Faculty Bibliography

BACKGROUND:To investigate the expression of vascular adhesion protein-1 (VAP-1) in joint tissues and serum in symptomatic knee osteoarthritis (SKOA) patients and examine whether VAP-1 levels predict increased risk of disease severity in a cross-sectional study. METHODS:Baseline VAP-1 expression and soluble VAP-1 (sVAP-1) levels were assessed in the synovium synovial fluid and in the serum in cohorts of patients with tibiofemoral medial knee OA and healthy subjects. Standardized fixed-flexion poster anterior knee radiographs scored for Kellgren-Lawrence (KL) grade (0-4) and medial joint space width (JSW). KL1/2 vs. KL3/4 scores defined early and advanced radiographic severity, respectively. Biochemical markers assessed in serum or synovial fluids (SF) comprised sVAP-1, interleukin 1 receptor antagonist (IL-1Ra), interleukin 6 (IL-6), soluble receptor for advanced glycation end-products (sRAGE), C-C motif chemokine ligand 2 (CCL2), C-C motif chemokine ligand 4 (CCL4), cluster of differentiation 163 (CD163), high sensitivity C-reactive protein (hsCRP), and matrix metalloproteinases (MMPs)-1,-3,-9. Associations between biomarkers and radiographic severity KL1/2 vs. KL3/4 (logistic regression controlling for covariates) and pain (Spearman correlation) were evaluated. RESULTS:Elevated levels of sVAP-1 observed in OA synovial fluid and VAP-1 expression in synovium based on immunohistochemical, microarray, and real-time quantitative polymerase chain reaction (qRT-PCR) analyses. However, serum sVAP-1 levels in OA patients were lower than in controls and inversely correlated with pain and inflammation markers (hsCRP and soluble RAGE). Soluble VAP-1 levels in serum were also lower in radiographically advanced (KL3/4) compared with early KL1/2 knee SKOA patients. CONCLUSION/CONCLUSIONS:Local (synovial fluid) semicarbazide-sensitive amine oxidase (SSAO)/sVAP-1 levels were elevated in OA and correlated with radiographic severity. However, systemic (serum) sVAP-1 levels were lower in SKOA patients than normal and inversely correlated with pain and inflammation markers. Serum sVAP-1 levels were higher in early (KL1/2) compared with advanced (KL3/4) SKOA patients.

OBJECTIVE:To validate a radial imaging spin-echo diffusion tensor (RAISED) sequence for high-resolution diffusion tensor imaging (DTI) of articular cartilage at 3 T. METHODS:The RAISED sequence implementation is described, including the used non-linear motion correction algorithm. The robustness to eddy currents was tested on phantoms, and accuracy of measurement was assessed with measurements of temperature-dependent diffusion of free water. Motion correction was validated by comparing RAISED with single-shot diffusion-weighted echo-planar imaging (EPI) measures. DTI was acquired in asymptomatic subjects (n = 6) and subjects with doubtful (Kellgren-Lawrence [KL] grade 1, n = 9) and mild (KL = 2, n = 9) symptomatic knee osteoarthritis (OA). MD and FA values without correction, and after all corrections, were calculated. A test-retest evaluation of the DTI acquisition on three asymptomatic and three OA subjects was also performed. RESULTS:The root mean squared coefficient of variation of the global test-restest reproducibility was 3.54% for MD and 5.34% for FA. MD was significantly increased in both femoral condyles (7-9%) of KL 1 and in the medial (11-17%) and lateral (10-12%) compartments of KL 2 subjects. Averaged FA presented a trend of lower values with increasing KL grade, which was significant for the medial femoral condyle (-11%) of KL 1 and all three compartments in KL 2 subjects (-18 to -11%). Group differences in MD and FA were only significant after motion correction. CONCLUSION/CONCLUSIONS:The RAISED sequence with the proposed reconstruction framework provides reproducible assessment of DTI parameters in vivo at 3 T and potentially the early stages of the disease in large regions of interest. KEY POINTS/CONCLUSIONS:• DTI of articular cartilage is feasible at 3T with a multi-shot RAISED sequence with non-linear motion correction. • RAISED sequence allows estimation of the diffusion indices MD and FA with test-retest errors below 4% (MD) and 6% (FA). • RAISED-based measurement of DTI of articular cartilage with non-linear motion correction holds potential to differentiate healthy from OA subjects.

