Clinica! and experimentai immunology.(lM)
`v. 14-7, no. 1 (Jan. 2067)
`Generafi Coiiection
`ER"! {IL-‘58:!
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`étfl’hOLOG SW
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`Immu’nologya‘
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`’v'Clinical and Experimental
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`Clinical and Experimental Immunology
`
`REVIEW ARTICLE
`
`doi:10.1111/j.1365-2249.2oo6.o3256.x
`
`C1-inhibitor concentrate home therapy for hereditary angioedema:
`a viable, effective treatment option
`
`
`
`ll. J. Longhurstf 8. Can“ and K. Khan“
`'b’ur/s tliltl '1/ic [tuition NHS' Trust. Department
`ofhumunuput/Iolagy Linn/nil. UK. ‘h‘tnls tlilt]
`’I‘lie [.ttllrloll NIH 'l‘rnst, lirpurmn’n/ tt/
`l’tit‘tlirltl'it‘ lx’t‘s/tiintui)’ Alta/icing f,(llltIU]l, UK,
`lllltf
`(ii't’llf ()rinoiul Street Hospital. [malty/I, UK
`
`Accepted for publication 13 October 2000
`(Zorrcspontlencc: l)r Hilary Longhurst, liarts
`and the London NI [8 'l‘rt.st, Department of
`lmmunopathology, 51753 Bartholomew (Ilosc,
`London l1( 11A 7lilz, UK.
`
`Summary
`
`Economic and political factors have led to the increased use of home therapy
`programmes for patients who have traditionally been treated in hospital.
`Many patients with hereditary angioedema (ll/\E) experience intermittent
`severe attacks that affect their quality of life and may be life—threatening.
`These attacks are treated with (ll—inhibitor concentrate which, for most
`
`patients, is infused at the local hospital. Home therapy programmes for HAE
`are currently being established. This paper reviews the extent of use of these
`programmes and summarizes the advantages and potential disadvantages of
`the concept so far.
`
`lZ—mail:
`Hiiary,Loughurstm‘bartsainlthelondonaihs. ul:~
`
`emergency
`deficiency,
`C1 inhibitor
`Keywords:
`angioedeina, home therapy, quality of life
`
`treatment,
`
`hereditary
`
`Re use of this article is permitted in accordance
`with the (.reativc (Iommons Deed. Attribution
`7 5, which does not permit commercial
`exploitation.
`
`OnlineOpen: This article is available free online at www.blackweli-synergy.com
`
`
`
`Economic and political factors have contributed to the
`increased use of home therapy programmes for patients who
`would have been treated previously in hospital. One group of
`patients who may benefit from home therapy is those with
`HAll. This paper uses published data (Medline) to assess the
`use of (ll-lNl'l concentrate home therapy in patients with
`llAll, and includes evaluations of both the recommenda—
`tions for patient
`selection for home therapy and the
`documented benefits of self-administration of (Ll-lNH
`
`replacement therapy.
`
`Methods
`
`Data have been collected from a Medline search of the
`
`English language literature to identify papers that included
`information on the use of Cl—lNl'l concentrate as home
`
`Introd uction
`
`is an autosontal dominant
`l’lereclitary angioedema (HALL)
`condition resulting from partial deficiency of Cl
`inhibitor
`t’t‘Ll-lNl i) ll]. 11 is a rare disease, thought to affect between
`one in 10000 and one in 50000 people worldwide [2]
`Acquired angioedema (AAL’), which is also due to (,‘llilNl-l
`deficiency,
`is phenotypically similar to HAE, although it
`is
`associated typically with lymphoprolilfl'alch‘ disease, or with
`autoantibodies to Cl-lNH |3i_
`Patients with ()1 ~lNH deficiency have reduced amounts of
`functional (IlrlNH, which at times of physiological or psy—
`chological stress is insufficient to control local inflammatory
`pathways, The complement and contact systems are actii
`voted, and excess bradykinin is generated [it].
