Pigmentation Disorders

Commonly known as neem or nimba, Azadirachta indica traditionally has been used as an oil or poultice to lighten skin pigment and reduce joint inflammation. Neem is a drought-resistant evergreen tree with thin serrated leaves, white fragrant flowers, and olivelike fruit (Figure 1). This plant is indigenous to India but also is readily found within tropical and semitropical environments throughout the Middle East, Southeast Asia, North Africa, and Australia.

Traditional Uses

For more than 4000 years, neem leaves, bark, fruit, and seeds have been used in food, insecticide, and herbal medicine cross-culturally in Indian Ayurvedic medicine and across Southeast Asia, particularly in Cambodia, Laos, Thailand, Myanmar, and Vietnam.^1-3 Because of its many essential nutrients—oleic acid, palmitic acid, stearic acid, linoleic acid, behenic acid, arachidic acid, and palmitoleic acid—and readily available nature, some ethnic groups include neem in their diet.⁴ Neem commonly is used as a seasoning in soups and rice, eaten as a cooked vegetable, infused into teas and tonics, and pickled with other spices.⁵

All parts of the neem tree—both externally and internally—have been utilized in traditional medicine for the treatment of various diseases and ailments. The flowers have been used to treat eye diseases and dyspepsia, the fruit has been employed as an anthelmintic, the seeds and leaves have been used for malaria treatment and insecticide, the stem bark has been used for the treatment of diarrhea, and the root bark has been used for skin diseases and inflammation.⁶ Neem oil is a yellow-brown bitter substance that often is utilized to treat skin diseases such as psoriasis, eczema, fungal infections, and abscesses.

Case Report—A 77-year-old man presented with a diffuse rash across the lower back. He reported that he had been using topical neem oil to alleviate lower back pain and arthritis for the last 6 months with noted relief and improvement of back pain. After roughly 3 to 4 months of using neem oil, he noted a rash on the lower back, bilateral flanks, and buttocks (Figure 2). The rash was asymptomatic, and he denied any pruritus, scaling, pain, or burning. The patient was referred to dermatology and received a diagnosis of chemical leukoderma secondary to contact with A indica. The patient was advised to stop using the topical neem oil, and the rash was simply monitored, as it was asymptomatic.

Bioactivity

Research has elucidated multiple bioactivity mechanisms of neem, including melanogenesis-inhibitory activity, toxicity against pests, antimalarial activity, and antioxidant activity.^1,7-9 Literature on the diverse phytochemical components of A indica indicate high levels of limonoids, flavonoids, and triterpenoids that are responsible for much of its antioxidant, anti-inflammatory, and insecticide properties.^1,10

Melanogenesis-Inhibitory Activity—To date, neem has been added to a number of cosmetic products used in Ayurvedic medicine. One study of isolated compounds in A indica showed superior inhibitory activities against melanogenesis with minimal toxicity to cells (86.5%–105.1% cell viability). Western blot analysis of samples extracted and isolated from neem root and bark showed melanogenesis-inhibitory activities in B16 melanoma cells through the inhibition of microphthalmia-associated transcription factor expression and decreased expression of tyrosinase, as well as tyrosinase-related proteins 1 and 2, which are largely responsible for melanin synthesis.¹¹ In another study, A indica flowers and their extracted constituents—6-deacetylnimbin and kaempferide—suggest melanogenesis-inhibitory activities in B16 melanoma cells with little to no toxicity to the cells (81.0%–111.7% cell viability).¹ In an evaluationof A indica seed extracts, some of the isolated limonoids and diterpenoids exhibited a marked melanogenesis-inhibitory effect (74%–91% reduction of melanin content) with no toxicity to the cell.⁵ All of these studies indicate that active compounds in neem root, bark, flowers, and seeds may be potential skin-lightening agents.

Toxicity Against Pests—Neem seeds have phytochemicals that convey some insecticidal properties. The seeds often are ground into a powder, combined with water, and sprayed onto crops to act as an insecticide. As a natural method of nonpesticidal management, A indica acts as an antifeedant, insect repellent, and egg-laying deterrent that protects crops from damage. Studies of A indica have noted effective nonpesticidal management against arthropod pests such as armyworm, termites, and the oriental fruit fly.^7,12,13

Antimalarial Activity—One study indicated that nimbolide, a limonoid from the neem plant, demonstrated antimalarial activity against Plasmodium falciparum. In separate cultures of asexual parasites and mature gametocytes, parasite numbers were less than 50% of the number in control cultures (8.0% vs 8.5% parasitemia, respectively).¹⁴ Thus, the lower parasite numbers indicated by this study highlight the antimalarial utility of nimbolide and neem oil.

Antioxidant and Anti-inflammatory Activity—Neem bark has been reported to have considerable antioxidant activity due to its high phenolic content.^1,15 One study showed that azadirachtin and nimbolide in neem exhibited concentration-dependent antiradical scavenging activity and antioxidant properties.¹⁶

The anti-inflammatory potential for neem may occur via the inhibition of the nuclear factor-κB signaling pathway, which is linked to cancer, inflammation, and apoptosis.¹⁷ It also has been observed that nimbidin within neem extracts—such as leaves, bark, and seed extract—suppresses the function of macrophages and neutrophils relevant to inflammation.¹⁶ Another study indicated neem’s anti-inflammatory activity due to the regulation of proinflammatory enzymes such as cyclooxygenase and lipoxygenase.¹⁸

Safety, Toxicity, and Risks

Ingestion—Although neem is safe to use in the general population, neem oil poisoning has been reported, particularly in young children. Ingesting large quantities of neem has resulted in vomiting, hepatic toxicity, metabolic acidosis, late neurologic sequelae, and encephalopathy in young children.¹⁹ The diagnosis of neem oil poisoning is based on patient history, clinical examination, and imaging findings. Poisoning can manifest as drowsiness, tachypnea, and generalized seizures.²⁰

Topical Application—Topical use of neem appears to be safe if the substance is diluted with other ingredients. However, direct application to the skin is not advised, as it may cause leukoderma and could induce allergic contact dermatitis and other allergic reactions.⁴

Final Thoughts

The use of neem extract for disease prevention and treatment has been prevalent around the world since ancient times. Neem has been documented to possess melanogenesis-inhibitory activity, toxicity against pests, antimalarial activity, and antioxidant activity by means of tyrosinase inhibition, phytochemical production, limonoid expression, and nuclear factor-κB regulation, respectively. However, topical use of neem may trigger a cutaneous response, highlighting the importance of considering a diagnosis of neem oil–induced chemical leukoderma when patients present with a hypopigmented rash and relevant history.

Commonly known as neem or nimba, Azadirachta indica traditionally has been used as an oil or poultice to lighten skin pigment and reduce joint inflammation. Neem is a drought-resistant evergreen tree with thin serrated leaves, white fragrant flowers, and olivelike fruit (Figure 1). This plant is indigenous to India but also is readily found within tropical and semitropical environments throughout the Middle East, Southeast Asia, North Africa, and Australia.

Traditional Uses

For more than 4000 years, neem leaves, bark, fruit, and seeds have been used in food, insecticide, and herbal medicine cross-culturally in Indian Ayurvedic medicine and across Southeast Asia, particularly in Cambodia, Laos, Thailand, Myanmar, and Vietnam.^1-3 Because of its many essential nutrients—oleic acid, palmitic acid, stearic acid, linoleic acid, behenic acid, arachidic acid, and palmitoleic acid—and readily available nature, some ethnic groups include neem in their diet.⁴ Neem commonly is used as a seasoning in soups and rice, eaten as a cooked vegetable, infused into teas and tonics, and pickled with other spices.⁵

All parts of the neem tree—both externally and internally—have been utilized in traditional medicine for the treatment of various diseases and ailments. The flowers have been used to treat eye diseases and dyspepsia, the fruit has been employed as an anthelmintic, the seeds and leaves have been used for malaria treatment and insecticide, the stem bark has been used for the treatment of diarrhea, and the root bark has been used for skin diseases and inflammation.⁶ Neem oil is a yellow-brown bitter substance that often is utilized to treat skin diseases such as psoriasis, eczema, fungal infections, and abscesses.

Case Report—A 77-year-old man presented with a diffuse rash across the lower back. He reported that he had been using topical neem oil to alleviate lower back pain and arthritis for the last 6 months with noted relief and improvement of back pain. After roughly 3 to 4 months of using neem oil, he noted a rash on the lower back, bilateral flanks, and buttocks (Figure 2). The rash was asymptomatic, and he denied any pruritus, scaling, pain, or burning. The patient was referred to dermatology and received a diagnosis of chemical leukoderma secondary to contact with A indica. The patient was advised to stop using the topical neem oil, and the rash was simply monitored, as it was asymptomatic.

Bioactivity

Research has elucidated multiple bioactivity mechanisms of neem, including melanogenesis-inhibitory activity, toxicity against pests, antimalarial activity, and antioxidant activity.^1,7-9 Literature on the diverse phytochemical components of A indica indicate high levels of limonoids, flavonoids, and triterpenoids that are responsible for much of its antioxidant, anti-inflammatory, and insecticide properties.^1,10

Melanogenesis-Inhibitory Activity—To date, neem has been added to a number of cosmetic products used in Ayurvedic medicine. One study of isolated compounds in A indica showed superior inhibitory activities against melanogenesis with minimal toxicity to cells (86.5%–105.1% cell viability). Western blot analysis of samples extracted and isolated from neem root and bark showed melanogenesis-inhibitory activities in B16 melanoma cells through the inhibition of microphthalmia-associated transcription factor expression and decreased expression of tyrosinase, as well as tyrosinase-related proteins 1 and 2, which are largely responsible for melanin synthesis.¹¹ In another study, A indica flowers and their extracted constituents—6-deacetylnimbin and kaempferide—suggest melanogenesis-inhibitory activities in B16 melanoma cells with little to no toxicity to the cells (81.0%–111.7% cell viability).¹ In an evaluationof A indica seed extracts, some of the isolated limonoids and diterpenoids exhibited a marked melanogenesis-inhibitory effect (74%–91% reduction of melanin content) with no toxicity to the cell.⁵ All of these studies indicate that active compounds in neem root, bark, flowers, and seeds may be potential skin-lightening agents.

Toxicity Against Pests—Neem seeds have phytochemicals that convey some insecticidal properties. The seeds often are ground into a powder, combined with water, and sprayed onto crops to act as an insecticide. As a natural method of nonpesticidal management, A indica acts as an antifeedant, insect repellent, and egg-laying deterrent that protects crops from damage. Studies of A indica have noted effective nonpesticidal management against arthropod pests such as armyworm, termites, and the oriental fruit fly.^7,12,13

Antimalarial Activity—One study indicated that nimbolide, a limonoid from the neem plant, demonstrated antimalarial activity against Plasmodium falciparum. In separate cultures of asexual parasites and mature gametocytes, parasite numbers were less than 50% of the number in control cultures (8.0% vs 8.5% parasitemia, respectively).¹⁴ Thus, the lower parasite numbers indicated by this study highlight the antimalarial utility of nimbolide and neem oil.

Antioxidant and Anti-inflammatory Activity—Neem bark has been reported to have considerable antioxidant activity due to its high phenolic content.^1,15 One study showed that azadirachtin and nimbolide in neem exhibited concentration-dependent antiradical scavenging activity and antioxidant properties.¹⁶

The anti-inflammatory potential for neem may occur via the inhibition of the nuclear factor-κB signaling pathway, which is linked to cancer, inflammation, and apoptosis.¹⁷ It also has been observed that nimbidin within neem extracts—such as leaves, bark, and seed extract—suppresses the function of macrophages and neutrophils relevant to inflammation.¹⁶ Another study indicated neem’s anti-inflammatory activity due to the regulation of proinflammatory enzymes such as cyclooxygenase and lipoxygenase.¹⁸

Safety, Toxicity, and Risks

Ingestion—Although neem is safe to use in the general population, neem oil poisoning has been reported, particularly in young children. Ingesting large quantities of neem has resulted in vomiting, hepatic toxicity, metabolic acidosis, late neurologic sequelae, and encephalopathy in young children.¹⁹ The diagnosis of neem oil poisoning is based on patient history, clinical examination, and imaging findings. Poisoning can manifest as drowsiness, tachypnea, and generalized seizures.²⁰

Topical Application—Topical use of neem appears to be safe if the substance is diluted with other ingredients. However, direct application to the skin is not advised, as it may cause leukoderma and could induce allergic contact dermatitis and other allergic reactions.⁴

Final Thoughts

The use of neem extract for disease prevention and treatment has been prevalent around the world since ancient times. Neem has been documented to possess melanogenesis-inhibitory activity, toxicity against pests, antimalarial activity, and antioxidant activity by means of tyrosinase inhibition, phytochemical production, limonoid expression, and nuclear factor-κB regulation, respectively. However, topical use of neem may trigger a cutaneous response, highlighting the importance of considering a diagnosis of neem oil–induced chemical leukoderma when patients present with a hypopigmented rash and relevant history.

Commonly known as neem or nimba, Azadirachta indica traditionally has been used as an oil or poultice to lighten skin pigment and reduce joint inflammation. Neem is a drought-resistant evergreen tree with thin serrated leaves, white fragrant flowers, and olivelike fruit (Figure 1). This plant is indigenous to India but also is readily found within tropical and semitropical environments throughout the Middle East, Southeast Asia, North Africa, and Australia.

Traditional Uses

For more than 4000 years, neem leaves, bark, fruit, and seeds have been used in food, insecticide, and herbal medicine cross-culturally in Indian Ayurvedic medicine and across Southeast Asia, particularly in Cambodia, Laos, Thailand, Myanmar, and Vietnam.^1-3 Because of its many essential nutrients—oleic acid, palmitic acid, stearic acid, linoleic acid, behenic acid, arachidic acid, and palmitoleic acid—and readily available nature, some ethnic groups include neem in their diet.⁴ Neem commonly is used as a seasoning in soups and rice, eaten as a cooked vegetable, infused into teas and tonics, and pickled with other spices.⁵

All parts of the neem tree—both externally and internally—have been utilized in traditional medicine for the treatment of various diseases and ailments. The flowers have been used to treat eye diseases and dyspepsia, the fruit has been employed as an anthelmintic, the seeds and leaves have been used for malaria treatment and insecticide, the stem bark has been used for the treatment of diarrhea, and the root bark has been used for skin diseases and inflammation.⁶ Neem oil is a yellow-brown bitter substance that often is utilized to treat skin diseases such as psoriasis, eczema, fungal infections, and abscesses.

Case Report—A 77-year-old man presented with a diffuse rash across the lower back. He reported that he had been using topical neem oil to alleviate lower back pain and arthritis for the last 6 months with noted relief and improvement of back pain. After roughly 3 to 4 months of using neem oil, he noted a rash on the lower back, bilateral flanks, and buttocks (Figure 2). The rash was asymptomatic, and he denied any pruritus, scaling, pain, or burning. The patient was referred to dermatology and received a diagnosis of chemical leukoderma secondary to contact with A indica. The patient was advised to stop using the topical neem oil, and the rash was simply monitored, as it was asymptomatic.

Bioactivity

Research has elucidated multiple bioactivity mechanisms of neem, including melanogenesis-inhibitory activity, toxicity against pests, antimalarial activity, and antioxidant activity.^1,7-9 Literature on the diverse phytochemical components of A indica indicate high levels of limonoids, flavonoids, and triterpenoids that are responsible for much of its antioxidant, anti-inflammatory, and insecticide properties.^1,10

Melanogenesis-Inhibitory Activity—To date, neem has been added to a number of cosmetic products used in Ayurvedic medicine. One study of isolated compounds in A indica showed superior inhibitory activities against melanogenesis with minimal toxicity to cells (86.5%–105.1% cell viability). Western blot analysis of samples extracted and isolated from neem root and bark showed melanogenesis-inhibitory activities in B16 melanoma cells through the inhibition of microphthalmia-associated transcription factor expression and decreased expression of tyrosinase, as well as tyrosinase-related proteins 1 and 2, which are largely responsible for melanin synthesis.¹¹ In another study, A indica flowers and their extracted constituents—6-deacetylnimbin and kaempferide—suggest melanogenesis-inhibitory activities in B16 melanoma cells with little to no toxicity to the cells (81.0%–111.7% cell viability).¹ In an evaluationof A indica seed extracts, some of the isolated limonoids and diterpenoids exhibited a marked melanogenesis-inhibitory effect (74%–91% reduction of melanin content) with no toxicity to the cell.⁵ All of these studies indicate that active compounds in neem root, bark, flowers, and seeds may be potential skin-lightening agents.

Toxicity Against Pests—Neem seeds have phytochemicals that convey some insecticidal properties. The seeds often are ground into a powder, combined with water, and sprayed onto crops to act as an insecticide. As a natural method of nonpesticidal management, A indica acts as an antifeedant, insect repellent, and egg-laying deterrent that protects crops from damage. Studies of A indica have noted effective nonpesticidal management against arthropod pests such as armyworm, termites, and the oriental fruit fly.^7,12,13

Antimalarial Activity—One study indicated that nimbolide, a limonoid from the neem plant, demonstrated antimalarial activity against Plasmodium falciparum. In separate cultures of asexual parasites and mature gametocytes, parasite numbers were less than 50% of the number in control cultures (8.0% vs 8.5% parasitemia, respectively).¹⁴ Thus, the lower parasite numbers indicated by this study highlight the antimalarial utility of nimbolide and neem oil.

Antioxidant and Anti-inflammatory Activity—Neem bark has been reported to have considerable antioxidant activity due to its high phenolic content.^1,15 One study showed that azadirachtin and nimbolide in neem exhibited concentration-dependent antiradical scavenging activity and antioxidant properties.¹⁶

The anti-inflammatory potential for neem may occur via the inhibition of the nuclear factor-κB signaling pathway, which is linked to cancer, inflammation, and apoptosis.¹⁷ It also has been observed that nimbidin within neem extracts—such as leaves, bark, and seed extract—suppresses the function of macrophages and neutrophils relevant to inflammation.¹⁶ Another study indicated neem’s anti-inflammatory activity due to the regulation of proinflammatory enzymes such as cyclooxygenase and lipoxygenase.¹⁸

Safety, Toxicity, and Risks

Ingestion—Although neem is safe to use in the general population, neem oil poisoning has been reported, particularly in young children. Ingesting large quantities of neem has resulted in vomiting, hepatic toxicity, metabolic acidosis, late neurologic sequelae, and encephalopathy in young children.¹⁹ The diagnosis of neem oil poisoning is based on patient history, clinical examination, and imaging findings. Poisoning can manifest as drowsiness, tachypnea, and generalized seizures.²⁰

Topical Application—Topical use of neem appears to be safe if the substance is diluted with other ingredients. However, direct application to the skin is not advised, as it may cause leukoderma and could induce allergic contact dermatitis and other allergic reactions.⁴

Final Thoughts

The use of neem extract for disease prevention and treatment has been prevalent around the world since ancient times. Neem has been documented to possess melanogenesis-inhibitory activity, toxicity against pests, antimalarial activity, and antioxidant activity by means of tyrosinase inhibition, phytochemical production, limonoid expression, and nuclear factor-κB regulation, respectively. However, topical use of neem may trigger a cutaneous response, highlighting the importance of considering a diagnosis of neem oil–induced chemical leukoderma when patients present with a hypopigmented rash and relevant history.

Internet platforms have become a common source of medical information for individuals with a broad range of skin conditions including vitiligo. The prevalence of vitiligo among US adults ranges from 0.76% to 1.11%, with approximately 40% of adult cases of vitiligo in the United States remaining undiagnosed.¹ The vitiligo community has become more inquisitive of the relationship between diet and vitiligo, turning to online sources for suggestions on diet modifications that may be beneficial for their condition. Although there is an abundance of online information, few diets or foods have been medically recognized to definitively improve or worsen vitiligo symptoms. We reviewed the top online web pages accessible to the public regarding diet suggestions that affect vitiligo symptoms. We then compared these online results to published peer-reviewed scientific literature.

Methods

Two independent online searches were performed by Researcher 1 (Y.A.) and Researcher 2 (I.M.) using Google Advanced Search. The independent searches were performed by the reviewers in neighboring areas of Chicago, Illinois, using the same Internet browser (Google Chrome). The primary search terms were diet and vitiligo along with the optional additional terms dietary supplement(s), food(s), nutrition, herb(s), or vitamin(s). Our search included any web pages published or updated from January 1, 2010, to December 31, 2021, and originally scribed in the English language. The domains “.com,” “.org,” “.edu,” and “.cc” were included.

