Key clinical point: Upadacitinib demonstrated superior efficacy over dupilumab for treatment of adults with moderate-to-severe atopic dermatitis (AD) with no new safety signals identified.

Major finding: At week 16, a higher proportion of patients achieved 75% improvement in Eczema Area and Severity Index with upadacitinib vs dupilumab (71.0% vs 61.1%; P = .006). Rates of serious treatment-emergent adverse events leading to drug discontinuation in upadacitinib vs dupilumab were 2.9% vs 1.2%, with no new safety risks observed for upadacitinib.

Study details: Findings are 24-week results of Heads up, a phase 3b trial including 692 adults with moderate-to-severe AD who were randomly assigned to receive oral upadacitinib, 30 mg once daily, or subcutaneous dupilumab, 300 mg every alternate week.

Disclosures: This study was funded by AbbVie. The authors declared serving as speaker, consultant, scientific advisor, clinical study investigator, and/or receiving personal fees and grants from various sources including AbbVie. Four authors declared being employees and/or shareholders of AbbVie.

Source: Blauvelt A et al. JAMA Dermatol. 2021 Aug 4. doi: 10.1001/jamadermatol.2021.3023.

Key clinical point: Upadacitinib demonstrated superior efficacy over dupilumab for treatment of adults with moderate-to-severe atopic dermatitis (AD) with no new safety signals identified.

Major finding: At week 16, a higher proportion of patients achieved 75% improvement in Eczema Area and Severity Index with upadacitinib vs dupilumab (71.0% vs 61.1%; P = .006). Rates of serious treatment-emergent adverse events leading to drug discontinuation in upadacitinib vs dupilumab were 2.9% vs 1.2%, with no new safety risks observed for upadacitinib.

Study details: Findings are 24-week results of Heads up, a phase 3b trial including 692 adults with moderate-to-severe AD who were randomly assigned to receive oral upadacitinib, 30 mg once daily, or subcutaneous dupilumab, 300 mg every alternate week.

Disclosures: This study was funded by AbbVie. The authors declared serving as speaker, consultant, scientific advisor, clinical study investigator, and/or receiving personal fees and grants from various sources including AbbVie. Four authors declared being employees and/or shareholders of AbbVie.

Source: Blauvelt A et al. JAMA Dermatol. 2021 Aug 4. doi: 10.1001/jamadermatol.2021.3023.

Key clinical point: Upadacitinib demonstrated superior efficacy over dupilumab for treatment of adults with moderate-to-severe atopic dermatitis (AD) with no new safety signals identified.

Major finding: At week 16, a higher proportion of patients achieved 75% improvement in Eczema Area and Severity Index with upadacitinib vs dupilumab (71.0% vs 61.1%; P = .006). Rates of serious treatment-emergent adverse events leading to drug discontinuation in upadacitinib vs dupilumab were 2.9% vs 1.2%, with no new safety risks observed for upadacitinib.

Study details: Findings are 24-week results of Heads up, a phase 3b trial including 692 adults with moderate-to-severe AD who were randomly assigned to receive oral upadacitinib, 30 mg once daily, or subcutaneous dupilumab, 300 mg every alternate week.

Disclosures: This study was funded by AbbVie. The authors declared serving as speaker, consultant, scientific advisor, clinical study investigator, and/or receiving personal fees and grants from various sources including AbbVie. Four authors declared being employees and/or shareholders of AbbVie.

Source: Blauvelt A et al. JAMA Dermatol. 2021 Aug 4. doi: 10.1001/jamadermatol.2021.3023.

Alcohol use is a known risk factor for gastrointestinal (GI) cancers. Now, new research indicates that this risk is more associated with frequent drinking – even in smaller amounts – compared with higher amounts or binge drinking, given similar weekly levels.

“The novel finding of the current study is that frequent drinking may be more dangerous than binge drinking with regard to GI cancers. Alcohol use is a known risk factor for gastrointestinal (GI) cancers. Now, new research indicates that this risk is more associated with frequent drinking – even in smaller amounts -- compared with higher amounts or binge drinking, given similar weekly levels.” first author Jung Eun Yook, MD, of Seoul (South Korea) National University Hospital, and colleagues reported in an article published Aug. 18, 2021, in JAMA Network Open (doi: 10.1001/jamanetworkopen.2021.20382).

“This finding suggests that repeated alcohol consumption events even at lower amounts of alcohol may have a greater carcinogenic effect on GI organs than the consumption of larger amounts of alcohol at a lower frequency,” the investigators wrote.

A possible reason behind the difference in risk may be that the chronic “carcinogenic insult” from regular alcohol use may promote cancer development, whereas less frequent, episodic alcohol exposures may allow physiologic recovery, said the authors.

The results are from a population-based study that involved 11,737,467 participants in the Korean National Health System database who did not have cancer and who took part in a national screening program between January 2009 and December 2010.

They were followed from the year after their screening until either they had received a diagnosis of a GI cancer, death occurred, or the end of December 2017.

During a median follow-up of 6.4 years, 319,202 (2.7%) of those in the study developed a GI cancer.

The increase in the risk associated with alcohol consumption was dose dependent.

Compared with those who did not consume alcohol, the risk of developing GI cancer was higher for mild drinkers (adjusted hazard ratio, 1.04; 95% confidence interval, 1.03-1.05), moderate drinkers (aHR, 1.14; 95% CI, 1.12-1.15), and heavy drinkers (aHR, 1.28; 95% CI, 1.26-1.29), after adjusting for age, sex, income, smoking status with intensity, regular exercise, body mass index, diabetes, hypertension, and dyslipidemia.

There was a linear association between the frequency of drinking and GI cancer risk, with an aHR of 1.39 for individuals who reported drinking every day (95% CI, 1.36-1.41). The risk for GI cancer increased with consumption of five to seven units per occasion (aHR, 1.15). Notably, there were no similar increases with higher intake, including intake of 8-14 units per occasion (aHR, 1.11; 95% CI, 1.09-1.12), and even up to more than 14 units per occasion (aHR, 1.11; 95%CI, 1.08-1.14), in comparison with an intake of 5-7 units per occasion.

“Given similar weekly alcohol consumption levels, the risk of GI cancer increased with a higher frequency of drinking and decreased with a higher amount per occasion,” the authors write.

“Most previous studies just assess alcohol consumption as a total amount, [such as] drinks per occasion times occasion per week equals drinks per week [and] grams per week,” coauthor Dong Wook Shin, MD, DrPH, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, said in an interview.

“But it was not known whether frequent drinking with small amount is more harmful than binge drinking, given a similar level of total drinking,” Dr. Shin said.

The increased risk associated with frequent drinking was generally similar with respect to esophageal, gastric, colorectal, biliary, and pancreatic cancer.

An exception was liver cancer, which showed a slightly decreased risk among mild drinkers (aHR, 0.91; 95% CI, 0.89-0.93).

Of note, the association between alcohol intake and the incidence of GI cancer was lower among women than men in terms of weekly consumption, frequency, and amount of alcohol consumed per occasion.

The associations between drinking and cancer type in terms of esophageal and liver cancers were similar between men and women. However, the alcohol-related risk for colorectal, biliary, and pancreatic cancers was less prominent for women.

Possible mechanisms related to regular drinking

A factor that might account for the increase in GI cancer risk with frequent drinking is that regular alcohol consumption “promotes the accumulation of cell divisions in the stem cells that maintain tissues in homeostasis,” the authors explained.

Another possible explanation is that long-term alcohol exposure may promote carcinogenesis, whereas less frequent exposure might allow “physiological homeostasis,” the authors wrote, adding that in vivo experiments have shown that duration and dose of alcohol exposure have been linked to cancer development.

Importantly, the findings support the importance of reducing the frequency of alcohol use to prevent cancer, the authors noted.

“Alcohol users who have a glass of wine or beer during dinner every day may develop more cancer than people who occasionally consume several drinks,” they cautioned.
 

Genetics, self-reporting considerations

In a related commentary, John D. Potter, MBBS, PhD, of the Research Center for Hauora and Health, Massey University, Wellington, New Zealand, noted that, in addition to supporting the known link between alcohol and cancers of the esophagus, colorectum, and liver, the study “strengthens evidence for a role of alcohol in stomach, biliary tract, and pancreas cancers.”

In comparison with nondrinkers, those who reported heavy drinking were much more likely to be smokers (51.6% vs. 9.0%); however, the study adjusted for smoking.

“Because the researchers were able to control for tobacco, this last finding [regarding the association with cancers of the stomach, biliary tract, and pancreas] is particularly informative,” Dr. Potter noted.

An important caveat is that more than a quarter of the Korean population is known to have an inactive form of the aldehyde dehydrogenase gene (ALDH2), which could have effects on alcohol metabolism as well as the risk for cancer, Dr. Potter wrote.

“This common polymorphism in ALDH2 (ALDH2 rs671 [c.1510G>A (Glu504Lys)]) has paradoxical effects,” he wrote.

“It increases the level of acetaldehyde in the blood of drinkers, which in turn increases the risk of cancer because acetaldehyde is a key player in the carcinogenicity of alcoholic beverages,” Dr. Potter explained. “On the other hand, the accumulation of acetaldehyde and the resultant flushing response are sufficiently unpleasant that they tend to reduce alcohol consumption among those with the Lys allele.”

The study results may therefore not be generalizable to a population in which the distribution of the variation in the ALDH2 enzyme differs, Dr. Potter added.

The lower prevalence of the inactive form (in North America, for instance) would mean that this lower prevalence was not a constraint on individuals’ drinking behavior as it is for some in Korea, Dr. Potter explained.

He noted another consideration: the underreporting of alcohol use is a well-known limitation of studies involving the assessment of alcohol consumption.

Dr. Shin agreed that underreporting is a limitation.

“People tend to underestimate their alcohol use,” Dr. Shin said in an interview.

However, he noted that “our study participants are health-screening participants aged 40 years and older, [and] people who participate in health screening tend to have higher awareness and better health behavior than nonparticipants.”

The authors and Dr. Potter disclosed no relevant financial relationships.

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

Alcohol use is a known risk factor for gastrointestinal (GI) cancers. Now, new research indicates that this risk is more associated with frequent drinking – even in smaller amounts – compared with higher amounts or binge drinking, given similar weekly levels.

“The novel finding of the current study is that frequent drinking may be more dangerous than binge drinking with regard to GI cancers. Alcohol use is a known risk factor for gastrointestinal (GI) cancers. Now, new research indicates that this risk is more associated with frequent drinking – even in smaller amounts -- compared with higher amounts or binge drinking, given similar weekly levels.” first author Jung Eun Yook, MD, of Seoul (South Korea) National University Hospital, and colleagues reported in an article published Aug. 18, 2021, in JAMA Network Open (doi: 10.1001/jamanetworkopen.2021.20382).

“This finding suggests that repeated alcohol consumption events even at lower amounts of alcohol may have a greater carcinogenic effect on GI organs than the consumption of larger amounts of alcohol at a lower frequency,” the investigators wrote.

A possible reason behind the difference in risk may be that the chronic “carcinogenic insult” from regular alcohol use may promote cancer development, whereas less frequent, episodic alcohol exposures may allow physiologic recovery, said the authors.

The results are from a population-based study that involved 11,737,467 participants in the Korean National Health System database who did not have cancer and who took part in a national screening program between January 2009 and December 2010.

They were followed from the year after their screening until either they had received a diagnosis of a GI cancer, death occurred, or the end of December 2017.

During a median follow-up of 6.4 years, 319,202 (2.7%) of those in the study developed a GI cancer.

The increase in the risk associated with alcohol consumption was dose dependent.

Compared with those who did not consume alcohol, the risk of developing GI cancer was higher for mild drinkers (adjusted hazard ratio, 1.04; 95% confidence interval, 1.03-1.05), moderate drinkers (aHR, 1.14; 95% CI, 1.12-1.15), and heavy drinkers (aHR, 1.28; 95% CI, 1.26-1.29), after adjusting for age, sex, income, smoking status with intensity, regular exercise, body mass index, diabetes, hypertension, and dyslipidemia.

There was a linear association between the frequency of drinking and GI cancer risk, with an aHR of 1.39 for individuals who reported drinking every day (95% CI, 1.36-1.41). The risk for GI cancer increased with consumption of five to seven units per occasion (aHR, 1.15). Notably, there were no similar increases with higher intake, including intake of 8-14 units per occasion (aHR, 1.11; 95% CI, 1.09-1.12), and even up to more than 14 units per occasion (aHR, 1.11; 95%CI, 1.08-1.14), in comparison with an intake of 5-7 units per occasion.

“Given similar weekly alcohol consumption levels, the risk of GI cancer increased with a higher frequency of drinking and decreased with a higher amount per occasion,” the authors write.

“Most previous studies just assess alcohol consumption as a total amount, [such as] drinks per occasion times occasion per week equals drinks per week [and] grams per week,” coauthor Dong Wook Shin, MD, DrPH, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, said in an interview.

“But it was not known whether frequent drinking with small amount is more harmful than binge drinking, given a similar level of total drinking,” Dr. Shin said.

The increased risk associated with frequent drinking was generally similar with respect to esophageal, gastric, colorectal, biliary, and pancreatic cancer.

An exception was liver cancer, which showed a slightly decreased risk among mild drinkers (aHR, 0.91; 95% CI, 0.89-0.93).

Of note, the association between alcohol intake and the incidence of GI cancer was lower among women than men in terms of weekly consumption, frequency, and amount of alcohol consumed per occasion.

The associations between drinking and cancer type in terms of esophageal and liver cancers were similar between men and women. However, the alcohol-related risk for colorectal, biliary, and pancreatic cancers was less prominent for women.

Possible mechanisms related to regular drinking

A factor that might account for the increase in GI cancer risk with frequent drinking is that regular alcohol consumption “promotes the accumulation of cell divisions in the stem cells that maintain tissues in homeostasis,” the authors explained.

Another possible explanation is that long-term alcohol exposure may promote carcinogenesis, whereas less frequent exposure might allow “physiological homeostasis,” the authors wrote, adding that in vivo experiments have shown that duration and dose of alcohol exposure have been linked to cancer development.

Importantly, the findings support the importance of reducing the frequency of alcohol use to prevent cancer, the authors noted.

“Alcohol users who have a glass of wine or beer during dinner every day may develop more cancer than people who occasionally consume several drinks,” they cautioned.
 

Genetics, self-reporting considerations

In a related commentary, John D. Potter, MBBS, PhD, of the Research Center for Hauora and Health, Massey University, Wellington, New Zealand, noted that, in addition to supporting the known link between alcohol and cancers of the esophagus, colorectum, and liver, the study “strengthens evidence for a role of alcohol in stomach, biliary tract, and pancreas cancers.”

In comparison with nondrinkers, those who reported heavy drinking were much more likely to be smokers (51.6% vs. 9.0%); however, the study adjusted for smoking.

“Because the researchers were able to control for tobacco, this last finding [regarding the association with cancers of the stomach, biliary tract, and pancreas] is particularly informative,” Dr. Potter noted.

An important caveat is that more than a quarter of the Korean population is known to have an inactive form of the aldehyde dehydrogenase gene (ALDH2), which could have effects on alcohol metabolism as well as the risk for cancer, Dr. Potter wrote.

“This common polymorphism in ALDH2 (ALDH2 rs671 [c.1510G>A (Glu504Lys)]) has paradoxical effects,” he wrote.

“It increases the level of acetaldehyde in the blood of drinkers, which in turn increases the risk of cancer because acetaldehyde is a key player in the carcinogenicity of alcoholic beverages,” Dr. Potter explained. “On the other hand, the accumulation of acetaldehyde and the resultant flushing response are sufficiently unpleasant that they tend to reduce alcohol consumption among those with the Lys allele.”

The study results may therefore not be generalizable to a population in which the distribution of the variation in the ALDH2 enzyme differs, Dr. Potter added.

The lower prevalence of the inactive form (in North America, for instance) would mean that this lower prevalence was not a constraint on individuals’ drinking behavior as it is for some in Korea, Dr. Potter explained.

He noted another consideration: the underreporting of alcohol use is a well-known limitation of studies involving the assessment of alcohol consumption.

Dr. Shin agreed that underreporting is a limitation.

“People tend to underestimate their alcohol use,” Dr. Shin said in an interview.

However, he noted that “our study participants are health-screening participants aged 40 years and older, [and] people who participate in health screening tend to have higher awareness and better health behavior than nonparticipants.”

The authors and Dr. Potter disclosed no relevant financial relationships.

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

Alcohol use is a known risk factor for gastrointestinal (GI) cancers. Now, new research indicates that this risk is more associated with frequent drinking – even in smaller amounts – compared with higher amounts or binge drinking, given similar weekly levels.

“The novel finding of the current study is that frequent drinking may be more dangerous than binge drinking with regard to GI cancers. Alcohol use is a known risk factor for gastrointestinal (GI) cancers. Now, new research indicates that this risk is more associated with frequent drinking – even in smaller amounts -- compared with higher amounts or binge drinking, given similar weekly levels.” first author Jung Eun Yook, MD, of Seoul (South Korea) National University Hospital, and colleagues reported in an article published Aug. 18, 2021, in JAMA Network Open (doi: 10.1001/jamanetworkopen.2021.20382).

“This finding suggests that repeated alcohol consumption events even at lower amounts of alcohol may have a greater carcinogenic effect on GI organs than the consumption of larger amounts of alcohol at a lower frequency,” the investigators wrote.

A possible reason behind the difference in risk may be that the chronic “carcinogenic insult” from regular alcohol use may promote cancer development, whereas less frequent, episodic alcohol exposures may allow physiologic recovery, said the authors.

The results are from a population-based study that involved 11,737,467 participants in the Korean National Health System database who did not have cancer and who took part in a national screening program between January 2009 and December 2010.

They were followed from the year after their screening until either they had received a diagnosis of a GI cancer, death occurred, or the end of December 2017.

During a median follow-up of 6.4 years, 319,202 (2.7%) of those in the study developed a GI cancer.

The increase in the risk associated with alcohol consumption was dose dependent.

Compared with those who did not consume alcohol, the risk of developing GI cancer was higher for mild drinkers (adjusted hazard ratio, 1.04; 95% confidence interval, 1.03-1.05), moderate drinkers (aHR, 1.14; 95% CI, 1.12-1.15), and heavy drinkers (aHR, 1.28; 95% CI, 1.26-1.29), after adjusting for age, sex, income, smoking status with intensity, regular exercise, body mass index, diabetes, hypertension, and dyslipidemia.

