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1.  Differences in multi-joint radiographic osteoarthritis phenotypes among African Americans and Caucasians: The Johnston County Osteoarthritis Project 
Arthritis and rheumatism  2011;63(12):3843-3852.
Objective
To define and contrast multiple joint radiographic osteoarthritis (rOA) phenotypes describing hand and whole-body rOA among African Americans and Caucasians.
Methods
We conducted a cross-sectional analysis in the Johnston County Osteoarthritis Project, using radiographic data for the hands, tibiofemoral (TFJ) and patellofemoral joints, hips, and lumbosacral spine (LS). Films were read for rOA by a single radiologist using standard atlases. Sixteen mutually exclusive hand (n=2083) and 32 whole-body rOA phenotypes (n=1419) were identified. Fisher’s exact tests, corrected for multiple comparisons, were used to compare phenotype frequencies by race and gender. Logistic regression was used to provide odds ratios adjusted for gender, age, and body mass index (BMI).
Results
Hand rOA phenotypes: African Americans compared with Caucasians had significantly less frequent rOA of the distal interphalangeal joints, in isolation and in combination with other hand joint sites, but comparable frequencies of rOA for other hand joint sites. Whole-body rOA phenotypes: African Americans compared with Caucasians had less frequent Hand rOA, in isolation and in combination with other joint sites. In contrast, African Americans compared with Caucasians had more than twice the odds of isolated TFJ rOA and 77% higher odds of TFJ and LS rOA together.
Conclusions
Even after adjustment for gender, age, and BMI, African Americans compared to Caucasians were less likely to have hand rOA phenotypes, but more likely to have knee rOA phenotypes involving the TFJ. African Americans may have a higher burden of multiple large joint OA involvement not captured by most definitions of “generalized OA.”
doi:10.1002/art.30610
PMCID: PMC3227756  PMID: 22020742
2.  The Prevalence of Knee Osteoarthritis in Elderly Community Residents in Korea 
Journal of Korean Medical Science  2010;25(2):293-298.
The purpose of this study was to estimate the prevalence of radiographic and symptomatic knee osteoarthritis (OA) among community residents and to elucidate the relevant risk factors. This prospective, population-based study was conducted on residents over 50 yr of age in Chuncheon. Subjects completed an interview based on a standardized questionnaire and clinical evaluation including standardized weight bearing semiflexed knee A-P radiographs. We defined a subject with the Kellgren and Lawrence grade ≥2 as having radiographic knee OA (ROA). Symptomatic knee OA (SOA) was defined by the presence of both ROA and knee pain. We obtained symptom information and radiographs from 504 subjects. The prevalence of ROA and SOA was 37.3% and 24.2%, respectively. The prevalence of both ROA and SOA was significantly higher among women than among men. Multivariate analysis revealed that the presence of hypertension, and a manual occupation were significantly associated with the presence of ROA and SOA. Lower level of education was significantly associated with the presence of ROA, and female sex with the presence of SOA. In conclusion, both ROA and SOA are common in the aged adult population of Korea, with preponderance for women.
doi:10.3346/jkms.2010.25.2.293
PMCID: PMC2811300  PMID: 20119586
Osteoarthritis, Knee; Risk Factors; Prevalence
3.  Urinary CTX‐II levels are associated with radiographic subtypes of osteoarthritis in hip, knee, hand, and facet joints in subject with familial osteoarthritis at multiple sites: the GARP study 
Annals of the Rheumatic Diseases  2005;65(3):360-365.
Objective
To assess the relation between the urinary concentrations of type II collagen C‐telopeptide (UCTX‐II) and radiographic signs of osteoarthritis (ROA) in the GARP (Genetics, Arthrosis and Progression) study.
Methods
UCTX‐II levels were measured in GARP study participants, who are sibling pairs predominantly with symptomatic osteoarthritis at multiple sites. Kellgren and Lawrence scores were used to assess ROA in the knees, hips, hands, and vertebral facet joints, and spinal disc degeneration. A proportionate score was made for each joint location, based on the number of joints with ROA. The sum total ROA score represents a measure of cartilage abnormalities within each patient. By using linear mixed models the total ROA score and the joint site specific ROA scores were correlated with the UCTX‐II level.
Results
In 302 subjects the mean (SD) and median (range) for UCTX‐II were 265 (168) and 219 (1346) ng/mmol creatine, respectively. There was a significant association between the total ROA score and UCTX‐II levels. Subsequent multivariate analysis showed that the joint site specific ROA score at all joint sites, except for spinal disc degeneration, contributed independently to this association.
Conclusions
The total ROA score of GARP patients, representing cartilage abnormalities at the most prevalent ROA joint locations, showed an excellent correlation with UCTX‐II levels. The specific ROA scores at the hip, hand, facet, and knee joints additively and independently explained this association. Even in patients with osteoarthritis at multiple sites, UCTX‐II may be a sensitive quantitative marker of ROA.
doi:10.1136/ard.2005.040642
PMCID: PMC1798062  PMID: 16079167
osteoarthritis; CTX‐II; GARP study; biomarker
4.  The Association of Disability and Pain with Individual and Community Socioeconomic Status in People with Hip Osteoarthritis 
Objective:
To examine associations between disability and socioeconomic status (SES) in persons with hip radiographic OA (rOA) or symptomatic OA (sxOA) in the Johnston County Osteoarthritis Project.
