Atopic dermatitis (AD), more commonly referred to as eczema, is a chronic pruritic inflammatory skin disease that frequently affects both children and adults. Atopic dermatitis is most common in urban and developed countries, with a prevalence of approximately 11% in the United States.¹ The pathophysiology of AD is complex and not fully understood, despite the increasing incidence of the disease.² A myriad of factors, including genetics, defects in the innate and adaptive immune response, and skin barrier abnormalities all contribute to the pathogenesis.^3,4 As a result of these abnormalities, patients with AD are more prone to damage from environmental irritants and allergens.

The diagnosis of AD is made clinically based on patient history and visual assessment of the skin.⁵ Atopic dermatitis follows a chronic and relapsing course characterized by severe pruritus and visible skin changes including xerosis, redness, blistering, oozing, crusting, scaling, thickening, and color change.^6,7 Due to the genetic predisposition to make IgE antibodies in response to common environmental and food antigens, patients also may develop allergic rhinitis, asthma, and food-induced anaphylaxis.^8,9 Patients also are susceptible to cutaneous viral, fungal, and bacterial infections, the most common of which is an infection with Staphylococcus aureus.¹⁰

Atopic dermatitis can have a substantial impact on quality of life, which has been revealed in studies linking chronic skin conditions to depression, impairment of self-esteem, and financial hardship.¹¹ Because skin appearance impacts how a person is initially perceived by others, patients often report feeling self-conscious about their disease and experience teasing or bullying.¹² To improve their physical appearance, patients may incur considerable medical expenses. According to 2 population-based studies comprising more than 60,000 adults aged 18 to 85 years, individuals with AD face substantial financial burdens and utilize the health care system more than those without the disease. On average, patients with AD spend $371 to $489 per year on costly out-of-pocket medical expenses and report more absences from work.¹³

Although there currently is no cure for AD, treatment is aimed at relieving its symptoms and preventing acute exacerbations as well as improving cosmetic appearance to enhance quality of life. Treatment must follow a stepwise approach, which focuses on hydrating the skin, repairing the dysfunctional epithelial barrier, and controlling inflammation. Thus, the standard of care focuses on avoiding skin irritants and triggers along with the use of moisturizers and topical corticosteroids (TCs). In patients with recurring severe disease, topical calcineurin inhibitors, phototherapy, and systemic agents also may be utilized.¹⁴

Avoiding Irritants and Triggers

Atopic dermatitis is worsened by skin contact with physical and chemical irritants. Exacerbating factors in AD include exposure to food allergens, dust, emotional stress, detergents, fragranced soaps, textiles, and ingredients in cosmetic products. Patients should be advised to use mild detergents and fragrance-free soaps and to avoid harsh materials such as wool. However, avoidance of specific ingredients in cosmetic products is not as straightforward because manufacturers are not required to disclose certain ingredients. In general, fragrances such as balsam of Peru and cinnamaldehyde, as well as preservatives such as parabens, isothiazolinones, and formaldehyde, should be avoided when selecting cosmetic products. Patients with AD should purchase fragrance-free products that are specifically formulated for sensitive skin. Additionally, patients should not apply makeup if their skin is irritated or oozing, as the flare may worsen.¹⁵

Moisturizers

Due to the impaired skin barrier function in patients with AD, regular application of fragrance-free moisturizers is essential to maintain hydration and to reduce xerosis. Various classes of moisturizers may be prescribed (eg, lotions, creams, gels, ointments) based on disease severity and patient preference. Light preparations such as lotions, creams, and gels have a high water content and generally are more appealing from a cosmetic standpoint because they do not create any residue on the skin. However, these options may require more frequent application because they are absorbed quickly. Heavy preparations such as ointments have longer-lasting effects due to their high oil content but tend to be less cosmetically appealing because of their greasiness.¹⁶

Although the amount and frequency of application of moisturizers has not been defined, liberal application several times daily is generally advised to minimize xerosis.¹⁷ Most physicians recommend applying moisturizer to the skin immediately after bathing to seal in moisture. Some patients prefer to use lotions and creams during the day because these products make the skin feel smooth and reserve the greasier ointments for nighttime application.

Topical Corticosteroids

Prescribed in conjunction with moisturizers, TCs are the mainstay of anti-inflammatory therapy in AD. Topical corticosteroids are classified into 7 groups based on potency, ranging from superpotent (class 1) to least potent (class 7). For acute AD flares, TCs should be applied daily for up to several weeks. Once the inflammation has resolved, it is recommended to apply TCs once to twice weekly to reduce the rate of relapse.¹⁸ Despite their effectiveness in the treatment of acute AD flares, TCs have a considerable side-effect profile. Potential adverse effects include skin atrophy, striae, telangiectasia, hypopigmentation, increased hair growth, steroid acne, growth retardation, and Cushing syndrome. Skin atrophy, which is the most common complication associated with TCs, results in shiny transparent skin, allowing for visualization of veins.^19,20 Although many of these side effects will resolve after discontinuing the TCs, they are aesthetically displeasing during treatment, making it crucial for physicians to educate their patients on the proper usage of TCs to prevent negative outcomes.

Topical Calcineurin Inhibitors

Topical calcineurin inhibitors (TCIs) are a class of anti-inflammatories that are used to overcome the adverse effects of TCs. They are approved as alternatives to TCs in patients who have failed to respond to other topical treatments as well as those who have developed cutaneous atrophy from the use of TCs or have AD in sensitive areas such as the face, neck, and/or skin folds. Unlike TCs, TCIs do not cause atrophy, striae, or discoloration of the skin, which makes them more desirable from a cosmetic perspective. Their mechanism of action is distinct from TCs in that they inhibit calcineurin-dependent T-cell activation, thus preventing the transcription of inflammatory cytokines.²¹ Two TCIs are currently available: tacrolimus ointment 0.03% and 0.1% concentrations for moderate to severe AD and pimecrolimus cream 1% for mild to moderate AD.²² Twice-daily application of TCIs is recommended to decrease inflammation and pruritus associated with AD. Studies also have shown that intermittent use of TCIs 3 times weekly can aid in reducing relapses.^23-25

The results from clinical trials demonstrate the rapid and continuous effects of both pimecrolimus and tacrolimus. In a controlled long-term study of adults, pimecrolimus provided significant relief of pruritus as soon as day 3 (P<.001).^26,27 Pimecrolimus also provides long-term relief by preventing disease progression to flares, which was exemplified in a study (N=713) with no flares in 51% of pimecrolimus patients at 12 months versus 28% in the conventional treatment group (P<.001).²⁸ Similarly, long-term studies of tacrolimus demonstrated an improvement of all symptoms of AD after 1 week of treatment. Maximal improvement was achieved with continued use of tacrolimus, and up to 1 year of tacrolimus use was found to be safe and effective.^29,30 Thus, TCIs have been proven to be an effective choice in maintenance therapy for AD and have a good safety profile. The most common adverse effects of TCIs are local skin reactions, such as stinging and burning at the site of application. Rare cases of skin cancer and lymphoma have been reported; however, a causal relationship has yet to be established.^31,32

Additional Therapies

Wet wrap therapy is effective for rapid control of flares and in controlling recalcitrant AD. Wet wraps function via several mechanisms; they provide a mechanical barrier against scratching, increase moisture and soften the skin, and enhance absorption of topical medications.^33,34 The following method is employed when using wet wraps: an emollient or TC is applied to the area, a tubular bandage soaked in warm water is wrapped over the area, and dry bandages are used to form the outermost layer. Although wet wrap therapy is beneficial in treating AD, it is labor intensive and may require the expertise of a nurse. Thus, unlike other therapies, which patients can easily apply without interfering with their day, wet wraps must be applied at home or in a hospital setting.

Light therapy is another effective method of controlling AD. Although multiple forms of UV phototherapy are beneficial for symptom control in AD, there is no definitive recommendation regarding the specific type of light therapy due to a lack of comparative studies. Natural sunlight, narrowband UVB, broadband UVB, UVA, oral or topical psoralen plus UVA, as well as UVA and UVB can all be utilized in the treatment of AD. However, similar to natural sunlight, artificial light therapy can cause burning, blistering, hyperpigmentation, dark spots, and wrinkles. Because society places a large emphasis on maintaining a youthful appearance, patients may be hesitant to use a treatment that could potentially advance the skin’s aging process. Thus, it is important that this therapy is properly controlled to prevent further skin damage.^35-37

When optimal topical regimens and phototherapy have failed to control AD, systemic immunomodulation therapies may be used. Currently, the most commonly used medications are cyclosporine 150 to 300 mg daily, methotrexate 7.5 to 25 mg weekly, mycophenolate mofetil 0.5 to 3 g daily, and azathioprine 1 to 3 mg/kg daily.^38,39 Decisions regarding the specific class of drugs should be based on the patient’s AD status, comorbidities, and personal preference.

Conclusion

Atopic dermatitis is a common chronic condition that can occur at any age and cause substantial physical, psychological, social, and/or emotional stress for patients and their families. Although TCs have been the standard of treatment for many years, ongoing concerns regarding their safety have led to the use of TCIs, which overcome some of the drawbacks of steroid therapy. Phototherapy and systemic immunosuppressant therapy are reserved for patients who have not responded to optimal topical therapies. Although several therapeutic avenues exist for patients, there is a need for the development of more effective and safer drugs. Furthermore, cosmetic products created specifically for patients with AD would be beneficial, as patients often struggle to select products that do not cause more harm than good. Given the complexity of the pathogenesis of AD, further research must focus on defining the specific pathways involved in the disease and targeting these pathways with therapies.

Atopic dermatitis (AD), more commonly referred to as eczema, is a chronic pruritic inflammatory skin disease that frequently affects both children and adults. Atopic dermatitis is most common in urban and developed countries, with a prevalence of approximately 11% in the United States.¹ The pathophysiology of AD is complex and not fully understood, despite the increasing incidence of the disease.² A myriad of factors, including genetics, defects in the innate and adaptive immune response, and skin barrier abnormalities all contribute to the pathogenesis.^3,4 As a result of these abnormalities, patients with AD are more prone to damage from environmental irritants and allergens.

The diagnosis of AD is made clinically based on patient history and visual assessment of the skin.⁵ Atopic dermatitis follows a chronic and relapsing course characterized by severe pruritus and visible skin changes including xerosis, redness, blistering, oozing, crusting, scaling, thickening, and color change.^6,7 Due to the genetic predisposition to make IgE antibodies in response to common environmental and food antigens, patients also may develop allergic rhinitis, asthma, and food-induced anaphylaxis.^8,9 Patients also are susceptible to cutaneous viral, fungal, and bacterial infections, the most common of which is an infection with Staphylococcus aureus.¹⁰

Atopic dermatitis can have a substantial impact on quality of life, which has been revealed in studies linking chronic skin conditions to depression, impairment of self-esteem, and financial hardship.¹¹ Because skin appearance impacts how a person is initially perceived by others, patients often report feeling self-conscious about their disease and experience teasing or bullying.¹² To improve their physical appearance, patients may incur considerable medical expenses. According to 2 population-based studies comprising more than 60,000 adults aged 18 to 85 years, individuals with AD face substantial financial burdens and utilize the health care system more than those without the disease. On average, patients with AD spend $371 to $489 per year on costly out-of-pocket medical expenses and report more absences from work.¹³

Although there currently is no cure for AD, treatment is aimed at relieving its symptoms and preventing acute exacerbations as well as improving cosmetic appearance to enhance quality of life. Treatment must follow a stepwise approach, which focuses on hydrating the skin, repairing the dysfunctional epithelial barrier, and controlling inflammation. Thus, the standard of care focuses on avoiding skin irritants and triggers along with the use of moisturizers and topical corticosteroids (TCs). In patients with recurring severe disease, topical calcineurin inhibitors, phototherapy, and systemic agents also may be utilized.¹⁴

Avoiding Irritants and Triggers

Atopic dermatitis is worsened by skin contact with physical and chemical irritants. Exacerbating factors in AD include exposure to food allergens, dust, emotional stress, detergents, fragranced soaps, textiles, and ingredients in cosmetic products. Patients should be advised to use mild detergents and fragrance-free soaps and to avoid harsh materials such as wool. However, avoidance of specific ingredients in cosmetic products is not as straightforward because manufacturers are not required to disclose certain ingredients. In general, fragrances such as balsam of Peru and cinnamaldehyde, as well as preservatives such as parabens, isothiazolinones, and formaldehyde, should be avoided when selecting cosmetic products. Patients with AD should purchase fragrance-free products that are specifically formulated for sensitive skin. Additionally, patients should not apply makeup if their skin is irritated or oozing, as the flare may worsen.¹⁵

Moisturizers

Due to the impaired skin barrier function in patients with AD, regular application of fragrance-free moisturizers is essential to maintain hydration and to reduce xerosis. Various classes of moisturizers may be prescribed (eg, lotions, creams, gels, ointments) based on disease severity and patient preference. Light preparations such as lotions, creams, and gels have a high water content and generally are more appealing from a cosmetic standpoint because they do not create any residue on the skin. However, these options may require more frequent application because they are absorbed quickly. Heavy preparations such as ointments have longer-lasting effects due to their high oil content but tend to be less cosmetically appealing because of their greasiness.¹⁶

Although the amount and frequency of application of moisturizers has not been defined, liberal application several times daily is generally advised to minimize xerosis.¹⁷ Most physicians recommend applying moisturizer to the skin immediately after bathing to seal in moisture. Some patients prefer to use lotions and creams during the day because these products make the skin feel smooth and reserve the greasier ointments for nighttime application.