From this initial search, Researcher 1 identified 312 web pages and Researcher 2 identified 314 web pages. Each reviewer sorted their respective search results to identify the number of eligible records to be screened. Records were defined as unique web pages that met the search criteria. After removing duplicates, Researcher 1 screened 102 web pages and Researcher 2 screened 76 web pages. Of these records, web pages were excluded if they did not include any diet recommendations for vitiligo patients. Each reviewer independently created a list of eligible records, and the independent lists were then merged for a total of 58 web pages. Among these 58 web pages, there were 24 duplicate records and 3 records that were deemed ineligible for the study due to lack of subject matter relevance. A final total of 31 web pages were included in the data analysis (Figure). Of the 31 records selected, the reviewers jointly evaluated each web page and recorded the diet components that were recommended for individuals with vitiligo to either include or avoid (eTable).

For comparison and support from published scientific literature, a search of PubMed articles indexed for MEDLINE was conducted using the terms diet and vitiligo. Relevant human clinical studies published in the English-language literature were reviewed for content regarding the relationship between diet and vitiligo.

Results

Our online search revealed an abundance of information regarding various dietary modifications suggested to aid in the management of vitiligo symptoms. Most web pages (27/31 [87%]) were not authored by medical professionals or dermatologists. There were 27 diet components mentioned 8 or more times within the 31 total web pages. These diet components were selected for further review via PubMed. Each item was searched on PubMed using the term “[respective diet component] and vitiligo” among all published literature in the English language. Our study focused on summarizing the data on dietary components for which we were able to gather scientific support. These data have been organized into the following categories: vitamins, fruits, omega-3 fatty acids, grains, minerals, vegetables, and nuts.

Vitamins—The online literature recommended inclusion of vitamin supplements, in particular vitamins D and B₁₂, which aligned with published scientific literature.^2,3 Eleven of 31 (35%) web pages recommended vitamin D in vitiligo. A 2010 study analyzing patients with vitiligo vulgaris (N=45) found that 68.9% of the cohort had insufficient (<30 ng/mL) 25-hydroxyvitamin D levels.² A prospective study of 30 individuals found that the use of tacrolimus ointment plus oral vitamin D supplementation was found to be more successful in repigmentation than topical tacrolimus alone.³ Vitamin D dosage ranged from 1500 IU/d if the patient’s serum 25-hydroxyvitamin D levels were less than 20 ng/mL to 3000 IU/d if the serum levels were less than 10 ng/mL for 6 months.

Dairy products are a source of vitamin D.^2,3 Of the web pages that mentioned dairy, a subtle majority (4/7 [57%]) recommended the inclusion of dairy products. Although many web pages did not specify whether oral vitamin D supplementation vs dietary food consumption is preferred, a 2013 controlled study of 16 vitiligo patients who received high doses of vitamin D supplementation with a low-calcium diet found that 4 patients showed 1% to 25% repigmentation, 5 patients showed 26% to 50% repigmentation, and 5 patients showed 51% to 75% repigmentation of the affected areas.⁴

Eleven of 31 (35%) web pages recommended inclusion of vitamin B₁₂ supplementation in vitiligo. A 2-year study with 100 participants showed that supplementation with folic acid and vitamin B₁₂ along with sun exposure yielded more effective repigmentation than either vitamins or sun exposure alone.⁵ An additional hypothesis suggested vitamin B₁₂ may aid in repigmentation through its role in the homocysteine pathway. Although the theory is unproven, it is proposed that inhibition of homocysteine via vitamin B₁₂ or folic acid supplementation may play a role in reducing melanocyte destruction and restoring melanin synthesis.⁶

There were mixed recommendations regarding vitamin C via supplementation and/or eating citrus fruits such as oranges. Although there are limited clinical studies on the use of vitamin C and the treatment of vitiligo, a 6-year prospective study from Madagascar consisting of approximately 300 participants with vitiligo who were treated with a combination of topical corticosteroids, oral vitamin C, and oral vitamin B₁₂ supplementation showed excellent repigmentation (defined by repigmentation of more than 76% of the originally affected area) in 50 participants.⁷

Fruits—Most web pages had mixed recommendations on whether to include or avoid certain fruits. Interestingly, inclusion of mangoes and apricots in the diet were highly recommended (9/31 [29%] and 8/31 [26%], respectively) while fruits such as oranges, lemons, papayas, and grapes were discouraged (10/31 [32%], 8/31 [26%], 6/31 [19%], and 7/31 [23%], respectively). Although some web pages suggested that vitamin C–rich produce including citrus and berries may help to increase melanin formation, others strongly suggested avoiding these fruits. There is limited information on the effects of citrus on vitiligo, but a 2022 study indicated that 5-demethylnobiletin, a flavonoid found in sweet citrus fruits, may stimulate melanin synthesis, which can possibly be beneficial for vitiligo.⁸

Omega-3 Fatty Acids—Seven of 31 (23%) web pages recommended the inclusion of omega-3 fatty acids for their role as antioxidants to improve vitiligo symptoms. Research has indicated a strong association between vitiligo and oxidative stress.⁹ A 2007 controlled clinical trial that included 28 vitiligo patients demonstrated that oral antioxidant supplementation in combination with narrowband UVB phototherapy can significantly decrease vitiligo-associated oxidative stress (P<.05); 8 of 17 (47%) patients in the treatment group saw greater than 75% repigmentation after antioxidant treatment.¹⁰

Grains—Five of 31 (16%) web pages suggested avoiding gluten—a protein naturally found in some grains including wheat, barley, and rye—to improve vitiligo symptoms. A 2021 review suggested that a gluten-free diet may be effective in managing celiac disease, and it is hypothesized that vitiligo may be managed with similar dietary adjustments.¹¹ Studies have shown that celiac disease and vitiligo—both autoimmune conditions—involve IL-2, IL-6, IL-7, and IL-21 in their disease pathways.^12,13 Their shared immunogenic mechanism may account for similar management options.

Upon review, 2 case reports were identified that discussed a relationship between a gluten-free diet and vitiligo symptom improvement. In one report, a 9-year-old child diagnosed with both celiac disease and vitiligo saw intense repigmentation of the skin after adhering to a gluten-free diet for 1 year.¹⁴ Another case study reported a 22-year-old woman with vitiligo whose symptoms improved after 1 month of a gluten-free diet following 2 years of failed treatment with a topical steroid and phototherapy.¹⁵

Seven of 31 (23%) web pages suggested that individuals with vitiligo should include wheat in their diet. There is no published literature discussing the relationship between vitiligo and wheat. Of the 31 web pages reviewed, 10 (32%) suggested including whole grain. There is no relevant scientific evidence or hypotheses describing how whole grains may be beneficial in vitiligo.

Minerals—Eight of 31 (26%) web pages suggested including zinc in the diet to improve vitiligo symptoms. A 2020 study evaluated how different serum levels of zinc in vitiligo patients might be affiliated with interleukin activity. Fifty patients diagnosed with active vitiligo were tested for serum levels of zinc, IL-4, IL-6, and IL-17.¹⁶ The results showed that mean serum levels of zinc were lower in vitiligo patients compared with patients without vitiligo. The study concluded that zinc could possibly be used as a supplement to improve vitiligo, though the dosage needs to be further studied and confirmed.¹⁶

Vegetables—Eleven of 31 (35%) web pages recommended leafy green vegetables and 13 of 31 (42%) recommended spinach for patients with vitiligo. Spinach and other leafy green vegetables are known to be rich in antioxidants, which may have protective effects against reactive oxygen species that are thought to contribute to vitiligo progression.^17,18

Nuts—Walnuts were recommended in 11 of 31 (35%) web pages. Nuts may be beneficial in reducing inflammation and providing protection against oxidative stress.⁹ However, there is no specific scientific literature that supports the inclusion of nuts in the diet to manage vitiligo symptoms.

Comment

With a growing amount of research suggesting that diet modifications may contribute to management of certain skin conditions, vitiligo patients often inquire about foods or supplements that may help improve their condition.¹⁹ Our review highlighted what information was available to the public regarding diet and vitiligo, with preliminary support of the following primary diet components: vitamin D, vitamin B₁₂, zinc, and omega-3 fatty acids. Our review showed no support in the literature for the items that were recommended to avoid. It is important to note that 27 of 31 (87%) web pages from our online search were not authored by medical professionals or dermatologists. Additionally, many web pages suggested conflicting information, making it difficult to draw concrete conclusions about what diet modifications will be beneficial to the vitiligo community. Further controlled clinical trials are warranted due to the lack of formal studies that assess the relationship between diet and vitiligo.

Internet platforms have become a common source of medical information for individuals with a broad range of skin conditions including vitiligo. The prevalence of vitiligo among US adults ranges from 0.76% to 1.11%, with approximately 40% of adult cases of vitiligo in the United States remaining undiagnosed.¹ The vitiligo community has become more inquisitive of the relationship between diet and vitiligo, turning to online sources for suggestions on diet modifications that may be beneficial for their condition. Although there is an abundance of online information, few diets or foods have been medically recognized to definitively improve or worsen vitiligo symptoms. We reviewed the top online web pages accessible to the public regarding diet suggestions that affect vitiligo symptoms. We then compared these online results to published peer-reviewed scientific literature.

Methods

Two independent online searches were performed by Researcher 1 (Y.A.) and Researcher 2 (I.M.) using Google Advanced Search. The independent searches were performed by the reviewers in neighboring areas of Chicago, Illinois, using the same Internet browser (Google Chrome). The primary search terms were diet and vitiligo along with the optional additional terms dietary supplement(s), food(s), nutrition, herb(s), or vitamin(s). Our search included any web pages published or updated from January 1, 2010, to December 31, 2021, and originally scribed in the English language. The domains “.com,” “.org,” “.edu,” and “.cc” were included.

From this initial search, Researcher 1 identified 312 web pages and Researcher 2 identified 314 web pages. Each reviewer sorted their respective search results to identify the number of eligible records to be screened. Records were defined as unique web pages that met the search criteria. After removing duplicates, Researcher 1 screened 102 web pages and Researcher 2 screened 76 web pages. Of these records, web pages were excluded if they did not include any diet recommendations for vitiligo patients. Each reviewer independently created a list of eligible records, and the independent lists were then merged for a total of 58 web pages. Among these 58 web pages, there were 24 duplicate records and 3 records that were deemed ineligible for the study due to lack of subject matter relevance. A final total of 31 web pages were included in the data analysis (Figure). Of the 31 records selected, the reviewers jointly evaluated each web page and recorded the diet components that were recommended for individuals with vitiligo to either include or avoid (eTable).

For comparison and support from published scientific literature, a search of PubMed articles indexed for MEDLINE was conducted using the terms diet and vitiligo. Relevant human clinical studies published in the English-language literature were reviewed for content regarding the relationship between diet and vitiligo.

Results

Our online search revealed an abundance of information regarding various dietary modifications suggested to aid in the management of vitiligo symptoms. Most web pages (27/31 [87%]) were not authored by medical professionals or dermatologists. There were 27 diet components mentioned 8 or more times within the 31 total web pages. These diet components were selected for further review via PubMed. Each item was searched on PubMed using the term “[respective diet component] and vitiligo” among all published literature in the English language. Our study focused on summarizing the data on dietary components for which we were able to gather scientific support. These data have been organized into the following categories: vitamins, fruits, omega-3 fatty acids, grains, minerals, vegetables, and nuts.

Vitamins—The online literature recommended inclusion of vitamin supplements, in particular vitamins D and B₁₂, which aligned with published scientific literature.^2,3 Eleven of 31 (35%) web pages recommended vitamin D in vitiligo. A 2010 study analyzing patients with vitiligo vulgaris (N=45) found that 68.9% of the cohort had insufficient (<30 ng/mL) 25-hydroxyvitamin D levels.² A prospective study of 30 individuals found that the use of tacrolimus ointment plus oral vitamin D supplementation was found to be more successful in repigmentation than topical tacrolimus alone.³ Vitamin D dosage ranged from 1500 IU/d if the patient’s serum 25-hydroxyvitamin D levels were less than 20 ng/mL to 3000 IU/d if the serum levels were less than 10 ng/mL for 6 months.

Dairy products are a source of vitamin D.^2,3 Of the web pages that mentioned dairy, a subtle majority (4/7 [57%]) recommended the inclusion of dairy products. Although many web pages did not specify whether oral vitamin D supplementation vs dietary food consumption is preferred, a 2013 controlled study of 16 vitiligo patients who received high doses of vitamin D supplementation with a low-calcium diet found that 4 patients showed 1% to 25% repigmentation, 5 patients showed 26% to 50% repigmentation, and 5 patients showed 51% to 75% repigmentation of the affected areas.⁴

Eleven of 31 (35%) web pages recommended inclusion of vitamin B₁₂ supplementation in vitiligo. A 2-year study with 100 participants showed that supplementation with folic acid and vitamin B₁₂ along with sun exposure yielded more effective repigmentation than either vitamins or sun exposure alone.⁵ An additional hypothesis suggested vitamin B₁₂ may aid in repigmentation through its role in the homocysteine pathway. Although the theory is unproven, it is proposed that inhibition of homocysteine via vitamin B₁₂ or folic acid supplementation may play a role in reducing melanocyte destruction and restoring melanin synthesis.⁶

There were mixed recommendations regarding vitamin C via supplementation and/or eating citrus fruits such as oranges. Although there are limited clinical studies on the use of vitamin C and the treatment of vitiligo, a 6-year prospective study from Madagascar consisting of approximately 300 participants with vitiligo who were treated with a combination of topical corticosteroids, oral vitamin C, and oral vitamin B₁₂ supplementation showed excellent repigmentation (defined by repigmentation of more than 76% of the originally affected area) in 50 participants.⁷

Fruits—Most web pages had mixed recommendations on whether to include or avoid certain fruits. Interestingly, inclusion of mangoes and apricots in the diet were highly recommended (9/31 [29%] and 8/31 [26%], respectively) while fruits such as oranges, lemons, papayas, and grapes were discouraged (10/31 [32%], 8/31 [26%], 6/31 [19%], and 7/31 [23%], respectively). Although some web pages suggested that vitamin C–rich produce including citrus and berries may help to increase melanin formation, others strongly suggested avoiding these fruits. There is limited information on the effects of citrus on vitiligo, but a 2022 study indicated that 5-demethylnobiletin, a flavonoid found in sweet citrus fruits, may stimulate melanin synthesis, which can possibly be beneficial for vitiligo.⁸

Omega-3 Fatty Acids—Seven of 31 (23%) web pages recommended the inclusion of omega-3 fatty acids for their role as antioxidants to improve vitiligo symptoms. Research has indicated a strong association between vitiligo and oxidative stress.⁹ A 2007 controlled clinical trial that included 28 vitiligo patients demonstrated that oral antioxidant supplementation in combination with narrowband UVB phototherapy can significantly decrease vitiligo-associated oxidative stress (P<.05); 8 of 17 (47%) patients in the treatment group saw greater than 75% repigmentation after antioxidant treatment.¹⁰

Grains—Five of 31 (16%) web pages suggested avoiding gluten—a protein naturally found in some grains including wheat, barley, and rye—to improve vitiligo symptoms. A 2021 review suggested that a gluten-free diet may be effective in managing celiac disease, and it is hypothesized that vitiligo may be managed with similar dietary adjustments.¹¹ Studies have shown that celiac disease and vitiligo—both autoimmune conditions—involve IL-2, IL-6, IL-7, and IL-21 in their disease pathways.^12,13 Their shared immunogenic mechanism may account for similar management options.

Upon review, 2 case reports were identified that discussed a relationship between a gluten-free diet and vitiligo symptom improvement. In one report, a 9-year-old child diagnosed with both celiac disease and vitiligo saw intense repigmentation of the skin after adhering to a gluten-free diet for 1 year.¹⁴ Another case study reported a 22-year-old woman with vitiligo whose symptoms improved after 1 month of a gluten-free diet following 2 years of failed treatment with a topical steroid and phototherapy.¹⁵

Seven of 31 (23%) web pages suggested that individuals with vitiligo should include wheat in their diet. There is no published literature discussing the relationship between vitiligo and wheat. Of the 31 web pages reviewed, 10 (32%) suggested including whole grain. There is no relevant scientific evidence or hypotheses describing how whole grains may be beneficial in vitiligo.

Minerals—Eight of 31 (26%) web pages suggested including zinc in the diet to improve vitiligo symptoms. A 2020 study evaluated how different serum levels of zinc in vitiligo patients might be affiliated with interleukin activity. Fifty patients diagnosed with active vitiligo were tested for serum levels of zinc, IL-4, IL-6, and IL-17.¹⁶ The results showed that mean serum levels of zinc were lower in vitiligo patients compared with patients without vitiligo. The study concluded that zinc could possibly be used as a supplement to improve vitiligo, though the dosage needs to be further studied and confirmed.¹⁶

Vegetables—Eleven of 31 (35%) web pages recommended leafy green vegetables and 13 of 31 (42%) recommended spinach for patients with vitiligo. Spinach and other leafy green vegetables are known to be rich in antioxidants, which may have protective effects against reactive oxygen species that are thought to contribute to vitiligo progression.^17,18

Nuts—Walnuts were recommended in 11 of 31 (35%) web pages. Nuts may be beneficial in reducing inflammation and providing protection against oxidative stress.⁹ However, there is no specific scientific literature that supports the inclusion of nuts in the diet to manage vitiligo symptoms.

Comment

With a growing amount of research suggesting that diet modifications may contribute to management of certain skin conditions, vitiligo patients often inquire about foods or supplements that may help improve their condition.¹⁹ Our review highlighted what information was available to the public regarding diet and vitiligo, with preliminary support of the following primary diet components: vitamin D, vitamin B₁₂, zinc, and omega-3 fatty acids. Our review showed no support in the literature for the items that were recommended to avoid. It is important to note that 27 of 31 (87%) web pages from our online search were not authored by medical professionals or dermatologists. Additionally, many web pages suggested conflicting information, making it difficult to draw concrete conclusions about what diet modifications will be beneficial to the vitiligo community. Further controlled clinical trials are warranted due to the lack of formal studies that assess the relationship between diet and vitiligo.

Internet platforms have become a common source of medical information for individuals with a broad range of skin conditions including vitiligo. The prevalence of vitiligo among US adults ranges from 0.76% to 1.11%, with approximately 40% of adult cases of vitiligo in the United States remaining undiagnosed.¹ The vitiligo community has become more inquisitive of the relationship between diet and vitiligo, turning to online sources for suggestions on diet modifications that may be beneficial for their condition. Although there is an abundance of online information, few diets or foods have been medically recognized to definitively improve or worsen vitiligo symptoms. We reviewed the top online web pages accessible to the public regarding diet suggestions that affect vitiligo symptoms. We then compared these online results to published peer-reviewed scientific literature.

Methods

Two independent online searches were performed by Researcher 1 (Y.A.) and Researcher 2 (I.M.) using Google Advanced Search. The independent searches were performed by the reviewers in neighboring areas of Chicago, Illinois, using the same Internet browser (Google Chrome). The primary search terms were diet and vitiligo along with the optional additional terms dietary supplement(s), food(s), nutrition, herb(s), or vitamin(s). Our search included any web pages published or updated from January 1, 2010, to December 31, 2021, and originally scribed in the English language. The domains “.com,” “.org,” “.edu,” and “.cc” were included.

From this initial search, Researcher 1 identified 312 web pages and Researcher 2 identified 314 web pages. Each reviewer sorted their respective search results to identify the number of eligible records to be screened. Records were defined as unique web pages that met the search criteria. After removing duplicates, Researcher 1 screened 102 web pages and Researcher 2 screened 76 web pages. Of these records, web pages were excluded if they did not include any diet recommendations for vitiligo patients. Each reviewer independently created a list of eligible records, and the independent lists were then merged for a total of 58 web pages. Among these 58 web pages, there were 24 duplicate records and 3 records that were deemed ineligible for the study due to lack of subject matter relevance. A final total of 31 web pages were included in the data analysis (Figure). Of the 31 records selected, the reviewers jointly evaluated each web page and recorded the diet components that were recommended for individuals with vitiligo to either include or avoid (eTable).

For comparison and support from published scientific literature, a search of PubMed articles indexed for MEDLINE was conducted using the terms diet and vitiligo. Relevant human clinical studies published in the English-language literature were reviewed for content regarding the relationship between diet and vitiligo.

