Melasma

For those who view fractional ablative laser–assisted drug delivery as a pie-in-the-sky procedure that will take years to work its way into routine clinical practice, think again.

According to Merete Haedersdal, MD, PhD, DMSc, fractional ablative laser–assisted drug delivery is now ready to be incorporated into daily practice for the treatment of actinic keratoses (AKs) and scars, which is off-label use.

“The groundwork has been established over a decade with more than 100 publications available on PubMed,” Dr. Haedersdal, professor of dermatology at the University of Copenhagen, said during a virtual course on laser and aesthetic skin therapy. “There is no doubt that by drilling tiny little holes or channels with ablative fractional lasers, we enhance drug delivery to the skin, and we also empower different topical treatment regimens. Also, laser-assisted drug delivery holds the potential to bring new innovations into established medicine.”

Many studies have demonstrated that clinicians can enhance drug uptake into the skin with the fractional 10,600 nm CO₂ laser, the fractional 2,940 nm erbium:YAG laser, and the 1,927 nm thulium laser, but proper tuning of the devices is key. The lower the density, the better, Dr. Haedersdal said.

“Typically, we use 5% density or 5% coverage, sometimes 10%-15%, but don’t go higher in order to avoid the risk of having a systemic uptake,” she said during the meeting, which was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine. “Also, the pulse energy for channel depth needs to be tailored to the specific dermatologic disease being treated,” she said, noting that for melasma, for example, “very low pulse energies” would be used, but they would be higher for treating thicker lesions, such as a hypertrophic scar.

Treatment with ablative fractional lasers enhances drug accumulation in the skin of any drug or substance applied to the skin, and clinical indications are expanding rapidly. Established indications include combining ablative fractional lasers and photodynamic therapy (PDT) for AKs and combining ablative fractional lasers and triamcinolone or 5-FU for scars. “Although we have a good body of evidence, particularly for AKs, it’s still an off-label use,” she emphasized.

Evolving indications include concomitant use of ablative fractional laser and vitamins and cosmeceuticals for rejuvenation; lidocaine for local anesthetics; tranexamic acid and hydroquinone for melasma; antifungals for onychomycosis; Botox for hyperhidrosis; minoxidil for alopecia; and betamethasone for vitiligo. A promising treatment for skin cancer “on the horizon,” she said, is the “combination of ablative fractional laser with PD1 inhibitors and chemotherapy.”

Data on AKs

Evidence supporting laser-assisted drug delivery for AKs comes from more than 10 randomized, controlled trials in the dermatology literature involving 400-plus immunocompetent and immunosuppressed patients. These trials have found ablative fractional laser–assisted PDT to be significantly more efficacious than PDT alone up to 12 months postoperatively and to foster lower rates of AK recurrence.

In a meta-analysis and systematic review, German researchers concluded that PDT combined with ablative laser treatment for AKs is more efficient but not more painful than either therapy alone. They recommended the combined regimen for patients with severe photodamage, field cancerization, and multiple AKs.

In 2020, an international consensus panel of experts, including Dr. Haedersdal, published recommendations regarding laser treatment of traumatic scars and contractures. The panel members determined that laser-assisted delivery of corticosteroids and antimetabolites was recommended for hypertrophic scars and cited triamcinolone acetonide suspension (TAC) as the most common corticosteroid used in combination with ablative fractional lasers. “It can be applied in concentrations of 40 mg/mL or less depending on the degree of hypertrophy,” they wrote.

In addition, they stated that 5-FU solution is “most commonly applied in a concentration of 50 mg/mL alone, or mixed with TAC in ratios of 9:1 or 3:1.”

According to the best available evidence, the clinical approach for hypertrophic scars supports combination treatment with ablative fractional laser and triamcinolone acetonide either alone or in combination with 5-FU. For atrophic scars, laser-assisted delivery of poly-L-lactic acid has been shown to be efficient. “Both of these treatments improve texture and thickness but also dyschromia and scar functionality,” said Dr. Haedersdal, who is also a visiting scientist at the Wellman Center for Photomedicine, Boston.

Commenting on patient safety with laser-assisted drug delivery, “the combination of lasers and topicals can be a powerful cocktail,” she said. “You can expect intensified local skin reactions. When treating larger areas, consider the risk of systemic absorption and the risk of potential toxicity. There is also the potential for infection with pathogens such as Staphylococcus aureus. The take-home message here is that you should only use the type and amount of drug no higher than administered during intradermal injection.”

Dr. Haedersdal disclosed that she has received equipment from Cherry Imaging, Cynosure-Hologic, MiraDry, and PerfAction Technologies. She has also received research grants from Leo Pharma, Lutronic, Mirai Medical, Novoxel, and Venus Concept.

For those who view fractional ablative laser–assisted drug delivery as a pie-in-the-sky procedure that will take years to work its way into routine clinical practice, think again.

According to Merete Haedersdal, MD, PhD, DMSc, fractional ablative laser–assisted drug delivery is now ready to be incorporated into daily practice for the treatment of actinic keratoses (AKs) and scars, which is off-label use.

“The groundwork has been established over a decade with more than 100 publications available on PubMed,” Dr. Haedersdal, professor of dermatology at the University of Copenhagen, said during a virtual course on laser and aesthetic skin therapy. “There is no doubt that by drilling tiny little holes or channels with ablative fractional lasers, we enhance drug delivery to the skin, and we also empower different topical treatment regimens. Also, laser-assisted drug delivery holds the potential to bring new innovations into established medicine.”

Many studies have demonstrated that clinicians can enhance drug uptake into the skin with the fractional 10,600 nm CO₂ laser, the fractional 2,940 nm erbium:YAG laser, and the 1,927 nm thulium laser, but proper tuning of the devices is key. The lower the density, the better, Dr. Haedersdal said.

“Typically, we use 5% density or 5% coverage, sometimes 10%-15%, but don’t go higher in order to avoid the risk of having a systemic uptake,” she said during the meeting, which was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine. “Also, the pulse energy for channel depth needs to be tailored to the specific dermatologic disease being treated,” she said, noting that for melasma, for example, “very low pulse energies” would be used, but they would be higher for treating thicker lesions, such as a hypertrophic scar.

Treatment with ablative fractional lasers enhances drug accumulation in the skin of any drug or substance applied to the skin, and clinical indications are expanding rapidly. Established indications include combining ablative fractional lasers and photodynamic therapy (PDT) for AKs and combining ablative fractional lasers and triamcinolone or 5-FU for scars. “Although we have a good body of evidence, particularly for AKs, it’s still an off-label use,” she emphasized.

Evolving indications include concomitant use of ablative fractional laser and vitamins and cosmeceuticals for rejuvenation; lidocaine for local anesthetics; tranexamic acid and hydroquinone for melasma; antifungals for onychomycosis; Botox for hyperhidrosis; minoxidil for alopecia; and betamethasone for vitiligo. A promising treatment for skin cancer “on the horizon,” she said, is the “combination of ablative fractional laser with PD1 inhibitors and chemotherapy.”

Data on AKs

Evidence supporting laser-assisted drug delivery for AKs comes from more than 10 randomized, controlled trials in the dermatology literature involving 400-plus immunocompetent and immunosuppressed patients. These trials have found ablative fractional laser–assisted PDT to be significantly more efficacious than PDT alone up to 12 months postoperatively and to foster lower rates of AK recurrence.

In a meta-analysis and systematic review, German researchers concluded that PDT combined with ablative laser treatment for AKs is more efficient but not more painful than either therapy alone. They recommended the combined regimen for patients with severe photodamage, field cancerization, and multiple AKs.

In 2020, an international consensus panel of experts, including Dr. Haedersdal, published recommendations regarding laser treatment of traumatic scars and contractures. The panel members determined that laser-assisted delivery of corticosteroids and antimetabolites was recommended for hypertrophic scars and cited triamcinolone acetonide suspension (TAC) as the most common corticosteroid used in combination with ablative fractional lasers. “It can be applied in concentrations of 40 mg/mL or less depending on the degree of hypertrophy,” they wrote.

In addition, they stated that 5-FU solution is “most commonly applied in a concentration of 50 mg/mL alone, or mixed with TAC in ratios of 9:1 or 3:1.”

According to the best available evidence, the clinical approach for hypertrophic scars supports combination treatment with ablative fractional laser and triamcinolone acetonide either alone or in combination with 5-FU. For atrophic scars, laser-assisted delivery of poly-L-lactic acid has been shown to be efficient. “Both of these treatments improve texture and thickness but also dyschromia and scar functionality,” said Dr. Haedersdal, who is also a visiting scientist at the Wellman Center for Photomedicine, Boston.

Commenting on patient safety with laser-assisted drug delivery, “the combination of lasers and topicals can be a powerful cocktail,” she said. “You can expect intensified local skin reactions. When treating larger areas, consider the risk of systemic absorption and the risk of potential toxicity. There is also the potential for infection with pathogens such as Staphylococcus aureus. The take-home message here is that you should only use the type and amount of drug no higher than administered during intradermal injection.”

Dr. Haedersdal disclosed that she has received equipment from Cherry Imaging, Cynosure-Hologic, MiraDry, and PerfAction Technologies. She has also received research grants from Leo Pharma, Lutronic, Mirai Medical, Novoxel, and Venus Concept.

For those who view fractional ablative laser–assisted drug delivery as a pie-in-the-sky procedure that will take years to work its way into routine clinical practice, think again.

According to Merete Haedersdal, MD, PhD, DMSc, fractional ablative laser–assisted drug delivery is now ready to be incorporated into daily practice for the treatment of actinic keratoses (AKs) and scars, which is off-label use.

“The groundwork has been established over a decade with more than 100 publications available on PubMed,” Dr. Haedersdal, professor of dermatology at the University of Copenhagen, said during a virtual course on laser and aesthetic skin therapy. “There is no doubt that by drilling tiny little holes or channels with ablative fractional lasers, we enhance drug delivery to the skin, and we also empower different topical treatment regimens. Also, laser-assisted drug delivery holds the potential to bring new innovations into established medicine.”

Many studies have demonstrated that clinicians can enhance drug uptake into the skin with the fractional 10,600 nm CO₂ laser, the fractional 2,940 nm erbium:YAG laser, and the 1,927 nm thulium laser, but proper tuning of the devices is key. The lower the density, the better, Dr. Haedersdal said.

“Typically, we use 5% density or 5% coverage, sometimes 10%-15%, but don’t go higher in order to avoid the risk of having a systemic uptake,” she said during the meeting, which was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine. “Also, the pulse energy for channel depth needs to be tailored to the specific dermatologic disease being treated,” she said, noting that for melasma, for example, “very low pulse energies” would be used, but they would be higher for treating thicker lesions, such as a hypertrophic scar.

Treatment with ablative fractional lasers enhances drug accumulation in the skin of any drug or substance applied to the skin, and clinical indications are expanding rapidly. Established indications include combining ablative fractional lasers and photodynamic therapy (PDT) for AKs and combining ablative fractional lasers and triamcinolone or 5-FU for scars. “Although we have a good body of evidence, particularly for AKs, it’s still an off-label use,” she emphasized.

Evolving indications include concomitant use of ablative fractional laser and vitamins and cosmeceuticals for rejuvenation; lidocaine for local anesthetics; tranexamic acid and hydroquinone for melasma; antifungals for onychomycosis; Botox for hyperhidrosis; minoxidil for alopecia; and betamethasone for vitiligo. A promising treatment for skin cancer “on the horizon,” she said, is the “combination of ablative fractional laser with PD1 inhibitors and chemotherapy.”

Data on AKs

Evidence supporting laser-assisted drug delivery for AKs comes from more than 10 randomized, controlled trials in the dermatology literature involving 400-plus immunocompetent and immunosuppressed patients. These trials have found ablative fractional laser–assisted PDT to be significantly more efficacious than PDT alone up to 12 months postoperatively and to foster lower rates of AK recurrence.

In a meta-analysis and systematic review, German researchers concluded that PDT combined with ablative laser treatment for AKs is more efficient but not more painful than either therapy alone. They recommended the combined regimen for patients with severe photodamage, field cancerization, and multiple AKs.

In 2020, an international consensus panel of experts, including Dr. Haedersdal, published recommendations regarding laser treatment of traumatic scars and contractures. The panel members determined that laser-assisted delivery of corticosteroids and antimetabolites was recommended for hypertrophic scars and cited triamcinolone acetonide suspension (TAC) as the most common corticosteroid used in combination with ablative fractional lasers. “It can be applied in concentrations of 40 mg/mL or less depending on the degree of hypertrophy,” they wrote.

In addition, they stated that 5-FU solution is “most commonly applied in a concentration of 50 mg/mL alone, or mixed with TAC in ratios of 9:1 or 3:1.”

According to the best available evidence, the clinical approach for hypertrophic scars supports combination treatment with ablative fractional laser and triamcinolone acetonide either alone or in combination with 5-FU. For atrophic scars, laser-assisted delivery of poly-L-lactic acid has been shown to be efficient. “Both of these treatments improve texture and thickness but also dyschromia and scar functionality,” said Dr. Haedersdal, who is also a visiting scientist at the Wellman Center for Photomedicine, Boston.

Commenting on patient safety with laser-assisted drug delivery, “the combination of lasers and topicals can be a powerful cocktail,” she said. “You can expect intensified local skin reactions. When treating larger areas, consider the risk of systemic absorption and the risk of potential toxicity. There is also the potential for infection with pathogens such as Staphylococcus aureus. The take-home message here is that you should only use the type and amount of drug no higher than administered during intradermal injection.”

Dr. Haedersdal disclosed that she has received equipment from Cherry Imaging, Cynosure-Hologic, MiraDry, and PerfAction Technologies. She has also received research grants from Leo Pharma, Lutronic, Mirai Medical, Novoxel, and Venus Concept.

In the opinion of R. Rox Anderson, MD, it’s only a matter of time before true robots make further inroads in dermatology.

“We humans just can’t do everything perfectly,” Dr. Anderson, a dermatologist who directs the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston, said during a virtual course on laser and aesthetic skin therapy. “We have limited speed and special accuracy and are not good at repetitive tasks. We can’t see in the UV or infrared, and we’re qualitative, not quantitative. ... We’re good at high-level visual assessment.”

During a presentation at the meeting, which was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center, he distinguished between robotics and true robots. A prime example of robotics in medicine is the Da Vinci Surgical System in which a human user “is controlling every movement of this device with capabilities that humans don’t have, such as fine movement and high magnification of imaging,” said Dr. Anderson, who conceived and developed many of the nonscarring laser treatments now widely used in dermatology. “In the military, we have drone aircraft. The pilot is perhaps thousands of miles away; it’s still run by a human being in every way.”

By contrast, true robots are devices in which a human being programs the rules for action but the action itself is not exactly predictable. Artificial intelligence enables robots to perform certain tasks. “If you look at an Amazon warehouse, there’s barely anyone there; robots are packing and unpacking the shelves,” Dr. Anderson said.

Currently, he said, one true robot exists in dermatology: the Food and Drug Administration–cleared ARTAS Robotic Hair Restoration System, which precisely dissects follicular units from the donor area and eliminates the potential for human error. The device “extracts single follicular units from the occipital scalp and makes them available to the surgeon to do an artistic human job of implanting them in the frontal scalp,” Dr. Anderson said.

He predicts that a Mohs surgery robot with image-guided laser ablation would “launch a sea change in the whole field of surgical oncology, and I believe we are in a good position to do it. Everything for this is now sitting on the shelf and it’s unbelievable to me that a company hasn’t accomplished it yet.”

He would also like to see a true laser robot for surgery of tumors that would enable clinicians to download an app for their existing laser instead of having to buy a new device. Currently, “it takes about a half second to make a good optical coherence tomography image of basal cell carcinoma,” he said. “That image could be used for real-time robotic human control of, say, a laser to extirpate the tumor.”

Dr. Anderson’s “wish list” of applications for treatment with a robotic fractional laser includes those that target the sweat glands, sebaceous glands, nerves, inflammatory cells, white hair, blood vessels, lymphatics, hair, tumors, nevi, cysts, and surface contour. “It might be possible to have one software-programmable laser robot for many different applications in dermatology,” he added.

Dr. Anderson reported having received research funding and/or consulting fees from numerous device and pharmaceutical companies.





 

In the opinion of R. Rox Anderson, MD, it’s only a matter of time before true robots make further inroads in dermatology.

“We humans just can’t do everything perfectly,” Dr. Anderson, a dermatologist who directs the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston, said during a virtual course on laser and aesthetic skin therapy. “We have limited speed and special accuracy and are not good at repetitive tasks. We can’t see in the UV or infrared, and we’re qualitative, not quantitative. ... We’re good at high-level visual assessment.”

During a presentation at the meeting, which was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center, he distinguished between robotics and true robots. A prime example of robotics in medicine is the Da Vinci Surgical System in which a human user “is controlling every movement of this device with capabilities that humans don’t have, such as fine movement and high magnification of imaging,” said Dr. Anderson, who conceived and developed many of the nonscarring laser treatments now widely used in dermatology. “In the military, we have drone aircraft. The pilot is perhaps thousands of miles away; it’s still run by a human being in every way.”

By contrast, true robots are devices in which a human being programs the rules for action but the action itself is not exactly predictable. Artificial intelligence enables robots to perform certain tasks. “If you look at an Amazon warehouse, there’s barely anyone there; robots are packing and unpacking the shelves,” Dr. Anderson said.

Currently, he said, one true robot exists in dermatology: the Food and Drug Administration–cleared ARTAS Robotic Hair Restoration System, which precisely dissects follicular units from the donor area and eliminates the potential for human error. The device “extracts single follicular units from the occipital scalp and makes them available to the surgeon to do an artistic human job of implanting them in the frontal scalp,” Dr. Anderson said.

He predicts that a Mohs surgery robot with image-guided laser ablation would “launch a sea change in the whole field of surgical oncology, and I believe we are in a good position to do it. Everything for this is now sitting on the shelf and it’s unbelievable to me that a company hasn’t accomplished it yet.”

He would also like to see a true laser robot for surgery of tumors that would enable clinicians to download an app for their existing laser instead of having to buy a new device. Currently, “it takes about a half second to make a good optical coherence tomography image of basal cell carcinoma,” he said. “That image could be used for real-time robotic human control of, say, a laser to extirpate the tumor.”

Dr. Anderson’s “wish list” of applications for treatment with a robotic fractional laser includes those that target the sweat glands, sebaceous glands, nerves, inflammatory cells, white hair, blood vessels, lymphatics, hair, tumors, nevi, cysts, and surface contour. “It might be possible to have one software-programmable laser robot for many different applications in dermatology,” he added.

Dr. Anderson reported having received research funding and/or consulting fees from numerous device and pharmaceutical companies.





 

In the opinion of R. Rox Anderson, MD, it’s only a matter of time before true robots make further inroads in dermatology.

“We humans just can’t do everything perfectly,” Dr. Anderson, a dermatologist who directs the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston, said during a virtual course on laser and aesthetic skin therapy. “We have limited speed and special accuracy and are not good at repetitive tasks. We can’t see in the UV or infrared, and we’re qualitative, not quantitative. ... We’re good at high-level visual assessment.”

