Hereditary Angioedema Zuraw, Bruce L
The New England journal of medicine,
09/2008, Volume:
359, Issue:
10
Journal Article
Peer reviewed
A 19-year-old woman presents to the emergency department with light-headedness, severe abdominal pain, and intractable nausea and vomiting that began 12 hours earlier. The patient reports previous ...episodes of abdominal pain and swelling of her hands and feet that have been attributed possibly to food allergies, which have recently become more frequent. How should her case be evaluated and treated?
A 19-year-old woman presents to the emergency department with light-headedness, severe abdominal pain, and intractable nausea and vomiting that began 12 hours earlier. How should her case be evaluated and treated?
Foreword
This
Journal
feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.
Stage
A 19-year-old woman presents to the emergency department with light-headedness, severe abdominal pain, and intractable nausea and vomiting that began 12 hours earlier. The patient reports previous episodes of abdominal pain and swelling of her hands and feet that have been attributed possibly to food allergies, which have recently become more frequent. There is no associated urticaria. Her only medication is an oral contraceptive that was started 3 months earlier. She notes a history of similar episodes in her father. She is afebrile, with a blood pressure of 75/40 mm Hg, a pulse of 120 beats per minute, and . . .
...it confirms that HAE with normal C1INH levels encompasses a diverse group of individual diseases. ...it broadens our concept of the underlying pathophysiology of HAE from an exclusive focus on the ...contact system to now including the vasculature itself. ...recently, HAE with normal C1INH levels was divided into patients with a known F12 mutation (HAE-FXII) and those without a F12 mutation (HAE-unknown).
HAE Pathophysiology and Underlying Mechanisms Zuraw, Bruce L.; Christiansen, Sandra C.
Clinical Reviews in Allergy & Immunology,
10/2016, Volume:
51, Issue:
2
Journal Article, Book Review
Peer reviewed
Remarkable progress in understanding the pathophysiology and underlying mechanisms of hereditary angioedema has led to the development of effective treatment for this disorder. Progress in three ...separate areas has catalyzed our understanding of hereditary angioedema. The first is the recognition that HAE type I and type II result from a deficiency in the plasma level of functional
C1 inhibitor
. This observation has led to a detailed understanding of the
SERPING1
mutations responsible for this deficiency as well as the molecular regulation of C1 inhibitor expression and function. The second is that the fundamental cause of swelling is enhanced contact system activation leading to increased generation of
bradykinin
. Substantial progress has been made in defining the parameters regulating
bradykinin
generation and catabolism as well as the receptors that transduce the biologic effects of kinins. The third is the understanding that tissue swelling in hereditary angioedema primarily involves the function of endothelial cell adherens junctions. This knowledge is driving increased attention to the role of endothelial biology in determining disease activity in hereditary angioedema. While there has been considerable progress made, large gaps still remain in our knowledge. Important areas that remain poorly understood include the factors that lead to very low plasma functional C1 inhibitor levels, the triggers of contact system activation in hereditary angioedema, and the role of the
bradykinin
B1 receptor. The phenotypic variability of hereditary angioedema has been extensively documented but never understood. The mechanisms discussed in this chapter likely contribute to this variability. Future progress in understanding these mechanisms should provide new means to improve the diagnosis and treatment of hereditary angioedema.
