Long-term Safety and Efficacy of Reslizumab in Patients with Eosinophilic Asthma.

BACKGROUND: In placebo-controlled trials, reslizumab, an anti-IL-5 monoclonal antibody, significantly reduced asthma exacerbations and improved lung function and asthma control in patients with eosinophilic asthma. OBJECTIVE: This open-label extension study evaluated safety and efficacy of reslizumab for up to 24 months. METHODS: After participation in 1 of 3 placebo-controlled, phase III trials in moderate-to-severe eosinophilic asthma, patients received reslizumab 3.0 mg/kg intravenously every 4 weeks for up to 24 months. Adverse events (AEs), lung function, and patient-reported asthma control were evaluated. RESULTS: In the open-label extension, 1,051 patients received ≥1 reslizumab dose (480 reslizumab-naïve, 571 reslizumab-experienced); median (range) exposure was 319 (36-840) and 343 (36-863) days in reslizumab-naïve and reslizumab-experienced patients, respectively. Continuous exposure, including during the placebo-controlled studies, was ≥12 months for 740 patients and ≥24 months for 249 patients. The most common AEs were worsening of asthma and nasopharyngitis. Serious AEs affected 78 of 1,051 (7%) patients; 18 of 1,051 (2%) discontinued treatment because of AEs; and there were 3 deaths (all non-treatment-related). Fifteen adult patients (15 of 1,023; 1%) had malignancies of diverse tissue types. Reslizumab-experienced patients maintained improved lung function and asthma control; reslizumab-naïve patients had improvements in these measures throughout open-label treatment. Blood eosinophil counts appeared to be returning to baseline after reslizumab discontinuation. CONCLUSIONS: In patients with moderate-to-severe eosinophilic asthma, intravenous reslizumab 3.0 mg/kg displays favorable long-term safety and sustained long-term efficacy. Initial improvements in lung function and asthma control were maintained for up to 2 years. These findings substantially add to our understanding of the long-term safety and efficacy of anti-IL-5 strategies.

Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL-23 receptor signaling and IL-17A production in patients with severe asthma.

BACKGROUND: Women have an increased prevalence of severe asthma compared with men. IL-17A is associated with severe asthma and requires IL-23 receptor (IL-23R) signaling, which is negatively regulated by let-7f microRNA. OBJECTIVE: We sought to Determine the mechanism by which 17ß-estradiol (E2) and progesterone (P4) increase IL-17A production. METHODS: IL-17A production was determined by using flow cytometry in TH17 cells from women (n = 14) and men (n = 15) with severe asthma. Cytokine levels were measured by using ELISA, and IL-23R and let-7f expression was measured by using quantitative PCR in TH17-differentiated cells from healthy women (n = 13) and men (n = 14). In sham-operated or ovariectomized female mice, 17ß-E2, P4, 17ß-E2+P4, or vehicle pellets were administered for 3 weeks before ex vivo TH17 cell differentiation. Airway neutrophil infiltration and CXCL1 (KC) expression were also determined in ovalbumin (OVA)-challenged wild-type female recipient mice with an adoptive transfer of OVA-specific TH17 cells from female and male mice. RESULTS: In patients with severe asthma and healthy control subjects, IL-17A production was increased in TH17 cells from women compared with men. IL-23R expression was increased and let-7f expression was decreased in TH17-differentiated cells from women compared with men. In ovariectomized mice IL-17A and IL-23R expression was increased and Let-7f expression was decreased in TH17 cells from mice administered 17ß-E2+P4 compared with those administered vehicle. Furthermore, transfer of female OVA-specific TH17 cells increased acute neutrophil infiltration in the lungs of OVA-challenged recipient mice compared with transfer of male OVA-specific TH17 cells. CONCLUSIONS: 17ß-E2+P4 increased IL-17A production from TH17 cells, providing a potential mechanism for the increased prevalence of severe asthma in women compared with men.

Safety of multiple aeroallergen rush immunotherapy using a modified schedule.

