A causal roadmap for generating high-quality real-world evidence.

Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.

Incidence of Serious Infections and Design of Utilization and Safety Studies for Biologic and Biosimilar Surveillance.

BACKGROUND: There is a need for postmarketing evidence generation for novel biologics and biosimilars. OBJECTIVE: To assess the feasibility, strengths, and limitations of the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) Distributed Research Network (DRN) to examine the utilization and comparative safety of immune-modulating agents among patients with autoimmune diseases. METHODS: We conducted a retrospective cohort study among patients enrolled in health insurance plans participating in the BBCIC DRN between January 1, 2006, and September 30, 2015. Eligible patients were adult (≥18 years) new users of a disease-modifying nonbiologic and/or biologic agent with a prior diagnosis of rheumatoid arthritis (RA), other inflammatory conditions (psoriasis, psoriatic arthritis, ankylosing spondylitis), or inflammatory bowel disease (IBD). Follow-up started at treatment initiation and ended at the earliest of outcome occurrence (serious infection); treatment discontinuation; or switching, death, disenrollment, or end of study period. The study leveraged the FDA Sentinel System infrastructure for data management and analysis; descriptive statistics of patient characteristics and unadjusted incidence rates of study outcomes during follow-up were calculated. RESULTS: Eligible patient drug episodes included 111,611 with RA (75% female), 61,050 with other inflammatory conditions (51% female), and 30,628 with IBD (52% female). Across all 3 cohorts, approximately half of the patient drug episodes initiated a biologic (50% in RA; 60% in psoriasis, psoriatic arthritis, ankylosing spondylitis; and 55% in IBD). The crude incidence rate of serious infection was 9.8 (9.5-10.0) cases per 100 person-years in RA, 7.1 (6.8-7.5) in other inflammatory conditions, and 14.2 (13.6-14.8) in IBD patients. CONCLUSIONS: This study successfully identified large numbers of new users of biologics and produced results that were consistent with those from earlier published studies. The BBCIC DRN is a potential resource for surveillance of biologics. DISCLOSURES: This study was funded by the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC). HealthCore conducted this study in collaboration with Harvard Pilgrim Health Care. Zhang and Sridhar were employed by HealthCore at the time of this study. Haynes is employed by HealthCore funded by PCORI, the NIH, and the FDA. Barr and Eichelberger were employed by AMCP at the time of this study. Lockhart is employed by the BBCIC. Holmes and Clewell are employed by AbbVie. Accrott is an employee of and shareholder in Amgen. Marshall and Brown are employed by Harvard Pilgrim Health Care. Barr is a shareholder in Roche/Genentech. Curtis has received research grants from and consults with the following: Amgen, AbbVie, BMS, CORRONA, Lilly, Janssen, Myriad, Pfizer, Roche, Regeneron, and UCB. Brown has received research grants from GSK and Pfizer and consulting fees from Bayer, Roche, and Jazz Pharmaceuticals, along with funding from the Reagan-Udall Foundation for the FDA to conduct studies for medical product manufacturers, including Eli Lilly, Novartis, Abbvie, and Merck. Brown is also funded by PCORI, the NIH, and the FDA. McMahill-Walraven subcontracts with Harvard Pilgrim Health Care Institute for public health and safety surveillance distributed data network activtities and with the FDA, GSK, and Pfizer. She also reports fees from Reagan Udall Foundation for the FDA and the Patient Centered Outcomes Research Institute.

Methodologic considerations for noninterventional studies of switching from reference biologic to biosimilars.

