Performance of knee image digital analysis of radiographs of patients with end-stage knee osteoarthritis

Objective: Knee Image Digital Analysis (KIDA) is standardized radiographic analysis software for measuring osteoarthritis (OA) characteristics. It was validated in mild OA, but used for severe OA as well. The current goal was to evaluate the performance of KIDA in severe OA. Design: Of 103 patients, standardized radiographs were performed before and one and 2 years after treatment for severe OA. All radiographs were evaluated on subchondral bone density, joint space width (JSW), osteophytes, eminence height, and joint angle, twice within years by the same observer. Part of the radiographs were randomly selected for reevaluation twice within 1 month and evaluation by another observer. The intraclass correlation coefficient (ICC), smallest detectable difference (SDD) and coefficient of variation (CV) were calculated; the SDD and CV were compared to those in mild OA. The relation of severity with KIDA parameters and with observer differences was calculated with linear regression. Results: Intra-observer ICCs were higher in the 98 severe radiographs reanalyzed within 1 month (all >0.8) than the 293 reanalyzed within years (all >0.5; most >0.8) and than inter-observer ICCs (all >0.7). SDDs and CVs were smaller when reanalyzed within a month and comparable to those in mild OA. Some parameters showed bias between readings. Severity showed significant relation with osteophytes and JSW parameters, and with the observer variation in these parameters (all P < 0.04). Conclusions: KIDA is a well-performing tool also for severe OA. In order to decrease variability and SDDs, images should be analyzed in a limited time frame and randomized order

Dextran-tryamine hydrogel maintains position and integrity under simulated loading in a human cadaver knee model

Objective: This dextran-tyramine hydrogel is a novel cartilage repair technique, filling focal cartilage defects to provide a cell-free scaffold for subsequent cartilage repair. We aim to asses this techniques’ operative feasibility in the knee joint and its ability to maintain position and integrity under expected loading conditions. Method: Seven fresh-frozen human cadaver legs (age range 55–88) were used to create 30 cartilage defects on the medial and lateral femoral condyles dependent of cartilage quality, starting with 1.0 ​cm2; augmenting to 1.5 ​cm2 and eventually 2.0 ​cm2. The defects were operatively filled with the injectable hydrogel scaffold. The knees were subsequently placed on a continues passive motion machine for 30 ​min of non-load bearing movement, mimicking post-operative rehabilitation. High resolution digital photographs documented the hydrogel scaffold after placement and directly after movement. Three independent observers blinded for the moment compared the photographs on outline attachment, area coverage and hydrogel integrity. Results: The operative procedure was uncomplicated in all defects, application of the hydrogel was straightforward and comparable to common cartilage repair techniques. No macroscopic iatrogenic damage was observed. The hydrogel scaffold remained predominately unchanged after non-load bearing movement. Outline attachment, area coverage and hydrogel integrity were unaffected in 87%, 93% and 83% of defects respectively. Larger defects appear to be more affected than smaller defects, although not statistically significant (p ​> ​0.05). Conclusion: The results of this study show operative feasibility of this cell-free hydrogel scaffold for chondral defects of the knee joint. Sustained outline attachment, area coverage and hydrogel integrity were observed after non-load bearing knee movement

The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review

OBJECTIVE: A fusion protein of interleukin-4 and interleukin-10 (IL4-10 FP) was developed as a disease-modifying osteoarthritis drug (DMOAD), and chondroprotection, anti-inflammation, and analgesia have been suggested. To better understand the mechanisms behind its potential as DMOAD, this systematic narrative review aims to assess the potential of IL-4, IL-10 and the combination of IL-4 and IL-10 for the treatment of osteoarthritis. It describes the chondroprotective, anti-inflammatory, and analgesic effects of IL-4, IL-10, and IL4-10 FP. DESIGN: PubMed and Embase were searched for publications that were published from 1990 until May 21, 2021 (moment of search). Key search terms were: Osteoarthritis, Interleukin-4, and Interleukin-10. This yielded 2,479 hits, of which 43 were included in this review. RESULTS: IL-4 and IL-10 showed mainly protective effects on osteoarthritic cartilage in vitro and in vivo, as did IL4-10 FP. Both cytokines showed anti-inflammatory effects, but also proinflammatory effects. Only in vitro IL4-10 FP showed purely anti-inflammatory effects, indicating that proinflammatory effects of one cytokine can be counteracted by the other when given as a combination. Only a few studies investigated the analgesic effects of IL-4, IL-10 or IL4-10 FP. In vitro, IL-4 and IL4-10 FP were able to decrease pain mediators. In vivo, IL-4, IL-10, and IL4-10 FP were able to reduce pain. CONCLUSIONS: In conclusion, this review describes overlapping, but also different modes of action for the DMOAD effects of IL-4 and IL-10, giving an explanation for the synergistic effects found when applied as combination, as is the case for IL4-10 FP

