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Omalizumab for Idiopathic Nonhistaminergic Angioedema: Evidence for Efficacy in 2 Patients

Omalizumab for Idiopathic Nonhistaminergic Angioedema: Evidence for Efficacy in 2 Patients Hindawi Case Reports in Immunology Volume 2018, Article ID 8067610, 3 pages https://doi.org/10.1155/2018/8067610 Case Report Omalizumab for Idiopathic Nonhistaminergic Angioedema: Evidence for Efficacy in 2 Patients 1,2 2 1,2 2 Enrico Brunetta , Dana Shiffer, Marco Folci, Maria I. S. Achenza, 1,3 1,3 1,2 1,3 Francesca Puggioni, Enrico Heffler, Raffaello Furlan, and Giorgio W. Canonica Department of Biomedical Sciences, Humanitas University, Milan, Italy Internal Medicine, Humanitas Research Hospital, Milan, Italy Personalized Medicine, Allergy and Asthma, Humanitas Research Hospital, Milan, Italy Correspondence should be addressed to Enrico Brunetta; enrico.brunetta@humanitas.it Received 20 May 2018; Accepted 5 July 2018; Published 22 July 2018 Academic Editor: Christian Drouet Copyright © 2018 Enrico Brunetta et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Presently, there is inconclusive evidence regarding the most eeff ctive treatment for idiopathic nonhistaminergic acquired angioedema (InH-AAE). Omalizumab may, however, prove to be a promising option. This case report describes two patients who presented with recurrent angioedema attacks, which was refractory to antihistamine therapy. Hence, they were treated with 300 mg omalizumab, every 4 weeks, for a period of 6 months. Both patients had shown a rapid response to the treatment and achieved complete resolution of symptoms without further AE attacks throughout the entire duration of the treatment period. Aeft r omalizumab’s suspension, one patient remained symptom free for the following 6 months and the other patient had recurrence of symptoms after 2 months for which he was retreated with omalizumab and once again became symptom free. Although omalizumab seems to be eeff ctive as a prophylactic treatment for InH-AAE, the determining factors leading to the dieff rences in time-to- relapse between patients aer ft its suspension remain unclear. Further studies are needed in order to better determine the potential therapeutic application of omalizumab and its role in maintenance therapy. 1. Introduction spontaneous urticarial (CSU) refractory to antihistamine therapy [22]. Since histamine and other mediators of acti- Idiopathic nonhistaminergic acquired angioedema (InH- vated mast cells are involved in angioedema, InH-AAE could AAE) accounts for 10% of acquired AE (AAE) cases. It is share similarities with patients who have CSU, which do not defined as a nonfamilial, nonhereditary AE where other respond to antihistamines. Recently a few case reports have known causes of AE have been excluded and is refrac- shown that omalizumab was associated with positive results tory to antihistamine treatment [1]. It is predominantly in patients with InH-AAE; however, data on its use in the seen in males, tends to occur between the ages of 36-42 disorder is still limited [4, 23–28]. years, and is associated with high recurrence rates [2, 3]. Presently, the underlying pathophysiological mechanisms 2. Case Report in InH-AAE remain unclear. Current treatment options include bradykinin receptor antagonist icatibant, ecallan- This case report describes 2 patients suffering from chronic tide, C1-esterase inhibitor (C1-INH) concentrate, progestin, recurring AE. For data use, an informed consent was obtained and antifibrinolytic agent tranexamic acid (TA) [4–17]. Few from both patients. The rfi st patient, a 30-year-old Caucasian cases have been described about the ecffi acy of dapsone, man, had a 6-year history of recurrent AE. Episodes lasted 48 fresh frozen plasma, rituximab, and cannabis [18–21]. Oma- hours, recurred at least twice weekly, and