Jonathan A. Bernstein

Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma

Memory CD4+ T cells that produce both Th2 and Th17 cytokines are increased in the blood of patients with atopic asthma and in the lungs of asthmatic mice, where they contribute to inflammation.

Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema.

BACKGROUND Hereditary angioedema due to C1 inhibitor deficiency is characterized by recurrent acute attacks of swelling that can be painful and sometimes life-threatening. METHODS We conducted two randomized trials to evaluate nanofiltered C1 inhibitor concentrate in the management of hereditary angioedema. The first study compared nanofiltered C1 inhibitor concentrate with placebo for treatment of an acute attack of angioedema. A total of 68 subjects (35 in the C1 inhibitor group and 33 in the placebo group) were given one or two intravenous injections of the study drug (1000 units each). The primary end point was the time to the onset of unequivocal relief. The second study was a crossover trial involving 22 subjects with hereditary angioedema that compared prophylactic twice-weekly injections of nanofiltered C1 inhibitor concentrate (1000 units) with placebo during two 12-week periods. The primary end point was the number of attacks of angioedema per period, with each subject acting as his or her own control. RESULTS In the first study, the median time to the onset of unequivocal relief from an attack was 2 hours in the subjects treated with C1 inhibitor concentrate but longer than 4 hours in those given placebo (P=0.02). In the second study, the number of attacks per 12-week period was 6.26 with C1 inhibitor concentrate given as prophylaxis, as compared with 12.73 with placebo (P<0.001); the subjects who received the C1 inhibitor concentrate also had significant reductions in both the severity and the duration of attacks, in the need for open-label rescue therapy, and in the total number of days with swelling. CONCLUSIONS In subjects with hereditary angioedema, nanofiltered C1 inhibitor concentrate shortened the duration of acute attacks. When used for prophylaxis, nanofiltered C1 inhibitor concentrate reduced the frequency of acute attacks. (Funded by Lev Pharmaceuticals; ClinicalTrials.gov numbers, NCT00289211, NCT01005888, NCT00438815, and NCT00462709.)

Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group

Angioedema is defined as localized and self‐limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s). When angioedema recurs without significant wheals, the patient should be diagnosed to have angioedema as a distinct disease. In the absence of accepted classification, different types of angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying angioedema. Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of angioedema.

Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks.

BACKGROUND Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder. OBJECTIVE To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema. METHODS This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours. RESULTS Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus. CONCLUSION C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief.

V75R576 IL-4 Receptor α Is Associated with Allergic Asthma and Enhanced IL-4 Receptor Function

Asthma is a complex polygenic disease. Many studies have implicated the importance of IL-4Rα in the development of allergic inflammation and its gene has been implicated in the genetics of asthma and atopy. In this study, we examined the functional consequences of two of the human IL-4Rα allelic variants that have been found to associate with asthma and atopy. We examined the effects of each variant alone and in combination on IL-4-dependent gene induction. We found that neither the Q576R nor the I75V variants affected IL-4-dependent CD23 expression. However, the combination of V75R576 resulted in expression of an IL-4Rα with enhanced sensitivity to IL-4. We next examined the genetics of five of the known IL-4Rα allelic variants in asthmatic and nonatopic populations. Strikingly, the association of V75/R576 with atopic asthma was greater than either allele alone and the association of R576 with atopic asthma was dependent on the coexistence of V75. A haplotype analysis revealed a single IL-4Rα haplotype that was associated with allergic asthma, VACRS, further confirming the importance of the V75 and R576 combination in the genetics of asthma. This is the first report demonstrating that a functional alteration in IL-4Rα requires the coexistence of two naturally occurring single nucleotide polymorphisms (snps) in combination; neither snp alone is sufficient. These data illustrate the importance of studying snps in combination, because the functional significance of a given snp may only be evident in a specific setting of additional snps in the same or different genes.