Topical Corticosteroids

Prescribed in conjunction with moisturizers, TCs are the mainstay of anti-inflammatory therapy in AD. Topical corticosteroids are classified into 7 groups based on potency, ranging from superpotent (class 1) to least potent (class 7). For acute AD flares, TCs should be applied daily for up to several weeks. Once the inflammation has resolved, it is recommended to apply TCs once to twice weekly to reduce the rate of relapse.¹⁸ Despite their effectiveness in the treatment of acute AD flares, TCs have a considerable side-effect profile. Potential adverse effects include skin atrophy, striae, telangiectasia, hypopigmentation, increased hair growth, steroid acne, growth retardation, and Cushing syndrome. Skin atrophy, which is the most common complication associated with TCs, results in shiny transparent skin, allowing for visualization of veins.^19,20 Although many of these side effects will resolve after discontinuing the TCs, they are aesthetically displeasing during treatment, making it crucial for physicians to educate their patients on the proper usage of TCs to prevent negative outcomes.

Topical Calcineurin Inhibitors

Topical calcineurin inhibitors (TCIs) are a class of anti-inflammatories that are used to overcome the adverse effects of TCs. They are approved as alternatives to TCs in patients who have failed to respond to other topical treatments as well as those who have developed cutaneous atrophy from the use of TCs or have AD in sensitive areas such as the face, neck, and/or skin folds. Unlike TCs, TCIs do not cause atrophy, striae, or discoloration of the skin, which makes them more desirable from a cosmetic perspective. Their mechanism of action is distinct from TCs in that they inhibit calcineurin-dependent T-cell activation, thus preventing the transcription of inflammatory cytokines.²¹ Two TCIs are currently available: tacrolimus ointment 0.03% and 0.1% concentrations for moderate to severe AD and pimecrolimus cream 1% for mild to moderate AD.²² Twice-daily application of TCIs is recommended to decrease inflammation and pruritus associated with AD. Studies also have shown that intermittent use of TCIs 3 times weekly can aid in reducing relapses.^23-25

The results from clinical trials demonstrate the rapid and continuous effects of both pimecrolimus and tacrolimus. In a controlled long-term study of adults, pimecrolimus provided significant relief of pruritus as soon as day 3 (P<.001).^26,27 Pimecrolimus also provides long-term relief by preventing disease progression to flares, which was exemplified in a study (N=713) with no flares in 51% of pimecrolimus patients at 12 months versus 28% in the conventional treatment group (P<.001).²⁸ Similarly, long-term studies of tacrolimus demonstrated an improvement of all symptoms of AD after 1 week of treatment. Maximal improvement was achieved with continued use of tacrolimus, and up to 1 year of tacrolimus use was found to be safe and effective.^29,30 Thus, TCIs have been proven to be an effective choice in maintenance therapy for AD and have a good safety profile. The most common adverse effects of TCIs are local skin reactions, such as stinging and burning at the site of application. Rare cases of skin cancer and lymphoma have been reported; however, a causal relationship has yet to be established.^31,32

Additional Therapies

Wet wrap therapy is effective for rapid control of flares and in controlling recalcitrant AD. Wet wraps function via several mechanisms; they provide a mechanical barrier against scratching, increase moisture and soften the skin, and enhance absorption of topical medications.^33,34 The following method is employed when using wet wraps: an emollient or TC is applied to the area, a tubular bandage soaked in warm water is wrapped over the area, and dry bandages are used to form the outermost layer. Although wet wrap therapy is beneficial in treating AD, it is labor intensive and may require the expertise of a nurse. Thus, unlike other therapies, which patients can easily apply without interfering with their day, wet wraps must be applied at home or in a hospital setting.

Light therapy is another effective method of controlling AD. Although multiple forms of UV phototherapy are beneficial for symptom control in AD, there is no definitive recommendation regarding the specific type of light therapy due to a lack of comparative studies. Natural sunlight, narrowband UVB, broadband UVB, UVA, oral or topical psoralen plus UVA, as well as UVA and UVB can all be utilized in the treatment of AD. However, similar to natural sunlight, artificial light therapy can cause burning, blistering, hyperpigmentation, dark spots, and wrinkles. Because society places a large emphasis on maintaining a youthful appearance, patients may be hesitant to use a treatment that could potentially advance the skin’s aging process. Thus, it is important that this therapy is properly controlled to prevent further skin damage.^35-37

When optimal topical regimens and phototherapy have failed to control AD, systemic immunomodulation therapies may be used. Currently, the most commonly used medications are cyclosporine 150 to 300 mg daily, methotrexate 7.5 to 25 mg weekly, mycophenolate mofetil 0.5 to 3 g daily, and azathioprine 1 to 3 mg/kg daily.^38,39 Decisions regarding the specific class of drugs should be based on the patient’s AD status, comorbidities, and personal preference.

Conclusion

Atopic dermatitis is a common chronic condition that can occur at any age and cause substantial physical, psychological, social, and/or emotional stress for patients and their families. Although TCs have been the standard of treatment for many years, ongoing concerns regarding their safety have led to the use of TCIs, which overcome some of the drawbacks of steroid therapy. Phototherapy and systemic immunosuppressant therapy are reserved for patients who have not responded to optimal topical therapies. Although several therapeutic avenues exist for patients, there is a need for the development of more effective and safer drugs. Furthermore, cosmetic products created specifically for patients with AD would be beneficial, as patients often struggle to select products that do not cause more harm than good. Given the complexity of the pathogenesis of AD, further research must focus on defining the specific pathways involved in the disease and targeting these pathways with therapies.

Atopic dermatitis (AD), more commonly referred to as eczema, is a chronic pruritic inflammatory skin disease that frequently affects both children and adults. Atopic dermatitis is most common in urban and developed countries, with a prevalence of approximately 11% in the United States.¹ The pathophysiology of AD is complex and not fully understood, despite the increasing incidence of the disease.² A myriad of factors, including genetics, defects in the innate and adaptive immune response, and skin barrier abnormalities all contribute to the pathogenesis.^3,4 As a result of these abnormalities, patients with AD are more prone to damage from environmental irritants and allergens.

The diagnosis of AD is made clinically based on patient history and visual assessment of the skin.⁵ Atopic dermatitis follows a chronic and relapsing course characterized by severe pruritus and visible skin changes including xerosis, redness, blistering, oozing, crusting, scaling, thickening, and color change.^6,7 Due to the genetic predisposition to make IgE antibodies in response to common environmental and food antigens, patients also may develop allergic rhinitis, asthma, and food-induced anaphylaxis.^8,9 Patients also are susceptible to cutaneous viral, fungal, and bacterial infections, the most common of which is an infection with Staphylococcus aureus.¹⁰

Atopic dermatitis can have a substantial impact on quality of life, which has been revealed in studies linking chronic skin conditions to depression, impairment of self-esteem, and financial hardship.¹¹ Because skin appearance impacts how a person is initially perceived by others, patients often report feeling self-conscious about their disease and experience teasing or bullying.¹² To improve their physical appearance, patients may incur considerable medical expenses. According to 2 population-based studies comprising more than 60,000 adults aged 18 to 85 years, individuals with AD face substantial financial burdens and utilize the health care system more than those without the disease. On average, patients with AD spend $371 to $489 per year on costly out-of-pocket medical expenses and report more absences from work.¹³

Although there currently is no cure for AD, treatment is aimed at relieving its symptoms and preventing acute exacerbations as well as improving cosmetic appearance to enhance quality of life. Treatment must follow a stepwise approach, which focuses on hydrating the skin, repairing the dysfunctional epithelial barrier, and controlling inflammation. Thus, the standard of care focuses on avoiding skin irritants and triggers along with the use of moisturizers and topical corticosteroids (TCs). In patients with recurring severe disease, topical calcineurin inhibitors, phototherapy, and systemic agents also may be utilized.¹⁴

Avoiding Irritants and Triggers

Atopic dermatitis is worsened by skin contact with physical and chemical irritants. Exacerbating factors in AD include exposure to food allergens, dust, emotional stress, detergents, fragranced soaps, textiles, and ingredients in cosmetic products. Patients should be advised to use mild detergents and fragrance-free soaps and to avoid harsh materials such as wool. However, avoidance of specific ingredients in cosmetic products is not as straightforward because manufacturers are not required to disclose certain ingredients. In general, fragrances such as balsam of Peru and cinnamaldehyde, as well as preservatives such as parabens, isothiazolinones, and formaldehyde, should be avoided when selecting cosmetic products. Patients with AD should purchase fragrance-free products that are specifically formulated for sensitive skin. Additionally, patients should not apply makeup if their skin is irritated or oozing, as the flare may worsen.¹⁵

Moisturizers

Due to the impaired skin barrier function in patients with AD, regular application of fragrance-free moisturizers is essential to maintain hydration and to reduce xerosis. Various classes of moisturizers may be prescribed (eg, lotions, creams, gels, ointments) based on disease severity and patient preference. Light preparations such as lotions, creams, and gels have a high water content and generally are more appealing from a cosmetic standpoint because they do not create any residue on the skin. However, these options may require more frequent application because they are absorbed quickly. Heavy preparations such as ointments have longer-lasting effects due to their high oil content but tend to be less cosmetically appealing because of their greasiness.¹⁶

Although the amount and frequency of application of moisturizers has not been defined, liberal application several times daily is generally advised to minimize xerosis.¹⁷ Most physicians recommend applying moisturizer to the skin immediately after bathing to seal in moisture. Some patients prefer to use lotions and creams during the day because these products make the skin feel smooth and reserve the greasier ointments for nighttime application.

Topical Corticosteroids

Prescribed in conjunction with moisturizers, TCs are the mainstay of anti-inflammatory therapy in AD. Topical corticosteroids are classified into 7 groups based on potency, ranging from superpotent (class 1) to least potent (class 7). For acute AD flares, TCs should be applied daily for up to several weeks. Once the inflammation has resolved, it is recommended to apply TCs once to twice weekly to reduce the rate of relapse.¹⁸ Despite their effectiveness in the treatment of acute AD flares, TCs have a considerable side-effect profile. Potential adverse effects include skin atrophy, striae, telangiectasia, hypopigmentation, increased hair growth, steroid acne, growth retardation, and Cushing syndrome. Skin atrophy, which is the most common complication associated with TCs, results in shiny transparent skin, allowing for visualization of veins.^19,20 Although many of these side effects will resolve after discontinuing the TCs, they are aesthetically displeasing during treatment, making it crucial for physicians to educate their patients on the proper usage of TCs to prevent negative outcomes.

