new research for vitiligo

Vitiligo Research

Vitiligo Advancements and Discoveries

There has been an increase in the amount of research being undertaken in vitiligo over recent years and dermatologists have an improved understanding of the natural history and different types of the condition. Here you will find a brief summary of research into several areas, with references to the original research articles, for those of you who wish to follow these up.

Researchers are looking at:

• The effectiveness of existing treatments;
• Possible causes of vitiligo;
• How the condition develops;
• Segmental vitiligo;
• The association of vitiligo with other conditions;
• The psychological effects of vitiligo.

It is hoped that the improvements in scientific understanding will in future lead to more effective treatments for vitiligo.

Are psychological interventions important for vitiligo patients?

Yes, a survey of vitiligo patients and healthcare professionals found that psychological interventions are important for managing the impact of vitiligo on patients’ lives.

A survey was conducted to identify psychological interventions for vitiligo. The survey was funded by the UK Dermatology Clinical Trials Network and involved patients and health professionals. The survey recorded personal data and focused on the effect of vitiligo on normal life, as well as the most difficult problems faced by patients and which approaches would be helpful.

• Patients with vitiligo reported key issues such as acceptance of their disease, the duration of the disease and managing embarrassment.
• Other concerns were participating in sporting activities and exposure to sunlight.
• Interventions considered useful by professionals to address these issues included cognitive behavioural therapy (CBT), acceptance and commitment therapy (ACT), and mindfulness therapy.

Psychological interventions for vitiligo are a research priority, but there is little published on appropriate therapy from both patient and clinician perspectives. The unique survey referenced here is therefore of value to the future treatment of vitiligo patients.

Will piperine treat vitiligo?

Although promising results have been seen in cell and animal studies, and early work toward clinical trials in humans is underway, the effectiveness and safety of piperine as a treatment for vitiligo in humans has yet to be fully established.

Ongoing research is being conducted, but funding is needed to support further studies. Therefore, it is unclear at this time whether piperine will ultimately prove to be an effective treatment for vitiligo.

Amala Soumyanath led the research that discovered piperine as a potential treatment for vitiligo. In her own words, she shares the story of her research journey and provides an update on the latest developments. Become a member today and access more resources and stories like this.

How was piperine discovered as a potential treatment for vitiligo?

Piperine was discovered as a potential treatment for vitiligo through research and testing of herbal extracts , where a water extract of black pepper was found to stimulate melanocyte growth and dendrite formation. The compound responsible for this effect was identified as piperine, which could be developed for use in treating vitiligo.

How was piperine validated as a “lead” molecule for the treatment of vitiligo?

Piperine was validated as a “lead” molecule for the treatment of vitiligo through studies conducted at King’s College London. They tested extracts from various herbs and found that piperine from black pepper was the most effective at stimulating the growth of pigment cells. Further studies were conducted to make chemical variations (analogs) of piperine and two of these analogs showed good activity.

All three compounds, piperine, THP, and RCHP, were found to stimulate the growth of pigment cells in mice, causing their skin to visibly darken. These studies allowed the researchers to secure international patents for the use of piperine and its analogs to treat vitiligo.

How was piperine’s effectiveness and safety in treating vitiligo validated?

Piperine’s effectiveness and safety in treating vitiligo were validated through a detailed plan for a clinical trial of piperine in patients with vitiligo. Prior to the clinical study, experiments were conducted to investigate the effects of piperine on human pigment cells, including melanocytes from the uninvolved skin of a vitiligo patient.

Piperine was found to stimulate the replication of human melanocytes in culture and when grown within a reconstructed skin model. Colleagues in OHSU’s Biomedical Engineering and Dermatology departments used innovative optical methods to image pigmentation and melanocytes in the skin models.

What were its effects on human pigment cells and melanoma?

Experiments funded by AdPharma, Inc. showed that piperine has an inhibitory effect on cultured melanoma cells and prevents melanoma cell growth in a reconstructed full-skin model. To further study this aspect, the HGF mouse model of melanoma was introduced to OHSU.

The effects of piperine in this model are currently being studied with pilot funding from the Department of Dermatology’s Jesse Ettelson Fund for the Advancement of Dermatology Research. These ongoing studies are essential to establish the safety of piperine.

What is the status of piperine for treating vitiligo in humans?

In 2013, the appointment of Professor Sancy Leachman, a dermatologist and expert in pigment cell biology, gave a significant boost to the project of developing piperine as a new treatment for vitiligo. Dr. Pamela Cassidy and Eric Smith also joined the team, and a core group is working to bring this discovery to the clinic. The current status of piperine as a treatment for vitiligo in humans remains unclear.

Amala Soumyanath’s Personal and Professional Journey to Develop a Treatment for Vitiligo

Amala Soumyanath’s journey began when she received a phone call from Maxine Whitton, an MBE-awarded vitiligo service provider, sparking an idea to develop piperine as a potential treatment for vitiligo. With dedication and persistence, Amala’s knowledge of drug development processes led her to develop piperine to the point of being tested in humans.

Her personal experience with vitiligo, developing noticeable patches in 2006, fueled her drive to find a treatment for this difficult condition. Alongside a team of talented researchers at OHSU, they continue to evaluate piperine’s efficacy and understand its effects on melanocytes, with Dr. Sancy Leachman leading the project and Amala as the ongoing champion.

Is piperine the new treatment for vitiligo?

Amala Soumyanath and her team at OHSU are developing piperine as a potential treatment for vitiligo. A “proof of concept” human study demonstrating piperine’s safety and efficacy could attract large pharmaceutical companies to move forward with the project, but funding is needed. Donations of any size can make a real difference to the project’s progress. While piperine shows promise as a treatment for vitiligo, further research is required before it can be established as a new treatment.

How can you help?

The team at OHSU is reaching out to the general community for funding to support their ongoing studies on piperine for vitiligo at both the clinical and basic science levels. Donations of any size from those affected by vitiligo or anyone interested in supporting the research can be made online to the Vitiligo Research Fund .

Read Amala Soumyanath’s full story here .

What impact does vitiligo have on a person’s quality of life?

Vitiligo can have a moderate to severe impact on a person’s quality of life, including depression, stigmatization, and impaired sex lives. The location of the lesions and cultural values related to appearance and status may also play a role. Research has found that:

• Quality of life is closely related to the patients’ apprehensions about their disease, psychosocial adjustment, and psychiatric morbidity.
• British Asian women with vitiligo often feel visibly different and have experienced stigmatization due to cultural values related to appearance, status, and myths linked to the cause of the condition.
• Quality of life impairment in women affected with vitiligo assessed using the DLQI was equal to the impairment caused by psoriasis.
• Vitiligo had a negative impact on the sex lives of women with vitiligo.

To learn more about the impact vitiligo has on an individual and their quality of life you can find the full articles below:

• Quality of life of patients with vitiligo attending the Regional Dermatology Training Center in Northern Tanzania
• Depression, anxiety and health‐related quality of life in children and adolescents with vitiligo
• Quality of life and psychological adaptation of Korean adolescents with vitiligo
• Vitiligo linked to stigmatization in British South Asian women: a qualitative study of the experiences of living with vitiligo
• Effect of vitiligo on self‐reported health‐related quality of life
• The Problems in Sexual Functions of Vitiligo and Chronic Urticaria Patients

Can thyroid issues cause vitiligo?

There is evidence to suggest that thyroid issues can be associated with vitiligo. The frequency of thyroid disease in vitiligo patients is higher compared to the general population, and it is recommended that all patients with vitiligo have their thyroid function checked.

In the course of their clinical work, dermatologists discovered:

• the frequency of thyroid disease in vitiligo patients was 15.1%, 
• autoimmune thyroid disease was 14.3% 
• and the presence of thyroid-specific autoantibodies was 20.8%.

To learn more about the association between thyroid issues and vitiligo you can find the full article here .

Does vitiligo increase your risk of skin cancer?

Although patients with vitiligo have a tendency to burn in the sun, a survey conducted by a team from The Netherlands found that patients with vitiligo have a threefold lower probability of developing malignant melanoma and non-melanoma skin cancer. The reasons for this are not yet fully understood.

Read the entire survey here and learn more about this on BBC iPlayer .

What is segmental vitiligo?

Segmental vitiligo is a form of vitiligo that presents with patches distributed unilaterally and locally . It has been compared with a possible mosaic or neurogenic background, but its distribution pattern is not entirely similar to any other skin condition. Cutaneous mosaicism may be involved in segmental vitiligo. However, the underlying mechanism of segmental vitiligo is still unknown.

Learn more about the distribution pattern of segmental vitiligo here .

How is vitiligo classified?

Segmental vitiligo is classified separately from all other forms of vitiligo, with the term ‘vitiligo’ being used as an umbrella term for all non-segmental forms, including mixed vitiligo in which segmental and non-segmental vitiligo are combined and which is considered a subgroup of vitiligo.

Experts recommend that disease stability is best assessed based on the stability of individual lesions rather than the overall stability of the condition.

Read the entire article about the classification of vitiligo here .

What is the Koebner phenomenon in relation to vitiligo and how can it be assessed?

The Koebner phenomenon (KP) refers to the development of vitiligo within an area of skin that has been damaged by localised, often mild trauma (e.g. an injury). Dr. N van Geel and colleagues of Ghent have looked at this phenomenon. They developed a new assessment method for KP, taking into account both the history and clinical examination of people with vitiligo; this seems to be a useful and valuable tool for assessing KP in daily practice.

The results support the hypothesis that KP may be used to assess and predict the course of vitiligo (access the entire article here ).

What is the relationship between Halo Nevi and vitiligo?

Halo nevi are common moles with a white ring around them, showing the sort of pigment loss that is seen in vitiligo. They may represent a distinct condition, but in some cases, they may be an initiating factor in the development of vitiligo, according to research by Dr. van Geel and researchers (access the entire article here ).

What are the mechanisms of pathogenesis of vitiligo?

The pathogenesis of vitiligo is believed to involve oxidative stress, which leads to an imbalance between reactive oxygen species (ROS) and the body’s ability to detoxify them. (Access the entire article here ).

