ARTICLE
Auteur(s) :, Stéphane NANCEY1,2, Nathalie
FREYMOND1, Amandine CATELAIN1, Florence
COUSIN1, Aurore ROZIERES3, Jean-François
NICOLAS1,3,*
1Unité d’Immunologie et Allergologie Clinique,
Service de Pneumologie, Centre Hospitalier Lyon-Sud, F-69495
Pierre-Bénite Cedex, France
2INSERM U 404, IFR 128, 21, av T Garnier, 69365 Lyon
Cedex 07
3INSERM U 503, IFR 128, 21, av T Garnier, 69365 Lyon
Cedex 07
*J.F. Nicolas, Fax: (+33) 4 78 86 15 28.
E-mail: jean-francois.nicolas@chu-lyon.fr
accepté le 9 Juin 2004
Urticaria is a common chronic skin disorder, which corresponds to
the activation of dermal mast cells. Once activated, they induce
inflammatory reactions by secreting chemical mediators stored in
pre-formed granules (essentially histamine, tryptase or
chymotrypsin), and by synthesizing leukotrienes, prostaglandins,
chemokines and cytokines after activation occurs [1]. The
anti-histamines remain the treatment of choice in urticaria ;
they act by blocking the effects of histamine on endothelial cells
in the superficial dermal blood vessels [2]. Corticosteroids (CS)
are sometimes used in the treatment of acute or chronic urticaria,
with major differences in prescription practices depending on the
medical specialty concerned. Allergologists are thus less likely to
prescribe CS than other physicians [3]. However, the efficacy of CS
in preventing or improving common forms of urticaria remains
debated as the results of clinical studies are often
contradictory.The aim of this study was to investigate the effects
of CS on the development of experimental urticaria, i.e. urticarial
lesions induced by prick-tests with histamine and codeine. The
histamine prick-test reflects the vascular reactivity of this
mediator with an increase in the endothelial permeability and
vasodilation. In contrast, the prick-test with codeine, an opiate
inducing mast cell degranulation by a ligand-receptor interaction,
illustrates the activation of mast cells and the liberation of
histamine and other mediators involved in the urticarial lesion.
Codeine seems, moreover, to have a directly relaxing effect on the
smooth muscles within the blood vessels. The anti-histamines are
capable of preventing urticaria induced by histamine and codeine.
Subjects and methods
Subjects
Thirteen healthy volunteers (7 women, 6 men average age
32 years, range 22-58 years), not using topical or systemic
treatments for at least three months, were included in this study.
At inclusion, all patients gave their written informed consent to
the protocol. These volunteers were divided into two groups :
- - 7 Volunteers, who formed group I (preventive
mode), received a daily application for 2 days of betametasone
dipropionate (DIPROSONE® ointment) over one half of the
anterior side of the left forearm, the other half remained free of
all topical applications. On the third day prick-tests to histamine
and codeine were carried out.
- - 6 Volunteers formed group II (curative mode). Two
series of prick-tests with histamine and codeine were undertaken on
their left forearm. In one of the two series, an intradermal
injection (IDR) of 50μl of methylprednisolone succinate
(SOLUMEDROL®, 20mg/ml) was given a few seconds after,
and at the same site as the tests.
Skin tests
One drop of standardized histamine phosphate (10mg/ml) or codeine
phosphate (Stallergènes, Antony, France) was placed on the skin
which was then pricked with a Stallerpoint (Stallergènes, Antony,
France). A “negative” control at the same time and using the same
conditions was systematically carried out with a drop of
Glycero-saline in order to exclude any potentially associated
dermographism. Reading of the tests took place after twenty
minutes, measuring the diameter of any papule and erythema which
was induced. Each lesion was then traced onto paper and the longest
perpendicular measurements of the diameter of both the papule and
the erythema were taken.
Statistical analysis
The results of the measurements of the size of the papules and
erythema for groups I and II were expressed as
averages ± standard deviation and compared using the
student t test. A difference of p<0.05 was considered
statistically significant.
Results
Effect of topical corticosteroids
Application of class III (strong) topical CS for 48 hours
before carrying out the prick tests had very little effect on the
urticarial lesions induced, at the 20 minute reading (( Fig. 1 )). In
fact only the erythema (flare) induced by histamine was less
intense on treated skin compared to contralateral non-treated skin
(24.5 ± 9 versus 19.3 ± 6 mm ;
p < 0.05). No differences were noted for erythema
induced by codeine nor for the papule (wheal) induced by histamine
or codeine. Topical corticosteroid treatment had no effect either
on the evolution of the induced urticaria : erythema and
papules appeared and disappeared at the same time in the treated
and non-treated areas.
