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van den Elzen et al. Clin Transl Allergy (2017) 7:4
DOI 10.1186/s13601-017-0141-3
RESEARCH
Eectiveness andsafety
ofantihistamines upto fourfold or higher
intreatment ofchronic spontaneous urticaria
Mignon T. van den Elzen* , Harmieke van Os‑Medendorp, Imke van den Brink, Karin van den Hurk,
Ouliana I. Kouznetsova, Alexander S. H. J. Lokin, Anna‑Marijke Laheij‑de Boer, Heike Röckmann,
Carla A. F. M. Bruijnzeel‑Koomen and André C. Knulst
Abstract
Background: Treatment with second‑generation antihistamines is recommended in patients with chronic spontane‑
ous urticaria (CSU). Some patients remain unresponsive even after up‑dosing up to fourfold. Many third line treatment
options have limited availability and/or give rise to significant side effects. We investigated effectiveness and safety of
antihistamine treatment with dosages up to fourfold and higher.
Methods: This retrospective analysis of patients’ records was performed in adult CSU patients suffering wheals
and/or angioedema (AE). Demographic, clinical, and therapeutic data was extracted from their medical records. We
recorded the type, maximum prescribed dosage, effectiveness, and reported side effects of antihistamine treatment.
Results: Of 200 screened patients, 178 were included. Treatment was commenced with a once daily dose of anti‑
histamines. Persisting symptoms meant that up‑dosing up to fourfold occurred in 138 (78%) of patients, yielding suf‑
ficient response in 41 (23%). Up‑dosing antihistamines was necessary in 110 (80%) patient with weals alone or weals
with angioedema and 28 (64%) with AE only (p = 0.039). Of the remaining 97 patients with insufficient response,
59 were treated with dosages higher than fourfold (median dosage 8, range 5–12). This was sufficient in 29 patients
(49%). Side effects were reported in 36 patients (20%), whereof 30 (17%) experienced somnolence. Side effects after
up‑dosing higher than fourfold were reported in six out of 59 patients (10%).
Conclusion: Up‑dosing antihistamines higher than fourfold dosage seems a feasible therapeutic option with regards
to effectiveness and safety. The need for third line therapies could be decreased by 49%, with a very limited increase
of reported side effects.
Keywords: Urticaria, Angioedema, Antihistamines, Refractory, Therapy
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Background
Chronic urticaria is either inducible (CINDU) or sponta-
neous (CSU) or both [1, 2]. Angioedema (AE) can occur
concurrently with urticaria in up to 40% of cases, and
may occur alone in up to 10–20% of cases [3]. Patients
suffering CSU can have wheals only, AE only, or both [1].
e therapeutic approach of chronic urticaria aims at
symptom relief. Licensed doses (1 tablet daily) of modern
second-generation antihistamines (sgAH) are the first
line treatment. An increase in the dose only up to four-
fold is recommended as second line treatment [1, 4].
However, every third to fourth patient will remain symp-
tomatic despite up-dosing up to fourfold [5], hence alter-
native treatments are needed for (partially) unresponsive
patients [1]. Current third-line—in the US guideline
fourth-line—treatment options consist of omalizumab,
cyclosporine A (CsA) or leukotriene receptor antagonist
montelukast [1, 4]. However, each of these options has
limitations: omalizumab is expensive and not reimbursed
worldwide. CsA has a high incidence of adverse effects.
Open Access
Clinical and
Translational Allergy
*Correspondence: melzen3@umcutrecht.nl
Department of Dermatology and Allergology, University Medical Center
Utrecht (G02.124), PO Box 85.500, 3508 GA Utrecht, The Netherlands
Page 2 of 8
van den Elzen et al. Clin Transl Allergy (2017) 7:4
For leukotriene receptor antagonists, the level of evi-
dence for efficacy is low [1].
In our tertiary center, refractory patients were treated
with antihistamines at varying dosages (including dos-
ages higher than fourfold), in order to avoid the use of
CsA as omalizumab had not yet been approved for treat-
ment of CSU. Despite a lack of controlled studies, experts
have reported benefit of dosing antihistamines higher
than fourfold in CSU patients [6]. e objective of this
study was to investigate the frequency of ineffective-
ness of treatment with antihistamines up to fourfold the
standard dose in patients with CSU, and to determine the
effectiveness and safety of antihistamine treatment above
fourfold the standard dose,.
