Therapeutic Options for Cosmetic Management of Atopic Dermatitis

Atopic dermatitis (AD) affects 15% to 20% of children and 1% to 3% of adults worldwide.¹ It is a condition that every dermatologist is familiar with treating. Currently, most treatments focus more on the medical management behind AD; this is why moisturizers, topical steroids, topical calcineurin inhibitors,     dupliumab (Dupixent), phototherapy, and other treatments work. All of these are great and needed treatments by most patients with AD, as they can help relieve the itch, get rid of the rash, and prevent future AD flare-ups.

Most patients are very thankful for these treatments, but many also want “quick fixes” and a relief from “the way their eczema looks.” Further, undertreatment can lead to feelings of depression and suicide.² These cosmetic concerns can be taken several different ways:

1. Patient may be concerned by how rash from eczema (the inflammation) looks;
2. Patient is concerned about the postinflammatory hyper- or hypopigmentation remaining from the AD; or
3. Patient may have areas of thickened skin from scratching.

Physicians are often good at medically treating the condition, but what can we do to help our patients more instantly and for the long-term from a cosmetic perspective?

The Focus of Cosmetic Treatment
The most important treatment for all cosmetic concerns for AD is prevention. The basis of treatment of every eczema patient should revolve around gentle skin care. This includes taking short (<5 minutes), lukewarm showers, using a gentle unscented soap, and moisturizing.

When a patient has a flare-up of eczema affecting greater than 5% to 10% total body surface area, controlling it with topical steroids can be difficult. Treating AD early with oral prednisone helps relieve the flare-up much quicker. It has been shown that using oral prednisone helps decrease the eosinophil and basophil response in an inflammatory condition.³ By stopping the inflammation early and aggressively, there is less chance of postinflammatory pigmentation changes because the rash resolves sooner.

Alterations in skin pigmentation can be a source of significant emotional distress in individuals, especially those with dark skin complexion in which alterations typically present more dramatically.⁴ Postinflammatory hyperpigmentation (PIH) is caused by excess melanin deposition following an inflammatory skin disorder, such as AD. Treatment of PIH can be more difficult than treating the preceding condition. Notably, though, the most important aspect of the treatment of pigmentation alterations is time. It can take several months to years for the pigmentation to return to a more normal state, during which the patient can still experience psychosocial complications from the cosmetic appearance.⁵

Further treatment of pigmentation alterations can be challenging and should focus on decreasing inflammation, exfoliation to encourage cell turnover, and, in the case of PIH, stopping and preventing melanocytic hyperactivity as well as breaking down deposited pigment for removal or release.⁶

Treatment Options for PIH
Photoprotection. First and foremost, sun protection is critical for any improvement to occur with PIH. Without proper photoprotection, PIH can be exacerbated, adding more distress and psychosocial problems for the patient. Dermatologists should educate their patients on sun safety, including:

• Using a broad-spectrum sunscreen with a minimum sun protection factor of 30 daily;
• Covering up skin when outdoors, especially the PIH-affected areas; and
• Seek shade when outdoors, particularly when the UV radiation levels are high.

Chemical intervention. Along with sun protection measures, topical lightening therapy can be effective for improvement in the appearance of PIH.⁶ Chemical-based products, such as tretinoin, hydroquinone, azelaic acid, kojic acid, or glycolic acid, have all been used with varying success.⁴ These different ingredients are often used in combination together and have different strengths. The one big problem surrounding these ingredients is that most cause some form of irritation that is usually compounded in patients with AD. Peels should only be used when an active flare-up has been resolved and when the patient is moisturizing to prevent additional irritation.

Retinoids, such as topical tretinoin, are derived from vitamin A and can be effective either alone or in combination with other agents for the treatment of PIH. These chemical compounds exert several biological effects on PIH, including modulating cell proliferation, differentiation, and cohesiveness; inducting apoptosis; and expressing anti-inflammatory properties.⁷ 

Hydroquinone, a phenolic compound, can be an effective tool in treating PIH. This compound prevents dihydroxyphenylalanine from converting to melanin by inhibiting tyrosinase, the rate-limiting enzyme for melanin production. In addition, hydroquinone may inhibit the synthesis of DNA and RNA have selective cytotoxicity toward melanocytes, and enhance melanosome degradation.⁸ 

Azelaic acid is a dicarboxylic acid isolate derived from the fungi that causes tinea versicolor. This chemical has two main mechanisms that cause depigmentation: tyrosinase inhibition and inhibition of DNA synthesis and mitochondrial enzymes, creating selective cytotoxic and antiproliferative effects toward abnormal melanocytes. Melanin synthesis is affected by tyrosinase, so inhibiting this enzyme is important in decreasing pigmentation.^9,10

Kojic acid is a fungal metabolite of species of Acetobacter, Aspergillus, and Penicillium that inhibits tyrosinase by chelating copper at the enzyme’s active site. This action, again, inhibits the rate-limiting enzyme in melanin synthesis, causing depigmentation. It should be noted that kojic acid is often used in combination with other ingredients as more clinical studies are needed to ascertain its effectiveness.⁹

Naturally derived products. Studies have shown that products containing natural ingredients have potential as nonprescription skin care options in the management in PIH.¹¹ These ingredients include soy, niacinamide, N-acetyl glucosamine, licorice extract, arbutin, vitamin c, emblica extract, lignin peroxidase, and glutathione.

