Magnetic resonance imaging predictors (cartilage, osteophytes and meniscus) of prevalent and 3-year incident medial and lateral tibiofemoral knee joint tenderness and patellofemoral grind.

OBJECTIVE: To identify magnetic resonance imaging (MRI) predictors (cartilage [C], osteophytes [O] and meniscus [M] scores) of prevalent and 3-year incident medial tibiofemoral (MTF) and lateral tibiofemoral (LTF) knee joint tenderness and patellofemoral (PF) grind.  METHODS: Population-based knee pain cohort aged 40-79 was assessed at baseline (N = 255), 3- and 7-year follow-up (N = 108 × 2 = 216). COM scores were measured at 6/8/6 subregions respectively. Age-sex-BMI adjusted logistic models predicted prevalence versus relevant COM predictors (medial, lateral or patellar / trochlear groove scores). Fully adjusted models also included all relevant COM predictors. Binary generalized estimating equations models predicting 3-year incidence were also adjusted for individual follow-up time between cycles. RESULTS: Significant predictors of prevalent MTF tenderness: medial femoral cartilage (fully adjusted odds ratio [aOR] 1.84; 95% confidence interval [CI] 1.11, 3.05), female (aOR = 3.05; 1.67, 5.58), BMI (aOR = 1.53 per 5 units BMI; 1.10, 2.11). Predictors of prevalent LTF tenderness: female (aOR = 2.18; 1.22, 3.90). There were no predictors of prevalent PF grind in the fully adjusted model. However, medial patellar osteophytes was predictive in the age-sex-BMI adjusted model. There were no predictors of 3-year incident MTF tenderness. Predictors of 3-year incident LTF tenderness: female (aOR = 3.83; 1.25, 11.77). Predictors of 3-year incident PF grind: lateral patellar osteophytes (aOR = 4.82; 1.69, 13.77). In the age-sex-BMI adjusted model, patellar cartilage was also a predictor. CONCLUSION: We explored potential MRI predictors of prevalent and 3-year incident MTF/LTF knee joint tenderness and PF grind. These findings could guide preemptive strategies aimed at reducing these symptoms in the present and future (3-year incidence).

A whole-joint, unidimensional, irreversible, and fine-grained MRI knee osteoarthritis severity score, based on cartilage, osteophytes and meniscus (OA-COM).

OBJECTIVE: To develop a whole-joint, unidimensional, irreversible, and fine-grained MRI knee osteoarthritis (OA) severity score, based on cartilage, osteophytes and meniscus (OA-COM), and to predict progression across different severity states using OA-COM as outcome and clinical variables as predictors. METHODS: Population-based knee pain cohort aged 40-79 was assessed at baseline and 7-year follow-up. OA-COM score was defined as the sum of MRI scores for cartilage, osteophytes and menisci, measured at 6, 8 and 6 sites, total score 0-54. To anchor severity levels, we fit cross-sectional logistic models using OA-COM to predict Kellgren-Lawrence (KL) grades in subsets at or one point below each grade. OA-COM threshold scores were selected on sensitivity, specificity, positive and negative predictive value. We developed longitudinal logistic models for OA-COM progression over each threshold over 7 years. Potential predictors included age, sex, BMI, malalignment, physical exam effusion, quadriceps weakness, and crepitus, selected on area under the receiver operating characteristic curve (AUC) and Akaike's Information Criterion (AIC). RESULTS: Optimal OA-COM thresholds were 12, 18, 24 and 30, for KL grades 1 to 4. Significant predictors of progression (depending on threshold) included physical exam effusion, malalignment and female sex, with other selected predictors age, BMI and crepitus. CONCLUSION: OA-COM (0-54 range) is a whole-joint, unidimensional, irreversible, and fine-grained MRI OA severity score reflecting cartilage, osteophytes and menisci. OA-COM scores 12, 18, 24 and 30 are equivalent to KL grades 1 to 4, while offering fine-grained differentiation of states between KL grades, and within pre-radiographic disease (KL = 0) or late-stage disease (KL = 4). In modeling, several clinical variables predicted progression across different states over 7 years.

Specific manifestations of knee osteoarthritis predict depression and anxiety years in the future: Vancouver Longitudinal Study of Early Knee Osteoarthritis.

