Two of the most vexing skin conditions dermatologists manage are melasma and vitiligo. Seemal Desai, M.D., board-certified dermatologist, clinical assistant professor in the department of dermatology at University of Texas, Southwestern Medical Center in Dallas, and medical director of Innovative Dermatology, discusses treatment options.
Two of the most vexing skin conditions that we manage as dermatologists are melasma and vitiligo. In one condition, too much pigmentation is present because of genetic, hormonal and environmental factors. In the other, there is a lack of melanin in the skin, presumably on an autoimmune basis. Seemal Desai, M.D., board-certified dermatologist, clinical assistant professor in the department of dermatology at University of Texas, Southwestern Medical Center in Dallas, and medical director of Innovative Dermatology, discusses treatment options for these two conditions with Dermatology Times editorial advisor, Norman Levine, M.D.
Dr. Norman Levine: I would like to talk about two specific problems with regard to dyspigmentation. The first one I would like to start with is melasma. What are our current treatment options and how well do they work?
Dr. Desai: I will preface my overview of melasma by saying that the majority of patients who I see for melasma end up on multiple combination therapies; I rarely have a melasma patient on monotherapy. I think that’s one of the things that becomes challenging for most dermatologists; they are not really used to doing combination therapies for melasma.
First-line treatments are topical, especially topical lightening agents and the prototypical one is hydroquinone. Not to be missed is the incorporation and use of topical retinoids, specifically tretinoin, adapalene, and tazarotene, along with low-potency and high-potency topical steroids.
In some circumstances, I have also used high potency topical steroids for very short duration on the face, without consequence; for example, class 1 topical steroids. The main issue here is that you have to discuss the risks and benefits with the patient, as well as administer the medication in a short pulse duration fashion. Again, this is not for every patient, but it can be useful in patients who do have an inflammatory component, mixed pathology, and/or you want some additional epidermal thinning to then help with cell turnover.
Triple combination therapy
Dr. Levine: Do you use that combination treatment which is already pre-formulated, or do you divide it up and pick and choose which of the agents you wish to use at one time?
Dr. Desai: The triple combination therapy is really in the literature as first-line, which is the hydroquinone, retinoid and steroids all-in-one.[i] However, I don’t always do that, as availability of the branded product had become an issue, and often cost plays a significant role for our patients. I actually make my own compound of the hydroquinone, retinoid, and steroid. But I add kojic acid in addition to that. So mine is actually a four-ingredient compound.
The reason I started doing this is was that the branded triple combination was discontinued for an extended period of time, which led to issues of access to therapy and then to me doing some more creation of my own formulation. So I don’t use the branded ready-made mixture, I actually make my own mixture.
Now if you don’t want to do that or cannot access a compounding pharmacy, you can still use that triple combination that is back on the market. It is available; the problem is, it that it can be expensive. So for patients who can’t afford that, they could use a prescription for a generic retinoid and a generic hydroquinone and apply those one layer at time, starting with the retinoid first at night. The steroid then doesn’t have to be necessarily used at night and can be used the following morning. Sometimes it helps with the retinoid dermatitis if the patient is going to experience that.
Dr. Levine: Now there is an old-fashioned product, Groot’s Cream, which is a high concentration of hydroquinone. Is that good, bad or indifferent?
Dr. Desai: Believe it or not, that product actually works. You bring up an interesting point, which is higher-strength hydroquinone. I do use higher-strength hydroquinone in patients who have failed at least an 8-12-week course of 4% hydroquinone combination therapy along with an additional treatment option, which in my practice second-line is chemical peel treatments. I highly encourage practitioners to incorporate chemical peels for the treatment of melasma in combination with a topical agent. A number of studies support that.[ii]
If one fails 8-12 weeks of 4% combination of hydroquinone therapy and at least two rounds of chemical peels, then I increase the strength of hydroquinone to 8%. I’ve actually gone as strong as 12% in some patients. The problem is, it is highly irritating in that concentration, but it works. Of course the other issue is that, as you increase the strength, you are increasing your risk of exogenous ochronosis from hydroquinone, which is a problem. There was a really nice paper published in the European literature that discusses the supervised use of hydroquinone in a limited duration supervised use of prescription topical hydroquinone had no more than a theoretical risk of malignancy, developing ochronosis or other long term safety side effects. You get into trouble when it’s long-term use that’s unsupervised and in high concentration. So I would say that higher hydroquinone is not something to be afraid of if you use it the right way, short duration, in the right patient setting, and with extensive counseling.[iii]
Dr. Levine: How do you use chemical peels in melasma?