Soy reduces the phagocytosis of melanosomes into keratinocytes, thereby causing reversible depigmentation.⁷ This is possible because of soy proteins, such as soybean trypsin inhibitor and Bowman-Birk inhibitor, inhibiting the activation of the protease-activated receptor 2 cell receptors on keratinocytes.¹² Overall, soy-based products are well-tolerated, making it an attractive option as an adjunct therapy.¹³ 

Niacinamide is a derivative of niacin that decreases the transfer of melanosomes to keratinocytes without inhibiting
either tyrosinase or cell proliferation. It may also decrease melanogenesis by affecting the cell-signaling pathway between keratinocytes.¹⁴ Additionally, niacinamide is notable for its stability, which is unaffected by factors such as light and moisture.⁷ 

N-acetyl glucosamine is a monosaccharide found in chitin, hyaluronic acid, and keratin sulfate. Because it inhibits the glycosylation of tyrosinase, a critical step in melanin production, N-acetyl glucosamine is a possible adjunct therapy for depigmentation therapy.¹⁵

Licorice is abstracted from the roots of Glycyrrhiza glabra and Glycyrrhiza uralensis.⁷ The resulting licorice root extract has several active ingredients, including glabridin, which inhibits tyrosinase similarly to previously discussed compounds, and liquiritin, which causes depigmentation by melanin dispersion and removal.¹⁶ Outside of dermatology practices, licorice root extract is popular in over-the-counter products because of its anti-inflammatory, antimicrobial, antiviral, and anticarcinogenic properties.  

In the treatment of PIH, vitamin C, or ascorbic acid, acts as a depigmentation therapy by two mechanisms. First, vitamin C interacts with copper ions at the tyrosinase active site; second, it reduces oxidized dopaquinone, a substrate in the melanin synthetic pathway.¹⁷ Vitamin C is known to also have anti-inflammatory and antioxidant properties, so it may possibly support the initial treatment of inflammation of AD.

Arbutin can be extracted from a number of sources, including the dried leaves of the bearberry shrub as well as pear, cranberry, and blueberry plants. Furthermore, arbutin is a derivative of hydroquinone that has no melanotoxic effects.¹³ Because of its structural similarities to tyrosinase, arbutin is thought to act as a depigmentation therapy by competing with tyrosinase’s catalytic functions.¹⁸

Treating Thickened Skin From AD 
Treating thickened skin from AD can also prove difficult. The mainstay of treatment includes topical corticosteroids, intralesional corticosteroids, phototherapy, and, most importantly, scratching cessation.¹⁹ Patients may struggle with avoiding to scratch their AD flare-ups, and this may cause significant distress to the patient. It is recommended that dermatologists treat these patients with a psychodermatologic lens. There are also procedures, such as chemical peels and, to a lesser degree, lasers, that can lead to some improvement in thickened skin.

Superficial chemical peels are generally effective for the management of PIH by helping to remove superficial pigment in the papillary dermis.⁷ Standard options include glycolic acid 20% to 70%, salicylic acid 20% to 30%, trichloroacetic acid 10% to 25%, or Jessner’s solution.^5,7 

The effectiveness of lasers still needs to be studied extensively in clinical studies, but they pose an interesting option as an adjunct or alternative for treatment. Pigment-specific lasers, including green (510 nm, 532 nm), red (694 nm), and near-infrared (755 nm, 1064 nm), selectively target intracellular melanosomes.²⁰ Laser treatment, however, is not so simple. Due to melanin’s broad absorption spectrum (250 nm-1200 nm), the pigmented epidermis can absorb some of the energy. This may cause complications such dyschromia, blistering, and scarring.²¹ The literature does contain several successful treatments outcomes of PIH with several different laser types.⁷

Conclusion 
Ultimately, it is the cosmesis of AD that bothers most patients. The best treatment, like most of medicine, is prevention. Resolving the inflammation is the first step to treating PIH, and time, ultimately, is the cornerstone of treatment. There are a multitude of options available for treating PIH and thickened skin, and dermatologists should become familiar with each option in order to help patients achieve successful cosmetic outcomes for AD.

Dr Madan is director of cosmetic dermatology and assistant clinical professor at Zucker School of Medicine at Hofstra University/Northwell in Hempstead, NY. 

Disclosure: The author reports no relevant financial relationships.

References
1. Avena-Woods C. Overview of atopic dermatitis. Am J Manag Care. 2017;23(8 suppl):S115-S123.

2. Ribera M, Ros S, Madrid B, et al. Consensus statement on the psychological needs of patients with chronic inflammatory skin diseases. Actas Dermosifiliogr. 2019;110(2):102-114. doi:10.1016/j.ad.2018.10.007

3. Charlesworth EN, Kagey-Sobotka A, Schleimer RP, Norman PS, Lichtenstein LM. Prednisone inhibits the appearance of inflammatory mediators and the influx of eosinophils and basophils associated with the cutaneous late-phase response to allergen. J Immunol. 1991;146(2):671-676.

