Cutis

Myth: Sunscreens cause cancer

Regular sunscreen use is recommended by the American Academy of Dermatology as a primary method of sun protection to reduce the risk of melanoma and other nonmelanoma skin cancers. However, due to reports in the media, patients often inquire if sunscreen ingredients, specifically oxybenzone and retinyl palmitate as well as nanoparticles, are toxic and actually cause malignant melanoma and other skin cancers rather than prevent them.

Overall, the known benefits of sunscreen use to minimize short-term and long-term damage to the skin from UV radiation outweigh any unproven claims of toxicity or human health hazard. Active ingredients in sunscreens, such as oxybenzone and retinyl palmitate, are regulated as over-the-counter drugs by the US Food and Drug Administration and have a long-standing history of providing effective broad-spectrum protection from UV radiation. Despite concerns that oxybenzone can penetrate the skin and effect hormone levels, there is no evidence supporting this claim. Although oxybenzone is absorbed by the body, it is subsequently excreted and has no potential for harmful buildup. It also has been suggested that retinyl palmitate generates free radicals that can lead to cancer formation; however, the risk has only been linked to UV exposure in isolation, and antioxidants in the body can theoretically neutralize these free radicals before they lead to cancer development.

Sunscreens containing nanoparticles of inorganic filters such as zinc oxide and titanium dioxide also have been scrutinized. These formulations have largely proven effective in protecting against UVA and UVB radiation, and claims that nanoparticles are small enough to penetrate the epidermis and be absorbed in the human bloodstream have been refuted.

The positive association between sunscreen use and risk of developing malignant melanoma may be due to selection bias and uncontrolled confounding in studies rather than proven toxicity of sunscreen ingredients. Results from a meta-analysis of 11 case-control studies indicated that there is no association and the researchers discussed the role of selection bias in contributing to the positive association between sunscreen use and melanoma development. For instance, some studies failed to control for factors that commonly are linked with increased melanoma risk (eg, red or fair hair color, blue eye color, presence of nevi, freckling). Also, increased sun exposure among patients who use sunscreens may have impacted study results.

Dermatologists should emphasize to concerned patients that long-term sunscreen use has been proven to reduce the incidence of melanoma. A 2011 Australian study evaluated the effects of long-term application of sunscreen on the risk of cutaneous melanoma in 1621 randomly selected participants who applied sunscreen in combination with 30 mg of beta-carotene or placebo supplements for 4 years and were observed for 10 more years. They observed a reduction in primary melanomas and invasive melanomas in the sunscreen group, concluding that melanoma may be preventable with regular sunscreen use in adults.

For patients who are still concerned, dermatologists can recommend sunscreens containing organic UV filters only. Education about factors that contribute to the increased rate of melanoma also is necessary. Longer lifespans, the thinning ozone layer, increased popularity of outdoor activities, exposed skin due to clothing style, use of tanning beds, earlier detection of skin cancer, and other factors may be responsible. Greater exposure to UV radiation rather than commercial sunscreens is the likely cause of skin cancer.

Myth: Sunscreens cause cancer

Regular sunscreen use is recommended by the American Academy of Dermatology as a primary method of sun protection to reduce the risk of melanoma and other nonmelanoma skin cancers. However, due to reports in the media, patients often inquire if sunscreen ingredients, specifically oxybenzone and retinyl palmitate as well as nanoparticles, are toxic and actually cause malignant melanoma and other skin cancers rather than prevent them.

Overall, the known benefits of sunscreen use to minimize short-term and long-term damage to the skin from UV radiation outweigh any unproven claims of toxicity or human health hazard. Active ingredients in sunscreens, such as oxybenzone and retinyl palmitate, are regulated as over-the-counter drugs by the US Food and Drug Administration and have a long-standing history of providing effective broad-spectrum protection from UV radiation. Despite concerns that oxybenzone can penetrate the skin and effect hormone levels, there is no evidence supporting this claim. Although oxybenzone is absorbed by the body, it is subsequently excreted and has no potential for harmful buildup. It also has been suggested that retinyl palmitate generates free radicals that can lead to cancer formation; however, the risk has only been linked to UV exposure in isolation, and antioxidants in the body can theoretically neutralize these free radicals before they lead to cancer development.

Sunscreens containing nanoparticles of inorganic filters such as zinc oxide and titanium dioxide also have been scrutinized. These formulations have largely proven effective in protecting against UVA and UVB radiation, and claims that nanoparticles are small enough to penetrate the epidermis and be absorbed in the human bloodstream have been refuted.

The positive association between sunscreen use and risk of developing malignant melanoma may be due to selection bias and uncontrolled confounding in studies rather than proven toxicity of sunscreen ingredients. Results from a meta-analysis of 11 case-control studies indicated that there is no association and the researchers discussed the role of selection bias in contributing to the positive association between sunscreen use and melanoma development. For instance, some studies failed to control for factors that commonly are linked with increased melanoma risk (eg, red or fair hair color, blue eye color, presence of nevi, freckling). Also, increased sun exposure among patients who use sunscreens may have impacted study results.

Dermatologists should emphasize to concerned patients that long-term sunscreen use has been proven to reduce the incidence of melanoma. A 2011 Australian study evaluated the effects of long-term application of sunscreen on the risk of cutaneous melanoma in 1621 randomly selected participants who applied sunscreen in combination with 30 mg of beta-carotene or placebo supplements for 4 years and were observed for 10 more years. They observed a reduction in primary melanomas and invasive melanomas in the sunscreen group, concluding that melanoma may be preventable with regular sunscreen use in adults.

For patients who are still concerned, dermatologists can recommend sunscreens containing organic UV filters only. Education about factors that contribute to the increased rate of melanoma also is necessary. Longer lifespans, the thinning ozone layer, increased popularity of outdoor activities, exposed skin due to clothing style, use of tanning beds, earlier detection of skin cancer, and other factors may be responsible. Greater exposure to UV radiation rather than commercial sunscreens is the likely cause of skin cancer.

Myth: Sunscreens cause cancer

Regular sunscreen use is recommended by the American Academy of Dermatology as a primary method of sun protection to reduce the risk of melanoma and other nonmelanoma skin cancers. However, due to reports in the media, patients often inquire if sunscreen ingredients, specifically oxybenzone and retinyl palmitate as well as nanoparticles, are toxic and actually cause malignant melanoma and other skin cancers rather than prevent them.

Overall, the known benefits of sunscreen use to minimize short-term and long-term damage to the skin from UV radiation outweigh any unproven claims of toxicity or human health hazard. Active ingredients in sunscreens, such as oxybenzone and retinyl palmitate, are regulated as over-the-counter drugs by the US Food and Drug Administration and have a long-standing history of providing effective broad-spectrum protection from UV radiation. Despite concerns that oxybenzone can penetrate the skin and effect hormone levels, there is no evidence supporting this claim. Although oxybenzone is absorbed by the body, it is subsequently excreted and has no potential for harmful buildup. It also has been suggested that retinyl palmitate generates free radicals that can lead to cancer formation; however, the risk has only been linked to UV exposure in isolation, and antioxidants in the body can theoretically neutralize these free radicals before they lead to cancer development.

Sunscreens containing nanoparticles of inorganic filters such as zinc oxide and titanium dioxide also have been scrutinized. These formulations have largely proven effective in protecting against UVA and UVB radiation, and claims that nanoparticles are small enough to penetrate the epidermis and be absorbed in the human bloodstream have been refuted.

The positive association between sunscreen use and risk of developing malignant melanoma may be due to selection bias and uncontrolled confounding in studies rather than proven toxicity of sunscreen ingredients. Results from a meta-analysis of 11 case-control studies indicated that there is no association and the researchers discussed the role of selection bias in contributing to the positive association between sunscreen use and melanoma development. For instance, some studies failed to control for factors that commonly are linked with increased melanoma risk (eg, red or fair hair color, blue eye color, presence of nevi, freckling). Also, increased sun exposure among patients who use sunscreens may have impacted study results.

Dermatologists should emphasize to concerned patients that long-term sunscreen use has been proven to reduce the incidence of melanoma. A 2011 Australian study evaluated the effects of long-term application of sunscreen on the risk of cutaneous melanoma in 1621 randomly selected participants who applied sunscreen in combination with 30 mg of beta-carotene or placebo supplements for 4 years and were observed for 10 more years. They observed a reduction in primary melanomas and invasive melanomas in the sunscreen group, concluding that melanoma may be preventable with regular sunscreen use in adults.

For patients who are still concerned, dermatologists can recommend sunscreens containing organic UV filters only. Education about factors that contribute to the increased rate of melanoma also is necessary. Longer lifespans, the thinning ozone layer, increased popularity of outdoor activities, exposed skin due to clothing style, use of tanning beds, earlier detection of skin cancer, and other factors may be responsible. Greater exposure to UV radiation rather than commercial sunscreens is the likely cause of skin cancer.

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.

Myth: Psoriasis treatments may cause depression

It has been well documented that patients with inflammatory diseases such as psoriasis have an increased risk for depression. One population-based cohort study in the United Kingdom reported the risk of depression was greater in patients with severe psoriasis versus mild psoriasis. Younger psoriasis patients also had a higher risk compared to older patients. A US population-based study also reported that psoriasis was associated with major depression, but the severity of psoriasis and patient's age were unrelated. Therefore, all psoriasis patients may be at risk.

