All PASI 100 responses to psoriasis therapy are not the same, Andrew Blauvelt, MD, declared at the virtual annual meeting of the American Academy of Dermatology.

He presented a first-of-its-kind study that potentially opens the door to a new, more rigorous standard for treatment success in psoriasis: Not simply cleared lesional skin as captured by a Psoriasis Area and Severity Index (PASI) 100 response, but also clearance of residual psoriasis signs and symptoms – as well as what he termed “molecular clearance.”

“We’ve found that clearing skin with drugs utilizing different mechanisms of action may lead to differential consequences for our patients,” observed Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.

A PASI 100 response, traditionally considered an elusive goal for the great majority of patients with severe psoriasis, can now often be achieved using today’s top-tier, high-performance biologics. But Dr. Blauvelt and his coinvestigators are interested in pushing even beyond PASI 100 to a new frontier of therapeutic benefit.

He presented a secondary analysis of the previously reported VOYAGE 1 and 2 head-to-head randomized trials of guselkumab (Tremfya) versus adalimumab (Humira) for treatment of moderate to severe psoriasis. This new analysis, which focused exclusively on PASI 100 responders by week 24, demonstrated that patients with a PASI 100 response to guselkumab, an interleukin (IL)-23 inhibitor, had significantly fewer persistent symptoms and signs of psoriasis than those whose skin clearance was attained using adalimumab, a tumor necrosis factor (TNF) inhibitor.

Moreover, the investigators showed that the gene expression profile of PASI 100 responders who were free of signs and symptoms was more normalized than that of patients with residual symptoms despite their cleared skin.

The analysis included 16 participants in the VOYAGE trials who achieved PASI 100 at week 24 on guselkumab and 5 who did so on adalimumab. At baseline and again at week 24, these individuals completed the Psoriasis Symptoms and Signs Diary (PSSD). Also, biopsies of lesional and nonlesional skin were obtained at baseline and of cleared lesional skin at week 24 for transcriptomic microarray analysis of the expression of many thousands of genes.
 

Persistent psoriasis symptoms despite cleared skin

The PSSD involves patient ratings of various psoriasis symptoms and signs. Total scores can range from 0 (symptom- and sign-free) up to 100. At week 24, a significantly higher proportion of guselkumab-treated PASI 100 responders had a total PSSD score of zero: 55%, versus 43% in the adalimumab group. This was consistently true across the board for each of the individual signs and symptoms assessed. For example, 61% of the guselkumab group gave themselves a zero for itch, as did 50% of the adalimumab group. Sixty-four percent on guselkumab and 52% on adalimumab reported being free of redness. And 78% of the guselkumab group reported being pain-free, compared with 69% with adalimumab, Dr. Blauvelt reported.

Gene expression analysis

At baseline, more than 2,300 dysregulated genes were identified in lesional skin while functioning normally in nonlesional skin. The great majority of these initially dysregulated genes became normalized in cleared lesional skin in PASI 100 responders at week 24. However, 25 of the genes remained dysregulated in cleared lesional skin, meaning they displayed less than 75% of normal function. Ten of these 25 genes with dysregulated expression at follow-up showed abnormal function in patients with residual symptoms despite cleared skin, but they functioned normally in those without persistent symptoms. This raises the possibility that the residual symptoms of psoriasis were attributable to the abnormal gene functioning, according to Dr. Blauvelt.

Of note, 9 of the 10 dysregulated genes in cleared lesional skin of patients with residual symptoms were present in the adalimumab group; these included two genes localized to the epidermal differentiation complex as well as the psoriasis-specific proline-rich 9 gene known as PRR9, which is induced by IL-17A. In contrast, only four genes, none of which were localized to the epidermal differentiation complex, were insufficiently normalized in the cleared lesional skin of guselkumab-treated PASI-100 responders.

“Nothing like this analysis has ever been done before,” the dermatologist observed. “It’s a pilot study. Perhaps with more data like this, we’ll be using this type of information in clinical practice to go beyond clearing patients’ skin.”

Dr. Blauvelt reported serving as a scientific advisor to and paid clinical investigator for Janssen, which sponsored the study, as well as for roughly two dozen other pharmaceutical companies.

[email protected]

All PASI 100 responses to psoriasis therapy are not the same, Andrew Blauvelt, MD, declared at the virtual annual meeting of the American Academy of Dermatology.

He presented a first-of-its-kind study that potentially opens the door to a new, more rigorous standard for treatment success in psoriasis: Not simply cleared lesional skin as captured by a Psoriasis Area and Severity Index (PASI) 100 response, but also clearance of residual psoriasis signs and symptoms – as well as what he termed “molecular clearance.”

“We’ve found that clearing skin with drugs utilizing different mechanisms of action may lead to differential consequences for our patients,” observed Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.

A PASI 100 response, traditionally considered an elusive goal for the great majority of patients with severe psoriasis, can now often be achieved using today’s top-tier, high-performance biologics. But Dr. Blauvelt and his coinvestigators are interested in pushing even beyond PASI 100 to a new frontier of therapeutic benefit.

He presented a secondary analysis of the previously reported VOYAGE 1 and 2 head-to-head randomized trials of guselkumab (Tremfya) versus adalimumab (Humira) for treatment of moderate to severe psoriasis. This new analysis, which focused exclusively on PASI 100 responders by week 24, demonstrated that patients with a PASI 100 response to guselkumab, an interleukin (IL)-23 inhibitor, had significantly fewer persistent symptoms and signs of psoriasis than those whose skin clearance was attained using adalimumab, a tumor necrosis factor (TNF) inhibitor.

Moreover, the investigators showed that the gene expression profile of PASI 100 responders who were free of signs and symptoms was more normalized than that of patients with residual symptoms despite their cleared skin.

The analysis included 16 participants in the VOYAGE trials who achieved PASI 100 at week 24 on guselkumab and 5 who did so on adalimumab. At baseline and again at week 24, these individuals completed the Psoriasis Symptoms and Signs Diary (PSSD). Also, biopsies of lesional and nonlesional skin were obtained at baseline and of cleared lesional skin at week 24 for transcriptomic microarray analysis of the expression of many thousands of genes.
 

Persistent psoriasis symptoms despite cleared skin

The PSSD involves patient ratings of various psoriasis symptoms and signs. Total scores can range from 0 (symptom- and sign-free) up to 100. At week 24, a significantly higher proportion of guselkumab-treated PASI 100 responders had a total PSSD score of zero: 55%, versus 43% in the adalimumab group. This was consistently true across the board for each of the individual signs and symptoms assessed. For example, 61% of the guselkumab group gave themselves a zero for itch, as did 50% of the adalimumab group. Sixty-four percent on guselkumab and 52% on adalimumab reported being free of redness. And 78% of the guselkumab group reported being pain-free, compared with 69% with adalimumab, Dr. Blauvelt reported.

Gene expression analysis

At baseline, more than 2,300 dysregulated genes were identified in lesional skin while functioning normally in nonlesional skin. The great majority of these initially dysregulated genes became normalized in cleared lesional skin in PASI 100 responders at week 24. However, 25 of the genes remained dysregulated in cleared lesional skin, meaning they displayed less than 75% of normal function. Ten of these 25 genes with dysregulated expression at follow-up showed abnormal function in patients with residual symptoms despite cleared skin, but they functioned normally in those without persistent symptoms. This raises the possibility that the residual symptoms of psoriasis were attributable to the abnormal gene functioning, according to Dr. Blauvelt.

Of note, 9 of the 10 dysregulated genes in cleared lesional skin of patients with residual symptoms were present in the adalimumab group; these included two genes localized to the epidermal differentiation complex as well as the psoriasis-specific proline-rich 9 gene known as PRR9, which is induced by IL-17A. In contrast, only four genes, none of which were localized to the epidermal differentiation complex, were insufficiently normalized in the cleared lesional skin of guselkumab-treated PASI-100 responders.

“Nothing like this analysis has ever been done before,” the dermatologist observed. “It’s a pilot study. Perhaps with more data like this, we’ll be using this type of information in clinical practice to go beyond clearing patients’ skin.”

Dr. Blauvelt reported serving as a scientific advisor to and paid clinical investigator for Janssen, which sponsored the study, as well as for roughly two dozen other pharmaceutical companies.

[email protected]

All PASI 100 responses to psoriasis therapy are not the same, Andrew Blauvelt, MD, declared at the virtual annual meeting of the American Academy of Dermatology.

He presented a first-of-its-kind study that potentially opens the door to a new, more rigorous standard for treatment success in psoriasis: Not simply cleared lesional skin as captured by a Psoriasis Area and Severity Index (PASI) 100 response, but also clearance of residual psoriasis signs and symptoms – as well as what he termed “molecular clearance.”

“We’ve found that clearing skin with drugs utilizing different mechanisms of action may lead to differential consequences for our patients,” observed Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.

A PASI 100 response, traditionally considered an elusive goal for the great majority of patients with severe psoriasis, can now often be achieved using today’s top-tier, high-performance biologics. But Dr. Blauvelt and his coinvestigators are interested in pushing even beyond PASI 100 to a new frontier of therapeutic benefit.

He presented a secondary analysis of the previously reported VOYAGE 1 and 2 head-to-head randomized trials of guselkumab (Tremfya) versus adalimumab (Humira) for treatment of moderate to severe psoriasis. This new analysis, which focused exclusively on PASI 100 responders by week 24, demonstrated that patients with a PASI 100 response to guselkumab, an interleukin (IL)-23 inhibitor, had significantly fewer persistent symptoms and signs of psoriasis than those whose skin clearance was attained using adalimumab, a tumor necrosis factor (TNF) inhibitor.

Moreover, the investigators showed that the gene expression profile of PASI 100 responders who were free of signs and symptoms was more normalized than that of patients with residual symptoms despite their cleared skin.

The analysis included 16 participants in the VOYAGE trials who achieved PASI 100 at week 24 on guselkumab and 5 who did so on adalimumab. At baseline and again at week 24, these individuals completed the Psoriasis Symptoms and Signs Diary (PSSD). Also, biopsies of lesional and nonlesional skin were obtained at baseline and of cleared lesional skin at week 24 for transcriptomic microarray analysis of the expression of many thousands of genes.
 