`It
`is
`this
`increased bradykinin production that is believed to be the
`main factor in the development ot‘local oedema l4]. Oedema
`may occur at any site, but most commonly affects the sub—
`cutaneous tissue, causing swelling of the limbs, face, trunk or
`genitalia ll]. Oedema can also affect the mucous membranes
`of the gastrointestinal (GI) tract, causing abdominal pain,
`often with diarrhoea and/or vomiting, and the mucous
`membranes of the larynx, causing laryngeal oedema, which
`may lead to death by asphyxiation [5e7l.
`
`therapy in patients with HAE. The search included the years
`from 1985, the year that pasteurized Cl—lNH concentrate
`replacement therapy was introduced, to August 2006. The
`keywords used for
`the search were ‘Cl—inhibitor’,
`(Cl—
`inhibitor concentrate: ‘Cliesterase inhibitor‘, ‘Ci—esterase
`inhibitor concentrate’,
`‘(Il—INH’,
`‘(Il—lNll
`concentrate),
`‘(31 151’ and ‘C1 l'il concentrate, combined with ‘Clrinhibitor
`inhibitor
`
`deficiency’,
`
`‘Cllil
`
`deficiency’,
`
`‘Cl-esterase
`
`© 2006 The Authotta)
`Journal compilation © 2006 British Soctety tor immunology, Clinical and Experimenta/ linl'nunolOQY. 147: ‘i let 7
`
`11
`
`Page 3 of 10
`
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`
`

`

`H. J. Longhurst eta).
`
`Table 1. Papers detailing the use of Cl inhibitor (Cl-INH) concentrate home therapy in patients with hereditary angioedema (HAE)*.
`No. of
`Home therapy programme
`Author
`Publication
`patients
`entry requirements
`Regimen
`Outcome
`
`
`Levi et a].
`
`Basic & Clin
`lmmunol 2006
`
`43
`
`(31 HAE,
`12 AAE)
`
`Rusicke er (1LT
`
`[AC1 2006
`Abstract
`
`163
`(HAE and
`AAE, exact
`numbers
`not stated)
`
`Attack frequency > 1/3 weeks
`(on-demand treatment),
`> 1/10 days (prophylaxis)
`Proven Cl-INH deficiency
`Completion of education
`programme
`Not stated
`50% of clinic IAIAE
`cohort included
`
`Bork et ai.
`
`'l‘ransfusion 2005
`
`25
`
`Attack frequency > l/month
`
`Kreuz et til.
`
`Blood 2004
`Abstract
`
`Kreuz ct nlxl‘
`
`Bork 8c Witzke
`
`liiomed Progress
`199‘)
`lACI 1988
`
`23
`
`5
`
`2
`
`lntolerant of, or resistant to
`danazol
`
`Not stated
`
`Decreased time to onset of
`relief and attack duration (on-
`demand group)
`Decreased frequency of attacks
`(prophylaxis group)
`
`Reduced consumption of ClelNH
`Prevention of severe attacks
`Reduced hospitalization
`Reduced absence from school
`or work
`
`Cl-INl—l on
`demand
`(n = 31)
`Cl-INH every
`5—7 days
`(II = 12)
`Cl-lNIl on
`demand (first
`line for
`children) or
`prophylactically
`(interval
`not stated)
`Cl—lNH on
`demand
`
`(li—INH every
`3—4 days
`Ci-INH every
`4-5 days
`
`Not stated but short onset—to-
`treatment time assoriaied with
`less severe and shorter duration
`of attacks
`Improved Qol.
`Reduced frequency of attacks
`Reduced frequency of life
`threatening attacks
`No adverse events
`Reduced frequency of attacks
`‘Largely symptom free’
`Reduced attack frequency and
`Optimal oral prophylaxis
`severity
`(1 HAE,
`Attack frequency > l/weck
`Limited duration ofbcnefit in
`1 AAE)
`Proven Cl—INH deficiency
`patient with AAE
`
`"I’atients suffered from HAE unless otherwise stated. TReportiug on the same cohort.
`
`‘HAE’, ‘hereditary
`deficiency’, ‘hereditary angio(o)edema’,
`angioneurotic (o)edema’ and ‘HANE’. These groups ofkey-
`words were then put together, alone and in combination,
`with the search terms ‘home’, ‘self—administration’,
`‘self—
`administered’, ‘outpatient’ and ‘home—based’. The articles
`were retrieved and analysed. Pertinent articles known to the
`authors but not appearing in the Medline search results were
`also analysed.