4. Stratigos AJ, Katsambas AD. Optimal management of recalcitrant disorders of hyperpigmentation in dark-skinned patients. Am J Clin Dermatol. 2004;5(3):161-168. doi:10.2165/00128071-200405030-00004

5. Desai SR. Hyperpigmentation therapy: a review. J Clin Aesthet Dermatol. 2014;7(8):13-17.

6. Sofen B, Prado G, Emer J. Melasma and post inflammatory hyperpigmentation: management update and expert opinion. Skin Therapy Lett. 2016;21(1):1-7.

7. Davis EC, Callender VD. Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color. J Clin Aesthet Dermatol. 2010;3(7):20-31.

8. Ebanks JP, Wickett RR, Boissy RE. Mechanisms regulating skin pigmentation: the rise and fall of complexion coloration. Int J Mol Sci. 2009;10(9):4066-4087. doi:10.3390/ijms10094066

9. Shokeen D. Postinflammatory hyperpigmentation in patients with skin of color. Cutis. 2016;97(1):E9-E11.

10. Iozumi K, Hoganson GE, Pennella R, Everett MA, Fuller BB. Role of tyrosinase as the determinant of pigmentation in cultured human melanocytes. J Invest Dermatol. 1993;100(6):806-811. doi:10.1111/1523-1747.ep12476630

11. Alexis AF, Blackcloud P. Natural ingredients for darker skin types: growing options for hyperpigmentation. J Drugs Dermatol. 2013;12(9 suppl):S123-S127.

12. Paine C, Sharlow E, Liebel F, Eisinger M, Shapiro S, Seiberg M. An alternative approach to depigmentation by soybean extracts via inhibition of the PAR-2 pathway.
J Invest Dermatol. 2001;116(4):587-595. doi: 10.1046/j.1523-1747.2001.01291.x

13. Draelos ZD. Skin lightening preparation and the hydroquinone controversy. Dermatol Ther. 2007;20(5):308-313. doi:10.111/j.1529-8019.2007.00144.x

14. Hakozaki T, Minwalla L, Zhuang J, et al. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol. 2002;147(1):20-31. doi:10.1046/j.1365-2133.2002.04834.x 

15. Bissett DL, Robinson LR, Raleigh PS, et al. Reduction in the appearance of facial hyperpigmentation by topical N-acetyl glucosamine. J Cosmet Dermatol. 2007;6(1):20-26. doi:10.1111/j.1473-2165.2007.00295.x 

16. Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigment Cell Res. 1998;11(6):355-361. doi:10.1111/j.1600-0749.1998.tb00494.x

17. Badreshia-Bansal S, Draelos ZD. Insight into skin lightening cosmeceuticals for women of color. J Drugs Dermatol. 2007;6(1):32-39. 

18. Zhu W, Gao J. The use of botanical extracts as topical skin-lightening agents for the improvement of skin pigmentation disorders. J Investig Dermatol Symp Proc. 2008;13(1):20-24. doi:10.1038/jidsymp.2008.8 

19. Lotti T, Buggiani G, Prignano F. Prurigo nodularis and lichen simplex chronicus. Dermatol Ther. 2008;21(1):42-46. doi:10.1111/j.1529-8019.2008.00168.x

20. Alster TS, Tanzi EL. Laser surgery in dark skin. Skinmed. 2003;2(2):80-85. doi:10.1111/j.1540-9740.2003.01664.x

21. Battle EF Jr, Hobbs LM. Laser therapy on darker ethnic skin. Dermatol Clin. 2003;21(4):713-723. doi:10.1016/s0733-8635(03)00086-x

Atopic dermatitis (AD) affects 15% to 20% of children and 1% to 3% of adults worldwide.¹ It is a condition that every dermatologist is familiar with treating. Currently, most treatments focus more on the medical management behind AD; this is why moisturizers, topical steroids, topical calcineurin inhibitors,     dupliumab (Dupixent), phototherapy, and other treatments work. All of these are great and needed treatments by most patients with AD, as they can help relieve the itch, get rid of the rash, and prevent future AD flare-ups.

Most patients are very thankful for these treatments, but many also want “quick fixes” and a relief from “the way their eczema looks.” Further, undertreatment can lead to feelings of depression and suicide.² These cosmetic concerns can be taken several different ways:

1. Patient may be concerned by how rash from eczema (the inflammation) looks;
2. Patient is concerned about the postinflammatory hyper- or hypopigmentation remaining from the AD; or
3. Patient may have areas of thickened skin from scratching.

Physicians are often good at medically treating the condition, but what can we do to help our patients more instantly and for the long-term from a cosmetic perspective?

The Focus of Cosmetic Treatment
The most important treatment for all cosmetic concerns for AD is prevention. The basis of treatment of every eczema patient should revolve around gentle skin care. This includes taking short (<5 minutes), lukewarm showers, using a gentle unscented soap, and moisturizing.

When a patient has a flare-up of eczema affecting greater than 5% to 10% total body surface area, controlling it with topical steroids can be difficult. Treating AD early with oral prednisone helps relieve the flare-up much quicker. It has been shown that using oral prednisone helps decrease the eosinophil and basophil response in an inflammatory condition.³ By stopping the inflammation early and aggressively, there is less chance of postinflammatory pigmentation changes because the rash resolves sooner.

