Associations between anterior knee pain and 2-year patellofemoral cartilage worsening: The MOST study.

OBJECTIVE: Anterior knee pain (AKP) is associated with patellofemoral osteoarthritis (PFOA), but longitudinal studies are lacking. If AKP precedes PFOA, it may create an opportunity to identify and intervene earlier in the disease process. The purpose of this study was to examine the longitudinal relation of AKP to worsening patellofemoral (PF) cartilage over two years. DESIGN: Participants were recruited from the Multicenter Osteoarthritis Study, a longitudinal study of individuals with or at risk for knee osteoarthritis (OA). Exclusion criteria included bilateral knee replacements, arthritis other than OA, and radiographic PFOA. At baseline, participants completed a knee pain map questionnaire and underwent knee magnetic resonance imaging (MRI). Imaging was repeated at 2-year follow-up. Exposure was presence of frequent AKP. Outcome was worsening cartilage damage in the PF joint defined as increase in MRI Osteoarthritis Knee Score from baseline to 2 years. Log-binomial models were used to calculate risk ratios (RR). RESULTS: One knee from 1083 participants (age 56.7 ± 6.6 years; body mass index 28.0 ± 4.9 kg/m2) was included. Frequent AKP and frequent isolated AKP were present at baseline in 14.5% and 3.6%, respectively. Frequent AKP was associated with an increased risk (RR: 1.78, 95% confidence interval: 1.21, 2.62) of 2-year worsening cartilage damage in the lateral PF compartment. No association was found between frequent AKP and worsening in the medial PF joint. CONCLUSION: Frequent AKP at baseline was associated with worsening cartilage damage in the lateral PF joint over 2 years.

Can gait patterns be explained by joint structure in people with and without radiographic knee osteoarthritis? Data from the IMI-APPROACH cohort.

OBJECTIVE: To determine the association between joint structure and gait in patients with knee osteoarthritis (OA). METHODS: IMI-APPROACH recruited 297 clinical knee OA patients. Gait data was collected (GaitSmart®) and OA-related joint measures determined from knee radiographs (KIDA) and MRIs (qMRI/MOAKS). Patients were divided into those with/without radiographic OA (ROA). Principal component analyses (PCA) were performed on gait parameters; linear regression models were used to evaluate whether image-based structural and demographic parameters were associated with gait principal components. RESULTS: Two hundred seventy-one patients (age median 68.0, BMI 27.0, 77% female) could be analyzed; 149 (55%) had ROA. PCA identified two components: upper leg (primarily walking speed, stride duration, hip range of motion [ROM], thigh ROM) and lower leg (calf ROM, knee ROM in swing and stance phases). Increased age, BMI, and radiographic subchondral bone density (sclerosis), decreased radiographic varus angle deviation, and female sex were statistically significantly associated with worse lower leg gait (i.e. reduced ROM) in patients without ROA (R2 = 0.24); in ROA patients, increased BMI, radiographic osteophytes, MRI meniscal extrusion and female sex showed significantly worse lower leg gait (R2 = 0.18). Higher BMI was significantly associated with reduced upper leg function for non-ROA patients (R2 = 0.05); ROA patients with male sex, higher BMI and less MRI synovitis showed significantly worse upper leg gait (R2 = 0.12). CONCLUSION: Structural OA pathology was significantly associated with gait in patients with clinical knee OA, though BMI may be more important. While associations were not strong, these results provide a significant association between OA symptoms (gait) and joint structure.

MRI underestimates presence and size of knee osteophytes using CT as a reference standard.

OBJECTIVE: To explore the diagnostic performance of routine magnetic resonance imaging (MRI) for the cross-sectional assessment of osteophytes (OPs) in all three knee compartments using computed tomography (CT) as a reference standard. METHODS: The Strontium Ranelate Efficacy in Knee Osteoarthritis (SEKOIA) trial explored the effect of 3 years of treatment with strontium ranelate in patients with primary knee OA. OPs were scored for the baseline visit only using a modified MRI Osteoarthritis Knee Score (MOAKS) scoring system in the patellofemoral (PFJ), the medial tibiofemoral (TFJ) and the lateral TFJ. Size was assessed from 0 to 3 in 18 locations. Descriptive statistics were used to describe differences in ordinal grading between CT and MRI. In addition, weighted-kappa statistics were employed to assess agreement between scoring using the two methods. Sensitivity, specificity, positive predictive value and negative predictive value as well as area under the curve (AUC) measures of diagnostic performance were employed using CT as the reference standard. RESULTS: Included were 74 patients with available MRI and CT data. Mean age was 62.9 ± 7.5 years. Altogether 1,332 locations were evaluated. For the PFJ, MRI detected 141 (72%) of 197 CT-defined OPs with a w-kappa of 0.58 (95% CI [0.52-0.65]). In the medial TFJ, MRI detected 178 (81%) of 219 CT-OPs with a w-kappa of 0.58 (95% CI [0.51-0.64]). For the lateral compartment these numbers were 84 (70%) of 120 CT-OPs with a w-kappa of 0.58 (95% CI [0.50-0.66]). CONCLUSION: MRI underestimates presence of osteophytes in all three knee compartments. CT may be helpful particularly regarding assessment of small osteophytes particularly in early disease.

