Biomarkers and longitudinal changes in lumbar spine degeneration and low back pain: the Johnston County Osteoarthritis Project.

OBJECTIVE: To determine if baseline biomarkers are associated with longitudinal changes in the worsening of disc space narrowing (DSN), vertebral osteophytes (OST), and low back pain (LBP). DESIGN: Paired baseline (2003-2004) and follow-up (2006-2010) lumbar spine radiographs from the Johnston County Osteoarthritis Project were graded for severity of DSN and OST. LBP severity was self-reported. Concentrations of analytes (cytokines, proteoglycans, and neuropeptides) were quantified by immunoassay. Pressure-pain threshold (PPT), a marker of sensitivity to pressure pain, was measured with a standard dolorimeter. Binary logistic regression models were used to estimate odd ratios (OR) and 95% confidence intervals (CI) of biomarker levels with DSN, OST, or LBP. Interactions were tested between biomarker levels and the number of affected lumbar spine levels or LBP. RESULTS: We included participants (n = 723) with biospecimens, PPT, and paired lumbar spine radiographic data. Baseline Lumican, a proteoglycan reflective of extracellular matrix changes, was associated with longitudinal changes in DSN worsening (OR = 3.19 [95% CI 1.22, 8.01]). Baseline brain-derived neuropathic factor, a neuropeptide, (OR = 1.80 [95% CI 1.03, 3.16]) was associated with longitudinal changes in OST worsening, which may reflect osteoclast genesis. Baseline hyaluronic acid (OR = 1.31 [95% CI 1.01, 1.71]), indicative of systemic inflammation, and PPT (OR = 1.56 [95% CI 1.02, 2.31]) were associated with longitudinal increases in LBP severity. CONCLUSION: These findings suggest that baseline biomarkers are associated with longitudinal changes occurring in structures of the lumbar spine (DSN vs OST). Markers of inflammation and perceived pressure pain sensitivity were associated with longitudinal worsening of LBP.

Hip symptoms are associated with premature mortality: the Johnston County Osteoarthritis Project.

OBJECTIVE: To investigate the impact of hip osteoarthritis (OA) and/or hip symptoms on excess mortality. DESIGN: We analyzed data from 3,919 individuals in a community-based prospective cohort of African Americans and Caucasians age ≥45 years. Women ≥50 years of age and all men underwent supine anteroposterior pelvic radiography at baseline, with the participant's feet in 15 degrees of internal rotation. Hip radiographic (rOA) was defined as a Kellgren-Lawrence grade of ≥2 in at least one hip. Participants completed questionnaires at baseline to determine presence of hip symptoms and covariate status. Participants with symptomatic hip rOA (SxOA) are a subset of individuals with hip rOA and symptoms in the same hip. Multiple imputation was used to impute missing values of covariates. Mortality was determined through 2015 and follow-up time was calculated from baseline assessment until death or censoring which took place when a participant was lost to follow-up or reached the end of study period. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). We carried out additional analyses stratified by sex, race, age and obesity. RESULTS: Mean follow-up time was 14.2 years during which 1762 deaths occurred. There were 29.9% participants in our population with hip rOA at baseline. Compared to those with neither hip rOA nor hip symptoms, we observed an increased risk of all-cause mortality in participants with hip symptoms alone (HR = 1.28, 95% CI = 1.13-1.46), but no association for hip rOA either with or without symptoms. In stratified analyses we observed increased associations for hip symptoms alone and hip sxOA in those <65 years (43% and 39% increase, respectively) and in Caucasians (34% and 21% increase, respectively). CONCLUSIONS: Individuals who had hip symptoms without hip rOA had an increased risk of mortality. These effects were particularly strong for those who were <65 years of age and Caucasians. Effective interventions to identify those with hip pain in order to lessen it could reduce premature mortality.

Incidence and progression of hand osteoarthritis in a large community-based cohort: the Johnston County Osteoarthritis Project.