Gene expression signatures of synovial fluid multipotential stromal cells (MSCs) in advanced knee osteoarthritis and following knee joint distraction

Osteoarthritis (OA) is the most common musculoskeletal disorder. Although joint replacement remains the standard of care for knee OA patients, knee joint distraction (KJD), which works by temporarily off-loading the joint for 6–8 weeks, is becoming a novel joint-sparing alternative for younger OA sufferers. The biological mechanisms behind KJD structural improvements remain poorly understood but likely involve joint-resident regenerative cells including multipotent stromal cells (MSCs). In this study, we hypothesized that KJD leads to beneficial cartilage-anabolic and anti-catabolic changes in joint-resident MSCs and investigated gene expression profiles of synovial fluid (SF) MSCs following KJD as compared with baseline. To obtain further insights into the effects of local biomechanics on MSCs present in late OA joints, SF MSC gene expression was studied in a separate OA arthroplasty cohort and compared with subchondral bone (SB) MSCs from medial (more loaded) and lateral (less loaded) femoral condyles from the same joints. In OA arthroplasty cohort (n = 12 patients), SF MSCs expressed lower levels of ossification- and hypotrophy-related genes [bone sialoprotein (IBSP), parathyroid hormone 1 receptor (PTH1R), and runt-related transcription factor 2 (RUNX2)] than did SB MSCs. Interestingly, SF MSCs expressed 5- to 50-fold higher levels of transcripts for classical extracellular matrix turnover molecules matrix metalloproteinase 1 (MMP1), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), and tissue inhibitor of metalloproteinase-3 (TIMP3), all (p < 0.05) potentially indicating greater cartilage remodeling ability of OA SF MSCs, compared with SB MSCs. In KJD cohort (n = 9 patients), joint off-loading resulted in sustained, significant increase in SF MSC colonies’ sizes and densities and a notable transcript upregulation of key cartilage core protein aggrecan (ACAN) (weeks 3 and 6), as well as reduction in pro-inflammatory C–C motif chemokine ligand 2 (CCL2) expression (weeks 3 and 6). Additionally, early KJD changes (week 3) were marked by significant increases in MSC chondrogenic commitment markers gremlin 1 (GREM1) and growth differentiation factor 5 (GDF5). In combination, our results reveal distinct transcriptomes on joint-resident MSCs from different biomechanical environments and show that 6-week joint off-loading leads to transcriptional changes in SF MSCs that may be beneficial for cartilage regeneration. Biomechanical factors should be certainly considered in the development of novel MSC-based therapies for OA

The fear for adverse bleeding and cardiovascular events in hemophilia patients using (non-)selective non-steroidal anti-inflammatory drugs: A systematic review reporting on safety

(Non-)selective non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for musculoskeletal related pain. These cheap and easily accessible drugs may be of great value for hemophilia patients in developing countries and countries with a high rate of opioid poisoning, but also in developed countries due to potential joint protective effects. However, fear for adverse bleeding and cardiovascular events during the use of these drugs restrains prescription within this population. To give a complete overview of all publications reporting on safety, a systematic search till March 2021 was performed. All studies were reviewed and critically appraised and this resulted in 19 studies eligible for inclusion. Most studies with (non-)selective NSAIDs showed no evident risk for relevant adverse bleeding or cardiovascular events. However, some studies had a high risk of bias and studies reporting on cardiovascular events were limited. Future studies with longitudinal follow-up in well-defined large patient populations, including older patients, focusing on both adverse bleeding and cardiovascular events are required to confirm the alleged safe use

