Presentation is loading. Please wait.

Presentation is loading. Please wait.

Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond  Angelo Agostoni,

Published byJohan Hermanto Modified over 5 years ago

Similar presentations

Presentation on theme: "Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond  Angelo Agostoni,"— Presentation transcript:

1 Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond  Angelo Agostoni, MD, Emel Aygören-Pürsün, MD, Karen E. Binkley, MD, FRCPC, Alvaro Blanch, Konrad Bork, MD, Laurence Bouillet, MD, CCA, Christoph Bucher, MD, Anthony J Castaldo, MPA, Marco Cicardi, MD, Alvin E Davis, MD, Caterina De Carolis, MD, Christian Drouet, PhD, Christiane Duponchel, Henriette Farkas, MD, PhD, Kálmán Fáy, MD, Béla Fekete, MD, PhD, DSc, Bettina Fischer, MD, Luigi Fontana, MD, George Füst, MD, PhD, DSc, Roberto Giacomelli, MD, Albrecht Gröner, PhD, C. Erik Hack, MD, PhD, George Harmat, MD, PhD, John Jakenfelds, MD, Mathias Juers, MD, Lajos Kalmár, Pál N. Kaposi, MD, PhD, István Karádi, MD, PhD, DSc, Arianna Kitzinger, Tímea Kollár, MD, Wolfhart Kreuz, MD, PhD, Peter Lakatos, MD, PhD, DSc, Hilary J. Longhurst, MA, MRCP, PhD, MRCPath, Margarita Lopez-Trascasa, MD, PhD, Inmaculada Martinez-Saguer, MD, Nicole Monnier, PhD, István Nagy, Éva Németh, Erik Waage Nielsen, MD, PhD, Jan H. Nuijens, MD, PhD, Caroline O'Grady, RGN, Emanuela Pappalardo, PhD, Vincenzo Penna, Carlo Perricone, Roberto Perricone, MD, Ursula Rauch, Olga Roche, Eva Rusicke, Peter J Späth, PhD, FAMH, George Szendei, MD, Edit Takács, MD, Attila Tordai, MD, PhD, Lennart Truedsson, MD, PhD, Lilian Varga, PhD, Beáta Visy, MD, Kayla Williams, BS, MA, MFA, Andrea Zanichelli, Lorenza Zingale, MD  Journal of Allergy and Clinical Immunology  Volume 114, Issue 3, Pages S51-S131 (September 2004) DOI: /j.jaci Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

2 Fig 1 Facial edema. Photo: Dermatologische Klinik, Universitätsspital Zurich, Switzerland. Brunello Wüthrich, MD. Reprinted with permission from Swiss Medical Weekly.43a Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

3 Fig 2 Penile edema. Photo credit: Dr. Martin Ludovic.
Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

4 Fig 3 Various erythematous rashes preceding or accompanying angioedema episodes. A1, Facial erythema marginatum; A2, close view. Photo credit: Brunello Wüthrich, MD. Reprinted with permission from Swiss Medical Weekly.43a B1, Mottling on chest; B2, close view. Photo credit: George Harmat, MD. Reprinted with permission from Acta Dermato-Venereologica.46 Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

5 Fig 4 Sagittal sonogram during an abdominal HAE attack. A significant amount of fluid can be seen in the pouch of Douglas, with a swollen intestinal loop visible (arrow) floating in the free fluid. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

6 Fig 5 Transverse sonogram during an abdominal HAE attack, showing bowel and pancreas. Longitudinal section of a swollen bowel: the intestinal wall is edematously thickened (arrows); in addition, the reflectivity of the pancreas is increased. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

7 Fig 6 Sonogram during an abdominal attack of HAE, showing kidney and spleen. Section of a thickened intestinal wall (large arrow) and a small amount of fluid (small arrow) between the left kidney and the spleen. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

8 Fig 7 Sagittal and transverse sonograms during an HAE attack before and after treatment. Sagittal sections are shown above, transverse below. A, A large amount of free peritoneal fluid has accumulated in the pouch of Douglas and, in the sagittal section, a floating intestinal loop is visible. The urinary bladder appears below. B, Soon after treatment with C1-INH concentrate, the amount of peritoneal fluid is somewhat decreased. C, Only a minimal amount of fluid is present in the pouch of Douglas 24 hours after C1-INH treatment. Several sonograms have previously been published in slightly different format.78,81 Transverse panels B and C reprinted with permission from Acta Paediatrica.81 Sagittal panels A-C reprinted with permission from the European Journal of Gastroenterology and Hepatology.78 Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

