Fecal metabolomics reveals products of dysregulated proteolysis and altered microbial metabolism in obesity-related osteoarthritis.

OBJECTIVE: The objective of this exploratory study was to determine if perturbations in gut microbial composition and the gut metabolome could be linked to individuals with obesity and osteoarthritis (OA). METHODS: Fecal samples were collected from obese individuals diagnosed with radiographic hand plus knee OA (n = 59), defined as involvement of at least 3 joints across both hands, and a Kellgren-Lawrence (KL) grade 2-4 (or total knee replacement) in at least one knee. Controls (n = 33) were without hand OA and with KL grade 0-1 knees. Fecal metabolomes were analyzed by a UHPLC/Q Exactive HFx mass spectrometer. Microbiome composition was determined in fecal samples by 16 S ribosomal RNA amplicon sequencing (rRNA-seq). Stepwise logistic regression models were built to determine microbiome and/or metabolic characteristics of OA. RESULTS: Untargeted metabolomics analysis indicated that OA cases had significantly higher levels of di- and tripeptides and significant perturbations in microbial metabolites including propionic acid, indoles, and other tryptophan metabolites. Pathway analysis revealed several significantly perturbed pathways associated with OA including leukotriene metabolism, amino acid metabolism and fatty acid utilization. Logistic regression models selected metabolites associated with the gut microbiota and leaky gut syndrome as significant predictors of OA status, particularly when combined with the rRNA-seq data. CONCLUSIONS: Adults with obesity and knee plus hand OA have distinct fecal metabolomes characterized by increased products of proteolysis, perturbations in leukotriene metabolism, and changes in microbial metabolites compared with controls. These metabolic perturbations indicate a possible role of dysregulated proteolysis in OA.

Statistical shape modeling of the hip and the association with hip osteoarthritis: a systematic review.

OBJECTIVE: To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis. DESIGN: We conducted a systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle-Ottawa Scale (NOS) for risk of bias assessment. RESULTS: Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion). CONCLUSIONS: Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations.

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 association between walking speed from short- and standard-distance tests with the risk of all-cause mortality among adults with radiographic knee osteoarthritis: data from three large United States cohort studies.

OBJECTIVE: Adults with radiographic knee OA (rKOA) are at increased risk of mortality and walking difficulty may modify this relation. Little is known about specific aspects of walking difficulty that increase mortality risk. We investigated the association of walking speed (objective measure of walking difficulty) with mortality and examined the threshold that best discriminated this risk in adults with rKOA. METHODS: Participants with rKOA from the Johnston County Osteoarthritis Project (JoCoOA, longitudinal population-based cohort), Osteoarthritis Initiative and Multicenter Osteoarthritis Study (OAI and MOST, cohorts of individuals with or at high risk of knee OA) were included. Baseline speed was measured via 2.4-meter (m) walk test (short-distance) in JoCoOA and 20-m walk test (standard-distance) in OAI and MOST. To examine the association of walking speed with mortality risk over 9 years, hazard ratios (HR) and 95% confidence intervals (CI) were calculated from Cox regression models adjusted for potential confounders. A Maximal Likelihood Ratio Chi-square Approach was utilized to identify an optimal threshold of walking speed predictive of mortality. RESULTS: Deaths after 9 years of follow-up occurred in 23.3% (290/1244) of JoCoOA and 5.9% (249/4215) of OAI + MOST. Walking 0.2 m/s slower during short- and standard-distance walk tests was associated with 23% (aHR [95%CI]; 1.23 [1.10, 1.39]) and 25% (1.25 [1.09, 1.43]) higher mortality risk, respectively. Walking <0.5 m/s on short-distance and <1.2 m/s standard-distance walk tests, best discriminated those with and without mortality risk. CONCLUSION: Slower walking speed measured via short- and standard-distance walk tests was associated with increased mortality risk in adults with rKOA.

A machine learning approach to knee osteoarthritis phenotyping: data from the FNIH Biomarkers Consortium.

