ARTICLE
Auteur(s) : Anette Bygum,
Klaus Ejner Andersen, Carsten Sauer Mikkelsen
Department of Dermatology, Odense University Hospital, 5000
Odense C, Denmark
accepté le 15 Novembre 2008
Hereditary angioedema (HAE) is a relatively rare genetic
disorder, usually caused by an inherited deficiency of C1 esterase
inhibitor (C1-INH) [1]. The condition is characterised by
unpredictable episodic angioedema swellings involving the skin,
gastrointestinal tract or other organs, of which life-threatening
oedema of the larynx is the most serious consequence. The estimated
prevalence of HAE is between 1 in 10,000 and 1 in 50,000 persons
[1-3], making HAE unfamiliar to many physicians. A key issue
for patients with HAE is the delay in diagnosis and subsequent
suboptimal treatment, particularly during acute attacks, which can
lead to severe medical, psychological and economic consequences [4,
5]. Despite its rarity, in a recent overview produced by the
European Dermatology Forum, HAE has been included in the group of
skin diseases with a high public health impact [6].
In some patients, severe swelling attacks occur on a frequent
basis, restricting school, work or social life. While prophylaxis
with danazol or tranexamic acid is possible [7], potential severe
side-effects and limited effectiveness mean that emergency
treatment is often necessary [4, 8]. Owing to the serious nature of
acute HAE attacks with oral, pharyngeal or laryngeal involvement,
patients require prompt treatment with intravenous C1-INH
concentrate (typically 500-1500 units) [9, 10]. C1-INH treatment is
also recommended for severe and painful abdominal attacks [5,
9].
Self-administration of C1-INH concentrate, a relatively new
treatment option, has been introduced in a number of countries to
improve access to acute HAE treatment [11-13]. C1-INH therapy has
been available since 1973 and is licensed for treatment of acute
HAE attacks in several countries worldwide including, from 2008,
the US. It is also available on special access in a number of
additional countries [13]. Currently, no C1-INH replacement product
is licensed in Denmark, but Berinert® P (CSL Behring,
Marburg, Germany) can be used on a named-patient basis with
permission from the Danish Medical Agency.
In 2001, an HAE Comprehensive Care Centre was established in
Odense University Hospital in Denmark. The centre applies
international standards to diagnose, treat and manage patients with
HAE effectively, and aims to improve patients’ quality of life
(QOL) [10, 14]. The centre admits patients from the entire country
referred by their family physicians, allergologists,
dermatologists, internists, paediatricians, or by other hospital
departments. In Denmark, there were 88 registered HAE patients in
2008 and 67 of these were enrolled in the centre.
The aim of this study was to report the effects of
self-administered home therapy with intravenous C1-INH concentrate
on the QOL of Danish patients with HAE using the Dermatology Life
Quality Index (DLQI) and the 36-Item Short Form Survey (SF-36)
[15-18].
Methods
Study population
During 2002, all patients registered at the Odense University
Hospital with HAE attacks requiring emergency department
administration of C1-INH concentrate more than once per month were
offered to be taught self-administration. In all cases,
prophylactic therapy with tranexamic acid or danazol provided
insufficient efficacy or was contraindicated. Two women of fertile
age had only had 5 severe HAE attacks during the last year but more
frequent attacks during previous years. They both felt seriously
distressed by their disease and prophylactic treatment did not
provide optimal control. Therefore, these patients were also
offered home treatment. A total of 9 patients were invited to
join the home therapy programme and 7 accepted. In 5 patients,
prophylactic therapy had been stopped at least 3 months before the
study; the remaining 2 patients continued prophylaxis after
entering the study but discontinued after 3 months due to lack of
effect or side effects. All patients gave written consent under the
Danish guidelines. Children were excluded from the study.
Home therapy programme
Participants were trained to self-administer C1-INH concentrate on
demand between September 2002 and June 2006. Participants were
trained by two nurses, all under the supervision of one physician.
Education for home treatment with C1-INH concentrate followed an
established protocol (table 1), compiled
in accordance with international recommendations [10, 11, 13].
Patients were trained individually for 3-6 hours, if possible with
an infusion partner (a household member willing to help with the
procedure). The trigger for C1-INH treatment in the study was an
angioedema attack affecting the face, mouth and
pharynx/larynx/upper airway (potentially compromising the airway),
a painful abdominal attack or progressive limb swelling.
Patients continued to receive their usual care, including
twice-yearly visits to the centre and a hotline access in case of
acute problems. At follow-up visits, all intermediate attacks were
documented with information on the trigger, location, treatment and
adverse events. Blood samples were taken annually for viral assays,
and stored frozen for subsequent assessment if necessary.
