Prevalence and progression of arterial calcifications on computed tomography in humans with knee osteoarthritis.

OBJECTIVES: Ectopic bone deposition plays an important role in osteoarthritis (OA) and in arterial wall disease. We aimed to investigate the prevalence and progression of arterial calcifications on whole-body computed tomography (CT) in persons with knee OA. METHODS: We included 118 (36 male) participants who satisfied the clinical American College of Rheumatology classification criteria for knee OA. Baseline investigations included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Kellgren-Lawrence grading. At baseline and after two years, a whole-body CT was performed using the same scanner and protocol. Calcifications were quantified in the carotid, brachiocephalic, coronary, thoracic aortic, abdominal aortic, iliac, femoropopliteal and crural arteries. Multivariable linear and logistic regression modeling was used for analyses. RESULTS: At baseline males were 66.9 ± 7.7 and females were 68.0 ± 5.6 years old. Calcifications were common, all participants except two females had some calcification, and prevalence ranged between 41.8% and 94.4% for various arterial beds. Baseline femoropopliteal calcifications were associated with a higher Kellgren-Lawrence grade (more severe knee OA). Median annual progression rate was 13.1% in males and 15.7% in females. Structural OA severity was not associated with progression, but a five points lower (worse) WOMAC was associated with 1% faster progression of arterial calcifications (p= 0.008). CONCLUSION: Around age 70 nearly all persons with knee OA have arterial calcifications, which progress substantially. For further investigation into shared causality intervention studies are needed.

Towards Personalized Treatment in Haemophilia: The Role of Genetic Factors in Iron and Heme Control to Identify Patients at Risk for Haemophilic Arthropathy.

The treatment landscape for haemophilia is changing rapidly, creating opportunities for personalized treatment. As major morbidity is still caused by haemophilic arthropathy, understanding the factors affecting joint damage and joint damage progression might lead to more individualized treatment regimens. We investigated the association of HFE mutations or HMOX1 polymorphisms affecting iron/heme handling with radiographic joint damage in 252 haemophilia patients (severe and moderate). Although iron levels and transferrin saturation were significantly increased in the 95 patients with an HFE mutation, neither carrying this mutation nor the HMOX1 polymorphism was associated with radiographic joint damage, and the same was true after adjustment for well-known factors associated with arthropathy. In conclusion, this study does not support the hypothesis that HFE mutations or HMOX1 polymorphisms can be used to predict the development of haemophilic arthropathy.

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.

Myostatin and CXCL11 promote nervous tissue macrophages to maintain osteoarthritis pain.

Pain is the most debilitating symptom of knee osteoarthritis (OA) that can even persist after total knee replacement. The severity and duration of pain do not correlate well with joint tissue alterations, suggesting other mechanisms may drive pain persistence in OA. Previous work identified that macrophages accumulate in the dorsal root ganglia (DRG) containing the somas of sensory neurons innervating the injured knee joint in a mouse OA model and acquire a M1-like phenotype to maintain pain. Here we aimed to unravel the mechanisms that govern DRG macrophage accumulation and programming. The accumulation of F4/80+iNOS+ (M1-like) DRG macrophages was detectable at day 3 after mono-iodoacetate (MIA)-induced OA in the mouse. Depletion of macrophages prior to induction of OA resolved pain-like behaviors by day 7 without affecting the initial development of pain-like behaviors. Analysis of DRG transcript identified CXCL11 and myostatin. CXCL11 and myostatin were increased at 3 weeks post OA induction, with CXCL11 expression partially localized in satellite glial cells and myostatin in sensory neurons. Blocking CXCL11 or myostatin prevented the persistence of OA pain, without affecting the initiation of pain. CXCL11 neutralization reduced the number of total and F4/80+iNOS+ DRG macrophages, whilst myostatin inhibition diminished the programming of F4/80+iNOS+ DRG macrophages. Intrathecal injection of recombinant CXCL11 did not induce pain-associated behaviors. In contrast, intrathecal myostatin increased the number of F4/80+iNOS+ DRG macrophages concurrent with the development of mechanical hypersensitivity that was prevented by macrophages depletion or CXCL11 blockade. Finally, myostatin inhibition during established OA, resolved pain and F4/80+iNOS+ macrophage accumulation in the DRG. In conclusion, DRG macrophages maintain OA pain, but are not required for the induction of OA pain. Myostatin is a key ligand in neuro-immune communication that drives the persistence of pain in OA through nervous tissue macrophages and represent a novel therapeutic target for the treatment of OA pain.

