ARTICLE
Cold urticaria occurs as wheals and/or angioedema that develop after
exposure to cold. Clinical cases show a broad spectrum ranging from mild
localised forms to severe anaphylactic reactions.
Cold urticaria is classified into acquired (ACU) and familial forms.
The former is the most frequent and may be associated to cryoglobulinemia
and various immunological disorders [1]. The cold cube test is positive
in approximately 80 % of cases.
Pathogenesis is unknown and an immunological reaction to a cold-dependent
skin component has been hypothesised [2]. Immunoglobulins are responsible
for the positive passive transfer reaction that is found in 20-30 %
of ACU patients [3-5]. Mast cells, activated either directly or via complement
activation, play a pivotal role as well [1].
Old generation H1-type antihistamines are the standard therapeutic option
[1], but sedative and anti-cholinergic side effects are common and may
lead to therapy interruption. New H1-type antihistamines are well tolerated
but efficacy is often poor. Doxepin, penicillin and cold tolerance induction
have been used for selected patients with variable results [6, 7].
The present study aims to evaluate whether high doses (25 mg t.i.d.)
of cinnarizine [1 diphenyl-methyl 4(phenyl 2 propenyl) piperazine]
could represent a safe and effective treatment option for ACU patients
who developed adverse effects to old H1-type antihistamines and had poor
or no improvement with new second generation antihistamines.
Materials and methods
Fourteen patients (4 males and 10 females) were enrolled in
the study after they had given informed consent. Their mean age was 30.4 years
(range 11-50 years). Mean duration of ACU was 48.9 months (range
7-102 months). Patients were recruited among cases where oral hydroxizine
(12 mg b.i.d.) therapy had to be discontinued due to side effects
and oral cetirizine (10 mg daily) gave poor results.
Routine blood chemistries, haematology and urinalysis as well as cryoglobulins,
total IgE and evaluation of complement activity (CH50, C3, and C4) were
performed. Patients with detectable cryoglobulins underwent blood investigations
for antibodies to and antigens of hepatitis B or C viruses and chest X-ray.
The cold cube test (CCT) was delivered as follows: a beaker filled with
ice slurry was applied on the patient’s forearm for 5 minutes
and the wheal formation was evaluated in the following 10 minutes.
CCT was performed before and after the treatment. Patients unresponsive
to the CCT underwent an additional provocative test:
an arm was immersed in cold water for 5-15 minutes until an urticarial
reaction developed.
Cinnarizine at the dose of 25 mg t.i.d. was administrated for three
months, and then it was gently tapered off and stopped within two months.
Cinnarizine was tapered off as follows: 25 mg/die for one month and
25 mg every other day for the following month. Patients were evaluated
monthly for one year and adverse effects were carefully registered.
The therapeutic response was considered as complete when the disease
disappeared and the CCT or immersion of the arm in cold water did not
trigger an urticarial reaction. A good response means that the reaction
could still be triggered although the threshold of the cold stimulus was
substantially increased in the patient's evaluation after cold exposure
during daily life and the degree and duration of the wheal reaction to
the provocative tests were reduced. No change or mild improvement was
considered as a treatment failure.
Results
All patients had urticaria limited to skin surfaces that were exposed
to cold. Anaphylactic like reactions occurred in 2 patients after
diving.
ACU was idiopathic in 10 (71.4 %) patients. Blood chemistry, haematology
and urinalysis of these patients gave normal findings. Two out of them
showed a high IgE blood level and reported an association with atopic
rhinitis and atopic asthma, respectively.
Cryoglobulins were detected in the serum of the remaining 4 cases
(28.6 %). Monoclonal immunoglobulins could not be investigated because
cryoglobulins were present in very small amounts. However, physical examination
did not disclose clinical lesions as well as symptoms suggesting a systemic
disease. In addition, findings of laboratory investigations (routine blood
chemistries, haematology, urinalysis, serum protein electrophoresis, total
IgE, evaluation of complement activity CH50, C3 and C4, antibodies to
and antigens of hepatitis B and C viruses) as well as chest X-ray were
always negative or within normal limits. The allergic and the cryoglobulin
positive patients did not receive any other therapy during the present
trial.
CCT was positive in 11 out of 14 patients (78.6 %), within
five minutes after cold stimulus was stopped (Table
I). The remaining patients showed a localised urticarial response
following 5- 15 minutes of immersion of an arm into cold water. Routine
laboratory tests were always negative or within normal limits.
Thirteen patients (92.8 %) completed the trial. One patient interrupted
the therapy because of severe vertigo. A complete or good response was obtained
in 8 (57.1 %) and 2 (14.3 %) patients, respectively. Three patients
were unresponsive (21.4 %). The therapeutic response was not apparently
influenced by the duration of the disease. Tapering off or stopping the
cinnarizine treatment was followed by the relapse of ACU in 7 cases
(50.0 %). These patients were amenable to a second treatment cycle.
Six patients (42.9 %) had a persistent remission (Table
I).
Beside the patient with severe vertigo leading to cinnarizine withdrawal,
three additional patients reported mild and transitory adverse effects,
including epigastralgia, weight gain and drowsiness.
Discussion
We evaluated 14 patients affected by ACU. Ratios of idiopathic
versus secondary forms and positivity to CCT are in general accordance
with results of previous epidemiological studies [1]. Unlike previous
investigations [1], we have not found clinical as well as laboratory differences
among the three CCT negative patients and the remaining, CCT positive
patients.
In all patients, standard therapy with an old generation H1-type antihistamine,
hydroxyzine, was withdrawn due to adverse effects, e.g. drowsiness and
weight gain. A new second-generation H1-type antihistamine, cetirizine,
gave less frequent and milder adverse effects but offered poor or no relief.
High dose cinnarizine induced a complete or good control of cold-induced
symptoms in 71.4 % of the patients. The percentage of persistent
remission (42.9 %) was high and,
if a relapse occurred, it was responsive to a second treatment cycle.
The treatment was well tolerated: three patients had mild and transient
adverse effects that disappeared without reduction of the dosage of cinnarizine.
A single patient had severe vertigo leading to therapy withdrawal.
Cinnarizine inhibits the calcium ion transport
across smooth muscle cell membrane. Due to vasoactive properties, it is
licensed for the treatment of kinetosis and arteriosclerosis. In addition,
it has antiallergic properties due to the antagonistic activity against
vasoactive amines, including histamine, and does not interfere with mediators’
release [8]. It is an inhibitor of complement activation as well [8-10].
It proved to be effective and well-tolerated in the treatment of chronic
idiopathic urticaria and the present results seem to expand its possible
therapeutic use to the treatment of ACU. Low doses of cinnarizine (10 mg
t.i.d.) were found less effective than doxepin (10 mg t.i.d.) in
a double blind trial enrolling a small group of ACU patients [11]. However,
in the present study, a high dose (25 mg t.i.d.) of cinnarizine was
delivered and therapeutic results were excellent. In addition, doxepin
is a tricyclic antidepressant with strong anti-cholinergic and sedative
activities as well as several potential cutaneous and cardiovascular adverse
effects. Therefore its use may be recommended only for selected patients
resistant to better-tolerated drugs.
CONCLUSION
In conclusion, the excellent results of the present study suggest that
high doses of cinnarizine represent an effective and well-tolerated therapeutic
option for ACU patients who developed adverse effects to old H1- antihistamines
and had a poor or no improvement with new second-generation antihistamines.
Article accepted on 4/11/2002
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