Methods
Study design andsubjects
A retrospective analysis of patients’ records was per-
formed in patients visiting our tertiary dermatology and
allergology clinic for the evaluation of chronic urticaria
and/or angioedema in 2012 (before registration of omali-
zumab), and for each patient all available data were col-
lected up to 2014. Adult patients suffering CSU (wheals
and/or AE for at least 6weeks) were selected. All patients
with other diagnoses including acute urticaria (dura-
tion of symptoms less than 6weeks), CINDU including
symptomatic dermographism, urticaria or angioedema
caused by allergy or of other known causes, urticaria pig-
mentosa and urticaria vasculitis were excluded. Medical
records were screened to verify inclusion and exclusion
criteria. To be recognized as a representative sample, 159
patients were needed (based on a margin of error of 5%,
a confidence interval of 95% and an eligible population
of 268 patients) [7]. To have a representation of both AE
patients and patients with wheals, all 100 available AE
patients and 100 additional patients with wheals were
screened for inclusion in the study. Patients with wheals
were randomly selected based on their unique patient
identification number in the electronic medical record
system; dossiers of the patients with the lowest num-
bers were screened until 100 patients with wheals were
included.
Data were collected as described below, and used in
strictly anonymous form, according to the code of con-
duct for medical research approved by the hospital’s
Medical Ethical Committee. Written informed consent
for the publication of this report was not required from
the patients, as approved by the Ethics Committee, pro-
tocol number 13-459.
Treatment regimen
e local treatment protocol, as shown in Fig.1, com-
menced with the approved dosage of antihistamine, and
in case of persisting symptoms up-dosing occurred up to
fourfold. Higher than fourfold dosages were only used in
patients who remained symptomatic at fourfold antihis-
tamine dosages. Treatment adjustments were performed
individually by all prescribing physicians of the depart-
ment. Patients often were already on antihistamine treat-
ment prior to their first visit at the clinic. In this case,
they did not have to start at the licensed dosage, but
could further follow the local protocol. All treatment was
open. At the start of the study, standard disease-specific
questionnaires were not yet available and therefore not
used.
Data collection
After inclusion, data was collected from electronic
patient records. Data regarding demographic and thera-
peutic characteristics until 2014 was extracted manually
from the electronic medical records from each patient’s
first visit to the clinic. Outcome variables were the type
All CSU patients:
Start licensed dose
Sufficient
response
Insufficient
response
Up-dose up to
fourfold
Re-evaluate every
3-6 months Re-evaluate every
3-6 months
Up-dose higher
than fourfold
Complete response
Partial response,
patient satisfied
Partial response,
patient not satisfied
No response
Re-evaluate every
3-6 months
Need for add-on
treatment
Add-on treatment
Licensed dose = 1 tablet daily of one of
the following antihistamines:
- cetirizine 10 mg
- desloratadine 5 mg
- ebastine 10 mg
- fexofenadine 120 mg
- levocetirizine 5 mg
- loratadine 10 mg
- rupatadine 10 mg
Up-dosing up to fourfold: preferably by
up-dosing to max 4 tablets of the
antihistamines mentioned in the left
box, or max 4 tablets of the following:
- clemastine 1 mg
- hydroxyzine 10 mg
Up-dosing higher than fourfold:
preferably by combining two of the
antihistamines mentioned in the left
boxes, max 4 tablets per type of
antihistamine.
Sufficient
response
Insufficient
response
Fig. 1 Local treatment protocol. When patients were already on antihistamine treatment prior to their first visit at the clinic, they could further fol‑
low the local protocol. Evaluation was planned every 3–6 months, or earlier if symptoms are intolerable
Page 3 of 8
van den Elzen et al. Clin Transl Allergy (2017) 7:4
of antihistamines patients were treated with, the maximal
prescribed dosage, treatment results, and reported side
effects.
