A case of toxic epidermal necrolysis with hand‐foot syndrome‐like rash following tirabrutinib treatment

Tirabrutinib is a type of Bruton's tyrosine kinase (BTK) inhibitor. BTK is part of the tyrosine-protein kinase expressed in the hepatocellular carcinoma family of cytoplasmic tyrosine kinases and is primarily expressed in B cells. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug reactions with high mortality rates. This report presents a case of TEN with a hand-foot syndrome (HFS)-like rash following tirabrutinib treatment. A 43-year-old male patient was administered tirabrutinib for primary central nervous system lymphoma. He was originally taking betamethasone (1 mg/day) for cerebral edema, esomeprazole magnesium hydrate for gastric ulcer, and nifedipine for hypertension. Twenty-three days after introducing tirabrutinib, he developed erythema with erosions on the extremities and trunk and vesicles on the palms and soles. Conjunctival hyperemia and mild oral erosions were also observed. Tirabrutinib was discontinued after 26 days of treatment. The following day, the trunk erosions and blisters on the palms and soles enlarged, accompanied by a fever over 38°C, so intravenous immunoglobulin therapy (400 mg/kg/day for 5 days) and oral prednisolone (1 mg/kg/day) were initiated. However, 2 days later, erythema and erosions continued to worsen, thus pulse methylprednisolone therapy (1000 mg/day for 3 days) was added. Also, 3 more days later, marked blisters resembling HFS were observed around the nails and in weight-bearing areas (Figure 1a,b). Despite 7 days of treatment, the erosions had spread to the entire back (Figure 1c). The mucosal lesions were relatively mild (Figure 1d). Histopathology revealed massive epidermal keratinocyte necrosis. (Figure 1e). The drug-induced lymphocyte stimulation test taken 14 days after the eruption's onset was positive only for tirabrutinib (stimulation index: 2.11). TEN was diagnosed based on clinical and pathological findings. The rash gradually improved, and the prednisolone was tapered off. Complete re-epithelialization occurred in about 4 weeks, with no recurrence. So far, two cases of SJS/TEN with tirabrutinib have been reported1, 2 and, interestingly, all three cases, including our case, have in common that the mucosal lesion was mild (Miyazawa H., Kawano N., personal communication). Thus, a mild mucosal lesion may be indicative of SJS/TEN with tirabrutinib, although the mechanism is unclear and it is based on limited number of cases. In the present case, marked blisters and erythema around the nail and weight-bearing areas were observed. BTK is involved in platelet aggregation and angiogenesis, and BTK inhibitor also inhibits epidermal growth factor receptor in keratinocytes.3, 4 In areas prone to physical stimulation, such as the hands and feet, BTK inhibitors that extravasate from blood vessels may cause damage to keratinocytes. We considered the possibility that blisters and erythema around the nail and weight-bearing areas may not be solely attributable to TEN but could also be related to the unique mechanism of action of tirabrutinib. Our case developed TEN with an HFS-like rash following tirabrutinib administration. Given the severe impact of these symptoms on quality of life, patients on tirabrutinib must be closely monitored for these symptoms. We would like to thank Drs. Hajime Miyazawa and Nao Kawano for sharing helpful information about the cases they have experienced. None. None declared.