According to research (access the entire article here ): 

• Mitochondria within melanocytes and blood cells generate reactive oxygen species (ROS) that may be relevant in vitiligo development.
• Modification of membrane lipid components in vitiligo cells may cause mitochondrial impairment and the production of intracellular ROS after exposure to mild stress.
• Autoimmunity plays a role in the pathogenesis of vitiligo, with tyrosine hydroxylase identified as an autoantigen target.
• Tyrosine hydroxylase antibodies are more frequent in people with active non-segmental vitiligo (23%) but not in the segmental type.

How does vitiligo affect the layers of skin?

Genetic studies show that susceptibility to vitiligo is related to proteins or parts of the pigment cell involved in the immune system (access the entire article here ). Research from Dalian, China, reveals that alterations in skin biophysical properties, such as stratum corneum (SC) hydration, melanin and erythema index, are lower in vitiligo-affected skin (access the entire article here ). 

However, no difference in skin surface acidity was observed, and the SC integrity was similar in involved and uninvolved areas. Barrier recovery in vitiligo-involved areas was significantly delayed compared to uninvolved areas.

What are the systemic treatment options for vitiligo?

It is difficult to find a systemic treatment for vitiligo at the moment (one that affects the whole body). Some of the commonly used systemic treatments for vitiligo include:

• Ginkgo biloba – taking 60 mg of Ginkgo biloba BID was associated with a significant improvement in total Vitiligo Area Scoring Index (VASI) and Vitiligo European Task Force (VETF) scores, but more clinical trials are needed (access the entire article here ).
• Piperine – has been suggested as a potential treatment for vitiligo, yet only a few studies have been conducted and most have been on animals (access the entire article here ).
• Cosmetic camouflage – not only conceals the depigmented patches but has been shown to improve the quality of life in patients (access the entire article here )

What are the surgical treatment options for vitiligo?

Surgical treatment options for vitiligo involve transplanting melanocytes from normally pigmented skin to the depigmented areas and are only suitable for patients with stable vitiligo. It has been proven that suspending melanocytes in the patient’s own serum (plasma in the blood) can improve the effectiveness of the transplant (access the entire article here ).

Another new procedure called ReCell involves taking a sample of normal skin, separating out the skin cells, and spraying them onto the vitiligo patches (access the entire article here). Studies comparing Recell with conventional transplantation have shown varying degrees of repigmentation, but it is not widely available in the UK (access the entire article here ).

What are effective topical treatments and light therapies for vitiligo?

Creams or ointments, known as topical immunomodulators, are usually the first line of treatment for vitiligo. Topical tacrolimus and pimecrolimus have been found to be effective for localised vitiligo. Targeted narrow-band ultraviolet B (UVB) light treatment using the Excimer laser is also known to be effective, but not widely available. Other lasers such as the Q-switched ruby laser have been shown to induce depigmentation more quickly, but with more discomfort.

To learn more about effective topical treatments and light therapies for vitiligo you can find the full articles below:

• Comparative Therapeutic Evaluation of Different Topicals and Narrow Band Ultraviolet B Therapy
• Pimecrolimus: a new choice in the treatment of vitiligo?
• Laser for treating vitiligo: a randomized study
• Treatment of vitiligo: advantages and disadvantages, indications for use and outcomes

Table of contents

FDA Approves New Vitiligo Treatment, Ruxolitinib (Opzelura)

The JAK inhibitor cream is the first medication that can restore pigment in people with this autoimmune disease.

On July 18, the U.S. Food and Drug Administration (FDA) approved ruxolitinib ( Opzelura ) cream 1.5 percent as a treatment for the most common form of vitiligo, according to a statement by Incyte, the manufacturer of the drug.

Vitiligo is a chronic autoimmune condition that causes patches of skin to lose pigment and turn milky white. The most prevalent form is nonsegmental (also known as generalized) vitiligo, in which white patches appear symmetrically on both sides of the body, such as on both hands or both knees, often covering large areas.

Ruxolitinib is the first medication that can restore pigment in patients with nonsegmental vitiligo. The FDA approved Incyte’s ruxolitinib cream for adults and children ages 12 and up.

“This approval is monumental,” says Daniel Gutierrez, MD , assistant professor of dermatology at NYU Grossman School of Medicine and dermatologist at NYU Langone Health in New York City, who was not involved in the drug development. “With Opzelura, we will have an FDA-approved pharmaceutical treatment option that can actually bring back color in patients who have vitiligo,” says Dr. Gutierrez.

He adds that prior to ruxolitinib, the only FDA-approved medication for vitiligo was monobenzyl ether of hydroquinone, a topical drug that removes pigment from skin to even out tones.

What Is Vitiligo?

Researchers estimate that between 1.9 and 2.8 million adults in the United States have vitiligo, with perhaps 40 percent of adults with vitiligo going undiagnosed.

Vitiligo causes immune cells to destroy melanocytes, the skin cells that produce pigment, according to the National Institute of Arthritis and Musculoskeletal and Skin Diseases . “This makes vitiligo much more noticeable in patients of color — people whose skin is much more richly pigmented — because there is going to be much more of a contrast between the unaffected skin and the skin affected by the vitiligo,” says Gutierrez.

Vitiligo can occur at any age, but most people experience the initial symptoms before age 30.

About 50 Percent of People Using Ruxolitinib Had Significant Repigmentation After One Year

Ruxolitinib belongs to a class of drugs called Janus kinase (JAK) inhibitors. While doctors prescribe oral JAK inhibitors for diseases such as rheumatoid arthritis, ruxolitinib is the only topical JAK inhibitor approved in the United States.

The FDA previously approved ruxolitinib for mild to moderate atopic dermatitis (eczema) , in the fall of 2021.

JAK inhibitors work by decreasing the activity of the immune system, blocking certain enzymes that cause inflammation.

Patients using ruxolitinib apply the cream twice daily to the affected areas, covering up to 10 percent of their body’s surface area. It may take 24 weeks or more for people with vitiligo to see satisfactory results, according to Incyte.

The FDA based its approval on data from a clinical trial program that compared ruxolitinib to a placebo cream in more than 600 people (age 12 and older) with nonsegmental vitiligo. Investigators used the Vitiligo Area Scoring Index (VASI), a tool used to gauge disease severity and to measure improvements in face and body repigmentation.

In the two trials, by week 24 approximately 30 percent of people treated with ruxolitinib experienced significant improvements (at least 75 percent) as measured by VASI, which was the goal of the study. At one year, about 50 percent of those using the medication achieved that level of repigmentation.

“People using Opzelura had much more improvement in their vitiligo — very meaningful — compared to the placebo,” says Gutierrez.

The most common side effects seen in the trials were application-site acne, redness and itchiness, pharynx and nasal cavity inflammation, headache, urinary tract infection, and fever.

Ruxolitinib Comes With a Black Box Warning

The FDA added a black box warning to ruxolitinib, based on data showing that people taking oral JAK inhibitors faced a small increased risk of serious infections, major heart issues, clotting (thrombosis), cancer, and even death.

“However, in the clinical trials for people using ruxolitinib as a topical cream, the concentrations of the drug found in the blood were observed to be much lower compared to people who take ruxolitinib orally,” says Gutierrez. The same risks were not observed in the ruxolitinib trials, but the FDA is taking a “better safe than sorry” approach by including a warning on the box, he adds.

A conversation with your healthcare provider is the best way to determine whether the benefits of ruxolitinib outweigh the potential risks, as well as the need for any baseline and/or ongoing monitoring.

Patients Can Use Ruxolitinib on Their Face

Although dermatologists sometimes prescribe topical steroids off-label for vitiligo, there are risks when applying these medications to the face — the area where loss of pigment can impact appearance the most, says Gutierrez.

When used on the face, topical steroids can cause an acne-like rash that can persist for many months, called perioral dermatitis . Plus, “they can cause atrophy or dispigmentation, meaning you can have skin color changes. They can also thin the skin, cause stretch marks, and cause the growth of small blood vessels in the area,” Gutierrez says.

Ruxolitinib does not pose these risks, notes Gutierrez.

FDA Approval Means Better Access to Vitiligo Treatment

The FDA’s approval of ruxolitinib will definitely improve access to the drug by validating it as medically necessary. “Because vitiligo just creates a color change in the skin — there’s no itching or dermatitis under normal circumstances — sometimes it’s considered a cosmetic condition, meaning it’s not medically necessary to treat,” Gutierrez says. As a result, some insurers have declined to cover vitiligo treatments , according to the Vitiligo Research Foundation .

“However, this condition can dramatically impact how a patient sees themselves and how they present to the world. Vitiligo can cause significant psychological distress and negatively impact quality of life,” says Gutierrez.

“Vitiligo disproportionately impacts patients of color,” he adds. “This approval is an important step in improving a health disparity that does exist, and hopefully there will be more treatment options for vitiligo in the pipeline.”

How Much Will Ruxolitinib Cost?

The current Wholesale Acquisition Cost pricing is $1,950 for a 60 gram tube of Opzelura, according to Gabriella Greig, a spokesperson for Incyte. The actual cost to the consumer will vary depending on insurance coverage and how much of the cream is required for treatment.

“Incyte is committed to working with insurance providers in the U.S. to ensure eligible patients who can benefit from Incyte’s products have access to them,” says Greig. The company offers a  copay savings card on its website for people with commercial insurance.

A new treatment is restoring skin coloration to some with vitiligo. It's giving patients hope.

• Vitiligo is an autoimmune disorder that leads to the loss of skin pigmentation.
• A recent study shows a medicated cream called ruxolitinib is extremely effective in about one-third of patients.
• The cream is giving patients hope that even if they don't benefit from the treatment there will soon be others.

Sarah Hayden owns a lot of turtlenecks. She also has chunky necklaces and tons of makeup – anything to cover up the blotchy white skin on her face, neck, hands and knees.

When she was about 23, Hayden was diagnosed with vitiligo, a noncontagious skin condition that leads to the loss of pigmentation. It struck first on the back of her neck and then, as with many people, slowly progressed under her eyes and across her face, before jumping down to her knees, elbows and fingertips. 

Once, when she stepped into a hot tub, a woman made a comment about how people with skin conditions shouldn't be in hot tubs and paraded herself and her daughter out. Hayden pretended it didn't matter. That she still felt beautiful on the inside. 

It was only when she joined a clinical trial for an experimental drug and her vitiligo began to recede that she "realized that having the skin condition affected me more than I thought it did," said Hayden, now 41, of Hood River, Oregon. 