OBJECTIVE: Knee osteoarthritis (KOA) is a heterogeneous condition representing a variety of potentially distinct phenotypes. The purpose of this study was to apply innovative machine learning approaches to KOA phenotyping in order to define progression phenotypes that are potentially more responsive to interventions. DESIGN: We used publicly available data from the Foundation for the National Institutes of Health (FNIH) osteoarthritis (OA) Biomarkers Consortium, where radiographic (medial joint space narrowing of ≥0.7 mm), and pain progression (increase of ≥9 Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] points) were defined at 48 months, as four mutually exclusive outcome groups (none, both, pain only, radiographic only), along with an extensive set of covariates. We applied distance weighted discrimination (DWD), direction-projection-permutation (DiProPerm) testing, and clustering methods to focus on the contrast (z-scores) between those progressing by both criteria ("progressors") and those progressing by neither ("non-progressors"). RESULTS: Using all observations (597 individuals, 59% women, mean age 62 years and BMI 31 kg/m2) and all 73 baseline variables available in the dataset, there was a clear separation among progressors and non-progressors (z = 10.1). Higher z-scores were seen for the magnetic resonance imaging (MRI)-based variables than for demographic/clinical variables or biochemical markers. Baseline variables with the greatest contribution to non-progression at 48 months included WOMAC pain, lateral meniscal extrusion, and serum N-terminal pro-peptide of collagen IIA (PIIANP), while those contributing to progression included bone marrow lesions, osteophytes, medial meniscal extrusion, and urine C-terminal crosslinked telopeptide type II collagen (CTX-II). CONCLUSIONS: Using methods that provide a way to assess numerous variables of different types and scalings simultaneously in relation to an outcome of interest enabled a data-driven approach that identified key variables associated with a progression phenotype.

Osteoarthritis year in review 2017: clinical.

This review is based on a systematic review of the literature relevant to clinical topics in osteoarthritis (OA) performed for the time period February 22, 2016 to April 1, 2017. A PubMed search using the terms "osteoarthritis" and "treatment or epidemiology" returned over 800 papers, of which 57 are reviewed here, with inclusion primarily based on relevance to clinical OA. Epidemiologic studies in this time frame focused on the incidence and prevalence of OA, comorbidities and mortality in relation to OA (particularly obesity and cardiovascular disease), and multiple joint involvement. Papers on therapeutic approaches to OA considered: non-pharmacologic options, a number of topical, oral, and intra-articular therapies, as well as the cost-effectiveness of some OA treatments. There an enormous need to identify novel strategies to reduce the impact of this highly prevalent and debilitating condition.

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.

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.

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.

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.

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.

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.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hip osteoarthritis.

The ability to assess the efficacy and effectiveness of an intervention for the treatment of hip osteoarthritis (OA) requires strong clinical trial methodology. This consensus paper provides recommendations based on a narrative literature review and best judgment of the members of the committee for clinical trials of hip OA. We provide recommendations on clinical trial design, outcome measures, including structural (radiography), and patient and physician global assessments, performance based measures, molecular markers and experimental endpoints including MRI imaging. This information can be utilized by sponsors of trials for new therapeutic agents for hip OA.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hand osteoarthritis.

Hand osteoarthritis (OA) is a very frequent disease, but yet understudied. However, a lot of works have been published in the past 10 years, and much has been done to better understand its clinical course and structural progression. Despite this new knowledge, few therapeutic trials have been conducted in hand OA. The last OARSI recommendations for the conduct of clinical trials in hand OA dates back to 2006. The present recommendations aimed at updating previous recommendations, by incorporating new data. The purpose of this expert opinion, consensus driven exercise is to provide evidence-based guidance on the design, execution and analysis of clinical trials in hand OA, where published evidence is available, supplemented by expert opinion, where evidence is lacking, to perform clinical trials in hand OA, both for symptom and for structure-modification. They indicate core outcome measurement sets for studies in hand OA, and list the methods and instruments that should be used to measure symptoms or structure. For both symptom- and structure-modification, at least pain, physical function, patient global assessment, HR-QoL, joint activity and hand strength should be assessed. In addition, for structure-modification trials, structural progression should be measured by radiographic changes. We also provide a research agenda listing many unsolved issues that seem to most urgently need to be addressed from the perspective of performing "good" clinical trials in hand OA. These updated OARSI recommendations should allow for better standardizing the conduct of clinical trials in hand OA in the next future.