Topical Calcineurin Inhibitors

Topical calcineurin inhibitors (TCIs) are a class of anti-inflammatories that are used to overcome the adverse effects of TCs. They are approved as alternatives to TCs in patients who have failed to respond to other topical treatments as well as those who have developed cutaneous atrophy from the use of TCs or have AD in sensitive areas such as the face, neck, and/or skin folds. Unlike TCs, TCIs do not cause atrophy, striae, or discoloration of the skin, which makes them more desirable from a cosmetic perspective. Their mechanism of action is distinct from TCs in that they inhibit calcineurin-dependent T-cell activation, thus preventing the transcription of inflammatory cytokines.²¹ Two TCIs are currently available: tacrolimus ointment 0.03% and 0.1% concentrations for moderate to severe AD and pimecrolimus cream 1% for mild to moderate AD.²² Twice-daily application of TCIs is recommended to decrease inflammation and pruritus associated with AD. Studies also have shown that intermittent use of TCIs 3 times weekly can aid in reducing relapses.^23-25

The results from clinical trials demonstrate the rapid and continuous effects of both pimecrolimus and tacrolimus. In a controlled long-term study of adults, pimecrolimus provided significant relief of pruritus as soon as day 3 (P<.001).^26,27 Pimecrolimus also provides long-term relief by preventing disease progression to flares, which was exemplified in a study (N=713) with no flares in 51% of pimecrolimus patients at 12 months versus 28% in the conventional treatment group (P<.001).²⁸ Similarly, long-term studies of tacrolimus demonstrated an improvement of all symptoms of AD after 1 week of treatment. Maximal improvement was achieved with continued use of tacrolimus, and up to 1 year of tacrolimus use was found to be safe and effective.^29,30 Thus, TCIs have been proven to be an effective choice in maintenance therapy for AD and have a good safety profile. The most common adverse effects of TCIs are local skin reactions, such as stinging and burning at the site of application. Rare cases of skin cancer and lymphoma have been reported; however, a causal relationship has yet to be established.^31,32

Additional Therapies

Wet wrap therapy is effective for rapid control of flares and in controlling recalcitrant AD. Wet wraps function via several mechanisms; they provide a mechanical barrier against scratching, increase moisture and soften the skin, and enhance absorption of topical medications.^33,34 The following method is employed when using wet wraps: an emollient or TC is applied to the area, a tubular bandage soaked in warm water is wrapped over the area, and dry bandages are used to form the outermost layer. Although wet wrap therapy is beneficial in treating AD, it is labor intensive and may require the expertise of a nurse. Thus, unlike other therapies, which patients can easily apply without interfering with their day, wet wraps must be applied at home or in a hospital setting.

Light therapy is another effective method of controlling AD. Although multiple forms of UV phototherapy are beneficial for symptom control in AD, there is no definitive recommendation regarding the specific type of light therapy due to a lack of comparative studies. Natural sunlight, narrowband UVB, broadband UVB, UVA, oral or topical psoralen plus UVA, as well as UVA and UVB can all be utilized in the treatment of AD. However, similar to natural sunlight, artificial light therapy can cause burning, blistering, hyperpigmentation, dark spots, and wrinkles. Because society places a large emphasis on maintaining a youthful appearance, patients may be hesitant to use a treatment that could potentially advance the skin’s aging process. Thus, it is important that this therapy is properly controlled to prevent further skin damage.^35-37

When optimal topical regimens and phototherapy have failed to control AD, systemic immunomodulation therapies may be used. Currently, the most commonly used medications are cyclosporine 150 to 300 mg daily, methotrexate 7.5 to 25 mg weekly, mycophenolate mofetil 0.5 to 3 g daily, and azathioprine 1 to 3 mg/kg daily.^38,39 Decisions regarding the specific class of drugs should be based on the patient’s AD status, comorbidities, and personal preference.

Conclusion

Atopic dermatitis is a common chronic condition that can occur at any age and cause substantial physical, psychological, social, and/or emotional stress for patients and their families. Although TCs have been the standard of treatment for many years, ongoing concerns regarding their safety have led to the use of TCIs, which overcome some of the drawbacks of steroid therapy. Phototherapy and systemic immunosuppressant therapy are reserved for patients who have not responded to optimal topical therapies. Although several therapeutic avenues exist for patients, there is a need for the development of more effective and safer drugs. Furthermore, cosmetic products created specifically for patients with AD would be beneficial, as patients often struggle to select products that do not cause more harm than good. Given the complexity of the pathogenesis of AD, further research must focus on defining the specific pathways involved in the disease and targeting these pathways with therapies.

The best diagnosis is:

a. granular cell tumor
b. intradermal nevus
c. Langerhans cell disease
d. mastocytosis
e. multicentric reticulohistiocytosis

Monomorphic cell infiltrate in the upper dermis (H&E, original magnification ×100).

A closer view reveals cuboidal or spindle cells with basal hyperpigmentation (H&E, original magnification ×200).

Continue to the next page for the diagnosis >>

Mastocytosis

Mastocytosis is a clonal proliferation of mast cells in the skin and various systems of the body including the bone marrow, liver, lymph nodes, and gastrointestinal tract.^1,2 Mast cell proliferation is closely associated with germline and acquired activating KIT mutations.^3-5 Adult-onset mastocytosis is likely to involve several organs, whereas pediatric mastocytosis usually affects only the skin and is self-limiting. Patients with profound mast cell infiltration in the skin or other organs are likely to have attacks of flushing, palpitation, or diarrhea resulting from the degranulation of mast cells and release of histamine.^6,7 In a majority of patients with advanced systemic mastocytosis, mast cells are positive for the Ki-1 antigen (CD30), whereas in most patients with indolent systemic mastocytosis, only a few mast cells are positive for CD30.⁸ Recently, CD30 was reported as a new drug target in patients with CD30⁺ advanced systemic mastocytosis.⁹ Because the skin frequently is involved and easily accessible in comparison with other organs, skin biopsy often is performed to establish a diagnosis of mastocytosis. Cutaneous mastocytosis comprises urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans; approximately 80% of all cases have urticaria pigmentosa.^10-12 In cutaneous mastocytosis, skin biopsy typically shows monomorphous mast cell infiltrate mostly in the upper third of the dermis. The density of mast cells varies according to the clinical variant. For example, a lesion of telangiectasia macularis eruptiva perstans has only a perivascular mast cell infiltrate, whereas a solitary mastocytoma has sheets of mast cells in the dermis, sometimes extending into the subcutis. A skin biopsy of the brown macule on the waist showed a number of cuboidal or spindle mast cells in the upper dermis with occasional eosinophils. These mast cells are monomorphous, and no mitotic figures, necrotic cells, or atypical cells are seen. Mast cells have metachromatic granules in the cytoplasm, which can be seen with toluidine blue or Giemsa stain. CD117 (c-kit) also is positive. Mast cells in urticaria pigmentosa easily may be mistaken for nevus cells. Hyperpigmentation of the basal layer, a characteristic feature seen in urticaria pigmentosa, also may erroneously suggest a diagnosis of a melanocytic nevus.

Granular cell tumors predominantly affect the oral cavity, but the skin also can be involved. It comprises a fascicular infiltrate of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (Figure 1).¹³ Cell membranes are not always distinct. Although the nuclei usually are small and centrally located, irregular and plump nuclei with distinct nucleoli also may be seen. The overlying epidermis tends to be hyperplastic. Granular cell tumor is considered a group of lesions of varying histogenesis. Cases in which tumors originated from a neural crest–derived peripheral nerve–related cell as well as a Schwann cell have been reported.^14,15 The origin of granular cell tumors is controversial.

Figure 1. Granular cell tumor showing fascicles of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (H&E, original magnification ×200).

Figure 2. Intradermal nevus showing nests with melanin in the uppermost area of the lesion and neurotized nevus cells in the lower part (H&E, original magnification ×100). Pseudovascular spaces are seen on the right side.

Intradermal nevus usually has nests and cords of nevus cells in the upper dermis. The uppermost melanocytes often contain a moderate amount of melanin, whereas nevus cells in the mid and lower dermis usually do not contain melanin (Figure 2). Shrinkage during tissue processing maycause clefts between nevus cells, resulting in pseudovascular spaces.¹⁶ The deeper dermis may have a neuroid appearance with spindle-shaped cells and Meissner corpuscle–like structures.¹⁷

Although Langerhans cell disease was formerly known as Langerhans cell histiocytosis and subdivided into several clinical subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, these clinical subtypes commonly overlapped. Langerhans cell disease is now used as a terminology that encompasses all subtypes.^18,19 Langerhans cell disease is characterized by a proliferation of Langerhans cells with a variable mixture of other inflammatory cells. The constituent cells are large and ovoid with a distinct folded or lobulated, often kidney-shaped nucleus.²⁰ Langerhans cells usually infiltrate the upper dermis and occasionally the epidermis (Figure 3). CD1a, HLA-DR, S-100 protein, and langerin are positive in Langerhans cells.²¹

Figure 3. Langerhans cell disease showing an infiltrate of large and ovoid Langerhans cells with a distinct folded or lobulated, often kidney-shaped nucleus in the upper dermis and epidermis (H&E, original magnification ×200).

Figure 4. Multicentric reticulohistiocytosis showing a mixture of mononuclear and multinucleate histiocytes with abundant eosinophilic and finely granular cytoplasm (H&E, original magnification ×200).

Multicentric reticulohistiocytosis is characterized by a combination of papulonodular cutaneous lesions and severe arthropathy.²² An irregular mixture of mononuclear and multinucleate histiocytes showing abundant eosinophilic and finely granular cytoplasm, often with a ground-glass appearance, is seen along with lymphocytic infiltration (Figure 4).²³ A few giant cells may be seen in early lesions; older lesions more commonly have giant cells and fibrosis.

The best diagnosis is:

a. granular cell tumor
b. intradermal nevus
c. Langerhans cell disease
d. mastocytosis
e. multicentric reticulohistiocytosis

Monomorphic cell infiltrate in the upper dermis (H&E, original magnification ×100).

A closer view reveals cuboidal or spindle cells with basal hyperpigmentation (H&E, original magnification ×200).

Continue to the next page for the diagnosis >>

Mastocytosis

Mastocytosis is a clonal proliferation of mast cells in the skin and various systems of the body including the bone marrow, liver, lymph nodes, and gastrointestinal tract.^1,2 Mast cell proliferation is closely associated with germline and acquired activating KIT mutations.^3-5 Adult-onset mastocytosis is likely to involve several organs, whereas pediatric mastocytosis usually affects only the skin and is self-limiting. Patients with profound mast cell infiltration in the skin or other organs are likely to have attacks of flushing, palpitation, or diarrhea resulting from the degranulation of mast cells and release of histamine.^6,7 In a majority of patients with advanced systemic mastocytosis, mast cells are positive for the Ki-1 antigen (CD30), whereas in most patients with indolent systemic mastocytosis, only a few mast cells are positive for CD30.⁸ Recently, CD30 was reported as a new drug target in patients with CD30⁺ advanced systemic mastocytosis.⁹ Because the skin frequently is involved and easily accessible in comparison with other organs, skin biopsy often is performed to establish a diagnosis of mastocytosis. Cutaneous mastocytosis comprises urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans; approximately 80% of all cases have urticaria pigmentosa.^10-12 In cutaneous mastocytosis, skin biopsy typically shows monomorphous mast cell infiltrate mostly in the upper third of the dermis. The density of mast cells varies according to the clinical variant. For example, a lesion of telangiectasia macularis eruptiva perstans has only a perivascular mast cell infiltrate, whereas a solitary mastocytoma has sheets of mast cells in the dermis, sometimes extending into the subcutis. A skin biopsy of the brown macule on the waist showed a number of cuboidal or spindle mast cells in the upper dermis with occasional eosinophils. These mast cells are monomorphous, and no mitotic figures, necrotic cells, or atypical cells are seen. Mast cells have metachromatic granules in the cytoplasm, which can be seen with toluidine blue or Giemsa stain. CD117 (c-kit) also is positive. Mast cells in urticaria pigmentosa easily may be mistaken for nevus cells. Hyperpigmentation of the basal layer, a characteristic feature seen in urticaria pigmentosa, also may erroneously suggest a diagnosis of a melanocytic nevus.

Granular cell tumors predominantly affect the oral cavity, but the skin also can be involved. It comprises a fascicular infiltrate of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (Figure 1).¹³ Cell membranes are not always distinct. Although the nuclei usually are small and centrally located, irregular and plump nuclei with distinct nucleoli also may be seen. The overlying epidermis tends to be hyperplastic. Granular cell tumor is considered a group of lesions of varying histogenesis. Cases in which tumors originated from a neural crest–derived peripheral nerve–related cell as well as a Schwann cell have been reported.^14,15 The origin of granular cell tumors is controversial.

Figure 1. Granular cell tumor showing fascicles of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (H&E, original magnification ×200).

Figure 2. Intradermal nevus showing nests with melanin in the uppermost area of the lesion and neurotized nevus cells in the lower part (H&E, original magnification ×100). Pseudovascular spaces are seen on the right side.

Intradermal nevus usually has nests and cords of nevus cells in the upper dermis. The uppermost melanocytes often contain a moderate amount of melanin, whereas nevus cells in the mid and lower dermis usually do not contain melanin (Figure 2). Shrinkage during tissue processing maycause clefts between nevus cells, resulting in pseudovascular spaces.¹⁶ The deeper dermis may have a neuroid appearance with spindle-shaped cells and Meissner corpuscle–like structures.¹⁷

Although Langerhans cell disease was formerly known as Langerhans cell histiocytosis and subdivided into several clinical subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, these clinical subtypes commonly overlapped. Langerhans cell disease is now used as a terminology that encompasses all subtypes.^18,19 Langerhans cell disease is characterized by a proliferation of Langerhans cells with a variable mixture of other inflammatory cells. The constituent cells are large and ovoid with a distinct folded or lobulated, often kidney-shaped nucleus.²⁰ Langerhans cells usually infiltrate the upper dermis and occasionally the epidermis (Figure 3). CD1a, HLA-DR, S-100 protein, and langerin are positive in Langerhans cells.²¹

Figure 3. Langerhans cell disease showing an infiltrate of large and ovoid Langerhans cells with a distinct folded or lobulated, often kidney-shaped nucleus in the upper dermis and epidermis (H&E, original magnification ×200).

