The Diagnosis: Bullous/Hemorrhagic Lichen Sclerosus et Atrophicus

Histopathologic examination revealed hyperkeratosis of the stratum corneum and thinning of the epidermis (Figure). Subepidermal edema and hemorrhage in the papillary dermis were seen. There were dilated vessels beneath the edema in the reticular dermis, as well as perivascular, perifollicular, and interstitial lymphocytic inflammation. No cytologic atypia characteristic of squamous cell carcinoma (SCC) and angiosarcoma or large lymphatic channels characteristic of lymphangioma were noted. Based on clinicopathologic correlation, the diagnosis of the bullous/hemorrhagic form of lichen sclerosus et atrophicus (LS&A) was made. The patient was treated with high-potency topical steroids with notable symptomatic improvement and rapid resolution of the hemorrhagic lesion.

Lichen sclerosus et atrophicus is a chronic inflammatory condition with a predilection for the anogenital region, though rare cases of extragenital involvement have been reported. It is seen in both sexes and across all age groups, with notably higher prevalence in females in the fifth and sixth decades of life.^1,2 Lichen sclerosus et atrophicus can be difficult to diagnose, as these patients may present to a variety of specialists, may be embarrassed by the condition and reluctant for full evaluation, or may have asymptomatic lesions.^2,3 Rare cases of isolated extragenital involvement and hemorrhagic or bullous lesions further complicate the diagnosis.^1,2 Despite these difficulties, diagnosis is essential, as there is potential for cosmetically and functionally detrimental scarring as well as atrophy and development of overlying malignancies. Lichen sclerosus et atrophicus is not curable and rarely remits spontaneously, but appropriate treatment strategies can help control the symptoms of the condition as well as its most devastating sequelae.³

For females, classic LS&A is most common in theprepubertal, perimenopausal, or postmenopausal periods, commonly involving the vulva or perineum. Symptoms include pruritus, burning sensation, dysuria, dyspareunia, and labial stenosis, among others. For males, most cases involve the glans penis in prepubertal boys or middleaged men, and symptoms include pruritus, new-onset phimosis, decreased sensation, painful erections, dysuria, and urinary obstruction.^1-3 An estimated 97% of patients have some form of genital involvement with only 2.5% showing isolated extragenital involvement, though the latter may be underdiagnosed, as this area is more likely to be asymptomatic.^3-6 Extragenital LS&A most often involves the neck and shoulders. The classic appearance of LS&A includes shiny, white-red macules and papules that ultimately coalesce into atrophic plaques and can be accompanied by fissuring or scarring, especially in the genital area.² There is an increased risk for SCC associated with genital LS&A.¹

Bullous/hemorrhagic LS&A has been described as a rare phenotype. One case report cited an increased incidence of this subtype in patients with exclusively extragenital lesions, and the authors considered blister formation to be a characteristic feature of extragenital LS&A. The pathogenesis of blister formation and hemorrhage in LS&A is not completely understood, but trauma is thought to play a role due to decreased stress tolerance from atrophic skin.⁴ Furthermore, distortion of blood vessel architecture in LS&A has been described with loss of the capillary network and enlargement of vessels along  the dermoepidermal junction, which also could play a role in hemorrhage. Differential diagnosis of the bullous/hemorrhagic type of LS&A includes bullous pemphigoid, bullous lichen planus, or bullous scleroderma.⁷ In our more exophytic hemorrhagic case, malignancies such as SCC or angiosarcoma also had to be considered. Unlike genital LS&A, extragenital LS&A including the bullous/hemorrhagic variant has not been linked to an increasedrisk for malignancy.^1,5

The mainstay of treatment of all forms of LS&A is high-potency topical steroids, but topical retinoids, tacrolimus, and UVA phototherapy also have been used. Bullous/hemorrhagic lesions often resolve quickly with topical steroids, leaving behind more classic plaques in their place, which can be more refractory to treatment.^5,7

The Diagnosis: Bullous/Hemorrhagic Lichen Sclerosus et Atrophicus

Histopathologic examination revealed hyperkeratosis of the stratum corneum and thinning of the epidermis (Figure). Subepidermal edema and hemorrhage in the papillary dermis were seen. There were dilated vessels beneath the edema in the reticular dermis, as well as perivascular, perifollicular, and interstitial lymphocytic inflammation. No cytologic atypia characteristic of squamous cell carcinoma (SCC) and angiosarcoma or large lymphatic channels characteristic of lymphangioma were noted. Based on clinicopathologic correlation, the diagnosis of the bullous/hemorrhagic form of lichen sclerosus et atrophicus (LS&A) was made. The patient was treated with high-potency topical steroids with notable symptomatic improvement and rapid resolution of the hemorrhagic lesion.

Lichen sclerosus et atrophicus is a chronic inflammatory condition with a predilection for the anogenital region, though rare cases of extragenital involvement have been reported. It is seen in both sexes and across all age groups, with notably higher prevalence in females in the fifth and sixth decades of life.^1,2 Lichen sclerosus et atrophicus can be difficult to diagnose, as these patients may present to a variety of specialists, may be embarrassed by the condition and reluctant for full evaluation, or may have asymptomatic lesions.^2,3 Rare cases of isolated extragenital involvement and hemorrhagic or bullous lesions further complicate the diagnosis.^1,2 Despite these difficulties, diagnosis is essential, as there is potential for cosmetically and functionally detrimental scarring as well as atrophy and development of overlying malignancies. Lichen sclerosus et atrophicus is not curable and rarely remits spontaneously, but appropriate treatment strategies can help control the symptoms of the condition as well as its most devastating sequelae.³

For females, classic LS&A is most common in theprepubertal, perimenopausal, or postmenopausal periods, commonly involving the vulva or perineum. Symptoms include pruritus, burning sensation, dysuria, dyspareunia, and labial stenosis, among others. For males, most cases involve the glans penis in prepubertal boys or middleaged men, and symptoms include pruritus, new-onset phimosis, decreased sensation, painful erections, dysuria, and urinary obstruction.^1-3 An estimated 97% of patients have some form of genital involvement with only 2.5% showing isolated extragenital involvement, though the latter may be underdiagnosed, as this area is more likely to be asymptomatic.^3-6 Extragenital LS&A most often involves the neck and shoulders. The classic appearance of LS&A includes shiny, white-red macules and papules that ultimately coalesce into atrophic plaques and can be accompanied by fissuring or scarring, especially in the genital area.² There is an increased risk for SCC associated with genital LS&A.¹

Bullous/hemorrhagic LS&A has been described as a rare phenotype. One case report cited an increased incidence of this subtype in patients with exclusively extragenital lesions, and the authors considered blister formation to be a characteristic feature of extragenital LS&A. The pathogenesis of blister formation and hemorrhage in LS&A is not completely understood, but trauma is thought to play a role due to decreased stress tolerance from atrophic skin.⁴ Furthermore, distortion of blood vessel architecture in LS&A has been described with loss of the capillary network and enlargement of vessels along  the dermoepidermal junction, which also could play a role in hemorrhage. Differential diagnosis of the bullous/hemorrhagic type of LS&A includes bullous pemphigoid, bullous lichen planus, or bullous scleroderma.⁷ In our more exophytic hemorrhagic case, malignancies such as SCC or angiosarcoma also had to be considered. Unlike genital LS&A, extragenital LS&A including the bullous/hemorrhagic variant has not been linked to an increasedrisk for malignancy.^1,5

The mainstay of treatment of all forms of LS&A is high-potency topical steroids, but topical retinoids, tacrolimus, and UVA phototherapy also have been used. Bullous/hemorrhagic lesions often resolve quickly with topical steroids, leaving behind more classic plaques in their place, which can be more refractory to treatment.^5,7

The Diagnosis: Bullous/Hemorrhagic Lichen Sclerosus et Atrophicus

Histopathologic examination revealed hyperkeratosis of the stratum corneum and thinning of the epidermis (Figure). Subepidermal edema and hemorrhage in the papillary dermis were seen. There were dilated vessels beneath the edema in the reticular dermis, as well as perivascular, perifollicular, and interstitial lymphocytic inflammation. No cytologic atypia characteristic of squamous cell carcinoma (SCC) and angiosarcoma or large lymphatic channels characteristic of lymphangioma were noted. Based on clinicopathologic correlation, the diagnosis of the bullous/hemorrhagic form of lichen sclerosus et atrophicus (LS&A) was made. The patient was treated with high-potency topical steroids with notable symptomatic improvement and rapid resolution of the hemorrhagic lesion.

Lichen sclerosus et atrophicus is a chronic inflammatory condition with a predilection for the anogenital region, though rare cases of extragenital involvement have been reported. It is seen in both sexes and across all age groups, with notably higher prevalence in females in the fifth and sixth decades of life.^1,2 Lichen sclerosus et atrophicus can be difficult to diagnose, as these patients may present to a variety of specialists, may be embarrassed by the condition and reluctant for full evaluation, or may have asymptomatic lesions.^2,3 Rare cases of isolated extragenital involvement and hemorrhagic or bullous lesions further complicate the diagnosis.^1,2 Despite these difficulties, diagnosis is essential, as there is potential for cosmetically and functionally detrimental scarring as well as atrophy and development of overlying malignancies. Lichen sclerosus et atrophicus is not curable and rarely remits spontaneously, but appropriate treatment strategies can help control the symptoms of the condition as well as its most devastating sequelae.³

For females, classic LS&A is most common in theprepubertal, perimenopausal, or postmenopausal periods, commonly involving the vulva or perineum. Symptoms include pruritus, burning sensation, dysuria, dyspareunia, and labial stenosis, among others. For males, most cases involve the glans penis in prepubertal boys or middleaged men, and symptoms include pruritus, new-onset phimosis, decreased sensation, painful erections, dysuria, and urinary obstruction.^1-3 An estimated 97% of patients have some form of genital involvement with only 2.5% showing isolated extragenital involvement, though the latter may be underdiagnosed, as this area is more likely to be asymptomatic.^3-6 Extragenital LS&A most often involves the neck and shoulders. The classic appearance of LS&A includes shiny, white-red macules and papules that ultimately coalesce into atrophic plaques and can be accompanied by fissuring or scarring, especially in the genital area.² There is an increased risk for SCC associated with genital LS&A.¹

Bullous/hemorrhagic LS&A has been described as a rare phenotype. One case report cited an increased incidence of this subtype in patients with exclusively extragenital lesions, and the authors considered blister formation to be a characteristic feature of extragenital LS&A. The pathogenesis of blister formation and hemorrhage in LS&A is not completely understood, but trauma is thought to play a role due to decreased stress tolerance from atrophic skin.⁴ Furthermore, distortion of blood vessel architecture in LS&A has been described with loss of the capillary network and enlargement of vessels along  the dermoepidermal junction, which also could play a role in hemorrhage. Differential diagnosis of the bullous/hemorrhagic type of LS&A includes bullous pemphigoid, bullous lichen planus, or bullous scleroderma.⁷ In our more exophytic hemorrhagic case, malignancies such as SCC or angiosarcoma also had to be considered. Unlike genital LS&A, extragenital LS&A including the bullous/hemorrhagic variant has not been linked to an increasedrisk for malignancy.^1,5

The mainstay of treatment of all forms of LS&A is high-potency topical steroids, but topical retinoids, tacrolimus, and UVA phototherapy also have been used. Bullous/hemorrhagic lesions often resolve quickly with topical steroids, leaving behind more classic plaques in their place, which can be more refractory to treatment.^5,7

Postnflammatory hyperpigmentation (PIH) is an acquired hypermelanosis that can occur in children and adults following an inflammatory cutaneous disease or trauma. Postinflammatory hyperpigmentation may last for months to even years. Although PIH may occur in all skin types, it is more common and presents with greater severity and intensity in individuals with skin of color. By the year 2050, 1 in 3 US residents is projected to be Hispanic.¹ It is projected that by 2044, non-Hispanic white individuals (all ages) will make up less than 50% of the US population.² Currently, the majority of the US residents younger than 18 years are minorities. The majority minority population in the United States already exists in those younger than 18 years and is predicted to occur in the adult population by 2044.²

Effective treatment options and management strategies for PIH in adults with skin of color have been described in the literature.³ Due to a paucity of research, the approach to management of PIH in children with skin of color has been based on clinical experience and lessons learned from adult patients. This article focuses on management of PIH in pediatric patients with skin of color, which includes black/African American, African-Caribbean, Hispanic, Asian, Pacific Islander, and American Indian individuals.

Underlying Inflammatory Dermatoses Resulting in PIH

There are numerous conditions that may result in PIH, including but not limited to atopic dermatitis (AD), acne, arthropod bites, and injuries to the skin. Postinflammatory hyperpigmentation may have more of a psychological impact than the inciting disease or injury itself. The most important step in the approach to managing PIH is treating the underlying inflammatory condition that caused the pigmentation.

Parents/guardians may report a chief concern of dark spots, manchas (stains), blemishes, or stains on the skin, often with no mention of a coexisting inflammatory dermatosis. Parents/guardians of children with skin of color often have personally experienced PIH and may be determined to shield their children from similar angst associated with the condition. Although physicians may see just another pediatric patient with PIH, the child’s parents/guardians may see a condition that will be readily perceptible during major life events, such as the child’s prom or even his/her wedding day. Promptly diagnosing and instituting early treatment of inflammatory conditions associated with PIH may accelerate resolution and prevent worsening of the pigmentation.³

Select inflammatory dermatoses that are common in children with skin of color and may lead to PIH are highlighted below. Although this list is not comprehensive, the approach and management strategies should prompt creation of plans that keep PIH in mind when treating primary inflammatory skin diseases.

Atopic Dermatitis
Atopic dermatitis may induce PIH or hypopigmentation of the skin in children with skin of color. Developing a plan for AD flare prevention, as well as management of mild, moderate, and severe AD flares, is imperative in pediatric patients. Prevention plans should include gentle skin care, twice-daily application of emollients to the full body, and reduction of Staphylococcus aureus loads on the skin. The treatment action plan for mild to moderate flares may include topical corticosteroids, immunomodulators, and nonsteroidal agents. Treatment options for severe AD or patients who were unsuccessfully treated with other therapies may include phototherapy, biologics, and methotrexate, among others.⁴ Creating action plans for AD flares is a vital step in the prevention of PIH in patients with skin of color. Additionally, PIH should not be considered a sign of AD treatment failure.

Acne
Acne is a common skin disorder seen in patients with skin of color.⁵ A prospective observational study found that 34.3% of 683 children aged 9 to 14 years in a pediatric ambulatory clinic had acne.⁶ The number of preadolescents with acne is growing. Most cases are not associated with underlying endocrinopathy.⁷ With the growing population of children with skin of color in the United States along with the increasing childhood acne rate and subsequent inherent risk for hyperpigmentation, early acne interventions should be considered in pediatric acne patients with skin of color to reduce the impact of PIH in those at risk.

In a survey study of 313 adult acne patients with skin of color, 37.2% reported the presence of dark marks lasting 4 months or longer.⁵ Regardless of the severity of the acne, treatment should be initiated as tolerated in those with PIH. Adolescent acne patients with skin of color may develop PIH that is more severe and longer lasting than the acne itself.

The foundation for treatment of acne in adolescent skin of color patients is the same as those without skin of color, including topical retinoids, topical antibiotics, oral antibiotics, and isotretinoin when needed. Topical tretinoin, adapalene, azelaic acid, and tazarotene not only treat acne but also are a valuable part of the treatment armamentarium for PIH. Several studies in adults with skin of color have demonstrated improvement of PIH from the use of topical retinoids alone.^8-10 Despite wanting to treat the acne aggressively, special guidance should be given to prevent retinoid dermatitis, which may lead to PIH.¹⁰ Demonstrating the application of the topical acne medications, discussing how to avoid potential side effects, and giving permission to skip applications, if needed, may empower families to make adjustments between visits to limit irritation that might prompt further PIH. Incorporating α-hydroxy acid–based cleansers, α-hydroxy acid–based chemical peels, or salicylic acid chemical peels may be warranted in the setting of intense PIH. Selecting treatments that not only help the inflammatory disease leading to the PIH but also can help improve the pigmentation are preferred; however, the risks and benefits have to be weighed because many treatments that work well for PIH also may cause irritation, leading to new or worsening PIH.

Arthropod Bites
Arthropod bites cause inflamed pruritic papules and nodules, and the resulting PIH in those with darker skin types may be quite dramatic. Parents/guardians should be instructed to have a low-potency topical corticosteroid on hand to use on bites for a few days when they appear, which will not only help with the inflammation associated with the bite but also will help decrease pruritus and subsequently skin injury from scratching. In homes with pets, checking animals routinely for fleas and other infestations is helpful. In the setting of repeated arthropod bites in the spring and summer, applying bug repellant with 10% to 30% DEET (N,N-diethyl-meta-toluamide) on the child’s clothing and exposed body areas before playing outside or in the morning before school or camp may prevent some bites. There are DEET alternatives, such as picaridin, that may be used. Product instructions should be followed when using insect repellants in the pediatric population.¹¹

PIH Management Strategies

Gentle Skin Care Routine
There are misconceptions that areas of hyperpigmentation on the skin are caused by dirt and that scrubbing the skin harder may help to lighten the affected areas. Parents/guardians may report that the child’s skin looks dirty or, in the setting of acne, view dirt as the cause of the skin condition, which may prompt the patient to scrub the skin and the friction further worsens the PIH. Use of daily gentle cleansers and moisturizers is advised to keep the skin moisturized and free of further potential irritation and dryness that may prompt scratching or flares of the underlying condition.

Photoprotection
During the treatment course for PIH, using sun protection is helpful to prevent further darkening of the PIH areas. Sun protection may be in the form of broad-spectrum sunscreen, hats, or sun-protective clothing. Patients should be encouraged to apply sunscreen daily and to reapply every 2 hours and after water-based activities.¹² For pediatric and adolescent populations, practicing sun-protective behaviors before school or outdoor activities also should be advised, as many families only think about sun protection in the setting of sunny vacation activities. Research has demonstrated that individuals with skin of color may not realize that they can be affected by skin cancer,¹³ thus they may not have any experience selecting, applying, or regularly using sunscreens. Products that do not leave a white hue on the skin are suggested for adolescents who may be sensitive about their appearance following sunscreen application.

Skin Lightening Treatments

Although the most important therapy for PIH is to treat the underlying inflammatory conditions, some parents/guardians may desire additional options due to the extent of involvement of the PIH, its psychological impact on the child, or adverse effect on the child’s quality of life.¹⁴ In adolescents, incorporating an α-hydroxy acid–based cleanser, glycolic acid chemical peels, salicylic acid chemical peels, and topical cosmeceuticals may be warranted in the setting of intense PIH and acne. However, irritation may lead to further dyspigmentation.

