Associations between anterior knee pain and 2-year patellofemoral cartilage worsening: The MOST study.

OBJECTIVE: Anterior knee pain (AKP) is associated with patellofemoral osteoarthritis (PFOA), but longitudinal studies are lacking. If AKP precedes PFOA, it may create an opportunity to identify and intervene earlier in the disease process. The purpose of this study was to examine the longitudinal relation of AKP to worsening patellofemoral (PF) cartilage over two years. DESIGN: Participants were recruited from the Multicenter Osteoarthritis Study, a longitudinal study of individuals with or at risk for knee osteoarthritis (OA). Exclusion criteria included bilateral knee replacements, arthritis other than OA, and radiographic PFOA. At baseline, participants completed a knee pain map questionnaire and underwent knee magnetic resonance imaging (MRI). Imaging was repeated at 2-year follow-up. Exposure was presence of frequent AKP. Outcome was worsening cartilage damage in the PF joint defined as increase in MRI Osteoarthritis Knee Score from baseline to 2 years. Log-binomial models were used to calculate risk ratios (RR). RESULTS: One knee from 1083 participants (age 56.7 ± 6.6 years; body mass index 28.0 ± 4.9 kg/m2) was included. Frequent AKP and frequent isolated AKP were present at baseline in 14.5% and 3.6%, respectively. Frequent AKP was associated with an increased risk (RR: 1.78, 95% confidence interval: 1.21, 2.62) of 2-year worsening cartilage damage in the lateral PF compartment. No association was found between frequent AKP and worsening in the medial PF joint. CONCLUSION: Frequent AKP at baseline was associated with worsening cartilage damage in the lateral PF joint over 2 years.

Fatty acids and osteoarthritis: the MOST study.

OBJECTIVE: Inflammation worsens joint destruction in osteoarthritis (OA) and aggravates pain. Saturated and n-6 fatty acids (FAs) increase, whereas n-3 FAs reduce inflammation. We examined whether FA levels affected the development of OA. DESIGN: We studied participants from the Multicenter Osteoarthritis study (MOST) at risk of developing knee OA. After baseline, repeated knee x-rays and MRIs were obtained and knee symptoms queried through 60 month follow-up. Using baseline fasting samples, serum FAs were analyzed with standard assays. After excluding participants with baseline OA, we defined two sets of cases: those developing radiographic OA and those developing symptomatic OA (knee pain and radiographic OA). Controls did not develop these outcomes. Additionally, we examined worsening of MRI cartilage loss and synovitis and of knee pain using WOMAC and evaluated the number of hand joints affected by nodules. In regression models, we tested the association of each OA outcome with levels of saturated, n-3 and n-6 FAs adjusting for age, sex, BMI, education, race, baseline pain and depressive symptoms. RESULTS: We studied 260 cases with incident symptomatic and 259 with incident radiographic OA. Mean age was 61 years (61% women). We found no signficant nor suggestive associations of FA levels with incident OA (e.g., for incident symptomatic OA, OR per s.d. increase in n-3 FA 1.00 (0.85, 1.18) nor with any OA outcome in knee or hand. CONCLUSION: Despite previously described effects on systemic inflammation, blood levels of FAs were not associated with risk of later knee OA or other OA outcomes.

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.

The impact of alcohol use on tuberculosis treatment outcomes: a systematic review and meta-analysis.

