C1 Inhibitor Research Articles

Hereditary Angioedema Attacks in Patients Receiving Long-Term Prophylaxis: A Systematic Review.

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 60IU/kg twice weekly at 16weeks, and 44% for lanadelumab 300mg every second week at 6months (77% during steady-state [days 70-182]); there was no difference in attack-free rate for berotralstat 150mg versus placebo at 24weeks. 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.

Mendelian Randomization Estimates the Effects of Plasma and Cerebrospinal Fluid Proteins on Intelligence, Fluid Intelligence Score, and Cognitive Performance.

Observational studies have revealed associations between levels of plasma and cerebrospinal fluid (CSF) proteins and cognition-related traits. However, these associations may be influenced by confounding factors inherent in observational research. This study aims to identify plasma and CSF proteins associated with intelligence, fluid intelligence score, and cognitive performance through the application of Mendelian randomization (MR). Proteomic quantitative trait locus (pQTL) data for plasma and CSF proteins were sourced from existing genome-wide association study (GWAS). Intelligence, fluid intelligence score, and cognitive performance GWAS summary statistics provided comprehensive data for two-sample MR analysis. Extensive sensitivity analyses, including Steiger testing, reverse MR analysis, and Bayesian co-localization, were conducted to validate associations and identify shared genetic variants. Phenotype scanning explored potential pleiotropic effects. MR analysis identified several proteins in plasma and CSF significantly associated with intelligence, fluid intelligence scores, and cognitive performance. For intelligence, negatively associated proteins in plasma include endoplasmic reticulum aminopeptidase 2 (ERAP2) and secretogranin III (SCG3), while positively associated proteins are myeloperoxidase (MPO), signal regulatory protein alpha (SIRPA), regulator of microtubule dynamics 1 (RMDN1), and endoplasmic reticulum lectin 1 (ERLEC1). In CSF, C1-esterase inhibitor and carboxypeptidase E (CBPE) both exhibited positive associations with intelligence. For fluid intelligence scores, negatively associated proteins in plasma are copine 1 (CPNE1) and SCG3, while positively associated proteins are nudix hydrolase 12 (NUDT12) and RMDN1.In CSF, Macrophage Stimulating Protein (MSP) demonstrated a significant negative impact. For cognitive performance, negatively associated proteins in plasma include ERAP2, tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1), and SCG3, while positively associated proteins are NUDT12, RMDN1, ERLEC1, and ectonucleotide pyrophosphatase/phosphodiesterase family member 5 (ENPP5). In CSF, C1-esterase inhibitor was positively associated, while MSP and soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 1(sTie-1) showed a negative association. Bayesian co-localization analysis revealed significant genetic overlaps between SIRPA, RMDN1, and ERLEC1 in plasma with intelligence; NUDT12 and SCG3 in plasma with fluid intelligence scores; and TIE1, NUDT12, RMDN1, ERLEC1, and ENPP5 in plasma with cognitive performance. Additionally, significant co-localization was identified between C1-esterase inhibitor and CBPE in CSF with intelligence, as well as between C1-esterase inhibitor and sTie-1 in CSF with cognitive performance. Reverse causality analysis confirmed the causal direction from proteins to cognitive traits. This study identifies specific plasma and CSF proteins that significantly impact intelligence, fluid intelligence scores, and cognitive performance. These proteins could serve as biomarkers and targets for future research and therapeutic interventions aimed at sustaining cognitive abilities and reducing impairment risks.

A mechanistic model of in vitro plasma activation to evaluate therapeutic kallikrein-kinin system inhibitors.