For each patient antihistamine use was recorded as
daily treatment as well as rescue medication., e type,
maximal prescribed dosage, treatment results including
clinical symptoms of wheals, angioedema, and itch, and
reported side effects were also recorded. Antihistamines
were prescribed prior to or during consultations at this
tertiary hospital. In the Netherlands, all types and dos-
ages of antihistamines are reimbursed, hence prescribing
is not affected by insurance. e doctor’s reported effect
from each treatment option was allocated by the inves-
tigators into one of two categories: sufficient or insuffi-
cient. Disagreements were discussed and resolved. When
the dose of antihistamines was raised and further infor-
mation was missing, it was interpreted that lower doses
did not reach sufficient response. e reported effect
from dosages higher than fourfold was further subdi-
vided into four different categories: (1) no effect (2) insuf-
ficient effect and patient not satisfied, (3) partial disease
control, and patient satisfied, or (4) completely free of
symptoms. If information was unclear category alloca-
tion was performed by two investigators. Up-dosing
higher than fourfold was preferably performed by com-
bining more than one type of antihistamine. In these
cases the effect of one specific antihistamine was unclear
and was not included for analysis. In case of side effects,
the type of side effect as reported in the medical record,
as well as the corresponding eliciting dosage of antihis-
tamines, were recorded. Additional blood tests were not
performed routinely.
Analyses
Descriptive statistics were performed using IBM SPSS
Statistics version 21. To explore differences in the pro-
portion of patients with sufficient or insufficient effect
from antihistamines in the three subgroups of patients
(wheals only, AE only, and both wheals and AE), patients
with unknown effect of treatment were excluded, and
the Pearson Chi Square (Chi square) test was used. e
Fisher-Freeman-Halton exact (Fischer’s exact) test was
used in cases of low numbers.
Results
Population
Of the 200 screened patients, 178 patients (121 [68%]
female; median age 48.2years [range 20–87]) were diag-
nosed with CSU and were included in the study, includ-
ing 10 patients who suffered both CSU and CINDU. Five
of 200 were excluded due to angioedema with known
causes (1 with HAE, 1 with specific allergy, and 3 with
ACEi-AE) and 17 were excluded since they had only
inducible symptoms (CINDU). Of the included 178, 43
patients (24%) had wheals only, 44 (25%) had AE only,
and the remaining 91 (51%) suffered both symptoms.
e median disease duration before the first consulta-
tion at our University referral center was 1year (range
0–41.5years). Ninety-four patients (53%) reported that
they had previously visited another dermatologist or
allergologist for evaluation of wheals and/or AE. All visits
per patient were reviewed, and this comprised a median
number of visits of 2 (range 1–57) and an additional
median number of 2 consultations per telephone (range
0–24).
Maximum doses andeectiveness ofantihistamines
All 178 included patients were initially treated with the
licensed, once daily, dosage of antihistamines (Fig. 2).
Of them, 27 patients (15%) used antihistamines only on
demand. In 138 patients (78%) the licensed dose was inef-
fective and in all these refractory patients the dose was
raised up to fourfold. is remained ineffective in 97
(70%). Subsequently, 59 of these 97 patients were treated
with higher doses of antihistamines by combining two
types of second generation antihistamines with a maxi-
mum of eightfold the licensed dose. e median maximal
combined dose of antihistamines in these 59 was eight-
fold (range 5–8), however in 8 individuals the dose was
raised further (range 9–12). Ten of 59 patients (17%)
subsequently became completely free of symptoms, and
nineteen patients (32%) had sufficient results. us, in
49% of patients a higher than fourfold dose reduced or
completely eliminated symptoms. e remaining 38 of
the 97 refractory patients received no further treatment
(n=28), or further treatment was unknown (n=8), or
they received other types of therapy including ultravio-
let (UV) treatment (n=2), for which effectiveness results
were not included in the current study (Fig.2).
Need forup‑dosing inwheals versusAE withoutwheals
Up-dosing up to fourfold was necessary more frequently
in patients with wheals (wheals only: 35 of 43 patients;
81%, wheals and AE: 75 of 91 patients; 82%) than in AE
without wheals (28 of 44 patients; 64%; p=0.039). How-
ever, when looking specifically at those with only one of
the two symptoms, there was no statistically significant
difference between wheals only and AE only (p=0.053,
Table1a).