The medicated cream she used as part of that trial, ruxolitinib, was  approved by the Food and Drug Administration  this summer. Late Wednesday, The New England Journal of Medicine published a study showing ruxolitinib  cream is extremely effective in about one-third of patients who use it for at least six months.

What is vitiligo and its treatment?

Somewhere between half a percent and 2% of people worldwide have vitiligo, which is now understood to be an autoimmune disorder, where the immune system attacks the cells in the skin that provide pigment.

Famous people with vitiligo include Michael Jackson, model Winnie Harlow, actor and director Jon Hamm, comedian Steve Martin, commentator and comedian Joe Rogan, and NFL player-turned coach Karl Dunbar.

The condition can be particularly distressing for people with naturally dark skin because the light blotches stand out even more.

Only one treatment has previously been approved by the FDA and it removes more coloration, to avoid blotchiness, rather than restoring the skin's natural color as ruxolitinib cream can sometimes do.

Right now, many patients are treated with steroids, which don't work well, or given controlled phototherapy sessions, which can be hard to access for people who live far from a center that offers it, said Dr. David Rosmarin, a lead author on the new study.

MORE: For patients with earliest stage of breast cancer, how much treatment is enough?

How ruxolitinib works 

The use of ruxolitinib cream reflects a new understanding of vitiligo, Rosmarin said. It works by tamping down an overactive immune response. "We are now better at modulating, rebalancing" that arm of the immune system, Rosmarin said. 

About 30% of the 450 people who received active treatment as part of two studies saw a dramatic improvement in facial pigmentation after six months. Up to half did after a year of treatment, indicating that the cream became more potent over time. More than 80% of people in both trials were white and only 3% to 5% were Black or Asian. 

Formulated as a cream ruxolitinib does not affect the whole body, so side effects are relatively minor, usually just some acne where the cream is used, Rosmarin said.

Ruxolitinib cream seems to work best on the head and neck, with hands and feet the hardest to repigment, Rosmarin said. It's not yet known whether someone can take ruxolitinib for a period of time and then stop, or whether vitiligo will return without constant dosing. 

Commercial insurers and Medicare have been covering ruxolitinib cream, Rosmarin said, now that there's "broad agreement in the medical community that it is a medical not cosmetic condition and treatment should be covered." One tube of the cream costs about $2,000 and can last anywhere from a few weeks to a few months, depending on how much skin needs to be covered.

The amount of time a patient had vitiligo didn't affect their likelihood of success.

People who had poliosis vitiligo, or a total loss of pigmentation leading to pure white hairs, did not improve on the drug, said Dr. Brett King, who was not directly involved in the study but consults for Incyte, the Delaware-based company that makes ruxolitinib cream and sells it under the brand name Opzelura.

Researchers are also developing other approaches to treating vitiligo for those who don't see much improvement with ruxolitinib cream, Rosmarin said.

The study and recent approval of ruxolitinib cream "sets a pathway for other treatments to hopefully move forward," he said. "This is just the start."

RESEARCH: These rats have human cells in their brains. They may help scientists understand autism and schizophrenia.

The origins of the new approach date to 2017 when King, an associate professor of dermatology at Yale University, decided to test a rheumatoid arthritis drug in a mouse that works in the same way as ruxolitinib. It seemed to help, so he gave it to a patient who had the condition "from nose to toes," he said. Her dramatic improvement "was our first clue" that his approach might work.

"When you have an observation, but in particular one anchored in science, not just in chance observation, it leads to paradigm shifts in how we think about disease and treat disease," King said.

The success with ruxolitinib will encourage other drug companies to develop vitiligo treatments, he said.

Because it takes so long to see a benefit from ruxolitinib cream, it would be useful to find a way of distinguishing patients who will respond well from those who won't, Dr. Liv Eidsmo wrote in an editorial accompanying the new study.

Eidsmo, a dermatologist and researcher at Karolinska University Hospital in Sweden, also pointed out that it's not clear what will happen if patients stop using the cream and raised concerns about the lack of diversity among trial participants, who were largely white. 

Still, she wrote, thanks to ruxolitinib, "patients with vitiligo finally have the hope of efficient treatments."

WHAT DOCS WANT YOU TO KNOW: Study raises questions about colonoscopies 

'It gave me back something I lost'

Hayden is one of those lucky patients. 

The cream has returned about 90% of the pigment to her face. Even her hands, considered the hardest to reach for the drug, have mostly cleared up.

"It gave me back something I lost," said Hayden, who was wearing a V-neck shirt and a thin gold necklace on a recent video call. On weekends, she no longer insists on wearing makeup before leaving the house.

An instructional coach in her town's school district, Hayden had almost no side effects from the cream and didn't find it a burden to spread on her face, chest and hands twice a day during the two-year trial. "It was just part of my morning routine," she said, "and it was part of my bedtime routine after I brushed my teeth."

The treatment changed her relationship with the sun. Before, she would wear high SPF sunblock, a hat and long sleeves if she was in the sun for long periods. With vitiligo, she said "you are either normal or burnt," there was no such thing as a tan.

During the trial, she said, she was encouraged to get limited amounts of sun exposure to promote skin regeneration. "Now, I feel like when I'm in the sunlight, it's regenerative instead of harmful," she said. "I have to be careful, but it's not the same burden as it was." 

Hayden said she's grateful to have been able to participate in the research to help others avoid some of the same challenges she's faced.

"That really kind of fueled my 'why' for engaging in the trial," she said. "Not just for my own hope and excitement – which it did 100% and I would do it again in a heartbeat – but also potentially having this available to other people living with vitiligo."

Contact Karen Weintraub at [email protected].

Health and patient safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial input.

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• 30 June 2020
• Correction 06 July 2020

Temprian Therapeutics: developing a gene-based treatment for vitiligo

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Charles Schmidt is a freelance writer in Portland, Maine.

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doi: https://doi.org/10.1038/d41586-020-01808-5

This article is part of Nature Outlook: The Spinoff Prize 2020 , an editorially independent supplement produced with the financial support of third parties. About this content .

Updates & Corrections

Correction 06 July 2020 : An earlier version of this profile gave the wrong specialty for Caroline Le Poole and the wrong campus for Northwestern University.

Mosenson, J. A. et al. Sci. Transl. Med. 5 , 174ra28 (2013).

Article   PubMed   Google Scholar  

Henning, S. W. et al. J. Invest. Dermatol. 138 , 2531–2539 (2018).

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Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the international Vitiligo Task Force-Part 2: Specific treatment recommendations

Affiliations.

• 1 Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hospital Saint-André, ImmunoConcept, CNRS UMR 5164, Bordeaux University, Bordeaux, France.
• 2 Department of Dermatology, Ghent University Hospital, Ghent, Belgium.
• 3 Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hospital Saint-André, BRIC, UMR 1312, Inserm, University Bordeaux, Bordeaux, France.
• 4 Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, The Netherlands.
• 5 Department of Dermatology, University Hospital of Nice, Nice, France.
• 6 Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
• 7 Department of Dermatology, Henry Ford Health, Detroit, Michigan, USA.
• 8 Department of Dermatology, University Hospital Henri Mondor, EpiDermE EA 7379, Université Paris-Est Créteil Val de Marne, Créteil, France.
• 9 Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.
• 10 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
• 11 Skin Research Institute of Singapore, ASTAR, Singapore, Singapore.
• 12 Department of Dermatology Integrated Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
• 13 Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan.
• 14 Department of Dermatology, Tufts University School of Medicine, Boston, Massachusetts, USA.
• 15 Chroma Dermatology, Pigment and Skin of Colour Centre, Wheelers Hill, Victoria, Australia.
• 16 Department of Dermatology, The Royal Children's Hospital, Parkville, Victoria, Australia.
• 17 Department of Dermatology, Westville Hospital, Durban, South Africa.
• 18 Deutscher Vitiligo-Bund e.V., Adelsdorf, Germany.
• 19 Department of Dermatology, Venereology & Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
• 20 Department of Dermatology, Kindai University Nara Hospital, Ikoma, Japan.
• 21 Vitiligo.nl, The Hague, The Netherlands.
• 22 Vitiligo International Patient Organisations, Paris, France.
• 23 Association Française du Vitiligo, Paris, France.
• 24 Department of Dermatology, Microbiology and Immunology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
• 25 Photodermatology and Vitiligo Treatment Unit, Israelite Hospital, Roma.
• 26 Department of Dermatology, College of Medicine, Dongguk University Ilsan Hospital, Goyang, Korea.
• 27 Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
• 28 Pigmentation Research and Therapeutics, Osaka Metropolitan University, Osaka, Japan.
• 29 Department of Dermatology, Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
• 30 Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
• 31 Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India.
• 32 Vitiligo & Pigmentation Institute of Southern California, Los Angeles, California, USA.
• 33 Skin Physicians Pte Ltd, Singapore, Singapore.
• 34 Department of Dermatology, Jaslok Hospital and Research Hospital and South Mumbai Dermatology Clinic, Mumbai, India.
• 35 Department of Dermatology, Faculty of Medicine Cairo University, Cairo, Egypt.
• 36 New Cross Hospital, The Royal Wolverhampton NHS Trust, Wolverhampton, UK.
• 37 Department of Dermatology, University Hospital Münster, Münster, Germany.
• 38 Department of Dermatology, Mohammed V University, Ibn Sina University Hospital, Rabat, Morocco.
• 39 Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Amsterdam Institute for Infection and Immunity, VU University, Amsterdam, The Netherlands.
• 40 Department of Dermatology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
• 41 Department of Dermatology, Clinica Dermatologica Moragas, Barcelona, Spain.
• 42 Dermatology, Andrology, and Venereology Department, Ain Shams University, Cairo, Egypt.
• 43 Unicamillus International University, Rome, Italy.
• PMID: 37715487
• DOI: 10.1111/jdv.19450

Background: The treatment of vitiligo can be challenging. Up-to-date agreed consensus recommendations on the use of topical and systemic therapies to facilitate the clinical management of vitiligo are currently lacking.

Objectives: To develop internationally agreed-upon expert-based recommendations for the treatment of vitiligo.

Methods: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in different online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence for different topics included in the algorithms. A survey was then given to a core group of eight experts to resolve the remaining issues. Subsequently, the recommendations were finalized and validated based on further input from the entire group during two live meetings.

