OBJECTIVE:Systemic sclerosis (SSc) can affect flexor tendons, contributing to hand function problems and reduced quality of life. Tendon changes are currently assessed with ultrasonography and measured manually, a time-consuming process prone to interobserver variability. This study aimed to develop and evaluate an automated method for standardized measurement of finger flexor tendon thickness on longitudinal ultrasonography images in patients with SSc. METHODS:In this proof-of-concept study, ultrasonography images were obtained from the multicenter HANDSOME cohort. The training dataset included 687 images from 59 individuals. The independent testing dataset consisted of 150 images from 15 individuals. A deep learning-based pipeline using nnU-Net was developed to automatically segment the flexor tendon, metacarpal head, and proximal phalanx base. The metacarpophalangeal joint was subsequently localized, after which tendon thickness was automatically measured perpendicular to the tendon. Automated measurements were compared with manual expert measurements. RESULTS:Automated tendon-thickness measurements were successfully obtained in all images (100%). The model demonstrated high segmentation performance, with Dice similarity coefficients of 0.90 for the flexor tendon, 0.83 for the proximal phalanx base, and 0.76 for the metacarpal head. Automated thickness measurements showed strong agreement with manual measurements (intraclass correlation coefficient 0.83). The mean absolute measurement error was 0.25 mm, corresponding to a relative measurement error of 8.0%. Visual expert evaluation classified 90% of automated segmentations as clinically acceptable. CONCLUSION:Automated analysis of longitudinal hand ultrasonography images enables accurate measurement of flexor tendon thickness. This approach may facilitate standardized tendon assessment and support studies investigating tendon involvement.

Objective This study aimed to divide leg malalignment into different categories of valgus and varus of the femur, tibia, and intra-articular knee joint and investigates whether knee osteoarthritis (OA) patients are susceptible for changes of such leg deformities over time. Design This study included 317 radiographs and CT-images on baseline and 24 months of 169 patients (median age 67, 78.2 % female) of the prospective European IMI-APPROACH cohort, enrolled for knee OA. Femoral, tibial, and intra-articular geometry was determined. Different categories were analysed based on varus or valgus in the femur, in the tibia, or within the intra-articular joint. Changes of these variables over time and their correlations were determined with mixed model analysis. Results Femurs tended to become more varus-like over the two-year follow up (0.3°, 95 % CI 0.6°–0.1°, p = 0.02), bony valgus femurs became more varus shaped (1.1°, 95 % CI:1.7°–0.5°, p < 0.001). Patients with bone varus and a normal joint line convergence angle (JLCA) showed a significant increase in intra-articular joint varus, with a mean JLCA increase of 1.1°(95 % CI:0.4°–1.7°, p = 0.005). By two years, they reached the threshold for defining intra-articular joint varus deformity, with a JLCA of 2.0°. Conclusions Substantial intra-articular joint and bone varus progression was observed within two years. This study shows that bone deformity is to some extent a dynamic process and there is a growing varus malalignment in the intra-articular knee joint and bones. Thereby this study emphasizes the importance of leg malalignment for progression of intra-articular knee joint changes in early OA.

Background Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease frequently associated with hand involvement, leading to significant functional impairment. Imaging techniques provide unique opportunities to visualize and quantify structural and functional abnormalities of the hand, supporting diagnosis, monitoring, and treatment evaluation. This systematic review summarizes the imaging techniques used in SSc. Methods A systematic search of PubMed and Embase was conducted. Eligible studies included original research articles in English that applied or evaluated imaging techniques of the hands in SSc, published after 2000. Ultrasound and nailfold capillaroscopy were excluded, given their established use. Screening was performed independently by two authors. Findings were synthesized by clinical manifestations, study quality was assessed using the QUADAS-2 tool. Results Sixty-one studies met the inclusion criteria. In total, 25 distinct imaging techniques were identified, enabling assessment of various hand structures, including vascular involvement, inflammation, fibrosis, calcifications, erosions, and bone marrow edema. Vascular imaging was most extensively studied, particularly in the context of Raynaud’s phenomenon and digital ischemia, with multiple techniques demonstrating impaired perfusion and altered thermoregulatory responses. MRI consistently detected subclinical inflammatory and erosive changes of joints and soft tissues,. CT-based techniques provided detailed assessment of calcinosis cutis, while optical and photoacoustic methods showed promise for quantifying skin fibrosis. Conclusion Imaging techniques provide valuable, complementary insights into hand involvement in SSc, often revealing subclinical disease. Despite promising results, limited standardization and longitudinal validation currently restrict clinical implementation. Future studies should focus on harmonizing protocols and validating against clinically meaningful outcomes.