Topical ammonium lactate 12% is lactic acid neutralized with ammonium hydroxide that is formulated as a lotion or a cream. It is used to hydrate dry skin and may decrease corneocyte cohesion.¹⁵ Topical ammonium lactate also has been used anecdotally for PIH on the body during periods of watchful waiting.

Topical hydroquinone, the gold standard for treating hyperpigmentation,^3,16 is not approved in children, but some parents/guardians elect to utilize hydroquinone off label to accelerate the clearing of distressing PIH in adolescents. Careful consideration including a discussion of potential risks and alternatives (eg, watchful waiting) should be highlighted.

In the setting of chronic inflammatory conditions that recur and remit, potentially irritating topical treatments should be used only during periods when symptoms of inflammation such as itching or erythema are absent.

Conclusion

Despite the best management efforts, PIH in some patients with skin of color may be present for months to years. In the pediatric skin of color population, treatment of the underlying inflammatory condition, gentle skin care, use of photoprotection, and time may be all that is needed for PIH resolution. With their parent/guardians’ consent, adolescents distressed by PIH may decide to pursue more aggressive, potentially irritating treatments. Above all, the most important management in the setting of PIH is to treat the underlying inflammatory condition causing the PIH and set reasonable expectations. For challenging cases, pediatric dermatologists with special expertise in treating pediatric and adolescent patients with skin of color may be consulted.

Postnflammatory hyperpigmentation (PIH) is an acquired hypermelanosis that can occur in children and adults following an inflammatory cutaneous disease or trauma. Postinflammatory hyperpigmentation may last for months to even years. Although PIH may occur in all skin types, it is more common and presents with greater severity and intensity in individuals with skin of color. By the year 2050, 1 in 3 US residents is projected to be Hispanic.¹ It is projected that by 2044, non-Hispanic white individuals (all ages) will make up less than 50% of the US population.² Currently, the majority of the US residents younger than 18 years are minorities. The majority minority population in the United States already exists in those younger than 18 years and is predicted to occur in the adult population by 2044.²

Effective treatment options and management strategies for PIH in adults with skin of color have been described in the literature.³ Due to a paucity of research, the approach to management of PIH in children with skin of color has been based on clinical experience and lessons learned from adult patients. This article focuses on management of PIH in pediatric patients with skin of color, which includes black/African American, African-Caribbean, Hispanic, Asian, Pacific Islander, and American Indian individuals.

Underlying Inflammatory Dermatoses Resulting in PIH

There are numerous conditions that may result in PIH, including but not limited to atopic dermatitis (AD), acne, arthropod bites, and injuries to the skin. Postinflammatory hyperpigmentation may have more of a psychological impact than the inciting disease or injury itself. The most important step in the approach to managing PIH is treating the underlying inflammatory condition that caused the pigmentation.

Parents/guardians may report a chief concern of dark spots, manchas (stains), blemishes, or stains on the skin, often with no mention of a coexisting inflammatory dermatosis. Parents/guardians of children with skin of color often have personally experienced PIH and may be determined to shield their children from similar angst associated with the condition. Although physicians may see just another pediatric patient with PIH, the child’s parents/guardians may see a condition that will be readily perceptible during major life events, such as the child’s prom or even his/her wedding day. Promptly diagnosing and instituting early treatment of inflammatory conditions associated with PIH may accelerate resolution and prevent worsening of the pigmentation.³

Select inflammatory dermatoses that are common in children with skin of color and may lead to PIH are highlighted below. Although this list is not comprehensive, the approach and management strategies should prompt creation of plans that keep PIH in mind when treating primary inflammatory skin diseases.

Atopic Dermatitis
Atopic dermatitis may induce PIH or hypopigmentation of the skin in children with skin of color. Developing a plan for AD flare prevention, as well as management of mild, moderate, and severe AD flares, is imperative in pediatric patients. Prevention plans should include gentle skin care, twice-daily application of emollients to the full body, and reduction of Staphylococcus aureus loads on the skin. The treatment action plan for mild to moderate flares may include topical corticosteroids, immunomodulators, and nonsteroidal agents. Treatment options for severe AD or patients who were unsuccessfully treated with other therapies may include phototherapy, biologics, and methotrexate, among others.⁴ Creating action plans for AD flares is a vital step in the prevention of PIH in patients with skin of color. Additionally, PIH should not be considered a sign of AD treatment failure.

Acne
Acne is a common skin disorder seen in patients with skin of color.⁵ A prospective observational study found that 34.3% of 683 children aged 9 to 14 years in a pediatric ambulatory clinic had acne.⁶ The number of preadolescents with acne is growing. Most cases are not associated with underlying endocrinopathy.⁷ With the growing population of children with skin of color in the United States along with the increasing childhood acne rate and subsequent inherent risk for hyperpigmentation, early acne interventions should be considered in pediatric acne patients with skin of color to reduce the impact of PIH in those at risk.

In a survey study of 313 adult acne patients with skin of color, 37.2% reported the presence of dark marks lasting 4 months or longer.⁵ Regardless of the severity of the acne, treatment should be initiated as tolerated in those with PIH. Adolescent acne patients with skin of color may develop PIH that is more severe and longer lasting than the acne itself.

The foundation for treatment of acne in adolescent skin of color patients is the same as those without skin of color, including topical retinoids, topical antibiotics, oral antibiotics, and isotretinoin when needed. Topical tretinoin, adapalene, azelaic acid, and tazarotene not only treat acne but also are a valuable part of the treatment armamentarium for PIH. Several studies in adults with skin of color have demonstrated improvement of PIH from the use of topical retinoids alone.^8-10 Despite wanting to treat the acne aggressively, special guidance should be given to prevent retinoid dermatitis, which may lead to PIH.¹⁰ Demonstrating the application of the topical acne medications, discussing how to avoid potential side effects, and giving permission to skip applications, if needed, may empower families to make adjustments between visits to limit irritation that might prompt further PIH. Incorporating α-hydroxy acid–based cleansers, α-hydroxy acid–based chemical peels, or salicylic acid chemical peels may be warranted in the setting of intense PIH. Selecting treatments that not only help the inflammatory disease leading to the PIH but also can help improve the pigmentation are preferred; however, the risks and benefits have to be weighed because many treatments that work well for PIH also may cause irritation, leading to new or worsening PIH.

Arthropod Bites
Arthropod bites cause inflamed pruritic papules and nodules, and the resulting PIH in those with darker skin types may be quite dramatic. Parents/guardians should be instructed to have a low-potency topical corticosteroid on hand to use on bites for a few days when they appear, which will not only help with the inflammation associated with the bite but also will help decrease pruritus and subsequently skin injury from scratching. In homes with pets, checking animals routinely for fleas and other infestations is helpful. In the setting of repeated arthropod bites in the spring and summer, applying bug repellant with 10% to 30% DEET (N,N-diethyl-meta-toluamide) on the child’s clothing and exposed body areas before playing outside or in the morning before school or camp may prevent some bites. There are DEET alternatives, such as picaridin, that may be used. Product instructions should be followed when using insect repellants in the pediatric population.¹¹

PIH Management Strategies

Gentle Skin Care Routine
There are misconceptions that areas of hyperpigmentation on the skin are caused by dirt and that scrubbing the skin harder may help to lighten the affected areas. Parents/guardians may report that the child’s skin looks dirty or, in the setting of acne, view dirt as the cause of the skin condition, which may prompt the patient to scrub the skin and the friction further worsens the PIH. Use of daily gentle cleansers and moisturizers is advised to keep the skin moisturized and free of further potential irritation and dryness that may prompt scratching or flares of the underlying condition.

Photoprotection
During the treatment course for PIH, using sun protection is helpful to prevent further darkening of the PIH areas. Sun protection may be in the form of broad-spectrum sunscreen, hats, or sun-protective clothing. Patients should be encouraged to apply sunscreen daily and to reapply every 2 hours and after water-based activities.¹² For pediatric and adolescent populations, practicing sun-protective behaviors before school or outdoor activities also should be advised, as many families only think about sun protection in the setting of sunny vacation activities. Research has demonstrated that individuals with skin of color may not realize that they can be affected by skin cancer,¹³ thus they may not have any experience selecting, applying, or regularly using sunscreens. Products that do not leave a white hue on the skin are suggested for adolescents who may be sensitive about their appearance following sunscreen application.

Skin Lightening Treatments

Although the most important therapy for PIH is to treat the underlying inflammatory conditions, some parents/guardians may desire additional options due to the extent of involvement of the PIH, its psychological impact on the child, or adverse effect on the child’s quality of life.¹⁴ In adolescents, incorporating an α-hydroxy acid–based cleanser, glycolic acid chemical peels, salicylic acid chemical peels, and topical cosmeceuticals may be warranted in the setting of intense PIH and acne. However, irritation may lead to further dyspigmentation.

Topical ammonium lactate 12% is lactic acid neutralized with ammonium hydroxide that is formulated as a lotion or a cream. It is used to hydrate dry skin and may decrease corneocyte cohesion.¹⁵ Topical ammonium lactate also has been used anecdotally for PIH on the body during periods of watchful waiting.

Topical hydroquinone, the gold standard for treating hyperpigmentation,^3,16 is not approved in children, but some parents/guardians elect to utilize hydroquinone off label to accelerate the clearing of distressing PIH in adolescents. Careful consideration including a discussion of potential risks and alternatives (eg, watchful waiting) should be highlighted.

In the setting of chronic inflammatory conditions that recur and remit, potentially irritating topical treatments should be used only during periods when symptoms of inflammation such as itching or erythema are absent.

Conclusion

Despite the best management efforts, PIH in some patients with skin of color may be present for months to years. In the pediatric skin of color population, treatment of the underlying inflammatory condition, gentle skin care, use of photoprotection, and time may be all that is needed for PIH resolution. With their parent/guardians’ consent, adolescents distressed by PIH may decide to pursue more aggressive, potentially irritating treatments. Above all, the most important management in the setting of PIH is to treat the underlying inflammatory condition causing the PIH and set reasonable expectations. For challenging cases, pediatric dermatologists with special expertise in treating pediatric and adolescent patients with skin of color may be consulted.

Postnflammatory hyperpigmentation (PIH) is an acquired hypermelanosis that can occur in children and adults following an inflammatory cutaneous disease or trauma. Postinflammatory hyperpigmentation may last for months to even years. Although PIH may occur in all skin types, it is more common and presents with greater severity and intensity in individuals with skin of color. By the year 2050, 1 in 3 US residents is projected to be Hispanic.¹ It is projected that by 2044, non-Hispanic white individuals (all ages) will make up less than 50% of the US population.² Currently, the majority of the US residents younger than 18 years are minorities. The majority minority population in the United States already exists in those younger than 18 years and is predicted to occur in the adult population by 2044.²

Effective treatment options and management strategies for PIH in adults with skin of color have been described in the literature.³ Due to a paucity of research, the approach to management of PIH in children with skin of color has been based on clinical experience and lessons learned from adult patients. This article focuses on management of PIH in pediatric patients with skin of color, which includes black/African American, African-Caribbean, Hispanic, Asian, Pacific Islander, and American Indian individuals.

Underlying Inflammatory Dermatoses Resulting in PIH

There are numerous conditions that may result in PIH, including but not limited to atopic dermatitis (AD), acne, arthropod bites, and injuries to the skin. Postinflammatory hyperpigmentation may have more of a psychological impact than the inciting disease or injury itself. The most important step in the approach to managing PIH is treating the underlying inflammatory condition that caused the pigmentation.

Parents/guardians may report a chief concern of dark spots, manchas (stains), blemishes, or stains on the skin, often with no mention of a coexisting inflammatory dermatosis. Parents/guardians of children with skin of color often have personally experienced PIH and may be determined to shield their children from similar angst associated with the condition. Although physicians may see just another pediatric patient with PIH, the child’s parents/guardians may see a condition that will be readily perceptible during major life events, such as the child’s prom or even his/her wedding day. Promptly diagnosing and instituting early treatment of inflammatory conditions associated with PIH may accelerate resolution and prevent worsening of the pigmentation.³

Select inflammatory dermatoses that are common in children with skin of color and may lead to PIH are highlighted below. Although this list is not comprehensive, the approach and management strategies should prompt creation of plans that keep PIH in mind when treating primary inflammatory skin diseases.

Atopic Dermatitis
Atopic dermatitis may induce PIH or hypopigmentation of the skin in children with skin of color. Developing a plan for AD flare prevention, as well as management of mild, moderate, and severe AD flares, is imperative in pediatric patients. Prevention plans should include gentle skin care, twice-daily application of emollients to the full body, and reduction of Staphylococcus aureus loads on the skin. The treatment action plan for mild to moderate flares may include topical corticosteroids, immunomodulators, and nonsteroidal agents. Treatment options for severe AD or patients who were unsuccessfully treated with other therapies may include phototherapy, biologics, and methotrexate, among others.⁴ Creating action plans for AD flares is a vital step in the prevention of PIH in patients with skin of color. Additionally, PIH should not be considered a sign of AD treatment failure.

Acne
Acne is a common skin disorder seen in patients with skin of color.⁵ A prospective observational study found that 34.3% of 683 children aged 9 to 14 years in a pediatric ambulatory clinic had acne.⁶ The number of preadolescents with acne is growing. Most cases are not associated with underlying endocrinopathy.⁷ With the growing population of children with skin of color in the United States along with the increasing childhood acne rate and subsequent inherent risk for hyperpigmentation, early acne interventions should be considered in pediatric acne patients with skin of color to reduce the impact of PIH in those at risk.

In a survey study of 313 adult acne patients with skin of color, 37.2% reported the presence of dark marks lasting 4 months or longer.⁵ Regardless of the severity of the acne, treatment should be initiated as tolerated in those with PIH. Adolescent acne patients with skin of color may develop PIH that is more severe and longer lasting than the acne itself.

The foundation for treatment of acne in adolescent skin of color patients is the same as those without skin of color, including topical retinoids, topical antibiotics, oral antibiotics, and isotretinoin when needed. Topical tretinoin, adapalene, azelaic acid, and tazarotene not only treat acne but also are a valuable part of the treatment armamentarium for PIH. Several studies in adults with skin of color have demonstrated improvement of PIH from the use of topical retinoids alone.^8-10 Despite wanting to treat the acne aggressively, special guidance should be given to prevent retinoid dermatitis, which may lead to PIH.¹⁰ Demonstrating the application of the topical acne medications, discussing how to avoid potential side effects, and giving permission to skip applications, if needed, may empower families to make adjustments between visits to limit irritation that might prompt further PIH. Incorporating α-hydroxy acid–based cleansers, α-hydroxy acid–based chemical peels, or salicylic acid chemical peels may be warranted in the setting of intense PIH. Selecting treatments that not only help the inflammatory disease leading to the PIH but also can help improve the pigmentation are preferred; however, the risks and benefits have to be weighed because many treatments that work well for PIH also may cause irritation, leading to new or worsening PIH.

Arthropod Bites
Arthropod bites cause inflamed pruritic papules and nodules, and the resulting PIH in those with darker skin types may be quite dramatic. Parents/guardians should be instructed to have a low-potency topical corticosteroid on hand to use on bites for a few days when they appear, which will not only help with the inflammation associated with the bite but also will help decrease pruritus and subsequently skin injury from scratching. In homes with pets, checking animals routinely for fleas and other infestations is helpful. In the setting of repeated arthropod bites in the spring and summer, applying bug repellant with 10% to 30% DEET (N,N-diethyl-meta-toluamide) on the child’s clothing and exposed body areas before playing outside or in the morning before school or camp may prevent some bites. There are DEET alternatives, such as picaridin, that may be used. Product instructions should be followed when using insect repellants in the pediatric population.¹¹

PIH Management Strategies

Gentle Skin Care Routine
There are misconceptions that areas of hyperpigmentation on the skin are caused by dirt and that scrubbing the skin harder may help to lighten the affected areas. Parents/guardians may report that the child’s skin looks dirty or, in the setting of acne, view dirt as the cause of the skin condition, which may prompt the patient to scrub the skin and the friction further worsens the PIH. Use of daily gentle cleansers and moisturizers is advised to keep the skin moisturized and free of further potential irritation and dryness that may prompt scratching or flares of the underlying condition.

Photoprotection
During the treatment course for PIH, using sun protection is helpful to prevent further darkening of the PIH areas. Sun protection may be in the form of broad-spectrum sunscreen, hats, or sun-protective clothing. Patients should be encouraged to apply sunscreen daily and to reapply every 2 hours and after water-based activities.¹² For pediatric and adolescent populations, practicing sun-protective behaviors before school or outdoor activities also should be advised, as many families only think about sun protection in the setting of sunny vacation activities. Research has demonstrated that individuals with skin of color may not realize that they can be affected by skin cancer,¹³ thus they may not have any experience selecting, applying, or regularly using sunscreens. Products that do not leave a white hue on the skin are suggested for adolescents who may be sensitive about their appearance following sunscreen application.

Skin Lightening Treatments

Although the most important therapy for PIH is to treat the underlying inflammatory conditions, some parents/guardians may desire additional options due to the extent of involvement of the PIH, its psychological impact on the child, or adverse effect on the child’s quality of life.¹⁴ In adolescents, incorporating an α-hydroxy acid–based cleanser, glycolic acid chemical peels, salicylic acid chemical peels, and topical cosmeceuticals may be warranted in the setting of intense PIH and acne. However, irritation may lead to further dyspigmentation.

Topical ammonium lactate 12% is lactic acid neutralized with ammonium hydroxide that is formulated as a lotion or a cream. It is used to hydrate dry skin and may decrease corneocyte cohesion.¹⁵ Topical ammonium lactate also has been used anecdotally for PIH on the body during periods of watchful waiting.

Topical hydroquinone, the gold standard for treating hyperpigmentation,^3,16 is not approved in children, but some parents/guardians elect to utilize hydroquinone off label to accelerate the clearing of distressing PIH in adolescents. Careful consideration including a discussion of potential risks and alternatives (eg, watchful waiting) should be highlighted.

In the setting of chronic inflammatory conditions that recur and remit, potentially irritating topical treatments should be used only during periods when symptoms of inflammation such as itching or erythema are absent.

