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`Page 1 of 84
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`CSL EXHIBIT 1069
`CSL v. Shire
`
`CSL EXHIBIT 1069
`CSL v. Shire
`
`Page 1 of 84
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`

`

`6th C1 Inhibitor Deficiency Workshop
`Budapest 22-24 May 2009
`
`
`Organized by
`• European C1-INH Deficiency Working Group
`International Patient Organization
`•
`for C1 Inhibitor Deficiencies
`• Hungarian Society for Immunology
`• Foundation for the Prevention and Treatment of Fatal
`Angio-oedematous Diseases
`• Welcome to Hungaria
`
`Patron of the event
`István Karádi M.D., D.Sc., Ph.D.
`DEAN OF THE FACULTY OF MEDICINE,
`SEMMELWEIS UNIVERSITY BUDAPEST
`
`Scientific Program Committee
`Angelo Agostoni
`Tom Bowen
`Konrad Bork
`George Füst
`Marco Cicardi
`Teresa Caballero
`Cristian Drouet
`Henriette Farkas
`Michael Frank
`Peter Späth
`Bruce Zuraw
`
`Workshop Organizing Committee
`George Füst (president) Éva Németh
`Henriette Farkas (secretary) Ibolya Czaller
`Lilian Varga (secretary) Judit Gács
`George Harmat (secretary) Zsuzsanna Kelemen
`Gábor Széplaki Katalin Kristóf
`Beáta Visy Dorottya Csuka
`
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`Congress Secretariat
`Henriette Farkas
`Lilian Varga
`Semmelweis University, Kútvölgyi Clinical Centre,
`3rd Department of Internal Medicine
`Address: H-1125 Budapest, Kútvölgyi út 4., Hungary
`Phone:
`(36 1) 325 1481
`Fax:
`(36 1) 225 3899
`e-mail: haenet@haenet.hu
`
`Venue & dates
`The 6th C1 Inhibitor Deficiency Workshop will take place at:
`
`Europa Congress Center Budapest, (Hungary)
`between 22 and 24 May, 2009
`
`Phone:
`
`Address:
`
`ECC Hungary Budapest
`H-1021 Budapest, Hárshegyi utca 5-7.
`Szabó Orsolya
`(36 1) 391 5153
`(36 1) 391 5171
`Fax:
`szabo.ecc@t-online.hu
`e-mail:
`Website: www.ecc-hunguesthotels.hu
`
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`Dear Friends,
`I would like to extend our very cordial welcome to every par-
`ticipant of the Sixth C1 Inhibitor Deficiency Workshop.
`The purpose of this event is to establish a forum for presenting
`novel findings, which might enhance the screening and diag-
`nostic work-up of patients with C1 inhibitor deficiency, offer
`improved solutions for their management, as well as contribute
`to improving the quality of their lives. As with other uncom-
`mon disorders, it is important to epitomize regional expe-
`rience, to discuss diverse concepts, and to develop consensus
`recommendations.
`Additionally, this is an occasion for rejoicing over the progress
`made. The pioneering conference of a small community of
`European experts, held a decade ago, has evolved into a large-
`scale event attracting worldwide interest. Nowadays, col-
`leagues regularly attend from the USA, Canada, Argentina,
`and China. Moreover, it is a pleasure to greet first-time dele-
`gates from Brazil, South Africa, Greece, and Turkey – these
`countries we might consider „uncharted land” as regards their
`challenges and achievements in the field of hereditary angioe-
`dema.
`The scientific program of the Workshop offers a variety of
`novelties in diagnostics, pathomechanism, and research into
`the improvement of therapeutic modalities. Experience with
`the use of approved pharmaceutical agents – and what is more,
`of investigational products – is accumulating at a very agreea-
`ble pace; this information will also be recited here. In agree-
`ment with our mission to better the management of patients
`with hereditary angioedema, this Workshop has on its agenda
`the drafting of specific recommendations on two important
`issues that is, the care of female patients during pregnancy, as
`well as the self-administration of medication. These are the
`assignments for us to complete in the next couple of days and
`to this end, I wish you all great success in your effort.
`
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`Finally, we would like to express our gratitude to each of our
`Sponsors, whose contributions were essential in turning our
`plans into reality.
`Let me conclude this address by expressing my hope for plea-
`sant and fruitful days, which will enrich us all with a new, col-
`lective experience.