BACKGROUND: To evaluate whether knee osteoarthritis (OA) manifestations predict depression and anxiety using cross-sectional and longitudinal prediction models. METHODS: A population-based cohort (n = 122) with knee pain, aged 40-79, was evaluated at baseline, 3 and 7 years. Baseline predictors were: age decade; sex; BMI ≥ 25; physical exam knee effusion; crepitus; malalignment; quadriceps atrophy; flexion; flexion contracture; Kellgren-Lawrence (KL) x-ray grade (0/1/2/3+); WOMAC pain ≥25; WOMAC stiffness ≥25; self-reported knee swelling; and knee OA diagnosis (no/probable/definite). Depression and anxiety, cutoffs 5+ and 7+ respectively, were measured via the Hospital Anxiety and Depression Scale. We fit logistic models at each cycle using multivariable models selected via lowest Akaike's information criterion. RESULTS: Baseline depression model: sex (female OR = 0.27; 0.10, 0.76) and KL grade (KL 1 OR = 4.21; 1.31, 13.48). Three-year depression model: KL grade (KL 1 OR = 18.92; 1.73, 206.25). Seven-year depression model: WOMAC stiffness ≥25 (OR = 3.49; 1.02, 11.94) and flexion contracture ≥1 degree (OR = 0.23; 0.07, 0.81). Baseline anxiety model: knee swelling (OR = 4.11; 1.51, 11.13) and age (50-59 vs. 40-49 OR = 0.31 [0.11, 0.85]; 60-69 OR = 0.07 [0.01, 0.42]). Three-year anxiety model: WOMAC stiffness ≥25 (OR = 5.80; 1.23, 27.29) and KL grade (KL 1 OR = 6.25; 1.04, 37.65). Seven-year anxiety model: sex (female OR = 2.71; 0.87, 8.46). CONCLUSION: Specific knee OA-related manifestations predict depression and anxiety cross-sectionally, 3 years in the future, and for depression, 7 years in the future. This information may prove useful to clinicians in helping to identify patients most at risk of present or future depression and anxiety, thus facilitating preemptive discussions that may help counter that risk.

Association of Knee Effusion Detected by Physical Examination With Bone Marrow Lesions: Cross-Sectional and Longitudinal Analyses of a Population-Based Cohort.

OBJECTIVE: To determine the association of effusion detected by physical examination with the prevalence of bone marrow lesions (BMLs) on magnetic resonance imaging (MRI), and the incidence/progression of BMLs over 3 years in subjects with knee osteoarthritis. METHODS: A population-based cohort with knee pain (n = 255) was assessed for effusion on physical examination. On MRI, BMLs were graded 0-3 (none, mild, moderate, severe), and incidence/progression was defined as a worsening of the sum of BML scores over 6 surfaces by ≥1 grade. We analyzed the full cohort and a mild disease subsample with a Kellgren/Lawrence (K/L) grade <3. Cross-sectional logistic and longitudinal exponential regression analyses were performed, adjusted for age, sex, body mass index (BMI) and pain. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for effusion detected by physical examination versus BMLs (prevalence and incidence/progression). RESULTS: The weighted mean age was 56.7 years, the mean BMI was 26.5, 56.3% were women, 20.1% had effusion on physical examination, and 80.7% had a K/L grade <3. Effusion on physical examination was significantly associated with prevalent BMLs in the full cohort (odds ratio [OR] 6.10 [95% confidence interval (95% CI) 2.77-13.44]) and in the K/L grade <3 cohort (OR 6.88 [95% CI 2.76-17.15]). In the full cohort, sensitivity, specificity, PPV, and NPV were 34.6, 92.5, 79.9, and 62.1%, respectively, and in the K/L <3 cohort 31.7, 94.0, 75.5, and 70.1%, respectively. Longitudinally, effusion on physical examination was not significantly associated with BML incidence/progression in the full cohort (hazard ratio [HR] 1.83 [95% CI 0.95-3.52]) or in the K/L grade <3 cohort (HR 1.73 [95% CI 0.69-4.33]). In the two cohorts, sensitivity, specificity, PPV, and NPV were 32.0, 82.2, 42.2, and 74.9%, respectively, and 21.2, 85.6, 30.1, and 78.8% respectively. CONCLUSION: BMLs on MRI can be predicted from physical examination effusion cross-sectionally, with a high PPV of 79.9%. Assessment for knee effusion on physical examination is useful for determining potential candidates with BMLs before costly MRI screening for recruitment into clinical trials.