Serum transforming growth factor-beta 1 is not a robust biomarker of incident and progressive radiographic osteoarthritis at the hip and knee: the Johnston County Osteoarthritis Project.

PURPOSE: To test whether serum transforming growth factor-beta 1 (TGF-beta1) predicts incident and progressive hip or knee radiographic OA (rOA). METHODS: Serum TGF-beta1 was measured for 330 participants aged 45 years and older in the Johnston County Osteoarthritis Project, with paired longitudinal films available for 618 hips and 658 knees. Incident and progressive rOA were defined using Kellgren-Lawrence (K-L) grade as well as osteophyte (OST) and joint space narrowing (JSN) scores. Natural logarithm transformation was used to produce near-normal distributions for continuous TGF-beta1 (lnTGF-beta1). Separate multivariable Weibull regression models were used to provide hazard ratios (HRs) for a 1-unit increase lnTGF-beta1 with each rOA outcome, accounting for variable follow-up times and clustering by individual, adjusted for age, race, gender, and body mass index (BMI). Interaction terms were considered statistically significant at P<0.10. RESULTS: The mean (+/-SD) age of the sample was 61.9+/-9.7 years, the mean BMI was 30.3+/-6.9 kg/m(2), with 60.6% women and 42.4% AA. The mean (+/-SD) TGF-beta1 was 17.8+/-6.1 ng/ml; follow-up time was 6.1+/-1.3 years. There were no significant interactions by race or gender. HRs showed no significant relationship between lnTGF-beta1 and incident or progressive rOA, OST, or JSN, at the knee or the hip. CONCLUSIONS: Levels of TGF-beta1 do not predict incident or progressive rOA, OST, or JSN at the hip or knee in this longitudinal, population-based study, making it unlikely that TGF-beta1 will be a robust biomarker for rOA in future studies.

A consensus-based framework for conducting and reporting osteoarthritis phenotype research.

BACKGROUND: The concept of osteoarthritis (OA) heterogeneity is evolving and gaining renewed interest. According to this concept, distinct subtypes of OA need to be defined that will likely require recognition in research design and different approaches to clinical management. Although seemingly plausible, a wide range of views exist on how best to operationalize this concept. The current project aimed to provide consensus-based definitions and recommendations that together create a framework for conducting and reporting OA phenotype research. METHODS: A panel of 25 members with expertise in OA phenotype research was composed. First, panel members participated in an online Delphi exercise to provide a number of basic definitions and statements relating to OA phenotypes and OA phenotype research. Second, panel members provided input on a set of recommendations for reporting on OA phenotype studies. RESULTS: Four Delphi rounds were required to achieve sufficient agreement on 11 definitions and statements. OA phenotypes were defined as subtypes of OA that share distinct underlying pathobiological and pain mechanisms and their structural and functional consequences. Reporting recommendations pertaining to the study characteristics, study population, data collection, statistical analysis, and appraisal of OA phenotype studies were provided. CONCLUSIONS: This study provides a number of consensus-based definitions and recommendations relating to OA phenotypes. The resulting framework is intended to facilitate research on OA phenotypes and increase combined efforts to develop effective OA phenotype classification. Success in this endeavor will hopefully translate into more effective, differentiated OA management that will benefit a multitude of OA patients.

Failure of serum transforming growth factor-beta (TGF-beta1) 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 transforming growth factor-beta (TGF-beta1) 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> or =2. Individual radiographic features (IRFs) were rated 0-3. TGF-beta1 was measured using a sandwich enzyme-linked immunosorbent assay (ELISA). General linear models were used to estimate associations between lnTGF-beta1 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-beta1 levels were higher among AAs compared to Whites, and among women compared to men (P<0.009). Mean lnTGF-beta1 levels were higher in those with knee osteophytes (OST), but this association was not significant after adjustment. There were no other significant differences in mean lnTGF-beta1 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-beta1 and knee OST was seen among AAs (P<0.06). CONCLUSIONS: Although serum TGF-beta1 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-beta1 is unlikely to be useful as a stand-alone biomarker in OA studies. A possible association between TGF-beta1 and OST in AAs cannot be excluded.