Re-testing of patients’ skills for self-administering C1-INH was
not undertaken, as patients self-infused regularly and therefore
retained their skills.
Table 1 Home therapy educational programme
|
Background information on the disease and treatment
possibilities
|
|
Indications for administration of C1-INH concentrate
|
|
Storage, reconstitution and administration of C1-INH concentrate
through venepuncture with a butterfly needle
|
|
Hygiene and how to work properly with needles and syringes
|
|
Documentation of each C1-INH concentrate replacement and swelling
attack in a diary with registration of adverse effects
|
|
Instruction in handling a potential allergic response with
epinephrine (Epipen®)
|
|
Instruction in emergency treatment at the local hospital in case of
treatment failure
|
|
Advice as to when to consult a physician if the attack symptoms are
atypical or accompanied by fever
|
Quality-of-life questionnaires
There is a lack of literature about QOL in patients with HAE and,
as yet, no HAE-specific questionnaires exist. Changes in QOL in
patients receiving C1-INH as home treatment were therefore measured
using a well-validated dermatology QOL questionnaire, the DLQI, and
a general health measures tool, the SF-36. QOL assessments were
conducted just before patients began home therapy, and again in
September 2006 once patients had received home therapy for 3-48
months (mean 29 months). QOL assessments were conducted by
telephone interview by the same person and in the same order (DLQI
followed by SF-36) to ensure consistency. Neither questionnaire
focussed on acute attacks of HAE; instead, both related to
retrospective time periods.
DLQI has a maximum score of 30 and a minimum of 0; the higher
the score, the more QOL is impaired. In dermatology, a change of at
least 5 is considered to be clinically meaningful; this can also be
used as a benchmark for the skin component of HAE [19].
General health measures cross-validated with the DLQI include
the generic questionnaire SF-36, which has been validated across a
number of medical conditions including a number of dermatological
conditions [20]. The SF-36 was constructed to survey health status
and was designed for use in clinical practice and research, health
policy evaluations and general population surveys [18]. We used the
Danish manual of SF-36 (IQOLA SF-36 Danish Special Version
1.1).
Statistical analysis
QOL outcomes from the DLQI and SF-36 were analysed descriptively
for the periods before and after self-administration of C1-INH. In
addition, paired t-tests were used to analyse whether SF-36 results
differed significantly before and after learning self-injection,
and a corresponding parametric 95% confidence interval was
calculated for the mean difference between ‘raw’ scores. Results
from the SF-36 can also be reported as a physical component summary
(PCS) scale and as a mental component summary (MCS) scale. Both
summary scales were calculated by multiplying each of the eight
individual SF-36 scores by their respective factor score
coefficients. Given the small sample size in the study, only strong
effects were expected to be statistically detected. P values <
0.05 were considered to be statistically significant.
Results
Nine of 67 patients with proven C1-INH deficiency were eligible for
inclusion in the study. Seven patients chose to participate in the
home therapy programme, while the remaining two did not want to
inject themselves. The seven study participants (age range 19-41
years, mean 32.4 years) had very frequent or severe angioedema
attacks compromising their family life, education or work, leading
to psychological distress. All seven patients had hereditary C1-INH
deficiency with a normal C1q, and had experienced symptoms since
childhood. Patients had been using home therapy for 3 months to 4
years at the time of the post-treatment questionnaire, while the
total home treatment observation period ranged from 27 to 72
months.
Prior to their education in home therapy, the patients had
between 5 and 60 angioedema attacks per year, with a median
duration of 3 days per attack. This made them potentially unable to
engage in normal social activities for between 15 and 180 days each
year. Background data for the study population are shown in table 2. All patients were trained
successfully, and 5 had infusion partners.
Complications of home therapy
Although no adverse incidents occurred during the follow-up period
as a direct consequence of the treatment, two patients required
intervention, each on a single occasion. Patient 6 had to call an
ambulance once because of difficulty in getting venous access. The
ambulance personnel were able to assist her and a hospital visit
was not necessary. Patient 4 experienced one treatment failure (a
feeling of swelling in his throat despite treatment with two
1000-unit doses of C1-INH concentrate over 1 day) that caused him
to go to the hospital, where a febrile pharyngeal infection was
diagnosed, and he was treated with antibiotics. He remained under
observation in the intensive care unit for the first night.