Alcohol use is associated with increased risk of developing tuberculosis (TB) disease, yet the impact of alcohol use on TB treatment outcomes has not been summarized. We aimed to quantitatively review evidence of the relationship between alcohol use and poor TB treatment outcomes. We conducted a systematic review of PubMed, EMBASE, and Web of Science (January 1980-May 2018). We categorized studies as having a high- or low-quality alcohol use definition and examined poor treatment outcomes individually and as two aggregated definitions (i.e., including or excluding loss to follow-up [LTFU]). We analyzed drug-susceptible (DS-) and multidrug-resistant (MDR-) TB studies separately. Our systematic review yielded 111 studies reporting alcohol use as a predictor of DS- and MDR-TB treatment outcomes. Alcohol use was associated with increased odds of poor treatment outcomes (i.e., death, treatment failure, and LTFU) in DS (OR 1.99, 95% CI 1.57-2.51) and MDR-TB studies (OR 2.00, 95% CI 1.73-2.32). This association persisted for aggregated poor treatment outcomes excluding LTFU, each individual poor outcome, and across sub-group and sensitivity analyses. Only 19% of studies used high-quality alcohol definitions. Alcohol use significantly increased the risk of poor treatment outcomes in both DS- and MDR-TB patients. This study highlights the need for improved assessment of alcohol use in TB outcomes research and potentially modified treatment guidelines for TB patients who consume alcohol.

The sensitivity to change for lower disease activity is greater than for higher disease activity in rheumatoid arthritis trials.

OBJECTIVE: To test whether rheumatoid arthritis (RA) trials treatment efficacy versus control is better detected for patients with lower tender joint counts (TJC) or swollen joint counts (SJC) than for higher counts. METHODS: Using data from six large multicentre trials (N = 2002) and an intent-to-treat approach at 6 months, two subtrials were created within each trial, the lower disease activity group (defined by TJC less than overall median) and the higher disease activity group. The same approach was used for SJC. Active treatment was tested for treatment control differences using several RA trial outcome measures: ACR20, EULAR response, ACRHybrid. Sample sizes needed for higher TJC and SJC RA trials versus lower TJC and SJC trials were compared. RESULTS: Subtrials of subjects with lower TJC were found to have much higher sensitivity to change than those of subjects with higher TJC across all trials and outcome measures. A trial with lower TJC patients would require a smaller sample size than those with higher TJC patients. Results were not consistent for SJC subgroups. Three reasons were found for sensitivity to change of lower TJC: compared with higher TJC, those with lower TJC showed greater response to active treatment. SUBJECTS: with higher TJC on control treatment had greater percentage improvement and more variable responses than those in the lower TJC group. CONCLUSIONS: In RA trials, patients with lower disease activity within the range of current trial eligibility are more likely to show treatment efficacy than patients with higher disease activity. Lowering thresholds especially for TJC in trials may make it easier to detect treatment effects in RA.

Premorbid knee osteoarthritis is not characterised by diffuse thinness: the Framingham Osteoarthritis Study.

OBJECTIVE: It is hypothesised that, like low bone density and fracture, thin cartilage predisposes to osteoarthritis (OA). Inferences about the effects of cartilage thickness on the development of OA can be made by evaluating the status of an unaffected non-diseased contralateral knee, in persons with unilateral OA, which we shall label the "premorbid knee". The primary objective of this analysis was to compare cartilage thickness in premorbid knees with non-OA knees drawn from persons without any knee OA to determine if cartilage in the premorbid knee was thinner than in the knee drawn from someone without OA in either knee. METHODS: From 2002 to 2005, The Framingham Osteoarthritis Study recruited subjects without respect to OA from the community. We obtained posteroanterior, semiflexed and lateral films of both knees and knee magnetic resonance imaging to quantify cartilage volume in one knee. The cartilage plates of the patella, medial and lateral femur, medial and lateral tibia were quantified, using a 3D FLASH-water excitation sequence (in plane resolution 0.3x0.3 mm, 512 matrix, slice thickness 1.5 mm) and digital post-processing, involving three-dimensional reconstruction. Radiographs were used to define the OA status of knees with disease defined as Kellgren and Lawrence grade > or = 2 and or patellofemoral OA on the lateral film. Of 1020 participants included in this analysis, 720 had no OA in either knee (no-knee OA sample), and 55 subjects had no OA in the knee that was examined using magnetic resonance imaging and OA in the contralateral knee (premorbid knee OA sample). We compared cartilage thickness and percentage of cartilage coverage (total bone interface covered with cartilage) between these groups. After initial plate-specific univariate comparisons we performed a multiple regression to assess the association between OA status (premorbid versus no OA knee) and cartilage thickness adjusting for age, sex and body mass index. We used the Generalised Estimating Equation to account for correlation between plates. To further determine if the cartilage was diffusely thinned or had only increased areas of denuded cartilage, we removed plates with denuded areas (less than 95% cartilage coverage) from the analysis. RESULTS: 55% of subjects were women. There was no difference in cartilage thickness between the premorbid knees and the no-knee OA sample. After adjusting for age, sex and body mass index and removing plates with less than 95% coverage from the analysis, we found the same or even thicker cartilage in premorbid knees compared with the knee OA sample. CONCLUSIONS: Premorbid knees do not have diffuse cartilage thinness. Rather the cartilage is normal or thicker with denuded areas suggesting that this may be the initial pathology rather than diffuse thinning.

