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Background: Most patients with diabetic kidney disease (DKD) experience disease progression despite receiving standard care therapy. Oxidative stress is associated with DKD severity and risk of progression, but currently approved therapies do not directly attenuate the pathologic consequences of oxidative stress. GS-4997 is a once daily, oral molecule that inhibits Apoptosis Signal-regulating Kinase 1 (ASK1), which is a key mediator of the deleterious effects of oxidative stress. Methods: We describe the rationale and design of a Phase 2 placebo-controlled clinical trial investigating the effects of GS-4997 in patients with T2DM and stage 3/4 DKD receiving standard of care therapy. Approximately, 300 subjects will be randomized in a stratified manner, based on the estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio, to one of four arms in this dose-ranging study. The primary endpoint is change in eGFR at 48 weeks, and the key secondary endpoint is change in albuminuria. Conclusion: Guided by the biology of oxidative stress signaling through ASK1, the biology of DKD pathogenesis, and solid statistical methods, the decisions made for this Phase 2 study regarding delineating study population, efficacy outcomes, treatment period and statistical methods represent innovative attempts to resolve challenges specific to DKD study design. more...

Respiratory syncytial virus (RSV) is a common cause of infant hospitalizations and is increasingly recognized as a cause of considerable morbidity and mortality. No accepted antiviral treatment exists.We conducted a double-blind, placebo-controlled study of GS-5806, an oral RSV-entry inhibitor, in healthy adults who received a clinical challenge strain of RSV intranasally. Participants were monitored for 12 days. At the time of a positive test for RSV infection or 5 days after inoculation, whichever occurred first, participants were randomly assigned to receive GS-5806 or placebo in one of seven sequential cohorts. Cohorts 1 to 4 received a first dose of 50 mg of GS-5806 and then 25 mg daily for the next 4 days, cohort 5 received a first dose of 50 mg and then 25 mg daily for the next 2 days, cohort 6 received one 100-mg dose, and cohort 7 received a first dose of 10 mg and then 5 mg daily for the next 4 days. Dose selection for cohorts 5, 6, and 7 occurred after an interim analysis of data for cohorts 1 to 4. The primary end point was the area under the curve (AUC) for the viral load, which was assessed after administration of the first dose through the 12th day after inoculation. Secondary end points were mucus weight and symptom scores.Among the 54 participants in cohorts 1 to 4 who were infected with RSV, active treatment was associated with a lower viral load (adjusted mean, 250.7 vs. 757.7 log10 plaque-forming-unit equivalents [PFUe] × hours per milliliter; P0.001), lower total mucus weight (mean, 6.9 g vs. 15.1 g; P=0.03), and a lower AUC for the change from baseline in symptom scores (adjusted mean, -20.2 vs. 204.9 × hours; P=0.005). The results were similar in cohorts 5, 6, and 7. Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving GS-5806.Treatment with GS-5806 reduced the viral load and the severity of clinical disease in a challenge study of healthy adults. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01756482.). more...

IL-17 signaling has been implicated in development and persistence of asthma. Cytokine-targeted strategies blocking IL-17 receptor signaling may be beneficial in asthma treatment.To determine efficacy and safety of brodalumab, a human anti-IL-17 receptor A monoclonal antibody, in subjects with inadequately controlled moderate to severe asthma taking regular inhaled corticosteroids.Three hundred two subjects were randomized to brodalumab (140, 210, or 280 mg) or placebo. Primary endpoint was change in Asthma Control Questionnaire (ACQ) score from baseline to Week 12. Secondary endpoints included FEV1, symptom scores, and symptom-free days. Prespecified subgroup analyses were conducted to identify potential responsive subpopulations. Analyses included randomized subjects receiving one or more doses of investigational product using last-observation-carried-forward imputation.Demographics and baseline characteristics were generally balanced among groups (n = 302; n = 226 brodalumab). For the overall study population, no treatment differences were observed. Nine prespecified subgroups were examined without corrections for multiple testing. In only the high-reversibility subgroup (post-bronchodilator FEV1 improvement ≥ 20%; n = 112) was an ACQ change with nominal significance noted; ACQ responses were nominally significant in the 210-mg group (estimated treatment difference, 0.53) but not significant in the higher 280-mg group (estimated treatment difference, 0.38). Adverse events, generally balanced among groups, were most commonly asthma, upper respiratory tract infection, and injection site reaction.Inhibition of IL-17 receptor A did not produce a treatment effect in subjects with asthma. The results of the high-reversibility subgroup analysis are of uncertain significance, requiring further study of brodalumab in this asthma subpopulation. Clinical trial registered with www.clinicaltrials.gov (NCT01199289). more...

