ARTICLE
It is well known in Japan that fluorouracil agents induce discoid lupus
erythematosus (DLE)-like eruptions. The frequency of DLE-like eruption
is about 10% among all cases of drug eruptions induced by fluorouracil
agents, based on the statistical report of Fukuda [1].
UFT, a combination of uracil and tegafur, is a second generation anticancer
agent. Tegafur is an antimetabolite which is slowly converted to 5-fluorouracil
(5-FU) in vivo. The uracil in UFT slows the degradation of 5-FU
by dihydropyrimidine dehydrogenase, which results in higher 5-FU concentrations
in tumors than achieved with tegafur alone or comparable doses of intravenous
5-FU [2, 3].
UFT has been used for a long time, especially for the treatment of gastrointestinal
adenocarcinoma, in Japan and other Asian countries [3]. Since 1996, it
has been used in South America and Russia and has been extensively studied
for the treatment of various types of cancer in North America and Europe
[3, 4]. Gastrointestinal disturbances, pancytopenia, and hepatic dysfunction
have been reported as major adverse effects of UFT [2-4]. Recently, we
encountered a case of DLE-like lesions induced by UFT. Herein, we report
a case and summarize the clinical features of UFT-induced DLE-like eruptions
which have been reported in Japan.
Case report
A 64-year-old Japanese woman with a history of lung cancer, which was
resected in February 1998, was studied. After the operation, UFT (300
mg/day) was administered from February 1998 to November 1999. In July
1999, she developed round erythema over her right cheek, after which she
received topical corticosteroid therapy for 2 months. She was referred
to our hospital in October 1999 however, because the eruption did not
regress.
On initial examination, the erythema was irregular in shape and had
indistinct margins (Fig. 1).
A skin biopsy specimen taken from the right malar site revealed atrophy
of the epidermis, a slight liquefaction of the basal cell layer, and patchy
lymphocytic infiltration in the perivascular and perifollicular regions
(Fig. 2). Direct immunofluorescence
(IF) examination was negative.
A test for antinuclear antibody (ANA) was weakly positive (80 fold),
and rheumatoid factor was slightly elevated (7.6 IU/ml). ANA was determined
by an indirect IF technique in our hospital, and more than 40 fold has
been estimated as positive. Complement component levels were within normal
limits. There were no abnormal laboratory test results, including anti-DNA
antibodies, anti-SS-A/Ro antibodies and anti-SS-B/La antibodies.
After discontinuation of the UFT, the erythema regressed within 2 months.
The ANA titer of our present case changed to be negative (x 20) in August
2000.
Review of literature
Fluorouracil agents include tegafur, fluorouracil and UFT. Table
I shows the clinical classification of skin eruptions induced
by fluorouracil agents based on the statistical report of Fukuda [1] and
the present case. The keratotic, vesicular pigmented type accounted for
45% of cases and DLE-like eruptions for about 10%.
Table II shows the features
of skin eruptions induced by the 3 different fluorouracil agents which
are commonly used in Japan. Among them, tegafur induced skin eruptions
most frequently. The mean age of onset and the major type of skin eruptions
were similar for each drug. The ratio of DLE-like eruptions differed for
each drug. UFT showed the highest frequency (18%).
Table III shows the
statistics of 17 cases with DLE-like skin eruptions induced by fluorouracil
agents. The mean duration before eruption development was almost 8 months,
but the mean regression time of eruptions after the discontinuation of
drugs was almost 1 month.
Table IV shows a comparison
of 17 cases of fluorouracil induced DLE-like eruptions, including the
31 cases of DLE which we experienced. We examined gender differences,
age, the most frequent sites of eruption, the positive ratio of ANA and
the results of the lupus band test (LBT), clinical course and photosensitivity.
Female predominance and early onset are characteristic of DLE. Sun exposure
sites are commonly affected in both groups. The positive ANA ratio was
relatively higher in drug induced DLE-like eruption than in DLE. Despite
the high ratio of ANA among cases of drug induced DLE-like eruption, all
of the ANA disappeared within 1 year after discontinuation. The positive
LBT ratio was much higher in DLE than in drug induced DLE-like eruption.