Quadriceps Weakness and Risk of Knee Cartilage Loss Seen on Magnetic Resonance Imaging in a Population-based Cohort with Knee Pain.

OBJECTIVE: To determine whether baseline quadriceps weakness predicts cartilage loss assessed on magnetic resonance imaging (MRI). METHODS: Subjects aged 40-79 with knee pain (n = 163) were recruited from a random population sample and examined for quadriceps weakness with manual isometric strength testing, using a 3-point scoring system (0 = poor resistance, 1 = moderate resistance, 2 = full resistance), which was dichotomized as normal (grade 2) versus weak (grade 0/1). MRI of the more symptomatic knee was obtained at baseline and at mean of 3.3 years. Cartilage was graded 0-4 on MRI. Exponential regression analysis was used to evaluate whether quadriceps weakness was associated with whole knee cartilage loss, and in secondary analyses with compartment-specific cartilage loss, adjusted for age, sex, body mass index, Western Ontario and McMaster Universities Osteoarthritis Arthritis Index pain score, and baseline MRI cartilage score. RESULTS: Of 163 subjects, 54% were female, with a mean age of 57.7 years. Quadriceps weakness was seen in 11.9% of the subjects. Weakness was a predictor of whole knee cartilage loss (HR 3.48, 95% CI 1.30-9.35). Quadriceps weakness was associated with cartilage loss in the medial tibiofemoral (TF) compartment (HR 4.60, 95% CI 1.25-17.02), while no significant association was found with lateral TF (HR 1.53, 95% CI 0.24-9.78) or patellofemoral compartment (HR 2.76, 95% CI 0.46-16.44). CONCLUSION: In this symptomatic, population-based cohort, quadriceps weakness predicted whole knee and medial TF cartilage loss after 3 years. To our knowledge, this is the first study to show that a simple clinical examination of quadriceps strength can predict the risk of knee cartilage loss.

Association of body mass index with knee cartilage damage in an asymptomatic population-based study.

BACKGROUND: Cartilage changes are an important early finding of osteoarthritis (OA), which can exist even before symptoms. Our objective was to determine the prevalence of knee cartilage damage on magnetic resonance imaging (MRI) in an asymptomatic population-based cross-sectional study and to evaluate the association of body mass index (BMI) with cartilage damage. METHODS: Subjects, aged 40-79 years, without knee pain (n = 73) were recruited as a random population sample and assessed for BMI (kg/m2), including current BMI (measured), past BMI at age 25 (self-reported) and change in BMI. Knee cartilage was scored semi-quantitatively (grades 0-4) on MRI. In primary analysis, cartilage damage was defined as ≥2 (at least moderate) and in a secondary analysis as ≥3 (severe). We also conducted a sensitivity analysis by dichotomizing current BMI as <25 vs. ≥25. Logistic regression was used to evaluate the association of each BMI variable with prevalent MRI-detected cartilage damage, adjusted for age and sex. RESULTS: Of 73 subjects, knee cartilage damage ≥2 and ≥3 was present in 65.4% and 28.7%, respectively. The median current BMI was 26.1, median past BMI 21.6, and median change in BMI was a gain of 2.8. For cartilage damage ≥2, current BMI had a non-statistically significant OR of 1.65 per 5 units (95% CI 0.93-2.92). For cartilage damage ≥3, current BMI showed a trend towards statistical significance with an OR of 1.70 per 5 units (95% CI 0.99-2.92). Past BMI and change in BMI were not significantly associated with cartilage damage. Current BMI ≥ 25 was statistically significantly associated with cartilage damage ≥2 (OR 3.04 (95% CI 1.10-8.42)), but not for ≥3 (OR 2.63 (95% CI 0.86-8.03)). CONCLUSIONS: MRI-detected knee cartilage damage was highly prevalent in this asymptomatic population-based cohort. We report a trend towards significance of BMI with cartilage damage severity. Subjects with abnormal current BMI (≥25) had a 3-fold increased odds of cartilage damage ≥2, compared to those with normal BMI. This study lends support towards the role of obesity in the pathogenesis of knee cartilage damage at an asymptomatic stage of disease.

Associations between MRI features versus knee pain severity and progression: Data from the Vancouver Longitudinal Study of Early Knee Osteoarthritis.

