Faculty Bibliography

BACKGROUND: A lack of biomarkers that identify patients at risk for severe osteoarthritis (OA) complicates development of disease-modifying OA drugs. OBJECTIVE: To determine whether inflammatory genetic markers could stratify patients with knee OA into high and low risk for destructive disease. METHODS: Genotype associations with knee OA severity were assessed in two Caucasian populations. Fifteen single nucleotide polymorphisms (SNPs) in six inflammatory genes were evaluated for association with radiographic severity and with synovial fluid mediators in a subset of the patients. RESULTS: Interleukin 1 receptor antagonist (IL1RN) SNPs (rs419598, rs315952 and rs9005) predicted Kellgren-Lawrence scores independently in each population. One IL1RN haplotype was associated with lower odds of radiographic severity (OR=0.15; 95% CI 0.065 to 0.349; p<0.0001), greater joint space width and lower synovial fluid cytokine levels. Carriage of the IL1RN haplotype influenced the age relationship with severity. CONCLUSION: IL1RN polymorphisms reproducibly contribute to disease severity in knee OA and may be useful biomarkers for patient selection in disease-modifying OA drug trials

PURPOSE: Prior investigations of magnetic resonance imaging (MRI) biomarkers of cartilage loss in knee osteoarthritis (OA) suggest that trials of interventions which affect this biomarker with adequate statistical power would require large clinical studies of 1-2 years duration. We hypothesized that smaller, shorter duration, 'Proof of Concept' (PoC) studies might be achievable by: (1) selecting a population at high risk of rapid medial tibio-femoral (TF) progression, in conjunction with; (2) high-field MRI (3T), and; (3) using advanced image analysis. The primary outcome was the cartilage thickness in the central medial femur. METHODS: Multi-centre, non-randomized, observational cohort study at four sites in the US. Eligible participants were females with knee pain, a body mass index (BMI)> or =25 kg/m(2), symptomatic radiographic evidence of medial TF OA, and varus mal-alignment. The 29 participants had a mean age of 62 years, mean BMI of 36 kg/m(2), with eight index knees graded as Kellgren-Lawrence (K&L)=2 and 21 as K&L=3. Eligible participants had four MRI scans of one knee: two MRIs (1 week apart) were acquired as a baseline with follow-up MRI at 3 and 6 months. A trained operator, blind to time-point but not subject, manually segmented the cartilage from the Dual Echo Steady State water excitation MR images. Anatomically corresponding regions of interest were identified on each image by using a three-dimensional statistical shape model of the endosteal bone surface, and the cartilage thickness (with areas denuded of cartilage included as having zero thickness - ThCtAB) within each region was calculated. The percentage change from baseline at 3 and 6 months was assessed using a log-scale analysis of variance (ANOVA) model including baseline as a covariate. The primary outcome was the change in cartilage thickness within the aspect of central medial femoral condyle exposed within the meniscal window (w) during articulation, neglecting cartilage edges [nuclear (n)] (nwcMF x ThCtAB), with changes in other regions considered as secondary endpoints. RESULTS: Anatomical mal-alignment ranged from -1.9 degrees to 6.3 degrees , with mean 0.9 degrees . With one exception, no changes in ThCtAB were detected at the 5% level for any of the regions of interest on the TF joint at 3 or 6 months of follow-up. The change in the primary variable (nwcMF x ThCtAB) from (mean) baseline at 3 months from the log-scale ANOVA model was -2.1% [95% confidence interval (CI) (-4.4%, +0.2%)]. The change over 6 months was 0.0% [95% CI (-2.7%, +2.8%)]. The 95% CI for the change from baseline did not include zero for the cartilage thickness within the meniscal window of the lateral tibia (wLT x ThCtAB) at 6 month follow-up (-1.5%, 95% CI [-2.9, -0.2]), but was not significant at the 5% level after correction for multiple comparisons. CONCLUSIONS: The small inconsistent compartment changes, and the relatively high variabilities in cartilage thickness changes seen over time in this study, provide no additional confidence for a 3- or 6-month PoC study using a patient population selected on the basis of risk for rapid progression with the MRI acquisition and analyses employed