Low body mass index and latent tuberculous infection: a systematic review and meta-analysis.

BACKGROUND: The well-documented association between underweight and increased incidence of active tuberculosis (TB) has not been extended to incidence or prevalence of latent tuberculous infection (LTBI). DESIGN: After identifying studies that reported a categorical measure of body mass index (BMI) and used the tuberculin skin test (TST) or QuantiFERON®-TB Gold In-Tube (QFT) to measure LTBI, a maximum likelihood random-effects model was used to examine the pooled association between LTBI and low BMI (<18.5 kg/m2), compared with 1) normal BMI (18.5-25 kg/m2) and 2) a complementary group of all others, i.e., non-underweight subjects (BMI 18.5 kg/m2). RESULTS: Among studies using TST, the odds ratios (ORs) showed a slight, non-statistically significant decrease in the odds of TST positivity in underweight persons compared with both groups (non-underweight, OR 0.88, 95%CI 0.73-1.05; normal weight, OR 0.96, 95%CI 0.77-1.20). Among studies using QFT, the OR suggested slightly decreased, yet non-significant, odds of QFT positivity in underweight compared with non-underweight subjects (OR 0.92, 95%CI 0.68-1.26), and significantly decreased odds of QFT positivity in underweight compared with normal weight subjects (OR 0.84, 95%CI 0.73-0.98). CONCLUSION: These results suggest that underweight persons are not at an increased risk of LTBI. Screening this population for LTBI would not increase the yield of identified LTBI.

Electrophysiologic abnormalities in AL (primary) amyloidosis with cardiac involvement.

OBJECTIVES: This study sought to determine the spectrum of electrophysiologic abnormalities found in patients with cardiac involvement due to AL (primary) amyloidosis and to evaluate the prognostic implications, particularly in relation to subsequent sudden death. BACKGROUND: Only case reports, but no series of invasive electrophysiologic studies, exist in patients with cardiac AL. METHODS: Twenty-five patients with biopsy-proven AL and cardiac involvement underwent standard invasive electrophysiologic studies. RESULTS: The function of the sinus and the atrioventricular node was preserved in most patients, but the infra-His (HV) conduction times were usually abnormal. The mean (+/-SD) HV interval for the 25 patients was 79 +/- 18 ms (range 50 to 110), and 23 patients (92%) had an abnormally prolonged interval (> 55 ms). Marked HV prolongation (> or = 80 ms) occurred in 12 patients, 6 of whom had an interval > or = 100 ms. Among the 23 patients who died during follow-up, HV prolongation was the sole independent predictor of sudden death by multivariate analysis (p = 0.05). CONCLUSIONS: Patients with cardiac AL are prone to disease in the His-Purkinje system. Prolongation of the HV interval is common and may not be suspected from the surface electrocardiogram in the presence of a narrow QRS complex. These patients have a high prevalence of sudden death, of which the HV interval is an independent predictor. The association of HV prolongation and sudden death is probably multifactorial, representing either a marker of severe myocardial infiltration with an increased propensity to lethal ventricular arrhythmias or electromechanical dissociation, or indicating severe conduction system disease eventually leading to complete atrioventricular block and bradycardic death.

