Janet T. Holbrook

Efficacy of Esomeprazole for Treatment of Poorly Controlled Asthma

BACKGROUND Gastroesophageal reflux is common among patients with asthma but often causes mild or no symptoms. It is not known whether treatment of gastroesophageal reflux with proton-pump inhibitors in patients who have poorly controlled asthma without symptoms of gastroesophageal reflux can substantially improve asthma control. METHODS In a parallel-group, double-blind trial, we randomly assigned 412 participants with inadequately controlled asthma, despite treatment with inhaled corticosteroids, and with minimal or no symptoms of gastroesophageal reflux to receive either 40 mg of esomeprazole twice a day or matching placebo. Participants were followed for 24 weeks with the use of daily asthma diaries, spirometry performed once every 4 weeks, and questionnaires that asked about asthma symptoms. We used ambulatory pH monitoring to ascertain the presence or absence of gastroesophageal reflux in the participants. The primary outcome was the rate of episodes of poor asthma control, as assessed on the basis of entries in asthma diaries. RESULTS Episodes of poor asthma control occurred with similar frequency in the placebo and esomeprazole groups (2.3 and 2.5 events per person-year, respectively; P=0.66). There was no treatment effect with respect to individual components of the episodes of poor asthma control or with respect to secondary outcomes, including pulmonary function, airway reactivity, asthma control, symptom scores, nocturnal awakening, or quality of life. The presence of gastroesophageal reflux, which was documented by pH monitoring in 40% of participants with minimal or no symptoms, did not identify a subgroup of patients that benefited from treatment with proton-pump inhibitors. There were fewer serious adverse events among patients receiving esomeprazole than among those receiving placebo (11 vs. 17). CONCLUSIONS Despite a high prevalence of asymptomatic gastroesophageal reflux among patients with poorly controlled asthma, treatment with proton-pump inhibitors does not improve asthma control. Asymptomatic gastroesophageal reflux is not a likely cause of poorly controlled asthma. (ClinicalTrials.gov number, NCT00069823.)

Brief Communication: High Incidence of Venous Thrombotic Events among Patients with Wegener Granulomatosis: The Wegener's Clinical Occurrence of Thrombosis (WeCLOT) Study