Osteoarthritis year in review 2022: imaging.

PURPOSE: This narrative review summarizes original research focusing on imaging in osteoarthritis (OA) published between April 1st 2021 and March 31st 2022. We only considered English publications that were in vivo human studies. METHODS: The PubMed, Medline, Embase, Scopus, and ISI Web of Science databases were searched for "Osteoarthritis/OA" studies based on the search terms: "Radiography", "Ultrasound/US", "Computed Tomography/CT", "DXA", "Magnetic Resonance Imaging/MRI", "Artificial Intelligence/AI", and "Deep Learning". This review highlights the anatomical focus of research on the structures within the tibiofemoral, patellofemoral, hip, and hand joints. There is also a noted focus on artificial intelligence applications in OA imaging. RESULTS: Over the last decade, the increasing trend of using open-access large databases has reached a plateau (from 17 to 37). Compositional MRI has had the most prominent use in OA imaging and its biomarkers have been used in the detection of preclinical OA and prediction of OA outcomes. Most noteworthy, there has been an accelerated rate of publications on the implications of artificial intelligence, used in developing prediction models and performing trabecular texture analysis, in OA imaging (from 17 to 154). CONCLUSIONS: While imaging has maintained its key role in OA research, publication trends have shown an emphasis on the integration of AI. During the past year, MRI has maintained the highest prevalence in usage while US and CT remain as readily available modalities. Finally, there has been a notable uptake in the development and validation of AI techniques used to perform texture analysis and predict OA progression.

Test-retest precision and longitudinal cartilage thickness loss in the IMI-APPROACH cohort.

OBJECTIVE: To investigate the test-retest precision and to report the longitudinal change in cartilage thickness, the percentage of knees with progression and the predictive value of the machine-learning-estimated structural progression score (s-score) for cartilage thickness loss in the IMI-APPROACH cohort - an exploratory, 5-center, 2-year prospective follow-up cohort. DESIGN: Quantitative cartilage morphology at baseline and at least one follow-up visit was available for 270 of the 297 IMI-APPROACH participants (78% females, age: 66.4 ± 7.1 years, body mass index (BMI): 28.1 ± 5.3 kg/m2, 55% with radiographic knee osteoarthritis (OA)) from 1.5T or 3T MRI. Test-retest precision (root mean square coefficient of variation) was assessed from 34 participants. To define progressor knees, smallest detectable change (SDC) thresholds were computed from 11 participants with longitudinal test-retest scans. Binary logistic regression was used to evaluate the odds of progression in femorotibial cartilage thickness (threshold: -211 µm) for the quartile with the highest vs the quartile with the lowest s-scores. RESULTS: The test-retest precision was 69 µm for the entire femorotibial joint. Over 24 months, mean cartilage thickness loss in the entire femorotibial joint reached -174 µm (95% CI: [-207, -141] µm, 32.7% with progression). The s-score was not associated with 24-month progression rates by MRI (OR: 1.30, 95% CI: [0.52, 3.28]). CONCLUSION: IMI-APPROACH successfully enrolled participants with substantial cartilage thickness loss, although the machine-learning-estimated s-score was not observed to be predictive of cartilage thickness loss. IMI-APPROACH data will be used in subsequent analyses to evaluate the impact of clinical, imaging, biomechanical and biochemical biomarkers on cartilage thickness loss and to refine the machine-learning-based s-score. GOV IDENTIFICATION: NCT03883568.

Imaging in Osteoarthritis.