A trend was observed that up-dosing higher than
fourfold was also necessary more often in patients with
wheals (17; 40%) compared to AE only (7; 16%; p=0.056,
Table1a).
Response to antihistamine dosages higher than four-
fold dichotomized as sufficient (29 patients [58%]) versus
insufficient (21 patients [42%]) did not differ between the
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van den Elzen et al. Clin Transl Allergy (2017) 7:4
three diagnosis groups (p=0.530, Table1b), or between
patients with wheals only or AE only (p=0.620).
Types ofantihistamines
e 178 patients received a total of 354 antihistamine
prescriptions. As shown in Table2, the most frequently
prescribed antihistamines were levocetirizine (71% of
patients), desloratadine (56%) and fexofenadine (23%). A
total of 35 patients (20%) were treated with clemastine,
and 26 patients (15%) were treated with hydroxyzine.
Since 12 patients were treated with both hydroxyzine and
clemastine at any time during their disease, a total of 49
patients (28%) received first-generation antihistamines
(fgAH). All patients who were treated with fgAH were
refractory to licensed doses: 13 (27%) received fgAH as
part of up-dosing up to fourfold, and the remaining 36
(73%) received fgAH in addition to sgAH to reach total
dosages of antihistamines higher than fourfold. Clem-
astine was up-dosed in 11 patients up to 3mg per 24h
period, and hydroxyzine in nine patients up to 75mg per
24h.
Safety ofantihistamines
Of the 178 patients 36 (20%) reported side effects upon
treatment with antihistamines independent of the dos-
age. Fifteen of 36 patients reported side effects for
two (n= 14) or three (n = 1) different antihistamines
(Table 3). Somnolence (Fig. 3a) was reported in 30 of
36 patients (83%), including 5 patients (10%) treated
with fgAH and 28 (16%) with sgAH. Six out of 36 (17%)
reported side effects only during treatment with dosages
higher than fourfold (Fig.3b). ey consisted of somno-
lence in five patients and were unclear in 1. Vomiting or
diarrhea were not reported by any of the patients.
Discussion
In CSU patients refractory to up to fourfold doses of
antihistamines, higher than fourfold dosages reduced or
completely eliminated symptoms in an additional 49%.
Side effects were reported in 20% of patients and con-
sisted mainly of somnolence. After up-dosing higher than
fourfold only 6 out of 59 patients (10%) reported side
effects.
In more than half of the total population response
remained insufficient despite antihistamine treatment
up to fourfold, consistent with previous studies [8–10].
Up-dosing higher than fourfold, with a median dose of
eight tablets daily, was effective in half of patients includ-
ing those with wheals only, with AE only, and with both
symptoms. is is promising, since antihistamines have
low costs as opposed to CsA or omalizumab, and they are
available worldwide [1]. ere is a lack of rationale for the
dosage of fourfold being the maximum. In contrast, in
both CSU and in cold urticaria, treatment with four tab-
lets per day was shown to be more effective than three
tablets per day, which in turn was more beneficial than
two tablets or one tablet per day, indicating that higher
doses could be more effective [9, 11]. Moreover, hydrox-
yzine is prescribed up to 200mg/day, and because 30mg
of hydroxyzine equals about 10mg cetirizine [11]. Two-
hundred mg equals a dose of 60mg cetirizine/day, con-
siderably higher than fourfold. Since such high dosages
of hydroxyzine are used in daily practice, it was likely
that higher dosages of other antihistamines could also be
effective. Additionally, hydroxyzine is a first generation
antihistamine with considerably more side-effects than
cetirizine. We conclude that many patients indeed had
a favorable response to higher doses of antihistamines
when doses up to fourfold were insufficient.
