Contact
allergy to corticosteroids is now a well-established phenomenon, and cases from
all over the world have been reported in the literature. The incidence of the reactions observed,
however, varies and depends on several factors such as the nature and amount of
corticosteroids used in each country, prescription habits, the awareness among
the medical profession of the importance of corticosteroid sensitivity, the
selection of the patients and their referral to test centers, the routine
testing of screening agents for corticosteroid sensitivity as well as of all
the corticosteroids used by the patient, and the test and reading methods.
Patients
with contact allergy to corticosteroids generally present with a chronic
dermatitis that is not exacerbated by but fails to respond to corticosteroid
therapy. Indeed, the allergenic and
simultaneous anti-inflammatory effects of topical corticosteroids cause a non-specific
self-supporting eczematous condition, which is rarely recognized as a
potentially iatrogenic sensitivity.
Although
infrequent relative to the large scale of their use, allergic reactions may
also arise to the corticosteroids administered by inhalation in the treatment
of rhinitis or bronchial asthma.
Generalized reactions may, of course, also occur after systemic
administration (oral, intravenous, or intra-articular). The lesions may manifest themselves as eczema,
exanthema, purpura, urticaria, and so on.
In
general, corticosteroid-sensitive patients react upon patch testing to several
corticosteroids. This may in part be
because most of them have used large numbers of corticosteroids and would thus
be vulnerable to concomitant sensitization.
However, irrefutable proof for the existence of cross-reactions is
provided by reactions to substances to which the patient has never been
exposed. Studies in this regard can
have practical consequences for the identification of screening agents and for
advice regarding the topical and systemic corticosteroids the
corticosteroid-sensitive patient can safely use.
Our
earlier studies had led us to suggest four groups of cross-reacting molecules,
which, in the light of new findings (to be published elsewhere in detail), have
to be subclassified as regards the ester-type corticosteroids (Table 1).
Indeed,
when testing Group D molecules, contact allergic reactions are frequently
observed with substances such as hydrocortisone-17-butyrate, -aceponate and
-butyrate, as well as methylprednisolone aceponate and prednicarbate than with
molecules such as betamethasone and its esters such as valerate and
dipropionate, diflucortolone valerate, diflorasone diacetate, clobetasone
proprionate, clobetasone butyrate, and also the newer mometasone furoate and
fluticasone propionate (now classified as Group D1). The former esters can be classified as the more sensitizing D2
corticosteroid molecules. They are
"pro-drug" corticosteroids that, because of there high lipophilicity,
easily penetrate the skin where they break down into the corresponding
structures with the hydroxyl groups at the C21 and/or C17 positions.
As
regards the influence of the skin metabolization of corticosteroids, recent
patch-test results (data to be published elsewhere in detail) have shown that,
for instance, positive reactions to "labile" molecules such as
prednicarbate and methylprednisolone aceponate correlate significantly with
reactions obtained with Group A corticosteroids (p < 0.01), to which the
metabolized prednisolone and methylprednisolone belong. This mechanism might also account for
cross-reactions that have been observed between hydrocortisone and
hydrocortisone-17-butyrate (our own data), the latter being able to be
converted to hydrocortisone-21-butyrate, which is rapidly hydrolyzed to form
hydrocortisone. However, individual
skin-metabolization characteristics certainly influence the cross-sensitivity
patterns observed.
Thus
not only the molecular configuration but also their factors such as the
presence of certain substituents, the solubility in the vehicle used, skin
penetration, and skin metabolization seem to be critical for the sensitization
and cross-sensitization potential of individual corticosteroids.
As
most contact allergies are missed if corticosteroids are not routinely tested,
it is useful to add two or three screening corticosteroids to the standard
series: tixocortol pivalate (0.1 % pet.), budesonide (0.1 % pet.) and
sometimes also hydrocortisone-17-butyrate (1 % ethanol). Should a corticosteroid sensitivity be
detected, more extensive corticosteroid series should be tested, if possible,
to determine cross-reactivity patterns so that appropriate advice for the
future can be given both for local and for systemic corticosteroid therapy.
Table
1: Classification of corticosteroids in function of
cross-reaction patterns
- Characteristics
of the group: no methyl substitution on C16, no side chain on C17, possibly
short side chain on C21
- Typical
members: cloprednol, fludrocortisone acetate, hydrocortisone,
methylprednisolone, prednisolone, tixocortol pivalate
- Possible
cross reactions outside the group with D2 group labile steroids: hydrocortisone
aceponate, hydrocortisone-17-butyrate, methylprednisolone aceponate,
prednicarbate
- Characteristics of the group: Cis diol or ketal function on C16 and C17, possibly a side chain on C21
- Typical
members: budesonide (R- & S-isomer), amcinonide, desonide,
fluocinolon acetonide, triamcinolon acetonide
- Characteristics of the group: methyl substitution on C16, no side chain on C17, possibly a side chain on C21
- Typical
members: betamethasone, dexamethasone, flumethasone pivalate, halomethasone
- Characteristics
of the group: methyl substitution on C16 (so far halogenation on the basis
structure) side chain ester on C17, often on C21 also
- Typical
members: betamethasone dipropionate; betamethasone-17-valerate, clobetasol
propionate, fluticasone propionate, mometasone furoate
- Characteristics
of the group: no methyl substitution on C16, (up till now no halogenation of
the four ring structure), side chain ester on C17, possibly a side chain on
C21)
- Typical
members: hydrocortisone aceponate, hydrocortisone buteprate,
hydrocortisone-17-butyrate, methylprednisolone aceponate, prednicarbate
- Possible
cross reactions outside the group: budesonide S-isomer, group A corticosteroids
1.
Matura M.
Contact allergy for locally applied corticosteroids. Thesis submitted in fulfillment of the
requirements for the Degree of Doctor in Medical Sciences, Leuven, Belgium,
1998.
2.
Goossens A, Matura M. Contactallergie voor corticosteroïden: recente
ontwikkelingen. Nederlands Tijdschrift
voor Dermatologie en Venereologie, 1999, 9:263-265.