Alterations in skin pigmentation can be a source of significant emotional distress in individuals, especially those with dark skin complexion in which alterations typically present more dramatically.⁴ Postinflammatory hyperpigmentation (PIH) is caused by excess melanin deposition following an inflammatory skin disorder, such as AD. Treatment of PIH can be more difficult than treating the preceding condition. Notably, though, the most important aspect of the treatment of pigmentation alterations is time. It can take several months to years for the pigmentation to return to a more normal state, during which the patient can still experience psychosocial complications from the cosmetic appearance.⁵

Further treatment of pigmentation alterations can be challenging and should focus on decreasing inflammation, exfoliation to encourage cell turnover, and, in the case of PIH, stopping and preventing melanocytic hyperactivity as well as breaking down deposited pigment for removal or release.⁶

Treatment Options for PIH
Photoprotection. First and foremost, sun protection is critical for any improvement to occur with PIH. Without proper photoprotection, PIH can be exacerbated, adding more distress and psychosocial problems for the patient. Dermatologists should educate their patients on sun safety, including:

• Using a broad-spectrum sunscreen with a minimum sun protection factor of 30 daily;
• Covering up skin when outdoors, especially the PIH-affected areas; and
• Seek shade when outdoors, particularly when the UV radiation levels are high.

Chemical intervention. Along with sun protection measures, topical lightening therapy can be effective for improvement in the appearance of PIH.⁶ Chemical-based products, such as tretinoin, hydroquinone, azelaic acid, kojic acid, or glycolic acid, have all been used with varying success.⁴ These different ingredients are often used in combination together and have different strengths. The one big problem surrounding these ingredients is that most cause some form of irritation that is usually compounded in patients with AD. Peels should only be used when an active flare-up has been resolved and when the patient is moisturizing to prevent additional irritation.

Retinoids, such as topical tretinoin, are derived from vitamin A and can be effective either alone or in combination with other agents for the treatment of PIH. These chemical compounds exert several biological effects on PIH, including modulating cell proliferation, differentiation, and cohesiveness; inducting apoptosis; and expressing anti-inflammatory properties.⁷ 

Hydroquinone, a phenolic compound, can be an effective tool in treating PIH. This compound prevents dihydroxyphenylalanine from converting to melanin by inhibiting tyrosinase, the rate-limiting enzyme for melanin production. In addition, hydroquinone may inhibit the synthesis of DNA and RNA have selective cytotoxicity toward melanocytes, and enhance melanosome degradation.⁸ 

Azelaic acid is a dicarboxylic acid isolate derived from the fungi that causes tinea versicolor. This chemical has two main mechanisms that cause depigmentation: tyrosinase inhibition and inhibition of DNA synthesis and mitochondrial enzymes, creating selective cytotoxic and antiproliferative effects toward abnormal melanocytes. Melanin synthesis is affected by tyrosinase, so inhibiting this enzyme is important in decreasing pigmentation.^9,10

Kojic acid is a fungal metabolite of species of Acetobacter, Aspergillus, and Penicillium that inhibits tyrosinase by chelating copper at the enzyme’s active site. This action, again, inhibits the rate-limiting enzyme in melanin synthesis, causing depigmentation. It should be noted that kojic acid is often used in combination with other ingredients as more clinical studies are needed to ascertain its effectiveness.⁹

Atopic dermatitis (AD) affects 15% to 20% of children and 1% to 3% of adults worldwide.¹ It is a condition that every dermatologist is familiar with treating. Currently, most treatments focus more on the medical management behind AD; this is why moisturizers, topical steroids, topical calcineurin inhibitors,     dupliumab (Dupixent), phototherapy, and other treatments work. All of these are great and needed treatments by most patients with AD, as they can help relieve the itch, get rid of the rash, and prevent future AD flare-ups.

Most patients are very thankful for these treatments, but many also want “quick fixes” and a relief from “the way their eczema looks.” Further, undertreatment can lead to feelings of depression and suicide.² These cosmetic concerns can be taken several different ways:

1. Patient may be concerned by how rash from eczema (the inflammation) looks;
2. Patient is concerned about the postinflammatory hyper- or hypopigmentation remaining from the AD; or
3. Patient may have areas of thickened skin from scratching.

Physicians are often good at medically treating the condition, but what can we do to help our patients more instantly and for the long-term from a cosmetic perspective?

The Focus of Cosmetic Treatment
The most important treatment for all cosmetic concerns for AD is prevention. The basis of treatment of every eczema patient should revolve around gentle skin care. This includes taking short (<5 minutes), lukewarm showers, using a gentle unscented soap, and moisturizing.

When a patient has a flare-up of eczema affecting greater than 5% to 10% total body surface area, controlling it with topical steroids can be difficult. Treating AD early with oral prednisone helps relieve the flare-up much quicker. It has been shown that using oral prednisone helps decrease the eosinophil and basophil response in an inflammatory condition.³ By stopping the inflammation early and aggressively, there is less chance of postinflammatory pigmentation changes because the rash resolves sooner.

