Cutis

In 2010, two separate reports of cutaneous vasculitic/vasculopathic eruptions in patients with recent exposure to levamisole-contaminated cocaine (LCC) were published in the literature.^1,2 Since then, additional reports have been published.^3-6 Retiform purpura associated with cocaine use appears to be a similar condition, perhaps lying at one end of the spectrum of LCC-induced cutaneous vascular disease.^7,8 Although some patients have been described as having nausea and vomiting,^8,9 including one with a sudden drop in hemoglobin to 5.8 g/dL (reference range, 14.0–17.5 g/dL),¹⁰ there are no known reported cases of LCC and levamisole-induced vasculopathy in organ systems other than the skin. Herein, we report the case of a patient with levamisole-induced vasculopathy (LIV) demonstrating endoscopic evidence of gastric hemorrhage with features similar to those involving the skin.

Case Report

A 35-year-old woman with a history of hepatitis C, intravenous drug abuse, and bipolar disorder presented to the emergency department with painful necrotic lesions on the head, neck, arms, and legs of several days’ duration. Approximately 1 year prior she had been admitted to the hospital with similar lesions, with eventual partial necrosis of the left earlobe. The patient reported she had last used crack cocaine 3 days prior to the development of the lesions. A urine drug screen was positive for lorazepam, alprazolam, buprenorphine, methadone, tetrahydrocannabinol, and cocaine. She also reported abdominal pain and gastric reflux of recent onset but denied any history of gastrointestinal tract disease. During the previous admission, the patient demonstrated antinuclear antibodies at a titer of greater than 1:160 (normal, <1:40) in a smooth pattern as well as positive perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and positive cryoglobulins. Physical examination yielded purpuric and hemorrhagic patches and plaques on the nose, bilateral ears (Figure 1A), face (Figure 1B), arms, and legs. Older lesions exhibited evidence of evolving erosion and ulceration. A biopsy of a lesion on the right arm was obtained, demonstrating extensive epidermal necrosis, hemorrhage, fibrin thrombi within dermal blood vessels, fibrinoid mural necrosis, perivascular neutrophils, and leukocytoclasis (Figure 2). These findings were consistent with LIV caused by exposure to LCC. A complete blood cell count was unremarkable. She was started on pain management and was given prednisone to treat the cutaneous eruption. Because of continued reports of epigastric pain and discomfort on swallowing, an upper gastrointestinal endoscopy was performed. Numerous esophageal erosions and gastric submucosal hemorrhages similar to those on the skin were noted (Figure 3). Pathology taken at the time of the endoscopy demonstrated mucosal erosions, but an evaluation for vascular insult was not possible, as submucosal tissue was not obtained. As the skin lesions began to heal, the gastric symptoms gradually subsided, and the patient was released from the hospital after 7 days.

Comment

Levamisole-Contaminated Cocaine
Cocaine is a crystalline alkaloid obtained from the leaves of the coca plant.⁷ Fifty percent of globally produced cocaine is consumed in the United States.¹⁰ There are 2 to 5 million cocaine users in the United States; in 2009, a reported 1.6 million US adults admitted to having used cocaine in the previous month.^4,11,12 Cocaine has been known to be cut with similar-appearing substances including lactose and mannitol, though caffeine, acetaminophen, methylphenidate, and other ingredients have been utilized.⁷

Levamisole is a synthetic imidazothiazole derivative initially developed for use as an immunomodulatory agent in patients with rheumatoid arthritis.⁴ It was later paired with 5-fluorouracil for administration in patients with carcinomas of the colon and breasts.^4,13 In 2000, the drug was withdrawn from the US market for use in humans after an association between levamisole and agranulocytosis was noted in 2.5% to 13% of patients taking the drug for rheumatoid arthritis or as an adjuvant therapy for breast carcinoma.^9,12 It still is available for veterinary use as an anthelmintic and is administered to humans in other countries. Levamisole acts as an immunomodulator by enhancing macrophage chemotaxis and upregulating T-cell functions as well as stimulating neutrophil chemotaxis and dendritic cell maturation.⁴ It also is known to generate autoantibodies including lupus anticoagulant, p-ANCA, c-ANCA, and antinuclear antibodies.^7,14 Levamisole is known to exhibit cutaneous reactions. In 1999, Rongioletti et al¹⁴ reported 5 children with purpura of the ears who had been given levamisole for pediatric nephrotic syndrome. Involvement of other body areas was noted. Three patients developed lupus anticoagulant antibodies, 3 exhibited p-ANCA antibodies, and 1 was positive for c-ANCA antibodies. The investigators noted an exceptionally long latency period of 12 to 44 months after starting the drug. Histologically a vasculopathic/vasculitic process was noted.¹⁴ Direct immunofluorescence studies of affected skin in LIV have demonstrated IgM, IgA, IgG, C3, and fibrin staining of blood vessels.^4,15 Anti–human elastase antibodies are considered both sensitive and specific for LIV and serve to differentiate it from cocaine-induced pseudovasculitis.^4,7

In April 2008, the New Mexico Department of Health began evaluating several unexplained cases of agranulocytosis and noted that 11 of 21 cases were associated with cocaine use.⁹ Later that year, public health workers in Alberta and British Columbia, Canada, reported finding traces of levamisole in clinical specimens and drug paraphernalia of cocaine users with agranulocytosis. Officials from the New Mexico Department of Health learned of these findings and investigated the cases, finding 7 of 9 patients with idiopathic agranulocytosis had recent exposure to cocaine. None of the 21 total patients experienced any skin findings. Nausea and vomiting were common symptoms, but abdominal pain was described in only 2 patients from an additional investigation in Washington. Both of these patients used crack cocaine, and one had a positive urine test for levamisole.⁹

The presence of levamisole initially was detected by the US Drug Enforcement Administration in 2003. By July 2009, 69% of cocaine and 3% of heroin seized by this agency was noted to contain levamisole.¹⁶ From 2003 to 2009, the concentration of levamisole contamination rose to 10%.⁴ A 2011 study found levamisole in 194 of 249 cocaine-positive urine samples.¹⁶

It is unclear why cocaine producers add levamisoleto their product. Possibilities include increasing the drug’s bulk or enhancing its stimulatory effects.¹² Chang et al¹⁷ posited that levamisole increases the stimulatory and euphoric effects of cocaine by increasing dopamine levels in the brain. Additionally, levamisole is metabolized to aminorex, an amphetaminelike hallucinogen that suppresses appetite, in patients with LCC.¹³ Vagi et al¹² interviewed 10 patients who had been hospitalized for agranulocytosis secondary to use of LCC. None were aware of the presence of this additive, suggesting it was not used as a marketing tool.

Cutaneous Vasculopathy
Levamisole-induced vasculopathy (also called levamisole-induced cutaneous vasculopathy¹¹) initially was reported by 2 separate groups in 2010.^1,2 Patients typically present with tender purpuric to hemorrhagic papules, plaques, and bullae with an affinity to affect the ears, nose, and face, though other areas of the body can be affected. A pattern of retiform purpura may precede these findings in some patients. Women are disproportionately affected.¹¹ Crack cocaine use is overrepresented in LIV compared to insufflation or snorting of the drug. Affected patients may exhibit systemic symptoms including myalgia, arthralgia, and frank arthritis.¹⁰ Additionally, 15% to 80% of patients exhibit positive antinuclear antibodies, anticardiolipin antibodies, lupus anticoagulant antibodies, p-ANCA antibodies, and c-ANCA antibodies. Magro and Wang⁸ hypothesized that levamisole acting in conjunction with cocaine rather than the effects of levamisole alone is responsible for some of these findings.

Histologically, the features of a vasculopathic process are noted in some patients with the presence of frank vasculitis.¹ The vasculopathic component demonstrates vessel dilatation with thrombosis, eosinophilic deposits, and erythrocyte extravasation. Patients with frank vasculitis exhibit fibrinoid vessel wall necrosis and fibrin deposition, extravasated erythrocytes, endothelial cell atypia, and leukocytoclasia.³ Jacob et al³ noted interstitial and perivascular neovascularization in affected tissue, believed to represent one stage in the evolution of medium vessel vasculitis. Intercellular adhesion molecule 1 has been reported in affected vessel walls with endothelial caspase 3 expression and C5b-9 deposition.⁸ Magro and Wang⁸ believe the retiform purpura seen in the early stages of some of these patients with LIV represents a thrombotic dynamic with C5b-9 deposition and enhanced apoptosis. Overt vasculitis follows later, subsequent to the effect of ANCA antibodies and upregulated intercellular adhesion molecule 1 expression on vessel walls.

The clinical course of LIV typically is 2 to 3 weeks for lesion resolution; however, normalization of serologies may require 2 to 14 months. Observation and pain control with or without administration of systemic steroids is sufficient for most patients, but skin grafting, wound debridement, cyclosporine, mycophenolate mofetil, and plasmapheresis also have been employed.^4,5 Morbidity may be substantive. One report noted LCC to be responsible for 3 cases of pulmonary hemorrhage and acute progression to chronic renal failure in another 2 patients.¹⁵ Ching and Smith¹⁸ described a patient with 52% total body surface area involvement who required skin grafting, nasal amputation, patellectomy, central upper lip excision, and amputation of the leg above the knee.

Gastrointestinal Presentation
Patients with LIV have been reported to exhibit abdominal pain, but our patient exhibited a rare presentation of visualized gastrointestinal purpura. Although support for a vasculitic/vasculopathic process requires a tissue diagnosis, the endoscopic appearance of gastric vasculitis is similar to that of cutaneous vasculitis.¹⁹ Clinicians caring for patients exposed to LCC should bear in mind that the vascular insults associated with LIV are not restricted solely to the skin.

In 2010, two separate reports of cutaneous vasculitic/vasculopathic eruptions in patients with recent exposure to levamisole-contaminated cocaine (LCC) were published in the literature.^1,2 Since then, additional reports have been published.^3-6 Retiform purpura associated with cocaine use appears to be a similar condition, perhaps lying at one end of the spectrum of LCC-induced cutaneous vascular disease.^7,8 Although some patients have been described as having nausea and vomiting,^8,9 including one with a sudden drop in hemoglobin to 5.8 g/dL (reference range, 14.0–17.5 g/dL),¹⁰ there are no known reported cases of LCC and levamisole-induced vasculopathy in organ systems other than the skin. Herein, we report the case of a patient with levamisole-induced vasculopathy (LIV) demonstrating endoscopic evidence of gastric hemorrhage with features similar to those involving the skin.

Case Report

A 35-year-old woman with a history of hepatitis C, intravenous drug abuse, and bipolar disorder presented to the emergency department with painful necrotic lesions on the head, neck, arms, and legs of several days’ duration. Approximately 1 year prior she had been admitted to the hospital with similar lesions, with eventual partial necrosis of the left earlobe. The patient reported she had last used crack cocaine 3 days prior to the development of the lesions. A urine drug screen was positive for lorazepam, alprazolam, buprenorphine, methadone, tetrahydrocannabinol, and cocaine. She also reported abdominal pain and gastric reflux of recent onset but denied any history of gastrointestinal tract disease. During the previous admission, the patient demonstrated antinuclear antibodies at a titer of greater than 1:160 (normal, <1:40) in a smooth pattern as well as positive perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and positive cryoglobulins. Physical examination yielded purpuric and hemorrhagic patches and plaques on the nose, bilateral ears (Figure 1A), face (Figure 1B), arms, and legs. Older lesions exhibited evidence of evolving erosion and ulceration. A biopsy of a lesion on the right arm was obtained, demonstrating extensive epidermal necrosis, hemorrhage, fibrin thrombi within dermal blood vessels, fibrinoid mural necrosis, perivascular neutrophils, and leukocytoclasis (Figure 2). These findings were consistent with LIV caused by exposure to LCC. A complete blood cell count was unremarkable. She was started on pain management and was given prednisone to treat the cutaneous eruption. Because of continued reports of epigastric pain and discomfort on swallowing, an upper gastrointestinal endoscopy was performed. Numerous esophageal erosions and gastric submucosal hemorrhages similar to those on the skin were noted (Figure 3). Pathology taken at the time of the endoscopy demonstrated mucosal erosions, but an evaluation for vascular insult was not possible, as submucosal tissue was not obtained. As the skin lesions began to heal, the gastric symptoms gradually subsided, and the patient was released from the hospital after 7 days.

Comment

Levamisole-Contaminated Cocaine
Cocaine is a crystalline alkaloid obtained from the leaves of the coca plant.⁷ Fifty percent of globally produced cocaine is consumed in the United States.¹⁰ There are 2 to 5 million cocaine users in the United States; in 2009, a reported 1.6 million US adults admitted to having used cocaine in the previous month.^4,11,12 Cocaine has been known to be cut with similar-appearing substances including lactose and mannitol, though caffeine, acetaminophen, methylphenidate, and other ingredients have been utilized.⁷

Levamisole is a synthetic imidazothiazole derivative initially developed for use as an immunomodulatory agent in patients with rheumatoid arthritis.⁴ It was later paired with 5-fluorouracil for administration in patients with carcinomas of the colon and breasts.^4,13 In 2000, the drug was withdrawn from the US market for use in humans after an association between levamisole and agranulocytosis was noted in 2.5% to 13% of patients taking the drug for rheumatoid arthritis or as an adjuvant therapy for breast carcinoma.^9,12 It still is available for veterinary use as an anthelmintic and is administered to humans in other countries. Levamisole acts as an immunomodulator by enhancing macrophage chemotaxis and upregulating T-cell functions as well as stimulating neutrophil chemotaxis and dendritic cell maturation.⁴ It also is known to generate autoantibodies including lupus anticoagulant, p-ANCA, c-ANCA, and antinuclear antibodies.^7,14 Levamisole is known to exhibit cutaneous reactions. In 1999, Rongioletti et al¹⁴ reported 5 children with purpura of the ears who had been given levamisole for pediatric nephrotic syndrome. Involvement of other body areas was noted. Three patients developed lupus anticoagulant antibodies, 3 exhibited p-ANCA antibodies, and 1 was positive for c-ANCA antibodies. The investigators noted an exceptionally long latency period of 12 to 44 months after starting the drug. Histologically a vasculopathic/vasculitic process was noted.¹⁴ Direct immunofluorescence studies of affected skin in LIV have demonstrated IgM, IgA, IgG, C3, and fibrin staining of blood vessels.^4,15 Anti–human elastase antibodies are considered both sensitive and specific for LIV and serve to differentiate it from cocaine-induced pseudovasculitis.^4,7

In April 2008, the New Mexico Department of Health began evaluating several unexplained cases of agranulocytosis and noted that 11 of 21 cases were associated with cocaine use.⁹ Later that year, public health workers in Alberta and British Columbia, Canada, reported finding traces of levamisole in clinical specimens and drug paraphernalia of cocaine users with agranulocytosis. Officials from the New Mexico Department of Health learned of these findings and investigated the cases, finding 7 of 9 patients with idiopathic agranulocytosis had recent exposure to cocaine. None of the 21 total patients experienced any skin findings. Nausea and vomiting were common symptoms, but abdominal pain was described in only 2 patients from an additional investigation in Washington. Both of these patients used crack cocaine, and one had a positive urine test for levamisole.⁹

The presence of levamisole initially was detected by the US Drug Enforcement Administration in 2003. By July 2009, 69% of cocaine and 3% of heroin seized by this agency was noted to contain levamisole.¹⁶ From 2003 to 2009, the concentration of levamisole contamination rose to 10%.⁴ A 2011 study found levamisole in 194 of 249 cocaine-positive urine samples.¹⁶

It is unclear why cocaine producers add levamisoleto their product. Possibilities include increasing the drug’s bulk or enhancing its stimulatory effects.¹² Chang et al¹⁷ posited that levamisole increases the stimulatory and euphoric effects of cocaine by increasing dopamine levels in the brain. Additionally, levamisole is metabolized to aminorex, an amphetaminelike hallucinogen that suppresses appetite, in patients with LCC.¹³ Vagi et al¹² interviewed 10 patients who had been hospitalized for agranulocytosis secondary to use of LCC. None were aware of the presence of this additive, suggesting it was not used as a marketing tool.

Cutaneous Vasculopathy
Levamisole-induced vasculopathy (also called levamisole-induced cutaneous vasculopathy¹¹) initially was reported by 2 separate groups in 2010.^1,2 Patients typically present with tender purpuric to hemorrhagic papules, plaques, and bullae with an affinity to affect the ears, nose, and face, though other areas of the body can be affected. A pattern of retiform purpura may precede these findings in some patients. Women are disproportionately affected.¹¹ Crack cocaine use is overrepresented in LIV compared to insufflation or snorting of the drug. Affected patients may exhibit systemic symptoms including myalgia, arthralgia, and frank arthritis.¹⁰ Additionally, 15% to 80% of patients exhibit positive antinuclear antibodies, anticardiolipin antibodies, lupus anticoagulant antibodies, p-ANCA antibodies, and c-ANCA antibodies. Magro and Wang⁸ hypothesized that levamisole acting in conjunction with cocaine rather than the effects of levamisole alone is responsible for some of these findings.

Histologically, the features of a vasculopathic process are noted in some patients with the presence of frank vasculitis.¹ The vasculopathic component demonstrates vessel dilatation with thrombosis, eosinophilic deposits, and erythrocyte extravasation. Patients with frank vasculitis exhibit fibrinoid vessel wall necrosis and fibrin deposition, extravasated erythrocytes, endothelial cell atypia, and leukocytoclasia.³ Jacob et al³ noted interstitial and perivascular neovascularization in affected tissue, believed to represent one stage in the evolution of medium vessel vasculitis. Intercellular adhesion molecule 1 has been reported in affected vessel walls with endothelial caspase 3 expression and C5b-9 deposition.⁸ Magro and Wang⁸ believe the retiform purpura seen in the early stages of some of these patients with LIV represents a thrombotic dynamic with C5b-9 deposition and enhanced apoptosis. Overt vasculitis follows later, subsequent to the effect of ANCA antibodies and upregulated intercellular adhesion molecule 1 expression on vessel walls.

The clinical course of LIV typically is 2 to 3 weeks for lesion resolution; however, normalization of serologies may require 2 to 14 months. Observation and pain control with or without administration of systemic steroids is sufficient for most patients, but skin grafting, wound debridement, cyclosporine, mycophenolate mofetil, and plasmapheresis also have been employed.^4,5 Morbidity may be substantive. One report noted LCC to be responsible for 3 cases of pulmonary hemorrhage and acute progression to chronic renal failure in another 2 patients.¹⁵ Ching and Smith¹⁸ described a patient with 52% total body surface area involvement who required skin grafting, nasal amputation, patellectomy, central upper lip excision, and amputation of the leg above the knee.

