Neurology

Three previously described clinical phenotypes of obstructive sleep apnea (OSA) have been validated in a large and diverse Hispanic/Latino community-based population for the first time, according to findings presented at the virtual annual meeting of the Associated Professional Sleep Societies.

The three OSA symptom profiles present in this population – labeled “minimally symptomatic,” “disturbed sleep,” and “daytime sleepiness” – are consistent with recent findings from the Sleep Apnea Global Interdisciplinary Consortium, which were published in Sleep, but there are notable differences in the prevalence of these clusters, with the minimally symptomatic cluster much more prevalent than in prior research, reported Kevin Gonzalez, of the University of California, San Diego.

“Other biopsychosocial factors may be contributing to OSA phenotypes among Hispanics and Latinos,” Mr. Gonzalez said in his presentation. Prior research to characterize the heterogeneity of sleep apnea has not included a diverse Latino population, he emphasized.

The adults studied were aged 18-74 years and participants in the multisite Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a comprehensive study of Hispanic/Latino health and disease in the United States. Their respiratory events were measured overnight in HCHS/SOL sleep reading centers with an ARES Unicorder 5.2, B-Alert. Sleep patterns and risk factors were assessed using the Sleep Heart Health Study Sleep Habits Questionnaire and the Epworth Sleepiness Scale.

Participants meeting the criteria for moderate to severe OSA (with an Apnea Hypopnea Index of 15 or above) were included in the analysis (n = 1,623). Their average age was 52.4 ± 13.9 years, and 34.1% were female.

To identify phenotype clusters, investigators performed a latent class analysis using 15 common OSA symptoms and a survey weighted to adjust for selection bias. The three clusters offering the “best” fit for the data aligned with the previously reported phenotypes and identified daytime sleepiness in 15.3%, disturbed sleep (insomnia-like symptoms) in 37.7%, and minimally symptomatic (a low symptom profile) in 46.9%.

These phenotypes were reported in the European Respiratory Journal in 2014 in a cluster analysis of data from a sleep apnea cohort in Iceland and later replicated in the analysis of data from the Sleep Apnea Global Interdisciplinary Consortium published in Sleep in 2018. The consortium study also added two additional phenotypes, labeled “upper airway symptoms dominant” and “sleepiness dominant.”

The prevalence of a “minimally symptomatic group” in the new analysis of the Hispanics/Latinos in the United States is much higher than reported in these prior studies, at least partly, the investigators believed, because the “prior studies were clinical samples, and the people who were minimally symptomatic didn’t get to the sleep centers,” Mr. Gonzalez said in an interview after the meeting.

Patients with a phenotype of daytime sleepiness – the most common phenotype in prior research – constituted only a minority in the Hispanic/Latino population, he said.

Alberto Ramos, MD, of the University of Miami and the principal investigator, said in an interview that the research team is currently analyzing “if and how these different [phenotypic] clusters could affect the incidence of comorbidities” recorded in the HCHS/SOL study, such as hypertension, diabetes, cardiovascular disease, and cognitive decline.

For now, he said, the findings suggest that OSA may be especially underrecognized in Hispanics and Latinos and that there is more research to be done to better identify and stratify patients with varying symptomatology for more personalized treatment and for clinical trial selection. “Maybe we should expand our criteria ... broaden our [recognition] of the presentation of sleep apnea and the symptoms associated with it, not only in Hispanics but maybe in the general population,” Dr. Ramos said.

In commenting on the study, Krishna M. Sundar, MD, FCCP, director of the Sleep-Wake Center at the University of Utah, Salt Lake City, said that insomnia and daytime sleepiness are “key associations with obstructive sleep apnea and may predict different outcomes with untreated OSA.” Such heterogeneity is “only beginning to be appreciated,” he said. “The expression of OSA with these symptoms points to how OSA impacts quality of life” and how symptomatology in addition to Apnea Hypopnea Index “may be an important determinant of treatment benefit and compliance.”

The investigators reported no relevant disclosures. Dr. Sundar said that he is cofounder of Hypnoscure, software for population management of sleep apnea, but with no monies received.
 

Three previously described clinical phenotypes of obstructive sleep apnea (OSA) have been validated in a large and diverse Hispanic/Latino community-based population for the first time, according to findings presented at the virtual annual meeting of the Associated Professional Sleep Societies.

The three OSA symptom profiles present in this population – labeled “minimally symptomatic,” “disturbed sleep,” and “daytime sleepiness” – are consistent with recent findings from the Sleep Apnea Global Interdisciplinary Consortium, which were published in Sleep, but there are notable differences in the prevalence of these clusters, with the minimally symptomatic cluster much more prevalent than in prior research, reported Kevin Gonzalez, of the University of California, San Diego.

“Other biopsychosocial factors may be contributing to OSA phenotypes among Hispanics and Latinos,” Mr. Gonzalez said in his presentation. Prior research to characterize the heterogeneity of sleep apnea has not included a diverse Latino population, he emphasized.

The adults studied were aged 18-74 years and participants in the multisite Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a comprehensive study of Hispanic/Latino health and disease in the United States. Their respiratory events were measured overnight in HCHS/SOL sleep reading centers with an ARES Unicorder 5.2, B-Alert. Sleep patterns and risk factors were assessed using the Sleep Heart Health Study Sleep Habits Questionnaire and the Epworth Sleepiness Scale.

Participants meeting the criteria for moderate to severe OSA (with an Apnea Hypopnea Index of 15 or above) were included in the analysis (n = 1,623). Their average age was 52.4 ± 13.9 years, and 34.1% were female.

To identify phenotype clusters, investigators performed a latent class analysis using 15 common OSA symptoms and a survey weighted to adjust for selection bias. The three clusters offering the “best” fit for the data aligned with the previously reported phenotypes and identified daytime sleepiness in 15.3%, disturbed sleep (insomnia-like symptoms) in 37.7%, and minimally symptomatic (a low symptom profile) in 46.9%.

These phenotypes were reported in the European Respiratory Journal in 2014 in a cluster analysis of data from a sleep apnea cohort in Iceland and later replicated in the analysis of data from the Sleep Apnea Global Interdisciplinary Consortium published in Sleep in 2018. The consortium study also added two additional phenotypes, labeled “upper airway symptoms dominant” and “sleepiness dominant.”

The prevalence of a “minimally symptomatic group” in the new analysis of the Hispanics/Latinos in the United States is much higher than reported in these prior studies, at least partly, the investigators believed, because the “prior studies were clinical samples, and the people who were minimally symptomatic didn’t get to the sleep centers,” Mr. Gonzalez said in an interview after the meeting.

Patients with a phenotype of daytime sleepiness – the most common phenotype in prior research – constituted only a minority in the Hispanic/Latino population, he said.

Alberto Ramos, MD, of the University of Miami and the principal investigator, said in an interview that the research team is currently analyzing “if and how these different [phenotypic] clusters could affect the incidence of comorbidities” recorded in the HCHS/SOL study, such as hypertension, diabetes, cardiovascular disease, and cognitive decline.

For now, he said, the findings suggest that OSA may be especially underrecognized in Hispanics and Latinos and that there is more research to be done to better identify and stratify patients with varying symptomatology for more personalized treatment and for clinical trial selection. “Maybe we should expand our criteria ... broaden our [recognition] of the presentation of sleep apnea and the symptoms associated with it, not only in Hispanics but maybe in the general population,” Dr. Ramos said.

In commenting on the study, Krishna M. Sundar, MD, FCCP, director of the Sleep-Wake Center at the University of Utah, Salt Lake City, said that insomnia and daytime sleepiness are “key associations with obstructive sleep apnea and may predict different outcomes with untreated OSA.” Such heterogeneity is “only beginning to be appreciated,” he said. “The expression of OSA with these symptoms points to how OSA impacts quality of life” and how symptomatology in addition to Apnea Hypopnea Index “may be an important determinant of treatment benefit and compliance.”

The investigators reported no relevant disclosures. Dr. Sundar said that he is cofounder of Hypnoscure, software for population management of sleep apnea, but with no monies received.
 

Three previously described clinical phenotypes of obstructive sleep apnea (OSA) have been validated in a large and diverse Hispanic/Latino community-based population for the first time, according to findings presented at the virtual annual meeting of the Associated Professional Sleep Societies.

The three OSA symptom profiles present in this population – labeled “minimally symptomatic,” “disturbed sleep,” and “daytime sleepiness” – are consistent with recent findings from the Sleep Apnea Global Interdisciplinary Consortium, which were published in Sleep, but there are notable differences in the prevalence of these clusters, with the minimally symptomatic cluster much more prevalent than in prior research, reported Kevin Gonzalez, of the University of California, San Diego.

“Other biopsychosocial factors may be contributing to OSA phenotypes among Hispanics and Latinos,” Mr. Gonzalez said in his presentation. Prior research to characterize the heterogeneity of sleep apnea has not included a diverse Latino population, he emphasized.

The adults studied were aged 18-74 years and participants in the multisite Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a comprehensive study of Hispanic/Latino health and disease in the United States. Their respiratory events were measured overnight in HCHS/SOL sleep reading centers with an ARES Unicorder 5.2, B-Alert. Sleep patterns and risk factors were assessed using the Sleep Heart Health Study Sleep Habits Questionnaire and the Epworth Sleepiness Scale.

Participants meeting the criteria for moderate to severe OSA (with an Apnea Hypopnea Index of 15 or above) were included in the analysis (n = 1,623). Their average age was 52.4 ± 13.9 years, and 34.1% were female.

To identify phenotype clusters, investigators performed a latent class analysis using 15 common OSA symptoms and a survey weighted to adjust for selection bias. The three clusters offering the “best” fit for the data aligned with the previously reported phenotypes and identified daytime sleepiness in 15.3%, disturbed sleep (insomnia-like symptoms) in 37.7%, and minimally symptomatic (a low symptom profile) in 46.9%.

These phenotypes were reported in the European Respiratory Journal in 2014 in a cluster analysis of data from a sleep apnea cohort in Iceland and later replicated in the analysis of data from the Sleep Apnea Global Interdisciplinary Consortium published in Sleep in 2018. The consortium study also added two additional phenotypes, labeled “upper airway symptoms dominant” and “sleepiness dominant.”

The prevalence of a “minimally symptomatic group” in the new analysis of the Hispanics/Latinos in the United States is much higher than reported in these prior studies, at least partly, the investigators believed, because the “prior studies were clinical samples, and the people who were minimally symptomatic didn’t get to the sleep centers,” Mr. Gonzalez said in an interview after the meeting.

Patients with a phenotype of daytime sleepiness – the most common phenotype in prior research – constituted only a minority in the Hispanic/Latino population, he said.

Alberto Ramos, MD, of the University of Miami and the principal investigator, said in an interview that the research team is currently analyzing “if and how these different [phenotypic] clusters could affect the incidence of comorbidities” recorded in the HCHS/SOL study, such as hypertension, diabetes, cardiovascular disease, and cognitive decline.

For now, he said, the findings suggest that OSA may be especially underrecognized in Hispanics and Latinos and that there is more research to be done to better identify and stratify patients with varying symptomatology for more personalized treatment and for clinical trial selection. “Maybe we should expand our criteria ... broaden our [recognition] of the presentation of sleep apnea and the symptoms associated with it, not only in Hispanics but maybe in the general population,” Dr. Ramos said.

In commenting on the study, Krishna M. Sundar, MD, FCCP, director of the Sleep-Wake Center at the University of Utah, Salt Lake City, said that insomnia and daytime sleepiness are “key associations with obstructive sleep apnea and may predict different outcomes with untreated OSA.” Such heterogeneity is “only beginning to be appreciated,” he said. “The expression of OSA with these symptoms points to how OSA impacts quality of life” and how symptomatology in addition to Apnea Hypopnea Index “may be an important determinant of treatment benefit and compliance.”

The investigators reported no relevant disclosures. Dr. Sundar said that he is cofounder of Hypnoscure, software for population management of sleep apnea, but with no monies received.
 

Insomnia disorder appears to play a causal role in the development of new stressful life events, especially “dependent” events for which individuals are at least partly responsible, said the investigators of an ongoing longitudinal study of people who have experienced involuntary job loss.

The “stress-generation hypothesis” has been applied for several decades in the context of depression. It posits that depressed individuals generate more stressful life events – events that create family conflict or disrupt careers, for instance – than individuals who are not depressed.

The new analysis of individuals with involuntary job loss suggests that the same can be said of insomnia. “Insomnia disorder is associated with fatigue, daytime sleepiness, impaired concentration, and difficulties in emotional regulation,” Iva Skobic, MSPH, MA, a PhD student at the University of Arizona, Tucson, said at the virtual annual meeting of the Associated Professional Sleep Societies.

“These may lead to impaired decision-making, interpersonal conflicts, difficulty meeting deadlines and keeping commitments, and other sources [of stressful life events],” she said. “This extension of the stress-generation hypothesis has important implications for harm reduction interventions for insomnia disorder.”

Investigators conducted a cross-lagged panel analysis using baseline and 3-month follow-up data from 137 individuals who completed a standardized, textual life event measure called the Life Events and Difficulties Schedule after having lost their jobs involuntarily. Participants were interviewed and their events were rated for severity by a consensus panel using operationalized criteria. The analysis employed linear regression controlling for covariates (age, gender, and race) and logistic regression that controlled for insomnia at baseline. Insomnia disorder was defined as meeting ICSD-2/3 criteria using the Duke Structured Interview for Sleep Disorders.

The findings: Insomnia disorder at baseline predicted the number of stressful life events (either dependent or interpersonal) generated within 3 months (beta, 0.70; standard error, 0.31; Tscore, 2.27; P = .03). Conversely, the number of stressful events at baseline did not predict insomnia (odds ratio, 0.97; 95% confidence interval, 0.73-1.29). There also was a trend toward increased generation of dependent events specifically among those with insomnia disorder.

Participants were a mean age of 42 years, and all had been in their previous place of employment for at least 6 months. Nearly 60% met the diagnostic threshold for insomnia at baseline. They were part of a larger ongoing study examining the linkages between job loss and sleep disturbances, obesity, and mental health – the Assessing Daily Activity Patterns through Occupational Transitions (ADAPT) study, supported by the National Heart, Lung, and Blood Institute.

This analysis on insomnia was completed before the COVID-19 pandemic began, but it and other analyses soon to be reported are highly relevant to the economic climate, said Patricia Haynes, PhD, principal investigator of ADAPT and a coauthor of the insomnia study, in an interview after the meeting.