Results

Our online search revealed an abundance of information regarding various dietary modifications suggested to aid in the management of vitiligo symptoms. Most web pages (27/31 [87%]) were not authored by medical professionals or dermatologists. There were 27 diet components mentioned 8 or more times within the 31 total web pages. These diet components were selected for further review via PubMed. Each item was searched on PubMed using the term “[respective diet component] and vitiligo” among all published literature in the English language. Our study focused on summarizing the data on dietary components for which we were able to gather scientific support. These data have been organized into the following categories: vitamins, fruits, omega-3 fatty acids, grains, minerals, vegetables, and nuts.

Vitamins—The online literature recommended inclusion of vitamin supplements, in particular vitamins D and B₁₂, which aligned with published scientific literature.^2,3 Eleven of 31 (35%) web pages recommended vitamin D in vitiligo. A 2010 study analyzing patients with vitiligo vulgaris (N=45) found that 68.9% of the cohort had insufficient (<30 ng/mL) 25-hydroxyvitamin D levels.² A prospective study of 30 individuals found that the use of tacrolimus ointment plus oral vitamin D supplementation was found to be more successful in repigmentation than topical tacrolimus alone.³ Vitamin D dosage ranged from 1500 IU/d if the patient’s serum 25-hydroxyvitamin D levels were less than 20 ng/mL to 3000 IU/d if the serum levels were less than 10 ng/mL for 6 months.

Dairy products are a source of vitamin D.^2,3 Of the web pages that mentioned dairy, a subtle majority (4/7 [57%]) recommended the inclusion of dairy products. Although many web pages did not specify whether oral vitamin D supplementation vs dietary food consumption is preferred, a 2013 controlled study of 16 vitiligo patients who received high doses of vitamin D supplementation with a low-calcium diet found that 4 patients showed 1% to 25% repigmentation, 5 patients showed 26% to 50% repigmentation, and 5 patients showed 51% to 75% repigmentation of the affected areas.⁴

Eleven of 31 (35%) web pages recommended inclusion of vitamin B₁₂ supplementation in vitiligo. A 2-year study with 100 participants showed that supplementation with folic acid and vitamin B₁₂ along with sun exposure yielded more effective repigmentation than either vitamins or sun exposure alone.⁵ An additional hypothesis suggested vitamin B₁₂ may aid in repigmentation through its role in the homocysteine pathway. Although the theory is unproven, it is proposed that inhibition of homocysteine via vitamin B₁₂ or folic acid supplementation may play a role in reducing melanocyte destruction and restoring melanin synthesis.⁶

There were mixed recommendations regarding vitamin C via supplementation and/or eating citrus fruits such as oranges. Although there are limited clinical studies on the use of vitamin C and the treatment of vitiligo, a 6-year prospective study from Madagascar consisting of approximately 300 participants with vitiligo who were treated with a combination of topical corticosteroids, oral vitamin C, and oral vitamin B₁₂ supplementation showed excellent repigmentation (defined by repigmentation of more than 76% of the originally affected area) in 50 participants.⁷

Fruits—Most web pages had mixed recommendations on whether to include or avoid certain fruits. Interestingly, inclusion of mangoes and apricots in the diet were highly recommended (9/31 [29%] and 8/31 [26%], respectively) while fruits such as oranges, lemons, papayas, and grapes were discouraged (10/31 [32%], 8/31 [26%], 6/31 [19%], and 7/31 [23%], respectively). Although some web pages suggested that vitamin C–rich produce including citrus and berries may help to increase melanin formation, others strongly suggested avoiding these fruits. There is limited information on the effects of citrus on vitiligo, but a 2022 study indicated that 5-demethylnobiletin, a flavonoid found in sweet citrus fruits, may stimulate melanin synthesis, which can possibly be beneficial for vitiligo.⁸

Omega-3 Fatty Acids—Seven of 31 (23%) web pages recommended the inclusion of omega-3 fatty acids for their role as antioxidants to improve vitiligo symptoms. Research has indicated a strong association between vitiligo and oxidative stress.⁹ A 2007 controlled clinical trial that included 28 vitiligo patients demonstrated that oral antioxidant supplementation in combination with narrowband UVB phototherapy can significantly decrease vitiligo-associated oxidative stress (P<.05); 8 of 17 (47%) patients in the treatment group saw greater than 75% repigmentation after antioxidant treatment.¹⁰

Grains—Five of 31 (16%) web pages suggested avoiding gluten—a protein naturally found in some grains including wheat, barley, and rye—to improve vitiligo symptoms. A 2021 review suggested that a gluten-free diet may be effective in managing celiac disease, and it is hypothesized that vitiligo may be managed with similar dietary adjustments.¹¹ Studies have shown that celiac disease and vitiligo—both autoimmune conditions—involve IL-2, IL-6, IL-7, and IL-21 in their disease pathways.^12,13 Their shared immunogenic mechanism may account for similar management options.

Upon review, 2 case reports were identified that discussed a relationship between a gluten-free diet and vitiligo symptom improvement. In one report, a 9-year-old child diagnosed with both celiac disease and vitiligo saw intense repigmentation of the skin after adhering to a gluten-free diet for 1 year.¹⁴ Another case study reported a 22-year-old woman with vitiligo whose symptoms improved after 1 month of a gluten-free diet following 2 years of failed treatment with a topical steroid and phototherapy.¹⁵

Seven of 31 (23%) web pages suggested that individuals with vitiligo should include wheat in their diet. There is no published literature discussing the relationship between vitiligo and wheat. Of the 31 web pages reviewed, 10 (32%) suggested including whole grain. There is no relevant scientific evidence or hypotheses describing how whole grains may be beneficial in vitiligo.

Minerals—Eight of 31 (26%) web pages suggested including zinc in the diet to improve vitiligo symptoms. A 2020 study evaluated how different serum levels of zinc in vitiligo patients might be affiliated with interleukin activity. Fifty patients diagnosed with active vitiligo were tested for serum levels of zinc, IL-4, IL-6, and IL-17.¹⁶ The results showed that mean serum levels of zinc were lower in vitiligo patients compared with patients without vitiligo. The study concluded that zinc could possibly be used as a supplement to improve vitiligo, though the dosage needs to be further studied and confirmed.¹⁶

Vegetables—Eleven of 31 (35%) web pages recommended leafy green vegetables and 13 of 31 (42%) recommended spinach for patients with vitiligo. Spinach and other leafy green vegetables are known to be rich in antioxidants, which may have protective effects against reactive oxygen species that are thought to contribute to vitiligo progression.^17,18

Nuts—Walnuts were recommended in 11 of 31 (35%) web pages. Nuts may be beneficial in reducing inflammation and providing protection against oxidative stress.⁹ However, there is no specific scientific literature that supports the inclusion of nuts in the diet to manage vitiligo symptoms.

Comment

With a growing amount of research suggesting that diet modifications may contribute to management of certain skin conditions, vitiligo patients often inquire about foods or supplements that may help improve their condition.¹⁹ Our review highlighted what information was available to the public regarding diet and vitiligo, with preliminary support of the following primary diet components: vitamin D, vitamin B₁₂, zinc, and omega-3 fatty acids. Our review showed no support in the literature for the items that were recommended to avoid. It is important to note that 27 of 31 (87%) web pages from our online search were not authored by medical professionals or dermatologists. Additionally, many web pages suggested conflicting information, making it difficult to draw concrete conclusions about what diet modifications will be beneficial to the vitiligo community. Further controlled clinical trials are warranted due to the lack of formal studies that assess the relationship between diet and vitiligo.

TOPLINE:

Nearly half of the US Food and Drug Administration (FDA) approvals for dermatologic drugs between 2012 and 2022 were considered first in class or first in indication.

METHODOLOGY:

• Only five new drugs for diseases treated mostly by dermatologists were approved by the FDA between 1999 and 2009.
• In a cross-sectional analysis to characterize the frequency and degree of innovation of dermatologic drugs approved more recently, researchers identified new and supplemental dermatologic drugs approved between January 1, 2012, and December 31, 2022, from FDA lists, Centers for Medicare & Medicaid Services CenterWatch, and peer-reviewed articles.
• They used five proxy measures to estimate each drug’s degree of innovation: FDA designation (first in class, advance in class, or addition to class), independent clinical usefulness ratings, and benefit ratings by health technology assessment organizations.

TAKEAWAY:

• The study authors identified 52 new drug applications and 26 supplemental new indications approved by the FDA for dermatologic indications between 2012 and 2022.
• Of the 52 new drugs, the researchers categorized 11 (21%) as first in class and 13 (25%) as first in indication.
• An analysis of benefit ratings available for 38 of the drugs showed that 15 (39%) were rated as being clinically useful or having high added therapeutic benefit.
• Of the 10 supplemental new indications with ratings by any organization, 3 (30%) were rated as clinically useful or having high added therapeutic benefit.

IN PRACTICE:

While innovative drug development in dermatology may have increased, “these findings also highlight opportunities to develop more truly innovative dermatologic agents, particularly for diseases with unmet therapeutic need,” the authors wrote.

SOURCE:

First author Samir Kamat, MD, of the Medical Education Department at Icahn School of Medicine at Mount Sinai, New York City, and corresponding author Ravi Gupta, MD, MSHP, of the Internal Medicine Division at Johns Hopkins University, Baltimore, Maryland, led the research. The study was published online as a research letter on December 20, 2023, in JAMA Dermatology.

LIMITATIONS:

They include the use of individual indications to assess clinical usefulness and benefit ratings. Many drugs, particularly supplemental indications, lacked such ratings. Reformulations of already marketed drugs or indications were not included.

DISCLOSURES:

Dr. Kamat and Dr. Gupta had no relevant disclosures. Three coauthors reported having received financial support outside of the submitted work.

A version of this article appeared on Medscape.com.

TOPLINE:

Nearly half of the US Food and Drug Administration (FDA) approvals for dermatologic drugs between 2012 and 2022 were considered first in class or first in indication.

METHODOLOGY:

• Only five new drugs for diseases treated mostly by dermatologists were approved by the FDA between 1999 and 2009.
• In a cross-sectional analysis to characterize the frequency and degree of innovation of dermatologic drugs approved more recently, researchers identified new and supplemental dermatologic drugs approved between January 1, 2012, and December 31, 2022, from FDA lists, Centers for Medicare & Medicaid Services CenterWatch, and peer-reviewed articles.
• They used five proxy measures to estimate each drug’s degree of innovation: FDA designation (first in class, advance in class, or addition to class), independent clinical usefulness ratings, and benefit ratings by health technology assessment organizations.

TAKEAWAY:

• The study authors identified 52 new drug applications and 26 supplemental new indications approved by the FDA for dermatologic indications between 2012 and 2022.
• Of the 52 new drugs, the researchers categorized 11 (21%) as first in class and 13 (25%) as first in indication.
• An analysis of benefit ratings available for 38 of the drugs showed that 15 (39%) were rated as being clinically useful or having high added therapeutic benefit.
• Of the 10 supplemental new indications with ratings by any organization, 3 (30%) were rated as clinically useful or having high added therapeutic benefit.

IN PRACTICE:

While innovative drug development in dermatology may have increased, “these findings also highlight opportunities to develop more truly innovative dermatologic agents, particularly for diseases with unmet therapeutic need,” the authors wrote.

SOURCE:

First author Samir Kamat, MD, of the Medical Education Department at Icahn School of Medicine at Mount Sinai, New York City, and corresponding author Ravi Gupta, MD, MSHP, of the Internal Medicine Division at Johns Hopkins University, Baltimore, Maryland, led the research. The study was published online as a research letter on December 20, 2023, in JAMA Dermatology.

LIMITATIONS:

They include the use of individual indications to assess clinical usefulness and benefit ratings. Many drugs, particularly supplemental indications, lacked such ratings. Reformulations of already marketed drugs or indications were not included.

DISCLOSURES:

Dr. Kamat and Dr. Gupta had no relevant disclosures. Three coauthors reported having received financial support outside of the submitted work.

A version of this article appeared on Medscape.com.

TOPLINE:

Nearly half of the US Food and Drug Administration (FDA) approvals for dermatologic drugs between 2012 and 2022 were considered first in class or first in indication.

METHODOLOGY:

• Only five new drugs for diseases treated mostly by dermatologists were approved by the FDA between 1999 and 2009.
• In a cross-sectional analysis to characterize the frequency and degree of innovation of dermatologic drugs approved more recently, researchers identified new and supplemental dermatologic drugs approved between January 1, 2012, and December 31, 2022, from FDA lists, Centers for Medicare & Medicaid Services CenterWatch, and peer-reviewed articles.
• They used five proxy measures to estimate each drug’s degree of innovation: FDA designation (first in class, advance in class, or addition to class), independent clinical usefulness ratings, and benefit ratings by health technology assessment organizations.

TAKEAWAY:

• The study authors identified 52 new drug applications and 26 supplemental new indications approved by the FDA for dermatologic indications between 2012 and 2022.
• Of the 52 new drugs, the researchers categorized 11 (21%) as first in class and 13 (25%) as first in indication.
• An analysis of benefit ratings available for 38 of the drugs showed that 15 (39%) were rated as being clinically useful or having high added therapeutic benefit.
• Of the 10 supplemental new indications with ratings by any organization, 3 (30%) were rated as clinically useful or having high added therapeutic benefit.

IN PRACTICE:

While innovative drug development in dermatology may have increased, “these findings also highlight opportunities to develop more truly innovative dermatologic agents, particularly for diseases with unmet therapeutic need,” the authors wrote.

SOURCE:

First author Samir Kamat, MD, of the Medical Education Department at Icahn School of Medicine at Mount Sinai, New York City, and corresponding author Ravi Gupta, MD, MSHP, of the Internal Medicine Division at Johns Hopkins University, Baltimore, Maryland, led the research. The study was published online as a research letter on December 20, 2023, in JAMA Dermatology.

LIMITATIONS:

They include the use of individual indications to assess clinical usefulness and benefit ratings. Many drugs, particularly supplemental indications, lacked such ratings. Reformulations of already marketed drugs or indications were not included.

DISCLOSURES:

Dr. Kamat and Dr. Gupta had no relevant disclosures. Three coauthors reported having received financial support outside of the submitted work.

A version of this article appeared on Medscape.com.

Nasal tanning spray is a recent phenomenon that has been gaining popularity among consumers on TikTok and other social media platforms. The active ingredient in the tanning spray is melanotan II—a synthetic analog of α‒melanocyte-stimulating hormone,^1,2 a naturally occurring hormone responsible for skin pigmentation. α‒Melanocyte-stimulating hormone is a derivative of the precursor proopiomelanocortin, an agonist on the melanocortin-1 receptor that promotes formation of eumelanin.^1,3 Eumelanin then provides pigmentation to the skin.³ Apart from its use for tanning, melanotan II has been reported to increase sexual function and aid in weight loss.¹

Melanotan II is not approved by the US Food and Drug Administration; however, injectable formulations can be obtained illegally on the Internet as well as at some tanning salons and beauty parlors.⁴ Although injectable forms of melanotan II have been used for years to artificially increase skin pigmentation, the newly hyped nasal tanning sprays are drawing the attention of consumers. The synthetic chemical spray is inhaled into the nasal mucosae, where it is readily absorbed into the bloodstream to act on melanocortin receptors throughout the body, thus enhancing skin pigmentation.² Because melanotan II is not approved, there is no guarantee that the product purchased from those sources is pure; therefore, consumers risk inhaling or injecting contaminated chemicals.⁵

In a 2017 study, Kirk and Greenfield⁶ cited self-image as a common concern among participants who expressed a preference for appearing tanned.⁶ Societal influence and standards to which young adults, particularly young women, often are accustomed drive some to take steps to achieve tanned skin, which they view as more attractive and healthier than untanned skin.^7,8

Social media consumption is a significant risk factor for developing or exacerbating body dissatisfaction among impressionable teenagers and young adults, who may be less risk averse and therefore choose to embrace trends such as nasal tanning sprays to enhance their appearance, without considering possible consequences. Most young adults, and even teens, are aware of the risks associated with tanning beds, which may propel them to seek out what they perceive as a less-risky tanning alternative such as a tanner delivered via a nasal route, but it is unlikely that this group is fully informed about the possible dangers of nasal tanning sprays.

It is crucial for dermatologists and other clinicians to provide awareness and education about the potential harm of nasal tanning sprays. Along with the general risks of using an unregulated substance, common adverse effects include acne, facial flushing, gastrointestinal tract upset, and sensitivity to sunlight (Table).^1,9,10 Several case reports have linked melanotan II to cutaneous changes, including dysplastic nevi and even melanoma.¹ Less common complications, such as renal infarction and priapism, also have been observed with melanotan II use.^9,10

Even with the known risks involving tanning beds and skin cancer, an analysis by Kream et al¹¹ in 2020 showed that 90% (441/488) of tanning-related videos on TikTok promoted a positive view of tanning. Of these TikTok videos involving pro-tanning trends, 3% (12/441) were specifically about melanotan II nasal spray, injection, or both, which has only become more popular since this study was published.¹¹

Dermatologists should be aware of the impact that tanning trends, such as nasal tanning spray, can have on all patients and initiate discussions regarding the risks of using these products with patients as appropriate. Alternatives to nasal tanning sprays such as spray-on tans and self-tanning lotions are safer ways for patients to achieve a tanned look without the health risks associated with melanotan II.

Nasal tanning spray is a recent phenomenon that has been gaining popularity among consumers on TikTok and other social media platforms. The active ingredient in the tanning spray is melanotan II—a synthetic analog of α‒melanocyte-stimulating hormone,^1,2 a naturally occurring hormone responsible for skin pigmentation. α‒Melanocyte-stimulating hormone is a derivative of the precursor proopiomelanocortin, an agonist on the melanocortin-1 receptor that promotes formation of eumelanin.^1,3 Eumelanin then provides pigmentation to the skin.³ Apart from its use for tanning, melanotan II has been reported to increase sexual function and aid in weight loss.¹

Melanotan II is not approved by the US Food and Drug Administration; however, injectable formulations can be obtained illegally on the Internet as well as at some tanning salons and beauty parlors.⁴ Although injectable forms of melanotan II have been used for years to artificially increase skin pigmentation, the newly hyped nasal tanning sprays are drawing the attention of consumers. The synthetic chemical spray is inhaled into the nasal mucosae, where it is readily absorbed into the bloodstream to act on melanocortin receptors throughout the body, thus enhancing skin pigmentation.² Because melanotan II is not approved, there is no guarantee that the product purchased from those sources is pure; therefore, consumers risk inhaling or injecting contaminated chemicals.⁵

In a 2017 study, Kirk and Greenfield⁶ cited self-image as a common concern among participants who expressed a preference for appearing tanned.⁶ Societal influence and standards to which young adults, particularly young women, often are accustomed drive some to take steps to achieve tanned skin, which they view as more attractive and healthier than untanned skin.^7,8

Social media consumption is a significant risk factor for developing or exacerbating body dissatisfaction among impressionable teenagers and young adults, who may be less risk averse and therefore choose to embrace trends such as nasal tanning sprays to enhance their appearance, without considering possible consequences. Most young adults, and even teens, are aware of the risks associated with tanning beds, which may propel them to seek out what they perceive as a less-risky tanning alternative such as a tanner delivered via a nasal route, but it is unlikely that this group is fully informed about the possible dangers of nasal tanning sprays.

It is crucial for dermatologists and other clinicians to provide awareness and education about the potential harm of nasal tanning sprays. Along with the general risks of using an unregulated substance, common adverse effects include acne, facial flushing, gastrointestinal tract upset, and sensitivity to sunlight (Table).^1,9,10 Several case reports have linked melanotan II to cutaneous changes, including dysplastic nevi and even melanoma.¹ Less common complications, such as renal infarction and priapism, also have been observed with melanotan II use.^9,10

Even with the known risks involving tanning beds and skin cancer, an analysis by Kream et al¹¹ in 2020 showed that 90% (441/488) of tanning-related videos on TikTok promoted a positive view of tanning. Of these TikTok videos involving pro-tanning trends, 3% (12/441) were specifically about melanotan II nasal spray, injection, or both, which has only become more popular since this study was published.¹¹

Dermatologists should be aware of the impact that tanning trends, such as nasal tanning spray, can have on all patients and initiate discussions regarding the risks of using these products with patients as appropriate. Alternatives to nasal tanning sprays such as spray-on tans and self-tanning lotions are safer ways for patients to achieve a tanned look without the health risks associated with melanotan II.

