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Background: Hereditary angioedema (HAE) is a genetic disorder characterized by re-occurring swelling episodes called "attacks," usually in the limbs, face, airways, and intestinal tract. New prophylactic therapies have reduced the frequency of these attacks. This study describes results from a literature review and clinician interviews assessing patient HAE symptom experiences and timing, and then evaluates whether existing patient-reported outcome (PRO) tools adequately reflect this experience., Methods: A targeted literature review as well as interviews with key opinion leaders (KOLs), were conducted to capture information about the patient experience and their symptoms. An assessment of various PROs was then conducted to determine how well they each covered HAE symptoms and impacts., Results: Nineteen HAE symptoms were identified. KOLs reported that patients on prophylactic therapy experienced some symptoms indicating an attack was imminent, but then never experienced an attack. The comparison of the different PROs found that the Hereditary Angioedema Patient-Reported Outcome was the instrument that most thoroughly examined the symptoms of patients with HAE., Conclusions: Given the introduction of new prophylactic therapies, further research is needed to determine the effect of being attack-free for longer periods of time on health-related quality of life., (© 2022. The Author(s).)

Accurate and timely diagnosis of primary immunodeficiencies (PID) is an ongoing effort. Individuals with PID can be severely impacted by their disease and many experience chronic complications, treatment burden, and reduced quality of life (QoL). This review focuses on the impact of delayed diagnosis and treatment burden on patient QoL and outcomes. Adults tend to experience longer delays in diagnosis than pediatric populations. The median diagnostic delay has reduced over recent decades, but remains high for some antibody deficiency variants, such as common variable immunodeficiency. The largest burden impacting QoL tends to be poorly controlled disease and persistent chronic conditions rather than treatment burden. Hospitalization, physician/emergency room visits, and bronchiectasis were the most expensive PID complications prior to diagnosis and cost analyses estimate cost reductions once appropriate treatment is initiated. A combination of poor awareness, lack of infrastructure, and resources supporting national registries play a major role in delayed diagnosis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Long-term prophylaxis with subcutaneous C1-inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) in patients with hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE) was evaluated in an open-label extension follow-up study to the international, double-blind, placebo-controlled COMPACT study. The current analysis evaluated patient-reported health-related quality of life (HRQoL) data from 126 patients in the open-label extension study randomized to treatment with C1-INH(SC) 40 IU/kg (n = 63) or 60 IU/kg (n = 63) twice weekly for 52 weeks. HRQoL was evaluated at the beginning of the open-label study and at various time points using the European Quality of Life-5 Dimensions Questionnaire (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication. The disease-specific Angioedema Quality of Life Questionnaire (AE-QoL) and HAE quality of life questionnaire (HAE-QoL) instruments were administered in a subset of patients. Statistical significance was determined by change-from-baseline 95% confidence intervals (CIs) excluding zero. No adjustment for multiplicity was done., Results: Mean baseline EQ-5D scores (Health State Value, 0.90; Visual Analog Scale, 81.32) were slightly higher (better) than United States population norms (0.825, 80.0, respectively) and mean HADS anxiety (5.48) and depression (2.88) scores were within "normal" range (0-7). Yet, patients using C1-INH(SC) 60 IU/kg demonstrated significant improvement from baseline to end-of-study on the EQ-5D Health State Value (mean change [95% CI], 0.07 [0.01, 0.12] and Visual Analog Scale (7.45 [3.29, 11.62]). In the C1-INH(SC) 60 IU/kg group, there were significant improvements in the HADS anxiety scale (mean change [95% CI], - 1.23 [- 2.08, - 0.38]), HADS depression scale (- 0.95 [- 1.57, - 0.34]), and WPAI-assessed presenteeism (mean change [95% CI], - 23.33% [- 34.86, - 11.81]), work productivity loss (- 26.68% [- 39.92, - 13.44]), and activity impairment (- 16.14% [- 26.36, - 5.91]). Clinically important improvements were achieved in ≥ 25% of patients for all domains except WPAI-assessed absenteeism (which was very low at baseline). Mean AE-QoL total score by visit ranged from 13.39 to 17.89 (scale 0-100; lower scores = less impairment). Mean HAE-QoL global scores at each visit (115.7-122.3) were close to the maximum (best) possible score of 135., Conclusions: Long-term C1-INH(SC) replacement therapy in patients with C1-INH-HAE leads to significant and sustained improvements in multiple measures of HRQoL. Trial registration A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema, NCT02316353. Registered December 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02316353 .

