Epidemiology and Management of Acquired Angioedema Due to C1 Inhibitor Deficiency

AAE-C1-INH (acquired angioedema owing to C1-inhibitor (C1-INH) deficiency) is a dangerous illness that can lead to asphyxiation due to laryngeal edoema. Only around 1% to 2% of angioedema cases are classified as HAE or AAE, with HAE being 10 times more prevalent than AAE. The sole clinical distinction between HAE and AAE is the age at which symptoms appea, AAE-C1-INH is usually diagnosed after 40 years of age. There is no licensed therapy for AAE-C1-INH at this time. AAE-C1-INH attacks are treated with HAE-C1-INH medicines such plasma-derived C1-INH concentrate (pdC1-INH) and the bradykinin B2 receptor antagonist, icatibant. These on-demand medications are thought to be most helpful when provided early in the attack. However, there is a scarcity of published data on the efficacy and safety of AAE-C1-INH therapies.

Angioedema Without Wheals: Challenges in Laboratorial Diagnosis

Angioedema is a prevailing symptom in different diseases, frequently occurring in the presence of urticaria. Recurrent angioedema without urticaria (AE) can be hereditary (HAE) and acquired (AAE), and several subtypes can be distinguished, although clinical presentation is quite similar in some of them. They present with subcutaneous and mucosal swellings, affecting extremities, face, genitals, bowels, and upper airways. AE is commonly misdiagnosed due to restricted access and availability of appropriate laboratorial tests. HAE with C1 inhibitor defect is associated with quantitative and/or functional deficiency. Although bradykinin-mediated disease results mainly from disturbance in the kallikrein–kinin system, traditionally complement evaluation has been used for diagnosis. Diagnosis is established by nephelometry, turbidimetry, or radial immunodiffusion for quantitative measurement of C1 inhibitor, and chromogenic assay or ELISA has been used for functional C1-INH analysis. Wrong handling of the samples can lead to misdiagnosis and, consequently, mistaken inappropriate approaches. Dried blood spot (DBS) tests have been used for decades in newborn screening for certain metabolic diseases, and there has been growing interest in their use for other congenital conditions. Recently, DBS is now proposed as an efficient tool to diagnose HAE with C1 inhibitor deficiency, and its use would improve the access to outbound areas and family members. Regarding HAE with normal C1 inhibitor, complement assays’ results are normal and the genetic sequencing of target genes, such as exon 9 of F12 and PLG, is the only available method. New methods to measure cleaved high-molecular-weight kininogen and activated plasma kallikrein have emerged as potential biochemical tests to identify bradykinin-mediated angioedema. Validated biomarkers of kallikrein–kinin system activation could be helpful in differentiating mechanisms of angioedema. Our aim is to focus on the capability to differentiate histaminergic AE from bradykinin-mediated AE. In addition, we will describe the challenges developing specific tests like direct bradykinin measurements. The need for quality tests to improve the diagnosis is well represented by the variability of results in functional assays.

Malignancy and immune disorders in patients with hereditary angioedema

Background Hereditary angioedema (HAE) is an inherited condition manifesting as recurrent angioedema episodes which is caused by deficiency or dysfunction of C1 inhibitor. Although complement dysregulation has historically been shown to be associated with various malignancy and immune disorders, it is currently not known if HAE patients are at an increased risk of developing malignancy or autoimmune conditions. Case presentation We reviewed the charts of 49 HAE patients and identified 6 patients who had a co-existing malignancy diagnosis (two with breast cancer, one with melanoma, one with pancreatic cancer, one with renal cancer and one with cervical dysplasia) and 6 patients who had a diagnosis of a co-existing immune disorder (two with rheumatoid arthritis, two with ulcerative colitis, one with chronic urticaria with hypothyroidism and one with Sjogren’s syndrome). Nearly all malignancy cases occurred in older HAE patients (> 50 years) and malignancy was diagnosed before HAE in 3 of the patients. Conclusions Our case series identified multiple hereditary angioedema (HAE) patients with co-existing malignancy and immune disorders. Based on these findings, we would advocate that physicians managing HAE patients should maintain a high index of suspicion for these conditions and that in patients with angioedema, C1 inhibitor deficiency and malignancy, a diagnosis of HAE should still be considered in addition to acquired angioedema (AAE).

Clinical Characteristics and Management of Angioedema Attacks in Polish Adult Patients with Hereditary Angioedema Due to C1-Inhibitor Deficiency

Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is a rare disease characterized by recurrent swellings. This study aims to determine (i) the clinical characteristics of the HAE patient population from Poland, and (ii) real-life patients’ treatment practices. A cross-sectional study involved 138 adult HAE patients (88 females, 50 males) treated in six regional HAE centers in Poland. Consecutive patients during routine follow-up visits underwent a structured medical interview on the clinical characteristics of the course and treatment of HAE attacks within the last six months. A total of 118 of 138 patients was symptomatic. They reported in total 2835 HAE attacks predominantly peripheral and abdominal, treated with plasma-derived C1-INH (61.4%), icatibant (36.7%) and recombinant C1-INH (1.9%). An amount of 116 patients carried the rescue medication with them while traveling, and 74 patients self-administrated on demand treatment. There were twice as many symptomatic women (n = 78) as there were men (n = 40). Women treated their HAE attacks significantly more often than men. Older patients (≥65 years) reported a longer delay in diagnosis, and practiced the self-administration of rescue medication less frequently in comparison to other patients. Clinical features of the surveyed population are similar to other European, but not Asian, HAE patient groups. Self-administration still remains an unmet medical need. Some distinct HAE patients may require special attention due to the severe course of the disease (females) or a delay in diagnosis (the elderly).