Results: The recommendations provided summarize the latest evidence regarding the use of topical therapies (steroids, calcineurin inhibitors and Jak-inhibitors) and systemic therapies, including steroids and other systemic immunomodulating or antioxidant agents. The different modalities of phototherapies (NB-UVB, photochemotherapy, excimer devices and home phototherapy), which are often combined with other therapies, are also summarized. Interventional approaches as well as depigmentation strategies are presented for specific indications. Finally, the status of innovative and targeted therapies under development is discussed.

Conclusions: This international consensus statement culminated in expert-based clinical practice recommendations for the treatment of vitiligo. The development of new therapies is ongoing in vitiligo, and this will likely improve the future management of vitiligo, a disease that still has many unmet needs.

© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.

• Combined Modality Therapy
• Photochemotherapy*
• Phototherapy
• Steroids / therapeutic use
• Treatment Outcome
• Ultraviolet Therapy*
• Vitiligo* / drug therapy
• Vitiligo* / therapy

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FAQ Other Questions

Contrary to popular belief, vitiligo is not a cosmetic disorder but a systemic disease affecting the largest body organ and other vital systems, with multiple comorbidities. Fo...

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Extracts of the tropical fern Polypodium leucotomos appear to have beneficial properties for the vitiligious skin. Polypodium leucotomos (also classified as Polypodium aureum) a...

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Though it is not always easy to treat vitiligo, there is much to be gained by clearly understanding the diagnosis, the future implications, treatment options and their outcomes.

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Project Background

The study of multifactorial diseases, such as vitiligo, requires analysis of complex interplay of symptoms, treatments and outcomes across a large number of people. Population surveys and biobanks are indispensable research tools, required for downstream therapy development. Even small collections of biosamples may be extremely precious for researcher in academic institution or biopharma company.

Until recently, vitiligo researchers were generally limited to conducting studies on patient samples they could acquire themselves. When the Foundation started there were no centralized biological database along with the pre-existing body of the clinical management or the historical study data, which is required in order to proceed with the development of specific therapies. We have run a special investigation study to determine whether VRF shall establish its own biobank.

Then the project's leadership crafted a careful strategy for vitiligo biobank development, with special attention paid to the security and confidentiality of the donor's information. 'Future proofing' involves collecting and processing samples to permit the widest possible range of scientific uses, while avoiding approaches that would impede possible future uses.

We have started the first Vitiligo Biobank with a 100+ sample collection from the completed research project in genetics in late January 2013. Three months later, it held approximately 1,000 biosamples and detailed clinical profiles. Our target number is 10,000 samples and we encourage patients to donate samples . The primary biorepository is located in Moscow (Russia) with networked locations in 11 countries.

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Study reveals the economic burden for patients with vitiligo in the US is significant

by Elsevier

A novel study in the Journal of Investigative Dermatology , shows that patients with vitiligo incur significantly higher health care costs than people without this skin condition. The findings reveal an unmet need for cost-effective treatments and highlight the importance of fully identifying the drivers of economic burden for patients with vitiligo.

Lead investigator Khaled Ezzedine, MD, Ph.D., Department of Dermatology, AP-HP, Henri Mondor University Hospital, and Epidemiology in Dermatology and Evaluation of Therapeutics (EpiDermE)—EA 7379, Université Paris-Est Créteil (UPEC), explains, "Data regarding the economic burden of vitiligo are scarce and outdated. Our study quantifies the health care costs and health care resource utilization (HCRU) among patients with vitiligo. Determining medical costs will help identify the main expenditure predictors and spending patterns."

Vitiligo, a chronic autoimmune disorder that affects 0.5-2.0% of the United States population, is characterized by skin depigmentation caused by the loss of melanocytes. Patients with vitiligo incur direct costs associated with their condition through medical fees, pharmacy expenses, and out-of-pocket costs (e.g., sunscreens, protective clothing, cosmetic concealers, and camouflage products). They may also experience indirect costs owing to psychosocial effects, loss of work productivity, and lost opportunities (e.g., marriage, career choice, promotions, salary increases, or education).

Dr. Ezzedine continues, "Patients with vitiligo are often reported to have psychological problems , such as depression, anxiety, and shame, leading to low self-esteem and social isolation. Higher costs for patients with vitiligo than for persons without it may partly be explained by a higher risk of mental health conditions as well as other comorbidities among patients with vitiligo, including thyroid disease, diabetes, and alopecia areata that impact the cost of the disease."

For this retrospective cohort analysis, the Merative MarketScan Commercial Database, health care costs, and HCRU were evaluated for 49,512 patients with vitiligo compared to 99,024 people without vitiligo in the US between January 2007 and December 2021.

Outcomes included all-cause and vitiligo-related costs (2021 dollars) and all-cause HCRU, including mental health-related HCRU. Patients with vitiligo incurred significantly higher all-cause costs ($15,551 vs. $7,735) and vitiligo-related costs ($3,490 vs. $54) costs than controls. Mental health-related HCRU was also significantly higher among patients with vitiligo. Taken together, health care costs and HCRU were significantly higher among patients with vitiligo than among controls.

In this analysis, the increased costs were associated with significantly higher inpatient costs, ER visits, ambulatory visits, number of prescriptions and prescriptions costs, and other costs (e.g., medical equipment and home health care ), illustrating the importance of independently evaluating the economic burden of different skin conditions. The results from this study show that the economic burden of vitiligo was comparable with those of other well-studied dermatologic conditions, such as atopic dermatitis and psoriasis.

This study shows that the increased health care costs for patients with vitiligo versus those of non-vitiligo controls were driven by medical costs rather than pharmacy costs, and the increased HCRU was primarily the result of outpatient visits compared with inpatient or ER visits, which aligns with the main cost drivers identified in studies of the economic burden of atopic dermatitis and psoriasis.

Dr. Ezzedine concludes, "The health care costs and HCRU for patients in the US with vitiligo in this study were significantly higher than for patients without a vitiligo diagnosis. The economic burden was markedly higher for patients receiving treatment with systemic effects or with new mental health diagnoses than for the total vitiligo population. These findings reveal an unmet need for cost-effective treatments and highlight the importance of fully identifying the drivers of economic burden for patients with vitiligo."

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• General Dermatology
• Actinic Keratosis
• Precision Medicine and Biologics
• Rare Disease
• Psoriatic Arthritis
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• Skin Cancer
• Hidradenitis Suppurativa
• Pigmentary Disorders
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• Practice Management

Vitiligo’s Emerging Drug Pipeline

Ruxolitinib cream 1.5% may soon be the first FDA-approved treatment for repigmentation of vitiligo. Experts share what dermatologists need to know regarding efficacy, safety, and cost of this topical drug.

Vitiligo’s cause is unknown, but its detrimental effect on patients’ quality of life is clear. 1 Medications for this skin disease may work slower than patients anticipate, causing them to feel hopeless, according to Pearl E. Grimes, MD, FAAD, a clinical professor of dermatology at the David Geffen School of Medicine at UCLA and founder and director of the Vitiligo and Pigmentation Institute of Southern California in Los Angeles.

Discouraged patients may give up and quit treatment, creating tension in their relationship with their physician, Grimes continued. “So many patients that I see come in with the mindset that there is going to be a quick fix for vitiligo. When they don’t see changes in perhaps 2 weeks or 4 weeks, they abandon treatment,” she said.

But the future—possibly the very near future—holds promise. Treatments in the pipeline offer quicker results and a relatively safe profile; there’s even hope of one day finding a cure for this disease, said Seemal Desai, MD, FAAD, an assistant professor in the Department of Dermatology at UT Southwestern and founder and director of Innovative Dermatology in Dallas, Texas. But meanwhile, unmet needs remain, Grimes and Desai agreed.

The drugs’ different mechanism of action will tackle inflammation, perhaps by targeting inflammatory cytokine pathways and increasing production of melanocytes, Desai said. “I think the mechanism [of action] helps to explain and [helps us] better understand the pathophysiology of the disease,” he said. Approval of the first such treatment for vitiligo may be imminent: Ruxolitinib cream 1.5% (Opzelura; Incyte), a topical Janise kinase (JAK) inhibitor, initially had a Prescription Drug User Fee Act (PDUFA) date of April 18, 2022, but has since been extended 3 months to July 18, 2022. 2,3

Patients who have active unstable disease or chronic and refractory disease or have head and neck involvement are ideal candidates for the new medications. Desai emphasized that these treatments, especially JAK inhibitors, are meant for specific disease states. “These aren’t going to be the type of product in...a 1-pound jar that patients can slather [on from] head to toe,” he said. Instead, they are meant to be used in conjunction with other therapies such as oral antioxidants, systemic steroids, and narrow-band UV-B for targeted phototherapy. Grimes agreed with Desai’s comments, adding that she does not think ruxolitinib 1.5% cream will replace current treatments, which, when used in combination—particularly for lesions on the face and neck—do work.

The issue, she continued, is how the role of existing treatments might change. “My guess is that we will use these drugs as a primary and as a secondary approach,” Grimes said. Other treatments on the horizon are IL-15 and CXCL10 blockades and other more selective JAK inhibitors, such as TYK and TEC inhibitors, Desai said. 4,5

The broadening treatment horizon raises a burning question: Will these treatments be affordable and accessible? Grimes said the drugs have the potential to be expensive and, if not covered by insurance, cost prohibitive. Many physicians will have to work with insurance carriers to help patients get ruxolitinib covered, she said.

Grimes is hopeful that vitiligo will soon have a robust armamentarium, mirroring that of psoriasis, and shares Desai’s hope of a cure.

For more details, visit dermatologytimes. com, where Grimes and Desai discuss onboarding patients, the risks and rewards of treatments, safety signals to heed when beginning a new regimen, and what the latest in research.