Methods:
Cross-sectional analyses were conducted on individuals with hip rOA (708) or sxOA (251). rOA was defined as Kellgren-Lawrence ≥ 2. Educational attainment (<12 years or ≥12 years) and occupation (managerial or non-managerial) were individual SES measures. Census block group poverty rate (<12%, 12-25%, ≥25%) was the community SES measure. Disability was measured by the HAQ-DI and the WOMAC (function, pain, total). Covariates included age, gender, race, BMI, and presence of knee symptoms. Analyses examined associations of disability with each SES effect separately, followed by multivariable analyses using all SES variables, adjusting for covariates.
Results:
In models with single SES variables adjusted for covariates, WOMAC scores were associated significantly (p<0.05) with low educational attainment and non-managerial occupation in rOA and sxOA. HAQ was significantly associated with low educational attainment in rOA and sxOA and with high community poverty in rOA. In models including all SES variables, the patterns of association were similar although with diminished significance. There was indication that education was more strongly associated with HAQ and WOMAC function, while occupation was more strongly associated with WOMAC pain.
Conclusion:
Our data provide evidence that individual SES is an important factor to consider when examining disability and pain outcomes in older adults with hip OA.
doi:10.2174/1874312901105010051
PMCID: PMC3204417  PMID: 22046207
Disability; hip osteoarthritis; socioeconomic status; educational attainment; occupation; community poverty; pain.
5.  Gender difference in symptomatic radiographic knee osteoarthritis in the Knee Clinical Assessment – CAS(K): A prospective study in the general population 
Background
A recent study of adults aged ≥50 years reporting knee pain found an excess of radiographic knee osteoarthritis (knee ROA) in symptomatic males compared to females. This was independent of age, BMI and other clinical signs and symptoms. Since this finding contradicts many previous studies, our objective was to explore four possible explanations for this gender difference: X-ray views, selection, occupation and non-articular conditions.
Methods
A community-based prospective study. 819 adults aged ≥50 years reporting knee pain in the previous 12 months were recruited by postal questionnaires to a research clinic involving plain radiography (weight-bearing posteroanterior semiflexed, supine skyline and lateral views), clinical interview and physical examination. Any knee ROA, ROA severity, tibiofemoral joint osteoarthritis (TJOA) and patellofemoral joint osteoarthritis (PJOA) were defined using all three radiographic views. Occupational class was derived from current or last job title. Proportions of each gender with symptomatic knee ROA were expressed as percentages, stratified by age; differences between genders were expressed as percentage differences with 95% confidence intervals.
Results
745 symptomatic participants were eligible and had complete X-ray data. Males had a higher occurrence (77%) of any knee ROA than females (61%). In 50–64 year olds, the excess in men was mild knee OA (particularly PJOA); in ≥65 year olds, the excess was both mild and moderate/severe knee OA (particularly combined TJOA/PJOA). This male excess persisted when using the posteroanterior view only (64% vs. 52%). The lowest level of participation in the clinic was symptomatic females aged 65+. Within each occupational class there were more males with symptomatic knee ROA than females. In those aged 50–64 years, non-articular conditions were equally common in both genders although, in those aged 65+, they occurred more frequently in symptomatic females (41%) than males (31%).
Conclusion
The excess of knee ROA among symptomatic males in this study seems unlikely to be attributable to the use of comprehensive X-ray views. Although prior occupational exposures and the presence of non-articular conditions cannot be fully excluded, selective non-participation bias seems the most likely explanation. This has implications for future study design.
doi:10.1186/1471-2474-9-82
PMCID: PMC2443794  PMID: 18547403
6.  A genetic association study of the IGF-1 gene and radiological osteoarthritis in a population-based cohort study (the Rotterdam study) 
Annals of the Rheumatic Diseases  1998;57(6):371-374.
OBJECTIVE—A genetic association study was performed to investigate whether radiographical osteoarthritis (ROA) was associated with specific genotypes of the insulin-like growth factor I (IGF-1) gene.
METHODS—Subjects aged 55-65 years were selected from a population-based study of which ROA at the knee, hip, spine, and hand was assessed. Genotypes were determined of a polymorphism in the promoter region of the IGF-1 gene.
RESULTS—The IGF-1 locus was significantly associated with the presence of ROA (overall adjusted OR for heterozygous subjects = 1.9, 95% CI 1.2, 3.1 and for homozygous subjects 3.6, 95% CI 0.8, 16.2).
CONCLUSION—These results suggest that variation at the IGF-1 locus is associated with ROA development and may play a part in ROA pathogenesis. To confirm these findings replication in another population-based sample is needed.

 Keywords: osteoarthritis; genetics; IGF-1
PMCID: PMC1752614  PMID: 9771213
7.  Insulin-like growth factor I gene promoter polymorphism, collagen type II α1 (COL2A1) gene, and the prevalence of radiographic osteoarthritis: the Rotterdam Study 
Annals of the Rheumatic Diseases  2004;63(5):544-548.
Objective: To examine the role of an IGF-I gene promoter polymorphism in the prevalence of radiographic osteoarthritis (ROA), and study its interaction with the COL2A1 gene.
Methods: Individuals genotyped for IGF-I (n = 1546) and COL2A1 gene polymorphisms (n = 808) were selected from a random sample (n = 1583) derived from the Rotterdam study. The presence of ROA was defined as a Kellgren score of 2 or more in at least one of four joints (knee, hip, hand, and spine). Genotype specific odds ratios (OR) were adjusted for age, sex, body mass index, and bone mineral density using logistic regression. Interaction with the COL2A1 genotype was tested.