Summary Background The risk of case-fatality following hospitalisation for asthma has not been well characterised. We describe trends in 30 day case-fatality following hospitalisation for asthma in adults in Scotland from 1981 to 2009. Methods Using the Scottish Morbidity Record Scheme (SMR01) with all asthma hospitalisations for adults (≥18 years) with ICD9 493 and ICD10 J45–J46 in the principal diagnostic position at discharge (1981–2009). These data were linked to mortality data from the General Register Office for Scotland (GROS), with asthma case-fatality defined as death within 30 days of asthma admission (in or out of hospital). Logistic regression was used to explore the impact of age, sex, previous asthma admission (in the 12 months prior to hospitalisation), socioeconomic deprivation, year of admission and co-morbidity on 30-day case-fatality. Results There were a total of 116 457 asthma hospitalisations; a total of 1000 (0.9%) hospitalisations resulted in a post-admission death (within 30 days of admission). Odds ratios for unadjusted and adjusted case-fatality showed a decreased risk of case-fatality from the mid-1990s onwards when compared to case-fatality in 1981. Advancing age and co-morbid diagnoses of respiratory failure, cancer, renal failure, cor pulmonale, coronary heart disease and respiratory infection were associated with increased likelihood of death. Conclusions 30 day case-fatality has declined over the last three decades, comparable to case-fatality reported in other parts of the UK. This decline may be in part due to improved guidelines, protocols and disease management for asthma over the last 30 years. The likelihood of death 30 days following an asthma admission increased with age group and was associated with respiratory failure, renal failure and cancer. more...

Given the growing prevalence of asthma in USA, it is important to understand its national burden from the patient's perspective. The objective of this research is to examine the national burden of asthma and poor asthma control on health function, health perception and preference-based health-related quality of life (HRQL).The Medical Expenditure Panel Survey (MEPS), a nationally representative survey, was used to estimate the impact of asthma and indicators of poor asthma control on health function, self-rated health perception and preference-based HRQL using multivariate regression methods controlling for socioeconomic, clinical and demographic characteristics. Two HRQL instruments were used: SF-12v2 Physical Component Scale (PCS-12) and Mental Component Scale (MCS-12); EQ-5D-3L index and visual analogue scale (VAS). Two multivariate regression methods were used, Censored Least Absolute Deviation [EQ-5D-3L and VAS (due to censoring)] and Ordinary Least Squares (OLS) (PCS-12 and MCS-12).After controlling for covariates, asthma resulted in a statistically significant reduction in preference-based HRQL, health perception and physical and mental function (EQ-5D -0.023; VAS -2.21; PCS-12 -2.36; MCS-12 -0.96). Likewise, experiencing an exacerbation in the previous year and using more than three canisters of quick-relief medication in the previous 3 months were both associated with a statistically significant and clinically meaningful reduction in all four measures.Asthma itself and especially indicators of poor asthma control were associated with a deleterious effect on health function, preference-based HRQL and self-perceived health status. Given the prevalence of asthma, poorly controlled asthma constitutes a significant national burden in USA. more...