There was a linear association between the frequency of drinking and GI cancer risk, with an aHR of 1.39 for individuals who reported drinking every day (95% CI, 1.36-1.41). The risk for GI cancer increased with consumption of five to seven units per occasion (aHR, 1.15). Notably, there were no similar increases with higher intake, including intake of 8-14 units per occasion (aHR, 1.11; 95% CI, 1.09-1.12), and even up to more than 14 units per occasion (aHR, 1.11; 95%CI, 1.08-1.14), in comparison with an intake of 5-7 units per occasion.

“Given similar weekly alcohol consumption levels, the risk of GI cancer increased with a higher frequency of drinking and decreased with a higher amount per occasion,” the authors write.

“Most previous studies just assess alcohol consumption as a total amount, [such as] drinks per occasion times occasion per week equals drinks per week [and] grams per week,” coauthor Dong Wook Shin, MD, DrPH, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, said in an interview.

“But it was not known whether frequent drinking with small amount is more harmful than binge drinking, given a similar level of total drinking,” Dr. Shin said.

The increased risk associated with frequent drinking was generally similar with respect to esophageal, gastric, colorectal, biliary, and pancreatic cancer.

An exception was liver cancer, which showed a slightly decreased risk among mild drinkers (aHR, 0.91; 95% CI, 0.89-0.93).

Of note, the association between alcohol intake and the incidence of GI cancer was lower among women than men in terms of weekly consumption, frequency, and amount of alcohol consumed per occasion.

The associations between drinking and cancer type in terms of esophageal and liver cancers were similar between men and women. However, the alcohol-related risk for colorectal, biliary, and pancreatic cancers was less prominent for women.

Possible mechanisms related to regular drinking

A factor that might account for the increase in GI cancer risk with frequent drinking is that regular alcohol consumption “promotes the accumulation of cell divisions in the stem cells that maintain tissues in homeostasis,” the authors explained.

Another possible explanation is that long-term alcohol exposure may promote carcinogenesis, whereas less frequent exposure might allow “physiological homeostasis,” the authors wrote, adding that in vivo experiments have shown that duration and dose of alcohol exposure have been linked to cancer development.

Importantly, the findings support the importance of reducing the frequency of alcohol use to prevent cancer, the authors noted.

“Alcohol users who have a glass of wine or beer during dinner every day may develop more cancer than people who occasionally consume several drinks,” they cautioned.
 

Genetics, self-reporting considerations

In a related commentary, John D. Potter, MBBS, PhD, of the Research Center for Hauora and Health, Massey University, Wellington, New Zealand, noted that, in addition to supporting the known link between alcohol and cancers of the esophagus, colorectum, and liver, the study “strengthens evidence for a role of alcohol in stomach, biliary tract, and pancreas cancers.”

In comparison with nondrinkers, those who reported heavy drinking were much more likely to be smokers (51.6% vs. 9.0%); however, the study adjusted for smoking.

“Because the researchers were able to control for tobacco, this last finding [regarding the association with cancers of the stomach, biliary tract, and pancreas] is particularly informative,” Dr. Potter noted.

An important caveat is that more than a quarter of the Korean population is known to have an inactive form of the aldehyde dehydrogenase gene (ALDH2), which could have effects on alcohol metabolism as well as the risk for cancer, Dr. Potter wrote.

“This common polymorphism in ALDH2 (ALDH2 rs671 [c.1510G>A (Glu504Lys)]) has paradoxical effects,” he wrote.

“It increases the level of acetaldehyde in the blood of drinkers, which in turn increases the risk of cancer because acetaldehyde is a key player in the carcinogenicity of alcoholic beverages,” Dr. Potter explained. “On the other hand, the accumulation of acetaldehyde and the resultant flushing response are sufficiently unpleasant that they tend to reduce alcohol consumption among those with the Lys allele.”

The study results may therefore not be generalizable to a population in which the distribution of the variation in the ALDH2 enzyme differs, Dr. Potter added.

The lower prevalence of the inactive form (in North America, for instance) would mean that this lower prevalence was not a constraint on individuals’ drinking behavior as it is for some in Korea, Dr. Potter explained.

He noted another consideration: the underreporting of alcohol use is a well-known limitation of studies involving the assessment of alcohol consumption.

Dr. Shin agreed that underreporting is a limitation.

“People tend to underestimate their alcohol use,” Dr. Shin said in an interview.

However, he noted that “our study participants are health-screening participants aged 40 years and older, [and] people who participate in health screening tend to have higher awareness and better health behavior than nonparticipants.”

The authors and Dr. Potter disclosed no relevant financial relationships.

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

Eight months after a psychology journal retracted a pair of articles that were “unethical, scientifically flawed, and based on racist ideas and agenda,” the publication has pulled three more papers – all at least a quarter century old – for the same reason.

All five papers were written by J. Philippe Rushton, formerly of the University of Western Ontario, who died in 2012. As we wrote in December 2020, Rushton published dubious studies that promoted tropes of white supremacy, including that Blacks are less intelligent than Whites and that:

East Asians and their descendants average a larger brain size, greater intelligence, more sexual restraint, slower rates of maturation, and greater law abidingness and social organization than do Europeans and their descendants, who average higher scores on these dimensions than Africans and their descendants.

Here’s the new notice, whose language mirrors that of the earlier retraction statement:

The following articles have been retracted from Psychological Reports:

Rushton, J. P. (1987). An Evolutionary Theory of Health, Longevity, and Personality: Sociobiology and r/K Reproductive Strategies . Psychological Reports, 60, 539-49.

Rushton, J. P. (1992). Contributions to the History of Psychology: XC. Evolutionary Biology and Heritable Traits (with Reference to Oriental-White-Black Differences): The 1989 AAAS Paper . Psychological Reports, 71, 811-21.

Rushton, J. P. (1995). Race and Crime: International Data 1989-1990 . Psychological Reports, 76, 207-312.

This retraction is following a review that found that the research was unethical, scientifically flawed, and based on racist ideas and agenda. Specifically, these publications authored by Philippe Rushton on the subject of intelligence and race have been rejected based on the following findings:

A better understanding of the human genome (Yudell et al., 2016)

An inappropriately applied ecological theory that explains differences between species’ reproductive strategies to humans (Allen et al., 1992 ; Anderson, 1991)

A misuse of population genetic measures and misconceptions about heritability (Bailey, 1997)

Ignoring alternative explanations or evidence that did not support the racist theories being presented (Cain & Vanderwolf, 1990)

Rushton’s findings have not been replicated (Peregrine, Ember, & Ember, 2003)

Together, the papers have been cited 48 times, according to Clarivate Analytics’ Web of Science. At the time of this writing, none of the original abstracts include a link to the retraction notice.

When we wrote about the Rushton case last year, we received a copy of an email from the journal saying that it would be retracting Rushton’s 1992 paper, “Contributions to the History of Psychology: XC. Evolutionary Biology and Heritable Traits” along with the other two articles. That didn’t happen at the time.

We asked Cory Scherer, the editor of Psychological Reports, about the eight-month gap between retractions. He told us:

I got an email from a researcher who brought these articles to our attention and when I read them I moved fast on the first retraction and the rest were found when that retraction was already written and in press. I didn’t want to add them to the original retraction until I did my due diligence about the second set found.

Our search of the journal’s website turned up eight articles in total by Rushton in the journal, of which three remain unretracted. Mr. Scherer said he has created a committee to review the remnant papers to see if they require retraction.

Eight months after a psychology journal retracted a pair of articles that were “unethical, scientifically flawed, and based on racist ideas and agenda,” the publication has pulled three more papers – all at least a quarter century old – for the same reason.

All five papers were written by J. Philippe Rushton, formerly of the University of Western Ontario, who died in 2012. As we wrote in December 2020, Rushton published dubious studies that promoted tropes of white supremacy, including that Blacks are less intelligent than Whites and that:

East Asians and their descendants average a larger brain size, greater intelligence, more sexual restraint, slower rates of maturation, and greater law abidingness and social organization than do Europeans and their descendants, who average higher scores on these dimensions than Africans and their descendants.

Here’s the new notice, whose language mirrors that of the earlier retraction statement:

The following articles have been retracted from Psychological Reports:

Rushton, J. P. (1987). An Evolutionary Theory of Health, Longevity, and Personality: Sociobiology and r/K Reproductive Strategies . Psychological Reports, 60, 539-49.

Rushton, J. P. (1992). Contributions to the History of Psychology: XC. Evolutionary Biology and Heritable Traits (with Reference to Oriental-White-Black Differences): The 1989 AAAS Paper . Psychological Reports, 71, 811-21.

Rushton, J. P. (1995). Race and Crime: International Data 1989-1990 . Psychological Reports, 76, 207-312.

This retraction is following a review that found that the research was unethical, scientifically flawed, and based on racist ideas and agenda. Specifically, these publications authored by Philippe Rushton on the subject of intelligence and race have been rejected based on the following findings:

A better understanding of the human genome (Yudell et al., 2016)

An inappropriately applied ecological theory that explains differences between species’ reproductive strategies to humans (Allen et al., 1992 ; Anderson, 1991)

A misuse of population genetic measures and misconceptions about heritability (Bailey, 1997)

Ignoring alternative explanations or evidence that did not support the racist theories being presented (Cain & Vanderwolf, 1990)

Rushton’s findings have not been replicated (Peregrine, Ember, & Ember, 2003)

Together, the papers have been cited 48 times, according to Clarivate Analytics’ Web of Science. At the time of this writing, none of the original abstracts include a link to the retraction notice.

When we wrote about the Rushton case last year, we received a copy of an email from the journal saying that it would be retracting Rushton’s 1992 paper, “Contributions to the History of Psychology: XC. Evolutionary Biology and Heritable Traits” along with the other two articles. That didn’t happen at the time.

We asked Cory Scherer, the editor of Psychological Reports, about the eight-month gap between retractions. He told us:

I got an email from a researcher who brought these articles to our attention and when I read them I moved fast on the first retraction and the rest were found when that retraction was already written and in press. I didn’t want to add them to the original retraction until I did my due diligence about the second set found.

Our search of the journal’s website turned up eight articles in total by Rushton in the journal, of which three remain unretracted. Mr. Scherer said he has created a committee to review the remnant papers to see if they require retraction.

Eight months after a psychology journal retracted a pair of articles that were “unethical, scientifically flawed, and based on racist ideas and agenda,” the publication has pulled three more papers – all at least a quarter century old – for the same reason.

All five papers were written by J. Philippe Rushton, formerly of the University of Western Ontario, who died in 2012. As we wrote in December 2020, Rushton published dubious studies that promoted tropes of white supremacy, including that Blacks are less intelligent than Whites and that:

East Asians and their descendants average a larger brain size, greater intelligence, more sexual restraint, slower rates of maturation, and greater law abidingness and social organization than do Europeans and their descendants, who average higher scores on these dimensions than Africans and their descendants.

Here’s the new notice, whose language mirrors that of the earlier retraction statement:

The following articles have been retracted from Psychological Reports:

Rushton, J. P. (1987). An Evolutionary Theory of Health, Longevity, and Personality: Sociobiology and r/K Reproductive Strategies . Psychological Reports, 60, 539-49.

Rushton, J. P. (1992). Contributions to the History of Psychology: XC. Evolutionary Biology and Heritable Traits (with Reference to Oriental-White-Black Differences): The 1989 AAAS Paper . Psychological Reports, 71, 811-21.

Rushton, J. P. (1995). Race and Crime: International Data 1989-1990 . Psychological Reports, 76, 207-312.

This retraction is following a review that found that the research was unethical, scientifically flawed, and based on racist ideas and agenda. Specifically, these publications authored by Philippe Rushton on the subject of intelligence and race have been rejected based on the following findings:

A better understanding of the human genome (Yudell et al., 2016)

An inappropriately applied ecological theory that explains differences between species’ reproductive strategies to humans (Allen et al., 1992 ; Anderson, 1991)

A misuse of population genetic measures and misconceptions about heritability (Bailey, 1997)

Ignoring alternative explanations or evidence that did not support the racist theories being presented (Cain & Vanderwolf, 1990)

Rushton’s findings have not been replicated (Peregrine, Ember, & Ember, 2003)

Together, the papers have been cited 48 times, according to Clarivate Analytics’ Web of Science. At the time of this writing, none of the original abstracts include a link to the retraction notice.

When we wrote about the Rushton case last year, we received a copy of an email from the journal saying that it would be retracting Rushton’s 1992 paper, “Contributions to the History of Psychology: XC. Evolutionary Biology and Heritable Traits” along with the other two articles. That didn’t happen at the time.

We asked Cory Scherer, the editor of Psychological Reports, about the eight-month gap between retractions. He told us:

I got an email from a researcher who brought these articles to our attention and when I read them I moved fast on the first retraction and the rest were found when that retraction was already written and in press. I didn’t want to add them to the original retraction until I did my due diligence about the second set found.

Our search of the journal’s website turned up eight articles in total by Rushton in the journal, of which three remain unretracted. Mr. Scherer said he has created a committee to review the remnant papers to see if they require retraction.

Due to the high cost of newer chemotherapy agents, institutions search for strategies to minimize drug cost and drug waste. Programmed death-1 (PD-1) inhibitors, nivolumab and pembrolizumab, are commonly used in the treatment of solid tumors; however, the agents cost thousands of dollars per dose. Nivolumab and pembrolizumab were initially approved using weight-based dosing, but package labeling for both agents now includes fixed dosing.^1,2 A combination of these 2 dosing strategies could be used by institutions depending on individual patient’s weight to maximize cost savings, minimize drug waste, and maintain safety and efficacy of PD-1 inhibitors. Irrespective of dosing strategy, the development of immune-related adverse events (IrAEs) has been demonstrated with PD-1 inhibitors as a result of the mechanism of action.

PD-1 expression suppresses T cell activity to prevent the development of autoimmunity; however, this is also a mechanism in which tumor cells can evade the host immune system.^3-5 Binding of PD-1 and programmed death-ligand 1 (PD-L1) suppresses T cell activity, whereas the inhibition of PD-1 and PD-L1 results in T cell activation.^4,5 Increased T cell activity elicits the anticancer effect, but also contributes to the development of IrAEs^.4,5 Hypothyroidism is one of the most common IrAEs, with a reported incidence of 9% with nivolumab therapy and 8.5% with pembrolizumab.^1,2

Data from the US Department of Veterans Affairs (VA) medical centers is stored in the centralized Corporate Data Warehouse (CDW). VA researchers can obtain approval to use CDW data, which allows for large scale retrospective review of veterans who have received care at VA medical centers (VAMCs). This study aimed to describe the PD-1 inhibitor dosing used within VAMCs and identify actual and potential cost savings. Due to the frequency of immunemediated hypothyroidism and objective data that can be obtained from CDW reports, the study estimated the incidence of immune-mediated hypothyroidism within the veteran population as a safety outcome.

Background

The US Food and Drug Administration (FDA) initially approved dosing for IV nivolumab at 3 mg/kg of patient body weight every 2 weeks and for IV pembrolizumab 2 mg/kg of patient body weight every 3 weeks.^1,2 Subsequent pharmacokinetic studies found that these agents have similar exposure and efficacy with fixed doses of nivolumab 240 mg IV every 2 weeks and pembrolizumab 200 mg IV every 3 weeks; in 2016, FDA labeling shifted from weight-based dosing to fixed dosing for most solid tumor indications.^6-9 Depending on patient weight, a combination of weightbased and fixed dosing could be used by institutions to maximize cost-savings opportunities, minimize drug waste, and maintain clinical efficacy with PD-1 inhibitors. For example, a patient initiating nivolumab who weighs 80 kg would receive 240 mg for both weight-based (3 mg/kg x 80 kg = 240 mg) and fixed dosing; therefore, no cost-savings opportunities would be available. However, for a patient who weighs ≤ 73.3 kg, it would be more costeffective to use weight-based dosing vs the fixed dose. Since nivolumab is available in 40- mg, 100-mg, and 240-mg vials with similar unit prices, a combination of vial sizes could be used to minimize drug waste. Alternatively, for a patient who weighs ≥ 86.7 kg, it would be more cost-effective to administer the fixed, 240 mg dose when compared with the weightbased dose. Pembrolizumab is available only in a 100-mg vial; therefore, weight-based dosing may result in drug waste.

IrAEs can be seen with PD-1 inhibitors due to increased T cell activity, which is independent of dosing strategy and can affect any organ system. However, immune-mediated hypothyroidism has been commonly seen with PD-1 inhibitors. For patients with immunemediated hypothyroidism, levothyroxine can be considered for asymptomatic patients with thyroid- stimulating hormone (TSH) > 10 uIU/mL with normal thyroxine (T4), or patients with clinical primary hypothyroidism (TSH > 10 uIU/mL with low free T4 and clinical symptoms). Additionally, since hypothyroidism usually follows immunotherapy induced thyrotoxicosis, thyroid function tests should be monitored and levothyroxine initiated if TSH is > 10 uIU/mL for these patients.^10,11

Hypothyroidism also can be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events. Hypothyroidism is considered grade 1 when hypothyroidism is demonstrated through clinical or diagnostic observations only and the patient is asymptomatic and no intervention needed. Grade 2 occurs when the patient is symptomatic and limits instrumental activities of daily living (ADLs), prompting thyroid replacement therapy. In grade 3, patients experience severe symptoms that restrict self-care ADLs, and hospitalization is indicated. Grade 4 has life-threatening consequences, and urgent intervention is indicated. Grade 5 results in the death of the patient.¹²

Electronic health records (EHRs) of veterans who receive care at a VAMC are stored in CDW and available through the VA Informatics and Computing Infrastructure (VINCI), which provides access to data while ensuring veterans’ privacy and data security. This feature of the VA EHR allows for analysis of data across the VA health care system, and larger data sets can be used for retrospective chart reviews.

Using reports from CDW, the primary objective of this study was to describe the dosing strategy used for PD-1 inhibitors, and the primary safety outcome was to determine the incidence of immune-mediated hypothyroidism. The secondary objective was to estimate potential cost-savings opportunities using a combination of PD-1 inhibitor dosing strategies.