But are some therapies associated with an increased risk of depression? Increased concentrations of proinflammatory cytokines such as tumor necrosis factor α have been associated with depression apart from psoriasis. Administering immunomodulating agents has been shown to increase the risk of depression.

Depression has been cited as an adverse effect of apremilast in the drug's package insert, which states, "Before using [apremilast] in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment." In clinical trials, 1.3% (12/920) of participants treated with apremilast reported depression compared to 0.4% (2/506) treated with placebo. Dermatologists should remain vigilant about monitoring for symptoms of depression in patients treated with apremilast.

However, depression in the context of autoimmune disorders or any disorder with increased inflammation has responded to treatment with tumor necrosis factor α antagonists. The relationship between depression and inflammation suggests that there is an inflammatory subtype of depression and use of anti-inflammatory agents may treat both inflammation and depression.

Disease control has been shown to improve symptoms of depression in psoriasis patients. A study of 618 patients with moderate to severe psoriasis who were treated with etanercept or placebo for 12 weeks revealed that more patients receiving etanercept experienced 50% improvement in 2 rating scales of depression compared to placebo.

Excessive worrying, a form of psychological distress, can impact treatment outcomes in patients with psoriasis. A 2003 study found that patients with psoriasis who are classified as high-level worriers may benefit from adjunctive psychological intervention before and during treatment. In this cohort of psoriasis patients receiving psoralen plus UVA (PUVA) therapy, high-level worry was the only significant predictor of time taken for PUVA to clear psoriasis (P=.01). Patients in the high-level worry group cleared with PUVA treatment at a rate of 1.8 times slower than the low-level worry group.

In conclusion, psoriasis patients should follow the treatment plan outlined by dermatologists, as improving psoriasis symptoms may help alleviate depression or prevent it from occurring. Patients with a history of depression should be monitored carefully by dermatologists or referred to another health care professional, and patients as well as family and friends should be encouraged to report any depression symptoms.

Expert Commentary

The prescribing information for apremilast lists a warning (but not a black-box warning) for depression. Long-term registries will determine if there is truly an increased risk of depression when taking apremilast. When I counsel patients before prescribing apremilast, I mention this potential increased risk of depression as noted in the prescribing information, but I tell them that the risk is very low and that a true risk has not yet been determined in long-term registries. I mention to patients that if they really do feel depressed after starting apremilast, they should stop taking apremilast and contact me.

Long-term registries for etanercept, adalimumab, infliximab, and ustekinumab do not indicate an increased risk for depression. Intuitively, if a patient with severe psoriasis has depression worsened by their psoriasis, it stands to reason that improving their skin will likely improve their mood, which clinical trials have shown using patient-related outcomes.

—Jashin J. Wu, MD (Los Angeles, California)

Myth: Psoriasis treatments may cause depression

It has been well documented that patients with inflammatory diseases such as psoriasis have an increased risk for depression. One population-based cohort study in the United Kingdom reported the risk of depression was greater in patients with severe psoriasis versus mild psoriasis. Younger psoriasis patients also had a higher risk compared to older patients. A US population-based study also reported that psoriasis was associated with major depression, but the severity of psoriasis and patient's age were unrelated. Therefore, all psoriasis patients may be at risk.

But are some therapies associated with an increased risk of depression? Increased concentrations of proinflammatory cytokines such as tumor necrosis factor α have been associated with depression apart from psoriasis. Administering immunomodulating agents has been shown to increase the risk of depression.

Depression has been cited as an adverse effect of apremilast in the drug's package insert, which states, "Before using [apremilast] in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment." In clinical trials, 1.3% (12/920) of participants treated with apremilast reported depression compared to 0.4% (2/506) treated with placebo. Dermatologists should remain vigilant about monitoring for symptoms of depression in patients treated with apremilast.

However, depression in the context of autoimmune disorders or any disorder with increased inflammation has responded to treatment with tumor necrosis factor α antagonists. The relationship between depression and inflammation suggests that there is an inflammatory subtype of depression and use of anti-inflammatory agents may treat both inflammation and depression.

Disease control has been shown to improve symptoms of depression in psoriasis patients. A study of 618 patients with moderate to severe psoriasis who were treated with etanercept or placebo for 12 weeks revealed that more patients receiving etanercept experienced 50% improvement in 2 rating scales of depression compared to placebo.

Excessive worrying, a form of psychological distress, can impact treatment outcomes in patients with psoriasis. A 2003 study found that patients with psoriasis who are classified as high-level worriers may benefit from adjunctive psychological intervention before and during treatment. In this cohort of psoriasis patients receiving psoralen plus UVA (PUVA) therapy, high-level worry was the only significant predictor of time taken for PUVA to clear psoriasis (P=.01). Patients in the high-level worry group cleared with PUVA treatment at a rate of 1.8 times slower than the low-level worry group.

In conclusion, psoriasis patients should follow the treatment plan outlined by dermatologists, as improving psoriasis symptoms may help alleviate depression or prevent it from occurring. Patients with a history of depression should be monitored carefully by dermatologists or referred to another health care professional, and patients as well as family and friends should be encouraged to report any depression symptoms.

Expert Commentary

The prescribing information for apremilast lists a warning (but not a black-box warning) for depression. Long-term registries will determine if there is truly an increased risk of depression when taking apremilast. When I counsel patients before prescribing apremilast, I mention this potential increased risk of depression as noted in the prescribing information, but I tell them that the risk is very low and that a true risk has not yet been determined in long-term registries. I mention to patients that if they really do feel depressed after starting apremilast, they should stop taking apremilast and contact me.

Long-term registries for etanercept, adalimumab, infliximab, and ustekinumab do not indicate an increased risk for depression. Intuitively, if a patient with severe psoriasis has depression worsened by their psoriasis, it stands to reason that improving their skin will likely improve their mood, which clinical trials have shown using patient-related outcomes.

—Jashin J. Wu, MD (Los Angeles, California)

Myth: Psoriasis treatments may cause depression

It has been well documented that patients with inflammatory diseases such as psoriasis have an increased risk for depression. One population-based cohort study in the United Kingdom reported the risk of depression was greater in patients with severe psoriasis versus mild psoriasis. Younger psoriasis patients also had a higher risk compared to older patients. A US population-based study also reported that psoriasis was associated with major depression, but the severity of psoriasis and patient's age were unrelated. Therefore, all psoriasis patients may be at risk.

But are some therapies associated with an increased risk of depression? Increased concentrations of proinflammatory cytokines such as tumor necrosis factor α have been associated with depression apart from psoriasis. Administering immunomodulating agents has been shown to increase the risk of depression.

Depression has been cited as an adverse effect of apremilast in the drug's package insert, which states, "Before using [apremilast] in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment." In clinical trials, 1.3% (12/920) of participants treated with apremilast reported depression compared to 0.4% (2/506) treated with placebo. Dermatologists should remain vigilant about monitoring for symptoms of depression in patients treated with apremilast.

However, depression in the context of autoimmune disorders or any disorder with increased inflammation has responded to treatment with tumor necrosis factor α antagonists. The relationship between depression and inflammation suggests that there is an inflammatory subtype of depression and use of anti-inflammatory agents may treat both inflammation and depression.

Disease control has been shown to improve symptoms of depression in psoriasis patients. A study of 618 patients with moderate to severe psoriasis who were treated with etanercept or placebo for 12 weeks revealed that more patients receiving etanercept experienced 50% improvement in 2 rating scales of depression compared to placebo.

Excessive worrying, a form of psychological distress, can impact treatment outcomes in patients with psoriasis. A 2003 study found that patients with psoriasis who are classified as high-level worriers may benefit from adjunctive psychological intervention before and during treatment. In this cohort of psoriasis patients receiving psoralen plus UVA (PUVA) therapy, high-level worry was the only significant predictor of time taken for PUVA to clear psoriasis (P=.01). Patients in the high-level worry group cleared with PUVA treatment at a rate of 1.8 times slower than the low-level worry group.

In conclusion, psoriasis patients should follow the treatment plan outlined by dermatologists, as improving psoriasis symptoms may help alleviate depression or prevent it from occurring. Patients with a history of depression should be monitored carefully by dermatologists or referred to another health care professional, and patients as well as family and friends should be encouraged to report any depression symptoms.

Expert Commentary

The prescribing information for apremilast lists a warning (but not a black-box warning) for depression. Long-term registries will determine if there is truly an increased risk of depression when taking apremilast. When I counsel patients before prescribing apremilast, I mention this potential increased risk of depression as noted in the prescribing information, but I tell them that the risk is very low and that a true risk has not yet been determined in long-term registries. I mention to patients that if they really do feel depressed after starting apremilast, they should stop taking apremilast and contact me.

Long-term registries for etanercept, adalimumab, infliximab, and ustekinumab do not indicate an increased risk for depression. Intuitively, if a patient with severe psoriasis has depression worsened by their psoriasis, it stands to reason that improving their skin will likely improve their mood, which clinical trials have shown using patient-related outcomes.

