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

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

A D3-vitamin-szint és a betegség súlyossága közötti kapcsolat vizsgálata herediter angioödémában

Absztrakt: Bevezetés: Az elmúlt évtized során számos közlemény látott napvilágot a D3-vitamin szérumszintje és különböző, részben immunpatomechanizmusú kórképek előfordulási gyakorisága, aktivitása közötti összefüggések elemzéséről. Célkitűzés: Korrelációt kerestünk a C1-inhibitor deficientiájában kialakuló herediter angioödémában szenvedő betegeink angioödémás rohamainak száma, lokalizációja és a felhasznált C1-inhibitor-pótlás mennyisége, valamint D-vitamin-szintjük között. Módszer: Az Országos Angioödéma Referencia Központban 2013–2014-ben gondozott 175, C1-inhibitor-deficientia következtében kialakuló herediter angioödémában szenvedő beteg közül 118 beteg D3-vitamin-szintjét határoztuk meg a téli–tavaszi (111 fő) és a nyári–őszi időszakban (105 fő). A komplement laboratóriumi eredmények és klinikai adatok az Országos Angioödéma Regiszterből és a betegnaplókból származtak. Eredmények: Betegeink mintegy 59,5%-a a téli–tavaszi időszakban, 27,6%-a a nyári–őszi időszakban, 23,5%-a pedig mindkét szezonban a D3-vitamin-hiányos csoportba (D3-vitamin-szint <20 ng/ml) tartozott. A téli–tavaszi és nyári–őszi D3-vitamin-szintek között szignifikáns különbséget találtunk (p<0,0001). A két időszakban az angioödémás rohamok akut kezelésére felhasznált C1-inhibitor-koncentrátum-ampullák száma között szignifikáns különbséget észleltünk (p = 0,01). A D3-vitamin-szint, valamint az adott időperiódusban elszenvedett rohamszám és a felhasznált C1-inhibitor-koncentrátum-ampullák száma között korrelációt egyik szezonban sem találtunk. Következtetések: Bár eddigi eredményeink alapján a herediter angioödémás betegek D3-vitamin-szintje és az elszenvedett angioödémás rohamok gyakorisága, lokalizációja között összefüggést kimutatni nem lehetett, a téli–tavaszi időszakban mégis nagyobb igény mutatkozott a rohamok kezelésére (több ampulla fogyott). Mivel betegeink körében a vártnál is gyakoribb D3-vitamin-hiányt találtunk, ez mindenképpen vitaminpótlást indokol. Orv Hetil. 2019; 160(25): 987–993. | Abstract: Introduction: In recent years, many papers analyzed the relationship between serum vitamin D3 level and the frequency and activity of various diseases at least partially attributed to immune mechanisms. Aim: We looked for correlations among the number and location of edematous episodes occurring in patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) and the quantity of the C1-inhibitor used for supplementation as well as the vitamin D3 levels of patients. Method: We measured vitamin D3 levels in 118 of the 175 C1-INH-HAE patients of the National Angioedema Reference Center during the winter–spring (n = 111) and the summer–autumn periods (n = 105) in 2013–2014. Complement levels and clinical data were extracted from the National Angioedema Registry and from patient diaries. Results: The proportion of vitamin D3 deficient patients (serum level <20 ng/ml) was approximately 59.5% during winter–spring, 27.6% in summer–autumn, and 23.5% during both periods. There was a significant difference between vitamin D3 serum levels measured in the winter–spring or in the summer–autumn months (p<0.0001). The same applies to the number of the vials of C1-inhibitor concentrate administered as acute treatment for angioedema attacks (p = 0.01). In any season, vitamin D3 level did not correlate with the number of attacks experienced by the patients during the given period or of the vials of C1-inhibitor concentrate administered. Conclusions: We could not demonstrate a relationship between vitamin D3 level and the frequency or location of edematous episodes in HAE patients. The need for treatment (as reflected by the number of the vials administered) was higher in the winter–spring period. As vitamin D3 deficiency was more severe than expected in our patients, supplementation is clearly necessary. Orv Hetil. 2019; 160(25): 987–993

Comprehensive study into the activation of the plasma enzyme systems during attacks of hereditary angioedema due to C1-inhibitor deficiency.

BACKGROUND: The activation of plasma enzyme systems contributes to hereditary angioedema attacks. We aimed to study the activation markers of the fibrinolytic, coagulation, and contact systems in a larger number of paired samples obtained from the same C1-INH-HAE patients in symptom-free periods and during attacks. METHODS: Eleven parameters (Factors XI, XII, and C1-inhibitor activity; the concentrations of the D-dimer, prothrombin fragments 1 + 2, plasminogen, plasminogen activator inhibitor-1 [PAI-1], thrombin-anti-thrombin III [TAT] complex, fibrinogen) were measured along with prothrombin time and activated partial thromboplastin time (aPTT), using commercial kits. We compared these markers in samples obtained from the same 39 patients during attack-free periods and during 62 edematous episodes. Forty healthy subjects of matching sex and age served as controls. RESULTS: Compared with the healthy controls, significantly higher FXI and FXII activity (p = 0.0007, p = 0.005), as well as D-dimer (p < 0.0001), prothrombin fragments 1 + 2 (p < 0.0001), and TAT (p = 0.0303) levels were ascertained in the patients during symptom-free periods. The evaluation of samples from symptom-free periods or obtained during attacks revealed the increase of FXII activity, as well as of the concentration of D-dimer, prothrombin fragments 1 + 2, and TAT during edematous episodes. PAI-1 level, prothrombin time, and aPTT decreased significantly during attacks, compared with symptom-free periods. D-dimer level was significantly higher during multiple- vs. single-site attacks. CONCLUSIONS: Comparing a large number of paired samples from symptom-free periods or from edematous episodes allowed accurate appraisal of the changes occurring during attacks. Moreover, our study pointed out that individual episodes may be characterized by different marker patterns