OBJECTIVE:Phenotypic changes of chondrocytes toward hypertrophy might be fundamental in the pathogenesis of OA, of which type X collagen (Col10) is a well-known marker. The purpose was to develop a specific immunoassay for blood quantification of a newly identified neo-epitope of type X collagen to assess its diagnostic value for radiographic knee osteoarthritis (OA). METHODS:A neo-epitope of Col10 was identified in urine samples from OA patients. A monoclonal antibody against the neo-epitope was produced in Balb/C mice. The enzyme responsible for the cleavage was identified. Immunohistochemical detection of this neo-epitope was performed on human OA cartilage. An immunoassay (Col10neo) was developed and quantified in two clinical studies: the C4Pain-003 and the NYU OA progression study. ROC curve analysis was carried out to evaluate the discriminative power of Col10neo between OA and RA. RESULTS:A neo-epitope specific mAb was produced. The Cathepsin K-generated neo-epitope was localized to the pericellular matrix of chondrocytes, while its presence was extended and more prominent in superficial fibrillation in the cartilage with advanced degradation. In the C4Pain study, a higher level of Col10neo was seen in subjects with greater KL grade. The group of the highest tertile of Col10neo included more subjects with KL3-4. In the NYU study, Col10neo was statistically higher in OA than control or RA. ROC curve analysis revealed area under the curve was 0.88 (95% CI 0.81-0.94). CONCLUSION/CONCLUSIONS:Our findings indicate that Col10neo linked to hypertrophic chondrocytes could be used as a diagnostic biochemical marker for knee OA.

Purpose: To obtain knee ultrasound (KUS) imaging and assessments on an ongoing community-based cohort study to provide additional information regarding features of knee OA beyond what is found on radiographs. Method(s): A radiology technologist was trained to obtain standardized bilateral KUS images of consecutive individuals attending the 4^th follow-up visit (T4) of the Johnston County OA Project in 2017-18 per a written protocol. A scoring atlas was developed and subsequently revised to allow for semi-quantitative grading of key features by four US-trained rheumatologists, all of whom had input into the training and development activities. Weighted kappa statistics were generated for each feature, by side and combined, along with Kendall coefficients of concordance and percentage agreement. This was first done on initial random selection of 50 participants, followed by discussion via web conference and second round of scoring on 15 participants (11 women/4 men; 11 white/4 African American) selected to represent a range of scores by feature; the latter is presented here. The mean, SD, median, and scoring range was calculated for each feature across the four readers. Result(s): The protocol includes 7 views per knee: Longitudinal and transverse suprapatellar in 30 degrees flexion (for effusion, synovitis by gray scale and color power Doppler (CPD)), medial and lateral longitudinal (for osteophytes, meniscal damage), suprapatellar transverse in maximal flexion (for cartilage damage) and posterior transverse (for cysts). The feature scores (11 score features per knee, see Table) were consistent with mild to moderate pathology in these 30 knees that were selected to represent a range of disease. In particular, mean and median scores for effusion/synovitis and medial cartilage damage demonstrated moderate disease severity. The overall reliability was in the fair to moderate (0.2-0.6) range, and was better for features of synovitis by CPD, osteophytes, and cartilage damage compared with effusion/synovitis by gray scale and meniscal damage (Table). Reliability as assessed simultaneously for all readers by the Kendall coefficient was somewhat better than as assessed by pairwise weighted kappa statistics. The next steps for this project will be to score the full set of 200 participants' US images (400 knees) from T4 and to assess these (likely again as a mean or median) in conjunction with radiographic and symptomatic data in these same knees. [Figure presented] Conclusion(s): US of the knee has been added to the protocol of the Johnston County OA Project and will provide additional information beyond the already extensive radiographic, symptomatic, and clinical data on these participants in a feasible and sustainable way. Further work will characterize the cross-sectional and longitudinal associations among US, radiographic and other features in the parent cohort as well as the new Johnston County Health Study cohort (a new enrollment cohort beginning at age 35 and including Hispanic individuals).

