New thoughts, therapies for vitiligo

New knowledge of the pathogenesis of vitiligo (ICD-10-CM L80) has given rise to new treatments and new hope for sufferers of this condition, says Pearl E. Grimes, M.D. She is director of the Vitiligo and Pigmentation Institute of Southern California and clinical professor of dermatology at The University of California Los Angeles David Geffen School of Medicine.

65-year-old African-American female treated for six months with NBUVB phototherapy and four afamelanotide implants. Photo: Pearl Grimes, M.D.Dr. Grimes spoke about vitiligo at MauiDerm 2016. Thanks to genetic research over the past decade, she says that "We now know that probably 90% of the genes that have been identified in vitiligo are immune-susceptibility genes; 10% are pigment-related genes." Such a genetic predisposition can lead to "sick melanocytes," she says. "Melanocytes from people with vitiligo do not grow as well in culture.¹ There are probably some inherent defects in these melanocytes that may tie back to the genetics of the disease."

Oxidative stress might be the primary event that initiates the immune dysfunction that leads to vitiligo, says Dr. Grimes. "In vitiligo, we know that hydrogen peroxide is up, [while] catalase-a major oxidative stress fighting molecule-is down. Alterations in the body's innate ability to protect against oxidative damage may play a role in releasing autoantigens and neo-antigens, she says. This leads to a major influx of CD8 lymphocytes-the major players in mediating the destruction of melanocytes in vitiligo. Studies suggest that these cytotoxic lymphocytes are increased in the blood and infiltrating into the epidermis in the areas of damaged melanocytes, she says: "Interferon (IFN)γ is key in mediating the destruction of melanocytes. This cytokine stimulates CXCL10, a chemokine that serves as a homing molecule that helps to attract CD8 cytotoxic lymphocytes into the skin."

White patches, bruised souls

Far from just a skin ailment, the white patches of vitiligo can devastate patients' self-image. For example, a beautiful 40-year-old patient recently told Dr. Grimes that the final straw of her self-esteem snapped when the mere sight of her face caused a stranger's toddler to point at her and cry. "In response to that incident, the patient said, ‘I don't go out. I don't date anymore, I have isolated myself, and I feel ugly.' That's a common story on the spectrum of patients' experiences."

When a patient presents with vitiligo, "It's probably the longest and most detailed consultation I do. We take a very detailed history-looking at family history, time of disease onset, disease progression, associated symptoms, associated autoimmune illnesses and medications-to tease out any other causative factors that may be contributing to pigment loss."

While getting the patient's medical history, Dr. Grimes also subtly explores the disease's psychological impact. Rather than asking direct, probing questions, "I go about it in a subdued, roundabout way-trying to let them talk about it first. I want them to be comfortable." Instead of asking what impact vitiligo has had on their quality of life, she may ask about changes in patients' daily routines, activities or hobbies. "Some will say, 'I wear makeup all the time, even on my hands.'" Many patients limit social and recreational activities that require going out in public.

Dr. Grimes also performs a detailed physical exam, complete with photos, and a thorough laboratory assessment. "By the time I finish that consultation, I'm able to put together a treatment regimen based on that patient's symptoms." She also assembles a healthcare team for each patient that, if needed, includes an immunologist or rheumatologist and a mental-health professional.

If a patient has limited disease, "I can treat them with a topical regimen involving topical corticosteroids and topical calcineurin inhibitors."

Next: How to stabilize and repigment

Read: Expert insights for vitiligo and melasma

Stabilization and repigmentation

Patients with more than 10% to 15% involvement often will need phototherapy, which helps with both stabilization and repigmentation, according to Dr. Grimes. "I tell patients they must be in for the long haul-treatment for 6 to 12 months-and we will continue beyond that if patients are achieving an optimal response."

Phototherapy is safe and easy to perform, she says. Although complications can include sunburn, "We are not seeing any skin cancers-melanoma or nonmelanoma. Vitiligo is probably protective for melanoma." Phototherapy stimulates melanoblasts in the outer root sheaths of hair follicles to migrate to areas that need repigmentation, Dr. Grimes says. "But it's also immunosuppressive in that it decreases the inflammatory immune response. It also has the ability to upregulate growth factors for melanocytes, such as alpha-melanocyte-stimulating hormone (α- MSH), basic fibroblast growth factor, endothelin 1 and others. And it decreases production of pro-inflammatory cytokines. It creates a more favorable environment for repigmentation."

