Background: Hereditary angioedema (HAE) caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. We have recently found that patients with C1-INH-HAE have increased plasma levels of vascular endothelial growth factors (VEGFs) and angiopoietins (Angs), which have been associated with vascular permeability in several diseases. Among these and other factors, blood endothelial cells and vascular permeability can be modulated by extracellular or secreted phospholipases A2 (sPLA2s). Objective: We sought to investigate the enzymatic activity and biological functions of sPLA2 in patients with C1-INH-HAE. Methods: sPLA2 enzymatic activity was evaluated in the plasma from 109 adult patients with C1-INH-HAE and 68 healthy donors in symptom-free period and attacks. Plasma level of group IIA sPLA2 (hGIIA) protein was measured in selected samples. The effect of C1-INH-HAE plasma on endothelial permeability was examined in vitro using a vascular permeability assay. The role of hGIIA was determined using highly specific sPLA2 indole inhibitors. The effect of recombinant hGIIA on C1-INH activity was examined in vitro by functional assay. Results: Plasma sPLA2 activity and hGIIA levels are increased in symptom-free C1-INH-HAE patients compared to controls. sPLA2 activity negatively correlates with C1-INH protein level and function. C1-INH-HAE plasma increases endothelial permeability in vitro, and this effect is partially reverted by a specific hGIIA enzymatic inhibitor. Finally, recombinant hGIIA inhibits C1-INH activity in vitro. Conclusions: sPLA2 enzymatic activity (likely attributable to hGIIA), which is increased in C1-INH-HAE patients, can promote vascular permeability and impairs C1-INH activity. Our results may pave the way for investigating the functions of sPLA2s (in particular hGIIA) in the pathophysiology of C1-INH-HAE and may inform the development of new therapeutic targets.
C1-inhibitor (C1-INH) related hereditary angioedema (C1-INH-HAE) is a rare pathological condition caused by a deficiency or a functional alteration of serum protein C1-INH. Clinical manifestations are represented by recurrent, potentially life-threatening episodes of cutaneous or mucosal oedema. The present study analysed the effectiveness of a specific short-term prophylaxis protocol for the management of C1-INH-HAE patients requiring chronic periodontitis treatment.
Purpose of review We aim to explore the most recent insights into the pathogenesis of recurrent angioedema caused by different mechanisms and then focus on the management and treatment approaches available. Recent findings The recently developed DANCE consensus classification identifies five types of angioedema: mast cell-mediated (AE-MC), bradykinin-mediated, because of intrinsic vascular endothelium dysfunction (AE-VE), drug-induced (AE-DI), and due to unknown mechanisms (AE-UNK). These subtypes require different management with treatment choices targeting the main pathogenetic pathways involved in each form. For AE-MC and AE-BK, the therapeutic landscape has been significantly widened in recent years. Conversely, there is a lack of consensus for the hereditary forms because of newly discovered mutations ( factor 12 , plasminogen, kininogen-1 , myoferlin, angiopoietin-1 , heparan sulfate 3-O-sulfotransferase 6 ) and AE-UNK. Summary Recurrent angioedema can present with or without wheals. Angioedema without wheals may be driven by bradykinin and/or mast cell mediators. The different forms respond to specific drugs and require a different management. For its potentially life-threatening and disfiguring features, angioedema should be promptly recognized and effectively treated. For this reason, enhancing awareness about various angioedema subtypes and their management provide a useful tool for the clinical practice.
Background
Complement-mediated acquired angioedema (AAE) is a rare condition characterized by an increased degradation of C1-esterase inhibitor (C1-INH) associated with lymphoproliferative disorders (AAE type I) or caused by autoantibodies against C1-INH (AAE type II). Reduced C1-INH activity leads to uncontrolled bradykinin formation and to angioedema symptoms. There is no established treatment for AAE. Replacement with plasma-derived C1-INH is effective in most patients with life-threatening attack; however, icatibant, a bradykinin B2 receptor antagonist, may represent an alternative treatment.
Abstract Icatibant, a bradykinin B2 receptor antagonist, is an established treatment for acute attacks of hereditary angioedema ( HAE ) with C1‐inhibitor (C1‐ INH ) deficiency. We describe our experience with icatibant in eight patients with angioedema because of acquired C1‐ INH deficiency ( AAE ). Forty‐eight moderate‐to‐severe attacks were treated with subcutaneous icatibant 30 mg; two moderate attacks resolved without treatment. The median (range) duration of treated attacks (onset to complete resolution) was 9.33 (1.67–39.00) h; durations of the untreated attacks were 72 and 96 h. Symptom improvement following icatibant treatment occurred in 0.5 (0.25–2.10) h and complete resolution in 6.75 (0.50–30.75) h. A single icatibant injection achieved complete symptom resolution in 47 attacks; one facial attack required a second injection. One peripheral attack responded less quickly than other treated attacks. Five patients reported transient injection site reactions. Icatibant appeared to provide effective symptom relief and was generally well tolerated.
