Rosacea is a common chronic inflammatory disease that typically affects centrofacial skin, particularly the convexities of the forehead, nose, cheeks, and chin. Occasionally, involvement of the scalp, neck, or upper trunk can occur.¹ Rosacea is more common in light-skinned individuals and has been called the “curse of the Celts,”² but it also can affect Asian individuals and patients of African descent. Although rosacea affects women more frequently, men are more likely to develop severe disease with complications such as rhinophyma. Diagnosis is made on clinical grounds, and histologic confirmation rarely is necessary.

Despite its high incidence and recent advances, the pathogenesis of rosacea is still poorly understood. A combination of factors, such as aberrations in innate immunity,³ neurovascular dysregulation, dilated blood and lymphatic vessels, and a possible genetic predisposition seem to be involved.⁴ Presence of commensal Demodex folliculorum mites may be a contributing factor for papulopustular disease.

Patients can present with a range of clinical features, such as transient or persistent facial erythema, telangiectasia, papules, pustules, edema, thickening, plaque formation, and ocular manifestations. Associated burning and stinging also may occur. Rosacea-related erythema (eg, lesional and perilesional erythema) can be caused by inflammatory lesions or can present independent of lesions in the case of diffuse facial erythema. Due to the diversity of clinical signs and limited knowledge regarding its etiology, rosacea is best regarded as a syndrome and has been classified into 4 subtypes—erythematotelangiectatic, papulopustular, phymatous, and ocular—and 1 variant (granulomatous rosacea).⁵ The most common phymatous changes affect the nose, with hypertrophy and lymphedema of subcutaneous tissues. Other sites that can be affected are the ears, forehead, and chin. Ocular manifestations affect approximately 50% of rosacea patients,⁶ ranging from conjunctivitis and blepharitis to keratitis and corneal ulceration, thereby requiring ophthalmologic assessment.

Because rosacea affects facial appearance, it can have a devastating impact on the patient’s quality of life, leading to social isolation. Although there is no cure available for rosacea, lifestyle modification and treatment can reduce or control its features, which tend to exacerbate and remit. There are a number of possible triggers for rosacea that ideally should be avoided such as sun exposure, hot or cold weather, heavy exercise, emotional stress, and consumption of alcohol and spicy foods. It is essential to consider disease subtype as well as the signs and symptoms presenting in each individual patient when approaching therapy selection. Most well-established US Food and Drug Administration (FDA)–approved treatments of rosacea target the papulopustular aspect of disease, including the erythema associated with the lesions. These treatments include topical and systemic antibiotics and azelaic acid. Non–FDA-approved agents such as topical and systemic retinoids, topical calcineurin inhibitors, and topical benzoyl peroxide also are used, though there is limited evidence of their efficacy.⁷

Management options for diffuse facial erythema and telangiectasia, however, are limited. Standard rosacea treatments often are not efficacious in treating these aspects of the disease, thereby requiring an alternative approach. This article reviews devices and topical agents currently available for the management of rosacea.

Skin Care
The skin of rosacea patients often is sensitive and prone to irritation; therefore, a good skin care regimen is an integral part of disease management and should include a gentle cleanser, moisturizer, and sunscreen.⁸ Lipid-free liquid cleansers or synthetic detergent (syndet) cleansers with a neutral to slightly acidic pH (ie, similar to the pH of normal skin) are ideal.⁹ Following cleansing, the skin should be gently dried. It may be beneficial to wait up to 30 minutes before application of a moisturizer to avoid irritation. Hydrating moisturizers should be free of irritants or abrasives, allowing maintenance of stratum corneum pH in an acid range of 4 to 6. Green-tinted makeup can be a useful tool in covering areas of erythema.

Devices
A variety of devices targeting hemoglobin are reported to be effective for the management of erythema and telangiectasia in rosacea patients, including the 595-nm pulsed dye laser (PDL), the potassium titanyl phosphate (KTP) laser, the 1064-nm Nd:YAG laser, and noncoherent intense pulsed light (IPL) sources.

The major chromophore in blood vessels is oxyhemoglobin, with 2 major absorption bands in the visible light spectrum at 542 and 577 nm. There also is notable albeit lesser absorption in the near-infrared range from 700 to 1100 nm.¹⁰ Following absorption by oxyhemoglobin, light energy is converted to thermal energy, which diffuses in the blood vessel causing photocoagulation, mechanical injury, and finally thrombosis.

Pulsed Dye Laser (585–595 nm)

Among the vascular lasers, the PDL has a long safety record. It was the first laser that used the concept of selective photothermolysis for treatment of vascular lesions.^11,12 The first PDLs had a wavelength of 577 nm, while current PDLs have wavelengths of 585 or 595 nm with longer pulse durations and circular or oval spot sizes that are ideal for treatment of dermal vessels. The main disadvantage of PDLs is the development of posttreatment purpura. The longer pulse durations of KTP lasers avoid damage to cutaneous vasculature and eliminate the risk for bruising. Nonetheless, the wavelength of the PDL provides a greater depth of penetration due to its substantial absorption by cutaneous vasculature compared to the shorter wavelength of the KTP laser.

Although newer-generation PDLs still have the potential to cause purpura, various attempts have been made to minimize this risk, such as the use of longer pulse durations, multiple minipulses or “pulselets,”¹³ and multiple passes. Separate parameters may need to be used when treating linear vessels and diffuse erythema, with longer pulse durations required for larger vessels. The Figure shows a rosacea patient with facial telangiectasia before and after 1 treatment with a PDL.

According to Alam et al,¹⁴ purpuric settings were more efficacious in a comparison of variable-pulsed PDLs for facial telangiectasia. In 82% (9/11) of cases, greater reduction in telangiectasia density was noted on the side of the face that had been treated with purpuric settings versus the other side of the face.¹⁴ Purpuric settings are particularly effective in treating larger vessels, while finer telangiectatic vessels may respond to purpura-free settings.

In a study of 12 participants treated with a 595-nm PDL at a pulse duration of 6 ms and fluences from 7 to 9 J/cm², no lasting purpura was seen; however, while 9 participants achieved more than 25% improvement after a single treatment, only 2 participants achieved more than 75% improvement.¹⁵ Nonetheless, some patients may prefer this potentially less effective treatment method to avoid the socially embarrassing side effect of purpura.

In a study of 12 rosacea patients, a 75% reduction in telangiectasia scores was noted after a mean of 3 treatments with the 585-nm PDL using 450-ms pulse durations. Purpura occurred in all patients.¹⁶ In another study by Madan and Ferguson,¹⁷ 18 participants with nasal telangiectasia that had been resistant to the traditional round spot, 595-nm PDL and/or 532-nm KTP laser were treated with a 3x10-mm elliptical spot, ultra-long pulse, 595-nm PDL with a 40-ms pulse duration and double passes. Complete clearance was seen in 10 (55.6%) participants and 8 (44.4%) showed more than 80% improvement. No purpura was associated with the treatment.¹⁷

Further studies comparing the efficacy of nonpurpuric and purpuric settings in the same patient would allow us to determine the most effective option for future treatment.

KTP Laser (532 nm)

Potassium titanyl phosphate lasers have the disadvantage of higher melanin absorption, which can lead to epidermal damage with postinflammatory hyperpigmentation. Their use is limited to lighter skin types. Because of its shorter wavelength, the KTP laser is best used to treat superficial telangiectasia. The absence of posttreatment purpura can make KTP lasers a popular alternative to PDLs.¹⁷ Uebelhoer et al¹⁸ performed a split-face study in 15 participants to compare the 595-nm PDL and 532-nm KTP laser. Although both treatments were effective, the KTP laser achieved 62% clearance after the first treatment and 85% clearance 3 weeks after the third treatment compared to 49% and 75%, respectively, for the PDL. Interestingly, the degree of swelling and erythema posttreatment were greater on the KTP laser–treated side.¹⁸

Nd:YAG (1064 nm)

The wavelength of the Nd:YAG laser targets the lower absorption peak of oxyhemoglobin. In a study of 15 participants with facial telangiectasia who were treated with a  1064-nm Nd:YAG laser at day 0 and day 30 using a 3-mm spot size, a fluence of 120 to 170 J/cm,² and 5- to 40-ms pulse durations, 73% (11/15) showed moderate to significant improvement at day 0 and day 30 and 80% improvement at 3 months’ follow-up.¹⁹ In a split-face study of 14 patients, treatment with the 595-nm PDL with a fluence of 7.5 J/cm², pulse duration of 6 ms, and spot size of 10 mm was compared with the 1064-nm Nd:YAG laser with a fluence of 6 J/cm², pulse duration of 0.3 ms, and spot size of 8 mm.²⁰ Erythema improved by 6.4% from baseline on the side treated with the PDL. Although participants rated the Nd:YAG laser treatment as less painful, they were more satisfied with the results of the PDL treatment.²⁰ In another split-face study comparing the 595-nm PDL and 1064-nm Nd:YAG laser, greater improvement was reported with the Nd:YAG laser, though the results were not statistically significant.²¹

Intense Pulsed Light

While lasers use selective photothermolysis, IPL devices emit noncoherent light at a wavelength of 500 to 1200 nm. Cutoff filters allow for selective tissue damage depending on the absorption spectra of the tissue. Longer wavelengths are effective for the treatment of deeper vessels, while shorter wavelengths target more superficial vessels; however, the shorter wavelengths can interact with melanin and should be avoided in darker skin types. In a phase 3 open trial, 34 participants were treated with IPL with a 560-nm cutoff filter and fluences of 24 to 32 J/cm². The mean reduction of erythema following 4 treatments was 39% on the cheeks and 22% on the chin; side effects were minimal.²²

Photodynamic Therapy

Photodynamic therapy is an effective and widely used treatment method for a number of skin conditions. Following its success in the treatment of acne, it also has been used in the management of rosacea, though the exact mechanism of action remains unclear.

Photodynamic therapy involves topical application of a photosensitizing agent (eg, 5-aminolevulinic acid, methyl aminolevulinate [MAL]) followed by exposure to red or blue light. The photosensitizing agent accumulates semiselectively in abnormal skin tissue and is converted to protoporphyrin IX, which induces a toxic skin reaction through reactive oxygen radicals in the presence of visible light.²³ Photodynamic therapy generally is well tolerated. The primary side effects are pain, burning, and stinging.

In 3 of 4 (75%) patients treated with MAL and red light, rosacea clearance was noted after 2 to 3 sessions. Remission lasted for 3 months in 2 (66.7%) participants and for 9 months in 1 (33.3%) participant.²⁴ In another study, 17 patients were treated with MAL and red light. Results were good in 10 participants (58.8%), fair in 4 (23.5%), and poor in 3 (17.6%).²³

ALPHA-Adrenergic Receptor Agonists

Recently, the α-adrenergic receptor agonists brimonidine tartrate and oxymetazoline have been found to be effective in controlling diffuse facial erythema of rosacea, which is thought to arise from vasomotor instability and abnormal vasodilation of the superficial cutaneous vasculature. Brimonidine tartrate is a potent α₂-agonist that is mainly used for treatment of open-angle glaucoma. In 2 phase 3 controlled studies, once-daily application of brimonidine tartrate gel 0.5% was found to be effective and safe in reducing the erythema of rosacea.²⁵ Brimonidine tartrate gel is the first FDA-approved treatment of facial erythema associated with rosacea. Possible side effects are erythema worse than baseline (4%), flushing (3%), and burning (2%).²⁶ Oxymetazoline is a potent α₁- and partial α₂-agonist that is available as a nasal decongestant. Oxymetazoline solution 0.05% used once daily has been shown in case reports to reduce rosacea-associated erythema for several hours.²⁷

Nicotinamide

Nicotinamide is the amide form of niacin, which has both anti-inflammatory properties and a stabilizing effect on epidermal barrier function.²⁸ Although topical application of nicotinamide has been used in the treatment of inflammatory dermatoses such as rosacea,^28,29 niacin can lead to cutaneous vasodilation and thus flushing. It has been hypothesized to potentially enhance the effect of PDL if used as pretreatment for rosacea-associated erythema.³⁰

Conclusion
Rosacea can have a substantial impact on patient quality of life. Recent advances in treatment options and rapidly advancing knowledge of laser therapy are providing dermatologists with powerful tools for rosacea clearance. Lasers and IPL are effective treatments of the erythematotelangiectatic aspect of the disease, and careful selection of devices and treatment parameters can reduce unwanted side effects.

Rosacea is a common chronic inflammatory disease that typically affects centrofacial skin, particularly the convexities of the forehead, nose, cheeks, and chin. Occasionally, involvement of the scalp, neck, or upper trunk can occur.¹ Rosacea is more common in light-skinned individuals and has been called the “curse of the Celts,”² but it also can affect Asian individuals and patients of African descent. Although rosacea affects women more frequently, men are more likely to develop severe disease with complications such as rhinophyma. Diagnosis is made on clinical grounds, and histologic confirmation rarely is necessary.

Despite its high incidence and recent advances, the pathogenesis of rosacea is still poorly understood. A combination of factors, such as aberrations in innate immunity,³ neurovascular dysregulation, dilated blood and lymphatic vessels, and a possible genetic predisposition seem to be involved.⁴ Presence of commensal Demodex folliculorum mites may be a contributing factor for papulopustular disease.

Patients can present with a range of clinical features, such as transient or persistent facial erythema, telangiectasia, papules, pustules, edema, thickening, plaque formation, and ocular manifestations. Associated burning and stinging also may occur. Rosacea-related erythema (eg, lesional and perilesional erythema) can be caused by inflammatory lesions or can present independent of lesions in the case of diffuse facial erythema. Due to the diversity of clinical signs and limited knowledge regarding its etiology, rosacea is best regarded as a syndrome and has been classified into 4 subtypes—erythematotelangiectatic, papulopustular, phymatous, and ocular—and 1 variant (granulomatous rosacea).⁵ The most common phymatous changes affect the nose, with hypertrophy and lymphedema of subcutaneous tissues. Other sites that can be affected are the ears, forehead, and chin. Ocular manifestations affect approximately 50% of rosacea patients,⁶ ranging from conjunctivitis and blepharitis to keratitis and corneal ulceration, thereby requiring ophthalmologic assessment.

Because rosacea affects facial appearance, it can have a devastating impact on the patient’s quality of life, leading to social isolation. Although there is no cure available for rosacea, lifestyle modification and treatment can reduce or control its features, which tend to exacerbate and remit. There are a number of possible triggers for rosacea that ideally should be avoided such as sun exposure, hot or cold weather, heavy exercise, emotional stress, and consumption of alcohol and spicy foods. It is essential to consider disease subtype as well as the signs and symptoms presenting in each individual patient when approaching therapy selection. Most well-established US Food and Drug Administration (FDA)–approved treatments of rosacea target the papulopustular aspect of disease, including the erythema associated with the lesions. These treatments include topical and systemic antibiotics and azelaic acid. Non–FDA-approved agents such as topical and systemic retinoids, topical calcineurin inhibitors, and topical benzoyl peroxide also are used, though there is limited evidence of their efficacy.⁷

Management options for diffuse facial erythema and telangiectasia, however, are limited. Standard rosacea treatments often are not efficacious in treating these aspects of the disease, thereby requiring an alternative approach. This article reviews devices and topical agents currently available for the management of rosacea.

