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.

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.

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 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.

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.

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.

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.

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.

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.

Symmetry and clustering of symptomatic hand osteoarthritis in elderly men and women: the Framingham Study.

OBJECTIVE: While symmetry and clustering of radiographic hand osteoarthritis (OA) have been described in middle-aged women, these have not been studied in elderly individuals and similar investigations are lacking for symptomatic hand OA. The goal of this study was to study patterns of joint involvement in symptomatic hand OA among elderly Caucasian men and women. METHODS: Using data from the Framingham Osteoarthritis Study, we defined a joint as having symptomatic OA if it had symptoms and radiographic OA (Kellgren and Lawrence grade > or =2). We assessed clustering of symptomatic OA using a chi(2)-test and evaluated the interrelationship of occurrence of symptomatic OA among different joints with generalized estimating equations. RESULTS: Of 976 subjects (age 71-99 yr, 36% men) examined, symptomatic OA more often affected multiple hand joints in an individual than would be expected by chance (P<0.001). The presence of symptomatic OA at a particular joint was strongly associated with symptomatic OA in the same joint of the opposite hand, followed by other joints in the same row of the same hand, and then other joints in the same ray of the same hand. The symmetrical pattern of symptomatic OA was more apparent in women than in men. CONCLUSION: Our study demonstrates that symptomatic OA often affects multiple hand joints, and is more likely to cluster by row than by ray. The disease also occurs in a remarkably symmetrical pattern, especially in women.

Effect of dose-intensive intravenous melphalan and autologous blood stem-cell transplantation on al amyloidosis-associated renal disease.

BACKGROUND: Dose-intensive intravenous melphalan with autologous blood stem-cell transplantation induces remission of the plasma cell dyscrasia in a substantial proportion of patients with AL amyloidosis. The impact of this treatment on associated renal disease is not known. OBJECTIVE: To determine the effect of dose-intensive intravenous melphalan and autologous blood stem-cell transplantation on AL amyloidosis-associated renal disease. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENTS: 65 patients with AL amyloidosis and urinary protein excretion greater than 1 g/24 h who received dose-intensive intravenous melphalan and autologous blood stem-cell transplantation between 1 July 1994 and 30 June 1998. MEASUREMENTS: 24-hour urinary protein excretion, serum cholesterol level, serum albumin level, creatinine clearance, urine and serum immunoelectrophoresis, and bone marrow biopsy. Renal response was defined as a greater than 50% reduction in urinary protein excretion in the absence of a 25% or greater reduction in creatinine clearance. Complete hematologic response was defined as absence of detectable monoclonal protein in serum and urine and a bone marrow specimen containing less than 5% plasma cells without clonal dominance of kappa or lambda isotype. RESULTS: Among the 50 patients who survived for at least 12 months, proteinuria, hypoalbuminemia, and hypercholesterolemia improved during follow-up; 36% met criteria for a renal response. Median 24-hour urinary protein excretion decreased from a baseline value of 9.6 g/24 h to 1.6 g/24 h at 12 months among patients with complete hematologic response, and 71% met criteria for a renal response. Twenty-hour urinary protein excretion did not decrease during follow-up among patients with persistent plasma cell disease, and only 11% had a renal response at 12 months (P < 0.001 for hematologic responders vs. nonresponders). CONCLUSION: Dose-intensive intravenous melphalan with autologous blood stem-cell transplantation improves the nephrotic syndrome in patients with AL amyloidosis-associated renal disease. The benefit is largely limited to patients achieving eradication of the underlying plasma cell dyscrasia.

Problems in the development and validation of questionnaire-based screening instruments for ascertaining cases with symptomatic knee osteoarthritis: the Framingham Study.