The kallikrein-kinin system (KKS) is a complex biochemical pathway that plays a crucial role in regulating several physiological processes, including inflammation, coagulation, and blood pressure. Dysregulation of the KKS has been associated with several pathological conditions such as hereditary angioedema (HAE), hypertension, and stroke. Developing an accurate quantitative model of the KKS may provide a better understanding of its role in health and disease and facilitate the rapid and targeted development of effective therapies for KKS-related disorders. Here, we present a novel, detailed mechanistic model of the plasma KKS, elucidating the processes of Factor XII (FXII) activation, the kallikrein feedback loop, cleavage of high molecular weight kininogen leading to bradykinin (BK) production, and the impact of inhibitors. The model incorporates both surface and solution-phase reactions of all proteins in the KKS, describing how binding site concentration affects the rate of surface reactions. The model was calibrated and validated using a variety of published and in-house experimental datasets, which encompass a range of dextran sulphate (DXS) concentrations to initiate contact activation and various KKS inhibitors to block bradykinin production. Our mathematical model showed that a trace amount of activated FXII is required for subsequent FXII activation. The model also reveals a bell-shaped curve relationship between the activation of the KKS and the number of DXS surface binding sites. Simulations of BK generation in healthy and HAE plasma demonstrated the impact of C1 esterase inhibitor (C1inh) deficiency via increased peak BK levels and accelerated formation in HAE plasma. The efficacy of KKS inhibitors, such as CSL312, ecallantide, and C1inh, was also evaluated, with CSL312 showing the most potent inhibition of BK generation. The present model represents a valuable framework for studying the intricate interactions within the plasma KKS and provides a better understanding of the mechanism of action of various KKS-targeted therapies.

Identification of a novel mutation in the SERPING1 gene in a 17-year-old Chinese girl with type I hereditary angioedema

Identification of a novel mutation in the SERPING1 gene in a 17-year-old Chinese girl with type I hereditary angioedema

Unmet needs in the management of hereditary angioedema from the perspective of Brazilian patients

IntroductionHereditary angioedema (HAE) is a rare genetic disease characterized by recurrent, potentially life-threatening angioedema episodes. Despite its severity, including the risk of asphyxiation, HAE often remains underdiagnosed. The disease significantly impacts patient quality of life (QoL), leading to anxiety, depression, and avoidance behaviors due to the unpredictable nature of attacks. Understanding the perspectives of patients is crucial for identifying unmet needs in managing this complex condition. ObjectiveThis study aimed to gather real-world insights from Brazilian patients with C1 inhibitor deficiency HAE to identify their unmet needs and assess their perceptions of the effectiveness of current care in preventing and treating HAE attacks. MethodsA cross-sectional study utilized a SurveyMonkey questionnaire distributed to HAE patients through ABRANGHE via email. Participants provided informed consent, and their responses were anonymous. The questionnaire, developed with input from experts and patients, covered aspects of HAE diagnosis, treatment experiences, and QoL assessments. ResultsThe survey included 178 HAE patients, predominantly female (81%), aged 30–50 years (58%), and college-educated (62%). The most common HAE defect was C1–INH deficiency (53%), followed by HAE-nC1INH (23%), with nearly a quarter unaware of their specific defect. Diagnosis delays were prevalent, with a significant number reporting 13–50 attacks annually (33%) and 15% experiencing more than 50 attacks per year. Laryngeal involvement was reported by 26% of respondents. Most patients (69%) attended regular follow-ups, with 72% on prophylactic treatment and 67% managing acute attacks. The most used acute treatment was Icatibant (49%), followed by pdC1INH (24%). However, confusion regarding medication use persisted, with 45% incorrectly believing that oral medications could effectively treat attacks. Key unmet needs identified included improved access to emergency rooms during attacks (73%), better availability of prophylactic treatment (69%), and enhanced access to specialized care (63%). Patients also emphasized the need for psychological support, increased awareness of HAE, and educational initiatives for patients and healthcare providers. DiscussionThis study highlighted significant challenges in HAE management among Brazilian patients, particularly concerning delayed diagnosis, misconceptions about treatment, and inadequate access to specialized care and prophylactic treatments. The high frequency of emergency room visits underscores the difficulties in managing the disease. The substantial burden of HAE on QoL emphasizes the urgent need for improved physician education, streamlined diagnostic processes, and equitable access to effective medications and specialized care facilities. Addressing these gaps is crucial to better support HAE patients, improve diagnostic timeliness, enhance treatment efficacy, and ultimately enhance the overall quality of life for individuals living with HAE.