`
`
`
`George Füst
`President of the Local Committee
`
`Lilian Varga
`
` Secretary of the Local Committee
`
`Henriette Farkas
`Secretary of the Local Committee
`
`4
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`
`
`Friday, 22 May
`
`16:30-17:00 Welcome coffee
`17:00-19:30 Opening Ceremony
` Chairpersons: G Füst, H Farkas, L Varga
`Greeting of guests
`George Füst
`István Karádi
`(Dean of Semmelweis University Faculty of Medicine)
`Lilian Varga
`Henriette Farkas
`George Harmat
`World music
`by the Ensemble “Hetedhét”
`
`„For HAE Patients” Award
` to Konrad Bork
` presented by Marco Cicardi
`
`Opening lecture
`Konrad Bork:
`Hereditary angioedema: the past and the future
`Invited experts’ lectures
`Christian Drouet: Molecular identification of angioedema
` László Cervenak:
` Endothelial cell function and dysfunction
` _________________
` G Füst, G Széplaki, D Csuka, L Varga, H Farkas:
`Increase in the yearly attack frequency in HAE patients
`treated with danazol for 6 years
`
`19:30 Welcome Dinner with Water Ballet Show
`
`5
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`Saturday, 23 May
`
`08:30-10:00
`
` Basic Science and Diagnosis
` Chairpersons: C Drouet, P Späth, A Zanichelli
`
`
`1. B Favier, F Csopaki, Y Usson, S Caccia, D Ponard,
`N Monnier, M Cicardi, C Drouet:
` Biosynthesis of mutant C1 Inhibitor proteins
`2. M Speletas, K Boukas, E Papadopoulou-Alataki,
`E Tsitsami, AE Germenis:
` A double nucleotide substitution leading to a stop codon
`responsible for hereditary angioedema
`3. H Jiang, H-M Zhang, M.M. Frank:
` Subcutaneous (SQ) versus intravenous (IV) infusion of C1
`Inhibitor (inh) on blood levels in swine
`4. K Joseph, TE Tholanikunnel, I Kalfus, AP Kaplan:
` Infusion of C1 Inhibitor as therapy for swelling in
`hereditary angioedema patients reverses abnormalities of
`the plasma bradykinin-forming pathway and fibrinolysis
`5. C Drouet, D Ponard, I Boccon-Gibod, L Bouillet,
`L Martin, G Kanny, D-A Moneret-Vautrin, A Bygum,
`J-L Bosson, J-L Quesada, M López-Trascasa:
` HAE severity risk is associated with plasma kininase
`activities
`6. A Zanichelli, L Maggioni, M Cicardi:
` Plasma kallikrein activation in hereditary angioedema
`7. L Varga, Zs Kelemen, D Moldovan, E Mihály, B Visy,
`G Széplaki, D Csuka, G Füst, H Farkas:
` Baseline level of functional C1 inhibitor correlates with
`disease scores in hereditary angioedema
`
`
`
`6
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`Saturday, 23 May – continued
`
`8. D Csuka, L Varga, B Visy, G Széplaki, I Czaller,
`É Németh, H Farkas:
` The level of C1rC1sC1-INH complexes is elevated in
`hereditary angioedema and correlates with disease severity
`9. Y Zhi, H Zhang:
`Laboratory testing for functional C1 inhibitor in China:
` normal value and the assay of influencing factors on it
`10. E Rusicke, I Martinez-Saguer, E Aygoeren-Pürsün,
` T Klingebiel, I Stierbrück, H Stoll, W Kreuz:
` Age-related reference ranges of C1-INH activity and
` antigen are important for early diagnosis in paediatric
` HAE patients
`
`10:00-10:30 Coffee break with Poster Discussion
`(Posters 1-4)
`10:30-12:10 Pregnancy, Quality of Life, Clinical Aspects
` Chairpersons: N Prior, G Porebski, U Huffer
`
`1. H Farkas, I Czaller, R Felvinci, B Visy, D Csuka, L Varga,
`F Tóth:
`Management of pregnant women with HAE-
`long-term survay
`2. JHC Gooi, J Shillito:
`Pregnancy and childbirth in women with C1 Inh deficiency
`3. K Obtulowicz, G Porebski, B Bilo, M Stobiecki,
`A Obtulowicz:
` Hereditary angioedema in pregnancy – case series study
`4. I Martinez-Saguer, E Rusicke, E Aygören-Pürsün,