Subclinical synovial proliferation in patients with severe haemophilia A: The value of ultrasound screening and biochemical markers.

AIM: Subclinical bleeding and inflammation play a role in progression of haemophilic arthropathy. Synovial proliferation is predictive of joint bleeding and its early detection may guide treatment changes and prevent arthropathy progression. This study evaluated the prevalence of active and inactive subclinical synovial proliferation and investigated potential biochemical blood/urine markers to identify patients with active subclinical synovial proliferation. METHODS: This cross-sectional study included patients with severe haemophilia A born 1970-2006 who were evaluated during routine clinic visits. Patients with (a history of) inhibitors or recent joint bleeding were excluded. Elbows, knees and ankles were examined for subclinical synovial proliferation by ultrasound and physical examination. Active synovial proliferation was distinguished from inactive synovial proliferation using predefined criteria. Blood/urine biochemical markers (serum osteopontin, sVCAM-1, Coll2-1, COMP, CS846, TIMP, and urinary CTX-II) were compared individually and as combined indexes between patients with and without active synovial proliferation. RESULTS: This cohort consisted of 79 patients with a median age of 31 years (range 16.5-50.8 years) with 62/79 (78%) of the patients using continuous prophylaxis. The annualized joint bleeding rate over the last 5 years was .6 (.2-1.1). Active (17/79, 22%) and inactive subclinical synovial proliferation (17/79, 22%) were both prevalent in this cohort. Biochemical markers were not correlated with active subclinical synovial proliferation. CONCLUSION: Subclinical synovial proliferation, both active and inactive, was prevalent in patients with severe haemophilia A with access to prophylaxis and would be overlooked without routinely performed ultrasounds. Biochemical markers were unable to identify patients with active subclinical synovial proliferation.

Identifying multivariate disease trajectories and potential phenotypes of early knee osteoarthritis in the CHECK cohort.

OBJECTIVE: To gain better understanding of osteoarthritis (OA) heterogeneity and its predictors for distinguishing OA phenotypes. This could provide the opportunity to tailor prevention and treatment strategies and thus improve care. DESIGN: Ten year follow-up data from CHECK (1002 early-OA subjects with first general practitioner visit for complaints ≤6 months before inclusion) was used. Data were collected on WOMAC (pain, function, stiffness), quantitative radiographic tibiofemoral (TF) OA characteristics, and semi-quantitative radiographic patellofemoral (PF) OA characteristics. Using functional data analysis, distinctive sets of trajectories were identified for WOMAC, TF and PF characteristics, based on model fit and clinical interpretation. The probabilities of knee membership to each trajectory were used in hierarchical cluster analyses to derive knee OA phenotypes. The number and composition of potential phenotypes was selected again based on model fit (silhouette score) and clinical interpretation. RESULTS: Five trajectories representing different constant levels or changing WOMAC scores were identified. For TF and PF OA, eight and six trajectories respectively were identified based on (changes in) joint space narrowing, osteophytes and sclerosis. Combining the probabilities of knees belonging to these different trajectories resulted in six clusters ('phenotypes') of knees with different degrees of functional (WOMAC) and radiographic (PF) parameters; TF parameters were found not to significantly contribute to clustering. Including baseline characteristics as well resulted in eight clusters of knees, dominated by sex, menopausal status and WOMAC scores, with only limited contribution of PF features. CONCLUSIONS: Several stable and progressive trajectories of OA symptoms and radiographic features were identified, resulting in phenotypes with relatively independent symptomatic and radiographic features. Sex and menopausal status may be especially important when phenotyping knee OA patients, while radiographic features contributed less. Possible phenotypes were identified that, after validation, could aid personalized treatments and patients selection.

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.

Joint distraction using a purpose-built device for knee osteoarthritis: a prospective 2-year follow-up.

