ARTICLE
Auteur(s) :, Frédéric AUGEY1,*, Christine
DISSARD2, Isabelle NORMAND3, Michèle DAUMONT3
1Department of Dermatology, Centre hospitalier Lucien
Hussel 38209 Vienne Cedex, France
29 Allée Jean Moulin 38550 Péage de
Roussillon
3Department of Endocrinology, Centre hospitalier Lucien
Hussel 38209 Vienne Cedex
accepté le 28 Avril 2004
Generalized pustular psoriasis (GPP) is the most severe type of
psoriasis and is characterized by the sudden onset of diffuse
erythema, with a scattering of pustules, accompanied by high fever
and general malaise. It can be the first sign of a psoriatic
disease or a complication of common psoriasis due to hypocalcaemia,
pregnancy or severe stress [1]. Frequently there is no obvious
cause. Acute generalized exanthematous pustulosis is a differential
diagnosis of drug-induced GPP. The transformation of psoriasis
vulgaris into pustular psoriasis after the application of topical
corticosteroids or the abrupt withdrawal of corticoids is a
phenomenon which has long been known, although the mechanism of
action is not understood [2]. We report a case of GPP which was
only cured after the treatment of iatrogenic hypocortisolism which
had not initially been noticed.
Case report
A 41 year old Turkish woman, who had been living in France
since 1995 and with no relevant medical history apart from obesity,
had been treating a moderately severe psoriasis with 15 ml
lotion and 30 g Topsyne® (fluocinonide) ointment
which was renewed every 6 months. She was under no other
medication. At the end of November 2001 she suffered an outbreak of
small psoriatic plaques for which her dermatologist prescribed one
month of 30 g of tacalcitol ointment at 4 μg/g and
90 g Diprosalic® ointment (bethametasone
dipropionate + 2% salicylic acid). At the end of December
2001, less than one week after the end of this treatment, she
suffered a relapse which was associated with highly inflammed
psoriatic plaques and a few pustules. A PUVA therapy was started
but after only 5 sessions the patient was admitted to our
hospital, via the emergency department, on January 21 2002.
She presented with typical GPP (( Figure 1 )). Her overall
condition had greatly deteriorated. The biological examinations
demonstrated hyperleukocytosis at 26000 Giga/L with a majority
of polynuclear neutrophils. The C-reactive protein level was
235 mg/l and the calcium level was normal. Pustules, blood and
urine cultures were negative. Chest x-ray was normal. Streptocinase
titer was not performed. A pregnancy test was negative. No
histology test was carried out.
A rapid improvement was obtained with the daily application of
30 g Diprosone® cream (bethametasone dipropionate)
and the establishment of an oral isotretinoin treatment
(0.7 mg/kg/d). However, a relapse occurred three weeks later,
just after the progressive tapering of the topical
corticosteroids.
From February to September 2002 successive treatments were tried
with little success, oral methotrexate (25 mg/d) in
association with isotretinoin, then cyclosporin (4 mg/kg/d)
and finally etretinate (0.7 mg/kg/d). Only the topical
corticosteroids seemed to bring relief to the patient. She
presented with arterial hypertension (under cyclosporin), then with
Cushing’s syndrome and diabetes necessitating insulin, which were
further aggravated by a corticoid injection in August in Turkey, as
well as the topical corticosteroids.
In mid-September, during a new outbreak of GPP, the cortisol and
ACTH levels were found to be very low (cortisol level at 8h:
0.3 microgrammes/100 ml, N: 8-24; ACTH at
8h < 5 ng/l, N:14-26). The corticotropin
stimulation with ACTH also indicated a moderate imbalance (cortisol
level peaked at 17.5 microgrammes/100 ml at T+8h). A
clear reduction in the levels of testosterone and all the adrenal
hormones (delta 4 androstenedione, DHEAS) was shown, whereas
there were no anomalies in the other hypophysial secretions and the
prolactine level was normal. Parathormone and vitamine 25 OH
D3 had normal values. These examinations showed the characteristics
of adrenal axis suppression (with an insufficient response of the
adrenal gland to stimulation) due to iatrogenic causes. It was not
felt necessary to carry out further radiological
investigations.