9 Fig 8 Transverse sonogram during an abdominal HAE attack: liver and pancreas. Increased hepatic reflection (starry sky liver) and thickened, echogenic portal veins (arrow); the pancreatic region is also hyperechoic (double arrows). Reprinted with permission from Acta Paediatrica.81 Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

10 Fig 9 Transverse sonogram during an abdominal HAE attack: liver and cholecyst. Because of edematous swelling, the wall of the cholecyst is hyperechoic (large arrow) and the small portal veins are also more echogenic (small arrows) in contrast with the liver's overall decrease in echogenicity. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

11 Fig 10 Structure of C1NH gene.85,153 Arrowheads represent Alu elements.150 The positions of the 4 polymorphic sites are indicated by elongated arrows. Nucleotide numbers refer to the C1NH gene, with number 1 denoting the first nucleotide of exon 1. Accession number X54486. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

12 Fig 11 Mutation analysis of the C1NH gene by DHPLC showing data with insertion, point mutation, and deletion. Red and black profiles correspond to patient and control samples, respectively. A, A 10-nucleotide insertion in exon 3 causes the presence of heteroduplexes before and after normal homoduplex. B, A point mutation (A → G) in exon 4 causes the presence of heteroduplexes in close vicinity to a normal homoduplex. C, A 5-nucleotide deletion in exon 5 causes the presence of heteroduplexes before normal homoduplex. Drouet et al, Unpublished data, August 2003. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

13 Fig 12 Analysis of C1NH gene mutations by SSCA. A, SSCA of fragment including part of exon 3; lanes 1, 2, 4 HAE kindreds without mutations in this fragment; lane 3, mutation delAG [R18fsX33]. B, SSCA of fragment including part of exon 3; lane 1, healthy control; lanes 3, 4, HAE kindreds without mutations in this fragment; lane 2, mutation in exon 3: T2650C [F147S]. C, SSCA of fragment including exon 6; lanes 1, 3, 4, HAE kindreds without mutations in exon 6; lane 2, exon 6 mutation: C8823G [Y308Stop]. Lopez-Trascasa et al, Unpublished data, June 2003. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

14 Fig 13 Southern blot analysis of patients with HAE-I carrying rearrangements in the C1NH gene. The outer lanes (N) contain control DNA of unaffected individuals and flank different heterozygous deletions/duplications. BclI-digested DNA was hybridized with a full-length cDNA probe. The 20-kb BclI fragment contains the 8 exons of the C1NH gene. Data from Stoppa-Lyonnet et al.150 Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

15 Fig 14 Quantitative fluorescence multiplex analysis: exon-specific multiplex PCR results for exons 3, 4, 5, 7, and 8 from C1NH and a control exon from BRCA1. Red and blue profiles correspond to the patient and control samples, respectively. Deletions of exons 3 and 4 (A), duplication of exon 4 (B), deletion of exon 8 (C), and deletion of exon 4 (D) are clearly visible. ex, Exon. Modified from Duponchel et al.182 Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

16 Fig 15 Decision algorithm for mutation analyses of the C1NH gene. This algorithm takes into account the importance of mutations in the coding sequence and in the introns, and the abundance of rearrangements. Depending on the methods used, a preliminary screening of rearrangements may be preferred. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

17 Fig 16 α-1-Antitrypsin tertiary structure conserved among the serpin family α-1-antitrypsin is composed of 3 β-sheets (A in red, B in green, and C in yellow) and 9 α-helices (A-I in gray). The blue strand is the reactive center loop (RCL) with the P1 active amino acid. Reprinted with permission from Silverman et al.197 Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

18 Fig 17 Different pathways of kinin generation in C1-inhibitor deficiency state. Low C1-inhibitor leads to uncontrolled activation of factor XII, which generates kallikrein and plasmin. Kallikrein liberates bradykinin from HK, whereas plasmin cleaves off C2-kinin from activated C2. Activated C2 is continuously produced during baseline complement activation, which is increased as a result of insufficient control of autoactivation of C1 caused by C1-INH deficiency. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

19 Fig 18 Analysis of vascular permeability. Extravasation of Evans blue dye at 15 to 30 minutes was much more extensive in C1-INH–deficient mice (B) than in wild-type mice (A), particularly after the application of mustard oil to the left ears of the mice. (C) The difference in the amount of extravasation was clearly demonstrated by the rear footpads of mice of each genotype. Administration of human C1-INH resulted in reduced vascular permeability, as did the combination of Bk2R deficiency together with C1-INH deficiency. Reprinted with permission of the American Society for Clinical Investigation.9 Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

