Vitiligo Exchange: An Expert Panel Discussion of Two Clinical Cases

J Clin Aesthet Dermatol. 2024;17(12 Suppl 3):S9–S18. 

by James Del Rosso, DO; Iltefat Hamzavi, MD; and Pearl Grimes, MD

Affiliations. Dr. Del Rosso is the Clinical Editor-in-Chief of The Journal of Clinical and Aesthetic Dermatology; Adjunct Clinical Faculty in Dermatology at Touro University Nevada in Henderson, Nevada; Director of JDR Dermatology Research in Las Vegas, Nevada; Vice President of Clinical Research and Strategic Development at Advanced Dermatology and Cosmetic Surgery in Maitland, Florida. Dr. Grimes is the Founder and Director at the Vitiligo & Pigmentation Institute of Southern California in Los Angeles, California; Clinical Professor of Dermatology at the University of California, Los Angeles. Current President of the Global Vitiligo Foundation. Dr. Hamzavi is with Henry Ford Hospital in Detroit, Michigan; Hamzavi Dermatology Specialists; Board Member and Past President of the Global Vitiligo Foundation.

FUNDING: Funding for this article was provided by InCyte Corporation. 

DISCLOSURES: JDR has served as a researcher and consultant for Abbvie, Arcutis, Bausch Health, Beiersdorf, Dermavant, Ferndale, Incyte, L’Oreal, Pfizer, Regeneron, Sanofi, and Sun Pharma. PG has served as a researcher and consultant for Clinuvel, BOD Clinuvel, L’Oreal, Johnson & Johnson, LaserOptek, Merck, Versicolor Technologies, Incyte, Pfizer, AbbVie/Allergan, and Skinbetter Science. IH has served as an investigator and/or a consultant for AbbVie, Arcutis, Avita, Almirall, Boehringer Ingelheim, Galderma, Incyte, ITN, Janssen, Loreal/La Roche Posay, Novartis, Pfizer, Sonoma, UCB, Union Therapeutics, and Vimela. 

ABSTRACT: This article is based on a roundtable discussion in which three panelists review clinically relevant insights about vitiligo and discuss two cases that illustrate the multiple challenges faced by both patients and clinicians in managing this complex disease. The first is a 32-year-old White female patient with Fitzpatrick Skin Type III/IV with extensive depigmentation in the trunk area. The patient achieved 90-percent repigmentation with a combination therapy approach. Treatment included systemic corticosteroids, oral antioxidants, narrowband ultraviolet B phototherapy, and topical therapy initially with tacrolimus ointment followed by topical ruxolitinib cream. Patient counseling around variable rates of progressive repigmentation over time, the significance of combining therapeutic approaches, and the importance of treatment consistency are discussed. The second case is that of a White pediatric female patient with vitiligo, who was treated from the ages of 5 to 11 years, with a break in treatment due to the patient’s desire to discontinue treatment. Once treatment recommenced, the patient ultimately achieved 75-percent repigmentation within six months using a combination of narrowband ultraviolet B phototherapy, topical corticosteroids, and topical calcineurin inhibitors. The emotional burden of pediatric vitiligo for patients and their caregivers are discussed, along with joint decision making with this patient and her parents. This was followed by a discussion of the significance of the patient’s anti-nuclear antibody positivity and how this affects treatment approach in patients with vitiligo.

Keywords: Vitiligo, emotional burden, segmental, non-segmental, phototherapy, antioxidants, ruxolitinib

Introduction

Vitiligo is a chronic cutaneous disorder in which autoimmune-mediated melanocyte destruction leads to the development of depigmented patches of skin, hair, and/or mucous membranes.^1,2 It is the most common depigmenting disorder, with a reported global prevalence ranging up to 2.28 percent overall and to 2.16 percent in the pediatric population.³

Vitiligo affects people of all ethnicities and Fitzpatrick Skin Types (FST), and its prevalence is similar among males and females.⁴ Onset of non-segmental vitiligo, which accounts for 80 to 85 percent of vitiligo, is usually between 10 and 30 years of age, although up to 25 percent of patients with non-segmental vitiligo develop the disease in the first decade of life.⁴ Segmental vitiligo typically manifests earlier than non-segmental disease, with about 40 percent of segmental cases presenting before age 10.^5,6

Vitiligo has a profound negative impact on quality of life, including adverse psychosocial effects; these adverse effects are persistent over time due to the chronicity of the disease, its highly visible nature, and the slow and/or inconsistent progression of individual therapeutic responses.^7–9 Affected individuals may often experience embarrassment, shame, low self-esteem, discrimination, and stigmatization with consequences for impaired daily functioning and psychosocial well-being. Mental health conditions, particularly anxiety and depression, are also common in patients with vitiligo, even among those with limited disease, including <1% affected body surface area [BSA]).⁸