Alterations in skin pigmentation can be a source of significant emotional distress in individuals, especially those with dark skin complexion in which alterations typically present more dramatically.⁴ Postinflammatory hyperpigmentation (PIH) is caused by excess melanin deposition following an inflammatory skin disorder, such as AD. Treatment of PIH can be more difficult than treating the preceding condition. Notably, though, the most important aspect of the treatment of pigmentation alterations is time. It can take several months to years for the pigmentation to return to a more normal state, during which the patient can still experience psychosocial complications from the cosmetic appearance.⁵

Further treatment of pigmentation alterations can be challenging and should focus on decreasing inflammation, exfoliation to encourage cell turnover, and, in the case of PIH, stopping and preventing melanocytic hyperactivity as well as breaking down deposited pigment for removal or release.⁶

Treatment Options for PIH
Photoprotection. First and foremost, sun protection is critical for any improvement to occur with PIH. Without proper photoprotection, PIH can be exacerbated, adding more distress and psychosocial problems for the patient. Dermatologists should educate their patients on sun safety, including:

• Using a broad-spectrum sunscreen with a minimum sun protection factor of 30 daily;
• Covering up skin when outdoors, especially the PIH-affected areas; and
• Seek shade when outdoors, particularly when the UV radiation levels are high.

Chemical intervention. Along with sun protection measures, topical lightening therapy can be effective for improvement in the appearance of PIH.⁶ Chemical-based products, such as tretinoin, hydroquinone, azelaic acid, kojic acid, or glycolic acid, have all been used with varying success.⁴ These different ingredients are often used in combination together and have different strengths. The one big problem surrounding these ingredients is that most cause some form of irritation that is usually compounded in patients with AD. Peels should only be used when an active flare-up has been resolved and when the patient is moisturizing to prevent additional irritation.

Retinoids, such as topical tretinoin, are derived from vitamin A and can be effective either alone or in combination with other agents for the treatment of PIH. These chemical compounds exert several biological effects on PIH, including modulating cell proliferation, differentiation, and cohesiveness; inducting apoptosis; and expressing anti-inflammatory properties.⁷ 

Hydroquinone, a phenolic compound, can be an effective tool in treating PIH. This compound prevents dihydroxyphenylalanine from converting to melanin by inhibiting tyrosinase, the rate-limiting enzyme for melanin production. In addition, hydroquinone may inhibit the synthesis of DNA and RNA have selective cytotoxicity toward melanocytes, and enhance melanosome degradation.⁸ 

Azelaic acid is a dicarboxylic acid isolate derived from the fungi that causes tinea versicolor. This chemical has two main mechanisms that cause depigmentation: tyrosinase inhibition and inhibition of DNA synthesis and mitochondrial enzymes, creating selective cytotoxic and antiproliferative effects toward abnormal melanocytes. Melanin synthesis is affected by tyrosinase, so inhibiting this enzyme is important in decreasing pigmentation.^9,10

Kojic acid is a fungal metabolite of species of Acetobacter, Aspergillus, and Penicillium that inhibits tyrosinase by chelating copper at the enzyme’s active site. This action, again, inhibits the rate-limiting enzyme in melanin synthesis, causing depigmentation. It should be noted that kojic acid is often used in combination with other ingredients as more clinical studies are needed to ascertain its effectiveness.⁹

Naturally derived products. Studies have shown that products containing natural ingredients have potential as nonprescription skin care options in the management in PIH.¹¹ These ingredients include soy, niacinamide, N-acetyl glucosamine, licorice extract, arbutin, vitamin c, emblica extract, lignin peroxidase, and glutathione.

Soy reduces the phagocytosis of melanosomes into keratinocytes, thereby causing reversible depigmentation.⁷ This is possible because of soy proteins, such as soybean trypsin inhibitor and Bowman-Birk inhibitor, inhibiting the activation of the protease-activated receptor 2 cell receptors on keratinocytes.¹² Overall, soy-based products are well-tolerated, making it an attractive option as an adjunct therapy.¹³ 

Niacinamide is a derivative of niacin that decreases the transfer of melanosomes to keratinocytes without inhibiting
either tyrosinase or cell proliferation. It may also decrease melanogenesis by affecting the cell-signaling pathway between keratinocytes.¹⁴ Additionally, niacinamide is notable for its stability, which is unaffected by factors such as light and moisture.⁷ 

N-acetyl glucosamine is a monosaccharide found in chitin, hyaluronic acid, and keratin sulfate. Because it inhibits the glycosylation of tyrosinase, a critical step in melanin production, N-acetyl glucosamine is a possible adjunct therapy for depigmentation therapy.¹⁵

Licorice is abstracted from the roots of Glycyrrhiza glabra and Glycyrrhiza uralensis.⁷ The resulting licorice root extract has several active ingredients, including glabridin, which inhibits tyrosinase similarly to previously discussed compounds, and liquiritin, which causes depigmentation by melanin dispersion and removal.¹⁶ Outside of dermatology practices, licorice root extract is popular in over-the-counter products because of its anti-inflammatory, antimicrobial, antiviral, and anticarcinogenic properties.  