Osteoarthritis (OA) is the most frequent form of arthritis with major implications on both individual and public health care levels. The field of joint imaging, and particularly magnetic resonance imaging (MRI), has evolved rapidly due to the application of technical advances to the field of clinical research. This narrative review will provide an introduction to the different aspects of OA imaging aimed at an audience of scientists, clinicians, students, industry employees, and others who are interested in OA but who do not necessarily focus on OA. The current role of radiography and recent advances in measuring joint space width will be discussed. The status of cartilage morphology assessment and evaluation of cartilage biochemical composition will be presented. Advances in quantitative three-dimensional morphologic cartilage assessment and semi-quantitative whole-organ assessment of OA will be reviewed. Although MRI has evolved as the most important imaging method used in OA research, other modalities such as ultrasound, computed tomography, and metabolic imaging play a complementary role and will also be discussed.

Heterogeneity of cartilage damage in Kellgren and Lawrence grade 2 and 3 knees: the MOST study.

OBJECTIVE: Eligibility for clinical trials in osteoarthritis (OA) is usually limited to Kellgren-Lawrence (KL) grades 2 and 3 knees. Our aim was to describe the prevalence and severity of cartilage damage in KL 2 and 3 knees by compartment and articular subregion. DESIGN: The Multicenter Osteoarthritis (MOST) study is a cohort study of individuals with or at risk for knee OA. All baseline MRIs with radiographic disease severity KL2 and 3 were included. Knee MRIs were read for cartilage damage in 14 subregions. We determined the frequencies of no, any and widespread full-thickness cartilage damage by knee compartment, and the prevalence of any cartilage damage in 14 articular subregions. RESULTS: 665 knees from 665 participants were included (mean age 63.8 ± 7.9 years, 66.5% women). 372 knees were KL2 and 293 knees were KL3. There was no cartilage damage in 78 (21.0%) medial tibio-femoral joint (TFJ), 157 (42.2%) lateral TFJ and 62 (16.7%) patello-femoral joint (PFJ) compartments of KL2 knees, and 17 (5.8%), 115 (39.3%) and 35 (12.0%) compartments, respectively, of KL3 knees. There was widespread full-thickness damage in 94 (25.3%) medial TFJ, 36 (9.7%) lateral TFJ and 176 (47.3%) PFJ compartments of KL2 knees, and 217 (74.1%), 70 (23.9%) and 104 (35.5%) compartments, respectively, of KL3 knees. The subregions most likely to have any damage were central medial femur (80.5%), medial patella (69.8%) and central medial tibia (69.9). CONCLUSIONS: KL2 and KL3 knees vary greatly in cartilage morphology. Heterogeneity in the prevalence, severity and location of cartilage damage in in KL2 and 3 knees should be considered when planning disease modifying trials for knee OA.

Is meniscal status in the anterior cruciate ligament injured knee associated with change in bone surface area? An exploratory analysis of the KANON trial.

OBJECTIVES: To study bone shape changes as a potential early feature of post-traumatic structural knee OA development, we estimated the association between meniscal status in the anterior cruciate ligament (ACL) injured knee and longitudinal condyle changes in bone surface area. DESIGN: We used data from the KANON trial, including 121 young ACL-injured adults. We obtained baseline and 2-year follow-up knee MRIs. Our outcome was change in the bone surface areas (mean mm2, log-transformed) in 4 locations (femur, tibia, patella, and trochlea femur) in the medial and lateral compartment from baseline to 2 years. Meniscal pathology was defined as both present at baseline and newly developed (i.e., incident or progressed) using ACLOAS. We used multilevel linear regression adjusted for baseline bone area, age, sex, body mass index, treatment arm (i.e., early or optional delayed ACL reconstruction), and location. We analyzed medial and lateral compartment separately. We present results as percentage (%) bone area change difference with 95% confidence intervals (CI). RESULTS: We analyzed 109 subjects (median 27 (18-36) years, 83% men) due to missing MRI information. The bone surface area increased on average by ∼2% over 2 years. The differences between knees with and without baseline meniscal pathology were 1.1% (95%CI 0.0-2.3%) and 1.4% (95%CI 0.6-2.2%) in the medial and lateral compartment, respectively, and 1.2% (95%CI 0.3-2.0%) and 1.3% (95%CI 0.6-2.0%) for medial and lateral newly developed pathology, respectively. CONCLUSION: Our finding of ∼1% increase bone area in compartment with meniscal pathology suggests a potentially important association between meniscal integrity and early bone surface area changes after ACL injury. Trial registration number ISRCTN 84752559.

Osteoarthritis year in review 2019: imaging.

