Short summary

Hereditary angioedema (HAE) is a rare, genetic disease characterized by recurrent attacks of subcutaneous swellings. The Danish HAE Comprehensive care center at the Department of Dermatology, OUH follows 95% of all Danish patients diagnosed with HAE (and acquired C1 inhibitor deficiency, AAE) and thereby has access to a unique nationwide cohort.

A bio bank of blood samples and a database with clinical information from patients with HAE and AAE has been collected and forms the basis for two subprojects: investigation of complement activity as biomarker for HAE, and the role of misfolded serpins in the contact activation in HAE.

Rationale

Hereditary angioedema is caused by mutations in the gene encoding the protease inhibitor C1 inhibitor. It is diagnosed by measuring the levels of antigenic and functional C1 inhibitor in plasma, as well as the complement factor C4, which is decreased in HAE due to overconsumption in the complement system in the absence of sufficient amounts of C1 inhibitor. The lack of C1 inhibitor also affects the contact system, which ultimately leads to an overproduction of bradykinin. Bradykinin is the mediator of the angioedema attacks, but the exact mechanism of what triggers the attacks is not known. 

Complement activity as biomarker for HAE
The complement factor C4 is sometimes used as a screening measure for HAE, but there are cases of false negative test results when the patients are not having an attack. The aim of the subproject is to evaluate the complement activation in HAE patients by using ELISA assays for C4 and its activation product C4c. The ratio of C4c/C4 might be a more sensitive measurement for diagnosing HAE

The role of misfolded serpins in HAE
The aim of the subproject is to develop enzymatic methods for detecting recombinant and genuine C1 inhibitor polymers and for measuring contact dependent pathways and fibrinolytic activity. We will establish immunohistochemical techniques for detecting and measuring the quantity of misfolded C1 inhibitor polymers in plasma from HAE patients and compare the laboratory data with clinical data. The purpose of the study is to increase our knowledge of the mechanisms of HAE and thereby provide greater insight to treatment options.

In addition to these subprojects, our international collaborators are applying the material from the bio bank and database for the investigating of kallikrein and factor XIIf inhibition in HAE, and for enzymatic assays and genetic analysis of genes related to HAE by next generation sequencing.

Description of the cohort

The study cohort comprises patients (children and adults) with hereditary angioedema or acquired angioedema/acquired C1 inhibitor deficiency.

Data and biological material

Blood samples (plasma and serum)

Clinical data (age at onset, age at diagnosis, disease severity, types of treatment)

Collaborating researchers and departments

Department of Dermatology and Allergy Centre, Odense University Hospital

• Senior Hospital Physician and Associated Professor Anette Bygum, DMSc
• PhD-student Anne Åbom, MD

Allergy & Immunology, Diagnostic Laboratory Immunology, Internal Medicin and Rheumatology, University of South Carolina

• Professor Allen Kaplan, MD

Departamento de Biofisica, Universidade Federal de Sao Paulo, Brasilien

• Professor Joao Bosco Pesquero

Department of  Cancer and Inflammation Research, Institute of Molecular Medicin, University of Southern Denmark

• Post Doc. Yasseelan Palarasah
• Associated Professor Claus Koch
• Associated Professor Karsten Skjødt
• Associated Professor Søren Hansen

Unit for Thrombosis Research, Institute of Public Health, University of Southern Denmark, Esbjerg

• Senior Hospital Physician and Associated Professor Jørgen Brodersen Gram
• Associated Professor Johannes Jakobsen Sidelmann
• Daniel Madsen, PhD 
• PhD-student Daniel Biltoft

Publications associated with the project

Health-related quality of life in Danish patients with hereditary angioedema. / Aabom, A., Andersen, K.E., Perez-Fernández, E., Caballero, T., and Bygum, A. (2015). Acta Derm. Venereol. 95, 225-226.

A novel assay to diagnose hereditary angioedema utilizing inhibition of bradykinin-forming enzymes. / Joseph, K., Bains, S., Tholanikunnel, B.G., Bygum, A., Aabom, A., Koch, C., Farkas, H., Varga, L., Ghebrehiwet, B., and Kaplan, A.P. (2015). Allergy 70, 115-119.

Before and after, the impact of available on-demand treatment for HAE. / Christiansen, S. C., Bygum, A., Banerji, A., Busse, P., Li, H., Lumry, W., Davis-Lorton, M., Bernstein, J. A., Frank, M. M., Castaldo, A., Long, J. F., Riedl, M. & Zuraw, B. L. mar. 2015 I: Allergy and Asthma Proceedings. 36, 2, s. 145-150

Presence of C1-inhibitor polymers in a subset of patients suffering from hereditary angioedema. / Madsen, D.E., Hansen, S., Gram, J., Bygum, A., Drouet, C., and Sidelmann, J.J. (2014). PloS One 9, e112051.