Persistent psoriasis symptoms despite cleared skin

The PSSD involves patient ratings of various psoriasis symptoms and signs. Total scores can range from 0 (symptom- and sign-free) up to 100. At week 24, a significantly higher proportion of guselkumab-treated PASI 100 responders had a total PSSD score of zero: 55%, versus 43% in the adalimumab group. This was consistently true across the board for each of the individual signs and symptoms assessed. For example, 61% of the guselkumab group gave themselves a zero for itch, as did 50% of the adalimumab group. Sixty-four percent on guselkumab and 52% on adalimumab reported being free of redness. And 78% of the guselkumab group reported being pain-free, compared with 69% with adalimumab, Dr. Blauvelt reported.

Gene expression analysis

At baseline, more than 2,300 dysregulated genes were identified in lesional skin while functioning normally in nonlesional skin. The great majority of these initially dysregulated genes became normalized in cleared lesional skin in PASI 100 responders at week 24. However, 25 of the genes remained dysregulated in cleared lesional skin, meaning they displayed less than 75% of normal function. Ten of these 25 genes with dysregulated expression at follow-up showed abnormal function in patients with residual symptoms despite cleared skin, but they functioned normally in those without persistent symptoms. This raises the possibility that the residual symptoms of psoriasis were attributable to the abnormal gene functioning, according to Dr. Blauvelt.

Of note, 9 of the 10 dysregulated genes in cleared lesional skin of patients with residual symptoms were present in the adalimumab group; these included two genes localized to the epidermal differentiation complex as well as the psoriasis-specific proline-rich 9 gene known as PRR9, which is induced by IL-17A. In contrast, only four genes, none of which were localized to the epidermal differentiation complex, were insufficiently normalized in the cleared lesional skin of guselkumab-treated PASI-100 responders.

“Nothing like this analysis has ever been done before,” the dermatologist observed. “It’s a pilot study. Perhaps with more data like this, we’ll be using this type of information in clinical practice to go beyond clearing patients’ skin.”

Dr. Blauvelt reported serving as a scientific advisor to and paid clinical investigator for Janssen, which sponsored the study, as well as for roughly two dozen other pharmaceutical companies.

[email protected]

The experimental nonstimulant medication viloxazine extended-release, known as SPN-812, reduced symptoms of attention-deficit/hyperactivity disorder (ADHD) as soon as 1 week after dosing and was well tolerated in a randomized, placebo-controlled phase 3 study that included more than 400 children.

mik38/thinkstockphotos.com

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interviews.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The findings were published online July 25 in Clinical Therapeutics.
 

Novel modulating agent

Viloxazine extended-release is a novel multimodal serotonergic and noradrenergic modulating agent with activity at serotonin receptors and the norepinephrine transporter.

The phase 3 randomized controlled trial (RCT) tested the safety and efficacy of two doses of the drug given once daily to children aged 6-11 years with ADHD. About two-thirds were boys.

All participants had an ADHD-Rating Scale–5 (ADHD-RS-5) score of at least 28 and a Clinical Global Impression–Severity score of at least 4. None had taken ADHD medication for at least 1 week prior to randomization.

The intent-to-treat population included 460 children. Of these, 155 were randomly assigned to receive placebo, 147 to receive viloxazine 100 mg, and 158 to receive viloxazine 200 mg.

The primary efficacy endpoint was change from baseline in ADHD-RS-5 total score at week 6. Score changes for both the 100-mg (P = .0004) and the 200-mg (P < .0001) viloxazine groups met statistical significance compared with the placebo group.

Change from baseline in both the ADHD-RS-5 inattention and hyperactivity/impulsivity subscale scores was also significantly reduced in the 100-mg (P = .0006 and .0026, respectively) and 200-mg (P < .0001 and P < .0001, respectively) treatment groups compared with the placebo group.

Improvements occurred after 1 week of treatment and were maintained throughout the 6-week trial, “indicating an early and sustained effect,” the investigators wrote.
 

FDA target action date

The Clinical Global Impression–Improvement (CGI-I) score at 6 weeks was significantly improved in those receiving 100 mg (P = .0020) and 200 mg (P < .0001) of the active treatment compared with placebo.

The CGI-I responder rate, the percentage of children with a CGI-I score of 1 (very much improved) or 2 (much improved), was significantly higher at 6 weeks with viloxazine 100 mg and 200 mg vs. placebo (45% and 51% vs. 30%, respectively; P = .0065 and P = .0002).

These standard investigator-rated assessments were supported by two parent self-rated assessments: the Conners 3–Parent Short Form and the Weiss Functional Impairment Rating Scale–Parent Form.

Parents noted improvement not only in their children’s ADHD symptoms but also in ADHD-associated learning problems, executive functioning, defiance/aggression, peer relations, and functioning in different settings.

At both doses, once-daily viloxazine was generally well tolerated, with a low rate of discontinuation because of adverse events (<5%). Most adverse events were characterized as mild or moderate in severity and included somnolence (8.9%), decreased appetite (6.0%), and headache (5.4%).

On the basis of results of this study and others, the Food and Drug Administration accepted the company’s new drug application for viloxazine extended-release for ADHD in children and adolescents. The application has a target action date of Nov. 8, 2020.
 

Potential advantages

Commenting on the study in an interview, Dean Elbe, PharmD, clinical pharmacy specialist, child and adolescent mental health, BC Children’s Hospital, Vancouver, B.C., said that use of viloxazine to treat ADHD is “interesting.”

Dr. Elbe, who was not involved with the current research, noted that “it is actually an old drug that has been around since the mid-1970s in Europe as an antidepressant. It was removed from the market due to poor sales, not safety issues.”

Overall, on the basis of this study, viloxazine has potential to offer “modest improvements” over atomoxetine (Strattera), and the dosing may be “more straightforward and somewhat less challenging than with atomoxetine, with no taper up and no adjustment for poor 2D6 metabolizers,” Dr. Elbe noted.

“The onset of action appears somewhat quicker than we typically see with atomoxetine, so that is also helpful for parent and clinician acceptance and partially overcomes a perceived barrier with atomoxetine,” he said.

Dr. Elbe said he wonders, however, whether viloxazine will show “real-world clinical utility for both hyperactive-impulsive as well as inattentive symptoms. Although the study shows efficacy in both symptom clusters, so did the atomoxetine RCTs, and this has not been the clinical impression for atomoxetine.”

The study was funded by Supernus Pharmaceuticals. Dr. Cutler is a consultant for Supernus, as well as for Adlon Therapeutics, Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, NLS Pharma, Otsuka, Purdue, Shire, Sunovion, Takeda, and Tris Pharma. He has received speaker/promotional honoraria from Adlon Therapeutics, Arbor Pharmaceuticals, Lundbeck, Neos Therapeutics, Otsuka, Shire, Sunovion, Takeda, and Tris Pharma and has received research grants from Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Shire, Sunovion, Supernus Pharmaceuticals, Takeda, and Tris Pharma. A complete list of disclosures for the other authors is available in the original article. Dr. Elbe has reported no relevant financial relationships.
 

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

The experimental nonstimulant medication viloxazine extended-release, known as SPN-812, reduced symptoms of attention-deficit/hyperactivity disorder (ADHD) as soon as 1 week after dosing and was well tolerated in a randomized, placebo-controlled phase 3 study that included more than 400 children.

mik38/thinkstockphotos.com

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interviews.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The findings were published online July 25 in Clinical Therapeutics.
 

Novel modulating agent

Viloxazine extended-release is a novel multimodal serotonergic and noradrenergic modulating agent with activity at serotonin receptors and the norepinephrine transporter.

The phase 3 randomized controlled trial (RCT) tested the safety and efficacy of two doses of the drug given once daily to children aged 6-11 years with ADHD. About two-thirds were boys.

All participants had an ADHD-Rating Scale–5 (ADHD-RS-5) score of at least 28 and a Clinical Global Impression–Severity score of at least 4. None had taken ADHD medication for at least 1 week prior to randomization.

The intent-to-treat population included 460 children. Of these, 155 were randomly assigned to receive placebo, 147 to receive viloxazine 100 mg, and 158 to receive viloxazine 200 mg.

The primary efficacy endpoint was change from baseline in ADHD-RS-5 total score at week 6. Score changes for both the 100-mg (P = .0004) and the 200-mg (P < .0001) viloxazine groups met statistical significance compared with the placebo group.

Change from baseline in both the ADHD-RS-5 inattention and hyperactivity/impulsivity subscale scores was also significantly reduced in the 100-mg (P = .0006 and .0026, respectively) and 200-mg (P < .0001 and P < .0001, respectively) treatment groups compared with the placebo group.

Improvements occurred after 1 week of treatment and were maintained throughout the 6-week trial, “indicating an early and sustained effect,” the investigators wrote.
 

FDA target action date

The Clinical Global Impression–Improvement (CGI-I) score at 6 weeks was significantly improved in those receiving 100 mg (P = .0020) and 200 mg (P < .0001) of the active treatment compared with placebo.

The CGI-I responder rate, the percentage of children with a CGI-I score of 1 (very much improved) or 2 (much improved), was significantly higher at 6 weeks with viloxazine 100 mg and 200 mg vs. placebo (45% and 51% vs. 30%, respectively; P = .0065 and P = .0002).

These standard investigator-rated assessments were supported by two parent self-rated assessments: the Conners 3–Parent Short Form and the Weiss Functional Impairment Rating Scale–Parent Form.

Parents noted improvement not only in their children’s ADHD symptoms but also in ADHD-associated learning problems, executive functioning, defiance/aggression, peer relations, and functioning in different settings.

At both doses, once-daily viloxazine was generally well tolerated, with a low rate of discontinuation because of adverse events (<5%). Most adverse events were characterized as mild or moderate in severity and included somnolence (8.9%), decreased appetite (6.0%), and headache (5.4%).