Difficulties in diagnosing hereditary angioedema (HAE) with normal c1 inhibitor levels in a patient with a pathogenic mutation in the MEFV gene associated with familial Mediterranean fever

Hereditary angioedema (HAE) is an orphan disease that causes potentially life-threatening edema in various locations and remains serious problem in both pediatrics and adult clinical practice often disguised as various diseases. The HAE diagnosis with normal C1 inhibitor activity is particularly difficult. The purpose of this publication is to demonstrate unique clinical case of HAE with normal C1 inhibitor activity in young patient with a pathogenic mutation in the MEFV gene, which is associated with familial Mediterranean fever. Severe abdominal attacks in this patient have been regarded for a long time as a part of therapeutic pathology (gastroenteritis, gastritis, Familial Mediterranean fever), acute surgical and gynecological diseases, which led to late diagnosis verification. The HAE requires timely diagnosis, elimination of factors that provoke exacerbations and an immediate therapy administration, that significantly improves life quality of patients and helps prevent death.

The utility of shared decision making in the management of hereditary angioedema.

Background: Hereditary angioedema (HAE) is a complex disorder with a wide array of treatment options. Shared decision-making (SDM) should be used to ensure that patients are choosing their best treatment option. The goal was to develop and psychometrically test a brief instrument for assessing the patient's perspective of the SDM process during his or her clinical encounters with an HAE specialist/allergist. Method: We hypothesized that SDM could be used effectively to help patients in their choice of therapy for HAE. Ten HAE treating physicians from the United States with a total of 50 patients with HAE used SDM to help patients choose the best prophylactic therapies (oral kallikrein inhibitor, androgens, subcutaneous C1 inhibitor replacement therapy, intravenous C1 inhibitor replacement therapy, monoclonal antibody kallikrein inhibitor) for their HAE and then completed surveys to analyze the effectiveness of the implementation of SDM as a quality indicator in health services assessment. Results: The congruence of answers between the physicians and the patients was then analyzed; 90% of the patient-physician pairs agreed that the advantages and disadvantages of the treatment options were precisely explained; 92% of the patient-physician pairs agreed that the physician helped them understand all the information and that the physician asked them which treatment option they preferred; 88% of the pairs agreed that the different treatment options were thoroughly weighed and 92% of the pairs felt that they selected a treatment option together. Conclusion: In summary, SDM is being implemented by treating physicians to determine the best management options for their patients with HAE.

Prolonging the circulatory half-life of C1 esterase inhibitor via albumin fusion.

Hereditary Angioedema (HAE) is an autosomal dominant disease characterized by episodic swelling, arising from genetic deficiency in C1-esterase inhibitor (C1INH), a regulator of several proteases including activated Plasma kallikrein (Pka). Many existing C1INH treatments exhibit short circulatory half-lives, precluding prophylactic use. Hexahistidine-tagged truncated C1INH (trC1INH lacking residues 1-97) with Mutated N-linked Glycosylation Sites N216Q/N231Q/N330Q (H6-trC1INH(MGS)), its murine serum albumin (MSA) fusion variant (H6-trC1INH(MGS)-MSA), and H6-MSA were expressed in Pichia pastoris and purified via nickel-chelate chromatography. Following intravenous injection in mice, the mean terminal half-life of H6-trC1INH(MGS)-MSA was significantly increased versus that of H6-trC1INH(MGS), by 3-fold, while remaining ~35% less than that of H6-MSA. The extended half-life was achieved with minimal, but significant, reduction in the mean second order rate constant of Pka inhibition of H6-trC1INH(MGS)-MSA by 33% relative to that of H6-trC1INH(MGS). Our results validate albumin fusion as a viable strategy for half-life extension of a natural inhibitor and suggest that H6-trC1INH(MGS)-MSA is worthy of investigation in a murine model of HAE.

Rare connective tissue diseases in patients with C1-inhibitor deficiency hereditary angioedema: first evidence on prevalence and distribution from a large Italian cohort study.

