BackgroundSubchondral insufficiency fracture of the knee (SIFK) is a rare and rapidly progressing knee joint disease. The typical diagnostic finding of SIFK by magnetic resonance imaging (MRI) is a subchondral hypointense line around the bone marrow lesions (BMLs), which are also commonly observed in knee osteoarthritis (OA). Subchondral bone fracture and its repair reactions are implicated for SIFK. However, pathological changes of SIFK and BMLs and the mechanism by which SIFK is induced remain elusive. We aimed to examine characteristics of SIFK and OA by micro-computed tomography (micro-CT) and histology together with biomarker analysis.MethodsNineteen patients with femoral or tibial SIFK (10 F-SIFK and 9 T-SIFK patients) and 24 knee OA patients, who were diagnosed by radiography and MRI and underwent unicompartmental knee arthroplasty, were enrolled for this study, and their medial tibial plateaus were examined by micro-CT and pathology. Serum and urine biomarkers were also analyzed.ResultsAll the T-SIFK patients showed BMLs with a subchondral hypointense line by MRI. Micro-CT analysis revealed that the T-SIFK lesion comprises multiple subchondral bone fragments covered with articular cartilage. Histologically, the lesion was composed of articular cartilage-covered subchondral bone fragments, debris of bone and bone marrow, fibrogranulation tissue, cartilage and woven bone. The medial tibial plateaus from OA patients frequently exhibited eburnation, which was commonly accompanied by microfracture. All the BMLs observed in T-SIFK and OA were associated with fat necrosis, which was characterized by disrupted fat cells and foamy macrophage infiltration. The posterior tibial slope angle (12.84 ± 2.34° vs 9.58 ± 2.84°) and the rate of medial meniscal posterior root tears (68.4% vs 25.0%) were significantly higher in T-SIFK than OA. Numbers of grade 2 subchondral bone resorption pits in uninvolved areas of the medial tibial plateaus (2.32 ± 1.43 vs 0.72 ± 0.66) and the femoral condyles (5.53 ± 3.73 vs 1.50 ± 2.10) were significantly higher in T-SIFK than OA.ConclusionsOur data demonstrate that T-SIFK is generated by subchondral bone fracture and its repair reaction and suggest that fat necrosis of the bone marrow is involved in BML formation in T-SIFK and OA.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13075-026-03733-w.

Children and adolescents with juvenile idiopathic arthritis (JIA) are at increased risk for long-term physical and psychosocial complications, making physical activity (PA) and sedentary behaviour (SB) key modifiable lifestyle factors. Although increasingly acknowledged as relevant, data on the daily distribution of these behaviours in JIA remain scarce. This study aimed to (1) describe the time-use composition of SB and PA intensities in young people with JIA, (2) identify correlates of greater relative time spent in SB, and (3) compare movement behaviour patterns to matched population controls using a compositional data analysis (CoDA) approach. Patients aged 10–20 years with JIA and individually matched population controls wore hip-worn accelerometers (ActiGraph wGT3X-BT) for eight consecutive days. Movement behaviours were categorized into SB, light-intensity PA, and moderate-to-vigorous PA (MVPA) using validated, age-specific cut-points. CoDA with log-ratio transformations was used to model associations and compare groups. Diifferences in movement composition were assessed using adjusted multivariate analysis of variance (MANOVA). Data from 126 matched pairs (mean age: 15.0 ± 2.1 years; 67% female) were analysed. Patients spent, on average, 86% of waking time in SB, 8% in light-intensity PA, and 6% in MVPA. Overall, 76% did not meet the WHO recommendation of an average of ≥ 60 min of MVPA per day. Among those who did, 87% still spent ≥ 75% of their wear time sedentary. A greater proportion of SB relative to PA was associated with female gender (B = 0.13; p = 0.042), higher age (B = 0.06; p < 0.001), and higher BMI (B = 0.01; p = 0.049). Compared to controls, patients spent more time in SB, less in light-intensity PA, and slightly more in vigorous PA (all p < 0.001). Group differences remained significant after adjustment and were consistent across weekdays and weekends. Young people with well-controlled JIA show a distinctly unbalanced movement behaviour composition compared to controls, marked by a predominance of sedentary behaviour—even among those meeting PA guidelines. This highlights the limitations of threshold-based definitions and underscores the importance of assessing full daily movement patterns. Promoting light-intensity PA may offer a feasible strategy to reduce sedentary time, particularly in girls, older adolescents, and individuals with higher BMI. The study was registered in the German Clinical Trials Register (DRKS00022258).

