Dermatologic Therapy, Vol. 16, 2003, 40–44
Printed in the United States · All rights reserved
Copyright © Blackwell Publishing, Inc., 2003
DERMATOLOGIC THERAPY
ISSN 1396-0296
Diagnosis and treatment of
actinic prurigo
Hojyo-Tomoka
Original
Diagnosis
Article
andTherapy
treatment
et al. Ltd.of actinic prurigo
Blackwell
Oxford,
Dermatologic
DTH
2003
11396-0296
16
Blackwell
UK
Publishing
Publishing
MARÍA-TERESA HOJYO-TOMOKA, MARÍA-ELISA VEGA-MEMIJE,
ROBERTO CORTES-FRANCO, & LUCIANO DOMÍNGUEZ-SOTO
Department of Dermatology, Hospital General “Dr. Manuel Gea González,”
Mexico City, Mexico
ABSTRACT: Actinic prurigo (AP) is an idiopathic photodermatosis that affects mainly the mestizo
population in Latin America. It has an early onset, a slight predominance in women, and affects
the sun-exposed areas of the skin, causing erythematous papules and lichenified plaques secondary to intense and chronic pruritus. Lesions can be induced by both ultraviolet A (UVA) and ultraviolet B (UVB). An association with several human leukocyte antigen (HLA) alleles has been
reported. AP is unique among all photodermatoses in its remarkable response to thalidomide. In
the past the microscopic features of AP have been considered as nonspecific; however, the constant finding of dense lymphocytic inflammatory infiltrates and the immunogenetic features of
AP support the existence of an immunologic mechanism in its pathogenesis.
KEYWORDS: actinic prurigo, photosensitivity, thalidomide
Clinical presentations
Various types of photodermatoses are frequently
found throughout Latin America. Due to its geographical location, there is a high amount of
solar radiation most part of the year. Furthermore,
nutritional, economic, social, and particularly
race factors affect the features of these diseases.
Mestizo refers to people of mixed Indian and European ancestry; it predominates in Mexico, Guatemala,
Honduras, Colombia, Ecuador, Peru, and Bolivia, while
it is rare or nonexistent in Costa Rica, Venezuela,
Argentina, Uruguay, and Chile. In Nicaragua, Panama,
and Brazil, the mixed race population is different,
consisting of African and White ancestry (1).
One of the common photodermatoses is actinic
prurigo (AP). Its polymorphic clinical features, well
known to Latin American dermatologists, include
erythematous papules, crusts, excoriations, and
lichenified plaques due to chronic scratching
Address correspondence and reprint requests to: María-Teresa
Hojyo-Tomoka, MD, Department of Dermatology, Hospital
General “Dr. Manuel Gea González,” Calzada de Tlalpan 4800,
Toriello Guerra, Tlalpan 1400, Mexico City, Mexico, or email:
[email protected].
40
(Fig. 1). Vesicles are absent as a primary lesion, but
can be found as a result of secondary contact
dermatitis, eczema, and impetigo. AP affects sunexposed areas of the skin, such as the face (eyebrows,
malar regions, nose, lips), neck, V-area of the chest,
external regions of the arms and forearms, as well
as the dorsum of the hands (Fig. 2).
The onset is usually at an early age, when the
child is 4–5 years old and is constantly exposed to
the sun. This disease runs a chronic course, with
no remissions in patients seen in Latin American
countries, where there is no significant variation in
the sunlight throughout the year. In cases found in
Canada (2–4), the United States (5), and England
(6), the patient’s condition flares during the spring
and summer and improves or remits during the
winter. There is a predominance of women, with a ratio
of 2:1. AP affects the inhabitants of regions located at
altitudes greater than 1000 m above sea level, although cases have been found in coastal residents.
Involvement of the lips and the conjunctiva is
common, and it causes cheilitis and pseudopterygium. Both the upper and lower lips can be
affected, although it is found mainly on the lower
lip; the lesions are characterized by edema, scales,
fissures, and secondary ulceration.
Diagnosis and treatment of actinic prurigo
Fig. 1. Primary
lesions
are erythematous papules
with excoriations, crusts,
and lichenification.
Fig. 5. Eye lesion manifested by conjunctivitis,
watery
eyes,
and
pigmentation.
Fig. 6. Chronic affection
of conjunctiva with pseudopterigium formation.
Fig. 7. Microscopic finding
of a dense lymphocytic
infiltrate in a skin biopsy
specimen.
Fig. 8. Dense lymphocytic
infiltrate forming welldeveloped
germinal
centers in a lip lesion.
Fig. 2. Lesions occur in
the sun-exposed area of
the face (malar, supraciliar,
nose, lip, and conjunctiva).
Fig. 3. Severe lip involvement showing edema,
fissures, shallow ulcerations, and crusts.
Fig. 4. Mild lip involvement showing a dry lip
with scaling and crusts.