Conclusion

Despite the best management efforts, PIH in some patients with skin of color may be present for months to years. In the pediatric skin of color population, treatment of the underlying inflammatory condition, gentle skin care, use of photoprotection, and time may be all that is needed for PIH resolution. With their parent/guardians’ consent, adolescents distressed by PIH may decide to pursue more aggressive, potentially irritating treatments. Above all, the most important management in the setting of PIH is to treat the underlying inflammatory condition causing the PIH and set reasonable expectations. For challenging cases, pediatric dermatologists with special expertise in treating pediatric and adolescent patients with skin of color may be consulted.

Psoriasis is a chronic, immune-mediated, inflammatory disease affecting almost 2% of the population.^1-3 It is characterized by patches of raised reddish skin covered by silvery-white scales. Most patients have limited disease (<5% body surface area [BSA] involvement) that can be managed with topical agents.⁴ Topical corticosteroids (TCSs) are considered first-line therapy for mild to moderate disease because of the inflammatory nature of the condition and often are used in conjunction with systemic agents in more severe psoriasis.⁴

As many as 20% to 30% of patients with moderate to severe plaque psoriasis have inadequate disease control.⁵ Several factors may affect patient outcomes; however, drug selection and patient adherence are important given the chronic nature of the disease. A survey of 1200 patients with psoriasis reported nonadherence rates of 73% with topical therapy.⁶ In addition, patients tend to apply less than the recommended dose or abandon treatment altogether if rapid improvement does not occur^7,8; it is not uncommon for patients with psoriasis to mistakenly believe treatment will improve their condition within 1 to 2 weeks.⁹ Patient satisfaction with topical treatments is low, partly because of these false expectations and formulation issues. Treatments can be greasy and sticky, with unpleasant odors and the potential to stain clothes and linens.^7,10 Safety concerns with TCSs also limit their consecutive use beyond 2 to 4 weeks, which is not ideal for a disease that requires a long-term management strategy.

A potent/superpotent TCS that is administered once daily and has a safety profile that affords longer-term, once-daily treatment in an aesthetically pleasing formulation would seem ideal. Herein, we investigate the safety and tolerability of a novel low-concentration (0.01%) lotion formulation of halobetasol propionate (HP), reporting on the pooled data from 2 phase 3 clinical studies in participants with moderate to severe psoriasis.

METHODS
Study Design

We conducted 2 multicenter, double-blind, randomized, parallel-group phase 3 studies to assess the safety, tolerability, and efficacy of HP lotion 0.01% in participants with a clinical diagnosis of moderate to severe psoriasis with an investigator global assessment (IGA) score of 3 or 4 and an affected BSA of 3% to 12%. Participants were randomized (2:1) to receive HP lotion or vehicle applied topically to the affected area once daily for 8 weeks.

Inclusion and Exclusion Criteria
The studies included individuals of either sex aged 18 years or older. A target lesion was defined primarily to assess signs of psoriasis, measuring 16 to 100 cm², with a score of 3 (moderate) or higher for 2 of 3 different psoriasis signs—erythema, plaque elevation, and scaling—and summed score of 8 or higher, with no sign scoring less than 2. Participants who had pustular psoriasis or used phototherapy, photochemotherapy, or systemic psoriasis therapy within the prior 4 weeks or biologics within the prior 3 months, or those who were diagnosed with skin conditions that would interfere with the interpretation of results were excluded from the studies.

Study Oversight
Participants provided written informed consent before study-related procedures were performed, and the protocol and consent were approved by institutional review boards or ethics committees at all investigational sites. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.

Efficacy Assessment

A 5-point scale ranging from 0 (clear) to 4 (severe) was used by the investigator at each study visit to assess the overall psoriasis severity of the treatable areas. Treatment success (the percentage of participants with at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]) was evaluated at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Signs of psoriasis at the target lesion were assessed at each visit using individual 5-point scales ranging from 0 (clear) to 4 (severe). Treatment success was defined as at least a 2-grade improvement from baseline score for each of the key signs—erythema, plaque elevation, and scaling—and reported at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Affected BSA also was evaluated at each visit. In addition, an IGA×BSA composite score was calculated by multiplying the IGA by the BSA (range, 9–48 [eg, maximum IGA=4 and maximum BSA=12]) at each time point. The mean percentage change in IGA×BSA from baseline was calculated for each study visit. Additional end points included the achievement of a 50%, 75%, and 90% or greater reduction from baseline IGA×BSA score—IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90—at week 8.

Safety Assessment

Safety evaluations including adverse events (AEs), local skin reactions (LSRs), vital signs, laboratory evaluations, and physical examinations were performed. Information on reported and observed AEs was obtained at each visit. Routine safety laboratory tests were performed at screening, week 4, and week 8. An abbreviated physical examination was performed at baseline, week 8 (end of treatment), and week 12 (end of study). Treatment areas also were examined by the investigator at baseline and each subsequent visit for the presence or absence of marked known drug-related AEs including skin atrophy, striae, telangiectasia, and folliculitis.

LSR Assessment
Local skin reactions such as itching, dryness, and burning/stinging were evaluated at each study visit using 4-point scales ranging from 0 (clear) to 3 (severe). Given the nature of the disease, the presence of LSRs and symptoms at baseline is commonplace, and as such, these evaluations identified both improvement and any emergent issues.

Statistical Analysis

The primary study goal was to assess differences in treatment efficacy between HP lotion and vehicle with respect to IGA. All statistical processing was performed using SAS unless otherwise stated; statistical tests were 2-sided and performed at the 0.05 level of significance. Markov Chain Monte Carlo multiple imputation was the primary method used to handle missing efficacy data. No imputations were made for missing safety data. All participants were randomized, and the dispensed study drug was included in the intention-to-treat analysis set. This analysis was considered primary for the evaluation of efficacy. Data were analyzed using Cochran-Mantel-Haenszel tests, stratified by analysis center.

Body surface area data were analyzed in a post hoc analysis of covariance with factors of treatment and analysis center and baseline BSA as a covariate. P values for comparisons of percentage change in IGA×BSA were derived from a Wilcoxon rank sum test. For IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90, P values were derived from a Cochran-Mantel-Haenszel test. Last observation carried forward was used to impute data for IGA and BSA through week 8 prior to analysis.

The primary safety analysis was conducted at week 8 using the safety analysis set, which included all participants who were randomized, received at least 1 confirmed dose of the study drug, and had at least 1 postbaseline safety assessment. Adverse events were recorded and classified using the Medical Dictionary for Regulatory Activities (MedDRA, Version 18.0). A post hoc Wilcoxon rank sum test was conducted to compare itching, dryness, and burning/stinging scores at week 8 for HP lotion versus vehicle.

RESULTS
Participant Disposition

Overall, 430 participants were randomized (2:1) to HP lotion (n=285) or vehicle (n=145)(eFigure 1) and included in the intention-to-treat population. Across the 2 studies, 93.3% (n=266) of participants treated with HP lotion and 89.7% (n=130) of participants treated with vehicle completed treatment. The main reasons for study discontinuation with HP lotion were lost to follow-up (3.2%; n=9), participant request (1.8%; n=5), and AEs (1.4%; n=4). Participant request (4.8%; n=7), lost to follow-up (4.1%; n=6), and AEs (1.4%; n=2) also were the main reasons for treatment discontinuation in the vehicle arm.

A total of 426 participants were included in the safety population, with no postbaseline safety evaluation in 4 participants.

Baseline Participant Demographics
Demographic data were comparable across the 2 studies. The mean age (SD) was 52.6 (14.13) years. Overall, the majority of participants were male (58.8%; n=253) and white (86.5%; n=372)(eTable 1).

Efficacy Evaluation

IGA of Disease Severity
Halobetasol propionate lotion was consistently more effective than its vehicle in achieving treatment success (at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]). Halobetasol propionate lotion demonstrated statistically significant superiority over vehicle as early as week 2 (P=.003). By week 8, 37.43% of participants in the HP lotion group achieved treatment success compared with 10.03% in the vehicle group (P<.001)(Figure 1).

Overall, 39% of participants who had moderate disease (IGA score, 3) at baseline were treatment successes with HP lotion at week 8 compared with 11.53% of participants treated with vehicle; 27.97% of participants with severe disease (IGA score, 4) were treatment successes, with at least a 3-grade improvement in IGA. No participants with severe psoriasis who were treated with vehicle achieved treatment success at week 8. Efficacy was similar in female and male participants, allowing for vehicle effects.

Severity of Signs of Psoriasis (Erythema, Plaque Elevation, and Scaling) at Target Lesion Site
Halobetasol propionate lotion was statistically superior to vehicle in reducing the psoriasis signs of erythema, plaque elevation, and scaling at the target lesion from week 2. At week 8, treatment success (at least a 2-grade improvement from baseline) was achieved by 51.48% (erythema), 57.64% (plaque elevation), and 58.98% (scaling) of participants compared with 17.85%, 23.61%, and 22.82%, respectively, with vehicle (all P<.001)(Figure 2).

Safety Evaluation

Adverse event reports were low and similar between the active and vehicle groups. Overall, 61 participants (21.5%) treated with HP lotion reported AEs compared with 34 participants (23.9%) treated with vehicle (Table). The majority of participants treated with HP lotion (90.2%) had AEs that were mild or moderate. There was 1 AE of telangiectasia, not considered treatment related. There were 5 treatment-related AEs for HP lotion, all at the application site: dermatitis (0.7%; n=2), infection (0.4%; n=1), pruritus (0.4%; n=1), and discoloration (0.4%; n=1). There were no AE reports of skin atrophy or folliculitis.

Local Skin Reactions
Most LSRs at baseline were mild to moderate in severity. Itching was the most common, present in 76.8% of participants. Participant-reported burning/stinging was less common, reported by 40.6% of participants. Investigator-reported dryness was noted in 65.7% of participants. There was a rapid improvement in participant-reported itching as early as week 2 that was sustained to the end of the studies, with more gradual improvements in skin dryness and burning/stinging.

COMMENT

Plaque psoriasis is a chronic condition. The rationale behind the development of HP lotion 0.01% was to provide optimal topical treatment of moderate to severe psoriasis, allowing for the potential of prolonged use beyond the 2-week consecutive use normally applied to HP cream 0.05% in a light, once-daily, aesthetically pleasing lotion formulation that patients would prefer.

Treatment success was rapid and achieved in more than 37% of participants by week 8, with significant improvements in psoriasis signs and symptoms (erythema, plaque elevation, and scaling) compared with vehicle. However, IGA does not consider BSA involvement, a key aspect of disease severity,^11,12 and improvements in psoriasis signs of erythema, plaque elevation, and scaling were only assessed at the target lesion. Recently, the product of the IGA and BSA involvement (IGA×BSA) has been proposed as a simple alternative for assessing response to therapy that has been consistently shown to be highly correlated with the psoriasis area and severity index.^13-19 Halobetasol propionate lotion 0.01% achieved a 50% reduction in IGA×BSA score by week 8. This efficacy compares well with results reported with apremilast in patients with moderate plaque psoriasis.²⁰

Achieving clinically meaningful outcomes is an important aspect of disease management, especially in psoriasis with its disease burden and detriment to quality of life. It has been suggested that achieving a 75% or greater reduction from baseline IGA×BSA score (IGA×BSA-75) is an appropriate clinical goal.²⁰ In our investigation, IGA×BSA-75 was achieved by 39% of participants treated with HP lotion by week 8, which again compares favorably with 35% of participants in the apremilast study who achieved IGA×BSA-75 at week 16.²⁰

Physicians continue to have long-term safety concerns with TCSs,^4,11,12 participants remain concerned about the risk for skin thinning,¹³ and product labelling restricts HP cream 0.05% consecutive use to 2 weeks. In clinical experience, HP cream 0.05% is well tolerated, with potential local AEs similar to those experienced with other superpotent TCSs. In short-term clinical trials, local AEs at the site of application were reported in up to 13% of patients^21-26; itching, burning, or stinging were the most common local AEs (reported in 4.4% of patients).²⁷

There were minimal safety concerns in our 2 studies using an 8-week, once-daily treatment regimen with HP lotion 0.01%. Local AEs at the application site were reported in less than 1% of participants. Baseline itching, dryness, and burning/stinging all improved with treatment.

CONCLUSION

Halobetasol propionate lotion 0.01% provides rapid improvement in disease severity. Halobetasol propionate lotion was consistently more effective than vehicle in achieving treatment success; reducing the BSA affected by the disease; reducing erythema, plaque elevation, and scaling at the target lesion; and improving IGA×BSA score over 8 weeks, which is a realistic time frame to see improvement in psoriasis with a topical steroid. There were minimal safety concerns with prolonged use. Halobetasol propionate lotion may provide an effective and reasonable treatment option in patients with moderate to severe plaque psoriasis.

Acknowledgment
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of this article. Ortho Dermatologics funded Mr. Bulley’s activities pertaining to this article.

Psoriasis is a chronic, immune-mediated, inflammatory disease affecting almost 2% of the population.^1-3 It is characterized by patches of raised reddish skin covered by silvery-white scales. Most patients have limited disease (<5% body surface area [BSA] involvement) that can be managed with topical agents.⁴ Topical corticosteroids (TCSs) are considered first-line therapy for mild to moderate disease because of the inflammatory nature of the condition and often are used in conjunction with systemic agents in more severe psoriasis.⁴

As many as 20% to 30% of patients with moderate to severe plaque psoriasis have inadequate disease control.⁵ Several factors may affect patient outcomes; however, drug selection and patient adherence are important given the chronic nature of the disease. A survey of 1200 patients with psoriasis reported nonadherence rates of 73% with topical therapy.⁶ In addition, patients tend to apply less than the recommended dose or abandon treatment altogether if rapid improvement does not occur^7,8; it is not uncommon for patients with psoriasis to mistakenly believe treatment will improve their condition within 1 to 2 weeks.⁹ Patient satisfaction with topical treatments is low, partly because of these false expectations and formulation issues. Treatments can be greasy and sticky, with unpleasant odors and the potential to stain clothes and linens.^7,10 Safety concerns with TCSs also limit their consecutive use beyond 2 to 4 weeks, which is not ideal for a disease that requires a long-term management strategy.

A potent/superpotent TCS that is administered once daily and has a safety profile that affords longer-term, once-daily treatment in an aesthetically pleasing formulation would seem ideal. Herein, we investigate the safety and tolerability of a novel low-concentration (0.01%) lotion formulation of halobetasol propionate (HP), reporting on the pooled data from 2 phase 3 clinical studies in participants with moderate to severe psoriasis.

METHODS
Study Design

We conducted 2 multicenter, double-blind, randomized, parallel-group phase 3 studies to assess the safety, tolerability, and efficacy of HP lotion 0.01% in participants with a clinical diagnosis of moderate to severe psoriasis with an investigator global assessment (IGA) score of 3 or 4 and an affected BSA of 3% to 12%. Participants were randomized (2:1) to receive HP lotion or vehicle applied topically to the affected area once daily for 8 weeks.

Inclusion and Exclusion Criteria
The studies included individuals of either sex aged 18 years or older. A target lesion was defined primarily to assess signs of psoriasis, measuring 16 to 100 cm², with a score of 3 (moderate) or higher for 2 of 3 different psoriasis signs—erythema, plaque elevation, and scaling—and summed score of 8 or higher, with no sign scoring less than 2. Participants who had pustular psoriasis or used phototherapy, photochemotherapy, or systemic psoriasis therapy within the prior 4 weeks or biologics within the prior 3 months, or those who were diagnosed with skin conditions that would interfere with the interpretation of results were excluded from the studies.

Study Oversight
Participants provided written informed consent before study-related procedures were performed, and the protocol and consent were approved by institutional review boards or ethics committees at all investigational sites. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.

Efficacy Assessment

A 5-point scale ranging from 0 (clear) to 4 (severe) was used by the investigator at each study visit to assess the overall psoriasis severity of the treatable areas. Treatment success (the percentage of participants with at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]) was evaluated at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Signs of psoriasis at the target lesion were assessed at each visit using individual 5-point scales ranging from 0 (clear) to 4 (severe). Treatment success was defined as at least a 2-grade improvement from baseline score for each of the key signs—erythema, plaque elevation, and scaling—and reported at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Affected BSA also was evaluated at each visit. In addition, an IGA×BSA composite score was calculated by multiplying the IGA by the BSA (range, 9–48 [eg, maximum IGA=4 and maximum BSA=12]) at each time point. The mean percentage change in IGA×BSA from baseline was calculated for each study visit. Additional end points included the achievement of a 50%, 75%, and 90% or greater reduction from baseline IGA×BSA score—IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90—at week 8.

Safety Assessment

Safety evaluations including adverse events (AEs), local skin reactions (LSRs), vital signs, laboratory evaluations, and physical examinations were performed. Information on reported and observed AEs was obtained at each visit. Routine safety laboratory tests were performed at screening, week 4, and week 8. An abbreviated physical examination was performed at baseline, week 8 (end of treatment), and week 12 (end of study). Treatment areas also were examined by the investigator at baseline and each subsequent visit for the presence or absence of marked known drug-related AEs including skin atrophy, striae, telangiectasia, and folliculitis.

LSR Assessment
Local skin reactions such as itching, dryness, and burning/stinging were evaluated at each study visit using 4-point scales ranging from 0 (clear) to 3 (severe). Given the nature of the disease, the presence of LSRs and symptoms at baseline is commonplace, and as such, these evaluations identified both improvement and any emergent issues.

Statistical Analysis

The primary study goal was to assess differences in treatment efficacy between HP lotion and vehicle with respect to IGA. All statistical processing was performed using SAS unless otherwise stated; statistical tests were 2-sided and performed at the 0.05 level of significance. Markov Chain Monte Carlo multiple imputation was the primary method used to handle missing efficacy data. No imputations were made for missing safety data. All participants were randomized, and the dispensed study drug was included in the intention-to-treat analysis set. This analysis was considered primary for the evaluation of efficacy. Data were analyzed using Cochran-Mantel-Haenszel tests, stratified by analysis center.

Body surface area data were analyzed in a post hoc analysis of covariance with factors of treatment and analysis center and baseline BSA as a covariate. P values for comparisons of percentage change in IGA×BSA were derived from a Wilcoxon rank sum test. For IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90, P values were derived from a Cochran-Mantel-Haenszel test. Last observation carried forward was used to impute data for IGA and BSA through week 8 prior to analysis.

The primary safety analysis was conducted at week 8 using the safety analysis set, which included all participants who were randomized, received at least 1 confirmed dose of the study drug, and had at least 1 postbaseline safety assessment. Adverse events were recorded and classified using the Medical Dictionary for Regulatory Activities (MedDRA, Version 18.0). A post hoc Wilcoxon rank sum test was conducted to compare itching, dryness, and burning/stinging scores at week 8 for HP lotion versus vehicle.