Liver X receptors contribute to periodontal pathogen-elicited inflammation and oral bone loss.

Periodontal diseases are chronic oral inflammatory diseases that are polymicrobial in nature. The presence of specific bacteria in subgingival plaque such as Porphyromonas gingivalis is associated with microbial dysbiosis and the modulation of host immune response. Bacterially elicited innate immune activation and inflammation are key elements implicated in the destruction of soft and hard tissues supporting the teeth. Liver X receptors (LXRs) are nuclear hormone receptors with important function in lipid homeostasis, inflammation, and host response to infection; however, their contribution to chronic inflammatory diseases such as periodontal disease is not understood. The aim of this study was to define the contribution of LXRs in the development of immune response to P. gingivalis and to assess the roles that LXRs play in infection-elicited oral bone loss. Employing macrophages, we observed that P. gingivalis challenge led to reduced LXRα and LXRß gene expression compared with that observed with unchallenged wild-type cells. Myeloid differentiation primary response gene 88 (MyD88)-independent, Toll/interleukin-1 receptor-domain-containing adapter-inducing interferon-ß (TRIF)-dependent signaling affected P. gingivalis-mediated reduction in LXRα expression, whereas neither pathway influenced the P. gingivalis effect on LXRß expression. Employing LXR agonist and mice deficient in LXRs, we observed functional effects of LXRs in the development of a P. gingivalis-elicited cytokine response at the level of the macrophage, and participation of LXRs in P. gingivalis-elicited oral bone loss. These findings identify novel importance for LXRs in the pathogenesis of P. gingivalis infection-elicited inflammation and oral bone loss.

The validity of different definitions of radiographic worsening for longitudinal studies of knee osteoarthritis.

Several definitions have been used to characterize radiographic worsening of knee osteoarthritis in longitudinal studies, yet a valid definition with maximal power to detect differences between groups is not known. We used serial radiographs from the Framingham Osteoarthritis Study to compare five dichotomous definitions according to construct validity (strength of association) and discriminant power (power to reject null hypotheses of no difference) for 1) known risk factors for knee osteoarthritis, and 2) development of new knee pain. For risk factors: definitions that included scores for osteophytes (bone spurs) showed good construct validity and discriminant power; a definition using the Kellgren and Lawrence grade of overall knee osteoarthritis was conservative with good construct validity but low discriminant power; a definition based solely on ordinal assessment of joint space narrowing had weak construct validity and low discriminant power. All definitions had comparably strong associations with the development of new knee pain. Similar associations with new knee pain were found when the analysis was confined to either knees with no osteoarthritis at baseline or knees with prevalent osteoarthritis, with increased standard errors for prevalent osteoarthritis. Use of any of these definitions, other than joint space narrowing alone, would permit detection of associations with most known risk factors. Definitions incorporating both osteophytes and joint space narrowing offer the most precise estimation of the association of risk factors with disease worsening.

A consumer's guide to meta-analysis.

The same proponent of meta-analysis who feels that it offers the highest level of evidence of treatment efficacy has also warned that "it is easy to do a meta-analysis; it is hard to do one well" (1). This paper has listed a series of issues that should be addressed in the construction of a good meta-analysis. A meta-analysis protocol needs to be prepared. A concerted effort should be made to capture all published and unpublished studies that address the research question. These studies should then be compared to the inclusion and exclusion criteria from the protocol to determine which will be used in the meta-analysis. A random effects analysis should be performed on the studies. A test of the homogeneity of studies should be done. Funnel plots and the tolerance for null results should be computed to assess publication biases. Finally, sensitivity analyses should be performed. All of these issues need to be discussed in the report of the meta-analysis so that readers can judge the validity of the conclusions.

