Dermatology

A 2-YEAR-OLD BOY presented to the emergency room with a 1-day history of a diffuse, mildly pruritic rash and swelling of his knees, ankles, and feet following treatment of acute otitis media with amoxicillin for the previous 8 days. He was mildly febrile and consolable, but he was refusing to walk. His medical history was unremarkable.

Physical examination revealed erythematous annular wheals on his chest, face, back, and extremities. Lymphadenopathy and mucous membrane involvement were not present. A complete blood count (CBC) with differential, inflammatory marker tests, and a comprehensive metabolic panel were ordered. Given the joint swelling and rash, the patient was admitted for observation.

During his second day in the hospital, his skin lesions enlarged and several formed dusky blue centers (FIGURE 1A). He also developed swelling of his hands (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s lab work came back within normal range, except for an elevated white blood cell count (19,700/mm³; reference range, 4500-13,500/mm³). His mild systemic symptoms, skin lesions without blistering or necrosis, acral edema, and the absence of lymphadenopathy pointed to a diagnosis of urticaria multiforme.

Children with urticaria multiforme may have significant edema of the feet and may find walking difficult; this should not be confused with arthritis or arthralgias.

Urticaria multiforme, also called acute annular urticaria or acute urticarial hypersensitivity syndrome, is a histamine-mediated hypersensitivity reaction characterized by transient annular, polycyclic, urticarial lesions with central ecchymosis. The incidence and prevalence are not known. Urticaria multiforme is considered common, but it is frequently misdiagnosed.¹ It typically manifests in children ages 4 months to 4 years and begins with small erythematous macules, papules, and plaques that progress to large blanchable wheals with dusky blue centers.^1-3 Lesions are usually located on the face, trunk, and extremities and are often pruritic (60%-94%).^1-3 Individual lesions last less than 24 hours, but new ones may appear. The rash generally lasts 2 to 12 days.^1,3

Patients often report a preceding viral illness, otitis media, recent use of antibiotics, or recent immunizations. Dermatographism due to mast cell–mediated cutaneous hypersensitivity at sites of minor skin trauma is common (44%).¹ Patients often have associated facial or acral edema (72%).¹ Children with significant edema of the feet may find walking difficult, which should not be confused with arthritis or arthralgias. Generally, patients are nontoxic in appearance, and systemic symptoms are limited to a low-grade fever.^1-3

The diagnosis is made clinically and should not require a skin biopsy or extensive laboratory testing.When performed, laboratory studies, including CBC, erythrocyte sedimentation rate, C-reactive protein, and urinalysis are routinely normal.

Erythema multiforme and urticarial vasculitis are part of the differential

The differential diagnosis in this case includes erythema multiforme, Henoch-Schönlein purpura, serum sickness-like reaction, and urticarial vasculitis (TABLE^1,2,4).

Continue to: Erythema multiforme

Erythema multiforme is a common misdiagnosis in patients with urticaria multiforme.^1,2 The erythema multiforme rash has a “target” lesion with outer erythema and central ecchymosis, which may develop blisters or necrosis. Lesions are fixed and last 2 to 3 weeks. Unlike urticaria multiforme, patients with erythema multiforme commonly have mucous membrane erosions and occasionally ulcerations. Facial and acral edema is rare. Treatment is largely symptomatic and can include glucocorticoids. Antiviral medications may be used to treat recurrences.^1,2

Henoch-Schönlein purpura is an immunoglobulin A–mediated vasculitis that affects the skin, gastrointestinal tract, and joints.^4,5 Patients often present with arthralgias, gastrointestinal symptoms such as abdominal pain and bleeding, and a nonpruritic, erythematous rash that progresses to palpable purpura in dependent areas of the body. Treatment is generally symptomatic, but steroids may be used in severe cases.^4,5

Serum sickness-like reaction can manifest with angioedema and a similar urticarial rash (with central clearing) that lasts 1 to 6 weeks.^1,2,6,7 However, patients tend to have a high-grade fever, arthralgias, myalgias, and lymphadenopathy while dermatographism is absent. Treatment includes discontinuing the offending agent and the use of H1 and H2 antihistamines and steroids, in severe cases.

Urticarial vasculitis manifests as plaques or wheals lasting 1 to 7 days that may cause burning and pain but not pruritis.^2,5 Purpura or hypopigmentation may develop as the hives resolve. Angioedema and arthralgias are common, but dermatographism is not present. Triggers include infections, autoimmune disease, malignancy, and the use of certain medications. H1 and H2 blockers and nonsteroidal anti-inflammatory agents are first-line therapy.²

Step 1: Discontinue offending agents; Step 2: Recommend antihistamines

Treatment consists of discontinuing any offending agent (if suspected) and using systemic H1 or H2 antihistamines for symptom relief. Systemic steroids should only be given in refractory cases.

Continue to: Our patient's amoxicillin

Our patient’s amoxicillin was discontinued, and he was started on a 14-day course of cetirizine 5 mg bid and hydroxyzine 10 mg at bedtime. He was also started on triamcinolone 0.1% cream to be applied twice daily for 1 week. During his 3-day hospital stay, his fever resolved and his rash and edema improved.

During an outpatient follow-up visit with a pediatric dermatologist 2 weeks after discharge, the patient’s rash was still present and dermatographism was noted. In light of this, his parents were instructed to continue giving the cetirizine and hydroxyzine once daily for an additional 2 weeks and to return as needed.

A 2-YEAR-OLD BOY presented to the emergency room with a 1-day history of a diffuse, mildly pruritic rash and swelling of his knees, ankles, and feet following treatment of acute otitis media with amoxicillin for the previous 8 days. He was mildly febrile and consolable, but he was refusing to walk. His medical history was unremarkable.

Physical examination revealed erythematous annular wheals on his chest, face, back, and extremities. Lymphadenopathy and mucous membrane involvement were not present. A complete blood count (CBC) with differential, inflammatory marker tests, and a comprehensive metabolic panel were ordered. Given the joint swelling and rash, the patient was admitted for observation.

During his second day in the hospital, his skin lesions enlarged and several formed dusky blue centers (FIGURE 1A). He also developed swelling of his hands (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s lab work came back within normal range, except for an elevated white blood cell count (19,700/mm³; reference range, 4500-13,500/mm³). His mild systemic symptoms, skin lesions without blistering or necrosis, acral edema, and the absence of lymphadenopathy pointed to a diagnosis of urticaria multiforme.

Children with urticaria multiforme may have significant edema of the feet and may find walking difficult; this should not be confused with arthritis or arthralgias.

Urticaria multiforme, also called acute annular urticaria or acute urticarial hypersensitivity syndrome, is a histamine-mediated hypersensitivity reaction characterized by transient annular, polycyclic, urticarial lesions with central ecchymosis. The incidence and prevalence are not known. Urticaria multiforme is considered common, but it is frequently misdiagnosed.¹ It typically manifests in children ages 4 months to 4 years and begins with small erythematous macules, papules, and plaques that progress to large blanchable wheals with dusky blue centers.^1-3 Lesions are usually located on the face, trunk, and extremities and are often pruritic (60%-94%).^1-3 Individual lesions last less than 24 hours, but new ones may appear. The rash generally lasts 2 to 12 days.^1,3

Patients often report a preceding viral illness, otitis media, recent use of antibiotics, or recent immunizations. Dermatographism due to mast cell–mediated cutaneous hypersensitivity at sites of minor skin trauma is common (44%).¹ Patients often have associated facial or acral edema (72%).¹ Children with significant edema of the feet may find walking difficult, which should not be confused with arthritis or arthralgias. Generally, patients are nontoxic in appearance, and systemic symptoms are limited to a low-grade fever.^1-3

The diagnosis is made clinically and should not require a skin biopsy or extensive laboratory testing.When performed, laboratory studies, including CBC, erythrocyte sedimentation rate, C-reactive protein, and urinalysis are routinely normal.

Erythema multiforme and urticarial vasculitis are part of the differential

The differential diagnosis in this case includes erythema multiforme, Henoch-Schönlein purpura, serum sickness-like reaction, and urticarial vasculitis (TABLE^1,2,4).

Continue to: Erythema multiforme

Erythema multiforme is a common misdiagnosis in patients with urticaria multiforme.^1,2 The erythema multiforme rash has a “target” lesion with outer erythema and central ecchymosis, which may develop blisters or necrosis. Lesions are fixed and last 2 to 3 weeks. Unlike urticaria multiforme, patients with erythema multiforme commonly have mucous membrane erosions and occasionally ulcerations. Facial and acral edema is rare. Treatment is largely symptomatic and can include glucocorticoids. Antiviral medications may be used to treat recurrences.^1,2

Henoch-Schönlein purpura is an immunoglobulin A–mediated vasculitis that affects the skin, gastrointestinal tract, and joints.^4,5 Patients often present with arthralgias, gastrointestinal symptoms such as abdominal pain and bleeding, and a nonpruritic, erythematous rash that progresses to palpable purpura in dependent areas of the body. Treatment is generally symptomatic, but steroids may be used in severe cases.^4,5

Serum sickness-like reaction can manifest with angioedema and a similar urticarial rash (with central clearing) that lasts 1 to 6 weeks.^1,2,6,7 However, patients tend to have a high-grade fever, arthralgias, myalgias, and lymphadenopathy while dermatographism is absent. Treatment includes discontinuing the offending agent and the use of H1 and H2 antihistamines and steroids, in severe cases.

Urticarial vasculitis manifests as plaques or wheals lasting 1 to 7 days that may cause burning and pain but not pruritis.^2,5 Purpura or hypopigmentation may develop as the hives resolve. Angioedema and arthralgias are common, but dermatographism is not present. Triggers include infections, autoimmune disease, malignancy, and the use of certain medications. H1 and H2 blockers and nonsteroidal anti-inflammatory agents are first-line therapy.²

Step 1: Discontinue offending agents; Step 2: Recommend antihistamines

Treatment consists of discontinuing any offending agent (if suspected) and using systemic H1 or H2 antihistamines for symptom relief. Systemic steroids should only be given in refractory cases.

Continue to: Our patient's amoxicillin

Our patient’s amoxicillin was discontinued, and he was started on a 14-day course of cetirizine 5 mg bid and hydroxyzine 10 mg at bedtime. He was also started on triamcinolone 0.1% cream to be applied twice daily for 1 week. During his 3-day hospital stay, his fever resolved and his rash and edema improved.

During an outpatient follow-up visit with a pediatric dermatologist 2 weeks after discharge, the patient’s rash was still present and dermatographism was noted. In light of this, his parents were instructed to continue giving the cetirizine and hydroxyzine once daily for an additional 2 weeks and to return as needed.

A 2-YEAR-OLD BOY presented to the emergency room with a 1-day history of a diffuse, mildly pruritic rash and swelling of his knees, ankles, and feet following treatment of acute otitis media with amoxicillin for the previous 8 days. He was mildly febrile and consolable, but he was refusing to walk. His medical history was unremarkable.

Physical examination revealed erythematous annular wheals on his chest, face, back, and extremities. Lymphadenopathy and mucous membrane involvement were not present. A complete blood count (CBC) with differential, inflammatory marker tests, and a comprehensive metabolic panel were ordered. Given the joint swelling and rash, the patient was admitted for observation.

During his second day in the hospital, his skin lesions enlarged and several formed dusky blue centers (FIGURE 1A). He also developed swelling of his hands (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s lab work came back within normal range, except for an elevated white blood cell count (19,700/mm³; reference range, 4500-13,500/mm³). His mild systemic symptoms, skin lesions without blistering or necrosis, acral edema, and the absence of lymphadenopathy pointed to a diagnosis of urticaria multiforme.

Children with urticaria multiforme may have significant edema of the feet and may find walking difficult; this should not be confused with arthritis or arthralgias.

Urticaria multiforme, also called acute annular urticaria or acute urticarial hypersensitivity syndrome, is a histamine-mediated hypersensitivity reaction characterized by transient annular, polycyclic, urticarial lesions with central ecchymosis. The incidence and prevalence are not known. Urticaria multiforme is considered common, but it is frequently misdiagnosed.¹ It typically manifests in children ages 4 months to 4 years and begins with small erythematous macules, papules, and plaques that progress to large blanchable wheals with dusky blue centers.^1-3 Lesions are usually located on the face, trunk, and extremities and are often pruritic (60%-94%).^1-3 Individual lesions last less than 24 hours, but new ones may appear. The rash generally lasts 2 to 12 days.^1,3

Patients often report a preceding viral illness, otitis media, recent use of antibiotics, or recent immunizations. Dermatographism due to mast cell–mediated cutaneous hypersensitivity at sites of minor skin trauma is common (44%).¹ Patients often have associated facial or acral edema (72%).¹ Children with significant edema of the feet may find walking difficult, which should not be confused with arthritis or arthralgias. Generally, patients are nontoxic in appearance, and systemic symptoms are limited to a low-grade fever.^1-3

The diagnosis is made clinically and should not require a skin biopsy or extensive laboratory testing.When performed, laboratory studies, including CBC, erythrocyte sedimentation rate, C-reactive protein, and urinalysis are routinely normal.

