Beyond dermoscopy

By Jan Bowers, Contributing Writer, August 1, 2023

Dermoscopy has arrived. “While there are established practicing dermatologists who are not using it, it’s integrated across the residency programs,” said Ashfaq A. Marghoob, MD, FAAD, attending physician at Memorial Sloan Kettering Cancer Center. “In fact, we don’t even need to get on our soapbox anymore to advocate for its use, which is something I’ve done the last 25 years of my career.” Despite spending decades advocating for the technology, Dr. Marghoob characterizes the uptake of dermoscopy as rapid, “mainly because the instrument is relatively inexpensive, small enough to fit in your pocket, and easy to use at the bedside. The main hurdle in implementing it in practice was the steep learning curve required to understand what you’re seeing and to interpret it correctly.”

Another key advantage is dermoscopy’s broad utility in distinguishing malignant from non-malignant lesions, a capability virtually every practicing dermatologist can appreciate, Dr. Marghoob said. “Physicians have come to understand that you can see things with dermoscopy that you cannot see with the naked eye. A dermatologist can look at a clinically concerning lesion with dermoscopy, and most of the time the information seen through the scope provides them with sufficient information for them to render a diagnosis or narrow the differential diagnosis.”

A host of new technologies have emerged over the past several years as researchers seek to improve the diagnosis and treatment of serious and even life-threatening skin disorders. Some are already in clinical use at major academic medical centers, while others are at the very early stages of testing. DermWorld spoke with five dermatologists to discuss the promise and the pitfalls of three new technologies — reflectance confocal microscopy (RCM), gene therapy, and engineered T cell therapy — and to assess their potential impact on the practice of dermatology in the future.

Reflectance confocal microscopy

A passionate proponent of RCM, a noninvasive imaging technology, Jane M. Grant-Kels, MD, FAAD, maintained that “it will and should ultimately revolutionize the way we practice, because it will avoid a lot of patient suffering, scarring, and secondary infections while it gives us the kind of information we get with pathology. It’s a technology that allows us to see the skin on a cellular level without doing a biopsy.” Dr. Grant-Kels is vice chair of the department of dermatology (and founding chair emeritus of the department), founding director of the Cutaneous Oncology Center and Melanoma programs, and professor of dermatology, pathology, and pediatrics at the University of Connecticut Health Center.

RCM uses a low-power laser that emits monochromatic coherent light; an image appearing in grayscale is created through the detection of backscattered light from illuminated tissue. In a JAAD Case Reports introduction to RCM and its use in clinical practice (10.1016/j.jdcr.2018.09.019), the authors note that RCM imaging provides “nuclear and cellular morphology of the skin with a typical lateral (i.e., horizontal) resolution of 0.5 to 1 mm and axial resolution (i.e., vertical layer thickness) of between 3 and 5 mm to a depth of about 150 to 200 mm depending on the anatomical site.” The wide-probe RCM device VivaScope 1500 (Caliber Imaging and Diagnostics) creates individual optical sections in small 0.5- x 0.5-mm fields of view that are stitched together to create a mosaic that can visualize a lesion up to 8mm in diameter at 30x magnification comparable to histopathology. In addition, RCM “can create a stack of images at the same horizontal plane at sequential depths from the stratum corneum down to the underlying papillary dermis, termed an optical biopsy.”

RCM is used most frequently to determine whether a lesion is malignant when clinical and dermoscopic examination don’t provide a definitive answer, said Dr. Grant-Kels, particularly if the lesion is located in a cosmetically sensitive area or on the legs, “where biopsy sites have a tendency to heal slowly and can often get infected, especially in diabetics and older patients creating a huge problem.” She added that RCM can help dermatologists distinguish between a benign nevus and melanoma; squamous cell carcinoma in situ and psoriasis; and benign simulants such as lichen planus-like keratosis and a malignancy. “You can use it to make some diagnoses of inflammatory diseases, but since the depth of field is only about 200 microns into the skin, you only see the superficial dermis. Nonetheless, it is an extraordinarily useful technology.”