The following article explores clinical practice insights on vitiligo management through a case-based roundtable discussion between Clinical Editor-in-Chief of JCAD, James Del Rosso, DO, and two global vitiligo experts with extensive clinical, research, and educational experience, Iltefat Hamzavi, MD, and Pearl Grimes, MD. Before the case presentations, an opening discussion reviews the importance of evaluating the psychosocial and emotional burden in patients with vitiligo and tips for doing so, as well as dimensions of the physical evaluation of vitiligo, including identifying signs of progression and approaches to laboratory testing for comorbid autoimmune conditions. Oral antioxidant therapy is discussed prior to the presentation of two case reports, with subsequent discussion on patient counseling and disease management insights presented by these cases. 

Psychosocial and Emotional Burden of Vitiligo

Dr. Del Rosso: Recently, after long droughts in further understanding and improving the management of many chronic inflammatory dermatoses, we’ve seen a lot of significant advances, including with vitiligo. Before we begin with our case presentations, I’d like to discuss the burden of disease in vitiligo to paint a picture of what these patients within themselves are commonly coping with psychologically. Vitiligo does not produce physical symptoms such as burning, itching, and stinging, and so for many years, many people assumed it to be primarily a cosmetic condition. However, many of the patients with vitiligo that I see in my practice are dealing with depression and anxiety due to their condition, with younger patients sometimes experiencing social embarrassment and bullying at school. 

Dr. Hamzavi: One of the things about vitiligo that we must recognize is that it does have symptoms—it’s just that the main symptoms are psychosocial. If you look at studies like the VALIANT study by Bibeau et al,⁸ which evaluated over 3,000 people to look at these psychological variables across populations throughout the world, you find that the rates of depression and anxiety are much higher among people with vitiligo compared to the non-affected population. Globally, 55 percent of patients evaluated in the VALIANT study reported moderate to severe symptoms of depression according to the Patient Health Questionnaire (PHQ-9).^8,10 Therefore, I think it’s inaccurate to say that vitiligo is a condition without symptoms; rather, the symptoms are not acute or physical, such as itching, but you see significant stigmatization and psychosocial impacts. If we don’t address the psychosocial component of vitiligo, we’re not truly managing the full clinical impact of the condition on the patient. A lot of our outcome measures in clinical trials use the Vitiligo Area Severity Index (VASI), which is an objective measure of vitiligo, but the Patient Reported Outcomes are based more on psychosocial symptoms, including noticeability, stigmatization, and quality-of-life measures. With treatment, these symptoms associated with diminished quality of life improve in many patients.

Dr. Del Rosso: Dr. Grimes, how do you evaluate this psychosocial burden for the many patients with vitiligo and their caregivers that you see at your clinic? 

Dr. Grimes: Most of the patients that I care for every day, which include many children and adults, are individuals with vitiligo. One of the special things that I think we offer at the Vitiligo & Pigmentation Institute is a detailed evaluation of every new patient that we see. The average patient with vitiligo is probably in my office for at least an hour, and part of that visit encompasses gaining insight regarding the emotional trauma that my patients are going through. 

Emotional burden evaluation tips for community dermatologists. Dr. Del Rosso:  Being global experts in vitiligo, you’re seeing a lot of patients affected by the condition in clinics specifically dedicated to the treatment of vitiligo. However, many of our community dermatologists are often seeing patients with vitiligo less frequently, and may encounter time constraints or inconsistent experience within their practices in capturing the psychosocial aspects affecting individual patients with vitiligo. Do you have any insights for these physicians to help them and their staff more easily capture the same information that you might gather in a more prolonged appointment at a center dedicated to seeing vitiligo patients? 

Dr. Grimes: While it is unlikely that the average practice will have the same time and resources to achieve the level of evaluation that Dr. Hamzavi and I are able to in our specialty practices, I think one effective approach for community dermatologists would be to simply ensure that their medical staff, while taking basic intake data, also ask the patient how they’re adjusting to their vitiligo. Considering the psychosocial burden of the condition, that one extra step often gives the patient a greater sense of comfort that there is individual compassion from the staff. This simple step also gives dermatologists a better sense of how much extra support their patient needs regarding the burden and psychological manifestations of the condition. 

Dr. Del Rosso: One thing that I do with my staff is make sure that they’re making eye contact with the patient during their evaluation. Many times, their back is to the patient while they’re intaking patient data into the computer due to the modern-day pressure of capturing information electronically, which is often perceived as impersonal. Encouraging consistent eye contact during conversations about the emotional burden and other aspects of their condition is another small step towards fostering that connection. 

