Q&A With NIH Dermatology Consultation Service Director

Edward W. Cowen, MD, MHSc, senior clinician at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, leads the National Institutes of Health (NIH) Dermatology Consultation Service, conducts independent and collaborative research, and coordinates Dermatology Grand Rounds, Clinical Fellowship, and resident education programs at NIH. An internationally recognized expert in cutaneous graft vs host disease (GVHD), Cowen is also director emeritus of the American Board of Dermatology and serves on the editorial boards of JAMA Dermatology and the Journal of the American Academy of Dermatology.

Cowen, who earned his medical degree from the Penn State University College of Medicine, Hershey, Pennsylvania, and completed his dermatology residency at the University of Rochester, Rochester, New York, has written more than 200 research papers and book chapters. Some of his key discoveries include the identification of total body radiation as a risk factor for skin thickening in chronic GVHD and the first clinical series describing angiomatosis, calcinosis, alopecia areata, and vitiligo in the setting of chronic GVHD. His current research focuses on developing new treatments for skin fibrosis in patients with chronic GVHD and creating better assessment tools to measure disease activity.

In an interview, Cowen spoke about his research and other topics related to dermatology.

Who had the greatest influence on your decision to pursue a career in medicine?

Neither of my parents are in the medical field — my decision to become a physician is probably a bit of an amalgam of my mother’s kindness and altruism and my father’s analytic nature as a chemist.

What inspired you to pursue a career in dermatology, and what ultimately led you to join the NIH?

Dermatology is the best specialty in medicine. I am so fortunate to have encountered great mentors in medical school at Penn State, particularly Elizabeth Billingsley, MD, who showed me how much fun the specialty can be and taught me not to take myself too seriously. During residency at the University of Rochester, Mary Gail Mercurio, MD, shared a similar infectious enthusiasm and joy caring for patients. Near the end of residency, I learned that there was an NIH Clinical Fellowship that provided an opportunity to perform investigator-initiated research and also care for patients with rare skin diseases. It has been such a unique environment that I haven’t ever left. It was here at the NIH that I also had the good fortune to work with Maria Turner, MD, a master clinician and lifelong mentor who continues to provide both professional and personal guidance to this day.

A key area of your research is chronic GVHD. Based on your clinical and research experience, what are the most common challenges in diagnosing and treating chronic GVHD in dermatology? Can you describe how you collaborate with other NIH institutes and centers to enhance the understanding of optimal GVHD treatments?

There are many challenges to managing patients with chronic GVHD. One common hurdle is patient comorbidity — patients frequently suffer damage to other organ systems, such as the eyes, gastrointestinal tract, mouth, and lungs. Mobility is already challenging when extensive skin sclerosis has occurred but becomes even harder when vision, nutrition, or breathing are also compromised. However, one of the most satisfying aspects of caring for these patients is to see the inner strength of patients with GVHD as they overcome these obstacles.

The NIH multidisciplinary GVHD group provides a comprehensive 1-week assessment in which patients with GVHD undergo evaluation of all organ system activity by specialists from different intramural institutes. Patients also receive important assessments by specialists in nutrition, social work, pain and palliative care, and occupational therapy, among others. We then meet as a group to develop a consensus regarding medical interventions, lifestyle modifications, and supportive care measures for the patient. Treatment options may also include enrollment in a therapeutic clinical trial for GVHD at the NIH. The overarching goal of the group is to work together to advance our understanding of the disease and to improve the quality of life for patients living with GVHD.

What are the most effective treatment options for managing cutaneous GVHD?

The good news is that in the 20 years since our multidisciplinary group began caring for patients with GVHD, the field has advanced from no US Food and Drug Administration (FDA)–approved therapies to four drugs that are now indicated for chronic GVHD (ibrutinib, ruxolitinib, belumosudil, and axatilimab). Interestingly, each of these agents works through distinct immunologic mechanisms. The not-so-good news is that skin fibrosis associated with chronic GVHD is particularly difficult to treat, and better transparency is needed in clinical trials to determine which agent(s) are most effective for skin fibrosis. The lack of a validated outcome measure to accurately assess skin fibrosis has also hampered progress. Together with Alina Markova, MD, at Memorial Sloan Kettering Cancer Center, New York City, and Steven Pavletic, MD, PhD, at the National Cancer Institute, we are currently working to develop a consensus among dermatologists and transplant physicians to improve skin outcome measures and standardize trial reporting of skin outcomes to begin to address these issues.

How do you approach management when cutaneous GVHD is refractory to conventional therapies? What emerging treatments or clinical trials show promise for cutaneous GVHD?

