Recurrence of nivolumab-induced Stevens-Johnson syndrome due to tegafur/gimeracil/oteracil (TS-1®) after nivolumab discontinuation

Abstract

Nivolumab is an anti-programmed cell death (PD)-1 antibody used to treat various types of cancers [1]. It has been associated with dermatological immune-related adverse events (irAEs) including Stevens-Johnson syndrome (SJS) [1-3]. Among the few follow-up studies of nivolumabinduced SJS after nivolumab discontinuation, recurrence of nivolumab-induced SJS due to other drugs has not been reported. The anti-tumour agent, tegafur/gimeracil/oteracil (TS-1®), has been reported to induce SJS and toxic epidermal necrolysis [4, 5], yet little is known about TS1-induced SJS secondary to nivolumab. We present a case of nivolumab-induced SJS, which was followed by TS-1induced SJS five months after nivolumab discontinuation. A 70-year-old woman was complaining of dry cough and weight loss. Computed tomography revealed a tumour in the right lung apex. A biopsy specimen of this tumour confirmed lung adenocarcinoma. Because four cycles of chemotherapy with carboplatin and pemetrexed had little effect, treatment with nivolumab (240 mg/cycle) was started. Due to oral erosions after three cycles of nivolumab treatment, nivolumab was discontinued, but the oral erosions worsened and blisters appeared on the limbs (figure 1A, B). There was no evidence of viral infection and a peripheral blood test excluded an autoimmune bullous disease. A skin biopsy specimen from a blister of the foot revealed a subepidermal blister with necrotic keratinocytes, typical of SJS (figure 1C, D). The diagnosis of SJS due to nivolumab was made, and the patient was given systemic prednisolone (0.75 mg/kg/d), which attenuated the lesions. Five months after discontinuing nivolumab, we started treatment with TS-1 (40 mg/day) due to progression of lung cancer. One month later, oral erosion and blisters re-appeared (figure 1E, F), associated with high fever. A biopsy specimen from the blister of the foot (from the same site as the previous event) revealed findings similar to that of the previous biopsy (figure 1G, H). The patient was diagnosed with recurrent SJS and was treated with prednisolone (1 mg/kg/d). The lymphocyte transformation test was positive for TS-1 (stimulation index: 1833%; cut-off value: 180%). We present an unusual case of SJS following nivolumab treatment, which recurred probably due to TS-1. We highlight two clinically important findings. Firstly, in the present patient, SJS developed three months after nivolumab initiation. Previous studies have reported late-onset SJS during nivolumab treatment [6]. Also, the presence of nivolumab in patients one year after treatment discontinuation has been reported [7], suggesting that the risk of nivolumab-induced SJS may persist long after treatment discontinuation. Our case provides another example of such unusual clinical characteristics in nivolumab-induced SJS. Secondly, SJS may have recurred because of TS-1. It has been reported that SJS was induced by a drug following nivolumab treatment [8]. Similarly, in the present case, TS-1-induced skin toxicity concomitant with residual nivolumab may have led to SJS, though the precise mechanism is unclear. To our Nivolumab-induced