Context Are patients with Wegener granulomatosis at increased risk for venous thrombotic events (VTEs)? Contribution This prospective observational study found 16 VTEs in 167 patients with Wegener granulomatosis who had no history of VTE. The incidence of VTE was 7 per 100 person-years of follow-up. Implications Patients with Wegener granulomatosis probably have an increased risk for VTE compared with healthy populations who have less than 1 VTE per 100 person-years offollow-up. The Editors Wegener granulomatosis is characterized by inflammation of small- and medium-sized vessels and granulomatous inflammation of various organs (1, 2). The involvement of the venous system in Wegener granulomatosis has received little attention in the past, with only a few reported cases of venous thrombosis (3-5), and textbooks and review articles do not mention an increased risk for venous thrombotic events (VTEs) (1, 6, 7). Early in the enrollment phase of a multicenter treatment trial for Wegener granulomatosis (8-10), several patients had VTEs, including both deep venous thromboses and pulmonary emboli. This observation led to our investigation of VTE incidence in patients with Wegener granulomatosis. Methods Patients and Visit Schedule The Wegeners Granulomatosis Etanercept Trial (WGET) is a multicenter, randomized, double-blind, placebo-controlled study of the efficacy of etanercept, 25 mg subcutaneously twice weekly, in addition to conventional immunosuppressive therapy with glucocorticoids and either methotrexate or cyclophosphamide. Details of the trial design and study results have been published (8, 10). All patients fulfilled the modified American College of Rheumatology Classification Criteria for Wegener granulomatosis, had no history of either exposure to inhibitors of tumor necrosis factor- or a malignant condition, and had no evidence of active infection upon enrollment (8). All patients in WGET were enrolled and randomly assigned to either the active experimental medication or placebo during a period of active vasculitis (flare). Patients were evaluated at study visits every 3 months. Data collection included a full interim medical history with determination of Wegener granulomatosis disease activity, physical examination, laboratory studies, and assessment and review of adverse events. We measured Wegener granulomatosis disease activity by using the Birmingham Vasculitis Activity Score for Wegeners Granulomatosis (BVAS/WG) (11), which considers all manifestations of active disease present during the 28-day period before the date of assessment. A score of 1 or greater indicates active disease, and a score of 0 indicates remission. Patients were required to have a score of 3 or greater to be enrolled in the trial. Investigators measured cumulative disease damage with the Vasculitis Damage Index (12). Severe disease was defined as having a life- or organ-threatening manifestation; other patients were considered to have limited disease (8). The patients who we observed for incidence of VTEs included all 180 patients enrolled in WGET. Details of the baseline demographic and clinical characteristics of this study cohort have been published (9). Diagnosis and Documentation of VTEs All VTEs in WGET were considered serious adverse events necessitating a separate written report documenting the event and outcome (8). A patient was considered to have had a VTE if the event was clinically apparent and was confirmed by diagnostic studies. Clinical evidence of VTEs included edematous or painful limbs, dyspnea, hypoxemia, chest pain, hemoptysis, or other features of deep venous thrombosis or pulmonary embolism. Diagnostic confirmation included results of vascular ultrasonography, impedance plethysmography, ventilationperfusion scanning, computed tomographic angiography, spiral computed tomograpy, venography, or angiography. Investigators collected detailed clinical data on VTEs on all patients for all events that occurred before and during WGET. A study physician completed a separate standardized thrombosis event form for each VTE on the basis of information obtained from patients, nonstudy physicians, and medical records review. The form included the date of event, clinical details of event, diagnostic test results, and determination of Wegener granulomatosis disease status at the time of event. We excluded thromboses of hemodialysis vascular accesses from these analyses. For our investigation of VTE incidence, the observation period started with the date of enrollment of the first patient (9 June 2000) and ended 3 months after the final patient was enrolled (31 December 2002). Statistical Analyses We evaluated differences among patient characteristics in the Wegener granulomatosis cohort at the start of the observation period with the Wilcoxon rank-sum test for continuous variables and with either chi-square or Fisher exact tests for categorical variables (SAS, version 8.0, SAS Institute, Inc., Cary, North Carolina). We calculated the incidence rate and 95% CIs for VTEs by using Stata, version 8.0 (cii command) (Stata Corp., College Station, Texas). The cumulative incidence curve is based on KaplanMeier estimates. Role of the Funding Sources The National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, the U.S. Food and Drug Administration Office of Orphan Products, and the Amgen Corporation supported this study. The Amgen Corporation provided the data on the incidence of VTEs among patients with rheumatoid arthritis. The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the paper for publication. Results Patients We included data from all 180 study patients enrolled in WGET in our study. Table 1 outlines key demographic characteristics and clinic data for the entire cohort and the VTE subgroups. Table 1. Baseline Demographic Characteristics and Clinical Data of Full Study Cohort and Venous Thrombotic Event Subgroups within Wegener Granulomatosis Cohort Incidence Rates of VTE in Wegener Granulomatosis and Comparison Groups At the end of the observation period, 29 of 180 patients (16%) with Wegener granulomatosis had had a VTE at some time: 13 (7.2%) had a history of VTE before WGET enrollment and 16 (8.9%) had first-time VTEs during WGET. The 16 new VTEs among the 167 patients with no history of VTE occurred over 228 person-years of observation, yielding an incidence rate of 7.0 per 100 person-years (95% CI, 4.0 to 11.4). The rates of VTEs did not differ between the etanercept and placebo groups. Clinical Characteristics of Patients with VTEs Appendix Tables 1 and 2 outline the clinical details of all VTEs among the Wegener granulomatosis study sample during and before WGET, respectively. The median time from WGET enrollment (active disease) to VTE in patients who experienced an event was 2.07 months (range, 0.07 to 21.13 months). The Figure shows the time to first VTE for the Wegener granulomatosis group. No participant had more than 1 VTE during WGET. Figure. Time to first venous thrombotic event (VTE) among patients with Wegener granulomatosis. Ten of 16 patients (63%) had active Wegener granulomatosis at the time of the event during WGET. In addition, 11 of the 16 patients (69%) were found to have active Wegener granulomatosis on the study visit before the event, including 3 of the 7 patients whose Wegener granulomatosis was not active at the time of the event. Visits for these 3 patients occurred 14, 33, and 49 days, respectively, before the event. Thus, for 13 of 16 patients (81%) who had VTEs during WGET, Wegener granulomatosis was active at the time of the event or within 2 months before the event. Before WGET enrollment, 18 VTEs occurred among 13 patients. Information on Wegener granulomatosis disease status was available for 12 of 13 first VTEs: Wegener granulomatosis was active in 10 of 12 cases (83%) at the time of the event. Seven of the 13 first VTEs occurred within the 3 months before WGET randomization, including 3 VTEs occurring less than 2 weeks before randomization. We excluded these 7 events from prospective calculation of incident VTE. There were few differences between the 16 patients who had VTE during WGET and the 151 WGET participants who had no history of VTE (Table 1). Compared with participants who did not have an event, those who had a VTE were older at baseline (mean age, 57.5 years vs. 48.6 years; P= 0.039). Aspirin use did not differ between patients with or without VTEs (2 of 16 patients vs. 14 of 151 patients; P> 0.2). Length of hospitalization (4.5 days vs. 6.0 days; P> 0.2) and the proportion of patients hospitalized (50.0% vs. 34.4%, P> 0.2) also did not differ between patients with VTE during WGET and those without a VTE. Discussion To our knowledge, our study is the first to investigate the incidence of VTE in Wegener granulomatosis using a large, well-characterized study cohort and to identify deep venous thrombosis as an important clinical feature of Wegener granulomatosis. Most VTEs in the WGET occurred either during periods of unequivocally active disease or within 2 months of a documented disease flare. Similarly, most VTEs that occurred before the start of the WGET observation period were also associated with active vasculitis. These results suggest that the increased risk for thrombosis bears an important relationship to disease activity in Wegener granulomatosis. Comparison against other groups of patients with VTEs is helpful to appreciate the magnitude of the increased incidence of VTEs in Wegener granulomatosis (Table 2). In a healthy, male, Swedish population, 65 VTEs occurred over 30 years of follow-up, totaling 21007 observation-years and resulting in an incidence rate of first VTE of 0.31 per 100 person-years (CI, 0.4 to 0.4 per 100 person-years) (13). Comparison with this group is relevant because the age of the sample was similar to that of the WGET cohort; the cli