`
`Results
`
`We found six relevant papers: two case series [8,9] with tWO
`and 43 patients, respectively;
`two further papers [10,11]
`which included information describing patients on home
`therapy (although this was not the main focus of the papers);
`and two further case series, which were available in abstract
`form only [12,13]. The papers are detailed in Table 1.
`Patients were treated with C1—1N1—1, given either on
`demand at the onset of an attack or as regular prophylaxis.
`Cl-INH was self-administered or
`infused by a family
`member at home. The results showed that where prophylac-
`tic Cl-INH was given, patients experienced improved
`quality of life (QoL) and reduced severity, duration and
`
`frequency of attacks. In addition, Cl-INH had an excellent
`safety profile.
`
`Discussion
`
`Treatment of hereditary angioedema
`
`Frequent or severe HAE attacks are disabling for the patient.
`Consequently, such attacks are an indication for regular pro-
`phylaxis, usually with attenuated androgens such as danazol
`that
`increase hepatic production of Cl—INH [14,15].
`However, attenuated androgens may cause unacceptable side
`effects such as virilization [16] or hepatic abnormalities [17],
`or may be contraindicated otherwise, for example in women
`who wish to become pregnant [18]. Fibrinoiytic agents such
`as tranexamic acid or epsilon aminocaproic acid are alterna~
`tive prophylactic agents, although the evidence base for their
`use is less certain [19,20]. Despite prophylaxis, many patients
`continue to experience intermittent severe attacks that
`interrupt
`their activities of daily living and may be
`life—threatening. These attacks are treated with Cl-INl-I con-
`centrate, which in most cases brings about a response within
`30-90 min [21]. Licensed Cl-lNl-l products are available in
`
`12
`
`© 2006 The Author(s)
`Journal compilation © 2006 British Society for Immunology, Clinical and Experimental Immunology, 147: 11~17
`
`Page 4 of 10
`
`Page 4 of 10
`
`

`

`Germany, Austria, Switzerland, France, Hungary, Argentina,
`Japan (Ber-inert 1W, ZLB Behring, Marburg, Germany) and
`the Netherlands
`(Cetor’D,
`CLB, Amsterdam,
`the
`Netherlands). In other European countries, including the
`United Kingdom, and in the United States, Cl-INH is used
`on a named-patient basis, or is completely unavailable.
`Cl-lNl-l infusion is administered traditionally in hospital,
`usually in the emergency department. However,
`this
`approach can lead to delays in administering treatment.
`Emergency department staff may be unfamiliar with HAE
`and patients may not be triaged as urgent. Delays may occur
`in locating C1—INH, which is not a routine stock item for
`most hospitals. Such delays necessitate higher Cl-INH doses
`to control the attack, unnecessary hospital admissions and,
`occasionally,
`severe adverse incidents,
`including death
`[5,8,22]. Death rates from HAE-related laryngeal oedema of
`30—40% have been reported. Although the majority of
`deaths occur in undiagnosed patients,
`there remains an
`avoidable mortality in those who are diagnosed [1,5].
`Children with Cl-INH deficiency are not usually consid-
`ered for home therapy in the United Kingdom, as there are
`no paediatric home therapy programmes. Fortunately, HAE
`is usually mild in preadolescence. However, prophylactic
`options are limited: long-term attenuated androgens present
`significant risks, including growth retardation, and are not
`recommended [23,24]. Our literature search revealed that
`one German centre does provide home therapy for children
`severely affected with HAE, suggesting that this option is
`feasible for
`selected cases. Rusicke eta]. describe how
`on-demand Cl-INH therapy is their first-line therapy for
`children, with regular prophylaxis for those who experience
`very frequent attacks [13]. More than 50% of their cohort of
`325 patients infuse at home, although the proportion of
`these who are children is not stated. The authors claim that
`severe attacks are prevented, and hospital time and absence
`from school is reduced (although detailed figures are not
`supplied).