Erythema multiforme and urticarial vasculitis are part of the differential

The differential diagnosis in this case includes erythema multiforme, Henoch-Schönlein purpura, serum sickness-like reaction, and urticarial vasculitis (TABLE^1,2,4).

Continue to: Erythema multiforme

Erythema multiforme is a common misdiagnosis in patients with urticaria multiforme.^1,2 The erythema multiforme rash has a “target” lesion with outer erythema and central ecchymosis, which may develop blisters or necrosis. Lesions are fixed and last 2 to 3 weeks. Unlike urticaria multiforme, patients with erythema multiforme commonly have mucous membrane erosions and occasionally ulcerations. Facial and acral edema is rare. Treatment is largely symptomatic and can include glucocorticoids. Antiviral medications may be used to treat recurrences.^1,2

Henoch-Schönlein purpura is an immunoglobulin A–mediated vasculitis that affects the skin, gastrointestinal tract, and joints.^4,5 Patients often present with arthralgias, gastrointestinal symptoms such as abdominal pain and bleeding, and a nonpruritic, erythematous rash that progresses to palpable purpura in dependent areas of the body. Treatment is generally symptomatic, but steroids may be used in severe cases.^4,5

Serum sickness-like reaction can manifest with angioedema and a similar urticarial rash (with central clearing) that lasts 1 to 6 weeks.^1,2,6,7 However, patients tend to have a high-grade fever, arthralgias, myalgias, and lymphadenopathy while dermatographism is absent. Treatment includes discontinuing the offending agent and the use of H1 and H2 antihistamines and steroids, in severe cases.

Urticarial vasculitis manifests as plaques or wheals lasting 1 to 7 days that may cause burning and pain but not pruritis.^2,5 Purpura or hypopigmentation may develop as the hives resolve. Angioedema and arthralgias are common, but dermatographism is not present. Triggers include infections, autoimmune disease, malignancy, and the use of certain medications. H1 and H2 blockers and nonsteroidal anti-inflammatory agents are first-line therapy.²

Step 1: Discontinue offending agents; Step 2: Recommend antihistamines

Treatment consists of discontinuing any offending agent (if suspected) and using systemic H1 or H2 antihistamines for symptom relief. Systemic steroids should only be given in refractory cases.

Continue to: Our patient's amoxicillin

Our patient’s amoxicillin was discontinued, and he was started on a 14-day course of cetirizine 5 mg bid and hydroxyzine 10 mg at bedtime. He was also started on triamcinolone 0.1% cream to be applied twice daily for 1 week. During his 3-day hospital stay, his fever resolved and his rash and edema improved.

During an outpatient follow-up visit with a pediatric dermatologist 2 weeks after discharge, the patient’s rash was still present and dermatographism was noted. In light of this, his parents were instructed to continue giving the cetirizine and hydroxyzine once daily for an additional 2 weeks and to return as needed.

ON101 (Fespixon, Oneness Biotech), a first-in-class, macrophage-regulating, wound-healing cream for diabetic foot ulcers has shown benefit over absorbent dressings in a phase 3 trial, with another trial ongoing.

The product became available in Taiwan on July 4, 2021, after receiving regulatory approval from the Taiwan Food and Drug Administration based on efficacy and safety findings in a three-country phase 3 clinical trial.  

Oneness Biotech has also just started a second phase 3 trial in the United States, with a planned enrollment of 208 patients with diabetic foot ulcers, which will compare ON101 cream versus placebo cream, in addition to standard care, over 20 weeks.

The company expects to complete that trial and file a new drug application with the U.S. Food and Drug Administration in 2023, and a global launch is planned for 2025, said Oneness Biotech founder and CEO William Lu.
 

Current and upcoming trials

The Taiwan FDA approval of ON101 was based on a 236-patient clinical trial conducted in Taiwan, China, and the United States by Yu-Yao Huang MD, PhD, Chang Gung Memorial Hospital, Taoyuan City, Taiwan, and colleagues, which was published online Sept. 3, 2021, in JAMA Network Open.

The study results will also be presented during an oral session at the European Association for the Study of Diabetes meeting on Sept. 30.

The published trial showed that foot ulcers treated with ON101 cream were almost three times more likely to be completely healed at 16 weeks than those treated with standard care with an absorbent dressing (Aquacel Hydrofiber, ConvaTec) (odds ratio, 2.84; P < .001).

“The findings of this study suggest that ON101, a macrophage regulator that behaves differently from moisture-retaining dressings, represents an active-healing alternative for home and primary care of patients with chronic [diabetic foot ulcers],” the researchers concluded.

“ON101 was also granted a fast track designation by the U.S. FDA in March this year,” senior author Shun-Chen Chang, MD, Taipei Medical University–Shuang Ho Hospital, New Taipei City, Taiwan, said in an interview.

“Patients in the United States can access this new drug via the expanded access program or by participating in the second phase 3 trial in the United States,” added coauthor Shawn M. Cazzell, DPM, chief medical officer, Limb Preservation Platform, Fresno, Calif., who is involved with both trials.

It is “exciting” to have a new therapy for diabetic foot ulcers, said Dr. Cazzell, because they are serious and life-threatening.
 

Could cream with plant extracts surpass current care?

Current standard clinical care for diabetic foot ulcer consists of debridement, off-loading, infection control, and maintaining a moist environment with dressings, Huang and colleagues explain. If the foot ulcer does not respond, growth factors, tissue-engineering products, hyperbaric oxygen, or negative pressure wound therapies may be used.

However, the number of amputations from chronic diabetic foot ulcers that do not heal is increasing, pointing to a need for better treatment options.  

Hyperglycemia increases the ratio of M1 proinflammatory macrophages to M2 proregenerative macrophages, and accumulating evidence suggests this might be a potential treatment target.  

Researchers at Oneness Biotech showed that ON101, which is comprised of extracts from two plants, Plectranthus amboinicus and Centella asiatica, exerts a wound-healing effect by regulating the balance between M1 and M2 macrophages.

An extract of one plant suppresses inflammation, while an extract of the other increases collagen synthesis.

In preclinical studies, these two plant extracts had a synergistic effect on balancing the ratio of M1 to M2 macrophages and accelerating wound healing in a mouse model. This was followed by promising efficacy and safety results in two trials of 24 patients and 30 patients.
 

Significantly better healing with ON101 than standard care

For the current phase 3, randomized clinical trial, researchers enrolled patients in 21 clinics from November 2012 to May 2020.

To be eligible for the study, patients had to be 20-80 years old, with a hemoglobin A1c less than 12%. They also had to have a Wagner grade 1 or 2 foot ulcer that was 1-25 cm² after debridement, had been treated with standard care, and was present for at least 4 weeks.

Patients were a mean age of 57 years and 74% were men. They had a mean A1c of 8.1%, and 61% had had diabetes for more than 10 years.

Most (78%) of the diabetic foot ulcers were Wagner grade 2. The wounds had a mean area of 4.8 cm² and had been present for a mean of 7 months.

Patients were instructed on how to self-administer ON101 cream twice a day (treatment group, n = 122) or how to apply an absorbent dressing and change it daily or two or three times a week (standard care group, n = 114). All patients were allowed to apply a sterile gauze dressing.  

They visited the clinic every 2 weeks during the 16-week treatment phase and 12-week observation phase.

In the full analysis set, 74 patients (61%) in the ON101 group and 40 patients (35%) in the standard care group had complete wound healing after 16 weeks of treatment.

The subgroup of patients at higher risk of poor wound healing (A1c >9%, ulcer area >5 cm², and diabetic foot ulcer duration >6 months) also had significantly better healing with the ON101 cream than standard care.

There were seven (5.7%) treatment-emergent adverse events in the ON101 group versus five (4.4%) in the standard care group.

There were no treatment-related serious adverse events in the ON101 group versus one (0.9%) in the comparator group.

The study was funded by Oneness Biotech, Microbio Group, and Shanghai Haihe Pharmaceutical. One author has reported receiving fees from Oneness Biotech, and Dr. Chang has reported receiving a speakers fee from Oneness Biotech. The other authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ON101 (Fespixon, Oneness Biotech), a first-in-class, macrophage-regulating, wound-healing cream for diabetic foot ulcers has shown benefit over absorbent dressings in a phase 3 trial, with another trial ongoing.

The product became available in Taiwan on July 4, 2021, after receiving regulatory approval from the Taiwan Food and Drug Administration based on efficacy and safety findings in a three-country phase 3 clinical trial.  

Oneness Biotech has also just started a second phase 3 trial in the United States, with a planned enrollment of 208 patients with diabetic foot ulcers, which will compare ON101 cream versus placebo cream, in addition to standard care, over 20 weeks.

The company expects to complete that trial and file a new drug application with the U.S. Food and Drug Administration in 2023, and a global launch is planned for 2025, said Oneness Biotech founder and CEO William Lu.
 

Current and upcoming trials

The Taiwan FDA approval of ON101 was based on a 236-patient clinical trial conducted in Taiwan, China, and the United States by Yu-Yao Huang MD, PhD, Chang Gung Memorial Hospital, Taoyuan City, Taiwan, and colleagues, which was published online Sept. 3, 2021, in JAMA Network Open.

The study results will also be presented during an oral session at the European Association for the Study of Diabetes meeting on Sept. 30.

The published trial showed that foot ulcers treated with ON101 cream were almost three times more likely to be completely healed at 16 weeks than those treated with standard care with an absorbent dressing (Aquacel Hydrofiber, ConvaTec) (odds ratio, 2.84; P < .001).

“The findings of this study suggest that ON101, a macrophage regulator that behaves differently from moisture-retaining dressings, represents an active-healing alternative for home and primary care of patients with chronic [diabetic foot ulcers],” the researchers concluded.

“ON101 was also granted a fast track designation by the U.S. FDA in March this year,” senior author Shun-Chen Chang, MD, Taipei Medical University–Shuang Ho Hospital, New Taipei City, Taiwan, said in an interview.

“Patients in the United States can access this new drug via the expanded access program or by participating in the second phase 3 trial in the United States,” added coauthor Shawn M. Cazzell, DPM, chief medical officer, Limb Preservation Platform, Fresno, Calif., who is involved with both trials.

It is “exciting” to have a new therapy for diabetic foot ulcers, said Dr. Cazzell, because they are serious and life-threatening.
 

Could cream with plant extracts surpass current care?

Current standard clinical care for diabetic foot ulcer consists of debridement, off-loading, infection control, and maintaining a moist environment with dressings, Huang and colleagues explain. If the foot ulcer does not respond, growth factors, tissue-engineering products, hyperbaric oxygen, or negative pressure wound therapies may be used.

However, the number of amputations from chronic diabetic foot ulcers that do not heal is increasing, pointing to a need for better treatment options.  

Hyperglycemia increases the ratio of M1 proinflammatory macrophages to M2 proregenerative macrophages, and accumulating evidence suggests this might be a potential treatment target.  

Researchers at Oneness Biotech showed that ON101, which is comprised of extracts from two plants, Plectranthus amboinicus and Centella asiatica, exerts a wound-healing effect by regulating the balance between M1 and M2 macrophages.

An extract of one plant suppresses inflammation, while an extract of the other increases collagen synthesis.

In preclinical studies, these two plant extracts had a synergistic effect on balancing the ratio of M1 to M2 macrophages and accelerating wound healing in a mouse model. This was followed by promising efficacy and safety results in two trials of 24 patients and 30 patients.
 

Significantly better healing with ON101 than standard care

For the current phase 3, randomized clinical trial, researchers enrolled patients in 21 clinics from November 2012 to May 2020.

To be eligible for the study, patients had to be 20-80 years old, with a hemoglobin A1c less than 12%. They also had to have a Wagner grade 1 or 2 foot ulcer that was 1-25 cm² after debridement, had been treated with standard care, and was present for at least 4 weeks.

Patients were a mean age of 57 years and 74% were men. They had a mean A1c of 8.1%, and 61% had had diabetes for more than 10 years.

Most (78%) of the diabetic foot ulcers were Wagner grade 2. The wounds had a mean area of 4.8 cm² and had been present for a mean of 7 months.

Patients were instructed on how to self-administer ON101 cream twice a day (treatment group, n = 122) or how to apply an absorbent dressing and change it daily or two or three times a week (standard care group, n = 114). All patients were allowed to apply a sterile gauze dressing.  

They visited the clinic every 2 weeks during the 16-week treatment phase and 12-week observation phase.

In the full analysis set, 74 patients (61%) in the ON101 group and 40 patients (35%) in the standard care group had complete wound healing after 16 weeks of treatment.

