Person:

Lu, Bing

Introduction: Obesity's association with hand osteoarthritis cannot be fully explained by mechanical loading. We examined the relationship between adipokines and radiographic hand osteoarthritis severity and pain. Methods: In a pilot study of 44 hand osteoarthritis patients (39 women and 5 men), serum adipokine concentrations and hand x-ray Kallman-scores were analyzed using linear regression models. Secondary analyses examined correlates of hand pain. Results: The cohort had a mean age of 63.5 years for women and 72.6 for men; mean (standard deviation) Kallman-scores were 43.3(17.4) for women and 46.2(10.8) for men. Mean body-mass-index was 30 kg/m2 for women and men. Mean leptin concentration was 32.2 ng/ml (women) and 18.5 ng/ml (men); mean adiponectin-total was 7.9 ng/ml (women) and 5.3 ng/ml (men); mean resistin was 7.3 ng/ml (women) and 9.4 ng/ml (men). No association was found between Kallman-scores and adipokine concentrations (R2 = 0.00–0.04 unadjusted analysis, all p-values>0.22). Secondary analyses showed mean visual-analog-scale pain of 4.8(2.4) for women and 6.6(0.9) for men. Leptin, BMI, and history of coronary artery disease were found to be associated with visual-analog-scale scores for chronic hand pain (R2 = 0.36 unadjusted analysis, p-values≤0.04). Conclusion: In this pilot study, we found that adipokine serum concentrations were not associated with hand osteoarthritis radiographic severity; the most important correlates of joint damage were age and disease duration. Leptin serum concentration, BMI, and coronary artery disease were associated with the intensity of chronic hand OA pain.

PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease. The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the activation of T cells has remained controversial. In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood. Here we report the identification of an alternative splice form of human PTPN22, namely PTPN22.6. It lacks the nearly entire phosphatase domain and can function as a dominant negative isoform of the full length PTPN22. Although conversion of R620 to W620 in the context of PTPN22.1 attenuated T cell activation, expression of the tryptophan variant of PTPN22.6 reciprocally led to hyperactivation of human T cells. More importantly, the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis. Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis.

Introduction: Remission is an important goal of therapy in rheumatoid arthritis (RA), but data on duration of remission are lacking. Our objective was to describe the duration of remission in RA, assessed by different criteria. Methods: We evaluated patients from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) not in remission at baseline with at least 2 years of follow-up. Remission was assessed according to the Disease Activity Score 28-C-reactive protein (DAS28-CRP4), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) scores, and the recently proposed American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) criteria for remission. Analyses were performed by using Kaplan-Meier survival curves. Results: We identified 871 subjects with ≥2 years of follow-up. Of these subjects, 394 were in remission at one or more time-points and not in remission at baseline, according to at least one of the following criteria: DAS28-CRP < 2.6 (n = 309), DAS28-CRP < 2.3 (n = 275), SDAI (n = 168), CDAI (n = 170), and 2010 ACR/EULAR (n = 158). The median age for the 394 subjects at entrance to BRASS was 56 years; median disease duration was 8 years; 81% were female patients; and 72% were seropositive. Survival analysis performed separately for each remission criterion demonstrated that < 50% of subjects remained in remission 1 year later. Median remission survival time was 1 year. Kaplan-Meier curves of the various remission criteria did not significantly differ (P = 0.29 according to the log-rank test). Conclusions: This study shows that in clinical practice, a minority of RA patients are in sustained remission.

Introduction: Hydroxychloroquine (HCQ) is a common disease modifying therapy for the treatment of rheumatoid arthritis (RA). Prior research suggests that HCQ may reduce the risk of diabetes mellitus in patients with RA. To investigate the mechanism of this effect, we examined the effect of HCQ on insulin resistance, insulin sensitivity, and pancreatic β-cell secretion of insulin in non-diabetic, obese subjects. Methods We recruited 13 obese, non-diabetic subjects without systemic inflammatory conditions for an open-label longitudinal study of HCQ 6.5 mg per kilogram per day for six weeks. Subjects underwent an oral glucose tolerance test at three time points: 0 weeks (pre-treatment with HCQ), 6 weeks (at the end of the HCQ treatment), and 12 weeks (6 weeks post HCQ-treatment). The Matsuda Insulin Sensitivity Index (ISI), HOMA-IR, and HOMA-B were compared across time-points. Results: The mean age of the cohort was 49 years, 77% females and median body mass index was 36.1 kg/m2. After 6 weeks of HCQ therapy, ISI increased from a median (interquartile range) of 4.5 (2.3-7.8) to 8.9 (3.7-11.4) with a p-value of 0.040, and HOMA-IR decreased from a median of 2.1 (1.6-5.4) to 1.8 (1.02-2.1) with a p-value of 0.09. All these variables returned toward baseline at week 12. Conclusion: HCQ use for 6 weeks in non diabetic obese subjects was associated with a significant increase in ISI and trends toward reduced insulin resistance and insulin secretion. These data suggest that HCQ, a common medication used to treat RA, possesses beneficial effects upon insulin sensitization. Further study of the insulin sensitizing effects of HCQ in patients with RA is warranted.

