Neuropathic Pain in the IMI-APPROACH Knee Osteoarthritis Cohort: Prevalence and Phenotyping

The study is registered under clinicaltrials.gov nr: NCT03883568.[Abstract] Objectives: Osteoarthritis (OA) patients with a neuropathic pain (NP) component may represent a specific phenotype. This study compares joint damage, pain and functional disability between knee OA patients with a likely NP component, and those without a likely NP component. Methods: Baseline data from the Innovative Medicines Initiative Applied Public-Private Research enabling OsteoArthritis Clinical Headway knee OA cohort study were used. Patients with a painDETECT score ≥19 (with likely NP component, n=24) were matched on a 1:2 ratio to patients with a painDETECT score ≤12 (without likely NP component), and similar knee and general pain (Knee Injury and Osteoarthritis Outcome Score pain and Short Form 36 pain). Pain, physical function and radiographic joint damage of multiple joints were determined and compared between OA patients with and without a likely NP component. Results: OA patients with painDETECT scores ≥19 had statistically significant less radiographic joint damage (p≤0.04 for Knee Images Digital Analysis parameters and Kellgren and Lawrence grade), but an impaired physical function (p<0.003 for all tests) compared with patients with a painDETECT score ≤12. In addition, more severe pain was found in joints other than the index knee (p≤0.001 for hips and hands), while joint damage throughout the body was not different. Conclusions: OA patients with a likely NP component, as determined with the painDETECT questionnaire, may represent a specific OA phenotype, where local and overall joint damage is not the main cause of pain and disability. Patients with this NP component will likely not benefit from general pain medication and/or disease-modifying OA drug (DMOAD) therapy. Reserved inclusion of these patients in DMOAD trials is advised in the quest for successful OA treatments

Osteoarthritis in Pseudoxanthoma Elasticum Patients: An Explorative Imaging Study

Pseudoxanthoma elasticum (PXE) is a systemic disease affecting the skin, eyes, and cardiovascular system of patients. Cardiovascular disease is associated with osteoarthritis (OA), which is the most common cause of joint pain. There is a lack of systematic investigations on joint manifestations in PXE in the literature. In this explorative study, we aimed to investigate whether patients with PXE are more at risk for developing osseous signs of OA. Patients with PXE and hospital controls with whole-body low-dose CT examinations available were included. OA was assessed using the OsteoArthritis Computed Tomography (OACT)-score, which is a 4-point Likert scale, in the acromioclavicular (AC), glenohumeral (GH), facet, hip, knee, and ankle joints. Additionally, intervertebral disc degeneration was scored. Data were analyzed using ordinal logistic regression adjusted for age, body mass index (BMI), and smoking status. In total, 106 PXE patients (age 56 (48&ndash;64), 42% males, BMI 25.3 (22.7&ndash;28.2)) and 87 hospital controls (age 55 (43&ndash;67), 46% males, BMI 26.0 (22.5&ndash;29.2)) were included. PXE patients were more likely to have a higher OA score for the AC joints (OR 2.00 (1.12&ndash;3.61)), tibiofemoral joint (OR 2.63 (1.40&ndash;5.07)), and patellofemoral joint (2.22 (1.18&ndash;4.24)). For the other joints, the prevalence and severity of OA did not differ significantly. This study suggests that patients with PXE are more likely to have structural OA of the knee and AC joints, which needs clinical confirmation in larger groups and further investigation into the mechanism

Scoring Osteoarthritis Reliably in Large Joints and the Spine Using Whole-Body CT: OsteoArthritis Computed Tomography-Score (OACT-Score)