RESULTS
Participant Disposition

Overall, 430 participants were randomized (2:1) to HP lotion (n=285) or vehicle (n=145)(eFigure 1) and included in the intention-to-treat population. Across the 2 studies, 93.3% (n=266) of participants treated with HP lotion and 89.7% (n=130) of participants treated with vehicle completed treatment. The main reasons for study discontinuation with HP lotion were lost to follow-up (3.2%; n=9), participant request (1.8%; n=5), and AEs (1.4%; n=4). Participant request (4.8%; n=7), lost to follow-up (4.1%; n=6), and AEs (1.4%; n=2) also were the main reasons for treatment discontinuation in the vehicle arm.

A total of 426 participants were included in the safety population, with no postbaseline safety evaluation in 4 participants.

Baseline Participant Demographics
Demographic data were comparable across the 2 studies. The mean age (SD) was 52.6 (14.13) years. Overall, the majority of participants were male (58.8%; n=253) and white (86.5%; n=372)(eTable 1).

Efficacy Evaluation

IGA of Disease Severity
Halobetasol propionate lotion was consistently more effective than its vehicle in achieving treatment success (at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]). Halobetasol propionate lotion demonstrated statistically significant superiority over vehicle as early as week 2 (P=.003). By week 8, 37.43% of participants in the HP lotion group achieved treatment success compared with 10.03% in the vehicle group (P<.001)(Figure 1).

Overall, 39% of participants who had moderate disease (IGA score, 3) at baseline were treatment successes with HP lotion at week 8 compared with 11.53% of participants treated with vehicle; 27.97% of participants with severe disease (IGA score, 4) were treatment successes, with at least a 3-grade improvement in IGA. No participants with severe psoriasis who were treated with vehicle achieved treatment success at week 8. Efficacy was similar in female and male participants, allowing for vehicle effects.

Severity of Signs of Psoriasis (Erythema, Plaque Elevation, and Scaling) at Target Lesion Site
Halobetasol propionate lotion was statistically superior to vehicle in reducing the psoriasis signs of erythema, plaque elevation, and scaling at the target lesion from week 2. At week 8, treatment success (at least a 2-grade improvement from baseline) was achieved by 51.48% (erythema), 57.64% (plaque elevation), and 58.98% (scaling) of participants compared with 17.85%, 23.61%, and 22.82%, respectively, with vehicle (all P<.001)(Figure 2).

Safety Evaluation

Adverse event reports were low and similar between the active and vehicle groups. Overall, 61 participants (21.5%) treated with HP lotion reported AEs compared with 34 participants (23.9%) treated with vehicle (Table). The majority of participants treated with HP lotion (90.2%) had AEs that were mild or moderate. There was 1 AE of telangiectasia, not considered treatment related. There were 5 treatment-related AEs for HP lotion, all at the application site: dermatitis (0.7%; n=2), infection (0.4%; n=1), pruritus (0.4%; n=1), and discoloration (0.4%; n=1). There were no AE reports of skin atrophy or folliculitis.

Local Skin Reactions
Most LSRs at baseline were mild to moderate in severity. Itching was the most common, present in 76.8% of participants. Participant-reported burning/stinging was less common, reported by 40.6% of participants. Investigator-reported dryness was noted in 65.7% of participants. There was a rapid improvement in participant-reported itching as early as week 2 that was sustained to the end of the studies, with more gradual improvements in skin dryness and burning/stinging.

COMMENT

Plaque psoriasis is a chronic condition. The rationale behind the development of HP lotion 0.01% was to provide optimal topical treatment of moderate to severe psoriasis, allowing for the potential of prolonged use beyond the 2-week consecutive use normally applied to HP cream 0.05% in a light, once-daily, aesthetically pleasing lotion formulation that patients would prefer.

Treatment success was rapid and achieved in more than 37% of participants by week 8, with significant improvements in psoriasis signs and symptoms (erythema, plaque elevation, and scaling) compared with vehicle. However, IGA does not consider BSA involvement, a key aspect of disease severity,^11,12 and improvements in psoriasis signs of erythema, plaque elevation, and scaling were only assessed at the target lesion. Recently, the product of the IGA and BSA involvement (IGA×BSA) has been proposed as a simple alternative for assessing response to therapy that has been consistently shown to be highly correlated with the psoriasis area and severity index.^13-19 Halobetasol propionate lotion 0.01% achieved a 50% reduction in IGA×BSA score by week 8. This efficacy compares well with results reported with apremilast in patients with moderate plaque psoriasis.²⁰

Achieving clinically meaningful outcomes is an important aspect of disease management, especially in psoriasis with its disease burden and detriment to quality of life. It has been suggested that achieving a 75% or greater reduction from baseline IGA×BSA score (IGA×BSA-75) is an appropriate clinical goal.²⁰ In our investigation, IGA×BSA-75 was achieved by 39% of participants treated with HP lotion by week 8, which again compares favorably with 35% of participants in the apremilast study who achieved IGA×BSA-75 at week 16.²⁰

Physicians continue to have long-term safety concerns with TCSs,^4,11,12 participants remain concerned about the risk for skin thinning,¹³ and product labelling restricts HP cream 0.05% consecutive use to 2 weeks. In clinical experience, HP cream 0.05% is well tolerated, with potential local AEs similar to those experienced with other superpotent TCSs. In short-term clinical trials, local AEs at the site of application were reported in up to 13% of patients^21-26; itching, burning, or stinging were the most common local AEs (reported in 4.4% of patients).²⁷

There were minimal safety concerns in our 2 studies using an 8-week, once-daily treatment regimen with HP lotion 0.01%. Local AEs at the application site were reported in less than 1% of participants. Baseline itching, dryness, and burning/stinging all improved with treatment.

CONCLUSION

Halobetasol propionate lotion 0.01% provides rapid improvement in disease severity. Halobetasol propionate lotion was consistently more effective than vehicle in achieving treatment success; reducing the BSA affected by the disease; reducing erythema, plaque elevation, and scaling at the target lesion; and improving IGA×BSA score over 8 weeks, which is a realistic time frame to see improvement in psoriasis with a topical steroid. There were minimal safety concerns with prolonged use. Halobetasol propionate lotion may provide an effective and reasonable treatment option in patients with moderate to severe plaque psoriasis.

Acknowledgment
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of this article. Ortho Dermatologics funded Mr. Bulley’s activities pertaining to this article.

Psoriasis is a chronic, immune-mediated, inflammatory disease affecting almost 2% of the population.^1-3 It is characterized by patches of raised reddish skin covered by silvery-white scales. Most patients have limited disease (<5% body surface area [BSA] involvement) that can be managed with topical agents.⁴ Topical corticosteroids (TCSs) are considered first-line therapy for mild to moderate disease because of the inflammatory nature of the condition and often are used in conjunction with systemic agents in more severe psoriasis.⁴

As many as 20% to 30% of patients with moderate to severe plaque psoriasis have inadequate disease control.⁵ Several factors may affect patient outcomes; however, drug selection and patient adherence are important given the chronic nature of the disease. A survey of 1200 patients with psoriasis reported nonadherence rates of 73% with topical therapy.⁶ In addition, patients tend to apply less than the recommended dose or abandon treatment altogether if rapid improvement does not occur^7,8; it is not uncommon for patients with psoriasis to mistakenly believe treatment will improve their condition within 1 to 2 weeks.⁹ Patient satisfaction with topical treatments is low, partly because of these false expectations and formulation issues. Treatments can be greasy and sticky, with unpleasant odors and the potential to stain clothes and linens.^7,10 Safety concerns with TCSs also limit their consecutive use beyond 2 to 4 weeks, which is not ideal for a disease that requires a long-term management strategy.

A potent/superpotent TCS that is administered once daily and has a safety profile that affords longer-term, once-daily treatment in an aesthetically pleasing formulation would seem ideal. Herein, we investigate the safety and tolerability of a novel low-concentration (0.01%) lotion formulation of halobetasol propionate (HP), reporting on the pooled data from 2 phase 3 clinical studies in participants with moderate to severe psoriasis.

METHODS
Study Design

We conducted 2 multicenter, double-blind, randomized, parallel-group phase 3 studies to assess the safety, tolerability, and efficacy of HP lotion 0.01% in participants with a clinical diagnosis of moderate to severe psoriasis with an investigator global assessment (IGA) score of 3 or 4 and an affected BSA of 3% to 12%. Participants were randomized (2:1) to receive HP lotion or vehicle applied topically to the affected area once daily for 8 weeks.

Inclusion and Exclusion Criteria
The studies included individuals of either sex aged 18 years or older. A target lesion was defined primarily to assess signs of psoriasis, measuring 16 to 100 cm², with a score of 3 (moderate) or higher for 2 of 3 different psoriasis signs—erythema, plaque elevation, and scaling—and summed score of 8 or higher, with no sign scoring less than 2. Participants who had pustular psoriasis or used phototherapy, photochemotherapy, or systemic psoriasis therapy within the prior 4 weeks or biologics within the prior 3 months, or those who were diagnosed with skin conditions that would interfere with the interpretation of results were excluded from the studies.

Study Oversight
Participants provided written informed consent before study-related procedures were performed, and the protocol and consent were approved by institutional review boards or ethics committees at all investigational sites. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.

Efficacy Assessment

A 5-point scale ranging from 0 (clear) to 4 (severe) was used by the investigator at each study visit to assess the overall psoriasis severity of the treatable areas. Treatment success (the percentage of participants with at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]) was evaluated at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Signs of psoriasis at the target lesion were assessed at each visit using individual 5-point scales ranging from 0 (clear) to 4 (severe). Treatment success was defined as at least a 2-grade improvement from baseline score for each of the key signs—erythema, plaque elevation, and scaling—and reported at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Affected BSA also was evaluated at each visit. In addition, an IGA×BSA composite score was calculated by multiplying the IGA by the BSA (range, 9–48 [eg, maximum IGA=4 and maximum BSA=12]) at each time point. The mean percentage change in IGA×BSA from baseline was calculated for each study visit. Additional end points included the achievement of a 50%, 75%, and 90% or greater reduction from baseline IGA×BSA score—IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90—at week 8.

Safety Assessment

Safety evaluations including adverse events (AEs), local skin reactions (LSRs), vital signs, laboratory evaluations, and physical examinations were performed. Information on reported and observed AEs was obtained at each visit. Routine safety laboratory tests were performed at screening, week 4, and week 8. An abbreviated physical examination was performed at baseline, week 8 (end of treatment), and week 12 (end of study). Treatment areas also were examined by the investigator at baseline and each subsequent visit for the presence or absence of marked known drug-related AEs including skin atrophy, striae, telangiectasia, and folliculitis.

LSR Assessment
Local skin reactions such as itching, dryness, and burning/stinging were evaluated at each study visit using 4-point scales ranging from 0 (clear) to 3 (severe). Given the nature of the disease, the presence of LSRs and symptoms at baseline is commonplace, and as such, these evaluations identified both improvement and any emergent issues.

Statistical Analysis

The primary study goal was to assess differences in treatment efficacy between HP lotion and vehicle with respect to IGA. All statistical processing was performed using SAS unless otherwise stated; statistical tests were 2-sided and performed at the 0.05 level of significance. Markov Chain Monte Carlo multiple imputation was the primary method used to handle missing efficacy data. No imputations were made for missing safety data. All participants were randomized, and the dispensed study drug was included in the intention-to-treat analysis set. This analysis was considered primary for the evaluation of efficacy. Data were analyzed using Cochran-Mantel-Haenszel tests, stratified by analysis center.

Body surface area data were analyzed in a post hoc analysis of covariance with factors of treatment and analysis center and baseline BSA as a covariate. P values for comparisons of percentage change in IGA×BSA were derived from a Wilcoxon rank sum test. For IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90, P values were derived from a Cochran-Mantel-Haenszel test. Last observation carried forward was used to impute data for IGA and BSA through week 8 prior to analysis.

The primary safety analysis was conducted at week 8 using the safety analysis set, which included all participants who were randomized, received at least 1 confirmed dose of the study drug, and had at least 1 postbaseline safety assessment. Adverse events were recorded and classified using the Medical Dictionary for Regulatory Activities (MedDRA, Version 18.0). A post hoc Wilcoxon rank sum test was conducted to compare itching, dryness, and burning/stinging scores at week 8 for HP lotion versus vehicle.

RESULTS
Participant Disposition

Overall, 430 participants were randomized (2:1) to HP lotion (n=285) or vehicle (n=145)(eFigure 1) and included in the intention-to-treat population. Across the 2 studies, 93.3% (n=266) of participants treated with HP lotion and 89.7% (n=130) of participants treated with vehicle completed treatment. The main reasons for study discontinuation with HP lotion were lost to follow-up (3.2%; n=9), participant request (1.8%; n=5), and AEs (1.4%; n=4). Participant request (4.8%; n=7), lost to follow-up (4.1%; n=6), and AEs (1.4%; n=2) also were the main reasons for treatment discontinuation in the vehicle arm.

A total of 426 participants were included in the safety population, with no postbaseline safety evaluation in 4 participants.

Baseline Participant Demographics
Demographic data were comparable across the 2 studies. The mean age (SD) was 52.6 (14.13) years. Overall, the majority of participants were male (58.8%; n=253) and white (86.5%; n=372)(eTable 1).

Efficacy Evaluation

IGA of Disease Severity
Halobetasol propionate lotion was consistently more effective than its vehicle in achieving treatment success (at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]). Halobetasol propionate lotion demonstrated statistically significant superiority over vehicle as early as week 2 (P=.003). By week 8, 37.43% of participants in the HP lotion group achieved treatment success compared with 10.03% in the vehicle group (P<.001)(Figure 1).

Overall, 39% of participants who had moderate disease (IGA score, 3) at baseline were treatment successes with HP lotion at week 8 compared with 11.53% of participants treated with vehicle; 27.97% of participants with severe disease (IGA score, 4) were treatment successes, with at least a 3-grade improvement in IGA. No participants with severe psoriasis who were treated with vehicle achieved treatment success at week 8. Efficacy was similar in female and male participants, allowing for vehicle effects.

Severity of Signs of Psoriasis (Erythema, Plaque Elevation, and Scaling) at Target Lesion Site
Halobetasol propionate lotion was statistically superior to vehicle in reducing the psoriasis signs of erythema, plaque elevation, and scaling at the target lesion from week 2. At week 8, treatment success (at least a 2-grade improvement from baseline) was achieved by 51.48% (erythema), 57.64% (plaque elevation), and 58.98% (scaling) of participants compared with 17.85%, 23.61%, and 22.82%, respectively, with vehicle (all P<.001)(Figure 2).

Safety Evaluation

Adverse event reports were low and similar between the active and vehicle groups. Overall, 61 participants (21.5%) treated with HP lotion reported AEs compared with 34 participants (23.9%) treated with vehicle (Table). The majority of participants treated with HP lotion (90.2%) had AEs that were mild or moderate. There was 1 AE of telangiectasia, not considered treatment related. There were 5 treatment-related AEs for HP lotion, all at the application site: dermatitis (0.7%; n=2), infection (0.4%; n=1), pruritus (0.4%; n=1), and discoloration (0.4%; n=1). There were no AE reports of skin atrophy or folliculitis.

Local Skin Reactions
Most LSRs at baseline were mild to moderate in severity. Itching was the most common, present in 76.8% of participants. Participant-reported burning/stinging was less common, reported by 40.6% of participants. Investigator-reported dryness was noted in 65.7% of participants. There was a rapid improvement in participant-reported itching as early as week 2 that was sustained to the end of the studies, with more gradual improvements in skin dryness and burning/stinging.

COMMENT

Plaque psoriasis is a chronic condition. The rationale behind the development of HP lotion 0.01% was to provide optimal topical treatment of moderate to severe psoriasis, allowing for the potential of prolonged use beyond the 2-week consecutive use normally applied to HP cream 0.05% in a light, once-daily, aesthetically pleasing lotion formulation that patients would prefer.

Treatment success was rapid and achieved in more than 37% of participants by week 8, with significant improvements in psoriasis signs and symptoms (erythema, plaque elevation, and scaling) compared with vehicle. However, IGA does not consider BSA involvement, a key aspect of disease severity,^11,12 and improvements in psoriasis signs of erythema, plaque elevation, and scaling were only assessed at the target lesion. Recently, the product of the IGA and BSA involvement (IGA×BSA) has been proposed as a simple alternative for assessing response to therapy that has been consistently shown to be highly correlated with the psoriasis area and severity index.^13-19 Halobetasol propionate lotion 0.01% achieved a 50% reduction in IGA×BSA score by week 8. This efficacy compares well with results reported with apremilast in patients with moderate plaque psoriasis.²⁰

Achieving clinically meaningful outcomes is an important aspect of disease management, especially in psoriasis with its disease burden and detriment to quality of life. It has been suggested that achieving a 75% or greater reduction from baseline IGA×BSA score (IGA×BSA-75) is an appropriate clinical goal.²⁰ In our investigation, IGA×BSA-75 was achieved by 39% of participants treated with HP lotion by week 8, which again compares favorably with 35% of participants in the apremilast study who achieved IGA×BSA-75 at week 16.²⁰

Physicians continue to have long-term safety concerns with TCSs,^4,11,12 participants remain concerned about the risk for skin thinning,¹³ and product labelling restricts HP cream 0.05% consecutive use to 2 weeks. In clinical experience, HP cream 0.05% is well tolerated, with potential local AEs similar to those experienced with other superpotent TCSs. In short-term clinical trials, local AEs at the site of application were reported in up to 13% of patients^21-26; itching, burning, or stinging were the most common local AEs (reported in 4.4% of patients).²⁷

There were minimal safety concerns in our 2 studies using an 8-week, once-daily treatment regimen with HP lotion 0.01%. Local AEs at the application site were reported in less than 1% of participants. Baseline itching, dryness, and burning/stinging all improved with treatment.

CONCLUSION

Halobetasol propionate lotion 0.01% provides rapid improvement in disease severity. Halobetasol propionate lotion was consistently more effective than vehicle in achieving treatment success; reducing the BSA affected by the disease; reducing erythema, plaque elevation, and scaling at the target lesion; and improving IGA×BSA score over 8 weeks, which is a realistic time frame to see improvement in psoriasis with a topical steroid. There were minimal safety concerns with prolonged use. Halobetasol propionate lotion may provide an effective and reasonable treatment option in patients with moderate to severe plaque psoriasis.

Acknowledgment
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of this article. Ortho Dermatologics funded Mr. Bulley’s activities pertaining to this article.

