Effect of day care attendance on sensitization and atopic wheezing differs by Toll-like receptor 2 genotype in 2 population-based birth cohort studies.

BACKGROUND: Variation in the Toll-like receptor 2 gene (TLR2/-16934) is associated with allergic diseases among farmers' children but not among children not living on farms. OBJECTIVE: To test the hypothesis that the same genetic variant conferring protection in the farming environment is associated with reduced risk of developing allergic phenotypes among urban children attending day care in early life. METHODS: In 2 population-based birth cohorts (Manchester, United Kingdom, Manchester Asthma and Allergy Study [MAAS]; Tucson, Ariz, Tucson Infant Immune Study [IIS]), participants were recruited prenatally and followed prospectively (MAAS: 3, 5, 8 and 11 years; IIS: 1, 2, 3 and 5 years). We assessed allergic sensitization and atopic wheezing at each follow-up. RESULTS: A total of 727 children participated in Manchester and 263 in Tucson. We found no significant associations between TLR2/-16934 and sensitization and atopic wheeze in either cohort. However, a different pattern emerged when we explored the interaction between TLR2/-16934 and day care attendance on these outcomes. We found a significant interaction between day care and TLR2/-16934 on the development of sensitization in the longitudinal model in MAAS in that children carrying the T allele who attended day care were less likely to be sensitized than those who did not attend day care, whereas among AA homozygotes, the association tended to be in the opposite direction. In a longitudinal model in IIS, we found a significant interaction between day care attendance and TLR2/-16934 on the development atopic wheezing. Significant interactions between TLR2/-16934 and day care were maintained when adjusting for socioeconomic status. CONCLUSION: The effect of day care on sensitization and atopic wheezing may differ among children with different variants of the TLR2 gene.

Benefit design innovations to manage specialty pharmaceuticals.

BACKGROUND: Spending on specialty pharmaceuticals is rising faster than that for traditional drugs. In 2006, specialty drugs were the largest category driving drug costs and utilization trends. Even with effective management, expenditures on these agents are projected to increase exponentially in the coming years. OBJECTIVE: To review benefit design strategies used by payers to control costs and manage utilization of specialty pharmaceuticals. SUMMARY: The rapid growth in specialty pharmaceutical expenditures reflects the introduction of new agents, broader indications, and wider use in more common disease states. The true growth of the specialty pharmaceutical segment is obscured because many of these agents are reimbursed through the medical benefit, which often lacks the transparency necessary to accurately determine true cost and utilization trends. To date, efforts to control spending on biologics have been fragmented with most payers employing techniques for cost and utilization containment similar to those used for traditional pharmaceuticals. To ensure greater cost and utilization control, a benefit design that simultaneously provides optimal cost management, appropriate utilization, improved clinical management, enhanced clinical outcomes, and heightened patient safety should be established. CONCLUSION: Current management techniques for specialty pharmaceuticals often represent a stop-gap approach for controlling rising drug costs. Creation of a specialty pharmacy benefit can optimize cost and utilization management.

Specialty pharmacy cost management strategies of private health care payers.

BACKGROUND: The rate of increase in spending on specialty pharmaceuticals is outpacing by far the rate of increase in spending for other drugs. OBJECTIVE: To explore the strategies payers are using in response to challenges related to coverage, cost, clinical management, and access of specialty pharmaceuticals and to describe the potential implications for key stakeholders, including patients, physicians, and health care purchasers. METHODS: Sources of information were identified in the course of providing consulting services in the subject area of specialty pharmaceuticals to health plans, pharmacy benefit managers, employers, and pharmaceutical manufacturers. RESULTS: Specialty pharmaceuticals represent the fastest growing segment of drug spending due to new product approvals, high unit costs, and increasing use. Health care payers are faced with significant challenges related to coverage, cost, clinical management, and access. A variety of short- and long-term strategies have been employed to address these challenges. CONCLUSIONS: Current management techniques for specialty pharmaceuticals often represent a stop-gap approach for controlling rising drug costs. Optimum cost and care management methods will evolve as further research identifies the true clinical and economic value of various specialty pharmaceuticals.

Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings.

BACKGROUND: The response to lipopolysaccharide exposure is highly variable and might be a result of genetic diversity between individuals. The toll-like receptor 4 (TLR-4) is the principal receptor for lipopolysacharide. OBJECTIVES: We investigated the association between single-nucleotide polymorphisms in the TLR4 locus and levels of systemic inflammatory markers in response to lipopolysaccharide. METHODS: Healthy subjects (n = 116) were genotyped for the most frequent polymorphisms found in the promoter and coding region of the TLR4 gene (-2026A/T, -1607T/C, +896A/G, and +1196C/T relative to the translation start site). Subjects were challenged with 20 microg lipopolysaccharide by inhalation. RESULTS: Polymorphisms at +896 and +1196 were in complete linkage disequilibrium, and no homozygotes for the less common allele, G and T respectively, were found. After lipopolysaccharide inhalation, subjects heterozygous for either TLR-4/+896 or TLR4/+1196 had significantly lower numbers of white blood cell counts and lower levels of C-reactive protein and lipopolysaccharide-binding protein compared with homozygotes with the common allele. None of the heterozygous subjects (n = 18) except 1 were high responders to lipopolysaccharide (defined as a rise in C-reactive protein > 10 mg/L), whereas 36 of 98 homozygous subjects were high responders (P <.02). No association was observed between the TLR-4/-2026 and TLR-4/-1607 polymorphisms and lipopolysaccharide responsiveness. CONCLUSION: The single-nucleotide polymorphisms at position +896 or +1196 in the TLR-4 gene is associated with systemic inflammatory hyporesponsiveness to inhaled lipopolysaccharide.