Skin Care
The skin of rosacea patients often is sensitive and prone to irritation; therefore, a good skin care regimen is an integral part of disease management and should include a gentle cleanser, moisturizer, and sunscreen.⁸ Lipid-free liquid cleansers or synthetic detergent (syndet) cleansers with a neutral to slightly acidic pH (ie, similar to the pH of normal skin) are ideal.⁹ Following cleansing, the skin should be gently dried. It may be beneficial to wait up to 30 minutes before application of a moisturizer to avoid irritation. Hydrating moisturizers should be free of irritants or abrasives, allowing maintenance of stratum corneum pH in an acid range of 4 to 6. Green-tinted makeup can be a useful tool in covering areas of erythema.

Devices
A variety of devices targeting hemoglobin are reported to be effective for the management of erythema and telangiectasia in rosacea patients, including the 595-nm pulsed dye laser (PDL), the potassium titanyl phosphate (KTP) laser, the 1064-nm Nd:YAG laser, and noncoherent intense pulsed light (IPL) sources.

The major chromophore in blood vessels is oxyhemoglobin, with 2 major absorption bands in the visible light spectrum at 542 and 577 nm. There also is notable albeit lesser absorption in the near-infrared range from 700 to 1100 nm.¹⁰ Following absorption by oxyhemoglobin, light energy is converted to thermal energy, which diffuses in the blood vessel causing photocoagulation, mechanical injury, and finally thrombosis.

Pulsed Dye Laser (585–595 nm)

Among the vascular lasers, the PDL has a long safety record. It was the first laser that used the concept of selective photothermolysis for treatment of vascular lesions.^11,12 The first PDLs had a wavelength of 577 nm, while current PDLs have wavelengths of 585 or 595 nm with longer pulse durations and circular or oval spot sizes that are ideal for treatment of dermal vessels. The main disadvantage of PDLs is the development of posttreatment purpura. The longer pulse durations of KTP lasers avoid damage to cutaneous vasculature and eliminate the risk for bruising. Nonetheless, the wavelength of the PDL provides a greater depth of penetration due to its substantial absorption by cutaneous vasculature compared to the shorter wavelength of the KTP laser.

Although newer-generation PDLs still have the potential to cause purpura, various attempts have been made to minimize this risk, such as the use of longer pulse durations, multiple minipulses or “pulselets,”¹³ and multiple passes. Separate parameters may need to be used when treating linear vessels and diffuse erythema, with longer pulse durations required for larger vessels. The Figure shows a rosacea patient with facial telangiectasia before and after 1 treatment with a PDL.

According to Alam et al,¹⁴ purpuric settings were more efficacious in a comparison of variable-pulsed PDLs for facial telangiectasia. In 82% (9/11) of cases, greater reduction in telangiectasia density was noted on the side of the face that had been treated with purpuric settings versus the other side of the face.¹⁴ Purpuric settings are particularly effective in treating larger vessels, while finer telangiectatic vessels may respond to purpura-free settings.

In a study of 12 participants treated with a 595-nm PDL at a pulse duration of 6 ms and fluences from 7 to 9 J/cm², no lasting purpura was seen; however, while 9 participants achieved more than 25% improvement after a single treatment, only 2 participants achieved more than 75% improvement.¹⁵ Nonetheless, some patients may prefer this potentially less effective treatment method to avoid the socially embarrassing side effect of purpura.

In a study of 12 rosacea patients, a 75% reduction in telangiectasia scores was noted after a mean of 3 treatments with the 585-nm PDL using 450-ms pulse durations. Purpura occurred in all patients.¹⁶ In another study by Madan and Ferguson,¹⁷ 18 participants with nasal telangiectasia that had been resistant to the traditional round spot, 595-nm PDL and/or 532-nm KTP laser were treated with a 3x10-mm elliptical spot, ultra-long pulse, 595-nm PDL with a 40-ms pulse duration and double passes. Complete clearance was seen in 10 (55.6%) participants and 8 (44.4%) showed more than 80% improvement. No purpura was associated with the treatment.¹⁷

Further studies comparing the efficacy of nonpurpuric and purpuric settings in the same patient would allow us to determine the most effective option for future treatment.

KTP Laser (532 nm)

Potassium titanyl phosphate lasers have the disadvantage of higher melanin absorption, which can lead to epidermal damage with postinflammatory hyperpigmentation. Their use is limited to lighter skin types. Because of its shorter wavelength, the KTP laser is best used to treat superficial telangiectasia. The absence of posttreatment purpura can make KTP lasers a popular alternative to PDLs.¹⁷ Uebelhoer et al¹⁸ performed a split-face study in 15 participants to compare the 595-nm PDL and 532-nm KTP laser. Although both treatments were effective, the KTP laser achieved 62% clearance after the first treatment and 85% clearance 3 weeks after the third treatment compared to 49% and 75%, respectively, for the PDL. Interestingly, the degree of swelling and erythema posttreatment were greater on the KTP laser–treated side.¹⁸

Nd:YAG (1064 nm)

The wavelength of the Nd:YAG laser targets the lower absorption peak of oxyhemoglobin. In a study of 15 participants with facial telangiectasia who were treated with a  1064-nm Nd:YAG laser at day 0 and day 30 using a 3-mm spot size, a fluence of 120 to 170 J/cm,² and 5- to 40-ms pulse durations, 73% (11/15) showed moderate to significant improvement at day 0 and day 30 and 80% improvement at 3 months’ follow-up.¹⁹ In a split-face study of 14 patients, treatment with the 595-nm PDL with a fluence of 7.5 J/cm², pulse duration of 6 ms, and spot size of 10 mm was compared with the 1064-nm Nd:YAG laser with a fluence of 6 J/cm², pulse duration of 0.3 ms, and spot size of 8 mm.²⁰ Erythema improved by 6.4% from baseline on the side treated with the PDL. Although participants rated the Nd:YAG laser treatment as less painful, they were more satisfied with the results of the PDL treatment.²⁰ In another split-face study comparing the 595-nm PDL and 1064-nm Nd:YAG laser, greater improvement was reported with the Nd:YAG laser, though the results were not statistically significant.²¹

Intense Pulsed Light

While lasers use selective photothermolysis, IPL devices emit noncoherent light at a wavelength of 500 to 1200 nm. Cutoff filters allow for selective tissue damage depending on the absorption spectra of the tissue. Longer wavelengths are effective for the treatment of deeper vessels, while shorter wavelengths target more superficial vessels; however, the shorter wavelengths can interact with melanin and should be avoided in darker skin types. In a phase 3 open trial, 34 participants were treated with IPL with a 560-nm cutoff filter and fluences of 24 to 32 J/cm². The mean reduction of erythema following 4 treatments was 39% on the cheeks and 22% on the chin; side effects were minimal.²²

Photodynamic Therapy

Photodynamic therapy is an effective and widely used treatment method for a number of skin conditions. Following its success in the treatment of acne, it also has been used in the management of rosacea, though the exact mechanism of action remains unclear.

Photodynamic therapy involves topical application of a photosensitizing agent (eg, 5-aminolevulinic acid, methyl aminolevulinate [MAL]) followed by exposure to red or blue light. The photosensitizing agent accumulates semiselectively in abnormal skin tissue and is converted to protoporphyrin IX, which induces a toxic skin reaction through reactive oxygen radicals in the presence of visible light.²³ Photodynamic therapy generally is well tolerated. The primary side effects are pain, burning, and stinging.

In 3 of 4 (75%) patients treated with MAL and red light, rosacea clearance was noted after 2 to 3 sessions. Remission lasted for 3 months in 2 (66.7%) participants and for 9 months in 1 (33.3%) participant.²⁴ In another study, 17 patients were treated with MAL and red light. Results were good in 10 participants (58.8%), fair in 4 (23.5%), and poor in 3 (17.6%).²³

ALPHA-Adrenergic Receptor Agonists

Recently, the α-adrenergic receptor agonists brimonidine tartrate and oxymetazoline have been found to be effective in controlling diffuse facial erythema of rosacea, which is thought to arise from vasomotor instability and abnormal vasodilation of the superficial cutaneous vasculature. Brimonidine tartrate is a potent α₂-agonist that is mainly used for treatment of open-angle glaucoma. In 2 phase 3 controlled studies, once-daily application of brimonidine tartrate gel 0.5% was found to be effective and safe in reducing the erythema of rosacea.²⁵ Brimonidine tartrate gel is the first FDA-approved treatment of facial erythema associated with rosacea. Possible side effects are erythema worse than baseline (4%), flushing (3%), and burning (2%).²⁶ Oxymetazoline is a potent α₁- and partial α₂-agonist that is available as a nasal decongestant. Oxymetazoline solution 0.05% used once daily has been shown in case reports to reduce rosacea-associated erythema for several hours.²⁷

Nicotinamide

Nicotinamide is the amide form of niacin, which has both anti-inflammatory properties and a stabilizing effect on epidermal barrier function.²⁸ Although topical application of nicotinamide has been used in the treatment of inflammatory dermatoses such as rosacea,^28,29 niacin can lead to cutaneous vasodilation and thus flushing. It has been hypothesized to potentially enhance the effect of PDL if used as pretreatment for rosacea-associated erythema.³⁰

Conclusion
Rosacea can have a substantial impact on patient quality of life. Recent advances in treatment options and rapidly advancing knowledge of laser therapy are providing dermatologists with powerful tools for rosacea clearance. Lasers and IPL are effective treatments of the erythematotelangiectatic aspect of the disease, and careful selection of devices and treatment parameters can reduce unwanted side effects.

Rosacea is a common chronic inflammatory disease that typically affects centrofacial skin, particularly the convexities of the forehead, nose, cheeks, and chin. Occasionally, involvement of the scalp, neck, or upper trunk can occur.¹ Rosacea is more common in light-skinned individuals and has been called the “curse of the Celts,”² but it also can affect Asian individuals and patients of African descent. Although rosacea affects women more frequently, men are more likely to develop severe disease with complications such as rhinophyma. Diagnosis is made on clinical grounds, and histologic confirmation rarely is necessary.

Despite its high incidence and recent advances, the pathogenesis of rosacea is still poorly understood. A combination of factors, such as aberrations in innate immunity,³ neurovascular dysregulation, dilated blood and lymphatic vessels, and a possible genetic predisposition seem to be involved.⁴ Presence of commensal Demodex folliculorum mites may be a contributing factor for papulopustular disease.

Patients can present with a range of clinical features, such as transient or persistent facial erythema, telangiectasia, papules, pustules, edema, thickening, plaque formation, and ocular manifestations. Associated burning and stinging also may occur. Rosacea-related erythema (eg, lesional and perilesional erythema) can be caused by inflammatory lesions or can present independent of lesions in the case of diffuse facial erythema. Due to the diversity of clinical signs and limited knowledge regarding its etiology, rosacea is best regarded as a syndrome and has been classified into 4 subtypes—erythematotelangiectatic, papulopustular, phymatous, and ocular—and 1 variant (granulomatous rosacea).⁵ The most common phymatous changes affect the nose, with hypertrophy and lymphedema of subcutaneous tissues. Other sites that can be affected are the ears, forehead, and chin. Ocular manifestations affect approximately 50% of rosacea patients,⁶ ranging from conjunctivitis and blepharitis to keratitis and corneal ulceration, thereby requiring ophthalmologic assessment.

Because rosacea affects facial appearance, it can have a devastating impact on the patient’s quality of life, leading to social isolation. Although there is no cure available for rosacea, lifestyle modification and treatment can reduce or control its features, which tend to exacerbate and remit. There are a number of possible triggers for rosacea that ideally should be avoided such as sun exposure, hot or cold weather, heavy exercise, emotional stress, and consumption of alcohol and spicy foods. It is essential to consider disease subtype as well as the signs and symptoms presenting in each individual patient when approaching therapy selection. Most well-established US Food and Drug Administration (FDA)–approved treatments of rosacea target the papulopustular aspect of disease, including the erythema associated with the lesions. These treatments include topical and systemic antibiotics and azelaic acid. Non–FDA-approved agents such as topical and systemic retinoids, topical calcineurin inhibitors, and topical benzoyl peroxide also are used, though there is limited evidence of their efficacy.⁷

Management options for diffuse facial erythema and telangiectasia, however, are limited. Standard rosacea treatments often are not efficacious in treating these aspects of the disease, thereby requiring an alternative approach. This article reviews devices and topical agents currently available for the management of rosacea.

Skin Care
The skin of rosacea patients often is sensitive and prone to irritation; therefore, a good skin care regimen is an integral part of disease management and should include a gentle cleanser, moisturizer, and sunscreen.⁸ Lipid-free liquid cleansers or synthetic detergent (syndet) cleansers with a neutral to slightly acidic pH (ie, similar to the pH of normal skin) are ideal.⁹ Following cleansing, the skin should be gently dried. It may be beneficial to wait up to 30 minutes before application of a moisturizer to avoid irritation. Hydrating moisturizers should be free of irritants or abrasives, allowing maintenance of stratum corneum pH in an acid range of 4 to 6. Green-tinted makeup can be a useful tool in covering areas of erythema.

Devices
A variety of devices targeting hemoglobin are reported to be effective for the management of erythema and telangiectasia in rosacea patients, including the 595-nm pulsed dye laser (PDL), the potassium titanyl phosphate (KTP) laser, the 1064-nm Nd:YAG laser, and noncoherent intense pulsed light (IPL) sources.

The major chromophore in blood vessels is oxyhemoglobin, with 2 major absorption bands in the visible light spectrum at 542 and 577 nm. There also is notable albeit lesser absorption in the near-infrared range from 700 to 1100 nm.¹⁰ Following absorption by oxyhemoglobin, light energy is converted to thermal energy, which diffuses in the blood vessel causing photocoagulation, mechanical injury, and finally thrombosis.

Pulsed Dye Laser (585–595 nm)

Among the vascular lasers, the PDL has a long safety record. It was the first laser that used the concept of selective photothermolysis for treatment of vascular lesions.^11,12 The first PDLs had a wavelength of 577 nm, while current PDLs have wavelengths of 585 or 595 nm with longer pulse durations and circular or oval spot sizes that are ideal for treatment of dermal vessels. The main disadvantage of PDLs is the development of posttreatment purpura. The longer pulse durations of KTP lasers avoid damage to cutaneous vasculature and eliminate the risk for bruising. Nonetheless, the wavelength of the PDL provides a greater depth of penetration due to its substantial absorption by cutaneous vasculature compared to the shorter wavelength of the KTP laser.

Although newer-generation PDLs still have the potential to cause purpura, various attempts have been made to minimize this risk, such as the use of longer pulse durations, multiple minipulses or “pulselets,”¹³ and multiple passes. Separate parameters may need to be used when treating linear vessels and diffuse erythema, with longer pulse durations required for larger vessels. The Figure shows a rosacea patient with facial telangiectasia before and after 1 treatment with a PDL.

According to Alam et al,¹⁴ purpuric settings were more efficacious in a comparison of variable-pulsed PDLs for facial telangiectasia. In 82% (9/11) of cases, greater reduction in telangiectasia density was noted on the side of the face that had been treated with purpuric settings versus the other side of the face.¹⁴ Purpuric settings are particularly effective in treating larger vessels, while finer telangiectatic vessels may respond to purpura-free settings.

In a study of 12 participants treated with a 595-nm PDL at a pulse duration of 6 ms and fluences from 7 to 9 J/cm², no lasting purpura was seen; however, while 9 participants achieved more than 25% improvement after a single treatment, only 2 participants achieved more than 75% improvement.¹⁵ Nonetheless, some patients may prefer this potentially less effective treatment method to avoid the socially embarrassing side effect of purpura.

