Ecallantide is a novel treatment for attacks of hereditary angioedema due to C1 inhibitor deficiency

Hereditary angioedema (HAE) resulting from the deficiency of the C1 inhibitor protein is a rare disease, characterized by paroxysms of edema formation in the subcutis and in the submucosa. Edema can cause obstruction of the upper airway, which may lead to suffocation. Prompt elimination of edema is necessary to save patients from this life-threatening condition. Essentially, these edematous attacks are related to the activation of the kinin-kallikrein system and the consequent release of bradykinin. Ecallantide (known as DX-88 previously), a potent and specific inhibitor of plasma kallikrein is an innovative medicinal product. This is the only agent approved recently by the FDA for all localizations of edematous HAE attacks. Its advantages include no risk of viral contamination, high selectivity, very rapid onset of action, good tolerability, and straightforward subcutaneous administration. Owing to the risk of anaphylaxis, ecallantide should be administered by a health care professional. A postmarketing survey to improve risk-assessment and risk-minimization has been launched. The results of these studies may lead to the approval of ecallantide for self-administration

Diagnosis and Treatment of Bradykinin-Mediated Angioedema: Outcomes from an Angioedema Expert Consensus Meeting

Several types of angioedema exist beyond hereditary angioedema (HAE) types I/II; however, the diagnostic and treatment needs of these conditions are not well understood. Noticeably, there are no licensed treatments available for other forms of angioedema beyond HAE types I/II, and similarly they are unresponsive to conventional antihistamine/glucocorticoid treatment. A group of angioedema experts met in Budapest in May 2013 to discuss such issues, presenting their experience, reviewing available literature and identifying unmet diagnostic and treatment needs in three different angioedema types: HAE with normal C1-inhibitor (C1-INH; previously referred to as type III HAE); nonallergic angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema (ACEI-AAE), and acquired angioedema due to C1-INH deficiency (C1-INH-AAE). The group identified unmet diagnostic and treatment needs in HAE-nC1-INH, C1-INH-AAE and ACEI-AAE, explored remedies and made recommendations on how to diagnose and treat these forms of angioedema. The group discussed the difficulties associated with using diagnostic markers, such as the level and function of C1-INH, C1q and C4 to reliably diagnose the angioedema type, and considered the use of genetic testing to identify mutations in FXII or XPNPEP2 that have been associated with HAE-nC1-INH and ACEI-AAE, respectively. Due to the lack of approved treatments for HAE-nC1-INH, ACEI-AAE and C1-INH-AAE, the group presented several case studies in which therapies approved for treatment of HAE types I/II, such as icatibant, ecallantide and pasteurized, nanofiltered C1-INH, were successful. It was uniformly agreed that further studies are needed to improve the diagnosis and treatment of angioedema other than HAE types I/II. (c) 2014 S. Karger AG, Basel

A danazolkezelés hatása C1-inhibitor-hiány okozta hereditaer angiooedemás gyermekek növekedésére

Absztrakt: Bevezetés: Az attenuált androgéneket gyakran alkalmazzák C1-inhibitor-hiányos hereditaer angiooedema akut epizódjainak megelőzésére. Praepubertason túli alkalmazásuk az epifízisfugák korai záródásához, ezáltal növekedés-visszamaradáshoz vezethet. Célkitűzés: A danazol hereditaer angiooedemás gyermekek hossznövekedésére kifejtett hatásának felmérése. Módszer: Retrospektív tanulmányunk negyvenkettő, 21 évesnél idősebb hereditaer angiooedemás beteg adatait elemezte. A betegek esetében meghatároztuk a várható testmagasságtól való eltérést, majd azt a betegek neme, valamint a 21 éves kor előtt végzett danazolkezelés összdózisa és időtartama függvényében elemeztük. Danazollal 16 éves kora előtt kezelt betegek esetében összefüggést kerestünk a várható testmagasságtól való eltérés, valamint a kezelés időtartama, illetve kumulatív dózisa között. Eredmények: Nem találtunk szignifikáns különbséget a várható testmagasságtól való eltérésben danazolt szedő/nem szedő, illetve fiú és leány betegek között. Ezt a különbséget a danazol dózisa és alkalmazásának időtartama 16 vagy 21 évesnél fiatalabb korban végzett kezelés esetén sem befolyásolta. Következtetések: A danazol a minimális hatékony dózisban alkalmazva nem befolyásolta a növekedést. Orv Hetil. 2017; 158(32): 1269–1276. | Abstract: Introduction: Attenuated androgens are used for the prevention of angioedema attacks of hereditary angioedema with C1-inhibitor deficiency. After prepuberty, their use can lead to growth retardation. Aim: We assessed the effect of danazol on the growth of pediatric patients with hereditary angioedema. Method: In the retrospective study on 42 patients diagnosed with hereditary angioedema, we calculated the deviation from the mid-parental target height, and analyzed it against the gender, the dose and duration of danazol treatment administered before the age of 21 years and before the age of 16 years. Results: Regarding the deviation from the mid-parental target height, we did not find any significant difference between patients taking vs. not taking danazol, males vs. females taking danazol. The dose and the duration of danazol treatment did not influence that value neither before 21, nor before 16 years of age. Conclusions: Our findings suggest that treatment with the lowest effective doses of danazol does not influence growth. Orv Hetil. 2017; 158(32): 1269–1276