Adherence to the American Heart Association’s Life’s Simple 7 is associated with lower incidence of peripheral artery disease and less decline in ankle brachial index, according to the results of a retrospective analysis of patients in the Multi-Ethnic Study of Atherosclerosis (MESA) trial.

“These results support the use of LS7 to prevent PAD and decline in ABI in multiple racial/ethnic groups,” according to Jonathan T. Unkart, MD, of the department of medicine and public health, University of California, San Diego, and his colleagues.

MESA recruited 6,814 men and women aged 45-84 years who were free of clinical cardiovascular disease. The cohort comprised 53% women and had the following racial/ethnic composition: 38% non-Hispanic white; 28% African American; 23% Hispanic, and 11% Asian. MESA consisted of six exams, with the baseline exam occurring from 2000 to 2002, including assessment of all LS7 components and PAD assessment using ABI calculated on both left and right sides. The final exam was performed from 2010 to 2012.

As background, the metrics for Life’s Simple 7 consist of total cholesterol, blood pressure, blood glucose, smoking status, body mass index, physical activity, and adherence to a healthy diet score. Each element can be scored 2 points for optimum, 1 for average, and 0 for inadequate. The investigators assessed overall LS7 scores on a continuous 0-14 scale, as well as the overall categorical indications of inadequate, average, and optimum. Cox proportional hazard models were used to assess the association of individual LS7 components by overall LS7 with incident PAD, according to the researchers.

Interactions of race/ethnicity by LS7 score were assessed on a multiplicative scale for both incident PAD and decline in ABI outcomes, adjusted for age, sex, education, and income (Am J Prev Med. 2019;56:262-70).

A total of 5,529 participants had complete LS7 information and met inclusion criteria to assess incident PAD. Over a median follow-up of 9.2 years, 251 (4.5%) participants developed incident PAD and 419 (9.8%) participants had a decline of at least 0.15 in ABI. In addition, each point higher on the continuous LS7 scale was associated with 0.94-fold lower odds of decline in ABI (odds ratio, 0.94; 95% confidence interval, 0.87-0.97; P =.003).

Each point higher on the continuous LS7 scale was associated with a 17% lower rate of incident PAD (HR, 0.83; 95% CI, 0.78-0.88; P less than .001), according to the researchers.

mlesney@mdedge.com

SOURCE: Unkart JT et al. Am J Prev Med 2019;56:262-270.

Adherence to the American Heart Association’s Life’s Simple 7 is associated with lower incidence of peripheral artery disease and less decline in ankle brachial index, according to the results of a retrospective analysis of patients in the Multi-Ethnic Study of Atherosclerosis (MESA) trial.

“These results support the use of LS7 to prevent PAD and decline in ABI in multiple racial/ethnic groups,” according to Jonathan T. Unkart, MD, of the department of medicine and public health, University of California, San Diego, and his colleagues.

MESA recruited 6,814 men and women aged 45-84 years who were free of clinical cardiovascular disease. The cohort comprised 53% women and had the following racial/ethnic composition: 38% non-Hispanic white; 28% African American; 23% Hispanic, and 11% Asian. MESA consisted of six exams, with the baseline exam occurring from 2000 to 2002, including assessment of all LS7 components and PAD assessment using ABI calculated on both left and right sides. The final exam was performed from 2010 to 2012.

As background, the metrics for Life’s Simple 7 consist of total cholesterol, blood pressure, blood glucose, smoking status, body mass index, physical activity, and adherence to a healthy diet score. Each element can be scored 2 points for optimum, 1 for average, and 0 for inadequate. The investigators assessed overall LS7 scores on a continuous 0-14 scale, as well as the overall categorical indications of inadequate, average, and optimum. Cox proportional hazard models were used to assess the association of individual LS7 components by overall LS7 with incident PAD, according to the researchers.

Interactions of race/ethnicity by LS7 score were assessed on a multiplicative scale for both incident PAD and decline in ABI outcomes, adjusted for age, sex, education, and income (Am J Prev Med. 2019;56:262-70).

A total of 5,529 participants had complete LS7 information and met inclusion criteria to assess incident PAD. Over a median follow-up of 9.2 years, 251 (4.5%) participants developed incident PAD and 419 (9.8%) participants had a decline of at least 0.15 in ABI. In addition, each point higher on the continuous LS7 scale was associated with 0.94-fold lower odds of decline in ABI (odds ratio, 0.94; 95% confidence interval, 0.87-0.97; P =.003).

Each point higher on the continuous LS7 scale was associated with a 17% lower rate of incident PAD (HR, 0.83; 95% CI, 0.78-0.88; P less than .001), according to the researchers.

mlesney@mdedge.com

SOURCE: Unkart JT et al. Am J Prev Med 2019;56:262-270.

Adherence to the American Heart Association’s Life’s Simple 7 is associated with lower incidence of peripheral artery disease and less decline in ankle brachial index, according to the results of a retrospective analysis of patients in the Multi-Ethnic Study of Atherosclerosis (MESA) trial.

“These results support the use of LS7 to prevent PAD and decline in ABI in multiple racial/ethnic groups,” according to Jonathan T. Unkart, MD, of the department of medicine and public health, University of California, San Diego, and his colleagues.

MESA recruited 6,814 men and women aged 45-84 years who were free of clinical cardiovascular disease. The cohort comprised 53% women and had the following racial/ethnic composition: 38% non-Hispanic white; 28% African American; 23% Hispanic, and 11% Asian. MESA consisted of six exams, with the baseline exam occurring from 2000 to 2002, including assessment of all LS7 components and PAD assessment using ABI calculated on both left and right sides. The final exam was performed from 2010 to 2012.

As background, the metrics for Life’s Simple 7 consist of total cholesterol, blood pressure, blood glucose, smoking status, body mass index, physical activity, and adherence to a healthy diet score. Each element can be scored 2 points for optimum, 1 for average, and 0 for inadequate. The investigators assessed overall LS7 scores on a continuous 0-14 scale, as well as the overall categorical indications of inadequate, average, and optimum. Cox proportional hazard models were used to assess the association of individual LS7 components by overall LS7 with incident PAD, according to the researchers.

Interactions of race/ethnicity by LS7 score were assessed on a multiplicative scale for both incident PAD and decline in ABI outcomes, adjusted for age, sex, education, and income (Am J Prev Med. 2019;56:262-70).

A total of 5,529 participants had complete LS7 information and met inclusion criteria to assess incident PAD. Over a median follow-up of 9.2 years, 251 (4.5%) participants developed incident PAD and 419 (9.8%) participants had a decline of at least 0.15 in ABI. In addition, each point higher on the continuous LS7 scale was associated with 0.94-fold lower odds of decline in ABI (odds ratio, 0.94; 95% confidence interval, 0.87-0.97; P =.003).

Each point higher on the continuous LS7 scale was associated with a 17% lower rate of incident PAD (HR, 0.83; 95% CI, 0.78-0.88; P less than .001), according to the researchers.

mlesney@mdedge.com

SOURCE: Unkart JT et al. Am J Prev Med 2019;56:262-270.

Statin therapy appears to reduce the risk of major vascular events for patients of all age groups, but there is less evidence that older patients with evidence of occlusive vascular disease benefit from the treatment, according to a recent meta-analysis of 28 trials from the Cholesterol Treatment Trialists’ Collaboration published in The Lancet.

Louise Koenig/MDedge News

Statins are “useful and affordable drug[s] that reduce heart attacks and strokes in older patients. Until now there has been an evidence gap and we wanted to look at their efficacy and safety in older people,” Jordan Fulcher, BSc (Med), MBBS, from the Cholesterol Treatment Trialists’ (CTT) Collaboration and the University of Sydney stated in a press release. “Our analysis indicates that major cardiovascular events were reduced by about a fifth, per mmol/L lower LDL cholesterol, by statin therapy across all age groups. Despite previous concerns, we found no adverse effect on cancer or nonvascular mortality in any age group.”

The researchers examined 186,854 participants from 28 CTT trials undergoing statin therapy, of whom 14,483 (8%) were older than 75 years. Patients were divided into six groups based on age and examined the risk of major cardiovascular events such as stroke, coronary revascularization and major coronary events, as well as the incidence of cancer and vascular mortality.

Among all age groups, there was a significant reduction in major vascular events, with a 21% proportional per 1.0-mmol/L reduction in LDL cholesterol (risk ratio, 0.79; 95% confidence interval, 0.77-0.81) among patients receiving statin therapy or a more intensive statin regimen, and there was a 24% proportional reduction (RR, 0.76; 95% CI, 0.73-0.79) of major coronary events per 1.0-mmol/L reduction in LDL cholesterol, with older age resulting in a lower proportional reduction of major coronary events (P = .009). The researchers also found a proportional reduction of coronary revascularization procedures by 25% (RR, 0.75; 95% CI, 0.73-0.78) and stroke by 16% (RR, 0.84; 95% CI, 0.80-0.89) among patients of any age group receiving statin therapy or more intensive statin regimen, with no significant differences between age groups.

There was a 12% proportional reduction in vascular mortality per 1.0-mmol/L reduction in LDL cholesterol (RR, 0.88; 95% CI, 0.85-0.91), but this statistic did not remain significant after the researchers excluded four trials that included patients with heart failure or who were receiving renal dialysis. After excluding these trials from the overall analysis, the researchers found the smaller proportional reductions persisted for older patients for major coronary events (P = .01) but was no longer significant for major vascular events.

The researchers noted their study was limited by the highly selected patient population, low percentage of patients older than 75 years, including trials with efficacy endpoints where some nonserious adverse events may not have been recorded, and not including some trials in the meta-analysis if they were not part of the CTT.

This study was funded by Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation. The authors have reported personal fees, grants, and consulting fees from Abbott, Aegerion, Amgen, Arisaph, AstraZeneca, Bayer, Beckmann, Berlin-Chemie, Boehringer Ingelheim, Daiichi Sankyo, Dalcor, DuPont, Esperion, GlaxoSmithKline, ISIS Pharmaceuticals, Kowa, Mylan, Pfizer, Roche, Sanofi, Singulex, The Medicines Company, and Vatera Capital, as well as the British Heart Foundation, Cancer Research UK, National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Council, Nuffield Department of Population Health, Weill Cornell Medicine, and UK Biobank.

SOURCE: Fulcher J et al. Lancet. 2019;393:407-15.

Statin therapy appears to reduce the risk of major vascular events for patients of all age groups, but there is less evidence that older patients with evidence of occlusive vascular disease benefit from the treatment, according to a recent meta-analysis of 28 trials from the Cholesterol Treatment Trialists’ Collaboration published in The Lancet.

Louise Koenig/MDedge News

Statins are “useful and affordable drug[s] that reduce heart attacks and strokes in older patients. Until now there has been an evidence gap and we wanted to look at their efficacy and safety in older people,” Jordan Fulcher, BSc (Med), MBBS, from the Cholesterol Treatment Trialists’ (CTT) Collaboration and the University of Sydney stated in a press release. “Our analysis indicates that major cardiovascular events were reduced by about a fifth, per mmol/L lower LDL cholesterol, by statin therapy across all age groups. Despite previous concerns, we found no adverse effect on cancer or nonvascular mortality in any age group.”

The researchers examined 186,854 participants from 28 CTT trials undergoing statin therapy, of whom 14,483 (8%) were older than 75 years. Patients were divided into six groups based on age and examined the risk of major cardiovascular events such as stroke, coronary revascularization and major coronary events, as well as the incidence of cancer and vascular mortality.

Among all age groups, there was a significant reduction in major vascular events, with a 21% proportional per 1.0-mmol/L reduction in LDL cholesterol (risk ratio, 0.79; 95% confidence interval, 0.77-0.81) among patients receiving statin therapy or a more intensive statin regimen, and there was a 24% proportional reduction (RR, 0.76; 95% CI, 0.73-0.79) of major coronary events per 1.0-mmol/L reduction in LDL cholesterol, with older age resulting in a lower proportional reduction of major coronary events (P = .009). The researchers also found a proportional reduction of coronary revascularization procedures by 25% (RR, 0.75; 95% CI, 0.73-0.78) and stroke by 16% (RR, 0.84; 95% CI, 0.80-0.89) among patients of any age group receiving statin therapy or more intensive statin regimen, with no significant differences between age groups.

There was a 12% proportional reduction in vascular mortality per 1.0-mmol/L reduction in LDL cholesterol (RR, 0.88; 95% CI, 0.85-0.91), but this statistic did not remain significant after the researchers excluded four trials that included patients with heart failure or who were receiving renal dialysis. After excluding these trials from the overall analysis, the researchers found the smaller proportional reductions persisted for older patients for major coronary events (P = .01) but was no longer significant for major vascular events.

The researchers noted their study was limited by the highly selected patient population, low percentage of patients older than 75 years, including trials with efficacy endpoints where some nonserious adverse events may not have been recorded, and not including some trials in the meta-analysis if they were not part of the CTT.

This study was funded by Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation. The authors have reported personal fees, grants, and consulting fees from Abbott, Aegerion, Amgen, Arisaph, AstraZeneca, Bayer, Beckmann, Berlin-Chemie, Boehringer Ingelheim, Daiichi Sankyo, Dalcor, DuPont, Esperion, GlaxoSmithKline, ISIS Pharmaceuticals, Kowa, Mylan, Pfizer, Roche, Sanofi, Singulex, The Medicines Company, and Vatera Capital, as well as the British Heart Foundation, Cancer Research UK, National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Council, Nuffield Department of Population Health, Weill Cornell Medicine, and UK Biobank.

SOURCE: Fulcher J et al. Lancet. 2019;393:407-15.

Statin therapy appears to reduce the risk of major vascular events for patients of all age groups, but there is less evidence that older patients with evidence of occlusive vascular disease benefit from the treatment, according to a recent meta-analysis of 28 trials from the Cholesterol Treatment Trialists’ Collaboration published in The Lancet.

Louise Koenig/MDedge News

Statins are “useful and affordable drug[s] that reduce heart attacks and strokes in older patients. Until now there has been an evidence gap and we wanted to look at their efficacy and safety in older people,” Jordan Fulcher, BSc (Med), MBBS, from the Cholesterol Treatment Trialists’ (CTT) Collaboration and the University of Sydney stated in a press release. “Our analysis indicates that major cardiovascular events were reduced by about a fifth, per mmol/L lower LDL cholesterol, by statin therapy across all age groups. Despite previous concerns, we found no adverse effect on cancer or nonvascular mortality in any age group.”

The researchers examined 186,854 participants from 28 CTT trials undergoing statin therapy, of whom 14,483 (8%) were older than 75 years. Patients were divided into six groups based on age and examined the risk of major cardiovascular events such as stroke, coronary revascularization and major coronary events, as well as the incidence of cancer and vascular mortality.

Among all age groups, there was a significant reduction in major vascular events, with a 21% proportional per 1.0-mmol/L reduction in LDL cholesterol (risk ratio, 0.79; 95% confidence interval, 0.77-0.81) among patients receiving statin therapy or a more intensive statin regimen, and there was a 24% proportional reduction (RR, 0.76; 95% CI, 0.73-0.79) of major coronary events per 1.0-mmol/L reduction in LDL cholesterol, with older age resulting in a lower proportional reduction of major coronary events (P = .009). The researchers also found a proportional reduction of coronary revascularization procedures by 25% (RR, 0.75; 95% CI, 0.73-0.78) and stroke by 16% (RR, 0.84; 95% CI, 0.80-0.89) among patients of any age group receiving statin therapy or more intensive statin regimen, with no significant differences between age groups.

There was a 12% proportional reduction in vascular mortality per 1.0-mmol/L reduction in LDL cholesterol (RR, 0.88; 95% CI, 0.85-0.91), but this statistic did not remain significant after the researchers excluded four trials that included patients with heart failure or who were receiving renal dialysis. After excluding these trials from the overall analysis, the researchers found the smaller proportional reductions persisted for older patients for major coronary events (P = .01) but was no longer significant for major vascular events.

The researchers noted their study was limited by the highly selected patient population, low percentage of patients older than 75 years, including trials with efficacy endpoints where some nonserious adverse events may not have been recorded, and not including some trials in the meta-analysis if they were not part of the CTT.

This study was funded by Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation. The authors have reported personal fees, grants, and consulting fees from Abbott, Aegerion, Amgen, Arisaph, AstraZeneca, Bayer, Beckmann, Berlin-Chemie, Boehringer Ingelheim, Daiichi Sankyo, Dalcor, DuPont, Esperion, GlaxoSmithKline, ISIS Pharmaceuticals, Kowa, Mylan, Pfizer, Roche, Sanofi, Singulex, The Medicines Company, and Vatera Capital, as well as the British Heart Foundation, Cancer Research UK, National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Council, Nuffield Department of Population Health, Weill Cornell Medicine, and UK Biobank.

SOURCE: Fulcher J et al. Lancet. 2019;393:407-15.

WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.

Neil Osterweil/MDedge News

But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.

“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
 

Checkpoint inhibitors and the heart

Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.

Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).

Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.

Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.

The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.

“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.

Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.

The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.

Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.

“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.

Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
 

CAR-T cells and cardiac disease

The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.

In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.

Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.

Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.

Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.

Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.

Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.

Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.

Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,

Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.

Dr. Cornell reported having nothing to disclose.

WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.

Neil Osterweil/MDedge News

But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.

“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
 

Checkpoint inhibitors and the heart

Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.

Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).

Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.

Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.

The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.

“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.

Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.

The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.

Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.

“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.

Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
 

CAR-T cells and cardiac disease

The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.

In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.

Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.

Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.

Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.

Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.

Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.

Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.

Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,

Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.

Dr. Cornell reported having nothing to disclose.

WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.

Neil Osterweil/MDedge News

But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.

“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
 

Checkpoint inhibitors and the heart

Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.

Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).

Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.

Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.

The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.

“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.

Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.

The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.

Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.

“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.

Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
 

CAR-T cells and cardiac disease

The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.

In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.

Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.

Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.

Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.

Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.

Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.

Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.

Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,

Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.

Dr. Cornell reported having nothing to disclose.

