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Osteoarthritis (OA) of the knee is a top cause of disability among the elderly. Total knee replacement (TKR) has been available as an effective and definite surgical method to treat severe OA of the knee. However, TKR is a significant procedure with potential risk for serious complications and high costs. Alternative lower risk therapies that can delay or obviate TKR are valuable to those who are poor candidates for surgery or wish to avoid TKR as long as possible. Given the chondroprotective effects of hyaluronic acid (HA) injections, they are a safe and effective treatment to improve pain, function, and longevity of the knee. Thus, HA features the potential to delay or obviate TKR. We aim to study the safety and effectiveness of repeated courses of HA on the time to TKR over a 3-year period using data from a large US health plan administrative claims database. Retrospective analyses were conducted by identifying knee OA patients during the selection period (2007-2010). The follow-up period was 36 months, post-index date of initial HA injection. Procedural outcomes and adverse events of interest were tabulated and analyzed. A Cox proportional hazards model was used to model the risk of TKR. A total of 50,389 patients who received HA for treatment of knee OA and met the study inclusion criteria were analyzed. Successive courses of HA showed a good safety profile and led to high proportions of patients without TKR 3 years after treatment initiation. Multivariate statistical modeling showed that multiple courses of HA injections significantly decreased the rates of TKR (95.0% without TKR for ≥5 courses vs 71.6% without TKR for 1 course; hazard ratio, 0.138; P < .0001). Repeated courses of treatment with HA are safe and are associated with the delay of TKR for up to 3 years. Additional research is needed to evaluate the effect of repeated HA courses on delaying TKR beyond a 3-year time horizon.

Background: Intra-articular injection of hyaluronic acid (HA) for knee osteoarthritis (OA) effectively reduces pain and delays total knee replacement (TKR) surgery; however, little is known about relative differences in clinical and cost outcomes among different HA products. Objective: To compare disease-specific costs and risk of TKR among patients receiving different HA treatments in a commercially insured cohort of patients with knee OA in the USA. Method: Retrospective analyses using IMS Health’s PharMetrics Plus Health Plan Claims Database were conducted by identifying knee OA patients with claims indicating initiation of HA treatment at an ‘index date’ during the selection period (2007–2010). Patients were required to be continuously enrolled in the database for 12 months preindex to 36 months postindex. A generalized linear model (GLM) with a gamma distribution and log-link function was used to model aggregate patient-based changes in disease-specific costs. A Cox proportional hazards model (PHM) was used to model the risk of TKR. Both multivariate models included covariates such as age, gender, comorbidities, and preindex healthcare costs. Results: 50,389 patients with HA treatment for knee OA were identified. 18,217 (36.2%) patients were treated with HA products indicated for five injections per treatment course (Supartz and Hyalgan). The remainder were treated with HA products indicated for fewer than five injections per treatment course, with 20,518 patients (40.7%) receiving Synvisc; 6,263 (12.4%), Euflexxa; and 5,391 (10.7%), Orthovisc. Synvisc- and Orthovisc-injected patients had greater disease-specific costs compared to Supartz/Hyalgan (9.0%, p

Objective: To assess the continued effectiveness and safety of Gel-200 following observation and open-label retreatment in an extension protocol following a randomized, double-blind, phosphate buffered saline (PBS)-controlled trial (initial treatment trial). Design: Patients who completed initial blinded treatment were allowed to enroll into this extension protocol that permitted retreatment with Gel-200 when eligibility criteria were met. Retreatment was administered with a Gel-200 injection, without knowledge of initial treatment assignment (Gel-200 or PBS). Retreated patients were followed for up to 13 weeks. In the extension phase, durability of response following the first injection was analyzed by time to retreatment eligibility. During separate extension and retreatment phases, responses were assessed by WOMAC pain, stiffness, and physical function subscores, total score, and global assessments of disease activity (patient, physician) as well as safety of Gel-200. Results: In the extension phase, time-to-event analyses through 26 weeks following the initial injection showed statistically significantly longer times to retreatment in patients receiving Gel-200 compared with PBS ( P < 0.05). Retreatment with Gel-200, e.g., a second injection, resulted in statistically significant improvements from retreatment baseline in all outcome measures ( P < 0.0001). The incidence and type of adverse events after retreatment were comparable to those observed following initial injection of Gel-200 without allergic reactions, including “pseudosepsis” or unanticipated treatment-related serious adverse events. Conclusions: These data demonstrate that a single injection of Gel-200 resulted in durable effectiveness through 26 weeks and that repeated treatment with Gel-200 relieved symptomatic osteoarthritis with a favorable safety profile.

