HCPLive®: How has knowledge regarding the etiology/pathogenesis of vitiligo evolved in recent years?
Amit G. Pandya, MD, FAAD: There have been a lot of discoveries [concerning] the pathogenesis of vitiligo over the past 10 years. It turns out that melanocytes are the start of the pathogenesis of vitiligo. Melanocytes are inherently unstable, because they’re producing a large amount of melanin. The production of this protein causes the unfolded protein response and many reactive oxygen species to be produced within melanocytes. That stress on the melanocyte causes the secretion of various mediators that stimulate the innate immune system and the local area. Other things can add to this stress and increase reactive oxygen species, such as trauma, UV light, and even chemicals. You have this response [from] the melanocytes and the surrounding area that causes the activation of local natural killer cells and, especially, the dendritic cells in the immune system. These dendritic cells then migrate to the local draining lymph nodes, and they present these melanocytic antigens to naïve T cells. This causes the production of a large number of autoreactive, melanocyte-specific, cytotoxic, CD8-positive T cells, which then are released into the circulation. These are the cells that subsequently cause the adaptive immune response that causes widespread vitiligo.
The patient [tends to] develop vitiligo in many areas of the body, and it can occur due to trauma, it can [be] due to other forms of stress, but it often occurs in places [for no obvious] reason. These cytotoxic T cells come out of the bloodstream, they crawl into the epidermis, they find the melanocytes, they secrete various enzymes, they kill the monocytes, and we see areas of depigmentation in the skin.
HCPLive®: Are there certain cases that are not straightforward when the diagnosis is vitiligo?
Pandya: When you’re going to manage a patient with vitiligo, the most important thing is to make sure you’ve got the right diagnosis, and there are several conditions that are on the differential diagnosis of vitiligo. You have to make sure [that patients don’t have conditions] like tinea versicolor, which is a cutaneous infection caused by a yeast-like organism. Also, some patients have nevus depigmentosus, and that would be usually a single lesion, sometimes more than 1 lesion, in which you have this area of hypopigmentation that occurs early in life in children. Once it appears, it really doesn’t spread. Nevus depigmentosus tends to have more irregular edges as opposed to vitiligo, which has smooth edges. Another condition in the differential diagnosis is idiopathic guttate hypomelanosis, and this [may be] due to chronic sun damage and senescent melanocytes that leave these areas of what looks like depigmentation, especially on the arms and leg; they [usually tend to measure] less than 6 millimeters in diameter, and they don’t spread much beyond that in size. There are other conditions, such as pityriasis alba, in which inflammatory cells, perhaps from eczema, cause melanocytes to temporarily reduce production of melanin, and a lighter area of the skin [appears]. Patients come in often with these disorders concerned that they might be vitiligo. It’s really up to us to look at the pattern, the size, and the distribution and, sometimes, even do a biopsy or a scraping to determine the correct diagnosis and to rule out these other diseases before we make the diagnosis of vitiligo.
HCPLive®: What is the real-world impact of this condition on the patient and their quality of life?
Pandya: Even though vitiligo doesn’t seem to affect internal organs except the thyroid gland, it can have profound psychological implications. I tell patients, “Inside, you’re likely very normal.” [They] need to have [their] thyroid checked, usually once a year to [monitor their thyroid-stimulating hormone level], but, otherwise, their hearts, their lungs, their kidneys, [and] their livers [are] normal.
However, patients [with vitiligo] can [experience] a profound effect on their psychological well-being. It can affect their careers. Many patients don’t want to be in careers in which they’re in the public eye, and they’re giving presentations, because, they say, “Doctor, people look at my vitiligo, and they’re not listening to me.” It can have a profound social impact in terms of their relationships that they develop with friends or [with] intimate relationships. They may be reluctant to form these relationships because of their vitiligo. Certainly, it can cause various psychological disorders: anxiety, depression, suicidal ideation in many patients, and body dysmorphic disorder. There are many psychological comorbidities in patients with vitiligo that have been found and published [in studies].
It can have an economic impact. These patients often have a high burden of disease in terms of treatment. They need to go, sometimes, 3 times a week to the doctor’s office; there’s a lot of expenses with that. Trying to purchase medications for their vitiligo can have an economic burden. Also, they may be afraid to even seek a job, because they’re concerned about the way they look and how people will treat them. There are many psychological implications that patients have with the diagnosis of vitiligo, and we, as clinicians, need to keep this in mind when we’re evaluating patients.
HCPLive®: What is the role of the health care professional in motivating patients and setting expectations in successfully managing and treating vitiligo?