Gastrointestinal Presentation
Patients with LIV have been reported to exhibit abdominal pain, but our patient exhibited a rare presentation of visualized gastrointestinal purpura. Although support for a vasculitic/vasculopathic process requires a tissue diagnosis, the endoscopic appearance of gastric vasculitis is similar to that of cutaneous vasculitis.¹⁹ Clinicians caring for patients exposed to LCC should bear in mind that the vascular insults associated with LIV are not restricted solely to the skin.

In 2010, two separate reports of cutaneous vasculitic/vasculopathic eruptions in patients with recent exposure to levamisole-contaminated cocaine (LCC) were published in the literature.^1,2 Since then, additional reports have been published.^3-6 Retiform purpura associated with cocaine use appears to be a similar condition, perhaps lying at one end of the spectrum of LCC-induced cutaneous vascular disease.^7,8 Although some patients have been described as having nausea and vomiting,^8,9 including one with a sudden drop in hemoglobin to 5.8 g/dL (reference range, 14.0–17.5 g/dL),¹⁰ there are no known reported cases of LCC and levamisole-induced vasculopathy in organ systems other than the skin. Herein, we report the case of a patient with levamisole-induced vasculopathy (LIV) demonstrating endoscopic evidence of gastric hemorrhage with features similar to those involving the skin.

Case Report

A 35-year-old woman with a history of hepatitis C, intravenous drug abuse, and bipolar disorder presented to the emergency department with painful necrotic lesions on the head, neck, arms, and legs of several days’ duration. Approximately 1 year prior she had been admitted to the hospital with similar lesions, with eventual partial necrosis of the left earlobe. The patient reported she had last used crack cocaine 3 days prior to the development of the lesions. A urine drug screen was positive for lorazepam, alprazolam, buprenorphine, methadone, tetrahydrocannabinol, and cocaine. She also reported abdominal pain and gastric reflux of recent onset but denied any history of gastrointestinal tract disease. During the previous admission, the patient demonstrated antinuclear antibodies at a titer of greater than 1:160 (normal, <1:40) in a smooth pattern as well as positive perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and positive cryoglobulins. Physical examination yielded purpuric and hemorrhagic patches and plaques on the nose, bilateral ears (Figure 1A), face (Figure 1B), arms, and legs. Older lesions exhibited evidence of evolving erosion and ulceration. A biopsy of a lesion on the right arm was obtained, demonstrating extensive epidermal necrosis, hemorrhage, fibrin thrombi within dermal blood vessels, fibrinoid mural necrosis, perivascular neutrophils, and leukocytoclasis (Figure 2). These findings were consistent with LIV caused by exposure to LCC. A complete blood cell count was unremarkable. She was started on pain management and was given prednisone to treat the cutaneous eruption. Because of continued reports of epigastric pain and discomfort on swallowing, an upper gastrointestinal endoscopy was performed. Numerous esophageal erosions and gastric submucosal hemorrhages similar to those on the skin were noted (Figure 3). Pathology taken at the time of the endoscopy demonstrated mucosal erosions, but an evaluation for vascular insult was not possible, as submucosal tissue was not obtained. As the skin lesions began to heal, the gastric symptoms gradually subsided, and the patient was released from the hospital after 7 days.

Comment

Levamisole-Contaminated Cocaine
Cocaine is a crystalline alkaloid obtained from the leaves of the coca plant.⁷ Fifty percent of globally produced cocaine is consumed in the United States.¹⁰ There are 2 to 5 million cocaine users in the United States; in 2009, a reported 1.6 million US adults admitted to having used cocaine in the previous month.^4,11,12 Cocaine has been known to be cut with similar-appearing substances including lactose and mannitol, though caffeine, acetaminophen, methylphenidate, and other ingredients have been utilized.⁷

Levamisole is a synthetic imidazothiazole derivative initially developed for use as an immunomodulatory agent in patients with rheumatoid arthritis.⁴ It was later paired with 5-fluorouracil for administration in patients with carcinomas of the colon and breasts.^4,13 In 2000, the drug was withdrawn from the US market for use in humans after an association between levamisole and agranulocytosis was noted in 2.5% to 13% of patients taking the drug for rheumatoid arthritis or as an adjuvant therapy for breast carcinoma.^9,12 It still is available for veterinary use as an anthelmintic and is administered to humans in other countries. Levamisole acts as an immunomodulator by enhancing macrophage chemotaxis and upregulating T-cell functions as well as stimulating neutrophil chemotaxis and dendritic cell maturation.⁴ It also is known to generate autoantibodies including lupus anticoagulant, p-ANCA, c-ANCA, and antinuclear antibodies.^7,14 Levamisole is known to exhibit cutaneous reactions. In 1999, Rongioletti et al¹⁴ reported 5 children with purpura of the ears who had been given levamisole for pediatric nephrotic syndrome. Involvement of other body areas was noted. Three patients developed lupus anticoagulant antibodies, 3 exhibited p-ANCA antibodies, and 1 was positive for c-ANCA antibodies. The investigators noted an exceptionally long latency period of 12 to 44 months after starting the drug. Histologically a vasculopathic/vasculitic process was noted.¹⁴ Direct immunofluorescence studies of affected skin in LIV have demonstrated IgM, IgA, IgG, C3, and fibrin staining of blood vessels.^4,15 Anti–human elastase antibodies are considered both sensitive and specific for LIV and serve to differentiate it from cocaine-induced pseudovasculitis.^4,7

In April 2008, the New Mexico Department of Health began evaluating several unexplained cases of agranulocytosis and noted that 11 of 21 cases were associated with cocaine use.⁹ Later that year, public health workers in Alberta and British Columbia, Canada, reported finding traces of levamisole in clinical specimens and drug paraphernalia of cocaine users with agranulocytosis. Officials from the New Mexico Department of Health learned of these findings and investigated the cases, finding 7 of 9 patients with idiopathic agranulocytosis had recent exposure to cocaine. None of the 21 total patients experienced any skin findings. Nausea and vomiting were common symptoms, but abdominal pain was described in only 2 patients from an additional investigation in Washington. Both of these patients used crack cocaine, and one had a positive urine test for levamisole.⁹

The presence of levamisole initially was detected by the US Drug Enforcement Administration in 2003. By July 2009, 69% of cocaine and 3% of heroin seized by this agency was noted to contain levamisole.¹⁶ From 2003 to 2009, the concentration of levamisole contamination rose to 10%.⁴ A 2011 study found levamisole in 194 of 249 cocaine-positive urine samples.¹⁶

It is unclear why cocaine producers add levamisoleto their product. Possibilities include increasing the drug’s bulk or enhancing its stimulatory effects.¹² Chang et al¹⁷ posited that levamisole increases the stimulatory and euphoric effects of cocaine by increasing dopamine levels in the brain. Additionally, levamisole is metabolized to aminorex, an amphetaminelike hallucinogen that suppresses appetite, in patients with LCC.¹³ Vagi et al¹² interviewed 10 patients who had been hospitalized for agranulocytosis secondary to use of LCC. None were aware of the presence of this additive, suggesting it was not used as a marketing tool.

Cutaneous Vasculopathy
Levamisole-induced vasculopathy (also called levamisole-induced cutaneous vasculopathy¹¹) initially was reported by 2 separate groups in 2010.^1,2 Patients typically present with tender purpuric to hemorrhagic papules, plaques, and bullae with an affinity to affect the ears, nose, and face, though other areas of the body can be affected. A pattern of retiform purpura may precede these findings in some patients. Women are disproportionately affected.¹¹ Crack cocaine use is overrepresented in LIV compared to insufflation or snorting of the drug. Affected patients may exhibit systemic symptoms including myalgia, arthralgia, and frank arthritis.¹⁰ Additionally, 15% to 80% of patients exhibit positive antinuclear antibodies, anticardiolipin antibodies, lupus anticoagulant antibodies, p-ANCA antibodies, and c-ANCA antibodies. Magro and Wang⁸ hypothesized that levamisole acting in conjunction with cocaine rather than the effects of levamisole alone is responsible for some of these findings.

Histologically, the features of a vasculopathic process are noted in some patients with the presence of frank vasculitis.¹ The vasculopathic component demonstrates vessel dilatation with thrombosis, eosinophilic deposits, and erythrocyte extravasation. Patients with frank vasculitis exhibit fibrinoid vessel wall necrosis and fibrin deposition, extravasated erythrocytes, endothelial cell atypia, and leukocytoclasia.³ Jacob et al³ noted interstitial and perivascular neovascularization in affected tissue, believed to represent one stage in the evolution of medium vessel vasculitis. Intercellular adhesion molecule 1 has been reported in affected vessel walls with endothelial caspase 3 expression and C5b-9 deposition.⁸ Magro and Wang⁸ believe the retiform purpura seen in the early stages of some of these patients with LIV represents a thrombotic dynamic with C5b-9 deposition and enhanced apoptosis. Overt vasculitis follows later, subsequent to the effect of ANCA antibodies and upregulated intercellular adhesion molecule 1 expression on vessel walls.

The clinical course of LIV typically is 2 to 3 weeks for lesion resolution; however, normalization of serologies may require 2 to 14 months. Observation and pain control with or without administration of systemic steroids is sufficient for most patients, but skin grafting, wound debridement, cyclosporine, mycophenolate mofetil, and plasmapheresis also have been employed.^4,5 Morbidity may be substantive. One report noted LCC to be responsible for 3 cases of pulmonary hemorrhage and acute progression to chronic renal failure in another 2 patients.¹⁵ Ching and Smith¹⁸ described a patient with 52% total body surface area involvement who required skin grafting, nasal amputation, patellectomy, central upper lip excision, and amputation of the leg above the knee.

Gastrointestinal Presentation
Patients with LIV have been reported to exhibit abdominal pain, but our patient exhibited a rare presentation of visualized gastrointestinal purpura. Although support for a vasculitic/vasculopathic process requires a tissue diagnosis, the endoscopic appearance of gastric vasculitis is similar to that of cutaneous vasculitis.¹⁹ Clinicians caring for patients exposed to LCC should bear in mind that the vascular insults associated with LIV are not restricted solely to the skin.

The Diagnosis: Bacterial Infection

The tetrad arrangement of organisms seen in this case was classic for Micrococcus and Sarcina species. Both are gram-positive cocci that occur in tetrads, but Micrococcus is aerobic and catalase positive, whereas Sarcina species are anaerobic, catalase negative, acidophilic, and form spores in alkaline pH.¹ Although difficult to definitively differentiate on light microscopy, micrococci are smaller in size, ranging from 0.5 to 2.0 μm, and occur in tight clusters, as seen in this case (quiz images), in contrast to Sarcina species, which are relatively larger (1.8-3.0 μm).² Sarcinae typically are found in soil and air, are considered pathogenic, and are associated with gastric symptoms (Sarcina ventriculi).¹Sarcina species also are reported to colonize the skin of patients with diabetes mellitus, but no pathogenic activity is known in the skin.³Micrococcus species, with the majority being Micrococcus luteus, are part of the normal flora of the human skin as well as the oral and nasal cavities. Occasional reports of pneumonia, endocarditis, meningitis, arthritis, endophthalmitis, and sepsis have been reported in immunocompromised individuals.⁴ In the skin, Micrococcus is a commensal organism; however, Micrococcus sedentarius has been associated with pitted keratolysis, and reports of Micrococcus folliculitis in human immunodeficiency virus patients also are described in the literature.^5,6 Micrococci are considered opportunistic bacteria and may worsen and prolong a localized cutaneous infection caused by other organisms under favorable conditions.⁷Micrococcus luteus is one of the most common bacteria cultured from skin and soft tissue infections caused by fungal organisms.⁸ Depending on the immune status of an individual, use of broad-spectrum antibiotic and/or elimination of favorable milieu (ie, primary pathogen, breaks in skin) usually treats the infection.

Because of the rarity of infections caused and being part of the normal flora, the clinical implications of subtyping and sensitivity studies via culture or molecular studies may not be important; however, incidental presence of these organisms with unfamiliar morphology may cause confusion for the dermatopathologist. An extremely small size (0.5-2.0 μm) compared to red blood cells (7-8 μm) and white blood cells (10-12 μm) in a tight tetrad arrangement should raise the suspicion for Micrococcus.1 The refractive nature of these organisms from a thick extracellular layer can mimic fungus or plant matter; a negative Grocott-Gomori methenamine-silver stain in this case helped in not only differentiating but also ruling out secondary fungal infection. Finally, a Gram stain with violet staining of these organisms reaffirmed the diagnosis of gram-positive bacterial organisms, most consistent with Micrococcus species (Figure 1). Culture studies were not performed because of contamination of the tissue specimen and resolution of the patient's symptoms.

The presence of foreign material in the skin may be traumatic, occupational, cosmetic, iatrogenic, or self-inflicted, including a wide variety of substances that appear in different morphological forms on hematoxylin and eosin (H&E)-stained sections, depending on their structure and physiochemical properties.⁹ Although not all foreign bodies may polarize, examining the sample under polarized light is considered an important step to narrow down the differential diagnosis. The tissue reaction is primarily dependent on the nature of the substance and duration, consisting of histiocytes, macrophages, plasma cells, lymphocytes, and fibrosis.⁹ Activated histiocytes, multinucleated giant cells, and granulomas are classic findings that generally are seen surrounding and engulfing the foreign material (Figure 2). In addition to foreign material, substances such as calcium salts, urate crystals, extruded keratin, ruptured cysts, and hair follicles may act as foreign materials and can incite a tissue response.⁹ Absence of histiocytic response, granuloma formation, and fibrosis in a lesion of 1 month's duration made the tetrad bodies unlikely to be foreign material.

Demodex mites are superficial inhabitants of human skin that are acquired shortly after birth, live in or near pilosebaceous units, and obtain nourishment from skin cells and sebum.^10,11 The mites can be recovered on 10% of skin biopsies, most commonly on the face due to high sebum production.¹⁰ Adult mites range from 0.1 to 0.4 mm in length and are round to oval in shape. Females lay eggs inside the hair follicle or sebaceous glands.¹¹ They usually are asymptomatic, but their infestation may become pathogenic, especially in immunocompromised individuals.¹⁰ The clinical picture may resemble bacterial folliculitis, rosacea, and perioral dermatitis, while histology typically is characterized by spongiosis, lymphohistiocytic inflammation around infested follicles, and mite(s) in follicular infundibula (Figure 3). Sometimes the protrusion of mites and keratin from the follicles is seen as follicular spines on histology and referred to as pityriasis folliculorum.

Deposits of urate crystals in skin occur from the elevated serum uric acid levels in gout. The cutaneous deposits are mainly in the dermis and subcutaneous tissue and are extremely painful.¹² Urate crystals get dissolved during formalin fixation and leave needlelike clefts in a homogenous, lightly basophilic material on H&E slide (Figure 4). For the same reason, polarized microscopy also is not helpful despite the birefringent nature of urate crystals.¹²

Fungal yeast forms appear round to oval under light microscopy, ranging from 2 to 100 μm in size.¹³ The common superficial forms involving the epidermis or hair follicles similar to the current case of bacterial infection include Malassezia and dermatophyte infections. Malassezia is part of the normal flora of sebum-rich areas of skin and is associated with superficial infections such as folliculitis, atopic dermatitis, psoriasis, seborrheic dermatitis, and dandruff.¹⁴Malassezia appear as clusters of yeast cells that are pleomorphic and round to oval in shape, ranging from 2 to 6 μm in size. It forms hyphae in its pathogenic form and gives rise to the classic spaghetti and meatball-like appearance that can be highlighted by periodic acid-Schiff (Figure 5) and Grocott-Gomori methenamine-silver special stains. Dermatophytes include 3 genera--Trichophyton, Microsporum, and Epidermophyton--with at least 40 species that causes skin infections in humans.¹⁴ Fungal spores and hyphae forms are restricted to the stratum corneum. The hyphae forms may not be apparent on H&E stain, and periodic acid-Schiff staining is helpful in visualizing the fungal elements. The presence of neutrophils in the corneal layer, basket weave hyperkeratosis, and presence of fungal hyphae within the corneal layer fissures (sandwich sign) are clues to the dermatophyte infection.¹⁵ Other smaller fungi such as Histoplasma capsulatum (2-4 μm), Candida (3-5 μm), and Pneumocystis (2-5 μm) species can be found in skin in disseminated infections, usually affecting immunocompromised individuals.¹³Histoplasma is a basophilic yeast that exhibits narrow-based budding and appears clustered within or outside of macrophages. Candida species generally are dimorphic, and yeasts are found intermingled with filamentous forms. Pneumocystis infection in skin is extremely rare, and the fungi appear as spherical or crescent-shaped bodies in a foamy amorphous material.¹⁶

The Diagnosis: Bacterial Infection

The tetrad arrangement of organisms seen in this case was classic for Micrococcus and Sarcina species. Both are gram-positive cocci that occur in tetrads, but Micrococcus is aerobic and catalase positive, whereas Sarcina species are anaerobic, catalase negative, acidophilic, and form spores in alkaline pH.¹ Although difficult to definitively differentiate on light microscopy, micrococci are smaller in size, ranging from 0.5 to 2.0 μm, and occur in tight clusters, as seen in this case (quiz images), in contrast to Sarcina species, which are relatively larger (1.8-3.0 μm).² Sarcinae typically are found in soil and air, are considered pathogenic, and are associated with gastric symptoms (Sarcina ventriculi).¹Sarcina species also are reported to colonize the skin of patients with diabetes mellitus, but no pathogenic activity is known in the skin.³Micrococcus species, with the majority being Micrococcus luteus, are part of the normal flora of the human skin as well as the oral and nasal cavities. Occasional reports of pneumonia, endocarditis, meningitis, arthritis, endophthalmitis, and sepsis have been reported in immunocompromised individuals.⁴ In the skin, Micrococcus is a commensal organism; however, Micrococcus sedentarius has been associated with pitted keratolysis, and reports of Micrococcus folliculitis in human immunodeficiency virus patients also are described in the literature.^5,6 Micrococci are considered opportunistic bacteria and may worsen and prolong a localized cutaneous infection caused by other organisms under favorable conditions.⁷Micrococcus luteus is one of the most common bacteria cultured from skin and soft tissue infections caused by fungal organisms.⁸ Depending on the immune status of an individual, use of broad-spectrum antibiotic and/or elimination of favorable milieu (ie, primary pathogen, breaks in skin) usually treats the infection.

