On physical examination erythema vesicle

On physical examination, erythema, vesicle formation, and erosions involving the lip, face, neck, trunk, limbs, and genitals were observed (Figure 1). His laboratory investigation results on admission were as follows: white blood cell count, 1.246 × 109/L; absolute neutrophil count, 81.7%; eosinophil count, 0%; hemoglobin level, 110 g/L; and platelet count, 232 × 109/L. Levels of antinuclear antibody, ds-DNA, and anti-BP180 antibody were within normal ranges. Nikolsky\'s sign was negative. Ophthalmological evaluation did not reveal any eye involvement. A skin biopsy specimen taken from his right thigh showed slight hyperkeratosis, many necrotic keratinocytes in the epidermis, subepidermal bulla formation, and vacuolar degeneration of the basal layer with infiltrations mainly comprising lymphocytes and eosinophils. In addition, lymphocytes and eosinophils had infiltrated the vessels of the superficial SCH 527123 (Figure 2). On the 23rd day, the eruption was improved and therefore we discontinued oral PSL. The drug-induced lymphocyte stimulation test (DLST) performed at that point was negative for TS-1 (stimulation index, 162%). On the 43rd day (20 days after discontinuing PSL), the results of closed patch tests performed using 50%, 25%, and 12.5% TS-1 on the lesional area were negative, but the DLST result was positive (stimulation index, 366%). We diagnosed the condition as TS-1-associated. SJS was diagnosed on the basis of the clinical course and laboratory results.
Discussion A total of 25 cases involving TS-1-associated drug eruptions were analyzed (Table 1). Levels of antinuclear antibody were positive in Cases 1 and 23. The results of patch tests were negative in Cases 2, 11, 13, 17, and our case. The DLST results were positive in Case 2 and our case, but the results were negative in Cases 13, 15, and 17. The results of drug challenge test were positive in Cases 1, 4, 9, 11, and 12. In patients who are suspected to develop allergic reactions, DLST involving the incorporation of [3H]thymidine ratio into the DNA of lymphocytes derived from patients, is generally employed for identifying drugs that could induce allergy. However, DLST results may show a false-negative response because of steroid, antitumor, and immunosuppressive drugs. Immediately after the onset of drug allergies, patients are also thought to be more susceptible to false-negative reactions. In view of the occurrence of false-negative results, the possibility of drug-induced allergy in patients receiving TS-1 should be carefully evaluated using a combination of other clinical examinations. Common features of drug-related lupus are as follows: rare cutaneous manifestations, a high incidence of antihistone antibodies, and reversible symptoms after withdrawal of offending agents. The frequency of discoid lupus erythematosus-like eruption is about 10% among all cases of drug eruptions induced by FU, based on the statistical report of Fukuda, but the finding is the proportion of drug-related lupus (9 of 24; 37.5%) in this study. Basal cells are the target cells most affected by FU agents, because they are stem cells and are multipotent. Therefore, basal cells damaged by FU agents seem to be highly susceptible to ultraviolet light (UVL) irradiation, which induces liquefaction changes and patchy lymphocytic infiltrations. Drug-related lupus by FU agent may be an excellent model for understanding the pathomechanisms of development of discoid lesions. Bleomycin and cisplatin are known to induce systemic sclerosis-like reactions in a genetically susceptible host. Similarly, toxic effects or immune system modulation by the FU might be responsible for systemic sclerosis-like reactions. FU exerts its antitumor effects through several mechanisms, including inhibition of RNA synthesis and function, inhibition of thymidylate synthase activity, and incorporation into DNA, leading to DNA strand breaks. When FU is orally administered, extensive first-pass metabolism of FU in the gastrointestinal wall and liver decreases FU plasma levels and causes severe intestinal mucosal damage. The potent inhibition of dihydropyrimidine dehydrogenase by gimeracil present in TS-1 may expose the patient to a high level of active FU metabolite. This may induce a high incidence of drug eruption.