Nasal tanning spray is a recent phenomenon that has been gaining popularity among consumers on TikTok and other social media platforms. The active ingredient in the tanning spray is melanotan II—a synthetic analog of α‒melanocyte-stimulating hormone,^1,2 a naturally occurring hormone responsible for skin pigmentation. α‒Melanocyte-stimulating hormone is a derivative of the precursor proopiomelanocortin, an agonist on the melanocortin-1 receptor that promotes formation of eumelanin.^1,3 Eumelanin then provides pigmentation to the skin.³ Apart from its use for tanning, melanotan II has been reported to increase sexual function and aid in weight loss.¹

Melanotan II is not approved by the US Food and Drug Administration; however, injectable formulations can be obtained illegally on the Internet as well as at some tanning salons and beauty parlors.⁴ Although injectable forms of melanotan II have been used for years to artificially increase skin pigmentation, the newly hyped nasal tanning sprays are drawing the attention of consumers. The synthetic chemical spray is inhaled into the nasal mucosae, where it is readily absorbed into the bloodstream to act on melanocortin receptors throughout the body, thus enhancing skin pigmentation.² Because melanotan II is not approved, there is no guarantee that the product purchased from those sources is pure; therefore, consumers risk inhaling or injecting contaminated chemicals.⁵

In a 2017 study, Kirk and Greenfield⁶ cited self-image as a common concern among participants who expressed a preference for appearing tanned.⁶ Societal influence and standards to which young adults, particularly young women, often are accustomed drive some to take steps to achieve tanned skin, which they view as more attractive and healthier than untanned skin.^7,8

Social media consumption is a significant risk factor for developing or exacerbating body dissatisfaction among impressionable teenagers and young adults, who may be less risk averse and therefore choose to embrace trends such as nasal tanning sprays to enhance their appearance, without considering possible consequences. Most young adults, and even teens, are aware of the risks associated with tanning beds, which may propel them to seek out what they perceive as a less-risky tanning alternative such as a tanner delivered via a nasal route, but it is unlikely that this group is fully informed about the possible dangers of nasal tanning sprays.

It is crucial for dermatologists and other clinicians to provide awareness and education about the potential harm of nasal tanning sprays. Along with the general risks of using an unregulated substance, common adverse effects include acne, facial flushing, gastrointestinal tract upset, and sensitivity to sunlight (Table).^1,9,10 Several case reports have linked melanotan II to cutaneous changes, including dysplastic nevi and even melanoma.¹ Less common complications, such as renal infarction and priapism, also have been observed with melanotan II use.^9,10

Even with the known risks involving tanning beds and skin cancer, an analysis by Kream et al¹¹ in 2020 showed that 90% (441/488) of tanning-related videos on TikTok promoted a positive view of tanning. Of these TikTok videos involving pro-tanning trends, 3% (12/441) were specifically about melanotan II nasal spray, injection, or both, which has only become more popular since this study was published.¹¹

Dermatologists should be aware of the impact that tanning trends, such as nasal tanning spray, can have on all patients and initiate discussions regarding the risks of using these products with patients as appropriate. Alternatives to nasal tanning sprays such as spray-on tans and self-tanning lotions are safer ways for patients to achieve a tanned look without the health risks associated with melanotan II.

The increased risk of vitiligo found in recipients of stem cell and solid organ transplants, especially those who develop graft-versus-host disease (GVHD), requires careful monitoring, according to authors of a study published online in JAMA Dermatology December 13.

In the cohort study, the greatest risk occurred with hematopoietic stem cell transplants (HSCTs) and in cases involving GVHD. Kidney and liver transplants carried slight increases in risk.

“The findings suggest that early detection and management of vitiligo lesions can be improved by estimating the likelihood of its development in transplant recipients and implementing a multidisciplinary approach for monitoring,” wrote the authors, from the departments of dermatology and biostatistics, at the Catholic University of Korea, Seoul.

Using claims data from South Korea’s National Health Insurance Service database, the investigators compared vitiligo incidence among 23,829 patients who had undergone solid organ transplantation (SOT) or HSCT between 2010 and 2017 versus that of 119,145 age- and sex-matched controls. At a mean observation time of 4.79 years in the transplant group (and 5.12 years for controls), the adjusted hazard ratio (AHR) for vitiligo among patients who had undergone any transplant was 1.73. AHRs for HSCT, liver transplants, and kidney transplants were 12.69, 1.63, and 1.50, respectively.

Patients who had undergone allogeneic HSCT (AHR, 14.43) or autologous transplants (AHR, 5.71), as well as those with and without GVHD (24.09 and 8.21, respectively) had significantly higher vitiligo risk than the control group.

Among those with GVHD, HSCT recipients (AHR, 16.42) and those with allogeneic grafts (AHR, 16.81) had a higher vitiligo risk than that of control patients.

In a subgroup that included 10,355 transplant recipients who underwent posttransplant health checkups, investigators found the highest vitiligo risk — AHR, 25.09 versus controls — among HSCT recipients with comorbid GVHD. However, patients who underwent SOT, autologous HSCT, or HSCT without GVHD showed no increased vitiligo risk in this analysis. “The results of health checkup data analysis may differ from the initial analysis due to additional adjustments for lifestyle factors and inclusion of only patients who underwent a health checkup,” the authors wrote.

Asked to comment on the results, George Han, MD, PhD, who was not involved with the study, told this news organization, “this is an interesting paper where the primary difference from previous studies is the new association between GVHD in hematopoietic stem cell transplant recipients and vitiligo.” Prior research had shown higher rates of vitiligo in HSCT recipients without making the GVHD distinction. Dr. Han is associate professor of dermatology in the Hofstra/Northwell Department of Dermatology, Hyde Park, New York.

Although GVHD may not be top-of-mind for dermatologists in daily practice, he said, the study enhances their understanding of vitiligo risk in HSCT recipients. “In some ways,” Dr. Han added, “the association makes sense, as the activated T cells from the graft attacking the skin in the HSCT recipient follow many of the mechanisms of vitiligo, including upregulating interferon gamma and the CXCR3/CXCL10 axis.”

Presently, he said, dermatologists worry more about solid organ recipients than about HSCT recipients because the long-term immunosuppression required by SOT increases the risk of squamous cell carcinoma (SCC). “However, the risk of skin cancers also seems to be elevated in HSCT recipients, and in this case the basal cell carcinoma (BCC):SCC ratio is not necessarily reversed as we see in solid organ transplant recipients. So the mechanisms are a bit less clear. Interestingly, acute and chronic GVHD have both been associated with increased risks of BCC and SCC/BCC, respectively.”

Overall, Dr. Han said, any transplant recipient should undergo yearly skin checks not only for skin cancers, but also for other skin conditions such as vitiligo. “It would be nice to see this codified into official guidelines, which can vary considerably but are overall more consistent in solid organ transplant recipients than in HSCT recipients. No such guidelines seem to be available for HSCTs.”

The study was funded by the Basic Research in Science & Engineering program through the National Research Foundation of Korea, which is funded by the country’s Ministry of Education. The study authors had no disclosures. Dr. Han reports no relevant financial interests.

The increased risk of vitiligo found in recipients of stem cell and solid organ transplants, especially those who develop graft-versus-host disease (GVHD), requires careful monitoring, according to authors of a study published online in JAMA Dermatology December 13.

In the cohort study, the greatest risk occurred with hematopoietic stem cell transplants (HSCTs) and in cases involving GVHD. Kidney and liver transplants carried slight increases in risk.

“The findings suggest that early detection and management of vitiligo lesions can be improved by estimating the likelihood of its development in transplant recipients and implementing a multidisciplinary approach for monitoring,” wrote the authors, from the departments of dermatology and biostatistics, at the Catholic University of Korea, Seoul.

Using claims data from South Korea’s National Health Insurance Service database, the investigators compared vitiligo incidence among 23,829 patients who had undergone solid organ transplantation (SOT) or HSCT between 2010 and 2017 versus that of 119,145 age- and sex-matched controls. At a mean observation time of 4.79 years in the transplant group (and 5.12 years for controls), the adjusted hazard ratio (AHR) for vitiligo among patients who had undergone any transplant was 1.73. AHRs for HSCT, liver transplants, and kidney transplants were 12.69, 1.63, and 1.50, respectively.

Patients who had undergone allogeneic HSCT (AHR, 14.43) or autologous transplants (AHR, 5.71), as well as those with and without GVHD (24.09 and 8.21, respectively) had significantly higher vitiligo risk than the control group.

Among those with GVHD, HSCT recipients (AHR, 16.42) and those with allogeneic grafts (AHR, 16.81) had a higher vitiligo risk than that of control patients.

In a subgroup that included 10,355 transplant recipients who underwent posttransplant health checkups, investigators found the highest vitiligo risk — AHR, 25.09 versus controls — among HSCT recipients with comorbid GVHD. However, patients who underwent SOT, autologous HSCT, or HSCT without GVHD showed no increased vitiligo risk in this analysis. “The results of health checkup data analysis may differ from the initial analysis due to additional adjustments for lifestyle factors and inclusion of only patients who underwent a health checkup,” the authors wrote.

Asked to comment on the results, George Han, MD, PhD, who was not involved with the study, told this news organization, “this is an interesting paper where the primary difference from previous studies is the new association between GVHD in hematopoietic stem cell transplant recipients and vitiligo.” Prior research had shown higher rates of vitiligo in HSCT recipients without making the GVHD distinction. Dr. Han is associate professor of dermatology in the Hofstra/Northwell Department of Dermatology, Hyde Park, New York.

Although GVHD may not be top-of-mind for dermatologists in daily practice, he said, the study enhances their understanding of vitiligo risk in HSCT recipients. “In some ways,” Dr. Han added, “the association makes sense, as the activated T cells from the graft attacking the skin in the HSCT recipient follow many of the mechanisms of vitiligo, including upregulating interferon gamma and the CXCR3/CXCL10 axis.”

Presently, he said, dermatologists worry more about solid organ recipients than about HSCT recipients because the long-term immunosuppression required by SOT increases the risk of squamous cell carcinoma (SCC). “However, the risk of skin cancers also seems to be elevated in HSCT recipients, and in this case the basal cell carcinoma (BCC):SCC ratio is not necessarily reversed as we see in solid organ transplant recipients. So the mechanisms are a bit less clear. Interestingly, acute and chronic GVHD have both been associated with increased risks of BCC and SCC/BCC, respectively.”

Overall, Dr. Han said, any transplant recipient should undergo yearly skin checks not only for skin cancers, but also for other skin conditions such as vitiligo. “It would be nice to see this codified into official guidelines, which can vary considerably but are overall more consistent in solid organ transplant recipients than in HSCT recipients. No such guidelines seem to be available for HSCTs.”

The study was funded by the Basic Research in Science & Engineering program through the National Research Foundation of Korea, which is funded by the country’s Ministry of Education. The study authors had no disclosures. Dr. Han reports no relevant financial interests.

The increased risk of vitiligo found in recipients of stem cell and solid organ transplants, especially those who develop graft-versus-host disease (GVHD), requires careful monitoring, according to authors of a study published online in JAMA Dermatology December 13.

In the cohort study, the greatest risk occurred with hematopoietic stem cell transplants (HSCTs) and in cases involving GVHD. Kidney and liver transplants carried slight increases in risk.

“The findings suggest that early detection and management of vitiligo lesions can be improved by estimating the likelihood of its development in transplant recipients and implementing a multidisciplinary approach for monitoring,” wrote the authors, from the departments of dermatology and biostatistics, at the Catholic University of Korea, Seoul.

Using claims data from South Korea’s National Health Insurance Service database, the investigators compared vitiligo incidence among 23,829 patients who had undergone solid organ transplantation (SOT) or HSCT between 2010 and 2017 versus that of 119,145 age- and sex-matched controls. At a mean observation time of 4.79 years in the transplant group (and 5.12 years for controls), the adjusted hazard ratio (AHR) for vitiligo among patients who had undergone any transplant was 1.73. AHRs for HSCT, liver transplants, and kidney transplants were 12.69, 1.63, and 1.50, respectively.

Patients who had undergone allogeneic HSCT (AHR, 14.43) or autologous transplants (AHR, 5.71), as well as those with and without GVHD (24.09 and 8.21, respectively) had significantly higher vitiligo risk than the control group.

Among those with GVHD, HSCT recipients (AHR, 16.42) and those with allogeneic grafts (AHR, 16.81) had a higher vitiligo risk than that of control patients.

In a subgroup that included 10,355 transplant recipients who underwent posttransplant health checkups, investigators found the highest vitiligo risk — AHR, 25.09 versus controls — among HSCT recipients with comorbid GVHD. However, patients who underwent SOT, autologous HSCT, or HSCT without GVHD showed no increased vitiligo risk in this analysis. “The results of health checkup data analysis may differ from the initial analysis due to additional adjustments for lifestyle factors and inclusion of only patients who underwent a health checkup,” the authors wrote.

Asked to comment on the results, George Han, MD, PhD, who was not involved with the study, told this news organization, “this is an interesting paper where the primary difference from previous studies is the new association between GVHD in hematopoietic stem cell transplant recipients and vitiligo.” Prior research had shown higher rates of vitiligo in HSCT recipients without making the GVHD distinction. Dr. Han is associate professor of dermatology in the Hofstra/Northwell Department of Dermatology, Hyde Park, New York.

Although GVHD may not be top-of-mind for dermatologists in daily practice, he said, the study enhances their understanding of vitiligo risk in HSCT recipients. “In some ways,” Dr. Han added, “the association makes sense, as the activated T cells from the graft attacking the skin in the HSCT recipient follow many of the mechanisms of vitiligo, including upregulating interferon gamma and the CXCR3/CXCL10 axis.”

Presently, he said, dermatologists worry more about solid organ recipients than about HSCT recipients because the long-term immunosuppression required by SOT increases the risk of squamous cell carcinoma (SCC). “However, the risk of skin cancers also seems to be elevated in HSCT recipients, and in this case the basal cell carcinoma (BCC):SCC ratio is not necessarily reversed as we see in solid organ transplant recipients. So the mechanisms are a bit less clear. Interestingly, acute and chronic GVHD have both been associated with increased risks of BCC and SCC/BCC, respectively.”

Overall, Dr. Han said, any transplant recipient should undergo yearly skin checks not only for skin cancers, but also for other skin conditions such as vitiligo. “It would be nice to see this codified into official guidelines, which can vary considerably but are overall more consistent in solid organ transplant recipients than in HSCT recipients. No such guidelines seem to be available for HSCTs.”

The study was funded by the Basic Research in Science & Engineering program through the National Research Foundation of Korea, which is funded by the country’s Ministry of Education. The study authors had no disclosures. Dr. Han reports no relevant financial interests.

Dietary supplements have a role in the integrative treatment of vitiligo, largely through antioxidant pathways and as an adjuvant to phototherapy, Ammar Ahmed, MD, associate professor of dermatology at Dell Medical School at the University of Texas, Austin, said at the annual Integrative Dermatology Symposium.

Data on the use of dietary supplements for vitiligo are scarce and of limited quality, but existing studies and current understanding of the pathogenesis of vitiligo have convinced Dr. Ahmed to recommend oral Ginkgo biloba, vitamin C, vitamin E, and alpha-lipoic acid – as well as vitamin D if levels are insufficient – for patients receiving phototherapy, and outside of phototherapy when patients express interest, he said.

Sally Kubetin/MDedge News

Vitamins C and E, and alpha-lipoic acid: In a randomized controlled trial of 35 patients with nonsegmental vitiligo conducted at the San Gallicano Dermatological Institute in Rome, those who received an antioxidant cocktail (alpha-lipoic acid, 100 mg; vitamin C, 100 mg; vitamin E, 40 mg; and polyunsaturated fatty acids) for 2 months before and during narrow-band ultraviolet-B (NB-UVB) therapy had significantly more repigmentation than that of patients who received NB-UVB alone. Forty-seven percent of those in the antioxidant group obtained greater than 75% repigmentation at 6 months vs. 18% in the control arm.

“This is a pretty high-quality trial. They even did in-vitro analysis showing that the antioxidant group had decreased measures of oxidative stress in the melanocytes,” Dr. Ahmed said. A handout he provided to patients receiving UVB therapy includes recommendations for vitamin C, vitamin E, and alpha-lipoic acid supplementation.

Another controlled prospective study of 130 patients with vitiligo, also conducted in Italy, utilized a different antioxidant cocktail in a tablet – Phyllanthus emblica (known as Indian gooseberry), vitamin E, and carotenoids – taken three times a day, in conjunction with standard topical therapy and phototherapy. At 6 months, a significantly higher number of patients receiving the cocktail had mild repigmentation and were less likely to have no repigmentation compared with patients who did not receive the antioxidants. “Nobody did really great, but the cocktail group did a little better,” he said. “So there’s promise.”
 

Vitamin D: In-vitro studies show that vitamin D may protect melanocytes against oxidative stress, and two small controlled trials showed improvement in vitiligo with vitamin D supplementation (1,500-5,000 IU daily) and no NB-UVB therapy. However, a recent, higher-quality 6-month trial that evaluated 5,000 IU/day of vitamin D in patients with generalized vitiligo showed no advantage over NB-UVB therapy alone. “I tell patients, if you’re insufficient, take vitamin D (supplements) to get your levels up,” Dr. Ahmed sad. “But if you’re already sufficient, I’m not confident there will be a significant benefit.”

Ginkgo biloba: A small double-blind controlled trial randomized 47 patients with limited and slow-spreading vitiligo to receive Ginkgo biloba extract 40 mg three times a day or placebo. At 6 months, 10 patients who received the extract had greater than 75% repigmentation compared with 2 patients in the placebo group. Patients receiving Ginkgo biloba, which has immunomodulatory and antioxidant properties, were also significantly more likely to have disease stabilization.

“I tend to recommend it to patients not doing phototherapy, as well as those receiving phototherapy, especially since the study showed benefit as a monotherapy,” Dr. Ahmed said in an interview after the meeting.

Phenylalanine: Various oral and/or topical formulations of this amino acid and precursor to tyrosine/melanin have been shown to have repigmentation effects when combined with UVA phototherapy or sunlight, but the studies are of limited quality and the oral dosages studied (50 mg/kg per day to 100 mg/kg per day) appear to be a bit high, Dr. Ahmed said at the meeting. “It can add up in cost, and I worry a little about side effects, so I don’t recommend it as much.”

Polypodium leucotomos (PL): This plant extract, from a fern native to Central America and parts of South America, is familiar as a photoprotective supplement, he said, and a few randomized controlled trials show that it may improve repigmentation outcomes, especially on the hands and neck, when combined with NB-UVB in patients with vitiligo.

One of these trials, published in 2021, showed greater than 50% repigmentation at 6 months in 48% of patients with generalized vitiligo who received oral PL (480 mg twice a day) and NB-UVB, versus 22% in patients receiving NB-UVB alone. PL may be “reasonable to consider, though it can get a little pricey,” he said.

Other supplements: Nigella sativa seed oil (black seed oil) and the Ayurvedic herb Picrorhiza kurroa (also known as kutki), have shown some promise and merit further study in vitiligo, Dr. Ahmed said. Data on vitamin B12 and folate are mixed, and there is no evidence of a helpful role of zinc for vitiligo, he noted at the meeting.

Overall, there is a “paucity of large, high-quality trials for [complementary] therapies for vitiligo,” Dr. Ahmed said. “We need big randomized controlled trials ... and we need stratification. The problem is a lot of these studies don’t stratify: Is the patient active or inactive, for instance? Do they have poliosis or not?” Also missing in many studies are data on safety and adverse events. “Is that because of an excellent safety profile or lack of scientific rigor? I don’t know.”

Future approaches to vitiligo management will likely integrate alternative/nutritional modalities with conventional medical treatments, newer targeted therapies, and surgery when necessary, he said. In the case of surgery, he referred to the June 2023 Food and Drug Administration approval of the RECELL Autologous Cell Harvesting Device for repigmentation of stable depigmented vitiligo lesions, an office-based grafting procedure.

The topical Janus kinase (JAK) inhibitor ruxolitinib (Opzelura) approved in 2022 for nonsegmental vitiligo, he said, produced “good, not great” results in two pivotal phase 3 trials . At 24 weeks, about 30% of patients on the treatment achieved at least a 75% improvement in the facial Vitiligo Area Scoring Index (F-VASI75), compared with about 10% of patients in the placebo groups.

Asked to comment on antioxidant pathways and the potential of complementary therapies for vitiligo, Jason Hawkes, MD, a dermatologist in Rocklin, Calif., who also spoke at the IDS meeting, said that oxidative stress is among the processes that may contribute to melanocyte degeneration seen in vitiligo.