Results: Overall, no association was found between the IGF-I polymorphism and ROA. In subjects aged 65 years or younger (n = 971), the prevalence of ROA increased with the absence of the 192 base pair (bp) allele (p for trend = 0.03). Compared with homozygotes for the 192 bp allele, the prevalence of ROA was 1.4 times higher in heterozygotes (95% confidence interval, 1.0 to 1.8) and 1.9 times higher in non-carriers (1.1 to 3.3). There was evidence of interaction between the IGF-I and COL2A1 genes. Individuals with the risk genotype of both genes had an increased prevalence of ROA (OR 3.4 (1.1 to 10.7)). No effect was observed in subjects older than 65 years.
Conclusions: Subjects with genetically determined low IGF-I expression (non-carriers of the 192 bp allele) may be at increased risk of ROA before the age of 65 years. Furthermore, an interaction between the IGF-I and COL2A1 genes is suggested.
doi:10.1136/ard.2003.010751
PMCID: PMC1754973  PMID: 15082485
8.  Is symptomatic knee osteoarthritis a risk factor for a fast decline in gait speed? Results from the Osteoarthritis Initiative 
Arthritis care & research  2013;65(2):187-194.
Objectives
Gait speed is an important marker of health in adults and slows with aging. While knee osteoarthritis (OA) can result in difficulty walking, it is not known if radiographic knee OA (ROA) and/or knee pain are associated with a fast decline trajectory of gait speed over time.
Methods
Gait speed trajectories were constructed using a multinomial modeling strategy from repeated 20-meter walk tests measured annually over four years among participants from the Osteoarthritis Initiative (OAI), a prospective cohort study of adults with or at high risk of knee OA aged 45 to 79 at baseline. We grouped participants into four knee OA categories (having neither ROA nor knee pain, ROA only, knee pain only, or symptomatic knee OA (ROA and pain)) and examined their association with trajectories of gait speed using a multivariable polytomous regression model adjusting for age and other potential confounders.
Results
Of the 4179 participants (mean age (sd) = 61.1 (9.1), women =57.6%, mean BMI =28.5 (4.8) kg/m2), 5% (n=205) were in a fast decline trajectory slowing 2.75%/year. People with symptomatic knee OA had almost a 9-fold risk (OR = 8.9, 95% CI [3.1, 25.5]) of being in a fast decline trajectory compared with those with neither pain nor ROA. Participants with knee pain had 4.5 times the odds of fast decline (95% CI [1.4, 14.6]) and those with ROA only had a slight but non-statistically significant increased risk.
Conclusions
People with symptomatic knee OA have the highest risk of fast decline trajectory of gait speed compared with people with ROA or pain alone.
doi:10.1002/acr.21816
PMCID: PMC3529801  PMID: 22899342
Gait speed; Knee Osteoarthritis; Trajectory
9.  Differences in Multi-joint Symptomatic Osteoarthritis Phenotypes by Race and Gender: The Johnston County Osteoarthritis Project 
Arthritis and rheumatism  2013;65(2):373-377.
Objective
To determine race and gender differences in phenotypes (patterns) of multiple joint symptomatic osteoarthritis (sOA) involvement.
Methods
We performed a cross-sectional analysis of sOA phenotypes in a community-based cohort, for those with sOA data for the hands, knees, hips, and lumbosacral spine (LS) collected at a single visit (2003–10). Mutually exclusive phenotypes describing all combinations of these 4 sites were compared using Fisher exact tests. For phenotypes occurring in more than 40 persons, logistic regression adjusted for race, gender, age, and body mass index (BMI) was performed and interactions by race and gender were assessed.
Results
The sample included 1650 participants, 36% men, 32% African American, with a mean age of 66 years and BMI 31 kg/m2. Overall, 13% had hand, 25% knee, 11% hip, and 28% had LS sOA. African Americans compared with Caucasians were less likely to have Hand Only or in some combination, but more likely to have Knee Only. Men compared to women were less likely to have Hand Only, but more likely to have LS Only.
Conclusions
There are differences in phenotypes of multiple joint sOA involvement by race and gender that may influence definitions of multiple joint, or “generalized” OA.
doi:10.1002/art.37775
PMCID: PMC3558926  PMID: 23359309
10.  Associations of educational attainment, occupation and community poverty with knee osteoarthritis in the Johnston County (North Carolina) osteoarthritis project 
Arthritis Research & Therapy  2011;13(5):R169.
Introduction
The purpose of this study was to examine data from the Johnston County Osteoarthritis (OA) Project for independent associations of educational attainment, occupation and community poverty with tibiofemoral knee OA.
Methods
A cross-sectional analysis was conducted on 3,591 individuals (66% Caucasian and 34% African American). Educational attainment (< 12 years or ≥12 years), occupation (non-managerial or not), and Census block group household poverty rate (< 12%, 12 to 25%, > 25%) were examined separately and together in logistic models adjusting for covariates of age, gender, race, body mass index (BMI), smoking, knee injury and occupational activity score. Outcomes were presence of radiographic knee OA (rOA), symptomatic knee OA (sxOA), bilateral rOA and bilateral sxOA.
Results
When all three socioeconomic status (SES) variables were analyzed simultaneously, low educational attainment was significantly associated with rOA (odds ratio (OR) = 1.44, 95% confidence interval (CI) 1.20, 1.73), bilateral rOA (OR = 1.43, 95% CI 1.13, 1.81), and sxOA (OR = 1.66, 95% CI 1.34, 2.06), after adjusting for covariates. Independently, living in a community of high household poverty rate was associated with rOA (OR = 1.83, 95% CI 1.43, 2.36), bilateral rOA (OR = 1.56, 95% CI 1.12, 2.16), and sxOA (OR = 1.36, 95% CI 1.00, 1.83). Occupation had no significant independent association beyond educational attainment and community poverty.
