Review of Type III Non-Hereditary Angioedema Patients in Manitoba.

Introduction: Non-hereditary angioedema with normal C1 esterase inhibitor level and function (NHAE-nC1INH) is a novel entity. The diagnosis of NHAE-nC1INH requires a high index of suspicion, given that there are no laboratory tests to conrm the diagnosis. There is limited evidence on the treatment ecacy for short- and long-term prophylaxis, and acute attacks. The aim of the study is to describe a cohort of NHAE-nC1INH in Manitoba, including an estimate of prevalence, as well as to analyze the response to plasma derived C1esterase inhibitor (pdC1INH), and a bradykinin-2 receptor antagonist (Icatibant). Methods: A retrospective chart review of patients diagnosed with normal C1 esterase level and function angioedema seen at the Clinical Immunology and Allergy Clinic at the Health Sciences Centre in Winnipeg, Manitoba, was done. Inclusion criteria included the following: (1) Reside within Manitoba (2) Aged 18 years and older (3) Angioedema without urticaria (4) Normal C1-INH antigenic level and function (5) No symptom resolution with antihistamines, epinephrine or corticosteroids. (6) No family history. Five patients were included in the study who met the above inclusion criteria. The ve patients charts were reviewed. Response to pdC1INH and Icatibant were dened as time to improvement of angioedema symptoms. Results: Four out of ve patients had an effective response to pdC1INH for prophylactic treatment and for on-demand treatment for angioedema episodes. pdC1INH was ineffective in 1 patient for prophylaxis and on-demand treatment; tranexamic acid was successful for prophylactic treatment in 1 patient who did not respond to pdC1INH for prophylaxis and for on-demand treatment. 3 of 5 patients have tried Icatibant. All three patients were not responsive to Icatibant. Conclusion: This study suggests that pdC1INH may be an ecacious treatment option for NHAE-nC1INH patients. Larger studies are required to better elucidate the effectiveness of on-demand and prophylactic treatment for NHAE-nC1INH.


Introduction
Recurrent angioedema is a serious, potentially life threatening condition characterized by swelling of the subcutaneous and submucosal tissue involving the skin, gastrointestinal tract, and the upper respiratory tract leading to airway compromise, asphyxiation and potentially death. 1-7, 9,10 Angioedema can be histamine, cytokine or bradykinin-mediated. Three types of hereditary bradykinin-mediated angioedema have been described. Types I and II are associated with low quantitative and qualitative of C1 esterase inhibitor (C1INH), respectively, as a result of a mutation in the C1-INH gene, SERPING 1. Type III hereditary angioedema, now known as HAE with normal C1INH (HAE-nC1INH), described by Binkley et al. in 2000, is associated with normal levels of C1 level and function. To date there are four types of HAE-nC1INH: mutation of the Factor XII gene, angiopoietin gene, plasminogen gene and of unknown origin. 1,3-5,7−11 Recently, a novel type of non-hereditary angioedema with normal C1 esterase inhibitor level and function (NHAE-nC1INH) has been described.
The diagnosis of NHAE-nC1INH requires a high level suspicion given there are no laboratory tests to con rm the diagnosis of NHAE-nC1INH. 7 The patient must not have a family history of angioedema, no urticaria and have no symptomatic response to antihistamines, steroids or epinephrine. 1 There is limited evidence on the treatment e cacy for short-and long-term prophylaxis, and acute attacks. 5 For types I and II HAE, plasma derived C1INH (pdC1INH), has been approved in Canada for prophylaxis and treatment for acute angioedema attacks. 4 A bradykinin-2 receptor antagonist, Icatibant, has been approved in Canada and in other countries for symptomatic treatment for Type I and II HAE based on three Phase III trials. 5,11 However, it has not been approved for NHAE-or HAE-nC1INH.
The exact prevalence and incidence of NHAE-nC1INH is unknown. McKibbin et al. characterized six patients in Manitoba, Canada, with HAE-nC1INH, and analyzed each patient's response to C1INH, tranexamic acid and to a bradykinin-2 receptor antagonist. 1 The aim of this study is to analyze the prevalence of NHAE-nC1INH in Manitoba as well as to analyze the response to C1INH, tranexamic acid and to a bradykinin-2 receptor antagonist. University of Manitoba's Research Ethics Board approval was obtained for this study.

Methods
The information abstracted in this study included, gender, age, site of angioedema, prophylactic medication, medication for treatment, and time to response of treatment. The time to response of treatment was de ned as the number of hours from the time the treatment was given to resolution.