In patients with Hereditary Angioedema (HAE) related to primary C1 inhibitor deficiency (C1INH), the defective clearance of immune complexes and apoptotic materials along with impairment of normal humoral response potentially leads to autoimmunity. Few studies report evidence on autoimmune diseases in C1INH-HAE, but no large population studies focus on rare connective tissue diseases (RCTDs). We aim at evaluating for the first time prevalence and distribution of RCTDs - Systemic Lupus Erytematosus (SLE), primary Sjogren Syndrome (SjS), primary antiphospholipid syndrome (APS), Systemic Sclerosis (SSc), and mixed connective tissue diseases (MCTD) in a large Italian cohort of C1INH-HAE patients. A multicenter observational study includes C1INH-HAE patients from ITACA Centers throughout Italy (time frame Sept 2023-March 2024). Inclusion criteria are i. a defined diagnosis of type I or type II C1INH-HAE; ii. age ≥15 years (puberty already occurred); iii. enrollment in the ITACA Registry. The diagnosis of SLE, primary SjS, primary APS, SSc, and MCTD are made in accordance with international classification criteria. Data are collected from a total of 855 C1INH-HAE patients referring to 15 ITACA Centers. Patients with concomitant RCTDs were 18/855 (2.1%) with F:M ratio 3.5 and a prevalent type I C1INH-HAE diagnosis (87.2%). A diagnosis of SLE results in 44.5% of cases (n=8) while the remaining diagnoses are primary SjS (22.2%, n=4), primary APS (16.6%, n=3), SSc (11.2%, n=2), and a single case of MCTD (5.5%). The female gender is prevalent in all the RCTDs. Patients on long term prophylaxis (LTP) are significantly prevalent in RCTDs group than in the whole C1INH-HAE population (p<0.01). A relevant prevalence of RCTDs is documented in C1INH-HAE patients, mainly SLE. Patients with RCTDs are on LTP in a significant proportion supporting the idea of a bidirectional link between C1INH-HAE and autoimmunity.

Hereditary Angioedema and Venous Thromboembolism: Where There's Smoke, There's Fire.

C1-inhibitor deficiency-associated hereditary angioedema (C1INH-HAE) is a rare congenital swelling disorder caused by mutations in the SERPING1 gene. Despite evidence of a systemic procoagulant state in C1INH-HAE, dogma held that this disorder was not associated with thrombotic pathologies. Recent population scale epidemiological evidence has directly challenged this, with C1INH-HAE being associated with a significantly increased risk of venous thromboembolism (VTE). This review considers the growing body of evidence supporting associations between HAE and both a systemic procoagulant state and an increased risk of VTE. In the setting of C1INH-HAE, the relationship between the observed procoagulant and thrombotic phenotypes is a prime example of "where there's smoke, there's fire." This review also discusses the impact of C1INH-HAE disease modifying therapies on coagulation and VTE. Further, the utility of preclinical mouse models of C1-inhibitor deficiency is considered.

Unveiling the Complexities of Hereditary Angioedema

Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder, constituting approximately 2% of all clinical cases of angioedema, with a global prevalence estimated between 1 in 50,000 and 1 in 150,000 individuals. The condition affects individuals of all genders and ethnic backgrounds without significant variation. HAE is classified into three types. Type I HAE, which accounts for 85% of cases, is characterized by a deficiency of the C1 esterase inhibitor (C1-INH) gene. Type II HAE, making up 15% of cases, involves a dysfunctional C1-INH. Type III HAE, which represents about 5% to 10% of cases, is often estrogen-dependent and although several mutations have been identified, it typically involves normal C1-INH activity. Despite the differences in C1-INH functionality, all three types of HAE manifest with similar clinical symptoms. HAE leads to recurrent episodes of non-pruritic angioedema, which occurs in the absence of urticaria. Breakthroughs in understanding HAE pathophysiology have revolutionized treatment, leading to the development of highly targeted therapies for both acute management and long-term prevention. Meanwhile, cutting-edge advancements in omics technologies are unlocking new possibilities for biomarker discovery, paving the way for more precise diagnoses and personalized treatment strategies that could significantly enhance patient outcomes. This review will delve into the intricate pathophysiology, diverse clinical presentations, and diagnostic challenges of HAE while exploring emerging biomarkers and innovative approaches to therapeutic management and prevention strategies. Additionally, it will underscore the vital importance of screening family members of affected individuals, even when symptoms are not present.