—Jashin J. Wu, MD (Los Angeles, California)

The Diagnosis: Epidermotropic CD8⁺ T-Cell Lymphoma

Epidermotropic CD8⁺ T-cell lymphoma is a rare aggressive form of cutaneous T-cell lymphoma (CTCL), accounting for less than 1% of all cases.¹ Since this subtype of CTCL was first described in 1999 by Berti et al,² approximately 45 cases have been reported in the literature.¹ It typically is found in elderly men and presents as disseminated or localized papules, patches, plaques, nodules, and tumors, often with central necrosis, ulceration, crusting, and hemorrhage (Figure 1).^1,3 These lesions rapidly progress and can affect any skin site, but acral accentuation and mucosal involvement are common.⁴ Due to the rapidly progressive nature of this disease, patients typically present with widespread plaque- and tumor-stage disease.³ Frequency of systemic spread is high, with metastasis to the central nervous system, lungs, and testes being most common. Lymph nodes typically are spared, helping to differentiate this form of CTCL from classic mycosis fungoides.

Diagnosis of epidermotropic CD8⁺ T-cell lymphoma is based on a combination of clinical, histopathologic, and immunohistochemical features. Histopathologic components include epidermotropism, particularly in the basal cell layer, in a pagetoid or linear pattern. A second feature is a dermal infiltrate consisting of a nodular or diffuse pattern of atypical lymphocytes that extend to the subcutaneous fat (Figure 2). All cases of epidermotropic CD8⁺ T-cell lymphoma express the CD8⁺ phenotype and most have a high Ki-67 proliferation index and are CD3, CD45RA, and/or T-cell intracellular antigen 1 positive.¹

Due to its aggressive nature, epidermotropic CD8⁺ T-cell lymphoma has a poor prognosis, with an average 5-year survival rate of 18% and median survival of 22.5 months.³ Treatment proves difficult as conventional therapies for CD4⁺ CTCL have proven ineffective for epidermotropic CD8⁺ T-cell lymphoma. Partial response has been seen with bexarotene alone and with total skin electron beam therapy combined with oral retinoids.¹

The Diagnosis: Epidermotropic CD8⁺ T-Cell Lymphoma

Epidermotropic CD8⁺ T-cell lymphoma is a rare aggressive form of cutaneous T-cell lymphoma (CTCL), accounting for less than 1% of all cases.¹ Since this subtype of CTCL was first described in 1999 by Berti et al,² approximately 45 cases have been reported in the literature.¹ It typically is found in elderly men and presents as disseminated or localized papules, patches, plaques, nodules, and tumors, often with central necrosis, ulceration, crusting, and hemorrhage (Figure 1).^1,3 These lesions rapidly progress and can affect any skin site, but acral accentuation and mucosal involvement are common.⁴ Due to the rapidly progressive nature of this disease, patients typically present with widespread plaque- and tumor-stage disease.³ Frequency of systemic spread is high, with metastasis to the central nervous system, lungs, and testes being most common. Lymph nodes typically are spared, helping to differentiate this form of CTCL from classic mycosis fungoides.

Diagnosis of epidermotropic CD8⁺ T-cell lymphoma is based on a combination of clinical, histopathologic, and immunohistochemical features. Histopathologic components include epidermotropism, particularly in the basal cell layer, in a pagetoid or linear pattern. A second feature is a dermal infiltrate consisting of a nodular or diffuse pattern of atypical lymphocytes that extend to the subcutaneous fat (Figure 2). All cases of epidermotropic CD8⁺ T-cell lymphoma express the CD8⁺ phenotype and most have a high Ki-67 proliferation index and are CD3, CD45RA, and/or T-cell intracellular antigen 1 positive.¹

Due to its aggressive nature, epidermotropic CD8⁺ T-cell lymphoma has a poor prognosis, with an average 5-year survival rate of 18% and median survival of 22.5 months.³ Treatment proves difficult as conventional therapies for CD4⁺ CTCL have proven ineffective for epidermotropic CD8⁺ T-cell lymphoma. Partial response has been seen with bexarotene alone and with total skin electron beam therapy combined with oral retinoids.¹

The Diagnosis: Epidermotropic CD8⁺ T-Cell Lymphoma

Epidermotropic CD8⁺ T-cell lymphoma is a rare aggressive form of cutaneous T-cell lymphoma (CTCL), accounting for less than 1% of all cases.¹ Since this subtype of CTCL was first described in 1999 by Berti et al,² approximately 45 cases have been reported in the literature.¹ It typically is found in elderly men and presents as disseminated or localized papules, patches, plaques, nodules, and tumors, often with central necrosis, ulceration, crusting, and hemorrhage (Figure 1).^1,3 These lesions rapidly progress and can affect any skin site, but acral accentuation and mucosal involvement are common.⁴ Due to the rapidly progressive nature of this disease, patients typically present with widespread plaque- and tumor-stage disease.³ Frequency of systemic spread is high, with metastasis to the central nervous system, lungs, and testes being most common. Lymph nodes typically are spared, helping to differentiate this form of CTCL from classic mycosis fungoides.

Diagnosis of epidermotropic CD8⁺ T-cell lymphoma is based on a combination of clinical, histopathologic, and immunohistochemical features. Histopathologic components include epidermotropism, particularly in the basal cell layer, in a pagetoid or linear pattern. A second feature is a dermal infiltrate consisting of a nodular or diffuse pattern of atypical lymphocytes that extend to the subcutaneous fat (Figure 2). All cases of epidermotropic CD8⁺ T-cell lymphoma express the CD8⁺ phenotype and most have a high Ki-67 proliferation index and are CD3, CD45RA, and/or T-cell intracellular antigen 1 positive.¹

Due to its aggressive nature, epidermotropic CD8⁺ T-cell lymphoma has a poor prognosis, with an average 5-year survival rate of 18% and median survival of 22.5 months.³ Treatment proves difficult as conventional therapies for CD4⁺ CTCL have proven ineffective for epidermotropic CD8⁺ T-cell lymphoma. Partial response has been seen with bexarotene alone and with total skin electron beam therapy combined with oral retinoids.¹

As a chronic inflammatory skin disease well known for its poor cosmesis including scarring, residual macular erythema, and postinflammatory pigment alteration, acne vulgaris may, according to recent research, confer some antiaging benefits to affected patients. In a research letter published online on September 27 in the Journal of Investigative Dermatology, Ribero et al analyzed white blood cells and found that women who said they had acne had longer telomeres (the "caps" at the end of chromosomes that protect them from deteriorating following repeated cell replication). Telomere length, or rather shortening, has been correlated with age-related degenerative change, according to Saum et al (Exp Gerontol. 2014;58:250-255), and therefore the thinking is that in women with acne, something is going on that maintains the length of the cellular guardians. Let's clarify a couple things to help us all understand the why and what.

The impetus of this study, according to Ribero et al, was the observation that women with acne show signs of aging later than those who have never had acne. I personally have not witnessed this finding in my patients, and given that acne in its essence is a disease of chronic inflammation resulting from, for example, persistent activation of toll-like receptor 2 (TLR2) and NOD-like receptor family pyrin domain containing 3 (NLRP3) pattern recognition receptors, one would think the skin damage accrued would make these individuals look older, right? Last I checked, pitted scarring does not make one immediately think of the fountain of youth.

The results from the study show that there is a link between acne and longer telomeres, but the study did not show that telomere length is a cause of acne, that women with longer telomeres had fewer signs of skin aging, or that women with acne lived longer.

Given these points, Ribero et al concluded that "delayed skin aging may be due to reduced senescence," which means that skin aging may be delayed because the longer telomeres in the cells protect them from deterioration. They did find that the expression of one gene in particular was reduced in women with acne--the regulatory gene zinc finger protein 420, ZNF420--suggesting that those without acne may produce more of a particular protein linked to that gene, though the significance is unclear.

What's the issue?

This study is interesting, but it is important not to make any broad conclusions, such as those who get acne will live longer or look younger longer regardless of other factors such as acne treatment, comorbidities, or even environmental factors. This study may give more support for the genetic contribution of acne, but much more work is needed to determine the clinical relevance. For starters, what about men?

Would you assure your acne patients that their disease may be for their own cosmetic good?

We want to know your views! Tell us what you think.

As a chronic inflammatory skin disease well known for its poor cosmesis including scarring, residual macular erythema, and postinflammatory pigment alteration, acne vulgaris may, according to recent research, confer some antiaging benefits to affected patients. In a research letter published online on September 27 in the Journal of Investigative Dermatology, Ribero et al analyzed white blood cells and found that women who said they had acne had longer telomeres (the "caps" at the end of chromosomes that protect them from deteriorating following repeated cell replication). Telomere length, or rather shortening, has been correlated with age-related degenerative change, according to Saum et al (Exp Gerontol. 2014;58:250-255), and therefore the thinking is that in women with acne, something is going on that maintains the length of the cellular guardians. Let's clarify a couple things to help us all understand the why and what.

The impetus of this study, according to Ribero et al, was the observation that women with acne show signs of aging later than those who have never had acne. I personally have not witnessed this finding in my patients, and given that acne in its essence is a disease of chronic inflammation resulting from, for example, persistent activation of toll-like receptor 2 (TLR2) and NOD-like receptor family pyrin domain containing 3 (NLRP3) pattern recognition receptors, one would think the skin damage accrued would make these individuals look older, right? Last I checked, pitted scarring does not make one immediately think of the fountain of youth.