Background/Objectives: Tenosynovitis is a common feature of psoriatic arthritis (PsA) and is typically assessed using semi-quantitative magnetic resonance imaging (MRI) scoring. However, visual scoring s variability. This study evaluates a fully automated, deep-learning approach for ankle tenosynovitis segmentation and volume-based quantification from MRI in psoriatic arthritis (PsA) patients. Methods: We analyzed 364 ankle 3T MRI scans from 71 PsA patients. Four tenosynovitis pathologies were manually scored and used to create ground truth segmentations through a human-machine workflow. For each pathology, 30 annotated scans were used to train a deep-learning segmentation model based on the nnUNet framework, and 20 scans were used for testing, ensuring patient-level disjoint sets. Model performance was evaluated using Dice scores. Volumetric pathology measurements from test scans were compared to radiologist scores using Spearman correlation. Additionally, 218 serial MRI pairs were assessed to analyze the relationship between changes in pathology volume and changes in visual scores. Results: The segmentation model achieved promising performance on the test set, with mean Dice scores ranging from 0.84 to 0.92. Pathology volumes correlated with visual scores across all test MRIs (Spearman ρ = 0.52-0.62). Volume-based quantification captured changes in inflammation over time and identified subtle progression not reflected in semi-quantitative scores. Conclusions: Our automated segmentation tool enables fast and accurate quantification of ankle tenosynovitis in PsA patients. It may enhance sensitivity to disease progression and complement visual scoring through continuous, volume-based metrics.

Cartilage surface mapping is a technique that can visualize 3D cartilage thickness variation throughout a joint without a need for arbitrary regional definitions. The objective of this cross-sectional study was to utilize this technique to evaluate the cartilage thickness distribution in knee osteoarthritis patients and to analyze to what extent it depends on demographic, radiographic, and MRI structural pathology strata. Patients of the IMI-APPROACH cohort were included, with MRIs obtained at 1.5 T or 3 T. Tibial and femoral cartilage segmentation and registration with a canonical surface were performed semi-automatically. Kellgren-Lawrence and OARSI grading were performed on knee radiographs; MOAKS scoring was performed on MRI scans. The association of demographics and radiographic and MRI scorings with cartilage thickness distribution was analyzed with general linear models using statistical parametric mapping. Two hundred eighty-seven patients were included. Male sex and height were positively associated with cartilage thickness particularly in the trochlea and medial femur, respectively, with differences up to 0.5 mm (male vs female), while radiographic joint space narrowing and bone marrow lesions showed region-specific negative associations (up to 0.14–0.5 mm per grade). Kellgren-Lawrence grade, MOAKS meniscal extrusion, and osteophytes showed patterns of positive and negative associations, with increasing grades showing reduced local tibiofemoral cartilage thickness, but greater thickness in the trochlea (both up to 0.2–0.3 mm per grade). Decreased height, female sex, and increasing tibiofemoral pathology were associated with thinner tibiofemoral cartilage. Unexpected results such as consistently thicker cartilage in the anterior femur with increasing disease or osteophytosis states provide opportunities for future research.

