MIAMI—The sublingual apomorphine film APL-130277 (APL) is effective and well-tolerated for the acute management of off episodes in patients with Parkinson’s disease, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress.

APL is in development for the acute, intermittent treatment of off episodes associated with Parkinson’s disease, including end-of-dose wearing off (including early morning off); partial, delayed, or no on; and unpredictable off.

Evaluating the Efficacy and Safety of APL

To evaluate the efficacy and safety of APL, C. Warren Olanow, MD, Professor Emeritus and Chair Emeritus of Neurology and Professor of Neuroscience at the Mount Sinai School of Medicine in New York City, and colleagues conducted a double-blind, placebo-controlled trial.

Eligible participants were 18 or older, had idiopathic Parkinson’s disease according to UK Brain Bank criteria, were stage I–III according to the modified Hoehn and Yahr scale when on, and had a clinically meaningful response to levodopa with well-defined, early-morning off episodes. They had one or more off episodes per day and a total daily off time of two or more hours when receiving stable doses of levodopa qid or carbidopa–levodopa extended-release capsules tid for four or more weeks, or monoamine oxidase B inhibitors for eight or more weeks.

Patients with atypical or secondary parkinsonism, a major psychiatric disorder, or mouth cankers or sores were excluded. Patients who had undergone a neurosurgical procedure for Parkinson’s disease, received continuous subcutaneous apomorphine infusion, or received Duopa also were excluded. Finally, patients currently taking 5-HT3 antagonists, selective dopamine antagonists (excluding quetiapine or clozapine), or dopamine-depleting agents were excluded.

The APL dose (10 mg to 35 mg) to produce a full on was determined during the open-label titration phase. During the double-blind treatment phase, researchers randomized patients to the dose of APL identified during the titration phase or placebo that could be self-administered as many as five times per day for 12 weeks. Movement Disorder Society Unified Parkinson’s Disease Rating Scale, Part III (MDS-UPDRS-III) scores were determined monthly before dosing and at 15, 30, 45, 60, and 90 minutes post dose. The primary end point was the change in MDS-UPDRS-III score at 30 minutes post dose at 12 weeks. The key secondary end point was the percentage of patients with a patient-determined full on response within 30 minutes at 12 weeks. Safety assessments were also performed.

Treated Patients Were More Likely to Be On

A total of 109 patients were randomized to the double-blind treatment phase, and had a mean of 3.9 off episodes per day. Participants’ mean age was 62.7, and 37.6% of participants were female. More than 90% of participants were white.

In all, 80 patients completed the study. The least squares mean change from predose to 30 minutes post dose for the MDS-UPDRS-III score at 12 weeks was –11.1 and –3.5 for the APL and placebo groups, respectively (mean difference, –7.6). Similar results were observed at day 1 and weeks 4 and 8.

The difference between treatment arms in motor score became significant at 15 minutes and remained significant until 90 minutes. There was a significant difference favoring APL over placebo in the percentage of patients achieving a self-rated full on response at 30 minutes post dose at week 12. A home dosing diary showed that a larger percentage of patients receiving APL were on within 30 minutes post dose (least squares mean, 78.70%), compared with controls (least squares mean, 31.10%).

In the double-blind treatment phase, the overall discontinuation rate was 16.4% for placebo and 37.0% for APL. The discontinuation rate due to adverse events was 9.1% and 27.8% for placebo and APL, respectively. Discontinuation due to adverse events was the most common reason. During the double-blind treatment phase of APL, the most frequent adverse events were nausea (27.8%), somnolence (13%), and dizziness (9.3%). Most treatment-emergent adverse events were mild to moderate. Six patients experienced severe adverse events in the placebo and APL groups combined. Three patients experienced serious adverse events combined. One patient in the APL group died from cardiac arrest considered possibly related to treatment by the investigator. Oral adverse events occurred in 31.5% of patients in the APL group versus 7.3% of controls. These events were generally mild and reversible, said the researchers.

—Erica Tricarico

MIAMI—The sublingual apomorphine film APL-130277 (APL) is effective and well-tolerated for the acute management of off episodes in patients with Parkinson’s disease, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress.

APL is in development for the acute, intermittent treatment of off episodes associated with Parkinson’s disease, including end-of-dose wearing off (including early morning off); partial, delayed, or no on; and unpredictable off.

Evaluating the Efficacy and Safety of APL

To evaluate the efficacy and safety of APL, C. Warren Olanow, MD, Professor Emeritus and Chair Emeritus of Neurology and Professor of Neuroscience at the Mount Sinai School of Medicine in New York City, and colleagues conducted a double-blind, placebo-controlled trial.

Eligible participants were 18 or older, had idiopathic Parkinson’s disease according to UK Brain Bank criteria, were stage I–III according to the modified Hoehn and Yahr scale when on, and had a clinically meaningful response to levodopa with well-defined, early-morning off episodes. They had one or more off episodes per day and a total daily off time of two or more hours when receiving stable doses of levodopa qid or carbidopa–levodopa extended-release capsules tid for four or more weeks, or monoamine oxidase B inhibitors for eight or more weeks.

Patients with atypical or secondary parkinsonism, a major psychiatric disorder, or mouth cankers or sores were excluded. Patients who had undergone a neurosurgical procedure for Parkinson’s disease, received continuous subcutaneous apomorphine infusion, or received Duopa also were excluded. Finally, patients currently taking 5-HT3 antagonists, selective dopamine antagonists (excluding quetiapine or clozapine), or dopamine-depleting agents were excluded.

The APL dose (10 mg to 35 mg) to produce a full on was determined during the open-label titration phase. During the double-blind treatment phase, researchers randomized patients to the dose of APL identified during the titration phase or placebo that could be self-administered as many as five times per day for 12 weeks. Movement Disorder Society Unified Parkinson’s Disease Rating Scale, Part III (MDS-UPDRS-III) scores were determined monthly before dosing and at 15, 30, 45, 60, and 90 minutes post dose. The primary end point was the change in MDS-UPDRS-III score at 30 minutes post dose at 12 weeks. The key secondary end point was the percentage of patients with a patient-determined full on response within 30 minutes at 12 weeks. Safety assessments were also performed.

Treated Patients Were More Likely to Be On

A total of 109 patients were randomized to the double-blind treatment phase, and had a mean of 3.9 off episodes per day. Participants’ mean age was 62.7, and 37.6% of participants were female. More than 90% of participants were white.

In all, 80 patients completed the study. The least squares mean change from predose to 30 minutes post dose for the MDS-UPDRS-III score at 12 weeks was –11.1 and –3.5 for the APL and placebo groups, respectively (mean difference, –7.6). Similar results were observed at day 1 and weeks 4 and 8.

The difference between treatment arms in motor score became significant at 15 minutes and remained significant until 90 minutes. There was a significant difference favoring APL over placebo in the percentage of patients achieving a self-rated full on response at 30 minutes post dose at week 12. A home dosing diary showed that a larger percentage of patients receiving APL were on within 30 minutes post dose (least squares mean, 78.70%), compared with controls (least squares mean, 31.10%).

In the double-blind treatment phase, the overall discontinuation rate was 16.4% for placebo and 37.0% for APL. The discontinuation rate due to adverse events was 9.1% and 27.8% for placebo and APL, respectively. Discontinuation due to adverse events was the most common reason. During the double-blind treatment phase of APL, the most frequent adverse events were nausea (27.8%), somnolence (13%), and dizziness (9.3%). Most treatment-emergent adverse events were mild to moderate. Six patients experienced severe adverse events in the placebo and APL groups combined. Three patients experienced serious adverse events combined. One patient in the APL group died from cardiac arrest considered possibly related to treatment by the investigator. Oral adverse events occurred in 31.5% of patients in the APL group versus 7.3% of controls. These events were generally mild and reversible, said the researchers.

—Erica Tricarico

MIAMI—The sublingual apomorphine film APL-130277 (APL) is effective and well-tolerated for the acute management of off episodes in patients with Parkinson’s disease, according to research presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress.

APL is in development for the acute, intermittent treatment of off episodes associated with Parkinson’s disease, including end-of-dose wearing off (including early morning off); partial, delayed, or no on; and unpredictable off.

Evaluating the Efficacy and Safety of APL

To evaluate the efficacy and safety of APL, C. Warren Olanow, MD, Professor Emeritus and Chair Emeritus of Neurology and Professor of Neuroscience at the Mount Sinai School of Medicine in New York City, and colleagues conducted a double-blind, placebo-controlled trial.

Eligible participants were 18 or older, had idiopathic Parkinson’s disease according to UK Brain Bank criteria, were stage I–III according to the modified Hoehn and Yahr scale when on, and had a clinically meaningful response to levodopa with well-defined, early-morning off episodes. They had one or more off episodes per day and a total daily off time of two or more hours when receiving stable doses of levodopa qid or carbidopa–levodopa extended-release capsules tid for four or more weeks, or monoamine oxidase B inhibitors for eight or more weeks.

Patients with atypical or secondary parkinsonism, a major psychiatric disorder, or mouth cankers or sores were excluded. Patients who had undergone a neurosurgical procedure for Parkinson’s disease, received continuous subcutaneous apomorphine infusion, or received Duopa also were excluded. Finally, patients currently taking 5-HT3 antagonists, selective dopamine antagonists (excluding quetiapine or clozapine), or dopamine-depleting agents were excluded.

The APL dose (10 mg to 35 mg) to produce a full on was determined during the open-label titration phase. During the double-blind treatment phase, researchers randomized patients to the dose of APL identified during the titration phase or placebo that could be self-administered as many as five times per day for 12 weeks. Movement Disorder Society Unified Parkinson’s Disease Rating Scale, Part III (MDS-UPDRS-III) scores were determined monthly before dosing and at 15, 30, 45, 60, and 90 minutes post dose. The primary end point was the change in MDS-UPDRS-III score at 30 minutes post dose at 12 weeks. The key secondary end point was the percentage of patients with a patient-determined full on response within 30 minutes at 12 weeks. Safety assessments were also performed.

Treated Patients Were More Likely to Be On

A total of 109 patients were randomized to the double-blind treatment phase, and had a mean of 3.9 off episodes per day. Participants’ mean age was 62.7, and 37.6% of participants were female. More than 90% of participants were white.

In all, 80 patients completed the study. The least squares mean change from predose to 30 minutes post dose for the MDS-UPDRS-III score at 12 weeks was –11.1 and –3.5 for the APL and placebo groups, respectively (mean difference, –7.6). Similar results were observed at day 1 and weeks 4 and 8.

The difference between treatment arms in motor score became significant at 15 minutes and remained significant until 90 minutes. There was a significant difference favoring APL over placebo in the percentage of patients achieving a self-rated full on response at 30 minutes post dose at week 12. A home dosing diary showed that a larger percentage of patients receiving APL were on within 30 minutes post dose (least squares mean, 78.70%), compared with controls (least squares mean, 31.10%).

In the double-blind treatment phase, the overall discontinuation rate was 16.4% for placebo and 37.0% for APL. The discontinuation rate due to adverse events was 9.1% and 27.8% for placebo and APL, respectively. Discontinuation due to adverse events was the most common reason. During the double-blind treatment phase of APL, the most frequent adverse events were nausea (27.8%), somnolence (13%), and dizziness (9.3%). Most treatment-emergent adverse events were mild to moderate. Six patients experienced severe adverse events in the placebo and APL groups combined. Three patients experienced serious adverse events combined. One patient in the APL group died from cardiac arrest considered possibly related to treatment by the investigator. Oral adverse events occurred in 31.5% of patients in the APL group versus 7.3% of controls. These events were generally mild and reversible, said the researchers.

—Erica Tricarico

Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare entity that presents with linear and pruritic psoriasiform plaques and most commonly occurs during childhood. It represents a dysregulation of keratinocytes exhibiting genetic mosaicism.^1,2 Epidermal nevi may derive from keratinocytic, follicular, sebaceous, apocrine, or eccrine origin. Inflammatory linear verrucous epidermal nevus is classified under the keratinocytic type of epidermal nevus and represents approximately 6% of all epidermal nevi.³ The condition presents as erythematous and verrucous plaques along the lines of Blaschko.^2,4 There is a predilection for the legs, and girls are 4 times more commonly affected than boys.¹ Cases of ILVEN are predominantly sporadic, though rare familial cases have been reported.⁴

Inflammatory linear verrucous epidermal nevus is notoriously refractory to treatment. First-line therapies include topical agents such as corticosteroids, calcipotriol, retinoids, and 5-fluorouracil.^3,4 Other treatments include intralesional corticosteroids, cryotherapy, electrodesiccation and curettage, and surgical excision.³ Several case reports have shown promising results using the pulsed dye and ablative CO2 lasers.^5-8

Case Report

An otherwise healthy 20-year-old woman presented with dry, pruritic, red lesions on the right leg that had been present and stable since she was an infant (2 weeks of age). Her medical history included acne vulgaris, but she denied any personal or family history of psoriasis as well as any arthralgia or arthritis. Physical examination revealed discrete, oval, hyperkeratotic, scaly, red plaques on the lateral right leg with a larger hyperkeratotic, linear, red plaque extending from the right popliteal fossa to the posterior thigh (Figure 1A). The nails, scalp, buttocks, and upper extremities were unaffected. Bacterial culture of the right leg demonstrated Staphylococcus aureus colonization. Biopsy of the right popliteal fossa showed psoriasiform dermatitis with psoriasiform hyperplasia, a slightly verruciform surface, broad zones of superficial pallor, and parakeratosis with conspicuous colonies of bacteria (Figure 2).

Following the positive bacterial culture, the patient was treated with a short course of oral doxycycline, which did not alter the clinical appearance of the lesions or improve symptoms of pruritus. Pruritus improved moderately with topical corticosteroid treatment, but clinically the lesions appeared unchanged. The plaque on the superior right leg was treated with a superpulsed CO₂ laser and the plaque on the inferior right leg was treated with a fractional CO₂ laser, both with minimal improvement.

Because of the clinical and histopathologic similarities of the patient's lesions to psoriasis, a trial of the UV 308-nm excimer laser was initiated. Following initial test spots, she completed a total of 18 treatments to all lesions with noticeable clinical improvement (Figure 1B). Initially, the patient returned for treatment biweekly for approximately 5 weeks with 2 small spots being targeted at each session, with an average surface area of approximately 16 cm². She was started at 225 mJ/cm² with 25% increases at each session and ultimately reached up to 1676 mJ/cm² at the end of the 10 sessions. She tolerated the procedure well with some minor blistering. Treatment was deferred for 3 months due to the patient's schedule, then biweekly treatments resumed for 4 weeks, totaling 8 more sessions. At that time, all lesions on the right leg were targeted, with an average surface area of approximately 100 cm². The laser settings were initiated at 225 mJ/cm² with 20% increases at each session and ultimately reached 560 mJ/cm². The treatment was well tolerated throughout; however, the patient initially reported residual pruritus. The plaques continued to improve, and most notably, there was thinning of the hyperkeratotic scale of the plaques in addition to decreased erythema and complete resolution of pruritus. Ultimately, treatment was discontinued because of lack of insurance coverage and financial burden. The patient was lost to follow-up.

Comment

Presentation
Inflammatory linear verrucous epidermal nevus is a rare type of keratinocytic epidermal nevus⁴ that clinically presents as small, discrete, pruritic, scaly plaques coalescing into a linear plaque along the lines of Blaschko.⁹ Considerable pruritus and resistance to treatment are hallmarks of the disease.¹⁰ Histopathologically, ILVEN is characterized by alternating orthokeratosis and parakeratosis with a lack of neutrophils in an acanthotic epidermis.^11-13 Inflammatory linear verrucous epidermal nevus presents at birth or in early childhood. Adult onset is rare.^9,14 Approximately 75% of lesions present by 5 years of age, with a majority occurring within the first 6 months of life.¹⁵ The differential diagnosis includes linear psoriasis, epidermal nevi, linear lichen planus, linear verrucae, linear lichen simplex chronicus, and mycosis fungoides.^4,11

Differentiation From Psoriasis
Despite the histopathologic overlap with psoriasis, ILVEN exhibits fewer Ki-67-positive keratinocyte nuclei (proliferative marker) and more cytokeratin 10-positive cells (epidermal differentiation marker) than psoriasis.¹⁶ Furthermore, ILVEN has demonstrated fewer CD4⁻, CD8⁻, CD45RO⁻, CD2⁻, CD25⁻, CD94⁻, and CD161⁺ cells within the dermis and epidermis than psoriasis.¹⁶

The clinical presentations of ILVEN and psoriasis may be similar, as some patients with linear psoriasis also present with psoriatic plaques along the lines of Blaschko.¹⁷ Additionally, ILVEN may be a precursor to psoriasis. Altman and Mehregan1 found that ILVEN patients who developed psoriasis did so in areas previously affected by ILVEN; however, they continued to distinguish the 2 pathologies as distinct entities. Another early report also hypothesized that the dermoepidermal defect caused by epidermal nevi provided a site for the development of psoriatic lesions because of the Koebner phenomenon.¹⁸

Patients with ILVEN also have been found to have extracutaneous manifestations and symptoms commonly seen in psoriasis patients. A 2012 retrospective review revealed that 37% (7/19) of patients with ILVEN also had psoriatic arthritis, cutaneous psoriatic lesions, and/or nail pitting. The authors concluded that ILVEN may lead to the onset of psoriasis later in life and may indicate an underlying psoriatic predisposition.¹⁹ Genetic theories also have been proposed, stating that ILVEN may be a mosaic of psoriasis2 or that a postzygotic mutation leads to the predisposition for developing psoriasis.²⁰

Treatment
Inflammatory linear verrucous epidermal nevus frequently is refractory to treatment; however, the associated pruritus and distressing cosmesis make treatment attempts worthwhile.¹¹ No single therapy has been found to be successful in all patients. A widely used first-line treatment is topical or intralesional corticosteroids, with the former typically used with occlusion.¹³ Other treatments include adalimumab, calcipotriol,^22,23 tretinoin,²⁴ and 5-fluorouracil.²⁴ Physical modalities such as cryotherapy, electrodesiccation, and dermabrasion have been reported with varying success.^15,24 Surgical treatments include tangential²⁵ and full-thickness excisions.²⁶

The CO₂ laser also has demonstrated success. One study showed considerable improvement of pruritus and partial resolution of lesions only 5 weeks following a single CO₂ laser treatment.⁵ Another study showed promising results when combining CO₂ pulsed laser therapy with fractional CO₂ laser treatment.⁶ Other laser therapies including the argon²⁷ and flashlamp-pumped pulsed dye lasers⁸ have been used with limited success. The use of light therapy and lasers in psoriasis have now increased the treatment options for ILVEN based on the rationale of their shared histopathologic characteristics. Photodynamic therapy also has been attempted because of its successful use in psoriasis patients. It has been found to be successful in diminishing ILVEN lesions and associated pruritus after a few weeks of therapy; however, treatment is limited by the associated pain and requirement for local anesthesia.²⁸

The excimer laser is a form of targeted phototherapy that emits monochromatic light at 308 nm.²⁹ It is ideal for inflammatory skin lesions because the UVB light induces apoptosis.³⁰ Psoriasis lesions treated with the excimer laser show a decrease in keratinocyte proliferation, which in turn reverses epidermal acanthosis and causes T-cell depletion due to upregulation of p53.^29,31 This mechanism of action addresses the overproliferation of keratinocytes mediated by T cells in psoriasis and contributes to the success of excimer laser treatment.³¹ A considerable advantage is its localized treatment, resulting in lower cumulative doses of UVB and reducing the possible carcinogenic and phototoxic risks of whole-body phototherapy.³²

One study examined the antipruritic effects of the excimer laser following the treatment of epidermal hyperinnervation leading to intractable pruritus in patients with atopic dermatitis. The researchers suggested that a potential explanation for the antipruritic effect of the excimer laser may be secondary to nerve degeneration.³³ Additionally, low doses of UVB light also may inhibit mast cell degranulation and prevent histamine release, further supporting the antipruritic properties of excimer laser.³⁴

In our patient, failed treatment with other modalities led to trial of excimer laser therapy because of the overlapping clinical and histopathologic findings with psoriasis. Excimer laser improved the clinical appearance and overall texture of the ILVEN lesions and decreased pruritus. The reasons for treatment success may be two-fold. By decreasing the number of keratinocytes and mast cells, the excimer laser may have improved the epidermal hyperplasia and pruritus in the ILVEN lesions. Alternatively, because the patient had ILVEN lesions since infancy, psoriasis may have developed in the location of the ILVEN lesions due to koebnerization, resulting in the clinical response to excimer therapy; however, she had no other clinical evidence of psoriasis.

Because of the recalcitrance of ILVEN lesions to conventional therapies, it is important to investigate therapies that may be of possible benefit. Our novel case documents successful use of the excimer laser in the treatment of ILVEN. 