On the basis of results of this study and others, the Food and Drug Administration accepted the company’s new drug application for viloxazine extended-release for ADHD in children and adolescents. The application has a target action date of Nov. 8, 2020.
 

Potential advantages

Commenting on the study in an interview, Dean Elbe, PharmD, clinical pharmacy specialist, child and adolescent mental health, BC Children’s Hospital, Vancouver, B.C., said that use of viloxazine to treat ADHD is “interesting.”

Dr. Elbe, who was not involved with the current research, noted that “it is actually an old drug that has been around since the mid-1970s in Europe as an antidepressant. It was removed from the market due to poor sales, not safety issues.”

Overall, on the basis of this study, viloxazine has potential to offer “modest improvements” over atomoxetine (Strattera), and the dosing may be “more straightforward and somewhat less challenging than with atomoxetine, with no taper up and no adjustment for poor 2D6 metabolizers,” Dr. Elbe noted.

“The onset of action appears somewhat quicker than we typically see with atomoxetine, so that is also helpful for parent and clinician acceptance and partially overcomes a perceived barrier with atomoxetine,” he said.

Dr. Elbe said he wonders, however, whether viloxazine will show “real-world clinical utility for both hyperactive-impulsive as well as inattentive symptoms. Although the study shows efficacy in both symptom clusters, so did the atomoxetine RCTs, and this has not been the clinical impression for atomoxetine.”

The study was funded by Supernus Pharmaceuticals. Dr. Cutler is a consultant for Supernus, as well as for Adlon Therapeutics, Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, NLS Pharma, Otsuka, Purdue, Shire, Sunovion, Takeda, and Tris Pharma. He has received speaker/promotional honoraria from Adlon Therapeutics, Arbor Pharmaceuticals, Lundbeck, Neos Therapeutics, Otsuka, Shire, Sunovion, Takeda, and Tris Pharma and has received research grants from Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Shire, Sunovion, Supernus Pharmaceuticals, Takeda, and Tris Pharma. A complete list of disclosures for the other authors is available in the original article. Dr. Elbe has reported no relevant financial relationships.
 

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

The experimental nonstimulant medication viloxazine extended-release, known as SPN-812, reduced symptoms of attention-deficit/hyperactivity disorder (ADHD) as soon as 1 week after dosing and was well tolerated in a randomized, placebo-controlled phase 3 study that included more than 400 children.

mik38/thinkstockphotos.com

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interviews.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The findings were published online July 25 in Clinical Therapeutics.
 

Novel modulating agent

Viloxazine extended-release is a novel multimodal serotonergic and noradrenergic modulating agent with activity at serotonin receptors and the norepinephrine transporter.

The phase 3 randomized controlled trial (RCT) tested the safety and efficacy of two doses of the drug given once daily to children aged 6-11 years with ADHD. About two-thirds were boys.

All participants had an ADHD-Rating Scale–5 (ADHD-RS-5) score of at least 28 and a Clinical Global Impression–Severity score of at least 4. None had taken ADHD medication for at least 1 week prior to randomization.

The intent-to-treat population included 460 children. Of these, 155 were randomly assigned to receive placebo, 147 to receive viloxazine 100 mg, and 158 to receive viloxazine 200 mg.

The primary efficacy endpoint was change from baseline in ADHD-RS-5 total score at week 6. Score changes for both the 100-mg (P = .0004) and the 200-mg (P < .0001) viloxazine groups met statistical significance compared with the placebo group.

Change from baseline in both the ADHD-RS-5 inattention and hyperactivity/impulsivity subscale scores was also significantly reduced in the 100-mg (P = .0006 and .0026, respectively) and 200-mg (P < .0001 and P < .0001, respectively) treatment groups compared with the placebo group.

Improvements occurred after 1 week of treatment and were maintained throughout the 6-week trial, “indicating an early and sustained effect,” the investigators wrote.
 

FDA target action date

The Clinical Global Impression–Improvement (CGI-I) score at 6 weeks was significantly improved in those receiving 100 mg (P = .0020) and 200 mg (P < .0001) of the active treatment compared with placebo.

The CGI-I responder rate, the percentage of children with a CGI-I score of 1 (very much improved) or 2 (much improved), was significantly higher at 6 weeks with viloxazine 100 mg and 200 mg vs. placebo (45% and 51% vs. 30%, respectively; P = .0065 and P = .0002).

These standard investigator-rated assessments were supported by two parent self-rated assessments: the Conners 3–Parent Short Form and the Weiss Functional Impairment Rating Scale–Parent Form.

Parents noted improvement not only in their children’s ADHD symptoms but also in ADHD-associated learning problems, executive functioning, defiance/aggression, peer relations, and functioning in different settings.

At both doses, once-daily viloxazine was generally well tolerated, with a low rate of discontinuation because of adverse events (<5%). Most adverse events were characterized as mild or moderate in severity and included somnolence (8.9%), decreased appetite (6.0%), and headache (5.4%).

On the basis of results of this study and others, the Food and Drug Administration accepted the company’s new drug application for viloxazine extended-release for ADHD in children and adolescents. The application has a target action date of Nov. 8, 2020.
 

Potential advantages

Commenting on the study in an interview, Dean Elbe, PharmD, clinical pharmacy specialist, child and adolescent mental health, BC Children’s Hospital, Vancouver, B.C., said that use of viloxazine to treat ADHD is “interesting.”

Dr. Elbe, who was not involved with the current research, noted that “it is actually an old drug that has been around since the mid-1970s in Europe as an antidepressant. It was removed from the market due to poor sales, not safety issues.”

Overall, on the basis of this study, viloxazine has potential to offer “modest improvements” over atomoxetine (Strattera), and the dosing may be “more straightforward and somewhat less challenging than with atomoxetine, with no taper up and no adjustment for poor 2D6 metabolizers,” Dr. Elbe noted.

“The onset of action appears somewhat quicker than we typically see with atomoxetine, so that is also helpful for parent and clinician acceptance and partially overcomes a perceived barrier with atomoxetine,” he said.

Dr. Elbe said he wonders, however, whether viloxazine will show “real-world clinical utility for both hyperactive-impulsive as well as inattentive symptoms. Although the study shows efficacy in both symptom clusters, so did the atomoxetine RCTs, and this has not been the clinical impression for atomoxetine.”

The study was funded by Supernus Pharmaceuticals. Dr. Cutler is a consultant for Supernus, as well as for Adlon Therapeutics, Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, NLS Pharma, Otsuka, Purdue, Shire, Sunovion, Takeda, and Tris Pharma. He has received speaker/promotional honoraria from Adlon Therapeutics, Arbor Pharmaceuticals, Lundbeck, Neos Therapeutics, Otsuka, Shire, Sunovion, Takeda, and Tris Pharma and has received research grants from Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Shire, Sunovion, Supernus Pharmaceuticals, Takeda, and Tris Pharma. A complete list of disclosures for the other authors is available in the original article. Dr. Elbe has reported no relevant financial relationships.
 

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

Cachexia developed in 56% of adults with systemic lupus erythematosus over a 5-year period, and 18% did not recover their weight, based on data from more than 2,000 patients.

Sara Freeman/MDedge News

Although weight loss is common in patients with systemic lupus erythematosus (SLE), cachexia, a disorder of involuntary weight loss, is largely undescribed in SLE patients, wrote George Stojan, MD, of Johns Hopkins University, Baltimore, and colleagues. Cachexia has been described in a range of disorders, including heart failure, renal disease, and rheumatoid arthritis, they said. “Cachexia has been shown to lead to progressive functional impairment, treatment-related complications, poor quality of life, and increased mortality,” they added.

In a study published in Arthritis Care & Research, the investigators reviewed data from the Hopkins Lupus Cohort, consisting of all SLE patients seen at a single center who are followed at least quarterly.

The study population included 2,452 SLE patients older than 18 years who had their weight assessed at each clinic visit. The average follow-up period was 7.75 years, and the average number of weight measurements per patient was nearly 24.

Cachexia was defined as a 5% stable weight loss in 6 months without starvation relative to the average weight in all prior cohort visits; and/or weight loss of more than 2% without starvation relative to the average weight in all prior cohort visits in addition to a body mass index less than 20 kg/m².

Overall, the risk for cachexia within 5 years of entering the study was significantly higher in patients with a BMI less than 20, current steroid use, vasculitis, lupus nephritis, serositis, hematologic lupus, positive anti-double strand DNA (anti-dsDNA), anti-Smith (anti-Sm), and antiribonucleoprotein (anti-RNP), the researchers noted. After adjustment for prednisone use, cachexia remained significantly associated with lupus nephritis, vasculitis, serositis, and hematologic lupus.

Future organ damage including cataracts, retinal change or optic atrophy, cognitive impairment, cerebrovascular accidents, cranial or peripheral neuropathy, pulmonary hypertension, pleural fibrosis, angina or coronary bypass, bowel infarction or resection, osteoporosis, avascular necrosis, and premature gonadal failure were significantly more likely among patients with intermittent cachexia, compared with those with continuous or no cachexia. Patients with continuous cachexia were significantly more likely to experience an estimated glomerular filtration rate less than 50 mL/min/1.73 m², proteinuria greater than 3.5 g/day, and end-stage renal disease.

The patients who never developed cachexia were significantly less likely to develop malignancies, diabetes, valvular disease, or cardiomyopathy than were those who did have cachexia, the researchers said.

The mechanisms of action for cachexia in SLE remain unclear, but studies in cancer patients may provide some guidance, the researchers noted. “Tumors secrete a range of procachexia factors thought to be unique to cancer-related cachexia, and colloquially termed the ‘tumor secretome,’ ” they said. “Every single proinflammatory cytokine mentioned as part of the tumor secretome has a role in lupus pathogenesis,” suggesting a possible common pathway to cachexia across different diseases, they said.

The study findings were limited by several factors, mainly the use of BMI to measure weight “since BMI is a rather poor indicator of percent of body fat,” the researchers noted. “Ideally, cachexia would be defined as sarcopenia based on body composition evaluation with a dual x-ray absorptiometry,” they wrote.

