Divya Shokeen, MD

CenterWatch (http://www.centerwatch.com/) is an online resource that provides directories, analysis, and market research of medications that are either under clinical evaluation or available for use in patients. A list of currently approved drugs by the US Food and Drug Administration (FDA) also is available by specialty. It is important for dermatologists in-training to know about recently approved drugs and those that are in the pipeline, as these treatments may benefit patients who are unresponsive to other previously used medications. New drugs also may be useful for physicians who have a difficult time getting insurance to cover prescriptions for their patients, as most new medications have built-in patient assistance.

New Drugs in Dermatology

Actinic Keratosis

Ameluz (aminolevulinic acid hydrochloride)(Biofrontera AG) is a new drug that was approved in May 2016 for treatment of mild to moderate actinic keratosis on the face and scalp.¹ It is only intended for in-office use on patients who may not be candidates for other treatment options for actinic keratosis. The product is a gel formulation that should be applied to cover the lesions and approximately 5 mm of the surrounding area with a film of approximately 1-mm thickness. The entire treatment area is then illuminated with a red light source, either with a narrow spectrum around 630 nm with a light dose of approximately 37 J/cm² or a broader and continuous spectrum in the range of 570 to 670 nm with a light dose between 75 and 200 J/cm².¹ Similar to the previously used aminolevulinic acid treatment method for actinic keratosis, the patient may experience a burning stinging sensation throughout the treatment and the skin will then proceed to peel.

Psoriasis and Psoriatic Arthritis

Taltz (ixekizumab)(Eli Lilly and Company) was approved by the FDA in March 2016 for the treatment of moderate to severe plaque psoriasis.² It is a humanized IL-17A antagonist that works when IgG4 monoclonal antibodies selectively bind with IL-17A cytokines and inhibit their interaction with the IL-17 receptor. Although this injectable medication is approved for the treatment of psoriasis, it also can potentially be used off label for the treatment of psoriatic arthritis and rheumatoid arthritis. The approved dosage is 160 mg (two 80-mg injections) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks.² Injectable immunomodulatory medications such as ixekizumab are ideal for patients in whom topical treatments and light therapy failed and they continue to have serious psoriatic discomfort as well as for those who have substantial body surface area coverage.

Melanoma

Cotellic (cobimetinib)(Genentech USA, Inc) was FDA approved in November 2015.⁴ Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1. Mitogen-activated protein kinase MEK1 and MEK2 are regulators of the extracellular signal-­related kinase pathway, which promotes cellular proliferation. This pathway is key, as melanomas that have a BRAF V600E and kinase mutation continue to proliferate due to the constitutive activation of MEK1 and MEK2, further promoting cellular proliferation. Cobimetinib is approved for the treatment of melanoma in patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in conjunction with vemurafenib. Zelboraf (vemurafenib)(Genentech USA, Inc), another inhibitor of BRAF V600E, also is used for the treatment of unresectable melanomas and was initially approved in 2011.⁵

BRAF is a serine/threonine protein kinase. When unregulated, it results in the deregulation of cell proliferation. According to Ascierto et al,⁶ 50% of melanomas have a BRAF mutation, with nearly 90% of them with a V600E mutation. Hence, since the advent of direct chemotherapeutic agents such as BRAF inhibitors, clinical trials have shown notable reduction in mortality and morbidity of melanoma patients with BRAF mutations.⁶

Imlygic (talimogene laherparepvec)(Amgen, Inc) is a modified oncolytic viral therapy.⁷ This treatment was approved by the FDA in 2015 and replicates within tumors to produce granulocyte-macrophage colony-stimulating factor protein, which promotes an antitumor immune response within unresectable cutaneous, subcutaneous, and nodal melanoma lesions. Although it is not a gene-directed therapy, the melanoma does not require a specific mutation for treatment. Again, this medication is better served in conjunction with other melanoma chemotherapeutic and surgical interventions.

Submental Fat

Kybella (deoxycholic acid)(Allergan) is a nonhuman, nonanimal, synthetically created compound that is naturally found within the human body for the breakdown and absorption of dietary fat.⁸ This drug was FDA approved in 2015 for the improvement of the appearance of moderate subcutaneous fat under the chin. Patients are evaluated in clinic to determine if the submental fat would be responsive to an injectable or require more radical surgical intervention based on desired outcomes. The treatment is administered as 0.2-mL injections (up to a total of 10 mL) spaced 1-cm apart and ideally is repeated at regular intervals to evaluate for efficacy.

Basal Cell Carcinoma

Odomzo (sonidegib)(Novartis Corporation) was FDA approved in 2015 for locally advanced basal cell carcinoma.⁹ Odomzo is a smoothened antagonist that inhibits the hedgehog signaling pathway. Smoothened is a transmembrane protein that allows for signal transduction of hedgehog proteins.¹⁰ Protein patched homolog 1 binds to smoothened protein and prevents the signal transduction through the cell for Gli family zinc factor 1 to continue protein translation; however, when PTCH is mutated and can no longer bind to smoothened, tumor formation results, specifically basal cell carcinoma. Hence, sonidegib is for the treatment of basal cell carcinomas that have persisted despite radiation treatment and/or surgery as well as for patients who have multiple basal cell carcinomas that can no longer be treated with surgery or radiation.

Final Thoughts

Overall, although there are several medications that can be used in conjunction for treatment of dermatological conditions, it always is recommended to know what is in the pipeline as FDA-approved medications for dermatology.

CenterWatch (http://www.centerwatch.com/) is an online resource that provides directories, analysis, and market research of medications that are either under clinical evaluation or available for use in patients. A list of currently approved drugs by the US Food and Drug Administration (FDA) also is available by specialty. It is important for dermatologists in-training to know about recently approved drugs and those that are in the pipeline, as these treatments may benefit patients who are unresponsive to other previously used medications. New drugs also may be useful for physicians who have a difficult time getting insurance to cover prescriptions for their patients, as most new medications have built-in patient assistance.

New Drugs in Dermatology

Actinic Keratosis

Ameluz (aminolevulinic acid hydrochloride)(Biofrontera AG) is a new drug that was approved in May 2016 for treatment of mild to moderate actinic keratosis on the face and scalp.¹ It is only intended for in-office use on patients who may not be candidates for other treatment options for actinic keratosis. The product is a gel formulation that should be applied to cover the lesions and approximately 5 mm of the surrounding area with a film of approximately 1-mm thickness. The entire treatment area is then illuminated with a red light source, either with a narrow spectrum around 630 nm with a light dose of approximately 37 J/cm² or a broader and continuous spectrum in the range of 570 to 670 nm with a light dose between 75 and 200 J/cm².¹ Similar to the previously used aminolevulinic acid treatment method for actinic keratosis, the patient may experience a burning stinging sensation throughout the treatment and the skin will then proceed to peel.

Psoriasis and Psoriatic Arthritis

Taltz (ixekizumab)(Eli Lilly and Company) was approved by the FDA in March 2016 for the treatment of moderate to severe plaque psoriasis.² It is a humanized IL-17A antagonist that works when IgG4 monoclonal antibodies selectively bind with IL-17A cytokines and inhibit their interaction with the IL-17 receptor. Although this injectable medication is approved for the treatment of psoriasis, it also can potentially be used off label for the treatment of psoriatic arthritis and rheumatoid arthritis. The approved dosage is 160 mg (two 80-mg injections) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks.² Injectable immunomodulatory medications such as ixekizumab are ideal for patients in whom topical treatments and light therapy failed and they continue to have serious psoriatic discomfort as well as for those who have substantial body surface area coverage.

Melanoma

Cotellic (cobimetinib)(Genentech USA, Inc) was FDA approved in November 2015.⁴ Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1. Mitogen-activated protein kinase MEK1 and MEK2 are regulators of the extracellular signal-­related kinase pathway, which promotes cellular proliferation. This pathway is key, as melanomas that have a BRAF V600E and kinase mutation continue to proliferate due to the constitutive activation of MEK1 and MEK2, further promoting cellular proliferation. Cobimetinib is approved for the treatment of melanoma in patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in conjunction with vemurafenib. Zelboraf (vemurafenib)(Genentech USA, Inc), another inhibitor of BRAF V600E, also is used for the treatment of unresectable melanomas and was initially approved in 2011.⁵

BRAF is a serine/threonine protein kinase. When unregulated, it results in the deregulation of cell proliferation. According to Ascierto et al,⁶ 50% of melanomas have a BRAF mutation, with nearly 90% of them with a V600E mutation. Hence, since the advent of direct chemotherapeutic agents such as BRAF inhibitors, clinical trials have shown notable reduction in mortality and morbidity of melanoma patients with BRAF mutations.⁶

Imlygic (talimogene laherparepvec)(Amgen, Inc) is a modified oncolytic viral therapy.⁷ This treatment was approved by the FDA in 2015 and replicates within tumors to produce granulocyte-macrophage colony-stimulating factor protein, which promotes an antitumor immune response within unresectable cutaneous, subcutaneous, and nodal melanoma lesions. Although it is not a gene-directed therapy, the melanoma does not require a specific mutation for treatment. Again, this medication is better served in conjunction with other melanoma chemotherapeutic and surgical interventions.

Submental Fat

Kybella (deoxycholic acid)(Allergan) is a nonhuman, nonanimal, synthetically created compound that is naturally found within the human body for the breakdown and absorption of dietary fat.⁸ This drug was FDA approved in 2015 for the improvement of the appearance of moderate subcutaneous fat under the chin. Patients are evaluated in clinic to determine if the submental fat would be responsive to an injectable or require more radical surgical intervention based on desired outcomes. The treatment is administered as 0.2-mL injections (up to a total of 10 mL) spaced 1-cm apart and ideally is repeated at regular intervals to evaluate for efficacy.

Basal Cell Carcinoma

Odomzo (sonidegib)(Novartis Corporation) was FDA approved in 2015 for locally advanced basal cell carcinoma.⁹ Odomzo is a smoothened antagonist that inhibits the hedgehog signaling pathway. Smoothened is a transmembrane protein that allows for signal transduction of hedgehog proteins.¹⁰ Protein patched homolog 1 binds to smoothened protein and prevents the signal transduction through the cell for Gli family zinc factor 1 to continue protein translation; however, when PTCH is mutated and can no longer bind to smoothened, tumor formation results, specifically basal cell carcinoma. Hence, sonidegib is for the treatment of basal cell carcinomas that have persisted despite radiation treatment and/or surgery as well as for patients who have multiple basal cell carcinomas that can no longer be treated with surgery or radiation.

Final Thoughts

Overall, although there are several medications that can be used in conjunction for treatment of dermatological conditions, it always is recommended to know what is in the pipeline as FDA-approved medications for dermatology.

CenterWatch (http://www.centerwatch.com/) is an online resource that provides directories, analysis, and market research of medications that are either under clinical evaluation or available for use in patients. A list of currently approved drugs by the US Food and Drug Administration (FDA) also is available by specialty. It is important for dermatologists in-training to know about recently approved drugs and those that are in the pipeline, as these treatments may benefit patients who are unresponsive to other previously used medications. New drugs also may be useful for physicians who have a difficult time getting insurance to cover prescriptions for their patients, as most new medications have built-in patient assistance.

New Drugs in Dermatology

Actinic Keratosis

Ameluz (aminolevulinic acid hydrochloride)(Biofrontera AG) is a new drug that was approved in May 2016 for treatment of mild to moderate actinic keratosis on the face and scalp.¹ It is only intended for in-office use on patients who may not be candidates for other treatment options for actinic keratosis. The product is a gel formulation that should be applied to cover the lesions and approximately 5 mm of the surrounding area with a film of approximately 1-mm thickness. The entire treatment area is then illuminated with a red light source, either with a narrow spectrum around 630 nm with a light dose of approximately 37 J/cm² or a broader and continuous spectrum in the range of 570 to 670 nm with a light dose between 75 and 200 J/cm².¹ Similar to the previously used aminolevulinic acid treatment method for actinic keratosis, the patient may experience a burning stinging sensation throughout the treatment and the skin will then proceed to peel.