Dr. Hamzavi: To evaluate emotional burden in my patients, I simply ask them, “On a daily basis, how often do you think about your vitiligo?” If they tell me they think about their vitiligo every day, I regard that as a more severe patient. 

Physical Evaluation of Vitiligo

Types of vitiligo and identifying signs of progression. Dr. Hamzavi: During the physical evaluation in my patients, I categorize them into one of two groups: segmental and non-segmental vitiligo. Non-segmental vitiligo crosses the midline, tends to be progressive, and might require a more extensive skin exam than segmental vitiligo. Segmental vitiligo comprises about 15 percent of patients and tends to appear on only one segment of the body. Segmental vitiligo tends to respond to the same treatments as non-segmental vitiligo but is more amenable to surgical interventions and tends to affect younger people. About 80 to 85 percent of patients are affected by non-segmental vitiligo, and in these patients, I double check for signs of progressive vitiligo. There are three signs of progressive vitiligo: 1) confetti-like macules, similar in appearance to paint thrown against a wall; 2) Koebnerization; and 3) trichrome vitiligo. 

Dr. Del Rosso: Are those signs localized to the same affected region, or can they appear throughout the body?

Dr. Hamzavi: These would appear throughout the affected areas on the body as a whole. A patient with progressive disease may display Koebnerization on an affected area on one side of the torso, and trichrome vitiligo on an affected area on the legs. Going back to my psychosocial evaluation of the patient, if the patient discloses that they think about their vitiligo every day, and they also show signs of progressive disease, I know that they’re going to be impacted to a much greater degree as their condition continues to progress. 

Approaches to laboratory testing for comorbid autoimmune disease. Dr. Del Rosso: I’ve seen patients with vitiligo who come in with concerns after finding information on the internet regarding possible thyroid disease as a comorbid condition of vitiligo. Upon initial patient assessment, what thyroid laboratory assessments do you perform for your patients with vitiligo?

Dr. Grimes: For every new patient that I see here at the Institute, regardless of whether it’s an adult or a child, we order a standard panel of labs that includes a complete blood count (CBC) with a differential, a comprehensive metabolic panel, a thyroid panel (thyroid-stimulating hormone [TSH], free T4, and a thyroid peroxidase antibody), an anti-nuclear antibody (ANA), and vitamin D levels. I generally recommend that my patients repeat those tests every 1 to 2 years.

Dr. Del Rosso: Do you test both the anti-thyroid peroxidase and the anti-thyroid globulin antibodies? 

Dr. Grimes: We used to do a thyroid globulin antibody many years ago, but our standard now is just a thyroid peroxidase antibody. What we find is that if at baseline, the patient has a positive thyroid peroxidase antibody, albeit their thyroid function tests are normal, that patient is at a much higher risk of developing thyroid disease over time. Therefore, we use that test to determine how closely we need to follow those patients regarding the development of future comorbid thyroid disease. Regarding vitamin D testing, we’ve been looking at this for many years and we pick up such a high incidence of vitamin D deficiency in patients with vitiligo; it is a major player in modulating the immune response. 

Dr. Del Rosso: Dr. Hamzavi, in this same vein, what advice would you give to busy clinicians on how to approach these laboratory considerations, specifically around possible comorbid thyroid disease? What would you consider to be the basic laboratory testing that clinicians should order?

Dr. Hamzavi: I think it’s important to look at the prevalence and incidence of the different autoimmune diseases. I tend to be a minimalist and base my testing decisions on symptoms. The one test I do is a basic TSH, because 17 to 25 percent of patients, depending upon the study you’re looking at, over a ten-year period, develop thyroid disease.^11–14 Therefore, I usually do a TSH every three years, since that is the most common comorbid disease. Other than the TSH, I test based upon the symptoms that I’m observing in the patient. If a patient is photosensitive, I’ll test for an ANA. If they report visual symptoms or hearing issues, I’ll check hearing and additional autoimmune antibodies. 

Dr. Del Rosso: What autoimmune antibodies would you be checking for related to hearing and vision? 

Dr. Hamzavi: For vision, specifically photophobia, I check ANA. For hearing, I would check for middle frequency hearing loss. In vitiligo, there is an autoimmune hearing loss that sometimes occurs. If my patients reference that as a daily event, then I’ll order a mid-frequency hearing test. Except for the TSH, which I only do every three years, I don’t do any of these tests unless there are symptoms. There are no official standards on these testing protocols, so clinicians normally have varying methods when it comes to testing.

Dr. Del Rosso: Dr. Hamzavi, do you evaluate vitamin D levels similar to Dr. Grimes?