Plaque psoriasis is a chronic inflammatory disease with a complex pathogenesis. Cutaneous dendritic cells drive the activation and proliferation of T cells with production of several immunomodulators, such as tumor necrosis factor (TNF) α, IL-17, IL-12, and IL-23. Because multiple systemic therapies are efficacious, treatment selection depends on side-effect profiles, availability, and patient preference. Activation of the TNF-α pathway is not unique to psoriasis. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. One study in mice demonstrated that TNF-α drives endothelial and vascular wall dysfunction in sickle cell anemia. In this study, use of the TNF-α blocker etanercept in mice with homozygous sickle cell anemia (HbSS) disease resulted in amelioration of TNF-mediated clinical features shared by sickle mice and humans.¹

Sickle cell anemia is caused by a structural defect in hemoglobin that results in hemolysis and chronic anemia. The most common type of hemoglobin in adults without sickle cell anemia is HbAA. Homozygous sickle cell anemia patients carry 2 abnormal S alleles, whereas in sickle cell trait, patients carry both the S and normal A alleles (HbSA). Hemoglobin C is a structural variant of HbA that results in lower solubility in red blood cells. Patients with hemoglobin SC disease (HbSC) have S and C alleles.² We present a case of a patient with moderate to severe plaque psoriasis and heterozygous sickle cell anemia treated with adalimumab.

Case Report

A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area) and HbSC. She reported chronic dull arthralgia in the ankles that was worse at night. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. The diffuse bone pain had gradually worsened over the years and was treated by hematology with ibuprofen and ketorolac. At presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on the potential for improvement in HbSC. Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and the HbSC pain decreased from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. After initiation of adalimumab, she reported decreased use of pain medication with no sickle cell pain crises.

Tumor necrosis factor α blockers are commonly used for moderate to severe plaque psoriasis. To our knowledge, there have been no reported human studies showing TNF-α blockade as a potential treatment of sickle cell disease. Increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and severity of sickle cell disease by playing an integral role in the development of vascular wall dysfunction and ischemia.³ Inflammatory mediators in HbSS disease, such as heparan sulfate from the endothelial glycocalyx and heme from hemolysis, act on monocytes to release TNF-α.¹ Through this effect on the endothelium, TNF-α impedes blood flow during sickle cell crisis, leading to worsening ischemia and resultant painful infarction.³ Analysis of cytokine levels in HbSS patients showed significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in comparison to nondiseased controls (HbAA), indicating a possible role of TNF-α in the pathogenesis of the crisis state.³ These studies suggest that TNF-α inhibition may reduce the initiation of vaso-occlusive crisis and decrease the subsequent ischemia related to a sickle cell crisis.

Although these findings were observational and limited to a single patient, the 50% decrease in pain level and use of pain medications reported to her hematologist independent of her dermatology visits coincided with the initiation of adalimumab. Although radiographs showed possible psoriatic changes of the distal metatarsal row, her described sickle cell pain and pain crises were atypical for psoriatic arthralgia. Tumor necrosis factor α inhibitors could be the drug of choice to treat patients with psoriasis with concomitant HbSS or HbSC disease due to the blockade of a common inflammatory mediator. Further studies are indicated to analyze the in vivo role of TNF-α inhibition in sickle cell disease.

Plaque psoriasis is a chronic inflammatory disease with a complex pathogenesis. Cutaneous dendritic cells drive the activation and proliferation of T cells with production of several immunomodulators, such as tumor necrosis factor (TNF) α, IL-17, IL-12, and IL-23. Because multiple systemic therapies are efficacious, treatment selection depends on side-effect profiles, availability, and patient preference. Activation of the TNF-α pathway is not unique to psoriasis. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. One study in mice demonstrated that TNF-α drives endothelial and vascular wall dysfunction in sickle cell anemia. In this study, use of the TNF-α blocker etanercept in mice with homozygous sickle cell anemia (HbSS) disease resulted in amelioration of TNF-mediated clinical features shared by sickle mice and humans.¹

Sickle cell anemia is caused by a structural defect in hemoglobin that results in hemolysis and chronic anemia. The most common type of hemoglobin in adults without sickle cell anemia is HbAA. Homozygous sickle cell anemia patients carry 2 abnormal S alleles, whereas in sickle cell trait, patients carry both the S and normal A alleles (HbSA). Hemoglobin C is a structural variant of HbA that results in lower solubility in red blood cells. Patients with hemoglobin SC disease (HbSC) have S and C alleles.² We present a case of a patient with moderate to severe plaque psoriasis and heterozygous sickle cell anemia treated with adalimumab.

Case Report

A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area) and HbSC. She reported chronic dull arthralgia in the ankles that was worse at night. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. The diffuse bone pain had gradually worsened over the years and was treated by hematology with ibuprofen and ketorolac. At presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on the potential for improvement in HbSC. Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and the HbSC pain decreased from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. After initiation of adalimumab, she reported decreased use of pain medication with no sickle cell pain crises.

Tumor necrosis factor α blockers are commonly used for moderate to severe plaque psoriasis. To our knowledge, there have been no reported human studies showing TNF-α blockade as a potential treatment of sickle cell disease. Increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and severity of sickle cell disease by playing an integral role in the development of vascular wall dysfunction and ischemia.³ Inflammatory mediators in HbSS disease, such as heparan sulfate from the endothelial glycocalyx and heme from hemolysis, act on monocytes to release TNF-α.¹ Through this effect on the endothelium, TNF-α impedes blood flow during sickle cell crisis, leading to worsening ischemia and resultant painful infarction.³ Analysis of cytokine levels in HbSS patients showed significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in comparison to nondiseased controls (HbAA), indicating a possible role of TNF-α in the pathogenesis of the crisis state.³ These studies suggest that TNF-α inhibition may reduce the initiation of vaso-occlusive crisis and decrease the subsequent ischemia related to a sickle cell crisis.

Although these findings were observational and limited to a single patient, the 50% decrease in pain level and use of pain medications reported to her hematologist independent of her dermatology visits coincided with the initiation of adalimumab. Although radiographs showed possible psoriatic changes of the distal metatarsal row, her described sickle cell pain and pain crises were atypical for psoriatic arthralgia. Tumor necrosis factor α inhibitors could be the drug of choice to treat patients with psoriasis with concomitant HbSS or HbSC disease due to the blockade of a common inflammatory mediator. Further studies are indicated to analyze the in vivo role of TNF-α inhibition in sickle cell disease.

Plaque psoriasis is a chronic inflammatory disease with a complex pathogenesis. Cutaneous dendritic cells drive the activation and proliferation of T cells with production of several immunomodulators, such as tumor necrosis factor (TNF) α, IL-17, IL-12, and IL-23. Because multiple systemic therapies are efficacious, treatment selection depends on side-effect profiles, availability, and patient preference. Activation of the TNF-α pathway is not unique to psoriasis. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. One study in mice demonstrated that TNF-α drives endothelial and vascular wall dysfunction in sickle cell anemia. In this study, use of the TNF-α blocker etanercept in mice with homozygous sickle cell anemia (HbSS) disease resulted in amelioration of TNF-mediated clinical features shared by sickle mice and humans.¹

Sickle cell anemia is caused by a structural defect in hemoglobin that results in hemolysis and chronic anemia. The most common type of hemoglobin in adults without sickle cell anemia is HbAA. Homozygous sickle cell anemia patients carry 2 abnormal S alleles, whereas in sickle cell trait, patients carry both the S and normal A alleles (HbSA). Hemoglobin C is a structural variant of HbA that results in lower solubility in red blood cells. Patients with hemoglobin SC disease (HbSC) have S and C alleles.² We present a case of a patient with moderate to severe plaque psoriasis and heterozygous sickle cell anemia treated with adalimumab.

Case Report

A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area) and HbSC. She reported chronic dull arthralgia in the ankles that was worse at night. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. The diffuse bone pain had gradually worsened over the years and was treated by hematology with ibuprofen and ketorolac. At presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on the potential for improvement in HbSC. Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and the HbSC pain decreased from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. After initiation of adalimumab, she reported decreased use of pain medication with no sickle cell pain crises.

Tumor necrosis factor α blockers are commonly used for moderate to severe plaque psoriasis. To our knowledge, there have been no reported human studies showing TNF-α blockade as a potential treatment of sickle cell disease. Increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and severity of sickle cell disease by playing an integral role in the development of vascular wall dysfunction and ischemia.³ Inflammatory mediators in HbSS disease, such as heparan sulfate from the endothelial glycocalyx and heme from hemolysis, act on monocytes to release TNF-α.¹ Through this effect on the endothelium, TNF-α impedes blood flow during sickle cell crisis, leading to worsening ischemia and resultant painful infarction.³ Analysis of cytokine levels in HbSS patients showed significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in comparison to nondiseased controls (HbAA), indicating a possible role of TNF-α in the pathogenesis of the crisis state.³ These studies suggest that TNF-α inhibition may reduce the initiation of vaso-occlusive crisis and decrease the subsequent ischemia related to a sickle cell crisis.

Although these findings were observational and limited to a single patient, the 50% decrease in pain level and use of pain medications reported to her hematologist independent of her dermatology visits coincided with the initiation of adalimumab. Although radiographs showed possible psoriatic changes of the distal metatarsal row, her described sickle cell pain and pain crises were atypical for psoriatic arthralgia. Tumor necrosis factor α inhibitors could be the drug of choice to treat patients with psoriasis with concomitant HbSS or HbSC disease due to the blockade of a common inflammatory mediator. Further studies are indicated to analyze the in vivo role of TNF-α inhibition in sickle cell disease.

Click here to read the supplement. 

Learn about the latest research on the development of the skin microbiome in infancy (including the neonatal period), the essential role of a healthy skin microbiome, and practical advice for patients.

Click here to read the supplement. 

Learn about the latest research on the development of the skin microbiome in infancy (including the neonatal period), the essential role of a healthy skin microbiome, and practical advice for patients.

Click here to read the supplement. 

Learn about the latest research on the development of the skin microbiome in infancy (including the neonatal period), the essential role of a healthy skin microbiome, and practical advice for patients.

CASE Patient with early pregnancy failure opts for surgical management

A 36-year-old woman (G3P2) at 9 weeks from her last menstrual period presents for an initial obstetric examination. On transvaginal ultrasound, her ObGyn notes an embryo measuring 9 weeks without cardiac activity. The ObGyn informs her of the early pregnancy failure diagnosis and offers bereavement support, and then reviews the available options: expectant management with follow-up in 2 weeks, medical management with mifepristone and misoprostol, and surgical management with a dilation and curettage (D&C). The patient is interested in expedited treatment and thus selects D&C, and the staff books the next available operating room (OR) slot for her the subsequent week. Over the weekend, the patient calls to report heavy bleeding and passage of clots, and the ObGyn’s practice partner takes her to the OR for a D&C for incomplete abortion.

Early pregnancy failure occurs in about 1 in 5 pregnancies. Treatment options include expectant, medical, or surgical management. Surgical management is classically offered in the OR via D&C. With the advent of manual vacuum aspiration (MVA) using a 60-mL handheld syringe aspirator, office-based treatment of pregnancy failure has become more widely available.

In this article we make the case for why, in appropriate clinical situations, office-based uterine aspiration, compared with uterine aspiration in the OR, should be the standard for surgical management of early pregnancy failure, for these reasons:

1. equivalent safety profile

2. reduced costs, and 

3. patient-centered characteristics.

1 Office-based procedures are safe

Suction curettage is one of the most common surgical procedures for a woman to undergo during her lifetime, and it has an excellent safety profile. Authors of a recent systematic review found that major surgical complications, including transfusion and uterine perforation requiring repair, occurred in less than 0.1% of all uterine aspiration procedures.¹ Importantly, this complication rate did not differ by inpatient or outpatient site of procedure.

Anesthesia-related complications at the time of aspiration also are extremely rare, and they are less likely to occur in the office setting than in surgical centers or hospital-based clinics (<0.2% and <0.5%, respectively).¹ This may be a result of the types of anesthesia offered at varying locations, given that local analgesia or moderate sedation is likely used in office-based procedures while deep sedation or general anesthesia may be employed at other practice locations.

Studies specifically designed to determine the safety of suction aspiration by practice location have yielded similar results. Researchers who conducted a systematic review comparing the safety of procedures done at ambulatory surgical centers with office-based procedures found no difference in safety between procedures performed in these 2 settings.² These findings were confirmed by results from a large retrospective cohort study that reviewed more than 50,000 aspiration procedures performed in ambulatory surgical centers versus private offices.³ In that study, only 0.32% of women had any major adverse event, and there were no statistically significant differences in complication rates between settings.³

Complication rates based on procedure type are similar for MVA and electric suction aspiration. Early studies revealed no difference in the need for reaspiration or other complications for MVA compared with electric suction.⁴ This was later confirmed by a systematic review that found no significant differences in safety by type of suction overall, and a possible trend toward fewer uterine perforations with MVA.⁵ When procedures were assessed by gestational age, additional trends toward the safety of MVA emerged. For example, in procedures performed at less than 50 days’ gestational age, estimated blood loss and severe pain occurred less commonly during procedures performed using MVA.⁵

Continue to: 2 Office-based procedures are less expensive

2 Office-based procedures are less expensive

There has been a trend in recent decades to obtain cost savings by moving appropriately selected gynecologic procedures from the operative suite to the outpatient setting. Because of MVA’s minimal up-front and ongoing costs, office-based suction aspiration is one of the most cost-effective procedures performed in the outpatient setting.

Dalton and colleagues, for example, demonstrated that in women diagnosed with early pregnancy failure, suction curettage is 50% less expensive when performed in the office as compared to in the operating suite.⁶ Likewise, in a cohort of patients who presented to the emergency department with an incomplete abortion, Blumenthal and colleagues showed a 41% procedural cost reduction by offering D&C in the outpatient setting instead of the OR.⁷ Waiting times and mean procedure times also were reduced by nearly half.

Recent studies have broadened cost analyses beyond the comparison of inpatient versus outpatient procedures. A multicenter trial of women with first-trimester pregnancy failure compared the costs of medication management with those of surgical procedures; as expected, the cost of D&C in the OR was significantly more expensive than medication management.⁸ However, MVA in the office was less expensive than medication management, due largely to the increased cost of managing medication failures.

In addition, a recent, well-designed decision model study demonstrated that offering women with early pregnancy failure a greater array of management options decreases costs.⁹ The study compared the costs when women were offered the most common options, expectant management or uterine evacuation in the OR, versus the costs when additional options were also offered. When options were expanded to include medication management and MVA in the office, costs decreased by nearly 20% overall.⁹

3 Office-based procedures are more patient centered

The benefits of surgical management of an early pregnancy failure include very high success rates (98%) and convenient timing. Among women who elect surgical management, a desire to expedite the process in a predictable fashion is a common factor in their decision.^10,11 It is unsurprising then that 68% of patients will select an office-based procedure if they do not perceive that the clinician has a setting preference.⁶

When surgical management is performed in the OR, scheduling delays are common. Such delays can be clinically important: Women progressing to a miscarriage while awaiting surgical treatment may be at risk for urgent, unplanned interval procedures for incomplete abortion, and they may be dissatisfied with the inability to access the desired management. While women are highly satisfied after treatment for early pregnancy failure in general,⁶ OR treatment can cause dissatisfaction because patients miss more work days or need assistance at home.¹² In a cross-sectional study, patients who elected office-based aspiration reported less delay to treatment (less than 2 hours) compared with women who elected OR procedures (more than 12 hours), and shorter time to procedure initiation was a satisfier.¹³

Women also note fear of the hospital setting and general anesthesia, and they tend to see hospital-based services as more invasive.¹¹ Clinicians can offer anesthesia in the outpatient setting with nonsteroidal anti-inflammatory medications and a paracervical block, oral sedation with an anxiolytic, or in some cases intravenous (IV) sedation with conscious sedation.

Continue to: Our process for office-based uterine aspiration

Our process for office-based uterine aspiration

We follow the step-by-step process outlined below for performing office-based uterine aspiration. Clinicians should review their clinic’s protocols prior to implementing such a plan.

Review the patient history and pregnancy dating. Patients with serious medical conditions, such as history of postabortion hemorrhage or a bleeding disorder, may not be appropriate candidates for an office-based procedure. We perform bedside ultrasonography to confirm pregnancy dating and diagnosis of pregnancy failure.

Review consent for the procedure and sedation. Risks of office-based uterine aspiration are the same as those for D&C: bleeding, uterine perforation, and failure to fully evacuate the uterus. Benefits include rapid, safe evacuation of the pregnancy. Alternative treatments include expectant or medical management.

For pain management, we start by discussing expectations with the patient. Providing general anesthesia in the outpatient setting is not safe; many women are satisfied, however, with local anesthesia with or without sedation.

Local anesthesia may be given using a paracervical block with 2 mL of 1% lidocaine at the tenaculum site followed by 18 mL divided between the 4 and 8 o’clock positions. In our practice, we are trained providers of conscious sedation, so additionally we offer IV fentanyl 100 μg and IV midazolam 2 mg given prior to the procedure.

Provide antibiotic prophylaxis. The American College of Obstetricians and Gynecologists and the Society for Family Planning recommend doxycycline 200 mg orally as a preoperative prophylaxis for office-based uterine aspiration.^14,15 Metronidazole is an acceptable alternative for patients who have medication allergies.

Prepare the surgical field. To complete this procedure, you will need the following equipment:

• one MVA kit that includes an aspirator, curettes, and dilators (FIGURE)
• 20 mL 1% lidocaine, divided into two 10-mL syringes with a 22-gauge 3.5-inch spinal needle
• speculum
• cervical antiseptic prep
• single-tooth tenaculum
• ring forceps.

Perform the MVA procedure. A full description of how to perform the MVA procedure using the Ipas MVA Plus Aspirator device is available online at http://provideaccess.org/wp-content/uploads/2012/09/4Performing-MVA-Us ing-the-Ipas-MVA-Plus.pdf.

A good option for many women

A D&C in the OR remains an appropriate option for patients who are clinically unstable due to heavy vaginal bleeding. With highly sensitive home urine pregnancy tests, pregnancies often are diagnosed before clinically apparent miscarriage. In fact, many such patients are diagnosed with pregnancy failure in the office, as was our patient in the case scenario. For such women, office-based management of early pregnancy failure is preferred because it is safe, cost-effective, and patient centered.

CASE Patient with early pregnancy failure opts for surgical management

A 36-year-old woman (G3P2) at 9 weeks from her last menstrual period presents for an initial obstetric examination. On transvaginal ultrasound, her ObGyn notes an embryo measuring 9 weeks without cardiac activity. The ObGyn informs her of the early pregnancy failure diagnosis and offers bereavement support, and then reviews the available options: expectant management with follow-up in 2 weeks, medical management with mifepristone and misoprostol, and surgical management with a dilation and curettage (D&C). The patient is interested in expedited treatment and thus selects D&C, and the staff books the next available operating room (OR) slot for her the subsequent week. Over the weekend, the patient calls to report heavy bleeding and passage of clots, and the ObGyn’s practice partner takes her to the OR for a D&C for incomplete abortion.

