Medical Literature - 2024

Akeret K, Thomson BR, Ghosh S, Nolte M, Fischer U, Humar R, Regli L, Schaer DJ, Hugelshofer M, Buzzi RM

Nov/2024. Fluids and barriers of the CNS

BACKGROUND: Preclinical studies indicate that the systemic application of C1-inhibitor, clinically used to treat hereditary angioedema, reduces secondary brain injury after ischemic stroke. This study assessed the effect of C1-inhibitor on secondary brain injury after hemorrhagic stroke. METHODS: We used an established striatal whole-blood injection mouse model to mimic intracerebral hemorrhage-related secondary brain injury. Based on the spatiotemporal dynamics in our model, we calculated the necessary sample size (n = 24) and determined the most sensitive time point to detect potential group differences (48 h) prior to the experiments. The experimental setup, tissue processing and image analysis adhered to our published protocol. We randomized mice into three groups: C1-inhibitor treatment, placebo, and sham. Histology was standardized by taking eight anatomically predefined slices across the entire lesion. Lesion size, vascular leakage, and inflammatory responses were assessed using automated thresholding and dextran/ICAM1/CD45 intensity mapping. Investigators were blinded to group allocation during the experiment, tissue processing, and image analysis. RESULTS: Whole blood injection resulted in significantly larger lesion size and more pronounced vascular leakage and cellular inflammation compared to the sham group. However, there was no difference in lesion size or inflammatory markers between the C1-inhibitor and placebo groups. In addition, there was no difference in the inflammatory response of the choroid plexus, which has been identified as a central organ orchestrating inflammation after intracerebral hemorrhage. CONCLUSION: The protective effect of C1-inhibitor might be isolated to pathophysiological processes with a predominant thromboinflammatory component, as in ischemia-reperfusion, but less so in permanent ischemia or intracerebral hemorrhage. Copyright © 2024. The Author(s).

21(1):91

Available online at: https://dx.doi.org/10.1186/s12987-024-00594-w

Anderson J, Soteres D, Tachdjian R, Mellor J, Earl L, Connolly H, Wynne-Cattanach K, Moran K, Sing K, Schultz BG, Juethner S

Nov/2024. Allergy and asthma proceedings

Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by painful, debilitating, and potentially fatal swelling attacks. Lanadelumab is approved as long-term prophylaxis (LTP) in patients with HAE. However, real-world data on LTP use in patients with HAE are limited. Objective: To describe clinical characteristics, attack history, and quality of life (QoL) of patients with HAE type I/II who were receiving lanadelumab or other LTPs. Methods: Data were drawn from the Adelphi HAE Disease Specific Program, a cross-sectional survey of HAE physicians conducted in the United States from July to November 2021. Physician-reported disease characteristics, HAE attack frequency, and QoL were compared among patients receiving lanadelumab or other LTPs for at least 12 months. Results: Physicians reported data for 144 patients, of whom 29 had received lanadelumab and 115 had received another prophylaxis for at least 12 months. The mean +/- standard deviation number of attacks in the previous 12 months was lower among patients receiving lanadelumab than other LTPs (2.3 +/- 3.1 versus 3.4 +/- 2.8, respectively; p = 0.075). Although both groups had similar current disease activity and severity, more patients receiving lanadelumab versus other LTPs had high disease activity (51.7% versus 12.5%, respectively; p < 0.0001) and disease severity rated as severe (51.7% versus 16.1%, respectively; p = 0.0001) at diagnosis. Physicians reported that more patients who received lanadelumab had good or very good QoL (72.4%) than those receiving other LTPs (36.5%) (p = 0.003). Conclusion: Analysis of these findings suggests lower attack frequency, lower symptomatic impact, and better QoL in patients treated with lanadelumab than another prophylaxis in a real-world setting.

45(6):426-433

Available online at: https://dx.doi.org/10.2500/aap.2024.45.240046

Baynova K, Cimbollek S, Quiralte J, Garcia R, Lucena JM, Lasa Luaces E, Lara Jimenez MA, Alvarez Nieto J, Moreto J, Gonzalez-Quevedo T

Jun/2024. Journal of investigational allergology & clinical immunology

34(3):198-199

Available online at: https://dx.doi.org/10.18176/jiaci.0948

Buttgereit T, Vera Ayala C, Aykanat S, Weller K, Gutsche A, Maurer M, Magerl M

May/2024. Frontiers in immunology

Introduction: Lanadelumab is a first-line long-term prophylaxis (LTP) in hereditary angioedema (HAE). Real-life data on its long-term efficacy and safety are limited. It is unknown whether patients using lanadelumab need short-term prophylaxis (STP). Objectives: To provide 4-year follow-up data for our first 34 patients treating with lanadelumab. Methods: Patients were assessed for their current injection interval, attacks, treatment satisfaction, disease control (AECT), quality of life impairment (AE-QoL), events that can induce attacks, and the use of STP since the start of their treatment with lanadelumab. Results: Of 34 patients who started lanadelumab treatment, 32 were still using it after 4 years, with a median injection interval of 33 (range 14-90) days. HAE patients (n=28) reported longer intervals, i.e. 35 (14-90) days, than patients with angioedema due to acquired C1 inhibitor deficiency (n=4, 23 (14-31) days). With their current injection intervals, used for a mean duration of 29 +/- 17 months, patients reported a yearly attack rate of 0.3 +/- 0.1. More than 70% of patients were attack-free since starting their current injection interval. All patients reported well-controlled disease, i.e. >=10 points in the AECT; 21 patients had complete control (16 points). AE-QoL scores improved further compared to our initial report, most prominently in the fears/shame domain (-6 points). Treatment satisfaction was very high. No angioedema occurred after 146 of 147 potentially attack-inducing medical procedures without STP. Conclusions: Our results demonstrate the long-term efficacy and safety of lanadelumab in real-life and question the need for STP in patients who use effective LTP. Copyright © 2024 Buttgereit, Vera Ayala, Aykanat, Weller, Gutsche, Maurer and Magerl.