Table 2 Patient characteristics and history for the
seven patients with hereditary angioedema receiving C1 esterase
inhibitor home therapy
|
Patient number
|
1
|
2
|
|
3
|
4
|
|
5
|
6
|
7
|
|
Gender/age (years)
|
F/19
|
M/40
|
|
M/34
|
M/41
|
|
F/40
|
F/34
|
M/19
|
|
Age at HAE onset (years) (mean: 4.4)
|
10
|
10
|
|
2
|
2
|
|
1
|
5
|
1
|
|
Age at diagnosis (years) (mean: 15.0)
|
15
|
19
|
|
14
|
16
|
|
11
|
19
|
11
|
|
HAE attacks in year prior to home treatment education (n)
|
5
|
> 24
|
|
> 24
|
60
|
|
5
|
12-24
|
12-24
|
|
Total hospitalisations due to HAE (n)
|
11+
|
11+
|
|
5
|
3
|
|
2
|
5+
|
10+
|
|
Previous prophylactic therapy/duration/ reason for stopping
|
TA
|
TA
|
DA
|
TA
|
TA
|
DA
|
DA
|
TA
|
TA
|
|
3 years
|
2 years
|
16 years
|
2 years
|
9 years
|
11 years
|
2 years
|
8 years
|
1 year
|
|
WI
|
WI
|
AE
|
WI
|
WI, AE
|
WI, AE
|
AE
|
WI
|
WI, AE
|
|
Follow-up period since beginning home therapy (months)
|
39
|
72
|
|
52
|
67
|
|
27
|
52
|
63
|
Quality-of-life questionnaires
Figure 1 shows
the summary of DLQI scores for each patient before and after
self-injection of C1-INH. The mean DLQI before establishing home
therapy was 12.6 (standard deviation [SD], 4.65) and after
establishment of home therapy, it reduced to 2.7 (SD 1.38; P <
0.001). This represents a 9.9 unit (79%) reduction and, based on
the cut-off of ≥ 5, can be considered clinically significant.
Similarly, SF-36 scores demonstrated an improvement in QOL
associated with self-injection of C1-INH concentrate. Mean scores
increased significantly after home therapy for all SF-36 parameters
(table 3), and the increase ranged from
14 to 96%. Cumulative mean scores for the physical and
psychological components also increased significantly after home
therapy (table 4). All patients had
physical, psychological and social difficulties attributable to HAE
prior to self-administration and, in all cases, home therapy
resulted in significantly improved QOL and reduced use of emergency
services (P < 0.05).
Table 3 SF-36 scores before and after education in home
therapy with C1-INH concentrate – mean values for the seven
patients (with data transformed to 0-100% scale in brackets)
|
Before self-injection
|
After self-injection
|
Change in SF-36 score (mean)
|
95% CI for increase
|
P-value
|
|
Physical function
|
26.00 (80.0%)
|
28.71 (93.6%)
|
2.71 (13.6%)
|
[0.74-4.69]
|
0.0153*
|
|
Role physical
|
4.14 (3.6%)
|
8.00 (100%)
|
3.86 (96.4%)
|
[3.51-4.21]
|
< 0.0001*
|
|
Bodily pain
|
2.90 (9.0%)
|
9.74 (77.4%)
|
6.84 (68.4%)
|
[5.02-8.67]
|
0.0001*
|
|
General health
|
9.34 (21.7%)
|
21.17 (80.9%)
|
11.83 (59.2%)
|
[6.71-16.95]
|
0.0013*
|
|
Mental health
|
16.43 (45.7%)
|
28.14 (92.6%)
|
11.71 (46.9%)
|
[6.83-16.60]
|
0.0011*
|
|
Role emotional
|
4.57 (52.4%)
|
6.00 (100%)
|
1.43 (47.6%)
|
[0.03-2.83]
|
0.0465*
|
|
Social function
|
6.43 (55.4%)
|
9.43 (92.9%)
|
3.00 (37.5%)
|
[1.23-77.00]
|
0.0060*
|
|
Vitality
|
12.14 (40.7%)
|
20.43 (82.1%)
|
8.29 (41.4%)
|
[4.76-11.82]
|
0.0012*
|
Table 4 Cumulative mean SF-36 scores before and after
self-injection of C1-INH concentrate
|
Before self-injection
|
After self-injection
|
95% CI for increase
|
P-value
|
|
Physical component
|
30.95
|
51.96
|
[15.29-26.73]
|
0.0001*
|
|
Psychological component
|
39.08
|
58.99
|
[9.58-30.23]
|
0.0033*
|
Discussion
The unpredictable, painful and sometimes life-threatening attacks
make HAE very stressful for patients and their families. Home
treatment with C1-INH concentrate, for use at the earliest sign of
an attack, can alleviate the distress and improve QOL for patients
and their families. After training, all patients in the present
study were able to treat severe angioedema attacks. Patients were
seen at follow-up visits twice a year to control adherence to the
home therapy programme; infusion skills were maintained in all
patients.