Statistical and study design issues in assessing the quality and outcomes of care in rheumatic diseases.

As we have pointed out in this article, a health care study should have a well-defined intent that is matched to the study type, population of interest, and outcome. Care must be taken to collect samples in a meaningful way, so that results can be generalized to larger populations. Outcomes must be selected carefully to ensure that they will be sensitive to the types of care being considered, and only a few main outcomes should be selected so as to preserve the level of statistical significance of the research results. Sample sizes should be sufficient to detect an effect of reasonable size, after accounting for attrition in longitudinal studies and rates of occurrence with dichotomous outcomes. If the study purpose is to compare multiple institutions or health care providers, statistical adjustments for case mix will generally be required. Outcome research is an expanding area of development for rheumatology care and for medical care in general. It offers the promise of the use of administrative data bases to answer questions that are important both to arthritis researchers and to consumers of rheumatology care. As with all areas of clinical research, we must maintain appropriate levels of statistical rigor to protect the integrity of the results. Inadequate attention to the design and analysis of data can compromise research results before a study even gets started, and health care research studies have as many potential statistical pitfalls as other types of clinical research.

Familial and primary (AL) cardiac amyloidosis: echocardiographically similar diseases with distinctly different clinical outcomes.

OBJECTIVE: To determine whether patients with myocardial amyloidosis due either to AL (primary) amyloid or familial amyloid have distinguishing echocardiographic or electrocardiographic features; and to compare the prevalence of heart failure and survival in the two types of amyloidosis in relation to echocardiographic findings. DESIGN: Blinded group comparison of randomly selected cases of cardiac amyloidosis. SETTING: International referral centre for amyloid research and treatment. PATIENTS: 36 patients with cardiac amyloid heart disease, of whom 12 had familial and 24 had primary AL amyloidosis. RESULTS: Familial and AL echocardiograms were morphologically indistinguishable, with similar left ventricular wall thickness, mean (SD) 15.4 (2.3) nu 15.8 (2.5) mm, respectively; right ventricular wall thickness was also similar between amyloid types: 9.6 (2.8) nu 9.7 (6.5) mm, respectively. Doppler indices of left and right ventricular function, left ventricular volume, and ejection fraction were also similar. Low voltage electrocardiograms (< 0.5 mV) were more common in the AL (16/24, 67%) than in the familial group (4/12, 25%), P < 0.05. The one year survival for familial and AL forms was 92% (11/12) nu 38% (6/24), respectively, with virtually all deaths due to cardiac causes. CONCLUSIONS: Although cardiac involvement is echocardiographically indistinguishable, cardiac mortality is very different between the two forms of amyloidosis. Preservation of electrocardiographic voltage in familial amyloidosis suggests that the particular biochemical characteristics of distinct types of amyloid fibril have different pathological effects on the myocardium. This distinction becomes critical in the evaluation, treatment, and management of patients who have a diagnosis within the spectrum of the protein deposition diseases.

Complete anterior cruciate ligament tear and the risk for cartilage loss and progression of symptoms in men and women with knee osteoarthritis.