Neurocognitive deficits are considered promising endophenotypes for gene discovery in schizophrenia. Understanding the heritability and genetic inter-relationships of neurocognitive traits could support their use as alternatives to diagnosis. Participants were 85 adults from 17 multiplex Canadian families with familial schizophrenia linked to 1q23 who had neurocognitive testing results available. Heritability of 13 standard measures assessing motor skills, processing speed, verbal, and visuospatial memory, attention/working memory, executive functioning, and IQ was estimated using variance component models and SOLAR software. We then investigated bivariate relationships between those variables found to be heritable. IQ showed the highest heritability (h(2) = 0.64-0.74) and seven other neurocognitive measures, reflecting immediate and delayed verbal memory, attention/working memory, delayed visual memory, processing speed and motor skills, showed significant heritability (h(2) = 0.31-0.62) under one or more of the models assessed. A schizophrenia diagnostic covariate was significant (P < 0.0001) for all heritable variables. Bivariate analyses suggested that memory-IQ and visuomotor-processing speed formed two groups of heritable traits. The results provide further evidence of the heritability of selected neurocognitive measures, and their relationship to schizophrenia and underlying genetic architecture. Composite measures of memory or processing speed may be heritable phenotypes useful for studies of neurocognition.

This paper summarizes the contributions of group 8 to the Genetic Analysis Workshop 15. Group 8 focused on ways to address the possibility that genetic and environmental effects on phenotype may not be independent, but instead may interact in ways that could play important roles in determining phenotype. Among the eight contributors to this group, all three data sets (expression data, rheumatoid arthritis data, and simulated data) were analyzed. Contributions to this section fell into the two broad categories of refining the data (e.g. stratifying or weighting based on a covariate value) and explicitly modeling the interactions. The contributions also illustrate that there are at least two possible goals for such studies. One goal is simply to identify factors contributing to phenotype in the presence of interactions that might mask the signal to univariate methods. A related but distinct goal is to characterize an interaction (e.g. to determine if the interaction is significant). Genet. Epidemiol. 31(Suppl. 1):S68–S74, 2007. © 2007 Wiley-Liss, Inc.

SummaryObjectiveTo compare the safety and efficacy of a single intra-articular (IA) injection of a new cross-linked hyaluronic acid product, Gel-200, with phosphate buffered saline (PBS, control) in a multi-center randomized controlled trial in patients with symptomatic osteoarthritis (OA) of the knee.DesignPatients were randomized 2:1 to receive a single injection of Gel-200 or PBS, after joint aspiration. The primary measure of effectiveness was Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscores by 100-mm Visual Analog Scale (VAS); secondary outcomes included: total WOMAC, physical function, and stiffness subscores; patient and physician global assessments of disease activity, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT–OARSI) strict responders, as well as safety of Gel-200.ResultsOf 379 patients randomized, safety was evaluated in 377 and efficacy in 375 (98.9% randomized) in the intent-to-treat population. Effectiveness of Gel-200 by WOMAC pain subscores was statistically significant at week 13 (P=0.037). Mean improvements from baseline in WOMAC pain subscores consistently favored Gel-200 at each visit. Effectiveness of Gel-200 treatment was statistically significant over weeks 3–13 by WOMAC total score, physical function, and physician global evaluations (P