Because of the rarity of infections caused and being part of the normal flora, the clinical implications of subtyping and sensitivity studies via culture or molecular studies may not be important; however, incidental presence of these organisms with unfamiliar morphology may cause confusion for the dermatopathologist. An extremely small size (0.5-2.0 μm) compared to red blood cells (7-8 μm) and white blood cells (10-12 μm) in a tight tetrad arrangement should raise the suspicion for Micrococcus.1 The refractive nature of these organisms from a thick extracellular layer can mimic fungus or plant matter; a negative Grocott-Gomori methenamine-silver stain in this case helped in not only differentiating but also ruling out secondary fungal infection. Finally, a Gram stain with violet staining of these organisms reaffirmed the diagnosis of gram-positive bacterial organisms, most consistent with Micrococcus species (Figure 1). Culture studies were not performed because of contamination of the tissue specimen and resolution of the patient's symptoms.

The presence of foreign material in the skin may be traumatic, occupational, cosmetic, iatrogenic, or self-inflicted, including a wide variety of substances that appear in different morphological forms on hematoxylin and eosin (H&E)-stained sections, depending on their structure and physiochemical properties.⁹ Although not all foreign bodies may polarize, examining the sample under polarized light is considered an important step to narrow down the differential diagnosis. The tissue reaction is primarily dependent on the nature of the substance and duration, consisting of histiocytes, macrophages, plasma cells, lymphocytes, and fibrosis.⁹ Activated histiocytes, multinucleated giant cells, and granulomas are classic findings that generally are seen surrounding and engulfing the foreign material (Figure 2). In addition to foreign material, substances such as calcium salts, urate crystals, extruded keratin, ruptured cysts, and hair follicles may act as foreign materials and can incite a tissue response.⁹ Absence of histiocytic response, granuloma formation, and fibrosis in a lesion of 1 month's duration made the tetrad bodies unlikely to be foreign material.

Demodex mites are superficial inhabitants of human skin that are acquired shortly after birth, live in or near pilosebaceous units, and obtain nourishment from skin cells and sebum.^10,11 The mites can be recovered on 10% of skin biopsies, most commonly on the face due to high sebum production.¹⁰ Adult mites range from 0.1 to 0.4 mm in length and are round to oval in shape. Females lay eggs inside the hair follicle or sebaceous glands.¹¹ They usually are asymptomatic, but their infestation may become pathogenic, especially in immunocompromised individuals.¹⁰ The clinical picture may resemble bacterial folliculitis, rosacea, and perioral dermatitis, while histology typically is characterized by spongiosis, lymphohistiocytic inflammation around infested follicles, and mite(s) in follicular infundibula (Figure 3). Sometimes the protrusion of mites and keratin from the follicles is seen as follicular spines on histology and referred to as pityriasis folliculorum.

Deposits of urate crystals in skin occur from the elevated serum uric acid levels in gout. The cutaneous deposits are mainly in the dermis and subcutaneous tissue and are extremely painful.¹² Urate crystals get dissolved during formalin fixation and leave needlelike clefts in a homogenous, lightly basophilic material on H&E slide (Figure 4). For the same reason, polarized microscopy also is not helpful despite the birefringent nature of urate crystals.¹²

Fungal yeast forms appear round to oval under light microscopy, ranging from 2 to 100 μm in size.¹³ The common superficial forms involving the epidermis or hair follicles similar to the current case of bacterial infection include Malassezia and dermatophyte infections. Malassezia is part of the normal flora of sebum-rich areas of skin and is associated with superficial infections such as folliculitis, atopic dermatitis, psoriasis, seborrheic dermatitis, and dandruff.¹⁴Malassezia appear as clusters of yeast cells that are pleomorphic and round to oval in shape, ranging from 2 to 6 μm in size. It forms hyphae in its pathogenic form and gives rise to the classic spaghetti and meatball-like appearance that can be highlighted by periodic acid-Schiff (Figure 5) and Grocott-Gomori methenamine-silver special stains. Dermatophytes include 3 genera--Trichophyton, Microsporum, and Epidermophyton--with at least 40 species that causes skin infections in humans.¹⁴ Fungal spores and hyphae forms are restricted to the stratum corneum. The hyphae forms may not be apparent on H&E stain, and periodic acid-Schiff staining is helpful in visualizing the fungal elements. The presence of neutrophils in the corneal layer, basket weave hyperkeratosis, and presence of fungal hyphae within the corneal layer fissures (sandwich sign) are clues to the dermatophyte infection.¹⁵ Other smaller fungi such as Histoplasma capsulatum (2-4 μm), Candida (3-5 μm), and Pneumocystis (2-5 μm) species can be found in skin in disseminated infections, usually affecting immunocompromised individuals.¹³Histoplasma is a basophilic yeast that exhibits narrow-based budding and appears clustered within or outside of macrophages. Candida species generally are dimorphic, and yeasts are found intermingled with filamentous forms. Pneumocystis infection in skin is extremely rare, and the fungi appear as spherical or crescent-shaped bodies in a foamy amorphous material.¹⁶

The Diagnosis: Bacterial Infection

The tetrad arrangement of organisms seen in this case was classic for Micrococcus and Sarcina species. Both are gram-positive cocci that occur in tetrads, but Micrococcus is aerobic and catalase positive, whereas Sarcina species are anaerobic, catalase negative, acidophilic, and form spores in alkaline pH.¹ Although difficult to definitively differentiate on light microscopy, micrococci are smaller in size, ranging from 0.5 to 2.0 μm, and occur in tight clusters, as seen in this case (quiz images), in contrast to Sarcina species, which are relatively larger (1.8-3.0 μm).² Sarcinae typically are found in soil and air, are considered pathogenic, and are associated with gastric symptoms (Sarcina ventriculi).¹Sarcina species also are reported to colonize the skin of patients with diabetes mellitus, but no pathogenic activity is known in the skin.³Micrococcus species, with the majority being Micrococcus luteus, are part of the normal flora of the human skin as well as the oral and nasal cavities. Occasional reports of pneumonia, endocarditis, meningitis, arthritis, endophthalmitis, and sepsis have been reported in immunocompromised individuals.⁴ In the skin, Micrococcus is a commensal organism; however, Micrococcus sedentarius has been associated with pitted keratolysis, and reports of Micrococcus folliculitis in human immunodeficiency virus patients also are described in the literature.^5,6 Micrococci are considered opportunistic bacteria and may worsen and prolong a localized cutaneous infection caused by other organisms under favorable conditions.⁷Micrococcus luteus is one of the most common bacteria cultured from skin and soft tissue infections caused by fungal organisms.⁸ Depending on the immune status of an individual, use of broad-spectrum antibiotic and/or elimination of favorable milieu (ie, primary pathogen, breaks in skin) usually treats the infection.

Because of the rarity of infections caused and being part of the normal flora, the clinical implications of subtyping and sensitivity studies via culture or molecular studies may not be important; however, incidental presence of these organisms with unfamiliar morphology may cause confusion for the dermatopathologist. An extremely small size (0.5-2.0 μm) compared to red blood cells (7-8 μm) and white blood cells (10-12 μm) in a tight tetrad arrangement should raise the suspicion for Micrococcus.1 The refractive nature of these organisms from a thick extracellular layer can mimic fungus or plant matter; a negative Grocott-Gomori methenamine-silver stain in this case helped in not only differentiating but also ruling out secondary fungal infection. Finally, a Gram stain with violet staining of these organisms reaffirmed the diagnosis of gram-positive bacterial organisms, most consistent with Micrococcus species (Figure 1). Culture studies were not performed because of contamination of the tissue specimen and resolution of the patient's symptoms.

The presence of foreign material in the skin may be traumatic, occupational, cosmetic, iatrogenic, or self-inflicted, including a wide variety of substances that appear in different morphological forms on hematoxylin and eosin (H&E)-stained sections, depending on their structure and physiochemical properties.⁹ Although not all foreign bodies may polarize, examining the sample under polarized light is considered an important step to narrow down the differential diagnosis. The tissue reaction is primarily dependent on the nature of the substance and duration, consisting of histiocytes, macrophages, plasma cells, lymphocytes, and fibrosis.⁹ Activated histiocytes, multinucleated giant cells, and granulomas are classic findings that generally are seen surrounding and engulfing the foreign material (Figure 2). In addition to foreign material, substances such as calcium salts, urate crystals, extruded keratin, ruptured cysts, and hair follicles may act as foreign materials and can incite a tissue response.⁹ Absence of histiocytic response, granuloma formation, and fibrosis in a lesion of 1 month's duration made the tetrad bodies unlikely to be foreign material.

Demodex mites are superficial inhabitants of human skin that are acquired shortly after birth, live in or near pilosebaceous units, and obtain nourishment from skin cells and sebum.^10,11 The mites can be recovered on 10% of skin biopsies, most commonly on the face due to high sebum production.¹⁰ Adult mites range from 0.1 to 0.4 mm in length and are round to oval in shape. Females lay eggs inside the hair follicle or sebaceous glands.¹¹ They usually are asymptomatic, but their infestation may become pathogenic, especially in immunocompromised individuals.¹⁰ The clinical picture may resemble bacterial folliculitis, rosacea, and perioral dermatitis, while histology typically is characterized by spongiosis, lymphohistiocytic inflammation around infested follicles, and mite(s) in follicular infundibula (Figure 3). Sometimes the protrusion of mites and keratin from the follicles is seen as follicular spines on histology and referred to as pityriasis folliculorum.

Deposits of urate crystals in skin occur from the elevated serum uric acid levels in gout. The cutaneous deposits are mainly in the dermis and subcutaneous tissue and are extremely painful.¹² Urate crystals get dissolved during formalin fixation and leave needlelike clefts in a homogenous, lightly basophilic material on H&E slide (Figure 4). For the same reason, polarized microscopy also is not helpful despite the birefringent nature of urate crystals.¹²

Fungal yeast forms appear round to oval under light microscopy, ranging from 2 to 100 μm in size.¹³ The common superficial forms involving the epidermis or hair follicles similar to the current case of bacterial infection include Malassezia and dermatophyte infections. Malassezia is part of the normal flora of sebum-rich areas of skin and is associated with superficial infections such as folliculitis, atopic dermatitis, psoriasis, seborrheic dermatitis, and dandruff.¹⁴Malassezia appear as clusters of yeast cells that are pleomorphic and round to oval in shape, ranging from 2 to 6 μm in size. It forms hyphae in its pathogenic form and gives rise to the classic spaghetti and meatball-like appearance that can be highlighted by periodic acid-Schiff (Figure 5) and Grocott-Gomori methenamine-silver special stains. Dermatophytes include 3 genera--Trichophyton, Microsporum, and Epidermophyton--with at least 40 species that causes skin infections in humans.¹⁴ Fungal spores and hyphae forms are restricted to the stratum corneum. The hyphae forms may not be apparent on H&E stain, and periodic acid-Schiff staining is helpful in visualizing the fungal elements. The presence of neutrophils in the corneal layer, basket weave hyperkeratosis, and presence of fungal hyphae within the corneal layer fissures (sandwich sign) are clues to the dermatophyte infection.¹⁵ Other smaller fungi such as Histoplasma capsulatum (2-4 μm), Candida (3-5 μm), and Pneumocystis (2-5 μm) species can be found in skin in disseminated infections, usually affecting immunocompromised individuals.¹³Histoplasma is a basophilic yeast that exhibits narrow-based budding and appears clustered within or outside of macrophages. Candida species generally are dimorphic, and yeasts are found intermingled with filamentous forms. Pneumocystis infection in skin is extremely rare, and the fungi appear as spherical or crescent-shaped bodies in a foamy amorphous material.¹⁶

Maximizing productivity is prudent for outpatient subspecialty clinics to improve access to care. The outpatient dermatology clinic at Parkland Health and Hospital System in Dallas, Texas, which is a safety-net hospital in Dallas County, decreased wait times for new patients (from 377 to 48 days) and follow-up patients (from 95 to 34 days) from May 2012 to September 2015.¹ Changes in clinic productivity measures that occur with decreased wait times are not well characterized; therefore, we sought to address this knowledge gap. We propose that decreased wait times are associated with improvement in additional clinic productivity measures, specifically decreases in nonattendance and cycle times (defined as time between patient check-in and discharge) as well as increases in referrals.

In our retrospective cohort study of patients seen in the Parkland outpatient dermatology clinic between fiscal year (FY) 2012 and FY 2015 (between October 2011 and September 2015), we collected data on patient nonattendance rates, cycle times, and referral volumes. Categorical variables were compared using χ² tests, and changes in cycle times were analyzed using 2-way analysis of variance. P<.05 was considered statistically significant.

There were 52,775 scheduled clinic visits from FY 2012 to FY 2015. The overall proportion of patient nonattendance rates decreased from 34.6% (4202/12,141) to 31.4% (4429/14,119)(P<.001)(Figure), despite an increase in completed patient visits during the study period (7939 vs 9690). New patient nonattendance rates decreased from 42.9% (1831/4269) to 30.2% (1474/4874)(P<.001). The number of completed visits for new patients increased from 2438 in FY 2012 to 3400 in FY 2015. Follow-up nonattendance rates increased from 30.1% (2371/7872) to 32.0% (2955/9245)(P<.001). Follow-up completed visits increased from 5501 in FY 2012 to 6290 in FY 2015. Overall, average cycle time showed a trend to decrease from 159 to 123 minutes (22.6%)(Figure). Average cycle times were reduced from 159 to 128 minutes (19.5%) for new patients and from 161 to 115 minutes (28.6%) for follow-up patients (P=.02). Overall, referrals increased by 14.1% (816/5799)(P<.001), which was largely due to the increase in volume of referrals observed between FY 2014 (n=5770) and FY 2015 (n=6615).

We have demonstrated that decreased wait times can be associated with improvements in clinic productivity measures, namely decreased nonattendance rates and cycle times and increased referrals. Patient nonattendance is a burden on clinic resources and has been described in the dermatology clinic setting.^2-6 Increased likelihood of nonattendance has been associated with prolonged wait times.^3,7 We propose that decreased wait times can lead to diminished nonattendance rates, as patients are more likely to keep their appointments rather than seek other providers for dermatologic care. The difference in trends between new patient and follow-up nonattendance rates may be attributed to the larger relative increase in completed new patient visits compared to follow-ups during the study period.

Furthermore, the decrease in average cycle time reflected our clinic’s ability to see a larger number of patients per clinic, with subsequently shorter wait times. The greater reduction in cycle times for follow-up patients may be attributed to the increased continuity of providers who had previously seen these patients. Although the cycle times may seem high in our clinic compared to other practice settings, we believe that this marker of productivity is widely applicable to various clinic settings, including private practices and other outpatient specialty clinics. Increased clinic referrals can be a downstream effect of decreased wait times due to improvements in access to care, as shown in other specialty clinics.⁸ Effects of confounding variables on referral volumes, including nationwide health insurance changes during our study period, could not be ruled out.

Limitations of this study include unavailable data on patient and provider satisfaction and changes in patients’ health insurance. This study provides evidence of changes in clinical productivity measures associated with decreased wait times that can demonstrate widespread benefits to the health system.

Acknowledgments
The authors would like to thank Michael Estabrooks, RN, and Trung Vu for providing aggregate data, as well as Linda Hynan, PhD, for statistical advice (all Dallas, Texas).

Maximizing productivity is prudent for outpatient subspecialty clinics to improve access to care. The outpatient dermatology clinic at Parkland Health and Hospital System in Dallas, Texas, which is a safety-net hospital in Dallas County, decreased wait times for new patients (from 377 to 48 days) and follow-up patients (from 95 to 34 days) from May 2012 to September 2015.¹ Changes in clinic productivity measures that occur with decreased wait times are not well characterized; therefore, we sought to address this knowledge gap. We propose that decreased wait times are associated with improvement in additional clinic productivity measures, specifically decreases in nonattendance and cycle times (defined as time between patient check-in and discharge) as well as increases in referrals.

In our retrospective cohort study of patients seen in the Parkland outpatient dermatology clinic between fiscal year (FY) 2012 and FY 2015 (between October 2011 and September 2015), we collected data on patient nonattendance rates, cycle times, and referral volumes. Categorical variables were compared using χ² tests, and changes in cycle times were analyzed using 2-way analysis of variance. P<.05 was considered statistically significant.

There were 52,775 scheduled clinic visits from FY 2012 to FY 2015. The overall proportion of patient nonattendance rates decreased from 34.6% (4202/12,141) to 31.4% (4429/14,119)(P<.001)(Figure), despite an increase in completed patient visits during the study period (7939 vs 9690). New patient nonattendance rates decreased from 42.9% (1831/4269) to 30.2% (1474/4874)(P<.001). The number of completed visits for new patients increased from 2438 in FY 2012 to 3400 in FY 2015. Follow-up nonattendance rates increased from 30.1% (2371/7872) to 32.0% (2955/9245)(P<.001). Follow-up completed visits increased from 5501 in FY 2012 to 6290 in FY 2015. Overall, average cycle time showed a trend to decrease from 159 to 123 minutes (22.6%)(Figure). Average cycle times were reduced from 159 to 128 minutes (19.5%) for new patients and from 161 to 115 minutes (28.6%) for follow-up patients (P=.02). Overall, referrals increased by 14.1% (816/5799)(P<.001), which was largely due to the increase in volume of referrals observed between FY 2014 (n=5770) and FY 2015 (n=6615).

We have demonstrated that decreased wait times can be associated with improvements in clinic productivity measures, namely decreased nonattendance rates and cycle times and increased referrals. Patient nonattendance is a burden on clinic resources and has been described in the dermatology clinic setting.^2-6 Increased likelihood of nonattendance has been associated with prolonged wait times.^3,7 We propose that decreased wait times can lead to diminished nonattendance rates, as patients are more likely to keep their appointments rather than seek other providers for dermatologic care. The difference in trends between new patient and follow-up nonattendance rates may be attributed to the larger relative increase in completed new patient visits compared to follow-ups during the study period.

Furthermore, the decrease in average cycle time reflected our clinic’s ability to see a larger number of patients per clinic, with subsequently shorter wait times. The greater reduction in cycle times for follow-up patients may be attributed to the increased continuity of providers who had previously seen these patients. Although the cycle times may seem high in our clinic compared to other practice settings, we believe that this marker of productivity is widely applicable to various clinic settings, including private practices and other outpatient specialty clinics. Increased clinic referrals can be a downstream effect of decreased wait times due to improvements in access to care, as shown in other specialty clinics.⁸ Effects of confounding variables on referral volumes, including nationwide health insurance changes during our study period, could not be ruled out.

Limitations of this study include unavailable data on patient and provider satisfaction and changes in patients’ health insurance. This study provides evidence of changes in clinical productivity measures associated with decreased wait times that can demonstrate widespread benefits to the health system.

Acknowledgments
The authors would like to thank Michael Estabrooks, RN, and Trung Vu for providing aggregate data, as well as Linda Hynan, PhD, for statistical advice (all Dallas, Texas).