Rush immunotherapy (RIT) accelerates the build-up phase of traditional IT. The biggest potential benefit of using RIT is decreased time to symptomatic improvement. However, aeroallergen RIT carries an increased risk of systemic reaction (SR) compared with traditional IT. This study was designed to assess the safety of a modified 1-day multiple aeroallergen RIT protocol. A retrospective chart review was performed of 138 patients from an outpatient, university-based allergy practice who underwent RIT between November 2007 and February 2011. The RIT protocol consisted of eight injections over 5 hours, and stopped at one 10-fold dilution below the maintenance vial. All patients were premedicated on the same day of RIT with prednisone and histamine 1 and 2 receptor blockers. Primary end point observed was rate of SR. One hundred thirty-eight patients received a total of 2911 RIT injections. Thirty- eight patients (28%) had SRs. The SR rate per injection was 1.3%. Most of the reactions (82%) occurred after the last dose of the protocol. No patients with SR had severe anaphylaxis requiring emergency department support or hospitalization. The post-RIT SR rate was within the range seen with traditional IT. Well-controlled asthmatic patients were not at increased risk of SR compared with nonasthmatic patients. Modification of RIT to end at one 10-fold dilution below the maintenance vial for multiple aeroallergen RIT did not significantly decrease the SR rate compared with other protocols that end at the maintenance vial. Unlike hymenoptera RIT, aeroallergen RIT continues to be associated with a high risk of SR compared with traditional IT.

Comparison of the sedating effects of levocetirizine and cetirizine: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Compared with placebo, levocetirizine has been found to be less sedating than cetirizine in separate trials. However, whether levocetirizine is less sedating than its parent drug cetirizine has not yet been studied in a randomized trial. OBJECTIVE: To determine whether levocetirizine is less sedating than cetirizine. METHODS: We conducted a randomized, double-blind, crossover, placebo-controlled trial examining sedation and allergy symptoms in patients with perennial allergic rhinitis who had previously reported significant sedation with cetirizine. Enrollment ran from January 28, 2009, to February 25, 2009. All patients completed the study by April 17, 2009. Thirty patients enrolled, and 29 patients completed the study (1 patient did not return her questionnaire). In a double-blind fashion, the 29 study participants received levocetirizine, 5 mg daily for 1 week, cetirizine, 10 mg daily for 1 week, and an equivalent placebo pill for 1 week in randomized order with washout periods before each treatment arm. At the end of each washout period and each treatment period, participants completed a 1-page questionnaire. This questionnaire included questions about sedation or sleepiness in the form of a modified Epworth Sleepiness Scale, a Likert scale measuring general or global sedation, and allergy symptoms as measured by the total rhinitis symptom score. RESULTS: Sedation as measured by both the modified Epworth Sleepiness Scale and the Likert scale was not significantly different between the levocetirizine and cetirizine treatments. CONCLUSIONS: In patients with a perceived history of sedation with cetirizine, most were able to tolerate levocetirizine. However, this controlled trial also suggests that many of these patients would tolerate cetirizine if given in a masked manner. Therefore, patients with a history of mild to moderate sedation with cetirizine are unlikely to experience a different sedation profile with levocetirizine.

A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patients with asthma.

RATIONALE: 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. OBJECTIVES: To evaluate efficacy and safety of AMG 317 in patients with moderate to severe asthma. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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).

Use of olopatadine ophthalmic solution and reactivity of histamine skin testing.

The significant morbidity of allergic rhinitis and allergic conjunctivitis necessitates that diagnosis must be as accurate as possible. However, the very drugs used to treat allergic symptoms have been found to suppress histamine-induced skin testing, making the diagnosis very challenging. Oral formulations of antihistamines are well known to diminish skin test reactivity, but ocular application has never been studied to our knowledge. This study was performed to evaluate whether olopatadine hydrochloride 0.2% ophthalmic solution suppressed histamine-induced wheals and flares on skin-prick testing. A randomized, double-blinded, placebo-controlled, single-center, cross-over pilot study was performed that compared histamine-induced wheal and flare areas after 7-10 days of treatment with both olopatadine 0.2% ophthalmic solution and artificial tears, allowing for a 7- to 10-day washout period between medications. From a total of 24 patients randomized, 21 subjects completed the study, 86% of whom were female. There were no statistically significant differences among both the wheal and the flare areas when comparing treatment with olopatadine and placebo, under the 5% significance level. Although characterized by a small sample size and a preponderance of female subjects, our data suggest that olopatadine does not suppress wheal and flare areas during allergy testing, and discontinuation in preparation for skin-prick testing does not appear to be necessary.

Accidental needle sticks, the Occupational Safety and Health Administration, and the fallacy of public policy.