Treatment with hydrocortisone at a replacement dose
(15 mg/d) was started on 15 September and the topical
corticosteroids were completely stopped two weeks later. Only
etretinate was continued.
The clinical improvement was marked from the start of the
hydrocortisone therapy. No further relapse of the pustular
psoriasis was observed. There was only a moderate common psoriasis.
Etretinate was tapered off over 6 months and successive dosage
of cortisol followed by immediate stimulation tests with
Synacthene® confirmed the progressive normalisation of
the adrenal functions. Hydrocortisone was stopped in August 2003
and the patient has since remained clinically healthy as the
diabetes mellitus disappeared.
Discussion
Our patient presented with a transformation of moderately severe
psoriasis vulgaris into GPP which could not be explained by any
classic processes. Meladinine could not be the triggering factor as
the patient already had several pustules before the PUVA therapy
and stopping this drug brought no improvement.
The responsability of iatrogenic adrenal insufficiency in the
worsening of psoriasis seems very likely for the following reasons:
there was a rapid response of the eruptions to each application of
topical corticosteroids, in contrast to the failure of other
treatments; there was a marked clinical improvement from the start
of hydrocortisone replacement; the treatment tapering corresponded
to the normalisation of the cortisol levels which led to clinical
recovery in a few weeks and to the end of all treatment within one
year. On the other hand, the initial irregularities in the
endocrinological investigations are only a weak element of proof as
any topical corticoid therapy of bethametasone dipropionate above
49 g per week is likely to lead to adrenal axis suppression
with a low risk of clinical signs [3]. Moreover, the patient had
received a delayed corticoid injection one and a half months before
the first endocrinological tests. Endocrinological disturbances
induced by topical glucocorticoids (GC) have been known since their
appearance on the market 50 years ago and have resulted in
numerous publications reporting acute adrenal suppression [4-7].
Studies of controlled groups of patients (particularly pediatric)
have given conflicting results, sometimes indicating subclinical
adrenal consequences [8]. For the past ten years most attention has
been paid to inhaled GC and their reputation for harmlessness is
being reconsidered. One of the present authors has published a
similar systemic effect associated with diabetes [9]. The
occurrence of this undesirable effect remains low but it should not
be ignored. Iatrogenic adrenal axis suppression may be poorly
recognised as the clinical signs (asthenia, joint pains, nausea,
vomitting…) are not specific and are hidden, as are the biological
signs, by a misleading appearance of iatrogenic hypercorticism:
Cushing-like features, arterial hypertension, diabetes…[10].
The extent of adrenal blocking by a GC depends on several
factors such as affinity of the molecule for its receptors. Studies
have shown that about 6% of patients have a high sensitivity to GC
due to primitive abnormalities to GC receptors [11].
We suggest that our patient was extremely sensitive to GC as the
first pustules appeared following the withdrawal of bethametasone
dipropionate which had been given weekly at a fairly high dosage
(30 g) but for a short period (3 weeks). Inflammatory
dermatoses (eczema, psoriasis, urticaria…) are not considered to be
complications of adrenal insufficiency. M Dupin et al., however,
reported a lasting and spectacular improvement after treatment of
severe atopy with hydrocortisone supplements in two patients, a man
aged 77 and a girl of 16, in whom iatrogenic hypocortisolism
had been found [12].
Several studies have demonstrated that endogen GC inhibit the
production of pro-inflammatory cytokines (IL1, IL6, TNF alpha...)
by a feed-back mechanism [13-15]. Moreover blunted adrenocortical
responses to stress have been shown in different forms of chronic
manifestations of atopy, especially in atopic dermatitis
[16-18].
We believe, in the light of our observation and those of Dupin
et al., that testing of the cortisol level should be undertaken in
severe chronic inflammatory dermatoses whenever the history
suggests a corticodependence, as a simple treatment with
hydrocortisone and progressive tapering of the other steroid can
lead to a cure.
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