Conclusion

Our case of ILVEN in a woman that had been present since infancy highlights the disease pathology as well as a potential new treatment modality. The patient was refractory to first-line treatments and was concerned about the cosmetic appearance of the lesions. The patient was subsequently treated with a trial of a 308-nm excimer laser with clinical improvement of the lesions. It is possible that the similarity of ILVEN and psoriasis may have contributed to the clinical improvement in our patient, but the mechanism of action remains unknown. Due to the paucity of evidence regarding optimal treatment of ILVEN, the current case offers dermatologists an option for patients who are refractory to other treatments.
 

Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare entity that presents with linear and pruritic psoriasiform plaques and most commonly occurs during childhood. It represents a dysregulation of keratinocytes exhibiting genetic mosaicism.^1,2 Epidermal nevi may derive from keratinocytic, follicular, sebaceous, apocrine, or eccrine origin. Inflammatory linear verrucous epidermal nevus is classified under the keratinocytic type of epidermal nevus and represents approximately 6% of all epidermal nevi.³ The condition presents as erythematous and verrucous plaques along the lines of Blaschko.^2,4 There is a predilection for the legs, and girls are 4 times more commonly affected than boys.¹ Cases of ILVEN are predominantly sporadic, though rare familial cases have been reported.⁴

Inflammatory linear verrucous epidermal nevus is notoriously refractory to treatment. First-line therapies include topical agents such as corticosteroids, calcipotriol, retinoids, and 5-fluorouracil.^3,4 Other treatments include intralesional corticosteroids, cryotherapy, electrodesiccation and curettage, and surgical excision.³ Several case reports have shown promising results using the pulsed dye and ablative CO2 lasers.^5-8

Case Report

An otherwise healthy 20-year-old woman presented with dry, pruritic, red lesions on the right leg that had been present and stable since she was an infant (2 weeks of age). Her medical history included acne vulgaris, but she denied any personal or family history of psoriasis as well as any arthralgia or arthritis. Physical examination revealed discrete, oval, hyperkeratotic, scaly, red plaques on the lateral right leg with a larger hyperkeratotic, linear, red plaque extending from the right popliteal fossa to the posterior thigh (Figure 1A). The nails, scalp, buttocks, and upper extremities were unaffected. Bacterial culture of the right leg demonstrated Staphylococcus aureus colonization. Biopsy of the right popliteal fossa showed psoriasiform dermatitis with psoriasiform hyperplasia, a slightly verruciform surface, broad zones of superficial pallor, and parakeratosis with conspicuous colonies of bacteria (Figure 2).

Following the positive bacterial culture, the patient was treated with a short course of oral doxycycline, which did not alter the clinical appearance of the lesions or improve symptoms of pruritus. Pruritus improved moderately with topical corticosteroid treatment, but clinically the lesions appeared unchanged. The plaque on the superior right leg was treated with a superpulsed CO₂ laser and the plaque on the inferior right leg was treated with a fractional CO₂ laser, both with minimal improvement.

Because of the clinical and histopathologic similarities of the patient's lesions to psoriasis, a trial of the UV 308-nm excimer laser was initiated. Following initial test spots, she completed a total of 18 treatments to all lesions with noticeable clinical improvement (Figure 1B). Initially, the patient returned for treatment biweekly for approximately 5 weeks with 2 small spots being targeted at each session, with an average surface area of approximately 16 cm². She was started at 225 mJ/cm² with 25% increases at each session and ultimately reached up to 1676 mJ/cm² at the end of the 10 sessions. She tolerated the procedure well with some minor blistering. Treatment was deferred for 3 months due to the patient's schedule, then biweekly treatments resumed for 4 weeks, totaling 8 more sessions. At that time, all lesions on the right leg were targeted, with an average surface area of approximately 100 cm². The laser settings were initiated at 225 mJ/cm² with 20% increases at each session and ultimately reached 560 mJ/cm². The treatment was well tolerated throughout; however, the patient initially reported residual pruritus. The plaques continued to improve, and most notably, there was thinning of the hyperkeratotic scale of the plaques in addition to decreased erythema and complete resolution of pruritus. Ultimately, treatment was discontinued because of lack of insurance coverage and financial burden. The patient was lost to follow-up.

Comment

Presentation
Inflammatory linear verrucous epidermal nevus is a rare type of keratinocytic epidermal nevus⁴ that clinically presents as small, discrete, pruritic, scaly plaques coalescing into a linear plaque along the lines of Blaschko.⁹ Considerable pruritus and resistance to treatment are hallmarks of the disease.¹⁰ Histopathologically, ILVEN is characterized by alternating orthokeratosis and parakeratosis with a lack of neutrophils in an acanthotic epidermis.^11-13 Inflammatory linear verrucous epidermal nevus presents at birth or in early childhood. Adult onset is rare.^9,14 Approximately 75% of lesions present by 5 years of age, with a majority occurring within the first 6 months of life.¹⁵ The differential diagnosis includes linear psoriasis, epidermal nevi, linear lichen planus, linear verrucae, linear lichen simplex chronicus, and mycosis fungoides.^4,11

Differentiation From Psoriasis
Despite the histopathologic overlap with psoriasis, ILVEN exhibits fewer Ki-67-positive keratinocyte nuclei (proliferative marker) and more cytokeratin 10-positive cells (epidermal differentiation marker) than psoriasis.¹⁶ Furthermore, ILVEN has demonstrated fewer CD4⁻, CD8⁻, CD45RO⁻, CD2⁻, CD25⁻, CD94⁻, and CD161⁺ cells within the dermis and epidermis than psoriasis.¹⁶

The clinical presentations of ILVEN and psoriasis may be similar, as some patients with linear psoriasis also present with psoriatic plaques along the lines of Blaschko.¹⁷ Additionally, ILVEN may be a precursor to psoriasis. Altman and Mehregan1 found that ILVEN patients who developed psoriasis did so in areas previously affected by ILVEN; however, they continued to distinguish the 2 pathologies as distinct entities. Another early report also hypothesized that the dermoepidermal defect caused by epidermal nevi provided a site for the development of psoriatic lesions because of the Koebner phenomenon.¹⁸

Patients with ILVEN also have been found to have extracutaneous manifestations and symptoms commonly seen in psoriasis patients. A 2012 retrospective review revealed that 37% (7/19) of patients with ILVEN also had psoriatic arthritis, cutaneous psoriatic lesions, and/or nail pitting. The authors concluded that ILVEN may lead to the onset of psoriasis later in life and may indicate an underlying psoriatic predisposition.¹⁹ Genetic theories also have been proposed, stating that ILVEN may be a mosaic of psoriasis2 or that a postzygotic mutation leads to the predisposition for developing psoriasis.²⁰

Treatment
Inflammatory linear verrucous epidermal nevus frequently is refractory to treatment; however, the associated pruritus and distressing cosmesis make treatment attempts worthwhile.¹¹ No single therapy has been found to be successful in all patients. A widely used first-line treatment is topical or intralesional corticosteroids, with the former typically used with occlusion.¹³ Other treatments include adalimumab, calcipotriol,^22,23 tretinoin,²⁴ and 5-fluorouracil.²⁴ Physical modalities such as cryotherapy, electrodesiccation, and dermabrasion have been reported with varying success.^15,24 Surgical treatments include tangential²⁵ and full-thickness excisions.²⁶

The CO₂ laser also has demonstrated success. One study showed considerable improvement of pruritus and partial resolution of lesions only 5 weeks following a single CO₂ laser treatment.⁵ Another study showed promising results when combining CO₂ pulsed laser therapy with fractional CO₂ laser treatment.⁶ Other laser therapies including the argon²⁷ and flashlamp-pumped pulsed dye lasers⁸ have been used with limited success. The use of light therapy and lasers in psoriasis have now increased the treatment options for ILVEN based on the rationale of their shared histopathologic characteristics. Photodynamic therapy also has been attempted because of its successful use in psoriasis patients. It has been found to be successful in diminishing ILVEN lesions and associated pruritus after a few weeks of therapy; however, treatment is limited by the associated pain and requirement for local anesthesia.²⁸

The excimer laser is a form of targeted phototherapy that emits monochromatic light at 308 nm.²⁹ It is ideal for inflammatory skin lesions because the UVB light induces apoptosis.³⁰ Psoriasis lesions treated with the excimer laser show a decrease in keratinocyte proliferation, which in turn reverses epidermal acanthosis and causes T-cell depletion due to upregulation of p53.^29,31 This mechanism of action addresses the overproliferation of keratinocytes mediated by T cells in psoriasis and contributes to the success of excimer laser treatment.³¹ A considerable advantage is its localized treatment, resulting in lower cumulative doses of UVB and reducing the possible carcinogenic and phototoxic risks of whole-body phototherapy.³²

One study examined the antipruritic effects of the excimer laser following the treatment of epidermal hyperinnervation leading to intractable pruritus in patients with atopic dermatitis. The researchers suggested that a potential explanation for the antipruritic effect of the excimer laser may be secondary to nerve degeneration.³³ Additionally, low doses of UVB light also may inhibit mast cell degranulation and prevent histamine release, further supporting the antipruritic properties of excimer laser.³⁴

In our patient, failed treatment with other modalities led to trial of excimer laser therapy because of the overlapping clinical and histopathologic findings with psoriasis. Excimer laser improved the clinical appearance and overall texture of the ILVEN lesions and decreased pruritus. The reasons for treatment success may be two-fold. By decreasing the number of keratinocytes and mast cells, the excimer laser may have improved the epidermal hyperplasia and pruritus in the ILVEN lesions. Alternatively, because the patient had ILVEN lesions since infancy, psoriasis may have developed in the location of the ILVEN lesions due to koebnerization, resulting in the clinical response to excimer therapy; however, she had no other clinical evidence of psoriasis.

Because of the recalcitrance of ILVEN lesions to conventional therapies, it is important to investigate therapies that may be of possible benefit. Our novel case documents successful use of the excimer laser in the treatment of ILVEN. 

Conclusion

Our case of ILVEN in a woman that had been present since infancy highlights the disease pathology as well as a potential new treatment modality. The patient was refractory to first-line treatments and was concerned about the cosmetic appearance of the lesions. The patient was subsequently treated with a trial of a 308-nm excimer laser with clinical improvement of the lesions. It is possible that the similarity of ILVEN and psoriasis may have contributed to the clinical improvement in our patient, but the mechanism of action remains unknown. Due to the paucity of evidence regarding optimal treatment of ILVEN, the current case offers dermatologists an option for patients who are refractory to other treatments.
 

Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare entity that presents with linear and pruritic psoriasiform plaques and most commonly occurs during childhood. It represents a dysregulation of keratinocytes exhibiting genetic mosaicism.^1,2 Epidermal nevi may derive from keratinocytic, follicular, sebaceous, apocrine, or eccrine origin. Inflammatory linear verrucous epidermal nevus is classified under the keratinocytic type of epidermal nevus and represents approximately 6% of all epidermal nevi.³ The condition presents as erythematous and verrucous plaques along the lines of Blaschko.^2,4 There is a predilection for the legs, and girls are 4 times more commonly affected than boys.¹ Cases of ILVEN are predominantly sporadic, though rare familial cases have been reported.⁴

Inflammatory linear verrucous epidermal nevus is notoriously refractory to treatment. First-line therapies include topical agents such as corticosteroids, calcipotriol, retinoids, and 5-fluorouracil.^3,4 Other treatments include intralesional corticosteroids, cryotherapy, electrodesiccation and curettage, and surgical excision.³ Several case reports have shown promising results using the pulsed dye and ablative CO2 lasers.^5-8

Case Report

An otherwise healthy 20-year-old woman presented with dry, pruritic, red lesions on the right leg that had been present and stable since she was an infant (2 weeks of age). Her medical history included acne vulgaris, but she denied any personal or family history of psoriasis as well as any arthralgia or arthritis. Physical examination revealed discrete, oval, hyperkeratotic, scaly, red plaques on the lateral right leg with a larger hyperkeratotic, linear, red plaque extending from the right popliteal fossa to the posterior thigh (Figure 1A). The nails, scalp, buttocks, and upper extremities were unaffected. Bacterial culture of the right leg demonstrated Staphylococcus aureus colonization. Biopsy of the right popliteal fossa showed psoriasiform dermatitis with psoriasiform hyperplasia, a slightly verruciform surface, broad zones of superficial pallor, and parakeratosis with conspicuous colonies of bacteria (Figure 2).

Following the positive bacterial culture, the patient was treated with a short course of oral doxycycline, which did not alter the clinical appearance of the lesions or improve symptoms of pruritus. Pruritus improved moderately with topical corticosteroid treatment, but clinically the lesions appeared unchanged. The plaque on the superior right leg was treated with a superpulsed CO₂ laser and the plaque on the inferior right leg was treated with a fractional CO₂ laser, both with minimal improvement.

Because of the clinical and histopathologic similarities of the patient's lesions to psoriasis, a trial of the UV 308-nm excimer laser was initiated. Following initial test spots, she completed a total of 18 treatments to all lesions with noticeable clinical improvement (Figure 1B). Initially, the patient returned for treatment biweekly for approximately 5 weeks with 2 small spots being targeted at each session, with an average surface area of approximately 16 cm². She was started at 225 mJ/cm² with 25% increases at each session and ultimately reached up to 1676 mJ/cm² at the end of the 10 sessions. She tolerated the procedure well with some minor blistering. Treatment was deferred for 3 months due to the patient's schedule, then biweekly treatments resumed for 4 weeks, totaling 8 more sessions. At that time, all lesions on the right leg were targeted, with an average surface area of approximately 100 cm². The laser settings were initiated at 225 mJ/cm² with 20% increases at each session and ultimately reached 560 mJ/cm². The treatment was well tolerated throughout; however, the patient initially reported residual pruritus. The plaques continued to improve, and most notably, there was thinning of the hyperkeratotic scale of the plaques in addition to decreased erythema and complete resolution of pruritus. Ultimately, treatment was discontinued because of lack of insurance coverage and financial burden. The patient was lost to follow-up.

Comment

Presentation
Inflammatory linear verrucous epidermal nevus is a rare type of keratinocytic epidermal nevus⁴ that clinically presents as small, discrete, pruritic, scaly plaques coalescing into a linear plaque along the lines of Blaschko.⁹ Considerable pruritus and resistance to treatment are hallmarks of the disease.¹⁰ Histopathologically, ILVEN is characterized by alternating orthokeratosis and parakeratosis with a lack of neutrophils in an acanthotic epidermis.^11-13 Inflammatory linear verrucous epidermal nevus presents at birth or in early childhood. Adult onset is rare.^9,14 Approximately 75% of lesions present by 5 years of age, with a majority occurring within the first 6 months of life.¹⁵ The differential diagnosis includes linear psoriasis, epidermal nevi, linear lichen planus, linear verrucae, linear lichen simplex chronicus, and mycosis fungoides.^4,11

Differentiation From Psoriasis
Despite the histopathologic overlap with psoriasis, ILVEN exhibits fewer Ki-67-positive keratinocyte nuclei (proliferative marker) and more cytokeratin 10-positive cells (epidermal differentiation marker) than psoriasis.¹⁶ Furthermore, ILVEN has demonstrated fewer CD4⁻, CD8⁻, CD45RO⁻, CD2⁻, CD25⁻, CD94⁻, and CD161⁺ cells within the dermis and epidermis than psoriasis.¹⁶

The clinical presentations of ILVEN and psoriasis may be similar, as some patients with linear psoriasis also present with psoriatic plaques along the lines of Blaschko.¹⁷ Additionally, ILVEN may be a precursor to psoriasis. Altman and Mehregan1 found that ILVEN patients who developed psoriasis did so in areas previously affected by ILVEN; however, they continued to distinguish the 2 pathologies as distinct entities. Another early report also hypothesized that the dermoepidermal defect caused by epidermal nevi provided a site for the development of psoriatic lesions because of the Koebner phenomenon.¹⁸

Patients with ILVEN also have been found to have extracutaneous manifestations and symptoms commonly seen in psoriasis patients. A 2012 retrospective review revealed that 37% (7/19) of patients with ILVEN also had psoriatic arthritis, cutaneous psoriatic lesions, and/or nail pitting. The authors concluded that ILVEN may lead to the onset of psoriasis later in life and may indicate an underlying psoriatic predisposition.¹⁹ Genetic theories also have been proposed, stating that ILVEN may be a mosaic of psoriasis2 or that a postzygotic mutation leads to the predisposition for developing psoriasis.²⁰

Treatment
Inflammatory linear verrucous epidermal nevus frequently is refractory to treatment; however, the associated pruritus and distressing cosmesis make treatment attempts worthwhile.¹¹ No single therapy has been found to be successful in all patients. A widely used first-line treatment is topical or intralesional corticosteroids, with the former typically used with occlusion.¹³ Other treatments include adalimumab, calcipotriol,^22,23 tretinoin,²⁴ and 5-fluorouracil.²⁴ Physical modalities such as cryotherapy, electrodesiccation, and dermabrasion have been reported with varying success.^15,24 Surgical treatments include tangential²⁵ and full-thickness excisions.²⁶

The CO₂ laser also has demonstrated success. One study showed considerable improvement of pruritus and partial resolution of lesions only 5 weeks following a single CO₂ laser treatment.⁵ Another study showed promising results when combining CO₂ pulsed laser therapy with fractional CO₂ laser treatment.⁶ Other laser therapies including the argon²⁷ and flashlamp-pumped pulsed dye lasers⁸ have been used with limited success. The use of light therapy and lasers in psoriasis have now increased the treatment options for ILVEN based on the rationale of their shared histopathologic characteristics. Photodynamic therapy also has been attempted because of its successful use in psoriasis patients. It has been found to be successful in diminishing ILVEN lesions and associated pruritus after a few weeks of therapy; however, treatment is limited by the associated pain and requirement for local anesthesia.²⁸

The excimer laser is a form of targeted phototherapy that emits monochromatic light at 308 nm.²⁹ It is ideal for inflammatory skin lesions because the UVB light induces apoptosis.³⁰ Psoriasis lesions treated with the excimer laser show a decrease in keratinocyte proliferation, which in turn reverses epidermal acanthosis and causes T-cell depletion due to upregulation of p53.^29,31 This mechanism of action addresses the overproliferation of keratinocytes mediated by T cells in psoriasis and contributes to the success of excimer laser treatment.³¹ A considerable advantage is its localized treatment, resulting in lower cumulative doses of UVB and reducing the possible carcinogenic and phototoxic risks of whole-body phototherapy.³²

One study examined the antipruritic effects of the excimer laser following the treatment of epidermal hyperinnervation leading to intractable pruritus in patients with atopic dermatitis. The researchers suggested that a potential explanation for the antipruritic effect of the excimer laser may be secondary to nerve degeneration.³³ Additionally, low doses of UVB light also may inhibit mast cell degranulation and prevent histamine release, further supporting the antipruritic properties of excimer laser.³⁴

In our patient, failed treatment with other modalities led to trial of excimer laser therapy because of the overlapping clinical and histopathologic findings with psoriasis. Excimer laser improved the clinical appearance and overall texture of the ILVEN lesions and decreased pruritus. The reasons for treatment success may be two-fold. By decreasing the number of keratinocytes and mast cells, the excimer laser may have improved the epidermal hyperplasia and pruritus in the ILVEN lesions. Alternatively, because the patient had ILVEN lesions since infancy, psoriasis may have developed in the location of the ILVEN lesions due to koebnerization, resulting in the clinical response to excimer therapy; however, she had no other clinical evidence of psoriasis.

Because of the recalcitrance of ILVEN lesions to conventional therapies, it is important to investigate therapies that may be of possible benefit. Our novel case documents successful use of the excimer laser in the treatment of ILVEN. 

Conclusion

Our case of ILVEN in a woman that had been present since infancy highlights the disease pathology as well as a potential new treatment modality. The patient was refractory to first-line treatments and was concerned about the cosmetic appearance of the lesions. The patient was subsequently treated with a trial of a 308-nm excimer laser with clinical improvement of the lesions. It is possible that the similarity of ILVEN and psoriasis may have contributed to the clinical improvement in our patient, but the mechanism of action remains unknown. Due to the paucity of evidence regarding optimal treatment of ILVEN, the current case offers dermatologists an option for patients who are refractory to other treatments.
 

MALMO, SWEDEN – Methicillin-resistant Staphylococcus aureus gets the blame in the Americas as the main cause of a great wave of community-acquired severe invasive staphylococcal infections in children and adolescents during the past nearly 2 decades, but many European pediatric infectious disease specialists believe that Panton-Valentine leukocidin (PVL), a frequent co-traveler with MRSA, is the true bad actor.

Bruce Jancin/MDedge News

“The American literature focused first on MRSA, but we’ve seen very similar, very severe cases with MSSA [methicillin-susceptible S. aureus] PVL-positive and MRSA PVL-positive infections,” Pablo Rojo, MD, PhD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.

“It is only because at the beginning there were so many MRSA cases in the States that they thought that was the driver of the disease. It is still unclear. There is still a discussion. But I wanted to bring you my opinion and that of many other authors that it’s mostly PVL-associated,” added Dr. Rojo of Complutense University in Madrid.

