The dappled dilemma facing vitiligo science

Scientist John Harris doesn’t like to say the word “cure.” But
after his discovery last year of a new strategy to alleviate a skin
condition known as vitiligo, he now talks of a future in which
long-term relief may be possible for the millions of people who
have it.

Excited to share the results with non-scientists, Harris wrote about his findings in July 2018
for an online publication called The Conversation. He
expected enthusiasm. Instead, he was blindsided by a wave of online
hostility. “It was ‘F you. F you. You don’t even have vitiligo.
What do you know?” recalls Harris, director of the Vitiligo Clinic
and Research Center at the University of Massachusetts Medical
School in Worcester.

The backlash stemmed from Harris’s choice of language: In his
article, he had twice referred to vitiligo as “disfiguring,” once
in the headline and again in the first sentence. Many people did
not read past that word. “That just totally triggered people,” says
Alicia Roufs, head of the Minnesota chapter of VITFriends, a
national support group for those with vitiligo.

“I am losing my pigment. This does not classify as a
disfigurement,” wrote one of the moderators of Vitiligo Pride, a Facebook group that counts around
6,000 members. If her dermatologist used such terms, she wrote in
response to Harris’s article, she would tell the doctor to “stick
it” and walk out.

In vitiligo, a faulty immune reaction kills off pigment cells
called melanocytes and leaves patches of white skin. Considered an
autoimmune disorder, vitiligo often emerges in adolescence or
later, occurring in an estimated 1 percent of the world’s
population and affecting all ethnic groups equally — although the
depigmentation is more obvious on darker skin and carries greater
social stigma in certain cultures. More than 50 separate gene
changes have been linked to a greater risk of developing vitiligo,
but what actually triggers it is unclear. (Some areas of the body,
such as the face, are more likely to be affected, as are areas of
the skin that have had trauma.)

In some small percentage of people, the patches clear up
spontaneously, but most linger for life. That can take a
psychological and emotional toll: Surveys show that the majority of
people with vitiligo experience shame and insecurity; for some such
feelings can bloom into clinical depression. And as with other
kinds of immune activity gone awry, it can be hard on other parts
of the body as well.

Studies suggest between 15 percent and 25 percent of those with
vitiligo have at least one additional autoimmune
disorder
, including thyroid disease, inflammatory bowel disease
and lupus. And because melanocytes also populate the inner ear,
various tissues of the eyeball and even a layer of the brain’s
protective coating, individuals with vitiligo can experience
hearing loss, vision impairments and occasional neurological
abnormalities.

Yet because the changes wrought by vitiligo are mostly cosmetic,
some in the vitiligo community have been working, with some
success, to push back against defining it as a disease. In news
reports, the face of vitiligo is Winnie Harlow, a supermodel who
thrives with dappled skin. The online conversation is now dominated
by social media influencers who promote messages of inclusivity and
diversity on Instagram, Facebook and elsewhere. There, vitiligo is
portrayed as beautiful, a skin-deep condition worth embracing, not
fixing.

The public face of vitiligo: fashion model Winnie Harlow is shown in a green ball gown.

The public face of vitiligo: fashion model Winnie Harlow on the
red carpet.

CREDIT: MICKAEL CHAVET / PROJECT DAYBREAK / ALAMY
STOCK PHOTO

But while Harris and other physicians say that they share the
goal of decreasing the stigma associated with vitiligo, they have,
just as this message of empowerment is going viral, found what
could be antidotes. Based on a better understanding of how the
immune system attacks pigment cells, they have devised a number of
potential ways to stop it. Some remedies show promising results in
mice; others are already being tested in people, with more on the
way.

Scientifically, it’s an exciting time in vitiligo — even
investors are beginning to see the promise. Last month, after
securing funding from a British venture capital firm, Harris
launched Villaris Therapeutics, the first fully-funded biotech
startup to focus primarily on vitiligo drug development.

Which makes for strange days: Those who have committed their
careers to studying and treating the autoimmune problem now find
themselves caught between two competing narratives. To secure
research money from funding agencies and to convince drug companies
that vitiligo treatments are worth pursuing — even just to get
insurance coverage for their patients’ medicines — they must
emphasize the serious nature of the condition. But doing so risks
alienating the very people they aim to help.

“It’s something we all have to navigate very carefully,” says
Prashiela Manga, a pigment cell biologist at New York
University.