hereditary angioedema attack what happens to vasoactive mediators

Abstract Hereditary angioedema is a disabling, life-threatening condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) leading to bradykinin accumulation and recurrent episodes of edema attack. Vascular leakage is a complex process sustained by the coordinated production of several permeabilizing factors including vascular endothelial growth factors (VEGFs), angiopoietins (ANGPTs) and phospholipase A2 enzymes (PLA2). We previously reported that patients with C1-INH-HAE in remission have increased plasma levels of VEGFs, ANGPTs and secreted PLA2. In this study, we sought to analyze plasma levels of these mediators in 15 patients with C1-INH-HAE during the acute attack compared to remission. Plasma concentrations of VEGF-A, VEGF-C and VEGF-D were not altered during attack compared to remission. Moreover, VEGF-D concentrations were not altered also in remission phase compared to controls. Concentrations of ANGPT1, a vascular stabilizer, were increased during attacks compared to symptoms-free periods, whereas ANGPT2 levels were not altered. The ANGPT2/ANGPT1 ratio was decreased during angioedema attacks. Platelet activating factor acetylhydrolase activity was increased in patients with C1-INH-HAE in remission compared to controls and was decreased during angioedema attacks. Our results emphasize the complexity by which several vasoactive mediators are involved not only in the pathophysiology of C1-INH-HAE, but also during angioedema attacks and its resolution

FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy

Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data.A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR).Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters.Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G

Secreted phospholipases A2 in hereditary angioedema with C1-inhibitor deficiency

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

Complement genetic variants and FH desialylation in S. pneumoniae-Haemolytic Uraemic Syndrome

15 p.-8 fig.-3 tab.Haemolytic Uraemic Syndrome associated with Streptococcus pneumoniae infections (SP-HUS) is a clinically well-known entity that generally affects infants, and could have a worse prognosis than HUS associated to E. coli infections. It has been assumed that complement genetic variants associated with primary atypical HUS cases (aHUS) do not contribute to SP-HUS, which is solely attributed to the action of the pneumococcal neuraminidase on the host cellular surfaces. We previously identified complement pathogenic variants and risk polymorphisms in a few Hungarian SP-HUS patients, and have now extended these studies to a cohort of 13 Spanish SP-HUS patients. Five patients presented rare complement variants of unknown significance, but the frequency of the risk haplotypes in the CFH-CFHR3-CFHR1 region was similar to the observed in aHUS. Moreover, we observed desialylation of Factor H (FH) and the FH-Related proteins in plasma samples from 2 Spanish and 4 Hungarian SP-HUS patients. To analyze the functional relevance of this finding, we compared the ability of native and “in vitro” desialylated FH in: (a) binding to C3b-coated microtiter plates; (b) proteolysis of fluid-phase and surface-bound C3b by Factor I; (c) dissociation of surface bound-C3bBb convertase; (d) haemolytic assays on sheep erythrocytes. We found that desialylated FH had reduced capacity to control complement activation on sheep erythrocytes, suggesting a role for FH sialic acids on binding to cellular surfaces. We conclude that aHUS-risk variants in the CFH-CFHR3-CFHR1 region could also contribute to disease-predisposition to SP-HUS, and that transient desialylation of complement FH by the pneumococcal neuraminidase may have a role in disease pathogenesis.This study was funded by the Spanish Instituto de Salud Carlos III (ISCIII) and the European Regional Development Fund from the European Union (grants PI16/00723 and PI19/00970 to PS-C). IG and EA are supported by the Spanish Autonomous Region of Madrid (Complement II-CM network; S2017/BMD-3673). IG was also supported by the Spanish Fundación Senefro (http://www.senefro.org/). The study was also supported by the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the molecular biology thematic programme of the Semmelweis University, by the National Office for Innovation and Research (KH130355 to ZP), and by the MSCA-ITN (Horizon 2020) CORVOS (Grant 860044 to ZP). DC was supported by the Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences (PPD2018-016/2018).Peer reviewe

Frequency of the virilising effects of attenuated androgens reported by women with hereditary angioedema.

BACKGROUND: Danazol, a drug extensively used in the management of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), has various side effects. This study investigated the virilizing actions of this drug in 31 danazol-treated female patients with HAE-C1-INH. We compared our findings with those of healthy controls and with literature data. METHODS: The patients were interviewed individually about the type and severity of the virilizing effects, as well as about their satisfaction with danazol therapy. RESULTS: The average duration of danazol treatment was 10.31 years [2 to 23] and its mean daily dose was 131.7 mg [33 to 200]. The most common adverse effects were hirsutism (n = 14), weight gain (n = 13), and menstrual disturbances (n = 8). The severity of danazol adverse effects did not differ by duration of treatment or by daily drug dose. The mean level of patient satisfaction with the treatment was high. The comparison of age-matched healthy controls and of HAE-C1-INH patients receiving danazol did not demonstrate a statistically higher incidence of any of the monitored symptoms in the danazol group. CONCLUSIONS: Our findings indicate that long-term danazol treatment – using the lowest effective dose – has only a mild virilizing effect