Psoriasis and Psoriatic Arthritis

Taltz (ixekizumab)(Eli Lilly and Company) was approved by the FDA in March 2016 for the treatment of moderate to severe plaque psoriasis.² It is a humanized IL-17A antagonist that works when IgG4 monoclonal antibodies selectively bind with IL-17A cytokines and inhibit their interaction with the IL-17 receptor. Although this injectable medication is approved for the treatment of psoriasis, it also can potentially be used off label for the treatment of psoriatic arthritis and rheumatoid arthritis. The approved dosage is 160 mg (two 80-mg injections) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks.² Injectable immunomodulatory medications such as ixekizumab are ideal for patients in whom topical treatments and light therapy failed and they continue to have serious psoriatic discomfort as well as for those who have substantial body surface area coverage.

Melanoma

Cotellic (cobimetinib)(Genentech USA, Inc) was FDA approved in November 2015.⁴ Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1. Mitogen-activated protein kinase MEK1 and MEK2 are regulators of the extracellular signal-­related kinase pathway, which promotes cellular proliferation. This pathway is key, as melanomas that have a BRAF V600E and kinase mutation continue to proliferate due to the constitutive activation of MEK1 and MEK2, further promoting cellular proliferation. Cobimetinib is approved for the treatment of melanoma in patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in conjunction with vemurafenib. Zelboraf (vemurafenib)(Genentech USA, Inc), another inhibitor of BRAF V600E, also is used for the treatment of unresectable melanomas and was initially approved in 2011.⁵

BRAF is a serine/threonine protein kinase. When unregulated, it results in the deregulation of cell proliferation. According to Ascierto et al,⁶ 50% of melanomas have a BRAF mutation, with nearly 90% of them with a V600E mutation. Hence, since the advent of direct chemotherapeutic agents such as BRAF inhibitors, clinical trials have shown notable reduction in mortality and morbidity of melanoma patients with BRAF mutations.⁶

Imlygic (talimogene laherparepvec)(Amgen, Inc) is a modified oncolytic viral therapy.⁷ This treatment was approved by the FDA in 2015 and replicates within tumors to produce granulocyte-macrophage colony-stimulating factor protein, which promotes an antitumor immune response within unresectable cutaneous, subcutaneous, and nodal melanoma lesions. Although it is not a gene-directed therapy, the melanoma does not require a specific mutation for treatment. Again, this medication is better served in conjunction with other melanoma chemotherapeutic and surgical interventions.

Submental Fat

Kybella (deoxycholic acid)(Allergan) is a nonhuman, nonanimal, synthetically created compound that is naturally found within the human body for the breakdown and absorption of dietary fat.⁸ This drug was FDA approved in 2015 for the improvement of the appearance of moderate subcutaneous fat under the chin. Patients are evaluated in clinic to determine if the submental fat would be responsive to an injectable or require more radical surgical intervention based on desired outcomes. The treatment is administered as 0.2-mL injections (up to a total of 10 mL) spaced 1-cm apart and ideally is repeated at regular intervals to evaluate for efficacy.

Basal Cell Carcinoma

Odomzo (sonidegib)(Novartis Corporation) was FDA approved in 2015 for locally advanced basal cell carcinoma.⁹ Odomzo is a smoothened antagonist that inhibits the hedgehog signaling pathway. Smoothened is a transmembrane protein that allows for signal transduction of hedgehog proteins.¹⁰ Protein patched homolog 1 binds to smoothened protein and prevents the signal transduction through the cell for Gli family zinc factor 1 to continue protein translation; however, when PTCH is mutated and can no longer bind to smoothened, tumor formation results, specifically basal cell carcinoma. Hence, sonidegib is for the treatment of basal cell carcinomas that have persisted despite radiation treatment and/or surgery as well as for patients who have multiple basal cell carcinomas that can no longer be treated with surgery or radiation.

Final Thoughts

Overall, although there are several medications that can be used in conjunction for treatment of dermatological conditions, it always is recommended to know what is in the pipeline as FDA-approved medications for dermatology.

When I am in clinic, I often get at least 3 to 4 inquiries each day from patients about the necessity for dietary restrictions or alterations as well as the benefits of these changes in limiting their dermatological disease processes. I usually am restricted in my response because the research rarely indicates benefits of one diet versus another; however, this discussion has recently become a heavily researched area as patients have come to value natural nonpharmaceutical approaches to their holistic care. In this article, a few dietary restrictions and supplements are reviewed that may have a beneficial effect in managing patients with acne vulgaris and atopic dermatitis.

Acne Vulgaris

In 1969 Fulton et al¹ conducted one of the first few trials on acne and diet management. In this crossover, patient-blinded, interventional study, patients were divided into 2 subgroups (N=65): 1 adolescent patient with moderate acne was compared to 1 male prisoner given a chocolate bar for 4 weeks or a control bar with equivalent caloric index. The results indicated no change in acne vulgaris lesions based on either intervention; however, there were obvious deficiencies in the study including small sample size, inappropriate grouping of an adolescent patient versus a prisoner, and limited study period.¹

Since then, multiple studies have been conducted with parallel participants, large sample sizes, and at least a 12-week study period. In 2005, Adebamowo et al² studied 47,355 women using a validated food frequency questionnaire that determined the amount of dairy consumed, specifically skim milk. The study showed a positive link between increased dairy consumption and acne formation; however, again due to the retrospective analysis and recall bias, it is difficult to determine if a link can truly be noted between acne and dairy in this study.²

More recently, LaRosa et al³ conducted a study that included 225 participants aged 14 to 19 years. Excluding participants with lactose intolerance and current use of oral contraceptives and isotretinoin, the study placed 120 participants in the test group versus 105 participants in the control group. The study was conducted using 3 telephone interviews and a 24-hour diet recall technique. The results supported a link between acne and skim milk consumption. Again, although the studied relied on participant self-reports of diet and followed a case-control design, a possible association was suspected but not validated.³ A longitudinal, questionnaire-based population study performed by Ulvestad et al⁴ included 2489 patients. This study further evaluated recall of dairy product consumption at 15 to 16 years of age and then 3 years later acne severity was self-assessed and reported at 18 to 19 years of age. Overall, this evaluation indicated that a high intake of dairy products and acne in adolescence have been positively associated. However, it was another retrospective study with recall bias.⁴ In 2009 Melnick and Schmitz⁵ concluded that milk causes the body to elevate both insulin and insulinlike growth factor 1 levels. In another study by Melnick⁶ in 2011, a definitive link between increased insulin and insulinlike growth factor 1 signaling in promoting comedogenesis was reported. Given the few studies that show the potential link between dairy products and acne, this dairy-free diet can be considered as a diet recommendation for acne patients.

Atopic Dermatitis

A Cochrane review conducted in 2012 regarding dietary supplements as a treatment of atopic dermatitis evaluated randomized controlled trials (N=596). Supplementation with vitamin D, fish oil, olive oil, zinc sulfate, selenium, vitamin E, pyridoxine, sea buckthorn seed oil, hempseed oil, sunflower oil (linoleic acid), and docosahexaenoic acid were evaluated among all the studies reviewed for atopic dermatitis.⁷ Bronsnick et al⁸ conducted a review of evidence supporting vitamin supplementation and atopic dermatitis, and for the most part determined that the studies had insufficient evidence. The only positive correlation was noted with prebiotics and probiotics in another Cochrane review in 2013, which evaluated 4 studies with 1428 infants showing prebiotic supplementation reduced atopic dermatitis.⁹ In 2014 Panduru et al¹⁰ evaluated 16 studies in a meta-analysis that showed how probiotics were possibly beneficial in both general and high-risk atopic populations. Specifically, a subgroup analysis showed that Lactobacillus and Lactobacillus with Bifidobacterium also can be protective against atopic dermatitis.¹⁰ Lastly, diet avoidance in pregnancy or during lactation in infants up to 18 months of age did not have any effect on improving the infant’s atopic dermatitis based on a 2012 Cochrane review that included 952 participants.¹¹

Conclusion

Overall, there are some benefits to dietary restrictions and supplementation as indicated by the studies reviewed here; however, the extent to which these changes contribute to disease manifestation has only been linked, not definitively proven. Randomized controlled trials with large sample sizes, double-blind studies, and appropriately controlled studies with comparative patient populations are difficult to obtain, as diet cannot be completely restrictive for every patient. Patients should be provided with the latest data supporting a possible link between dairy consumption and acne production as well as prebiotics or probiotics during pregnancy and at infancy to reduce the risk for atopic dermatitis with the caveat of association. That said, future studies might prove that dietary and environmental alterations may prevent disease progression or appearance far more than previously assumed.

When I am in clinic, I often get at least 3 to 4 inquiries each day from patients about the necessity for dietary restrictions or alterations as well as the benefits of these changes in limiting their dermatological disease processes. I usually am restricted in my response because the research rarely indicates benefits of one diet versus another; however, this discussion has recently become a heavily researched area as patients have come to value natural nonpharmaceutical approaches to their holistic care. In this article, a few dietary restrictions and supplements are reviewed that may have a beneficial effect in managing patients with acne vulgaris and atopic dermatitis.

Acne Vulgaris

In 1969 Fulton et al¹ conducted one of the first few trials on acne and diet management. In this crossover, patient-blinded, interventional study, patients were divided into 2 subgroups (N=65): 1 adolescent patient with moderate acne was compared to 1 male prisoner given a chocolate bar for 4 weeks or a control bar with equivalent caloric index. The results indicated no change in acne vulgaris lesions based on either intervention; however, there were obvious deficiencies in the study including small sample size, inappropriate grouping of an adolescent patient versus a prisoner, and limited study period.¹

Since then, multiple studies have been conducted with parallel participants, large sample sizes, and at least a 12-week study period. In 2005, Adebamowo et al² studied 47,355 women using a validated food frequency questionnaire that determined the amount of dairy consumed, specifically skim milk. The study showed a positive link between increased dairy consumption and acne formation; however, again due to the retrospective analysis and recall bias, it is difficult to determine if a link can truly be noted between acne and dairy in this study.²

More recently, LaRosa et al³ conducted a study that included 225 participants aged 14 to 19 years. Excluding participants with lactose intolerance and current use of oral contraceptives and isotretinoin, the study placed 120 participants in the test group versus 105 participants in the control group. The study was conducted using 3 telephone interviews and a 24-hour diet recall technique. The results supported a link between acne and skim milk consumption. Again, although the studied relied on participant self-reports of diet and followed a case-control design, a possible association was suspected but not validated.³ A longitudinal, questionnaire-based population study performed by Ulvestad et al⁴ included 2489 patients. This study further evaluated recall of dairy product consumption at 15 to 16 years of age and then 3 years later acne severity was self-assessed and reported at 18 to 19 years of age. Overall, this evaluation indicated that a high intake of dairy products and acne in adolescence have been positively associated. However, it was another retrospective study with recall bias.⁴ In 2009 Melnick and Schmitz⁵ concluded that milk causes the body to elevate both insulin and insulinlike growth factor 1 levels. In another study by Melnick⁶ in 2011, a definitive link between increased insulin and insulinlike growth factor 1 signaling in promoting comedogenesis was reported. Given the few studies that show the potential link between dairy products and acne, this dairy-free diet can be considered as a diet recommendation for acne patients.

