Without dedicated scientists, we wouldn’t have the treatments that we have today. But what drives these scientists to do the work that they do? What motivates the research scientists, the clinicians, and the experts, especially in the challenging field of rare disease therapies and treatments? Our Derek Ansel, Clinical Strategy Lead, and Sara Webb, Clinical Team Manager, spoke with Dr. Aimee Payne, an Associate Professor of Dermatology at the University of Pennsylvania, to learn more.
Dr. Payne is a clinician who provides care for patients with pemphigus vulgaris, a rare skin blistering disease. She has been seeing patients with pemphigus since 2002 and started her research in 2004. Dr. Payne continues to research novel treatments and to ultimately find a cure for patients with pemphigus:
Tell us about your background.
Inadvertently, I have studied rare disease my entire academic career. During my undergraduate training in biology at Stanford, I studied DNA repair defects in xeroderma pigmentosum, a rare inherited skin cancer syndrome, with Gilbert Chu, MD. He convinced me to pursue MD-PhD training after college.
At Washington University in St. Louis, I researched copper metabolism in Menkes’ and Wilson disease with Jonathan Gitlin, MD for my PhD thesis. This is where I began to appreciate the rare disease community from the research perspective – there were very few labs around the world focusing on copper research, so I was quite enthused that our studies could make an impact on the understanding of disease pathophysiology. When I came to the University of Pennsylvania for my dermatology residency and postdoctoral fellowship under the mentorship of John Stanley, MD, I chose to focus on the autoimmune blistering skin disease pemphigus as my clinical and research area of specialty, given the challenge and complexity of medical care, the many unanswered research questions as to how autoimmunity occurs in pemphigus, and the collaborative and supportive nature of the pemphigus research community. More recently, I have become engaged with the International Pemphigus and Pemphigoid Foundation, which is focused on patient education and advocacy, and have very much appreciated the closeknit nature of the rare disease community from the patient perspective.
What is pemphigus? What are the differences between pemphigus and bullous pemphigoid?
Pemphigus and bullous pemphigoid are rare autoimmune diseases caused when the immune system mistakenly attacks the skin and/or mucous membranes, resulting in potentially life-threatening blistering. In pemphigus, the immune system attacks a protein responsible for holding skin cells together, whereas in pemphigoid the immune system attacks proteins responsible for attaching the upper epidermal layer of the skin to the lower dermal layers, which causes deep tense blisters and potentially scarring. Both are devastating due to the potential for disfiguring and painful blisters that can prevent normal eating, drinking, talking, and other activities of daily living.
How did you become interested in pemphigus?
Pemphigus is a potentially fatal disease that has to be treated judiciously with therapies, most of which suppress the immune system in order to reduce production of the disease-causing antibodies. Chronic immune suppression risks serious and potentially fatal infections, among other side effects, so clinical care is challenging due to the need to balance the risks and benefits of therapy, and it is important to coach patients through this difficult journey. From a research perspective, pemphigus is considered one of the best-defined autoimmune diseases in humans, so I became fascinated with taking a precision medicine approach to pemphigus research to better understand the B cell repertoire in pemphigus in the hopes of developing better targeted therapies for disease.
Can you explain your journey into an Associate Professor of Dermatology at the University of Pennsylvania?
For my postdoctoral fellowship, I wanted to better understand what causes pemphigus at the molecular level. When a patient is hospitalized with near total body blistering, how many different antibodies are causing disease - is there one antibody at very high concentrations or thousands of different antibodies? Are there shared features of these autoantibodies between patients that we could potentially target for therapy, such as gene or amino acid sequences? How do pemphigus antibodies make skin blister at the cellular level? These are the types of questions that I wanted to devote my career to studying, so I wrote grants to the American Skin Association, Dermatology Foundation, and eventually the National Institutes of Health, which helped me to set up my research laboratory as a tenure-track professor and hire in research staff and trainees to help answer these questions. Over the last decade we have described several shared features of the variable and constant regions of the antibodies that cause pemphigus, and have described the cellular signaling pathways that lead to or modulate skin cell blistering.
What is a typical day like for you?
I spend about 80% of my academic time on basic and translational research in my laboratory. The rest of the time I’m in clinic seeing patients with pemphigus and the related autoimmune blistering disease pemphigoid, teaching, or advising students and fellows through my roles as the Associate Director of Penn’s Medical Scientist (MD-PhD) Training Program and co-chair of the dermatology research residency program.
How does the University of Pennsylvania support you and your research goals?
