Avner Reshef

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.)

Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: Consensus report of an International Working Group

To cite this article: Cicardi M, Bork K, Caballero T, Craig T, Li HH, Longhurst H, Reshef A, Zuraw B on behalf of HAWK (Hereditary Angioedema International Working Group). Evidence‐based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy 2012; 67: 147–157.

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.

Immunoglobulin E antibody reactivity to the major shrimp allergen, tropomyosin, in unexposed Orthodox Jews

Background Assessment of allergic (IgE antibody‐mediated) reactions to foods may become complicated by cross‐reactivity that can occur among certain food families and between foods and seemingly unrelated allergens.

Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial

BACKGROUND The For Angioedema Subcutaneous Treatment (FAST)-3 study was a phase III, randomized, double-blind, placebo-controlled study of icatibant (bradykinin B(2) receptor antagonist) in subjects with hereditary angioedema (HAE) resulting from C1-INH deficiency or dysfunction (type I/II). OBJECTIVE To investigate icatibant efficacy and safety in subjects with acute HAE attacks. METHODS Subjects with moderate to very severe cutaneous or abdominal symptoms received icatibant (n = 43) or placebo (n = 45). Five subjects with laryngeal (mild-to-moderate) first attacks received icatibant (n = 3) or placebo (n = 2), and 5 subjects with severe laryngeal first attacks received open-label icatibant. RESULTS Cutaneous or abdominal attacks: icatibant significantly reduced median times (vs placebo) to 50% or more reduction in symptom severity (2.0 vs 19.8 hours; P < .001, primary endpoint), onset of primary symptom relief (1.5 vs 18.5 hours; P < .001, key secondary endpoint), or almost complete symptom relief (8.0 vs 36.0 hours; P = .012) and provided a shorter time to initial symptom relief (0.8 vs 3.5 hours; P < .001). For laryngeal attacks, median time to 50% or more reduction in symptom severity was 2.5 hours (icatibant) and 3.2 hours (placebo). No icatibant-treated subject required rescue medication before symptom relief occurred. The incidence of adverse events (AEs) was similar in icatibant- and placebo-treated subjects (41% and 52%, respectively). All icatibant-treated subjects experienced injection site reactions, but none reported clinically relevant changes in safety parameters or serious AEs. CONCLUSIONS FAST-3 demonstrated that icatibant was effective and generally well tolerated in subjects with acute HAE attacks. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00912093.

The Hypereosinophilic Syndrome Associated with CD4+CD3″ Helper Type 2 (Th2) Lymphocytes

We describe herein the clinical and laboratory manifestations of a unique group of patients (pts) presenting with hypereosinophilic syndrome (HES) who were treated in our medical centers for 4–13 years. Skin biopsies, flow cytometry of peripheral blood mononuclear cells (PBMC), assays for cytokines and immunoglobulin (Ig) production in vitro, and Southern blots of T-cell receptor (TCR) genes were performed. All four pts had a persistent hypereosinophilia (>1.9 × 109/L) and chronic skin rash. Three of four had elevated IgE, thrombotic manifestations and lung involvement (asthma and/or infiltrates), and one had deforming sero-negative arthritis of the hands. 66–95% of their peripheral T-cells expressed CD4 but not CD3 or TCR molecules on the cell surface membrane. Activated CD4+CD3- cells secreted interleukin (IL)- 4 and/or 5, and were required for maximal IgE secretion by autologous B-cells. Two pts had evidence of rearrangement of TCR genes of the CD4+CD3- cells, one of whom died of anaplastic lymphoma. In conclusion, HES with CD4+CD3- lymphocytosis may be associated with high serum IgE, dermatological, pulmonary, thrombotic and rheumatic manifestations which may be due to Th2 effects of CD4+CD3-cells migrating to end organs. Fatal systemic lymphoid malignancy may also develop in some pts with monoclonal expansion of the CD4+CD3- T-cells.

Open‐label, multicenter study of self‐administered icatibant for attacks of hereditary angioedema

Historically, treatment for hereditary angioedema (HAE) attacks has been administered by healthcare professionals (HCPs). Patient self‐administration could reduce delays between symptom onset and treatment, and attack burden. The primary objective was to assess the safety of self‐administered icatibant in patients with HAE type I or II. Secondary objectives included patient convenience and clinical efficacy of self‐administration.

Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study.

Hereditary angioedema (HAE) owing to C1 inhibitor deficiency is an autosomal dominant disorder, characterized by recurrent, potentially life‐threatening, localized attacks of tissue swelling. Current treatment involves the infusion of C1 inhibitor protein (C1‐INH) isolated from human plasma.

Angiotensin-converting enzyme inhibitor-induced angioedema in a community hospital emergency department

BACKGROUND Angiotensin-converting enzyme inhibitors (ACE-Is) are associated with angioedema, a potentially life-threatening adverse reaction. Although multiple studies have been conducted in tertiary care emergency departments (EDs), scarce data are available about the presentation and management of ACE-I-induced angioedema (AIIA) in the community hospital ED. OBJECTIVE To describe the frequency, presentation, and management of AIIA in patients seen in a community hospital ED. METHODS A 5-year medical record review of all patients seen with angioedema at a community hospital ED. Data abstraction focused on demographic factors, initial clinical characteristics, and ED management and disposition of patients with AIIA. RESULTS We identified 166 ED visits for angioedema, including a subset of 50 visits for AIIA (30%; 95% confidence interval, 23%-38%). The AIIA was significantly more likely to be associated with an age of 65 years or older (P = .02), unilateral symptoms (P = .02), and absence of urticaria or itching (P < .001). The ED treatment choices and admission rates were similar between patients with and without AIIA. Community hospital admission rates for AIIA (14%) were significantly lower than those from a comparable tertiary care study (41%) (P = .003); ambulance transport to the ED was nearly 3-fold higher in the tertiary care center study (P = .006). Admission was most strongly related to lack of improvement (P < .001) and history of angioedema in AIIA (P = .009). CONCLUSIONS Angioedema frequency, presentation, and management are similar in community and tertiary care EDs (30%). Urticaria or itching may help differentiate AIIA from allergic reactions, which are otherwise similar in community ED presentation and management.

Recombinant human C1 inhibitor for the prophylaxis of hereditary angioedema attacks: a pilot study

Hereditary angioedema (HAE) is a disease characterized by recurrent tissue swelling affecting various body locations. Recent literature shows that patients with frequent attacks may benefit from long‐term prophylaxis. This study evaluated the safety and prophylactic effect of weekly administrations of recombinant C1INH (rhC1INH).