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.

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.

Cognitive impairment screening in second offense DUI programs.

Patients enrolled in alcohol treatment programs for driving under the influence (DUI) offenders are at elevated risk of cognitive impairment, but are not systematically screened. We developed a 30-min screening battery that can be administered in a group setting to test patients' ability to handle the cognitive demands of psychoeducational treatment. Testing of 134 volunteers identified 73% as having one or more clinically significant cognitive deficits. A majority of subjects scored below the 50th percentile on tests of word fluency, vocabulary, sustained attention, memory, executive functioning, and impulse control. The prevalence of cognitive impairment in the repeat DUI offender population is extremely high, making DUI treatment programs an ideal venue for screening and referral. Treatment programs should be responsive to the special needs of this population, incorporating teaching techniques that address short attention span, poor memory, lack of verbal fluency, and lack of impulse control.

Osteosarcoma metastatic to the pancreas in young patients.

Two rare cases of pancreatic metastases from osteosarcoma are reported. Metastatic spread occurred after treatment with chemotherapy. This unusual phenomenon represents an alternation in the natural history of osteosarcoma with increased long-term survival of patients who are successfully treated with chemotherapy.