Conclusions
Both educational attainment and community SES were independently associated with knee OA after adjusting for primary risk factors for knee OA.
doi:10.1186/ar3492
PMCID: PMC3308104  PMID: 22011570
knee osteoarthritis; educational attainment; occupation; community poverty; socioeconomic status
11.  Do worsening knee radiographs mean greater chance of severe functional limitation? The Multicenter Osteoarthritis Study 
Arthritis care & research  2010;62(10):1433-1439.
Objective
Development of functional limitation is thought to be unrelated to changes in severity of radiographic knee osteoarthritis (ROA). We evaluated the relation of change in ROA to the incidence of severe functional limitation.
Methods
Participants of the Multicenter Osteoarthritis (MOST) Study, a cohort study of persons with or at high risk of knee OA were evaluated at 0 and 30 months. Subjects were classified as having no, incident, stable, or worsening ROA. Incidence of severe functional limitation was defined as 1) WOMAC physical function scores (≥ 36/68) and 2) walking speed (≤ 1.0 m/s) at 30 months. The relation of change in ROA to the incidence of severe functional limitation was evaluated by calculating risk ratios adjusted for potential confounders.
Results
Of the 2110 subjects included (mean age 62, mean BMI 30 kg/m2, female 60%), 53% had no, 6% incident, 14% stable, and 27% worsening ROA. Persons with incident ROA had 1.9 and 1.8 times the risk by WOMAC physical function and walking speed, respectively, to have incident severe functional limitation compared with those with no ROA over 30 months. Compared with those with stable ROA, persons with worsening ROA had 2.2 and 2.5 times the risk of incident severe functional limitation, respectively.
Conclusion
Changes in structural disease are associated with the development of severe functional limitations in persons with or even those at high risk of knee OA.
doi:10.1002/acr.20247
PMCID: PMC2939286  PMID: 20506398
12.  Rates of change and Sensitivity to Change in Cartilage Morphology in Healthy Knees and in Knees with Mild, Moderate, and End Stage Radiographic Osteoarthritis 
Arthritis care & research  2011;63(3):311-319.
Objective
To study the longitudinal rate of (and sensitivity to) change of knee cartilage thickness across defined stages of radiographic osteoarthritis (ROA), specifically healthy knees and knees with end-stage ROA.
Methods
One knee of 831 Osteoarthritis Initiative (OAI) participants was examined: 112 healthy, without ROA or risk factors for knee OA, and 719 ROA knees: 310 calculated Kellgren Lawrence [cKLG] grade 2, 300 cKLG3, and 109 cKLG4. Subregional change in thickness was assessed after segmentation of weight-bearing femorotibial cartilage at baseline and at one year from coronal MRI. Regional and ordered values (OV) of change were compared by baseline ROA status.
Results
Healthy knees displayed small changes in plates and subregions (±0.7%; standardized response mean [SRM] ±0.15), with OVs being symmetrically distributed around zero. In cKLG2 knees, changes in cartilage thickness were small (≤1%; minimal SRM -0.22) and not significantly different from healthy knees. Knees with cKLG3 showed substantial loss of cartilage thickness (up to -2.5%; minimal SRM -0.35), with OV changes being significantly (p<0.05) greater than those in healthy knees. cKLG4 knees displayed the largest rate of loss across ROA grades (up to -3.9%; minimal SRM -0.51), with OV changes also significantly (p<0.05) greater than in healthy knees.
Conclusion
MRI-based cartilage thickness showed high rates of loss in knees with moderate and end-stage ROA, and small rates (indistinguishable from healthy knees) in mild ROA. From the perspective of sensitivity to change, end-stage ROA knees need not be excluded from longitudinal studies using MRI cartilage morphology as an endpoint.
doi:10.1002/acr.20370
PMCID: PMC3106126  PMID: 20957657
End-stage; Radiographic osteoarthritis; sensitivity to change; cartilage thickness; magnetic resonance imaging
13.  Failure of serum transforming growth factor-beta (TGF-β1) as a biomarker of radiographic osteoarthritis at the knee and hip: A cross-sectional analysis in the Johnston County Osteoarthritis Project 
PURPOSE
To assess associations between serum TGF-β1 and radiographic knee and hip osteoarthritis (rOA) in African American (AA) and White men and women.
METHODS
Baseline data from 330 participants in the Johnston County Osteoarthritis Project were used in the analysis. Radiographs were scored with the Kellgren-Lawrence scale and rOA defined as grade ≥ 2. Individual radiographic features (IRFs) were rated 0–3. TGF-β1 was measured using a sandwich ELISA. General linear models were used to estimate associations between lnTGF-β1 and rOA presence, laterality or severity, and IRF presence and severity, adjusting for age, gender, race, and body mass index. Interactions by race and gender were considered significant at p < 0.1.
RESULTS
Mean lnTGF-β1 levels were higher among AAs compared to Whites, and among women compared to men (p<0.009). Mean lnTGF-β1 levels were higher in those with knee OST, but this association was not significant after adjustment. There were no other significant differences in mean lnTGF-β1 levels by presence, laterality, or severity of knee or hip rOA or IRFs. No race or gender interactions were identified, although a borderline significant association between lnTGF-β1 and knee OST was seen among AAs (p < 0.06).