Insomnia is a frequent comorbidity of depression and shares many of its symptoms, from increased fatigue to emotional dysregulation and an increased risk of maladaptive coping strategies. “Interestingly, the literature on the stress-generation hypothesis posits that these very symptoms are on the casual pathway between depression and stressful life events,” said Ms. Skobic at the meeting.

In commenting on the study, Krishna M. Sundar, MD, medical director of the Sleep-Wake Center at the University of Utah, Salt Lake City, noted that the analysis did not include any measure of the severity of insomnia. Still, he said, “finding an association [with stress generation] at [just] 3 months with the presence of insomnia disorder is quite interesting.”

There were higher rates of insomnia in the sample than depression, Dr. Haynes said, but the analysis did not control for depression or take it into account.

“We know [from prior research] that stress clearly leads to insomnia. The big [takeaway] here is that insomnia can also lead to more stress,” she said. “It’s important to think of it as a reciprocal relationship. If we can potentially treat insomnia, we may be able to stop that cycle of other stressful events that affect both [the individuals] and others as well.”

Ms. Skobic had no disclosures.

Insomnia disorder appears to play a causal role in the development of new stressful life events, especially “dependent” events for which individuals are at least partly responsible, said the investigators of an ongoing longitudinal study of people who have experienced involuntary job loss.

The “stress-generation hypothesis” has been applied for several decades in the context of depression. It posits that depressed individuals generate more stressful life events – events that create family conflict or disrupt careers, for instance – than individuals who are not depressed.

The new analysis of individuals with involuntary job loss suggests that the same can be said of insomnia. “Insomnia disorder is associated with fatigue, daytime sleepiness, impaired concentration, and difficulties in emotional regulation,” Iva Skobic, MSPH, MA, a PhD student at the University of Arizona, Tucson, said at the virtual annual meeting of the Associated Professional Sleep Societies.

“These may lead to impaired decision-making, interpersonal conflicts, difficulty meeting deadlines and keeping commitments, and other sources [of stressful life events],” she said. “This extension of the stress-generation hypothesis has important implications for harm reduction interventions for insomnia disorder.”

Investigators conducted a cross-lagged panel analysis using baseline and 3-month follow-up data from 137 individuals who completed a standardized, textual life event measure called the Life Events and Difficulties Schedule after having lost their jobs involuntarily. Participants were interviewed and their events were rated for severity by a consensus panel using operationalized criteria. The analysis employed linear regression controlling for covariates (age, gender, and race) and logistic regression that controlled for insomnia at baseline. Insomnia disorder was defined as meeting ICSD-2/3 criteria using the Duke Structured Interview for Sleep Disorders.

The findings: Insomnia disorder at baseline predicted the number of stressful life events (either dependent or interpersonal) generated within 3 months (beta, 0.70; standard error, 0.31; Tscore, 2.27; P = .03). Conversely, the number of stressful events at baseline did not predict insomnia (odds ratio, 0.97; 95% confidence interval, 0.73-1.29). There also was a trend toward increased generation of dependent events specifically among those with insomnia disorder.

Participants were a mean age of 42 years, and all had been in their previous place of employment for at least 6 months. Nearly 60% met the diagnostic threshold for insomnia at baseline. They were part of a larger ongoing study examining the linkages between job loss and sleep disturbances, obesity, and mental health – the Assessing Daily Activity Patterns through Occupational Transitions (ADAPT) study, supported by the National Heart, Lung, and Blood Institute.

This analysis on insomnia was completed before the COVID-19 pandemic began, but it and other analyses soon to be reported are highly relevant to the economic climate, said Patricia Haynes, PhD, principal investigator of ADAPT and a coauthor of the insomnia study, in an interview after the meeting.

Insomnia is a frequent comorbidity of depression and shares many of its symptoms, from increased fatigue to emotional dysregulation and an increased risk of maladaptive coping strategies. “Interestingly, the literature on the stress-generation hypothesis posits that these very symptoms are on the casual pathway between depression and stressful life events,” said Ms. Skobic at the meeting.

In commenting on the study, Krishna M. Sundar, MD, medical director of the Sleep-Wake Center at the University of Utah, Salt Lake City, noted that the analysis did not include any measure of the severity of insomnia. Still, he said, “finding an association [with stress generation] at [just] 3 months with the presence of insomnia disorder is quite interesting.”

There were higher rates of insomnia in the sample than depression, Dr. Haynes said, but the analysis did not control for depression or take it into account.

“We know [from prior research] that stress clearly leads to insomnia. The big [takeaway] here is that insomnia can also lead to more stress,” she said. “It’s important to think of it as a reciprocal relationship. If we can potentially treat insomnia, we may be able to stop that cycle of other stressful events that affect both [the individuals] and others as well.”

Ms. Skobic had no disclosures.

Insomnia disorder appears to play a causal role in the development of new stressful life events, especially “dependent” events for which individuals are at least partly responsible, said the investigators of an ongoing longitudinal study of people who have experienced involuntary job loss.

The “stress-generation hypothesis” has been applied for several decades in the context of depression. It posits that depressed individuals generate more stressful life events – events that create family conflict or disrupt careers, for instance – than individuals who are not depressed.

The new analysis of individuals with involuntary job loss suggests that the same can be said of insomnia. “Insomnia disorder is associated with fatigue, daytime sleepiness, impaired concentration, and difficulties in emotional regulation,” Iva Skobic, MSPH, MA, a PhD student at the University of Arizona, Tucson, said at the virtual annual meeting of the Associated Professional Sleep Societies.

“These may lead to impaired decision-making, interpersonal conflicts, difficulty meeting deadlines and keeping commitments, and other sources [of stressful life events],” she said. “This extension of the stress-generation hypothesis has important implications for harm reduction interventions for insomnia disorder.”

Investigators conducted a cross-lagged panel analysis using baseline and 3-month follow-up data from 137 individuals who completed a standardized, textual life event measure called the Life Events and Difficulties Schedule after having lost their jobs involuntarily. Participants were interviewed and their events were rated for severity by a consensus panel using operationalized criteria. The analysis employed linear regression controlling for covariates (age, gender, and race) and logistic regression that controlled for insomnia at baseline. Insomnia disorder was defined as meeting ICSD-2/3 criteria using the Duke Structured Interview for Sleep Disorders.

The findings: Insomnia disorder at baseline predicted the number of stressful life events (either dependent or interpersonal) generated within 3 months (beta, 0.70; standard error, 0.31; Tscore, 2.27; P = .03). Conversely, the number of stressful events at baseline did not predict insomnia (odds ratio, 0.97; 95% confidence interval, 0.73-1.29). There also was a trend toward increased generation of dependent events specifically among those with insomnia disorder.

Participants were a mean age of 42 years, and all had been in their previous place of employment for at least 6 months. Nearly 60% met the diagnostic threshold for insomnia at baseline. They were part of a larger ongoing study examining the linkages between job loss and sleep disturbances, obesity, and mental health – the Assessing Daily Activity Patterns through Occupational Transitions (ADAPT) study, supported by the National Heart, Lung, and Blood Institute.

This analysis on insomnia was completed before the COVID-19 pandemic began, but it and other analyses soon to be reported are highly relevant to the economic climate, said Patricia Haynes, PhD, principal investigator of ADAPT and a coauthor of the insomnia study, in an interview after the meeting.

Insomnia is a frequent comorbidity of depression and shares many of its symptoms, from increased fatigue to emotional dysregulation and an increased risk of maladaptive coping strategies. “Interestingly, the literature on the stress-generation hypothesis posits that these very symptoms are on the casual pathway between depression and stressful life events,” said Ms. Skobic at the meeting.

In commenting on the study, Krishna M. Sundar, MD, medical director of the Sleep-Wake Center at the University of Utah, Salt Lake City, noted that the analysis did not include any measure of the severity of insomnia. Still, he said, “finding an association [with stress generation] at [just] 3 months with the presence of insomnia disorder is quite interesting.”

There were higher rates of insomnia in the sample than depression, Dr. Haynes said, but the analysis did not control for depression or take it into account.

“We know [from prior research] that stress clearly leads to insomnia. The big [takeaway] here is that insomnia can also lead to more stress,” she said. “It’s important to think of it as a reciprocal relationship. If we can potentially treat insomnia, we may be able to stop that cycle of other stressful events that affect both [the individuals] and others as well.”

Ms. Skobic had no disclosures.

The earlier the anti-inflammatory drug colchicine is initiated after a myocardial infarction (MI) the greater the benefit, a new COLCOT analysis suggests.

The parent trial was conducted in patients with a recent MI because of the intense inflammation present at that time, and added colchicine 0.5 mg daily to standard care within 30 days following MI.

As previously reported, colchicine significantly reduced the risk of the primary end point – a composite of cardiovascular (CV) death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring revascularization – by 23% compared with placebo.

This new analysis shows the risk was reduced by 48% in patients receiving colchicine within 3 days of an MI (4.3% vs. 8.3%; adjusted hazard ratio, 0.52; 95% confidence interval, 0.32-0.84, P = .007).

Risk of a secondary efficacy end point – CV death, resuscitated cardiac arrest, MI, or stroke – was reduced by 45% over an average follow up of 22.7 months (3.3% vs 6.1%; adjusted HR, 0.55; 95% CI, 0.32-0.95, P = .031).

“We believe that our results support an early, in-hospital initiation of adjunctive colchicine for post-MI prevention,” Nadia Bouabdallaoui, MD, Montreal Heart Institute, Quebec, Canada, said during an online session devoted to colchicine at the European Society of Cardiology Congress 2020.

Session moderator Massimo Imazio, MD, professor of cardiology at the University of Turin, Italy, said the improved outcomes suggest that earlier treatment is better – a finding that parallels his own experience using colchicine in patients with pericarditis.

“This substudy is very important because this is probably also the year in cardiovascular applications [that] early use of the drug could improve outcomes,” he said.

Positive data have been accumulating for colchicine from COLCOT, LoDoCo, and, most recently, the LoDoCo2 trial, even as another anti-inflammatory drug, methotrexate, flamed out as secondary prevention in the CIRT trial.

The new COLCOT substudy included 4,661 of the 4,745 original patients and examined treatment initiation using three strata: within 0-3 days (n = 1,193), 4-7 days (n = 720), and 8-30 days (n = 2,748). Patients who received treatment within 3 days were slightly younger, more likely to be smokers, and to have a shorter time from MI to randomization (2.1 days vs 5.1 days vs. 20.8 days, respectively).

In the subset receiving treatment within 3 days, those assigned to colchicine had the same number of cardiac deaths as those given placebo (2 vs. 2) but fewer resuscitated cardiac arrests (1 vs. 3), MIs (17 vs. 29), strokes (1 vs. 5), and urgent hospitalizations for angina requiring revascularization (6 vs. 17).

“A larger trial might have allowed for a better assessment of individual endpoints and subgroups,” observed Bouabdallaoui.

Although there is growing support for colchicine, experts caution that the drug many not be for everyone. In COLCOT, 1 in 10 patients were unable to tolerate the drug, largely because of gastrointestinal (GI) issues.
 

Pharmacogenomics substudy

A second COLCOT substudy aimed to identify genetic markers predictive of colchicine response and to gain insights into the mechanisms behind this response. It included 767 patients treated with colchicine and another 755 treated with placebo – or about one-third the patients in the original trial.

A genome-wide association study did not find a significant association for the primary CV endpoint, although a prespecified subgroup analysis in men identified an interesting region on chromosome 9 (variant: rs10811106), which just missed reaching genomewide significance, said Marie-Pierre Dubé, PhD, director of the Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre at the Montreal Heart Institute.

In addition, the genomewide analysis found two significant regions for GI events: one on chromosome 6 (variant: rs6916345) and one on chromosome 10 (variant: rs74795203).

For each of the identified regions, the researchers then tested the effect of the allele in the placebo group and the interaction between the genetic variant and treatment with colchicine. For the chromosome 9 region in males, there was no effect in the placebo group and a significant interaction in the colchicine group.

For the significant GI event findings, there was a small effect for the chromosome 6 region in the placebo group and a very significant interaction with colchicine, Dubé said. Similarly, there was no effect for the chromosome 10 region in the placebo group and a significant interaction with colchicine.

Additional analyses in stratified patient populations showed that males with the protective allele (CC) for the chromosome 9 region represented 83% of the population. The primary CV endpoint occurred in 3.2% of these men treated with colchicine and 6.3% treated with placebo (HR, 0.46; 95% CI, 0.24 - 0.86).

For the gastrointestinal events, 25% of patients carried the risk allele (AA) for the chromosome 6 region and 36.9% of these had GI events when treated with colchicine versus 18.6% when treated with placebo (HR, 2.42; 95% CI, 1.57-3.72).

Similarly, 13% of individuals carried one or two copies of the risk allele (AG+GG) for the chromosome 10 region and the risk of GI events in these was nearly four times higher with colchicine (47.1% vs. 18.9%; HR, 3.98; 95% CI 2.24-7.07).

Functional genomic analyses of the identified regions were also performed and showed that the chromosome 9 locus overlaps with the SAXO1 gene, a stabilizer of axonemal microtubules 1.

“The leading variant at this locus (rs10811106 C allele) correlated with the expression of the HAUS6 gene, which is involved in microtubule generation from existing microtubules, and may interact with the effect of colchicine, which is known to inhibit microtubule formation,” observed Dubé. 

Also, the chromosome 6 locus associated with gastrointestinal events was colocalizing with the Crohn’s disease locus, adding further support for this region.

“The results support potential personalized approaches to inflammation reduction for cardiovascular prevention,” Dubé said.

This is a post hoc subgroup analysis, however, and replication is necessary, ideally in prospective randomized trials, she noted.

The substudy is important because it provides further insights into the link between colchicine and microtubule polymerization, affecting the activation of the inflammasome, session moderator Imazio said.

“Second, it is important because pharmacogenomics can help us to better understand the optimal responder to colchicine and colchicine resistance,” he said. “So it can be useful for personalized medicine, leading to the proper use of the drug for the proper patient.”

COLCOT was supported by the government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations. Bouabdallaoui has disclosed no relevant financial relationships. Dubé reported grants from the government of Quebec; personal fees from DalCor and GlaxoSmithKline; research support from AstraZeneca, Pfizer, Servier, Sanofi; and minor equity interest in DalCor. Dubé is also coauthor of patents on pharmacogenomics-guided CETP inhibition, and pharmacogenomics markers of response to colchicine.  

This article first appeared on Medscape.com.

The earlier the anti-inflammatory drug colchicine is initiated after a myocardial infarction (MI) the greater the benefit, a new COLCOT analysis suggests.

The parent trial was conducted in patients with a recent MI because of the intense inflammation present at that time, and added colchicine 0.5 mg daily to standard care within 30 days following MI.