OBJECTIVE: To describe the incidence and progression of radiographic and symptomatic hand osteoarthritis (rHOA and sxHOA) in a large community-based cohort. DESIGN: Data were from the Johnston County OA Project (1999-2015, 12 ± 1.2 years follow-up, age 45+). Participants had bilateral hand radiographs each visit, read for Kellgren-Lawrence grade (KLG) at 30 joints. We defined rHOA as KLG ≥2 in ≥1 joint. SxHOA was defined in a hand/joint with rHOA and self-reported symptoms or tenderness on exam. Incidence was assessed in those without, while progression was assessed in those with, baseline rHOA. Proportions or medians are reported; differences by sex and race were assessed using models appropriate for dichotomous or continuous definitions, additionally adjusted for age, education, body mass index (BMI), and weight change. RESULTS: Of 800 participants (68% women, 32% African American, mean age 60 years), 327 had baseline rHOA and were older, more often white and female, than those without rHOA (n = 473). The incidence of HOA was high, for rHOA (60%) and for sxHOA (13%). Women were more likely than men to have incident HOA, particularly for distal interphalangeal joint radiographic osteoarthritis (DIP rOA) (adjusted odds ratios (aOR) 1.60 95% confidence intervals (95% CI) [1.03, 2.49]) and sxHOA (aOR 2.98 [1.50, 5.91]). Progressive HOA was more similar by sex, although thumb base rOA progressed more frequently in women than in men (aOR 2.56 [1.44, 4.55]). Particularly HOA incidence, but also progression, was more frequent among whites compared with African Americans. CONCLUSION: This study provides much needed information about the natural history of HOA, a common and frequently debilitating condition, in the general population.

Differences between race and sex in measures of hip morphology: a population-based comparative study.

OBJECTIVE: This paper aims to (i) identify differences in measures of hip morphology between four racial groups using anteroposterior (AP) hip x-rays, and (ii) examine whether these differences vary by sex. METHODS: 912 hip x-rays (456 individuals) from four racial groups (European Caucasians, American Caucasians, African Americans and Chinese) were obtained. Males and females (45-75 years) with no radiographic hip OA (Kellgren and Lawrence < Grade 2 or Croft < Grade 1) were included. Eleven features of hip joint morphology were analysed. Linear regression with generalised estimating equations (GEE) was used to determine race and sex differences in hip morphology. Post-hoc Bonferroni procedure was used to adjust for multiple comparisons. RESULTS: The final analysis included 875 hips. Chinese hips showed significant differences for the majority of measures to other racial groups. Chinese were characterised by more shallow and narrow acetabular sockets, reduced femoral head coverage, smaller femoral head diameter, and a lesser angle of alignment between the femoral neck and shaft. Variation was found between other racial groups, but with few statistically significant differences. The average of lateral centre edge angle, minimum neck width and neck length differed between race and sex (p-value for interaction < 0.05). CONCLUSIONS: Significant differences were found in measures of morphology between Chinese hips compared to African Americans or Caucasian groups; these may explain variation in hip OA prevalence rates between these groups and the lower rate of hip OA in Chinese. Sex differences were also identified, which may further explain male-female prevalence differences for OA.

The impact of painful knee osteoarthritis on mortality: a community-based cohort study with over 24 years of follow-up.

