Faculty Bibliography

Background/Purpose: Osteoarthritis (OA) etiopathogenesis includes an inflammatory component. Published reports indicate that synovial fluid urate levels, even in patients without gout, associate with OA prevalence/severity. Whether serum urate (sUA), the precursor for gout and a biomarker for cardiovascular and kidney disease, may serve as a biomarker to convey or predict OA risk is not known. We investigated whether sUA levels associate with knee OA radiographic severity and contrast MRI-measured quantitative synovial volume (SV), and whether sUA levels predict radiographic progression, in a gout-free knee OA cohort. Methods: We assessed sUA in 88 gout-free subjects who completed a 24-month prospective, natural history knee OA study. Subjects had symptomatic medial knee OA, met ACR knee OA criteria and had BMI <33 at study entry. sUA was measured (enzyme-colorimetry) in serum frozen and banked at baseline. At baseline and 24 months, patients underwent standardized weight-bearing fixed-flexion posteroanterior knee radiographs (SynaFlexerTM). Twenty-seven subjects additionally had a dynamic gadolinium-enhanced 3.0T knee MRI that was read for quantitative synovial volume (SV). A musculoskeletal radiologist, blinded to subject data, determined joint space width (JSW) and Kellgren-Lawrence (KL) grades at each time point. Joint space narrowing (JSN) was determined as JSW change from baseline to 24 months. Pearson's correlations, student's t-tests, one-way ANOVA with post hoc Tukey-Kramer tests, ROC and AUC curves were used in statistical analyses, as appropriate. Results: sUA correlated with JSN in both univariate (r=0.40, p<0.01) and multivariate analyses (adjusting for age, gender and BMI, r=0.28, p=0.010). There was a significant difference in mean JSN after dichotomization of sUA at 6.8mg/dL, the solubility point for serum urate, even after adjustment for age, gender and BMI (JSN [+/-SEM] of 0.90mm+/-0.20mm for sUA>6.8; JSN [+/-SEM] of 0.31mm+/-0.09mm for sUA<6.8, p<0.01). Baseline sUA distinguished progressors (JSN>0.2mm), and fast progressors (JSN>0.5mm), from non-progressors (JSN<0.0mm) in multivariate analyses (area under the receiver operating characteristic curve [AUC] 0.626, p=0.027; AUC 0.620, p=0.045, respectively). sUA also correlated with SV (r=0.44, p=0.0040), a possible marker of JSN, though this correlation did not persist after controlling for age, gender and BMI (r=0.13, p=0.562). Conclusion: In non-gout patients with knee OA, sUA levels predict JSN and may serve as a biomarker for OA progression. (Figure presented)

Background/Purpose: Osteoarthritis (OA) is a disease characterized by pain and tissue destruction, in some cases concomitant with inflammation. The link between pain and tissue destruction is yet unknown, and there is a lack objective quantifiable parameters. Collagens are the main structural proteins of the joint extracellular matrix. The degradation of especially type I (connective tissue), II (cartilage), III (synovium) and IV (basement membrane) collagens have been shown to be elevated in OA. So we investigated whether biomarkers reflecting collagen degradation were associated with knee OA representing with different pain and inflammatory phenotypes. Methods: 111 knee OA patients, 62% women, from NYUHJD progression cohort study with varying degree of OA were included: mean (SD) age, 62 (10); mean(SD) BMI, 27(4); NSAID users, 23%; radiographic OA (KL>2) 68%; and bilateral knee OA; 87%. Pain was assessed by VASpain and WOMAC at baseline (BL) at a 2- year follow-up (FU) visit. Median (IQR) were 39 (13-69) and 37 (13-52) for BL VASpain and WOMACpain. 4 BL serum biomarkers of type I, II, III and IV collagen degradation (C1M, C2M, C3M, C4M), and the 2 inflammatory biomarkers CRPM and hsCRP, were assessed. Data were log2 transformed. Associations between BL biomarkers, BL pain and change (CHG) pain scores were assessed by multivariate linear model including gender, age, BMI, KLsignalknee, bilateral knee OA and NSAID use. Patients with cont. mild/moderate pain had a BL VASpain<54 and FU VASpain<30, cont. moderate/severe pain had VASpain>30 at baseline and FU, and transitional severe pain had either VASpain-BL<30 and VASpain-FU>54 or VASpain-BL>54 and VASpain-FU<30 (ref). Patients with; low biochemical disease activity index (bDAI) low in CRPM (<12nM) moderate bDAI were high in CRPM but low in hsCRP (<5), and high bDAI (flare) were high in CRPM and hsCRP. Results: BL association between pain and biomarkers C2M (beta -17.9, p<0.0001) and KLsignalknee (beta -5.4, p=0.0031) were significantly associated with WOMAC pain. C2M (beta -12.4, p=0.0033), C3M (beta -19.9, p=0.059), age (beta -0.84, p<0.0018), KLsignalknee (beta 8.9, p=0.0021) and bilateral knee OA (beta -12.2, p=0.087) were associated with VASpain. Association between BL biomarkers and CHG pain C2M (beta 13.3, p=0.0016), age (beta 0.5, p=0.029) and bilateral OA (beta -12.0, p=0.043) were significantly associated with delta WOMACpain. Only age, BMI and NSAID use was associated with CHG VASpain. Association between pain phenotypes and BL biomarkers Patients with cont. mild/moderate pain had significantly higher C2M compared patients with transitional severe pain (p=0.0014) and cont. moderate/severe pain (p=0.04). Biomarker, BL pain and CHG pain in patients w. inflammatory OA Patient with low bDAI had lower WOMACpain (p<0.05) and VASpain(p<0.1). C1M was higher (p<0.05) in the flare group compared to the low and moderate bDAI groups. C3M was higher (p<0.05) in the moderate bDAI group than the low DAI group. Conclusion: Different collagen degradation products are linked differentially to different phenotypes. Cartilage degradation (C2M) was consistently linked to CHG pain phenotypes, whereas it was not associated with an inflammatory phenotype. In contrast, C1M and C3M were linked to inflammatory and flared OA