Methods

This was a retrospective study including data stored in CDW. The study was approved by the Durham VA Health Care System Institutional Review Board and VINCI/Data Access request tracker. Data were limited to nivolumab and pembrolizumab because they received earlier FDA approval, had multiple solid tumor indications, and 2 FDA-approved dosing strategies. The incidence of IrAEs was limited to hypothyroidism, which could be objectively verified with laboratory monitoring of thyroid function tests, including TSH, free or total T4, and triiodothyronine (T3), all of which were available in CDW data. Additionally, most patients with hypothyroidism initiate treatment with levothyroxine. Prescription refill history could also be retrieved using CDW reports.

Hypothyroidism was defined as T4 below lower limit of normal (LLN), TSH above upper limit of normal (ULN), or any increase in levothyroxine dosage. Patients were excluded if they received PD-1 inhibitor for an indication other than solid tumor treatment, such as hematologic malignancy, or if dosing did not follow weight-based or fixed-dosing strategies, such as nivolumab 1 mg/kg when used in combination with ipilimumab, or pembrolizumab 10 mg/kg. The primary endpoint was the percentage of orders for each dosing strategy, and the primary safety outcome was the incidence of immune-mediated hypothyroidism. Secondary endpoints included estimated cost savings and cost-savings opportunities through nivolumab dose rounding and incidence of levothyroxine initiation or dose change. Descriptive statistics were used for the primary and secondary endpoints.

A report in CDW identified patients who received a dose of nivolumab or pembrolizumab between January 1, 2015 and July 1, 2017 at any VAMC. The CDW report obtained weight at time of PD-1 inhibitor therapy initiation, dose of PD-1 inhibitor given, administration date of PD-1 inhibitor, and VA site. Depending on PD-1 inhibitor administered, weight in kg was multiplied by 3 mg/kg or 2 mg/kg to obtain patient’s anticipated weight-based nivolumab and pembrolizumab dose, respectively. The calculated weight-based dose, fixed dose, and administered dose were compared to infer dosing strategy used at the time of ordering. If the patient’s weight-based dose was within 10% of the fixed dose, the order was categorized as converging because the doses were too similar to determine which dosing strategy was intended.

After determination of dosing strategy, the nivolumab orders were evaluated for actual vs missed cost savings. The cost-savings evaluation included only nivolumab orders because nivolumab is available in a 40-mg, 100-mg, and 240-mg vials and, therefore, has more potential for dose-rounding opportunities with minimal drug waste compared with pembrolizumab, which is available only in a 100-mg vial. Actual cost savings included patients who weighed ≤ 73.3 kg and received nivolumab dose based on 3 mg/kg or patients who weighed ≥ 86.7 kg and received nivolumab 240 mg (fixed dose). Missed cost savings comprised patients who weighed ≤ 73.3 kg who received 240 mg nivolumab or patients who weighed ≥ 86.7 kg and received a nivolumab dose > 240 mg. The cost difference between the dose given and theoretical cost-effective dose was calculated to determine actual and potential cost savings. Converging orders were not included in the cost-savings analysis as the intended nivolumab dose could not be determined. An additional cost analysis of nivolumab orders prescribed between September 1, 2016 and July 1, 2017 was also performed because nivolumab fixed dosing was FDA-approved for most solid tumor indications in September 2016.

To determine the incidence of immunemediated hypothyroidism for patients who received a dose of a PD-1 inhibitor at a VAMC, a CDW report with thyroid function laboratory values (TSH, T4, or T3), including reference range values based on specific VA site, and levothyroxine prescriptions issued during PD-1 inhibitor therapy was obtained. A patient was considered to have experienced immune-mediated hypothyroidism if the patient’s laboratory values demonstrated T4 below the LLN, TSH above the ULN, or if the medication fill history demonstrated levothyroxine initiation or a levothyroxine dose increase.

Results 

The CDW report identified 32,769 total PD-1 inhibitor orders. There were 3982 orders that did not meet inclusion criteria or inadequate data were obtained with CDW report and were excluded (Figure). The remaining 28,787 PD-1 inhibitor orders were evaluated for actual or missed cost savings. The distribution of dosing strategies can be found in Table 1.

Nivolumab accounted for 81.5% of all PD-1 inhibitor orders. Using the most cost-effective nivolumab dosing, the actual cost savings was estimated to be $8,514,300 with potential additional $5,591,250 of missed cost-savings opportunities. There were 8013 nivolumab orders written between September 1, 2016 and July 1, 2017. Cost-effective dosing was used in 4687 of these orders, which accounted for a cost savings of $5,198,570. The remaining 3326 orders had a missed cost-savings opportunity, which accounted for an additional $2,907,180 potential cost savings (Table 2).

PD-1 inhibitors were used for the treatment of 3249 unique patients. Based on abnormal thyroid function tests and levothyroxine initiation or dose increase, it is estimated that 514 (15.8%) patients experienced hypothyroidism during PD-1 inhibitor therapy. However, prior to PD-1 inhibitor therapy, 274 patients were receiving levothyroxine, suggesting baseline thyroid dysfunction. Of these patients, 152 (55.5%) patients maintained the same levothyroxine dose during PD-1 inhibitor therapy, but 91 (33.2%) required a levothyroxine dose increase. There were 187 patients who initiated levothyroxine during PD-1 inhibitor therapy (Table 3).

Discussion

Changes in FDA-approved dosing for PD-1 inhibitors allowed a combination of dosing strategies. Depending on patient weight, a weight-based or fixed-dosing strategy can be used to reduce drug cost while maintaining equivalent efficacy. This study evaluated use of dose rounding for PD-1 inhibitors within the VA health care system to identify actual and potential cost savings. To our knowledge, this is the first study to demonstrate cost savings through use of a combination of PD-1 inhibitor dosing strategies. Using CDW, researchers were able to review PD-1 dosing from all VAMCs and include a larger number of orders in a single retrospective study.

Nivolumab was the primary agent used within VAMCs. Depending on the indication, pembrolizumab requires PD-1 expression testing prior to its use in several solid tumor indications. Consequently, additional testing and patient eligibility is needed prior to use. Both PD-1 inhibitors were primarily dosed based on patient weight since this was the first FDAapproved dosing strategy. Nivolumab had more orders categorized as converging, which may be due to the therapeutic weight-based dose of 3 mg/kg for nivolumab vs 2 mg/kg for pembrolizumab. The calculated weight-based dose of nivolumab for an 80-kg patient is 240 mg, which also is the fixed dose. A 80-kg patient on pembrolizumab at 2 mg/kg would receive a 160-mg dose, whereas the fixed dose of pembrolizumab is 200 mg. Pembrolizumab is available only in a 100-mg vial, which limits opportunities for dose rounding without drug waste and could explain the higher amount of pembrolizumab orders in the fixed-dose category.

In this review of PD-1 inhibitor orders over approximately a 2.5-year study period, we identified $8,514,300 estimated cost savings with $5,591,250 estimated missed cost savings. When looking at orders administered after FDA approval for nivolumab-fixed dosing in September 2016, there was substantial cost savings of $5,198,570 with the potential for an additional $2,907,180 missed cost savings. Due to lower drug acquisition costs within the VA health care system, there may be higher cost-savings opportunities within other health care systems.

Through review of abnormal thyroid laboratory values and levothyroxine initiation or dose changes, this study estimated the incidence of hypothyroidism in patients receiving PD-1 inhibitor therapy at the VA. The incidence of primary hypothyroidism identified in this study was slightly higher at 15.8% compared with the 8.5 to 9.0% incidence reported from clinical trials.^1,2 There are several reasons why the incidence of hypothyroidism appeared higher in this study. Abnormal laboratory values were not assessed for the degree of deviation from the reference range; any TSH above the ULN, T4 below the LLN, or levothyroxine dose increase was included as thyroid dysfunction in this review. There is also the potential for endogenous age-related thyroid fluctuation, and the development of hypothyroidism may not have been related to PD-1 inhibitor therapy. Within this patient population, 8.4% were receiving levothyroxine prior to PD-1 inhibitor initiation indicating baseline thyroid dysfunction, and it is unclear whether levothyroxine dose increases were due to PD-1 inhibitor or endogenous fluctuation.

Limitations

There are several limitations to acknowledge. The dosing strategy and apparent dose rounding was determined by investigator inference and may not accurately represent the intended dosing strategy. This study did not address efficacy of PD-1 inhibitor and dosing strategy; however, clinical trials have demonstrated equivalent efficacy to generate the change in FDA-approved dosing. Additionally, FDA approval for nivolumab fixed dosing was indication specific. Starting in September 2016, many solid tumor indications had fixed dosing approved, but this approval was not necessarily all encompassing.

While the use of CDW allowed for a greater number of PD-1 inhibitor orders to be included in retrospective review, there also were limitations of the CDW report. The patient weight was limited to weight at time of therapy initiation. Due to the potential for weight changes, nivolumab dosing may have seemed inappropriate to investigators, and thereby excluded. Based on data available from CDW reports, hypothyroidism could not be graded according to NCI Common Terminology Criteria for Adverse Events, and the incidence of clinically significant hypothyroidism could not be determined.

Conclusions

With increasing drug acquisition costs, particularly among antineoplastic agents, health care systems frequently seek out cost-savings opportunities. Using a combination of weightbased and fixed-dosing strategies for PD-1 inhibitors can be a mechanism to achieve costsavings. Through the identification of the dosing strategy used for PD-1 inhibitors, we were able to identify and report instances for potential cost-savings opportunities among veterans treated within VA health care system. Use of CDW allows for data from all VAMCs to be evaluated in a single retrospective chart review, which allows for the inclusion of a larger sample size. This study identified a substantial cost savings for nivolumab through a combination of weight-based and fixed-dosing strategies. Due to the novel mechanism of action, ongoing realworld evaluation of adverse events and IrAEs is warranted.

Dosing strategies with nivolumab and pembrolizumab continue to evolve. In March 2018, nivolumab 480 mg IV every 4 weeks was FDA approved and in April 2020, pembrolizumab 400 mg IV every 6 weeks was FDA approved.^13,14 While the drug costs will remain the same, extended interval dosing strategies have cost avoidance such as fewer clinic appointments, resulting in decreased staffing costs and decreased patient travel. Additional studies will be needed to evaluate the cost and safety of the recently approved dosing strategies

Due to the high cost of newer chemotherapy agents, institutions search for strategies to minimize drug cost and drug waste. Programmed death-1 (PD-1) inhibitors, nivolumab and pembrolizumab, are commonly used in the treatment of solid tumors; however, the agents cost thousands of dollars per dose. Nivolumab and pembrolizumab were initially approved using weight-based dosing, but package labeling for both agents now includes fixed dosing.^1,2 A combination of these 2 dosing strategies could be used by institutions depending on individual patient’s weight to maximize cost savings, minimize drug waste, and maintain safety and efficacy of PD-1 inhibitors. Irrespective of dosing strategy, the development of immune-related adverse events (IrAEs) has been demonstrated with PD-1 inhibitors as a result of the mechanism of action.

PD-1 expression suppresses T cell activity to prevent the development of autoimmunity; however, this is also a mechanism in which tumor cells can evade the host immune system.^3-5 Binding of PD-1 and programmed death-ligand 1 (PD-L1) suppresses T cell activity, whereas the inhibition of PD-1 and PD-L1 results in T cell activation.^4,5 Increased T cell activity elicits the anticancer effect, but also contributes to the development of IrAEs^.4,5 Hypothyroidism is one of the most common IrAEs, with a reported incidence of 9% with nivolumab therapy and 8.5% with pembrolizumab.^1,2

Data from the US Department of Veterans Affairs (VA) medical centers is stored in the centralized Corporate Data Warehouse (CDW). VA researchers can obtain approval to use CDW data, which allows for large scale retrospective review of veterans who have received care at VA medical centers (VAMCs). This study aimed to describe the PD-1 inhibitor dosing used within VAMCs and identify actual and potential cost savings. Due to the frequency of immunemediated hypothyroidism and objective data that can be obtained from CDW reports, the study estimated the incidence of immune-mediated hypothyroidism within the veteran population as a safety outcome.

Background

The US Food and Drug Administration (FDA) initially approved dosing for IV nivolumab at 3 mg/kg of patient body weight every 2 weeks and for IV pembrolizumab 2 mg/kg of patient body weight every 3 weeks.^1,2 Subsequent pharmacokinetic studies found that these agents have similar exposure and efficacy with fixed doses of nivolumab 240 mg IV every 2 weeks and pembrolizumab 200 mg IV every 3 weeks; in 2016, FDA labeling shifted from weight-based dosing to fixed dosing for most solid tumor indications.^6-9 Depending on patient weight, a combination of weightbased and fixed dosing could be used by institutions to maximize cost-savings opportunities, minimize drug waste, and maintain clinical efficacy with PD-1 inhibitors. For example, a patient initiating nivolumab who weighs 80 kg would receive 240 mg for both weight-based (3 mg/kg x 80 kg = 240 mg) and fixed dosing; therefore, no cost-savings opportunities would be available. However, for a patient who weighs ≤ 73.3 kg, it would be more costeffective to use weight-based dosing vs the fixed dose. Since nivolumab is available in 40- mg, 100-mg, and 240-mg vials with similar unit prices, a combination of vial sizes could be used to minimize drug waste. Alternatively, for a patient who weighs ≥ 86.7 kg, it would be more cost-effective to administer the fixed, 240 mg dose when compared with the weightbased dose. Pembrolizumab is available only in a 100-mg vial; therefore, weight-based dosing may result in drug waste.

IrAEs can be seen with PD-1 inhibitors due to increased T cell activity, which is independent of dosing strategy and can affect any organ system. However, immune-mediated hypothyroidism has been commonly seen with PD-1 inhibitors. For patients with immunemediated hypothyroidism, levothyroxine can be considered for asymptomatic patients with thyroid- stimulating hormone (TSH) > 10 uIU/mL with normal thyroxine (T4), or patients with clinical primary hypothyroidism (TSH > 10 uIU/mL with low free T4 and clinical symptoms). Additionally, since hypothyroidism usually follows immunotherapy induced thyrotoxicosis, thyroid function tests should be monitored and levothyroxine initiated if TSH is > 10 uIU/mL for these patients.^10,11

Hypothyroidism also can be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events. Hypothyroidism is considered grade 1 when hypothyroidism is demonstrated through clinical or diagnostic observations only and the patient is asymptomatic and no intervention needed. Grade 2 occurs when the patient is symptomatic and limits instrumental activities of daily living (ADLs), prompting thyroid replacement therapy. In grade 3, patients experience severe symptoms that restrict self-care ADLs, and hospitalization is indicated. Grade 4 has life-threatening consequences, and urgent intervention is indicated. Grade 5 results in the death of the patient.¹²

Electronic health records (EHRs) of veterans who receive care at a VAMC are stored in CDW and available through the VA Informatics and Computing Infrastructure (VINCI), which provides access to data while ensuring veterans’ privacy and data security. This feature of the VA EHR allows for analysis of data across the VA health care system, and larger data sets can be used for retrospective chart reviews.

Using reports from CDW, the primary objective of this study was to describe the dosing strategy used for PD-1 inhibitors, and the primary safety outcome was to determine the incidence of immune-mediated hypothyroidism. The secondary objective was to estimate potential cost-savings opportunities using a combination of PD-1 inhibitor dosing strategies.

Methods

This was a retrospective study including data stored in CDW. The study was approved by the Durham VA Health Care System Institutional Review Board and VINCI/Data Access request tracker. Data were limited to nivolumab and pembrolizumab because they received earlier FDA approval, had multiple solid tumor indications, and 2 FDA-approved dosing strategies. The incidence of IrAEs was limited to hypothyroidism, which could be objectively verified with laboratory monitoring of thyroid function tests, including TSH, free or total T4, and triiodothyronine (T3), all of which were available in CDW data. Additionally, most patients with hypothyroidism initiate treatment with levothyroxine. Prescription refill history could also be retrieved using CDW reports.

Hypothyroidism was defined as T4 below lower limit of normal (LLN), TSH above upper limit of normal (ULN), or any increase in levothyroxine dosage. Patients were excluded if they received PD-1 inhibitor for an indication other than solid tumor treatment, such as hematologic malignancy, or if dosing did not follow weight-based or fixed-dosing strategies, such as nivolumab 1 mg/kg when used in combination with ipilimumab, or pembrolizumab 10 mg/kg. The primary endpoint was the percentage of orders for each dosing strategy, and the primary safety outcome was the incidence of immune-mediated hypothyroidism. Secondary endpoints included estimated cost savings and cost-savings opportunities through nivolumab dose rounding and incidence of levothyroxine initiation or dose change. Descriptive statistics were used for the primary and secondary endpoints.

A report in CDW identified patients who received a dose of nivolumab or pembrolizumab between January 1, 2015 and July 1, 2017 at any VAMC. The CDW report obtained weight at time of PD-1 inhibitor therapy initiation, dose of PD-1 inhibitor given, administration date of PD-1 inhibitor, and VA site. Depending on PD-1 inhibitor administered, weight in kg was multiplied by 3 mg/kg or 2 mg/kg to obtain patient’s anticipated weight-based nivolumab and pembrolizumab dose, respectively. The calculated weight-based dose, fixed dose, and administered dose were compared to infer dosing strategy used at the time of ordering. If the patient’s weight-based dose was within 10% of the fixed dose, the order was categorized as converging because the doses were too similar to determine which dosing strategy was intended.

After determination of dosing strategy, the nivolumab orders were evaluated for actual vs missed cost savings. The cost-savings evaluation included only nivolumab orders because nivolumab is available in a 40-mg, 100-mg, and 240-mg vials and, therefore, has more potential for dose-rounding opportunities with minimal drug waste compared with pembrolizumab, which is available only in a 100-mg vial. Actual cost savings included patients who weighed ≤ 73.3 kg and received nivolumab dose based on 3 mg/kg or patients who weighed ≥ 86.7 kg and received nivolumab 240 mg (fixed dose). Missed cost savings comprised patients who weighed ≤ 73.3 kg who received 240 mg nivolumab or patients who weighed ≥ 86.7 kg and received a nivolumab dose > 240 mg. The cost difference between the dose given and theoretical cost-effective dose was calculated to determine actual and potential cost savings. Converging orders were not included in the cost-savings analysis as the intended nivolumab dose could not be determined. An additional cost analysis of nivolumab orders prescribed between September 1, 2016 and July 1, 2017 was also performed because nivolumab fixed dosing was FDA-approved for most solid tumor indications in September 2016.