` T Klingebiel, W Kreuz:
` Management of HAE patients during pregnancy and
` delivery- A prospective evaluation of 35 pregnancies
` and 37 newborns
`
`7
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`Saturday, 23 May – continued
`
`5. K Bork, A Castaldo, W Lumry, M Vernon, AM Rentz,
` M Blaustein, D Wilson:
` Humanistic burden of hereditary angioedema: health-
` related quality of life, depression, productivity, and social
` consequences
`6. W Kreuz, I Martinez-Saguer, E Rusicke,E Aygören-Pürsün,
` T Klingebiel:
` Impact of the Frankfurt HAE therapy protocol on health-
` related quality of life (HRQoL) in 50 patients with
` hereditary angioedema
`7. N Prior, T Caballero, C Gómez-Traseira, E Remor,
` DV-IHAE QoL group:
` Update in the development of an international specific
` questionnaire for the assessment of health-related
` quality of life in adult patients with hereditary
` angioedema due to C1 inhibitor deficiency (IHAE-QoL)
`8. S von Mackensen, E Rusicke, M Cicardi, W Kreuz:
` Health-related quality of life (HRQoL) in children and
` adults with hereditary angioedema (HAE)
`9. C Gómez-Traseira, T Caballero, N. Prior, E. Perez,
` MC Lopez Serrano:
` Thyroid alterations in patients with hereditary C1 inhibitor
` deficiency
`10. A Reshef, I Leibovich, M Kidon:
` A survey of prodromal signs and symptoms of hereditary
` angioedema
`
`
`
`8
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`Saturday, 23 May – continued
`
`
`12:10-12:55 Round Table Discussion 1:
` International Consensus on Pregnancy
`Moderators: T Caballero, T Bowen, L Bouillet, H Farkas
`
`12:55-14:00 Lunch break
`
`14:00-16:00 Visit to the Hospital in the Rock
`
`16:00-16:30 Coffee break
`
`16:30-18:00 National Surveys, Self-administration
` Chairpersons: B Zuraw, A Bygum, J Björkander
`1. L Bouillet, I Boccon-Gibod, D Ponard, N Monnier,
` JL Lunardi, JL Bosson, JL Quesada, C Drouet, C Massot:
` Hereditary angioedema type I: disease expression among
` 210 patients
`2. A Bygum:
` Hereditary angio-oedema (HAE) in Denmark –
` a nationwide survey
`3. MM Esser, AEC Clark, B Rosenkranz:
` Investigation of hereditary angioedema – current situation
` in South Africa
`4. U Huffer, L Schauf, G Kruse:
` Clinical manifestation of HAE – results of a survey in
` Germany
`5. P Nordenfelt, L Mallbris, MP Nilsson, A Lindfors,
` CF Wahlgren, L Lundblad, B Nilsson, L Nordvall,
` L Truedsson, P Hellström, S Werner, J Björkander:
` Sweha a Swedish project of HAE in Sweden –
` First findings
`
`9
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`Saturday, 23 May – continued
`
`6. B WA Wuillemin, B Wais, PJ Späth:
` Facets of hereditary angioedema in a cohort of
` Swiss patients
`7. AS Grumach, S Valle, AT França, E Mansour,
` MMS Vilela, A Pires-Correia, RN Constantino-Silva,
` K Rocha, DM Vasconcelos, N Chouffi-Barros,
` MF Silva, AJS Duarte:
` HAE in Brazil: the influece of an educative program to
` improve diagnosis
`8. Zuraw, D Davis, A Castaldo:
` Safety and efficacy of physician supervised self-managed
` C1 inhibitor individual replacement therapy
`9. B Zuraw, D Davis, A Castaldo:
` Tolerability and efficacy of attenuated anabolic
` androgen therapy in 731 HAE patients
`
`18:00-18:45 Round Table Discussion 2:
`International Consensus on
`Self-administration
`Moderators: H Longhurst, W Kreuz, A Castaldo,
`T Craig, B Zuraw
`
`20:00- Gala Dinner
`with the ‘Perfect Party Company’
`
`10
`
`
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`Sunday, 24 May
`08:20-09:20 Therapy
` Chairpersons: A Reshef, I Martinez-Saguer,
`H Li
`
`
`E Aygören-Pürsün, R Schubert, C Königs, E Rusicke,
`1.