20 Fig 19 Spectrophotometric analysis of vascular permeability in the small intestine. Quantitation of extravasated Evans blue dye in C1INH−/− mice treated with an ACE inhibitor (captopril), a Bk1R antagonist (des-Arg9,[Leu8]-bradykinin; Bk1RA), and a Bk2R antagonist (Hoe140). Reprinted with permission of the American Society for Clinical Investigation.9 Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

21 Fig 20 Spectrophotometric analysis of vascular permeability in footpads. Quantitation of Evans blue dye extracted from the paws of mice of the indicated genotypes, either treated or not treated with intravenous C1-INH (C1I), DX-88 (DX), or Hoe140 (Hoe). Reprinted with permission of the American Society for Clinical Investigation.9 Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

22 Fig 21 Pathways for bradykinin generation and metabolism. On the endothelium, bradykinin generation likely initiates independent of factor XII; however, once kallikrein is generated, it soon catalyzes factor XII activation, thus amplifying the response. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

23 Fig 22 Correlation in female patients with HAE between serum progesterone (A) and SHBG concentrations (B) and the number of edematous attacks in the year after blood sampling. Spearman correlation coefficients and their significance (P values) are indicated. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

24 Fig 23 Underlying angioedema disease in 44 women who had induction or exacerbation of recurrent angioedema caused by OCs or HRT. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

25 Fig 24 Assessment of C4 antigen concentration by polyclonal anti-C4 antibodies. Assessment of C4 antigen levels by polyclonal anti-C4 antibodies might serve as a simple follow up parameter for therapy. Upper left and right panels depict C1-INH versus C4 antigen concentrations in 111 plasma samples from 21 patients with HAE-I. In the left panel, the individual C1-INH concentrations are plotted against C4 concentrations in plasma samples from patients with various therapeutic managements. Open square, no therapy; inversed open triangle, therapy with tranexamic acid; closed circle, therapy with danazol; closed triangle, therapy with stanozolol. Open squares and triangles represent samples from patients with current or recent bacterial or viral infections and therapy with danazol or stanozolol. Open squares with a crossing line indicate samples from an asymptomatic woman, a member of a family with concomitant heterozygous C1-INH deficiency and factor I protein gene mutation, herself heterozygous for C1-INH only. In the right panel, the means (±1 SD) of concentration ranges are depicted. The lower left panel indicates clinical manifestation of the C1-INH deficiency in 111 patients with HAE-I: closed circles give C1-INH concentration in plasma collected after an attack, and open circles indicate mean C1-INH concentrations of 2 assessments between which an attack occurred. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

26 Fig 25 Work-up flow sheet for patients with a clinical history of idiopathic or unknown origin abdominal symptoms or angioedema. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

27 Fig 26 Adverse events attributable to HAE or AAE in patients with and without a supply of C1 inhibitor at home. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

28 Fig 27 Effect of long-term danazol treatment on serum concentrations of C4 (A) and C1-INH (B) in children with HAE. Baseline values are compared with those measured in the first serum sample obtained after treatment had been initiated. C4 levels were determined in 8 children. Patients with high concentrations of nonfunctional C1-INH (233, 214, and 297%) were excluded from the comparison. Danazol treatment significantly increased both C4 and C1-INH levels (P=.002 and P=.0156, respectively; Wilcoxon signed-rank test). Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

29 Fig 28 Flow of data in the European HAE Register. PC, Personal computer. Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

30 Fig 29 Window for accessing the European HAE Register.
Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

31 Fig 30 European HAE Register visit form.
Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

32 Fig 31 Hungarian HAE Center patient accrual.
Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

33 Fig 32 Hungarian HAE Center: flow of responsibilities.
Journal of Allergy and Clinical Immunology  , S51-S131DOI: ( /j.jaci ) Copyright © 2004 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Download ppt "Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond  Angelo Agostoni,"

Similar presentations

Case Presentation June 25, 2004 H. Henry Li, MD, PhD Institute for Asthma and Allergy.

Case Presentation June 25, 2004 H. Henry Li, MD, PhD Institute for Asthma and Allergy.
Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond  Angelo Agostoni,

Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond  Angelo Agostoni,
Hereditary angioedema: A decade of human C1-inhibitor concentrate therapy  Henriette Farkas, MD, PhD, DSc, László Jakab, MD, György Temesszentandrási,

Hereditary angioedema: A decade of human C1-inhibitor concentrate therapy  Henriette Farkas, MD, PhD, DSc, László Jakab, MD, György Temesszentandrási,
MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers  Thomas X. Lu,

MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers  Thomas X. Lu,
Treatment of attacks with plasma-derived C1-inhibitor concentrate in pediatric hereditary angioedema patients  Henriette Farkas, MD, PhD, DSc, Dorottya.

