For years, Erica Howell watched her young daughter struggle with arthritis and eye inflammation, which caused frequent pain and limited mobility. She has a rare genetic disease called Blau syndrome, a condition that starts in childhood and affects the skin, joints, and eyes. With no cure available, Howell’s daughter has tried countless treatments in search of relief but found limited results.
Newfound hope, however, arrived when the Howell family agreed to test out a new theory by researcher Ruth Napier, PhD, associate professor of rheumatology at the University of Colorado Anschutz Department of Medicine, who is leading breakthrough discoveries.
“After the first two weeks, she was functioning significantly better,” Howell says of her daughter. “It was very exciting.”
A second patient of Napier’s has shown even more promising results that have now lasted for months. And in both cases, researchers learned a lot about the disease and pathways for treating not only Blau syndrome, but potentially many other autoimmune conditions.
Napier, who playfully calls herself a mouse doctor because her interactions are primarily with her 300 lab mice, always knew she wanted to study microbiology and genetics. She began her academic medical career with an interest in studying how the human body’s immune system protects itself against bacteria.
But along the way, her microbiology research revealed connections with the field of rheumatology — a medical subspecialty focused on autoimmune disorders and issues affecting the joints, muscles, and connective tissues.
Now, her research is focused on helping crack some of medicine’s most complex questions about how and why the body’s own immune system can sometimes turn on itself. In particular, Napier’s lab is seeking to understand the function of NOD2, a gene that plays a key role in the body’s immune system.
“It has taken so long to get here,” Napier says. “There is no rare disease fund. We’re finally getting to the point where we can pitch grants that are less about one rare disease and more about how genes like NOD2 contribute to multiple rare diseases, which are more likely to appeal to broader funding sources.”
Although her findings might one day be key in understanding the underlying mechanisms behind autoimmune conditions that affect millions of people, it’s a small group of patients who have Blau syndrome, including Howell’s daughter, who are proving key to Napier’s research so far.
Blau syndrome is a rare condition believed to impact fewer than one in a million children or fewer than 1,000 people in the United States. All patients with Blau syndrome have a mutation in the NOD2 gene that causes the disease, making them an ideal group to study.
Napier first met patients with Blau syndrome after posting one of her research papers on social media. The post made its way to the friend of someone impacted by the disorder.
“I became singularly focused,” Napier says. “I couldn’t let it go.”
NOD2 was previously known to be a gene that controlled how the body’s immune system was able to detect bacteria. It was believed that a mutation in the gene was causing increased immune system function, leading to Blau syndrome. Yet, that theory wasn’t consistent with results from blood samples taken from patients.
Over the past few years, Napier's lab — spearheaded by immunology PhD student Leah Huey — was able to determine that although the gene plays a role in activating the immune system by detecting bacteria, it also plays a role in preventing an overreaction of the immune system by controlling T cells, a white blood cell necessary for immune systems to work properly. This means that NOD2 not only activates the immune system but also keeps it from being overly activated.
“I just think it’s a master regulator of the immune system,” Napier says. “It’s all a gradient. Is it turned up too much, or turned down too much? Should we turn it up or down?”
Ruth Napier, PhD, far left, smiles with members of her research team.
Napier and Huey’s research revealed that one of the ways the NOD2 gene works is by triggering cytokines, or molecules, which cause inflammation. After sharing these findings with leaders at CU Anschutz, they were encouraged to explore how their research could help patients.
Napier believed that one existing drug used for psoriasis and axial spondyloarthritis might be helpful in treating symptoms associated with Blau syndrome. She identified two patients willing to test her theory: Howell’s daughter, now a teenager, and an adult woman who was severely limited by the disease and struggling to find therapies.
Howell described thinking through the decision to enroll her daughter in Napier’s study. Her family was interested, but also nervous.
“You have to keep this disease very well controlled,” Howell says. “Our daughter was managing her treatment semi-successfully and it’s risky to try something new, but she was continuing to have more and more problems.
“She’s been through so much in the past 15 years. She has been promised a lot and tried all of these other drugs.”
Howell says that part of the reason the family ultimately agreed to try the new plan was because they were able to talk together with Napier and her daughter’s rheumatologist. As a team, they came up with a plan to add the new treatment, instead of using it to replace all of her current medications.
Howell also said she trusted Napier because she has worked with her closely for years in her role as the executive director of the Cure Blau Foundation, an organization that has funded some of Napier’s studies.
“Her involvement makes a huge difference for patients with Blau syndrome,” Howell says. “She truly wants to understand their experience. She’s so committed to finding practical knowledge that's going to help patients now.”
Napier says the patients she meets informs her work in big ways.
“There have been times that I’ve been completely lost and questioning whether what I’m doing is helping,” Napier says. “But then we will discover something new in the lab and it all clicks. It helps me make sense of their experience and hopefully improve the quality of their lives.”
Within a couple of weeks of trying the medication, Napier’s two patients both noticed significant improvements. The adult woman, who was previously in a wheelchair, is now up and hiking. Howell’s daughter was able to move around a lot easier and is still seeing some improvements.
“When I first heard that they were responding to the treatment, I was optimistic but wanted to keep a level head while I waited for the data to be analyzed,” Napier says.
Now, she’s in talks about collaborating with industry partners on a new investigation that might shine more light on whether this drug can one day be a cure for Blau syndrome. She has also filed a provisional patent with CU Anschutz for the treatment.
At the same time, Napier’s lab recently received funding through the CU Anschutz Department of Ophthalmology’s Vision Science Research and Translation Accelerator (VISTA) Program to determine if patients at Children’s Hospital Colorado and UCHealth University of Colorado Hospital with a diagnosis of juvenile idiopathic arthritis, the most common form of arthritis in children under 16, might actually have Blau syndrome instead. Napier also received the prestigious Rheumatology Research Foundation Innovation Award to investigate how NOD2 is controlling T cells and disease in Blau syndrome.
Working with so many talented and passionate people at CU Anschutz is amazing, Napier says.
“Everyone has been so supportive of me,” she says. “People are excited about the work and want to show up for us. They want to do well. That all comes from the top. There’s a real culture of support and innovation.”
And outside the hospital, her research is giving people like Howell’s family new hope.
“We’re so much more well equipped than before,” Howell says. “It’s exciting.”
About the main image: Napier smiles with Howell's daughter.