` I Martinez Saguer, W Kreuz:
` Anaphylactic reaction against pdC1-Inhibitor
` concentrate in a patient with hereditary angioedema
`JW Baker, A Sheffer,J Christensen, D Hurewitz,
`2.
` R.Lazar,I Kalfus,A Banerji:
` Cinryze™ replacement therapy in hereditary
` angioedema and pregnancy
`T Craig, M Riedl, M Dykewicz, R Gower, J Baker,
`3.
` F Edelman, D Hurewitz, J Jacobs, I Kalfus:
` When should prophylactic therapy be considered for
` hereditary angioedema?
`CM Farber, C Espina-Cardoso:
`4.
` Icatibant in a type III angioedema patient
`5. A Malbrán, P Di Marco, Fernández Romero DS
` Treatment of hereditary angioedema with icatibant.
` Report of 163 attacks.
`
`09:20-11:00 Clinical Trials
` Chairpersons: M Cicardi, M M Frank, D Moldovan
`
`TJ Craig, RJ Levy, RL Wasserman, AK Bewtra,
`1.
` DS Hurewitz, K Obtulowicz, A Reshef, PC Kiessling,
` J Bernstein:
` Treatment of HAE with C1 inhibitor in a randomized,
` placebo-controlled, dose-finding study of acute
` abdominal and facial attacks (I.M.P.A.C.T.1)
`
`11
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`Sunday, 24 May – continued
`
`3.
`
` MM Frank representing the Cinryze Study Group:
`2.
` Safety and efficacy of nanofiltered C1 inhibitor
` concentrate for acute and prophylactic treatment of
` hereditary angioedema due to C1 inhibitor deficiency
` JJ Hofstra, I Kleine Budde, G Choi1, E van Twuyver,
` M Levi1, FWG Leebeek, JGR de Monchy, PF Ypma,
` H Nienhuis, PFW Strengers:
` Pharmacokinetics, clinical efficacy and safety of plasma-
` derived nanofiltered C1 inhibitor concentrate for
` treatment of hereditary and acquired angioedema
`4. RJ Levy, RL Wasserman, AK Bewtra, DS Hurewitz,
`J Moy, WH Yang, PC Kiessling, TJ Craig from the
`I.M.P.A.C.T.2 study group
` C1 inhibitor in the treatment of 789 acute HAE attacks
` in an ongoing, prospective, open-label study in North
` America (I.M.P.A.C.T.2)
`5. C Kramer, R van Beem, A Koenderman, J Over,
` P Strengers:
` Development of a new generation of plasma-derived
` C1-inhibitor concentrate
`6. H Li, A Sheffer, R Levy, W Pullman, P Horn:
` Integrated analysis of two Phase 3, double-blind,
` placebo-controlled studies of ecallantide for the
` treatment of acute attacks of hereditary angioedema
`7. D Moldovan, RJ Levy, S Visscher, A Relan, JH Nuijens,
` CE Hack:
` Interim results from ongoing open-label studies with
` recombinant C1 inhibitor (Rhucin; rC1INH) for
` treatment of patients with acute attacks of hereditary
` angioedema
`
`12
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`Sunday, 24 May – continued
`
`
`11:00-11:30 Coffee break with Poster Discussion
`(Posters 5-6)
`
`
`11:30-13:00 HAE III, Case Reports, Institutional Policy
` Chairpersons: K Bork, JHC Gooi, L Varga
`
`1.
`
`K Bork, K Wulff, J Hardt, G Witzke, P Staubach:
` Hereditary angioedema due to missense mutations in the
` factor XII gene: Clinical features, trigger factors,
` and therapy
`CM Farber, P Späth:
`2.
` Non-allergic, non-infectious angioedema.
` A single physician’s experience
`C Gómez-Traseira, A López-Lera, T Caballero, N Prior,
`3.
` C Drouet, M López-Trascasa:
` Oestrogen dependent hereditary angioedema with normal
` C1 inhibitor caused by a mutation in coagulation factor
` XII in a Spanish family
`F Foieni, M Cicardi, A Zanichelli:
` The acquired deficiency of the C1-inhibitor:
` lymphoproliferation and angioedema
`I Bonnaud, V Rouaud, JP Cottier, CM Farber:
`5.