15:1405317

Available online at: https://dx.doi.org/10.3389/fimmu.2024.1405317

Cohn DM, Renne T

Oct/2024. Journal of internal medicine

Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic disorder characterized by recurrent attacks of swelling. Local vasodilation and vascular leakage are stimulated by the vasoactive peptide bradykinin, which is excessively produced due to dysregulation of the activated factor XII (FXIIa)-driven kallikrein-kinin system. There is a need for novel treatments for HAE that provide greater efficacy, improved quality of life, minimal adverse effects, and reduced treatment burden over current first-line therapies. FXIIa is emerging as an attractive therapeutic target for interference with HAE attacks. In this review, we draw on preclinical, experimental animal, and in vitro studies, providing an overview on targeting FXIIa as the basis for pharmacologic interference in HAE. We highlight that there is a range of FXIIa inhibitors in development for different therapeutic areas. Of these, garadacimab, an FXIIa-targeted inhibitory monoclonal antibody, is the most advanced and has shown potential as a novel long-term prophylactic treatment for patients with HAE in clinical trials. The evidence from these trials is summarized and discussed, and we propose areas for future research where targeting FXIIa may have therapeutic potential beyond HAE. Copyright © 2024 The Author(s). Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

296(4):311-326

Available online at: https://dx.doi.org/10.1111/joim.20008

Costanzo G, Sambugaro G, Firinu D

Dec/2024. Current opinion in allergy and clinical immunology

PURPOSE OF REVIEW: For decades, treatment options for hereditary angioedema (HAE) were limited by major adverse effects, insufficient efficacy, and difficult routes of administration. However, the growing body of knowledge regarding HAE pathophysiology has led to the development of innovative drugs for self-administered, on-demand therapy and for short- and long-term prophylaxis. This review provides a comprehensive overview of the approved drugs and the development of HAE treatments. RECENT FINDINGS: The implementation of new therapies will improve the application of individualized action plans based on the key goals of minimizing the number of attacks and meeting the complex needs of patients. SUMMARY: HAE is a rare genetic disease with a high impact on patients' quality of life due to the unpredictability and variable severity of attacks. Advances in HAE research have allowed optimization of attack management and individualization of therapeutic approaches. Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.

24(6):488-495

Available online at: https://dx.doi.org/10.1097/ACI.0000000000001042

Craig T, Tachdjian R, Bernstein JA, Anderson J, Nurse C, Watt M, Yu M, Juethner S

Dec/2024. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

BACKGROUND: Lanadelumab was well tolerated and effective in preventing hereditary angioedema (HAE) attacks in the phase 3, double-blind, placebo-controlled Hereditary angioEdema Long-term Prophylaxis (HELP) study and subsequent HELP open-label extension (OLE) study (NCT02741596). OBJECTIVE: To evaluate outcomes from HELP OLE for adolescent patients aged 12 to 17 years. METHODS: The HELP OLE study comprised patients who completed the HELP study (rollovers) and new eligible (lanadelumab-naive) patients. Rollovers received a single dose of lanadelumab 300 mg at the last HELP study visit (day 0). Treatment was then paused until patients experienced their first investigator-confirmed HAE attack, after which lanadelumab 300 mg was administered every 2 weeks for up to 33 months (4 wk/mo). Lanadelumab-naive patients received lanadelumab 300 mg every 2 weeks from day 0. Patient-reported outcomes included Angioedema Quality of Life Questionnaire. Safety was monitored throughout the study. RESULTS: The subgroup analysis included 21 patients (8 rollovers and 13 lanadelumab-naive patients); 95.2% completed at least 30 months in the study. The mean (SD) monthly attack rate decreased from 1.58 (1.0) at baseline to 0.11 (0.2) during treatment (mean, 94.7% reduction). A total of 8 (38.1%) patients were attack-free during treatment and, on average, 99.1% of days were attack-free (mean, 27.7 d/mo). Patients reported a mean (SD) Angioedema Quality of Life Questionnaire total score of 27.5 (17.5) at baseline vs 7.5 (13.2) at the end of the study. There were 12 (57.1%) patients who reported treatment-related treatment-emergent adverse events; however, there were no treatment-related serious adverse events. CONCLUSION: Lanadelumab provided long-term efficacy in preventing HAE attacks, was associated with clinically meaningful improvements in health-related quality of life and high levels of treatment satisfaction, and was well tolerated in adolescent patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02741596. Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

133(6):712-719.e1

Available online at: https://dx.doi.org/10.1016/j.anai.2024.08.001

Craig TJ, Levy DS, Reshef A, Lumry WR, Martinez-Saguer I, Jacobs JS, Yang WH, Ritchie B, Aygoren-Pursun E, Keith PK, Busse P, Feuersenger H, Alexandru Bica M, Jacobs I, Pragst I, Magerl M

