Increased TNF-α in SJS/TEN induced by PD-1 inhibitors supports the combination therapy of etanercept and systemic corticosteroids.

[BACKGROUND] Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis (SJS/TEN) induced by programmed cell death protein 1 (PD-1) inhibitors is a life-threatening condition. Although the exact pathogenesis remains unknown, its treatment mainly relies on high-dose systemic corticosteroids. Given the vital role of tumor necrosis factor-alpha (TNF-α) in classic SJS/TEN, this study sought to investigate the expression of TNF-α and evaluate the effectiveness and safety of combination therapy of etanercept and systemic corticosteroids in PD-1 inhibitor-induced SJS/TEN.

[METHODS] PD-1 inhibitor-induced SJS/TEN patients (n = 5) meeting diagnostic criteria, including skin biopsy-confirmed full-thickness epidermal necrosis with PD-1 as the sole culprit drug by ALDEN scoring, were enrolled in the study. Single-cell RNA sequencing (scRNA-seq) was conducted on lesional skin from one index patient (blister, erythema, and normal sites). Immunofluorescence staining for TNF-α was performed on samples from all five patients. Finally, a combination therapy of etanercept and systemic corticosteroids was administered to the patients, and the re-epithelization time, corticosteroid treatment duration, and prednisone cumulative dose were analyzed.

[RESULTS] scRNA-seq revealed significantly increased TNF-α expression in lesional skin compared with normal skin (p < 0.05), primarily from macrophages, which represented the predominant cell population in the lesion. Immunofluorescence confirmed TNF-α elevation in all five patients (p < 0.05). Besides, combination therapy resulted in rapid re-epithelialization (5.75 ± 1.48 days), a shorter steroid duration (17.75 ± 2.86 days), and reduced cumulative prednisone use (9.83 ± 3.71 mg/kg). No treatment-related severe adverse events occurred. One patient subsequently received a PD-1 inhibitor after recovery and tolerated the re-treatment without complication.

[CONCLUSIONS] Our findings demonstrated upregulation of TNF-α expression in PD-1 inhibitor-induced SJS/TEN, mainly derived from macrophages. The combination of etanercept and systemic corticosteroids exhibits huge potential for treating this patient population.