OBJECTIVE: To determine whether a complete anterior cruciate ligament (ACL) tear, a frequent incidental finding on magnetic resonance imagings (MRIs) of individuals with established knee osteoarthritis (OA), increases the risk for further knee OA progression. METHODS: We examined 265 participants (43% women) with symptomatic knee OA in a 30-month, prospective, natural history study of knee OA. The more symptomatic knee was imaged using MRI at baseline, 15 and 30 months. Cartilage was scored at the medial and lateral tibiofemoral joint and at the patellofemoral joint using the Whole-Organ MRI Score (WORMS) semi-quantitative method. Complete ACL tear was determined on baseline MRI. At each visit, knee pain was assessed using a knee-specific visual analog scale and physical function was assessed using the Western Ontario and McMaster Universities (WOMAC) physical function subscale. RESULTS: There were 49 participants (19%) with complete ACL tear at baseline. Adjusting for age, body mass index, gender and baseline cartilage scores, complete ACL tear increased the risk for cartilage loss at the medial tibiofemoral compartment [odds ratio (OR): 1.8, 95% confidence interval (CI): 1.1, 3.2]. However, following adjustment for the presence of medial meniscal tears, no increased risk for cartilage loss was further seen (OR: 1.1, 95% CI: 0.6, 1.8). Knee pain and physical function were similar over follow-up between those with and without a complete ACL tear. CONCLUSIONS: Individuals with knee OA and incidental complete ACL tear have an increased risk for cartilage loss that appears to be mediated by concurrent meniscal pathology. The presence of a complete ACL tear did not influence the level of knee pain or physical function over short-term follow-up.

Cigarette smoking and the risk for cartilage loss and knee pain in men with knee osteoarthritis.

OBJECTIVE: To examine the effects of smoking on cartilage loss and pain at the knee in individuals with knee osteoarthritis. METHODS: 159 men with symptomatic knee osteoarthritis who participated in a 30-month, prospective, natural history study of knee osteoarthritis were examined. The more symptomatic knee was imaged using magnetic resonance imaging (MRI) at baseline, and again at 15 and 30 months of follow-up. Cartilage was scored using the Whole-Organ MRI Score semiquantitative method at the medial and lateral tibiofemoral joints and at the patellofemoral joint. At baseline and follow-up visits, the severity of knee pain was assessed using a Visual Analogue Scale pain score (0-100 mm). RESULTS: Among the 159 men, 19 (12%) were current smokers at baseline. Current smokers were younger (mean (standard deviation (SD)) age 62 (9) v 69 (9) years) and leaner (mean (SD) body mass index (BMI): 28.9 (3.2) v 31.3 (4.8) kg/m(2)) than men who were not current smokers. When adjusted for age, BMI and baseline cartilage scores, men who were current smokers were found to have an increased risk for cartilage loss at the medial tibiofemoral joint (odds ratio (OR) 2.3, 95% confidence interval (CI) 1.0 to 5.4) and the patellofemoral joint (OR 2.5, 95% CI 1.1 to 5.7). Current smokers also had higher adjusted pain scores at baseline (60.5 v 45.0, p<0.05) and at follow-up (59.4 v 44.3, p<0.05) than men who were not current smokers. CONCLUSIONS: Men with knee osteoarthritis who smoke sustain greater cartilage loss and have more severe knee pain than men who do not smoke.

Urinary pentosidine does not predict cartilage loss among subjects with symptomatic knee OA: the BOKS Study.