OBJECTIVE: Knee distraction treatment for end-stage osteoarthritis successfully postpones arthroplasty for years. Studies performed thus far used general intended use, patient-personalised or custom-made devices. In this study, for the first time, a device specifically designed for knee distraction is evaluated. DESIGN: 65 patients (≤65 years) with end-stage knee osteoarthritis indicated for arthroplasty received knee distraction. Before, 1-year and 2-year post-treatment, questionnaires were filled out and knee radiographs made. Adverse events and self-reported pain medication were registered. RESULTS: Forty-nine patients completed 2-year follow-up: one patient did not complete treatment, three patients received arthroplasty in the first and four patients in the second year follow-up. Eight patients were lost to follow-up in the second year. The total Western Ontario and McMaster Universities Osteoarthritis Index score showed a clinically relevant improvement at 1 and 2 years (+26 and +24 points), as did all subscales (all p<0.001). The minimum radiographic joint space width improved over 1 (+0.5 mm; p<0.001) and 2 (+0.4 mm; p=0.015) years, as did the physical Short-Form 36 (+10 points; p<0.001). The most common adverse event was pin tract infection, experienced by 66% of patients, in 88% successfully treated with oral antibiotics. In two cases, hospitalisation and/or intravenous antibiotics were needed. Eight patients experienced device-related complications. None of the complications influenced 2-year outcomes. Before treatment, 42% of patients used pain medication, which had nearly been halved 1 (23%; p=0.02) and 2 years (29%; p=0.27) post-treatment. CONCLUSIONS: Patients treated with a general applicable, for knee distraction purpose-built device showed, despite adverse events, significant clinical and structural improvement over 2 years. TRIAL REGISTRATION NUMBER: NL7986.

Machine-learning predicted and actual 2-year structural progression in the IMI-APPROACH cohort.

In the Innovative Medicine's Initiative Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) knee osteoarthritis (OA) study, machine learning models were trained to predict the probability of structural progression (s-score), predefined as >0.3 mm/year joint space width (JSW) decrease and used as inclusion criterion. The current objective was to evaluate predicted and observed structural progression over 2 years according to different radiographic and magnetic resonance imaging (MRI)-based structural parameters. Radiographs and MRI scans were acquired at baseline and 2-year follow-up. Radiographic (JSW, subchondral bone density, osteophytes), MRI quantitative (cartilage thickness), and MRI semiquantitative [SQ; cartilage damage, bone marrow lesions (BMLs), osteophytes] measurements were obtained. The number of progressors was calculated based on a change exceeding the smallest detectable change (SDC) for quantitative measures or a full SQ-score increase in any feature. Prediction of structural progression based on baseline s-scores and Kellgren-Lawrence (KL) grades was analyzed using logistic regression. Among 237 participants, around 1 in 6 participants was a structural progressor based on the predefined JSW-threshold. The highest progression rate was seen for radiographic bone density (39%), MRI cartilage thickness (38%), and radiographic osteophyte size (35%). Baseline s-scores could only predict JSW progression parameters (most P>0.05), while KL grades could predict progression of most MRI-based and radiographic parameters (P<0.05). In conclusion, between 1/6 and 1/3 of participants showed structural progression during 2-year follow-up. KL scores were observed to outperform the machine-learning-based s-scores as progression predictor. The large amount of data collected, and the wide range of disease stage, can be used for further development of more sensitive and successful (whole joint) prediction models. Trial Registration: Clinicaltrials.gov number NCT03883568.

Structural changes after ankle joint distraction in haemophilic arthropathy: an explorative study investigating biochemical markers and 3D joint space width.

INTRODUCTION: Ankle joint distraction (AJD) is a promising treatment for patients with severe haemophilic ankle arthropathy (HAA). However, some patients showed no clinical improvement after AJD and these differences may be related to structural differences. AIM: Primarily to quantify the structural changes after AJD in patients with HAA by the use of 3D joint space width (JSW) measurements and biochemical markers and secondarily to correlate these findings with clinical pain/function. METHODS: Patients with haemophilia A/B who underwent AJD were included for this study. Bone contours on MRI (performed before and 12 and 36 months after AJD) were drawn manually and percentage change in JSW was calculated. Blood/urine (before and 6, 12, 24 and 36 months after AJD) was collected for biomarker measurement (COMP, CS846, C10C, CALC2, PRO-C2, CTX-II) and combined indexes of markers were calculated. Mixed effects models were used for analyses on group level. Structural changes were compared with clinical parameters. RESULTS: Eight patients were evaluated. On group level, percentage changes in JSW showed a slight decrease after 12 months followed by a non-statistically significant increase in JSW after 36 months compared to baseline. Biochemical marker collagen/cartilage formation also showed an initial decrease, followed by a trend towards net formation 12, 24 and 36 months after AJD. On individual patient level, no clear correlations between structural changes and clinical parameters were observed. CONCLUSION: Cartilage restoration activity on group level in patients with HAA after AJD was in concordance with clinical improvements. Correlating structural modifications with clinical parameters in the individual patient remains difficult.

