Severe blistering eruptions induced by immune checkpoint inhibitors: a multicentre international study of 32 cases

Abstract

Among dermatologic adverse events induced by immune checkpoint inhibitors (ICI), bullous life-threatening reactions are rare. To better define the clinical and histological features, treatment, and prognosis of ICI-related severe blistering cutaneous eruptions. This retrospective case series was conducted between 2014/05/15 and 2021/04/15 by the dermatology departments of four international registries involved in drug reactions. Inclusion criteria were age ≥18 years old, skin eruption with blisters with detachment covering ≥1% body surface area and at least one mucous membrane involved, available pictures, and ICI as suspect drug. Autoimmune bullous disorders were excluded. Each participant medical team gave his own diagnosis conclusion: epidermal necrolysis (EN), severe lichenoid dermatosis (LD), or unclassified dermatosis (UD). After a standardized review of pictures, cases were reclassified by four experts in EN or LD/UD. Skin biopsies were blindly reviewed. Thirty-two patients were included. Median time to onset was 52 days (3-420 days). Cases were originally diagnosed as EN in 21 cases and LD/ UD in 11 cases. After review by experts, 10/21 EN were reclassified as LD/UD. The following manifestations were more frequent or severe in EN: fever, purpuric macules, blisters, ocular involvement, and maximal detachment. Most patients were treated with topical with or without systemic corticosteroids. Eight patients (25%) died in the acute phase. The culprit ICI was not resumed in 92% of cases. In three patients, another ICI was given with a good tolerance. Histology did not reveal significant differences between groups. Severe blistering cutaneous drug reactions induced by ICI are often overdiagnosed as EN. Consensus for management is pending.

Pustular Lichenoid Eruptions Induced by Immune Checkpoint Inhibitors: Two Case Reports and a Review of the Literature

“…Indeed, grade 3 (according to the Common Terminology Criteria for Adverse Events) adverse events were observed in our 2 patients and immunotherapy was discontinued in the majority of the reported cases of pustular lichenoid eruptions. Ingen-Housz-Oro et al 10 described their experience of immune-related severe blistering lichenoid dermatitis. In this retrospective study, immunotherapy was discontinued in most cases.…”

High Grade Dermatologic Adverse Events Associated With Immune Checkpoint Blockade for Cancer

“…True SJS/TEN due to ICB may be overdiagnosed ( 17 ) due to the similarity with and novelty of SJS/TEN-like reactions. Because SJS/TEN-like reactions to ICB present variably along a clinical spectrum, they have been described by various terms including: high grade lichenoid dermatosis or unclassified dermatosis ( 17 ), lichenoid mucocutaneous eruptions ( 57 ), and progressive immunotherapy-related mucocutaneous eruption (PIRME) further complicating definitive diagnosis of this pattern of reactions ( 18 ).…”

“…True SJS/TEN due to ICB may be overdiagnosed ( 17 ) due to the similarity with and novelty of SJS/TEN-like reactions. Because SJS/TEN-like reactions to ICB present variably along a clinical spectrum, they have been described by various terms including: high grade lichenoid dermatosis or unclassified dermatosis ( 17 ), lichenoid mucocutaneous eruptions ( 57 ), and progressive immunotherapy-related mucocutaneous eruption (PIRME) further complicating definitive diagnosis of this pattern of reactions ( 18 ). Differentiating true SJS/TEN from DAE mimickers is integral to a patient’s cancer care, as emerging evidence suggests that although ICB challenge should not be attempted in cases of true SJS/TEN, it may be achievable after SJS/TEN-like reactions have improved ( 18 ).…”

“…Because cases of SJS/TEN in the FAERS database are voluntarily reported and unverified, they likely include SJS/TEN-like reactions, which mimic SJS/TEN but vary in severity and clinical course. While ipilimumab has not independently been associated with SJS/TEN-like reactions, emerging evidence suggests anti-PD-1/PD-L1 therapies are associated more frequently with SJS/TEN-like reactions ( Figures 1A–C ) than true SJS/TEN ( 17 , 18 ). Unlike true SJS/TEN, which presents acutely, some SJS/TEN-like reactions to anti-PD-1/PD-L1 blockade progress from mild DAEs over a few to several weeks.…”

“…Although SJS/TEN-like reactions resemble true SJS/TEN on histopathology ( Figure 1D ), with characteristic findings such as full-thickness epidermal necrolysis, subepidermal clefting, and interface dermatitis, severe clinical symptoms such as fever, ocular involvement, and maximal detachment are much rarer and seen in as few as 8% of patients ( 17 ).…”