Figure 4. Multicentric reticulohistiocytosis showing a mixture of mononuclear and multinucleate histiocytes with abundant eosinophilic and finely granular cytoplasm (H&E, original magnification ×200).

Multicentric reticulohistiocytosis is characterized by a combination of papulonodular cutaneous lesions and severe arthropathy.²² An irregular mixture of mononuclear and multinucleate histiocytes showing abundant eosinophilic and finely granular cytoplasm, often with a ground-glass appearance, is seen along with lymphocytic infiltration (Figure 4).²³ A few giant cells may be seen in early lesions; older lesions more commonly have giant cells and fibrosis.

The best diagnosis is:

a. granular cell tumor
b. intradermal nevus
c. Langerhans cell disease
d. mastocytosis
e. multicentric reticulohistiocytosis

Monomorphic cell infiltrate in the upper dermis (H&E, original magnification ×100).

A closer view reveals cuboidal or spindle cells with basal hyperpigmentation (H&E, original magnification ×200).

Continue to the next page for the diagnosis >>

Mastocytosis

Mastocytosis is a clonal proliferation of mast cells in the skin and various systems of the body including the bone marrow, liver, lymph nodes, and gastrointestinal tract.^1,2 Mast cell proliferation is closely associated with germline and acquired activating KIT mutations.^3-5 Adult-onset mastocytosis is likely to involve several organs, whereas pediatric mastocytosis usually affects only the skin and is self-limiting. Patients with profound mast cell infiltration in the skin or other organs are likely to have attacks of flushing, palpitation, or diarrhea resulting from the degranulation of mast cells and release of histamine.^6,7 In a majority of patients with advanced systemic mastocytosis, mast cells are positive for the Ki-1 antigen (CD30), whereas in most patients with indolent systemic mastocytosis, only a few mast cells are positive for CD30.⁸ Recently, CD30 was reported as a new drug target in patients with CD30⁺ advanced systemic mastocytosis.⁹ Because the skin frequently is involved and easily accessible in comparison with other organs, skin biopsy often is performed to establish a diagnosis of mastocytosis. Cutaneous mastocytosis comprises urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans; approximately 80% of all cases have urticaria pigmentosa.^10-12 In cutaneous mastocytosis, skin biopsy typically shows monomorphous mast cell infiltrate mostly in the upper third of the dermis. The density of mast cells varies according to the clinical variant. For example, a lesion of telangiectasia macularis eruptiva perstans has only a perivascular mast cell infiltrate, whereas a solitary mastocytoma has sheets of mast cells in the dermis, sometimes extending into the subcutis. A skin biopsy of the brown macule on the waist showed a number of cuboidal or spindle mast cells in the upper dermis with occasional eosinophils. These mast cells are monomorphous, and no mitotic figures, necrotic cells, or atypical cells are seen. Mast cells have metachromatic granules in the cytoplasm, which can be seen with toluidine blue or Giemsa stain. CD117 (c-kit) also is positive. Mast cells in urticaria pigmentosa easily may be mistaken for nevus cells. Hyperpigmentation of the basal layer, a characteristic feature seen in urticaria pigmentosa, also may erroneously suggest a diagnosis of a melanocytic nevus.

Granular cell tumors predominantly affect the oral cavity, but the skin also can be involved. It comprises a fascicular infiltrate of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (Figure 1).¹³ Cell membranes are not always distinct. Although the nuclei usually are small and centrally located, irregular and plump nuclei with distinct nucleoli also may be seen. The overlying epidermis tends to be hyperplastic. Granular cell tumor is considered a group of lesions of varying histogenesis. Cases in which tumors originated from a neural crest–derived peripheral nerve–related cell as well as a Schwann cell have been reported.^14,15 The origin of granular cell tumors is controversial.

Figure 1. Granular cell tumor showing fascicles of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (H&E, original magnification ×200).

Figure 2. Intradermal nevus showing nests with melanin in the uppermost area of the lesion and neurotized nevus cells in the lower part (H&E, original magnification ×100). Pseudovascular spaces are seen on the right side.

Intradermal nevus usually has nests and cords of nevus cells in the upper dermis. The uppermost melanocytes often contain a moderate amount of melanin, whereas nevus cells in the mid and lower dermis usually do not contain melanin (Figure 2). Shrinkage during tissue processing maycause clefts between nevus cells, resulting in pseudovascular spaces.¹⁶ The deeper dermis may have a neuroid appearance with spindle-shaped cells and Meissner corpuscle–like structures.¹⁷

Although Langerhans cell disease was formerly known as Langerhans cell histiocytosis and subdivided into several clinical subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, these clinical subtypes commonly overlapped. Langerhans cell disease is now used as a terminology that encompasses all subtypes.^18,19 Langerhans cell disease is characterized by a proliferation of Langerhans cells with a variable mixture of other inflammatory cells. The constituent cells are large and ovoid with a distinct folded or lobulated, often kidney-shaped nucleus.²⁰ Langerhans cells usually infiltrate the upper dermis and occasionally the epidermis (Figure 3). CD1a, HLA-DR, S-100 protein, and langerin are positive in Langerhans cells.²¹

Figure 3. Langerhans cell disease showing an infiltrate of large and ovoid Langerhans cells with a distinct folded or lobulated, often kidney-shaped nucleus in the upper dermis and epidermis (H&E, original magnification ×200).

Figure 4. Multicentric reticulohistiocytosis showing a mixture of mononuclear and multinucleate histiocytes with abundant eosinophilic and finely granular cytoplasm (H&E, original magnification ×200).

Multicentric reticulohistiocytosis is characterized by a combination of papulonodular cutaneous lesions and severe arthropathy.²² An irregular mixture of mononuclear and multinucleate histiocytes showing abundant eosinophilic and finely granular cytoplasm, often with a ground-glass appearance, is seen along with lymphocytic infiltration (Figure 4).²³ A few giant cells may be seen in early lesions; older lesions more commonly have giant cells and fibrosis.

The Diagnosis: Bilateral Auricular Tophaceous Gout

Histopathologic evaluation with hematoxylin and eosin staining demonstrated clusters of abundant granular amorphous material within the subcutaneous tissue (Figure 1). The overlying epidermis and dermis were unremarkable. The granular amorphous material demonstrated numerous monosodium urate crystals under polarized light (Figure 2). At a return visit following the biopsy results, the patient reported a history of a single episode of monoarticular gouty arthritis involving the right hallux approximately 6 months after the onset of the skin lesions. With the added clinical history and the biopsy results, his serum uric acid level was obtained and was found to be elevated at 9.2 mg/dL (reference range, 3.5–8 mg/dL).

In our patient, the clinical differential diagnosis included calcium deposits, weathering nodules, and tophaceous gout. The differential diagnosis of auricular lesions is broad, and benign lesions may mimic cancerous entities such as basal cell carcinoma and squamous cell carcinoma.¹ Therefore a detailed history, thorough physical examination, and tissue sampling are key to establishing the correct diagnosis. Our patient’s history of monoarticular gouty arthritis was only elucidated after a diagnosis of bilateral auricular tophaceous gout was made based on the biopsy results.

Subcutaneous tophi represent a chronic state of hyperuricemia and tend to manifest after long-standing polyarthritis and repeated acute gout attacks.^2-5 These lesions develop in approximately 50% of gout patients and usually occur an average of 11.6 years after the onset of disease.² There is a subset of individuals that are at higher risk for developing tophi, including elderly and female patients, diuretic and chronic nonsteroidal anti-inflammatory drug users, patients with a history of cyclosporine therapy, and patients with underlying chronic renal insufficiency.^2,6,7 The most commonly affected tissues are those with poor blood supply and lower temperatures, such as the ear helix and first metacarpal joint.⁴ The auricle is the most common site of tophi on the head and neck. Tophi of the helices are generally asymptomatic and nontender; however, tophi can become large, inflamed, and ulcerated, causing pressure and discomfort.² Combination treatment with dietary modification and antihyperuricemic therapy (eg, allopurinol) has been shown to reduce the size of lesions and prevent future tophi formation. However, these results may take months, warranting excision of large and symptomatic lesions.^4,8

Our case is unusual in that the onset of the auricular lesions predated the articular gout by 6 months. Gouty tophi as the initial presentation of hyperuricemia is rare; however, tophi formation without concomitant arthritis has been reported.^2,3,7,9 Wernick et al⁷ described 6 patients presenting with tophi before the onset of inflammatory arthritis that they attributed to changes in active inflammation by age (eg, elderly patients were more commonly immunosuppressed), chronic illnesses, and anti-inflammatory medications (eg, nonsteroidal anti-inflammatory drugs). Another possible explanation for this atypical presentation is misdiagnosis caused by other forms of arthritis (eg, rheumatoid arthritis, osteoarthritis) masking acute gout episodes. It also has been reported that monosodium urate crystals can be found in synovial fluid with no inflammation and therefore no symptoms.⁷

Tophi, although rare, may be the sole clinical manifestation of underlying gouty disease. It is important to be aware of this atypical presentation to prevent misdiagnosis and provide appropriate treatment.

The Diagnosis: Bilateral Auricular Tophaceous Gout

Histopathologic evaluation with hematoxylin and eosin staining demonstrated clusters of abundant granular amorphous material within the subcutaneous tissue (Figure 1). The overlying epidermis and dermis were unremarkable. The granular amorphous material demonstrated numerous monosodium urate crystals under polarized light (Figure 2). At a return visit following the biopsy results, the patient reported a history of a single episode of monoarticular gouty arthritis involving the right hallux approximately 6 months after the onset of the skin lesions. With the added clinical history and the biopsy results, his serum uric acid level was obtained and was found to be elevated at 9.2 mg/dL (reference range, 3.5–8 mg/dL).

In our patient, the clinical differential diagnosis included calcium deposits, weathering nodules, and tophaceous gout. The differential diagnosis of auricular lesions is broad, and benign lesions may mimic cancerous entities such as basal cell carcinoma and squamous cell carcinoma.¹ Therefore a detailed history, thorough physical examination, and tissue sampling are key to establishing the correct diagnosis. Our patient’s history of monoarticular gouty arthritis was only elucidated after a diagnosis of bilateral auricular tophaceous gout was made based on the biopsy results.

Subcutaneous tophi represent a chronic state of hyperuricemia and tend to manifest after long-standing polyarthritis and repeated acute gout attacks.^2-5 These lesions develop in approximately 50% of gout patients and usually occur an average of 11.6 years after the onset of disease.² There is a subset of individuals that are at higher risk for developing tophi, including elderly and female patients, diuretic and chronic nonsteroidal anti-inflammatory drug users, patients with a history of cyclosporine therapy, and patients with underlying chronic renal insufficiency.^2,6,7 The most commonly affected tissues are those with poor blood supply and lower temperatures, such as the ear helix and first metacarpal joint.⁴ The auricle is the most common site of tophi on the head and neck. Tophi of the helices are generally asymptomatic and nontender; however, tophi can become large, inflamed, and ulcerated, causing pressure and discomfort.² Combination treatment with dietary modification and antihyperuricemic therapy (eg, allopurinol) has been shown to reduce the size of lesions and prevent future tophi formation. However, these results may take months, warranting excision of large and symptomatic lesions.^4,8

Our case is unusual in that the onset of the auricular lesions predated the articular gout by 6 months. Gouty tophi as the initial presentation of hyperuricemia is rare; however, tophi formation without concomitant arthritis has been reported.^2,3,7,9 Wernick et al⁷ described 6 patients presenting with tophi before the onset of inflammatory arthritis that they attributed to changes in active inflammation by age (eg, elderly patients were more commonly immunosuppressed), chronic illnesses, and anti-inflammatory medications (eg, nonsteroidal anti-inflammatory drugs). Another possible explanation for this atypical presentation is misdiagnosis caused by other forms of arthritis (eg, rheumatoid arthritis, osteoarthritis) masking acute gout episodes. It also has been reported that monosodium urate crystals can be found in synovial fluid with no inflammation and therefore no symptoms.⁷

Tophi, although rare, may be the sole clinical manifestation of underlying gouty disease. It is important to be aware of this atypical presentation to prevent misdiagnosis and provide appropriate treatment.