CONCLUSIONS
Although serum TGF-β1 varied by race and gender and several rOA variables, there were no independent significant associations with presence, laterality, or severity of knee or hip rOA by K-L grade or IRFs, suggesting that serum TGF-β1 is unlikely to be useful as a stand-alone biomarker in OA studies. A possible association between TGF-β1 and OST in AAs cannot be excluded.
doi:10.1016/j.joca.2008.11.010
PMCID: PMC2746496  PMID: 19091605
Biomarkers; Transforming growth factor-beta (TGF-β1); Radiography
14.  The association between leptin, interleukin-6, and hip radiographic osteoarthritis in older people: a cross-sectional study 
Introduction
The associations between leptin, interleukin (IL)-6, and hip radiographic osteoarthritis (OA) have not been reported, and their roles in obesity-related hip OA are unclear. The aim of this study was to describe the associations between leptin, IL-6, and hip radiographic osteoarthritis (ROA) in older adults.
Methods
A cross-sectional sample of 193 randomly selected subjects (mean age, 63 years; range, 52 to 78 years; 48% female subjects) were studied. Hip ROA, including joint-space narrowing (JSN) and osteophytes, was determined by anteroposterior radiograph. Serum levels of leptin and interleukin (IL)-6 were measured with radioimmunoassay. Fat mass was measured with dual-energy x-ray absorptiometry (DXA). Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated.
Results
In multivariable analysis, hip JSN was associated with serum levels of leptin in the whole sample (β = 0.046 per μg/L, P = 0.024 for superior; β = 0.068 per μg/L, P = 0.004 for axial compartment) and IL-6 only in females (β = 0.241 per pg/ml, P = 0.002 for superior; β = 0.239 per pg/ml, P = 0.001 for axial compartment). The positive associations between body-composition measures (BMI, WHR, percentage total fat mass, and percentage trunk fat mass) and hip JSN in women became nonsignificant after adjustment for leptin but not for IL-6. No significant associations were found between leptin, IL-6, and the presence or severity of osteophytes.
Conclusions
This study suggests that metabolic and inflammatory mechanisms may play a role in the etiology of hip OA and that the associations between body composition and hip JSN are mediated by leptin, particularly in women.
doi:10.1186/ar3022
PMCID: PMC2911879  PMID: 20482813
15.  Radiographic assessment of the femorotibial joint of the CCLT rabbit experimental model of osteoarthritis 
BMC Medical Imaging  2010;10:3.
Background
The purposes of the study were to determine the relevance and validity of in vivo non-invasive radiographic assessment of the CCLT (Cranial Cruciate Ligament Transection) rabbit model of osteoarthritis (OA) and to estimate the pertinence, reliability and reproducibility of a radiographic OA (ROA) grading scale and associated radiographic atlas.
Methods
In vivo non-invasive extended non weight-bearing radiography of the rabbit femorotibial joint was standardized. Two hundred and fifty radiographs from control and CCLT rabbits up to five months after surgery were reviewed by three readers. They subsequently constructed an original semi-quantitative grading scale as well as an illustrative atlas of individual ROA feature for the medial compartment. To measure agreements, five readers independently scored the same radiographic sample using this atlas and three of them performed a second reading. To evaluate the pertinence of the ROA grading scale, ROA results were compared with gross examination in forty operated and ten control rabbits.
Results
Radiographic osteophytes of medial femoral condyles and medial tibial condyles were scored on a four point scale and dichotomously for osteophytes of medial fabella. Medial joint space width was scored as normal, reduced or absent. Each ROA features was well correlated with gross examination (p < 0.001). ICCs of each ROA features demonstrated excellent agreement between readers and within reading. Global ROA score gave the highest ICCs value for between (ICC 0.93; CI 0.90-0.96) and within (ICC ranged from 0.94 to 0.96) observer agreements. Among all individual ROA features, medial joint space width scoring gave the highest overall reliability and reproducibility and was correlated with both meniscal and cartilage macroscopic lesions (rs = 0.68 and rs = 0.58, p < 0.001 respectively). Radiographic osteophytes of the medial femoral condyle gave the lowest agreements while being well correlated with the macroscopic osteophytes (rs = 0.64, p < 0.001).
Conclusion
Non-invasive in vivo radiography of the rabbit femorotibial joint is feasible, relevant and allows a reproducible grading of experimentally induced OA lesion. The radiographic grading scale and atlas presented could be used as a template for in vivo non invasive grading of ROA in preclinical studies and could allow future comparisons between studies.
doi:10.1186/1471-2342-10-3
PMCID: PMC2828401  PMID: 20089151
16.  Static knee alignment measurements among Caucasians and African-Americans: The Johnston County Osteoarthritis Project 
The Journal of rheumatology  2009;36(9):1987-1990.
Objective
To determine if knee alignment measures differ between African Americans and Caucasians without radiographic knee osteoarthritis (rOA).
Methods
A single knee was randomly selected from 175 participants in the Johnston County Osteoarthritis Project without rOA in either knee. Anatomic axis, condylar, tibial plateau, and condylar plateau angles were measured by one radiologist; means were compared and adjusted for age and body mass index (BMI).
Results
There were no significant differences in knee alignment measurements between Caucasians and AfrAm among men or women.
Conclusions
Observed differences in knee rOA occurrence between AfrAm and Caucasians are not explained by differences in static knee alignment.
doi:10.3899/jrheum.081294
PMCID: PMC2853360  PMID: 19605676
Knee osteoarthritis; racial differences; knee alignment
17.  Whole blood lead levels are associated with radiographic and symptomatic knee osteoarthritis: a cross-sectional analysis in the Johnston County Osteoarthritis Project 
Introduction
Lead (Pb) is known to affect bone, and recent evidence suggests that it has effects on cartilage as well. As osteoarthritis (OA) is a highly prevalent disease affecting bone and cartilage, we undertook the present analysis to determine whether whole blood Pb levels are associated with radiographic and symptomatic OA (rOA and sxOA, respectively) of the knee.