Jun/2024. The Lancet. Haematology

BACKGROUND: Garadacimab is a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII. This study evaluated long-term efficacy, health-related quality of life (HRQoL), and safety data for garadacimab in adults with hereditary angioedema. METHODS: This global phase 2 study comprised a treatment period 1 (TP1: 12 weeks, double-blind, placebo-controlled) and a treatment period 2 (TP2: >=44-week open-label extension). Patients aged 18-65 years with clinically confirmed hereditary angioedema were eligible. In TP1, 32 patients were randomly assigned (1:1:1:1) to receive subcutaneous garadacimab (75 mg, 200 mg, or 600 mg) or placebo every 4 weeks (once monthly). Randomisation was done using interactive response technology via block randomisation (block sizes 1-4). Subsequently, six additional patients in TP1 were assigned to open-label garadacimab 400 mg every 2 weeks. At the start of TP2, patients were re-randomised (if receiving placebo, garadacimab 75 mg, or garadacimab 400 mg) or continued to receive garadacimab 200 mg or garadacimab 600 mg once monthly. After a protocol amendment on March 20, 2020, patients originally assigned to the 600 mg dose were down-titrated to 200 mg at their next visit. The primary endpoint (published previously) was monthly attack rate for patients receiving 200 mg or 600 mg garadacimab in TP1 in the intention-to-treat population. Here, we assessed the impact of garadacimab on patient-reported and investigator-reported outcomes and HRQoL as well as long-term efficacy and safety. This trial is registered with ClinicalTrials.gov, NCT03712228, and is completed. FINDINGS: Of 54 patients screened between Oct 29, 2018, and Aug 28, 2019, 32 randomised and six open-label patients completed TP1 and entered TP2 (20 in the garadacimab 200 mg group; 18 in the garadacimab 600 mg group; total 38 patients). Median age was 39.0 years (IQR 27.0-53.0), and 21 patients (55%) were female and 17 (45%) were male. In TP2, the median garadacimab exposure was 87.9 weeks (IQR 50.0-106.6) in the garadacimab 200 mg group and 44.1 weeks (24.1-56.1) in the garadacimab 600 mg group. Median monthly attack rates were 0.0 (IQR 0.0-0.1) in the garadacimab 200 mg group and 0.1 (0.0-0.4) in the garadacimb 600 mg group. Median reduction in monthly attack rate versus run-in was 100% (IQR 98-100) with garadacimab 200 mg. HRQoL improvements observed during TP1 with garadacimab were sustained throughout TP2. TP2 safety signals were consistent with TP1. Two patients experienced serious adverse events of diverticular perforation and asthma (not garadacimab-related). Treatment-emergent adverse events were mostly mild or moderate in severity. The most common adverse events were headache (nine of 38, 24%) and abdominal pain (seven of 38, 18%). There were no treatment-related deaths. INTERPRETATION: Once-monthly garadacimab for more than 2 years in patients with hereditary angioedema was well tolerated and efficacious in reducing monthly attack rate and improving HRQoL. These results reveal the potential of long-term prophylactic treatment with 200 mg once-monthly garadacimab towards complete disease control of patients with hereditary angioedema. FUNDING: CSL Behring. Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

11(6):e436-e447

Available online at: https://dx.doi.org/10.1016/S2352-3026(24)00081-4

Dias de Castro E, Pinhal AL, Braganca M, Parente Freixo J, Martinho A

Jun/2024. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

BACKGROUND: Hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) is a rare genetic disease with similar phenotype to HAE-C1-INH but different genetic background. Currently, 6 subtypes are recognized, based on the underlying mutations. Several aspects need further clarification. OBJECTIVE: To assess clinical features of patients with genetically characterized HAE-nC1-INH from the North of Portugal. METHODS: Retrospective assessment of clinical data from all patients with HAE-nC1-INH followed at a HAE Reference Center. RESULTS: A total of 41 patients were identified, 4 with no family history. The FXII mutation Thr328Lys (38 carriers) was the most prevalent. There were 3 new potentially disease-causing variants linked to HAE-nC1-INH identified (c.529+4A>G:FXII; Cys248*:Kininogen-1; and Arg261His:Plasminogen). The HAE-FXII cohort included 82% females and 71.8% symptomatic patients. Penetrance rate was significantly higher in females (81.3% vs 28.6%; P = .012). A hormonal influence was observed in 96.2% of the symptomatic females, although 62.5% remained symptomatic after oral estrogen withdrawal. Trauma and dental procedures were frequent triggers (82.6% and 45.5%, respectively). Main locations were facial (described by 96%), lips (82.1%), and eyelids (64.3%). One patient reported erythema marginatum as prodrome. Plasma-derived C1-INH was effective as short-term prophylaxis in all treated patients, but only in 80% as on-demand treatment. Icatibant was effectively used on demand in 9 patients, but with relapses in 5 (57%). CONCLUSION: We described a large Portuguese series of patients with HAE-nC1-INH genetically characterized. Differences with others may contribute to improve current unmet needs and raise awareness of this rare disease. We highlighted the identification of 3 new variants (additional molecular studies are ongoing) and the report of erythema marginatum in HAE-nC1-INH. Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

132(6):730-736

Available online at: https://dx.doi.org/10.1016/j.anai.2024.01.027

Do T, Riedl MA

Aug/2024. Immunology and allergy clinics of North America

Angioedema is characterized by transient movement of fluid from the vasculature into the interstitial space leading to subcutaneous or submucosal non-pitting edema. Current evidence suggests that most angioedema conditions can be grouped into 2 categories: mast cell-mediated (previously termed histaminergic) or bradykinin-mediated angioedema. Although effective therapies for mast cell-mediated angioedema have existed for decades, specific therapies for bradykinin-mediated angioedema have more recently been developed. In recent years, rigorous studies of these therapies in treating hereditary angioedema (HAE) have led to regulatory approvals of medication for HAE management thereby greatly expanding HAE treatment options. Copyright © 2024 Elsevier Inc. All rights reserved.