The Diagnosis: Bilateral Auricular Tophaceous Gout

Histopathologic evaluation with hematoxylin and eosin staining demonstrated clusters of abundant granular amorphous material within the subcutaneous tissue (Figure 1). The overlying epidermis and dermis were unremarkable. The granular amorphous material demonstrated numerous monosodium urate crystals under polarized light (Figure 2). At a return visit following the biopsy results, the patient reported a history of a single episode of monoarticular gouty arthritis involving the right hallux approximately 6 months after the onset of the skin lesions. With the added clinical history and the biopsy results, his serum uric acid level was obtained and was found to be elevated at 9.2 mg/dL (reference range, 3.5–8 mg/dL).

In our patient, the clinical differential diagnosis included calcium deposits, weathering nodules, and tophaceous gout. The differential diagnosis of auricular lesions is broad, and benign lesions may mimic cancerous entities such as basal cell carcinoma and squamous cell carcinoma.¹ Therefore a detailed history, thorough physical examination, and tissue sampling are key to establishing the correct diagnosis. Our patient’s history of monoarticular gouty arthritis was only elucidated after a diagnosis of bilateral auricular tophaceous gout was made based on the biopsy results.

Subcutaneous tophi represent a chronic state of hyperuricemia and tend to manifest after long-standing polyarthritis and repeated acute gout attacks.^2-5 These lesions develop in approximately 50% of gout patients and usually occur an average of 11.6 years after the onset of disease.² There is a subset of individuals that are at higher risk for developing tophi, including elderly and female patients, diuretic and chronic nonsteroidal anti-inflammatory drug users, patients with a history of cyclosporine therapy, and patients with underlying chronic renal insufficiency.^2,6,7 The most commonly affected tissues are those with poor blood supply and lower temperatures, such as the ear helix and first metacarpal joint.⁴ The auricle is the most common site of tophi on the head and neck. Tophi of the helices are generally asymptomatic and nontender; however, tophi can become large, inflamed, and ulcerated, causing pressure and discomfort.² Combination treatment with dietary modification and antihyperuricemic therapy (eg, allopurinol) has been shown to reduce the size of lesions and prevent future tophi formation. However, these results may take months, warranting excision of large and symptomatic lesions.^4,8

Our case is unusual in that the onset of the auricular lesions predated the articular gout by 6 months. Gouty tophi as the initial presentation of hyperuricemia is rare; however, tophi formation without concomitant arthritis has been reported.^2,3,7,9 Wernick et al⁷ described 6 patients presenting with tophi before the onset of inflammatory arthritis that they attributed to changes in active inflammation by age (eg, elderly patients were more commonly immunosuppressed), chronic illnesses, and anti-inflammatory medications (eg, nonsteroidal anti-inflammatory drugs). Another possible explanation for this atypical presentation is misdiagnosis caused by other forms of arthritis (eg, rheumatoid arthritis, osteoarthritis) masking acute gout episodes. It also has been reported that monosodium urate crystals can be found in synovial fluid with no inflammation and therefore no symptoms.⁷

Tophi, although rare, may be the sole clinical manifestation of underlying gouty disease. It is important to be aware of this atypical presentation to prevent misdiagnosis and provide appropriate treatment.

What does your patient need to know at the first visit? Does it apply to patients of all genders, ages, and races?

There are 3 scenarios in which antibiotics are used in dermatology. First, there is the treatment of a bona fide, verified skin infection, which may range from the relatively simple (impetigo) to the complex (botryomycosis) to the exotic (fish tank granuloma). The second scenario is antibiotic administration, often due to ancillary properties such as anti-inflammatory effects, in the management of noninfectious disorders, such as familial benign pemphigus or pityriasis lichenoides et varioliformis acuta. I try hard to avoid antibiotic use in these situations unless all else fails. The third scenario involves use of antibiotics at the patient’s request, usually associated with the phrase “just in case it’s infected.” In my opinion, this practice is completely ill advised.

Male and female patients of all ages, ethnic origins, and socioeconomic backgrounds are woefully uninformed regarding the promise and peril of antibiotics. I want patients to buy into the concept of good antibiotic stewardship. Thus, patients should understand that there must be a specific and justifiable reason for antibiotic use and that the recommended dose and duration of treatment should not be altered. In some situations, antibiotic therapy is intended to be of short duration, while in other situations, such therapy may be quite protracted. Patients also need to know at the outset of treatment when we plan to transition from a short-term, antibiotic-based modality to a long-term nonantibiotic maintenance regimen, which is especially true for acne and rosacea. I try to limit antibiotic use in these disorders to 3 months. Furthermore, patients should always be educated about the potential side effects associated with the particular antibiotic being prescribed. Hoarding and sharing leftover antibiotics should be strongly and explicitly discouraged.

Finally, patients must be educated that taking shortcuts when prescribing antibiotics may lead to therapeutic failure, worsening disease, or serious long-term adverse consequences. For example, rational antibiotic use may require the added expense of an initial and/or subsequent test-of-cure culture and sensitivity. Is that swollen and tender hand following a cat bite due to Pasteurella multocida or methicillin-resistant Staphylococcus aureus? Is that new eruption in an atopic patient due to secondary impetigo or eczema herpeticum? Other laboratory testing also may be required, such as a follow-up serology after treating syphilis. Patients need to know why laboratory tests are being ordered and how the tests complement direct antibiotic intervention.

What are your go-to treatments? What are the side effects?

I am a fan of subantimicrobial-dose doxycycline for both rosacea (on label) and acne (off label). Studies have shown that neither quantitative nor qualitative changes occur in the cutaneous, oral, or gastrointestinal flora. Thus, I avoid contributing to the emerging global crisis of antimicrobial resistance. I am also a proponent of topical antibiotics whenever appropriate and reasonable. Mupirocin and retapamulin, for example, are quite effective for routine cases of impetigo. When incision and drainage alone are insufficient to resolve methicillin-resistant S aureus furunculosis, I prefer either trimethoprim-sulfamethoxazole or doxycycline. Of course, other specific oral and even parenteral antibiotics are appropriate for select disease states.

Although antibiotics generally are well tolerated, there are many possible side effects. Hypersensitivity reactions, ranging from self-limited fixed drug and pruritic maculopapular eruptions through acute urticaria to anaphylaxis, may occur with any antibiotic. Clostridium difficile–associated diarrhea also may occur in conjunction with the use of any antibacterial drug, especially those with a broad spectrum of activity. Nausea and headache are mild but common side effects of these agents. All tetracycline derivatives may be photosensitizers and may provoke intracranial hypertension. Minocycline may lead to hyperpigmentation of skin and teeth, vestibular disturbances (ie, dizziness, ataxia, vertigo, tinnitus) and rarely autoimmune hepatitis. Macrolide antibiotics have been linked to serious cardiotoxicity, and quinolone antibiotics have been linked to tendonitis/tendon rupture, cardiotoxicity, and insomnia. Many antibiotics can result in vaginal yeast infections. There is some evidence that prolonged antibiotic use may precipitate inflammatory bowel disease, especially in those who are genetically predisposed.

Finally, keep in mind that antibiotic administration changes the normal cutaneous flora, which may interfere with the normal antimicrobial and anti-inflammatory homeostatic roles played by resident skin microflora. Antibiotic administration also changes the gut flora and, in this manner, may help promote the development of resistant microbes.

How do you keep patients compliant with treatment?

The most important step to assure adherence is adequate pretreatment education. Whether short-term or long-term antibiotic treatment is anticipated, I always schedule a follow-up office visit in approximately 2 weeks to check on clinical progress and reinforce good habits. Younger patients benefit from periodic reminders using emails, text messages, and tweets.

What do you do if they refuse treatment?

In some instances, antibiotic phobia in patients can be totally accepted and alternative treatments explored. As an example, laser and light therapy, hormonal manipulation, zinc-based nutritional supplements, and intensive nonantibiotic topical combination drugs can supplant antibiotics for the management of acne.

What resources do you recommend to patients for more information?

There are some excellent resources online for patients such as “Using Antibiotics Wisely” and “Get Smart: Know When Antibiotics Work.”

What does your patient need to know at the first visit? Does it apply to patients of all genders, ages, and races?

There are 3 scenarios in which antibiotics are used in dermatology. First, there is the treatment of a bona fide, verified skin infection, which may range from the relatively simple (impetigo) to the complex (botryomycosis) to the exotic (fish tank granuloma). The second scenario is antibiotic administration, often due to ancillary properties such as anti-inflammatory effects, in the management of noninfectious disorders, such as familial benign pemphigus or pityriasis lichenoides et varioliformis acuta. I try hard to avoid antibiotic use in these situations unless all else fails. The third scenario involves use of antibiotics at the patient’s request, usually associated with the phrase “just in case it’s infected.” In my opinion, this practice is completely ill advised.

Male and female patients of all ages, ethnic origins, and socioeconomic backgrounds are woefully uninformed regarding the promise and peril of antibiotics. I want patients to buy into the concept of good antibiotic stewardship. Thus, patients should understand that there must be a specific and justifiable reason for antibiotic use and that the recommended dose and duration of treatment should not be altered. In some situations, antibiotic therapy is intended to be of short duration, while in other situations, such therapy may be quite protracted. Patients also need to know at the outset of treatment when we plan to transition from a short-term, antibiotic-based modality to a long-term nonantibiotic maintenance regimen, which is especially true for acne and rosacea. I try to limit antibiotic use in these disorders to 3 months. Furthermore, patients should always be educated about the potential side effects associated with the particular antibiotic being prescribed. Hoarding and sharing leftover antibiotics should be strongly and explicitly discouraged.

Finally, patients must be educated that taking shortcuts when prescribing antibiotics may lead to therapeutic failure, worsening disease, or serious long-term adverse consequences. For example, rational antibiotic use may require the added expense of an initial and/or subsequent test-of-cure culture and sensitivity. Is that swollen and tender hand following a cat bite due to Pasteurella multocida or methicillin-resistant Staphylococcus aureus? Is that new eruption in an atopic patient due to secondary impetigo or eczema herpeticum? Other laboratory testing also may be required, such as a follow-up serology after treating syphilis. Patients need to know why laboratory tests are being ordered and how the tests complement direct antibiotic intervention.

What are your go-to treatments? What are the side effects?

I am a fan of subantimicrobial-dose doxycycline for both rosacea (on label) and acne (off label). Studies have shown that neither quantitative nor qualitative changes occur in the cutaneous, oral, or gastrointestinal flora. Thus, I avoid contributing to the emerging global crisis of antimicrobial resistance. I am also a proponent of topical antibiotics whenever appropriate and reasonable. Mupirocin and retapamulin, for example, are quite effective for routine cases of impetigo. When incision and drainage alone are insufficient to resolve methicillin-resistant S aureus furunculosis, I prefer either trimethoprim-sulfamethoxazole or doxycycline. Of course, other specific oral and even parenteral antibiotics are appropriate for select disease states.

Although antibiotics generally are well tolerated, there are many possible side effects. Hypersensitivity reactions, ranging from self-limited fixed drug and pruritic maculopapular eruptions through acute urticaria to anaphylaxis, may occur with any antibiotic. Clostridium difficile–associated diarrhea also may occur in conjunction with the use of any antibacterial drug, especially those with a broad spectrum of activity. Nausea and headache are mild but common side effects of these agents. All tetracycline derivatives may be photosensitizers and may provoke intracranial hypertension. Minocycline may lead to hyperpigmentation of skin and teeth, vestibular disturbances (ie, dizziness, ataxia, vertigo, tinnitus) and rarely autoimmune hepatitis. Macrolide antibiotics have been linked to serious cardiotoxicity, and quinolone antibiotics have been linked to tendonitis/tendon rupture, cardiotoxicity, and insomnia. Many antibiotics can result in vaginal yeast infections. There is some evidence that prolonged antibiotic use may precipitate inflammatory bowel disease, especially in those who are genetically predisposed.

Finally, keep in mind that antibiotic administration changes the normal cutaneous flora, which may interfere with the normal antimicrobial and anti-inflammatory homeostatic roles played by resident skin microflora. Antibiotic administration also changes the gut flora and, in this manner, may help promote the development of resistant microbes.

How do you keep patients compliant with treatment?

The most important step to assure adherence is adequate pretreatment education. Whether short-term or long-term antibiotic treatment is anticipated, I always schedule a follow-up office visit in approximately 2 weeks to check on clinical progress and reinforce good habits. Younger patients benefit from periodic reminders using emails, text messages, and tweets.

What do you do if they refuse treatment?