Abstract Objective Nanofiltered C1-inhibitor (C1INH-nf) is approved for prophylactic treatment of hereditary angioedema. This study assessed the efficacy and safety of C1INH-nf as prophylactic ...therapy in a large cohort of patients with hereditary angioedema. Methods An open-label multicenter extension study was performed involving 146 subjects with hereditary angioedema who were treated with C1INH-nf for up to 2.6 years in centers throughout the United States. Subjects were to be treated with C1INH-nf 1000 units every 3 to 7 days. The primary efficacy variable was the number of attacks of angioedema experienced. Results Subjects experienced a 93.7% reduction in attacks while taking prophylactic C1INH-nf (0.19 attacks per month; interquartile range, 0.00-0.64) compared with the historical rate of attacks. Some 87.7% reported an attack frequency of 1 or less attack per month during prophylactic C1INH-nf and 34.9% had no attacks during the study. Some 7.5% of subjects experienced relatively frequent attacks despite twice-weekly C1INH-nf. Although twice-weekly dosing was highly effective in most subjects, once-weekly dosing provided adequate control in a subgroup of subjects. No clinical characteristics predicted the response to prophylactic C1INH-nf, including historical attack frequency. C1INH-nf was well tolerated. Conclusion Prophylactic C1INH-nf is highly effective and safe, and provides durable prophylaxis in the majority of patients with hereditary angioedema. The recommended dose of C1INH-nf 1000 units twice weekly is supported by this open-label study. Individual patients may benefit from further dose adjustment on the basis of response to therapy and individual treatment goals.
Monoclonal antibodies (mAbs) have been shown to be effective and generally safe across a continually expanding list of therapeutic areas. We describe the advantages and limitations of mAbs as a ...therapeutic option compared with small molecules. Specifically, we discuss a novel mAb in the treatment of hereditary angioedema (HAE), a rare and potentially life-threatening condition characterized by recurrent unpredictable swelling attacks. HAE is mediated by dysregulation of plasma kallikrein activity leading to overproduction of bradykinin. Current prophylactic treatment for HAE includes androgens or replacement of the endogenous plasma kallikrein inhibitor, C1 inhibitor. However, there remains an unmet need for an effective, less burdensome treatment option. Lanadelumab is a fully human mAb targeting plasma kallikrein. Results from clinical trials, including a pivotal Phase 3 study and its ensuing open-label extension study, demonstrated that lanadelumab is associated with few treatment-related adverse events and reduced the rate of HAE attacks. This novel treatment option has the potential to significantly improve the lives of patients with HAE.
This article addresses the potential mechanistic links between hypertension and asthma as well as the influence of coexisting conditions. An approach to the treatment of hypertension in adult ...patients with asthma is outlined.
BACKGROUND: Chronic persistent asthma is characterized by ongoing airway inflammation and airway remodeling. The processes leading to airway remodeling are poorly understood, and there is increasing ...evidence that even aggressive anti-inflammatory therapy does not completely prevent this process. We sought to investigate whether TGFβ1 stimulates bronchial epithelial cells to undergo transition to a mesenchymal phenotype, and whether this transition can be abrogated by corticosteroid treatment or enhanced by the pro-inflammatory cytokine IL-1β. METHODS: BEAS-2B and primary normal human bronchial epithelial cells were stimulated with TGFβ1 and expression of epithelial and mesenchymal markers assessed by quantitative real-time PCR, immunoblotting, immunofluorescence microscopy and zymography. In some cases the epithelial cells were also incubated with corticosteroids or IL-1β. Results were analyzed using non-parametric statistical tests. RESULTS: Treatment of BEAS-2B or primary human bronchial epithelial cells with TGFβ1 significantly reduced the expression level of the epithelial adherence junction protein E-cadherin. TGFβ1 then markedly induced mesenchymal marker proteins such as collagen I, tenascin C, fibronectin and α-smooth muscle actin mRNA in a dose dependant manner. The process of mesenchymal transition was accompanied by a morphological change towards a more spindle shaped fibroblast cell type with a more motile and invasive phenotype. Corticosteroid pre-treatment did not significantly alter the TGFβ1 induced transition but IL-1β enhanced the transition. CONCLUSION: Our results indicate, that TGFβ1 can induce mesenchymal transition in the bronchial epithelial cell line and primary cells. Since asthma has been strongly associated with increased expression of TGFβ1 in the airway, epithelial to mesenchymal transition may contribute to the contractile and fibrotic remodeling process that accompanies chronic asthma.