Maximizing productivity is prudent for outpatient subspecialty clinics to improve access to care. The outpatient dermatology clinic at Parkland Health and Hospital System in Dallas, Texas, which is a safety-net hospital in Dallas County, decreased wait times for new patients (from 377 to 48 days) and follow-up patients (from 95 to 34 days) from May 2012 to September 2015.¹ Changes in clinic productivity measures that occur with decreased wait times are not well characterized; therefore, we sought to address this knowledge gap. We propose that decreased wait times are associated with improvement in additional clinic productivity measures, specifically decreases in nonattendance and cycle times (defined as time between patient check-in and discharge) as well as increases in referrals.

In our retrospective cohort study of patients seen in the Parkland outpatient dermatology clinic between fiscal year (FY) 2012 and FY 2015 (between October 2011 and September 2015), we collected data on patient nonattendance rates, cycle times, and referral volumes. Categorical variables were compared using χ² tests, and changes in cycle times were analyzed using 2-way analysis of variance. P<.05 was considered statistically significant.

There were 52,775 scheduled clinic visits from FY 2012 to FY 2015. The overall proportion of patient nonattendance rates decreased from 34.6% (4202/12,141) to 31.4% (4429/14,119)(P<.001)(Figure), despite an increase in completed patient visits during the study period (7939 vs 9690). New patient nonattendance rates decreased from 42.9% (1831/4269) to 30.2% (1474/4874)(P<.001). The number of completed visits for new patients increased from 2438 in FY 2012 to 3400 in FY 2015. Follow-up nonattendance rates increased from 30.1% (2371/7872) to 32.0% (2955/9245)(P<.001). Follow-up completed visits increased from 5501 in FY 2012 to 6290 in FY 2015. Overall, average cycle time showed a trend to decrease from 159 to 123 minutes (22.6%)(Figure). Average cycle times were reduced from 159 to 128 minutes (19.5%) for new patients and from 161 to 115 minutes (28.6%) for follow-up patients (P=.02). Overall, referrals increased by 14.1% (816/5799)(P<.001), which was largely due to the increase in volume of referrals observed between FY 2014 (n=5770) and FY 2015 (n=6615).

We have demonstrated that decreased wait times can be associated with improvements in clinic productivity measures, namely decreased nonattendance rates and cycle times and increased referrals. Patient nonattendance is a burden on clinic resources and has been described in the dermatology clinic setting.^2-6 Increased likelihood of nonattendance has been associated with prolonged wait times.^3,7 We propose that decreased wait times can lead to diminished nonattendance rates, as patients are more likely to keep their appointments rather than seek other providers for dermatologic care. The difference in trends between new patient and follow-up nonattendance rates may be attributed to the larger relative increase in completed new patient visits compared to follow-ups during the study period.

Furthermore, the decrease in average cycle time reflected our clinic’s ability to see a larger number of patients per clinic, with subsequently shorter wait times. The greater reduction in cycle times for follow-up patients may be attributed to the increased continuity of providers who had previously seen these patients. Although the cycle times may seem high in our clinic compared to other practice settings, we believe that this marker of productivity is widely applicable to various clinic settings, including private practices and other outpatient specialty clinics. Increased clinic referrals can be a downstream effect of decreased wait times due to improvements in access to care, as shown in other specialty clinics.⁸ Effects of confounding variables on referral volumes, including nationwide health insurance changes during our study period, could not be ruled out.

Limitations of this study include unavailable data on patient and provider satisfaction and changes in patients’ health insurance. This study provides evidence of changes in clinical productivity measures associated with decreased wait times that can demonstrate widespread benefits to the health system.

Acknowledgments
The authors would like to thank Michael Estabrooks, RN, and Trung Vu for providing aggregate data, as well as Linda Hynan, PhD, for statistical advice (all Dallas, Texas).

Just when you might have thought dermatologic therapies were peaking, along came another banner year in atopic dermatitis (AD). Last year we saw the landmark launch of dupilumab, the first US Food and Drug Administration (FDA)–approved biologic therapy for AD. Dupilumab addresses a novel mechanism of AD in adults by blocking IL-4 and IL-13, which both play a central role in the type 2 helper T cell (T_H2) axis on the dual development of barrier-impaired skin and aberrant immune response including IgE to cutaneous aggravating agents with resultant inflammation. Additional information has shown direct effects to reduce itch in AD.¹ A 12-week study of dupilumab monotherapy showed that 85% (47/55) of treated patients had at least a 50% reduction in Eczema Area and Severity Index (EASI) score and 40% (22/55) were clear or almost clear on the investigator global assessment. With concomitant corticosteroid therapy, 100% of patients achieved EASI-50.² Also notable, 2017 ushered in the appearance of a novel iteration of the 30-year-old concept of phosphodiesterase inhibition with the approval of the topical agent crisaborole for AD treatment in patients 2 years and older, which has been shown to be effective in both children and adults.^3,4 However, despite these leaps of advancement in the care of AD, by no means has the condition been cured.

Atopic dermatitis has remained an incurable disease due to many factors: (1) variable immunologic and environmental triggers and patient disease course; (2) intolerance to therapeutic agents, including an enhanced sense of stinging and/or reactivity; (3) poor access to novel therapies among underserved patient populations; (4) lack of available data and information on variable treatment response by ethnicity and race; and (5) the absence of biologic treatments for severe childhood AD to modify long-term recurrence and progression of atopy, which is probably the most important issue, as the majority of AD cases start in children 5 years and younger.

Instituting a treatment today to provide children with disease-free skin for a lifetime truly is the Holy Grail in pediatric dermatology. To aid in the progress toward this goal, a deeper understanding of the manifestation of pediatric versus adult AD is now being investigated. It is clear that with adult chronicity, type 1 helper T cell (T_H1) axis activity and prolonged defects are triggered in barrier maturation; however, recent data have started to demonstrate that the youngest patients have different issues in lipid maturation and lack T_H1 activation. In particular, fatty acyl-CoA reductase 2 and fatty acid 2-hydroxylase is preferentially downregulated in children.⁵ It appears that the young immune system may be ripe for immune modification, which previously has been demonstrated with wild-type viral infections of varicella in children.⁶ However, future research will focus on what kind of tweaks to the immune system are required.

To encapsulate the AD pipeline, we will review drug trials that are in active recruitment as well as recently published data, which constitute an exciting group full of modifications of current therapies and agents with novel mechanisms of action. Paller et al⁷ and Renert-Yuval and Guttman-Yassky⁸ published detailed analyses of the recent pipeline for systemic therapies. In the realm of systemic agents, the main therapies in development are alternative immunomodulation mechanisms and biologic agents targeting a variety of immune checkpoints. Oral treatments and intravenous, intradermal, and subcutaneous injections will offer AD patients a variety of therapeutic options and potentially provide help for the needle-phobic patient.

Therapies targeting new mechanisms of action include Janus kinase (JAK) inhibitors, which have shown promising results for alopecia areata and vitiligo vulgaris. These agents may create selective modification of the immune system and are being tested topically and orally (Clinicaltrials.gov identifier NCT03011892). One phase 2a trial of topical tofacitinib showed superior efficacy over placebo, supporting class benefit, but drug development has been stopped for this agent.⁹ Another recent phase 2 trial of systemic baricitinib plus topical corticosteroids for treatment of AD demonstrated good efficacy (ie, EASI-50) versus topical corticosteroids alone (61% vs 37%).¹⁰

Another mechanism that currently is being studied includes a topical IL-4 and IL-13 inhibitor, which would hopefully mimic the efficacy of dupilumab, antioxidant therapies, and antimicrobials (NCT03351777, NCT03381625, NCT02910011). A new G protein–coupled receptor 19 (also known as membrane-type bile acid receptor or TGR5 receptor) agonist represents a novel mechanistic approach (NCT03492398), as does the liver X receptors (LXR) agonist, which is intended to enhance barrier function and thereby reduce inflammation (NCT03175354). Ammonia-oxidizing bacteria are being tested with a putative mechanism of increased nitic oxide release (NCT03235024), while nitric oxide alone also is being tested (NCT03431610). Although most of the aforementioned agents are in phase 1 and 2 trials, excitement is mounting over a phase 3 trial for IDP-124 lotion (NCT03058783), though extensive data have not yet been released from the manufacturer, as well as a phase 4 trial for crisaborole in infants and toddlers aged 3 to 24 months (NCT03356977). If the trial is successful and the drug is approved, crisaborole would be the first FDA-approved topical nonsteroidal prescription agent for that age group. Interestingly, 2 systemic agents are being tested in children younger than 18 years with AD, including a phase 3 trial of PF-04965842, a JAK1 selective inhibitor, in children aged 12 years and older (NCT03575871), and a phase 4 trial of omalizumab in children aged 4 to 19 years (NCT02300701). Omalizumab is an anti-IgE antibody with indications for allergic asthma and chronic idiopathic urticaria.

Data on the outcome of a phase 3 trial of dupilumab in adolescents has been released but not yet published by the manufacturer and shows promising results in children aged 12 to 17 years, both in reduction of EASI score and in achieving clear or almost clear skin.¹¹ Interestingly, limited data available from a press release reported similar results with dupilumab injection every 2 weeks versus every 4 weeks, which may give alternative dosing regimens in this age group once approved¹¹; however, publication has yet to occur for the latter data.

Other mechanistic agents include blockade of cytokines and interleukins, particularly those involved in type 2 helper T cell (T_H2) activity, such as thymic stromal lymphopoietin (a cytokine), as well as targeted single inhibition of IL-4, IL-5, IL-13, and IL-31 and/or their receptors. Nemolizumab, an anti–IL-31 receptor A antibody, is showing promise in the control of AD-associated itch and reduction in EASI scores.¹² Stem cell therapy, anti–OX-40 receptor monoclonal antibody, anti–IL-17C monoclonal antibody, anti–IL-33 monoclonal antibody, and neurokinin-1 receptor antagonist (NCT01941537, NCT03100344, NCT03054428, NCT03160885, NCT02888704, NCT03269773, NCT03568162, NCT03568071, NCT03533751, NCT03568331, NCT03540160) round out the roster of agents entering further trials in AD.

The future of AD therapy is anyone’s guess. Having entered the biologic era with dupilumab, we have a high bar set for efficacy and safety of AD therapies, yet there remains a core group of AD patients who have not yet achieved clearance or refuse injectables; therefore, adjunctive or alternative therapeutics are still needed. Furthermore, we still have not identified who will best benefit long-term from systemic intervention and how to best effect long-term disease control with biologics or novel agents, and choosing the therapy based on patient disease characteristics or serotyping has not yet come of age. It is exciting to think about what next year will bring!

Just when you might have thought dermatologic therapies were peaking, along came another banner year in atopic dermatitis (AD). Last year we saw the landmark launch of dupilumab, the first US Food and Drug Administration (FDA)–approved biologic therapy for AD. Dupilumab addresses a novel mechanism of AD in adults by blocking IL-4 and IL-13, which both play a central role in the type 2 helper T cell (T_H2) axis on the dual development of barrier-impaired skin and aberrant immune response including IgE to cutaneous aggravating agents with resultant inflammation. Additional information has shown direct effects to reduce itch in AD.¹ A 12-week study of dupilumab monotherapy showed that 85% (47/55) of treated patients had at least a 50% reduction in Eczema Area and Severity Index (EASI) score and 40% (22/55) were clear or almost clear on the investigator global assessment. With concomitant corticosteroid therapy, 100% of patients achieved EASI-50.² Also notable, 2017 ushered in the appearance of a novel iteration of the 30-year-old concept of phosphodiesterase inhibition with the approval of the topical agent crisaborole for AD treatment in patients 2 years and older, which has been shown to be effective in both children and adults.^3,4 However, despite these leaps of advancement in the care of AD, by no means has the condition been cured.

Atopic dermatitis has remained an incurable disease due to many factors: (1) variable immunologic and environmental triggers and patient disease course; (2) intolerance to therapeutic agents, including an enhanced sense of stinging and/or reactivity; (3) poor access to novel therapies among underserved patient populations; (4) lack of available data and information on variable treatment response by ethnicity and race; and (5) the absence of biologic treatments for severe childhood AD to modify long-term recurrence and progression of atopy, which is probably the most important issue, as the majority of AD cases start in children 5 years and younger.

Instituting a treatment today to provide children with disease-free skin for a lifetime truly is the Holy Grail in pediatric dermatology. To aid in the progress toward this goal, a deeper understanding of the manifestation of pediatric versus adult AD is now being investigated. It is clear that with adult chronicity, type 1 helper T cell (T_H1) axis activity and prolonged defects are triggered in barrier maturation; however, recent data have started to demonstrate that the youngest patients have different issues in lipid maturation and lack T_H1 activation. In particular, fatty acyl-CoA reductase 2 and fatty acid 2-hydroxylase is preferentially downregulated in children.⁵ It appears that the young immune system may be ripe for immune modification, which previously has been demonstrated with wild-type viral infections of varicella in children.⁶ However, future research will focus on what kind of tweaks to the immune system are required.

To encapsulate the AD pipeline, we will review drug trials that are in active recruitment as well as recently published data, which constitute an exciting group full of modifications of current therapies and agents with novel mechanisms of action. Paller et al⁷ and Renert-Yuval and Guttman-Yassky⁸ published detailed analyses of the recent pipeline for systemic therapies. In the realm of systemic agents, the main therapies in development are alternative immunomodulation mechanisms and biologic agents targeting a variety of immune checkpoints. Oral treatments and intravenous, intradermal, and subcutaneous injections will offer AD patients a variety of therapeutic options and potentially provide help for the needle-phobic patient.

Therapies targeting new mechanisms of action include Janus kinase (JAK) inhibitors, which have shown promising results for alopecia areata and vitiligo vulgaris. These agents may create selective modification of the immune system and are being tested topically and orally (Clinicaltrials.gov identifier NCT03011892). One phase 2a trial of topical tofacitinib showed superior efficacy over placebo, supporting class benefit, but drug development has been stopped for this agent.⁹ Another recent phase 2 trial of systemic baricitinib plus topical corticosteroids for treatment of AD demonstrated good efficacy (ie, EASI-50) versus topical corticosteroids alone (61% vs 37%).¹⁰

Another mechanism that currently is being studied includes a topical IL-4 and IL-13 inhibitor, which would hopefully mimic the efficacy of dupilumab, antioxidant therapies, and antimicrobials (NCT03351777, NCT03381625, NCT02910011). A new G protein–coupled receptor 19 (also known as membrane-type bile acid receptor or TGR5 receptor) agonist represents a novel mechanistic approach (NCT03492398), as does the liver X receptors (LXR) agonist, which is intended to enhance barrier function and thereby reduce inflammation (NCT03175354). Ammonia-oxidizing bacteria are being tested with a putative mechanism of increased nitic oxide release (NCT03235024), while nitric oxide alone also is being tested (NCT03431610). Although most of the aforementioned agents are in phase 1 and 2 trials, excitement is mounting over a phase 3 trial for IDP-124 lotion (NCT03058783), though extensive data have not yet been released from the manufacturer, as well as a phase 4 trial for crisaborole in infants and toddlers aged 3 to 24 months (NCT03356977). If the trial is successful and the drug is approved, crisaborole would be the first FDA-approved topical nonsteroidal prescription agent for that age group. Interestingly, 2 systemic agents are being tested in children younger than 18 years with AD, including a phase 3 trial of PF-04965842, a JAK1 selective inhibitor, in children aged 12 years and older (NCT03575871), and a phase 4 trial of omalizumab in children aged 4 to 19 years (NCT02300701). Omalizumab is an anti-IgE antibody with indications for allergic asthma and chronic idiopathic urticaria.

Data on the outcome of a phase 3 trial of dupilumab in adolescents has been released but not yet published by the manufacturer and shows promising results in children aged 12 to 17 years, both in reduction of EASI score and in achieving clear or almost clear skin.¹¹ Interestingly, limited data available from a press release reported similar results with dupilumab injection every 2 weeks versus every 4 weeks, which may give alternative dosing regimens in this age group once approved¹¹; however, publication has yet to occur for the latter data.

Other mechanistic agents include blockade of cytokines and interleukins, particularly those involved in type 2 helper T cell (T_H2) activity, such as thymic stromal lymphopoietin (a cytokine), as well as targeted single inhibition of IL-4, IL-5, IL-13, and IL-31 and/or their receptors. Nemolizumab, an anti–IL-31 receptor A antibody, is showing promise in the control of AD-associated itch and reduction in EASI scores.¹² Stem cell therapy, anti–OX-40 receptor monoclonal antibody, anti–IL-17C monoclonal antibody, anti–IL-33 monoclonal antibody, and neurokinin-1 receptor antagonist (NCT01941537, NCT03100344, NCT03054428, NCT03160885, NCT02888704, NCT03269773, NCT03568162, NCT03568071, NCT03533751, NCT03568331, NCT03540160) round out the roster of agents entering further trials in AD.

The future of AD therapy is anyone’s guess. Having entered the biologic era with dupilumab, we have a high bar set for efficacy and safety of AD therapies, yet there remains a core group of AD patients who have not yet achieved clearance or refuse injectables; therefore, adjunctive or alternative therapeutics are still needed. Furthermore, we still have not identified who will best benefit long-term from systemic intervention and how to best effect long-term disease control with biologics or novel agents, and choosing the therapy based on patient disease characteristics or serotyping has not yet come of age. It is exciting to think about what next year will bring!

Just when you might have thought dermatologic therapies were peaking, along came another banner year in atopic dermatitis (AD). Last year we saw the landmark launch of dupilumab, the first US Food and Drug Administration (FDA)–approved biologic therapy for AD. Dupilumab addresses a novel mechanism of AD in adults by blocking IL-4 and IL-13, which both play a central role in the type 2 helper T cell (T_H2) axis on the dual development of barrier-impaired skin and aberrant immune response including IgE to cutaneous aggravating agents with resultant inflammation. Additional information has shown direct effects to reduce itch in AD.¹ A 12-week study of dupilumab monotherapy showed that 85% (47/55) of treated patients had at least a 50% reduction in Eczema Area and Severity Index (EASI) score and 40% (22/55) were clear or almost clear on the investigator global assessment. With concomitant corticosteroid therapy, 100% of patients achieved EASI-50.² Also notable, 2017 ushered in the appearance of a novel iteration of the 30-year-old concept of phosphodiesterase inhibition with the approval of the topical agent crisaborole for AD treatment in patients 2 years and older, which has been shown to be effective in both children and adults.^3,4 However, despite these leaps of advancement in the care of AD, by no means has the condition been cured.

Atopic dermatitis has remained an incurable disease due to many factors: (1) variable immunologic and environmental triggers and patient disease course; (2) intolerance to therapeutic agents, including an enhanced sense of stinging and/or reactivity; (3) poor access to novel therapies among underserved patient populations; (4) lack of available data and information on variable treatment response by ethnicity and race; and (5) the absence of biologic treatments for severe childhood AD to modify long-term recurrence and progression of atopy, which is probably the most important issue, as the majority of AD cases start in children 5 years and younger.