As previously reported, colchicine significantly reduced the risk of the primary end point – a composite of cardiovascular (CV) death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring revascularization – by 23% compared with placebo.

This new analysis shows the risk was reduced by 48% in patients receiving colchicine within 3 days of an MI (4.3% vs. 8.3%; adjusted hazard ratio, 0.52; 95% confidence interval, 0.32-0.84, P = .007).

Risk of a secondary efficacy end point – CV death, resuscitated cardiac arrest, MI, or stroke – was reduced by 45% over an average follow up of 22.7 months (3.3% vs 6.1%; adjusted HR, 0.55; 95% CI, 0.32-0.95, P = .031).

“We believe that our results support an early, in-hospital initiation of adjunctive colchicine for post-MI prevention,” Nadia Bouabdallaoui, MD, Montreal Heart Institute, Quebec, Canada, said during an online session devoted to colchicine at the European Society of Cardiology Congress 2020.

Session moderator Massimo Imazio, MD, professor of cardiology at the University of Turin, Italy, said the improved outcomes suggest that earlier treatment is better – a finding that parallels his own experience using colchicine in patients with pericarditis.

“This substudy is very important because this is probably also the year in cardiovascular applications [that] early use of the drug could improve outcomes,” he said.

Positive data have been accumulating for colchicine from COLCOT, LoDoCo, and, most recently, the LoDoCo2 trial, even as another anti-inflammatory drug, methotrexate, flamed out as secondary prevention in the CIRT trial.

The new COLCOT substudy included 4,661 of the 4,745 original patients and examined treatment initiation using three strata: within 0-3 days (n = 1,193), 4-7 days (n = 720), and 8-30 days (n = 2,748). Patients who received treatment within 3 days were slightly younger, more likely to be smokers, and to have a shorter time from MI to randomization (2.1 days vs 5.1 days vs. 20.8 days, respectively).

In the subset receiving treatment within 3 days, those assigned to colchicine had the same number of cardiac deaths as those given placebo (2 vs. 2) but fewer resuscitated cardiac arrests (1 vs. 3), MIs (17 vs. 29), strokes (1 vs. 5), and urgent hospitalizations for angina requiring revascularization (6 vs. 17).

“A larger trial might have allowed for a better assessment of individual endpoints and subgroups,” observed Bouabdallaoui.

Although there is growing support for colchicine, experts caution that the drug many not be for everyone. In COLCOT, 1 in 10 patients were unable to tolerate the drug, largely because of gastrointestinal (GI) issues.
 

Pharmacogenomics substudy

A second COLCOT substudy aimed to identify genetic markers predictive of colchicine response and to gain insights into the mechanisms behind this response. It included 767 patients treated with colchicine and another 755 treated with placebo – or about one-third the patients in the original trial.

A genome-wide association study did not find a significant association for the primary CV endpoint, although a prespecified subgroup analysis in men identified an interesting region on chromosome 9 (variant: rs10811106), which just missed reaching genomewide significance, said Marie-Pierre Dubé, PhD, director of the Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre at the Montreal Heart Institute.

In addition, the genomewide analysis found two significant regions for GI events: one on chromosome 6 (variant: rs6916345) and one on chromosome 10 (variant: rs74795203).

For each of the identified regions, the researchers then tested the effect of the allele in the placebo group and the interaction between the genetic variant and treatment with colchicine. For the chromosome 9 region in males, there was no effect in the placebo group and a significant interaction in the colchicine group.

For the significant GI event findings, there was a small effect for the chromosome 6 region in the placebo group and a very significant interaction with colchicine, Dubé said. Similarly, there was no effect for the chromosome 10 region in the placebo group and a significant interaction with colchicine.

Additional analyses in stratified patient populations showed that males with the protective allele (CC) for the chromosome 9 region represented 83% of the population. The primary CV endpoint occurred in 3.2% of these men treated with colchicine and 6.3% treated with placebo (HR, 0.46; 95% CI, 0.24 - 0.86).

For the gastrointestinal events, 25% of patients carried the risk allele (AA) for the chromosome 6 region and 36.9% of these had GI events when treated with colchicine versus 18.6% when treated with placebo (HR, 2.42; 95% CI, 1.57-3.72).

Similarly, 13% of individuals carried one or two copies of the risk allele (AG+GG) for the chromosome 10 region and the risk of GI events in these was nearly four times higher with colchicine (47.1% vs. 18.9%; HR, 3.98; 95% CI 2.24-7.07).

Functional genomic analyses of the identified regions were also performed and showed that the chromosome 9 locus overlaps with the SAXO1 gene, a stabilizer of axonemal microtubules 1.

“The leading variant at this locus (rs10811106 C allele) correlated with the expression of the HAUS6 gene, which is involved in microtubule generation from existing microtubules, and may interact with the effect of colchicine, which is known to inhibit microtubule formation,” observed Dubé. 

Also, the chromosome 6 locus associated with gastrointestinal events was colocalizing with the Crohn’s disease locus, adding further support for this region.

“The results support potential personalized approaches to inflammation reduction for cardiovascular prevention,” Dubé said.

This is a post hoc subgroup analysis, however, and replication is necessary, ideally in prospective randomized trials, she noted.

The substudy is important because it provides further insights into the link between colchicine and microtubule polymerization, affecting the activation of the inflammasome, session moderator Imazio said.

“Second, it is important because pharmacogenomics can help us to better understand the optimal responder to colchicine and colchicine resistance,” he said. “So it can be useful for personalized medicine, leading to the proper use of the drug for the proper patient.”

COLCOT was supported by the government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations. Bouabdallaoui has disclosed no relevant financial relationships. Dubé reported grants from the government of Quebec; personal fees from DalCor and GlaxoSmithKline; research support from AstraZeneca, Pfizer, Servier, Sanofi; and minor equity interest in DalCor. Dubé is also coauthor of patents on pharmacogenomics-guided CETP inhibition, and pharmacogenomics markers of response to colchicine.  

This article first appeared on Medscape.com.

The earlier the anti-inflammatory drug colchicine is initiated after a myocardial infarction (MI) the greater the benefit, a new COLCOT analysis suggests.

The parent trial was conducted in patients with a recent MI because of the intense inflammation present at that time, and added colchicine 0.5 mg daily to standard care within 30 days following MI.

As previously reported, colchicine significantly reduced the risk of the primary end point – a composite of cardiovascular (CV) death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring revascularization – by 23% compared with placebo.

This new analysis shows the risk was reduced by 48% in patients receiving colchicine within 3 days of an MI (4.3% vs. 8.3%; adjusted hazard ratio, 0.52; 95% confidence interval, 0.32-0.84, P = .007).

Risk of a secondary efficacy end point – CV death, resuscitated cardiac arrest, MI, or stroke – was reduced by 45% over an average follow up of 22.7 months (3.3% vs 6.1%; adjusted HR, 0.55; 95% CI, 0.32-0.95, P = .031).

“We believe that our results support an early, in-hospital initiation of adjunctive colchicine for post-MI prevention,” Nadia Bouabdallaoui, MD, Montreal Heart Institute, Quebec, Canada, said during an online session devoted to colchicine at the European Society of Cardiology Congress 2020.

Session moderator Massimo Imazio, MD, professor of cardiology at the University of Turin, Italy, said the improved outcomes suggest that earlier treatment is better – a finding that parallels his own experience using colchicine in patients with pericarditis.

“This substudy is very important because this is probably also the year in cardiovascular applications [that] early use of the drug could improve outcomes,” he said.

Positive data have been accumulating for colchicine from COLCOT, LoDoCo, and, most recently, the LoDoCo2 trial, even as another anti-inflammatory drug, methotrexate, flamed out as secondary prevention in the CIRT trial.

The new COLCOT substudy included 4,661 of the 4,745 original patients and examined treatment initiation using three strata: within 0-3 days (n = 1,193), 4-7 days (n = 720), and 8-30 days (n = 2,748). Patients who received treatment within 3 days were slightly younger, more likely to be smokers, and to have a shorter time from MI to randomization (2.1 days vs 5.1 days vs. 20.8 days, respectively).

In the subset receiving treatment within 3 days, those assigned to colchicine had the same number of cardiac deaths as those given placebo (2 vs. 2) but fewer resuscitated cardiac arrests (1 vs. 3), MIs (17 vs. 29), strokes (1 vs. 5), and urgent hospitalizations for angina requiring revascularization (6 vs. 17).

“A larger trial might have allowed for a better assessment of individual endpoints and subgroups,” observed Bouabdallaoui.

Although there is growing support for colchicine, experts caution that the drug many not be for everyone. In COLCOT, 1 in 10 patients were unable to tolerate the drug, largely because of gastrointestinal (GI) issues.
 

Pharmacogenomics substudy

A second COLCOT substudy aimed to identify genetic markers predictive of colchicine response and to gain insights into the mechanisms behind this response. It included 767 patients treated with colchicine and another 755 treated with placebo – or about one-third the patients in the original trial.

A genome-wide association study did not find a significant association for the primary CV endpoint, although a prespecified subgroup analysis in men identified an interesting region on chromosome 9 (variant: rs10811106), which just missed reaching genomewide significance, said Marie-Pierre Dubé, PhD, director of the Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre at the Montreal Heart Institute.

In addition, the genomewide analysis found two significant regions for GI events: one on chromosome 6 (variant: rs6916345) and one on chromosome 10 (variant: rs74795203).

For each of the identified regions, the researchers then tested the effect of the allele in the placebo group and the interaction between the genetic variant and treatment with colchicine. For the chromosome 9 region in males, there was no effect in the placebo group and a significant interaction in the colchicine group.

For the significant GI event findings, there was a small effect for the chromosome 6 region in the placebo group and a very significant interaction with colchicine, Dubé said. Similarly, there was no effect for the chromosome 10 region in the placebo group and a significant interaction with colchicine.

Additional analyses in stratified patient populations showed that males with the protective allele (CC) for the chromosome 9 region represented 83% of the population. The primary CV endpoint occurred in 3.2% of these men treated with colchicine and 6.3% treated with placebo (HR, 0.46; 95% CI, 0.24 - 0.86).

For the gastrointestinal events, 25% of patients carried the risk allele (AA) for the chromosome 6 region and 36.9% of these had GI events when treated with colchicine versus 18.6% when treated with placebo (HR, 2.42; 95% CI, 1.57-3.72).

Similarly, 13% of individuals carried one or two copies of the risk allele (AG+GG) for the chromosome 10 region and the risk of GI events in these was nearly four times higher with colchicine (47.1% vs. 18.9%; HR, 3.98; 95% CI 2.24-7.07).

Functional genomic analyses of the identified regions were also performed and showed that the chromosome 9 locus overlaps with the SAXO1 gene, a stabilizer of axonemal microtubules 1.

“The leading variant at this locus (rs10811106 C allele) correlated with the expression of the HAUS6 gene, which is involved in microtubule generation from existing microtubules, and may interact with the effect of colchicine, which is known to inhibit microtubule formation,” observed Dubé. 

Also, the chromosome 6 locus associated with gastrointestinal events was colocalizing with the Crohn’s disease locus, adding further support for this region.

“The results support potential personalized approaches to inflammation reduction for cardiovascular prevention,” Dubé said.

This is a post hoc subgroup analysis, however, and replication is necessary, ideally in prospective randomized trials, she noted.

The substudy is important because it provides further insights into the link between colchicine and microtubule polymerization, affecting the activation of the inflammasome, session moderator Imazio said.

“Second, it is important because pharmacogenomics can help us to better understand the optimal responder to colchicine and colchicine resistance,” he said. “So it can be useful for personalized medicine, leading to the proper use of the drug for the proper patient.”

COLCOT was supported by the government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations. Bouabdallaoui has disclosed no relevant financial relationships. Dubé reported grants from the government of Quebec; personal fees from DalCor and GlaxoSmithKline; research support from AstraZeneca, Pfizer, Servier, Sanofi; and minor equity interest in DalCor. Dubé is also coauthor of patents on pharmacogenomics-guided CETP inhibition, and pharmacogenomics markers of response to colchicine.  

This article first appeared on Medscape.com.

Investigators in Switzerland are testing an application for smartphones that they hope will elucidate subtle signs of disease progression in multiple sclerosis (MS)—beyond what standard imaging and clinical biomarkers can tell them.

At the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020, researchers at the University Hospital and University of Basel in Switzerland, presented data on their dreaMS app. The investigators are validating the app in a nonblinded cohort of 30 people with MS in the early to middle stages of progression and 30 controls without MS.

The application comprises a series of active tests measuring movement, fine motor skills, cognition, and vision, as well as questionnaires to assess quality of life, walking ability, and fatigue in people with Expanded Disability Status Scale (EDSS) scores of 6.5 or lower. A wrist device, used concurrently with the app, passively monitors subjects’ step count, heart rate, and different measures of activity.

If validated, such smartphone-based “digital biomarkers” will provide clinicians and investigators with a steadier flow of information for assessing MS disease progression and informing clinical decision-making. In June, Ludwig Kappos, MD, the app study’s senior researcher, co-authored an analysis of randomized trial data that argued for discarding the standard categories of relapsing and progressive MS in favor of seeing the disease as a continuum, in which progression can and does occur in the absence of relapses.

The digital biomarker work builds on that more unified view of the disease, Dr. Kappos said in an interview.

Outside of disease exacerbations or relapses, “progression can be very difficult to capture, especially in the first stage of the disease because of compensation in the central nervous system,” he said. “Our ability to see these very slight changes during a neurological examination is limited even if we do it very thoroughly. But by having these more frequent assessments we may be able to.”

Smartphone-gleaned biomarkers may have implications for prognosis and for choice of therapy, Dr. Kappos added. “We expect that these digital biomarkers will be even more sensitive and to be able to recognize before severe deficits are evident who is a candidate for a more intensive treatment and who is not.”

At the MSVirtual2020 congress, Dr. Kappos’s colleagues at the university Johannes Lorscheider, MD, and Yvonne Naegelin, MD, presented their feasibility and acceptance study currently underway in 60 volunteers. One of the concerns the investigators have had was whether engaged users would remain with the app. “We have designed the tests as little challenges to help keep people interested—we want to make these tests as appealing as possible,” Dr. Kappos said.

In this study, the reliability of each test is determined by intra-class correlation and median coefficient of variation. Preliminary reliability testing with healthy controls showed intra-class correlation coefficients of greater than 60% for the digital biomarkers and greater than 80% for at least one in every domain.

Once the best tests are selected and the app is fine-tuned, the group intends to embark on larger studies of the digital biomarkers. The next, planned for 2021, will recruit approximately 400 patients from the Swiss MS cohort, whose 1,000-some MS participants are followed with standardized examination and imaging protocols across healthcare centers.

