Journal of Dermatological Treatment.

2009; 20:194197
ISSN 0954-6634 print/ISSN 1471-1753 online 2009 Informa UK Ltd.
DOI: 10.1080/09546630802607495
ORIGINAL ARTICLE
Effcacy of leukotriene receptor antagonist with an anti-H1 receptor
antagonist for treatment of chronic idiopathic urticaria
KONG-SANG WAN
Department of Pediatric, Taipei City Hospital, Renai Branch, Taiwan and School of Medicine, National Yang-Ming
University, Taipei, Taiwan
Abstract
Background: Chronic idiopathic urticaria (CIU) is often diffcult to treat. Although histamine-releasing activity is detectable
for up to 50% of CIU patients, antihistamine therapy provides only a limited response. Objective: This study aimed to assess
the clinical effcacy of combined leukotriene receptor antagonist (LRA) and H1 antihistamine, H1 and H2 antihistamine,
and two H1 antihistamines as a synergistic therapeutic regimen for treating CIU compared with a matched placebo modality.
Methods: A total of 120 newly diagnosed adult patients were evaluated. Patients were single blinded and randomly assigned
to one of four medication groups that received the following regimens for 4 weeks: Group A, combination of sedating H1
antihistamine and non-sedating H1 antihistamine; Group B, combination of H1 antihistamine and H2 antihistamine; Group C,
combination of H1 antihistamine and LRA; and Group D, matched placebo medication. The primary measure of treatment
effcacy was the daily urticaria activity score (UAS) of wheal and itch. A positive therapeutic response was defned as a
reduction to < 25% of baseline weekly UAS, while a relapse was a return to > 75% of baseline weekly UAS. Results: In all,
107 patients completed the trial medication. At the end of 4 weeks, the UAS score as a response to treatment was 23.3% for
Group A, 63.3% for Group B, 53.3% for Group C, and no real change for the placebo treatment group. Conclusions: The
combination of LRA and H1 receptor antagonist is promising for CIU treatment and is reasonably well tolerated by patients.
The combination of H1- and H2-receptor antagonists provided the greatest treatment effcacy by the measures used in this
small study.
Key words: Antagonist, anti-histamine, chronic urticaria, H2-receptor, histamine, hive, leukotriene, receptor, therapy
Introduction
Urticarial episodes that continue for more than
6 weeks without any physical, allergic, infectious,
drug-related or vasculitic cause are typically termed
chronic idiopathic urticaria (CIU) (13). Its incidence
and prevalence is 0.13% in the general population
worldwide (4) and approximately 4050% of cases
with no identifable cause are believed to have an
associated autoimmune profle that plays a patho-
genic role (5). About one-third of CIU patients have
IgG autoantibodies against high-affnity IgE receptors
(FcR1) or against IgE that may be involved in the
pathophysiology of CIU (6,7).
Vonakis et al. proposed that in basophils of CIU,
observed changes in FcRI signalling pathway mole-
cule expression might underlie changes in its release. As
such, CIU patients can be segregated on the basophil
functional phenotype (8). The activation of cutaneous
mast cells with the release of histamine and other vaso-
active or pro-infammatory mediators is thought by
some to be the fnal common pathway for the induction
of CIU (9).
Moreover, evidence showed that the FcR1 344C>T
polymorphism may contribute to the development of
aspirin-intolerant chronic urticaria (10). Although
H1-receptor antagonists (H1RA), either administered
alone or in combination therapy, are the frst-line
Correspondence: Kong-Sang Wan, Taipei City Hospital, Renai Branch, No.10, Sec.4, Renai Road, Da An District, Taipei City 106, Taiwan, Fax: 886 2 26599002.
E-mail: gwan1998@gmail.com

(Recevied 29 October 2008; accepted 29 October 2008)
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195 K-S Wan
treatment regimens for CIU (7,11), such a therapeutic
modality may provide little beneft in the context of
clinical improvement for involved patients (11,12).
Normal skin mast cells have been reported to express
H2 and H4 receptors at the mRNA and protein level
(13). Cysteinyl leukotrienes have also been demon-
strated to elicit potent local effects upon cutaneous
vasculature and are reported to be able to prolong the
infammatory process for some types of urticaria (14).
Therefore, it is likely that H2-receptor antagonists
(H2RA) and leukotriene-receptor antagonists may
be effective in the treatment of CIU, although some
controversy may exist regarding the addition of a
histamine H2-receptor antagonist or a leukotriene
antagonist (7,15).