During a presentation at the meeting, which was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center, he distinguished between robotics and true robots. A prime example of robotics in medicine is the Da Vinci Surgical System in which a human user “is controlling every movement of this device with capabilities that humans don’t have, such as fine movement and high magnification of imaging,” said Dr. Anderson, who conceived and developed many of the nonscarring laser treatments now widely used in dermatology. “In the military, we have drone aircraft. The pilot is perhaps thousands of miles away; it’s still run by a human being in every way.”

By contrast, true robots are devices in which a human being programs the rules for action but the action itself is not exactly predictable. Artificial intelligence enables robots to perform certain tasks. “If you look at an Amazon warehouse, there’s barely anyone there; robots are packing and unpacking the shelves,” Dr. Anderson said.

Currently, he said, one true robot exists in dermatology: the Food and Drug Administration–cleared ARTAS Robotic Hair Restoration System, which precisely dissects follicular units from the donor area and eliminates the potential for human error. The device “extracts single follicular units from the occipital scalp and makes them available to the surgeon to do an artistic human job of implanting them in the frontal scalp,” Dr. Anderson said.

He predicts that a Mohs surgery robot with image-guided laser ablation would “launch a sea change in the whole field of surgical oncology, and I believe we are in a good position to do it. Everything for this is now sitting on the shelf and it’s unbelievable to me that a company hasn’t accomplished it yet.”

He would also like to see a true laser robot for surgery of tumors that would enable clinicians to download an app for their existing laser instead of having to buy a new device. Currently, “it takes about a half second to make a good optical coherence tomography image of basal cell carcinoma,” he said. “That image could be used for real-time robotic human control of, say, a laser to extirpate the tumor.”

Dr. Anderson’s “wish list” of applications for treatment with a robotic fractional laser includes those that target the sweat glands, sebaceous glands, nerves, inflammatory cells, white hair, blood vessels, lymphatics, hair, tumors, nevi, cysts, and surface contour. “It might be possible to have one software-programmable laser robot for many different applications in dermatology,” he added.

Dr. Anderson reported having received research funding and/or consulting fees from numerous device and pharmaceutical companies.





 

To better understand melasma, it is important for researchers to find groups of patients with confirmed disease for future clinical study. A recent research letter published in JAMA Dermatology suggests the ICD-10 code for melasma is a good identifier for patients with confirmed melasma, and might be a helpful tool for researchers interested in conducting retrospective studies of this patient population.

“Overall, our results support the validity of using the ICD-10 code for melasma to identify patients with a diagnosis of melasma for future studies,” Nicholas Theodosakis, MD, PhD, of the department of dermatology at Massachusetts General Hospital, Boston, and colleagues wrote in their research letter. “Despite some variability in diagnostic confidence, most patients were ultimately classified as moderately or highly likely to have a true diagnosis of melasma.”

Dr. Theodosakis and colleagues evaluated data from 5,322 adult patients in the Mass General Brigham Research Patient Data Registry between October 2015 and January 2021 who had an encounter that used the ICD-10 code for melasma (L81.1). The researchers then validated the ICD-10 code by examining the medical records of 300 patients (5.6%), confirming that melasma was the clinician’s favored diagnosis and that the patient met secondary diagnostic criteria. Confidence was rated in categories of “low confidence,” “moderate confidence,” “high confidence,” and “maximum confidence” based on secondary criteria such as hyperpigmentation of the face and upper body, hormone-related therapy exposure before diagnosis, pregnancy history, and dermatologist-confirmed diagnosis.

The patients who had their medical records examined for confirmed melasma were primarily women (285 patients; 95.0%) and were a mean 48.4 years old at diagnosis.

Of those in the validation cohort, melasma was the preferred diagnosis for clinicians of 291 patients (97.0%), while 274 patients (91.3%) had secondary diagnostic criteria of hyperpigmentation of the face and upper body and 252 patients (84.0%) had received a diagnosis from a dermatologist. Other less common secondary diagnostic criteria of the patient group were a history of having received hormone-related therapy before a melasma diagnosis (148 patients; 49.3%) and a history of pregnancy (168 patients; 56.0%). Based on identification of secondary diagnostic criteria, confidence in melasma diagnosis was high for 208 patients (69.3%), moderate for 61 patients (20.3%), and low for 31 patients (10.3%).

Dr. Theodosakis and colleagues noted their study was limited by its retrospective nature and the presence of a small validation cohort. “Despite these limitations, our findings provide a framework for identifying cohorts to evaluate the clinical course and treatment of melasma,” the authors concluded.

One of the authors reported relationships with companies including AbbVie, Acom, Boehringer Ingelheim, Concert, Digital Diagnostics, and Eli Lilly in the form of personal fees, equity, royalties and/or licensing, or medical advisory board positions outside the submitted work; another author reported being an advisory board member and consultant for and receiving honoraria from Incyte, Castle Biosciences, Galderma, and Sanofi outside the submitted work. The other authors reported no relevant conflicts of interest.

To better understand melasma, it is important for researchers to find groups of patients with confirmed disease for future clinical study. A recent research letter published in JAMA Dermatology suggests the ICD-10 code for melasma is a good identifier for patients with confirmed melasma, and might be a helpful tool for researchers interested in conducting retrospective studies of this patient population.

“Overall, our results support the validity of using the ICD-10 code for melasma to identify patients with a diagnosis of melasma for future studies,” Nicholas Theodosakis, MD, PhD, of the department of dermatology at Massachusetts General Hospital, Boston, and colleagues wrote in their research letter. “Despite some variability in diagnostic confidence, most patients were ultimately classified as moderately or highly likely to have a true diagnosis of melasma.”

Dr. Theodosakis and colleagues evaluated data from 5,322 adult patients in the Mass General Brigham Research Patient Data Registry between October 2015 and January 2021 who had an encounter that used the ICD-10 code for melasma (L81.1). The researchers then validated the ICD-10 code by examining the medical records of 300 patients (5.6%), confirming that melasma was the clinician’s favored diagnosis and that the patient met secondary diagnostic criteria. Confidence was rated in categories of “low confidence,” “moderate confidence,” “high confidence,” and “maximum confidence” based on secondary criteria such as hyperpigmentation of the face and upper body, hormone-related therapy exposure before diagnosis, pregnancy history, and dermatologist-confirmed diagnosis.

The patients who had their medical records examined for confirmed melasma were primarily women (285 patients; 95.0%) and were a mean 48.4 years old at diagnosis.

Of those in the validation cohort, melasma was the preferred diagnosis for clinicians of 291 patients (97.0%), while 274 patients (91.3%) had secondary diagnostic criteria of hyperpigmentation of the face and upper body and 252 patients (84.0%) had received a diagnosis from a dermatologist. Other less common secondary diagnostic criteria of the patient group were a history of having received hormone-related therapy before a melasma diagnosis (148 patients; 49.3%) and a history of pregnancy (168 patients; 56.0%). Based on identification of secondary diagnostic criteria, confidence in melasma diagnosis was high for 208 patients (69.3%), moderate for 61 patients (20.3%), and low for 31 patients (10.3%).

Dr. Theodosakis and colleagues noted their study was limited by its retrospective nature and the presence of a small validation cohort. “Despite these limitations, our findings provide a framework for identifying cohorts to evaluate the clinical course and treatment of melasma,” the authors concluded.

One of the authors reported relationships with companies including AbbVie, Acom, Boehringer Ingelheim, Concert, Digital Diagnostics, and Eli Lilly in the form of personal fees, equity, royalties and/or licensing, or medical advisory board positions outside the submitted work; another author reported being an advisory board member and consultant for and receiving honoraria from Incyte, Castle Biosciences, Galderma, and Sanofi outside the submitted work. The other authors reported no relevant conflicts of interest.

To better understand melasma, it is important for researchers to find groups of patients with confirmed disease for future clinical study. A recent research letter published in JAMA Dermatology suggests the ICD-10 code for melasma is a good identifier for patients with confirmed melasma, and might be a helpful tool for researchers interested in conducting retrospective studies of this patient population.

“Overall, our results support the validity of using the ICD-10 code for melasma to identify patients with a diagnosis of melasma for future studies,” Nicholas Theodosakis, MD, PhD, of the department of dermatology at Massachusetts General Hospital, Boston, and colleagues wrote in their research letter. “Despite some variability in diagnostic confidence, most patients were ultimately classified as moderately or highly likely to have a true diagnosis of melasma.”

Dr. Theodosakis and colleagues evaluated data from 5,322 adult patients in the Mass General Brigham Research Patient Data Registry between October 2015 and January 2021 who had an encounter that used the ICD-10 code for melasma (L81.1). The researchers then validated the ICD-10 code by examining the medical records of 300 patients (5.6%), confirming that melasma was the clinician’s favored diagnosis and that the patient met secondary diagnostic criteria. Confidence was rated in categories of “low confidence,” “moderate confidence,” “high confidence,” and “maximum confidence” based on secondary criteria such as hyperpigmentation of the face and upper body, hormone-related therapy exposure before diagnosis, pregnancy history, and dermatologist-confirmed diagnosis.

The patients who had their medical records examined for confirmed melasma were primarily women (285 patients; 95.0%) and were a mean 48.4 years old at diagnosis.

Of those in the validation cohort, melasma was the preferred diagnosis for clinicians of 291 patients (97.0%), while 274 patients (91.3%) had secondary diagnostic criteria of hyperpigmentation of the face and upper body and 252 patients (84.0%) had received a diagnosis from a dermatologist. Other less common secondary diagnostic criteria of the patient group were a history of having received hormone-related therapy before a melasma diagnosis (148 patients; 49.3%) and a history of pregnancy (168 patients; 56.0%). Based on identification of secondary diagnostic criteria, confidence in melasma diagnosis was high for 208 patients (69.3%), moderate for 61 patients (20.3%), and low for 31 patients (10.3%).

Dr. Theodosakis and colleagues noted their study was limited by its retrospective nature and the presence of a small validation cohort. “Despite these limitations, our findings provide a framework for identifying cohorts to evaluate the clinical course and treatment of melasma,” the authors concluded.

One of the authors reported relationships with companies including AbbVie, Acom, Boehringer Ingelheim, Concert, Digital Diagnostics, and Eli Lilly in the form of personal fees, equity, royalties and/or licensing, or medical advisory board positions outside the submitted work; another author reported being an advisory board member and consultant for and receiving honoraria from Incyte, Castle Biosciences, Galderma, and Sanofi outside the submitted work. The other authors reported no relevant conflicts of interest.

The spotlight continues to shine on vitiligo as Lego has released the first-ever mini-character featuring the hallmark dark and light skin patches of the disease.

The character appears with the customizable array of players to assemble for a table football team.

It’s the latest representation of the disease as toymakers diversify their lines.

In May 2022, Mattel released a Ken doll with vitiligo after a Barbie with vitiligo was released in 2020. Rainbow High and other toy makers also have character versions.

The Lego addition follows a big summer medically for vitiligo as the first treatment was approved for repigmentation. In July, a cream formulation of ruxolitinib (Opzelura), a Janus kinase inhibitor, became the first repigmentation treatment approved by the Food and Drug Administration for nonsegmental vitiligo, the most common form of the disease.

Vitiligo is estimated to affect 1.9 million–2.8 million adults in the United States and more than 100 million people worldwide. It cuts across races and genders and can be psychologically painful for many who live with it.

John E. Harris, MD, director of the Vitiligo Clinic and Research Center at the University of Massachusetts, Worcester, wrote about the Lego character in his blog “Speaking of Vitiligo ...” saying: “I could not be more excited. This new minifigure also serves as a way to educate both children and adults who are not familiar with vitiligo about the disease.”

He noted that until recently vitiligo representation in kids’ toys has been limited. “By adding diversity such as representations of vitiligo in toys, it can help remove stigmas associated with vitiligo and give children more options that they can relate to.”

Erika Page of Richmond, Va., who founded and edits the vitiligo blog “Living Dappled,” told this news organization she was thrilled to see the new Lego character.

“Growing up I didn’t know anyone who looked like me, let alone a toy or a character,” she said. The message the representations send is important not just for the kids but for the parents of kids with vitiligo who want to help their kids in any way they can.

Ms. Page was diagnosed with vitiligo at age 7 and struggled emotionally in her high school and college years when she often looked in the mirror, saw “giraffe-like” spots, and cried. Over time she lost 100% of her pigment to the condition and today at age 33, lives with universal vitiligo or overall very pale skin.

She founded the Living Dappled blog 6 years ago to help people with the disease feel less alone. The Lego character will also help with that, she said.

“Growing up with vitiligo was so isolating and you felt so different,” Ms. Page said. “Today we see billboards and models and dolls and now Legos that look like us. I hope this is a first of many to come for Lego.”

Dr. Harris and Ms. Page declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The spotlight continues to shine on vitiligo as Lego has released the first-ever mini-character featuring the hallmark dark and light skin patches of the disease.

The character appears with the customizable array of players to assemble for a table football team.

It’s the latest representation of the disease as toymakers diversify their lines.

In May 2022, Mattel released a Ken doll with vitiligo after a Barbie with vitiligo was released in 2020. Rainbow High and other toy makers also have character versions.

The Lego addition follows a big summer medically for vitiligo as the first treatment was approved for repigmentation. In July, a cream formulation of ruxolitinib (Opzelura), a Janus kinase inhibitor, became the first repigmentation treatment approved by the Food and Drug Administration for nonsegmental vitiligo, the most common form of the disease.

Vitiligo is estimated to affect 1.9 million–2.8 million adults in the United States and more than 100 million people worldwide. It cuts across races and genders and can be psychologically painful for many who live with it.

John E. Harris, MD, director of the Vitiligo Clinic and Research Center at the University of Massachusetts, Worcester, wrote about the Lego character in his blog “Speaking of Vitiligo ...” saying: “I could not be more excited. This new minifigure also serves as a way to educate both children and adults who are not familiar with vitiligo about the disease.”

He noted that until recently vitiligo representation in kids’ toys has been limited. “By adding diversity such as representations of vitiligo in toys, it can help remove stigmas associated with vitiligo and give children more options that they can relate to.”

Erika Page of Richmond, Va., who founded and edits the vitiligo blog “Living Dappled,” told this news organization she was thrilled to see the new Lego character.

“Growing up I didn’t know anyone who looked like me, let alone a toy or a character,” she said. The message the representations send is important not just for the kids but for the parents of kids with vitiligo who want to help their kids in any way they can.

Ms. Page was diagnosed with vitiligo at age 7 and struggled emotionally in her high school and college years when she often looked in the mirror, saw “giraffe-like” spots, and cried. Over time she lost 100% of her pigment to the condition and today at age 33, lives with universal vitiligo or overall very pale skin.

She founded the Living Dappled blog 6 years ago to help people with the disease feel less alone. The Lego character will also help with that, she said.

“Growing up with vitiligo was so isolating and you felt so different,” Ms. Page said. “Today we see billboards and models and dolls and now Legos that look like us. I hope this is a first of many to come for Lego.”

Dr. Harris and Ms. Page declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The spotlight continues to shine on vitiligo as Lego has released the first-ever mini-character featuring the hallmark dark and light skin patches of the disease.

The character appears with the customizable array of players to assemble for a table football team.

It’s the latest representation of the disease as toymakers diversify their lines.

In May 2022, Mattel released a Ken doll with vitiligo after a Barbie with vitiligo was released in 2020. Rainbow High and other toy makers also have character versions.

The Lego addition follows a big summer medically for vitiligo as the first treatment was approved for repigmentation. In July, a cream formulation of ruxolitinib (Opzelura), a Janus kinase inhibitor, became the first repigmentation treatment approved by the Food and Drug Administration for nonsegmental vitiligo, the most common form of the disease.

Vitiligo is estimated to affect 1.9 million–2.8 million adults in the United States and more than 100 million people worldwide. It cuts across races and genders and can be psychologically painful for many who live with it.

John E. Harris, MD, director of the Vitiligo Clinic and Research Center at the University of Massachusetts, Worcester, wrote about the Lego character in his blog “Speaking of Vitiligo ...” saying: “I could not be more excited. This new minifigure also serves as a way to educate both children and adults who are not familiar with vitiligo about the disease.”

He noted that until recently vitiligo representation in kids’ toys has been limited. “By adding diversity such as representations of vitiligo in toys, it can help remove stigmas associated with vitiligo and give children more options that they can relate to.”

Erika Page of Richmond, Va., who founded and edits the vitiligo blog “Living Dappled,” told this news organization she was thrilled to see the new Lego character.

“Growing up I didn’t know anyone who looked like me, let alone a toy or a character,” she said. The message the representations send is important not just for the kids but for the parents of kids with vitiligo who want to help their kids in any way they can.

Ms. Page was diagnosed with vitiligo at age 7 and struggled emotionally in her high school and college years when she often looked in the mirror, saw “giraffe-like” spots, and cried. Over time she lost 100% of her pigment to the condition and today at age 33, lives with universal vitiligo or overall very pale skin.

She founded the Living Dappled blog 6 years ago to help people with the disease feel less alone. The Lego character will also help with that, she said.

“Growing up with vitiligo was so isolating and you felt so different,” Ms. Page said. “Today we see billboards and models and dolls and now Legos that look like us. I hope this is a first of many to come for Lego.”

Dr. Harris and Ms. Page declared no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Disorders of hyperpigmentation—melasma, postinflammatory hyperpigmentation, lichen planus pigmentosus, erythema dyschromicum perstans, and pigmented contact dermatitis, among others—are common and challenging to treat. Although they can affect individuals of all skin types, they most commonly are seen in skin of color; in fact, dyspigmentation is one of the most common chief concerns for which individuals of color see a dermatologist.^1,2

For many years, hydroquinone (HQ) was one of the main options available for use as a lightening agent. Although effective, it has the risk of causing irritant dermatitis, potentially leading to further dyspigmentation, in addition to the risk of ochronosis with long-term use. It remains an important and useful treatment for pigmentary disorders, but there are numerous other lightening agents that also can be considered in the treatment of disorders of hyperpigmentation.

Herein, we provide recommendations for traditional and newer non-HQ lightening agents that can be considered when treating disorders of hyperpigmentation.

Traditional Non-HQ Lightening Agents

Retinoids—Retinoids are topical vitamin A derivatives that have been used safely and effectively for decades in the treatment of pigmentary disorders. Retinoids have multiple mechanisms of action in improving pigmentation. In addition to impeding tyrosinase induction, they inhibit pigment transfer to keratinocytes and lead to accelerated pigment loss due to epidermal shedding.³ Over-the-counter formulations include retinol, retinaldehyde, and adapalene. Prescription formulations include tretinoin and tazarotene in different strengths and vehicle formulations.⁴

Glycolic Acid—Glycolic acid is derived from sugarcane and is considered an α-hydroxy acid that leads to rapid desquamation of pigmented keratinocytes.⁵ Glycolic acid can not only be used in chemical peels but also in topical creams. It is the most common α-hydroxy acid peel and is sometimes paired with HQ and other topical lightening agents for increased penetration. Glycolic acid peels are available in concentrations of 20% to 70% and can be used at various depths. When used incorrectly, it can cause redness, burning, and even skin discoloration; however, when used at the proper concentrations and depth according to Fitzpatrick skin type, there typically are no notable adverse effects, and clinical results are favorable.