Dr. Desai: Chemical peels have really become a huge part of my practice for several reasons:
I tell patients who have melasma that they need to do, on average, at least three chemical peels to really start noticing any improvement; however, the ideal is a series of five peels. I usually space those every two to three weeks apart.
For a brand new patient who comes in with melasma, I will prescribe a combination lightening agent, retinoid, and steroid along with a physical blocker sunscreen. I also have an extensive conversation about photoprotection. After a month, I check in with the patient to see how the therapy is going, and then I often start the chemical peel treatments.
My go-to chemical peel for a new melasma patient are either 30% glycolic acid or 30% salicylic acid. The only time I choose salicylic over glycolic is if the patient is extremely oily and had large prominent sebaceous pores, or if the patient has acne with melasma. The salicylic will help the comedonal and cystic lesions as well as the pigmentation.
There is no reason you can’t do salicylic acid peeling on a patient with no acne, the point is to stimulate collagen growth and help desquamate the epidermis and those keratinocytes. But glycolic tends to work well and the studies do favor glycolic for melasma.
The preparation is very easy. I use acetone or alcohol to remove the debris on the skin. I then apply the acid solution, allow it to penetrate for about two to three minutes, and then apply a neutralizing agent as well as a good emollient and sunscreen. The key is to make sure the patient has stopped the prescribed retinoid or the combination five to seven days before the peel.
I have patients sign a consent form that goes over the risks and benefits of chemical peels, just like any other procedure. In this case, they also initial that they have discontinued the retinoid at least five to seven days before the procedure.
Two to three weeks later, the patient returns for the next peel. The patient can reinstitute the topical regimen in between the peels. I have had great success with this, and patients like it because it’s not very expensive.
Dr. Levine: Is there any role for lasers in the treatment of melasma?
Dr. Desai: Yes, I do laser therapy. Ideally the one that I use is the Q-switched Nd:YAG. The reason is the frequency and the pulse duration: The Q-switched is a much faster treatment in terms of its pulse duration. Again, I pretreat with hydroquinone, lightening agent, and sunscreen prior to the treatment and perform three to four sessions spaced apart monthly. There are some good studies supporting this, too.[iv]
I will also perform laser treatments on patients with skin of color; however, one has to have a really motivated patient. I would not do laser first-line prior to peel. Unless the patient is absolutely adamant, I start with the peels. If the peels don’t have good results, I move up to the next treatment option, which could be laser therapy, higher strength hydroquinone, non-hydroquinone based lightening agents, or other modalities.
Dr. Levine: If a person comes in who clearly has a major risk for continued melasma - they are on birth control pills, they are pregnant, etc. - will you try to treat them aggressively in the face of having the risk factor?
Dr. Desai: This issue comes up a lot. I do treat women who have had one pregnancy and who are postpartum, then develop melasma, but still plan on additional pregnancies. I have the discussion with them about the etiology and root cause of what is most likely causing the condition. Studies in the past five to six years have found that there are triggers for melasma, are primarily hormonal in many cases, but it’s more of a multifactorial condition than we realize. So it’s probably not just the hormonal influence that’s triggering the condition to perpetuate. It’s probably triggering the onset.
We know melasma can be epidermal, dermal or mixed, and the long-term problem if melasma continues untreated is that pigmentation is going to go deeper into the dermis where you are going to get a lot of pigment incontinence. Once you get that dermal pigment or that mixed pathology melasma (that) you see on biopsy, it’s virtually impossible to get rid of that dermal pigment. So treating it aggressively early on when you mostly have epidermal involvement is key.
This brings me to one other point, which is biopsy. If I have a patient who comes in who is not responding to therapy, I consider alternatives to melasma. I think there is a gut instinct to put patients with facial hyperpigmentation in the melasma box, but it’s not always the case. A small 2mm punch biopsy from the lateral part of the face, such as the lateral zygoma, actually heals very well with minimal scarring. The biopsy is going to give you a lot of insight into what treatments you can tailor for that patient.
So I do encourage my colleagues to think about that if (they) have a patient who is not responding to therapy or has somewhat of an atypical presentation.
Dr. Levine: Do patients with vitiligo need a workup for an associated autoimmune disease?