Totalpopulation
178
Licensed dose:
178
Sufficient:40(22%)
Insufficient:138 (78%)
Up to fourfold dose:
138
Higher than fourfold dose:
59
No effect:1(2%)
Insufficient: 20 (34%)
Sufficient: 19 (32%)
No symptoms: 10 (17%)
Unknown: n=9
Needfor additional treatment:97
(54% of population)
Need foradditional
treatment reducedby49%
No furthertherapy:28
Other 2
Unknown: 8
Sufficient:41(23%)
Insufficient:97(54%)
Fig. 2 Antihistamine dosages and results. The following dosages
were considered as standard dose: levocetirizine 5 mg, desloratadine
5 mg, fexofenadine 180 mg, clemastine 1 mg, hydroxyzine 25 mg,
cetirizine 10 mg, loratadine 10 mg, acrivastine 8 mg three times daily
Page 5 of 8
van den Elzen et al. Clin Transl Allergy (2017) 7:4
e effect of antihistamines, but only up to fourfold,
has been studied previously, but very few head-to-head
studies have been performed [9, 12]. Some studies have
examined antihistamines up to fourfold [9, 13], or four
tablets daily [8]. e latter may be somewhat confusing,
for instance for fexofenadine where both 120 and 180mg
tablets are available. ere are also studies available where
only twofold dosages were the maximum [10]. Some stud-
ies showed preponderance of efficacy of higher dosages in
the treatment of chronic spontaneous urticaria [8–10, 14],
and cold and cholinergic urticaria [15–18]. In contrast, in
some other studies comparable efficacy of standard and
higher dosages was found [19–22].
e most frequently used antihistamine were sgAH.
e use of fgAH is discouraged in the European guide-
line [1] since serious side-effects of these old sedating
antihistamines have been reported, including lethal over-
doses. Additionally, in the elderly they increase the risk
of impaired cognition, inattention, disorganized speech,
altered consciousness, and falls [1]. Yet, a substantial
number of patients was treated with fgAH at some time
during their disease: clemastine was prescribed to 20%
Table 1 Frequencies ofup-dosing (a) andeectiveness ofantihistamine dosages higher thanfourfold (b)
*One patient suering wheals only reported no eect of up-dosing to vefold or higher, this case is included in the group of patients with insucient eect. There
was no statistically signicant dierence in treatment result between the three groups (Fischer’s exact p=0.530) nor in those with wheals only (included for analysis:
n=17) and AE only (n=7, Fischer’s exact p=0.620)
a Percentages are shown per row to enable comparison between diagnoses groups. Patients are shown in their maximum dosage group, thus patients who received
vefold or higher have previously been treated with lower doses. Numbers therefore dier from Fig.1. There was no statistically signicant dierence in frequency
of up-dosing between the three groups (Chi square p=0.053), and also not between those with wheals only (included for analysis: n=35) and AE only (n=28; Chi
square p=0.056). n.a. not applicable
b Percentages are shown per row to enable comparison between diagnoses groups. Eect of treatment was unknown in nine patients, the numbers of patients
therefore dier from Table1a
(a) Frequencies of up-dosinga
Symptoms Licensed dose
n (%) Up tofourfold
n (%) Higher thanfourfold
n (%) Total n (%)
AE only 16 (36) 21 (48) 7 (16) 44 (100%)
Wheals only 8 (19) 18 (42) 17 (40) 43 (100%)
AE and wheals 16 (18) 40 (44) 35 (38) 91 (100%)
(b) Eectiveness of antihistamine dosages higher than fourfoldb
Symptoms Insucient*
n (%) Sucient
n (%) No symptoms
n (%) Total n (%)
AE only 2 (33) 2 (33) 2 (33) 6 (100%)
Wheals only 7 (58) 3 (25) 2 (17) 12 (100%)
AE and wheals 12 (38) 14 (44) 6 (19) 32 (100%)
Table 2 Frequency ofuse andfrequency ofsatisfying result perantihistamine
Frequency data are presented as numbers and percentages of the total population (n=178), and frequencies of sucient response are presented as percentages of
those treated with the specic antihistamine
*In 1 patient it was unknown which dose caused sucient eect. n.a. not applicable. Please note that in most patients where up-dosing higher than fourfold
occurred, this was done by combining more than one type of antihistamine. In these cases the eect of one specic antihistamine was unclear and was not included
in this analysis
Antihistamine Frequency
n (%) Sucient eect oflicensed
dose
n (%)
Sucient eect afterup‑
dosing
n (%)
Dose withsucient
eect median (range)
Levocetirizine 5 mg 126 (71) 15 (12) 26 (21) 2 (0–6)
Desloratadine 5 mg* 99 (56) 1 (1) 15 (15) 4 (1–6)
Fexofenadine 180 mg 41 (23) 5 (12) 2 (5) 1 (0–2)
Clemastine 1 mg 35 (20) 1 (3) 2 (6) 2 (1–2)
Hydroxyzine 25 mg 26 (15) 0 (0) 1 (4) 3 (n.a.)
