Arthritis & Rheumatology

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.

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 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.

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.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by sustained type I interferon signalling and widespread immune dysregulation. Low-density neutrophils (LDNs) are expanded in SLE and display pro-inflammatory and tissue-damaging properties. However, their metabolic phenotype remains poorly defined. Here, we performed a comprehensive metabolic characterisation of circulating LDNs and normal-density neutrophils (NDNs) from patients with SLE and matched healthy individuals (HC). Neutrophil subsets were isolated from peripheral blood of SLE patients and HC donors using a two-step protocol of negative selection and Percoll density centrifugation. Immunophenotyping phenotype was carried out by flow cytometry to assess phenotypic expression of common neutrophil markers CD15, CD16, CD10, CD66b, CD62L, MPO, and IL-1{beta}. Bioenergetic profiling of LDNs and NDNs was performed in situ using the Seahorse MitoStress test to measure oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Metabolic flexibility and phenotypic alterations were assessed in LDNs and NDNs following inhibiting mitochondrial metabolism with oligomycin and glycolysis with 2DG. We found that SLE LDNs exhibit an immature phenotype compared with autologous and healthy NDNs, as determined transcriptionally by C/EBP{varepsilon} and by surface protein expression levels of CD10. Both LDNs and NDNs from SLEDAI[≥]4 patients demonstrated significantly elevated ECAR relative to HC neutrophils. Further, SLE LDNs displayed enhanced metabolic flexibility, with the capacity to switch towards a glycolytic phenotype under metabolic stress conditions. Inhibition of glycolysis altered the inflammatory and maturation-associated phenotype of both SLE neutrophil subsets, indicating a direct link between cellular metabolism and pathogenic neutrophil function. Collectively, these findings identify fundamental metabolic alterations in SLE neutrophil subsets and support neutrophil immunometabolism as a potential therapeutic target in SLE.

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

BackgroundPatients with systemic lupus erythematosus (SLE) face markedly increased cardiovascular disease (CVD) risk driven by mechanisms beyond traditional risk factors. Thoracic aortic perivascular adipose tissue (tPVAT) is dysfunctional in lupus and exacerbates endothelial dysfunction, yet the molecular basis of this dysfunction remains poorly defined. MethodsIntegrated multi-omics profiling, including bulk RNA-seq, untargeted proteomics, lipidomics, and high-dimensional spectral flow cytometry, was performed on tPVAT from 15-week-old MRL/lpr mice (active lupus, n = 4-6) and MRL control mice (n = 5-6). Adipogenic differentiation capacity of tPVAT adipose stromal and progenitor cells (ASPCs) from MRL/lpr was assessed by Oil Red O staining at 5 (pre-dieasea) and 15 weeks (active disease), with subcutaneous ASPCs used as depot controls. ResultsTranscriptomic profiling of tPVAT from MRL/lpr mice identified 2,742 upregulated and 1,494 downregulated genes (adjusted p < 0.001, |log2FC| > 1), with strong activation of interferon, IL6-JAK-STAT3, and TNFA signaling pathways together with suppression of fatty acid metabolism, oxidative phosphorylation, and adipogenic pathways. Proteomic and lipidomic analyses were concordant, revealing broad downregulation of mitochondrial bioenergetic machinery, depletion of cardiolipin and acylcarnitines, and enrichment of ceramide phosphoinositols and lysophosphatidylcholines. Cardiolipin strongly correlated with the mitochondrial/metabolic protein module (r = 0.95) and inversely with the immune/inflammatory protein module (r = -0.92). Spectral flow cytometry confirmed marked CD45+ leukocyte infiltration dominated by T cells, together with a significantly reduced Treg/CD4+ ratio indicating loss of local immunoregulatory balance. ASPCs derived from PVAT of 15-week-old MRL/lpr mice exhibited impaired white and beige adipogenic differentiation, while APCs from PVAT of 5-week-old MRL/lpr mice, and from subcutaneous adipose tissues of 15-week-old MRL/lpr mice, had normal white and beige differentiation, consistent with an acquired, depot-specific, disease-stage-dependent progenitor defect in PVAT of MRL/lpr mice. ConclusionsLupus tPVAT undergoes a concordant cross-platform molecular reprogramming of mitochondrial bioenergetic genes coupled with establishment of an interferon-dominant immune niche and acquired loss of ASPC adipogenic capacity. These findings provide a molecular framework for lupus PVAT dysfunction and identify restoration of mitochondrial function, suppression of interferon-driven inflammation, and renewal of progenitor differentiation as potential therapeutic strategies for lupus vasculopathy.

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.

Anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies identify a distinct dermatomyositis subset frequently associated with rapidly progressive interstitial lung disease (RP-ILD). While these antibodies are established disease markers, their direct contribution to pulmonary fibrosis is poorly defined. This study investigated the pathogenic effects of patient-derived polyclonal anti-MDA5 antibodies on IMR-90 human lung fibroblasts. Recombinant human MDA5 protein was produced in HEK293F cells and utilized to selectively isolate autoantibodies from a patients plasma via affinity chromatography. Fibroblasts were stimulated with MDA5, anti-MDA5 antibodies, or both. Real-Time Cell Analysis (RTCA) showed a statistically significant increase in cell impedance following treatment with an MDA5-anti-MDA5 mixture compared with controls, accompanied by a reduction in cell doubling time. MTT assays showed that neither MDA5 nor anti-MDA5, nor their immunocomplex, exerted acute cytotoxic effects in cell culture. Direct cell counting revealed a significant increase in fibroblast proliferation in response to the MDA5-anti-MDA5 combination. Molecular characterization by RT-qPCR revealed a significant alteration of TLR2, TLR7, and endothelin-1 (ET-1) mRNA levels. ELISA assays detected an increased secretion of pro-collagen and type I interferons in culture supernatants. All these results were mainly, but not only, observed in the MDA5/anti-MDA5-exposed cells. Our results suggest that anti-MDA5 autoantibodies and MDA5 antigen complex are not merely disease biomarkers, but active pathogenic drivers that stimulate proliferation and pro-fibrotic responses in lung fibroblasts. This mechanism may contribute to the rapid tissue remodeling characteristic of RP-ILD, supporting the development of targeted therapeutic strategies to mitigate fibrosis in this high-mortality patient subset.

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.

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.

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.

Long-lived plasma cells (LLPC) sustain humoral immunity but also contribute to the persistence of pathogenic autoantibodies in autoimmune diseases. New therapies targeting LLPC are therefore desirable. Recent studies have shown increased expression of Slc12a2, encoding the Na+ -K+ -Cl- cotransporter (NKCC1), in LLPC. This study investigated whether NKCC1 activity was required for plasma cell survival, persistence or secretion of antibodies. Across in vitro and in vivo settings, mouse plasma cell survival was undiminished by treatment with the NKCC1 inhibitor bumetanide. Acute in vivo bumetanide treatment did not diminish plasma cell numbers, nor show any demonstrable impact on the survival of phenotypically mature I-A/I-EloSLAMF6lo plasma cells. With genetic plasma cell timestamping, even the survival of persistent LLPC was unaffected by bumetanide. Plasma cell secretory capacity, assessed by measuring IgM and IgG2b secretion in culture over three days, was also unaltered by bumetanide. Overall, these results show that pharmacological inhibition of NKCC1 is not sufficient to impair plasma cell survival, persistence or antibody secretion. Despite elevated Slc12a2 mRNA expression in LLPC, NKCC1 alone does not represent a critical plasma cell survival pathway, highlighting the resilience of plasma cells and the challenges associated with therapeutically targeting LLPC.

Age-associated B cells (ABCs) expand in systemic lupus erythematosus (SLE) and contribute to pathogenic humoral immunity, but the mechanisms that restrain their differentiation remain unclear. Here, we identify the transcription factor IKZF2 (Helios) as a regulator that limits ABC differentiation. Transcriptomic and functional analyses showed that suppression of oxidative phosphorylation (OXPHOS) in B cells promoted ABC differentiation and was accompanied by reduced IKZF2 expression. Pharmacologic modulation of mitochondrial metabolism further demonstrated that OXPHOS inhibition promoted, whereas OXPHOS activation restrained, ABC differentiation. Integrative analyses revealed reduced IKZF2 expression in selected B cell subsets from patients with SLE. Functional suppression of IKZF2 enhanced ABC differentiation and attenuated the inhibitory effects of OXPHOS activation, indicating that IKZF2 mediates metabolic control of B cell fate. Mechanistically, IKZF2 restrained early ABC-associated gene programs, including ITGAX and TBX21. Circulating miR-1285-3p in small extracellular vesicles, elevated in SLE, suppressed OXPHOS and recapitulated these effects. Together, these findings identify an OXPHOS-IKZF2 axis that restrains pathogenic B cell differentiation and links extracellular microRNA-mediated metabolic stress to ABC formation in SLE. One-sentence summarySmall EV-associated miR-1285-3p in SLE promotes ABC differentiation by suppressing OXPHOS and relieving IKZF2-mediated restraint.