were characterized lizumab, an anti-IgE monoclonal antibody, is the rfi st bio- by swelling of the lips, eyelids, and face. The second patient, a logical agent currently licensed for the treatment of chronic 49-year-old Caucasian man, had a history of weekly recurring 2 Case Reports in Immunology and ultimately resulted in complete symptom resolution. Although TA and C1-INH concentrates seem to be effective as prophylaxistreatmentsforInH-AAE,theyareassociatedwith lower rates of complete response compared to omalizumab [4]. Omalizumab’s exact mechanism of action in InH-AAE is unclear. It is known to prevent circulating IgE from binding 20 to high affinity immunoglobulin E receptors (Fc 𝜀 RI) and causes downregulation of Fc𝜀 RI receptors on basophils and mast cells in AH refractory CSU cases [30]. A recent case report demonstrated a marked reduction in the density of 01234568 12 Fc𝜀 RI on basophils following omalizumab administration. Time (months) It was therefore proposed that activated mast cells may Figure 1: Time course of omalizumab’s eeff ct on AE-QoL score potentially induce AE, by yet other unknown mediators, in the two patients (clear and black squares) with InH-AAE. Both which is nonhistamine related [4]. Omalizumab efficacy leads patients showed a rapid response to omalizumab and during the to considering whether InH-AAE could be a CSU variant 6-month treatment the patients were free of AE attacks. Two without manifestation of wheals. months after suspension one patient (black squares) had symptom Interestingly, the patients responded differently after recurrences and therefore was retreated with omalizumab. omalizumab suspension. One patient remained symptom free for 6 months, while the other experienced AE recur- rences aer ft 2 months. Symptom relapse seems to occur in most patients following omalizumab discontinuation [23, AE attacks for more than 6 months, involving the limbs and 24]. u Th s, long-term prophylactic treatment may be required face, with each attack lasting 2-3 days. in order to prevent recurrences [2]. The determining factors In both patients, episodes were not trigger related; there leading to differences in time-to-relapse between patients was no history of atopy, drug/food allergy, or family history after omalizumab suspension remain unclear. of AE. Neither the patient had taken angiotensin-converting Further studies should aim to investigate the potential enzyme inhibitors or gliptins. Wheals, upper airway involve- effects of omalizumab therapy on long-term symptom remis- ment, and abdominal pain were absent during attacks. The sion as well as its role as a maintenance therapy in patients patients had no response to H1-antihistamine treatment at with InH-AAE. 4 times the recommended daily dose. Physical examinations were unremarkable with no findings suggesting the presence of rheumatologic or autoimmune disorders. Abbreviations For both patients no abnormalities were found on AE: Angioedema laboratory tests, which included complete blood count, InH-AAE: Idiopathic nonhistaminergic acquired serum protein electrophoresis/immunofixation, complement angioedema (C3/C4) levels, IgE levels, C1q, C1 esterase inhibitor lev- AE-QoL: Angioedema quality of life score els, and function and thyroid stimulating hormone levels. C1-INH: C1-esterase inhibitor ANA, ENA, anti-thyroid peroxidase antibody, and anti- TA: Tranexamic acid thyroglobulin antibody were absent. Autologous serum skin CSU: Chronic spontaneous urticarial test was positive in the first patient. Fc𝜀 RI: High affinity immunoglobulin E receptors. The patients were treated with 300 mg omalizumab administered subcutaneously every 4 weeks for 6 months, following the conventional CSU protocol. In the rfi st patient, Conflicts of Interest clinical improvement was seen aer ft the rfi st omalizumab dose with the AE quality of life score (AE-QoL) decreasing The authors declare that they have no conflicts of interest. from 73 to 17 [29]. He remained AE attack free during the entire treatment period and for 6 months after treatment References suspension (Figure 1). In the second patient, the AE-QoL decreased from 52 to 17 a week following the rfi st omalizumab [1] M. Cicardi,W.Aberer, A. Banerji etal.,“Classification, diag- dose. During the treatment period he was AE attack free with nosis, and approach to treatment for angioedema: Consensus report from the Hereditary Angioedema International Work- complete symptom resolution. Two months after treatment ing Group,” Allergy: European Journal of Allergy and Clinical suspension, the AE attacks recurred and treatment was Immunology, vol.69,no.5,pp.602–616, 2014. resumed. At the 4 months follow-up visit he was symptom free (Figure 1). [2] M.A.Wu,F.Perego,A. Zanichelli, and M.Cicardi, “Angioedema Phenotypes: Disease Expression and Classifica- tion,” Clinical Reviews in Allergy & Immunology, vol.51,no.2, 3. Discussion pp. 162–169, 2016. In both patients, the beneficial effects from the omalizumab [3] M. Mansi, A. Zanichelli, A. Coerezza et al., “Presentation, treatment were seen soon after the rfi st dose was administered diagnosis and treatment of angioedema without wheals: a AE-QoL Case Reports in Immunology 3 retrospective analysis of a cohort of 1058 patients,” Journal of [20] A. Frenkel, A. Roy-Shapira, B. Evgeni, K. Leonid, A. Borer, and Internal Medicine,vol.277,no.5,pp.585–593,2015. M. Klein, “Life rTh eatening Idiopathic Recurrent Angioedema Responding to Cannabis,” Case Reports in Immunology,vol. [4] M.C.Bucher, T.Petkovic,A.Helbling, and U.C.Steiner, 2015, Article ID 780824, 3 pages, 2015. “Idiopathic non-histaminergic acquired angioedema: a case series and discussion of published clinical trials,” Clinical and [21] D.Franzen,T.Ursprung,B.Wuthrich,andA.Reber,“Idiopathic Translational Allergy, vol.7,no.1,2017. non-histaminergic angio-oedema aeft r routine extubation suc- cessfully treated with fresh frozen plasma,” Anaesthesia,vol. 61, [5] R. A. o Th mpson and D. D. Felix-Davies, “Response of “idio- no. 7, pp. 698–701, 2006. pathic” recurrent angioneurotic oedema to tranexamic acid,” British Medical Journal, vol.2,no. 6137, p.608,1978. [22] A. M. Gime´nez-Arnau, E.Toubi,A.M.Marsland, and M. Maurer, “Clinical management of urticaria using omalizumab: [6] O. M. Haka ˚ nsson, “Menstruation-related angioedema treated The first licensed biological therapy available for chronic with tranexamic acid,” Acta Obstetricia et Gynecologica Scandi- spontaneous urticaria,” Journal of the European Academy of navica, vol.67,no. 6,pp.571-572, 1988. Dermatology and Venereology,vol.30, pp.25–32, 2016. [7] M.Cicardi,L. Bergamaschini, L. C.Zingale,D.Gioffr´ e, and A. [23] C. Faisant, A. Du Thanh, C. Mansard, A. Deroux, I. Boccon- Agostoni, “Idiopathic nonhistaminergic angioedema,” Ameri- Gibod, and L. Bouillet, “Idiopathic Non-histaminergic Angioe- can Journal of Medicine,vol.106, no.6,pp.650–654,1999. dema: Successful Treatment with Omalizumab in Five Patients,” [8] A.Du-aTh nh,N.Raison-Peyron,C. Drouet, and B.Guillot, Journal of Clinical Immunology,vol. 37, no.1, pp. 80–84, 2017. “Efficacy of tranexamic acid in sporadic idiopathic bradykinin [24] J. P. Mun˜oz, A.F.Casado,A.C.Taboada, L.Campos Munoz ˜ , angioedema,” Allergy: European Journal of Allergy and Clinical and E. L. Bran, “Successful treatment of refractory idiopathic Immunology,vol. 65, no.6, pp. 793–795, 2010. angio-oedema with omalizumab: Review of the literature and [9] C. Wintenberger, I. Boccon-Gibod, D. Launay et al., “Tranex- function of IgE in angio-oedema,” Clinical and Experimental amic acid as maintenance treatment for non-histaminergic Dermatology,vol. 41, no.4, pp. 399–402,2016. angioedema: Analysis of efficacy and safety in 37 