BACKGROUND: Current Occupational Safety and Health Administration (OSHA) guidelines mandate the use of safety needles when allergy injections are given. Safety needles for intradermal testing remain optional. Whether safety needles reduce the number of accidental needle sticks (ANSs) in the outpatient setting has yet to be proven. OBJECTIVE: To determine the rate of ANSs with new (safety) needles vs old needles used in allergy immunotherapy and intradermal testing. METHODS: Allergy practices from 22 states were surveyed by e-mail. RESULTS: Seventy practices (28%) responded to the survey. Twice as many ANSs occurred in practices giving immunotherapy when using new needles vs old needles (P < .01). The rate of ANSs was roughly the same for intradermal testing with new needles vs old needles. CONCLUSIONS: These findings further question whether OSHA's guidelines for safety needle use in outpatient practice need revision and if allergy practices might be excluded from the requirement to use safety needles.

Nasal cytology: a marker of clinically silent inflammation in patients with obstructive sleep apnea and a predictor of noncompliance with nasal CPAP therapy.

STUDY OBJECTIVES: Patients with obstructive sleep apnea treated with nasal continuous positive airway pressure (CPAP) often complain of nasal side effects. We studied patients before and after initiation of nasal CPAP to see how treatment affected nasal function and markers of nasal inflammation. We searched for pretreatment findings that might help to predict noncompliance. METHODS: Nasal symptom scores, nasal flow by anterior rhinomanometry, mediator levels (intercellular adhesion molecule-1, interleukin-6, interleukin-8 and interleukin-13), and nasal scrapes for cytology were obtained at baseline and monthly for up to 3 months of nasal CPAP therapy. Compliance was assessed from the patient's report and by recording hours of usage for up to 19 months of follow-up. RESULTS: Thirty-eight patients with newly diagnosed obstructive sleep apnea were classified as having no rhinitis (42%), allergic rhinitis (37%), or nonallergic rhinitis (21%). There was no significant difference in compliance in patients with and without rhinitis. Compliant and noncompliant patients showed no significant differences in their baseline nasal symptom scores, nasal flow, and mediator levels. Nasal neutrophil counts before treatment were greater in noncompliant than in compliant patients (p = .004) and greater in those discontinuing because of nasal symptoms than in patients who quit for other reasons (p = .05). There was a positive correlation between neutrophil counts and nasal bacterial scores, both before and after treatment with nasal CPAP. CONCLUSIONS: Patients with increased neutrophil counts in the nasal scrape before beginning nasal CPAP are at increased risk of discontinuing therapy. They appear to have subclinical nasal inflammation that cannot be identified from clinical assessment, nasal symptom scores or rhinomanometry.

Natural history and clinical features of aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinosinusitis, nasal polyposis, asthma and precipitation of asthma, and rhinitis attacks after ingestion of aspirin (ASA) and most other nonsteroidal antiinflammatory drugs (NSAIDs). Although precipitation of asthma attacks by ingestion of ASA and other NSAIDs is considered a hallmark of the syndrome, the respiratory mucosal inflammatory disease process begins and continues in the absence of ongoing or even intermittent exposure to ASA or NSAIDs. The typical patient with AERD is an adult who develops refractory chronic rhinitis in the third or fourth decade of life. The chronic rhinitis evolves into chronic eosinophilic rhinosinusitis with associated nasal polyposis. Anosmia appears in most patients. CT of the sinuses most often demonstrates pansinusitis and patients often undergo multiple sinus operations resulting in only limited temporary benefit. During the evolution of the sinus disease persistent asthma develops. Finally, if patients are exposed to ASA or NSAIDs acute respiratory reactions begin to occur. Despite subsequent avoidance of ASA and other NSAIDs, the respiratory mucosal inflammatory disease persists, often requiring systemic corticosteroids for control of both upper- and lower-respiratory tract symptoms. Adequate control of asthma can often only be accomplished with the simultaneous control of the associated rhinosinusitis. With few exceptions, once AERD develops it remains for the remainder of the patient s life.

Food Allergy.

Although many emerging therapies demonstrate theoretical and practical promise, strict elimination of the allergenic food remains the only proven therapy for food hypersensitivity. Given such therapeutic limitations, accurate diagnosis and thorough patient education are critical for proper management. This is particularly important for individuals with anaphylactic potential, as food allergy is currently the single leading cause of anaphylaxis treated in hospital emergency departments.