Faculty Bibliography

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.

Purpose: We and others have demonstrated low grade inflammation exists in OA joint tissues, where it may contribute to disease pathogenesis. In the current studies we assessed whether inflammatory events occurring within joint tissues were reported in the peripheral blood leukocytes (PBLs) of patients with symptomatic knee OA (SKOA). Methods: PBL inflammatory gene expression (IL-1, TNFalpha, COX-2) was assessed in two independent cohorts of patients with SKOA, and a cohort of healthy control subjects: 1) 111 patients with tibiofemoral medial OA and 21 healthy volunteers from the NYUHJD Cohort, and 2) 200 patients from the OAI progression cohort who had "high quality radiographs", at both baseline and 24 months, and had KL2 or 3 in the signal knee at baseline. Radiographic progression was defined as narrowing of medial joint space width (JSW) in the signal knee between baseline and 24-months in each cohort. Radiographic progressors were defined as subjects who had JSN >0.0, 0.2 and 0.5mm over 24 months. For measuring predictive performance, we used the area under the curve (AUC) of a receiver operating characteristics (ROC). OAI SKOA subjects were dichotomized as radiographic non-progressors (JSN <0.0 mm) and progressors (JSN>0.0mm) for association studies. Results: Elevated PBL expression of IL-1, TNFalpha or COX-2 identified SKOA patients who were "fast progressors" (mean JSN 0= 0.71, 0.75 and 0.71 mm / 24 months, respectively) compared to patients with levels below the median. In a multivariable model, anthropometric traits alone (BMI, gender, age) did not predict progression, whereas addition of PBL gene expressions improved prediction of fast progressors (JSN>0.5mm). We next examined inflammatory gene expression in PBLs of radiographic progressors in the OAI cohort. Similar to the NYUHJD cohort, elevated expression of IL-1beta, TNFalpha and COX-2 mRNA distinguished radiographic progressors from non-progressors (Table 1). PBL IL-1beta expression found to be strongest predictor of all three radiographic progressors. In multivariate models that combine all three markers did not improve upon IL-1beta predictivity. We thus conclude that either the signal in TNFalpha and Cox-2 is already subsumed by IL-1beta and/or that it is not easy to capture the non-overlapping signals without increasing the sample size (i.e., fitting a stronger multivariate predictor will require more sample size). Conclusions: We identified, and confirmed in two cohorts, increased inflammatory gene expression (IL-1, TNFalpha or COX-2) by PBLs that predict radiographic progression in patients with SKOA. The data indicate that inflammatory events within joint tissues of patients with SKOA are reported in the peripheral blood. These PBL transcriptome signals of local joint inflammation merit further study as potential biomarkers for OA disease progression. (Table Presented)