` A case of pseudo- stroke in hereditary angioedema
`6. M Cancian1, AL Andres, R Bendo, L Maggioni,
` R Senter, G Vettore, G Realdi:
` Recurrent pancreatitis in HAE
`
`4.
`
`
`
`
`
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`Sunday, 24 May – continued
`
`
`7. A López-Lera, R Mena de la Cruz, S Garrido, G Fontán,
`M López-Trascasa:
` Genetic and immunological studies in two homozygous
` C1-inhibitor deficient families.
`8. Y Romanyshyn, L Kostyuchenko:
` Family case of HAE: the first expirience in Ukraine.
`9. I Boccon-Gibod, L Bouillet, D Ponard, N Monnier,
` JL Lunardi, JL Bosson, JL Quesada, C Drouet,
` C Massot:
` A National Angioedema Reference Center in France:
` Set up and first two year’s overview
`10. G Harmat:
` Rare disease policy in Europe
`
`
`
`Posters:
`1. D Roem, IGA Wagenaar-Bos, S Zeerleder, D Wouters,
` R J Bennink, KM de Bruin, KJDM Herscheid,
` J Verbeek, CE Hack , SM van Ham:
` The effect of glycosylation on clearance, biodistribution
` and activity of C1-Inhibitor
`2. L Zabrodska, I Gogunska:
` The kallikrein activity, the contents of α2-
` macroglobulin and α1-inhibitor of proteinases in blood
` serum of the patients with angioneurotic edema
`3.
` Gy Schaffer, D Csuka, H Farkas, L Cervenak:
` Endothelial plasma markers in HAE
`
`
`
`
`
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`Sunday, 24 May – continued
`
`
`4. T Mészáros, G Füst, H Farkas, B Fekete, Gy Nagy,
` E Kiss, P Gergely, M Zéher, Z Griger, L Czirják,
` R Hóbor, Á Haris, K Polner,L Varga:
` Autoantibodies against the C1-Inhibitor
` in systemic lupus erythematosus
`5. A Relan, A Baboeram, S Visscher, G Haase, JH Nuijens,
` B Giannetti, CE Hack:
` Evaluation of the immunosafety of a recombinant
` C1-inhibitor product (Rhucin, rC1INH)
` 6. L Bouillet, I Boccon-Gibod, D Ponard,
` C Dumestre-Perard, JY Cesbron, C Massot:
` Effective symptomatic treatment with icatibant of two
` hereditary angioedema type I patients with anti-C1-
` esterase-inhibitor antibodies
`
`
`13:00-13:15 Closing remarks by P Späth
`
`13:15-14:00 Lunch break
`
`14:00- Departure
`
`
`
`15
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`
`
`A B S T R A C T S
`
`
`
`Page 17 of 84
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`16
`16
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`Anaphylactic reaction against pdC1-Inhibitor concentrate in a patient
`with hereditary angioedema
`
` E
`
` Aygören-Pürsün, R Schubert, C Königs, E Rusicke, I Martinez Saguer, W Kreuz
`
`
`University Hospital, Johann Wolfgang Goethe University, Center of Pediatrics,
`Frankfurt/Main, Germany
`
`The pasteurized plasma derived (pd) C1-Inhibitor (C1-INH) concentrate Berinert® is
`licensed for therapy of acute angioedema in patients with Hereditary Angioedema
`(HAE) in Germany and is also used in many other countries. Allergic reactions to the
`preparation have not yet been reported in the literature. The preparation has a good
`safety record, which shows 8 allergic/anaphylactic reactions with 400.000 administra-
`tions according to the manufacturer.
`
` A
`
` 47-year old female with a history of chronic contact urticaria (nickel-induced) and
`autoimmune thyreoditis, suffering from HAE type 1 received 1000 U pdC1-INH con-
`centrate for therapy of angioedema. Within 30 minutes she developed acute urticaria
`and hypotension, which required hospital admission. The patient showed urticarial
`reaction on three further occasions with different batches, despite premedication with
`antihistaminics and corticosteroids, once accompanied by severe arterial hypotension
`which required administration of epinephrine. However, all four angioedema respond-
`ed rapidly to 500-1000 U of pdC1-INH concentrate.
