Managing melasma

By Jan Bowers, contributing writer

The emotional toll of melasma on patients can be devastating. A hyperpigmentation disorder which affects mostly women of reproductive age with Fitzpatrick skin types IV through VI — especially those of Asian, Hispanic, and African descent — melasma can provoke embarrassment and self-consciousness to a degree that impairs patients’ social relationships and daily activities. Six patients interviewed as part of a pilot study on the effect of melasma on self-esteem (Int J Womens Dermatol. 2018; 4:38-42) reported decreased self-esteem, restricted sense of freedom, avoidance of social situations, and frustration with costly and ineffective treatments.

Considered a lifelong, chronic condition, melasma can be managed, but not cured. Many patients respond to traditional first-line therapy: topical lightening agents such as hydroquinone or a triple combination cream formulated with hydroquinone, tretinoin, and a corticosteroid, accompanied by stringent photoprotection measures. Patients whose melasma does not improve with topical therapy can be treated with chemical peels, low-fluence lasers, and oral tranexamic acid, widely used in Asia and just beginning to penetrate the U.S. market. New oral and topical agents are being tested as researchers continue to explore the complex pathogenesis of the disorder.

Melanocytes run amok

Patients with melasma don’t have an excess number of melanocytes, but their melanocytes are in a permanent state of pigment-producing overdrive. What causes melanocytes to overproduce melanin isn’t precisely known. “We have a great deal of information about melasma, but we really understand very little,” said Arielle N.B. Kauvar, MD, founding director of New York Laser & Skin Care and clinical professor of dermatology at New York University Medical Center. “It’s important to understand the pathophysiology information that we have to date, because that has a bearing on how we treat melasma. Obviously, the biggest stimulus for melasma is ultraviolet light, but visible light certainly contributes, and it appears that infrared light may have a role as well.” In addition to UV light exposure, hormones associated with pregnancy and oral contraceptives have long been implicated as triggers of melasma. And, although “we don’t know what role genetics play, in some populations there’s a very high incidence of family members involved,” said Dr. Kauvar.

More recent research points to several additional culprits, said Seemal R. Desai, MD, clinical assistant professor of dermatology at the University of Texas Southwestern Medical Center, member of the AAD Board of Directors, and immediate past president of the Skin of Color Society. “There’s more work being done now showing that it’s not just overactive tyrosinase enzyme activity making melanin, but there are several other factors at play,” he noted. “One is increased vascular endothelial growth factor (VEGF); there’s an increased role of mast cells that are involved potentially in the dermis of patients with melasma; the Wnt signaling pathway may have a role. There is a lot pointing to the fact that we can now view melasma in a way we previously haven’t, as almost being an inflammatory process to some degree.” The significance of VEGF, which is stimulated by UV light, is unknown. “However, it is possible that it stimulates melanocytes directly or causes the skin to develop more blood vessels underneath the epidermis, and those increased blood vessels bring in factors that stimulate melanocytes to make more pigment,” explained Amit Pandya, MD, clinical professor of dermatology at the University of Texas Southwestern Medical Center. “We also know that the fibroblasts that are under the epidermis in the skin of melasma secrete some factor, perhaps fibroblast growth factor (FGF), which stimulates melanocytes from melasma skin to make more pigment when these fibroblasts and melanocytes are incubated together. This stimulation is not seen with fibroblasts from buttock skin, which is sun-protected.”

Dr. Pandya credits former Academy president Henry Lim, MD, Iltefat Hamzavi, MD, and their colleagues at Henry Ford Hospital with discovering the potential role of visible light in melasma. “They found that if you expose the backs of people with darker skin types to visible light, they will form pigmentation on their back, and that effect lasts for more than two weeks,” he noted. “So perhaps melasma is also induced by visible light. Even though that hasn’t been proven definitively, some of us are now telling patients to layer on a visible light sunscreen containing iron oxide on top of the standard UV protective sunscreen.”

Given that melasma is considered a lifelong, chronic condition that cannot be cured, what options are available to manage melasma?

Oral tranexamic acid

The efficacy of a relatively new agent in treatment of melasma was discovered almost by accident. “Tranexamic acid (TA) is a fibrinolytic agent that works by blocking the production of arachidonic acid prostaglandins via the fibrinogen-fibrin cascade,” said Dr. Desai. “It then blocks pro-inflammatory proteins that turn on the pigment production. I explain to my patients that in melasma, the pigment, or melanin, is being produced excessively as a result of an overactive enzyme and other factors. It’s like thinking of the process as the engine of a fancy sports car like a Porsche that is going super-fast. Our goal is to slow down that engine from that of a Porsche to more like one of a Hyundai. I have found that this concept helps patients understand the process better, and also helps me better explain the chronic nature of melasma.”