PURPOSE: As more biosimilars become available in the United States, postapproval noninterventional studies describing biosimilar switching and comparing effectiveness and/or safety between switchers and nonswitchers will play a key role in generating real-world evidence to inform clinical practices and policy decisions. Ensuring sound methodology is critical for making valid inferences from these studies. METHODS: The Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) convened a workgroup consisting of academic researchers, industry scientists, and practicing clinicians to establish best practice recommendations for the conduct of noninterventional studies of biosimilar and reference biologic switching. The workgroup members participated in eight teleconferences between August 2017 and February 2018 to discuss specific topics and build consensus. RESULTS: This report provides workgroup recommendations covering five main considerations relating to noninterventional studies describing reference biologic to biosimilar switching and comparing reference biologic to biosimilars for safety and effectiveness in the presence of switching at treatment initiation and during follow-up: (a) selecting appropriate data sources from a range of available options including insurance claims, electronic health records, and registries; (b) study designs; (c) outcomes of interest including health care utilization and clinical endpoints; (d) analytic approaches including propensity scores, disease risk scores, and instrumental variables; and (e) special considerations including avoiding designs that ignore history of biologic use, avoiding immortal time bias, exposure misclassification, and accounting for postindex switching. CONCLUSION: Recommendations provided in this report provide a framework that may be helpful in designing and critically evaluating postapproval noninterventional studies involving reference biologic to biosimilar switching.

Capture of biologic and biosimilar dispensings in a consortium of U.S.-based claims databases: Utilization of national drug codes and Healthcare Common Procedure Coding System modifiers in medical claims.

PURPOSE: To assess the capture of biologics (originator and biosimilar) in the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) Distributed Research Network (DRN), with a focus on medical claim National Drug Code (NDC), a new data field, and Healthcare Common Procedure Coding System (HCPCS) modifier. METHODS: We conducted a repeated cross-sectional study among patients with medical and pharmacy benefits enrolled in insurance plans participating in the BBCIC DRN between 1 January 2013 and 30 September 2017. We calculated the proportion of medical claims with ≥1 NDC and identified select biologics using four different approaches: (a) specific HCPCS alone, (b) specific HCPCS and NDC, (c) non-specific HCPCS with NDC, and (d) HCPCS with modifiers (applicable to biosimilars). Numbers of dispensings were calculated for each biologic by approach and select patient and claim characteristics. RESULTS: More than 1.5 million eligible participants contributed approximately 4 million person-years of data, including 1.2 billion medical claims. The proportion of medical claims with ≥1 NDC increased from 1.2% in 2013 to 3.0% in 2017. Medical claim NDCs identified 39% and 28% of vedolizumab dispensed in 2014 and 2015 and 30% of Epogen/Procrit dispensed overall. Out of 26,381 filgrastim biosimilar dispensings identified, 51% had a HCPCS modifier and 12% had a medical claim NDC for Zarxio. HCPCS modifiers and medical claim NDCs were present for 38% and 3% of all infliximab biosimilars dispensed (total n = 1,244). CONCLUSIONS: Medical claim NDC and HCPCS modifier improves identification of select biologics without product-specific HCPCS code, thereby facilitating product-specific biologic research.

Mapping from the International Classification of Diseases (ICD) 9th to 10th Revision for Research in Biologics and Biosimilars Using Administrative Healthcare Data.

PURPOSE: The Centers for Medicare and Medicaid Services (CMS) mandated the transition from ICD-9 to ICD-10 codes on October 1, 2015. Postmarketing surveillance of newly marketed drugs, including novel biologics and biosimilars, requires a robust approach to convert ICD-9 to ICD-10 codes for study variables. We examined three mapping methods for health conditions (HCs) of interest to the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) and compared their prevalence. METHODS: Using CMS General Equivalence Mappings, we applied forward-backward mapping (FBM) to 108 HCs and secondary mapping (SM) and tertiary mapping (TM) to seven preselected HCs. A physician reviewed the mapped ICD-10 codes. The prevalence of the 108 HCs defined by ICD-9 versus ICD-10 codes was examined in BBCIC's distributed research network (September 1, 2012 to March 31, 2018). We visually assessed prevalence trends of these HCs and applied a threshold of 20% level change in ICD-9 versus ICD-10 prevalence. RESULTS: Nearly four times more ICD-10 codes were mapped by SM and TM than FBM, but most were irrelevant or nonspecific. For conditions like myocardial infarction, SM or TM did not generate additional ICD-10 codes. Through visual inspection, one-fifth of the HCs had inconsistent ICD-9 versus ICD-10 prevalence trends. 13% of HCs had a level change greater than +/-20%. CONCLUSION: FBM is generally the most efficient way to convert ICD-9 to ICD-10 codes, yet manual review of converted ICD-10 codes is recommended even for FBM. The lack of existing guidance to compare the performance of ICD-9 with ICD-10 codes led to challenges in empirically determining the quality of conversions.