The R576 IL-4 receptor α allele correlates with asthma severity☆☆☆★

Abstract Background: Atopic disorders, including asthma, are very prevalent, affecting up to 40% of populations, and their incidence is on the rise. Although environmental factors are important in the development of atopy, there is a strong genetic predisposition. Several genes and chromosomal regions have been linked to atopy and asthma, supporting the polygenic nature of these disorders. IL-4 and IL-13 are T H 2 cytokines with numerous activities that contribute to allergic inflammation and asthma. Both IL-4 and IL-13 use the IL-4 receptor α chain (IL-4Rα) as a component of their respective receptor systems. Allelic variants of IL-4Rα have been reported, and the R576IL-4Rα allele was recently shown to be a risk factor for atopy. Objective: We sought to determine whether the R576 allele was associated with the prevalence or clinical severity of asthma. Methods: We developed a rapid, reliable, PCR-based assay to screen individuals for the R576IL-4Rα allele and used this assay to genotype prospectively recruited individuals with asthma (n = 149) and control subjects (n = 57). Results: There was a strong association of R576IL-4Rα with the prevalence and clinical severity of asthma. In a prospective cohort, homozygosity for R576 was significantly increased in individuals with asthma (n = 149, P = .03; relative risk 8.2) compared with controls (n = 57). Furthermore, 1 or 2 copies R576IL-4Rα correlated with asthma severity establishing a genotype-phenotype relationship and suggesting a gene dosage effect. Conclusions: Thus R576IL-4Rα acts as an allergic asthma susceptibility and disease-modifying gene and may serve as a clinically useful marker of asthma severity. (J Allergy Clin Immunol 1999;104:1008-14.)

Overview of diisocyanate occupational asthma

Surveillance programs established around the world have determined that diisocyanate chemicals are the most common cause of occupational asthma. In the United States approximately 100,000 workers are exposed to these chemical compounds in the workplace each year and 5-10% of these workers will develop occupational asthma. There are no known reliable risk factors or biomarkers which can be used to predict which exposed worker will develop diisocyanate-occupational asthma. Diisocyanate-occupational asthma workers manifest characteristic physiologic responses after specific bronchoprovocation which correlate with pathologic changes in their airways. However, the mechanism(s) for diisocyanate-occupational asthma remains unclear. Specific IgE antibody production to diisocyanates is found in only 10-30% of these workers. Bronchial biopsies and bronchoalveolar lavage have confirmed the presence of T-lymphocytes and eosinophils in the airways of these workers suggesting that T-cell mediated immune responses are more likely to play a central role in this disease. It is essential to diagnose diisocyanate-occupational asthma as early as possible in order to prevent or reduce the significant asthma morbidity associated with continuous long term exposure to these chemicals. Treatment of choice is removal of the worker from further exposure. Prospective studies evaluating larger populations of diisocyanate-exposed workers is essential for a better understanding of the pathogenesis and natural course of diisocyanate-occupational asthma.

Aspirin challenge and desensitization for aspirin-exacerbated respiratory disease: a practice paper

Aspirin desensitization is indicated for patients who have aspirin-exacerbated respiratory disease and whose asthma and/or rhinosinusitis is suboptimally controlled with inhaled corticosteroids and leukotriene-modifying drugs. In this practice paper, the general requirements for aspirin desensitization are presented, the locations where desensitizations can be safely performed are outlined, prechallenge patient preparation is discussed, an oral aspirin challenge protocol is presented, treatment of adverse reactions is reviewed, and maintenance of aspirin desensitization is discussed.

The low prevalence of occupational asthma and antibody-dependent sensitization to diphenylmethane diisocyanate in a plant engineered for minimal exposure to diisocyanates

BACKGROUND Diisocyanate chemicals are leading causes of occupational asthma (OA). METHODS We conducted a cross-sectional study of 243 workers exposed to diphenylmethane diisocyanate (MDI) in a urethane mold plant that had been designed to minimize MDI exposure (levels were maintained below 0.005 ppm and were continuously monitored). All participants were screened by questionnaire and tests for serum antibodies to MDI-human serum albumin (HSA). On the basis of questionnaire responses, diagnoses were derived that included OA; non-OA; work-related and non-work-related rhinitis; and lower respiratory irritant responses. Serial peak expiratory flow rate studies were performed for 2 weeks in 43 workers with and in 23 workers without lower respiratory symptoms. RESULTS Results of serial peak expiratory flow rate studies were abnormal in 3 (33%) of 9 workers with OA, in 2 (50%) of 4 with non-OA, and in 2 (9%) of 23 case control subjects. A significant association was found between peak flow rate variability and a questionnaire asthma diagnosis (chi 2 p < 0.002). Physicians confirmed three cases of OA, one of which occurred in a control worker who was free of symptoms. In all three cases asthma symptoms remitted after the worker left the workplace. Serum specific IgE and IgG levels were elevated in 2 of 243 workers, one of whom was prick test positive to MDI-HSA and had had cutaneous anaphylaxis after MDI exposure. CONCLUSIONS On the basis of these cases, specific work activities associated with exposure to MDI were identified and corrective measures were instituted. Strict control and monitoring of ambient MDI exposure was associated with a low prevalence of specific sensitization to MDI and a lower than expected prevalence of OA.