OBJECTIVE: To provide a narrative review of original articles on osteoarthritis (OA) imaging published between April 1, 2018 and March 30, 2019. METHODS: All original research articles on OA imaging published in English between April 1, 2018 and March 30, 2019 were identified using a PubMed database search. The search terms of "Osteoarthritis" or "OA" were combined with the search terms "Radiography", "X-Rays", "Magnetic Resonance Imaging", "MRI", "Ultrasound", "US", "Computed Tomography", "Dual Energy X-Ray Absorptiometry", "DXA", "DEXA", "CT", "Nuclear Medicine", "Scintigraphy", "Single-Photon Emission Computed Tomography", "SPECT", "Positron Emission Tomography", "PET", "PET-CT", or "PET-MRI". Articles were reviewed to determine relevance based upon the following criteria: 1) study involved human subjects with OA or risk factors for OA and 2) study involved imaging to evaluate OA disease status or OA treatment response. Relevant articles were ranked according to scientific merit, with the best publications selected for inclusion in the narrative report. RESULTS: The PubMed search revealed a total of 1257 articles, of which 256 (20.4%) were considered relevant to OA imaging. Two-hundred twenty-six (87.1%) articles involved the knee joint, while 195 (76.2%) articles involved the use of magnetic resonance imaging (MRI). The proportion of published studies involving the use of MRI was higher than previous years. An increasing number of articles were also published on imaging of subjects with joint injury and on deep learning application in OA imaging. CONCLUSION: MRI and other imaging modalities continue to play an important role in research studies designed to better understand the pathogenesis, progression, and treatment of OA.

Association of knee OA structural phenotypes to risk for progression: a secondary analysis from the Foundation for National Institutes of Health Osteoarthritis Biomarkers study (FNIH).

PURPOSE: Aim was to stratify the knee MRIs of the Foundation for National Institutes of Health Osteoarthritis Biomarkers Consortium (FNIH) cohort into distinct structural phenotypes based on semiquantitative assessment and to determine risk for pain and structural progression over 48 months. METHODS: The study sample from the FNIH project was selected as a nested case-control study with knees showing either 1) radiographic and pain progression (i.e., "composite" cases), 2) radiographic progression only ("JSL"), 3) pain progression only, and 4) neither radiographic nor pain progression. MRI was performed on 3T systems. MRIs were read according to the MOAKS scoring system. Knees were stratified into subchondral bone, cartilage/meniscus and inflammatory phenotypes using the baseline visits. The relation of each phenotype to risk of being in the combined JSL plus composite outcome or composite case only group compared to those not having that phenotype was determined using logistic regression. Only KL2 and 3 and those without root tears were included. RESULTS: 485 knees were included. 362 (75%) did not have any phenotype, while 95 (20%) had the bone phenotype, 22 (5%) the cartilage/meniscus phenotype and 19 (4%) the inflammatory phenotype. The bone phenotype was associated with a higher odds of the combined JSL plus composite outcome and composite outcome only (OR 1.81; [95%CI 1.14,2.85] and 1.65; 95%CI [1.04,2.61]) while the inflammatory (OR 0.96 [95%CI 0.38,2.42] and 1.25; 95%CI [0.48,3.25]) and the cartilage/meniscus phenotypes were not significantly associated with outcome (OR 1.30 95%CI [0.55,3.07] and 0.99; 95%CI [0.40,2,49]). CONCLUSIONS: The bone phenotype was associated with increased risk of having both radiographic and pain progression. Phenotypic stratification may be useful to consider when selecting patients for inclusion in clinical trials.

Molecular and imaging biomarkers of local inflammation at 2 years after anterior cruciate ligament injury do not associate with patient reported outcomes at 5 years.

OBJECTIVE: To estimate the association between molecular or imaging inflammatory biomarkers at 2 years after anterior cruciate ligament (ACL) injury and patient-reported outcomes at 5 years. METHODS: For 116 ACL-injured patients, molecular biomarkers of inflammation (synovial fluid and serum cytokines) and Hoffa- and effusion-synovitis as visualized on magnetic resonance imaging (MRI) were assessed 2 years post-injury. Knee injury and Osteoarthritis Outcome Score (KOOS) and SF-36 were assessed at 2 and 5 years. We used multiple imputation to handle biomarker values that were below the level of detection or missing, and linear regression for statistical analyses. RESULTS: None of the synovial fluid cytokines or imaging biomarkers of inflammation at 2 years were associated with any of the patient-reported outcomes at 5 years. With each log10 unit higher of serum tumor necrosis factor concentration the knee-related quality of life of KOOS was increased (i.e., better outcome) by 35 (95% confidence interval 7 to 63) points. No other serum biomarker measured at 2 years was associated with patient-reported outcome at 5 years. CONCLUSION: Local joint inflammation assessed by biomarkers in synovial fluid and Hoffa- and effusion-synovitis on MRI at 2 years after an ACL injury did not associate with patient-reported outcomes at 5 years. Thus, chronic inflammation in the ACL-injured knee, as reflected by the biomarkers studied here, seems not to be a key determinant for the long-term patient-reported outcomes.