References:

• Vitiligo. American Osteopathic College of Dermatology. Accessed April 7, 2022. https://www.aocd.org/page/Vitiligo
• Incyte announces acceptance and priority review of sNDA for ruxolitinib cream (Opzelura) as a treatment for patients with vitiligo. Incyte. Accessed Decem- ber 15, 2021. https://investor.incyte.com/press-releases/press-releases/2021/ Incyte-Announces-Acceptance-and-Priority-Review-of-sNDA-for-Ruxolitinib- Cream-Opzelura-as-a-Treatment-for-Patients-with-Vitiligo/default.aspx
• FDA extends review of Opzelura for skin condition. Formulary Watch®. March 14, 2022. Accessed April 19, 2022. https://www.formularywatch.com/view/ fda-extends-review-of-opzelura-for-skin-condition
• Evaluation of Amg 714 for Vitiligo (REVEAL). ClinicalTrials.gov. Updated November 1, 2021. Accessed April 6, 2022. https://clinicaltrials.gov/ct2/show/ NCT04338581
• Rashighi M, Agarwal P, Richmond JM, et al. CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci Transl Med. 2014;6(223):223ra23. doi:10.1126/scitranslmed.3007811

VYNE Therapeutics Provides Updates on VYN201 for Nonsegmental Vitiligo and VYN202 for Inflammatory Diseases

ReV Up Your Vitiligo Treatment Strategies

Patients With Vitiligo Have Decreased Risk of Subsequent Pulmonary Embolism, Peripheral Vascular Disease

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Study Becomes First to Demonstrate Efficacy of Topical Isoniazid in Melasma

Fire Needle Combined With Excimer Laser Safe, Effective Therapy for Vitiligo, Review Finds

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MINI REVIEW article

Advances in vitiligo: update on therapeutic targets.

• Department of Dermatology, Jiangsu Province People’s Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China

Vitiligo, whose treatment remains a serious concern and challenge, is an autoimmune skin disease characterized by patches of depigmentation. The increasing application of molecular-targeted therapy in skin diseases, such as psoriasis and systemic lupus erythematosus, has dramatically improved their condition. Besides, there is a favorable effect of repigmentation in the treatment of the above diseases combined with vitiligo, implying that molecular-targeted therapy may also have utility in vitiligo treatment. Recently, the role of cytokine and signaling pathways in vitiligo pathogenesis are increasingly recognized. Thus, investigations are underway targeting the molecules described above. In this paper, we present a synopsis of current practices in vitiligo treatment and introduce the improvement in identifying new molecular targets and applying molecular-targeted therapies, including those under development in vitiligo treatment, providing valuable insight into establishing further precision medicine for vitiligo patients.

1 Introduction

Vitiligo is a primary, circumscribed, or generalized depigmentation of the skin and mucosa, related to genetic factors, self-destruction of melanocytes, cytokines, autoimmunity, and oxidative stress ( 1 ). While the detailed molecular mechanisms still require further investigation. In recent years, various studies have showed that the IFN-γ-CXCL9/10-CXCR3 axis appears to be important in vitiligo, via inhibiting melanogenesis, inducing apoptosis of melanocytes, and further recruiting T cells to the skin. These are all involved in the JAK/STAT pathway. In addition, cytokine, including HSP70i, IL-15, IL-17/23, TNF as well as wnt signaling pathway, Tregs, miRNAs have also been proved to be involved in the pathogenesis of vitiligo.

Vitiligo can be treated by different modalities of phototherapy, surgical procedures, and topical therapies, such as glucocorticosteroids, immunosuppressive agents, calcineurin inhibitors, and vitamin D. However, current treatments for vitiligo remain suboptimal, which may not be equally effective in all vitiligo patients, and it would be inconvenient for patients to visit clinics for phototherapy. Targeted therapies, such as biologics targeting cytokines and small-molecule inhibitors targeting intracellular signaling molecules, are recently emerging as promising therapeutics for autoimmune diseases. Their applications also promote our understanding of the detailed molecular mechanism of vitiligo and are essential for guiding a more precise vitiligo treatment. In this article, details of the roles that related cytokines and pathways play as well as the efficacy of targeted therapy have been described.

2 Current treatment

Topical, systemic treatment, and phototherapy are useful for stabilization and repigmentation of vitiligo. Treatment modalities are chosen in the individual patient, based on disease severity, disease activity (stable versus progressive disease), patient preference (including cost and accessibility), and response evaluation. For rapidly progressive disease, low-dose oral glucocorticoids and phototherapy are useful in stabilizing the disease. Therapeutic options for stable, segmental vitiligo include topical therapies (eg, topical corticosteroids, topical calcineurin inhibitors), targeted phototherapy, and surgical therapy (tissue grafts and cellular grafts) ( Table 1 ) ( 14 ). In recent years, attempts have been made to improve the repigmentation of vitiligo phototherapy by combination therapies, including NB-UVB with glucocorticoids ( 15 ), and topical calcineurin inhibitors ( 16 ). While their positive results were not confirmed in all studies. However, the method of treatment described, which were nonspecific, general, off-label, non-targeted with modest efficacy led to the problem of recurrence after stopping treatment. Therefore, efforts should be made to achieve a more comprehensive understanding of vitiligo pathogenesis to develop novel effective therapies ( Table 2 ).

Table 1 Current treatment modalities for vitiligo.

Table 2 Molecular-targeted therapies for the treatment of vitiligo.

3 Small molecules

3.1 emerging therapeutics targeting janus-activated kinase (jak) signaling.

The Janus kinases family consists of JAK1, JAK2, JAK3, and TYK2, which is engaged in the important JAK/STAT pathway, exhibiting pleiotropic effects on transducing multiple extracellular signals involved in regulating proliferative signaling, differentiation, migration, and apoptotic properties ( 28 ).

There are no licensed JAK/STAT inhibitors available against dermatological problems, however, some of them (ruxolitinib and tofacitinib) are used to treat other conditions such as myelofibrosis and RA. However, off-label usage of these medications in the treatment of vitiligo has shown promising outcomes.

JAK-STAT inhibitors promote Sonic Hedgehog and Wnt signaling in epidermal pigmentation, with the former inducing the migration, proliferation, and differentiation of melanocyte ( 29 ). Expanding our knowledge of these medications’ efficacy and safety profiles, as well as their use in dermatological conditions, is critical for establishing their risk-benefit ratio.

3.1.1 Tofacitinib

Tofacitinib is an FDA-cleared JAK1/3 inhibitor for treating RA, PsA, and active ulcerative colitis.

Tofacitinib 5-10 mg QD/BID has demonstrated superior efficacy against vitiligo, with improvement ratios of 5.4% in 5/10 patients with sun-exposed areas or areas treated only with phototherapy ( 30 ), and a reduced rate in vitiligo area scoring index (VASI) score of 4.68 at baseline to 3.95 at 5 months in another trial ( 31 ). In addition, a decline in the number of CD8 + T cells and chemokines, such as CXCL9 and CXCL10 has been observed after tofacitinib treatment, but no variations were observed for the percentage of melanocyte-specific T cells ( 30 ).

Unfortunately, this oral medication is associated with a host of systemic side effects, including infections, malignancies, and cytopenia. Thus, topical JAK inhibitors may be more preferred. 11 vitiligo patients treated with 2% tofacitinib cream twice a day in conjunction with NB-UVB therapy thrice-weekly demonstrated a mean improvement of 70% in facial VASI. There was also a significant difference between facial and non-facial lesions (P=0.022) ( 32 ).

3.1.2 Ruxolitinib

Ruxolitinib, the first Jakinib to get FDA approval, is a JAK1/2 inhibitor designed to deal with polycythemia vera and intermediate- and high-risk primary myelofibrosis ( 33 ).

Studies have shown that except for JAK inhibition, ruxolitinib also inhibited the differentiation and migration of DCs in vitiligo, increasing CD8 + cytotoxic T cell responses ( 34 ). In a double-blind phase 2 trial, 157 recruited vitiligo patients were randomized, in a 1:1:1:1:1 ratio, to receive topical ruxolitinib cream 1.5% BID, 1.5% QD, 0.5% QD, 0.15% QD, or a vehicle for 24 weeks, with the result showing considerably decreased CXCL9 and CXCL10 expression in 1.5% BID and 1.5% QD groups, and more individuals in groups receiving ruxolitinib cream 1.5% BID, 1.5% QD and 0.5% QD achieving F-VASI50, during which 1.5% BID group produced the highest responses in F-VASI50 (58%), F-VASI75 (52%), and F-VASI90 (33%). Besides, three positive responsive groups demonstrated significant repigmentation of vitiligo lesions and acceptable tolerability with a follow-up period of 52 weeks ( 35 ). Vitiligo on the face appears to respond more vigorously to therapy than non-facial lesions, reinforced by a 20-week, open-label trial in which patients with significant facial involvement experienced a 76% improvement in facial VASI scores ( 36 ). Furthermore, better repigmentation rates could be achieved both in oral and topical ruxolitinib treatment combined with phototherapy ( 37 ).

3.1.3 Baricitinib

Baricitinib is a selective JAK1/2 inhibitor that inhibits signal transduction of numerous proinflammatory cytokines ( 38 ), approved for the treatment of RA. To our knowledge, there was only one case report describing repigmentation in vitiligo patients with baricitinib 4 mg daily for the treatment of RA. Besides, an ongoing phase 2 trial (NCT04822584) in which patients received a combination therapy of baricitinib 4mg/d and phototherapy is being performed.

3.1.4 Ifidancitinib (ATI-50002)

Ifidancitinib is another dual JAK1/3 inhibitor for alopecia areata treatment, which is now undergoing phase II clinical trials for its application in vitiligo treatment. Patients with facial NSV(NCT03468855) receiving topical ATI-50002 BID for 24 weeks presented with an improved F-VASI and the Vitiligo Noticeability Scale (VNS) ( 39 ).

3.1.5 Ritlecitinib (PF-06651600) and Brepocitinib (PF-06700841)

Ritlecitinib, an irreversible inhibitor of JAK3 and tyrosine kinase applicable to the treatment of moderate-to-severe RA ( 40 ) and Brepocitinib, a TYK2/JAK1 inhibitor, are currently undergoing evaluation of their efficacy and safety profile in active NSV in combination with phototherapy (NCT03715829) ( 41 ).

3.1.6 Cerdulatinib (PRT062070)

Cerdulatinib, an SYK/JAK dual kinase inhibitor ( 42 ), has been assessed (NCT04103060) for its safety and tolerability for vitiligo treatment in topical formation (0.37% cerudulatinib gel BID).