Home phototherapy is ideal for patients who can't get to the office two or three times weekly, she says. "That's the situation for many adults," especially if they have children with vitiligo and otherwise busy lives. Dr. Grimes' practice possesses 15 years' experience with home-based narrowband UVB (NBUVB) phototherapy, which in one study proved superior to office-based excimer laser treatment.²

"Home phototherapy is safe and extremely well-tolerated. We've had very few complications. But you must teach patients how to use the unit. The key value is that they are more consistent" with treatment than they would be if they had to go to the office. "I'm not going to say it's better than what we can achieve in the office. But there's enough efficacy to suggest that it's clearly value added for someone who can't come into the office regularly."

Among oral options for stabilizing vitiligo, says Dr. Grimes, steroid mini-pulse therapy delivers therapeutic doses while minimizing-although not entirely avoiding-steroid side effects. "You can give dexamethasone 5 mg, or a lower dose of betamethasone on two consecutive days a week." Multiple studies have shown that this approach can facilitate stabilization for many patients, she says.

In other recent studies, oral mini-pulses of 2.5 mg dexamethasone performed comparably to methotrexate 10 mg weekly³ and minocycline 100 mg daily.⁴ Along with antibacterial effects, she says, "Minocycline has antioxidant and anti-inflammatory properties; it can prevent cellular apoptosis; and it's been shown that it can decrease production of a number of pro-inflammatory cytokines including IFNγ and tumor necrosis factor (TNF)α, both of which have been implicated in vitiligo."

Emerging treatments

For repigmentation, afamelanotide upregulates melanoblasts in the outer root sheath of the hair follicle, stimulating melanoblast differentiation and increased melanin production, says Dr. Grimes. "It probably also stimulates melanocyte proliferation." A linear analog of α-MSH, afamelanotide also may possess immunomodulatory properties, she adds. "In our phase 2 study, the combination of afamelanotide and UVB was significantly superior to NBUVB monotherapy."⁵

A recently completed phase 2 vitiligo study in Singapore corroborates the U.S. study's findings, says Dr. Grimes. "Hopefully, a phase 3 study will be underway in the United States within the next year."

Additionally, she says, several studies have shown prostaglandin F2a analogues (latanoprost, bimatoprost) to be efficacious in vitiligo, either as monotherapy or in combination with NBUVB.⁶ These drugs can cause periorbital hyperpigmentation in patients with glaucoma. "That was the template for our interest in using them for vitiligo. These prostaglandin F2a analogues increase melanocyte proliferation and the transfer of melanin to epidermal keratinocytes," she says.

Because Janus kinase (JAK) inhibitors block the IFNγ-CXCL10 pathway, "There's enormous interest in tofacitinib and ruxolitinib. Unfortunately only two cases have been published."

Intralesional corticosteroids may also facilitate repigmentation, says Dr. Grimes. "I limit intralesional Kenalog (triamcinolone acetanide 2.5 to 3 mg/cc, Bristol-Myers Squibb) to acral areas because I don't want patients to get any corticosteroid side effects such as atrophy in other affected areas."

Disclosures: Dr. Grimes has performed clinical research and/or served as a consultant for Allergan, Clinuvel, Galderma, Johnson & Johnson, Kythera, Procter & Gamble, Merz, Suneva and Valeant.

References

1. Boissy RE, Liu YY, Medrano EE, Nordlund JJ. Structural aberration of the rough endoplasmic reticulum and melanosome compartmentalization in long-term cultures of melanocytes from vitiligo patients. J Invest Dermatol. 1991;97(3):395-404.

2. Tien Guan ST, Theng C, Chang A. Randomized, parallel group trial comparing home-based phototherapy with institution-based 308 excimer lamp for the treatment of focal vitiligo vulgaris. J Am Acad Dermatol. 2015;72(4):733-5.

3.  Singh A, Kanwar AJ, Parsad D, Mahajan R. Randomized controlled study to evaluate the effectiveness of dexamethasone oral minipulse therapy versus oral minocycline in patients with active vitiligo vulgaris. Indian J Dermatol Venereol Leprol. 2014;80(1):29-35.

4. Singh H, Kumaran MS, Bains A, Parsad D. A Randomized Comparative Study of Oral Corticosteroid Minipulse and Low-Dose Oral Methotrexate in the Treatment of Unstable Vitiligo. Dermatology. 2015;231(3):286-90.

5. Grimes PE, Hamzavi I, Lebwohl M, Ortonne JP, Lim HW. The efficacy of afamelanotide and narrowband UV-B phototherapy for repigmentation of vitiligo. JAMA Dermatol. 2013;149(1):68-73.

6. Anbar TS, El-Ammawi TS, Abdel-Rahman AT, Hanna MR. The effect of latanoprost on vitiligo: a preliminary comparative study. Int J Dermatol. 2015;54(5):587-93.