Types of Dermatologic Immune-Related Adverse Events and New Treatment Approaches

Dermatologic immune-related adverse events (irAEs) are one of many side effects of immunotherapy that can significantly affect patients’ quality of life and treatment success. New research is shedding light on the diversity of skin irAEs and how to effectively manage them. 

Immunotherapy A type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. A therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. Some immunotherapies only target certain cells of the immune system. Others affect the immune system in a general way. Types of immunotherapy include cytokines, vaccines, bacillus Calmette-Guerin (BCG) and some monoclonal antibodies. Side effects A problem that occurs when treatment affects healthy tissues or organs. Some side effects of cancer treatment are nausea, vomiting, fatigue, pain, decreased blood cell counts, hair loss and mouth sores.
Drs. Grivas and Bhatia

The latest techniques use biomarkers and histology to select targeted treatment agents. “We learned this strategy from medical oncologists who use immunotherapy to target certain types of cancer cells,” says Mario E. Lacouture, MD, director of the Oncodermatology Program at Memorial Sloan Kettering Cancer Center.

Dr. Lacouture presented the latest research on skin irAEs for a Fred Hutchinson Cancer Center panel series. Fred Hutch physicians Shailender Bhatia, MD, and Petros Grivas, MD, PhD, co-hosted the event held in late September. 

Fred Hutch — recently created by the merger of Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center — provides a range of educational programs to advance oncology care standards throughout the Seattle region and beyond.

“We know that patients who experience dermatologic irAEs have longer survival,” says Dr. Bhatia. “But identifying and managing those toxicities can be a challenge. Having the most up-to-date information is essential and can help prevent interruption or discontinuation of therapy due to toxicities.” 

Skin irAEs Vary in Phenotype, Histology and Immunology

Dermatologic toxicities are among the most common irAEs and are often first to appear, sometimes within a few weeks of therapy. Understanding the different types of skin irAEs and their biology can help doctors select the best dermatologic agents to treat them. 

Phenotypes of Skin irAEs Resemble Nonimmune-Related Skin Diseases

Many clinical trials describe skin irAEs as a “rash,” but the picture is far more complex. Skin irAEs have several phenotypes that look like typical dermatologic conditions, including: 

  • Bullous pemphigoid
  • Eczema
  • Lichenoid rash 
  • Maculopapular rash 
  • Pruritis itching with no visible rash
  • Psoriasiform rash
  • Urticaria

New Collaboration Takes a Deeper Look at Skin irAEs  

Dr. Lacouture and his colleagues at Memorial Sloan Kettering are currently collaborating with researchers at National Jewish Health in Colorado on a study to examine the pathways that mediate skin irAEs. “Our goal is to describe the skin irAE phenotypes more clearly and correlate them with biomarkers in the skin and blood,” says Dr. Lacouture.

The study, which began in 2020, has yielded some notable highlights:

  • The appearance of skin toxicities often show a consistent pattern in timing. Maculopapular rashes typically appear within the first few weeks of starting treatment. Other dermatologic irAEs, such as bullous pemphigoid, lichenoid rash, and pruritis, often occur later. 
  • Based on an analysis of more than 90 blood markers, including cell counts and cytokines, skin IRAE phenotypes show distinct patterns.
  • The extent of body surface area affected, assessed using 3-D total body photography, varies by phenotype. Maculopapular rashes typically cover a larger area of the body compared with lichenoid rashes, which are more localized. Total body photography technology is evolving for grading skin irAEs and potentially determining phenotypes. 
  • Histologic analyses show different types of immune cell infiltrates in the skin. For example, eosinophils are nearly absent in urticaria but are more common in pruritis and bullous pemphigoid.

Immunology and Histology of Skin irAEs

Research by Dr. Lacouture and others have pinpointed biomarkers in blood and skin that can serve as targets for therapy. The main blood biomarkers associated with irAEs include circulating eosinophils, interleukin (IL)-6, immunoglobulin E (IgE) and tumor necrosis factor (TNF)-a. Histologically, eosinophils, neutrophils and immunoglobulins are the most common infiltrates found in the skin. 

The specific histological and immunological characteristics of several skin irAE phenotypes include:

Immunotherapy A type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. A therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. Some immunotherapies only target certain cells of the immune system. Others affect the immune system in a general way. Types of immunotherapy include cytokines, vaccines, bacillus Calmette-Guerin (BCG) and some monoclonal antibodies.
Phenotype Biomarker Histology
Psoriasis TNF-a, IL-6 Neutrophils
Blisters Desmoglein (DSG) 1 and 3, Bullous Pemphigoid (BP) 180 and 230 IgA, IgG, IgM
Eczema IL-4 Eosinophils
Pruritis IgE Eosinophils

Management of Dermatologic irAEs

Current guidelines recommend systemic corticosteroids as the first-line treatment for irAEs. But new targeted treatment strategies, based on biomarkers and histology, may offer better relief for patients. 