Background The D-prostanoid receptor and the chemoattractant receptor homologous molecule expressed on T H 2 cells (CRTH2) are implicated in asthma pathogenesis. AMG 853 is a potent, selective, orally bioavailable, small-molecule dual antagonist of human D-prostanoid and CRTH2. Objective We sought to determine the efficacy and safety of AMG 853 compared with placebo in patients with inadequately controlled asthma. Methods Adults with moderate-to-severe asthma were randomized to placebo; 5, 25, or 100 mg of oral AMG 853 twice daily; or 200 mg of AMG 853 once daily for 12 weeks. All patients continued their inhaled corticosteroids. Long-acting β-agonists were not allowed during the treatment period. Allowed concomitant medications included short-acting β-agonists and a systemic corticosteroid burst for asthma exacerbation. The primary end point was change in total Asthma Control Questionnaire score from baseline to week 12. Secondary and exploratory end points included FEV 1 , symptom scores, rescue short-acting β-agonist use, and exacerbations. Results Among treated patients, no effect over placebo (n = 79) was observed in mean changes in Asthma Control Questionnaire scores at 12 weeks (placebo, −0.492; range for AMG 853 groups [n = 317], −0.444 to −0.555). No significant differences between the active and placebo groups were observed for secondary end points. The most commonly reported adverse events were asthma, upper respiratory tract infection, and headache; 9 patients experienced serious adverse events, all of which were deemed unrelated to study treatment by the investigator. Conclusion AMG 853 as an add-on to inhaled corticosteroid therapy demonstrated no associated risks but was not effective at improving asthma symptoms or lung function in patients with inadequately controlled moderate-to-severe asthma. more...

Dipeptidyl peptidase-4 (DPP-4) inhibition is a well- characterized treatment for type 2 diabetes mellitus (T2DM). The objective of this model-based meta-analysis was to describe the time course of HbA1c response after dosing with alogliptin (ALOG), saxagliptin (SAXA), sitagliptin (SITA), or vildagliptin (VILD). Publicly available data involving late-stage or marketed DPP-4 inhibitors were leveraged for the analysis. Nonlinear mixed-effects modeling was performed to describe the relationship between DPP-4 inhibition and mean response over time. Plots of the relationship between metrics of DPP-4 inhibition (ie, weighted average inhibition [WAI], time above 80% inhibition, and trough inhibition) and response after 12 weeks of daily dosing were evaluated. The WAI was most closely related to outcome, although other metrics performed well. A model was constructed that included fixed effects for placebo and drug and random effects for intertrial variability and residual error. The relationship between WAI and outcome was nonlinear, with an increasing response up to 98% WAI. Response to DPP-4 inhibitors could be described with a single drug effect. The WAI appears to be a useful index of DPP-4 inhibition related to HbA1c. Biomarker to response relationships informed by model-based meta-analysis can be leveraged to support study designs including optimization of dose, duration of therapy, and patient population. more...

For AMG 317, a fully human monoclonal antibody to interleukin receptor IL-4Rα, we developed a population pharmacokinetic (PK) model by fitting data from four early phase clinical trials of intravenous and subcutaneous (SC) routes simultaneously, investigated important PK covariates, and explored the relationship between exposure and IgE response. Data for 294 subjects and 2183 AMG 317 plasma concentrations from three Phase 1 and 1 Phase 2 studies were analyzed by nonlinear mixed effects modeling using first-order conditional estimation with interaction. The relationship of IgE response with post hoc estimates of exposure generated from the final PK model was explored based on data from asthmatic patients. The best structural model was a two-compartment quasi-steady-state target-mediated drug disposition model with linear and non-linear clearances. For a typical 80-kg, 40-year subject, linear clearance was 35.0 mL/hr, central and peripheral volumes of distribution were 1.78 and 5.03 L, respectively, and SC bioavailability was 24.3%. Body weight was an important covariate on linear clearance and central volume; age influenced absorption rate. A significant treatment effect was observable between the cumulative AUC and IgE response measured. The population PK model adequately described AMG 317 PK from IV and SC routes over a 60-fold range of doses with two dosing strengths across multiple studies covering healthy volunteers and patients with mild to severe asthma. IgE response across a range of doses and over the sampling time points was found to be related to cumulative AMG 317 exposure. more...