Dr. Desai: Every new patient who comes to me with vitiligo gets evaluated for an associated autoimmune disease. I have a vitiligo questionnaire, which covers the maternal and the paternal history if they’re both known. We talk about autoimmune pathology and more specifically look for the most common associated autoimmune disease, which will be thyroid dysfunction; specifically, hyperthyroidism. I also look for diabetes, which is also very common; pernicious anemia, which is somewhat more rare; rheumatoid arthritis; and other connective tissue diseases that can be associated.
Usually the main tests I perform are the thyroid-stimulating hormone (TSH) and reflex T4 and an antinuclear antibody test.
I used to do a TSH only, but I talked with some colleagues in India and Asia about different types of vitiligo pathology, and heard that sometimes the TSH can be normal, but you can still have a T4 abnormality associated with the systemic thyroid receptor. So I now do TSH with reflex T4.
I also check for iron, similar to a patient with hair loss, where we check for iron to make sure their ferritin load is normal. And then there have been some studies that have shown the importance of checking vitamin B12 and folic acid for vitamin levels, which can be associated also in rare cases.
I don’t do that for every single patient, nor do I check vitamin D for every single patient, one of the reasons is that we know that vitamin D is abnormal in so many patients with or without vitiligo, that it leads you into, ‘What’s causing what?’. I usually leave that up to the primary care doctor who is checking that as part of the routine physical. If there is a large abnormality in the vitamin D, supplementation obviously is very helpful and there are reports that vitamin D supplementation helps vitiligo.
Dr. Levine: Insurance carriers often deny payments for the treatment of vitiligo. What can we tell the third-party payers to persuade them that this is a genuine medical condition with import to the health of the patient?
Dr. Desai: I deal with this every day, including denials on phototherapy, denials for calcineurin inhibitors, even denials right now for certain topical steroids. The cost of generics has gone up significantly. What I do is I send an appeal to the insurance company.
I write a letter that bypasses the prior authorization department, because what’s going to happen is most of these insurance companies are set up with these automated computer systems that are just “trained” to deny things. I encourage colleagues to do this, too:
I write a letter that goes directly to the medical director of the insurance company that discusses the systemic associations with vitiligo. There are some new studies - including one that was published in the Journal of the European Academy of Dermatology and Venereology[v] last year - that show that vitiligo is a systemic inflammatory disease, similar to systemic inflammatory diseases like psoriasis. That systemic inflammatory pathology, we know, can then lead to other sequelae, including other systemic conditions like psoriasis, atherosclerosis, heart disease, metabolic syndrome. If you have lab abnormalities, you’ve already got a slam-dunk; if you don’t have lab abnormalities, then you talk more about the systemic implications and how that has been proven.
I type up some of those studies if needed, and then I make sure that (the medical directors) know that this is a medically necessary condition to treat, which also has a psychological impact. I don’t think we should be scared to discuss that impact with our patients and to talk to them about depressed moods. We know that vitiligo is very stigmatizing in certain ethnic cultures and has a huge psychosocial impact, and charts should be documented accordingly.
So as an aside, when you do review of systems with the patient, you need to ask about mood and talk about that, because it’s so underreported and undertreated.
Treatment options for vitiligo
Dr. Levine: What treatment options do we now have for vitiligo?
Dr. Desai: First-line for me continues to be class 1 topical steroids along with calcineurin inhibitors. I tend to pulse those, meaning I use the class 1 steroids for approximately two weeks duration b.i.d., followed by the calcineurin inhibitors, pulsing two weeks b.i.d. Many of the vitiligo experts do this. I spent time with Jim Nordlund, M.D., many years ago and used a lot of his tips from his years of vitiligo experience.
So those are mainstays, and then phototherapy of course. Specifically, I use narrowband UVB two to three times a week for all skin types. I have also started doing a lot of excimer laser, which targets more localized disease, and (is an) inexpensive treatment as well, (it) does have a CPT code for insurance, and it is covered by many payers. It’s great where you don’t have to expose the patient’s full body to UV light for patients with localized disease.
I hardly do PUVA (psoralen and ultraviolet A) anymore, mainly due to the photosensitizing effects of the Oxsoralen (methoxsalen, Valeant).
There are some new things coming out. There is a new drug that has been studied in large centers, called afamelanotide - which is an alpha-MSH analogue - and it’s designed to actually stimulate the melanocytes to repigment in combination with the use of phototherapy.