OBJECTIVE: To investigate the impact of knee osteoarthritis (OA) and/or knee pain on excess mortality. METHOD: We analyzed data from 4,182 participants in a community-based prospective cohort study of African American and Caucasian men and women aged ≥45 years. Participants completed knee radiographs and questionnaires at baseline and at up to three follow-ups to determine knee OA (rOA), knee pain and covariate status. Mortality was determined through 2015. We used Cox proportional hazards regression with time-varying covariates (TVC) to estimate hazard ratios (HR) and 95% confidence intervals (CI). Additional analyses stratified by sex, race and age were carried out. RESULTS: Median follow-up time was 14.6 years during which 1822 deaths occurred. Baseline knee radiographic osteoarthritis (rOA) was 27.7%, 38.8% at first follow-up, 52.6% at second follow-up and 61.9% at the third follow-up. Knee rOA with pain and knee pain alone were both associated with a >15% increase in premature all-cause mortality. In analyses stratified by sex, race and age, associations between knee pain, with or without knee rOA, and all-cause death were found among women, Caucasians, those ≤65 years of age, and those with a body mass index (BMI)≥30, with observed increased risks of death between 21% and 65%. We observed similar, somewhat attenuated, results for cardiovascular disease (CVD) deaths. CONCLUSION: In models taking into account variables that change over time, individuals who had knee pain, alone or with knee rOA, had increased mortality. These effects were particularly strong among those obese. Effective interventions to reduce knee pain, particularly those including weight management and prevention of comorbidities, could reduce mortality.

Associations between the chemokine biomarker CCL2 and knee osteoarthritis outcomes: the Johnston County Osteoarthritis Project.

OBJECTIVE: Our study analyzes the association between chemokine-ligand-2 (CCL2) serum concentrations at baseline and knee radiographic osteoarthritis (OA) (knee-rOA), knee-rOA progression, individual radiographic features and knee symptomatic OA at 5-year follow-up. DESIGN: OA outcomes were analyzed in a community-based cohort including a baseline enrollment and a 5-year follow-up. Baseline CCL2 serum concentrations were assessed by multiplex assay and associated with presence or progression of individual radiographic features at 5-year follow-up. Separate multiple logistic regression models were used to examine adjusted associations between baseline CCL2 and each of the knee OA variables at follow-up. CCL2 at baseline was modeled as an explanatory variable, whereas each of the knee OA variables at follow-up served as the response variables. Models were adjusted for age, BMI, race, and sex. Trend tests were conducted to assess any linear effect on outcomes across CCL2 tertiles. RESULTS: Participants (n = 168) had a median age of 57-years and median BMI of 29 kg/m2. About 63% of all participants were women, and 58% Caucasian (42% African American). In adjusted logistic models, continuous log-CCL2 was significantly associated with knee-rOA. For each unit increase in log CCL2, the odds of having knee-rOA at follow-up was increased by 72%. CCL2 tertiles showed significant linear associations with presence and progression of knee-rOA and medial joint space narrowing (JSN), but not with presence or progression of osteophytes, bone sclerosis, knee symptoms, or symptomatic knee-rOA. CONCLUSIONS: Serum CCL2 may help to elucidate some mechanisms of joint destruction and identify individuals with higher odds of structural knee changes.

Harmonising measures of knee and hip osteoarthritis in population-based cohort studies: an international study.

OBJECTIVE: Population-based osteoarthritis (OA) cohorts provide vital data on risk factors and outcomes of OA, however the methods to define OA vary between cohorts. We aimed to provide recommendations for combining knee and hip OA data in extant and future population cohort studies, in order to facilitate informative individual participant level analyses. METHOD: International OA experts met to make recommendations on: 1) defining OA by X-ray and/or pain; 2) compare The National Health and Nutrition Examination Survey (NHANES)-type OA pain questions; 3) the comparability of the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) scale to NHANES-type OA pain questions; 4) the best radiographic scoring method; 5) the usefulness of other OA outcome measures. Key issues were explored using new analyses in two population-based OA cohorts (Multicenter Osteoarthritis Study; MOST and Osteoarthritis Initiative OAI). RESULTS: OA should be defined by both symptoms and radiographs, with symptoms alone as a secondary definition. Kellgren and Lawrence (K/L) grade ≥2 should be used to define radiographic OA (ROA). The variable wording of pain questions can result in varying prevalence between 41.0% and 75.4%, however questions where the time anchor is similar have high sensitivity and specificity (91.2% and 89.9% respectively). A threshold of 3 on a 0-20 scale (95% CI 2.1, 3.9) in the WOMAC pain subscale demonstrated equivalence with the preferred NHANES-type question. CONCLUSION: This research provides recommendations, based on expert agreement, for harmonising and combining OA data in existing and future population-based cohorts.