Methods
The analysis was conducted using cross-sectional data from the Johnston County Osteoarthritis Project, a rural, population-based study, including whole blood Pb levels, bilateral posteroanterior weight-bearing knee radiography and knee symptom data. rOA assessment included joint-based presence (Kellgren-Lawrence (K-L) grade 2 or higher) and severity (none, K-L grade 0 or 1; mild, K-L grade 2; moderate or severe, K-L grade 3 or 4), as well as person-based laterality (unilateral or bilateral). SxOA was deemed present (joint-based) in a knee on the basis of K-L grade 2 or higher with symptoms, with symptoms rated based on severity (0, rOA without symptoms; 1, rOA with mild symptoms; 2, rOA with moderate or severe symptoms) and in person-based analyses was either unilateral or bilateral. Generalized logit or proportional odds regression models were used to examine associations between the knee OA status variables and natural log-transformed blood Pb (ln Pb), continuously and in quartiles, controlling for age, race, sex, body mass index (BMI), smoking and alcohol drinking.
Results
Those individuals with whole blood Pb data (N = 1,669) had a mean (±SD) age of 65.4 (±11.0) years and a mean BMI of 31.2 (±7.1) kg/m2, including 66.6% women and 35.4% African-Americans, with a median blood Pb level of 1.8 μg/dl (range, 0.3 to 42.0 μg/dl). In joint-based analyses, for every 1-U increase in ln Pb, the odds of prevalent knee rOA were 20% higher (aOR, 1.20; 95% CI, 1.01 to 1.44), while the odds of more severe rOA were 26% higher (aOR, 1.26; 95% CI, 1.05 to 1.50, under proportional odds). In person-based analyses, the odds of bilateral rOA were 32% higher for each 1-U increase in ln Pb (aOR, 1.32; 95% CI, 1.03 to 1.70). Similarly for knee sxOA, for each 1-U increase in ln Pb, the odds of having sxOA were 16% higher, the odds of having more severe symptoms were 17% higher and the odds of having bilateral knee symptoms were 25% higher. Similar findings were obtained with regard to ln Pb in quartiles.
Conclusions
Increases in the prevalence and severity measures for both radiographically and symptomatically confirmed knee OA (although statistically significant only for rOA) were observed with increasing levels of blood Pb, suggesting that Pb may be a potentially modifiable environmental risk factor for OA.
doi:10.1186/ar3270
PMCID: PMC3132016  PMID: 21362189
18.  Longitudinal Changes in Intermuscular Fat Volume and Quadriceps Muscle Volume in the Thighs of Female Osteoarthritis Initiative Participants 
Arthritis care & research  2012;64(1):22-29.
Objectives
To quantify rates of change in quadriceps muscle (QM) and intermuscular fat (IMF) volumes over 2-years in women in the Osteoarthritis Initiative (OAI) study and examine group differences between those with radiographic OA (ROA) and those without (non-ROA).
Methods
The OAI database was queried for women ≥50 years old in the incident and progression cohorts with and without ROA at baseline. Mid-thigh MRI scans (15 contiguous slices, 5 mm slice thickness) of eligible women were randomly selected and anonymized. Image pairs were registered. QM and IMF were segmented in the 12 most proximal matching slices with the segmenter blinded to image time point. Age-adjusted differences in QM and IMF volume changes between groups were tested using ANCOVA.
Results
41 women without ROA (mean (SD) age 60.7 (7.6) yrs) and 45 with ROA (mean (SD) age 64.5 (6.7) yrs) were included. Mean QM and IMF volume changes in the non-ROA group were -4.1 (11.1) cm3 and 3.4 (7.1) cm3, respectively, and -5.4 (13.5) cm3 and 3.1 (7.4) cm3 in the ROA group, respectively. Age-adjusted between-group differences in QM and IMF changes were not significant (p>0.05).
Conclusions
Two-year changes in QM and IMF volume appear consistent with ageing and do not seem to be related to OA status. Direct comparison with a control cohort without OA risk factors could confirm this. Since group assignment was based on baseline data, there may have been women in the non-ROA group who developed radiographic OA over follow-up resulting in some overlap between groups.
doi:10.1002/acr.20628
PMCID: PMC3251718  PMID: 21905259
19.  Association of Bone Scintigraphic Abnormalities with Knee Malalignment and Pain 
Annals of the rheumatic diseases  2008;68(11):1673-1679.
Objective
We evaluated the information content of knee bone scintigraphy, including pattern, localization and intensity of retention relative to radiographic features of knee osteoarthritis (rOA), knee alignment, and knee symptoms.
Methods
A total of 308 knees (159 subjects) with symptomatic and radiographic knee OA (rOA) of at least one knee were assessed by late phase technetium-99m-methylene disphosphonate bone scintigraph, fixed-flexion knee radiograph, full limb radiograph for knee alignment, and for self-reported knee symptom severity. Generalized linear models were used to control for within subject correlation of knee data.
Results
The compartmental localization (medial versus lateral) and intensity of knee bone scan retention were associated with the pattern (varus versus valgus) (p<0.001) and severity (p=0.0008) of knee malalignment, and localization and severity of rOA (p<0.0001). Bone scan agent retention in the tibiofemoral, but not patellofemoral compartment, was associated with severity of knee symptoms (p=0.0009), and persisted after adjusting for rOA (p=0.0012).
