HAE international home therapy consensus document

Hereditary angioedema (HAE) is an autosomal dominant condition caused by a partial deficiency of C1 inhibitor (C1INH). C1INH controls a variety of local inflammatory pathways. Insufficient regulation of the classical complement pathway causes consumption of the complement component C4, resulting in typical diagnostic abnormalities. Insufficient inhibition of kallikrein results in overproduction of bradykinin, and episodic swelling from excess local bradykinin[1]. Swellings are typically of slow onset over several hours and last 1-5 days, although some patients may also experience rapid onset swellings[2]. Almost any part of the body may be affected, although the subcutaneous and submucosal structures of limbs, genitals, face, mouth and bowel are the usual sites of swelling. Swellings are referred to as acute attacks and are interspersed by asymptomatic periods of days, weeks or months[3–5].

Attacks are associated with reversible disability. Abdominal attacks are associated with the extreme pain of bowel obstruction or visceral swelling, and with vomiting or diarrhoea[3, 6]. Patients are typically unable to undertake their daily activities of living for one or more days, and may be less productive for a few days subsequent to attack because of residual angioedema and fatigue. Peripheral swellings may prevent wearing of shoes, operation of machinery or may cause disfigurement, thus interfering with work or other activities[7].

Laryngeal swellings comprise a small minority (around 2%) of attacks but may cause death from airway obstruction[2]. Although for most patients laryngeal attacks are infrequent and the case fatality of each attack is low, there is a significant lifetime mortality[3, 8]. Fear of laryngeal attacks and the need for access to lifesaving, specialist emergency treatment confers considerable restrictions on patients and their families. In particular, travel for work or pleasure is often curtailed. Attacks are more likely to occur at times of emotional stress, and therefore are more likely to occur during examinations or busy periods at work. Thus, those affected by HAE and their families are subject to employment and educational disadvantage[9–11].

The frequency and severity of attacks is reduced by oral prophylaxis with attenuated androgens or tranexamic acid, or by regular intravenous infusion of C1INH concentrate[12–14]. However, prophylaxis does not completely abolish attacks[14]. Moreover, many patients cannot benefit from oral prophylaxis because of contraindications, side effects, or lack of efficacy[13, 15, 16]. Immediate access to effective acute treatment is therefore required for all patients.

Replacement therapy with plasma-derived C1INH (pdC1INH) is effective and has been used successfully for over 25 years to attenuate or prevent attacks at all sites [17–19]. More recently, icatibant, a bradykinin receptor inhibitor, and ecallantide, a kallikrein inhibitor, have been shown to be effective at treating attacks[20, 21]. Icatibant was licensed for acute angioedema attacks in patients with C1-inhibitor deficiency in the European Union and several other countries in 2008. Ecallantide was licensed for acute attacks in the USA in 2009. After treatment with either icatibant, ecallantide or C1INH, onset of relief can be expected within 30 to 60 minutes, with full resolution taking a few hours to longer than 24 hours in established attacks[14, 17, 20–23]. Observational studies demonstrate faster relief and reduced attack severity when C1INH is given early [6, 24]. Similarly, icatibant or ecallantide may be more effective when given early, although this is yet to be demonstrated in clinical studies.

The requirement to travel to a medical facility for acute treatment implies at least half a day away from home, school, or work. In the emergency room setting, patients with HAE attacks may not be prioritised over competing emergencies such as patients with heart attacks, stroke or severe injury. This leads to further delay, with increased risk of treatment failure and longer recovery times. Health care staff, unfamiliar with HAE, are reluctant to treat early, when signs are mild or absent, contributing further to the delay and disability. Owing to the reversibility of most attacks, patients themselves may choose to stay at home with symptomatic treatment rather than struggle with access to therapy in the emergency room. This increases absenteeism from work, school, or home responsibilities. For laryngeal attacks, such delay may be fatal. Even where acute treatment is available, it is estimated that only 5-25% of attacks receive definitive treatment (Cicardi, personal communication). Home infusion programmes have been established in centres with an interest in HAE, and have the potential to overcome many of the difficulties associated with health care facility-based treatment[25–28].

Experience shows that access to self or assisted infusion with C1INH reduces severity and duration of attacks, improves HAE-related quality of life, reduces time off work, education or domestic duties, is safe, and is very popular with participants[23–30]. Self infusion is endorsed by the UK, Danish and Canadian-Hungarian consensuses[25, 31–34]. Neither UK nor the Canadian Consensus documents place restrictions on entry to the programme, other than to note that the diagnosis of HAE should be proven, prophylactic therapy optimised (UK document) and that an 'infusion partner' (UK) or 'instruction and support' (Canadian- Hungarian) should be available[27, 31–34]. The Danish home therapy programme considers patients who have more than one moderate or severe attack every 4 weeks, although in practice, these restrictions are relaxed where necessary[25, 27].

The C1 inhibitor deficiency workshop was first held in 1999 in Vizegrád, Hungary and has been a biennial Hungarian event since then. It brings together patients, physicians, nurses, basic and clinical scientists, blood product suppliers and representatives of the pharmaceutical industry with a common interest in HAE and its management. Similarly, the Canadian Hereditary Angioedema Network (CHAEN)/Réseau d'angioedème héréditaire du Canada (RAHC) has organised conferences in 2003, 2006 and 2010, with the aim of developing and updating consensus recommendations for HAE management http://www.haecanada.com. These workshops are attended by experts from all over the world and represent an unprecedented opportunity to pool experience and to share information, with the aim of improving the physical, psychological and economic wellbeing of those affected by HAE. This article summarises consensus opinion, resulting from debates at the Hungarian C1 Inhibitor 2009 Workshop and the Canadian Hereditary Angioedema Network (CHAEN)/Réseau d'angioedème héréditaire du Canada (RAHC) consensus meeting held in Toronto in May 2010 (Appendix 1). Home therapy/self-administration in this article, refers to treatment given in a non-health care setting; given by the patient, a trained relative or friend, outside of a healthcare facility.

Participants at the 6^th C1 Inhibitor Deficiency Workshop, held in Budapest in May 2009, were invited to a moderated discussion with the aim of forming a consensus approach to home therapy for patients with HAE. Published literature was found using a PubMed search, with the terms "C1 inhibitor" or "hereditary angioedema" and "home therapy" or "self-infusion". Additional data were found from references in the papers found in the search and from abstracts known to the authors, not listed in PubMed. These data were summarised by HL and presented as a basis for further discussion. The discussion was chaired by a physician/immunologist (HL) and moderated by a representative of the US patients' association (JL), adult and paediatric physicians, and physician scientists (TC, WK, BZ). The consensus document summarising discussions was drafted by HL and the facilitators (TC, WK, BZ). This draft was used as a basis for debate and modification at the Canadian Toronto May 2010 Consensus Meeting. To date, most self-administration treatment has been limited to plasma-derived C1INH (pdC1INH) replacement but is expected to involve other agents as they become available (icatibant, recombinant C1INH, other therapies as they become licensed and available).

Every patient with HAE should have the immediate means to control an acute attack quickly and effectively, in order to minimise impact on physical, social and economic wellbeing to themselves and their family. Similar to the haemophilia home care model that has worked so well for many years[35], the option of home and self-administration offers the prospect of achieving the aim of 'each C1 inhibitor deficient (HAE) patient to be able to manage his/her symptoms proactively in such a way that they maintain personal safety and minimal disruption in living a healthy and productive life'[32].