Epidermal necrolysis in the context of immuno‐oncologic medication as well as kinase inhibitors and biologics

Abstract

Background: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe, primarily drug-induced reactions of skin and mucosa. Since they differ in the extent of skin detachment but not in etiology, they are grouped together as epidermal necrolysis (EN). Due to nationwide registration, representative data are available at the German Center for the Documentation of Severe Skin Reactions (dZh). Here, an increasing number of case notifications in the context with new immuno-oncologic drugs, kinase inhibitors and biologics have been observed.Material and methods: Of 4,150 cases notifications between January 2003 and February 2019, 102 cases with exposure to these drug groups underwent systematic analysis, validation and causality assessment.Results: Two cases of EN to vemurafenib were confirmed and one case to afatinib and pembrolizumab, respectively. In 14 EN cases other drugs -predominantly allopurinol or cotrimoxazole -were the causative agent. Fourteen cases were EN-like reactions: six bullous lichenoid drug eruptions (DE) to pembrolizumab (2), obinutuzumab, nivolumab, rituximab, infliximab/nivolumab, and eight multiforme-like DE to rituximab (2), adalimumab, ramucirumab, bevacizumab, vemurafenib, sorafenib (2). Lichenoid DE were differentiated from EN through histopathology and by the protracted course of EN, multiforme-like DE by variable skin manifestations with only sparse epidermolysis or mucosal involvement.Conclusions: A correct diagnosis is highly relevant in terms of prognosis and use of these drugs in malignoma treatment. Re-exposure is contraindicated in EN, but possible in other DE after rigorous risk-benefit evaluation.

Severe side effects of targeted therapies

“…The contribution of Ziemer and colleagues addresses the manifestation of SJS and TEN as severe mostly drug-induced reactions of the skin and mucosa under new immunologic therapies, kinase inhibitors and biologics [4]. They evaluated a German cohort of an international registry study of the German Center for the Documentation of Severe Skin Reactions.…”

“…In Germany, alone in 2018, more than 80 million defined daily doses of biologics were prescribed to patients with statutory health insurance, suffering from Crohn's disease, psoriasis, multiple sclerosis or rheumatoid arthritis including juvenile forms [5]. The majority of SJS/TEN cases (14 out of 19) in the study of Ziemer et al were attributed to other drugs, alone 10 of these 14 cases to the well-known inducers of SJS/TEN, allopurinol and co-trimoxazole [4].…”

“…The majority of SJS/TEN cases (14 out of 19) in the study of Ziemer et al. were attributed to other drugs, alone 10 of these 14 cases to the well‐known inducers of SJS/TEN, allopurinol and co‐trimoxazole [4].…”

Schwere Nebenwirkungen bei zielgerichteten Therapien

“…Bezüglich der SJS/EN Fälle wurden in der Untersuchung von Ziemer et al. bei einer Mehrzahl der Patienten (14 Fälle) andere Medikamente als Ursache gewertet, in allein 10 der 14 Fälle die bekannten SJS/TEN‐Auslöser Allopurinol und Cotrimoxazol [4].…”

“…Der Beitrag von Ziemer und Mitarbeitern widmet sich dem Auftreten von Stevens‐Johnson‐Syndrom und der toxischen epidermalen Nekrolyse als schwere überwiegend arzneimittelinduzierte Haut‐Schleimhautreaktionen unter neuen immunonkologischen Therapien, Kinaseinhibitoren und Biologika [4]. Hierzu wurde die deutsche Kohorte einer internationalen Registerstudie des Dokumentationszentrums schwerer Hautreaktionen ausgewertet.…”