Roberta Glass

Two independent alleles at 6q23 associated with risk of rheumatoid arthritis

To identify susceptibility alleles associated with rheumatoid arthritis, we genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and carried out an association analysis in comparison to publicly available genotype data for 1,211 related individuals from the Framingham Heart Study. After evaluating and adjusting for technical and population biases, we identified a SNP at 6q23 (rs10499194, ∼150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genome-wide association (GWA) scan and in 5,541 additional case-control samples (P = 10−3, GWA scan; P < 10−6, replication; P = 10−9, combined). In a concurrent study, the Wellcome Trust Case Control Consortium (WTCCC) has reported strong association of rheumatoid arthritis susceptibility to a different SNP located 3.8 kb from rs10499194 (rs6920220; P = 5 × 10−6 in WTCCC). We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23.

Reducing Risks to Children in Vehicles With Passenger Airbags

This review examines the risk that passenger airbags pose for children and discusses behavioral and technologic measures aimed at protecting children from airbag deployment. Although airbags reduce fatal crash injuries among adult drivers and passengers, this safety technology increases mortality risk among children younger than age 12. The magnitude of the risk is multiplied when children are unrestrained or restrained improperly. As new vehicles are resold to buyers who tend to be less safety-conscious than new car owners, the number of children endangered by passenger airbag deployment may increase. For vehicles already in the fleet, strong measures are required to secure children in the rear seat and increase the proper use of appropriate restraint systems through police enforcement of laws. One promising strategy is to amend child passenger safety laws to require that parents secure children in the rear seats. For future vehicles, a mandatory performance standard should be adopted that suppresses airbag deployment automatically if a child is located in the front passenger seat. Other promising improvements in airbag design also are discussed. Major changes in passenger airbag design must be evaluated in a broad analytical framework that considers the welfare of adults as well as children.

Associations between Human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study

Background: HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA). Objective: We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis. Methods: A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions. Results: In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18–4.25), and RF+ (OR 2.53, 95% CI 1.83–3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24–2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27–2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01–2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA. Conclusions: In this large clinical cohort, we replicated the association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.

The relationship between focal erosions and generalized osteoporosis in postmenopausal women with rheumatoid arthritis.

OBJECTIVE Among rheumatoid arthritis (RA) patients who have had the disease for 10 years, more than half have focal erosions, and the risk of fracture is doubled. However, there is little information about the potential relationship between focal erosions and bone mineral density (BMD). The aim of this study was to determine whether lower BMD is associated with higher erosion scores among patients with RA. METHODS We enrolled 163 postmenopausal women with RA, none of whom were taking osteoporosis medications. Patients underwent dual x-ray absorptiometry at the hip and spine and hand radiography, and completed a questionnaire. The hand radiographs were scored using the Sharp method, and the relationship between BMD and erosions was measured using Spearmans correlation coefficients and adjusted linear regression models. RESULTS Patients had an average disease duration of 13.7 years, and almost all were taking a disease-modifying antirheumatic drug. Sixty-three percent were rheumatoid factor (RF) positive. The median modified Health Assessment Questionnaire score was 0.7, and the average Disease Activity Score in 28 joints was 3.8. The erosion score was significantly correlated with total hip BMD (r=-0.33, P<0.0001), but not with lumbar spine BMD (r=-0.09, P=0.27). Hip BMD was significantly lower in RF-positive patients versus RF-negative patients (P=0.02). In multivariable models that included age, body mass index, and cumulative oral glucocorticoid dose, neither total hip BMD nor lumbar spine BMD was significantly associated with focal erosions. CONCLUSION Our results suggest that hip BMD is associated with focal erosions among postmenopausal women with RA, but that this association disappears after multivariable adjustment. While BMD and erosions may be correlated with bone manifestations of RA, their relationship is complex and influenced by other disease-related factors.

Child Passenger Safety: Decisions about Seating Location, Airbag Exposure, and Restraint Use

The installation of passenger-side airbags in new vehicles complicates efforts to maximize child safety in motor vehicle crashes. It has been recommended by both public and private organizations that children sit in the rear seat with proper restraint to achieve maximum safety. Drivers now need to decide whether a child should be restrained, where the child should be seated (front versus rear), and whether the child should be seated in front of a passenger-side airbag. This research was undertaken to determine which choice minimizes the risk of fatality to children. Using data from the U.S. Fatality Analysis Reporting System for calendar years 1989 to 1998, fatal vehicle crashes with child passengers younger than 13 years were analyzed. The effectiveness of passenger-side airbags and rear seating for children, by age category and restraint use, was estimated using the double-pair comparison method. For each of four age categories, the fatality risk of each possible combination of restraint use, seating location, and airbag presence was also estimated using logistic regression. Passenger airbags were associated with an increase in child fatality risk of 31% for restrained children, and 84% for unrestrained children. Passenger airbags did appear to offer protection to restrained 9- to 12-year-old children. Restraint use and rear seating were associated with statistically significant reductions in the odds of a child dying in a crash. In order to minimize child fatality risk, parents should seat children in the rear of the vehicle while using the proper child restraint system, especially in vehicles with passenger airbags. These findings support current public education efforts in the United States.