A standardized method to assess structural osteoarthritis (OA) burden thorough the body lacks from literature. Such a method can be valuable in developing personalized treatments for OA. We developed a reliable scoring system to evaluate OA in large joints and the spine&mdash;the OsteoArthritis Computed Tomography (OACT) score, using a convenience sample of 197 whole-body low-dose non-contrast CTs. An atlas, containing example images as reference points for training and scoring, are presented. Each joint was graded between 0&ndash;3. The total OA burden was calculated by summing scores of individual joints. Intra- and inter-observer reliability was tested 25 randomly selected scans (N = 600 joints). Intra-observer reliability and inter-observer reliability between three observers was assessed using intraclass correlation coefficient (ICC) and square-weighted kappa statistics. The square-weighted kappa for intra-observer reliability for OACT-score at joint-level ranged from 0.79 to 0.95; the ICC for the total OA grade was 0.97 (95%-CI, 0.94 to 0.99). Square-weighted kappa for interobserver reliability ranged from 0.48 to 0.95; the ICC for the total OA grade was 0.95 (95%-CI, 0.90 to 0.98). The OACT score, a new reproducible CT-based grading system reflecting OA burden in large joints and the spine, has a satisfactory reproducibility. The atlas can be used for research purposes, training, educational purposes and systemic grading of OA on CT-scans

Osteoarthritis: Getting the picture

Osteoarthritis (OA) is a debilitating disease that causes a giant socioeconomic burden. Until now, there is no drug to limit disease progression. There are important steps towards a drug for OA. First, we need to be able to predict in which patients the disease will progress and at what time using accurate prediction models. We may use this knowledge to better identify “early OA” patients and include patients who are expected to progress in clinical trials. Second, we need to select the right patient for the right treatment. This can be achieved by defining robust phenoor endotypes of OA and tailoring treatments towards specific pathomechanisms within pheno/endotypes. Third, we need a better understanding of pathologic mechanisms in OA to identify treatment targets. Fourth, we need to develop sensitive outcome markers for follow-up. In this thesis, small steps brought us closer to reaching these four goals

Statistical Shape Modeling of US Images to Predict Hip Dysplasia Development in Infants

Background: The current widely applied Graf classification used on US images for developmental dysplasia of the hip in infants does not enable prediction of the development and outcome of well-centered stable dysplastic hips (Graf type II). Purpose: To use statistical shape modeling on US images to identify acetabular shape characteristics of Graf type II hips, which enable prediction of the development of Graf type II hips, and to identify which hips benefit from Pavlik harness treatment. Materials and Methods: In this secondary analysis of a prospective multicenter randomized trial on treatment of 104 infants aged 3-4 months with Graf type IIb or IIc hip dysplasia conducted between 2009 and 2015, a statistical shape model was developed on baseline US images. With multivariable logistic regression adjusted for infant sex and treatment (Pavlik harness treatment vs active observation), shape modes were correlated with the outcomes of persistent hip dysplasia on US images (a angle,60°) after 12-week follow-up and residual hip dysplasia on pelvic radiographs (Tönnis classification: acetabular index greater than 2 standard deviations) around 1 year of age. An interaction term (treatment with mode) was used to investigate if this result depended on treatment. Results: Baseline US images were available in 97 infants (mean age, 3.37 years 6 0.43 [standard deviation]; 89 [92%] girls; 90 cases of Graf type IIb hip dysplasia; 52 cases treated with Pavlik harness). Shape modes 2 and 3 of the statistical shape modeling were associated with persistent hip dysplasia on US images (odds ratio [OR] = 0.43; P = .007 and OR = 2.39; P = .02, respectively). Mode 2 was also associated with residual hip dysplasia on pelvic radiographs (OR = 0.09; P = .002). The interaction term remained significant after multivariable analysis, indicating that Pavlik harness treatment was beneficial in patients with negative mode 2 values (OR = 12.46; P = .01). Conclusion: Statistical shape modeling of US images of infants with Graf type II dysplastic hips predicted which hips developed to normal or remained dysplastic and identified hips that benefited from Pavlik harness treatment.</p

Three-dimensional analysis of shape variations and symmetry of the fibula, tibia, calcaneus and talus