In a study of 12 rosacea patients, a 75% reduction in telangiectasia scores was noted after a mean of 3 treatments with the 585-nm PDL using 450-ms pulse durations. Purpura occurred in all patients.¹⁶ In another study by Madan and Ferguson,¹⁷ 18 participants with nasal telangiectasia that had been resistant to the traditional round spot, 595-nm PDL and/or 532-nm KTP laser were treated with a 3x10-mm elliptical spot, ultra-long pulse, 595-nm PDL with a 40-ms pulse duration and double passes. Complete clearance was seen in 10 (55.6%) participants and 8 (44.4%) showed more than 80% improvement. No purpura was associated with the treatment.¹⁷

Further studies comparing the efficacy of nonpurpuric and purpuric settings in the same patient would allow us to determine the most effective option for future treatment.

KTP Laser (532 nm)

Potassium titanyl phosphate lasers have the disadvantage of higher melanin absorption, which can lead to epidermal damage with postinflammatory hyperpigmentation. Their use is limited to lighter skin types. Because of its shorter wavelength, the KTP laser is best used to treat superficial telangiectasia. The absence of posttreatment purpura can make KTP lasers a popular alternative to PDLs.¹⁷ Uebelhoer et al¹⁸ performed a split-face study in 15 participants to compare the 595-nm PDL and 532-nm KTP laser. Although both treatments were effective, the KTP laser achieved 62% clearance after the first treatment and 85% clearance 3 weeks after the third treatment compared to 49% and 75%, respectively, for the PDL. Interestingly, the degree of swelling and erythema posttreatment were greater on the KTP laser–treated side.¹⁸

Nd:YAG (1064 nm)

The wavelength of the Nd:YAG laser targets the lower absorption peak of oxyhemoglobin. In a study of 15 participants with facial telangiectasia who were treated with a  1064-nm Nd:YAG laser at day 0 and day 30 using a 3-mm spot size, a fluence of 120 to 170 J/cm,² and 5- to 40-ms pulse durations, 73% (11/15) showed moderate to significant improvement at day 0 and day 30 and 80% improvement at 3 months’ follow-up.¹⁹ In a split-face study of 14 patients, treatment with the 595-nm PDL with a fluence of 7.5 J/cm², pulse duration of 6 ms, and spot size of 10 mm was compared with the 1064-nm Nd:YAG laser with a fluence of 6 J/cm², pulse duration of 0.3 ms, and spot size of 8 mm.²⁰ Erythema improved by 6.4% from baseline on the side treated with the PDL. Although participants rated the Nd:YAG laser treatment as less painful, they were more satisfied with the results of the PDL treatment.²⁰ In another split-face study comparing the 595-nm PDL and 1064-nm Nd:YAG laser, greater improvement was reported with the Nd:YAG laser, though the results were not statistically significant.²¹

Intense Pulsed Light

While lasers use selective photothermolysis, IPL devices emit noncoherent light at a wavelength of 500 to 1200 nm. Cutoff filters allow for selective tissue damage depending on the absorption spectra of the tissue. Longer wavelengths are effective for the treatment of deeper vessels, while shorter wavelengths target more superficial vessels; however, the shorter wavelengths can interact with melanin and should be avoided in darker skin types. In a phase 3 open trial, 34 participants were treated with IPL with a 560-nm cutoff filter and fluences of 24 to 32 J/cm². The mean reduction of erythema following 4 treatments was 39% on the cheeks and 22% on the chin; side effects were minimal.²²

Photodynamic Therapy

Photodynamic therapy is an effective and widely used treatment method for a number of skin conditions. Following its success in the treatment of acne, it also has been used in the management of rosacea, though the exact mechanism of action remains unclear.

Photodynamic therapy involves topical application of a photosensitizing agent (eg, 5-aminolevulinic acid, methyl aminolevulinate [MAL]) followed by exposure to red or blue light. The photosensitizing agent accumulates semiselectively in abnormal skin tissue and is converted to protoporphyrin IX, which induces a toxic skin reaction through reactive oxygen radicals in the presence of visible light.²³ Photodynamic therapy generally is well tolerated. The primary side effects are pain, burning, and stinging.

In 3 of 4 (75%) patients treated with MAL and red light, rosacea clearance was noted after 2 to 3 sessions. Remission lasted for 3 months in 2 (66.7%) participants and for 9 months in 1 (33.3%) participant.²⁴ In another study, 17 patients were treated with MAL and red light. Results were good in 10 participants (58.8%), fair in 4 (23.5%), and poor in 3 (17.6%).²³

ALPHA-Adrenergic Receptor Agonists

Recently, the α-adrenergic receptor agonists brimonidine tartrate and oxymetazoline have been found to be effective in controlling diffuse facial erythema of rosacea, which is thought to arise from vasomotor instability and abnormal vasodilation of the superficial cutaneous vasculature. Brimonidine tartrate is a potent α₂-agonist that is mainly used for treatment of open-angle glaucoma. In 2 phase 3 controlled studies, once-daily application of brimonidine tartrate gel 0.5% was found to be effective and safe in reducing the erythema of rosacea.²⁵ Brimonidine tartrate gel is the first FDA-approved treatment of facial erythema associated with rosacea. Possible side effects are erythema worse than baseline (4%), flushing (3%), and burning (2%).²⁶ Oxymetazoline is a potent α₁- and partial α₂-agonist that is available as a nasal decongestant. Oxymetazoline solution 0.05% used once daily has been shown in case reports to reduce rosacea-associated erythema for several hours.²⁷

Nicotinamide

Nicotinamide is the amide form of niacin, which has both anti-inflammatory properties and a stabilizing effect on epidermal barrier function.²⁸ Although topical application of nicotinamide has been used in the treatment of inflammatory dermatoses such as rosacea,^28,29 niacin can lead to cutaneous vasodilation and thus flushing. It has been hypothesized to potentially enhance the effect of PDL if used as pretreatment for rosacea-associated erythema.³⁰

Conclusion
Rosacea can have a substantial impact on patient quality of life. Recent advances in treatment options and rapidly advancing knowledge of laser therapy are providing dermatologists with powerful tools for rosacea clearance. Lasers and IPL are effective treatments of the erythematotelangiectatic aspect of the disease, and careful selection of devices and treatment parameters can reduce unwanted side effects.

The new pelvic exam guidelines from the American College of Physicians may be a relief for women who would prefer to forgo the annual ritual, but they could also lead to variation in well-woman care, depending on which type of specialist provides that care.

The guidelines advise physicians to skip annual pelvic examinations in otherwise healthy, asymptomatic women who are not pregnant (Ann. Intern. Med. 2014;161:67-72).

The evidence-based clinical practice guidelines recommend that cervical cancer screening be limited to the visual inspection of the cervix and cervical swabs for cancer and human papillomavirus. They recommend against performing a speculum examination of the vagina and cervix, and a bimanual examination of the adnexa, uterus, ovaries, and bladder. The recommendation does not apply to using the Pap smear to screen for cervical cancer.

The diagnostic accuracy of the pelvic exam in detecting gynecologic cancer or infections is low, the ACP said, and carries the risk of false positives that can lead to unnecessary testing and procedures. The embarrassment and discomfort of the exam may also keep some women from seeking care, the ACP stated in the guidelines.

But that advice conflicts with an August 2012 policy statement from the American College of Obstetricians and Gynecologists, which recommends that pelvic exams be performed in asymptomatic adults as part of an annual well-woman visit. However, citing a lack of evidence, the opinion leaves the decision about when and how often to perform the exams in the hands of physicians and patients (Obstet. Gynecol. 2012;120:421-4).

Following the release of the ACP guidelines, ACOG issued a statement renewing its support for the pelvic exam, but saying that the ACOG policy was a "complement" to the new ACP recommendations. ACOG said that the use of the exam is "supported by the clinical experiences of gynecologists treating their patients."

It’s a position shared by Dr. Jill Rabin, professor of obstetrics and gynecology at Hofstra North Shore–LIJ School of Medicine and head of urogynecology at Long Island Jewish Medical Center in New Hyde Park, N.Y. She currently performs a full pelvic exam during the well-woman visit and plans to continue doing so.

"I want every woman to get a full exam every year and whoever does it, they should do a good job," Dr. Rabin said.

She praised the ACP guideline, saying that she agreed that there was a lack of evidence and that the exams can create anxiety and embarrassment. But pelvic exams are also essential in uncovering conditions such as pelvic floor weakness, fibroids, and vulvovaginal atrophy, Dr. Rabin said. And the exam provides a unique opportunity for women to bring up concerns that they might not raise during a history taking, she said, such as symptoms of incontinence.

As for the lack of evidence, Dr. Rabin said researchers should begin those studies even if they take decades to provide complete answers.

"There’s a lot that we do in life where we don’t have the studies," she said. "But lack of the evidence doesn’t mean that there’s lack of value."

And Dr. Rabin isn’t alone in doing a full pelvic exam. A recent survey of ob.gyns. found that nearly all perform bimanual pelvic examinations in asymptomatic women for a variety of reasons including patient reassurance, detection of ovarian cancer, or identification of benign uterine and ovarian conditions (Am. J. Obstet. Gynecol. 2013;208:109.e1-7).

Dr. Molly Cooke, the ACP’s immediate past president and a member of the group’s Clinical Practice Guidelines Committee, said that for years she performed pelvic exams in asymptomatic patients mainly out of "habit," rather than evidence. But with the ACP’s new guidelines, she plans to change her approach.

Going forward, Dr. Cooke said she will discuss the utility of the pelvic exam with patients and explain that the evidence indicates that the bimanual exam does not produce meaningful information and could lead them astray. She said she expects that most patients will agree to forgo the pelvic exam when presented with the evidence.

As for ob.gyns. who may continue to perform pelvic exams routinely in asymptomatic patients, Dr. Cooke said that they are essentially making a "faith-based" assertion about the usefulness of the exam.

Dr. Cooke said the ACP recommendations are meant to apply to all clinicians who provide well-woman care. "We don’t see any reason why the guideline isn’t as useful and applicable to a nurse practitioner, a gynecologist, a family physician, and an internist," she said.

The new ACP guidelines are being well received by some internists and family physicians who are feeling the pressure to cram more and more preventive care into a short visit.

"You really have to think about the opportunity cost here," said Dr. Giang Nguyen of the Hospital of the University of Pennsylvania, Philadelphia.

"When we take those extra minutes out of a visit, which might only be 15 minutes long, you’re preventing the patient and the provider from using that time for things that we have strong evidence for, like counseling about weight management, talking about smoking cessation, reviewing other parts of their sexual history that maybe would be useful to talk about in order to prevent future illness," he added.

Given the shortage of primary care physicians, Dr. Nguyen said spending visit time on screenings that aren’t evidence based essentially reduces access to care.

The American Academy of Family Physicians doesn’t have a recommendation for or against performing screening pelvic exams. As part of the Choosing Wisely campaign, the AAFP issued a clinical recommendation against requiring a pelvic exam or other physical exam to prescribe oral contraceptives.

[email protected]

On Twitter @MaryEllenNY

The new pelvic exam guidelines from the American College of Physicians may be a relief for women who would prefer to forgo the annual ritual, but they could also lead to variation in well-woman care, depending on which type of specialist provides that care.

The guidelines advise physicians to skip annual pelvic examinations in otherwise healthy, asymptomatic women who are not pregnant (Ann. Intern. Med. 2014;161:67-72).

The evidence-based clinical practice guidelines recommend that cervical cancer screening be limited to the visual inspection of the cervix and cervical swabs for cancer and human papillomavirus. They recommend against performing a speculum examination of the vagina and cervix, and a bimanual examination of the adnexa, uterus, ovaries, and bladder. The recommendation does not apply to using the Pap smear to screen for cervical cancer.

The diagnostic accuracy of the pelvic exam in detecting gynecologic cancer or infections is low, the ACP said, and carries the risk of false positives that can lead to unnecessary testing and procedures. The embarrassment and discomfort of the exam may also keep some women from seeking care, the ACP stated in the guidelines.

But that advice conflicts with an August 2012 policy statement from the American College of Obstetricians and Gynecologists, which recommends that pelvic exams be performed in asymptomatic adults as part of an annual well-woman visit. However, citing a lack of evidence, the opinion leaves the decision about when and how often to perform the exams in the hands of physicians and patients (Obstet. Gynecol. 2012;120:421-4).

Following the release of the ACP guidelines, ACOG issued a statement renewing its support for the pelvic exam, but saying that the ACOG policy was a "complement" to the new ACP recommendations. ACOG said that the use of the exam is "supported by the clinical experiences of gynecologists treating their patients."

It’s a position shared by Dr. Jill Rabin, professor of obstetrics and gynecology at Hofstra North Shore–LIJ School of Medicine and head of urogynecology at Long Island Jewish Medical Center in New Hyde Park, N.Y. She currently performs a full pelvic exam during the well-woman visit and plans to continue doing so.

"I want every woman to get a full exam every year and whoever does it, they should do a good job," Dr. Rabin said.

She praised the ACP guideline, saying that she agreed that there was a lack of evidence and that the exams can create anxiety and embarrassment. But pelvic exams are also essential in uncovering conditions such as pelvic floor weakness, fibroids, and vulvovaginal atrophy, Dr. Rabin said. And the exam provides a unique opportunity for women to bring up concerns that they might not raise during a history taking, she said, such as symptoms of incontinence.

As for the lack of evidence, Dr. Rabin said researchers should begin those studies even if they take decades to provide complete answers.

"There’s a lot that we do in life where we don’t have the studies," she said. "But lack of the evidence doesn’t mean that there’s lack of value."

And Dr. Rabin isn’t alone in doing a full pelvic exam. A recent survey of ob.gyns. found that nearly all perform bimanual pelvic examinations in asymptomatic women for a variety of reasons including patient reassurance, detection of ovarian cancer, or identification of benign uterine and ovarian conditions (Am. J. Obstet. Gynecol. 2013;208:109.e1-7).

Dr. Molly Cooke, the ACP’s immediate past president and a member of the group’s Clinical Practice Guidelines Committee, said that for years she performed pelvic exams in asymptomatic patients mainly out of "habit," rather than evidence. But with the ACP’s new guidelines, she plans to change her approach.

Going forward, Dr. Cooke said she will discuss the utility of the pelvic exam with patients and explain that the evidence indicates that the bimanual exam does not produce meaningful information and could lead them astray. She said she expects that most patients will agree to forgo the pelvic exam when presented with the evidence.

As for ob.gyns. who may continue to perform pelvic exams routinely in asymptomatic patients, Dr. Cooke said that they are essentially making a "faith-based" assertion about the usefulness of the exam.

Dr. Cooke said the ACP recommendations are meant to apply to all clinicians who provide well-woman care. "We don’t see any reason why the guideline isn’t as useful and applicable to a nurse practitioner, a gynecologist, a family physician, and an internist," she said.

The new ACP guidelines are being well received by some internists and family physicians who are feeling the pressure to cram more and more preventive care into a short visit.

"You really have to think about the opportunity cost here," said Dr. Giang Nguyen of the Hospital of the University of Pennsylvania, Philadelphia.

"When we take those extra minutes out of a visit, which might only be 15 minutes long, you’re preventing the patient and the provider from using that time for things that we have strong evidence for, like counseling about weight management, talking about smoking cessation, reviewing other parts of their sexual history that maybe would be useful to talk about in order to prevent future illness," he added.

Given the shortage of primary care physicians, Dr. Nguyen said spending visit time on screenings that aren’t evidence based essentially reduces access to care.