Background: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) (HAEnCI) is associated with skin swellings, abdominal attacks, and the risk of asphyxia due to upper airway obstruction. Several different gene mutations linked to the HAE phenotype have been identified. Our aim was to qualitatively assess and describe the clinical differentiators of these genetically identified HAEnCI types. To achieve this, we performed a systematic literature review of patients with angioedema symptoms and a genetically confirmed diagnosis of an HAEnCI type., Results: A systematic literature search, conducted in March 2020, returned 132 records, 43 of which describe patients with symptoms of angioedema and a genetically confirmed diagnosis of an HAEnCI type. Overall, this included 602 patient cases from 220 families. HAEnCI with a mutation in the coagulation factor XII gene (F12) (HAE-FXII) was diagnosed in 446 patients from 185 families (male:female ratio = 1:10). Estrogens (oral contraceptives, hormonal replacement therapy, and pregnancy) negatively impacted the course of disease in most female patients (252 of 277). Asphyxia occurred in 2 of 446 patients. On-demand and/or long-term prophylaxis treatment included C1-INH concentrates, icatibant, progestins, and tranexamic acid. HAEnCI with a specific mutation in the plasminogen gene (HAE-PLG) was diagnosed in 146 patients from 33 families (male:female ratio = 1:3). Estrogens had a negative influence on the course of disease in the minority of female patients (14 of 62). Tongue swelling was an important clinical feature. Asphyxia occurred in 3 of 146 patients. On-demand treatment with icatibant and C1-INH concentrate and long-term prophylaxis with progestins and tranexamic acid were effective. HAEnCI with a specific mutation in the angiopoietin-1 gene (HAE-ANGPT1) was diagnosed in 4 patients from 1 family and HAEnCI with a specific mutation in the kininogen-1 gene (HAE-KNG1) in 6 patients from 1 family., Conclusions: A number of clinical differentiators for the different types of HAEnCI have been identified which may support clinicians to narrow down the correct diagnosis of HAEnCI prior to genetic testing and thereby guide appropriate treatment and management decisions. However, confirmation of the causative gene mutation by genetic testing will always be required.

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., Competing Interests: Donald S. Levy, is a consultant with Takeda, Biocryst, CSL Behring, Pharming; is a speaker for Takeda and CSL Behring; has received clinical research grants from CSL Behring. Teresa Caballero has received grant research, grant support and/or speaker/consultancy fees from BioCryst, CSL Behring, Merck, Novartis, Octapharma, Pharming, and Shire (a Takeda company); has received funding to attend conferences/educational events from CSL Behring, Novartis and Shire; is/has been a clinical trial/registry investigator for Biocryst, CSL Behring, Novartis, Pharming and Shire; and is a researcher from the IdiPAZ program for promoting research activities. Iftikhar Hussain is a speaker for CSL Behring, Grifols, and Optionse; is/has been on the advisory board for Blueprint Medicine and Pfizer; is Principal Investigator for Adare, Sanofi, Cara Therapeutics, Dermira, Lilly, Pfizer, Abbvie, CSL Behring, Astra-Zeneca, and Genentech, ALK. Avner Reshef has received research funding, travel grants, and/or speaker honorarium-consultation fee from CSL-Behring, Pharming, BioCryst, Takeda-Shire, Teva, Stallergens. John Anderson has potential conflicts of interest with CSL Behring, Takeda, BioCryst. James Baker has no conflicts of interest. Lawrence B. Schwartz is/has been HAE clinical trial principal investigator for CSL Behring and Takeda; is/has been on the advisory board for CSL Behring LLC, Takeda Pharmaceuticals, Pharming Healthcare, and BioCryst Pharmaceuticals. Marco Cicardi has potential conflicts of interest with CSL Behring, Shire, and Pharming. Subhransu Prusty, Henrike Feuersenger, and Ingo Pragst are/have been CSL Behring employees. Michael Manning has received grant support from CSL Behring, Takeda/Shire, BioCryst, and KalVista; is a speaker for CSL Behring, Takeda/Shire, and Pharming; is a consultant with and on the advisory boards for CSL Behring, Takeda/Shire, BioCryst, and Pharming., (© Donald Levy et al., 2020; Published by Mary Ann Liebert, Inc.)