Peripheral helper T (Tph) cells, a recently identified Th cell subset, have been implicated in various autoimmune diseases. However, their role in granulomatosis with polyangiitis (GPA) remains unclear. This study aimed to investigate the potential clinical significance of circulating Tph cells (cTph) in GPA. Peripheral blood mononuclear cells were collected from 74 remission GPA-patients, 26 active GPA-patients and 22 age- and sex-matched healthy controls. Flow cytometry was used to quantify cTph cells and their subset distribution. Single-cell multi-omics profiling was performed in an independent cohort (5 remission GPA-patients, 5 active GPA-patients and 5 healthy controls). Plasma IL-21 levels were measured by enzyme-linked immunosorbent assay, and associations between cTph cells and clinical parameters were evaluated. active GPA-patients showed an increased frequency and absolute number of cTph compared to remission GPA-patients, and both GPA groups exhibited cTph2-skewed distribution compared to healthy controls. Remission GPA-patients with generalized disease exhibited higher cTph frequencies than those with localized disease. cTph cells from active GPA-patients displayed an activated phenotype and a transcriptional profile marked by pro-inflammatory and survival-associated genes. Plasma IL-21 levels did not differ significantly between the three groups. Notably, absolute counts of memory cTph and cTph2 cells correlated positively with clinical markers of disease activity, and were significantly elevated in GPA patients with higher cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) titers. cTph cells are expanded and exhibit an activated, pro-inflammatory profile with a cTph2-skewed distribution in active GPA-patients. Their association with disease activity may support a potential role in disease pathogenesis and highlight their potential as therapeutic targets, warranting further investigation.

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is difficult to manage due to the heterogeneous disease course. There is a high need for new biomarkers to identify patients at high risk for ILD progression. Fibroblast activation protein (FAP) has gained interest as a biomarker to reflect fibrotic activity. As circulating FAP (cFAP) can be measured in blood, we aimed to investigate the value of cFAP in SSc-ILD. cFAP concentrations were determined in plasma samples of 210 patients with systemic sclerosis (SSc) using an enzyme-linked immunosorbent assay. We compared cFAP in baseline and repeated longitudinal samples between SSc patients with (n = 63) and without ILD (n = 147). Furthermore, we investigated the correlation between cFAP and ILD progression at follow-up. In an exploratory analysis, we also investigated if cFAP was associated with other disease-related clinical features and all-cause mortality. cFAP levels were not different between SSc patients with- and without ILD, both at baseline (median 91.5 and 97.7 ng/mL respectively; p = 0.80) or during follow-up. Furthermore, we found no association between cFAP at baseline and ILD progression at 1, 2 and 5 years of follow-up. Notably, cFAP levels were elevated at baseline in patients with higher skin scores (mRSS ≥ 10 compared to mRSS < 10; p = 0.01). Finally, we did not find an association between cFAP and all-cause mortality at 5 and 10 years of follow-up. In conclusion, cFAP does not seem useful as a biomarker in SSc-ILD. However, the association between cFAP and skin score deserves further investigation.

Rheumatoid arthritis (RA) is an aggressive, systemic autoimmune disease in which overactivated macrophages play a critical role in its pathogenesis. This study aimed to explore the potential role of glycolytic reprogramming in the production of proinflammatory cytokines by macrophages in RA. The Seahorse assay was conducted on RA or healthy control (HC) serum-treated human monocyte-derived macrophages (HMDMs) to evaluate glycolysis levels. RNA sequencing was performed to identify activated signaling pathways and key molecules in HMDMs stimulated by RA serum. The proinflammatory cytokines and hypoxia-inducible factor 1α (HIF-1α) were verified by Western blotting and quantitative polymerase chain reaction (qPCR). We found that HMDMs stimulated with RA serum showed higher aerobic glycolysis levels than those treated with HC serum, along with higher expression of glycolysis-related genes, including hexokinase2 (HK2), pyruvate kinase L/R (PKLR), and phosphoglycerate kinase 1 (PGK1). Furthermore, RA serum-treated macrophages exhibited a higher level of interleukin-1 beta (IL-1β), and the expression of IL-1β positively correlated with HK2. Inhibition of glycolysis by 3-bromopyruvate (3BrPA) or HK2 knockdown significantly suppressed IL-1β production in macrophages. The HIF-1α-associated signaling pathways and HIF-1α protein levels were also elevated in RA serum-treated macrophages. Inhibition of glycolysis by 3BrPA or knockdown of HK2 reduced HIF-1α. Inhibiting HIF-1α can suppress IL-1β production of RA serum-treated macrophages, and vice versa. TNF-α and IL-1β enhanced HIF-1α and IL-1β expression in macrophages, an effect attenuated by glycolysis inhibition. Blocking TNF-α and IL-1β in RA serum diminished both glycolysis and IL-1β production. Our findings demonstrate that RA serum triggers aerobic glycolysis in macrophages, which promotes HIF-1α to drive IL-1β production. Notably, IL-1β within RA serum amplifies its own expression via this glycolysis-HIF-1α axis, establishing a pathogenic positive feedback loop in RA.