Atopic Dermatitis

A Cochrane review conducted in 2012 regarding dietary supplements as a treatment of atopic dermatitis evaluated randomized controlled trials (N=596). Supplementation with vitamin D, fish oil, olive oil, zinc sulfate, selenium, vitamin E, pyridoxine, sea buckthorn seed oil, hempseed oil, sunflower oil (linoleic acid), and docosahexaenoic acid were evaluated among all the studies reviewed for atopic dermatitis.⁷ Bronsnick et al⁸ conducted a review of evidence supporting vitamin supplementation and atopic dermatitis, and for the most part determined that the studies had insufficient evidence. The only positive correlation was noted with prebiotics and probiotics in another Cochrane review in 2013, which evaluated 4 studies with 1428 infants showing prebiotic supplementation reduced atopic dermatitis.⁹ In 2014 Panduru et al¹⁰ evaluated 16 studies in a meta-analysis that showed how probiotics were possibly beneficial in both general and high-risk atopic populations. Specifically, a subgroup analysis showed that Lactobacillus and Lactobacillus with Bifidobacterium also can be protective against atopic dermatitis.¹⁰ Lastly, diet avoidance in pregnancy or during lactation in infants up to 18 months of age did not have any effect on improving the infant’s atopic dermatitis based on a 2012 Cochrane review that included 952 participants.¹¹

Conclusion

Overall, there are some benefits to dietary restrictions and supplementation as indicated by the studies reviewed here; however, the extent to which these changes contribute to disease manifestation has only been linked, not definitively proven. Randomized controlled trials with large sample sizes, double-blind studies, and appropriately controlled studies with comparative patient populations are difficult to obtain, as diet cannot be completely restrictive for every patient. Patients should be provided with the latest data supporting a possible link between dairy consumption and acne production as well as prebiotics or probiotics during pregnancy and at infancy to reduce the risk for atopic dermatitis with the caveat of association. That said, future studies might prove that dietary and environmental alterations may prevent disease progression or appearance far more than previously assumed.

When I am in clinic, I often get at least 3 to 4 inquiries each day from patients about the necessity for dietary restrictions or alterations as well as the benefits of these changes in limiting their dermatological disease processes. I usually am restricted in my response because the research rarely indicates benefits of one diet versus another; however, this discussion has recently become a heavily researched area as patients have come to value natural nonpharmaceutical approaches to their holistic care. In this article, a few dietary restrictions and supplements are reviewed that may have a beneficial effect in managing patients with acne vulgaris and atopic dermatitis.

Acne Vulgaris

In 1969 Fulton et al¹ conducted one of the first few trials on acne and diet management. In this crossover, patient-blinded, interventional study, patients were divided into 2 subgroups (N=65): 1 adolescent patient with moderate acne was compared to 1 male prisoner given a chocolate bar for 4 weeks or a control bar with equivalent caloric index. The results indicated no change in acne vulgaris lesions based on either intervention; however, there were obvious deficiencies in the study including small sample size, inappropriate grouping of an adolescent patient versus a prisoner, and limited study period.¹

Since then, multiple studies have been conducted with parallel participants, large sample sizes, and at least a 12-week study period. In 2005, Adebamowo et al² studied 47,355 women using a validated food frequency questionnaire that determined the amount of dairy consumed, specifically skim milk. The study showed a positive link between increased dairy consumption and acne formation; however, again due to the retrospective analysis and recall bias, it is difficult to determine if a link can truly be noted between acne and dairy in this study.²

More recently, LaRosa et al³ conducted a study that included 225 participants aged 14 to 19 years. Excluding participants with lactose intolerance and current use of oral contraceptives and isotretinoin, the study placed 120 participants in the test group versus 105 participants in the control group. The study was conducted using 3 telephone interviews and a 24-hour diet recall technique. The results supported a link between acne and skim milk consumption. Again, although the studied relied on participant self-reports of diet and followed a case-control design, a possible association was suspected but not validated.³ A longitudinal, questionnaire-based population study performed by Ulvestad et al⁴ included 2489 patients. This study further evaluated recall of dairy product consumption at 15 to 16 years of age and then 3 years later acne severity was self-assessed and reported at 18 to 19 years of age. Overall, this evaluation indicated that a high intake of dairy products and acne in adolescence have been positively associated. However, it was another retrospective study with recall bias.⁴ In 2009 Melnick and Schmitz⁵ concluded that milk causes the body to elevate both insulin and insulinlike growth factor 1 levels. In another study by Melnick⁶ in 2011, a definitive link between increased insulin and insulinlike growth factor 1 signaling in promoting comedogenesis was reported. Given the few studies that show the potential link between dairy products and acne, this dairy-free diet can be considered as a diet recommendation for acne patients.

Atopic Dermatitis

A Cochrane review conducted in 2012 regarding dietary supplements as a treatment of atopic dermatitis evaluated randomized controlled trials (N=596). Supplementation with vitamin D, fish oil, olive oil, zinc sulfate, selenium, vitamin E, pyridoxine, sea buckthorn seed oil, hempseed oil, sunflower oil (linoleic acid), and docosahexaenoic acid were evaluated among all the studies reviewed for atopic dermatitis.⁷ Bronsnick et al⁸ conducted a review of evidence supporting vitamin supplementation and atopic dermatitis, and for the most part determined that the studies had insufficient evidence. The only positive correlation was noted with prebiotics and probiotics in another Cochrane review in 2013, which evaluated 4 studies with 1428 infants showing prebiotic supplementation reduced atopic dermatitis.⁹ In 2014 Panduru et al¹⁰ evaluated 16 studies in a meta-analysis that showed how probiotics were possibly beneficial in both general and high-risk atopic populations. Specifically, a subgroup analysis showed that Lactobacillus and Lactobacillus with Bifidobacterium also can be protective against atopic dermatitis.¹⁰ Lastly, diet avoidance in pregnancy or during lactation in infants up to 18 months of age did not have any effect on improving the infant’s atopic dermatitis based on a 2012 Cochrane review that included 952 participants.¹¹

Conclusion

Overall, there are some benefits to dietary restrictions and supplementation as indicated by the studies reviewed here; however, the extent to which these changes contribute to disease manifestation has only been linked, not definitively proven. Randomized controlled trials with large sample sizes, double-blind studies, and appropriately controlled studies with comparative patient populations are difficult to obtain, as diet cannot be completely restrictive for every patient. Patients should be provided with the latest data supporting a possible link between dairy consumption and acne production as well as prebiotics or probiotics during pregnancy and at infancy to reduce the risk for atopic dermatitis with the caveat of association. That said, future studies might prove that dietary and environmental alterations may prevent disease progression or appearance far more than previously assumed.

As young physicians, we are taught to be as objective as possible when evaluating a patient; however, cognitive biases are regularly encountered in day-to-day patient experiences and can unfortunately influence our clinical decision-making skills to be subpar.

Consider the following case: An overweight 74-year-old man with diabetes mellitus and a nonhealing ulceration on the left lower extremity presented to the emergency department for repeat evaluation. He previously had been treated by an outside dermatologist for stasis dermatitis and was being managed with compression, elevation, and lubrication of both lower extremities. Often, the initial reaction is to conclude that the patient does in fact have an ulceration associated with stasis dermatitis and changing the management strategy or performing a biopsy would not change the outcome. However, this response limits the potential to provide the patient with a thorough examination. If the patient is treated with the same management strategies that previously failed rather than delving into all the causes for nonhealing ulceration on the left lower extremity, a vital diagnosis could be missed. In this scenario, when the patient was ultimately biopsied, the diagnosis was an ulcerative squamous cell carcinoma.

These subconscious predetermined decisions regarding difficult patient encounters come from the physician’s heuristics, a process of decision-making wherein a snap judgment about a patient occurs because it is similar to prior patient encounters or a set of views from prior knowledge of the disease.^1,2

A recent article by Cohen and Burgin³ elucidated a set of cognitive biases that often are encountered in dermatology practices, including affective, anchoring, availability, and confirmation biases; zebra retreat; and Sutton’s slip.

Affective Bias

Affective bias is a process in which emotions regarding a patient interaction alter the objective prospective and reasoning of a patient. For example, consider the case of a pemphigus vulgaris patient who does not want to be on prednisone due to weight gain and persistently presents to the dermatology clinic insisting that the physician taper the dosage. To avoid the constant frustration and upsetting the patient further, the dermatologist tapers the dosage of prednisone prematurely and the patient has a flare.

Anchoring Bias

Anchoring bias occurs when initial information regarding a patient causes one to jump to a conclusion rather than developing a thorough history. An example may be if an infant presents with a mole on the nasal dorsum that the patient’s father reports has only been present for a short while. Without performing imaging studies or asking for further history, the physician decides to biopsy the lesion. The biopsy results show a neural mass, such that a nasal glioma cannot be ruled out. In this bias, magnetic resonance imaging would have been prudent prior to biopsy and premature action.

Availability Bias

Availability bias refers to a diagnosis that immediately comes to mind, as it is common or recently encountered, such as in the example presented at the beginning of this column about the patient with squamous cell carcinoma.

Confirmation Bias

Confirmation bias caters to elucidating information that confirms your own clinical suspicion as opposed to determining the true cause of the disease etiology. Consider the following example: An obese patient presents with a history of painful sores on the bilateral lower extremities. The physician asks specifically about diabetes mellitus and mobility. When the patient answers yes to poor mobility and diabetes mellitus, the physician asks questions confirming an initial suspected diagnosis of stasis dermatitis. Unfortunately, as the patient continues to get worse, it is revealed that his medication history indicates he has been taking sulfasalazine for several years, and it is eventually determined that the patient has cutaneous Crohn disease.

Zebra Retreat

This bias describes a physician’s unwillingness to consider a diagnosis because it is very obscure, even if it is correct. For example, the case of the patient described in the previous example with a diagnosis of cutaneous Crohn disease also can be considered as an example of zebra retreat. Because the clinician may rarely think of this diagnosis due to its infrequent presentation, he/she may not consider doing a biopsy or investigate further.

Sutton’s Slip

This bias describes a situation in which a physician disregards a problem because a thorough examination is not performed, which is classically noted when physicians treat their family and friends. If asked about a mole or lesion regarding its questionable nature, a dermatologist may either disregard it or not evaluate it carefully, as the person is in a casual setting.

Final Thoughts

Although there are several other types of cognitive biases, those described here show that on several occasions, dermatologists can be swayed toward an incorrect diagnosis simply because of a subconscious thought process. Often times, such as in multiple-choice examinations, initial guesses are usually the best answers, but care has to be taken when in a clinical setting. Our patients rarely are good historians and do not present in well-written question stems. The biases emphasize that dermatologists in training should keep their minds open, focus on getting a clear and concise history, and use their knowledge as a tool to derive a well thought-out answer.

As young physicians, we are taught to be as objective as possible when evaluating a patient; however, cognitive biases are regularly encountered in day-to-day patient experiences and can unfortunately influence our clinical decision-making skills to be subpar.

Consider the following case: An overweight 74-year-old man with diabetes mellitus and a nonhealing ulceration on the left lower extremity presented to the emergency department for repeat evaluation. He previously had been treated by an outside dermatologist for stasis dermatitis and was being managed with compression, elevation, and lubrication of both lower extremities. Often, the initial reaction is to conclude that the patient does in fact have an ulceration associated with stasis dermatitis and changing the management strategy or performing a biopsy would not change the outcome. However, this response limits the potential to provide the patient with a thorough examination. If the patient is treated with the same management strategies that previously failed rather than delving into all the causes for nonhealing ulceration on the left lower extremity, a vital diagnosis could be missed. In this scenario, when the patient was ultimately biopsied, the diagnosis was an ulcerative squamous cell carcinoma.

These subconscious predetermined decisions regarding difficult patient encounters come from the physician’s heuristics, a process of decision-making wherein a snap judgment about a patient occurs because it is similar to prior patient encounters or a set of views from prior knowledge of the disease.^1,2

A recent article by Cohen and Burgin³ elucidated a set of cognitive biases that often are encountered in dermatology practices, including affective, anchoring, availability, and confirmation biases; zebra retreat; and Sutton’s slip.

