Rare diseases are a puzzle for the scientists and clinicians who study and manage them — and the patients suffering from them too. Take Sweet syndrome: an inflammatory disorder in which a patient’s neutrophils (a type of white blood cell) attack their own skin as if it were an infection. Challenging to diagnose and treat, Sweet syndrome looks and responds to treatments differently from patient to patient, requiring constant innovation and creativity.
For one Sweet syndrome patient at Penn Dermatology, the clinical team — including her physician, Misha Rosenbach, MD — wanted new options for her care. Although she had been treated with corticosteroids that controlled her Sweet syndrome at high doses, the side effects were devastating. She had been hospitalized four times in only two years for flares of her disease.
Due to the complex and personalized nature of Sweet syndrome, Rosenbach felt she would respond best to a targeted treatment: one that could control her neutrophilic inflammation with fewer side effects. Discovering such a treatment would be possible only with the momentum of an entire team.
The Translators of Insight into Individualized Care
To investigate this approach, Rosenbach, an associate professor of Dermatology in the Perelman School of Medicine, turned to his partner in the department’s translational research program, Thomas H. Leung, MD, PhD. A collaborative comprised of Leung, Rosenbach, Robert G. Micheletti, MD, and William James, MD had been studying patients with neutrophilic diseases such as Sweet syndrome to find consistent patterns underlying the disorders: mutations, signals, or other factors that might explain the origin of Sweet syndrome in some — or all — of their patients.
Together, they conducted genomic profiling of this single patient’s samples, and found something electrifying: a mutation in her neutrophils had caused increased production of the receptor to IL-1, a well-established inflammatory signal. This change encouraged her neutrophils to migrate more readily and drove her clinical symptoms.
Back in the clinic, Rosenbach found that treating the patient with a targeted therapy blocking IL-1 resulted in complete remission of her Sweet syndrome and enabled her to taper off her corticosteroids for three years (and counting!). Her life was transformed: no more side effects, symptoms, or hospital stays.
Taking insights like these from patients into the lab — and then translating them into action to guide therapy — requires the kind of seamless collaboration between scientists and clinicians that is a cornerstone of Penn Medicine. “Our partnerships with Dr. Rosenbach and other clinicians are prime examples of how Penn Dermatology facilitates research translation,” Leung notes. “To offer a successful new therapy to even one patient is incredibly motivating and is the first step to revolutionizing care.”
The research team’s insights were published in the Journal of Clinical Investigation last November. Already, this case has inspired similar research studies for two additional rare skin disorders. Because rare diseases like Sweet syndrome often affect critical body functions, further studies will improve our overall understanding of genes and biology, inspiring a ‘halo effect’ of research.
“We are eager to lead personalized medicine approaches for our patients at Penn Dermatology, to match patients with effective targeted therapies that treat their disease with the fewest side effects,” notes Rosenbach.
A Crucial Family Partnership
Jerry and Joan Berstein
For the Sweet syndrome team, support from the Berstein family has been fundamental to their ability to conduct this personalized medicine-based research.
When Joan Berstein first sought a diagnosis for her skin disorder, she was dismayed by the lack of answers. Her diagnosis was “trial and error,” according to son Jeff Berstein, and required input from dozens of experts. She would joke she had seen a hundred doctors before her eventual diagnosis of Sweet syndrome at Penn Dermatology in 2012.
Far from allowing the complexity and rarity of her disorder to deter her, Joan became a staunch advocate for her fellow Sweet syndrome patients. She formed a close partnership with William James, MD, her primary clinician, and quickly came to realize the essential need for research funding for this rare disorder.
“She recognized that rare disorders like Sweet syndrome don’t get a lot of funding, and many people aren’t even aware they exist. [My parents] felt that there was a deep need for other patients like her to have hope for new treatment options,” Jeff Berstein says. Joan and her husband, Jerry, made their first contribution to Penn Dermatology’s Sweet syndrome research program in 2015.
Though Joan passed in 2020, she left a legacy that will impact the lives of countless Sweet syndrome patients — and more, as research insights contribute to biological understanding in other diseases, too.
Behind Every Therapy, A Team
In studying rare diseases, all types of collaborators — from patients to donors, basic scientists and clinicians — hold a piece of the puzzle. As a vital part of the team, the Berstein family meets regularly with James and the Sweet syndrome researchers to hear about their steady progress. Joan would always attend these updates, equal parts rapt attention and enthusiasm; now, it’s become a family affair, with Joan’s grandchildren present at the latest research update last fall.
“Who else can better understand the urgency of this work than our patients and their families?” James says. “Our patients contribute in so many ways: through time in clinic, participation in studies and trials, samples for our biobank, and even funds to launch new projects. Joan has been such a committed partner and she and her family are a major part of the progress we’re making now.”
“[My mother] would be so thrilled to see the progress right now,” Jeff says. “She really felt she was making a difference.” Thanks to the Berstein family’s support, the team has published five more studies across a host of related diseases, termed “neutrophilic dermatoses,” with more on the way.
Philanthropy: The Piece That Makes Progress Possible
Because of the speed required of personalized medicine, some of the most vital partners in the puzzle of rare diseases are Penn Medicine’s community of donors who contribute funds to accelerate research timelines. Traditional sources of support, such as government grants, can take three years from submission to funding — time which makes innovative, early-stage investigational work harder to get off the ground. Philanthropy, by contrast, provides flexible, immediate resources to open new avenues of investigation.
To learn more about supporting Penn Dermatology and personalized medicine for rare diseases like Sweet syndrome, reach out to Caitlin Crowe Doelp at 215-746-2167 or ccrowe@upenn.edu.