Medical Literature - 2020

Villavicencio MF, Craig T 5/2020 Expert review of clinical immunology

INTRODUCTION: HAE is a very debilitating disease that causes significant distress for patients not only during an acute attack but also constant fear for a subsequent attack. It is important to address long-term prophylactic (LTP) therapy to prevent attacks, decrease morbidity and increase the quality of life. When discussing LTP, the drug burden, convenience and efficacy must be taken into account.

AREAS COVERED: We review the literature and the different phases of clinical trials leading up to approval by the US FDA of subcutaneous highly concentrated C1-Inhibitor (SC-C1-INH), called Haegarda. The dose approved is of 60 IU/kg twice weekly showing significant improvement in the reduction of attacks and need for on-demand therapy for attacks with minimal side effects.

EXPERT OPINION: SC-C1-INH has added significantly to the armamentarium of physicians that treat HAE. The ability to achieve a steady state of C1-INH above 40% function is key to the success of the drug. The drug burden is an SC injection twice a week that exceeds the newly approved lanadelumab. The benefit may be that the protein that is deficient in HAE is replaced and with this the complement, fibrinolytic, coagulation pathways, and contact system are also regulated; however, evidence that this is of benefit is still lacking.

Available from: dx.doi.org/10.1080/1744666X.2020.1750953

Colarusso C, Terlizzi M, Pinto A, Sorrentino R 11/2020 British Journal of Pharmacology

The newly identified coronavirus SARS-CoV-2 that spread from China is causing the pandemic COVID-19 with a fatality rate from 5-15%. It causes fever, cough, myalgia, fatigue up to dyspnoea, responsible for hospitalization and artificial oxygenation. SARS-CoV-2 infects human cells using ACE2, the transmembrane protease serine 2 (TMPRSS2) and the SARS-CoV-2 main protease (Mpro ). Once bound to ACE2 and the other two proteases in concert they allow the virus replication and spread throughout the body. Our attention has been focused on the role of ACE2 as its binding to by the virus increases bradykinin and its metabolites, which facilitate inflammation in the lung (causing cough and fever), coagulation and the complement system. These three systems are involved in angioedema, cardiovascular dysfunction and sepsis, pathologies which occur in COVID-19 patients. Thus, we propose that blocking the kallikrein-kinin system with lanadelumab, approved for hereditary angioedema, will prevent facilitation of these 3 systems.

LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc. Copyright © 2020 The British Pharmacological Society.

Available from: dx.doi.org/10.1111/bph.15154

Lumry W, Templeton T, Omert L, Levy D 5/2020 Journal of Infusion Nursing

Hereditary angioedema (HAE) is a debilitating condition caused by a functional C1-inhibitor (C1-INH) deficiency and characterized clinically by episodes of subcutaneous or submucosal swelling. C1-INH replacement is highly effective for preventing HAE attacks and can improve health-related quality of life. Once available only for intravenous use, C1-INH is now available as a subcutaneous formulation for self-administration, shown to provide sustained plasma levels of C1-INH and reducing the monthly median HAE attack rate by 95% versus placebo in the phase 3 COMPACT study. Subcutaneously administered C1-INH satisfies multiple unmet needs in the management of patients with HAE.

Available from: dx.doi.org/10.1097/NAN.0000000000000365

Longhurst H, Farkas H 5/2020 Expert Opinion on Biological Therapy

Introduction: Hereditary angioedema, a disabling condition, with high mortality when untreated, is caused by C1 inhibitor deficiency and other regulatory disorders of bradykinin production or metabolism. This review covers the remarkable progress made in biological therapies for this rare disorder. Areas covered: Over the past 10 years, several evidence-based parenteral treatments have been licensed, including two plasma-derived C1 inhibitor replacement therapies and one recombinant C1 inhibitor replacement for acute treatment of angioedema attacks and synthetic peptides for inhibition of kallikrein or bradykinin B2 receptors, with oral small molecule treatments currently in clinical trial. Moreover, recent advances in prophylaxis by subcutaneous C1 inhibitor to restore near-normal plasma function or by humanized antibody inhibition of kallikrein have resulted in freedom from symptoms for a high proportion of those treated. Expert opinion: This plethora of treatment possibilities has come about as a result of recent scientific advances. Collaboration between patient groups, basic and clinical scientists, physicians, nurses, and the pharmaceutical industry has underpinned this translation of basic science into treatments and protocols. These in their turn have brought huge improvements in prognosis, quality of life and economic productivity to patients, their families, and the societies in which they live.

Available from: dx.doi.org/10.1080/14712598.2020.1724280

Kaplan AP, Pawaskar D, Chiao J 3/2020 The journal of allergy and clinical immunology. In practice

Hereditary angioedema (HAE) is caused by deficiency or dysfunction in the C1 inhibitor (C1-INH) protein. C1-INH replacement therapy is used to treat patients with HAE to restore the missing or dysfunctional protein. In vitro studies showed that C1-INH inhibits prekallikrein activation and bradykinin formation in a dose-dependent manner when added to the plasma of patients with HAE. HAE is highly variable in clinical presentation, and early studies suggested that there was not a clear relationship between functional C1-INH levels and disease activity. Later, a threshold of approximately 40% functional C1-INH was identified, above which patients’ risk of an attack was diminished. Long-term prophylaxis with plasma-derived C1-INH effectively reduces attack frequency and severity. Pharmacokinetic modeling shows that functional C1-INH levels are associated with the relative risk of having an attack. Subcutaneous administration of C1-INH results in consistently high levels of functional C1-INH activity, whereas intravenous administration results in periods of low trough functional C1-INH activity before the next scheduled dose, increasing the risk of an angioedema attack. These studies suggest that measurement of functional C1-INH activity may be useful as a biomarker of the risk of an attack in patients with HAE who are receiving long-term prophylaxis with plasma-derived C1-INH. Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Available from: sciencedirect.com/science/article/abs/pii/S2213219819308682

Levy D, Craig T, Keith PK, Krishnarajah G, Beckerman R, Prusty S 5/2020 Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

BACKGROUND: Hereditary angioedema (HAE) is caused by a SERPING1 gene defect resulting in decreased (Type I) or dysfunctional (Type II) C1 esterase inhibitor (C1-INH). The prevalence of autoimmune diseases (ADs) in patients with HAE appears to be higher than the general population. A systematic literature review was conducted to examine the co-occurrence between HAE and ADs.

METHODS: PubMed/EMBASE were searched for English-language reviews, case reports, observational studies, retrospective studies, and randomized controlled trials up to 04/15/2018 (04/15/2015-04/15/2018 for EMBASE) that mentioned patients with HAE Type I or II and comorbid ADs. Non-human or in vitro studies and publications of C1-INH deficiency secondary to lymphoproliferative disorders or angiotensin-converting-enzyme inhibitors were excluded.

RESULTS: Of the 2880 records screened, 76 met the eligibility criteria and 155 individual occurrences of co-occurring HAE and AD were mentioned. The most common ADs were systemic lupus erythematosus (30 mentions), thyroid disease (21 mentions), and glomerulonephritis (16 mentions). When ADs were grouped by MedDRA v21.0 High Level Terms, the most common were: Lupus Erythematosus and Associated Conditions, n = 52; Endocrine Autoimmune Disorders, n = 21; Gastrointestinal Inflammatory Conditions, n = 16; Glomerulonephritis and Nephrotic Syndrome, n = 16; Rheumatoid Arthritis and Associated Conditions, n = 11; Eye, Salivary Gland and Connective Tissue Disorders, n = 10; and Immune and Associated Conditions Not Elsewhere Classified, n = 5.

