Courtenay L. Kessler

Joint space narrowing and Kellgren–Lawrence progression in knee osteoarthritis: an analytic literature synthesis

OBJECTIVE While the interpretation of cartilage findings on magnetic resonance imaging (MRI) evolves, plain radiography remains the standard method for assessing progression of knee osteoarthritis (OA). We sought to describe factors that explain variability in published estimates of radiographic progression in knee OA. DESIGN We searched PubMed between January 1985 and October 2006 to identify studies that assessed radiographic progression using either joint space narrowing (JSN) or the Kellgren-Lawrence (K-L) scale. We extracted cohort characteristics [age, gender, and body mass index (BMI)] and technical and other study factors (radiographic approach, study design, OA-related cohort composition). We performed meta-regression analyses of the effects of these variables on both JSN and K-L progression. RESULTS Of 239 manuscripts identified, 34 met inclusion criteria. The mean estimated annual JSN rate was 0.13 +/- 0.15 mm/year. While we found no significant association between JSN and radiographic approach among observational studies, full extension was associated with greater estimated JSN among randomized control trials (RCTs). Overall, observational studies that used the semi-flexed approach reported greater JSN than RCTs that used the same approach. The overall mean risk of K-L progression by at least one grade was 5.6 +/- 4.9%, with higher risk associated with shorter study duration, OA definition (K-L > or = 2 vs K-L > or = 1) and cohorts composed of subjects with both incident and prevalent OA. CONCLUSION While radiographic approach and study design were associated with JSN, OA definition, cohort composition and study duration were associated with risk of K-L progression. These findings may inform the design of disease modifying osteoarthritis drug (DMOAD) trials and assist clinicians in optimal timing of OA treatments.

Impact of Knee Osteoarthritis on Health Care Resource Utilization in a US Population-Based National Sample

Objective:We sought to estimate the impact of knee osteoarthritis (OA) on health care utilization. Research Design:Using the 2003 Medicare Current Beneficiary Survey, a population-based survey of Medicare beneficiaries linked to Medicare claims, we selected a national cohort of community-dwelling persons aged 65 and older with knee OA and a sex- and age-matched comparison cohort without any form of OA. We distinguished following 4 components of health care utilization: physician (MD) office visits, non-MD office visits, inpatient hospital stays, and emergency department visits. We built multiple regression models to determine whether knee OA affects utilization, controlling for comorbidity count, obesity, functional limitation, education, race, and working status. Results:A total of 545 Medicare Current Beneficiary Survey participants with knee OA were matched with 1090 OA-free individuals. Mean age in both cohorts was 76 years; approximately 70% were female. Knee OA and OA-free subjects differed significantly in obesity (Knee OA: 37%, OA-free: 20%), % with ≥2 comorbidities (Knee OA: 69%, OA-free: 43%), and functional limitation (Knee OA: 42%, OA-free: 26%). In multivariable regression models, the knee OA cohort had on average 6.0 more annual MD visits (95% confidence interval [CI]: 4.7, 7.4) and 3.8 more non-MD visits (95% CI: 2.8, 4.7) than the OA-free cohort. The knee OA cohort also had 28% more hospital stays (odds ratio [OR] = 1.3, 95% CI: 1.0, 1.6), a difference attributable to total joint replacements. Conclusions:This first national, population-based study of health care utilization in persons with knee OA documents considerable excess utilization attributable to knee OA, independent of comorbidity, and other patient characteristics.

Determinants of Self-Reported Health Status in a Population-Based Sample of Persons with Radiographic Knee Osteoarthritis

OBJECTIVE Knee osteoarthritis (OA) is highly prevalent and disabling. Patients with radiographic knee OA may experience pain and functional impairment, which can diminish their health status. Our objective was to determine factors associated with self-reported health status in a national population-based sample with radiographic knee OA. METHODS Our sample included all of the Third National Health and Nutrition Examination Survey (NHANES-III) participants who underwent a knee radiograph and were found to have radiographic OA (defined as Kellgren/Lawrence grade 2 or higher). Self-reported health status was determined by asking the participant to rate their overall health as excellent, very good, good, fair, or poor. Self-reported health status was analyzed as an ordinal variable using cumulative logit regression, as a dichotomous variable (excellent/very good/good versus fair/poor) using logistic regression, and as a continuous variable after transformation using linear regression. RESULTS A total of 1,021 (42%) of NHANES-III participants with a knee radiograph were included in this analysis. The multivariable analyses were performed on 1,009 (99%) of the eligible participants with complete data. We found that nonwhite race, lower income, more comorbidities, and greater functional limitation were associated with worse self-reported health status in all 3 multivariable analyses. CONCLUSION This study has quantified the role of clinical, radiographic, and socioeconomic factors associated with self-reported health status in a population-based sample of patients with knee OA. Self-reported health status in patients with knee OA was associated with functional status and comorbidity.

Geographic diversity of low-volume hospitals in total knee replacement: implications for regionalization policies.