In this letter to the editor, we present results of claims data analysis. This claims data analysis supports a hypothesis that in patients with hereditary angioedema due to C1-esterase inhibitor (C1-INH) deficiency, the occurrence and/or symptomatology of coexisting autoimmune disease may be positively influenced by a replacement therapy with plasma derived C1-INH., Competing Interests: Competing interestsHF is a speaker and consultant to CSL Behring, Pharming, Biocryst, Octapharma, and Shire. DL is a researcher, speaker, and consultant to CSL Behring and speaker and consultant to Takeda. MF is a consultant to CSL Behring. DS, MB, and SP are employees of CSL Behring. MB also holds company’s stock., (© The Author(s) 2020.)

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., Competing Interests: Competing interestsDL is a consultant, investigator, and/or speaker for Biocryst, CSL Behring, and Shire/Takeda. PKK is a consultant, investigator, and/or speaker for CSL Behring and Shire/Takeda, and serves on the Board of Directors for CHAEN (Canadian Hereditary Angioedema Network). TC is a consultant, investigator, and/or speaker for Biocryst, CSL Behring, Grifols, and Shire, and serves on the Board of Directors for the AAAAI and Mid-Atlantic ALA and on the Board of the Medical Advisors for the HAE-A of America. GK was an employee of CSL Behring at the time of the study. RB is an employee of Maple Health Group LLC, which provides contracted services to CSL Behring. SP is an employee of CSL Behring., (© The Author(s) 2020.)

Background: Hereditary angioedema (HAE) is a debilitating disorder resulting from C1-esterase inhibitor (C1-INH) deficiency. In the COMPACT phase 3 study the prophylactic use of a subcutaneous C1 inhibitor (C1-INH [SC], HAEGARDA ® , CSL Behring) twice weekly significantly reduced the frequency of acute edema attacks. Analysis of treatment effects by subgroups, onset of effect, and other exploratory analysis have not been reported., Methods: This is a post hoc exploratory analysis on data from the randomized, placebo-controlled COMPACT study. 90 patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH (SC) 40 or 60 IU/kg of body weight twice weekly for 16 weeks, preceded or followed by a placebo period. The pre-specified primary efficacy endpoint was the time-normalized number of HAE attacks, and pre-specified secondary efficacy endpoints were the percentage of patients with a certain treatment response (≥ 50% reduction on C1-INH (SC) versus placebo in the time-normalized number of attacks) and the time-normalized number of use of rescue medication. Pre-specified exploratory endpoints included severity of attacks, alone and combined with rescue medication use. Post hoc analyses included exploration of onset of effect and clinical assessment of patients with < 50% of response., Results: Subgroup findings by various patient characteristics showed a consistent preventive effect of C1-INH (SC). In a post hoc analysis of attacks, the onset of the preventive effect within the first 2 weeks after treatment initiation in COMPACT showed that 10/43 patients (23%) experienced attacks of any severity with 60 IU/kg versus 34/42 patients (81%) with placebo. The need for rescue medication was tenfold lower with 60 IU/kg (35 treated attacks) versus placebo (358 treated attacks). A qualitative analysis of the 4 patients treated with 60 IU/kg and with < 50% reduction of attacks demonstrated a reduction in severity of attacks, rescue medication