The subgroup of patients at higher risk of poor wound healing (A1c >9%, ulcer area >5 cm², and diabetic foot ulcer duration >6 months) also had significantly better healing with the ON101 cream than standard care.

There were seven (5.7%) treatment-emergent adverse events in the ON101 group versus five (4.4%) in the standard care group.

There were no treatment-related serious adverse events in the ON101 group versus one (0.9%) in the comparator group.

The study was funded by Oneness Biotech, Microbio Group, and Shanghai Haihe Pharmaceutical. One author has reported receiving fees from Oneness Biotech, and Dr. Chang has reported receiving a speakers fee from Oneness Biotech. The other authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ON101 (Fespixon, Oneness Biotech), a first-in-class, macrophage-regulating, wound-healing cream for diabetic foot ulcers has shown benefit over absorbent dressings in a phase 3 trial, with another trial ongoing.

The product became available in Taiwan on July 4, 2021, after receiving regulatory approval from the Taiwan Food and Drug Administration based on efficacy and safety findings in a three-country phase 3 clinical trial.  

Oneness Biotech has also just started a second phase 3 trial in the United States, with a planned enrollment of 208 patients with diabetic foot ulcers, which will compare ON101 cream versus placebo cream, in addition to standard care, over 20 weeks.

The company expects to complete that trial and file a new drug application with the U.S. Food and Drug Administration in 2023, and a global launch is planned for 2025, said Oneness Biotech founder and CEO William Lu.
 

Current and upcoming trials

The Taiwan FDA approval of ON101 was based on a 236-patient clinical trial conducted in Taiwan, China, and the United States by Yu-Yao Huang MD, PhD, Chang Gung Memorial Hospital, Taoyuan City, Taiwan, and colleagues, which was published online Sept. 3, 2021, in JAMA Network Open.

The study results will also be presented during an oral session at the European Association for the Study of Diabetes meeting on Sept. 30.

The published trial showed that foot ulcers treated with ON101 cream were almost three times more likely to be completely healed at 16 weeks than those treated with standard care with an absorbent dressing (Aquacel Hydrofiber, ConvaTec) (odds ratio, 2.84; P < .001).

“The findings of this study suggest that ON101, a macrophage regulator that behaves differently from moisture-retaining dressings, represents an active-healing alternative for home and primary care of patients with chronic [diabetic foot ulcers],” the researchers concluded.

“ON101 was also granted a fast track designation by the U.S. FDA in March this year,” senior author Shun-Chen Chang, MD, Taipei Medical University–Shuang Ho Hospital, New Taipei City, Taiwan, said in an interview.

“Patients in the United States can access this new drug via the expanded access program or by participating in the second phase 3 trial in the United States,” added coauthor Shawn M. Cazzell, DPM, chief medical officer, Limb Preservation Platform, Fresno, Calif., who is involved with both trials.

It is “exciting” to have a new therapy for diabetic foot ulcers, said Dr. Cazzell, because they are serious and life-threatening.
 

Could cream with plant extracts surpass current care?

Current standard clinical care for diabetic foot ulcer consists of debridement, off-loading, infection control, and maintaining a moist environment with dressings, Huang and colleagues explain. If the foot ulcer does not respond, growth factors, tissue-engineering products, hyperbaric oxygen, or negative pressure wound therapies may be used.

However, the number of amputations from chronic diabetic foot ulcers that do not heal is increasing, pointing to a need for better treatment options.  

Hyperglycemia increases the ratio of M1 proinflammatory macrophages to M2 proregenerative macrophages, and accumulating evidence suggests this might be a potential treatment target.  

Researchers at Oneness Biotech showed that ON101, which is comprised of extracts from two plants, Plectranthus amboinicus and Centella asiatica, exerts a wound-healing effect by regulating the balance between M1 and M2 macrophages.

An extract of one plant suppresses inflammation, while an extract of the other increases collagen synthesis.

In preclinical studies, these two plant extracts had a synergistic effect on balancing the ratio of M1 to M2 macrophages and accelerating wound healing in a mouse model. This was followed by promising efficacy and safety results in two trials of 24 patients and 30 patients.
 

Significantly better healing with ON101 than standard care

For the current phase 3, randomized clinical trial, researchers enrolled patients in 21 clinics from November 2012 to May 2020.

To be eligible for the study, patients had to be 20-80 years old, with a hemoglobin A1c less than 12%. They also had to have a Wagner grade 1 or 2 foot ulcer that was 1-25 cm² after debridement, had been treated with standard care, and was present for at least 4 weeks.

Patients were a mean age of 57 years and 74% were men. They had a mean A1c of 8.1%, and 61% had had diabetes for more than 10 years.

Most (78%) of the diabetic foot ulcers were Wagner grade 2. The wounds had a mean area of 4.8 cm² and had been present for a mean of 7 months.

Patients were instructed on how to self-administer ON101 cream twice a day (treatment group, n = 122) or how to apply an absorbent dressing and change it daily or two or three times a week (standard care group, n = 114). All patients were allowed to apply a sterile gauze dressing.  

They visited the clinic every 2 weeks during the 16-week treatment phase and 12-week observation phase.

In the full analysis set, 74 patients (61%) in the ON101 group and 40 patients (35%) in the standard care group had complete wound healing after 16 weeks of treatment.

The subgroup of patients at higher risk of poor wound healing (A1c >9%, ulcer area >5 cm², and diabetic foot ulcer duration >6 months) also had significantly better healing with the ON101 cream than standard care.

There were seven (5.7%) treatment-emergent adverse events in the ON101 group versus five (4.4%) in the standard care group.

There were no treatment-related serious adverse events in the ON101 group versus one (0.9%) in the comparator group.

The study was funded by Oneness Biotech, Microbio Group, and Shanghai Haihe Pharmaceutical. One author has reported receiving fees from Oneness Biotech, and Dr. Chang has reported receiving a speakers fee from Oneness Biotech. The other authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An expert panel of 48 dermatologists from 13 countries has developed recommendations to guide efforts aimed at preventing cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients.

The recommendations were published online on Sept. 1 in JAMA Dermatology.

Because of lifelong immunosuppression, solid organ transplant recipients (SOTRs) have a risk of CSCC that is 20-200 times higher than in the general population and despite a growing literature on prevention of CSCC in these patients, uncertainty remains regarding best practices for various patient scenarios.

Paul Massey, MD, MPH, of the department of dermatology, Brigham and Women’s Hospital, Boston, and colleagues used a Delphi process to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs.

The survey design was guided by a novel actinic damage and skin cancer index (AD-SCI) made up of six ordinal stages corresponding to an increasing burden of actinic damage and CSCC.

The AD-SCI stage-based recommendations were established when consensus was reached (80% or higher concordance) or near consensus was reached (70%-80% concordance) among panel members.

For five of the six AD-SCI stages, the panel was able to make recommendations. Key recommendations include:
 

• Cryotherapy for scattered AK.
• Field therapy for AK when grouped in one site, unless AKs are thick, in which case field therapy and cryotherapy are recommended.
• Combination lesion-directed and field therapy with fluorouracil for field cancerized skin.
• Initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple CSCCs at a high rate (10 per year) or develop high-risk CSCC (defined by a tumor with roughly ≥20% risk of nodal metastasis). The panel did not make a recommendation as to the best immunosuppression modification strategy to pursue.

Lingering questions

The panel was unable to reach consensus on a recommendation for SOTRs with a first low-risk CSCC, reflecting “clinical equipoise” in this situation and the need for further study in this clinical scenario, they say.

The panel did not make a recommendation for use of nicotinamide or capecitabine in any of the six stages, which is “notable,” they acknowledge, given results of a double-blind randomized controlled trial in immunocompetent patients demonstrating benefit in preventing AKs and CSCCs, as reported previously.

Nearly three-quarters of the panel felt that a lack of efficacy data specifically for the SOTR population limited their use of nicotinamide. “Given the low cost, high safety, and demonstration of CSCC reduction in non-SOTRs, nicotinamide administration may be an area for further consideration and expanded study,” the panel wrote.

As for capecitabine, the panel notes that case series in SOTRs have found efficacy for chemoprevention, but randomized controlled studies are lacking. More than half of the panel noted that they did not have routine access to capecitabine in their practice.

The panel recommended routine skin surveillance and sunscreen use for all patients.

“These recommendations reflect consensus among expert transplant dermatologists and the incorporation of limited and sometimes contradictory evidence into real-world clinical experience across a range of CSCC disease severity,” the panel said.

“Areas of consensus may aid physicians in establishing best practices regarding prevention of CSCC in SOTRs in the setting of limited high level of evidence data in this population,” they added.

This research had no specific funding. Author disclosures included serving as a consultant to Regeneron, Sanofi, and receiving research funding from Castle Biosciences, Regeneron, Novartis, and Genentech. A complete list of disclosures for panel members is available with the original article.

An expert panel of 48 dermatologists from 13 countries has developed recommendations to guide efforts aimed at preventing cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients.

The recommendations were published online on Sept. 1 in JAMA Dermatology.

Because of lifelong immunosuppression, solid organ transplant recipients (SOTRs) have a risk of CSCC that is 20-200 times higher than in the general population and despite a growing literature on prevention of CSCC in these patients, uncertainty remains regarding best practices for various patient scenarios.

Paul Massey, MD, MPH, of the department of dermatology, Brigham and Women’s Hospital, Boston, and colleagues used a Delphi process to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs.

The survey design was guided by a novel actinic damage and skin cancer index (AD-SCI) made up of six ordinal stages corresponding to an increasing burden of actinic damage and CSCC.

The AD-SCI stage-based recommendations were established when consensus was reached (80% or higher concordance) or near consensus was reached (70%-80% concordance) among panel members.

For five of the six AD-SCI stages, the panel was able to make recommendations. Key recommendations include:
 

• Cryotherapy for scattered AK.
• Field therapy for AK when grouped in one site, unless AKs are thick, in which case field therapy and cryotherapy are recommended.
• Combination lesion-directed and field therapy with fluorouracil for field cancerized skin.
• Initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple CSCCs at a high rate (10 per year) or develop high-risk CSCC (defined by a tumor with roughly ≥20% risk of nodal metastasis). The panel did not make a recommendation as to the best immunosuppression modification strategy to pursue.

Lingering questions

The panel was unable to reach consensus on a recommendation for SOTRs with a first low-risk CSCC, reflecting “clinical equipoise” in this situation and the need for further study in this clinical scenario, they say.

The panel did not make a recommendation for use of nicotinamide or capecitabine in any of the six stages, which is “notable,” they acknowledge, given results of a double-blind randomized controlled trial in immunocompetent patients demonstrating benefit in preventing AKs and CSCCs, as reported previously.

Nearly three-quarters of the panel felt that a lack of efficacy data specifically for the SOTR population limited their use of nicotinamide. “Given the low cost, high safety, and demonstration of CSCC reduction in non-SOTRs, nicotinamide administration may be an area for further consideration and expanded study,” the panel wrote.

As for capecitabine, the panel notes that case series in SOTRs have found efficacy for chemoprevention, but randomized controlled studies are lacking. More than half of the panel noted that they did not have routine access to capecitabine in their practice.

The panel recommended routine skin surveillance and sunscreen use for all patients.

“These recommendations reflect consensus among expert transplant dermatologists and the incorporation of limited and sometimes contradictory evidence into real-world clinical experience across a range of CSCC disease severity,” the panel said.

“Areas of consensus may aid physicians in establishing best practices regarding prevention of CSCC in SOTRs in the setting of limited high level of evidence data in this population,” they added.

This research had no specific funding. Author disclosures included serving as a consultant to Regeneron, Sanofi, and receiving research funding from Castle Biosciences, Regeneron, Novartis, and Genentech. A complete list of disclosures for panel members is available with the original article.

An expert panel of 48 dermatologists from 13 countries has developed recommendations to guide efforts aimed at preventing cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients.

The recommendations were published online on Sept. 1 in JAMA Dermatology.

Because of lifelong immunosuppression, solid organ transplant recipients (SOTRs) have a risk of CSCC that is 20-200 times higher than in the general population and despite a growing literature on prevention of CSCC in these patients, uncertainty remains regarding best practices for various patient scenarios.

Paul Massey, MD, MPH, of the department of dermatology, Brigham and Women’s Hospital, Boston, and colleagues used a Delphi process to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs.

The survey design was guided by a novel actinic damage and skin cancer index (AD-SCI) made up of six ordinal stages corresponding to an increasing burden of actinic damage and CSCC.

The AD-SCI stage-based recommendations were established when consensus was reached (80% or higher concordance) or near consensus was reached (70%-80% concordance) among panel members.

