Faculty Bibliography

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: 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)