Immune-related side effects, monitoring, steroids, and when treatment is paused
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The checkpoint inhibitors used for advanced melanoma — anti–PD-1 drugs such as pembrolizumab and nivolumab, the nivolumab-plus-ipilimumab combination, and nivolumab plus relatlimab — work by releasing brakes on the immune system. The same released brakes can let the immune system inflame healthy organs. Those reactions are called immune-related adverse events, or irAEs. How they work and what they achieve is covered in how immunotherapy treats advanced melanoma.
Their side effects are different from those of chemotherapy: there is usually no hair loss, and nausea and low blood counts are uncommon. Instead, almost any organ can become inflamed, most often the skin, gut, liver, and hormone glands. Many people get through treatment with only mild problems, but a minority develop serious ones, and the combination of ipilimumab and nivolumab carries a much higher risk than anti–PD-1 alone.
This article explains the reactions organ by organ, the routine monitoring used to catch them early, the general management ladder, why some effects need lifelong hormone replacement, and the red-flag symptoms that mean you should call your team or go to the emergency room the same day. For where side effects fit into the wider path after diagnosis, see what to expect after a melanoma diagnosis.
An irAE behaves more like a temporary autoimmune disease than like a drug allergy. Reactions can appear after a single dose, during treatment, or weeks to months after the last one. Because the immune system has a long memory, some irAEs need weeks of treatment to settle.
Each reaction is graded on a standard 1-to-4 scale: grade 1 is mild, grade 2 moderate, grade 3 severe, grade 4 life-threatening. That grade, together with which organ is involved, drives every decision about steroids and about holding or stopping the drug.
The regimen makes a large difference to the odds. With single-agent anti–PD-1, serious (grade 3 or 4) side effects occur in roughly 10–20% of people. With nivolumab plus relatlimab the figure is under one in five. With nivolumab plus ipilimumab it rises to a little over half, and those reactions tend to come sooner and hit more than one organ at once.
The most common irAE. Usually an itchy rash or dry skin; sometimes patches of lost pigment (vitiligo), which is harmless. Managed with moisturizers, topical steroid creams, and antihistamines. A rare blistering rash, or one covering much of the body, is treated urgently and can mean stopping the drug.
Looser or more frequent stools, cramping, or blood or mucus in the stool. This is one of the more common serious reactions with ipilimumab-containing regimens. Mild cases are managed with fluids and anti-diarrheal medicine; more than a few extra stools a day, or any blood, prompts holding the drug and starting corticosteroids. Colitis that does not respond to steroids is treated with a second drug such as infliximab or vedolizumab.
Usually silent and picked up as rising liver enzymes on routine bloodwork; sometimes yellowing of the skin or eyes, dark urine, or right-sided abdominal pain. Managed by holding the drug and, if significant, corticosteroids, with mycophenolate added if steroids alone are not enough.
The thyroid is affected most often — frequently a brief overactive phase followed by an underactive one that needs thyroid hormone tablets. Less commonly the pituitary gland (hypophysitis) or the adrenal glands are involved, causing severe fatigue, low blood pressure, headache, or low sodium; rarely, the pancreas is attacked, causing sudden type 1 diabetes. These are discussed in more detail below.
Inflammation of lung tissue causing a new or worsening cough, breathlessness, or chest tightness. It is uncommon but potentially serious, so any new breathing symptom is checked promptly with a scan. It usually means holding the drug and starting corticosteroids, and moderate-to-severe cases often mean stopping it permanently.
Usually detected as a rising creatinine level on blood tests, with few symptoms. Managed by holding the drug and, when needed, corticosteroids; kidney function usually recovers.
Inflammation of the heart muscle (myocarditis), and neurologic reactions affecting nerves or muscles (spreading numbness, weakness, drooping eyelids, trouble swallowing or breathing), are uncommon but can be dangerous. They are treated as emergencies with high-dose steroids and, in nearly all cases, permanent discontinuation of the drug.
Because several irAEs cause no symptoms until they are advanced, monitoring is built into every treatment cycle:
Keeping a simple daily note of new symptoms between visits helps the team catch a reaction while it is still mild and easy to reverse.
National guidelines from the American Society of Clinical Oncology and others tie management to the grade of the reaction:
A steroid course lasting more than a few weeks comes with its own supportive care — stomach protection, sometimes an antibiotic to prevent a specific pneumonia, and monitoring of blood sugar and bone health. Taking steroids for an irAE does not appear to cancel out immunotherapy's benefit against the melanoma.
Endocrine irAEs are the main exception to the "hold and treat with steroids" pattern. When the immune system damages a hormone gland, the missing hormone often does not come back — but it can be replaced, and immunotherapy can usually continue.
Once the hormone is replaced and the person is stable, the checkpoint inhibitor is generally resumed. An endocrinologist typically co-manages these situations.
Do not wait for your next appointment if you have any of the following. Call your care team the same day, and if it is severe, go to the emergency room:
Tell any clinician you see — including in an emergency room — that you are on immunotherapy, because the treatment for these reactions (steroids and other immune suppressants) is different from the usual approach and needs to start quickly.
Several studies have found that people who develop irAEs — vitiligo and thyroid problems in particular — are somewhat more likely to have their melanoma respond. It is a tendency across groups of patients, not a rule for any one person: plenty of people respond well with no side effects at all, and having a side effect is not a goal to aim for.
Whatever the possible link, a severe reaction is still treated as a severe reaction. When an irAE reaches grade 3 or 4, or involves the heart, lungs, or nervous system, the drug is held or stopped and the inflammation is brought under control first. Immune memory means the melanoma benefit often continues even after treatment is paused.
The side effects of melanoma immunotherapy come from an over-active immune system rather than a toxic drug, so the response is to calm that inflammation — usually with corticosteroids — and to decide, based on how severe the reaction is and which organ is involved, whether to continue, pause, or stop. Routine bloodwork and a low threshold for reporting symptoms are what keep most reactions mild and reversible.
Some effects, especially on the hormone glands, are permanent and need lifelong replacement — but even then, treatment against the melanoma can usually continue. For how these drugs work and what they achieve, see how immunotherapy treats advanced melanoma, and for the questions worth bringing to each specialist, see what to ask your care team about advanced melanoma.
Disclaimer: This article is for educational purposes only and not a substitute for professional medical advice. Always consult a qualified dermatologist or oncologist about your personal diagnosis and treatment plan.
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