However, additional studies are needed to determine the best-suited drug regimen and recommended dosage forms and doses to attain the optimum curative effect and minimal toxicity. As the occurrence of depigmentation after the withdrawal of JAK inhibitors, the mechanisms underlying need further exploration, and more work need to be done to corroborate the effectiveness in combination with other therapies.

3.2 Wnt signaling and its agonists

It has been shown that Wnt/β-catenin signaling plays a pivotal role in the proliferation, migration, and differentiation of melanocytes in vitiligo patients ( 29 ), which could be inhibited by oxidative stress ( 43 ). In addition, the Wnt/β-catenin pathway participates in the activation of MITF and its downstream enzymes ( 44 ). Intradermal injection of IWR-1 (inhibitor of Wnt response 1), a chemical inhibitor of β-catenin activation, and small interfering RNA (siRNA) against Wnt7α suppressed the number of epidermal melanocytes ( 45 ). This evidence suggested that stimulation of Wnt signaling may be an adjuvant therapy for vitiligo treatment. Micro-injury ( 46 ) as well as some phenanthridine-derived Wnt-specific agonists binding with the Axin protein have been proved to promote melanogenesis ( 47 ) and induce repigmentation.

3.3 Emerging therapeutics targeting microRNAs (miRNAs)

MiRNAs, which are a highly conservative small class of non-coding RNA molecules, participate in mRNA expression regulation via degradation or repression of mRNA translation ( 48 ). Previous studies have demonstrated that miRNAs were associated with genetic polymorphisms (e.g., miR-196a-2 rs11614913), immune response (e.g., miR-133b, miR-224-3p, miR-4712-3p, miR-3940-5p, miR-21−5p), oxidative stress (e.g., miR-135a, miR-9, miR-34a, miR-183, miR-184, miR-1, miR-25, miR-211, miR-383, miR-577, miR-421) and melanocyte functions (e.g., miR-434-5p, miR-330-5p, miR-137, miR-148, miR-145, miR-155, miR-203, miR-125, miR-377, miR-2909, miR-200c, hsa-miR-149-5p) ( 49 – 54 ), participating in pathological mechanism of vitiligo. These findings suggest that miRNAs may be involved in vitiligo pathogenesis via the modulation of vital genes expression in melanocytes and serve as novel therapeutic targets for vitiligo therapy.

There are two strategies for the therapeutic application of miRNAs: 1) anti-miRNAs, locked-nucleic acids (LNA), or antagomiRs ( 55 ) can be used to counteract the over-activation of miRNA. Short tandem target mimic (STTM)- miR-508-3p has been validated to upregulate SOX6 expression, leading to increased expression of key melanogenic genes CREB, MITF, TYR, and TYRP1/2 with increased melanogenesis ( 56 ). Besides, STTM-miR-143-5p also upregulates the expression of MYO5A, leading to an increase in the level of MITF, TYR, TYRP1, melanin, and Rab27a ( 57 ). 2) miRNA replacement, involving the reintroduction of a gene-suppressor miRNA mimic or AAV (adeno-associated virus)-mediated miRNA gain-of-function to modulate gene expression ( 55 ). A study demonstrated that the migratory capacity of melanocytes was altered by the application of miR-211 mimic through the p53-TRPM1/miR-211-MMP9 axis ( 58 ).

3.4 Emerging therapeutics targeting regulatory T-cells (Tregs)

Tregs are a suppressive CD4 + T cell subset that possesses a capacity to suppress self-reactive T cell activation and expansion ( 59 ). A clear decrease in Treg cells was observed in vitiligo skin within lesional, non-lesional, and perilesional sections ( 60 ), indicating that increasing the number of Tregs with normal function might be an important therapeutic intervention for vitiligo treatment.

Infusing purified populations of Tregs is the most direct way for the supply of Tregs. The current methods mainly include polyclonally-expanded Tregs, antigen-specific Tregs, and engineered Treg cells. In a mouse model of vitiligo, adoptive transfer of polyclonal Tregs may be effective in the short-term ( 61 ), which might however impart systemic immunosuppression ( 62 ). Besides, a TCR transgenic mouse with spontaneous vitiligo, receiving CAR Tregs treatment, developed a significant delay in depigmentation ( 63 ).

However, a limitation of infusing purified populations of Tregs might be the technical difficulty for therapeutic agent delivery to specific cells. A topical application of Tregs or the combination with CCR4 Treg homing receptor ligand CCL22 ( 64 ) by local needle-free jet injection of DNA ( 20 ) or CCL22-encoding plasmid DNA ( 64 ) may help resolve that issue. Besides, various strategies have been applied towards the modulation of Tregs function by targeting Treg-intrinsic pathways and functional modulators for Tregs. HO-1, a functional modulator of Tregs, was decreased in vitiligo Tregs. Treatment with Hemin, an agonist of HO-1, was found to enhance HO-1-induced restoration of Tregs function by up-regulating IL-10 expression ( 65 ). In addition, therapeutic method for microbiota modulation, such as neomycin treatment can significantly delay depigmentation in vitiligo mice and promote the infiltration of Tregs to the skin ( 66 ). Rapamycin, an inhibitor of PI3Kakt-mTORC1 signaling ( 67 ), efficiently halts the depigmentation process by increasing the abundance of Treg in h3TA2 mice, which effect lasted till 6 weeks after treatment ( 61 ). At present, a phase 2 clinical trial(NCT05342519) is underway for assessing the efficacy of the application of 0.1% topical rapamycin ( 68 ) (2022). In addition, nanoparticles containing rapamycin and autoantigen HEL46-61(NPHEL46-61/Rapa) were synthesized, the administration of which halted the disease progression ( 69 ). Also, the calcium-NFATc1-signaling pathway may be involved in defective Tregs function, indicating a potential therapeutic target for vitiligo treatment ( 70 ).

4 Cytokine-targeted therapies

Multiple monoclonal antibodies are available for vitiligo treatment, targeting IFN-γ, CXCL10, CXCR3, HSP70i, IL-15, IL-17/23, and TNF. In addition to full-size immunoglobulin, affibodies and nanobodies, composed of considerably smaller proteins, are currently being developed, which have higher bioavailability as well as affinity and specificity to the targeted molecules.

4.1 IFN-γ and the inhibitors

The IFN-γ-CXCL9/10-CXCR3 axis may be crucial for vitiligo pathogenesis, contributing to disease progression by inhibiting melanogenesis, inducing apoptosis of melanocytes, and further recruiting T cells to the skin ( Figure 1 ) ( 71 ). A study showed a higher expression of IFN-γ mRNA in non-lesional and perilesional skin, especially in active vitiligo ( 72 ), which is associated with disease activity ( 73 ).

Figure 1 1) The immune pathogenesis of vitiligo: (A) CD8 + T cell expression of IFN-γ in vitiligo lesions activated the JAK/STAT pathway after binding to IFN-γ receptor, thus facilitating the release of CXCL9/10. The binding of CXCL9/10 to CXCR3 increased CXCR3+ T cells recruitment; (B) Maintenance of vitiligo lesions was influenced by the function of IL-15-dependent TRM cells, which produce IFN-γ and TNF-α. 2)Targeted therapeutic interventions in vitiligo mainly include therapies targeting IFN-γ-CXCL9/10-CXCR3 axis (IFN-γ neutralizing antibody, CXCL10 neutralizing antibody, and CXCR3 depleting antibody, as well as JAK inhibitors), anti-CD122 antibody (IL-15 receptor subunit) to decrease IFN-γ production and deplete autoreactive CD8 + TRM cells, TNF inhibitor to inhibit autoantibody production, and PD-L1 fusion protein to reduce the numbers of melanocyte-reactive T cells.

Anti-IFN-γ can have been proved to be effective in rheumatoid arthritis (RA), multiple sclerosis (MS), prevention of corneal rejection, autoimmune skin diseases, and others. In a recent study, vitiligo induction mice, treated with intraperitoneal injection with IFN-γ neutralizing antibody (XMG-6) at a dose of 100-500 μg twice a week, presented with significant improvement of depigmentation ( 17 ), with the same trend observed in vitiligo patients. Four patients who received intradermal perilesional injections presented with repigmentation of the treated area and boundary retreat ( 74 ). More research is warranted to be initiated for further definition of the role that IFN-γ plays in vitiligo and to examine whether IFN-γ neutralization would be more viable in reversing skin depigmentation.

4.2 CXCL10 and the inhibitors

Recent studies report a Th1/IFN-γ immune response in both human and a mouse model of vitiligo that involves elevated CXCL9, 10, and 11 productions, among which CXCL10 participated in the targeted migration of T cells ( 18 ), triggering an immune cell infiltration at the early stage ( 72 ), and involved in the downregulation of keratinocyte glycoprotein non-metastatic melanoma protein B (GPNMB) ( 75 ). A study showed that mice receiving CXCL10 neutralizing antibodies developed more repigmentation after 4 weeks’ treatment, which continued for an additional 4 weeks ( 18 ), thereby supporting CXCL10 suppression as a great therapeutic strategy.

4.3 CXCR3 antibodies

CXCR3 has been proved to be expressed in skin lesions, autoreactive T cells ( 18 ), and the vast majority of skin infiltrating CD8 + resident memory T cells (TRM), which stimulate the secretion of IFN-γ and TNF-α ( 76 ).

In a study, vitiligo mice with >75% depigmentation on their tails are treated with CXCR3 depleting antibodies for 7-8 weeks, which significantly reversed the clinical disease in a perifollicular pattern and a diminution of PMEL in the epidermis, with slightly reduced host CD8 + T cell numbers ( 19 ) compared to neutralizing antibody treatment ( 18 ). Although these results are preliminary, they may provide justification for further studies in targeting CXCR3 in vitiligo ( 19 ), which proposes the use of a depleting Ab to create a greater clinical efficacy by removing autoreactive cells rather than modulating their migration phenotype.

4.4 Inducible HSP70 (HSP70i) DNA

Indeed, HSP70i is the core participant in vitiligo predominantly through HSP70i-plasmacytoid dendritic cells (pDCs)-IFN-α-CXCL9 and CXCL10-cytotoxic T lymphocyte (CTL) axis. Pmel-1 mice vaccinated with HSP70i encoding DNA exhibited significant depigmentation, rarely seen in models knockout for HSP70i, indicating that elevated HSP70i expression alone would be enough to induce depigmentation in vitiligo prone animals ( 77 ). A study revealed that the expression of HSP-70 mRNA in skin lesions of active vitiligo patients was much higher ( 78 ), correlated with the disease activity.