`
`Laboratory assessment in symptom-free intervals revealed normal eosinophil count
`and normal total serum IgE (7 IU/ml). Specific IgE-antibodies against pdC1INH con-
`centrate were not detectable. On a cellular level basophil activation following incuba-
`tion with pdC1-INH concentrate could be demonstrated in vitro. This case demon-
`strates that pdC1-INH concentrate may, if very rarely, lead to non-IgE mediated aller-
`gic reactions in susceptible individuals.
`
`
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`Cinryze™ replacement therapy in hereditary angioedema and pregnancy
`JW Baker1, A Sheffer2, J Christensen3, D Hurewitz4, R Lazar5, I Kalfus6, A Banerji7
`1Allergy, Asthma and Dermatology Research Center, Lake Oswego, OR, 2Brigham
`and Women's Hospital Harvard Medical School, Boston, MA, 3Nevada Access to
`Research & Education Society, Las Vegas, NV, 4Allergy Clinic of Tulsa, Tulsa, OK,
`5Grand Traverse Allergy, Traverse City, MA, 6M2G Consulting, New York, NY,
`7Massachusetts General Hospital Harvard Medical School, Boston, MA.
`Pregnancy may increase the number and severity of hereditary angioedema (HAE)
`attacks. Currently available therapies in the United States are generally contraindi-
`cated and should be used with caution. Angioedema attacks in pregnant women may
`be prevented with C1 inhibitor replacement therapy.
`Six patients received 1000U of Cinryze (C1 inhibitor-nf) replacement therapy 1-2
`times per week as prophylaxis of HAE attacks during pregnancy. One patient self
`administered Cetor, a Dutch C1 inhibitor product, after the first two trimesters. An
`additional patient received Cinryze 1000U immediately prior to delivery and again
`two days later. Data on frequency of HAE attacks and number of emergency medical
`visits prior to and following initiation of Cinryze replacement therapy were gathered.
`Side effects were monitored. All six of the women treated through pregnancy had
`normal healthy deliveries. The seventh, who received Cinryze pre and post delivery
`had normal healthy delivery as well. Of note, one patient underwent emergency C-
`section after developing preeclampsia secondary to a motor vehicle accident. No pa-
`tient treated with Cinryze replacement therapy suffered HAE related complications
`during her pregnancy. Number of attacks and number of emergency medical visits
`were reduced by >85%. No adverse events secondary to Cinryze were reported.
`Cinryze replacement therapy is a safe and effective treatment of HAE in pregnancy
`and should be considered as part of the standard of care during pregnancy and delivery
`for patients with HAE. Self-administration of Cinryze could be a welcome therapeutic
`option in treating this disease.
`
`
`
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`A National Angioedema Reference Center in France: set up and first two year’s
`overview.
`
` Boccon-Gibod1,2, L Bouillet1,2, D Ponard3, N Monnier2,4, JL Lunardi2,4, JL Bosson5,
`JL Quesada5, C Drouet2,6 , C Massot1,2
`
`1Clinique universitaire de médecine interne, CHU de Grenoble , 2Centre de référence
`de l’angioedème non histaminique, CHU de Grenoble , 3Laboratoire d’immunologie,
`CHU de Grenoble , 4Laboratoire de biochimie de l’ADN, CHU de Grenoble, 5Centre
`6Laboratoire d’exploration de
`d’investigation clinique, CHU de Grenoble ,
`l’angioedème, CHU de Grenoble
`
`The National Angioedema Reference Center was set up in a context of the French
`National Rare Diseases Plan. This plan was deployed between 2005 and 2008. This
`deployment resulted in approving 131 Rare Diseases Certified Centers. The main goal
`is to enable any patient to have access to diagnosis and treatment, regardless of how
`rare the disease is. The objective of the initial five years phase of each center is com-
`posed of 10 axes: •In depth understanding of the disease epidemiology •Ease and
`simplify treatment reimbursement •Develop an expertise network to facilitate the
`handling of the patients wherever they live •Establish partnership with pharmacology
`industry to promote, develop and ease the access of orphan drugs •In case the rare
`disease leads to disabilities, set up a partnership with specialized disabilities Centers
`•Promote hospital program research (PHRC) •Develop disease acknowledge for pa-
`tients & health professionals •Help health professionals to identify rare diseases diag-
`nosis •Organize the screening and diagnosis access •Develop national and European
`partnership.