Kojic Acid—Kojic acid is a natural metabolite derived from fungi and is widely used in Asian countries. It works by inhibiting the catecholase activity of tyrosinase⁶ and typically is available in concentrations of 1% to 4%. A study suggested that a concentration of 1% or less typically is safe to use for prolonged periods without adverse effects. Although not more effective than HQ as a monotherapy, kojic acid has been shown to haveimproved efficacy when used in combination with other lightening agents.⁷

Azelaic Acid—Azelaic acid works by inhibiting tyrosinase, mitochondrial oxidoreductase activation, and DNA synthesis. It preferentially targets heavily pigmented melanocytes and possesses anti-inflammatory and antibacterial properties.⁸ A 20% concentration of azelaic acid was compared to HQ 4% for the treatment of melasma, and results revealed that the liposomal form of azelaic acid was considerably more tolerable than HQ 4% and also more effective.⁹

Licorice Extracts—Licorice extracts have been safely used in several cosmeceutical skin lightening products.¹⁰ The main active compounds in licorice root are glabridin and liquiritin, which work to disperse melanin. These compounds often are used topically at concentrations of 10% to 40%. A study by Amer and Metwalli¹¹ found that topical liquiritin produced a reduction of pigmentary intensity, with 80% of patients showing an excellent response, which was described as no difference between the previously pigmented area and the normal skin surrounding it.

Aloesin—Aloesin is a low-molecular-weight glycoprotein found in aloe vera plants. Its mechanism of action includes competitive inhibition of the dihydroxyphenylalanine oxidation site, resulting in the inhibition of tyrosinase.¹² It often is combined with arbutin for an enhanced lightening effect.

Niacinamide—Niacinamide is a form of vitamin B₃ that works by suppressing the transfer of melanosomes to keratinocytes.¹³ In addition to its skin lightening effects, it also is photoprotective and antimicrobial, and its tolerability and safety have led to its inclusion in many cosmeceutical and prescription products.¹⁴

Ascorbic Acid—Ascorbic acid affects the monopherase activity of tyrosinase, thus reducing the synthesis of melanin. It also serves as an antioxidant in the skin by preventing the production of free radicals that can induce melanogenesis.¹⁵ Although it tends to be well tolerated with a low adverse effect profile, its relative instability and varying permeability can present a challenge. It is less effective as a monotherapy, so it often is combined with other lightening ingredients for greater efficacy.

Corticosteroids—Topical corticosteroids are anti-inflammatory and impact melanogenesis, though the mechanism of action of the latter has not been fully elucidated.^16,17 Low- to mid-potency topical steroids often are used in conjunction with skin lightening products to diminish irritation and decrease inflammation.¹⁸ However, prolonged use of corticosteroids can lead to cutaneous adverse effects such as striae, hypopigmentation, and acne, as well as systemic side effects if there is sufficient absorption over time.

Soybean Extracts—Soybean extracts contain serine protease inhibitors that reduce the transfer of melanosomes into keratinocytes by inhibiting the PAR-2 (protease-activated receptor 2) pathway.^19,20

Ellagic Acid—Ellagic acid is found in common plants such as eucalyptus and strawberry as well as green tea.²¹ It works as an antioxidant and decreases melanogenesis through inhibition of tyrosinase activity.

Paper Mulberry—Paper mulberry extract comes from the roots of the Broussonetia papyrifera tree and functions by inhibiting tyrosinase activity. It is widely used in South Africa and Europe.²²

Resveratrol—Resveratrol is an ingredient extracted from Morus alba L and functions as an antimelanogentic agent by directly inhibiting tyrosinase as well as transcriptional and posttranscriptional processing of tyrosinase.²³ It also holds antiproliferative, anti-inflammatory, and antioxidant properties and has widely been used for antiaging and skin lightening purposes.²⁴

Newer Non-HQ Lightening Agents

Silymarin—Silymarin (also known as milk thistle [Silybum marianum]), is a polyphenolic flavonoid that possesses anticarcinogenic, antioxidant, and anti-inflammatory properties. It prevents melanin production in a dose-dependent manner by inhibiting levodopa (L-dopa) oxidation activity of tyrosinase and also reduces the expression of tyrosinase protein.²⁵ In combination with vitamins C and E and hexylresorcinol, silymarin has been found to reduce the effects of photodamage, brighten skin, improve evenness and lines, as well as improve global facial appearance.²⁶

Malassezin—Malassezin is an indole produced by Malessezia furfur yeast and has recently been investigated for melanogenesis suppression. Grimes et al²⁷ assessed the efficacy of topical malassezin in 7 patients with facial hyperpigmentation applied twice daily for 14 weeks. Punch biopsies were taken at weeks 0, 8, 14, and 22. Biopsies from weeks 8 and 14 demonstrated reduced epidermal melanin compared to baseline in all participants; however, at 22 weeks, biopsies showed no difference in melanin content compared to baseline, indicating a temporary process induced by the malassezin.²⁷ More clinical studies are needed to investigate this further.

N-acetyl-glucosamine—N-acetyl-glucosamine is an aminosaccharide that inhibits the glycosylation of tyrosinase as well as its function in melanogenesis.²⁸ It is synthesized and included in topical products for wound healing, rhytides, moisturization, and pigmentation disorders.

Topical Tranexamic Acid—Tranexamic acid traditionally has been used orally for the treatment of menorrhagia but also has been found to be beneficial as a therapy for hyperpigmentation and erythema. Tranexamic acid interferes with plasmin activity, thus indirectly inhibiting melanogenesis while also inhibiting angiogenesis by targeting vascular endothelial growth factor (VEGF) receptors.²⁹ It also leads to an increase in the levels of β-endorphin and μ-opioid receptors as well as the expression of estrogen receptor β on the surface of mast cells.³⁰ Its oral benefit led to the development of topical formulations, typically in 2% to 5% concentrations. It has proven particularly beneficial in the treatment of melasma due to its effects on improving pigmentation, erythema, and skin barrier function.³¹ Topical tranexamic acid has a relatively high safety profile, with minor side effects such as transient skin irritation and erythema being reported.³²

Cysteamine—Cysteamine inhibits tyrosinase, peroxidase, and chelating copper ions necessary for melanogenesis. It has proven to be effective in treating melasma and chronic severe postinflammatory hyperpigmentation when used in a 5% cream formulation.^33,34 Lima et al³⁵ were the first to compare the effects of topical cysteamine to HQ in the treatment of facial melasma. They found that the mean reduction in modified Melasma Area and Severity Index score was 24% for cysteamine and 41% for HQ after 60 days. There were no severe adverse effects with either treatment group.³⁵

Final Thoughts

Hydroquinone remains the gold standard for treatment of hyperpigmentation; however, its side-effect profile and risk of ochronosis with long-term use has ushered in various other safe and effective skin lightening agents that can be used as monotherapies or in combination with other lightening agents. Many of these products also can be used effectively with procedural treatments such as chemical peels, lasers, and microneedling for enhanced absorption and efficacy. As newer agents are developed, additional well-designed studies will be needed to determine their safety and efficacy in different skin types as well as their role in the treatment of pigmentary disorders.

Disorders of hyperpigmentation—melasma, postinflammatory hyperpigmentation, lichen planus pigmentosus, erythema dyschromicum perstans, and pigmented contact dermatitis, among others—are common and challenging to treat. Although they can affect individuals of all skin types, they most commonly are seen in skin of color; in fact, dyspigmentation is one of the most common chief concerns for which individuals of color see a dermatologist.^1,2

For many years, hydroquinone (HQ) was one of the main options available for use as a lightening agent. Although effective, it has the risk of causing irritant dermatitis, potentially leading to further dyspigmentation, in addition to the risk of ochronosis with long-term use. It remains an important and useful treatment for pigmentary disorders, but there are numerous other lightening agents that also can be considered in the treatment of disorders of hyperpigmentation.

Herein, we provide recommendations for traditional and newer non-HQ lightening agents that can be considered when treating disorders of hyperpigmentation.

Traditional Non-HQ Lightening Agents

Retinoids—Retinoids are topical vitamin A derivatives that have been used safely and effectively for decades in the treatment of pigmentary disorders. Retinoids have multiple mechanisms of action in improving pigmentation. In addition to impeding tyrosinase induction, they inhibit pigment transfer to keratinocytes and lead to accelerated pigment loss due to epidermal shedding.³ Over-the-counter formulations include retinol, retinaldehyde, and adapalene. Prescription formulations include tretinoin and tazarotene in different strengths and vehicle formulations.⁴

Glycolic Acid—Glycolic acid is derived from sugarcane and is considered an α-hydroxy acid that leads to rapid desquamation of pigmented keratinocytes.⁵ Glycolic acid can not only be used in chemical peels but also in topical creams. It is the most common α-hydroxy acid peel and is sometimes paired with HQ and other topical lightening agents for increased penetration. Glycolic acid peels are available in concentrations of 20% to 70% and can be used at various depths. When used incorrectly, it can cause redness, burning, and even skin discoloration; however, when used at the proper concentrations and depth according to Fitzpatrick skin type, there typically are no notable adverse effects, and clinical results are favorable.

Kojic Acid—Kojic acid is a natural metabolite derived from fungi and is widely used in Asian countries. It works by inhibiting the catecholase activity of tyrosinase⁶ and typically is available in concentrations of 1% to 4%. A study suggested that a concentration of 1% or less typically is safe to use for prolonged periods without adverse effects. Although not more effective than HQ as a monotherapy, kojic acid has been shown to haveimproved efficacy when used in combination with other lightening agents.⁷

Azelaic Acid—Azelaic acid works by inhibiting tyrosinase, mitochondrial oxidoreductase activation, and DNA synthesis. It preferentially targets heavily pigmented melanocytes and possesses anti-inflammatory and antibacterial properties.⁸ A 20% concentration of azelaic acid was compared to HQ 4% for the treatment of melasma, and results revealed that the liposomal form of azelaic acid was considerably more tolerable than HQ 4% and also more effective.⁹

Licorice Extracts—Licorice extracts have been safely used in several cosmeceutical skin lightening products.¹⁰ The main active compounds in licorice root are glabridin and liquiritin, which work to disperse melanin. These compounds often are used topically at concentrations of 10% to 40%. A study by Amer and Metwalli¹¹ found that topical liquiritin produced a reduction of pigmentary intensity, with 80% of patients showing an excellent response, which was described as no difference between the previously pigmented area and the normal skin surrounding it.

Aloesin—Aloesin is a low-molecular-weight glycoprotein found in aloe vera plants. Its mechanism of action includes competitive inhibition of the dihydroxyphenylalanine oxidation site, resulting in the inhibition of tyrosinase.¹² It often is combined with arbutin for an enhanced lightening effect.

Niacinamide—Niacinamide is a form of vitamin B₃ that works by suppressing the transfer of melanosomes to keratinocytes.¹³ In addition to its skin lightening effects, it also is photoprotective and antimicrobial, and its tolerability and safety have led to its inclusion in many cosmeceutical and prescription products.¹⁴

Ascorbic Acid—Ascorbic acid affects the monopherase activity of tyrosinase, thus reducing the synthesis of melanin. It also serves as an antioxidant in the skin by preventing the production of free radicals that can induce melanogenesis.¹⁵ Although it tends to be well tolerated with a low adverse effect profile, its relative instability and varying permeability can present a challenge. It is less effective as a monotherapy, so it often is combined with other lightening ingredients for greater efficacy.

Corticosteroids—Topical corticosteroids are anti-inflammatory and impact melanogenesis, though the mechanism of action of the latter has not been fully elucidated.^16,17 Low- to mid-potency topical steroids often are used in conjunction with skin lightening products to diminish irritation and decrease inflammation.¹⁸ However, prolonged use of corticosteroids can lead to cutaneous adverse effects such as striae, hypopigmentation, and acne, as well as systemic side effects if there is sufficient absorption over time.

Soybean Extracts—Soybean extracts contain serine protease inhibitors that reduce the transfer of melanosomes into keratinocytes by inhibiting the PAR-2 (protease-activated receptor 2) pathway.^19,20

Ellagic Acid—Ellagic acid is found in common plants such as eucalyptus and strawberry as well as green tea.²¹ It works as an antioxidant and decreases melanogenesis through inhibition of tyrosinase activity.

Paper Mulberry—Paper mulberry extract comes from the roots of the Broussonetia papyrifera tree and functions by inhibiting tyrosinase activity. It is widely used in South Africa and Europe.²²

Resveratrol—Resveratrol is an ingredient extracted from Morus alba L and functions as an antimelanogentic agent by directly inhibiting tyrosinase as well as transcriptional and posttranscriptional processing of tyrosinase.²³ It also holds antiproliferative, anti-inflammatory, and antioxidant properties and has widely been used for antiaging and skin lightening purposes.²⁴

Newer Non-HQ Lightening Agents

Silymarin—Silymarin (also known as milk thistle [Silybum marianum]), is a polyphenolic flavonoid that possesses anticarcinogenic, antioxidant, and anti-inflammatory properties. It prevents melanin production in a dose-dependent manner by inhibiting levodopa (L-dopa) oxidation activity of tyrosinase and also reduces the expression of tyrosinase protein.²⁵ In combination with vitamins C and E and hexylresorcinol, silymarin has been found to reduce the effects of photodamage, brighten skin, improve evenness and lines, as well as improve global facial appearance.²⁶

Malassezin—Malassezin is an indole produced by Malessezia furfur yeast and has recently been investigated for melanogenesis suppression. Grimes et al²⁷ assessed the efficacy of topical malassezin in 7 patients with facial hyperpigmentation applied twice daily for 14 weeks. Punch biopsies were taken at weeks 0, 8, 14, and 22. Biopsies from weeks 8 and 14 demonstrated reduced epidermal melanin compared to baseline in all participants; however, at 22 weeks, biopsies showed no difference in melanin content compared to baseline, indicating a temporary process induced by the malassezin.²⁷ More clinical studies are needed to investigate this further.

N-acetyl-glucosamine—N-acetyl-glucosamine is an aminosaccharide that inhibits the glycosylation of tyrosinase as well as its function in melanogenesis.²⁸ It is synthesized and included in topical products for wound healing, rhytides, moisturization, and pigmentation disorders.

Topical Tranexamic Acid—Tranexamic acid traditionally has been used orally for the treatment of menorrhagia but also has been found to be beneficial as a therapy for hyperpigmentation and erythema. Tranexamic acid interferes with plasmin activity, thus indirectly inhibiting melanogenesis while also inhibiting angiogenesis by targeting vascular endothelial growth factor (VEGF) receptors.²⁹ It also leads to an increase in the levels of β-endorphin and μ-opioid receptors as well as the expression of estrogen receptor β on the surface of mast cells.³⁰ Its oral benefit led to the development of topical formulations, typically in 2% to 5% concentrations. It has proven particularly beneficial in the treatment of melasma due to its effects on improving pigmentation, erythema, and skin barrier function.³¹ Topical tranexamic acid has a relatively high safety profile, with minor side effects such as transient skin irritation and erythema being reported.³²

Cysteamine—Cysteamine inhibits tyrosinase, peroxidase, and chelating copper ions necessary for melanogenesis. It has proven to be effective in treating melasma and chronic severe postinflammatory hyperpigmentation when used in a 5% cream formulation.^33,34 Lima et al³⁵ were the first to compare the effects of topical cysteamine to HQ in the treatment of facial melasma. They found that the mean reduction in modified Melasma Area and Severity Index score was 24% for cysteamine and 41% for HQ after 60 days. There were no severe adverse effects with either treatment group.³⁵

Final Thoughts

Hydroquinone remains the gold standard for treatment of hyperpigmentation; however, its side-effect profile and risk of ochronosis with long-term use has ushered in various other safe and effective skin lightening agents that can be used as monotherapies or in combination with other lightening agents. Many of these products also can be used effectively with procedural treatments such as chemical peels, lasers, and microneedling for enhanced absorption and efficacy. As newer agents are developed, additional well-designed studies will be needed to determine their safety and efficacy in different skin types as well as their role in the treatment of pigmentary disorders.

Disorders of hyperpigmentation—melasma, postinflammatory hyperpigmentation, lichen planus pigmentosus, erythema dyschromicum perstans, and pigmented contact dermatitis, among others—are common and challenging to treat. Although they can affect individuals of all skin types, they most commonly are seen in skin of color; in fact, dyspigmentation is one of the most common chief concerns for which individuals of color see a dermatologist.^1,2

For many years, hydroquinone (HQ) was one of the main options available for use as a lightening agent. Although effective, it has the risk of causing irritant dermatitis, potentially leading to further dyspigmentation, in addition to the risk of ochronosis with long-term use. It remains an important and useful treatment for pigmentary disorders, but there are numerous other lightening agents that also can be considered in the treatment of disorders of hyperpigmentation.

Herein, we provide recommendations for traditional and newer non-HQ lightening agents that can be considered when treating disorders of hyperpigmentation.

Traditional Non-HQ Lightening Agents

Retinoids—Retinoids are topical vitamin A derivatives that have been used safely and effectively for decades in the treatment of pigmentary disorders. Retinoids have multiple mechanisms of action in improving pigmentation. In addition to impeding tyrosinase induction, they inhibit pigment transfer to keratinocytes and lead to accelerated pigment loss due to epidermal shedding.³ Over-the-counter formulations include retinol, retinaldehyde, and adapalene. Prescription formulations include tretinoin and tazarotene in different strengths and vehicle formulations.⁴

Glycolic Acid—Glycolic acid is derived from sugarcane and is considered an α-hydroxy acid that leads to rapid desquamation of pigmented keratinocytes.⁵ Glycolic acid can not only be used in chemical peels but also in topical creams. It is the most common α-hydroxy acid peel and is sometimes paired with HQ and other topical lightening agents for increased penetration. Glycolic acid peels are available in concentrations of 20% to 70% and can be used at various depths. When used incorrectly, it can cause redness, burning, and even skin discoloration; however, when used at the proper concentrations and depth according to Fitzpatrick skin type, there typically are no notable adverse effects, and clinical results are favorable.

Kojic Acid—Kojic acid is a natural metabolite derived from fungi and is widely used in Asian countries. It works by inhibiting the catecholase activity of tyrosinase⁶ and typically is available in concentrations of 1% to 4%. A study suggested that a concentration of 1% or less typically is safe to use for prolonged periods without adverse effects. Although not more effective than HQ as a monotherapy, kojic acid has been shown to haveimproved efficacy when used in combination with other lightening agents.⁷

Azelaic Acid—Azelaic acid works by inhibiting tyrosinase, mitochondrial oxidoreductase activation, and DNA synthesis. It preferentially targets heavily pigmented melanocytes and possesses anti-inflammatory and antibacterial properties.⁸ A 20% concentration of azelaic acid was compared to HQ 4% for the treatment of melasma, and results revealed that the liposomal form of azelaic acid was considerably more tolerable than HQ 4% and also more effective.⁹

Licorice Extracts—Licorice extracts have been safely used in several cosmeceutical skin lightening products.¹⁰ The main active compounds in licorice root are glabridin and liquiritin, which work to disperse melanin. These compounds often are used topically at concentrations of 10% to 40%. A study by Amer and Metwalli¹¹ found that topical liquiritin produced a reduction of pigmentary intensity, with 80% of patients showing an excellent response, which was described as no difference between the previously pigmented area and the normal skin surrounding it.