In some instances, antibiotic phobia in patients can be totally accepted and alternative treatments explored. As an example, laser and light therapy, hormonal manipulation, zinc-based nutritional supplements, and intensive nonantibiotic topical combination drugs can supplant antibiotics for the management of acne.

What resources do you recommend to patients for more information?

There are some excellent resources online for patients such as “Using Antibiotics Wisely” and “Get Smart: Know When Antibiotics Work.”

What does your patient need to know at the first visit? Does it apply to patients of all genders, ages, and races?

There are 3 scenarios in which antibiotics are used in dermatology. First, there is the treatment of a bona fide, verified skin infection, which may range from the relatively simple (impetigo) to the complex (botryomycosis) to the exotic (fish tank granuloma). The second scenario is antibiotic administration, often due to ancillary properties such as anti-inflammatory effects, in the management of noninfectious disorders, such as familial benign pemphigus or pityriasis lichenoides et varioliformis acuta. I try hard to avoid antibiotic use in these situations unless all else fails. The third scenario involves use of antibiotics at the patient’s request, usually associated with the phrase “just in case it’s infected.” In my opinion, this practice is completely ill advised.

Male and female patients of all ages, ethnic origins, and socioeconomic backgrounds are woefully uninformed regarding the promise and peril of antibiotics. I want patients to buy into the concept of good antibiotic stewardship. Thus, patients should understand that there must be a specific and justifiable reason for antibiotic use and that the recommended dose and duration of treatment should not be altered. In some situations, antibiotic therapy is intended to be of short duration, while in other situations, such therapy may be quite protracted. Patients also need to know at the outset of treatment when we plan to transition from a short-term, antibiotic-based modality to a long-term nonantibiotic maintenance regimen, which is especially true for acne and rosacea. I try to limit antibiotic use in these disorders to 3 months. Furthermore, patients should always be educated about the potential side effects associated with the particular antibiotic being prescribed. Hoarding and sharing leftover antibiotics should be strongly and explicitly discouraged.

Finally, patients must be educated that taking shortcuts when prescribing antibiotics may lead to therapeutic failure, worsening disease, or serious long-term adverse consequences. For example, rational antibiotic use may require the added expense of an initial and/or subsequent test-of-cure culture and sensitivity. Is that swollen and tender hand following a cat bite due to Pasteurella multocida or methicillin-resistant Staphylococcus aureus? Is that new eruption in an atopic patient due to secondary impetigo or eczema herpeticum? Other laboratory testing also may be required, such as a follow-up serology after treating syphilis. Patients need to know why laboratory tests are being ordered and how the tests complement direct antibiotic intervention.

What are your go-to treatments? What are the side effects?

I am a fan of subantimicrobial-dose doxycycline for both rosacea (on label) and acne (off label). Studies have shown that neither quantitative nor qualitative changes occur in the cutaneous, oral, or gastrointestinal flora. Thus, I avoid contributing to the emerging global crisis of antimicrobial resistance. I am also a proponent of topical antibiotics whenever appropriate and reasonable. Mupirocin and retapamulin, for example, are quite effective for routine cases of impetigo. When incision and drainage alone are insufficient to resolve methicillin-resistant S aureus furunculosis, I prefer either trimethoprim-sulfamethoxazole or doxycycline. Of course, other specific oral and even parenteral antibiotics are appropriate for select disease states.

Although antibiotics generally are well tolerated, there are many possible side effects. Hypersensitivity reactions, ranging from self-limited fixed drug and pruritic maculopapular eruptions through acute urticaria to anaphylaxis, may occur with any antibiotic. Clostridium difficile–associated diarrhea also may occur in conjunction with the use of any antibacterial drug, especially those with a broad spectrum of activity. Nausea and headache are mild but common side effects of these agents. All tetracycline derivatives may be photosensitizers and may provoke intracranial hypertension. Minocycline may lead to hyperpigmentation of skin and teeth, vestibular disturbances (ie, dizziness, ataxia, vertigo, tinnitus) and rarely autoimmune hepatitis. Macrolide antibiotics have been linked to serious cardiotoxicity, and quinolone antibiotics have been linked to tendonitis/tendon rupture, cardiotoxicity, and insomnia. Many antibiotics can result in vaginal yeast infections. There is some evidence that prolonged antibiotic use may precipitate inflammatory bowel disease, especially in those who are genetically predisposed.

Finally, keep in mind that antibiotic administration changes the normal cutaneous flora, which may interfere with the normal antimicrobial and anti-inflammatory homeostatic roles played by resident skin microflora. Antibiotic administration also changes the gut flora and, in this manner, may help promote the development of resistant microbes.

How do you keep patients compliant with treatment?

The most important step to assure adherence is adequate pretreatment education. Whether short-term or long-term antibiotic treatment is anticipated, I always schedule a follow-up office visit in approximately 2 weeks to check on clinical progress and reinforce good habits. Younger patients benefit from periodic reminders using emails, text messages, and tweets.

What do you do if they refuse treatment?

In some instances, antibiotic phobia in patients can be totally accepted and alternative treatments explored. As an example, laser and light therapy, hormonal manipulation, zinc-based nutritional supplements, and intensive nonantibiotic topical combination drugs can supplant antibiotics for the management of acne.

What resources do you recommend to patients for more information?

There are some excellent resources online for patients such as “Using Antibiotics Wisely” and “Get Smart: Know When Antibiotics Work.”

To the Editor:

The term pemphigus describes a group of autoimmune blistering diseases that are histologically characterized by intraepidermal blisters caused by acantholysis. There are several types of pemphigus foliaceus, such as classic and endemic pemphigus foliaceus, pemphigus erythematosus, pemphigus herpetiformis, and drug-induced pemphigus foliaceus.¹

Figure 1. Multiple erosions and crusted lesions were present on the back.

Figure 2. Subcorneal bulla containing acantholytic keratinocytes and neutrophils (H&E, original magnification ×100).

Drug-induced pemphigus foliaceus in patients treated with penicillamine for rheumatoid arthritis (RA) is well documented in the literature.² An association between pemphigus foliaceus and RA without penicillamine therapy is rare. We present a case of a patient with a history of RA who developed this bullous disease.

A 67-year-old woman with a 15-year history of seropositive RA presented with widespread skin lesions of 4 weeks’ duration. Confluent scaly crusted erosions on an erythematous base were present on the back (Figure 1), chest, and abdomen. There was no alteration of the mucous membranes. Medical treatment consisted of methotrexate (10 mg weekly), folic acid (5 mg twice weekly), prednisolone (5 mg daily), and ketoprofen (50 mg daily). Routine blood analysis was unremarkable, except for a positive rheumatoid factor. Histologic examination showed a subcorneal bulla containing acantholytic keratinocytes and neutrophils. There was a mild lymphocytic and eosinophilic infiltrate in the papillary dermis (Figure 2).

Determination of anti-desmoglein 1 and 3 antibodies was performed by a commercial enzyme-linked immunosorbent assay. Desmoglein 1 antibodies were positive with titers of 30 U/mL (positive, ≥20 U/mL), whereas desmoglein 3 antibody was negative. Thus, a diagnosis of pemphigus foliaceus was established. The polymerase chain reaction ligation-based typing method and the nucleotide sequence was used to examine the protein drought-repressed 4 gene complex, DR4, which tested positive.

Based on a diagnosis of pemphigus foliaceus, the patient’s corticosteroid treatment was changed from 5 mg daily of prednisolone to 40 mg daily of methylprednisolone, leading to marked improvement of the cutaneous lesions. After tapering the steroid dosage over a period of 3 months, no relapse occurred.

Pemphigus foliaceus is a rare autoimmune blistering disease. It can be induced by drugs, such as penicillamine and captopril.^2,3 Captopril, an angiotensin-converting enzyme inhibitor, is closely related to penicillamine structurally. Both drugs have highly active thiol groups capable of reducing disulfide bonds and inducing acantholysis.⁴ The drugs taken by our patient typically are not known to induce pemphigus foliaceus.

The association of pemphigus foliaceus with RA in the absence of penicillamine therapy was first described by Wilkinson et al.⁴ Since then, additional cases have been published.^5,6 Pemphigus foliaceus also has been described with other autoimmune conditions such as autoimmune thyroid disease.⁷

Rheumatoid arthritis has been genetically linked to the HLA-DR4 gene complex, which also was found in our patient. Patients with pemphigus foliaceus and RA have an increased frequency of the class II major histocompatibility complex, serologically defined HLA-DR4, and HLA-DRw6 haplotypes.⁴ Therefore, we believe that the association of pemphigus foliaceus and RA in our patient might not be fortuitous.

To the Editor:

The term pemphigus describes a group of autoimmune blistering diseases that are histologically characterized by intraepidermal blisters caused by acantholysis. There are several types of pemphigus foliaceus, such as classic and endemic pemphigus foliaceus, pemphigus erythematosus, pemphigus herpetiformis, and drug-induced pemphigus foliaceus.¹

Figure 1. Multiple erosions and crusted lesions were present on the back.

Figure 2. Subcorneal bulla containing acantholytic keratinocytes and neutrophils (H&E, original magnification ×100).

Drug-induced pemphigus foliaceus in patients treated with penicillamine for rheumatoid arthritis (RA) is well documented in the literature.² An association between pemphigus foliaceus and RA without penicillamine therapy is rare. We present a case of a patient with a history of RA who developed this bullous disease.

A 67-year-old woman with a 15-year history of seropositive RA presented with widespread skin lesions of 4 weeks’ duration. Confluent scaly crusted erosions on an erythematous base were present on the back (Figure 1), chest, and abdomen. There was no alteration of the mucous membranes. Medical treatment consisted of methotrexate (10 mg weekly), folic acid (5 mg twice weekly), prednisolone (5 mg daily), and ketoprofen (50 mg daily). Routine blood analysis was unremarkable, except for a positive rheumatoid factor. Histologic examination showed a subcorneal bulla containing acantholytic keratinocytes and neutrophils. There was a mild lymphocytic and eosinophilic infiltrate in the papillary dermis (Figure 2).

Determination of anti-desmoglein 1 and 3 antibodies was performed by a commercial enzyme-linked immunosorbent assay. Desmoglein 1 antibodies were positive with titers of 30 U/mL (positive, ≥20 U/mL), whereas desmoglein 3 antibody was negative. Thus, a diagnosis of pemphigus foliaceus was established. The polymerase chain reaction ligation-based typing method and the nucleotide sequence was used to examine the protein drought-repressed 4 gene complex, DR4, which tested positive.

Based on a diagnosis of pemphigus foliaceus, the patient’s corticosteroid treatment was changed from 5 mg daily of prednisolone to 40 mg daily of methylprednisolone, leading to marked improvement of the cutaneous lesions. After tapering the steroid dosage over a period of 3 months, no relapse occurred.

Pemphigus foliaceus is a rare autoimmune blistering disease. It can be induced by drugs, such as penicillamine and captopril.^2,3 Captopril, an angiotensin-converting enzyme inhibitor, is closely related to penicillamine structurally. Both drugs have highly active thiol groups capable of reducing disulfide bonds and inducing acantholysis.⁴ The drugs taken by our patient typically are not known to induce pemphigus foliaceus.

The association of pemphigus foliaceus with RA in the absence of penicillamine therapy was first described by Wilkinson et al.⁴ Since then, additional cases have been published.^5,6 Pemphigus foliaceus also has been described with other autoimmune conditions such as autoimmune thyroid disease.⁷

Rheumatoid arthritis has been genetically linked to the HLA-DR4 gene complex, which also was found in our patient. Patients with pemphigus foliaceus and RA have an increased frequency of the class II major histocompatibility complex, serologically defined HLA-DR4, and HLA-DRw6 haplotypes.⁴ Therefore, we believe that the association of pemphigus foliaceus and RA in our patient might not be fortuitous.

To the Editor:

The term pemphigus describes a group of autoimmune blistering diseases that are histologically characterized by intraepidermal blisters caused by acantholysis. There are several types of pemphigus foliaceus, such as classic and endemic pemphigus foliaceus, pemphigus erythematosus, pemphigus herpetiformis, and drug-induced pemphigus foliaceus.¹

Figure 1. Multiple erosions and crusted lesions were present on the back.

Figure 2. Subcorneal bulla containing acantholytic keratinocytes and neutrophils (H&E, original magnification ×100).

Drug-induced pemphigus foliaceus in patients treated with penicillamine for rheumatoid arthritis (RA) is well documented in the literature.² An association between pemphigus foliaceus and RA without penicillamine therapy is rare. We present a case of a patient with a history of RA who developed this bullous disease.