OBJECTIVE: To determine if screening for symptomatic knee osteoarthritis (OA) for clinical trials and epidemiologic studies could be satisfactorily done without performing knee radiographs and to develop efficient screening instruments for symptomatic knee OA based on self-reported symptoms and functional limitations. METHODS: We administered a mailed questionnaire containing many different questions on knee symptoms and functional limitations to 1,921 participants of the Framingham Study who had previously been screened for symptomatic OA with a history and knee radiographs. Recursive partitioning methods (using the Classification and Regression Trees [CART] program) were used to create a set of screening instruments for symptomatic knee OA, which was defined as knee symptoms on most days and radiographic evidence of OA. Three screening instruments were developed to maximize the sensitivity, specificity, and efficiency. RESULTS: The sensitive instrument had 84% sensitivity and 73% specificity. The specific instrument had 46% sensitivity and 94% specificity. The efficient instrument had 56% sensitivity and 85% specificity. Sensitivity was lower and specificity was higher when these instruments were used to screen for radiographic OA. All instruments had higher sensitivity but lower specificity when used for older subjects (age >60) with greater disease prevalence. However, using any of these instruments as a single-step screening mechanism resulted in considerable misclassification. CONCLUSION: We conclude that none of these instruments has adequate diagnostic test performance to serve as a single-step evaluation of the presence or absence of symptomatic knee OA.

Use of the Americans with Disabilities Act by persons with rheumatic diseases and factors associated with use.

OBJECTIVE: This study examined use of the Americans With Disabilities Act (ADA) among persons with rheumatic diseases and assessed which factors were associated with use. METHODS: A mail survey was conducted among adult patients recruited from 21 rheumatology practices. Subjects answered questions about their inclination to use the ADA in the community or at work and about factors thought to be associated with use. The outcome was stage of behavior change, the behavior being use of the ADA. Ordinal logistic regression identified independent correlates of the outcome. RESULTS: Of 631 subjects, 47% experienced an ADA-resolvable barrier to community activity, and 63% of 183 employed subjects needed a job accommodation or experienced health discrimination. However, only 7% of the full sample and 10% of the employed subgroup had used the ADA. Factors associated with use were detailed knowledge, perception of being disabled, skill in requesting use, and health professional use suggestion. CONCLUSIONS: Although many persons with rheumatic diseases experience community barriers or need workplace accommodations, they currently underutilize the ADA. Use could be enhanced by health professional suggestion and referral or by community programs designed to address the factors identified.

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.

Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis.

CONTEXT: Glucosamine and chondroitin preparations are widely touted in the lay press as remedies for osteoarthritis (OA), but uncertainty about their efficacy exists among the medical community. OBJECTIVE: To evaluate benefit of glucosamine and chondroitin preparations for OA symptoms using meta-analysis combined with systematic quality assessment of clinical trials of these preparations in knee and/or hip OA. DATA SOURCES: We searched for human clinical trials in MEDLINE (1966 to June 1999) and the Cochrane Controlled Trials Register using the terms osteoarthritis, osteoarthrosis, degenerative arthritis, glucosamine, chondroitin, and glycosaminoglycans. We also manually searched review articles, manuscripts, and supplements from rheumatology and OA journals and sought unpublished data by contacting content experts, study authors, and manufacturers of glucosamine or chondroitin. STUDY SELECTION: Studies were included if they were published or unpublished double-blind, randomized, placebo-controlled trials of 4 or more weeks' duration that tested glucosamine or chondroitin for knee or hip OA and reported extractable data on the effect of treatment on symptoms. Fifteen of 37 studies were included in the analysis. DATA EXTRACTION: Reviewers performed data extraction and scored each trial using a quality assessment instrument. We computed an effect size from the intergroup difference in mean outcome values at trial end, divided by the SD of the outcome value in the placebo group (0.2, small effect; 0.5, moderate; 0.8, large), and applied a correction factor to reduce bias. We tested for trial heterogeneity and publication bias and stratified for trial quality and size. We pooled effect sizes using a random effects model. DATA SYNTHESIS: Quality scores ranged from 12.3% to 55.4% of the maximum, with a mean (SD) of 35.5% (12%). Only 1 study described adequate allocation concealment and 2 reported an intent-to-treat analysis. Most were supported or performed by a manufacturer. Funnel plots showed significant asymmetry (P< or =.01) compatible with publication bias. Tests for heterogeneity were nonsignificant after removing 1 outlier trial. The aggregated effect sizes were 0.44 (95% confidence interval [CI], 0.24-0.64) for glucosamine and 0.78 (95% CI, 0.60-0.95) for chondroitin, but they were diminished when only high-quality or large trials were considered. The effect sizes were relatively consistent for pain and functional outcomes. CONCLUSIONS: Trials of glucosamine and chondroitin preparations for OA symptoms demonstrate moderate to large effects, but quality issues and likely publication bias suggest that these effects are exaggerated. Nevertheless, some degree of efficacy appears probable for these preparations.