Dr. Hamzavi:  Where I practice in Michigan, we tend to have more overcast skies and less sunlight exposure than in southern California and Las Vegas. If they haven’t had vitamin D tested by their primary care doctor, I will test for it, because deficiency is so common. I’ll often just ask my patients to supplement with 1,000 IU to 2,000 IU of vitamin D daily as a standard protocol without testing for deficiency, since I do think everybody in the Midwest region of the United States should be supplementing with vitamin D.

Oral Antioxidant Treatment in Patients with Vitiligo

Dr. Grimes: We believe that patients with vitiligo do not handle oxidative stress well, and that inability to handle oxidative stress exposes them to an aberrant immune response, an activation of the innate and active immune response, which ultimately activates the interferon Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway that drives the destruction of melanocytes.

Dr. Del Rosso: I am glad you mentioned oxidative stress in vitiligo, as I have seen that discussed as an important contributor to the pathophysiology of vitiligo.^15,16 To this point, Dr. Hamzavi, do you use antioxidant treatments in your patients with vitiligo?

Dr. Hamzavi: We have a lot of data showing that oxidative stress is a factor in vitiligo, and we have a fair amount of randomized, controlled trials showing that interventions with antioxidants are effective. Three oral antioxidant agents stand out in this context: Polypodium leucotomos extract (PLE), Ginkgo biloba, which is a natural antioxidant from traditional Chinese medicine, and superoxide dismutase in combination with phototherapy.^17–23 Alpha lipoic acid is also referenced, but the three former agents have been evaluated in a small number of controlled trials and are the three antioxidants that I commonly use in my patients with vitiligo. The challenge with over-the-counter antioxidants is that the brand names of these formulations become important to ensure the stability of the antioxidants. I try to work with certain brands that I know have a supply chain that is monitored and that encloses expiration dates. It’s important to note that these agents when used adjunctively can help stabilize the condition, but rarely will do much on their own. Therefore, oral antioxidants should be used as part of a combination of therapies. 

Dr. Del Rosso: Do you have any insight on possible adverse events associated with these antioxidant agents? 

Dr. Hamzavi: Ginkgo biloba can sometimes cause a bleeding tendency, so we need to be careful when the patient is undergoing any dental or surgical procedures. This is especially true in elderly patients, so I tend to stay away from its use in this patient population. Alpha lipoic acid can sometimes cause changes in glycemic levels. PLE can occasionally cause nausea and superoxide dismutase can cause bloating in rare instances, but for the most part, these agents are safe and well tolerated. 

Dr. Del Rosso: Going back to your important comment on formulation, we do know of one formulation of PLE (Heliocare®, Ferndale) that has been evaluated extensively in comparison to multiple other formulations and shown to be consistent in how it is harvested, manufactured, and with consistency of its polyphenol contents and various recognized outcome measures. There are many PL and PLE formulations out there and you generally don’t know what you’re getting unless they’ve been properly evaluated and validated. 

Case 1 Presentation

In a case that illustrates the combination of several therapeutic options, a 32-year-old White woman with Fitzpatrick Skin Type III presented to Dr. Hamzavi’s clinic with a long-term history (>5 years) of vitiligo and 75-percent affected BSA and progressive disease that yielded extensive depigmentation of the trunk (Figure 1). The patient had a family history of vitiligo, psoriasis, thyroid dysfunction, and type I diabetes. Her Vitiligo Noticeability Scale (VNS) score upon presentation was 1, where 1=more noticeable; 2=as noticeable; 3=slightly less noticeable; 4=a lot less noticeable; 5=no longer noticeable. The patient’s Dermatology Life Quality Index (DLQI) and PHQ measures were 21 and 6, respectively, upon presentation, indicating a dramatic effect of her condition on her quality of life. Prior to presenting to Dr. Hamzavi’s clinic, the patient had failed previous treatment with NB-UVB phototherapy and topical agents. The psychosocial symptoms of her condition included avoiding leaving her home, avoiding romantic relationships, and feelings of limited opportunities for advancement in her career. Upon presenting to Dr. Hamzavi’s clinic, she received a full physical evaluation and a standard thyroid check, which revealed uncontrolled hypothyroidism. This was subsequently addressed via thyroid replacement therapy through the patient’s primary care physician. The patient’s vitiligo was then treated with oral dexamethasone 4mg on Saturdays and Sundays for three months; this was combined with NB-UVB phototherapy twice per week (57 sessions over 6 months, 1,000 mJ/cm²) in accordance with current treatment recommendations,²⁴ topical therapy, which started with tacrolimus ointment 0.1% BID and eventually switched to ruxolitinib 1.5% cream BID, and oral antioxidants. The topical tacrolimus was used initially based on an insurance company step-therapy requirement. After six months, this treatment combination yielded notable improvement (Figure 2), with roughly 90-percent repigmentation. Noticeablility of the patient’s vitiligo, according to the VNS, went from 1 (more noticeable) to 5 (no longer noticeable) following her treatment. Additionally, DLQI was reduced from 21 to 9, and PHQ was reduced from 6 to 2—indicating a marked improvement in her quality of life. 