In this study, two QOL assessment tools (the DLQI and the SF-36)
were used to assess the benefits of C1-INH home therapy. Neither of
these widely used questionnaires has been validated for HAE, but we
believe they were the best tools available. Home therapy with
C1-INH produced a significant improvement in QOL. The mean DLQI
score of 12.6 prior to self-administration is consistent with
results from a dermatology clinic in the UK where mean DLQI scores
were 8.9–12.5 in patients with pruritus, psoriasis and atopic
eczema [15]. In the same study, the mean score in 100 healthy
volunteers was 0.5. After learning to self-administer C1-INH
concentrate, the DLQI score reduced by 9.9 units (79%) in our
patients which, based on the proposed cut-off from dermatology
patients (≥ 5) [19], can be considered to be clinically
significant. The SF-36 data also showed considerable improvement in
all parameters. The cumulative mean scores for the physical
component improved from 30.95 to 51.96 and the mental component
from 39.08 to 58.99.
During follow-up visits, all patients felt that they had gained
control of their disease and their lives, and were no longer afraid
of life-threatening upper airway attacks or painful abdominal
attacks. Following entry into the home therapy programme, all
patients experienced substantial improvements in QOL and were able
to undertake normal and working family life including travelling.
In fact, one patient, who had experienced more frequent and severe
attacks during pregnancy before entering the programme, was
sufficiently rehabilitated to consider having another child.
Patients 4 and 6 were using prophylactic treatment just before
entering the study and for the first 3 months of the study period.
Patient 4 had adverse effects of weight gain, myalgia and
aggressiveness from danazol and, therefore, it is possible that his
QOL before self-injection could have been impaired by danazol. The
other 5 patients had stopped prophylaxis at least 3 months before
the study. Optimally, a control group of patients not participating
in the home infusion programme should have been included. As our
study was uncontrolled, some of the improvement in QOL could have
been related to factors other than the home infusion programme
(e.g. increased standard of care owing to participation in the
study).
The infusion partners served as security for the patients, but
in practice this support was rarely needed. Furthermore, the
presence or absence of an infusion partner would not be expected to
affect the QOL since patients self-administered personally. The
only published data using validated QOL instruments in HAE patients
are from a study by Poon and co-workers, who measured and compared
DLQI scores in different urticarial conditions including five
patients with HAE [21]. This study suggested that the DLQI could be
applied to this patient population. However, the DLQI has several
limitations in HAE. It seems to be designed primarily for chronic
diseases with exacerbations (e.g. psoriasis, atopic dermatitis) and
refers to pruritus, which is not associated with HAE, as the main
symptom. Moreover, it does not take into account the acute
abdominal attacks of angioedema. A specific HAE QOL
questionnaire is currently under development in Spain, and will be
translated and validated in other countries, including Denmark
[22]. This disease-specific questionnaire is expected to give more
detailed and relevant data on QOL in HAE patients in the years
ahead. In three case series, improved QOL for HAE patients with
access to home therapy has been mentioned without further
qualification by validated QOL tools [12, 23, 24].
The use of QOL instruments gives a greater insight into the
specific issues that patients encounter, allowing their progress to
be monitored once home therapy is established. This information may
be important for those treating HAE and allocating health care
resources.
Published data indicate that home therapy does not affect the
overall consumption of C1-INH concentrate, compared with optimal
hospital-based treatment [11-13]. In this study, home therapy was
associated with increased consumption, but this was attributable to
previous under-treatment due to difficulties in accessing emergency
treatment. Costs arising from C1-INH therapy must be considered in
light of the fact that untreated attacks represent a significant
cost in social, pharmacoeconomic and QOL terms [13]. Home therapy
may also benefit healthcare systems as patients have fewer
healthcare visits and fewer episodes of hospitalisation.
Furthermore, time off work is markedly reduced in self-injecting
patients [23].
Home therapy is reflective of the changing nature of the
relationship between patients and medical professionals, with many
patients now expecting to take a more active role in the management
of their conditions. In our experience, home therapy with C1-INH
concentrate is not associated with side-effects, apart from one
patient who experienced difficulties getting venous access. We find
home therapy very valuable and now offer this treatment option to
all adult patients requiring C1-INH infusions at least every 3
months. The home therapy programme with C1-INH infusions can be
combined with prophylactic treatment with danazol or tranexamic
acid. In selected cases and in cooperation with the paediatric
department, we now also offer the home treatment programme to
children with help from their parents.
Acknowledgements
The authors are grateful to Fritz Schindel for statistical analysis
and Professor Andrew Y Finlay for providing permission to use the
DLQI in this research study and to publish these results. This
study was supported by an investigational grant from CSL Behring.
CSL Behring had no input into the study design or results. The
authors have no conflict of interest to declare.
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