The study was supported by the National Institutes of Health and the NIH Roadmap for Medical Research. The researchers had no financial conflicts to disclose.

SOURCE: Stojan G et al. Arthritis Care Res. 2020 Aug 2. doi: 10.1002/acr.24395.

Cachexia developed in 56% of adults with systemic lupus erythematosus over a 5-year period, and 18% did not recover their weight, based on data from more than 2,000 patients.

Sara Freeman/MDedge News

Although weight loss is common in patients with systemic lupus erythematosus (SLE), cachexia, a disorder of involuntary weight loss, is largely undescribed in SLE patients, wrote George Stojan, MD, of Johns Hopkins University, Baltimore, and colleagues. Cachexia has been described in a range of disorders, including heart failure, renal disease, and rheumatoid arthritis, they said. “Cachexia has been shown to lead to progressive functional impairment, treatment-related complications, poor quality of life, and increased mortality,” they added.

In a study published in Arthritis Care & Research, the investigators reviewed data from the Hopkins Lupus Cohort, consisting of all SLE patients seen at a single center who are followed at least quarterly.

The study population included 2,452 SLE patients older than 18 years who had their weight assessed at each clinic visit. The average follow-up period was 7.75 years, and the average number of weight measurements per patient was nearly 24.

Cachexia was defined as a 5% stable weight loss in 6 months without starvation relative to the average weight in all prior cohort visits; and/or weight loss of more than 2% without starvation relative to the average weight in all prior cohort visits in addition to a body mass index less than 20 kg/m².

Overall, the risk for cachexia within 5 years of entering the study was significantly higher in patients with a BMI less than 20, current steroid use, vasculitis, lupus nephritis, serositis, hematologic lupus, positive anti-double strand DNA (anti-dsDNA), anti-Smith (anti-Sm), and antiribonucleoprotein (anti-RNP), the researchers noted. After adjustment for prednisone use, cachexia remained significantly associated with lupus nephritis, vasculitis, serositis, and hematologic lupus.

Future organ damage including cataracts, retinal change or optic atrophy, cognitive impairment, cerebrovascular accidents, cranial or peripheral neuropathy, pulmonary hypertension, pleural fibrosis, angina or coronary bypass, bowel infarction or resection, osteoporosis, avascular necrosis, and premature gonadal failure were significantly more likely among patients with intermittent cachexia, compared with those with continuous or no cachexia. Patients with continuous cachexia were significantly more likely to experience an estimated glomerular filtration rate less than 50 mL/min/1.73 m², proteinuria greater than 3.5 g/day, and end-stage renal disease.

The patients who never developed cachexia were significantly less likely to develop malignancies, diabetes, valvular disease, or cardiomyopathy than were those who did have cachexia, the researchers said.

The mechanisms of action for cachexia in SLE remain unclear, but studies in cancer patients may provide some guidance, the researchers noted. “Tumors secrete a range of procachexia factors thought to be unique to cancer-related cachexia, and colloquially termed the ‘tumor secretome,’ ” they said. “Every single proinflammatory cytokine mentioned as part of the tumor secretome has a role in lupus pathogenesis,” suggesting a possible common pathway to cachexia across different diseases, they said.

The study findings were limited by several factors, mainly the use of BMI to measure weight “since BMI is a rather poor indicator of percent of body fat,” the researchers noted. “Ideally, cachexia would be defined as sarcopenia based on body composition evaluation with a dual x-ray absorptiometry,” they wrote.

The study was supported by the National Institutes of Health and the NIH Roadmap for Medical Research. The researchers had no financial conflicts to disclose.

SOURCE: Stojan G et al. Arthritis Care Res. 2020 Aug 2. doi: 10.1002/acr.24395.

Cachexia developed in 56% of adults with systemic lupus erythematosus over a 5-year period, and 18% did not recover their weight, based on data from more than 2,000 patients.

Sara Freeman/MDedge News

Although weight loss is common in patients with systemic lupus erythematosus (SLE), cachexia, a disorder of involuntary weight loss, is largely undescribed in SLE patients, wrote George Stojan, MD, of Johns Hopkins University, Baltimore, and colleagues. Cachexia has been described in a range of disorders, including heart failure, renal disease, and rheumatoid arthritis, they said. “Cachexia has been shown to lead to progressive functional impairment, treatment-related complications, poor quality of life, and increased mortality,” they added.

In a study published in Arthritis Care & Research, the investigators reviewed data from the Hopkins Lupus Cohort, consisting of all SLE patients seen at a single center who are followed at least quarterly.

The study population included 2,452 SLE patients older than 18 years who had their weight assessed at each clinic visit. The average follow-up period was 7.75 years, and the average number of weight measurements per patient was nearly 24.

Cachexia was defined as a 5% stable weight loss in 6 months without starvation relative to the average weight in all prior cohort visits; and/or weight loss of more than 2% without starvation relative to the average weight in all prior cohort visits in addition to a body mass index less than 20 kg/m².

Overall, the risk for cachexia within 5 years of entering the study was significantly higher in patients with a BMI less than 20, current steroid use, vasculitis, lupus nephritis, serositis, hematologic lupus, positive anti-double strand DNA (anti-dsDNA), anti-Smith (anti-Sm), and antiribonucleoprotein (anti-RNP), the researchers noted. After adjustment for prednisone use, cachexia remained significantly associated with lupus nephritis, vasculitis, serositis, and hematologic lupus.

Future organ damage including cataracts, retinal change or optic atrophy, cognitive impairment, cerebrovascular accidents, cranial or peripheral neuropathy, pulmonary hypertension, pleural fibrosis, angina or coronary bypass, bowel infarction or resection, osteoporosis, avascular necrosis, and premature gonadal failure were significantly more likely among patients with intermittent cachexia, compared with those with continuous or no cachexia. Patients with continuous cachexia were significantly more likely to experience an estimated glomerular filtration rate less than 50 mL/min/1.73 m², proteinuria greater than 3.5 g/day, and end-stage renal disease.

The patients who never developed cachexia were significantly less likely to develop malignancies, diabetes, valvular disease, or cardiomyopathy than were those who did have cachexia, the researchers said.

The mechanisms of action for cachexia in SLE remain unclear, but studies in cancer patients may provide some guidance, the researchers noted. “Tumors secrete a range of procachexia factors thought to be unique to cancer-related cachexia, and colloquially termed the ‘tumor secretome,’ ” they said. “Every single proinflammatory cytokine mentioned as part of the tumor secretome has a role in lupus pathogenesis,” suggesting a possible common pathway to cachexia across different diseases, they said.

The study findings were limited by several factors, mainly the use of BMI to measure weight “since BMI is a rather poor indicator of percent of body fat,” the researchers noted. “Ideally, cachexia would be defined as sarcopenia based on body composition evaluation with a dual x-ray absorptiometry,” they wrote.

The study was supported by the National Institutes of Health and the NIH Roadmap for Medical Research. The researchers had no financial conflicts to disclose.

SOURCE: Stojan G et al. Arthritis Care Res. 2020 Aug 2. doi: 10.1002/acr.24395.

Darth Vader is, to me, one of the most intimidating villains in movie history. I was 11 when Star Wars came out. I even cleaned my room so my mother would take me to see it.

When Darth Vader first walked on screen, it was striking. A tall, imposing figure in black, with harsh mechanical respirations. There was no question of who the bad guy was. As the movie progressed his darkness became more frightening until, in the first lightsaber battle any of us had seen, he cut down the benevolent Obi-Wan Kenobi.

Last year my family went to Disneyland. While browsing the park’s stores we saw numerous Darth Vader items ... with him now available as a teddy bear, and on T-shirts riding carousels and the Dumbo ride.

From terrifying villain to cutesy toy in 43 years.* Quite the fall from glory.

Diseases are often (and hopefully) like that. Syphilis, once the most common, feared, and incurable neurologic disease is now, for most, just a nuisance. The butt of jokes and sexual innuendos, rendered harmless by Alexander Fleming’s discoveries.

Bit by bit we see other diseases tamed. Multiple sclerosis, though still serious, becomes better controlled every year as new agents come out. The cure for Parkinson’s disease remains elusive, but agents to control the symptoms and improve quality of life are available. Even HIV, the most feared disease of the 80s and 90s, has been beaten back from a terrible death sentence to one where patients lead normal lives with antiviral therapy.

Today we face a new enemy, the COVID-19 pandemic. So far we have no definite treatments, nor shortage of ideas. Many companies are racing to develop a vaccine, and will likely, at some point, find one, but what and when are still in the future. Hopefully, like previously devastating illnesses, COVID-19 will be brought under control, too.

Alzheimer’s disease, for all practical purposes, remains untreatable and rightfully feared. Perhaps the only ones more terrifying are those we’ve reduced to just three letters: ALS (amyotrophic lateral sclerosis) and GBM (glioblastoma multiforme). Both have terrible courses and, in spite of years of research, nothing even close to an effective treatment.

I hope that changes, and soon, for all those affected by these (and many other) terrible disorders.

Like the Darth Vader teddy bear, I’ll be happy to see them become shells of their former selves, with the dread they bring now reduced to the lesser trepidation seen when facing a serious, but treatable, illness.

*Correction, 8/11/20: An earlier version of this column misstated the number of years since Star Wars debuted.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Darth Vader is, to me, one of the most intimidating villains in movie history. I was 11 when Star Wars came out. I even cleaned my room so my mother would take me to see it.

When Darth Vader first walked on screen, it was striking. A tall, imposing figure in black, with harsh mechanical respirations. There was no question of who the bad guy was. As the movie progressed his darkness became more frightening until, in the first lightsaber battle any of us had seen, he cut down the benevolent Obi-Wan Kenobi.

Last year my family went to Disneyland. While browsing the park’s stores we saw numerous Darth Vader items ... with him now available as a teddy bear, and on T-shirts riding carousels and the Dumbo ride.

From terrifying villain to cutesy toy in 43 years.* Quite the fall from glory.