Introduction Systemic lupus erythematosus is a genetically complex disease. Currently, the precise allelic polymorphisms associated with this condition remain largely unidentified. In part this reflects the fact that multiple genes, each having a relatively minor effect, act in concert to produce disease. Given this complexity, analysis of subclinical phenotypes may aid in the identification of susceptibility alleles. Here, we used flow cytometry to investigate whether some of the immune abnormalities that are seen in the peripheral blood lymphocyte population of lupus patients are seen in their first-degree relatives. Methods Peripheral blood mononuclear cells were isolated from the subjects, stained with fluorochrome-conjugated monoclonal antibodies to identify various cellular subsets, and analyzed by flow cytometry. Results We found reduced proportions of natural killer (NK)T cells among 367 first-degree relatives of lupus patients as compared with 102 control individuals. There were also slightly increased proportions of memory B and T cells, suggesting increased chronic low-grade activation of the immune system in first-degree relatives. However, only the deficiency of NKT cells was associated with a positive anti-nuclear antibody test and clinical autoimmune disease in family members. There was a significant association between mean parental, sibling, and proband values for the proportion of NKT cells, suggesting that this is a heritable trait. Conclusions The findings suggest that analysis of cellular phenotypes may enhance the ability to detect subclinical lupus and that genetically determined altered immunoregulation by NKT cells predisposes first-degree relatives of lupus patients to the development of autoimmunity.

Background Angiogenesis appears to be a first-order event in psoriatic arthritis (PsA). Among angiogenic factors, the cytokines vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and fibroblast growth factors 1 and 2 (FGF1 and FGF2) play a central role in the initiation of angiogenesis. Most of these cytokines have been shown to be upregulated in or associated with psoriasis, rheumatoid arthritis (RA) or ankylosing spondylitis (AS). As these diseases share common susceptibility associations with PsA, investigation of these angiogenic factors is warranted. Methods Two hundred and fifty-eight patients with PsA and 154 ethnically matched controls were genotyped using a Sequenom chip-based MALDI-TOF mass spectrometry platform. Four SNPs in the VEGF gene, three SNPs in the EGF gene and one SNP each in FGF1 and FGF2 genes were evaluated. Statistical analysis was performed using Fisher's exact test, and the Cochrane-Armitage trend test. Associations with haplotypes were estimated by using weighted logistic models, where the individual haplotype estimates were obtained using Phase v2.1. Results We have observed an increased frequency in the T allele of VEGF +936 (rs3025039) in control subjects when compared to our PsA patients [Fisher's exact p-value = 0.042; OR 0.653 (95% CI: 0.434, 0.982)]. Haplotyping of markers revealed no significant associations. Conclusion The T allele of VEGF in +936 may act as a protective allele in the development of PsA. Further studies regarding the role of pro-angiogenic markers in PsA are warranted.

Functional single nucleotide polymorphisms within the ectoplasmic domain of the Toll-like receptor 4 (TLR4) gene have been shown to result in an endotoxin-hyporesponsive phenotype and aberrant signal transduction for bacterial agonists. TLR4 is in proximity to a genome-wide linkage peak in 9q32-33. Given the proposed function and location of TLR4, we examined the association of 2 functional variants of TLR4 in patients with ankylosing spondylitis (AS) in Newfoundland.In total, 101 AS patients and 100 ethnically matched controls were genotyped, using the Sequenom MassArray platform, for 2 functional variants in the TLR4 gene: Asp299Gly (A/G polymorphism) and Thr399Ile (C/T polymorphism).The minor allele frequency for the Asp299Gly variant (G) was significantly higher in AS cases compared to controls (7.5% vs 2.6%, respectively; OR 3.10, p = 0.037). The minor allele frequency for the Thr399Ile variant (T) for cases and controls was 7.4% vs 3.0% (OR 2.59, p = 0.071). Haplotype analysis using Haploview noted a higher proportion of GT in the cases (for GT, chi-squared p = 0.023).Given the functional role of TLR4 variants in the innate immune system, larger studies are now warranted to elucidate the association of TLR4 variants in AS.