Lansoprazole for children with poorly controlled asthma: a randomized controlled trial.

CONTEXT Asymptomatic gastroesophageal reflux (GER) is prevalent in children with asthma. Untreated GER has been postulated to be a cause of inadequate asthma control in children despite inhaled corticosteroid treatment, but it is not known whether treatment with proton pump inhibitors improves asthma control. OBJECTIVE To determine whether lansoprazole is effective in reducing asthma symptoms in children without overt GER. DESIGN, SETTING, AND PARTICIPANTS The Study of Acid Reflux in Children With Asthma, a randomized, masked, placebo-controlled, parallel clinical trial that compared lansoprazole with placebo in children with poor asthma control who were receiving inhaled corticosteroid treatment. Three hundred six participants enrolled from April 2007 to September 2010 at 19 US academic clinical centers were followed up for 24 weeks. A subgroup had an esophageal pH study before randomization. INTERVENTION Participating children were randomly assigned to receive either lansoprazole, 15 mg/d if weighing less than 30 kg or 30 mg/d if weighing 30 kg or more (n = 149), or placebo (n = 157). MAIN OUTCOME MEASURES The primary outcome measure was change in Asthma Control Questionnaire (ACQ) score (range, 0-6; a 0.5-unit change is considered clinically meaningful). Secondary outcome measures included lung function measures, asthma-related quality of life, and episodes of poor asthma control. RESULTS The mean age was 11 years (SD, 3 years). The mean difference in change (lansoprazole minus placebo) in the ACQ score was 0.2 units (95% CI, 0.0-0.3 units). There were no statistically significant differences in the mean difference in change for the secondary outcomes of forced expiratory volume in the first second (0.0 L; 95% CI, -0.1 to 0.1 L), asthma-related quality of life (-0.1; 95% CI, -0.3 to 0.1), or rate of episodes of poor asthma control (relative risk, 1.2; 95% CI, 0.9-1.5). Among the 115 children with esophageal pH studies, the prevalence of GER was 43%. In the subgroup with a positive pH study, no treatment effect for lansoprazole vs placebo was observed for any asthma outcome. Children treated with lansoprazole reported more respiratory infections (relative risk, 1.3 [95% CI, 1.1-1.6]). CONCLUSION In this trial of children with poorly controlled asthma without symptoms of GER who were using inhaled corticosteroids, the addition of lansoprazole, compared with placebo, improved neither symptoms nor lung function but was associated with increased adverse events. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00442013.