Diseases are often (and hopefully) like that. Syphilis, once the most common, feared, and incurable neurologic disease is now, for most, just a nuisance. The butt of jokes and sexual innuendos, rendered harmless by Alexander Fleming’s discoveries.

Bit by bit we see other diseases tamed. Multiple sclerosis, though still serious, becomes better controlled every year as new agents come out. The cure for Parkinson’s disease remains elusive, but agents to control the symptoms and improve quality of life are available. Even HIV, the most feared disease of the 80s and 90s, has been beaten back from a terrible death sentence to one where patients lead normal lives with antiviral therapy.

Today we face a new enemy, the COVID-19 pandemic. So far we have no definite treatments, nor shortage of ideas. Many companies are racing to develop a vaccine, and will likely, at some point, find one, but what and when are still in the future. Hopefully, like previously devastating illnesses, COVID-19 will be brought under control, too.

Alzheimer’s disease, for all practical purposes, remains untreatable and rightfully feared. Perhaps the only ones more terrifying are those we’ve reduced to just three letters: ALS (amyotrophic lateral sclerosis) and GBM (glioblastoma multiforme). Both have terrible courses and, in spite of years of research, nothing even close to an effective treatment.

I hope that changes, and soon, for all those affected by these (and many other) terrible disorders.

Like the Darth Vader teddy bear, I’ll be happy to see them become shells of their former selves, with the dread they bring now reduced to the lesser trepidation seen when facing a serious, but treatable, illness.

*Correction, 8/11/20: An earlier version of this column misstated the number of years since Star Wars debuted.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Darth Vader is, to me, one of the most intimidating villains in movie history. I was 11 when Star Wars came out. I even cleaned my room so my mother would take me to see it.

When Darth Vader first walked on screen, it was striking. A tall, imposing figure in black, with harsh mechanical respirations. There was no question of who the bad guy was. As the movie progressed his darkness became more frightening until, in the first lightsaber battle any of us had seen, he cut down the benevolent Obi-Wan Kenobi.

Last year my family went to Disneyland. While browsing the park’s stores we saw numerous Darth Vader items ... with him now available as a teddy bear, and on T-shirts riding carousels and the Dumbo ride.

From terrifying villain to cutesy toy in 43 years.* Quite the fall from glory.

Diseases are often (and hopefully) like that. Syphilis, once the most common, feared, and incurable neurologic disease is now, for most, just a nuisance. The butt of jokes and sexual innuendos, rendered harmless by Alexander Fleming’s discoveries.

Bit by bit we see other diseases tamed. Multiple sclerosis, though still serious, becomes better controlled every year as new agents come out. The cure for Parkinson’s disease remains elusive, but agents to control the symptoms and improve quality of life are available. Even HIV, the most feared disease of the 80s and 90s, has been beaten back from a terrible death sentence to one where patients lead normal lives with antiviral therapy.

Today we face a new enemy, the COVID-19 pandemic. So far we have no definite treatments, nor shortage of ideas. Many companies are racing to develop a vaccine, and will likely, at some point, find one, but what and when are still in the future. Hopefully, like previously devastating illnesses, COVID-19 will be brought under control, too.

Alzheimer’s disease, for all practical purposes, remains untreatable and rightfully feared. Perhaps the only ones more terrifying are those we’ve reduced to just three letters: ALS (amyotrophic lateral sclerosis) and GBM (glioblastoma multiforme). Both have terrible courses and, in spite of years of research, nothing even close to an effective treatment.

I hope that changes, and soon, for all those affected by these (and many other) terrible disorders.

Like the Darth Vader teddy bear, I’ll be happy to see them become shells of their former selves, with the dread they bring now reduced to the lesser trepidation seen when facing a serious, but treatable, illness.

*Correction, 8/11/20: An earlier version of this column misstated the number of years since Star Wars debuted.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Key clinical point: Age, disability, and obesity were independent risk factors for severe COVID-19 in patients with multiple sclerosis (MS).

Major finding: Higher age (odds ratio [OR] per 10 years, 1.9; 95% confidence interval [CI], 1.4-2.5), Expanded Disability Severity Status scores of ≥6 (OR, 6.3; 95% CI, 2.8-14.4), and obesity (OR, 3.0; 95% CI, 1.03-8.7) were independently associated with severe COVID-19 (severity score ≥3) Modification of disease-modifying therapies had no association with COVID-19 outcomes.

Study details: A multicenter, retrospective, observational cohort study analyzed data for 347 MS patients with confirmed or highly suspected COVID-19.

Disclosures: The study did not receive any specific funding. The authors reported relationships with multiple pharmaceutical companies and institutions.

Citation: Louapre C et al. JAMA Neurol. 2020 Jun 26. doi: 10.1001/jamaneurol.2020.2581.

Key clinical point: Age, disability, and obesity were independent risk factors for severe COVID-19 in patients with multiple sclerosis (MS).

Major finding: Higher age (odds ratio [OR] per 10 years, 1.9; 95% confidence interval [CI], 1.4-2.5), Expanded Disability Severity Status scores of ≥6 (OR, 6.3; 95% CI, 2.8-14.4), and obesity (OR, 3.0; 95% CI, 1.03-8.7) were independently associated with severe COVID-19 (severity score ≥3) Modification of disease-modifying therapies had no association with COVID-19 outcomes.

Study details: A multicenter, retrospective, observational cohort study analyzed data for 347 MS patients with confirmed or highly suspected COVID-19.

Disclosures: The study did not receive any specific funding. The authors reported relationships with multiple pharmaceutical companies and institutions.

Citation: Louapre C et al. JAMA Neurol. 2020 Jun 26. doi: 10.1001/jamaneurol.2020.2581.

Key clinical point: Age, disability, and obesity were independent risk factors for severe COVID-19 in patients with multiple sclerosis (MS).

Major finding: Higher age (odds ratio [OR] per 10 years, 1.9; 95% confidence interval [CI], 1.4-2.5), Expanded Disability Severity Status scores of ≥6 (OR, 6.3; 95% CI, 2.8-14.4), and obesity (OR, 3.0; 95% CI, 1.03-8.7) were independently associated with severe COVID-19 (severity score ≥3) Modification of disease-modifying therapies had no association with COVID-19 outcomes.

Study details: A multicenter, retrospective, observational cohort study analyzed data for 347 MS patients with confirmed or highly suspected COVID-19.

Disclosures: The study did not receive any specific funding. The authors reported relationships with multiple pharmaceutical companies and institutions.

Citation: Louapre C et al. JAMA Neurol. 2020 Jun 26. doi: 10.1001/jamaneurol.2020.2581.

Key clinical point: Treatment with rituximab could effectively reduce disability levels and relapse rates in patients with multiple sclerosis (MS).

Major finding: The mean Expanded Disability Status Scale (EDSS) scores decreased by 0.29 (95% confidence interval [CI], 0.16-0.42) after rituximab treatment. Analysis of 3 studies showed a mean reduction in annualized relapse rates (–1.24; 95% CI, –1.04 to –1.44) after rituximab treatment. The overall proportion of adverse effects was 23% (95% CI, 20%-26%).

Study details: A systematic review and meta-analysis of 7 studies including 399 patients with MS treated with rituximab.

Disclosures: No information was available on funding and conflicts of interest.

Citation: Ghajarzadeh M et al. Autoimmun Rev. 2020 Jun 10. doi:10.1016/j.autrev.2020.102585.

Key clinical point: Treatment with rituximab could effectively reduce disability levels and relapse rates in patients with multiple sclerosis (MS).

Major finding: The mean Expanded Disability Status Scale (EDSS) scores decreased by 0.29 (95% confidence interval [CI], 0.16-0.42) after rituximab treatment. Analysis of 3 studies showed a mean reduction in annualized relapse rates (–1.24; 95% CI, –1.04 to –1.44) after rituximab treatment. The overall proportion of adverse effects was 23% (95% CI, 20%-26%).

Study details: A systematic review and meta-analysis of 7 studies including 399 patients with MS treated with rituximab.

Disclosures: No information was available on funding and conflicts of interest.

Citation: Ghajarzadeh M et al. Autoimmun Rev. 2020 Jun 10. doi:10.1016/j.autrev.2020.102585.

Key clinical point: Treatment with rituximab could effectively reduce disability levels and relapse rates in patients with multiple sclerosis (MS).

Major finding: The mean Expanded Disability Status Scale (EDSS) scores decreased by 0.29 (95% confidence interval [CI], 0.16-0.42) after rituximab treatment. Analysis of 3 studies showed a mean reduction in annualized relapse rates (–1.24; 95% CI, –1.04 to –1.44) after rituximab treatment. The overall proportion of adverse effects was 23% (95% CI, 20%-26%).

Study details: A systematic review and meta-analysis of 7 studies including 399 patients with MS treated with rituximab.

Disclosures: No information was available on funding and conflicts of interest.

Citation: Ghajarzadeh M et al. Autoimmun Rev. 2020 Jun 10. doi:10.1016/j.autrev.2020.102585.

Key clinical point: The prevalence of enlarged perivascular spaces (EPVS) on magnetic resonance imaging is higher in patients with multiple sclerosis (MS), with higher EPVS burden vs. controls. This supports a potential role of EPVS in MS etiopathogenesis and its use as marker with prognostic potential.

Major finding: Whole brain EPVSs were more common in patients with MS vs. controls (odds ratio [OR], 4.61; P = .001). Patients with MS had a larger EPVS volume (standardized mean difference [SMD], 0.88; P = .01), area (SMD, 0.79; P = .06), and count (SMD, 0.46; P less than .0001) compared with controls.

Study details: Systematic review and meta-analysis of 9 studies including 457 patients with MS and 352 control participants.

Disclosures: This study was supported by grants of the Swiss National Science Foundation and the Region of Stockholm. The authors declared no conflict of interest.

Citation: Granberg T et al. J Neurol. 2020 Jun 13. doi: 10.1007/s00415-020-09971-5.