Aloesin—Aloesin is a low-molecular-weight glycoprotein found in aloe vera plants. Its mechanism of action includes competitive inhibition of the dihydroxyphenylalanine oxidation site, resulting in the inhibition of tyrosinase.¹² It often is combined with arbutin for an enhanced lightening effect.

Niacinamide—Niacinamide is a form of vitamin B₃ that works by suppressing the transfer of melanosomes to keratinocytes.¹³ In addition to its skin lightening effects, it also is photoprotective and antimicrobial, and its tolerability and safety have led to its inclusion in many cosmeceutical and prescription products.¹⁴

Ascorbic Acid—Ascorbic acid affects the monopherase activity of tyrosinase, thus reducing the synthesis of melanin. It also serves as an antioxidant in the skin by preventing the production of free radicals that can induce melanogenesis.¹⁵ Although it tends to be well tolerated with a low adverse effect profile, its relative instability and varying permeability can present a challenge. It is less effective as a monotherapy, so it often is combined with other lightening ingredients for greater efficacy.

Corticosteroids—Topical corticosteroids are anti-inflammatory and impact melanogenesis, though the mechanism of action of the latter has not been fully elucidated.^16,17 Low- to mid-potency topical steroids often are used in conjunction with skin lightening products to diminish irritation and decrease inflammation.¹⁸ However, prolonged use of corticosteroids can lead to cutaneous adverse effects such as striae, hypopigmentation, and acne, as well as systemic side effects if there is sufficient absorption over time.

Soybean Extracts—Soybean extracts contain serine protease inhibitors that reduce the transfer of melanosomes into keratinocytes by inhibiting the PAR-2 (protease-activated receptor 2) pathway.^19,20

Ellagic Acid—Ellagic acid is found in common plants such as eucalyptus and strawberry as well as green tea.²¹ It works as an antioxidant and decreases melanogenesis through inhibition of tyrosinase activity.

Paper Mulberry—Paper mulberry extract comes from the roots of the Broussonetia papyrifera tree and functions by inhibiting tyrosinase activity. It is widely used in South Africa and Europe.²²

Resveratrol—Resveratrol is an ingredient extracted from Morus alba L and functions as an antimelanogentic agent by directly inhibiting tyrosinase as well as transcriptional and posttranscriptional processing of tyrosinase.²³ It also holds antiproliferative, anti-inflammatory, and antioxidant properties and has widely been used for antiaging and skin lightening purposes.²⁴

Newer Non-HQ Lightening Agents

Silymarin—Silymarin (also known as milk thistle [Silybum marianum]), is a polyphenolic flavonoid that possesses anticarcinogenic, antioxidant, and anti-inflammatory properties. It prevents melanin production in a dose-dependent manner by inhibiting levodopa (L-dopa) oxidation activity of tyrosinase and also reduces the expression of tyrosinase protein.²⁵ In combination with vitamins C and E and hexylresorcinol, silymarin has been found to reduce the effects of photodamage, brighten skin, improve evenness and lines, as well as improve global facial appearance.²⁶

Malassezin—Malassezin is an indole produced by Malessezia furfur yeast and has recently been investigated for melanogenesis suppression. Grimes et al²⁷ assessed the efficacy of topical malassezin in 7 patients with facial hyperpigmentation applied twice daily for 14 weeks. Punch biopsies were taken at weeks 0, 8, 14, and 22. Biopsies from weeks 8 and 14 demonstrated reduced epidermal melanin compared to baseline in all participants; however, at 22 weeks, biopsies showed no difference in melanin content compared to baseline, indicating a temporary process induced by the malassezin.²⁷ More clinical studies are needed to investigate this further.

N-acetyl-glucosamine—N-acetyl-glucosamine is an aminosaccharide that inhibits the glycosylation of tyrosinase as well as its function in melanogenesis.²⁸ It is synthesized and included in topical products for wound healing, rhytides, moisturization, and pigmentation disorders.

Topical Tranexamic Acid—Tranexamic acid traditionally has been used orally for the treatment of menorrhagia but also has been found to be beneficial as a therapy for hyperpigmentation and erythema. Tranexamic acid interferes with plasmin activity, thus indirectly inhibiting melanogenesis while also inhibiting angiogenesis by targeting vascular endothelial growth factor (VEGF) receptors.²⁹ It also leads to an increase in the levels of β-endorphin and μ-opioid receptors as well as the expression of estrogen receptor β on the surface of mast cells.³⁰ Its oral benefit led to the development of topical formulations, typically in 2% to 5% concentrations. It has proven particularly beneficial in the treatment of melasma due to its effects on improving pigmentation, erythema, and skin barrier function.³¹ Topical tranexamic acid has a relatively high safety profile, with minor side effects such as transient skin irritation and erythema being reported.³²

Cysteamine—Cysteamine inhibits tyrosinase, peroxidase, and chelating copper ions necessary for melanogenesis. It has proven to be effective in treating melasma and chronic severe postinflammatory hyperpigmentation when used in a 5% cream formulation.^33,34 Lima et al³⁵ were the first to compare the effects of topical cysteamine to HQ in the treatment of facial melasma. They found that the mean reduction in modified Melasma Area and Severity Index score was 24% for cysteamine and 41% for HQ after 60 days. There were no severe adverse effects with either treatment group.³⁵

Final Thoughts

Hydroquinone remains the gold standard for treatment of hyperpigmentation; however, its side-effect profile and risk of ochronosis with long-term use has ushered in various other safe and effective skin lightening agents that can be used as monotherapies or in combination with other lightening agents. Many of these products also can be used effectively with procedural treatments such as chemical peels, lasers, and microneedling for enhanced absorption and efficacy. As newer agents are developed, additional well-designed studies will be needed to determine their safety and efficacy in different skin types as well as their role in the treatment of pigmentary disorders.

BOSTON – Though hydroquinone, retinoids, steroids, and triple combination cream remain gold standards for the topical treatment of melasma, new synthetic and botanical topicals are emerging as adjuvant and alternative treatments, according to Nada Elbuluk, MD, MSc.

One such agent is topical tranexamic acid, an antifibrinolytic medication that inhibits plasminogen activator from converting plasminogen in epidermal basal cells and keratinocytes to plasmin. “What makes tranexamic acid exciting is that it’s not just targeting melanogenesis; it’s also targeting the vascular component of melasma,” Dr. Elbuluk, director of the University of Southern California Skin of Color Center and Pigmentary Disorders Program, said at the annual meeting of the American Academy of Dermatology. “We really don’t have any topical agents that are doing that.”

Topical tranexamic acid is available in cream and solution formulations ranging from 2% to 5%. It has been studied in different drug delivery carriers (liposomal, liquid crystalline nanoparticle, and glycol co-enhancer carriers), has been combined with other lightening agents, and has been found to reduce Melasma Area and Severity Index (MASI) scores and reduce melanin while also improving erythema. “That’s where it really stands out from hydroquinone and triple combination cream,” Dr. Elbuluk said.

One study of patients with melasma found that topical tranexamic acid can decrease the number of CD31-positive vessels and expression of vascular endothelial growth factor (VEGF), and downregulated endothelin-1.

“Compared to hydroquinone, some studies have found a similar efficacy; others have found it inferior,” she continued. “But none of our patients can be on hydroquinone yearlong, so you have to bring in other agents that are efficacious. This is why you could consider having patients on topical tranexamic acid at different times of the year. It can cause some irritation for patients, but overall, it’s pretty well tolerated, and patients are often very happy with the overall improvement in the texture and appearance of their skin.”

Another emerging option, flutamide, is an anti-androgenic agent used topically and orally to treat acne, hirsutism, and hair loss. “It has not been excessively studied for melasma, but it may improve the condition through modifying alpha-MSH [alpha melanocyte-stimulating hormone] or cAMP [cyclic adenosine monophosphate] agents that play a role in melanin synthesis,” Dr. Elbuluk said. A randomized, controlled trial of 74 women with melasma treated with 1% flutamide vs. 4% hydroquinone showed a significant improvement in the MASI score and patient satisfaction but no difference in the mexameter melanin assay results.

“We need more data, but I think this is the right approach for us to start thinking about different factors that are addressing all of the components of the pathogenesis of melasma,” she said.

Other synthetic topicals that are being used or studied for melasma include N-acetyl glucosamine, linoleic acid, pidobenzone, methimazole, metformin, magnolignan, N-acetyl-4-S-cysteaminylphenol, dioic acid, melatonin, and silymarin.


 

Botanicals

Botanically-derived topicals for melasma are also being evaluated, including niacinamide, an anti-inflammatory agent that inhibits melanosome transfer to keratinocytes. Niacinamide decreases mast cell infiltrate and solar elastosis and enhances the epidermal barrier.

The antioxidants ascorbic acid (vitamin C) and zinc are also being studied. Ascorbic acid has photoprotective effects, inhibits tyrosinase, and promotes collagen synthesis. “One of the challenges with vitamin C is that it’s not very stable and it has limited permeability and bioavailability in the skin,” Dr. Elbuluk said. Zinc, meanwhile, boasts anti-inflammatory, photoprotective, and exfoliative properties and is a cofactor in wound healing.

Other botanical lightening agents being studied, in addition to silymarin, include arbutin, aloe vera, bakuchiol, soy, Ananas comosus (pineapple), parsley, Bellis perennis (daisy), mulberry extract, ellagic acid, gentisic acid, cinnamic acid, Hippophae rhamnoides (sea buckthorn), Cassia fistula extracts, licorice root extract, lignin peroxidase, and Polypodium leucotomos.

“I do think there really is a place for these in our therapeutic armamentarium, but we need more studies,” she said. “There aren’t many randomized, controlled studies looking at these agents specifically.” A recent systematic review on the efficacy and safety of topical therapy with botanical products for treating melasma included 12 trials composed of 695 patients from seven countries. The authors concluded that the trials lacked sufficient pooled evidence on efficacy and safety. However, many of the studies showed that these agents did improve melasma and MASI scores.

Platelet-rich plasma

Platelet-rich plasma (PRP) is being used as monotherapy and adjuvant therapy for melasma. “It’s believed to release platelet-derived growth factors, which can affect collagen synthesis,” Dr. Elbuluk explained. “It also has effects on TGF-B1 [transforming growth factor-beta 1], which inhibits melanin synthesis and epidermal growth factor, which has a downstream effect on lowering melanin production.”

A 2021 systematic review of 10 studies involving 395 adults with melasma found that PRP plus microneedling was most efficacious compared with PRP alone or combined with intradermal injection.

A separate systematic review of seven trials evaluating PRP for melasma found that most studies showed moderate improvements in melasma, which led the researchers to assign a moderate grade recommendation to PRP for melasma.

“I think we need more studies, but you may see PRP being used more commonly for melasma,” Dr. Elbuluk said. “The reality with melasma is that you are rarely using just one agent. Combination therapies are often superior to monotherapies in efficacy.” Combination therapy does not include just topicals, she added, but consideration of topicals with procedural modalities “and figuring out what your patient can tolerate and what they can afford.”

Since melasma is a chronic condition, “you want to emphasize to your patients that there is no cure for melasma. We are constantly trying to keep it in remission and keep it in control. That’s an active process.”



Other emerging topical therapies

Meanwhile, researchers continue to evaluate new targets for emerging treatments including a topical combination of an anti-estrogen with a VEGF inhibitor. In a separate pilot study of six women with melasma, investigators described treatment success with a novel combination of 12% hydroquinone, 6% kojic acid, and 5% vitamin C cream. “It’s the right thinking, combining different factors that address different aspects of pathogenesis of melasma,” Dr. Elbuluk said.

The mode of topical drug delivery also plays a role in treatment success. For example, she said, liposomal formulations have been found to enhance drug delivery and skin permeation and to improve the moisturizing effect, stability, and tolerability.

Dr. Elbuluk disclosed that she is a consultant for Avita, Scientis, VisualDx, Zosana, Incyte, La Roche-Posay, and Beiersdorf. She is an advisory board member for Allergan, Galderma, Incyte, and Janssen.

BOSTON – Though hydroquinone, retinoids, steroids, and triple combination cream remain gold standards for the topical treatment of melasma, new synthetic and botanical topicals are emerging as adjuvant and alternative treatments, according to Nada Elbuluk, MD, MSc.

One such agent is topical tranexamic acid, an antifibrinolytic medication that inhibits plasminogen activator from converting plasminogen in epidermal basal cells and keratinocytes to plasmin. “What makes tranexamic acid exciting is that it’s not just targeting melanogenesis; it’s also targeting the vascular component of melasma,” Dr. Elbuluk, director of the University of Southern California Skin of Color Center and Pigmentary Disorders Program, said at the annual meeting of the American Academy of Dermatology. “We really don’t have any topical agents that are doing that.”

Topical tranexamic acid is available in cream and solution formulations ranging from 2% to 5%. It has been studied in different drug delivery carriers (liposomal, liquid crystalline nanoparticle, and glycol co-enhancer carriers), has been combined with other lightening agents, and has been found to reduce Melasma Area and Severity Index (MASI) scores and reduce melanin while also improving erythema. “That’s where it really stands out from hydroquinone and triple combination cream,” Dr. Elbuluk said.

One study of patients with melasma found that topical tranexamic acid can decrease the number of CD31-positive vessels and expression of vascular endothelial growth factor (VEGF), and downregulated endothelin-1.

“Compared to hydroquinone, some studies have found a similar efficacy; others have found it inferior,” she continued. “But none of our patients can be on hydroquinone yearlong, so you have to bring in other agents that are efficacious. This is why you could consider having patients on topical tranexamic acid at different times of the year. It can cause some irritation for patients, but overall, it’s pretty well tolerated, and patients are often very happy with the overall improvement in the texture and appearance of their skin.”

Another emerging option, flutamide, is an anti-androgenic agent used topically and orally to treat acne, hirsutism, and hair loss. “It has not been excessively studied for melasma, but it may improve the condition through modifying alpha-MSH [alpha melanocyte-stimulating hormone] or cAMP [cyclic adenosine monophosphate] agents that play a role in melanin synthesis,” Dr. Elbuluk said. A randomized, controlled trial of 74 women with melasma treated with 1% flutamide vs. 4% hydroquinone showed a significant improvement in the MASI score and patient satisfaction but no difference in the mexameter melanin assay results.

“We need more data, but I think this is the right approach for us to start thinking about different factors that are addressing all of the components of the pathogenesis of melasma,” she said.

Other synthetic topicals that are being used or studied for melasma include N-acetyl glucosamine, linoleic acid, pidobenzone, methimazole, metformin, magnolignan, N-acetyl-4-S-cysteaminylphenol, dioic acid, melatonin, and silymarin.


 

Botanicals

Botanically-derived topicals for melasma are also being evaluated, including niacinamide, an anti-inflammatory agent that inhibits melanosome transfer to keratinocytes. Niacinamide decreases mast cell infiltrate and solar elastosis and enhances the epidermal barrier.

The antioxidants ascorbic acid (vitamin C) and zinc are also being studied. Ascorbic acid has photoprotective effects, inhibits tyrosinase, and promotes collagen synthesis. “One of the challenges with vitamin C is that it’s not very stable and it has limited permeability and bioavailability in the skin,” Dr. Elbuluk said. Zinc, meanwhile, boasts anti-inflammatory, photoprotective, and exfoliative properties and is a cofactor in wound healing.

Other botanical lightening agents being studied, in addition to silymarin, include arbutin, aloe vera, bakuchiol, soy, Ananas comosus (pineapple), parsley, Bellis perennis (daisy), mulberry extract, ellagic acid, gentisic acid, cinnamic acid, Hippophae rhamnoides (sea buckthorn), Cassia fistula extracts, licorice root extract, lignin peroxidase, and Polypodium leucotomos.

“I do think there really is a place for these in our therapeutic armamentarium, but we need more studies,” she said. “There aren’t many randomized, controlled studies looking at these agents specifically.” A recent systematic review on the efficacy and safety of topical therapy with botanical products for treating melasma included 12 trials composed of 695 patients from seven countries. The authors concluded that the trials lacked sufficient pooled evidence on efficacy and safety. However, many of the studies showed that these agents did improve melasma and MASI scores.

Platelet-rich plasma

Platelet-rich plasma (PRP) is being used as monotherapy and adjuvant therapy for melasma. “It’s believed to release platelet-derived growth factors, which can affect collagen synthesis,” Dr. Elbuluk explained. “It also has effects on TGF-B1 [transforming growth factor-beta 1], which inhibits melanin synthesis and epidermal growth factor, which has a downstream effect on lowering melanin production.”

A 2021 systematic review of 10 studies involving 395 adults with melasma found that PRP plus microneedling was most efficacious compared with PRP alone or combined with intradermal injection.

A separate systematic review of seven trials evaluating PRP for melasma found that most studies showed moderate improvements in melasma, which led the researchers to assign a moderate grade recommendation to PRP for melasma.

“I think we need more studies, but you may see PRP being used more commonly for melasma,” Dr. Elbuluk said. “The reality with melasma is that you are rarely using just one agent. Combination therapies are often superior to monotherapies in efficacy.” Combination therapy does not include just topicals, she added, but consideration of topicals with procedural modalities “and figuring out what your patient can tolerate and what they can afford.”

Since melasma is a chronic condition, “you want to emphasize to your patients that there is no cure for melasma. We are constantly trying to keep it in remission and keep it in control. That’s an active process.”



Other emerging topical therapies

Meanwhile, researchers continue to evaluate new targets for emerging treatments including a topical combination of an anti-estrogen with a VEGF inhibitor. In a separate pilot study of six women with melasma, investigators described treatment success with a novel combination of 12% hydroquinone, 6% kojic acid, and 5% vitamin C cream. “It’s the right thinking, combining different factors that address different aspects of pathogenesis of melasma,” Dr. Elbuluk said.

The mode of topical drug delivery also plays a role in treatment success. For example, she said, liposomal formulations have been found to enhance drug delivery and skin permeation and to improve the moisturizing effect, stability, and tolerability.

Dr. Elbuluk disclosed that she is a consultant for Avita, Scientis, VisualDx, Zosana, Incyte, La Roche-Posay, and Beiersdorf. She is an advisory board member for Allergan, Galderma, Incyte, and Janssen.

BOSTON – Though hydroquinone, retinoids, steroids, and triple combination cream remain gold standards for the topical treatment of melasma, new synthetic and botanical topicals are emerging as adjuvant and alternative treatments, according to Nada Elbuluk, MD, MSc.