Characteristics and temporal trends in patient registries: focus on the life sciences industry, 1981-2012.

PURPOSE: Patient registries are used to monitor safety, examine real-world effectiveness, and may potentially contribute to comparative effectiveness research. To our knowledge, life sciences industry (LSI)-sponsored registries have not been systematically categorized. This study represents a first step toward understanding such registries over time. METHODS: Studies described as registries were identified in the ClinicalTrials.gov database. Characteristics from these registry records were abstracted and analyzed. RESULTS: Of 1202 registries identified, approximately 47% reported LSI sponsorship. These 562 LSI registries varied in focus: medical devices (n = 193, 34%), specific drugs (n = 173, 31%), procedures (n = 29, 5%), or particular diseases (n = 139, 25%). Thirty-three registries (<6%) evaluated pregnancy outcomes. The most common therapeutic area was cardiovascular (n = 234, 42%); others included endocrinology, immunology, oncology, musculoskeletal disorders, and neurology. The two most often measured outcomes were clinical effectiveness and safety, each of which appeared in 363/562 (65%) of LSI registries. Other outcomes included real-world clinical practice patterns (n = 122, 22%), patient-reported outcomes (n = 106, 19%), disease epidemiology/natural history (n = 69, 12%), and economic outcomes (n = 30, 5%). The number of LSI registries and their geographic diversity has increased over time. CONCLUSIONS: The LSI registries represent a substantial proportion of all patient registries documented in ClinicalTrials.gov. These prospective studies are growing in number and encompass diverse therapeutic areas and geographic regions. Most registries measure multiple outcomes and capture real-world data that may be unavailable through other study designs. This classification of LSI registries documents their use for studying heterogeneity of diseases, examining treatment patterns, measuring patient-reported outcomes, examining economic outcomes, and performing comparative effectiveness research.

Gastrointestinal perforation associated with bevacizumab use in metastatic colorectal cancer: results from a large treatment observational cohort study.

BACKGROUND: Bevacizumab prolongs overall and progression-free survival when added to fluorouracil-based chemotherapy in patients with metastatic colorectal cancer in randomised controlled trials (RCTs). However, gastrointestinal perforation (GIP) occurs in 1-2% of treated patients. We sought to describe the incidence, temporal pattern, outcomes and potential risk factors for GIP in a large, community-based observational cohort study of patients treated with bevacizumab. PATIENTS AND METHODS: Baseline patient and tumour characteristics, including potential GIP risk factors, were collected at study entry. Treatment, targeted adverse events, progression events and survival data were recorded every 3 months. Detailed clinical information was collected for all patients experiencing a GIP event. Effects of baseline risk factors on GIP risk were investigated using Cox proportional hazards regression. RESULTS: Of 1953 evaluable patients followed for a median of 20.1 months, 37 (1.9%) experienced GIP. Most GIP events were surgically managed with successful outcomes; four events were fatal. The majority of GIP events (26/37) occurred ≤6 months after starting bevacizumab (median, 3.35 months). Univariate and multivariate analyses showed that age ≥65 years was significantly associated with lower GIP risk. In multivariate analyses, intact primary tumour and prior adjuvant radiotherapy were significantly associated with increased risk of GIP within 6 months after starting bevacizumab. A regression analysis that assessed the risk of GIP over time showed no cumulative risk associated with bevacizumab exposure. CONCLUSION: The observed rate of GIP in this large, community-based experience was consistent with rates reported in RCTs. Most events were successfully managed with surgical intervention.

The utility of changes in serum levels of C-terminal telopeptide of type I collagen in predicting patient response to oral monthly ibandronate therapy.