Instituting a treatment today to provide children with disease-free skin for a lifetime truly is the Holy Grail in pediatric dermatology. To aid in the progress toward this goal, a deeper understanding of the manifestation of pediatric versus adult AD is now being investigated. It is clear that with adult chronicity, type 1 helper T cell (T_H1) axis activity and prolonged defects are triggered in barrier maturation; however, recent data have started to demonstrate that the youngest patients have different issues in lipid maturation and lack T_H1 activation. In particular, fatty acyl-CoA reductase 2 and fatty acid 2-hydroxylase is preferentially downregulated in children.⁵ It appears that the young immune system may be ripe for immune modification, which previously has been demonstrated with wild-type viral infections of varicella in children.⁶ However, future research will focus on what kind of tweaks to the immune system are required.

To encapsulate the AD pipeline, we will review drug trials that are in active recruitment as well as recently published data, which constitute an exciting group full of modifications of current therapies and agents with novel mechanisms of action. Paller et al⁷ and Renert-Yuval and Guttman-Yassky⁸ published detailed analyses of the recent pipeline for systemic therapies. In the realm of systemic agents, the main therapies in development are alternative immunomodulation mechanisms and biologic agents targeting a variety of immune checkpoints. Oral treatments and intravenous, intradermal, and subcutaneous injections will offer AD patients a variety of therapeutic options and potentially provide help for the needle-phobic patient.

Therapies targeting new mechanisms of action include Janus kinase (JAK) inhibitors, which have shown promising results for alopecia areata and vitiligo vulgaris. These agents may create selective modification of the immune system and are being tested topically and orally (Clinicaltrials.gov identifier NCT03011892). One phase 2a trial of topical tofacitinib showed superior efficacy over placebo, supporting class benefit, but drug development has been stopped for this agent.⁹ Another recent phase 2 trial of systemic baricitinib plus topical corticosteroids for treatment of AD demonstrated good efficacy (ie, EASI-50) versus topical corticosteroids alone (61% vs 37%).¹⁰

Another mechanism that currently is being studied includes a topical IL-4 and IL-13 inhibitor, which would hopefully mimic the efficacy of dupilumab, antioxidant therapies, and antimicrobials (NCT03351777, NCT03381625, NCT02910011). A new G protein–coupled receptor 19 (also known as membrane-type bile acid receptor or TGR5 receptor) agonist represents a novel mechanistic approach (NCT03492398), as does the liver X receptors (LXR) agonist, which is intended to enhance barrier function and thereby reduce inflammation (NCT03175354). Ammonia-oxidizing bacteria are being tested with a putative mechanism of increased nitic oxide release (NCT03235024), while nitric oxide alone also is being tested (NCT03431610). Although most of the aforementioned agents are in phase 1 and 2 trials, excitement is mounting over a phase 3 trial for IDP-124 lotion (NCT03058783), though extensive data have not yet been released from the manufacturer, as well as a phase 4 trial for crisaborole in infants and toddlers aged 3 to 24 months (NCT03356977). If the trial is successful and the drug is approved, crisaborole would be the first FDA-approved topical nonsteroidal prescription agent for that age group. Interestingly, 2 systemic agents are being tested in children younger than 18 years with AD, including a phase 3 trial of PF-04965842, a JAK1 selective inhibitor, in children aged 12 years and older (NCT03575871), and a phase 4 trial of omalizumab in children aged 4 to 19 years (NCT02300701). Omalizumab is an anti-IgE antibody with indications for allergic asthma and chronic idiopathic urticaria.

Data on the outcome of a phase 3 trial of dupilumab in adolescents has been released but not yet published by the manufacturer and shows promising results in children aged 12 to 17 years, both in reduction of EASI score and in achieving clear or almost clear skin.¹¹ Interestingly, limited data available from a press release reported similar results with dupilumab injection every 2 weeks versus every 4 weeks, which may give alternative dosing regimens in this age group once approved¹¹; however, publication has yet to occur for the latter data.

Other mechanistic agents include blockade of cytokines and interleukins, particularly those involved in type 2 helper T cell (T_H2) activity, such as thymic stromal lymphopoietin (a cytokine), as well as targeted single inhibition of IL-4, IL-5, IL-13, and IL-31 and/or their receptors. Nemolizumab, an anti–IL-31 receptor A antibody, is showing promise in the control of AD-associated itch and reduction in EASI scores.¹² Stem cell therapy, anti–OX-40 receptor monoclonal antibody, anti–IL-17C monoclonal antibody, anti–IL-33 monoclonal antibody, and neurokinin-1 receptor antagonist (NCT01941537, NCT03100344, NCT03054428, NCT03160885, NCT02888704, NCT03269773, NCT03568162, NCT03568071, NCT03533751, NCT03568331, NCT03540160) round out the roster of agents entering further trials in AD.

The future of AD therapy is anyone’s guess. Having entered the biologic era with dupilumab, we have a high bar set for efficacy and safety of AD therapies, yet there remains a core group of AD patients who have not yet achieved clearance or refuse injectables; therefore, adjunctive or alternative therapeutics are still needed. Furthermore, we still have not identified who will best benefit long-term from systemic intervention and how to best effect long-term disease control with biologics or novel agents, and choosing the therapy based on patient disease characteristics or serotyping has not yet come of age. It is exciting to think about what next year will bring!

Dermatologists are uniquely equipped amongst clinicians to make bedside diagnoses because of the focus on histopathology and microscopy inherent in our training. This skill is highly valuable in both an inpatient and outpatient setting because it may lead to a rapid diagnosis or be a useful adjunct in the initial clinical decision-making process. Although expert microscopists may be able to garner relevant information from scraping almost any type of lesion, bedside microscopy primarily is used by dermatologists in the United States for consideration of infectious etiologies of a variety of cutaneous manifestations.^1,2

Basic Principles

Lesions that should be considered for bedside microscopic analysis in outpatient settings are scaly lesions, vesiculobullous lesions, inflammatory papules, and pustules¹; microscopic evaluation also can be useful for myriad trichoscopic considerations.^3,4 In some instances, direct visualization of the pathogen is possible (eg, cutaneous fungal infections, demodicidosis, scabetic infections), and in other circumstances reactive changes of keratinocytes or the presence of specific cell types can aid in diagnosis (eg, ballooning degeneration and multinucleation of keratinocytes in herpetic lesions, an abundance of eosinophils in erythema toxicum neonatorum). Different types of media are used to best prepare tissue based on the suspected etiology of the condition.

One major stumbling block for residents when beginning to perform bedside testing is the lack of dimensional understanding of the structures they are searching for; for example, medical students and residents often may mistake fibers for dermatophytes, which typically are much larger than fungal hyphae. Familiarizing oneself with the basic dimensions of different cell types or pathogens in relation to each other (Table) will help further refine the beginner’s ability to effectively search for and identify pathogenic features. This concept is further schematized in Figure 1 to help visualize scale differences.

Image courtesy of Bogdan Mohora, MS (Austin, Texas).

Examination of the Specimen

Slide preparation depends on the primary lesion in consideration and will be discussed in greater detail in the following sections. Once the slide is prepared, place it on the microscope stage and adjust the condenser and light source for optimal visualization. Scan the specimen in a gridlike fashion on low power (usually ×10) and then inspect suspicious findings on higher power (×40 or higher).

Dermatomycoses

Fungal infections of the skin can present as annular papulosquamous lesions, follicular pustules or papules, bullous lesions, hypopigmented patches, and mucosal exudate or erosions, among other manifestations.⁵ Potassium hydroxide (KOH) is the classic medium used in preparation of lesions being assessed for evidence of fungus because it leads to lysis of keratinocytes for better visualization of fungal hyphae and spores. Other media that contain KOH and additional substrates such as dimethyl sulfoxide or chlorazol black E can be used to better highlight fungal elements.⁶

Dermatophytosis
Dermatophytes lead to superficial infection of the epidermis and epidermal appendages and present in a variety of ways, including site-specific infections manifesting typically as erythematous, annular or arcuate scaling (eg, tinea faciei, tinea corporis, tinea cruris, tinea manus, tinea pedis), alopecia with broken hair shafts, black dots, boggy nodules and/or scaling of the scalp (eg, tinea capitis, favus, kerion), and dystrophic nails (eg, onychomycosis).^5,7 For examination of lesional skin scrapings, one can either use clear cellophane tape against the skin to remove scale, which is especially useful in the case of pediatric patients, and then press the tape against a slide prepared with several drops of a KOH-based medium to directly visualize without a coverslip, or scrape the lesion with a No. 15 blade and place the scales onto the glass slide, with further preparation as described below.⁸ For assessment of alopecia or dystrophic nails, scrape lesional skin with a No. 15 blade to obtain affected hair follicles and proximal subungual debris, respectively.^6,9

Once the cellular debris has been obtained and placed on the slide, a coverslip can be overlaid and KOH applied laterally to be taken up across the slide by capillary action. Allow the slide to sit for at least 5 minutes before analyzing to better visualize fungal elements. Both tinea and onychomycosis will show branching septate hyphae extending across keratinocytes; a common false-positive is identifying overlapping keratinocyte edges, which are a similar size, but they can be distinguished from fungi because they do not cross multiple keratinocytes.^1,8 Tinea capitis may demonstrate similar findings or may reveal hair shafts with spores contained within or surrounding it, corresponding to endothrix or ectothrix infection, respectively.⁵

Pityriasis Versicolor and Malassezia Folliculitis
Pityriasis versicolor presents with hypopigmented to pink, finely scaling ovoid papules, usually on the upper back, shoulders, and neck, and is caused by Malassezia furfur and other Malassezia species.⁵ Malassezia folliculitis also is caused by this fungus and presents with monomorphic follicular papules and pustules. Scrapings from the scaly papules will demonstrate keratinocytes with the classic “spaghetti and meatballs” fungal elements, whereas Malassezia folliculitis demonstrates only spores.^5,7

Candidiasis
One possible outpatient presentation of candidiasis is oral thrush, which can exhibit white mucosal exudate or erythematous patches. A tongue blade can be used to scrape the tongue or cheek wall, with subsequent preparatory steps with application of KOH as described for dermatophytes. Cutaneous candidiasis most often develops in intertriginous regions and will exhibit erosive painful lesions with satellite pustules. In both cases, analysis of the specimen will show shorter fatter hyphal elements than seen in dermatophytosis, with pseudohyphae, blunted ends, and potentially yeast forms.⁵

Vesiculobullous Lesions

The Tzanck smear has been used since the 1940s to differentiate between etiologies of blistering disorders and is now most commonly used for the quick identification of herpetic lesions.¹ The test is performed by scraping the base of a deroofed vesicle, pustule, or bulla, and smearing the cellular materials onto a glass slide. The most commonly utilized media for staining in the outpatient setting at my institution (University of Texas Dell Medical School, Austin) is Giemsa, which is composed of azure II–eosin, glycerin, and methanol. It stains nuclei a reddish blue to pink and the cytoplasm blue.¹⁰ After being applied to the slide, the cells are allowed to air-dry for 5 to 10 minutes, and Giemsa stain is subsequently applied and allowed to incubate for 15 minutes, then rinsed carefully with water and directly examined.

Other stains that can be used to perform the Tzanck smear include commercial preparations that may be more accessible in the inpatient settings such as the Wright-Giemsa, Quik-Dip, and Diff-Quick.^1,10

Examination of a Tzanck smear from a herpetic lesion will yield acantholytic, enlarged keratinocytes up to twice their usual size (referred to as ballooning degeneration), and multinucleation. In addition, molding of the nuclei to each other within the multinucleated cells and margination of the nuclear chromatin may be appreciated (Figure 2). Intranuclear inclusion bodies, also known as Cowdry type A bodies, can be seen that are nearly the size of red blood cells but are rare to find, with only 10% of specimens exhibiting this finding in a prospective review of 299 patients with herpetic vesiculobullous lesions.¹¹ Evaluation of the contents of blisters caused by bullous pemphigoid and erythema toxicum neonatorum may yield high densities of eosinophils with normal keratinocyte morphology (Figure 3). Other blistering eruptions such as pemphigus vulgaris and bullous drug eruptions also have characteristic findings.^1,2

Image courtesy of Aron Gewirtzman, MD (Austin, Texas).

Image courtesy of Rachel McAndrew, MD (Austin, Texas).

Gout Preparation

Gout is a systemic disease caused by uric acid accumulation that can present with joint pain and white to red nodules on digits, joints, and ears (known as tophi). Material may be expressed from tophi and examined immediately by polarized light microscopy to confirm the diagnosis.⁵ Specimens will demonstrate needle-shaped, negatively birefringent monosodium urate crystals on polarized light microscopy (Figure 4). An ordinary light microscope can be converted for such use with the lenses of inexpensive polarized sunglasses, placing one lens between the light source and specimen and the other lens between the examiner’s eye and the specimen.¹²

Image courtesy of Paul Massey, MD (Boston, Massachusetts).

Parasitic Infections

Two common parasitic infections identified in outpatient dermatology clinics are scabies mites and Demodex mites. Human scabies is extremely pruritic and caused by infestation with Sarcoptes scabiei var hominis; the typical presentation in an adult is erythematous and crusted papules, linear burrows, and vesiculopustules, especially of the interdigital spaces, wrists, axillae, umbilicus, and genital region.^1,13 Demodicidosis presents with papules and pustules on the face, usually in a patient with background rosacea and diffuse erythema.^1,5,14

If either of these conditions are suspected, mineral oil should be used to prepare the slide because it will maintain viability of the organisms, which are visualized better in motion. Adult scabies mites are roughly 10 times larger than keratinocytes, measuring approximately 250 to 450 µm in length with 8 legs.¹³ Eggs also may be visualized within the cellular debris and typically are 100 to 150 µm in size and ovoid in shape. Of note, polariscopic examination may be a useful adjunct for evaluation of scabies because scabetic spines and scybala (or fecal material) are polarizable.¹⁵

Two types of Demodex mites typically are found in the skin: Demodex folliculorum, which are similarly sized to scabies mites with a more oblong body and occur most commonly in mature hair follicles (eg, eyelashes), and Demodex brevis, which are about half the size (150–200 µm) and live in the sebaceous glands of vellus hairs (Figure 5).¹⁴ Both of these mites have 8 legs, similar to the scabies mite.

Image courtesy of Candelario Antonio Rodriguez Vivian, MD (Monterrey, Mexico).

Hair Preparations

Hair preparations for bulbar examination (eg, trichogram) may prove useful in the evaluation of many types of alopecia, and elaboration on this topic is beyond the scope of this article. Microscopic evaluation of the hair shaft may be an underutilized technique in the outpatient setting and is capable of yielding a variety of diagnoses, including monilethrix, pili torti, and pili trianguli et canaliculi, among others.³ One particularly useful scenario for hair shaft examination (usually of the eyebrow) is in the setting of a patient with severe atopic dermatitis or a baby with ichthyosiform erythroderma, as discovery of trichorrhexis invaginata is pathognomonic for the diagnosis of Netherton syndrome.¹⁶ Lastly, evaluation of the hair shaft in patients with patchy and diffuse hair loss whose clinical impression is reminiscent of alopecia areata, or those with concerns of inability to grow hair beyond a short length, may lead to diagnosis of loose anagen syndrome, especially if more than 70% of hair fibers examined exhibit the classic findings of a ruffled proximal cuticle and lack of root sheath.⁴

Final Thoughts

Bedside microscopy is a rapid and cost-sensitive way to confirm diagnoses that are clinically suspected and remains a valuable tool to acquire during residency training.

Dermatologists are uniquely equipped amongst clinicians to make bedside diagnoses because of the focus on histopathology and microscopy inherent in our training. This skill is highly valuable in both an inpatient and outpatient setting because it may lead to a rapid diagnosis or be a useful adjunct in the initial clinical decision-making process. Although expert microscopists may be able to garner relevant information from scraping almost any type of lesion, bedside microscopy primarily is used by dermatologists in the United States for consideration of infectious etiologies of a variety of cutaneous manifestations.^1,2

Basic Principles

Lesions that should be considered for bedside microscopic analysis in outpatient settings are scaly lesions, vesiculobullous lesions, inflammatory papules, and pustules¹; microscopic evaluation also can be useful for myriad trichoscopic considerations.^3,4 In some instances, direct visualization of the pathogen is possible (eg, cutaneous fungal infections, demodicidosis, scabetic infections), and in other circumstances reactive changes of keratinocytes or the presence of specific cell types can aid in diagnosis (eg, ballooning degeneration and multinucleation of keratinocytes in herpetic lesions, an abundance of eosinophils in erythema toxicum neonatorum). Different types of media are used to best prepare tissue based on the suspected etiology of the condition.

One major stumbling block for residents when beginning to perform bedside testing is the lack of dimensional understanding of the structures they are searching for; for example, medical students and residents often may mistake fibers for dermatophytes, which typically are much larger than fungal hyphae. Familiarizing oneself with the basic dimensions of different cell types or pathogens in relation to each other (Table) will help further refine the beginner’s ability to effectively search for and identify pathogenic features. This concept is further schematized in Figure 1 to help visualize scale differences.

Image courtesy of Bogdan Mohora, MS (Austin, Texas).

Examination of the Specimen

Slide preparation depends on the primary lesion in consideration and will be discussed in greater detail in the following sections. Once the slide is prepared, place it on the microscope stage and adjust the condenser and light source for optimal visualization. Scan the specimen in a gridlike fashion on low power (usually ×10) and then inspect suspicious findings on higher power (×40 or higher).