Background/Objectives:Centers performing low volumes of total knee replacements (TKR) have worse outcomes of TKR than higher volume centers. Regionalization policies that shift patients to higher volume centers are being considered as a means of improving TKR outcomes. We sought to describe geographic diversity in the distribution of low-volume centers and examine state level characteristics associated with states that have a higher proportion of low-volume centers and/or a higher proportion of TKRs performed in low-volume centers. Methods:We used U.S. Census data and geocoded Medicare claims to ascertain state-level demographic factors, procedure volume, and TKR rates and to conduct our state level analysis. We defined 2 outcomes: 1) proportion of all hospitals with a low annual TKR volume (<26 per year in the Medicare population); and 2) proportion of all TKRs in the Medicare population performed in low-volume centers. We examined linear associations among the 2 outcomes and state factors, and used multivariate regression to identify factors associated independently with these outcomes. Results:Half of hospitals performing TKR in the Medicare population were low-volume centers, accounting for 13% of TKRs. Multivariate analysis revealed lower TKR rates, higher proportion of rural areas and larger state area were associated with a higher proportion of low-volume hospitals in a state. Lower proportion of elderly residents, higher population density and higher proportion of rural areas predicted a higher proportion of TKRs performed in low-volume centers. Conclusions:The distribution of low-volume hospitals among U.S. states varies substantially. Regionalization of TKR may require different strategies in states with small and large numbers of low-volume centers.

Professionalism and evolving concepts of quality.

For much of the twentieth century, quality of care was defined specifically in terms of physician characteristics and behaviors. High-quality physicians were well trained, knowledgeable, skillful, and compassionate. More recently, quality of care has been defined in terms of systems of care. High-quality organizations develop and adopt practices to reduce adverse events and optimize outcomes. This essay discusses this transformation from physician-based to organization-based concepts of quality and the consequences for patient care and medical professionalism.

A2 IMPACT OF GENDER ON QUALITY-ADJUSTED LIFE EXPECTANCY LOSSES DUE TO KNEE OSTEOARTHRITIS IN THE US ELDERLY POPULATION

Purpose: Aiming at regeneration of permanent cartilage like joint cartilage, this study screened natural and synthetic compound libraries to discover a novel compound inducing chondrogenic differentiation without hypertrophy. We further investigated the underlying molecular mechanism. Methods: As an efficient monitoring system for chondrogenic differentiation, we established stable lines of mouse chondrogenic ATDC5 cells expressing green fluorescent protein under the control of type II collagen promoter fused with four repeats of a Sox9 enhancer (COL2GFP). Chondrogenic differentiation was assessed by real-time RT-PCR for COL2, aggrecan, chondromodulin-1 and COL10, toluidine blue and Alcian blue stainings, and quantitative GAG assay in cultures of mouse embryonic stem cells or immature mesenchymal C3H10T1/2 cells. The downstream molecules were screened by a microarray analysis using C3H10T1/2 cells. The COL2 promoter activity was determined using HuH-7 cells transfected with a luciferase-reporter gene construct containing the COL2 promoter above, and the specific binding to the identified region was verified by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). For functional analyses, we performed adenoviral overexpression of the gene or the small interfering RNA in C3H10T1/2 cells, and compared the chondrogenic differentiation as described above with respective empty-vector controls. Molecular interactions were examined by immunoprecipitation, mammalian two-hybrid system, and immunohistochemistry in the mouse growth plate. Finally, cartilage formation in full-thickness defects of mouse knee cartilage was histologically evaluated after transplantation of cell-sheets of mouse rib chondrocytes with or without TM treatment. Results: The COL2-GFP system showed that a small thienoindazolederivative compound T-198946 (TM) most strongly induced the GFP fluorescence as early as after 48 h of treatment. TM was confirmed to enhance chondrogenic differentiation but inhibit the further hypertrophic differentiation in the cultures of precursor cells. The microarray screening revealed that Runx1 was most strongly induced by TM among 581 up-regulated genes including Sox5 and Sox6. Deletion, mutagenesis, and tandem-repeat analyses of the luciferase assay identified the core responsive element of Runx1 in the COL2 promoter to be between the −293 and −288 bp region containing a putative Runx-binding motif. EMSA and ChIP assays confirmed the specific binding of Runx1 to this region. Although chondrogenic differentiation of C3H10T1/2 cells was little enhanced by the Runx1 overexpression alone, it was much enhanced by co-transfection with Sox5, 6, and 9 (the Sox trio), without inducing the hypertrophy, as true of the effect of TM treatment. Gene-silencing of Runx1, Sox5/6, or Sox9 suppressed the TM effect on chondrogenic differentiation. In fact, Runx1 and the Sox trio were co-localized in the proliferative and pre-hypertrophic chondrocytes of the mouse growth plate, and their physical interaction was confirmed by immunoprecipitation and two-hybrid analysis. Finally, cell-sheets of TM-treated chondrocytes filled the defects with cartilaginous tissue, while the control cell-sheets did not. Conclusions: A novel small compound TM promotes chondrogenic differentiation without inducing hypertrophy, through production of Runx1 that cooperatively functions with the Sox trio. TM will herald a new era of regenerative medicine of permanent cartilage, thus realizing an epochal treatment of osteoarthritis. A2 IMPACT OF GENDER ON QUALITY-ADJUSTED LIFE EXPECTANCY LOSSES DUE TO KNEE OSTEOARTHRITIS IN THE US ELDERLY POPULATION