Background: Accelerated knee osteoarthritis may be a unique subset of knee osteoarthritis, which is associated with greater knee pain and disability. Identifying risk factors for accelerated knee osteoarthritis is vital to recognizing people who will develop accelerated knee osteoarthritis and initiating early interventions. The geometry of an articular surface (e.g., coronal tibial slope), which is a determinant of altered joint biomechanics, may be an important risk factor for incident accelerated knee osteoarthritis. We aimed to determine if baseline coronal tibial slope is associated with incident accelerated knee osteoarthritis or common knee osteoarthritis. Methods: We conducted a case–control study using data and images from baseline and the first 4 years of follow-up in the Osteoarthritis Initiative. We included three groups: 1) individuals with incident accelerated knee osteoarthritis, 2) individuals with common knee osteoarthritis progression, and 3) a control group with no knee osteoarthritis at any time. We did 1:1:1 matching for the 3 groups based on sex. Weight-bearing, fixed flexion posterior-anterior knee radiographs were obtained at each visit. One reader manually measured baseline coronal tibial slope on the radiographs. Baseline femorotibial angle was measured on the radiographs using a semi-automated program. To assess the relationship between slope (predictor) and incident accelerated knee osteoarthritis or common knee osteoarthritis (outcomes) compared with no knee osteoarthritis (reference outcome), we performed multinomial logistic regression analyses adjusted for sex. Results: The mean baseline slope for incident accelerated knee osteoarthritis, common knee osteoarthritis, and no knee osteoarthritis were 3.1(2.0), 2.7(2.1), and 2.6(1.9); respectively. A greater slope was associated with an increased risk of incident accelerated knee osteoarthritis (OR = 1.15 per degree, 95 % CI = 1.01 to 1.32) but not common knee osteoarthritis (OR = 1.04, 95 % CI = 0.91 to 1.19). These findings were similar when adjusted for recent injury. Among knees with varus malalignment a greater slope increases the odds of incident accelerated knee osteoarthritis; there is no significant relationship between slope and incident accelerated knee osteoarthritis among knees with normal alignment. Conclusions: Coronal tibial slope, particularly among knees with malalignment, may be an important risk factor for incident accelerated knee osteoarthritis.

Objectives: We examine the prospective association of soft drink consumption with radiographic progression of knee osteoarthritis (OA). Design: Prospective cohort study. Setting: This study used data from the osteoarthritis initiative (OAI). Participants: In OAI, 2149 participants with radiographic knee OA and having dietary data at baseline were followed up to 12, 24, 36 and 48 months. Measures The soft drink consumption was assessed with a Block Brief Food Frequency Questionnaire completed at baseline. To evaluate knee OA progression, we used quantitative medial tibiofemoral joint space width (JSW) based on plain radiographs. The multivariate linear models for repeated measures were used to test the independent association between soft drink intake and the change in JSW over time, while adjusting for body mass index and other potential confounding factors. Results: In stratified analyses by gender, we observed a significant dose–response relationship between baseline soft drink intake and adjusted mean change of JSW in men. With increasing levels of soft drink intake (none, ≤1, 2–4 and ≥5 times/week), the mean decreases of JSW were 0.31, 0.39, 0.34 and 0.60 mm, respectively. When we further stratified by obesity, a stronger dose–response relationship was found in non-obese men. In obese men, only the highest soft drink level (≥5 times/week) was associated with increased change in JSW compared with no use. In women, no significant association was observed. Conclusions: Our results suggest that frequent consumption of soft drinks may be associated with increased OA progression in men. Replication of these novel findings in other studies demonstrating the reduction in soft drink consumption leads to delay in OA progression is needed.