Berotralstat for hereditary angioedema with C1 inhibitor deficiency: a practical guide for clinicians.

Berotralstat for hereditary angioedema with C1 inhibitor deficiency: a practical guide for clinicians.

Long-term safety and efficacy of garadacimab for preventing hereditary angioedema attacks: Phase 3 open-label extension study.

Hereditary angioedema (HAE) is a chronic, unpredictable disease. Long-term prophylactic treatments that offer durable efficacy, safety, and convenience are required to assist patients in achieving complete disease control, per international guidelines. We report an interim analysis of an ongoing phase 3 (VANGUARD) open-label extension (OLE) study evaluating the long-term safety and efficacy of garadacimab for HAE prophylaxis. Adults and adolescents aged ≥12 years with HAE previously participating in phase 2 and pivotal phase 3 (VANGUARD) studies were rolled over to an OLE, alongside newly enrolled patients. Patients received garadacimab 200 mg subcutaneously, once monthly for ≥12 months. The primary endpoint was treatment-emergent adverse events (TEAEs) in patients with C1 inhibitor deficiency/dysfunction. At data cut-off (February 13, 2023; N = 161), median (interquartile range) exposure was 13.8 months (11.9-16.3). For the primary endpoint, 133/159 patients experienced ≥1 TEAE (524 events), equivalent to 0.23 events/administration and 2.84 events/patient-year. Garadacimab-related TEAEs (13% of patients, 52 events) were most commonly injection-site reactions (ISRs). No deaths occurred. One patient discontinued treatment due to garadacimab-related moderate ISR. Most TEAEs were mild/moderate; three events were serious (COVID-19, two events; abdominal HAE attack, one event) and not garadacimab related. No abnormal bleeding, thromboembolic, severe hypersensitivity, or anaphylactic events were observed. Mean HAE attack rate decreased by 95% from the run-in period; 60% of patients were attack-free. Almost all patients (93%) rated their response to garadacimab as "good" or "excellent." Garadacimab has a favorable safety profile suitable for long-term use and provides durable protection against HAE attacks.

Initial Experience of Long-Term Prophylaxis with Lanadelumab for Hereditary Angioedema in China: A Clinical Observation Study on Six Patients

Plain Language SummaryHereditary angioedema (HAE) is a rare genetic disease characterized by recurring episodes of painful swelling of the subcutaneous and submucosal tissue, and its pathogenesis is due to the deficiency or dysfunction C1-esterase inhibitors. HAE attacks can affect many areas of the body, but most frequently involve the extremities, gastrointestinal tract, genitals, face, and upper airway. Swelling of the larynx can occur, with potentially fatal consequences owing to asphyxiation. Since 2020, China has had the only first-line treatment drug that can prevent HAE attacks – lanadelumab. Our study evaluated the efficacy and safety of lanadelumab by observing the 6 patients in China mainland who were the first to use it. Our research showed that lanadelumab can prevent the attack of HAE, greatly improve the quality of life of patients, and has good safety. A reasonable dosage plan can ensure stable therapeutic effects of lanadelumab. In addition, the efficacy of lanadelumab remained stable during COVID-19 vaccination and infection.