A problem in the skin

Harris never set out to become a world-leading expert on
vitiligo. His grandmother and great uncle had it, but he realized
that only recently, and vitiligo was not on his radar in the late
1990s when he entered an MD-PhD program in Worcester, less than an
hour’s drive from his hometown in rural Massachusetts.

Photo of John Harris, vitiligo researcher and physician.

Research dermatologist John Harris at the World Vitiligo Day
Conference he hosted in 2018 in Worcester, Massachusetts.

CREDIT: MARK SKALNY PHOTOGRAPHY

A general interest in autoimmunity took Harris to a diabetes
lab, where he focused on how the body trains its immune cells not
to attack its own tissues, a problem in type 1 diabetes and all
other autoimmune diseases. Harris didn’t want to specialize in
diabetes, though. He was floundering for an academic direction when
late one night he met a patient who would offer him professional
clarity.

The young woman had landed in intensive care after
simultaneously developing four new autoimmune disorder: diabetes,
thyroiditis, pernicious anemia and vitiligo — a rare, but not entirely unheard of, occurrence. As
Harris examined the woman, placing his stethoscope over a large
milky-white patch of skin on her back, he thought to himself: “I
can actually get the skin and study that.” He decided then and
there to become a dermatologist, and to focus his research on
vitiligo and devising new ways to correct the immune problems that
robbed the skin of pigment.

Currently, the only FDA-approved drug for vitiligo — called
monobenzone or Benoquin — actually worsens it, stripping the body
of all remaining pigment cells to give the skin a more uniform
tone. To restore skin color — which is to say, to treat
vitiligo — the most effective therapy involves ultraviolet light.
Zaps of UV radiation promote the regrowth of pigment-producing
melanocytes
and may help establish a healthier immune balance
in the skin, as researchers describe in the 2019 Annual Review
of Pathology
. Doctors also commonly prescribe steroids and
other drugs to further tamp down the immune assault and preserve
melanocyte function.

None of these treatments is a cure-all, though. Light therapy,
for example, demands frequent clinic visits over many months, and
even then only a minority of patients experience marked
improvements in skin color. Making matters worse for some are the
complications beyond the skin — mental health struggles chief among
them.“The psychosocial impact of vitiligo is profound, and it’s
really not to be underestimated,” says Nada Elbuluk, director of
the University of Southern California’s Skin of Color Center and
Pigmentary Disorders Clinic.

When Harris began studying vitiligo in 2008, he looked for an
existing animal model that might let him test new ways to counter
the self-directed immune attack involved. There was a breed of
chicken that lost its feather pigmentation, and a mouse with black
fur that turned white. Yet despite having immune cells that
targeted pigment-producing cells, neither animal showed signs of
skin lightening, the hallmark of the condition in humans. So Harris
set out to engineer an animal model that did.

Vitiligo supermodel

First, he needed a mouse with dark skin — the blackness of the
“Black 6” strain typically used in lab studies only goes fur-deep.
Harris found one: a colony of mice engineered to make melanocytes
throughout their skin. He added a vitiligo-inducing immunity flaw
into the mice, and white spots appeared on their ears, noses, feet
and tails a month or so later.

Harris unveiled the new animal model in 2012. Using
those mice, he managed to identify an immune-modulating drug that
could protect pigment cells from an immune attack and prevent the
skin from mottling.

Photo shows a brown-furred mouse with depigmentation on its tail and ears. This is the mouse model John Harris uses to study vitiligo therapies.

Depigmentation is clearly visible on tail and ears of John
Harris’s mouse model of vitiligo.

CREDIT: VINCENT AZZOLINO / HARRIS LAB

While it’s still unclear what initially triggers vitiligo,
scientists have made a lot of progress on understanding the
molecular events that ultimately kill the pigment-producing cells.
A large fraction of the genes
linked to vitiligo
are important in the immune system, notes
Richard Spritz, a pediatrician and geneticist at the University of
Colorado School of Medicine in Aurora. It suggests that “vitiligo
may be part of a normal immune surveillance in the skin … that’s
gone wild a little bit.” And in people, it’s clear that a person’s
own T cells, mistakenly targeting the self, spearhead the
destruction.