For five of the six AD-SCI stages, the panel was able to make recommendations. Key recommendations include:
 

• Cryotherapy for scattered AK.
• Field therapy for AK when grouped in one site, unless AKs are thick, in which case field therapy and cryotherapy are recommended.
• Combination lesion-directed and field therapy with fluorouracil for field cancerized skin.
• Initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple CSCCs at a high rate (10 per year) or develop high-risk CSCC (defined by a tumor with roughly ≥20% risk of nodal metastasis). The panel did not make a recommendation as to the best immunosuppression modification strategy to pursue.

Lingering questions

The panel was unable to reach consensus on a recommendation for SOTRs with a first low-risk CSCC, reflecting “clinical equipoise” in this situation and the need for further study in this clinical scenario, they say.

The panel did not make a recommendation for use of nicotinamide or capecitabine in any of the six stages, which is “notable,” they acknowledge, given results of a double-blind randomized controlled trial in immunocompetent patients demonstrating benefit in preventing AKs and CSCCs, as reported previously.

Nearly three-quarters of the panel felt that a lack of efficacy data specifically for the SOTR population limited their use of nicotinamide. “Given the low cost, high safety, and demonstration of CSCC reduction in non-SOTRs, nicotinamide administration may be an area for further consideration and expanded study,” the panel wrote.

As for capecitabine, the panel notes that case series in SOTRs have found efficacy for chemoprevention, but randomized controlled studies are lacking. More than half of the panel noted that they did not have routine access to capecitabine in their practice.

The panel recommended routine skin surveillance and sunscreen use for all patients.

“These recommendations reflect consensus among expert transplant dermatologists and the incorporation of limited and sometimes contradictory evidence into real-world clinical experience across a range of CSCC disease severity,” the panel said.

“Areas of consensus may aid physicians in establishing best practices regarding prevention of CSCC in SOTRs in the setting of limited high level of evidence data in this population,” they added.

This research had no specific funding. Author disclosures included serving as a consultant to Regeneron, Sanofi, and receiving research funding from Castle Biosciences, Regeneron, Novartis, and Genentech. A complete list of disclosures for panel members is available with the original article.

For some patients with atopic dermatitis, disease activity may increase into mid-adulthood, and this subtype of AD may be linked with poorer physical and mental health, giving reason to observe patients beyond the pediatric stage, according to a cohort study of more than 30,000 patients.

Early-life environmental factors, such as tobacco smoke exposure, were not reliable predictors of increasing AD into mid-adulthood, suggesting that a patient’s contemporaneous environment may impact disease course throughout life, reported lead author Katrina Abuabara, MD, associate professor of dermatology at the University of California, San Francisco, and colleagues.

“There is a lack of studies that prospectively examine the course of atopic eczema beyond adolescence/early adulthood, and a more comprehensive understanding of disease activity across the life span is needed,” the investigators wrote in JAMA Dermatology. “Data on long-term disease course may offer insight into mechanisms for disease onset and persistence, are important when counseling patients, and would establish baseline trajectories for future studies of whether new treatments can modify disease course and development of comorbidities.”

The present study included 30,905 patients from two population-based birth cohorts: the 1958 National Childhood Development Study (NCDS) and the 1970 British Cohort Study (BCS70). Follow-up data were collected between 1958 and 2016 via nine waves of standardized questionnaires, and subtypes of atopic eczema patterns were identified “based on parent-reported or self-reported atopic eczema period prevalence.”

This measure “was previously shown to coincide with standardized clinical examinations among children in the NCDS, and a similar questionnaire demonstrated high sensitivity and specificity for physician-diagnosed atopic eczema in U.S. populations,” the investigators noted.

Latent class analysis identified four disease subtypes based on probability of reporting prevalent AD into midlife: low (88%-91%), decreasing (4%), increasing (2%-6%), and persistently high (2%-3%) probability.

Next, the investigators looked for associations between these subtypes and established early-life risk factors, such as history of breastfeeding and childhood smoke exposure. None of the childhood environmental factors differentiated between high versus decreasing disease in adulthood, or increasing versus decreasing disease in adulthood. In contrast, female sex predicted the high versus decreasing adult subtype (odds ratio, 1.99; 95% confidence interval, 1.66-2.38), and the increasing versus decreasing adult subtype (OR, 1.99; 95% CI, 1.69-2.35).

These findings suggest that “disease trajectory is modifiable and may be influenced by environmental factors throughout life,” the investigators wrote.

Further analysis uncovered associations between adult AD subtypes and other health outcomes. For example, compared with adults in the low probability group, those in the high probability group were significantly more likely to report rhinitis (OR, 2.70; 95% CI, 2.24-3.26) and asthma (OR, 3.45; 95% CI, 2.82-4.21). Adults with the increasing subtype also had elevated rates of asthma and rhinitis, along with worse self-reported mental health at age 42 (OR, 1.45; 95% CI, 1.23-1.72) and poor general health at age 46/50 (OR, 1.29; 95% CI, 1.09-1.53).

“When extending the window of observation beyond childhood, clear subtypes of atopic eczema based on patterns of disease activity emerged,” the investigators concluded. “In particular, a newly identified subtype with increasing probability of activity in adulthood warrants additional attention given associations with poor self-reported physical and mental health in midlife.”

Commenting on these results, Robert Sidbury, MD, professor of dermatology at the University of Washington, Seattle, said that this is an “important study” because it adds to our understanding of natural disease course over time.

This knowledge, as a pediatric dermatologist, will help Dr. Sidbury answer one of the most common questions he hears from parents: When is it going to stop?

“Trying to put a little bit more evidence-based heft behind the answer ... is really important,” he said in an interview.

Based on available data, up to 10% of children with AD may have disease activity into adulthood, according to Dr. Sidbury, who is also chief of dermatology at Seattle Children’s Hospital.

“I would hazard to guess that most of those adults who have atopic dermatitis – at least the ones who had it in childhood – were told that they would grow out of it,” he said. “And so I think awareness is important – that [resolution with age] does not always happen.”

The findings also support the possibility that AD is a systemic disease, and that underlying immune dysregulation may be linked with serious health consequences later in life, Dr. Sidbury said, noting that “the stakes get higher and higher when you start speculating in that way.”

According to Dr. Sidbury, the reported link between childhood AD and poor midlife health raises questions about how modifiable the disease course may be, particularly in response to earlier intervention with emerging AD medications, which “seem to be much more effective and potent.”

“Will the advent of these medications and their adoption and use in treatment perhaps have a significant impact, not just on the prevention of atopic dermatitis itself, but maybe other comorbidities?” he asked.

For the time being, this question remains unanswered.

The study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Wellcome Trust. Dr. Abuabara received grants from the National Institutes of Health during the study, as well as personal fees from Target RWE and Pfizer outside of this study. One author reported receiving NIH grants during the study, another reported receiving grants from the Wellcome Trust and the Innovative Medicine Initiative Horizon 2020 (BIOMAP project) during the study; there were no other disclosures. Dr. Sidbury disclosed relationships with Galderma, Regeneron, and Pfizer.
 

For some patients with atopic dermatitis, disease activity may increase into mid-adulthood, and this subtype of AD may be linked with poorer physical and mental health, giving reason to observe patients beyond the pediatric stage, according to a cohort study of more than 30,000 patients.

Early-life environmental factors, such as tobacco smoke exposure, were not reliable predictors of increasing AD into mid-adulthood, suggesting that a patient’s contemporaneous environment may impact disease course throughout life, reported lead author Katrina Abuabara, MD, associate professor of dermatology at the University of California, San Francisco, and colleagues.

“There is a lack of studies that prospectively examine the course of atopic eczema beyond adolescence/early adulthood, and a more comprehensive understanding of disease activity across the life span is needed,” the investigators wrote in JAMA Dermatology. “Data on long-term disease course may offer insight into mechanisms for disease onset and persistence, are important when counseling patients, and would establish baseline trajectories for future studies of whether new treatments can modify disease course and development of comorbidities.”

The present study included 30,905 patients from two population-based birth cohorts: the 1958 National Childhood Development Study (NCDS) and the 1970 British Cohort Study (BCS70). Follow-up data were collected between 1958 and 2016 via nine waves of standardized questionnaires, and subtypes of atopic eczema patterns were identified “based on parent-reported or self-reported atopic eczema period prevalence.”

This measure “was previously shown to coincide with standardized clinical examinations among children in the NCDS, and a similar questionnaire demonstrated high sensitivity and specificity for physician-diagnosed atopic eczema in U.S. populations,” the investigators noted.

Latent class analysis identified four disease subtypes based on probability of reporting prevalent AD into midlife: low (88%-91%), decreasing (4%), increasing (2%-6%), and persistently high (2%-3%) probability.

Next, the investigators looked for associations between these subtypes and established early-life risk factors, such as history of breastfeeding and childhood smoke exposure. None of the childhood environmental factors differentiated between high versus decreasing disease in adulthood, or increasing versus decreasing disease in adulthood. In contrast, female sex predicted the high versus decreasing adult subtype (odds ratio, 1.99; 95% confidence interval, 1.66-2.38), and the increasing versus decreasing adult subtype (OR, 1.99; 95% CI, 1.69-2.35).

These findings suggest that “disease trajectory is modifiable and may be influenced by environmental factors throughout life,” the investigators wrote.

Further analysis uncovered associations between adult AD subtypes and other health outcomes. For example, compared with adults in the low probability group, those in the high probability group were significantly more likely to report rhinitis (OR, 2.70; 95% CI, 2.24-3.26) and asthma (OR, 3.45; 95% CI, 2.82-4.21). Adults with the increasing subtype also had elevated rates of asthma and rhinitis, along with worse self-reported mental health at age 42 (OR, 1.45; 95% CI, 1.23-1.72) and poor general health at age 46/50 (OR, 1.29; 95% CI, 1.09-1.53).

“When extending the window of observation beyond childhood, clear subtypes of atopic eczema based on patterns of disease activity emerged,” the investigators concluded. “In particular, a newly identified subtype with increasing probability of activity in adulthood warrants additional attention given associations with poor self-reported physical and mental health in midlife.”

Commenting on these results, Robert Sidbury, MD, professor of dermatology at the University of Washington, Seattle, said that this is an “important study” because it adds to our understanding of natural disease course over time.

This knowledge, as a pediatric dermatologist, will help Dr. Sidbury answer one of the most common questions he hears from parents: When is it going to stop?

“Trying to put a little bit more evidence-based heft behind the answer ... is really important,” he said in an interview.

Based on available data, up to 10% of children with AD may have disease activity into adulthood, according to Dr. Sidbury, who is also chief of dermatology at Seattle Children’s Hospital.

“I would hazard to guess that most of those adults who have atopic dermatitis – at least the ones who had it in childhood – were told that they would grow out of it,” he said. “And so I think awareness is important – that [resolution with age] does not always happen.”

The findings also support the possibility that AD is a systemic disease, and that underlying immune dysregulation may be linked with serious health consequences later in life, Dr. Sidbury said, noting that “the stakes get higher and higher when you start speculating in that way.”

According to Dr. Sidbury, the reported link between childhood AD and poor midlife health raises questions about how modifiable the disease course may be, particularly in response to earlier intervention with emerging AD medications, which “seem to be much more effective and potent.”

“Will the advent of these medications and their adoption and use in treatment perhaps have a significant impact, not just on the prevention of atopic dermatitis itself, but maybe other comorbidities?” he asked.

For the time being, this question remains unanswered.

The study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Wellcome Trust. Dr. Abuabara received grants from the National Institutes of Health during the study, as well as personal fees from Target RWE and Pfizer outside of this study. One author reported receiving NIH grants during the study, another reported receiving grants from the Wellcome Trust and the Innovative Medicine Initiative Horizon 2020 (BIOMAP project) during the study; there were no other disclosures. Dr. Sidbury disclosed relationships with Galderma, Regeneron, and Pfizer.
 

For some patients with atopic dermatitis, disease activity may increase into mid-adulthood, and this subtype of AD may be linked with poorer physical and mental health, giving reason to observe patients beyond the pediatric stage, according to a cohort study of more than 30,000 patients.

Early-life environmental factors, such as tobacco smoke exposure, were not reliable predictors of increasing AD into mid-adulthood, suggesting that a patient’s contemporaneous environment may impact disease course throughout life, reported lead author Katrina Abuabara, MD, associate professor of dermatology at the University of California, San Francisco, and colleagues.

“There is a lack of studies that prospectively examine the course of atopic eczema beyond adolescence/early adulthood, and a more comprehensive understanding of disease activity across the life span is needed,” the investigators wrote in JAMA Dermatology. “Data on long-term disease course may offer insight into mechanisms for disease onset and persistence, are important when counseling patients, and would establish baseline trajectories for future studies of whether new treatments can modify disease course and development of comorbidities.”