Background Direct correlation of assessments of a validated composite measure such as the Asthma Control Questionnaire (ACQ) and risk of exacerbation has not been previously demonstrated in a randomized controlled trial. Objective To evaluate the ability of the ACQ score over time to predict risk of a future asthma exacerbation. Methods This analysis included data from a 12-week placebo-controlled trial (N = 292) of AMG 317, an IL-4 receptor α antagonist, in patients with moderate to severe atopic asthma. At baseline, patients had an ACQ score ≥1.5. Exacerbations were defined as requirement for systemic corticosteroids. A Cox proportional hazards model was used, with ACQ score as the time-dependent covariate. The analysis was repeated for individual components of the ACQ. Results Each 1-point increase in ACQ was associated with a 50% increased risk of exacerbation (hazard ratio, 1.50; 95% CI, 1.03-2.20) for the following 2-week period. Evaluation of individual ACQ components also demonstrated a similar trend, though each to a lesser degree than the full composite ACQ. Conclusion Although based on a retrospective analysis, with small number of exacerbations, these findings support the utility of the composite ACQ score measurement to predict risk of future exacerbation in clinical trials and clinical practice. The composite ACQ score measurement was found to be a better predictor of future risk than individual ACQ components. more...

Asthma control is recognized as a critical aspect of the evaluation and management of the disease. Here we evaluate and compare existing instruments for measuring asthma control in an attempt to evaluate their clinical utility. Based on a literature review, we identified validated instruments used to assess asthma control in adults. We examined the specific measurement properties and the strengths and weaknesses of each instrument, and evaluated a single instrument, the Asthma Control Questionnaire (ACQ), more closely as an example, evaluating its applicability in the clinical setting. Our review identified five validated instruments designed to measure asthma control: the Asthma Control Questionnaire (ACQ), Asthma Control Scoring System (ACSS), Asthma Control Test (ACT), Asthma Therapy Assessment Questionnaire (ATAQ), and the Lara Asthma Symptom Scale (LASS). None of the instruments covered all relevant control characteristics, but most were aligned with guideline definitions of control. All instruments demonstrated validity and responsiveness, with some measure of reliability. All instruments were short and easily administered, easy to interpret, and all had evidence to support their use in clinical decision making. more...

Objective To investigate the effect of etanercept therapy on radiographic progression in patients with ankylosing spondylitis (AS). Methods Patients with AS who had previously participated in a 24-week randomized, double-blind, placebo-controlled trial of etanercept therapy were enrolled in a 72-week open-label extension. Radiographs of the cervical and lumbar spine from patients who received etanercept (25 mg twice weekly) for up to 96 weeks were compared with radiographs from patients in a large prevalence cohort (Outcome Assessments in Ankylosing Spondylitis International Study [OASIS]) who had not been treated with anti–tumor necrosis factor α (anti-TNFα) agents. Radiographs obtained at 2 time points up to 96 weeks apart from patients in both study populations were digitized and read by 2 independent readers who were blinded with regard to patient group and sequence. The primary end point was the 96-week change in the modified Stoke AS Spine Score (mSASSS). Results A total of 257 patients treated with etanercept were compared with 175 unselected patients from the OASIS study. There was no significant difference in the change in the mSASSS from baseline among patients who received etanercept (mean ± SD 0.91 ± 2.45) versus those from the OASIS group (0.95 ± 3.18). Conclusion Unlike other inflammatory rheumatic diseases such as rheumatoid arthritis and psoriatic arthritis, structural progression in AS seems to be independent of TNF, despite the fact that TNF is responsible for the signs and symptoms due to inflammation in this disease. more...

To assess the safety and efficacy of brodalumab, a human anti-interleukin-17 receptor monoclonal antibody, in patients with moderate-to-severe Crohn's disease (CD).Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study in patients with moderate-to-severe CD and evidence of active inflammation. Patients were randomized 1:1:1:1 to receive brodalumab (210, 350, or 700 mg at baseline and week 4) or placebo. The primary end point was proportion of patients achieving Crohn's disease activity index (CDAI) remission (≤150) at week 6. Secondary end points included proportion of patients with CDAI response (reduction from baseline of ≥100) at week 6 and change from baseline in CDAI at week 6.The study was terminated early based on an imbalance in worsening CD in active treatment groups. At the time of termination, 130 patients had been randomized. At week 6, remission rates were 3% (210 mg), 15% (350 mg), 9% (700 mg), and 3% (placebo) and CDAI response occurred in 16% (210 mg), 27% (350 mg), 15% (700 mg), and 13% (placebo) of patients. Mean change in CDAI at week 6 was -8.7 (95.3) (210 mg), -35.4 (105.6) (350 mg), -0.6 (105.9) (700 mg), and -28.2 (86.0) (placebo). Besides worsening of CD, overall incidences of adverse events were similar across treatment groups.Treatment with brodalumab resulted in a disproportionate number of cases of worsening CD in patients with active CD and no evidence of meaningful efficacy. These analyses did not suggest additional safety risks of brodalumab beyond worsening of CD symptoms in patients with active CD. more...