“This is a very well characterized group of patients who are followed continuously with state-of-the-art neurological examinations, high-end MRI, and blood biomarkers,” Dr. Kappos said. “We want to see if we can add value by using digital biomarkers.”

The dreaMS app project is an independent investigator-initiated venture in cooperation with a technological partner. The study was supported by the Swiss Innovation Agency. The University Hospital Basel has received research funding for clinical trials from a number of pharmaceutical manufacturers.

SOURCE: Lorscheider J, et al. MSVirtual2020. Abstract P0069.

Investigators in Switzerland are testing an application for smartphones that they hope will elucidate subtle signs of disease progression in multiple sclerosis (MS)—beyond what standard imaging and clinical biomarkers can tell them.

At the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020, researchers at the University Hospital and University of Basel in Switzerland, presented data on their dreaMS app. The investigators are validating the app in a nonblinded cohort of 30 people with MS in the early to middle stages of progression and 30 controls without MS.

The application comprises a series of active tests measuring movement, fine motor skills, cognition, and vision, as well as questionnaires to assess quality of life, walking ability, and fatigue in people with Expanded Disability Status Scale (EDSS) scores of 6.5 or lower. A wrist device, used concurrently with the app, passively monitors subjects’ step count, heart rate, and different measures of activity.

If validated, such smartphone-based “digital biomarkers” will provide clinicians and investigators with a steadier flow of information for assessing MS disease progression and informing clinical decision-making. In June, Ludwig Kappos, MD, the app study’s senior researcher, co-authored an analysis of randomized trial data that argued for discarding the standard categories of relapsing and progressive MS in favor of seeing the disease as a continuum, in which progression can and does occur in the absence of relapses.

The digital biomarker work builds on that more unified view of the disease, Dr. Kappos said in an interview.

Outside of disease exacerbations or relapses, “progression can be very difficult to capture, especially in the first stage of the disease because of compensation in the central nervous system,” he said. “Our ability to see these very slight changes during a neurological examination is limited even if we do it very thoroughly. But by having these more frequent assessments we may be able to.”

Smartphone-gleaned biomarkers may have implications for prognosis and for choice of therapy, Dr. Kappos added. “We expect that these digital biomarkers will be even more sensitive and to be able to recognize before severe deficits are evident who is a candidate for a more intensive treatment and who is not.”

At the MSVirtual2020 congress, Dr. Kappos’s colleagues at the university Johannes Lorscheider, MD, and Yvonne Naegelin, MD, presented their feasibility and acceptance study currently underway in 60 volunteers. One of the concerns the investigators have had was whether engaged users would remain with the app. “We have designed the tests as little challenges to help keep people interested—we want to make these tests as appealing as possible,” Dr. Kappos said.

In this study, the reliability of each test is determined by intra-class correlation and median coefficient of variation. Preliminary reliability testing with healthy controls showed intra-class correlation coefficients of greater than 60% for the digital biomarkers and greater than 80% for at least one in every domain.

Once the best tests are selected and the app is fine-tuned, the group intends to embark on larger studies of the digital biomarkers. The next, planned for 2021, will recruit approximately 400 patients from the Swiss MS cohort, whose 1,000-some MS participants are followed with standardized examination and imaging protocols across healthcare centers.

“This is a very well characterized group of patients who are followed continuously with state-of-the-art neurological examinations, high-end MRI, and blood biomarkers,” Dr. Kappos said. “We want to see if we can add value by using digital biomarkers.”

The dreaMS app project is an independent investigator-initiated venture in cooperation with a technological partner. The study was supported by the Swiss Innovation Agency. The University Hospital Basel has received research funding for clinical trials from a number of pharmaceutical manufacturers.

SOURCE: Lorscheider J, et al. MSVirtual2020. Abstract P0069.

Investigators in Switzerland are testing an application for smartphones that they hope will elucidate subtle signs of disease progression in multiple sclerosis (MS)—beyond what standard imaging and clinical biomarkers can tell them.

At the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020, researchers at the University Hospital and University of Basel in Switzerland, presented data on their dreaMS app. The investigators are validating the app in a nonblinded cohort of 30 people with MS in the early to middle stages of progression and 30 controls without MS.

The application comprises a series of active tests measuring movement, fine motor skills, cognition, and vision, as well as questionnaires to assess quality of life, walking ability, and fatigue in people with Expanded Disability Status Scale (EDSS) scores of 6.5 or lower. A wrist device, used concurrently with the app, passively monitors subjects’ step count, heart rate, and different measures of activity.

If validated, such smartphone-based “digital biomarkers” will provide clinicians and investigators with a steadier flow of information for assessing MS disease progression and informing clinical decision-making. In June, Ludwig Kappos, MD, the app study’s senior researcher, co-authored an analysis of randomized trial data that argued for discarding the standard categories of relapsing and progressive MS in favor of seeing the disease as a continuum, in which progression can and does occur in the absence of relapses.

The digital biomarker work builds on that more unified view of the disease, Dr. Kappos said in an interview.

Outside of disease exacerbations or relapses, “progression can be very difficult to capture, especially in the first stage of the disease because of compensation in the central nervous system,” he said. “Our ability to see these very slight changes during a neurological examination is limited even if we do it very thoroughly. But by having these more frequent assessments we may be able to.”

Smartphone-gleaned biomarkers may have implications for prognosis and for choice of therapy, Dr. Kappos added. “We expect that these digital biomarkers will be even more sensitive and to be able to recognize before severe deficits are evident who is a candidate for a more intensive treatment and who is not.”

At the MSVirtual2020 congress, Dr. Kappos’s colleagues at the university Johannes Lorscheider, MD, and Yvonne Naegelin, MD, presented their feasibility and acceptance study currently underway in 60 volunteers. One of the concerns the investigators have had was whether engaged users would remain with the app. “We have designed the tests as little challenges to help keep people interested—we want to make these tests as appealing as possible,” Dr. Kappos said.

In this study, the reliability of each test is determined by intra-class correlation and median coefficient of variation. Preliminary reliability testing with healthy controls showed intra-class correlation coefficients of greater than 60% for the digital biomarkers and greater than 80% for at least one in every domain.

Once the best tests are selected and the app is fine-tuned, the group intends to embark on larger studies of the digital biomarkers. The next, planned for 2021, will recruit approximately 400 patients from the Swiss MS cohort, whose 1,000-some MS participants are followed with standardized examination and imaging protocols across healthcare centers.

“This is a very well characterized group of patients who are followed continuously with state-of-the-art neurological examinations, high-end MRI, and blood biomarkers,” Dr. Kappos said. “We want to see if we can add value by using digital biomarkers.”

The dreaMS app project is an independent investigator-initiated venture in cooperation with a technological partner. The study was supported by the Swiss Innovation Agency. The University Hospital Basel has received research funding for clinical trials from a number of pharmaceutical manufacturers.

SOURCE: Lorscheider J, et al. MSVirtual2020. Abstract P0069.

Compared with placebo, satralizumab reduces the risk of severe relapse in patients with neuromyelitis optica spectrum disorder (NMOSD), according to investigators. The drug also was associated with a lower likelihood of using acute relapse therapy.

These results were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

NMOSD is characterized by acute relapses that are unpredictable and lead to the accumulation of disability. “Patients with NMOSD often recover poorly from relapses, therefore, the primary goal for disease management is to reduce attack frequency,” said Ingo Kleiter, MD, medical director of Marianne-Strauß-Klinik in Berg, Germany. “In the two phase 3 trials SAkuraSky and SAkuraStar, the IL-6 receptor inhibitor satralizumab was found to significantly reduce the risk of relapses versus placebo.” Satralizumab is a humanized, monoclonal, recycling antibody that targets the interleukin-6 receptor.

Dr. Kleiter and colleagues examined pooled data from the two phase 3 trials of satralizumab to determine the treatment’s effect on relapse severity in patients with NMOSD. Participants in those trials received placebo or 120 mg of satralizumab at weeks 0, 2, 4, and every 4 weeks thereafter.

For their research, the investigators analyzed data from the pooled intention-to-treat population in the double-blind periods of both studies. To evaluate the severity of protocol-defined relapses, they compared patients’ Expanded Disability Status Scale (EDSS) scores at the time of relapse with their scores before the relapse (i.e., their scores at the last scheduled study visit). Using the visual Functional Systems Score (FSS), Dr. Kleiter and colleagues performed a similar analysis on optic neuritis relapses. They categorized a protocol-defined relapse as severe if it entailed a change of two or more points on the EDSS or visual FSS. The investigators conducted Kaplan-Meier analyses to evaluate the time to first severe protocol-defined relapse. They also compared the number of patients receiving acute therapy for any relapse between treatment groups.
 

Safety profile confirmed

Dr. Kleiter and colleagues included 178 patients in their analyses. A total of 27 of 104 patients (26%) who received satralizumab had a protocol-defined relapse, compared with 34 of 74 patients (46%) who received placebo. The number and proportion of severe protocol-defined relapses were lower in the satralizumab group (5 of 27 events [19%]), compared with the placebo group (12 of 34 events [35%]). In addition, the number and proportion of severe protocol-defined optic neuritis relapses were lower in patients receiving satralizumab (2 of 8 events [25%]), compared with those receiving placebo (5 of 13 events [39%]). Compared with placebo, satralizumab was associated with a 79% reduction in the risk of severe protocol-defined relapse (hazard ratio, 0.21).

A lower proportion of patients receiving satralizumab was prescribed acute relapse therapy (38%), compared with patients receiving placebo (58%). The odds ratio of receiving a prescription of acute relapse therapy was 0.46 among patients receiving satralizumab.

The activity of IL-6 may cause neurologic damage in patients with NMOSD through astrocytic damage, disruption of the blood–brain barrier, and T cell polarization. “It is proposed that through inhibiting IL-6 across these multiple mechanisms, satralizumab reduces the risk and severity of NMOSD attacks,” Dr. Kleiter said.

To date, the rates of infection and serious infection for patients treated with satralizumab in the combined double-blind and open-label extension periods have been consistent with those for patients treated with satralizumab in the double-blind portion. These rates have not increased over time. Satralizumab is administered as a subcutaneous injection every 4 weeks, and treatment can be self-administered at the discretion of the managing physician. “These data provide reassurance to physicians about the overall profile of satralizumab, with respect to efficacy and safety in the longer term,” said Dr. Kleiter.
 

Does satralizumab differ from other new agents?

The main strength of the study is that sufficient numbers of relapses were available for analysis in the active and control groups, said Achim Berthele, MD, associate professor of neurology at the Technical University of Munich. This allowed the researchers to examine whether satralizumab led to a better outcome after each relapse, which it did. “A weakness is how the severity of relapses was quantified,” said Dr. Berthele. “The EDSS as a measure is not linear, and its functional systems are not clinically equivalent. However, the whole NMOSD community is struggling with this problem.”

The study’s implications for neurologists’ clinical practice are unclear, however. “Although the results presented are encouraging, the data are still too small to say with certainty that satralizumab does indeed improve the outcome of relapses,” said Dr. Berthele. “It is also an open question whether satralizumab differs in this respect from the other new immunotherapeutic agents.”

Investigators must collect further data on the outcome of relapses that occur during treatment with modern immunomodulatory therapy, Dr. Berthele added. Future research could examine whether the new anti-inflammatory immunotherapeutic agents also are suitable drugs for relapse therapy. Another salient question is whether clinical vigilance or relapse therapy in NMOSD has improved in general. “This is what Kleiter and colleagues show as well: The number of severe relapses under placebo was much lower than expected,” said Dr. Berthele.

Chugai/Roche funded the study. Dr. Kleiter has received compensation for consulting, speaking, or serving on advisory boards for Alexion, Biogen, Celgene, Merck, and Roche. Dr. Berthele was not involved in any of the satralizumab trials, but is an investigator and coauthor of the PREVENT trial of eculizumab.

egreb@mdedge.com

SOURCE: Kleiter I, et al. MSVirtual2020. Abstract FC01.03.

Compared with placebo, satralizumab reduces the risk of severe relapse in patients with neuromyelitis optica spectrum disorder (NMOSD), according to investigators. The drug also was associated with a lower likelihood of using acute relapse therapy.

These results were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

NMOSD is characterized by acute relapses that are unpredictable and lead to the accumulation of disability. “Patients with NMOSD often recover poorly from relapses, therefore, the primary goal for disease management is to reduce attack frequency,” said Ingo Kleiter, MD, medical director of Marianne-Strauß-Klinik in Berg, Germany. “In the two phase 3 trials SAkuraSky and SAkuraStar, the IL-6 receptor inhibitor satralizumab was found to significantly reduce the risk of relapses versus placebo.” Satralizumab is a humanized, monoclonal, recycling antibody that targets the interleukin-6 receptor.

Dr. Kleiter and colleagues examined pooled data from the two phase 3 trials of satralizumab to determine the treatment’s effect on relapse severity in patients with NMOSD. Participants in those trials received placebo or 120 mg of satralizumab at weeks 0, 2, 4, and every 4 weeks thereafter.

For their research, the investigators analyzed data from the pooled intention-to-treat population in the double-blind periods of both studies. To evaluate the severity of protocol-defined relapses, they compared patients’ Expanded Disability Status Scale (EDSS) scores at the time of relapse with their scores before the relapse (i.e., their scores at the last scheduled study visit). Using the visual Functional Systems Score (FSS), Dr. Kleiter and colleagues performed a similar analysis on optic neuritis relapses. They categorized a protocol-defined relapse as severe if it entailed a change of two or more points on the EDSS or visual FSS. The investigators conducted Kaplan-Meier analyses to evaluate the time to first severe protocol-defined relapse. They also compared the number of patients receiving acute therapy for any relapse between treatment groups.
 

Safety profile confirmed

Dr. Kleiter and colleagues included 178 patients in their analyses. A total of 27 of 104 patients (26%) who received satralizumab had a protocol-defined relapse, compared with 34 of 74 patients (46%) who received placebo. The number and proportion of severe protocol-defined relapses were lower in the satralizumab group (5 of 27 events [19%]), compared with the placebo group (12 of 34 events [35%]). In addition, the number and proportion of severe protocol-defined optic neuritis relapses were lower in patients receiving satralizumab (2 of 8 events [25%]), compared with those receiving placebo (5 of 13 events [39%]). Compared with placebo, satralizumab was associated with a 79% reduction in the risk of severe protocol-defined relapse (hazard ratio, 0.21).

A lower proportion of patients receiving satralizumab was prescribed acute relapse therapy (38%), compared with patients receiving placebo (58%). The odds ratio of receiving a prescription of acute relapse therapy was 0.46 among patients receiving satralizumab.

