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458?Differences of Complement Activation Profile between Type I and Type II of Hereditary Angioedema Due to C1-inhibitor Deficiency.

ABSTRACT: BackgroundIn hereditary angioedema (HAE), diverse mutations in the C1-inhibitor gene may produce either normal C1-inhibitor protein in insufficient quantities (HAE type I), or a dysfunctional protein in normal or even excessive amounts (HAE type II). Previously, we have found strong association between baseline level of functional C1-inhibitor and severity of HAE. Our aim was to investigate complement activation products in HAE, during a follow-up period, and to analyze the relationship between these products and severity of disease.Methods107 HAE patients (96 HAE type I, 11 type II) and 113 healthy control subjects were included. C1rC1sC1-INH, C3bBbP, and SC5b-9 levels were determined using ELISA methods in single EDTA-plasma samples of controls and in 4 samples from patients taken in 4 subsequent years. Between-group differences were evaluated with the Mann-Whitney test, and correlations were calculated using non-parametric Spearman's correlation coefficients.ResultsMedian levels of C1rC1sC1-INH (60 U/mL [40–113] vs 8 U/mL [4–10]; P < 0.0001) and SC5b-9 (0.6 U/mL [0.4–1.2] vs 1.8[0.9–2.8]; P < 0.0001) differed between patients and controls. Significant differences were found between HAE type I and type II as regards median C1rC1sC1-INH level (54 U/mL [33–97] vs 31 U/mL [21–49], P < 0.0001), and in an opposite manner with C3bBbP median levels (6 U/mL [4–12] vs 10 U/mL [8–17], P = 0.0002). Level of C1rC1sC1-INH correlated with the number of attacks (r = 0.3546, P = 0.0004) in HAE type I, but not in HAE type II. Dividing the patients into 2 subgroups based on danazol therapy, significant association (r = 0.3705, P = 0.0026) was found between level of C1rC1sC1-INH and annual attack number only in patients not treated with danazol. Similar results were found as regards the number of C1-inhibitor vials administered, which correlated with the level of C1rC1sC1-INH only in HAE type I (r = 0.4288, P < 0.0001) and in patients not treated with danazol (r = 0.4783, P < 0.0001).ConclusionsMonitoring the level of C1rC1sC1-INH is mostly informative in HAE type I patients, who are not treated with danazol. No correlation was found in HAE type II patients between level of C1rC1sC1-INH and disease severity markers. As this observation may be explained by the small number of HAE type II patients, multicenter studies are needed, including more HAE type II patients.

SUBMITTER: Csuka D

PROVIDER: S-EPMC3513152 | biostudies-other | 2012 Feb

REPOSITORIES: biostudies-other

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Project description:BackgroundHereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating subcutaneous and mucosal edema. Gastrointestinal attacks are painful, of sudden onset and often mistaken for acute abdomen leading to unnecessary surgery. The purpose of this study was to analyze symptom presentation of gastrointestinal angioedema in pediatric and adult HAE patients.MethodsInformation collected during the clinical development of ecallantide for treatment of acute HAE attacks included affected anatomic location, accompanying symptoms, medical history, and pain assessments. Efficacy endpoints included Treatment Outcome Score (TOS, maximum score = 100; minimally important difference = 30), a point-in-time measure of treatment response, and time to treatment response.ResultsForty-nine percent of 521 HAE attacks only involved abdominal symptoms. The most commonly reported abdominal symptoms were distension (77%), cramping (73%) and nausea (67%). The most common pain descriptors were tender, tiring-exhausting, aching, cramping and sickening. White blood cell counts were elevated (>10 × 10(9)/L) in 23% of attacks (mean ± SD: 15.1 ± 11.27 × 10(9)/L). A high proportion of patients reported a history of abdominal surgery, including appendectomy (23%), cholecystectomy (16.4%), and hysterectomy (8.2%). Mean TOS at 4 hours post ecallantide was 77 ± 33 versus 29 ± 65 for placebo. Median time to significant symptom resolution was 165 minutes (95% CI 136, 167) for ecallantide versus >4 hours (95% CI 161, >4 hours) for placebo. Anaphylactic reactions occurred in 6 of the 149 treated patients.ConclusionsHAE should be considered in the differential diagnosis of patients with recurrent discrete episodes of severe, unexplained crampy abdominal pain associated with nausea.Trials registrationThe data used in the analysis were gathered across multiple clinical trials conducted during the clinical development program for ecallantide. All of the studies were conducted using Good Clinical Practices (GCP) and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Each site that participated in the clinical trials obtained the appropriate IRB or Ethics Committee approval prior to enrolling any patients. All patients provided written informed consent prior to undergoing any study-related procedures. Pediatric patients provided written assent and their parents or guardians gave written informed consent.The following trials have been registered at http://www.clinicaltrials.gov: EDEMA2 (identifier NCT01826916); EDEMA3 (identifier NCT00262080); EDEMA4 (identifier NCT00457015); and DX-88/19 (identifier NCT00456508).

Project description:Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA) are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T). Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444) or group 2 (missense, excluding mutations at Arg444). Significant differences were found in the clinical severity score (P = 0.005), prevalence of laryngeal (P = 0.040) and facial (P = 0.013) oedema, and long-term prophylaxis (P = 0.023) between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038). Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a clear effect on C1-INH function might be responsible for a more severe disease phenotype.

Project description:BackgroundHereditary 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 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).ObjectiveWe sought to investigate the enzymatic activity and biological functions of sPLA2 in patients with C1-INH-HAE.MethodssPLA2s 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.ResultsPlasma sPLA2 activity and hGIIA levels are increased in symptom-free C1-INH-HAE patients compared with 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.ConclusionsPLA2 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.

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458?Differences of Complement Activation Profile between Type I and Type II of Hereditary Angioedema Due to C1-inhibitor Deficiency.

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