The immunopathogenesis of vitiligo is “multilayered and complex,” he said. “While the T lymphocyte plays a central role in this disease, there are other genetic and biologic processes [including oxidative stress] that also contribute to the destruction of melanocytes.”

Reducing oxidative stress in the body and skin via supplements such as vitamin E, coenzyme Q10, and alpha-lipoic acid “may represent complementary treatments used for the treatment of vitiligo,” said Dr. Hawkes. And as more is learned about the pathogenic role of oxidative stress and its impact on diseases of pigmentation, “therapeutic targeting of the antioxidation-related signaling pathways in the skin may represent a novel treatment for vitiligo or other related conditions.”

Dr. Hawkes disclosed ties with AbbVie, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, LEO, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Dr. Hawkes disclosed serving as an investigator and advisory board member for Avita and an investigator for Pfizer.

Dietary supplements have a role in the integrative treatment of vitiligo, largely through antioxidant pathways and as an adjuvant to phototherapy, Ammar Ahmed, MD, associate professor of dermatology at Dell Medical School at the University of Texas, Austin, said at the annual Integrative Dermatology Symposium.

Data on the use of dietary supplements for vitiligo are scarce and of limited quality, but existing studies and current understanding of the pathogenesis of vitiligo have convinced Dr. Ahmed to recommend oral Ginkgo biloba, vitamin C, vitamin E, and alpha-lipoic acid – as well as vitamin D if levels are insufficient – for patients receiving phototherapy, and outside of phototherapy when patients express interest, he said.

Sally Kubetin/MDedge News

Vitamins C and E, and alpha-lipoic acid: In a randomized controlled trial of 35 patients with nonsegmental vitiligo conducted at the San Gallicano Dermatological Institute in Rome, those who received an antioxidant cocktail (alpha-lipoic acid, 100 mg; vitamin C, 100 mg; vitamin E, 40 mg; and polyunsaturated fatty acids) for 2 months before and during narrow-band ultraviolet-B (NB-UVB) therapy had significantly more repigmentation than that of patients who received NB-UVB alone. Forty-seven percent of those in the antioxidant group obtained greater than 75% repigmentation at 6 months vs. 18% in the control arm.

“This is a pretty high-quality trial. They even did in-vitro analysis showing that the antioxidant group had decreased measures of oxidative stress in the melanocytes,” Dr. Ahmed said. A handout he provided to patients receiving UVB therapy includes recommendations for vitamin C, vitamin E, and alpha-lipoic acid supplementation.

Another controlled prospective study of 130 patients with vitiligo, also conducted in Italy, utilized a different antioxidant cocktail in a tablet – Phyllanthus emblica (known as Indian gooseberry), vitamin E, and carotenoids – taken three times a day, in conjunction with standard topical therapy and phototherapy. At 6 months, a significantly higher number of patients receiving the cocktail had mild repigmentation and were less likely to have no repigmentation compared with patients who did not receive the antioxidants. “Nobody did really great, but the cocktail group did a little better,” he said. “So there’s promise.”
 

Vitamin D: In-vitro studies show that vitamin D may protect melanocytes against oxidative stress, and two small controlled trials showed improvement in vitiligo with vitamin D supplementation (1,500-5,000 IU daily) and no NB-UVB therapy. However, a recent, higher-quality 6-month trial that evaluated 5,000 IU/day of vitamin D in patients with generalized vitiligo showed no advantage over NB-UVB therapy alone. “I tell patients, if you’re insufficient, take vitamin D (supplements) to get your levels up,” Dr. Ahmed sad. “But if you’re already sufficient, I’m not confident there will be a significant benefit.”

Ginkgo biloba: A small double-blind controlled trial randomized 47 patients with limited and slow-spreading vitiligo to receive Ginkgo biloba extract 40 mg three times a day or placebo. At 6 months, 10 patients who received the extract had greater than 75% repigmentation compared with 2 patients in the placebo group. Patients receiving Ginkgo biloba, which has immunomodulatory and antioxidant properties, were also significantly more likely to have disease stabilization.

“I tend to recommend it to patients not doing phototherapy, as well as those receiving phototherapy, especially since the study showed benefit as a monotherapy,” Dr. Ahmed said in an interview after the meeting.

Phenylalanine: Various oral and/or topical formulations of this amino acid and precursor to tyrosine/melanin have been shown to have repigmentation effects when combined with UVA phototherapy or sunlight, but the studies are of limited quality and the oral dosages studied (50 mg/kg per day to 100 mg/kg per day) appear to be a bit high, Dr. Ahmed said at the meeting. “It can add up in cost, and I worry a little about side effects, so I don’t recommend it as much.”

Polypodium leucotomos (PL): This plant extract, from a fern native to Central America and parts of South America, is familiar as a photoprotective supplement, he said, and a few randomized controlled trials show that it may improve repigmentation outcomes, especially on the hands and neck, when combined with NB-UVB in patients with vitiligo.

One of these trials, published in 2021, showed greater than 50% repigmentation at 6 months in 48% of patients with generalized vitiligo who received oral PL (480 mg twice a day) and NB-UVB, versus 22% in patients receiving NB-UVB alone. PL may be “reasonable to consider, though it can get a little pricey,” he said.

Other supplements: Nigella sativa seed oil (black seed oil) and the Ayurvedic herb Picrorhiza kurroa (also known as kutki), have shown some promise and merit further study in vitiligo, Dr. Ahmed said. Data on vitamin B12 and folate are mixed, and there is no evidence of a helpful role of zinc for vitiligo, he noted at the meeting.

Overall, there is a “paucity of large, high-quality trials for [complementary] therapies for vitiligo,” Dr. Ahmed said. “We need big randomized controlled trials ... and we need stratification. The problem is a lot of these studies don’t stratify: Is the patient active or inactive, for instance? Do they have poliosis or not?” Also missing in many studies are data on safety and adverse events. “Is that because of an excellent safety profile or lack of scientific rigor? I don’t know.”

Future approaches to vitiligo management will likely integrate alternative/nutritional modalities with conventional medical treatments, newer targeted therapies, and surgery when necessary, he said. In the case of surgery, he referred to the June 2023 Food and Drug Administration approval of the RECELL Autologous Cell Harvesting Device for repigmentation of stable depigmented vitiligo lesions, an office-based grafting procedure.

The topical Janus kinase (JAK) inhibitor ruxolitinib (Opzelura) approved in 2022 for nonsegmental vitiligo, he said, produced “good, not great” results in two pivotal phase 3 trials . At 24 weeks, about 30% of patients on the treatment achieved at least a 75% improvement in the facial Vitiligo Area Scoring Index (F-VASI75), compared with about 10% of patients in the placebo groups.

Asked to comment on antioxidant pathways and the potential of complementary therapies for vitiligo, Jason Hawkes, MD, a dermatologist in Rocklin, Calif., who also spoke at the IDS meeting, said that oxidative stress is among the processes that may contribute to melanocyte degeneration seen in vitiligo.

The immunopathogenesis of vitiligo is “multilayered and complex,” he said. “While the T lymphocyte plays a central role in this disease, there are other genetic and biologic processes [including oxidative stress] that also contribute to the destruction of melanocytes.”

Reducing oxidative stress in the body and skin via supplements such as vitamin E, coenzyme Q10, and alpha-lipoic acid “may represent complementary treatments used for the treatment of vitiligo,” said Dr. Hawkes. And as more is learned about the pathogenic role of oxidative stress and its impact on diseases of pigmentation, “therapeutic targeting of the antioxidation-related signaling pathways in the skin may represent a novel treatment for vitiligo or other related conditions.”

Dr. Hawkes disclosed ties with AbbVie, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, LEO, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Dr. Hawkes disclosed serving as an investigator and advisory board member for Avita and an investigator for Pfizer.

Dietary supplements have a role in the integrative treatment of vitiligo, largely through antioxidant pathways and as an adjuvant to phototherapy, Ammar Ahmed, MD, associate professor of dermatology at Dell Medical School at the University of Texas, Austin, said at the annual Integrative Dermatology Symposium.

Data on the use of dietary supplements for vitiligo are scarce and of limited quality, but existing studies and current understanding of the pathogenesis of vitiligo have convinced Dr. Ahmed to recommend oral Ginkgo biloba, vitamin C, vitamin E, and alpha-lipoic acid – as well as vitamin D if levels are insufficient – for patients receiving phototherapy, and outside of phototherapy when patients express interest, he said.

Sally Kubetin/MDedge News

Vitamins C and E, and alpha-lipoic acid: In a randomized controlled trial of 35 patients with nonsegmental vitiligo conducted at the San Gallicano Dermatological Institute in Rome, those who received an antioxidant cocktail (alpha-lipoic acid, 100 mg; vitamin C, 100 mg; vitamin E, 40 mg; and polyunsaturated fatty acids) for 2 months before and during narrow-band ultraviolet-B (NB-UVB) therapy had significantly more repigmentation than that of patients who received NB-UVB alone. Forty-seven percent of those in the antioxidant group obtained greater than 75% repigmentation at 6 months vs. 18% in the control arm.

“This is a pretty high-quality trial. They even did in-vitro analysis showing that the antioxidant group had decreased measures of oxidative stress in the melanocytes,” Dr. Ahmed said. A handout he provided to patients receiving UVB therapy includes recommendations for vitamin C, vitamin E, and alpha-lipoic acid supplementation.

Another controlled prospective study of 130 patients with vitiligo, also conducted in Italy, utilized a different antioxidant cocktail in a tablet – Phyllanthus emblica (known as Indian gooseberry), vitamin E, and carotenoids – taken three times a day, in conjunction with standard topical therapy and phototherapy. At 6 months, a significantly higher number of patients receiving the cocktail had mild repigmentation and were less likely to have no repigmentation compared with patients who did not receive the antioxidants. “Nobody did really great, but the cocktail group did a little better,” he said. “So there’s promise.”
 

Vitamin D: In-vitro studies show that vitamin D may protect melanocytes against oxidative stress, and two small controlled trials showed improvement in vitiligo with vitamin D supplementation (1,500-5,000 IU daily) and no NB-UVB therapy. However, a recent, higher-quality 6-month trial that evaluated 5,000 IU/day of vitamin D in patients with generalized vitiligo showed no advantage over NB-UVB therapy alone. “I tell patients, if you’re insufficient, take vitamin D (supplements) to get your levels up,” Dr. Ahmed sad. “But if you’re already sufficient, I’m not confident there will be a significant benefit.”

Ginkgo biloba: A small double-blind controlled trial randomized 47 patients with limited and slow-spreading vitiligo to receive Ginkgo biloba extract 40 mg three times a day or placebo. At 6 months, 10 patients who received the extract had greater than 75% repigmentation compared with 2 patients in the placebo group. Patients receiving Ginkgo biloba, which has immunomodulatory and antioxidant properties, were also significantly more likely to have disease stabilization.

“I tend to recommend it to patients not doing phototherapy, as well as those receiving phototherapy, especially since the study showed benefit as a monotherapy,” Dr. Ahmed said in an interview after the meeting.

Phenylalanine: Various oral and/or topical formulations of this amino acid and precursor to tyrosine/melanin have been shown to have repigmentation effects when combined with UVA phototherapy or sunlight, but the studies are of limited quality and the oral dosages studied (50 mg/kg per day to 100 mg/kg per day) appear to be a bit high, Dr. Ahmed said at the meeting. “It can add up in cost, and I worry a little about side effects, so I don’t recommend it as much.”

Polypodium leucotomos (PL): This plant extract, from a fern native to Central America and parts of South America, is familiar as a photoprotective supplement, he said, and a few randomized controlled trials show that it may improve repigmentation outcomes, especially on the hands and neck, when combined with NB-UVB in patients with vitiligo.

One of these trials, published in 2021, showed greater than 50% repigmentation at 6 months in 48% of patients with generalized vitiligo who received oral PL (480 mg twice a day) and NB-UVB, versus 22% in patients receiving NB-UVB alone. PL may be “reasonable to consider, though it can get a little pricey,” he said.

Other supplements: Nigella sativa seed oil (black seed oil) and the Ayurvedic herb Picrorhiza kurroa (also known as kutki), have shown some promise and merit further study in vitiligo, Dr. Ahmed said. Data on vitamin B12 and folate are mixed, and there is no evidence of a helpful role of zinc for vitiligo, he noted at the meeting.

Overall, there is a “paucity of large, high-quality trials for [complementary] therapies for vitiligo,” Dr. Ahmed said. “We need big randomized controlled trials ... and we need stratification. The problem is a lot of these studies don’t stratify: Is the patient active or inactive, for instance? Do they have poliosis or not?” Also missing in many studies are data on safety and adverse events. “Is that because of an excellent safety profile or lack of scientific rigor? I don’t know.”

Future approaches to vitiligo management will likely integrate alternative/nutritional modalities with conventional medical treatments, newer targeted therapies, and surgery when necessary, he said. In the case of surgery, he referred to the June 2023 Food and Drug Administration approval of the RECELL Autologous Cell Harvesting Device for repigmentation of stable depigmented vitiligo lesions, an office-based grafting procedure.

The topical Janus kinase (JAK) inhibitor ruxolitinib (Opzelura) approved in 2022 for nonsegmental vitiligo, he said, produced “good, not great” results in two pivotal phase 3 trials . At 24 weeks, about 30% of patients on the treatment achieved at least a 75% improvement in the facial Vitiligo Area Scoring Index (F-VASI75), compared with about 10% of patients in the placebo groups.

Asked to comment on antioxidant pathways and the potential of complementary therapies for vitiligo, Jason Hawkes, MD, a dermatologist in Rocklin, Calif., who also spoke at the IDS meeting, said that oxidative stress is among the processes that may contribute to melanocyte degeneration seen in vitiligo.

The immunopathogenesis of vitiligo is “multilayered and complex,” he said. “While the T lymphocyte plays a central role in this disease, there are other genetic and biologic processes [including oxidative stress] that also contribute to the destruction of melanocytes.”

Reducing oxidative stress in the body and skin via supplements such as vitamin E, coenzyme Q10, and alpha-lipoic acid “may represent complementary treatments used for the treatment of vitiligo,” said Dr. Hawkes. And as more is learned about the pathogenic role of oxidative stress and its impact on diseases of pigmentation, “therapeutic targeting of the antioxidation-related signaling pathways in the skin may represent a novel treatment for vitiligo or other related conditions.”

Dr. Hawkes disclosed ties with AbbVie, Arcutis, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, LEO, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, and UCB. Dr. Hawkes disclosed serving as an investigator and advisory board member for Avita and an investigator for Pfizer.

The Diagnosis: Lelis Syndrome

Histopathology revealed spongiotic dermatitis with marked acanthosis and hyperkeratosis (Figure, A) with fungal colonization of the stratum corneum (Figure, B). Our patient was diagnosed with Lelis syndrome (also referred to as ectodermal dysplasia with acanthosis nigricans syndrome), a rare condition with hypotrichosis and hypohidrosis resulting from ectodermal dysplasia.^1,2 The pruritic rash was diagnosed as chronic dermatitis due to fungal colonization in the setting of acanthosis nigricans. The fungal infection was treated with a 4-week course of oral fluconazole 200 mg/wk, ketoconazole cream 2% twice daily, and discontinuation of topical steroids, resulting in the thinning of the plaques on the neck and antecubital fossae as well as resolution of the pruritus. Following antifungal treatment, our patient was started on tazarotene cream 0.1% for acanthosis nigricans.

Ectodermal dysplasias are inherited disorders with abnormalities of the skin, hair, sweat glands, nails, teeth, and sometimes internal organs.³ Patients with Lelis syndrome may have other manifestations of ectodermal dysplasia in addition to hypohidrosis and hypotrichosis, including deafness and abnormal dentition,^1,3 as seen in our patient. Intellectual disability has been described in many types of ectodermal dysplasia, including Lelis syndrome, but the association may be obscured by neurologic damage after repeat episodes of hyperthermia in infancy due to anhidrosis or hypohidrosis.⁴

When evaluating the differential diagnoses, the presence of hypotrichosis and hypohidrosis indicating ectodermal dysplasia is key. Confluent and reticulated papillomatosis presents with hyperkeratosis, papillomatosis, and focal acanthosis on histopathology. It can present on the neck and antecubital fossae; however, it is not associated with hypohidrosis and hypotrichosis.⁵ Although activating fibroblast growth factor receptor, FGFR, mutations have been implicated in the development of acanthosis nigricans in a variety of syndromes, these diagnoses are associated with abnormalities in skeletal development such as craniosynostosis and short stature; hypotrichosis and hypohidrosis are not seen.^6,7 HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome typically presents in the prepubertal period with obesity and insulin resistance; acanthosis nigricans and alopecia can occur due to insulin resistance and hyperandrogenism, but concurrent clitoromegaly and hirsutism are common.⁶ Sudden onset of extensive acanthosis nigricans also is among the paraneoplastic dermatoses; it has been associated with multiple malignancies, but in these cases, hypotrichosis and hypohidrosis are not observed. Adenocarcinomas are the most common neoplasms associated with paraneoplastic acanthosis nigricans, which occurs through growth factor secretion by tumor cells stimulating hyperkeratosis and papillomatosis.⁶

Lelis syndrome is rare, and our case is unique because the patient had severe manifestations of acanthosis nigricans and hypotrichosis. Because the inheritance pattern and specific genetics of the condition have not been fully elucidated, the diagnosis primarily is clinical.^1,8 Diagnosis may be complicated by the variety of other signs that can accompany acanthosis nigricans, hypohidrosis, and hypotrichosis.^1,2 The condition also may alter or obscure presentation of other dermatologic conditions, as in our case.

Although there is no cure for Lelis syndrome, one case report described treatment with acitretin that resulted in marked improvement of the patient’s hyperkeratosis and acanthosis nigricans.⁹ Due to lack of health insurance coverage of acitretin, our patient was started on tazarotene cream 0.1% for acanthosis nigricans. General treatment of ectodermal dysplasia primarily consists of multidisciplinary symptom management, including careful monitoring of temperature and heat intolerance as well as provision of dental prosthetics.^4,10 For ectodermal dysplasias caused by identified genetic mutations, prenatal interventions targeting gene pathways offer potentially curative treatment.¹⁰ However, for Lelis syndrome, along with many other disorders of ectodermal dysplasia, mitigation of signs and symptoms remains the primary treatment objective. Despite its rarity, increased awareness of Lelis syndrome is important to increase knowledge of ectodermal dysplasia syndromes and allow for the investigation of potential treatment options.

The Diagnosis: Lelis Syndrome

Histopathology revealed spongiotic dermatitis with marked acanthosis and hyperkeratosis (Figure, A) with fungal colonization of the stratum corneum (Figure, B). Our patient was diagnosed with Lelis syndrome (also referred to as ectodermal dysplasia with acanthosis nigricans syndrome), a rare condition with hypotrichosis and hypohidrosis resulting from ectodermal dysplasia.^1,2 The pruritic rash was diagnosed as chronic dermatitis due to fungal colonization in the setting of acanthosis nigricans. The fungal infection was treated with a 4-week course of oral fluconazole 200 mg/wk, ketoconazole cream 2% twice daily, and discontinuation of topical steroids, resulting in the thinning of the plaques on the neck and antecubital fossae as well as resolution of the pruritus. Following antifungal treatment, our patient was started on tazarotene cream 0.1% for acanthosis nigricans.

Ectodermal dysplasias are inherited disorders with abnormalities of the skin, hair, sweat glands, nails, teeth, and sometimes internal organs.³ Patients with Lelis syndrome may have other manifestations of ectodermal dysplasia in addition to hypohidrosis and hypotrichosis, including deafness and abnormal dentition,^1,3 as seen in our patient. Intellectual disability has been described in many types of ectodermal dysplasia, including Lelis syndrome, but the association may be obscured by neurologic damage after repeat episodes of hyperthermia in infancy due to anhidrosis or hypohidrosis.⁴

When evaluating the differential diagnoses, the presence of hypotrichosis and hypohidrosis indicating ectodermal dysplasia is key. Confluent and reticulated papillomatosis presents with hyperkeratosis, papillomatosis, and focal acanthosis on histopathology. It can present on the neck and antecubital fossae; however, it is not associated with hypohidrosis and hypotrichosis.⁵ Although activating fibroblast growth factor receptor, FGFR, mutations have been implicated in the development of acanthosis nigricans in a variety of syndromes, these diagnoses are associated with abnormalities in skeletal development such as craniosynostosis and short stature; hypotrichosis and hypohidrosis are not seen.^6,7 HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome typically presents in the prepubertal period with obesity and insulin resistance; acanthosis nigricans and alopecia can occur due to insulin resistance and hyperandrogenism, but concurrent clitoromegaly and hirsutism are common.⁶ Sudden onset of extensive acanthosis nigricans also is among the paraneoplastic dermatoses; it has been associated with multiple malignancies, but in these cases, hypotrichosis and hypohidrosis are not observed. Adenocarcinomas are the most common neoplasms associated with paraneoplastic acanthosis nigricans, which occurs through growth factor secretion by tumor cells stimulating hyperkeratosis and papillomatosis.⁶

Lelis syndrome is rare, and our case is unique because the patient had severe manifestations of acanthosis nigricans and hypotrichosis. Because the inheritance pattern and specific genetics of the condition have not been fully elucidated, the diagnosis primarily is clinical.^1,8 Diagnosis may be complicated by the variety of other signs that can accompany acanthosis nigricans, hypohidrosis, and hypotrichosis.^1,2 The condition also may alter or obscure presentation of other dermatologic conditions, as in our case.