The activity of IL-6 may cause neurologic damage in patients with NMOSD through astrocytic damage, disruption of the blood–brain barrier, and T cell polarization. “It is proposed that through inhibiting IL-6 across these multiple mechanisms, satralizumab reduces the risk and severity of NMOSD attacks,” Dr. Kleiter said.

To date, the rates of infection and serious infection for patients treated with satralizumab in the combined double-blind and open-label extension periods have been consistent with those for patients treated with satralizumab in the double-blind portion. These rates have not increased over time. Satralizumab is administered as a subcutaneous injection every 4 weeks, and treatment can be self-administered at the discretion of the managing physician. “These data provide reassurance to physicians about the overall profile of satralizumab, with respect to efficacy and safety in the longer term,” said Dr. Kleiter.
 

Does satralizumab differ from other new agents?

The main strength of the study is that sufficient numbers of relapses were available for analysis in the active and control groups, said Achim Berthele, MD, associate professor of neurology at the Technical University of Munich. This allowed the researchers to examine whether satralizumab led to a better outcome after each relapse, which it did. “A weakness is how the severity of relapses was quantified,” said Dr. Berthele. “The EDSS as a measure is not linear, and its functional systems are not clinically equivalent. However, the whole NMOSD community is struggling with this problem.”

The study’s implications for neurologists’ clinical practice are unclear, however. “Although the results presented are encouraging, the data are still too small to say with certainty that satralizumab does indeed improve the outcome of relapses,” said Dr. Berthele. “It is also an open question whether satralizumab differs in this respect from the other new immunotherapeutic agents.”

Investigators must collect further data on the outcome of relapses that occur during treatment with modern immunomodulatory therapy, Dr. Berthele added. Future research could examine whether the new anti-inflammatory immunotherapeutic agents also are suitable drugs for relapse therapy. Another salient question is whether clinical vigilance or relapse therapy in NMOSD has improved in general. “This is what Kleiter and colleagues show as well: The number of severe relapses under placebo was much lower than expected,” said Dr. Berthele.

Chugai/Roche funded the study. Dr. Kleiter has received compensation for consulting, speaking, or serving on advisory boards for Alexion, Biogen, Celgene, Merck, and Roche. Dr. Berthele was not involved in any of the satralizumab trials, but is an investigator and coauthor of the PREVENT trial of eculizumab.

egreb@mdedge.com

SOURCE: Kleiter I, et al. MSVirtual2020. Abstract FC01.03.

Compared with placebo, satralizumab reduces the risk of severe relapse in patients with neuromyelitis optica spectrum disorder (NMOSD), according to investigators. The drug also was associated with a lower likelihood of using acute relapse therapy.

These results were presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

NMOSD is characterized by acute relapses that are unpredictable and lead to the accumulation of disability. “Patients with NMOSD often recover poorly from relapses, therefore, the primary goal for disease management is to reduce attack frequency,” said Ingo Kleiter, MD, medical director of Marianne-Strauß-Klinik in Berg, Germany. “In the two phase 3 trials SAkuraSky and SAkuraStar, the IL-6 receptor inhibitor satralizumab was found to significantly reduce the risk of relapses versus placebo.” Satralizumab is a humanized, monoclonal, recycling antibody that targets the interleukin-6 receptor.

Dr. Kleiter and colleagues examined pooled data from the two phase 3 trials of satralizumab to determine the treatment’s effect on relapse severity in patients with NMOSD. Participants in those trials received placebo or 120 mg of satralizumab at weeks 0, 2, 4, and every 4 weeks thereafter.

For their research, the investigators analyzed data from the pooled intention-to-treat population in the double-blind periods of both studies. To evaluate the severity of protocol-defined relapses, they compared patients’ Expanded Disability Status Scale (EDSS) scores at the time of relapse with their scores before the relapse (i.e., their scores at the last scheduled study visit). Using the visual Functional Systems Score (FSS), Dr. Kleiter and colleagues performed a similar analysis on optic neuritis relapses. They categorized a protocol-defined relapse as severe if it entailed a change of two or more points on the EDSS or visual FSS. The investigators conducted Kaplan-Meier analyses to evaluate the time to first severe protocol-defined relapse. They also compared the number of patients receiving acute therapy for any relapse between treatment groups.
 

Safety profile confirmed

Dr. Kleiter and colleagues included 178 patients in their analyses. A total of 27 of 104 patients (26%) who received satralizumab had a protocol-defined relapse, compared with 34 of 74 patients (46%) who received placebo. The number and proportion of severe protocol-defined relapses were lower in the satralizumab group (5 of 27 events [19%]), compared with the placebo group (12 of 34 events [35%]). In addition, the number and proportion of severe protocol-defined optic neuritis relapses were lower in patients receiving satralizumab (2 of 8 events [25%]), compared with those receiving placebo (5 of 13 events [39%]). Compared with placebo, satralizumab was associated with a 79% reduction in the risk of severe protocol-defined relapse (hazard ratio, 0.21).

A lower proportion of patients receiving satralizumab was prescribed acute relapse therapy (38%), compared with patients receiving placebo (58%). The odds ratio of receiving a prescription of acute relapse therapy was 0.46 among patients receiving satralizumab.

The activity of IL-6 may cause neurologic damage in patients with NMOSD through astrocytic damage, disruption of the blood–brain barrier, and T cell polarization. “It is proposed that through inhibiting IL-6 across these multiple mechanisms, satralizumab reduces the risk and severity of NMOSD attacks,” Dr. Kleiter said.

To date, the rates of infection and serious infection for patients treated with satralizumab in the combined double-blind and open-label extension periods have been consistent with those for patients treated with satralizumab in the double-blind portion. These rates have not increased over time. Satralizumab is administered as a subcutaneous injection every 4 weeks, and treatment can be self-administered at the discretion of the managing physician. “These data provide reassurance to physicians about the overall profile of satralizumab, with respect to efficacy and safety in the longer term,” said Dr. Kleiter.
 

Does satralizumab differ from other new agents?

The main strength of the study is that sufficient numbers of relapses were available for analysis in the active and control groups, said Achim Berthele, MD, associate professor of neurology at the Technical University of Munich. This allowed the researchers to examine whether satralizumab led to a better outcome after each relapse, which it did. “A weakness is how the severity of relapses was quantified,” said Dr. Berthele. “The EDSS as a measure is not linear, and its functional systems are not clinically equivalent. However, the whole NMOSD community is struggling with this problem.”

The study’s implications for neurologists’ clinical practice are unclear, however. “Although the results presented are encouraging, the data are still too small to say with certainty that satralizumab does indeed improve the outcome of relapses,” said Dr. Berthele. “It is also an open question whether satralizumab differs in this respect from the other new immunotherapeutic agents.”

Investigators must collect further data on the outcome of relapses that occur during treatment with modern immunomodulatory therapy, Dr. Berthele added. Future research could examine whether the new anti-inflammatory immunotherapeutic agents also are suitable drugs for relapse therapy. Another salient question is whether clinical vigilance or relapse therapy in NMOSD has improved in general. “This is what Kleiter and colleagues show as well: The number of severe relapses under placebo was much lower than expected,” said Dr. Berthele.

Chugai/Roche funded the study. Dr. Kleiter has received compensation for consulting, speaking, or serving on advisory boards for Alexion, Biogen, Celgene, Merck, and Roche. Dr. Berthele was not involved in any of the satralizumab trials, but is an investigator and coauthor of the PREVENT trial of eculizumab.

egreb@mdedge.com

SOURCE: Kleiter I, et al. MSVirtual2020. Abstract FC01.03.

Two important lessons about managing patients with multiple sclerosis (MS) and COVID-19 have emerged from a hospital clinic in Madrid that managed COVID-infected patients with MS through the peak of the pandemic: Combined polymeric chain reaction and serology testing helped avoid disease reactivation in asymptomatic carriers during the pandemic peak, although after the peak PCR alone proved just as effective; and infected MS patients could stay on their MS medications while being treated for COVID-19, as fewer than one in five required hospitalization.

Virginia Meca-Lallana, MD, a neurologist and coordinator of the demyelinating diseases unit at the Hospital of the University of the Princess in Madrid, and colleagues presented their findings in two posters at the Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“MS treatments don’t seem to make the prognosis of COVID-19 worse, but it is very important to evaluate other risk factors,” Dr. Meca-Lallana said in an interview. “MS treatments prevent the patients’ disability, and it is very important not to stop them if it isn’t necessary.”

The results arose from a multidisciplinary safety protocol involving neurology, microbiology, and preventive medicine that the University of Princess physicians developed to keep MS stable in patients diagnosed with SARS-CoV-2.

The researchers obtained 152 PCR nasopharyngeal swabs and 140 serology tests in 90 patients with MS over 3 months before starting a variety of MS treatments: Natalizumab (96 tests), ocrelizumab (36), rituximab (3), methylprednisolone (7), cladribine (4), and dimethyl fumarate (3). The protocol identified 7 asymptomatic carriers—7.8% of the total population—5 of whom had positive immunoglobulin M and G serology. The study also confirmed 5 patients with positive IgM+IgG serology post-infection, but no COVID-19 reactivations were detected after implementation of the protocol.

“The safety protocol reached its objective of avoiding disease reactivation and clinical activation in asymptomatic carriers,” Dr. Meca-Lallana said.

The second poster she presented reported on the real-world experience with SARS-CoV-2 in the MS unit at her hospital. The observational, prospective study included 41 cases, 38 of which were relapsing-remitting MS and the remainder progressive MS. The patients had MS for an average of 9 years.

“We need more patients to draw more robust conclusions, but in our patients, MS treatments seem safe in this situation,” Dr. Meca-Lallana said. “We did not discontinue treatments, and after our first results, we only delayed treatments in patients with any additional comorbidity or when coming to the hospital was not safe.”

A total of 39 patients were taking disease-modifying therapies (DMTs): 46.3% with oral agents, 39% with monoclonal antibodies, and 10% with injectable agents; 27 patients were previously treated with other DMTs. The median Expanded Disability Status Scale (EDSS) was 2.5, and 11 patients had clinical activity the previous year. Eighteen cases were confirmed by PCR or serology, or both, and 23 were diagnosed clinically.

Among the patients with MS and COVID-19, 17% were admitted to the hospital. Six patients had pneumonia, but none required admission to the intensive care unit, and no deaths occurred. Three patients had other comorbidities. Admitted patients tended to be older and had higher EDSS scores, although the difference was not statistically significant. MS worsened in 7 patients, and 10 patients stopped or paused DMTs because of the infection.

“Multiple sclerosis is a weakening illness,” Dr. Meca-Lallana said. “MS treatments do not seem to make the prognosis of COVID-19 worse, but it is very important to evaluate other risk factors.”

The SARS-CoV-2 infection does not seem to result in a more aggressive form of the disease in MS patients, and selective immunosuppression may improve their outcomes, she noted.

“MS treatments avoid the patient’s disability,” the investigator added, “and it is very important not to stop them if it isn’t necessary.”

Dr. Meca-Lallana had no relevant financial disclosures.

Two important lessons about managing patients with multiple sclerosis (MS) and COVID-19 have emerged from a hospital clinic in Madrid that managed COVID-infected patients with MS through the peak of the pandemic: Combined polymeric chain reaction and serology testing helped avoid disease reactivation in asymptomatic carriers during the pandemic peak, although after the peak PCR alone proved just as effective; and infected MS patients could stay on their MS medications while being treated for COVID-19, as fewer than one in five required hospitalization.

Virginia Meca-Lallana, MD, a neurologist and coordinator of the demyelinating diseases unit at the Hospital of the University of the Princess in Madrid, and colleagues presented their findings in two posters at the Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“MS treatments don’t seem to make the prognosis of COVID-19 worse, but it is very important to evaluate other risk factors,” Dr. Meca-Lallana said in an interview. “MS treatments prevent the patients’ disability, and it is very important not to stop them if it isn’t necessary.”

The results arose from a multidisciplinary safety protocol involving neurology, microbiology, and preventive medicine that the University of Princess physicians developed to keep MS stable in patients diagnosed with SARS-CoV-2.

The researchers obtained 152 PCR nasopharyngeal swabs and 140 serology tests in 90 patients with MS over 3 months before starting a variety of MS treatments: Natalizumab (96 tests), ocrelizumab (36), rituximab (3), methylprednisolone (7), cladribine (4), and dimethyl fumarate (3). The protocol identified 7 asymptomatic carriers—7.8% of the total population—5 of whom had positive immunoglobulin M and G serology. The study also confirmed 5 patients with positive IgM+IgG serology post-infection, but no COVID-19 reactivations were detected after implementation of the protocol.

“The safety protocol reached its objective of avoiding disease reactivation and clinical activation in asymptomatic carriers,” Dr. Meca-Lallana said.

The second poster she presented reported on the real-world experience with SARS-CoV-2 in the MS unit at her hospital. The observational, prospective study included 41 cases, 38 of which were relapsing-remitting MS and the remainder progressive MS. The patients had MS for an average of 9 years.

“We need more patients to draw more robust conclusions, but in our patients, MS treatments seem safe in this situation,” Dr. Meca-Lallana said. “We did not discontinue treatments, and after our first results, we only delayed treatments in patients with any additional comorbidity or when coming to the hospital was not safe.”

A total of 39 patients were taking disease-modifying therapies (DMTs): 46.3% with oral agents, 39% with monoclonal antibodies, and 10% with injectable agents; 27 patients were previously treated with other DMTs. The median Expanded Disability Status Scale (EDSS) was 2.5, and 11 patients had clinical activity the previous year. Eighteen cases were confirmed by PCR or serology, or both, and 23 were diagnosed clinically.

Among the patients with MS and COVID-19, 17% were admitted to the hospital. Six patients had pneumonia, but none required admission to the intensive care unit, and no deaths occurred. Three patients had other comorbidities. Admitted patients tended to be older and had higher EDSS scores, although the difference was not statistically significant. MS worsened in 7 patients, and 10 patients stopped or paused DMTs because of the infection.

“Multiple sclerosis is a weakening illness,” Dr. Meca-Lallana said. “MS treatments do not seem to make the prognosis of COVID-19 worse, but it is very important to evaluate other risk factors.”

The SARS-CoV-2 infection does not seem to result in a more aggressive form of the disease in MS patients, and selective immunosuppression may improve their outcomes, she noted.

“MS treatments avoid the patient’s disability,” the investigator added, “and it is very important not to stop them if it isn’t necessary.”

Dr. Meca-Lallana had no relevant financial disclosures.