The American Academy of Family Physicians doesn’t have a recommendation for or against performing screening pelvic exams. As part of the Choosing Wisely campaign, the AAFP issued a clinical recommendation against requiring a pelvic exam or other physical exam to prescribe oral contraceptives.

[email protected]

On Twitter @MaryEllenNY

The new pelvic exam guidelines from the American College of Physicians may be a relief for women who would prefer to forgo the annual ritual, but they could also lead to variation in well-woman care, depending on which type of specialist provides that care.

The guidelines advise physicians to skip annual pelvic examinations in otherwise healthy, asymptomatic women who are not pregnant (Ann. Intern. Med. 2014;161:67-72).

The evidence-based clinical practice guidelines recommend that cervical cancer screening be limited to the visual inspection of the cervix and cervical swabs for cancer and human papillomavirus. They recommend against performing a speculum examination of the vagina and cervix, and a bimanual examination of the adnexa, uterus, ovaries, and bladder. The recommendation does not apply to using the Pap smear to screen for cervical cancer.

The diagnostic accuracy of the pelvic exam in detecting gynecologic cancer or infections is low, the ACP said, and carries the risk of false positives that can lead to unnecessary testing and procedures. The embarrassment and discomfort of the exam may also keep some women from seeking care, the ACP stated in the guidelines.

But that advice conflicts with an August 2012 policy statement from the American College of Obstetricians and Gynecologists, which recommends that pelvic exams be performed in asymptomatic adults as part of an annual well-woman visit. However, citing a lack of evidence, the opinion leaves the decision about when and how often to perform the exams in the hands of physicians and patients (Obstet. Gynecol. 2012;120:421-4).

Following the release of the ACP guidelines, ACOG issued a statement renewing its support for the pelvic exam, but saying that the ACOG policy was a "complement" to the new ACP recommendations. ACOG said that the use of the exam is "supported by the clinical experiences of gynecologists treating their patients."

It’s a position shared by Dr. Jill Rabin, professor of obstetrics and gynecology at Hofstra North Shore–LIJ School of Medicine and head of urogynecology at Long Island Jewish Medical Center in New Hyde Park, N.Y. She currently performs a full pelvic exam during the well-woman visit and plans to continue doing so.

"I want every woman to get a full exam every year and whoever does it, they should do a good job," Dr. Rabin said.

She praised the ACP guideline, saying that she agreed that there was a lack of evidence and that the exams can create anxiety and embarrassment. But pelvic exams are also essential in uncovering conditions such as pelvic floor weakness, fibroids, and vulvovaginal atrophy, Dr. Rabin said. And the exam provides a unique opportunity for women to bring up concerns that they might not raise during a history taking, she said, such as symptoms of incontinence.

As for the lack of evidence, Dr. Rabin said researchers should begin those studies even if they take decades to provide complete answers.

"There’s a lot that we do in life where we don’t have the studies," she said. "But lack of the evidence doesn’t mean that there’s lack of value."

And Dr. Rabin isn’t alone in doing a full pelvic exam. A recent survey of ob.gyns. found that nearly all perform bimanual pelvic examinations in asymptomatic women for a variety of reasons including patient reassurance, detection of ovarian cancer, or identification of benign uterine and ovarian conditions (Am. J. Obstet. Gynecol. 2013;208:109.e1-7).

Dr. Molly Cooke, the ACP’s immediate past president and a member of the group’s Clinical Practice Guidelines Committee, said that for years she performed pelvic exams in asymptomatic patients mainly out of "habit," rather than evidence. But with the ACP’s new guidelines, she plans to change her approach.

Going forward, Dr. Cooke said she will discuss the utility of the pelvic exam with patients and explain that the evidence indicates that the bimanual exam does not produce meaningful information and could lead them astray. She said she expects that most patients will agree to forgo the pelvic exam when presented with the evidence.

As for ob.gyns. who may continue to perform pelvic exams routinely in asymptomatic patients, Dr. Cooke said that they are essentially making a "faith-based" assertion about the usefulness of the exam.

Dr. Cooke said the ACP recommendations are meant to apply to all clinicians who provide well-woman care. "We don’t see any reason why the guideline isn’t as useful and applicable to a nurse practitioner, a gynecologist, a family physician, and an internist," she said.

The new ACP guidelines are being well received by some internists and family physicians who are feeling the pressure to cram more and more preventive care into a short visit.

"You really have to think about the opportunity cost here," said Dr. Giang Nguyen of the Hospital of the University of Pennsylvania, Philadelphia.

"When we take those extra minutes out of a visit, which might only be 15 minutes long, you’re preventing the patient and the provider from using that time for things that we have strong evidence for, like counseling about weight management, talking about smoking cessation, reviewing other parts of their sexual history that maybe would be useful to talk about in order to prevent future illness," he added.

Given the shortage of primary care physicians, Dr. Nguyen said spending visit time on screenings that aren’t evidence based essentially reduces access to care.

The American Academy of Family Physicians doesn’t have a recommendation for or against performing screening pelvic exams. As part of the Choosing Wisely campaign, the AAFP issued a clinical recommendation against requiring a pelvic exam or other physical exam to prescribe oral contraceptives.

[email protected]

On Twitter @MaryEllenNY

Acne vulgaris typically is associated with adolescence and young adulthood; however, it also can affect neonates, infants, and small children.¹ Acne neonatorum occurs in up to 20% of newborns. The clinical importance of neonatal acne lies in its differentiation from infectious diseases, the exclusion of virilization as its underlying cause, and the possible implication of severe acne in adolescence.² Neonatal acne also must be distinguished from acne that is induced by application of topical oils and ointments (acne venenata) and from acneform eruptions induced by acnegenic maternal medications such as hydantoin (fetal hydantoin syndrome) and lithium.³

Neonatal Acne (Acne Neonatorum)

Clinical Presentation

Neonatal acne (acne neonatorum) typically presents as small closed comedones on the forehead, nose, and cheeks (Figure 1).⁴ Accompanying sebaceous hyperplasia often is noted.⁵ Less frequently, open comedones, inflammatory papules, and pustules may develop.⁶ Neonatal acne may be evident at birth or appear during the first 4 weeks of life⁷ and is more commonly seen in boys.⁸

Etiology

Several factors may be pivotal in the etiology of neonatal acne, including increased sebum excretion, stimulation of the sebaceous glands by maternal or neonatal androgens,⁴ and colonization of sebaceous glands by Malassezia species.² Increased sebum excretion occurs during the neonatal period due to enlarged sebaceous glands,² which may result from the substantial production of β-hydroxysteroids from the relatively large adrenal glands.^9,10 After 6 months of age, the size of the sebaceous glands and the sebum excretion rate decrease.^9,10

Both maternal and neonatal androgens have been implicated in the stimulation of sebaceous glands in neonatal acne.² The neonatal adrenal gland produces high levels of dehydroepiandrosterone,² which stimulate sebaceous glands until around 1 year of age when dehydroepiandrosterone levels drop off as a consequence of involution of the neonatal adrenal gland.¹¹ Testicular androgens provide additional stimulation to the sebaceous glands, which may explain why neonatal acne is more common in boys.¹ Neonatal acne may be an inflammatory response to Malassezia species; however, Malassezia was not isolated in a series of patients,¹²  suggesting that neonatal acne is an early presentation of comedonal acne and not a response to Malassezia.^2,12

Differential Diagnosis

There are a number of acneform eruptions that should be considered in the differential diagnosis,³ including bacterial folliculitis, secondary syphilis,¹³ herpes simplex virus and varicella zoster virus,¹⁴ and skin colonization by fungi of Malassezia species.¹⁵ Other neonatal eruptions such as erythema toxicum neonatorum,¹⁶ transient neonatal pustular melanosis, and milia and pustular miliaria, as well as a drug eruption associated with hydantoin, lithium, or halogens should be considered.¹⁷ The relationship between neonatal acne and neonatal cephalic pustulosis, which is characterized by papules and pustules without comedones, is controversial; some consider them to be 2 different entities,¹⁴ while others do not.¹⁸

Treatment

Guardians should be reassured that neonatal acne is mild, self-limited, and generally resolves spontaneously without scarring in approximately 1 to 3 months.^1,2 In most cases, no treatment is needed.¹⁹ If necessary, comedones may be treated with azelaic acid cream 20% or tretinoin cream 0.025% to 0.05%.^1,2 For inflammatory lesions, erythromycin solution 2% and benzoyl peroxide gel 2.5% may be used.^1,20 Severe or recalcitrant disease warrants a workup for congenital adrenal hyperplasia, a virilizing tumor, or underlying endocrinopathy.¹⁹

Infantile Acne Vulgaris

Clinical Presentation

Infantile acne vulgaris shares similarities with neonatal acne^21,22 in that they both affect the face, predominantly the cheeks, and have a male predominance (Figure 2).^1,10 However, by definition, onset of infantile acne typically occurs later than acne neonatorum, usually at 3 to 6 months of age.^1,4 Lesions are more pleomorphic and inflammatory than in neonatal acne. In addition to closed and open comedones, infantile acne may be first evident with papules, pustules, severe nodules, and cysts with scarring potential (Figure 3).^1,2,5 Accordingly, treatment may be required. Most cases of infantile acne resolve by 4 or 5 years of age, but some remain active into puberty.¹ Patients with a history of infantile acne have an increased incidence of acne vulgaris during adolescence compared to their peers, with greater severity and enhanced risk for scarring.^4,23

Etiology

The etiology of infantile acne remains unclear.² Similar to neonatal acne, infantile acne may be a result of elevated androgens produced by the fetal adrenal glands as well as by the testes in males.¹¹ For example, a child with infantile acne had elevated luteinizing hormone, follicle-stimulating hormone, and testosterone levels.²⁴ Therefore, hyperandrogenism should be considered as an etiology. Other causes also have been suggested. Rarely, an adrenocortical tumor may be associated with persistent infantile acne with signs of virilization and rapid development.²⁵Malassezia was implicated in infantile acne in a 6-month-old infant who was successfully treated with ketoconazole cream 2%.²⁶

Differential Diagnosis

Infantile acne often is misdiagnosed because it is rarely considered in the differential diagnosis. When closed comedones predominate, acne venenata induced by topical creams, lotions, or oils may be etiologic. Chloracne also should be considered.¹⁴

Treatment

Guardians should be educated about the likely chronicity of infantile acne, which may require long-term treatment, as well as the possibility that acne may recur in severe form during puberty.¹ The treatment strategy for infantile acne is similar to treatment of acne at any age, with topical agents including retinoids (eg, tretinoin, benzoyl peroxide) and topical antibacterials (eg, erythromycin). Twice-daily erythromycin 125 to 250 mg is the treatment of choice when oral antibiotics are indicated. Tetracyclines are contraindicated in treatment of neonatal and infantile acne. Intralesional injections with low-concentration triamcinolone acetonide, cryotherapy, or topical corticosteroids for a short period of time can be used to treat deep nodules and cysts.² Acne that is refractory to treatment with oral antibiotics alone or combined with topical treatments poses a dilemma, given the potential cosmetic sequelae of scarring and quality-of-life concerns. Because reducing or eliminating dairy intake appears beneficial for adolescents with moderate to severe acne,²⁷ this approach may represent a good option for infantile acne.

Conclusion

Neonatal and infantile acne vulgaris may be overlooked or misdiagnosed. It is important to consider and treat. Early childhood acne may represent a virilization syndrome.

Acne vulgaris typically is associated with adolescence and young adulthood; however, it also can affect neonates, infants, and small children.¹ Acne neonatorum occurs in up to 20% of newborns. The clinical importance of neonatal acne lies in its differentiation from infectious diseases, the exclusion of virilization as its underlying cause, and the possible implication of severe acne in adolescence.² Neonatal acne also must be distinguished from acne that is induced by application of topical oils and ointments (acne venenata) and from acneform eruptions induced by acnegenic maternal medications such as hydantoin (fetal hydantoin syndrome) and lithium.³

Neonatal Acne (Acne Neonatorum)

Clinical Presentation

Neonatal acne (acne neonatorum) typically presents as small closed comedones on the forehead, nose, and cheeks (Figure 1).⁴ Accompanying sebaceous hyperplasia often is noted.⁵ Less frequently, open comedones, inflammatory papules, and pustules may develop.⁶ Neonatal acne may be evident at birth or appear during the first 4 weeks of life⁷ and is more commonly seen in boys.⁸

Etiology

Several factors may be pivotal in the etiology of neonatal acne, including increased sebum excretion, stimulation of the sebaceous glands by maternal or neonatal androgens,⁴ and colonization of sebaceous glands by Malassezia species.² Increased sebum excretion occurs during the neonatal period due to enlarged sebaceous glands,² which may result from the substantial production of β-hydroxysteroids from the relatively large adrenal glands.^9,10 After 6 months of age, the size of the sebaceous glands and the sebum excretion rate decrease.^9,10

Both maternal and neonatal androgens have been implicated in the stimulation of sebaceous glands in neonatal acne.² The neonatal adrenal gland produces high levels of dehydroepiandrosterone,² which stimulate sebaceous glands until around 1 year of age when dehydroepiandrosterone levels drop off as a consequence of involution of the neonatal adrenal gland.¹¹ Testicular androgens provide additional stimulation to the sebaceous glands, which may explain why neonatal acne is more common in boys.¹ Neonatal acne may be an inflammatory response to Malassezia species; however, Malassezia was not isolated in a series of patients,¹²  suggesting that neonatal acne is an early presentation of comedonal acne and not a response to Malassezia.^2,12

Differential Diagnosis

There are a number of acneform eruptions that should be considered in the differential diagnosis,³ including bacterial folliculitis, secondary syphilis,¹³ herpes simplex virus and varicella zoster virus,¹⁴ and skin colonization by fungi of Malassezia species.¹⁵ Other neonatal eruptions such as erythema toxicum neonatorum,¹⁶ transient neonatal pustular melanosis, and milia and pustular miliaria, as well as a drug eruption associated with hydantoin, lithium, or halogens should be considered.¹⁷ The relationship between neonatal acne and neonatal cephalic pustulosis, which is characterized by papules and pustules without comedones, is controversial; some consider them to be 2 different entities,¹⁴ while others do not.¹⁸

Treatment

Guardians should be reassured that neonatal acne is mild, self-limited, and generally resolves spontaneously without scarring in approximately 1 to 3 months.^1,2 In most cases, no treatment is needed.¹⁹ If necessary, comedones may be treated with azelaic acid cream 20% or tretinoin cream 0.025% to 0.05%.^1,2 For inflammatory lesions, erythromycin solution 2% and benzoyl peroxide gel 2.5% may be used.^1,20 Severe or recalcitrant disease warrants a workup for congenital adrenal hyperplasia, a virilizing tumor, or underlying endocrinopathy.¹⁹

Infantile Acne Vulgaris

Clinical Presentation

Infantile acne vulgaris shares similarities with neonatal acne^21,22 in that they both affect the face, predominantly the cheeks, and have a male predominance (Figure 2).^1,10 However, by definition, onset of infantile acne typically occurs later than acne neonatorum, usually at 3 to 6 months of age.^1,4 Lesions are more pleomorphic and inflammatory than in neonatal acne. In addition to closed and open comedones, infantile acne may be first evident with papules, pustules, severe nodules, and cysts with scarring potential (Figure 3).^1,2,5 Accordingly, treatment may be required. Most cases of infantile acne resolve by 4 or 5 years of age, but some remain active into puberty.¹ Patients with a history of infantile acne have an increased incidence of acne vulgaris during adolescence compared to their peers, with greater severity and enhanced risk for scarring.^4,23

Etiology

The etiology of infantile acne remains unclear.² Similar to neonatal acne, infantile acne may be a result of elevated androgens produced by the fetal adrenal glands as well as by the testes in males.¹¹ For example, a child with infantile acne had elevated luteinizing hormone, follicle-stimulating hormone, and testosterone levels.²⁴ Therefore, hyperandrogenism should be considered as an etiology. Other causes also have been suggested. Rarely, an adrenocortical tumor may be associated with persistent infantile acne with signs of virilization and rapid development.²⁵Malassezia was implicated in infantile acne in a 6-month-old infant who was successfully treated with ketoconazole cream 2%.²⁶

Differential Diagnosis

Infantile acne often is misdiagnosed because it is rarely considered in the differential diagnosis. When closed comedones predominate, acne venenata induced by topical creams, lotions, or oils may be etiologic. Chloracne also should be considered.¹⁴

Treatment

Guardians should be educated about the likely chronicity of infantile acne, which may require long-term treatment, as well as the possibility that acne may recur in severe form during puberty.¹ The treatment strategy for infantile acne is similar to treatment of acne at any age, with topical agents including retinoids (eg, tretinoin, benzoyl peroxide) and topical antibacterials (eg, erythromycin). Twice-daily erythromycin 125 to 250 mg is the treatment of choice when oral antibiotics are indicated. Tetracyclines are contraindicated in treatment of neonatal and infantile acne. Intralesional injections with low-concentration triamcinolone acetonide, cryotherapy, or topical corticosteroids for a short period of time can be used to treat deep nodules and cysts.² Acne that is refractory to treatment with oral antibiotics alone or combined with topical treatments poses a dilemma, given the potential cosmetic sequelae of scarring and quality-of-life concerns. Because reducing or eliminating dairy intake appears beneficial for adolescents with moderate to severe acne,²⁷ this approach may represent a good option for infantile acne.