Scientific and clinical progress together with the development of effective novel therapeutic options has engendered multiple important changes in the diagnosis and management of hereditary ...angioedema (HAE). We now update and extend the 2013 United States Hereditary Angioedema Association Medical Advisory Board guidelines for the treatment and management of HAE. The guidelines are based on a comprehensive literature review with recommendations indicating both the strength of our recommendation and the quality of the underlying evidence. Guidelines are provided regarding the classification, diagnosis, on-demand treatment, prophylactic treatment, special considerations for women and children, development of a comprehensive management and monitoring plan, and assessment of burden of illness for both HAE due to C1 inhibitor deficiency and HAE with normal C1 inhibitor. Advances in HAE treatment now allow the development of management plans that can help many patients with HAE lead a normal life. Achieving this goal requires that physicians be familiar with the diagnostic and therapeutic transformations that have occurred in recent years.
Background The association between obesity and asthma severity and control in children is not well understood. Objective The objective of this study was to examine the association of childhood body ...mass index (BMI) percentile for age of 85% or greater with the number of β-agonist canisters dispensed, corticosteroid courses, emergency department visits, and hospitalizations for asthma. Methods A retrospective cohort of 32,321 children aged 5 to 17 years and given a diagnosis of asthma who received at least 1 asthma (controller or rescue) medication and were enrolled in Kaiser Permanente from 2004-2008 was identified. Outcomes from electronic medical records included β-agonist canister and nebulizer units dispensed per year, hospitalizations and emergency department visits for asthma exacerbations, and oral corticosteroid courses. Potential confounding factors known to influence asthma outcomes were also collected: demographics, parental education level, asthma controller use, gastroesophageal reflux disease diagnosis, and diabetes mellitus diagnosis. Multiple logistic regression models were used to measure the independent association of BMI status with outcomes. Results Even after adjusting for demographics, parental education level, asthma controller use, and gastroesophageal reflux disease and diabetes mellitus diagnoses, overweight (BMI percentile for age, 85% to 94%) and obese (BMI percentile for age, ≥95%) children were more likely to have increased β-agonists dispensed (odds ratio of 1.15 95% CI, 1.02-1.27 and odds ratio of 1.17 95% CI, 1.06-1.29, respectively) and increased risk for oral corticosteroids dispensed (odds ratio of 1.21 95% CI, 1.13-1.29 and odds ratio of 1.28 95% CI, 1.21-1.36, respectively) compared with normal-weight (BMI percentile for age, 16% to 84%) children. Conclusions Our findings suggest that childhood obesity is associated with an increased risk of worse asthma control and exacerbations.
Background Aspirin-exacerbated respiratory disease (AERD) is characterized by tissue eosinophilia and mast cell activation, including abundant production of prostaglandin D2 (PGD2 ). Group 2 innate ...lymphoid cells (ILC2s), which promote tissue eosinophilia and mast cell responses, undergo chemotaxis and cytokine production in response to PGD2 , but it is unknown whether ILC2s are active in patients with AERD. Objective We sought to determine whether ILC2 numbers change in peripheral blood and the nasal mucosa during COX-1 inhibitor–induced reactions in patients with AERD. Methods Blood and nasal scrapings were collected at baseline, during reactions, and after completion of ketorolac/aspirin challenge/desensitization in 12 patients with AERD. ILC2s and eosinophils were quantitated by means of flow cytometry. Urine was also collected, and quantification of PGD2 metabolite and leukotriene E4 levels was done by using ELISA. Baseline and nonsteroidal anti-inflammatory drug reaction clinical data were correlated with cell changes. Results ILC2 numbers significantly increased in nasal mucosal samples and decreased in blood at the time of COX-1 inhibitor reactions in 12 patients with AERD. These changes were not observed in 2 patients without AERD. Furthermore, eosinophil numbers decreased in blood concurrently with significant increases in urinary PGD2 metabolite and leukotriene E4 levels. The magnitude of increases in nasal mucosal ILC2 numbers positively correlated with maximum symptom scores during challenges. Furthermore, blood ILC2 numbers during the reaction correlated with time for the reaction to resolve, possibly reflecting reaction severity. Conclusions ILC2s are recruited to the nasal mucosa during COX-1 inhibitor–induced reactions in patients with AERD, correlating with enhanced production of prostaglandins and leukotrienes.
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