OBJECTIVE: To determine associations between features of osteoarthritis (OA) on MRI and knee pain severity and knee pain progression. DESIGN: Baseline, 3.3- and 7.5-year assessments were performed for 122 subjects with baseline knee pain (age 40-79), sample-weighted for population (with knee pain) representativeness. MRIs were scored for: osteophytes (0:absent to 3:large); cartilage (0:normal to 4:full thickness defect; 0/1 collapsed); subchondral sclerosis (0:none to 3:>50% of site), subchondral cyst (0:absent to 3:severe), bone marrow lesions (0:none to 3:≥50% of site); and meniscus (0:normal to 3:maceration/resection), in 6-8 regions each. Per feature, scores were averaged across regions. Effusion/synovitis (0:absent to 3:severe) was analyzed as ≥2 vs. <2. Linear models predicted WOMAC knee pain severity (0-100), and binary models predicted 10+ (minimum perceptible clinical improvement [MPCI]) and 20+ (minimum clinically important difference [MCID]) increases. Models were adjusted for age, sex, BMI (and follow-up time for longitudinal models). RESULTS: Pain severity was associated with osteophytes (7.17 per unit average; 95% CI = 3.19, 11.15) and subchondral sclerosis (11.03; 0.68, 21.39). MPCI-based pain increase was associated with osteophytes (odds ratio per unit average 3.20; 1.36, 7.55), subchondral sclerosis (5.69; 1.06, 30.44), meniscal damage (1.68; 1.08, 2.61) and effusion/synovitis ≥2 (2.25; 1.07, 4.71). MCID-based pain increase was associated with osteophytes (3.79; 1.41, 10.20) and cartilage defects (2.42; 1.24, 4.74). CONCLUSIONS: Of the features investigated, only osteophytes were consistently associated with pain cross-sectionally and longitudinally in all models. This suggests an important role of bone in early knee osteoarthritis.

Comparison of hemagglutination inhibition and microbead array assays for the measurement of influenza antibody levels in HIV-infected adults.

INTRODUCTION: Determining vaccine responsiveness is challenging in immune compromised individuals. The microbead array (MBA) assay is a rapid, inexpensive test for evaluating influenza vaccine immunogenicity. MBA performance was compared to hemagglutination inhibition assay (HAI) utilizing HIV seropositive vaccine recipient specimens. METHODS: CTN 253 evaluated standard dose, single antigen, inactivated split adjuvanted (AS03(A)) H1N1 influenza vaccine (Arepanrix) vs standard dose plus booster. CTN237 evaluated three doses of a seasonal, trivalent killed split non-adjuvanted influenza vaccine (Fluviral). Samples of convenience from 75 CTN 253 and 58 CTN 237 participants were evaluated by MBA and HAI. MBA seroreactivity cut-offs of 500 and 1000 mean fluorescent intensity were used to compare those derived by HAI [titer ≥40 (seroprotection) and 4-fold titer increase from baseline (seroconversion)]. RESULTS: CTN253: Using a MBA cut-off of 500, 75% and 59% had seroreactive titers at visit 2 and 78% and 61% at visit 3 for the single versus double dose study arms. Many participants were categorized differently by the HAI and MBA tests, with raw agreement of 59% at visit 2 and 57% at visit 3. CTN 237: Baseline MBA medians (IQR) were 803 (12-2626) for the A/Brisbane strain and 460 (14-1758) for the B/Florida strain. Using a cut-off of 500 yielded for the A/Brisbane strain seroreactivity rates of 44%, 58%, and 63% were observed for the three doses of vaccine tested. The raw agreement was 47%. B/Florida strain analyses yielded similar results. For all strains assessed in both studies, no relationship between MBA values and baseline variables was identified. CONCLUSION: The concordance of results between the MBA assay and the HAI assay is very low. MBA assay may be more sensitive than the HAI assay suggesting that it was either detecting more false-positive results and/or that the HAI assay had more false negative.

Association of Body Mass Index With Incidence and Progression of Knee Effusion on Magnetic Resonance Imaging and on Knee Examination.