The nature of the patient’s vitiligo necessitates maintaining her treatment regimen to the current day, but she has reported a subsequent decrease in her psychosocial symptoms following her marked improvement.

Case 1 Expert Panel Discussion

Patient counseling. Counseling around treatment response and consistency. Dr. Del Rosso: In Figure 2, the patient is still showing areas of speckled depigmentation. Does that still affect her emotionally? 

Dr. Hamzavi: We have to filter out our own biases when it comes to evaluating perceived treatment success in vitiligo. When my patients achieve an 80- to 85-percent degree of improvement, that often improves their quality of life. For this patient, the improvement we see here made her much more comfortable with her condition. For you and I, that may not be enough, because there’s still visible areas of depigmentation. As available treatments continue to improve, we’ll get to complete repigmentation, and she may likely achieve this with continuation of her current therapy. We’re hoping to achieve complete repigmentation in more patients with some of the upcoming oral Janus kinase (JAK) inhibitors on the horizon for vitiligo. However, even the oral JAK inhibitors often require combination therapy. We need to be using combination therapy to treat vitiligo effectively, especially in the non-segmental, generalized type.

Counseling around treatment response and consistency. Dr. Del Rosso: In my mind, you can get marginal repigmentation that comes in from the side without any repigmentation coming from the follicles. That is great, but I’m really encouraged when I see follicular repigmentation; I take that as a sign that they’re probably going to respond better due to the follicular source of melanin production. However, there’s a period of time when the repigmented area appears very speckled looking and may not be visibly appealing to some patients at that point in time. I have patients ask me if they’re going to retain this speckled looking appearance. I tell them that it represents new sources of melanin pigment that is very likely to fill in and achieve complete or near-complete repigmentation. Repigmentation of vitiligo takes time that is measured in several weeks to months and any new source of increased melanin pigmentation is a welcome sight to see. 

Dr. Hamzavi: Correct. There are three forms of repigmentation: follicular, which is the most common, marginal, which repigments around the edges of the affected area, and combination, which is the least likely. Some oral agents, in combination with phototherapy, will yield combination repigmentation. We also sometimes see a mismatched color repigmentation, especially in FST III or IV skin treated with phototherapy, where the newly pigmented skin will appear darker than the normal skin. However, this blends in over about six months to a year. 

Dr. Grimes: I agree with the points made by Dr. Hamzavi and Dr. Del Rosso—the follicular pattern of repigmentation does indeed portend the best prognosis for substantial repigmentation. When we see border repigmentation, it suggests that rather than a follicular response, pigment cells are dividing in the epidermis and migrating in much more slowly and inefficiently. If a patient is going to respond really well, we want to see the follicular response, but we’ll take anything that we can get from the borders. There is a rare cohort of patients who will have a reservoir of residual melanocytes—these patients can display diffuse repigmentation within a lesion. I describe it as follicular border with a less common diffuse pattern. To Dr. Hamzavi’s point regarding the temporarily darker areas of repigmentation, I’ve had patients express concern upon seeing this. However, I reassure them that with time, the hyperpigmentation will subside. Once those areas begin to coalesce, the hyperpigmentation begins to fade and match the normal skin.

Patient counseling through regional repigmentation. Dr. Del Rosso: There are certain locations that are harder to achieve repigmentation. Dr. Hamzavi, when this patient was being treated, were there areas that responded sooner than other areas?

Dr. Hamzavi: There’s a regional approach to vitiligo. Dr. Seemal Desai has a nice saying, “The face is fabulous.”²⁵ The face often responds faster and better compared to other areas; there’s a greater degree of response, and more people respond on the face. The torso, the upper legs, and the upper arms follow in terms of degree and speed of response. The areas that are the least likely to respond to treatment are the tips of the fingers and tips of the toes. This is why vitiligo experts aggressively treat with systemic phototherapy and topical agents the minute that they see anything around the fingernails—because once a patient depigments in that area, it can be notably difficult to repigment. So, in summary: The face is fabulous, tips not so much, and everything else is in between. 

Dr. Del Rosso: It is not uncommon for the genital region in either gender to be affected by vitiligo. How responsive to therapy is genital vitiligo? 

