ARTICLE
Of the side effects of topical corticosteroid treatment, only the "classic"
local side effects (skin atrophy, risk of infection, etc.) and systemic
side effects (suppression of the hypothalamic-pituitary-adrenal axes)
were taken into consideration in the past. The new molecules were developed
to improve the relationship of anti-inflammatory potential to such adverse
effects.
Fluticasone propionate (commercialized as Cutivate®,
Flixoderm®, Flixoval®, and Flutivate®
by Glaxo Operations, Durham, England), which is derived from androstane
17-b carboxylic acid (Fig. 1),
was synthesized to have maximal efficacy with a minimum of adverse effects.
It is a highly lipophilic molecule, a potent agonist of the corticosteroid
cellular receptor, and has low progesterone activity and a low or negligible
effect on mineralocorticoid, estrogen, and androgen receptors. It has
a high affinity for the glucocorticoid receptor and a high half-life,
which makes it a potent anti-inflammatory agent. It undergoes an important
first-pass effect in the liver and metabolizes quickly to the inactive
17-carboxylic acid, which reduces the risk of adverse effects [1].
Several studies have shown that it is effective in the treatment of
moderate to severe psoriasis and eczema (one application per day). It
has also been approved by the FDA for the treatment of atopic dermatitis
in children under the age of 3 months.
In recent years, contact allergy to corticosteroids has received increasing
attention, and an overall frequency of positive patch-test reactions to
certain corticosteroids has been found to be 2.6% in consecutively tested
patients in Europe [2]. Moreover, cross-reactions are frequent and occur
in specific patterns [3] (Table
I).
In order to study the allergenic and cross-sensitization potential of
fluticasone propionate, we analyzed the results of patch testing with
this molecule both with persons who had used it to treat eczema as well
as persons with a known contact allergy to other corticosteroids. The
ingredients of the vehicle were also considered (Table
II).
The population
The total population was 6,509 subjects, all of whom had been investigated
for contact allergy between 5 February 1990 (the date on which fluticasone
propionate was tested for the first time in our center) and 30 November
1999.
In addition to the European standard series, the following corticosteroids
were routinely tested: tixocortol pivalate 1% pet. (6,509 subjects) and
budesonide diluted 0.1% pet., which was introduced on 1 April 1993 (3,501
subjects) and diluted 0.1% in ethanol since 5 October 1998 (762 more subjects).
Hydrocortisone-17-butyrate 1% eth. has been routinely tested since 1 January
1997 (1,917 subjects).
Fluticasone propionate 1% eth. was patch tested in a total of 206 subjects:
118 of them had actually used the product (89 used the cream and 29 the
ointment); 155 subjects were tested with an extended corticosteroid series
(Table III) in which it
is included.
The non-active ingredients of the Cutivate® formulations
(Table II) to which contact
allergic reactions occur and that were patch tested were propylene glycol,
which was routinely tested 10% aq. since 1 April 1993 (4,277 subjects),
imidazolidinylurea 2% pet. (1,179 subjects), cetyl alcohol 20% pet. (2,999
subjects), and isopropyl myristate 10% eth. (344 subjects). The last three
were tested only when a cosmetic or iatrogenic allergy was suspected.
Sorbitan sesquioleate 20% pet. has been tested routinely in the standard
series since 1 October 1997 (1,441 subjects).
Materials and methods
The patch-test materials used were van der Bend® chambers
(van der Bend, Brielle, The Netherlands) mounted on Micropore®
(3M Health care, Borken Germany) and fixed on the back of the patients
with Mefix® (Mölnlycke, Göteborg, Sweden). The
readings were performed at 48 and 72/96 hrs and often also after 6 or
7 days.
Case reports of the patients reacting to
fluticasone propionate
Case 1
LC, a 56-year-old man, was referred to us in January 1995 because of
generalized skin eruptions that had occurred once after administration
of a budesonide-containing inhalation product, once after a Xylocaine®
injection by an orthopedist, and once after a betamethasone-dipropionate
injection. He was not atopic but had had an intolerance reaction to deodorant
and after-shave lotion. Previous patch tests had revealed a contact allergy
to balsam of Peru and budesonide. Further tests with the corticosteroid
series produced multiple positive patch-test reactions (Table
IV). Among them was betamethasone dipropionate, which was clinically
relevant. Fluticasone propionate produced a + reaction (erythema and infiltration)
after 72 hrs and erythema after 96 hrs.
Case 2
DKD, a 41-year old non-atopic woman consulted us in February 1995, because
of edema of the face and upper chest, which, according to the patient,
had appeared after the administration of a corticosteroid injection (methylprednisolone)
for an orthopedic disorder in her back. The use of a hydrocortisone-17-butyrate
cream had provoked eczematous lesions at the application sites and itching,
erythematous and vesicular dermatitis on the eyelids, as well as edema
of the buccal mucosa. Patch testing revealed a contact allergy to nickel,
which could explain her intolerance to costume jewelry, and to budesonide.