OBJECTIVE: Age-related changes in articular cartilage are likely to play a role in the etiology of osteoarthritis (OA). One of the major changes in the extracellular matrix of cartilage is the age-related accumulation of advanced glycation end products (AGEs). Pentosidine, an AGE crosslink, is one of the few characterized AGEs and is considered an adequate marker for the many AGEs that are formed in vivo. We used data from a longitudinal observation study to determine if urinary pentosidine could serve as a marker to predict cartilage loss. METHODS: We conducted a prospective analysis of data from the Boston Osteoarthritis of the Knee Study (BOKS); a completed natural history study of knee OA. All subjects in the study met American College of Rheumatology (ACR) criteria for knee OA. Knee magnetic resonance (MR) images were scored for cartilage in 14 plates of the knee using the Whole Organ Magnetic Resonance Imaging Score (WORMS) semiquantitative grading scheme. Within the BOKS population, a nested sample of 127 subjects (39% of the whole sample) who had both baseline pentosidine and longitudinal magnetic resonance imaging (MRI) measurements (MRIs performed at baseline and 30 months later) was assessed. Urinary pentosidine was assayed and normalized to creatinine to account for differences in urine concentrations. We analyzed the data using three different methods to assess if baseline measures of pentosidine predicted subsequent cartilage loss on MRI. These were (1) analysis 1: logistic regression with the outcome cartilage loss in any plate; (2) analysis 2: proportional odds model where the outcome was defined as 0=no cartilage loss, 1=cartilage loss in one plate, 2=cartilage loss in two plates, and 3=cartilage loss in at least three plates; and (3) analysis 3: Poisson regression with the outcome the number of plates with cartilage loss. All analyses were adjusted for age, sex and Body Mass Index (BMI). RESULTS: At baseline the mean (standard deviation) age was 67 (9) years and 54% were male. The results for the three analytic steps are as follows: Analysis 1: the odds ratio for cartilage loss is 1.01 (95% confidence interval (CI) 0.93-1.09) with 1 unit increase in pentosidine. Analysis 2: the odds ratio for more cartilage loss is 0.99 (95% CI 0.92-1.06) with 1 unit increase in pentosidine. Analysis 3: the relative number of plates with cartilage loss decreased was 1.00 (95% CI 0.95-1.03) with a 1 unit increase in pentosidine. CONCLUSION: Urinary pentosidine does not predict knee cartilage loss. Previous studies have suggested that local content within cartilage of AGEs is elevated in persons at high risk for progression. Our data suggest that these changes are not measurable systemically. Alternatively, urinary pentosidine levels reflect cartilage degradation in all joints (thus whole body cartilage breakdown) and may therefore not relate to OA severity in a single knee joint.

Change in joint space width: hyaline articular cartilage loss or alteration in meniscus?

OBJECTIVE: To explore the relative contribution of hyaline cartilage morphologic features and the meniscus to the radiographic joint space. METHODS: The Boston Osteoarthritis of the Knee Study is a natural history study of symptomatic knee osteoarthritis (OA). Baseline and 30-month followup assessments included knee magnetic resonance imaging (MRI) and fluoroscopically positioned weight-bearing knee radiographs. Cartilage and meniscal degeneration were scored on MRI in the medial and lateral tibiofemoral joints using a semiquantitative grading system. Meniscal position was measured to the nearest millimeter. The dependent variable was joint space narrowing (JSN) on the plain radiograph (possible range 0-3). The predictor variables were MRI cartilage score, meniscal degeneration, and meniscal position measures. We first conducted a cross-sectional analysis using multivariate regression to determine the relative contribution of meniscal factors and cartilage morphologic features to JSN, adjusting for body mass index (BMI), age, and sex. The same approach was used for change in JSN and change in predictor variables. RESULTS: We evaluated 264 study participants with knee OA (mean age 66.7 years, 59% men, mean BMI 31.4 kg/m(2)). The results from the models demonstrated that meniscal position and meniscal degeneration each contributed to prediction of JSN, in addition to the contribution by cartilage morphologic features. For change in medial joint space, both change in meniscal position and change in articular cartilage score contributed substantially to narrowing of the joint space. CONCLUSION: The meniscus (both its position and degeneration) accounts for a substantial proportion of the variance explained in JSN, and the change in meniscal position accounts for a substantial proportion of change in JSN.

Lack of association between chondrocalcinosis and increased risk of cartilage loss in knees with osteoarthritis: results of two prospective longitudinal magnetic resonance imaging studies.