44(3):561-576

Available online at: https://www.immunology.theclinics.com/article/S0889-8561(24)00031-6/

Farinha IC, Tavares B, Sousa N, Almeida E, Lozoya C, Regateiro FS, Todo-Bom A, Faria E

Jan/2024. European annals of allergy and clinical immunology

Summary: Background. Due to similarities between the pathophysiological mechanisms of hereditary angioedema (HAE) and COVID-19, it has been hypothesized that SARS-CoV-2 infection may trigger HAE attacks or, alternatively, that HAE patients may experience different of COVID-19 disease severity. Furthermore, the potential for COVID-19 vaccination to trigger angioedema attacks in patients with HAE is still not completely defined. The objective is to characterize the exacerbations and clinical manifestations associated with COVID-19 infection and describe the adverse effects of COVID-19 vaccination in patients with HAE. Methods. Retrospective observational, descriptive, non-interventional, multicenter study conducted in four Allergy Units and Departments in Central Portugal between March 2020 and July 2022. HAE patient data were obtained from electronic medical records. Results. The study included 34 patients (67.6% female): 26 with HAE type 1, 5 with HAE type 2, and 3 with HAE with normal C1 inhibitor. Most patients with HAE type 1 and 2 were receiving long-term prophylaxis. Among the 32 patients who received COVID-19 vaccination, 86 doses, were administered with one angioedema attack (1.2%) associated with vaccination. A small increase in the average number of attacks was observed in the year following COVID vaccination (7.1 versus 6.2 in the previous year, p = 0.029), however, this difference is unlikely to be clinically significant, as the context of the COVID-19 pandemic likely introduced numerous confounders. During the study period, 16 HAE patients had COVID-19, all presenting with mild disease. Four out of 16 patients (25%) reported angioedema attacks during COVID-19, and 43.8% during the convalescence period (3 months after infection). Conclusions. Patients with HAE can safely receive COVID-19 vaccination. The severity of COVID-19 infection does not appear to be increased in HAE patients.

56(1):34-41

Available online at: https://dx.doi.org/10.23822/EurAnnACI.1764-1489.295

Holmes A, Srinivasan C, Borle J, Blain H, Ritchie B, Adatia A

Jul/2024. Frontiers in immunology

Hereditary angioedema due to C1 inhibitor deficiency (HAE) is a rare inborn error of immunity that presents with episodic swelling. Management is multifaceted and includes on-demand treatment of swelling episodes, short-term prophylaxis to prevent swelling episodes from procedures, and long-term prophylaxis (LTP) to prevent angioedema on an ongoing basis. All approved on-demand therapies are parenteral, necessitating patient training for home administration, particularly intravenous C1 inhibitor. These complexities can result in care gaps for rural HAE patients. We conducted a cross-sectional study at our Angioedema Center of Reference and Excellence to assess the care provided to urban and rural patients. The proportion of patients receiving LTP, proportion of patients diagnosed as children, and disease control measured using the Angioedema Control Test (AECT) were collected. Logistic and Poisson regression models adjusted for age and sex were used to compare the two groups. The proportion using LTP was similar at 62% and 61% in urban and rural patients, respectively (odds ratio [OR] 1.01 (CI 95% 0.34-2.99)). Among urban patients, 52% were diagnosed as children compared to 60% among rural residents (1.43 (0.37-5.56)). The mean (IQR) AECT score was 14.0 (8.5-15.5) in urban patients and 13.0 (10.0-14.0) in rural patients (Poisson beta -0.001 (-0.23-0.23). These data indicate that rural patients received similar high-quality care. We attribute these findings to the centralized care model employed in which HAE patients in the region are seen at a single comprehensive care clinic. Copyright © 2024 Holmes, Srinivasan, Borle, Blain, Ritchie and Adatia.

15:1413547

Available online at: https://dx.doi.org/10.3389/fimmu.2024.1413547

Jindal AK, Barman P, Basu S, Tyagi R, Sil A, Chawla S, Machhua S, Kaur G, Sharma S, Dhaliwal M, Bishnoi A, Vinay K, Vignesh P, Pilania RK, Suri D, Garg R, Rawat A, Kumaran SM, Dogra S, Farkas H, Longhurst H, Singh S

Dec/2024. Immunologic research

Hereditary angioedema (HAE) is a rare genetic disorder. The pattern of HAE is different in children as compared to adults. There is limited literature from developing countries where all first-line treatments are either unavailable or not easily accessible. Data of children with HAE were retrieved from medical records of patients registered in the Pediatric Immunodeficiency Clinic at our institute. Of the 206 patients with HAE, 61 were diagnosed before the age of 18 years. Male: female ratio was 1.1:1. Median age at onset of symptoms and diagnosis were 6.2 years (range 1-17 years) and 10.7 years (range 1.5-18 years) respectively. Median delay in diagnosis was 4.9 years (range 0-16 years). The commonest presentation was facial swelling (51/61) followed by swelling of extremities (47/61). Laryngeal edema and abdominal symptoms were reported in 28/61 and 31/61 patients respectively. Abdominal attacks were found to be less common in children as compared to adults. Most patients in our cohort received fresh-frozen plasma (n = 5/61) as on-demand therapy. Long-term prophylaxis included attenuated androgens (n = 25/61) and tranexamic acid (n = 23/61). Median duration of follow-up was 2242 patient months. One patient died on follow-up in this cohort. This is the largest single-centre cohort of pediatric HAE from resource-constrained settings. Facial attacks were more common, and there were significant delays in diagnosis when the age of onset of symptoms was younger. Gastrointestinal symptoms were less common in children than adults. HIGHLIGHTS: One of the largest single-centre cohorts of pediatric HAE and the only one from resource-constrained settings. There were significant delays in diagnosis when the age of onset of symptoms was younger. Abdominal attacks were found to be less common in children as compared to adults. Copyright © 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