Further tests with the corticosteroid series gave positive reactions
to both Group B (acetonides) and Group D2 (labile ester) corticosteroids
(among these also to hydrocortisone-17-butyrate), as well as to fluticasone
propionate (Table IV)
(negative after 48 hrs, + after 72 hrs, - after 96 hrs. The reaction
to hydrocortisone-17-butyrate could explain the exacerbation of the lesions
the patient had presented upon its application, and probably also the
reaction to the methylprednisolone injection (Table
I).
Case 3
LL, a 41-year old non-atopic man, was referred to us in September 1995
for further patch testing. The dermatologist he had consulted had diagnosed
a contact allergy to balsam of Peru, fragrance mix, propylene glycol,
budesonide, and tixocortol pivalate. The skin complaints consisted of
itching and erythematous papules starting at the axillae and spreading
to the neck, arms and back. Corticosteroids had been used both locally
(triamcinolone acetonide, dexamethasone) and systemically (betamethasone).
Patch testing with the corticosteroid series revealed multiple positive
reactions to several corticosteroids (Table
IV), including fluticasone propionate (++ after 48 hrs, +? after
96 hrs).
It was thought that the patient had developed contact eczema from fragrances
in a deodorant, followed by iatrogenic dermatitis to corticosteroids.
Case 4
CE, a 34-year old atopic man, who had been suffering for 2 years from
an eczematous eruption on the dorsal and interdigital sides of both hands
as well as on the wrists, consulted us May 1996. Intermittently, he also
presented skin lesions at the pretibial area. He had used several multiple
corticosteroids, both locally and systemically, including clobetasol propionate,
betamethasone dipropionate and betamethasone valerate, fluocortolone (and
its esters), prednisolone, and triamcinolone acetonide.
His dermatitis seemed to be clearly related to his work, where he was
involved in beer brewing and cleaning, and especially with the wearing
of rubber gloves. In addition to positive patch test reactions to paraphenylene
diamine, 1% pet., diaminodiphenyl methane, 0.5% pet., and diphenylthiourea
1% pet. (which could explain his intolerance to rubber gloves and adhesive
tape), multiple positive reactions to corticosteroids were observed (Table
IV). Fluticasone propionate gave the following reactions: + ?
after 48 hrs, + after 96 and 168 hrs.
The patient had noticed a worsening of the lesions after the application
of a preparation containing clobetasol propionate.
Case 5
EE, a 71-year old woman, suffering from venous insufficiency of the
lower extremities and for 4 months also from recurrent leg ulcers, presented
in January 1998 with strongly itching, erythematous, and vesicular peri-ulcer
eczema at the inner sides of both lower legs. She had used several antiseptic,
antibiotic, and corticosteroid creams. Her personal history of atopy was
negative, but she did have an intolerance to adhesive tape.
Patch testing revealed multiple positive reactions to neomycin, colophony,
fragrance mix, balsam of Peru, wool alcohols, Euxyl K400 (1.5% pet.),
tixocortol pivalate, and sorbitan sesquioleate.
Testing with the pharmaceutical series gave positive reactions to cetrimide
(0.05 aq.), iodine (0.25%), cetyl alcohol (20% pet.), nonoxynol (2% aq.),
bacitracine (20% pet), benzoic acid (5% pet.), sorbic acid (2% pet.) and
merbromine (2% aq.). Further testing revealed positive reactions to corticosteroids
of all the groups, including fluticasone propionate (Table
IV), which reacted + after 72 hrs and ++ after 168 hrs. She also
reacted to ethanol (++ after 72 hrs and + after 168 hrs).
The relevance of the positive reactions to the corticosteroids could
not be determined since no information was available about the topical
pharmaceutical products the patient had used.
Case 6
SR, a 49-year old non-atopic woman with a known contact allergy to several
corticosteroids was referred to our department in January 1998 because
of suspicion of a reaction to hormonal substitution therapy: progesterone
had to be stopped because of itching erythema and edema of the eyelids.
She had had similar complaints with other hormonal products. The history
further revealed generalized itching and erythema after peri-articular
injection of betamethasone dipropionate and erythema and exacerbation
of eczema after topical application of a betamethasone valerate preparation.
Patch tests revealed several positive reactions to almost all the corticosteroids
as well as to progesterone (Table
IV). Fluticasone propionate reacted ++ after 48 hrs and 72 hrs.
