Laurence Bouillet

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.)

Disease expression in women with hereditary angioedema

OBJECTIVE Fluctuations in sex hormones can trigger angioedema attacks in women with hereditary angioedema. Combined oral contraceptive therapies, as well as pregnancy, can induce severe attacks. The course of angioedema may be very variable in different women. STUDY DESIGN Within the PREHAEAT project launched by the European Union, data on 150 postpubertal women with hereditary angioedema were collected in 8 countries, using a patient-based questionnaire. RESULTS Puberty worsened the disease for 62%. Combined oral contraceptives worsened the disease for 79%, whereas progestogen-only pills improved it for 64%. During pregnancies, 38% of women had more attacks, but 30% had fewer attacks. Vaginal delivery was usually uncomplicated. Attacks occurred within 48 hours in only 6% of cases. Those more severely affected during menses had more symptoms during pregnancies, suggesting a hormone-sensitive phenotype for some patients. CONCLUSION The course of angioedema in women with C1 inhibitor deficiency is affected by physiologic hormonal changes; consequently, physicians should take these into account when advising on management.

Hereditary Angioedema Attacks Resolve Faster and Are Shorter after Early Icatibant Treatment

Background Attacks of hereditary angioedema (HAE) are unpredictable and, if affecting the upper airway, can be lethal. Icatibant is used for physician- or patient self-administered symptomatic treatment of HAE attacks in adults. Its mode of action includes disruption of the bradykinin pathway via blockade of the bradykinin B2 receptor. Early treatment is believed to shorten attack duration and prevent severe outcomes; however, evidence to support these benefits is lacking. Objective To examine the impact of timing of icatibant administration on the duration and resolution of HAE type I and II attacks. Methods The Icatibant Outcome Survey is an international, prospective, observational study for patients treated with icatibant. Data on timings and outcomes of icatibant treatment for HAE attacks were collected between July 2009–February 2012. A mixed-model of repeated measures was performed for 426 attacks in 136 HAE type I and II patients. Results Attack duration was significantly shorter in patients treated <1 hour of attack onset compared with those treated ≥1 hour (6.1 hours versus 16.8 hours [p<0.001]). Similar significant effects were observed for <2 hours versus ≥2 hours (7.2 hours versus 20.2 hours [p<0.001]) and <5 hours versus ≥5 hours (8.0 hours versus 23.5 hours [p<0.001]). Treatment within 1 hour of attack onset also significantly reduced time to attack resolution (5.8 hours versus 8.8 hours [p<0.05]). Self-administrators were more likely to treat early and experience shorter attacks than those treated by a healthcare professional. Conclusion Early blockade of the bradykinin B2 receptor with icatibant, particularly within the first hour of attack onset, significantly reduced attack duration and time to attack resolution.

Type III hereditary angio-oedema: clinical and biological features in a French cohort

To cite this article: Vitrat‐Hincky V, Gompel A, Dumestre‐Perard C, Boccon‐Gibod I, Drouet C, Cesbron JY, Lunardi J, Massot C, Bouillet L. Type III hereditary angio‐oedema: clinical and biological features in a French cohort. Allergy 2010; 65: 1331–1336.