Corticosteroid treatment: Pros and cons

Current guidelines recommend systemic corticosteroids as first-line treatment for irAEs. In general, corticosteroids are very effective, though side effects are common. Long-term use of corticosteroids can cause: 

  • Dyspepsia
  • Mood and sleep problems
  • Myopathy 
  • Secondary infections 

Corticosteroids have other limitations. Patients can develop corticosteroid resistance or have contraindications to corticosteroid therapy. And not all dermatological conditions respond well. 

For example, idiopathic psoriasis, eczema and pruritis usually return after corticosteroid treatment. For these conditions, dermatologists typically only use corticosteroids as a bridge to a biologic drug or may skip them altogether. 

Biologics for Skin irAEs

As common treatments for many types of skin diseases, biologics provide excellent options for dermatologic irAEs. Based on biomarker and histological information, current indications for therapies include:

  • Dupilumab (IL-4 inhibitor) for eczema
  • Omalizumab (IgE inhibitor) for urticaria, pruritis
  • Rituximab (CD-20 inhibitor) for bullous pemphigoid
  • Tocilizumab (IL-6 inhibitor) or infliximab (TNF- inhibitor) for psoriasis, lichenoid rash and maculopapular rash 

Benralizumab — an approved agent for eosinophilic asthma — is another promising biologic agent. Dr. Lacouture is currently investigating benralizumab for patients who have skin irAEs and high blood levels of eosinophils (ClinicalTrials.gov Identifier: NCT04552288). 

Guidance for medical oncologists 

For grade 2 or 3 skin irAEs, Dr. Lacouture recommends the following approach:

  1. Order blood work: Prior to any oral steroids, obtain a CBC with differential (for eosinophil levels) and biomarker analyses for IL-6, IgE and TNF-. 
  2. Provide itch relief: Prescribe the strongest topical steroid available, such as triamcinolone 0.1% cream (1 pound) or clobetasol .05% in a spray, liquid or foam. Oral options for itch relief include pregabalin or a short course of oral steroids (0.5 mg/kg).
  3. Refer to a dermatologist: A 2022 study found that patients with skin irAEs who were referred to a dermatologist were 10 times more likely to retry immunotherapy compared to those not evaluated by a dermatologist. Progression-free survival and overall survival also increased if they saw a dermatologist. 

Can you treat patients prophylactically? 

Dr. Lacouture doesn’t recommend treating patients prophylactically at this time. Research studies have shown that adding a biologic such as tocilizumab or omalizumab to immunotherapy agents improves outcomes. But skin irAEs are unpredictable, he says. Currently, there is not enough data to justify treating patients before they develop skin toxicities. 

Provider education at Fred Hutch

Dr. Lacouture’s presentation was the sixth in a series of panel discussions to help providers better understand irAEs. View Dr. Lacouture’s entire presentation

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Corticosteroid Any steroid hormone made in the outer part of the adrenal gland. They are also made in the laboratory. They have many different effects in the body and are used to treat many different conditions. Any steroid hormone made in the adrenal cortex (the outer part of the adrenal gland). They are also made in the laboratory. Corticosteroids have many different effects in the body and are used to treat many different conditions. They may be used as hormone replacement, to suppress the immune system and to treat some side effects of cancer and its treatment. Corticosteroids are also used to treat certain lymphomas and lymphoid leukemias. Corticosteroid Any steroid hormone made in the outer part of the adrenal gland. They are also made in the laboratory. They have many different effects in the body and are used to treat many different conditions. Any steroid hormone made in the adrenal cortex (the outer part of the adrenal gland). They are also made in the laboratory. Corticosteroids have many different effects in the body and are used to treat many different conditions. They may be used as hormone replacement, to suppress the immune system and to treat some side effects of cancer and its treatment. Corticosteroids are also used to treat certain lymphomas and lymphoid leukemias. Grade In cancer, a grade is a description of a tumor based on how abnormal the cancer cells and tissue look under a microscope and how quickly the cancer cells are likely to grow and spread. In cancer, a grade is a description of a tumor based on how abnormal the cancer cells and tissue look under a microscope and how quickly the cancer cells are likely to grow and spread. Low-grade cancer cells look more like normal cells and tend to grow and spread more slowly than high-grade cancer cells. Grading systems are different for each type of cancer. They are used to help plan treatment and determine prognosis. Also called histologic grade and tumor grade. Immunotherapy A type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. A therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection and other diseases. Some immunotherapies only target certain cells of the immune system. Others affect the immune system in a general way. Types of immunotherapy include cytokines, vaccines, bacillus Calmette-Guerin (BCG) and some monoclonal antibodies. Progression In medicine, the course of a disease, such as cancer, as it becomes worse or spreads in the body. Side effects A problem that occurs when treatment affects healthy tissues or organs. Some side effects of cancer treatment are nausea, vomiting, fatigue, pain, decreased blood cell counts, hair loss and mouth sores. Steroid A type of drug used to relieve swelling and inflammation. Some steroid drugs may also have antitumor effects. Steroid A type of drug used to relieve swelling and inflammation. Some steroid drugs may also have antitumor effects.