CONCLUSIONS: Based on literature reports, systemic lupus erythematosus is the most common AD co-occurring with HAE Type I and II. Cause and effect for co-occurring HAE and AD has not been clinically established but could be related to lack of sufficient C1-INH function. Copyright © The Author(s) 2020.

Available from: ncbi.nlm.nih.gov/pmc/articles/PMC7254644

Liu S, Xu Q, Xu Y, Wang X, Zhi Y 4/2020 European Journal of Jermatology : EJD

BACKGROUND: Hereditary angioedema (HAE) is a rare, inherited disorder characterized by unpredictable and recurrent cutaneous and mucosal oedema.

OBJECTIVES: This study aimed to identify the current status of HAE management in China.

MATERIALS AND METHODS: An internet-based survey was sent to 129 patients with type 1 and 2 HAE diagnosed between 1983 and 2017; a total of 107 patients provided complete disease management information.

RESULTS: The survey response rate was 82.9% (107 responders). Ten patients reported 18 fresh frozen plasma (FFP) transfusions for the main purpose of treating lethal laryngeal oedema. Two patients reported adverse events. Eighty-nine (83.2%) patients had taken danazol for long-term prophylaxis, and 74 (69.2%) were on long-term danazol prophylaxis. Among patients on long-term prophylaxis, 56 (75.7%) patients reported a decrease in their annual attack frequency after taking danazol. Twenty-five (33.8%) patients had an attack frequency of no more than once per year. The most common side effects were menstrual disorders, weight gain, osteoarticular pain, acne, and sebaceous hypersecretion. Patients with higher education levels, positive family histories, and laryngeal oedema attacks before medication tended to show better adherence. Patients maintaining high or medium adherence showed better control of laryngeal and gastrointestinal involvement than patients with low adherence. Four (3.7%) patients reported current or past use of tranexamic acid.

CONCLUSION: Attenuated androgen and FFP transfusions remain the mainstay in China, where specifically targeted drugs are currently lacking. Maintaining good medication adherence should be recommended to achieve improved disease control.

Available from: dx.doi.org/10.1684/ejd.2020.3758

Vergallo C, Torrieri G, Provenzani R, Miettinen S, Moslova K, Varjosalo M, Cristiano MC, Fresta M, Celia C, Santos HA, Cilurzo F, Di Marzio L 1/2020 International Journal of Pharmaceutics

Stanozolol (STZ) is a drug used to treat serious disorders like aplastic anemia and hereditary angioedema. It is also indicated as an adjunct therapy for the treatment of vascular disorders and growth failures. Encouraging results obtained using animal models demonstrated that STZ increases bone formation and mineralization, thus improving both density and biomechanical properties. Like natural androgens, such as TST and 5alpha-dihydrotestosterone (5alpha-DHT), STZ binds androgen receptor (AR) to activate AR-mediated signaling. Despite its therapeutic effects, this synthetic anabolic-androgenic steroid (AAS), or 5alpha-DHT derivative, due to its high lipophilicity, is poor soluble in water. Thus, to increase the water solubility and stability of STZ, as well as its bioavailability and efficacy, an innovative PEGylated STZ (STZ conjugated with (MeO-PEG-NH2)10kDa, (MeO-PEG-NH)10kDa-STZ) was synthesized. As confirmed by chromatography (RP-HPLC) and spectrometry (ATR-FTIR, 1H NMR, elemental CHNS(O) analysis, MALDI-TOF/TOF) analyses, a very pure, stable and soluble compound was obtained. Acetylcholinesterase (AChE) competitive ELISA demonstrated that the resulting PEGylated STZ competes against biological TST, especially at lower concentrations. Cytotoxicity of increasing concentrations (1, 10, 25 or 50microM) of STZ and/or (MeO-PEG-NH)10kDa-STZ was also evaluated for up 80h by performing the MTT assay on human osteosarcoma Saos-2 cells, which express AR and are responsive to STZ. PEGylation mitigated cytotoxicity of STZ, by increasing the cell viability values, especially at higher drug concentrations. Furthermore, these results suggest that (MeO-PEG-NH)10kDa-STZ is a promising and reliable drug to be used in clinical conditions in which TST is required. Copyright © 2019 Elsevier B.V. All rights reserved.

Available from: dx.doi.org/10.1016/j.ijpharm.2019.118826

Hide M, Fukunaga A, Maehara J, Eto K, Hao J, Vardi M, Nomoto Y 4/2020 Allergology International

BACKGROUND: Hereditary angioedema (HAE) is a genetic disease characterized by recurrent swelling episodes affecting the skin, gastrointestinal mucosa, and upper respiratory tract.

METHODS: A phase 3, single-arm, open-label study was performed to evaluate a selective bradykinin B2 receptor antagonist, icatibant, for the treatment of acute attacks in Japanese patients with HAE Type I or II. After the onset of an acute attack, icatibant 30 mg was administered by the patient or a healthcare professional via subcutaneous injection in the abdomen.

RESULTS: Eight patients who had an attack affecting the skin (n = 4), abdomen (n = 3), or larynx (n = 1) were treated with icatibant (3 of the injections were self-administered). The median time to onset of symptom relief was 1.75 h (95% confidence interval, 1.00-2.50), and all patients had symptom relief within 5 h after administration. The time to maximum plasma concentration of icatibant was 1.79 h, and the maximum plasma concentration was 405 ng/ml. Seven patients experienced an injection site reaction, and 3 patients had adverse events (2 patients had a worsening or repeat HAE attack 29.0 and 18.3 h after icatibant administration, respectively, and 1 had headache).

CONCLUSIONS: Although the number of patients is small, the efficacy and tolerability of icatibant for acute attacks were demonstrated in Japanese patients with HAE, regardless of self-administration or administration by healthcare professional. Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

Available from: dx.doi.org/10.1016/j.alit.2019.08.012

Andrasi N, Veszeli N, Holdonner A, Temesszentandrasi G, Kohalmi KV, Varga L, Farkas H 3/2020 International Immunopharmacology

OBJECTIVE: Conestat alpha, a C1-inhibitor produced by recombinant technology (rhC1-INH) is an acute treatment for edematous attacks occurring in hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE). Our study evaluated the efficacy and safety of rhC1-INH administered during HAE attacks, and for short-term prophylaxis (STP).

MATERIALS & METHOD: Our prospective study analyzed the course of 544 HAE attacks experienced by the 21 C1-INH-HAE patients treated, as well as the outcome of 97 instances of STP implemented with rhC1-INH. Using a purpose-designed questionnaire, the patients recorded relevant, treatment-related information.

RESULTS: Time to the administration of rhC1-INH was 90.0 min (median) after the onset of HAE attacks. The symptoms started to improve as early as 60 min after the injection of rhC1-INH, and the attack resolved 730.0 min after treatment. The interval between the onset of the HAE attack and the administration of rhC1-INH correlated with time until the onset of improvement (R = 0.2053 p < 0.0001), and with time to the complete resolution of symptoms (R = 0.2805, p < 0.0001). Nine patients received STP with rhC1-INH in 97 instances. STP successfully prevented the HAE attack within 72 h of the event on 93/97 occasions. No local and serious systemic adverse events/effects were observed.