One such agent is topical tranexamic acid, an antifibrinolytic medication that inhibits plasminogen activator from converting plasminogen in epidermal basal cells and keratinocytes to plasmin. “What makes tranexamic acid exciting is that it’s not just targeting melanogenesis; it’s also targeting the vascular component of melasma,” Dr. Elbuluk, director of the University of Southern California Skin of Color Center and Pigmentary Disorders Program, said at the annual meeting of the American Academy of Dermatology. “We really don’t have any topical agents that are doing that.”

Topical tranexamic acid is available in cream and solution formulations ranging from 2% to 5%. It has been studied in different drug delivery carriers (liposomal, liquid crystalline nanoparticle, and glycol co-enhancer carriers), has been combined with other lightening agents, and has been found to reduce Melasma Area and Severity Index (MASI) scores and reduce melanin while also improving erythema. “That’s where it really stands out from hydroquinone and triple combination cream,” Dr. Elbuluk said.

One study of patients with melasma found that topical tranexamic acid can decrease the number of CD31-positive vessels and expression of vascular endothelial growth factor (VEGF), and downregulated endothelin-1.

“Compared to hydroquinone, some studies have found a similar efficacy; others have found it inferior,” she continued. “But none of our patients can be on hydroquinone yearlong, so you have to bring in other agents that are efficacious. This is why you could consider having patients on topical tranexamic acid at different times of the year. It can cause some irritation for patients, but overall, it’s pretty well tolerated, and patients are often very happy with the overall improvement in the texture and appearance of their skin.”

Another emerging option, flutamide, is an anti-androgenic agent used topically and orally to treat acne, hirsutism, and hair loss. “It has not been excessively studied for melasma, but it may improve the condition through modifying alpha-MSH [alpha melanocyte-stimulating hormone] or cAMP [cyclic adenosine monophosphate] agents that play a role in melanin synthesis,” Dr. Elbuluk said. A randomized, controlled trial of 74 women with melasma treated with 1% flutamide vs. 4% hydroquinone showed a significant improvement in the MASI score and patient satisfaction but no difference in the mexameter melanin assay results.

“We need more data, but I think this is the right approach for us to start thinking about different factors that are addressing all of the components of the pathogenesis of melasma,” she said.

Other synthetic topicals that are being used or studied for melasma include N-acetyl glucosamine, linoleic acid, pidobenzone, methimazole, metformin, magnolignan, N-acetyl-4-S-cysteaminylphenol, dioic acid, melatonin, and silymarin.


 

Botanicals

Botanically-derived topicals for melasma are also being evaluated, including niacinamide, an anti-inflammatory agent that inhibits melanosome transfer to keratinocytes. Niacinamide decreases mast cell infiltrate and solar elastosis and enhances the epidermal barrier.

The antioxidants ascorbic acid (vitamin C) and zinc are also being studied. Ascorbic acid has photoprotective effects, inhibits tyrosinase, and promotes collagen synthesis. “One of the challenges with vitamin C is that it’s not very stable and it has limited permeability and bioavailability in the skin,” Dr. Elbuluk said. Zinc, meanwhile, boasts anti-inflammatory, photoprotective, and exfoliative properties and is a cofactor in wound healing.

Other botanical lightening agents being studied, in addition to silymarin, include arbutin, aloe vera, bakuchiol, soy, Ananas comosus (pineapple), parsley, Bellis perennis (daisy), mulberry extract, ellagic acid, gentisic acid, cinnamic acid, Hippophae rhamnoides (sea buckthorn), Cassia fistula extracts, licorice root extract, lignin peroxidase, and Polypodium leucotomos.

“I do think there really is a place for these in our therapeutic armamentarium, but we need more studies,” she said. “There aren’t many randomized, controlled studies looking at these agents specifically.” A recent systematic review on the efficacy and safety of topical therapy with botanical products for treating melasma included 12 trials composed of 695 patients from seven countries. The authors concluded that the trials lacked sufficient pooled evidence on efficacy and safety. However, many of the studies showed that these agents did improve melasma and MASI scores.

Platelet-rich plasma

Platelet-rich plasma (PRP) is being used as monotherapy and adjuvant therapy for melasma. “It’s believed to release platelet-derived growth factors, which can affect collagen synthesis,” Dr. Elbuluk explained. “It also has effects on TGF-B1 [transforming growth factor-beta 1], which inhibits melanin synthesis and epidermal growth factor, which has a downstream effect on lowering melanin production.”

A 2021 systematic review of 10 studies involving 395 adults with melasma found that PRP plus microneedling was most efficacious compared with PRP alone or combined with intradermal injection.

A separate systematic review of seven trials evaluating PRP for melasma found that most studies showed moderate improvements in melasma, which led the researchers to assign a moderate grade recommendation to PRP for melasma.

“I think we need more studies, but you may see PRP being used more commonly for melasma,” Dr. Elbuluk said. “The reality with melasma is that you are rarely using just one agent. Combination therapies are often superior to monotherapies in efficacy.” Combination therapy does not include just topicals, she added, but consideration of topicals with procedural modalities “and figuring out what your patient can tolerate and what they can afford.”

Since melasma is a chronic condition, “you want to emphasize to your patients that there is no cure for melasma. We are constantly trying to keep it in remission and keep it in control. That’s an active process.”



Other emerging topical therapies

Meanwhile, researchers continue to evaluate new targets for emerging treatments including a topical combination of an anti-estrogen with a VEGF inhibitor. In a separate pilot study of six women with melasma, investigators described treatment success with a novel combination of 12% hydroquinone, 6% kojic acid, and 5% vitamin C cream. “It’s the right thinking, combining different factors that address different aspects of pathogenesis of melasma,” Dr. Elbuluk said.

The mode of topical drug delivery also plays a role in treatment success. For example, she said, liposomal formulations have been found to enhance drug delivery and skin permeation and to improve the moisturizing effect, stability, and tolerability.

Dr. Elbuluk disclosed that she is a consultant for Avita, Scientis, VisualDx, Zosana, Incyte, La Roche-Posay, and Beiersdorf. She is an advisory board member for Allergan, Galderma, Incyte, and Janssen.

The Food and Drug Administration issued warning letters to 12 companies selling over-the-counter (OTC) skin lightening products, the agency announced on April 19. All the products contain hydroquinone as the active ingredient, and don’t meet the requirements to be sold legally over the counter. The letters were dated April 13.

The 12 products with hydroquinone are “unapproved drugs and are not generally recognized as safe and effective” (abbreviated as GRASE), the FDA said.

Among the side effects associated with hydroquinone products reported to the FDA are skin rashes, facial swelling, and skin discoloration or ochronosis. The discoloration can be permanent, the FDA said. The lighteners are marketed for use on age or dark spots on the skin associated with melasma.

Tri-Luma, a prescription product for the treatment of moderate to severe melasma of the face, is the only FDA-approved drug containing hydroquinone, according to the FDA. It contains 4% hydroquinone and two other ingredients. It is meant to be used under the supervision of a health care professional. Tri-Luma is indicated for up to 8 weeks of treatment for moderate to severe melasma of the face. The OTC products contain up to 2%. (Generic versions of 4% hydroquinone are available by prescription, dermatologists said.)

“Hydroquinone is a very effective medication, and that’s exactly what it is, a medication,” said Lily Talakoub, MD, a dermatologist in McLean, Va., who supports the FDA action. “It’s very effective and very safe to use in the right hands, but when it is overused or used in the wrong situation, it can cause problems.” Those problems often occur, she said, when there is no health care professional overseeing the use of the OTC products, and when people use them over the long term.

The FDA action to ban the OTC products is “very appropriate,” said dermatologist Pooja Sodha, MD, assistant professor and director of the Center for Laser and Cosmetic Dermatology at George Washington University, Washington. “We know patients pick this up [an OTC product] and use it without physician oversight.” When patients use the products longer than is appropriate, which is also common, it can worsen the initial skin issue, she said.

The action follows reforms finalized under the CARES Act (Coronavirus Aid, Relief and Economic Security Act), which included not only COVID-19 response efforts but also updated the method in which certain OTC drugs are regulated. Manufacturers of the skin lightening products that don’t have FDA approval had been told to remove the products from the market by September 2020.

The recent letters were sent to a dozen companies still marketing their products without an FDA new drug approval. The agency asked the companies to take prompt action and respond with 15 days, stating what they have done to correct the violations.

The 12 companies are AMBI Enterprises, Clinical Formula, Elements Brands Inc., Genomma Lab USA, Intilight/Dr Thomas Balshi, M&M Beauty and Wellness, Neoteric Cosmetics/Scott’s Liquid Gold, Skin Authority, Skin Pro, Skin PS Brands, True Earth Health Products, and Ultimark Products.

Health care professionals and consumers can report adverse reactions associated with these products to the FDA’s MedWatch Adverse Event Reporting program.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration issued warning letters to 12 companies selling over-the-counter (OTC) skin lightening products, the agency announced on April 19. All the products contain hydroquinone as the active ingredient, and don’t meet the requirements to be sold legally over the counter. The letters were dated April 13.

The 12 products with hydroquinone are “unapproved drugs and are not generally recognized as safe and effective” (abbreviated as GRASE), the FDA said.

Among the side effects associated with hydroquinone products reported to the FDA are skin rashes, facial swelling, and skin discoloration or ochronosis. The discoloration can be permanent, the FDA said. The lighteners are marketed for use on age or dark spots on the skin associated with melasma.

Tri-Luma, a prescription product for the treatment of moderate to severe melasma of the face, is the only FDA-approved drug containing hydroquinone, according to the FDA. It contains 4% hydroquinone and two other ingredients. It is meant to be used under the supervision of a health care professional. Tri-Luma is indicated for up to 8 weeks of treatment for moderate to severe melasma of the face. The OTC products contain up to 2%. (Generic versions of 4% hydroquinone are available by prescription, dermatologists said.)

“Hydroquinone is a very effective medication, and that’s exactly what it is, a medication,” said Lily Talakoub, MD, a dermatologist in McLean, Va., who supports the FDA action. “It’s very effective and very safe to use in the right hands, but when it is overused or used in the wrong situation, it can cause problems.” Those problems often occur, she said, when there is no health care professional overseeing the use of the OTC products, and when people use them over the long term.

The FDA action to ban the OTC products is “very appropriate,” said dermatologist Pooja Sodha, MD, assistant professor and director of the Center for Laser and Cosmetic Dermatology at George Washington University, Washington. “We know patients pick this up [an OTC product] and use it without physician oversight.” When patients use the products longer than is appropriate, which is also common, it can worsen the initial skin issue, she said.

The action follows reforms finalized under the CARES Act (Coronavirus Aid, Relief and Economic Security Act), which included not only COVID-19 response efforts but also updated the method in which certain OTC drugs are regulated. Manufacturers of the skin lightening products that don’t have FDA approval had been told to remove the products from the market by September 2020.

The recent letters were sent to a dozen companies still marketing their products without an FDA new drug approval. The agency asked the companies to take prompt action and respond with 15 days, stating what they have done to correct the violations.

The 12 companies are AMBI Enterprises, Clinical Formula, Elements Brands Inc., Genomma Lab USA, Intilight/Dr Thomas Balshi, M&M Beauty and Wellness, Neoteric Cosmetics/Scott’s Liquid Gold, Skin Authority, Skin Pro, Skin PS Brands, True Earth Health Products, and Ultimark Products.

Health care professionals and consumers can report adverse reactions associated with these products to the FDA’s MedWatch Adverse Event Reporting program.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration issued warning letters to 12 companies selling over-the-counter (OTC) skin lightening products, the agency announced on April 19. All the products contain hydroquinone as the active ingredient, and don’t meet the requirements to be sold legally over the counter. The letters were dated April 13.

The 12 products with hydroquinone are “unapproved drugs and are not generally recognized as safe and effective” (abbreviated as GRASE), the FDA said.

Among the side effects associated with hydroquinone products reported to the FDA are skin rashes, facial swelling, and skin discoloration or ochronosis. The discoloration can be permanent, the FDA said. The lighteners are marketed for use on age or dark spots on the skin associated with melasma.

Tri-Luma, a prescription product for the treatment of moderate to severe melasma of the face, is the only FDA-approved drug containing hydroquinone, according to the FDA. It contains 4% hydroquinone and two other ingredients. It is meant to be used under the supervision of a health care professional. Tri-Luma is indicated for up to 8 weeks of treatment for moderate to severe melasma of the face. The OTC products contain up to 2%. (Generic versions of 4% hydroquinone are available by prescription, dermatologists said.)

“Hydroquinone is a very effective medication, and that’s exactly what it is, a medication,” said Lily Talakoub, MD, a dermatologist in McLean, Va., who supports the FDA action. “It’s very effective and very safe to use in the right hands, but when it is overused or used in the wrong situation, it can cause problems.” Those problems often occur, she said, when there is no health care professional overseeing the use of the OTC products, and when people use them over the long term.

The FDA action to ban the OTC products is “very appropriate,” said dermatologist Pooja Sodha, MD, assistant professor and director of the Center for Laser and Cosmetic Dermatology at George Washington University, Washington. “We know patients pick this up [an OTC product] and use it without physician oversight.” When patients use the products longer than is appropriate, which is also common, it can worsen the initial skin issue, she said.

The action follows reforms finalized under the CARES Act (Coronavirus Aid, Relief and Economic Security Act), which included not only COVID-19 response efforts but also updated the method in which certain OTC drugs are regulated. Manufacturers of the skin lightening products that don’t have FDA approval had been told to remove the products from the market by September 2020.

The recent letters were sent to a dozen companies still marketing their products without an FDA new drug approval. The agency asked the companies to take prompt action and respond with 15 days, stating what they have done to correct the violations.

The 12 companies are AMBI Enterprises, Clinical Formula, Elements Brands Inc., Genomma Lab USA, Intilight/Dr Thomas Balshi, M&M Beauty and Wellness, Neoteric Cosmetics/Scott’s Liquid Gold, Skin Authority, Skin Pro, Skin PS Brands, True Earth Health Products, and Ultimark Products.

Health care professionals and consumers can report adverse reactions associated with these products to the FDA’s MedWatch Adverse Event Reporting program.

A version of this article first appeared on Medscape.com.

To the Editor:

Several mole and skin tag removal products are available online and over the counter (OTC).¹ Patients concerned with the cosmetic appearance of nevi may use these products as a do-it-yourself alternative to surgical removal. However, these products have the potential to cause harm.² Beyond the cosmetic adverse effects of skin necrosis and scar formation, these products can mask premalignant and malignant skin lesions.² Herein, we describe a patient with a family history of melanoma who developed facial and chest ulcerations with necrosis after applying an OTC mole and skin tag removal product.

A 45-year-old woman with fair skin presented to a clinic with multiple superficial ulcerations measuring approximately 1 cm in diameter with necrotic black bases and erythematous rims on the face, right side of the upper chest, and left earlobe after using the Ariella Mole Corrector and Skin Tag Remover and Repair Lotion Set, an OTC mole and skin tag removal product. The patient reported using the product 24 hours prior for the cosmetic removal of multiple nevi. After applying the product, she observed that it “immediately melted [her] skin” and the areas where the product was applied “turned black.” She reported that the product was applied to the skin for no longer than 30 seconds, after which she developed the necrotic lesions (Figure). After removing the product, she applied an OTC ointment containing bacitracin, neomycin, and polymyxin B to the lesions.

The patient had no history of nonmelanoma skin cancers or atypical nevi. She had a family history of melanoma in her mother and maternal uncle. The treatment plan was aimed primarily at reducing scar formation. We advised frequent application of petroleum-based ointments for moisture and overlying silicone scar tape to protect the area from photodamage and promote wound healing. We further advocated for sun protection and the use of a physical sunscreen on the lesions as they healed. We discussed potential laser-based scar revision options in the future.

With more than 180 reviews on Amazon and almost 70% of these reviews made within the month prior to compiling this manuscript, the Ariella Mole Corrector and Skin Tag Remover and Repair Lotion Set appeared to be popular; however, the product currently is unavailable on Amazon. Testimonials and before-and-after pictures advertising the product show an all-natural, safe, and effective method as an alternative to surgical removal of skin tags and nevi. The product website claims that skin tags and moles will “fall off naturally within 7 to 10 days” and the product can be used for “almost all skin types.” Users are instructed to apply the removal product and wipe it off when the skin surrounding the mole becomes swollen. The product kit also includes a repair lotion, which claims to help heal the skin after scab formation and scar development.

The ingredients listed on the product packaging are salicylic acid 25%, Melaleuca alternifolia (tea tree) leaf oil, propylene glycol, hydroxyethylcellulose, and alcohol. Salicylic acid 25% is a superficial peeling agent that penetrates the epidermis to the dermoepidermal junction. The potential side effects are mild and include superficial desquamation and epidermolysis.³ The Ariella Mole Corrector and Skin Tag Remover and Repair Lotion Set is not regulated by the US Food and Drug Administration and may contain variable concentrations of salicylic acid and other unknown compounds. Higher concentrations of salicylic acid can penetrate the full thickness of the epidermis into the papillary dermis, which can result in postinflammatory pigmentation, superficial infection, scarring, and deeper desquamation and epidermolysis.³ The product website advertises the use of only natural ingredients and an “advanced blend of concentrated natural ingredients contributing a broad spectrum of healing properties” in the formula. Although these claims are attractive to patients seeking alternatives to surgical approaches to nevi removal, the unfounded claims and unregulated ingredients may pose a threat to unsuspecting consumers.

Other OTC and “all-natural” mole removal products previously have been reported to cause harm.²Sanguinaria canadensis, also known as bloodroot, contains an alkaloid compound (sanguinarine) that has been shown to induce mitochondrial apoptosis and activation of Bcl-2 proteins in keratinocytes.⁴ Some products, such as Wart & Mole Vanish cream, may claim not to contain bloodroot specifically. However, sanguinarine can be extracted from other plants and may be listed as Argemone mexicana, Chelidonium majus, or Macleaya cordata in the ingredients list.⁵ The use of alternative medicine products such as black or yellow salve for the removal of suspected skin cancers also is not recommended because these escharotic treatments have not been proven safe or effective, and the manufacturing process for these compounds is unregulated.^6,7 Self-treatment with alternative remedies for nevi or suspected skin cancers has been associated with progression of disease and even death due to metastatic spread.²

Self-removal of moles is concerning because the nevi are masked by necrotic lesions and can no longer be assessed by dermoscopy or histopathology. Furthermore, the compounds in the Ariella Mole Corrector and Skin Tag Remover and Repair Lotion Set may have unknown effects on the transformation of premalignant cells. They also may mask an underlying process for which clinically proven and effective treatments such as cryotherapy, prescription topical agents, and surgical excision are warranted. Awareness of this product and similar products is important to educate patients on the harmful effects they may cause.

To the Editor:

Several mole and skin tag removal products are available online and over the counter (OTC).¹ Patients concerned with the cosmetic appearance of nevi may use these products as a do-it-yourself alternative to surgical removal. However, these products have the potential to cause harm.² Beyond the cosmetic adverse effects of skin necrosis and scar formation, these products can mask premalignant and malignant skin lesions.² Herein, we describe a patient with a family history of melanoma who developed facial and chest ulcerations with necrosis after applying an OTC mole and skin tag removal product.