Dermatomycoses

Fungal infections of the skin can present as annular papulosquamous lesions, follicular pustules or papules, bullous lesions, hypopigmented patches, and mucosal exudate or erosions, among other manifestations.⁵ Potassium hydroxide (KOH) is the classic medium used in preparation of lesions being assessed for evidence of fungus because it leads to lysis of keratinocytes for better visualization of fungal hyphae and spores. Other media that contain KOH and additional substrates such as dimethyl sulfoxide or chlorazol black E can be used to better highlight fungal elements.⁶

Dermatophytosis
Dermatophytes lead to superficial infection of the epidermis and epidermal appendages and present in a variety of ways, including site-specific infections manifesting typically as erythematous, annular or arcuate scaling (eg, tinea faciei, tinea corporis, tinea cruris, tinea manus, tinea pedis), alopecia with broken hair shafts, black dots, boggy nodules and/or scaling of the scalp (eg, tinea capitis, favus, kerion), and dystrophic nails (eg, onychomycosis).^5,7 For examination of lesional skin scrapings, one can either use clear cellophane tape against the skin to remove scale, which is especially useful in the case of pediatric patients, and then press the tape against a slide prepared with several drops of a KOH-based medium to directly visualize without a coverslip, or scrape the lesion with a No. 15 blade and place the scales onto the glass slide, with further preparation as described below.⁸ For assessment of alopecia or dystrophic nails, scrape lesional skin with a No. 15 blade to obtain affected hair follicles and proximal subungual debris, respectively.^6,9

Once the cellular debris has been obtained and placed on the slide, a coverslip can be overlaid and KOH applied laterally to be taken up across the slide by capillary action. Allow the slide to sit for at least 5 minutes before analyzing to better visualize fungal elements. Both tinea and onychomycosis will show branching septate hyphae extending across keratinocytes; a common false-positive is identifying overlapping keratinocyte edges, which are a similar size, but they can be distinguished from fungi because they do not cross multiple keratinocytes.^1,8 Tinea capitis may demonstrate similar findings or may reveal hair shafts with spores contained within or surrounding it, corresponding to endothrix or ectothrix infection, respectively.⁵

Pityriasis Versicolor and Malassezia Folliculitis
Pityriasis versicolor presents with hypopigmented to pink, finely scaling ovoid papules, usually on the upper back, shoulders, and neck, and is caused by Malassezia furfur and other Malassezia species.⁵ Malassezia folliculitis also is caused by this fungus and presents with monomorphic follicular papules and pustules. Scrapings from the scaly papules will demonstrate keratinocytes with the classic “spaghetti and meatballs” fungal elements, whereas Malassezia folliculitis demonstrates only spores.^5,7

Candidiasis
One possible outpatient presentation of candidiasis is oral thrush, which can exhibit white mucosal exudate or erythematous patches. A tongue blade can be used to scrape the tongue or cheek wall, with subsequent preparatory steps with application of KOH as described for dermatophytes. Cutaneous candidiasis most often develops in intertriginous regions and will exhibit erosive painful lesions with satellite pustules. In both cases, analysis of the specimen will show shorter fatter hyphal elements than seen in dermatophytosis, with pseudohyphae, blunted ends, and potentially yeast forms.⁵

Vesiculobullous Lesions

The Tzanck smear has been used since the 1940s to differentiate between etiologies of blistering disorders and is now most commonly used for the quick identification of herpetic lesions.¹ The test is performed by scraping the base of a deroofed vesicle, pustule, or bulla, and smearing the cellular materials onto a glass slide. The most commonly utilized media for staining in the outpatient setting at my institution (University of Texas Dell Medical School, Austin) is Giemsa, which is composed of azure II–eosin, glycerin, and methanol. It stains nuclei a reddish blue to pink and the cytoplasm blue.¹⁰ After being applied to the slide, the cells are allowed to air-dry for 5 to 10 minutes, and Giemsa stain is subsequently applied and allowed to incubate for 15 minutes, then rinsed carefully with water and directly examined.

Other stains that can be used to perform the Tzanck smear include commercial preparations that may be more accessible in the inpatient settings such as the Wright-Giemsa, Quik-Dip, and Diff-Quick.^1,10

Examination of a Tzanck smear from a herpetic lesion will yield acantholytic, enlarged keratinocytes up to twice their usual size (referred to as ballooning degeneration), and multinucleation. In addition, molding of the nuclei to each other within the multinucleated cells and margination of the nuclear chromatin may be appreciated (Figure 2). Intranuclear inclusion bodies, also known as Cowdry type A bodies, can be seen that are nearly the size of red blood cells but are rare to find, with only 10% of specimens exhibiting this finding in a prospective review of 299 patients with herpetic vesiculobullous lesions.¹¹ Evaluation of the contents of blisters caused by bullous pemphigoid and erythema toxicum neonatorum may yield high densities of eosinophils with normal keratinocyte morphology (Figure 3). Other blistering eruptions such as pemphigus vulgaris and bullous drug eruptions also have characteristic findings.^1,2

Image courtesy of Aron Gewirtzman, MD (Austin, Texas).

Image courtesy of Rachel McAndrew, MD (Austin, Texas).

Gout Preparation

Gout is a systemic disease caused by uric acid accumulation that can present with joint pain and white to red nodules on digits, joints, and ears (known as tophi). Material may be expressed from tophi and examined immediately by polarized light microscopy to confirm the diagnosis.⁵ Specimens will demonstrate needle-shaped, negatively birefringent monosodium urate crystals on polarized light microscopy (Figure 4). An ordinary light microscope can be converted for such use with the lenses of inexpensive polarized sunglasses, placing one lens between the light source and specimen and the other lens between the examiner’s eye and the specimen.¹²

Image courtesy of Paul Massey, MD (Boston, Massachusetts).

Parasitic Infections

Two common parasitic infections identified in outpatient dermatology clinics are scabies mites and Demodex mites. Human scabies is extremely pruritic and caused by infestation with Sarcoptes scabiei var hominis; the typical presentation in an adult is erythematous and crusted papules, linear burrows, and vesiculopustules, especially of the interdigital spaces, wrists, axillae, umbilicus, and genital region.^1,13 Demodicidosis presents with papules and pustules on the face, usually in a patient with background rosacea and diffuse erythema.^1,5,14

If either of these conditions are suspected, mineral oil should be used to prepare the slide because it will maintain viability of the organisms, which are visualized better in motion. Adult scabies mites are roughly 10 times larger than keratinocytes, measuring approximately 250 to 450 µm in length with 8 legs.¹³ Eggs also may be visualized within the cellular debris and typically are 100 to 150 µm in size and ovoid in shape. Of note, polariscopic examination may be a useful adjunct for evaluation of scabies because scabetic spines and scybala (or fecal material) are polarizable.¹⁵

Two types of Demodex mites typically are found in the skin: Demodex folliculorum, which are similarly sized to scabies mites with a more oblong body and occur most commonly in mature hair follicles (eg, eyelashes), and Demodex brevis, which are about half the size (150–200 µm) and live in the sebaceous glands of vellus hairs (Figure 5).¹⁴ Both of these mites have 8 legs, similar to the scabies mite.

Image courtesy of Candelario Antonio Rodriguez Vivian, MD (Monterrey, Mexico).

Hair Preparations

Hair preparations for bulbar examination (eg, trichogram) may prove useful in the evaluation of many types of alopecia, and elaboration on this topic is beyond the scope of this article. Microscopic evaluation of the hair shaft may be an underutilized technique in the outpatient setting and is capable of yielding a variety of diagnoses, including monilethrix, pili torti, and pili trianguli et canaliculi, among others.³ One particularly useful scenario for hair shaft examination (usually of the eyebrow) is in the setting of a patient with severe atopic dermatitis or a baby with ichthyosiform erythroderma, as discovery of trichorrhexis invaginata is pathognomonic for the diagnosis of Netherton syndrome.¹⁶ Lastly, evaluation of the hair shaft in patients with patchy and diffuse hair loss whose clinical impression is reminiscent of alopecia areata, or those with concerns of inability to grow hair beyond a short length, may lead to diagnosis of loose anagen syndrome, especially if more than 70% of hair fibers examined exhibit the classic findings of a ruffled proximal cuticle and lack of root sheath.⁴

Final Thoughts

Bedside microscopy is a rapid and cost-sensitive way to confirm diagnoses that are clinically suspected and remains a valuable tool to acquire during residency training.

Dermatologists are uniquely equipped amongst clinicians to make bedside diagnoses because of the focus on histopathology and microscopy inherent in our training. This skill is highly valuable in both an inpatient and outpatient setting because it may lead to a rapid diagnosis or be a useful adjunct in the initial clinical decision-making process. Although expert microscopists may be able to garner relevant information from scraping almost any type of lesion, bedside microscopy primarily is used by dermatologists in the United States for consideration of infectious etiologies of a variety of cutaneous manifestations.^1,2

Basic Principles

Lesions that should be considered for bedside microscopic analysis in outpatient settings are scaly lesions, vesiculobullous lesions, inflammatory papules, and pustules¹; microscopic evaluation also can be useful for myriad trichoscopic considerations.^3,4 In some instances, direct visualization of the pathogen is possible (eg, cutaneous fungal infections, demodicidosis, scabetic infections), and in other circumstances reactive changes of keratinocytes or the presence of specific cell types can aid in diagnosis (eg, ballooning degeneration and multinucleation of keratinocytes in herpetic lesions, an abundance of eosinophils in erythema toxicum neonatorum). Different types of media are used to best prepare tissue based on the suspected etiology of the condition.

One major stumbling block for residents when beginning to perform bedside testing is the lack of dimensional understanding of the structures they are searching for; for example, medical students and residents often may mistake fibers for dermatophytes, which typically are much larger than fungal hyphae. Familiarizing oneself with the basic dimensions of different cell types or pathogens in relation to each other (Table) will help further refine the beginner’s ability to effectively search for and identify pathogenic features. This concept is further schematized in Figure 1 to help visualize scale differences.

Image courtesy of Bogdan Mohora, MS (Austin, Texas).

Examination of the Specimen

Slide preparation depends on the primary lesion in consideration and will be discussed in greater detail in the following sections. Once the slide is prepared, place it on the microscope stage and adjust the condenser and light source for optimal visualization. Scan the specimen in a gridlike fashion on low power (usually ×10) and then inspect suspicious findings on higher power (×40 or higher).

Dermatomycoses

Fungal infections of the skin can present as annular papulosquamous lesions, follicular pustules or papules, bullous lesions, hypopigmented patches, and mucosal exudate or erosions, among other manifestations.⁵ Potassium hydroxide (KOH) is the classic medium used in preparation of lesions being assessed for evidence of fungus because it leads to lysis of keratinocytes for better visualization of fungal hyphae and spores. Other media that contain KOH and additional substrates such as dimethyl sulfoxide or chlorazol black E can be used to better highlight fungal elements.⁶

Dermatophytosis
Dermatophytes lead to superficial infection of the epidermis and epidermal appendages and present in a variety of ways, including site-specific infections manifesting typically as erythematous, annular or arcuate scaling (eg, tinea faciei, tinea corporis, tinea cruris, tinea manus, tinea pedis), alopecia with broken hair shafts, black dots, boggy nodules and/or scaling of the scalp (eg, tinea capitis, favus, kerion), and dystrophic nails (eg, onychomycosis).^5,7 For examination of lesional skin scrapings, one can either use clear cellophane tape against the skin to remove scale, which is especially useful in the case of pediatric patients, and then press the tape against a slide prepared with several drops of a KOH-based medium to directly visualize without a coverslip, or scrape the lesion with a No. 15 blade and place the scales onto the glass slide, with further preparation as described below.⁸ For assessment of alopecia or dystrophic nails, scrape lesional skin with a No. 15 blade to obtain affected hair follicles and proximal subungual debris, respectively.^6,9

Once the cellular debris has been obtained and placed on the slide, a coverslip can be overlaid and KOH applied laterally to be taken up across the slide by capillary action. Allow the slide to sit for at least 5 minutes before analyzing to better visualize fungal elements. Both tinea and onychomycosis will show branching septate hyphae extending across keratinocytes; a common false-positive is identifying overlapping keratinocyte edges, which are a similar size, but they can be distinguished from fungi because they do not cross multiple keratinocytes.^1,8 Tinea capitis may demonstrate similar findings or may reveal hair shafts with spores contained within or surrounding it, corresponding to endothrix or ectothrix infection, respectively.⁵

Pityriasis Versicolor and Malassezia Folliculitis
Pityriasis versicolor presents with hypopigmented to pink, finely scaling ovoid papules, usually on the upper back, shoulders, and neck, and is caused by Malassezia furfur and other Malassezia species.⁵ Malassezia folliculitis also is caused by this fungus and presents with monomorphic follicular papules and pustules. Scrapings from the scaly papules will demonstrate keratinocytes with the classic “spaghetti and meatballs” fungal elements, whereas Malassezia folliculitis demonstrates only spores.^5,7

Candidiasis
One possible outpatient presentation of candidiasis is oral thrush, which can exhibit white mucosal exudate or erythematous patches. A tongue blade can be used to scrape the tongue or cheek wall, with subsequent preparatory steps with application of KOH as described for dermatophytes. Cutaneous candidiasis most often develops in intertriginous regions and will exhibit erosive painful lesions with satellite pustules. In both cases, analysis of the specimen will show shorter fatter hyphal elements than seen in dermatophytosis, with pseudohyphae, blunted ends, and potentially yeast forms.⁵

Vesiculobullous Lesions

The Tzanck smear has been used since the 1940s to differentiate between etiologies of blistering disorders and is now most commonly used for the quick identification of herpetic lesions.¹ The test is performed by scraping the base of a deroofed vesicle, pustule, or bulla, and smearing the cellular materials onto a glass slide. The most commonly utilized media for staining in the outpatient setting at my institution (University of Texas Dell Medical School, Austin) is Giemsa, which is composed of azure II–eosin, glycerin, and methanol. It stains nuclei a reddish blue to pink and the cytoplasm blue.¹⁰ After being applied to the slide, the cells are allowed to air-dry for 5 to 10 minutes, and Giemsa stain is subsequently applied and allowed to incubate for 15 minutes, then rinsed carefully with water and directly examined.

Other stains that can be used to perform the Tzanck smear include commercial preparations that may be more accessible in the inpatient settings such as the Wright-Giemsa, Quik-Dip, and Diff-Quick.^1,10

Examination of a Tzanck smear from a herpetic lesion will yield acantholytic, enlarged keratinocytes up to twice their usual size (referred to as ballooning degeneration), and multinucleation. In addition, molding of the nuclei to each other within the multinucleated cells and margination of the nuclear chromatin may be appreciated (Figure 2). Intranuclear inclusion bodies, also known as Cowdry type A bodies, can be seen that are nearly the size of red blood cells but are rare to find, with only 10% of specimens exhibiting this finding in a prospective review of 299 patients with herpetic vesiculobullous lesions.¹¹ Evaluation of the contents of blisters caused by bullous pemphigoid and erythema toxicum neonatorum may yield high densities of eosinophils with normal keratinocyte morphology (Figure 3). Other blistering eruptions such as pemphigus vulgaris and bullous drug eruptions also have characteristic findings.^1,2

Image courtesy of Aron Gewirtzman, MD (Austin, Texas).

Image courtesy of Rachel McAndrew, MD (Austin, Texas).

Gout Preparation

Gout is a systemic disease caused by uric acid accumulation that can present with joint pain and white to red nodules on digits, joints, and ears (known as tophi). Material may be expressed from tophi and examined immediately by polarized light microscopy to confirm the diagnosis.⁵ Specimens will demonstrate needle-shaped, negatively birefringent monosodium urate crystals on polarized light microscopy (Figure 4). An ordinary light microscope can be converted for such use with the lenses of inexpensive polarized sunglasses, placing one lens between the light source and specimen and the other lens between the examiner’s eye and the specimen.¹²

Image courtesy of Paul Massey, MD (Boston, Massachusetts).

Parasitic Infections

Two common parasitic infections identified in outpatient dermatology clinics are scabies mites and Demodex mites. Human scabies is extremely pruritic and caused by infestation with Sarcoptes scabiei var hominis; the typical presentation in an adult is erythematous and crusted papules, linear burrows, and vesiculopustules, especially of the interdigital spaces, wrists, axillae, umbilicus, and genital region.^1,13 Demodicidosis presents with papules and pustules on the face, usually in a patient with background rosacea and diffuse erythema.^1,5,14

If either of these conditions are suspected, mineral oil should be used to prepare the slide because it will maintain viability of the organisms, which are visualized better in motion. Adult scabies mites are roughly 10 times larger than keratinocytes, measuring approximately 250 to 450 µm in length with 8 legs.¹³ Eggs also may be visualized within the cellular debris and typically are 100 to 150 µm in size and ovoid in shape. Of note, polariscopic examination may be a useful adjunct for evaluation of scabies because scabetic spines and scybala (or fecal material) are polarizable.¹⁵

Two types of Demodex mites typically are found in the skin: Demodex folliculorum, which are similarly sized to scabies mites with a more oblong body and occur most commonly in mature hair follicles (eg, eyelashes), and Demodex brevis, which are about half the size (150–200 µm) and live in the sebaceous glands of vellus hairs (Figure 5).¹⁴ Both of these mites have 8 legs, similar to the scabies mite.

Image courtesy of Candelario Antonio Rodriguez Vivian, MD (Monterrey, Mexico).

Hair Preparations

Hair preparations for bulbar examination (eg, trichogram) may prove useful in the evaluation of many types of alopecia, and elaboration on this topic is beyond the scope of this article. Microscopic evaluation of the hair shaft may be an underutilized technique in the outpatient setting and is capable of yielding a variety of diagnoses, including monilethrix, pili torti, and pili trianguli et canaliculi, among others.³ One particularly useful scenario for hair shaft examination (usually of the eyebrow) is in the setting of a patient with severe atopic dermatitis or a baby with ichthyosiform erythroderma, as discovery of trichorrhexis invaginata is pathognomonic for the diagnosis of Netherton syndrome.¹⁶ Lastly, evaluation of the hair shaft in patients with patchy and diffuse hair loss whose clinical impression is reminiscent of alopecia areata, or those with concerns of inability to grow hair beyond a short length, may lead to diagnosis of loose anagen syndrome, especially if more than 70% of hair fibers examined exhibit the classic findings of a ruffled proximal cuticle and lack of root sheath.⁴

Final Thoughts

Bedside microscopy is a rapid and cost-sensitive way to confirm diagnoses that are clinically suspected and remains a valuable tool to acquire during residency training.

Dermal fillers are considered Class III medical devices by the US Food and Drug Administration (FDA).¹ Reports of adverse events (AEs) for medical devices are made public by the FDA to allow for transparent postmarketing surveillance.²The AE trends extracted from these historical data may help distinguish between expected learning curves of new dermal fillers versus unsafe products that may require FDA intervention. Considering that aesthetic treatments are not medically necessary, a low risk profile is paramount and determining what constitutes normal learning curves is important for impartial assessment of AEs as new fillers come on the market. The concept of a 3-year learning curve can be an important tool for safety monitoring going forward, creating a bar for quality that could trigger increased surveillance if a product fails to meet an expected arc of diminished AEs over time. This study serves to evaluate historical AE data and to establish learning curves for FDA-approved dermal fillers.

Methods

We searched the OpenFDA Device Adverse Event Report Browser (http://openfda.shinyapps.io/devicereports/) for reported AEs within the FDA product code LMH (Implant, Dermal, For Aesthetic Use) that were received from January 1, 1983, to December 31, 2017. For each reported AE, information related to the date of the reported event and the device brand name were recorded. Devices implicated in each AE were classified based on primary composition according to the following 5 categories: collagen, hyaluronic acid (HA), hydroxylapatite, poly-L-lactic acid (PLLA), and polymethyl methacrylate (PMMA). Inaccurate entries of reported AEs or those intended for nonaesthetic use were excluded from the study. A total of 8530 AEs were included in the study. To normalize the data, we obtained annual reports for the number of procedures performed by filler type from the American Society of Plastic Surgeons (ASPS) cosmetic procedure trends. ³ We calculated the annual AE rates for each approved filler by dividing the number of AEs by the number of procedures performed that year.

