One of the most challenging questions Lynn Hassman, MD, PhD, an associate professor in the University of Colorado Anschutz Department of Ophthalmology, regularly confronts is which treatment will save the vision of a patient with uveitis, a complex type of eye inflammation that can lead to blindness.
Current treatment options fail for roughly 50% of patients with chronic uveitis, a broad term that refers to a group of inflammatory diseases occurring inside the eye, Hassman explains. These diseases, of which there are at least 25 different types, can affect multiple parts of the eye, such as the iris, retina, blood vessels, or choroid.
Researchers are still investigating why uveitis occurs, its different subtypes, and how to tailor treatment approaches to improve the overall response rate. Hassman and a team of CU Anschutz ophthalmologists are working to find answers through the Center for Ocular Inflammation, an endowed program at the Sue Anschutz-Rodgers Eye Center that offers integrative patient care and conducts research related to ocular inflammatory diseases.
“As ophthalmologists, we have an extraordinary ability to observe and describe inflammation in the eye. We can use advanced imaging technology to quantify the amount of blood vessel inflammation, the extent of retinal damage, and the impact on the patient’s visual field,” Hassman says. “But none of this data reveals the right treatment for each patient. That’s because those clinical descriptions don’t tell us what is happening at the molecular level inside the eye.
“We know that the mechanisms that cause uveitis differ between patients because the same treatment may work for one patient and fail another. We need to learn how uveitis differs from patient to patient, so that we can match the right immune therapies to each patient’s disease state,” she adds. “To address this problem, we have partnered with our patients to create a uveitis biorepository, which is a bank of patient data and clinical samples. We use this resource to learn more about uveitis, directly from our patients, so we can understand this disease at the mechanistic level.”
Lynn Hassman, MD, PhD, working in her lab at CU Anschutz.
The Center for Ocular Inflammation Uveitis Biorepository holds samples of blood and/or ocular fluid (fluid from the eyeball) that more than 2,100 patients with uveitis have voluntarily donated for research.
“We rely on our patients as partners with us in this research aimed at understanding why a therapy may work for one patient but not another,” Hassman says. “Some patients feel that participation is a little silver lining on a terrible situation, because their donations can contribute to making the future better for someone else.”
The samples, which are securely stored and preserved on the CU Anschutz campus, are typically collected twice: first, when the patient has active disease, and again when their disease is in remission, so that researchers can understand each person’s disease and health states, Hassman explains. The samples are also linked to de-identified clinical data, such as the type of inflammation and biologic markers the patient had.
Such information is critical, given the heterogeneity — the diversity and variance — between patients with uveitis.
“When we looked through the clinical data from our patients at the Sue Anschutz-Rodgers Eye Center, we learned that the existing criteria of uveitis subtypes only describe about half of the patients,” she says. “The other half are experiencing a condition that doesn’t fit exactly into an existing box.”
The biologic specimens connected to this clinical data give investigators like Hassman the opportunity to understand at molecular levels what is happening in the eyes of patients with uveitis and the different ways this condition can manifest.
“For certain patients with significant inflammation in the front part of their eye, we can take a sample, about a drop of fluid, from the patients’ eyes. We use advanced technologies like single-cell RNA sequencing to get a detailed description of every single cell that is in that sample,” she says. “We can sample a few thousand to roughly 20,000 cells per patient and precisely identify the types of immune cells that are in each patient’s eye. Those samples are incredibly valuable.”
Hassman and her colleagues have collected ocular fluid samples from roughly 50 patients, and they have analyzed 23 of them so far. They learned from this initial cohort that particular types of immune cells differ between patients, and this diversity appears to be related to treatment response.
“We’re continuing to collect samples so we can create a robust atlas of the immune cells that are in eyes with many types of uveitis,” Hassman says. “We want to understand the full spectrum of disease at the molecular level and how this relates to treatment outcomes. We hope to eventually identify immunologic biomarkers that help us predict which immune therapy will work best for each patient.”
A close-up visual of a microscope in Hassman's lab at CU Anschutz.