Exploring the differences between radiographic joint space width and MRI cartilage thickness changes using data from the IMI-APPROACH cohort.

OBJECTIVE: Longitudinal weight-bearing radiographic joint space width (JSW) and non-weight-bearing MRI-based cartilage thickness changes often show weak correlations. The current objective was to investigate these correlations, and to explore the influence of different factors that could contribute to longitudinal differences between the two methods. METHODS: The current study included 178 participants with medial osteoarthritis (OA) out of the 297 knee OA participants enrolled in the IMI-APPROACH cohort. Changes over 2 years in medial JSW (ΔJSWmed), minimum JSW (ΔJSWmin), and medial femorotibial cartilage thickness (ΔMFTC) were assessed using linear regression, using measurements from radiographs and MRI acquired at baseline, 6 months, and 1 and 2 years. Pearson R correlations were calculated. The influence of cartilage quality (T2 mapping), meniscal extrusion (MOAKS scoring), potential pain-induced unloading (difference in knee-specific pain scores), and increased loading (BMI) on the correlations was analyzed by dividing participants in groups based on each factor separately, and comparing correlations (slope and strength) between groups using linear regression models. RESULT: Correlations between ΔMFTC and ΔJSWmed and ΔJSWmin were statistically significant (p < 0.004) but weak (R < 0.35). Correlations were significantly different between groups based on cartilage quality and on meniscal extrusion: only patients with the lowest T2 values and with meniscal extrusion showed significant moderate correlations. Pain-induced unloading or BMI-induced loading did not influence correlations. CONCLUSIONS: While the amount of loading does not seem to make a difference, weight-bearing radiographic JSW changes are a better reflection of non-weight-bearing MRI cartilage thickness changes in knees with higher quality cartilage and with meniscal extrusion.

Artificial intelligence in osteoarthritis: repair by knee joint distraction shows association of pain, radiographic and immunological outcomes.

OBJECTIVES: Knee joint distraction (KJD) has been associated with clinical and structural improvement and SF marker changes. The current objective was to analyse radiographic changes after KJD using an automatic artificial intelligence-based measurement method and relate these to clinical outcome and SF markers. METHODS: Twenty knee osteoarthritis patients were treated with KJD in regular care. Radiographs and WOMAC were collected before and ∼1 year post-treatment. SF was aspirated before, during and after treatment; biomarker levels were assessed by immunoassay. Radiographs were analysed to obtain compartmental minimum and standardized joint space width (JSW), Kellgren-Lawrence (KL) grades, compartmental joint space narrowing (JSN) scores, and osteophytosis and sclerosis scores. Results were analysed for the most affected compartment (MAC) and least affected compartment. Radiographic changes were analysed using the Wilcoxon signed rank test for categorical and paired t-test for continuous variables. Linear regression was used to calculate associations between changes in JSW, WOMAC pain and SF markers. RESULTS: Sixteen patients could be evaluated. JSW, KL and JSN improved in around half of the patients, significant only for MAC JSW (P < 0.05). MAC JSW change was positively associated with WOMAC pain change (P < 0.04). Greater monocyte chemoattractant protein 1 (MCP-1) and lower TGFß-1 increases were significantly associated with changes in MAC JSW (P < 0.05). MCP-1 changes were positively associated with WOMAC pain changes (P < 0.05). CONCLUSION: Automatic radiographic measurements show improved joint structure in most patients after KJD in regular care. MAC JSW increased significantly and was associated with SF biomarker level changes and even with improvements in pain as experienced by these patients.