Background/Purpose: Obesity is a common risk factor for knee osteoarthritis (KOA). While it is intuitive that bariatric weight loss improves knee pain, it is not clear how much is due to decreased mechanical load vs metabolic changes. Methods: Patients were screened for knee pain prior to sleeve gastrectomy, gastric bypass, or laparoscopic gastric banding. We required pain for >15 days/month and VAS pain > 30, excluding lupus, inflammatory arthritis, crystal disease, psoriasis, and bilateral knee replacement. Enrolled patients took standing knee xrays for Kellgren-Lawrence (KL) grading. We measured BMI and used the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire at baseline and 1, 3, 6 and 12 months, calculating % excess weight loss (%EWL) and deltaKOOS. We collected blood at baseline and followup to study biomarkers for predicting KOOS scores. Results: Of 536 patients considering bariatric surgery, we found 308 with knee pain and enrolled 176 (91.5% female; BMI 43.6 kg/m2+/-7, 32-61; age 42 +/-11, 18-73) well distributed in xray severity (KL0-4). For the 150 patients who had surgery, knee improvement paralleled weight loss at the followups. At 1 year, %EWL correlated well with deltaKOOS pain (R = .262, n = 114, p = 0.005), similar to other intervals and to other KOOS measures. The sleeve and bypass (n=72 and 27) vs banding (n=15) resulted in higher deltaKOOS pain at 1 year: 32.9 +/-21.3 and 30.7 +/-22.6 vs 10.2 +/-21.4, p=0.001. Sleeve and bypass patients also achieved a higher % of their potential deltaKOOS pain improvement than did banding (65.2% and 60.1% vs 16.8% of remaining KOOS points to 100), and a higher % of patients improved to any degree (93.1% and 88.9% vs 66.7%). Radiographic severity did not predict deltaKOOS at 1 year, nor did the presence of key comorbidities. Patients lost weight in a near-linear fashion through 1 year (Fig. 1), but their KOOS improvements plateaued at 1 month. This held true in sleeve and bypass subgroups (with altered anatomy), while banding showed less consistent deltaKOOS despite a similar trend in %EWL. Baseline leptin levels in obese KOA were higher than non-obese KOA and non-obese/non-OA controls from other cohorts (100.2 +/-61.9 vs 26.2 +/-16.7 and 15.4+/-13.8, p<0.001). Similarly, IL-1Ra, a potential marker of OA progression, was much higher than non-obese KOA or controls (1123+/-940 vs 324.0+/-145.6 and 272+/-130.0, p<0.001). Within obese KOA, higher leptin levels predicted worse xrays (KL0/1 vs KL2/3/4, p = 0.037). After 1 year, mean leptin and IL1-Ra from obese KOA patients had decreased (p<0.001). Conclusion: Bariatric surgery improves knee OA symptoms proportionally to %EWL. Most relief occurs during the 1st month before much weight loss, suggesting a metabolic impact beyond mechanical load reduction on joints - at least with the sleeve and bypass that alter digestive anatomy. Leptin and IL-1Ra serum levels are elevated in obese KOA vs non-obese KOA and controls - and fall after bariatric surgery which could contribute to knee pain relief