In the treatment of PIH, vitamin C, or ascorbic acid, acts as a depigmentation therapy by two mechanisms. First, vitamin C interacts with copper ions at the tyrosinase active site; second, it reduces oxidized dopaquinone, a substrate in the melanin synthetic pathway.¹⁷ Vitamin C is known to also have anti-inflammatory and antioxidant properties, so it may possibly support the initial treatment of inflammation of AD.

Arbutin can be extracted from a number of sources, including the dried leaves of the bearberry shrub as well as pear, cranberry, and blueberry plants. Furthermore, arbutin is a derivative of hydroquinone that has no melanotoxic effects.¹³ Because of its structural similarities to tyrosinase, arbutin is thought to act as a depigmentation therapy by competing with tyrosinase’s catalytic functions.¹⁸

Treating Thickened Skin From AD 
Treating thickened skin from AD can also prove difficult. The mainstay of treatment includes topical corticosteroids, intralesional corticosteroids, phototherapy, and, most importantly, scratching cessation.¹⁹ Patients may struggle with avoiding to scratch their AD flare-ups, and this may cause significant distress to the patient. It is recommended that dermatologists treat these patients with a psychodermatologic lens. There are also procedures, such as chemical peels and, to a lesser degree, lasers, that can lead to some improvement in thickened skin.

Superficial chemical peels are generally effective for the management of PIH by helping to remove superficial pigment in the papillary dermis.⁷ Standard options include glycolic acid 20% to 70%, salicylic acid 20% to 30%, trichloroacetic acid 10% to 25%, or Jessner’s solution.^5,7 

The effectiveness of lasers still needs to be studied extensively in clinical studies, but they pose an interesting option as an adjunct or alternative for treatment. Pigment-specific lasers, including green (510 nm, 532 nm), red (694 nm), and near-infrared (755 nm, 1064 nm), selectively target intracellular melanosomes.²⁰ Laser treatment, however, is not so simple. Due to melanin’s broad absorption spectrum (250 nm-1200 nm), the pigmented epidermis can absorb some of the energy. This may cause complications such dyschromia, blistering, and scarring.²¹ The literature does contain several successful treatments outcomes of PIH with several different laser types.⁷

Conclusion 
Ultimately, it is the cosmesis of AD that bothers most patients. The best treatment, like most of medicine, is prevention. Resolving the inflammation is the first step to treating PIH, and time, ultimately, is the cornerstone of treatment. There are a multitude of options available for treating PIH and thickened skin, and dermatologists should become familiar with each option in order to help patients achieve successful cosmetic outcomes for AD.

Dr Madan is director of cosmetic dermatology and assistant clinical professor at Zucker School of Medicine at Hofstra University/Northwell in Hempstead, NY. 

Disclosure: The author reports no relevant financial relationships.

References
1. Avena-Woods C. Overview of atopic dermatitis. Am J Manag Care. 2017;23(8 suppl):S115-S123.

2. Ribera M, Ros S, Madrid B, et al. Consensus statement on the psychological needs of patients with chronic inflammatory skin diseases. Actas Dermosifiliogr. 2019;110(2):102-114. doi:10.1016/j.ad.2018.10.007

3. Charlesworth EN, Kagey-Sobotka A, Schleimer RP, Norman PS, Lichtenstein LM. Prednisone inhibits the appearance of inflammatory mediators and the influx of eosinophils and basophils associated with the cutaneous late-phase response to allergen. J Immunol. 1991;146(2):671-676.

4. Stratigos AJ, Katsambas AD. Optimal management of recalcitrant disorders of hyperpigmentation in dark-skinned patients. Am J Clin Dermatol. 2004;5(3):161-168. doi:10.2165/00128071-200405030-00004

5. Desai SR. Hyperpigmentation therapy: a review. J Clin Aesthet Dermatol. 2014;7(8):13-17.

6. Sofen B, Prado G, Emer J. Melasma and post inflammatory hyperpigmentation: management update and expert opinion. Skin Therapy Lett. 2016;21(1):1-7.

7. Davis EC, Callender VD. Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color. J Clin Aesthet Dermatol. 2010;3(7):20-31.

8. Ebanks JP, Wickett RR, Boissy RE. Mechanisms regulating skin pigmentation: the rise and fall of complexion coloration. Int J Mol Sci. 2009;10(9):4066-4087. doi:10.3390/ijms10094066

9. Shokeen D. Postinflammatory hyperpigmentation in patients with skin of color. Cutis. 2016;97(1):E9-E11.

10. Iozumi K, Hoganson GE, Pennella R, Everett MA, Fuller BB. Role of tyrosinase as the determinant of pigmentation in cultured human melanocytes. J Invest Dermatol. 1993;100(6):806-811. doi:10.1111/1523-1747.ep12476630

11. Alexis AF, Blackcloud P. Natural ingredients for darker skin types: growing options for hyperpigmentation. J Drugs Dermatol. 2013;12(9 suppl):S123-S127.