INTRODUCTION:The majority of all patients with systemic sclerosis (SSc) experience hand function impairment. The exact cause for this impairment is yet unknown. As impaired hand function hugely impacts daily functioning and quality of life, there is a high unmet need for effective treatments. With the availability of new imaging modalities, biomarkers and laboratory techniques, opportunities arise to increase insights into the factors contributing to hand function impairment. The objective of this study is to identify risk factors and underlying mechanisms leading to hand function impairment in SSc. METHODS AND ANALYSIS:This is a longitudinal observational multicentre study in patients with very early diagnosis of systemic sclerosis and SSc under care of the Department of Rheumatology and Clinical Immunology of the University Medical Centre Utrecht (UMCU), St Antonius Hospital Nieuwegein, UMC Groningen (UMCG), Leiden UMC (LUMC), Radboudumc or Royal Free Hospital (RFH) London. Patients will be followed for 2 years. Medical history, clinical status, nailfold capillaroscopy, skin assessments, serum biomarker analysis, ultrasound, elastography and MRI will be performed, and results related to hand function measurements will be analysed. ETHICS AND DISSEMINATION:This study was approved by the Medical Research Ethics Committee NedMec (MREC NedMec) in the Netherlands and by HRA and Health and Care Research Wales in the UK. Results will be published in scientific journals and presented at scientific congresses and patient meetings. TRIAL REGISTRATION NUMBER:NCT06133244. PROTOCOL VERSION:V1.3 6-06-2024.

Objective To analyze and synthesize the information available from five pivotal, large-scale, multicenter, observational studies (CHECK, OAI, FNIH Biomarkers Consortium, IMI-APPROACH, and MOST) focusing on knee osteoarthritis (OA), which can be used to elucidate disease progression, risk factors, and the effectiveness of potential interventions. Design For this narrative review, a comprehensive literature search and data extraction from official web pages and scientific databases were conducted to compare methodologies, in- and exclusion criteria, outcomes, and cohort characteristics across the studies. Thematic, comparative, and qualitative analyses were employed to identify trends, commonalities, and disparities among the findings. Results The studies collectively enhanced understanding of the onset and progression of knee OA, and in several of the studies, hip OA, emphasizing the importance of both systemic and local risk factors. Advanced imaging and biomarkers are important components in all the cohorts, with the goal of aiding early diagnosis and tracking disease progression. All cohorts evaluated unique markers generally not available in the other cohorts, while other factors overlap, suggesting possibilities for combining or cross-validating between cohorts. Conclusions The collaborative efforts of major OA research significantly advance our understanding of knee OA. These studies highlight the importance of a multifaceted approach, integrating advanced imaging, biomarkers, and longitudinal data to tackle the complexities of OA. By synthesizing findings and addressing knowledge gaps such as heterogeneity of patients and used measurements, and use of novel pain measures, future research can develop more effective diagnostic tools and treatments, ultimately enhancing the quality of life for OA patients.

INTRODUCTION In knee OA, radiographic JSW is used as a surrogate for MRI-measured cartilage thickness, though they often do not correlate well. Variations in positioning between radiography (weight-bearing semi-flexion) and MRI (non-weight-bearing extension) may contribute to discrepancies. OBJECTIVE This study aimed to evaluate differences in 3D JSW and cartilage thickness distribution between these positions in knee OA patients. METHODS 21 symptomatic knee OA patients (KLG 2/3) were included. Exclusion criteria included prior knee surgery, MRI ineligibility, inability to stand unassisted for 15 minutes, or knee width > 15 cm (knee coil limit). A knee MRI protocol was performed using a 0.25T weight-bearing MRI system (G-scan Brio, Esaote). A coronal 3D dual-echo SSFP sequence (SHARC) was acquired to obtain images with an isotropic resolution of 0.66mm in both extended and flexed knee positions under weight-bearing conditions by rotating the system to 81°. Both scans were repeated under non-weight-bearing conditions by rotating the system to a horizontal position (0°). Knee flexion angles were measured, and the femur and tibia bones were segmented in 3D Slicer. 3D models were exported to Stradview to measure the tibia-femur distance at each vertex as a measure of JSW. The models and data were registered to canonical surfaces in wxRegSurf and further analyzed in MATLAB using the Surfstat package for statistical parametric mapping to derive p-values corrected for multiple vertex-wise comparisons. RESULTS The average knee angles of the 21 patients were 7.4±3.7° (extended) and 19.1±5.5° (flexed). The average JSW ranged from 3.1 mm to 14.7 mm across patients (Figure 1). A significantly smaller JSW for weight-bearing vs non-weight-bearing conditions, particularly in the outer medial and posterior lateral tibia for extended positions, and in the posterior medial tibia for flexed positions, was seen (Figure 2). Flexion increased the JSW in the anterior tibia and decreased it in the posterior tibia, particularly laterally in weight-bearing positions. CONCLUSION JSW distribution in knee OA patients varies significantly depending on both weight-bearing and knee flexion angle, and radiographic JSW measurements may not accurately reflect the joint space in non-weight-bearing positions, such as those used in MRI, especially in the lateral compartment. Currently ongoing cartilage analyses will indicate to which extent these JSW variations are attributable to changes in cartilage thickness or meniscal positioning.

