A new chapter in vitiligo management

By Emily Margosian, Assistant Editor, March 1, 2024

Since the Bronze Age, humans have recorded cases of vitiligo — and attempted to cure it.

“3,400 years ago, ancient Indian texts called the Vedas actually wrote about vitiligo specifically and described how to treat it,” said John Harris, MD, PhD, FAAD, director and founder of the Vitiligo Clinic and Research Center at University of Massachusetts Medical School. “There are two reasons why that’s important. One, it’s a disease that has been stigmatized for a long time, and still is today. Second, the treatment they used — seeds from a plant called Psoralea corylifolia — contained a chemical, psoralen, that is still used in vitiligo therapy today. Essentially, we’ve been using a therapy that’s thousands of years old without much progress or innovation. That’s what makes the new treatment approvals so poignant.”

Vitiligo affects approximately 1% of the global population, equally divided among male and female patients (doi: 10.1016/j.det.2016.11.014). While multiple autoimmune diseases have been associated with vitiligo, the most profound complication is often its devastating psychosocial impact on patients, affecting both self-esteem and quality of life.

However, despite a long wait, hope may be on the horizon for vitiligo patients and their dermatologists. “This is the most exciting time in my 30 years of practice when it comes to vitiligo,” said Amit Pandya, MD, FAAD, president of the Global Vitiligo Foundation. “Up until recently, we really have not had any FDA-approved treatments for vitiligo. Now we do, and there are more coming down the pipeline.”

A new FDA approval

In 2022, the FDA approved topical ruxolitinib, a Janus kinase (JAK) inhibitor, for the treatment of nonsegmental vitiligo in patients aged 12 or older.

“This was such an important advancement because it’s the first and only treatment that is FDA-approved for the repigmentation of vitiligo,” said Brett King, MD, PhD, FAAD, associate professor of dermatology at Yale School of Medicine. “Previously, the only other FDA-approved agent for vitiligo was monobenzone, which depigments the skin. However, it’s rarely somebody’s goal to depigment their skin further. What we want is to return people’s skin to its normal color, and ruxolitinib cream was the first thoroughly tested, and ultimately approved, treatment to do that.”

Topical ruxolitinib had previously been approved in 2021 for the treatment of atopic dermatitis. However, the use of JAK inhibitors in vitiligo treatment is a recent development, according to Dr. Pandya. “We didn’t even know that JAK inhibitors would be helpful for treating vitiligo until maybe 10 years ago,” he said. “We’ve been attacking vitiligo with other treatments for a long time — steroids, topical calcineurin inhibitors, and phototherapy — which have their own mechanism of action. This is a brand new mechanism of action which may turn out to be more effective, and more important, in the management of vitiligo than the way we’ve been treating in the past.”

“This was such an important advancement because it’s the first and only treatment that is FDA-approved for the repigmentation of vitiligo.”

In phase 3 trials of ruxolitinib, at 24 weeks, 30% of patients receiving twice daily treatment achieved at least a 75% improvement in the Facial Vitiligo Area Scoring Index (F-VASI75). At 52 weeks, 50% of patients saw improvement (doi: 10.1056/NEJMoa2118828). The most common side effects were application-site acne and skin irritation. “It was generally very well tolerated. Patients like it. It can be applied anywhere on the body, including the eyelids, and you don’t have to worry about certain side effects like you would with steroids,” said Dr. Pandya.

In clinical trials, ruxolitinib showed the best results on the face, whereas lesions on the hands and feet showed the least improvement. “There is complexity to vitiligo treatment that is underappreciated,” said Dr. King. “First, and most important, the response to treatment is drastically different across body sites that are commonly involved; in particular the face often responds well and glabrous skin (where there are no hair follicles) responds poorly or not at all to treatment. Other body sites have the potential to respond but usually do not respond nearly as well as the face. Second, the velocity of improvement/repigmentation in vitiligo is very slow relative to other skin diseases, highlighted by the ruxolitinib trial results in which a year of treatment is necessary in order for 50% of patients to achieve F-VASI75.” Third, according to Dr. King, is that treatment response of face and non-glabrous sites, in general, can be enhanced dramatically (both speed and depth of response) with concomitant NB-UVB phototherapy. “All of this illustrates,” Dr. King said, “that vitiligo is a challenging disease to treat.”

Patients with vitiligo on areas of the body regularly exposed to the sun and still possessing pigmented hair also tend to be better candidates for treatment with ruxolitinib. “Vitiligo causes destruction of melanocytes in the epidermis, which gives you the white patches. In some patients, the vitiligo can be so severe that it kills the melanocytes at the base of hair and causes it to turn white. So, pigmented hair is an important prognostic sign,” explained Dr. Pandya. “With further studies, we’re also seeing better results with ruxolitinib when we add phototherapy to the mix. The body really needs some type of light exposure for the melanocytes to repigment the skin. This is part of why the face has a better response, because it’s exposed to more light during day-to-day life.”