Conclusion

Neonatal and infantile acne vulgaris may be overlooked or misdiagnosed. It is important to consider and treat. Early childhood acne may represent a virilization syndrome.

Acne vulgaris typically is associated with adolescence and young adulthood; however, it also can affect neonates, infants, and small children.¹ Acne neonatorum occurs in up to 20% of newborns. The clinical importance of neonatal acne lies in its differentiation from infectious diseases, the exclusion of virilization as its underlying cause, and the possible implication of severe acne in adolescence.² Neonatal acne also must be distinguished from acne that is induced by application of topical oils and ointments (acne venenata) and from acneform eruptions induced by acnegenic maternal medications such as hydantoin (fetal hydantoin syndrome) and lithium.³

Neonatal Acne (Acne Neonatorum)

Clinical Presentation

Neonatal acne (acne neonatorum) typically presents as small closed comedones on the forehead, nose, and cheeks (Figure 1).⁴ Accompanying sebaceous hyperplasia often is noted.⁵ Less frequently, open comedones, inflammatory papules, and pustules may develop.⁶ Neonatal acne may be evident at birth or appear during the first 4 weeks of life⁷ and is more commonly seen in boys.⁸

Etiology

Several factors may be pivotal in the etiology of neonatal acne, including increased sebum excretion, stimulation of the sebaceous glands by maternal or neonatal androgens,⁴ and colonization of sebaceous glands by Malassezia species.² Increased sebum excretion occurs during the neonatal period due to enlarged sebaceous glands,² which may result from the substantial production of β-hydroxysteroids from the relatively large adrenal glands.^9,10 After 6 months of age, the size of the sebaceous glands and the sebum excretion rate decrease.^9,10

Both maternal and neonatal androgens have been implicated in the stimulation of sebaceous glands in neonatal acne.² The neonatal adrenal gland produces high levels of dehydroepiandrosterone,² which stimulate sebaceous glands until around 1 year of age when dehydroepiandrosterone levels drop off as a consequence of involution of the neonatal adrenal gland.¹¹ Testicular androgens provide additional stimulation to the sebaceous glands, which may explain why neonatal acne is more common in boys.¹ Neonatal acne may be an inflammatory response to Malassezia species; however, Malassezia was not isolated in a series of patients,¹²  suggesting that neonatal acne is an early presentation of comedonal acne and not a response to Malassezia.^2,12

Differential Diagnosis

There are a number of acneform eruptions that should be considered in the differential diagnosis,³ including bacterial folliculitis, secondary syphilis,¹³ herpes simplex virus and varicella zoster virus,¹⁴ and skin colonization by fungi of Malassezia species.¹⁵ Other neonatal eruptions such as erythema toxicum neonatorum,¹⁶ transient neonatal pustular melanosis, and milia and pustular miliaria, as well as a drug eruption associated with hydantoin, lithium, or halogens should be considered.¹⁷ The relationship between neonatal acne and neonatal cephalic pustulosis, which is characterized by papules and pustules without comedones, is controversial; some consider them to be 2 different entities,¹⁴ while others do not.¹⁸

Treatment

Guardians should be reassured that neonatal acne is mild, self-limited, and generally resolves spontaneously without scarring in approximately 1 to 3 months.^1,2 In most cases, no treatment is needed.¹⁹ If necessary, comedones may be treated with azelaic acid cream 20% or tretinoin cream 0.025% to 0.05%.^1,2 For inflammatory lesions, erythromycin solution 2% and benzoyl peroxide gel 2.5% may be used.^1,20 Severe or recalcitrant disease warrants a workup for congenital adrenal hyperplasia, a virilizing tumor, or underlying endocrinopathy.¹⁹

Infantile Acne Vulgaris

Clinical Presentation

Infantile acne vulgaris shares similarities with neonatal acne^21,22 in that they both affect the face, predominantly the cheeks, and have a male predominance (Figure 2).^1,10 However, by definition, onset of infantile acne typically occurs later than acne neonatorum, usually at 3 to 6 months of age.^1,4 Lesions are more pleomorphic and inflammatory than in neonatal acne. In addition to closed and open comedones, infantile acne may be first evident with papules, pustules, severe nodules, and cysts with scarring potential (Figure 3).^1,2,5 Accordingly, treatment may be required. Most cases of infantile acne resolve by 4 or 5 years of age, but some remain active into puberty.¹ Patients with a history of infantile acne have an increased incidence of acne vulgaris during adolescence compared to their peers, with greater severity and enhanced risk for scarring.^4,23

Etiology

The etiology of infantile acne remains unclear.² Similar to neonatal acne, infantile acne may be a result of elevated androgens produced by the fetal adrenal glands as well as by the testes in males.¹¹ For example, a child with infantile acne had elevated luteinizing hormone, follicle-stimulating hormone, and testosterone levels.²⁴ Therefore, hyperandrogenism should be considered as an etiology. Other causes also have been suggested. Rarely, an adrenocortical tumor may be associated with persistent infantile acne with signs of virilization and rapid development.²⁵Malassezia was implicated in infantile acne in a 6-month-old infant who was successfully treated with ketoconazole cream 2%.²⁶

Differential Diagnosis

Infantile acne often is misdiagnosed because it is rarely considered in the differential diagnosis. When closed comedones predominate, acne venenata induced by topical creams, lotions, or oils may be etiologic. Chloracne also should be considered.¹⁴

Treatment

Guardians should be educated about the likely chronicity of infantile acne, which may require long-term treatment, as well as the possibility that acne may recur in severe form during puberty.¹ The treatment strategy for infantile acne is similar to treatment of acne at any age, with topical agents including retinoids (eg, tretinoin, benzoyl peroxide) and topical antibacterials (eg, erythromycin). Twice-daily erythromycin 125 to 250 mg is the treatment of choice when oral antibiotics are indicated. Tetracyclines are contraindicated in treatment of neonatal and infantile acne. Intralesional injections with low-concentration triamcinolone acetonide, cryotherapy, or topical corticosteroids for a short period of time can be used to treat deep nodules and cysts.² Acne that is refractory to treatment with oral antibiotics alone or combined with topical treatments poses a dilemma, given the potential cosmetic sequelae of scarring and quality-of-life concerns. Because reducing or eliminating dairy intake appears beneficial for adolescents with moderate to severe acne,²⁷ this approach may represent a good option for infantile acne.

Conclusion

Neonatal and infantile acne vulgaris may be overlooked or misdiagnosed. It is important to consider and treat. Early childhood acne may represent a virilization syndrome.

Patient receiving chemotherapy

Credit: Rhoda Baer

Adding the Plk1 inhibitor volasertib to chemotherapy can prolong survival in older patients with previously untreated acute myeloid leukemia (AML), researchers have reported in Blood.

In a phase 2 study, AML patients aged 65 or older who were ineligible for intensive induction therapy had higher response and survival rates when they received volasertib plus low-dose cytarabine (LDAC),  compared to LDAC alone.

However, adverse events, such as febrile neutropenia and infections, were more common with volasertib.

“These clinical trial results . . . are important and have informed future research for this rare disease, where new treatment options are greatly needed,” said study author Hartmut Döhner, MD, of the University Hospital Ulm in Germany.

“The established approach to treat younger AML patients is an intensive chemotherapy regimen, [but] older patients often cannot tolerate these chemotherapy doses and have very limited treatment options.”

To test volasertib as a potential option, the researchers enrolled and treated 87 patients with previously untreated AML who were ineligible for intensive induction therapy. Their median age was 75 years.

Patients received LDAC at 20 mg BID subcutaneously on days 1 through 10 (n=45) or LDAC plus volasertib at 350 mg intravenously on days 1 and 15, every 4 weeks (n=42). Overall, patient demographics and baseline disease characteristics were balanced between the treatment arms.

The response rate (complete response or complete response with incomplete blood count recovery) was more than doubled for patients receiving volasertib and LDAC compared to LDAC alone. The rates were 31% (13/42) and 13.3% (6/45), respectively (odds ratio, 2.91; P=0.052).

Responses in patients receiving volasertib and LDAC were observed across all genetic groups, including 5 of 14 patients with adverse genetics.

Remissions with the combination treatment appeared to be more durable than those observed with LDAC alone. The median relapse-free survival was 18.5 months and 10.0 months, respectively.

The median event-free survival was prolonged in patients receiving volasertib as well. Their event-free survival was 5.6 months, compared to 2.3 months for patients who received LDAC alone (hazard ratio 0.57,

P=0.021).

Patients who received volasertib also experienced improvements in overall survival. The median overall survival was 8.0 months for the volasertib arm and 5.2 months for the LDAC-alone arm (hazard ratio 0.63; P=0.047).

Patients receiving volasertib and LDAC had higher rates of adverse events than patients in the LDAC-alone arm. Events of note included grade 3 febrile neutropenia (38% vs 7%), grade 3 infections (38% vs 7%) and grade 3 gastrointestinal events (21% vs 7%).

Based on these results, researchers are now investigating volasertib in combination with LDAC in a randomized, double-blind, phase 3 trial for AML called POLO-AML-2.

Patient receiving chemotherapy

Credit: Rhoda Baer

Adding the Plk1 inhibitor volasertib to chemotherapy can prolong survival in older patients with previously untreated acute myeloid leukemia (AML), researchers have reported in Blood.

In a phase 2 study, AML patients aged 65 or older who were ineligible for intensive induction therapy had higher response and survival rates when they received volasertib plus low-dose cytarabine (LDAC),  compared to LDAC alone.

However, adverse events, such as febrile neutropenia and infections, were more common with volasertib.

“These clinical trial results . . . are important and have informed future research for this rare disease, where new treatment options are greatly needed,” said study author Hartmut Döhner, MD, of the University Hospital Ulm in Germany.

“The established approach to treat younger AML patients is an intensive chemotherapy regimen, [but] older patients often cannot tolerate these chemotherapy doses and have very limited treatment options.”

To test volasertib as a potential option, the researchers enrolled and treated 87 patients with previously untreated AML who were ineligible for intensive induction therapy. Their median age was 75 years.

Patients received LDAC at 20 mg BID subcutaneously on days 1 through 10 (n=45) or LDAC plus volasertib at 350 mg intravenously on days 1 and 15, every 4 weeks (n=42). Overall, patient demographics and baseline disease characteristics were balanced between the treatment arms.

The response rate (complete response or complete response with incomplete blood count recovery) was more than doubled for patients receiving volasertib and LDAC compared to LDAC alone. The rates were 31% (13/42) and 13.3% (6/45), respectively (odds ratio, 2.91; P=0.052).

Responses in patients receiving volasertib and LDAC were observed across all genetic groups, including 5 of 14 patients with adverse genetics.

Remissions with the combination treatment appeared to be more durable than those observed with LDAC alone. The median relapse-free survival was 18.5 months and 10.0 months, respectively.

The median event-free survival was prolonged in patients receiving volasertib as well. Their event-free survival was 5.6 months, compared to 2.3 months for patients who received LDAC alone (hazard ratio 0.57,

P=0.021).

Patients who received volasertib also experienced improvements in overall survival. The median overall survival was 8.0 months for the volasertib arm and 5.2 months for the LDAC-alone arm (hazard ratio 0.63; P=0.047).

Patients receiving volasertib and LDAC had higher rates of adverse events than patients in the LDAC-alone arm. Events of note included grade 3 febrile neutropenia (38% vs 7%), grade 3 infections (38% vs 7%) and grade 3 gastrointestinal events (21% vs 7%).

Based on these results, researchers are now investigating volasertib in combination with LDAC in a randomized, double-blind, phase 3 trial for AML called POLO-AML-2.

Patient receiving chemotherapy

Credit: Rhoda Baer

Adding the Plk1 inhibitor volasertib to chemotherapy can prolong survival in older patients with previously untreated acute myeloid leukemia (AML), researchers have reported in Blood.

In a phase 2 study, AML patients aged 65 or older who were ineligible for intensive induction therapy had higher response and survival rates when they received volasertib plus low-dose cytarabine (LDAC),  compared to LDAC alone.

However, adverse events, such as febrile neutropenia and infections, were more common with volasertib.

“These clinical trial results . . . are important and have informed future research for this rare disease, where new treatment options are greatly needed,” said study author Hartmut Döhner, MD, of the University Hospital Ulm in Germany.

“The established approach to treat younger AML patients is an intensive chemotherapy regimen, [but] older patients often cannot tolerate these chemotherapy doses and have very limited treatment options.”

To test volasertib as a potential option, the researchers enrolled and treated 87 patients with previously untreated AML who were ineligible for intensive induction therapy. Their median age was 75 years.

Patients received LDAC at 20 mg BID subcutaneously on days 1 through 10 (n=45) or LDAC plus volasertib at 350 mg intravenously on days 1 and 15, every 4 weeks (n=42). Overall, patient demographics and baseline disease characteristics were balanced between the treatment arms.

The response rate (complete response or complete response with incomplete blood count recovery) was more than doubled for patients receiving volasertib and LDAC compared to LDAC alone. The rates were 31% (13/42) and 13.3% (6/45), respectively (odds ratio, 2.91; P=0.052).

Responses in patients receiving volasertib and LDAC were observed across all genetic groups, including 5 of 14 patients with adverse genetics.

Remissions with the combination treatment appeared to be more durable than those observed with LDAC alone. The median relapse-free survival was 18.5 months and 10.0 months, respectively.

The median event-free survival was prolonged in patients receiving volasertib as well. Their event-free survival was 5.6 months, compared to 2.3 months for patients who received LDAC alone (hazard ratio 0.57,

P=0.021).

Patients who received volasertib also experienced improvements in overall survival. The median overall survival was 8.0 months for the volasertib arm and 5.2 months for the LDAC-alone arm (hazard ratio 0.63; P=0.047).