In order to evaluate the clinical effcacy of combi-
nation-treatment regimens, combined H1RAs,
leukotriene receptor antagonist (LRA)/H1RA, and
H2RA/H1RA were used and compared with a matched
placebo in terms of therapeutic beneft for newly
diagnosed CIU patients.
Patients and methods
A total of 120 newly diagnosed CIU patients were
single blinded and randomly assigned to one of four
groups after obtaining informed consent. Each group
had a 1-week run-in period to wash out the previous
antihistamine used for treatment. Those with recent
use of systemic corticosteroids or immunosuppressants
were excluded. The patients were then randomized
to receive one of the following treatment protocols
for a period of 4 weeks: (a) oral hydroxyzine 25 mg
plus cetirizine 5 mg twice a day; (b) oral hydroxyzine
25 mg plus famotidine 20 mg twice a day; (c) oral
hydroxyzine 25 mg twice a day plus montelukast
5 mg twice a daily; and (d) oral placebo twice a day.
Patients completed a daily record for the preceding
24 h of the number of small (diameter < 3 cm) and
large (> 3 cm) skin wheals, according a specifc
classifcation number, and with scoring as follows:
zero, < 10 wheals; 1, 1015 small wheals or < 10 large
wheals; 3, almost entirely covered with wheals. The
relative severity of itch was scored as: zero, none; 1, mild;
2, moderate; 3, severe. The possible weekly aggregate
urticaria activity score (UAS) therefore ranged from
zero to 42.
Patients also provided a 10-cm visual analogue
scale score (VAS) from zero (none) to 10 (worst) during
each outpatient clinic visit that indicated the overall
severity of their urticaria over the previous 2 weeks.
The same investigating physician who was blinded to
the treatment regimens saw the patient. A response
to medication was defned as a reduction of weekly
UAS to < 25% of baseline and a relapse as a return
to > 75% of baseline UAS.
Statistical analysis
Primary assessment of treatment effcacy was based
on the differences between results for each treatment
group compared with the placebo in the context of total
symptom score and score for every symptom associ-
ated with the urticaria. The Statistical Package for the
Social Sciences (version 1.0 for Windows; SPSS Inc.,
Chicago, IL, USA) programs processed the resulting
data. A p-value < 0.05 was considered signifcant.
Results
The 120 patients were randomized for treatment, with
30 patients allocated to each of four treatment groups
(Table I). Patient compliance was excellent; however,
13 of 30 patients from the placebo group dropped out
after experiencing no real beneft following therapy
for 12 weeks. Comparing the treatment results of the
three combination treatment groups, there was sig-
nifcantly improved UAS in the H2RA/H1RA and
LRA/H1RA combined treatment modalities (p < 0.05).
The UAS responses in group A, B, and C were similar.
Moreover, all three treatment groups revealed sig-
nifcant difference in terms of UAS when compared
with the corresponding result for the placebo group
(p < 0.05). The relative response (improvement per-
centage) as measured by the UAS for Groups A, B,
C, and D were 23.3%, 63.3%, 53.3%, and 0%,
respectively (Table II).
Comparing the results of applying H2RA/H1RA
and LRA/H1RA combination regimens for CIU
treatment, the relative effcacy of the H2RA/H1RA
combination modality was signifcantly more satis-
factory. No severe adverse effects were observed with
the montelukast combination group, which had toler-
ability similar to that of the placebo group. The most
common event associated with these treatment proto-
cols was a transitory and mild to moderate sedation that
might be due to the presence of hydroxyzine (eight
in group A, six in group B, and six in group C).
Discussion
CIU is a disabling and distressing disease that has a
negative infuence on quality of life (16). The duration
of skin wheals for CIU is often longer than 12 hours
and is usually not effectively controlled by conventional
antihistamine therapy alone (12). The pathogenesis of
CIU appears to be multifactorial (17,18). The release
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Leukotriene receptor antagonist in chronic idiopathic urticaria 196
of mast-cell mediators under various stimulations
leads to skin infammation and the accumulation and
activation of other leukocytes, including eosinophils,
neutrophils and possibly basophils (9,16). Altered
basophile degranulation phenotypes are also found in
CIU patients.
Though quality-of-life impairment is similar in CIU
basophile subsets, those with a basophil responder
phenotype report longer disease duration, higher
frequencies of emergency department consults, and
signifcantly more severe itching (19). Leukotrienes are
one of the released mediators that interact functionally
in allergic reactions against a background of imbal-
anced T-cell clues and result in preferential cytokine
production following the T-helper 2 profle (20).