Purpose: Obesity is a modifiable risk factor of knee osteoarthritis (KOA). While diet, exercise and other conservative treatments can have limited and often transient beneficial effects, an alternative strategy would target weight loss via surgery to delay or avoid joint replacement. Some retrospective data, including a study from our group, have in fact shown sustained improvement in KOA pain after bariatric surgery. We initiated a prospective study to evaluate painful KOA in the obese population, and track whether weight loss after bariatric surgery affects KOA-related pain and physical function. Methods: We screened consecutive patients prior to laparoscopic adjustable gastric banding (LAGB), sleeve gastrectomy, or gastric bypass (RYGB), at NYU Langone Medical Center and Bellevue Hospital Center. Patients age >21 with knee pain for >1 month and a visual analog scale pain score >30mm were enrolled, excluding those with lupus, rheumatoid arthritis, psoriatic arthritis, or psoriasis. Baseline pre-op assessments included x-rays for OA severity by Kellgren-Lawrence (KL) grade, the Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) with a Likert scale calculated from the KOOS. Patients were consented for optional tissue collection (blood, urine and intra-operative adipose samples) for future biomarker analysis. They are (still) completing the questionnaires and being measured for BMI and % excess weight loss (%EWL) at 1,3,6 and 12 month post-op intervals. Results: In total, we screened 537 patients planning to have bariatric surgery, found that 309 (58%) of them reported knee pain - and enrolled 176who met criteria and consented for the study. Our cohort is 89.7% female, with a mean BMI of 43.6 kg/m2+/-7 (31.6-60.6), a mean age of 42.4 +/-11 (18-73), and radiographic severity as follows: KL0=43 (25%), KL1=34 (19%), KL2=38 (22%), KL3=34 (19%), KL4=27 (15%). The mean pre-op KOOS scores were 45.4 for pain and 46.0 for ADL (0=worst, 100=best), the mean pre-op WOMAC pain score (Likert scale) was 11 (0=best, 20=worst), and the mean overall WOMAC index was 52 (0=best, 96=worst). Before surgery, a higher KL correlated with symptoms; mean KOOS pain was 53.2, 48.1 and 36.7 for KL0, KL1-2, and KL3-4 (p=0.00002 for KL0 vs KL3-4, and p=0.0005 for KL1-2 vs KL3-4), with similar trends across other KOOS and WOMAC scores. Higher BMI also trended with worse pre-op knee symptoms, as the tertiles with the lowest and highest BMIs (31-39 and 46-61) had mean KOOS pain scores of 46.8 and 43.7 (p=0.37). While 23 ultimately decided against weight loss surgery, we are collecting post-operative data on the 153 patients (40 RYGB=26%, 93 sleeve=61%, 20 LAGB=13%). Improvement in average KOOS and WOMAC scores over baseline has been observed at all intervals (67, 71, 65, and 42 responses at 1,3,6,12 month visits), with more improvement farther after surgery. At 6 months post-op, mean KOOS scores available thus far improved 29 points for pain, with mean WOMAC pain and index improving by 6 and 22 points. The %EWL correlated with knee symptoms at each interval and for all followups combined, as the smallest and largest %EWL quartiles (4-29%, 54-92%) showed mean improvements of 18 and 31 points (p=0.03) in KOOS pain - mirrored across KOOS and WOMAC scores. RYGB and sleeve yielded higher %EWL than LAGB (44%, 43% vs. 37%) across all intervals, and greater improvement in mean KOOS and WOMAC scores (e.g. mean KOOS pain increased by 28, 29 and 8). Neither presence nor severity of KOA severity affected knee pain improvement from weight loss. Conclusions: These data suggest that bariatric surgery improves patients' KOA pain proportional to percent excess weight loss, with durability over time. RYGB and sleeve gastrectomy have more impact on knee symptoms than LAGB. While patients with worse KL grades report more baseline pain and disability, as expected, x-ray severity did not impact the response to surgical weight loss

BACKGROUND: Gout and osteoarthritis (OA) are the most prevalent arthritides, but their relationship is neither well established nor well understood. OBJECTIVES: We assessed whether a diagnosis of gout or asymptomatic hyperuricemia (AH) is associated with increased prevalence/severity of knee OA. METHODS: One hundred nineteen male patients aged 55 to 85 years were sequentially enrolled from the primary care clinics of an urban Veterans Affairs hospital, assessed and categorized into 3 groups: gout (American College of Rheumatology Classification Criteria), AH (serum urate >/=6.8 mg/dL, no gout), and control (serum urate <6.8 mg/dL, no gout). Twenty-five patients from each group subsequently underwent formal assessment of knee OA presence and severity (American College of Rheumatology Clinical/Radiographic Criteria, Kellgren-Lawrence grade). Musculoskeletal ultrasound was used to detect monosodium urate deposition at the knees and first metatarsophalangeal joints. RESULTS: The study showed 68.0% of gout, 52.0% of AH, and 28.0% of age-matched control subjects had knee OA (gout vs control, P = 0.017). Odds ratio for knee OA in gout versus control subjects was 5.46 prior to and 3.80 after adjusting for body mass index. Gout subjects also had higher Kellgren-Lawrence grades than did the control subjects (P = 0.001). Subjects with sonographically detected monosodium urate crystal deposition on cartilage were more likely to have OA than those without (60.0 vs 27.5%, P = 0.037), with crystal deposition at the first metatarsophalangeal joints correlating most closely with OA knee involvement. CONCLUSIONS: Knee OA was more prevalent in gout patients versus control subjects and intermediate in AH. Knee OA was more severe in gout patients versus control subjects.