ARTICLE
Papuloerythroderma, first described by Ofuji et al., is a chronic,
recalcitrant disorder of unknown aetiology [1] and its intense pruritus
occasionally disturbs the quality of life of the afflicted individual.
Because only sporadic cases have been reported, there is no recommended
choice of treatment. Treatment with potent topical steroids is of limited
benefit for resolution of the skin lesion, and barely brings about quick
relief of pruritus [1-7]. Systemic steroids (30-60 mg/day) are usually
effective [1, 3, 4, 6, 8, 9], but tapering doses often results in recurrence
or exacerbation of the disease [1, 3, 9]. Furthermore, in light of the
fact that papuloerythroderma usually affects elderly individuals, prolonged
administration of systemic steroids should not be proposed as the prime
choice of treatment because of their potential adverse effects, and they
may be contraindicated for patients with diabetus mellitus, hypertension,
and peptic ulcers. Photochemotherapy is effective in certain cases, and
appears to be a promising therapy [5, 7, 9]. The necessity for regular
and frequent visits to clinics, however, makes it a rather inconvenient
treatment for out-patients. Therefore, a simple and more effective treatment
with minor adverse reactions is suggested.
In this paper we report the efficacy of etretinate therapy on papuloerythroderma.
Seven cases were treated with moderate doses of etretinate and all of
them responded well to the treatment. In the dermatological literature
so far published, our report contains the largest number of cases treated
by an identical therapy, and, therefore, validates the efficacy of etretinate
for the rare dermatoses.
Case reports
The clinical information of the 7 cases of papuloerythroderma treated
with etretinate is presented in Table
I. All the patients were male, ranging in age from 65 to 84 years
old with an average age of 75.1. Before being diagnosed as papuloerythroderma,
all the 7 cases had suffered from recurrent episodes of pruritic papular
eruption of unidentified aetiology developing on the back, abdomen, extensor
surface of the extremities, and buttocks. The clinical diagnoses for these
preceding eruptions were chronic eczema (Case 1-3) and chronic prurigo
multiforme (Case 4-7), whose duration ranged from 2 months to 12 years.
None of them had a previous history of hay fever, asthma, or atopic dermatitis.
The preceding skin lesions showed repeated exacerbation and remission
without obvious predisposing events. In all of these seven cases, during
the course of the treatment with topical steroids, the pruritus became
more and more severe and the pre-existing papular lesions started to coalesce,
rapidly evolving into an erythrodermatous lichenified plaque with no seropapular/vesicular
component (Fig. 1A), becoming
quite resistant to treatment with potent topical steroids and oral anti-histamines.
The coalescent plaques were separated by a zone of normal-appearing skin
so that some of the typical lesions presented a cobble stone-like appearance
(Fig. 2A). Such erythrodermatous
plaque was equally distributed on the back, buttock, lower abdomen, and
extensor surface of the thigh, and in some cases distributed on the anterior
chest, upper arm, and calf as well. The antecubital, popliteal fossae,
axillaes, and the large creases in the abdomen were spared. When the coalescent
erythrodermatous plaque fully developed, all these cases were diagnosed
as papuloerythroderma based on their typical dermatological manifestations.
All the patients were in excellent condition except for the cutaneous
problems. Abnormal laboratory findings were peripheral blood eosinophilia
(Case 1, 3, and 5), elevated levels of serum lactate dehydrogenase (LDH)
(Case 1, 3, 4, 5, and 7), and slightly elevated plasma IgE levels (Case
2, 3 and 5, data not shown). Skin biopsies of the plaque lesions showed
dense to moderate perivascular and interstitial infiltration of mononuclear
cells admixed with variable populations of eosinophil (not shown).
The patients were initially given 0.2-0.6 mg/kg/day
etretinate in two doses. The starting dose of etretinate was tentatively
set at 0.5 mg/kg/day (30 mg/day) because even an elderly patient could
easily tolerate it. Depending on the extent of cutaneous involvement and
resistance of the lesion to topical steroids, the initial dose was adjusted
as in Case 6 (0.2 mg/kg/day) and Case 3 (0.36 mg/kg/day). The preceding
treatment with oral anti-histamines and topical steroids was also continued.
The details of treatment and the clinical response in each individual
are summarized in Table II.
All the patients except for Case 3 showed a quick and excellent response
to the treatment; both the papuloerythrodermatous and papular lesions
started to lose their erythematous hue and flatten, and the intense pruritus
rapidly diminished within a couple of weeks. These patients were relieved
of severe pruritus and markedly reduced the amounts of daily usage of
topical steroids. The cutaneous lesions almost completely disappeared
leaving heavy pigmentation (Fig.
1B) within 2-5 weeks. Only Case 3 showed a slow response to the
treatment; the papular lesions waxed and waned for nearly 5 months despite
continuous treatment with etretinate. Once remission was achieved, etretinate
was tapered and eventually discontinued in 3 cases (Case 1, 6, and 7).
Case 6 has remained in complete remission for 16 months since then. Case
1 experienced bouts of recurrence of localized papular eruption after
the cessation of etretinate, which was successfully managed by a brief
course of topical steroid treatment. Case 7 remained in complete remission
for 6 months. However, coalescent papular lesions with intense pruritus
recurrred (Fig. 2B)
and etretinate therapy was started again at 0.4 mg/kg/day with a good
response and remission was maintained with 0.2 mg/kg/day etretinate. In
Case 2, complete remission was rapidly achieved without any topical steroid
treatment, and the remission was maintained with 0.16 mg/kg/day etretinate.