Bone turnover markers may provide a more rapid indication of patient response to osteoporosis treatment than bone mineral density (BMD) measurements. This post hoc analysis of data from the MOBILE (Monthly Oral iBandronate In LadiEs) study assessed the relationship between increases in BMD at 12 mo from baseline after starting ibandronate treatment and changes in bone resorption marker serum C-terminal telopeptide of type I collagen (sCTX) from baseline at 3 and 6 mo. MOBILE enrolled postmenopausal women aged 55-80 yr with mean lumbar spine (LS) BMD T-score of -2.5 to -5.0. This analysis included women who received 150-mg monthly oral ibandronate (n=323). A high proportion of women were classified as BMD responders after 1 yr (BMD increase was >/=0%, i.e., 74-91% depending on skeletal site; BMD increase was >/=3%, i.e., 34-67%). Women with larger decreases in sCTX were more likely to be BMD responders. The percent increase in LS BMD at 12 mo was significantly associated with the percent decrease in sCTX at 3 mo from baseline (Pearson correlation coefficient: -0.19, p=0.0016). In linear regression models, percent decrease in sCTX at 3 mo from baseline was a significant predictor of 1-yr LS BMD response (R(2)=0.61, p=0.0007). These data suggest that 3-mo changes in sCTX levels are associated with 1-yr LS BMD increases in postmenopausal women treated with once-monthly oral ibandronate.

Relationships among self-management, patient perceptions of care, and health economic outcomes for decision-making and clinical practice in type 2 diabetes.

OBJECTIVES: Type 2 diabetes (T2D) treatment involves complex interactions between biological, psychological, and behavioral factors of care, requiring multifaceted efforts in clinical practice and disease management to reduce health and economic burdens. We aimed to quantify correlations among these factors and characterize their level of inclusion in economic analyses that are part of informed medical decision-making. METHODS: A comprehensive, stepwise systematic literature review was performed on published articles dated 1993 to 2008 using medical subject heading and keyword searches in electronic reference libraries. Data were collected using standardized techniques and were analyzed descriptively. RESULTS: A total of 97 articles fulfilling all inclusion criteria were reviewed, including 16 on economic models (17% of articles). Most studies were retrospective (41 of 97; 42%) and from managed care perspectives (66%). Oral antidiabetic drugs were a central focus, appearing in 83% of studies. Patient behaviors, particularly medication adherence and persistence in real-world settings, are well researched (n=65) and may influence diabetes outcomes, cardiovascular risk, mortality rates, and treatment-specific resource use (e.g., hospitalizations) and costs (

Study of the impact of oseltamivir on the risk for pneumonia and other outcomes of influenza, 2000-2005.

CONTEXT: Influenza results in large numbers of secondary complications and hospitalizations. OBJECTIVE: To assess the impact of oseltamivir on influenza-related complications and hospitalizations by analyzing health insurance claims data for 6 influenza seasons. DESIGN: A retrospective cohort study utilizing claims data from the 2000-2005 influenza seasons. SETTING: Claims data were obtained from Thomson Healthcare MarketScan Research Databases. PATIENTS: Patients prescribed oseltamivir within 1 day of influenza diagnosis were compared to those prescribed no antiviral therapy (controls). OUTCOMES: Frequencies of pneumonia, other respiratory illnesses, and otitis media, and rates of hospitalization, were compared for the oseltamivir and no antiviral groups. Expenditure was also analyzed. Relative risk (RR) for each outcome was assessed using Cox proportional hazards regression. RESULTS: Overall, 31,674 patients received oseltamivir and were propensity matched to patients with no antiviral prescription. Oseltamivir reduced the risk of diagnosis of pneumonia by 15% (RR 0.85, 95% confidence interval [CI] 0.73, 0.98), other respiratory illnesses by 20% (RR 0.80, 95% CI: 0.76, 0.83), and otitis media and its complications by 31% (RR 0.69, 95% CI: 0.61, 0.79). The greatest reductions in pneumonia risk, of 57% and 52%, were observed for children aged 6-12 years (RR 0.43, 95% CI: 0.26, 0.71) and 1-2 years (RR 0.48, 95% CI: 0.24, 0.99), respectively. Overall, hospitalization rates were reduced by 38% (RR 0.62, 95% CI: 0.52, 0.74) in the oseltamivir group compared with the no antiviral group. Total adjusted expenditures in the oseltamivir and no antiviral groups were not significantly different. CONCLUSIONS: Oseltamivir reduced the relative risk of influenza-related complications and hospitalization when prescribed immediately upon presentation of influenza.