CONCLUSIONS: Treatment with rhC1-INH is effective and safe both for acute management, and for STP. Following the onset of an HAE attack, early administration of rhC1-INH may reduce time to the improvement and to the complete resolution of symptoms. Repeated administration of rhC1-INH does not impair its efficacy. Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Available from: dx.doi.org/10.1016/j.intimp.2020.106216

Hofman ZLM, van den Elzen MT, Kuijpers J, de Maat S, Hack CE, Knulst AC, Rockmann H, Maas C 3/2020 Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

BACKGROUND: Chronic spontaneous urticaria (CSU) is characterized by recurrent itchy weals and/or angioedema and is believed to be driven by mast cell activation. It was shown that excessive mast cell activation during anaphylaxis initiates contact activation, resulting in bradykinin release. Evidence for bradykinin release was never demonstrated in CSU.

OBJECTIVE: To study biomarkers of bradykinin release in CSU.

METHODS: Plasma samples of CSU patients were collected during routine visits at the outpatient clinic. Cleaved high molecular weight kininogen (cHK) was used as a biomarker for bradykinin release. cHK, factor XIIa-C1-inhibitor (FXIIa-C1-INH), kallikrein-C1-INH, plasmin-antiplasmin (PAP) complexes and soluble urokinase-type plasminogen activator receptor (suPAR) levels were determined by ELISA. Clinical data and data on tryptase levels were collected from medical records. cHK levels were compared to previously determined levels in hereditary angioedema (HAE).

RESULTS: One hundred seventeen samples from 88 CSU patients and 28 samples from healthy controls were analysed. Median cHK level in CSU was 9.1% (range: 1.4%-21.5%), significantly increased compared to healthy controls (median 6.0% range: 0%-19.9%; P = .0005) and comparable to HAE (n = 46, median 10.3%, range 0%-44.3%, P > .9999). cHK levels normalized in patients during disease remission (median 6.5% range 1.5%-20.8%) but were not dependent on the presence of angioedema, acute angioedema attacks or response to antihistamines. Surprisingly, cHK levels were inversely correlated to serum tryptase (r = -0.65 P = .0137). C1-INH complexes and suPAR levels were not elevated in patients compared to healthy controls. PAP-complex levels in patients were elevated compared to healthy controls but there was no correlation between PAP-complex and cHK levels.

CONCLUSIONS: cHK levels are elevated in symptomatic CSU patients compared to healthy controls, indicating increased bradykinin production. Increased cHK levels are not limited to patients with angioedema.

CLINICAL RELEVANCE: If elevated bradykinin generation has clinical implications in the pathology of CSU is open to debate. Copyright © 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.

Available from: dx.doi.org/10.1111/cea.13558

Gompel A, Fain O, Boccon-Gibod I, Gobert D, Bouillet L 1/2020 International Immunopharmacology

Gonadal hormones, estrogen and androgen are strongly involved in the control of the bradykinin production. Estrogen may worsen whereas androgen can be part of the long-term prophylactic treatment. In this review, we will describe the potential impact of estrogen in the pathophysiology of hereditary angioedema (HAE). Then we will review the different hormone treatments and their implication on the course of HAE in women and men: contraception, Assisted Reproductive Technology (ART), menopause, hormone dependent cancers in women and men, treatment of hyperandrogenism in women. Copyright © 2019 Elsevier B.V. All rights reserved.

Available from: dx.doi.org/10.1016/j.intimp.2019.106080

Brooks JP, Radojicic C, Riedl MA, Newcomer SD, Banerji A, Hsu FI 6/2020 The journal of allergy and clinical immunology. In practice

Consensus guidelines recommend plasma-derived C1 inhibitor (C1-INH) as first-line treatment in pregnant women with hereditary angioedema (HAE). We conducted a systematic review of the literature that describes experience with plasma-derived C1-INH during pregnancy. A literature search of PubMed was conducted in November 2018 using variants of “hereditary angioedema” and “pregnancy.” English language articles that presented original data about the use of plasma-derived C1-INH during pregnancy were selected for data extraction. The search returned 253 unique records, of which 40 described the use of C1-INH during pregnancy (91 patients, 136 pregnancies). When the number of doses was reported, a total of 1562 doses were administered ranging from 500 to 3000 IU. Infusions were administered during all 3 trimesters and were most commonly administered during the third trimester. Overall, 1,490,500 IU of plasma-derived C1-INH were administered during pregnancy. Of the 128 fetuses for which outcomes were reported, 3 (2%) resulted in spontaneous abortion, 1 (1%) was stillborn, and 1 (1%) was a vanishing twin. Use of plasma-derived C1-INH in women with HAE during pregnancy has been widely reported in the scientific literature and has a favorable safety profile, supporting treatment guideline recommendations. Copyright © 2020. Published by Elsevier Inc.

Available from: jaci-inpractice.org/article/S2213-2198(20)30250-6/pdf

Busse PJ, Christiansen SC 3/2020 New England Journal of Medicine

Available from: dx.doi.org/10.1056/NEJMra1808012

Gabos G, Nadasan V, Mihaly E, Dobru D 9/2020 Iranian journal of immunology : IJI

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic potentially life-threatening disease characterized by episodic non-pruritic subcutaneous and submucosal edema attacks in different parts of the body.

OBJECTIVE: To assess the status of Romanian HAE patients after the recent introduction of a new therapy through a nationwide program.

METHODS: This cross-sectional observational study included patients from the Romanian HAE Registry.

RESULTS: The study included 84 patients with HAE type I (91.7%) and type II (8.3%). The mean delay in diagnosis was 2.4 years in children and 16.7 years in adults (p=0.019). Stress and tiredness were the most frequent trigger factors. The majority of the HAE episodes involved subcutaneous (89.3%), abdominal (77.4%), genital (51.2%), facial (41.7%), and laryngeal (39.3%) symptoms during the preceding 12 months. One or several misdiagnoses were reported in 83.33% patients and 44.1 % of the patients were subjected to or proposed unnecessary surgery during abdominal episodes. Plasma-derived C1-INH (pdC1-INH) and recombinant C1-INH (rhC1-INH) were respectively used in 10 (11.9%) and 13 (15.5%) of the HAE patients for life-threatening attacks over the past 12 months. Forty-three (51.19%) patients practiced home treatment with subcutaneous injection of the bradykinin B2-receptor antagonist for acute HAE attacks.

CONCLUSION: The significantly lower delay observed in children suggests an improvement in the awareness of C1-INH-HAE among physicians in recent years. The management of HAE in Romania has been somewhat enhanced as the majority of HAE patients have recently gained access to pdC1-INH, rhC1-INH, and bradykinin B2-receptor antagonist.

Available from: dx.doi.org/10.22034/iji.2020.85416.1709

Wahn V, Aberer W, Aygoren-Pursun E, Bork K, Eberl W, Fashauer M, Kruger R, Magerl M, Martinez-Saguer I, Spath P, Staubach-Renz P, Weber-Chrysochoou C 11/2020 Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology

BACKGROUND/METHODS: At a consensus meeting in August 2018, pediatricians and dermatologists from German-speaking countries discussed the therapeutic strategy for the treatment of pediatric patients with type I and II hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) for Germany, Austria, and Switzerland, taking into account the current marketing approval status. HAE-C1-INH is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible and an optimal management of the disease are important to avoid ineffective therapies and to properly treat swelling attacks. This article provides recommendations for developing appropriate treatment strategies in the management of HAE-C1-INH in pediatric patients in German-speaking countries. An overview of available drugs in this age-group is provided, together with their approval status, and study results obtained in adults and pediatric patients.