Two important lessons about managing patients with multiple sclerosis (MS) and COVID-19 have emerged from a hospital clinic in Madrid that managed COVID-infected patients with MS through the peak of the pandemic: Combined polymeric chain reaction and serology testing helped avoid disease reactivation in asymptomatic carriers during the pandemic peak, although after the peak PCR alone proved just as effective; and infected MS patients could stay on their MS medications while being treated for COVID-19, as fewer than one in five required hospitalization.

Virginia Meca-Lallana, MD, a neurologist and coordinator of the demyelinating diseases unit at the Hospital of the University of the Princess in Madrid, and colleagues presented their findings in two posters at the Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“MS treatments don’t seem to make the prognosis of COVID-19 worse, but it is very important to evaluate other risk factors,” Dr. Meca-Lallana said in an interview. “MS treatments prevent the patients’ disability, and it is very important not to stop them if it isn’t necessary.”

The results arose from a multidisciplinary safety protocol involving neurology, microbiology, and preventive medicine that the University of Princess physicians developed to keep MS stable in patients diagnosed with SARS-CoV-2.

The researchers obtained 152 PCR nasopharyngeal swabs and 140 serology tests in 90 patients with MS over 3 months before starting a variety of MS treatments: Natalizumab (96 tests), ocrelizumab (36), rituximab (3), methylprednisolone (7), cladribine (4), and dimethyl fumarate (3). The protocol identified 7 asymptomatic carriers—7.8% of the total population—5 of whom had positive immunoglobulin M and G serology. The study also confirmed 5 patients with positive IgM+IgG serology post-infection, but no COVID-19 reactivations were detected after implementation of the protocol.

“The safety protocol reached its objective of avoiding disease reactivation and clinical activation in asymptomatic carriers,” Dr. Meca-Lallana said.

The second poster she presented reported on the real-world experience with SARS-CoV-2 in the MS unit at her hospital. The observational, prospective study included 41 cases, 38 of which were relapsing-remitting MS and the remainder progressive MS. The patients had MS for an average of 9 years.

“We need more patients to draw more robust conclusions, but in our patients, MS treatments seem safe in this situation,” Dr. Meca-Lallana said. “We did not discontinue treatments, and after our first results, we only delayed treatments in patients with any additional comorbidity or when coming to the hospital was not safe.”

A total of 39 patients were taking disease-modifying therapies (DMTs): 46.3% with oral agents, 39% with monoclonal antibodies, and 10% with injectable agents; 27 patients were previously treated with other DMTs. The median Expanded Disability Status Scale (EDSS) was 2.5, and 11 patients had clinical activity the previous year. Eighteen cases were confirmed by PCR or serology, or both, and 23 were diagnosed clinically.

Among the patients with MS and COVID-19, 17% were admitted to the hospital. Six patients had pneumonia, but none required admission to the intensive care unit, and no deaths occurred. Three patients had other comorbidities. Admitted patients tended to be older and had higher EDSS scores, although the difference was not statistically significant. MS worsened in 7 patients, and 10 patients stopped or paused DMTs because of the infection.

“Multiple sclerosis is a weakening illness,” Dr. Meca-Lallana said. “MS treatments do not seem to make the prognosis of COVID-19 worse, but it is very important to evaluate other risk factors.”

The SARS-CoV-2 infection does not seem to result in a more aggressive form of the disease in MS patients, and selective immunosuppression may improve their outcomes, she noted.

“MS treatments avoid the patient’s disability,” the investigator added, “and it is very important not to stop them if it isn’t necessary.”

Dr. Meca-Lallana had no relevant financial disclosures.

For patients with primary progressive multiple sclerosis (MS), longer exposure to disease-modifying therapy (DMT) may delay the time at which a patient is restricted to a wheelchair. Reducing the delay to treatment initiation, as well as treating younger patients, might improve long-term disability outcomes, according to a new study. 

“To optimize treatment decision-making in primary progressive MS, further profiling of the best candidates for treatment is needed,” said the researchers. The study was presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Ocrelizumab remains the only treatment available for patients with primary progressive MS. In clinical trials, other drugs have failed to reduce disability progression in this population. Mattia Fonderico, a doctoral student and research assistant at the University of Florence (Italy), and colleagues reviewed data from the Italian MS Registry to examine whether DMT affects the attainment of given disability outcomes.

Patients with longer exposure were younger at baseline

Patients eligible for inclusion in the study had primary progressive MS, at least three evaluations using the Expanded Disability Status Scale (EDSS), and 3 years’ follow-up. The investigators defined the baseline for untreated patients as the first EDSS evaluation. For treated patients, the baseline was the date of DMT initiation.

Using multivariable Cox regression models, Ms. Fonderico and colleagues examined the effect of DMT on the risk of reaching EDSS scores of 6 (i.e., requirement for intermittent or unilateral constant walking assistance) and 7 (i.e., restriction to a wheelchair) as a dichotomous variable and as a time-dependent covariate. The researchers adjusted the data for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, and annualized relapse rate. They compared outcomes with an as-treated analysis and chose cohorts with similar baseline characteristics using propensity-score matching. In addition, Ms. Fonderico and colleagues also analyzed quartiles of DMT exposure.

The investigators included 1,214 patients (671 women) in their analysis. The population’s mean age at baseline was 48.7 years, and its mean EDSS score was 4.1. A total of 626 patients (52%) received DMT during follow-up. Approximately 57% of DMTs were platform therapies, and 43% were high-efficacy therapies.

Mean follow-up duration was 11.6 years. By the end of follow-up, 994 patients (82%) reached an EDSS score of 6, and 539 (44%) reached an EDSS score of 7. Multivariable Cox regression models indicated that DMT, analyzed as a dichotomous variable, did not affect the risk of reaching EDSS 6 (adjusted hazard ratio, 1.1) or EDSS 7 (aHR, 0.93). Longer DMT exposure, however, significantly reduced the risk of reaching EDSS 7 (aHR, 0.73).

Compared with patients with shorter exposure to DMT, patients in the highest quartile of DMT exposure were younger at baseline (mean age, 44.1 years) and initiated DMT closer to disease onset (mean time to DMT initiation was 6.8 years). The propensity score matching analysis confirmed these findings.

The investigators did not consider MRI variables, which Ms. Fonderico acknowledged was a weakness of the study. In addition, they did not analyze the effect of superimposed relapses.

 

A new perspective on primary progressive MS?

These results suggest that primary progressive MS behaves like relapsing-remitting MS, said Gavin Giovannoni, MD, PhD, chair of neurology at Queen Mary University of London. That is, they suggest that primary progressive MS “is modifiable by a DMT and that the earlier you treat, the better the outcome.” The results also indicate that neurologists commonly prescribe DMT off label in Italy, he added.

A weakness of the study is that it was not randomized. Furthermore, “EDSS [evaluations] tend not be done properly in routine clinical practice,” said Dr. Giovannoni. Still, the study raises an important question for future research. “Why have we missed the treatment effect in previous trials?” asked Dr. Giovannoni. Whether previous trials were too short or underpowered could be investigated, he added.

Study funding was not reported. Ms. Fonderico had no relevant disclosures. Dr. Giovannoni had no relevant disclosures.

egreb@mdedge.com

For patients with primary progressive multiple sclerosis (MS), longer exposure to disease-modifying therapy (DMT) may delay the time at which a patient is restricted to a wheelchair. Reducing the delay to treatment initiation, as well as treating younger patients, might improve long-term disability outcomes, according to a new study. 

“To optimize treatment decision-making in primary progressive MS, further profiling of the best candidates for treatment is needed,” said the researchers. The study was presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Ocrelizumab remains the only treatment available for patients with primary progressive MS. In clinical trials, other drugs have failed to reduce disability progression in this population. Mattia Fonderico, a doctoral student and research assistant at the University of Florence (Italy), and colleagues reviewed data from the Italian MS Registry to examine whether DMT affects the attainment of given disability outcomes.

Patients with longer exposure were younger at baseline

Patients eligible for inclusion in the study had primary progressive MS, at least three evaluations using the Expanded Disability Status Scale (EDSS), and 3 years’ follow-up. The investigators defined the baseline for untreated patients as the first EDSS evaluation. For treated patients, the baseline was the date of DMT initiation.

Using multivariable Cox regression models, Ms. Fonderico and colleagues examined the effect of DMT on the risk of reaching EDSS scores of 6 (i.e., requirement for intermittent or unilateral constant walking assistance) and 7 (i.e., restriction to a wheelchair) as a dichotomous variable and as a time-dependent covariate. The researchers adjusted the data for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, and annualized relapse rate. They compared outcomes with an as-treated analysis and chose cohorts with similar baseline characteristics using propensity-score matching. In addition, Ms. Fonderico and colleagues also analyzed quartiles of DMT exposure.

The investigators included 1,214 patients (671 women) in their analysis. The population’s mean age at baseline was 48.7 years, and its mean EDSS score was 4.1. A total of 626 patients (52%) received DMT during follow-up. Approximately 57% of DMTs were platform therapies, and 43% were high-efficacy therapies.

Mean follow-up duration was 11.6 years. By the end of follow-up, 994 patients (82%) reached an EDSS score of 6, and 539 (44%) reached an EDSS score of 7. Multivariable Cox regression models indicated that DMT, analyzed as a dichotomous variable, did not affect the risk of reaching EDSS 6 (adjusted hazard ratio, 1.1) or EDSS 7 (aHR, 0.93). Longer DMT exposure, however, significantly reduced the risk of reaching EDSS 7 (aHR, 0.73).

Compared with patients with shorter exposure to DMT, patients in the highest quartile of DMT exposure were younger at baseline (mean age, 44.1 years) and initiated DMT closer to disease onset (mean time to DMT initiation was 6.8 years). The propensity score matching analysis confirmed these findings.

The investigators did not consider MRI variables, which Ms. Fonderico acknowledged was a weakness of the study. In addition, they did not analyze the effect of superimposed relapses.

 

A new perspective on primary progressive MS?

These results suggest that primary progressive MS behaves like relapsing-remitting MS, said Gavin Giovannoni, MD, PhD, chair of neurology at Queen Mary University of London. That is, they suggest that primary progressive MS “is modifiable by a DMT and that the earlier you treat, the better the outcome.” The results also indicate that neurologists commonly prescribe DMT off label in Italy, he added.

A weakness of the study is that it was not randomized. Furthermore, “EDSS [evaluations] tend not be done properly in routine clinical practice,” said Dr. Giovannoni. Still, the study raises an important question for future research. “Why have we missed the treatment effect in previous trials?” asked Dr. Giovannoni. Whether previous trials were too short or underpowered could be investigated, he added.

Study funding was not reported. Ms. Fonderico had no relevant disclosures. Dr. Giovannoni had no relevant disclosures.

egreb@mdedge.com

For patients with primary progressive multiple sclerosis (MS), longer exposure to disease-modifying therapy (DMT) may delay the time at which a patient is restricted to a wheelchair. Reducing the delay to treatment initiation, as well as treating younger patients, might improve long-term disability outcomes, according to a new study. 

“To optimize treatment decision-making in primary progressive MS, further profiling of the best candidates for treatment is needed,” said the researchers. The study was presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Ocrelizumab remains the only treatment available for patients with primary progressive MS. In clinical trials, other drugs have failed to reduce disability progression in this population. Mattia Fonderico, a doctoral student and research assistant at the University of Florence (Italy), and colleagues reviewed data from the Italian MS Registry to examine whether DMT affects the attainment of given disability outcomes.

Patients with longer exposure were younger at baseline

Patients eligible for inclusion in the study had primary progressive MS, at least three evaluations using the Expanded Disability Status Scale (EDSS), and 3 years’ follow-up. The investigators defined the baseline for untreated patients as the first EDSS evaluation. For treated patients, the baseline was the date of DMT initiation.

Using multivariable Cox regression models, Ms. Fonderico and colleagues examined the effect of DMT on the risk of reaching EDSS scores of 6 (i.e., requirement for intermittent or unilateral constant walking assistance) and 7 (i.e., restriction to a wheelchair) as a dichotomous variable and as a time-dependent covariate. The researchers adjusted the data for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, and annualized relapse rate. They compared outcomes with an as-treated analysis and chose cohorts with similar baseline characteristics using propensity-score matching. In addition, Ms. Fonderico and colleagues also analyzed quartiles of DMT exposure.

The investigators included 1,214 patients (671 women) in their analysis. The population’s mean age at baseline was 48.7 years, and its mean EDSS score was 4.1. A total of 626 patients (52%) received DMT during follow-up. Approximately 57% of DMTs were platform therapies, and 43% were high-efficacy therapies.

Mean follow-up duration was 11.6 years. By the end of follow-up, 994 patients (82%) reached an EDSS score of 6, and 539 (44%) reached an EDSS score of 7. Multivariable Cox regression models indicated that DMT, analyzed as a dichotomous variable, did not affect the risk of reaching EDSS 6 (adjusted hazard ratio, 1.1) or EDSS 7 (aHR, 0.93). Longer DMT exposure, however, significantly reduced the risk of reaching EDSS 7 (aHR, 0.73).

Compared with patients with shorter exposure to DMT, patients in the highest quartile of DMT exposure were younger at baseline (mean age, 44.1 years) and initiated DMT closer to disease onset (mean time to DMT initiation was 6.8 years). The propensity score matching analysis confirmed these findings.

The investigators did not consider MRI variables, which Ms. Fonderico acknowledged was a weakness of the study. In addition, they did not analyze the effect of superimposed relapses.

 

A new perspective on primary progressive MS?

These results suggest that primary progressive MS behaves like relapsing-remitting MS, said Gavin Giovannoni, MD, PhD, chair of neurology at Queen Mary University of London. That is, they suggest that primary progressive MS “is modifiable by a DMT and that the earlier you treat, the better the outcome.” The results also indicate that neurologists commonly prescribe DMT off label in Italy, he added.

A weakness of the study is that it was not randomized. Furthermore, “EDSS [evaluations] tend not be done properly in routine clinical practice,” said Dr. Giovannoni. Still, the study raises an important question for future research. “Why have we missed the treatment effect in previous trials?” asked Dr. Giovannoni. Whether previous trials were too short or underpowered could be investigated, he added.

Study funding was not reported. Ms. Fonderico had no relevant disclosures. Dr. Giovannoni had no relevant disclosures.

egreb@mdedge.com

In contrast to findings of previous research, low levels of von Willebrand Factor (VWF) and blood group O were not associated with a first-ever intracerebral hemorrhage (ICH), according to a study published in Thrombosis Research.