Population-based prevalence of multiple radiographically-defined hip morphologies: the Johnston County Osteoarthritis Project.

OBJECTIVE: To provide the first prevalence estimates of different radiographic hip morphologies relevant to dysplasia and femoroacetabular impingement in a well-characterized USA population-based cohort. METHODS: Cross-sectional data were from the baseline examination (1991-1997) of a large population-based prospective longitudinal cohort study (The Johnston County Osteoarthritis Project). HipMorf software (Oxford, UK) was used to assess hip morphology on anteroposterior (AP) pelvis radiographs. Weighted, sex-stratified prevalence estimates and 95% confidence intervals for four key hip morphologies (AP alpha angle, triangular index sign, lateral center edge angle (LCEA), and protrusio acetabula) were derived and further stratified by age, race and body mass index (BMI). RESULTS: A total of 5192 hips from 2596 individuals were included (31% African American, 43% male, mean age 63 years, mean BMI 29 kg/m2). Cam morphology was seen in more than 25% of men and 10% of women. Mild dysplasia was present in about 1/3 of men and women, while pincer morphology was identified in 7% of men and 10% of women. Femoral side (cam) morphologies were more common and more frequently bilateral among men, while pincer morphologies were more common in women; mixed morphologies were infrequent. African-Americans were more likely to have protrusio acetabula than whites. CONCLUSION: We report the first population-based prevalence estimates of radiographic hip morphologies relevant to femoroacetabular impingement (FAI) and dysplasia in the USA. These morphologies are very common, with » men and 1/10 women having cam morphology, 1/3 of all adults having mild dysplasia, and 1/15 men and 1/10 women having pincer morphology in at least one hip.

Biomarkers reflect differences in osteoarthritis phenotypes of the lumbar spine: the Johnston County Osteoarthritis Project.

OBJECTIVE: To determine differences in biomarker levels between radiographic phenotypes of facet joint osteoarthritis (FOA) only, spine OA only ((disc space narrowing (DSN) and vertebral osteophytes (OST)) or the combination of FOA and spine OA. DESIGN: A cross-sectional analysis of data from 555 participants in the Johnston County Osteoarthritis Project was performed. Lumbar spine levels were graded by severity (OST and DSN) and presence (FOA) of degeneration. Biomarkers included hyaluronan (HA) and type II collagen (CTX-II). Adjusted risk ratios (aRRR) were estimated using multinomial regression, with adjustment for age, race, sex, body mass index (BMI), and radiographic OA (knee, hip, hand). Interactions were tested between sex, race and low back symptoms. RESULTS: FOA only was present in 22.4%, 14.5% had spine OA only, and 34.6% had the combination of FOA and spine OA. Compared to the reference group of neither FOA or spine OA, a one unit higher ln HA level was associated with 31% higher relative risk ratio (RRR = 1.31 (95% 1.03, 1.67)) of having FOA only, while, a one unit higher lnuCTX-II level was associated with 84% higher relative risk ratio (RRR = 1.84 (95% CI 1.19, 2.84)) of having spine OA only. No significant interactions were identified. CONCLUSION: Interestingly, OA affecting the synovial facet joint was associated with a marker of inflammation (HA). Spine OA, affecting intervertebral discs that contain collagen type II, was associated with a marker reflecting collagen type II degradation (CTX-II). These findings suggest that biomarkers may reflect the different pathophysiologic processes of lumbar spine OA phenotypes.

Annual incidence rates of hip symptoms and three hip OA outcomes from a U.S. population-based cohort study: the Johnston County Osteoarthritis Project.