To determine the incidence of immunemediated hypothyroidism for patients who received a dose of a PD-1 inhibitor at a VAMC, a CDW report with thyroid function laboratory values (TSH, T4, or T3), including reference range values based on specific VA site, and levothyroxine prescriptions issued during PD-1 inhibitor therapy was obtained. A patient was considered to have experienced immune-mediated hypothyroidism if the patient’s laboratory values demonstrated T4 below the LLN, TSH above the ULN, or if the medication fill history demonstrated levothyroxine initiation or a levothyroxine dose increase.

Results 

The CDW report identified 32,769 total PD-1 inhibitor orders. There were 3982 orders that did not meet inclusion criteria or inadequate data were obtained with CDW report and were excluded (Figure). The remaining 28,787 PD-1 inhibitor orders were evaluated for actual or missed cost savings. The distribution of dosing strategies can be found in Table 1.

Nivolumab accounted for 81.5% of all PD-1 inhibitor orders. Using the most cost-effective nivolumab dosing, the actual cost savings was estimated to be $8,514,300 with potential additional $5,591,250 of missed cost-savings opportunities. There were 8013 nivolumab orders written between September 1, 2016 and July 1, 2017. Cost-effective dosing was used in 4687 of these orders, which accounted for a cost savings of $5,198,570. The remaining 3326 orders had a missed cost-savings opportunity, which accounted for an additional $2,907,180 potential cost savings (Table 2).

PD-1 inhibitors were used for the treatment of 3249 unique patients. Based on abnormal thyroid function tests and levothyroxine initiation or dose increase, it is estimated that 514 (15.8%) patients experienced hypothyroidism during PD-1 inhibitor therapy. However, prior to PD-1 inhibitor therapy, 274 patients were receiving levothyroxine, suggesting baseline thyroid dysfunction. Of these patients, 152 (55.5%) patients maintained the same levothyroxine dose during PD-1 inhibitor therapy, but 91 (33.2%) required a levothyroxine dose increase. There were 187 patients who initiated levothyroxine during PD-1 inhibitor therapy (Table 3).

Discussion

Changes in FDA-approved dosing for PD-1 inhibitors allowed a combination of dosing strategies. Depending on patient weight, a weight-based or fixed-dosing strategy can be used to reduce drug cost while maintaining equivalent efficacy. This study evaluated use of dose rounding for PD-1 inhibitors within the VA health care system to identify actual and potential cost savings. To our knowledge, this is the first study to demonstrate cost savings through use of a combination of PD-1 inhibitor dosing strategies. Using CDW, researchers were able to review PD-1 dosing from all VAMCs and include a larger number of orders in a single retrospective study.

Nivolumab was the primary agent used within VAMCs. Depending on the indication, pembrolizumab requires PD-1 expression testing prior to its use in several solid tumor indications. Consequently, additional testing and patient eligibility is needed prior to use. Both PD-1 inhibitors were primarily dosed based on patient weight since this was the first FDAapproved dosing strategy. Nivolumab had more orders categorized as converging, which may be due to the therapeutic weight-based dose of 3 mg/kg for nivolumab vs 2 mg/kg for pembrolizumab. The calculated weight-based dose of nivolumab for an 80-kg patient is 240 mg, which also is the fixed dose. A 80-kg patient on pembrolizumab at 2 mg/kg would receive a 160-mg dose, whereas the fixed dose of pembrolizumab is 200 mg. Pembrolizumab is available only in a 100-mg vial, which limits opportunities for dose rounding without drug waste and could explain the higher amount of pembrolizumab orders in the fixed-dose category.

In this review of PD-1 inhibitor orders over approximately a 2.5-year study period, we identified $8,514,300 estimated cost savings with $5,591,250 estimated missed cost savings. When looking at orders administered after FDA approval for nivolumab-fixed dosing in September 2016, there was substantial cost savings of $5,198,570 with the potential for an additional $2,907,180 missed cost savings. Due to lower drug acquisition costs within the VA health care system, there may be higher cost-savings opportunities within other health care systems.

Through review of abnormal thyroid laboratory values and levothyroxine initiation or dose changes, this study estimated the incidence of hypothyroidism in patients receiving PD-1 inhibitor therapy at the VA. The incidence of primary hypothyroidism identified in this study was slightly higher at 15.8% compared with the 8.5 to 9.0% incidence reported from clinical trials.^1,2 There are several reasons why the incidence of hypothyroidism appeared higher in this study. Abnormal laboratory values were not assessed for the degree of deviation from the reference range; any TSH above the ULN, T4 below the LLN, or levothyroxine dose increase was included as thyroid dysfunction in this review. There is also the potential for endogenous age-related thyroid fluctuation, and the development of hypothyroidism may not have been related to PD-1 inhibitor therapy. Within this patient population, 8.4% were receiving levothyroxine prior to PD-1 inhibitor initiation indicating baseline thyroid dysfunction, and it is unclear whether levothyroxine dose increases were due to PD-1 inhibitor or endogenous fluctuation.

Limitations

There are several limitations to acknowledge. The dosing strategy and apparent dose rounding was determined by investigator inference and may not accurately represent the intended dosing strategy. This study did not address efficacy of PD-1 inhibitor and dosing strategy; however, clinical trials have demonstrated equivalent efficacy to generate the change in FDA-approved dosing. Additionally, FDA approval for nivolumab fixed dosing was indication specific. Starting in September 2016, many solid tumor indications had fixed dosing approved, but this approval was not necessarily all encompassing.

While the use of CDW allowed for a greater number of PD-1 inhibitor orders to be included in retrospective review, there also were limitations of the CDW report. The patient weight was limited to weight at time of therapy initiation. Due to the potential for weight changes, nivolumab dosing may have seemed inappropriate to investigators, and thereby excluded. Based on data available from CDW reports, hypothyroidism could not be graded according to NCI Common Terminology Criteria for Adverse Events, and the incidence of clinically significant hypothyroidism could not be determined.

Conclusions

With increasing drug acquisition costs, particularly among antineoplastic agents, health care systems frequently seek out cost-savings opportunities. Using a combination of weightbased and fixed-dosing strategies for PD-1 inhibitors can be a mechanism to achieve costsavings. Through the identification of the dosing strategy used for PD-1 inhibitors, we were able to identify and report instances for potential cost-savings opportunities among veterans treated within VA health care system. Use of CDW allows for data from all VAMCs to be evaluated in a single retrospective chart review, which allows for the inclusion of a larger sample size. This study identified a substantial cost savings for nivolumab through a combination of weight-based and fixed-dosing strategies. Due to the novel mechanism of action, ongoing realworld evaluation of adverse events and IrAEs is warranted.

Dosing strategies with nivolumab and pembrolizumab continue to evolve. In March 2018, nivolumab 480 mg IV every 4 weeks was FDA approved and in April 2020, pembrolizumab 400 mg IV every 6 weeks was FDA approved.^13,14 While the drug costs will remain the same, extended interval dosing strategies have cost avoidance such as fewer clinic appointments, resulting in decreased staffing costs and decreased patient travel. Additional studies will be needed to evaluate the cost and safety of the recently approved dosing strategies

Due to the high cost of newer chemotherapy agents, institutions search for strategies to minimize drug cost and drug waste. Programmed death-1 (PD-1) inhibitors, nivolumab and pembrolizumab, are commonly used in the treatment of solid tumors; however, the agents cost thousands of dollars per dose. Nivolumab and pembrolizumab were initially approved using weight-based dosing, but package labeling for both agents now includes fixed dosing.^1,2 A combination of these 2 dosing strategies could be used by institutions depending on individual patient’s weight to maximize cost savings, minimize drug waste, and maintain safety and efficacy of PD-1 inhibitors. Irrespective of dosing strategy, the development of immune-related adverse events (IrAEs) has been demonstrated with PD-1 inhibitors as a result of the mechanism of action.

PD-1 expression suppresses T cell activity to prevent the development of autoimmunity; however, this is also a mechanism in which tumor cells can evade the host immune system.^3-5 Binding of PD-1 and programmed death-ligand 1 (PD-L1) suppresses T cell activity, whereas the inhibition of PD-1 and PD-L1 results in T cell activation.^4,5 Increased T cell activity elicits the anticancer effect, but also contributes to the development of IrAEs^.4,5 Hypothyroidism is one of the most common IrAEs, with a reported incidence of 9% with nivolumab therapy and 8.5% with pembrolizumab.^1,2

Data from the US Department of Veterans Affairs (VA) medical centers is stored in the centralized Corporate Data Warehouse (CDW). VA researchers can obtain approval to use CDW data, which allows for large scale retrospective review of veterans who have received care at VA medical centers (VAMCs). This study aimed to describe the PD-1 inhibitor dosing used within VAMCs and identify actual and potential cost savings. Due to the frequency of immunemediated hypothyroidism and objective data that can be obtained from CDW reports, the study estimated the incidence of immune-mediated hypothyroidism within the veteran population as a safety outcome.

Background

The US Food and Drug Administration (FDA) initially approved dosing for IV nivolumab at 3 mg/kg of patient body weight every 2 weeks and for IV pembrolizumab 2 mg/kg of patient body weight every 3 weeks.^1,2 Subsequent pharmacokinetic studies found that these agents have similar exposure and efficacy with fixed doses of nivolumab 240 mg IV every 2 weeks and pembrolizumab 200 mg IV every 3 weeks; in 2016, FDA labeling shifted from weight-based dosing to fixed dosing for most solid tumor indications.^6-9 Depending on patient weight, a combination of weightbased and fixed dosing could be used by institutions to maximize cost-savings opportunities, minimize drug waste, and maintain clinical efficacy with PD-1 inhibitors. For example, a patient initiating nivolumab who weighs 80 kg would receive 240 mg for both weight-based (3 mg/kg x 80 kg = 240 mg) and fixed dosing; therefore, no cost-savings opportunities would be available. However, for a patient who weighs ≤ 73.3 kg, it would be more costeffective to use weight-based dosing vs the fixed dose. Since nivolumab is available in 40- mg, 100-mg, and 240-mg vials with similar unit prices, a combination of vial sizes could be used to minimize drug waste. Alternatively, for a patient who weighs ≥ 86.7 kg, it would be more cost-effective to administer the fixed, 240 mg dose when compared with the weightbased dose. Pembrolizumab is available only in a 100-mg vial; therefore, weight-based dosing may result in drug waste.

IrAEs can be seen with PD-1 inhibitors due to increased T cell activity, which is independent of dosing strategy and can affect any organ system. However, immune-mediated hypothyroidism has been commonly seen with PD-1 inhibitors. For patients with immunemediated hypothyroidism, levothyroxine can be considered for asymptomatic patients with thyroid- stimulating hormone (TSH) > 10 uIU/mL with normal thyroxine (T4), or patients with clinical primary hypothyroidism (TSH > 10 uIU/mL with low free T4 and clinical symptoms). Additionally, since hypothyroidism usually follows immunotherapy induced thyrotoxicosis, thyroid function tests should be monitored and levothyroxine initiated if TSH is > 10 uIU/mL for these patients.^10,11

Hypothyroidism also can be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events. Hypothyroidism is considered grade 1 when hypothyroidism is demonstrated through clinical or diagnostic observations only and the patient is asymptomatic and no intervention needed. Grade 2 occurs when the patient is symptomatic and limits instrumental activities of daily living (ADLs), prompting thyroid replacement therapy. In grade 3, patients experience severe symptoms that restrict self-care ADLs, and hospitalization is indicated. Grade 4 has life-threatening consequences, and urgent intervention is indicated. Grade 5 results in the death of the patient.¹²

Electronic health records (EHRs) of veterans who receive care at a VAMC are stored in CDW and available through the VA Informatics and Computing Infrastructure (VINCI), which provides access to data while ensuring veterans’ privacy and data security. This feature of the VA EHR allows for analysis of data across the VA health care system, and larger data sets can be used for retrospective chart reviews.

Using reports from CDW, the primary objective of this study was to describe the dosing strategy used for PD-1 inhibitors, and the primary safety outcome was to determine the incidence of immune-mediated hypothyroidism. The secondary objective was to estimate potential cost-savings opportunities using a combination of PD-1 inhibitor dosing strategies.

Methods

This was a retrospective study including data stored in CDW. The study was approved by the Durham VA Health Care System Institutional Review Board and VINCI/Data Access request tracker. Data were limited to nivolumab and pembrolizumab because they received earlier FDA approval, had multiple solid tumor indications, and 2 FDA-approved dosing strategies. The incidence of IrAEs was limited to hypothyroidism, which could be objectively verified with laboratory monitoring of thyroid function tests, including TSH, free or total T4, and triiodothyronine (T3), all of which were available in CDW data. Additionally, most patients with hypothyroidism initiate treatment with levothyroxine. Prescription refill history could also be retrieved using CDW reports.

Hypothyroidism was defined as T4 below lower limit of normal (LLN), TSH above upper limit of normal (ULN), or any increase in levothyroxine dosage. Patients were excluded if they received PD-1 inhibitor for an indication other than solid tumor treatment, such as hematologic malignancy, or if dosing did not follow weight-based or fixed-dosing strategies, such as nivolumab 1 mg/kg when used in combination with ipilimumab, or pembrolizumab 10 mg/kg. The primary endpoint was the percentage of orders for each dosing strategy, and the primary safety outcome was the incidence of immune-mediated hypothyroidism. Secondary endpoints included estimated cost savings and cost-savings opportunities through nivolumab dose rounding and incidence of levothyroxine initiation or dose change. Descriptive statistics were used for the primary and secondary endpoints.

A report in CDW identified patients who received a dose of nivolumab or pembrolizumab between January 1, 2015 and July 1, 2017 at any VAMC. The CDW report obtained weight at time of PD-1 inhibitor therapy initiation, dose of PD-1 inhibitor given, administration date of PD-1 inhibitor, and VA site. Depending on PD-1 inhibitor administered, weight in kg was multiplied by 3 mg/kg or 2 mg/kg to obtain patient’s anticipated weight-based nivolumab and pembrolizumab dose, respectively. The calculated weight-based dose, fixed dose, and administered dose were compared to infer dosing strategy used at the time of ordering. If the patient’s weight-based dose was within 10% of the fixed dose, the order was categorized as converging because the doses were too similar to determine which dosing strategy was intended.

After determination of dosing strategy, the nivolumab orders were evaluated for actual vs missed cost savings. The cost-savings evaluation included only nivolumab orders because nivolumab is available in a 40-mg, 100-mg, and 240-mg vials and, therefore, has more potential for dose-rounding opportunities with minimal drug waste compared with pembrolizumab, which is available only in a 100-mg vial. Actual cost savings included patients who weighed ≤ 73.3 kg and received nivolumab dose based on 3 mg/kg or patients who weighed ≥ 86.7 kg and received nivolumab 240 mg (fixed dose). Missed cost savings comprised patients who weighed ≤ 73.3 kg who received 240 mg nivolumab or patients who weighed ≥ 86.7 kg and received a nivolumab dose > 240 mg. The cost difference between the dose given and theoretical cost-effective dose was calculated to determine actual and potential cost savings. Converging orders were not included in the cost-savings analysis as the intended nivolumab dose could not be determined. An additional cost analysis of nivolumab orders prescribed between September 1, 2016 and July 1, 2017 was also performed because nivolumab fixed dosing was FDA-approved for most solid tumor indications in September 2016.

To determine the incidence of immunemediated hypothyroidism for patients who received a dose of a PD-1 inhibitor at a VAMC, a CDW report with thyroid function laboratory values (TSH, T4, or T3), including reference range values based on specific VA site, and levothyroxine prescriptions issued during PD-1 inhibitor therapy was obtained. A patient was considered to have experienced immune-mediated hypothyroidism if the patient’s laboratory values demonstrated T4 below the LLN, TSH above the ULN, or if the medication fill history demonstrated levothyroxine initiation or a levothyroxine dose increase.

Results 

The CDW report identified 32,769 total PD-1 inhibitor orders. There were 3982 orders that did not meet inclusion criteria or inadequate data were obtained with CDW report and were excluded (Figure). The remaining 28,787 PD-1 inhibitor orders were evaluated for actual or missed cost savings. The distribution of dosing strategies can be found in Table 1.

Nivolumab accounted for 81.5% of all PD-1 inhibitor orders. Using the most cost-effective nivolumab dosing, the actual cost savings was estimated to be $8,514,300 with potential additional $5,591,250 of missed cost-savings opportunities. There were 8013 nivolumab orders written between September 1, 2016 and July 1, 2017. Cost-effective dosing was used in 4687 of these orders, which accounted for a cost savings of $5,198,570. The remaining 3326 orders had a missed cost-savings opportunity, which accounted for an additional $2,907,180 potential cost savings (Table 2).

PD-1 inhibitors were used for the treatment of 3249 unique patients. Based on abnormal thyroid function tests and levothyroxine initiation or dose increase, it is estimated that 514 (15.8%) patients experienced hypothyroidism during PD-1 inhibitor therapy. However, prior to PD-1 inhibitor therapy, 274 patients were receiving levothyroxine, suggesting baseline thyroid dysfunction. Of these patients, 152 (55.5%) patients maintained the same levothyroxine dose during PD-1 inhibitor therapy, but 91 (33.2%) required a levothyroxine dose increase. There were 187 patients who initiated levothyroxine during PD-1 inhibitor therapy (Table 3).

Discussion

Changes in FDA-approved dosing for PD-1 inhibitors allowed a combination of dosing strategies. Depending on patient weight, a weight-based or fixed-dosing strategy can be used to reduce drug cost while maintaining equivalent efficacy. This study evaluated use of dose rounding for PD-1 inhibitors within the VA health care system to identify actual and potential cost savings. To our knowledge, this is the first study to demonstrate cost savings through use of a combination of PD-1 inhibitor dosing strategies. Using CDW, researchers were able to review PD-1 dosing from all VAMCs and include a larger number of orders in a single retrospective study.

Nivolumab was the primary agent used within VAMCs. Depending on the indication, pembrolizumab requires PD-1 expression testing prior to its use in several solid tumor indications. Consequently, additional testing and patient eligibility is needed prior to use. Both PD-1 inhibitors were primarily dosed based on patient weight since this was the first FDAapproved dosing strategy. Nivolumab had more orders categorized as converging, which may be due to the therapeutic weight-based dose of 3 mg/kg for nivolumab vs 2 mg/kg for pembrolizumab. The calculated weight-based dose of nivolumab for an 80-kg patient is 240 mg, which also is the fixed dose. A 80-kg patient on pembrolizumab at 2 mg/kg would receive a 160-mg dose, whereas the fixed dose of pembrolizumab is 200 mg. Pembrolizumab is available only in a 100-mg vial, which limits opportunities for dose rounding without drug waste and could explain the higher amount of pembrolizumab orders in the fixed-dose category.

