Immunotherapy has transformed oncology by harnessing the body’s defense systems to target and destroy malignant cells. This approach often uses specialized drugs known as immune checkpoint inhibitors, which release the natural “brakes” on T-cells, allowing them to activate and attack cancer. While highly effective, this systemic activation can lead to unintended consequences known as immune-related adverse events (irAEs). Skin reactions, or rashes, are among the most frequently observed irAEs, occurring in a large percentage of patients receiving these medications. Because of their commonality and potential severity, a uniform classification system is necessary for consistent clinical care.
Understanding Immunotherapy Rashes
The mechanism behind immunotherapy rashes involves T-cell activation mistakenly targeting healthy cells in the skin. This heightened immune surveillance leads to inflammation as T-cells infiltrate the skin layers, causing damage and the visible signs of a rash. The resulting skin inflammation is essentially an autoimmune-like reaction induced by the medication, similar to other autoimmune conditions.
Maculopapular rash (MPR) is the most common type of skin reaction. It presents as small, flat, reddish spots (macules) and slightly raised bumps (papules) that often merge into larger patches. This eruption typically begins on the trunk and limbs, often sparing the face, palms, and soles. Pruritus, or intense itching, is also frequently reported and can occur either alongside a visible rash or as an isolated symptom on otherwise normal-appearing skin.
The onset of these skin reactions can vary, but maculopapular rashes often appear relatively early in the treatment course, typically within the first few weeks to months after starting the checkpoint inhibitor. Other phenotypes, such as lichenoid eruptions (flat-topped, purplish bumps) or psoriasiform rashes (scaly, red plaques), are also observed. Recognizing these distinct appearances is the first step, but assessing the severity requires a standardized, objective measure to guide treatment decisions.
The Standardized Grading System
The medical community uses the Common Terminology Criteria for Adverse Events (CTCAE) to ensure consistency in reporting and managing these adverse events across different clinics and clinical trials. CTCAE is the universal system used to classify the severity of side effects related to cancer therapy, including skin reactions. This system uses a numerical scale from 1 to 4, with each grade corresponding to escalating levels of severity and impact on the patient’s daily life.
Grade 1 (Mild)
Grade 1 represents a mild skin reaction, defined as a maculopapular rash covering less than 10% of the total body surface area (BSA). Symptoms, such as mild itching or redness, are mild enough that they do not interfere with the patient’s routine daily activities. Intervention is generally not indicated beyond simple supportive care measures.
Grade 2 (Moderate)
A Grade 2 skin reaction is considered moderate, affecting between 10% and 30% of the total BSA. This level of reaction begins to have a tangible impact on the patient. The symptoms are severe enough to limit age-appropriate instrumental activities of daily living (ADL), such as shopping, managing finances, or driving, indicating a functional limitation due to the rash.
Grade 3 (Severe)
The classification advances to Grade 3 when the skin reaction becomes severe, often covering more than 30% of the total BSA. A Grade 3 reaction is significant enough to limit the patient’s capacity for self-care ADLs, which include basic tasks like bathing, dressing, and feeding themselves. This severity often necessitates hospitalization or a prolongation of an existing hospitalization for more intensive medical management.
Grade 4 (Life-Threatening)
Grade 4 is reserved for life-threatening consequences, which include severe, systemic reactions requiring urgent medical intervention. Although rare, these severe reactions can manifest as aggressive blistering conditions like Stevens-Johnson syndrome (SJS) or Toxic Epidermal Necrolysis (TEN), which involve extensive epidermal detachment. Any skin toxicity that is immediately life-threatening or disabling falls under this most serious classification.
Grade-Specific Management and Action Steps
Management of an immunotherapy-induced rash is tailored to the CTCAE grade, balancing toxicity control with the desire to continue cancer treatment.
Grade 1 Management
For a Grade 1 skin reaction, the primary action is supportive care, and immunotherapy is typically continued without interruption. Treatment involves applying mild-to-moderate potency topical corticosteroids to the affected areas to reduce local inflammation. Patients should also use over-the-counter emollients and oral antihistamines for symptom relief, particularly to control any associated pruritus.
Grade 2 Management
When a rash progresses to Grade 2, the approach becomes more cautious due to moderate severity and functional limitation. Initial steps involve increasing the strength of the topical corticosteroid to a moderate-to-high potency agent. The clinical team often considers temporarily withholding the immunotherapy dose until the rash improves to Grade 1 or less. If the rash is extensive or does not show improvement within a few days of intensified topical therapy, a low-to-moderate dose of oral corticosteroids, such as prednisone at 0.5 to 1 mg/kg per day, may be necessary.
Grade 3 Management
A Grade 3 skin reaction mandates aggressive management due to the severe nature of the toxicity. The immunotherapy treatment must be held until symptoms resolve to Grade 1 or less. High-dose systemic corticosteroids are initiated, typically starting with prednisone at 1 mg/kg per day, which may be increased to 2 mg/kg per day if the rash does not respond quickly. This level of reaction often requires urgent consultation with a dermatologist and may necessitate inpatient care for close monitoring and management of the high-dose immunosuppression.
Grade 4 Management
For a Grade 4 skin reaction, which signifies a life-threatening event like SJS or TEN, the protocol requires immediate medical intervention and permanent discontinuation of the checkpoint inhibitor. These patients require immediate hospitalization and aggressive immunosuppression, often with high-dose intravenous (IV) corticosteroids. In cases where the rash is refractory to initial steroid treatment, other immunosuppressive agents, such as mycophenolate mofetil or infliximab, may be considered to control the severe immune-mediated inflammation. Once immunotherapy is discontinued, it is not reintroduced.