72(6):1479-1488

Available online at: https://dx.doi.org/10.1007/s12026-024-09547-9

Keskin S, Pak Y, Celestin J

Jun/2024. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

132(6):774-776

Available online at: https://dx.doi.org/10.1016/j.anai.2024.02.009

Lamacchia D, Nappi E, Marzio V, Locatelli F, Messina MR, Heffler E

Aug/2024. Current opinion in allergy and clinical immunology

PURPOSE OF REVIEW: The aim of this review is to provide an account of the focus of therapeutic strategies for hereditary angioedema (HAE), give a brief overview of those used in the past and set aside and toughly discuss those currently available as first line. Further research is ongoing and the future therapeutic approaches that are still in different phases of study will be reviewed as well. RECENT FINDINGS: In the last two decades, major research advancements on HAE pathophysiology and management were made and numerous novel therapeutic options are now available. Compared to the past, drugs available nowadays are more effective, well tolerated, and possibly have a more convenient administration route. Moreover, numerous other drugs with innovative mechanisms of action are under development. SUMMARY: HAE is a rare genetic disease that if not promptly treated, it can lead to death from asphyxiation. Furthermore, due to its disfiguring and painful manifestations, HAE implies an important burden on the quality of life. Recently, following great research progresses on HAE therapy, evidence-based guidelines on HAE management were released. The therapeutic landscape of HAE is still under florid development, and it is possible novel treatments will remarkably revolutionize HAE management in the future. Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.

24(4):257-265

Available online at: https://dx.doi.org/10.1097/ACI.0000000000000992

Longhurst HJ, Cancian M, Grivcheva-Panovska V, Koleilat M, Magerl M, Savic S, Stobiecki M, Tachdjian R, Healy B, Yea CM, Audhya PK, Bouillet L

Dec/2024. Clinical reviews in allergy & immunology

Long-term prophylaxis (LTP) has been shown to reduce the frequency of hereditary angioedema (HAE) attacks; however, attacks occurring in patients receiving LTP have not been well characterized. The objective of this systematic review was to evaluate the proportion of type I/II HAE (HAE-C1INH) patients who experience attacks while receiving LTP, the characteristics of these attacks, and associated on-demand therapy use. A systematic search was conducted in PubMed to identify studies reporting LTP use with plasma-derived C1 inhibitor (pdC1INH), lanadelumab, berotralstat, androgens, or antifibrinolytics in patients with HAE-C1INH. Forty-five primary studies met the inclusion criteria. In phase 3 trials, attack-free rates were 40% for subcutaneous pdC1INH 60 IU/kg twice weekly at 16 weeks, and 44% for lanadelumab 300 mg every second week at 6 months (77% during steady-state [days 70-182]); there was no difference in attack-free rate for berotralstat 150 mg versus placebo at 24 weeks. Phase 3 studies reported a lower average attack severity with subcutaneous and intravenous pdC1INH versus placebo. With lanadelumab and berotralstat, the prophylactic treatment effect was more pronounced in peripheral attacks than in abdominal and laryngeal attacks. Laryngeal attacks accounted for 2%-7% of all attacks in observational and interventional studies, regardless of the LTP agent received. On-demand therapy was used in 49%-94% of attacks occurring in the presence of LTP. In conclusion, patients receiving LTP experienced attacks in all anatomic locations, including the larynx. Most attacks were treated with on-demand therapy, although outcomes were not reported. Access to on-demand therapy remains essential for all people with HAE-C1INH. Copyright © 2024. The Author(s).

67(1-3):83-95

Available online at: https://dx.doi.org/10.1007/s12016-024-09006-1

Oduro-Kwateng E, Soliman MES

Jun/2024. Cell biochemistry and biophysics

Human plasma kallikrein (PKa) is a member of the serine protease family and serves as a key mediator of the kallikrein-kinin system (KKS), which is known for its regulatory roles in inflammation, vasodilation, blood pressure, and coagulation. Genetic dysregulation of KKS leads to Hereditary Angioedema (HAE), which is characterized by spontaneous, painful swelling in various body regions. Importantly, HAE frequently coexists with various cancers. Despite substantial efforts towards the development of PKa inhibitors for HAE, there remains a need for bifunctional agents addressing both anti-cancer and anti-HAE aspects, especially against carcinoma-associated comorbid HAE conditions. Consequently, we investigated the therapeutic potential of the anti-glutamine prodrug, isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate (DRP-104), and its active form, 6-Diazo-5-oxo-l-norleucine (DON), recognized for their anti-cancer properties, as novel PKa inhibitors. Utilizing structure-based in silico methods, we conducted a comparative analysis with berotralstat, a clinically approved HAE prophylactic, and sebetralstat, an investigational HAE therapeutic agent, in Phase 3 clinical trials. Inhibiting PKa with DON resulted in relatively heightened structural stability, rigidity, restricted protein folding, and solvent-accessible loop exposure, contributing to increased intra-atomic hydrogen bond formation. Conversely, PKa inhibition with DRP-104 induced restricted residue flexibility and significantly disrupted the critical SER195-HIS57 arrangement in the catalytic triad. Both DON and DRP-104, along with the reference drugs, induced strong cooperative intra-residue motion and bidirectional displacement in the PKa architecture. The results revealed favorable binding kinetics of DON/DRP-104, showing thermodynamic profiles that were either superior or comparable to those of the reference drugs. These findings support their consideration for clinical investigations into the management of carcinoma-associated HAE. Copyright © 2024. The Author(s).