The present study included 30,905 patients from two population-based birth cohorts: the 1958 National Childhood Development Study (NCDS) and the 1970 British Cohort Study (BCS70). Follow-up data were collected between 1958 and 2016 via nine waves of standardized questionnaires, and subtypes of atopic eczema patterns were identified “based on parent-reported or self-reported atopic eczema period prevalence.”

This measure “was previously shown to coincide with standardized clinical examinations among children in the NCDS, and a similar questionnaire demonstrated high sensitivity and specificity for physician-diagnosed atopic eczema in U.S. populations,” the investigators noted.

Latent class analysis identified four disease subtypes based on probability of reporting prevalent AD into midlife: low (88%-91%), decreasing (4%), increasing (2%-6%), and persistently high (2%-3%) probability.

Next, the investigators looked for associations between these subtypes and established early-life risk factors, such as history of breastfeeding and childhood smoke exposure. None of the childhood environmental factors differentiated between high versus decreasing disease in adulthood, or increasing versus decreasing disease in adulthood. In contrast, female sex predicted the high versus decreasing adult subtype (odds ratio, 1.99; 95% confidence interval, 1.66-2.38), and the increasing versus decreasing adult subtype (OR, 1.99; 95% CI, 1.69-2.35).

These findings suggest that “disease trajectory is modifiable and may be influenced by environmental factors throughout life,” the investigators wrote.

Further analysis uncovered associations between adult AD subtypes and other health outcomes. For example, compared with adults in the low probability group, those in the high probability group were significantly more likely to report rhinitis (OR, 2.70; 95% CI, 2.24-3.26) and asthma (OR, 3.45; 95% CI, 2.82-4.21). Adults with the increasing subtype also had elevated rates of asthma and rhinitis, along with worse self-reported mental health at age 42 (OR, 1.45; 95% CI, 1.23-1.72) and poor general health at age 46/50 (OR, 1.29; 95% CI, 1.09-1.53).

“When extending the window of observation beyond childhood, clear subtypes of atopic eczema based on patterns of disease activity emerged,” the investigators concluded. “In particular, a newly identified subtype with increasing probability of activity in adulthood warrants additional attention given associations with poor self-reported physical and mental health in midlife.”

Commenting on these results, Robert Sidbury, MD, professor of dermatology at the University of Washington, Seattle, said that this is an “important study” because it adds to our understanding of natural disease course over time.

This knowledge, as a pediatric dermatologist, will help Dr. Sidbury answer one of the most common questions he hears from parents: When is it going to stop?

“Trying to put a little bit more evidence-based heft behind the answer ... is really important,” he said in an interview.

Based on available data, up to 10% of children with AD may have disease activity into adulthood, according to Dr. Sidbury, who is also chief of dermatology at Seattle Children’s Hospital.

“I would hazard to guess that most of those adults who have atopic dermatitis – at least the ones who had it in childhood – were told that they would grow out of it,” he said. “And so I think awareness is important – that [resolution with age] does not always happen.”

The findings also support the possibility that AD is a systemic disease, and that underlying immune dysregulation may be linked with serious health consequences later in life, Dr. Sidbury said, noting that “the stakes get higher and higher when you start speculating in that way.”

According to Dr. Sidbury, the reported link between childhood AD and poor midlife health raises questions about how modifiable the disease course may be, particularly in response to earlier intervention with emerging AD medications, which “seem to be much more effective and potent.”

“Will the advent of these medications and their adoption and use in treatment perhaps have a significant impact, not just on the prevention of atopic dermatitis itself, but maybe other comorbidities?” he asked.

For the time being, this question remains unanswered.

The study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Wellcome Trust. Dr. Abuabara received grants from the National Institutes of Health during the study, as well as personal fees from Target RWE and Pfizer outside of this study. One author reported receiving NIH grants during the study, another reported receiving grants from the Wellcome Trust and the Innovative Medicine Initiative Horizon 2020 (BIOMAP project) during the study; there were no other disclosures. Dr. Sidbury disclosed relationships with Galderma, Regeneron, and Pfizer.
 

ANSWER

The correct answer is that new hairs growing in to replace those lost from alopecia areata tend to be white (choice “b”). They usually regain their normal color, eventually.

DISCUSSION

Alopecia areata is an autoimmune phenomenon implying an increased tendency to develop other autoimmune diseases (eg, vitiligo [choice “a”], which can appear initially in the scalp).

This case turned out to be simple but had the potential to be far more serious. The biopsy of the dark patch showed benign seborrheic keratosis, but it was possible that another section could have demonstrated features of melanoma (choice “c”). When present, melanoma can occasionally trigger an immune response that destroys pigment cells in hair follicles, causing the hairs to lose their pigment. This is why the entire dark patch was later excised. Fortunately, the pathology report ruled out melanoma.

While it has been reported that stress can cause hair to turn gray (choice “d”), there were better (and more accurate) explanations for this patient’s presentation.

This case, though fairly straightforward, serves as a reminder that it is our job as clinicians to connect the dots to rule out worst-case scenarios.

Outcome

This patient’s hair all grew back, regaining its normal color, without any treatment.

ANSWER

The correct answer is that new hairs growing in to replace those lost from alopecia areata tend to be white (choice “b”). They usually regain their normal color, eventually.

DISCUSSION

Alopecia areata is an autoimmune phenomenon implying an increased tendency to develop other autoimmune diseases (eg, vitiligo [choice “a”], which can appear initially in the scalp).

This case turned out to be simple but had the potential to be far more serious. The biopsy of the dark patch showed benign seborrheic keratosis, but it was possible that another section could have demonstrated features of melanoma (choice “c”). When present, melanoma can occasionally trigger an immune response that destroys pigment cells in hair follicles, causing the hairs to lose their pigment. This is why the entire dark patch was later excised. Fortunately, the pathology report ruled out melanoma.

While it has been reported that stress can cause hair to turn gray (choice “d”), there were better (and more accurate) explanations for this patient’s presentation.

This case, though fairly straightforward, serves as a reminder that it is our job as clinicians to connect the dots to rule out worst-case scenarios.

Outcome

This patient’s hair all grew back, regaining its normal color, without any treatment.

ANSWER

The correct answer is that new hairs growing in to replace those lost from alopecia areata tend to be white (choice “b”). They usually regain their normal color, eventually.

DISCUSSION

Alopecia areata is an autoimmune phenomenon implying an increased tendency to develop other autoimmune diseases (eg, vitiligo [choice “a”], which can appear initially in the scalp).

This case turned out to be simple but had the potential to be far more serious. The biopsy of the dark patch showed benign seborrheic keratosis, but it was possible that another section could have demonstrated features of melanoma (choice “c”). When present, melanoma can occasionally trigger an immune response that destroys pigment cells in hair follicles, causing the hairs to lose their pigment. This is why the entire dark patch was later excised. Fortunately, the pathology report ruled out melanoma.

While it has been reported that stress can cause hair to turn gray (choice “d”), there were better (and more accurate) explanations for this patient’s presentation.

This case, though fairly straightforward, serves as a reminder that it is our job as clinicians to connect the dots to rule out worst-case scenarios.

Outcome

This patient’s hair all grew back, regaining its normal color, without any treatment.

Consumer advocacy group Public Citizen filed a lawsuit on Sept. 8 on behalf of the Post-Finasteride Syndrome Foundation (PFSF) against the Food and Drug Administration for the agency’s failure to act on a petition submitted by the foundation 4 years ago.

The September 2017 petition requested that the FDA take the popular hair-loss drug (1 mg finasteride, Propecia) off the market because of evidence of serious risk of patient injury, including depression and suicidal ideation. 

As an alternative, PFSF requested that the FDA require the drug’s manufacturers revise the safety information on the labeling and add boxed warnings to disclose the potential for side effects, another of which is erectile dysfunction.

Public Citizen points to a recent analysis of the VigiBase global database, which tracks adverse effects from global pharmacovigilance agencies, lists 356 reports of suicidality and 2,926 reports of psychological adverse events in finasteride users. Yet, 4 years after submitting the petition, the FDA has neither granted nor denied it.

The lawsuit claims that FDA has acted unlawfully in failing to act on PFSF’s petition, and further cites “88 cases of completed suicide associated with finasteride use” per data from the VigiBase database.

“On the same day that PFSF submitted the petition, FDA’s docket management division acknowledged receipt and assigned the petition a docket number,” Michael Kirkpatrick, the Public Citizen attorney serving as lead counsel for PFSF, told this news organization.

Yet, to date, “there has been no substantive response to the petition. The lawsuit filed today seeks to force FDA to issue a decision on PFSF’s petition,” Mr. Kirkpatrick said.

“The FDA needs to act in a timely way to protect the public from the risks associated with use of Propecia. The FDA’s failure to act exposes consumers to potentially life-threatening harm,” he added in a statement.

The complaint filed today by Public Citizen in the U.S. District Court for the District of Columbia is available online. 

This news organization reached out to the FDA for comment but did not receive a response by press time.
 

A version of this article first appeared on Medscape.com.

Consumer advocacy group Public Citizen filed a lawsuit on Sept. 8 on behalf of the Post-Finasteride Syndrome Foundation (PFSF) against the Food and Drug Administration for the agency’s failure to act on a petition submitted by the foundation 4 years ago.

The September 2017 petition requested that the FDA take the popular hair-loss drug (1 mg finasteride, Propecia) off the market because of evidence of serious risk of patient injury, including depression and suicidal ideation. 

As an alternative, PFSF requested that the FDA require the drug’s manufacturers revise the safety information on the labeling and add boxed warnings to disclose the potential for side effects, another of which is erectile dysfunction.

Public Citizen points to a recent analysis of the VigiBase global database, which tracks adverse effects from global pharmacovigilance agencies, lists 356 reports of suicidality and 2,926 reports of psychological adverse events in finasteride users. Yet, 4 years after submitting the petition, the FDA has neither granted nor denied it.

The lawsuit claims that FDA has acted unlawfully in failing to act on PFSF’s petition, and further cites “88 cases of completed suicide associated with finasteride use” per data from the VigiBase database.

“On the same day that PFSF submitted the petition, FDA’s docket management division acknowledged receipt and assigned the petition a docket number,” Michael Kirkpatrick, the Public Citizen attorney serving as lead counsel for PFSF, told this news organization.

Yet, to date, “there has been no substantive response to the petition. The lawsuit filed today seeks to force FDA to issue a decision on PFSF’s petition,” Mr. Kirkpatrick said.

“The FDA needs to act in a timely way to protect the public from the risks associated with use of Propecia. The FDA’s failure to act exposes consumers to potentially life-threatening harm,” he added in a statement.

The complaint filed today by Public Citizen in the U.S. District Court for the District of Columbia is available online. 

This news organization reached out to the FDA for comment but did not receive a response by press time.
 

A version of this article first appeared on Medscape.com.

Consumer advocacy group Public Citizen filed a lawsuit on Sept. 8 on behalf of the Post-Finasteride Syndrome Foundation (PFSF) against the Food and Drug Administration for the agency’s failure to act on a petition submitted by the foundation 4 years ago.

The September 2017 petition requested that the FDA take the popular hair-loss drug (1 mg finasteride, Propecia) off the market because of evidence of serious risk of patient injury, including depression and suicidal ideation. 

As an alternative, PFSF requested that the FDA require the drug’s manufacturers revise the safety information on the labeling and add boxed warnings to disclose the potential for side effects, another of which is erectile dysfunction.

Public Citizen points to a recent analysis of the VigiBase global database, which tracks adverse effects from global pharmacovigilance agencies, lists 356 reports of suicidality and 2,926 reports of psychological adverse events in finasteride users. Yet, 4 years after submitting the petition, the FDA has neither granted nor denied it.

The lawsuit claims that FDA has acted unlawfully in failing to act on PFSF’s petition, and further cites “88 cases of completed suicide associated with finasteride use” per data from the VigiBase database.

“On the same day that PFSF submitted the petition, FDA’s docket management division acknowledged receipt and assigned the petition a docket number,” Michael Kirkpatrick, the Public Citizen attorney serving as lead counsel for PFSF, told this news organization.

Yet, to date, “there has been no substantive response to the petition. The lawsuit filed today seeks to force FDA to issue a decision on PFSF’s petition,” Mr. Kirkpatrick said.

“The FDA needs to act in a timely way to protect the public from the risks associated with use of Propecia. The FDA’s failure to act exposes consumers to potentially life-threatening harm,” he added in a statement.

The complaint filed today by Public Citizen in the U.S. District Court for the District of Columbia is available online. 

This news organization reached out to the FDA for comment but did not receive a response by press time.
 

A version of this article first appeared on Medscape.com.

This was a vigorous response to the 5-FU treatment and was actually within the range of expected outcomes for a patient with a heavy burden of AKs. The erythema and superficial skin flaking spared areas unaffected by pre-cancers.