`The National Angioedema Reference Center (CREAK) with clinic, biologic and ge-
`netic units mainly located in Grenoble has been certified on July 2006. Thanks to the
`creation of CREAK, which was set up as a result of the French Rare Disease Plan, we
`have created a network of expertise based on twelve geographic locations which effi-
`ciently share information about their patients. We have also created a lot of awareness
`through standardized handling process that physicians and hospitals can follow for
`best diagnosis and treatment. The patient himself is given an individual booklet tar-
`geted to any health professional to take appropriate care of the patient in case of
`emergency. The creation of the CREAK resulted in a solid platform that became the
`official basis of several research programs (PHRC) gathering clinic, biologic and
`genetic data.
`
`
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`Page 20 of 84
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`A case of pseudo- stroke in hereditary angioedema
`
` I
`
` Bonnaud1, V Rouaud1, JP Cottier1, CM Farber2
`
`
`1CHRU Bretonneau, France, 2Hôpital Erasme Anderlecht, Belgique
`We report a case of pseudo- stroke in a patient with hereditary angioedema, (HAE)
`totally regressive after injection of C1-inhibitor therapy.
`Hereditary angioedema is a rare autosomal dominant disease caused by a serpin inhi-
`bitor deficiency. It is an inhibitor of several complement proteases and of plasmin, a
`fibrinolysis inhibitor. A 61 year-old man was diagnosed with HAE at the age of 14.
`He was treated with Danatrol for 8 years; under this treatment, he had 3-6 gastro-
`intestinal and facial attacks per year. He presented in our stroke unit with brief attacks
`of right-sided deficits, each lasting for 30 minutes. Blood pressure, cardio-vascular
`and abdominal examination were normal. C4 and CH50 were markedly decreased. C1
`INH esterase level was 0.09g/l. MRI showed bilateral hyperintensities in T2 FLAIR
`weighted sequences, and a left paraventricular hypersignal in other sequences. The
`EEG showed diffuse slow waves on the left derivations. During the next 24 hours, 20
`attacks of 20 minutes’ duration followed. At this point, a diagnosis of pseudo-stroke
`was evoked. After consultation, 1000 units of C1 INH were injected IV. Four minutes
`after the injection, symptoms disappeared. Patient is still asymptomatic. MRI was
`unchanged.
`We believe that this is the first report of HAE presenting as a pseudo-stroke.
`
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`Page 21 of 84
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`

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`Hereditary angioedema due to missense mutations in the factor XII gene: Clin-
`ical features, trigger factors, and therapy
`K Bork1, K Wulff2, J Hardt3, G Witzke1, P Staubach1
`1Department of Dermatology, Johannes Gutenberg University, Mainz, Germany;
`2Institute of Human Genetics, Ernst Moritz Arndt University, Greifswald, Germany;
`and 3Department of Medical Psychology and Medical Sociology, Johannes Gutenberg
`University, Mainz, Germany
`Hereditary angioedema due to mutations in the factor XII gene is a recently described
`disease entity that occurs mainly in women. It differs from hereditary angioedema due
`to C1 inhibitor deficiency. Aim was to assess the clinical symptoms, factors triggering
`acute attacks, and treatments of this disease. Thirty-five female patients with heredita-
`ry angioedema and the factor XII mutations p.Thr309Lys and p.Thr309Arg who came
`from 13 unrelated families were studied. The observation period was 8.4 years on
`average (range: 2 – 26 yrs). Patients had on average 12.7 +/- 7 9 angioedema attacks
`per year. Recurrent facial swellings occurred in all patients; skin swellings other than
`facial, abdominal pain attacks, tongue swellings, and laryngeal edema occurred less
`frequently. Some factors that triggered angiodema attacks were trauma, physical pres-
`sure, and emotional stress. Clinical symptoms started mainly after intake of oral con-
`traceptives (17 women) or pregnancy (three women). Exacerbation of the symptoms
`occurred after oral contraceptive use (eight women), pregnancy (seven women), hor-
`mone replacement therapy (three women), intake of angiotensin-converting enzyme
`inhibitors (two women), and an angiotensin1 receptor blocker (one woman). Effective
`treatments included C1 inhibitor concentrate for angioedema attacks (six women) and,
`for prophylaxis, progesterone (eight women), danazol (two women), and tranexamic
`acid (one woman). No difference between patients with the mutations p.Thr309Arg
`and those with p.Thr309Lys was found. Facial swelling is a cardinal symptom of this
`condition. Estrogens may have a great influence but this influence is highly variable.