Affective Bias

Affective bias is a process in which emotions regarding a patient interaction alter the objective prospective and reasoning of a patient. For example, consider the case of a pemphigus vulgaris patient who does not want to be on prednisone due to weight gain and persistently presents to the dermatology clinic insisting that the physician taper the dosage. To avoid the constant frustration and upsetting the patient further, the dermatologist tapers the dosage of prednisone prematurely and the patient has a flare.

Anchoring Bias

Anchoring bias occurs when initial information regarding a patient causes one to jump to a conclusion rather than developing a thorough history. An example may be if an infant presents with a mole on the nasal dorsum that the patient’s father reports has only been present for a short while. Without performing imaging studies or asking for further history, the physician decides to biopsy the lesion. The biopsy results show a neural mass, such that a nasal glioma cannot be ruled out. In this bias, magnetic resonance imaging would have been prudent prior to biopsy and premature action.

Availability Bias

Availability bias refers to a diagnosis that immediately comes to mind, as it is common or recently encountered, such as in the example presented at the beginning of this column about the patient with squamous cell carcinoma.

Confirmation Bias

Confirmation bias caters to elucidating information that confirms your own clinical suspicion as opposed to determining the true cause of the disease etiology. Consider the following example: An obese patient presents with a history of painful sores on the bilateral lower extremities. The physician asks specifically about diabetes mellitus and mobility. When the patient answers yes to poor mobility and diabetes mellitus, the physician asks questions confirming an initial suspected diagnosis of stasis dermatitis. Unfortunately, as the patient continues to get worse, it is revealed that his medication history indicates he has been taking sulfasalazine for several years, and it is eventually determined that the patient has cutaneous Crohn disease.

Zebra Retreat

This bias describes a physician’s unwillingness to consider a diagnosis because it is very obscure, even if it is correct. For example, the case of the patient described in the previous example with a diagnosis of cutaneous Crohn disease also can be considered as an example of zebra retreat. Because the clinician may rarely think of this diagnosis due to its infrequent presentation, he/she may not consider doing a biopsy or investigate further.

Sutton’s Slip

This bias describes a situation in which a physician disregards a problem because a thorough examination is not performed, which is classically noted when physicians treat their family and friends. If asked about a mole or lesion regarding its questionable nature, a dermatologist may either disregard it or not evaluate it carefully, as the person is in a casual setting.

Final Thoughts

Although there are several other types of cognitive biases, those described here show that on several occasions, dermatologists can be swayed toward an incorrect diagnosis simply because of a subconscious thought process. Often times, such as in multiple-choice examinations, initial guesses are usually the best answers, but care has to be taken when in a clinical setting. Our patients rarely are good historians and do not present in well-written question stems. The biases emphasize that dermatologists in training should keep their minds open, focus on getting a clear and concise history, and use their knowledge as a tool to derive a well thought-out answer.

As young physicians, we are taught to be as objective as possible when evaluating a patient; however, cognitive biases are regularly encountered in day-to-day patient experiences and can unfortunately influence our clinical decision-making skills to be subpar.

Consider the following case: An overweight 74-year-old man with diabetes mellitus and a nonhealing ulceration on the left lower extremity presented to the emergency department for repeat evaluation. He previously had been treated by an outside dermatologist for stasis dermatitis and was being managed with compression, elevation, and lubrication of both lower extremities. Often, the initial reaction is to conclude that the patient does in fact have an ulceration associated with stasis dermatitis and changing the management strategy or performing a biopsy would not change the outcome. However, this response limits the potential to provide the patient with a thorough examination. If the patient is treated with the same management strategies that previously failed rather than delving into all the causes for nonhealing ulceration on the left lower extremity, a vital diagnosis could be missed. In this scenario, when the patient was ultimately biopsied, the diagnosis was an ulcerative squamous cell carcinoma.

These subconscious predetermined decisions regarding difficult patient encounters come from the physician’s heuristics, a process of decision-making wherein a snap judgment about a patient occurs because it is similar to prior patient encounters or a set of views from prior knowledge of the disease.^1,2

A recent article by Cohen and Burgin³ elucidated a set of cognitive biases that often are encountered in dermatology practices, including affective, anchoring, availability, and confirmation biases; zebra retreat; and Sutton’s slip.

Affective Bias

Affective bias is a process in which emotions regarding a patient interaction alter the objective prospective and reasoning of a patient. For example, consider the case of a pemphigus vulgaris patient who does not want to be on prednisone due to weight gain and persistently presents to the dermatology clinic insisting that the physician taper the dosage. To avoid the constant frustration and upsetting the patient further, the dermatologist tapers the dosage of prednisone prematurely and the patient has a flare.

Anchoring Bias

Anchoring bias occurs when initial information regarding a patient causes one to jump to a conclusion rather than developing a thorough history. An example may be if an infant presents with a mole on the nasal dorsum that the patient’s father reports has only been present for a short while. Without performing imaging studies or asking for further history, the physician decides to biopsy the lesion. The biopsy results show a neural mass, such that a nasal glioma cannot be ruled out. In this bias, magnetic resonance imaging would have been prudent prior to biopsy and premature action.

Availability Bias

Availability bias refers to a diagnosis that immediately comes to mind, as it is common or recently encountered, such as in the example presented at the beginning of this column about the patient with squamous cell carcinoma.

Confirmation Bias

Confirmation bias caters to elucidating information that confirms your own clinical suspicion as opposed to determining the true cause of the disease etiology. Consider the following example: An obese patient presents with a history of painful sores on the bilateral lower extremities. The physician asks specifically about diabetes mellitus and mobility. When the patient answers yes to poor mobility and diabetes mellitus, the physician asks questions confirming an initial suspected diagnosis of stasis dermatitis. Unfortunately, as the patient continues to get worse, it is revealed that his medication history indicates he has been taking sulfasalazine for several years, and it is eventually determined that the patient has cutaneous Crohn disease.

Zebra Retreat

This bias describes a physician’s unwillingness to consider a diagnosis because it is very obscure, even if it is correct. For example, the case of the patient described in the previous example with a diagnosis of cutaneous Crohn disease also can be considered as an example of zebra retreat. Because the clinician may rarely think of this diagnosis due to its infrequent presentation, he/she may not consider doing a biopsy or investigate further.

Sutton’s Slip

This bias describes a situation in which a physician disregards a problem because a thorough examination is not performed, which is classically noted when physicians treat their family and friends. If asked about a mole or lesion regarding its questionable nature, a dermatologist may either disregard it or not evaluate it carefully, as the person is in a casual setting.

Final Thoughts

Although there are several other types of cognitive biases, those described here show that on several occasions, dermatologists can be swayed toward an incorrect diagnosis simply because of a subconscious thought process. Often times, such as in multiple-choice examinations, initial guesses are usually the best answers, but care has to be taken when in a clinical setting. Our patients rarely are good historians and do not present in well-written question stems. The biases emphasize that dermatologists in training should keep their minds open, focus on getting a clear and concise history, and use their knowledge as a tool to derive a well thought-out answer.

Vitiligo is a common, asymptomatic, acquired depigmentation disorder that is caused by an unknown etiology. Lesions appear as sharply demarcated, depigmented macules and patches that are scattered symmetrically or unsymmetrically over the body. The presentation can be delineated based on the segmental or nonsegmental nature of the disease. According to the revised classification/nomenclature of vitiligo,¹ the disorder can be classified as nonsegmental, segmental, mixed, or unclassified. The pathogenesis of the vitiligo disease process is due to multiple modalities that contribute to melanocyte loss. Theories for melanocyte destruction include but are not limited to autoimmunity, biochemicals, epidermal cytokines, increased hydrogen peroxide and free radicals, and humoral and cellular immune alteration.^2,3

Despite its long history, the most frustrating aspect of the vitiligo disease process remains its treatment due to limited efficacy, frequent application of topicals, and the need for high-potency steroids. Medical therapies usually are the first line of treatment and are most effective with few side effects for bilateral nonsegmental or evolving vitiligo.² Some of the primary therapies with the highest efficacies appear to be calcipotriene and psoralen plus UVA, psoralen plus UVA as monotherapy, excimer laser, narrowband UVB, oral steroids, 8-methoxypsoralen, tacrolimus, and topical steroids.⁴ The theory is that these treatments would be successful if the patient had active melanocytes in the external root sheath that would be able to repigment a patch of vitiligo.⁵ Hence, it would be more difficult to treat areas such as the dorsal aspect of the fingers and toes because they lack hair-bearing areas with melanocytes.⁶ The alternative approach to treating vitiligo patches would be surgical intervention techniques, as they provide melanocytic cells to a previously depigmented area.^3,5 The focus of this article is to evaluate the efficacy and appropriate use of some of the surgical procedures that can be used in the treatment of vitiligo patients.

Candidate Selection

First, vitiligo patients for whom first-line treatment with medical therapies has failed are candidates for surgical techniques. The second vital component is to clinically confirm the diagnosis of vitiligo as opposed to other genetic, infectious, or autoimmune causes of pigment loss. Lastly, the vitiligo patch should be stable. A stable vitiligo patch does not continue to progress and is no longer responsive to topical medications that are meant to repigment for a discernible period of time.⁷

Classification of Disease Stage

To classify the stage of vitiligo prior to surgical intervention, Gauthier⁸ created a basic grading system: grade I, with partial depletion of epidermal melanocytes in a vitiligo patch that responds to repigmentation in a follicular pattern evenly such as on the face and neck; grade II, with complete depletion of epidermal melanocytes with a usual follicular pattern of repigmentation; and grade III, indicating complete depletion of follicular melanocytes with no hope of response to medical therapy. According to Rusfianti and Wirohadidjodjo,² the surgical techniques that have developed over the years for treatment of grade III vitiligo patients include split-thickness skin grafting, suction blister grafting, miniature punch grafting, and cultured melanocyte transplantation.

Surgical Techniques

Split-thickness skin grafting is an older procedure that entails the use of a harvesting graft site with no pigment loss and dermabrasion of the recipient area to allow interaction with the wound bed.⁹ With proper care and minimal movement or wrinkling of the graft site, patients can have repigmentation without skip areas.

Suction blister grafting is another tried and tested surgical intervention. Hasegawa et al¹⁰ conducted a study of 15 patients (13 males, 2 females; age range, 16–38 years) diagnosed with segmental vitiligo who were treated using the suction blister grafting technique with CO₂ laser resurfacing. Patients were recruited 1 month prior to initiating therapy and no other treatments were used during the month or in conjunction with the surgical intervention. Suction blisters were harvested from the left thigh and transferred in saline to the recipient site, which was abraded with 1 pass of the short-pulse CO₂ laser system. The recipient sites were then closed with 7-0 nylon sutures and covered tightly with tie-over dressings for at least 1 week. Within 6 months of the procedure, a treatment response of 100% was seen in 15 patients, making it an effective method for treatment-resistant vitiligo patients.¹⁰

Miniature punch grafting is another possible treatment option for resistant cases of vitiligo. Mapar et al¹¹ conducted a study in 25 patients (21 women, 4 men; age range, 20–47 years) who had been diagnosed with stable vitiligo (ie, no progression in the last 2 years) and were treated with single hair follicle transplant versus miniature punch grafting. The theory behind the study was to use the melanocytic reservoir noted in the normal hair follicle to repigment the vitiligo patch. With follow-up of both methods of treatment, there was no statistical difference in treatment results.¹¹ A similar study was conducted by Malakar and Lahiri¹² in patients with lip leukoderma (a variant of vitiligo). One hundred eight patients (41 males, 67 females; age range, 14–62 years) who had been diagnosed with stable lip leukoderma (ie, stable vitiligo for at least 6 months) underwent treatment via autologous miniature punch grafting. Punch biopsies were performed in donor sites of the buttocks and upper thighs with 72% of patients noting complete repigmentation. Complications noted were herpes labialis–induced lip leukoderma, which ultimately led to rejection of the graft site.¹² Overall, however, miniature punch grafting is a viable surgical option in stable vitiligo patients.