Effect of systemic corticosteroids
The injection of corticoids immediately after provocation of the
urticarial lesion resulted in an increase of the erythema observed
with histamine and codeine, in comparison with nontreated skin ((
Fig. 2 )).
With certain patients, the differences observed in the erythema
were pronounced (( Fig. 3 )) and were
associated with an increase in the size of the papule.
Nevertheless, the overall statistical analysis of all the subjects
treated with injected CS failed to detect an effect on urticarial
papules. As with topical CS, the timescale for the appearance and
disappearance of skin reactions to histamine and codeine were
similar for treated and non-treated skin.
Discussion
Our results show that CS have little effect on histamine- and
codeine-induced urticaria. They have no effect on the development
of urticarial papules (wheals), which are typically the first
lesions in urticaria. On the other hand they have an effect on
erythema (flares), which corresponds to a local vasodilatation of
small dermal vessels, in response to histamine. Interestingly, the
effects of CS on erythema differ with the type of drug
administration. Topical CS reduce the size of the wheal, which is
one of their classical pharmacological properties [4]. In fact the
strong anti-inflammatory properties of topical CS are proportional
to their vasoconstriction effects, and are the basis of the
McKenzie test, which compares and ranks the efficacy of different
corticoids on human skin [5]. In contrast, corticoids injected
intradermally immediately after the urticaria has been triggered
induce an increase in erythema. This effect, which may first appear
paradoxical, could probably be explained as the result on the
dermal vessels of a high local concentration of CS in this model.
Our observations can be compared to the known secondary effects of
high doses of CS administered in pill form and accompanied by
erythema on the face and on the chest. Recent experiments showed
that high doses of CS, administered transdermally, result in dermal
vasodilation, while moderate doses induced vasoconstriction [6].
Thus, in our model, it is possible that the injected CS add their
vasodilating properties to those of histamine, which leads to an
increase in the erythema observed after a histamine or codeine
prick.
Local or systemic treatment with CS is widely used in numerous
human diseases, including outbreaks of acute urticaria [4]. Our
results do not support the recommendation of corticoids in the
treatment of the common form of urticaria as neither topical nor
systemic forms reduce the erythema and/or edema. On the other hand
clinical experience shows that CS are efficacious in certain forms
of systemic urticaria such as those associated with cutaneous
vasculitis and auto-immune urticarias (lupus, thyroiditis). These
systemic urticarias are very different from the common forms of
urticaria on clinical, pathological and therapeutic backgrounds. In
these clinical forms the urticarial lesion is due to a polymorphous
inflammatory and immune cell infiltrate and not to a simple dermal
edema [7, 8]. It is thus logical that CS are effective in these
systemic urticarias, due to their anti-inflammatory and
immunosuppressive properties.
The interpretation of prick-tests in patients undergoing
corticoid therapy has been controversial. Our results show that
topical and systemic CS do not prevent prick-tests for histamine
and codeine from being positive, even if they modify one of the
parameters of the evaluation (erythema). These results confirm
other studies showing that topical and systemic CS do not affect
the interpretation of tests of immediate hypersensitivity [9, 10],
even if they are responsible for modifications in the results. Cole
et al. showed that topical CS, applied over three weeks,
were responsible for a local reduction in the number of mast cells
and level of histamine in the tissues treated while the
degranulation functions of the mast cells remained intact [9]. The
effects of long term corticosteroid therapy on skin reactivity
induced by histamine and codeine have also been studied. [10-12].
While the reaction induced by histamine is not affected, the
degranulation of mast cells provoked by codeine was significantly
reduced with prolonged cortisone treatment [11]. These effects of
long-term CS do not prevent the use of prick-tests as they do not
modify the results of skin tests for immediate hypersensitivity
[10]. In conclusion, CS have no effect on acute experimental
urticaria as they are not able to block the mast cell degranulation
induced by codeine or to inhibit histaminic erythema. Thus, skin
tests for immediate hypersensitivity can be carried out on patients
under topical or systemic corticosteroid treatment.
Whether the present results obtained in healthy volunteers and
showing that CS had no effect on experimental urticaria can be
extended to patients suffering from outbreaks of acute urticaria
remains to be studied.
Acknowledgment
We are indebted to Jenny Messenger for translating this
article.
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