world behavior. Therefore, understanding how gait changes with shorter, more intense bouts of activity may provide valuable insight into the pain experience. MethodsAdults with (n=19) and without (n=19) knee OA wore inertial measurement units (IMUs) while completing bouts of walking before and after two bouts of stair navigation (two flights). We tested whether pain and gait (speed, stride length, and lower extremity joint ranges of motion (ROM)) changed differently between adults with and without knee OA in response to multiple bouts of stair activity. FindingsThere were no significant interactions between group and stair bouts for any variable. When stratifying the OA group by those who did and did not experience pain, those who experienced a change in pain also had a greater change in early stance knee ROM in response to bouts of stairs. InterpretationThe observed changes suggest that knee kinematics may be more sensitive to acute changes in pain than gait speed or stride length. These differences were detectable using IMUs and therefore our results support the use of IMUs to measure concurrent pain and gait mechanics in less controlled and real-world settings.

The adult skeletal muscle regenerates robustly upon injury, but this regenerative capacity rapidly declines with age. In this study, we identify the lanthionine synthetase C-Like (LanCL) proteins, mammalian homologs of the bacterial peptide cyclase LanC, as positive regulators of muscle regeneration in middle-aged mice. In a barium chloride-induced injury model, we found the protein levels of LanCL1 and LanCL2 to increase during an early phase of regeneration in middle-aged (12-month-old) but not young adult (4-month-old) mice. Utilizing a mouse line lacking all three LanCL proteins (LanCL triple KO or LTKO), we examined a potential role of LanCL in injury-induced muscle regeneration. Consistent with an age-dependent function of LanCL, we observed a delayed regeneration of the tibialis anterior (TA) muscle after injury, as reflected by reduced sizes of regenerating myofibers in middle-aged (but not young) LTKO compared to age-matched WT mice. Although the pool size of quiescent satellite cells (Pax7+) was comparable between 12-month-old LTKO and WT muscles without injury, the number of Pax7+ cells was significantly higher in regenerating LTKO muscles at day 5 after injury, accompanied by drastically decreased numbers of MyoD+ and MyoG+ cells, as well as increased numbers of proliferating cells. In addition, we detected elevated expression of pro-inflammatory cytokines in regenerating LTKO muscles, while the number of macrophages was similar comparing LTKO and WT muscles. Taken together, our observations suggest that in aging muscles LanCLs are important for proper timing of inflammation resolution and regeneration upon injury. New & NoteworthyPhysiological roles of the mammalian homologs of bacterial LanC, LanCLs, are poorly understood. Our work uncovers a function of LanCLs in post-injury regeneration of aging skeletal muscles. Middle-aged LanCL triple KO mice displayed a delay in satellite cell differentiation and regenerative myofiber formation, as well as persistent inflammatory cytokine expression, suggesting that LanCLs may have an age-dependent role in modulating inflammation in the injured muscles to facilitate regeneration.

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.

ObjectiveSystemic sclerosis (SSc) predominantly affects females but exhibits greater disease severity in males, suggesting sex differences underlying SSc pathogenesis. We sought to define sex-associated alterations in the peripheral immune landscape of patients with SSc. MethodsWe performed high-dimensional immune profiling of PBMCs from 37 healthy donors (68% female) and 37 patients with SSc (11 limited, 26 diffuse; 68% female) using 30-color spectral flow cytometry, quantifying 56 immune cell subsets per donor. We conducted sex-stratified comparisons and correlation analysis, and used principal component analysis followed by linear discriminant analysis to derive a sex-discriminant immune cellular module. ResultsDiffuse cutaneous SSc (dcSSc) was associated with a distinct immune landscape characterized by increased monocyte and decreased natural killer-like and B cell frequencies, suggesting a myeloid-skewed peripheral immunophenotype. Males exhibited greater enrichment of innate immune subsets, including monocyte and dendritic cell subsets, while females exhibited greater enrichment of adaptive immune subsets. Among T cells, dcSSc was associated with coordinated remodeling across CD4+ and CD8+ subsets, including expansion of stem cell memory T cells (Tscm), and increased regulatory T cells, Th17 skewing, and decreased effector-memory CD8+ subsets. Females exhibited greater proportions of naive- and Tscm, and males exhibited higher proportions of effector-memory subsets. Integrating these data, we identified a sex-discriminant immune module comprised of 20 cell types that distinguishes males and females with dcSSc. ConclusionsSSc is associated with sex-specific differences in the peripheral immune landscape. A sex-associated immune program, further amplified in disease, may contribute to the paradox of female-biased susceptibility and male-biased severity in SSc.