Dr. Hamzavi: In my experience, the genital area should respond within the first six months of topical treatment, and if it doesn’t, it’s not going to respond at all, and this includes both male and female genital areas. It is very challenging to elicit a treatment response in the non-hair-bearing areas of the female genitalia, but they can respond if you treat them early enough. 

Dr. Del Rosso: How do you counsel patients through this process of variable repigmentation rates across different locations?

Dr. Hamzavi: I remind them that vitiligo takes time. To effectively treat vitiligo, dermatologists need to counsel their patients around the fact that treatment is going to take weeks to months. The speed of response is not going to be like psoriasis or atopic dermatitis. If we don’t disclose a realistic treatment timeline at the first visit, the patient may become discouraged and be lost to follow up within a few weeks when they aren’t seeing a response. There are subgroups of patients who will display rapid response to phototherapy. These patients respond to phototherapy within about 12 weeks, and they normally show the best overall response. Another subgroup shows minimal response to phototherapy, and it might take them up to 72 treatments to see even follicular repigmentation. But often, patients are just looking for some hope and a few freckles, so we need to allow enough time for that to happen. If a patient doesn’t respond with significant repigmentation within about 24 phototherapy treatments, they probably will not see a tremendous degree of repigmentation. Importantly, phototherapy combined with a topical, like tacrolimus or ruxolitinib, or a systemic, like oral corticosteroid therapy or an oral JAK inhibitor, are always going to yield better outcomes than phototherapy alone. Lastly, durability of response and maintenance are important considerations. After repigmentation is achieved, we need to maintain with topical therapy twice per week, or phototherapy once per week in patients with more extensive disease. The memory T-cells are present, so if a patient stops treatment completely, they will return to your clinic with recurring depigmentation forty percent of the time. With maintenance via topical treatments and phototherapy, the rate of recurrence drops to about nine percent. 

Dr. Del Rosso: Often, patients with significant depigmentation seek out treatment and are told that they have limited chances for improvement, or have tried treatment previously with little success, and so they feel discouraged. How do you talk to your patients to ensure that they’re sticking with their treatment long enough to see results?

Dr. Hamzavi: I show patients pictures of the best-case scenario responses to treatment that have been achieved in the adequate time period that I’m recommending. I disclose that while I can’t guarantee the best-case scenario level of response to treatment, to have a chance at achieving this, they need to stick with treatment for at least three months, and ideally six months. If they are unable to stay with treatment for that length of time, I might not be the physician for them. 

Incorporating topical treatment in patients with extensive depigmentation. Dr. Del Rosso: In this patient, we’re seeing extensive depigmentation across a large area of the trunk. Regarding topical therapy, we’re not going to instruct a patient to bathe in the topical therapy that we’re prescribing. For a topical treatment like ruxolitinib cream, for example, there is the limitation to use on up to a 10-percent body surface area. Considering this, how do you incorporate these topicals into a patient like this? 

Dr. Hamzavi: I think this is a good example of that. We took this patient from almost 90-percent depigmentation to 90-percent repigmentation, and now you can use your topical therapies on those smaller patches. You wouldn’t use topicals on a patient like this when they first come into the clinic. We use our systemic treatments initially, then discontinue the systemic dexamethasone and use phototherapy twice per week while continuing to use a topical—this patient is now using topical ruxolitinib, and most of those smaller areas have repigmented.

Switching from tacrolimus to ruxolitinib. Dr. Del Rosso: Regarding the change from topical tacrolimus to topical ruxolitinib, was that based on availability of the newer agent? Topical tacrolimus is a calcineurin inhibitor that is frequently used for vitiligo, but it hasn’t been approved for use by the United States Food and Drug Administration. Did you decide to switch the patient to ruxolitinib once it was approved for vitiligo, or were there other factors involved in that decision?

Dr. Hamzavi: Most insurance companies in Michigan, where I practice, require step therapy. I had to start with the tacrolimus, and then after step therapy I was able to get ruxolitinib approved for use on the localized areas in this patient. 