A 67-year-old woman with a 15-year history of seropositive RA presented with widespread skin lesions of 4 weeks’ duration. Confluent scaly crusted erosions on an erythematous base were present on the back (Figure 1), chest, and abdomen. There was no alteration of the mucous membranes. Medical treatment consisted of methotrexate (10 mg weekly), folic acid (5 mg twice weekly), prednisolone (5 mg daily), and ketoprofen (50 mg daily). Routine blood analysis was unremarkable, except for a positive rheumatoid factor. Histologic examination showed a subcorneal bulla containing acantholytic keratinocytes and neutrophils. There was a mild lymphocytic and eosinophilic infiltrate in the papillary dermis (Figure 2).

Determination of anti-desmoglein 1 and 3 antibodies was performed by a commercial enzyme-linked immunosorbent assay. Desmoglein 1 antibodies were positive with titers of 30 U/mL (positive, ≥20 U/mL), whereas desmoglein 3 antibody was negative. Thus, a diagnosis of pemphigus foliaceus was established. The polymerase chain reaction ligation-based typing method and the nucleotide sequence was used to examine the protein drought-repressed 4 gene complex, DR4, which tested positive.

Based on a diagnosis of pemphigus foliaceus, the patient’s corticosteroid treatment was changed from 5 mg daily of prednisolone to 40 mg daily of methylprednisolone, leading to marked improvement of the cutaneous lesions. After tapering the steroid dosage over a period of 3 months, no relapse occurred.

Pemphigus foliaceus is a rare autoimmune blistering disease. It can be induced by drugs, such as penicillamine and captopril.^2,3 Captopril, an angiotensin-converting enzyme inhibitor, is closely related to penicillamine structurally. Both drugs have highly active thiol groups capable of reducing disulfide bonds and inducing acantholysis.⁴ The drugs taken by our patient typically are not known to induce pemphigus foliaceus.

The association of pemphigus foliaceus with RA in the absence of penicillamine therapy was first described by Wilkinson et al.⁴ Since then, additional cases have been published.^5,6 Pemphigus foliaceus also has been described with other autoimmune conditions such as autoimmune thyroid disease.⁷

Rheumatoid arthritis has been genetically linked to the HLA-DR4 gene complex, which also was found in our patient. Patients with pemphigus foliaceus and RA have an increased frequency of the class II major histocompatibility complex, serologically defined HLA-DR4, and HLA-DRw6 haplotypes.⁴ Therefore, we believe that the association of pemphigus foliaceus and RA in our patient might not be fortuitous.

WASHINGTON – Acne patients are telling the truth when they describe feeling isolated, rejected, and stigmatized – and now there are data to prove it.

Dr. Alexa B. Kimball, professor of dermatology at Harvard Medical School, Boston, found that almost 70% of people surveyed believe that those with acne are unattractive and hesitate to be seen with them. Her survey of 56 people also found that they harbor fears that acne is infectious and can be transmitted, that it’s caused by poor hygiene and diet.

“The widespread misconceptions about acne contribute to negative perceptions, which can affect patients’ quality of life and social interaction,” Dr. Kimball said. “When our patients describe these feelings, they are describing their real, day-to-day life experiences.”

See more of her comments on treating patients with acne in this video.

[email protected]

WASHINGTON – Acne patients are telling the truth when they describe feeling isolated, rejected, and stigmatized – and now there are data to prove it.

Dr. Alexa B. Kimball, professor of dermatology at Harvard Medical School, Boston, found that almost 70% of people surveyed believe that those with acne are unattractive and hesitate to be seen with them. Her survey of 56 people also found that they harbor fears that acne is infectious and can be transmitted, that it’s caused by poor hygiene and diet.

“The widespread misconceptions about acne contribute to negative perceptions, which can affect patients’ quality of life and social interaction,” Dr. Kimball said. “When our patients describe these feelings, they are describing their real, day-to-day life experiences.”

See more of her comments on treating patients with acne in this video.

[email protected]

WASHINGTON – Acne patients are telling the truth when they describe feeling isolated, rejected, and stigmatized – and now there are data to prove it.

Dr. Alexa B. Kimball, professor of dermatology at Harvard Medical School, Boston, found that almost 70% of people surveyed believe that those with acne are unattractive and hesitate to be seen with them. Her survey of 56 people also found that they harbor fears that acne is infectious and can be transmitted, that it’s caused by poor hygiene and diet.

“The widespread misconceptions about acne contribute to negative perceptions, which can affect patients’ quality of life and social interaction,” Dr. Kimball said. “When our patients describe these feelings, they are describing their real, day-to-day life experiences.”

See more of her comments on treating patients with acne in this video.

[email protected]

D. Holt, Arkansas

S. Bhansali, MD, California

E. Bhansin, BS, DO, California

A. Bogart, MD, California

D. Donald, MD, California

S. Evans, FNP, California

R. Godbout, California

E. Gustafson, MD, California

M. Hasan, MD, California

M. Kantor, MD, California

M. McClellan, California

A. Milin, MD, California

E. Nguyen, California

J. Young, BSN, RN, California

M. Hicks, MD, Colorado

J. Tyler, DO, Colorado

P. Sharma, MHA, Connecticut

J. Meyer, DO, Florida

M. Prabhu, ACMPE, Florida

K. Slazinski, MD, MA, Florida

P. Zipper, Florida

S. Gayle, MD, Georgia

N. Palmer, DO, Georgia

R. Schaefer, MD, Hawaii

E. Diehl, MD, Iowa

C. Kuehn, MD, Iowa

A. Buchwach, MD, Illinois

F. Evangelista, MD, Illinois

S. Kurup, Illinois

J. Shanahan, Illinois

U. Tekin, MD, Illinois

C. Dennis, Massachusetts

D. Gewanter, Massachusetts

S. Master, MD, Massachusetts

C. Mathew, MD, Massachusetts

M. Sakr, MD, Massachusetts

M. Mason, PA-C, Maryland

M. Kowalczyk, ACNP, Minnesota

M. Doose, MD, Minnesota

F. Abualrub, Missouri

R. Adkison, DO, Missouri

S. Katukoori, MD, Missouri

A. Persaud, PA-C, Missouri

L. Gerstle, NP, Montana

S. Brown, MD, North Carolina

S. Okorie, New Jersey

P. Mathew, MD, New Mexico

A. Turney, DO, Nevada

J. Chester, MD, New York

C. Flynn, DO, New York

M. Hoefer, PMGR, New York

M. Islam, MD, New York

C. Karno, MD, New York

S. Mir, New York

P. Nadkarni, MD, New York

A. Rana, New York

G. Rubinfeld, New York

A. Black, MBA, Ohio

R. Cartabuke, MHA, Ohio

P. He, DO, Ohio

R. Rivero, DO, Ohio

K. Welch, Ohio

S. Parker, APRN-BC, Oklahoma

T. Basra, MD, MBBS, Oregon

B. Baxter, Oregon

S. Mehta, MD, Oregon

V. Karper, ACNP, Pennsylvania

D. Messner, MSN, NP, Pennsylvania

M. Scoulos-Hanson, Pennsylvania

K. Willoughby, MD, Pennsylvania

R. Yazdanfar, MD, Pennsylvania

J. Hennessey, CCFP, Canada

J. Brown, MD, South Carolina

K. Medlin, RN, South Carolina

K. Kays, Tennessee

M. Begum, MD, Texas

S. Blinchevsky, MD, Texas

C. Ciborowski, Texas

K. Gupta, MD, Texas

H. Lam, MD, Texas

A. Owens, Texas

K. Salciccioli, BSE, Texas

D. Lundberg, Wisconsin

H. Peto, Wisconsin

B. Quinn, MD, Wisconsin

N. Ros, PhD, Spain

S. Takeuchi, MD, Japan

D. Holt, Arkansas

S. Bhansali, MD, California

E. Bhansin, BS, DO, California

A. Bogart, MD, California

D. Donald, MD, California

S. Evans, FNP, California

R. Godbout, California

E. Gustafson, MD, California

M. Hasan, MD, California

M. Kantor, MD, California

M. McClellan, California

A. Milin, MD, California

E. Nguyen, California

J. Young, BSN, RN, California

M. Hicks, MD, Colorado

J. Tyler, DO, Colorado

P. Sharma, MHA, Connecticut

J. Meyer, DO, Florida

M. Prabhu, ACMPE, Florida

K. Slazinski, MD, MA, Florida

P. Zipper, Florida

S. Gayle, MD, Georgia

N. Palmer, DO, Georgia

R. Schaefer, MD, Hawaii

E. Diehl, MD, Iowa

C. Kuehn, MD, Iowa

A. Buchwach, MD, Illinois

F. Evangelista, MD, Illinois

S. Kurup, Illinois

J. Shanahan, Illinois

U. Tekin, MD, Illinois

C. Dennis, Massachusetts

D. Gewanter, Massachusetts

S. Master, MD, Massachusetts

C. Mathew, MD, Massachusetts

M. Sakr, MD, Massachusetts

M. Mason, PA-C, Maryland

M. Kowalczyk, ACNP, Minnesota

M. Doose, MD, Minnesota

F. Abualrub, Missouri

R. Adkison, DO, Missouri

S. Katukoori, MD, Missouri

A. Persaud, PA-C, Missouri

L. Gerstle, NP, Montana

S. Brown, MD, North Carolina

S. Okorie, New Jersey

P. Mathew, MD, New Mexico

A. Turney, DO, Nevada

J. Chester, MD, New York

C. Flynn, DO, New York

M. Hoefer, PMGR, New York

M. Islam, MD, New York

C. Karno, MD, New York

S. Mir, New York

P. Nadkarni, MD, New York

A. Rana, New York

G. Rubinfeld, New York

A. Black, MBA, Ohio

R. Cartabuke, MHA, Ohio

P. He, DO, Ohio

R. Rivero, DO, Ohio

K. Welch, Ohio

S. Parker, APRN-BC, Oklahoma

T. Basra, MD, MBBS, Oregon

B. Baxter, Oregon

S. Mehta, MD, Oregon

V. Karper, ACNP, Pennsylvania

D. Messner, MSN, NP, Pennsylvania

M. Scoulos-Hanson, Pennsylvania

K. Willoughby, MD, Pennsylvania

R. Yazdanfar, MD, Pennsylvania

J. Hennessey, CCFP, Canada

J. Brown, MD, South Carolina

K. Medlin, RN, South Carolina

K. Kays, Tennessee

M. Begum, MD, Texas

S. Blinchevsky, MD, Texas

C. Ciborowski, Texas

K. Gupta, MD, Texas

H. Lam, MD, Texas

A. Owens, Texas

K. Salciccioli, BSE, Texas

D. Lundberg, Wisconsin

H. Peto, Wisconsin

B. Quinn, MD, Wisconsin

N. Ros, PhD, Spain

S. Takeuchi, MD, Japan

D. Holt, Arkansas

S. Bhansali, MD, California

E. Bhansin, BS, DO, California

A. Bogart, MD, California

D. Donald, MD, California

S. Evans, FNP, California

R. Godbout, California

E. Gustafson, MD, California

M. Hasan, MD, California

M. Kantor, MD, California

M. McClellan, California

A. Milin, MD, California

E. Nguyen, California

J. Young, BSN, RN, California

M. Hicks, MD, Colorado

J. Tyler, DO, Colorado

P. Sharma, MHA, Connecticut

J. Meyer, DO, Florida

M. Prabhu, ACMPE, Florida

K. Slazinski, MD, MA, Florida

P. Zipper, Florida

S. Gayle, MD, Georgia

N. Palmer, DO, Georgia

R. Schaefer, MD, Hawaii

E. Diehl, MD, Iowa

C. Kuehn, MD, Iowa

A. Buchwach, MD, Illinois

F. Evangelista, MD, Illinois

S. Kurup, Illinois

J. Shanahan, Illinois

U. Tekin, MD, Illinois

C. Dennis, Massachusetts

D. Gewanter, Massachusetts

S. Master, MD, Massachusetts

C. Mathew, MD, Massachusetts

M. Sakr, MD, Massachusetts

M. Mason, PA-C, Maryland

M. Kowalczyk, ACNP, Minnesota

M. Doose, MD, Minnesota

F. Abualrub, Missouri

R. Adkison, DO, Missouri

S. Katukoori, MD, Missouri

A. Persaud, PA-C, Missouri

L. Gerstle, NP, Montana

S. Brown, MD, North Carolina

S. Okorie, New Jersey

P. Mathew, MD, New Mexico

A. Turney, DO, Nevada

J. Chester, MD, New York

C. Flynn, DO, New York

M. Hoefer, PMGR, New York

M. Islam, MD, New York

C. Karno, MD, New York

S. Mir, New York

P. Nadkarni, MD, New York

A. Rana, New York

G. Rubinfeld, New York

A. Black, MBA, Ohio

R. Cartabuke, MHA, Ohio

P. He, DO, Ohio

R. Rivero, DO, Ohio

K. Welch, Ohio

S. Parker, APRN-BC, Oklahoma

T. Basra, MD, MBBS, Oregon

B. Baxter, Oregon

S. Mehta, MD, Oregon

V. Karper, ACNP, Pennsylvania

D. Messner, MSN, NP, Pennsylvania

M. Scoulos-Hanson, Pennsylvania

K. Willoughby, MD, Pennsylvania

R. Yazdanfar, MD, Pennsylvania

J. Hennessey, CCFP, Canada

J. Brown, MD, South Carolina

K. Medlin, RN, South Carolina

K. Kays, Tennessee

M. Begum, MD, Texas

S. Blinchevsky, MD, Texas

C. Ciborowski, Texas

K. Gupta, MD, Texas

H. Lam, MD, Texas

A. Owens, Texas

K. Salciccioli, BSE, Texas

D. Lundberg, Wisconsin

H. Peto, Wisconsin

B. Quinn, MD, Wisconsin

N. Ros, PhD, Spain

S. Takeuchi, MD, Japan

The US Food and Drug Administration (FDA) has approved Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein) for the treatment of hemophilia B.