OBJECTIVE: Estimate annual incidence rates (IRs) of hip symptoms and three osteoarthritis (OA) outcomes (radiographic, symptomatic, and severe radiographic) overall and by race, sociodemographic characteristics, and hip OA risk factors. DESIGN: Analyze baseline (1991-1997) and first follow-up (1999-2003) data (n = 1446) from the Johnston County Osteoarthritis Project, a population-based, prospective study of adults ≥45 years in North Carolina. Hip symptoms were pain, aching, and/or stiffness on most days, or groin pain. Radiographic and severe radiographic OA were Kellgren-Lawrence (KL) grades ≥2 and ≥3, respectively. Symptomatic OA was radiographic OA with symptoms in the same hip. Sociodemographics were age, gender, race, highest attained education, and annual household income. Hip OA risk factors were self-reported body mass index (BMI) at age 18 years, clinically measured BMI at baseline, and history of hip injury. RESULTS: Annual IRs (median = 5.5 years follow-up) were 37, 23, 13, and 2.9 per 1000 person-years for hip symptoms, and radiographic, symptomatic, and severe radiographic hip OA, respectively. We found low IRs of radiographic and symptomatic hip OA among African Americans and high IRs of hip symptoms among the obese and the very poor. Across outcomes, IRs were highest for those with hip injury. CONCLUSION: No prior studies have reported IRs of hip symptoms; IRs of radiographic and severe radiographic hip OA were similar to, and the IR of symptomatic hip OA was higher than, previous estimates. Prevention efforts should target low socioeconomic status (SES) populations and obese adults; interventions for hip OA and hip symptoms are imperative for those with hip injuries.

Clinical algorithms to aid osteoarthritis guideline dissemination.

BACKGROUND: Numerous scientific organisations have developed evidence-based recommendations aiming to optimise the management of osteoarthritis (OA). Uptake, however, has been suboptimal. The purpose of this exercise was to harmonize the recent recommendations and develop a user-friendly treatment algorithm to facilitate translation of evidence into practice. METHODS: We updated a previous systematic review on clinical practice guidelines (CPGs) for OA management. The guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation for quality and the standards for developing trustworthy CPGs as established by the National Academy of Medicine (NAM). Four case scenarios and algorithms were developed by consensus of a multidisciplinary panel. RESULTS: Sixteen guidelines were included in the systematic review. Most recommendations were directed toward physicians and allied health professionals, and most had multi-disciplinary input. Analysis for trustworthiness suggests that many guidelines still present a lack of transparency. A treatment algorithm was developed for each case scenario advised by recommendations from guidelines and based on panel consensus. CONCLUSION: Strategies to facilitate the implementation of guidelines in clinical practice are necessary. The algorithms proposed are examples of how to apply recommendations in the clinical context, helping the clinician to visualise the patient flow and timing of different treatment modalities.

Model-based evaluation of cost-effectiveness of nerve growth factor inhibitors in knee osteoarthritis: impact of drug cost, toxicity, and means of administration.

OBJECTIVE: Studies suggest nerve growth factor inhibitors (NGFi) relieve pain but may accelerate disease progression in some patients with osteoarthritis (OA). We sought cost and toxicity thresholds that would make NGFi a cost-effective treatment for moderate-to-severe knee OA. DESIGN: We used the Osteoarthritis Policy (OAPol) model to estimate the cost-effectiveness of NGFi compared to standard of care (SOC) in OA, using Tanezumab as an example. Efficacy and rates of accelerated OA progression were based on published studies. We varied the price/dose from $200 to $1000. We considered self-administered subcutaneous (SC) injections (no administration cost) vs provider-administered intravenous (IV) infusion ($69-$433/dose). Strategies were defined as cost-effective if their incremental cost-effectiveness ratio (ICER) was less than $100,000/quality-adjusted life year (QALY). In sensitivity analyses we varied efficacy, toxicity, and costs. RESULTS: SOC in patients with high levels of pain led to an average discounted quality-adjusted life expectancy of 11.15 QALYs, a lifetime risk of total knee replacement surgery (TKR) of 74%, and cumulative discounted direct medical costs of $148,700. Adding Tanezumab increased QALYs to 11.42, reduced primary TKR utilization to 63%, and increased costs to between $155,400 and $199,500. In the base-case analysis, Tanezumab at $600/dose was cost-effective when delivered outside of a hospital. At $1000/dose, Tanezumab was not cost-effective in all but the most optimistic scenario. Only at rates of accelerated OA progression of 10% or more (10-fold higher than reported values) did Tanezumab decrease QALYs and fail to represent a viable option. CONCLUSIONS: At $100,000/QALY, Tanezumab would be cost effective if priced ≤$400/dose in all settings except IV hospital delivery.