Rheumatoid arthritis (RA) associated interstitial lung disease (ILD) is the most common pulmonary manifestations of RA, with a progressive course and a poor survival. An early detection and better treatment is essential to improve outcome. We evaluated 16 analytes that could be relevant for the development of RA ILD. In an inception cohort of 1118 early RA patients, pulmonary fibrosis (PF) were identified in 60 patients after a mean follow-up of 5.3 years using high resolution computer tomography (HRCT). As controls, 124 early RA patients without PF and 94 matched population controls without known rheumatic disease were studied. Analysis of antibodies against histones 3 and 4 derived citrullinated peptides (CitH3/H4), and cytokines/chemokines levels were performed in plasma samples collected at RA diagnosis using in-house ELISA and Luminex analysis. Anti-CitH3(114-135) antibodies were the only antibody with increased frequency and levels in patients with PF versus without PF. The highest OR for PF development were found when combining positivity for anti-CitH3(114-135) and -CitH4(31-50) antibodies, OR 2.26. Levels of IL1α, IL1ß, TNFα, VEGFA and MIPα remained significantly elevated in patients with PF compared without PF, after adjustments and Bonferroni corrections. Several of the cytokines/chemokines correlated significantly with the histone antibodies in patients without PF. Partial least squares discriminant analysis including antibodies against citrullinated histon peptides and cytokines/chemokines identified significantly in PF in non-smokers. Antibodies against CitH3 peptides and several of the analysed cytokines/chemokines in samples collected at diagnosis were associated with subsequent delevopment of PF in patients with RA.

"Pauci-immune" and "fibroblast-rich" synovial pathotypes are predictors of resistance to multi-drug immunosuppression. For these "difficult-to-treat" (D2T) endotypes of rheumatoid arthritis (RA), depletion of arthritogenic fibroblast-like synoviocytes (FLS) has emerged as promising treatment strategy. Profiling at a single-cell level has enabled the molecular characterization of distinct subpopulations of arthritogenic FLS. Advances in molecular engineering have empowered the development of multiple modalities (anti-FLS antibodies, T-cell engagers, cytotoxic cells with chimeric receptors recognizing FLS-specific antigens) to achieve depletion of arthritogenic subpopulations of FLS with unprecedented selectivity. A recently published study highlighted in this article, adds apoptosis-promoting aptamers in the armamentarium of the FLS-killing pipeline.

BackgroundRheumatoid arthritis (RA) and Psoriatic arthritis (PsA) are systemic auto-immune diseases of unknown aetiology that lead to systemic inflammation and synovial joint destruction. Identification of specific serum proteins that selectively regulate these diseases, or which precede disease development could have great potential as disease biomarkers and predictors.MethodsSerum levels of C-reactive protein (CRP), sICAM-1, sVCAM-1, Serum amyloid A (SAA), Matrix metalloproteinases (MMPs 1, 3 and 9) and metabolic markers: Active Glucose-dependent Insulinotropic polypeptide (GIP), active Glucagon-like peptide-1 (GLP-1), C-Peptide, Glucagon, Insulin, Leptin, Pancreatic Polypeptide (PP) were measured by Meso Scale Discovery (MSD) multiplex analysis assay.ResultsSerum levels of sICAM-1, MMP1, MMP3, PP, c-Peptide, CRP and SAA were specifically upregulated in RA, but not in PsA disease, displaying high sensitivity (ROC curves). In the early phase of the disease, these markers may be suitable for discriminating RA from PsA patients. Differences in sex, BMI, and disease activity were observed. This is the first study which directly compare serum metabolic markers between diseases and identifies specific disease signatures between RA and PsA. In addition, this study identified that CRP, SAA, GLP-1, GIP-1, Leptin and PP serum protein precede disease onset, as they are already altered in the serum of ‘individuals at risk’ of developing RA. Of these, CRP, SAA, Leptin and PP might predict IAR conversion to RA+, thus making them suitable candidates for disease prediction.ConclusionsAltogether, this study identifies selective serum markers associated with RA and PsA, which are pathotype-specific and are predictors of RA disease onset.

Osteoarthritis (OA) is a complex disorder driven by the combination of environmental and genetic factors. Given its high global prevalence and heterogeneity, developing effective and personalized treatment methods is crucial. This requires identifying new disease mechanisms, drug targets, and biomarkers. Various omics approaches have been applied to identify OA-related genes, pathways, and biomarkers, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics. These omics studies have generated vast datasets that are shaping the field of OA research. The emergence of high-resolution methodologies, such as single-cell and spatial omics techniques, further enhances our ability to dissect molecular complexities within the OA microenvironment. By integrating these multi-layered datasets, researchers can uncover central signaling hubs and disease mechanisms, ultimately facilitating the development of targeted therapies and precision medicine approaches for OA treatment.