Abstract The worldwide prevalence and incidence of diabetes and obesity are increasing in pandemic proportions. This is particularly relevant for China, where an extremely large population is growing, aging, and urbanizing. We thus conducted a prospective study to examine the prevalence and incidence of impaired fasting glucose (IFG) and diabetes, the rate at which fasting blood glucose rises, and the major modifiable risk factors associated with these outcomes in a large Chinese population from the Kailuan prospective study. A prospective cohort included 100,279 Chinese participants, aged 18 years or more, who had available information on fasting blood glucose concentrations at the start of the study (2006). Examination surveys were conducted every 2 years in 2008 and 2010. For the analyses of incident diabetes, we included 76,869 participants who were free of diabetes, cardiovascular disease, and cancer at the baseline and participants in the 2008 and/or 2010 follow-up. Diabetes was defined by a fasting blood glucose concentration ≥7 mmol/L, self-reported history, or active treatment with insulin or any oral hypoglycemic agent. IFG was defined by a fasting blood glucose concentration between 5.6 and 6.9 mmol/L. During the 4-year study, the prevalence of diabetes and IFG rose from 6.6% to 7.7%, and 17.3% to 22.6%, respectively. There were 17,811 incident cases of IFG and 4867 incident cases of diabetes. The age-standardized incident rate of IFG and diabetes were 62.6/1000 person-years (51.2/1000 person-years in women and 73.8/1000 person-years in men) and 10.0/1000 person-years (7.8/1000 person-years in women and 12.1/1000 person-years in men), respectively. We observed steady increases in fasting blood glucose with body anthropometrics and in every defined category of body mass index, including in those traditionally considered to be well within the “normal” range. In this large longitudinal study of Chinese adults, we observed a high prevalence and incidence of IFG and diabetes over 4 years of follow-up. Our findings are alarming for Chinese public health since steady rises in fasting blood glucose were seen across all permutations of body habitus, even apparently very lean individuals.

Background: Greater age and body mass index are strong risk factors for osteoarthritis (OA). Older and overweight individuals may be more susceptible to OA because these factors alter tissue turnover in menisci, articular cartilage, and bone via altered glucose homeostasis and inflammation. Understanding the role of inflammation and glucose homeostasis on structural features of early-stage OA may help identify therapeutic targets to delay or prevent the onset of OA among subsets of adults with these features. We examined if serum concentrations of glucose homeostasis (glucose, glycated serum protein [GSP]) or inflammation (C-reactive protein [CRP]) were associated with prevalent knee bone marrow lesions (BMLs) or effusion among adults without knee OA. Methods: We conducted a cross-sectional study using baseline data from the Osteoarthritis Initiative. We selected participants who had no radiographic knee OA but were at high risk for knee OA. Blinded staff conducted assays for CRP, GSP, and glucose. Readers segmented BML volume and effusion using semi-automated programs. Our outcomes were prevalent BML (knee with a BML volume > 1 cm3) and effusion (knee with an effusion volume > 7.5 cm3). We used logistic regression models with CRP, GSP, or glucose concentrations as the predictors. We adjusted for age, sex, body mass index (BMI), and Physical Activity Scale for the Elderly (PASE) scores. Results: We included 343 participants: mean age = 59 ± 9 years, BMI = 27.9 ± 4.5 kg/m2, PASE score = 171 ± 82, and 64% female. Only CRP was associated with BML prevalence (odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.09 to 1.87). For effusion, we found an interaction between BMI and CRP: only among adults with a BMI <25 kg/m2 was there a significant trend towards a positive association between CRP and effusion (OR = 1.40, 95% CI = 1.00 to 1.97). We detected a U-shaped relationship between GSP and effusion prevalence. Fasting glucose levels were not significantly associated with the presence of baseline effusion or BML. Conclusions: Among individuals without knee OA, CRP may be related to the presence of BMLs and effusion among normal weight individuals. Abnormal GSP may be associated with effusion. Future studies should explore whether inflammation and glucose homeostasis are predictive of symptomatic knee OA.

Introduction: Numerous studies across different health systems have documented that many patients with rheumatoid arthritis (RA) do not receive disease-modifying anti-rheumatic drugs (DMARDs). Relatively little is known about correlates of DMARD use and whether there are socioeconomic and demographic disparities. We examined DMARD use during 2001 to 2006 in the Medicare Current Beneficiary Survey (MCBS), a longitudinal US survey of randomly selected Medicare beneficiaries. Methods: Participants in MCBS with RA were included in the analyses, and DMARD use was based on an in-home assessment of all medications. Variables included as potential correlates of DMARD use in weighted regression models included race/ethnicity, insurance, income, education, rheumatology visit, region, age, gender, comorbidity index, and calendar year. Results: The cohort consisted of 509 MCBS participants with a diagnosis code for RA. Their median age was 70 years, 72% were female, and 24% saw a rheumatologist. Rates of DMARD use ranged from 37% among those <75 years of age to 25% of those age 75 to 84 and 4% of those age 85 and older. The multivariable adjusted predictors of DMARD use include: visit with a rheumatologist in the prior year (odds ratio, OR, 7.74, 95% CI, 5.37, 11.1) and older patient age (compared with <75 years, ages 75 to 84, OR 0.58, 95% CI 0.37, 0.92, and 85 and over, OR 0.09, 95% CI 0.02, 0.31). In those without a rheumatology visit, lower income and older age were associated with a significantly reduced probability of DMARD use; no association of DMARD use with income or age was observed for subjects seen by rheumatologists. Race and ethnicity were not significantly associated with receipt of DMARDs. Conclusions: Among individuals not seeing rheumatologists, lower income and older age were associated with a reduced probability of DMARD use.