Fluorouracil induced DLE-like eruptions however, regressed within 2 months
after the discontinuation of drugs, whereas idiopathic DLE tends to persist
for a long time.
Discussion
Lupus-like disease can be precipitated by cardiovascular, antimicrobial,
anticonvulsant, or antihypertensive agents [5-8]. Recently, lupus-like
disease has also been induced by minocyline, nitrofurantoin and so on
[9]. Common features of drug-induced LE are as follows: rare cutaneous
manifestations, a high incidence of antihistone antibodies, and improvement
after cessation of offending agents [7]. Dubois [10] estimated that 18%
and 26% of patients with procainamide- and hydralazine-induced LE, respectively,
had skin lesions, in contrast to 71.5% of patients with SLE. Alarcon-Segovia
et al. [11] and Blomgren et al. [12] estimated that 2% and
5% of patients with hydralazine- and procainamide-induced LE, respectively,
had skin changes.
UFT has been used for a long time, especially in the treatment of gastrointestinal
adenocarcinoma in Japan. The number of patients who received fluorouracil
agents is estimated as 79,000-81,000 a year in Japan, which is based on
the reports of Japanese major pharmaceutical companies (personal communications).
Ohnuki et al. [13] reported that the incidence of skin eruptions
induced by fluorouracil agents was almost 4% among 227 patients who received
such agents. Interview form on UFT reports that 1.77% of 29,586 patients
had skin eruptions [14]. DLE-like eruptions are almost 10% of all types
induced by fluorouracil agents (Table
I), which was collected from case reports in medical journals.
In addition to the skin eruptions described in Table
I, a few rare types such as palmoplantar erythrodysesthetic keratoderma
[15] and scleroderma-like reaction [16] have also been recently reported.
The most characteristic finding is that all patients with UFT-induced
LE have skin lesions resembling DLE-like eruptions.
Pavlidakey et al. [7] described a positive
ANA rate is more than 95% of patients with both drug-induced LE and idiopathic
LE. The present study however showed a relatively lower incidence (66%)
of positive ANA rate in patients with fluorouracil agent induced DLE-like
eruption. The difference may be attributed to differences in the drugs
themselves. Berglund et al. [17] showed that positive ANA titers
were found in 19% to 26% of patients receiving treatment with chlorpromazine,
irrespective of other clinical or laboratory findings. In contrast, ANA
appeared in < 0.005% of patients receiving UFT [14]. It is likely that
chlorpromazine predisposes patients to high positive ANA rate while receiving
such agents. Furthermore, drug-induced LE is characterized by a high incidence
of antihistone antibodies but a low incidence of anti-native DNA antibodies
[7]. Information regarding antihistone antibody levels in fluorouracil
agent-induced LE is very limited at present.
Although little information on photosensitivity has been reported among
cases of fluorouracil agent-induced DLE-like eruption, fluorouracil induced-photosensitivity
was first investigated by Horio and his associates [18, 19]. They reported
that the action spectrum was primarily in the UVA range and the related
reactions were photoallergic in nature. All 17 cases summarized in Table
III had skin lesions mainly on photoexposed areas. Basal cells
are the target cells most affected by fluorouracil agents, because they
are stem cells and are multi potential. Therefore, basal cells damaged
by fluorouracil agents seem to be highly susceptible to ultraviolet light
(UVL) irradiation, which induces liquefaction changes and patchy lymphocytic
infiltrations. The presence of ANA titer in these cases might be the result
of tissue degeneration by UVL, as a result of fluorouracil agents.
We believe that fluorouracil agent-induced DLE-like eruption is an excellent
model for better understanding the pathomechanisms of development of discoid
lesions in LE, and further study may provide new insights into autoimmune
interface dermatitis.
CONCLUSION
Acknowledgements
This work was supported in part by grants from the Japanese Ministry
of Science, Culture, Education and Sports.
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