Although there is no cure for Lelis syndrome, one case report described treatment with acitretin that resulted in marked improvement of the patient’s hyperkeratosis and acanthosis nigricans.⁹ Due to lack of health insurance coverage of acitretin, our patient was started on tazarotene cream 0.1% for acanthosis nigricans. General treatment of ectodermal dysplasia primarily consists of multidisciplinary symptom management, including careful monitoring of temperature and heat intolerance as well as provision of dental prosthetics.^4,10 For ectodermal dysplasias caused by identified genetic mutations, prenatal interventions targeting gene pathways offer potentially curative treatment.¹⁰ However, for Lelis syndrome, along with many other disorders of ectodermal dysplasia, mitigation of signs and symptoms remains the primary treatment objective. Despite its rarity, increased awareness of Lelis syndrome is important to increase knowledge of ectodermal dysplasia syndromes and allow for the investigation of potential treatment options.

The Diagnosis: Lelis Syndrome

Histopathology revealed spongiotic dermatitis with marked acanthosis and hyperkeratosis (Figure, A) with fungal colonization of the stratum corneum (Figure, B). Our patient was diagnosed with Lelis syndrome (also referred to as ectodermal dysplasia with acanthosis nigricans syndrome), a rare condition with hypotrichosis and hypohidrosis resulting from ectodermal dysplasia.^1,2 The pruritic rash was diagnosed as chronic dermatitis due to fungal colonization in the setting of acanthosis nigricans. The fungal infection was treated with a 4-week course of oral fluconazole 200 mg/wk, ketoconazole cream 2% twice daily, and discontinuation of topical steroids, resulting in the thinning of the plaques on the neck and antecubital fossae as well as resolution of the pruritus. Following antifungal treatment, our patient was started on tazarotene cream 0.1% for acanthosis nigricans.

Ectodermal dysplasias are inherited disorders with abnormalities of the skin, hair, sweat glands, nails, teeth, and sometimes internal organs.³ Patients with Lelis syndrome may have other manifestations of ectodermal dysplasia in addition to hypohidrosis and hypotrichosis, including deafness and abnormal dentition,^1,3 as seen in our patient. Intellectual disability has been described in many types of ectodermal dysplasia, including Lelis syndrome, but the association may be obscured by neurologic damage after repeat episodes of hyperthermia in infancy due to anhidrosis or hypohidrosis.⁴

When evaluating the differential diagnoses, the presence of hypotrichosis and hypohidrosis indicating ectodermal dysplasia is key. Confluent and reticulated papillomatosis presents with hyperkeratosis, papillomatosis, and focal acanthosis on histopathology. It can present on the neck and antecubital fossae; however, it is not associated with hypohidrosis and hypotrichosis.⁵ Although activating fibroblast growth factor receptor, FGFR, mutations have been implicated in the development of acanthosis nigricans in a variety of syndromes, these diagnoses are associated with abnormalities in skeletal development such as craniosynostosis and short stature; hypotrichosis and hypohidrosis are not seen.^6,7 HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome typically presents in the prepubertal period with obesity and insulin resistance; acanthosis nigricans and alopecia can occur due to insulin resistance and hyperandrogenism, but concurrent clitoromegaly and hirsutism are common.⁶ Sudden onset of extensive acanthosis nigricans also is among the paraneoplastic dermatoses; it has been associated with multiple malignancies, but in these cases, hypotrichosis and hypohidrosis are not observed. Adenocarcinomas are the most common neoplasms associated with paraneoplastic acanthosis nigricans, which occurs through growth factor secretion by tumor cells stimulating hyperkeratosis and papillomatosis.⁶

Lelis syndrome is rare, and our case is unique because the patient had severe manifestations of acanthosis nigricans and hypotrichosis. Because the inheritance pattern and specific genetics of the condition have not been fully elucidated, the diagnosis primarily is clinical.^1,8 Diagnosis may be complicated by the variety of other signs that can accompany acanthosis nigricans, hypohidrosis, and hypotrichosis.^1,2 The condition also may alter or obscure presentation of other dermatologic conditions, as in our case.

Although there is no cure for Lelis syndrome, one case report described treatment with acitretin that resulted in marked improvement of the patient’s hyperkeratosis and acanthosis nigricans.⁹ Due to lack of health insurance coverage of acitretin, our patient was started on tazarotene cream 0.1% for acanthosis nigricans. General treatment of ectodermal dysplasia primarily consists of multidisciplinary symptom management, including careful monitoring of temperature and heat intolerance as well as provision of dental prosthetics.^4,10 For ectodermal dysplasias caused by identified genetic mutations, prenatal interventions targeting gene pathways offer potentially curative treatment.¹⁰ However, for Lelis syndrome, along with many other disorders of ectodermal dysplasia, mitigation of signs and symptoms remains the primary treatment objective. Despite its rarity, increased awareness of Lelis syndrome is important to increase knowledge of ectodermal dysplasia syndromes and allow for the investigation of potential treatment options.

NEW YORK – Many inflammatory diseases, such as psoriasis and atopic dermatitis (AD), can present differently in patients with darker skin types, but it is the pigmentary changes themselves that are often a dominant concern for parents, according to pediatric dermatologist Candrice R. Heath, MD.

Skin diseases pose a greater risk of both hyper- and hypopigmentation in patients with darker skin types, but the fear and concern that this raises for permanent disfigurement is not limited to Blacks, Dr. Heath, assistant professor of pediatric dermatology at Temple University, Philadelphia, said at the Skin of Color Update 2023.

“Culturally, pigmentation changes can be huge. For people of Indian descent, for example, pigmentary changes like light spots on the skin might be an obstacle to marriage, so it can really be life changing,” she added.

In patients with darker skin tones presenting with an inflammatory skin disease, such as AD or psoriasis, Dr. Heath advised asking specifically about change in skin tone even if it is not readily apparent. In pediatric patients, it is also appropriate to include parents in this conversation.
 

Consider the parent’s perspective

“When you are taking care of a child or adolescent, the patient is likely to be concerned about changes in pigmentation, but it is important to remember that the adult in the room might have had their own journey with brown skin and has dealt with the burden of pigment changes,” Dr. Heath said.

For the parent, the pigmentation changes, rather than the inflammation, might be the governing issue and the reason that he or she brought the child to the clinician. Dr. Heath suggested that it is important for caregivers to explicitly recognize their concern, explain that addressing the pigmentary changes is part of the treatment plan, and to create realistic expectations about how long pigmentary changes will take to resolve.

As an example, Dr. Heath recounted a difficult case of a Black infant with disseminated hyperpigmentation and features that did not preclude pathology other than AD. Dr. Heath created a multifaceted treatment plan to address the inflammation in distinct areas of the body that included low-strength topical steroids for the face, stronger steroids for the body, and advice on scalp and skin care.

“I thought this was a great treatment plan out of the gate – I was covering all of the things on my differential list – I thought that the mom would be thinking, this doctor is amazing,” Dr. Heath said.
 

Pigmentary changes are a priority

However, that was not what the patient’s mother was thinking. Having failed to explicitly recognize her concern about the pigmentation changes and how the treatment would address this issue, the mother was disappointed.

“She had one question: Will my baby ever be one color? That was her main concern,” said Dr. Heath, indicating that other clinicians seeing inflammatory diseases in children with darker skin types can learn from her experience.

“Really, you have to acknowledge that the condition you are treating is causing the pigmentation change, and we do see that and that we have a treatment plan in place,” she said.

Because of differences in how inflammatory skin diseases present in darker skin types, there is plenty of room for a delayed diagnosis for clinicians who do not see many of these patients, according to Dr. Heath. Follicular eczema, which is common in skin of color, often presents with pruritus but differences in the appearance of the underlying disease can threaten a delay in diagnosis.

In cases of follicular eczema with itch in darker skin, the bumps look and feel like goose bumps, which “means that the eczema is really active and inflamed,” Dr. Heath said. When the skin becomes smooth and the itch dissipates, “you know that they are under great control.”

Psoriasis is often missed in children with darker skin types based on the misperception that it is rare. Although it is true that it is less common in Blacks than Whites, it is not rare, according to Dr. Heath. In inspecting the telltale erythematous plaque–like lesions, clinicians might start to consider alternative diagnoses when they do not detect the same erythematous appearance, but the reddish tone is often concealed in darker skin.

She said that predominant involvement in the head and neck and diaper area is often more common in children of color and that nail or scalp involvement, when present, is often a clue that psoriasis is the diagnosis.

Again, because many clinicians do not think immediately of psoriasis in darker skin children with lesions in the scalp, Dr. Heath advised this is another reason to include psoriasis in the differential diagnosis.

“If you have a child that has failed multiple courses of treatment for tinea capitis and they have well-demarcated plaques, it’s time to really start to think about pediatric psoriasis,” she said.
 

Restoring skin tone can be the priority

Asked to comment on Dr. Heath’s advice about the importance of acknowledging pigmentary changes associated with inflammatory skin diseases in patients of color, Jenna Lester, MD, the founding director of the Skin of Color Clinic at the University of California, San Francisco, called it an “often unspoken concern of patients.”

“Pigmentary changes that occur secondary to an inflammatory condition should be addressed and treated alongside the inciting condition,” she agreed.

Even if changes in skin color or skin tone are not a specific complaint of the patients, Dr. Lester also urged clinicians to raise the topic. If change in skin pigmentation is part of the clinical picture, this should be targeted in the treatment plan.

“In acne, for example, often times I find that patients are as worried about postinflammatory hyperpigmentation as they are about their acne,” she said, reiterating the advice provided by Dr. Heath.

Dr. Heath has financial relationships with Arcutis, Janssen, Johnson & Johnson, Lilly, and Regeneron. Dr. Lester reported no potential conflicts of interest.

NEW YORK – Many inflammatory diseases, such as psoriasis and atopic dermatitis (AD), can present differently in patients with darker skin types, but it is the pigmentary changes themselves that are often a dominant concern for parents, according to pediatric dermatologist Candrice R. Heath, MD.

Skin diseases pose a greater risk of both hyper- and hypopigmentation in patients with darker skin types, but the fear and concern that this raises for permanent disfigurement is not limited to Blacks, Dr. Heath, assistant professor of pediatric dermatology at Temple University, Philadelphia, said at the Skin of Color Update 2023.

“Culturally, pigmentation changes can be huge. For people of Indian descent, for example, pigmentary changes like light spots on the skin might be an obstacle to marriage, so it can really be life changing,” she added.

In patients with darker skin tones presenting with an inflammatory skin disease, such as AD or psoriasis, Dr. Heath advised asking specifically about change in skin tone even if it is not readily apparent. In pediatric patients, it is also appropriate to include parents in this conversation.
 

Consider the parent’s perspective

“When you are taking care of a child or adolescent, the patient is likely to be concerned about changes in pigmentation, but it is important to remember that the adult in the room might have had their own journey with brown skin and has dealt with the burden of pigment changes,” Dr. Heath said.

For the parent, the pigmentation changes, rather than the inflammation, might be the governing issue and the reason that he or she brought the child to the clinician. Dr. Heath suggested that it is important for caregivers to explicitly recognize their concern, explain that addressing the pigmentary changes is part of the treatment plan, and to create realistic expectations about how long pigmentary changes will take to resolve.

As an example, Dr. Heath recounted a difficult case of a Black infant with disseminated hyperpigmentation and features that did not preclude pathology other than AD. Dr. Heath created a multifaceted treatment plan to address the inflammation in distinct areas of the body that included low-strength topical steroids for the face, stronger steroids for the body, and advice on scalp and skin care.

“I thought this was a great treatment plan out of the gate – I was covering all of the things on my differential list – I thought that the mom would be thinking, this doctor is amazing,” Dr. Heath said.
 

Pigmentary changes are a priority

However, that was not what the patient’s mother was thinking. Having failed to explicitly recognize her concern about the pigmentation changes and how the treatment would address this issue, the mother was disappointed.

“She had one question: Will my baby ever be one color? That was her main concern,” said Dr. Heath, indicating that other clinicians seeing inflammatory diseases in children with darker skin types can learn from her experience.

“Really, you have to acknowledge that the condition you are treating is causing the pigmentation change, and we do see that and that we have a treatment plan in place,” she said.

Because of differences in how inflammatory skin diseases present in darker skin types, there is plenty of room for a delayed diagnosis for clinicians who do not see many of these patients, according to Dr. Heath. Follicular eczema, which is common in skin of color, often presents with pruritus but differences in the appearance of the underlying disease can threaten a delay in diagnosis.

In cases of follicular eczema with itch in darker skin, the bumps look and feel like goose bumps, which “means that the eczema is really active and inflamed,” Dr. Heath said. When the skin becomes smooth and the itch dissipates, “you know that they are under great control.”

Psoriasis is often missed in children with darker skin types based on the misperception that it is rare. Although it is true that it is less common in Blacks than Whites, it is not rare, according to Dr. Heath. In inspecting the telltale erythematous plaque–like lesions, clinicians might start to consider alternative diagnoses when they do not detect the same erythematous appearance, but the reddish tone is often concealed in darker skin.

She said that predominant involvement in the head and neck and diaper area is often more common in children of color and that nail or scalp involvement, when present, is often a clue that psoriasis is the diagnosis.

Again, because many clinicians do not think immediately of psoriasis in darker skin children with lesions in the scalp, Dr. Heath advised this is another reason to include psoriasis in the differential diagnosis.

“If you have a child that has failed multiple courses of treatment for tinea capitis and they have well-demarcated plaques, it’s time to really start to think about pediatric psoriasis,” she said.
 

Restoring skin tone can be the priority

Asked to comment on Dr. Heath’s advice about the importance of acknowledging pigmentary changes associated with inflammatory skin diseases in patients of color, Jenna Lester, MD, the founding director of the Skin of Color Clinic at the University of California, San Francisco, called it an “often unspoken concern of patients.”

“Pigmentary changes that occur secondary to an inflammatory condition should be addressed and treated alongside the inciting condition,” she agreed.

Even if changes in skin color or skin tone are not a specific complaint of the patients, Dr. Lester also urged clinicians to raise the topic. If change in skin pigmentation is part of the clinical picture, this should be targeted in the treatment plan.

“In acne, for example, often times I find that patients are as worried about postinflammatory hyperpigmentation as they are about their acne,” she said, reiterating the advice provided by Dr. Heath.

Dr. Heath has financial relationships with Arcutis, Janssen, Johnson & Johnson, Lilly, and Regeneron. Dr. Lester reported no potential conflicts of interest.

NEW YORK – Many inflammatory diseases, such as psoriasis and atopic dermatitis (AD), can present differently in patients with darker skin types, but it is the pigmentary changes themselves that are often a dominant concern for parents, according to pediatric dermatologist Candrice R. Heath, MD.

Skin diseases pose a greater risk of both hyper- and hypopigmentation in patients with darker skin types, but the fear and concern that this raises for permanent disfigurement is not limited to Blacks, Dr. Heath, assistant professor of pediatric dermatology at Temple University, Philadelphia, said at the Skin of Color Update 2023.

“Culturally, pigmentation changes can be huge. For people of Indian descent, for example, pigmentary changes like light spots on the skin might be an obstacle to marriage, so it can really be life changing,” she added.

In patients with darker skin tones presenting with an inflammatory skin disease, such as AD or psoriasis, Dr. Heath advised asking specifically about change in skin tone even if it is not readily apparent. In pediatric patients, it is also appropriate to include parents in this conversation.
 

Consider the parent’s perspective

“When you are taking care of a child or adolescent, the patient is likely to be concerned about changes in pigmentation, but it is important to remember that the adult in the room might have had their own journey with brown skin and has dealt with the burden of pigment changes,” Dr. Heath said.

For the parent, the pigmentation changes, rather than the inflammation, might be the governing issue and the reason that he or she brought the child to the clinician. Dr. Heath suggested that it is important for caregivers to explicitly recognize their concern, explain that addressing the pigmentary changes is part of the treatment plan, and to create realistic expectations about how long pigmentary changes will take to resolve.

As an example, Dr. Heath recounted a difficult case of a Black infant with disseminated hyperpigmentation and features that did not preclude pathology other than AD. Dr. Heath created a multifaceted treatment plan to address the inflammation in distinct areas of the body that included low-strength topical steroids for the face, stronger steroids for the body, and advice on scalp and skin care.

“I thought this was a great treatment plan out of the gate – I was covering all of the things on my differential list – I thought that the mom would be thinking, this doctor is amazing,” Dr. Heath said.
 

Pigmentary changes are a priority

However, that was not what the patient’s mother was thinking. Having failed to explicitly recognize her concern about the pigmentation changes and how the treatment would address this issue, the mother was disappointed.

“She had one question: Will my baby ever be one color? That was her main concern,” said Dr. Heath, indicating that other clinicians seeing inflammatory diseases in children with darker skin types can learn from her experience.

“Really, you have to acknowledge that the condition you are treating is causing the pigmentation change, and we do see that and that we have a treatment plan in place,” she said.

Because of differences in how inflammatory skin diseases present in darker skin types, there is plenty of room for a delayed diagnosis for clinicians who do not see many of these patients, according to Dr. Heath. Follicular eczema, which is common in skin of color, often presents with pruritus but differences in the appearance of the underlying disease can threaten a delay in diagnosis.

In cases of follicular eczema with itch in darker skin, the bumps look and feel like goose bumps, which “means that the eczema is really active and inflamed,” Dr. Heath said. When the skin becomes smooth and the itch dissipates, “you know that they are under great control.”

Psoriasis is often missed in children with darker skin types based on the misperception that it is rare. Although it is true that it is less common in Blacks than Whites, it is not rare, according to Dr. Heath. In inspecting the telltale erythematous plaque–like lesions, clinicians might start to consider alternative diagnoses when they do not detect the same erythematous appearance, but the reddish tone is often concealed in darker skin.

She said that predominant involvement in the head and neck and diaper area is often more common in children of color and that nail or scalp involvement, when present, is often a clue that psoriasis is the diagnosis.

Again, because many clinicians do not think immediately of psoriasis in darker skin children with lesions in the scalp, Dr. Heath advised this is another reason to include psoriasis in the differential diagnosis.

“If you have a child that has failed multiple courses of treatment for tinea capitis and they have well-demarcated plaques, it’s time to really start to think about pediatric psoriasis,” she said.
 

Restoring skin tone can be the priority

Asked to comment on Dr. Heath’s advice about the importance of acknowledging pigmentary changes associated with inflammatory skin diseases in patients of color, Jenna Lester, MD, the founding director of the Skin of Color Clinic at the University of California, San Francisco, called it an “often unspoken concern of patients.”

“Pigmentary changes that occur secondary to an inflammatory condition should be addressed and treated alongside the inciting condition,” she agreed.

Even if changes in skin color or skin tone are not a specific complaint of the patients, Dr. Lester also urged clinicians to raise the topic. If change in skin pigmentation is part of the clinical picture, this should be targeted in the treatment plan.

“In acne, for example, often times I find that patients are as worried about postinflammatory hyperpigmentation as they are about their acne,” she said, reiterating the advice provided by Dr. Heath.

Dr. Heath has financial relationships with Arcutis, Janssen, Johnson & Johnson, Lilly, and Regeneron. Dr. Lester reported no potential conflicts of interest.

Short-term use of JAK inhibitors for a dermatologic indication appears to not be associated with an increased risk of all-cause mortality, major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE), results from a systematic literature review, and meta-analysis showed.