The bones forming the talocrural joint (TCJ) and subtalar joint (STJ) are often assumed to be bilaterally symmetric. Therefore, the contralateral limb (i.e. the fibula, tibia, calcaneus and talus) is used as a template or an intra-subject control in clinical and research practice. However, the validity of the symmetry assumption is controversial, because insufficient information is available on the shape variations and bilateral (a)symmetry of the fibula, tibia, calcaneus and talus. Using three-dimensional spatially dense sampled representations of bone shapes extracted from bilateral computed tomography scans of 66 individuals (55 male, mean age: 61 ± 10 years; 11 female, mean age: 53 ± 15 years), we analyzed whether: (i) similar shape patterns exist in the left and right bones of the same type; (ii) gender has an effect on bone shape variations; (iii) intra-subject shape variation is smaller than that of inter-subject for a given shape variance direction. For the first set of analyses, all left and right instances of the same type of bone were considered as two separate groups, and statistically compared with each other on multiple aspects including group location (central tendency), variance-covariance scale (dispersion) and orientation (covariance structure) using distance-based permutational tests. For the second and third sets of analyses, all left and right bones of the same type were pooled into one group, and shape variations in the TCJ and STJ bones were extracted using principal component analysis. The effects of gender on age-adjusted bone shape differences were assessed using an analysis of covariance. Moreover, intra-class correlation was employed to evaluate intra- and inter-subject bone shape variations. For each bone type, both sides had similar shape patterns (Ppermutational-values > 0.05). After Bonferroni adjustment, gender led to shape differences, which were mainly in the lateral and medial condyles of the tibia (P = 0.003), the length and height of the calcaneus (P < 0.001), the posterior and anterior talar articular surfaces of the calcaneus (P = 0.001), and in the posterior aspect of the talus (P = 0.001). Intra-subject shape variations in the tibial tuberosity together with the diameter of the tibia, and the curvature of the fibula shaft and the diameter of the fibula were as high as those of inter-subject. This result suggests that the shape symmetry assumption could be violated for some specific shape variations in the fibula and tibia

MRI-based synthetic CT in the detection of knee osteoarthritis: Comparison with CT

Magnetic resonance Imaging is the gold standard for assessment of soft tissues; however, X-ray-based techniques are required for evaluating bone-related pathologies. This study evaluated the performance of synthetic computed tomography (sCT), a novel MRI-based bone visualization technique, compared with CT, for the scoring of knee osteoarthritis. sCT images were generated from the 3T T1-weighted gradient-echo MR images using a trained machine learning algorithm. Two readers scored the severity of osteoarthritis in tibiofemoral and patellofemoral joints according to OACT, which enables the evaluation of osteoarthritis, from its characteristics of joint space narrowing, osteophytes, cysts and sclerosis in CT (and sCT) images. Cohen's κ was used to assess the interreader agreement for each modality, and intermodality agreement of CT- and sCT-based scores for each reader. We also compared the confidence level of readers for grading CT and sCT images using confidence scores collected during grading. Inter-reader agreement for tibiofemoral and patellofemoral joints were almost-perfect for both modalities (κ = 0.83–0.88). The intermodality agreement of osteoarthritis scores between CT and sCT was substantial to almost-perfect for tibiofemoral (κ = 0.63 and 0.84 for the two readers) and patellofemoral joints (κ = 0.78 and 0.81 for the two readers). The analysis of diagnosis confidence scores showed comparable visual quality of the two modalities, where both are showing acceptable confidence levels for scoring OA. In conclusion, in this single-center study, sCT and CT were comparable for the scoring of knee OA.</p

Predicting the mechanical Hip-Knee-Ankle angle accurately from standard knee radiographs, a cross-validation experiment in 100 patients

Background and purpose — Being able to predict the hip–knee–ankle angle (HKAA) from standard knee radiographs allows studies on malalignment in cohorts lacking full-limb radiography. We aimed to develop an automated image analysis pipeline to measure the femoro-tibial angle (FTA) from standard knee radiographs and test various FTA definitions to predict the HKAA. Patients and methods — We included 110 pairs of standard knee and full-limb radiographs. Automatic search algorithms found anatomic landmarks on standard knee radiographs. Based on these landmarks, the FTA was automatically calculated according to 9 different definitions (6 described in the literature and 3 newly developed). Pearson and intra-class correlation coefficient [ICC]) were determined between the FTA and HKAA as measured on full-limb radiographs. Subsequently, the top 4 FTA definitions were used to predict the HKAA in a 5-fold cross-validation setting. Results — Across all pairs of images, the Pearson correlations between FTA and HKAA ranged between 0.83 and 0.90. The ICC values from 0.83 to 0.90. In the cross-validation experiments to predict the HKAA, these values decreased only minimally. The mean absolute error for the best method to predict the HKAA from standard knee radiographs was 1.8° (SD 1.3). Interpretation — We showed that the HKAA can be automatically predicted from standard knee radiographs with fair accuracy and high correlation compared with the true HKAA. Therefore, this method enables research of the relationship between malalignment and knee pathology in large (epidemiological) studies lacking full-limb radiography.</p

Unravelling the hip-spine dilemma from the CHECK-cohort: Is sagittal pelvic morphology linked to radiographic signs of femoroacetabular impingement?