patients,” [25] M. F. Sands, J. W. Blume, and S. A. Schwartz, “Successful treat- Clinical & Experimental Immunology, vol. 178, no. 1, pp. 112–117, ment of 3 patients with recurrent idiopathic angioedema with omalizumab,” eTh Journal of Allergy and Clinical Immunology , [10] M. C. Stahl, C. K. Harris, S. Matto, and J. A. Bernstein, “Idio- vol. 120, no. 4, pp. 979–981, 2007. pathic nonhistaminergic angioedema successfully treated with [26] A. Von Websky, K. Reich, V. Steinkraus, and K. Breuer, ecallantide, icatibant, and C1 esterase inhibitor replacement,” “Complete remission of severe chronic recurrent angioedema Journal of Allergy and Clinical Immunology: In Practice,vol.2, of unknown cause with omalizumab,” Journal of the German no. 6, pp. 818-819, 2014. Society of Dermatology, vol. 11, no. 7, pp. 677-678, 2013. [11] A. Berry and R. Firszt, “Successful treatment of idiopathic [27] A. B. Ozturk and E. Kocaturk, “Omalizumab in recurring larynx angioedema with ecallantide,” Journal of Allergy and Clinical angioedema: a case report,” Asia Pacific Allergy ,vol. 4, no. 2, p. Immunology: In Practice, vol.1,no.3, pp. 297-298,2013. 129, 2014. [12] T.B.Dy,M.Rasheed,P.Parikh,and L.Bernstein,“Resolution [28] J. Azofra,C.D´ıaz, I. Antep ´ ara, I. Jaur ´ egui, A. Soriano, and of an acute attack of idiopathic angioedema with ecallantide,” M. Ferrer, “Positive response to omalizumab in patients with Annals of Allergy, Asthma & Immunology, vol. 111, no. 3, pp. 224– acquired idiopathic nonhistaminergic angioedema,” Annals of 226, 2013. Allergy, Asthma & Immunology,vol.114, no.5, pp.418–419e1, [13] I.Del Corso, I.Puxeddu,E.Sardano et al., “Treatment of idiopathic nonhistaminergic angioedema with bradykinin B2 [29] K. Weller, M. Magerl, A. Peveling-Oberhag, P. Martus, P. receptor antagonist icatibant,” Annals of Allergy, Asthma & Staubach,and M. Maurer,“eTh Angioedema Quality of Life Immunology, vol. 108,no. 6, pp.460-461, 2012. Questionnaire (AE-QoL) – assessment of sensitivity to change [14] V. Montinaro, G. Loizzo, A. Zito, G. Castellano, and L. Gesualdo, and minimal clinically important difference,” Allergy: European “Successful treatment of a facial attack of angioedema with icat- Journal of Allergy and Clinical Immunology, vol.71,no.8,pp. ibant in a patient with idiopathic angioedema,” The American 1203–1209, 2016. Journal of Emergency Medicine,vol.31,no.8,pp.1295–e6,2013. [30] A.P. Kaplan, A.M.Gime´nez-Arnau, and S. S. Saini, “Mecha- [15] J.Shroba,J.Hanson, and J.Portnoy, “Current treatment nisms of action that contribute to efficacy of omalizumab in options for idiopathic angioedema,” Annals of Allergy, Asthma chronic spontaneous urticaria,” Allergy: European Journal of & Immunology, vol. 115,no. 5, pp.429–433, 2015. Allergy and Clinical Immunology,vol.72,no.4,pp.519–533,2017. [16] C. Gravante, L. Carucci, M. Bova, A. Petraroli, A. Genovese, and G. Marone, “Prophylactic treatment with plasma-derived C1 inhibitor in idiopathic non-histaminergic angioedema,” Pediatric Allergy and Immunology,vol. 27, no.6, pp. 658-659, [17] C. Saule, I. Boccon-Gibod, O. Fain et al., “Benefits of progestin contraception in non-allergic angioedema,” Clinical & Experi- mental Allergy,vol.43,no.4,pp.475–482,2013. [18] P. Gonza`lez,V. Soriano,T. Caballero, and E. Niveiro, “Idiopatic angioedema treated with dapsone,” Allergologia et Immunopathologia, vol.33, no.1,pp.54–56, 2005. [19] S. Ghazan-Shahi and A. K. Ellis, “Severe steroid-dependent idiopathic angioedema with response to rituximab,” Annals of Allergy, Asthma & Immunology,vol.107, no.4, pp. 374–376,2011. 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Omalizumab for Idiopathic Nonhistaminergic Angioedema: Evidence for Efficacy in 2 Patients