Key clinical point: The prevalence of enlarged perivascular spaces (EPVS) on magnetic resonance imaging is higher in patients with multiple sclerosis (MS), with higher EPVS burden vs. controls. This supports a potential role of EPVS in MS etiopathogenesis and its use as marker with prognostic potential.

Major finding: Whole brain EPVSs were more common in patients with MS vs. controls (odds ratio [OR], 4.61; P = .001). Patients with MS had a larger EPVS volume (standardized mean difference [SMD], 0.88; P = .01), area (SMD, 0.79; P = .06), and count (SMD, 0.46; P less than .0001) compared with controls.

Study details: Systematic review and meta-analysis of 9 studies including 457 patients with MS and 352 control participants.

Disclosures: This study was supported by grants of the Swiss National Science Foundation and the Region of Stockholm. The authors declared no conflict of interest.

Citation: Granberg T et al. J Neurol. 2020 Jun 13. doi: 10.1007/s00415-020-09971-5.

Key clinical point: The prevalence of enlarged perivascular spaces (EPVS) on magnetic resonance imaging is higher in patients with multiple sclerosis (MS), with higher EPVS burden vs. controls. This supports a potential role of EPVS in MS etiopathogenesis and its use as marker with prognostic potential.

Major finding: Whole brain EPVSs were more common in patients with MS vs. controls (odds ratio [OR], 4.61; P = .001). Patients with MS had a larger EPVS volume (standardized mean difference [SMD], 0.88; P = .01), area (SMD, 0.79; P = .06), and count (SMD, 0.46; P less than .0001) compared with controls.

Study details: Systematic review and meta-analysis of 9 studies including 457 patients with MS and 352 control participants.

Disclosures: This study was supported by grants of the Swiss National Science Foundation and the Region of Stockholm. The authors declared no conflict of interest.

Citation: Granberg T et al. J Neurol. 2020 Jun 13. doi: 10.1007/s00415-020-09971-5.

Key clinical point: Treatment with hookworm was safe and possibly associated with an immunobiological effect in relapsing multiple sclerosis.

Major finding: During 3-9 months postinfection, no significant difference was detected between hookworm and placebo groups in total number of new T2 lesions, newly enhancing T1-weighted lesions, or T2 enlarging lesions. Hookworm group was somewhat less likely to have any magnetic resonance imaging activity (odds ratio, 0.33), higher percentage of CD4+CD25^highCD127^negT cells in peripheral blood (4.4% vs. 3.9%; P = .01), and lower relapse rate per patient (14.3% vs. 30.6%). No patients withdrew because of adverse effects. The only differing adverse event was more application-site skin discomfort in the hookworm group (82.86% vs. 27.78%).

Study details: In this phase 2 trial, 71 patients with relapsing MS without disease-modifying treatment were randomly assigned (1:1) to receive 25 Necator americanus larvae transcutaneously or placebo.

Disclosures: This study was supported by the MS Society of the Great Britain and Northern Ireland, the Forman Hardy Charitable Trust via the University of Nottingham, and an unrestricted grant from Bayer-Schering. Some of the investigators reported receiving grants and personal fees from multiple pharmaceutical companies.

Citation: Tanasescu R et al. JAMA Neurol. 2020 Jun 15. doi: 10.1001/jamaneurol.2020.1118.

Key clinical point: Treatment with hookworm was safe and possibly associated with an immunobiological effect in relapsing multiple sclerosis.

Major finding: During 3-9 months postinfection, no significant difference was detected between hookworm and placebo groups in total number of new T2 lesions, newly enhancing T1-weighted lesions, or T2 enlarging lesions. Hookworm group was somewhat less likely to have any magnetic resonance imaging activity (odds ratio, 0.33), higher percentage of CD4+CD25^highCD127^negT cells in peripheral blood (4.4% vs. 3.9%; P = .01), and lower relapse rate per patient (14.3% vs. 30.6%). No patients withdrew because of adverse effects. The only differing adverse event was more application-site skin discomfort in the hookworm group (82.86% vs. 27.78%).

Study details: In this phase 2 trial, 71 patients with relapsing MS without disease-modifying treatment were randomly assigned (1:1) to receive 25 Necator americanus larvae transcutaneously or placebo.

Disclosures: This study was supported by the MS Society of the Great Britain and Northern Ireland, the Forman Hardy Charitable Trust via the University of Nottingham, and an unrestricted grant from Bayer-Schering. Some of the investigators reported receiving grants and personal fees from multiple pharmaceutical companies.

Citation: Tanasescu R et al. JAMA Neurol. 2020 Jun 15. doi: 10.1001/jamaneurol.2020.1118.

Key clinical point: Treatment with hookworm was safe and possibly associated with an immunobiological effect in relapsing multiple sclerosis.

Major finding: During 3-9 months postinfection, no significant difference was detected between hookworm and placebo groups in total number of new T2 lesions, newly enhancing T1-weighted lesions, or T2 enlarging lesions. Hookworm group was somewhat less likely to have any magnetic resonance imaging activity (odds ratio, 0.33), higher percentage of CD4+CD25^highCD127^negT cells in peripheral blood (4.4% vs. 3.9%; P = .01), and lower relapse rate per patient (14.3% vs. 30.6%). No patients withdrew because of adverse effects. The only differing adverse event was more application-site skin discomfort in the hookworm group (82.86% vs. 27.78%).

Study details: In this phase 2 trial, 71 patients with relapsing MS without disease-modifying treatment were randomly assigned (1:1) to receive 25 Necator americanus larvae transcutaneously or placebo.

Disclosures: This study was supported by the MS Society of the Great Britain and Northern Ireland, the Forman Hardy Charitable Trust via the University of Nottingham, and an unrestricted grant from Bayer-Schering. Some of the investigators reported receiving grants and personal fees from multiple pharmaceutical companies.

Citation: Tanasescu R et al. JAMA Neurol. 2020 Jun 15. doi: 10.1001/jamaneurol.2020.1118.

Findings from a large randomized, controlled trial do not support the use of vitamin D3 supplementation for adults for the sole purpose of preventing depression.

Among adults aged 50 years or older who were without clinically relevant depressive symptoms at baseline, vitamin D3 supplementation taken over 5 years did not reduce the risk for depression or make a difference in the quality of mood.

“The study is among the largest of its kind ever, and it was able to address whether vitamin D3 supplementation is useful for what we call ‘universal prevention’ of depression,” Olivia Okereke, MD, Massachusetts General Hospital, Boston, said in an interview.

“These results tell us that there is no benefit to using vitamin D3 supplements for the sole purpose of preventing depression in the general population of middle-aged and older adults,” said Dr. Okereke.

“Because of the high dose and long duration of treatment and the randomized placebo-controlled design, we can have high confidence in results,” she added.

The study was published online August 4 in JAMA.
 

The VITAL-DEP trial

The findings are based on 18,353 older adults (mean age, 67.5 years; 49% women) in the VITAL-DEP study; 16,657 were at risk for incident depression (ie, had no history of depression), and 1696 were at risk for recurrent depression (i.e., had a history of depression but had not undergone treatment for depression within the past 2 years).

Roughly half were randomly allocated to receive vitamin D3 (2000 IU/d of cholecalciferol) and half to receive matching placebo for a median of 5.3 years. The participants’ mean level of 25-hydroxyvitamin D was 31.1 ng/mL; for about 12%, levels were lower than 20 ng/mL.

The risk for depression or clinically relevant depressive symptoms (total of incident and recurrent cases) was not significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years). The hazard ratio was 0.97 (95% confidence interval, 0.87-1.09; P = .62).

“Cumulative incidence curves showed lack of separation between treatment groups over the entire follow-up,” the researchers report.

There was also no significant between-group difference in the other primary outcome – the mean difference in mood scores on the eight-item Patient Health Questionnaire depression scale (PHQ-8).

The mean difference for change between treatment groups in PHQ-8 scores was not significantly different from 0 over the entire follow-up (0.01 points; 95% CI, −0.04 to 0.05 points) or at any point during follow-up.

To date, 13 randomized clinical trials have examined the effects of vitamin D3 supplementation on depression or mood during middle age or in older adults, and all except one reported null findings, Dr. Okereke and colleagues noted in their article.

The current study is the only one large enough to examine vitamin D3 supplementation for the universal prevention of depression, they point out.

Although the findings do not support vitamin D3 supplementation for depression prevention, Dr. Okereke said, “we cannot yet exclude the possibility of benefit of vitamin D3 for preventing depression among subgroups with certain health risk factors. We also know that vitamin D is essential for bone health, and this study does not tell us whether vitamin D3 is useful for prevention of other health outcomes.”

VITAL-DEP was supported by a grant from the National Institute of Mental Health. Pharmavite donated the vitamin D3, matching placebos, and packaging in the form of calendar packs. Dr. Okereke reported receiving royalties from Springer Publishing for a book on the prevention of late-life depression.

This article first appeared on Medscape.com.

Findings from a large randomized, controlled trial do not support the use of vitamin D3 supplementation for adults for the sole purpose of preventing depression.

Among adults aged 50 years or older who were without clinically relevant depressive symptoms at baseline, vitamin D3 supplementation taken over 5 years did not reduce the risk for depression or make a difference in the quality of mood.

“The study is among the largest of its kind ever, and it was able to address whether vitamin D3 supplementation is useful for what we call ‘universal prevention’ of depression,” Olivia Okereke, MD, Massachusetts General Hospital, Boston, said in an interview.

“These results tell us that there is no benefit to using vitamin D3 supplements for the sole purpose of preventing depression in the general population of middle-aged and older adults,” said Dr. Okereke.

“Because of the high dose and long duration of treatment and the randomized placebo-controlled design, we can have high confidence in results,” she added.

The study was published online August 4 in JAMA.
 

The VITAL-DEP trial

The findings are based on 18,353 older adults (mean age, 67.5 years; 49% women) in the VITAL-DEP study; 16,657 were at risk for incident depression (ie, had no history of depression), and 1696 were at risk for recurrent depression (i.e., had a history of depression but had not undergone treatment for depression within the past 2 years).