Treatment of attacks with plasma-derived C1-inhibitor concentrate in pediatric hereditary angioedema patients  Henriette Farkas, MD, PhD, DSc, Dorottya.
Erika Kajdácsi, MSc, Péter K

Erika Kajdácsi, MSc, Péter K
Cor a 1–reactive T cells and IgE are predominantly cross-reactive to Bet v 1 in patients with birch pollen–associated food allergy to hazelnut  Claudia.

Cor a 1–reactive T cells and IgE are predominantly cross-reactive to Bet v 1 in patients with birch pollen–associated food allergy to hazelnut  Claudia.
Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency  Fleur Bossi, PhD, Fabio Fischetti, MD, Domenico.

Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency  Fleur Bossi, PhD, Fabio Fischetti, MD, Domenico.
Dipeptidyl peptidase IV deficiency increases susceptibility to angiotensin-converting enzyme inhibitor–induced peritracheal edema  James Brian Byrd, MD,

Dipeptidyl peptidase IV deficiency increases susceptibility to angiotensin-converting enzyme inhibitor–induced peritracheal edema  James Brian Byrd, MD,
Centre for Primary Immunodeficiencies, Masaryk University Brno, CR

Centre for Primary Immunodeficiencies, Masaryk University Brno, CR
Exploring the repertoire of IgE-binding self-antigens associated with atopic eczema  Sabine Zeller, MSc, Claudio Rhyner, PhD, Norbert Meyer, MD, Peter.

Exploring the repertoire of IgE-binding self-antigens associated with atopic eczema  Sabine Zeller, MSc, Claudio Rhyner, PhD, Norbert Meyer, MD, Peter.
Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations  Steven de Maat, MSc, Jenny Björkqvist,

Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations  Steven de Maat, MSc, Jenny Björkqvist,
Human nuclear factor κB essential modulator mutation can result in immunodeficiency without ectodermal dysplasia  Jordan S. Orange, MD, PhD, Ofer Levy,

Human nuclear factor κB essential modulator mutation can result in immunodeficiency without ectodermal dysplasia  Jordan S. Orange, MD, PhD, Ofer Levy,
A novel splice variant of FcγRIIa: A risk factor for anaphylaxis in patients with hypogammaglobulinemia  Joris van der Heijden, MSc, Judy Geissler, Edwin.

A novel splice variant of FcγRIIa: A risk factor for anaphylaxis in patients with hypogammaglobulinemia  Joris van der Heijden, MSc, Judy Geissler, Edwin.
Epigenetic mechanisms silence a disintegrin and metalloprotease 33 expression in bronchial epithelial cells  Youwen Yang, PhD, Hans Michael Haitchi, MD,

Epigenetic mechanisms silence a disintegrin and metalloprotease 33 expression in bronchial epithelial cells  Youwen Yang, PhD, Hans Michael Haitchi, MD,
by Cheng-Han Huang, Ying Chen, Marion E. Reid, and Christine Seidl

by Cheng-Han Huang, Ying Chen, Marion E. Reid, and Christine Seidl
Cor a 1–reactive T cells and IgE are predominantly cross-reactive to Bet v 1 in patients with birch pollen–associated food allergy to hazelnut  Claudia.

Cor a 1–reactive T cells and IgE are predominantly cross-reactive to Bet v 1 in patients with birch pollen–associated food allergy to hazelnut  Claudia.
MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers  Thomas X. Lu,

MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers  Thomas X. Lu,
Combined newborn screening for familial hemophagocytic lymphohistiocytosis and severe T- and B-cell immunodeficiencies  Stephan Borte, MD, Marie Meeths,

Combined newborn screening for familial hemophagocytic lymphohistiocytosis and severe T- and B-cell immunodeficiencies  Stephan Borte, MD, Marie Meeths,
Combined DOCK8 and CLEC7A mutations causing immunodeficiency in 3 brothers with diarrhea, eczema, and infections  Darrell L. Dinwiddie, PhD, Stephen F.

Combined DOCK8 and CLEC7A mutations causing immunodeficiency in 3 brothers with diarrhea, eczema, and infections  Darrell L. Dinwiddie, PhD, Stephen F.

Similar presentations

Ads by Google