ARTICLE
Auteur(s) : Kunio Izu1,2, Ryosuke
Hino1, Hideka Isoda1,2, Daiki
Nakashima1, Kenji Kabashima1, Yoshiki Tokura1
1Department of Dermatology, University of
Occupational and Environmental Health, 1-1 Iseigaoka,
Yahatanishi-ku, Iseigaoka, Kitakyushu 807-8555, Japan
2Section of Dermatology, Kyushu Kosei Nenkin Hospital,
Kitakyushu, Japan
accepté le 24 Juin 2008
Ketoprofen is a nonsteroidal anti-inflammatory reagent and it is
clinically used as a topical drug to remove pain. It is well known
to induce photocontact dermatitis as an adverse effect [1-3]. When
exposed to sunlight, the ketoprofen-applied skin exhibits
eczematous dermatitis [1], and this photocontact dermatitis is
characterized by a prolongation of photosensitivity at the applied
sites [3]. The action spectrum is ultraviolet A (UVA) light [4],
similar to other photoallergic drugs.
Photosensitive substances are divided into phototoxic and
photoallergic ones, and the photoallergic chemicals are further
subdivided into prohapten and photohapten [4]. Prohapten is
converted to ordinary hapten by UV exposure, and the altered
chemical can bind to proteins, forming a complete antigen. On the
other hand, a photohapten needs to coexist with a protein upon
exposure to UV, and the UV-photo-degradated residue of a
photohapten affords a binding site to the protein [5, 6]. It is
thought that the vast majority of photoallergic chemicals are
photohapten rather than prohapten [4-6], and ketoprofen also
belongs to photohaptens [7].
By using a mouse model of photosensitivity to ketoprofen, we
have shown that skin-applied ketoprofen can bind to epidermal
Langerhans cells upon UVA irradiation of the skin. This
photohapten-modification stimulates Langerhans cells to express
major histocompatibility complex class II and costimulatory
molecules such as CD86 with morphological changes [7]. Therefore,
ketoprofen plus UVA not only forms the photoantigen but also
induces the maturation of this antigen-presenting dendritic cell.
Langerhans cells that bear the photoantigen emigrate to the
regional lymph nodes and sensitize T cells. Upon challenge with
ketoprofen and UVA, the sensitized T cells are restimulated and
induce photodermatitis. The sensitivity is a T-cell mediated
response, in which both CD4+ and CD8+ T cells
are involved in the elicitation of full-blown photoallergy [8].
Here we report a patient with photocontact dermatitis to
ketoprofen, manifesting as erythema multiforme that occurred not
only on the ketoprofen-applied site but also on other non-applied
areas. We found that the patient had circulating lymphocytes
reactive with ketoprofen photoantigens by the lymphocyte
stimulation test, using ketoprofen-photomodified cells with a
photohaptenic moiety.
Case report
A 74-year-old Japanese man was referred to us on September 11,
2006, because of a generalized eruption and a high temperature. For
the treatment of arthralgia, the patient had been topically applied
with a ketoprofen-containing tape on the inner aspect of his left
elbow since June of 2006. On September 7, the patient was exposed
to sunlight, and next day, he developed an itchy eruption on the
left elbow, which spread to the four extremities, trunk and
buttocks.
On examination, the patient had a high temperature
(38 oC) and exhibited grouping red papules and
vesicles on the tape-applied, rectangular area of the inner left
elbow (figure 1,
top). The same type of papulovesiclular lesions were also scattered
on the right forearm, lower limbs, buttocks, and trunk. In
addition, there were bullae and erosions on his soft palate, buccal
mucosa, and lips. Peripheral blood examination revealed a normal
leukocyte count with mild neutrophilia and a high level of
C-reactive protein (4.32 mg/dL; normal, < 0.2 mg/dL).
Other blood chemistry values were within normal limits. There was
no elevation of anti-human simplex virus-1 IgG antibodies or
anti-mycoplasma antibodies in a comparison of the 2-week interval
paired sera.
We started to treat the patient with oral administration of
prednisolone, 20 mg daily, but the eruption increased in
numbers and each lesion was exacerbated to form a target or bull’s
eye appearance on September 13 (figure 1, middle). On the
left elbow, the primary papulovesicular lesions were coalesced into
a red rectangular plaque. The dose of prednisolone was increased to
30 mg daily, and on September 15, the eruption and oral
enanthema began to subside, leaving peripheral violaceous
pigmentation (figure
1, bottom). Prednisolone was tapered and stopped 2 weeks
later. He had no recurrence of the eruption.
A biopsy specimen from the right forearm exhibited a dermal
infiltrate of lymphocytes, which invaded into the epidermis with
intercellular edema and vacuolization of basal keratinocytes (figure 2, left). The
infiltrate was mainly perivascular, and extravasation of
erythrocytes was observed. An immunohistochemical study revealed
that CD4+ T cells predominated in the dermis (figure 2, middle), and
CD8+ T cells invaded into the epidermis (figure 2, right).