Osteoarthritis (OA) is a multifactorial, mechano-inflammatory joint disorder characterized by cartilage degradation, synovial inflammation, and subchondral bone remodeling. Despite its high prevalence and significant impact on quality of life, no disease-modifying treatments have been approved. In many other disease areas, advanced omics technologies are impacting the development of advanced therapies. In OA, omics technologies such as genomics, transcriptomics, proteomics, and metabolomics have significantly increased our understanding of OA pathogenesis by uncovering molecular pathways driving disease progression. However, we have yet to see any tangible impact on the development of effective disease-modifying therapies. This review focuses on single- and multi-omics studies in OA, emphasizing their role in identifying molecular subtypes (endotypes) and therapeutic subtypes (theratypes). Multi-omics integration has revealed crosstalk between inflammatory, metabolic, and degradative processes, while spatial proteomics is beginning to provide insights into synovial tissue heterogeneity. However, challenges such as data complexity, lack of standardized frameworks, and limited translational validation hinder rapid progress. Future work will need to leverage artificial intelligence, single-cell, and spatial omics within longitudinal cohort studies. By addressing these challenges, omics-driven research holds promise for helping clinicians differentiating patients presenting with OA and psoriatic arthritis (PsA) affecting the hands or knees, developing personalized OA therapies, and achieving true disease modification beyond symptomatic relief.

OBJECTIVE:Knee osteoarthritis (OA) is a heterogeneous disease with different endotypes and phenotypes, resulting in patients' varying clinical and structural progression. Several genomic markers have been associated with knee OA presence. This study aimed to find new associations of these genetic markers with knee OA progression and to investigate the risk of knee OA progression using a polygenic risk score (PRS). METHODS:Data from knee OA patients (n = 297) from the IMI-APPROACH cohort with detailed measurements on disease progression were used. Knee OA progression definitions were based on the decrease in minimum joint space width in mm (minJSW; primary outcome), increase in pain on the Knee injury and Osteoarthritis Outcome Score (KOOS), and presence of radiographic OA (based on the Kellgren-Lawrence score) over 24 months. 30 previously reported single nucleotide polymorphisms (SNPs) associated with presence of OA irrespective of affected joints or knee OA specifically were investigated. We performed a SNP based genome-wide association analysis using the disease progression definitions. Furthermore, a PRS was created using the 30 presence SNPs to predict knee OA progression. RESULTS:Existing genetic markers for knee OA presence were not found to be associated with knee OA progression. The PRS of the SNPs for knee OA presence did also not show significant predictive value for knee OA progression. Unexpectedly, nineteen different variants were associated significantly (P < 5 × 10-8) with minJSW decrease. Ten SNPs are located near protein coding genes PLCL2, CDYL2, and NTNG1, and several SNPs are located in or near long non-coding RNAs (lncRNA). CONCLUSIONS:The 30 OA risk SNPs individually and combined in a PRS are not associated with progression of knee OA in the IMI-APPROACH cohort. 19 different SNPs were associated with minJSW decrease. We demonstrated how to employ multiple bioinformatics tools to, despite a limited dataset, still prioritise potential biomarkers for associations to knee OA progression.