Patients receiving volasertib and LDAC had higher rates of adverse events than patients in the LDAC-alone arm. Events of note included grade 3 febrile neutropenia (38% vs 7%), grade 3 infections (38% vs 7%) and grade 3 gastrointestinal events (21% vs 7%).

Based on these results, researchers are now investigating volasertib in combination with LDAC in a randomized, double-blind, phase 3 trial for AML called POLO-AML-2.

Vial of HPV vaccine

Credit: Jan Christian

Previous research has suggested a potential association between the quadrivalent human papillomavirus (HPV) vaccine and venous thromboembolism (VTE).

But a new analysis of more than 500,000 women suggests the vaccine does not increase the risk of VTE.

Nikolai Madrid Scheller, of Statens Serum Institut in Copenhagen, Denmark, and his colleagues conducted the analysis and recounted the results in a letter to JAMA.

The team used data from Danish national registries to evaluate the potential link between quadrivalent HPV vaccination and VTE.

They collected information on vaccination, the use of oral contraceptives, the use of anticoagulants, and the outcome of a first hospital diagnosis of VTE not related to pregnancy, surgery, or cancer.

They included 1,613,798 Danish women ages 10 to 44. Thirty-one percent (n=500,345) of the women received the quadrivalent HPV vaccine.

In all, there were 4375 incident cases of VTE. Twenty percent (n=889) of these women were vaccinated during the study period.

The researchers compared the incidence rates of VTE during predefined risk periods after each vaccine dose with all other observed periods in each individual (control periods). The main risk period was 1 to 42 days from vaccination.

The team found no association between the vaccine and VTE during the 42-day risk period. The crude incidence rate was 0.126 events per person-year for the risk period and 0.159 events per person-year for the control period. The incidence ratio was 0.77.

Results were similar when the researchers performed subgroup analyses by age, including only anticoagulant recipients, only exposed cases, or when adjusting for oral contraceptive use.

“Our results, which were consistent after adjustment for oral contraceptive use and in girls and young women as well as mid-adult women, do not provide support for an increased risk of VTE following quadrivalent HPV vaccination,” the researchers concluded.

Vial of HPV vaccine

Credit: Jan Christian

Previous research has suggested a potential association between the quadrivalent human papillomavirus (HPV) vaccine and venous thromboembolism (VTE).

But a new analysis of more than 500,000 women suggests the vaccine does not increase the risk of VTE.

Nikolai Madrid Scheller, of Statens Serum Institut in Copenhagen, Denmark, and his colleagues conducted the analysis and recounted the results in a letter to JAMA.

The team used data from Danish national registries to evaluate the potential link between quadrivalent HPV vaccination and VTE.

They collected information on vaccination, the use of oral contraceptives, the use of anticoagulants, and the outcome of a first hospital diagnosis of VTE not related to pregnancy, surgery, or cancer.

They included 1,613,798 Danish women ages 10 to 44. Thirty-one percent (n=500,345) of the women received the quadrivalent HPV vaccine.

In all, there were 4375 incident cases of VTE. Twenty percent (n=889) of these women were vaccinated during the study period.

The researchers compared the incidence rates of VTE during predefined risk periods after each vaccine dose with all other observed periods in each individual (control periods). The main risk period was 1 to 42 days from vaccination.

The team found no association between the vaccine and VTE during the 42-day risk period. The crude incidence rate was 0.126 events per person-year for the risk period and 0.159 events per person-year for the control period. The incidence ratio was 0.77.

Results were similar when the researchers performed subgroup analyses by age, including only anticoagulant recipients, only exposed cases, or when adjusting for oral contraceptive use.

“Our results, which were consistent after adjustment for oral contraceptive use and in girls and young women as well as mid-adult women, do not provide support for an increased risk of VTE following quadrivalent HPV vaccination,” the researchers concluded.

Vial of HPV vaccine

Credit: Jan Christian

Previous research has suggested a potential association between the quadrivalent human papillomavirus (HPV) vaccine and venous thromboembolism (VTE).

But a new analysis of more than 500,000 women suggests the vaccine does not increase the risk of VTE.

Nikolai Madrid Scheller, of Statens Serum Institut in Copenhagen, Denmark, and his colleagues conducted the analysis and recounted the results in a letter to JAMA.

The team used data from Danish national registries to evaluate the potential link between quadrivalent HPV vaccination and VTE.

They collected information on vaccination, the use of oral contraceptives, the use of anticoagulants, and the outcome of a first hospital diagnosis of VTE not related to pregnancy, surgery, or cancer.

They included 1,613,798 Danish women ages 10 to 44. Thirty-one percent (n=500,345) of the women received the quadrivalent HPV vaccine.

In all, there were 4375 incident cases of VTE. Twenty percent (n=889) of these women were vaccinated during the study period.

The researchers compared the incidence rates of VTE during predefined risk periods after each vaccine dose with all other observed periods in each individual (control periods). The main risk period was 1 to 42 days from vaccination.

The team found no association between the vaccine and VTE during the 42-day risk period. The crude incidence rate was 0.126 events per person-year for the risk period and 0.159 events per person-year for the control period. The incidence ratio was 0.77.

Results were similar when the researchers performed subgroup analyses by age, including only anticoagulant recipients, only exposed cases, or when adjusting for oral contraceptive use.

“Our results, which were consistent after adjustment for oral contraceptive use and in girls and young women as well as mid-adult women, do not provide support for an increased risk of VTE following quadrivalent HPV vaccination,” the researchers concluded.

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

Age limits on clinical trials must be more flexible to allow more adolescent and young adult (AYA) cancer patients the opportunity to access new treatments, according to a report published in The Lancet Oncology.

The report’s authors discovered that expanding age eligibility criteria for cancer trials increased the enrollment of AYA patients and patients belonging to other age groups. But there is still room for improvement, according to the authors.

“[R]ight now, too many of our young patients are needlessly falling through the gap between pediatric and adult cancer trials,” said Lorna Fern, PhD, of University College London Hospitals in the UK.

“By encouraging doctors to take into account the full age range of patients affected by individual types of cancer, we’ve shown that it’s possible to design trials that include teenage cancer patients and, importantly, that better match the underlying biology of the disease and the people affected.”

To assess AYA enrollment in cancer trials, Dr Fern and her colleagues looked at 68,275 cancer patients aged 0 to 59 years. They were diagnosed with leukemias, lymphomas, or solid tumor malignancies between April 1, 2005, and March 31, 2010.

During this 6-year period, trial participation increased among all age groups. There was a 13% increase in participation among 15- to 19-year-olds (from 24% to 37%), a 5% increase among 20- to 24-year-olds (from 13% to 18%), and a 6% increase among 0- to 14-year-olds (from 52% to 58%).

Dr Fern and her colleagues said the rise in enrollment, particularly among AYAs, was due to increased availability and access to trials; increased awareness from healthcare professionals, patients, and the public about research; and the opening of trials with broader age limits that allow AYAs to enter trials.

In light of this study, Cancer Research UK has started asking researchers to justify age restrictions on new studies, in an effort to recruit more AYA cancer patients onto its trials.

“[I]t’s vital that effective treatments are being developed to tackle cancer across all age brackets,” said Kate Law, Cancer Research UK’s director of clinical trials.

“We now only accept age limits on our clinical trials if they are backed up by hard evidence, which will hopefully mean more young cancer patients get the chance to contribute to research and have the latest experimental treatments.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

Age limits on clinical trials must be more flexible to allow more adolescent and young adult (AYA) cancer patients the opportunity to access new treatments, according to a report published in The Lancet Oncology.

The report’s authors discovered that expanding age eligibility criteria for cancer trials increased the enrollment of AYA patients and patients belonging to other age groups. But there is still room for improvement, according to the authors.

“[R]ight now, too many of our young patients are needlessly falling through the gap between pediatric and adult cancer trials,” said Lorna Fern, PhD, of University College London Hospitals in the UK.

“By encouraging doctors to take into account the full age range of patients affected by individual types of cancer, we’ve shown that it’s possible to design trials that include teenage cancer patients and, importantly, that better match the underlying biology of the disease and the people affected.”

To assess AYA enrollment in cancer trials, Dr Fern and her colleagues looked at 68,275 cancer patients aged 0 to 59 years. They were diagnosed with leukemias, lymphomas, or solid tumor malignancies between April 1, 2005, and March 31, 2010.

During this 6-year period, trial participation increased among all age groups. There was a 13% increase in participation among 15- to 19-year-olds (from 24% to 37%), a 5% increase among 20- to 24-year-olds (from 13% to 18%), and a 6% increase among 0- to 14-year-olds (from 52% to 58%).

Dr Fern and her colleagues said the rise in enrollment, particularly among AYAs, was due to increased availability and access to trials; increased awareness from healthcare professionals, patients, and the public about research; and the opening of trials with broader age limits that allow AYAs to enter trials.

In light of this study, Cancer Research UK has started asking researchers to justify age restrictions on new studies, in an effort to recruit more AYA cancer patients onto its trials.

“[I]t’s vital that effective treatments are being developed to tackle cancer across all age brackets,” said Kate Law, Cancer Research UK’s director of clinical trials.

“We now only accept age limits on our clinical trials if they are backed up by hard evidence, which will hopefully mean more young cancer patients get the chance to contribute to research and have the latest experimental treatments.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

Age limits on clinical trials must be more flexible to allow more adolescent and young adult (AYA) cancer patients the opportunity to access new treatments, according to a report published in The Lancet Oncology.

The report’s authors discovered that expanding age eligibility criteria for cancer trials increased the enrollment of AYA patients and patients belonging to other age groups. But there is still room for improvement, according to the authors.

“[R]ight now, too many of our young patients are needlessly falling through the gap between pediatric and adult cancer trials,” said Lorna Fern, PhD, of University College London Hospitals in the UK.

“By encouraging doctors to take into account the full age range of patients affected by individual types of cancer, we’ve shown that it’s possible to design trials that include teenage cancer patients and, importantly, that better match the underlying biology of the disease and the people affected.”

To assess AYA enrollment in cancer trials, Dr Fern and her colleagues looked at 68,275 cancer patients aged 0 to 59 years. They were diagnosed with leukemias, lymphomas, or solid tumor malignancies between April 1, 2005, and March 31, 2010.

During this 6-year period, trial participation increased among all age groups. There was a 13% increase in participation among 15- to 19-year-olds (from 24% to 37%), a 5% increase among 20- to 24-year-olds (from 13% to 18%), and a 6% increase among 0- to 14-year-olds (from 52% to 58%).

Dr Fern and her colleagues said the rise in enrollment, particularly among AYAs, was due to increased availability and access to trials; increased awareness from healthcare professionals, patients, and the public about research; and the opening of trials with broader age limits that allow AYAs to enter trials.

In light of this study, Cancer Research UK has started asking researchers to justify age restrictions on new studies, in an effort to recruit more AYA cancer patients onto its trials.

“[I]t’s vital that effective treatments are being developed to tackle cancer across all age brackets,” said Kate Law, Cancer Research UK’s director of clinical trials.

“We now only accept age limits on our clinical trials if they are backed up by hard evidence, which will hopefully mean more young cancer patients get the chance to contribute to research and have the latest experimental treatments.”

Photo from Penn Medicine

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the T-cell therapy CTL019 to treat adults and children with relapsed or refractory acute lymphoblastic leukemia (ALL).

The therapy consists of a patient’s own T cells genetically engineered to produce chimeric antigen receptors (CARs) directed against CD19.

CTL019 is the first personalized cellular therapy for cancer to receive breakthrough designation from the FDA.

Breakthrough designation is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over available therapies.

The breakthrough designation for CTL019 is based on early trial results in adults and children with ALL.

At ASH 2013, researchers presented results of the first 27 ALL patients (22 children and 5 adults) treated with CTL019. Eighty-nine percent of the patients achieved a complete response to the treatment. Six patients relapsed during follow-up, which ranged from 2 months to 18 months.

There was also a high rate of toxicity, particularly cytokine release syndrome, but this was resolved via treatment with the IL-6 agonist tocilizumab.

The first pediatric ALL patient to receive CTL019 celebrated the second anniversary of her cancer remission in May. And the first adult patient remains in remission 1 year after receiving the therapy.

“Our early findings reveal tremendous promise for a desperate group of patients, many of whom have been able to return to their normal lives at school and work after receiving this new, personalized immunotherapy,” said Carl June, MD, of the University of Pennsylvania.

“Receiving the FDA’s breakthrough designation is an essential step in our work with Novartis to expand this therapy to patients across the world who desperately need new options to help them fight this disease.”

In August 2012, the University of Pennsylvania announced an exclusive global research and licensing agreement with Novartis to further study, develop, and commercialize personalized CAR T-cell therapies for the treatment of cancers.

Trials of CTL019 began in the summer of 2010 in patients with relapsed and refractory chronic lymphocytic leukemia, and they are now underway for patients with ALL, non-Hodgkin lymphoma, and myeloma.

CTL019 cells are a patients’ own T cells genetically engineered to express an anti-CD19 scFv coupled to CD3ζ signaling and 4-1BB co-stimulatory domains. The cells are activated and expanded ex vivo with anti-CD3 and anti-CD28 beads, then infused into patients.

Photo from Penn Medicine

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the T-cell therapy CTL019 to treat adults and children with relapsed or refractory acute lymphoblastic leukemia (ALL).

The therapy consists of a patient’s own T cells genetically engineered to produce chimeric antigen receptors (CARs) directed against CD19.

CTL019 is the first personalized cellular therapy for cancer to receive breakthrough designation from the FDA.

Breakthrough designation is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over available therapies.

The breakthrough designation for CTL019 is based on early trial results in adults and children with ALL.

At ASH 2013, researchers presented results of the first 27 ALL patients (22 children and 5 adults) treated with CTL019. Eighty-nine percent of the patients achieved a complete response to the treatment. Six patients relapsed during follow-up, which ranged from 2 months to 18 months.

There was also a high rate of toxicity, particularly cytokine release syndrome, but this was resolved via treatment with the IL-6 agonist tocilizumab.

The first pediatric ALL patient to receive CTL019 celebrated the second anniversary of her cancer remission in May. And the first adult patient remains in remission 1 year after receiving the therapy.

“Our early findings reveal tremendous promise for a desperate group of patients, many of whom have been able to return to their normal lives at school and work after receiving this new, personalized immunotherapy,” said Carl June, MD, of the University of Pennsylvania.

“Receiving the FDA’s breakthrough designation is an essential step in our work with Novartis to expand this therapy to patients across the world who desperately need new options to help them fight this disease.”

In August 2012, the University of Pennsylvania announced an exclusive global research and licensing agreement with Novartis to further study, develop, and commercialize personalized CAR T-cell therapies for the treatment of cancers.

Trials of CTL019 began in the summer of 2010 in patients with relapsed and refractory chronic lymphocytic leukemia, and they are now underway for patients with ALL, non-Hodgkin lymphoma, and myeloma.

CTL019 cells are a patients’ own T cells genetically engineered to express an anti-CD19 scFv coupled to CD3ζ signaling and 4-1BB co-stimulatory domains. The cells are activated and expanded ex vivo with anti-CD3 and anti-CD28 beads, then infused into patients.

Photo from Penn Medicine

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the T-cell therapy CTL019 to treat adults and children with relapsed or refractory acute lymphoblastic leukemia (ALL).

The therapy consists of a patient’s own T cells genetically engineered to produce chimeric antigen receptors (CARs) directed against CD19.