Cultured melanocyte transplantation, or a noncultured epidermal suspension, was first initiated in 1992.¹³ Silpa-Archa et al¹⁴ conducted an open, split-comparison study of 6 vitiligo patients (5 women, 1 man; age range, 20–65 years) with stable lesions. Fifty percent of patients received autologous pigmented skin cellular suspension, which was applied to vitiligo-affected skin that was treated with a fractionated CO₂ laser, and 50% received dermabrasion. Composite dressing was placed overlying the site with dressing removal in 1 week. The degree of repigmentation was based on a modified vitiligo area scoring index scale of poor (0%–25%), fair (26%–50%), good (51%–75%), very good (76%–90%), or excellent (91%–100%). Overall repigmentation was very good to excellent in all 6 patients.¹⁴ Potentially, this method can far improve the surgical treatment options for future vitiligo patients.

Final Thoughts

Overall, when evaluating surgical interventions for the treatment of vitiligo, careful consideration of the patient’s disease progression, failed therapies, outcome expectations, and repigmentation is warranted prior to initiating any procedure. For appropriate candidates, a range of surgical methodologies has proven to be effective in treatment of stable vitiligo patients.

Vitiligo is a common, asymptomatic, acquired depigmentation disorder that is caused by an unknown etiology. Lesions appear as sharply demarcated, depigmented macules and patches that are scattered symmetrically or unsymmetrically over the body. The presentation can be delineated based on the segmental or nonsegmental nature of the disease. According to the revised classification/nomenclature of vitiligo,¹ the disorder can be classified as nonsegmental, segmental, mixed, or unclassified. The pathogenesis of the vitiligo disease process is due to multiple modalities that contribute to melanocyte loss. Theories for melanocyte destruction include but are not limited to autoimmunity, biochemicals, epidermal cytokines, increased hydrogen peroxide and free radicals, and humoral and cellular immune alteration.^2,3

Despite its long history, the most frustrating aspect of the vitiligo disease process remains its treatment due to limited efficacy, frequent application of topicals, and the need for high-potency steroids. Medical therapies usually are the first line of treatment and are most effective with few side effects for bilateral nonsegmental or evolving vitiligo.² Some of the primary therapies with the highest efficacies appear to be calcipotriene and psoralen plus UVA, psoralen plus UVA as monotherapy, excimer laser, narrowband UVB, oral steroids, 8-methoxypsoralen, tacrolimus, and topical steroids.⁴ The theory is that these treatments would be successful if the patient had active melanocytes in the external root sheath that would be able to repigment a patch of vitiligo.⁵ Hence, it would be more difficult to treat areas such as the dorsal aspect of the fingers and toes because they lack hair-bearing areas with melanocytes.⁶ The alternative approach to treating vitiligo patches would be surgical intervention techniques, as they provide melanocytic cells to a previously depigmented area.^3,5 The focus of this article is to evaluate the efficacy and appropriate use of some of the surgical procedures that can be used in the treatment of vitiligo patients.

Candidate Selection

First, vitiligo patients for whom first-line treatment with medical therapies has failed are candidates for surgical techniques. The second vital component is to clinically confirm the diagnosis of vitiligo as opposed to other genetic, infectious, or autoimmune causes of pigment loss. Lastly, the vitiligo patch should be stable. A stable vitiligo patch does not continue to progress and is no longer responsive to topical medications that are meant to repigment for a discernible period of time.⁷

Classification of Disease Stage

To classify the stage of vitiligo prior to surgical intervention, Gauthier⁸ created a basic grading system: grade I, with partial depletion of epidermal melanocytes in a vitiligo patch that responds to repigmentation in a follicular pattern evenly such as on the face and neck; grade II, with complete depletion of epidermal melanocytes with a usual follicular pattern of repigmentation; and grade III, indicating complete depletion of follicular melanocytes with no hope of response to medical therapy. According to Rusfianti and Wirohadidjodjo,² the surgical techniques that have developed over the years for treatment of grade III vitiligo patients include split-thickness skin grafting, suction blister grafting, miniature punch grafting, and cultured melanocyte transplantation.

Surgical Techniques

Split-thickness skin grafting is an older procedure that entails the use of a harvesting graft site with no pigment loss and dermabrasion of the recipient area to allow interaction with the wound bed.⁹ With proper care and minimal movement or wrinkling of the graft site, patients can have repigmentation without skip areas.

Suction blister grafting is another tried and tested surgical intervention. Hasegawa et al¹⁰ conducted a study of 15 patients (13 males, 2 females; age range, 16–38 years) diagnosed with segmental vitiligo who were treated using the suction blister grafting technique with CO₂ laser resurfacing. Patients were recruited 1 month prior to initiating therapy and no other treatments were used during the month or in conjunction with the surgical intervention. Suction blisters were harvested from the left thigh and transferred in saline to the recipient site, which was abraded with 1 pass of the short-pulse CO₂ laser system. The recipient sites were then closed with 7-0 nylon sutures and covered tightly with tie-over dressings for at least 1 week. Within 6 months of the procedure, a treatment response of 100% was seen in 15 patients, making it an effective method for treatment-resistant vitiligo patients.¹⁰

Miniature punch grafting is another possible treatment option for resistant cases of vitiligo. Mapar et al¹¹ conducted a study in 25 patients (21 women, 4 men; age range, 20–47 years) who had been diagnosed with stable vitiligo (ie, no progression in the last 2 years) and were treated with single hair follicle transplant versus miniature punch grafting. The theory behind the study was to use the melanocytic reservoir noted in the normal hair follicle to repigment the vitiligo patch. With follow-up of both methods of treatment, there was no statistical difference in treatment results.¹¹ A similar study was conducted by Malakar and Lahiri¹² in patients with lip leukoderma (a variant of vitiligo). One hundred eight patients (41 males, 67 females; age range, 14–62 years) who had been diagnosed with stable lip leukoderma (ie, stable vitiligo for at least 6 months) underwent treatment via autologous miniature punch grafting. Punch biopsies were performed in donor sites of the buttocks and upper thighs with 72% of patients noting complete repigmentation. Complications noted were herpes labialis–induced lip leukoderma, which ultimately led to rejection of the graft site.¹² Overall, however, miniature punch grafting is a viable surgical option in stable vitiligo patients.

Cultured melanocyte transplantation, or a noncultured epidermal suspension, was first initiated in 1992.¹³ Silpa-Archa et al¹⁴ conducted an open, split-comparison study of 6 vitiligo patients (5 women, 1 man; age range, 20–65 years) with stable lesions. Fifty percent of patients received autologous pigmented skin cellular suspension, which was applied to vitiligo-affected skin that was treated with a fractionated CO₂ laser, and 50% received dermabrasion. Composite dressing was placed overlying the site with dressing removal in 1 week. The degree of repigmentation was based on a modified vitiligo area scoring index scale of poor (0%–25%), fair (26%–50%), good (51%–75%), very good (76%–90%), or excellent (91%–100%). Overall repigmentation was very good to excellent in all 6 patients.¹⁴ Potentially, this method can far improve the surgical treatment options for future vitiligo patients.

Final Thoughts

Overall, when evaluating surgical interventions for the treatment of vitiligo, careful consideration of the patient’s disease progression, failed therapies, outcome expectations, and repigmentation is warranted prior to initiating any procedure. For appropriate candidates, a range of surgical methodologies has proven to be effective in treatment of stable vitiligo patients.

Vitiligo is a common, asymptomatic, acquired depigmentation disorder that is caused by an unknown etiology. Lesions appear as sharply demarcated, depigmented macules and patches that are scattered symmetrically or unsymmetrically over the body. The presentation can be delineated based on the segmental or nonsegmental nature of the disease. According to the revised classification/nomenclature of vitiligo,¹ the disorder can be classified as nonsegmental, segmental, mixed, or unclassified. The pathogenesis of the vitiligo disease process is due to multiple modalities that contribute to melanocyte loss. Theories for melanocyte destruction include but are not limited to autoimmunity, biochemicals, epidermal cytokines, increased hydrogen peroxide and free radicals, and humoral and cellular immune alteration.^2,3

Despite its long history, the most frustrating aspect of the vitiligo disease process remains its treatment due to limited efficacy, frequent application of topicals, and the need for high-potency steroids. Medical therapies usually are the first line of treatment and are most effective with few side effects for bilateral nonsegmental or evolving vitiligo.² Some of the primary therapies with the highest efficacies appear to be calcipotriene and psoralen plus UVA, psoralen plus UVA as monotherapy, excimer laser, narrowband UVB, oral steroids, 8-methoxypsoralen, tacrolimus, and topical steroids.⁴ The theory is that these treatments would be successful if the patient had active melanocytes in the external root sheath that would be able to repigment a patch of vitiligo.⁵ Hence, it would be more difficult to treat areas such as the dorsal aspect of the fingers and toes because they lack hair-bearing areas with melanocytes.⁶ The alternative approach to treating vitiligo patches would be surgical intervention techniques, as they provide melanocytic cells to a previously depigmented area.^3,5 The focus of this article is to evaluate the efficacy and appropriate use of some of the surgical procedures that can be used in the treatment of vitiligo patients.

Candidate Selection

First, vitiligo patients for whom first-line treatment with medical therapies has failed are candidates for surgical techniques. The second vital component is to clinically confirm the diagnosis of vitiligo as opposed to other genetic, infectious, or autoimmune causes of pigment loss. Lastly, the vitiligo patch should be stable. A stable vitiligo patch does not continue to progress and is no longer responsive to topical medications that are meant to repigment for a discernible period of time.⁷

Classification of Disease Stage

To classify the stage of vitiligo prior to surgical intervention, Gauthier⁸ created a basic grading system: grade I, with partial depletion of epidermal melanocytes in a vitiligo patch that responds to repigmentation in a follicular pattern evenly such as on the face and neck; grade II, with complete depletion of epidermal melanocytes with a usual follicular pattern of repigmentation; and grade III, indicating complete depletion of follicular melanocytes with no hope of response to medical therapy. According to Rusfianti and Wirohadidjodjo,² the surgical techniques that have developed over the years for treatment of grade III vitiligo patients include split-thickness skin grafting, suction blister grafting, miniature punch grafting, and cultured melanocyte transplantation.

Surgical Techniques

Split-thickness skin grafting is an older procedure that entails the use of a harvesting graft site with no pigment loss and dermabrasion of the recipient area to allow interaction with the wound bed.⁹ With proper care and minimal movement or wrinkling of the graft site, patients can have repigmentation without skip areas.

Suction blister grafting is another tried and tested surgical intervention. Hasegawa et al¹⁰ conducted a study of 15 patients (13 males, 2 females; age range, 16–38 years) diagnosed with segmental vitiligo who were treated using the suction blister grafting technique with CO₂ laser resurfacing. Patients were recruited 1 month prior to initiating therapy and no other treatments were used during the month or in conjunction with the surgical intervention. Suction blisters were harvested from the left thigh and transferred in saline to the recipient site, which was abraded with 1 pass of the short-pulse CO₂ laser system. The recipient sites were then closed with 7-0 nylon sutures and covered tightly with tie-over dressings for at least 1 week. Within 6 months of the procedure, a treatment response of 100% was seen in 15 patients, making it an effective method for treatment-resistant vitiligo patients.¹⁰

Miniature punch grafting is another possible treatment option for resistant cases of vitiligo. Mapar et al¹¹ conducted a study in 25 patients (21 women, 4 men; age range, 20–47 years) who had been diagnosed with stable vitiligo (ie, no progression in the last 2 years) and were treated with single hair follicle transplant versus miniature punch grafting. The theory behind the study was to use the melanocytic reservoir noted in the normal hair follicle to repigment the vitiligo patch. With follow-up of both methods of treatment, there was no statistical difference in treatment results.¹¹ A similar study was conducted by Malakar and Lahiri¹² in patients with lip leukoderma (a variant of vitiligo). One hundred eight patients (41 males, 67 females; age range, 14–62 years) who had been diagnosed with stable lip leukoderma (ie, stable vitiligo for at least 6 months) underwent treatment via autologous miniature punch grafting. Punch biopsies were performed in donor sites of the buttocks and upper thighs with 72% of patients noting complete repigmentation. Complications noted were herpes labialis–induced lip leukoderma, which ultimately led to rejection of the graft site.¹² Overall, however, miniature punch grafting is a viable surgical option in stable vitiligo patients.