Articular cartilage, an avascular, matrix-rich tissue, is thought to have limited repair, thereby contributing to osteoarthritis (OA), the common degenerative disease of joints. Cartilage regeneration does occur, however, in OA joints that are mechanically off-loaded. Here we show that mechanical stress, through release of matrix-bound growth factors, reprogrammes chondrocytes, the primary cells of cartilage, into ‘mechano-activated chondroprogenitors’ (MACs). Studying OA joint fluid before and after mechanical off-loading, reveals evidence of chronic MAC activity, which switches back to a chondrogenic one when mechanical stress is removed. Taken together, we conclude that OA is a disease of ‘arrested repair’ in which mechanical stress signals need to be switched off before full repair can occur. This novel paradigm uncovers exciting new treatment opportunities. ### Competing Interest Statement T.L.V. has received grant support for STEpUP OA from Pfizer, Novartis, UCB, Fidia, Biosplice, Galapagos and received ad hoc personal consultancy fees from Zoetis. C.D.B. and A.J.R. have received research grant funding through the institution from Biosplice Therapeutics (formerly Samumed LLC). C.D.B. has received consultancy fees from UCB and Galapagos. Centre for OA Pathogenesis Versus Arthritis Grants, 20205, 21621 Versus Arthritis, 20783 German Academic Exchange Service, https://ror.org/039djdh30, DAAD Dutch Arthritis Society, LLP-9 ZonMW-NWO talent program, VENI UKRI Future Leaders Fellowship, MR/S016538, MR/Y003470/1 Reumafonds grant, ISP14-3-301/16-1-404 Tissue Engineering and Regenerative Therapies Centre Versus Arthritis grant, 21156 Versus Arthritis project grant, 20775

OBJECTIVES:To compare inflammatory and structural differences in active PsA between DMARD-naive and DMARD-failure patients using diverse imaging approaches for future analyses. Additionally, to explore the influence of patient characteristics (clinical and demographic variables) on imaging findings. METHODS:Of the 80 patients included from the first cohort of the ongoing multicentre TOFA-PREDICT trial, 40 were DMARD-naive and 40 were DMARD-failure (csDMARD failure; one prior bDMARD excluding etanercept was allowed), all meeting classification criteria for PsA with a minimum disease duration of eight weeks. Baseline conventional radiographs of hands and feet, MRIs of both ankles, and whole-body [18F]-fluorodeoxyglucose PET/CT (18F-FDG PET/CT) were evaluated for inflammatory and structural imaging parameters, including Sharp-van der Heijde (SHS), Heel Enthesitis Magnetic Resonance Imaging Scoring System (HEMRIS) and Deauville synovitis scoring. Differences between groups and the influence of patient characteristics were examined with multiple linear regression. RESULTS:At baseline, patient characteristics were similar between groups. Imaging parameters showed limited inflammation and structural damage. Inflammatory imaging parameters were not significantly different (P > 0.200). Among structural parameters, only HEMRIS Achilles tendon structural damage was significantly different (P = 0.024, R2 = 0.071) and SHS Joint Space Narrowing was not statistically significant (P = 0.050, R2 = 0.048) with higher values for both in DMARD failures. After correction of patient characteristics, these differences in imaging disappeared (both P > 0.600). CONCLUSION:At baseline, PsA patient groups were comparable concerning structural and inflammatory imaging parameters, especially after correcting for patient characteristics. Thus, DMARD-naive and DMARD-failure patient groups may be combined in future PsA progression and treatment decision studies. TRIAL REGISTRATION:www.clinicaltrialsregister.eu. EudraCT: 2017-003900-28.