The researchers compared 176 cases of ICH with 349 age- and sex-matched controls. The mean patient age was 57 years, and 50% were women. The median time from baseline blood sampling to the first ICH was 5.6 years, according to the study reported by Kristina Johansson of Umeå (Sweden) University and her colleagues.
 

Complicated picture

The level of VWF differed significantly among blood groups: In individuals with blood group O, the mean VWF level was 1.29 kIU/L; for blood group A, it was 1.52 kIU/L; for blood group AB, 1.59 kIU/L; and in blood group B, 1.76 kIU/L. However, there was no difference in VWF concentration between cases and controls.

The researchers found no association between blood group O and the risk of ICH, a finding previously seen in other studies. They did, however, find that, in the limited number of patients with blood group B there was an association with a lower risk of ICH, compared with blood group A (odds ratio, 0.47; 95% confidence interval, 0.23-0.95).

“To our knowledge this is the largest prospective study investigating the association between VWF, ABO blood group and ICH. We found no association between VWF or blood group O and risk of future ICH,” the researchers concluded.

The study was funded by public institutions in Sweden. The authors declared that they had no conflicts.
 

mlesney@mdedge.com

SOURCE: Johansson K et al. Thromb Res. 2020 Jul 5;195:77-80.

In contrast to findings of previous research, low levels of von Willebrand Factor (VWF) and blood group O were not associated with a first-ever intracerebral hemorrhage (ICH), according to a study published in Thrombosis Research.

The researchers compared 176 cases of ICH with 349 age- and sex-matched controls. The mean patient age was 57 years, and 50% were women. The median time from baseline blood sampling to the first ICH was 5.6 years, according to the study reported by Kristina Johansson of Umeå (Sweden) University and her colleagues.
 

Complicated picture

The level of VWF differed significantly among blood groups: In individuals with blood group O, the mean VWF level was 1.29 kIU/L; for blood group A, it was 1.52 kIU/L; for blood group AB, 1.59 kIU/L; and in blood group B, 1.76 kIU/L. However, there was no difference in VWF concentration between cases and controls.

The researchers found no association between blood group O and the risk of ICH, a finding previously seen in other studies. They did, however, find that, in the limited number of patients with blood group B there was an association with a lower risk of ICH, compared with blood group A (odds ratio, 0.47; 95% confidence interval, 0.23-0.95).

“To our knowledge this is the largest prospective study investigating the association between VWF, ABO blood group and ICH. We found no association between VWF or blood group O and risk of future ICH,” the researchers concluded.

The study was funded by public institutions in Sweden. The authors declared that they had no conflicts.
 

mlesney@mdedge.com

SOURCE: Johansson K et al. Thromb Res. 2020 Jul 5;195:77-80.

In contrast to findings of previous research, low levels of von Willebrand Factor (VWF) and blood group O were not associated with a first-ever intracerebral hemorrhage (ICH), according to a study published in Thrombosis Research.

The researchers compared 176 cases of ICH with 349 age- and sex-matched controls. The mean patient age was 57 years, and 50% were women. The median time from baseline blood sampling to the first ICH was 5.6 years, according to the study reported by Kristina Johansson of Umeå (Sweden) University and her colleagues.
 

Complicated picture

The level of VWF differed significantly among blood groups: In individuals with blood group O, the mean VWF level was 1.29 kIU/L; for blood group A, it was 1.52 kIU/L; for blood group AB, 1.59 kIU/L; and in blood group B, 1.76 kIU/L. However, there was no difference in VWF concentration between cases and controls.

The researchers found no association between blood group O and the risk of ICH, a finding previously seen in other studies. They did, however, find that, in the limited number of patients with blood group B there was an association with a lower risk of ICH, compared with blood group A (odds ratio, 0.47; 95% confidence interval, 0.23-0.95).

“To our knowledge this is the largest prospective study investigating the association between VWF, ABO blood group and ICH. We found no association between VWF or blood group O and risk of future ICH,” the researchers concluded.

The study was funded by public institutions in Sweden. The authors declared that they had no conflicts.
 

mlesney@mdedge.com

SOURCE: Johansson K et al. Thromb Res. 2020 Jul 5;195:77-80.

A novel biomarker could help identify progression in Parkinson’s disease, distinguish it from other neurodegenerative disorders, and monitor response to treatments. Although the biomarker, neurofilament light chain (NfL), is not especially specific, it is the first blood-based biomarker for Parkinson’s disease.

Neurofilaments are components of the neural cytoskeleton, where they maintain structure along with other functions. Following axonal damage, NfL gets released into extracellular fluids. Previously, NfL has been detected in cerebrospinal fluid (CSF) in patients with multiple sclerosis and neurodegenerative dementias. NfL in the CSF can distinguish Parkinson’s disease (PD) from multiple system atrophy and progressive supranuclear palsy.

That’s useful, but a serum marker would open new doors. “An easily accessible biomarker that will serve as an indicator of diagnosis, disease state, and progression, as well as a marker of response to therapeutic intervention is needed. A biomarker will strengthen the ability to select patients for inclusion or stratification within clinical trials,” commented Okeanis Vaou, MD, director of the movement disorders program at St. Elizabeth’s Medical Center in Brighton, Mass. Dr. Vaou was not involved in the study, which was published Aug. 15 in Movement Disorders.
 

A potential biomarker?

To determine if serum NfL levels would correlate with CSF values and had potential as a biomarker, a large, multi-institutional team of researchers led by Brit Mollenhauer, MD, of the University Medical Center Goettingen (Germany), and Danielle Graham, MD, of Biogen, drew data from a prospective, longitudinal, single-center project called the De Novo Parkinson’s disease (DeNoPa) cohort.

The researchers analyzed data from 176 subjects, including drug-naive patients with newly diagnosed PD; age, sex, and education matched healthy controls; and patients who were initially diagnosed with Parkinson’s disease but had their diagnoses changed to a cognate or neurodegenerative disorder (OND). The researchers also drew 514 serum samples from the prospective longitudinal, observational, international multicenter study Parkinson’s Progression Marker Initiative (PPMI) cohort.

In the DeNoPa cohort, OND patients had the highest median CSF NfL levels at baseline (839 pg/mL) followed by PD patients (562 pg/mL) and healthy controls (494 pg/mL; P = .01). There was a strong correlation between CSF and serum NfL levels in a cross-sectional exploratory study with the PPMI cohort.

Age and sex covariates in the PPMI cohort explained 51% of NfL variability. After adjustment for age and sex, baseline median blood NfL levels were highest in the OND group (16.23 pg/mL), followed by the genetic PD group (13.36 pg/mL), prodromal participants (12.20 pg/mL), PD patients (11.73 pg/mL), unaffected mutation carriers (11.63 pg/mL), and healthy controls (11.05 pg/mL; F test P < .0001). Median serum NfL increased by 3.35% per year of age (P < .0001), and median serum NfL was 6.79% higher in women (P = .0002).

Doubling of adjusted serum NfL levels were associated with a median increase in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale total score of 3.45 points (false-discovery rate–adjusted P = .0115), a median decrease in Symbol Digit Modality Test total score of 1.39 (FDR P = .026), a median decrease in Hopkins Verbal Learning Tests with discrimination recognition score of 0.3 (FDR P = .03), and a median decrease in Hopkins Verbal Learning Tests with retention score of 0.029 (FDR P = .04).
 

More specific markers needed

The findings are intriguing, said Dr Vaou, but “we need to acknowledge that increased NfL levels are not specific enough to Parkinson’s disease and reflect neuronal and axonal damage. Therefore, there is a need for more specific markers to support diagnostic accuracy, rate of progression, and ultimate prognosis. A serum NfL assay may be useful to clinicians evaluating patients with PD or OND diagnosis and mitigate the misdiagnosis of atypical PD. NfL may be particularly useful in differentiating PD from cognate disorders such as multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies.”

The current success is the result of large patient databases containing phenotypic data, imaging, and tests of tissue, blood, and cerebrospinal fluid, along with collaborations between advocacy groups, academia, and industry, according to Dr. Vaou. As that work continues, it could uncover more specific biomarkers “that will allow us not only to help with diagnosis and treatment but with disease progression, inclusion, recruitment and stratification in clinical studies, as well as (be an) indicator of response to therapeutic intervention of an investigational drug.”

The study was funded by the Michael J. Fox Foundation for Parkinson’s Research. Dr. Vaou had no relevant financial disclosures.

SOURCE: Mollenhauer B et al. Mov Disord. 2020 Aug 15. doi: 10.1002/mds.28206.

A novel biomarker could help identify progression in Parkinson’s disease, distinguish it from other neurodegenerative disorders, and monitor response to treatments. Although the biomarker, neurofilament light chain (NfL), is not especially specific, it is the first blood-based biomarker for Parkinson’s disease.

Neurofilaments are components of the neural cytoskeleton, where they maintain structure along with other functions. Following axonal damage, NfL gets released into extracellular fluids. Previously, NfL has been detected in cerebrospinal fluid (CSF) in patients with multiple sclerosis and neurodegenerative dementias. NfL in the CSF can distinguish Parkinson’s disease (PD) from multiple system atrophy and progressive supranuclear palsy.

That’s useful, but a serum marker would open new doors. “An easily accessible biomarker that will serve as an indicator of diagnosis, disease state, and progression, as well as a marker of response to therapeutic intervention is needed. A biomarker will strengthen the ability to select patients for inclusion or stratification within clinical trials,” commented Okeanis Vaou, MD, director of the movement disorders program at St. Elizabeth’s Medical Center in Brighton, Mass. Dr. Vaou was not involved in the study, which was published Aug. 15 in Movement Disorders.
 

A potential biomarker?

To determine if serum NfL levels would correlate with CSF values and had potential as a biomarker, a large, multi-institutional team of researchers led by Brit Mollenhauer, MD, of the University Medical Center Goettingen (Germany), and Danielle Graham, MD, of Biogen, drew data from a prospective, longitudinal, single-center project called the De Novo Parkinson’s disease (DeNoPa) cohort.

The researchers analyzed data from 176 subjects, including drug-naive patients with newly diagnosed PD; age, sex, and education matched healthy controls; and patients who were initially diagnosed with Parkinson’s disease but had their diagnoses changed to a cognate or neurodegenerative disorder (OND). The researchers also drew 514 serum samples from the prospective longitudinal, observational, international multicenter study Parkinson’s Progression Marker Initiative (PPMI) cohort.

In the DeNoPa cohort, OND patients had the highest median CSF NfL levels at baseline (839 pg/mL) followed by PD patients (562 pg/mL) and healthy controls (494 pg/mL; P = .01). There was a strong correlation between CSF and serum NfL levels in a cross-sectional exploratory study with the PPMI cohort.

Age and sex covariates in the PPMI cohort explained 51% of NfL variability. After adjustment for age and sex, baseline median blood NfL levels were highest in the OND group (16.23 pg/mL), followed by the genetic PD group (13.36 pg/mL), prodromal participants (12.20 pg/mL), PD patients (11.73 pg/mL), unaffected mutation carriers (11.63 pg/mL), and healthy controls (11.05 pg/mL; F test P < .0001). Median serum NfL increased by 3.35% per year of age (P < .0001), and median serum NfL was 6.79% higher in women (P = .0002).

Doubling of adjusted serum NfL levels were associated with a median increase in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale total score of 3.45 points (false-discovery rate–adjusted P = .0115), a median decrease in Symbol Digit Modality Test total score of 1.39 (FDR P = .026), a median decrease in Hopkins Verbal Learning Tests with discrimination recognition score of 0.3 (FDR P = .03), and a median decrease in Hopkins Verbal Learning Tests with retention score of 0.029 (FDR P = .04).
 

More specific markers needed

The findings are intriguing, said Dr Vaou, but “we need to acknowledge that increased NfL levels are not specific enough to Parkinson’s disease and reflect neuronal and axonal damage. Therefore, there is a need for more specific markers to support diagnostic accuracy, rate of progression, and ultimate prognosis. A serum NfL assay may be useful to clinicians evaluating patients with PD or OND diagnosis and mitigate the misdiagnosis of atypical PD. NfL may be particularly useful in differentiating PD from cognate disorders such as multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies.”

The current success is the result of large patient databases containing phenotypic data, imaging, and tests of tissue, blood, and cerebrospinal fluid, along with collaborations between advocacy groups, academia, and industry, according to Dr. Vaou. As that work continues, it could uncover more specific biomarkers “that will allow us not only to help with diagnosis and treatment but with disease progression, inclusion, recruitment and stratification in clinical studies, as well as (be an) indicator of response to therapeutic intervention of an investigational drug.”

The study was funded by the Michael J. Fox Foundation for Parkinson’s Research. Dr. Vaou had no relevant financial disclosures.

SOURCE: Mollenhauer B et al. Mov Disord. 2020 Aug 15. doi: 10.1002/mds.28206.

A novel biomarker could help identify progression in Parkinson’s disease, distinguish it from other neurodegenerative disorders, and monitor response to treatments. Although the biomarker, neurofilament light chain (NfL), is not especially specific, it is the first blood-based biomarker for Parkinson’s disease.

Neurofilaments are components of the neural cytoskeleton, where they maintain structure along with other functions. Following axonal damage, NfL gets released into extracellular fluids. Previously, NfL has been detected in cerebrospinal fluid (CSF) in patients with multiple sclerosis and neurodegenerative dementias. NfL in the CSF can distinguish Parkinson’s disease (PD) from multiple system atrophy and progressive supranuclear palsy.

That’s useful, but a serum marker would open new doors. “An easily accessible biomarker that will serve as an indicator of diagnosis, disease state, and progression, as well as a marker of response to therapeutic intervention is needed. A biomarker will strengthen the ability to select patients for inclusion or stratification within clinical trials,” commented Okeanis Vaou, MD, director of the movement disorders program at St. Elizabeth’s Medical Center in Brighton, Mass. Dr. Vaou was not involved in the study, which was published Aug. 15 in Movement Disorders.
 

A potential biomarker?

To determine if serum NfL levels would correlate with CSF values and had potential as a biomarker, a large, multi-institutional team of researchers led by Brit Mollenhauer, MD, of the University Medical Center Goettingen (Germany), and Danielle Graham, MD, of Biogen, drew data from a prospective, longitudinal, single-center project called the De Novo Parkinson’s disease (DeNoPa) cohort.

The researchers analyzed data from 176 subjects, including drug-naive patients with newly diagnosed PD; age, sex, and education matched healthy controls; and patients who were initially diagnosed with Parkinson’s disease but had their diagnoses changed to a cognate or neurodegenerative disorder (OND). The researchers also drew 514 serum samples from the prospective longitudinal, observational, international multicenter study Parkinson’s Progression Marker Initiative (PPMI) cohort.