With an admitted bias as an NIH clinical researcher, I recommend that patients with skin GVHD who are refractory to therapy consider evaluation at a Dermatology Department or Transplant Center with expertise in GVHD management. Ideally, this would be a site that also offers access to clinical trial enrollment. As mentioned previously, evidence-based recommendations for skin disease management are limited by the skin assessment tools used in existing trials. Now that several FDA-approved agents are available, I am excited about the potential for tissue or blood biomarkers to direct patients toward a specific treatment based on the underlying mechanism driving their GVHD symptoms.

You were one of the authors of a recentcohort study of 112 patients with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, which found that the most common skin histopathologic findings were leukocytoclastic vasculitis, neutrophilic dermatosis, and perivascular dermatitis. Have any other notable findings emerged since this study was published?

VEXAS is a fascinating, new inflammatory condition that was first described at the NIH in late 2020. It is due to an acquired pathogenic variant in a gene on the X chromosome, so most affected individuals are men. To date, most men diagnosed with VEXAS are also older than 50 years, an age group in which one might not immediately consider a genetic disorder. One of our goals with the recent cohort study was to help dermatologists and dermatopathologists diagnose patients with VEXAS syndrome earlier in their disease course. Skin disease was a presenting feature in the majority of patients in our cohort. We also found that subtle histopathologic features differentiate the neutrophilic skin in VEXAS from Sweet syndrome. Regarding emerging findings, my experience with novel syndromes first described in small NIH cohorts is that these conditions are initially defined by a relatively rare clinical feature or set of features; however, once the condition becomes more widely recognized and genetic testing is more broadly employed, the spectrum of disease manifestations becomes much more pleomorphic. In this case of VEXAS, I suspect the overall incidence of “chondritis” will decrease as more patients undergo screening for the disease based on subtler skin findings or less specific hematologic findings. Population-wide genome studies have already demonstrated that there are mild and even clinically asymptomatic patients who harbor disease causing variants in the gene associated with VEXAS.

In your time at the NIH, you’ve contributed to the identification of many novel syndromes, including deficiency of the interleukin 1 (IL) 1 receptor antagonist (DIRA), GATA2 deficiency, and, most recently, the recognition of a nail abnormality (onychopapilloma) as a new cutaneous finding inBAP1 tumor predisposition syndrome. Can you please comment on this research and how it influences or will influence future treatments?

It is very rewarding to collaborate on the identification of new conditions, particularly when they lead to effective treatments, such as the use of IL-1 blockade for DIRA syndrome, a syndrome first described by Raphaela Goldbach-Mansky, MD, at the NIH in 2009. Most recently, we identified characteristic nail changes in approximately 90% of adults with BAP1 tumor predisposition syndrome, a condition associated with cutaneous and ocular melanoma, renal cell carcinoma, and mesothelioma, among other malignancies. Early screening for malignancy in this population is potentially lifesaving, particularly for conditions such as ocular melanoma and renal cell carcinoma, which may be asymptomatic until the cancers become advanced. Furthermore, the nail changes can be diagnosed relatively easily by patients as well as healthcare providers. At the very first lecture, I spoke about this finding after it was published; a dermatologist in the audience diagnosed himself based on his nail findings, and, soon after, genetic testing confirmed the diagnosis. He and his family are now undergoing cancer screening.

As the director of the Dermatology Branch Clinical Fellowship, you’ve mentored many aspiring dermatology researchers. What do you see as the key challenges currently facing dermatology researchers?

I have learned that each fellow comes to the NIH with their own long-term aspirations and that my role is to try to maximize their potential. They have gone on to careers in clinical research, laboratory research, and administration/leadership, and all have been successful on their own terms. Our specialty needs to do a better job identifying and fostering individuals with a commitment to dermatology research, particularly those who are interested in independent clinical and translational work. It is challenging to be competitive for grants focused on investigator-initiated clinical research because preliminary clinical data are difficult to obtain. At the same time, academic departments are unable or unwilling to support unfunded research, and aspiring young investigators are often faced with increasing clinical demands on their time.

Could you comment on the new therapeutics, such as Janus kinase inhibitors and dupilumab, that have shown effectiveness for multiple dermatologic indications, rather than just one or two?

It is an exciting time to practice dermatology. Immunotherapy and targeted cancer therapies have revolutionized the treatment of melanoma. There are also many more options for patients with inflammatory skin disease compared with just 5-10 years ago. Traditionally, the pharmaceutical industry has focused on common conditions such as atopic dermatitis and psoriasis, but increasingly well-designed trials are demonstrating the potential of these agents repurposed to treat less common diseases for which we have had limited options, such as alopecia areata, vitiligo, and hidradenitis suppurativa. The publication of practice-changing trials for these skin diseases in high-profile journals such as The New England Journal of Medicine will result in better treatment options for our patients in the months and years ahead.