CTL019 is the first personalized cellular therapy for cancer to receive breakthrough designation from the FDA.

Breakthrough designation is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over available therapies.

The breakthrough designation for CTL019 is based on early trial results in adults and children with ALL.

At ASH 2013, researchers presented results of the first 27 ALL patients (22 children and 5 adults) treated with CTL019. Eighty-nine percent of the patients achieved a complete response to the treatment. Six patients relapsed during follow-up, which ranged from 2 months to 18 months.

There was also a high rate of toxicity, particularly cytokine release syndrome, but this was resolved via treatment with the IL-6 agonist tocilizumab.

The first pediatric ALL patient to receive CTL019 celebrated the second anniversary of her cancer remission in May. And the first adult patient remains in remission 1 year after receiving the therapy.

“Our early findings reveal tremendous promise for a desperate group of patients, many of whom have been able to return to their normal lives at school and work after receiving this new, personalized immunotherapy,” said Carl June, MD, of the University of Pennsylvania.

“Receiving the FDA’s breakthrough designation is an essential step in our work with Novartis to expand this therapy to patients across the world who desperately need new options to help them fight this disease.”

In August 2012, the University of Pennsylvania announced an exclusive global research and licensing agreement with Novartis to further study, develop, and commercialize personalized CAR T-cell therapies for the treatment of cancers.

Trials of CTL019 began in the summer of 2010 in patients with relapsed and refractory chronic lymphocytic leukemia, and they are now underway for patients with ALL, non-Hodgkin lymphoma, and myeloma.

CTL019 cells are a patients’ own T cells genetically engineered to express an anti-CD19 scFv coupled to CD3ζ signaling and 4-1BB co-stimulatory domains. The cells are activated and expanded ex vivo with anti-CD3 and anti-CD28 beads, then infused into patients.

Under British common law, suicide was a felony if committed by a person "in the years of discretion," in other words, by an adult, who was "of sound mind." An adult who killed himself while insane was not considered a criminal. While the offender obviously could not be punished, he also could not be buried in hallowed ground, and all of his property was seized by the crown. Surviving family members were not allowed to inherit.

While no state defines suicide itself as a crime by statute, there are still common law and statutory prohibitions against aiding or abetting, or encouraging, a suicide. Laws surrounding assisted suicide might seem remote or irrelevant now, but clinicians should be aware that this is changing on an almost monthly basis, and impetus is building through the support of various advocacy groups, such as Compassion & Choices, Final Exit Network,and the Euthanasia Research and Guidance Organization (ERGO).

My own interest in this topic was spurred when a recent Maryland gubernatorial candidate ran on a platform that included a plan to introduce legislation to allow physician-assisted suicide. Presently, our state defines assisted suicide as a felony offense punishable by 1 year of incarceration and a $10,000 fine, and there have been two criminal prosecutions for assisted suicide in recent years.

Nationally, 39 states have prohibitions against assisted suicide defined either by specific statute or contained within the definition of manslaughter. Some states ban assisted suicide by case law, some through the adoption of common law. Presently, five states allow physician-assisted suicide. Oregon, Washington, and Montana were among the first states to allow this. New Mexico and Vermont adopted legislation this year in January and May, respectively.

Most states have modeled their laws after the original physician-assisted suicide law, Oregon’s Death With Dignity Act. For psychiatrists involved in legislative affairs, familiarity with this law is essential.

Under the Death With Dignity Act, a person might be eligible to request physician aid in dying if he is an adult resident of the state, is able to make and communicate medical decisions, and has a 6-month prognosis as medically confirmed by two physicians. The patient must make an initial oral and written request, then repeat the oral request no sooner than 15 days later. The written request must be submitted on a state-mandated form witnessed by two people who can neither be blood relatives nor estate benefactors.

There is a requirement for informed consent, specifically that the person must know his medical diagnosis as well as the risk of taking the life-ending medication and the expected result of this act. There must be documented consideration of alternatives to suicide.

While there is a statutory mandate to refer patients for counseling if depression is suspected, there is no requirement that the patient seeking suicide be screened for this disorder or even have a capacity assessment performed by a psychiatrist.

Out of curiosity, I copied the text of the physician-assisted suicide request form through two text analyzing applications to determine the readability of the document. My two tests revealed that the form required between a 12th grade to college-level reading comprehension level. For comparison purposes, my average prison clinic patient has a 9th-grade education with a 6th-grade reading level.

The most easily understood sentence in the entire document was the instruction at the bottom of the form: "PLEASE MAKE A COPY OF THIS FORM TO KEEP IN YOUR HOME."

This makes sense when you consider the demographics of those who seek physician-assisted suicide in Oregon. Most were white, college educated, over age 65 years, and suffered from cancer or chronic respiratory disease. Since the law was passed, 752 out of 1,173 people, or 64% of those given prescriptions, ended their lives. Only 2 of the 71 people who died in 2013 were referred for psychiatric or psychological evaluation. Most died of suicide within the year; however, some died the following year.

Without discussing the merits and controversy of physician-assisted suicide per se, we can at least identify some obvious weaknesses in copy-and-paste legislation between states. A law that appears tailored for an educated majority culture, which accepts capacity at face value despite clearly concerning circumstances, would at least require substantial revision for a region with high rates of illiteracy or mental illness.

Other questions also are looming on the horizon: Should qualifying conditions be limited to medical conditions only? Could an advance directive include an option to request assisted suicide proactively, prior to a 6-month prognosis, or could it be requested through a designated proxy? If a patient has both a psychiatric disorder and a terminal medical condition, should laws for involuntary psychiatric care still apply?

Dr. Lawrence Egbert, retired anesthesiologist and former medical director of Final Exit Network, foretold these questions in a Washington Post interview in which he stated he "is also willing, in extreme cases, he says, to serve as an ‘exit guide’ for patients who have suffered from depression for extended periods of time."

Only time will tell how these issues play out, but with some background on the topic our profession can at least begin the discussion.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

Under British common law, suicide was a felony if committed by a person "in the years of discretion," in other words, by an adult, who was "of sound mind." An adult who killed himself while insane was not considered a criminal. While the offender obviously could not be punished, he also could not be buried in hallowed ground, and all of his property was seized by the crown. Surviving family members were not allowed to inherit.

While no state defines suicide itself as a crime by statute, there are still common law and statutory prohibitions against aiding or abetting, or encouraging, a suicide. Laws surrounding assisted suicide might seem remote or irrelevant now, but clinicians should be aware that this is changing on an almost monthly basis, and impetus is building through the support of various advocacy groups, such as Compassion & Choices, Final Exit Network,and the Euthanasia Research and Guidance Organization (ERGO).

My own interest in this topic was spurred when a recent Maryland gubernatorial candidate ran on a platform that included a plan to introduce legislation to allow physician-assisted suicide. Presently, our state defines assisted suicide as a felony offense punishable by 1 year of incarceration and a $10,000 fine, and there have been two criminal prosecutions for assisted suicide in recent years.

Nationally, 39 states have prohibitions against assisted suicide defined either by specific statute or contained within the definition of manslaughter. Some states ban assisted suicide by case law, some through the adoption of common law. Presently, five states allow physician-assisted suicide. Oregon, Washington, and Montana were among the first states to allow this. New Mexico and Vermont adopted legislation this year in January and May, respectively.

Most states have modeled their laws after the original physician-assisted suicide law, Oregon’s Death With Dignity Act. For psychiatrists involved in legislative affairs, familiarity with this law is essential.

Under the Death With Dignity Act, a person might be eligible to request physician aid in dying if he is an adult resident of the state, is able to make and communicate medical decisions, and has a 6-month prognosis as medically confirmed by two physicians. The patient must make an initial oral and written request, then repeat the oral request no sooner than 15 days later. The written request must be submitted on a state-mandated form witnessed by two people who can neither be blood relatives nor estate benefactors.

There is a requirement for informed consent, specifically that the person must know his medical diagnosis as well as the risk of taking the life-ending medication and the expected result of this act. There must be documented consideration of alternatives to suicide.

While there is a statutory mandate to refer patients for counseling if depression is suspected, there is no requirement that the patient seeking suicide be screened for this disorder or even have a capacity assessment performed by a psychiatrist.

Out of curiosity, I copied the text of the physician-assisted suicide request form through two text analyzing applications to determine the readability of the document. My two tests revealed that the form required between a 12th grade to college-level reading comprehension level. For comparison purposes, my average prison clinic patient has a 9th-grade education with a 6th-grade reading level.

The most easily understood sentence in the entire document was the instruction at the bottom of the form: "PLEASE MAKE A COPY OF THIS FORM TO KEEP IN YOUR HOME."

This makes sense when you consider the demographics of those who seek physician-assisted suicide in Oregon. Most were white, college educated, over age 65 years, and suffered from cancer or chronic respiratory disease. Since the law was passed, 752 out of 1,173 people, or 64% of those given prescriptions, ended their lives. Only 2 of the 71 people who died in 2013 were referred for psychiatric or psychological evaluation. Most died of suicide within the year; however, some died the following year.

Without discussing the merits and controversy of physician-assisted suicide per se, we can at least identify some obvious weaknesses in copy-and-paste legislation between states. A law that appears tailored for an educated majority culture, which accepts capacity at face value despite clearly concerning circumstances, would at least require substantial revision for a region with high rates of illiteracy or mental illness.

Other questions also are looming on the horizon: Should qualifying conditions be limited to medical conditions only? Could an advance directive include an option to request assisted suicide proactively, prior to a 6-month prognosis, or could it be requested through a designated proxy? If a patient has both a psychiatric disorder and a terminal medical condition, should laws for involuntary psychiatric care still apply?

Dr. Lawrence Egbert, retired anesthesiologist and former medical director of Final Exit Network, foretold these questions in a Washington Post interview in which he stated he "is also willing, in extreme cases, he says, to serve as an ‘exit guide’ for patients who have suffered from depression for extended periods of time."

Only time will tell how these issues play out, but with some background on the topic our profession can at least begin the discussion.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

Under British common law, suicide was a felony if committed by a person "in the years of discretion," in other words, by an adult, who was "of sound mind." An adult who killed himself while insane was not considered a criminal. While the offender obviously could not be punished, he also could not be buried in hallowed ground, and all of his property was seized by the crown. Surviving family members were not allowed to inherit.

While no state defines suicide itself as a crime by statute, there are still common law and statutory prohibitions against aiding or abetting, or encouraging, a suicide. Laws surrounding assisted suicide might seem remote or irrelevant now, but clinicians should be aware that this is changing on an almost monthly basis, and impetus is building through the support of various advocacy groups, such as Compassion & Choices, Final Exit Network,and the Euthanasia Research and Guidance Organization (ERGO).

My own interest in this topic was spurred when a recent Maryland gubernatorial candidate ran on a platform that included a plan to introduce legislation to allow physician-assisted suicide. Presently, our state defines assisted suicide as a felony offense punishable by 1 year of incarceration and a $10,000 fine, and there have been two criminal prosecutions for assisted suicide in recent years.

Nationally, 39 states have prohibitions against assisted suicide defined either by specific statute or contained within the definition of manslaughter. Some states ban assisted suicide by case law, some through the adoption of common law. Presently, five states allow physician-assisted suicide. Oregon, Washington, and Montana were among the first states to allow this. New Mexico and Vermont adopted legislation this year in January and May, respectively.

Most states have modeled their laws after the original physician-assisted suicide law, Oregon’s Death With Dignity Act. For psychiatrists involved in legislative affairs, familiarity with this law is essential.

Under the Death With Dignity Act, a person might be eligible to request physician aid in dying if he is an adult resident of the state, is able to make and communicate medical decisions, and has a 6-month prognosis as medically confirmed by two physicians. The patient must make an initial oral and written request, then repeat the oral request no sooner than 15 days later. The written request must be submitted on a state-mandated form witnessed by two people who can neither be blood relatives nor estate benefactors.

There is a requirement for informed consent, specifically that the person must know his medical diagnosis as well as the risk of taking the life-ending medication and the expected result of this act. There must be documented consideration of alternatives to suicide.

While there is a statutory mandate to refer patients for counseling if depression is suspected, there is no requirement that the patient seeking suicide be screened for this disorder or even have a capacity assessment performed by a psychiatrist.

Out of curiosity, I copied the text of the physician-assisted suicide request form through two text analyzing applications to determine the readability of the document. My two tests revealed that the form required between a 12th grade to college-level reading comprehension level. For comparison purposes, my average prison clinic patient has a 9th-grade education with a 6th-grade reading level.

The most easily understood sentence in the entire document was the instruction at the bottom of the form: "PLEASE MAKE A COPY OF THIS FORM TO KEEP IN YOUR HOME."

This makes sense when you consider the demographics of those who seek physician-assisted suicide in Oregon. Most were white, college educated, over age 65 years, and suffered from cancer or chronic respiratory disease. Since the law was passed, 752 out of 1,173 people, or 64% of those given prescriptions, ended their lives. Only 2 of the 71 people who died in 2013 were referred for psychiatric or psychological evaluation. Most died of suicide within the year; however, some died the following year.

Without discussing the merits and controversy of physician-assisted suicide per se, we can at least identify some obvious weaknesses in copy-and-paste legislation between states. A law that appears tailored for an educated majority culture, which accepts capacity at face value despite clearly concerning circumstances, would at least require substantial revision for a region with high rates of illiteracy or mental illness.

Other questions also are looming on the horizon: Should qualifying conditions be limited to medical conditions only? Could an advance directive include an option to request assisted suicide proactively, prior to a 6-month prognosis, or could it be requested through a designated proxy? If a patient has both a psychiatric disorder and a terminal medical condition, should laws for involuntary psychiatric care still apply?

Dr. Lawrence Egbert, retired anesthesiologist and former medical director of Final Exit Network, foretold these questions in a Washington Post interview in which he stated he "is also willing, in extreme cases, he says, to serve as an ‘exit guide’ for patients who have suffered from depression for extended periods of time."

Only time will tell how these issues play out, but with some background on the topic our profession can at least begin the discussion.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

Belinostat, a histone deacetylase inhibitor, has been approved for treating peripheral T-cell lymphoma, based on the results of the BELIEF study that found an overall response rate of nearly 26% among treated patients.

This is the third drug approved for this rare, aggressive form of non-Hodgkin’s lymphoma (NHL) since 2009, according to the Food and Drug Administration statement announcing the approval on July 3.

The other two drugs are pralatrexate injection (Folotyn), a folate analogue metabolic inhibitor approved in 2009 for treating relapsed or refractory peripheral T-cell lymphoma (PTCL); and romidepsin (Istodax), a histone deacetylase (HDAC) inhibitor approved in 2011 for treating PTCL in patients who have received at least one previous treatment.

This is an accelerated approval, which is based on surrogate or intermediate endpoints considered by the FDA as "reasonably likely to predict clinical benefit for patients with serious conditions with unmet medical needs." Confirmatory trials that verify the clinical benefit are required for full approval; otherwise, the approval can be withdrawn by the FDA. Belinostat will be marketed as Beleodaq by Spectrum Pharmaceuticals, which also markets Folotyn.

HDAC inhibitors "catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins," and in vitro, belinostat "caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells," according to a statement on the approval, issued by Spectrum on July 7. "Belinostat shows preferential cytotoxicity towards tumor cells compared to normal cells," and it "inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations," the statement said.