Results
The study population included 5 patients, 3 females, and 2 males, with an age range of 30-56 years. 4 of 5 patients had an effective response to pdC1INH for prophylactic treatment and for on-demand treatment of angioedema episodes. pdC1INH was ineffective in 1 patient for prophylaxis and on-demand treatment; tranexamic acid was successful for prophylactic treatment in the 1 patient who did not respond to pdCIINH. 3 of 5 patients have tried Icatibant. All three patients did not respond to Icatibant. Patient 1 is a 53-year-old female with previous episodes of angioedema involving her face, lips, tongue and abdomen, who was responsive to pdC1INH, and now is in remission since starting menopause. Previously, her symptoms completely resolved within 24 hours of receiving pdC1INH. Since being in remission she now only receives pdC1INH as needed for infrequent episodes of angioedema. She has never tried Icatibant. Patient 2 is a 38-year-old female, with hypothyroidism on levothyroxine, who develops recurrent episodes of facial and abdominal angioedema, lasting 3-5 days without treatment. Her angioedema episodes worsened post-partum with each of her three children. Despite prophylactic treatment of 1500U of pdC1INH intravenous three times a week, she continues to have recurrent episodes of angioedema two to three times per week. The symptoms resolve within 1-2 hours with pdC1INH for acute treatment. Has never had access to Icatibant. Patient 3 is a 49-year-old female, with asthma, chronic rhinosinusitis with nasal polyps and GERD, with recurrent episodes of angioedema involving her tongue, throat, abdomen and vagina, not responsive to 1500U of pdC1INH intravenous three times a week, Tranexamic acid 500 mg BID and Montelukast 10 mg po daily. Despite the prophylactic treatment, she continues to have recurrent angioedema episodes three times per week. The symptoms resolve within 2 hours with pdC1INH for acute treatment for 75% of the episodes. Acute episodes of angioedema were not responsive to Icatibant. Patient 4 is a 30-year-old male who has recurrent episodes of angioedema involving his lips and scrotum. He has had no further episodes since initiating pdC1INH 1500 intravenous three times per week. No response to Icatibant Patient 5 is a 56-year-old male with recurrent swelling of face, lips, tongue and hands. pdC1INH as prophylaxis and as on-demand treatment was unsuccessful. He responded to Icatibant within 2 hours, although on 2 occasions, Icatibant had no effect, and the angioedema persisted for 24 hours. The number of episodes signi cantly reduced with tranexamic acid prescribed prophylactically. He had one mild episode following missing one dose of Tranexamic acid, since starting Tranexamic acid 12 months ago. days without treatment. 7,9,10 The episodes are exacerbated with physical trauma, stress, sleep deprivation, illness, menstruation, pregnancy oral contraceptives, hormone replacement therapy, and/or angiotensin-converting enzyme inhibitors. 4,7,9,10 Most current treatment options for HAE-nC1INH are aimed to reduce the production and/or biologic effects of bradykinin, which is the main culprit causing the angioedema episodes. To date, there are no randomized, controlled studies of on-demand and prophylactic treatment in patients with HAE-nC1INH or NHAE-nC1INH. 5 Numerous randomized, controlled studies have shown success with the on-demand and prophylactic treatments used for Type I and II HAE. Plasma-derived C1INH seems to be effective used both as an on-demand and prophylactic treatment, even though patients with nC1INH have no de ciency or dysfunction of C1INH. A study completed in 2016 by Bork and colleagues concluded a mean duration of an episode acutely treated with pdC1INH was 26.6 hours compared to 64.2 hours without treatment. 12 This study concluded a mean duration of an episode acutely treated with pdC1INH was 15 to 15.2 hours compared to 57.6 to 67.2 hours without treatment. Icatibant, a bradykinin-2 receptor antagonist, has also shown to be an effective on-demand treatment. Boccon-Gibod and Bouillet concluded, symptom improvement within a median of 40 minutes with Icatibant. 11 In this study, no patients responded successfully to Icatibant. However, some studies have reported individuals having no response or delayed responses to Icatibant. Inactivated plasma kallikrein (eg Ecallantide) and fresh frozen plasma have been shown to be effective in 1 patient in HAE-nC1INH not responding to pdC1INH or Icatibant. Several studies have shown effective response to transexamic acid, an anti brinolytic, in patients with  In this study 4 of 5 had an effective response to pdC1INH for on-demand treatment, and 3 out of 5 had reduction in the number of episodes with pdC1INH. One of the patients who responded to pdC1INH ondemand treatment did not have reduction in the number of episodes with pdC1INH prophylaxis. In addition, one patient had reduction in the number of weekly episodes with pdC1INH prophylaxis, however, still had frequent episodes. No severe or serious adverse effects were reported. One patient responded successfully to tranexamic acid as a prophylactic treatment, and was nonresponsive to C1INH for prophylactic and on-demand treatment, and nonresponsive to Icatibant. Unfortunately public and private insurance in Manitoba will not cover the cost of Icatibant in these individuals; hence few have had the opportunity to try it.
In The main limitation of this study is the low number of individuals included. It is very possible that not all individuals treated for this condition in our clinic are accounted for in the study. The diagnosis of NHAE-nC1INH is challenging. It requires a high-level of clinical suspicion, as well as, the patients to be knowledgeable about their family history. Currently, there are no laboratory tests to con rm the diagnosis of NHAE-nC1INH.

Conclusions
Non-hereditary angioedema with normal C1 inhibitor is a rare entity, characterized by recurrent, angioedema affecting the skin, upper airway and gastrointestinal tract, unresponsive to antihistamine, corticosteroid and epinephrine. To date, there are no approved on-demand and prophylactic treatments for NHAE-nC1INH. This small study showed a trend of effectiveness for on demand therapy with pdC1INH, an inconclusive response with pdC1INH prophylaxis and no response with Icatibant.