'Ancient episteme' and the nature of fossils: a correction of a modern scholarly error.

Beginning the nineteenth-century and continuing down to the present, many authors writing on the history of geology and paleontology have attributed the theory that fossils were inorganic formations produced within the earth, rather than by the deposition of living organisms, to the ancient Greeks and Romans. Some have even gone so far as to claim this was the consensus view in the classical period up through the Middle Ages. In fact, such a notion was entirely foreign to ancient and medieval thought and only appeared within the manifold of 'Renaissance episteme,' the characteristics of which have often been projected backwards by some historians onto earlier periods. This paper endeavors to correct this error, explain the development of the Renaissance view, describe certain ancient precedents thereof, and trace the history of the misinterpretation in the literature.

Cost-effectiveness of nonsteroidal anti-inflammatory drugs and opioids in the treatment of knee osteoarthritis in older patients with multiple comorbidities.

OBJECTIVE: To evaluate long-term clinical and economic outcomes of naproxen, ibuprofen, celecoxib or tramadol for OA patients with cardiovascular disease (CVD) and diabetes. DESIGN: We used the Osteoarthritis Policy Model to examine treatment with these analgesics after standard of care (SOC) - acetaminophen and corticosteroid injections - failed to control pain. NSAID regimens were evaluated with and without proton pump inhibitors (PPIs). We evaluated over-the-counter (OTC) regimens where available. Estimates of treatment efficacy (pain reduction, occurring in ∼57% of patients on all regimens) and toxicity (major cardiac or gastrointestinal toxicity or fractures, risk ranging from 1.09% with celecoxib to 5.62% with tramadol) were derived from published literature. Annual costs came from Red Book Online(®). Outcomes were discounted at 3%/year and included costs, quality-adjusted life expectancy, and incremental cost-effectiveness ratios (ICERs). Key input parameters were varied in sensitivity analyses. RESULTS: Adding ibuprofen to SOC was cost saving, increasing QALYs by 0.07 while decreasing cost by $800. Incorporating OTC naproxen rather than ibuprofen added 0.01 QALYs and increased costs by $300, resulting in an ICER of $54,800/QALY. Using prescription naproxen with OTC PPIs led to an ICER of $76,700/QALY, while use of prescription naproxen with prescription PPIs resulted in an ICER of $252,300/QALY. Regimens including tramadol or celecoxib cost more but added fewer QALYs and thus were dominated by several of the naproxen-containing regimens. CONCLUSIONS: In patients with multiple comorbidities, naproxen- and ibuprofen-containing regimens are more effective and cost-effective in managing OA pain than opioids, celecoxib or SOC.

Inflammation (or synovitis)-driven osteoarthritis: an opportunity for personalizing prognosis and treatment?