ANGIOEDEMA DUE TO ACQUIRED C1-INHIBITOR DEFICIENCY- A CASE STUDY

Angioedema is a self-limited, localized swelling that involves subcutaneous tissue or mucosa of the face and other areas. It affects males and females equally, usually during the 3rd and 4th decades of life. We present a patient with angioedema of the head, neck, upper trunk and both upper limb with a typical clinical picture of an acquired type and with a low level of C1-INH. Initially the patient was treated with a combination of drugs for allergy. However, the swelling did not respond to the therapy and patient had a history of recurrent admission in our hospital with the complaint swelling over face and shortness of breath. After the 3rd day, the edema began reducing progressively

Psychometric study of the SF-36v2 in hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE)

Background The generic 36-item Short-Form Health Survey (SF-36v2) has been used to assess health related quality of life in adult patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) even though it has not yet been validated for use in this specific disease. Objective This study aims to validate the SF-36v2 for use in adult patients with C1-INH-HAE. Results There was a very low item non-response rate (1-3.4%), with a high ceiling effect in 25/35 items and a low floor effect in 3/35 items. A moderate ceiling effect was observed in 5/8 dimensions of the SF-36v2, whereas no floor effect was noticed in any of the dimensions. Internal consistency was good to excellent with Cronbach's alpha coefficient ranging between 0.82 and 0.93 for the different dimensions. Construct validity was good: seven out of the 8 hypotheses defined on clinical criteria were confirmed, discriminant validity assessment showed significant differences among patients with different C1-INH-HAE severity, convergent validity showed a good correlation among the physical and mental component summaries of the SF-36v2 and the HAE-QoL total score (0.45 and 0.64 respectively, P < 0.001). Test- retest reliability was high with intraclass correlation coefficient varying from 0.758 to 0.962. The minimal clinically important difference was calculated by distribution methods and small differences in the domain scores and in the component summaries scores were shown to be meaningful. Conclusions The psychometric properties of the SF-36v2 show it can be a useful tool to assess HRQoL in adult patients with C1-INH-HAE, although with some content validity limitation. Methods The psychometric properties of the SF-36v2 were evaluated in an international setting based on responses from 290 adult C1-INH-HAE patients in 11 countries.

Hereditary Angioedema (HAE) with a mutation in the plasminogen gene: a retrospective study of a cohort of 14 patients from Russia

BACKGROUND: In 2018, a new form of hereditary angioedema without C1-inhibitor deficiency hereditary angioedema with a mutation in the plasminogen gene was identified. The world scientific literature describes a small number of patients with this form of the disease and, therefore, new research is relevant. AIMS: To identify the sociodemographic and clinical features of patients with hereditary angioedema with plasminogen gene mutation; to evaluate the treatment efficacy; to conduct a comparative analysis in a group of patients with hereditary angioedema type I/II. MATERIAL AND METHODS: 14 patients (1 male and 13 females, mean age 51.6413.55 years) with hereditary angioedema with c.988AG mutation in the plasminogen gene (p.Lys330Glu; K330E) were enrolled in a retrospective study. The comparison group included 194 patients with hereditary angioedema type I/II (56 males and 138 females, mean age 37.0316.23 years). RESULTS: The average age at disease onset in patients with hereditary angioedema with a mutation in the plasminogen gene is 25.0710.46 years, which is significantly higher than in patients with hereditary angioedema type I/II 11.588.92 years (p 0.001). Peripheral angioedema was reported in 21.4% of patients with hereditary angioedema with a mutation in the plasminogen gene, abdominal attacks in 28.6%, which is less common than in patients with hereditary angioedema type I/II (peripheral edema 97.4%, p 0.001; abdominal attacks 86.6%, p 0.001). Face and neck angioedema was observed in all patients with hereditary angioedema with a mutation in the plasminogen gene (100%) and in 72.2% of patients in the group of hereditary angioedema type I/II (p=0.023). 85.7% of patients with hereditary angioedema with a mutation in the plasminogen gene had edema of the tongue. A decrease in the severity and duration of 28 out of 29 attacks by an average of 71.4% was reported by 4/5 of patients who used icatibant (Firazyr); 3/4 of patients reported a decrease in the frequency of attacks during treatment with tranexamic acid. CONCLUSIONS: The diseases manifestation in adulthood, the predominance of face and tongue angioedema are common features of hereditary angioedema with a mutation in the plasminogen gene. The efficacy of tranexamic acid and icatibant was demonstrated in the observed cohort of patients.