“There remains a knowledge gap regarding the risk of JAK inhibitor use and VTE and/or MACE in the dermatologic population,” researchers led by Michael S. Garshick, MD, a cardiologist at New York University Langone Health, wrote in their study, which was published online in JAMA Dermatology . “Pooled safety studies suggest that the risk of MACE and VTE may be lower in patients treated with JAK inhibitors for a dermatologic indication than the risk observed in the ORAL Surveillance study, which may be related to the younger age and better health status of those enrolled in trials for dermatologic indications.” The results of that study, which included patients with rheumatoid arthritis only, resulted in the addition of a boxed warning in the labels for topical and oral JAK inhibitors regarding the increased risk of MACE, VTE, serious infections, malignancies, and death .

For the review – thought to be the first to specifically evaluate these risks for dermatologic indications – the researchers searched PubMed and ClinicalTrials.gov from inception through April 1, 2023, for phase 3 dermatology randomized clinical trials (RCTs) to evaluate the risk of MACE, VTE, and all-cause mortality with JAK inhibitors, compared with placebo or an active comparator in the treatment of immune-mediated inflammatory skin diseases. They followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and used a random-effects model and the DerSimonian-Laird method to calculate adverse events with odds ratios.

The database search yielded 35 RCTs with a total of 20,651 patients. Their mean age was 38.5 years, 54% were male, and the mean follow-up time was 4.9 months. Of the 35 trials, most (21) involved patients with atopic dermatitis, followed by psoriasis/psoriatic arthritis (9 trials), alopecia areata (3 trials) and vitiligo (2 trials).

The researchers found no significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (odds ratio, 0.83; 95% confidence interval, 0.44-1.57) or in VTE (OR, 0.52; 95% CI, 0.26-1.04).

In a secondary analysis, which included additional psoriatic arthritis RCTs, no significant differences between the treatment and placebo/active comparator groups were observed. Similarly, subgroup analyses of oral versus topical JAK inhibitors and a sensitivity analysis that excluded pediatric trials showed no significant differences between patients exposed to JAK inhibitors and those not exposed.

The researchers acknowledged certain limitations of the review, including the lack of access to patient-level data, the fact that most trials only included short-term follow-up, and that the findings have limited generalizability to an older patient population. “It remains unclear if the cardiovascular risks of JAK inhibitors are primarily due to patient level cardiovascular risk factors or are drug mediated,” they concluded. “Dermatologists should carefully select patients and assess baseline cardiovascular risk factors when considering JAK therapy. Cardiovascular risk assessment should continue for the duration of treatment.”

Raj Chovatiya, MD, PhD, assistant professor of dermatology and director of the center for eczema and itch at Northwestern University, Chicago, who was asked to comment on the study results, characterized the findings as reassuring to dermatologists who may be reluctant to initiate therapy with JAK inhibitors based on concerns about safety signals for MACE, VTE, and all-cause mortality.

“These data systematically show that across medications and across conditions, there doesn’t appear to be an increased signal for these events during the short-term, placebo-controlled period which generally spans a few months in most studies,” he told this news organization. The findings, he added, “align well with our clinical experience to date for JAK inhibitor use in inflammatory skin disease. Short-term safety, particularly in relation to boxed warning events such MACE, VTE, and all-cause mortality, have generally been favorable with real-world use. It’s good to have a rigorous statistical analysis to refer to when setting patient expectations.”

However, he noted that these data only examined short-term safety during the placebo or active comparator-controlled periods. “Considering that events like MACE or VTE may take many months or years to manifest, continued long-term data generation is needed to fully answer the question of risk,” he said.

Dr. Garshick disclosed that he received grants from Pfizer and personal fees from Bristol Myers Squibb during the conduct of the study and personal fees from Kiniksa Pharmaceuticals outside the submitted work. Several other coauthors reported having advisory board roles and/or having received funding or support from several pharmaceutical companies. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, investigator, and/or a member of the advisory board for several pharmaceutical companies, including those that develop JAK inhibitors.

Short-term use of JAK inhibitors for a dermatologic indication appears to not be associated with an increased risk of all-cause mortality, major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE), results from a systematic literature review, and meta-analysis showed.

“There remains a knowledge gap regarding the risk of JAK inhibitor use and VTE and/or MACE in the dermatologic population,” researchers led by Michael S. Garshick, MD, a cardiologist at New York University Langone Health, wrote in their study, which was published online in JAMA Dermatology . “Pooled safety studies suggest that the risk of MACE and VTE may be lower in patients treated with JAK inhibitors for a dermatologic indication than the risk observed in the ORAL Surveillance study, which may be related to the younger age and better health status of those enrolled in trials for dermatologic indications.” The results of that study, which included patients with rheumatoid arthritis only, resulted in the addition of a boxed warning in the labels for topical and oral JAK inhibitors regarding the increased risk of MACE, VTE, serious infections, malignancies, and death .

For the review – thought to be the first to specifically evaluate these risks for dermatologic indications – the researchers searched PubMed and ClinicalTrials.gov from inception through April 1, 2023, for phase 3 dermatology randomized clinical trials (RCTs) to evaluate the risk of MACE, VTE, and all-cause mortality with JAK inhibitors, compared with placebo or an active comparator in the treatment of immune-mediated inflammatory skin diseases. They followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and used a random-effects model and the DerSimonian-Laird method to calculate adverse events with odds ratios.

The database search yielded 35 RCTs with a total of 20,651 patients. Their mean age was 38.5 years, 54% were male, and the mean follow-up time was 4.9 months. Of the 35 trials, most (21) involved patients with atopic dermatitis, followed by psoriasis/psoriatic arthritis (9 trials), alopecia areata (3 trials) and vitiligo (2 trials).

The researchers found no significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (odds ratio, 0.83; 95% confidence interval, 0.44-1.57) or in VTE (OR, 0.52; 95% CI, 0.26-1.04).

In a secondary analysis, which included additional psoriatic arthritis RCTs, no significant differences between the treatment and placebo/active comparator groups were observed. Similarly, subgroup analyses of oral versus topical JAK inhibitors and a sensitivity analysis that excluded pediatric trials showed no significant differences between patients exposed to JAK inhibitors and those not exposed.

The researchers acknowledged certain limitations of the review, including the lack of access to patient-level data, the fact that most trials only included short-term follow-up, and that the findings have limited generalizability to an older patient population. “It remains unclear if the cardiovascular risks of JAK inhibitors are primarily due to patient level cardiovascular risk factors or are drug mediated,” they concluded. “Dermatologists should carefully select patients and assess baseline cardiovascular risk factors when considering JAK therapy. Cardiovascular risk assessment should continue for the duration of treatment.”

Raj Chovatiya, MD, PhD, assistant professor of dermatology and director of the center for eczema and itch at Northwestern University, Chicago, who was asked to comment on the study results, characterized the findings as reassuring to dermatologists who may be reluctant to initiate therapy with JAK inhibitors based on concerns about safety signals for MACE, VTE, and all-cause mortality.

“These data systematically show that across medications and across conditions, there doesn’t appear to be an increased signal for these events during the short-term, placebo-controlled period which generally spans a few months in most studies,” he told this news organization. The findings, he added, “align well with our clinical experience to date for JAK inhibitor use in inflammatory skin disease. Short-term safety, particularly in relation to boxed warning events such MACE, VTE, and all-cause mortality, have generally been favorable with real-world use. It’s good to have a rigorous statistical analysis to refer to when setting patient expectations.”

However, he noted that these data only examined short-term safety during the placebo or active comparator-controlled periods. “Considering that events like MACE or VTE may take many months or years to manifest, continued long-term data generation is needed to fully answer the question of risk,” he said.

Dr. Garshick disclosed that he received grants from Pfizer and personal fees from Bristol Myers Squibb during the conduct of the study and personal fees from Kiniksa Pharmaceuticals outside the submitted work. Several other coauthors reported having advisory board roles and/or having received funding or support from several pharmaceutical companies. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, investigator, and/or a member of the advisory board for several pharmaceutical companies, including those that develop JAK inhibitors.

Short-term use of JAK inhibitors for a dermatologic indication appears to not be associated with an increased risk of all-cause mortality, major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE), results from a systematic literature review, and meta-analysis showed.

“There remains a knowledge gap regarding the risk of JAK inhibitor use and VTE and/or MACE in the dermatologic population,” researchers led by Michael S. Garshick, MD, a cardiologist at New York University Langone Health, wrote in their study, which was published online in JAMA Dermatology . “Pooled safety studies suggest that the risk of MACE and VTE may be lower in patients treated with JAK inhibitors for a dermatologic indication than the risk observed in the ORAL Surveillance study, which may be related to the younger age and better health status of those enrolled in trials for dermatologic indications.” The results of that study, which included patients with rheumatoid arthritis only, resulted in the addition of a boxed warning in the labels for topical and oral JAK inhibitors regarding the increased risk of MACE, VTE, serious infections, malignancies, and death .

For the review – thought to be the first to specifically evaluate these risks for dermatologic indications – the researchers searched PubMed and ClinicalTrials.gov from inception through April 1, 2023, for phase 3 dermatology randomized clinical trials (RCTs) to evaluate the risk of MACE, VTE, and all-cause mortality with JAK inhibitors, compared with placebo or an active comparator in the treatment of immune-mediated inflammatory skin diseases. They followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and used a random-effects model and the DerSimonian-Laird method to calculate adverse events with odds ratios.

The database search yielded 35 RCTs with a total of 20,651 patients. Their mean age was 38.5 years, 54% were male, and the mean follow-up time was 4.9 months. Of the 35 trials, most (21) involved patients with atopic dermatitis, followed by psoriasis/psoriatic arthritis (9 trials), alopecia areata (3 trials) and vitiligo (2 trials).

The researchers found no significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (odds ratio, 0.83; 95% confidence interval, 0.44-1.57) or in VTE (OR, 0.52; 95% CI, 0.26-1.04).

In a secondary analysis, which included additional psoriatic arthritis RCTs, no significant differences between the treatment and placebo/active comparator groups were observed. Similarly, subgroup analyses of oral versus topical JAK inhibitors and a sensitivity analysis that excluded pediatric trials showed no significant differences between patients exposed to JAK inhibitors and those not exposed.

The researchers acknowledged certain limitations of the review, including the lack of access to patient-level data, the fact that most trials only included short-term follow-up, and that the findings have limited generalizability to an older patient population. “It remains unclear if the cardiovascular risks of JAK inhibitors are primarily due to patient level cardiovascular risk factors or are drug mediated,” they concluded. “Dermatologists should carefully select patients and assess baseline cardiovascular risk factors when considering JAK therapy. Cardiovascular risk assessment should continue for the duration of treatment.”

Raj Chovatiya, MD, PhD, assistant professor of dermatology and director of the center for eczema and itch at Northwestern University, Chicago, who was asked to comment on the study results, characterized the findings as reassuring to dermatologists who may be reluctant to initiate therapy with JAK inhibitors based on concerns about safety signals for MACE, VTE, and all-cause mortality.

“These data systematically show that across medications and across conditions, there doesn’t appear to be an increased signal for these events during the short-term, placebo-controlled period which generally spans a few months in most studies,” he told this news organization. The findings, he added, “align well with our clinical experience to date for JAK inhibitor use in inflammatory skin disease. Short-term safety, particularly in relation to boxed warning events such MACE, VTE, and all-cause mortality, have generally been favorable with real-world use. It’s good to have a rigorous statistical analysis to refer to when setting patient expectations.”

However, he noted that these data only examined short-term safety during the placebo or active comparator-controlled periods. “Considering that events like MACE or VTE may take many months or years to manifest, continued long-term data generation is needed to fully answer the question of risk,” he said.

Dr. Garshick disclosed that he received grants from Pfizer and personal fees from Bristol Myers Squibb during the conduct of the study and personal fees from Kiniksa Pharmaceuticals outside the submitted work. Several other coauthors reported having advisory board roles and/or having received funding or support from several pharmaceutical companies. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, investigator, and/or a member of the advisory board for several pharmaceutical companies, including those that develop JAK inhibitors.

Most subjects covered in this column are botanical ingredients used for multiple conditions in topical skin care. The focus this month, though, is a natural agent garnering attention primarily for one indication. Present in many mammals and in various cells in the human body (and particularly highly concentrated in human milk), cysteamine is a stable aminothiol that acts as an antioxidant as a result of the degradation of coenzyme A and is known to play a protective function.¹ Melasma, an acquired recurrent, chronic hyperpigmentary disorder, continues to be a treatment challenge and is often psychologically troublesome for those affected, approximately 90% of whom are women.² Individuals with Fitzpatrick skin types IV and V who reside in regions where UV exposure is likely are particularly prominent among those with melasma.² While triple combination therapy (also known as Kligman’s formula) continues to be the modern gold standard of care for melasma (over the last 30 years),³ cysteamine, a nonmelanocytotoxic molecule, is considered viable for long-term use and safer than the long-time skin-lightening gold standard over several decades, hydroquinone (HQ), which is associated with safety concerns.⁴ This month’s column is a review of recent findings on the efficacy and safety of cysteamine for the treatment of melasma.

Toa55/iStock/Getty Images

Recent history and the 2015 study

Prior to 2015, the quick oxidation and malodorous nature of cysteamine rendered it unsuitable for use as a topical agent. However, stabilization efforts resulted in a product that first began to show efficacy that year.⁵

Mansouri et al. conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy of topical cysteamine 5% to treat epidermal melasma in 2015. Over 4 months, 50 volunteers (25 in each group) applied either cysteamine cream or placebo on lesions once nightly. The mean differences at baseline between pigmented and normal skin were 75.2 ± 37 in the cysteamine group and 68.9 ± 31 in the placebo group. Statistically significant differences between the groups were identified at the 2- and 4-month points. At 2 months, the mean differences were 39.7 ± 16.6 in the cysteamine group and 63.8 ± 28.6 in the placebo group; at 4 months, the respective differences were 26.2 ± 16 and 60.7 ± 27.3. Melasma area severity index (MASI) scores were significantly lower in the cysteamine group compared with the placebo group at the end of the study, and investigator global assessment scores and patient questionnaire results revealed substantial comparative efficacy of cysteamine cream.⁶ Topical cysteamine has also demonstrated notable efficacy in treating senile lentigines, which typically do not respond to topical depigmenting products.⁵

Farshi et al. used Dermacatch as a novel measurement tool to ascertain the efficacy of cysteamine cream for treating epidermal melasma in a 2018 report of a randomized, double-blind, placebo-controlled study with 40 patients. During the 4-month trial, cysteamine cream or placebo was applied nightly before sleep. Investigators measured treatment efficacy through Dermacatch, and Mexameter skin colorimetry, MASI scores, investigator global assessments, and patient questionnaires at baseline, 2 months, and 4 months. Through all measurement methods, cysteamine was found to reduce melanin content of melasma lesions, with Dermacatch performing reliably and comparably to Mexameter.⁷ Since then, cysteamine has been compared to several first-line melasma therapies.
 

Reviews

A 2019 systematic review by Austin et al. of randomized controlled trials (RCTs) on topical treatments for melasma identified 35 original RCTs evaluating a wide range of approximately 20 agents. They identified cysteamine, triple combination therapy, and tranexamic acid as the products netting the most robust recommendations. The researchers characterized cysteamine as conferring strong efficacy and reported anticancer activity while triple combination therapy poses the potential risk of ochronosis and tranexamic acid may present the risk for thrombosis. They concluded that more research is necessary, though, to establish the proper concentration and optimal formulation of cysteamine as a frontline therapy.⁸

More reviews have since been published to further clarify where cysteamine stands among the optimal treatments for melasma. In a May 2022 systematic PubMed review of topical agents used to treat melasma, González-Molina et al. identified 80 papers meeting inclusion criteria (double or single blinded, prospective, controlled or RCTs, reviews of literature, and meta-analysis studies), with tranexamic acid and cysteamine among the novel well-tolerated agents. Cysteamine was not associated with any severe adverse effects and is recommended as an adjuvant and maintenance therapy.³

A September 2022 review by Niazi et al. found that while the signaling mechanisms through which cysteamine suppresses melasma are not well understood, the topical application of cysteamine cream is seen as safe and effective alone or in combination with other products to treat melasma.²

A systematic review and meta-analysis reported by Gomes dos Santos-Neto et al. at the end of 2022 considered the efficacy of depigmenting formulations containing 5% cysteamine for treating melasma. The meta-analysis covered six studies, with 120 melasma patients treated. The conclusion was that 5% cysteamine was effective with adverse effects unlikely.⁹

Baumann Cosmetic &amp; Research Institute

Cysteamine vs. hydroquinone

In 2020, Lima et al. reported the results of a quasi-randomized, multicenter, evaluator-blinded comparative study of topical 0.56% cysteamine and 4% HQ in 40 women with facial melasma. (Note that this study originally claimed a 5% cysteamine concentration, but a letter to the editor of the International Journal of Dermatology in 2020 disputed this and proved it was 0.56%) For 120 days, volunteers applied either 0.56% cysteamine or 4% HQ nightly. Tinted sunscreen (SPF 50; PPD 19) use was required for all participants. There were no differences in colorimetric evaluations between the groups, both of which showed progressive depigmenting, or in photographic assessments. The HQ group demonstrated greater mean decreases in modified melasma area severity index (mMASI) scores (41% for HQ and 24% for cysteamine at 60 days; 53% for HQ and 38% for cysteamine at 120 days). The investigators observed that while cysteamine was safe, well tolerated, and effective, it was outperformed by HQ in terms of mMASI and melasma quality of life (MELASQoL) scores.¹⁰

Early the next year, results of a randomized, double-blind, single-center study in 20 women, conducted by Nguyen et al. comparing the efficacy of cysteamine cream with HQ for melasma treatment were published. Participants were given either treatment over 16 weeks. Ultimately, five volunteers in the cysteamine group and nine in the HQ group completed the study. There was no statistically significant difference in mMASI scores between the groups. In this notably small study, HQ was tolerated better. The researchers concluded that their findings supported the argument of comparable efficacy between cysteamine and HQ, with further studies needed to establish whether cysteamine would be an appropriate alternative to HQ.¹¹ Notably, HQ was banned by the Food and Drug Administration in 2020 in over-the-counter products.
 

Cysteamine vs. Kligman’s formula

Early in 2021, Karrabi et al. published the results of a randomized, double-blind clinical trial of 50 subjects with epidermal melasma to compare cysteamine 5% with Modified Kligman’s formula. Over 4 months, participants applied once daily either cysteamine cream 5% (15 minutes exposure) or the Modified Kligman’s formula (4% hydroquinone, 0.05% retinoic acid and 0.1% betamethasone) for whole night exposure. At 2 and 4 months, a statistically significant difference in mMASI score was noted, with the percentage decline in mMASI score nearly 9% higher in the cysteamine group. The investigators concluded that cysteamine 5% demonstrated greater efficacy than the Modified Kligman’s formula and was also better tolerated.¹²

Cysteamine vs. tranexamic acid

Later that year, Karrabi et al. published the results of a single-blind, randomized clinical trial assessing the efficacy of tranexamic acid mesotherapy compared with cysteamine 5% cream in 54 melasma patients. For 4 consecutive months, the cysteamine 5% cream group applied the cream on lesions 30 minutes before going to sleep. Every 4 weeks until 2 months, a physician performed tranexamic acid mesotherapy (0.05 mL; 4 mg/mL) on individuals in the tranexamic acid group. The researchers concluded, after measurements using both a Dermacatch device and the mMASI, that neither treatment was significantly better than the other but fewer complications were observed in the cysteamine group.¹³

Safety

In 2022, Sepaskhah et al. assessed the effects of a cysteamine 5% cream and compared it with HQ 4%/ascorbic acid 3% cream for epidermal melasma in a single-blind, randomized controlled trial. Sixty-five of 80 patients completed the study. The difference in mMASI scores after 4 months was not significant between the groups nor was the improvement in quality of life, but the melanin index was significantly lower in the HQ/ascorbic acid group compared with the less substantial reduction for the cysteamine group. Nevertheless, the researchers concluded that cysteamine is a safe and suitable substitute for HQ/ascorbic acid.⁴

Conclusion

In the last decade, cysteamine has been established as a potent depigmenting agent. Its suitability and desirability as a top consideration for melasma treatment also appears to be compelling. More RCTs comparing cysteamine and other topline therapies are warranted, but current evidence shows that cysteamine is an effective and safe therapy for melasma.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at dermnews@mdedge.com.