RESULTS/CONCLUSION: Currently, plasma-derived C1 inhibitor concentrates have the broadest approval status and are considered the best available option for on-demand treatment of HAE-C1-INH attacks and for short- and long-term prophylaxis across all pediatric age-groups in German-speaking countries. For on-demand treatment of children aged 2 years and older, recombinant C1-INH and bradykinin-receptor antagonist icatibant are alternatives. For long-term prophylaxis in adolescents, the parenteral kallikrein inhibitor lanadelumab has recently been approved and can be recommended due to proven efficacy and safety. Copyright © 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Available from: dx.doi.org/10.1111/pai.13309

Kaplan AP 11/2020 Allergy and asthma proceedings

The future therapies for hereditary angioedema will likely involve the development of oral agents as alternatives to parenteral administration of drugs, specific targeting of proteins and/or enzymes that are not yet possible (e.g., factor XIIa), new agents that target the beta2 receptor with sustained action properties, testing of products to determine whether the beta1 receptor contributes significantly to attacks of angioedema, disrupting protein synthesis by using RNA technology as an alternative to enzyme inhibition, and, finally, gene therapy to attempt to cure the disease. Complete inhibition of attacks may well require sustained blood levels of C1 inhibitor that exceed 85% of normal, and it may be possible to delete the prekallikrein gene (analogous to familial prekallikrein deficiency), which is the one factor that might alleviate bradykinin formation, even by factor XII-independent initiating mechanisms, with the possible exception of Mannose Associated Serine Protease 1 (MASP-1) cleavage of high molecular weight kininogen (HK). Deletion of the light chain of high-molecular-weight kininogen would eliminate all possibilities for bradykinin formation, except tissue kallikrein cleavage of low-molecular-weight kininogen to support normal physiologic function to at least 50%.

Available from: dx.doi.org/10.2500/aap.2020.41.200056

Li HH 11/2020 Allergy and asthma proceedings

Hereditary Angioedema (HAE) is a potentially life-threatening condition. With episodic, unpredictable swelling, HAE negatively affect the quality of life for those affected individuals. To reduce the morbidity and mortality of HAE are the primary goal for the disease management. In addition to have access to therapeutic drugs for their acute HAE attacks, many patients require long term prophylaxis (LTP) to reduce their attack frequency and severity. Preventing HAE attack by regular administration of medicine has become an important part of HAE disease management. Over the past few years, growing number of therapeutic options for the HAE LTP have made it possible for physicians to choose the most appropriate and effective treatment for individual patients. C1 INH concentrate and plasma kallikrein inhibitors (IV or SC) have largely replaced the oder modality of treatment consisting different androgen derivatives or antifibrinolytics. Additional options, such as oral kallikrein inhibitor, antisense RNA/plasma kallikrein, anti-Factor 12a, bradykinin receptor blocker or future gene therapy are under clinical investigation. The significant cost and the uncertainty of its long term safety may be the primary limiting factors for its clinical application. The limited data for young children and pregnant women pose additional challenge for physicians to assess the risk and benefit when considering LTP treatment.

Available from: dx.doi.org/10.2500/aap.2020.41.200092

Christiansen SC, Zuraw BL 11/2020 Allergy and asthma proceedings

The availability of effective acute treatment for angioedema has been fundamental in reducing the burden of illness for patients with hereditary angioedema (HAE). In building on the foundation of scientific advances that elucidate the pathomechanism(s) of attacks related to vascular permeability, novel targeted on-demand treatments have been developed and approved. These therapies have provided the means to arrest episodes of swelling, which, in the past, had the potential to inexorably lead to morbidity, and even mortality, for patients with HAE. Access to these medications, along with an emphasis on early administration and guidance that all attacks are candidates for treatment, has shifted the management paradigm for HAE. Although unmet needs remain, these acute therapies, coupled with advances in prophylactic treatment, have furthered the goal for all patients with HAE to live a normal life.

Available from: dx.doi.org/10.2500/aap.2020.41.200066

Johnston DT, Smith RC 11/2020 Allergy and asthma proceedings

Patients with hereditary angioedema (HAE) can experience attacks at any age; however, the onset of swelling is typically in childhood. Unlike adults, this population is uniquely vulnerable; attacks in young children may be subtle, resemble other diseases, and often lead to a delay in diagnosis. Misdiagnosis contributes to significant delays in treatment, painful attacks, increased emotional stress, unnecessary procedures, and a potential risk of death. Older children may hide their symptoms due to anxiety or fear of social isolation. Attacks typically become more severe and more frequent during and after puberty. The impact of HAE attacks on school attendance and school performance may prevent future career or education opportunities. Living with HAE poses significant psychosocial stress on children and their families. In the United States, medical treatments for acute attacks in children approved for self-administration are limited to intravenous therapies, which complicates early treatment. To provide optimal care, we suggest that physicians screen all children with a family history of HAE, appreciate the dynamic nature of the disease during adolescence, proactively assess the psychosocial impact of disease, and continually reassess the treatment plan.

Available from: dx.doi.org/10.2500/aap.2020.41.200042

Yakaboski E, Motazedi T, Banerji A 11/2020 Allergy and asthma proceedings

There are several challenges that arise in caring for women with hereditary angioedema (HAE). Most notably, the disease course during pregnancy is unpredictable, but studies show that plasma-derived C1-inhibitor is effective and safe for treatment of attacks as well as long-term prophylaxis (LTP) in select patients. Vaginal deliveries are preferred to caesarean sections, and epidural anesthesia is preferred to general anesthesia in lowering the risk of an acute attack. Lactation postpartum may increase HAE attacks. With regard to contraception, combined oral contraceptive pills that contain estrogen exacerbate symptoms. Similarly, estrogen-replacement therapy in menopause may increase attacks and is contraindicated. Fertility is not impacted by HAE itself or by HAE medications. The risk of breast cancer and female reproductive cancer in women with HAE is comparable with that of the general population, but, in patients with HAE and breast cancer, LTP with androgens is contraindicated. Estrogen modulators, e.g., tamoxifen, should be used with caution. Here, we reviewed these special considerations and others that are vital to providers in caring for women with HAE.

Available from: dx.doi.org/10.2500/aap.2020.41.200077

Piotrowicz-Wojcik K, Porebski G 3/2020 Otolaryngologia Polska

BACKGROUND: Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) is a rare genetic disease that runs in the family. As a result of the disease, acute swellings of the subcutaneous tissue and mucous membranes of the digestive and respiratory systems, including the larynx, occur. Any attack of the disease involving the throat and larynx is particularly dangerous and requires knowledge of clinical determinants of the disease and its proper management.

Available from: dx.doi.org/10.5604/01.3001.0014.0619

Levy DS, Farkas H, Riedl MA, Hsu FI, Brooks JP, Cicardi M, Feuersenger H, Pragst I, Reshef A 2/2020 Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

BACKGROUND: Women with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) experience more frequent and severe angioedema attacks compared with men. Fluctuations in female sex hormones can influence HAE attack frequency and severity. Subcutaneous C1-INH (C1-INH [SC]) is indicated as routine prophylaxis to prevent HAE attacks. In this post hoc subgroup analysis, we evaluated the efficacy and safety of C1-INH (SC) in female subjects with HAE-C1INH enrolled in an open-label extension of the pivotal phase III COMPACT trial.

METHODS: In this multicenter, randomized, parallel-arm trial, eligible subjects (age >= 6 years with >= 4 attacks over 2 consecutive months) received C1-INH (SC) 40 IU/kg or 60 IU/kg twice weekly for 52 to 140 weeks. Analyses of efficacy endpoints were performed for all female subjects and those of childbearing age (age >= 15 to <= 45 years), including subjects who became pregnant during the evaluation period.