Cultured melanocyte transplantation, or a noncultured epidermal suspension, was first initiated in 1992.¹³ Silpa-Archa et al¹⁴ conducted an open, split-comparison study of 6 vitiligo patients (5 women, 1 man; age range, 20–65 years) with stable lesions. Fifty percent of patients received autologous pigmented skin cellular suspension, which was applied to vitiligo-affected skin that was treated with a fractionated CO₂ laser, and 50% received dermabrasion. Composite dressing was placed overlying the site with dressing removal in 1 week. The degree of repigmentation was based on a modified vitiligo area scoring index scale of poor (0%–25%), fair (26%–50%), good (51%–75%), very good (76%–90%), or excellent (91%–100%). Overall repigmentation was very good to excellent in all 6 patients.¹⁴ Potentially, this method can far improve the surgical treatment options for future vitiligo patients.

Final Thoughts

Overall, when evaluating surgical interventions for the treatment of vitiligo, careful consideration of the patient’s disease progression, failed therapies, outcome expectations, and repigmentation is warranted prior to initiating any procedure. For appropriate candidates, a range of surgical methodologies has proven to be effective in treatment of stable vitiligo patients.

As dermatology residents, the telephone calls we get at 2 am usually are the toughest for 2 reasons: (1) we rarely get calls at 2 am, and (2) it usually means there is a case to rule out Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Stevens-Johnson syndrome and TEN are severe mucocutaneous eruptions that usually develop due to drug reactions and involve a continuum of conjunctivitis, mucocutaneous sloughing, keratinocyte death, and bullae development. Body surface area (BSA) coverage determines the distinction between SJS and TEN; less than 10% BSA affected indicates SJS, 10% to 30% BSA affected indicates overlap between SJS and TEN, and greater than 30% BSA affected indicates TEN.¹ The mortality rates for these conditions range from 1% to 5% in SJS versus 25% to 30% in TEN.²

Being driven and dedicated residents, we rise to the challenge by arranging appropriate consultations, obtaining frozen section biopsies, providing recommendations to remove unnecessary medications, and offering skin care management. However, what comes next? Intravenous immunoglobulin (IVIG)? Cyclosporine? Or is it appropriate to allow the reaction to continue its course? Dermatology programs have a varying standard of care due to the limited number of studies conducted on SJS/TEN patients. Few studies have relayed the efficacy of cyclosporine; however, published results have shown that cyclosporine can decrease the overall mortality risk and minimize disease progression.^2-5 In this article, I will review some of the key studies conducted in the last 5 years regarding the use of cyclosporine in the therapeutic plan for SJS/TEN.

In one retrospective analysis conducted by Kirchhof et al¹ in 2014, 35 patients with SJS/TEN who were treated with IVIG and 15 who were treated with cyclosporine were evaluated for mortality benefit. Two patients were treated with both cyclosporine and IVIG and were included in both arms of the study. Overall, the evaluation indicated that cyclosporine can potentially have a better overall advantage in treatment of SJS/TEN over IVIG.¹ Although this study had an uneven number of patients treated with IVIG versus cyclosporine, a nonstandardized way of comparing patients with early SJS to TEN patients, and no double-blind randomized trial, cyclosporine may still show benefit over IVIG.

Singh et al⁶ conducted an uncontrolled open study in a tertiary care center (July 2011–June 2012) that showed a similar result of benefit with cyclosporine in SJS, SJS/TEN, and TEN patients. Eleven participants were included in the study based on SCORTEN (Score of Toxic Epidermal Necrosis) criteria (age, >40 years; heart rate, >120 BPM; serum blood urea nitrogen level, >28 mg/dL; body surface area affected, >10%; serum bicarbonate, >20 mEq/L; serum glucose, >252 mg/dL). They were treated with cyclosporine 3 mg/kg for 7 days and then tapered over another 7 days. Six participants were treated with corticosteroids. Participants treated with cyclosporine reepithelialized in 16.7 days compared to 23 days with corticosteroids. The hospital stay was 18.09 days in participants treated with cyclosporine versus 26 days in those treated with corticosteroids. Lastly, 2 participants who were treated with corticosteroids died as opposed to none with cyclosporine.⁶ Although the power of this study also was limited and it was not a randomized, double-blind, controlled trial, it provides more evidence that cyclosporine can be efficacious in SJS/TEN patients.

A phase 2 open trial conducted by Valeyrie-Allanore et al⁷ evaluated the benefit and efficacy of cyclosporine in SJS/TEN patients. There were 29 participants at the start of the study (SJS, n=10; SJS/TEN, n=12; TEN, n=7) and 26 completed treatment. Cyclosporine was administered orally at 3 mg/kg for 10 days and tapered over the following month. This study noted 3 basic principles: First, patients tolerated cyclosporine well; second, limited disease progression was noted in 62% (18/29) of participants around day 3 and in only about 35% (11/29) of IVIG patients; and third, no deaths were noted in all participants.⁷

Final Thoughts

Case reports have indicated that cyclosporine may be effective in limiting progression of SJS/TEN; however, a double-blind study has not validated this finding. Hence, patients should be evaluated on a case-by-case basis to determine if they should be treated with cyclosporine or IVIG or simply complete the course of the disease process with supportive care.

As dermatology residents, the telephone calls we get at 2 am usually are the toughest for 2 reasons: (1) we rarely get calls at 2 am, and (2) it usually means there is a case to rule out Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Stevens-Johnson syndrome and TEN are severe mucocutaneous eruptions that usually develop due to drug reactions and involve a continuum of conjunctivitis, mucocutaneous sloughing, keratinocyte death, and bullae development. Body surface area (BSA) coverage determines the distinction between SJS and TEN; less than 10% BSA affected indicates SJS, 10% to 30% BSA affected indicates overlap between SJS and TEN, and greater than 30% BSA affected indicates TEN.¹ The mortality rates for these conditions range from 1% to 5% in SJS versus 25% to 30% in TEN.²

Being driven and dedicated residents, we rise to the challenge by arranging appropriate consultations, obtaining frozen section biopsies, providing recommendations to remove unnecessary medications, and offering skin care management. However, what comes next? Intravenous immunoglobulin (IVIG)? Cyclosporine? Or is it appropriate to allow the reaction to continue its course? Dermatology programs have a varying standard of care due to the limited number of studies conducted on SJS/TEN patients. Few studies have relayed the efficacy of cyclosporine; however, published results have shown that cyclosporine can decrease the overall mortality risk and minimize disease progression.^2-5 In this article, I will review some of the key studies conducted in the last 5 years regarding the use of cyclosporine in the therapeutic plan for SJS/TEN.

In one retrospective analysis conducted by Kirchhof et al¹ in 2014, 35 patients with SJS/TEN who were treated with IVIG and 15 who were treated with cyclosporine were evaluated for mortality benefit. Two patients were treated with both cyclosporine and IVIG and were included in both arms of the study. Overall, the evaluation indicated that cyclosporine can potentially have a better overall advantage in treatment of SJS/TEN over IVIG.¹ Although this study had an uneven number of patients treated with IVIG versus cyclosporine, a nonstandardized way of comparing patients with early SJS to TEN patients, and no double-blind randomized trial, cyclosporine may still show benefit over IVIG.

Singh et al⁶ conducted an uncontrolled open study in a tertiary care center (July 2011–June 2012) that showed a similar result of benefit with cyclosporine in SJS, SJS/TEN, and TEN patients. Eleven participants were included in the study based on SCORTEN (Score of Toxic Epidermal Necrosis) criteria (age, >40 years; heart rate, >120 BPM; serum blood urea nitrogen level, >28 mg/dL; body surface area affected, >10%; serum bicarbonate, >20 mEq/L; serum glucose, >252 mg/dL). They were treated with cyclosporine 3 mg/kg for 7 days and then tapered over another 7 days. Six participants were treated with corticosteroids. Participants treated with cyclosporine reepithelialized in 16.7 days compared to 23 days with corticosteroids. The hospital stay was 18.09 days in participants treated with cyclosporine versus 26 days in those treated with corticosteroids. Lastly, 2 participants who were treated with corticosteroids died as opposed to none with cyclosporine.⁶ Although the power of this study also was limited and it was not a randomized, double-blind, controlled trial, it provides more evidence that cyclosporine can be efficacious in SJS/TEN patients.

A phase 2 open trial conducted by Valeyrie-Allanore et al⁷ evaluated the benefit and efficacy of cyclosporine in SJS/TEN patients. There were 29 participants at the start of the study (SJS, n=10; SJS/TEN, n=12; TEN, n=7) and 26 completed treatment. Cyclosporine was administered orally at 3 mg/kg for 10 days and tapered over the following month. This study noted 3 basic principles: First, patients tolerated cyclosporine well; second, limited disease progression was noted in 62% (18/29) of participants around day 3 and in only about 35% (11/29) of IVIG patients; and third, no deaths were noted in all participants.⁷

Final Thoughts

Case reports have indicated that cyclosporine may be effective in limiting progression of SJS/TEN; however, a double-blind study has not validated this finding. Hence, patients should be evaluated on a case-by-case basis to determine if they should be treated with cyclosporine or IVIG or simply complete the course of the disease process with supportive care.

As dermatology residents, the telephone calls we get at 2 am usually are the toughest for 2 reasons: (1) we rarely get calls at 2 am, and (2) it usually means there is a case to rule out Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Stevens-Johnson syndrome and TEN are severe mucocutaneous eruptions that usually develop due to drug reactions and involve a continuum of conjunctivitis, mucocutaneous sloughing, keratinocyte death, and bullae development. Body surface area (BSA) coverage determines the distinction between SJS and TEN; less than 10% BSA affected indicates SJS, 10% to 30% BSA affected indicates overlap between SJS and TEN, and greater than 30% BSA affected indicates TEN.¹ The mortality rates for these conditions range from 1% to 5% in SJS versus 25% to 30% in TEN.²

Being driven and dedicated residents, we rise to the challenge by arranging appropriate consultations, obtaining frozen section biopsies, providing recommendations to remove unnecessary medications, and offering skin care management. However, what comes next? Intravenous immunoglobulin (IVIG)? Cyclosporine? Or is it appropriate to allow the reaction to continue its course? Dermatology programs have a varying standard of care due to the limited number of studies conducted on SJS/TEN patients. Few studies have relayed the efficacy of cyclosporine; however, published results have shown that cyclosporine can decrease the overall mortality risk and minimize disease progression.^2-5 In this article, I will review some of the key studies conducted in the last 5 years regarding the use of cyclosporine in the therapeutic plan for SJS/TEN.