Natural killer cells are important cytolytic cells in innate immunity. We have characterized human NK cells of spleen, lymph nodes, and tonsils. More than 95% of peripheral blood and 85% of spleen NK cells are CD56dimCD16+ and express perforin, the natural cytotoxicity receptors (NCRs) NKp30 and NKp46, as well as in part killer cell Ig-like receptors (KIRs). In contrast, NK cells in lymph nodes have mainly a CD56brightCD16− phenotype and lack perforin. In addition, they lack KIRs and all NCR expression, except low levels of NKp46. The NK cells of tonsils also lack perforin, KIRs, NKp30, and CD16, but partially express NKp44 and NKp46. Upon IL-2 stimulation, however, lymph node and tonsilar NK cells up-regulate NCRs, express perforin, and acquire cytolytic activity for NK-sensitive target cells. In addition, they express CD16 and KIRs upon IL-2 activation, and therefore display a phenotype similar to peripheral blood NK cells. We hypothesize that IL-2 can mobilize the NK cells of secondary lymphoid tissues to mediate natural killing during immune responses. Because lymph nodes harbor 40% and peripheral blood only 2% of all lymphocytes in humans, this newly characterized perforin− NK cell compartment in lymph nodes and related tissues probably outnumbers perforin+ NK cells. These results also suggest secondary lymphoid organs as a possible site of NK cell differentiation and self-tolerance acquisition. more...

Objective.To evaluate the efficacy and safety of brodalumab, a human monoclonal antibody inhibitor of the interleukin 17 receptor, in subjects with rheumatoid arthritis (RA).Methods.Patients (n = 252) with inadequate response to methotrexate (MTX) were randomized to receive subcutaneous injections of brodalumab (70 mg, 140 mg, or 210 mg) or placebo. The primary endpoint was the American College of Rheumatology 50% response (ACR50) at Week 12.Results.Demographics and baseline characteristics were generally balanced among treatment groups. At Week 12, ACR50 occurred in 16% (70 mg), 16% (140 mg), 10% (210 mg), and 13% (placebo; all nonsignificant vs placebo) of subjects. No significant treatment effects were observed for the secondary endpoints, including ACR20, ACR70, and Disease Activity Score in 28 joints. Incidences of all adverse events (AE), including serious AE (SAE), were similar across treatment groups. A total of 7 subjects reported SAE during the study (2 in the placebo group and 5 in the brodalumab groups), none of which was treatment related. There was 1 death (cardiopulmonary failure) ∼1 week after the last dose in the 140 mg group.Conclusion.Our study failed to find evidence of meaningful clinical efficacy with brodalumab treatment in subjects with RA who had an inadequate response to MTX. These preliminary results do not support further evaluation of brodalumab as a treatment for RA. Clinicaltrials.gov number: NCT00950989. more...

Asthma, a serious chronic lung disease affecting approximately 26 million Americans, remains clinical and economic burdens on the healthcare system. Although associations between uncontrolled asthma and poor health outcomes is known, the extent of this impact of uncontrolled asthma on economic outcomes in the United States (US) is unknown. We sought to determine the relationship between asthma, asthma control and economic outcomes in the US.The 2008-2010 Medical Expenditure Panel Surveys were used to estimate the impact of uncontrolled asthma (asthma-related emergency department [ED] visit, use of3 canisters of quick-relief inhaler in past 3 months or asthma attack in past 12 months) on medical expenditures, utilization and productivity. Estimates were generated using multivariate regression controlling for sociodemographics and comorbidity.Medical expenditures attributable to asthma were up to $4423 greater for those with markers of uncontrolled asthma compared with those who did not have asthma. Frequency of hospital discharges were up to 4.6-fold greater for those with uncontrolled asthma than those without asthma (p 0.01), while all others with asthma did not have significantly more discharges. ED visits were up to 1.8-fold greater for those with uncontrolled asthma compared with those without asthma (p 0.01). Productivity was significantly (p 0.01) decreased (more likely to be unemployed, more days absent from work and more activity limitations) for those with uncontrolled asthma.In recent national data, individuals with asthma and markers of uncontrolled asthma had higher medical expenditures, greater utilization and decreased productivity. more...