`Various treatment options are available.
`
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`Page 22 of 84
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`Humanistic burden of hereditary angioedema: health-related quality of life, de-
`pression, productivity, and social consequences
`K Bork1, A Castaldo2, W Lumry3, M Vernon4, AM Rentz4, M Blaustein5, D Wilson6
`1Johannes Gutenberg University, Mainz, Germany; 2United States Hereditary Angioe-
`dema Association, Honolulu, HI; 3AARA Research Center, Dallas, TX; 4United Bio-
`Source Corporation, Center for Health Outcomes Research, Bethesda, MD; 5Dyax
`Corp., Cambridge, MA; 6Massachusetts General Hospital Institute of Health Profes-
`sions, Boston, MA
`
`Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized
`by unpredictable acute attacks of swelling of the extremities, genitals, face, intes-
`tines, and larynx. This study assessed the health-related quality of life (HRQL) and
`economic burdens of HAE via a Web-based survey of US patients. The survey
`evaluated the impact of HAE on education, employment, social activity, and fami-
`ly life and included questions specifically about HAE experience and 3 standar-
`dized instruments: the 12-item Short Form (SF®-12) Health Survey, the Hamilton
`Depression Inventory–Short Form (HDI-SF), and the Work Productivity and Ac-
`tivity Impairment (WPAI) tool. It was approved by an institutional review board,
`and all participants provided informed consent. Of the 457 respondents (345 wom-
`en, 112 men), 94% experienced an HAE attack within the prior 12 months (mean
`26.9 episodes per year; mean duration of 61.3 hours). HAE patients reported
`significant decrements relative to historic population norms on the SF-12 Physical
`Component Summary (mean: 43.7 vs 49.6; P<0.0001) and Mental Component
`Summary (mean: 42.6 vs 49.4; P<0.0001). Patients with HAE had a higher mean
`HDI-SF score than population norms (P<0.001); 42.5% of HAE patients scored
`>8.5 on the HDI-SF, indicative of clinical depression. Productivity was markedly
`impaired in all WPAI categories, including 34% overall work impairment. Pa-
`tients missed a mean of 3.3 work days due to their most recent HAE attack. Over-
`all, annual direct and indirect costs for an average HAE patient total US $44,597;
`annual costs correlate with average attack severity ($11,587 for mild attacks vs
`$104,857 for severe attacks). Based on this study, HAE imparts significant eco-
`nomic and social burdens in terms of annual costs, HRQL decrements, increased
`depression, and reduced productivity.
`
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`Page 23 of 84
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`Hereditary angioedema type I: disease expression among 210 patients
`L Bouillet1,2 , I Boccon-Gibod2, D Ponard3, N Monnier2,4, JL Lunardi2,4, JL Bosson5,
`JL Quesada5, C Drouet2,6 , C Massot1,2
`1Clinique universitaire de médecine interne ; 2Centre de référence de l’angioedème
`non histaminique ; 3Laboratoire d’immunologie ; 4Laboratoire de biochimie de
`5Centre d’investigation
`6Laboratoire d’exploration de
`l’ADN ;
`clinique ;
`l’angioedème ; CHU de Grenoble, France
`Hereditary angioedema associated with C1Inh deficiency is a rare disease. Since the
`first disease description in 1882 by Quincke, a lot of clinical data allowed a better
`understanding of the disease. In 2004, a severity score evaluation tool was established
`by European experts for clinical studies. With this score, we have realised a prospec-
`tive study to identify severity factors of the disease.
`We have collected and analyzed clinical data of 210 patients (PHRC plan). Each pa-
`tient had C1Inh function < 30% of the normal range and a mutation identified on
`C1Inh gene. Data were collected in France by internists or dermatologists.
`Average age of the first symptom is 10 years (5-17) and 64% were women. The aver-
`age the diagnosis delay is 10 years (6-14). 53% of patients presented severe score (1
`and 2) and 15% are asymptomatic. 45% of patient