Relevance of Biomarkers in Serum vs. Synovial Fluid in Patients with Knee Osteoarthritis

The association between structural changes and pain sensation in osteoarthritis (OA) remains unclear. Joint deterioration in OA leads to the release of protein fragments that can either systemically (serum) or locally (synovial fluid; SF) be targeted as biomarkers and describe structural changes and potentially pain. Biomarkers of collagen type I (C1M), type II (C2M), type III (C3M), type X (C10C), and aggrecan (ARGS) degradation were measured in the serum and SF of knee OA patients. Spearman’s rank correlation was used to assess the correlation of the biomarkers’ levels between serum and SF. Linear regression adjusted for confounders was used to evaluate the associations between the biomarkers’ levels and clinical outcomes. The serum C1M levels were negatively associated with subchondral bone density. The serum C2M levels were negatively associated with KL grade and positively associated with minimum joint space width (minJSW). The C10C levels in SF were negatively associated with minJSW and positively associated with KL grade and osteophyte area. Lastly, the serum C2M and C3M levels were negatively associated with pain outcomes. Most of the biomarkers seemed to mainly be associated with structural outcomes. The overall biomarkers of extracellular matrix (ECM) remodeling in serum and SF may provide different information and reflect different pathogenic processes

Biochemical marker research in hemophilic arthropathy: A systematic review

Hemophilic arthropathy (HA) causes major morbidity. Breakthrough therapies reduce the bleeding frequency tremendously, but well-defined joint outcome assessments with a focus on early changes and subclinical damage are lacking. Biomarkers reflecting joint tissue turnover/inflammation might be useful to predict invalidating arthropathy. This systematic review summarized and categorized publications on blood/urinary biomarkers in HA to provide leads for implementation. A PubMed/EMBASE search was performed on September 9, 2019. All publications were assessed and allocated to one or several BIPED-categories, based on the utility of biomarkers. Of the initial 1307 publications found, 27 were eligible for inclusion. The majority (81%, n = 32/42) was cross-sectional in design, including relatively small numbers of patients (median 44, interquartile range 35-78). Fourteen percent (n = 6/42) investigated dynamic changes around a bleeding or treatment. Only two studies investigated the prognostic value of biomarkers. Most promising biomarkers were serum Coll2-1, COL-18N, COMP, C1,2C, C2M, CS846, MIF, plasma sVCAM-1 and urinary CTX-II. Comparing performances and pooling data was not possible due to heterogeneity. Currently, biomarker research in HA is still in an explorative stage and not yet sufficient for translation into daily practice. Clearly, larger homogeneous longitudinal studies in well-defined populations should be performed for further development

Subchondral bone changes after joint distraction treatment for end stage knee osteoarthritis

Objective: Increased subchondral cortical bone plate thickness and trabecular bone density are characteristic of knee osteoarthritis (OA). Knee joint distraction (KJD) is a joint-preserving knee OA treatment where the joint is temporarily unloaded. It has previously shown clinical improvement and cartilage regeneration, indicating reversal of OA-related changes. The purpose of this research was to explore 3D subchondral bone changes after KJD treatment using CT imaging. Design: Twenty patients were treated with KJD and included to undergo knee CT imaging before, one, and two years after treatment. Tibia and femur segmentation and registration to canonical surfaces were performed semi-automatically. Cortical bone thickness and trabecular bone density were determined using an automated algorithm. Statistical parametric mapping (SPM) with two-tailed F-tests was used to analyze whole-joint changes. Results: Data was available of 16 patients. Subchondral cortical bone plate thickness and trabecular bone density were higher in the weight-bearing region of the most affected compartment (MAC; mostly medial). Especially the MAC showed a decrease in thickness and density in the first year after treatment, which was sustained towards the second year. Conclusions: KJD treatment results in bone changes that include thinning of the subchondral cortical bone plate and decrease of subchondral trabecular bone density in the first two years after treatment, potentially indicating a partial normalization of subchondral bone