Leukotrienes can also elicit a potent local effect on
the cutaneous vasculature. Thus, administration of
leukotriene antagonists may be reasonably expected
to be effective in treating CIU.
Moreover, human mast cells constitutively express
H1, H2 and H4 receptors and histamine-binding to
the receptors is strongly inhibited by either H1- or
H2-specifc antagonists (13). The suggested CIU
pharmacotherapy should therefore abrogate the effects
of histamine and other pro-infammatory mediators
on cutaneous vasculature and infammatory cells that
participate in the pathogenesis of the urticaria (21).
However, there seems to be some controversy as
to whether a combination of H1 anti-receptor
antihistamine with anti-leukotrienes or H2 anti-
receptor antihistamine can be effective therapeutics
for CIU patients (7,15).
The results of this comparative study demonstrate
that the therapeutic combination of H2RA and
H1RA refects a notable effcacy. The relative response
(improvement percentage) as measured by application
of UAS approached 63.3%. The corresponding rela-
tive response (improvement percentage) for the LRA/
H1RA combination regimen was 53.3%, suggesting
that this therapeutic protocol might also be a safe and
effective alternative therapeutic agent for CIU.
In contrast, it has been reported elsewhere that
combined therapy with H1RA and LRA is effective
only for patients featuring autoimmune and autologous
serum skin-test positive urticaria (14,15). A study by
Spector and Tan reported that CIU treatment was
maximized with antihistamines, antileukotrienes, and
histamine-2 blockers with no improvement, systemic
steroids provided only temporary relief, and anti-IgE
antibody (omalizumab) might have benefcial effects (5).
Sedating and non-sedating H1RA combined treatment
was the least effective treatment regimens investigated,
with a response (improvement percentage) of only
23.3% by UAS.
The profle of the adverse reactions (principally,
patient sedation) of treatment modalities for Groups
A, B and C was similar for all groups, suggesting that
this sedative response might be mediated by hydroxyzine.
Table II. Reduction in urticaria activity score (UAS) of the four study groups after 4 weeks of treatment.
Baseline UAS (n) UAS after 4 weeks of
treatment (n)
Positive therapeutic
response reduction to
< 25% of baseline UAS (%)
p-value
H1RA + H1RA (Group A) 33.3 (30) 21.8 (7) 23.3% < 0.05
H1RA + H2RA (Group B) 33.9 (30) 21.2 (19) 63.3% < 0.05
H1RA + LRA (Group C) 35.2 (30) 22.6 (16) 53.3% < 0.05
Placebo (Group D) 31.2 (30) 31.2 (17) (13 withdraw) 0% NS
UAS = urticaria activity score; H1RA = H1-receptor antagonists; H2RA = H2-receptor antagonists; LRA = leukotriene receptor antagonist.
Table I. Characteristics of the study participants.
Group A Hydroxyzine +
cetirizine
Group B Hydroxyzine +
famotidine
Group C Hydroxyzine +
montelukast
Group D Placebo p-value
Number of patients 30 30 30 30 NS
Mean age (years) 31 (1845) 36.4 (2052) 34.8 (2054) 33.2 (1848) NS
Sex (M/F) 12/18 10/20 11/19 13/17 NS
Time since onset of
urticaria (months)
15.2 (625) 20.3 (735) 19.7 (1228) 16.7 (630) NS
Mean baseline UAS 33.3 (2840) 33.9 (3038) 35.2 (3042) 31.2 (2738) NS
UAS = urticaria activity score.
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197 K-S Wan
Although the side effect profle of antihistamines was
different between generations, there are consider-
ations even within generations, especially regarding
sedation and possible effects on learning (22).
Several large, well-controlled clinical trials of treat-
ment options for CIU showed levocetirizine to be
consistently effcacious and well-tolerated in relieving
the symptoms (23). Meltzer and Gillman also pro-
posed that fexofenadine HCl 180 mg was superior to
desloratadine 5 mg in histamine-induced wheal-and-
fare suppression, suggesting the increased in vivo
H1-receptor antagonist potency of fexofenadine (24).
The study limitations include the number of partici-
pants, a lack of different second-generation antihista-
mine comparison, and only single-blinded methodology.
A working knowledge of the diseases that can present
with urticarial lesions is essential to accurately diagnose
and effectively treat this symptomatic condition (25).
Acknowledgement
The author expresses sincere thanks the Merck Sharp &
Dohme (I.A.) Corp, Taiwan Branch, for providing the
montelukast in this study.
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