Immune checkpoint inhibitor-induced lichen planus (ICI-LP) is a cutaneous immune related adverse event (irAE) that shares key clinicopathologic features with spontaneous lichen planus (LP) but differs histologically and in the sex distribution of its incidence, and may therefore reflect a distinct tissue inflammatory state. To define the cellular programs that distinguish ICI-LP from LP, we profiled lesional skin by single cell and spatial transcriptomic approaches. We found few differences in the T cell and keratinocyte compartments between ICI-LP and LP, which shared similar inflammatory signatures. Rather, the dominant transcriptional features differentiating these two eruptions occurred within the fibroblast and myeloid cell compartments. Fibroblasts in ICI-LP were enriched for IGF1, FGF7, and androgen-response-associated programs, whereas myeloid cells exhibited amplified JAK-STAT and interferon-responsive states spanning both type I and type II interferon signatures. The potential role of androgen response in shaping lichenoid inflammation was supported by a striking loss of androgen receptor expression in lesional keratinocytes by immunohistochemistry. Furthermore, using spatial RNA and transcriptomic approaches, we identified anatomically segregated IFNG, IL17A, and IL13 niches within lesional skin, suggesting that regional immune compartmentalization with differences in local immunoregulation may explain the mixed inflammatory features reported in both ICI-LP and LP. Collectively, these data indicate that ICI-LP is not simply a more inflamed form of LP, but a distinct form of the disease with more prominent inflammatory perturbations within stromal and innate immune cell populations.

Delayed wound healing in advanced age is associated with prolonged inflammation, but the mechanisms that impair inflammatory resolution in this context remain poorly defined. Neutrophils are essential for early repair, but their persistence is predicted to disrupt resolution and delay healing. Here we show that aged mice exhibit impaired wound closure accompanied by sustained neutrophil infiltration from days 7-14 post-injury, long after neutrophils have resolved in young wounds. In aged skin, macrophage abundance and neutrophil-macrophage interactions were reduced, consistent with reduced macrophage-mediated clearance. Instead, neutrophils preferentially localised to perivascular regions, consistent with ongoing recruitment. Transcriptomic profiling demonstrated that young wounds transitioned from inflammatory to reparative programs, whereas aged wounds retained inflammatory signatures, including enrichment for neutrophil chemotaxis and LPS-response pathways. Notably, Ccl3, Cxcl2 and Cxcl3 remained elevated in aged wounds. Analysis of human chronic ulcers identified macrophages as a major source of these transcripts, and aged mouse wounds possessed more CCL3+ macrophages than in young. Targeted blockade of CCL3 beginning at day 4 post-injury reduced neutrophil accumulation, accelerated wound closure, and rescued key features of age-impaired healing, when administered after the initial inflammatory phase. Together, these findings identify persistent CCL3 expression as a contributor to sustained neutrophil recruitment and impaired repair in advanced age. Therapeutically targeting this pathway offers a strategy to restore timely resolution and improve healing outcomes.

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.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is characterized by prepubertal abrupt onset of obsessive-compulsive disorder (OCD). The sine qua non is group A streptococcus (GAS) infection, which is hypothesized to elicit an IgG-class anti-GAS antibody response that cross-reacts with antigens in the basal ganglia. However, the association between GAS antibody (GAS-IgG) levels and PANDAS has been inconsistent, and qualitative differences in GAS-IgG profiles have not been carefully evaluated in well-phenotyped cohorts. Moreover, independent studies have yet to converge on anti-neural autoantibodies that are specific to PANDAS. Here, we used phage display immunoprecipitation sequencing (PhIP-Seq) to perform ultra-deep anti-pathogen antibody repertoire profiling of serum from definitive pediatric PANDAS patients (N = 34) collected as part of a prior double-blind, placebo-controlled clinical trial of intravenous immunoglobulin (IVIg). PANDAS cases were compared to pediatric controls without a history of neuropsychiatric illness (N = 31). To assess for objective evidence of neuroglial injury, serum neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) levels were compared to healthy pediatric controls. Within PANDAS, NfL and GFAP levels were compared between pre- and post-treatment sera. To evaluate for central autoantibodies, a subset of baseline cerebrospinal fluid (CSF) samples (N = 25) was profiled by full-length human protein microarray. Though GAS reactivity by PhIP-Seq was well correlated with clinical anti-DNaseB and anti-streptolysin O titers, there were no quantitative or qualitative differences in GAS-IgG profiles between PANDAS and controls. Furthermore, NfL and GFAP levels did not differ between cases and controls. Within PANDAS, changes in NfL or GFAP levels at six weeks did not differ between placebo and IVIg groups. However, CSF autoantibody profiling by protein microarray revealed infrequent but notable candidate autoantibodies. In one patient, we identified autoantibodies against Argonaute family proteins (AGO-IgG), a marker of autoimmune sensory neuropathy. Longitudinal measurement of AGO-IgG in sera revealed that titers were unchanged after placebo, but decreased after IVIg, coinciding with symptomatic improvement, including a decrease in that patients CY-BOCS score. Overall, these results do not support an etiologic role for GAS-IgG in PANDAS. However, some individuals diagnosed with PANDAS may harbor anti-neural autoantibodies.

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

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.