RESULTS: Overall, 91% (69/76) of female subjects were classified as responders (>= 50% reduction in HAE attacks relative to the pre-study period); 82% experienced < 1 attack/4 weeks. The median number of attacks/month was 0.10, with 96% median reduction in attacks relative to the pre-study period. Results were similar in the subgroup of subjects of childbearing age. Four women who became pregnant during the trial and were exposed to C1-INH (SC) during the first trimester delivered healthy babies with no congenital abnormalities.

CONCLUSIONS: C1-INH (SC) prophylaxis was safe and effective in women with HAE-C1INH, including those of childbearing age. Four women exposed to C1-INH (SC) during the first trimester had uneventful pregnancies and delivered healthy babies. Trial registration Clinicaltrials.gov identifier NCT02316353 (Registered December 10, 2014); clinicaltrials.gov/ct2/show/NCT02316353. Copyright © The Author(s) 2020.

Available from: ncbi.nlm.nih.gov/pmc/articles/PMC7001333

Levy D, Caballero T, Hussain I, Reshef A, Anderson J, Baker J, Schwartz LB, Cicardi M, Prusty S, Feuersenger H, Pragst I, Manning ME 9/2020 Pediatric allergy, immunology, and pulmonology

BACKGROUND: Hereditary angioedema (HAE) due to C1 inhibitor (C1INH) deficiency is characterized by recurrent attacks of edema of the skin and mucosal tissues. Symptoms usually present during childhood (mean age at first attack, 10 years). Earlier symptom onset may predict a more severe disease course. Subcutaneous (SC) C1INH is indicated for routine prophylaxis to prevent HAE attacks in adolescents and adults. We analyzed the long-term efficacy of C1INH (SC) in subjects <=17 years old treated in an open-label extension (OLE) of the pivotal phase III Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1 Inhibitor Replacement Therapy (COMPACT) trial.

METHODS: Eligible subjects (age >=6 years, with >=4 attacks over 2 consecutive months before entry into the OLE or placebo-controlled COMPACT trial) were treated with C1INH (SC) 40 or 60 IU/kg twice weekly for 52-140 weeks. Subgroup analyses by age (<=17 vs. >17 years) were performed for key efficacy endpoints.

RESULTS: Ten subjects were <=17 years old [mean (range) age, 13.3 (8-16) years, 3 subjects <12 years old; exposure range, 51-133 weeks]. All 10 pediatric subjects experienced >=50% reduction (mean, 93%) in number of attacks versus the prestudy period, with a 97% reduction in the median number of attacks/month (0.11). All subjects had <1 attack/4-week period and 4 had <1 attack/year (1 subject was attack free). No subject discontinued treatment due to a treatment-related adverse event.

CONCLUSIONS: Data from pediatric subjects treated with C1INH (SC) for up to 2.55 years and adult subjects revealed similar efficacy. C1INH (SC) is effective and well tolerated as long-term prophylaxis in children, adolescents, and adults with HAE. Copyright © Donald Levy et al., 2020; Published by Mary Ann Liebert, Inc.

Available from: dx.doi.org/10.1089/ped.2020.1143

Bernstein JA, Schwartz L, Yang W, Baker J, Anderson J, Farkas H, Aygoren-Pursun E, Bygum A, Jacobs I, Feuersenger H, Pragst I, Riedl MA 9/2020 Annals of Allergy, Asthma, & Immunology

BACKGROUND: Patients aged 65 years and older with hereditary angioedema (HAE) owing to C1-inhibitor (C1-INH) deficiency may have an altered response to treatment and are at higher risk for treatment-related adverse events (AEs) because of comorbidities and polypharmacy.

OBJECTIVE: To investigate the safety and efficacy of subcutaneous C1 esterase inhibitor (C1-INH) in patients aged 65 years and older treated in an open-label extension of a phase 3 trial.

METHODS: Eligible patients (>=4 attacks for more than 2 consecutive months) were randomized to receive twice-weekly subcutaneous C1-INH with a dosage of 40 IU/kg or 60 IU/kg for 52 to 140 weeks. Safety end points and efficacy outcomes were evaluated for patients aged 65 years and above and younger than 65 years.

RESULTS: Of the 126 patients treated, 10 were 65 years and older (mean age [range], 68 [65-72 years]). A total of 8 of 10 patients had multiple comorbidities, and 6 of these 10 patients were taking more than 5 non-HAE-related drugs concomitantly. AEs occurring in more than 1 patient included injection site bruising (n = 2, related), injection site pain (n = 2, related), urinary tract infection (n = 2, unrelated), and diarrhea (n = 2, unrelated). No thromboembolic events or cases of anaphylaxis were reported. Two patients aged 65 years and older experienced unrelated serious AEs (dehydration and hypokalemia in 1 and pneumonia and an HAE attack leading to hospitalization in another). A total of 6 of 9 evaluable patients were responders, with a greater than or equal to 50% reduction in HAE attacks vs prestudy; 6 of 10 patients had less than 1 attack over 4 weeks and 3 were attack-free (median attack rate, 0.52 attacks per month).

Available from: dx.doi.org/10.1016/j.anai.2020.05.015

Simon TL, Kalina U, Laske R, Mycroft S, Widmer E, Roth NJ 3/2020 Allergy & Asthma Proceedings

BACKGROUND: Replacement therapy with plasma-derived C1-inhibitor (C1-INH) has been used for decades to treat patients with hereditary angioedema (HAE) with C1-INH deficiency.

OBJECTIVE: This article reviewed the rationale for using C1-INH replacement therapy in patients with HAE and the process of manufacturing plasma-derived C1-INH.

METHODS: The manufacture of C1-INH is an involved and carefully monitored process that includes screening and selection of prospective donors, the collection of source plasma, and purification with dedicated pathogen reduction steps. Donor eligibility is determined by restrictive criteria established and monitored by regulatory agencies as well as voluntary standards implemented by plasma collection centers that exceed government regulations. Individual and pooled donations are tested for transfusion-transmissible infections, including hepatitis B virus, hepatitis C virus, human immunodeficiency virus, parvovirus B19, and hepatitis A virus, by using enzyme-linked immunosorbent assays or nucleic acid amplification technologies. Frozen plasma that is cleared for manufacturing undergoes controlled thawing and centrifugation, and the resulting supernatant (i.e., cryoprecipitate-depleted plasma) is used to manufacture several plasma-derived therapies, including C1-INH. In addition to chromatography steps, the manufacturing process consists of dedicated and effective pathogen reduction steps, including pasteurization, hydrophobic interaction chromatography or polyethylene glycol precipitation, and virus filtration. Manufacturers continuously monitor the safety profile of C1-INH products by robust pharmacovigilance processes that enable systematic collection and evaluation of all suspected adverse drug reaction reports as well as evaluation of safety information from all other sources.

RESULTS AND CONCLUSION: These procedures used in donor screening, donation and manufacturing pool testing, manufacturing, and pharmacovigilance ensure that plasma-derived C1-INH products have the safety, quality, identity, potency, and purity that is necessary to provide the intended therapeutic effect.

Available from: dx.doi.org/10.2500/aap.2020.41.190021

Bernstein JA, Tyson C, Relan A, Adams P, Magar R 2/2020 Journal of Managed Care & Specialty Pharmacy

BACKGROUND: Hereditary angioedema (HAE) is a rare C1-inhibitor (C1-INH) deficiency disease. Low levels of functional C1-INH can lead to recurrent attacks of severe swelling occurring in areas such as the limbs, face, gastrointestinal tract, and throat. These attacks are both painful and disabling and, if not treated promptly and effectively, can result in hospitalization or death. Agents targeting the specific physiologic pathway of HAE attacks can offer improved outcomes with limited side effects compared with nonspecific therapies. However, these treatments display varying efficacy in HAE patients, including the need to redose or seek additional care if the treatment does not resolve symptoms effectively.