12. Paine C, Sharlow E, Liebel F, Eisinger M, Shapiro S, Seiberg M. An alternative approach to depigmentation by soybean extracts via inhibition of the PAR-2 pathway.
J Invest Dermatol. 2001;116(4):587-595. doi: 10.1046/j.1523-1747.2001.01291.x

13. Draelos ZD. Skin lightening preparation and the hydroquinone controversy. Dermatol Ther. 2007;20(5):308-313. doi:10.111/j.1529-8019.2007.00144.x

14. Hakozaki T, Minwalla L, Zhuang J, et al. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol. 2002;147(1):20-31. doi:10.1046/j.1365-2133.2002.04834.x 

15. Bissett DL, Robinson LR, Raleigh PS, et al. Reduction in the appearance of facial hyperpigmentation by topical N-acetyl glucosamine. J Cosmet Dermatol. 2007;6(1):20-26. doi:10.1111/j.1473-2165.2007.00295.x 

16. Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigment Cell Res. 1998;11(6):355-361. doi:10.1111/j.1600-0749.1998.tb00494.x

17. Badreshia-Bansal S, Draelos ZD. Insight into skin lightening cosmeceuticals for women of color. J Drugs Dermatol. 2007;6(1):32-39. 

18. Zhu W, Gao J. The use of botanical extracts as topical skin-lightening agents for the improvement of skin pigmentation disorders. J Investig Dermatol Symp Proc. 2008;13(1):20-24. doi:10.1038/jidsymp.2008.8 

19. Lotti T, Buggiani G, Prignano F. Prurigo nodularis and lichen simplex chronicus. Dermatol Ther. 2008;21(1):42-46. doi:10.1111/j.1529-8019.2008.00168.x

20. Alster TS, Tanzi EL. Laser surgery in dark skin. Skinmed. 2003;2(2):80-85. doi:10.1111/j.1540-9740.2003.01664.x

21. Battle EF Jr, Hobbs LM. Laser therapy on darker ethnic skin. Dermatol Clin. 2003;21(4):713-723. doi:10.1016/s0733-8635(03)00086-x

Naturally derived products. Studies have shown that products containing natural ingredients have potential as nonprescription skin care options in the management in PIH.¹¹ These ingredients include soy, niacinamide, N-acetyl glucosamine, licorice extract, arbutin, vitamin c, emblica extract, lignin peroxidase, and glutathione.

Soy reduces the phagocytosis of melanosomes into keratinocytes, thereby causing reversible depigmentation.⁷ This is possible because of soy proteins, such as soybean trypsin inhibitor and Bowman-Birk inhibitor, inhibiting the activation of the protease-activated receptor 2 cell receptors on keratinocytes.¹² Overall, soy-based products are well-tolerated, making it an attractive option as an adjunct therapy.¹³ 

Niacinamide is a derivative of niacin that decreases the transfer of melanosomes to keratinocytes without inhibiting
either tyrosinase or cell proliferation. It may also decrease melanogenesis by affecting the cell-signaling pathway between keratinocytes.¹⁴ Additionally, niacinamide is notable for its stability, which is unaffected by factors such as light and moisture.⁷ 

N-acetyl glucosamine is a monosaccharide found in chitin, hyaluronic acid, and keratin sulfate. Because it inhibits the glycosylation of tyrosinase, a critical step in melanin production, N-acetyl glucosamine is a possible adjunct therapy for depigmentation therapy.¹⁵

Licorice is abstracted from the roots of Glycyrrhiza glabra and Glycyrrhiza uralensis.⁷ The resulting licorice root extract has several active ingredients, including glabridin, which inhibits tyrosinase similarly to previously discussed compounds, and liquiritin, which causes depigmentation by melanin dispersion and removal.¹⁶ Outside of dermatology practices, licorice root extract is popular in over-the-counter products because of its anti-inflammatory, antimicrobial, antiviral, and anticarcinogenic properties.  

In the treatment of PIH, vitamin C, or ascorbic acid, acts as a depigmentation therapy by two mechanisms. First, vitamin C interacts with copper ions at the tyrosinase active site; second, it reduces oxidized dopaquinone, a substrate in the melanin synthetic pathway.¹⁷ Vitamin C is known to also have anti-inflammatory and antioxidant properties, so it may possibly support the initial treatment of inflammation of AD.

Arbutin can be extracted from a number of sources, including the dried leaves of the bearberry shrub as well as pear, cranberry, and blueberry plants. Furthermore, arbutin is a derivative of hydroquinone that has no melanotoxic effects.¹³ Because of its structural similarities to tyrosinase, arbutin is thought to act as a depigmentation therapy by competing with tyrosinase’s catalytic functions.¹⁸

Treating Thickened Skin From AD 
Treating thickened skin from AD can also prove difficult. The mainstay of treatment includes topical corticosteroids, intralesional corticosteroids, phototherapy, and, most importantly, scratching cessation.¹⁹ Patients may struggle with avoiding to scratch their AD flare-ups, and this may cause significant distress to the patient. It is recommended that dermatologists treat these patients with a psychodermatologic lens. There are also procedures, such as chemical peels and, to a lesser degree, lasers, that can lead to some improvement in thickened skin.