Objective To determine whether an elevated serum total cholesterol level in a first-available sample obtained at a systemic lupus erythematosus (SLE) clinic is associated with worse renal outcome in patients with SLE. Methods Survival analysis methods were used on prospectively gathered data on 1,060 patients with SLE who were registered in the University of Toronto Lupus Databank. The effect of total cholesterol and 15 additional variables on the outcomes of renal deterioration, end-stage renal disease (ESRD), and death was assessed using Cox proportional hazards methods. Results In 474 (45%) of the 1,060 patients, the total cholesterol level exceeded 5.2 mmoles/liter. In the entire study group, the median total cholesterol level was 5.1 mmoles/liter (range 1.6–17.1). During a mean followup period of 8.8 years, 93 patients (9%) experienced renal deterioration, 42 patients (4%) had ESRD, and 161 deaths occurred, 48 (30%) of which were associated with renal dysfunction (renal death), and 113 (70%) of which were not associated with renal dysfunction (nonrenal death). Kaplan-Meier survival estimates for each outcome were statistically significantly different between patients with normal versus those with elevated total cholesterol levels (cutoff 5.2 mmoles/liter), with a worse outcome observed among those with an elevated total cholesterol concentration. In multivariate analyses, total cholesterol level (hazard ratio [HR] 1.17, 95 confidence interval [95% CI] 1.01–1.36), serum creatinine level (HR 1.06, 95% CI 1.04–1.07), proteinuria (HR 2.44, 95% CI 1.25–4.76), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (HR 1.44, 95% CI 1.16–1.80), and corticosteroid dose (HR 1.01, 95% CI 1.00–1.02) were associated with renal deterioration. Significant predictors of ESRD were baseline proteinuria (HR 6.24, 95% CI 1.96–19.88) and serum creatinine level (HR 1.15, 95% CI 1.08–1.22). The total cholesterol level was correlated with death (HR 1.20, 95% CI 1.11–1.29), retaining statistical significance for renal death (HR 1.33, 95% CI 1.20–1.47) but not for nonrenal death (HR 1.12, 95% CI 0.99–1.25). Conclusion Those results indicate that an elevated serum total cholesterol level in a first-available sample obtained at an SLE clinic is associated with adverse renal outcomes and mortality.

We propose a multinomial logistic regression method which permits estimation and likelihood ratio tests for allele effects, their interactions with continuous covariates, and assessment of the degree of population stratification in genetic association studies of case-parent triads. Our approach overcomes the constraint imposed by the categorical nature of explanatory variables in the log-linear model. We also demonstrate that the multinomial logistic method can yield efficient inference in the presence of missing parental genotype data via the use of the Expectation-Maximization (EM) algorithm. We performed simulations to compare the multinomial logistic model with the case-pseudosibling conditional logistic model approach, both of which permit the incorporation of continuous covariates. Simulation results indicate that the multinomial logistic model and the conditional logistic model lead to similar estimates in large samples. A simulation-based method of sample size estimation is also used to show that the two models are approximately equivalent in sample size requirements. When parental genotype data are missing, either completely at random or dependent on covariates, the use of the EM algorithm gives multinomial logistic model greater power. Since the multinomial logistic model offers the possibility of assessing the degree of population stratification in the sample and can also provide efficient inference in the presence of missing parental genotypes, the proposed model has an important application in epidemiological family-based association studies.

Systemic lupus erythematosus is a genetically complex disease. Currently, the precise allelic polymorphisms associated with this condition remain largely unidentified. In part this reflects the fact that multiple genes, each having a relatively minor effect, act in concert to produce disease. Given this complexity, analysis of subclinical phenotypes may aid in the identification of susceptibility alleles. Here, we used flow cytometry to investigate whether some of the immune abnormalities that are seen in the peripheral blood lymphocyte population of lupus patients are seen in their first-degree relatives. Peripheral blood mononuclear cells were isolated from the subjects, stained with fluorochrome-conjugated monoclonal antibodies to identify various cellular subsets, and analyzed by flow cytometry. We found reduced proportions of natural killer (NK)T cells among 367 first-degree relatives of lupus patients as compared with 102 control individuals. There were also slightly increased proportions of memory B and T cells, suggesting increased chronic low-grade activation of the immune system in first-degree relatives. However, only the deficiency of NKT cells was associated with a positive anti-nuclear antibody test and clinical autoimmune disease in family members. There was a significant association between mean parental, sibling, and proband values for the proportion of NKT cells, suggesting that this is a heritable trait. The findings suggest that analysis of cellular phenotypes may enhance the ability to detect subclinical lupus and that genetically determined altered immunoregulation by NKT cells predisposes first-degree relatives of lupus patients to the development of autoimmunity.