82(2):1159-1177

Available online at: https://dx.doi.org/10.1007/s12013-024-01266-0

Pagnier A, Dermesropian A, Kevorkian-Verguet C, Bourgoin-Heck M, Hoarau C, Reumaux H, Nugues F, Audouin-Pajot C, Blanc S, Carbasse A, Jurquet AL, Voidey M, Villedieu M, Bouillet L, Boccon-Gibod I

Dec/2024. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology

BACKGROUND: Hereditary angioedema (HAE) in children has specific features and requires multidisciplinary management. METHODS: We performed a literature search and underwent in-depth discussions to provide practical tools for physicians. RESULTS: HAE is a rare, life-threatening genetic disorder. Its epidemiology is poorly documented in children. Clinical manifestations usually appear during childhood or early adolescence. Classical signs, often preceded by prodromal symptoms, include transient, localized, non-pitting, non-pruritic swelling of deep dermal/subcutaneous or mucosal/submucosal tissues, leading to oedema of the extremities, face, lips, tongue, trunk and genitals, recurring gastrointestinal symptoms and laryngeal edema possibly causing asphyxiation and death. Diagnosis is often delayed due to low awareness in the medical community, and particularly challenging in case of isolated abdominal crises or atypical presentation and in neonates or infants. It relies on biological tests (measurement of serum/plasma levels of C1INH function, C1INH protein, and C4), genetic testing in selected cases, and imaging for differential diagnosis of acute abdominal crises. Main differential diagnosis for peripheral oedema is mast cell-mediated oedema that accounts for 95% of angioedema in clinical practice. Quality of life can be significantly impaired. Disease management includes treatment of attacks, short-term and long-term prophylaxis, psychological support, avoidance of triggers, patients' and parents' education and coordination of all stakeholders, ideally within a specialized healthcare network. New plasma kallikrein inhibitors, namely lanadelumab (subcutaneous route) and berotralstat (oral route) have facilitated long-term prophylaxis thanks to improved usability. CONCLUSION: Diagnostic and treatment of HAE are particularly challenging in children and require specific management by multiple stakeholders. Copyright © 2024 The Author(s). Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

35(12):e14268

Available online at: https://dx.doi.org/10.1111/pai.14268

Petersen RS, Fijen LM, Apfelbacher C, Magerl M, Weller K, Aberer W, Adatia A, Audhya P, Bara NA, Betschel S, Boccon-Gibod I, Bouillet L, Brodszki N, Busse PJ, Buttgereit T, Bygum A, Cancian M, Craig T, Csuka D, Farkas H, Fomina D, Gil-Serrano J, Gompels M, Guidos Fogelbach G, Guilarte M, Hide M, Kiani-Alikhan S, Kinaciyan T, Lenten A, Lleonart R, Longhurst H, Lumry WR, Malbran A, Malinauskiene L, Matta Campos JJ, Mendivil J, Nieto-Martinez SA, Peter JG, Porebski G, Reshef A, Riedl M, Valerieva A, Waserman S, Maurer M, Cohn DM

Jun/2024. The journal of allergy and clinical immunology. In practice

BACKGROUND: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS: A total of 58 worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes. Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.

12(6):1614-1621

Available online at: https://dx.doi.org/10.1016/j.jaip.2024.04.007

Radojicic C, Anderson J

May/2024. Allergy and asthma proceedings

Background: A diagnosis of hereditary angioedema (HAE) with normal C1 esterase inhibitor (HAE-nl-C1-INH) can be challenging and pharmacologic management is not well defined. Objective: The objective was to discuss practical considerations in the clinical management of HAE-nl-C1-INH by using illustrative clinical vignettes to highlight and/or address select challenges. Methods: This was a narrative review. Results: Symptoms of HAE-nl-C1-INH overlap with HAE types I and II; the heterogeneity of presentation and symptom burden are diagnostic challenges. A patient history, with particular attention to whether urticaria or other symptoms of mast cell mediator release are present, is important because such symptoms would strongly suggest a mast cell-mediated pathway. A family history of angioedema is informative but a lack thereof does not rule out diagnosis. Expected laboratory findings would be normal for C4, C1-INH level and function, and Complement 1q; a genetic mutational analysis may be helpful, but current assays do not include all known mutations; most cases are categorized as unknown. To align with guideline-directed treatment approaches, the following stepwise approach is suggested for suspected HAE-nl-C1-INH: (1) thoroughly investigate the possibility of response to histaminergic and/or mast cell-targeting treatments; (2) if patients with normal C4, C1-INH level and/or function fail adequate trials with histamine/mast cell-directed therapy or have a mutation that suggests bradykinin pathway involvement, follow HAE type I and II treatment guidelines. Response to medications approved for HAE types I/II provides compelling support for a high clinical suspicion of HAE-nl-C1-INH. De-labeling an HAE-nl-C1-INH diagnosis may be appropriate if the initial diagnosis was made without adequate evaluation or if new information and/or testing indicates that the patient does not actually have HAE. Conclusion: Key unmet needs in HAE-nl-C1-INH include lack of confirmatory biomarker(s) for diagnosis and lack of prospective controlled clinical studies of pharmacologic products in this patient population.