Assessment of associations between etanercept treatment and rare adverse events has been limited by the size of clinical trial populations. The authors examined the collective safety of etanercept in clinical trials across approved indications.Forty-nine U.S. and non-U.S. trials of etanercept, involving up to 13,977 patients for approved indications, with final trial reports as of May 2006, were selected from the Amgen Inc. clinical trials database. Exposure-adjusted rates of serious infections, opportunistic infections, malignancies, and deaths were reported by trial, indication, and dosage.Rates of serious infections were generally similar between etanercept and controls. Overall rates of opportunistic infections and tuberculosis were low. The standardized incidence ratio (SIR) (95% CI) for malignancy was 1.00 (0.83-1.19) for all etanercept patients across all indications. The SIR for lymphoma for patients with rheumatoid arthritis was 3.45 (1.83-5.89); all other indications reported SIRs similar to those observed in the general population. The SIRs for cutaneous squamous cell carcinoma in patients with psoriasis relative to the general population with high or low sun exposure were 2.09 (1.27-3.22) and 4.96 (3.03-7.66), respectively. SIRs were less than 1.0 for all other indications regardless of sun exposure. Rates of melanoma and basal cell carcinoma were not significantly different from those in the general population. There was no increase in mortality associated with etanercept use relative to control populations.These data support the overall tolerability of etanercept across approved indications. more...

Objective.To investigate the correlation between the Disease Activity Score using a 28-joint count (DAS28) based on physician-derived joint counts and the DAS28 based on patient-derived joint counts (Pt-DAS28) in rheumatoid arthritis (RA).Methods.Data from a multicenter, open-label study investigating the immunogenicity of etanercept (ETN) were analyzed. ETN-naive patients with active RA received ETN 50 mg once weekly alone or with methotrexate (MTX). Joint counts were performed at baseline, Week 12, and Week 24 by the physician and patient independently. Patients received instruction in performing joint assessments.Results.Of 447 patients enrolled (ETN, n = 218; ETN + MTX, n = 229), most were women (79%) and the mean age was 54.5 years. Correlation coefficients between DAS28 and Pt-DAS28 were ≥ 0.57 at baseline, Week 12, and Week 24. At Week 24, 48%, 39%, and 12% of patients could be classified as having low, moderate, or high disease activity, respectively, using DAS28. Using Pt-DAS28, 43%, 39%, and 18% were similarly classified. Agreement in the category of disease activity classification occurred in 72% of patients (kappa = 0.55). At Week 24, 78% of patients using DAS28 and 72% of patients using Pt-DAS28 were classified as moderate or good European League Against Rheumatism responders.Conclusion.These results support the possible use of patient-derived tender and swollen joint counts to aid in the assessment of disease activity and clinical response in patients with RA. more...

IL-4 and IL-13 share many biological functions important in the development of allergic airway inflammation and are implicated in the pathogenesis of asthma. AMG 317 is a fully human monoclonal antibody to IL-4Ralpha that blocks both IL-4 and IL-13 pathways.To evaluate efficacy and safety of AMG 317 in patients with moderate to severe asthma.In this phase 2, randomized, double-blind, placebo-controlled study, patients received weekly subcutaneous injections of placebo or AMG 317 (75-300 mg) for 12 weeks, followed by a 4-week follow-up period. The primary endpoint was change from baseline at Week 12 in Asthma Control Questionnaire (ACQ) symptom score.Mean ACQ change (SE) was -0.49 (0.09) in placebo (n = 74), and -0.43 (0.11), -0.58 (0.12), and -0.70 (0.09) in the AMG 317 75 mg (n = 73), 150 mg (n = 73), and 300 mg (n = 74) groups, respectively (treatment effect P = 0.25). No statistically significant differences were observed in the secondary endpoints. Numerical decreases in number of and time to exacerbations were noted in patients receiving AMG 317 150 mg and 300 mg. Preplanned analyses by tertile of baseline ACQ revealed that patients with higher baseline ACQ scores (or=2.86) were more likely to respond to AMG 317. Serious adverse events were reported in three patients, each noted as not related to study drug.AMG 317 did not demonstrate clinical efficacy across the overall group of patients. Clinically significant improvements were observed in several outcome measures in patients with higher baseline ACQ scores. AMG 317 was safe and well tolerated in this study population. Clinical trial registered with www.clinicaltrials.gov (NCT 00436670). more...