OBJECTIVE: To analyze the expected cost and utility per HAE attack when treated on-demand with HAE therapies indicated for the treatment of acute attacks.

METHODS: A decision-tree model was developed using TreeAge Pro software. Four on-demand HAE treatments were included: ecallantide, icatibant, plasma-derived (pd)C1-INH, and recombinant human (rh)C1-INH. The model uses probabilities for redosing, self-administration versus health care provider administration, and risk of hospitalization. Costs within the model consisted of the HAE treatments and associated health care system expenses. Nonattack baseline utility and attack utility were implemented for effectiveness calculations; time to attack resolution was considered as well. Effectiveness and overall costs per attack were calculated and used to estimate cost per quality-adjusted life-year (QALY). Variability and ranges in cost-effectiveness were determined using probabilistic sensitivity analyses. Finally, a budget impact model for a health plan with 1 million covered lives was also developed.

RESULTS: The base case model outputs show costs and calculated effectiveness per attack at $12,905 and 0.806 for rhC1-INH, $14,806 and 0.765 for icatibant, $14,668 and 0.769 for pdC1-INH, and $21,068 and 0.792 for ecallantide, respectively. Cost per QALY was calculated using 26.9 attacks per person-year, leading to results of $420,941 for rhC1-INH, $488,349 for icatibant, $483,892 for pdC1-INH, and $689,773 for ecallantide. Sensitivity analyses demonstrate that redose rates (from 3% for rhC1-INH to 44% for icatibant) are a primary driver of variability in cost-effectiveness. Annual health plan costs from the budget impact model are calculated as $6.94 million for rhC1-INH, $7.97 million for icatibant, $7.90 million for pdC1-INH, and $11.33 million for ecallantide.

CONCLUSIONS: Accounting for patient well-being and additional cost components of HAE attacks generates a better estimation of cost-effectiveness than drug cost alone. Results from this model indicate that rhC1-INH is the dominant treatment option with lower expected costs and higher calculated effectiveness than comparators. Further analyses reinforce the idea that low redose rates contribute to improved cost-effectiveness.

DISCLOSURES: Funding support was contributed by Pharming Healthcare. Relan and Adams are employed by Pharming Healthcare. Tyson and Magar are employed by AHRM, which received fees to perform the analysis and develop the manuscript. Bernstein reports grants, personal fees, and nonfinancial support from Shire, CSL Behring, and Pharming Healthcare; grants and personal fees from Biocryst; and nonfinancial support from HAEA, unrelated to this study.

Available from: dx.doi.org/10.18553/jmcp.2019.19217

Kapoor A, Garg BK, Zhou Z, Lu P, Chockalingam PS 4/2020 International Immunopharmacology

Hereditary angioedema (HAE) types I and II are characterized by functional C1 inhibitor (fC1-INH) deficiency which results in bradykinin overproduction. Sensitive, specific and robust methods to quantitate fC1-INH in human samples are required for diagnosing HAE and/or to measure pharmacodynamic activity of C1-INH drugs in clinical studies. To date, three methods have been reported in literature to measure fC1-INH: conventional chromogenic assay measuring residual C1-esterase activity, and immunoassays based on functional binding to either activated complement C1s or Factor XIIa/kallikrein. We used three qualified/validated fit-for purpose methods to quantitate fC1-INH in human plasma and to conduct a parallel comparison for diagnostic purposes and as a read-out for pharmacodynamic activity. Sensitivity and specificity were determined from the Receiver Operator Characteristics (ROC) curve analysis of the three fC1-INH methods through testing of fifty healthy control vs. HAE plasma samples. fC1-INH profile of fifteen HAE subjects, who underwent different treatment regimen in a cross-over Shire C1-INH clinical study, was analyzed in these three methods in parallel. A correlation analysis performed between these methods using data generated from clinical samples showed that profiles obtained from different fC1-INH methods matched for individual HAE subjects. Our findings suggest that functional binding immunoassay methods serve as reliable alternates for conventional chromogenic method to quantitate fC1-INH in human plasma samples with a better dynamic range of detection and ease of use. Of the two immunoassays used in this study, FXIIa-binding method gave better sensitivity, specificity, and correlation to the chromogenic method as a diagnostic method to distinguish HAE samples from healthy controls. Copyright © 2020 Elsevier B.V. All rights reserved.

Available from: dx.doi.org/10.1016/j.intimp.2020.106348

Tanaka KA, Mondal S, Morita Y, Williams B, Strauss ER, Cicardi M 7/2020 Anesthesia & Analgesia

Hereditary angioedema (HAE) is a rare autosomal dominant disorder mostly due to the deficiency of C1-esterase inhibitor (C1-INH). Reduced C1-INH activity below ~38% disrupts homeostasis of bradykinin (BK) formation by increasing kallikrein activation and causes recurrent angioedema attacks affecting the face, extremities, genitals, bowels, oropharynx, and larynx. HAE symptoms can be debilitating and potentially life-threatening. The recent clinical developments of biological and pharmacological agents have immensely improved acute and long-term care of patients with moderate-to-severe HAE. The therapies are given as on-demand and/or prophylaxis, and self-administration is highly recommended and performed with some agents via intravenous or subcutaneous route. Perioperative clinicians need to be familiar with the symptoms and diagnosis of HAE as well as available therapies because of the potential need for airway management, sedation, or anesthesia for various medical and surgical procedures and postoperative care. Cardiovascular surgery using cardiopulmonary bypass is a unique condition in which heparinized blood comes into direct contact with an artificial surface while pulmonary circulation, a major reserve of angiotensin-converting enzyme (ACE), becomes excluded. These changes result in systemic kallikrein activation and BK formation even in non-HAE patients. The objectives of this review are (1) to review pathophysiology of HAE and laboratory testing, (2) to summarize pertinent pharmacological data on the prophylactic and on-demand treatment strategies, and (3) to discuss available clinical data for perioperative management in cardiovascular surgery.

Available from: dx.doi.org/10.1213/ANE.0000000000004710

Wang Y, Marier JF, Kassir N, Chang C, Martin P 11/2020 Clinical and translational science

There are several challenges that arise in caring for women with hereditary angioedema (HAE). Most notably, the disease course during pregnancy is unpredictable, but studies show that plasma-derived C1-inhibitor is effective and safe for treatment of attacks as well as long-term prophylaxis (LTP) in select patients. Vaginal deliveries are preferred to caesarean sections, and epidural anesthesia is preferred to general anesthesia in lowering the risk of an acute attack. Lactation postpartum may increase HAE attacks. With regard to contraception, combined oral contraceptive pills that contain estrogen exacerbate symptoms. Similarly, estrogen-replacement therapy in menopause may increase attacks and is contraindicated. Fertility is not impacted by HAE itself or by HAE medications. The risk of breast cancer and female reproductive cancer in women with HAE is comparable with that of the general population, but, in patients with HAE and breast cancer, LTP with androgens is contraindicated. Estrogen modulators, e.g., tamoxifen, should be used with caution. Here, we reviewed these special considerations and others that are vital to providers in caring for women with HAE.