A 45-year-old woman with fair skin presented to a clinic with multiple superficial ulcerations measuring approximately 1 cm in diameter with necrotic black bases and erythematous rims on the face, right side of the upper chest, and left earlobe after using the Ariella Mole Corrector and Skin Tag Remover and Repair Lotion Set, an OTC mole and skin tag removal product. The patient reported using the product 24 hours prior for the cosmetic removal of multiple nevi. After applying the product, she observed that it “immediately melted [her] skin” and the areas where the product was applied “turned black.” She reported that the product was applied to the skin for no longer than 30 seconds, after which she developed the necrotic lesions (Figure). After removing the product, she applied an OTC ointment containing bacitracin, neomycin, and polymyxin B to the lesions.

The patient had no history of nonmelanoma skin cancers or atypical nevi. She had a family history of melanoma in her mother and maternal uncle. The treatment plan was aimed primarily at reducing scar formation. We advised frequent application of petroleum-based ointments for moisture and overlying silicone scar tape to protect the area from photodamage and promote wound healing. We further advocated for sun protection and the use of a physical sunscreen on the lesions as they healed. We discussed potential laser-based scar revision options in the future.

With more than 180 reviews on Amazon and almost 70% of these reviews made within the month prior to compiling this manuscript, the Ariella Mole Corrector and Skin Tag Remover and Repair Lotion Set appeared to be popular; however, the product currently is unavailable on Amazon. Testimonials and before-and-after pictures advertising the product show an all-natural, safe, and effective method as an alternative to surgical removal of skin tags and nevi. The product website claims that skin tags and moles will “fall off naturally within 7 to 10 days” and the product can be used for “almost all skin types.” Users are instructed to apply the removal product and wipe it off when the skin surrounding the mole becomes swollen. The product kit also includes a repair lotion, which claims to help heal the skin after scab formation and scar development.

The ingredients listed on the product packaging are salicylic acid 25%, Melaleuca alternifolia (tea tree) leaf oil, propylene glycol, hydroxyethylcellulose, and alcohol. Salicylic acid 25% is a superficial peeling agent that penetrates the epidermis to the dermoepidermal junction. The potential side effects are mild and include superficial desquamation and epidermolysis.³ The Ariella Mole Corrector and Skin Tag Remover and Repair Lotion Set is not regulated by the US Food and Drug Administration and may contain variable concentrations of salicylic acid and other unknown compounds. Higher concentrations of salicylic acid can penetrate the full thickness of the epidermis into the papillary dermis, which can result in postinflammatory pigmentation, superficial infection, scarring, and deeper desquamation and epidermolysis.³ The product website advertises the use of only natural ingredients and an “advanced blend of concentrated natural ingredients contributing a broad spectrum of healing properties” in the formula. Although these claims are attractive to patients seeking alternatives to surgical approaches to nevi removal, the unfounded claims and unregulated ingredients may pose a threat to unsuspecting consumers.

Other OTC and “all-natural” mole removal products previously have been reported to cause harm.²Sanguinaria canadensis, also known as bloodroot, contains an alkaloid compound (sanguinarine) that has been shown to induce mitochondrial apoptosis and activation of Bcl-2 proteins in keratinocytes.⁴ Some products, such as Wart & Mole Vanish cream, may claim not to contain bloodroot specifically. However, sanguinarine can be extracted from other plants and may be listed as Argemone mexicana, Chelidonium majus, or Macleaya cordata in the ingredients list.⁵ The use of alternative medicine products such as black or yellow salve for the removal of suspected skin cancers also is not recommended because these escharotic treatments have not been proven safe or effective, and the manufacturing process for these compounds is unregulated.^6,7 Self-treatment with alternative remedies for nevi or suspected skin cancers has been associated with progression of disease and even death due to metastatic spread.²

Self-removal of moles is concerning because the nevi are masked by necrotic lesions and can no longer be assessed by dermoscopy or histopathology. Furthermore, the compounds in the Ariella Mole Corrector and Skin Tag Remover and Repair Lotion Set may have unknown effects on the transformation of premalignant cells. They also may mask an underlying process for which clinically proven and effective treatments such as cryotherapy, prescription topical agents, and surgical excision are warranted. Awareness of this product and similar products is important to educate patients on the harmful effects they may cause.

To the Editor:

Several mole and skin tag removal products are available online and over the counter (OTC).¹ Patients concerned with the cosmetic appearance of nevi may use these products as a do-it-yourself alternative to surgical removal. However, these products have the potential to cause harm.² Beyond the cosmetic adverse effects of skin necrosis and scar formation, these products can mask premalignant and malignant skin lesions.² Herein, we describe a patient with a family history of melanoma who developed facial and chest ulcerations with necrosis after applying an OTC mole and skin tag removal product.

A 45-year-old woman with fair skin presented to a clinic with multiple superficial ulcerations measuring approximately 1 cm in diameter with necrotic black bases and erythematous rims on the face, right side of the upper chest, and left earlobe after using the Ariella Mole Corrector and Skin Tag Remover and Repair Lotion Set, an OTC mole and skin tag removal product. The patient reported using the product 24 hours prior for the cosmetic removal of multiple nevi. After applying the product, she observed that it “immediately melted [her] skin” and the areas where the product was applied “turned black.” She reported that the product was applied to the skin for no longer than 30 seconds, after which she developed the necrotic lesions (Figure). After removing the product, she applied an OTC ointment containing bacitracin, neomycin, and polymyxin B to the lesions.

The patient had no history of nonmelanoma skin cancers or atypical nevi. She had a family history of melanoma in her mother and maternal uncle. The treatment plan was aimed primarily at reducing scar formation. We advised frequent application of petroleum-based ointments for moisture and overlying silicone scar tape to protect the area from photodamage and promote wound healing. We further advocated for sun protection and the use of a physical sunscreen on the lesions as they healed. We discussed potential laser-based scar revision options in the future.

With more than 180 reviews on Amazon and almost 70% of these reviews made within the month prior to compiling this manuscript, the Ariella Mole Corrector and Skin Tag Remover and Repair Lotion Set appeared to be popular; however, the product currently is unavailable on Amazon. Testimonials and before-and-after pictures advertising the product show an all-natural, safe, and effective method as an alternative to surgical removal of skin tags and nevi. The product website claims that skin tags and moles will “fall off naturally within 7 to 10 days” and the product can be used for “almost all skin types.” Users are instructed to apply the removal product and wipe it off when the skin surrounding the mole becomes swollen. The product kit also includes a repair lotion, which claims to help heal the skin after scab formation and scar development.

The ingredients listed on the product packaging are salicylic acid 25%, Melaleuca alternifolia (tea tree) leaf oil, propylene glycol, hydroxyethylcellulose, and alcohol. Salicylic acid 25% is a superficial peeling agent that penetrates the epidermis to the dermoepidermal junction. The potential side effects are mild and include superficial desquamation and epidermolysis.³ The Ariella Mole Corrector and Skin Tag Remover and Repair Lotion Set is not regulated by the US Food and Drug Administration and may contain variable concentrations of salicylic acid and other unknown compounds. Higher concentrations of salicylic acid can penetrate the full thickness of the epidermis into the papillary dermis, which can result in postinflammatory pigmentation, superficial infection, scarring, and deeper desquamation and epidermolysis.³ The product website advertises the use of only natural ingredients and an “advanced blend of concentrated natural ingredients contributing a broad spectrum of healing properties” in the formula. Although these claims are attractive to patients seeking alternatives to surgical approaches to nevi removal, the unfounded claims and unregulated ingredients may pose a threat to unsuspecting consumers.

Other OTC and “all-natural” mole removal products previously have been reported to cause harm.²Sanguinaria canadensis, also known as bloodroot, contains an alkaloid compound (sanguinarine) that has been shown to induce mitochondrial apoptosis and activation of Bcl-2 proteins in keratinocytes.⁴ Some products, such as Wart & Mole Vanish cream, may claim not to contain bloodroot specifically. However, sanguinarine can be extracted from other plants and may be listed as Argemone mexicana, Chelidonium majus, or Macleaya cordata in the ingredients list.⁵ The use of alternative medicine products such as black or yellow salve for the removal of suspected skin cancers also is not recommended because these escharotic treatments have not been proven safe or effective, and the manufacturing process for these compounds is unregulated.^6,7 Self-treatment with alternative remedies for nevi or suspected skin cancers has been associated with progression of disease and even death due to metastatic spread.²

Self-removal of moles is concerning because the nevi are masked by necrotic lesions and can no longer be assessed by dermoscopy or histopathology. Furthermore, the compounds in the Ariella Mole Corrector and Skin Tag Remover and Repair Lotion Set may have unknown effects on the transformation of premalignant cells. They also may mask an underlying process for which clinically proven and effective treatments such as cryotherapy, prescription topical agents, and surgical excision are warranted. Awareness of this product and similar products is important to educate patients on the harmful effects they may cause.

When establishing a treatment plan for patients with melasma, counseling them about realistic expectations is key.

“It’s important that they understand that this is a chronic condition, so it does require long-term maintenance therapy,” Arisa E. Ortiz, MD, said at the virtual annual Masters of Aesthetics Symposium. “We can improve melasma, but it’s difficult to cure melasma.”

While hydroquinone and other bleaching agents are typical treatment mainstays, chemical peels with glycolic acid, trichloroacetic acid, and salicylic acid can benefit some individuals. “For chemical peels, I really like glycolic acid peels because there is no downtime; it peels at the microscopic level,” said Dr. Ortiz, who is director of laser and cosmetic dermatology at the University of California, San Diego. “This is something they may need to repeat monthly, and having a week of peeling may be difficult to go through every month.”

Other common melasma treatments include lasers, intense pulsed light (IPL), and oral medications. “I personally am not impressed with microdermabrasion for melasma, so I don’t use that very much,” she said. “With laser treatment, you want to make sure you’re using low-energy lasers so that it doesn’t exacerbate or make them relapse or rebound.”

While hydroquinone is a mainstay of therapy, “you can’t use it chronically because of the risk of ochronosis (permanent darkening), so you do need to take drug holidays,” Dr. Ortiz said. “During those drug holidays, you want to make sure patients have a nonhydroquinone bleaching agent so that they don’t flare.” Options include lignin peroxidase, oligopeptide, Lytera, Melaplex, 4-n-butylresorcinol, Cysteamine cream, tranexamic acid, and oral antioxidants.

In a study sponsored by SkinMedica, investigators conducted a randomized, double-blind, half-face study in females with moderate to severe facial hyperpigmentation to assess the efficacy and tolerability of three new skin brightener formulations containing SMA-432, a prostaglandin E₂ inhibitor, compared with topical 4% hydroquinone (J Drugs Dermatol 2012 Dec;11[12]:1478-82). They found that the nonhydroquinone skin formulations were better tolerated and were just as effective as 4% hydroquinone.

In a separate unpublished study of 22 females, investigators assessed the efficacy of the U.SK Advanced Defense Booster, which contains ferulic acid, maslinic acid, peptides, and olive leaf extract. They observed that 98% of patients saw improvement after 28 days of treatment.

When it comes to using lasers for melasma treatment, low-energy devices provide the best outcomes. “I prefer using something like the 1927-nm fractional diode lasers at 3.75% density, really low densities because there’s less risk for rebound,” Dr. Ortiz said. “They also enhance skin permeability for the use of topicals.”

In an observational study of 27 female patients with refractory melasma, Arielle Kauvar, MD, director of New York Laser & Skin Care, combined microdermabrasion with the Q-switched Nd:YAG (Lasers in Surgery and Medicine 2012; 44:117-24). “The settings she used were very low fluence, so there was no clinical endpoint or no whitening,” Dr. Ortiz said. Specifically, she used a laser at 1.6-2 J/cm² with a 5- or 6-mm spot size immediately following microdermabrasion for 4 weeks. “She got a good improvement using a skin care regimen of sunscreen, hydroquinone, and tretinoin or vitamin C,” she said. “Remission lasted at least 6 months.”

In a study presented at the 2019 annual meeting of the America Society for Laser Medicine and Surgery, Dr. Ortiz and Tanya Greywal, MD, of the University of California, San Diego, used three passes of the 10764-nm Nd:YAG laser to treat 10 subjects with melasma skin types 2-5. The device has a 650-microsecond pulse duration, a 6-mm spot size, and an energy mode of 11-14 J/cm³. “There was no downtime with these patients, and they saw a mean improvement of 26%-50% as early as 3 weeks,” she said. “Patients did require multiple treatments to see adequate resolution, but no anesthesia or numbing cream was required. This is a good option for patients who need chronic maintenance treatment.”

Topicals also play a key role following the laser treatment of melasma. Dr. Ortiz characterized clobetasol as “kind of like the magic ointment.” She uses one application immediately post procedure “whenever I’m worried about a patient having postinflammatory hyperpigmentation or if I don’t want melasma patients to rebound. It can help reduce swelling and inflammation to decrease the risk of postinflammatory hyperpigmentation.”

Researchers have discovered that there is a vascular component to melasma. Paul M. Friedman, MD, of the Dermatology and Laser Surgery Center, Houston, and his colleagues used spectrocolorimetry to detect an underlying prominent vascular component in 11 patients with melasma (Lasers Surg Med 2017 Jan;49[1]:20-6). They determined that melasma lesions exhibiting subtle or subclinical telangiectatic erythema may be improved by combined vascular-targeted laser therapy together with fractional low-powered diode laser therapy. “A parallel improvement in telangiectatic erythema suggests a relationship between the underlying vasculature and hyperpigmentation,” said Dr. Ortiz, who was not affiliated with the study. “So, patients who have a vascular component to their melasma actually can get improved efficacy.”

Another strategy for melasma patients involves oral treatment with Polypodium leucotomos extract (PLE), a fern from the Polypodiaceae family with antioxidant properties that has been shown to be photoprotective against UVA and UVB radiation. “I like to think of it as an internal sunscreen,” Dr. Ortiz said. “It does not replace your external sunscreen, but it adds extra protection. It has been shown to significantly reduce the severity of sunburn and decrease the risk of UV radiation–induced skin cancer, as well as prevent skin aging.” The purported mechanism of action includes decreasing UV-mediated oxidative damage to DNA, enhancing the activity of endogenous antioxidant systems, increasing the minimal erythema dose, blocking UV radiation–induced cyclooxygenase-2 expression, reducing UV-induced immune suppression, and promoting p53 suppressor gene expression.

In a pilot placebo-controlled study of melasma patients on their normal regimen of hydroquinone and sunscreen, 40 Asian patients with melasma were randomized to receive either oral PLE supplementation or placebo for 12 weeks (J Clin Aesthet Dermatol 2018 Mar;11[3]:14-9). They found that PLE significantly improved and accelerated the outcome reached with hydroquinone and sunscreen from the first month of treatment, compared with placebo.

Dr. Ortiz next discussed the role of oral tranexamic acid, an antifibrinolytic, procoagulant agent that is approved by the Food and Drug Administration for the treatment of menorrhagia and for prevention of hemorrhage in patients with hemophilia undergoing tooth extractions. “It is a synthetic lysine derivative that inhibits plasminogen activation by blocking lysine-binding sites on the plasminogen molecule, and it’s a game changer for melasma treatment,” she said. “One of the side effects is that it inhibits melanogenesis and neovascularization. It’s been effective for melasma, but its use is limited by the risk for thromboembolism. It’s a slight increased risk, something patients should be aware of, but not something that should scare us away from prescribing it.”

In a study of 561 patients with melasma, 90% improved after a median treatment duration of 4 months, and only 7% had side effects (J Am Acad Dermatol 2016;75:385-92). The most common side effects were abdominal bloating and pain. One patient developed a DVT during treatment, but that person was found to have a protein S deficiency.

The daily dosing of tranexamic acid for menorrhagia is 3,900 mg daily, while the dose for melasma has ranged from 500 mg-1,500 mg per day, Dr. Ortiz said. It’s available as a 650-mg pill in the United States. “I prescribe 325 mg twice a day, but studies have shown that 650 mg once a day is just as effective,” she said.

Prior to prescribing tranexamic acid, Dr. Ortiz does not order labs, but she performs an extensive history of present illness. She does not prescribe it in patients with an increased risk of clotting, including people who smoke and those who take oral contraceptives or are on hormone supplementation. Use is also contraindicated in people with a current malignancy, those with a history of stroke or DVT, and those who have any clotting disorder.

She concluded her presentation by noting that she favors a combination approach to treating melasma patients that starts with a broad spectrum sunscreen and PLE. “For bleaching, I like to use 12% hydroquinone with 6% kojic acid in VersaBase,” she said. “Once I get them in better control, then I switch them to 4% hydroquinone for maintenance. I use glycolic peels, low-energy lasers, and tranexamic acid if the melasma is severe, and they have no contraindications. A combination approach really achieves the best results, and counseling is key.”

Dr. Ortiz disclosed having financial relationships with numerous pharmaceutical and device companies. She is also cochair of MOA.

dbrunk@mdedge.com

When establishing a treatment plan for patients with melasma, counseling them about realistic expectations is key.

“It’s important that they understand that this is a chronic condition, so it does require long-term maintenance therapy,” Arisa E. Ortiz, MD, said at the virtual annual Masters of Aesthetics Symposium. “We can improve melasma, but it’s difficult to cure melasma.”

While hydroquinone and other bleaching agents are typical treatment mainstays, chemical peels with glycolic acid, trichloroacetic acid, and salicylic acid can benefit some individuals. “For chemical peels, I really like glycolic acid peels because there is no downtime; it peels at the microscopic level,” said Dr. Ortiz, who is director of laser and cosmetic dermatology at the University of California, San Diego. “This is something they may need to repeat monthly, and having a week of peeling may be difficult to go through every month.”

Other common melasma treatments include lasers, intense pulsed light (IPL), and oral medications. “I personally am not impressed with microdermabrasion for melasma, so I don’t use that very much,” she said. “With laser treatment, you want to make sure you’re using low-energy lasers so that it doesn’t exacerbate or make them relapse or rebound.”

While hydroquinone is a mainstay of therapy, “you can’t use it chronically because of the risk of ochronosis (permanent darkening), so you do need to take drug holidays,” Dr. Ortiz said. “During those drug holidays, you want to make sure patients have a nonhydroquinone bleaching agent so that they don’t flare.” Options include lignin peroxidase, oligopeptide, Lytera, Melaplex, 4-n-butylresorcinol, Cysteamine cream, tranexamic acid, and oral antioxidants.

In a study sponsored by SkinMedica, investigators conducted a randomized, double-blind, half-face study in females with moderate to severe facial hyperpigmentation to assess the efficacy and tolerability of three new skin brightener formulations containing SMA-432, a prostaglandin E₂ inhibitor, compared with topical 4% hydroquinone (J Drugs Dermatol 2012 Dec;11[12]:1478-82). They found that the nonhydroquinone skin formulations were better tolerated and were just as effective as 4% hydroquinone.