Blocking HSP70i activity might have the potential to reverse vitiligo development. A recent study showed that a Sinclair swine, receiving HSP70iQ435A-encoding DNA treatment, showed remarkable repigmentation with an initial influx of T cells and increased CD4/CD8 ratios ( 20 ), which was also detected in mice with HSP70i Q435A -encoding DNA treatment, resulting in 76% restoration of skin pigmentation. Furthermore, the treatment halted T cells accumulation and transition to T cell phenotype in mice and human skin, engaging HSP70i Q435A DNA delivery as a potent effective therapeutic intervention for vitiligo ( 79 ).

4.5 IL-15 and the inhibitors

It has been established that IL-15 seems to participate in IL-17 regulation and maintenance of TRM signals ( 80 ), with the latter responsible for long-term maintenance and potential relapse of vitiligo ( 81 ). The study has demonstrated a higher serum level of IL-15 in vitiligo patients than in controls, highly associated with epidermal H 2 O 2 content and the disease activity ( 82 , 83 ).

In vitiligo mice, an anti-CD122 antibody that targets IL-15 signaling was reported to effectively reverse depigmentation. Anti-CD122 therapy, either systemically or locally, decreases TRM-induced IFN-γ production and results in long-term repigmentation. These findings consider CD122-targeted drugs as a valid therapy method, which results in effective and long-lasting responses in vitiligo and other tissue-specific autoimmune disorders involving TRM ( 21 ).

4.6 PD-1/PD-L1 pathway

Involvement of the PD-1/PD-L1 pathway has been shown in many autoimmune diseases, including RA, MS, and vitiligo. PD-L1 expression was found limited in normal skin, and only expressed on dermal T cells, and increased in primary melanocytes and fibroblasts after exposure to IFN-γ. No such effect was seen in vitiligo patients, indicating the absence of self-protection ability for melanocytes against T-cell attack during vitiligo pathogenesis. In agreement with this, treatment with PD-L1 fusion protein reduced the numbers of melanocyte-reactive T cells, inhibited the activation of Vβ12-expressing T cells, and increased Tregs numbers, reversing depigmentation in a Pmel-1 T-cell receptor transgenic vitiligo mouse model ( 26 ). However, PD-L1 treatment may still call for extended phototherapy treatment, especially NB-UVB therapy, which likely upregulates PD-L1 expression in an NF-κB-dependent manner ( 84 ), indicating a combination use of local PD-1/PD-L1 agonistic treatment and NB-UVB therapy as a promising option.

4.7 Other cytokine-targeted therapies under investigation

4.7.1 il-17/23 and the inhibitors.

Studies on the effect of IL-17/23 in vitiligo resulted in contradictory findings. On one hand, Th17 cells and IL-17 in vitiligo patients may inhibit function-related factors, repress melanogenesis, and dramatically induct other Th17 type cytokines as well as IL-1β production from dermal fibroblasts and keratinocytes ( 85 ). Elevated Th17 cells and IL-17/23 levels in skin lesions and serum of vitiligo patients, were positively correlated with disease activity ( 86 , 87 ), and decreased after narrowband ultraviolet B (NBUVB) treatment ( 88 ). Primary melanocyte culture showed an increased expression of MITF and its downstream genes, increased melanin pigment, and cell proliferation after blockade with anti-IL-17RA ( 22 ). Besides, incidences of repigmentation have been documented in ustekinumab treatment of vitiligo ( 23 ). However, secukinumab treatment in patients with active non‐segmental vitiligo (NSV) contributed to disease progression in 7/8 patients with no general reduction in CXCL9/10, sCD25/27, Th1 cells, or cytotoxic cells, resulting in early termination of study ( 89 ). There are also reports of ustekinumab-induced new-onset vitiligo and alopecia areata. The above studies showed IL-17/23 signal may not play a direct role in vitiligo pathogenesis, which needs further investigation to confirm this conjecture.

4.7.2 TNF and the inhibitors

As an anti-inflammatory mediator, TNF-α is considered to play a role in vitiligo, which may promote apoptosis in melanocytes, induce B-cell activation, increase autoantibody production, and inhibit melanogenesis ( 90 ). Recent data has shown a significantly higher expression of TNF-α in vitiligo skin. TNF inhibitors are beneficial in the treatment of plaque-type psoriasis, psoriatic arthritis (PsA), RA, and inflammatory bowel disease (IBD), arousing growing interest in their use in vitiligo.

Infliximab is a chimeric anti-TNF-α monoclonal antibody specifically binding to both soluble and membrane-bound TNF ( 91 , 92 ). Intravenous infliximab is widely licensed in the treatment of RA, psoriasis, ankylosing spondylitis (AS), IBD, uveitis, and Behcet’s disease. A 24-year-old patient with ankylosing spondylitis and refractory vitiligo improved significantly following six months of infliximab therapy at a dose of 5mg/kg intravenously in weeks 0, 2, and 6, and then every eight weeks for ten months ( 24 ). Besides, Etanercept is a monoclonal antibody targeted against TNF-α ( 93 ), which has been approved for the treatment of RA, juvenile RA, AS, psoriasis, and PsA. Treatment with etanercept 50 mg subcutaneously once or twice weekly for at least 2 months has shown a great curative effect on established vitiligo ( 94 ).

However, it has been shown that anti‐TNF‐α agents, especially adalimumab and infliximab ( 95 ), may exacerbate established vitiligo and induce new-onset vitiligo during treatment of other autoimmune diseases, including AS ( 96 ), Crohn’s disease ( 97 ), ulcerative colitis ( 98 ), psoriasis ( 99 ), and RA ( 100 ). The mechanism responsible for the TNF-α inhibitors-induced vitiligo is not fully understood. On the one hand, TNF-α inhibitors may increase the nucleosome-mediated autoantibody formation, interfere with the cytotoxic T-cell suppression of autoreactive B cells, and decrease Treg synthesis and activation. Additionally, infliximab increases pDC-produced IFN-γ, participating in further T cells recruiting. Although very rare, new-onset or exacerbations of vitiligo can occur in the anti‐TNF‐α treatment of other autoimmune diseases, the risk of which must not be ignored.

4.7.3 Rituximab

Rituximab has specific affinity for the B-lymphocyte transmembrane protein, CD20, which is expressed on B cells ( 101 ), participating in the activation of the CD8 + T cells and the ensuing autoreactive reaction ( 102 ). Rituximab is licensed for the treatment of lymphomas, leukemias, transplant rejection crisis, and a series of autoimmune diseases ( 103 , 104 ). An intravenous infusion of Rituximab was administered to five active disseminated vitiligo patients, the three of whom exhibited a considerable improvement in both the disease’s symptoms and histology ( 25 ).

4.7.4 Abatacept

Abatacept, a fusion protein consisting of IgG1 coupled to the extracellular domain of CTLA-4 via the immunoglobulin’s Fc region, was licensed for treating moderate to severe RA. Ten eligible patients with active vitiligo have been included to receive self-injections of 125mg abatacept weekly from week 0 to week 24. Secondary endpoints will be evaluated during a 32-week follow-up visit ( 105 ).

5 Future therapeutic prospects

As a future direction, new therapeutic approaches should be developed to reduce vitiligo progression. Among the new approaches being developed, the strategy of targeting the IFN-γ-CXCL9/10-CXCR3 axis has been clinically tested. OPZELURA has been indicated for the topical treatment of nonsegmental vitiligo in adult and pediatric patients 12 years of age and older. MiRNA-based therapeutics are also in development. However, the absence of organ or tissue selectivity may also lead to off-target side effects, which must be considered and excluded in the process of miRNA-based therapeutics development. Besides, a suitable vector system, as well as the assurance of chemical and biological stability should also be taken into account. Adoptive Treg cell therapy has also been the research hotspot in recent years. However, it has always been a difficult point for reassurance for safety and the development of the delivery system.

Treating vitiligo remains a challenge. As is presented in this paper, a greater variety of precision treatments is currently being studied. With a better understanding and further validation of these therapeutic targets, patients can be stratified to achieve individualized treatment.

6 Conclusion

Current models of treatment for vitiligo are often nonspecific and general. Various therapy options are available for active vitiligo patients, including systemic glucocorticoids, phototherapy, and systemic immunosuppressants. While stable vitiligo patients may benefit from topical corticosteroids, topical calcineurin inhibitors, phototherapy, as well as transplantation procedures. Recently, a better understanding of the pathophysiological processes of vitiligo led to the advent of novel targeted therapies. To date, JAK inhibitors are the only category that has been proved to have a good tolerability profile and functional outcomes in vitiligo treatment, even though the risk of activation of latent infection and systemic side effects still existed, like other immunosuppressive agents. Research is in progress to investigate the important cytokines involved in the pathogenesis of vitiligo, including IFN-γ, CXCL10, CXCR3, HSP70i, IL-15, IL-17/23, and TNF, the blockade of which has undergone preliminary attempts in animal models and some patients. In addition, studies on miRNA-based therapeutics as well as adoptive Treg cell therapy are still primary, and more studies are necessary.

Author contributions

YFF and YL contributed to the conceptual design, writing, editing, and generation of figures for this manuscript. All authors contributed to the article and approved the submitted version.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: vitiligo, targeted therapy, JAK inhibitors, biological, treatment, miRNA - microRNA, Treg

Citation: Feng Y and Lu Y (2022) Advances in vitiligo: Update on therapeutic targets. Front. Immunol. 13:986918. doi: 10.3389/fimmu.2022.986918

Received: 05 July 2022; Accepted: 04 August 2022; Published: 31 August 2022.

Reviewed by:

Copyright © 2022 Feng and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Yan Lu, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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New treatment could reverse hair loss caused by an autoimmune skin disease

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Researchers at MIT, Brigham and Women’s Hospital, and Harvard Medical School have developed a potential new treatment for alopecia areata, an autoimmune disorder that causes hair loss and affects people of all ages, including children.

For most patients with this type of hair loss, there is no effective treatment. The team developed a microneedle patch that can be painlessly applied to the scalp and releases drugs that help to rebalance the immune response at the site, halting the autoimmune attack.