use, and symptom days which was considered a clinically meaningful treatment effect., Conclusions: C1-INH (SC) prophylaxis demonstrated a preventive treatment effect with evidence of benefit within 2 weeks. A consistent treatment effect at recommended C1-INH (SC) dosing was evident in all subgroups of patients with type I/II HAE and by various measures of disease and treatment burden. Trial registration EU Clinical Trials Register, 2013-000916-10, Registered 10 December 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000916-10; ClinicalTrials.gov Register, NCT01912456, Registered 31 July 2013, https://clinicaltrials.gov/ct2/show/NCT01912456., Competing Interests: Competing interestsHHL received institutional support from CSL Behring for the conduct of this study, and travel expenses and/or consultancy fees and speaker’s honoraria from CSL Behring, Shire/Dyax/ViroPharma, and Salix/Pharming. TC is a speaker for CSL Behring, Grifols and Dyax/Shire. He performs research for BioCryst, Boehringer Ingelheim, CSL Behring, Genentech, GlaxoSmithKline, Grifols, Merck, Novartis, Pharming, Sanofi, and Shire. He has received consultancy fees and/or speaker’s honoraria from BioCryst, Bellrose, CSL Behring, Dyax, Merck, Novartis, Pharming Technologies, and Shire, and has received non-financial support from CSL Behring, Shire, and Grifols. BZ reports grant support from the Department of Defense and consultancy fees from Alnylam, Arrowhead Pharmaceuticals, BioCryst Pharmaceuticals, Nektar, CSL Behring, and Shire, and led the Scientific Steering Committee for this study. HJL has received grant support from CSL Behring, consultancy fees, and speaker’s honoraria from CSL Behring, Pharming, and Shire, and travel support from CSL Behring. MC has received grants from Shire and personal fees from Alnylam, BioCryst Pharmaceuticals, CSL Behring, Dyax, KalVista Pharming Technologies, Shire, Sobi (Swedish Orphan Biovitrum), and ViroPharma. KB reports personal fees from CSL Behring and Shire, outside the submitted work. HB received consultancy fees and speaker’s honoraria from CSL Behring, Pharming, and Shire. WL reports grant support from BioCryst Pharmaceuticals, CSL Behring, and Shire/Viropharma/Dyax; consultancy fees paid to his institution from Adverum, BioCryst Pharmaceuticals, CSL Behring, Pharming Technologies, and Shire/Virophama/Dyax; speaker’s fees from Pharming Technologies, Shire/Viropharma and CSL Behring; and non-financial support from the US Hereditary Angioedema Association outside the submitted work. JB reports grant support and personal fees from BioCryst Pharmaceuticals, CSL Behring, and Shire, outside the submitted work. MM reports grant support and consultant/speaker’s fees from CSL Behring, Shire, Dyax, and Shire; and personal fees from Salix and Pharming Technologies, outside the submitted work. DL has served on the speaker’s bureau, as a consultant, on a steering committee, and as a clinical investigator for CSL Behring. MR has received research grants from BioCryst Pharmaceuticals, CSL Behring, Dyax, Pharming Technologies, and Shire; consultant fees from Adverum Biotechnologies, Alnylam Pharmaceuticals, BioCryst Pharmaceuticals, CSL Behring, Global Blood Therapeutics, Ionis Pharmaceuticals, KalVista Pharmaceuticals, Pharming Technologies, and Shire; speaker’s honoraria from CSL Behring, Shire, and Pharming; and is an uncompensated advisory board member for the US Hereditary Angioedema Association. TM, SP HF and IP are employees of CSL Behring.