The influence of trigger factors on hereditary angioedema due to C1-inhibitor deficiency

Background: Hereditary angioedema (HAE) resulting from C1-inhibitor deficiency is characterized by attacks of subcutaneous and submucosal edema. Many factors have been presumed to induce edema. Our study analyzed these factors in a fairly large patient population. Methods. In the first stage of our study, we analyzed the data recorded by 92 subjects in their patient diaries over seven years. The second phase included 27 HAE patients, who had been completing the diary entry 'Trigger factors' every day for seven months whether or not they had experienced an attack. Results: During the initial stage, 91% of the subjects described some factor possibly related to the onset of an attack. They could identify a trigger factor - most commonly (21%) mental stress - in 30% of the 3176 attacks. We found a significant (p < 0.001) difference in the distribution of the trigger factors of the edematous attacks of different locations. The 27 participants of the second phase identified 882 potential trigger factors and recorded 365 attacks. Of these, 246 (67%) occurred on days when the patients identified a potential trigger factor. The likelihood of edema-formation associated with the latter was as follows: menstruation - 63%, infection - 38%, mental stress - 26%, physical exertion - 25%, meteorological changes - 21%, fatigue - 17%. Conclusion: This analysis of the trigger factors explored, for the first time, their potential role in inducing HAE attacks. Our findings might open new perspectives in extending the indications for edema-prophylaxis, and could contribute to a better understanding of the pathomechanism of HAE attacks. © 2014Zotter et al.; licensee BioMed Central Ltd

Serum fetuin-A, tumor necrosis factor alpha and C-reactive protein concentrations in patients with hereditary angioedema with C1-inhibitor deficiency

Abstract Background and aims Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is characterized by localized, non-pitting, and transient swelling of submucosal or subcutaneous region. Human fetuin-A is a multifunctional glycoprotein that belongs to the proteinase inhibitor cystatin superfamily and has structural similarities to the high molecular weight kininogen. Fetuin-A is also known a negative acute phase reactant with anti-inflammatory characteristics. In this study we aimed to determine serum fetuin-A, C-reactive protein (CRP) and tumor necrosis factor alpha (TNFα) concentrations in patients with C1-INH-HAE during symptom-free period and during attacks and compare them to those of healthy controls. Further we analyzed possible relationship among these parameters as well as D-dimer levels which was known as marker of HAE attacks. Patients and methods Serum samples of 25 C1-INH-HAE patients (8 men, 17 women, age: 33.1 ± 6.9 years, mean ± SD) were compared to 25 healthy controls (15 men, 10 women, age: 32.5 ± 7.8 years). Serum fetuin-A and TNFα concentrations were determined by ELISA, CRP and D-dimer by turbidimetry. Results Compared to healthy controls patients with C1-INH-HAE in the symptom-free period had significantly decreased serum fetuin-A 258 μg/ml (224–285) vs. 293 μg/ml (263–329), (median (25–75% percentiles, p = 0.035) and TNFα 2.53 ng/ml (1.70–2.83) vs. 3.47 ng/ml (2.92–4.18, p = 0.0008) concentrations. During HAE attacks fetuin-A levels increased from 258 (224–285) μg/ml to 287 (261–317) μg/ml (p = 0.021). TNFα and CRP levels did not change significantly. We found no significant correlation among fetuin-A CRP, TNFα and D-dimer levels in any of these three groups. Conclusions Patients with C1-INH-HAE have decreased serum fetuin-A concentrations during the symptom-free period. Given the anti-inflammatory properties of fetuin-A, the increase of its levels may contribute to the counter-regulation of edema formation during C1-INH-HAE attacks