Gelsolin is a bivalent Ca(2+)-modulated actin-binding protein that severs, nucleates, and caps filaments. In order to gain a better understanding of the capping mechanism we have studied N- and C-terminal gelsolin fragments, 14NT and 41CT, each of which contains a single functional actin-binding site. The very tight binding measured between gelsolin and the barbed filament end requires gelsolin to greatly decrease the dissociation rate constant of the terminal actin from this end. A mechanism that could account for the observed decrease in dissociation is one in which gelsolin links two actin monomers so that they dissociate more slowly as a dimer. This cannot be the only mechanism, however, since, as shown here, 14NT and 41CT, fragments with single actin-binding sites, decrease the dissociation rate of the capped terminal actin molecule. The observations suggest that these fragments induce a conformational change in the actin monomer that either increases the affinity or alters the kinetics of the terminal actin-actin bond. The available data argue for strengthening of the terminal actin-actin bond. more...

Objective To evaluate the safety and efficacy of up to 8 years of etanercept treatment in patients with polyarticular-course juvenile rheumatoid arthritis (JRA). Methods Patients with JRA who previously participated in a randomized controlled trial (RCT) of etanercept were eligible to receive etanercept in a long-term open-label extension (OLE) trial. Safety end points included the incidences of serious adverse events (SAEs), medically important infections (MIIs), and death. Efficacy end points included the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement. Results Of the 69 patients originally enrolled in the RCT, 58 (84%) participated in the OLE, for a total of 318 patient-years of etanercept exposure. A total of 42 of the 58 patients (72%) entered the fourth year of continuous etanercept treatment, and 26 patients (45%) entered the eighth year. Sixteen patients (23% of those entering the RCT) reported 39 SAEs. The overall rate of SAEs (0.12 per patient-year) did not increase with long-term exposure to etanercept. The rate of MIIs (0.03 per patient-year) remained low; 1 new MII was reported in patients with ≥5 years of etanercept exposure. No cases of tuberculosis, opportunistic infections, malignancies, lymphomas, lupus, demyelinating disorders, or deaths were reported. An ACR Pedi 70 response or higher was achieved by 100% of patients with 8 years of data (11 of 11) and by 61% of patients according to the last observation carried forward data (28 of 46). Conclusion These data suggest that the acceptable safety profile of etanercept therapy is maintained for up to 8 years in this population of JRA patients. Improvements in the signs and symptoms of JRA were also maintained for up to 8 years. more...

We find that CD11c + cells with many markers of dendritic cells (DCs) are a major cell type in the skin lesions of psoriasis. These CD11c + cells, which are evident in both epidermis and dermis, are the sites for the expression of two mediators of inflammation, inducible nitric oxide synthase (iNOS) and TNF-α in diseased skin. These cells express HLA-DR, CD40, and CD86, lack the Langerin and CD14 markers of Langerhans cells and monocytes, respectively, and to a significant extent express the DC maturation markers DC-LAMP and CD83. Treatment of psoriasis with efalizumab (anti-CD11a, Raptiva) strongly reduces infiltration by these DCs in patients responding to this agent. Disease activity after therapy was more related to DC infiltrates and iNOS mRNA levels than T cell infiltrates, and CD11c + cells responded more quickly to therapy than epidermal keratinocytes. Our results suggest that a type of DC, which resembles murine “Tip-DCs” that can accumulate during infection, has proinflammatory effects in psoriasis through nitric oxide and TNF-α production, and can be an important target for suppressive therapies. more...