`Recently, consensus documents providing recommenda-
`tions on the management of HAF. have been published by
`expert panels in Canada and the United Kingdom [18,25].
`Both the Canadian and UK documents recommend offering
`patients the option of home therapy. In spite of a recent
`increase in interest in home therapy in those countries where
`Cl-INH is available [9], there is little published literature on
`this topic and a relative lack of information available for
`health—care professionals.
`
`Home therapy in hereditary angioedema
`
`attack per month, repeated hospital admissions result in
`severe disruption to everyday life, affecting the ability to
`work and carry out domestic duties, impairing patients’ con-
`fidence to travel too far from the local hospital and creating
`anxiety. For these patients, or for patients living in remote
`areas where access to a hospital may be difficult, home
`therapy (self-infusion or infusion by a family member) is
`usually the best option and is likely to result
`in greatly
`improved QoL.
`
`Patient selection for home therapy in hereditary
`angioedema
`
`The available data suggest that patients included on Cl—INH
`home infusion programmes must
`fulfil certain criteria
`[8—13]: patients must have proven Cl—INl-l deficiency as
`determined by typical symptoms, low Cl—lNl-i protein or
`function and low C4 complement. Genetic diagnosis is not
`widely available, but may be useful where diagnosis is
`unclear. Oral prophylaxis must be optimized. Patients must
`have sufficiently frequent attacks; the recommended fre-
`quency varies between centres, but is usually a minimum of
`one attack every 3 months [18]. However, patients with less
`frequent attacks may also benefit from home therapy and
`should be considered on an individual basis. Patients should
`
`be motivated to comply with the home therapy programme
`and be fully informed as to the risks and benefits. Cl—INH
`should be stored at 2—8°C, although limited data suggest that
`lyophilized Cl-lNH concentrate may be stable at room tem-
`perature (25°C) for up to 6 months [26]. Twenty-four—hour
`access to help and advice should be available, including the
`option of emergency hospital treatment [18].
`Training programmes in the United Kingdom and the
`Netherlands include practical aspects ofCl—INH administra—
`tion: hygiene and cannulation techniques,
`as well
`as
`indications for Cl—INH infusion and management of
`emergencies [9,18]. Attacks should be severe enough to
`warrant Cl-lNl—I treatment — usually severe abdominal pain
`or orofacial oedema — but not so severe as to require
`hospitalization; for example, attacks causing symptoms of
`laryngeal obstruction. H0wever,
`if airway obstruction is
`imminent, treatment may be expedited by home administra-
`tion of Cl-INH concentrate while awaiting the arrival of
`ambulance transport to hospital. Patients should be advised
`to consult a physician if the symptoms of an attack are atypi-
`cal, as the onset of an appendicitis or G1 infection may
`present with symptoms similar to abdominal attacks of HAE.
`
`The need for home therapy in hereditary angioedema
`
`As C1~INH can be difficult to Obtain at short notice, practi-
`tioners are strongly recommended to ensure that patients
`have a supply of Cl-INH to keep in the refrigerator at home
`[5,18,25,26]. For the majority of patients, who have infre-
`quent attacks, Cl—INH is taken to the local hospital for
`infusion. For those patients experiencing more than one
`
`Government directives supporting home therapy
`
`In many countries, the relationship between patient and
`medical professionals is changing. Nurses and paramedics
`are taking on tasks that were previously the responsibility of
`doctors, and many patients expect to take an active role in
`their own management. Facilitated by the internet,
`the
`
`© 2006 The Author(s)
`Journal compilation © 2006 British Society for Immunology, Clinical and Experimental lmmuno/ogy, 147: 11—17
`
`13
`
`Page 5 of 10
`
`Page 5 of 10
`
`

`

`H. J. Longhurst etal.
`
`growth of self-help groups such as the UK Primary Immu—
`nodeficiency Association (PiA) and HAP,
`International
`(HAEI) has enabled patients to ‘network’ on a far wider scale
`than previously. Patients are increasingly aware of initiatives
`that can improve their QoL and, as a result, many patients
`are requesting the option of home therapy. Initiatives such as
`the UK NHS Plan and ‘Expert Patient’ programmes seek to
`give patients the knowledge and confidence to take a more
`active role in their own management [27,28].