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Hindawi Case Reports in Immunology Volume 2018, Article ID 8067610, 3 pages https://doi.org/10.1155/2018/8067610 Case Report Omalizumab for Idiopathic Nonhistaminergic Angioedema: Evidence for Efficacy in 2 Patients 1,2 2 1,2 2 Enrico Brunetta , Dana Shiffer, Marco Folci, Maria I. S. Achenza, 1,3 1,3 1,2 1,3 Francesca Puggioni, Enrico Heffler, Raffaello Furlan, and Giorgio W. Canonica Department of Biomedical Sciences, Humanitas University, Milan, Italy Internal Medicine, Humanitas Research Hospital, Milan, Italy Personalized Medicine, Allergy and Asthma, Humanitas Research Hospital, Milan, Italy Correspondence should be addressed to Enrico Brunetta; enrico.brunetta@humanitas.it Received 20 May 2018; Accepted 5 July 2018; Published 22 July 2018 Academic Editor: Christian Drouet Copyright © 2018 Enrico Brunetta et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Presently, there is inconclusive evidence regarding the most eeff ctive treatment for idiopathic nonhistaminergic acquired angioedema (InH-AAE). Omalizumab may, however, prove to be a promising option. This case report describes two patients who presented with recurrent angioedema attacks, which was refractory to antihistamine therapy. Hence, they were treated with 300 mg omalizumab, every 4 weeks, for a period of 6 months. Both patients had shown a rapid response to the treatment and achieved complete resolution of symptoms without further AE attacks throughout the entire duration of the treatment period. Aeft r omalizumab’s suspension, one patient remained symptom free for the following 6 months and the other patient had recurrence of symptoms after 2 months for which he was retreated with omalizumab and once again became symptom free. Although omalizumab seems to be eeff ctive as a prophylactic treatment for InH-AAE, the determining factors leading to the dieff rences in time-to- relapse between patients aer ft its suspension remain unclear. Further studies are needed in order to better determine the potential therapeutic application of omalizumab and its role in maintenance therapy. 1. Introduction spontaneous urticarial (CSU) refractory to antihistamine therapy [22]. Since histamine and other mediators of acti- Idiopathic nonhistaminergic acquired angioedema (InH- vated mast cells are involved in angioedema, InH-AAE could AAE) accounts for 10% of acquired AE (AAE) cases. It is share similarities with patients who have CSU, which do not defined as a nonfamilial, nonhereditary AE where other respond to antihistamines. Recently a few case reports have known causes of AE have been excluded and is refrac- shown that omalizumab was associated with positive results tory to antihistamine treatment [1]. It is predominantly in patients with InH-AAE; however, data on its use in the seen in males, tends to occur between the ages of 36-42 disorder is still limited [4, 23–28]. years, and is associated with high recurrence rates [2, 3]. Presently, the underlying pathophysiological mechanisms 2. Case Report in InH-AAE remain unclear. Current treatment options include bradykinin receptor antagonist icatibant, ecallan- This case report describes 2 patients suffering from chronic tide, C1-esterase inhibitor (C1-INH) concentrate, progestin, recurring AE. For data use, an informed consent was obtained and antifibrinolytic agent tranexamic acid (TA) [4–17]. Few from both patients. The rfi st patient, a 30-year-old Caucasian cases have been described about the ecffi acy of dapsone, man, had a 6-year history of recurrent AE. Episodes lasted 48 fresh frozen plasma, rituximab, and cannabis [18–21]. Oma- hours, recurred at least twice weekly, and were characterized lizumab, an anti-IgE monoclonal antibody, is the rfi st bio- by swelling of the lips, eyelids, and face. The second patient, a logical agent currently licensed for the treatment of chronic 49-year-old Caucasian man, had a history of weekly recurring 2 Case Reports in Immunology and ultimately resulted in complete symptom resolution. Although