Results

The trends of different filler types depicting the number of procedures performed over time are shown in Figure 1. Data from the ASPS dated back to 2005; therefore, the number of procedures performed prior to that were extrapolated with knowledge of products’ approval dates and market share, indicated by a dotted line. To determine AE rates for each year, we divided the number of AEs by the number of reported procedures for each filler type. The AE rates are displayed graphically in Figures 2 and 3 with superimposed FDA approval dates for each filler.⁴

Two major peaks in reported AE rates for all fillers were noted in the late 1990s and late 2000s, mostly associated with collagen and PLLA fillers, respectively (Figure 2). Overall, there has been a low rate of AEs associated with HA fillers since their initial approval in the early 2000s.

Comment

Our study is unique in that it analyzes reported AE data over a 34-year period for injectable dermal fillers. To our knowledge, this novel method of calculating AE rates across dermal fillers and for individual products is the first of its kind that facilitates usage-normalized comparison of different filler types.

All OpenFDA data are self-reported and therefore have inherent limitations. Anyone can enter information on AEs in this system, including both patients and health care providers, so the quality of the input may be variable. However, this output is the only representation we have for nearly 35 years of AE history for this burgeoning category of popular aesthetic treatments. Another study limitation is that not everyone may know that reporting an AE in the OpenFDA is an option; therefore, we may be missing a portion of AEs due to underreporting. Underreporting may be especially at play in the years before the Internet was prevalent for residential use since access to the Internet would be required to report an AR on the website. However, examining the available data provides an important window into valuable information on complications that have occurred and have been reported for FDA-approved dermal fillers.

An additional challenge in constructing this study was assessing the total number of injectable dermal filler treatments being performed annually across filler types for normalization of the data. Although the absolute numbers of filler use as captured by the ASPS are smaller than the true total filler use across all injectors, the relative use of different filler products will be similar across all specialties because it reflects product popularity. Annual surveys on aesthetic procedures also are conducted by the American Society for Dermatologic Surgery and the American Association for Facial Plastic and Reconstructive Surgery, but neither one captures the relative usage of different filler types. Because individual filler companies do not publish their annual sales numbers by product, the ASPS data give us the best gauge of relative use of fillers by product type given the available information. We conclude that the comparison of AE rates would remain the same even if we had data for total annual filler use across specialties.

Our graphical depiction of the data clearly demonstrates the low AE profile of HA fillers, which is in line with the general consensus of their safety that has contributed to their vast popularity; however, this study represents the first time usage-normalized AE rates are compared to other filler compositions. Hyaluronic acid fillers have the unique feature of being able to be dissolved with the hyaluronidase enzyme, which can limit adverse event potential as compared to other ingredient classes of filler types and may be reflected in their low overall AE profile. The AE rate spike and resolution for collagen fillers represent what we refer to as a “normal learning curve” based on our analysis of the data set as a whole, suggesting an appropriate time course of increased familiarity with the product without inherent issues with the product itself. Multiple sequential anatomic site indications were approved for hydroxylapatite fillers from 2006 through 2015, which may have yielded overlapping learning curves for each approval, resulting in a rather uniform AE rate. The early drop-off in AE rates after the 2015 anatomic site approval may represent the beginning of a normal learning curve, and continued surveillance of AE rates would be of value to confirm this trend. We saw a similar 3-year learning curve for PLLA fillers as the curve for collagen fillers, suggesting a normal learning curve and no out-of-line safety issues. Polymethylmethacrylate fillers were approved in 2006 and were taken off the market for a period in the late 2000s, explaining the drop-off. Once they were back on the market, we do not see a typical learning curve for PMMA, which may warrant surveillance for safety by both clinicians and the FDA.

Conclusion

Our study represents a novel method of evaluating the safety of medical devices, specifically aesthetic fillers. We showed that every AE rate curve for different filler types tells a story. Reactions to AEs for new fillers should be placed in the context of whether they seem to be following the established learning curve.

Dermal fillers are considered Class III medical devices by the US Food and Drug Administration (FDA).¹ Reports of adverse events (AEs) for medical devices are made public by the FDA to allow for transparent postmarketing surveillance.²The AE trends extracted from these historical data may help distinguish between expected learning curves of new dermal fillers versus unsafe products that may require FDA intervention. Considering that aesthetic treatments are not medically necessary, a low risk profile is paramount and determining what constitutes normal learning curves is important for impartial assessment of AEs as new fillers come on the market. The concept of a 3-year learning curve can be an important tool for safety monitoring going forward, creating a bar for quality that could trigger increased surveillance if a product fails to meet an expected arc of diminished AEs over time. This study serves to evaluate historical AE data and to establish learning curves for FDA-approved dermal fillers.

Methods

We searched the OpenFDA Device Adverse Event Report Browser (http://openfda.shinyapps.io/devicereports/) for reported AEs within the FDA product code LMH (Implant, Dermal, For Aesthetic Use) that were received from January 1, 1983, to December 31, 2017. For each reported AE, information related to the date of the reported event and the device brand name were recorded. Devices implicated in each AE were classified based on primary composition according to the following 5 categories: collagen, hyaluronic acid (HA), hydroxylapatite, poly-L-lactic acid (PLLA), and polymethyl methacrylate (PMMA). Inaccurate entries of reported AEs or those intended for nonaesthetic use were excluded from the study. A total of 8530 AEs were included in the study. To normalize the data, we obtained annual reports for the number of procedures performed by filler type from the American Society of Plastic Surgeons (ASPS) cosmetic procedure trends. ³ We calculated the annual AE rates for each approved filler by dividing the number of AEs by the number of procedures performed that year.

Results

The trends of different filler types depicting the number of procedures performed over time are shown in Figure 1. Data from the ASPS dated back to 2005; therefore, the number of procedures performed prior to that were extrapolated with knowledge of products’ approval dates and market share, indicated by a dotted line. To determine AE rates for each year, we divided the number of AEs by the number of reported procedures for each filler type. The AE rates are displayed graphically in Figures 2 and 3 with superimposed FDA approval dates for each filler.⁴

Two major peaks in reported AE rates for all fillers were noted in the late 1990s and late 2000s, mostly associated with collagen and PLLA fillers, respectively (Figure 2). Overall, there has been a low rate of AEs associated with HA fillers since their initial approval in the early 2000s.

Comment

Our study is unique in that it analyzes reported AE data over a 34-year period for injectable dermal fillers. To our knowledge, this novel method of calculating AE rates across dermal fillers and for individual products is the first of its kind that facilitates usage-normalized comparison of different filler types.

All OpenFDA data are self-reported and therefore have inherent limitations. Anyone can enter information on AEs in this system, including both patients and health care providers, so the quality of the input may be variable. However, this output is the only representation we have for nearly 35 years of AE history for this burgeoning category of popular aesthetic treatments. Another study limitation is that not everyone may know that reporting an AE in the OpenFDA is an option; therefore, we may be missing a portion of AEs due to underreporting. Underreporting may be especially at play in the years before the Internet was prevalent for residential use since access to the Internet would be required to report an AR on the website. However, examining the available data provides an important window into valuable information on complications that have occurred and have been reported for FDA-approved dermal fillers.

An additional challenge in constructing this study was assessing the total number of injectable dermal filler treatments being performed annually across filler types for normalization of the data. Although the absolute numbers of filler use as captured by the ASPS are smaller than the true total filler use across all injectors, the relative use of different filler products will be similar across all specialties because it reflects product popularity. Annual surveys on aesthetic procedures also are conducted by the American Society for Dermatologic Surgery and the American Association for Facial Plastic and Reconstructive Surgery, but neither one captures the relative usage of different filler types. Because individual filler companies do not publish their annual sales numbers by product, the ASPS data give us the best gauge of relative use of fillers by product type given the available information. We conclude that the comparison of AE rates would remain the same even if we had data for total annual filler use across specialties.

Our graphical depiction of the data clearly demonstrates the low AE profile of HA fillers, which is in line with the general consensus of their safety that has contributed to their vast popularity; however, this study represents the first time usage-normalized AE rates are compared to other filler compositions. Hyaluronic acid fillers have the unique feature of being able to be dissolved with the hyaluronidase enzyme, which can limit adverse event potential as compared to other ingredient classes of filler types and may be reflected in their low overall AE profile. The AE rate spike and resolution for collagen fillers represent what we refer to as a “normal learning curve” based on our analysis of the data set as a whole, suggesting an appropriate time course of increased familiarity with the product without inherent issues with the product itself. Multiple sequential anatomic site indications were approved for hydroxylapatite fillers from 2006 through 2015, which may have yielded overlapping learning curves for each approval, resulting in a rather uniform AE rate. The early drop-off in AE rates after the 2015 anatomic site approval may represent the beginning of a normal learning curve, and continued surveillance of AE rates would be of value to confirm this trend. We saw a similar 3-year learning curve for PLLA fillers as the curve for collagen fillers, suggesting a normal learning curve and no out-of-line safety issues. Polymethylmethacrylate fillers were approved in 2006 and were taken off the market for a period in the late 2000s, explaining the drop-off. Once they were back on the market, we do not see a typical learning curve for PMMA, which may warrant surveillance for safety by both clinicians and the FDA.

Conclusion

Our study represents a novel method of evaluating the safety of medical devices, specifically aesthetic fillers. We showed that every AE rate curve for different filler types tells a story. Reactions to AEs for new fillers should be placed in the context of whether they seem to be following the established learning curve.

Dermal fillers are considered Class III medical devices by the US Food and Drug Administration (FDA).¹ Reports of adverse events (AEs) for medical devices are made public by the FDA to allow for transparent postmarketing surveillance.²The AE trends extracted from these historical data may help distinguish between expected learning curves of new dermal fillers versus unsafe products that may require FDA intervention. Considering that aesthetic treatments are not medically necessary, a low risk profile is paramount and determining what constitutes normal learning curves is important for impartial assessment of AEs as new fillers come on the market. The concept of a 3-year learning curve can be an important tool for safety monitoring going forward, creating a bar for quality that could trigger increased surveillance if a product fails to meet an expected arc of diminished AEs over time. This study serves to evaluate historical AE data and to establish learning curves for FDA-approved dermal fillers.

Methods

We searched the OpenFDA Device Adverse Event Report Browser (http://openfda.shinyapps.io/devicereports/) for reported AEs within the FDA product code LMH (Implant, Dermal, For Aesthetic Use) that were received from January 1, 1983, to December 31, 2017. For each reported AE, information related to the date of the reported event and the device brand name were recorded. Devices implicated in each AE were classified based on primary composition according to the following 5 categories: collagen, hyaluronic acid (HA), hydroxylapatite, poly-L-lactic acid (PLLA), and polymethyl methacrylate (PMMA). Inaccurate entries of reported AEs or those intended for nonaesthetic use were excluded from the study. A total of 8530 AEs were included in the study. To normalize the data, we obtained annual reports for the number of procedures performed by filler type from the American Society of Plastic Surgeons (ASPS) cosmetic procedure trends. ³ We calculated the annual AE rates for each approved filler by dividing the number of AEs by the number of procedures performed that year.

Results

The trends of different filler types depicting the number of procedures performed over time are shown in Figure 1. Data from the ASPS dated back to 2005; therefore, the number of procedures performed prior to that were extrapolated with knowledge of products’ approval dates and market share, indicated by a dotted line. To determine AE rates for each year, we divided the number of AEs by the number of reported procedures for each filler type. The AE rates are displayed graphically in Figures 2 and 3 with superimposed FDA approval dates for each filler.⁴

Two major peaks in reported AE rates for all fillers were noted in the late 1990s and late 2000s, mostly associated with collagen and PLLA fillers, respectively (Figure 2). Overall, there has been a low rate of AEs associated with HA fillers since their initial approval in the early 2000s.

Comment

Our study is unique in that it analyzes reported AE data over a 34-year period for injectable dermal fillers. To our knowledge, this novel method of calculating AE rates across dermal fillers and for individual products is the first of its kind that facilitates usage-normalized comparison of different filler types.

All OpenFDA data are self-reported and therefore have inherent limitations. Anyone can enter information on AEs in this system, including both patients and health care providers, so the quality of the input may be variable. However, this output is the only representation we have for nearly 35 years of AE history for this burgeoning category of popular aesthetic treatments. Another study limitation is that not everyone may know that reporting an AE in the OpenFDA is an option; therefore, we may be missing a portion of AEs due to underreporting. Underreporting may be especially at play in the years before the Internet was prevalent for residential use since access to the Internet would be required to report an AR on the website. However, examining the available data provides an important window into valuable information on complications that have occurred and have been reported for FDA-approved dermal fillers.

An additional challenge in constructing this study was assessing the total number of injectable dermal filler treatments being performed annually across filler types for normalization of the data. Although the absolute numbers of filler use as captured by the ASPS are smaller than the true total filler use across all injectors, the relative use of different filler products will be similar across all specialties because it reflects product popularity. Annual surveys on aesthetic procedures also are conducted by the American Society for Dermatologic Surgery and the American Association for Facial Plastic and Reconstructive Surgery, but neither one captures the relative usage of different filler types. Because individual filler companies do not publish their annual sales numbers by product, the ASPS data give us the best gauge of relative use of fillers by product type given the available information. We conclude that the comparison of AE rates would remain the same even if we had data for total annual filler use across specialties.

Our graphical depiction of the data clearly demonstrates the low AE profile of HA fillers, which is in line with the general consensus of their safety that has contributed to their vast popularity; however, this study represents the first time usage-normalized AE rates are compared to other filler compositions. Hyaluronic acid fillers have the unique feature of being able to be dissolved with the hyaluronidase enzyme, which can limit adverse event potential as compared to other ingredient classes of filler types and may be reflected in their low overall AE profile. The AE rate spike and resolution for collagen fillers represent what we refer to as a “normal learning curve” based on our analysis of the data set as a whole, suggesting an appropriate time course of increased familiarity with the product without inherent issues with the product itself. Multiple sequential anatomic site indications were approved for hydroxylapatite fillers from 2006 through 2015, which may have yielded overlapping learning curves for each approval, resulting in a rather uniform AE rate. The early drop-off in AE rates after the 2015 anatomic site approval may represent the beginning of a normal learning curve, and continued surveillance of AE rates would be of value to confirm this trend. We saw a similar 3-year learning curve for PLLA fillers as the curve for collagen fillers, suggesting a normal learning curve and no out-of-line safety issues. Polymethylmethacrylate fillers were approved in 2006 and were taken off the market for a period in the late 2000s, explaining the drop-off. Once they were back on the market, we do not see a typical learning curve for PMMA, which may warrant surveillance for safety by both clinicians and the FDA.

Conclusion

Our study represents a novel method of evaluating the safety of medical devices, specifically aesthetic fillers. We showed that every AE rate curve for different filler types tells a story. Reactions to AEs for new fillers should be placed in the context of whether they seem to be following the established learning curve.

The Diagnosis: Bowenoid Papulosis 

A 4-mm punch biopsy was performed from the active border of brown plaques on the dorsal penis. Histopathology revealed parakeratotic hyperkeratosis, acanthosis, loss of maturation in epithelium, and full-size atypia (Figure 1). Ki-67 index was 90% positive in the epidermis (Figure 2). Staining for p16 and human papillomavirus (HPV) screening was positive for HPV type 16 (Figure 3). Serologic tests for other sexually transmitted infections were negative. A diagnosis of penile bowenoid papulosis (BP) with grade 3 penile intraepithelial neoplasia was made, and treatment with topical 5-fluorouracil (5-FU) was initiated. Almost total regression was appreciated at 1-month follow-up (Figure 4), and he also was recurrence free at 1-year follow-up.

Penile intraepithelial neoplasia (PIN), or penile squamous cell carcinoma in situ, is a rare disease with high morbidity and mortality rates. Clinically, PIN is comprised of a clinical spectrum including 3 different entities: erythroplasia of Queyrat, Bowen disease, and BP.¹ Histologically, PIN also is classified into 3 subtypes according to histological depth of epidermal atypia.¹

Bowenoid papulosis usually is characterized by multiple red-brown or flesh-colored papules that most commonly appear on the shaft or glans of the penis. Bowenoid papulosis frequently is associated with high-risk types of HPV, such as HPV type 16, and is sometimes difficult to differentiate clinically from pigmented condyloma acuminatum. The clinical lesions of BP usually are less papillomatous, smoother topped, more polymorphic, and more coalescent compared to common genital viral condyloma acuminatum.² Bowenoid papulosis usually is seen in young (<30 years of age) sexually active men, unlike the patches or plaques of erythroplasia of Queyrat or Bowen disease, which are seen in older men aged 45 to 75 years. Bowenoid papulosis also has a lower malignancy potential than erythroplasia of Queyrat and Bowen disease.²

Penile melanosis, penile lentigo, and seborrheic keratosis comprise the differential diagnosis of dark spots on the penis and also should be kept in mind. Penile melanosis is the most common cause of dark spots on the penis. When the dark spots have irregular borders and change in color, they may be misdiagnosed as malignant lesions such as melanoma.³ In most cases, biopsy is indicated. Histologically, penile melanosis is characterized by hyperpigmentation of the basal cell layer with no melanocytic hyperplasia. Treatment is unnecessary in most cases.

Penile lentigo presents as small flat pigmented spots on the penile skin with clearly defined margins surrounded by normal-appearing skin. Histologically, it is characterized by hyperplasia of melanocytes above the basement membrane of the epidermis.³

Penile pigmented seborrheic keratosis is a rare clinical entity that can be easily misinterpreted as condyloma acuminatum. Histologically, it is characterized by basal cell hyperplasia with cystic formation in the thickened epidermis. Excisional biopsy may be the only way to rule out malignant disease.

Treatment options for PIN include cryotherapy, CO₂ or Nd:YAG lasers, photodynamic therapy, topical 5-FU or imiquimod therapy, and surgical excision such as Mohs micrographic surgery.^4-9 Although these therapeutic modalities usually are effective, recurrence is common.⁶ The patients' discomfort and poor cosmetic and functional outcomes from the surgical removal of lesions also present a challenge in treatment planning. 

In our patient, we quickly achieved a good result with topical 5-FU, though the disease was in local advanced stage. It is important for clinicians to consider 5-FU as an effective treatment option for PIN before planning surgery.