Are contrast-enhanced and non-contrast MRI findings reflecting synovial inflammation in knee osteoarthritis: a meta-analysis of observational studies.

OBJECTIVE: To determine the correlation between knee synovitis assessed on contrast-enhanced (CE) and non-contrast enhanced (NCE) magnetic resonance imaging (MRI) with histology in patients with knee osteoarthritis. METHODS: A comprehensive literature search was performed, and related articles published through July 2018 were extracted. Spearman correlation coefficients of MRI-based scores with histology reports were pooled using random effects model. To evaluate presence of publication bias, Egger test was performed. RESULTS: Of 2377 identified records, eight studies consisting of 246 MRI exams were included. Two studies reported results of dynamic CE (DCE)-MRI examinations (81 knees) and two studies reported results of NCE-MRI. There were moderate positive correlations between CE-MRI scores and macroscopic (r = 0.53 (95% Confidence Interval (CI):0.37-0.66), P < 0.001) as well as microscopic (r = 0.56 (0.39-0.69), P < 0.001) histology. DCE-MRI were strongly correlated (r = 0.71 (0.58-0.80), P-value<0.001), with microscopic histology reports, while the correlation for NCE-MRI was low positive (r = 0.44 (0.20-0.63), P < 0.001). Meta-regression analysis showed that pooled correlation coefficients of DCE-MRI were significantly higher than CE-MRI (Slope = 0.29, SE = 0.13, P-value = 0.02). CE-MRI were also correlated with inflammatory infiltrate (r = 0.42), while the correlations for cell number of synovial lining (r = 0.27) and level of fibrosis (r = 0.29, P < 0.001) were very low. CONCLUSION: Static and dynamic CE-MRI evaluation of knee synovitis were positively correlated with macroscopic and microscopic features of synovial membrane inflammation. Among the features of synovial tissue inflammation, CE-MRI scores correlated best with the inflammatory infiltrates of synovial tissue. Paucity of current evidence warrants further studies to assess performance of NCE-MRI on determining knee synovitis.

Association of baseline and change in tibial and femoral cartilage thickness and development of widespread full-thickness cartilage loss in knee osteoarthritis - data from the Osteoarthritis Initiative.

OBJECTIVE: To investigate whether baseline cartilage thickness and its longitudinal change are associated with incident widespread full-thickness cartilage loss (wsFTCL) in knee osteoarthritis, and whether there are optimal cut-off values for predicting wsFTCL. METHODS: Central medial tibial (cMT) and femoral (cMF) cartilage were assessed using quantitative magnetic resonance imaging data from the Osteoarthritis Initiative cohort (N = 600 knees). Cartilage thickness was measured at baseline and 12 months. wsFTCL was defined semi-quantitatively (scores 2 and 3 from the MRI Osteoarthritis Knee Score) and its incidence at 24 months recorded. Logistic regression was used to determine the odds of developing wsFTCL for baseline and for each 0.1 mm decrease in cartilage thickness. Cut-off values were investigated using the minimal-p method and area under the Receiver Operating Characteristic curves (AUC). RESULTS: Incident wsFTCL was observed in 66 (12%) and 73 (14%) knees in cMT and cMF, respectively. Lower baseline cMT and cMF cartilage thickness values were associated with wsFTCL (OR = 1.20; 95% CI: 1.11, 1.28 and OR = 1.15; 95% CI: 1.06 to 1.24, respectively). Optimal cut-off AUCs for the tibia and femur were 0.64 (0.57-0.70) and 0.63 (0.57-0.69), respectively. Longitudinal decrease in femoral, but not tibial, cartilage thickness was associated with incident wsFTCL (OR = 1.77; 95% CI: 1.30 to 2.40); optimal cut-off AUC 0.65 (95% CI: 0.58-0.72). CONCLUSION: Lower baseline cMT and baseline/change (decrease) over 12 months in cMF cartilage thickness were associated with incident, location-specific, wsFTCL at 24 months. Optimal cut-off values were relatively low and of uncertain utility for predicting incident wsFTCL.

Evaluating the structural effects of intra-articular sprifermin on cartilage and non-cartilaginous tissue alterations, based on sqMRI assessment over 2 years.