Cetirizine 10 mg* 16 (9) 2 (13) 2 (13) 1.5 (1–4)
Loratadine 10 mg 9 (5) 0 (0) 1 (11) 2 (n.a.)
Acrivastine 3 × 8 mg 2 (1) 0 (0) 0 (0) n.a.
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van den Elzen et al. Clin Transl Allergy (2017) 7:4
and hydroxyzine to 15%. It was previously suggested that
some physicians were not fully aware of the content of
the most recent guidelines and therefore did not follow
them [23]. However, the successful use of fgAH after fail-
ure of treatment with sgAH has been described [24]. Fur-
thermore, the US guideline does support the use of fgAH
in patients who do not achieve control of their condition
with higher-dose second-generation antihistamines [4].
Our results support that the addition of not only sgAH
but also of fgAH can lead to sufficient disease control
when either licensed doses of sgAH, or dosages up to
fourfold had failed.
Somnolence was reported by a minority of patients.
It is well known that somnolence is one of the most
reported unwanted effects of antihistamines. It occurs
even when using sgAH [9] in up to 23% of patients [8],
and it does not significantly increase when comparing
with baseline somnolence [9], or when antihistamine
doses are increased [8]. is was confirmed in our study
for even higher dosages. Patients treated with fgAH did
not report sedation more often than those treated with
only sgAH. A possible explanation for this is that fgAH
were mostly used in low dosages in addition to high dos-
ages of sgAH, whereas often times relatively high doses
of fgAH are used [24–26]. Very few of the side effects
(10%) were reported only when antihistamine dosages
were raised higher than fourfold. For desloratadine it
was previously shown that dosages up to ninefold did not
lead to clinically relevant adverse effects [27]. e low
frequency of somnolence in the current study is likely to
be an underestimation of unwanted effects due to miss-
ing information or recall bias, and since patients were
not all actively asked about side effects, including but not
limited to somnolence. It could also be caused by toler-
ance to somnolence which can develop within 4 days
of subsequent use of H1 antihistamines [24, 28]. It was
hypothesized that this is caused by adapted neurophar-
macological effects [28]. On the other hand, it remains
difficult to distinguish somnolence caused by treatment
Table 3 Frequency ofside eects perantihistamine
Data are presented as numbers and percentages of patients treated with this antihistamine. Patients may have reported side eects upon treatment with more than
one antihistamine, therefore the numbers do not match the total number of patients reporting at least one side eect. “Other” side eects occurred in one patient
each, unless otherwise specied. Percentages are rounded and may therefore not match within one row. Please note that a low frequency of side eects may be due
to a low frequency of use for the specic antihistamine, and to a lack of updating in the study population since only patient-reported side eects were shown
Antihistamine Frequency
n (%) Somnolence
n (%) Other
n (%) Other side eects
Levocetirizine 5 mg 28 (22) 22 (17) 6 (5) Weight gain (n = 2), palpitations, increase of symptoms, unclear (n = 2)
Desloratadine 5 mg 14 (14) 9 (9) 5 (5) Palpitations, headache, increase of symptoms (n = 2), unclear (n = 2)
Fexofenadine 180 mg 2 (5) 1 (2) 1 (2) Increase of symptoms
Clemastine 1 mg 3 (9) 2 (6) 1 (3) Increased intra‑ocular pressure
Hydroxyzine 25 mg 3 (12) 3 (12) 0 (0) n.a.
Cetirizine 10 mg 0 (0) 0 (0) 0 (0) n.a.
Loratadine 10 mg 1 (11) 1 (11) 0 (0) n.a.
Acrivastine 3 × 8 mg 0 (0) n.a n.a n.a.