OBJECTIVE: To evaluate the relationship between chondrocalcinosis and the progression of knee osteoarthritis (OA) using longitudinal magnetic resonance imaging (MRI) assessments. METHODS: Longitudinal knee MRIs were obtained in the Boston OA Knee Study (BOKS) and in the Health, Aging and Body Composition (Health ABC) Study. Chondrocalcinosis was determined as present or absent on baseline knee radiographs. Cartilage morphology was graded on paired longitudinal MRIs using the Whole-Organ Magnetic Resonance Imaging Score in 5 cartilage subregions of each of the medial and lateral tibiofemoral joints. Cartilage loss in a subregion was defined as an increase in the cartilage score of > or = 1 (0-4 scale). The risk for change in the number of subregions with cartilage loss was assessed using Poisson regression, with generalized estimating equations to account for correlations. Analyses were adjusted for age, sex, body mass index, baseline cartilage score, and presence of damaged menisci. RESULTS: In BOKS, 23 of the 265 included knees (9%) had chondrocalcinosis. In Health ABC, 373 knees were included, of which 69 knees (18.5%) had chondrocalcinosis. In BOKS, knees with chondrocalcinosis had a lower risk of cartilage loss compared with knees without chondrocalcinosis (adjusted risk ratio [RR] 0.4, 95% confidence interval [95% CI] 0.2-0.7) (P = 0.002), and there was no difference in risk in Health ABC (adjusted RR 0.9, 95% CI 0.6-1.5) (P = 0.7). Stratification by intact versus damaged menisci produced similar results within each cohort. CONCLUSION: In knees with OA, the presence of chondrocalcinosis was not associated with increased cartilage loss. These findings do not support the hypothesis that chondrocalcinosis worsens OA progression.

Osteophytes and progression of knee osteoarthritis.

OBJECTIVES: Osteophytes are thought to stabilize an osteoarthritic joint, thereby preventing structural progression. Meagre longitudinal data suggest, however, that they are associated with an increased risk of structural progression. Our objective was to evaluate the effect of osteophyte size on radiographic progression in osteoarthritis (OA). METHODS: Using data from a natural history study of persons with symptomatic knee OA, we obtained fluoroscopically positioned postero-anterior (PA) radiographs at baseline, 15 and 30 months. Using an atlas, osteophyte size was scored on a scale of 0-3 at each of four sites on the PA film and, for each knee, both compartment-specific (i.e. medial; lateral) and overall osteophyte scores were computed. Progression was defined as an increase over follow-up in medial or lateral joint space narrowing, based on a semiquantitative grading. Mechanical alignment was assessed using long limb films at the 15 month examination. Logistic regression was used to evaluate the relation of osteophyte size with progression, adjusting for age, gender and body mass index, and with and without adjustment for alignment. RESULTS: Of 270 subjects who had 470 eligible knees with follow-up, 104 (22%) knees showed progression. Overall, osteophyte score modestly increased the risk of progression [odds ratio (OR) per S.D. increase of osteophyte score=1.4 (95% CI 1.1, 1.8, P=0.02)], but this effect weakened and became non-significant after adjustment for limb alignment (OR=1.3). Compartment osteophyte score was strongly associated with malalignment to the side of the osteophyte (e.g. medial osteophyte and varus). Compartment-specific osteophyte score markedly increased the risk of ipsilateral progression (e.g. medial osteophytes --> medial progression) [OR per S.D.=1.9 (95% CI 1.5, 2.5, P<0.001)] and decreased the risk of contralateral progression [OR per S.D.= 0.6 (95% CI 0.5, 0.8, P=0.002)], but these associations diminished when we adjusted for limb alignment (OR=1.5 and 0.7 respectively). CONCLUSIONS: Large osteophytes do not affect the risk of structural progression. They are strongly associated with malalignment to the side of the osteophyte, and any relation they have with progression is partly explained by the association of malalignment with progression.

Nonparametric inference in factorial designs with censored data.

A method is proposed for testing the hypotheses of no main effects and no interaction in factorial designs with several observations per cell. The method uses the fact that these hypotheses can be expressed in terms of a vector of contrasts. It is based on the observation that nonparametric estimation of these contrasts is no more difficult than estimation of the location difference in the two-sample problem. To implement the method with censored data, a new extension of the Hodges-Lehmann estimator is proposed. The estimator is simple to compute and its variance is easily evaluated. A simulation study examines the performance of the proposed estimation and testing method in the context of a two-by-two design, and a real data set from a three-way layout with heavy censoring is analyzed.