`
`Established home therapy programmes
`
`Intravenous home therapy programmes exist for a variety of
`conditions,
`including intravenous immunoglobulins for
`antibody deficiency [29,30] and intravenous antibiotics for
`patients with a variety of underlying conditions [31—36].
`These programmes have helped establish the feasibility and
`cost-effectiveness of home therapy. However, perhaps the
`closest parallel with Cl-lNl-I home therapy programmes is
`haemophilia home therapy. Like C1~INH, clotting factors for
`haemophilia can be used prophylactically or as an emergency
`treatment.
`
`Home therapy has been available in haemophilia since the
`19805 and is now considered ‘routine’. Most paediatric
`patients are receiving home therapy by 18 months of age, as
`it is impractical for them to attend hospital several times a
`week for treatment or preventative therapy [37]. For children
`at high risk of bleeding, regular prophylaxis with clotting
`factors can be given; for others, prompt treatment of any
`bleeds or prophylaxis of high-risk events is preferable.
`Current UK guidelines [38] suggest regular prophylaxis for
`those who have declared themselves phenotypically severe
`(by virtue of two of more haemarthroses) and, for the others,
`access to coagulation factors for administration at home, a
`local hospital or a haemophilia centre.
`
`Benefits of home therapy
`
`The results of our Medline search included a recent paper by
`Levi et (11., who reported the experiences of 31 patients with
`Cl-INH deficiency who were trained to self—administer
`C1 -INH [9]. Patients, who all suffered from frequent, severe
`angioedema attacks, self-administered 1000 units ofCl-INII
`concentrate shortly after the onset of severe abdominal, oro-
`facial or laryngeal attacks. Twelve patients, who had very
`frequent attacks (> 1 every 10 days) were treated additionally
`with prophylactic C1 -INH concentrate every 5—7 days. Mean
`follow—up was 3-5 years (range 0-9—5-1). All patients were
`trained successfully, and reported very low levels of technical
`failure with venepuncture (< 200). There were no adverse
`events of sufficient severity to require medical assistance.
`Self-administration of
`regular prophylactic CI-INH
`concentrate resulted in a significant reduction in attack
`frequency, with seven of 12 patients reporting complete
`freedom from attacks. Patients self-treating attacks reported
`
`a significant reduction in time to start of symptomatic relief,
`and in time to complete resolution of the attack, compared
`with the five ‘historical control' attacks immediately prior to
`entry into the self-administration programme. Historical
`control attacks did not respond significantly differently to
`Cl-INH concentrate compared with attacks in control
`patients who did not self-administer. The authors attributed
`the reduction in time to onset of relief and attack duration to
`the reduced attack-to-treatment time associated with self—
`administration. These observations are in accordance with
`
`Bork’s observational study, which reported that abdominal
`attacks treated with Cl—INH concentrate within 2 h of onset
`
`showed significant reduction in time to onset of relief com—
`pared with attacks where treatment was delayed [11]. This
`study did not report separate outcomes on the subgroup of
`25 patients who self-infused. However, Rusicke ctal. [l3]
`commented on the reduced attack-to-treatment time asso-
`
`ciated with home therapy. Reduced attack frequency was also
`reported by Bork etal. [11], Kreuz etal. [12] and Rusicke
`at al. [13] in patients who infused prophylactically.
`Reports from other home therapy programmes also
`indicate major benefits. Immunoglobulin home therapy is
`associated with greater patient independence, convenience,
`comfort and economic benefit
`[39,40]. A recent study
`showed that home therapy significantly improved health,
`school/social
`functioning (in children) and significantly
`reduced emotional distress and limitations on personal time
`[40]. In a similar study, home therapy with immunoglobulin
`significantly improved QoL [41]. Patients in both surveys
`preferred home— to hospital—based therapy [40,41]. For
`patients with haemophilia, home therapy is associated with
`reduced pain and disability, improved QoL and reduced hos-
`pitalization and time offwork or school [38] . The availability
`of home therapy has also been associated with improved life
`expectancy [42]. Two of the case series in our analysis men-
`tioned improved QoL for HAE patients with access to home
`therapy, although formal studies are lacking [12,13].
