Drug eruption due to Bufferin® showing erythema exsudativum multiforme with a photo-recall-like phenomenon

ARTICLE

Among the various types of adverse drug reactions, photo-recall and photo-recall-like phenomena are very rare. The former manifest as recurrent radiation or sunlight dermatitis, "recalled" by a chemotherapeutic agent on the areas previously affected by radiation dermatitis or sunburn. The latter is erythema exsudativum multiforme (EEM). EEM-like dermatitis is recalled by other kinds of drugs in the skin previously affected by severe sunburn [1-5]. We herein describe a patient who showed episodic attacks of EEM with a photo-recall-like phenomenon due to Bufferin^®, a combination of aspirin and dialuminate.

Case report

A 21 year-old-woman developed several erythematous eruptions, 2 to 3 cm in diameter, on the abdominal area, hips and back after taking two tablets of Bufferin^® (aspirin 330 mg, dialuminate 150 mg/tablet), because of dysmenorrhea. She felt a simultaneous burning sensation on the chest skin, where she had experienced severe sunburn eight months earlier. The patient had experienced such episodes twice before her consultation with us, which had virtually disappeared on immediate discontinuation of the drug.

Physical examination disclosed purpuric macules involving her upper chest, the dorsal aspect of both thighs and the back, almost coinciding with the areas where she had been severely sunburned while swimming, eight months earlier (Fig. 1A). The target-like eruptions with a central exudating area were scattered on the unexposed area of the back and abdomen (Fig. 1B). In addition to these skin eruptions, edematous, vesicular or erosive lesions were noted in the vulvar and oral mucosa (Fig. 1C).

The histology of a specimen biopsied from a target-like lesion on the unexposed back area showed eosinophilic necrosis of the epidermis and mild perivascular infiltration of mononuclear cells in the edematous dermis (Fig. 2A). On the other hand, the histology of the purpuric eruptions in the previously sunburned skin area showed an intact epidermis, a moderate increase in the concentration of melanocytes and a dense extravasation of red blood cells into the edematous dermis (Fig. 2B).

The patient was diagnosed as having erythema exsudativum multiforme (EEM) with a photo-recall-like phenomenon due to an adverse drug reaction: systemic administration of betamethasone (1.5 mg/day initially and tapered) was given. The acute inflammation immediately improved and only a purpuric pigmentation remained. After the steroid agent was tapered, a quarter of a tablet of Bufferin^® (aspirin 82.5 mg, dialuminate 37.5 mg), suspected as the most likely causal agent in this case, was administered after obtaining the informed consent of the patient. After about an hour, the patient felt a slight, irritating sensation over the whole body, and a fresh erythematous color returned to the previously sunburned area. The patient has not taken Bufferin^® since, and no recurrence of the eruption has been reported.

Discussion

The usual types of photo-related drug eruptions are induced by exposure to relatively low doses of sunlight after intake of drugs. On the other hand, a photo-recall phenomenon is a sunburn-damaged like dermatitis, induced by drug intake, presenting at those skin regions previously damaged by radiation or sunburn. This rare phenomenon was first described by D'Angio [1], who reported this in patients under treatment with actinomycin D many months after initial radiation therapy for malignancies, he assigned the name of "recalled radiation dermatitis". Vogler et al. [2] also described a patient showing an enhanced erythema confined to the sun-exposed areas after treatment with methotrexate. Furthermore, based on the results of scheduled administration of methotrexate and ultraviolet light irradiation to patients with psoriasis, Möler [3] demonstrated a biphasic inflammatory reaction to the radiation, modulated by the drug.

The initial report of photo-recall phenomena occurring with drugs other than chemotherapeutic agents was in 1984 by Shelley et al. [4], who presented two such cases. The first patient was given trimetprim-sulfamethoxasole and the second patient, codeine. In 1990, Flax [5] also reported a similar case with a different reaction pattern from that of Shelley et al. in a patient who used cefazolin and gentamycin sulfate one month after sustaining severe sunburn. He described this case as a photo-recall-like reaction.

The purpuric eruption after intake of Buffern^® generated in the previously sun-damaged areas of the back and chest seen in our case was thought to be a photo-recall-like phenomenon. An interesting finding in our case was that target-like eruptions of EEM were also noted in unexposed areas. The histology of these two types of eruption was different; mild infiltration and erythrocytic extravasation with an intact epidermis in the former, and dense infiltration of mononuclear cells with a necrotic epidermis in the latter. In spite of the histological differences of these eruptions, we believe that both of types of eruptions are consistent with those of EEM because the histology of EEM can differ between individual eruptions and the different stages [6, 7].

The details of the pathomechanism of the photo-recall phenomenon are unknown, but it is interesting that the causative drugs of the cases of photo-recall phenomenon reported are almost always chemotherapeutic agents reacting with nuclear substances in the cell. Unrecognized, persisting changes in the nucleus, due to the preceding radiation or sunlight exposure may interact with the subsequent administration of nucleotropic drugs for chemotherapy.

In our case, the eruption observed on the skin area previously damaged by sun-exposure was purpuric erythema. In our case, the allergic reaction of Bufferin^® may have induced the inflammation in the sunlight-effected vasculature.

Cutaneous reactions to analgesic-antipyretics and nonsteroidal anti-inflammatory drugs were reported in 1993 [8]. These drugs are sometimes referred to as aspirin-like drugs. In particular, feprazone has been responsible for inducing erythema multiforme/Stevens Johnson syndrome with an exceedingly high frequency. The mechanism is unclear, but immunologically, with regard to erythema multiforme and Stevens Johnson syndrome, the toxic epidermal necrolysis and bullous reactions are similar to those involved in graft-versus-host disease where delayed T cell-mediated immune reactions are mediated by drug specific CD8⁺ T cells [9].

REFERENCES

1. D'Angio GJ, Farber S, Charlotte L. Potentiation of X-ray effects by actinomycin D. Radiology 1959; 73: 175-7.

2. Vogler WR, Huguley CM Jr, Kerr W. Toxicity and antitumor effect of divided doses of methotrexate. Arch Intern Med 1965; 115: 285-93.

3. Möler H. Reactivation of acute inflammation by methotrexate. J Invest Dermatol 1969; 52: 437-41.

4. Shelley WB, Shelly ED, Cambell AC, Weigensberg IJ. Drug eruptions presenting at sites of prior radiation damage (sunlight and electron-beam). J Am Acad Dermatol 1984; 11: 53-7.

5. Flax SH, Uhle P. Photo-recall-like phenomenon following the use of cefazoline and gentamicin sulfate. Cutis 1990; 46: 59-61.

6. David Elder, Elenitsas R, Jawolsky C, Johnson B Jr. Erythema multiforme. Lever's histopathology of the skin, 8th edition, Lippincott-Raven 1996; 945-7.

7. Imamura S, Horio T, Yanase K, Taniguchi S, Miyachi Y, Takao T, Yoshioka A, Fujita M. Erythema multiforme: pathomechanism of papular erythema and target lesion. J Dermatol 1992; 19: 524-33.

8. Gruppo Italiano Studi eoidemiologici in dermatologia. Cutaneous reactions to analgesic-antipyretics and nonsteroidal anti-inflammatory drugs. Dermatology 1993; 186: 164-9.

9. Barbaud A, Bene M-C, Faure G. Immunological physiopathology of cutaneous adverse drug reactions. Eur J Dermatol 1997; 7: 319-23.