The results from the study show that there is a link between acne and longer telomeres, but the study did not show that telomere length is a cause of acne, that women with longer telomeres had fewer signs of skin aging, or that women with acne lived longer.

Given these points, Ribero et al concluded that "delayed skin aging may be due to reduced senescence," which means that skin aging may be delayed because the longer telomeres in the cells protect them from deterioration. They did find that the expression of one gene in particular was reduced in women with acne--the regulatory gene zinc finger protein 420, ZNF420--suggesting that those without acne may produce more of a particular protein linked to that gene, though the significance is unclear.

What's the issue?

This study is interesting, but it is important not to make any broad conclusions, such as those who get acne will live longer or look younger longer regardless of other factors such as acne treatment, comorbidities, or even environmental factors. This study may give more support for the genetic contribution of acne, but much more work is needed to determine the clinical relevance. For starters, what about men?

Would you assure your acne patients that their disease may be for their own cosmetic good?

We want to know your views! Tell us what you think.

As a chronic inflammatory skin disease well known for its poor cosmesis including scarring, residual macular erythema, and postinflammatory pigment alteration, acne vulgaris may, according to recent research, confer some antiaging benefits to affected patients. In a research letter published online on September 27 in the Journal of Investigative Dermatology, Ribero et al analyzed white blood cells and found that women who said they had acne had longer telomeres (the "caps" at the end of chromosomes that protect them from deteriorating following repeated cell replication). Telomere length, or rather shortening, has been correlated with age-related degenerative change, according to Saum et al (Exp Gerontol. 2014;58:250-255), and therefore the thinking is that in women with acne, something is going on that maintains the length of the cellular guardians. Let's clarify a couple things to help us all understand the why and what.

The impetus of this study, according to Ribero et al, was the observation that women with acne show signs of aging later than those who have never had acne. I personally have not witnessed this finding in my patients, and given that acne in its essence is a disease of chronic inflammation resulting from, for example, persistent activation of toll-like receptor 2 (TLR2) and NOD-like receptor family pyrin domain containing 3 (NLRP3) pattern recognition receptors, one would think the skin damage accrued would make these individuals look older, right? Last I checked, pitted scarring does not make one immediately think of the fountain of youth.

The results from the study show that there is a link between acne and longer telomeres, but the study did not show that telomere length is a cause of acne, that women with longer telomeres had fewer signs of skin aging, or that women with acne lived longer.

Given these points, Ribero et al concluded that "delayed skin aging may be due to reduced senescence," which means that skin aging may be delayed because the longer telomeres in the cells protect them from deterioration. They did find that the expression of one gene in particular was reduced in women with acne--the regulatory gene zinc finger protein 420, ZNF420--suggesting that those without acne may produce more of a particular protein linked to that gene, though the significance is unclear.

What's the issue?

This study is interesting, but it is important not to make any broad conclusions, such as those who get acne will live longer or look younger longer regardless of other factors such as acne treatment, comorbidities, or even environmental factors. This study may give more support for the genetic contribution of acne, but much more work is needed to determine the clinical relevance. For starters, what about men?

Would you assure your acne patients that their disease may be for their own cosmetic good?

We want to know your views! Tell us what you think.

To the Editor:

A 32-year-old woman presented with a recurrent painful eruption on the scalp of 1 year's duration. The lesion occurred on the left temporal region 1 week prior to menstruation and spontaneously resolved following menses; it recurred every month for 1 year. She had no notable medical history. She had taken oral contraceptive pills for 4 years and stopped 2 years prior to the development of the lesions. Dermatologic examination revealed a purple-colored, violaceous, centrally elevated, painful plaque that measured 2 cm in diameter in the left temporal region of the scalp (Figure, A). Laboratory test results were within reference range. The lesion spontaneously resolved with mild residual erythema at a follow-up visit after menstruation (Figure, B).

Because the eruption occurred and relapsed with the patient's menstrual cycle, we suspected progesterone hypersensitivity. An intradermal skin test was performed on the forearm with 0.05 mL of medroxyprogesterone acetate, and saline was used as a negative control. An indurated erythematous nodule occurred on the progesterone-treated side within 6 hours. Based on these findings and the patient's history, she was diagnosed with autoimmune progesterone dermatitis (APD). We recommended her to use gonadotropin-releasing hormone agonists as treatment, but the patient refused. At 6-month follow-up she had recurrent lesions but did not report any concerns.

Autoimmune progesterone dermatitis is a rare condition that is characterized by cyclical skin eruptions, typically occurring in the luteal phase of the menstrual cycle with spontaneous resolution after menses.^1,2 It was first described by Geber3 in a patient with cyclical urticarial lesions. In 1964, Shelley et al⁴ characterized APD in a 27-year-old woman with a pruritic vesicular eruption with cyclical premenstrual exacerbations. Although it is believed there is no genetic predisposition to APD, a case series involving 3 sisters demonstrated that genetic susceptibility might play a role in the etiology.⁵ The etiology of APD is still unknown. It is thought to represent an autoimmune reaction to endogenous or exogenous progesterone.¹ Our patient also had used oral contraceptives for 4 years and this exogenous progesterone might have played a role in the sensitization of the patient and the development of this autoimmune reaction.

The clinical features of APD usually begin 3 to 10 days prior to menstruation and end 1 to 2 days after menses. Autoimmune progesterone dermatitis can present in a variety of forms including eczema, erythema multiforme, erythema annulare centrifugum, fixed drug eruption, stomatitis, folliculitis, urticaria, and angioedema.⁶ A case of APD presenting with petechiae and purpura has been reported.⁷ There are no specific histologic findings for APD.⁸ Demonstration of progesterone sensitivity with a progesterone challenge test is the mainstay of diagnosis. Immediate urticaria may occur in some patients, with others experiencing a delayed reaction peaking at 24 to 96 hours.⁹ The main criteria of APD include the following: recurrent cyclic lesions related to the menstrual cycle; positive intradermal progesterone skin test; and prevention of lesions by inhibiting ovulation.¹ Two of these criteria were positive in our patient, but we did not use any medications to prevent ovulation at the patient's request.

Current treatment modalities often attempt to inhibit the secretion of endogenous progesterone by suppressing ovulation. Oral contraceptives and conjugated estrogens have limited efficacy rates.⁸ Gonadotropin-releasing hormone agonists (ie, buserelin, triptorelin) have been used with success.^1,6 Tamoxifen and danazol are other treatment options. For cases refractory to medical treatments, bilateral oophorectomy can be considered a definitive treatment.⁶

Autoimmune progesterone dermatitis may present in many different clinical forms. It should be considered in the differential diagnosis in patients with recurrent skin lesions related to menstrual cycle both in women of childbearing age and in men taking synthetic progesterone.

To the Editor:

A 32-year-old woman presented with a recurrent painful eruption on the scalp of 1 year's duration. The lesion occurred on the left temporal region 1 week prior to menstruation and spontaneously resolved following menses; it recurred every month for 1 year. She had no notable medical history. She had taken oral contraceptive pills for 4 years and stopped 2 years prior to the development of the lesions. Dermatologic examination revealed a purple-colored, violaceous, centrally elevated, painful plaque that measured 2 cm in diameter in the left temporal region of the scalp (Figure, A). Laboratory test results were within reference range. The lesion spontaneously resolved with mild residual erythema at a follow-up visit after menstruation (Figure, B).

Because the eruption occurred and relapsed with the patient's menstrual cycle, we suspected progesterone hypersensitivity. An intradermal skin test was performed on the forearm with 0.05 mL of medroxyprogesterone acetate, and saline was used as a negative control. An indurated erythematous nodule occurred on the progesterone-treated side within 6 hours. Based on these findings and the patient's history, she was diagnosed with autoimmune progesterone dermatitis (APD). We recommended her to use gonadotropin-releasing hormone agonists as treatment, but the patient refused. At 6-month follow-up she had recurrent lesions but did not report any concerns.

Autoimmune progesterone dermatitis is a rare condition that is characterized by cyclical skin eruptions, typically occurring in the luteal phase of the menstrual cycle with spontaneous resolution after menses.^1,2 It was first described by Geber3 in a patient with cyclical urticarial lesions. In 1964, Shelley et al⁴ characterized APD in a 27-year-old woman with a pruritic vesicular eruption with cyclical premenstrual exacerbations. Although it is believed there is no genetic predisposition to APD, a case series involving 3 sisters demonstrated that genetic susceptibility might play a role in the etiology.⁵ The etiology of APD is still unknown. It is thought to represent an autoimmune reaction to endogenous or exogenous progesterone.¹ Our patient also had used oral contraceptives for 4 years and this exogenous progesterone might have played a role in the sensitization of the patient and the development of this autoimmune reaction.

The clinical features of APD usually begin 3 to 10 days prior to menstruation and end 1 to 2 days after menses. Autoimmune progesterone dermatitis can present in a variety of forms including eczema, erythema multiforme, erythema annulare centrifugum, fixed drug eruption, stomatitis, folliculitis, urticaria, and angioedema.⁶ A case of APD presenting with petechiae and purpura has been reported.⁷ There are no specific histologic findings for APD.⁸ Demonstration of progesterone sensitivity with a progesterone challenge test is the mainstay of diagnosis. Immediate urticaria may occur in some patients, with others experiencing a delayed reaction peaking at 24 to 96 hours.⁹ The main criteria of APD include the following: recurrent cyclic lesions related to the menstrual cycle; positive intradermal progesterone skin test; and prevention of lesions by inhibiting ovulation.¹ Two of these criteria were positive in our patient, but we did not use any medications to prevent ovulation at the patient's request.