45(3):147-157

Available online at: https://dx.doi.org/10.2500/aap.2024.45.240010

Raja A, Shuja MH, Raja S, Qammar A, Kumar S, Khurram L, Haque MA

Dec/2024. Archives of dermatological research

Hereditary angioedema with C1 inhibitor deficiency (HAE-C1-INH) is a rare disorder characterized by recurrent, potentially life-threatening swelling in various parts of the body, including the limbs, face, and airways Current treatments focus primarily on symptomatic relief and the management of acute attacks, without targeting the underlying genetic cause or the dysregulated bradykinin production. Donidalorsen, a novel antisense oligonucleotide, addresses a key driver of HAE-C1-INH by targeting prekallikrein (PKK) to reduce bradykinin levels. This meta-analysis evaluates the efficacy and safety of Donidalorsen versus placebo, focusing on two dosing regimens: 4-week and 8-week intervals. Data from two randomized controlled trials (110 patients) revealed that Donidalorsen significantly reduced the frequency of HAE-C1-INH attacks, with the 4-week regimen showing superior outcomes compared to the 8-week dosing. The 4-week group also experienced fewer moderate or severe attacks and a reduced need for on-demand therapy. Adverse events were comparable between the Donidalorsen and placebo groups. These findings suggest that more frequent dosing may optimize treatment outcomes in HAE-C1-INH. Copyright © 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

317(1):110

Available online at: https://dx.doi.org/10.1007/s00403-024-03652-3

Riedl MA, Farkas H, Aygoren-Pursun E, Psarros F, Soteres DF, Staevska M, Cancian M, Hagin D, Honda D, Melamed I, Savic S, Stobiecki M, Busse PJ, Dias de Castro E, Agmon-Levin N, Gower R, Kessel A, Kurowski M, Lleonart R, Grivcheva Panovska V, Wedner HJ, Audhya PK, Hao J, Iverson M, Smith MD, Yea CM, Lumry WR, Zanichelli A, Bernstein JA, Maurer M, Cohn DM

Jul/2024. The New England journal of medicine

BACKGROUND: Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy. METHODS: In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours. RESULTS: A total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported. CONCLUSIONS: Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.). Copyright © 2024 Massachusetts Medical Society.

391(1):32-43

Available online at: https://dx.doi.org/10.1056/NEJMoa2314192

Riedl MA, Tachdjian R, Lumry WR, Craig T, Karakaya G, Gelincik A, Stobiecki M, Jacobs JS, Gokmen NM, Reshef A, Gompels MM, Manning ME, Bordone L, Newman KB, Treadwell S, Wang S, Yarlas A, Cohn DM

Jul/2024. The New England journal of medicine

BACKGROUND: Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25. RESULTS: A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity. CONCLUSIONS: Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.). Copyright © 2024 Massachusetts Medical Society.

391(1):21-31

Available online at: https://www.researchgate.net/publication/381043132_Efficacy_and_Safety_of_Donidalorsen_for_Hereditary_Angioedema

Sarkar A, Nwagwu C, Craig T

Jul/2024. The Medical clinics of North America

Hereditary angioedema is a rare autosomal dominant condition characterized by episodes of swelling of the upper airway, intestines, and skin. The disorder is characterized by deficiency in C1 esterase inhibitor (C1-INH) or a decrease in functional C1-INH. Treatment options include on demand therapy (treatment of acute attacks), long-term prophylaxis, and short-term prophylaxis. Corticosteroids, epinephrine, and antihistamines are not effective for this form of angioedema. The high mortality in patients undiagnosed underscores a need for broader physician awareness to identify these patients and initiate therapy. Copyright © 2023 Elsevier Inc. All rights reserved.

108(4):747-755

Available online at: https://dx.doi.org/10.1016/j.mcna.2023.08.005

Scatoni A, Roberts Z, Boskey ER, Staffa S, Roden RC, Redwood E, Grimstad F

Jul/2024. Women's health (London, England)

BACKGROUND: Danazol is a synthetic progestin with androgenic effects that is approved by the Food and Drug Administration for treatment of endometriosis, benign fibrocystic breast disease, and hereditary angioedema. In recent years, increasing numbers of transgender and nonbinary individuals seeking menstrual suppression have been offered danazol due to its potential to both induce amenorrhea and cause reversible androgenic side effects including pigmentation of vellus hairs and voice changes, which may be desirable in this population. There are currently no studies assessing use of danazol within the transgender population for menstrual suppression. OBJECTIVE: This study's primary aim was to evaluate the use of danazol as a menstrual suppression agent in transgender patients. DESIGN: This was a retrospective multisite cohort study of all individuals who had been on danazol at two tertiary care centers between 2000 and 2022. METHODS: All patients prescribed danazol were identified using a search of the electronic medical records. For demographic purposes, comparisons were made between those who did and did not use danazol for the purpose of menstrual suppression. A detailed chart review was then performed to analyze the experiences of menstrual suppression in transgender and nonbinary patients. RESULTS: Most transgender and nonbinary patients on danazol for menstrual suppression remained on it at their most recent follow-up visit, and many charts noted improvements in gender dysphoria, pelvic pain, dysmenorrhea, endometriosis, and heavy menstrual bleeding. Most transgender patients achieved amenorrhea. CONCLUSION: Danazol may be a reasonable option for menstrual suppression in transgender and nonbinary patients. Our findings show its potential to not only induce amenorrhea but cause desired androgenic symptoms and improve gender dysphoria, pelvic pain, dysmenorrhea, endometriosis, and heavy bleeding. While the androgenic effects of danazol are less desirable in cisgender populations, it is an attractive option for menstrual suppression in transgender and nonbinary patients.