Conclusion
To our knowledge, this is the first study describing a relationship between knee malalignment, joint symptom severity, and compartment specific abnormalities by bone scintigraphy. This work demonstrates that bone scintigraphy as a sensitive and quantitative indicator of symptomatic knee OA. Used selectively, bone scintigraphy is a dynamic imaging modality that holds great promise as a clinical trial screening tool and outcome measure.
doi:10.1136/ard.2008.094722
PMCID: PMC3684623  PMID: 18981032
osteoarthritis; bone scintigraphy; malalignment; knee
20.  Radiographic thumb osteoarthritis: frequency, patterns and associations with pain and clinical assessment findings in a community-dwelling population 
Rheumatology (Oxford, England)  2010;50(4):735-739.
Objectives. The aim of this study was to investigate: (i) the frequency and patterns of radiographic OA (ROA) in the thumb joints; and (ii) associations between thumb ROA and the clinical characteristics of thumb OA in older adults with hand pain or problems.
Methods. Participants were 592 community-dwelling older adults with hand pain or hand problems who attended a research clinic. Hand X-rays were taken and 32 joints were scored for the presence of ROA. The occurrence and pattern of ROA in the hand were examined. Univariable and multivariable associations of thumb pain and clinical assessments (nodes, deformity, enlargement, thenar muscle wasting, grind test, Kapandji index, Finkelstein’s test and thumb extension) with ROA were investigated.
Results. The first CMC and thumb IP joints were the hand joints most frequently affected with ROA. The thumb (thumb IP, first MCP, first CMC, trapezioscaphoid) was the most commonly affected joint group (n = 412). Isolated thumb ROA occurred more frequently than in any other isolated joint group. Multivariable analyses showed that older age, thumb pain, thenar muscle wasting and presence of nodes, deformity or enlargement best determined the presence of thumb ROA.
Conclusion. The first CMC and thumb IP joints were frequently affected with ROA. Prevalence estimates of ROA would be underestimated if these were not scored. One-third of the individuals with thumb ROA did not have involvement of the first CMC joint. The presence of thumb ROA was strongly associated with a combination of older age, thumb pain and clinical features of OA.
doi:10.1093/rheumatology/keq371
PMCID: PMC3060622  PMID: 21134961
Epidemiology; Osteoarthritis; Thumb; Radiography; Pain; Clinical features; Clinical assessment
21.  Prevalence and pattern of radiographic hand osteoarthritis and association with pain and disability (the Rotterdam study) 
Annals of the Rheumatic Diseases  2004;64(5):682-687.
Objective: To investigate the prevalence and pattern of radiographic osteoarthritis (ROA) of the hand joints and its association with self reported hand pain and disability.
Methods: Baseline data on a population based study (age ⩾55 years) were used (n = 3906). Hand ROA was defined as the presence of Kellgren–Lawrence grade ⩾2 radiological changes in two of three groups of hand joints in each hand. The presence of hand pain during the previous month was defined as hand pain. The health assessment questionnaire was used to measure hand disability.
Results: 67% of the women and 54.8% of the men had ROA in at least one hand joint. DIP joints were affected in 47.3% of participants, thumb base in 35.8%, PIP joints in 18.2%, and MCP joints in 8.2% (right or left hand). ROA of other joint groups (right hand) co-occurred in 56% of DIP involvement, 88% of PIP involvement, 86% of MCP involvement, and 65% of thumb base involvement. Hand pain showed an odds ratio of 1.9 (1.5 to 2.4) with the ROA of the hand (right). Hand disability showed an odds ratio of 1.5 (1.1 to 2.1) with ROA of the hand (right or left).
Conclusions: Hand ROA is common in the elderly, especially in women. Co-occurrence of ROA in different joint groups of the hand is more common than single joint disease. There is a modest to weak association between ROA of the hand and hand pain/disability, varying with the site of involvement.
doi:10.1136/ard.2004.023564
PMCID: PMC1755481  PMID: 15374852
22.  Body mass index associated with onset and progression of osteoarthritis of the knee but not of the hip: The Rotterdam Study 
Annals of the Rheumatic Diseases  2006;66(2):158-162.
Objective
To investigate the relationship between body mass index (BMI) and the incidence and progression of radiological knee as well as of radiological hip osteoarthritis.
Design
Cohort study.
Setting
Population based.
Participants
3585 people aged ⩾55 years were selected from the Rotterdam Study, on the basis of the availability of radiographs of baseline and follow‐up.
Main outcome measures
Incidence of knee or hip osteoarthritis was defined as minimally grade 2 at follow‐up and grade 0 or 1 at baseline. The progression of osteoarthritis was defined as a decrease in joint space width.
Methods
x Rays of the knee and hip at baseline and follow‐up (mean follow‐up of 6.6 years) were evaluated. BMI was measured at baseline.
Results
A high BMI (>27 kg/m2) at baseline was associated with incident knee osteoarthritis (odds ratio (OR) 3.3), but not with incident hip osteoarthritis. A high BMI was also associated with progression of knee osteoarthritis (OR 3.2). For the hip, a significant association between progression of osteoarthritis and BMI was not found.
Conclusion
On the basis of these results, we conclude that BMI is associated with the incidence and progression of knee osteoarthritis. Furthermore, it seems that BMI is not associated with the incidence and progression of hip osteoarthritis.
doi:10.1136/ard.2006.053538
PMCID: PMC1798486  PMID: 16837490
23.  Independent associations of socioeconomic factors with disability and pain in adults with knee osteoarthritis 
Background
The purpose of this study is to explore the relationship between function, pain and stiffness outcomes with individual and community socioeconomic status (SES) measures among individuals with radiographic knee osteoarthritis (rOA).