INTRODUCTION/BACKGROUND:Bariatric surgery reduces obesity and knee osteoarthritis (OA) pain, but some patients improve more than others. We aimed to identify characteristics that predict this knee pain improvement. METHODS:We reviewed NYU Langone Health bariatrics records (2002-2015) and called eligible patients reporting pre-operative knee pain. Patients were asked to rate their pain on a 10-point scale at three time points: before surgery, one year post-surgery, and time of survey administration. Subjects were asked about pre-operative knee injuries and surgeries, presence of OA in other joints, and OA family history. Data were analyzed using paired t-tests and ANOVA. RESULTS:Of 125 eligible patients reporting knee pain, we analyzed the 120 patients who had laparoscopic gastric band (LAGB) surgery. The cohort was 78.3% female, with an average age at surgery of 49.7 ± 10.2 years. There was no correlation between pre-operative body mass index (BMI) and knee pain reduction at one year post-LAGB, but the subgroup with the most BMI improvement reported the most knee improvement (p = 0.043). We found significantly better pain reduction after one year in younger patients (p = 0.009). Those with prior knee injuries improved less than those who were injury-free (p = 0.044), but a history of prior knee surgery was not similarly significant. Patients with multifocal OA improved less (p = 0.001). CONCLUSION/CONCLUSIONS:Younger knee OA patients and those without prior knee injury or other OA involvement, experience more knee pain relief from LAGB weight loss surgery. LAGB may be a viable treatment option for knee OA pain, irrespective of the degree of obesity.

OBJECTIVE:The aims of this study were to systematically review clinimetrics of commonly assessed ultrasound pathologies in knee, hip and hand osteoarthritis (OA), and to conduct a meta-analysis for each clinimetric. METHODS:Medline, Embase, and Cochrane Library databases were searched from their inceptions to September 2016. According to the Outcome Measures in Rheumatology (OMERACT) Instrument Selection Algorithm, data extraction focused on ultrasound technical features and performance metrics. Methodological quality was assessed with modified 19-item Downs and Black score and 11-item Quality Appraisal of Diagnostic Reliability (QAREL) score. Separate meta-analyses were performed for clinimetrics: (1) inter-rater/intra-rater reliability; (2) construct validity; (3) criteria validity; and (4) internal/external responsiveness. Statistical Package for the Social Sciences (SPSS), Excel and Comprehensive Meta-analysis were used. RESULT/RESULTS:Our search identified 1126 records; of these, 100 were eligible, including a total of 8542 patients and 32,373 joints. The average Downs and Black score was 13.01, and average QAREL was 5.93. The stratified meta-analysis was performed only for knee OA, which demonstrated moderate to substantial reliability [minimum kappa > 0.44(0.15,0.74), minimum intraclass correlation coefficient (ICC) > 0.82(0.73-0.89)], weak construct validity against pain (r = 0.12 to 0.27), function (r = 0.15 to 0.23), and blood biomarkers (r = 0.01 to 0.21), but weak to strong correlation with plain radiography (r = 0.13 to 0.60), strong association with Magnetic Resonance Imaging (MRI) [minimum r = 0.60(0.52,0.67)] and strong discrimination against symptomatic patients (OR = 3.08 to 7.46). There was strong criterion validity against cartilage histology [r = 0.66(-0.05,0.93)], and small to moderate internal [standardized mean difference(SMD) = 0.20 to 0.58] and external (r = 0.35 to 0.43) responsiveness to interventions. CONCLUSION/CONCLUSIONS:Ultrasound demonstrated strong criterion validity with cartilage histology, poor to strong correlation with patient findings and MRI, moderate reliability, and low responsiveness to interventions. PROSPERO REGISTRATION NO/UNASSIGNED:CRD42016039954.