The intensity of the cheilitis fluctuates from
an acute phase with severe exudative lesions and
yellowish adherent crusting (Fig. 3) to a chronic
phase with dry and scaling lips (Fig. 4). The cheilitis is chronic and recurrent; it exacerbates with
sun exposure. Conjunctival involvement includes
hyperemia, photophobia, and increased lacrimation
in its early stages. Later, there is brown pigmentation, hypertrophy of the papillae, and pseudopterygium formation associated with pruritus (7)
(Figs. 5 and 6).
Histology and immunohistochemistry
For a long time the histopathologic characteristics of AP were considered nonspecific. However,
based on more recent data obtained from a large
number of patients, these features are now considered to be distinctive, consisting of hyperkeratosis,
ortho- or parakeratosis, regular acanthosis (this is
a constant finding which correlates well with the
clinical lesions), and thickening of the basal lamina. The superficial dermis shows a perivascular
dense lymphocytic infiltrate, which rarely affects
the middermis. There is not adnexal involvement
or actinic elastosis (Fig. 7).
In lip biopsy specimens, there is hyperkeratosis
with parakeratosis, regular acanthosis, spongiosis,
and vacuolization of the basal cell layer. There
may be epithelial ulceration. In the dermis one
finds stromal edema, and dilated and congestive
vessels. The dense lymphoplasmocytic infiltrate can
have a band-like distribution, or form follicles or
germinal centers (in up to 80% of the cases) (Fig. 8);
abundant eosinophils are usually present.
Biopsy specimens of the affected conjunctiva
show epithelial hyperplasia alternating with atrophy. Vacuolization of the basal cell layer is always
present, as well as dilated capillaries in the dermis.
The inflammatory infiltrate consists of lymphocytes
that accumulate and form lymphoid follicles (88%
of the cases). Eosinophils and melanophages are
present in most cases (Fig. 9).
The presence of lymphoid follicles in skin biopsy
specimens has been observed when there is a loss
of epidermis (ulceration), which supports the protective role of the stratum corneum, and provides
an explanation as to why these follicles are more
frequently observed in the mucosae. With the
use of immunohistochemical techniques, such as
immunoperoxidase and immunophosphatase
staining, the inflammatory cells forming follicles
have been shown to be T and B lymphocytes. The
T cells (CD45+, IL2+) (Fig. 10) are in the periphery
41
Hojyo-Tomoka et al.
Immunogenetics and
pathophysiology
Fig. 9. Dense lymphocytic
infiltrate with follicles in
a conjunctiva lesion.
Fig. 10. Immunoperoxidase
staining showing dense
lymphocytic infiltrate with
T cells in the periphery of
lymphoid follicles.
Fig. 12. Induction of a
clinical lesion with repeated exposure to three
to five times the MED UVB
dose for several consecutive days.
Fig. 11. Immunoperoxidase
techniques show B cells
present in the center of
the follicles.
AP is associated with certain ethnic groups of
North and South America, which suggests a genetic
predisposition. There are reports of several human
leukocyte antigen (HLA) alleles in association with
AP. In Cree Indians from Saskatchewan, Canada
(9), the most common antigens were HLA-A24 and
HLA-Cw4. In the Chimila Indians from Colombia
(10), a high frequency of HLA-Cw4 was found, and
in Mexicans we reported an increased occurrence
of HLA-A28 and HLA-B39(B16), as well as a very
strong association with HLA-DR4 (DRB1*0407) (11).
Meanwhile, English investigators have also
reported AP patients with HLA-DR4 (DRB*0407)
(12). In the Inuit Indians of Canada, an association
with HLA-DR4 (DRB1*14) was found (13).
The English patients with polymorphic light
eruption (PMLE) (14) did not show an association
with a particular HLA, which suggested that HLADR4 (DRB1*0407) can be utilized as a marker to
distinguish these two diseases, AP and PMLE. One
can speculate that HLA alleles may have a causal
role in determining the response to a peptide
antigen, probably induced by solar radiation, that
would initiate the cutaneous reaction.
Differential diagnosis
Several conditions need to be considered.
and the B cells (CD20+) are in the center (Fig. 11).
Furthermore, there are abundant eosinophils and
extracellular deposits of IgM, IgG, and C3 in the
papillary dermis. The keratinocytes show immunoreactivity with calprotectine and tumor necrosis
factor (TNF)-α (8).
Photobiology
Our experience with phototests shows that the
minimal erythema dose (MED) of ultraviolet B (UVB)
was in the range of 50–60 mJ/cm2, and experimental
induction of lesions using a MED of UVB of 3–5 mJ/
cm2/day for 15 days was successful in 100% of the
cases (Fig. 12). With ultraviolet A (UVA) the lesions
were produced with daily radiation of 2.5 J/cm2 for
10 days in 90% of the patients. Consequently we
were able to prove that these patients react to a
broad spectrum of radiation (UVA and UVB) and
their MEDs to UVB and UVA are usually normal.
42
Atopic dermatitis with photosensitivity
Most patients with atopic dermatitis have characteristic cutaneous manifestations, however, in
some the dermatitis might be exacerbated by
exposure to solar radiation. In these cases a personal and/or familial history of atopy, an early
onset, the presence of xerosis, sparing of the tip of
the nose, and a good response to topical or systemic corticosteroids and topical emollients can
help differentiate it from AP.