Early pregnancy failure occurs in about 1 in 5 pregnancies. Treatment options include expectant, medical, or surgical management. Surgical management is classically offered in the OR via D&C. With the advent of manual vacuum aspiration (MVA) using a 60-mL handheld syringe aspirator, office-based treatment of pregnancy failure has become more widely available.

In this article we make the case for why, in appropriate clinical situations, office-based uterine aspiration, compared with uterine aspiration in the OR, should be the standard for surgical management of early pregnancy failure, for these reasons:

1. equivalent safety profile

2. reduced costs, and 

3. patient-centered characteristics.

1 Office-based procedures are safe

Suction curettage is one of the most common surgical procedures for a woman to undergo during her lifetime, and it has an excellent safety profile. Authors of a recent systematic review found that major surgical complications, including transfusion and uterine perforation requiring repair, occurred in less than 0.1% of all uterine aspiration procedures.¹ Importantly, this complication rate did not differ by inpatient or outpatient site of procedure.

Anesthesia-related complications at the time of aspiration also are extremely rare, and they are less likely to occur in the office setting than in surgical centers or hospital-based clinics (<0.2% and <0.5%, respectively).¹ This may be a result of the types of anesthesia offered at varying locations, given that local analgesia or moderate sedation is likely used in office-based procedures while deep sedation or general anesthesia may be employed at other practice locations.

Studies specifically designed to determine the safety of suction aspiration by practice location have yielded similar results. Researchers who conducted a systematic review comparing the safety of procedures done at ambulatory surgical centers with office-based procedures found no difference in safety between procedures performed in these 2 settings.² These findings were confirmed by results from a large retrospective cohort study that reviewed more than 50,000 aspiration procedures performed in ambulatory surgical centers versus private offices.³ In that study, only 0.32% of women had any major adverse event, and there were no statistically significant differences in complication rates between settings.³

Complication rates based on procedure type are similar for MVA and electric suction aspiration. Early studies revealed no difference in the need for reaspiration or other complications for MVA compared with electric suction.⁴ This was later confirmed by a systematic review that found no significant differences in safety by type of suction overall, and a possible trend toward fewer uterine perforations with MVA.⁵ When procedures were assessed by gestational age, additional trends toward the safety of MVA emerged. For example, in procedures performed at less than 50 days’ gestational age, estimated blood loss and severe pain occurred less commonly during procedures performed using MVA.⁵

Continue to: 2 Office-based procedures are less expensive

2 Office-based procedures are less expensive

There has been a trend in recent decades to obtain cost savings by moving appropriately selected gynecologic procedures from the operative suite to the outpatient setting. Because of MVA’s minimal up-front and ongoing costs, office-based suction aspiration is one of the most cost-effective procedures performed in the outpatient setting.

Dalton and colleagues, for example, demonstrated that in women diagnosed with early pregnancy failure, suction curettage is 50% less expensive when performed in the office as compared to in the operating suite.⁶ Likewise, in a cohort of patients who presented to the emergency department with an incomplete abortion, Blumenthal and colleagues showed a 41% procedural cost reduction by offering D&C in the outpatient setting instead of the OR.⁷ Waiting times and mean procedure times also were reduced by nearly half.

Recent studies have broadened cost analyses beyond the comparison of inpatient versus outpatient procedures. A multicenter trial of women with first-trimester pregnancy failure compared the costs of medication management with those of surgical procedures; as expected, the cost of D&C in the OR was significantly more expensive than medication management.⁸ However, MVA in the office was less expensive than medication management, due largely to the increased cost of managing medication failures.

In addition, a recent, well-designed decision model study demonstrated that offering women with early pregnancy failure a greater array of management options decreases costs.⁹ The study compared the costs when women were offered the most common options, expectant management or uterine evacuation in the OR, versus the costs when additional options were also offered. When options were expanded to include medication management and MVA in the office, costs decreased by nearly 20% overall.⁹

3 Office-based procedures are more patient centered

The benefits of surgical management of an early pregnancy failure include very high success rates (98%) and convenient timing. Among women who elect surgical management, a desire to expedite the process in a predictable fashion is a common factor in their decision.^10,11 It is unsurprising then that 68% of patients will select an office-based procedure if they do not perceive that the clinician has a setting preference.⁶

When surgical management is performed in the OR, scheduling delays are common. Such delays can be clinically important: Women progressing to a miscarriage while awaiting surgical treatment may be at risk for urgent, unplanned interval procedures for incomplete abortion, and they may be dissatisfied with the inability to access the desired management. While women are highly satisfied after treatment for early pregnancy failure in general,⁶ OR treatment can cause dissatisfaction because patients miss more work days or need assistance at home.¹² In a cross-sectional study, patients who elected office-based aspiration reported less delay to treatment (less than 2 hours) compared with women who elected OR procedures (more than 12 hours), and shorter time to procedure initiation was a satisfier.¹³

Women also note fear of the hospital setting and general anesthesia, and they tend to see hospital-based services as more invasive.¹¹ Clinicians can offer anesthesia in the outpatient setting with nonsteroidal anti-inflammatory medications and a paracervical block, oral sedation with an anxiolytic, or in some cases intravenous (IV) sedation with conscious sedation.

Continue to: Our process for office-based uterine aspiration

Our process for office-based uterine aspiration

We follow the step-by-step process outlined below for performing office-based uterine aspiration. Clinicians should review their clinic’s protocols prior to implementing such a plan.

Review the patient history and pregnancy dating. Patients with serious medical conditions, such as history of postabortion hemorrhage or a bleeding disorder, may not be appropriate candidates for an office-based procedure. We perform bedside ultrasonography to confirm pregnancy dating and diagnosis of pregnancy failure.

Review consent for the procedure and sedation. Risks of office-based uterine aspiration are the same as those for D&C: bleeding, uterine perforation, and failure to fully evacuate the uterus. Benefits include rapid, safe evacuation of the pregnancy. Alternative treatments include expectant or medical management.

For pain management, we start by discussing expectations with the patient. Providing general anesthesia in the outpatient setting is not safe; many women are satisfied, however, with local anesthesia with or without sedation.

Local anesthesia may be given using a paracervical block with 2 mL of 1% lidocaine at the tenaculum site followed by 18 mL divided between the 4 and 8 o’clock positions. In our practice, we are trained providers of conscious sedation, so additionally we offer IV fentanyl 100 μg and IV midazolam 2 mg given prior to the procedure.

Provide antibiotic prophylaxis. The American College of Obstetricians and Gynecologists and the Society for Family Planning recommend doxycycline 200 mg orally as a preoperative prophylaxis for office-based uterine aspiration.^14,15 Metronidazole is an acceptable alternative for patients who have medication allergies.

Prepare the surgical field. To complete this procedure, you will need the following equipment:

• one MVA kit that includes an aspirator, curettes, and dilators (FIGURE)
• 20 mL 1% lidocaine, divided into two 10-mL syringes with a 22-gauge 3.5-inch spinal needle
• speculum
• cervical antiseptic prep
• single-tooth tenaculum
• ring forceps.

Perform the MVA procedure. A full description of how to perform the MVA procedure using the Ipas MVA Plus Aspirator device is available online at http://provideaccess.org/wp-content/uploads/2012/09/4Performing-MVA-Us ing-the-Ipas-MVA-Plus.pdf.

A good option for many women

A D&C in the OR remains an appropriate option for patients who are clinically unstable due to heavy vaginal bleeding. With highly sensitive home urine pregnancy tests, pregnancies often are diagnosed before clinically apparent miscarriage. In fact, many such patients are diagnosed with pregnancy failure in the office, as was our patient in the case scenario. For such women, office-based management of early pregnancy failure is preferred because it is safe, cost-effective, and patient centered.

CASE Patient with early pregnancy failure opts for surgical management

A 36-year-old woman (G3P2) at 9 weeks from her last menstrual period presents for an initial obstetric examination. On transvaginal ultrasound, her ObGyn notes an embryo measuring 9 weeks without cardiac activity. The ObGyn informs her of the early pregnancy failure diagnosis and offers bereavement support, and then reviews the available options: expectant management with follow-up in 2 weeks, medical management with mifepristone and misoprostol, and surgical management with a dilation and curettage (D&C). The patient is interested in expedited treatment and thus selects D&C, and the staff books the next available operating room (OR) slot for her the subsequent week. Over the weekend, the patient calls to report heavy bleeding and passage of clots, and the ObGyn’s practice partner takes her to the OR for a D&C for incomplete abortion.

Early pregnancy failure occurs in about 1 in 5 pregnancies. Treatment options include expectant, medical, or surgical management. Surgical management is classically offered in the OR via D&C. With the advent of manual vacuum aspiration (MVA) using a 60-mL handheld syringe aspirator, office-based treatment of pregnancy failure has become more widely available.

In this article we make the case for why, in appropriate clinical situations, office-based uterine aspiration, compared with uterine aspiration in the OR, should be the standard for surgical management of early pregnancy failure, for these reasons:

1. equivalent safety profile

2. reduced costs, and 

3. patient-centered characteristics.

1 Office-based procedures are safe

Suction curettage is one of the most common surgical procedures for a woman to undergo during her lifetime, and it has an excellent safety profile. Authors of a recent systematic review found that major surgical complications, including transfusion and uterine perforation requiring repair, occurred in less than 0.1% of all uterine aspiration procedures.¹ Importantly, this complication rate did not differ by inpatient or outpatient site of procedure.

Anesthesia-related complications at the time of aspiration also are extremely rare, and they are less likely to occur in the office setting than in surgical centers or hospital-based clinics (<0.2% and <0.5%, respectively).¹ This may be a result of the types of anesthesia offered at varying locations, given that local analgesia or moderate sedation is likely used in office-based procedures while deep sedation or general anesthesia may be employed at other practice locations.

Studies specifically designed to determine the safety of suction aspiration by practice location have yielded similar results. Researchers who conducted a systematic review comparing the safety of procedures done at ambulatory surgical centers with office-based procedures found no difference in safety between procedures performed in these 2 settings.² These findings were confirmed by results from a large retrospective cohort study that reviewed more than 50,000 aspiration procedures performed in ambulatory surgical centers versus private offices.³ In that study, only 0.32% of women had any major adverse event, and there were no statistically significant differences in complication rates between settings.³

Complication rates based on procedure type are similar for MVA and electric suction aspiration. Early studies revealed no difference in the need for reaspiration or other complications for MVA compared with electric suction.⁴ This was later confirmed by a systematic review that found no significant differences in safety by type of suction overall, and a possible trend toward fewer uterine perforations with MVA.⁵ When procedures were assessed by gestational age, additional trends toward the safety of MVA emerged. For example, in procedures performed at less than 50 days’ gestational age, estimated blood loss and severe pain occurred less commonly during procedures performed using MVA.⁵

Continue to: 2 Office-based procedures are less expensive

2 Office-based procedures are less expensive

There has been a trend in recent decades to obtain cost savings by moving appropriately selected gynecologic procedures from the operative suite to the outpatient setting. Because of MVA’s minimal up-front and ongoing costs, office-based suction aspiration is one of the most cost-effective procedures performed in the outpatient setting.

Dalton and colleagues, for example, demonstrated that in women diagnosed with early pregnancy failure, suction curettage is 50% less expensive when performed in the office as compared to in the operating suite.⁶ Likewise, in a cohort of patients who presented to the emergency department with an incomplete abortion, Blumenthal and colleagues showed a 41% procedural cost reduction by offering D&C in the outpatient setting instead of the OR.⁷ Waiting times and mean procedure times also were reduced by nearly half.

Recent studies have broadened cost analyses beyond the comparison of inpatient versus outpatient procedures. A multicenter trial of women with first-trimester pregnancy failure compared the costs of medication management with those of surgical procedures; as expected, the cost of D&C in the OR was significantly more expensive than medication management.⁸ However, MVA in the office was less expensive than medication management, due largely to the increased cost of managing medication failures.

In addition, a recent, well-designed decision model study demonstrated that offering women with early pregnancy failure a greater array of management options decreases costs.⁹ The study compared the costs when women were offered the most common options, expectant management or uterine evacuation in the OR, versus the costs when additional options were also offered. When options were expanded to include medication management and MVA in the office, costs decreased by nearly 20% overall.⁹

3 Office-based procedures are more patient centered

The benefits of surgical management of an early pregnancy failure include very high success rates (98%) and convenient timing. Among women who elect surgical management, a desire to expedite the process in a predictable fashion is a common factor in their decision.^10,11 It is unsurprising then that 68% of patients will select an office-based procedure if they do not perceive that the clinician has a setting preference.⁶

When surgical management is performed in the OR, scheduling delays are common. Such delays can be clinically important: Women progressing to a miscarriage while awaiting surgical treatment may be at risk for urgent, unplanned interval procedures for incomplete abortion, and they may be dissatisfied with the inability to access the desired management. While women are highly satisfied after treatment for early pregnancy failure in general,⁶ OR treatment can cause dissatisfaction because patients miss more work days or need assistance at home.¹² In a cross-sectional study, patients who elected office-based aspiration reported less delay to treatment (less than 2 hours) compared with women who elected OR procedures (more than 12 hours), and shorter time to procedure initiation was a satisfier.¹³

Women also note fear of the hospital setting and general anesthesia, and they tend to see hospital-based services as more invasive.¹¹ Clinicians can offer anesthesia in the outpatient setting with nonsteroidal anti-inflammatory medications and a paracervical block, oral sedation with an anxiolytic, or in some cases intravenous (IV) sedation with conscious sedation.

Continue to: Our process for office-based uterine aspiration

Our process for office-based uterine aspiration

We follow the step-by-step process outlined below for performing office-based uterine aspiration. Clinicians should review their clinic’s protocols prior to implementing such a plan.

Review the patient history and pregnancy dating. Patients with serious medical conditions, such as history of postabortion hemorrhage or a bleeding disorder, may not be appropriate candidates for an office-based procedure. We perform bedside ultrasonography to confirm pregnancy dating and diagnosis of pregnancy failure.

Review consent for the procedure and sedation. Risks of office-based uterine aspiration are the same as those for D&C: bleeding, uterine perforation, and failure to fully evacuate the uterus. Benefits include rapid, safe evacuation of the pregnancy. Alternative treatments include expectant or medical management.

For pain management, we start by discussing expectations with the patient. Providing general anesthesia in the outpatient setting is not safe; many women are satisfied, however, with local anesthesia with or without sedation.

Local anesthesia may be given using a paracervical block with 2 mL of 1% lidocaine at the tenaculum site followed by 18 mL divided between the 4 and 8 o’clock positions. In our practice, we are trained providers of conscious sedation, so additionally we offer IV fentanyl 100 μg and IV midazolam 2 mg given prior to the procedure.

Provide antibiotic prophylaxis. The American College of Obstetricians and Gynecologists and the Society for Family Planning recommend doxycycline 200 mg orally as a preoperative prophylaxis for office-based uterine aspiration.^14,15 Metronidazole is an acceptable alternative for patients who have medication allergies.

Prepare the surgical field. To complete this procedure, you will need the following equipment:

• one MVA kit that includes an aspirator, curettes, and dilators (FIGURE)
• 20 mL 1% lidocaine, divided into two 10-mL syringes with a 22-gauge 3.5-inch spinal needle
• speculum
• cervical antiseptic prep
• single-tooth tenaculum
• ring forceps.

Perform the MVA procedure. A full description of how to perform the MVA procedure using the Ipas MVA Plus Aspirator device is available online at http://provideaccess.org/wp-content/uploads/2012/09/4Performing-MVA-Us ing-the-Ipas-MVA-Plus.pdf.

A good option for many women

A D&C in the OR remains an appropriate option for patients who are clinically unstable due to heavy vaginal bleeding. With highly sensitive home urine pregnancy tests, pregnancies often are diagnosed before clinically apparent miscarriage. In fact, many such patients are diagnosed with pregnancy failure in the office, as was our patient in the case scenario. For such women, office-based management of early pregnancy failure is preferred because it is safe, cost-effective, and patient centered.

Most people know that preterm birth is a major contributor to perinatal morbidity and mortality. Consequently, strict guidelines have been enforced to prevent non–medically indicated scheduled deliveries before 39 weeks’ gestation. Fewer people recognize that late-term birth is also an important and avoidable contributor to perinatal morbidity. To improve pregnancy outcomes, we may need enhanced guidelines about minimizing expectant management of pregnancy beyond 41 weeks’ gestation.

For the fetus, what is the optimal duration of a healthy pregnancy?