In this review of PD-1 inhibitor orders over approximately a 2.5-year study period, we identified $8,514,300 estimated cost savings with $5,591,250 estimated missed cost savings. When looking at orders administered after FDA approval for nivolumab-fixed dosing in September 2016, there was substantial cost savings of $5,198,570 with the potential for an additional $2,907,180 missed cost savings. Due to lower drug acquisition costs within the VA health care system, there may be higher cost-savings opportunities within other health care systems.

Through review of abnormal thyroid laboratory values and levothyroxine initiation or dose changes, this study estimated the incidence of hypothyroidism in patients receiving PD-1 inhibitor therapy at the VA. The incidence of primary hypothyroidism identified in this study was slightly higher at 15.8% compared with the 8.5 to 9.0% incidence reported from clinical trials.^1,2 There are several reasons why the incidence of hypothyroidism appeared higher in this study. Abnormal laboratory values were not assessed for the degree of deviation from the reference range; any TSH above the ULN, T4 below the LLN, or levothyroxine dose increase was included as thyroid dysfunction in this review. There is also the potential for endogenous age-related thyroid fluctuation, and the development of hypothyroidism may not have been related to PD-1 inhibitor therapy. Within this patient population, 8.4% were receiving levothyroxine prior to PD-1 inhibitor initiation indicating baseline thyroid dysfunction, and it is unclear whether levothyroxine dose increases were due to PD-1 inhibitor or endogenous fluctuation.

Limitations

There are several limitations to acknowledge. The dosing strategy and apparent dose rounding was determined by investigator inference and may not accurately represent the intended dosing strategy. This study did not address efficacy of PD-1 inhibitor and dosing strategy; however, clinical trials have demonstrated equivalent efficacy to generate the change in FDA-approved dosing. Additionally, FDA approval for nivolumab fixed dosing was indication specific. Starting in September 2016, many solid tumor indications had fixed dosing approved, but this approval was not necessarily all encompassing.

While the use of CDW allowed for a greater number of PD-1 inhibitor orders to be included in retrospective review, there also were limitations of the CDW report. The patient weight was limited to weight at time of therapy initiation. Due to the potential for weight changes, nivolumab dosing may have seemed inappropriate to investigators, and thereby excluded. Based on data available from CDW reports, hypothyroidism could not be graded according to NCI Common Terminology Criteria for Adverse Events, and the incidence of clinically significant hypothyroidism could not be determined.

Conclusions

With increasing drug acquisition costs, particularly among antineoplastic agents, health care systems frequently seek out cost-savings opportunities. Using a combination of weightbased and fixed-dosing strategies for PD-1 inhibitors can be a mechanism to achieve costsavings. Through the identification of the dosing strategy used for PD-1 inhibitors, we were able to identify and report instances for potential cost-savings opportunities among veterans treated within VA health care system. Use of CDW allows for data from all VAMCs to be evaluated in a single retrospective chart review, which allows for the inclusion of a larger sample size. This study identified a substantial cost savings for nivolumab through a combination of weight-based and fixed-dosing strategies. Due to the novel mechanism of action, ongoing realworld evaluation of adverse events and IrAEs is warranted.

Dosing strategies with nivolumab and pembrolizumab continue to evolve. In March 2018, nivolumab 480 mg IV every 4 weeks was FDA approved and in April 2020, pembrolizumab 400 mg IV every 6 weeks was FDA approved.^13,14 While the drug costs will remain the same, extended interval dosing strategies have cost avoidance such as fewer clinic appointments, resulting in decreased staffing costs and decreased patient travel. Additional studies will be needed to evaluate the cost and safety of the recently approved dosing strategies

Steeve Verdieu was at his workstation in his bedroom when the shaking started the morning of Aug. 14. He jumped under his desk and held on as a 7.2-magnitude earthquake tore through his childhood home in southern Haiti.

Mr. Verdieu, 25, said all he could think about was 2010, when a strong earthquake hit the country and left more than 200,000 people dead.

“Most of these adults that are in their mid-20s and 30s have vivid memories,” according to John Fitts, assistant director of Sent To Serve. He started working in the nonprofit sector in Haiti after the 2010 earthquake.

“I can’t even relate to it,” Mr. Fitts said. “If you didn’t live through it, you cannot relate.”

Mr. Verdieu emerged to find his family alive and his home in crumbles.

“In the neighborhood, we have only one child who died the day of the earthquake, but mentally, everybody feels bad,” he said. “Also, we are really frustrated right now because it tends to rain, and everybody is outside right now. So, we are a little bit afraid.”

Mr. Verdieu said that his community has not seen or heard of government authorities coming to offer guidance on next steps.

So, he started posting photos and videos to his Twitter account to seek help.
 

Surviving to heal

Many Haitians are forced to quickly turn the page after major crises, said Mr. Fitts.

“Survival overrides emotional shock,” he said. “They’re not going to have time. They’re not going to think emotional wellness at this point. It’s not addressed because they don’t have the opportunity to address it. So, it gets buried.”

More rural areas of Haiti were hit hardest by the recent earthquake, which killed over 2,000 people.

Many people were left without shelter and had limited access to food, clean drinking water, and medical help for those severely injured.

But current problems in Haiti, like shaky leadership after the recent assassination of the country’s president, left many people with no direction on what to do next.

With no information coming in, many, like Mr. Verdieu, took to social media or tried calling family and friends to find help on their own.

Having access to basic needs, like food and water, lessens the emotional trauma after these types of disasters, according to Betty Jean, a licensed professional counselor and global mental health and trauma consultant.

“When there is a crisis like an earthquake, the number one thing people need is a sense of safety and that there are entities that are concerned about their overall well-being,” said Ms. Jean, who is Haitian. “The emotional and mental support that we have to provide to people begins first with attending to those primary needs.”

But that’s not always possible in Haiti, mostly because of poor infrastructure, according to Caleb Lucien, founder of Hosean International Ministries.

“For example, the earthquake took place in the south of Haiti,” said Mr. Lucien, who is Haitian. “There has been some gang violence blocking passage from Port-au-Prince [the capital] to the south. Because of the gang fighting, it has been difficult to take the risk of traveling by road. So, airplanes from the capital city have been trying to get supplies there.”
 

More than resilient

Haitians are usually applauded for their inner strength to keep pushing amid crises. But it’s important to understand that there is often grief behind their resiliency, according to Ms. Jean.

“Sometimes I struggle with that word,” she said. “When I say resilient, I mean they will survive. But we are talking about a traumatized people. I definitely believe the people of Haiti are a people that have PTSD. The Haitian people have not yet fully healed from the first earthquake. I don’t think there was time. And many Haitians are suffering silently right now.”

The trauma shows itself in various ways, said Wilford Marous, entrepreneur and founder of the Haitian Chamber of Commerce in Great Britain.

“I went traveling in Europe with some colleagues of mine to attend some conferences, and one of them, who is Haitian, refused to sleep in a building because he believed it was too high,” he said. “He still had this fear of the earthquake.”

Children are often most affected, Mr. Fitts said.

“They don’t know what to do with it,” he said. “Their parents are not there necessarily to give them the emotional support that they need because they’re just trying to survive when things like this happen. So, a lot of things don’t get addressed and they’re taught early on to move on.”

Hosean International Ministries evacuated 1,500 people after the earthquake in 2010, and 750 of them were kids. The group stayed on the charity’s campground, and children had the chance to continue their education through its school system.

“Kids had issues sleeping,” Mr. Lucien said. “They are dealing with the loss of their loved ones. Some of them lost their moms. Some lost their brothers and sisters. So, we had to work with them and try to get them through that process.”

The charity offered children and their parents counseling sessions to lessen some of the emotional impact after the earthquake.
 

Common trauma responses

But keep in mind that symptoms like depression and sleeplessness would be common for most people going through mental health crises, such as major natural disasters or war, said Guglielmo Schininà, head of mental health and psychosocial support at the International Organization for Migration.

“It’s important not to jump to conclusions with diagnoses for mental illness or disorders,” Mr. Schininà said. “Suffering exists and suffering is not a mental disorder and shouldn’t be treated as such. In other situations, psychological effects like these could be symptoms of mental disorders. But in this situation, these are just normal reactions.”

Alongside trauma from natural disasters, many Haitians are angry about the chaos in the country, given the number of resources brought to Haiti over the past decade, according to Ms. Jean.

“We should have had better infrastructure, better roads, lights, emergency plans, trauma hospitals,” she said. “The resources were there.”

The constant lack of safety and security within the country can have ugly outcomes, she said.

“A lot of the political instability, rebels, gang activity, and war within those in politics has been because oppositions feel that those who are in power have not done a very good job of upgrading the Haitian lifestyle,” Ms. Jean said.

Unity and public togetherness are key in times like these, Mr. Marous said. He suggests finding creative ways to promote widespread healing.

“Even if it’s trying to start some sort of healing process through the media,” he said. “Having someone talk to the population, even on TV, 1 hour in the morning. That might be a way to offer some sort of help to the population at large.”
 

Strategic rebuilding

Haitians across the world are rallying together to keep spirits high, while also helping with recovery efforts, Ms. Jean said.

“We have to step in for the morale of the young people,” she said. “They’re tired. They’re hungry. They want to be cared for. So, our role in the diaspora is really critical in helping Haitians come out of this very traumatic time.”

Hosean International Ministries is organizing and sending supplies to parts of Haiti hardest hit by the earthquake. The ministry is also helping to rebuild some of the homes destroyed by the earthquake.

It’s important to keep in mind lessons learned from past recovery efforts, said Mr. Lucien.

“What we need to do is work with local leaders, asking them exactly what it is that they need,” he said. “The tendency is to rush and say what you’re going to bring. People brought things in 2010 that were not needed. Look for people on the ground, and work with them to provide the help.”

“My call to the international community is how can we come alongside of this resilient nation to alleviate some of the pressure,” Jean said. “But whether or not the help comes, I do believe the Haitian people, yet again, will rise day to day, until we restore and rebuild again.”

This is certainly true for Mr. Verdieu.

He has already launched an online campaign to rebuild his home.

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

Steeve Verdieu was at his workstation in his bedroom when the shaking started the morning of Aug. 14. He jumped under his desk and held on as a 7.2-magnitude earthquake tore through his childhood home in southern Haiti.

Mr. Verdieu, 25, said all he could think about was 2010, when a strong earthquake hit the country and left more than 200,000 people dead.

“Most of these adults that are in their mid-20s and 30s have vivid memories,” according to John Fitts, assistant director of Sent To Serve. He started working in the nonprofit sector in Haiti after the 2010 earthquake.

“I can’t even relate to it,” Mr. Fitts said. “If you didn’t live through it, you cannot relate.”

Mr. Verdieu emerged to find his family alive and his home in crumbles.

“In the neighborhood, we have only one child who died the day of the earthquake, but mentally, everybody feels bad,” he said. “Also, we are really frustrated right now because it tends to rain, and everybody is outside right now. So, we are a little bit afraid.”

Mr. Verdieu said that his community has not seen or heard of government authorities coming to offer guidance on next steps.

So, he started posting photos and videos to his Twitter account to seek help.
 

Surviving to heal

Many Haitians are forced to quickly turn the page after major crises, said Mr. Fitts.

“Survival overrides emotional shock,” he said. “They’re not going to have time. They’re not going to think emotional wellness at this point. It’s not addressed because they don’t have the opportunity to address it. So, it gets buried.”

More rural areas of Haiti were hit hardest by the recent earthquake, which killed over 2,000 people.

Many people were left without shelter and had limited access to food, clean drinking water, and medical help for those severely injured.

But current problems in Haiti, like shaky leadership after the recent assassination of the country’s president, left many people with no direction on what to do next.

With no information coming in, many, like Mr. Verdieu, took to social media or tried calling family and friends to find help on their own.

Having access to basic needs, like food and water, lessens the emotional trauma after these types of disasters, according to Betty Jean, a licensed professional counselor and global mental health and trauma consultant.

“When there is a crisis like an earthquake, the number one thing people need is a sense of safety and that there are entities that are concerned about their overall well-being,” said Ms. Jean, who is Haitian. “The emotional and mental support that we have to provide to people begins first with attending to those primary needs.”

But that’s not always possible in Haiti, mostly because of poor infrastructure, according to Caleb Lucien, founder of Hosean International Ministries.

“For example, the earthquake took place in the south of Haiti,” said Mr. Lucien, who is Haitian. “There has been some gang violence blocking passage from Port-au-Prince [the capital] to the south. Because of the gang fighting, it has been difficult to take the risk of traveling by road. So, airplanes from the capital city have been trying to get supplies there.”
 

More than resilient

Haitians are usually applauded for their inner strength to keep pushing amid crises. But it’s important to understand that there is often grief behind their resiliency, according to Ms. Jean.

“Sometimes I struggle with that word,” she said. “When I say resilient, I mean they will survive. But we are talking about a traumatized people. I definitely believe the people of Haiti are a people that have PTSD. The Haitian people have not yet fully healed from the first earthquake. I don’t think there was time. And many Haitians are suffering silently right now.”

The trauma shows itself in various ways, said Wilford Marous, entrepreneur and founder of the Haitian Chamber of Commerce in Great Britain.

“I went traveling in Europe with some colleagues of mine to attend some conferences, and one of them, who is Haitian, refused to sleep in a building because he believed it was too high,” he said. “He still had this fear of the earthquake.”

Children are often most affected, Mr. Fitts said.

“They don’t know what to do with it,” he said. “Their parents are not there necessarily to give them the emotional support that they need because they’re just trying to survive when things like this happen. So, a lot of things don’t get addressed and they’re taught early on to move on.”

Hosean International Ministries evacuated 1,500 people after the earthquake in 2010, and 750 of them were kids. The group stayed on the charity’s campground, and children had the chance to continue their education through its school system.

“Kids had issues sleeping,” Mr. Lucien said. “They are dealing with the loss of their loved ones. Some of them lost their moms. Some lost their brothers and sisters. So, we had to work with them and try to get them through that process.”

The charity offered children and their parents counseling sessions to lessen some of the emotional impact after the earthquake.
 

Common trauma responses

But keep in mind that symptoms like depression and sleeplessness would be common for most people going through mental health crises, such as major natural disasters or war, said Guglielmo Schininà, head of mental health and psychosocial support at the International Organization for Migration.

“It’s important not to jump to conclusions with diagnoses for mental illness or disorders,” Mr. Schininà said. “Suffering exists and suffering is not a mental disorder and shouldn’t be treated as such. In other situations, psychological effects like these could be symptoms of mental disorders. But in this situation, these are just normal reactions.”

Alongside trauma from natural disasters, many Haitians are angry about the chaos in the country, given the number of resources brought to Haiti over the past decade, according to Ms. Jean.

“We should have had better infrastructure, better roads, lights, emergency plans, trauma hospitals,” she said. “The resources were there.”

The constant lack of safety and security within the country can have ugly outcomes, she said.

“A lot of the political instability, rebels, gang activity, and war within those in politics has been because oppositions feel that those who are in power have not done a very good job of upgrading the Haitian lifestyle,” Ms. Jean said.

Unity and public togetherness are key in times like these, Mr. Marous said. He suggests finding creative ways to promote widespread healing.

“Even if it’s trying to start some sort of healing process through the media,” he said. “Having someone talk to the population, even on TV, 1 hour in the morning. That might be a way to offer some sort of help to the population at large.”
 

Strategic rebuilding

Haitians across the world are rallying together to keep spirits high, while also helping with recovery efforts, Ms. Jean said.

“We have to step in for the morale of the young people,” she said. “They’re tired. They’re hungry. They want to be cared for. So, our role in the diaspora is really critical in helping Haitians come out of this very traumatic time.”

Hosean International Ministries is organizing and sending supplies to parts of Haiti hardest hit by the earthquake. The ministry is also helping to rebuild some of the homes destroyed by the earthquake.

It’s important to keep in mind lessons learned from past recovery efforts, said Mr. Lucien.

“What we need to do is work with local leaders, asking them exactly what it is that they need,” he said. “The tendency is to rush and say what you’re going to bring. People brought things in 2010 that were not needed. Look for people on the ground, and work with them to provide the help.”

“My call to the international community is how can we come alongside of this resilient nation to alleviate some of the pressure,” Jean said. “But whether or not the help comes, I do believe the Haitian people, yet again, will rise day to day, until we restore and rebuild again.”

This is certainly true for Mr. Verdieu.

He has already launched an online campaign to rebuild his home.

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

Steeve Verdieu was at his workstation in his bedroom when the shaking started the morning of Aug. 14. He jumped under his desk and held on as a 7.2-magnitude earthquake tore through his childhood home in southern Haiti.

Mr. Verdieu, 25, said all he could think about was 2010, when a strong earthquake hit the country and left more than 200,000 people dead.

“Most of these adults that are in their mid-20s and 30s have vivid memories,” according to John Fitts, assistant director of Sent To Serve. He started working in the nonprofit sector in Haiti after the 2010 earthquake.

“I can’t even relate to it,” Mr. Fitts said. “If you didn’t live through it, you cannot relate.”

Mr. Verdieu emerged to find his family alive and his home in crumbles.

“In the neighborhood, we have only one child who died the day of the earthquake, but mentally, everybody feels bad,” he said. “Also, we are really frustrated right now because it tends to rain, and everybody is outside right now. So, we are a little bit afraid.”

Mr. Verdieu said that his community has not seen or heard of government authorities coming to offer guidance on next steps.

So, he started posting photos and videos to his Twitter account to seek help.
 

Surviving to heal

Many Haitians are forced to quickly turn the page after major crises, said Mr. Fitts.

“Survival overrides emotional shock,” he said. “They’re not going to have time. They’re not going to think emotional wellness at this point. It’s not addressed because they don’t have the opportunity to address it. So, it gets buried.”

More rural areas of Haiti were hit hardest by the recent earthquake, which killed over 2,000 people.

Many people were left without shelter and had limited access to food, clean drinking water, and medical help for those severely injured.

But current problems in Haiti, like shaky leadership after the recent assassination of the country’s president, left many people with no direction on what to do next.

With no information coming in, many, like Mr. Verdieu, took to social media or tried calling family and friends to find help on their own.

