Could tiny, microscopic cells in someone’s eyeball hold key information on the best way to treat eye inflammation? It’s a question physician-scientists like Lynn Hassman, MD, PhD, assistant professor in the University of Colorado Department of Ophthalmology, have been working on for years, and new research represents a step forward in Hassman’s ultimate goal of helping ophthalmologists across the globe better tailor the treatments they use for patients.
Hassman specializes in treating and researching ocular inflammation and immunology, particularly a condition called uveitis — a broad term for a type of eye inflammation that can lead to vision problems and permanent blindness.
“When we say uveitis, generally, we mean inflammation on the inside of the eye. This area of the eye is immunologically protected, as not many cells have access to that area, so something really has to go wrong to have severe inflammation in there,” says Hassman, a member of the CU Center for Ocular Inflammation.
Much is still unknown about uveitis, including its causes, subtypes, and the best methods to treat it. However, recent research by Hassman and her colleagues shows that patients with uveitis have different patterns of immune cell types affecting their eyes, which may be why a drug that works for one patient does not work for another. With further investigation, Hassman hopes to develop strategies to distinguish the different immunologic variations of uveitis and reveal which drugs work best for each.
“I hope to find something better for patients who don’t have success with our standard therapies,” Hassman says. “By proving that there are unique aspects to the immune response in each patient’s eye, I think this research is the first step toward finding the right cure for each patient.”
Uveitis can affect the different layers of the eye and cause a variety of symptoms, Hassman explains. For patients experiencing inflammation of a blood vessel, for example, they may lose their vision. Inflammation in the middle of the eye can cause small floaters in the eye, whereas inflammation in the front part of the eye can lead to severe pain and light sensitivity. Other patients may experience general blurriness.
Uveitis is common, with an estimated 80,000 to 168,000 cases each year in the United States, according to Cleveland Clinic. Yet, for most patients, the cause of their uveitis is unknown.
“For a minority of patients, uveitis results from infection by a virus or bacteria,” she says. “Most patients I see, however, have an autoimmune disease affecting their eye, and a little more than half of the patients have no clear etiology or cause for their uveitis, which can be frustrating.”
To treat non-infectious uveitis, Hassman employs a personalized approach, often starting with giving the patient steroids to help reduce the inflammation and protect their vision. However, these steroids have a lot of side effects, so they can only be used for a shorter time. For patients whose uveitis is chronic, they are transitioned to steroid-sparing immunosuppressant drugs like adalimumab, which is sold under the brand name Humira.
“If a patient has a condition like multiple sclerosis or another autoimmune disease, then we often start with drugs that are known to work for that organ system and for the eye — but it’s a lot of trial and error,” she says. “Humira works roughly 50% to 70% of the time, but I want to be able to tell my patient that a given drug will have a 95% chance of curing their eye disease. We’re not there yet.”
Hassman suspects Humira doesn’t work for everyone because the drug inhibits a specific molecule called tumor necrosis factor alpha (TNF-α).
“My hypothesis is that of the patients who fail Humira, many may have eye inflammation that is driven by something other than TNF-α. If true, then blocking TNF-α won’t fix the problem,” she says. “That was the inspiration for this research.”
In her study, Hassman and her colleagues obtained small fluid samples from the eyes of 23 patients with uveitis. They used single-cell RNA sequencing to perform immune cell profiling, or to analyze and identify the different types of cells in the fluid.
“We found that there were different compositions of immune cells in different groups of patients. It appears there are endotypes within uveitis, which means that there are discrete groups within uveitis that have different disease mechanisms,” she says. “Learning that is really the first step toward identifying the right treatment for the right patient.”
One group of patients, for example, had more innate immune cells, which are usually the first immune cells to respond when there are inflammatory issues. Those cells typically would respond to Humira, meaning the drug would be effective.
However, other groups of patients had more clonally expanded T cells and B cells, which are other types of immune cells. This suggests that the inflammation in those patients’ eyes had been going on for a while, Hassman explains, and there could be specific antigens or triggers that are driving their inflammation that may not respond to Humira.
“Uveitis is one word for a very heterogeneous, diverse group of individually rare diseases. Traditionally, in our clinical trials and our general approach to patients, we treat them all the same way,” she says. “Our research shows that at the immunologic level, uveitis is not one disease, but it’s many diseases. Now, we’re starting to have the tools to dissect that, which I think will radically improve the success of our treatment approach.”
Hassman is continuing to delve into the data from the 23 patient samples, and she is currently analyzing one key cell type that she thinks may be a big reason why Humira doesn’t work for some patients.
“In about a third of these patients, we see clonally expanded B cells. We also noticed that those patients tend to have more chronic disease and to have already failed some of the standard therapies,” she says. “We suspect that in one uveitis endotype, B cells are an important driver of inflammation.”
As part of this analysis, Hassman and her colleagues are also comparing the patients’ eye fluid samples to peripheral blood biomarkers to help define the cell types inside the eye.
“Having that biomarker may help us one day establish a clinical trial where we can test if patients with a certain biomarker respond better to a different type of therapy,” she says.
Given the diversity of uveitis, Hassman is also working to collect more patient samples.
“One current effort in our lab is developing protocols that allow groups at other institutions to send us samples that we can study,” she says. “We’re also working on creating a big, shareable resource that people across the globe can use, so they can plug their data into the database when they have new information to share.
“I envision this work will continue to get better as new technologies are developed,” she continues. “I hope that we can one day have a curated data set that anyone can use to find the therapies that will work best for their patients.”