Methods
Cross-sectional data from the Johnston County Osteoarthritis Project were analyzed for adults age 45 and older with knee rOA (n = 782) and a subset with both radiographic and symptomatic knee OA (n = 471). Function, pain and stiffness were measured using the Western Ontario and McMasters Universities Index of Osteoarthritis (WOMAC). Individual SES measures included educational attainment (<12 years, ≥12 years) and occupation type (managerial, non-managerial), while community SES was measured using Census block group poverty rate (<12%, 12-25%, ≥25%). SES measures were individually and simultaneously examined in linear regression models adjusting for age, gender, race, body mass index (BMI), occupational physical activity score (PAS), comorbidity count, and presence of hip symptoms.
Results
In analyses among all individuals with rOA, models which included individual SES measures were observed to show that occupation was significantly associated with WOMAC Function (β =2.91, 95% Confidence Interval (CI) = 0.68-5.14), WOMAC Pain (β =0.93, 95% CI = 0.26-1.59) and WOMAC Total scores (β =4.05, 95% CI = 1.04-7.05), and education was significantly associated with WOMAC Function (β =3.57, 95% CI = 1.25-5.90) and WOMAC Total (β =4.56, 95% CI = 1.41-7.70) scores. In multivariable models including all SES measures simultaneously, most associations were attenuated. However, statistically significant results for education remained between WOMAC Function (β =2.83, 95% CI = 0.38-5.28) and WOMAC Total (β =3.48, 95% CI = 0.18-6.78), as well as for the association between occupation and WOMAC Pain (β =0.78, 95% CI = 0.08-1.48). In rOA subgroup analyses restricted to those with symptoms, we observed a significant increase in WOMAC Pain (β =1.36, 95% CI = 0.07-2.66) among individuals living in a block group with poverty rates greater than 25%, an association that remained when all SES measures were considered simultaneously (β =1.35, 95% CI = 0.06-2.64).
Conclusions
Lower individual and community SES are both associated with worse function and pain among adults with knee rOA.
doi:10.1186/1471-2474-14-297
PMCID: PMC3906978  PMID: 24134116
Osteoarthritis; Knee; Pain evaluation; Education; Occupation; Poverty; Social class; Socioeconomic
24.  Genetic mechanisms of knee osteoarthritis: a population based case–control study 
Annals of the Rheumatic Diseases  2004;63(10):1255-1259.
Objective: To compare subjects who had at least one parent with a total knee replacement for severe primary knee osteoarthritis with age and sex matched controls who had no family history of knee osteoarthritis
Design: Population based case–control study of 188 matched pairs (mean age 45 years, range 26 to 60).
Methods: Articular cartilage volume and bone size were determined at the patella and at the medial tibial and lateral tibial compartments by processing images acquired using T1 weighted, fat saturated magnetic resonance imaging. Radiographic osteoarthritis (ROA) was assessed from a standing semiflexed radiograph scored for joint space narrowing and osteophytosis. Knee pain was assessed by questionnaire. Height, weight, body mass index (BMI), lower limb muscle strength, and endurance fitness were measured by standard protocols.
Results: Compared with the controls, index offspring had higher BMI (27.8 v 26.0 kg/m2, p = 0.02), weaker lower limb muscles (127 v 135 kg, p = 0.006), more knee pain (47% v 22%, p<0.001), and greater medial tibial bone area (17.6 v 17.1 cm2, p = 0.01). With the exception of BMI, these differences persisted in multivariate analysis. There was a non-significant trend to higher cartilage volume at tibial sites and increased ROA in the offspring in the total and subgroup analyses, but no difference in height and endurance fitness.
Conclusions: BMI, muscle strength, knee pain, and medial tibial bone area, but not cartilage volume, appear to play a role in the genetic regulation and development of knee osteoarthritis.
doi:10.1136/ard.2003.015875
PMCID: PMC1754782  PMID: 15361382
25.  No Association Between Markers of Inflammation and Osteoarthritis of the Hands and Knees 
The Journal of rheumatology  2011;38(8):1665-1670.
Objective
Local inflammation plays a prominent role in osteoarthritis (OA). This could be reflected in the presence of elevated soluble inflammatory markers. We conducted analyses to assess the association of inflammatory markers with radiographic OA of the hands and knees in a large community-based cohort.
Methods
The Framingham Offspring cohort consists of the adult children of the original cohort and their spouses. In 1998–2001 these subjects provided blood specimens that were tested for 17 markers of systemic inflammation. In 2002–2005 these subjects had radiographs of both knees and hands. Each hand and knee joint was assigned a Kellgren and Lawrence (KL) score (0–4). We used logistic regression with generalized estimating equations and adjustment for age, sex, and body mass index to examine the association between each inflammatory marker and the presence of radiographic OA (ROA = KL grade ≥ 2) in any joint. We also constructed models for hand joints and knee joints alone.
Results
Radiographs and measures of inflammation were done for 1235 subjects (56% women, mean age 65 yrs). Of that group, 729 subjects (59%) had ROA in ≥ 1 hand or knee joint: 179 (14.3%) had knee OA, and 694 (56.2%) had hand OA. There were no significant associations between any marker of inflammation and ROA.
Conclusion
In this large sample, in which OA was carefully assessed and multiple markers measured, we found no evidence of an association between any inflammatory marker and the presence of radiographic OA.
doi:10.3899/jrheum.100971
PMCID: PMC3193179  PMID: 21572158
OSTEOARTHRITIS; BIOLOGICAL MARKERS; INFLAMMATION

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