Effect of oseltamivir on the risk of pneumonia and use of health care services in children with clinically diagnosed influenza.

OBJECTIVE: To evaluate the effectiveness of oseltamivir in reducing the rate of complications of influenza in children. RESEARCH DESIGN AND METHODS: Anonymous, patient-level data from Medstat's MarketScan Research Database between 2000 and 2004 were used to identify children with influenza, aged 1-12 years. Patients who received a prescription for oseltamivir within 1 day of influenza diagnosis were compared with those who received no antiviral therapy. MAIN OUTCOME MEASURES: Primary and secondary study outcomes included occurrence of pneumonia within 14 days of onset of influenza, rates of hospitalization for pneumonia, antibiotic use, numbers of healthcare services utilized, and healthcare expenditures. RESULTS: In total, 4447 (17.9%) children received a prescription for oseltamivir within 1 day of when they were first clinically diagnosed with influenza, and 20 407 (82.1%) children received no antiviral treatment. Overall, children who received oseltamivir for the treatment of physician-diagnosed influenza were 51.7% less likely to be clinically diagnosed with pneumonia at a subsequent medical encounter (relative risk 0.483; 95% CI: 0.326, 0.717). This benefit was associated with reductions in antibiotic use, outpatient and emergency room visits, and savings in outpatient medical expenditures. Net expenditures per patient were not significantly different between children receiving oseltamivir and those who received no antiviral treatment (-$16; 95% CI: -13 dollars , +40 dollars) although pharmacy expenditures were higher. Wide regional variations in oseltamivir use were noted. LIMITATIONS: The study was restricted to patients with employer-sponsored health insurance. The lack of a virologic diagnosis of influenza, and an index date based on the first diagnosis of influenza rather than first exposure or symptom onset, may have resulted in a conservative estimate of treatment effect. CONCLUSIONS: Oseltamivir may reduce the risk of influenza-related morbidity in children when prescribed upon presentation of clinically diagnosed influenza. The use of oseltamivir in children may play an important role in managing influenza outbreaks.

Identifying challenges and opportunities in clinical research informatics: analysis of a facilitated discussion at the 2006 AMIA Annual Symposium.

Clinical Research Informatics (CRI) is a rapidly developing sub-domain of Biomedical Informatics that has seen considerable growth in recent years. While there are numerous activities and initiatives ongoing in this domain, systematic consideration and analysis of the challenges and opportunities that exist in this area are lacking. To begin to address this gap in knowledge and inform next steps in advancing this developing domain, we conducted a facilitated discussion among a diverse group of interested participants attending a meeting of the Clinical Research Informatics Working Group at the AMIA 2006 annual symposium. Findings from our analysis of these data are presented here and indicate a broad array of challenges and opportunities facing this developing area. These findings add new information to the limited literature regarding CRI and should provide direction for those working to set the CRI research and development agenda.

Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases.

OBJECTIVE: To characterize the relationships between adherence (complance and persistence) to bisphosphonate therapy and risk of specific fracture types in postmenopausal women. PATIENTS AND METHODS: Data were collected from 45 employers and 100 health plans in the continental United States from 2 claims databases during a 5-year period (January 1, 1999, through December 31, 2003). Claims from patients receiving a bisphosphonate prescription (alendronate or risedronate) were evaluated for 6 months before the Index prescription and during 24 months of follow-up to determine total, vertebral, and nonvertebral osteoporotic fractures, persistence (no gap in refills for >30 days during 24 months), and refill compliance (medication possession ratio > or = 0.80). RESULTS: The eligible cohort included 35,537 women (age, > or = 45 years) who received a bisphosphonate prescription. A subgroup with a specified diagnosis of postmenopausal osteoporosis was also evaluated. Forty-three percent were refill compliant, and 20% persisted with bisphosphonate therapy during the 24-month study period. Total, vertebral, nonvertebral, and hip fractures were significantly lower in refill-compliant and persistent patients, with relative risk reductions of 20% to 45%. The relationship between adherence and fracture risk remained significant after adjustment for baseline age, concomitant medications, and fracture history. There was a progressive relationship between refill compliance and fracture risk reduction, commencing at refill compliance rates of approximately 50% and becoming more pronounced at compliance rates of 75% and higher. CONCLUSIONS: Adherence to bisphosphonate therapy was associated with significantly fewer fractures at 24 months. Increasing refill compliance levels were associated with progressively lower fracture rates. These findings suggest that incremental changes in medication-taking habits could improve clinical outcomes of osteoporosis treatment.