In a separate unpublished study of 22 females, investigators assessed the efficacy of the U.SK Advanced Defense Booster, which contains ferulic acid, maslinic acid, peptides, and olive leaf extract. They observed that 98% of patients saw improvement after 28 days of treatment.

When it comes to using lasers for melasma treatment, low-energy devices provide the best outcomes. “I prefer using something like the 1927-nm fractional diode lasers at 3.75% density, really low densities because there’s less risk for rebound,” Dr. Ortiz said. “They also enhance skin permeability for the use of topicals.”

In an observational study of 27 female patients with refractory melasma, Arielle Kauvar, MD, director of New York Laser & Skin Care, combined microdermabrasion with the Q-switched Nd:YAG (Lasers in Surgery and Medicine 2012; 44:117-24). “The settings she used were very low fluence, so there was no clinical endpoint or no whitening,” Dr. Ortiz said. Specifically, she used a laser at 1.6-2 J/cm² with a 5- or 6-mm spot size immediately following microdermabrasion for 4 weeks. “She got a good improvement using a skin care regimen of sunscreen, hydroquinone, and tretinoin or vitamin C,” she said. “Remission lasted at least 6 months.”

In a study presented at the 2019 annual meeting of the America Society for Laser Medicine and Surgery, Dr. Ortiz and Tanya Greywal, MD, of the University of California, San Diego, used three passes of the 10764-nm Nd:YAG laser to treat 10 subjects with melasma skin types 2-5. The device has a 650-microsecond pulse duration, a 6-mm spot size, and an energy mode of 11-14 J/cm³. “There was no downtime with these patients, and they saw a mean improvement of 26%-50% as early as 3 weeks,” she said. “Patients did require multiple treatments to see adequate resolution, but no anesthesia or numbing cream was required. This is a good option for patients who need chronic maintenance treatment.”

Topicals also play a key role following the laser treatment of melasma. Dr. Ortiz characterized clobetasol as “kind of like the magic ointment.” She uses one application immediately post procedure “whenever I’m worried about a patient having postinflammatory hyperpigmentation or if I don’t want melasma patients to rebound. It can help reduce swelling and inflammation to decrease the risk of postinflammatory hyperpigmentation.”

Researchers have discovered that there is a vascular component to melasma. Paul M. Friedman, MD, of the Dermatology and Laser Surgery Center, Houston, and his colleagues used spectrocolorimetry to detect an underlying prominent vascular component in 11 patients with melasma (Lasers Surg Med 2017 Jan;49[1]:20-6). They determined that melasma lesions exhibiting subtle or subclinical telangiectatic erythema may be improved by combined vascular-targeted laser therapy together with fractional low-powered diode laser therapy. “A parallel improvement in telangiectatic erythema suggests a relationship between the underlying vasculature and hyperpigmentation,” said Dr. Ortiz, who was not affiliated with the study. “So, patients who have a vascular component to their melasma actually can get improved efficacy.”

Another strategy for melasma patients involves oral treatment with Polypodium leucotomos extract (PLE), a fern from the Polypodiaceae family with antioxidant properties that has been shown to be photoprotective against UVA and UVB radiation. “I like to think of it as an internal sunscreen,” Dr. Ortiz said. “It does not replace your external sunscreen, but it adds extra protection. It has been shown to significantly reduce the severity of sunburn and decrease the risk of UV radiation–induced skin cancer, as well as prevent skin aging.” The purported mechanism of action includes decreasing UV-mediated oxidative damage to DNA, enhancing the activity of endogenous antioxidant systems, increasing the minimal erythema dose, blocking UV radiation–induced cyclooxygenase-2 expression, reducing UV-induced immune suppression, and promoting p53 suppressor gene expression.

In a pilot placebo-controlled study of melasma patients on their normal regimen of hydroquinone and sunscreen, 40 Asian patients with melasma were randomized to receive either oral PLE supplementation or placebo for 12 weeks (J Clin Aesthet Dermatol 2018 Mar;11[3]:14-9). They found that PLE significantly improved and accelerated the outcome reached with hydroquinone and sunscreen from the first month of treatment, compared with placebo.

Dr. Ortiz next discussed the role of oral tranexamic acid, an antifibrinolytic, procoagulant agent that is approved by the Food and Drug Administration for the treatment of menorrhagia and for prevention of hemorrhage in patients with hemophilia undergoing tooth extractions. “It is a synthetic lysine derivative that inhibits plasminogen activation by blocking lysine-binding sites on the plasminogen molecule, and it’s a game changer for melasma treatment,” she said. “One of the side effects is that it inhibits melanogenesis and neovascularization. It’s been effective for melasma, but its use is limited by the risk for thromboembolism. It’s a slight increased risk, something patients should be aware of, but not something that should scare us away from prescribing it.”

In a study of 561 patients with melasma, 90% improved after a median treatment duration of 4 months, and only 7% had side effects (J Am Acad Dermatol 2016;75:385-92). The most common side effects were abdominal bloating and pain. One patient developed a DVT during treatment, but that person was found to have a protein S deficiency.

The daily dosing of tranexamic acid for menorrhagia is 3,900 mg daily, while the dose for melasma has ranged from 500 mg-1,500 mg per day, Dr. Ortiz said. It’s available as a 650-mg pill in the United States. “I prescribe 325 mg twice a day, but studies have shown that 650 mg once a day is just as effective,” she said.

Prior to prescribing tranexamic acid, Dr. Ortiz does not order labs, but she performs an extensive history of present illness. She does not prescribe it in patients with an increased risk of clotting, including people who smoke and those who take oral contraceptives or are on hormone supplementation. Use is also contraindicated in people with a current malignancy, those with a history of stroke or DVT, and those who have any clotting disorder.

She concluded her presentation by noting that she favors a combination approach to treating melasma patients that starts with a broad spectrum sunscreen and PLE. “For bleaching, I like to use 12% hydroquinone with 6% kojic acid in VersaBase,” she said. “Once I get them in better control, then I switch them to 4% hydroquinone for maintenance. I use glycolic peels, low-energy lasers, and tranexamic acid if the melasma is severe, and they have no contraindications. A combination approach really achieves the best results, and counseling is key.”

Dr. Ortiz disclosed having financial relationships with numerous pharmaceutical and device companies. She is also cochair of MOA.

dbrunk@mdedge.com

When establishing a treatment plan for patients with melasma, counseling them about realistic expectations is key.

“It’s important that they understand that this is a chronic condition, so it does require long-term maintenance therapy,” Arisa E. Ortiz, MD, said at the virtual annual Masters of Aesthetics Symposium. “We can improve melasma, but it’s difficult to cure melasma.”

While hydroquinone and other bleaching agents are typical treatment mainstays, chemical peels with glycolic acid, trichloroacetic acid, and salicylic acid can benefit some individuals. “For chemical peels, I really like glycolic acid peels because there is no downtime; it peels at the microscopic level,” said Dr. Ortiz, who is director of laser and cosmetic dermatology at the University of California, San Diego. “This is something they may need to repeat monthly, and having a week of peeling may be difficult to go through every month.”

Other common melasma treatments include lasers, intense pulsed light (IPL), and oral medications. “I personally am not impressed with microdermabrasion for melasma, so I don’t use that very much,” she said. “With laser treatment, you want to make sure you’re using low-energy lasers so that it doesn’t exacerbate or make them relapse or rebound.”

While hydroquinone is a mainstay of therapy, “you can’t use it chronically because of the risk of ochronosis (permanent darkening), so you do need to take drug holidays,” Dr. Ortiz said. “During those drug holidays, you want to make sure patients have a nonhydroquinone bleaching agent so that they don’t flare.” Options include lignin peroxidase, oligopeptide, Lytera, Melaplex, 4-n-butylresorcinol, Cysteamine cream, tranexamic acid, and oral antioxidants.

In a study sponsored by SkinMedica, investigators conducted a randomized, double-blind, half-face study in females with moderate to severe facial hyperpigmentation to assess the efficacy and tolerability of three new skin brightener formulations containing SMA-432, a prostaglandin E₂ inhibitor, compared with topical 4% hydroquinone (J Drugs Dermatol 2012 Dec;11[12]:1478-82). They found that the nonhydroquinone skin formulations were better tolerated and were just as effective as 4% hydroquinone.

In a separate unpublished study of 22 females, investigators assessed the efficacy of the U.SK Advanced Defense Booster, which contains ferulic acid, maslinic acid, peptides, and olive leaf extract. They observed that 98% of patients saw improvement after 28 days of treatment.

When it comes to using lasers for melasma treatment, low-energy devices provide the best outcomes. “I prefer using something like the 1927-nm fractional diode lasers at 3.75% density, really low densities because there’s less risk for rebound,” Dr. Ortiz said. “They also enhance skin permeability for the use of topicals.”

In an observational study of 27 female patients with refractory melasma, Arielle Kauvar, MD, director of New York Laser & Skin Care, combined microdermabrasion with the Q-switched Nd:YAG (Lasers in Surgery and Medicine 2012; 44:117-24). “The settings she used were very low fluence, so there was no clinical endpoint or no whitening,” Dr. Ortiz said. Specifically, she used a laser at 1.6-2 J/cm² with a 5- or 6-mm spot size immediately following microdermabrasion for 4 weeks. “She got a good improvement using a skin care regimen of sunscreen, hydroquinone, and tretinoin or vitamin C,” she said. “Remission lasted at least 6 months.”

In a study presented at the 2019 annual meeting of the America Society for Laser Medicine and Surgery, Dr. Ortiz and Tanya Greywal, MD, of the University of California, San Diego, used three passes of the 10764-nm Nd:YAG laser to treat 10 subjects with melasma skin types 2-5. The device has a 650-microsecond pulse duration, a 6-mm spot size, and an energy mode of 11-14 J/cm³. “There was no downtime with these patients, and they saw a mean improvement of 26%-50% as early as 3 weeks,” she said. “Patients did require multiple treatments to see adequate resolution, but no anesthesia or numbing cream was required. This is a good option for patients who need chronic maintenance treatment.”

Topicals also play a key role following the laser treatment of melasma. Dr. Ortiz characterized clobetasol as “kind of like the magic ointment.” She uses one application immediately post procedure “whenever I’m worried about a patient having postinflammatory hyperpigmentation or if I don’t want melasma patients to rebound. It can help reduce swelling and inflammation to decrease the risk of postinflammatory hyperpigmentation.”

Researchers have discovered that there is a vascular component to melasma. Paul M. Friedman, MD, of the Dermatology and Laser Surgery Center, Houston, and his colleagues used spectrocolorimetry to detect an underlying prominent vascular component in 11 patients with melasma (Lasers Surg Med 2017 Jan;49[1]:20-6). They determined that melasma lesions exhibiting subtle or subclinical telangiectatic erythema may be improved by combined vascular-targeted laser therapy together with fractional low-powered diode laser therapy. “A parallel improvement in telangiectatic erythema suggests a relationship between the underlying vasculature and hyperpigmentation,” said Dr. Ortiz, who was not affiliated with the study. “So, patients who have a vascular component to their melasma actually can get improved efficacy.”

Another strategy for melasma patients involves oral treatment with Polypodium leucotomos extract (PLE), a fern from the Polypodiaceae family with antioxidant properties that has been shown to be photoprotective against UVA and UVB radiation. “I like to think of it as an internal sunscreen,” Dr. Ortiz said. “It does not replace your external sunscreen, but it adds extra protection. It has been shown to significantly reduce the severity of sunburn and decrease the risk of UV radiation–induced skin cancer, as well as prevent skin aging.” The purported mechanism of action includes decreasing UV-mediated oxidative damage to DNA, enhancing the activity of endogenous antioxidant systems, increasing the minimal erythema dose, blocking UV radiation–induced cyclooxygenase-2 expression, reducing UV-induced immune suppression, and promoting p53 suppressor gene expression.

In a pilot placebo-controlled study of melasma patients on their normal regimen of hydroquinone and sunscreen, 40 Asian patients with melasma were randomized to receive either oral PLE supplementation or placebo for 12 weeks (J Clin Aesthet Dermatol 2018 Mar;11[3]:14-9). They found that PLE significantly improved and accelerated the outcome reached with hydroquinone and sunscreen from the first month of treatment, compared with placebo.

Dr. Ortiz next discussed the role of oral tranexamic acid, an antifibrinolytic, procoagulant agent that is approved by the Food and Drug Administration for the treatment of menorrhagia and for prevention of hemorrhage in patients with hemophilia undergoing tooth extractions. “It is a synthetic lysine derivative that inhibits plasminogen activation by blocking lysine-binding sites on the plasminogen molecule, and it’s a game changer for melasma treatment,” she said. “One of the side effects is that it inhibits melanogenesis and neovascularization. It’s been effective for melasma, but its use is limited by the risk for thromboembolism. It’s a slight increased risk, something patients should be aware of, but not something that should scare us away from prescribing it.”

In a study of 561 patients with melasma, 90% improved after a median treatment duration of 4 months, and only 7% had side effects (J Am Acad Dermatol 2016;75:385-92). The most common side effects were abdominal bloating and pain. One patient developed a DVT during treatment, but that person was found to have a protein S deficiency.

The daily dosing of tranexamic acid for menorrhagia is 3,900 mg daily, while the dose for melasma has ranged from 500 mg-1,500 mg per day, Dr. Ortiz said. It’s available as a 650-mg pill in the United States. “I prescribe 325 mg twice a day, but studies have shown that 650 mg once a day is just as effective,” she said.

Prior to prescribing tranexamic acid, Dr. Ortiz does not order labs, but she performs an extensive history of present illness. She does not prescribe it in patients with an increased risk of clotting, including people who smoke and those who take oral contraceptives or are on hormone supplementation. Use is also contraindicated in people with a current malignancy, those with a history of stroke or DVT, and those who have any clotting disorder.

She concluded her presentation by noting that she favors a combination approach to treating melasma patients that starts with a broad spectrum sunscreen and PLE. “For bleaching, I like to use 12% hydroquinone with 6% kojic acid in VersaBase,” she said. “Once I get them in better control, then I switch them to 4% hydroquinone for maintenance. I use glycolic peels, low-energy lasers, and tranexamic acid if the melasma is severe, and they have no contraindications. A combination approach really achieves the best results, and counseling is key.”

Dr. Ortiz disclosed having financial relationships with numerous pharmaceutical and device companies. She is also cochair of MOA.

dbrunk@mdedge.com

Melasma has such a high recurrence rate that, once the facial hyperpigmentation has been cleared, it’s best that treatment never entirely stops, Amit G. Pandya, MD, said at the virtual annual meeting of the American Academy of Dermatology.

He recommended alternating between a less-intensive maintenance therapy regimen in the winter months and an acute care regimen in the sunnier summer months. But in order to treat melasma effectively, it is first necessary to differentiate it from the numerous other possible causes of facial hyperpigmentation. And that is largely a matter of location.



Location, location, location

Melasma has a distinctive symmetric bilateral distribution: “Melasma likes the central area of the forehead, whereas the lateral areas of the forehead are more involved in lichen planus pigmentosus. Melanoma likes the area above the eyebrow or under the eyebrow. However, it does not go below the superior orbital rim or above the inferior orbital rim,”said Dr. Pandya, a dermatologist at the Palo Alto Medical Foundation in Sunnyvale, Calif., who is also on the faculty at the University of Texas Southwestern Medical Center, Dallas.

Melasma is common on the bridge of the nose, but usually not along the nasolabial fold, where hyperpigmentation is much more likely to be due to seborrheic dermatitis or drug-induced hyperpigmentation. Melasma doesn’t affect the tip of the nose; that’s more likely a sign of sarcoidosis or drug-induced hyperpigmentation. Melasma is common on the zygomatic prominence, while acanthosis nigricans favors the concave area below the zygomatic prominence. And melasma stays above the mandible; pigmentation below the mandible is more suggestive of poikiloderma of Civatte. Lentigines are scattered broadly across sun-exposed areas of the face. They also tend to be less symmetrical than melasma, the dermatologist continued.



Acute treatment

Dr. Pandya’s acute treatment algorithm begins with topical 4% hydroquinone in patients who’ve never been on it before. A response to the drug, which blocks the tyrosine-to-melanin pathway, takes 4-6 weeks, with maximum effect not seen until 3-6 months or longer. Bluish-grey ochronosis is a rare side effect at the 4% concentration but becomes more common at higher concentrations or when the drug is used in combination therapy.

“Hydroquinone is a workhorse, the oldest and most effective depigmenting agent,” he said.

If the patient hasn’t responded positively by 3 months, Dr. Pandya moves on to daily use of the triple-drug combination of fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% known as Tri-Luma, a kinder, gentler descendant of the 45-year-old Kligman-Willis compounded formula comprised of 0.1% dexamethasone, 5% hydroquinone, and 0.1% tretinoin.

If Tri-Luma also proves ineffective, Dr. Pandya turns to oral tranexamic acid. This is off-label therapy for the drug, a plasmin inhibitor, which is approved for the treatment of menorrhagia. But oral tranexamic acid is widely used for treatment of melasma in East Asia, and Dr. Pandya and others have evaluated it in placebo-controlled clinical trials. His conclusion is that oral tranexamic acid appears to be safe and effective for treatment of melasma.

“The drug is not approved for melasma, it’s approved for menorrhagia, so every doctor has to decide how much risk they want to take. The evidence suggests 500 mg per day is a good dose,” he said.

The collective clinical trials experience with oral tranexamic acid for melasma shows a side effect profile consisting of mild GI upset, headache, and myalgia. While increased thromboembolic risk is a theoretic concern, it hasn’t been an issue in the published studies, which typically exclude patients with a history of thromboembolic disease from enrollment. Patient satisfaction with the oral agent is high, according to Dr. Pandya.

In one randomized, open-label, 40-patient study, oral tranexamic acid plus a triple-combination cream featuring fluocinolone 0.01%, hydroquinone 2%, and tretinoin 0.05%, applied once a day, was significantly more effective and faster-acting than the topical therapy alone. At 8 weeks, the dual-therapy group averaged an 88% improvement in the Melasma Activity and Severity Index (MASI) scores, compared with 55% with the topical therapy alone (Indian J Dermatol. Sep-Oct 2015;60[5]:520).

Cysteamine 5% cream, which is available over the counter as Cyspera but is pricey, showed promising efficacy in a 40-patient, randomized, double-blind trial (J Dermatolog Treat. 2018 Mar;29[2]:182-9). Dr. Pandya said he’s looking forward to seeing further studies.

Chemical peels can be used, but multiple treatment sessions using a superficial peeling agent are required, and even then “the efficacy is usually not profound,” according to Dr. Pandya. Together with two colleagues he recently published a comprehensive systematic review of 113 published studies of all treatments for melasma in nearly 7,000 patients (Am J Clin Dermatol. 2020 Apr;21(2):173-225).

Newer lasers with various pulse lengths, fluences, wave lengths, and treatment frequency show “some promise,” but there have also been published reports of hypopigmentation and rebound hyperpigmentation. The optimal laser regimen remains elusive, he said.



