Vitiligo: The bench has reached the bedside

Pearl Grimes, MD: “This new awakening offers hope and optimism for patients. There has been an amazing paradigm shift that encompasses new research on the causes of vitiligo, new targets for treatment, and emerging therapies.”

Vitiligo has long been a beast of a disease, devastating the psyches of millions of victims who were often told there are no treatments. However, a new day is dawning as researchers uncover the disease’s genetic roots and pathogenesis and develop new and exciting treatments.

“This is a disease that has been neglected for so very long. It’s been in a tenuous sleep for decades,” said Pearl Grimes, MD. “Vitiligo, the big sleeper, has awakened in the last three to four years and is emerging against all odds. This new awakening offers hope and optimism for patients. There has been an amazing paradigm shift that encompasses new research on the causes of vitiligo, new targets for treatment, and emerging therapies.”

Dr. Grimes explained these advances in an interview about her Everett C. Fox, MD Memorial Award and Lectureship address. During Friday’s Plenary, she presented “Vitiligo, The Big Sleeper: From Fallacies and Frustration to New Discoveries.”

Treatment remains elusive, but progressing

“Vitiligo affects 2-5 million people, just in the United States,” said Dr. Grimes. “There are no FDA-approved drugs for re-pigmentation of vitiligo, which is pretty tragic. Moreover, there are few vitiligo specialists in the U.S. Despite prominent advances, many patients, to this day, are still told there is no treatment for vitiligo.” Dr. Grimes is director of the Vitiligo & Pigmentation Institute of Southern California and a clinical professor of dermatology at the University of California, Los Angeles.

Advances in vitiligo research have seen the light of day in the last few years, but it took a decade of research to open windows and doors on the disease. Researchers have identified the majority of the genes involved. Most of these genes are immune regulators, and some others affect melanocyte function and regulation. Genetic factors probably influence the unhealthy melanocytes observed in the healthy skin of patients with vitiligo, she said.

“These cells are just abnormal to begin with, before there is any evidence of immune activation or substantial oxidative stress. We’ve learned a heck of a lot more recently on the role of oxidative stress in driving the destructive process,” Dr. Grimes said. “We think that oxidative stress is the player in inciting the immune response that can generate auto-antigens that drive the inflammatory process.”

Nrf2-ARE pathway

Recent studies have focused on the Nrf2-ARE pathway, which protects cells from oxidative stress, she said. Nrf2-ARE also helps decrease inflammation and fibrosis while increasing cytoprotection.

“There is exciting new work showing that Nrf2-ARE is significantly deficient in patients with vitiligo,” Dr. Grimes said. “If it is deficient, it can’t induce the antioxidant enzymes that protect the cells from oxidative stress, such as superoxide dismutase and glutathione.”

Agents that upregulate NRF2-ARE include aspirin, dimethyl fumarate, carnosol, gingko biloba, curcumin, and broccoli.

This information is driving the development of new treatment strategies to reverse vitiligo and restore pigmentation to the skin. These involve existing drugs that are now being studied in clinical trials. Drugs being tested based on this science are the JAK inhibitors tofacitinib and ruxoltinib, which have been shown to induce repigmentation.

Novel agents

A recent study documented the efficacy of histamine as a repigmenting agent for vitiligo. Other novel agents include afamelanotide and prostaglandin F2α agonists. Such analogues increase melanogenesis and melanocyte proliferation. Two of these analogues are latanoprost and bimatoprost, Dr. Grimes said. WNT agonists also show promise. Recent work documents substantial efficacy of checkpoint inhibitors in the treatment of melanoma. Several investigators have suggested that targeting immune checkpoints such as CTLA-4 and PD-L1 could theoretically impact tolerance in patients with vitiligo and serve as promising new long-term treatments for this disease.

Looking forward

Existing treatments that continue to be used by patients with vitiligo include topical systemic steroids, calcineurin inhibitors, and phototherapy. Phototherapy is important because it is essential in stimulating melanocyte migration and growth, Dr. Grimes said.

“The big sleeper has awakened, and it is an exciting and intriguing time,” she said. “We are truly at a watershed moment. The science is there, and the interest is there, so I think the future is bright. We will have better treatments for patients devastated by vitiligo because the bench has finally reached the bedside, catapulting us to new therapeutic peaks.”

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