Background/Purpose: In 2008, 18% of rheumatology fellowship program (RFP) program directors (PDs) included musculoskeletal ultrasound (MSUS) in their training programs. Overall goal of this study was to assess the current state and ascertain the needs for MSUS education among RFPs. The objective of this study was to determine if fellowship program size impacts inclusion of MSUS in training. Methods: Out of two surveys sent via QualtricsTM in 2015, a 13-item needs assessment survey was sent to all RFP PDs determining implementation of MSUS teaching including machine accessibility, faculty training, and institutional support. The second survey assessed teaching and evaluation methods used. For the first survey, Fischer's Exact Test was used to test differences between fellowship programs based on size. Small programs were defined as programs with 1-2 fellows yearly, while big programs were those with at least 3 fellows yearly. Results: Out of 113 RFPs, 103 (91%) PDs responded to the needs assessment survey. In total, 94% of RFPs are currently offering some form of MSUS training. Of 73 small programs, 91.8% offered MSUS training; 97.1% of big programs offered MSUS training. By large, there was no statistically significant difference between small and big programs (p=0.429). Majority of both small and big programs (81.8 vs. 93.9%) cited at least one faculty who was competent in performing MSUS (p=0.212). Majority of the teaching was done by a key clinical faculty member other than the PD (39.7% vs. 54.5%). Majority owned an US machine (72.1 vs. 87.9%; p=0.037). When asked if they wanted MSUS to be part of the Rheumatology fellowship training curriculum, majority wanted its inclusion however most wanted it they wanted MSUS to be part of the Rheumatology fellowship training curriculum, majority wanted its inclusion however most wanted it only to be optional (66.2% vs. 66.7%), as compared to those wanted it to be a standard requirement (29.4% vs. 30.3%). Conclusion: MSUS has become prevalent among RFPs. The size of a fellowship program is not a factor in determining inclusion of a MSUS teaching program. Small programs have comparable capacity to include MSUS in teaching programs when compared to big programs. There is openness to including MSUS in Rheumatology fellowship training, whether as an optional or standard part of the curriculum

Background/Purpose: Growing numbers of studies show increased expression in Osteoarthritis (OA) of inflammatory cytokines, such as IL-1beta and TNFalpha, in joint tissues and peripheral blood mononuclear (PBM) cells. The IL1 receptor antagonist (IL1RN) gene cluster region has been associated with susceptibility to knee OA, thereby further implicating inflammation in OA pathogenesis. In these studies, we examined the association of IL-1RN haplotype with the radiographic severity of symptomatic knee OA (SKOA). Methods: Genomic DNA from SKOA patients from three cohorts (NYU I, NYU-II and O

Background/Purpose: Gout is an independent risk factor for cardiovascular disease (CVD). Investigators studying the relationship between gout and CVD have focused on acute coronary outcomes, with limited evidence available regarding peripheral arterial function. Using high-resolution ultrasound imaging of the brachial artery, we examined endothelial and smooth muscle arterial function in gout subjects versus healthy controls. Methods: 34 untreated male gout subjects and 64 healthy control males were included. By enrollment criteria some gout subjects, but no healthy controls, had coronary artery disease (CAD) or diabetes, or were current smokers. Demographics and medical history were recorded. Participants underwent brachial artery flow-mediated dilation (FMD; arterial response to blood flow after transient interruption using a distal blood pressure cuff) and nitroglycerine-mediated dilation (NMD) to assess endothelium-dependent and independent arterial smooth muscle responsiveness, respectively. Dynamic ultrasound images were assessed by two independent observers, with results reported as percentage change in arterial diameter from baseline. Results: Compared with healthy controls, gout subjects had a higher prevalence of CAD (21% vs 0%, p<0.05), chronic kidney disease (76% vs 0, p<0.05), hypertension (71% vs 22%, p<0.05) and hyperlipidemia (50% vs 18%, p<0.05), but a similar low prevalence of diabetes (6% vs 0%, p=0.12). 29% of gout patients were current smokers (p vs control<0.05). Gout subjects were slightly older (58.9 vs 53.2 years, p<0.05), and significantly more gout patients were African American (44% vs 8%). Both FMD (2.20+/-3.12 vs 3.56+/-2.50, p=0.021) and NMD (16.69+/-9.01 vs 24.51+/-7.18, p=0.00002) were significantly reduced in the gout group vs controls. Gout nonsmokers, white gout patients, and gout patients lacking specific co-morbidities persisted in having decreased FMD and NMD compared with controls. Gout patients with versus without specific co-morbidities had similar degrees of impaired FMD and NMD. Analysis of the gout group showed an inverse Pearson correlation between FMD and CRP (R=-0.42, p=0.017), a trend for inverse Pearson correlation between FMD and serum urate (R=-0.31, p= 0.08); but no correlation between NMD and CRP or serum urate. Conclusion: Compared with healthy controls, patients with gout have reduced arterial function as measured by FMD and NMD. While the increased prevalence of comorbidities among gout patients may contribute to diminished arterial function, it appears to be insufficient to explain the endothelial and smooth muscle dysfunction observed. Hyperuricemia and chronic inflammation may contribute to endothelial dysfunction among gout patients, but do not appear to contribute to smooth muscle dysfunction. Whether appropriate gout therapy may improve FMD and NMD in gout patients remains to be determined. (Figure Presented)