C1 esterase inhibitor (C1-INH) for the off-label treatment of angiotensin-converting enzyme inhibitor induced angioedema

Introduction: Currently, C1 esterase inhibitor (C1-INH) is indicated for hereditary angioedema (HAE) but is utilized off-label for angiotensin- converting enzyme inhibitors (ACEi) induced angioedema (AAE). There is no standard of care for the treatment of AAE, however patients may receive a combination of epinephrine, corticosteroids, fresh frozen plasma (FFP), tranexamic acid (TXA), and histamine 1 and 2 receptor antagonists (H1RA, H2RA). C1-INH place is therapy is not well defined. Materials &amp; Methods: A retrospective chart review was conducted from patients at a large academic medical center who received C1-INH for AAE between January 2012 and May 2022. Variables and outcomes of interest were receipt of alternative angioedema treatment prior to C1-INH, time of C1-INH administration, dose of C1-INH, need for intubation or surgical airway placement, duration of intubation, and hospital length of stay. Results: All patients received additional medications for angioedema prior to C1-INH administration. Steroids and H1RAs were most common. The dose of C1-INH ranged from 11.7 IU/kg to 23.2 IU/kg with an average dose of 19.3 IU/kg. Five patients required airway support with four requiring intubation (30.8%) and one requiring a surgical airway. Conclusions: This retrospective review of 13 patients showed mixed results for C1-INH to prevent intubation in AAE. Providers should consider limiting the use of C1-INH to patients who remain symptomatic after administering a combination of other therapies when there is an ongoing risk for airway compromise and adequate time for preparation, administration, and effect.

A novel assay of excess plasma kallikrein-kinin system activation in hereditary angioedema.

Cleaved high-molecular-weight kininogen (HKa) is a disease state biomarker of kallikrein-kinin system (KKS) activation in patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH), the endogenous inhibitor of plasma kallikrein (PKa). Develop an HKa-specific enzyme-linked immunosorbent assay (ELISA) to monitor KKS activation in the plasma of HAE-C1INH patients. A novel HKa-specific antibody was discovered by antibody phage display and used as a capture reagent to develop an HKa-specific ELISA. Specific HKa detection following KKS activation was observed in plasma from healthy controls but not in prekallikrein-, high-molecular-weight kininogen-, or coagulation factor XII (FXII)-deficient plasma. HKa levels in plasma collected from HAE-C1INH patients in a disease quiescent state were higher than in plasma from healthy controls and increased further in HAE-C1INH plasma collected during an angioedema attack. The specificity of the assay for PKa-mediated HKa generation in minimally diluted plasma activated with exogenous FXIIa was demonstrated using a specific monoclonal antibody inhibitor (lanadelumab, IC50 = 0.044 µM). An ELISA was developed for the specific and quantitative detection of HKa in human plasma to support HAE-C1INH drug development. Improved quantification of the HKa biomarker may facilitate further pathophysiologic insight into HAE-C1INH and other diseases mediated by a dysregulated KKS and may enable the design of highly potent inhibitors targeting this pathway.

Uncovering a novel SERPING1 pathogenic variant: insights into the aggregation of C1-INH in hereditary angioedema

BackgroundHereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterized by recurrent edema and a potentially fatal risk. Despite its severity, there is a notable lack of effective methods for predicting and preventing HAE attacks. This study aims to thoroughly investigate the underlying pathological mechanisms of HAE and identify potential biomarkers that could aid in its prediction and prevention.ResultsIn our investigation, we have discovered a novel pathogenic variant of the SERPING1 gene, specifically c.708T > G, in a Han family affected by HAE. Our observations indicate that this variant leads to an increase in the accumulation of C1-INH within the endoplasmic reticulum (ER), resulting in the upregulation of GRP75 protein expression. This cascade of events resulted in Ca2+ overload, disruption of mitochondrial structure and function, and eventually triggered apoptosis. Using siRNA to knock down GRP75 mitigates cellular calcium overload and mitochondrial damage induced by the SERPING1 mutation.ConclusionBased on our findings, we propose that the detection of intracellular Ca2+ concentration could serve as a valuable biomarker for predicting acute attacks of HAE in patients. This discovery holds significant implications for the development of more targeted and effective strategies in the management of HAE.

Hereditary Angioedema in Pregnancy: A Case Report and Review of Obstetric Anesthesia Management.