The product—a fusion protein linking recombinant coagulation factor IX with recombinant albumin—is intended for use in children and adults for routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand control and prevention of bleeding episodes, and for the perioperative management of bleeding.

Appropriate patients age 12 and older can go up to 14 days between Idelvion infusions. This dosing interval has been achieved while maintaining high levels of factor IX activity—above 5% over 14 days at 75 IU/kg.

Idelvion is the first FDA-approved recombinant factor IX therapy that can extend the dosing interval up to 14 days.

Idelvion is expected to be available in the US later this month. The product is being developed by CSL Behring. For more details on the drug, see the full prescribing information.

Phase 3 trial

The FDA approved Idelvion based on results of the PROLONG-9FP clinical development program. PROLONG-9FP includes phase 1, 2, and 3 studies evaluating the safety and efficacy of Idelvion in adults and children (ages 1 to 61) with hemophilia B.

Data from the phase 3 study were recently published in Blood. This study included 63 previously treated male patients with severe hemophilia B. They had a mean age of 33 (range, 12 to 61).

The patients were divided into 2 groups. Group 1 (n=40) received routine prophylaxis with Idelvion once every 7 days for 26 weeks, followed by a 7-, 10- or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively.

Group 2 received on-demand treatment with Idelvion for bleeding episodes for 26 weeks (n=23) and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks (n=19).

The median annualized bleeding rate (ABR) was 2.0 in the prophylaxis arm (group 1) and 23.5 in the on-demand treatment arm (group 2). The median spontaneous ABRs were 0.0 and 17.0, respectively.

For patients in group 2, there was a significant reduction in median ABRs when patients switched from on-demand treatment to prophylaxis—19.22 and 1.58, respectively (P<0.0001). And there was a significant reduction in median spontaneous ABRs—15.43 and 0.00, respectively (P<0.0001).

Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection of Idelvion.

None of the patients developed inhibitors or experienced thromboembolic events, anaphylaxis, or life-threatening adverse events (AEs).

There were 347 treatment-emergent AEs reported in 54 (85.7%) patients. The most common were nasopharyngitis (25.4%), headache (23.8%), arthralgia (4.3%), and influenza (11.1%).

Eleven mild/moderate AEs in 5 patients (7.9%) were considered possibly related to Idelvion. Two patients discontinued treatment due to AEs—1 with hypersensitivity and 1 with headache.

The US Food and Drug Administration (FDA) has approved Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein) for the treatment of hemophilia B.

The product—a fusion protein linking recombinant coagulation factor IX with recombinant albumin—is intended for use in children and adults for routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand control and prevention of bleeding episodes, and for the perioperative management of bleeding.

Appropriate patients age 12 and older can go up to 14 days between Idelvion infusions. This dosing interval has been achieved while maintaining high levels of factor IX activity—above 5% over 14 days at 75 IU/kg.

Idelvion is the first FDA-approved recombinant factor IX therapy that can extend the dosing interval up to 14 days.

Idelvion is expected to be available in the US later this month. The product is being developed by CSL Behring. For more details on the drug, see the full prescribing information.

Phase 3 trial

The FDA approved Idelvion based on results of the PROLONG-9FP clinical development program. PROLONG-9FP includes phase 1, 2, and 3 studies evaluating the safety and efficacy of Idelvion in adults and children (ages 1 to 61) with hemophilia B.

Data from the phase 3 study were recently published in Blood. This study included 63 previously treated male patients with severe hemophilia B. They had a mean age of 33 (range, 12 to 61).

The patients were divided into 2 groups. Group 1 (n=40) received routine prophylaxis with Idelvion once every 7 days for 26 weeks, followed by a 7-, 10- or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively.

Group 2 received on-demand treatment with Idelvion for bleeding episodes for 26 weeks (n=23) and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks (n=19).

The median annualized bleeding rate (ABR) was 2.0 in the prophylaxis arm (group 1) and 23.5 in the on-demand treatment arm (group 2). The median spontaneous ABRs were 0.0 and 17.0, respectively.

For patients in group 2, there was a significant reduction in median ABRs when patients switched from on-demand treatment to prophylaxis—19.22 and 1.58, respectively (P<0.0001). And there was a significant reduction in median spontaneous ABRs—15.43 and 0.00, respectively (P<0.0001).

Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection of Idelvion.

None of the patients developed inhibitors or experienced thromboembolic events, anaphylaxis, or life-threatening adverse events (AEs).

There were 347 treatment-emergent AEs reported in 54 (85.7%) patients. The most common were nasopharyngitis (25.4%), headache (23.8%), arthralgia (4.3%), and influenza (11.1%).

Eleven mild/moderate AEs in 5 patients (7.9%) were considered possibly related to Idelvion. Two patients discontinued treatment due to AEs—1 with hypersensitivity and 1 with headache.

The US Food and Drug Administration (FDA) has approved Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein) for the treatment of hemophilia B.

The product—a fusion protein linking recombinant coagulation factor IX with recombinant albumin—is intended for use in children and adults for routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand control and prevention of bleeding episodes, and for the perioperative management of bleeding.

Appropriate patients age 12 and older can go up to 14 days between Idelvion infusions. This dosing interval has been achieved while maintaining high levels of factor IX activity—above 5% over 14 days at 75 IU/kg.

Idelvion is the first FDA-approved recombinant factor IX therapy that can extend the dosing interval up to 14 days.

Idelvion is expected to be available in the US later this month. The product is being developed by CSL Behring. For more details on the drug, see the full prescribing information.

Phase 3 trial

The FDA approved Idelvion based on results of the PROLONG-9FP clinical development program. PROLONG-9FP includes phase 1, 2, and 3 studies evaluating the safety and efficacy of Idelvion in adults and children (ages 1 to 61) with hemophilia B.

Data from the phase 3 study were recently published in Blood. This study included 63 previously treated male patients with severe hemophilia B. They had a mean age of 33 (range, 12 to 61).

The patients were divided into 2 groups. Group 1 (n=40) received routine prophylaxis with Idelvion once every 7 days for 26 weeks, followed by a 7-, 10- or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively.

Group 2 received on-demand treatment with Idelvion for bleeding episodes for 26 weeks (n=23) and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks (n=19).

The median annualized bleeding rate (ABR) was 2.0 in the prophylaxis arm (group 1) and 23.5 in the on-demand treatment arm (group 2). The median spontaneous ABRs were 0.0 and 17.0, respectively.

For patients in group 2, there was a significant reduction in median ABRs when patients switched from on-demand treatment to prophylaxis—19.22 and 1.58, respectively (P<0.0001). And there was a significant reduction in median spontaneous ABRs—15.43 and 0.00, respectively (P<0.0001).

Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection of Idelvion.

None of the patients developed inhibitors or experienced thromboembolic events, anaphylaxis, or life-threatening adverse events (AEs).

There were 347 treatment-emergent AEs reported in 54 (85.7%) patients. The most common were nasopharyngitis (25.4%), headache (23.8%), arthralgia (4.3%), and influenza (11.1%).

Eleven mild/moderate AEs in 5 patients (7.9%) were considered possibly related to Idelvion. Two patients discontinued treatment due to AEs—1 with hypersensitivity and 1 with headache.

Influenza-like illness (ILI) activity in the 2015-2016 U.S. flu season declined for the first time since early January, according to the Centers for Disease Control and Prevention.

The proportion of outpatient visits for ILI was reported at 3.2% for the week ending Feb. 20, but the CDC has adjusted that figure to 3.3%, which makes the 3.2% reported for this most recent week (week 20 of the season, ending Feb. 27, 2016) a decrease from the week before.

Despite that drop, two states were at level 10 on the CDC’s 1-10 scale of ILI activity for the first time this season. Arizona had already reached level 10, and joining it there last week was North Carolina, moving up from level 8 the week before. Other states in the “high” range of activity were Arkansas, New Mexico, Tennessee, and Utah at level 9, and Illinois and Maryland at level 8, the CDC reported March 4. Puerto Rico, which had been at level 10 for several weeks, moved down to level 8.

States in the “moderate” range of activity for the week ending Feb. 27 were Florida and New Jersey at level 7 and Alabama, California, Hawaii, Kentucky, Mississippi, Oklahoma, and South Carolina at level 6. Altogether, there were 35 states at level 2 or higher, according to data from the CDC’s Outpatient Influenza-like Illness Surveillance Network.

Four pediatric ILI-related deaths were reported to the CDC during week 20, but three actually occurred during week 19. There have been 18 ILI-related deaths so far during the 2015-2016 season, the CDC said.

[email protected]

Influenza-like illness (ILI) activity in the 2015-2016 U.S. flu season declined for the first time since early January, according to the Centers for Disease Control and Prevention.

The proportion of outpatient visits for ILI was reported at 3.2% for the week ending Feb. 20, but the CDC has adjusted that figure to 3.3%, which makes the 3.2% reported for this most recent week (week 20 of the season, ending Feb. 27, 2016) a decrease from the week before.

Despite that drop, two states were at level 10 on the CDC’s 1-10 scale of ILI activity for the first time this season. Arizona had already reached level 10, and joining it there last week was North Carolina, moving up from level 8 the week before. Other states in the “high” range of activity were Arkansas, New Mexico, Tennessee, and Utah at level 9, and Illinois and Maryland at level 8, the CDC reported March 4. Puerto Rico, which had been at level 10 for several weeks, moved down to level 8.

States in the “moderate” range of activity for the week ending Feb. 27 were Florida and New Jersey at level 7 and Alabama, California, Hawaii, Kentucky, Mississippi, Oklahoma, and South Carolina at level 6. Altogether, there were 35 states at level 2 or higher, according to data from the CDC’s Outpatient Influenza-like Illness Surveillance Network.

Four pediatric ILI-related deaths were reported to the CDC during week 20, but three actually occurred during week 19. There have been 18 ILI-related deaths so far during the 2015-2016 season, the CDC said.

[email protected]

Influenza-like illness (ILI) activity in the 2015-2016 U.S. flu season declined for the first time since early January, according to the Centers for Disease Control and Prevention.

The proportion of outpatient visits for ILI was reported at 3.2% for the week ending Feb. 20, but the CDC has adjusted that figure to 3.3%, which makes the 3.2% reported for this most recent week (week 20 of the season, ending Feb. 27, 2016) a decrease from the week before.

Despite that drop, two states were at level 10 on the CDC’s 1-10 scale of ILI activity for the first time this season. Arizona had already reached level 10, and joining it there last week was North Carolina, moving up from level 8 the week before. Other states in the “high” range of activity were Arkansas, New Mexico, Tennessee, and Utah at level 9, and Illinois and Maryland at level 8, the CDC reported March 4. Puerto Rico, which had been at level 10 for several weeks, moved down to level 8.

States in the “moderate” range of activity for the week ending Feb. 27 were Florida and New Jersey at level 7 and Alabama, California, Hawaii, Kentucky, Mississippi, Oklahoma, and South Carolina at level 6. Altogether, there were 35 states at level 2 or higher, according to data from the CDC’s Outpatient Influenza-like Illness Surveillance Network.

Four pediatric ILI-related deaths were reported to the CDC during week 20, but three actually occurred during week 19. There have been 18 ILI-related deaths so far during the 2015-2016 season, the CDC said.

[email protected]