He was senior author of a multinational European and Israeli prospective study of risk factors associated with the severity of invasive community-acquired S. aureus infections in children, with invasive infection being defined as hospitalization for an infection with S. aureus isolated from a normally sterile body site such as blood, bone, or cerebrospinal fluid, or S. aureus pneumonia. They identified 152 affected children, 17% of whom had severe community-acquired invasive S. aureus, defined by death or admission to a pediatric intensive care unit due to respiratory failure or hemodynamic instability.

CDC/Janice Haney Carr

The prevalence of PVL-positive S. aureus infection in the overall invasive infection group was 19%, while 8% of the isolates were MRSA. In a multivariate analysis, PVL positivity was independently associated with a fivefold increased risk of severe S. aureus infection, while MRSA was not associated with a significantly increased risk. The other independent risk factors for severe outcome were pneumonia, with an adjusted 13-fold increased risk, and leukopenia at admission, with an associated 18-fold risk (Clin Microbiol Infect. 2016 Jul;22[7]:643.e1-6.).

Of note, the virulence of PVL stems from the pore-forming toxin’s ability to lyse white blood cells. Because a leukocyte count is always available once a patient reaches the ED, severe leukopenia as defined by a count of less than 3,000 cells/mm³ at admission becomes a useful early marker of the likely severity of any case of S. aureus invasive disease, according to Dr. Rojo.

He highlighted four key syndromes involving severe invasive S. aureus infection in previously healthy children and adolescents that entail a high likelihood of being PVL positive and should cause physicians to run – not walk – to start appropriate empiric therapy. He also described the treatment regimen that he and other European thought leaders recommend for severe PVL-positive S. aureus invasive infections.

The microbiologic diagnosis of PVL can be made by ELISA (enzyme-linked immunoassay) to detect the toxin in an S. aureus isolate, by a rapid monoclonal antibody test, or by polymerase chain reaction to detect PVL genes in an S. aureus isolate. But don’t wait for test results to initiate treatment because these are high-mortality syndromes, he advised.

“Many people tell me, ‘My lab doesn’t have a way to diagnose PVL.’ And it’s true, it’s not available in real life at many hospitals. My message to you is that you don’t need to wait for a microbiological diagnosis or the results to come back from a sample you have sent to the reference lab in the main referral center. We can base our diagnosis and decision to treat on clinical grounds if we focus on these four very uncommon syndromes involving invasive S. aureus infection. I think if you have any child with these symptoms you have to manage them on the assumption that PVL is present,” said Dr. Rojo, principal investigator of the European Project on Invasive S. aureus Pediatric Infections.

The four key syndromes

The four syndromes are severe S. aureus pneumonia, S. aureus bone and joint infections with multiple foci, S. aureus osteomyelitis complicated by deep vein thrombosis, and invasive S. aureus infection plus shock.

• Severe S. aureus pneumonia. Investigators at Claude Bernard University in Lyon, France, have done extensive pioneering work on severe PVL-positive S. aureus invasive infections in children. In an early paper, they highlighted the characteristics that distinguish severe PVL-positive pneumonia: it typically occurs in previously healthy children and adolescents without underlying comorbid conditions, and it is often preceded by a influenza-like syndrome followed by an acute severe pneumonia with hemoptysis. Mortality was very high in this early series, with nearly half of the patients being dead within the first several days after admission (Lancet. 2002 Mar 2;359[9308]:753-9).
• Severe osteomyelitis. Investigators at Baylor College of Medicine, Houston, were among the first to observe that osteomyelitis caused by PVL-positive strains of S. aureus are associated with more severe local disease, with multiple affected areas, bigger abscesses, a greater systemic inflammatory response, and more surgeries required compared with osteomyelitis caused by PVL-negative S. aureus (Pediatrics. 2006 Feb;117[2]:433-40).
• Osteomyelitis with deep vein thrombosis. When a child hospitalized for acute hematogenous osteomyelitis due to S. aureus develops difficulty breathing, that’s a red flag for a severe PVL-positive infection involving deep vein thrombosis. Indeed, investigators at the Leeds (England) General Infirmary have reported that deep vein thrombosis in the setting of S. aureus osteomyelitis is associated with a greater than eightfold increased likelihood of a PVL-positive infection (Br J Hosp Med [Lond]. 2015 Jan;76[1]:18-24). Also, patients with PVL-positive osteomyelitis and deep vein thrombosis are prone to formation of septic emboli.
• Osteomyelitis with septic shock. The Lyon group compared outcomes in 14 pediatric patients with PVL-positive S. aureus osteomyelitis and a control group of 17 patients with PVL-negative disease. All 14 PVL-positive patients had severe sepsis and 6 of them had septic shock. In contrast, none of the controls did. Median duration of hospitalization was 46 days in the PVL-positive group, compared with 13 days in controls (Pediatr Infect Dis J. 2007 Nov;26[11]:1042-8).

Treatment

No randomized trials exist to guide treatment, but Dr. Rojo recommends the protocol utilized by the Lyon group: a bactericidal antibiotic – vancomycin or a beta-lactam – to take on the S. aureus, coupled with a ribosomally active antibiotic – clindamycin or linezolid – to suppress the PVL toxin’s virulence expression. The French group cites both in vitro and in vivo evidence that clindamycin and linezolid in their standard dosing have such an antitoxin effect (Clin Microbiol Rev. 2017 Oct;30[4]:887-917).

In addition, Dr. Rojo recommends utilizing any of the commercially available intravenous immunoglobulin (IVIG) products on the basis of work by investigators at Vanderbilt University in Nashville, Tenn., who have demonstrated that these products contain functional neutralizing antibodies against S. aureus leukocidins. This observation provides a likely explanation for anecdotal reports of improved outcomes in IVIG-treated patients with toxin-associated staphylococcal disease (Antimicrob Agents Chemother. 2017 Oct 24;61[11]. pii: e00968-17).

Challenged as to when specifically he would use IVIG in light of the global shortage of immunoglobulins, Dr. Rojo replied: “Not in every invasive S. aureus infection, but in serious infections that are PVL positive. I think if you have a child with one of these four syndromes who is in a pediatric ICU, you should use it. I mean, the mortality is around 30% in healthy children, so you would not stop from giving it. The risk of giving IVIG is very low, no side effects, so I highly recommend it for these severe cases.”

He reported having no financial conflicts.

[email protected]

MALMO, SWEDEN – Methicillin-resistant Staphylococcus aureus gets the blame in the Americas as the main cause of a great wave of community-acquired severe invasive staphylococcal infections in children and adolescents during the past nearly 2 decades, but many European pediatric infectious disease specialists believe that Panton-Valentine leukocidin (PVL), a frequent co-traveler with MRSA, is the true bad actor.

Bruce Jancin/MDedge News

“The American literature focused first on MRSA, but we’ve seen very similar, very severe cases with MSSA [methicillin-susceptible S. aureus] PVL-positive and MRSA PVL-positive infections,” Pablo Rojo, MD, PhD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.

“It is only because at the beginning there were so many MRSA cases in the States that they thought that was the driver of the disease. It is still unclear. There is still a discussion. But I wanted to bring you my opinion and that of many other authors that it’s mostly PVL-associated,” added Dr. Rojo of Complutense University in Madrid.

He was senior author of a multinational European and Israeli prospective study of risk factors associated with the severity of invasive community-acquired S. aureus infections in children, with invasive infection being defined as hospitalization for an infection with S. aureus isolated from a normally sterile body site such as blood, bone, or cerebrospinal fluid, or S. aureus pneumonia. They identified 152 affected children, 17% of whom had severe community-acquired invasive S. aureus, defined by death or admission to a pediatric intensive care unit due to respiratory failure or hemodynamic instability.

CDC/Janice Haney Carr

The prevalence of PVL-positive S. aureus infection in the overall invasive infection group was 19%, while 8% of the isolates were MRSA. In a multivariate analysis, PVL positivity was independently associated with a fivefold increased risk of severe S. aureus infection, while MRSA was not associated with a significantly increased risk. The other independent risk factors for severe outcome were pneumonia, with an adjusted 13-fold increased risk, and leukopenia at admission, with an associated 18-fold risk (Clin Microbiol Infect. 2016 Jul;22[7]:643.e1-6.).

Of note, the virulence of PVL stems from the pore-forming toxin’s ability to lyse white blood cells. Because a leukocyte count is always available once a patient reaches the ED, severe leukopenia as defined by a count of less than 3,000 cells/mm³ at admission becomes a useful early marker of the likely severity of any case of S. aureus invasive disease, according to Dr. Rojo.

He highlighted four key syndromes involving severe invasive S. aureus infection in previously healthy children and adolescents that entail a high likelihood of being PVL positive and should cause physicians to run – not walk – to start appropriate empiric therapy. He also described the treatment regimen that he and other European thought leaders recommend for severe PVL-positive S. aureus invasive infections.

The microbiologic diagnosis of PVL can be made by ELISA (enzyme-linked immunoassay) to detect the toxin in an S. aureus isolate, by a rapid monoclonal antibody test, or by polymerase chain reaction to detect PVL genes in an S. aureus isolate. But don’t wait for test results to initiate treatment because these are high-mortality syndromes, he advised.

“Many people tell me, ‘My lab doesn’t have a way to diagnose PVL.’ And it’s true, it’s not available in real life at many hospitals. My message to you is that you don’t need to wait for a microbiological diagnosis or the results to come back from a sample you have sent to the reference lab in the main referral center. We can base our diagnosis and decision to treat on clinical grounds if we focus on these four very uncommon syndromes involving invasive S. aureus infection. I think if you have any child with these symptoms you have to manage them on the assumption that PVL is present,” said Dr. Rojo, principal investigator of the European Project on Invasive S. aureus Pediatric Infections.

The four key syndromes

The four syndromes are severe S. aureus pneumonia, S. aureus bone and joint infections with multiple foci, S. aureus osteomyelitis complicated by deep vein thrombosis, and invasive S. aureus infection plus shock.

• Severe S. aureus pneumonia. Investigators at Claude Bernard University in Lyon, France, have done extensive pioneering work on severe PVL-positive S. aureus invasive infections in children. In an early paper, they highlighted the characteristics that distinguish severe PVL-positive pneumonia: it typically occurs in previously healthy children and adolescents without underlying comorbid conditions, and it is often preceded by a influenza-like syndrome followed by an acute severe pneumonia with hemoptysis. Mortality was very high in this early series, with nearly half of the patients being dead within the first several days after admission (Lancet. 2002 Mar 2;359[9308]:753-9).
• Severe osteomyelitis. Investigators at Baylor College of Medicine, Houston, were among the first to observe that osteomyelitis caused by PVL-positive strains of S. aureus are associated with more severe local disease, with multiple affected areas, bigger abscesses, a greater systemic inflammatory response, and more surgeries required compared with osteomyelitis caused by PVL-negative S. aureus (Pediatrics. 2006 Feb;117[2]:433-40).
• Osteomyelitis with deep vein thrombosis. When a child hospitalized for acute hematogenous osteomyelitis due to S. aureus develops difficulty breathing, that’s a red flag for a severe PVL-positive infection involving deep vein thrombosis. Indeed, investigators at the Leeds (England) General Infirmary have reported that deep vein thrombosis in the setting of S. aureus osteomyelitis is associated with a greater than eightfold increased likelihood of a PVL-positive infection (Br J Hosp Med [Lond]. 2015 Jan;76[1]:18-24). Also, patients with PVL-positive osteomyelitis and deep vein thrombosis are prone to formation of septic emboli.
• Osteomyelitis with septic shock. The Lyon group compared outcomes in 14 pediatric patients with PVL-positive S. aureus osteomyelitis and a control group of 17 patients with PVL-negative disease. All 14 PVL-positive patients had severe sepsis and 6 of them had septic shock. In contrast, none of the controls did. Median duration of hospitalization was 46 days in the PVL-positive group, compared with 13 days in controls (Pediatr Infect Dis J. 2007 Nov;26[11]:1042-8).

Treatment

No randomized trials exist to guide treatment, but Dr. Rojo recommends the protocol utilized by the Lyon group: a bactericidal antibiotic – vancomycin or a beta-lactam – to take on the S. aureus, coupled with a ribosomally active antibiotic – clindamycin or linezolid – to suppress the PVL toxin’s virulence expression. The French group cites both in vitro and in vivo evidence that clindamycin and linezolid in their standard dosing have such an antitoxin effect (Clin Microbiol Rev. 2017 Oct;30[4]:887-917).

In addition, Dr. Rojo recommends utilizing any of the commercially available intravenous immunoglobulin (IVIG) products on the basis of work by investigators at Vanderbilt University in Nashville, Tenn., who have demonstrated that these products contain functional neutralizing antibodies against S. aureus leukocidins. This observation provides a likely explanation for anecdotal reports of improved outcomes in IVIG-treated patients with toxin-associated staphylococcal disease (Antimicrob Agents Chemother. 2017 Oct 24;61[11]. pii: e00968-17).

Challenged as to when specifically he would use IVIG in light of the global shortage of immunoglobulins, Dr. Rojo replied: “Not in every invasive S. aureus infection, but in serious infections that are PVL positive. I think if you have a child with one of these four syndromes who is in a pediatric ICU, you should use it. I mean, the mortality is around 30% in healthy children, so you would not stop from giving it. The risk of giving IVIG is very low, no side effects, so I highly recommend it for these severe cases.”

He reported having no financial conflicts.

[email protected]

MALMO, SWEDEN – Methicillin-resistant Staphylococcus aureus gets the blame in the Americas as the main cause of a great wave of community-acquired severe invasive staphylococcal infections in children and adolescents during the past nearly 2 decades, but many European pediatric infectious disease specialists believe that Panton-Valentine leukocidin (PVL), a frequent co-traveler with MRSA, is the true bad actor.

Bruce Jancin/MDedge News

“The American literature focused first on MRSA, but we’ve seen very similar, very severe cases with MSSA [methicillin-susceptible S. aureus] PVL-positive and MRSA PVL-positive infections,” Pablo Rojo, MD, PhD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.

“It is only because at the beginning there were so many MRSA cases in the States that they thought that was the driver of the disease. It is still unclear. There is still a discussion. But I wanted to bring you my opinion and that of many other authors that it’s mostly PVL-associated,” added Dr. Rojo of Complutense University in Madrid.

He was senior author of a multinational European and Israeli prospective study of risk factors associated with the severity of invasive community-acquired S. aureus infections in children, with invasive infection being defined as hospitalization for an infection with S. aureus isolated from a normally sterile body site such as blood, bone, or cerebrospinal fluid, or S. aureus pneumonia. They identified 152 affected children, 17% of whom had severe community-acquired invasive S. aureus, defined by death or admission to a pediatric intensive care unit due to respiratory failure or hemodynamic instability.

CDC/Janice Haney Carr

The prevalence of PVL-positive S. aureus infection in the overall invasive infection group was 19%, while 8% of the isolates were MRSA. In a multivariate analysis, PVL positivity was independently associated with a fivefold increased risk of severe S. aureus infection, while MRSA was not associated with a significantly increased risk. The other independent risk factors for severe outcome were pneumonia, with an adjusted 13-fold increased risk, and leukopenia at admission, with an associated 18-fold risk (Clin Microbiol Infect. 2016 Jul;22[7]:643.e1-6.).

Of note, the virulence of PVL stems from the pore-forming toxin’s ability to lyse white blood cells. Because a leukocyte count is always available once a patient reaches the ED, severe leukopenia as defined by a count of less than 3,000 cells/mm³ at admission becomes a useful early marker of the likely severity of any case of S. aureus invasive disease, according to Dr. Rojo.

He highlighted four key syndromes involving severe invasive S. aureus infection in previously healthy children and adolescents that entail a high likelihood of being PVL positive and should cause physicians to run – not walk – to start appropriate empiric therapy. He also described the treatment regimen that he and other European thought leaders recommend for severe PVL-positive S. aureus invasive infections.

The microbiologic diagnosis of PVL can be made by ELISA (enzyme-linked immunoassay) to detect the toxin in an S. aureus isolate, by a rapid monoclonal antibody test, or by polymerase chain reaction to detect PVL genes in an S. aureus isolate. But don’t wait for test results to initiate treatment because these are high-mortality syndromes, he advised.

“Many people tell me, ‘My lab doesn’t have a way to diagnose PVL.’ And it’s true, it’s not available in real life at many hospitals. My message to you is that you don’t need to wait for a microbiological diagnosis or the results to come back from a sample you have sent to the reference lab in the main referral center. We can base our diagnosis and decision to treat on clinical grounds if we focus on these four very uncommon syndromes involving invasive S. aureus infection. I think if you have any child with these symptoms you have to manage them on the assumption that PVL is present,” said Dr. Rojo, principal investigator of the European Project on Invasive S. aureus Pediatric Infections.

The four key syndromes

The four syndromes are severe S. aureus pneumonia, S. aureus bone and joint infections with multiple foci, S. aureus osteomyelitis complicated by deep vein thrombosis, and invasive S. aureus infection plus shock.

• Severe S. aureus pneumonia. Investigators at Claude Bernard University in Lyon, France, have done extensive pioneering work on severe PVL-positive S. aureus invasive infections in children. In an early paper, they highlighted the characteristics that distinguish severe PVL-positive pneumonia: it typically occurs in previously healthy children and adolescents without underlying comorbid conditions, and it is often preceded by a influenza-like syndrome followed by an acute severe pneumonia with hemoptysis. Mortality was very high in this early series, with nearly half of the patients being dead within the first several days after admission (Lancet. 2002 Mar 2;359[9308]:753-9).
• Severe osteomyelitis. Investigators at Baylor College of Medicine, Houston, were among the first to observe that osteomyelitis caused by PVL-positive strains of S. aureus are associated with more severe local disease, with multiple affected areas, bigger abscesses, a greater systemic inflammatory response, and more surgeries required compared with osteomyelitis caused by PVL-negative S. aureus (Pediatrics. 2006 Feb;117[2]:433-40).
• Osteomyelitis with deep vein thrombosis. When a child hospitalized for acute hematogenous osteomyelitis due to S. aureus develops difficulty breathing, that’s a red flag for a severe PVL-positive infection involving deep vein thrombosis. Indeed, investigators at the Leeds (England) General Infirmary have reported that deep vein thrombosis in the setting of S. aureus osteomyelitis is associated with a greater than eightfold increased likelihood of a PVL-positive infection (Br J Hosp Med [Lond]. 2015 Jan;76[1]:18-24). Also, patients with PVL-positive osteomyelitis and deep vein thrombosis are prone to formation of septic emboli.
• Osteomyelitis with septic shock. The Lyon group compared outcomes in 14 pediatric patients with PVL-positive S. aureus osteomyelitis and a control group of 17 patients with PVL-negative disease. All 14 PVL-positive patients had severe sepsis and 6 of them had septic shock. In contrast, none of the controls did. Median duration of hospitalization was 46 days in the PVL-positive group, compared with 13 days in controls (Pediatr Infect Dis J. 2007 Nov;26[11]:1042-8).

Treatment

No randomized trials exist to guide treatment, but Dr. Rojo recommends the protocol utilized by the Lyon group: a bactericidal antibiotic – vancomycin or a beta-lactam – to take on the S. aureus, coupled with a ribosomally active antibiotic – clindamycin or linezolid – to suppress the PVL toxin’s virulence expression. The French group cites both in vitro and in vivo evidence that clindamycin and linezolid in their standard dosing have such an antitoxin effect (Clin Microbiol Rev. 2017 Oct;30[4]:887-917).

In addition, Dr. Rojo recommends utilizing any of the commercially available intravenous immunoglobulin (IVIG) products on the basis of work by investigators at Vanderbilt University in Nashville, Tenn., who have demonstrated that these products contain functional neutralizing antibodies against S. aureus leukocidins. This observation provides a likely explanation for anecdotal reports of improved outcomes in IVIG-treated patients with toxin-associated staphylococcal disease (Antimicrob Agents Chemother. 2017 Oct 24;61[11]. pii: e00968-17).

Challenged as to when specifically he would use IVIG in light of the global shortage of immunoglobulins, Dr. Rojo replied: “Not in every invasive S. aureus infection, but in serious infections that are PVL positive. I think if you have a child with one of these four syndromes who is in a pediatric ICU, you should use it. I mean, the mortality is around 30% in healthy children, so you would not stop from giving it. The risk of giving IVIG is very low, no side effects, so I highly recommend it for these severe cases.”

He reported having no financial conflicts.

[email protected]

The FP recognized that the lesions on the back of the hands were due to sun damage and included actinic keratosis. However, he was concerned that some of the thicker lesions could be squamous cell carcinoma or SCC in situ.