Gearing up as if to deal with a foreign invader — or a tumor —
the T cells produce an immune-stimulating molecule called
interferon-gamma. Hearing the alarm, skin cells called
keratinocytes amplify the call, instigating a biochemical cascade
that attracts more misguided T cells to the skin. There, the immune
cells besiege the melanocytes. Compounding the problem, the ranks
of T cells produce even more interferon-gamma, resulting in a
vicious cycle of destruction and depigmentation.

The drug Harris found could quell this pernicious feedback loop
by inhibiting interferon-gamma. Stopping the T cells from flocking
to the skin seemed to give pigment cells a chance to thrive again.
But blocking interferon-gamma is not a good strategy for treating
vitiligo — the body needs the immune molecule to fight infections.
The only approved drug that targets interferon-gamma comes with
severe side effects and is used to treat a rare, life-threatening
blood disease. So Harris and his lab group looked for alternative
drug targets.

Graphic shows T cells kill the melanocytes in skin and hair follicles, and recruit additional T cells from the blood vessels to the skin. Immune signaling molecules play a role in the killing and the recruitment, so blocking those can help protect melanocytes. Once this immune cascade has been turned on, another type of T cell (the resident memory T cells) infiltrate the skin and persist, ready to start killing melanocytes again (if medicines that block immune signaling molecules are stopped.)

Circulating T cells normally guard the skin against viruses,
bacteria and other threats. But in someone with vitiligo the T
cells destroy melanocytes. The attack involves a cycle of cellular
destruction and depigmentation, in which the T cells release immune
signaling molecules that activate certain skin cells. These skin
cells signal for more T cells to arrive, and leads to more attacks
on melanocytes. Drugs developed to treat rheumatoid arthritis and
other diseases, called JAK inhibitors, can block this signaling to
help promote melanocyte regrowth. But stopping the drugs can bring
back the attack because of the presence of resident memory T cells
in the skin, which are influenced by interleukin-15. One promising
new strategy seeks to block IL-15 and kill the memory T cells.

They had some initial success, identifying two different immune
signaling molecules that, when blocked, could prevent color loss and even restore pigmentation in mice. But the work
didn’t persuade drug companies to invest in the approach. Instead,
most industry research on vitiligo centers on repurposing a class
of drugs already approved for treating a handful of autoimmune
diseases.

Healing in the light

Known as JAK inhibitors, these agents block a different family
of immune molecules, called the Janus kinase or JAK proteins, which
also rev up the body’s T cell attacks on itself. These drugs
arrived on the vitiligo scene after Brett King, a dermatologist at
Yale University, published a case report in 2015 describing his
off-label use of tofacitinib, a JAK-blocking agent from Pfizer.
Although the drug was proven then to work only for patients with
rheumatoid arthritis, King showed that it also helped to repigment the face, hands and arms of a
middle-aged woman with widespread vitiligo.

King noticed, however, that the woman’s pigment wasn’t returning
to skin concealed by her clothes. That prompted him to refer the
patient to Harris, who took samples of her skin — applying gentle
suction to create pus-filled blisters that he sucked dry with a
syringe — so they could take a closer look. Together, the
researchers showed that, on a molecular level, one needs light
exposure, either natural sunlight or UV phototherapy, to produce
a noticeable response to the drug.

Photos show method of creating a blister on a patch of vitiligo-affected skin used by the Harris lab to analyze the molecular players in the autoimmune condition.

To study the factors that influence vitiligo in people, John
Harris takes suction blister biopsies from healthy and diseased
skin.

CREDIT: JAMES STRASSNER AND MAGGI AHMED / HARRIS
LAB

David Rosmarin, a dermatologist at Tufts Medical Center in
Boston, independently came to much the same conclusion after one of
his patients on a different JAK inhibitor, Incyte’s ruxolitinib,
experienced repigmentation on all areas of his face except for the
forehead, which was shielded from the sun by a baseball cap the man
wore every day. “The treatment is really a two-part process,”
Rosmarin says: It appears that the JAK inhibitor largely helps
suppress the normal immune activation, and the light then
stimulates the pigment cells to come back.

Since King’s initial report, many vitiligo specialists around
the world have begun writing off-label prescriptions for
tofacitinib or ruxolitinib — either in pill form, as manufactured,
or as topical creams prepared by specialty compounding pharmacies.
Although no large randomized studies are yet complete, other drug
makers have also taken notice and started positioning their own
experimental JAK-targeted agents as treatments for vitiligo as
well.