The prevalence of pituitary adenomas: a systematic review.

BACKGROUND: Pituitary adenomas display an array of hormonal and proliferative activity. Once primarily classified according to size (microadenomas, < 1 cm; macroadenomas, > or = 1 cm), these tumors are now further classified according to immunohistochemistry and functional status. With these additional classifications in mind, the goals of the current study were to determine the prevalence of pituitary adenomas and to explore the clinical relevance of the findings. METHODS: The authors conducted a metaanalysis of all existing English-language articles in MEDLINE. They used the search string (pituitary adenoma or pituitary tumor) and prevalence and selected relevant autopsy and imaging evaluation studies for inclusion. RESULTS: The authors found an overall estimated prevalence of pituitary adenomas of 16.7% (14.4% in autopsy studies and 22.5% in radiologic studies). CONCLUSIONS: Given the high frequency of pituitary adenomas and their potential for causing clinical pathologies, the findings of the current study suggest that early diagnosis and treatment of pituitary adenomas should have far-reaching benefits.

Length of hospital stay and cost of Staphylococcus and Streptococcus infections among hospitalized patients.

BACKGROUND: Staphylococcus (Staph) and Streptococcus (Strep) infections are important causes of morbidity and mortality worldwide. The economic burden of these infections is also significant, especially among hospitalized patients. OBJECTIVE: The aim of this study was to estimate length of hospital stay (LOS) and total payments for hospital admissions for patients with Staph or Strep infection as a first (primary) or second or higher (comorbid) diagnosis. METHODS: From the 1994-1997 MarketScan inpatient database, admissions with Staph (n = 2,042) or Strep (n = 1,401) infection (905 as primary and 2,538 as comorbid diagnosis) and 89,899 control admissions without a diagnosis of gram-positive infection were identified. Crude and category-specific mean LOS and anti-log mean total payments were compared between admissions with Staph or Strep infection and admissions without a diagnosis of any gram-positive infection within major diagnostic categories and principal surgical procedures (SPs). RESULTS: For admissions with Staph or Strep infection as first (primary) diagnosis (n = 905), the mean LOS was 4.68 days (95% CI, 4.44-4.93) and 4.78 days (95% CI, 4.35-5.26), respectively. The mean total payments were $6,445 (95% CI, $6,045-$6,870) and $6,821 (95% CI, $6,149-$7,566), respectively. In contrast, the average LOS and total payment for the control group were 2.99 days (95% CI, 2.98-3.01) and $6,325 (95% CI, $6,284-$6,365). For admissions with infection as the comorbid diagnosis (n = 2,538), mean LOS and total payment were 4 days longer and $6,000 higher for Staph infections and 1.2 days longer and $1,200 higher for Strep infections than the control group. Within each SP, LOS and total payments were substantially higher for patients with Staph and Strep infections. CONCLUSIONS: The results of this study indicate that infections with the pathogens Staph and Strep substantially increase LOS and total payments among hospitalized patients.

Localization of the chemokine interleukin-8 and interleukin-8 receptors in human gingiva and cultured gingival keratinocytes.