Current treatment modalities often attempt to inhibit the secretion of endogenous progesterone by suppressing ovulation. Oral contraceptives and conjugated estrogens have limited efficacy rates.⁸ Gonadotropin-releasing hormone agonists (ie, buserelin, triptorelin) have been used with success.^1,6 Tamoxifen and danazol are other treatment options. For cases refractory to medical treatments, bilateral oophorectomy can be considered a definitive treatment.⁶

Autoimmune progesterone dermatitis may present in many different clinical forms. It should be considered in the differential diagnosis in patients with recurrent skin lesions related to menstrual cycle both in women of childbearing age and in men taking synthetic progesterone.

To the Editor:

A 32-year-old woman presented with a recurrent painful eruption on the scalp of 1 year's duration. The lesion occurred on the left temporal region 1 week prior to menstruation and spontaneously resolved following menses; it recurred every month for 1 year. She had no notable medical history. She had taken oral contraceptive pills for 4 years and stopped 2 years prior to the development of the lesions. Dermatologic examination revealed a purple-colored, violaceous, centrally elevated, painful plaque that measured 2 cm in diameter in the left temporal region of the scalp (Figure, A). Laboratory test results were within reference range. The lesion spontaneously resolved with mild residual erythema at a follow-up visit after menstruation (Figure, B).

Because the eruption occurred and relapsed with the patient's menstrual cycle, we suspected progesterone hypersensitivity. An intradermal skin test was performed on the forearm with 0.05 mL of medroxyprogesterone acetate, and saline was used as a negative control. An indurated erythematous nodule occurred on the progesterone-treated side within 6 hours. Based on these findings and the patient's history, she was diagnosed with autoimmune progesterone dermatitis (APD). We recommended her to use gonadotropin-releasing hormone agonists as treatment, but the patient refused. At 6-month follow-up she had recurrent lesions but did not report any concerns.

Autoimmune progesterone dermatitis is a rare condition that is characterized by cyclical skin eruptions, typically occurring in the luteal phase of the menstrual cycle with spontaneous resolution after menses.^1,2 It was first described by Geber3 in a patient with cyclical urticarial lesions. In 1964, Shelley et al⁴ characterized APD in a 27-year-old woman with a pruritic vesicular eruption with cyclical premenstrual exacerbations. Although it is believed there is no genetic predisposition to APD, a case series involving 3 sisters demonstrated that genetic susceptibility might play a role in the etiology.⁵ The etiology of APD is still unknown. It is thought to represent an autoimmune reaction to endogenous or exogenous progesterone.¹ Our patient also had used oral contraceptives for 4 years and this exogenous progesterone might have played a role in the sensitization of the patient and the development of this autoimmune reaction.

The clinical features of APD usually begin 3 to 10 days prior to menstruation and end 1 to 2 days after menses. Autoimmune progesterone dermatitis can present in a variety of forms including eczema, erythema multiforme, erythema annulare centrifugum, fixed drug eruption, stomatitis, folliculitis, urticaria, and angioedema.⁶ A case of APD presenting with petechiae and purpura has been reported.⁷ There are no specific histologic findings for APD.⁸ Demonstration of progesterone sensitivity with a progesterone challenge test is the mainstay of diagnosis. Immediate urticaria may occur in some patients, with others experiencing a delayed reaction peaking at 24 to 96 hours.⁹ The main criteria of APD include the following: recurrent cyclic lesions related to the menstrual cycle; positive intradermal progesterone skin test; and prevention of lesions by inhibiting ovulation.¹ Two of these criteria were positive in our patient, but we did not use any medications to prevent ovulation at the patient's request.

Current treatment modalities often attempt to inhibit the secretion of endogenous progesterone by suppressing ovulation. Oral contraceptives and conjugated estrogens have limited efficacy rates.⁸ Gonadotropin-releasing hormone agonists (ie, buserelin, triptorelin) have been used with success.^1,6 Tamoxifen and danazol are other treatment options. For cases refractory to medical treatments, bilateral oophorectomy can be considered a definitive treatment.⁶

Autoimmune progesterone dermatitis may present in many different clinical forms. It should be considered in the differential diagnosis in patients with recurrent skin lesions related to menstrual cycle both in women of childbearing age and in men taking synthetic progesterone.

In an article published online on September 1 in Endocrinology, Rehfeld et al discussed their results after testing 29 UV filters. They found that 13 of 29 filters tested had in vitro effects on Ca²⁺: 4-methylbenzylidene camphor, 3-benzylidene camphor, menthyl anthranilate, isoamyl p-methoxycinnamate, ethylhexyl salicylate, benzylidene camphor sulfonic acid, homosalate, ethylhexyl methoxycinnamate, octcrylene, butyl methoxydibenzoylmethane, and diethylamino hydroxybenzoyl hexyl benzoate.

This study was prompted by a prior study by Schiffer et al (EMBO Rep. 2014;15:758-765) on multiple endocrine disrupting chemicals of which 33 of 96 tested chemicals induced Ca²⁺ signals in human sperm cells in vitro. Of these previously tested chemicals, some of the chemical sunscreen filters were the most potent, leading to the current study.

Rehfeld et al sought to determine how the UV filters affected calcium signaling, which is a pathway that is essential for sperm cells to be able to swim healthily. These calcium-signaling pathways usually are triggered by progesterone, but the authors showed that 13 of 29 UV filters (45%) also commenced calcium signaling. This effect began at low doses of the chemicals, below the levels of some UV filters found in people after whole-body application of sunscreens.

What’s the issue?

Are these chemical UV filters mimicking progesterone in vivo and could it be interfering with sperm motility? A suboptimal progesterone-induced Ca²⁺ influx has been associated with reduced male fertility and CatSper (cation channel of sperm) is essential for male fertility (Hum Reprod. 1995;10:120-124).

The UV filters tested are widely available in Europe and the United States. Although this study was in vitro, the in vivo effects will need to be explored. It has been reported by Chivsvert et al (Anal Chim Acta. 2012;752:11-29) that some UV filters can be transcutaneously absorbed into bodily tissues, which could be potentially important for men trying to conceive or for reproductively challenged couples.

What do you discuss with your patients regarding sunscreen safety?

We want to know your views! Tell us what you think.

In an article published online on September 1 in Endocrinology, Rehfeld et al discussed their results after testing 29 UV filters. They found that 13 of 29 filters tested had in vitro effects on Ca²⁺: 4-methylbenzylidene camphor, 3-benzylidene camphor, menthyl anthranilate, isoamyl p-methoxycinnamate, ethylhexyl salicylate, benzylidene camphor sulfonic acid, homosalate, ethylhexyl methoxycinnamate, octcrylene, butyl methoxydibenzoylmethane, and diethylamino hydroxybenzoyl hexyl benzoate.

This study was prompted by a prior study by Schiffer et al (EMBO Rep. 2014;15:758-765) on multiple endocrine disrupting chemicals of which 33 of 96 tested chemicals induced Ca²⁺ signals in human sperm cells in vitro. Of these previously tested chemicals, some of the chemical sunscreen filters were the most potent, leading to the current study.

Rehfeld et al sought to determine how the UV filters affected calcium signaling, which is a pathway that is essential for sperm cells to be able to swim healthily. These calcium-signaling pathways usually are triggered by progesterone, but the authors showed that 13 of 29 UV filters (45%) also commenced calcium signaling. This effect began at low doses of the chemicals, below the levels of some UV filters found in people after whole-body application of sunscreens.

What’s the issue?

Are these chemical UV filters mimicking progesterone in vivo and could it be interfering with sperm motility? A suboptimal progesterone-induced Ca²⁺ influx has been associated with reduced male fertility and CatSper (cation channel of sperm) is essential for male fertility (Hum Reprod. 1995;10:120-124).

The UV filters tested are widely available in Europe and the United States. Although this study was in vitro, the in vivo effects will need to be explored. It has been reported by Chivsvert et al (Anal Chim Acta. 2012;752:11-29) that some UV filters can be transcutaneously absorbed into bodily tissues, which could be potentially important for men trying to conceive or for reproductively challenged couples.

What do you discuss with your patients regarding sunscreen safety?

We want to know your views! Tell us what you think.

In an article published online on September 1 in Endocrinology, Rehfeld et al discussed their results after testing 29 UV filters. They found that 13 of 29 filters tested had in vitro effects on Ca²⁺: 4-methylbenzylidene camphor, 3-benzylidene camphor, menthyl anthranilate, isoamyl p-methoxycinnamate, ethylhexyl salicylate, benzylidene camphor sulfonic acid, homosalate, ethylhexyl methoxycinnamate, octcrylene, butyl methoxydibenzoylmethane, and diethylamino hydroxybenzoyl hexyl benzoate.

This study was prompted by a prior study by Schiffer et al (EMBO Rep. 2014;15:758-765) on multiple endocrine disrupting chemicals of which 33 of 96 tested chemicals induced Ca²⁺ signals in human sperm cells in vitro. Of these previously tested chemicals, some of the chemical sunscreen filters were the most potent, leading to the current study.