Neda Shahriari, MD, FAAD, associate physician at Brigham and Women’s Hospital in the department of dermatology, recently completed her residency at UConn, where she studied RCM with Dr. Grant-Kels. She already misses having access to the technology, she said. “This past week I saw a patient who had a lesion on her face, and I was not sure what the lesion was. I would really have liked to have done some sort of further testing to be able to reassure the patient, but I wasn’t able to do that for her.” The patient resisted the suggestion of biopsy because of facial scarring, “so what I was left with was to have her come back in a couple of months to see if there are any changes. This is what I was forced to do, and honestly, I just wasn’t happy with it. This is one of the scenarios where RCM can be extremely useful — helping us with these challenging lesions on the face, or in pediatric patients too, where doing a biopsy is really difficult.” According to the JAAD Case Reports article, “when used as a second-level examination on dermoscopically equivocal lesions, RCM imaging can improve our ability to differentiate benign from malignant skin lesions, significantly reducing the number of unnecessary biopsies by 50-70%.” Dr. Grant-Kels confirmed that estimate based on her own studies.

Other potential applications of RCM include assessing the efficacy of topical treatment of nonmelanoma skin cancers and evaluating hyperpigmentation within a scar following surgery for melanoma, Dr. Shahriari noted. “Another way that RCM has been evaluated is use in Mohs surgery to map out margins,” she explained, “because parts of skin cancer are microscopic, RCM can show how far out the tumor is extending in a way that we can’t see with our eyes.”

The primary technical limitation of RCM is its depth. Beyond 200 microns, “the resolution drops,” said Dr. Shahriari. “That’s why there are advocates for combining RCM with optical coherence tomography (OCT), to be able to get the cellular resolution that RCM offers with the depth that OCT can give us.” Dr. Grant-Kels agreed that “the future, in my opinion, will be the combination of the two technologies. The person who’s reading the images will know the diagnosis and will also be able to tell the clinician how deep it goes.” While the JAAD Case Reports article cites studies showing cases of both false positive and false negative diagnoses with RCM, Dr. Grant-Kels insisted that the rates are very low. “If I look at an image and it’s a melanocytic lesion and I see features that are atypical but I’m not sure whether it’s a melanoma or an atypical nevus, I will tell them to biopsy it. But even with that we can eliminate 60-70% of unnecessary biopsies.”

The barriers to more widespread adoption of RCM in the U.S. include the cost of the equipment, pegged at approximately $100,000, uneven reimbursement for the procedure, and the time and effort required to train a clinician to read and interpret the images. Plus, “everybody’s used to doing a biopsy,” said Dr. Grant-Kels. “It’s easy to do a biopsy, and you get paid. Even though it’s FDA-approved, and it has a valued CPT code, not all insurance companies will pay for a confocal.” Acquiring the RCM image takes 20-30 minutes, depending on the equipment, and can be done by a nurse or other medical assistant. Learning to interpret images requires months of training, which is not always easy to come by. “Part of the challenge is that if this technology was widely used, it could easily be integrated into the residency curriculum for dermatology, as it is at UConn,” said Dr. Shahriari. “But nationwide it is not, so if people want to learn about it, they have to do some of the legwork themselves, like attending workshops and reading the CME articles that Dr. Grant-Kels and our team have published. I think it will be like dermoscopy: The more we know about it, the more uptake there is, then we can integrate it earlier on in the training of the dermatologist.” Dr. Grant-Kels noted that “many people buy the equipment and then send the images through the cloud to people like myself or Dr. Harold Rabinovitz who can interpret the images. You don’t really have to know how to interpret RCM images in order to incorporate it into your practice.”

