Management of hereditary angioedema: 2010 Canadian approach

C1-inhibitor (C1-INH) deficiency is a rare blood disorder resulting in angioedema attacks that are debilitating and may be life-threatening. Prophylaxis and therapy of events has changed since our first Canadian Consensus Conference on the diagnosis, therapy and management of HAE. We have formed the Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d'Angioédème Héréditaire (RCAH) - http://www.haecanada.com to advance care of patients with this disorder in Canada. We here present a review of management of HAE in Canada.


Introduction
C1 inhibitor (C1-INH) deficiency presents in congenital (hereditary angioedema, HAE) or acquired forms. There are three variants of hereditary angioedema (HAE): HAE-C1-INH Type I with low C1-INH protein and function (85% of cases; autosomal dominant); HAE-C1-INH Type II with normal protein but low function (15% of cases; autosomal dominant); and HAE Type III hereditary angioedema with normal C1 inhibitor protein and function (estrogen-dependent inherited form found mostly in females; some with defects in coagulation factor XII, HAE-FXII; others of unknown defect, HAE-Unknown) [1,2]. Acquired angioedema (AAE) is most frequently associated with lymphoproliferative and autoimmune disorders and with some medications including ACE inhibitors and plasmin activators [3,4]. Patients with HAE may experience recurrent soft tissue swellings, intestinal swellings, and abdominal pains, and may have life-threatening swellings of the airway. The incidence of HAE is estimated at 1:10,000 to 1:50,000. Risk of dying from airway obstruction is not clear but deaths from this complication if left untreated are not uncommon [1,5].
To learn from international experience in HAE, the first C1-INH Deficiency Workshop was convened by the Hungarian HAE Center in May 1999 and they have organized ongoing workshops every two years. The

Therapy
In Canada, blood products are provided without charge to the patient and are funded through an interprovincial-territorial funded government program. There is a central distribution system through Canadian Blood Services for nine of the ten provinces and three Territories or through Hema-Quebec in Quebec so national statistics are available for fractionation blood products. Nonblood products used in HAE are harder to track depending on how the product is distributed. Intravenous C1 inhibitor replacement therapy (C1INHRP, Beri-nert®, CSL Behring) has been licensed for use in Canada    from our report in 2003 where the utilization rate was between 0.3 and 1.7 infusions per HAE patient per year [6]. Without an active national patient registry and without an active replacement product tracking system, these data remain guesses and are not accurate. We propose instituting a national data base registry for HAE patients and a national tracking system for replacement product utilization for HAE in Canada again modeled after the Hemophilia Care Program in Canada. Dr. Bruce Ritchie is undertaking rewriting of the Hemophilia Program blood product tracking program (Canadian Hemophilia Assessment and Resource Management System, CHARMS) and will hopefully include C1INHRP and other HAE treatment product tracking. This utilization is approaching the previously reported figures from Drs. Cicardi and Zingale from their clinic in Milan where their patients received an average of 3.85 infusions per year for laryngeal edema, 7.93 infusions per year for abdominal edema, and 1.57 infusions per year for cutaneous edema [10]. We speculate that the increased utilization is due to improved diagnosis, increased patient awareness of prophylaxis and treatment options, and increased physician awareness of the diagnosis and management of this disorder. We hope that the several national and international conferences hosted in Canada in conjunction with the Canadian Hematology Society and the Canadian Society of Allergy and Clinical Immunology have brought this about raising the standard of care closer to that of many European Countries and showing utilization figures now approaching those of European countries with mature HAE management programs in place and where Berinert® has been available for therapy for about 25 years.

Home therapy
Again modeling the Hemophilia Home Care program, some HAE patients receive home care self or assisted administration on demand. Example of self or assisted administration may be found on the CHAEN/RCAH  website: http://haecanada.com/infusion/ (see Appendix 1). Other home therapy information and standards of care are reviewed by Dr. Hilary Longhurst [11,12]. In centres where home therapy has not yet been instituted, implementation of such HAE home therapy can be most rapidly accomplished by partnering with the local Hemophilia Home Care Clinic. We hope Comprehensive Care Clinics for HAE and other rare blood disorders will become established across Canada in parallel and partnership with Hemophilia clinics and Rare Blood Disorder clinics across Canada. Patients with rare disorders such as blood disorders receive optimum care through such Comprehensive Care Clinics and teams specialized in management of such complex disorders.

Summary
We believe management of HAE in Canada has improved over the past decade thanks to the efforts of first the Canadian Hereditary Angioedema Society (CHAES)/Société d'angioédème héréditaire du Canada (SAHC) and then the Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d'Angioédème Héréditaire (RCAH) http://www.haecanada.com. CHAEN/RCAH has a patient advisory group that has evolved from the original CHAES/SAHC and it is hoped that the HAE Patient Group will again formally organize and replace the current patient advisory committee of CHAEN/RCAH (this is being worked on by Barbara Mako, current Patient Advisory Group Chair). Clinical research in diagnosis, therapy, and management continues in HAE clinics in Canada and it hoped more clinics will join CHAEN/ RCAH and become involved in such clinical research. Comprehensive Care Clinics for HAE are slowly developing and we hope these will continue to evolve and collaborate with the National Rare Blood Disorders Organization (NRBDO) and the NRBDO clinics evolving there. Until new therapeutic products become licensed in Canada, use of these is under clinical trial studies or available through Health Canada Special Access Program. We are excited that the first licensing of a therapeutic product has finally occurred in 2010 (Berinert®) and anxiously wait licensing of other therapeutic options for HAE patients. CHAEN/RCAH members will remain involved in the ongoing development of international consensus approach and evidence based guidelines for HAE management.
We should remember: "It can be done -It must be done for the sake of our patients" (Tom Bowen). Comprehensive care for HAE is based on the recognition that HAE is a chronic disease and care is complex, requiring a highly specialized and multidisciplinary approach. A comprehensive care clinic must provide accountability for in-hospital and home use of expensive and potentially toxic treatments, track outcomes (both beneficial and adverse), and develop and meet Standards of Care for HAE.
Comprehensive HAE Clinics will Provide: 1 Best Clinical Treatment outcomes including: a. a comprehensive care team made up of nurse coordinator, clinician, social worker, data manager, pain management specialist, genetic counselor, and administrative support; b. access to specialized diagnostic testing; c. access to home treatment; d. a networked Patient Information System to facilitate product recalls -collect data on therapy outcome measures and safety, and facilitate participation in clinical trials e. access to clinical advances as they become available; f. access to 24 hour support; g. access to up-to-date standards of care, including standardized wallet cards; h. tracking and intermittent audit of quality outcomes including beneficial and adverse outcomes through secure, comprehensive and networked data management. 2 Education of patients and staff regarding: a. responsible Self/Family Care (home care model) with home and self infusion/administration instruction and support; b. developments in the cause, diagnosis, treatment, outcomes, and prognosis of HAE c. changes in the administrative management of the clinic 3 An environment conducive to research including: a. access to and support for clinical trials of new treatments; b. access to and support for translational research in diagnosis and prognosis; c. access to and support for psychosocial research such as quality of life studies.
4 An advisory or oversight board with patient group representation for each clinic