TA and C1-INH concentrates seem to be effective as prophylaxistreatmentsforInH-AAE,theyareassociatedwith lower rates of complete response compared to omalizumab [4]. Omalizumab’s exact mechanism of action in InH-AAE is unclear. It is known to prevent circulating IgE from binding 20 to high affinity immunoglobulin E receptors (Fc 𝜀 RI) and causes downregulation of Fc𝜀 RI receptors on basophils and mast cells in AH refractory CSU cases [30]. A recent case report demonstrated a marked reduction in the density of 01234568 12 Fc𝜀 RI on basophils following omalizumab administration. Time (months) It was therefore proposed that activated mast cells may Figure 1: Time course of omalizumab’s eeff ct on AE-QoL score potentially induce AE, by yet other unknown mediators, in the two patients (clear and black squares) with InH-AAE. Both which is nonhistamine related [4]. Omalizumab efficacy leads patients showed a rapid response to omalizumab and during the to considering whether InH-AAE could be a CSU variant 6-month treatment the patients were free of AE attacks. Two without manifestation of wheals. months after suspension one patient (black squares) had symptom Interestingly, the patients responded differently after recurrences and therefore was retreated with omalizumab. omalizumab suspension. One patient remained symptom free for 6 months, while the other experienced AE recur- rences aer ft 2 months. Symptom relapse seems to occur in most patients following omalizumab discontinuation [23, AE attacks for more than 6 months, involving the limbs and 24]. u Th s, long-term prophylactic treatment may be required face, with each attack lasting 2-3 days. in order to prevent recurrences [2]. The determining factors In both patients, episodes were not trigger related; there leading to differences in time-to-relapse between patients was no history of atopy, drug/food allergy, or family history after omalizumab suspension remain unclear. of AE. Neither the patient had taken angiotensin-converting Further studies should aim to investigate the potential enzyme inhibitors or gliptins. Wheals, upper airway involve- effects of omalizumab therapy on long-term symptom remis- ment, and abdominal pain were absent during attacks. The sion as well as its role as a maintenance therapy in patients patients had no response to H1-antihistamine treatment at with InH-AAE. 4 times the recommended daily dose. Physical examinations were unremarkable with no findings suggesting the presence of rheumatologic or autoimmune disorders. Abbreviations For both patients no abnormalities were found on AE: Angioedema laboratory tests, which included complete blood count, InH-AAE: Idiopathic nonhistaminergic acquired serum protein electrophoresis/immunofixation, complement angioedema (C3/C4) levels, IgE levels, C1q, C1 esterase inhibitor lev- AE-QoL: Angioedema quality of life score els, and function and thyroid stimulating hormone levels. C1-INH: C1-esterase inhibitor ANA, ENA, anti-thyroid peroxidase antibody, and anti- TA: Tranexamic acid thyroglobulin antibody were absent. Autologous serum skin CSU: Chronic spontaneous urticarial test was positive in the first patient. Fc𝜀 RI: High affinity immunoglobulin E receptors. The patients were treated with 300 mg omalizumab administered subcutaneously every 4 weeks for 6 months, following the conventional CSU protocol. In the rfi st patient, Conflicts of Interest clinical improvement was seen aer ft the rfi st omalizumab dose with the AE quality of life score (AE-QoL) decreasing The authors declare that they have no conflicts of interest. from 73 to 17 [29]. He remained AE attack free during the entire treatment period and for 6 months after treatment References suspension (Figure 1). In the second patient, the AE-QoL decreased from 52 to 17 a week following the rfi st omalizumab [1] M. Cicardi,W.Aberer, A. Banerji