Where children sit in motor vehicles: a comparison of selected European and American cities.

Objectives—To ascertain whether there are differences in child seating location between selected cities in the US and continental Europe, and if differences exist, to ascertain what factors predict them. Setting—Boston and New Orleans, which have no laws regarding child seating location, and Paris, Frankfurt, and Brussels, which for approximately 20 years have had laws requiring children under the ages of 10 or 12 to sit in the rear. Methods—Observations were made in the first quarter of 1997 at several locations in or near each city. The vehicle seating capacity, total number of occupants, the seating location of adults and children, and driver shoulder belt use were recorded for each vehicle with at least one child. The predictors of a vehicle having a child in the front were estimated using logistic regression. Results—Data on 5501 children riding in 3778 vehicles were collected. Adjusting for differences in vehicle seating capacity, occupant mix, and driver shoulder belt use, vehicles in the European cities are significantly less likely to have a child in the front seat than vehicles in the American cities. Conclusions—Cities with no history of laws prohibiting children from sitting in the front, vehicles with low seating capacity, vehicles with no adult (other than the driver) or many child passengers, and unbelted drivers were associated with a higher likelihood of children riding in the front seat. It is feasible for a society to insist, through custom and/or law, that children sit in the back seat.

Kids at Risk: Where American Children Sit in Passenger Vehicles

Abstract The risks that passenger-side airbags pose for children have caused renewed interest in where children should sit in motor vehicles. This study examines where children (dead or surviving) were sitting in passenger vehicles when fatal crashes occurred in the United States during the years 1985–1996. The major findings are that: (a) roughly one-third (32.5%) of children under the age of 13 in cars and minivans were seated in the front seat; (b) this behavior was most frequent among infants (45.4%); and (c) this behavior was more frequent when children were the only passengers in the vehicle (55.9%). Over the 12-year period analyzed, the percentage of children in the front seat has declined steadily among infants and toddlers but not among young children and subteens. The percentage of children in the front seat ranged from 40.0% in Massachusetts to 24.0% in Hawaii. When a child was seated in the front, the rear seat was completely empty in 65% of the crashes and completely full only 4% of the time. More systematic study of child seating behaviors is recommended.

Hand bone mineral density is associated with both total hip and lumbar spine bone mineral density in post-menopausal women with RA

OBJECTIVE RA is associated with localized bone loss in the hands, as well as generalized osteoporosis. We evaluated the relationship between hand digital X-ray radiogrammetry BMD (DXR-BMD) and total hip and lumbar spine BMD. METHODS We conducted a cross-sectional study of 138 post-menopausal women with RA. The DXR-BMD was calculated based on digitized hand radiographs. Measurements of the total hip and lumbar spine BMD were performed by a DXA-BMD (BMDa) scan. Patient and physician questionnaires and laboratory samples supplied information on relevant covariates. Separate multivariate linear regression models were constructed to determine the cross-sectional relationship between hand DXR-BMD (independent variable) and total hip or lumbar spine BMD (dependent variables). RESULTS The cohort comprised women with a median age of 61 years and RA disease duration of 13 years. Seventy-six per cent were either RF and/or anti-cyclic citrullinated peptide (anti-CCP) positive and most had moderate disease activity [median disease activity score-28 joint count (DAS28) 3.7]. Hand DXR-BMD was significantly associated with total hip BMD (beta = 0.61; P < 0.0001) and lumbar spine BMD (beta = 0.62; P < 0.0008) in adjusted models. CONCLUSIONS This study suggests that hand DXR-BMD is associated with both the total hip and lumbar spine BMD among post-menopausal women with RA. The relationship between bone loss in the hands and generalized osteoporosis should be further explored in longitudinal studies of patients with RA.

TNFα Inhibitors May Improve Asthma Symptoms: A Case Series of 12 Patients with Rheumatoid Arthritis and Asthma

Asthma is a chronic inflammatory disease that constitutes one of the leading causes of chronic obstructive pulmonary disease(1). Most patients with moderate or severe disease are treated with inhaled corticosteroids, but many patients have refractory disease(2). Treatment options for these refractory patients are limited; there are emerging data on the effectiveness of tumor necrosis factor alpha (TNF)α inhibitors(3–5), but there are no long-term studies. In this report, we studied a large prospective RA cohort, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), to identify a case series of patients with both RA and asthma, who were treated with TNFα inhibitors. We aimed to determine whether asthma symptoms correlated with TNFα inhibitor therapy.