Available from: dx.doi.org/10.1111/cts.12806

Martinez-Zapata MJ, Vernooij RW, Simancas-Racines D, Uriona Tuma SM, Stein AT, Moreno Carriles RMM, Vargas E, Bonfill Cosp X 11/2020 The Cochrane Database of Systematic Reviews

BACKGROUND: Chronic venous insufficiency (CVI) is a condition in which veins are unable to transport blood unidirectionally towards the heart. CVI usually occurs in the lower limbs. It might result in considerable discomfort, with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is the second update of a review first published in 2005.

OBJECTIVES: To assess the efficacy and safety of phlebotonics administered orally or topically for treatment of signs and symptoms of lower extremity CVI.

SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and Clinicaltrials.gov trials register up to 12 November 2019. We searched the reference lists of the articles retrieved by electronic searches for additional citations. We also contacted authors of unpublished studies.

SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of phlebotonics (rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, French maritime pine bark extract, grape seed extract and aminaftone) in patients with CVI at any stage of the disease.

DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardized mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence intervals (CIs) and percentage of heterogeneity (I2). Outcomes of interest were oedema, quality of life (QoL), assessment of CVI and adverse events. We used GRADE criteria to assess the certainty of the evidence.

MAIN RESULTS: We identified three new studies for this update. In total, 69 RCTs of oral phlebotonics were included, but only 56 studies (7690 participants, mean age 50 years) provided quantifiable data for the efficacy analysis. These studies used different phlebotonics (28 on rutosides, 11 on hidrosmine and diosmine, 10 on calcium dobesilate, two on Centella asiatica, two on aminaftone, two on French maritime pine bark extract and one on grape seed extract). No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Moderate-certainty evidence suggests that phlebotonics probably reduce oedema slightly in the lower legs, compared with placebo (RR 0.70, 95% CI 0.63 to 0.78; 13 studies; 1245 participants); and probably reduce ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; 15 studies; 2010 participants). Moderate-certainty evidence shows that phlebotonics probably make little or no difference in QoL compared with placebo (SMD -0.06, 95% CI -0.22 to 0.10; five studies; 1639 participants); and similarly, may have little or no effect on ulcer healing (RR 0.94, 95% CI 0.79 to 1.13; six studies; 461 participants; low-certainty evidence). Thirty-seven studies reported on adverse events. Pooled data suggest that phlebotonics probably increase adverse events slightly, compared to placebo (RR 1.14, 95% CI 1.02 to 1.27; 37 studies; 5789 participants; moderate-certainty evidence). Gastrointestinal disorders were the most frequently reported adverse events. We downgraded our certainty in the evidence from ‘high’ to ‘moderate’ because of risk of bias concerns, and further to ‘low’ because of imprecision.

AUTHORS’ CONCLUSIONS: There is moderate-certainty evidence that phlebotonics probably reduce oedema slightly, compared to placebo; moderate-certainty evidence of little or no difference in QoL; and low-certainty evidence that these drugs do not influence ulcer healing. Moderate-certainty evidence suggests that phlebotonics are probably associated with a higher risk of adverse events than placebo. Studies included in this systematic review provided only short-term safety data; therefore, the medium- and long-term safety of phlebotonics could not be estimated. Findings for specific groups of phlebotonics are limited due to small study numbers and heterogeneous results. Additional high-quality RCTs focusing on clinically important outcomes are needed to improve the evidence base. Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Available from: dx.doi.org/10.1002/14651858.CD003229.pub4

Hahn J, Trainotti S, Wigand MC, Schuler PJ, Hoffmann TK, Greve J 10/2020 Journal of drugs in dermatology : JDD

BACKGROUND AND OBJECTIVES: Patients with the rare disease hereditary angioedema (HAE) suffer from recurrent acute attacks of edema. There is no curative therapy, but the frequency of attacks and quality of life of severely affected patients can be improved by prophylactic therapy. The monoclonal antibody lanadelumab has been approved for routine prophylaxis in patients with HAE since November 2018.

PATIENTS AND METHODS: In this prospective assessment, a long-term therapy with lanadelumab was initiated in 12 adult patients with HAE. We analyzed their course of disease 6 months after the start of long-term prophylactic therapy using a validated quality-of-life questionnaire and evaluated the frequency and severity of attacks as well as side effects. Furthermore, the therapy with lanadelumab was compared with the previous medication.

RESULTS: To date, our study is the first prospective quality of life analysis in HAE patients under treatment with lanadelumab in real life conditions. Mean attack frequencies were reduced from 6.4 to 0.3 attacks per month and patient in our cohort (P<0.0001). No severe attacks occurred under lanadelumab prophylaxis. In all patients, quality of life increased significantly.

CONCLUSIONS: Lanadelumab is an effective but expensive long-term prophylaxis for HAE patients. A favorable side-effect profile has been shown. J Drugs Dermatol. 2020;19(10):978-983. doi:10.36849/JDD.2020.5269.

Available from: dx.doi.org/10.36849/JDD.2020.5269

Tachdjian R, Johnson KE, Casso D, Oliveria SA, Devercelli G, Jain G 5/2020 Allergy and asthma proceedings

BACKGROUND: There is limited real-world evidence on hereditary angioedema (HAE) patient characteristics and health-care resource utilization (HCRU); in addition, pediatric patients have been described in small cohorts.

OBJECTIVE: To describe patient characteristics, treatment patterns, and HCRU among adult and pediatric patients treated for HAE in a large U.S. cohort.

METHODS: This retrospective cohort study used an administrative claims data base (January 2006 to September 2015). Eligible patients with either >=1 pharmacy claim for HAE-indicated therapies (C1 inhibitors, ecallantide, icatibant) or >=2 medical claims with codes associated with HAE (per medical billing codes), and >=1 claim for androgens, fresh frozen plasma, tranexamic acid, or epsilon-aminocaproic acid formed a “treated cohort.” Three nonexclusive treated cohorts were assessed: overall, pediatric, and HCRU (>=2 years of continuous enrollment during 2010-2015).

RESULTS: Overall, 1429 patients received treatment (mean +/- standard deviation [SD] age, 38.8 +/-15.7 years; 62.4% female patients; mean +/- SD Charlson Comorbidity Index of 1.4 +/- 2.4). Common comorbidities were allergy or anaphylaxis (51.4%) and anxiety or depression (35.8%). Diagnoses indicative of HAE attacks included swelling and/or angioedema (78.5%), abdominal pain (55.6%), and asphyxiation (27.2%). Use of HAE-indicated medication rose between 2006 and 2015 to 81.8%, whereas androgen use declined (from 91.5% to 24.9%). Similar trends were observed in the pediatric treated cohort (n = 143). In the HCRU treated cohort (n = 538), HAE-related claims for emergency department and inpatient admissions were observed for 36.6% and 22.3% of patients, respectively.

CONCLUSION: In a large U.S. cohort of adult and pediatric patients who received treatments indicated or used for HAE, common comorbidities and trends in resource use denoted the substantial burden of attacks, which reflected a continued need that recently approved long-term prophylactic treatments may help to address.