Rehfeld et al sought to determine how the UV filters affected calcium signaling, which is a pathway that is essential for sperm cells to be able to swim healthily. These calcium-signaling pathways usually are triggered by progesterone, but the authors showed that 13 of 29 UV filters (45%) also commenced calcium signaling. This effect began at low doses of the chemicals, below the levels of some UV filters found in people after whole-body application of sunscreens.

What’s the issue?

Are these chemical UV filters mimicking progesterone in vivo and could it be interfering with sperm motility? A suboptimal progesterone-induced Ca²⁺ influx has been associated with reduced male fertility and CatSper (cation channel of sperm) is essential for male fertility (Hum Reprod. 1995;10:120-124).

The UV filters tested are widely available in Europe and the United States. Although this study was in vitro, the in vivo effects will need to be explored. It has been reported by Chivsvert et al (Anal Chim Acta. 2012;752:11-29) that some UV filters can be transcutaneously absorbed into bodily tissues, which could be potentially important for men trying to conceive or for reproductively challenged couples.

What do you discuss with your patients regarding sunscreen safety?

We want to know your views! Tell us what you think.

To the Editor:

Acute generalized exanthematous pustulosis (AGEP) is an acute skin reaction that is characterized by generalized, nonfollicular, pinhead-sized, sterile pustules on an erythematous and edematous background. The eruption can be accompanied by fever and neutrophilic leukocytosis. Skin symptoms arise quickly (within a few hours), most commonly following drug administration. The medications most frequently responsible are beta-lactam antibiotics, macrolides, calcium channel blockers, and antimalarials. Pustules spontaneously resolve in 15 days and generalized desquamation occurs approximately 2 weeks later. The estimated incidence rate of AGEP is approximately 1 to 5 cases per million per year. Acute localized exanthematous pustulosis (ALEP) is a less common form of AGEP. We report a case of ALEP localized on the face that was caused by flurbiprofen, a propionic acid derivative from the family of nonsteroidal anti-inflammatory drugs (NSAIDs).

A 40-year-old woman was referred to the dermatology department due to the sudden onset of multiple pustules on the face. One week earlier she started oral flurbiprofen (8.75 mg daily) for a sore throat. After 3 days of therapy, multiple pruritic, erythematous and edematous lesions appeared abruptly on the face with associated multiple small nonfollicular pustules. At presentation the patient was febrile (temperature, 38.2°C) and presented with bilateral ocular edema and superficial small nonfollicular pustules on an erythematous background over the face, scalp, and oral mucosa (Figure 1). The rest of the body was not involved. The patient denied prior adverse reactions to other drugs. The white blood cell count was 15,000/μL (reference range, 4500–11,000/μL), with an increased neutrophil count (12,000/μL [reference range, 1800–7800/μL]). The erythrocyte sedimentation rate and C-reactive protein level was elevated (erythrocyte sedimentation rate, 53 mm/h [reference range, 0–20 mm/h]; C-reactive protein, 98 mg/dL [reference range, 0–5 mg/dL]). Bacterial and fungal cultures of skin lesions were negative. The results of a viral polymerase chain reaction analysis proved the absence of varicella-zoster virus or herpes simplex virus. Histopathology of a skin biopsy specimen showed subcorneal pustules composed of neutrophils and eosinophils, epidermal spongiosis, some necrotic keratinocytes, vacuolization of the basal layer, papillary edema, and a perivascular neutrophil and lymphocyte infiltrate (Figure 2). A leukocytoclastic infiltrate within and around the walls of blood vessels at the superficial level of the dermis and red cell extravasation in the epidermis was present. She discontinued use of flurbiprofen and was treated with a systemic corticosteroid (methylprednisolone 0.5 mg/kg daily). The pustules rapidly resolved within 7 days after discontinuation of flurbiprofen and were followed by transient scaling and discrete residual hyperpigmentation.

Acute localized exanthematous pustulosis is a less common form of a pustular drug eruption in which lesions are consistent with AGEP but typically are localized to the face, neck, or chest. The definition of ALEP was introduced by Prange et al¹ to describe a woman who was diagnosed with a localized pustular eruption on the face without a generalized distribution as in AGEP. In the past, this localized eruption was described under different names (eg, localized pustular eruption, localized toxin follicular pustuloderma, nongeneralized acute exanthematic pustulosis).^2-5 According to a PubMed search of articles indexed for MEDLINE using the terms localized pustulosis, localized pustular eruption, and localized pustuloderma, only 16 separate cases of ALEP have been documented since the report by Prange et al.¹ The medications most frequently responsible are antibiotics. Three cases developed following administration of amoxicillin^2,5,6; 2 cases of amoxicillin–clavulanic acid^7,8; 1 of penicillin¹; 1 of azithromycin⁹; 1 of levofloxacin¹⁰; and 1 of combination of cephalosporin, sulfamethoxazole-trimethoprim, and vancomycin.¹¹ Other nonantibiotic causative drugs include sulfamethoxazole-trimethoprim,¹² infliximab,¹³ sorafenib,¹⁴ docetaxel,¹⁵ finasteride,¹⁶ ibuprofen,¹⁷ and paracetamol.¹⁸ In reported cases, the lesions are consistent with the characteristics of AGEP both clinically and histopathologically but are localized typically to the face, neck, or chest. In the majority of patients with ALEP, the absence of fever has been observed, but it does not appear distinctive for diagnosis. Our patient represents another case of ALEP with flurbiprofen as the causative drug. The close relationship between the administration of the drug and the development of the pustules, the rapid acute resolution as soon as treatment was interrupted, and the histologic findings all supported the diagnosis of ALEP following administration of flurbiprofen. This NSAID—2-fluoro-α-methyl-(1,1'-biphenyl)-4-acetic acid—is a prostaglandin synthetase inhibitor with anti-inflammatory activity. It is a propionic acid derivative that is similar to ibuprofen, which was once involved in the occurrence of ALEP.¹⁷ In 2009, Rastogi et al¹⁷ reported a case of a 64-year-old woman with an acute outbreak of multiple pustular lesions and underlying erythema affecting the cheeks and chin without fever who had been taking ibuprofen for a toothache. The case is similar to ours and confirms that NSAIDs can induce ALEP. Compared with other NSAIDs, propionic acid derivatives are usually well tolerated and serious adverse reactions rarely have been documented.¹⁹

The physiopathologic mechanisms of ALEP are unknown but likely are similar to AGEP. The demonstration of drug-specific positive patch test responses and in vitro lymphocyte proliferative responses in patients with a history of AGEP strongly suggests that this adverse cutaneous reaction occurs via a drug-specific T cell–mediated process.²⁰

Further study is needed to understand the etiopathogenesis of the localized form of the disease and to facilitate a correct diagnosis of this rare disorder.

To the Editor:

Acute generalized exanthematous pustulosis (AGEP) is an acute skin reaction that is characterized by generalized, nonfollicular, pinhead-sized, sterile pustules on an erythematous and edematous background. The eruption can be accompanied by fever and neutrophilic leukocytosis. Skin symptoms arise quickly (within a few hours), most commonly following drug administration. The medications most frequently responsible are beta-lactam antibiotics, macrolides, calcium channel blockers, and antimalarials. Pustules spontaneously resolve in 15 days and generalized desquamation occurs approximately 2 weeks later. The estimated incidence rate of AGEP is approximately 1 to 5 cases per million per year. Acute localized exanthematous pustulosis (ALEP) is a less common form of AGEP. We report a case of ALEP localized on the face that was caused by flurbiprofen, a propionic acid derivative from the family of nonsteroidal anti-inflammatory drugs (NSAIDs).

A 40-year-old woman was referred to the dermatology department due to the sudden onset of multiple pustules on the face. One week earlier she started oral flurbiprofen (8.75 mg daily) for a sore throat. After 3 days of therapy, multiple pruritic, erythematous and edematous lesions appeared abruptly on the face with associated multiple small nonfollicular pustules. At presentation the patient was febrile (temperature, 38.2°C) and presented with bilateral ocular edema and superficial small nonfollicular pustules on an erythematous background over the face, scalp, and oral mucosa (Figure 1). The rest of the body was not involved. The patient denied prior adverse reactions to other drugs. The white blood cell count was 15,000/μL (reference range, 4500–11,000/μL), with an increased neutrophil count (12,000/μL [reference range, 1800–7800/μL]). The erythrocyte sedimentation rate and C-reactive protein level was elevated (erythrocyte sedimentation rate, 53 mm/h [reference range, 0–20 mm/h]; C-reactive protein, 98 mg/dL [reference range, 0–5 mg/dL]). Bacterial and fungal cultures of skin lesions were negative. The results of a viral polymerase chain reaction analysis proved the absence of varicella-zoster virus or herpes simplex virus. Histopathology of a skin biopsy specimen showed subcorneal pustules composed of neutrophils and eosinophils, epidermal spongiosis, some necrotic keratinocytes, vacuolization of the basal layer, papillary edema, and a perivascular neutrophil and lymphocyte infiltrate (Figure 2). A leukocytoclastic infiltrate within and around the walls of blood vessels at the superficial level of the dermis and red cell extravasation in the epidermis was present. She discontinued use of flurbiprofen and was treated with a systemic corticosteroid (methylprednisolone 0.5 mg/kg daily). The pustules rapidly resolved within 7 days after discontinuation of flurbiprofen and were followed by transient scaling and discrete residual hyperpigmentation.