OBJECTIVE: To determine the association of body mass index (BMI) with incidence and progression of knee effusion on magnetic resonance imaging (MRI) and physical examination (PE) in a longitudinal cohort with knee pain. METHODS: A population-based cohort was assessed at baseline and 3 years (n = 163). BMI was categorized as normal (<25), overweight (25-29.9), and obese (≥30). Knee effusion was graded as 0-3 (absent/mild/moderate/severe) on MRI and 0-1 (absent/present) on PE. Progression of MRI effusion (MRIeff ) was an increase of ≥1 grade in those with grade 1 or 2 at baseline. Incident MRIeff and PE effusion (PEeff ) were any effusion at followup (>0) in those with grade 0 at baseline. A second type of incident MRIeff was effusion grade ≥2 at followup in those with grade <2 at baseline. Exponential regression analysis was used, adjusted for age, sex, and radiographic severity. RESULTS: Incident MRIeff ≥1, incident MRIeff ≥2, incident PEeff , and progression of MRIeff were seen in 14 of 73 (19%), 18 of 140 (13%), 26 of 127 (20%), and 18 of 86 (21%), respectively. There was a borderline statistical association of obesity with progression of MRIeff (hazard ratio [HR] 3.3 [95% confidence interval (95% CI) 1.0-11.2]) and with incident MRIeff ≥2 (HR 3.4 [95% CI 1.0-11.5]). BMI was not associated with incident MRIeff ≥1 (HR overweight 1.1 [95% CI 0.3-3.6], obese 1.0 [95% CI 0.2-5.0]). Overweight was associated with incident PEeff (HR 4.5 [95% CI 1.4-14.2]), while obesity was not statistically significant (HR 3.1 [95% CI 0.9-11.1]). CONCLUSION: Obesity was a risk factor for incident and progressive knee effusion in this population-based cohort. These findings highlight an important link between obesity and inflammation in knee osteoarthritis.

Association between short leukocyte telomere length and HIV infection in a cohort study: No evidence of a relationship with antiretroviral therapy.

BACKGROUND: Individuals infected with human immunodeficiency virus (HIV) appear to age faster than the general population, possibly related to HIV infection, antiretroviral therapy, and/or social/environmental factors. We evaluated leukocyte telomere length (LTL), a marker of cellular aging, in HIV-infected and uninfected adults. METHODS: Clinical data and blood were collected from Children and women: AntiRetrovirals and the Mechanism of Aging (CARMA) cohort study participants. Variables found to be important in univariate analysis were multivariate model candidates. RESULTS: Of the 229 HIV-infected and 166 HIV-uninfected participants, 76% were women, and 71% were current/previous smokers. In a multivariate model of all participants, older age (P < .001), HIV infection (P = .04), active hepatitis C virus (HCV) infection (P = .02), and smoking (P < .003) were associated with shorter LTL. An interaction was detected, whereby smoking was associated with shorter LTL in HIV-uninfected subjects only. Among those, age and smoking (P ≤ .01) were related to shorter LTL. In 2 models of HIV-infected individuals, age (P ≤ .002) and either active HCV infection (P = .05) or peak HIV RNA ≥100 000 copies/mL (P = .04) were associated with shorter LTL, whereas other HIV disease or treatment parameters were unrelated. CONCLUSIONS: Our results suggest that acquisition of HIV and viral load are primarily responsible for the association between HIV-positive status and shorter LTL. The lack of association between LTL and time since HIV diagnosis, antiretroviral treatment, or degree of immune suppression would implicate HIV infection-related factors rather than disease progression or treatment. Smoking effects on LTL appear masked by HIV, and HCV infection may accelerate LTL shortening, particularly in coinfected individuals. The effect of early therapeutic intervention on LTL in HIV and HCV infections should be evaluated.

Does moderate or severe nonspecific knee injury affect radiographic osteoarthritis incidence and progression?

BACKGROUND: Knee injuries can lead to radiographic osteoarthritis (ROA). Injuries may be "specific" (SI) including ligament or meniscal tears or patellar trauma, or "nonspecific" (NSI). Our objective is to understand the effect of knee NSI on ROA incidence and progression. METHODS: 163 people (sample-weighted for population representativeness) aged 40+ with history of knee pain had radiographs assessed on Kellgren Lawrence (KL) grade (0/1 collapsed) at baseline and follow-up (median 3.2 years apart). Progression was an increase in KL score. SIs and NSIs were labeled "severe" (walking aid for ≥1 week) or "moderate". One model treated SI and NSI as dichotomous (yes/no), and another as trichotomous (none/moderate/severe). Models were adjusted for age, sex, BMI, KL grade and follow-up time. RESULTS: SI/NSI history was none, moderate (7.8/24.4%) or severe (11.0/10.8%). Duration at baseline since SI/NSI ranged from <1 year to several decades (SI/NSI mean 4.6/6.5 years). SI was significantly associated with ROA incidence and progression (odds ratio (OR) = 2.90; 95% CI = 1.04, 8.09), but NSI showed no significant effect (OR = 1.36; 95% CI = 0.61, 3.02). In the trichotomous model, severe SI was significant (OR = 4.35, 95% CI = 1.26, 15.02), while moderate SI was not (OR = 1.51, 95% CI = 0.33, 6.84). NSI showed no effect: moderate OR = 1.51, 95% CI = 0.61, 3.74; severe OR = 0.90, 95% CI = 0.24, 3.40. This study had 80% power to detect an NSI OR of 2.9. CONCLUSION: We find no evidence that history of NSI affects knee ROA incidence and progression in a population with knee pain, adjusting for SI, age, sex, BMI, KL grade and follow-up time.