Chronic actinic dermatitis
Patients with this condition present with erythematous papules, plaques, and lichenification
on sun-exposed areas; they may have a positive
reaction to multiple contact photoallergens. It has
a marked predominance in older men.
The diagnostic criteria are based on phototest
results which show an abnormally low response to
Diagnosis and treatment of actinic prurigo
UVB, UVA, or visible light. Histopathologic changes
range from dense lymphocytic inflammatory infiltrate to infiltrate with atypical mononuclear cells
resembling lymphoma.
PMLE
Polymorphic light eruption has a worldwide distribution and affects all races. It is less frequent in Latin
American countries, presumably due to the yearround presence of sunlight. Its clinical picture (e.g.,
presence of vesicles), as well as its intermittent course
with complete remission, relapse, and exacerbation,
recurring yearly, usually with sun exposure in the
spring, is not observed in AP. The histopathology
never shows lymphocytic infiltrate forming follicles,
and it is not associated to any particular HLA antigens.
Other entities such as discoid lupus erythematosus and lymphocytic infiltrate are clinically distinctive, and as such are seldom mistaken for AP.
Treatment
As with all photodermatoses, the first and most
obvious measure to control AP is avoiding sun exposure with adequate clothing, sunglasses, a hat, or an
umbrella. In many cases we may need to treat other
diseases related to AP, such as contact dermatitis and
impetigo, before we can prescribe any type of sunscreen. A sun protection factor (SPF) greater than
15 with a proper vehicle is recommended. In our
experience, creams are more effective, since lotions
and gels may be poorly tolerated by damaged skin.
Topical and systemic corticosteroids and antibiotics are successful in treating the most frequent
complications of AP. Oral antihistamines will help
control the pruritus. Antimalarials are efficacious
for PMLE and discoid or systemic lupus erythematosus; however, they are not effective for AP.
Thalidomide has proven to be the most effective
drug in the treatment of AP (15,16). In fact, the
response to thalidomide may be a marker in the
diagnosis of AP (1,7). The initial dose is 100–200 mg/
day, according to the severity of the clinical
picture. It can be reduced when improvement is
observed. We have been able to control many of our
patients with a dose as low as 25 mg/week (Figs. 13
and 14). This drug must be used under strict safety
measures; for women of childbearing age we
administer intramuscular contraceptives and supply
thalidomide only in quantity sufficient for 1 month.
Reported side effects, such as peripheral
neuropathy, were not frequently observed in our
patients. Somnolence and increased appetite are
Fig. 13. An
before
treatment.
AP patient
thalidomide
Fig. 14. The same patient
as in Fig. 13 after 1 month
of thalidomide treatment.
observed in some patients and morbiliform exanthema may be seen, albeit rarely.
Discussion
AP is a photodermatosis that affects the Mestizo
population of Latin America. Although there have
been reports of cases in Indian communities in
Canada and the United States, it is interesting to
note that AP is not found in countries like Chile
and Uruguay, where the Mestizo population is
almost nonexistent. In Argentina there were some
reports among a Mestizo group located in the
northern region of the country. These last three
countries have a predominantly Caucasian population because of European immigration.
According to Birt and Davis (2,3), Lane et al. (4)
in Canada, and Fusaro and Johnson (5) in the
United States, there is a hereditary factor present
in AP. Yet Latin American authors found that
familial cases reported are not more than 15%. It is
probable that the difference reflects the different
population of patients affected in each of these
countries. In Canada and the United States, the
patients affected by this disease are part of the
closed Indian communities that represent a low
percentage of the general population, consequently
the American Indian genes are preserved among
them. The contrary is found in Latin America, where
the Mestizo group represents a very high percentage of the population. Therefore we can conclude
that there is a difference in the “race dilution.”
It is not clear yet if immunologic mechanisms
play a role in AP, but all available evidence points
in that direction. Due to the clinical, histopathologic,
43
Hojyo-Tomoka et al.
immunologic, and immunogenetic findings, as
well as its response to thalidomide, AP has enough
distinctive features to differentiate it from other
forms of chronic photodermatoses.
Conclusion
AP has epidemiologic, clinical, histopathologic,
immunogenetic, and immunopathologic features
that give it a distinctive character. The diagnosis of
this disease must be based on its clinical and
histopathologic characteristics. Lesions on the lips
and conjunctiva are specific, and the skin offers an
adequate histopathologic correlation. The experimental induction of AP lesions is possible with UVB
and UVA, but the radiation doses vary in every case.
In our experience, the best treatment is thalidomide, because of its rapid action, similar to its
effects in leprosy. However, thalidomide has been
indicated in other dermatoses, such as atopic
dermatitis and other inflammatory diseases. In AP
thalidomide induces remission of symptoms and
improves the lesions in 30–60 days.
The immunogenetic and immunopathologic
studies provide data involving possible pathogenesis of AP. The HLA-A28, B16, and DR4 antigens may represent a genetic susceptibility to AP
among the Mexican population, and the presence
of T and B lymphocytes in the lymphoid follicles or
germinal centers indicate that there is a role for
cellular and humoral factors in its pathogenesis.
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44
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