In the DeNoPa cohort, OND patients had the highest median CSF NfL levels at baseline (839 pg/mL) followed by PD patients (562 pg/mL) and healthy controls (494 pg/mL; P = .01). There was a strong correlation between CSF and serum NfL levels in a cross-sectional exploratory study with the PPMI cohort.

Age and sex covariates in the PPMI cohort explained 51% of NfL variability. After adjustment for age and sex, baseline median blood NfL levels were highest in the OND group (16.23 pg/mL), followed by the genetic PD group (13.36 pg/mL), prodromal participants (12.20 pg/mL), PD patients (11.73 pg/mL), unaffected mutation carriers (11.63 pg/mL), and healthy controls (11.05 pg/mL; F test P < .0001). Median serum NfL increased by 3.35% per year of age (P < .0001), and median serum NfL was 6.79% higher in women (P = .0002).

Doubling of adjusted serum NfL levels were associated with a median increase in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale total score of 3.45 points (false-discovery rate–adjusted P = .0115), a median decrease in Symbol Digit Modality Test total score of 1.39 (FDR P = .026), a median decrease in Hopkins Verbal Learning Tests with discrimination recognition score of 0.3 (FDR P = .03), and a median decrease in Hopkins Verbal Learning Tests with retention score of 0.029 (FDR P = .04).
 

More specific markers needed

The findings are intriguing, said Dr Vaou, but “we need to acknowledge that increased NfL levels are not specific enough to Parkinson’s disease and reflect neuronal and axonal damage. Therefore, there is a need for more specific markers to support diagnostic accuracy, rate of progression, and ultimate prognosis. A serum NfL assay may be useful to clinicians evaluating patients with PD or OND diagnosis and mitigate the misdiagnosis of atypical PD. NfL may be particularly useful in differentiating PD from cognate disorders such as multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies.”

The current success is the result of large patient databases containing phenotypic data, imaging, and tests of tissue, blood, and cerebrospinal fluid, along with collaborations between advocacy groups, academia, and industry, according to Dr. Vaou. As that work continues, it could uncover more specific biomarkers “that will allow us not only to help with diagnosis and treatment but with disease progression, inclusion, recruitment and stratification in clinical studies, as well as (be an) indicator of response to therapeutic intervention of an investigational drug.”

The study was funded by the Michael J. Fox Foundation for Parkinson’s Research. Dr. Vaou had no relevant financial disclosures.

SOURCE: Mollenhauer B et al. Mov Disord. 2020 Aug 15. doi: 10.1002/mds.28206.

Insomnia is “highly prevalent” in veterans with chronic pulmonary obstructive disease and is significantly associated with greater COPD-related health care utilization, according to an analysis of national Veterans Health Administration data.

“The study highlights the importance of exploring potential sleep disturbances and disorders in this population and suggests that a targeted treatment for insomnia may help to improve COPD outcomes in veterans with COPD and insomnia,” said Faith Luyster, PhD, assistant professor at the University of Pittsburgh, in an interview after the virtual annual meeting of the Associated Professional Sleep Societies, where she presented the findings.

Dr. Luyster and coinvestigators used an administrative database from the Veterans Affairs Corporate Data Warehouse to identify more than 1.5 million patients with COPD who used VHA services over a 6-year period (fiscal years 2011-2017). Insomnia was defined by ICD-9/10 diagnostic codes and/or a sedative-hypnotic prescription for at least 30 doses during any of these years.

Insomnia with COPD was prevalent in this sample of veterans at 37.3%. Compared with veterans without comorbid insomnia, those who had both COPD and insomnia (575,539 of the total 1,542,642) were older (69 vs. 64 years), more likely to be female (6.3% vs. 3.7%), more likely to be Black (14% vs. 11%) and more likely to be a current smoker (46.1% vs. 35.5%).

Those with both COPD and insomnia were also more likely to have a service-connected disability rating of 50% of greater; use supplemental oxygen; be divorced, widowed, or separated; have a higher body mass index; or have other medical or psychiatric conditions – in particular obstructive sleep apnea (39% vs. 7%), depression (21% vs. 5%), and PTSD (33% vs. 3%).

P values were < .001 for all of these demographic and clinical variables, Dr. Luyster reported at the meeting.

Comorbid insomnia clearly impacted health care utilization, she said. Veterans with insomnia in addition to COPD had more outpatient and ED visits (10.5 vs 6.9, and 1.6 vs. 1.4, respectively) and more hospitalizations (2.2 vs. 1.8) with a primary diagnostic code for COPD or COPD exacerbation (P < .001).

A negative binomial regression analysis (P < .001) showed that “even after controlling for demographic and other medical conditions, COPD patients with insomnia had greater rates of health care utilization relative to COPD patients without insomnia,” Dr. Luyster said in the interview.

Prior studies have suggested that disturbed sleep is a predictor of poorer longitudinal outcomes in COPD, even after controlling for COPD severity, but have not looked specifically at insomnia, she said.

Commenting on the study Octavian C. Ioachimescu, MD, PhD, of Emory University, Atlanta, and the Atlanta VA Medical Center in Decatur, said the criteria used to define insomnia – unadjudicated ICD diagnoses as well as sedative-hypnotic prescriptions – may explain part of the reported prevalence of insomnia. Even so, the findings add to existing literature demonstrating that COPD and insomnia are both common disorders among VHA patients, and that their frequent coexistence “could have adverse consequences on the overall health, functional status, long-term outcomes, and quality of life of these patients.”

Questions of causation are yet to be answered, he said. “Is it that uncontrolled or severe airflow obstruction causing frequent nocturnal arousals, dyspnea, orthopnea, overuse of inhaled sympathomimetics and heightened anxiety leads to insomnia? Or is it that insomnia – possibly in a cluster with other affective disorders such as depression, anxiety disorders, or PTSD – elicits more frequent or more severe symptoms of shortness of breath in those with smoking-induced airway and parenchymal lung disease, making the latter diagnosis more overt than in others?

“My bet is on a bidirectional causal relationship,” said Dr. Ioachimescu, an editorial board advisor of CHEST Physician.

“Regardless of the etiology [of insomnia in veterans with COPD],” Dr. Luyster said, “it’s important that [insomnia] be addressed and treated appropriately, whether that be through pharmacological treatment, or probably more ideally through [cognitive behavioral therapy] for insomnia.”

The study did not control for COPD severity, she said, because of the difficulty of extracting this data from the VA Corporate Data Warehouse. The study was funded by the VA Competitive Career Development Fund.Dr. Luyster reported that she had no disclosures. Dr. Ioachimescu also said he had no relevant disclosures.
 

Insomnia is “highly prevalent” in veterans with chronic pulmonary obstructive disease and is significantly associated with greater COPD-related health care utilization, according to an analysis of national Veterans Health Administration data.

“The study highlights the importance of exploring potential sleep disturbances and disorders in this population and suggests that a targeted treatment for insomnia may help to improve COPD outcomes in veterans with COPD and insomnia,” said Faith Luyster, PhD, assistant professor at the University of Pittsburgh, in an interview after the virtual annual meeting of the Associated Professional Sleep Societies, where she presented the findings.

Dr. Luyster and coinvestigators used an administrative database from the Veterans Affairs Corporate Data Warehouse to identify more than 1.5 million patients with COPD who used VHA services over a 6-year period (fiscal years 2011-2017). Insomnia was defined by ICD-9/10 diagnostic codes and/or a sedative-hypnotic prescription for at least 30 doses during any of these years.

Insomnia with COPD was prevalent in this sample of veterans at 37.3%. Compared with veterans without comorbid insomnia, those who had both COPD and insomnia (575,539 of the total 1,542,642) were older (69 vs. 64 years), more likely to be female (6.3% vs. 3.7%), more likely to be Black (14% vs. 11%) and more likely to be a current smoker (46.1% vs. 35.5%).

Those with both COPD and insomnia were also more likely to have a service-connected disability rating of 50% of greater; use supplemental oxygen; be divorced, widowed, or separated; have a higher body mass index; or have other medical or psychiatric conditions – in particular obstructive sleep apnea (39% vs. 7%), depression (21% vs. 5%), and PTSD (33% vs. 3%).

P values were < .001 for all of these demographic and clinical variables, Dr. Luyster reported at the meeting.

Comorbid insomnia clearly impacted health care utilization, she said. Veterans with insomnia in addition to COPD had more outpatient and ED visits (10.5 vs 6.9, and 1.6 vs. 1.4, respectively) and more hospitalizations (2.2 vs. 1.8) with a primary diagnostic code for COPD or COPD exacerbation (P < .001).

A negative binomial regression analysis (P < .001) showed that “even after controlling for demographic and other medical conditions, COPD patients with insomnia had greater rates of health care utilization relative to COPD patients without insomnia,” Dr. Luyster said in the interview.

Prior studies have suggested that disturbed sleep is a predictor of poorer longitudinal outcomes in COPD, even after controlling for COPD severity, but have not looked specifically at insomnia, she said.

Commenting on the study Octavian C. Ioachimescu, MD, PhD, of Emory University, Atlanta, and the Atlanta VA Medical Center in Decatur, said the criteria used to define insomnia – unadjudicated ICD diagnoses as well as sedative-hypnotic prescriptions – may explain part of the reported prevalence of insomnia. Even so, the findings add to existing literature demonstrating that COPD and insomnia are both common disorders among VHA patients, and that their frequent coexistence “could have adverse consequences on the overall health, functional status, long-term outcomes, and quality of life of these patients.”

Questions of causation are yet to be answered, he said. “Is it that uncontrolled or severe airflow obstruction causing frequent nocturnal arousals, dyspnea, orthopnea, overuse of inhaled sympathomimetics and heightened anxiety leads to insomnia? Or is it that insomnia – possibly in a cluster with other affective disorders such as depression, anxiety disorders, or PTSD – elicits more frequent or more severe symptoms of shortness of breath in those with smoking-induced airway and parenchymal lung disease, making the latter diagnosis more overt than in others?

“My bet is on a bidirectional causal relationship,” said Dr. Ioachimescu, an editorial board advisor of CHEST Physician.

“Regardless of the etiology [of insomnia in veterans with COPD],” Dr. Luyster said, “it’s important that [insomnia] be addressed and treated appropriately, whether that be through pharmacological treatment, or probably more ideally through [cognitive behavioral therapy] for insomnia.”

The study did not control for COPD severity, she said, because of the difficulty of extracting this data from the VA Corporate Data Warehouse. The study was funded by the VA Competitive Career Development Fund.Dr. Luyster reported that she had no disclosures. Dr. Ioachimescu also said he had no relevant disclosures.
 

Insomnia is “highly prevalent” in veterans with chronic pulmonary obstructive disease and is significantly associated with greater COPD-related health care utilization, according to an analysis of national Veterans Health Administration data.

“The study highlights the importance of exploring potential sleep disturbances and disorders in this population and suggests that a targeted treatment for insomnia may help to improve COPD outcomes in veterans with COPD and insomnia,” said Faith Luyster, PhD, assistant professor at the University of Pittsburgh, in an interview after the virtual annual meeting of the Associated Professional Sleep Societies, where she presented the findings.

Dr. Luyster and coinvestigators used an administrative database from the Veterans Affairs Corporate Data Warehouse to identify more than 1.5 million patients with COPD who used VHA services over a 6-year period (fiscal years 2011-2017). Insomnia was defined by ICD-9/10 diagnostic codes and/or a sedative-hypnotic prescription for at least 30 doses during any of these years.

Insomnia with COPD was prevalent in this sample of veterans at 37.3%. Compared with veterans without comorbid insomnia, those who had both COPD and insomnia (575,539 of the total 1,542,642) were older (69 vs. 64 years), more likely to be female (6.3% vs. 3.7%), more likely to be Black (14% vs. 11%) and more likely to be a current smoker (46.1% vs. 35.5%).

Those with both COPD and insomnia were also more likely to have a service-connected disability rating of 50% of greater; use supplemental oxygen; be divorced, widowed, or separated; have a higher body mass index; or have other medical or psychiatric conditions – in particular obstructive sleep apnea (39% vs. 7%), depression (21% vs. 5%), and PTSD (33% vs. 3%).

P values were < .001 for all of these demographic and clinical variables, Dr. Luyster reported at the meeting.

Comorbid insomnia clearly impacted health care utilization, she said. Veterans with insomnia in addition to COPD had more outpatient and ED visits (10.5 vs 6.9, and 1.6 vs. 1.4, respectively) and more hospitalizations (2.2 vs. 1.8) with a primary diagnostic code for COPD or COPD exacerbation (P < .001).

A negative binomial regression analysis (P < .001) showed that “even after controlling for demographic and other medical conditions, COPD patients with insomnia had greater rates of health care utilization relative to COPD patients without insomnia,” Dr. Luyster said in the interview.

Prior studies have suggested that disturbed sleep is a predictor of poorer longitudinal outcomes in COPD, even after controlling for COPD severity, but have not looked specifically at insomnia, she said.

Commenting on the study Octavian C. Ioachimescu, MD, PhD, of Emory University, Atlanta, and the Atlanta VA Medical Center in Decatur, said the criteria used to define insomnia – unadjudicated ICD diagnoses as well as sedative-hypnotic prescriptions – may explain part of the reported prevalence of insomnia. Even so, the findings add to existing literature demonstrating that COPD and insomnia are both common disorders among VHA patients, and that their frequent coexistence “could have adverse consequences on the overall health, functional status, long-term outcomes, and quality of life of these patients.”

Questions of causation are yet to be answered, he said. “Is it that uncontrolled or severe airflow obstruction causing frequent nocturnal arousals, dyspnea, orthopnea, overuse of inhaled sympathomimetics and heightened anxiety leads to insomnia? Or is it that insomnia – possibly in a cluster with other affective disorders such as depression, anxiety disorders, or PTSD – elicits more frequent or more severe symptoms of shortness of breath in those with smoking-induced airway and parenchymal lung disease, making the latter diagnosis more overt than in others?

“My bet is on a bidirectional causal relationship,” said Dr. Ioachimescu, an editorial board advisor of CHEST Physician.

“Regardless of the etiology [of insomnia in veterans with COPD],” Dr. Luyster said, “it’s important that [insomnia] be addressed and treated appropriately, whether that be through pharmacological treatment, or probably more ideally through [cognitive behavioral therapy] for insomnia.”

The study did not control for COPD severity, she said, because of the difficulty of extracting this data from the VA Corporate Data Warehouse. The study was funded by the VA Competitive Career Development Fund.Dr. Luyster reported that she had no disclosures. Dr. Ioachimescu also said he had no relevant disclosures.