Acquired Angioedema - Occurrence, Clinical Features and Associated Disorders in a Danish nationwide Patient Cohort. / Bygum A, Vestergaard H. Int Arch Allergy Immunol 2013; 162: 149-155.

Use of a C1 Inhibitor Concentrate in Adults >65 Years of Age with Hereditary Angioedema: Findings from the International Berinert (C1-INH) Registry. / Bygum A, Martinez-Saguer I, Bas M, Rosch J, Edelman J, Rojavin M, Williams-Herman D; Berinert Registry Investigators. Drugs Aging. 2016 Nov;33(11):819-827.

Estimation of EuroQol 5-Dimensions health status utility values in hereditary angioedema. / Aygören-Pürsün E, Bygum A, Beusterien K, Hautamaki E, Sisic Z, Boysen HB, Caballero T.Patient Prefer Adherence. 2016 Sep 6;10:1699-707.

Hereditary angioedema: 44 years of diagnostic delay. / Peterson MP, Bygum A. Dermatol Online J. 2016 Apr 18;22(4)

Safety and Usage of C1-Inhibitor in Hereditary Angioedema: Berinert Registry Data. / Riedl MA, Bygum A, Lumry W, Magerl M, Bernstein JA, Busse P, Craig T, Frank MM, Edelman J, Williams-Herman D, Feuersenger H, Rojavin M; Berinert Registry investigators. J Allergy Clin Immunol Pract. 2016 Sep-Oct;4(5):963-71.

Idiopathic Thrombocytopenic Purpura Misdiagnosed as Hereditary Angioedema. / Andersen MF, Bygum A. Case Rep Dermatol Med. 2015;2015:934247.

Real-life experience with long-term prophylactic C1 inhibitor concentrate treatment of patients with hereditary angioedema: Effectiveness and cost. / Rasmussen ER, Aagaard L, Bygum A. Ann Allergy Asthma Immunol. 2016 May;116(5):476-7.

Urticaria and Prodromal Symptoms Including Erythema Marginatum in Danish Patients with Hereditary Angioedema. / Rasmussen ER, de Freitas PV, Bygum A. Acta Derm Venereol. 2016 Mar;96(3):373-6.

Safety of C1-esterase inhibitor in acute and prophylactic therapy of hereditary angioedema: findings from the ongoing international Berinert patient registry. / Busse P, Bygum A, Edelman J, Lumry W, Machnig T, Martinez-Saguer I, Rojavin M. J Allergy Clin Immunol Pract. 2015 Mar-Apr;3(2):213-9.

Hereditary angioedema: children should be considered for training in self-administration. / Abdel-Karim O, Dizdarevic A, Bygum A. Pediatr Dermatol. 2014 Nov-Dec;31(6):e132-5.

Socioeconomic burden of hereditary angioedema: results from the hereditary angioedema burden of illness study in Europe. / Aygören-Pürsün E, Bygum A, Beusterien K, Hautamaki E, Sisic Z, Wait S, Boysen HB, Caballero T. Orphanet J Rare Dis. 2014 Jul 4;9:99.

Open-label, multicenter study of self-administered icatibant for attacks of hereditary angioedema. / Aberer W, Maurer M, Reshef A, Longhurst H, Kivity S, Bygum A, Caballero T, Bloom B, Nair N, Malbrán A. Allergy. 2014 Mar;69(3):305-14. 

The humanistic burden of hereditary angioedema: results from the Burden of Illness Study in Europe. / Caballero T, Aygören-Pürsün E, Bygum A, Beusterien K, Hautamaki E, Sisic Z, Wait S, Boysen HB. Allergy Asthma Proc. 2014 Jan-Feb;35(1):47-53. 

Hereditary angioedema - consequences of a new treatment paradigm in Denmark. / Bygum A. Acta Derm Venereol. 2014 Jul;94(4):436-41.

Hereditary angioedema in childhood: a challenging diagnosis you cannot afford to miss. / Kjaer L, Bygum A. Pediatr Dermatol. 2013 Jan-Feb;30(1):94-6.

Rapid resolution of erythema marginatum after icatibant in acquired angioedema. / Bygum A, Broesby-Olsen S. Acta Derm Venereol. 2011 Mar;91(2):185-6.

Mutational spectrum and phenotypes in Danish families with hereditary angioedema because of C1 inhibitor deficiency. / Bygum A, Fagerberg CR, Ponard D, Monnier N, Lunardi J, Drouet C. Allergy. 2011 Jan;66(1):76-84.