Psoriasis vulgaris, a skin disease that is considered to be the result of a type 1 autoimmune response, provides an opportunity for studying the changes that occur in a target-diseased tissue during innovative immunotherapies. To gain a more comprehensive picture of the response to an approved biological therapy, we studied alfacept, which is a CD2 binding fusion protein. We examined T cells, dendritic cells (DCs), and expression of a number of inflammatory genes. In 22 patients, 55% demonstrated a clear histological remission of the disease, with a 73% reduction in lesional lymphocytes and a 79% decrease in infiltrating CD8+cells. Only histological responders showed marked reductions in the tissue expression of inflammatory genes IFN-γ, signal transducer and activator of transcription 1, monokine induced by IFN-γ, inducible NO synthase, IL-8, and IL-23 subunits. Parallel decreases in CD83+and CD11c+DCs also were measured by immunohistochemistry. Because we observed that alefacept binds primarily to T cells and not DCs, we suggest that T cells are the primary target for therapy, but that DCs and a spectrum of type 1 inflammatory genes are coordinately suppressed. more...

T U E S D A Y 816 Effect of Inhaled Corticosteroids (ICS) Vs. Inhaled Corticosteroid with Long-Acting Beta2 Agonists (ICS/LABA) On Asthma Control: Results From National Asthma Survey Neetu Talreja, MD, Dennis K. Ledford, MD, FAAAAI, Richard F. Lockey, MD; Morsani College of Medicine University of South Florida and James A. Haley Veteran Hospital. RATIONALE: There is limited evidence for the comparative efficacy of ICS vs. ICS/LABA to treat asthma in children under 12 years. METHODS: Data from the 2003 National Asthma Survey were analyzed to compare asthma control in children (5 to 11 yrs) using ICS vs. ICS/LABA. Both short term (symptoms within last 2 weeks, day and night symptoms in last 30 days and use of systemic glucocorticoids in last 3 months) and long term (asthma exacerbation, emergency department visits, hospitalizations and activity limitations in the prior year) outcomes were compared. Demographics, availability of health insurance, indoor allergen exposure and asthma education were compared between the two groups. Asthma control in adult (18 to 44 years) and older population (>565 years) was also assessed for the same parameters. RESULTS: 134 children on ICS and 69 on ICS/LABA were identified. Baseline characteristics were similar in both groups. There were no differences in short and long term asthma outcomes between the two groups (p>0.05 for all outcome measures). Similar results were obtained with the adult and older population (p>0.05 for all outcome measures). ICS/LABAwas used for more than 6 months in 58% of children, 81% of adults and 46% of the older population. CONCLUSIONS: Asthma control in children using ICS vs. ICS/LABA was similar. So was asthma control using similar medications in the adult and older populations. LABA tolerance or the use of ICS/LABA in subjects with more severe asthma could explain these findings. more...

Background It is important to have an accurate picture of the sources and extent of medical expenditures and productivity loss to understand the nature and scope of the burden of asthma in the United States (US). Objective The current study aims to provide recent nationally representative estimates of direct and productivity-related costs attributable to asthma in adults in the US. Methods The 2003 and 2005 Medical Expenditure Panel Surveys were used to estimate the effect of asthma on medical expenditures, use, productivity, and chronic comorbidity among adults (≥18 years). Productivity-related outcome variables included employment, annual wages, missed work days, days spent sick in bed, and activity limitations. Multivariate regression was conducted, controlling for sociodemographics and comorbidity. Results Of 47,033 adults, 2,003 reported asthma. Compared with those without, subjects with asthma were significantly less likely to be employed (odds ratio, 0.78), spent 1.4 more days sick in bed annually, and were significantly more likely to have activity limitations or to be unable to work. Adults with asthma incurred an additional $1,907 (2008 US dollars) annually and experienced higher health care use and comorbidity. The total national medical expenditure attributable to adult asthma was $18 billion. Adults with asthma were more likely to be covered by Medicaid (30%) than the general adult population (10%). The largest contributors to medical expenditures for adults with asthma were prescription drugs, followed by inpatient hospitalizations and home health care. Conclusions In recent national data adult asthma is associated with a significant deleterious effect on direct and indirect costs in the US. more...