Download 54 Antihistamines in Atopic Eczema

Chapter 54
Antihistamines in Atopic Eczema
T. Zuberbier
54.1
Introduction
Atopic eczema is known as a chronically relapsing disorder where mainly activation of T cells leads to an
eczematous reaction of the skin. However, there is multiple evidence that IgE mediated reactions are an
aggravating factor in the majority of patients and both
an increase of mast cells and an increase of dermal histamine have been observed in atopic eczema.
While topical treatment in atopic eczema is the first
choice, antihistamines have been used for decades,
especially in children, as additional therapy to control
itching. However, the level of evidence was originally
poor and now only with the development of new, nonsedative antihistamines are large placebo-controlled,
double-blind randomized studies available.
In reviewing this topic, it is therefore important to
distinguish between the first generation, more or less
sedating antihistamines, and the second generation of
antihistamines, which have a lower or no sedative
effect and express various nonhistamine receptorrelated anti-inflammatory properties.
54.2
First-Generation Antihistamines
Various groups of first-generation antihistamines have
been marketed since the 1950s. Regarding the pharmacokinetics, all these substances have to be metabolized
to exert their action and the half-life is rather short,
within a few hours. The main disadvantages are dry
mouth, sedation, and impairment of cognitive functions [6, 5, 12, 13]. Unfortunately, even when given at
night, a hangover can occur quite frequently and needs
to be discussed with patients. Nevertheless, the use of
strongly sedating antihistamines has been favored by
many doctors in the past arguing that although the
antipruritic effect of antihistamines is not proven, the
sedative effect reduces the impulse of the patients to
scratch and thus is of value, especially since atopic dermatitis patients tend to damage their skin through
uncontrolled scratching in their sleep. However, especially in small children, the long-term use of these
sedating substances with an unknown effect on the
development of cognitive functions, for which undisturbed sleep with REM and non-REM phases is of
importance, can no longer be justified.
It may be argued that at least in acute conditions,
sedation is a true relief for the patient and it would not
be harmful to use these drugs for a short period. However, it might also be argued that in these conditions, a
combination of a modern-generation antihistamine
with a true short-acting sedative with no after-effects is
probably superior to the use of a sedating antihistamine.
Regarding efficacy, there are no large studies comparing different sedating first-generation antihistamines in atopic eczema. Comparing efficacy to placebo, several small studies with mainly negative results
are reviewed by Klein and Clark [7]. There is only one
multicenter, double-blind, placebo-controlled study
according to modern standards conducted in 155 children with atopic dermatitis [10], which shows that
chlorpheniramine is no more effective than placebo in
relieving the symptoms of atopic eczema with nocturnal itching in childhood.
The latter paper could lead to the assumption that
antihistamines in general are not helpful in relieving
pruritus in atopic eczema, but it must be remembered
that the new, second-generation antihistamines exert
not only an H1-antagonizing effect.
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54 Antihistamines in Atopic Eczema
54.3
Second-Generation Antihistamines
The first nonsedating antihistamines marketed were
terfenadine and astemizole, which later were found to
have cardiac side effects. Due to hepatic metabolism
through the P450 enzyme system and drug interactions, very high serum levels could be reached where
these two drugs showed a concentration-dependent
side effect.
The newer nonsedating antihistamines are, among
others, azelastine, cetirizine, desoxyloratadine, ebastine, fexofenadine levocetirizine (desoxyloratadine is the
active metabolite of loratadine, levocetirizine the active
metabolite of cetirizine). All of these substances are
considerably less sedating or nonsedating, even in concentrations higher than the recommended dosage.
Also, another frequent, and perhaps the most disturbing side effect of the older antihistamines, the development of a dry mouth, is rarely seen anymore. The reason for this is the change in chemical structure compared to the first generation. The newer agents are less
lipophilic and are mainly prevented from penetrating
the CNS. Also they express a higher and more specific
binding to the H1-receptor, with hardly any interaction
with the cholinergic receptors. Desloratadine, fexofenadine and levocetirizine are the active metabolites of
their predecessors and are excreted with no further
metabolism. A half-life of approximately 12 h ensures a
lasting action for 24 h. Although the modes of excretion
are different (Levocetirizine, mainly renal; fexofenadine and desoxyloratadine, mainly hepatic), all three of
these substances are nearly devoid of any drug interactions and also have no synergistic effects with ethanol.
Most important in the discussion of the value of
modern nonsedating antihistamines in the treatment
of atopic eczema are the nonhistamine receptor-related
anti-inflammatory properties of these substances.
Cetirizine inhibits eosinophil chemotaxis in vitro and
in vivo and reduces LTB4 release and the expression of
endothelial adhesion molecules (reviewed in [15].