OBJECTIVE: Sprifermin (recombinant human fibroblast growth factor-18), a potential disease-modifying osteoarthritis (OA) drug, demonstrated dose-dependent effects on femorotibial cartilage thickness (by quantitative magnetic resonance imaging [MRI]) in the phase II FORWARD study. This post-hoc analysis evaluated the potential effects of sprifermin on several articular structures in the whole joint over 24 months using semi-quantitative MRI assessment. DESIGN: Patients aged 40-85 years with symptomatic radiographic knee OA, Kellgren-Lawrence grade 2 or 3, and medial minimum joint space width ≥2.5 mm in the target knee were randomized (1:1:1:1:1) to receive three double-blinded, once-weekly, intra-articular injections of sprifermin 30 µg or 100 µg or placebo every 6 (q6mo) or 12 months. 1.5- or 3 T MRIs were read using the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system at baseline and 24 months. Change from baseline at 24 months on compartment and/or whole knee level was assessed for cartilage morphology, bone marrow lesions (BMLs), and osteophytes by delta-subregional and delta-sum (DSM) approaches. Menisci, Hoffa-synovitis, and effusion-synovitis were also evaluated for worsening. RESULTS: 549 patients were included. Dose-dependent treatment effects from baseline to 24 months were observed on cartilage morphology (sprifermin 100 µg q6mo vs placebo; mean DSM (95% confidence interval [CI]) -0.6 (-1.5, 0.2); less cartilage worsening) in the entire knee and BMLs sprifermin 100 µg q6mo vs placebo; mean DSM (95% CI) -0.2 (-0.5, 0.1) in the patellofemoral compartment. No effects over 24 months were observed on osteophytes, menisci, Hoffa-synovitis or effusion-synovitis. CONCLUSIONS: Positive effects associated with sprifermin were observed for cartilage morphology changes, and BML improvement. There were no meaningful negative or positive effects associated with sprifermin in the other joint tissues examined.

MRI-based screening for structural definition of eligibility in clinical DMOAD trials: Rapid OsteoArthritis MRI Eligibility Score (ROAMES).

PURPOSE: Our aim was to introduce a simplified MRI instrument, Rapid OsteoArthritis MRI Eligibility Score (ROAMES), for defining structural eligibility of patients for inclusion in disease-modifying osteoarthritis drug trials using a tri-compartmental anatomic approach that enables stratification of knees into different structural phenotypes and includes diagnoses of exclusion. We also aimed to define overlap between phenotypes and determine reliability. METHODS: 50 knees from the Foundation for National Institutes of Health Osteoarthritis Biomarkers study, a nested case-control study within the Osteoarthritis Initiative, were selected within pre-defined definitions of phenotypes as either inflammatory, subchondral bone, meniscus/cartilage, atrophic or hypertrophic. A focused scoring instrument was developed covering cartilage, meniscal damage, inflammation and osteophytes. Diagnoses of exclusion were meniscal root tears, osteonecrosis, subchondral insufficiency fracture, tumors, malignant marrow infiltration and acute traumatic changes. Reliability was determined using weighted kappa statistics. Descriptive statistics were used for determining concordance between the a priori phenotypic definition and ROAMES and overlap between phenotypes. RESULTS: ROAMES identified 43 of 50 (86%) pre-defined phenotypes correctly. Of the 50 participants, 27 (54%) had no additional phenotypes other than the pre-defined phenotype. 18 (36%) had one and 5 (10%) had two additional phenotypes. None had three or four additional phenotypes. All features of ROAMES showed almost perfect agreement. One case with osteonecrosis and one with a tumor were detected. CONCLUSIONS: ROAMES is able to screen and stratify potentially eligible knees into different structural phenotypes and record relevant diagnoses of exclusion. Reliability of the instrument showed almost perfect agreement.

Radiographically normal knees with contralateral joint space narrowing display greater change in cartilage transverse relaxation time than those with normal contralateral knees: a model of early OA? - data from the Osteoarthritis Initiative (OAI).