Effect of obesity on clinical presentation and response to treatment in asthma.

Obesity is a risk factor for being diagnosed with asthma, but there is conflicting evidence on whether obesity is a risk factor for lung function abnormalities characteristic of asthma. We studied a cohort of 488 subjects, 47% of whom were obese. Obese and non-obese subjects with asthma had similar airflow limitation and bronchodilator responsiveness, but obese participants had increased sleep disturbance and gastroesophageal reflux disease, higher cytokine levels, and a trend towards increased exacerbations when treated with theophylline. Obese and non-obese asthmatics have similar lung function abnormalities, but comorbidities and altered responses to medications may significantly affect asthma control in obese people.

Allergic Rhinitis and Sinusitis in Asthma: Differential Effects on Symptoms and Pulmonary Function

BACKGROUND Allergic rhinitis and sinusitis are frequently associated with asthma. The purpose of this study was to determine the impact of self-reported allergic rhinitis and sinusitis on lower airway disease in a large cohort of participants with well-characterized asthma. METHODS A cohort study of participants in two trials of the American Lung Association-Asthma Clinical Research Centers: 2,031 asthmatics in the Safety of Inactivated Influenza Vaccine in Asthma in Adults and Children (SIIVA) trial and 488 asthmatics in the Effectiveness of Low Dose Theophylline as Add-on Treatment in Asthma (LODO) trial. At baseline, participants reported the presence of allergic rhinitis and sinusitis, and then lung function and asthma control were measured. During the trials, participants were monitored for asthma exacerbations. RESULTS More than 70% of participants reported either allergic rhinitis or sinusitis. Sinusitis was more common in female patients (odds ratio, 1.46 [SIIVA]), those with gastroesophageal reflux disease (odds ratio, 2.21 [SIIVA]), and those of white race (odds ratio, 1.53 [SIIVA]). Similar associations were seen for allergic rhinitis. LODO participants with allergic rhinitis and sinusitis had increased asthma symptoms and a trend toward more sleep disturbance. Participants with allergic rhinitis had higher baseline lung function than those without allergic rhinitis measured by peak flow (91.2% vs 95.8% in the SIIVA trial). Participants with sinusitis had similar lung function to those without sinusitis. Participants with and without allergic rhinitis had similar exacerbation rates. In the LODO trial only, participants with sinusitis had increased asthma exacerbations (5.68 per patient per year vs 3.72 per patient per year). CONCLUSION Allergic rhinitis and sinusitis are associated with more severe asthmatic symptoms and, in patients with poorly controlled asthma, more exacerbations but are not associated with low lung function.

The multicenter uveitis steroid treatment trial: rationale, design, and baseline characteristics.