The systemic associations with knee osteoarthritis (KOA) are incompletely understood. This study explores aortic disease, musculoskeletal and organ findings in patients with KOA in relation to their symptoms or radiographic abnormalities. Full body computed tomography (CT) scans of 255 IMI-APPROACH participants were investigated using an automated analysis of multislice CT (Voronoi Health Analytics) that extracts aortic size and calcifications, and volumes and densities of bones, muscles, fat compartments and thoracic and abdominal organs. The CT measurements were primarily related to KOA as measured with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual scores and automated knee radiograph analysis of osteophytes, bone sclerosis and joint space width. The median age was 67 years, body mass index (BMI) 26.8 kg/m2 and 78

Background/Objectives: In the original canine groove model of osteoarthritis (OA), superficial scratches to the cartilage lead to slow progressive cartilage damage, with inflammation mimicking key aspects of human disease. The present study assesses a modified canine groove model with full-thickness cartilage grooves, gouged with a 3-mm biopsy punch, in the femoral condyles. This modified model enables the study of cartilage repair techniques, such as scaffold implantation. Methods: Cartilage defects were induced in the right knee of five mongrel dogs (four females, one male; 17 ± 4 months; 25.9 ± 2.0 kg) using the modified groove model, creating two full-thickness cartilage grooves on the femoral condyles. Data of a previously studied cohort of nine dogs (nine females; 18 ± 6 months; 17.6 ± 0.7 kg) with OA induced according to the original groove model served as the canine OA standard. Both groups were monitored up to 45 weeks post-surgery. Pain/function was assessed by force plate analysis, and cartilage integrity, chondrocyte activity, and synovial inflammation were evaluated on the surgically untouched tibial plateaus by macroscopic, histologic, and biochemical analyses. Results: Force plate analysis showed no significant changes in either group. Both models exhibited OA features. Experimental knees had more macroscopic and histologic damage, reduced proteoglycan content, and impaired retention of proteoglycans than controls. The modified groove model had less severe cartilage damage and synovial inflammation (p = 0.026, p = 0.017), with no other significant differences. Conclusions: The modified groove model induces OA at a slow pace, mirroring post-traumatic OA development in humans. It represents a mild OA model, comparable to the original groove model, and may be useful for evaluating cartilage repair strategies, such as scaffold implantation.

INTRODUCTION Articular cartilage was thought to have minimal repair capacity, but treatments like knee joint distraction show that regeneration is possible. Preliminary analyses have also suggested the possibility of spontaneous thickening of cartilage: thickening without external regenerative intervention. OBJECTIVE This study aims to evaluate spontaneous thickening in osteoarthritic knees. METHODS Patients from IMI-APPROACH and OAI cohorts were included. MRI-based mean medial and lateral cartilage thickness (ThCtAB; Chondrometrics) and knee radiographs were obtained at baseline, 1-year, and 2-year follow-up. Minimum medial and lateral joint space width (mJSW) and Kellgren-Lawrence grade (KLG) were automatically assessed from radiographs using KOALA (ImageBiopsy Lab). For each knee, mean whole-joint mJSW and ThCtAB changes over 2 years were calculated using linear regression. Knees were categorized as ‘thickening’ if both the mJSW and ThCtAB change were positive and as ‘thinning’ if both were negative; knees with inconsistent results were excluded. This approach was chosen because an increase in mJSW may reflect joint wedging or positional changes and increased ThCtAB may indicate swelling; especially in these expectedly relatively small changes, only an increase in both likely reflects true structural thickening.Patient characteristics and two-year changes were compared using Mann-Whitney U and chi-square tests. RESULTS Out of 1,457 knees analyzed, 203 (14%) demonstrated thickening and 658 (45%) thinning. Patients with thickening were younger, predominantly female, had less pain and a lower KLG compared to those with thinning (all p<0.05). Over 2 years, knees with thickening received significantly fewer injections (p=0.043) and showed greater improvements in both mJSW and ThCtAB (both p<0.001). Complete results are presented in Table 1. CONCLUSION Spontaneous cartilage thickening can occur in osteoarthritic knees and is more prevalent in younger females with less severe joint damage. Future research is needed to determine whether this thickening (repair) potential can be predicted and may guide regenerative treatment options.