TA is available in oral, topical, and injectable form (see sidebar). In addition to promoting clotting — the purpose for which TA was originally used — the reduction of plasmin moderates factors that stimulate pigmentation, including fibroblast growth factor and prostaglandin, Dr. Pandya explained. “In the 2000s, women were prescribed TA to treat excessive menstrual bleeding. In Asia, they noticed that women taking TA for menorrhagia saw improvement in their melasma.” Asian researchers launched studies to evaluate the safety of daily TA and to determine the optimal dose to control melasma. “They found that 250 mg twice a day was the ideal dose needed to improve melasma in the majority of treated patients,” Dr. Pandya said. The safety profile was also encouraging: The largest retrospective study of TA treatment, conducted in Singapore with 561 patients, found only one serious adverse event, a blood clot. “This patient had a history of deficiency of a coagulation factor and didn’t tell the doctor,” Dr. Pandya noted.

Urged by his Asian colleagues, “I tried TA on a few patients, and it worked,” Dr. Pandya related. “However, as a researcher I always want to have good placebo-controlled trials to guide my clinical practice, so we conducted one.” Using the modified Melasma Area and Severity Index (mMASI), the study (J Am Acad Dermatol. 2018;78(2):363-69) randomized 39 patients with moderate-to-severe melasma to receive 250 mg of TA or placebo twice daily. All patients used sunscreen. After three months of treatment, patients in the TA arm saw a 49% reduction in their mMASI score versus an 18% reduction in the placebo arm (a mean decrease in mMASI score of 4.2 vs. 1.4).

Dr. Pandya now uses oral TA in patients who do not show sufficient improvement after three to six months of topical therapy and sun protection. Safety is a primary concern: “I ask the patient: do you smoke, have you ever had a blood clot, do you take oral contraceptives, have you had two or more miscarriages, has a doctor ever told you that you have a clotting disorder, have you ever had a stroke or heart attack?” he said. If the answer to these questions is no, he prescribes TA. Although 250 mg is the standard dose in Asia, “in America it’s only sold as a 650 mg pill. I tell my patients to cut it in half and take half in the morning and half at bedtime, so the dose is 325 mg twice daily.” Dr. Pandya has his patients apply triple combination cream, sunscreen, and makeup containing iron oxide while they’re taking TA. On this regimen, it may take three months to a year to achieve clearance of melasma, he noted. In his experience side effects have been mild with a few patients who have experienced gastrointestinal upset or changes in menses. Because there’s no data regarding side effects when TA is used beyond one year, “after a year I take them off the medication for at least two months while continuing triple-combination cream. Many patients continue to do well after stopping TA but a significant number have a relapse, in which case I start it again.”

Dr. Kauvar said she uses TA in roughly 10% of her patients — those who don’t respond well enough to topical therapy, gentle exfoliation, and low-fluence lasers. “Usually within one to two months we see excellent clearance of melasma,” she noted. “I pre-treat my patients with TA prior to low energy laser and continue TA for an additional three months while topical therapy is maintained. I try to maintain patients on topical therapy alone as long as possible before resuming TA.”

Hyrdroquinone: Is it safe?

For many dermatologists, hydroquinone is the gold standard, go-to topical therapy for melasma and has been for 60 years. Yet it continues to be dogged by charges that it poses a risk of cancer and exogenous ochronosis. Today, those rumors are largely perpetrated on the internet by companies marketing competing products such as kojic acid, azelaic acid, and arbutin, said Amit Pandya, MD, but the controversy dates back to the mid-2000s.

“A Dutch group published an article (J Eur Acad Dermatol Venereol. 2006; 131:777-780) suggesting that hydroquinone may pose a cancer risk because the molecule is a metabolite of benzene, and benzene is a known carcinogen,” he said. “But there was, and still is, no evidence of a single person ever getting cancer from hydroquinone.” In a rebuttal of the article in the same issue (J Eur Acad Dermatol Venereol. 2006;20(7):781-7), a group of American and French dermatologists pointed to more than 40 years of efficacy and safety data, including lack of increased cancer risk among factory workers exposed to large amounts of hydroquinone used as a photographic developer and stabilizer for various products. They pointed out that hydroquinone is found in many foods we eat and our bodies have found ways to metabolize the drug safely. Around the same time, the U.S. Food and Drug Administration said it was considering removing hydroquinone from the market, citing the possible association with cancer and the risk of ochronosis, Dr. Pandya said. “They received almost 900 letters — including one from me, as then-president of the Skin of Color Society — urging them not to remove hydroquinone, and about 50 letters in favor of removing it.”