Ankle joint distraction is a promising alternative treatment for patients with severe haemophilic ankle arthropathy.

INTRODUCTION: Haemophilic ankle arthropathy (HAA) causes major morbidity. When conservative treatment fails, major surgical interventions are indicated. An alternative treatment to maintain joint mobility and postpone these interventions is desired. AIM: To gather prospective data on clinical/structural changes after ankle joint distraction (AJD) in HAA. METHODS: This study includes patients with severe HAA insufficiently responding to conservative treatment. AJD was performed during 8-10 weeks by use of an external frame. Questionnaires, physical examination and radiology were used to evaluate pain, function and structural changes before and 6, 12, 24 and 36 months after distraction. Mixed effect models were used for analysis. RESULTS: This study includes eight cases (21-53 years). The fixed effects estimates of the visual analogue score (0-10) improved from 7.5 at baseline to 3.4 (p = .023) 3 years after distraction. The Haemophilia Activities List (HAL, 0-100) for basic/complex lower extremities functions improved from respectively 29.6 and 31.5 to 54.3 (p = .015) and 50.7 (p = .031). Joint mobility was maintained. Magnetic resonance imaging (MRI) showed thickened cartilage and reduced bone marrow oedema and subchondral cysts. Pin tract infections (n = 6) were effectively treated and no adverse bleeding events occurred. At 3-year follow-up, in none of the patients the originally indicated arthrodesis was performed. CONCLUSION: This first prospective study showed that AJD in HAA results in decreased pain, improved function and decreased arthropathy-related MRI findings in the majority of patients for prolonged time. Although the study population is small and follow-up is relatively short, AJD may be promising to postpone invalidating interventions and might be a breakthrough treatment.

GaitSmart motion analysis compared to commonly used function outcome measures in the IMI-APPROACH knee osteoarthritis cohort.

BACKGROUND: There are multiple measures for assessment of physical function in knee osteoarthritis (OA), but each has its strengths and limitations. The GaitSmart® system, which uses inertial measurement units (IMUs), might be a user-friendly and objective method to assess function. This study evaluates the validity and responsiveness of GaitSmart® motion analysis as a function measurement in knee OA and compares this to Knee Injury and Osteoarthritis Outcome Score (KOOS), Short Form 36 Health Survey (SF-36), 30s chair stand test, and 40m self-paced walk test. METHODS: The 2-year Innovative Medicines Initiative-Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) knee OA cohort was conducted between January 2018 and April 2021. For this study, available baseline and 6 months follow-up data (n = 262) was used. Principal component analysis was used to investigate whether above mentioned function instruments could represent one or more function domains. Subsequently, linear regression was used to explore the association between GaitSmart® parameters and those function domains. In addition, standardized response means, effect sizes and t-tests were calculated to evaluate the ability of GaitSmart® to differentiate between good and poor general health (based on SF-36). Lastly, the responsiveness of GaitSmart® to detect changes in function was determined. RESULTS: KOOS, SF-36, 30s chair test and 40m self-paced walk test were first combined into one function domain (total function). Thereafter, two function domains were substracted related to either performance based (objective function) or self-reported (subjective function) function. Linear regression resulted in the highest R2 for the total function domain: 0.314 (R2 for objective and subjective function were 0.252 and 0.142, respectively.). Furthermore, GaitSmart® was able to distinguish a difference in general health status, and is responsive to changes in the different aspects of objective function (Standardized response mean (SRMs) up to 0.74). CONCLUSION: GaitSmart® analysis can reflect performance based and self-reported function and may be of value in the evaluation of function in knee OA. Future studies are warranted to validate whether GaitSmart® can be used as clinical outcome measure in OA research and clinical practice.

Knee joint distraction results in MRI cartilage thickness increase up to 10 years after treatment.