PURPOSE To describe the design and methods of the Multicenter Uveitis Steroid Treatment (MUST) trial and the baseline characteristics of enrolled patients. DESIGN Baseline data from a 1:1 randomized, parallel treatment design clinical trial at 23 clinical centers comparing systemic corticosteroid therapy (and immunosuppression when indicated) with fluocinolone acetonide implant placement. METHODS Eligible patients had active or recently active noninfectious intermediate uveitis, posterior uveitis, or panuveitis. The study design had 90% power (2-sided type I error rate, 0.05) to detect a 7.5-letter (1.5-line) difference between groups in the mean visual acuity change between baseline and 2 years. Secondary outcomes include ocular and systemic complications of therapy and quality of life. Baseline characteristics include demographic and clinical characteristics, quality of life, and reading center gradings of lens and fundus photographs, optical coherence tomography images, and fluorescein angiograms. RESULTS Over 3 years, 255 patients were enrolled (481 eyes with uveitis). At baseline, 50% of eyes with uveitis had best-corrected visual acuity worse than 20/40 (16% worse than 20/200). Lens opacities (39% of gradeable phakic eyes), macular edema (36%), and epiretinal membrane (48%) were common. Mean health utility was 74.1. CONCLUSIONS The MUST trial will compare fluocinolone acetonide implant versus systemic therapy for management of intermediate uveitis, posterior uveitis, and panuveitis. Patients with intermediate uveitis, posterior uveitis, or panuveitis enrolled in the trial had a high burden of reduced visual acuity, cataract, macular edema, and epiretinal membrane; overall quality of life was lower than expected based on visual acuity.

Original Research: ASTHMAAllergic Rhinitis and Sinusitis in Asthma: Differential Effects on Symptoms and Pulmonary Function

BACKGROUND Allergic rhinitis and sinusitis are frequently associated with asthma. The purpose of this study was to determine the impact of self-reported allergic rhinitis and sinusitis on lower airway disease in a large cohort of participants with well-characterized asthma. METHODS A cohort study of participants in two trials of the American Lung Association-Asthma Clinical Research Centers: 2,031 asthmatics in the Safety of Inactivated Influenza Vaccine in Asthma in Adults and Children (SIIVA) trial and 488 asthmatics in the Effectiveness of Low Dose Theophylline as Add-on Treatment in Asthma (LODO) trial. At baseline, participants reported the presence of allergic rhinitis and sinusitis, and then lung function and asthma control were measured. During the trials, participants were monitored for asthma exacerbations. RESULTS More than 70% of participants reported either allergic rhinitis or sinusitis. Sinusitis was more common in female patients (odds ratio, 1.46 [SIIVA]), those with gastroesophageal reflux disease (odds ratio, 2.21 [SIIVA]), and those of white race (odds ratio, 1.53 [SIIVA]). Similar associations were seen for allergic rhinitis. LODO participants with allergic rhinitis and sinusitis had increased asthma symptoms and a trend toward more sleep disturbance. Participants with allergic rhinitis had higher baseline lung function than those without allergic rhinitis measured by peak flow (91.2% vs 95.8% in the SIIVA trial). Participants with sinusitis had similar lung function to those without sinusitis. Participants with and without allergic rhinitis had similar exacerbation rates. In the LODO trial only, participants with sinusitis had increased asthma exacerbations (5.68 per patient per year vs 3.72 per patient per year). CONCLUSION Allergic rhinitis and sinusitis are associated with more severe asthmatic symptoms and, in patients with poorly controlled asthma, more exacerbations but are not associated with low lung function.

Randomized trial of the effect of drug presentation on asthma outcomes: The American Lung Association Asthma Clinical Research Centers

BACKGROUND Information that enhances expectations about drug effectiveness improves the response to placebos for pain. Although asthma symptoms often improve with placebo, it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit. OBJECTIVE The study objective was to determine whether response to placebo or a leukotriene antagonist (montelukast) can be augmented by messages that increase expectation of benefit. METHODS A randomized 20-center controlled trial enrolled 601 asthmatic patients with poor symptom control who were assigned to one of 5 study groups. Participants were randomly assigned to one of 4 treatment groups in a factorial design (ie, placebo with enhanced messages, placebo with neutral messages, montelukast with enhanced messages, or montelukast with neutral messages) or to usual care. Assignment to study drug was double masked, assignment to message content was single masked, and usual care was not masked. The enhanced message aimed to increase expectation of benefit from the drug. The primary outcome was mean change in daily peak flow over 4 weeks. Secondary outcomes included lung function and asthma symptom control. RESULTS Peak flow and other lung function measures were not improved in participants assigned to the enhanced message groups versus the neutral messages groups for either montelukast or placebo; no differences were noted between the neutral placebo and usual care groups. Placebo-treated participants had improved asthma control with the enhanced message but not montelukast-treated participants; the neutral placebo group did have improved asthma control compared with the usual care group after adjusting for baseline difference. Headaches were more common in participants provided messages that mentioned headache as a montelukast side effect. CONCLUSIONS Optimistic drug presentation augments the placebo effect for patient-reported outcomes (asthma control) but not lung function. However, the effect of montelukast was not enhanced by optimistic messages regarding treatment effectiveness.