Loratadine and desoxyloratadine modulate cytokine
release, especially IL-6 and IL-8, from human mast
cells and basophils [8] and reduce the expression of
endothelial adhesion molecules [9]. It has also been
shown that fexofenadine reduces the expression of cellular adhesion molecules and inhibits the eosinophilinduced release of IL-8, GMCSF, and soluble ICAM-1
from human nasal epithelial cells [1].
One of the major characteristics of atopic eczema is
the high influx of inflammatory cells for which the
upregulation of endothelial adhesion molecules is a
prerequisite. Boone et al. [2] demonstrated that in
atopic dermatitis, especially ICAM-1 and VCAM-1
were constantly upregulated. The same authors also
showed that cetirizine at a dosage of 20 mg (twice the
recommended dosage for allergic rhinitis) in contrast
to placebo significantly reduced the expression of
VCAM-1, whereas ICAM-1 was not affected. In comparison, the same authors looked at the endothelial
adhesion molecules in allergic contact dermatitis.
These patients showed the same levels of ICAM at baseline as patients with atopic dermatitis with low levels of
VCAM-1 expression. However, VCAM-1 expression
was upregulated after challenge with the relevant contact allergens.
54.4
Clinical Studies
There are only a few double-blind, placebo-controlled
studies available. Small studies with fewer than 40
patients included support efficacy with acrivastine,
cetirizine, loratadine, and terfenadine (reviewed in
[7]), but are criticized for methodology problems.
The first study in a large population to investigate
long-term treatment with an antihistamine in atopic
dermatitis was conducted in infants in a multinational, double-blind, randomized, placebo-controlled
trial (the ETAC trial). The investigators treated 817
children aged 12 – 24 months for 18 months with
either cetirizine (0.25 mg/kg) or placebo twice daily.
All infants suffered from moderate atopic eczema
with an average SCORAD of 25. The primary endpoint
of efficacy was the development of asthma, the secondary parameters were the consumption of concomitant medications for which all drugs except H1-antihistamines could be used by the patients, and the
severity of atopic eczema.
The severity of atopic eczema decreased significantly during the 18 months of treatment in both the placebo group and the cetirizine group, which is in line with
the natural course of atopic eczema in early childhood.
The number of infants who had accompanying symptoms of urticaria during the study period was significantly lower in the cetirizine group (5.8 % vs 16.2 %),
and the overall use of other treatments for atopic ecze-
References
ma was not different in both treatment groups. The
most interesting part of the study involves, however,
the different subgroups. In the subgroup of infants with
a SCORAD of 25, there was a statistically significant
corticosteroid-sparing effect. The effect on the onset of
asthma and the follow-up for another 18 months of the
infants enrolled in the ETAC study has been reported in
detail by Warner et al. [14]. Although there was no difference in the prevalence of asthma between active and
placebo treatment in the overall population, there were
highly significant changes in those children sensitized
to house dust mite or grass pollen. In these groups,
treatment with cetirizine for 18 months significantly
reduced the likelihood of developing asthma compared
to the treatment with placebo. At the end of the 18month treatment period, the overall percentage of children developing asthma was reduced by approximately
50 % in both house dust mite- and grass pollen-sensitized groups. This effect was maintained in the 18month follow-up period for those children sensitized
to grass pollen.
In another study comparing the effect of loratadine
vs placebo in 48 children with mild atopic eczema
(mean SCORAD 12) and additional treatment with
mometasone furoate 0.1 % cream, Chunharas et al. [3]
showed that after 14 days of external corticosteroid
therapy, atopic eczema was nearly fully cleared up,
independently of the comedication loratadine or placebo (SCORAD below 2 in both groups).
Regarding the safety of long-term use of cetirizine in
patients with atopic eczema, Stevenson et al. [11]
reported tests included in the above-mentioned ETAC
study. It was shown that there were no differences
between cetirizine high-dose treatment (0.25 mg/kg
twice daily) and placebo in terms of behavior, cognitive,
and psychomotor development or learning processes.
In conclusion, it can be summarized that the use of
first-generation antihistamines in atopic dermatitis is
usually not helpful due to the sedative effect. The application of modern, second-generation antihistamines
may be useful, possibly for the expression of non-H1receptor-related activities, which are dose-dependent.
The use appears to be beneficial in subgroups of
patients with more severe atopic eczema. In patients
with a low SCORAD, a topical therapy appears to be
sufficient. Of special interest is the fact that the early
use of antihistamines may prevent the development of
asthma in subpopulations at high risk. The administration of antihistamines over a long period appears to be
safe and should therefore be offered to those patients in
whom an additional benefit can be expected.
References
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