AKs manifest as rough, pink to brown macules or papules on sun-damaged skin and represent a precancerous change in keratinocytes that can lead to invasive squamous cell carcinoma. For this reason, AKs are often treated when they are observed. When targeting an entire “field” of AKs, a gold standard therapy is topical 5-FU. Prescribing 5-FU is safe and effective, but requires patient education, therapy customization, and anticipatory guidance.

Compared with other field treatments (eg, photodynamic therapy, topical diclofenac, imiquimod), 5-FU is the most successful and cost effective; it is first-line therapy and has the longest track record.^1,2 5-FU represses DNA synthesis. It’s helpful to describe 5-FU to patients as “fake DNA” that targets precancerous cells that are dividing rapidly. But a word of caution: Patients should be advised, in advance, to avoid significant sun exposure while using 5-FU, as the drug will lose its targeted effect and cause more generalized skin damage.

Physicians can modulate the severity of the response to 5-FU by decreasing the frequency or length of therapy by using a weaker (and more expensive) once daily 0.5% long-acting formulation. Additionally, to improve comfort, low-potency topical steroids such as hydrocortisone ointment 0.5% to 2.5% can be applied after completion of therapy to speed up the healing process. These adjustments improve tolerance of therapy, but the precise effect on efficacy is unknown.

Because of the degree of redness and erythema that developed in this patient, treatment was stopped a week early. There was also concern about possible bacterial involvement in the heavy skin sloughing, so the patient was given topical mupirocin ointment to apply TID for 7 days. Her skin cleared after 3 weeks and all previous AKs were clinically eliminated.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

This was a vigorous response to the 5-FU treatment and was actually within the range of expected outcomes for a patient with a heavy burden of AKs. The erythema and superficial skin flaking spared areas unaffected by pre-cancers.

AKs manifest as rough, pink to brown macules or papules on sun-damaged skin and represent a precancerous change in keratinocytes that can lead to invasive squamous cell carcinoma. For this reason, AKs are often treated when they are observed. When targeting an entire “field” of AKs, a gold standard therapy is topical 5-FU. Prescribing 5-FU is safe and effective, but requires patient education, therapy customization, and anticipatory guidance.

Compared with other field treatments (eg, photodynamic therapy, topical diclofenac, imiquimod), 5-FU is the most successful and cost effective; it is first-line therapy and has the longest track record.^1,2 5-FU represses DNA synthesis. It’s helpful to describe 5-FU to patients as “fake DNA” that targets precancerous cells that are dividing rapidly. But a word of caution: Patients should be advised, in advance, to avoid significant sun exposure while using 5-FU, as the drug will lose its targeted effect and cause more generalized skin damage.

Physicians can modulate the severity of the response to 5-FU by decreasing the frequency or length of therapy by using a weaker (and more expensive) once daily 0.5% long-acting formulation. Additionally, to improve comfort, low-potency topical steroids such as hydrocortisone ointment 0.5% to 2.5% can be applied after completion of therapy to speed up the healing process. These adjustments improve tolerance of therapy, but the precise effect on efficacy is unknown.

Because of the degree of redness and erythema that developed in this patient, treatment was stopped a week early. There was also concern about possible bacterial involvement in the heavy skin sloughing, so the patient was given topical mupirocin ointment to apply TID for 7 days. Her skin cleared after 3 weeks and all previous AKs were clinically eliminated.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

This was a vigorous response to the 5-FU treatment and was actually within the range of expected outcomes for a patient with a heavy burden of AKs. The erythema and superficial skin flaking spared areas unaffected by pre-cancers.

AKs manifest as rough, pink to brown macules or papules on sun-damaged skin and represent a precancerous change in keratinocytes that can lead to invasive squamous cell carcinoma. For this reason, AKs are often treated when they are observed. When targeting an entire “field” of AKs, a gold standard therapy is topical 5-FU. Prescribing 5-FU is safe and effective, but requires patient education, therapy customization, and anticipatory guidance.

Compared with other field treatments (eg, photodynamic therapy, topical diclofenac, imiquimod), 5-FU is the most successful and cost effective; it is first-line therapy and has the longest track record.^1,2 5-FU represses DNA synthesis. It’s helpful to describe 5-FU to patients as “fake DNA” that targets precancerous cells that are dividing rapidly. But a word of caution: Patients should be advised, in advance, to avoid significant sun exposure while using 5-FU, as the drug will lose its targeted effect and cause more generalized skin damage.

Physicians can modulate the severity of the response to 5-FU by decreasing the frequency or length of therapy by using a weaker (and more expensive) once daily 0.5% long-acting formulation. Additionally, to improve comfort, low-potency topical steroids such as hydrocortisone ointment 0.5% to 2.5% can be applied after completion of therapy to speed up the healing process. These adjustments improve tolerance of therapy, but the precise effect on efficacy is unknown.

Because of the degree of redness and erythema that developed in this patient, treatment was stopped a week early. There was also concern about possible bacterial involvement in the heavy skin sloughing, so the patient was given topical mupirocin ointment to apply TID for 7 days. Her skin cleared after 3 weeks and all previous AKs were clinically eliminated.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

Children with severe atopic dermatitis (AD) are about twice as likely to develop depression and internalizing behavior as those without this condition, according to a newly published cohort study of more than 11,000 children between the ages of 3 and 18 years.

Along with previous studies that have also linked AD to depression and other mental health issues in children, these data highlight the need for “clinical awareness of the psychosocial needs of children and adolescents with AD,” reported a multicenter team of investigators from the University of California, San Francisco, the University of Pennsylvania, and the London School of Hygiene and Tropical Medicine.

Unlike some previous studies, in this study, published online in JAMA Dermatology on Sept. 1, children were evaluated longitudinally, rather than at a single point in time, with a mean follow-up of 10 years. For those with active AD, compared with children without AD, the odds ratio for depression overall in any child with AD relative to those without AD was not significant after adjustment for variables such socioeconomic factors.

However, among children with severe AD, the risk was more than twofold greater even after adjustment (adjusted OR, 2.38; 95% confidence interval, 1.21- 4.72), reported the investigators, led by senior author Katrina Abuabara, MD, associate professor of dermatology and epidemiology at UCSF.
 

Internalizing symptoms seen with mild to severe AD

Internalizing behavior, which is closely linked to depression and describes a spectrum of inward-focusing activities, such as social withdrawal, was significantly more common in children with any degree of AD relative to those without AD: After adjustment, the risk climbed from a 29% increased risk in those with mild AD (aOR, 1.29; 95% CI, 1.06-1.57) to a more than 80% increased risk in children with moderate AD (aOR, 1.84; 95% CI, 1.40-2.41) and in children with severe AD (aOR, 1.90; 95% CI, 1.14-3.16).

In the study, depression was measured with the Short Moods and Feelings Questionnaire (SMFQ). Parental response to the Emotional Symptoms subscale of the Strength and Difficulties Questionnaire (SDQ) was used to measure internalizing behaviors.

The data were drawn from the Avon Longitudinal Study for Parents and Children (ALSPAC), a cohort that enrolled pregnant women in a defined area in southwest England and then followed children born from these pregnancies. Of the 14,062 children enrolled in ALSPAC, data from 11,181 children were available for this study.

In a previous meta-analysis of studies that have documented a link between AD and adverse effects on mood and mental health, an impact was identified in both children and adults. In children, AD was associated with a 27% increase in risk of depression (OR, 1.27; 95% CI, 1.12 -1.45). In adults, the risk was more than doubled (OR, 2.19; 95% CI, 1.87-2.57). The same meta-analysis found that the risk of suicidal ideation among adolescents and adults with AD was increased more than fourfold (OR, 4.32; 95% CI, 1.93-9.66).

In the ALSPAC data, the investigators were unable to find compelling evidence that sleep disturbances or concomitant asthma contributed to the increased risk of depression, which is a mechanism proposed by past investigators.

In an interview, Dr. Abuabara said that these and other data provide the basis for encouraging clinical awareness of the psychological needs of children with AD, but she suggested there is a gap in understanding what this means clinically. “We need more data on how dermatologists can effectively screen and manage these patients before we try to set expectations for clinical practice,” she said.

In addition, these data along with previously published studies suggest that change in mental health outcomes should be included in the evaluation of new therapies, according to Dr. Abuabara. She noted that there are several tools for evaluating mental health in children that might be appropriate, each with their own advantages and disadvantages.

“Ideally, recommendations would be issued through a group consensus process with patients, clinicians, researchers, and industry representatives working together as has been done for other outcomes through the Harmonizing Measures for Eczema (HOME) group,” Dr. Abuabara said.

 

Mental health assessments recommended

Others who have looked at the relationship between AD and depression have also recommended adding mental health outcomes to an assessment of efficacy for AD therapies.

Jonathan I. Silverberg, MD, PhD, MPH, associate professor of dermatology, George Washington University, Washington, is one such investigator. He is already monitoring depression systematically with the Hospital Anxiety and Depression Scale (HADS).

“HADS has been validated in AD and provides very important information about the emotional burden of AD,” explained Dr. Silverberg, whose most recent article on this topic appeared earlier this year. In that study, the relationship between AD and depression was found to be more pronounced in White children from families with lower incomes.

“Just a few hours ago, one of my patients thanked me for asking about their mental health and recognizing the holistic effects of AD,” Dr. Silverberg said.

The recent study based on ALSPAC data add to the evidence that AD, particularly severe AD, produces deleterious effects on mental health in children, and Dr. Silverberg believes clinicians should be acting on this evidence.

“I strongly encourage clinicians to routinely assess mental health. It will elevate the quality of care they provide, and their patients will appreciate them more for it,” he said.

Dr. Abuabara and another author report receiving research funding from Pfizer to their universities for unrelated work; there were no other disclosures. Dr. Silverberg reports financial relationships with more than 15 pharmaceutical companies.

Commentary by Lawrence F. Eichenfield, MD

More severe atopic dermatitis (AD) carries with it significant mental health concerns in children, as well as adults. Multiple studies have shown significantly higher rates of depression, anxiety, and “internalizing behaviors” (discussed as social withdrawal and other inward-focused activities) as well as attention-deficit/hyperactivity disorder. The study by Dr. Abuabara and colleagues is important as it followed children over time (an average of 10 years) and adjusted the data for socioeconomic factors, showing a rate of depression in children with severe AD twice that of those without. It appears that we are in the midst of a mental health crisis in children and teens, with markedly higher rates of pediatric and adolescent depression and anxiety, certainly influenced by COVID-19 societal changes. As the literature has developed on depression and AD, we have appreciated the importance of addressing this as part of our assessment of the disease effect on the individual and family, and it is one factor we consider in selections of systemic vs. topical therapies.  

Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. He disclosed that he has served as an investigator and/or consultant to AbbVie, Lilly, Pfizer, Regeneron, Sanofi-Genzyme, and Verrica.

A version of this article first appeared on Medscape.com.

This article was updated 6/18/22.

Children with severe atopic dermatitis (AD) are about twice as likely to develop depression and internalizing behavior as those without this condition, according to a newly published cohort study of more than 11,000 children between the ages of 3 and 18 years.

Along with previous studies that have also linked AD to depression and other mental health issues in children, these data highlight the need for “clinical awareness of the psychosocial needs of children and adolescents with AD,” reported a multicenter team of investigators from the University of California, San Francisco, the University of Pennsylvania, and the London School of Hygiene and Tropical Medicine.

Unlike some previous studies, in this study, published online in JAMA Dermatology on Sept. 1, children were evaluated longitudinally, rather than at a single point in time, with a mean follow-up of 10 years. For those with active AD, compared with children without AD, the odds ratio for depression overall in any child with AD relative to those without AD was not significant after adjustment for variables such socioeconomic factors.

However, among children with severe AD, the risk was more than twofold greater even after adjustment (adjusted OR, 2.38; 95% confidence interval, 1.21- 4.72), reported the investigators, led by senior author Katrina Abuabara, MD, associate professor of dermatology and epidemiology at UCSF.
 

Internalizing symptoms seen with mild to severe AD

Internalizing behavior, which is closely linked to depression and describes a spectrum of inward-focusing activities, such as social withdrawal, was significantly more common in children with any degree of AD relative to those without AD: After adjustment, the risk climbed from a 29% increased risk in those with mild AD (aOR, 1.29; 95% CI, 1.06-1.57) to a more than 80% increased risk in children with moderate AD (aOR, 1.84; 95% CI, 1.40-2.41) and in children with severe AD (aOR, 1.90; 95% CI, 1.14-3.16).

In the study, depression was measured with the Short Moods and Feelings Questionnaire (SMFQ). Parental response to the Emotional Symptoms subscale of the Strength and Difficulties Questionnaire (SDQ) was used to measure internalizing behaviors.

The data were drawn from the Avon Longitudinal Study for Parents and Children (ALSPAC), a cohort that enrolled pregnant women in a defined area in southwest England and then followed children born from these pregnancies. Of the 14,062 children enrolled in ALSPAC, data from 11,181 children were available for this study.