Infektív, genetikai és complement aktivációs tényezők szerepének vizsgálata az autoimmun betegségek patogenezisében = Investigation of the role of infective, genetic and complement activation factor in the pathogenesis of autoimmune disorders

Az MBL2 gén polimorfizmusa az SLE kialakulásának rizikó faktora. 315 SLE-s betegben és 182 kontrollban az MBL2 polimorfizmust vizsgáltuk. Kimutattuk, hogy az MBL2 polimorfizmusában a homozigóta SLE-s betegekben szignifikánsan fiatalabb életkorban (p=0,017) kezdődik a betegség. XA/XA homozigótákban a fiatalkorban kezdődő SLE (≤20 év) előfordulási gyakorisága különösen magas volt és gyakrabban lehetett igazolni a bőr manifesztációk (p=0,003) és a pleuritis/pericarditis (p=0,013) kialakulását. A Parvovírus B19 (PVB19) elleni antitestek szerepét vizsgáltuk felnőttkori SLE-ben. 76 beteg szérumában kimutattuk, hogy a PVB19-IgM és/vagy ?IgG antitest pozitivitás szignifikánsan gyakoribb a 30 év feletti SLE-ekben (p=0,003). 95 I-es és II-es típusú herediter angioneurotikus oedemas (HANO) betegen vizsgáltuk meg a C1-inhibitor autoantitestek (C1-INH-At) előfordulási gyakoriságát. Emelkedett IgM típusú C1-INH-At-eket találtunk a HANO-s betegek 31 %-ban (p<0,001). 217 HANO-s beteg adatait dolgoztuk fel a Helicobacter pylori (H. pylori) eradikáció szerepének tisztázására a rohamok megelőzésében. A sikeres eradikáció szignifikánsan csökkentette a hasi rohamok számát (p=0,006). 95 betegben igazoltuk, hogy a szérum antikoleszterin-antitest szintek szignifikánsan magasabbak HANO-ban, mint a 246 kontrollban (p<0,0001). | The polymorphism of the MBL2 gene is a risk factor for the development of SLE. We investigated the MBL2 polymorphisms in 315 SLE patients and 182 controls. Within the group of patients, we found that homozygotes for an MBL2 promoter polymorphism were significantly (p=0.017) younger at diagnosis than the other patients. The frequency of juvenile-onset SLE was high among XA/XA homozygotes (≤20 years) (17,4%) (p=0.004), as well as the development of cutan manifestations (p=0.003) and pleuritis/pericarditis (p=0.013). The role of antibodies was investigated against Parvovirus B19 in patients with adult onset SLE. We found higher anti-PVB19-IgM and/or ?IgG antibody titers in patients older than 30 years (p=0.003) in 76 serum samples of SLE. Serum samples were taken and tested for C1-INH-Abs from 95 patients with type I or II hereditary angioedema (HAE) and 54 individuals. Elevated IgM C1-INH-Abs levels were found in 31% of HAE patients (p<0.001). 217 patients were studied to detect any relationship between H. pylori infection and the occurrence of abdominal attacks in HAE patients. Successful eradication of H. pylori significantly (p=0.0006) reduced the number of abdominal attacks. Serum IgG type anticholesterin-antibody levels were higher in 95 of HAE patients, compared to 246 controls (p<0,0001)

Assessment of inhibitory antibodies in patients with hereditary angioedema treated with plasma-derived C1 inhibitor