Lymphocyte stimulation test
We could not perform patch or photopatch tests with ketoprofen,
because the patient’s consent was not given. Instead, a lymphocyte
stimulation test was done with ketoprofen-photomodified cells,
according to the previously reported method [9]. This response
reflects the proliferative response of T cells to a photohaptenic
moiety of the chemical [10]. Peripheral blood mononuclear cells
(PBMCs) were isolated from the patient’s heparinized blood by the
standard Ficoll-Paque method. An aliquot of PBMCs was used as
responders, while another aliquot was employed as stimulators after
photomodification with ketoprofen. The ketoprofen-photomodified
cells were prepared by UVA (1 J/cm2)-irradiation of
cells suspended in phosphate-buffered saline (PBS, pH 7.4)
containing 10–6 M ketoprofen and placed in a 10 cm
plastic dish [9, 10]. After washing in PBS,
ketoprofen-photomodified cells were resuspended in complete
RPMI-1640 medium [10]. Then, the non-treated PBMCs (2 ×
105/well) as responders and the ketoprofen-photomodified
PBMCs (5 × 104/well) as stimulators were co-cultured in
triplicate for 72 hours in 96-well microtiter plates, and
3H-thymidine (1 μCi/well) was pulsed for the last
12 hours. Cells were harvested and radioactivity was measured by a
liquid scintillation counter.
As shown in figure
3A, the addition of ketoprofen-photomodified cells to the
culture significantly enhanced the proliferation of responder PBMCs
(stimulation index, 2.52). As a control subject, we also tested the
response of PBMCs to ketoprofen-photomodified syngeneic PBMCs in a
56-year-old woman with ordinary photocontact dermatitis to
ketoprofen. This control patient exhibited no response of PBMCs to
the photomodified cells, as the simulation index was 1.30 (figure 3B). In a
normal healthy subject, the stimulation index was as low as 0.76.
When ketoprofen solutions irradiated or non-irradiated with UVA
(1 J/cm2) was added at a final concentration of
10–6-10–8 M instead of
ketoprofen-photomodified cells, neither of them stimulated PBMCs
(data not shown), suggesting that ketoprofen does not serve as a
prohapten [9, 10]. Thus, the results suggested that the patient had
circulating T cells responding to photohaptenic ketoprofen.
Discussion
Based on our mouse model of ketoprofen photosensitvity,
skin-applied ketoprofen binds to Langerhans cells upon UVA exposure
to the skin. Langerhans cells bearing a photohaptenic determinant
of ketoprofen sensitize T cells, thereby inducing photodermatitis
after photoelicitation with ketoprofen. CD4+ T cells are
essential for this photosensitivity and CD8+ T cells
enhance the response [8]. According to this mechanism, ketoprofen
plus UVA should evoke an eczematous reaction. In fact, a
considerable number of patients have been reported with
photocontact eczematous dermatitis to ketoprofen [1-3]. To our best
knowledge, the development of erythema multiforme both at the
primary ketoprofen-applied site and over non-applied areas has not
been reported. In ordinary contact dermatitis to chemicals,
erythema multiforme occasionally occurs as a unique manifestation
[11, 12]. Our patient documented that not only contact dermatitis
but also photocontact dermatitis can induce erythema multiforme as
a rare form of contactant-induced eruptions.
Instead of photopatch tests, the lymphocyte stimulation test was
used for definitely diagnosing our patient. This in vitro test is
usually performed by the addition of drugs to PBMC cultures. In
photosensitivity to drugs, however, UV irradiation is a
prerequisite even for in vitro evaluation. To solve this issue, we
established the lymphocyte stimulation test to drug-photomodified
patient’s PBMCs, which contain photoantigen-bearing monocytes and B
cells as antigen-presenting cells [9]. Using this method, we could
successfully detect the peripheral T cell response to a
photohaptenic determinant in ketoprofen, as found in quinolones and
piroxicum [9]. Since this T-cell response was not observed in a
patient with ordinary photocontact dermatitis to ketoprofen or in a
healthy volunteer, the occurrence of erythema multiforme seems to
be associated with the presence of relevant photohapten-reactive T
cells.
Our immunohistological study of the skin lesion showed that
CD8+ T cells invaded into the epidermis with
CD4+ T cells infiltrating in the dermis, as seen in
ordinary erythema multiforme due to orally administered drugs [13].
It is considered that, in this patient, a relatively high number of
the circulating photoantigen-reactive T cells led to an unusual
manifestation of erythema multiforme at skin areas separate from
the photocontact site.
Acknowledgements
Financial support: none. Conflict of interest: none.
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