etal.,“Classification, diag- dose. During the treatment period he was AE attack free with nosis, and approach to treatment for angioedema: Consensus report from the Hereditary Angioedema International Work- complete symptom resolution. Two months after treatment ing Group,” Allergy: European Journal of Allergy and Clinical suspension, the AE attacks recurred and treatment was Immunology, vol.69,no.5,pp.602–616, 2014. resumed. At the 4 months follow-up visit he was symptom free (Figure 1). [2] M.A.Wu,F.Perego,A. Zanichelli, and M.Cicardi, “Angioedema Phenotypes: Disease Expression and Classifica- tion,” Clinical Reviews in Allergy & Immunology, vol.51,no.2, 3. Discussion pp. 162–169, 2016. In both patients, the beneficial effects from the omalizumab [3] M. Mansi, A. Zanichelli, A. Coerezza et al., “Presentation, treatment were seen soon after the rfi st dose was administered diagnosis and treatment of angioedema without wheals: a AE-QoL Case Reports in Immunology 3 retrospective analysis of a cohort of 1058 patients,” Journal of [20] A. Frenkel, A. Roy-Shapira, B. Evgeni, K. Leonid, A. Borer, and Internal Medicine,vol.277,no.5,pp.585–593,2015. M. Klein, “Life rTh eatening Idiopathic Recurrent Angioedema Responding to Cannabis,” Case Reports in Immunology,vol. [4] M.C.Bucher, T.Petkovic,A.Helbling, and U.C.Steiner, 2015, Article ID 780824, 3 pages, 2015. “Idiopathic non-histaminergic acquired angioedema: a case series and discussion of published clinical trials,” Clinical and [21] D.Franzen,T.Ursprung,B.Wuthrich,andA.Reber,“Idiopathic Translational Allergy, vol.7,no.1,2017. non-histaminergic angio-oedema aeft r routine extubation suc- cessfully treated with fresh frozen plasma,” Anaesthesia,vol. 61, [5] R. A. o Th mpson and D. D. Felix-Davies, “Response of “idio- no. 7, pp. 698–701, 2006. pathic” recurrent angioneurotic oedema to tranexamic acid,” British Medical Journal, vol.2,no. 6137, p.608,1978. [22] A. M. Gime´nez-Arnau, E.Toubi,A.M.Marsland, and M. Maurer, “Clinical management of urticaria using omalizumab: [6] O. M. Haka ˚ nsson, “Menstruation-related angioedema treated The first licensed biological therapy available for chronic with tranexamic acid,” Acta Obstetricia et Gynecologica Scandi- spontaneous urticaria,” Journal of the European Academy of navica, vol.67,no. 6,pp.571-572, 1988. Dermatology and Venereology,vol.30, pp.25–32, 2016. [7] M.Cicardi,L. Bergamaschini, L. C.Zingale,D.Gioffr´ e, and A. [23] C. Faisant, A. Du Thanh, C. Mansard, A. Deroux, I. Boccon- Agostoni, “Idiopathic nonhistaminergic angioedema,” Ameri- Gibod, and L. Bouillet, “Idiopathic Non-histaminergic Angioe- can Journal of Medicine,vol.106, no.6,pp.650–654,1999. dema: Successful Treatment with Omalizumab in Five Patients,” [8] A.Du-aTh nh,N.Raison-Peyron,C. Drouet, and B.Guillot, Journal of Clinical Immunology,vol. 37, no.1, pp. 80–84, 2017. “Efficacy of tranexamic acid in sporadic idiopathic bradykinin [24] J. P. Mun˜oz, A.F.Casado,A.C.Taboada, L.Campos Munoz ˜ , angioedema,” Allergy: European Journal of Allergy and Clinical and E. L. Bran, “Successful treatment of refractory idiopathic Immunology,vol. 65, no.6, pp. 793–795, 2010. angio-oedema with omalizumab: Review of the literature and [9] C. Wintenberger, I. Boccon-Gibod, D. Launay et al., “Tranex- function of IgE in angio-oedema,” Clinical and Experimental amic acid as maintenance treatment for non-histaminergic Dermatology,vol. 41, no.4, pp. 399–402,2016. angioedema: Analysis of efficacy and safety in 37 patients,” [25] M. F. Sands, J. W. Blume, and S. A. Schwartz, “Successful treat- Clinical & Experimental Immunology, vol. 178, no. 1, pp. 112–117, ment of 3 patients with recurrent idiopathic angioedema with omalizumab,” eTh Journal of Allergy and Clinical Immunology , [10] M. C. Stahl, C. K. Harris, S. Matto, and J. A. 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