Osteoarthritis (OA) is often a progressive and disabling disease, which occurs in the setting of a variety of risk factors--such as advancing age, obesity and trauma--that collude to incite a cascade of pathophysiological events within joint tissues. An important emerging theme in OA is a broadening of focus from a disease of cartilage to one of the 'whole joint.' The synovium, bone and cartilage are each involved in pathological processes that lead to progressive joint degeneration. Additional themes that have emerged over the past decade are novel mechanisms of cartilage degradation and repair, the relationship between biomechanics and biochemical pathways, the importance of inflammation and the role of genetics. In this article, we review the molecular, clinical and imaging evidence that synovitis is not an 'incidental finding of OA', but plays a significant role in disease pathogenesis, and could therefore represent a target for future treatments

The use of musculoskeletal ultrasound (MSKUS) in rheumatology practice and research has increased steadily over the last decade. An ever-growing body of literature shows parity and even superiority of MSKUS when compared to physical examination, plain radiography, and more expensive and static imaging modalities such as MRI. While many use the modality for procedure guidance, investigators continue to demonstrate its ability to impact diagnoses in a variety of rheumatic diseases. Initial efforts focused on establishing MSKUS as a helpful tool for rheumatoid arthritis (RA), especially in the detection of synovitis and joint erosions, but numerous studies are validating the use of MSKUS as a helpful diagnostic tool for the spondyloarthropathies, crystal diseases, osteoarthritis, and other rheumatic diseases. Advances in ultrasound technology are translating into more sensitive and accurate studies. Within the research community, current efforts aim at maximizing the direct clinical impact of MSKUS by developing global or patient level assessments and simplified joint scoring systems, with improvements in intra- and inter-reader reproducibility

Fewer United States rheumatologists perform or utilize musculoskeletal ultrasound (MSUS) than those in Europe, though this disparity is narrowing. To document perceptions and use of MSUS in the U.S. rheumatology community, we sent an anonymous electronic survey to American College of Rheumatology (ACR) physicians and tailored versions to fellows and program directors. A separately-conducted survey was sent to a smaller group of rheumatologists already utilizing MSUS. Acknowledging survey bias, we found that 20% of rheumatologists and fellows who responded are utilizing MSUS, and those using it primarily do so for diagnosis and injection guidance. Many rheumatologists across the country think that ultrasound should become a standard tool in rheumatology training, practice, and research. Despite an inherent survey bias likely overstating interest in MSUS, this study is valuable as the first to document this trend among U.S. rheumatologists

Background: Determination of monosodium urate (MSU) deposition in joints by musculoskeletal ultrasound (MSK-US) could have implications for uric acid (UA) management in patients with gout and possibly asymptomatic hyperuricemia (AH). Recently, criteria for sonographic diagnosis of MSU crystal deposition have been developed, but reproducibility of readings using these criteria has not been well established. Methods: We consecutively recruited male patients ages 55-85 during primary care visits to an urban VA hospital. We assessed all patients for gout by ACR criteria, and obtained serum UA levels. Patients were divided into 3 groups: gout, AH (no gout, UA >= 6.9 mg/dL), and controls (no gout, UA <= 6.8 mg/dL). 50 patients (14 with gout, 17 with AH, and 19 controls) returned for subsequent evaluation which included MSK-US of knees and 1st metatarsalphalangeal (MTP) joints to evaluate for the double contour sign (knees) and tophi (MTPs). All images were read blindly by two observers trained in rheumatology and MSK-US. Kappa statistics were used to estimate the amount of agreement between ultrasound measures scored by the two raters. We also calculated the total percent of observations in agreement. Results: Evidence of MSU crystal deposition was found in the same 10 patients by both observers (6 gout, 3 AH, 1 control), and in 3 additional patients by one of the observers (1 gout, 2 AH). These findings were further analyzed by site. MSU crystal deposition was identified in a total of 14 common joints by both observers, and in 4 additional joints by the first observer and 6 additional joints by the second observer. Percentage agreement and kappa statistics for our three primary ultrasound measures were as follows; total joints (n=200, 95% agreement, kappa 0.709), femoral articular cartilage (n=100, 95% agreement, kappa 0.679) and 1st MTPs (n=100, 95% agreement, kappa 0.734). Additional analyses by left and right side are shown in the table below. Ratings on only 10 out of 200 joints were in disagreement. (Table Presented) Conclusions: Both percentage agreement and agreement beyond chance between the raters (as estimated by kappa statistics) were very high for the three ultrasound measures. These findings support the use of MSK-US as a reliable modality for detecting MSU deposition. Since MSU deposition is an indication for urate lowering, this type of imaging could be performed noninvasively at the bedside or in the clinic to help direct therapy in gout patients, with possible implications for treatment in AH patients as well should these findings be reproducible in larger cohorts