IL4-10 Fusion Protein Shows DMOAD Activity in a Rat Osteoarthritis Model

OBJECTIVE: Ideally, disease-modifying osteoarthritis (OA) drugs (DMOAD) should combine chondroprotective, anti-inflammatory, and analgesic effects in a single molecule. A fusion protein of interleukin-4 (IL-4) and IL-10 (IL4-10 FP) possesses these combined effects. In this study, the DMOAD activity of rat IL4-10 FP (rIL4-10 FP) was tested in a rat model of surgically induced OA under metabolic dysregulation. DESIGN: rIL4-10 FP was produced with HEK293F cells. Bioactivity of purified rIL4-10 FP was determined in a whole blood assay. Male Wistar rats ( n = 20) were fed a high-fat diet (HFD) to induce metabolic dysregulation. After 12 weeks, OA was induced according to the Groove model. Two weeks after OA induction, rats were randomly divided into 2 groups and treated with 10 weekly, intra-articular injections of either rIL4-10 FP ( n = 10) or phosphate buffered saline (PBS; n = 10). Possible antibody formation was evaluated using ELISA, cartilage degeneration and synovial inflammation were evaluated by histology and mechanical allodynia was evaluated using the von Frey test. RESULTS: Intra-articular injections with rIL4-10 FP significantly reduced cartilage degeneration ( P = 0.042) and decreased mechanical allodynia ( P < 0.001) compared with PBS. Only mild synovial inflammation was found (nonsignificant), limiting detection of putative anti-inflammatory effects. Multiple injections of rIL4-10 FP did not induce antibodies against rIL4-10 FP. CONCLUSION: rIL4-10 FP showed chondroprotective and analgesic activity in a rat OA model with moderate cartilage damage, mild synovial inflammation, and pain. Future studies will need to address whether less frequent intra-articular injections, for example, with formulations with increased residence time, would also lead to DMOAD activity

Osteochondritis Dissecans of the Knee Associated With Mechanical Overload

Background: Osteochondritis dissecans (OCD) of the knee is a rare but potentially incapacitating disorder in which subchondral bone detaches, leading to an osteochondral fragment that can become unstable and progress into a loose body. The exact cause is unknown, although several biological and mechanical factors have been described. Purpose: To provide insight into epidemiological data of a large cohort of patients affected by OCD of the knee and to identify potential factors contributing to the cause of this disorder. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 236 patients (259 knees) affected by OCD were included in our Knee Registry (2005-2022) and retrospectively analyzed. Patient characteristics were extracted from the medical records. Location and International Cartilage Regeneration & Joint Preservation Society grade (1-4) of OCD were assessed using magnetic resonance imaging. If available, a full-leg standing radiograph was used to assess alignment. Additionally, a statistical scoring system for instability risk was created. Results: A total of 263 OCD lesions were identified in 259 knees, 66.2% on the medial femoral condyle (MFC), 26.6% on the lateral femoral condyle (LFC), 3.8% on the trochlea, 2.7% on the patella, and 0.8% on the lateral tibia plateau. Male patients made up 57.6% of the sample, which had a mean age of 21.8 years. A very high percentage of patients (77.1%; n = 182) practiced sports, of whom 67.6% (n = 123) were engaged in high-impact sports. The location of the OCD lesions and the leg alignment (n = 110) were significantly correlated: MFC lesions were associated with more varus than valgus alignment (47.5% vs 11.3%) and patients with LFC lesions had more valgus than varus alignment (46.7% vs 20.0%; P =.002). Based on age, smoking, sports activity, and preceding trauma, a multivariable scoring system (0-11 points) was created. An increased risk of lesion instability was associated with an increased score: 29.0% at 0 points and 97.0% at 11 points. Conclusion: This study provides detailed epidemiological data for 236 patients affected by OCD of the knee. Older age, smoking, inactivity, and preceding trauma were predictive for instability of OCD lesions. There was an association between OCD of the MFC and varus malalignment and between OCD of the LFC and valgus malalignment. This finding, in combination with the high percentage of patients practicing high-impact sports, suggests an important role for mechanical overload in the pathogenesis of OCD