BRADYKININ RECEPTOR 2 ANTAGONIST (ICATIBANT) FOR HEREDITARY ANGIOEDEMA TYPE III ATTACKS

In 2000, a new type of hereditary angioedema (HAE) without C1 esterase inhibitor (C1-INH) deficiency, HAE type III, was reported.1,2 It occurred especially in women, and the diagnosis was based on recurrent attacks of subcutaneous or submucosal edema, no chronic relapsing urticaria, familial history, and normal C1INH protein and activity levels. Recent findings3 suggest that bradykinin may play a role in the pathogenesis of angioedema. The morbidity and mortality of HAE are related to abdominal attacks and laryngeal edema. Symptoms seem to be induced or worsened by estrogen.4 In these patients, C1-INH function is normal, and a missense gain-of-function mutation in the F12 gene can be found.5 Treatments for HAE type III are not established, but tranexamic acid seems to be effective for prophylaxis of symptoms. Until recently, the main shortterm treatment for severe HAE attacks was C1-INH concentrate.4 A new therapeutic agent, icatibant, a bradykinin B2 receptor antagonist, is effective for the treatment of HAE with C1-INH deficiency. The efficacy and safety of icatibant in patients with HAE (type I or II) presenting with moderate to severe cutaneous or abdominal attacks were tested in 2 double-blind, randomized, multicenter, phase 3 trials, FAST (For Angioedema Subcutaneous Treatment) 1 and 2.6 We report treatment outcomes in 3 women who fulfilled the diagnosis criteria of HAE type III (Table 1). Patients presented with recurrent severe abdominal attacks, edema of the face, and a family history of angioedema. The C1-INH function was moderately low when the patients took an estrogen-containing contraceptive pill or during pregnancy but was normal after it was discontinued or after delivery. We previously described these data in another patient with HAE type III.7 Levels of C1-INH protein and C4 were normal. All 3 patients had no mutation in the SERPING1 gene. Patient 1 had an identified mutation in the F12 gene. Patient 1 received 1 subcutaneous injection of icatibant, 30 mg, for a severe abdominal attack. Symptom improvement began 30 minutes later, with complete resolution of symptoms by 1 hour after icatibant administration. Patient 2 presented with an unusual severe abdominal attack combined with facial edema. An increase in her dose of tranexamic acid did not improve symptoms. She received an injection of icatibant. Symptoms were relieved within 2 hours. Patient 3 was treated for a severe abdominal attack. After the first injection of icatibant, relief of symptoms occurred within 30 minutes. Symptom recurrence after 6 hours necessitated a second injection of icatibant, which resulted in rapid alleviation of symptoms. For all the patients, icatibant administration was followed by a transient local erythematic reaction at the site of injection. No other adverse reactions to icatibant were noted in the 3 patients. We therefore conclude that icatibant is a safe and effective symptomatic treatment for severe attacks in patients with HAE type III.

Soluble VE-cadherin in rheumatoid arthritis patients correlates with disease activity: Evidence for tumor necrosis factor α–induced VE-cadherin cleavage

OBJECTIVE Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that principally attacks synovial joints. However, accelerated atherosclerosis and increased cardiovascular morbidity and mortality are major clinical consequences of endothelial dysfunction in RA patients. Tumor necrosis factor α (TNFα) is the major mediator of inflammation in RA, related to vascular injury by targeting VE-cadherin, an endothelium-specific adhesion molecule of vital importance for endothelium integrity and angiogenesis. We undertook this study to examine the mechanisms regulating VE-cadherin processing by TNFα and their occurrence in RA. METHODS Human umbilical vein endothelial cells were used in primary culture and treated with recombinant TNFα to study VE-cadherin cleavage. Cell lysates and conditioned media were analyzed by Western blotting for VE-cadherin cytoplasmic domain and extracellular domain (VE-90) generation, respectively. VE-90 was analyzed at baseline and at the 1-year followup in sera from 63 RA patients (from the Very Early Rheumatoid Arthritis cohort) with disease duration of <6 months. RESULTS TNFα induced a time-dependent shedding of VE-90 in cell media. This effect was prevented by tyrosine kinase inhibitors (genistein and PP2) or by knocking down Src kinase. In contrast, tyrosine phosphatase blockade enhanced VE-cadherin cleavage, confirming the requirement of tyrosine phosphorylation processes. In addition, using the matrix metalloproteinase (MMP) activator APMA and the MMP inhibitor GM6001, we demonstrated that MMPs are involved in TNFα-induced VE-cadherin cleavage. Of major importance, VE-90 was detected in sera from the 63 RA patients and was positively correlated with the Disease Activity Score at baseline and after 1-year followup. CONCLUSION These findings provide the first evidence of VE-cadherin proteolysis upon TNFα stimulation and suggest potential clinical relevance of soluble VE-cadherin in management of RA.

A case of hereditary angio‐oedema type III presenting with C1‐inhibitor cleavage and a missense mutation in the F12 gene