`A major issue for patients with HAE is the delay and
`difficulty in accessing emergency care. Better awareness of
`HAE among medical staff and better liaison with emergency
`departments is important, but can be difficult when medical
`staff change frequently, as is the case in most emergency
`departments. Patient education is
`important
`to ensure
`prompt attendance at hospital at an early stage of the attack.
`However, travelling time is likely to be a limiting factor. For
`those patients with rapid-onset attacks, or who live far from
`the hospital, the resulting delay may pose a significant risk.
`Access to emergency treatment can often be expedited only
`by self-infusion/home therapy.
`
`Home therapy for acquired angioedema
`
`Interestingly, the Levi study group included three patients
`with AAE, whose benefit did not differ significantly from
`those with HAE. Cl—INH concentrate appears effective in
`
`14
`
`© 2006 The Author(s)
`Journal compilation © 2006 British Society for Immunology, Clinical and Experimental Immunology, 147: 11—17
`
`Page 6 of 10
`
`Page 6 of 10
`
`

`

`the management of acute attacks of AAE, even when
`Cl-INH antibodies are present, although some patients may
`require higher doses or become resistant to treatment [1,3].
`Bork and Witzke reported a patient with frequent AAE
`attacks who was treated with Cl-INH 1000 units every
`Sdays [8]. Treatment was initially successful, but after
`10 months
`the patient became progressively resistant
`(Table 1). Despite reservations about its durability, CI—INH
`home therapy remains an option for patients with AAE.
`
`Funding and resources
`
`is currently considered an expensive treatment
`Cl—INl'I
`option (approximately £290l€425
`for 500 units). Home
`therapy has the potential to increase overall use of CLINH
`by treating attacks
`that would previously have gone
`untreated, although published data do not suggest that this is
`the case when compared with optimum hospital—based
`treatment [9].
`However, untreated attacks are costly in social, pharmaco-
`economic and QoL terms. HAE is a lifelong condition, which
`usually becomes symptomatic in adolescence. Attacks may
`be precipitated by emotional stress, minor infections or
`oestrogens [18,113]. Consequently, young adults are particu—
`larly at risk of frequent attacks and the lifetime economic
`cost of disrupted education and employment is likely to be
`considerable. Additionally, under-treated attacks — where the
`patient presents late A have major direct costs, as higher
`doses of Cl—INH are required and hospital admission is
`more probable [11]. Studies in antibody therapy and hae—
`mophilia show that home therapy is the most cost-effective
`option for delivering this type of care [44—46]. Cost—benefit
`studies in HAE are required urgently.
`Funding of treatments is coming under increased scrutiny
`in both insurance—based and taxation-based health—care
`
`systems. C1-INH is unlicensed in several countries. In the
`United States it is not Food and Drug Administration (FDA)
`approved, but can be administered for compassionate use.
`Without FDA approval, HAE sufferers must pay the entire
`cost of the therapy themselves. Licensing studies are under
`way for both plasma-derived and recombinant C1»INH and
`for other therapies for acute attacks of HAE. Access to
`Cl-INH, whether hospital- or home—based,
`is
`likely to
`remain suboptimal until
`licensed products are available.
`Even if licensed, the manufacturing costs of plasma-derived
`C1—INH are likely to be out of reach for many middle- and
`low-income countries.
`In the long term,
`recombinant
`Cl—INH or inhibitors of the bradykinin—lmllikrein pathway
`may provide a solution [47—49]. In theory, kallikrein- or
`bradykinin—pathway inhibitors also provide an option for
`patients with AAE who are resistant to CI-INH.
`
`Safety of Cl—inhibitor concentrate
`
`I-‘roducts used for home in fusion need to demonstrate a high
`standard of safety with respect to immunological or allergic
`
`Home therapy in hereditary angioedema
`
`reactions. Cl—INH is extremely well tolerated [1,50,51], and
`our analysis did not reveal any treatment—related adverse
`events [843]. However, because it
`is a plasma product,
`C1-INH raises particular concerns for patients and physi—
`cians regardin