When pregnancy progresses past the date of the confinement, the risk of fetal or newborn injury or death increases, especially after 41 weeks’ gestation. Analysis of this risk, day by day, suggests that after 40 weeks’ and 3 days’ gestation there is no medical benefit to the fetus to remain in utero because, compared with induced delivery, expectant management of the pregnancy is associated with a greater rate of fetal and newborn morbidity and mortality.¹

The fetal and newborn benefits of delivery, rather than expectant management, at term include: a decrease in stillbirth and perinatal death rates, a decrease in admissions to the neonatal intensive care unit (NICU), a decrease in meconium-stained amniotic fluid and meconium aspiration syndrome, a decrease in low Apgar scores, and a decrease in problems related to uteroplacental insufficiency, including oligohydramnios.² In a comprehensive meta-analysis, induction of labor at or beyond term reduced the risk of perinatal death or stillbirth by 67%, the risk of a 5-minute Apgar score below 7 by 30%, and the risk of NICU admission by 12%.² The number of women that would need to be induced to prevent 1 perinatal death was estimated to be 426.²

Maternal benefits of avoiding late-term pregnancy

The maternal benefits of avoiding continuing a pregnancy past 41 weeks’ gestation include a reduction in labor dystocia and the risk of cesarean delivery (CD).^2,3 In one clinical trial, 3,407 women with low-risk pregnancy were randomly assigned to induction of labor at 41 weeks’ gestation or expectant management, awaiting the onset of labor with serial antenatal monitoring (nonstress tests and assessment of amniotic fluid volume).⁴ The CD rate was lower among the women randomized to induction of labor at 41 weeks’ (21.2% vs 24.5% in the expectant management group, P = .03). The rate of meconium-stained fluid was lower in the induction of labor group (25.0% vs 28.7%, P = .009). The rate of CD due to fetal distress also was lower in the induction of labor group (5.7% vs 8.3%, P = .003). The risks of maternal postpartum hemorrhage, sepsis, and endometritis did not differ between the groups. There were 2 stillbirths in the expectant management group (2/1,706) and none in the induction of labor group (0/1,701). There were no neonatal deaths in this study.⁴

Obstetric management, including accurate dating of pregnancy and membrane sweeping at term, can help to reduce the risk that a pregnancy will progress beyond 41 weeks’ gestation.⁵

Continue to: Routinely use ultrasound to accurately establish gestational age

Routinely use ultrasound to accurately establish gestational age

First trimester ultrasound should be offered to all pregnant women because it is a more accurate assessment of gestational age and will result in fewer pregnancies that are thought to be at or beyond 41 weeks’ gestation.⁵ In a meta-analysis of 8 studies, including 25,516 women, early ultrasonography reduced the rate of intervention for postterm pregnancy by 42% (31/1,000 to 18/1,000 pregnant women).⁶

Membrane sweeping (or stripping)

Membrane sweeping, which causes the release of prostaglandins, has been reported to reduce the risk of late-term and postterm induction of labor.^7,8 In the most recent Cochrane review on the topic, sweeping membranes reduced the rate of induction of labor at 41 weeks by 41% and at 42 weeks by 72%.⁷ To avoid one induction of labor for late-term or postterm pregnancy, sweeping of membranes would need to be performed on 8 women. In a recent meta-analysis, membrane sweeping reduced the rate of induction of labor for postmaturity by 48%.⁹

Membrane sweeping is associated with pain and an increased rate of vaginal bleeding.¹⁰ It does not increase the rate of maternal or neonatal infection, however. It also does not reduce the CD rate. In the United Kingdom, the National Institute for Health and Clinical Excellence recommends that all clinicians have a discussion of membrane sweeping with their patients at 38 weeks’ gestation and offer membrane stripping at 40 weeks to increase the rate of timely spontaneous labor and to avoid the risks of prolonged pregnancy.¹¹ Of note, in one randomized study of women planning a trial of labor after CD, membrane sweeping did not impact the duration of pregnancy, onset of spontaneous labor, or the CD rate.¹²

Steps from an expert. A skillfull midwife practicing in the United Kingdom provides the following guidance on how to perform membrane sweeping.¹³

1. Prepare the patient. Explain the procedure, have the patient empty her bladder, and encourage relaxed breathing if the vaginal examination causes pain.
2. Abdominal exam. Assess uterine size, fetal lie and presentation, and fetal heart tones.
3. Vaginal exam. Ascertain cervical dilation, effacement, and position. If the cervix is closed a sweep may not be possible. In this case, massaging the vaginal fornices may help to release prostaglandins and stimulate uterine contractions. If the cervix is closed but soft, massage of the cervix may permit the insertion of a finger. If the cervix is favorable for sweeping, insert one finger in the cervix and rotate the finger in a circle to separate the amnion from the cervix.
4. After the procedure. Provide the woman with a sanitary pad and recommend acetaminophen and a warm bath if she has discomfort or painful contractions. Advise her to come to the maternity unit in the following situations: severe pain, significant bleeding, or spontaneous rupture of the membranes.

Membrane sweeping can be performed as frequently as every 3 days. Formal cervical ripening and induction of labor may need to be planned if membrane sweeping does not result in the initiation of regular contractions.

Continue to: Collaborative decision making

Collaborative decision making

All clinicians recognize the primacy of patient autonomy.¹⁴ Competent patients have the right to select the course of care that they believe is optimal. When a patient decides to continue her pregnancy past 41 weeks, it is helpful to endorse respect for the decision and inquire about the patient’s reasons for continuing the pregnancy. Understanding the patient’s concerns may begin a conversation that will result in the patient accepting a plan for induction near 41 weeks’ gestation. If the patient insists on expectant management well beyond 41 weeks, the medical record should contain a summary of the clinician recommendation to induce labor at or before 41 weeks’ gestation and the patient’s preference for expectant management and her understanding of the decision’s risks.

Obstetricians and midwives constantly face the challenge of balancing the desire to avoid meddlesome interference in a pregnancy with the need to act to prevent adverse pregnancy outcomes. The challenge is daunting. A comprehensive meta-analysis of the benefit of induction of labor at or beyond term, estimated that 426 inductions would need to be initiated to prevent one perinatal death.² From one perspective it is meddlesome to intervene on more than 400 women to prevent one perinatal death. However, substantial data indicate that expectant management of a well-dated pregnancy at 41 weeks’ gestation will result in adverse outcomes that likely could be prevented by induction of labor. If you ran an airline and could take an action to prevent one airplane crash for every 400 flights, you would likely move heaven and earth to try to prevent that disaster. Unless the patient strongly prefers expectant management, well-managed induction of labor at or before 41 weeks’ gestation is likely to reduce the rate of adverse pregnancy events and, hence, is warranted.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Most people know that preterm birth is a major contributor to perinatal morbidity and mortality. Consequently, strict guidelines have been enforced to prevent non–medically indicated scheduled deliveries before 39 weeks’ gestation. Fewer people recognize that late-term birth is also an important and avoidable contributor to perinatal morbidity. To improve pregnancy outcomes, we may need enhanced guidelines about minimizing expectant management of pregnancy beyond 41 weeks’ gestation.

For the fetus, what is the optimal duration of a healthy pregnancy?

When pregnancy progresses past the date of the confinement, the risk of fetal or newborn injury or death increases, especially after 41 weeks’ gestation. Analysis of this risk, day by day, suggests that after 40 weeks’ and 3 days’ gestation there is no medical benefit to the fetus to remain in utero because, compared with induced delivery, expectant management of the pregnancy is associated with a greater rate of fetal and newborn morbidity and mortality.¹

The fetal and newborn benefits of delivery, rather than expectant management, at term include: a decrease in stillbirth and perinatal death rates, a decrease in admissions to the neonatal intensive care unit (NICU), a decrease in meconium-stained amniotic fluid and meconium aspiration syndrome, a decrease in low Apgar scores, and a decrease in problems related to uteroplacental insufficiency, including oligohydramnios.² In a comprehensive meta-analysis, induction of labor at or beyond term reduced the risk of perinatal death or stillbirth by 67%, the risk of a 5-minute Apgar score below 7 by 30%, and the risk of NICU admission by 12%.² The number of women that would need to be induced to prevent 1 perinatal death was estimated to be 426.²

Maternal benefits of avoiding late-term pregnancy

The maternal benefits of avoiding continuing a pregnancy past 41 weeks’ gestation include a reduction in labor dystocia and the risk of cesarean delivery (CD).^2,3 In one clinical trial, 3,407 women with low-risk pregnancy were randomly assigned to induction of labor at 41 weeks’ gestation or expectant management, awaiting the onset of labor with serial antenatal monitoring (nonstress tests and assessment of amniotic fluid volume).⁴ The CD rate was lower among the women randomized to induction of labor at 41 weeks’ (21.2% vs 24.5% in the expectant management group, P = .03). The rate of meconium-stained fluid was lower in the induction of labor group (25.0% vs 28.7%, P = .009). The rate of CD due to fetal distress also was lower in the induction of labor group (5.7% vs 8.3%, P = .003). The risks of maternal postpartum hemorrhage, sepsis, and endometritis did not differ between the groups. There were 2 stillbirths in the expectant management group (2/1,706) and none in the induction of labor group (0/1,701). There were no neonatal deaths in this study.⁴

Obstetric management, including accurate dating of pregnancy and membrane sweeping at term, can help to reduce the risk that a pregnancy will progress beyond 41 weeks’ gestation.⁵

Continue to: Routinely use ultrasound to accurately establish gestational age

Routinely use ultrasound to accurately establish gestational age

First trimester ultrasound should be offered to all pregnant women because it is a more accurate assessment of gestational age and will result in fewer pregnancies that are thought to be at or beyond 41 weeks’ gestation.⁵ In a meta-analysis of 8 studies, including 25,516 women, early ultrasonography reduced the rate of intervention for postterm pregnancy by 42% (31/1,000 to 18/1,000 pregnant women).⁶

Membrane sweeping (or stripping)

Membrane sweeping, which causes the release of prostaglandins, has been reported to reduce the risk of late-term and postterm induction of labor.^7,8 In the most recent Cochrane review on the topic, sweeping membranes reduced the rate of induction of labor at 41 weeks by 41% and at 42 weeks by 72%.⁷ To avoid one induction of labor for late-term or postterm pregnancy, sweeping of membranes would need to be performed on 8 women. In a recent meta-analysis, membrane sweeping reduced the rate of induction of labor for postmaturity by 48%.⁹

Membrane sweeping is associated with pain and an increased rate of vaginal bleeding.¹⁰ It does not increase the rate of maternal or neonatal infection, however. It also does not reduce the CD rate. In the United Kingdom, the National Institute for Health and Clinical Excellence recommends that all clinicians have a discussion of membrane sweeping with their patients at 38 weeks’ gestation and offer membrane stripping at 40 weeks to increase the rate of timely spontaneous labor and to avoid the risks of prolonged pregnancy.¹¹ Of note, in one randomized study of women planning a trial of labor after CD, membrane sweeping did not impact the duration of pregnancy, onset of spontaneous labor, or the CD rate.¹²

Steps from an expert. A skillfull midwife practicing in the United Kingdom provides the following guidance on how to perform membrane sweeping.¹³

1. Prepare the patient. Explain the procedure, have the patient empty her bladder, and encourage relaxed breathing if the vaginal examination causes pain.
2. Abdominal exam. Assess uterine size, fetal lie and presentation, and fetal heart tones.
3. Vaginal exam. Ascertain cervical dilation, effacement, and position. If the cervix is closed a sweep may not be possible. In this case, massaging the vaginal fornices may help to release prostaglandins and stimulate uterine contractions. If the cervix is closed but soft, massage of the cervix may permit the insertion of a finger. If the cervix is favorable for sweeping, insert one finger in the cervix and rotate the finger in a circle to separate the amnion from the cervix.
4. After the procedure. Provide the woman with a sanitary pad and recommend acetaminophen and a warm bath if she has discomfort or painful contractions. Advise her to come to the maternity unit in the following situations: severe pain, significant bleeding, or spontaneous rupture of the membranes.

Membrane sweeping can be performed as frequently as every 3 days. Formal cervical ripening and induction of labor may need to be planned if membrane sweeping does not result in the initiation of regular contractions.

Continue to: Collaborative decision making

Collaborative decision making

All clinicians recognize the primacy of patient autonomy.¹⁴ Competent patients have the right to select the course of care that they believe is optimal. When a patient decides to continue her pregnancy past 41 weeks, it is helpful to endorse respect for the decision and inquire about the patient’s reasons for continuing the pregnancy. Understanding the patient’s concerns may begin a conversation that will result in the patient accepting a plan for induction near 41 weeks’ gestation. If the patient insists on expectant management well beyond 41 weeks, the medical record should contain a summary of the clinician recommendation to induce labor at or before 41 weeks’ gestation and the patient’s preference for expectant management and her understanding of the decision’s risks.

Obstetricians and midwives constantly face the challenge of balancing the desire to avoid meddlesome interference in a pregnancy with the need to act to prevent adverse pregnancy outcomes. The challenge is daunting. A comprehensive meta-analysis of the benefit of induction of labor at or beyond term, estimated that 426 inductions would need to be initiated to prevent one perinatal death.² From one perspective it is meddlesome to intervene on more than 400 women to prevent one perinatal death. However, substantial data indicate that expectant management of a well-dated pregnancy at 41 weeks’ gestation will result in adverse outcomes that likely could be prevented by induction of labor. If you ran an airline and could take an action to prevent one airplane crash for every 400 flights, you would likely move heaven and earth to try to prevent that disaster. Unless the patient strongly prefers expectant management, well-managed induction of labor at or before 41 weeks’ gestation is likely to reduce the rate of adverse pregnancy events and, hence, is warranted.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Most people know that preterm birth is a major contributor to perinatal morbidity and mortality. Consequently, strict guidelines have been enforced to prevent non–medically indicated scheduled deliveries before 39 weeks’ gestation. Fewer people recognize that late-term birth is also an important and avoidable contributor to perinatal morbidity. To improve pregnancy outcomes, we may need enhanced guidelines about minimizing expectant management of pregnancy beyond 41 weeks’ gestation.

For the fetus, what is the optimal duration of a healthy pregnancy?

When pregnancy progresses past the date of the confinement, the risk of fetal or newborn injury or death increases, especially after 41 weeks’ gestation. Analysis of this risk, day by day, suggests that after 40 weeks’ and 3 days’ gestation there is no medical benefit to the fetus to remain in utero because, compared with induced delivery, expectant management of the pregnancy is associated with a greater rate of fetal and newborn morbidity and mortality.¹

The fetal and newborn benefits of delivery, rather than expectant management, at term include: a decrease in stillbirth and perinatal death rates, a decrease in admissions to the neonatal intensive care unit (NICU), a decrease in meconium-stained amniotic fluid and meconium aspiration syndrome, a decrease in low Apgar scores, and a decrease in problems related to uteroplacental insufficiency, including oligohydramnios.² In a comprehensive meta-analysis, induction of labor at or beyond term reduced the risk of perinatal death or stillbirth by 67%, the risk of a 5-minute Apgar score below 7 by 30%, and the risk of NICU admission by 12%.² The number of women that would need to be induced to prevent 1 perinatal death was estimated to be 426.²

Maternal benefits of avoiding late-term pregnancy

The maternal benefits of avoiding continuing a pregnancy past 41 weeks’ gestation include a reduction in labor dystocia and the risk of cesarean delivery (CD).^2,3 In one clinical trial, 3,407 women with low-risk pregnancy were randomly assigned to induction of labor at 41 weeks’ gestation or expectant management, awaiting the onset of labor with serial antenatal monitoring (nonstress tests and assessment of amniotic fluid volume).⁴ The CD rate was lower among the women randomized to induction of labor at 41 weeks’ (21.2% vs 24.5% in the expectant management group, P = .03). The rate of meconium-stained fluid was lower in the induction of labor group (25.0% vs 28.7%, P = .009). The rate of CD due to fetal distress also was lower in the induction of labor group (5.7% vs 8.3%, P = .003). The risks of maternal postpartum hemorrhage, sepsis, and endometritis did not differ between the groups. There were 2 stillbirths in the expectant management group (2/1,706) and none in the induction of labor group (0/1,701). There were no neonatal deaths in this study.⁴

Obstetric management, including accurate dating of pregnancy and membrane sweeping at term, can help to reduce the risk that a pregnancy will progress beyond 41 weeks’ gestation.⁵

Continue to: Routinely use ultrasound to accurately establish gestational age

Routinely use ultrasound to accurately establish gestational age

First trimester ultrasound should be offered to all pregnant women because it is a more accurate assessment of gestational age and will result in fewer pregnancies that are thought to be at or beyond 41 weeks’ gestation.⁵ In a meta-analysis of 8 studies, including 25,516 women, early ultrasonography reduced the rate of intervention for postterm pregnancy by 42% (31/1,000 to 18/1,000 pregnant women).⁶

Membrane sweeping (or stripping)

Membrane sweeping, which causes the release of prostaglandins, has been reported to reduce the risk of late-term and postterm induction of labor.^7,8 In the most recent Cochrane review on the topic, sweeping membranes reduced the rate of induction of labor at 41 weeks by 41% and at 42 weeks by 72%.⁷ To avoid one induction of labor for late-term or postterm pregnancy, sweeping of membranes would need to be performed on 8 women. In a recent meta-analysis, membrane sweeping reduced the rate of induction of labor for postmaturity by 48%.⁹

Membrane sweeping is associated with pain and an increased rate of vaginal bleeding.¹⁰ It does not increase the rate of maternal or neonatal infection, however. It also does not reduce the CD rate. In the United Kingdom, the National Institute for Health and Clinical Excellence recommends that all clinicians have a discussion of membrane sweeping with their patients at 38 weeks’ gestation and offer membrane stripping at 40 weeks to increase the rate of timely spontaneous labor and to avoid the risks of prolonged pregnancy.¹¹ Of note, in one randomized study of women planning a trial of labor after CD, membrane sweeping did not impact the duration of pregnancy, onset of spontaneous labor, or the CD rate.¹²

Steps from an expert. A skillfull midwife practicing in the United Kingdom provides the following guidance on how to perform membrane sweeping.¹³

1. Prepare the patient. Explain the procedure, have the patient empty her bladder, and encourage relaxed breathing if the vaginal examination causes pain.
2. Abdominal exam. Assess uterine size, fetal lie and presentation, and fetal heart tones.
3. Vaginal exam. Ascertain cervical dilation, effacement, and position. If the cervix is closed a sweep may not be possible. In this case, massaging the vaginal fornices may help to release prostaglandins and stimulate uterine contractions. If the cervix is closed but soft, massage of the cervix may permit the insertion of a finger. If the cervix is favorable for sweeping, insert one finger in the cervix and rotate the finger in a circle to separate the amnion from the cervix.
4. After the procedure. Provide the woman with a sanitary pad and recommend acetaminophen and a warm bath if she has discomfort or painful contractions. Advise her to come to the maternity unit in the following situations: severe pain, significant bleeding, or spontaneous rupture of the membranes.

Membrane sweeping can be performed as frequently as every 3 days. Formal cervical ripening and induction of labor may need to be planned if membrane sweeping does not result in the initiation of regular contractions.

Continue to: Collaborative decision making

Collaborative decision making

All clinicians recognize the primacy of patient autonomy.¹⁴ Competent patients have the right to select the course of care that they believe is optimal. When a patient decides to continue her pregnancy past 41 weeks, it is helpful to endorse respect for the decision and inquire about the patient’s reasons for continuing the pregnancy. Understanding the patient’s concerns may begin a conversation that will result in the patient accepting a plan for induction near 41 weeks’ gestation. If the patient insists on expectant management well beyond 41 weeks, the medical record should contain a summary of the clinician recommendation to induce labor at or before 41 weeks’ gestation and the patient’s preference for expectant management and her understanding of the decision’s risks.

Obstetricians and midwives constantly face the challenge of balancing the desire to avoid meddlesome interference in a pregnancy with the need to act to prevent adverse pregnancy outcomes. The challenge is daunting. A comprehensive meta-analysis of the benefit of induction of labor at or beyond term, estimated that 426 inductions would need to be initiated to prevent one perinatal death.² From one perspective it is meddlesome to intervene on more than 400 women to prevent one perinatal death. However, substantial data indicate that expectant management of a well-dated pregnancy at 41 weeks’ gestation will result in adverse outcomes that likely could be prevented by induction of labor. If you ran an airline and could take an action to prevent one airplane crash for every 400 flights, you would likely move heaven and earth to try to prevent that disaster. Unless the patient strongly prefers expectant management, well-managed induction of labor at or before 41 weeks’ gestation is likely to reduce the rate of adverse pregnancy events and, hence, is warranted.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.