Roughly half were randomly allocated to receive vitamin D3 (2000 IU/d of cholecalciferol) and half to receive matching placebo for a median of 5.3 years. The participants’ mean level of 25-hydroxyvitamin D was 31.1 ng/mL; for about 12%, levels were lower than 20 ng/mL.

The risk for depression or clinically relevant depressive symptoms (total of incident and recurrent cases) was not significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years). The hazard ratio was 0.97 (95% confidence interval, 0.87-1.09; P = .62).

“Cumulative incidence curves showed lack of separation between treatment groups over the entire follow-up,” the researchers report.

There was also no significant between-group difference in the other primary outcome – the mean difference in mood scores on the eight-item Patient Health Questionnaire depression scale (PHQ-8).

The mean difference for change between treatment groups in PHQ-8 scores was not significantly different from 0 over the entire follow-up (0.01 points; 95% CI, −0.04 to 0.05 points) or at any point during follow-up.

To date, 13 randomized clinical trials have examined the effects of vitamin D3 supplementation on depression or mood during middle age or in older adults, and all except one reported null findings, Dr. Okereke and colleagues noted in their article.

The current study is the only one large enough to examine vitamin D3 supplementation for the universal prevention of depression, they point out.

Although the findings do not support vitamin D3 supplementation for depression prevention, Dr. Okereke said, “we cannot yet exclude the possibility of benefit of vitamin D3 for preventing depression among subgroups with certain health risk factors. We also know that vitamin D is essential for bone health, and this study does not tell us whether vitamin D3 is useful for prevention of other health outcomes.”

VITAL-DEP was supported by a grant from the National Institute of Mental Health. Pharmavite donated the vitamin D3, matching placebos, and packaging in the form of calendar packs. Dr. Okereke reported receiving royalties from Springer Publishing for a book on the prevention of late-life depression.

This article first appeared on Medscape.com.

Findings from a large randomized, controlled trial do not support the use of vitamin D3 supplementation for adults for the sole purpose of preventing depression.

Among adults aged 50 years or older who were without clinically relevant depressive symptoms at baseline, vitamin D3 supplementation taken over 5 years did not reduce the risk for depression or make a difference in the quality of mood.

“The study is among the largest of its kind ever, and it was able to address whether vitamin D3 supplementation is useful for what we call ‘universal prevention’ of depression,” Olivia Okereke, MD, Massachusetts General Hospital, Boston, said in an interview.

“These results tell us that there is no benefit to using vitamin D3 supplements for the sole purpose of preventing depression in the general population of middle-aged and older adults,” said Dr. Okereke.

“Because of the high dose and long duration of treatment and the randomized placebo-controlled design, we can have high confidence in results,” she added.

The study was published online August 4 in JAMA.
 

The VITAL-DEP trial

The findings are based on 18,353 older adults (mean age, 67.5 years; 49% women) in the VITAL-DEP study; 16,657 were at risk for incident depression (ie, had no history of depression), and 1696 were at risk for recurrent depression (i.e., had a history of depression but had not undergone treatment for depression within the past 2 years).

Roughly half were randomly allocated to receive vitamin D3 (2000 IU/d of cholecalciferol) and half to receive matching placebo for a median of 5.3 years. The participants’ mean level of 25-hydroxyvitamin D was 31.1 ng/mL; for about 12%, levels were lower than 20 ng/mL.

The risk for depression or clinically relevant depressive symptoms (total of incident and recurrent cases) was not significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years). The hazard ratio was 0.97 (95% confidence interval, 0.87-1.09; P = .62).

“Cumulative incidence curves showed lack of separation between treatment groups over the entire follow-up,” the researchers report.

There was also no significant between-group difference in the other primary outcome – the mean difference in mood scores on the eight-item Patient Health Questionnaire depression scale (PHQ-8).

The mean difference for change between treatment groups in PHQ-8 scores was not significantly different from 0 over the entire follow-up (0.01 points; 95% CI, −0.04 to 0.05 points) or at any point during follow-up.

To date, 13 randomized clinical trials have examined the effects of vitamin D3 supplementation on depression or mood during middle age or in older adults, and all except one reported null findings, Dr. Okereke and colleagues noted in their article.

The current study is the only one large enough to examine vitamin D3 supplementation for the universal prevention of depression, they point out.

Although the findings do not support vitamin D3 supplementation for depression prevention, Dr. Okereke said, “we cannot yet exclude the possibility of benefit of vitamin D3 for preventing depression among subgroups with certain health risk factors. We also know that vitamin D is essential for bone health, and this study does not tell us whether vitamin D3 is useful for prevention of other health outcomes.”

VITAL-DEP was supported by a grant from the National Institute of Mental Health. Pharmavite donated the vitamin D3, matching placebos, and packaging in the form of calendar packs. Dr. Okereke reported receiving royalties from Springer Publishing for a book on the prevention of late-life depression.

This article first appeared on Medscape.com.

When officials closed U.S. schools in March to limit the spread of COVID-19, they may have prevented more than 1 million cases over a 26-day period, a new estimate published online July 29 in JAMA suggests.

But school closures also left blind spots in understanding how children and schools affect disease transmission.

“School closures early in pandemic responses thwarted larger-scale investigations of schools as a source of community transmission,” researchers noted in a separate study, published online July 30 in JAMA Pediatrics, that examined levels of viral RNA in children and adults with COVID-19.

“Our analyses suggest children younger than 5 years with mild to moderate COVID-19 have high amounts of SARS-CoV-2 viral RNA in their nasopharynx, compared with older children and adults,” reported Taylor Heald-Sargent, MD, PhD, and colleagues. “Thus, young children can potentially be important drivers of SARS-CoV-2 spread in the general population, as has been demonstrated with respiratory syncytial virus, where children with high viral loads are more likely to transmit.”

Although the study “was not designed to prove that younger children spread COVID-19 as much as adults,” it is a possibility, Dr. Heald-Sargent, a pediatric infectious diseases specialist at Ann and Robert H. Lurie Children’s Hospital and assistant professor of pediatrics at Northwestern University, Chicago, said in a related news release. “We need to take that into account in efforts to reduce transmission as we continue to learn more about this virus.”.

The study included 145 patients with mild or moderate illness who were within 1 week of symptom onset. The researchers used reverse transcriptase–polymerase chain reaction (rt-PCR) on nasopharyngeal swabs collected at inpatient, outpatient, emergency department, or drive-through testing sites to measure SARS-CoV-2 levels. The investigators compared PCR amplification cycle threshold (CT) values for children younger than 5 years (n = 46), children aged 5-17 years (n = 51), and adults aged 18-65 years (n = 48); lower CT values indicate higher amounts of viral nucleic acid.

Median CT values for older children and adults were similar (about 11), whereas the median CT value for young children was significantly lower (6.5). The differences between young children and adults “approximate a 10-fold to 100-fold greater amount of SARS-CoV-2 in the upper respiratory tract of young children,” the researchers wrote.

“Behavioral habits of young children and close quarters in school and day care settings raise concern for SARS-CoV-2 amplification in this population as public health restrictions are eased,” they write.
 

Modeling the impact of school closures

In the JAMA study, Katherine A. Auger, MD, of Cincinnati Children’s Hospital Medical Center, and colleagues examined at the U.S. population level whether closing schools, as all 50 states did in March, was associated with relative decreases in COVID-19 incidence and mortality.

To isolate the effect of school closures, the researchers used an interrupted time series analysis and included other state-level nonpharmaceutical interventions and variables in their regression models.

“Per week, the incidence was estimated to have been 39% of what it would have been had schools remained open,” Dr. Auger and colleagues wrote. “Extrapolating the absolute differences of 423.9 cases and 12.6 deaths per 100,000 to 322.2 million residents nationally suggests that school closure may have been associated with approximately 1.37 million fewer cases of COVID-19 over a 26-day period and 40,600 fewer deaths over a 16-day period; however, these figures do not account for uncertainty in the model assumptions and the resulting estimates.”

Relative reductions in incidence and mortality were largest in states that closed schools when the incidence of COVID-19 was low, the authors found.
 

Decisions with high stakes

In an accompanying editorial, Julie M. Donohue, PhD, and Elizabeth Miller, MD, PhD, both affiliated with the University of Pittsburgh, emphasized that the results are estimates. “School closures were enacted in close proximity ... to other physical distancing measures, such as nonessential business closures and stay-at-home orders, making it difficult to disentangle the potential effect of each intervention.”

Although the findings “suggest a role for school closures in virus mitigation, school and health officials must balance this with academic, health, and economic consequences,” Dr. Donohue and Dr. Miller added. “Given the strong connection between education, income, and life expectancy, school closures could have long-term deleterious consequences for child health, likely reaching into adulthood.” Schools provide “meals and nutrition, health care including behavioral health supports, physical activity, social interaction, supports for students with special education needs and disabilities, and other vital resources for healthy development.”

In a viewpoint article also published in JAMA, authors involved in the creation of a National Academies of Sciences, Engineering, and Medicine reported on the reopening of schools recommend that districts “make every effort to prioritize reopening with an emphasis on providing in-person instruction for students in kindergarten through grade 5 as well as those students with special needs who might be best served by in-person instruction.

“To reopen safely, school districts are encouraged to ensure ventilation and air filtration, clean surfaces frequently, provide facilities for regular handwashing, and provide space for physical distancing,” write Kenne A. Dibner, PhD, of the NASEM in Washington, D.C., and coauthors.

Furthermore, districts “need to consider transparent communication of the reality that while measures can be implemented to lower the risk of transmitting COVID-19 when schools reopen, there is no way to eliminate that risk entirely. It is critical to share both the risks and benefits of different scenarios,” they wrote.

The JAMA modeling study received funding from the Agency for Healthcare Research and Quality and the National Institutes of Health. The NASEM report was funded by the Brady Education Foundation and the Spencer Foundation. The authors disclosed no relevant financial relationships.

A version of this story originally appeared on Medscape.com.

When officials closed U.S. schools in March to limit the spread of COVID-19, they may have prevented more than 1 million cases over a 26-day period, a new estimate published online July 29 in JAMA suggests.