BACKGROUND: The purpose of this study was to use MRI to determine if a loss of meniscal intra-substance integrity, as determined by T2* relaxation time, is associated with an increase of Kellgren-Lawrence (KL) grade, and if this was correlated with risk factors for cartilage degeneration, namely meniscal extrusion, contact area and anterior-posterior (AP) displacement. METHODS: Eleven symptomatic knees with a KL 2 to 4 and 11 control knees with a KL 0 to 1 were studied. A 3 Tesla MRI scanner was used to scan all knees at 15 degrees of flexion. With a 222N compression applied, a 3D SPACE sequence was obtained, followed by a spin echo 3D T2* mapping sequence. Next, an internal tibial torque of 5Nm was added and a second 3D SPACE sequence obtained. The MRI scans were post-processed to evaluate meniscal extrusion, contact area, AP displacement and T2* relaxation time. RESULTS: KL grade was correlated with T2* relaxation time for both the anterior medial meniscus (r=0.79, p<0.001) and the posterior lateral meniscus (r=0.55, p=0.009). In addition, T2* relaxation time was found to be correlated with risk factors for cartilage degeneration. The largest increases in meniscal extrusion and decreases in contact area were noted for those with meniscal tears (KL 3 to 4). All patients with KL 3 to 4 indicated evidence of meniscal tears. CONCLUSIONS: This suggests that a loss of meniscal integrity, in the form of intra-substance degeneration, is correlated with risk factors for cartilage degeneration.

OBJECTIVES: To evaluate the use of decision aids for hip and knee osteoarthritis (OA) regarding the potential risks and benefits of different treatment options. METHODS: A prospective, randomized controlled trial was conducted of 147 patients with advanced hip or knee OA to compare the effect of two decision aids (booklet-only vs. booklet with DVD). RESULTS: Both decision aid programs were well received and demonstrated improvements in patient knowledge and willingness to participate in treatment decisions. The decision aids, however, had a marginal effect on patient willingness to participate in OA management, with an increase of 0.11 and 0.6 on a scale of 2 (P = 0.58) between groups. CONCLUSIONS: The decision aids were accepted for most patients and effective in improving patient knowledge and willingness to participate in the decision process. Nevertheless, the addition of a more expensive DVD to the booklet program did not improve patient acceptance or knowledge.

OBJECTIVE: Pro- and anti-inflammatory mediators, such as IL-1beta and IL1Ra, are produced by joint tissues in osteoarthritis (OA), where they may contribute to pathogenesis. We examined whether inflammatory events occurring within joints are reflected in plasma of patients with symptomatic knee osteoarthritis (SKOA). DESIGN: 111 SKOA subjects with medial disease completed a 24-month prospective study of clinical and radiographic progression, with clinical assessment and specimen collection at 6-month intervals. The plasma biochemical marker IL1Ra was assessed at baseline and 18 months; other plasma biochemical markers were assessed only at 18 months, including IL-1beta, TNFalpha, VEGF, IL-6, IL-6Ralpha, IL-17A, IL-17A/F, IL-17F, CRP, sTNF-RII, and MMP-2. RESULTS: In cross-sectional studies, WOMAC (total, pain, function) and plasma IL1Ra were modestly associated with radiographic severity after adjustment for age, gender and body mass index (BMI). In addition, elevation of plasma IL1Ra predicted joint space narrowing (JSN) at 24 months. BMI did associate with progression in some but not all analyses. Causal graph analysis indicated a positive association of IL1Ra with JSN; an interaction between IL1Ra and BMI suggested either that BMI influences IL1Ra or that a hidden confounder influences both BMI and IL1Ra. Other protein biomarkers examined in this study did not associate with radiographic progression or severity. CONCLUSIONS: Plasma levels of IL1Ra were modestly associated with the severity and progression of SKOA in a causal fashion, independent of other risk factors. The findings may be useful in the search for prognostic biomarkers and development of disease-modifying OA drugs.