He discussed options with the patient, which included biopsy of the thickest lesions, cryotherapy, and/or field treatment with a topical agent. The decision was made to biopsy the 2 thickest and whitest lesions and do cryotherapy on some of the other lesions. Shave biopsies were performed and the patient was encouraged to wear sunscreen and minimize his sun exposure. (See the Watch & Learn video on “Shave biopsy.”) On the follow-up visit 2 weeks later, the FP noted that the biopsies and frozen areas were healing. Both biopsies were hypertrophic actinic keratoses only.

The FP then prescribed 5-fluorouracil to be used for 3 to 4 weeks on the remaining lesions on the backs of his hands and forearms. The patient was directed to treat the right arm first to allow more time for the left hand to heal. He was told to stop the 5-fluorouracil if the area became too painful. The patient was also told to treat his left arm the same way after allowing the right arm to heal. Any areas of skin ulceration could be treated with plain petrolatum, but no topical steroids are needed.

Six months later, the patient’s arms and hands looked much better.  The patient required regular follow-up.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Wah Y. Actinic keratosis and Bowen disease. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:969-976.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

The FP recognized that the lesions on the back of the hands were due to sun damage and included actinic keratosis. However, he was concerned that some of the thicker lesions could be squamous cell carcinoma or SCC in situ.

He discussed options with the patient, which included biopsy of the thickest lesions, cryotherapy, and/or field treatment with a topical agent. The decision was made to biopsy the 2 thickest and whitest lesions and do cryotherapy on some of the other lesions. Shave biopsies were performed and the patient was encouraged to wear sunscreen and minimize his sun exposure. (See the Watch & Learn video on “Shave biopsy.”) On the follow-up visit 2 weeks later, the FP noted that the biopsies and frozen areas were healing. Both biopsies were hypertrophic actinic keratoses only.

The FP then prescribed 5-fluorouracil to be used for 3 to 4 weeks on the remaining lesions on the backs of his hands and forearms. The patient was directed to treat the right arm first to allow more time for the left hand to heal. He was told to stop the 5-fluorouracil if the area became too painful. The patient was also told to treat his left arm the same way after allowing the right arm to heal. Any areas of skin ulceration could be treated with plain petrolatum, but no topical steroids are needed.

Six months later, the patient’s arms and hands looked much better.  The patient required regular follow-up.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Wah Y. Actinic keratosis and Bowen disease. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:969-976.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

The FP recognized that the lesions on the back of the hands were due to sun damage and included actinic keratosis. However, he was concerned that some of the thicker lesions could be squamous cell carcinoma or SCC in situ.

He discussed options with the patient, which included biopsy of the thickest lesions, cryotherapy, and/or field treatment with a topical agent. The decision was made to biopsy the 2 thickest and whitest lesions and do cryotherapy on some of the other lesions. Shave biopsies were performed and the patient was encouraged to wear sunscreen and minimize his sun exposure. (See the Watch & Learn video on “Shave biopsy.”) On the follow-up visit 2 weeks later, the FP noted that the biopsies and frozen areas were healing. Both biopsies were hypertrophic actinic keratoses only.

The FP then prescribed 5-fluorouracil to be used for 3 to 4 weeks on the remaining lesions on the backs of his hands and forearms. The patient was directed to treat the right arm first to allow more time for the left hand to heal. He was told to stop the 5-fluorouracil if the area became too painful. The patient was also told to treat his left arm the same way after allowing the right arm to heal. Any areas of skin ulceration could be treated with plain petrolatum, but no topical steroids are needed.

Six months later, the patient’s arms and hands looked much better.  The patient required regular follow-up.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Wah Y. Actinic keratosis and Bowen disease. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:969-976.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

SAN FRANCISCO—Lasmiditan may provide pain freedom in the acute treatment of migraine, according to data described at the 60th Annual Scientific Meeting of the American Headache Society. The treatment also may alleviate a patient’s most bothersome symptom (MBS).

Lasmiditan is a novel, centrally acting serotonin (5-HT_1F) agonist that has no vasoconstrictive effect. Linda A. Wietecha, BSN, MS, Medical Advisor for Migraine and Headache Disorders at Eli Lilly and Company in Indianapolis, and colleagues conducted two pivotal phase III studies of lasmiditan to evaluate its efficacy and safety as an acute treatment of migraine.

The two trials, SAMURAI and SPARTAN, were randomized, double-blinded, and placebo-controlled. Eligible participants had a Migraine Disability Assessment Score of 11 or higher (indicating moderate disability) and three to eight migraine attacks per month. The researchers randomized patients to a first dose of treatment, which was taken within four hours of onset of a migraine with moderate or worse severity that was not improving. In the SAMURAI trial, patients were randomized in equal groups to 200 mg of lasmiditan, 100 mg of lasmiditan, or placebo. In the SPARTAN study, patients were randomized in equal groups to 200 mg of lasmiditan, 100 mg of lasmiditan, 50 mg of lasmiditan, or placebo.

For rescue or recurrence treatment, patients took a randomly assigned second dose of the previously assigned lasmiditan dose or placebo. The primary and key secondary analyses compared the proportions of patients in the lasmiditan 200-mg group with that in the placebo group who were free of headache pain and free of their MBS at two hours after the first dose. Treatment-emergent adverse events (TEAEs) were used to assess safety. The investigators performed logistic regression to make comparisons.

At two hours after the first dose, significantly greater proportions of patients taking 200 mg of lasmiditan were free of headache pain and free of MBS, compared with controls. In SAMURAI, the rate of headache pain freedom was 32.2% in the 200-mg group and 15.3% among controls. In SPARTAN, the rate of headache pain freedom was 38.8% in the 200-mg group and 21.3% in controls. The rate of patients free of MBS in SAMURAI was 40.7% in the 200-mg group and 29.5% in controls. The rate of patients free of MBS in SPARTAN was 48.7% in the 200-mg group and 33.5% in controls. For both end points, the investigators also found significant differences for other lasmiditan dose groups, compared with placebo.

The most frequently reported TEAEs with lasmiditan (ie, those occurring with a frequency of 2% or greater and at a rate greater than that among controls) after the first dose were dizziness, paresthesia, somnolence, fatigue, nausea, and lethargy. Most events were mild to moderate in severity.

Suggested Reading

Färkkilä M, Diener HC, Géraud G, et al. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol. 2012;11(5):405-413.

SAN FRANCISCO—Lasmiditan may provide pain freedom in the acute treatment of migraine, according to data described at the 60th Annual Scientific Meeting of the American Headache Society. The treatment also may alleviate a patient’s most bothersome symptom (MBS).

Lasmiditan is a novel, centrally acting serotonin (5-HT_1F) agonist that has no vasoconstrictive effect. Linda A. Wietecha, BSN, MS, Medical Advisor for Migraine and Headache Disorders at Eli Lilly and Company in Indianapolis, and colleagues conducted two pivotal phase III studies of lasmiditan to evaluate its efficacy and safety as an acute treatment of migraine.

The two trials, SAMURAI and SPARTAN, were randomized, double-blinded, and placebo-controlled. Eligible participants had a Migraine Disability Assessment Score of 11 or higher (indicating moderate disability) and three to eight migraine attacks per month. The researchers randomized patients to a first dose of treatment, which was taken within four hours of onset of a migraine with moderate or worse severity that was not improving. In the SAMURAI trial, patients were randomized in equal groups to 200 mg of lasmiditan, 100 mg of lasmiditan, or placebo. In the SPARTAN study, patients were randomized in equal groups to 200 mg of lasmiditan, 100 mg of lasmiditan, 50 mg of lasmiditan, or placebo.

For rescue or recurrence treatment, patients took a randomly assigned second dose of the previously assigned lasmiditan dose or placebo. The primary and key secondary analyses compared the proportions of patients in the lasmiditan 200-mg group with that in the placebo group who were free of headache pain and free of their MBS at two hours after the first dose. Treatment-emergent adverse events (TEAEs) were used to assess safety. The investigators performed logistic regression to make comparisons.

At two hours after the first dose, significantly greater proportions of patients taking 200 mg of lasmiditan were free of headache pain and free of MBS, compared with controls. In SAMURAI, the rate of headache pain freedom was 32.2% in the 200-mg group and 15.3% among controls. In SPARTAN, the rate of headache pain freedom was 38.8% in the 200-mg group and 21.3% in controls. The rate of patients free of MBS in SAMURAI was 40.7% in the 200-mg group and 29.5% in controls. The rate of patients free of MBS in SPARTAN was 48.7% in the 200-mg group and 33.5% in controls. For both end points, the investigators also found significant differences for other lasmiditan dose groups, compared with placebo.

The most frequently reported TEAEs with lasmiditan (ie, those occurring with a frequency of 2% or greater and at a rate greater than that among controls) after the first dose were dizziness, paresthesia, somnolence, fatigue, nausea, and lethargy. Most events were mild to moderate in severity.

Suggested Reading

Färkkilä M, Diener HC, Géraud G, et al. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol. 2012;11(5):405-413.

SAN FRANCISCO—Lasmiditan may provide pain freedom in the acute treatment of migraine, according to data described at the 60th Annual Scientific Meeting of the American Headache Society. The treatment also may alleviate a patient’s most bothersome symptom (MBS).

Lasmiditan is a novel, centrally acting serotonin (5-HT_1F) agonist that has no vasoconstrictive effect. Linda A. Wietecha, BSN, MS, Medical Advisor for Migraine and Headache Disorders at Eli Lilly and Company in Indianapolis, and colleagues conducted two pivotal phase III studies of lasmiditan to evaluate its efficacy and safety as an acute treatment of migraine.

The two trials, SAMURAI and SPARTAN, were randomized, double-blinded, and placebo-controlled. Eligible participants had a Migraine Disability Assessment Score of 11 or higher (indicating moderate disability) and three to eight migraine attacks per month. The researchers randomized patients to a first dose of treatment, which was taken within four hours of onset of a migraine with moderate or worse severity that was not improving. In the SAMURAI trial, patients were randomized in equal groups to 200 mg of lasmiditan, 100 mg of lasmiditan, or placebo. In the SPARTAN study, patients were randomized in equal groups to 200 mg of lasmiditan, 100 mg of lasmiditan, 50 mg of lasmiditan, or placebo.

For rescue or recurrence treatment, patients took a randomly assigned second dose of the previously assigned lasmiditan dose or placebo. The primary and key secondary analyses compared the proportions of patients in the lasmiditan 200-mg group with that in the placebo group who were free of headache pain and free of their MBS at two hours after the first dose. Treatment-emergent adverse events (TEAEs) were used to assess safety. The investigators performed logistic regression to make comparisons.

At two hours after the first dose, significantly greater proportions of patients taking 200 mg of lasmiditan were free of headache pain and free of MBS, compared with controls. In SAMURAI, the rate of headache pain freedom was 32.2% in the 200-mg group and 15.3% among controls. In SPARTAN, the rate of headache pain freedom was 38.8% in the 200-mg group and 21.3% in controls. The rate of patients free of MBS in SAMURAI was 40.7% in the 200-mg group and 29.5% in controls. The rate of patients free of MBS in SPARTAN was 48.7% in the 200-mg group and 33.5% in controls. For both end points, the investigators also found significant differences for other lasmiditan dose groups, compared with placebo.

The most frequently reported TEAEs with lasmiditan (ie, those occurring with a frequency of 2% or greater and at a rate greater than that among controls) after the first dose were dizziness, paresthesia, somnolence, fatigue, nausea, and lethargy. Most events were mild to moderate in severity.

Suggested Reading

Färkkilä M, Diener HC, Géraud G, et al. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol. 2012;11(5):405-413.

To the Editor:

I read with interest the informative article by Sheu¹ published online in Cutis in February 2018, which succinctly described the pharmacologic characteristics of tranexamic acid, a synthetic lysine derivative, and its mechanism of action in the management of melasma by mitigating UV radiation-induced melanogenesis and neovascularization by inhibiting plasminogen activation. Additionally, the author summarized a study in which oral tranexamic acid was used to successfully treat melasma patients. After 4 months of treatment, 90% of 561 patients treated at a single center in Singapore demonstrated improvement in melasma severity.² Sheu¹ also discussed daily oral doses of tranexamic acid (500-1500 mg) that demonstrated improvement in melasma patients and reviewed potential adverse events (eg, abdominal pain and bloating, deep venous thrombosis, pulmonary embolism) for which patients should be screened and counseled prior to initiating treatment.

Recently, another study showed oral tranexamic acid to be an effective treatment in women with moderate to severe melasma. An important observation by the investigators was that once the initial phase of their study--250 mg of oral tranexamic acid twice daily and sunscreen applied to the face each morning and every 2 hours during daylight hours for 3 months--concluded and a second phase during which all participants only applied sunscreen for an additional 3 months, those with severe melasma lost most of their improvement.³ An adjuvant topical treatment, such as tranexamic acid or an inhibitor of tyrosinase (hydroquinone), might improve the results; however, initiating therapy with a topical agent whose mode of action is directed toward other melasma etiologic factors, such as the increased expression of estrogen receptors and vascular endothelial growth factor in affected skin, might be more beneficial.^4,5

I recently proposed a novel approach for melasma management that would be appropriate as an adjuvant topical therapy for patients concurrently being treated with oral tranexamic acid.⁶ The therapeutic intervention utilizes active agents that specifically affect etiologic factors in the pathogenesis of melasma--estrogen and angiogenesis--that previously have not been targeted topically. Indeed, the topical agent contains an antiestrogen--either a selective estrogen receptor modulator (eg, tamoxifen, raloxifene), aromatase inhibitor (eg, anastrozole, letrozole, exemestane), or a selective estrogen receptor degrader (eg, fulvestrant)--and a vascular endothelial growth factor inhibitor (eg, bevacizumab).⁶

In conclusion, the therapeutic armamentarium for managing patients with melasma includes topical agents, oral therapies, and physical modalities. Optimizing the approach to treating melasma patients should incorporate therapies that are specifically directed toward various etiologic factors of the condition. The concurrent use of a topical agent that contains an antiestrogen and an inhibitor of vascular endothelial growth factor in women with melasma who are being treated with oral tranexamic acid warrants further investigation to assess not only for enhanced but also sustained reduction in facial skin pigmentation.

To the Editor:

I read with interest the informative article by Sheu¹ published online in Cutis in February 2018, which succinctly described the pharmacologic characteristics of tranexamic acid, a synthetic lysine derivative, and its mechanism of action in the management of melasma by mitigating UV radiation-induced melanogenesis and neovascularization by inhibiting plasminogen activation. Additionally, the author summarized a study in which oral tranexamic acid was used to successfully treat melasma patients. After 4 months of treatment, 90% of 561 patients treated at a single center in Singapore demonstrated improvement in melasma severity.² Sheu¹ also discussed daily oral doses of tranexamic acid (500-1500 mg) that demonstrated improvement in melasma patients and reviewed potential adverse events (eg, abdominal pain and bloating, deep venous thrombosis, pulmonary embolism) for which patients should be screened and counseled prior to initiating treatment.

Recently, another study showed oral tranexamic acid to be an effective treatment in women with moderate to severe melasma. An important observation by the investigators was that once the initial phase of their study--250 mg of oral tranexamic acid twice daily and sunscreen applied to the face each morning and every 2 hours during daylight hours for 3 months--concluded and a second phase during which all participants only applied sunscreen for an additional 3 months, those with severe melasma lost most of their improvement.³ An adjuvant topical treatment, such as tranexamic acid or an inhibitor of tyrosinase (hydroquinone), might improve the results; however, initiating therapy with a topical agent whose mode of action is directed toward other melasma etiologic factors, such as the increased expression of estrogen receptors and vascular endothelial growth factor in affected skin, might be more beneficial.^4,5

I recently proposed a novel approach for melasma management that would be appropriate as an adjuvant topical therapy for patients concurrently being treated with oral tranexamic acid.⁶ The therapeutic intervention utilizes active agents that specifically affect etiologic factors in the pathogenesis of melasma--estrogen and angiogenesis--that previously have not been targeted topically. Indeed, the topical agent contains an antiestrogen--either a selective estrogen receptor modulator (eg, tamoxifen, raloxifene), aromatase inhibitor (eg, anastrozole, letrozole, exemestane), or a selective estrogen receptor degrader (eg, fulvestrant)--and a vascular endothelial growth factor inhibitor (eg, bevacizumab).⁶

In conclusion, the therapeutic armamentarium for managing patients with melasma includes topical agents, oral therapies, and physical modalities. Optimizing the approach to treating melasma patients should incorporate therapies that are specifically directed toward various etiologic factors of the condition. The concurrent use of a topical agent that contains an antiestrogen and an inhibitor of vascular endothelial growth factor in women with melasma who are being treated with oral tranexamic acid warrants further investigation to assess not only for enhanced but also sustained reduction in facial skin pigmentation.

To the Editor:

I read with interest the informative article by Sheu¹ published online in Cutis in February 2018, which succinctly described the pharmacologic characteristics of tranexamic acid, a synthetic lysine derivative, and its mechanism of action in the management of melasma by mitigating UV radiation-induced melanogenesis and neovascularization by inhibiting plasminogen activation. Additionally, the author summarized a study in which oral tranexamic acid was used to successfully treat melasma patients. After 4 months of treatment, 90% of 561 patients treated at a single center in Singapore demonstrated improvement in melasma severity.² Sheu¹ also discussed daily oral doses of tranexamic acid (500-1500 mg) that demonstrated improvement in melasma patients and reviewed potential adverse events (eg, abdominal pain and bloating, deep venous thrombosis, pulmonary embolism) for which patients should be screened and counseled prior to initiating treatment.

Recently, another study showed oral tranexamic acid to be an effective treatment in women with moderate to severe melasma. An important observation by the investigators was that once the initial phase of their study--250 mg of oral tranexamic acid twice daily and sunscreen applied to the face each morning and every 2 hours during daylight hours for 3 months--concluded and a second phase during which all participants only applied sunscreen for an additional 3 months, those with severe melasma lost most of their improvement.³ An adjuvant topical treatment, such as tranexamic acid or an inhibitor of tyrosinase (hydroquinone), might improve the results; however, initiating therapy with a topical agent whose mode of action is directed toward other melasma etiologic factors, such as the increased expression of estrogen receptors and vascular endothelial growth factor in affected skin, might be more beneficial.^4,5

I recently proposed a novel approach for melasma management that would be appropriate as an adjuvant topical therapy for patients concurrently being treated with oral tranexamic acid.⁶ The therapeutic intervention utilizes active agents that specifically affect etiologic factors in the pathogenesis of melasma--estrogen and angiogenesis--that previously have not been targeted topically. Indeed, the topical agent contains an antiestrogen--either a selective estrogen receptor modulator (eg, tamoxifen, raloxifene), aromatase inhibitor (eg, anastrozole, letrozole, exemestane), or a selective estrogen receptor degrader (eg, fulvestrant)--and a vascular endothelial growth factor inhibitor (eg, bevacizumab).⁶

In conclusion, the therapeutic armamentarium for managing patients with melasma includes topical agents, oral therapies, and physical modalities. Optimizing the approach to treating melasma patients should incorporate therapies that are specifically directed toward various etiologic factors of the condition. The concurrent use of a topical agent that contains an antiestrogen and an inhibitor of vascular endothelial growth factor in women with melasma who are being treated with oral tranexamic acid warrants further investigation to assess not only for enhanced but also sustained reduction in facial skin pigmentation.

LOS ANGELES—Current criteria are comparatively insensitive and nonspecific for distinguishing between corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), according to research presented at the 70th Annual Meeting of the American Academy of Neurology. Including adjunctive biomarkers with the criteria might improve their sensitivity.

It is reasonable to ask whether CBD and PSP should be considered one entity instead of two, said Jessica Weinstein, MD, clinical fellow at the University of California, San Francisco, School of Medicine. Such an approach could enrich clinical trials, given that the diseases are uncommon, she added.

Comparing Pathologic and Clinical Diagnoses

Although CBD and PSP have been considered distinct disorders, each is heterogeneous. The two disorders share symptoms such as limb rigidity, akinesia, postural instability, and behavioral changes. They also share symptoms with other clinical syndromes such as behavioral variant frontotemporal dementia. Furthermore, the Armstrong criteria for CBD include criteria for PSP, and the Höglinger criteria for PSP include criteria for CBD.

Dr. Weinstein and colleagues examined data for patients with autopsy-confirmed four-repeat tauopathies to evaluate the sensitivity and specificity of the Armstrong and Höglinger criteria for diagnosing CBD and PSP, respectively. Information was extracted from the Penn Integrated Neurodegenerative Disease Database. Neuropathologic diagnosis for participants in this database was determined using established criteria.

A researcher blinded to pathologic diagnosis coded each patient for the presence or absence of clinical features using data from his or her first clinical visit. The researcher assessed subjects for 34 features associated with CBD, PSP, behavioral-variant frontotemporal dementia, or primary progressive aphasia. Patients with absent or insufficient data were excluded.