1 Suzuki Y, Inagi R, Ando T et al. Human herpesvirus 6 infection as a risk factor for the development of severe drug-induced hypersensitivity syndrome. Arch Dermatol 1998; 134:1108–12. 2 Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses. Allergol Int 2006; 55:1–8. 3 Kano Y, Hirahara K, Sakuma K, Shiohara T. Several herpesviruses can reactivate in a severe drug-induced multiorgan reaction in the same sequential order as in graft-versus-host disease. Br J Dermatol 2006; 155:301–6. 4 Zaia JA. Viral infections associated with bone marrow transplantation. Hematol Oncol Clin North Am 1990; 4:603–23. 5 Zhang C, Todorov I, Zhang Z et al. Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations. Blood 2006; 107:2993–3001. 6 Ichiki Y, Bowlus CL, Shimoda S et al. T cell immunity and graftversus-host disease. Autoimmun Rev 2006; 5:1–9. 7 Jones-Caballero M, Fernandez-Herrera J, Cordoba-Guijarro S et al. Sclerodermatous graft-versus-host disease after donor leucocyte infusion. Br J Dermatol 1998; 139:889–92. 8 Schaffer JV, McNiff JM, Seropian S et al. Lichen sclerosus and eosinophilic fasciitis as manifestations of chronic graft-versus-host disease: expanding the sclerodermoid spectrum. J Am Acad Dermatol 2005; 53:591–601. 9 White JML, Devereux S, Pagliuca A et al. Koebnerizing sclerodermatous graft-versus-host disease caused by donor lymphocyte infusion and interferon-a. Br J Dermatol 2006; 155:621–3. 10 Chosidow O, Bagot M, Vernant JP et al. Sclerodermatous chronic graft-versus-host disease. Analysis of seven cases. J Am Acad Dermatol 1992; 26:49–55.

Benefits of progestin contraception in non-allergic angioedema

Hereditary angioedema attacks can be induced or worsened by oral contraceptive containing oestrogens.

Hereditary angioedema in women

Women with hereditary angioedema (HAE) are more likely to be symptomatic that men. Hormonal factors (puberty, contraception, pregnancy,....) play a significant role in the precipitation or worsening of the condition in women. So, combined contraceptive pills are not indicated and progestogen pill must be preferred. During pregnancy, attack rate can increase (38-48% of women). C1Inhibitor concentrate and tranexamic acid can be used during pregnancy. Attenuated androgens for long term prophylaxis are effective but side effects appear more often in female patients. These side effects are dose dependant and can be attenuated by titrating the dose down the lowest effective level.Women with hereditary angioedema (HAE) are more likely to be symptomatic that men. Hormonal factors (puberty, contraception, pregnancy,....) play a significant role in the precipitation or worsening of the condition in women. So, combined contraceptive pills are not indicated and progestogen pill must be preferred. During pregnancy, attack rate can increase (38-48% of women). C1Inhibitor concentrate and tranexamic acid can be used during pregnancy. Attenuated androgens for long term prophylaxis are effective but side effects appear more often in female patients. These side effects are dose dependant and can be attenuated by titrating the dose down the lowest effective level.

Diagnosis and treatment of bradykinin-mediated angioedema: Outcomes from an angioedema expert consensus meeting

Several types of angioedema exist beyond hereditary angioedema (HAE) types I/II; however, the diagnostic and treatment needs of these conditions are not well understood. Noticeably, there are no licensed treatments available for other forms of angioedema beyond HAE types I/II, and similarly they are unresponsive to conventional antihistamine/glucocorticoid treatment. A group of angioedema experts met in Budapest in May 2013 to discuss such issues, presenting their experience, reviewing available literature and identifying unmet diagnostic and treatment needs in three different angioedema types: HAE with normal C1-inhibitor (C1-INH; previously referred to as type III HAE); nonallergic angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema (ACEI-AAE), and acquired angioedema due to C1-INH deficiency (C1-INH-AAE). The group identified unmet diagnostic and treatment needs in HAE-nC1-INH, C1-INH-AAE and ACEI-AAE, explored remedies and made recommendations on how to diagnose and treat these forms of angioedema. The group discussed the difficulties associated with using diagnostic markers, such as the level and function of C1-INH, C1q and C4 to reliably diagnose the angioedema type, and considered the use of genetic testing to identify mutations in FXII or XPNPEP2 that have been associated with HAE-nC1-INH and ACEI-AAE, respectively. Due to the lack of approved treatments for HAE-nC1-INH, ACEI-AAE and C1-INH-AAE, the group presented several case studies in which therapies approved for treatment of HAE types I/II, such as icatibant, ecallantide and pasteurized, nanofiltered C1-INH, were successful. It was uniformly agreed that further studies are needed to improve the diagnosis and treatment of angioedema other than HAE types I/II. i 2014 S. Karger AG, Basel