References

1. Konar MC et al. J Trop Pediatr. 2020 Apr 1;66(2):129-35.

2. Niazi S et al. J Cosmet Dermatol. 2022 Sep;21(9):3867-75.

3. González-Molina V et al. J Clin Aesthet Dermatol. 2022 May;15(5):19-28.

4. Sepaskhah M et al. J Cosmet Dermatol. 2022 Jul;21(7):2871-8.

5. Desai S et al. J Drugs Dermatol. 2021 Dec 1;20(12):1276-9.

6. Mansouri P et al. Br J Dermatol. 2015 Jul;173(1):209-17.

7. Farshi S et al. J Dermatolog Treat. 2018 Mar;29(2):182-9.

8. Austin E et al. J Drugs Dermatol. 2019 Nov 1;18(11):S1545961619P1156X.

9. Gomes dos Santos-Neto A et al. Dermatol Ther. 2022 Dec;35(12):e15961.

10. Lima PB et al. Int J Dermatol. 2020 Dec;59(12):1531-6.

11. Nguyen J et al. Australas J Dermatol. 2021 Feb;62(1):e41-e46.

12. Karrabi M et al. Skin Res Technol. 2021 Jan;27(1):24-31.

13. Karrabi M et al. Arch Dermatol Res. 2021 Sep;313(7):539-47.

Most subjects covered in this column are botanical ingredients used for multiple conditions in topical skin care. The focus this month, though, is a natural agent garnering attention primarily for one indication. Present in many mammals and in various cells in the human body (and particularly highly concentrated in human milk), cysteamine is a stable aminothiol that acts as an antioxidant as a result of the degradation of coenzyme A and is known to play a protective function.¹ Melasma, an acquired recurrent, chronic hyperpigmentary disorder, continues to be a treatment challenge and is often psychologically troublesome for those affected, approximately 90% of whom are women.² Individuals with Fitzpatrick skin types IV and V who reside in regions where UV exposure is likely are particularly prominent among those with melasma.² While triple combination therapy (also known as Kligman’s formula) continues to be the modern gold standard of care for melasma (over the last 30 years),³ cysteamine, a nonmelanocytotoxic molecule, is considered viable for long-term use and safer than the long-time skin-lightening gold standard over several decades, hydroquinone (HQ), which is associated with safety concerns.⁴ This month’s column is a review of recent findings on the efficacy and safety of cysteamine for the treatment of melasma.

Toa55/iStock/Getty Images

Recent history and the 2015 study

Prior to 2015, the quick oxidation and malodorous nature of cysteamine rendered it unsuitable for use as a topical agent. However, stabilization efforts resulted in a product that first began to show efficacy that year.⁵

Mansouri et al. conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy of topical cysteamine 5% to treat epidermal melasma in 2015. Over 4 months, 50 volunteers (25 in each group) applied either cysteamine cream or placebo on lesions once nightly. The mean differences at baseline between pigmented and normal skin were 75.2 ± 37 in the cysteamine group and 68.9 ± 31 in the placebo group. Statistically significant differences between the groups were identified at the 2- and 4-month points. At 2 months, the mean differences were 39.7 ± 16.6 in the cysteamine group and 63.8 ± 28.6 in the placebo group; at 4 months, the respective differences were 26.2 ± 16 and 60.7 ± 27.3. Melasma area severity index (MASI) scores were significantly lower in the cysteamine group compared with the placebo group at the end of the study, and investigator global assessment scores and patient questionnaire results revealed substantial comparative efficacy of cysteamine cream.⁶ Topical cysteamine has also demonstrated notable efficacy in treating senile lentigines, which typically do not respond to topical depigmenting products.⁵

Farshi et al. used Dermacatch as a novel measurement tool to ascertain the efficacy of cysteamine cream for treating epidermal melasma in a 2018 report of a randomized, double-blind, placebo-controlled study with 40 patients. During the 4-month trial, cysteamine cream or placebo was applied nightly before sleep. Investigators measured treatment efficacy through Dermacatch, and Mexameter skin colorimetry, MASI scores, investigator global assessments, and patient questionnaires at baseline, 2 months, and 4 months. Through all measurement methods, cysteamine was found to reduce melanin content of melasma lesions, with Dermacatch performing reliably and comparably to Mexameter.⁷ Since then, cysteamine has been compared to several first-line melasma therapies.
 

Reviews

A 2019 systematic review by Austin et al. of randomized controlled trials (RCTs) on topical treatments for melasma identified 35 original RCTs evaluating a wide range of approximately 20 agents. They identified cysteamine, triple combination therapy, and tranexamic acid as the products netting the most robust recommendations. The researchers characterized cysteamine as conferring strong efficacy and reported anticancer activity while triple combination therapy poses the potential risk of ochronosis and tranexamic acid may present the risk for thrombosis. They concluded that more research is necessary, though, to establish the proper concentration and optimal formulation of cysteamine as a frontline therapy.⁸

More reviews have since been published to further clarify where cysteamine stands among the optimal treatments for melasma. In a May 2022 systematic PubMed review of topical agents used to treat melasma, González-Molina et al. identified 80 papers meeting inclusion criteria (double or single blinded, prospective, controlled or RCTs, reviews of literature, and meta-analysis studies), with tranexamic acid and cysteamine among the novel well-tolerated agents. Cysteamine was not associated with any severe adverse effects and is recommended as an adjuvant and maintenance therapy.³

A September 2022 review by Niazi et al. found that while the signaling mechanisms through which cysteamine suppresses melasma are not well understood, the topical application of cysteamine cream is seen as safe and effective alone or in combination with other products to treat melasma.²

A systematic review and meta-analysis reported by Gomes dos Santos-Neto et al. at the end of 2022 considered the efficacy of depigmenting formulations containing 5% cysteamine for treating melasma. The meta-analysis covered six studies, with 120 melasma patients treated. The conclusion was that 5% cysteamine was effective with adverse effects unlikely.⁹

Baumann Cosmetic &amp; Research Institute

Cysteamine vs. hydroquinone

In 2020, Lima et al. reported the results of a quasi-randomized, multicenter, evaluator-blinded comparative study of topical 0.56% cysteamine and 4% HQ in 40 women with facial melasma. (Note that this study originally claimed a 5% cysteamine concentration, but a letter to the editor of the International Journal of Dermatology in 2020 disputed this and proved it was 0.56%) For 120 days, volunteers applied either 0.56% cysteamine or 4% HQ nightly. Tinted sunscreen (SPF 50; PPD 19) use was required for all participants. There were no differences in colorimetric evaluations between the groups, both of which showed progressive depigmenting, or in photographic assessments. The HQ group demonstrated greater mean decreases in modified melasma area severity index (mMASI) scores (41% for HQ and 24% for cysteamine at 60 days; 53% for HQ and 38% for cysteamine at 120 days). The investigators observed that while cysteamine was safe, well tolerated, and effective, it was outperformed by HQ in terms of mMASI and melasma quality of life (MELASQoL) scores.¹⁰

Early the next year, results of a randomized, double-blind, single-center study in 20 women, conducted by Nguyen et al. comparing the efficacy of cysteamine cream with HQ for melasma treatment were published. Participants were given either treatment over 16 weeks. Ultimately, five volunteers in the cysteamine group and nine in the HQ group completed the study. There was no statistically significant difference in mMASI scores between the groups. In this notably small study, HQ was tolerated better. The researchers concluded that their findings supported the argument of comparable efficacy between cysteamine and HQ, with further studies needed to establish whether cysteamine would be an appropriate alternative to HQ.¹¹ Notably, HQ was banned by the Food and Drug Administration in 2020 in over-the-counter products.
 

Cysteamine vs. Kligman’s formula

Early in 2021, Karrabi et al. published the results of a randomized, double-blind clinical trial of 50 subjects with epidermal melasma to compare cysteamine 5% with Modified Kligman’s formula. Over 4 months, participants applied once daily either cysteamine cream 5% (15 minutes exposure) or the Modified Kligman’s formula (4% hydroquinone, 0.05% retinoic acid and 0.1% betamethasone) for whole night exposure. At 2 and 4 months, a statistically significant difference in mMASI score was noted, with the percentage decline in mMASI score nearly 9% higher in the cysteamine group. The investigators concluded that cysteamine 5% demonstrated greater efficacy than the Modified Kligman’s formula and was also better tolerated.¹²

Cysteamine vs. tranexamic acid

Later that year, Karrabi et al. published the results of a single-blind, randomized clinical trial assessing the efficacy of tranexamic acid mesotherapy compared with cysteamine 5% cream in 54 melasma patients. For 4 consecutive months, the cysteamine 5% cream group applied the cream on lesions 30 minutes before going to sleep. Every 4 weeks until 2 months, a physician performed tranexamic acid mesotherapy (0.05 mL; 4 mg/mL) on individuals in the tranexamic acid group. The researchers concluded, after measurements using both a Dermacatch device and the mMASI, that neither treatment was significantly better than the other but fewer complications were observed in the cysteamine group.¹³

Safety

In 2022, Sepaskhah et al. assessed the effects of a cysteamine 5% cream and compared it with HQ 4%/ascorbic acid 3% cream for epidermal melasma in a single-blind, randomized controlled trial. Sixty-five of 80 patients completed the study. The difference in mMASI scores after 4 months was not significant between the groups nor was the improvement in quality of life, but the melanin index was significantly lower in the HQ/ascorbic acid group compared with the less substantial reduction for the cysteamine group. Nevertheless, the researchers concluded that cysteamine is a safe and suitable substitute for HQ/ascorbic acid.⁴

Conclusion

In the last decade, cysteamine has been established as a potent depigmenting agent. Its suitability and desirability as a top consideration for melasma treatment also appears to be compelling. More RCTs comparing cysteamine and other topline therapies are warranted, but current evidence shows that cysteamine is an effective and safe therapy for melasma.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at dermnews@mdedge.com.

References

1. Konar MC et al. J Trop Pediatr. 2020 Apr 1;66(2):129-35.

2. Niazi S et al. J Cosmet Dermatol. 2022 Sep;21(9):3867-75.

3. González-Molina V et al. J Clin Aesthet Dermatol. 2022 May;15(5):19-28.

4. Sepaskhah M et al. J Cosmet Dermatol. 2022 Jul;21(7):2871-8.

5. Desai S et al. J Drugs Dermatol. 2021 Dec 1;20(12):1276-9.

6. Mansouri P et al. Br J Dermatol. 2015 Jul;173(1):209-17.

7. Farshi S et al. J Dermatolog Treat. 2018 Mar;29(2):182-9.

8. Austin E et al. J Drugs Dermatol. 2019 Nov 1;18(11):S1545961619P1156X.

9. Gomes dos Santos-Neto A et al. Dermatol Ther. 2022 Dec;35(12):e15961.

10. Lima PB et al. Int J Dermatol. 2020 Dec;59(12):1531-6.

11. Nguyen J et al. Australas J Dermatol. 2021 Feb;62(1):e41-e46.

12. Karrabi M et al. Skin Res Technol. 2021 Jan;27(1):24-31.

13. Karrabi M et al. Arch Dermatol Res. 2021 Sep;313(7):539-47.

Most subjects covered in this column are botanical ingredients used for multiple conditions in topical skin care. The focus this month, though, is a natural agent garnering attention primarily for one indication. Present in many mammals and in various cells in the human body (and particularly highly concentrated in human milk), cysteamine is a stable aminothiol that acts as an antioxidant as a result of the degradation of coenzyme A and is known to play a protective function.¹ Melasma, an acquired recurrent, chronic hyperpigmentary disorder, continues to be a treatment challenge and is often psychologically troublesome for those affected, approximately 90% of whom are women.² Individuals with Fitzpatrick skin types IV and V who reside in regions where UV exposure is likely are particularly prominent among those with melasma.² While triple combination therapy (also known as Kligman’s formula) continues to be the modern gold standard of care for melasma (over the last 30 years),³ cysteamine, a nonmelanocytotoxic molecule, is considered viable for long-term use and safer than the long-time skin-lightening gold standard over several decades, hydroquinone (HQ), which is associated with safety concerns.⁴ This month’s column is a review of recent findings on the efficacy and safety of cysteamine for the treatment of melasma.

Toa55/iStock/Getty Images

Recent history and the 2015 study

Prior to 2015, the quick oxidation and malodorous nature of cysteamine rendered it unsuitable for use as a topical agent. However, stabilization efforts resulted in a product that first began to show efficacy that year.⁵

Mansouri et al. conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy of topical cysteamine 5% to treat epidermal melasma in 2015. Over 4 months, 50 volunteers (25 in each group) applied either cysteamine cream or placebo on lesions once nightly. The mean differences at baseline between pigmented and normal skin were 75.2 ± 37 in the cysteamine group and 68.9 ± 31 in the placebo group. Statistically significant differences between the groups were identified at the 2- and 4-month points. At 2 months, the mean differences were 39.7 ± 16.6 in the cysteamine group and 63.8 ± 28.6 in the placebo group; at 4 months, the respective differences were 26.2 ± 16 and 60.7 ± 27.3. Melasma area severity index (MASI) scores were significantly lower in the cysteamine group compared with the placebo group at the end of the study, and investigator global assessment scores and patient questionnaire results revealed substantial comparative efficacy of cysteamine cream.⁶ Topical cysteamine has also demonstrated notable efficacy in treating senile lentigines, which typically do not respond to topical depigmenting products.⁵

Farshi et al. used Dermacatch as a novel measurement tool to ascertain the efficacy of cysteamine cream for treating epidermal melasma in a 2018 report of a randomized, double-blind, placebo-controlled study with 40 patients. During the 4-month trial, cysteamine cream or placebo was applied nightly before sleep. Investigators measured treatment efficacy through Dermacatch, and Mexameter skin colorimetry, MASI scores, investigator global assessments, and patient questionnaires at baseline, 2 months, and 4 months. Through all measurement methods, cysteamine was found to reduce melanin content of melasma lesions, with Dermacatch performing reliably and comparably to Mexameter.⁷ Since then, cysteamine has been compared to several first-line melasma therapies.
 

Reviews

A 2019 systematic review by Austin et al. of randomized controlled trials (RCTs) on topical treatments for melasma identified 35 original RCTs evaluating a wide range of approximately 20 agents. They identified cysteamine, triple combination therapy, and tranexamic acid as the products netting the most robust recommendations. The researchers characterized cysteamine as conferring strong efficacy and reported anticancer activity while triple combination therapy poses the potential risk of ochronosis and tranexamic acid may present the risk for thrombosis. They concluded that more research is necessary, though, to establish the proper concentration and optimal formulation of cysteamine as a frontline therapy.⁸

More reviews have since been published to further clarify where cysteamine stands among the optimal treatments for melasma. In a May 2022 systematic PubMed review of topical agents used to treat melasma, González-Molina et al. identified 80 papers meeting inclusion criteria (double or single blinded, prospective, controlled or RCTs, reviews of literature, and meta-analysis studies), with tranexamic acid and cysteamine among the novel well-tolerated agents. Cysteamine was not associated with any severe adverse effects and is recommended as an adjuvant and maintenance therapy.³

A September 2022 review by Niazi et al. found that while the signaling mechanisms through which cysteamine suppresses melasma are not well understood, the topical application of cysteamine cream is seen as safe and effective alone or in combination with other products to treat melasma.²

A systematic review and meta-analysis reported by Gomes dos Santos-Neto et al. at the end of 2022 considered the efficacy of depigmenting formulations containing 5% cysteamine for treating melasma. The meta-analysis covered six studies, with 120 melasma patients treated. The conclusion was that 5% cysteamine was effective with adverse effects unlikely.⁹

Baumann Cosmetic &amp; Research Institute

Cysteamine vs. hydroquinone

In 2020, Lima et al. reported the results of a quasi-randomized, multicenter, evaluator-blinded comparative study of topical 0.56% cysteamine and 4% HQ in 40 women with facial melasma. (Note that this study originally claimed a 5% cysteamine concentration, but a letter to the editor of the International Journal of Dermatology in 2020 disputed this and proved it was 0.56%) For 120 days, volunteers applied either 0.56% cysteamine or 4% HQ nightly. Tinted sunscreen (SPF 50; PPD 19) use was required for all participants. There were no differences in colorimetric evaluations between the groups, both of which showed progressive depigmenting, or in photographic assessments. The HQ group demonstrated greater mean decreases in modified melasma area severity index (mMASI) scores (41% for HQ and 24% for cysteamine at 60 days; 53% for HQ and 38% for cysteamine at 120 days). The investigators observed that while cysteamine was safe, well tolerated, and effective, it was outperformed by HQ in terms of mMASI and melasma quality of life (MELASQoL) scores.¹⁰

Early the next year, results of a randomized, double-blind, single-center study in 20 women, conducted by Nguyen et al. comparing the efficacy of cysteamine cream with HQ for melasma treatment were published. Participants were given either treatment over 16 weeks. Ultimately, five volunteers in the cysteamine group and nine in the HQ group completed the study. There was no statistically significant difference in mMASI scores between the groups. In this notably small study, HQ was tolerated better. The researchers concluded that their findings supported the argument of comparable efficacy between cysteamine and HQ, with further studies needed to establish whether cysteamine would be an appropriate alternative to HQ.¹¹ Notably, HQ was banned by the Food and Drug Administration in 2020 in over-the-counter products.
 

Cysteamine vs. Kligman’s formula

Early in 2021, Karrabi et al. published the results of a randomized, double-blind clinical trial of 50 subjects with epidermal melasma to compare cysteamine 5% with Modified Kligman’s formula. Over 4 months, participants applied once daily either cysteamine cream 5% (15 minutes exposure) or the Modified Kligman’s formula (4% hydroquinone, 0.05% retinoic acid and 0.1% betamethasone) for whole night exposure. At 2 and 4 months, a statistically significant difference in mMASI score was noted, with the percentage decline in mMASI score nearly 9% higher in the cysteamine group. The investigators concluded that cysteamine 5% demonstrated greater efficacy than the Modified Kligman’s formula and was also better tolerated.¹²

Cysteamine vs. tranexamic acid

Later that year, Karrabi et al. published the results of a single-blind, randomized clinical trial assessing the efficacy of tranexamic acid mesotherapy compared with cysteamine 5% cream in 54 melasma patients. For 4 consecutive months, the cysteamine 5% cream group applied the cream on lesions 30 minutes before going to sleep. Every 4 weeks until 2 months, a physician performed tranexamic acid mesotherapy (0.05 mL; 4 mg/mL) on individuals in the tranexamic acid group. The researchers concluded, after measurements using both a Dermacatch device and the mMASI, that neither treatment was significantly better than the other but fewer complications were observed in the cysteamine group.¹³

Safety

In 2022, Sepaskhah et al. assessed the effects of a cysteamine 5% cream and compared it with HQ 4%/ascorbic acid 3% cream for epidermal melasma in a single-blind, randomized controlled trial. Sixty-five of 80 patients completed the study. The difference in mMASI scores after 4 months was not significant between the groups nor was the improvement in quality of life, but the melanin index was significantly lower in the HQ/ascorbic acid group compared with the less substantial reduction for the cysteamine group. Nevertheless, the researchers concluded that cysteamine is a safe and suitable substitute for HQ/ascorbic acid.⁴

Conclusion

In the last decade, cysteamine has been established as a potent depigmenting agent. Its suitability and desirability as a top consideration for melasma treatment also appears to be compelling. More RCTs comparing cysteamine and other topline therapies are warranted, but current evidence shows that cysteamine is an effective and safe therapy for melasma.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at dermnews@mdedge.com.

References

1. Konar MC et al. J Trop Pediatr. 2020 Apr 1;66(2):129-35.

2. Niazi S et al. J Cosmet Dermatol. 2022 Sep;21(9):3867-75.

3. González-Molina V et al. J Clin Aesthet Dermatol. 2022 May;15(5):19-28.

4. Sepaskhah M et al. J Cosmet Dermatol. 2022 Jul;21(7):2871-8.

5. Desai S et al. J Drugs Dermatol. 2021 Dec 1;20(12):1276-9.

6. Mansouri P et al. Br J Dermatol. 2015 Jul;173(1):209-17.

7. Farshi S et al. J Dermatolog Treat. 2018 Mar;29(2):182-9.

8. Austin E et al. J Drugs Dermatol. 2019 Nov 1;18(11):S1545961619P1156X.

9. Gomes dos Santos-Neto A et al. Dermatol Ther. 2022 Dec;35(12):e15961.

10. Lima PB et al. Int J Dermatol. 2020 Dec;59(12):1531-6.

11. Nguyen J et al. Australas J Dermatol. 2021 Feb;62(1):e41-e46.

12. Karrabi M et al. Skin Res Technol. 2021 Jan;27(1):24-31.

13. Karrabi M et al. Arch Dermatol Res. 2021 Sep;313(7):539-47.