Criteria May Need Refinement

The population included 107 autopsy subjects, 37 of whom had a pathologic diagnosis of CBD and 70 of whom had a pathologic diagnosis of PSP. The investigators found no significant differences between the groups in age at death, age at onset, or disease duration. The percentage of females was higher in the CBD group. The percentage of patients evaluated in movement clinics, rather than cognitive clinics, was 8% for patients with CBD and 40% for patients with PSP.

Almost all clinical features were more prevalent in the PSP group than the CBD group, except limb dystonia, myoclonus, and alien limb syndrome. Language impairment (ie, speech apraxia; agrammatism; and impaired naming, single-word comprehension, and grammatical comprehension) was more prevalent in the CBD group, but this difference was not statistically significant. The PSP group had a significantly higher prevalence of falls, being chair bound, postural instability, and vertical saccades. The PSP group had more bradyphrenia than the CBD group, and the CBD group had more executive impairment than the PSP group.

The Armstrong criteria identified probable CBD with a sensitivity of 11% and a specificity of 100%. The specificity result “should be taken with a grain of salt because only four patients met criteria,” said Dr. Weinstein. Armstrong criteria identified possible CBD with 35% sensitivity and 34% specificity.

The Höglinger criteria identified probable PSP with 66% sensitivity and 70% specificity. They identified possible PSP with 63% sensitivity and 65% specificity. A post hoc analysis suggested that including grammar comprehension in the Höglinger criteria improved their sensitivity.

The study’s limitations include its retrospective design, potential for selection bias, and the uncertain generalizability of its results. Only one researcher coded patients’ clinical features, and many data were missing. Nevertheless, “it is studies like these that use the gold standard autopsy data and look backward that provide the heart of clinical diagnostic criteria,” said Dr. Weinstein.

Longitudinal, prospective studies could validate these results and potentially improve the Armstrong and Höglinger criteria.

—Erik Greb

Suggested Reading

Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80(5):496-503.

Höglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Mov Disord. 2017;32(6):853-864.

LOS ANGELES—Current criteria are comparatively insensitive and nonspecific for distinguishing between corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), according to research presented at the 70th Annual Meeting of the American Academy of Neurology. Including adjunctive biomarkers with the criteria might improve their sensitivity.

It is reasonable to ask whether CBD and PSP should be considered one entity instead of two, said Jessica Weinstein, MD, clinical fellow at the University of California, San Francisco, School of Medicine. Such an approach could enrich clinical trials, given that the diseases are uncommon, she added.

Comparing Pathologic and Clinical Diagnoses

Although CBD and PSP have been considered distinct disorders, each is heterogeneous. The two disorders share symptoms such as limb rigidity, akinesia, postural instability, and behavioral changes. They also share symptoms with other clinical syndromes such as behavioral variant frontotemporal dementia. Furthermore, the Armstrong criteria for CBD include criteria for PSP, and the Höglinger criteria for PSP include criteria for CBD.

Dr. Weinstein and colleagues examined data for patients with autopsy-confirmed four-repeat tauopathies to evaluate the sensitivity and specificity of the Armstrong and Höglinger criteria for diagnosing CBD and PSP, respectively. Information was extracted from the Penn Integrated Neurodegenerative Disease Database. Neuropathologic diagnosis for participants in this database was determined using established criteria.

A researcher blinded to pathologic diagnosis coded each patient for the presence or absence of clinical features using data from his or her first clinical visit. The researcher assessed subjects for 34 features associated with CBD, PSP, behavioral-variant frontotemporal dementia, or primary progressive aphasia. Patients with absent or insufficient data were excluded.

Criteria May Need Refinement

The population included 107 autopsy subjects, 37 of whom had a pathologic diagnosis of CBD and 70 of whom had a pathologic diagnosis of PSP. The investigators found no significant differences between the groups in age at death, age at onset, or disease duration. The percentage of females was higher in the CBD group. The percentage of patients evaluated in movement clinics, rather than cognitive clinics, was 8% for patients with CBD and 40% for patients with PSP.

Almost all clinical features were more prevalent in the PSP group than the CBD group, except limb dystonia, myoclonus, and alien limb syndrome. Language impairment (ie, speech apraxia; agrammatism; and impaired naming, single-word comprehension, and grammatical comprehension) was more prevalent in the CBD group, but this difference was not statistically significant. The PSP group had a significantly higher prevalence of falls, being chair bound, postural instability, and vertical saccades. The PSP group had more bradyphrenia than the CBD group, and the CBD group had more executive impairment than the PSP group.

The Armstrong criteria identified probable CBD with a sensitivity of 11% and a specificity of 100%. The specificity result “should be taken with a grain of salt because only four patients met criteria,” said Dr. Weinstein. Armstrong criteria identified possible CBD with 35% sensitivity and 34% specificity.

The Höglinger criteria identified probable PSP with 66% sensitivity and 70% specificity. They identified possible PSP with 63% sensitivity and 65% specificity. A post hoc analysis suggested that including grammar comprehension in the Höglinger criteria improved their sensitivity.

The study’s limitations include its retrospective design, potential for selection bias, and the uncertain generalizability of its results. Only one researcher coded patients’ clinical features, and many data were missing. Nevertheless, “it is studies like these that use the gold standard autopsy data and look backward that provide the heart of clinical diagnostic criteria,” said Dr. Weinstein.

Longitudinal, prospective studies could validate these results and potentially improve the Armstrong and Höglinger criteria.

—Erik Greb

Suggested Reading

Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80(5):496-503.

Höglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Mov Disord. 2017;32(6):853-864.

LOS ANGELES—Current criteria are comparatively insensitive and nonspecific for distinguishing between corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), according to research presented at the 70th Annual Meeting of the American Academy of Neurology. Including adjunctive biomarkers with the criteria might improve their sensitivity.

It is reasonable to ask whether CBD and PSP should be considered one entity instead of two, said Jessica Weinstein, MD, clinical fellow at the University of California, San Francisco, School of Medicine. Such an approach could enrich clinical trials, given that the diseases are uncommon, she added.

Comparing Pathologic and Clinical Diagnoses

Although CBD and PSP have been considered distinct disorders, each is heterogeneous. The two disorders share symptoms such as limb rigidity, akinesia, postural instability, and behavioral changes. They also share symptoms with other clinical syndromes such as behavioral variant frontotemporal dementia. Furthermore, the Armstrong criteria for CBD include criteria for PSP, and the Höglinger criteria for PSP include criteria for CBD.

Dr. Weinstein and colleagues examined data for patients with autopsy-confirmed four-repeat tauopathies to evaluate the sensitivity and specificity of the Armstrong and Höglinger criteria for diagnosing CBD and PSP, respectively. Information was extracted from the Penn Integrated Neurodegenerative Disease Database. Neuropathologic diagnosis for participants in this database was determined using established criteria.

A researcher blinded to pathologic diagnosis coded each patient for the presence or absence of clinical features using data from his or her first clinical visit. The researcher assessed subjects for 34 features associated with CBD, PSP, behavioral-variant frontotemporal dementia, or primary progressive aphasia. Patients with absent or insufficient data were excluded.

Criteria May Need Refinement

The population included 107 autopsy subjects, 37 of whom had a pathologic diagnosis of CBD and 70 of whom had a pathologic diagnosis of PSP. The investigators found no significant differences between the groups in age at death, age at onset, or disease duration. The percentage of females was higher in the CBD group. The percentage of patients evaluated in movement clinics, rather than cognitive clinics, was 8% for patients with CBD and 40% for patients with PSP.

Almost all clinical features were more prevalent in the PSP group than the CBD group, except limb dystonia, myoclonus, and alien limb syndrome. Language impairment (ie, speech apraxia; agrammatism; and impaired naming, single-word comprehension, and grammatical comprehension) was more prevalent in the CBD group, but this difference was not statistically significant. The PSP group had a significantly higher prevalence of falls, being chair bound, postural instability, and vertical saccades. The PSP group had more bradyphrenia than the CBD group, and the CBD group had more executive impairment than the PSP group.

The Armstrong criteria identified probable CBD with a sensitivity of 11% and a specificity of 100%. The specificity result “should be taken with a grain of salt because only four patients met criteria,” said Dr. Weinstein. Armstrong criteria identified possible CBD with 35% sensitivity and 34% specificity.

The Höglinger criteria identified probable PSP with 66% sensitivity and 70% specificity. They identified possible PSP with 63% sensitivity and 65% specificity. A post hoc analysis suggested that including grammar comprehension in the Höglinger criteria improved their sensitivity.

The study’s limitations include its retrospective design, potential for selection bias, and the uncertain generalizability of its results. Only one researcher coded patients’ clinical features, and many data were missing. Nevertheless, “it is studies like these that use the gold standard autopsy data and look backward that provide the heart of clinical diagnostic criteria,” said Dr. Weinstein.

Longitudinal, prospective studies could validate these results and potentially improve the Armstrong and Höglinger criteria.

—Erik Greb

Suggested Reading

Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80(5):496-503.

Höglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Mov Disord. 2017;32(6):853-864.

Dermoscopic examination has been proven to increase diagnostic accuracy and decrease unnecessary biopsies of both melanoma and nonmelanoma skin cancers.^1,2 Digital dermoscopy refers to acquiring and storing digital dermoscopic photographs via digital camera, smart image capture devices such as smartphones and tablets, or any other devices used for image acquisition. The stored images may then be used in a variety of ways, including sequential digital monitoring, teledermoscopy, and machine learning.

Sequential Digital Monitoring

Sequential digital dermoscopy imaging (SDDI) is the capture and storage of dermoscopic images of suspicious lesions that are then monitored over time for changes. Studies have shown that SDDI allows for early detection of melanomas and leads to a decrease in the number of unnecessary excisions.^3,4 A meta-analysis of SDDI found that the chance of detecting melanoma increased with the length of monitoring, which suggests that continued follow-up, especially in high-risk groups, is crucial.⁴

Teledermoscopy

Teledermatology (telederm) is on the rise in the United States, with the number of programs and consultations increasing yearly. One study showed a 48% increase in telederm programs in the last 5 years.⁵ Studies have shown the addition of digital dermoscopic images improved the diagnostic accuracy in telederm skin cancer screenings versus clinical images alone.^6,7

Telederm currently is practiced in 2 main models: live-interactive video consultation and storage of images for future consultation (store and forward). Medicare currently only reimburses live-interactive telederm for patients in nonmetropolitan areas and store-and-forward telederm pilot programs in Alaska and Hawaii; however, Medicaid does reimburse for store and forward in a handful of states.8 Similar to dermatoscope use during clinical examination, there currently is no additional reimbursement for teledermoscopy. Of note, a willingness-to-pay survey of 214 students from a southwestern university health center showed that participants were willing to pay an average (SD) of $55.27 ($39.11) out of pocket for a teledermoscopy/telederm evaluation, citing factors such as convenience.⁹

Direct-to-consumer telederm offers a new way for patients to receive care.¹⁰ Some dermatoscopes (eg, DermLite HÜD [3Gen], Molescope/Molescope II [Metaoptima Technology Inc]) currently are marketed directly to consumers along with telederm services to facilitate direct-to-patient teledermoscopy.^11,12

Machine Learning

Big data and machine learning has been hailed as the future of medicine and dermatology alike.¹³ Machine learning is a type of artificial intelligence that uses computational algorithms (eg, neural networks) that allow computer programs to automatically improve their accuracy (learn) by analyzing large data sets. In dermatology, machine learning has been most notably used to train computers to identify images of skin cancer by way of large image databases.^14-17 One algorithm, a convolutional neural network (CNN), made headlines in 2017 when it was able to identify dermoscopic and clinical images of skin cancer with comparable accuracy to a group of 21 dermatologists.¹⁴ In 2018, the International Skin Imaging Collaboration (ISIC) published results of a study of the diagnostic accuracy of 25 computer algorithms compared to 8 dermatologists using a set of 100 dermoscopic images of melanoma and benign nevi.¹⁵ Using the average sensitivity of the dermatologists (82%), the top fusion algorithm in the study had a sensitivity of 76% versus 59% for the dermatologists (P=.02). These results compared the mean sensitivity of the dermatologists, as some individual dermatologists outperformed the algorithm.¹⁵ More recently, another CNN was compared to 58 international dermatologists in the classification of a set of 100 dermoscopic images (20 melanoma and 80 melanocytic nevi).¹⁶ Using the mean sensitivity of the dermatologists (86.6%), the CNN had a specificity of 92.5% versus 71.3% for dermatologists (P<.01). In the second part of the study, the dermatologists were given some clinical information and close-up photographs of the lesions, which improved their average (SD) sensitivity and specificity to 88.9% (9.6%)(P=.19) and 75.7% (11.7%)(P<.05), respectively. When compared to the CNN at this higher sensitivity, the CNN still had a higher specificity than the dermatologists (82.5% vs 75.7% [P<.01]).¹⁶ However, in real-life clinical practice dermatologists perform better, not only because they can collect more in-person clinical information but also because humans gather more information during live examination than when they are interpreting close-up clinical and/or dermoscopic images. In a sense, we currently are limited to comparing data that is incommensurable.

Machine learning studies have other notable limitations, such as data sets that do not contain a full spectrum of skin lesions or less common lesions (eg, pigmented seborrheic keratoses, amelanotic melanomas) and variation in image databases used.^15,16 For machine algorithms to improve, they require access to high-quality and ideally standardized digital dermoscopic image databases. The ISIC and other organizations currently have databases specifically for this purpose, but more images are needed.¹⁸ As additional practitioners incorporate digital dermoscopy in their clinical practice, the potential for larger databases and more accurate algorithms becomes a possibility. 

Image Acquisition

Many devices are available for digital dermoscopic image acquisition, including dermatoscopes that attach to smartphones and/or digital cameras and all-in-one systems (eTable). The exact system employed will depend on the practitioner's requirements for price, portability, speed, image quality, and software. Digital single-lens reflex (DSLR) cameras boast the highest image quality, while video dermoscopy traditionally yields stored images with poor resolution.¹⁹ Macroscopic images obtained by other imaging devices, including spectral imaging devices and reflectance confocal microscopy, usually are yielded via video dermoscopy or a video camera to capture images; thus, stored images generally are not as high quality. 

Smartphones are increasingly used for clinical imaging in dermatology.²⁰ Although DSLR cameras still take the highest-quality images, current smartphone image quality is comparable to digital cameras.^21,22 Computational photography uses computer processing power to enhance image quality and may bring smartphone image quality closer to DSLR cameras.^22,23 Smartphones with newer dual-lens cameras have been reported to further improve image quality.²¹ Current smartphones have the option of enabling high-dynamic-range imaging, which combines multiple images taken with different exposures to create a single image with improved dynamic range of luminosity. It has been reported that high-dynamic-range imaging may even enhance dermoscopic features of more challenging hypopigmented skin cancers.²⁴

Standardizing Imaging

There has been a concerted effort to standardize digital dermatologic image acquisition.^25,26 Standardization promises to facilitate data analysis, improve collaboration, protect patient privacy, and improve patient care.^13,26,27 At the forefront of image standardization is the ISIC organization, which recently published its Delphi consensus guidelines on standards for lesion imaging, including dermoscopy.²⁶

The true holy grail of image standardization is the Digital Imaging and Communications in Medicine (DICOM) standard.^26-28 The DICOM is a comprehensive imaging standard for storage, annotation, transfer, and display of images, and it is most notable for its use in radiology. The DICOM also could be applied to new imaging modalities in dermatology (eg, optical coherence tomography, reflectance confocal microscopy). Past efforts to develop a DICOM standard for dermatology were undertaken by a working group that has since disbanded.²⁷ Work by the ISIC and many others will hopefully lead to adoption of the DICOM standard by dermatology at some point in the future. 

Protected Health Information

The Health Insurance Portability and Accountability Act (HIPAA) requires protected health information (PHI) to be stored in a secure manner with limited access that sufficiently protects identifiable patient information. Although dermoscopic images generally are deidentified, they often are stored alongside clinical photographs and data that contains PHI in clinical practice.

Image storage can take 2 forms: (1) physical local storage on internal and external hard drives or (2) remote storage (eg, cloud-based storage). Encryption is essential regardless of the method of storage. It is required by law that loss of nonencrypted PHI be reported to all potentially affected patients, the US Department of Health & Human Services, and local/state media depending on the number of patients affected. Loss of PHI can result in fines of up to $1.5 million.²⁹ On the contrary, loss of properly encrypted data would not be required to be reported.³⁰

As smart image acquisition devices begin to dominate the clinical setting, practitioners need to be vigilant in securing patient PHI. There are multiple applications (apps) that allow for secure encrypted digital dermoscopic image acquisition and storage on smartphones. Additionally, it is important to secure smartphones with complex passcodes (eg, a mix of special characters, numbers, uppercase and lowercase letters). Most dermatoscope manufacturers have apps for image acquisition and storage that can be tied into other platforms or storage systems (eg, DermLite app [3Gen], Handyscope [FotoFinder Systems GmbH], VEOS app [Canfield Scientific, Inc]).²⁸ Other options include syncing images with current electronic medical record technologies, transferring photographs to HIPAA-compliant cloud storage, or transferring photographs to an encrypted computer and/or external hard drive. Some tips for securing data based on HIPAA and other guidelines are listed in the Table.^30,31

Conclusion

The expansion of teledermoscopy alongside direct-to-patient services may create additional incentives for clinicians to incorporate digital dermoscopy into their practice. As more practitioners adopt digital dermoscopy, machine learning driven by technological advancements and larger image data sets could influence the future practice of dermatology. With the rise in digital dermoscopy by way of smartphones, additional steps must be taken to ensure patients' PHI is safeguarded. Digital dermoscopy is a dynamic field that will likely see continued growth in the coming years.

Dermoscopic examination has been proven to increase diagnostic accuracy and decrease unnecessary biopsies of both melanoma and nonmelanoma skin cancers.^1,2 Digital dermoscopy refers to acquiring and storing digital dermoscopic photographs via digital camera, smart image capture devices such as smartphones and tablets, or any other devices used for image acquisition. The stored images may then be used in a variety of ways, including sequential digital monitoring, teledermoscopy, and machine learning.

Sequential Digital Monitoring

Sequential digital dermoscopy imaging (SDDI) is the capture and storage of dermoscopic images of suspicious lesions that are then monitored over time for changes. Studies have shown that SDDI allows for early detection of melanomas and leads to a decrease in the number of unnecessary excisions.^3,4 A meta-analysis of SDDI found that the chance of detecting melanoma increased with the length of monitoring, which suggests that continued follow-up, especially in high-risk groups, is crucial.⁴

Teledermoscopy

Teledermatology (telederm) is on the rise in the United States, with the number of programs and consultations increasing yearly. One study showed a 48% increase in telederm programs in the last 5 years.⁵ Studies have shown the addition of digital dermoscopic images improved the diagnostic accuracy in telederm skin cancer screenings versus clinical images alone.^6,7

Telederm currently is practiced in 2 main models: live-interactive video consultation and storage of images for future consultation (store and forward). Medicare currently only reimburses live-interactive telederm for patients in nonmetropolitan areas and store-and-forward telederm pilot programs in Alaska and Hawaii; however, Medicaid does reimburse for store and forward in a handful of states.8 Similar to dermatoscope use during clinical examination, there currently is no additional reimbursement for teledermoscopy. Of note, a willingness-to-pay survey of 214 students from a southwestern university health center showed that participants were willing to pay an average (SD) of $55.27 ($39.11) out of pocket for a teledermoscopy/telederm evaluation, citing factors such as convenience.⁹

Direct-to-consumer telederm offers a new way for patients to receive care.¹⁰ Some dermatoscopes (eg, DermLite HÜD [3Gen], Molescope/Molescope II [Metaoptima Technology Inc]) currently are marketed directly to consumers along with telederm services to facilitate direct-to-patient teledermoscopy.^11,12

Machine Learning

Big data and machine learning has been hailed as the future of medicine and dermatology alike.¹³ Machine learning is a type of artificial intelligence that uses computational algorithms (eg, neural networks) that allow computer programs to automatically improve their accuracy (learn) by analyzing large data sets. In dermatology, machine learning has been most notably used to train computers to identify images of skin cancer by way of large image databases.^14-17 One algorithm, a convolutional neural network (CNN), made headlines in 2017 when it was able to identify dermoscopic and clinical images of skin cancer with comparable accuracy to a group of 21 dermatologists.¹⁴ In 2018, the International Skin Imaging Collaboration (ISIC) published results of a study of the diagnostic accuracy of 25 computer algorithms compared to 8 dermatologists using a set of 100 dermoscopic images of melanoma and benign nevi.¹⁵ Using the average sensitivity of the dermatologists (82%), the top fusion algorithm in the study had a sensitivity of 76% versus 59% for the dermatologists (P=.02). These results compared the mean sensitivity of the dermatologists, as some individual dermatologists outperformed the algorithm.¹⁵ More recently, another CNN was compared to 58 international dermatologists in the classification of a set of 100 dermoscopic images (20 melanoma and 80 melanocytic nevi).¹⁶ Using the mean sensitivity of the dermatologists (86.6%), the CNN had a specificity of 92.5% versus 71.3% for dermatologists (P<.01). In the second part of the study, the dermatologists were given some clinical information and close-up photographs of the lesions, which improved their average (SD) sensitivity and specificity to 88.9% (9.6%)(P=.19) and 75.7% (11.7%)(P<.05), respectively. When compared to the CNN at this higher sensitivity, the CNN still had a higher specificity than the dermatologists (82.5% vs 75.7% [P<.01]).¹⁶ However, in real-life clinical practice dermatologists perform better, not only because they can collect more in-person clinical information but also because humans gather more information during live examination than when they are interpreting close-up clinical and/or dermoscopic images. In a sense, we currently are limited to comparing data that is incommensurable.