OBJECTIVES: Knee joint distraction (KJD) has been shown to result in long-term clinical improvement and short-term cartilage restoration in young OA patients. The objective of the current study was to evaluate MRI cartilage thickness up to 10 years after KJD treatment, using a 3D surface-based approach. METHODS: Twenty end-stage knee OA patients were treated with KJD. MRI scans (1.5 T) were performed before and at 1, 2, 5, 7, and 10 years after treatment. Tibia and femur cartilage segmentation and registration to a canonical surface were performed semi-automatically. Statistical parametric mapping with linear mixed models was used to analyse whole-joint changes. The influence of baseline patient characteristics was analysed with statistical parametric mapping using linear regression. Relevant weight-bearing parts of the femur were selected to obtain the average cartilage thickness in the femur and tibia of the most- (MAC) and least-affected compartment. These compartmental changes over time were analysed using repeated measures ANOVA; missing data was imputed. In all cases, P <0.05 was considered statistically significant. RESULTS: One and 2 years post-treatment, cartilage in the MAC weight-bearing region was significantly thicker than pre-treatment, gradually thinning after 5 years, but still increased at 10 years post-treatment. Long-term results showed that areas in the least-affected compartment were significantly thicker than pre-treatment. Male sex and more severe OA at baseline somewhat predicted shorter-term benefit (P >0.05). Compartmental analyses showed significant short- and long-term thickness increase in the tibia and femur MAC (all P <0.05). CONCLUSION: KJD results in significant short- and long-term cartilage regeneration, up to 10 years post-treatment. TRIAL REGISTRATION: Netherlands Trial Register, https://www.trialregister.nl, NL419.

Return to Sport and Work after Randomization for Knee Distraction versus High Tibial Osteotomy: Is There a Difference?

Knee joint distraction (KJD) is a novel technique for relatively young knee osteoarthritis (OA) patients. With KJD, an external distraction device creates temporary total absence of contact between cartilage surfaces, which results in pain relief and possibly limits the progression of knee OA. Recently, KJD showed similar clinical outcomes compared with high tibial osteotomy (HTO). Yet, no comparative data exist regarding return to sport (RTS) and return to work (RTW) after KJD. Therefore, our aim was to compare RTS and RTW between KJD and HTO. We performed a cross-sectional follow-up study in patients <65 years who previously participated in a randomized controlled trial comparing KJD and HTO. Out of 62 eligible patients, 55 patients responded and 51 completed the questionnaire (16 KJDs and 35 HTOs) at 5-year follow-up. The primary outcome measures were the percentages of RTS and RTW. Secondary outcome measures included time to RTS/RTW, and pre- and postoperative Tegner's (higher is more active), and Work Osteoarthritis or Joint-Replacement Questionnaire (WORQ) scores (higher is better work ability). Patients' baseline characteristics did not differ. Total 1 year after KJD, 79% returned to sport versus 80% after HTO (not significant [n.s.]). RTS <6 months was 73 and 75%, respectively (n.s.). RTW 1 year after KJD was 94 versus 97% after HTO (n.s.), and 91 versus 87% <6 months (n.s.). The median Tegner's score decreased from 5.0 to 3.5 after KJD, and from 5.0 to 3.0 after HTO (n.s.). The mean WORQ score improvement was higher after HTO (16 ± 16) than after KJD (6 ± 13; p = 0.04). Thus, no differences were found for sport and work participation between KJD and HTO in our small, though first ever, cohort. Overall, these findings may support further investigation into KJD as a possible joint-preserving option for challenging "young" knee OA patients. The level of evidence is III.

Joint distraction for osteoarthritis: clinical evidence and molecular mechanisms.

Joint distraction, the prolonged mechanical separation of the bones at a joint, has emerged as a joint-preserving treatment for end-stage osteoarthritis, with the gradually growing promise of implementation in regular clinical practice. Joint distraction of the knee has been most extensively studied, with these studies showing prolonged symptomatic improvement in combination with repair of cartilage tissue in degenerated knee joints, supporting the concept that cartilage repair can translate into real clinical benefit. The reversal of tissue degeneration observed with joint distraction could be the result of one or a combination of various proposed mechanisms, including partial unloading, synovial fluid pressure oscillation, mechanical and biochemical changes in subchondral bone, adhesion and chondrogenic commitment of joint-derived mesenchymal stem cells or a change in the molecular milieu of the joint. The overall picture that emerges from the combined evidence is relevant for future research and treatment-related improvements of joint distraction and for translation of the insights gained about tissue repair to other joint-preserving techniques. It remains to be elucidated whether optimizing the biomechanical conditions during joint distraction can actually cure osteoarthritis rather than only providing temporary symptomatic relief, but even temporary relief might be relevant for society and patients, as it will delay joint replacement with a prosthesis at an early age and thereby avert revision surgery later in life. Most importantly, improved insights into the underlying mechanisms of joint repair might provide new leads for more targeted treatment options.