% of patients treated% of patients treated
0
5
10
15
20
25 Other
Somnolence
0
5
10
15
20
25 Higher than fourfold
Up to fourfold
Licensed
a
b
Fig. 3 Frequency of side effects, by a type of side effect, and
b maximum dose. The following dosages were considered as
standard dose: levocetirizine 5 mg, desloratadine 5 mg, fexofenadine
180 mg, clemastine 1 mg, hydroxyzine 25 mg, cetirizine 10 mg, lorata‑
dine 10 mg, acrivastine 8 mg three times daily
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van den Elzen et al. Clin Transl Allergy (2017) 7:4
from somnolence caused by sleep disturbances due to
the disease [8, 9]. Pruritus is most bothersome during
the evening and at night when it makes falling asleep dif-
ficult and wakes patients later in the night. is causes
chronic fatigue with a direct impact on QoL and physical
and emotional well-being [5]. Still, although the influence
of prolonged treatment on somnolence may be limited,
and improvement of urticarial symptoms reduces som-
nolence [9], urticaria patients report sleep difficulties
almost twice as often as control subjects [29], and our
results support that somnolence occurred in a minority
of urticaria patients [8].
A limitation of this study is the retrospective design.
erefore, precise documentation of results of treatment
was missing in some patients. Also, there was a lack of
objective measurements of effectiveness. With regard
to side effects, we presented these as collected from the
medical records. Somnolence was the most frequently
named side effect. Liver and kidney function tests were
not performed routinely. However, the extent of miss-
ing information was rather limited and different results
are therefore not expected. Furthermore, the EAACI/
GA2LEN/EDF/WAO urticaria guideline does not recom-
mend to combine antihistamines [1], since the mecha-
nism of action of sgAH is similar and mixing different
antihistamines would therefore theoretically not have
additional benefits [12]. In the current study we com-
bined different antihistamines. is was performed in
case dosages higher than fourfold were given, to limit
side-effects related to a specific antihistamine. Lastly,
CSU is a self-limiting disease. In the current study spon-
taneous remission may have occurred and this would
then be misinterpreted as effectiveness of treatment.
In conclusion, we show that by up-dosing antihista-
mines higher than fourfold, half of patients reached suffi-
cient treatment response while causing a limited increase
in side effects. e need for other third line therapies
could be decreased considerably. ese findings need
to be confirmed in a prospective controlled study. e
results are of special interest in case of side effects or
contraindications to currently proposed third line treat-
ments, or when they are locally not (yet) available.
Abbreviations
AE: angioedema; CINDU: chronic inducible urticaria; CsA: cyclosporine A; CSU:
chronic spontaneous urticaria; fgAH: first generation antihistamines; IH‑AAE:
idiopathic histaminergic acquired angioedema; InH‑AAE: idiopathic nonhista‑
minergic acquired angioedema; sgAH: second generation antihistamines.
Authors’ contributions
IB, KH, OK, AL, ME, and HO participated in database design, data extraction,
and performed the statistical analysis. AL, HR, CB, ME, and AK participated in
medical dossier completion. ME, HO, and AK participated in the study design
and ethics committee procedures. The manuscript was drafted by IB, KH, OK,
AL, ME, HO, HR, and AK, All authors read and approved the final manuscript.
Acknowledgements
We thank Andrew Walker for proofreading the manuscript. We thank Novartis
Pharma NL for providing an unrestricted grant to support this study.
Competing interests
MT. van den Elzen has received speakers fees from Novartis. A.C. Knulst is
member of the national and international Novartis omalizumab advisory
council, and has received speakers fees from Novartis and sponsoring for
scientific studies from Novartis and Pharming. All other authors declare that
they have no competing interests.
Availability of data and materials
Please contact author for data requests.
Ethics approval and consent to participate
The study was performed according to the code of conduct for medical
research approved by the University Medial Center Utrecht Medical Ethical
Committee (METC). Written informed consent for the publication of this report
was not required from the patients, as approved by the Ethics Committee,
protocol number 13‑459.
Funding
The database used for this study was funded by an unrestricted grant from
Novartis Pharma NL.
Received: 7 November 2016 Accepted: 3 February 2017
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