Background Limited data are available regarding C1 inhibitor (C1-INH) administration and anti–C1-INH antibodies. Objective To assess the incidence of antibody formation during treatment with pasteurized, nanofiltered plasma-derived C1-INH (pnfC1-INH) in patients with hereditary angioedema with C1-INH deficiency (C1-INH-HAE) and the comparative efficacy of pnfC1-INH in patients with and without antibodies. Methods In this multicenter, open-label study, patients with C1-INH-HAE (≥12 years of age) were given 20 IU/kg of pnfC1-INH per HAE attack that required treatment and followed up for 9 months. Blood samples were taken at baseline (day of first attack) and months 3, 6, and 9 and analyzed for inhibitory anti–C1-INH antibody (iC1-INH-Ab) and noninhibitory anti–C1-INH antibodies (niC1-INH-Abs). Results The study included 46 patients (69.6% female; mean age, 38.9 years; all white) who received 221 on-site pnfC1-INH infusions; most patients received 6 or fewer infusions. No patient tested positive (titer ≥1:50) for iC1-INH-Ab at any time during the study. Thirteen patients (28.2%) had detectable niC1-INH-Abs in 1 or more samples. Nine patients (19.6%) had detectable niC1-INH-Abs at baseline; 3 of these had no detectable antibodies after baseline. Of 10 patients (21.7%) with 1 or more detectable result for niC1-INH-Abs after baseline, 6 had detectable niC1-INH-Abs at baseline. Mean times to symptom relief onset and complete symptom resolution per patient were similar for those with or without anti–niC1-INH-Abs. Conclusion Administration of pnfC1-INH was not associated with iC1-INH-Ab formation in this population. Noninhibitory antibodies were detected in some patients but fluctuated during the study independently of pnfC1-INH administration and appeared to have no effect on pnfC1-INH efficacy

WAO guideline for the management of hereditary angioedema

Hereditary Angioedema (HAE) is a rare disease and for this reason proper diagnosis and appropriate therapy are often unknown or not available for physicians and other health care providers. For this reason we convened a group of specialists that focus upon HAE from around the world to develop not only a consensus on diagnosis and management of HAE, but to also provide evidence based grades, strength of evidence and classification for the consensus. Since both consensus and evidence grading were adhered to the document meets criteria as a guideline. The outcome of the guideline is to improve diagnosis and management of patients with HAE throughout the world and to help initiate uniform care and availability of therapies to all with the diagnosis no matter where the residence of the individual with HAE exists

Pectic homogalacturonan masks abundant sets of xyloglucan epitopes in plant cell walls

<p>Abstract</p> <p>Background</p> <p>Molecular probes are required to detect cell wall polymers <it>in-situ </it>to aid understanding of their cell biology and several studies have shown that cell wall epitopes have restricted occurrences across sections of plant organs indicating that cell wall structure is highly developmentally regulated. Xyloglucan is the major hemicellulose or cross-linking glycan of the primary cell walls of dicotyledons although little is known of its occurrence or functions in relation to cell development and cell wall microstructure.</p> <p>Results</p> <p>Using a neoglycoprotein approach, in which a XXXG heptasaccharide of tamarind seed xyloglucan was coupled to BSA to produce an immunogen, we have generated a rat monoclonal antibody (designated LM15) to the XXXG structural motif of xyloglucans. The specificity of LM15 has been confirmed by the analysis of LM15 binding using glycan microarrays and oligosaccharide hapten inhibition of binding studies. The use of LM15 for the analysis of xyloglucan in the cell walls of tamarind and nasturtium seeds, in which xyloglucan occurs as a storage polysaccharide, indicated that the LM15 xyloglucan epitope occurs throughout the thickened cell walls of the tamarind seed and in the outer regions, adjacent to middle lamellae, of the thickened cell walls of the nasturtium seed. Immunofluorescence analysis of LM15 binding to sections of tobacco and pea stem internodes indicated that the xyloglucan epitope was restricted to a few cell types in these organs. Enzymatic removal of pectic homogalacturonan from equivalent sections resulted in the abundant detection of distinct patterns of the LM15 xyloglucan epitope across these organs and a diversity of occurrences in relation to the cell wall microstructure of a range of cell types.</p> <p>Conclusion</p> <p>These observations support ideas that xyloglucan is associated with pectin in plant cell walls. They also indicate that documented patterns of cell wall epitopes in relation to cell development and cell differentiation may need to be re-considered in relation to the potential masking of cell wall epitopes by other cell wall components.</p