Interleukin-8 (IL-8) has been implicated in a wide variety of diseases. Previous studies have demonstrated the expression of IL-8 in periodontal tissues, yet little is known about the exact source(s), mechanisms and factors involved in gingival expression of IL-8. Additionally, nothing is known about the presence and distribution of IL-8 receptors (IL-8R) in gingival cells. Therefore it was hypothesized that, in vivo, periodontal pathogens induce IL-8 expression from gingival keratinocytes (GK) which enhances leukocyte, microvascular endothelial cell (MVEC) and GK migration via specific IL-8 receptors present on these cells. The objective of the present study was to determine the distribution of IL-8 and IL-8R in gingival tissues and cultured human GK in vitro. Standard immunohistochemical and immunocytochemical techniques were utilized in order to localize IL-8 and its receptors CXCR-1 and CXCR-2 in archival gingival specimens (eight periodontitis and four non-inflamed controls) and in cultured gingival keratinocytes. It was demonstrated that, in vivo, IL-8 and IL-8R were present in gingival epithelium, MVEC and leukocytes. In vitro studies verified the above results, by showing expression of IL-8 and IL-8R in cultured gingival keratinocytes. It is concluded that IL-8 and IL-8 receptors are expressed in gingival epithelium both in vivo and in vitro. This new evidence indicates that epithelium plays a critical role in the host defense against invading pathogens and that keratinocytes can actively respond to IL-8 and other host cytokines, via specific receptors.

Impact of chest pain on cost of migraine treatment with almotriptan and sumatriptan.

Chest-related symptoms occur with all triptans; up to 41% of patients with migraine who receive sumatriptan experience chest symptoms, and 10% of patients discontinue treatment. Thus, the cost of chest pain-related care was estimated in migraineurs receiving almotriptan 12.5 mg versus sumatriptan 50 mg. A population-based, retrospective cohort study used data to quantify the incidence and costs of chest pain-related diagnoses and procedures. An economic model was constructed to estimate annual cost savings per 1000 patients receiving almotriptan versus sumatriptan based on the reported rates of chest pain. Annual direct medical cost avoided was calculated for a hypothetical health plan covering 1 million lives. Among a cohort of 1390 patients, the incidence of chest pain-related diagnoses increased significantly by 43.6% with sumatriptan (P=.003). Aggregate costs for chest pain-related diagnoses and procedures increased from $22,713 to $30,234. Payments for inpatient hospital services, costs for primary care visits, and costs for outpatient hospital visits increased by over 100%, 53.1%, and 14.4%, respectively. The model predicted $11,215 in direct medical cost savings annually per 1000 patients treated with almotriptan versus sumatriptan. Annual direct medical costs avoided totaled $194,358, and when applied to recent estimates of 86 million lives currently covered by almotriptan treatment, translates into an annual cost savings of just under $17 million for chest pain and associated care. Thus, using almotriptan in place of sumatriptan will likely reduce the cost of chest pain-related care.

Cost savings in migraine associated with less chest pain on new triptan therapy.

OBJECTIVES: This article constructs an economic model to estimate cost of chest-pain-related care in migraine patients receiving almotriptan 12.5 mg compared with those receiving sumatriptan 50 mg. STUDY DESIGN: This population-based, retrospective cohort study used data from the MEDSTAT Marketscan database (Ann Arbor, Michigan) to quantify incidence and costs of chest-pain-related diagnoses and procedures. After a 6-month exclusion period, the study used a pre-post design, with baseline and treatment periods defined, respectively, as 5 months before and after receiving sumatriptan therapy. An economic model was constructed to estimate annual cost savings per 1,000 patients receiving almotriptan instead of sumatriptan as a function of differing rates of chest pain. Annual direct medical cost avoided was calculated for a hypothetical health plan covering 1 million lives. RESULTS: Among a cohort of 1,390 patients, the incidence of chest-pain-related diagnoses increased significantly (43.6%) with sumatriptan, from 110 during the baseline period to 158 during the treatment period (P= .003). Aggregate costs for chest-pain-related diagnoses and procedures increased 33.1%, from $22,713 to $30,234. Payments for inpatient hospital services rose 10-fold; costs for primary care visits and outpatient hospital visits rose 53.1% and 14.4%, respectively. Payments for angiography increased from $0 to $462, and costs for chest radiographs and electrocardiograms increased 58.7% and 31.2%, respectively. Sumatriptan treatment was associated with a 3-fold increase in payments for services for painful respiration and other chest pain. The model predicted $11,215 in direct medical cost savings annually per 1000 patients treated with almotriptan instead of sumatriptan. Annual direct medical costs avoided for the health plan totaled $195,913. CONCLUSION: Using almotriptan instead of sumatriptan will likely reduce the cost of chest-pain-related care for patients with migraine headaches.