Hereditary angioedema (HAE) is a rare disorder due to C1 esterase inhibitor deficiency, causing recurrent swelling. Pregnancy can exacerbate HAE due to estrogen fluctuations alongside peripartum stress and trauma. We present a pregnant patient with HAE who underwent induction of labor and vaginal delivery with neuraxial anesthesia. Management included C1-inhibitor prophylaxis, 48 hours of postpartum monitoring, and a self-treatment plan at discharge. Angioedema prevention involves timely anesthesia consultation, accessible emergency airway equipment, early neuraxial anesthesia, planned vaginal delivery, and 48 to 72 hours of close postpartum monitoring. Readily available C1-inhibitor and a multidisciplinary approach with these recommendations are crucial for peripartum management.

Elevated C1s/C1-INH in serum and plasma of myasthenia gravis patients

Myasthenia Gravis (MG) is an autoimmune neuromuscular disorder where acetylcholine receptor (AChR) antibodies induce membrane attack complex formation at the muscle membrane. The C1-inhibitor (C1-INH) regulates the classical pathway and is a promising marker in other autoimmune disorders. Treatment options for AChR antibody MG include complement inhibitors; nevertheless, the early pathway activation in MG remains unclear. Serum and plasma C1s-C1-INH levels were higher in MG patients than in matched healthy controls, supporting early classical pathway activation in most MG patients. These findings allow prospective validation studies of activated C1s as a putative treatment target and potential accompanying biomarker in MG.

Two pediatric hereditary angioedemathe families: case report and literature review

Objective: To summarize the clinical characteristics of two families with hereditary angioedema in children. Methods: A retrospective analysis was conducted on the general information, clinical manifestations, genetic variations, and laboratory test results of two families diagnosed with hereditary angioedema at Department of Rheumatology and Immunology, Shenzhen Children's Hospital from December 2022 to May 2023. And using keywords such as "children" "adolescent" "infant" "toddler" "pediatric" "hereditary angioedema" search for relevant literature from VIP, Wanfang, CNKI, PubMed, Web of Science and Google Scholar from the establishment of the database until January 2024 and summarize the diagnosis and clinical characteristics of hereditary angioed in children. Results: Case 1, female, 12 years old, presented with intermittent abdominal pain for 8 years, aggravated with vomiting for 2 days. Eight years ago, without a clear cause, case 1 experienced abdominal pain and underwent two abdominal surgeries. The concentration of C1 esterase inhibitor was 0.46 g/L, and the function of C1 esterase inhibitor was less than 0.01. The SERPING1 gene had a c.1396C>G variation, and she was diagnosed with hereditary angioedema type Ⅱ. Among the other 13 family members, 8 had swelling in different parts, and 2 had died. Case 2, female, 17 years old, was diagnosed with hereditary angioedema type Ⅰ due to intermittent limb swelling for more than 2 years. She had C4 of 0.09 g/L, C1 esterase inhibitor concentration of 0.05 g/L, C1 esterase inhibitor function <0.01, SERPING1 gene c.882C>G variation. Two out of the other 12 family members experienced intermittent skin swelling. Literature review meets the search criteria with 0 Chinese literature and 15 English literature, including a total of 524 cases of hereditary angioedema in children. Combined with 2 families in this group, there are 5 families with hereditary angioedema in children as the proband. The onset time is 1-15 years old, and the diagnosis delay time is -0.9 to 20.0 years. Two hundred and sixty-three cases (50.2%) of the children had a family history survey, of which 229 cases (87.1%) had a positive family history. Two hundred and fifty-seven cases (49.0%) had clear disease classification, with type Ⅰ being the main type, accounting for 234 cases (91.1%). The clinical symptoms of 296 children (56.5%) were described in detail, including 262 cases (88.5%) with skin edema in different parts, 176 cases (59.5%) with abdominal pain, and 61 cases (20.6%) with upper respiratory tract edema in the throat. Conclusions: Hereditary angioedema is mainly characterized by episodic skin and mucosal swelling, with individualized differences in the locations and characteristics of the onset. Hereditary angioedema in children is often overlooked, and patients with a positive family history of episodic skin and mucosal swelling need to actively undergo complement level testing.