Phototherapy considerations. Switching from tacrolimus to ruxolitinib. Emerging evidence shows the potential for enhancing melanocyte regeneration by the addition of phototherapy to topical ruxolitinib.²⁶ Nineteen patients who participated in a long-term extension of a Phase II dose-ranging study of topical ruxolitinib started NB-UVB while using topical ruxolitinib cream 1.5% twice daily. Phototherapy was received for a mean of 40 weeks and most often as thrice weekly sessions. At last follow-up, Facial Vitiligo Area Scoring Index (F-VASI) score improved from baseline (before starting phototherapy) in 79 percent of patients (mean change 50.2%), Total Vitiligo Area Scoring Index (T-VASI) score improved in 95 percent of patients (mean change 29.5%), and improvements were also seen in other analyzed F-VASI and T-VASI response parameters. The combination treatment was well-tolerated, and there were no treatment-related adverse events. Results are pending from a completed, prospective, Phase II study evaluating ruxolitinib cream with phototherapy in adolescents and adults with non-segmental vitiligo.²⁷

Dr. Del Rosso: When you’re using phototherapy combined with topical therapies, such as the topical ruxolitinib that was ultimately used in this patient, you don’t want the patient to apply the topical agent right before the phototherapy. I know phototherapy breaks down certain agents, so how do you instruct patients to use topical therapy when you’re also treating with phototherapy? 

Dr. Hamzavi: Ruxolitinib has been studied in combination with phototherapy in open-label extensions in the Phase II and Phase III clinical trials,²⁶ and it has been shown to be more effective in this combination versus alone, but the ruxolitinib needs to be applied after the phototherapy. All topical agents have some optical impact on the skin, so it’s better to avoid its use until after the phototherapy session is complete. 

Dr. Grimes: One of the approaches that we use here at the Institute for these larger areas is fluocinolone oil, a low-potency topical corticosteroid. I have patients use that every day in combination with NB-UVB phototherapy, and I’ve seen an excellent response with this combination protocol for larger areas in adults and children. We would use higher potency topical corticosteroids on smaller areas, but for patients with larger affected areas undergoing NB-UVB phototherapy, I use a lower strength topical corticosteroid on a more prolonged basis.

Phototherapy access and home phototherapy options. Dr. Del Rosso: Let’s say you didn’t have access to phototherapy for this patient. Do you think you could have achieved similar improvements?

Dr. Hamzavi: With this extent of depigmentation, it’s not likely. If a patient has a smaller affected surface area, we could get by with only topical and systemic agents. Systemic treatments work to stabilize the disease, so if a physician is encountering signs of vitiligo progression that we previously discussed, that progression can be halted using systemic treatments, such as the dexamethasone that I initially used when treating this patient. For patients with limited access to phototherapy and localized areas of vitiligo, at-home phototherapy is a viable option. We’ve published data²⁸ in which we tested over-the-counter phototherapy devices and we outlined which ones have a matching irradiance. Regarding efficacy, at-home phototherapy and in-office phototherapy are equivalent for the most part.²⁸

Case 2 Presentation

In a case that illustrates the long-term treatment of a pediatric patient, a White female patient with FST III presented in 2019 to Dr. Grimes’ clinic at the age of 5 years with rapidly progressive disease with affected areas on the face, trunk, upper and lower extremities, hands, and feet, with an affected BSA of 10 percent (Figures 3 and 4). The patient had no determinable precipitating factors for the depigmentation and was in overall excellent health, with no known history of comorbid autoimmune conditions and a negative family history of vitiligo. Dr. Grimes’ standard laboratory evaluation for this patient returned with a normal CBC with differential, an unremarkable comprehensive metabolic panel, normal TSH, normal free T4 and T3 levels, and negative for thyroid peroxidase antibodies. She was not vitamin D deficient. However, the patient was ANA positive (1:160); because of this relatively higher titer, a lupus panel was performed—which included complement component C3c and C4c, DNA antibody, ribosomal P antibody, Smith (Sm) antibody, Sm/RNP antibody, Sjogren’s antibodies (SS-A, SS-B), scleroderma antibody (Scl-70), and rheumatoid factor. However, these lupus panel antibodies were negative. Upon presentation at age 5, the patient began treatment with NB-UVB phototherapy, tacrolimus 0.03% ointment once daily, and oral prednisolone liquid (15 mg per 5 cc) with a dose of one-half teaspoon (7.5 mg) daily for two weeks. This resulted in the stabilization of her condition and the progressive repigmentation following one year of treatment. From 2021 to 2022, despite early repigmentation, there was progression of areas of depigmentation of the face, trunk, and extremities. The patient’s parents purchased a home phototherapy unit to avoid having to pull the child out of school for in-office appointments. While the parents were anxious about the progressing disease, the patient was becoming very resistant against further treatment of her condition. As a result, treatment was discontinued, with ongoing monitoring of her condition. In 2023, after substantial emotional support, the patient became cooperative towards treatment with NB-UVB phototherapy and topical therapy. In early 2024, the patient commenced treatments to the affected patches on the face. Within three months of seeing the improvements that were achieved in her facial area, she resumed NB-UVB phototherapy treatment to the other affected regions. After six months of NB-UVB phototherapy, topical corticosteroids, and topical calcineurin inhibitors, the patient achieved 75-percent pigmentation of the face, trunk and extremities (Figures 5 and 6).