Pandya: When I’m talking with patients, I make several points. One of the most important…is that it takes time for melanocytes to migrate and repigment these areas of depigmentation. It doesn’t happen quickly. Melanocytes can come in from the edges, but melanocytes can [also] come from the base of black hairs. They migrate up the sides of the hair and the outer root sheath, and then they fill in the epidermis, and this takes time. I need to set expectations with the patient and let them know that typically, with treatment (which usually includes topicals, phototherapy and, sometimes, oral therapy), they can expect an average of 25% improvement in 3 months, 50% improvement in 6 months, and 75% improvement in 9 months. After that, it often plateaus. I can’t guarantee that they will have 90% or 100% repigmentation, but, on average, those are the numbers that we see in various studies.
Areas like the hands will do poorly, and areas like the face will do better. I let them know that. I also talk to them about different aspects [of] prognosis. For example, if they have areas with white hairs, and I use a dermatoscope to look at the small villus hairs and see that the majority of their hairs are white, [then] they have a poorer prognosis [than do patients] who have all pigmented hairs. If they are young, they tend to have a better prognosis than [do] older patients. If they’ve had vitiligo for less than 2 years, they also have a better prognosis than [do] those who have had it for more than 2 years (especially for 10 years or longer). Certainly, areas that are prone to trauma (such as elbows, knees, ankles, wrists, hand, and feet) tend not to do as well as areas that are not exposed to a lot of trauma. Also, areas that have less of a concentration of hair follicles, such as the clavicle, do not do as well as areas that have a higher concentration of hair follicles, such as the face. These are some of the points that I do communicate.
I also tell the patient that I’m going to look for signs of activity. I look at their skin and see if they have confetti-like lesions or trichrome vitiligo, where the borders of the vitiligo lesions are hypopigmented or blurred. I also look for the Koebner phenomenon. If they have those type of lesions, then I know they have more active disease. I talk to them first about stabilization, then repigmentation, and then maintenance therapy. I tell them that we need to stop the disease from spreading, and then we need to try to repigment the lesions. Once we have repigmented, we need to reduce the frequency of phototherapy, reduce the application of topicals, and find [a] maintenance treatment [that] will maintain their disease in that improved state without it coming back.
HCPLive®: How do you ensure that patients are adhering to their treatment regimen?
Pandya: Compliance is, of course, extremely important [in achieving successful] treatment of vitiligo. When I see patients [on follow-up visits], I try to evaluate several things. First of all, I ask them how many treatments they are getting if they’re [receiving] phototherapy. Typically, I will treat 3 times a week (for example, Monday, Wednesday, and Friday) and ask them, “Are you getting 12 treatments per month?” I can often look at their medical record if they’re coming into my clinic to see how many times they have come in. Patients really need to try to come in [to receive a] majority of their treatments—I would say 75% or more—to get good results. I look for compliance from that standpoint. I also look for refills. Are they asking for refills of the topicals on a routine basis, or are they still on that first tube 6 months later? In [that] case, I know that they’re not using it properly. Of course, I will ask, “How many times a week do you apply it? How many applications do you [accomplish] in 1 week with your topical?”
I’ll also ask about oral therapy, for example. We will give dexamethasone minipulse therapy to patients with very active vitiligo and ask them how they’re doing with that and whether they have had any [adverse] effects. Then, with the examination of their skin, I often [can] correlate improvement with their compliance, because, of course, patients who are not very compliant will not show any improvement [percentage]-wise when it comes to stabilization and repigmentation of their skin.
HCPLive®: What factors shape the development of treatment goals, and how do you convey those goals to patients?
Pandya: When I talk to patients, I tell them that there are 3 pillars of treatment. One pillar is to reduce the stress on the skin, and, as I mentioned earlier, there are reactive oxygen species being made all the time in the skin because of the inherent defect of melanocytes in vitiligo patients, as well as life in general; UV damage, chemicals, [and/or] a trauma can cause the stress. I ask my patients to take oral antioxidants [like] vitamin C [and] vitamin E. I know [results concerning] gingko biloba have been published. [And] α-lipoic acid [and other antioxidants] are easy to find at the store. I also ask them to try to increase [ingestion of] antioxidants in their diet—for example, [eating] 5 servings of fruit and vegetables every day [and] a handful of nuts to try to improve [intake of] antioxidants. That’s the first pillar of therapy.
[For] the second pillar of therapy, I talk to them about [removing] those cytotoxic T cells from their skin. We want to try to clear those CD8-positive T cells from their skin, and we can do that with topical corticosteroids, topical immunomodulators, and, now, we’re using topical JAK inhibitors. They will cause those T cells to be cleared from their skin so that this damage to the melanocytes by the immune system can diminish.