Background. Polypharmacy is common in autoimmune rheumatic diseases (ARDs) and increases adverse drug events (ADEs), but comparative evidence across diseases is limited. We aimed to quantify ADE burden and identify medications associated with ADE risk across six ARDs, and to examine shared and disease specific patterns across diseases. Methods. We conducted a retrospective cohort study at a tertiary medical center (2010 to 2024). Adults with ankylosing spondylitis (AS), psoriatic arthritis (PsA), rheumatoid arthritis (RA), Sjogren's disease (SjD), systemic lupus erythematosus (SLE), or systemic sclerosis (SSc) were identified using diagnostic codes. ADEs were ascertained using validated case definitions. Medications were mapped to Anatomical Therapeutic Chemical classes; active exposure was defined within 30 days before the index date. Polypharmacy was defined as more than 5 concurrent medications (minor 5 to 10; major >10). Within each ARD, nested case control analyses matched on encounter type (1:4) were performed, and adjusted odds ratios (aORs) were estimated using conditional logistic regression. Findings. Among 10,578 patients, 3,154 (29.8%) experienced at least one ADE. ADE burden varied across diseases, with the highest prevalence observed in SSc (35.9%). Polypharmacy was common (57.3% minor, 39.4% major) and medication burden was consistently higher in ADE cases across encounter types (eg, SLE outpatient median 12 vs 6; inpatient 20 vs 10; emergency 17 vs 8). Across ARDs, the strongest associations with ADEs were observed for supportive and symptom directed therapies (acid suppressors, pain adjuncts, and sedative hypnotic/psychotropic medications), whereas conventional disease-modifying antirheumatic drugs (DMARDs) showed weaker associations. Disease-specific signatures included gastrointestinal agents in SSc (metoclopramide aOR 12.32), antibiotics and respiratory agents in AS (ciprofloxacin aOR 13.71, fluticasone aOR 8.88). Interpretation ADEs affect nearly one third of ARD patients and increase with medication burden. Risk concentrates in supportive and symptom directed therapies rather than DMARDs, with both shared and disease-specific patterns. Optimizing prescribing, particularly for pain management and corticosteroid use, can reduce medication-related harm.

BackgroundGastrointestinal (GI) involvement in systemic sclerosis (SSc) affects up to 90% of patients and is a major driver of morbidity and mortality. Despite its clinical importance, GI disease in SSc is highly heterogeneous, with upper and lower GI manifestations representing distinct phenotypic extremes whose underlying immunologic basis remains poorly defined. MethodsWe performed unbiased, proteome-wide autoantibody profiling using a human protein microarray comprising >21,000 full-length proteins (>80% of the human proteome). Sera from patients with SSc and isolated upper GI dysmotility (n=23), isolated lower GI dysmotility (n=17), and non-SSc controls (n=20) were analyzed. Enriched autoantibodies were identified using Fishers exact test, and unsupervised clustering was applied to define serology-based patient subsets and relate immune signatures to clinical phenotypes. ResultsDistinct autoantibody profiles differentiated patients with upper versus lower GI disease. Upper GI-predominant SSc was characterized by enrichment of previously unreported autoantibodies, including those targeting TiSSc1/2 (newly identified proteins encoded within the MIRLET7BHG locus), FAM9C, SPATA20, FAM110D, EMILIN1, CARD14, SMN1, KCTD7, and PHYHD1, whereas lower GI disease was associated with antibodies against HAO2, KLHL7, SUFU, APPL1, BNIP2, UCHL3, ZNF385A, LIMD1, MAGEA9, and PPP2R3C. Serology-driven clustering identified four reproducible subgroups with distinct patterns of GI, pulmonary, vascular, and autonomic involvement, defining clinically meaningful disease phenotypes that extend beyond traditional anatomic classification. ConclusionsProteome-scale serological profiling reveals previously unrecognized autoimmune signatures underlying GI heterogeneity in SSc. These findings support a shift from anatomy-based to serology-defined classification of SSc GI disease and provide a foundation for biomarker development, patient stratification, and precision medicine approaches in this population.