In a previous meta-analysis of studies that have documented a link between AD and adverse effects on mood and mental health, an impact was identified in both children and adults. In children, AD was associated with a 27% increase in risk of depression (OR, 1.27; 95% CI, 1.12 -1.45). In adults, the risk was more than doubled (OR, 2.19; 95% CI, 1.87-2.57). The same meta-analysis found that the risk of suicidal ideation among adolescents and adults with AD was increased more than fourfold (OR, 4.32; 95% CI, 1.93-9.66).

In the ALSPAC data, the investigators were unable to find compelling evidence that sleep disturbances or concomitant asthma contributed to the increased risk of depression, which is a mechanism proposed by past investigators.

In an interview, Dr. Abuabara said that these and other data provide the basis for encouraging clinical awareness of the psychological needs of children with AD, but she suggested there is a gap in understanding what this means clinically. “We need more data on how dermatologists can effectively screen and manage these patients before we try to set expectations for clinical practice,” she said.

In addition, these data along with previously published studies suggest that change in mental health outcomes should be included in the evaluation of new therapies, according to Dr. Abuabara. She noted that there are several tools for evaluating mental health in children that might be appropriate, each with their own advantages and disadvantages.

“Ideally, recommendations would be issued through a group consensus process with patients, clinicians, researchers, and industry representatives working together as has been done for other outcomes through the Harmonizing Measures for Eczema (HOME) group,” Dr. Abuabara said.

 

Mental health assessments recommended

Others who have looked at the relationship between AD and depression have also recommended adding mental health outcomes to an assessment of efficacy for AD therapies.

Jonathan I. Silverberg, MD, PhD, MPH, associate professor of dermatology, George Washington University, Washington, is one such investigator. He is already monitoring depression systematically with the Hospital Anxiety and Depression Scale (HADS).

“HADS has been validated in AD and provides very important information about the emotional burden of AD,” explained Dr. Silverberg, whose most recent article on this topic appeared earlier this year. In that study, the relationship between AD and depression was found to be more pronounced in White children from families with lower incomes.

“Just a few hours ago, one of my patients thanked me for asking about their mental health and recognizing the holistic effects of AD,” Dr. Silverberg said.

The recent study based on ALSPAC data add to the evidence that AD, particularly severe AD, produces deleterious effects on mental health in children, and Dr. Silverberg believes clinicians should be acting on this evidence.

“I strongly encourage clinicians to routinely assess mental health. It will elevate the quality of care they provide, and their patients will appreciate them more for it,” he said.

Dr. Abuabara and another author report receiving research funding from Pfizer to their universities for unrelated work; there were no other disclosures. Dr. Silverberg reports financial relationships with more than 15 pharmaceutical companies.

Commentary by Lawrence F. Eichenfield, MD

More severe atopic dermatitis (AD) carries with it significant mental health concerns in children, as well as adults. Multiple studies have shown significantly higher rates of depression, anxiety, and “internalizing behaviors” (discussed as social withdrawal and other inward-focused activities) as well as attention-deficit/hyperactivity disorder. The study by Dr. Abuabara and colleagues is important as it followed children over time (an average of 10 years) and adjusted the data for socioeconomic factors, showing a rate of depression in children with severe AD twice that of those without. It appears that we are in the midst of a mental health crisis in children and teens, with markedly higher rates of pediatric and adolescent depression and anxiety, certainly influenced by COVID-19 societal changes. As the literature has developed on depression and AD, we have appreciated the importance of addressing this as part of our assessment of the disease effect on the individual and family, and it is one factor we consider in selections of systemic vs. topical therapies.  

Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. He disclosed that he has served as an investigator and/or consultant to AbbVie, Lilly, Pfizer, Regeneron, Sanofi-Genzyme, and Verrica.

A version of this article first appeared on Medscape.com.

This article was updated 6/18/22.

Children with severe atopic dermatitis (AD) are about twice as likely to develop depression and internalizing behavior as those without this condition, according to a newly published cohort study of more than 11,000 children between the ages of 3 and 18 years.

Along with previous studies that have also linked AD to depression and other mental health issues in children, these data highlight the need for “clinical awareness of the psychosocial needs of children and adolescents with AD,” reported a multicenter team of investigators from the University of California, San Francisco, the University of Pennsylvania, and the London School of Hygiene and Tropical Medicine.

Unlike some previous studies, in this study, published online in JAMA Dermatology on Sept. 1, children were evaluated longitudinally, rather than at a single point in time, with a mean follow-up of 10 years. For those with active AD, compared with children without AD, the odds ratio for depression overall in any child with AD relative to those without AD was not significant after adjustment for variables such socioeconomic factors.

However, among children with severe AD, the risk was more than twofold greater even after adjustment (adjusted OR, 2.38; 95% confidence interval, 1.21- 4.72), reported the investigators, led by senior author Katrina Abuabara, MD, associate professor of dermatology and epidemiology at UCSF.
 

Internalizing symptoms seen with mild to severe AD

Internalizing behavior, which is closely linked to depression and describes a spectrum of inward-focusing activities, such as social withdrawal, was significantly more common in children with any degree of AD relative to those without AD: After adjustment, the risk climbed from a 29% increased risk in those with mild AD (aOR, 1.29; 95% CI, 1.06-1.57) to a more than 80% increased risk in children with moderate AD (aOR, 1.84; 95% CI, 1.40-2.41) and in children with severe AD (aOR, 1.90; 95% CI, 1.14-3.16).

In the study, depression was measured with the Short Moods and Feelings Questionnaire (SMFQ). Parental response to the Emotional Symptoms subscale of the Strength and Difficulties Questionnaire (SDQ) was used to measure internalizing behaviors.

The data were drawn from the Avon Longitudinal Study for Parents and Children (ALSPAC), a cohort that enrolled pregnant women in a defined area in southwest England and then followed children born from these pregnancies. Of the 14,062 children enrolled in ALSPAC, data from 11,181 children were available for this study.

In a previous meta-analysis of studies that have documented a link between AD and adverse effects on mood and mental health, an impact was identified in both children and adults. In children, AD was associated with a 27% increase in risk of depression (OR, 1.27; 95% CI, 1.12 -1.45). In adults, the risk was more than doubled (OR, 2.19; 95% CI, 1.87-2.57). The same meta-analysis found that the risk of suicidal ideation among adolescents and adults with AD was increased more than fourfold (OR, 4.32; 95% CI, 1.93-9.66).

In the ALSPAC data, the investigators were unable to find compelling evidence that sleep disturbances or concomitant asthma contributed to the increased risk of depression, which is a mechanism proposed by past investigators.

In an interview, Dr. Abuabara said that these and other data provide the basis for encouraging clinical awareness of the psychological needs of children with AD, but she suggested there is a gap in understanding what this means clinically. “We need more data on how dermatologists can effectively screen and manage these patients before we try to set expectations for clinical practice,” she said.

In addition, these data along with previously published studies suggest that change in mental health outcomes should be included in the evaluation of new therapies, according to Dr. Abuabara. She noted that there are several tools for evaluating mental health in children that might be appropriate, each with their own advantages and disadvantages.

“Ideally, recommendations would be issued through a group consensus process with patients, clinicians, researchers, and industry representatives working together as has been done for other outcomes through the Harmonizing Measures for Eczema (HOME) group,” Dr. Abuabara said.

 

Mental health assessments recommended

Others who have looked at the relationship between AD and depression have also recommended adding mental health outcomes to an assessment of efficacy for AD therapies.

Jonathan I. Silverberg, MD, PhD, MPH, associate professor of dermatology, George Washington University, Washington, is one such investigator. He is already monitoring depression systematically with the Hospital Anxiety and Depression Scale (HADS).

“HADS has been validated in AD and provides very important information about the emotional burden of AD,” explained Dr. Silverberg, whose most recent article on this topic appeared earlier this year. In that study, the relationship between AD and depression was found to be more pronounced in White children from families with lower incomes.

“Just a few hours ago, one of my patients thanked me for asking about their mental health and recognizing the holistic effects of AD,” Dr. Silverberg said.

The recent study based on ALSPAC data add to the evidence that AD, particularly severe AD, produces deleterious effects on mental health in children, and Dr. Silverberg believes clinicians should be acting on this evidence.

“I strongly encourage clinicians to routinely assess mental health. It will elevate the quality of care they provide, and their patients will appreciate them more for it,” he said.

Dr. Abuabara and another author report receiving research funding from Pfizer to their universities for unrelated work; there were no other disclosures. Dr. Silverberg reports financial relationships with more than 15 pharmaceutical companies.

Commentary by Lawrence F. Eichenfield, MD

More severe atopic dermatitis (AD) carries with it significant mental health concerns in children, as well as adults. Multiple studies have shown significantly higher rates of depression, anxiety, and “internalizing behaviors” (discussed as social withdrawal and other inward-focused activities) as well as attention-deficit/hyperactivity disorder. The study by Dr. Abuabara and colleagues is important as it followed children over time (an average of 10 years) and adjusted the data for socioeconomic factors, showing a rate of depression in children with severe AD twice that of those without. It appears that we are in the midst of a mental health crisis in children and teens, with markedly higher rates of pediatric and adolescent depression and anxiety, certainly influenced by COVID-19 societal changes. As the literature has developed on depression and AD, we have appreciated the importance of addressing this as part of our assessment of the disease effect on the individual and family, and it is one factor we consider in selections of systemic vs. topical therapies.  

Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. He disclosed that he has served as an investigator and/or consultant to AbbVie, Lilly, Pfizer, Regeneron, Sanofi-Genzyme, and Verrica.

A version of this article first appeared on Medscape.com.

This article was updated 6/18/22.

With more than 300 genetic skin disorders involving more than 1,000 genes and hundreds of genetic tests available on the market, it can be daunting for health care providers and families of pediatric patients to navigate the landscape.

“Testing options range from targeted variant testing and single-gene testing to exome and genome sequencing,” Gabriele Richard, MD, said at the annual meeting of the Society for Pediatric Dermatology. “It is not always easy to determine which testing is right.”

Increasingly, clinical genomic tests, including exome and genome sequencing, are used for patients with complex phenotypes, and possibly multiple disorders, who might have no diagnosis despite extensive prior testing, said Dr. Richard, medical director at Gaithersburg, Md.–based GeneDx., a molecular diagnostic laboratory that performs comprehensive testing for rare genetic disorders. These tests are also being used more for first-line testing in critically ill patients in the neonatal and pediatric intensive care units, and “have heralded a whole new era of gene and disease discovery,” she added.

Targeted variant testing is used for known familial variants, to test family members for carrier status and segregation, and to make a prenatal diagnosis, she said. Single-gene testing is available for most genes and has its place for conditions that can be clinically well-recognized, such as ichthyosis vulgaris, Darier disease, or Papillon-Lefèvre syndrome.

Specific tests for identifying gene deletions or duplications are exon-level microarrays, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray analysis. “The latter has been successful in identifying diseases causing chromosomal abnormalities in over 10% of cases overall,” Dr. Richard said. An example of a skin disorder is X-linked ichthyosis caused by a deletion of the steroid sulfatase locus in more than 95% of affected males, she said.

“However, the current staple of molecular diagnostic testing is multigene next-generation sequencing (NGS) panels, which allow you to interrogate two to hundreds of genes concurrently, including sequencing and deletion duplication testing.” These tests are the most cost effective, she said, and are available for almost any genodermatosis or group of disorders with overlapping phenotypes, such as albinism or ichthyosis, epidermolysis bullosa and skin fragility, ectodermal dysplasia, or porphyria. According to Dr. Richard, the diagnostic outcomes of NGS panels mainly depend on test indication, panel size and gene curation, age of onset, and prevailing inheritance pattern of disorders.

Her recommended criteria for distinguishing the myriad of available NGS panels include checking gene content, technical sensitivity of sequencing and deletion/duplication analysis, quality of variant interpretation and reporting, turn-around time, and available familial follow-up testing. “If a family might consider future prenatal diagnosis, choose the lab that performs prenatal and diagnostic testing,” Dr. Richard said. “Equally important are client services such as ease of ordering, insurance coverage, and the ability to determine out-of-pocket cost to patients.”

Resources that enable consumers to compare panel content, methodology, turnaround time, and other parameters include the Genetic Testing Registry (GTR) operated by the National Center for Biotechnology Information, and Concert Genetics, a genetic testing company. The National Society of Genetic Counselors also offers a searchable database for finding a genetic counselor.