“There’s a prevalence and a need in this space,” says Neal
Walker, CEO of Aclaris Therapeutics, a dermatology-focused startup
outside of Philadelphia with a JAK-blocking ointment now in
clinical development for vitiligo. “Some of the most devastating
conditions for patients are viewed as cosmetic,” he adds, and just
because vitiligo is not life-threatening “doesn’t mean it’s not
very important to the patient.”

Rosmarin is currently leading a trial, funded by Incyte,
comparing ruxolitinib cream to a placebo ointment in more than 150
people with vitiligo. (Harris is a site investigator for both the
Incyte and Aclaris trials.) In early testing, the topical treatment
produced dramatic responses for some patients, especially on the face, with only minor side
effects such as skin reddening and acne flare-ups. Trials to date
have focused on adults, but given that half of all vitiligo
patients are diagnosed before they turn 21, Rosmarin says he is
optimistic that future trials will include children and
teenagers.

Most vitiligo experts describe JAK inhibitors as the most
promising new treatments in clinical testing for vitiligo. But
they’re not a cure: “When you stop the drugs, the disease recurs
rapidly,” notes Julien Seneschal, a dermatologist at the University
of Bordeaux in France.

This tendency to relapse can be blamed on a unique type of
skin-dwelling immune cell. After an infection by a virus or other
pathogen, those cells — known as resident memory T cells — take
root in the skin and operate as watchdogs, barking up a molecular
storm (via interferon-gamma signaling) should they detect those
pathogens again. Normally, this offers a frontline defense against
future infections. In vitiligo, the cells misfire and flag
melanocytes as intruders instead.

JAK inhibitors and other drugs can dampen the activity of those
forget-me-not T cells, Seneschal says. “But they are not able to
remove them.”

Graphic shows variety of conditions in which memory T cells appear to play a role, including: infections, cancer, transplant rejection, allergies and asthma, inflammatory disease and autoimmunity.

Recent research has pointed to a role for resident memory T
cells in a variety of immune-related disorders, including
vitiligo.

Forcing cells to forget

The importance of resident memory T cells in vitiligo emerged two years
ago in reports from Seneschal’s team and an independent group led
by Liv Eidsmo from the Karolinska Institute in Sweden.
But it was Harris and his colleagues who showed that the memory T
cells were to blame for the persistence of vitiligo after stopping
treatment. They also discovered a way to encourage the immune system to forget.

Reporting last year in Science Translational Medicine
and described in Harris’s piece for The Conversation — his
team showed that the memory T cells found within skin patches of
people with vitiligo had unusually high levels of a particular
receptor, one that engages an important immune-signaling molecule
called interleukin-15. In mice treated for two weeks with an
antibody that blocked the receptor, and thus the interleukin-15
signals to the all-important T cells, the unwanted memory cells
disappeared and there were lasting improvements in skin color.

“The tail and the ear repigmented very well,” says Jillian
Richmond, an immunologist in Harris’s lab, “and the skin actually
continued to improve because the melanocytes were regenerating and
the memory T cells were not there to keep attacking.” The
researchers euthanized the mice eight weeks after stopping
treatment, but Richmond suspects that the benefit would have
continued had they kept the animals alive longer.

Developed by JN Biosciences in California, the antibody therapy
used in the mouse study has not been tested in humans, only
monkeys. But another drug that blocks the same receptor (called
CD122) has been, though not for vitiligo. The CD122 blocker was
evaluated in small clinical trials as a potential remedy for a few
different illnesses, including leukemia and celiac disease.

Through Villaris, Harris now hopes to license or discover a
CD122 inhibitor and launch clinical trials for vitiligo within the
next year or two. “We don’t have any treatments in dermatology that
you can give for three months and the patients are better for
years,” he says. “I think that could happen with this.” According
to Villaris CEO Andrea Epperly, the company raised $18 million in
its initial financing round — enough to fund the first-in-human
safety studies and a follow-up trial to test for effectiveness.

Photos show depigmented mouse tails before treatment and then after for a mouse model of vitiligo. New pigment is visible in the mouse tail treated with the antibody drug, but there’s been little change in the control mouse.

An antibody drug that blocks the action of the immune signaling
protein interleukin-15 (via the CD122 receptor) helped to
dramatically repigment the tail of a mouse with vitiligo, compared
with an untreated control, in experiments in John Harris’s lab.