In one retrospective analysis conducted by Kirchhof et al¹ in 2014, 35 patients with SJS/TEN who were treated with IVIG and 15 who were treated with cyclosporine were evaluated for mortality benefit. Two patients were treated with both cyclosporine and IVIG and were included in both arms of the study. Overall, the evaluation indicated that cyclosporine can potentially have a better overall advantage in treatment of SJS/TEN over IVIG.¹ Although this study had an uneven number of patients treated with IVIG versus cyclosporine, a nonstandardized way of comparing patients with early SJS to TEN patients, and no double-blind randomized trial, cyclosporine may still show benefit over IVIG.

Singh et al⁶ conducted an uncontrolled open study in a tertiary care center (July 2011–June 2012) that showed a similar result of benefit with cyclosporine in SJS, SJS/TEN, and TEN patients. Eleven participants were included in the study based on SCORTEN (Score of Toxic Epidermal Necrosis) criteria (age, >40 years; heart rate, >120 BPM; serum blood urea nitrogen level, >28 mg/dL; body surface area affected, >10%; serum bicarbonate, >20 mEq/L; serum glucose, >252 mg/dL). They were treated with cyclosporine 3 mg/kg for 7 days and then tapered over another 7 days. Six participants were treated with corticosteroids. Participants treated with cyclosporine reepithelialized in 16.7 days compared to 23 days with corticosteroids. The hospital stay was 18.09 days in participants treated with cyclosporine versus 26 days in those treated with corticosteroids. Lastly, 2 participants who were treated with corticosteroids died as opposed to none with cyclosporine.⁶ Although the power of this study also was limited and it was not a randomized, double-blind, controlled trial, it provides more evidence that cyclosporine can be efficacious in SJS/TEN patients.

A phase 2 open trial conducted by Valeyrie-Allanore et al⁷ evaluated the benefit and efficacy of cyclosporine in SJS/TEN patients. There were 29 participants at the start of the study (SJS, n=10; SJS/TEN, n=12; TEN, n=7) and 26 completed treatment. Cyclosporine was administered orally at 3 mg/kg for 10 days and tapered over the following month. This study noted 3 basic principles: First, patients tolerated cyclosporine well; second, limited disease progression was noted in 62% (18/29) of participants around day 3 and in only about 35% (11/29) of IVIG patients; and third, no deaths were noted in all participants.⁷

Final Thoughts

Case reports have indicated that cyclosporine may be effective in limiting progression of SJS/TEN; however, a double-blind study has not validated this finding. Hence, patients should be evaluated on a case-by-case basis to determine if they should be treated with cyclosporine or IVIG or simply complete the course of the disease process with supportive care.

Postinflammatory hyperpigmentation (PIH) develops as darkly pigmented macules that occur after an inflammatory process of the skin such as acne, folliculitis, eczema, or shaving irritation. Patients with Fitzpatrick skin types III to VI usually are most commonly affected, and for many, the remnant pigmentation can be an even greater concern than the original inflammatory process.^1,2 Reported treatments of PIH include tretinoin, hydroquinone, azelaic acid, and chemical peels. The ideal combination of therapy has yet to be delineated.

Tretinoin (Vitamin A Derivative)

Bulengo-Ransby et al³ performed one of the first clinical trials testing tretinoin cream 0.1% for PIH in patients with Fitzpatrick skin types IV to VI . The study included 54 patients (24 applied tretinoin and 30 applied a vehicle) with moderate to severe PIH on the face and arms. The patients were divided into therapy and placebo groups and were evaluated for 40 weeks. Changes were evaluated through colorimetry, light microscopy, histology, and photography, with significant clinical improvement in the tretinoin-treated group (P<.001).³ A double-blind, randomized study of 45 photoaged Chinese and Japanese patients using tretinoin cream 0.1% also was conducted for treatment of photoaging-associated hyperpigmented lesions of the face and hands. Assessment was done with clinical, colorimetric, and histological evaluation, with an overall statistical improvement noted in hyperpigmentation.⁴ Both of the above studies showed mild irritation (ie, retinoid dermatitis) with application of tretinoin, which creates a compliance issue in patients who are recommended to continue therapy with higher-strength tretinoin. This side-effect profile can be circumvented through gradual elevation in the strength of tretinoin.⁵

Combination Therapies

Combination therapies with tretinoin also have been used to improve PIH. Callender et al⁶ conducted a study evaluating the efficacy of clindamycin phosphate 1.2%–tretinoin 0.025% gel for the treatment of PIH secondary to mild to moderate acne in patients with Fitzpatrick skin types IV to VI. Thirty patients participated in the randomized, double-blinded, placebo-controlled study, with 15 patients in the clindamycin-tretinoin gel group and 15 in the placebo control group. Based on objective assessment using a chromameter and evaluator global acne severity scale score, clinical efficacy was demonstrated for treating acne and PIH as well as preventing further PIH.⁶

Hydroquinone Formulation (Tyrosine Inhibitor)

Hydroquinone bleaching cream has been the standard therapy for hyperpigmentation. It works by blocking the conversion of dihydroxyphenylalanine to melanin by inhibiting tyrosinase.⁷ Topical steroids directly inhibit the synthesis of melanin, and when combined with hydroquinone and tretinoin, they can be effective for short periods of time and may decrease the irritation of application.^7,8 The most widely accepted formula consists of a topical steroid (triamcinolone cream 0.1%) in combination with hydroquinone 4% and tretinoin cream 0.05%.⁸ In a similar 12-week open-label study of 25 patients with darker skin types, Grimes⁹ used an alternative combination formula of hydroquinone 4% and retinol 0.15%. Overall improvement and tolerance was demonstrated through the use of colorimetry measurement. A combination of hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01% also has been used effectively for the treatment of melasma.¹⁰ This formulation has been used more anecdotally for the treatment of PIH and has yet to have a randomized-controlled trial. The concern with repeated long-term use of hydroquinone remains. Permanent leukoderma, exogenous ochronosis, and hyperpigmentation of the surrounding normal skin (halo effect) can occur.

Azelaic Acid (Tyrosinase Inhibitor)

Azelaic acid is a dicarboxylic acid isolated from pityriasis versicolor that acts similar to a tyrosine inhibitor and has an antiproliferative effect toward abnormal melanocytes. Lowe et al¹¹ conducted a randomized, double-blind, vehicle-controlled trial in patients with Fitzpatrick skin types IV through VI with facial hyperpigmentation using azelaic acid cream 20%. Over the course of 24 weeks, patients noted a decrease in overall pigment using both an investigator subjective scale and chromometer analysis.¹¹

Kojic Acid (Tyrosinase Inhibitor)

Kojic acid is a tyrosinase inhibitor found in fungal metabolite species such as Acetobacter, Aspergillus, and Penicillium. It is commonly combined with other skin lightening agents such as hydroquinone or vitamin C to further enhance its efficacy. A randomized, 12-week, split-face study of Chinese women with melasma compared treatment with a glycolic acid 10%–hydroquinone 2% gel versus the combination plus kojic acid 2%. The results showed that 60% (24/40) of patients improved with the use of kojic acid as compared to those using the medication without kojic acid.¹² Anecdotal data suggest kojic acid may be effective for PIH¹³; however, no studies specifically for PIH have been conducted.

Chemical Peels

Chemical peels have been used for a number of years, though their benefits in patients with skin of color is still being elucidated. The ideal chemical peels for Fitzpatrick skin types IV through VI are superficial to medium-depth peeling agents and techniques.¹⁴ Glycolic acid is a naturally occurring α-hydroxy acid that causes an increase in collagen synthesis, stimulates epidermolysis, and disperses basal layer melanin. Neutralization of glycolic acid peels can be done with the use of water, sodium bicarbonate, or sodium hydroxide to avoid unnecessary epidermal damage. Multiple clinical trials have been conducted to determine the response of glycolic acid peels in clearing PIH in patients with skin of color. Kessler et al¹⁵ compared glycolic acid 30% to salicylic acid 30% in 20 patients with mild to moderate acne and associated PIH. Chemical peels were performed every 2 weeks for 12 weeks. The study showed that salicylic acid was better tolerated than glycolic acid and both were equally effective after the second application (P<.05) for PIH.¹⁵ Finally, another study conducted for PIH in patients with Fitzpatrick skin types III and IV utilized glycolic acid peels with 20%, 35%, and 70% concentrations. The results showed overall improvement of PIH and acne from the use of all concentrations of glycolic peels, though faster efficacy was noted at higher concentrations.¹⁶

Other self-neutralizing peeling agents include salicylic acid and Jessner solution. Salicylic acid is a β-hydroxy acid that works through keratolysis and disrupting intercellular linkages. Jessner solution is a combination of resorcinol 14%, lactic acid 14%, and salicylic acid 14% in an alcohol base. Salicylic acid is well-tolerated in patients with Fitzpatrick skin types I through VI and has been helpful in treating acne, rosacea, melasma, hyperpigmentation, texturally rough skin, and mild photoaging. Jessner peeling solution has been used for a number of years and works as a keratolytic agent causing intercellular and intracellular edema, and due to its self-neutralizing agent, it is fairly superficial.¹⁷ Overall, superficial peeling agents should be used on patients with darker skin types to avoid the risk for worsening dyspigmentation, keloid formation, or deep scarring.¹⁸

Conclusion

These treatments are only some of the topical and chemical modalities for PIH in patients with skin of color. The patient history, evaluation, skin type, and underlying medical problems should be considered prior to using any topical or peeling agent. Lastly, photoprotection should be heavily emphasized with both sun protective gear and use of broad-spectrum sunscreens with a high sun protection factor, as UV radiation can cause darkening of PIH areas regardless of skin type and can reverse the progress made by a given therapy.¹⁸

Postinflammatory hyperpigmentation (PIH) develops as darkly pigmented macules that occur after an inflammatory process of the skin such as acne, folliculitis, eczema, or shaving irritation. Patients with Fitzpatrick skin types III to VI usually are most commonly affected, and for many, the remnant pigmentation can be an even greater concern than the original inflammatory process.^1,2 Reported treatments of PIH include tretinoin, hydroquinone, azelaic acid, and chemical peels. The ideal combination of therapy has yet to be delineated.

Tretinoin (Vitamin A Derivative)

Bulengo-Ransby et al³ performed one of the first clinical trials testing tretinoin cream 0.1% for PIH in patients with Fitzpatrick skin types IV to VI . The study included 54 patients (24 applied tretinoin and 30 applied a vehicle) with moderate to severe PIH on the face and arms. The patients were divided into therapy and placebo groups and were evaluated for 40 weeks. Changes were evaluated through colorimetry, light microscopy, histology, and photography, with significant clinical improvement in the tretinoin-treated group (P<.001).³ A double-blind, randomized study of 45 photoaged Chinese and Japanese patients using tretinoin cream 0.1% also was conducted for treatment of photoaging-associated hyperpigmented lesions of the face and hands. Assessment was done with clinical, colorimetric, and histological evaluation, with an overall statistical improvement noted in hyperpigmentation.⁴ Both of the above studies showed mild irritation (ie, retinoid dermatitis) with application of tretinoin, which creates a compliance issue in patients who are recommended to continue therapy with higher-strength tretinoin. This side-effect profile can be circumvented through gradual elevation in the strength of tretinoin.⁵

Combination Therapies

Combination therapies with tretinoin also have been used to improve PIH. Callender et al⁶ conducted a study evaluating the efficacy of clindamycin phosphate 1.2%–tretinoin 0.025% gel for the treatment of PIH secondary to mild to moderate acne in patients with Fitzpatrick skin types IV to VI. Thirty patients participated in the randomized, double-blinded, placebo-controlled study, with 15 patients in the clindamycin-tretinoin gel group and 15 in the placebo control group. Based on objective assessment using a chromameter and evaluator global acne severity scale score, clinical efficacy was demonstrated for treating acne and PIH as well as preventing further PIH.⁶

Hydroquinone Formulation (Tyrosine Inhibitor)

Hydroquinone bleaching cream has been the standard therapy for hyperpigmentation. It works by blocking the conversion of dihydroxyphenylalanine to melanin by inhibiting tyrosinase.⁷ Topical steroids directly inhibit the synthesis of melanin, and when combined with hydroquinone and tretinoin, they can be effective for short periods of time and may decrease the irritation of application.^7,8 The most widely accepted formula consists of a topical steroid (triamcinolone cream 0.1%) in combination with hydroquinone 4% and tretinoin cream 0.05%.⁸ In a similar 12-week open-label study of 25 patients with darker skin types, Grimes⁹ used an alternative combination formula of hydroquinone 4% and retinol 0.15%. Overall improvement and tolerance was demonstrated through the use of colorimetry measurement. A combination of hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01% also has been used effectively for the treatment of melasma.¹⁰ This formulation has been used more anecdotally for the treatment of PIH and has yet to have a randomized-controlled trial. The concern with repeated long-term use of hydroquinone remains. Permanent leukoderma, exogenous ochronosis, and hyperpigmentation of the surrounding normal skin (halo effect) can occur.