The risk that hydroquinone may induce ochronosis is real, said Seemal R. Desai, MD, but the occurrence is rare and linked to strong formulations not available in the U.S. “In my own practice, I have never had a patient develop ochronosis, but I have seen it occur in patients I have seen previously, especially those using very high strengths of hydroquinone, like 8% or 10%, and using it continuously,” he noted. “They’re getting it from dangerous over-the-counter sources in other countries, where it’s touted as a skin-lightening agent. In the U.S., it’s only available over the counter in a 2% formulation. We recommend a prescription strength, which is usually 4%. It’s very important to dispel these myths, because people on social media are calling it a horrible, toxic drug — and that’s just not true.”

Polypodium leucotomos extract

Recently, there has been some buzz about a pill — containing the extract of a fern native to Central and South America — as a photoprotective agent. Polypodium leucotomos extract (PLE) is available over the counter in the U.S. and has been used to treat several photo-aggravated dermatologic disorders, including melasma, according to a review of published basic science and human studies (J Drugs Dermatol. 2015;14(3):254-9). Describing its mechanism of action, the review notes that, “PLE is believed to inhibit the photodamage process, increasing the minimal erythema dose (MED), by maintaining extracellular matrix integrity and preventing damage to DNA repair enzymes.” The review authors concluded that oral PLE is safe and can be prescribed for long-term use.

Does PLE benefit patients with melasma? A comprehensive look at new oral and topical therapies for melasma (Int J Womens Dermatol. 2019; 5:30-36) points to two randomized placebo-controlled studies that do show a statistically significant beneficial effect. Former AAD president Darrell S. Rigel, MD, clinical professor of dermatology at New York University Langone Medical Center, said he recommends his melasma patients use it in conjunction with sunscreen because “bottom line, I think it does make a difference, and I haven’t seen any side effects. I typically recommend they use the name brand pill, as opposed to the off-brand stuff, because that’s what has been tested.” A co-author of the JDD review article, Dr. Rigel said that because the pill also contains 500 mg of nicotinamide, patients should never take more than six pills a day, and two per day is the recommended dose. “I think it’s safe, and does augment the effectiveness of melasma treatments, but it’s not, itself, a melasma treatment. That’s really important to note.”

Dr. Pandya conducted his own randomized, placebo-controlled trial (JAMA Dermatol. 2013;149(8):981-3) and found that patients in both arms of the trial saw their melasma improve by 19%, a benefit he attributed to sunscreen. “So, I would say that based on our study, PLE, at this time, doesn’t work.”

Skin resurfacing and lasers

A pioneer in the use of lasers to treat pigment disorders, Dr. Kauvar reserves them for patients who have failed topical therapy and gentle exfoliation. In her view, melasma-affected skin has defective barrier function, and is hypersensitive to irritation and inflammation. “The inflammation can be from any source: irritation of the skin with products, an aggressive chemical peel, or a laser that causes thermal injury,” she remarked. “Almost every type of laser has been tried for melasma, but when they’re used at conventional settings for removal of sun freckles or other pigment issues, the resulting thermal effects produce inflammation, and can worsen melasma. It is important to keep all of these issues in mind when developing a treatment plan.”

Dr. Kauvar relies on two pigment lasers to treat patients with melasma: the Q-switched Nd:YAG and the picosecond Nd:YAG. For patients with visible telangiectasia in melasma affected skin, she also uses a pulsed dye laser or a pulsed 532nm KTP laser. At very low laser energies, it is possible to damage melanosomes without causing thermal injury. In this way, melanosomes are damaged or destroyed without inducing inflammation, she explained.

Dr. Kauvar performs a microdermabrasion just prior to using the laser “because at these low-laser energies, scattering at the skin surface diminishes laser skin penetration and targeting of dermal pigment. We perform two or three passes of the laser, painting over the entire surface of the skin, apply a corticosteroid cream, and ice the treated area immediately. A combination of a broad-spectrum sunscreen, hydroquinone, and a retinoid begin twice daily. For patients with sensitive skin, there are many other topical molecules to substitute, like vitamin C, kojic acid, and arbutin.” The laser treatments are administered once every four to six weeks and repeated three to five times. “Most individuals improve at least 50 or 75% and about 20% can achieve 90% or more clearance with this regimen,” she said. Patients who live in northern latitudes may not return for two or three years, while others will need treatment more frequently, Dr. Kauvar said.

Finally, dermatologists hammer home the importance of sun protection every day, but for melasma patients that message is especially critical. “When we see patients with melasma, we really need to counsel them that this is a chronic condition, which means that it does require lifelong photoprotection,” said Dr. Desai. “The most important thing we can tell them is: Let’s not forget sunscreen!”

Patient resources

Share with your patients the Academy’s educational pamphlet on melasma that details the causes of melasma and the potential treatment options.