Dr. Marghoob pointed out that new technologies such as RCM, OCT, multispectral imaging, and artificial intelligence (AI) “are being thrown at a group of lesions where we have already whittled it down to a very narrow field. With these added instruments, maybe we can save 30 biopsies out of 100 lesions. But it comes with all these hurdles: the expense of the machinery, the time sink for using it. You’d have to image a lot of lesions to justify buying a $100,000 piece of equipment.” He predicted that among the newer diagnostic technologies, AI will gain the broadest acceptance “because people will just use it to be the easy button. They may not even use dermoscopy anymore, just let the AI make the decision. And that will likely lead to an explosion in the number of biopsies, is my guess.”

Gene therapy

In contrast to imaging technologies, which have broad utility for the practicing dermatologist, two of the most advanced methods of gene therapy are being directed at treatment of a rare and devastating disease that dermatologists may never see: recessive dystrophic epidermolysis bullosa (RDEB), a painful and debilitating disorder characterized by skin fragility and development of wounds. “There are many different types of EB and thus many varying phenotypes,” said Emily Gorell, DO, a fellow in pediatric dermatology at Cincinnati Children’s Hospital Medical Center. “Patients with RDEB have chronic and severe wounds as well as numerous comorbidities and extracutaneous features; it’s a really horrible disease.” Researchers selected the subtype RDEB as an ideal target for gene therapy because it has a single underlying cause: mutations in a gene that encode collagen VII, a protein that binds the outer and middle layers of the skin together.

Prior to attending medical school, Dr. Gorell spent eight years as part of a team at Stanford Medicine investigating new therapies for RDEB. Since then, two distinct avenues of gene therapy treatment have emerged: a topical gel applied to wounds on a weekly basis, and autologous corrected keratinocyte sheets that are grown in a laboratory and grafted onto wounds as a potential one-time treatment.

The gel, formerly known as beremagene geperpavec (B-VEC), delivers a modified herpes simplex virus carrying two copies of COL7A1, the gene responsible for expressing collagen VII. The research team that developed the treatment published results of its phase 3 trial late last year in the New England Journal of Medicine (doi: 10.1056/NEJMoa2206663). The trial compared the results of treating paired wounds of similar size, region, and appearance in 31 patients aged six months or older. At three months, 71% of the wounds treated with B-VEC showed complete healing, compared with 22% of those treated with a placebo. Results at six months were 67% and 22%, respectively. Pruritis and mild systemic side effects occurred in patients receiving B-VEC. The gel received approval from the FDA in mid-May as a treatment for RDEB. Now called Vyjuvek (Krystal Biotech, Inc.), the gel is the first topical gene therapy to be approved in the U.S. and the first treatment to ever be FDA-approved for EB. “In an ideal world, the gel could be applied by a parent, but for now, per the label it must be applied by a health care professional,” Dr. Gorell remarked. Dr. Gorell is a sub-investigator on the open-label B-VEC study, currently being conducted at Cincinnati Children’s Hospital Medical Center.

The grafts, which have completed phase 3 trials but are not yet FDA-approved, have so far been applied to a different type of RDEB wound than the gel, explained Dr. Gorell. “We describe wounds that open and close and open again as recurrent wounds. And then patients also have wounds that just stay open and do not close at all, and those we call chronic wounds; some have been open for 10-20 years. The gene therapy grafts are all performed on chronic wounds, whereas until now, the gel has been mostly used on recurrent wounds, which tend to be a little bit smaller.” Candidates for the grafting procedure tend to be older patients, “although theoretically, in the future, we could start grafting patients when they’re young and prevent development of these chronic wounds.” Dr. Gorell described the process of creating and applying the grafts. “We take a biopsy from the patient. Now we send it off [to Abeona Therapeutics Inc., which owns the technology], but back in the early days, we had our own clean room at Stanford. The cells are transduced with the viral vector, and we grow up these corrected keratinocyte sheets that are about the size of a playing card, put them onto a Telfa backing and graft them onto the patient.” It takes about a month, start to finish, to create the sheets, Dr. Gorell said, adding that the surgery date may have to be moved up or back to accommodate the growth rate of the cells. The next hurdle is finding a surgeon who is “willing and able” to apply the graft, plus an anesthesiologist “who is familiar with the needs of EB patients. And then we also hospitalize patients for about a week afterwards, to minimize movement and allow the grafts to take.” Results of the phase 3 study of the grafts, now called EB-101, have not yet been published, but Abeona Therapeutics last year announced that the study demonstrated “statistically significant, clinically meaningful improvements in wound healing and pain reduction in large chronic RDEB wounds.”