Machine learning studies have other notable limitations, such as data sets that do not contain a full spectrum of skin lesions or less common lesions (eg, pigmented seborrheic keratoses, amelanotic melanomas) and variation in image databases used.^15,16 For machine algorithms to improve, they require access to high-quality and ideally standardized digital dermoscopic image databases. The ISIC and other organizations currently have databases specifically for this purpose, but more images are needed.¹⁸ As additional practitioners incorporate digital dermoscopy in their clinical practice, the potential for larger databases and more accurate algorithms becomes a possibility. 

Image Acquisition

Many devices are available for digital dermoscopic image acquisition, including dermatoscopes that attach to smartphones and/or digital cameras and all-in-one systems (eTable). The exact system employed will depend on the practitioner's requirements for price, portability, speed, image quality, and software. Digital single-lens reflex (DSLR) cameras boast the highest image quality, while video dermoscopy traditionally yields stored images with poor resolution.¹⁹ Macroscopic images obtained by other imaging devices, including spectral imaging devices and reflectance confocal microscopy, usually are yielded via video dermoscopy or a video camera to capture images; thus, stored images generally are not as high quality. 

Smartphones are increasingly used for clinical imaging in dermatology.²⁰ Although DSLR cameras still take the highest-quality images, current smartphone image quality is comparable to digital cameras.^21,22 Computational photography uses computer processing power to enhance image quality and may bring smartphone image quality closer to DSLR cameras.^22,23 Smartphones with newer dual-lens cameras have been reported to further improve image quality.²¹ Current smartphones have the option of enabling high-dynamic-range imaging, which combines multiple images taken with different exposures to create a single image with improved dynamic range of luminosity. It has been reported that high-dynamic-range imaging may even enhance dermoscopic features of more challenging hypopigmented skin cancers.²⁴

Standardizing Imaging

There has been a concerted effort to standardize digital dermatologic image acquisition.^25,26 Standardization promises to facilitate data analysis, improve collaboration, protect patient privacy, and improve patient care.^13,26,27 At the forefront of image standardization is the ISIC organization, which recently published its Delphi consensus guidelines on standards for lesion imaging, including dermoscopy.²⁶

The true holy grail of image standardization is the Digital Imaging and Communications in Medicine (DICOM) standard.^26-28 The DICOM is a comprehensive imaging standard for storage, annotation, transfer, and display of images, and it is most notable for its use in radiology. The DICOM also could be applied to new imaging modalities in dermatology (eg, optical coherence tomography, reflectance confocal microscopy). Past efforts to develop a DICOM standard for dermatology were undertaken by a working group that has since disbanded.²⁷ Work by the ISIC and many others will hopefully lead to adoption of the DICOM standard by dermatology at some point in the future. 

Protected Health Information

The Health Insurance Portability and Accountability Act (HIPAA) requires protected health information (PHI) to be stored in a secure manner with limited access that sufficiently protects identifiable patient information. Although dermoscopic images generally are deidentified, they often are stored alongside clinical photographs and data that contains PHI in clinical practice.

Image storage can take 2 forms: (1) physical local storage on internal and external hard drives or (2) remote storage (eg, cloud-based storage). Encryption is essential regardless of the method of storage. It is required by law that loss of nonencrypted PHI be reported to all potentially affected patients, the US Department of Health & Human Services, and local/state media depending on the number of patients affected. Loss of PHI can result in fines of up to $1.5 million.²⁹ On the contrary, loss of properly encrypted data would not be required to be reported.³⁰

As smart image acquisition devices begin to dominate the clinical setting, practitioners need to be vigilant in securing patient PHI. There are multiple applications (apps) that allow for secure encrypted digital dermoscopic image acquisition and storage on smartphones. Additionally, it is important to secure smartphones with complex passcodes (eg, a mix of special characters, numbers, uppercase and lowercase letters). Most dermatoscope manufacturers have apps for image acquisition and storage that can be tied into other platforms or storage systems (eg, DermLite app [3Gen], Handyscope [FotoFinder Systems GmbH], VEOS app [Canfield Scientific, Inc]).²⁸ Other options include syncing images with current electronic medical record technologies, transferring photographs to HIPAA-compliant cloud storage, or transferring photographs to an encrypted computer and/or external hard drive. Some tips for securing data based on HIPAA and other guidelines are listed in the Table.^30,31

Conclusion

The expansion of teledermoscopy alongside direct-to-patient services may create additional incentives for clinicians to incorporate digital dermoscopy into their practice. As more practitioners adopt digital dermoscopy, machine learning driven by technological advancements and larger image data sets could influence the future practice of dermatology. With the rise in digital dermoscopy by way of smartphones, additional steps must be taken to ensure patients' PHI is safeguarded. Digital dermoscopy is a dynamic field that will likely see continued growth in the coming years.

Dermoscopic examination has been proven to increase diagnostic accuracy and decrease unnecessary biopsies of both melanoma and nonmelanoma skin cancers.^1,2 Digital dermoscopy refers to acquiring and storing digital dermoscopic photographs via digital camera, smart image capture devices such as smartphones and tablets, or any other devices used for image acquisition. The stored images may then be used in a variety of ways, including sequential digital monitoring, teledermoscopy, and machine learning.

Sequential Digital Monitoring

Sequential digital dermoscopy imaging (SDDI) is the capture and storage of dermoscopic images of suspicious lesions that are then monitored over time for changes. Studies have shown that SDDI allows for early detection of melanomas and leads to a decrease in the number of unnecessary excisions.^3,4 A meta-analysis of SDDI found that the chance of detecting melanoma increased with the length of monitoring, which suggests that continued follow-up, especially in high-risk groups, is crucial.⁴

Teledermoscopy

Teledermatology (telederm) is on the rise in the United States, with the number of programs and consultations increasing yearly. One study showed a 48% increase in telederm programs in the last 5 years.⁵ Studies have shown the addition of digital dermoscopic images improved the diagnostic accuracy in telederm skin cancer screenings versus clinical images alone.^6,7

Telederm currently is practiced in 2 main models: live-interactive video consultation and storage of images for future consultation (store and forward). Medicare currently only reimburses live-interactive telederm for patients in nonmetropolitan areas and store-and-forward telederm pilot programs in Alaska and Hawaii; however, Medicaid does reimburse for store and forward in a handful of states.8 Similar to dermatoscope use during clinical examination, there currently is no additional reimbursement for teledermoscopy. Of note, a willingness-to-pay survey of 214 students from a southwestern university health center showed that participants were willing to pay an average (SD) of $55.27 ($39.11) out of pocket for a teledermoscopy/telederm evaluation, citing factors such as convenience.⁹

Direct-to-consumer telederm offers a new way for patients to receive care.¹⁰ Some dermatoscopes (eg, DermLite HÜD [3Gen], Molescope/Molescope II [Metaoptima Technology Inc]) currently are marketed directly to consumers along with telederm services to facilitate direct-to-patient teledermoscopy.^11,12

Machine Learning

Big data and machine learning has been hailed as the future of medicine and dermatology alike.¹³ Machine learning is a type of artificial intelligence that uses computational algorithms (eg, neural networks) that allow computer programs to automatically improve their accuracy (learn) by analyzing large data sets. In dermatology, machine learning has been most notably used to train computers to identify images of skin cancer by way of large image databases.^14-17 One algorithm, a convolutional neural network (CNN), made headlines in 2017 when it was able to identify dermoscopic and clinical images of skin cancer with comparable accuracy to a group of 21 dermatologists.¹⁴ In 2018, the International Skin Imaging Collaboration (ISIC) published results of a study of the diagnostic accuracy of 25 computer algorithms compared to 8 dermatologists using a set of 100 dermoscopic images of melanoma and benign nevi.¹⁵ Using the average sensitivity of the dermatologists (82%), the top fusion algorithm in the study had a sensitivity of 76% versus 59% for the dermatologists (P=.02). These results compared the mean sensitivity of the dermatologists, as some individual dermatologists outperformed the algorithm.¹⁵ More recently, another CNN was compared to 58 international dermatologists in the classification of a set of 100 dermoscopic images (20 melanoma and 80 melanocytic nevi).¹⁶ Using the mean sensitivity of the dermatologists (86.6%), the CNN had a specificity of 92.5% versus 71.3% for dermatologists (P<.01). In the second part of the study, the dermatologists were given some clinical information and close-up photographs of the lesions, which improved their average (SD) sensitivity and specificity to 88.9% (9.6%)(P=.19) and 75.7% (11.7%)(P<.05), respectively. When compared to the CNN at this higher sensitivity, the CNN still had a higher specificity than the dermatologists (82.5% vs 75.7% [P<.01]).¹⁶ However, in real-life clinical practice dermatologists perform better, not only because they can collect more in-person clinical information but also because humans gather more information during live examination than when they are interpreting close-up clinical and/or dermoscopic images. In a sense, we currently are limited to comparing data that is incommensurable.

Machine learning studies have other notable limitations, such as data sets that do not contain a full spectrum of skin lesions or less common lesions (eg, pigmented seborrheic keratoses, amelanotic melanomas) and variation in image databases used.^15,16 For machine algorithms to improve, they require access to high-quality and ideally standardized digital dermoscopic image databases. The ISIC and other organizations currently have databases specifically for this purpose, but more images are needed.¹⁸ As additional practitioners incorporate digital dermoscopy in their clinical practice, the potential for larger databases and more accurate algorithms becomes a possibility. 

Image Acquisition

Many devices are available for digital dermoscopic image acquisition, including dermatoscopes that attach to smartphones and/or digital cameras and all-in-one systems (eTable). The exact system employed will depend on the practitioner's requirements for price, portability, speed, image quality, and software. Digital single-lens reflex (DSLR) cameras boast the highest image quality, while video dermoscopy traditionally yields stored images with poor resolution.¹⁹ Macroscopic images obtained by other imaging devices, including spectral imaging devices and reflectance confocal microscopy, usually are yielded via video dermoscopy or a video camera to capture images; thus, stored images generally are not as high quality. 

Smartphones are increasingly used for clinical imaging in dermatology.²⁰ Although DSLR cameras still take the highest-quality images, current smartphone image quality is comparable to digital cameras.^21,22 Computational photography uses computer processing power to enhance image quality and may bring smartphone image quality closer to DSLR cameras.^22,23 Smartphones with newer dual-lens cameras have been reported to further improve image quality.²¹ Current smartphones have the option of enabling high-dynamic-range imaging, which combines multiple images taken with different exposures to create a single image with improved dynamic range of luminosity. It has been reported that high-dynamic-range imaging may even enhance dermoscopic features of more challenging hypopigmented skin cancers.²⁴

Standardizing Imaging

There has been a concerted effort to standardize digital dermatologic image acquisition.^25,26 Standardization promises to facilitate data analysis, improve collaboration, protect patient privacy, and improve patient care.^13,26,27 At the forefront of image standardization is the ISIC organization, which recently published its Delphi consensus guidelines on standards for lesion imaging, including dermoscopy.²⁶

The true holy grail of image standardization is the Digital Imaging and Communications in Medicine (DICOM) standard.^26-28 The DICOM is a comprehensive imaging standard for storage, annotation, transfer, and display of images, and it is most notable for its use in radiology. The DICOM also could be applied to new imaging modalities in dermatology (eg, optical coherence tomography, reflectance confocal microscopy). Past efforts to develop a DICOM standard for dermatology were undertaken by a working group that has since disbanded.²⁷ Work by the ISIC and many others will hopefully lead to adoption of the DICOM standard by dermatology at some point in the future. 

Protected Health Information

The Health Insurance Portability and Accountability Act (HIPAA) requires protected health information (PHI) to be stored in a secure manner with limited access that sufficiently protects identifiable patient information. Although dermoscopic images generally are deidentified, they often are stored alongside clinical photographs and data that contains PHI in clinical practice.

Image storage can take 2 forms: (1) physical local storage on internal and external hard drives or (2) remote storage (eg, cloud-based storage). Encryption is essential regardless of the method of storage. It is required by law that loss of nonencrypted PHI be reported to all potentially affected patients, the US Department of Health & Human Services, and local/state media depending on the number of patients affected. Loss of PHI can result in fines of up to $1.5 million.²⁹ On the contrary, loss of properly encrypted data would not be required to be reported.³⁰

As smart image acquisition devices begin to dominate the clinical setting, practitioners need to be vigilant in securing patient PHI. There are multiple applications (apps) that allow for secure encrypted digital dermoscopic image acquisition and storage on smartphones. Additionally, it is important to secure smartphones with complex passcodes (eg, a mix of special characters, numbers, uppercase and lowercase letters). Most dermatoscope manufacturers have apps for image acquisition and storage that can be tied into other platforms or storage systems (eg, DermLite app [3Gen], Handyscope [FotoFinder Systems GmbH], VEOS app [Canfield Scientific, Inc]).²⁸ Other options include syncing images with current electronic medical record technologies, transferring photographs to HIPAA-compliant cloud storage, or transferring photographs to an encrypted computer and/or external hard drive. Some tips for securing data based on HIPAA and other guidelines are listed in the Table.^30,31

Conclusion

The expansion of teledermoscopy alongside direct-to-patient services may create additional incentives for clinicians to incorporate digital dermoscopy into their practice. As more practitioners adopt digital dermoscopy, machine learning driven by technological advancements and larger image data sets could influence the future practice of dermatology. With the rise in digital dermoscopy by way of smartphones, additional steps must be taken to ensure patients' PHI is safeguarded. Digital dermoscopy is a dynamic field that will likely see continued growth in the coming years.

In November 2016, the US Food and Drug Administration expanded the approval of daratumumab for patients with multiple myeloma. The monoclonal antibody, which targets CD38, a protein that is highly expressed on the surface of multiple myeloma cells, was previously granted approval by the agency as a single agent for the treatment of patients who had received at least three previous therapies.

The current approval was for the use of daratumumab in two different combination regimens for the treatment of patients who have received one previous line of treatment. On the basis of improved progression-free survival (PFS), demonstrated in two randomized, open-label, phase 3 trials, daratumumab can now be used in combination with the immunomodulatory agent lenalidomide and dexamethasone, or the proteasome inhibitor bortezomib and dexamethasone, both standard therapies for the treatment of multiple myeloma.

In the POLLUX trial, 569 patients with relapsed/refractory multiple myeloma were randomized 1:1 to receive daratumumab in combination with lenalidomide-dexamethasone or lenalidomide-dexamethasone alone. The CASTOR trial randomized 498 patients with relapsed/refractory multiple myeloma 1:1 to daratumumab in combination with bortezomib-dexamethasone, or bortezomib-dexamethasone alone.

The eligibility and exclusion criteria for both trials were similar; patients had received at least one previous line of therapy, had documented progressive disease according to International Myeloma Working Group criteria, and had measurable disease on the basis of urine and/or serum assessments or serum-free, light-chain assay.

Patients with a neutrophil count of ≤1,000 cells/mm³, hemoglobin level of ≤7.5 g/dL, platelet count of <75,000 cells/mm³, creatinine clearance of ≤20 mL/min per 1.73m² body surface area (or <30 mL/min in the POLLUX trial), alanine aminotransferase or aspartate aminotransferase level ≥2.5 times the upper limit of normal (ULN) range, bilirubin level of ≥1.5 or more times the ULN range, disease refractory to bortezomib or lenalidomide, and unacceptable side effects from bortezomib or lenalidomide, were ineligible for these studies. In addition, patients with grade 2 or higher peripheral neuropathy or neuropathic pain, were excluded from the CASTOR study.

Randomization was stratified according to International Staging System disease stage at the time of screening (stage I, II or III, with higher stage indicating more severe disease), number of previous lines of therapy (1 vs 2, or 3 vs >3), and previous receipt of lenalidomide or bortezomib.

In the CASTOR trial, patients received up to eight 21-day cycles of bortezomib, administered subcutaneously at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 of cycles 1-8, and dexamethasone, administered orally or intravenously at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 for a total dose of 160 mg per cycle. Daratumumab was administered at a dose of 16 mg/kg intravenously once weekly on days 1, 8, and 15 during cycles 1 to 3, once every 3 weeks on day 1 of cycles 4-8, and once every 4 weeks thereafter.

In the POLLUX trial, patients were treated in 28-day cycles. Daratumumab was administered at the same dose as in the CASTOR trial, but on days 1, 8, 15 and 22 for 8 weeks during cycles 1 and 2, every 2 weeks on days 1 and 15 for 16 weeks during cycles 3 through 7, and every 4 weeks from then onwards. Lenalidomide was administered at a dose of 25 mg orally on days 1-21 of each cycle, and dexamethasone at a dose of 20 mg before infusion and 20 mg the following day.

The combination of daratumumab with lenalidomide-dexamethasone demonstrated a substantial improvement in PFS, compared with lenalidomide-dexamethasone alone (estimated PFS not yet reached vs 18.4 months, respectively; HR, 0.37; P < .0001), representing a 63% reduction in the risk of disease progression or death. Meanwhile, there was a 61% reduction in the risk of disease progression or death for the combination of daratumumab with bortezomib-dexamethasone in the CASTOR trial (estimated PFS not yet reached vs 7.2 months; HR: 0.39; P < .0001). The PFS benefit was observed across all prespecified subgroups in both studies.

In the CASTOR trial, over a median follow-up of 7.4 months, the overall response rate (ORR) was 82.9% for the combination arm, compared with 63.2% for the bortezomib-dexamethasone arm (P < .001), with a very good partial response (VGPR) or better rate of 59.2% compared with 29.1%, and a complete response (CR) rate of 19.2% compared with 9%. In the POLLUX trial, over a median follow-up of 13.5 months, ORR was 92.9% for the combination arm, compared with 76.4% for lenalidomide-dexamethasone, with a VGPR or better rate of 75.8% versus 44% and a CR rate of 43.1% versus 19.2%.

Overall, the safety profile for both combinations was consistent with what is usually observed with daratumumab monotherapy and lenalidomide-dexamethasone or bortezomib-dexamethasone combinations. The most frequently reported adverse events (AEs) were similar in both studies and included infusion reactions, diarrhea, and upper respiratory tract infection. In the POLLUX trial they also included nausea, fatigue, pyrexia, muscle spasm, cough, and dyspnea, whereas in the CASTOR trial patients also frequently experienced peripheral edema.

The most common grade 3/4 AEs in both trials were neutropenia (51.9% vs 37% in the POLLUX trial and 12.8 vs 4.2% in the CASTOR trial), thrombocytopenia (12.7% vs 13.5% and 45.3% vs 32.9%, respectively), and anemia (12.4% vs 19.6% and 14.4% vs 16%, respectively). The percentage of patients who discontinued treatment due to AEs was similar in both groups across the two studies; in the CASTOR trial discontinuations resulted most commonly from peripheral sensory neuropathy and pneumonia, while in the POLLUX trial, from pneumonia, pulmonary embolism and deterioration in general physical health.

The recommended dose for daratumumab in both combination regimens is 16 mg/kg intravenously, calculated on actual body weight. The dosing schedules begin with weekly administration during weeks 1-8 (when used in combination with lenalidomide-dexamethasone) and weeks 1-9 (for use with the bortezomib-dexamethasone combination), decreasing to every 2 weeks between weeks 9 and 24 or 10 and 24, respectively, and progressing to every 4 weeks from week 25 onward until disease progression and unacceptable toxicity.

Daratumumab is marketed as Darzalex by Janssen Biotech Inc. Neutropenia and thrombocytopenia have been added to the list of warnings and precautions for the prescribing information for these new indications. Complete blood cell count should be monitored periodically during treatment and daratumumab administration delayed to allow recovery of neutrophils or platelets. Supportive care with growth factors or transfusion should be considered in the event of neutropenia or thrombocytopenia, respectively.

In November 2016, the US Food and Drug Administration expanded the approval of daratumumab for patients with multiple myeloma. The monoclonal antibody, which targets CD38, a protein that is highly expressed on the surface of multiple myeloma cells, was previously granted approval by the agency as a single agent for the treatment of patients who had received at least three previous therapies.

The current approval was for the use of daratumumab in two different combination regimens for the treatment of patients who have received one previous line of treatment. On the basis of improved progression-free survival (PFS), demonstrated in two randomized, open-label, phase 3 trials, daratumumab can now be used in combination with the immunomodulatory agent lenalidomide and dexamethasone, or the proteasome inhibitor bortezomib and dexamethasone, both standard therapies for the treatment of multiple myeloma.