Surgical modalities are also being used to some extent, including suction blisters and mini-punch grafts, which is almost like taking a tiny 1-mm punch biopsy from a donor area and then applying it to the recipient’s depigmented skin, which is prepped either by erbium:YAG resurfacing or dermabrasion. You, then, place those tiny punches - the low pigmented skin on those areas - and you can get nice repigmentation in many areas. Many clinicians are doing this.
Hopefully there will be newer things out there. The problem is that there are a lot fewer people with vitiligo than with conditions like psoriasis and atopic dermatitis, so when the National Institutes of Health and other agencies look for things to fund, vitiligo gets shifted to the bottom. We need more studies and data to prove that there’s systemic implications and involvement, so we can get people treated and increase research funding.
Dr. Levine: Let us finish up with a brief discussion of a recently published study in the Blue Journal[vi] that concluded that patients with vitiligo actually have a lower incidence of skin cancer than those without the skin disease. First, comment on the study, and secondly, what implications does this have in patients who were thinking of using UVB phototherapy, for example?
Dr. Desai: I do know which study you’re talking about. That study was well done and similar studies have been done prior to that to support the same claim - which I do believe is that patients with vitiligo have a significantly lower risk of having skin cancer, particularly melanoma. The reason being is that those patients have a disruption of the melanocyte itself, thereby not allowing the tumor to develop.
I have a couple of comments on that: One is that this can be turned into a positive factor that you can mention to the patient. A lot of times when you’re treating patients with vitiligo, it’s a watch-and-wait kind of thing. So, from a practical day-to-day perspective, you are counseling a patient on the condition and what it’s all about and this may give the patient an improved sense that, ‘OK, maybe what I have is not so bad.’ You can tell the patient, ‘Well, you know the good news is you have a lower risk of getting skin cancer if you had to look at a positive of it.’
Second, this does not mean that we tell these patients they don’t need to wear sunscreen. They still need to limit exposure to UV light. Patients with vitiligo tend to have depigmented advancement of the condition when the area is damaged or traumatized. There are a number of reports I have seen that describe a situation whereby after sunburns, the healed skin becomes vitiliginous in patients who did not have vitiligo in certain parts of the body.
We still have to counsel patients on photoprotection. I tell my patients I want them to get cautious sunlight. I want them to get sunlight through a box, but not get burned, which sounds contradictory to the patient. I tell them to expose their bodies to the sunlight between 2 p.m. and 5 p.m. in the afternoon - when we know the sun is the strongest - for about 10 to 15 minutes with minimal sunscreen use. If the sun is very strong that day or you’re in part of the world closer to the equator, you may actually want the patient to use a light amount of base coat which would allow them to still get some of that darkening, but not the UVB-induced phototoxicity and burning. When we do phototherapy, again, it’s very important to incrementally adjust the dose of the phototherapy at each session, very carefully paying attention to redness to make sure these patients don’t burn. There are reports of patients who have done phototherapy who have gotten burned by the box and their vitiligo actually gets worse.
The important thing is to have a discussion to help the patient understand why you are giving them somewhat of a contradictory piece of advice on the surface, which isn’t contradictory, but it can look like that.
[i] Rendon M, Berneburg M, Arellano I, Picardo M. Treatment of melasma. J Am Acad Dermatol. 2006;54(5 Suppl 2):S272-81.
[ii] Grimes PE. The safety and efficacy of salicylic acid chemical peels in darker racial-ethnic groups. Dermatol Surg. 1999;25(1):18-22.
[iii] Nordlund JJ, Grimes PE, Ortonne JP. The safety of hydroquinone. J Eur Acad Dermatol Venereol. 2006;20(7):781-7.
[iv] Kauvar AN. Successful treatment of melasma using a combination of microdermabrasion and Q-switched Nd:YAG lasers. Lasers Surg Med. 2012;44(2):117-24.
[v] Chen YT, Chen YJ, Hwang CY, et al. Comorbidity profiles in association with vitiligo: a nationwide population-based study in Taiwan. J Eur Acad Dermatol Venereol. 2014;
[vi] Paradisi A, Tabolli S, Didona B, Sobrino L, Russo N, Abeni D. Markedly reduced incidence of melanoma and nonmelanoma skin cancer in a nonconcurrent cohort of 10,040 patients with vitiligo. J Am Acad Dermatol. 2014;71(6):1110-6.