20:17455057241265081

Available online at: https://dx.doi.org/10.1177/17455057241265081

Sexton D, Kichev A, Juethner S, Yeung D, MacDonald A, Anokian E, Li B

May/2024. Frontiers in immunology

Introduction: Plasma proteomics analyses were performed to identify novel disease state biomarkers of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) and investigate the biological consequences of specific plasma kallikrein inhibition with lanadelumab. Methods: Affinity proteomic analyses were performed using plasma from healthy controls (n=30) and patients with HAE-C1INH before (baseline, n=125) and after 6 months of treatment with lanadelumab (300 mg every 2 weeks, n=112) using the SomaScan platform. Results: Relative plasma levels for several proteins differed significantly between controls and patients with HAE-C1INH, and between matched baseline and post-treatment samples from patients with HAE-C1INH. As expected, C1 inhibitor and complement C4 were significantly lower (P<1.10e-39 false discovery rate [fdr], P<6.6e-25 fdr, respectively) in HAE-C1INH baseline plasma versus controls. Cleaved high-molecular-weight kininogen, a biomarker of excess kallikrein-kinin system (KKS) activation, was higher in HAE-C1INH baseline plasma versus controls (P<6.7e-6 fdr) and was reduced in HAE-C1INH plasma after lanadelumab treatment. Of 1041 identified proteins that differed significantly (P<0.05) from controls and HAE-C1INH baseline plasma, 120 proteins were no longer different between controls and patients with HAE-C1INH after 6 months of lanadelumab treatment. Canonical pathway and local network analyses of HAE-C1INH plasma proteomics suggest dysregulation in KKS, coagulation, cell adhesion, and connective tissue degradation that approach that of healthy controls following treatment with lanadelumab. Conclusion: Proteomic analyses of plasma from patients with HAE-C1INH before and after treatment with lanadelumab compared with healthy controls confirmed known HAE-C1INH biomarkers and identified additional potential biomarkers of plasma kallikrein dysregulation for further investigation. Copyright This work is authored by Sexton, Kichev, Juethner, Yeung, MacDonald, Anokian and Li. © 2025 Takeda Pharmaceuticals USA Inc.

15:1471168

Available online at: https://dx.doi.org/10.3389/fimmu.2024.1471168

Sexton D, Nguyen HQ, Juethner S, Luo H, Zhang Z, Jasper P, Zhu AZX

Dec/2024. Journal of pharmacokinetics and pharmacodynamics

Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare, debilitating, genetic disorder characterized by recurrent, unpredictable, attacks of edema. The clinical symptoms of HAE arise from excess bradykinin generation due to dysregulation of the plasma kallikrein-kinin system (KKS). A quantitative systems pharmacology (QSP) model that mechanistically describes the KKS and its role in HAE pathophysiology was developed based on HAE attacks being triggered by autoactivation of factor XII (FXII) to activated FXII (FXIIa), resulting in kallikrein production from prekallikrein. A base pharmacodynamic model was constructed and parameterized from literature data and ex vivo assays measuring inhibition of kallikrein activity in plasma of HAE patients or healthy volunteers who received lanadelumab. HAE attacks were simulated using a virtual patient population, with attacks recorded when systemic bradykinin levels exceeded 20 pM. The model was validated by comparing the simulations to observations from lanadelumab and plasma-derived C1-inhibitor clinical trials. The model was then applied to analyze the impact of nonadherence to a daily oral preventive therapy; simulations showed a correlation between the number of missed doses per month and reduced drug effectiveness. The impact of reducing lanadelumab dosing frequency from 300 mg every 2 weeks (Q2W) to every 4 weeks (Q4W) was also examined and showed that while attack rates with Q4W dosing were substantially reduced, the extent of reduction was greater with Q2W dosing. Overall, the QSP model showed good agreement with clinical data and could be used for hypothesis testing and outcome predictions. Copyright © 2024. Takeda Development Center Americas, Inc.

51(6):721-734

Available online at: https://dx.doi.org/10.1007/s10928-024-09919-6

Smith TD, Riedl MA

Oct/2024. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

Hereditary angioedema (HAE) is a rare genetic condition causing unpredictable and severe episodes of angioedema that are debilitating and life-threatening. Moreover, HAE can be classified into HAE due to C1-esterase inhibitor deficiency (HAE-C1INH) or HAE with normal C1INH. Moreover, HAE-C1INH is subcategorized as types I and II based on deficient or dysfunctional circulating C1INH protein resulting from inherited or spontaneous mutations in the SERPING1 gene leading to uncontrolled factor XII/plasma kallikrein activation and excessive bradykinin production. Bradykinin-2 receptor activation leads to vasodilation, increased vascular permeability, and smooth muscle contractions, resulting in subcutaneous or submucosal fluid extravasation that can affect the face, extremities, airway, and gastrointestinal and genitourinary systems. Furthermore, HAE with normal C1INH is caused by either a known or unknown genetic mutation, and the mechanisms are less well-established but most forms are thought to be related to bradykinin signaling with a similar presentation as HAE-C1INH despite normal levels of C1INH protein and function. Current HAE management strategies include on-demand and prophylactic treatments which replace C1INH, reduce kallikrein activity, or block bradykinin binding to the bradykinin B2 receptor. With the advent of additional small molecule inhibitors, monoclonal antibodies, RNA-targeted therapies, gene therapies, and gene modification approaches, preclinical studies and human clinical trials are underway to further expand therapeutic options in HAE. This review article will briefly summarize current HAE treatments and provide an overview of potential future therapies for HAE. Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

133(4):380-390

Available online at: https://dx.doi.org/10.1016/j.anai.2024.04.029

Yong PFK, Annals R, Diwakar L, Elkhalifa S, Gompels M, Jain R, Karim MY, Khan S, Metcalfe A, Noorani S, Steele C, Kiani-Alikhan S, Garcez T

Jun/2024. Clinical and experimental immunology

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development. Copyright © The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site-for further information please contact journals.permissions@oup.com.

217(1):109-116

Available online at: https://dx.doi.org/10.1093/cei/uxae020