Purpose: There is insufficient understanding regarding how generalized OA involving the hand and knee differs from isolated knee OA, which may result from other factors such as obesity or trauma. The purpose of these studies is to determine whether the presence of hand OA involving interphalangeal (IP) and first carpometacarpal (CMC) joints, alone or in combination, predicts progression of patients with symptomatic knee OA. Methods: Hand radiographs were obtained on 94 patients at NYUHJD who met ACR criteria for symptomatic knee OA, and who were enrolled in a two-year NIH-sponsored prospective study. The patients completed standardized fixed-flexion knee radiographs at baseline and 24 months, with progression the signal (more painful) knee OA determined by change in joint space width (JSW) and KL score. For these analyses, the patients were separated into two groups by results on their signal knee: 17 progressors, defined by at least 30% decreased JSW over 24 months, and 77 non-progressors. For each set of hand x-rays, 2 radiologists evaluated 18 IP joints and 2 CMC joints for joint space narrowing and/or osteophytes, and whether or not there was erosive change at the IP joints; we averaged the scores from the two readers. Results: Kappa scores between the two scoring radiologists for the IP and CMC joints, and for the presence of erosive IP disease, were 0.79, 0.87 and 0.96, respectively. The overall mean IP score was 5.6 and 1st CMC score was 0.9, while medians were 5 and 1.0, respectively. The 17 progressors had a higher average IP (but not CMC) score than the non-progressors, 7.2+/- 5.4 vs. 5.0+/-4.6, p=0.13. Since the IP scores were not normally distributed, we further analyzed data by dichotomizing the study populations into two groups using the median IP total (5) as the cutoff point. When so analyzed, the presence of hand OA increased the odds ratio of knee OA progression to 2.8 (p=0.096). Of interest, the severity of knee OA correlated with hand OA scores: the average total hand OA scores (out of 20 joints) increased with baseline KL score, with mean scores of 3.8+/-5.5, 6.1+/-6.1 and 7.2+/-5.6 for KL 1 to 3 (p=0.06). There is also an increasing trend of total hand OA joint scores by KL score (p=0.042) when dichotomized around the median (5 joints), and with IP scores alone (p=0.026). The 8 patients with radiographic evidence of erosive IP disease, as compared with the 31 non-erosive IP OA patients (>5 IP joints) and the 54 without IP OA, demonstrated faster knee OA progression over 2 years by average KL increases (1.00, 0.35, 0.30) and decreases in joint space width (0.65, 0.56, 0.36), although perhaps given small numbers, this was not statistically significant (p=0.839). Conclusions: In cross-sectional analysis, the quantitative burden of hand OA correlates with the radiographic severity of knee OA (KL). Moreover, radiographic hand OA at the IP joints, but not at the 1st CMC joint, predicts more rapid progression of knee OA. Erosive IP disease may be an even stronger predictor than non-erosive IP disease of accelerated progression of knee OA