But school closures also left blind spots in understanding how children and schools affect disease transmission.

“School closures early in pandemic responses thwarted larger-scale investigations of schools as a source of community transmission,” researchers noted in a separate study, published online July 30 in JAMA Pediatrics, that examined levels of viral RNA in children and adults with COVID-19.

“Our analyses suggest children younger than 5 years with mild to moderate COVID-19 have high amounts of SARS-CoV-2 viral RNA in their nasopharynx, compared with older children and adults,” reported Taylor Heald-Sargent, MD, PhD, and colleagues. “Thus, young children can potentially be important drivers of SARS-CoV-2 spread in the general population, as has been demonstrated with respiratory syncytial virus, where children with high viral loads are more likely to transmit.”

Although the study “was not designed to prove that younger children spread COVID-19 as much as adults,” it is a possibility, Dr. Heald-Sargent, a pediatric infectious diseases specialist at Ann and Robert H. Lurie Children’s Hospital and assistant professor of pediatrics at Northwestern University, Chicago, said in a related news release. “We need to take that into account in efforts to reduce transmission as we continue to learn more about this virus.”.

The study included 145 patients with mild or moderate illness who were within 1 week of symptom onset. The researchers used reverse transcriptase–polymerase chain reaction (rt-PCR) on nasopharyngeal swabs collected at inpatient, outpatient, emergency department, or drive-through testing sites to measure SARS-CoV-2 levels. The investigators compared PCR amplification cycle threshold (CT) values for children younger than 5 years (n = 46), children aged 5-17 years (n = 51), and adults aged 18-65 years (n = 48); lower CT values indicate higher amounts of viral nucleic acid.

Median CT values for older children and adults were similar (about 11), whereas the median CT value for young children was significantly lower (6.5). The differences between young children and adults “approximate a 10-fold to 100-fold greater amount of SARS-CoV-2 in the upper respiratory tract of young children,” the researchers wrote.

“Behavioral habits of young children and close quarters in school and day care settings raise concern for SARS-CoV-2 amplification in this population as public health restrictions are eased,” they write.
 

Modeling the impact of school closures

In the JAMA study, Katherine A. Auger, MD, of Cincinnati Children’s Hospital Medical Center, and colleagues examined at the U.S. population level whether closing schools, as all 50 states did in March, was associated with relative decreases in COVID-19 incidence and mortality.

To isolate the effect of school closures, the researchers used an interrupted time series analysis and included other state-level nonpharmaceutical interventions and variables in their regression models.

“Per week, the incidence was estimated to have been 39% of what it would have been had schools remained open,” Dr. Auger and colleagues wrote. “Extrapolating the absolute differences of 423.9 cases and 12.6 deaths per 100,000 to 322.2 million residents nationally suggests that school closure may have been associated with approximately 1.37 million fewer cases of COVID-19 over a 26-day period and 40,600 fewer deaths over a 16-day period; however, these figures do not account for uncertainty in the model assumptions and the resulting estimates.”

Relative reductions in incidence and mortality were largest in states that closed schools when the incidence of COVID-19 was low, the authors found.
 

Decisions with high stakes

In an accompanying editorial, Julie M. Donohue, PhD, and Elizabeth Miller, MD, PhD, both affiliated with the University of Pittsburgh, emphasized that the results are estimates. “School closures were enacted in close proximity ... to other physical distancing measures, such as nonessential business closures and stay-at-home orders, making it difficult to disentangle the potential effect of each intervention.”

Although the findings “suggest a role for school closures in virus mitigation, school and health officials must balance this with academic, health, and economic consequences,” Dr. Donohue and Dr. Miller added. “Given the strong connection between education, income, and life expectancy, school closures could have long-term deleterious consequences for child health, likely reaching into adulthood.” Schools provide “meals and nutrition, health care including behavioral health supports, physical activity, social interaction, supports for students with special education needs and disabilities, and other vital resources for healthy development.”

In a viewpoint article also published in JAMA, authors involved in the creation of a National Academies of Sciences, Engineering, and Medicine reported on the reopening of schools recommend that districts “make every effort to prioritize reopening with an emphasis on providing in-person instruction for students in kindergarten through grade 5 as well as those students with special needs who might be best served by in-person instruction.

“To reopen safely, school districts are encouraged to ensure ventilation and air filtration, clean surfaces frequently, provide facilities for regular handwashing, and provide space for physical distancing,” write Kenne A. Dibner, PhD, of the NASEM in Washington, D.C., and coauthors.

Furthermore, districts “need to consider transparent communication of the reality that while measures can be implemented to lower the risk of transmitting COVID-19 when schools reopen, there is no way to eliminate that risk entirely. It is critical to share both the risks and benefits of different scenarios,” they wrote.

The JAMA modeling study received funding from the Agency for Healthcare Research and Quality and the National Institutes of Health. The NASEM report was funded by the Brady Education Foundation and the Spencer Foundation. The authors disclosed no relevant financial relationships.

A version of this story originally appeared on Medscape.com.

When officials closed U.S. schools in March to limit the spread of COVID-19, they may have prevented more than 1 million cases over a 26-day period, a new estimate published online July 29 in JAMA suggests.

But school closures also left blind spots in understanding how children and schools affect disease transmission.

“School closures early in pandemic responses thwarted larger-scale investigations of schools as a source of community transmission,” researchers noted in a separate study, published online July 30 in JAMA Pediatrics, that examined levels of viral RNA in children and adults with COVID-19.

“Our analyses suggest children younger than 5 years with mild to moderate COVID-19 have high amounts of SARS-CoV-2 viral RNA in their nasopharynx, compared with older children and adults,” reported Taylor Heald-Sargent, MD, PhD, and colleagues. “Thus, young children can potentially be important drivers of SARS-CoV-2 spread in the general population, as has been demonstrated with respiratory syncytial virus, where children with high viral loads are more likely to transmit.”

Although the study “was not designed to prove that younger children spread COVID-19 as much as adults,” it is a possibility, Dr. Heald-Sargent, a pediatric infectious diseases specialist at Ann and Robert H. Lurie Children’s Hospital and assistant professor of pediatrics at Northwestern University, Chicago, said in a related news release. “We need to take that into account in efforts to reduce transmission as we continue to learn more about this virus.”.

The study included 145 patients with mild or moderate illness who were within 1 week of symptom onset. The researchers used reverse transcriptase–polymerase chain reaction (rt-PCR) on nasopharyngeal swabs collected at inpatient, outpatient, emergency department, or drive-through testing sites to measure SARS-CoV-2 levels. The investigators compared PCR amplification cycle threshold (CT) values for children younger than 5 years (n = 46), children aged 5-17 years (n = 51), and adults aged 18-65 years (n = 48); lower CT values indicate higher amounts of viral nucleic acid.

Median CT values for older children and adults were similar (about 11), whereas the median CT value for young children was significantly lower (6.5). The differences between young children and adults “approximate a 10-fold to 100-fold greater amount of SARS-CoV-2 in the upper respiratory tract of young children,” the researchers wrote.

“Behavioral habits of young children and close quarters in school and day care settings raise concern for SARS-CoV-2 amplification in this population as public health restrictions are eased,” they write.
 

Modeling the impact of school closures

In the JAMA study, Katherine A. Auger, MD, of Cincinnati Children’s Hospital Medical Center, and colleagues examined at the U.S. population level whether closing schools, as all 50 states did in March, was associated with relative decreases in COVID-19 incidence and mortality.

To isolate the effect of school closures, the researchers used an interrupted time series analysis and included other state-level nonpharmaceutical interventions and variables in their regression models.

“Per week, the incidence was estimated to have been 39% of what it would have been had schools remained open,” Dr. Auger and colleagues wrote. “Extrapolating the absolute differences of 423.9 cases and 12.6 deaths per 100,000 to 322.2 million residents nationally suggests that school closure may have been associated with approximately 1.37 million fewer cases of COVID-19 over a 26-day period and 40,600 fewer deaths over a 16-day period; however, these figures do not account for uncertainty in the model assumptions and the resulting estimates.”

Relative reductions in incidence and mortality were largest in states that closed schools when the incidence of COVID-19 was low, the authors found.
 

Decisions with high stakes

In an accompanying editorial, Julie M. Donohue, PhD, and Elizabeth Miller, MD, PhD, both affiliated with the University of Pittsburgh, emphasized that the results are estimates. “School closures were enacted in close proximity ... to other physical distancing measures, such as nonessential business closures and stay-at-home orders, making it difficult to disentangle the potential effect of each intervention.”

Although the findings “suggest a role for school closures in virus mitigation, school and health officials must balance this with academic, health, and economic consequences,” Dr. Donohue and Dr. Miller added. “Given the strong connection between education, income, and life expectancy, school closures could have long-term deleterious consequences for child health, likely reaching into adulthood.” Schools provide “meals and nutrition, health care including behavioral health supports, physical activity, social interaction, supports for students with special education needs and disabilities, and other vital resources for healthy development.”

In a viewpoint article also published in JAMA, authors involved in the creation of a National Academies of Sciences, Engineering, and Medicine reported on the reopening of schools recommend that districts “make every effort to prioritize reopening with an emphasis on providing in-person instruction for students in kindergarten through grade 5 as well as those students with special needs who might be best served by in-person instruction.

“To reopen safely, school districts are encouraged to ensure ventilation and air filtration, clean surfaces frequently, provide facilities for regular handwashing, and provide space for physical distancing,” write Kenne A. Dibner, PhD, of the NASEM in Washington, D.C., and coauthors.

Furthermore, districts “need to consider transparent communication of the reality that while measures can be implemented to lower the risk of transmitting COVID-19 when schools reopen, there is no way to eliminate that risk entirely. It is critical to share both the risks and benefits of different scenarios,” they wrote.

The JAMA modeling study received funding from the Agency for Healthcare Research and Quality and the National Institutes of Health. The NASEM report was funded by the Brady Education Foundation and the Spencer Foundation. The authors disclosed no relevant financial relationships.

A version of this story originally appeared on Medscape.com.