In the POLLUX trial, 569 patients with relapsed/refractory multiple myeloma were randomized 1:1 to receive daratumumab in combination with lenalidomide-dexamethasone or lenalidomide-dexamethasone alone. The CASTOR trial randomized 498 patients with relapsed/refractory multiple myeloma 1:1 to daratumumab in combination with bortezomib-dexamethasone, or bortezomib-dexamethasone alone.

The eligibility and exclusion criteria for both trials were similar; patients had received at least one previous line of therapy, had documented progressive disease according to International Myeloma Working Group criteria, and had measurable disease on the basis of urine and/or serum assessments or serum-free, light-chain assay.

Patients with a neutrophil count of ≤1,000 cells/mm³, hemoglobin level of ≤7.5 g/dL, platelet count of <75,000 cells/mm³, creatinine clearance of ≤20 mL/min per 1.73m² body surface area (or <30 mL/min in the POLLUX trial), alanine aminotransferase or aspartate aminotransferase level ≥2.5 times the upper limit of normal (ULN) range, bilirubin level of ≥1.5 or more times the ULN range, disease refractory to bortezomib or lenalidomide, and unacceptable side effects from bortezomib or lenalidomide, were ineligible for these studies. In addition, patients with grade 2 or higher peripheral neuropathy or neuropathic pain, were excluded from the CASTOR study.

Randomization was stratified according to International Staging System disease stage at the time of screening (stage I, II or III, with higher stage indicating more severe disease), number of previous lines of therapy (1 vs 2, or 3 vs >3), and previous receipt of lenalidomide or bortezomib.

In the CASTOR trial, patients received up to eight 21-day cycles of bortezomib, administered subcutaneously at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 of cycles 1-8, and dexamethasone, administered orally or intravenously at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 for a total dose of 160 mg per cycle. Daratumumab was administered at a dose of 16 mg/kg intravenously once weekly on days 1, 8, and 15 during cycles 1 to 3, once every 3 weeks on day 1 of cycles 4-8, and once every 4 weeks thereafter.

In the POLLUX trial, patients were treated in 28-day cycles. Daratumumab was administered at the same dose as in the CASTOR trial, but on days 1, 8, 15 and 22 for 8 weeks during cycles 1 and 2, every 2 weeks on days 1 and 15 for 16 weeks during cycles 3 through 7, and every 4 weeks from then onwards. Lenalidomide was administered at a dose of 25 mg orally on days 1-21 of each cycle, and dexamethasone at a dose of 20 mg before infusion and 20 mg the following day.

The combination of daratumumab with lenalidomide-dexamethasone demonstrated a substantial improvement in PFS, compared with lenalidomide-dexamethasone alone (estimated PFS not yet reached vs 18.4 months, respectively; HR, 0.37; P < .0001), representing a 63% reduction in the risk of disease progression or death. Meanwhile, there was a 61% reduction in the risk of disease progression or death for the combination of daratumumab with bortezomib-dexamethasone in the CASTOR trial (estimated PFS not yet reached vs 7.2 months; HR: 0.39; P < .0001). The PFS benefit was observed across all prespecified subgroups in both studies.

In the CASTOR trial, over a median follow-up of 7.4 months, the overall response rate (ORR) was 82.9% for the combination arm, compared with 63.2% for the bortezomib-dexamethasone arm (P < .001), with a very good partial response (VGPR) or better rate of 59.2% compared with 29.1%, and a complete response (CR) rate of 19.2% compared with 9%. In the POLLUX trial, over a median follow-up of 13.5 months, ORR was 92.9% for the combination arm, compared with 76.4% for lenalidomide-dexamethasone, with a VGPR or better rate of 75.8% versus 44% and a CR rate of 43.1% versus 19.2%.

Overall, the safety profile for both combinations was consistent with what is usually observed with daratumumab monotherapy and lenalidomide-dexamethasone or bortezomib-dexamethasone combinations. The most frequently reported adverse events (AEs) were similar in both studies and included infusion reactions, diarrhea, and upper respiratory tract infection. In the POLLUX trial they also included nausea, fatigue, pyrexia, muscle spasm, cough, and dyspnea, whereas in the CASTOR trial patients also frequently experienced peripheral edema.

The most common grade 3/4 AEs in both trials were neutropenia (51.9% vs 37% in the POLLUX trial and 12.8 vs 4.2% in the CASTOR trial), thrombocytopenia (12.7% vs 13.5% and 45.3% vs 32.9%, respectively), and anemia (12.4% vs 19.6% and 14.4% vs 16%, respectively). The percentage of patients who discontinued treatment due to AEs was similar in both groups across the two studies; in the CASTOR trial discontinuations resulted most commonly from peripheral sensory neuropathy and pneumonia, while in the POLLUX trial, from pneumonia, pulmonary embolism and deterioration in general physical health.

The recommended dose for daratumumab in both combination regimens is 16 mg/kg intravenously, calculated on actual body weight. The dosing schedules begin with weekly administration during weeks 1-8 (when used in combination with lenalidomide-dexamethasone) and weeks 1-9 (for use with the bortezomib-dexamethasone combination), decreasing to every 2 weeks between weeks 9 and 24 or 10 and 24, respectively, and progressing to every 4 weeks from week 25 onward until disease progression and unacceptable toxicity.

Daratumumab is marketed as Darzalex by Janssen Biotech Inc. Neutropenia and thrombocytopenia have been added to the list of warnings and precautions for the prescribing information for these new indications. Complete blood cell count should be monitored periodically during treatment and daratumumab administration delayed to allow recovery of neutrophils or platelets. Supportive care with growth factors or transfusion should be considered in the event of neutropenia or thrombocytopenia, respectively.

In November 2016, the US Food and Drug Administration expanded the approval of daratumumab for patients with multiple myeloma. The monoclonal antibody, which targets CD38, a protein that is highly expressed on the surface of multiple myeloma cells, was previously granted approval by the agency as a single agent for the treatment of patients who had received at least three previous therapies.

The current approval was for the use of daratumumab in two different combination regimens for the treatment of patients who have received one previous line of treatment. On the basis of improved progression-free survival (PFS), demonstrated in two randomized, open-label, phase 3 trials, daratumumab can now be used in combination with the immunomodulatory agent lenalidomide and dexamethasone, or the proteasome inhibitor bortezomib and dexamethasone, both standard therapies for the treatment of multiple myeloma.

In the POLLUX trial, 569 patients with relapsed/refractory multiple myeloma were randomized 1:1 to receive daratumumab in combination with lenalidomide-dexamethasone or lenalidomide-dexamethasone alone. The CASTOR trial randomized 498 patients with relapsed/refractory multiple myeloma 1:1 to daratumumab in combination with bortezomib-dexamethasone, or bortezomib-dexamethasone alone.

The eligibility and exclusion criteria for both trials were similar; patients had received at least one previous line of therapy, had documented progressive disease according to International Myeloma Working Group criteria, and had measurable disease on the basis of urine and/or serum assessments or serum-free, light-chain assay.

Patients with a neutrophil count of ≤1,000 cells/mm³, hemoglobin level of ≤7.5 g/dL, platelet count of <75,000 cells/mm³, creatinine clearance of ≤20 mL/min per 1.73m² body surface area (or <30 mL/min in the POLLUX trial), alanine aminotransferase or aspartate aminotransferase level ≥2.5 times the upper limit of normal (ULN) range, bilirubin level of ≥1.5 or more times the ULN range, disease refractory to bortezomib or lenalidomide, and unacceptable side effects from bortezomib or lenalidomide, were ineligible for these studies. In addition, patients with grade 2 or higher peripheral neuropathy or neuropathic pain, were excluded from the CASTOR study.

Randomization was stratified according to International Staging System disease stage at the time of screening (stage I, II or III, with higher stage indicating more severe disease), number of previous lines of therapy (1 vs 2, or 3 vs >3), and previous receipt of lenalidomide or bortezomib.

In the CASTOR trial, patients received up to eight 21-day cycles of bortezomib, administered subcutaneously at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 of cycles 1-8, and dexamethasone, administered orally or intravenously at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 for a total dose of 160 mg per cycle. Daratumumab was administered at a dose of 16 mg/kg intravenously once weekly on days 1, 8, and 15 during cycles 1 to 3, once every 3 weeks on day 1 of cycles 4-8, and once every 4 weeks thereafter.

In the POLLUX trial, patients were treated in 28-day cycles. Daratumumab was administered at the same dose as in the CASTOR trial, but on days 1, 8, 15 and 22 for 8 weeks during cycles 1 and 2, every 2 weeks on days 1 and 15 for 16 weeks during cycles 3 through 7, and every 4 weeks from then onwards. Lenalidomide was administered at a dose of 25 mg orally on days 1-21 of each cycle, and dexamethasone at a dose of 20 mg before infusion and 20 mg the following day.

The combination of daratumumab with lenalidomide-dexamethasone demonstrated a substantial improvement in PFS, compared with lenalidomide-dexamethasone alone (estimated PFS not yet reached vs 18.4 months, respectively; HR, 0.37; P < .0001), representing a 63% reduction in the risk of disease progression or death. Meanwhile, there was a 61% reduction in the risk of disease progression or death for the combination of daratumumab with bortezomib-dexamethasone in the CASTOR trial (estimated PFS not yet reached vs 7.2 months; HR: 0.39; P < .0001). The PFS benefit was observed across all prespecified subgroups in both studies.

In the CASTOR trial, over a median follow-up of 7.4 months, the overall response rate (ORR) was 82.9% for the combination arm, compared with 63.2% for the bortezomib-dexamethasone arm (P < .001), with a very good partial response (VGPR) or better rate of 59.2% compared with 29.1%, and a complete response (CR) rate of 19.2% compared with 9%. In the POLLUX trial, over a median follow-up of 13.5 months, ORR was 92.9% for the combination arm, compared with 76.4% for lenalidomide-dexamethasone, with a VGPR or better rate of 75.8% versus 44% and a CR rate of 43.1% versus 19.2%.

Overall, the safety profile for both combinations was consistent with what is usually observed with daratumumab monotherapy and lenalidomide-dexamethasone or bortezomib-dexamethasone combinations. The most frequently reported adverse events (AEs) were similar in both studies and included infusion reactions, diarrhea, and upper respiratory tract infection. In the POLLUX trial they also included nausea, fatigue, pyrexia, muscle spasm, cough, and dyspnea, whereas in the CASTOR trial patients also frequently experienced peripheral edema.

The most common grade 3/4 AEs in both trials were neutropenia (51.9% vs 37% in the POLLUX trial and 12.8 vs 4.2% in the CASTOR trial), thrombocytopenia (12.7% vs 13.5% and 45.3% vs 32.9%, respectively), and anemia (12.4% vs 19.6% and 14.4% vs 16%, respectively). The percentage of patients who discontinued treatment due to AEs was similar in both groups across the two studies; in the CASTOR trial discontinuations resulted most commonly from peripheral sensory neuropathy and pneumonia, while in the POLLUX trial, from pneumonia, pulmonary embolism and deterioration in general physical health.

The recommended dose for daratumumab in both combination regimens is 16 mg/kg intravenously, calculated on actual body weight. The dosing schedules begin with weekly administration during weeks 1-8 (when used in combination with lenalidomide-dexamethasone) and weeks 1-9 (for use with the bortezomib-dexamethasone combination), decreasing to every 2 weeks between weeks 9 and 24 or 10 and 24, respectively, and progressing to every 4 weeks from week 25 onward until disease progression and unacceptable toxicity.

Daratumumab is marketed as Darzalex by Janssen Biotech Inc. Neutropenia and thrombocytopenia have been added to the list of warnings and precautions for the prescribing information for these new indications. Complete blood cell count should be monitored periodically during treatment and daratumumab administration delayed to allow recovery of neutrophils or platelets. Supportive care with growth factors or transfusion should be considered in the event of neutropenia or thrombocytopenia, respectively.

Over the last decade the treatment of traumatic scars with lasers has emerged as a core component of multidisciplinary management. Military dermatologists have played a fundamental role in this shift by helping to develop new applications for existing technology and promulgate the techniques to reach additional providers and patients. Beyond scar management, the repurposing of adjunctive procedural techniques, such as sweat and hair reduction in amputees, also promises to enhance rehabilitation for many patients.

International engagement is a prominent and highly attractive feature of military practice, and military dermatologists routinely participate in disaster response missions, such as the 2010 Haiti earthquake,¹ and ongoing planned operations, such as Pacific Partnership in the Indo-Asia-Pacific region led by the US Navy.² In this article, I present a military perspective on the emerging niche of trauma dermatology and outline my more than 5 years of experience leveraging these skills to lead a multidisciplinary exchange in restorative medicine and burn scar management in Vietnam.

Trauma Dermatology

Over the course of the last decade, traumatic scar management has emerged as a staple of dermatologic surgery practice in some centers. Dermatologists hold the key to increasing patient access to effective outpatient care for symptomatic traumatic scars and other related issues using devices and techniques initially conceived for cosmetic applications.³ A major impetus for the considerable remodeling in our collective thoughts about traumatic scar management was the emergence of fractional laser technology in the mid-2000s. The remarkable, safe, reproducible, and durable benefits of fractional laser treatment of various scar types have created substantial momentum in recent years. The Naval Medical Center San Diego in California houses 1 of 3 centers of excellence in rehabilitation in the US military. Mastery of minimally invasive procedures to manage scars and other issues associated with trauma for the first time has established dermatologists as important partners in the overall rehabilitative effort.

My perspective on laser scar management has been previously described.^4,5 Ablative fractional laser resurfacing is the backbone of rehabilitative scar management.6 Although the literature in this field is still relatively immature, higher-quality studies are accumulating rapidly as the burn and surgical communities adopt the procedure more widely.^7-10 A considerable step forward in the dissemination of the procedure occurred recently with the development of category III Current Procedural Terminology (CPT) codes for ablative laser treatment of traumatic scars.¹¹ Category III CPT codes are temporary codes used for emerging procedures that have not yet been deemed medically necessary. Although individual insurance carriers can determine whether to cover these procedures and the corresponding level of reimbursement, regular use is important for ultimate elevation to category I codes by the American Medical Association over a 5-year observation period. The CPT codes 0479T (fractional ablative laser fenestration of burn and traumatic scars for functional improvement; first 100 cm² or part thereof, or 1% of body surface area of infants and children) and 0480T (fractional ablative laser fenestration of burn and traumatic scars for functional improvement; each additional 100 cm², or each additional 1% of body surface area of infants and children, or part thereof [list separately in addition to code for primary procedure]) are examples of these category III codes.¹¹

Nonablative fractional lasers; vascular-specific devices for erythematous scars; and long- and short-pulsed pigment-specific devices for hair and traumatic tattoo treatment, respectively, round out the commonly used laser platforms. For example, laser hair reduction can help improve the fit and comfort of prosthetic devices and has been shown to improve the overall quality of life for amputees.¹² Botulinum toxin can be an important component of treatment of excessive sweating induced by occlusive liners in prosthetics, and microwave eccrine ablation is an emerging potential option for longer-lasting sweat reduction in this population.^13-15 In addition to providing direct dermatology care and education, having members of the specialty in uniform has been a key to adopting new practical solutions to unsolved problems. 

Pacific Partnership

Pacific Partnership is the largest annual multinational humanitarian assistance and disaster preparedness mission in the Indo-Asia-Pacific region.¹⁶ It was started in 2006 following the tsunami that devastated parts of South and Southeast Asia in 2004. The recently concluded Pacific Partnership 2018 marked the 13th iteration of the annual mission led by the US Navy in collaboration with other partner nations, which in 2018 included Japan, Australia, Canada, the United Kingdom, France, Singapore, Korea, and Peru, as well as nongovernmental organizations and international governmental agencies. Host nation mission locations vary somewhat from year to year, but 2018 included visits of the hospital ship USNS Mercy and more than 800 personnel to Indonesia, Malaysia, Sri Lanka, and Vietnam. Medical/dental, engineering, and veterinary teams join with their counterparts in each host nation to conduct civic action projects, community health exchanges, medical care, and disaster response training activities.¹⁶

Rehabilitation As a Vehicle for Medical Exchange

Since approximately 2012 there has been an evolving paradigm in Pacific Partnership from an emphasis on maximizing direct patient care in changing locations to one focused on building lasting partnerships through subject matter expert exchange. Multidisciplinary scar management, including surgical and laser scar revision and physical and occupational therapy, is a very promising model for engagement. Potential advantages of this type of exchange include the following: developing nations have relatively high rates of burns and other forms of trauma as well as uneven access to acute and ongoing rehabilitative care; patients often are otherwise healthy and young; results are frequently profound and readily demonstrable; and it is a skill set that has become highly developed in the military system. Just as dermatologists are illustrating their utility in trauma rehabilitation at home, these procedural skills provide fertile ground for exchange overseas.

The Overseas Humanitarian Assistance Shared Information System is an online platform that allows users to apply for grants under the Asia-Pacific Regional Initiative. In 2013, I started the Burn Scar Treatment/Restorative Medicine exchange with a grant under this program. A multidisciplinary team representing the specialties of dermatology, hand surgery, plastic surgery, physical medicine and rehabilitation, and pulmonary critical care participated in the 2013 Asia Pacific Burn Congress hosted by the National Institute of Burns (NIB) in Hanoi, Vietnam, and then followed up with didactics and patient care alongside Vietnamese physicians in the management of disfiguring and debilitating scars from burns and other trauma. This pilot project consisted of three 2- to 3-week phases: 2 at the NIB in Hanoi and 1 with a delegation from the NIB visiting the Naval Medical Center San Diego. When initial project funds expired in 2014, the exchange was absorbed into Pacific Partnership 2014, which began a string of 4 consecutive annual Pacific Partnership engagements at Da Nang General Hospital in Vietnam. The 2 most recent exchanges, including the exchange associated with Pacific Partnership 2018, have taken place at Khanh Hoa General Hospital in Nha Trang, Vietnam. During this time the team has grown to include physical and occupational therapists as well as a wound care nurse.

The Burn Scar Treatment/Restorative Medicine exchange consists of side-by-side laser and surgical scar revision performed with our Vietnamese hosts in their own hospital. Our Vietnamese partners perform a large volume of reconstructive surgeries in their usual practice, so it truly has been a bilateral exchange incorporating some advanced technology and techniques with an emphasis on longitudinal multidisciplinary care. Importantly, the procedures are supplemented with preoperative and postoperative care as well as instruction provided by physical and occupational therapy and wound care professionals working alongside host nation support staff. Because the areas of involvement often are extensive and a patient may only be seen once in this setting, laser and surgical procedures often are performed concurrently in the host nation operating room. Anesthesia support is provided by the host nation. Basic consumable surgical supplies (eg, sutures, gloves, marking pens, staplers) are supplemented with mission funds. Special adjuncts for the most severe contractures have included negative pressure wound therapy and a collagen-based bilayer matrix wound dressing. Laser treatments have been performed on the vast majority of patients with an ablative fractional CO2 laser and laser-assisted delivery of corticosteroid in hypertrophic areas. Of note, use of the laser has been provided to our hosts by the manufacturer for each of the 7 iterations of the exchange, and the wound dressing manufacturer also has donated some of their product to the exchange through the nongovernmental organization Project Hope for 2 missions. To date, more than 300 patients have safely received life-changing treatment during the exchange, with some receiving multiple treatments (Figure). Although multiple treatments over time are ideal, even a single treatment session can result in considerable and lasting improvements in function and symptoms.¹⁷ The hospital ship USNS Mercy has the same laser technology and has brought advanced scar treatment techniques to the far corners of the Pacific.

Measuring overall success—treatment and international relations—in this setting can be challenging. On an individual patient level, the benefits of restoring the ability to walk and work as well as reducing pain and itching are manifest and transformative for both the patient and family; however, aggregating this information into high-quality outcome data is difficult given the heterogeneous nature of traumatic injuries, which is compounded in the setting of international engagement where the intersection between patient and visiting provider may be singular or difficult to predict, funding is limited, language frequently is a barrier, and documentation, privacy, and medical research guidelines may be unfamiliar or contradictory. The cumulative impact of these types of exchanges on the relationship between nations also is critical but difficult to measure. It is common sense that deepening personal and professional relationships in the medical setting over time can increase trust and mutual understanding, perhaps setting the stage for broader engagement in other more sensitive areas. Trust and understanding are rather nebulous concepts, but earlier this year marked the first visit of an American aircraft carrier to Da Nang since 1975, following 4 consecutive annual Pacific Partnership missions in the same city, which does carry the patina of successful engagement on a systemic level.

Final Thoughts

Based on my personal experience, I provide the following tips for building a successful, focused, long-term medical exchange.  