In the BELIEF study, an open-label, single-arm, nonrandomized study, 129 patients with relapsed or refractory PTCL were treated with belinostat, administered via an IV infusion, once a day on days 1-5 of a 21-day cycle, repeated every 3 weeks until the disease progressed or adverse effects became unacceptable. The overall response rate (complete and partial responses), the primary efficacy endpoint, was 25.8%. Nausea, vomiting, fatigue, pyrexia, and anemia were the most common adverse events associated with treatment, according to the FDA.

The company said that the drug is expected to be available in less than 3 weeks of approval (before July 24). The confirmatory trial is a phase III study that will evaluate belinostat plus CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone), compared with CHOP alone.

PTCL accounts for about 10%-15% of NHL cases in North America, according to the FDA, which cites National Cancer Institute estimates that 70,800 Americans will be diagnosed with NHL and 18,990 will die of NHL in 2014.

The prescribing information for belinostat is available here.

[email protected]

Belinostat, a histone deacetylase inhibitor, has been approved for treating peripheral T-cell lymphoma, based on the results of the BELIEF study that found an overall response rate of nearly 26% among treated patients.

This is the third drug approved for this rare, aggressive form of non-Hodgkin’s lymphoma (NHL) since 2009, according to the Food and Drug Administration statement announcing the approval on July 3.

The other two drugs are pralatrexate injection (Folotyn), a folate analogue metabolic inhibitor approved in 2009 for treating relapsed or refractory peripheral T-cell lymphoma (PTCL); and romidepsin (Istodax), a histone deacetylase (HDAC) inhibitor approved in 2011 for treating PTCL in patients who have received at least one previous treatment.

This is an accelerated approval, which is based on surrogate or intermediate endpoints considered by the FDA as "reasonably likely to predict clinical benefit for patients with serious conditions with unmet medical needs." Confirmatory trials that verify the clinical benefit are required for full approval; otherwise, the approval can be withdrawn by the FDA. Belinostat will be marketed as Beleodaq by Spectrum Pharmaceuticals, which also markets Folotyn.

HDAC inhibitors "catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins," and in vitro, belinostat "caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells," according to a statement on the approval, issued by Spectrum on July 7. "Belinostat shows preferential cytotoxicity towards tumor cells compared to normal cells," and it "inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations," the statement said.

In the BELIEF study, an open-label, single-arm, nonrandomized study, 129 patients with relapsed or refractory PTCL were treated with belinostat, administered via an IV infusion, once a day on days 1-5 of a 21-day cycle, repeated every 3 weeks until the disease progressed or adverse effects became unacceptable. The overall response rate (complete and partial responses), the primary efficacy endpoint, was 25.8%. Nausea, vomiting, fatigue, pyrexia, and anemia were the most common adverse events associated with treatment, according to the FDA.

The company said that the drug is expected to be available in less than 3 weeks of approval (before July 24). The confirmatory trial is a phase III study that will evaluate belinostat plus CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone), compared with CHOP alone.

PTCL accounts for about 10%-15% of NHL cases in North America, according to the FDA, which cites National Cancer Institute estimates that 70,800 Americans will be diagnosed with NHL and 18,990 will die of NHL in 2014.

The prescribing information for belinostat is available here.

[email protected]

Belinostat, a histone deacetylase inhibitor, has been approved for treating peripheral T-cell lymphoma, based on the results of the BELIEF study that found an overall response rate of nearly 26% among treated patients.

This is the third drug approved for this rare, aggressive form of non-Hodgkin’s lymphoma (NHL) since 2009, according to the Food and Drug Administration statement announcing the approval on July 3.

The other two drugs are pralatrexate injection (Folotyn), a folate analogue metabolic inhibitor approved in 2009 for treating relapsed or refractory peripheral T-cell lymphoma (PTCL); and romidepsin (Istodax), a histone deacetylase (HDAC) inhibitor approved in 2011 for treating PTCL in patients who have received at least one previous treatment.

This is an accelerated approval, which is based on surrogate or intermediate endpoints considered by the FDA as "reasonably likely to predict clinical benefit for patients with serious conditions with unmet medical needs." Confirmatory trials that verify the clinical benefit are required for full approval; otherwise, the approval can be withdrawn by the FDA. Belinostat will be marketed as Beleodaq by Spectrum Pharmaceuticals, which also markets Folotyn.

HDAC inhibitors "catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins," and in vitro, belinostat "caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells," according to a statement on the approval, issued by Spectrum on July 7. "Belinostat shows preferential cytotoxicity towards tumor cells compared to normal cells," and it "inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations," the statement said.

In the BELIEF study, an open-label, single-arm, nonrandomized study, 129 patients with relapsed or refractory PTCL were treated with belinostat, administered via an IV infusion, once a day on days 1-5 of a 21-day cycle, repeated every 3 weeks until the disease progressed or adverse effects became unacceptable. The overall response rate (complete and partial responses), the primary efficacy endpoint, was 25.8%. Nausea, vomiting, fatigue, pyrexia, and anemia were the most common adverse events associated with treatment, according to the FDA.

The company said that the drug is expected to be available in less than 3 weeks of approval (before July 24). The confirmatory trial is a phase III study that will evaluate belinostat plus CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone), compared with CHOP alone.

PTCL accounts for about 10%-15% of NHL cases in North America, according to the FDA, which cites National Cancer Institute estimates that 70,800 Americans will be diagnosed with NHL and 18,990 will die of NHL in 2014.

The prescribing information for belinostat is available here.

[email protected]

Hailey-Hailey disease (HHD), or benign familial chronic pemphigus, typically presents as suprabasal blisters with a perivascular and interstitial lymphocytic infiltrate (Figure 1).¹ Villi, or elongated dermal papillae lined with a single layer of basal cells, protrude into the bullae (Figure 2). In HHD lesions, the epidermis is thickened with scale-crust, and at least the lower half of the epidermis shows acantholysis. Despite the acantholytic changes, a few intact intercellular bridges remain, giving the appearance of a dilapidated brick wall (Figure 2). There may be dyskeratotic cells among the acantholytic cells, though they are scant in many cases. These acantholytic dyskeratotic cells have eosinophilic polygonal-shaped cytoplasm. Hailey-Hailey disease typically does not show adnexal extension of the acantholysis. Direct immunofluorescence is negative in HHD.

Pemphigus vulgaris is an autoimmune intraepidermal bullous disease that presents with suprabasal acantholysis (Figure 3).² The epidermis is not thickened and acantholysis is limited to the suprabasal layer. Acantholytic cells with eosinophils and/or neutrophils are found within the bullae. Perivascular and interstitial infiltrates of lymphocytes, eosinophils, and occasionally neutrophils are seen; however, the inflammatory cell infiltrate can vary from extensive to scant. Direct immunofluorescence usually reveals IgG and/or C3 deposition on the surface of the keratinocytes throughout the epidermis.

Pemphigus foliaceus is another autoimmune intraepidermal bullous disease that is characterized by acantholysis in the granular or upper spinous layers (Figure 4).³ The epidermis is not thickened. Sometimes acantholytic cells show dyskeratotic change (Figure 4). Some biopsy specimens do not contain the roof of the bullae; therefore, only erosion is seen and the diagnosis may be missed. Moreover, when only the adnexal epithelium shows acantholysis without epidermal involvement, diagnosis can be difficult.⁴ Acantholysis is accompanied with a superficial perivascular and interstitial inflammatory cell infiltrate consisting of lymphocytes, eosinophils, and occasionally neutrophils. The amount of inflammatory cell infiltrate may vary. Bullous impetigo and staphylococcal scalded skin syndrome reveal a similar histopathologic pattern. Direct immunofluorescence usually discloses IgG and/or C3 deposition on cell surfaces of keratinocytes in the entire or upper epidermis.

Herpesvirus infection shows ballooning (intracellular edema) of keratinocytes. Eventually acantholysis occurs and intraepidermal bullae are formed. In the bullae, virus-associated acantholytic keratinocytes, some that are multinucleated, can be easily found (Figure 5).⁵ These cells are larger than normal keratinocytes and have steel gray nuclei with peripheral accentuation. Some of these cells are necrotic, and the remains of necrotic multinucleated acantholytic cells are easily recognized. Adnexal epithelial cells occasionally are affected by herpesvirus infection; nuclear change is similar to the epidermis. A perivascular and interstitial infiltrate of lymphocytes and neutrophils is seen. Neutrophils accumulate within the old bullae, clinically manifesting as a pustule.

Darier disease is characterized by suprabasal clefts and acantholysis above the basal layer (Figure 6).⁶ Similar to HHD, villi protrude within the clefts (Figure 6). Conspicuous columns of parakeratosis above the acantholytic epidermis often are observed. Dyskeratotic cells exist among acantholytic ke-ratinocytes in the granular layer and parakeratotic column, which are known as corps ronds and crops grains, respectively. A scant to moderate lymphocytic infiltrate is found in the upper dermis.

Hailey-Hailey disease (HHD), or benign familial chronic pemphigus, typically presents as suprabasal blisters with a perivascular and interstitial lymphocytic infiltrate (Figure 1).¹ Villi, or elongated dermal papillae lined with a single layer of basal cells, protrude into the bullae (Figure 2). In HHD lesions, the epidermis is thickened with scale-crust, and at least the lower half of the epidermis shows acantholysis. Despite the acantholytic changes, a few intact intercellular bridges remain, giving the appearance of a dilapidated brick wall (Figure 2). There may be dyskeratotic cells among the acantholytic cells, though they are scant in many cases. These acantholytic dyskeratotic cells have eosinophilic polygonal-shaped cytoplasm. Hailey-Hailey disease typically does not show adnexal extension of the acantholysis. Direct immunofluorescence is negative in HHD.

Pemphigus vulgaris is an autoimmune intraepidermal bullous disease that presents with suprabasal acantholysis (Figure 3).² The epidermis is not thickened and acantholysis is limited to the suprabasal layer. Acantholytic cells with eosinophils and/or neutrophils are found within the bullae. Perivascular and interstitial infiltrates of lymphocytes, eosinophils, and occasionally neutrophils are seen; however, the inflammatory cell infiltrate can vary from extensive to scant. Direct immunofluorescence usually reveals IgG and/or C3 deposition on the surface of the keratinocytes throughout the epidermis.

Pemphigus foliaceus is another autoimmune intraepidermal bullous disease that is characterized by acantholysis in the granular or upper spinous layers (Figure 4).³ The epidermis is not thickened. Sometimes acantholytic cells show dyskeratotic change (Figure 4). Some biopsy specimens do not contain the roof of the bullae; therefore, only erosion is seen and the diagnosis may be missed. Moreover, when only the adnexal epithelium shows acantholysis without epidermal involvement, diagnosis can be difficult.⁴ Acantholysis is accompanied with a superficial perivascular and interstitial inflammatory cell infiltrate consisting of lymphocytes, eosinophils, and occasionally neutrophils. The amount of inflammatory cell infiltrate may vary. Bullous impetigo and staphylococcal scalded skin syndrome reveal a similar histopathologic pattern. Direct immunofluorescence usually discloses IgG and/or C3 deposition on cell surfaces of keratinocytes in the entire or upper epidermis.

Herpesvirus infection shows ballooning (intracellular edema) of keratinocytes. Eventually acantholysis occurs and intraepidermal bullae are formed. In the bullae, virus-associated acantholytic keratinocytes, some that are multinucleated, can be easily found (Figure 5).⁵ These cells are larger than normal keratinocytes and have steel gray nuclei with peripheral accentuation. Some of these cells are necrotic, and the remains of necrotic multinucleated acantholytic cells are easily recognized. Adnexal epithelial cells occasionally are affected by herpesvirus infection; nuclear change is similar to the epidermis. A perivascular and interstitial infiltrate of lymphocytes and neutrophils is seen. Neutrophils accumulate within the old bullae, clinically manifesting as a pustule.

Darier disease is characterized by suprabasal clefts and acantholysis above the basal layer (Figure 6).⁶ Similar to HHD, villi protrude within the clefts (Figure 6). Conspicuous columns of parakeratosis above the acantholytic epidermis often are observed. Dyskeratotic cells exist among acantholytic ke-ratinocytes in the granular layer and parakeratotic column, which are known as corps ronds and crops grains, respectively. A scant to moderate lymphocytic infiltrate is found in the upper dermis.

Hailey-Hailey disease (HHD), or benign familial chronic pemphigus, typically presents as suprabasal blisters with a perivascular and interstitial lymphocytic infiltrate (Figure 1).¹ Villi, or elongated dermal papillae lined with a single layer of basal cells, protrude into the bullae (Figure 2). In HHD lesions, the epidermis is thickened with scale-crust, and at least the lower half of the epidermis shows acantholysis. Despite the acantholytic changes, a few intact intercellular bridges remain, giving the appearance of a dilapidated brick wall (Figure 2). There may be dyskeratotic cells among the acantholytic cells, though they are scant in many cases. These acantholytic dyskeratotic cells have eosinophilic polygonal-shaped cytoplasm. Hailey-Hailey disease typically does not show adnexal extension of the acantholysis. Direct immunofluorescence is negative in HHD.

Pemphigus vulgaris is an autoimmune intraepidermal bullous disease that presents with suprabasal acantholysis (Figure 3).² The epidermis is not thickened and acantholysis is limited to the suprabasal layer. Acantholytic cells with eosinophils and/or neutrophils are found within the bullae. Perivascular and interstitial infiltrates of lymphocytes, eosinophils, and occasionally neutrophils are seen; however, the inflammatory cell infiltrate can vary from extensive to scant. Direct immunofluorescence usually reveals IgG and/or C3 deposition on the surface of the keratinocytes throughout the epidermis.

Pemphigus foliaceus is another autoimmune intraepidermal bullous disease that is characterized by acantholysis in the granular or upper spinous layers (Figure 4).³ The epidermis is not thickened. Sometimes acantholytic cells show dyskeratotic change (Figure 4). Some biopsy specimens do not contain the roof of the bullae; therefore, only erosion is seen and the diagnosis may be missed. Moreover, when only the adnexal epithelium shows acantholysis without epidermal involvement, diagnosis can be difficult.⁴ Acantholysis is accompanied with a superficial perivascular and interstitial inflammatory cell infiltrate consisting of lymphocytes, eosinophils, and occasionally neutrophils. The amount of inflammatory cell infiltrate may vary. Bullous impetigo and staphylococcal scalded skin syndrome reveal a similar histopathologic pattern. Direct immunofluorescence usually discloses IgG and/or C3 deposition on cell surfaces of keratinocytes in the entire or upper epidermis.

Herpesvirus infection shows ballooning (intracellular edema) of keratinocytes. Eventually acantholysis occurs and intraepidermal bullae are formed. In the bullae, virus-associated acantholytic keratinocytes, some that are multinucleated, can be easily found (Figure 5).⁵ These cells are larger than normal keratinocytes and have steel gray nuclei with peripheral accentuation. Some of these cells are necrotic, and the remains of necrotic multinucleated acantholytic cells are easily recognized. Adnexal epithelial cells occasionally are affected by herpesvirus infection; nuclear change is similar to the epidermis. A perivascular and interstitial infiltrate of lymphocytes and neutrophils is seen. Neutrophils accumulate within the old bullae, clinically manifesting as a pustule.

Darier disease is characterized by suprabasal clefts and acantholysis above the basal layer (Figure 6).⁶ Similar to HHD, villi protrude within the clefts (Figure 6). Conspicuous columns of parakeratosis above the acantholytic epidermis often are observed. Dyskeratotic cells exist among acantholytic ke-ratinocytes in the granular layer and parakeratotic column, which are known as corps ronds and crops grains, respectively. A scant to moderate lymphocytic infiltrate is found in the upper dermis.