Available from: dx.doi.org/10.2500/aap.2020.41.200011

Valerieva A, Staevska M, Jesenak M, Hrubiskova K, Sobotkova M, Zachova R, Hakl R, Andrejevic S, Suiter T, Grivcheva-Panovska V, Karadza-Lapic L, Soteres D, Shapiro R, Rumbyrt J, Tachdjian R, Mehta V, Hsu FI, Zanichelli A 2/2020 The journal of allergy and clinical immunology. In practice

Available from: jaci-inpractice.org/article/S2213-2198(19)30717-2/fulltext

Cai G, Barber C, Kalicinsky C 11/2020 Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

BACKGROUND: This is a retrospective review of the Winnipeg Regional Health Authority’s (WRHA) angioedema patients who were dispensed icatibant in hospital. Icatibant is a bradykinin B2 receptor antagonist indicated for Hereditary Angioedema (HAE) types I and II and is used off-label for HAE with normal C1INH (HAE-nC1INH) and ACE-inhibitor induced angioedema (ACEIIAE). The WRHA’s use of icatibant is regulated by the Allergist on call. We characterized icatibant’s use and the timeline from patient presentation, compared the real-world experience with the FAST-3 trial and hypothesized the factors which may affect response to icatibant.

METHODS: Background data were collected on patients. Angioedema attack-related data included administered medications, performed investigations and the timeline to endpoints such as onset of symptom relief. Data was analyzed in R with the package “survival.” Time-to-event data was analyzed using the Peto-Peto Prentice method or Mann-Whitney U-test. Data was also compared with published clinical trial data using the Sign Test. Fisher’s Exact Test was used to produce descriptive statistics.

RESULTS: Overall, 21 patients accounted for 23 angioedema attacks treated with icatibant. Approximately half the patients had a diagnosis of HAE-nC1IHN and half of ACEIIAE. Of those presenting with angioedema, 65% were first treated with conventional medication. Patients without a prior angioedema diagnosis were evaluated only 40-50% of the time for C4 levels or C1INH function or level. The median time from patients’ arrival to the emergency department until the Allergy consultant’s response was 1.77 h. Patients with HAE-nC1IHN had median times to onset of symptom relief and final clinical outcome (1.13 h, p = 0.34; 3.50 h, p = 0.11) similar to those reported in FAST-3 for HAE I/II. Patients with ACEIIAE had longer median times to onset of symptom relief (4.86 h, p = 0.01) than predicted.

CONCLUSIONS: HAE-nC1INH may be an appropriate indication for treatment with icatibant. Conversely, the results of this study do not support the use of icatibant for the treatment of ACEIIAE, concordant with a growing body of literature. Patients should be stratified into groups of more- or less-likely icatibant-responders through history and laboratory investigations in order to prevent potential delays.

Available from: ncbi.nlm.nih.gov/pmc/articles/PMC7656671

Riedl MA, Maurer M, Bernstein JA, Banerji A, Longhurst HJ, Li HH, Lu P, Hao J, Juethner S, Lumry WR, HELP Investigators 11/2020 Allergy

BACKGROUND: Lanadelumab demonstrated efficacy in preventing hereditary angioedema (HAE) attacks in the phase 3 HELP Study.

OBJECTIVE: To assess time to onset of effect and long-term efficacy of lanadelumab, based on exploratory findings from the HELP Study.

METHODS: Eligible patients with HAE type I/II received lanadelumab 150 mg every 4 weeks (q4wks), 300 mg q4wks, 300 mg q2wks, or placebo. Ad hoc analyses evaluated day 0-69 findings using a Poisson regression model accounting for overdispersion. Least-squares mean monthly HAE attack rate for lanadelumab was compared with placebo. Intrapatient comparisons for days 0-69 versus steady state (days 70-182) used a paired t test for continuous endpoints or Kappa statistics for categorical endpoints.

RESULTS: One hundred twenty-five patients were randomized and treated. During days 0-69, mean monthly attack rate was significantly lower with lanadelumab (0.41-0.76) vs placebo (2.04), including attacks requiring acute treatment (0.33-0.61 vs 1.66) and moderate/severe attacks (0.31-0.48 vs 1.33, all P <= .001). More patients receiving lanadelumab vs placebo were attack free (37.9%-48.1% vs 7.3%) and responders (85.7%-100% vs 26.8%). During steady state, the efficacy of lanadelumab vs placebo was similar or improved vs days 0-69. Intrapatient differences were significant with lanadelumab 300 mg q4wks for select outcomes. Lanadelumab efficacy was durable-HAE attack rate was consistently lower vs placebo, from the first 2 weeks of treatment through study end. Treatment emergent adverse events were comparable during days 0-69 and 70-182.

CONCLUSION: Protection with lanadelumab started from the first dose and continued throughout the entire study period. Copyright © 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

Available from: dx.doi.org/10.1111/all.14416

Zanichelli A, Ghezzi M, Santicchia I, Vacchini R, Cicardi M, Sparaco A, Donati G, Rania V, Busa A 3/2020 PLoS ONE

BACKGROUND: Patients affected by angioedema due to hereditary and acquired C1-inhibitor (C1-INH) deficiency (HAE and AAE, respectively) report trouble accessing dental care, due to the risk of a life-threatening oropharyngeal and laryngeal attack triggered by dental procedures. The aim of this study was to assess the identification of hurdles in receiving dental care, and the effectiveness of short-term prophylaxis (STP) in preventing angioedema attacks. In addition, the study evaluated the impact of dental care in angioedema disease. All patients affected by angioedema due to C1-INH deficiency who were treated in the dentistry outpatient department of ASST Fatebenefratelli Sacco hospital (Milan, Italy) between 2009 and 2017 were considered for the analysis. Data were collected from patients’ records.

RESULTS: Twenty-nine patients were analyzed (27 with HAE and 2 with AAE). Of these, 63.0% reported that they had previously experienced hurdles in accessing dental care. Among patients with pathological oral status, at the first visit, 59.26% patients had moderate-to-severe oral disease. Seventy-five dental procedures were performed in 20 patients. Sixty procedures were preceded by STP (58 with plasma-derived C1-INH and 2 with danazol) in patients with/without long-term prophylaxis (LTP). Post-procedural attacks occurred in two patients. One HAE patient undergoing a tooth extraction without STP/LTP experienced a laryngeal attack. The other post-procedural attack occurred in an AAE patient with anti-C1-INH antibodies with STP with pdC1-INH. The angioedema disease did not worsen in any patient after dental care, but improved in four of them.

CONCLUSIONS: Most C1-INH-HAE patients reported hurdles in receiving dental care. STP protects against attacks after dental procedures. Treating oral diseases results in improvement in the frequency of attacks.

Available from: dx.doi.org/10.1371/journal.pone.0230128

Burnham K, Reinert JP 7/2020 Expert Review of Clinical Pharmacology

INTRODUCTION: The exact risk of developing a thromboembolic event (TEE) while using complement 1 esterase inhibitors (C1-INHs) is currently undetermined for patients with hereditary angioedema (HAE). This systematic review aimed to define the potential risk of TEEs from these agents.

AREAS COVERED: This evaluation covers publications examining or mentioning the risk of TEEs in association with C1-INHs. A systematic literature search was conducted utilizing PubMed, Scopus, and ProQuest. This review utilized search results through January 2020 and followed the PRISMA recommendations for a systematic review. Articles not available in English and animal or in-vitro studies were excluded. For inclusion, studies had to be open-label, randomized-controlled, cross-sectional, or clinical observational studies. A total of 13 studies met inclusion criteria and yielded 1716 patients receiving at least one dose of C1-INH, though only 41 incidences of thrombosis were documented.

EXPERT OPINION: Significant heterogeneity exists in the available literature concerning both study design and the reporting of data; therefore, interpretation of thrombotic risk is difficult. TEEs are rarely reported in the literature, and they seem unlikely to occur in patients without underlying risk factors. Important risk factors include those found in the prescribing information of C1-INHs.

Available from: dx.doi.org/10.1080/17512433.2020.1776110