When a patient is diagnosed with uveitis, treatment typically starts with a type of anti-inflammatory steroid known as corticosteroids. These steroids “almost always work for treating eye inflammation,” Hassman explains, but they also come with numerous side effects to the eyes and body, including glaucoma, cataracts, weight gain, difficulty sleeping, elevated blood pressure, and bone loss.
“We can’t keep people on corticosteroids forever. They’re meant to be a bridge to a longer-term therapy that is safer and more targeted but also can be less effective since we aren’t sure which molecules to target for each patient,” Hassman says.
A common longer-term therapy drug for patients with chronic uveitis is adalimumab, which is sold under the brand name Humira. These drugs target tumor necrosis factor alpha (TNF-α), an “important molecule in many inflammatory responses,” Hassman says.
Overall, this therapy is highly effective for roughly 50% of uveitis patients, she explains.
“For about 25% of patients, blocking TNF-α results in no positive response,” she says. “For another 25% of patients, the drug is helpful, but patients still need some corticosteroids to keep their eye inflammation at bay. In my book, that’s not good enough.”
However, for patients who have a specific type of uveitis known as HLA-B27-associated acute anterior uveitis (meaning the inflammation affects the front portion of the eye), this therapy appears to be more effective.
“A lot of uveitis patients have this type of disease, along with a genetic marker: HLA-B27. This eye inflammation happens completely unpredictably, one eye at a time. It’s really painful, causes a lot of light sensitivity, and severely affects their vision,” Hassman says.
From patients’ eye samples, Hassman and her colleagues have learned that this type of uveitis has a higher amount of innate immune cells — such as macrophages, a specialized type of white blood cell — that are typically more responsive to medications that inhibit TNF-α, she explains.
“We find that this drug class works better for patients who have that specific diagnosis. It works closer to 75% of the time,” she says. “So, we’ve found a connection between the eye immune cells in one particular type of uveitis and the treatment response. We want to validate this finding and expand the concept to other types of uveitis.”
Hassman has spent years working to uncover more effective treatments for uveitis. Before joining CU Anschutz in 2023, she worked at Washington University in St. Louis, where she started a biorepository to collect uveitis patient samples.
The uveitis biorepository at CU Anschutz was established several years ago with the support of CU Anschutz Department of Ophthalmology Chair Naresh Mandava, MD, and Alan Palestine, MD, director of the Center for Ocular Inflammation and section chief of uveitis and ocular immunology. Once Hassman joined the department, she took a leadership role within the biorepository and brought with her roughly 600 patient samples collected at WashU to share with CU Anschutz.
Now, Hassman and colleagues at the Center for Ocular Inflammation are embarking on several research endeavors that hold promise for making pivotal discoveries. For example, her group is seeking funding to collect ocular fluid samples from patients before they start taking a TNF-α inhibitor, such as Humira, to identify molecular predictors of treatment success and failure. This research would be a collaborative effort with four different universities.
The Center for Ocular Inflammation team also plans to perform whole-genome sequencing — a process that identifies the entire DNA code of a person— on all of the biorepository samples, and to profile the peripheral blood immune cells and antibodies. This type of analysis helps fuel other collaborative studies, such as a current pilot study with Rush University in Illinois that aims to understand the genetic risk of a rare subtype of uveitis called birdshot chorioretinopathy, also known as birdshot uveitis.
The biorepository has also been helpful to Hassman in her own lab’s research, prompting investigations into B cells, a type of white blood cell that produces antibodies.
“We’ve found expanded populations of B cells in a small subset of our patients, and we hypothesize that they may contribute to the failure of TNF-α inhibitor drugs for some patients,” she says. “We have a few clues as to what the B cells might be reacting to, and we’re chasing that down in my lab right now.”
Hassman is always working to establish collaborations with other institutions across the country to conduct uveitis research, emphasizing the value of partnerships.
“This problem is never going to be tackled by one university, because uveitis is both rare and heterogeneous and we simply don’t have the numbers to fully understand the disease with just our patients’ samples. We need to make this a large, multi-institutional effort,” she says. “My ultimate goal is to be able to give each patient at least a 95% chance that the drug we pick will be safe and effective for them. And I think that is within our collective reach.”
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