Purpose: We have previously shown that carriage of an IL1RN haplotype (CTA) was associated with substantially lower odds of radiographic severity (KL score, joint space width [JSW]) (Ann Rheum Dis. 2010). In this 24 month prospective study we assessed whether IL1-RN haplotypes predicted disease progression in patients with symptomatic knee OA. Methods: Ninety-seven (N=97) patients from NYUHJD who met ACR criteria for symptomatic knee OA were genotyped for single nucleotide polymorphisms (SNPs) in the IL-1b and IL-1RN genes. Standardized fixed-flexion radiographs were taken on all patients at baseline and 24 months. Radiographic progression of signal (more painful) knee OA was determined by change in JSW over 24 months. To account for variations in baseline JSW, we defined progression as greater than 30% joint space narrowing (JSN) of the diseased compartment over 24 months, rather than in change in absolute JSW in millimeters. Results: Decreases in JSW ranged from zero to 3.7 mm over the 24 months; 19 of 97 patients exhibited < 30% JSN. (Figure presented) Patients with the IL-1RN (rs419598/rs315952/9005) TTG haplotype exhibited increased radiographic knee OA severity at baseline compared to those without TTG (p>0.08). These TTG patients exhibited increased risk for radiographic progression at 24 months that approached significance based on <=30% JSN [OR = 2.85; 95%CI=0.68-11.67; p>0.15]. In contrast, OA patients with IL-1RN CTA haplotype showed decreased risk for JSN over 24 months in the signal knee [OR= 0.33; 95%CI=0.170-1.014; p>0.05]. Differences in reported VAS pain between the CTA and TTG group were significant at 24 months (p> 0.01), indicating that while these patients were not distinguishable by radiograph or symptoms at onset, IL1RN haplotype predicted symptomatic differences at two years. Finally, the TTG haplotype group of patients expressed relatively increased IL-1b gene expression [15.683 +/- 9.407 (p>0.0001)] as assessed by TaqMan QPCR in peripheral blood leukocytes. The TTG patients also exhibited decreased sIL-1Ra [283.64 +/- 36.4 pg/ml (p>0.001) in plasma samples compared to IL-1RN CTA haplotype protective groups [IL-1b (fold change), 5.444 +/- 10.083; sIL-1Ra, 370.35 +/- 43.3pg/ml] of patients respectively. Conclusion: IL-1RN gene family polymorphisms, which appear to affect host production of IL-1Ra, merit evaluation as biomarkers that predict the risk of progression in patients with symptomatic knee OA

Objective: To evaluate the relationship of quantitative assessment of Bone Marrow Lesions (BML) with knee OA severity by radiographic findings. Methods: 58 OA patients (mean age 62+/-10, mean BMI 27+/-3, 59% female) underwent standardized nonfluoroscopic fixed-flexion knee radiographs. Two radiologists read the X-rays for KL grade, joint space width (JSW), and, using the OARSI atlas, joint space narrowing (JSN) and osteophytes; interreader agreement was assessed using Kappas and concordance correlation coefficients. Linear and logistic regression analysis was performed to assess associations while controlling the effects of age, sex and BMI. 3T-MRI included sagittal T2-weighted fat saturated spin-echo images (TR/TE=4000ms/75ms, FOV=15cm, matrix=256x128, slice thickness=3.0mm, receiver bandwidth 130Hz/pixel) and in/out of phase of FLASH images. Compartment-wise (medial tibial, lateral tibial, medial femur, lateral femur) BML volumes were quantified with T2-weighted fat saturated images and in/out of phase images respectively. BML volumes were dichotomized for statistical analysis. Results: KL score was a significant predictor of total BML volume (OR = 8.41, p = 0.0235). Medial tibial JSW, OARSI medial JSN, and medial tibial plateau osteophytes approached significance as predictors of BML volume at the medial tibia (OR = 0.71, p = 0.0551; OR = 2.16, p = 0.0597; and OR = 2.68, p = 0.0875, respectively). OARSI lateral JSN was a significant predictor of BML volume at the lateral tibia (OR = 3.62, p = 0.0169). Lateral tibial plateau osteophytes were predictors of total BML volume (OR = 4.58, p = 0.0299) and of BML volume at the lateral tibia (OR = 2.31, p = 0.0685). Lateral femoral condyle osteophytes approached significance as a predictor for BML at the lateral femur (OR = 2.25, p = 0.0651). Furthermore, quantitative BML volume strongly correlated with total quantitative synovial volume measured on MRI (beta= 0.22, p = 0.0003). Conclusions: Our data indicate that BML volume on MRI is a characteristic feature of progressive stages of OA, which not only correlates with JSN and osteophytes, but does so in a compartment-specific way. The data suggest that the altered mechanical forces that promote compartmental disease in OA lead to BML, JSN and osteophyte formation. Whether BML further contribute to cartilage loss, and are therefore targets of therapeutic intervention, remains to be determined