Having access to basic needs, like food and water, lessens the emotional trauma after these types of disasters, according to Betty Jean, a licensed professional counselor and global mental health and trauma consultant.

“When there is a crisis like an earthquake, the number one thing people need is a sense of safety and that there are entities that are concerned about their overall well-being,” said Ms. Jean, who is Haitian. “The emotional and mental support that we have to provide to people begins first with attending to those primary needs.”

But that’s not always possible in Haiti, mostly because of poor infrastructure, according to Caleb Lucien, founder of Hosean International Ministries.

“For example, the earthquake took place in the south of Haiti,” said Mr. Lucien, who is Haitian. “There has been some gang violence blocking passage from Port-au-Prince [the capital] to the south. Because of the gang fighting, it has been difficult to take the risk of traveling by road. So, airplanes from the capital city have been trying to get supplies there.”
 

More than resilient

Haitians are usually applauded for their inner strength to keep pushing amid crises. But it’s important to understand that there is often grief behind their resiliency, according to Ms. Jean.

“Sometimes I struggle with that word,” she said. “When I say resilient, I mean they will survive. But we are talking about a traumatized people. I definitely believe the people of Haiti are a people that have PTSD. The Haitian people have not yet fully healed from the first earthquake. I don’t think there was time. And many Haitians are suffering silently right now.”

The trauma shows itself in various ways, said Wilford Marous, entrepreneur and founder of the Haitian Chamber of Commerce in Great Britain.

“I went traveling in Europe with some colleagues of mine to attend some conferences, and one of them, who is Haitian, refused to sleep in a building because he believed it was too high,” he said. “He still had this fear of the earthquake.”

Children are often most affected, Mr. Fitts said.

“They don’t know what to do with it,” he said. “Their parents are not there necessarily to give them the emotional support that they need because they’re just trying to survive when things like this happen. So, a lot of things don’t get addressed and they’re taught early on to move on.”

Hosean International Ministries evacuated 1,500 people after the earthquake in 2010, and 750 of them were kids. The group stayed on the charity’s campground, and children had the chance to continue their education through its school system.

“Kids had issues sleeping,” Mr. Lucien said. “They are dealing with the loss of their loved ones. Some of them lost their moms. Some lost their brothers and sisters. So, we had to work with them and try to get them through that process.”

The charity offered children and their parents counseling sessions to lessen some of the emotional impact after the earthquake.
 

Common trauma responses

But keep in mind that symptoms like depression and sleeplessness would be common for most people going through mental health crises, such as major natural disasters or war, said Guglielmo Schininà, head of mental health and psychosocial support at the International Organization for Migration.

“It’s important not to jump to conclusions with diagnoses for mental illness or disorders,” Mr. Schininà said. “Suffering exists and suffering is not a mental disorder and shouldn’t be treated as such. In other situations, psychological effects like these could be symptoms of mental disorders. But in this situation, these are just normal reactions.”

Alongside trauma from natural disasters, many Haitians are angry about the chaos in the country, given the number of resources brought to Haiti over the past decade, according to Ms. Jean.

“We should have had better infrastructure, better roads, lights, emergency plans, trauma hospitals,” she said. “The resources were there.”

The constant lack of safety and security within the country can have ugly outcomes, she said.

“A lot of the political instability, rebels, gang activity, and war within those in politics has been because oppositions feel that those who are in power have not done a very good job of upgrading the Haitian lifestyle,” Ms. Jean said.

Unity and public togetherness are key in times like these, Mr. Marous said. He suggests finding creative ways to promote widespread healing.

“Even if it’s trying to start some sort of healing process through the media,” he said. “Having someone talk to the population, even on TV, 1 hour in the morning. That might be a way to offer some sort of help to the population at large.”
 

Strategic rebuilding

Haitians across the world are rallying together to keep spirits high, while also helping with recovery efforts, Ms. Jean said.

“We have to step in for the morale of the young people,” she said. “They’re tired. They’re hungry. They want to be cared for. So, our role in the diaspora is really critical in helping Haitians come out of this very traumatic time.”

Hosean International Ministries is organizing and sending supplies to parts of Haiti hardest hit by the earthquake. The ministry is also helping to rebuild some of the homes destroyed by the earthquake.

It’s important to keep in mind lessons learned from past recovery efforts, said Mr. Lucien.

“What we need to do is work with local leaders, asking them exactly what it is that they need,” he said. “The tendency is to rush and say what you’re going to bring. People brought things in 2010 that were not needed. Look for people on the ground, and work with them to provide the help.”

“My call to the international community is how can we come alongside of this resilient nation to alleviate some of the pressure,” Jean said. “But whether or not the help comes, I do believe the Haitian people, yet again, will rise day to day, until we restore and rebuild again.”

This is certainly true for Mr. Verdieu.

He has already launched an online campaign to rebuild his home.

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

The United States could get the COVID-19 pandemic under control by the spring of 2022 if enough Americans become vaccinated, Anthony S. Fauci, MD, said.

Speaking to Anderson Cooper on CNN, Dr. Fauci corrected the timeline he gave in an interview earlier with Mary Louise Kelly of NPR.

In the NPR interview, he had said that if “the overwhelming majority of the people vaccinated, I think as we get into the fall and the winter, we could start to really get some good control over this as we get into 2022.”

Dr. Fauci told Mr. Cooper that he listened to a recording of the NPR interview later and realized his mistake.

“I meant to say the spring of 2022,” Dr. Fauci told CNN. “I misspoke. My bad.”

Dr. Fauci, the head of the National Institute of Allergy and Infectious Diseases and the chief White House medical adviser, said the pandemic will be under control when the large majority of Americans have gotten vaccinated or been infected with COVID-19 and recovered, which offers some protection against the virus.

People who have been infected and recovered should still get vaccinated, he said.

“The degree of protection you could induce in someone who’s been infected and then recovered and then vaccinated is an enormous increase in the degree of protection,” Dr. Fauci said.

“I think we can get a degree of overall blanket protection of the community that as we get into the early part of 2022 ... we could start getting back to a degree of normality.”

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

The United States could get the COVID-19 pandemic under control by the spring of 2022 if enough Americans become vaccinated, Anthony S. Fauci, MD, said.

Speaking to Anderson Cooper on CNN, Dr. Fauci corrected the timeline he gave in an interview earlier with Mary Louise Kelly of NPR.

In the NPR interview, he had said that if “the overwhelming majority of the people vaccinated, I think as we get into the fall and the winter, we could start to really get some good control over this as we get into 2022.”

Dr. Fauci told Mr. Cooper that he listened to a recording of the NPR interview later and realized his mistake.

“I meant to say the spring of 2022,” Dr. Fauci told CNN. “I misspoke. My bad.”

Dr. Fauci, the head of the National Institute of Allergy and Infectious Diseases and the chief White House medical adviser, said the pandemic will be under control when the large majority of Americans have gotten vaccinated or been infected with COVID-19 and recovered, which offers some protection against the virus.

People who have been infected and recovered should still get vaccinated, he said.

“The degree of protection you could induce in someone who’s been infected and then recovered and then vaccinated is an enormous increase in the degree of protection,” Dr. Fauci said.

“I think we can get a degree of overall blanket protection of the community that as we get into the early part of 2022 ... we could start getting back to a degree of normality.”

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

The United States could get the COVID-19 pandemic under control by the spring of 2022 if enough Americans become vaccinated, Anthony S. Fauci, MD, said.

Speaking to Anderson Cooper on CNN, Dr. Fauci corrected the timeline he gave in an interview earlier with Mary Louise Kelly of NPR.

In the NPR interview, he had said that if “the overwhelming majority of the people vaccinated, I think as we get into the fall and the winter, we could start to really get some good control over this as we get into 2022.”

Dr. Fauci told Mr. Cooper that he listened to a recording of the NPR interview later and realized his mistake.

“I meant to say the spring of 2022,” Dr. Fauci told CNN. “I misspoke. My bad.”

Dr. Fauci, the head of the National Institute of Allergy and Infectious Diseases and the chief White House medical adviser, said the pandemic will be under control when the large majority of Americans have gotten vaccinated or been infected with COVID-19 and recovered, which offers some protection against the virus.

People who have been infected and recovered should still get vaccinated, he said.

“The degree of protection you could induce in someone who’s been infected and then recovered and then vaccinated is an enormous increase in the degree of protection,” Dr. Fauci said.

“I think we can get a degree of overall blanket protection of the community that as we get into the early part of 2022 ... we could start getting back to a degree of normality.”

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

The novel calcitonin gene-related peptide (CGRP) antagonist atogepant is safe and effective for the preventive treatment of migraine, full results from a phase 3 trial suggest.

AbbVie, the company developing the oral therapy, announced topline results of the ADVANCE trial of atogepant last year. Safety results were presented in April at the 2021 annual meeting of the American Academy of Neurology.

The full results were published online Aug. 19 in the New England Journal of Medicine ahead of the upcoming target action date of the U.S. Food and Drug Administration.

The multicenter study included nearly 900 patients who were randomly assigned to receive either placebo or one of three doses of atogepant for 12 weeks. The mean number of monthly migraine days decreased by about 4 for all three doses of the active treatment, compared with a reduction of 2.5 days with placebo.

All doses effective

The study included 873 patients with episodic migraine with or without aura. Patients who were not assigned to the placebo control group received either 10 mg, 30 mg, or 60 mg of atogepant once daily.

After a 4-week screening period, all patients received treatment for 12 weeks and then entered a 4-week safety follow-up period. In total, the participants completed eight scheduled clinical visits.

The mean reduction from baseline in the mean number of migraine days per month was 3.7 with the 10-mg dose of atogepant, 3.9 with the 30-mg dose, 4.2 with the 60-mg dose, and 2.5 with placebo. The differences between each active dose and placebo was statistically significant (P < .001).

Treatment with the CGRP inhibitor was also associated with a reduction in the mean number of headache days per month. The mean reduction from baseline was 3.9 days for the 10-mg dose, 4.0 days for the 30-mg dose, 4.2 days for the 60-mg dose, and 2.5 days for placebo (P < .001 for all comparisons with placebo).

In addition, for 55.6% of the 10-mg group, 58.7% of the 30-mg group, 60.8% of the 60-mg group, and 29.0% of the control group, there was a reduction of at least 50% in the 3-month average number of migraine days per month (P < .001 for each vs. placebo).

The most commonly reported adverse events (AEs) among patients who received atogepant were constipation (6.9%-7.7% across doses), nausea (4.4%-6.1%), and upper respiratory tract infection (1.4%-3.9%). Frequency of AEs did not differ between the active-treatment groups and the control group, and no relationships between AEs and atogepant dose were observed.
 

Multidose flexibility

“Side effects were pretty even across the board,” said Dr. Ailani. She noted that the reported AEs were expected because of atogepant’s mechanism of action. In addition, the rate of discontinuation in the study was low.

The proportion of participants who experienced a reduction in monthly migraine days of at least 50% grew as time passed. “By the end of this study, your chance of having a greater than 50% response is about 75%,” Dr. Ailani said.

“Imagine telling your patient, ‘You stick on this drug for 3 months, and I can almost guarantee you that you’re going to get better,’” she added.

Although the treatment has no drug-drug contraindications, drug-drug interactions may occur. “The availability of various doses would allow clinicians to adjust treatment to avoid potential drug-drug interactions,” said Dr. Ailani. “That multidose flexibility is very important.”

An FDA decision on atogepant could be made in the coming months. “I’m hopeful, as a clinician, that it is positive news, because we really have waited a long time for something like this,” Dr. Ailani said.

“You can easily identify patients who would do well on this medication,” she added.

In a different study of atogepant among patients with chronic migraine, there were recruitment delays because of the pandemic. That study is now almost complete, Dr. Ailani reported.
 

“Well-conducted study”

Commenting on the findings, Kathleen B. Digre, MD, chief of the division of headache and neuro-ophthalmology at the University of Utah Health, Salt Lake City, expressed enthusiasm for the experimental drug. “I’m excited to see another treatment modality for migraine,” said Dr. Digre, who was not involved with the research. “It was a very well-conducted study,” she added.

The treatment arms were almost identical in regard to disease severity, and all the doses showed an effect. Although the difference in reduction of monthly migraine days in comparison with placebo was numerically small, “for people who have frequent migraine, it’s important,” Dr. Digre said.

The results for atogepant should be viewed in a larger context, however. “Even though it’s a treatment that works better than placebo for well-matched controls, it may not be a medication that everybody’s going to respond to,” she noted. “And we can’t generalize it for some of the most disabled people, which is for chronic migraine,” she said.

It is significant that the study was published in the New England Journal of Medicine, Dr. Digre noted. “Sometimes migraine is dismissed as not important and not affecting people’s lives,” she said. “That makes me very happy to see migraine being taken seriously by our major journals.”

In addition, she noted that the prospects for FDA approval of atogepant seem favorable. “I’m hopeful that they will approve it, because it’s got a low side-effect profile, plus it’s effective.”

Migraine-specific preventive therapy has emerged only in the past few years. “I’m so excited to see this surge of preventive medicine for migraine,” Dr. Digre said. “It’s so important, because we see so many people who are disabled by migraine,” she added.

The study was funded by Allergan before atogepant was acquired by AbbVie. Dr. Ailani has received honoraria from AbbVie for consulting, has received compensation from Allergan and AbbVie for participating in a speakers’ bureau, and has received clinical trial grants from Allergan. Dr. Digre has reported no relevant financial relationships.

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

The novel calcitonin gene-related peptide (CGRP) antagonist atogepant is safe and effective for the preventive treatment of migraine, full results from a phase 3 trial suggest.

AbbVie, the company developing the oral therapy, announced topline results of the ADVANCE trial of atogepant last year. Safety results were presented in April at the 2021 annual meeting of the American Academy of Neurology.

The full results were published online Aug. 19 in the New England Journal of Medicine ahead of the upcoming target action date of the U.S. Food and Drug Administration.

The multicenter study included nearly 900 patients who were randomly assigned to receive either placebo or one of three doses of atogepant for 12 weeks. The mean number of monthly migraine days decreased by about 4 for all three doses of the active treatment, compared with a reduction of 2.5 days with placebo.

All doses effective

The study included 873 patients with episodic migraine with or without aura. Patients who were not assigned to the placebo control group received either 10 mg, 30 mg, or 60 mg of atogepant once daily.

After a 4-week screening period, all patients received treatment for 12 weeks and then entered a 4-week safety follow-up period. In total, the participants completed eight scheduled clinical visits.

The mean reduction from baseline in the mean number of migraine days per month was 3.7 with the 10-mg dose of atogepant, 3.9 with the 30-mg dose, 4.2 with the 60-mg dose, and 2.5 with placebo. The differences between each active dose and placebo was statistically significant (P < .001).

Treatment with the CGRP inhibitor was also associated with a reduction in the mean number of headache days per month. The mean reduction from baseline was 3.9 days for the 10-mg dose, 4.0 days for the 30-mg dose, 4.2 days for the 60-mg dose, and 2.5 days for placebo (P < .001 for all comparisons with placebo).

In addition, for 55.6% of the 10-mg group, 58.7% of the 30-mg group, 60.8% of the 60-mg group, and 29.0% of the control group, there was a reduction of at least 50% in the 3-month average number of migraine days per month (P < .001 for each vs. placebo).

The most commonly reported adverse events (AEs) among patients who received atogepant were constipation (6.9%-7.7% across doses), nausea (4.4%-6.1%), and upper respiratory tract infection (1.4%-3.9%). Frequency of AEs did not differ between the active-treatment groups and the control group, and no relationships between AEs and atogepant dose were observed.
 

Multidose flexibility

“Side effects were pretty even across the board,” said Dr. Ailani. She noted that the reported AEs were expected because of atogepant’s mechanism of action. In addition, the rate of discontinuation in the study was low.

The proportion of participants who experienced a reduction in monthly migraine days of at least 50% grew as time passed. “By the end of this study, your chance of having a greater than 50% response is about 75%,” Dr. Ailani said.

“Imagine telling your patient, ‘You stick on this drug for 3 months, and I can almost guarantee you that you’re going to get better,’” she added.

Although the treatment has no drug-drug contraindications, drug-drug interactions may occur. “The availability of various doses would allow clinicians to adjust treatment to avoid potential drug-drug interactions,” said Dr. Ailani. “That multidose flexibility is very important.”

An FDA decision on atogepant could be made in the coming months. “I’m hopeful, as a clinician, that it is positive news, because we really have waited a long time for something like this,” Dr. Ailani said.

“You can easily identify patients who would do well on this medication,” she added.

In a different study of atogepant among patients with chronic migraine, there were recruitment delays because of the pandemic. That study is now almost complete, Dr. Ailani reported.
 

“Well-conducted study”

Commenting on the findings, Kathleen B. Digre, MD, chief of the division of headache and neuro-ophthalmology at the University of Utah Health, Salt Lake City, expressed enthusiasm for the experimental drug. “I’m excited to see another treatment modality for migraine,” said Dr. Digre, who was not involved with the research. “It was a very well-conducted study,” she added.

The treatment arms were almost identical in regard to disease severity, and all the doses showed an effect. Although the difference in reduction of monthly migraine days in comparison with placebo was numerically small, “for people who have frequent migraine, it’s important,” Dr. Digre said.

The results for atogepant should be viewed in a larger context, however. “Even though it’s a treatment that works better than placebo for well-matched controls, it may not be a medication that everybody’s going to respond to,” she noted. “And we can’t generalize it for some of the most disabled people, which is for chronic migraine,” she said.

It is significant that the study was published in the New England Journal of Medicine, Dr. Digre noted. “Sometimes migraine is dismissed as not important and not affecting people’s lives,” she said. “That makes me very happy to see migraine being taken seriously by our major journals.”

In addition, she noted that the prospects for FDA approval of atogepant seem favorable. “I’m hopeful that they will approve it, because it’s got a low side-effect profile, plus it’s effective.”

Migraine-specific preventive therapy has emerged only in the past few years. “I’m so excited to see this surge of preventive medicine for migraine,” Dr. Digre said. “It’s so important, because we see so many people who are disabled by migraine,” she added.

The study was funded by Allergan before atogepant was acquired by AbbVie. Dr. Ailani has received honoraria from AbbVie for consulting, has received compensation from Allergan and AbbVie for participating in a speakers’ bureau, and has received clinical trial grants from Allergan. Dr. Digre has reported no relevant financial relationships.