OBJECTIVE: To develop a model of early osteoarthritis, by examining whether radiographically normal knees with contralateral joint space narrowing (JSN), but without contralateral trauma history, display greater longitudinal cartilage composition change (transverse relaxation time; T2) than subjects with bilaterally normal knees. METHODS: 120 radiographically normal knees (Kellgren Lawrence grade [KLG] 0) from the Osteoarthritis Initiative were studied. 60 case knees displayed definite contralateral radiographic knee osteoarthritis (KLG ≥ 2) whereas 60 reference subjects were bilaterally KLG0, and were matched 1:1 to cases based on age, sex, and BMI. All had multi-echo spin-echo MRI acquired at year (Y) 1 and 4 follow-up, with cartilage T2 being determined in superficial and deep cartilage layers across 16 femorotibial subregions. T2 across all regions was considered the primary analytic focus. RESULTS: Of 60 KLG0 case knees (30 female, age: 65.0 ± 8.8 y, BMI: 27.6 ± 4.4 kg/m2), 21/22/13/4 displayed contralateral JSN 0/1/2/3, respectively. The longitudinal increase in the deep layer cartilage T2 between Y1 and Y4 was significantly greater (P = 0.03; Cohen's D 0.50) in the 39 KLG0 case knees with contralateral JSN (1.2 ms; 95% confidence interval [CI] [0.4, 2.0]) than in matched KLG0 reference knees (0.1 ms; 95% CI [-0.5, 0.7]). No significant differences were identified in superficial T2 change. T2 at Y1 was significantly greater in case than in reference knees, particularly in the superficial layer of the medial compartment. CONCLUSIONS: Radiographically normal knees with contralateral, non-traumatic JSN represent an applicable model of early osteoarthritis, with deep layer cartilage composition (T2) changing more rapidly than in bilaterally normal knees. CLINICALTRIALS. GOV IDENTIFICATION: NCT00080171.

Cartilage loss in radiographically normal knees depends on radiographic status of the contralateral knee - data from the Osteoarthritis Initiative.

OBJECTIVE: To test whether radiographically normal knees with contralateral radiographic knee osteoarthritis (OA), but without contralateral trauma history, display greater cartilage thickness loss than knees from subjects with bilaterally radiographically normal knees. METHODS: 828 radiographically normal knees (Kellgren Lawrence grade [KLG] 0) from the Osteoarthritis Initiative [OAI] were studied; 150 case knees displayed definite radiographic knee OA (KLG ≥ 2) contralaterally, and had MRI double echo steady state (DESS) images available at 12 and 48 month follow-up. 678 reference knees displayed KLG0 at the contralateral side. Cartilage thickness change was determined in femorotibial subregions and location-independent cartilage thinning scores were computed. Case and reference knees were compared using ANCOVA. RESULTS: Of the 150 KLG0 case knees, 108 had a contralateral KLG2 knee (50 without, and 58 with joint space narrowing [JSN]), 31 a KLG3 and 11 a KLG4 knee. The cartilage thinning score tended to be greater in case than reference knees; the cartilage thinning score in KLG0 case knees with contralateral radiographic JSN (-858 µm; [95% confidence interval -1016, -701 µm]) was significantly greater (P = 0.0012) than that in bilaterally KLG0 reference knees (-634 µm; [-673, -596 µm]), whereas KLG0 knees with contralateral KLG2 without JSN only showed relatively small thinning scores (-530 µm, [-631, -428 µm]). Region-specific analysis suggested greater rates of cartilage loss in case than in reference knees in the lateral, rather than medial, femorotibial compartment. CONCLUSIONS: Radiographically normal knees with contralateral JSN may serve as a human model of early OA, for testing disease modifying drugs in clinical trials designed to prevent cartilage loss before the onset of radiographic change. CLINICALTRIALS. GOV IDENTIFICATION: NCT00080171.

Diagnostic performance of knee physical exam and participant-reported symptoms for MRI-detected effusion-synovitis among participants with early or late stage knee osteoarthritis: data from the Osteoarthritis Initiative.

OBJECTIVE: Evaluate the diagnostic performance of knee physical exam findings and participant-reported symptoms for MRI-detected effusion-synovitis (ES) among knees with early and late-stage osteoarthritis (OA). DESIGN: The Osteoarthritis Initiative (OAI) is a longitudinal study of participants with or at risk for knee OA. Two samples with MRI readings were available: 344 knees with early OA (312 participants) and 216 with late-stage OA (186 participants). Trained examiners performed bulge sign (BS) and patellar tap (PT) exams, and participants reported on knee swelling and pain with leg straightening. Effusion-synovitis on 3T non-contrast MRI was scored using the MRI Osteoarthritis Knee Score (MOAKS). Diagnostic performance of physical exam findings and symptoms was estimated with bootstrapped confidence intervals. RESULTS: For the early OA sample, the highest sensitivity for medium/large effusion-synovitis was achieved with a positive finding for any of the physical exam maneuvers and/or participant-reported symptoms (81.0 [95% CI: 70.0, 91.3]). Both knee symptoms in combination had a prevalence of 11.7% and yielded the highest estimated positive predictive value (PPV) (50.0 [95% CI: 34.2, 66.7]) and likelihood ratio positive (LR+) (5.2 [95% CI: 2.9, 9.7]). In late-stage OA knees, exam findings and symptoms provided minimal information beyond the prevalence. CONCLUSION: Patient report of both symptoms, or at least one positive exam finding and at least one symptom, could be used to identify knees at increased risk of effusion-synovitis in knees with early stage OA, either for screening purposes in clinical evaluation, or for study sample enrichment with an inflammatory phenotype; diagnostic performance was not sufficiently high for clinical diagnostic purposes.