Comparison between 2D radiographic weight-bearing joint space width and 3D MRI non-weight-bearing cartilage thickness measures in the knee using non-weight-bearing 2D and 3D CT as an intermediary.

BACKGROUND: In knee osteoarthritis, radiographic joint space width (JSW) is frequently used as a surrogate marker for cartilage thickness; however, longitudinal changes in radiographic JSW have shown poor correlations with those of magnetic resonance imaging (MRI) cartilage thickness. There are fundamental differences between the techniques: radiographic JSW represents two-dimensional (2D), weight-bearing, bone-to-bone distance, while on MRI three-dimensional (3D) non-weight-bearing cartilage thickness is measured. In this exploratory study, computed tomography (CT) was included as a third technique, as it can measure bone-to-bone under non-weight-bearing conditions. The objective was to use CT to compare the impact of weight-bearing versus non-weight-bearing, as well as bone-to-bone JSW versus actual cartilage thickness, in the knee. METHODS: Osteoarthritis patients (n = 20) who were treated with knee joint distraction were included. Weight-bearing radiographs, non-weight-bearing MRIs and CTs were acquired before and 2 years after treatment. The mean radiographic JSW and cartilage thickness of the most affected compartment were measured. From CT, the 3D median JSW was calculated and a 2D projectional image was rendered, positioned similarly and measured identically to the radiograph. Pearson correlations between the techniques were derived, both cross-sectionally and longitudinally. RESULTS: Fourteen patients could be analyzed. Cross-sectionally, all comparisons showed moderate to strong significant correlations (R = 0.43-0.81; all p < 0.05). Longitudinal changes over time were small; only the correlations between 2D CT and 3D CT (R = 0.65; p = 0.01) and 3D CT and MRI (R = 0.62; p = 0.02) were statistically significant. CONCLUSION: The poor correlation between changes in radiographic JSW and MRI cartilage thickness appears primarily to result from the difference in weight-bearing, and less so from measuring bone-to-bone distance versus cartilage thickness.

Dorsal Root Ganglia Macrophages Maintain Osteoarthritis Pain.

Pain is the major debilitating symptom of osteoarthritis (OA), which is difficult to treat. In OA patients joint tissue damage only poorly associates with pain, indicating other mechanisms contribute to OA pain. Immune cells regulate the sensory system, but little is known about the involvement of immune cells in OA pain. Here, we report that macrophages accumulate in the dorsal root ganglia (DRG) distant from the site of injury in two rodent models of OA. DRG macrophages acquired an M1-like phenotype, and depletion of DRG macrophages resolved OA pain in male and female mice. Sensory neurons innervating the damaged knee joint shape DRG macrophages into an M1-like phenotype. Persisting OA pain, accumulation of DRG macrophages, and programming of DRG macrophages into an M1-like phenotype were independent of Nav1.8 nociceptors. Inhibition of M1-like macrophages in the DRG by intrathecal injection of an IL4-IL10 fusion protein or M2-like macrophages resolved persistent OA pain. In conclusion, these findings reveal a crucial role for macrophages in maintaining OA pain independent of the joint damage and suggest a new direction to treat OA pain.SIGNIFICANCE STATEMENT In OA patients pain poorly correlates with joint tissue changes indicating mechanisms other than only tissue damage that cause pain in OA. We identified that DRG containing the somata of sensory neurons innervating the damaged knee are infiltrated with macrophages that are shaped into an M1-like phenotype by sensory neurons. We show that these DRG macrophages actively maintain OA pain remotely and independent of joint damage. The phenotype of these macrophages is crucial for a pain-promoting role. Targeting the phenotype of DRG macrophages with either M2-like macrophages or a cytokine fusion protein that skews macrophages into an M2-like phenotype resolves OA pain. Our work reveals a mechanism that contributes to the maintenance of OA pain distant from the affected knee joint and suggests that dorsal root ganglia macrophages are a target to treat osteoarthritis chronic pain.