Towards a Shared Language: Defining endocrine-immune-related adverse events

On behalf of the Endocrine Society’s Oncoendocrinology Special Interest Group, Ling Zhu, MBBChir, discusses her recent paper that addressed “the gap in standardized nomenclature, clinical, laboratory and radiological evaluations, and management principles of endocrine- immune-related adverse events (E-irAEs).” She also talks to corresponding author, Afreen Shariff, MD, about the need for nomenclature, the nature of the group’s collaboration, and the challenges along the way.

Immune checkpoint inhibitors (ICIs) have transformed the cancer treatment landscape but also introduced new complexities in the recognition and management of immune-related adverse events (irAEs), particularly those involving the endocrine system.

While several guidelines have provided valuable direction for clinicians, differences in terminology and diagnostic criteria across studies and clinical settings have led to variability in how endocrine irAEs are described and classified. This, in turn, poses challenges for data comparison and harmonization of care.

To address these gaps, we brought together an international panel of 25 experts across endocrinology, oncology, dermatology, and immunology. Using a two-round modified Delphi process guided by the RAND/UCLA Appropriateness Method, we achieved consensus on disease definitions, diagnostic workup, and severity grading for six major endocrine irAEs: ir-thyroiditis (thyrotoxic and hypothyroid phases), ir-Graves’ disease, ir-hypophysitis, ir-adrenalitis, and ir-type 1 diabetes mellitus. The results of this work were published as “Consensus-based disease definitions for endocrine immune-related adverse events of immune checkpoint inhibitors” in the October issue of the Journal for ImmunoTherapy of Cancer.

The framework establishes clear definite, probable, and possible diagnostic tiers, along with structured evaluation and severity grading tables aligned with CTCAE v5.0. Beyond providing diagnostic precision, the effort represents a shared commitment among oncologists and endocrinologists to create a common language for identifying and managing endocrine irAEs, improving both clinical communication and research consistency.

To get more details about the paper and the processes of the working group, I talked to corresponding author and principal investigator of the study, Afreen Shariff, MD, associate professor of medicine and member of the Duke Cancer Institute at Duke University School of Medicine in Durham, N.C.

What prompted the need for the standardization of disease definitions for endocrine irAEs?

Afreen Shariff: When immune checkpoint inhibitors (ICIs) became a mainstream treatment for many cancer types, we started seeing the emergence of endocrine toxicities affecting various endocrine organs. There was great variation in how patients were diagnosed and monitored. It was like we were speaking different languages while trying to communicate the same thing. This created a lot of confusion on nomenclature and criteria.

“The goal is to complement, not replace, existing guidelines by adding diagnostic clarity that supports consistent data reporting, clinical trials, and registry work. Ultimately, standardization leads to better recognition of endocrine irAEs, timely and appropriate treatment, and continuity of care.” — Afreen Shariff, MD, associate professor of medicine; member, Duke Cancer Institute at Duke University School of Medicine in Durham, N.C.

For instance, ICI-induced thyrotoxicosis (or hyperthyroidism as reported in some studies) and ICI-induced hypothyroidism are now known to be different presentations and stages of thyroiditis. Such inconsistency created problems in reporting, research comparison, and most importantly, patient safety. As endocrine irAEs often present subtly, lab interpretation and timing matter a lot. So, we wanted to develop a “common language,” a structured framework and agreement on terms and conditions that clinicians and researchers across disciplines could use to communicate, recognize, diagnose, and grade these events in a consistent way.

How did the collaboration come together?

Shariff: It grew organically initially by a few of us with a special interest in oncoendocrinology (many of whom are members of the Oncoendocrinology SIG), and later through the irAE Program with Project Data Sphere, which had already produced consensus-based definitions for neurologic and dermatologic irAEs. We realized endocrine events were the next major gap. A core group of endocrinologists from the U.S., Australia, and Singapore drafted the survey and definitions. Then we convened an international multidisciplinary panel of 25 experts in endocrinology, oncology, dermatology, immunology, and related specialties to participate in a two-round modified Delphi process. The RAND/UCLA Appropriateness Method gave us a rigorous yet flexible way to achieve consensus across disciplines.

What were some of the most interesting challenges along the way?

Shariff: Balancing precision with usability. We wanted the definitions to be detailed enough for researchers but still practical for clinicians in busy oncology clinics. For instance, defining what constitutes probable versus definite ir-hypophysitis or ir-adrenalitis meant reconciling endocrinology’s traditional diagnostic standards with real-world oncology practice. It helped that our panelists were experienced in both research and patient care.

How do you see these definitions adding value to existing guidelines?

Shariff: We aimed to provide granular guidance in the diagnostic process for clinicians by defining clinical, laboratory, and imaging criteria for diagnosis. We outlined definite, probable, and possible diagnostic tiers; structured evaluation tables for thyroid, pituitary, adrenal, and pancreatic irAEs; and severity grading linked to the CTCAE framework. The goal is to complement, not replace, existing guidelines by adding diagnostic clarity that supports consistent data reporting, clinical trials, and registry work. Ultimately, standardization leads to better recognition of endocrine irAEs, timely and appropriate treatment, and continuity of care.

Zhu is a senior consultant endocrinologist at Singapore General Hospital, Singapore. She graduated from the University of Cambridge in 2009 and obtained her MRCP (UK) in 2012. She completed her specialist training in endocrinology in 2017.  

Citation:

Zhu L, Cheung YM, Chiang C, Gallagher EJ, Hamnvik OR, Mammen J, et al. Consensus-based disease definitions for endocrine immune-related adverse events of immune checkpoint inhibitors. Journal for ImmunoTherapy of Cancer. 2025;13:e011865. https://doi.org/10.1136/jitc-2025-011865