The other three patients (Case 3, 4, and 5) stopped taking etretinate
without our permission after remission was achieved, and the cutaneous
lesions and intense pruritus recurred within 1-2 weeks after the cessation
of etretinate. Topical steroids and oral anti-histamines failed to control
the recurrence, and re-administration of the same doses of etretinate
as the initial ones readily induced remission. These patients experienced
a couple of recurrences of the disease on cessation of etretinate, each
of which responded promptly to re-administration of the initial dose of
etretinate. They remained in remission as long as they were regularly
taking 0.33-0.36 mg/kg/day etretinate. The adverse effects of etretinate
were all minor ones such as cheilitis, palmoplantar desquamation, and
paronychia, which were all managed successfully and well tolerated by
the patients. The elevated levels of serum LDH and peripheral blood eosinophilia
returned to normal levels during the remission period.
Discussion
Papuloerythroderma is a chronic, but self-healing disorder and slowly
subsides over the course of years [1]. There is, therefore, a small but
unlikely possibility that etretinate therapy coincided with the time of
spontaneous resolution in our 7 cases. The quick response of the pruritus
and cutaneous lesions, however, to administration of etretinate in all
cases except for Case 3, and the rapid recurrence of the cutaneous lesions
upon cessation or tapering of etretinate in 6 cases (Case 1, 2, 3, 4,
5, and 7), and the successful management of recurrence by re-administration
of etretinate in 4 cases (Case 3, 4, 5, and 7) all strongly suggest the
beneficial effect of the retinoid on the resolution of papuloerythroderma.
When the typical erythrodermatous lesion involves more than three quarters
of the trunk, which is usually the case in papuloerythroderma, we recommend
starting etretinate therapy with an initial dose of 0.5-0.6 mg/kg/day.
With the exception of Case 6 where an only 0.2 mg/kg/day initial dose
sufficed to achieve complete remission, a quick and excellent improvement
of the cutaneous lesion and pruritus is obtained within 2 weeks by these
initial doses. The much slower response to etretinate in Case 3 is probably
due to the lower initial dose (0.36 mg/kg/day). Once the remission is
achieved, etretinate can be tapered by 0.1-0.2 mg/kg/day over a period
of 2-4 weeks. Except for Case 1 and Case 6, all the patients required
0.16-0.36 mg/kg/day etretinate to maintain remission. Case 1 suffered
from bouts of recurrence after the cessation of etretinate. We believe
administration of a maintenance dose of etretinate would have prevented
recurrences. Only Case 6, who showed an excellent response to the small
initial dose of etretinate (0.2 mg/kg/day), remained in a disease-free
state for a prolonged period (16 months) after cessation of etretinate.
It is, therefore, not certain if etretinate is truly a cure for papuloerythroderma.
Probably maintenance doses of etretinate (0.2-0.4 mg/kg/day) would be
necessary for suppression of the disease activity in most cases.
Papuloerythroderma may be a disease entity composed
of heterogeneous disorders. In contrast to the original cases reported
by Ofuji et al. and the majority of subsequent cases, which were
all regarded as a benign cutaneous disease, a few cases of cutaneous T
cell lymphoma (CTCL) have been reported [2, 7]. The cutaneous manifestations
even in an individual also take heterogeneous forms; the skin rash starts
as a discrete papular form and eventually evolves into a coalescent plaque
form [1, 4, 6, 9]. Along with the evolutional change of clinical manifestations,
the histological features of papuloerythroderma may change as well because
eosinophil is not always conspicuous in the population of dermal infiltration
[1]. It remains to be ascertained if etretinate is universally effective
in papuloerythroderma regardless of the stage of its evolution, its histological
characteristics, or its aetiology.
Just as the pathogenesis of papuloerythroderma remains entirely unknown,
so also does the pathophysiological mechanism of the beneficial action
of etretinate on the disease. Beside the profound effects on various stem
cell differentiations, retinoids have anti-inflammatory and immunomodulatory
properties such as inhibition of neutrophil chemotaxis [10], suppression
of leukotrien C4 production in eosinophil [11], and stimulation
of killer T cell induction [12]. Since papuloerythroderma shows no evidence
of abnormal keratinocyte differentiation, etretinate may exert beneficial
effects on papuloerythroderma through its immunomodulatory and/or anti-inflammatory
action rather than its modulatory action on cell differentiation. At least
a subgroup of papuloerythroderma appears relevant to cutaneous lymphoproliferative
disorder since a few cases of CTCL developed from papuloerythroderma [2,
7]. The fact that both etretinate [13] and photochemotherapy are as effective
for relatively early stages of CTCL as they are for papuloerythroderma
implies that the disease may have something in common in its pathogenesis
with CTCL.
CONCLUSION
Moderate doses of etretinate is a safe and effective treatment modality
for papuloerythroderma, thus, a very useful agent in controlling the chronic,
recalcitrant cutaneous disorder in an ordinary out-patient clinic.
Acknowledgement
We are very grateful to Dr. Keiji Ohta, Osaka, Japan, for suggesting
we try etretinate on papuloerythroderma.
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