New Paper Alert! Defining Dermatologic Immune-Related Adverse Events: A Consensus-Driven Approach

Defining Dermatologic Immune-Related Adverse Events: A Consensus-Driven Approach

 Published in Journal for ImmunoTherapy of Cancer, on April 10, 2024

Authors: Steven T Chen, Yevgeniy R Semenov, Allireza Alloo, Daniel Q Bach, Allison Betof Warner, Amina Bougrine, Leeann Burton, Laura C Cappelli, Mariana Castells, Justine Cohen, Anna K Dewan, Riley Fadden, Lauren Guggina, Aparna Hegde, Victor Huang, Douglas B Johnson, Benjamin Kaffenberger, Daniela Kroshinsky, Shawn Kwatra, Bernice Kwong, Mario E Lacouture, Cecilia Larocca, Jonathan Leventhal, Alina Markova, Jon McDunn, Meghan J Mooradian, Jarushka Naidoo, Jennifer Choi, Vinod Nambudiri, Caroline A Nelson, Anisha B Patel, Julia Pimkina, Johnathan Rine, Krista M Rubin, Maxwell Sauder, Sheila Shaigany, Afreen Shariff, Ryan J Sullivan, Leyre Zubiri, Kerry L Reynolds, Nicole R LeBoeuf.

Introduction

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but their use is accompanied by an increasing incidence of immune-related adverse events (irAEs), including dermatologic irAEs (D-irAEs). D-irAEs are the most common and earliest to manifest, often with significant consequences for the patient. However, current guidelines lack clarity in terms of diagnostic criteria for D-irAEs, hampering effective management and research. This study aimed to develop consensus guidance for an approach to D-irAEs, including disease definitions and severity grading.

Methods

The authors convened a Dermatologic irAE Disease Definition Panel of 34 experts, including oncologists, dermatologists, a rheumatologist, and an allergist/immunologist from 22 institutions across the USA and internationally. Using a modified Delphi consensus process, the panel reached consensus on diagnostic criteria for 10 core D-irAE diagnoses: ICI-vitiligo, ICI-lichen planus, ICI-psoriasis, ICI-exanthem, ICI-bullous pemphigoid, ICI-Grover’s, ICI-eczematous, ICI-eruptive atypical squamous proliferation, ICI-pruritus without rash, and ICI-erosive mucocutaneous. A modified Delphi process was used with two iterations. A working group of oncodermatologists (SC, YS, NL) drafted a classification system with guidance statements and disease definitions to support the evaluation, diagnosis, and severity grading of D-irAEs. The proposed system was reviewed by a panel of dermatologists, oncologists, and irAE subspecialists who were recruited via email based on their experience and expertise. Informed consent was implied with participation in the study. The Delphi process involved two rounds of surveys, with group medians categorized into ranges (1–3 not usable, 4–6 uncertain, 7–9 usable). Consensus was reached when the median rating fell in the 7–9 range with agreement.

What We Learned: Key factors to help determine if a patient’s skin eruption is related to ICI therapy

• Timing – D-irAEs typically occur within 12 months of the last ICI infusion, with most cases arising within 12 weeks.
• Excluding other causes – A thorough patient history and baseline dermatologic exam are crucial to rule out pre-existing conditions.
• Concurrent non-dermatologic irAEs – The presence of other immune-related adverse events increases the likelihood of a D-irAE.
• Response to holding ICI and/or immunosuppressive treatment – Improvement with these interventions supports the diagnosis of a D-irAE.
• Autoantibodies – While their presence can be informative, the definitions focus on criteria suggesting a relationship to immunotherapy.
• Paraneoplastic syndromes – These must be distinguished from true irAEs, as the treatment implications differ significantly.

Key Highlights:

• The consensus definitions provide a standardized approach to D-irAE classification, including specific morphologic findings, symptoms, supportive examination findings, and levels of diagnostic certainty (definite, probable, and possible).
• The panel also reached a consensus on a standard evaluation for D-irAEs, with disease-specific exceptions detailed when necessary.
• The definitions address key unmet needs in the field, including adjudication of D-irAEs in clinical trials, classification for translational research, cohort studies, differentiating D-irAEs from alternative etiologies, grading severity, identifying subclinical or mild disease, and recognizing the spectrum of presentations.

Key Takeaway Messages:

• Importance of Multidisciplinary Approach: The involvement of oncologists, dermatologists, and irAE specialists is critical in developing and implementing these diagnostic criteria, ensuring their applicability across different clinical settings.
• Enhancement of Patient Care: By standardizing the approach to diagnosing and grading D-irAEs, clinicians can provide more targeted and effective treatments, potentially reducing the need to discontinue ICI therapy.
• Foundation for Future Research: These standardized definitions provide a framework for future studies, aiming to improve understanding and management of irAEs, ultimately enhancing outcomes for patients undergoing cancer treatment with ICIs.

Summary by Amalya Sargsyan, MD

Defining D-irAEs: consensus-based disease definitions for the diagnosis of dermatologic adverse events from immune checkpoint inhibitor therapy