Acute localized exanthematous pustulosis is a less common form of a pustular drug eruption in which lesions are consistent with AGEP but typically are localized to the face, neck, or chest. The definition of ALEP was introduced by Prange et al¹ to describe a woman who was diagnosed with a localized pustular eruption on the face without a generalized distribution as in AGEP. In the past, this localized eruption was described under different names (eg, localized pustular eruption, localized toxin follicular pustuloderma, nongeneralized acute exanthematic pustulosis).^2-5 According to a PubMed search of articles indexed for MEDLINE using the terms localized pustulosis, localized pustular eruption, and localized pustuloderma, only 16 separate cases of ALEP have been documented since the report by Prange et al.¹ The medications most frequently responsible are antibiotics. Three cases developed following administration of amoxicillin^2,5,6; 2 cases of amoxicillin–clavulanic acid^7,8; 1 of penicillin¹; 1 of azithromycin⁹; 1 of levofloxacin¹⁰; and 1 of combination of cephalosporin, sulfamethoxazole-trimethoprim, and vancomycin.¹¹ Other nonantibiotic causative drugs include sulfamethoxazole-trimethoprim,¹² infliximab,¹³ sorafenib,¹⁴ docetaxel,¹⁵ finasteride,¹⁶ ibuprofen,¹⁷ and paracetamol.¹⁸ In reported cases, the lesions are consistent with the characteristics of AGEP both clinically and histopathologically but are localized typically to the face, neck, or chest. In the majority of patients with ALEP, the absence of fever has been observed, but it does not appear distinctive for diagnosis. Our patient represents another case of ALEP with flurbiprofen as the causative drug. The close relationship between the administration of the drug and the development of the pustules, the rapid acute resolution as soon as treatment was interrupted, and the histologic findings all supported the diagnosis of ALEP following administration of flurbiprofen. This NSAID—2-fluoro-α-methyl-(1,1'-biphenyl)-4-acetic acid—is a prostaglandin synthetase inhibitor with anti-inflammatory activity. It is a propionic acid derivative that is similar to ibuprofen, which was once involved in the occurrence of ALEP.¹⁷ In 2009, Rastogi et al¹⁷ reported a case of a 64-year-old woman with an acute outbreak of multiple pustular lesions and underlying erythema affecting the cheeks and chin without fever who had been taking ibuprofen for a toothache. The case is similar to ours and confirms that NSAIDs can induce ALEP. Compared with other NSAIDs, propionic acid derivatives are usually well tolerated and serious adverse reactions rarely have been documented.¹⁹

The physiopathologic mechanisms of ALEP are unknown but likely are similar to AGEP. The demonstration of drug-specific positive patch test responses and in vitro lymphocyte proliferative responses in patients with a history of AGEP strongly suggests that this adverse cutaneous reaction occurs via a drug-specific T cell–mediated process.²⁰

Further study is needed to understand the etiopathogenesis of the localized form of the disease and to facilitate a correct diagnosis of this rare disorder.

To the Editor:

Acute generalized exanthematous pustulosis (AGEP) is an acute skin reaction that is characterized by generalized, nonfollicular, pinhead-sized, sterile pustules on an erythematous and edematous background. The eruption can be accompanied by fever and neutrophilic leukocytosis. Skin symptoms arise quickly (within a few hours), most commonly following drug administration. The medications most frequently responsible are beta-lactam antibiotics, macrolides, calcium channel blockers, and antimalarials. Pustules spontaneously resolve in 15 days and generalized desquamation occurs approximately 2 weeks later. The estimated incidence rate of AGEP is approximately 1 to 5 cases per million per year. Acute localized exanthematous pustulosis (ALEP) is a less common form of AGEP. We report a case of ALEP localized on the face that was caused by flurbiprofen, a propionic acid derivative from the family of nonsteroidal anti-inflammatory drugs (NSAIDs).

A 40-year-old woman was referred to the dermatology department due to the sudden onset of multiple pustules on the face. One week earlier she started oral flurbiprofen (8.75 mg daily) for a sore throat. After 3 days of therapy, multiple pruritic, erythematous and edematous lesions appeared abruptly on the face with associated multiple small nonfollicular pustules. At presentation the patient was febrile (temperature, 38.2°C) and presented with bilateral ocular edema and superficial small nonfollicular pustules on an erythematous background over the face, scalp, and oral mucosa (Figure 1). The rest of the body was not involved. The patient denied prior adverse reactions to other drugs. The white blood cell count was 15,000/μL (reference range, 4500–11,000/μL), with an increased neutrophil count (12,000/μL [reference range, 1800–7800/μL]). The erythrocyte sedimentation rate and C-reactive protein level was elevated (erythrocyte sedimentation rate, 53 mm/h [reference range, 0–20 mm/h]; C-reactive protein, 98 mg/dL [reference range, 0–5 mg/dL]). Bacterial and fungal cultures of skin lesions were negative. The results of a viral polymerase chain reaction analysis proved the absence of varicella-zoster virus or herpes simplex virus. Histopathology of a skin biopsy specimen showed subcorneal pustules composed of neutrophils and eosinophils, epidermal spongiosis, some necrotic keratinocytes, vacuolization of the basal layer, papillary edema, and a perivascular neutrophil and lymphocyte infiltrate (Figure 2). A leukocytoclastic infiltrate within and around the walls of blood vessels at the superficial level of the dermis and red cell extravasation in the epidermis was present. She discontinued use of flurbiprofen and was treated with a systemic corticosteroid (methylprednisolone 0.5 mg/kg daily). The pustules rapidly resolved within 7 days after discontinuation of flurbiprofen and were followed by transient scaling and discrete residual hyperpigmentation.

Acute localized exanthematous pustulosis is a less common form of a pustular drug eruption in which lesions are consistent with AGEP but typically are localized to the face, neck, or chest. The definition of ALEP was introduced by Prange et al¹ to describe a woman who was diagnosed with a localized pustular eruption on the face without a generalized distribution as in AGEP. In the past, this localized eruption was described under different names (eg, localized pustular eruption, localized toxin follicular pustuloderma, nongeneralized acute exanthematic pustulosis).^2-5 According to a PubMed search of articles indexed for MEDLINE using the terms localized pustulosis, localized pustular eruption, and localized pustuloderma, only 16 separate cases of ALEP have been documented since the report by Prange et al.¹ The medications most frequently responsible are antibiotics. Three cases developed following administration of amoxicillin^2,5,6; 2 cases of amoxicillin–clavulanic acid^7,8; 1 of penicillin¹; 1 of azithromycin⁹; 1 of levofloxacin¹⁰; and 1 of combination of cephalosporin, sulfamethoxazole-trimethoprim, and vancomycin.¹¹ Other nonantibiotic causative drugs include sulfamethoxazole-trimethoprim,¹² infliximab,¹³ sorafenib,¹⁴ docetaxel,¹⁵ finasteride,¹⁶ ibuprofen,¹⁷ and paracetamol.¹⁸ In reported cases, the lesions are consistent with the characteristics of AGEP both clinically and histopathologically but are localized typically to the face, neck, or chest. In the majority of patients with ALEP, the absence of fever has been observed, but it does not appear distinctive for diagnosis. Our patient represents another case of ALEP with flurbiprofen as the causative drug. The close relationship between the administration of the drug and the development of the pustules, the rapid acute resolution as soon as treatment was interrupted, and the histologic findings all supported the diagnosis of ALEP following administration of flurbiprofen. This NSAID—2-fluoro-α-methyl-(1,1'-biphenyl)-4-acetic acid—is a prostaglandin synthetase inhibitor with anti-inflammatory activity. It is a propionic acid derivative that is similar to ibuprofen, which was once involved in the occurrence of ALEP.¹⁷ In 2009, Rastogi et al¹⁷ reported a case of a 64-year-old woman with an acute outbreak of multiple pustular lesions and underlying erythema affecting the cheeks and chin without fever who had been taking ibuprofen for a toothache. The case is similar to ours and confirms that NSAIDs can induce ALEP. Compared with other NSAIDs, propionic acid derivatives are usually well tolerated and serious adverse reactions rarely have been documented.¹⁹

The physiopathologic mechanisms of ALEP are unknown but likely are similar to AGEP. The demonstration of drug-specific positive patch test responses and in vitro lymphocyte proliferative responses in patients with a history of AGEP strongly suggests that this adverse cutaneous reaction occurs via a drug-specific T cell–mediated process.²⁰

Further study is needed to understand the etiopathogenesis of the localized form of the disease and to facilitate a correct diagnosis of this rare disorder.

To the Editor:

Prior studies have assessed the quality of text-based dermatology information on the Internet using traditional search engine queries.¹ However, little is understood about the sources, accuracy, and quality of online dermatology images derived from direct image searches. Previous work has shown that direct search engine image queries were largely accurate for 3 pediatric dermatology diagnosis searches: atopic dermatitis, lichen striatus, and subcutaneous fat necrosis.² We assessed images obtained for common dermatologic conditions from a Google image search (GIS) compared to a traditional text-based Google web search (GWS).