Case 2 Expert Panel Discussion

Emotional burden of vitiligo in pediatric patients and their caregivers. Dr. Grimes: I want to highlight some of the important insights that we can gain from this case. We’ve discussed the burden of vitiligo in children. This patient’s desire to discontinue treatment presents an interesting dimension of that burden. Children with vitiligo can be bullied and the condition affects their self-worth and self-esteem. However, the reality is, when you force treatment on children who don’t want treatment, that can have its own psychologically harmful effects. In this case, the parents and I jointly made the decision that we would discontinue treatment but continue to monitor her condition and support her emotionally until she came to her own decision to return to treatment. Another point I’d like to emphasize is the emotional burden for parents of pediatric patients with vitiligo; we have definitive evidence showing that the burden is enormous for parents as well.²⁹ In the same way that we support the child through the psychosocial burden of vitiligo, we should be mindful of the effect that it is having on parents and strive to provide the same support to them. Providing this support can be difficult in a busy practice, but having just one member of your staff reach out and provide that support can go a long way in mitigating the psychosocial symptoms that patients with vitiligo and their involved family members are experiencing as part of this persistently bothersome condition.  In both this case and in Dr. Hamzavi’s case, providing emotional support, tailored to the needs of each patient, is a vital aspect of vitiligo management. 

The therapeutic significance of anti-nuclear antibody positivity. Unlike the thyroid antibody testing discussed earlier, which portends the greater likelihood of the patient developing thyroid disease, the ANA does not portend a greater likelihood that the patient is going to develop lupus. Lupus is one of the less common comorbid autoimmune diseases in patients with vitiligo. I view it as a marker of an aberrant immune response. If the ANA is higher—let’s say it’s over 1:1,280—then I’m ultra conservative in treating those patients with NB-UVB. 

Dr. Hamzavi: To add to that, when you have a patient with a positive ANA who either doesn’t respond to phototherapy or has a significant sensitivity, I’ve found success in adding 200mg of ibuprofen, taken about an hour before light treatment, or 480mg of PLE, taken an hour and a half prior to phototherapy, to improve the photoadaptive capacity. You won’t be able to achieve the same levels of dosing in phototherapy—you want to cap at about 1,000 mJ, but this can help these patients tolerate and respond to the phototherapy better.^30,31

Topical considerations for adolescents with vitiligo. A post-hoc analysis of data from the TRuE-V1 and TRuE-V2 clinical trials evaluated differences in rates of complete or near-complete repigmentation and repigmentation by body region between adolescents and adults who were initially randomized to 1.5% ruxolitinib cream and applied ruxolitinib cream for up to 104 weeks. A greater proportion of adolescents versus adults who applied topical ruxolitinib achieved complete facial repigmentation at Week 24, although there was no separation at Week 52. Additionally, rates of 75-percent and 90-percent total body improvement in vitiligo were greater among adolescents compared to adults at Weeks 24 and 52, and a greater proportion of adolescents achieved a 50-percent improvement in the lower extremities and feet at Week 52. Overall, results of the analysis suggest that adolescents with vitiligo may have a greater likelihood of achieving complete repigmentation with application of 1.5% ruxolitinib cream compared to adults.³²

Dr. Del Rosso: Regarding topical therapy in this case, this patient wasn’t a candidate for topical ruxolitinib due to age restrictions. However, if this patient was 13 or 14 years of age, would you have considered incorporating it into their treatment regimen?

Dr. Grimes: I would have. For my adolescent patients over the age of 12, it definitely has a role to play in their treatment, and we’re seeing excellent responses in this particular patient group.³³ We are at such an exciting watershed moment right now with the new therapies currently in Phase II and Phase III development for adults and children with vitiligo. I think within the next few years, we might also have oral JAK inhibitors approved for vitiligo. Dr. Hamzavi alluded to the fact that these topical and oral JAK inhibitors are best used in combination with phototherapy to achieve optimal outcomes, but in some patients, they may be able to be used as monotherapy. The landscape is certainly changing. 

Dr. Del Rosso: Thank you to both of you for your willingness to share your expertise, clinical insights, and extensive knowledge from clinical studies and publications about vitiligo. None of this happens without personally investing years of experience and dedication to managing patients with vitiligo and a strong desire to share what you know with your colleagues. Your efforts in assisting with this project are greatly appreciated. I know that I look forward to learning more from both of you about vitiligo and its management. There are certainly better approaches to therapy that are currently available compared to even the relatively recent past, and more good things are in the pipeline for people affected by vitiligo. 

References 

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