Faculty Bibliography

Background/Purpose: Persistent inflammation is a characteristic of several joint diseases, including OA. It is nowadays appreciated that this could be a result of a failure to (optimally) activate inflammation resolution pathways. Therefore, we investigated the presence of specialized pro-resolving lipid mediators (SPM) and their precursors as pathway markers of the resolution process in the joint of OA patients and controls. Methods: SF was obtained from knee OA (2 populations) and rheumatoid arthritis (RA) patients fulfilling the ACR criteria for OA and RA, respectively, and healthy controls. Lipid mediators (LMs) were determined by targeted lipidomics using liquid-chromatography mass spectrometry. Sixty different lipids including pro-inflammatory (e.g. prostaglandins, leukotrienes) and anti-inflammatory/pro-resolving LM (e.g. SPM), as well as their precursors can be detected with our technique. Results: SF from 24 OA and 12 RA patients were first studied. Thirty-seven lipids were detected in the soluble fraction of SF, including polyunsaturated fatty acids (PUFA) and their lipoxygenase (LOX) and cyclooxygenase (COX) pathway markers in both OA and RA patients. Among these, pro-inflammatory LM such as PGE2 and thromboxane B2, as well as the pathway markers of resolution and precursors of SPM, 17-HDHA and 18-HEPE, were detected. Except for the LOX products of arachidonic acid: 15-HETE, 6-trans-LTB4 and 20-OH- LTB4, which were lower in OA than in RA SF, all other lipid mediators and PUFA were comparable between OA and RA samples. Ratios of metabolites to their precursors indicated that both pro- (e.g. LTB4) and anti-inflammatory LOX products (e.g. 17- HDHA) are more efficiently generated in RA than in OA patients, while no differences were observed in COX products. Interestingly, the SPM resolvin D2 (RvD2) could also be detected, but only in the insoluble fraction (cells and undigested matrix), indicating that the resolution pathways are activated in OA. This expands our previous publication showing activation of resolution in RA patients. To assess the efficiency of activation of resolution in OA, we have performed targeted lipidomics on total SF in an additional study with 32 OA patients and 10 healthy controls. Confirming earlier data, most LMs were also detected in this study, including the pro-inflammatory PGE2, the SPM precursors 17-HDHA and 18-HEPE, and the SPM RvD2. Additionally, we detected 18S-resolvin E3 (18S-RvE3). Remarkably, both the absolute concentrations of the SPM RvD2 and 18S-RvE3, and the ratio to their precursors, 17-HDHA and 18-HEPE, were lower in OA compared to healthy SF, indicating less efficient generation of SPM in OA compared to healthy joints. In contrast, the proinflammatory lipid PGE2was higher in OA than in healthy SF, indicating that the lower activation of resolution is paired by a higher inflammatory load in OA compared with healthy individuals. Conclusion: By using a state-of-the-art technique, we show for the first time that resolution pathways are activated in OA patients. Importantly, resolution seems to be less efficiently activated than in healthy individuals, which could account for the persistent inflammation observed in OA and RA patients

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: 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/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: 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: Inflammatory mediators, such as PGE2 and IL-1beta, are produced by osteoarthritic joint tissues, where they may contribute to disease pathogenesis. We examined whether inflammation, reflected in plasma and peripheral blood leukocytes (PBLs) reflected presence of osteoarthritis (OA), progression or symptoms in patients with symptomatic knee osteoarthritis (SKOA). METHODS: SKOA patients were enrolled in a 24-month prospective study of radiographic progression. Standardized knee radiographs were obtained at baseline and 24 months. Biomarkers assessed at baseline included plasma lipids PGE2 and 15-HETE, and transcriptome analysis of PBLs by microarray and qPCR. RESULTS: Baseline PGE synthases (PGES) by PBL microarray gene expression, and plasma PGE2 distinguished SKOA patients from non-OA controls (AUCs 0.87 and 0.89 respectively, p<0.0001). Baseline plasma 15-HETE was significantly elevated in SKOA versus non-OA controls (p<0.019). In the 146 patients who completed the 24-month study, elevated baseline expression of IL-1beta, TNFalpha and COX-2 mRNA in PBLs predicted higher risk for radiographic progression by joint space narrowing (JSN). In a multivariate model, AUC point estimates of models containing COX-2 in combination with demographic traits overlap the confidence interval of the base model in two out of the three JSN outcome measures (JSN >0.0mm, >0.2mm and >0.5mm, AUC=0.62-0.67). CONCLUSION: Inflammatory plasma lipid biomarkers PGE2 and 15-HETE identify patients with SKOA. PBL inflammatory transcriptome identifies a subset of SKOA patients at higher risk for radiographic progression. These findings may reflect low-grade inflammation in OA and may be useful as diagnostic and prognostic biomarkers in clinical development of disease-modifying OA drugs

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.