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

The novel calcitonin gene-related peptide (CGRP) antagonist atogepant is safe and effective for the preventive treatment of migraine, full results from a phase 3 trial suggest.

AbbVie, the company developing the oral therapy, announced topline results of the ADVANCE trial of atogepant last year. Safety results were presented in April at the 2021 annual meeting of the American Academy of Neurology.

The full results were published online Aug. 19 in the New England Journal of Medicine ahead of the upcoming target action date of the U.S. Food and Drug Administration.

The multicenter study included nearly 900 patients who were randomly assigned to receive either placebo or one of three doses of atogepant for 12 weeks. The mean number of monthly migraine days decreased by about 4 for all three doses of the active treatment, compared with a reduction of 2.5 days with placebo.

All doses effective

The study included 873 patients with episodic migraine with or without aura. Patients who were not assigned to the placebo control group received either 10 mg, 30 mg, or 60 mg of atogepant once daily.

After a 4-week screening period, all patients received treatment for 12 weeks and then entered a 4-week safety follow-up period. In total, the participants completed eight scheduled clinical visits.

The mean reduction from baseline in the mean number of migraine days per month was 3.7 with the 10-mg dose of atogepant, 3.9 with the 30-mg dose, 4.2 with the 60-mg dose, and 2.5 with placebo. The differences between each active dose and placebo was statistically significant (P < .001).

Treatment with the CGRP inhibitor was also associated with a reduction in the mean number of headache days per month. The mean reduction from baseline was 3.9 days for the 10-mg dose, 4.0 days for the 30-mg dose, 4.2 days for the 60-mg dose, and 2.5 days for placebo (P < .001 for all comparisons with placebo).

In addition, for 55.6% of the 10-mg group, 58.7% of the 30-mg group, 60.8% of the 60-mg group, and 29.0% of the control group, there was a reduction of at least 50% in the 3-month average number of migraine days per month (P < .001 for each vs. placebo).

The most commonly reported adverse events (AEs) among patients who received atogepant were constipation (6.9%-7.7% across doses), nausea (4.4%-6.1%), and upper respiratory tract infection (1.4%-3.9%). Frequency of AEs did not differ between the active-treatment groups and the control group, and no relationships between AEs and atogepant dose were observed.
 

Multidose flexibility

“Side effects were pretty even across the board,” said Dr. Ailani. She noted that the reported AEs were expected because of atogepant’s mechanism of action. In addition, the rate of discontinuation in the study was low.

The proportion of participants who experienced a reduction in monthly migraine days of at least 50% grew as time passed. “By the end of this study, your chance of having a greater than 50% response is about 75%,” Dr. Ailani said.

“Imagine telling your patient, ‘You stick on this drug for 3 months, and I can almost guarantee you that you’re going to get better,’” she added.

Although the treatment has no drug-drug contraindications, drug-drug interactions may occur. “The availability of various doses would allow clinicians to adjust treatment to avoid potential drug-drug interactions,” said Dr. Ailani. “That multidose flexibility is very important.”

An FDA decision on atogepant could be made in the coming months. “I’m hopeful, as a clinician, that it is positive news, because we really have waited a long time for something like this,” Dr. Ailani said.

“You can easily identify patients who would do well on this medication,” she added.

In a different study of atogepant among patients with chronic migraine, there were recruitment delays because of the pandemic. That study is now almost complete, Dr. Ailani reported.
 

“Well-conducted study”

Commenting on the findings, Kathleen B. Digre, MD, chief of the division of headache and neuro-ophthalmology at the University of Utah Health, Salt Lake City, expressed enthusiasm for the experimental drug. “I’m excited to see another treatment modality for migraine,” said Dr. Digre, who was not involved with the research. “It was a very well-conducted study,” she added.

The treatment arms were almost identical in regard to disease severity, and all the doses showed an effect. Although the difference in reduction of monthly migraine days in comparison with placebo was numerically small, “for people who have frequent migraine, it’s important,” Dr. Digre said.

The results for atogepant should be viewed in a larger context, however. “Even though it’s a treatment that works better than placebo for well-matched controls, it may not be a medication that everybody’s going to respond to,” she noted. “And we can’t generalize it for some of the most disabled people, which is for chronic migraine,” she said.

It is significant that the study was published in the New England Journal of Medicine, Dr. Digre noted. “Sometimes migraine is dismissed as not important and not affecting people’s lives,” she said. “That makes me very happy to see migraine being taken seriously by our major journals.”

In addition, she noted that the prospects for FDA approval of atogepant seem favorable. “I’m hopeful that they will approve it, because it’s got a low side-effect profile, plus it’s effective.”

Migraine-specific preventive therapy has emerged only in the past few years. “I’m so excited to see this surge of preventive medicine for migraine,” Dr. Digre said. “It’s so important, because we see so many people who are disabled by migraine,” she added.

The study was funded by Allergan before atogepant was acquired by AbbVie. Dr. Ailani has received honoraria from AbbVie for consulting, has received compensation from Allergan and AbbVie for participating in a speakers’ bureau, and has received clinical trial grants from Allergan. Dr. Digre has reported no relevant financial relationships.

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

Many but not all children with juvenile idiopathic arthritis (JIA) can regain remission after stopping and then restarting treatment, according to preliminary data from the ongoing Recapture-JIA study that were presented in a symposium sponsored by the Rheumatology Research Foundation.

The aim of this study is to evaluate the risks of discontinuing treatment after a period when JIA has been well controlled. Such data are of increasing interest to parents now that many children with JIA are achieving sustained periods of remission, according to Sarah Ringold, MD, a pediatric rheumatologist and associate professor of pediatrics at Seattle Children’s Hospital.

In follow-up so far, “recapture rates range from 50% to 76%” depending on type of JIA, reported Dr. Ringold, who said that patients with systemic JIA have so far been the most likely to achieve a good response when treatment is restarted.

The study is being conducted through the Childhood Arthritis and Rheumatology Research Alliance, which has 71 participating centers and has accrued data on more than 10,000 children with rheumatic diseases. For the study, the researchers identified 384 children with JIA who were already enrolled in the CARRA registry and had discontinued medications and then subsequently restarted them, and they also enrolled a prospective cohort of patients new to the registry who presented with flare after discontinuing their medication. Dr. Ringold reported on 64 of the patients in the prospective cohort.
 

Median time to flare: 219 days

Of findings so far, disease recurrence after discontinuation has been generally characterized by flares “of moderate activity” several months to more than a year after treatment discontinuation, according to Dr. Ringold, who emphasized repeatedly that these data are preliminary. The median time to a flare after treatment discontinuation was approximately 7 months (219 days).

In the combined cohorts, the median age at onset of JIA was 4 years. The median age at time of discontinuation was 9 years. More than half (55%) were taking a conventional disease-modifying antirheumatic drug (DMARD) and 35% were taking a tumor necrosis factor inhibitor at the time that their therapy was discontinued.

Most JIA types are represented. The most common form is rheumatoid factor–negative oligoarticular JIA. The main outcome looked the rate of clinically inactive disease at 6 months in children who had discontinued therapy after a period of remission. They defined clinically inactive disease as a Physician’s Global Assessment of less than 1 and an active joint count of 0.

Systemic JIA recapture rate at 6 months: 76%

At the time of disease flare after treatment discontinuation across both the retrospective and prospective cohorts, the median clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS10; score range of 0-30) was 3.5. The recapture rate to clinically inactive disease at 6 months was 76% in those with systemic JIA and 50% in those with rheumatoid factor–positive polyarticular JIA. Other subtypes fell within this range. Rates of inactive disease at 6 months according to cJADAS10 score were lower, ranging from 26% with enthesitis-related arthritis/juvenile psoriatic arthritis to 57% with systemic JIA.

About 40% of those who restarted on therapy after a flare took the same medication again. About one-third of patients were restarted on glucocorticoids, mostly involving injections to inflamed joints, and data are not yet in about whether these were restarted alone or with other drugs, according to Dr. Ringold.

The final analysis of this study will explore clinical and laboratory variables associated with disease recapture. In the prospective cohort, which did not reach its planned enrollment of 150 children because the COVID pandemic, a broad array of these variables was evaluated at baseline.

Numerous studies have already looked at predictors of sustained remission after stopping medications of JIA, according to Dr. Ringold, but she said that there is relatively little information about outcomes in children who stop medications, flare, and are retreated. Other experts agree.

“We know little about how successfully DMARDs can be discontinued and used again after a disease flare,” reported Jens Klotsche, MD, a researcher at the German Rheumatism Research Center, which is part of the Leibniz Institute in Berlin. Dr. Klotsche, who is an author of a recent study that found etanercept effective for retreatment when children with JIA had discontinued therapy, agreed that “data from large cohort studies are necessary to support the treatment decisions by clinicians, parents, and patients.”

JIA recurrence risk is unclear

In a systematic review published 2 years ago, rates of flare following discontinuation of treatment for JIA were relatively high, but there were some limitations to this analysis, according to the lead author, Olha Halyabar, MD, a pediatric rheumatologist at Boston Children’s Hospital.

“The data in our systematic review showed that overall quality of evidence was low, with large variations and sometimes very different conclusions,” Dr. Halyabar said in an interview. She believes that the data generated by the CARRA analysis will be valuable, particularly in evaluating outcomes across subtypes.

“Even though, at this point, [previously published] reports indicate overall high rates of recurrence (>50% for some JIA subtypes), there are some encouraging studies from early treat-to-target strategies,” she said, adding that large datasets like those from CARRA offer an opportunity to gather data likely to be clinically useful.

Dr. Ringold cautioned that there are some limitations to the CARRA analysis, including some missing data from the retrospective cohort. She also pointed out that patients have been assessed at routine clinical visits rather than at standardized intervals, introducing a potential for bias.

For parents concerned about the costs, inconvenience, and side effects from sustained JIA treatment once remission is achieved, data from CARRA will allow clinicians to provide evidence-based counseling on balancing the risks of discontinuing therapy, including the likelihood of regaining remission when disease returns, against the goals of stopping treatment.

“Parents are having more conversations about when to stop medications,” Dr. Ringold said. She indicated that these data should be helpful for providing guidance.

Dr. Ringold, Dr. Klotsche, and Dr. Halyabar reported having no potential conflicts of interest.

Many but not all children with juvenile idiopathic arthritis (JIA) can regain remission after stopping and then restarting treatment, according to preliminary data from the ongoing Recapture-JIA study that were presented in a symposium sponsored by the Rheumatology Research Foundation.

The aim of this study is to evaluate the risks of discontinuing treatment after a period when JIA has been well controlled. Such data are of increasing interest to parents now that many children with JIA are achieving sustained periods of remission, according to Sarah Ringold, MD, a pediatric rheumatologist and associate professor of pediatrics at Seattle Children’s Hospital.

In follow-up so far, “recapture rates range from 50% to 76%” depending on type of JIA, reported Dr. Ringold, who said that patients with systemic JIA have so far been the most likely to achieve a good response when treatment is restarted.

The study is being conducted through the Childhood Arthritis and Rheumatology Research Alliance, which has 71 participating centers and has accrued data on more than 10,000 children with rheumatic diseases. For the study, the researchers identified 384 children with JIA who were already enrolled in the CARRA registry and had discontinued medications and then subsequently restarted them, and they also enrolled a prospective cohort of patients new to the registry who presented with flare after discontinuing their medication. Dr. Ringold reported on 64 of the patients in the prospective cohort.
 

Median time to flare: 219 days

Of findings so far, disease recurrence after discontinuation has been generally characterized by flares “of moderate activity” several months to more than a year after treatment discontinuation, according to Dr. Ringold, who emphasized repeatedly that these data are preliminary. The median time to a flare after treatment discontinuation was approximately 7 months (219 days).

In the combined cohorts, the median age at onset of JIA was 4 years. The median age at time of discontinuation was 9 years. More than half (55%) were taking a conventional disease-modifying antirheumatic drug (DMARD) and 35% were taking a tumor necrosis factor inhibitor at the time that their therapy was discontinued.

Most JIA types are represented. The most common form is rheumatoid factor–negative oligoarticular JIA. The main outcome looked the rate of clinically inactive disease at 6 months in children who had discontinued therapy after a period of remission. They defined clinically inactive disease as a Physician’s Global Assessment of less than 1 and an active joint count of 0.

Systemic JIA recapture rate at 6 months: 76%

At the time of disease flare after treatment discontinuation across both the retrospective and prospective cohorts, the median clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS10; score range of 0-30) was 3.5. The recapture rate to clinically inactive disease at 6 months was 76% in those with systemic JIA and 50% in those with rheumatoid factor–positive polyarticular JIA. Other subtypes fell within this range. Rates of inactive disease at 6 months according to cJADAS10 score were lower, ranging from 26% with enthesitis-related arthritis/juvenile psoriatic arthritis to 57% with systemic JIA.

About 40% of those who restarted on therapy after a flare took the same medication again. About one-third of patients were restarted on glucocorticoids, mostly involving injections to inflamed joints, and data are not yet in about whether these were restarted alone or with other drugs, according to Dr. Ringold.

The final analysis of this study will explore clinical and laboratory variables associated with disease recapture. In the prospective cohort, which did not reach its planned enrollment of 150 children because the COVID pandemic, a broad array of these variables was evaluated at baseline.

Numerous studies have already looked at predictors of sustained remission after stopping medications of JIA, according to Dr. Ringold, but she said that there is relatively little information about outcomes in children who stop medications, flare, and are retreated. Other experts agree.

“We know little about how successfully DMARDs can be discontinued and used again after a disease flare,” reported Jens Klotsche, MD, a researcher at the German Rheumatism Research Center, which is part of the Leibniz Institute in Berlin. Dr. Klotsche, who is an author of a recent study that found etanercept effective for retreatment when children with JIA had discontinued therapy, agreed that “data from large cohort studies are necessary to support the treatment decisions by clinicians, parents, and patients.”

JIA recurrence risk is unclear

In a systematic review published 2 years ago, rates of flare following discontinuation of treatment for JIA were relatively high, but there were some limitations to this analysis, according to the lead author, Olha Halyabar, MD, a pediatric rheumatologist at Boston Children’s Hospital.

“The data in our systematic review showed that overall quality of evidence was low, with large variations and sometimes very different conclusions,” Dr. Halyabar said in an interview. She believes that the data generated by the CARRA analysis will be valuable, particularly in evaluating outcomes across subtypes.

“Even though, at this point, [previously published] reports indicate overall high rates of recurrence (>50% for some JIA subtypes), there are some encouraging studies from early treat-to-target strategies,” she said, adding that large datasets like those from CARRA offer an opportunity to gather data likely to be clinically useful.

Dr. Ringold cautioned that there are some limitations to the CARRA analysis, including some missing data from the retrospective cohort. She also pointed out that patients have been assessed at routine clinical visits rather than at standardized intervals, introducing a potential for bias.

For parents concerned about the costs, inconvenience, and side effects from sustained JIA treatment once remission is achieved, data from CARRA will allow clinicians to provide evidence-based counseling on balancing the risks of discontinuing therapy, including the likelihood of regaining remission when disease returns, against the goals of stopping treatment.

“Parents are having more conversations about when to stop medications,” Dr. Ringold said. She indicated that these data should be helpful for providing guidance.

Dr. Ringold, Dr. Klotsche, and Dr. Halyabar reported having no potential conflicts of interest.

Many but not all children with juvenile idiopathic arthritis (JIA) can regain remission after stopping and then restarting treatment, according to preliminary data from the ongoing Recapture-JIA study that were presented in a symposium sponsored by the Rheumatology Research Foundation.

The aim of this study is to evaluate the risks of discontinuing treatment after a period when JIA has been well controlled. Such data are of increasing interest to parents now that many children with JIA are achieving sustained periods of remission, according to Sarah Ringold, MD, a pediatric rheumatologist and associate professor of pediatrics at Seattle Children’s Hospital.

In follow-up so far, “recapture rates range from 50% to 76%” depending on type of JIA, reported Dr. Ringold, who said that patients with systemic JIA have so far been the most likely to achieve a good response when treatment is restarted.

The study is being conducted through the Childhood Arthritis and Rheumatology Research Alliance, which has 71 participating centers and has accrued data on more than 10,000 children with rheumatic diseases. For the study, the researchers identified 384 children with JIA who were already enrolled in the CARRA registry and had discontinued medications and then subsequently restarted them, and they also enrolled a prospective cohort of patients new to the registry who presented with flare after discontinuing their medication. Dr. Ringold reported on 64 of the patients in the prospective cohort.
 

Median time to flare: 219 days

Of findings so far, disease recurrence after discontinuation has been generally characterized by flares “of moderate activity” several months to more than a year after treatment discontinuation, according to Dr. Ringold, who emphasized repeatedly that these data are preliminary. The median time to a flare after treatment discontinuation was approximately 7 months (219 days).

In the combined cohorts, the median age at onset of JIA was 4 years. The median age at time of discontinuation was 9 years. More than half (55%) were taking a conventional disease-modifying antirheumatic drug (DMARD) and 35% were taking a tumor necrosis factor inhibitor at the time that their therapy was discontinued.

Most JIA types are represented. The most common form is rheumatoid factor–negative oligoarticular JIA. The main outcome looked the rate of clinically inactive disease at 6 months in children who had discontinued therapy after a period of remission. They defined clinically inactive disease as a Physician’s Global Assessment of less than 1 and an active joint count of 0.

Systemic JIA recapture rate at 6 months: 76%

At the time of disease flare after treatment discontinuation across both the retrospective and prospective cohorts, the median clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS10; score range of 0-30) was 3.5. The recapture rate to clinically inactive disease at 6 months was 76% in those with systemic JIA and 50% in those with rheumatoid factor–positive polyarticular JIA. Other subtypes fell within this range. Rates of inactive disease at 6 months according to cJADAS10 score were lower, ranging from 26% with enthesitis-related arthritis/juvenile psoriatic arthritis to 57% with systemic JIA.

About 40% of those who restarted on therapy after a flare took the same medication again. About one-third of patients were restarted on glucocorticoids, mostly involving injections to inflamed joints, and data are not yet in about whether these were restarted alone or with other drugs, according to Dr. Ringold.

The final analysis of this study will explore clinical and laboratory variables associated with disease recapture. In the prospective cohort, which did not reach its planned enrollment of 150 children because the COVID pandemic, a broad array of these variables was evaluated at baseline.