The disabling and painful disease osteoarthritis (OA) is the most common form of arthritis. Strong evidence suggests that a subpopulation of OA patients has a form of OA driven by inflammation. Consequently, understanding when inflammation is the driver of disease progression and which OA patients might benefit from anti-inflammatory treatment is a topic of intense research in the OA field. We have reviewed the current literature on OA, with an emphasis on inflammation in OA, biochemical markers of structural damage, and anti-inflammatory treatments for OA. The literature suggests that the OA patient population is diverse, consisting of several subpopulations, including one associated with inflammation. This inflammatory subpopulation may be identified by a combination of novel serological inflammatory biomarkers. Preliminary evidence from small clinical studies suggests that this subpopulation may benefit from anti-inflammatory treatment currently reserved for other inflammatory arthritides.

Measures of hip morphology are related to development of worsening radiographic hip osteoarthritis over 6 to 13 year follow-up: the Johnston County Osteoarthritis Project.

OBJECTIVES: We sought to describe the effect of alterations in hip morphology with respect to worsening hip OA in a community-based sample including African American (AA) and white men and women. METHODS: This nested case-control study defined case hips as Kellgren Lawrence grade (KLG) <3 on baseline supine pelvis radiographs and KLG ≥3 or THR for OA at the 1st or 2nd follow-up visit (mean 6 and 13 years, respectively); control hips had KLG <3 at both visits, with gender/race distribution similar to cases. Hip morphology was assessed using HipMorf software (Oxford, UK). Descriptive means and standard errors were obtained from generalized estimating equation (GEE) models. Sex-stratified GEE regression models (accounting for within-person correlation), adjusted for age, race, BMI, and side were then employed. RESULTS: A total of 120 individuals (239 hips; 71 case/168 control) were included (25% male, 26% AA, mean age 62 years, BMI 30 kg/m(2)). Case hips tended to have greater baseline AP alpha angles, smaller minimum joint space width (mJSW) and more frequent triangular index signs. Adjusted results among men revealed that higher AP alpha angle, Gosvig ratio, and acetabular index were positively associated with case hips; coxa profunda was negatively associated. Among women, greater AP alpha angle, smaller mJSW, protrusio acetabuli, and triangular index sign were associated with case hips. CONCLUSIONS: We confirmed an increased risk of worsening hip OA due to baseline features of cam deformity among men and women, as well as protrusio acetabuli among women, and provide the first estimates of these measures in AAs.

Novel statistical methodology reveals that hip shape is associated with incident radiographic hip osteoarthritis among African American women.

INTRODUCTION: Hip shape is a risk factor for the development of hip osteoarthritis (OA), and current methods to assess hip shape from radiographs are limited; therefore this study explored current and novel methods to assess hip shape. METHODS: Data from a prior case-control study nested in the Johnston County OA Project were used, including 382 hips (from 342 individuals). Hips were classified by radiographic hip OA (RHOA) status as RHOA cases (baseline Kellgren Lawrence grade [KLG] 0 or 1, follow-up [mean 6 years] KLG ≥ 2) or controls (KLG = 0 or 1 at both baseline and follow-up). Proximal femur shape was assessed using a 60-point model as previously described. The current analysis explored commonly used principal component analysis (PCA), as well as novel statistical methodologies suited to high dimension low sample size settings (Distance Weighted Discrimination [DWD] and Distance Projection Permutation [DiProPerm] hypothesis testing) to assess differences between cases and controls. RESULTS: Using these novel methodologies, we were able to better characterize morphologic differences by sex and race. In particular, the proximal femurs of African American women demonstrated significantly different shapes between cases and controls, implying an important role for sex and race in the development of RHOA. Notably, discrimination was improved with the use of DWD and DiProPerm compared to PCA. CONCLUSIONS: DWD with DiProPerm significance testing provides improved discrimination of variation in hip morphology between groups, and enables subgroup analyses even under small sample sizes.

Plasma levels of interleukin-1 receptor antagonist (IL1Ra) predict radiographic progression of symptomatic knee osteoarthritis.

OBJECTIVE: Pro- and anti-inflammatory mediators, such as IL-1ß 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-1ß, TNFα, VEGF, IL-6, IL-6Rα, 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.