Case 7
TC, a 45-year old female leg-ulcer patient who had suffered for 3 months
from eczema on the arms and legs accompanied by a generalized id-like
spread, consulted us in August 1998. She had used multiple topical preparations,
including ones containing betamethasone dipropionate, diflucortolon valerate,
fluocortin butylester, and fluticasone propionate. According to the patient,
the lesions had aggravated after application of a cream containing clobetasol
propionate (Dermovate®) to treat stasis eczema of the lower
legs. The atopic history was negative but she reported an intolerance
to costume jewelry, which had not been confirmed by patch testing. Epicutaneous
tests revealed a contact allergy to colophony, budesonide, hydrocorticosone-17-butyrate,
clobetasol propionate (1% eth.) as well as to iodine (0.25% eth.).
The other corticosteroids giving positive reactions are given in Table
IV. Fluticasone propionate, also used by the patient, reacted
++ after 48 hrs and 72 hrs, and was still + after 168 hrs.
Results
Out of the 6,509 subjects investigated, 231 reacted to at least one
of the routinely tested corticosteroids, which means that the overall
frequency of corticosteroid contact allergy in this population is 3.4%.
Out of the 206 corticosteroid-allergic subjects tested with fluticasone
propionate, 7 (3.3%) presented with a clear (+ or ++) positive reaction
to it, but only one of them (case 7) had actually used Cutivate®
cream. The results of testing with the extended corticosteroid series
in these patients are given in Table
IV. The positive reactions to other allergens are given in Table
V.
With regard to the inactive ingredients present in Cutivate®
cream and ointment, we have observed the following positive reactions
(and percentages) in the subjects tested: 61 to propylene glycol (1.4%),
75 to sorbitan sesquioleate (5.2%), 46 to cetyl alcohol (1.6%), 22 to
imidazolidinyl urea (1.9%) and 4 to isopropyl myristate (1.2%). The last
three substances were tested in a selected population only.
Of the Cutivate® preparations, which were introduced
on the Belgian market in June 1997, 89 patients had used the cream and
other preparations that may have contained the same ingredients. Of these
patients, 2 reacted to propylene glycol, 2 to cetyl alcohol, 2 to imidazolidinyl
urea, and 1 to isopropyl myristate. Moreover, none of the sorbitan-sesquioleate
sensitive subjects had used Cutivate® ointment.
Discussion
Contact allergy to corticosteroids is a frequent finding in patients
investigated for contact allergy so the inclusion of certain "markers",
i.e. tixocortol pivalate and budesonide in the European standard
series [4], is justified. Corticosteroid-sensitive patients generally
react to several corticosteroid molecules as concomitant and cross-sensitization
reactions, the latter occurring within certain chemical groups (Table
I) [3].
Some of the subjects also reacted to progesterone, which, according
to the literature, is generally an expression of cross-sensitivity among
chemically related steroids [5] although, as in Case 6, there exceptionally
may be a relationship to autoimmune progesterone dermatitis [6].
As only one subject of the 7 fluticasone propionate-allergic patients
had actually been exposed to this molecule, most of the positive reactions
to it must be due to cross-sensitivity. As can be seen from Table 4, fluticasone-propionate
sensitivity seems to occur in subjects who react to several corticosteroid
groups, which is in agreement with the literature [7]. It has recently
been demonstrated that, among the ester-group corticosteroids, contact
allergic reactions are much more frequently observed with substances such
as hydrocortisone-17- butyrate, methylprednisolone aceponate, and prednicarbate
(Group D2), all of which are "labile" esters that metabolize easily in
the skin, in contrast to corticosteroid esters such as betamethasone esters
and also the newer molecules such as fluticasone propionate and also mometasone
furoate (Group D1) [3]. In addition to fluorination and methyl substitution
on C16, as occurs in the other low allergenic molecules, fluticasone propionate
has a unique substituent on C17 (Fig.
1) that may greatly influence its hapten-protein binding and hence
its allergenicity [3].
With regard to the other allergens observed, corticosteroid-sensitive
subjects generally present multiple positive reactions to other active
principles, vehicle components or preservatives (e.g. [8, 9]).
This holds particularly for leg ulcer/stasis dermatitis patients (cf.
also Table V). One of
our patients even reacted to ethanol (case 5), a finding that is not exceptional
in corticosteroid-sensitive subjects [10].
Although most of the subjects allergic to the non-active ingredients
in the Cutivate® preparations became sensitized by the
use of other locally applied pharmaceutical (or cosmetic) products containing
the same allergens, these preparations have, of course, to be avoided
in the future by these patients.
CONCLUSION
In agreement with the literature [11], we may conclude that the risk
of primary sensitization of fluticasone propionate and its frequency of
cross-reactions with other corticosteroids are low. Moreover, when cross-sensitization
does occur, it seems to be in patients who react to almost all corticosteroid
molecules.
With regard to contact allergy it may thus be regarded as a safe corticosteroid
that is not apt to give rise to corticosteroid sensitization and that
may also be used in most patients who have been previously sensitized
to corticosteroids.
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