A case of sintilimab‐induced SJS/TEN:Dermatologic adverse reactions associated with programmed cell death protein‐1 inhibitors

Dear Editor, A 27-year-old female presented to us with “mucocutaneous eruptions with blisters of the skin. ” Five months prior, the patient was diagnosed as undifferentiated nonkeratinizing carcinoma of the nasopharynx stage II disease(T2N1M0) in the Cancer Center of Sun Yat-sen University. Later, the patient was given albumin paclitaxel 400 mg and cisplatin 110 mg, and this chemotherapy was given every 3 weeks. The patient has accpcted the treatment for three times. Over 2 months ago, the chemotherapy was changed to immunotherapy, which was sintilimab 200 mg every 3 weeks. During this period, no drug which may cause eruptions were used, including chemotherapy and pain medication. Two weeks ago, the patient was treated with sintilimab 200 mg for the fourth time. On the same day, the oral ulcer appeared and was not treated. A week ago, round erythema and edema can be found on the face, neck, and back, with blisters at the center and redness on the edge, which progress to eye, nasal and oral mucosal hemorrhagic erosions (Figure 1). Later, the blisters ruptured, accompanied by severe pain and high fever, with a body temperature up to 39.3 C. After the routine anti-infection and antihistamine treatment, the erythema and edema did not fade, while the blisters developed with positive Nikolsky sign. After 3 days, the extremities were involved, the blisters gradually fused, and the areas of erosion gradually expanded. Relevant examinations were completed after transferred to our department: HB 103 g/L, WBC 2.08 10/L, PLT 254 10/L, Neut 1.90 10/L, Lymph 0.11 10/L, EO 0.01 10/L. Hypersensitive CRP protein was 93.45 mg/L. Skin histopathology revealed the apoptotic keratinocytes up to a full-thickness epidermal necrosis with subepidermal blister, and a sparse superficial inflammatory infiltrate can be found, which is consistent with Stevens-Johnson syndrome/toxic epidermal necrolysis. The patient was started on injection of methylprednisolone 80 mg intravenous daily and imipenem 2 g two times per day. She was also started on IV immunoglobulin (IVIG) 0.4 g/kg day for 5 days. The body temperature revealed normal after 5 days' treatment and the erosions resolved without further complications. Sintilimab is an antibody that against programmed cell death protein 1 (PD-1), which can block the interaction between PD-1 and its ligand and help T cells recover their antitumor effect. PD-1 inhibitors, known as immunologic origin and given their mechanism of triggering T-cell activation, thus induce specific adverse events. A variety of dermatologic manifestations can occur, including psoriasis, lichenoid erosions, vitiligo-like lesions, acneiform rashes, autoimmune skin diseases (e.g., dermatomyositis, bullous pemphigoid, alopecia areata), sarcoidosis and oral mucosal changes and rarely encountered reactions like SJS/TEN. Some researches suggested that abnormal regulation of T cells from disruption of PD-1/PDL-1 inhibitor causes overactive of these cells and exocytosis of certain cytokines into skin, subcutaneous tissues, and mucosa, leading to cytotoxic damage. Glucocorticoid, as the first-line therapeutic drug, can block the further development of allergic inflammation. So in this case, we give timely glucocorticoid intervention in the early stage of the disease and acquire satisfied effects. Epidermis necrosis is mainly mediated by fas–fasL pathway, and some researchers suggested immunoglobulin has the effect of blocking Fas receptors. Based on this, high dose (400 mg/kg day) immunoglobulin is often used for 3–5 days to better control the disease. Howerver, some results do not support the use of IVIGs in the treatment of SJS/TEN as its effect is not significant.