Superficial chemical peels are generally effective for the management of PIH by helping to remove superficial pigment in the papillary dermis.⁷ Standard options include glycolic acid 20% to 70%, salicylic acid 20% to 30%, trichloroacetic acid 10% to 25%, or Jessner’s solution.^5,7 

The effectiveness of lasers still needs to be studied extensively in clinical studies, but they pose an interesting option as an adjunct or alternative for treatment. Pigment-specific lasers, including green (510 nm, 532 nm), red (694 nm), and near-infrared (755 nm, 1064 nm), selectively target intracellular melanosomes.²⁰ Laser treatment, however, is not so simple. Due to melanin’s broad absorption spectrum (250 nm-1200 nm), the pigmented epidermis can absorb some of the energy. This may cause complications such dyschromia, blistering, and scarring.²¹ The literature does contain several successful treatments outcomes of PIH with several different laser types.⁷

Conclusion 
Ultimately, it is the cosmesis of AD that bothers most patients. The best treatment, like most of medicine, is prevention. Resolving the inflammation is the first step to treating PIH, and time, ultimately, is the cornerstone of treatment. There are a multitude of options available for treating PIH and thickened skin, and dermatologists should become familiar with each option in order to help patients achieve successful cosmetic outcomes for AD.

Dr Madan is director of cosmetic dermatology and assistant clinical professor at Zucker School of Medicine at Hofstra University/Northwell in Hempstead, NY. 

Disclosure: The author reports no relevant financial relationships.

References
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2. Ribera M, Ros S, Madrid B, et al. Consensus statement on the psychological needs of patients with chronic inflammatory skin diseases. Actas Dermosifiliogr. 2019;110(2):102-114. doi:10.1016/j.ad.2018.10.007

3. Charlesworth EN, Kagey-Sobotka A, Schleimer RP, Norman PS, Lichtenstein LM. Prednisone inhibits the appearance of inflammatory mediators and the influx of eosinophils and basophils associated with the cutaneous late-phase response to allergen. J Immunol. 1991;146(2):671-676.

4. Stratigos AJ, Katsambas AD. Optimal management of recalcitrant disorders of hyperpigmentation in dark-skinned patients. Am J Clin Dermatol. 2004;5(3):161-168. doi:10.2165/00128071-200405030-00004

5. Desai SR. Hyperpigmentation therapy: a review. J Clin Aesthet Dermatol. 2014;7(8):13-17.

6. Sofen B, Prado G, Emer J. Melasma and post inflammatory hyperpigmentation: management update and expert opinion. Skin Therapy Lett. 2016;21(1):1-7.

7. Davis EC, Callender VD. Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color. J Clin Aesthet Dermatol. 2010;3(7):20-31.

8. Ebanks JP, Wickett RR, Boissy RE. Mechanisms regulating skin pigmentation: the rise and fall of complexion coloration. Int J Mol Sci. 2009;10(9):4066-4087. doi:10.3390/ijms10094066

9. Shokeen D. Postinflammatory hyperpigmentation in patients with skin of color. Cutis. 2016;97(1):E9-E11.

10. Iozumi K, Hoganson GE, Pennella R, Everett MA, Fuller BB. Role of tyrosinase as the determinant of pigmentation in cultured human melanocytes. J Invest Dermatol. 1993;100(6):806-811. doi:10.1111/1523-1747.ep12476630

11. Alexis AF, Blackcloud P. Natural ingredients for darker skin types: growing options for hyperpigmentation. J Drugs Dermatol. 2013;12(9 suppl):S123-S127.

12. Paine C, Sharlow E, Liebel F, Eisinger M, Shapiro S, Seiberg M. An alternative approach to depigmentation by soybean extracts via inhibition of the PAR-2 pathway.
J Invest Dermatol. 2001;116(4):587-595. doi: 10.1046/j.1523-1747.2001.01291.x

13. Draelos ZD. Skin lightening preparation and the hydroquinone controversy. Dermatol Ther. 2007;20(5):308-313. doi:10.111/j.1529-8019.2007.00144.x

14. Hakozaki T, Minwalla L, Zhuang J, et al. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol. 2002;147(1):20-31. doi:10.1046/j.1365-2133.2002.04834.x 

15. Bissett DL, Robinson LR, Raleigh PS, et al. Reduction in the appearance of facial hyperpigmentation by topical N-acetyl glucosamine. J Cosmet Dermatol. 2007;6(1):20-26. doi:10.1111/j.1473-2165.2007.00295.x 

16. Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigment Cell Res. 1998;11(6):355-361. doi:10.1111/j.1600-0749.1998.tb00494.x

17. Badreshia-Bansal S, Draelos ZD. Insight into skin lightening cosmeceuticals for women of color. J Drugs Dermatol. 2007;6(1):32-39. 

18. Zhu W, Gao J. The use of botanical extracts as topical skin-lightening agents for the improvement of skin pigmentation disorders. J Investig Dermatol Symp Proc. 2008;13(1):20-24. doi:10.1038/jidsymp.2008.8 

19. Lotti T, Buggiani G, Prignano F. Prurigo nodularis and lichen simplex chronicus. Dermatol Ther. 2008;21(1):42-46. doi:10.1111/j.1529-8019.2008.00168.x

20. Alster TS, Tanzi EL. Laser surgery in dark skin. Skinmed. 2003;2(2):80-85. doi:10.1111/j.1540-9740.2003.01664.x

21. Battle EF Jr, Hobbs LM. Laser therapy on darker ethnic skin. Dermatol Clin. 2003;21(4):713-723. doi:10.1016/s0733-8635(03)00086-x