Leukocyte telomere length in HIV-infected and HIV-exposed uninfected children: shorter telomeres with uncontrolled HIV viremia.

OBJECTIVES: Nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV antiretroviral therapy can inhibit human telomerase reverse transcriptase. We therefore investigated whether in utero or childhood exposure to NRTIs affects leukocyte telomere length (LTL), a marker of cellular aging. METHODS: In this cross-sectional CARMA cohort study, we investigated factors associated with LTL in HIV-1-infected (HIV(+)) children (n = 94), HIV-1-exposed uninfected (HEU) children who were exposed to antiretroviral therapy (ART) perinatally (n = 177), and HIV-unexposed uninfected (HIV(-)) control children (n = 104) aged 0-19 years. Univariate followed by multivariate linear regression models were used to examine relationships of explanatory variables with LTL for: a) all subjects, b) HIV(+)/HEU children only, and c) HIV(+) children only. RESULTS: After adjusting for age and gender, there was no difference in LTL between the 3 groups, when considering children of all ages together. In multivariate models, older age and male gender were associated with shorter LTL. For the HIV(+) group alone, having a detectable HIV viral load was also strongly associated with shorter LTL (p = 0.007). CONCLUSIONS: In this large study, group rates of LTL attrition were similar for HIV(+), HEU and HIV(-) children. No associations between children's LTL and their perinatal ART exposure or HIV status were seen in linear regression models. However, the association between having a detectable HIV viral load and shorter LTL suggests that uncontrolled HIV viremia rather than duration of ART exposure may be associated with acceleration of blood telomere attrition.

Vitamin D supplementation does not increase immunogenicity of seasonal influenza vaccine in HIV-infected adults.

The influence of vitamin D on influenza vaccine immunogenicity in HIV was assessed using data from a phase 3, randomized trial conducted during the 2008-2009 influ-enza season. Thirty-three percent of participants were on supplemental vitamin D at baseline. Neither seroconversion nor seroprotection were predicted by vitamin D use for any of the 3 vaccine strains. There is no evidence of improved influenza vaccine immunogenicity with vitamin D supplementation in this HIV-positive population.

Influenza vaccine oculorespiratory syndrome incidence is reduced in HIV.

Clinical experience suggests Oculorespiratory Syndrome (ORS) following influenza vaccination is rare in HIV but this is not well evaluated. We assessed ORS incidence in a randomized influenza vaccine trial of HIV participants. The overall incidence was 0.8% suggesting that influenza vaccine ORS incidence is reduced in HIV.

Immunogenicity is not improved by increased antigen dose or booster dosing of seasonal influenza vaccine in a randomized trial of HIV infected adults.

INTRODUCTION: The risk of poor vaccine immunogenicity and more severe influenza disease in HIV necessitate strategies to improve vaccine efficacy. METHODS: A randomized, multi-centered, controlled, vaccine trial with three parallel groups was conducted at 12 CIHR Canadian HIV Trials Network sites. Three dosing strategies were used in HIV infected adults (18 to 60 years): two standard doses over 28 days, two double doses over 28 days and a single standard dose of influenza vaccine, administered prior to the 2008 influenza season. A trivalent killed split non-adjuvanted influenza vaccine (Fluviral™) was used. Serum hemagglutinin inhibition (HAI) activity for the three influenza strains in the vaccine was measured to assess immunogenicity. RESULTS: 297 of 298 participants received at least one injection. Baseline CD4 (median 470 cells/µL) and HIV RNA (76% of patients with viral load <50 copies/mL) were similar between groups. 89% were on HAART. The overall immunogenicity of influenza vaccine across time points and the three influenza strains assessed was poor (Range HAI ≥ 40 =  31-58%). Double dose plus double dose booster slightly increased the proportion achieving HAI titre doubling from baseline for A/Brisbane and B/Florida at weeks 4, 8 and 20 compared to standard vaccine dose. Increased immunogenicity with increased antigen dose and booster dosing was most apparent in participants with unsuppressed HIV RNA at baseline. None of 8 serious adverse events were thought to be immunization-related. CONCLUSION: Even with increased antigen dose and booster dosing, non-adjuvanted influenza vaccine immunogenicity is poor in HIV infected individuals. Alternative influenza vaccines are required in this hyporesponsive population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00764998.

