Motivated by a desire to help people deal with a disease that affected her as child, Emma Guttman-Yassky, MD, PhD, has dedicated her career to unmasking the mechanisms behind atopic dermatitis (AD) and promoting the development of therapeutics to treat it. Dr Guttman developed the only comprehensive molecular maps of AD, defining skin differentiation and immune-circuits characterizing this disease, and her research has influenced the development of paradigm-shifting interventions.
The Romanian born, Israeli-reared dermatologist is double-boarded in dermatology in Israel and in the United States, and is professor and vice chair in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York. She can be found treating patients 2 days a week and doing research 3 days a week either in Mount Sinai’s Laboratory for Inflammatory Skin Disease, which she heads, or in Mount Sinai’s Center for Excellence in Eczema.
In an interview with The Dermatologist, she discusses her groundbreaking findings in the field of eczema treatment, her life-long affinity to AD, and exciting new work in alopecia areata (AA), advancing new treatments for this disease as well.
Q. Why did you choose inflammatory skin disease and AD as your subject of research?
a. I had AD as a child, and for as long as I can remember, I’ve been fascinated by AD and inflammatory skin diseases. AD puts a huge burden on the quality of life for patients for so many reasons including the fact that we don’t sleep well. It has been shown that AD patients have more accidents and more divorces, among other things—you can imagine how anxious you are when you don’t sleep at all. In fact, that’s why I went into medicine—I wanted to cure other patients like me who had skin diseases.
Q. How is the paradigm of eczema treatment Changing?
a. As recently as 10 years ago, it was not clear that AD is an immune disease; there were many reports suggesting that it was primarily a barrier disease, and treatments should focus on barrier restoration. In fact, in 2006 when the filaggrin mutation was found, everyone focused on filaggrin, and that created a lot of confusion because, I think, drug companies didn’t know what they should target for AD. It was unclear whether they should target the barrier or they should target the immune abnormalities. Ultimately, my research was instrumental in cementing eczema as primarily an immune-driven disease. It does, however, have a barrier component—the epidermal barrier is abnormal, allowing penetration of antigens—but it is the activation of the cytokines that already starts in nonlesional skin and amplifies in acute lesions and even more in chronic disease that perpetuates the eczema.
Q. Can you give us some insight into how your research came upon this?
a. Using comparisons with another inflammatory skin disease, psoriasis, we were the first to put forward the idea that several inflammatory pathways are upregulated in AD. For years, people knew that there is involvement of TH2 cytokines in AD, including IL-4, IL-13, IL-5, and IL-31. We put forward the notion that AD involves more than the TH2 pathway; there is another new T cell, TH22 that is important. That T cell secretes IL-22, which is involved in creating the thickening of atopic lesions that are particularly in the chronic stage. TH1 and T-17, also contribute to the disease phenotype.
Q. Is there anything in particular that has helped make these discoveries possible?
a. Genomic studies played a huge role in the last 15 years in psoriasis discoveries as well as in AD and AA because these studies allow us to see the whole big picture of many immune and barrier genes that characterize the disease. We are also able to dive deeper using more sensitive tools, such as real-time polymerase chain reaction, to look at the different cytokines and chemokines and barrier measures that are up- or down-regulated. Genomic tools helped delineate the pathways that are involved and the specific molecules that are involved. Immunohistochemistry also helped to show reversibility of the epidermal phenotype with treatments. We now have developed good disease biomarkers that we are following with various treatments.
Q. What are some therapies for AD and eczema that offer the most promise?
a. In AD, there are major developments in several fields. One field is the development of biologic therapeutics that target the specific cytokines. An example here is dupilumab, which targets both TH2 cytokines IL-4 and IL-13. Dupilumab is [potentially] the first biologic that will be approved for AD. It finalized its phase 3 study with very promising results and a very good safety profile. It is pending FDA approval, and we are hoping for approval in the beginning of 2017. Crisaborole is another exciting treatment in the pipeline. It is a topical that targets phosphodiesterase-4 (PDE4). It was developed by Anacor and has since been bought by Pfizer. We hope it will gain FDA approval by the end of 2016 or beginning of 2017. We’re excited about crisaborole because we haven’t had anything new to give our patients topically since 2002, when the calcineurin antagonists were brought to the market. There are other biologic therapies in the pipeline targeting IL-31, the itch cytokine, IL-22, and others. There are also small molecules such as PDE4 antagonists (apremilast [Otzela] that is approved for psoriasis) and Janus kinase (JAK) inhibitors that are being actively tested as oral agents. It is important to have availability of oral treatments as well for moderate to severe patients as some patients will prefer an oral to an injectable, and we are aiming to have all options.
Q. Can you share any new research?
a. My research now extends to AA. We saw that many patients with AD also have AA, and recently showed that both patients with AA that have or do not have accompanying AD, have a disease profile that simulates AD, with increases in TH2, IL-23, PDE4, and also in TH1 (as patients with AD have in their chronic stage) (Figure). This opens the door for cytokine targeting treatments for AA. We published a report of 3 patients with AA who had massive hair regrowth with ustekinumab (Stelara), and we now see that these diseases have many similarities in the pathways that are elevated.1 The same translational revolution that’s been the case in psoriasis that extended to AD will also extend to AA.
I became interested in AA after I treated a patient with moderate to severe eczema who also had alopecia universalis. He received 90 mg ustekinumab and several months later he did not have any AD and he had full hair regrowth, and hair regrowth in patients with total body loss is almost nonexistent. We followed that with the study of 3 patients and all patients had hair regrowth. We also did biopsies and all of them had reversal in scalp biomarkers. I believe that some of the drugs that work for AD like dupilumab, may work in AA, as well as some drugs that work for psoriasis that target IL-23 (eg, ustekinumab) or PDE4 (eg, apremilast). JAK inhibitors also work as they target the TH2, TH1, and IL-23 axis, but to tease out the pathways that are important mechanistically we need targeted treatments. So, I think we may also start a new treatment paradigm for patients with AA.
Q. Where do you see the future of anti-inflammatory skin disease treatments?
a. In the future, will have many new specific biologics and small molecules available for chronic use by patients with these diseases that will be safer and better than current treatments. Biologics are an important avenue, but not all patients want to have an injection, so, we also need oral medications that will be safer than the options we have now because cyclosporine and prednisone have many side effects. I think we’ll see more and more small-molecule orals being developed. Maybe in the very far off distance, we’ll even see biologics that will be developed topically.
Q. Some describe this time as the “decade of eczema.’’ Do you agree and why?
a. I entirely agree. I think that the last decade was the “decade of psoriasis.” Psoriasis is really the best model we have now in medicine for translational science—meaning that the development of new treatments coupled with very good studies that showed reversal of disease in tissues helped us understand the pathway upregulated in psoriasis and develop new treatments. Now we are doing exactly the same in AD and I think we’ll do exactly the same in AA, and I don’t think it will take 10 years because we have learned so much from the psoriasis experience. I think there will be major developments in the next 5 years for AD and probably in AA, following the developments in AD.
1. Guttman-Yassky E, Ungar B, Noda S, et al. Extensive alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism. J Allerg Clin Immunol. 2016;137(1):301-304.