BLOG: What are the ocular side effects of immune checkpoint inhibitors?
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About a year ago, the ER called over to the eye clinic and said a patient had asked to be seen because he was having double vision.
He had noticed it for a couple of months, and it was not getting any better. He was 82 years old and had typical medical diagnoses like (controlled) hypertension and hyperlipidemia, but he also had renal carcinoma.
On my exam, I found a slight right upper lid ptosis (about 1 mm) and noncomitant strabismus that did not map to any single cranial nerve. The patient did not think his double vision varied during the day, but he could not really tell. He did not even notice the ptosis. Upon reading his chart I discovered the cancer diagnosis was relatively new, and 3 months ago his oncologists had started him on a new medication.
He was hospitalized, and we were able to examine him frequently. Most times the strabismus measured similar to the original findings, but it did vary slightly. The ptosis did not change on ice-pack test.
I walked in once while he was sleeping, and when I roused him, I looked at his eyelid — the ptosis was the same as it always was, with no improvement after rest. But one day his strabismus was dramatically different, and his ptosis was almost over his pupil.
Myasthenia gravis can be a tricky diagnosis. There are a lot of tests to help diagnosis it, but rarely do they all come out positive. Even the bloodwork is positive only half the time in ocular myasthenia gravis. You must have a high diagnostic suspicion, and you have to follow through if you cannot rule it out. Our patient went on to have a myasthenic crisis, despite the team knowing the diagnosis of myasthenia gravis. So, it can be difficult. His condition was determined to be caused by the medication — an immune checkpoint inhibitor — the oncology team started 3 months ago for his renal cancer.
Immune checkpoints are receptors on the surface of some cells in the body, stationed near the main T-cell receptor. When a T-cell binds to the cell via its receptor, it also tries to bind with the immune checkpoint receptor. It is a way for the body to make sure this cell is “self” — literally a check on the immune system. But some cancer cells adapt and find ways to mimic a normal cell’s checkpoint receptors. So, despite T-cells binding to the cancer cells, the T-cells do not initiate cell death because the cancer cell passes the checkpoint test.
These checkpoints were discovered in the 1990s and led to a Nobel Prize. It was such a vital finding, because now medication can be created to inhibit this checkpoint binding, thus increasing the rate a T-cell starts an immune reaction and hurting the cancer cell’s ability to hide. The first immune checkpoint discovered was called CTLA-4; its inhibitor, Yervoy (ipilimumab, Bristol Myers Squibb), came out in 2011 and is mostly used for melanoma. Since then, there have been many checkpoint inhibitors released for various types of cancers: Keytruda (pembrolizumab, Merck), Opdivo (nivolumab, Bristol Myers Squibb) and Libtayo (cemiplimab-rwlc, Regeneron/Sanofi) were introduced around 2014, and Tecentriq (atezolizumab, Genentech/Roche), Bavencio (avelumab, Merck KGaA/Pfizer) and Imfinzi (durvalumab, Medimmune/AstraZeneca) were introduced around 2017.
Immune checkpoint inhibitors (ICIs) have been shown to work well on certain types of cancers. But this article is about the side effects. As you might imagine, any medication that encourages T-cell activation will have a side effect of inflammation. Rash (dermatitis) and diarrhea (colitis) are the most common side effects of ICIs; cough and lung inflammation (pneumonitis) also may occur and can be serious.
Peripheral neurologic disorders, like myasthenia gravis, are not rare with ICIs. As eye doctors, we need to become acutely aware of these medications. We all scan our patients’ medication lists, looking for medications that jump out as related to the eye, and we need to add these medications to our mental list.
If your patient has a diagnosis of cancer, look to see if they are on an ICI, and, if they are, check them for inflammatory findings. The most common ocular side effects are dry eye and anterior uveitis, but as you can imagine there are a lot of inflammatory ocular conditions that could be attributed to medications. Have a low threshold to let the prescribing oncologist know about the ocular findings. It does not mean that the doctor will discontinue the medication, but he or she has a right to know about it. And for you it means that your patient should closely be followed because the inflammation could become severe.
Remember to check that medications list, and if your patient has an inflammation in any part of the eye, double check that list.
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