• Leverage your strengths and respect the strengths and style of practice of your hosts. A mind-set of exchange and not simply humanitarian care will be more successful. Your hosts are experts in a style of practice adapted to their surroundings and introducing new techniques that are grounded in the local practice patterns are more likely to be perpetuated.
• Collaboration with nongovernmental organizations and industry can be extremely helpful. Military and governmental organizations often are limited in funding, in the ways they can spend available funding, and in the receipt of donations. Appropriate coordination with civilian entities can elevate the exchange considerably by adding expertise and available assets as well as broadening the overall impact.  
• Engage the support staff as well as the physicians. You will leverage contact with families and enhance care over the long-term.
• The benefits of multiple interactions over time are manifest, for both the patients and the participants. Personal and professional relationships are intertwined and naturally mature over time. Go for singles and doubles first before swinging for the fences.
• Multidisciplinary work overseas informs and enhances collaboration at home.
• Adding regional experts in international research and assessment to these specialized medical teams may better capture the impact of future exchanges of any flavor.
• The model of creating a focused exchange with independent funding followed by incorporation of successful concepts into larger missions seems to be a worthy and reproducible approach for future projects of any variety.

Over the last decade the treatment of traumatic scars with lasers has emerged as a core component of multidisciplinary management. Military dermatologists have played a fundamental role in this shift by helping to develop new applications for existing technology and promulgate the techniques to reach additional providers and patients. Beyond scar management, the repurposing of adjunctive procedural techniques, such as sweat and hair reduction in amputees, also promises to enhance rehabilitation for many patients.

International engagement is a prominent and highly attractive feature of military practice, and military dermatologists routinely participate in disaster response missions, such as the 2010 Haiti earthquake,¹ and ongoing planned operations, such as Pacific Partnership in the Indo-Asia-Pacific region led by the US Navy.² In this article, I present a military perspective on the emerging niche of trauma dermatology and outline my more than 5 years of experience leveraging these skills to lead a multidisciplinary exchange in restorative medicine and burn scar management in Vietnam.

Trauma Dermatology

Over the course of the last decade, traumatic scar management has emerged as a staple of dermatologic surgery practice in some centers. Dermatologists hold the key to increasing patient access to effective outpatient care for symptomatic traumatic scars and other related issues using devices and techniques initially conceived for cosmetic applications.³ A major impetus for the considerable remodeling in our collective thoughts about traumatic scar management was the emergence of fractional laser technology in the mid-2000s. The remarkable, safe, reproducible, and durable benefits of fractional laser treatment of various scar types have created substantial momentum in recent years. The Naval Medical Center San Diego in California houses 1 of 3 centers of excellence in rehabilitation in the US military. Mastery of minimally invasive procedures to manage scars and other issues associated with trauma for the first time has established dermatologists as important partners in the overall rehabilitative effort.

My perspective on laser scar management has been previously described.^4,5 Ablative fractional laser resurfacing is the backbone of rehabilitative scar management.6 Although the literature in this field is still relatively immature, higher-quality studies are accumulating rapidly as the burn and surgical communities adopt the procedure more widely.^7-10 A considerable step forward in the dissemination of the procedure occurred recently with the development of category III Current Procedural Terminology (CPT) codes for ablative laser treatment of traumatic scars.¹¹ Category III CPT codes are temporary codes used for emerging procedures that have not yet been deemed medically necessary. Although individual insurance carriers can determine whether to cover these procedures and the corresponding level of reimbursement, regular use is important for ultimate elevation to category I codes by the American Medical Association over a 5-year observation period. The CPT codes 0479T (fractional ablative laser fenestration of burn and traumatic scars for functional improvement; first 100 cm² or part thereof, or 1% of body surface area of infants and children) and 0480T (fractional ablative laser fenestration of burn and traumatic scars for functional improvement; each additional 100 cm², or each additional 1% of body surface area of infants and children, or part thereof [list separately in addition to code for primary procedure]) are examples of these category III codes.¹¹

Nonablative fractional lasers; vascular-specific devices for erythematous scars; and long- and short-pulsed pigment-specific devices for hair and traumatic tattoo treatment, respectively, round out the commonly used laser platforms. For example, laser hair reduction can help improve the fit and comfort of prosthetic devices and has been shown to improve the overall quality of life for amputees.¹² Botulinum toxin can be an important component of treatment of excessive sweating induced by occlusive liners in prosthetics, and microwave eccrine ablation is an emerging potential option for longer-lasting sweat reduction in this population.^13-15 In addition to providing direct dermatology care and education, having members of the specialty in uniform has been a key to adopting new practical solutions to unsolved problems. 

Pacific Partnership

Pacific Partnership is the largest annual multinational humanitarian assistance and disaster preparedness mission in the Indo-Asia-Pacific region.¹⁶ It was started in 2006 following the tsunami that devastated parts of South and Southeast Asia in 2004. The recently concluded Pacific Partnership 2018 marked the 13th iteration of the annual mission led by the US Navy in collaboration with other partner nations, which in 2018 included Japan, Australia, Canada, the United Kingdom, France, Singapore, Korea, and Peru, as well as nongovernmental organizations and international governmental agencies. Host nation mission locations vary somewhat from year to year, but 2018 included visits of the hospital ship USNS Mercy and more than 800 personnel to Indonesia, Malaysia, Sri Lanka, and Vietnam. Medical/dental, engineering, and veterinary teams join with their counterparts in each host nation to conduct civic action projects, community health exchanges, medical care, and disaster response training activities.¹⁶

Rehabilitation As a Vehicle for Medical Exchange

Since approximately 2012 there has been an evolving paradigm in Pacific Partnership from an emphasis on maximizing direct patient care in changing locations to one focused on building lasting partnerships through subject matter expert exchange. Multidisciplinary scar management, including surgical and laser scar revision and physical and occupational therapy, is a very promising model for engagement. Potential advantages of this type of exchange include the following: developing nations have relatively high rates of burns and other forms of trauma as well as uneven access to acute and ongoing rehabilitative care; patients often are otherwise healthy and young; results are frequently profound and readily demonstrable; and it is a skill set that has become highly developed in the military system. Just as dermatologists are illustrating their utility in trauma rehabilitation at home, these procedural skills provide fertile ground for exchange overseas.

The Overseas Humanitarian Assistance Shared Information System is an online platform that allows users to apply for grants under the Asia-Pacific Regional Initiative. In 2013, I started the Burn Scar Treatment/Restorative Medicine exchange with a grant under this program. A multidisciplinary team representing the specialties of dermatology, hand surgery, plastic surgery, physical medicine and rehabilitation, and pulmonary critical care participated in the 2013 Asia Pacific Burn Congress hosted by the National Institute of Burns (NIB) in Hanoi, Vietnam, and then followed up with didactics and patient care alongside Vietnamese physicians in the management of disfiguring and debilitating scars from burns and other trauma. This pilot project consisted of three 2- to 3-week phases: 2 at the NIB in Hanoi and 1 with a delegation from the NIB visiting the Naval Medical Center San Diego. When initial project funds expired in 2014, the exchange was absorbed into Pacific Partnership 2014, which began a string of 4 consecutive annual Pacific Partnership engagements at Da Nang General Hospital in Vietnam. The 2 most recent exchanges, including the exchange associated with Pacific Partnership 2018, have taken place at Khanh Hoa General Hospital in Nha Trang, Vietnam. During this time the team has grown to include physical and occupational therapists as well as a wound care nurse.

The Burn Scar Treatment/Restorative Medicine exchange consists of side-by-side laser and surgical scar revision performed with our Vietnamese hosts in their own hospital. Our Vietnamese partners perform a large volume of reconstructive surgeries in their usual practice, so it truly has been a bilateral exchange incorporating some advanced technology and techniques with an emphasis on longitudinal multidisciplinary care. Importantly, the procedures are supplemented with preoperative and postoperative care as well as instruction provided by physical and occupational therapy and wound care professionals working alongside host nation support staff. Because the areas of involvement often are extensive and a patient may only be seen once in this setting, laser and surgical procedures often are performed concurrently in the host nation operating room. Anesthesia support is provided by the host nation. Basic consumable surgical supplies (eg, sutures, gloves, marking pens, staplers) are supplemented with mission funds. Special adjuncts for the most severe contractures have included negative pressure wound therapy and a collagen-based bilayer matrix wound dressing. Laser treatments have been performed on the vast majority of patients with an ablative fractional CO2 laser and laser-assisted delivery of corticosteroid in hypertrophic areas. Of note, use of the laser has been provided to our hosts by the manufacturer for each of the 7 iterations of the exchange, and the wound dressing manufacturer also has donated some of their product to the exchange through the nongovernmental organization Project Hope for 2 missions. To date, more than 300 patients have safely received life-changing treatment during the exchange, with some receiving multiple treatments (Figure). Although multiple treatments over time are ideal, even a single treatment session can result in considerable and lasting improvements in function and symptoms.¹⁷ The hospital ship USNS Mercy has the same laser technology and has brought advanced scar treatment techniques to the far corners of the Pacific.

Measuring overall success—treatment and international relations—in this setting can be challenging. On an individual patient level, the benefits of restoring the ability to walk and work as well as reducing pain and itching are manifest and transformative for both the patient and family; however, aggregating this information into high-quality outcome data is difficult given the heterogeneous nature of traumatic injuries, which is compounded in the setting of international engagement where the intersection between patient and visiting provider may be singular or difficult to predict, funding is limited, language frequently is a barrier, and documentation, privacy, and medical research guidelines may be unfamiliar or contradictory. The cumulative impact of these types of exchanges on the relationship between nations also is critical but difficult to measure. It is common sense that deepening personal and professional relationships in the medical setting over time can increase trust and mutual understanding, perhaps setting the stage for broader engagement in other more sensitive areas. Trust and understanding are rather nebulous concepts, but earlier this year marked the first visit of an American aircraft carrier to Da Nang since 1975, following 4 consecutive annual Pacific Partnership missions in the same city, which does carry the patina of successful engagement on a systemic level.

Final Thoughts

Based on my personal experience, I provide the following tips for building a successful, focused, long-term medical exchange.  

• Leverage your strengths and respect the strengths and style of practice of your hosts. A mind-set of exchange and not simply humanitarian care will be more successful. Your hosts are experts in a style of practice adapted to their surroundings and introducing new techniques that are grounded in the local practice patterns are more likely to be perpetuated.
• Collaboration with nongovernmental organizations and industry can be extremely helpful. Military and governmental organizations often are limited in funding, in the ways they can spend available funding, and in the receipt of donations. Appropriate coordination with civilian entities can elevate the exchange considerably by adding expertise and available assets as well as broadening the overall impact.  
• Engage the support staff as well as the physicians. You will leverage contact with families and enhance care over the long-term.
• The benefits of multiple interactions over time are manifest, for both the patients and the participants. Personal and professional relationships are intertwined and naturally mature over time. Go for singles and doubles first before swinging for the fences.
• Multidisciplinary work overseas informs and enhances collaboration at home.
• Adding regional experts in international research and assessment to these specialized medical teams may better capture the impact of future exchanges of any flavor.
• The model of creating a focused exchange with independent funding followed by incorporation of successful concepts into larger missions seems to be a worthy and reproducible approach for future projects of any variety.

Over the last decade the treatment of traumatic scars with lasers has emerged as a core component of multidisciplinary management. Military dermatologists have played a fundamental role in this shift by helping to develop new applications for existing technology and promulgate the techniques to reach additional providers and patients. Beyond scar management, the repurposing of adjunctive procedural techniques, such as sweat and hair reduction in amputees, also promises to enhance rehabilitation for many patients.

International engagement is a prominent and highly attractive feature of military practice, and military dermatologists routinely participate in disaster response missions, such as the 2010 Haiti earthquake,¹ and ongoing planned operations, such as Pacific Partnership in the Indo-Asia-Pacific region led by the US Navy.² In this article, I present a military perspective on the emerging niche of trauma dermatology and outline my more than 5 years of experience leveraging these skills to lead a multidisciplinary exchange in restorative medicine and burn scar management in Vietnam.

Trauma Dermatology

Over the course of the last decade, traumatic scar management has emerged as a staple of dermatologic surgery practice in some centers. Dermatologists hold the key to increasing patient access to effective outpatient care for symptomatic traumatic scars and other related issues using devices and techniques initially conceived for cosmetic applications.³ A major impetus for the considerable remodeling in our collective thoughts about traumatic scar management was the emergence of fractional laser technology in the mid-2000s. The remarkable, safe, reproducible, and durable benefits of fractional laser treatment of various scar types have created substantial momentum in recent years. The Naval Medical Center San Diego in California houses 1 of 3 centers of excellence in rehabilitation in the US military. Mastery of minimally invasive procedures to manage scars and other issues associated with trauma for the first time has established dermatologists as important partners in the overall rehabilitative effort.

My perspective on laser scar management has been previously described.^4,5 Ablative fractional laser resurfacing is the backbone of rehabilitative scar management.6 Although the literature in this field is still relatively immature, higher-quality studies are accumulating rapidly as the burn and surgical communities adopt the procedure more widely.^7-10 A considerable step forward in the dissemination of the procedure occurred recently with the development of category III Current Procedural Terminology (CPT) codes for ablative laser treatment of traumatic scars.¹¹ Category III CPT codes are temporary codes used for emerging procedures that have not yet been deemed medically necessary. Although individual insurance carriers can determine whether to cover these procedures and the corresponding level of reimbursement, regular use is important for ultimate elevation to category I codes by the American Medical Association over a 5-year observation period. The CPT codes 0479T (fractional ablative laser fenestration of burn and traumatic scars for functional improvement; first 100 cm² or part thereof, or 1% of body surface area of infants and children) and 0480T (fractional ablative laser fenestration of burn and traumatic scars for functional improvement; each additional 100 cm², or each additional 1% of body surface area of infants and children, or part thereof [list separately in addition to code for primary procedure]) are examples of these category III codes.¹¹

Nonablative fractional lasers; vascular-specific devices for erythematous scars; and long- and short-pulsed pigment-specific devices for hair and traumatic tattoo treatment, respectively, round out the commonly used laser platforms. For example, laser hair reduction can help improve the fit and comfort of prosthetic devices and has been shown to improve the overall quality of life for amputees.¹² Botulinum toxin can be an important component of treatment of excessive sweating induced by occlusive liners in prosthetics, and microwave eccrine ablation is an emerging potential option for longer-lasting sweat reduction in this population.^13-15 In addition to providing direct dermatology care and education, having members of the specialty in uniform has been a key to adopting new practical solutions to unsolved problems. 

Pacific Partnership

Pacific Partnership is the largest annual multinational humanitarian assistance and disaster preparedness mission in the Indo-Asia-Pacific region.¹⁶ It was started in 2006 following the tsunami that devastated parts of South and Southeast Asia in 2004. The recently concluded Pacific Partnership 2018 marked the 13th iteration of the annual mission led by the US Navy in collaboration with other partner nations, which in 2018 included Japan, Australia, Canada, the United Kingdom, France, Singapore, Korea, and Peru, as well as nongovernmental organizations and international governmental agencies. Host nation mission locations vary somewhat from year to year, but 2018 included visits of the hospital ship USNS Mercy and more than 800 personnel to Indonesia, Malaysia, Sri Lanka, and Vietnam. Medical/dental, engineering, and veterinary teams join with their counterparts in each host nation to conduct civic action projects, community health exchanges, medical care, and disaster response training activities.¹⁶

Rehabilitation As a Vehicle for Medical Exchange

Since approximately 2012 there has been an evolving paradigm in Pacific Partnership from an emphasis on maximizing direct patient care in changing locations to one focused on building lasting partnerships through subject matter expert exchange. Multidisciplinary scar management, including surgical and laser scar revision and physical and occupational therapy, is a very promising model for engagement. Potential advantages of this type of exchange include the following: developing nations have relatively high rates of burns and other forms of trauma as well as uneven access to acute and ongoing rehabilitative care; patients often are otherwise healthy and young; results are frequently profound and readily demonstrable; and it is a skill set that has become highly developed in the military system. Just as dermatologists are illustrating their utility in trauma rehabilitation at home, these procedural skills provide fertile ground for exchange overseas.

The Overseas Humanitarian Assistance Shared Information System is an online platform that allows users to apply for grants under the Asia-Pacific Regional Initiative. In 2013, I started the Burn Scar Treatment/Restorative Medicine exchange with a grant under this program. A multidisciplinary team representing the specialties of dermatology, hand surgery, plastic surgery, physical medicine and rehabilitation, and pulmonary critical care participated in the 2013 Asia Pacific Burn Congress hosted by the National Institute of Burns (NIB) in Hanoi, Vietnam, and then followed up with didactics and patient care alongside Vietnamese physicians in the management of disfiguring and debilitating scars from burns and other trauma. This pilot project consisted of three 2- to 3-week phases: 2 at the NIB in Hanoi and 1 with a delegation from the NIB visiting the Naval Medical Center San Diego. When initial project funds expired in 2014, the exchange was absorbed into Pacific Partnership 2014, which began a string of 4 consecutive annual Pacific Partnership engagements at Da Nang General Hospital in Vietnam. The 2 most recent exchanges, including the exchange associated with Pacific Partnership 2018, have taken place at Khanh Hoa General Hospital in Nha Trang, Vietnam. During this time the team has grown to include physical and occupational therapists as well as a wound care nurse.

The Burn Scar Treatment/Restorative Medicine exchange consists of side-by-side laser and surgical scar revision performed with our Vietnamese hosts in their own hospital. Our Vietnamese partners perform a large volume of reconstructive surgeries in their usual practice, so it truly has been a bilateral exchange incorporating some advanced technology and techniques with an emphasis on longitudinal multidisciplinary care. Importantly, the procedures are supplemented with preoperative and postoperative care as well as instruction provided by physical and occupational therapy and wound care professionals working alongside host nation support staff. Because the areas of involvement often are extensive and a patient may only be seen once in this setting, laser and surgical procedures often are performed concurrently in the host nation operating room. Anesthesia support is provided by the host nation. Basic consumable surgical supplies (eg, sutures, gloves, marking pens, staplers) are supplemented with mission funds. Special adjuncts for the most severe contractures have included negative pressure wound therapy and a collagen-based bilayer matrix wound dressing. Laser treatments have been performed on the vast majority of patients with an ablative fractional CO2 laser and laser-assisted delivery of corticosteroid in hypertrophic areas. Of note, use of the laser has been provided to our hosts by the manufacturer for each of the 7 iterations of the exchange, and the wound dressing manufacturer also has donated some of their product to the exchange through the nongovernmental organization Project Hope for 2 missions. To date, more than 300 patients have safely received life-changing treatment during the exchange, with some receiving multiple treatments (Figure). Although multiple treatments over time are ideal, even a single treatment session can result in considerable and lasting improvements in function and symptoms.¹⁷ The hospital ship USNS Mercy has the same laser technology and has brought advanced scar treatment techniques to the far corners of the Pacific.

Measuring overall success—treatment and international relations—in this setting can be challenging. On an individual patient level, the benefits of restoring the ability to walk and work as well as reducing pain and itching are manifest and transformative for both the patient and family; however, aggregating this information into high-quality outcome data is difficult given the heterogeneous nature of traumatic injuries, which is compounded in the setting of international engagement where the intersection between patient and visiting provider may be singular or difficult to predict, funding is limited, language frequently is a barrier, and documentation, privacy, and medical research guidelines may be unfamiliar or contradictory. The cumulative impact of these types of exchanges on the relationship between nations also is critical but difficult to measure. It is common sense that deepening personal and professional relationships in the medical setting over time can increase trust and mutual understanding, perhaps setting the stage for broader engagement in other more sensitive areas. Trust and understanding are rather nebulous concepts, but earlier this year marked the first visit of an American aircraft carrier to Da Nang since 1975, following 4 consecutive annual Pacific Partnership missions in the same city, which does carry the patina of successful engagement on a systemic level.

Final Thoughts

Based on my personal experience, I provide the following tips for building a successful, focused, long-term medical exchange.  

• Leverage your strengths and respect the strengths and style of practice of your hosts. A mind-set of exchange and not simply humanitarian care will be more successful. Your hosts are experts in a style of practice adapted to their surroundings and introducing new techniques that are grounded in the local practice patterns are more likely to be perpetuated.
• Collaboration with nongovernmental organizations and industry can be extremely helpful. Military and governmental organizations often are limited in funding, in the ways they can spend available funding, and in the receipt of donations. Appropriate coordination with civilian entities can elevate the exchange considerably by adding expertise and available assets as well as broadening the overall impact.  
• Engage the support staff as well as the physicians. You will leverage contact with families and enhance care over the long-term.
• The benefits of multiple interactions over time are manifest, for both the patients and the participants. Personal and professional relationships are intertwined and naturally mature over time. Go for singles and doubles first before swinging for the fences.
• Multidisciplinary work overseas informs and enhances collaboration at home.
• Adding regional experts in international research and assessment to these specialized medical teams may better capture the impact of future exchanges of any flavor.
• The model of creating a focused exchange with independent funding followed by incorporation of successful concepts into larger missions seems to be a worthy and reproducible approach for future projects of any variety.