CREDIT: JOHN HARRIS, CC BY-SA

Harris is clearly bullish on the prospects for a vitiligo
therapy. Before founding Villaris, he also persuaded the NIH to
fund a vitiligo trial, expected to launch later this year, that
will test an antibody drug targeting the interleukin-15 signaling
molecule itself, rather than the receptor. (Harris later recused
himself from participating because of competing commercial
interests.) Others are uncertain if the story is that simple and
are waiting to see if Harris’s findings can be validated in
patients.

“The potential is there for long-term remission,” says Iltefat
Hamzavi, a dermatologist at Henry Ford Hospital in Detroit. But
targeting memory T cells might not be enough. “This assumes that
everything is immune-based,” he says, “and there may be some
melanocyte defects that also cause the problem.”

There also could be unintended consequences of wiping out this
vigilant immune population from the skin, notes Mary Jo Turk, a
tumor immunologist at Dartmouth’s Geisel School of Medicine in New
Hampshire. In mice with vitiligo, Turk showed that memory T cells are critical in fending off
melanoma. A team from Australia reported earlier this year that
mice lacking these cells in the skin were more susceptible to developing cancer. “There’s always a
fine line between treating autoimmunity and releasing control
against cancer,” Turk says.

Only clinical trials will show whether these new approaches work
safely in patients. Such trials are expensive, though — and despite
Harris’s promising mouse data, many would-be financial backers had
trouble seeing past the social media discussions about acceptance
and empowerment. It was only after numerous rejections, Harris
says, that he found a funder that recognized the medical need and
market opportunity for a vitiligo treatment.

Tale of two narratives

The strength of the fight against stigma in the vitiligo
community was well illustrated by the swift — and overwhelmingly
negative — reaction that Harris received in 2018. And it didn’t
help that his story landed a week after Aerie, a lingerie brand,
launched a marketing campaign featuring young women that news
reports described as having “visible disabilities” and “chronic
illnesses.”

Alongside a wheelchair user, a Paralympian with Down syndrome, a
bald cancer survivor, a woman wearing an insulin pump and another
with an ostomy pouch — all in their skivvies — was an aspiring
model with vitiligo, the white spots on her chest, arms and face
clearly visible against her darker natural skin tone. The
insinuation in some readers’ minds: Vitiligo is just another
disabling disease.

“That’s the kind of thing that pisses me off,” Jasmine Abena
Colgan, a contemporary artist with vitiligo whose work focuses on
labor and pigmentation, told Knowable. “Calling us
diseased and ill and sick, it’s really close-minded,” she says.
“It’s not a disease. I can’t stress that enough.”

If that outlook works for Colgan, all the power to her, say
Harris and others. But some worry that the strong voices of people
like Colgan may drown out the whispers of those who are suffering —
desperately self-conscious teenagers, say, who avoid wearing shorts
so that no one will ask about the white spots on their knees. And
“if patients are not seen asking for better treatments, then it’s
hard to justify to companies that this is going to be a worthwhile
investment,” says Vaneeta Sheth, a dermatologist at the Lahey
Hospital and Medical Center outside Boston.

That concern, already widely shared across the medical
community, is beginning to ripple out to some vitiligo-focused
forums such as Living Dappled, a prominent vitiligo blog. “We have
these two conflicting narratives, and it’s alarming to me to see
the one outweighing the other,” says Erika Page, editor in chief of
the site. “The acceptance one is the one that’s splashy and all
over the media, but that doesn’t make that the truth. There is
still another truth, and we need to balance the narrative.”

For Harris, the effect of the movement became evident during a
conversation last year with a representative of a major
pharmaceutical firm. The company was just months away from
launching a large and expensive drug trial for vitiligo and, as
Harris tells it, “he came up and said, ‘It seems like people don’t
mind their vitiligo. They actually like it, John. Do we really need
to spend time creating a drug for this?’” (Harris managed to
convince the man otherwise, and the company’s trial went ahead late
last year.)

“It’s an interesting time that we’re in,” muses Victor Huang, a
vitiligo specialist at the University of California, Davis. “At the
same time as we are better understanding the impact on people’s
lives — and we’re able to measure rates of suicide, depression,
mood disorders, developmental issues as well as other autoimmune
conditions that go along with vitiligo and would strongly argue for
this being a medical condition — there is also a cultural shift
that is happening.” People are embracing their appearance, vitiligo
and all.

“It is a tightrope to walk,” Huang says. “But both perspectives
are valid and necessary.”