Frequency of bone marrow lesions and association with pain severity: results from a population-based symptomatic knee cohort.

OBJECTIVE: To evaluate the prevalence of bone marrow lesions (BML) and their association with pain severity in a population-based cohort of symptomatic early knee osteoarthritis (OA). METHODS: Subjects with knee pain (n = 255), age 40-79 years, were evaluated by radiograph and magnetic resonance imaging (MRI) and classified into OA stages: no OA (NOA), preradiographic OA (PROA), and radiographic OA (ROA). BML were graded 0-3 (none, mild, moderate, severe) in 6 regions and defined as (1) BMLsum = the sum of 6 scores; and (2) BMLmax = the worst score at any region. Pain was assessed by the Western Ontario and McMaster Universities OA Index (WOMAC). Linear regression analysis was completed to assess the association of Total WOMAC Pain (primary outcome) versus BMLsum or BMLmax. Secondary outcomes were WOMAC Pain on Walking and WOMAC Pain on Climbing Stairs. All analyses were adjusted for age, sex, body mass index, OA stage, joint effusion, and meniscal damage. RESULTS: BML were present in 11% of NOA, 38% of PROA, and 71% of ROA subjects (p < 0.001). No association was seen for BMLsum or BMLmax versus Total WOMAC Pain or Pain on Walking. However, BMLsum was associated with Pain on Climbing Stairs [regression coefficients (RC) = 0.09, 95% CI 0.00-0.18]. BMLmax was associated with Pain on Climbing Stairs, with the strongest association for severe BML (RC 0.60, 95% CI 0.04-1.17). CONCLUSION: BML were present in 38% of PROA and 71% of ROA subjects in this symptomatic knee cohort. BML were significantly associated with Pain on Climbing Stairs but not Total WOMAC or Pain on Walking.

Association of clinical findings with pre-radiographic and radiographic knee osteoarthritis in a population-based study.

OBJECTIVE: To determine the prevalence of pre-radiographic osteoarthritis (ROA) and ROA of the knee in a symptomatic population-based cohort, and to evaluate the clinical correlates of pre-ROA and ROA. METHODS: Subjects ages 40-79 years with knee pain were recruited as a random population sample and classified using magnetic resonance cartilage (MRC) scores (range 0-4) and Kellgren/Lawrence (K/L) scale grades (range 0-4) as no OA (MRC score<2, K/L grade<2), pre-ROA (MRC score ≥2, K/L grade<2), and ROA (MRC score≥2, K/L grade≥2). Logistic regression was used to evaluate the association of clinical variables with cartilage defects, comparing subjects with any cartilage defects (pre-ROA/ROA) with those without, and to determine associations with individual OA subgroups. RESULTS: Of 255 symptomatic subjects, no OA, pre-ROA, and ROA were seen in 13%, 49%, and 38%, respectively. The prevalence of pre-ROA/ROA compared with no OA was associated with age (odds ratio [OR] 2.89, 95% confidence interval [95% CI] 1.59-5.26), sports activity (OR 1.35, 95% CI 1.07-1.70), abnormal gait (OR 10.86, 95% CI 1.46-1,388.4), effusion (OR 16.58, 95% CI 2.22-2,120.5), and flexion contracture (OR 2.37, 95% CI 1.50-3.73). The prevalence of ROA versus no OA was significantly associated with age, body mass index, pain frequency, pain duration, severe knee injury, sports activity, gait, effusion, bony swelling, crepitus, flexion contracture, and flexion. The prevalence of pre-ROA versus no OA was increased with age, sports activity, effusion, and flexion contracture, and reduced with valgus malalignment. CONCLUSION: Cartilage defects were highly prevalent in this symptomatic population-based cohort, with 49% of subjects having pre-ROA and 38% having ROA. Prevalent cartilage defects were significantly associated with age, sports activity, abnormal gait, effusion, and flexion contracture.