I’m so grateful for Penn’s structural, financial, and moral support throughout my academic career. I benefitted from world-class mentors during my training, Financially, I was extremely fortunate to be supported by the Albert M. Kligman endowment, internal Penn grants, and gifts from donors, which helped me to cover my salary and research lab expenses during the times when my NIH and external grants weren’t enough to keep me afloat. In rare disease, grant funding can also be rare, so in this increasingly high-pressure environment I am fortunate to have had department chairs and medical school deans who value research inquiry over clinical profit. More recently, I’ve benefited from the incredible research infrastructure that Penn has built over the last decade to support the bench-to-bedside translation of novel therapies developed by the faculty, including regulatory experts, clinical operations, and GMP manufacturing facilities. When I started my lab in 2006, I would have never dreamed I’d be planning a clinical trial of a novel cell therapy for autoimmunity in humans and dogs, but Penn has allowed me to do just that.
Can you explain the diagnostic journey for these patients? Is differential diagnosis typical?
Due to the rarity of disease and the fact that not all medical schools have a dermatology curriculum, not all doctors have heard of pemphigus and pemphigoid, so diagnosis can often take months to years, which can be frustrating and also dangerous due to disease progression. Patients are often empirically treated for herpes or infection before being referred to a dermatologist for biopsy.
What are the current treatment options for pemphigus? Do they differ between countries?
Therapies mostly aim to suppress the immune system, including steroids, anti-inflammatories, and immunosuppressive agents such as rituximab, mycophenolate, azathioprine, and methotrexate. Adjunctive therapies such as plasmapheresis remove circulating antibodies through a dialysis-like procedure. Intravenous immunoglobulin is a therapy that dilutes out the disease-causing antibodies and also modulates or dampens immune reactions. Worldwide, steroids are considered first-line therapy for disease because they work quickly and are readily available, although other standard care therapies differ since therapies such as rituximab and mycophenolate may not be as widely available worldwide.
What is the work that you’re doing for pemphigus?
Recently, we’ve developed a novel targeted cellular therapy for pemphigus called desmoglein 3 chimeric autoantibody receptor T cells, or DSG3-CAART, which is based on an FDA-approved cell therapy that has induced striking long-term remissions of B cell cancers. B cells produce the disease-causing antibodies in pemphigus, so in general, any therapy that works for B cell cancer should work for pemphigus. DSG3-CAART is designed to program a patients’ T cells to seek out and kill only the disease-causing B cells, which we hope will lead to long-term remission of pemphigus without causing generalized immune suppression. We are currently focused on testing proof-of-concept in pemphigus, but ultimately, we hope that the CAART approach could prove to be valuable for many different autoimmune diseases.
What are some additional barriers that patients with this disease face?
Rituximab was the first FDA-approved therapy for pemphigus vulgaris in the last half a century, which was great news for the community, but currently steroids and rituximab are the only FDA-approved choices. Many patients can still face difficulty receiving rituximab due to insurance approval or reimbursement, as rituximab is approved for pemphigus vulgaris, but not pemphigus foliaceus or bullous pemphigoid, despite efficacy in these diseases and the lack of other FDA-approved therapies. Going forward, one of the biggest challenges for the field in general is the small number of young physicians and scientists choosing to specialize in blistering diseases – we need their ideas, energy, and efforts to allow basic and clinical research discoveries to continue to flourish in our field, and also to ensure that we have enough physicians trained in blistering diseases to take care of the patients who need them.
What other research is being completed for pemphigus?
There are several basic and clinical research studies ongoing in pemphigus. On the basic research front, researchers are examining B and T cell subsets and phenotypes, genetic predispositions, and environmental factors that may contribute to the onset of autoimmunity, cell biologic pathways that regulate skin cell adhesion, the microbiome, and many other exciting avenues of study. Clinically, groups worldwide are studying B cell depleting agents such as rituximab and Bruton tyrosine kinase inhibitors, inhibitors of the neonatal Fc receptor (which reduce total circulating antibodies), as well as novel immunotherapies that are designed to induce immunological tolerance (through peptide-coupled nanoparticles or red blood cells, or infusion of regulatory T cells that can suppress immune reactions). It is a great sign that so many companies are developing clinical programs in pemphigus, as we hope this will translate into more and better treatment options in the future.
What advice would you give someone who might be interested in learning more about pemphigus?
Contact the International Pemphigus and Pemphigoid Foundation, www.pemphigus.org. They are a great resource for not only patients, but also industry partners, rare disease organizations, and researchers who are interested in pemphigus.
Lastly, what do you like to do in your spare time when you’re not driving research or treating patients?
When I'm not working I enjoy the Philly food scene and walking my dog at the off-leash dog park.
This week’s Industry Watch is covering better understanding of disease, from the relationship between COVID-19 and the gut - to the intersection of…
Three Necessary Steps When Designing your New World Protocol
This article explores the design of a protocol that includes decentralized components. After a clinical-trial protocol has been developed, adding…
Partnering with Patients to Develop Meaningful Endpoints – Practical Considerations
Selection of appropriate endpoints for rare disease clinical studies can be challenging but is critical to assessing the efficacy of new medicines.…