Introduction: To date the aetiology of femoroacetabular impingement (FAI) is still not completely understood. There are mechanical theories that suggest symptomatic FAI is linked to sagittal pelvic morphology and spinopelvic-femoral dynamics. The aim of this study is to evaluate the relation of sagittal pelvic morphology and orientation to radiographic signs of FAI. Additionally, we test whether the relation between FAI and spinopelvic parameters differs in osteoarthritic hips. Methods: From a prospective, observational cohort study, 1002 patients between 45 and 65 years old with a first episode of knee or hip pain were followed for 8 years. All patients who had lateral lumbar radiographs and clinical and radiographic follow-up of the hips were included in the present study. Range of internal rotation of the hip as well as radiographic signs of FAI (alpha and Wiberg angle) and presence of hip osteoarthritis (Kellgren and Lawrence) were systematically measured at baseline. Pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS)) were measured at 8-year follow-up. Associations between PI, PT, SS and FAI parameters were tested using generalised estimating equations. Results: 421 subjects, 842 hips, were included. No significant relations between PI, PT or SS and alpha or Wiberg angle were found. Comparison of hips with and without radiological sign(s) of FAI showed no differences in PI, PT or SS. There was no relation between range of internal rotation of the hip and spinopelvic parameters. Conclusion: Sagittal pelvic morphology and orientation are not related to the presence of radiological signs of FAI in this study population.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Biomaterials & Tissue Biomechanic

Criteria for Early-Phase Diffuse Idiopathic Skeletal Hyperostosis : Development and Validation

Background: Diffuse idiopathic skeletal hyperostosis (DISH) is a condition characterized by the formation of new bone along the anterolateral spinal column at four adjacent vertebral bodies. Purpose: To propose and validate criteria for the early phase of DISH by using CT data from two large-scale retrospective cohorts, each with 5-year follow-up. Materials and Methods: For this retrospective study, CT data at baseline and follow-up in 1367 patients (cohort I) from 2004 to 2011 were evaluated by two observers to define no DISH, early-stage DISH, and definite DISH on the basis of interval development of consecutive complete or incomplete bone bridges. An independent group of 2267 participants from the COPDGene cohort from 2008 to 2016 was used to validate the early DISH criteria (cohort II). The sensitivity and specificity of early DISH criteria were based on findings in the last CT study as the reference standard by using a nested case-control design. k Values were calculated between seven readers and with a 3-month interval for one reader. Results: Cohort I consisted of 100% men, with a mean age of 60.0 years ± 5.6 (standard deviation) and a mean time between baseline and follow-up CT of 5.0 years ± 1.1. Cohort II consisted of 51% men, with a mean age of 59.9 years ± 8.6 and a mean time between baseline and follow-up CT of 5.4 years ± 0.5. In the derivation cohort, 55 patients comprised the early DISH group. Early DISH was defined as the presence of a spinal segment with a complete bone bridge with an adjacent segment of at least a near-complete bone bridge and another adjacent segment with at least the presence of newly formed bone or when three or more adjacent segments were recorded as showing a near-complete bone bridge. In the validation cohort, sensitivity for early DISH (vs no DISH) was 96% (99 of 103 participants; 95% confidence interval [CI]: 90%, 99%). The corresponding specificity was 83% (1695 of 2034 participants; 95% CI: 82%, 85%). The Fleiss k for interrater reliability was 0.78 (95% CI: 0.77, 0.78), and the k for intrarater reliability was 0.89 (95% CI: 0.82, 0.96). Conclusion: Early diffuse idiopathic skeletal hyperostosis (DISH) criteria had high sensitivity and specificity for predicting the development of DISH