Maintenance therapy

Dr. Pandya usually switches from hydroquinone to a different topical tyrosinase inhibitor for maintenance therapy, such as kojic acid, arbutin, or azelaic acid, all available OTC in many formulations. Alternatively, he might drop down to 2% hydroquinone for the winter months. Another option is triple-combination cream applied two or three times per week. A topical formulation of tranexamic acid is available, but studies of this agent in patients with melasma have yielded mixed results.

“I don’t think topical tranexamic acid is going to harm the patient, but I don’t think the efficacy is as good as with oral tranexamic acid,” he said.



Slap that melasma in irons

A comprehensive melasma management plan requires year-round frequent daily application of a broad spectrum sunscreen. And since it’s now evident that visible-wavelength light can worsen melasma through mechanisms similar to UVA and UVB, which are long recognized as the major drivers of the hyperpigmentation disorder, serious consideration should be given to the use of a tinted broad-spectrum sunscreen or makeup containing more than 3% iron oxide, which blocks visible light. In contrast, zinc oxide does not, Dr. Pandya noted.

In one influential study, aminolevulinic acid was applied on the arms of 20 patients; two sunscreens were applied on areas where the ALA was applied, and on one area, no sunscreen was applied. The minimal phototoxic dose of visible blue light was doubled with application of a broad-spectrum sunscreen containing titanium dioxide, zinc oxide, and 0.2% iron oxide, compared with no sunscreen, but increased 21-fold using a sunscreen containing titanium dioxide, zinc oxide, and 3.2% iron oxide (Dermatol Surg. 2008 Nov;34[11]:1469-76).

Moreover, in a double-blind, randomized trial including 61 patients with melasma, all on background 4% hydroquinone, those assigned to a broad-spectrum sunscreen containing iron oxide had a 78% improvement in MASI scores at 8 weeks, compared with a 62% improvement with a broad-spectrum UV-only sunscreen. Both sunscreens had a sun protection factor of at least 50 (Photodermatol Photoimmunol Photomed. 2014 Feb;30[1]:35-42).

Numerous sunscreen and makeup products containing more than 3% iron oxide are available OTC in various tints. It’s a matter of finding a color that matches the patient’s skin.

Concern has been raised that exposure to the visible blue light emitted by computer screens and cell phones could worsen melasma. Dr. Pandya noted that reassurance on that score was recently provided by French investigators. They measured the intensity of visible light at the wavelengths emitted by computer screens and laptops and determined that it was 100- to 1,000-fold less than sunlight in the same spectrum. They also conducted a prospective, randomized, split-face trial in 12 melasma patients. One side of the face was exposed to the visible blue light at the same wavelengths emitted by device screens, but at far greater intensity. Blinded evaluators found no split-face difference in modified MASI scores.

“These results suggest that at a 20-cm distance, a maximized use of a high-intensity computer screen for 8 hours per day during a 5-day period does not worsen melasma lesions. Although it is very unlikely that similar exposure during a longer period would start to affect melasma lesions, such a possibility cannot be ruled out,” according to the investigators (J Am Acad Dermatol. 2019 Dec 27;S0190-9622(19)33324-9. doi: 10.1016/j.jaad.2019.12.047).

Dr. Pandya reported serving as a consultant to Incyte, Pfizer, Viela Bio, and Villaris.

bjancin@mdedge.com

Melasma has such a high recurrence rate that, once the facial hyperpigmentation has been cleared, it’s best that treatment never entirely stops, Amit G. Pandya, MD, said at the virtual annual meeting of the American Academy of Dermatology.

He recommended alternating between a less-intensive maintenance therapy regimen in the winter months and an acute care regimen in the sunnier summer months. But in order to treat melasma effectively, it is first necessary to differentiate it from the numerous other possible causes of facial hyperpigmentation. And that is largely a matter of location.



Location, location, location

Melasma has a distinctive symmetric bilateral distribution: “Melasma likes the central area of the forehead, whereas the lateral areas of the forehead are more involved in lichen planus pigmentosus. Melanoma likes the area above the eyebrow or under the eyebrow. However, it does not go below the superior orbital rim or above the inferior orbital rim,”said Dr. Pandya, a dermatologist at the Palo Alto Medical Foundation in Sunnyvale, Calif., who is also on the faculty at the University of Texas Southwestern Medical Center, Dallas.

Melasma is common on the bridge of the nose, but usually not along the nasolabial fold, where hyperpigmentation is much more likely to be due to seborrheic dermatitis or drug-induced hyperpigmentation. Melasma doesn’t affect the tip of the nose; that’s more likely a sign of sarcoidosis or drug-induced hyperpigmentation. Melasma is common on the zygomatic prominence, while acanthosis nigricans favors the concave area below the zygomatic prominence. And melasma stays above the mandible; pigmentation below the mandible is more suggestive of poikiloderma of Civatte. Lentigines are scattered broadly across sun-exposed areas of the face. They also tend to be less symmetrical than melasma, the dermatologist continued.



Acute treatment

Dr. Pandya’s acute treatment algorithm begins with topical 4% hydroquinone in patients who’ve never been on it before. A response to the drug, which blocks the tyrosine-to-melanin pathway, takes 4-6 weeks, with maximum effect not seen until 3-6 months or longer. Bluish-grey ochronosis is a rare side effect at the 4% concentration but becomes more common at higher concentrations or when the drug is used in combination therapy.

“Hydroquinone is a workhorse, the oldest and most effective depigmenting agent,” he said.

If the patient hasn’t responded positively by 3 months, Dr. Pandya moves on to daily use of the triple-drug combination of fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% known as Tri-Luma, a kinder, gentler descendant of the 45-year-old Kligman-Willis compounded formula comprised of 0.1% dexamethasone, 5% hydroquinone, and 0.1% tretinoin.

If Tri-Luma also proves ineffective, Dr. Pandya turns to oral tranexamic acid. This is off-label therapy for the drug, a plasmin inhibitor, which is approved for the treatment of menorrhagia. But oral tranexamic acid is widely used for treatment of melasma in East Asia, and Dr. Pandya and others have evaluated it in placebo-controlled clinical trials. His conclusion is that oral tranexamic acid appears to be safe and effective for treatment of melasma.

“The drug is not approved for melasma, it’s approved for menorrhagia, so every doctor has to decide how much risk they want to take. The evidence suggests 500 mg per day is a good dose,” he said.

The collective clinical trials experience with oral tranexamic acid for melasma shows a side effect profile consisting of mild GI upset, headache, and myalgia. While increased thromboembolic risk is a theoretic concern, it hasn’t been an issue in the published studies, which typically exclude patients with a history of thromboembolic disease from enrollment. Patient satisfaction with the oral agent is high, according to Dr. Pandya.

In one randomized, open-label, 40-patient study, oral tranexamic acid plus a triple-combination cream featuring fluocinolone 0.01%, hydroquinone 2%, and tretinoin 0.05%, applied once a day, was significantly more effective and faster-acting than the topical therapy alone. At 8 weeks, the dual-therapy group averaged an 88% improvement in the Melasma Activity and Severity Index (MASI) scores, compared with 55% with the topical therapy alone (Indian J Dermatol. Sep-Oct 2015;60[5]:520).

Cysteamine 5% cream, which is available over the counter as Cyspera but is pricey, showed promising efficacy in a 40-patient, randomized, double-blind trial (J Dermatolog Treat. 2018 Mar;29[2]:182-9). Dr. Pandya said he’s looking forward to seeing further studies.

Chemical peels can be used, but multiple treatment sessions using a superficial peeling agent are required, and even then “the efficacy is usually not profound,” according to Dr. Pandya. Together with two colleagues he recently published a comprehensive systematic review of 113 published studies of all treatments for melasma in nearly 7,000 patients (Am J Clin Dermatol. 2020 Apr;21(2):173-225).

Newer lasers with various pulse lengths, fluences, wave lengths, and treatment frequency show “some promise,” but there have also been published reports of hypopigmentation and rebound hyperpigmentation. The optimal laser regimen remains elusive, he said.



Maintenance therapy

Dr. Pandya usually switches from hydroquinone to a different topical tyrosinase inhibitor for maintenance therapy, such as kojic acid, arbutin, or azelaic acid, all available OTC in many formulations. Alternatively, he might drop down to 2% hydroquinone for the winter months. Another option is triple-combination cream applied two or three times per week. A topical formulation of tranexamic acid is available, but studies of this agent in patients with melasma have yielded mixed results.

“I don’t think topical tranexamic acid is going to harm the patient, but I don’t think the efficacy is as good as with oral tranexamic acid,” he said.



Slap that melasma in irons

A comprehensive melasma management plan requires year-round frequent daily application of a broad spectrum sunscreen. And since it’s now evident that visible-wavelength light can worsen melasma through mechanisms similar to UVA and UVB, which are long recognized as the major drivers of the hyperpigmentation disorder, serious consideration should be given to the use of a tinted broad-spectrum sunscreen or makeup containing more than 3% iron oxide, which blocks visible light. In contrast, zinc oxide does not, Dr. Pandya noted.

In one influential study, aminolevulinic acid was applied on the arms of 20 patients; two sunscreens were applied on areas where the ALA was applied, and on one area, no sunscreen was applied. The minimal phototoxic dose of visible blue light was doubled with application of a broad-spectrum sunscreen containing titanium dioxide, zinc oxide, and 0.2% iron oxide, compared with no sunscreen, but increased 21-fold using a sunscreen containing titanium dioxide, zinc oxide, and 3.2% iron oxide (Dermatol Surg. 2008 Nov;34[11]:1469-76).

Moreover, in a double-blind, randomized trial including 61 patients with melasma, all on background 4% hydroquinone, those assigned to a broad-spectrum sunscreen containing iron oxide had a 78% improvement in MASI scores at 8 weeks, compared with a 62% improvement with a broad-spectrum UV-only sunscreen. Both sunscreens had a sun protection factor of at least 50 (Photodermatol Photoimmunol Photomed. 2014 Feb;30[1]:35-42).

Numerous sunscreen and makeup products containing more than 3% iron oxide are available OTC in various tints. It’s a matter of finding a color that matches the patient’s skin.

Concern has been raised that exposure to the visible blue light emitted by computer screens and cell phones could worsen melasma. Dr. Pandya noted that reassurance on that score was recently provided by French investigators. They measured the intensity of visible light at the wavelengths emitted by computer screens and laptops and determined that it was 100- to 1,000-fold less than sunlight in the same spectrum. They also conducted a prospective, randomized, split-face trial in 12 melasma patients. One side of the face was exposed to the visible blue light at the same wavelengths emitted by device screens, but at far greater intensity. Blinded evaluators found no split-face difference in modified MASI scores.

“These results suggest that at a 20-cm distance, a maximized use of a high-intensity computer screen for 8 hours per day during a 5-day period does not worsen melasma lesions. Although it is very unlikely that similar exposure during a longer period would start to affect melasma lesions, such a possibility cannot be ruled out,” according to the investigators (J Am Acad Dermatol. 2019 Dec 27;S0190-9622(19)33324-9. doi: 10.1016/j.jaad.2019.12.047).

Dr. Pandya reported serving as a consultant to Incyte, Pfizer, Viela Bio, and Villaris.

bjancin@mdedge.com

Melasma has such a high recurrence rate that, once the facial hyperpigmentation has been cleared, it’s best that treatment never entirely stops, Amit G. Pandya, MD, said at the virtual annual meeting of the American Academy of Dermatology.

He recommended alternating between a less-intensive maintenance therapy regimen in the winter months and an acute care regimen in the sunnier summer months. But in order to treat melasma effectively, it is first necessary to differentiate it from the numerous other possible causes of facial hyperpigmentation. And that is largely a matter of location.



Location, location, location

Melasma has a distinctive symmetric bilateral distribution: “Melasma likes the central area of the forehead, whereas the lateral areas of the forehead are more involved in lichen planus pigmentosus. Melanoma likes the area above the eyebrow or under the eyebrow. However, it does not go below the superior orbital rim or above the inferior orbital rim,”said Dr. Pandya, a dermatologist at the Palo Alto Medical Foundation in Sunnyvale, Calif., who is also on the faculty at the University of Texas Southwestern Medical Center, Dallas.

Melasma is common on the bridge of the nose, but usually not along the nasolabial fold, where hyperpigmentation is much more likely to be due to seborrheic dermatitis or drug-induced hyperpigmentation. Melasma doesn’t affect the tip of the nose; that’s more likely a sign of sarcoidosis or drug-induced hyperpigmentation. Melasma is common on the zygomatic prominence, while acanthosis nigricans favors the concave area below the zygomatic prominence. And melasma stays above the mandible; pigmentation below the mandible is more suggestive of poikiloderma of Civatte. Lentigines are scattered broadly across sun-exposed areas of the face. They also tend to be less symmetrical than melasma, the dermatologist continued.



Acute treatment

Dr. Pandya’s acute treatment algorithm begins with topical 4% hydroquinone in patients who’ve never been on it before. A response to the drug, which blocks the tyrosine-to-melanin pathway, takes 4-6 weeks, with maximum effect not seen until 3-6 months or longer. Bluish-grey ochronosis is a rare side effect at the 4% concentration but becomes more common at higher concentrations or when the drug is used in combination therapy.

“Hydroquinone is a workhorse, the oldest and most effective depigmenting agent,” he said.

If the patient hasn’t responded positively by 3 months, Dr. Pandya moves on to daily use of the triple-drug combination of fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% known as Tri-Luma, a kinder, gentler descendant of the 45-year-old Kligman-Willis compounded formula comprised of 0.1% dexamethasone, 5% hydroquinone, and 0.1% tretinoin.

If Tri-Luma also proves ineffective, Dr. Pandya turns to oral tranexamic acid. This is off-label therapy for the drug, a plasmin inhibitor, which is approved for the treatment of menorrhagia. But oral tranexamic acid is widely used for treatment of melasma in East Asia, and Dr. Pandya and others have evaluated it in placebo-controlled clinical trials. His conclusion is that oral tranexamic acid appears to be safe and effective for treatment of melasma.

“The drug is not approved for melasma, it’s approved for menorrhagia, so every doctor has to decide how much risk they want to take. The evidence suggests 500 mg per day is a good dose,” he said.

The collective clinical trials experience with oral tranexamic acid for melasma shows a side effect profile consisting of mild GI upset, headache, and myalgia. While increased thromboembolic risk is a theoretic concern, it hasn’t been an issue in the published studies, which typically exclude patients with a history of thromboembolic disease from enrollment. Patient satisfaction with the oral agent is high, according to Dr. Pandya.

In one randomized, open-label, 40-patient study, oral tranexamic acid plus a triple-combination cream featuring fluocinolone 0.01%, hydroquinone 2%, and tretinoin 0.05%, applied once a day, was significantly more effective and faster-acting than the topical therapy alone. At 8 weeks, the dual-therapy group averaged an 88% improvement in the Melasma Activity and Severity Index (MASI) scores, compared with 55% with the topical therapy alone (Indian J Dermatol. Sep-Oct 2015;60[5]:520).

Cysteamine 5% cream, which is available over the counter as Cyspera but is pricey, showed promising efficacy in a 40-patient, randomized, double-blind trial (J Dermatolog Treat. 2018 Mar;29[2]:182-9). Dr. Pandya said he’s looking forward to seeing further studies.

Chemical peels can be used, but multiple treatment sessions using a superficial peeling agent are required, and even then “the efficacy is usually not profound,” according to Dr. Pandya. Together with two colleagues he recently published a comprehensive systematic review of 113 published studies of all treatments for melasma in nearly 7,000 patients (Am J Clin Dermatol. 2020 Apr;21(2):173-225).

Newer lasers with various pulse lengths, fluences, wave lengths, and treatment frequency show “some promise,” but there have also been published reports of hypopigmentation and rebound hyperpigmentation. The optimal laser regimen remains elusive, he said.



Maintenance therapy

Dr. Pandya usually switches from hydroquinone to a different topical tyrosinase inhibitor for maintenance therapy, such as kojic acid, arbutin, or azelaic acid, all available OTC in many formulations. Alternatively, he might drop down to 2% hydroquinone for the winter months. Another option is triple-combination cream applied two or three times per week. A topical formulation of tranexamic acid is available, but studies of this agent in patients with melasma have yielded mixed results.

“I don’t think topical tranexamic acid is going to harm the patient, but I don’t think the efficacy is as good as with oral tranexamic acid,” he said.



Slap that melasma in irons

A comprehensive melasma management plan requires year-round frequent daily application of a broad spectrum sunscreen. And since it’s now evident that visible-wavelength light can worsen melasma through mechanisms similar to UVA and UVB, which are long recognized as the major drivers of the hyperpigmentation disorder, serious consideration should be given to the use of a tinted broad-spectrum sunscreen or makeup containing more than 3% iron oxide, which blocks visible light. In contrast, zinc oxide does not, Dr. Pandya noted.

In one influential study, aminolevulinic acid was applied on the arms of 20 patients; two sunscreens were applied on areas where the ALA was applied, and on one area, no sunscreen was applied. The minimal phototoxic dose of visible blue light was doubled with application of a broad-spectrum sunscreen containing titanium dioxide, zinc oxide, and 0.2% iron oxide, compared with no sunscreen, but increased 21-fold using a sunscreen containing titanium dioxide, zinc oxide, and 3.2% iron oxide (Dermatol Surg. 2008 Nov;34[11]:1469-76).

Moreover, in a double-blind, randomized trial including 61 patients with melasma, all on background 4% hydroquinone, those assigned to a broad-spectrum sunscreen containing iron oxide had a 78% improvement in MASI scores at 8 weeks, compared with a 62% improvement with a broad-spectrum UV-only sunscreen. Both sunscreens had a sun protection factor of at least 50 (Photodermatol Photoimmunol Photomed. 2014 Feb;30[1]:35-42).

Numerous sunscreen and makeup products containing more than 3% iron oxide are available OTC in various tints. It’s a matter of finding a color that matches the patient’s skin.

Concern has been raised that exposure to the visible blue light emitted by computer screens and cell phones could worsen melasma. Dr. Pandya noted that reassurance on that score was recently provided by French investigators. They measured the intensity of visible light at the wavelengths emitted by computer screens and laptops and determined that it was 100- to 1,000-fold less than sunlight in the same spectrum. They also conducted a prospective, randomized, split-face trial in 12 melasma patients. One side of the face was exposed to the visible blue light at the same wavelengths emitted by device screens, but at far greater intensity. Blinded evaluators found no split-face difference in modified MASI scores.

“These results suggest that at a 20-cm distance, a maximized use of a high-intensity computer screen for 8 hours per day during a 5-day period does not worsen melasma lesions. Although it is very unlikely that similar exposure during a longer period would start to affect melasma lesions, such a possibility cannot be ruled out,” according to the investigators (J Am Acad Dermatol. 2019 Dec 27;S0190-9622(19)33324-9. doi: 10.1016/j.jaad.2019.12.047).

Dr. Pandya reported serving as a consultant to Incyte, Pfizer, Viela Bio, and Villaris.

bjancin@mdedge.com