Background Recombinant Necator americanus Glutathione-S-Transferase-1 ( Na -GST-1) formulated on Alhydrogel ( Na -GST-1/Alhydrogel) is being developed to prevent anemia and other complications of N. americanus infection. Antibodies induced by vaccination with recombinant Na -GST-1 are hypothesized to interfere with the blood digestion pathway of adult hookworms in the host. Phase 1 trials have demonstrated the safety of Na -GST-1 formulated on Alhydrogel, but further optimization of the vaccine adjuvant formulation may improve humoral immune responses, thereby increasing the likelihood of vaccine efficacy. Methods A randomized, observer-blind, dose escalation Phase 1 trial was conducted in 24 healthy, hookworm-naïve adults. In each cohort of 12 participants, 4 were randomized to receive 100 µg of Na -GST-1/Alhydrogel and 8 to receive 30 µg or 100 µg of Na -GST-1/Alhydrogel plus the Cytosine-phospho-Guanine (CpG) oligodeoxynucleotide Toll-like receptor-9 agonist, CpG 10104, in the first and second cohorts, respectively. Progression to the second cohort was dependent upon evaluation of 7-day safety data after all participants in the first cohort had received the first dose of vaccine. Three intramuscular injections of study product were administered on days 0, 56, and 112, after which participants were followed for 6 months. IgG and IgG subclass antibody responses to Na -GST-1 were measured by qualified indirect ELISAs at pre- and post-vaccination time points. Results Na -GST-1/Alhydrogel administered with or without CpG 10104 was well-tolerated. The most common solicited adverse events were mild injection site tenderness and pain, and mild headache. There were no vaccine-related serious adverse events or adverse events of special interest. Both dose concentrations of Na -GST-1/Alhydrogel plus CpG 10104 had significantly higher post-vaccination levels of antigen-specific IgG antibody compared to Na -GST-1/Alhydrogel without CpG, starting after the second injection. Peak anti- Na -GST-1 IgG levels were observed between 2 and 4 weeks following the third dose, regardless of Na -GST-1 formulation. IgG levels decreased but remained significantly above baseline in all groups by day 290, at which point all participants (20 of 20 evaluable participants) still had detectable IgG. Longitudinal antigen-specific IgG1 and IgG3 subclass responses mirrored those of total IgG, whereas IgG4 responses were lower in the groups that received the vaccine with the CpG adjuvant compared to the non-CpG group. Conclusions Vaccination of hookworm-naïve adults with Na -GST-1/Alhydrogel plus CpG 10104 was safe and minimally reactogenic. Addition of CpG 10104 to Na -GST-1/Alhydrogel resulted in significant improvement in IgG responses against the vaccine antigen. These promising results have led to inclusion of the CpG 10104 formulation of Na -GST-1/Alhydrogel in a Phase 2 proof-of-concept controlled human infection trial.
Abstract Background Hereditary angioedema associated to C1 inhibitor deficiency (C1-INH-HAE) is a pathological condition characterized by episodes of subcutaneous swelling and it is frequently associated with discomfort and social impairment of the patients, due to the anxiety experienced for an unpreventable manifestation of an attack during daily life. In children increased level of stress and alexithymia have been associated to C1-INH-HAE, and the latter correlated also with the severity of the disease. We hypothesized that the involvement of psychological issues may impact on the severity of C1-INH-HAE in adult patients as well, interfering with their ability to engage with the management of the disease. Methods 28 adult patients with C1-INH-HAE were evaluated for clinical (C1-INH-HAE Severity Score) and psychological factors (alexithymia, emotion regulation, stress, patient health engagement, general severity index) by means of validated questionnaires. Results Mean age (standard deviation [SD]) was 45 (11) years and time from diagnosis was 20 (12) years. The mean C1-INH-HAE severity score was 6.4. Alexithymia was absent in 22 (78%) patients. Moderate and high stress levels were present in 17 (61%) and 4 (14%) patients, respectively. Moderate-high discomfort was experienced by 9 (36%) patients and a discomfort beyond the clinical attention threshold was shown by 3 (12%) patients. Stress correlated with patient health engagement and with psychological discomfort. Conclusions In C1-INH-HAE, patients health engagement and moderate-high psychological discomfort are linked with stress but not with the severity of the disease or alexithymia. A better patient health engagement may be a target for psychological intervention in clinics to ameliorate the stress perceived by C1-INH-HAE patients.