Osteolytic bone diseases are driven by excessive osteoclast formation and bone resorption. While cGAS-STING signaling is known to regulate bone homeostasis via macrophage-intrinsic mechanisms, its role in osteoblast-mediated control of osteoclastogenesis remains poorly defined. Here, we show that cGAS-STING activation of macrophages suppresses their osteoclastogenic potential while promoting immune activation. In osteoblasts, cGAS-STING triggers IRF3-mediated IFN-{beta} production and, notably, shifts the OPG-RANKL axis toward increased osteoprotegerin. In transwell co-culture, pre-activated osteoblasts reduce osteoclast differentiation of strain-matched macrophages. Mechanistically, osteoblast-derived IFN-{beta} is sufficient to inhibit osteoclastogenesis in a paracrine manner. Furthermore, autocrine IFN-{beta} signaling appears to modulate the OPG-RANKL axis, although additional regulatory factors may contribute. Together, these findings identify cGAS-STING-IFN-{beta} signaling as a dual regulator of osteoclastogenesis, acting directly on macrophages and indirectly via osteoblast-derived anti-osteoclastogenic mediators. This highlights osteoblasts as cGAS-STING-responsive bystander cells within the bone microenvironment that can be targeted as an alternative strategy to limit pathological bone resorption. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/724040v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@167dfcorg.highwire.dtl.DTLVardef@a95477org.highwire.dtl.DTLVardef@e88c77org.highwire.dtl.DTLVardef@15de567_HPS_FORMAT_FIGEXP M_FIG C_FIG

ObjectiveTo determine whether pyroptosis-related transcription in systemic sclerosis skin forms a translayer spatial architecture rather than a single coextensive inflammatory program. MethodsWe reanalyzed public Visium formalin-fixed paraffin-embedded skin sections (4 healthy controls, 9 systemic sclerosis) from a discovery cohort and tested prespecified endpoints in 10 independent systemic sclerosis sections. The tissue section was the inferential unit. Epidermal versus dermal contrasts within each section were evaluated for inflammasome-related and gasdermin genes, followed by cell2location spatial deconvolution and partial correlation adjusted for endothelial context in the dermis. ResultsNLRP1, PYCARD, and CASP4 displayed epidermal bias in all 13 discovery sections, whereas GSDMD displayed dermal bias in all 13. This spatial separation was detectable in healthy skin and appeared stronger in systemic sclerosis. A tier 1 triad captured the epidermal signal better than broader composites (dilution 35.5%; P = 0.0002). In an independent systemic sclerosis cohort, the dermal gasdermin endpoint retained its direction in 8 of 10 sections and the epidermal inflammasome-related endpoint in 10 of 10. Spatial deconvolution indicated that dermal GSDMD associated most strongly with estimated endothelial abundance in both healthy and systemic sclerosis skin. The IFN{gamma}-GSDMD association remained positive after endothelial adjustment across sections, compatible with an additional IFN{gamma} component. ConclusionSystemic sclerosis skin harbors a reproducible translayer pyroptosis-related transcriptional architecture in which upstream epidermal inflammasome-related transcription and dermal GSDMD expression are spatially dissociated. This organization, detectable in healthy skin and often stronger in SSc, may warrant future mechanistic and therapeutic interrogation by compartment.

Systemic lupus erythematosus (SLE) is associated with infection susceptibility and altered innate immune function. Monocyte metabolism is linked to appropriate cytokine release and bacterial containment. We investigated cytokine production and metabolic programming in the monocyte population from SLE patients and healthy controls following lipopolysaccharide (LPS) stimulation. SLE monocytes displayed increased IL-10, TNF, and IL-8 production, with impaired IL-1{beta} induction. Metabolic profiling revealed altered substrate use, with increased glucose dependence and reduced fatty acid and amino acid oxidation after LPS stimulation. SLE patients exhibited reduced numbers of classical monocytes, expansion of intermediate monocytes, and dysregulated subset-specific metabolic reprogramming in response to LPS. This descriptive study provides a cornerstone for (i) understanding infection susceptibility in SLE, (ii) subset-resolved immunometabolic profiling as a tool in autoimmunity, and (iii) developing future metabolic-targeted therapeutic strategies HighlightsO_LIDescriptive mapping shows SLE monocytes are proinflammatory with glucose dependence after LPS C_LIO_LIClassical and intermediate SLE subsets show divergent baseline metabolic preferences versus healthy C_LIO_LISLE subsets display aberrant LPS responses, i.e.. increased glucose and reduced fatty acid oxidation C_LIO_LIThis study provides a cornerstone for subset-resolved immunometabolism in infection susceptibility. C_LI

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.