Exome sequencing includes the coding sequences of about 20,000 genes and has an average depth of 50 to about 150 reads. “It is a phenotype-driven test where only select variants are being reported fitting the phenotype,” Dr. Richard said. “The outcome of exome and genome sequencing much depends on optimization of bioinformatic pipelines and tools.” Besides small sequence variants, exome sequencing is able to identify a variety of different types of disease-causing variants, such as gene copy number variants seen in about 6% of positive cases, mosaicism, regions of homozygosity, uniparental disomy, and other unusual events and is cost effective.

Whole-genome sequencing, meanwhile, includes the entire genome, particularly noncoding regions, and has an average depth of more than 30 reads. “It’s based on single-molecule sequencing, has longer reads and more uniform coverage, compared to exome sequencing,” she said. “Higher cost, variant interpretation, and lack of coverage by payers are still presenting challenges for genome sequencing.” Genome sequencing can be done in a day or less.

According to diagnostic outcomes based on 280,000 individuals including 125,000 probands from GeneDx data, a definitive diagnosis was made in 26% of probands, of which 2.8% had more than one diagnostic finding and 1.8% had actionable secondary findings. In addition, 7% of the variants were found in candidate genes; 31% of probands had variants of uncertain significance, while 36% tested negative. “Nevertheless, the diagnostic yield of exome sequencing depends on the phenotype and cohort studied,” Dr. Richard continued.

At her company, she said, the highest positive rate is for multiple congenital anomalies (34%), skeletal system abnormalities (30%), and nervous system abnormalities (29%). Trio testing – the concurrent analysis of both biological parents and proband for all genes – “is a critical factor for success,” she added. “It not only improves the variant calling because we have three times the data and increases test sensitivity, it also provides more certain results, determines inheritance and allows for detection of parental mosaicism.”

According to Dr. Richard, trio testing has a one-third higher diagnostic rate than sequencing of the proband alone. Citing a published prospective study that compiled data from eight different exome- and genome-sequencing studies in critically ill neonates and children, trio testing made it possible to make a genetic diagnosis in up to 58% of children.

Whole-genome sequencing is estimated to have a 5%-10% higher diagnostic rate than exome sequencing. “However, we are still a ways away from using it as a routine diagnostic test for all test indications,” Dr. Richard said. “Automation, special bioinformatics algorithms and databases, and combination of genome sequencing with mRNA sequencing are being explored and built to further improve the diagnostic yield.”

Dr. Richard had no disclosures other than being an employee of GeneDx.

dbrunk@mdedge.com

With more than 300 genetic skin disorders involving more than 1,000 genes and hundreds of genetic tests available on the market, it can be daunting for health care providers and families of pediatric patients to navigate the landscape.

“Testing options range from targeted variant testing and single-gene testing to exome and genome sequencing,” Gabriele Richard, MD, said at the annual meeting of the Society for Pediatric Dermatology. “It is not always easy to determine which testing is right.”

Increasingly, clinical genomic tests, including exome and genome sequencing, are used for patients with complex phenotypes, and possibly multiple disorders, who might have no diagnosis despite extensive prior testing, said Dr. Richard, medical director at Gaithersburg, Md.–based GeneDx., a molecular diagnostic laboratory that performs comprehensive testing for rare genetic disorders. These tests are also being used more for first-line testing in critically ill patients in the neonatal and pediatric intensive care units, and “have heralded a whole new era of gene and disease discovery,” she added.

Targeted variant testing is used for known familial variants, to test family members for carrier status and segregation, and to make a prenatal diagnosis, she said. Single-gene testing is available for most genes and has its place for conditions that can be clinically well-recognized, such as ichthyosis vulgaris, Darier disease, or Papillon-Lefèvre syndrome.

Specific tests for identifying gene deletions or duplications are exon-level microarrays, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray analysis. “The latter has been successful in identifying diseases causing chromosomal abnormalities in over 10% of cases overall,” Dr. Richard said. An example of a skin disorder is X-linked ichthyosis caused by a deletion of the steroid sulfatase locus in more than 95% of affected males, she said.

“However, the current staple of molecular diagnostic testing is multigene next-generation sequencing (NGS) panels, which allow you to interrogate two to hundreds of genes concurrently, including sequencing and deletion duplication testing.” These tests are the most cost effective, she said, and are available for almost any genodermatosis or group of disorders with overlapping phenotypes, such as albinism or ichthyosis, epidermolysis bullosa and skin fragility, ectodermal dysplasia, or porphyria. According to Dr. Richard, the diagnostic outcomes of NGS panels mainly depend on test indication, panel size and gene curation, age of onset, and prevailing inheritance pattern of disorders.

Her recommended criteria for distinguishing the myriad of available NGS panels include checking gene content, technical sensitivity of sequencing and deletion/duplication analysis, quality of variant interpretation and reporting, turn-around time, and available familial follow-up testing. “If a family might consider future prenatal diagnosis, choose the lab that performs prenatal and diagnostic testing,” Dr. Richard said. “Equally important are client services such as ease of ordering, insurance coverage, and the ability to determine out-of-pocket cost to patients.”

Resources that enable consumers to compare panel content, methodology, turnaround time, and other parameters include the Genetic Testing Registry (GTR) operated by the National Center for Biotechnology Information, and Concert Genetics, a genetic testing company. The National Society of Genetic Counselors also offers a searchable database for finding a genetic counselor.

Exome sequencing includes the coding sequences of about 20,000 genes and has an average depth of 50 to about 150 reads. “It is a phenotype-driven test where only select variants are being reported fitting the phenotype,” Dr. Richard said. “The outcome of exome and genome sequencing much depends on optimization of bioinformatic pipelines and tools.” Besides small sequence variants, exome sequencing is able to identify a variety of different types of disease-causing variants, such as gene copy number variants seen in about 6% of positive cases, mosaicism, regions of homozygosity, uniparental disomy, and other unusual events and is cost effective.

Whole-genome sequencing, meanwhile, includes the entire genome, particularly noncoding regions, and has an average depth of more than 30 reads. “It’s based on single-molecule sequencing, has longer reads and more uniform coverage, compared to exome sequencing,” she said. “Higher cost, variant interpretation, and lack of coverage by payers are still presenting challenges for genome sequencing.” Genome sequencing can be done in a day or less.

According to diagnostic outcomes based on 280,000 individuals including 125,000 probands from GeneDx data, a definitive diagnosis was made in 26% of probands, of which 2.8% had more than one diagnostic finding and 1.8% had actionable secondary findings. In addition, 7% of the variants were found in candidate genes; 31% of probands had variants of uncertain significance, while 36% tested negative. “Nevertheless, the diagnostic yield of exome sequencing depends on the phenotype and cohort studied,” Dr. Richard continued.

At her company, she said, the highest positive rate is for multiple congenital anomalies (34%), skeletal system abnormalities (30%), and nervous system abnormalities (29%). Trio testing – the concurrent analysis of both biological parents and proband for all genes – “is a critical factor for success,” she added. “It not only improves the variant calling because we have three times the data and increases test sensitivity, it also provides more certain results, determines inheritance and allows for detection of parental mosaicism.”

According to Dr. Richard, trio testing has a one-third higher diagnostic rate than sequencing of the proband alone. Citing a published prospective study that compiled data from eight different exome- and genome-sequencing studies in critically ill neonates and children, trio testing made it possible to make a genetic diagnosis in up to 58% of children.

Whole-genome sequencing is estimated to have a 5%-10% higher diagnostic rate than exome sequencing. “However, we are still a ways away from using it as a routine diagnostic test for all test indications,” Dr. Richard said. “Automation, special bioinformatics algorithms and databases, and combination of genome sequencing with mRNA sequencing are being explored and built to further improve the diagnostic yield.”

Dr. Richard had no disclosures other than being an employee of GeneDx.

dbrunk@mdedge.com

With more than 300 genetic skin disorders involving more than 1,000 genes and hundreds of genetic tests available on the market, it can be daunting for health care providers and families of pediatric patients to navigate the landscape.

“Testing options range from targeted variant testing and single-gene testing to exome and genome sequencing,” Gabriele Richard, MD, said at the annual meeting of the Society for Pediatric Dermatology. “It is not always easy to determine which testing is right.”

Increasingly, clinical genomic tests, including exome and genome sequencing, are used for patients with complex phenotypes, and possibly multiple disorders, who might have no diagnosis despite extensive prior testing, said Dr. Richard, medical director at Gaithersburg, Md.–based GeneDx., a molecular diagnostic laboratory that performs comprehensive testing for rare genetic disorders. These tests are also being used more for first-line testing in critically ill patients in the neonatal and pediatric intensive care units, and “have heralded a whole new era of gene and disease discovery,” she added.

Targeted variant testing is used for known familial variants, to test family members for carrier status and segregation, and to make a prenatal diagnosis, she said. Single-gene testing is available for most genes and has its place for conditions that can be clinically well-recognized, such as ichthyosis vulgaris, Darier disease, or Papillon-Lefèvre syndrome.

Specific tests for identifying gene deletions or duplications are exon-level microarrays, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray analysis. “The latter has been successful in identifying diseases causing chromosomal abnormalities in over 10% of cases overall,” Dr. Richard said. An example of a skin disorder is X-linked ichthyosis caused by a deletion of the steroid sulfatase locus in more than 95% of affected males, she said.

“However, the current staple of molecular diagnostic testing is multigene next-generation sequencing (NGS) panels, which allow you to interrogate two to hundreds of genes concurrently, including sequencing and deletion duplication testing.” These tests are the most cost effective, she said, and are available for almost any genodermatosis or group of disorders with overlapping phenotypes, such as albinism or ichthyosis, epidermolysis bullosa and skin fragility, ectodermal dysplasia, or porphyria. According to Dr. Richard, the diagnostic outcomes of NGS panels mainly depend on test indication, panel size and gene curation, age of onset, and prevailing inheritance pattern of disorders.

Her recommended criteria for distinguishing the myriad of available NGS panels include checking gene content, technical sensitivity of sequencing and deletion/duplication analysis, quality of variant interpretation and reporting, turn-around time, and available familial follow-up testing. “If a family might consider future prenatal diagnosis, choose the lab that performs prenatal and diagnostic testing,” Dr. Richard said. “Equally important are client services such as ease of ordering, insurance coverage, and the ability to determine out-of-pocket cost to patients.”

Resources that enable consumers to compare panel content, methodology, turnaround time, and other parameters include the Genetic Testing Registry (GTR) operated by the National Center for Biotechnology Information, and Concert Genetics, a genetic testing company. The National Society of Genetic Counselors also offers a searchable database for finding a genetic counselor.

Exome sequencing includes the coding sequences of about 20,000 genes and has an average depth of 50 to about 150 reads. “It is a phenotype-driven test where only select variants are being reported fitting the phenotype,” Dr. Richard said. “The outcome of exome and genome sequencing much depends on optimization of bioinformatic pipelines and tools.” Besides small sequence variants, exome sequencing is able to identify a variety of different types of disease-causing variants, such as gene copy number variants seen in about 6% of positive cases, mosaicism, regions of homozygosity, uniparental disomy, and other unusual events and is cost effective.

Whole-genome sequencing, meanwhile, includes the entire genome, particularly noncoding regions, and has an average depth of more than 30 reads. “It’s based on single-molecule sequencing, has longer reads and more uniform coverage, compared to exome sequencing,” she said. “Higher cost, variant interpretation, and lack of coverage by payers are still presenting challenges for genome sequencing.” Genome sequencing can be done in a day or less.

According to diagnostic outcomes based on 280,000 individuals including 125,000 probands from GeneDx data, a definitive diagnosis was made in 26% of probands, of which 2.8% had more than one diagnostic finding and 1.8% had actionable secondary findings. In addition, 7% of the variants were found in candidate genes; 31% of probands had variants of uncertain significance, while 36% tested negative. “Nevertheless, the diagnostic yield of exome sequencing depends on the phenotype and cohort studied,” Dr. Richard continued.

At her company, she said, the highest positive rate is for multiple congenital anomalies (34%), skeletal system abnormalities (30%), and nervous system abnormalities (29%). Trio testing – the concurrent analysis of both biological parents and proband for all genes – “is a critical factor for success,” she added. “It not only improves the variant calling because we have three times the data and increases test sensitivity, it also provides more certain results, determines inheritance and allows for detection of parental mosaicism.”

According to Dr. Richard, trio testing has a one-third higher diagnostic rate than sequencing of the proband alone. Citing a published prospective study that compiled data from eight different exome- and genome-sequencing studies in critically ill neonates and children, trio testing made it possible to make a genetic diagnosis in up to 58% of children.

Whole-genome sequencing is estimated to have a 5%-10% higher diagnostic rate than exome sequencing. “However, we are still a ways away from using it as a routine diagnostic test for all test indications,” Dr. Richard said. “Automation, special bioinformatics algorithms and databases, and combination of genome sequencing with mRNA sequencing are being explored and built to further improve the diagnostic yield.”

Dr. Richard had no disclosures other than being an employee of GeneDx.

dbrunk@mdedge.com