Image results for 32 unique dermatologic search terms were analyzed (Table 1). These search terms were selected using the results of a prior study that identified the most common dermatologic diagnoses that led users to the 2 most popular dermatology-specific websites worldwide: the American Academy of Dermatology (www.aad.org) and DermNet New Zealand (www.dermnetnz.org).³ The Alexa directory (www.alexa.com), a large publicly available Internet analytics resource, was used to determine the most common dermatology search terms that led a user to either www.dermnetnz.org or www.aad.org. In addition, searches for the 3 most common types of skin cancer—melanoma, squamous cell carcinoma, and basal cell carcinoma—were included. Each term was entered into a GIS and a GWS. The first 10 results, which represent 92% of the websites ultimately visited by users,⁴ were analyzed. The source, diagnostic accuracy, and Fitzpatrick skin type of the images was determined. Website sources were organized into 11 categories. All data collection occurred within a 1-week period in August 2015.

A total of 320 images were analyzed. In the GIS, private websites (36%), dermatology association websites (28%), and general health information websites (10%) were the 3 most common sources. In the GWS, health information websites (35%), private websites (21%), and dermatology association websites (20%) accounted for the most common sources (Table 2). The majority of images were of Fitzpatrick skin types I and II (89%) and nearly all images were diagnostically accurate (98%). There was no statistically significant difference in accuracy of diagnosis between physician-associated websites (100% accuracy) versus nonphysician-associated sites (98% accuracy, P=.25).

Our results showed high diagnostic accuracy among the top GIS results for common dermatology search terms. Diagnostic accuracy did not vary between websites that were physician associated versus those that were not. Our results are comparable to the reported accuracy of online dermatologic health information.¹ In GIS results, the majority of images were provided by private websites, whereas the top websites in GWS results were health information websites.

Only 1% of images were of Fitzpatrick skin types VI and VII. Presentation of skin diseases is remarkably different based on the patient’s skin type.⁵ The shortage of readily accessible images of skin of color is in line with the lack of familiarity physicians and trainees have with dermatologic conditions in ethnic skin.⁶

Based on the results from this analysis, providers and patients searching for dermatologic conditions via a direct GIS should be cognizant of several considerations. Although our results showed that GIS was accurate, the searcher should note that image-based searches are not accompanied by relevant text that can help confirm relevancy and accuracy. Image searches depend on textual tags added by the source website. Websites that represent dermatological associations and academic centers can add an additional layer of confidence for users. Patients and clinicians also should be aware that the consideration of a patient’s Fitzpatrick skin type is critical when assessing the relevancy of a GIS result. In conclusion, search results via GIS queries are accurate for the dermatological diagnoses tested but may be lacking in skin of color variations, suggesting a potential unmet need based on our growing ethnic skin population.

To the Editor:

Prior studies have assessed the quality of text-based dermatology information on the Internet using traditional search engine queries.¹ However, little is understood about the sources, accuracy, and quality of online dermatology images derived from direct image searches. Previous work has shown that direct search engine image queries were largely accurate for 3 pediatric dermatology diagnosis searches: atopic dermatitis, lichen striatus, and subcutaneous fat necrosis.² We assessed images obtained for common dermatologic conditions from a Google image search (GIS) compared to a traditional text-based Google web search (GWS).

Image results for 32 unique dermatologic search terms were analyzed (Table 1). These search terms were selected using the results of a prior study that identified the most common dermatologic diagnoses that led users to the 2 most popular dermatology-specific websites worldwide: the American Academy of Dermatology (www.aad.org) and DermNet New Zealand (www.dermnetnz.org).³ The Alexa directory (www.alexa.com), a large publicly available Internet analytics resource, was used to determine the most common dermatology search terms that led a user to either www.dermnetnz.org or www.aad.org. In addition, searches for the 3 most common types of skin cancer—melanoma, squamous cell carcinoma, and basal cell carcinoma—were included. Each term was entered into a GIS and a GWS. The first 10 results, which represent 92% of the websites ultimately visited by users,⁴ were analyzed. The source, diagnostic accuracy, and Fitzpatrick skin type of the images was determined. Website sources were organized into 11 categories. All data collection occurred within a 1-week period in August 2015.

A total of 320 images were analyzed. In the GIS, private websites (36%), dermatology association websites (28%), and general health information websites (10%) were the 3 most common sources. In the GWS, health information websites (35%), private websites (21%), and dermatology association websites (20%) accounted for the most common sources (Table 2). The majority of images were of Fitzpatrick skin types I and II (89%) and nearly all images were diagnostically accurate (98%). There was no statistically significant difference in accuracy of diagnosis between physician-associated websites (100% accuracy) versus nonphysician-associated sites (98% accuracy, P=.25).

Our results showed high diagnostic accuracy among the top GIS results for common dermatology search terms. Diagnostic accuracy did not vary between websites that were physician associated versus those that were not. Our results are comparable to the reported accuracy of online dermatologic health information.¹ In GIS results, the majority of images were provided by private websites, whereas the top websites in GWS results were health information websites.

Only 1% of images were of Fitzpatrick skin types VI and VII. Presentation of skin diseases is remarkably different based on the patient’s skin type.⁵ The shortage of readily accessible images of skin of color is in line with the lack of familiarity physicians and trainees have with dermatologic conditions in ethnic skin.⁶

Based on the results from this analysis, providers and patients searching for dermatologic conditions via a direct GIS should be cognizant of several considerations. Although our results showed that GIS was accurate, the searcher should note that image-based searches are not accompanied by relevant text that can help confirm relevancy and accuracy. Image searches depend on textual tags added by the source website. Websites that represent dermatological associations and academic centers can add an additional layer of confidence for users. Patients and clinicians also should be aware that the consideration of a patient’s Fitzpatrick skin type is critical when assessing the relevancy of a GIS result. In conclusion, search results via GIS queries are accurate for the dermatological diagnoses tested but may be lacking in skin of color variations, suggesting a potential unmet need based on our growing ethnic skin population.

To the Editor:

Prior studies have assessed the quality of text-based dermatology information on the Internet using traditional search engine queries.¹ However, little is understood about the sources, accuracy, and quality of online dermatology images derived from direct image searches. Previous work has shown that direct search engine image queries were largely accurate for 3 pediatric dermatology diagnosis searches: atopic dermatitis, lichen striatus, and subcutaneous fat necrosis.² We assessed images obtained for common dermatologic conditions from a Google image search (GIS) compared to a traditional text-based Google web search (GWS).

Image results for 32 unique dermatologic search terms were analyzed (Table 1). These search terms were selected using the results of a prior study that identified the most common dermatologic diagnoses that led users to the 2 most popular dermatology-specific websites worldwide: the American Academy of Dermatology (www.aad.org) and DermNet New Zealand (www.dermnetnz.org).³ The Alexa directory (www.alexa.com), a large publicly available Internet analytics resource, was used to determine the most common dermatology search terms that led a user to either www.dermnetnz.org or www.aad.org. In addition, searches for the 3 most common types of skin cancer—melanoma, squamous cell carcinoma, and basal cell carcinoma—were included. Each term was entered into a GIS and a GWS. The first 10 results, which represent 92% of the websites ultimately visited by users,⁴ were analyzed. The source, diagnostic accuracy, and Fitzpatrick skin type of the images was determined. Website sources were organized into 11 categories. All data collection occurred within a 1-week period in August 2015.

A total of 320 images were analyzed. In the GIS, private websites (36%), dermatology association websites (28%), and general health information websites (10%) were the 3 most common sources. In the GWS, health information websites (35%), private websites (21%), and dermatology association websites (20%) accounted for the most common sources (Table 2). The majority of images were of Fitzpatrick skin types I and II (89%) and nearly all images were diagnostically accurate (98%). There was no statistically significant difference in accuracy of diagnosis between physician-associated websites (100% accuracy) versus nonphysician-associated sites (98% accuracy, P=.25).

Our results showed high diagnostic accuracy among the top GIS results for common dermatology search terms. Diagnostic accuracy did not vary between websites that were physician associated versus those that were not. Our results are comparable to the reported accuracy of online dermatologic health information.¹ In GIS results, the majority of images were provided by private websites, whereas the top websites in GWS results were health information websites.

Only 1% of images were of Fitzpatrick skin types VI and VII. Presentation of skin diseases is remarkably different based on the patient’s skin type.⁵ The shortage of readily accessible images of skin of color is in line with the lack of familiarity physicians and trainees have with dermatologic conditions in ethnic skin.⁶

Based on the results from this analysis, providers and patients searching for dermatologic conditions via a direct GIS should be cognizant of several considerations. Although our results showed that GIS was accurate, the searcher should note that image-based searches are not accompanied by relevant text that can help confirm relevancy and accuracy. Image searches depend on textual tags added by the source website. Websites that represent dermatological associations and academic centers can add an additional layer of confidence for users. Patients and clinicians also should be aware that the consideration of a patient’s Fitzpatrick skin type is critical when assessing the relevancy of a GIS result. In conclusion, search results via GIS queries are accurate for the dermatological diagnoses tested but may be lacking in skin of color variations, suggesting a potential unmet need based on our growing ethnic skin population.