More JAK inhibitors in the pipeline

While topical ruxolitinib is the first FDA-approved JAK inhibitor for the treatment of vitiligo, it is unlikely to be the last. Three oral JAK inhibitors are currently in phase 3 clinical trials for vitiligo: JAK3 inhibitor ritlecitinib (approved in June of 2023 for adolescents and adults with severe alopecia areata), JAK1 inhibitor upadacitinib (approved in January 2021 for atopic dermatitis), and JAK1 inhibitor povorcitinib.

“This is important, because we need a systemic,” said Dr. Harris. “If you’re using a topical, it’s only approved for up to 10% of your body coverage, and people often have more than that. Also, if the vitiligo is actively spreading, a topical doesn’t cut it. For example, if you’re getting a new spot on your back, that topical is not going to prevent that because you’re only putting the topical where you see disease. However, if you have a pill that you take, you can treat the vitiligo and prevent it from spreading to other areas as well. That’s one of the big keys moving forward — also having an oral systemic treatment in our toolbox.”

IL-15 inhibition: A pathway to relapse prevention?

Beyond JAK inhibitors, vitiligo researchers have also turned their attention to interleukin-15 (IL-15) inhibition to address the high rate of recurrence among vitiligo patients after stopping therapy. “We don’t have a good durable remission right now with the current treatments. When you stop treatment, vitiligo often comes back in the same spot,” said Dr. Pandya.

In animal studies, researchers found that resident memory T cells were the cause of vitiligo relapse after therapy (doi: 10.1016/j.jid.2018.10.032). “Vitiligo relapses at a rate of about 40% within a year of stopping treatment. That tells us there’s memory there; the skin remembers it’s supposed to have vitiligo,” explained Dr. Harris, a co-author of the study. “With vitiligo, T cells go into the skin and kill melanocytes, thinking they’re protecting you from something. Afterwards, they leave some cells behind as memory cells in case that perceived threat ever comes back to that location.”

While JAK inhibitors and other treatments may disrupt the cytotoxic T cells causing the loss of skin pigmentation seen in vitiligo, they do not prevent or remove the resident memory T cells that resume activity once treatment is stopped. “JAK inhibitors don’t remove those cells. They just turn them off,” said Dr. Harris. “However, we found that those resident memory T cells require IL-15 for their survival. In the mouse model, when we blocked IL-15, not only did vitiligo get better, but it also erased the memory of the cells left in the skin, preventing relapse.”

Currently, research is underway to determine whether IL-15 inhibition can treat vitiligo in humans. “That’s the main objective of the current clinical trial being conducted by the Immune Tolerance Network at the NIH,” said Dr. King, who is principal investigator of the study. “The concept is that those resident memory T cells driving the attack on melanocytes rely on IL-15 to survive. If we can make those cells go away, the message that recruits immune cells to the skin and drives melanocyte destruction goes away.”

Role for established therapies

As promising new treatments become available and progress through the pipeline, do established therapies still have a place in vitiligo management? Experts agree — the answer is yes.

“Phototherapy really is a mainstay,” said Dr. Pandya. “Treating vitiligo is a multi-step process. You can’t just use one arm of treatment in isolation. First, we want to stop T cells from attacking the skin and disperse them, whether that’s using steroids, topical calcineurin inhibitors, JAK inhibitors, oral JAK inhibitors, or even oral steroids. However, then you need to stimulate the melanocytes to repopulate the skin and bring the color back. Right now, the only thing available to aid with that is phototherapy.”

“Phototherapy is something we’ve been using for thousands of years, and the reason why is because it works.”

“Phototherapy is something we’ve been using for thousands of years, and the reason why is because it works,” agreed Dr. Harris. “These new therapies — topical JAK inhibitors, oral JAK inhibitors, and even IL-15 inhibitors, I anticipate — will be enhanced by sun exposure or phototherapy. The melanocytes get stimulated and that causes them to pigment and regrow. The other therapies turn off the autoimmune attack. It’s a nice pairing. There’s a good rationale that new therapies will still be paired with phototherapy if the patient has access to it.”

According to Dr. King, exposure to light is a key facet in the multistep approach needed to treat vitiligo, and a clue as to why areas like the face respond better to current treatments. “Whether you live in Alaska or Brazil, the face sees light every day, and that is one explanation for why we see better treatment results with facial vitiligo than other body sites,” he said. “I really stand by the idea that repigmenting vitiligo is a two-step process. You need to suppress inflammation and melanocyte destruction, and then you need to stimulate melanocytes to come to life and go out into the depigmented skin and put color back. It can happen spontaneously, but it happens much more reliably under the influence of light. I don’t see phototherapy going away.”

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