Azelaic Acid (Tyrosinase Inhibitor)

Azelaic acid is a dicarboxylic acid isolated from pityriasis versicolor that acts similar to a tyrosine inhibitor and has an antiproliferative effect toward abnormal melanocytes. Lowe et al¹¹ conducted a randomized, double-blind, vehicle-controlled trial in patients with Fitzpatrick skin types IV through VI with facial hyperpigmentation using azelaic acid cream 20%. Over the course of 24 weeks, patients noted a decrease in overall pigment using both an investigator subjective scale and chromometer analysis.¹¹

Kojic Acid (Tyrosinase Inhibitor)

Kojic acid is a tyrosinase inhibitor found in fungal metabolite species such as Acetobacter, Aspergillus, and Penicillium. It is commonly combined with other skin lightening agents such as hydroquinone or vitamin C to further enhance its efficacy. A randomized, 12-week, split-face study of Chinese women with melasma compared treatment with a glycolic acid 10%–hydroquinone 2% gel versus the combination plus kojic acid 2%. The results showed that 60% (24/40) of patients improved with the use of kojic acid as compared to those using the medication without kojic acid.¹² Anecdotal data suggest kojic acid may be effective for PIH¹³; however, no studies specifically for PIH have been conducted.

Chemical Peels

Chemical peels have been used for a number of years, though their benefits in patients with skin of color is still being elucidated. The ideal chemical peels for Fitzpatrick skin types IV through VI are superficial to medium-depth peeling agents and techniques.¹⁴ Glycolic acid is a naturally occurring α-hydroxy acid that causes an increase in collagen synthesis, stimulates epidermolysis, and disperses basal layer melanin. Neutralization of glycolic acid peels can be done with the use of water, sodium bicarbonate, or sodium hydroxide to avoid unnecessary epidermal damage. Multiple clinical trials have been conducted to determine the response of glycolic acid peels in clearing PIH in patients with skin of color. Kessler et al¹⁵ compared glycolic acid 30% to salicylic acid 30% in 20 patients with mild to moderate acne and associated PIH. Chemical peels were performed every 2 weeks for 12 weeks. The study showed that salicylic acid was better tolerated than glycolic acid and both were equally effective after the second application (P<.05) for PIH.¹⁵ Finally, another study conducted for PIH in patients with Fitzpatrick skin types III and IV utilized glycolic acid peels with 20%, 35%, and 70% concentrations. The results showed overall improvement of PIH and acne from the use of all concentrations of glycolic peels, though faster efficacy was noted at higher concentrations.¹⁶

Other self-neutralizing peeling agents include salicylic acid and Jessner solution. Salicylic acid is a β-hydroxy acid that works through keratolysis and disrupting intercellular linkages. Jessner solution is a combination of resorcinol 14%, lactic acid 14%, and salicylic acid 14% in an alcohol base. Salicylic acid is well-tolerated in patients with Fitzpatrick skin types I through VI and has been helpful in treating acne, rosacea, melasma, hyperpigmentation, texturally rough skin, and mild photoaging. Jessner peeling solution has been used for a number of years and works as a keratolytic agent causing intercellular and intracellular edema, and due to its self-neutralizing agent, it is fairly superficial.¹⁷ Overall, superficial peeling agents should be used on patients with darker skin types to avoid the risk for worsening dyspigmentation, keloid formation, or deep scarring.¹⁸

Conclusion

These treatments are only some of the topical and chemical modalities for PIH in patients with skin of color. The patient history, evaluation, skin type, and underlying medical problems should be considered prior to using any topical or peeling agent. Lastly, photoprotection should be heavily emphasized with both sun protective gear and use of broad-spectrum sunscreens with a high sun protection factor, as UV radiation can cause darkening of PIH areas regardless of skin type and can reverse the progress made by a given therapy.¹⁸

Postinflammatory hyperpigmentation (PIH) develops as darkly pigmented macules that occur after an inflammatory process of the skin such as acne, folliculitis, eczema, or shaving irritation. Patients with Fitzpatrick skin types III to VI usually are most commonly affected, and for many, the remnant pigmentation can be an even greater concern than the original inflammatory process.^1,2 Reported treatments of PIH include tretinoin, hydroquinone, azelaic acid, and chemical peels. The ideal combination of therapy has yet to be delineated.

Tretinoin (Vitamin A Derivative)

Bulengo-Ransby et al³ performed one of the first clinical trials testing tretinoin cream 0.1% for PIH in patients with Fitzpatrick skin types IV to VI . The study included 54 patients (24 applied tretinoin and 30 applied a vehicle) with moderate to severe PIH on the face and arms. The patients were divided into therapy and placebo groups and were evaluated for 40 weeks. Changes were evaluated through colorimetry, light microscopy, histology, and photography, with significant clinical improvement in the tretinoin-treated group (P<.001).³ A double-blind, randomized study of 45 photoaged Chinese and Japanese patients using tretinoin cream 0.1% also was conducted for treatment of photoaging-associated hyperpigmented lesions of the face and hands. Assessment was done with clinical, colorimetric, and histological evaluation, with an overall statistical improvement noted in hyperpigmentation.⁴ Both of the above studies showed mild irritation (ie, retinoid dermatitis) with application of tretinoin, which creates a compliance issue in patients who are recommended to continue therapy with higher-strength tretinoin. This side-effect profile can be circumvented through gradual elevation in the strength of tretinoin.⁵

Combination Therapies

Combination therapies with tretinoin also have been used to improve PIH. Callender et al⁶ conducted a study evaluating the efficacy of clindamycin phosphate 1.2%–tretinoin 0.025% gel for the treatment of PIH secondary to mild to moderate acne in patients with Fitzpatrick skin types IV to VI. Thirty patients participated in the randomized, double-blinded, placebo-controlled study, with 15 patients in the clindamycin-tretinoin gel group and 15 in the placebo control group. Based on objective assessment using a chromameter and evaluator global acne severity scale score, clinical efficacy was demonstrated for treating acne and PIH as well as preventing further PIH.⁶

Hydroquinone Formulation (Tyrosine Inhibitor)

Hydroquinone bleaching cream has been the standard therapy for hyperpigmentation. It works by blocking the conversion of dihydroxyphenylalanine to melanin by inhibiting tyrosinase.⁷ Topical steroids directly inhibit the synthesis of melanin, and when combined with hydroquinone and tretinoin, they can be effective for short periods of time and may decrease the irritation of application.^7,8 The most widely accepted formula consists of a topical steroid (triamcinolone cream 0.1%) in combination with hydroquinone 4% and tretinoin cream 0.05%.⁸ In a similar 12-week open-label study of 25 patients with darker skin types, Grimes⁹ used an alternative combination formula of hydroquinone 4% and retinol 0.15%. Overall improvement and tolerance was demonstrated through the use of colorimetry measurement. A combination of hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01% also has been used effectively for the treatment of melasma.¹⁰ This formulation has been used more anecdotally for the treatment of PIH and has yet to have a randomized-controlled trial. The concern with repeated long-term use of hydroquinone remains. Permanent leukoderma, exogenous ochronosis, and hyperpigmentation of the surrounding normal skin (halo effect) can occur.

Azelaic Acid (Tyrosinase Inhibitor)

Azelaic acid is a dicarboxylic acid isolated from pityriasis versicolor that acts similar to a tyrosine inhibitor and has an antiproliferative effect toward abnormal melanocytes. Lowe et al¹¹ conducted a randomized, double-blind, vehicle-controlled trial in patients with Fitzpatrick skin types IV through VI with facial hyperpigmentation using azelaic acid cream 20%. Over the course of 24 weeks, patients noted a decrease in overall pigment using both an investigator subjective scale and chromometer analysis.¹¹

Kojic Acid (Tyrosinase Inhibitor)

Kojic acid is a tyrosinase inhibitor found in fungal metabolite species such as Acetobacter, Aspergillus, and Penicillium. It is commonly combined with other skin lightening agents such as hydroquinone or vitamin C to further enhance its efficacy. A randomized, 12-week, split-face study of Chinese women with melasma compared treatment with a glycolic acid 10%–hydroquinone 2% gel versus the combination plus kojic acid 2%. The results showed that 60% (24/40) of patients improved with the use of kojic acid as compared to those using the medication without kojic acid.¹² Anecdotal data suggest kojic acid may be effective for PIH¹³; however, no studies specifically for PIH have been conducted.

Chemical Peels

Chemical peels have been used for a number of years, though their benefits in patients with skin of color is still being elucidated. The ideal chemical peels for Fitzpatrick skin types IV through VI are superficial to medium-depth peeling agents and techniques.¹⁴ Glycolic acid is a naturally occurring α-hydroxy acid that causes an increase in collagen synthesis, stimulates epidermolysis, and disperses basal layer melanin. Neutralization of glycolic acid peels can be done with the use of water, sodium bicarbonate, or sodium hydroxide to avoid unnecessary epidermal damage. Multiple clinical trials have been conducted to determine the response of glycolic acid peels in clearing PIH in patients with skin of color. Kessler et al¹⁵ compared glycolic acid 30% to salicylic acid 30% in 20 patients with mild to moderate acne and associated PIH. Chemical peels were performed every 2 weeks for 12 weeks. The study showed that salicylic acid was better tolerated than glycolic acid and both were equally effective after the second application (P<.05) for PIH.¹⁵ Finally, another study conducted for PIH in patients with Fitzpatrick skin types III and IV utilized glycolic acid peels with 20%, 35%, and 70% concentrations. The results showed overall improvement of PIH and acne from the use of all concentrations of glycolic peels, though faster efficacy was noted at higher concentrations.¹⁶

Other self-neutralizing peeling agents include salicylic acid and Jessner solution. Salicylic acid is a β-hydroxy acid that works through keratolysis and disrupting intercellular linkages. Jessner solution is a combination of resorcinol 14%, lactic acid 14%, and salicylic acid 14% in an alcohol base. Salicylic acid is well-tolerated in patients with Fitzpatrick skin types I through VI and has been helpful in treating acne, rosacea, melasma, hyperpigmentation, texturally rough skin, and mild photoaging. Jessner peeling solution has been used for a number of years and works as a keratolytic agent causing intercellular and intracellular edema, and due to its self-neutralizing agent, it is fairly superficial.¹⁷ Overall, superficial peeling agents should be used on patients with darker skin types to avoid the risk for worsening dyspigmentation, keloid formation, or deep scarring.¹⁸

Conclusion

These treatments are only some of the topical and chemical modalities for PIH in patients with skin of color. The patient history, evaluation, skin type, and underlying medical problems should be considered prior to using any topical or peeling agent. Lastly, photoprotection should be heavily emphasized with both sun protective gear and use of broad-spectrum sunscreens with a high sun protection factor, as UV radiation can cause darkening of PIH areas regardless of skin type and can reverse the progress made by a given therapy.¹⁸