Association of biomarkers with pre-radiographically defined and radiographically defined knee osteoarthritis in a population-based study.

OBJECTIVE: To evaluate 10 biomarkers in magnetic resonance imaging (MRI)-determined, pre-radiographically defined osteoarthritis (pre-ROA) and radiographically defined OA (ROA) in a population-based cohort of subjects with symptomatic knee pain. METHODS: Two hundred one white subjects with knee pain, ages 40-79 years, were classified into OA subgroups according to MRI-based cartilage (MRC) scores (range 0-4) and Kellgren/Lawrence (K/L) grades of radiographic severity (range 0-4): no OA (MRC score 0, K/L grade<2), pre-ROA (MRC score>or=1, K/L grade<2), or ROA (MRC score>or=1, K/L grade>or=2). Urine and serum samples were assessed for levels of the following biomarkers: urinary biomarkers C-telopeptide of type II collagen (uCTX-II), type II and types I and II collagen cleavage neoepitopes (uC2C and uC1,2C, respectively), and N-telopeptide of type I collagen, and serum biomarkers sC1,2C, sC2C, C-propeptide of type II procollagen (sCPII), chondroitin sulfate 846 epitope, cartilage oligomeric matrix protein, and hyaluronic acid. Multicategory logistic regression was performed to evaluate the association of OA subgroup with individual biomarker levels and biomarker ratios, adjusted for age, sex, and body mass index. RESULTS: The risk of ROA versus no OA increased with increasing levels of uCTX-II (odds ratio [OR] 3.12, 95% confidence interval [95% CI] 1.35-7.21), uC2C (OR 2.13, 95% CI 1.04-4.37), and uC1,2C (OR 2.07, 95% CI 1.06-4.04), and was reduced in association with high levels of sCPII (OR 0.53, 95% CI 0.30-0.94). The risk of pre-ROA versus no OA increased with increasing levels of uC2C (OR 2.06, 95% CI 1.05-4.01) and uC1,2C (OR 2.06, 95% CI 1.12-3.77). The ratios of type II collagen degradation markers to collagen synthesis markers were better than individual biomarkers at differentiating the OA subgroups, e.g., the ratio of [uCTX-II][uC1,2C] to sCPII was associated with a risk of ROA versus no OA of 3.47 (95% CI 1.34-9.03) and a risk of pre-ROA versus no OA of 2.56 (95% CI 1.03-6.40). CONCLUSION: Different cartilage degradation markers are associated with pre-ROA than are associated with ROA, indicating that their use as diagnostic markers depends on the stage of OA. Biomarker ratios contrasting cartilage degradation with cartilage synthesis are better able to differentiate OA stages compared with levels of the individual markers.

Reliability of the hip examination in osteoarthritis: effect of standardization.

OBJECTIVE: To assess the reliability of the physical examination of the hip in osteoarthritis (OA) among rheumatologists and orthopedic surgeons, and to evaluate the benefits of standardization. METHODS: Thirty-five physical signs and techniques were evaluated using a 6 x 6 Latin square design. Subjects with mild to severe hip OA, based on physical and radiographic signs, were examined in random order prior to and following standardization of physical examination techniques. For dichotomous signs, agreement was calculated as the prevalence-adjusted bias-adjusted kappa (PABAK), whereas for continuous and ordinal signs a reliability coefficient was calculated using analysis of variance. A PABAK >0.60 and a reliability coefficient >0.80 were considered to indicate adequate reliability. RESULTS: Adequate post-standardization reliability was achieved for 25 (71%) of 35 signs. The most highly reliable signs included true and apparent leg length discrepancy > or =1.5 cm; hip flexion, abduction, adduction, and extension strength; log roll test for hip pain; internal rotation and flexion range of motion; and Thomas test for flexion contracture. The standardization process was associated with substantial improvements in reliability for a number of physical signs, although minimal or no change was noted for some. Only 1 sign, Trendelenburg's sign, was highly unreliable post-standardization. CONCLUSION: With the exception of gait, a comprehensive hip examination can be performed with adequate reliability. Post-standardization reliability is improved compared with pre-standardization reliability for some physical signs. The application of these findings to future OA studies will contribute to improved outcome assessments in OA.