Risk of elevated intraocular pressure and glaucoma in patients with uveitis: results of the multicenter uveitis steroid treatment trial.

OBJECTIVE To report the 2-year incidence of raised intraocular pressure (IOP) and glaucomatous optic nerve damage in patients with uveitis randomized to either fluocinolone acetonide (FA) implants or systemic therapy. Secondarily, we sought to explore patient and eye characteristics associated with IOP elevation or nerve damage. DESIGN A randomized, partially masked trial in which patients were randomized to either FA implants or systemic therapy. PARTICIPANTS Patients aged ≥ 13 years with noninfectious intermediate, posterior, or panuveitis active within the prior 60 days for which systemic corticosteroids were indicated were eligible. METHODS Visual fields were obtained at baseline and every 12 months using the Humphrey 24-2 Swedish interactive threshold algorithm (SITA) fast protocol. Stereoscopic optic nerve photos were taken at baseline and at 3-, 6-, 12-, and 24-month follow-up visits. Masked examiners measured IOP at every study visit. MAIN OUTCOME MEASURES Glaucoma was diagnosed based on an increase in optic nerve cup-to-disc ratio with visual field worsening or increased cup-to-disc ratio alone, for cases where visual field change was not evaluable, because of missing data or severe visual field loss at baseline. RESULTS Most patients were treated as assigned; among those evaluated for glaucoma, 97% and 10% of patients assigned to implant and systemic treatment, respectively, received implants. More patients (65%) assigned to implants experienced an IOP elevation of ≥ 10 mmHg versus 24% assigned to systemic treatment (P<0.001). Similarly, 69% of patients assigned to the implant required IOP-lowering therapy versus 26% in the systemic group (P<0.001). Glaucomatous optic nerve damage developed in 23% versus 6% (P<0.001) of implant and systemic patients, respectively. In addition to treatment assignment, black race, use of IOP-lowering medications, and uveitis activity at baseline were associated with incident glaucoma (P<0.05). CONCLUSIONS Implant-assigned eyes had about a 4-fold risk of developing IOP elevation of ≥ 10 mmHg and incident glaucomatous optic neuropathy over the first 2 years compared with those assigned to systemic therapy. Central visual acuity was unaffected. Aggressive IOP monitoring with early treatment (often including early filtration surgery) is needed to avoid glaucoma when vision-threatening inflammation requires implant therapy. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Methacholine challenge test: Diagnostic characteristics in asthmatic patients receiving controller medications

BACKGROUND The methacholine challenge test (MCT) is commonly used to assess airway hyperresponsiveness, but the diagnostic characteristics have not been well studied in asthmatic patients receiving controller medications after the use of high-potency inhaled corticosteroids became common. OBJECTIVES We investigated the ability of the MCT to differentiate participants with a physicians diagnosis of asthma from nonasthmatic participants. METHODS We conducted a cohort-control study in asthmatic participants (n= 126) who were receiving regular controller medications and nonasthmatic control participants (n= 93) to evaluate the sensitivity and specificity of the MCT. RESULTS The overall sensitivity was 77% and the specificity was 96% with a threshold PC(20) (the provocative concentration of methacholine that results in a 20% drop in FEV(1)) of 8 mg/mL. The sensitivity was significantly lower in white than in African American participants (69% vs 95%, P= .015) and higher in atopic compared with nonatopic (82% vs 52%, P= .005). Increasing the PC(20) threshold from 8 to 16 mg/mL did not noticeably improve the performance characteristics of the test. African American race, presence of atopy, and lower percent predicted FEV(1) were associated with a positive test result. CONCLUSIONS The utility of the MCT to rule out a diagnosis of asthma depends on racial and atopic characteristics. Clinicians should take into account the reduced sensitivity of the MCT in white and nonatopic asthmatic patients when using this test for the diagnosis of asthma.