In a study of mice, the researchers found that this treatment allowed hair to regrow and dramatically reduced inflammation at the treatment site, while avoiding systemic immune effects elsewhere in the body. This strategy could also be adapted to treat other autoimmune skin diseases such as vitiligo, atopic dermatitis, and psoriasis, the researchers say.

“This innovative approach marks a paradigm shift. Rather than suppressing the immune system, we’re now focusing on regulating it precisely at the site of antigen encounter to generate immune tolerance,” says Natalie Artzi, a principal research scientist in MIT’s Institute for Medical Engineering and Science, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, and an associate faculty member at the Wyss Institute of Harvard University.

Artzi and Jamil R. Azzi, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, are the senior authors of the new study , which appears in the journal Advanced Materials . Nour Younis, a Brigham and Women’s postdoc, and Nuria Puigmal, a Brigham and Women’s postdoc and former MIT research affiliate, are the lead authors of the paper.

The researchers are now working on launching a company to further develop the technology, led by Puigmal, who was recently awarded a Harvard Business School Blavatnik Fellowship.

Direct delivery

Alopecia areata, which affects more than 6 million Americans, occurs when the body’s own T cells attack hair follicles, leading the hair to fall out. The only treatment available to most patients — injections of immunosuppressant steroids into the scalp — is painful and patients often can’t tolerate it.

Some patients with alopecia areata and other autoimmune skin diseases can also be treated with immunosuppressant drugs that are given orally, but these drugs lead to widespread suppression of the immune system, which can have adverse side effects.

“This approach silences the entire immune system, offering relief from inflammation symptoms but leading to frequent recurrences. Moreover, it increases susceptibility to infections, cardiovascular diseases, and cancer,” Artzi says.

A few years ago, at a working group meeting in Washington, Artzi happened to be seated next to Azzi (the seating was alphabetical), an immunologist and transplant physican who was seeking new ways to deliver drugs directly to the skin to treat skin-related diseases.

Their conversation led to a new collaboration, and the two labs joined forces to work on a microneedle patch to deliver drugs to the skin. In 2021, they reported that such a patch can be used to prevent rejection following skin transplant. In the new study, they began applying this approach to autoimmune skin disorders.

“The skin is the only organ in our body that we can see and touch, and yet when it comes to drug delivery to the skin, we revert to systemic administration. We saw great potential in utilizing the microneedle patch to reprogram the immune system locally,” Azzi says.

The microneedle patches used in this study are made from hyaluronic acid crosslinked with polyethylene glycol (PEG), both of which are biocompatible and commonly used in medical applications. With this delivery method, drugs can pass through the tough outer layer of the epidermis, which can’t be penetrated by creams applied to the skin.

“This polymer formulation allows us to create highly durable needles capable of effectively penetrating the skin. Additionally, it gives us the flexibility to incorporate any desired drug,” Artzi says. For this study, the researchers loaded the patches with a combination of the cytokines IL-2 and CCL-22. Together, these immune molecules help to recruit regulatory T cells, which proliferate and help to tamp down inflammation. These cells also help the immune system learn to recognize that hair follicles are not foreign antigens, so that it will stop attacking them.

Hair regrowth

The researchers found that mice treated with this patch every other day for three weeks had many more regulatory T cells present at the site, along with a reduction in inflammation. Hair was able to regrow at those sites, and this growth was maintained for several weeks after the treatment ended. In these mice, there were no changes in the levels of regulatory T cells in the spleen or lymph nodes, suggesting that the treatment affected only the site where the patch was applied.

In another set of experiments, the researchers grafted human skin onto mice with a humanized immune system. In these mice, the microneedle treatment also induced proliferation of regulatory T cells and a reduction in inflammation.

The researchers designed the microneedle patches so that after releasing their drug payload, they can also collect samples that could be used to monitor the progress of the treatment. Hyaluronic acid causes the needles to swell about tenfold after entering the skin, which allows them to absorb interstitial fluid containing biomolecules and immune cells from the skin.

Following patch removal, researchers can analyze samples to measure levels of regulatory T cells and inflammation markers. This could prove valuable for monitoring future patients who may undergo this treatment.

The researchers now plan to further develop this approach for treating alopecia, and to expand into other autoimmune skin diseases.

The research was funded by the Ignite Fund and Shark Tank Fund awards from the Department of Medicine at Brigham and Women’s Hospital.

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New treatment could reverse hair loss caused by an autoimmune skin disease

A microneedle patch that delivers immune-regulating molecules can teach t cells not to attack hair follicles, helping hair to regrow.

Researchers at MIT, Brigham and Women's Hospital, and Harvard Medical School have developed a potential new treatment for alopecia areata, an autoimmune disorder that causes hair loss and affects people of all ages, including children.

For most patients with this type of hair loss, there is no effective treatment. The team developed a microneedle patch that can be painlessly applied to the scalp and releases drugs that help to rebalance the immune response at the site, halting the autoimmune attack.

In a study of mice, the researchers found that this treatment allowed hair to regrow and dramatically reduced inflammation at the treatment site, while avoiding systemic immune effects elsewhere in the body. This strategy could also be adapted to treat other autoimmune skin diseases such as vitiligo, atopic dermatitis, and psoriasis, the researchers say.

"This innovative approach marks a paradigm shift. Rather than suppressing the immune system, we're now focusing on regulating it precisely at the site of antigen encounter to generate immune tolerance," says Natalie Artzi, a principal research scientist in MIT's Institute for Medical Engineering and Science, an associate professor of medicine at Harvard Medical School and Brigham and Women's Hospital, and an associate faculty member at the Wyss Institute of Harvard University.

Artzi and Jamil R. Azzi, an associate professor of medicine at Harvard Medical School and Brigham and Women's Hospital, are the senior authors of the new study, which appears in the journal Advanced Materials . Nour Younis, a Brigham and Women's postdoc, and Nuria Puigmal, a Brigham and Women's postdoc and former MIT research affiliate, are the lead authors of the paper.

The researchers are now working on launching a company to further develop the technology, led by Puigmal, who was recently awarded a Harvard Business School Blavatnik Fellowship.

Direct delivery

Alopecia areata, which affects more than 6 million Americans, occurs when the body's own T cells attack hair follicles, leading the hair to fall out. The only treatment available to most patients -- injections of immunosuppressant steroids into the scalp -- is painful and patients often can't tolerate it.

Some patients with alopecia areata and other autoimmune skin diseases can also be treated with immunosuppressant drugs that are given orally, but these drugs lead to widespread suppression of the immune system, which can have adverse side effects.

"This approach silences the entire immune system, offering relief from inflammation symptoms but leading to frequent recurrences. Moreover, it increases susceptibility to infections, cardiovascular diseases, and cancer," Artzi says.

A few years ago, at a working group meeting in Washington, Artzi happened to be seated next to Azzi (the seating was alphabetical), an immunologist and transplant physican who was seeking new ways to deliver drugs directly to the skin to treat skin-related diseases.

Their conversation led to a new collaboration, and the two labs joined forces to work on a microneedle patch to deliver drugs to the skin. In 2021, they reported that such a patch can be used to prevent rejection following skin transplant. In the new study, they began applying this approach to autoimmune skin disorders.

"The skin is the only organ in our body that we can see and touch, and yet when it comes to drug delivery to the skin, we revert to systemic administration. We saw great potential in utilizing the microneedle patch to reprogram the immune system locally," Azzi says.

The microneedle patches used in this study are made from hyaluronic acid crosslinked with polyethylene glycol (PEG), both of which are biocompatible and commonly used in medical applications. With this delivery method, drugs can pass through the tough outer layer of the epidermis, which can't be penetrated by creams applied to the skin.

"This polymer formulation allows us to create highly durable needles capable of effectively penetrating the skin. Additionally, it gives us the flexibility to incorporate any desired drug," Artzi says. For this study, the researchers loaded the patches with a combination of the cytokines IL-2 and CCL-22. Together, these immune molecules help to recruit regulatory T cells, which proliferate and help to tamp down inflammation. These cells also help the immune system learn to recognize that hair follicles are not foreign antigens, so that it will stop attacking them.

Hair regrowth

The researchers found that mice treated with this patch every other day for three weeks had many more regulatory T cells present at the site, along with a reduction in inflammation. Hair was able to regrow at those sites, and this growth was maintained for several weeks after the treatment ended. In these mice, there were no changes in the levels of regulatory T cells in the spleen or lymph nodes, suggesting that the treatment affected only the site where the patch was applied.

In another set of experiments, the researchers grafted human skin onto mice with a humanized immune system. In these mice, the microneedle treatment also induced proliferation of regulatory T cells and a reduction in inflammation.

The researchers designed the microneedle patches so that after releasing their drug payload, they can also collect samples that could be used to monitor the progress of the treatment. Hyaluronic acid causes the needles to swell about tenfold after entering the skin, which allows them to absorb interstitial fluid containing biomolecules and immune cells from the skin.

Following patch removal, researchers can analyze samples to measure levels of regulatory T cells and inflammation markers. This could prove valuable for monitoring future patients who may undergo this treatment.

The researchers now plan to further develop this approach for treating alopecia, and to expand into other autoimmune skin diseases.

The research was funded by the Ignite Fund and Shark Tank Fund awards from the Department of Medicine at Brigham and Women's Hospital.

• Immune System
• Diseases and Conditions
• Skin Cancer
• Human Biology
• Hair follicle
• Baldness treatments
• Rheumatoid arthritis
• Domestic goat

Story Source:

Materials provided by Massachusetts Institute of Technology . Original written by Anne Trafton. Note: Content may be edited for style and length.

Journal Reference :

• Nour Younis, Núria Puigmal, Abdallah El Kurdi, Andrew Badaoui, Dongliang Zhang, Claudia Morales, Anis Saad, Diane Cruz, Nadim Al Rahy, Andrea Daccache, Triana Huerta, Christa Deban, Ahmad Halawi, John Choi, Pere Dosta, Christine Lian, Natalie Artzi, Jamil R. Azzi. Microneedle‐mediated Delivery of Immunomodulators Restores Immune Privilege in Hair Follicles and Reverses Immune‐Mediated Alopecia . Advanced Materials , 2024; DOI: 10.1002/adma.202312088

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