Association of patella alta with worsening of patellofemoral osteoarthritis-related structural damage: data from the Osteoarthritis Initiative.

OBJECTIVES: To determine the association between Insall-Salvati ratio (ISR), a measure of patella alta, and worsening of Magnetic Resonance Imaging (MRI)-based osteoarthritis (OA)-related patellofemoral joint structural damages over 24-month in participants of the Osteoarthritis Initiative (OAI). DESIGN: Using weighted random sampling method, we selected a sample of 500 knees (from 1,677 knees with available baseline and 24-months MRI OA Knee Score (MOAKS) measurements), which is OAI-representative regarding knee OA-related factors (i.e., baseline age, sex, body mass index (BMI), and radiographic Kellgren-Lawrence grading). The ISR was measured in all enrolled knees using baseline sagittal 3T-MRI plane by three radiologists. Baseline and 24-month MOAKS variables for patellofemoral bone marrow lesions (BMLs), cartilage damages, and osteophytes were extracted, and the associations between ISR and 24-month worsening of these 3T-MRI features were evaluated using multivariable regression models. After computing receiver operating characteristic curves, the optimal cutoff point of ISR for indicating worsening of patellofemoral OA was determined. P-values were adjusted for multiple comparisons and false discovery rate (FDR) adjusted P-values were reported. RESULTS: In this longitudinal analysis, 24-month worsening of BML (odds ratio [OR] (95% confidence interval [95% CI]):11.18 (3.35-39.6), adjusted-p-value:<0.001) and cartilage scores (OR:7.39 (1.62-34.71), adjusted-p-value:0.042) in lateral patella was associated with higher baseline ISR. However, higher ISR was not statistically associated with medial patellar or medial and lateral trochlear BML or cartilage scores worsening. We determined the optimal cutoff point of ISR≥1.14 (95% CI: 1.083-1.284) for predicting lateral patellofemoral OA-related structural damages worsening over 24-months (sensitivity:73.73%; specificity: 66.67%). CONCLUSIONS: Given the uncertainly surrounding the results, our overall findings suggest that ISR could be considered as a predictor of lateral patellofemoral OA-related structural damages worsening with the optimal cutoff point of ≥1.14 using knee sagittal MRI measurements.

Towards prevention of post-traumatic osteoarthritis: report from an international expert working group on considerations for the design and conduct of interventional studies following acute knee injury.

OBJECTIVE: There are few guidelines for clinical trials of interventions for prevention of post-traumatic osteoarthritis (PTOA), reflecting challenges in this area. An international multi-disciplinary expert group including patients was convened to generate points to consider for the design and conduct of interventional studies following acute knee injury. DESIGN: An evidence review on acute knee injury interventional studies to prevent PTOA was presented to the group, alongside overviews of challenges in this area, including potential targets, biomarkers and imaging. Working groups considered pre-identified key areas: eligibility criteria and outcomes, biomarkers, injury definition and intervention timing including multi-modality interventions. Consensus agreement within the group on points to consider was generated and is reported here after iterative review by all contributors. RESULTS: The evidence review identified 37 studies. Study duration and outcomes varied widely and 70% examined surgical interventions. Considerations were grouped into three areas: justification of inclusion criteria including the classification of injury and participant age (as people over 35 may have pre-existing OA); careful consideration in the selection and timing of outcomes or biomarkers; definition of the intervention(s)/comparator(s) and the appropriate time-window for intervention (considerations may be particular to intervention type). Areas for further research included demonstrating the utility of patient-reported outcomes, biomarkers and imaging outcomes from ancillary/cohort studies in this area, and development of surrogate clinical trial endpoints that shorten the duration of clinical trials and are acceptable to regulatory agencies. CONCLUSIONS: These considerations represent the first international consensus on the conduct of interventional studies following acute knee joint trauma.