Finally, I tell them about the third pillar of therapy, and that is to stimulate monocytes to repigment their skin. Of course, the number 1 way that we do that is with phototherapy, [which] will stimulate those melanocytes to repigment the areas. It will also cause them to migrate up the sides, at the sides of the hairs, and then fill in the skin. After about 3 or 4 months, [when it reaches certain doses, the phototherapy] will actually cause immunosuppression of the skin to help clear out the T cells. It has a dual function when you get to the higher doses after the patient has been on the treatment for a few months. Patients are able to understand that [combination of these 3 pillars of therapy will be most effective in treating] their vitiligo.
HCPLive®: What patient factors would you consider when you are choosing between different therapeutic options for these patients?
Pandya: When treating a patient with vitiligo, of course, the most important aspect is going to be making treatment decisions on a shared basis with the patient. Patients can have very different expectations when it comes to vitiligo. Some patients simply want it to be stable, so that it doesn’t spread to more visible areas. Some people want the lesions to be repigmented 100%, or they don’t want to have treatment at all. Others want to see the maximum repigmentation they can achieve. Some patients simply [want] the hands treated most of all, and they’re not so concerned about other areas. Others want other specific areas [to be] treated.
There are many different desires that patients have for their vitiligo. One of the first things I ask is, “What do you want to achieve with treatment, and what bothers you the most about your vitiligo?” Once I hear that, then I can guide the treatment decisions. For example, if a patient says that they want an area of vitiligo treated that has completely white hairs—it has not responded to treatment in the past, and it’s exactly the same—then I might say, “If you really want this treated, and your disease is stable, then we need to go to surgical modalities (for example, either skin transplant or melanocyte transplant of their skin).” If patients, however, want to have as much of their body repigmented as possible, then I might treat them with full-body phototherapy as opposed to more localized treatment. The most important factor is to talk with the patient, determine what their goals are, and then customize your treatment plan based on their desires.
Another important factor in treatment decision-making is the patient’s time and ability to afford the treatments. Patients may not be able to come into my office 3 times a week for treatment, they may not be able to afford the various treatments, [and] they may not have insurance coverage. This is an important part of the conversation that I have with patients.
HCPLive®: Why are there differences in response based on the different body parts, and why does it generally take so long to treat or repigment the body parts?
Pandya: The response of vitiligo can vary depending on which part of the body [is being treated]. One of the most important factors is the presence of hairs. When vitiligo occurs, the T cells kill the melanocytes of the epidermis, and, sometimes, they kill the melanocytes at the base of the black hairs, and the hairs grow out white. [In that case], there is no source of melanocytes from which they can become repopulated in the epidermis with treatments like phototherapy and various topical oral agents. This is 1 of the reasons why the hands, the feet, the ankles, [and] the wrists are so difficult to treat; there are no hair follicles there. Once the fingers [lose their pigment], for example, it is very difficult to get them to repigment. It also seems to be difficult to repigment in areas that move a lot, that have a lot of motion, and it’s not clear why those areas tend to be difficult; part of it could be trauma. We also know that areas of the body where the hairs turn white are more difficult to treat. Finally, areas where there’s a lesser concentration of hair follicles (such as the clavicle area, which has a poor concentration of hair follicles) tend to be more difficult to treat. These are some of the reasons why there is a variation of response in different areas of the body.
The reason [that] it takes so long to repigment likely has to do with melanocytes [needing] a while to recover from the shock of being attacked by the immune system. Once they recover, they need to start to proliferate—to extend their dendrites, to produce melanin, to deliver those melanosomes to adjacent keratinocytes, and then to migrate into the vitiligo lesion itself. This takes time, this migration. It’s faster in areas with hair follicles. You’ll start seeing a lot of little dots around the hair follicles, but when the melanocytes are simply coming from the margins, it’s a slow process. You’re talking about just a few millimeters every 3 months to come in from the margins.
HCPLive®: Looking to the future of vitiligo treatment, can you share insights regarding any notable newer therapies?
Pandya: This is a very exciting time for the treatment of vitiligo and for me. [During] my entire career, I have not seen studies for drugs to treat vitiligo that [have shown the progression that we see] today. We now have multiple topical and oral medications being studied for the treatment of vitiligo. (Editor’s note: This interview was conducted before the FDA approval of ruxolitinib).One of these medications is topical ruxolitinib, which is a JAK inhibitor. Phase 3 studies [of this agent have already been completed], and over 50% of [treated] patients [achieved] over 50% of…what we call a F-VASI50 [≥ 50% improvement from baseline in the facial vitiligo area scoring index] after 6 months of application. This is simply [by using] the cream without phototherapy treatment, [and it] is very exciting that a cream applied twice a day for 6 months can get over half the color back on your face with no other treatment. On the body, after 6 months, there was about 25% repigmentation overall…with just the cream alone. I’m sure that with phototherapy, we are going to see much higher responses.