The Diagnosis: Bowenoid Papulosis 

A 4-mm punch biopsy was performed from the active border of brown plaques on the dorsal penis. Histopathology revealed parakeratotic hyperkeratosis, acanthosis, loss of maturation in epithelium, and full-size atypia (Figure 1). Ki-67 index was 90% positive in the epidermis (Figure 2). Staining for p16 and human papillomavirus (HPV) screening was positive for HPV type 16 (Figure 3). Serologic tests for other sexually transmitted infections were negative. A diagnosis of penile bowenoid papulosis (BP) with grade 3 penile intraepithelial neoplasia was made, and treatment with topical 5-fluorouracil (5-FU) was initiated. Almost total regression was appreciated at 1-month follow-up (Figure 4), and he also was recurrence free at 1-year follow-up.

Penile intraepithelial neoplasia (PIN), or penile squamous cell carcinoma in situ, is a rare disease with high morbidity and mortality rates. Clinically, PIN is comprised of a clinical spectrum including 3 different entities: erythroplasia of Queyrat, Bowen disease, and BP.¹ Histologically, PIN also is classified into 3 subtypes according to histological depth of epidermal atypia.¹

Bowenoid papulosis usually is characterized by multiple red-brown or flesh-colored papules that most commonly appear on the shaft or glans of the penis. Bowenoid papulosis frequently is associated with high-risk types of HPV, such as HPV type 16, and is sometimes difficult to differentiate clinically from pigmented condyloma acuminatum. The clinical lesions of BP usually are less papillomatous, smoother topped, more polymorphic, and more coalescent compared to common genital viral condyloma acuminatum.² Bowenoid papulosis usually is seen in young (<30 years of age) sexually active men, unlike the patches or plaques of erythroplasia of Queyrat or Bowen disease, which are seen in older men aged 45 to 75 years. Bowenoid papulosis also has a lower malignancy potential than erythroplasia of Queyrat and Bowen disease.²

Penile melanosis, penile lentigo, and seborrheic keratosis comprise the differential diagnosis of dark spots on the penis and also should be kept in mind. Penile melanosis is the most common cause of dark spots on the penis. When the dark spots have irregular borders and change in color, they may be misdiagnosed as malignant lesions such as melanoma.³ In most cases, biopsy is indicated. Histologically, penile melanosis is characterized by hyperpigmentation of the basal cell layer with no melanocytic hyperplasia. Treatment is unnecessary in most cases.

Penile lentigo presents as small flat pigmented spots on the penile skin with clearly defined margins surrounded by normal-appearing skin. Histologically, it is characterized by hyperplasia of melanocytes above the basement membrane of the epidermis.³

Penile pigmented seborrheic keratosis is a rare clinical entity that can be easily misinterpreted as condyloma acuminatum. Histologically, it is characterized by basal cell hyperplasia with cystic formation in the thickened epidermis. Excisional biopsy may be the only way to rule out malignant disease.

Treatment options for PIN include cryotherapy, CO₂ or Nd:YAG lasers, photodynamic therapy, topical 5-FU or imiquimod therapy, and surgical excision such as Mohs micrographic surgery.^4-9 Although these therapeutic modalities usually are effective, recurrence is common.⁶ The patients' discomfort and poor cosmetic and functional outcomes from the surgical removal of lesions also present a challenge in treatment planning. 

In our patient, we quickly achieved a good result with topical 5-FU, though the disease was in local advanced stage. It is important for clinicians to consider 5-FU as an effective treatment option for PIN before planning surgery.

The Diagnosis: Bowenoid Papulosis 

A 4-mm punch biopsy was performed from the active border of brown plaques on the dorsal penis. Histopathology revealed parakeratotic hyperkeratosis, acanthosis, loss of maturation in epithelium, and full-size atypia (Figure 1). Ki-67 index was 90% positive in the epidermis (Figure 2). Staining for p16 and human papillomavirus (HPV) screening was positive for HPV type 16 (Figure 3). Serologic tests for other sexually transmitted infections were negative. A diagnosis of penile bowenoid papulosis (BP) with grade 3 penile intraepithelial neoplasia was made, and treatment with topical 5-fluorouracil (5-FU) was initiated. Almost total regression was appreciated at 1-month follow-up (Figure 4), and he also was recurrence free at 1-year follow-up.

Penile intraepithelial neoplasia (PIN), or penile squamous cell carcinoma in situ, is a rare disease with high morbidity and mortality rates. Clinically, PIN is comprised of a clinical spectrum including 3 different entities: erythroplasia of Queyrat, Bowen disease, and BP.¹ Histologically, PIN also is classified into 3 subtypes according to histological depth of epidermal atypia.¹

Bowenoid papulosis usually is characterized by multiple red-brown or flesh-colored papules that most commonly appear on the shaft or glans of the penis. Bowenoid papulosis frequently is associated with high-risk types of HPV, such as HPV type 16, and is sometimes difficult to differentiate clinically from pigmented condyloma acuminatum. The clinical lesions of BP usually are less papillomatous, smoother topped, more polymorphic, and more coalescent compared to common genital viral condyloma acuminatum.² Bowenoid papulosis usually is seen in young (<30 years of age) sexually active men, unlike the patches or plaques of erythroplasia of Queyrat or Bowen disease, which are seen in older men aged 45 to 75 years. Bowenoid papulosis also has a lower malignancy potential than erythroplasia of Queyrat and Bowen disease.²

Penile melanosis, penile lentigo, and seborrheic keratosis comprise the differential diagnosis of dark spots on the penis and also should be kept in mind. Penile melanosis is the most common cause of dark spots on the penis. When the dark spots have irregular borders and change in color, they may be misdiagnosed as malignant lesions such as melanoma.³ In most cases, biopsy is indicated. Histologically, penile melanosis is characterized by hyperpigmentation of the basal cell layer with no melanocytic hyperplasia. Treatment is unnecessary in most cases.

Penile lentigo presents as small flat pigmented spots on the penile skin with clearly defined margins surrounded by normal-appearing skin. Histologically, it is characterized by hyperplasia of melanocytes above the basement membrane of the epidermis.³

Penile pigmented seborrheic keratosis is a rare clinical entity that can be easily misinterpreted as condyloma acuminatum. Histologically, it is characterized by basal cell hyperplasia with cystic formation in the thickened epidermis. Excisional biopsy may be the only way to rule out malignant disease.

Treatment options for PIN include cryotherapy, CO₂ or Nd:YAG lasers, photodynamic therapy, topical 5-FU or imiquimod therapy, and surgical excision such as Mohs micrographic surgery.^4-9 Although these therapeutic modalities usually are effective, recurrence is common.⁶ The patients' discomfort and poor cosmetic and functional outcomes from the surgical removal of lesions also present a challenge in treatment planning. 

In our patient, we quickly achieved a good result with topical 5-FU, though the disease was in local advanced stage. It is important for clinicians to consider 5-FU as an effective treatment option for PIN before planning surgery.

The Diagnosis: Eruptive Blue Nevus

All biopsies demonstrated similar histologic features, including an intradermal proliferation of heavily pigmented, spindle-shaped dendritic melanocytes (Figure). The dermal pigment was most pronounced in the grossly darker papules, and there was not a substantial amount of background pigmentation at the stratum basale. Cytologic atypia, foci of necrosis, and mitotic activity were absent from all sections. There was no definitive junctional component identified, no multinucleated giant cells, and there was no overlying epidermal aberration. With some background pigmentation seen histologically, nevus spilus was considered, but because this acute eruption occurred in a young adult without appreciable gross background hyperpigmentation, the clinical context led to a diagnosis of eruptive blue nevus. After communicating the findings to the patient, he declined further treatment.

Eruptive blue nevus is an exceptionally rare subtype of blue nevus with few cases reported since the 1940s.^1-9 Generally, each case report found a triggering event that could possibly have precipitated the acute proliferation and evolution of nevi. Triggering events can include bullous processes such as erythema multiforme² and Stevens-Johnson syndrome,³ severe sunburn,⁴ trauma,⁵ immunosuppression,⁶ and a variety of endocrinopathies. No such history could be identified in our patient, except the biopsy.

Common blue nevi are benign, usually congenital, well-circumscribed, solitary, blue-gray macules or papules. Half of blue nevi cases are found on the dorsal aspects of the hands and feet but can present anywhere (eg, face, scalp, wrists, sacrum, buttocks). The blue-gray color appreciated clinically is attributed to the Tyndall effect, which occurs when long-wavelength light--red, orange, and yellow--is absorbed by the melanin deep in the dermis, while short-wavelength visible light--blue, violet, and indigo--is reflected with backscattering. On polarized dermoscopy, a homogeneous blue-gray hue is appreciated, but lighter segments may be present when collagen deposition is robust. Histopathologic findings confirm spindle-shaped dendritic melanocytes in the dermis without epidermal involvement. It generally is accepted that the etiology of these benign nevi is a failed migration of neural crest cells to the epidermis.^10,11 Although the common blue nevus may be simple to diagnose, several subtypes have been described in the literature, including combined blue nevus, desmoplastic blue nevus, hypomelanotic/amelanotic blue nevus, and epithelioid blue nevus of Carney complex, and excluding a malignant process is of monumental importance.^7,12

Biopsy is recommended for common blue nevi in the evaluation of newly acquired lesions, expansion of previously stable nevi, or for nevi larger than 10 mm in diameter. The nature of eruptive blue nevi warrants a biopsy to exclude melanoma or another malignant process. While the Becker nevus may manifest in adolescent males, it is clinically distinct from an eruptive blue nevus due to the size, relative homogeneity, and presence of hair within the lesion. Cutaneous amyloidosis may appear clinically similar to an eruptive blue nevus, but globular or amorphous material was not present in the papillary dermis of biopsied lesions in our patient. Since there was no cellular atypia or mitotic activity, melanoma and other malignancies were ruled out. Lastly, NAME syndrome by definition must include atrial myxomas, myxoid neurofibromas, and ephelides in addition to the nevi; however, our patient had only nevi and few ephelides. Once the diagnosis is established and benign nature confirmed, treatment is not necessarily required. If the patient elects to remove the lesion for aesthetic reasons, an excision into the subcutaneous fat is required to ensure complete removal of deep dermal melanocytes. Prior excisions of eruptive blue nevi have had no recurrence after more than 10 months.^8,9

The Diagnosis: Eruptive Blue Nevus

All biopsies demonstrated similar histologic features, including an intradermal proliferation of heavily pigmented, spindle-shaped dendritic melanocytes (Figure). The dermal pigment was most pronounced in the grossly darker papules, and there was not a substantial amount of background pigmentation at the stratum basale. Cytologic atypia, foci of necrosis, and mitotic activity were absent from all sections. There was no definitive junctional component identified, no multinucleated giant cells, and there was no overlying epidermal aberration. With some background pigmentation seen histologically, nevus spilus was considered, but because this acute eruption occurred in a young adult without appreciable gross background hyperpigmentation, the clinical context led to a diagnosis of eruptive blue nevus. After communicating the findings to the patient, he declined further treatment.

Eruptive blue nevus is an exceptionally rare subtype of blue nevus with few cases reported since the 1940s.^1-9 Generally, each case report found a triggering event that could possibly have precipitated the acute proliferation and evolution of nevi. Triggering events can include bullous processes such as erythema multiforme² and Stevens-Johnson syndrome,³ severe sunburn,⁴ trauma,⁵ immunosuppression,⁶ and a variety of endocrinopathies. No such history could be identified in our patient, except the biopsy.

Common blue nevi are benign, usually congenital, well-circumscribed, solitary, blue-gray macules or papules. Half of blue nevi cases are found on the dorsal aspects of the hands and feet but can present anywhere (eg, face, scalp, wrists, sacrum, buttocks). The blue-gray color appreciated clinically is attributed to the Tyndall effect, which occurs when long-wavelength light--red, orange, and yellow--is absorbed by the melanin deep in the dermis, while short-wavelength visible light--blue, violet, and indigo--is reflected with backscattering. On polarized dermoscopy, a homogeneous blue-gray hue is appreciated, but lighter segments may be present when collagen deposition is robust. Histopathologic findings confirm spindle-shaped dendritic melanocytes in the dermis without epidermal involvement. It generally is accepted that the etiology of these benign nevi is a failed migration of neural crest cells to the epidermis.^10,11 Although the common blue nevus may be simple to diagnose, several subtypes have been described in the literature, including combined blue nevus, desmoplastic blue nevus, hypomelanotic/amelanotic blue nevus, and epithelioid blue nevus of Carney complex, and excluding a malignant process is of monumental importance.^7,12

Biopsy is recommended for common blue nevi in the evaluation of newly acquired lesions, expansion of previously stable nevi, or for nevi larger than 10 mm in diameter. The nature of eruptive blue nevi warrants a biopsy to exclude melanoma or another malignant process. While the Becker nevus may manifest in adolescent males, it is clinically distinct from an eruptive blue nevus due to the size, relative homogeneity, and presence of hair within the lesion. Cutaneous amyloidosis may appear clinically similar to an eruptive blue nevus, but globular or amorphous material was not present in the papillary dermis of biopsied lesions in our patient. Since there was no cellular atypia or mitotic activity, melanoma and other malignancies were ruled out. Lastly, NAME syndrome by definition must include atrial myxomas, myxoid neurofibromas, and ephelides in addition to the nevi; however, our patient had only nevi and few ephelides. Once the diagnosis is established and benign nature confirmed, treatment is not necessarily required. If the patient elects to remove the lesion for aesthetic reasons, an excision into the subcutaneous fat is required to ensure complete removal of deep dermal melanocytes. Prior excisions of eruptive blue nevi have had no recurrence after more than 10 months.^8,9

The Diagnosis: Eruptive Blue Nevus

All biopsies demonstrated similar histologic features, including an intradermal proliferation of heavily pigmented, spindle-shaped dendritic melanocytes (Figure). The dermal pigment was most pronounced in the grossly darker papules, and there was not a substantial amount of background pigmentation at the stratum basale. Cytologic atypia, foci of necrosis, and mitotic activity were absent from all sections. There was no definitive junctional component identified, no multinucleated giant cells, and there was no overlying epidermal aberration. With some background pigmentation seen histologically, nevus spilus was considered, but because this acute eruption occurred in a young adult without appreciable gross background hyperpigmentation, the clinical context led to a diagnosis of eruptive blue nevus. After communicating the findings to the patient, he declined further treatment.

Eruptive blue nevus is an exceptionally rare subtype of blue nevus with few cases reported since the 1940s.^1-9 Generally, each case report found a triggering event that could possibly have precipitated the acute proliferation and evolution of nevi. Triggering events can include bullous processes such as erythema multiforme² and Stevens-Johnson syndrome,³ severe sunburn,⁴ trauma,⁵ immunosuppression,⁶ and a variety of endocrinopathies. No such history could be identified in our patient, except the biopsy.

Common blue nevi are benign, usually congenital, well-circumscribed, solitary, blue-gray macules or papules. Half of blue nevi cases are found on the dorsal aspects of the hands and feet but can present anywhere (eg, face, scalp, wrists, sacrum, buttocks). The blue-gray color appreciated clinically is attributed to the Tyndall effect, which occurs when long-wavelength light--red, orange, and yellow--is absorbed by the melanin deep in the dermis, while short-wavelength visible light--blue, violet, and indigo--is reflected with backscattering. On polarized dermoscopy, a homogeneous blue-gray hue is appreciated, but lighter segments may be present when collagen deposition is robust. Histopathologic findings confirm spindle-shaped dendritic melanocytes in the dermis without epidermal involvement. It generally is accepted that the etiology of these benign nevi is a failed migration of neural crest cells to the epidermis.^10,11 Although the common blue nevus may be simple to diagnose, several subtypes have been described in the literature, including combined blue nevus, desmoplastic blue nevus, hypomelanotic/amelanotic blue nevus, and epithelioid blue nevus of Carney complex, and excluding a malignant process is of monumental importance.^7,12

Biopsy is recommended for common blue nevi in the evaluation of newly acquired lesions, expansion of previously stable nevi, or for nevi larger than 10 mm in diameter. The nature of eruptive blue nevi warrants a biopsy to exclude melanoma or another malignant process. While the Becker nevus may manifest in adolescent males, it is clinically distinct from an eruptive blue nevus due to the size, relative homogeneity, and presence of hair within the lesion. Cutaneous amyloidosis may appear clinically similar to an eruptive blue nevus, but globular or amorphous material was not present in the papillary dermis of biopsied lesions in our patient. Since there was no cellular atypia or mitotic activity, melanoma and other malignancies were ruled out. Lastly, NAME syndrome by definition must include atrial myxomas, myxoid neurofibromas, and ephelides in addition to the nevi; however, our patient had only nevi and few ephelides. Once the diagnosis is established and benign nature confirmed, treatment is not necessarily required. If the patient elects to remove the lesion for aesthetic reasons, an excision into the subcutaneous fat is required to ensure complete removal of deep dermal melanocytes. Prior excisions of eruptive blue nevi have had no recurrence after more than 10 months.^8,9

The Cutis Editorial Board is now accepting applications for the 2019 Resident Corner column. The Editorial Board will select 2 residents to serve as the Resident Corner columnists for 1 year (3 articles each). Articles are posted online only but will be referenced in Index Medicus. All applicants must be current residents and will still be in residency throughout 2019.

For consideration, send your curriculum vitae along with a brief (not to exceed 500 words) statement of why you enjoy Cutis and what you can offer your fellow residents in contributing a monthly column.

All materials should be submitted via email as 1 Word document to Melissa Sears by November 1. The residents who are selected to write the column for the upcoming year will be notified by November 15.

We look forward to continuing to educate dermatology residents on topics that are most important to them!

The Cutis Editorial Board is now accepting applications for the 2019 Resident Corner column. The Editorial Board will select 2 residents to serve as the Resident Corner columnists for 1 year (3 articles each). Articles are posted online only but will be referenced in Index Medicus. All applicants must be current residents and will still be in residency throughout 2019.

For consideration, send your curriculum vitae along with a brief (not to exceed 500 words) statement of why you enjoy Cutis and what you can offer your fellow residents in contributing a monthly column.

All materials should be submitted via email as 1 Word document to Melissa Sears by November 1. The residents who are selected to write the column for the upcoming year will be notified by November 15.

We look forward to continuing to educate dermatology residents on topics that are most important to them!

The Cutis Editorial Board is now accepting applications for the 2019 Resident Corner column. The Editorial Board will select 2 residents to serve as the Resident Corner columnists for 1 year (3 articles each). Articles are posted online only but will be referenced in Index Medicus. All applicants must be current residents and will still be in residency throughout 2019.

For consideration, send your curriculum vitae along with a brief (not to exceed 500 words) statement of why you enjoy Cutis and what you can offer your fellow residents in contributing a monthly column.

All materials should be submitted via email as 1 Word document to Melissa Sears by November 1. The residents who are selected to write the column for the upcoming year will be notified by November 15.

We look forward to continuing to educate dermatology residents on topics that are most important to them!