While encouraged by the trial results of both methods, Dr. Gorell admitted, “I have no idea how much the grafts are going to cost and what hurdles there will be for insurance to pay for them. By the time this goes to press, we will have some experience with Vyjuvek, which we know costs many thousands of dollars per treatment. However, this is an incredibly exciting time in EB. For so many years, we had nothing, and now we’re possibly on the verge of having two effective disease-modifying treatments. The patients are happy just to have something within reach — they want it yesterday.”

Engineered T cell therapy

Another rare but potentially life-threatening disease, mucosal pemphigus vulgaris (PV), is the target of efforts to pit engineered chimeric autoantibody receptor (CAAR) T cells against a subset of autoimmune B cells that attack a patient’s own tissues. “There are different types of pemphigus vulgaris,” explained Aimee S. Payne, MD, PhD, FAAD, professor of dermatology at the University of Pennsylvania. “With mucosal PV, your body has mistakenly made antibodies against a protein expressed in the mucous membranes, and it causes mucosal blistering that can be very painful. Patients can’t eat or drink without pain, and it can become life-threatening if they have problems with nutrition.”

The current standard of care for PV is rituximab, which targets all B cells and globally suppresses the immune system, Dr. Payne said. “It works temporarily, but disease will relapse, so you have to give repetitive treatments, risking serious infection.” Now in phase 1 clinical trials, a new therapy developed in Dr. Payne’s lab at Penn attempts to “engineer the immune system to correct its own mistakes. With advancements in technology, we’re now able to understand how to program T cells to ideally eliminate just the B cells that are misbehaving. The holy grail for autoimmune disease therapy has been not to wipe out the entire immune system, but to find the markers of the autoimmune cells and target them specifically.”

After collecting blood from the patient, the white cells are harvested and enriched for T cells, which are then programmed and transduced with a lentivirus, Dr. Payne said. “Then we expand them in a dish, test them to make sure they are what we think they are, and infuse the engineered T cells back into the patient.” PV is an ideal candidate for CAAR T cell therapy because “we know exactly what the target is, a protein called desmoglein 3 that’s expressed in your mucous membranes.” Once the engineered T cells find their target, “they are designed to proliferate to make more of themselves, so they can kill even more of the B cells,” Dr. Payne said. “Furthermore, they have the potential to make memory CAAR T cells that can potentially last for the lifetime of the individual and help protect against disease recurrence.”

Early results of the phase 1 trial show a good safety profile, Dr. Payne said. “Now we’re exploring the safety and preliminary efficacy of the therapy starting with a dose escalation and also evaluating the added benefit of a preconditioning regimen with IVIG, cyclophosphamide, and potentially fludarabine, which may help to provide long-term efficacy.” Dr. Payne noted that the CAAR T cell technology built on the pioneering efforts of Carl H. June, MD, and others to deploy engineered anti-CD19 chimeric antigen receptor (CAR) T cells against B cell leukemias and lymphomas. Commenting on the outlook for T cell therapy, Dr. Payne notes, “this is where it starts to go beyond skin because if you scan the universe of B cell-mediated diseases, you can start to look at several different diseases, that can be amenable to CAAR T cell therapy or anti-CD19 CAR T cell therapy, including myasthenia gravis, membranous nephropathy, systemic lupus erythematosus, myositis, and more.” The biotech company she co-founded, Cabaletta Bio, has been granted Fast Track Designation by the FDA to investigate CAR T cell therapy for systemic lupus erythematosus and lupus nephritis, and recently received IND clearance to evaluate CAR T cell therapy for myositis.

Additional DermWorld Resources