D2.274 - Late-onset toxic epidermal necrolysis (TEN) associated with nivolumab: attention to possible cofactors

Toxic epidermal necrolysis (TEN) is a severe, rare, and potentially fatal skin reaction, most commonly induced by drugs such as antibiotics, anticonvulsants, or nonsteroidal anti-inflammatory drugs (NSAIDs). Recently, associations with immune checkpoint inhibitors (ICIs), such as nivolumab, have been described, although exceptionally. TEN related to ICIs may within first weeks or very late, with latencies from days to over 100 weeks; cases of very late onset are rarely reported.

We present a 68-year-old female with clear cell renal carcinoma treated with nivolumab. Initially, she received biweekly doses for one year (2022–2023), developing blistering lesions on hands, feet, and one lower limb approximately one week after each dose, which resolved after topical silver treatment. 

In December 2024, nivolumab resumed monthly. After the second and third doses, lesions recurred, partially responsive to corticosteroids and silver. Last dose: June 16, 2025. On July 17, after a CT scan with iodinated contrast, lesions generalized with intense pruritus; intercurrent etoricoxib use noted. The patient had two severe hospital admissions:

- September 2025: involvement of 70% body surface area (BSA), oral and vaginal mucosa involved, Nikolsky positive, requiring burn unit admission.

- November 2025: 25–30% BSA, milder episode. 

Punch skin biopsies, histopathology study, direct immunofluorescence, skin tests, and lymphocyte activation tests (LAT) against nivolumab, iodinated contrast, and parecoxib were performed.

- Analytical tests: normal leukocytes and eosinophils, normal renal and hepatic function, slightly elevated inflammatory markers with no evidence of systemic infection.

- Biopsies: subepidermal blister with epidermal necrosis and eosinophils in the dermis, consistent with TEN. Immunofluorescence: nonspecific deposits, ruling out an autoimmune process.

- Prick test and intradermal reaction: negative for iodinated contrast media (gadovist, xenetix, iomeprol, omnipaque, ultravist). 

- LAT: negative for contrast media and parecoxib; positive for nivolumab.

Given these findings, strict avoidance of nivolumab was recommended.

TEN associated with ICIs can occur very late, highlighting the need for prolonged monitoring. Cofactors such as iodinated contrast media and NSAIDs such as etoricoxib can precipitate severe exacerbations. Allergy testing and discontinuation of the causative drug are key to preventing potentially fatal recurrences.