There’s also an oral JAK inhibitor by Incyte that is currently [being tested] in phase 2 studies, [and those results will] be exciting to see. Ruxolitinib did achieve its primary outcome measure. The oral JAK inhibitor [provided better results than did] placebo at the end of the 6-month study. It’s interesting that after 6 months, there was about 25% repigmentation; [however], after 12 months, there was more like 60% to 70% repigmentation of the face just with this oral JAK inhibitor. That was exciting to see.
There is also an anti–IL-15 antibody study that’s ongoing right now. We don’t know the results of that, but [that agent] is designed to affect the resident memory T cells, which [may] be the reason why vitiligo comes back in the exact same spot when it does return. By removing these resident memory T cells, perhaps, [a patient] can have a durable remission. This anti–IL-15 antibody, which is [delivered as] a subcutaneous injection, is an exciting [agent], and, hopefully, we’ll see the results of that study soon.
Finally, afamelanotide is a melanocyte-stimulating hormone analogue [that] was studied several years ago. [When] you combine afamelanotide (an implant applied under the skin) with narrowband UV-B therapy, you get faster results when it comes to repigmentation and stimulation of the melanocytes than [when you use] narrowband UV-B alone. There are many studies that are ongoing, [and] several have been completed. I am really looking forward to seeing our new armamentarium for vitiligo in the near future.
HCPLive®: What advice do you have for primary care providers and dermatologists in recognizing and treating vitiligo?
Pandya: The most important messages [for] health care providers who are seeing patients with vitiligo is, number 1, to really listen to the patient, to find out what they want to achieve with treatment of their vitiligo and express to them that it takes a while to see that improvement. I would ask the patient to commit to about 9 months of treatment to really see a difference. I would also highly suggest [obtaining] baseline photographs, seeing the patient every 2 to 3 months, and taking photographs at every visit so that you can see the 10% or 20% improvement in the lesions. If you don’t do that, it’ll be difficult for you to determine if there’s been 10% or 20% improvement. It certainly [is difficult] for the patient to determine [such progress, and] that often causes pessimism and [abandonment of] treatment. When you see that improvement in the photographs, you will be motivated when you see future patients, and you will understand how [an area affected by] vitiligo truly can be repigmented as long as one has patience and the right outlook in terms of expectations for treatment.
I would also recommend that health care providers look for signs of activity (such as confetti-like lesions, trichrome lesions, and the Koebner phenomenon), because those patients who have those lesions need to be treated aggressively—perhaps with oral mini-pulse dexamethasone, phototherapy, and topicals all combined—to stop it from spreading, because those patients are in danger of rapidly worsening vitiligo.
Finally, I would recommend that health care providers support patients and talk to them about the psychological effects of vitiligo. If the patient appears to be depressed or have significant psychological issues, perhaps [the provider can] recommend counseling or refer them to a psychiatrist to help them deal with this condition while they’re undergoing treatment.
Often, patients ask me, “Doctor, am I going to be on phototherapy forever? Am I going to have to be on this pill or these creams forever?” And I tell them, “Vitiligo will improve. At some point, [however], you will hit a plateau.” In other words, they will come in 1 day, and they will not be any better than their last visit. At that point, what I do is move into maintenance therapy. If they’re on phototherapy 3 times a week, I will drop them to twice a week for a month and see if the vitiligo comes back, [and] then once a week for a month to see if the vitiligo [returns], [and] then once every other week for 2 months [to] see if the vitiligo comes back. If it doesn’t, I stop phototherapy. If it does come back, I try to put them on maintenance therapy, perhaps once a week, so that the vitiligo can be stable.
[I adopt] the same [approach] with topical therapy. Once they have reached maximum repigmentation, I drop the topical [steroid] therapy, [for example], especially the strong ones. I typically will give them once a day, 5 days per week (for example, Monday through Friday) when I’m trying to repigment. For maintenance therapy, I will drop down to just twice a week. And that would include topical steroids [and] topical immunomodulators, such as tacrolimus and pimecrolimus; I usually use them twice a day. Once again, for maintenance therapy, I’ll just drop to twice a week in the areas where they have vitiligo but also [in] the areas where they used to have vitiligo, so it doesn’t come back. I think this maintenance therapy is really important.
I also give all my patients information about great [online] resources where they can get more good information about vitiligo. There are many websites [that offer] confusing messages about vitiligo. I send them to good locations, such as the Global Vitiligo Foundation website, where they can get accurate, up to date, scientifically-based information about vitiligo to guide their treatment.