Numerous studies have already looked at predictors of sustained remission after stopping medications of JIA, according to Dr. Ringold, but she said that there is relatively little information about outcomes in children who stop medications, flare, and are retreated. Other experts agree.

“We know little about how successfully DMARDs can be discontinued and used again after a disease flare,” reported Jens Klotsche, MD, a researcher at the German Rheumatism Research Center, which is part of the Leibniz Institute in Berlin. Dr. Klotsche, who is an author of a recent study that found etanercept effective for retreatment when children with JIA had discontinued therapy, agreed that “data from large cohort studies are necessary to support the treatment decisions by clinicians, parents, and patients.”

JIA recurrence risk is unclear

In a systematic review published 2 years ago, rates of flare following discontinuation of treatment for JIA were relatively high, but there were some limitations to this analysis, according to the lead author, Olha Halyabar, MD, a pediatric rheumatologist at Boston Children’s Hospital.

“The data in our systematic review showed that overall quality of evidence was low, with large variations and sometimes very different conclusions,” Dr. Halyabar said in an interview. She believes that the data generated by the CARRA analysis will be valuable, particularly in evaluating outcomes across subtypes.

“Even though, at this point, [previously published] reports indicate overall high rates of recurrence (>50% for some JIA subtypes), there are some encouraging studies from early treat-to-target strategies,” she said, adding that large datasets like those from CARRA offer an opportunity to gather data likely to be clinically useful.

Dr. Ringold cautioned that there are some limitations to the CARRA analysis, including some missing data from the retrospective cohort. She also pointed out that patients have been assessed at routine clinical visits rather than at standardized intervals, introducing a potential for bias.

For parents concerned about the costs, inconvenience, and side effects from sustained JIA treatment once remission is achieved, data from CARRA will allow clinicians to provide evidence-based counseling on balancing the risks of discontinuing therapy, including the likelihood of regaining remission when disease returns, against the goals of stopping treatment.

“Parents are having more conversations about when to stop medications,” Dr. Ringold said. She indicated that these data should be helpful for providing guidance.

Dr. Ringold, Dr. Klotsche, and Dr. Halyabar reported having no potential conflicts of interest.

The benefits of low-dose colchicine (Colcrys) are consistent if started months or years after acute coronary syndrome (ACS) in patients with stable coronary artery disease, a new LoDoCo2 subanalysis suggests.

As previously reported, the parent trial showed that adding colchicine 0.5 mg daily to standard care reduced the risk of the primary endpoint – a composite of cardiovascular (CV) death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization – by 31% compared with placebo.

In the new analysis, led by Tjerk S.J. Opstal, MD, the anti-inflammatory agent was equally effective in reducing the risk of the primary endpoint in patients with no prior ACS, a recent ACS (6-24 months), remote ACS (2-7 years), or very remote ACS (> 7 years), with no interaction found between groups (P = .59).

The incidence of the primary endpoint per 100 person-years and hazard ratios (HRs) for the four groups with colchicine and placebo are as follows:

• No prior ACS: 2.8 vs. 3.4; HR, 0.81 (95% confidence interval, 0.52-1.27).
• Recent ACS: 2.4 vs. 3.3; HR, 0.75 (95% CI, 0.51-1.10).
• Remote ACS: 1.8 vs. 3.2; HR, 0.55 (95% CI, 0.37-0.82)
• Very remote ACS: 3.0 vs. 4.3; HR, 0.70 (95% CI, 0.51-0.96).

The results were reported Aug. 23 in the Journal of the American College of Cardiology.

In contrast, however, a recent subgroup analysis from the COLCOT trial reported an even greater reduction in its primary composite CV endpoint when colchicine was started within 3 days of an MI.

“The result of COLCOT could imply that initiation of colchicine treatment would be best suited directly after myocardial infarction,” Dr. Opstal, from Radboud University Medical Center, Nijmegen, the Netherlands, said in an interview. “Our subanalysis shows that later initiation of colchicine therapy in patients visiting outpatient clinics years after their ACS events is equally effective. As such, colchicine therapy should not be limited to patients with recent ACS, and should be considered in all patients with coronary artery disease.”

Dr. Opstal pointed out that the two trials targeted different populations. COLCOT enrolled 4,765 patients within a month of MI, whereas LoDoCo2 enrolled 5,522 patients who were clinically stable for at least 6 months after an ACS or coronary revascularization.

Overall, 864 LoDoCo2 patients had no prior ACS and 86% had a history of ACS, of which 1,479 were recent, 1,582 were remote, and 1,597 were very remote.

Patients with a history of very remote ACS had a numerically higher event rate for the primary outcome, but the difference was not statistically significant and could be attributed to a play of chance, noted Dr. Opstal.

The team presumed patients with more recent prior ACS would remain at higher risk of ACS recurrence than would those with a more remote ACS that had proved to be clinically stable under standard medical therapy. But, he said, the data show they were at equal risk of the primary outcome.

“This implies that current optimal medical therapy does not result in an attenuation of residual risk over time regardless of whether patients are clinically stable, and that the ongoing process of atherosclerosis results in continuously elevated risk, which warrants new avenues of therapy, such as anti-inflammatory medication,” Dr. Opstal said.

In a binary analysis, there was no difference in composite cardiovascular events between patients with and without prior ACS (HR, 0.67 vs. HR, 0.81; P value for interaction, 0.43).

Dr. Opstal observed that a lack of statistical power precludes any definitive conclusions and that a large randomized controlled trial in patients with established coronary artery disease (CAD) but no prior ACS would elucidate whether early initiation of colchicine is “warranted at the moment CAD is established but before a first ACS event, as is common practice with acetylsalicylic acid and statins.”

In addition, the ongoing OASIS 9 trial will answer the question of whether patients with an estimated glomerular filtration rate of 30-60 mL/min can safely use low-dose colchicine. The gout medication is contraindicated in patients with severe renal or hepatic impairment and in patients on drugs that inhibit both CYP3A4 or the P-glycoprotein.

In an accompanying editorial, colchicine researchers Jean-Claude Tardif, MD, and Guillaume Marquis-Gravel, MD, of the Montreal Heart Institute, Quebec, Canada, suggest that study design features likely explain the discord between the LoDoCo2 and COLCOT subgroup analyses and the lack of difference in CV event rates between patients with and without prior ACS.

The editorialists say lingering questions remain, including the value of colchicine in patients with diabetes or peripheral artery disease without known CAD, but they also point out that three 2021 meta-analyses confirmed large reductions in the risk of CV events, MI, and coronary revascularization with low-dose colchicine.

“In light of the positive results from LoDoCo2, COLCOT, and meta-analyses; its good tolerability profile; and cost-effectiveness, inflammation reduction with low-dose colchicine should be considered to treat patients with coronary disease in the absence of severe renal dysfunction,” Dr. Tardif and Dr. Marquis-Gravel concluded.

The study was supported by the National Health Medical Research Council of Australia; a grant from the Sir Charles Gairdner Research Advisory Committee; the Withering Foundation; the Netherlands Heart Foundation; the Netherlands Organization for Health Research and Development; and a consortium of Teva, Disphar, and Tiofarma in the Netherlands. The funders had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript. Dr. Opstal reports no relevant financial relationships. Coauthor disclosures are listed in the original article.

Dr. Tardif has received grant support from Amarin, AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Novartis, Pfizer, RegenXBio, and Sanofi; has received honoraria from AstraZeneca, DalCor Pharmaceuticals, HLS Therapeutics, Pendopharm, and Sanofi; has minor equity interest in DalCor Pharmaceuticals; and is mentioned as an author on submitted patents on pharmacogenomics-guided CETP inhibition, use of colchicine after myocardial infarction, and use of colchicine in COVID-19 (he has waived his rights in the colchicine patents and does not stand to gain financially). Dr. Marquis-Gravel has received research grants from Bayer, has received speaker honoraria from Novartis, and has served on national advisory boards for Servier, JAMP, and Bayer.
 

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

The benefits of low-dose colchicine (Colcrys) are consistent if started months or years after acute coronary syndrome (ACS) in patients with stable coronary artery disease, a new LoDoCo2 subanalysis suggests.

As previously reported, the parent trial showed that adding colchicine 0.5 mg daily to standard care reduced the risk of the primary endpoint – a composite of cardiovascular (CV) death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization – by 31% compared with placebo.

In the new analysis, led by Tjerk S.J. Opstal, MD, the anti-inflammatory agent was equally effective in reducing the risk of the primary endpoint in patients with no prior ACS, a recent ACS (6-24 months), remote ACS (2-7 years), or very remote ACS (> 7 years), with no interaction found between groups (P = .59).

The incidence of the primary endpoint per 100 person-years and hazard ratios (HRs) for the four groups with colchicine and placebo are as follows:

• No prior ACS: 2.8 vs. 3.4; HR, 0.81 (95% confidence interval, 0.52-1.27).
• Recent ACS: 2.4 vs. 3.3; HR, 0.75 (95% CI, 0.51-1.10).
• Remote ACS: 1.8 vs. 3.2; HR, 0.55 (95% CI, 0.37-0.82)
• Very remote ACS: 3.0 vs. 4.3; HR, 0.70 (95% CI, 0.51-0.96).

The results were reported Aug. 23 in the Journal of the American College of Cardiology.

In contrast, however, a recent subgroup analysis from the COLCOT trial reported an even greater reduction in its primary composite CV endpoint when colchicine was started within 3 days of an MI.

“The result of COLCOT could imply that initiation of colchicine treatment would be best suited directly after myocardial infarction,” Dr. Opstal, from Radboud University Medical Center, Nijmegen, the Netherlands, said in an interview. “Our subanalysis shows that later initiation of colchicine therapy in patients visiting outpatient clinics years after their ACS events is equally effective. As such, colchicine therapy should not be limited to patients with recent ACS, and should be considered in all patients with coronary artery disease.”

Dr. Opstal pointed out that the two trials targeted different populations. COLCOT enrolled 4,765 patients within a month of MI, whereas LoDoCo2 enrolled 5,522 patients who were clinically stable for at least 6 months after an ACS or coronary revascularization.

Overall, 864 LoDoCo2 patients had no prior ACS and 86% had a history of ACS, of which 1,479 were recent, 1,582 were remote, and 1,597 were very remote.

Patients with a history of very remote ACS had a numerically higher event rate for the primary outcome, but the difference was not statistically significant and could be attributed to a play of chance, noted Dr. Opstal.

The team presumed patients with more recent prior ACS would remain at higher risk of ACS recurrence than would those with a more remote ACS that had proved to be clinically stable under standard medical therapy. But, he said, the data show they were at equal risk of the primary outcome.

“This implies that current optimal medical therapy does not result in an attenuation of residual risk over time regardless of whether patients are clinically stable, and that the ongoing process of atherosclerosis results in continuously elevated risk, which warrants new avenues of therapy, such as anti-inflammatory medication,” Dr. Opstal said.

In a binary analysis, there was no difference in composite cardiovascular events between patients with and without prior ACS (HR, 0.67 vs. HR, 0.81; P value for interaction, 0.43).

Dr. Opstal observed that a lack of statistical power precludes any definitive conclusions and that a large randomized controlled trial in patients with established coronary artery disease (CAD) but no prior ACS would elucidate whether early initiation of colchicine is “warranted at the moment CAD is established but before a first ACS event, as is common practice with acetylsalicylic acid and statins.”

In addition, the ongoing OASIS 9 trial will answer the question of whether patients with an estimated glomerular filtration rate of 30-60 mL/min can safely use low-dose colchicine. The gout medication is contraindicated in patients with severe renal or hepatic impairment and in patients on drugs that inhibit both CYP3A4 or the P-glycoprotein.

In an accompanying editorial, colchicine researchers Jean-Claude Tardif, MD, and Guillaume Marquis-Gravel, MD, of the Montreal Heart Institute, Quebec, Canada, suggest that study design features likely explain the discord between the LoDoCo2 and COLCOT subgroup analyses and the lack of difference in CV event rates between patients with and without prior ACS.

The editorialists say lingering questions remain, including the value of colchicine in patients with diabetes or peripheral artery disease without known CAD, but they also point out that three 2021 meta-analyses confirmed large reductions in the risk of CV events, MI, and coronary revascularization with low-dose colchicine.

“In light of the positive results from LoDoCo2, COLCOT, and meta-analyses; its good tolerability profile; and cost-effectiveness, inflammation reduction with low-dose colchicine should be considered to treat patients with coronary disease in the absence of severe renal dysfunction,” Dr. Tardif and Dr. Marquis-Gravel concluded.

The study was supported by the National Health Medical Research Council of Australia; a grant from the Sir Charles Gairdner Research Advisory Committee; the Withering Foundation; the Netherlands Heart Foundation; the Netherlands Organization for Health Research and Development; and a consortium of Teva, Disphar, and Tiofarma in the Netherlands. The funders had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript. Dr. Opstal reports no relevant financial relationships. Coauthor disclosures are listed in the original article.

Dr. Tardif has received grant support from Amarin, AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Novartis, Pfizer, RegenXBio, and Sanofi; has received honoraria from AstraZeneca, DalCor Pharmaceuticals, HLS Therapeutics, Pendopharm, and Sanofi; has minor equity interest in DalCor Pharmaceuticals; and is mentioned as an author on submitted patents on pharmacogenomics-guided CETP inhibition, use of colchicine after myocardial infarction, and use of colchicine in COVID-19 (he has waived his rights in the colchicine patents and does not stand to gain financially). Dr. Marquis-Gravel has received research grants from Bayer, has received speaker honoraria from Novartis, and has served on national advisory boards for Servier, JAMP, and Bayer.
 

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

The benefits of low-dose colchicine (Colcrys) are consistent if started months or years after acute coronary syndrome (ACS) in patients with stable coronary artery disease, a new LoDoCo2 subanalysis suggests.

As previously reported, the parent trial showed that adding colchicine 0.5 mg daily to standard care reduced the risk of the primary endpoint – a composite of cardiovascular (CV) death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization – by 31% compared with placebo.

In the new analysis, led by Tjerk S.J. Opstal, MD, the anti-inflammatory agent was equally effective in reducing the risk of the primary endpoint in patients with no prior ACS, a recent ACS (6-24 months), remote ACS (2-7 years), or very remote ACS (> 7 years), with no interaction found between groups (P = .59).

The incidence of the primary endpoint per 100 person-years and hazard ratios (HRs) for the four groups with colchicine and placebo are as follows:

• No prior ACS: 2.8 vs. 3.4; HR, 0.81 (95% confidence interval, 0.52-1.27).
• Recent ACS: 2.4 vs. 3.3; HR, 0.75 (95% CI, 0.51-1.10).
• Remote ACS: 1.8 vs. 3.2; HR, 0.55 (95% CI, 0.37-0.82)
• Very remote ACS: 3.0 vs. 4.3; HR, 0.70 (95% CI, 0.51-0.96).

The results were reported Aug. 23 in the Journal of the American College of Cardiology.

In contrast, however, a recent subgroup analysis from the COLCOT trial reported an even greater reduction in its primary composite CV endpoint when colchicine was started within 3 days of an MI.

“The result of COLCOT could imply that initiation of colchicine treatment would be best suited directly after myocardial infarction,” Dr. Opstal, from Radboud University Medical Center, Nijmegen, the Netherlands, said in an interview. “Our subanalysis shows that later initiation of colchicine therapy in patients visiting outpatient clinics years after their ACS events is equally effective. As such, colchicine therapy should not be limited to patients with recent ACS, and should be considered in all patients with coronary artery disease.”

Dr. Opstal pointed out that the two trials targeted different populations. COLCOT enrolled 4,765 patients within a month of MI, whereas LoDoCo2 enrolled 5,522 patients who were clinically stable for at least 6 months after an ACS or coronary revascularization.

Overall, 864 LoDoCo2 patients had no prior ACS and 86% had a history of ACS, of which 1,479 were recent, 1,582 were remote, and 1,597 were very remote.

Patients with a history of very remote ACS had a numerically higher event rate for the primary outcome, but the difference was not statistically significant and could be attributed to a play of chance, noted Dr. Opstal.

The team presumed patients with more recent prior ACS would remain at higher risk of ACS recurrence than would those with a more remote ACS that had proved to be clinically stable under standard medical therapy. But, he said, the data show they were at equal risk of the primary outcome.

“This implies that current optimal medical therapy does not result in an attenuation of residual risk over time regardless of whether patients are clinically stable, and that the ongoing process of atherosclerosis results in continuously elevated risk, which warrants new avenues of therapy, such as anti-inflammatory medication,” Dr. Opstal said.

In a binary analysis, there was no difference in composite cardiovascular events between patients with and without prior ACS (HR, 0.67 vs. HR, 0.81; P value for interaction, 0.43).

Dr. Opstal observed that a lack of statistical power precludes any definitive conclusions and that a large randomized controlled trial in patients with established coronary artery disease (CAD) but no prior ACS would elucidate whether early initiation of colchicine is “warranted at the moment CAD is established but before a first ACS event, as is common practice with acetylsalicylic acid and statins.”

In addition, the ongoing OASIS 9 trial will answer the question of whether patients with an estimated glomerular filtration rate of 30-60 mL/min can safely use low-dose colchicine. The gout medication is contraindicated in patients with severe renal or hepatic impairment and in patients on drugs that inhibit both CYP3A4 or the P-glycoprotein.

In an accompanying editorial, colchicine researchers Jean-Claude Tardif, MD, and Guillaume Marquis-Gravel, MD, of the Montreal Heart Institute, Quebec, Canada, suggest that study design features likely explain the discord between the LoDoCo2 and COLCOT subgroup analyses and the lack of difference in CV event rates between patients with and without prior ACS.

The editorialists say lingering questions remain, including the value of colchicine in patients with diabetes or peripheral artery disease without known CAD, but they also point out that three 2021 meta-analyses confirmed large reductions in the risk of CV events, MI, and coronary revascularization with low-dose colchicine.

“In light of the positive results from LoDoCo2, COLCOT, and meta-analyses; its good tolerability profile; and cost-effectiveness, inflammation reduction with low-dose colchicine should be considered to treat patients with coronary disease in the absence of severe renal dysfunction,” Dr. Tardif and Dr. Marquis-Gravel concluded.

The study was supported by the National Health Medical Research Council of Australia; a grant from the Sir Charles Gairdner Research Advisory Committee; the Withering Foundation; the Netherlands Heart Foundation; the Netherlands Organization for Health Research and Development; and a consortium of Teva, Disphar, and Tiofarma in the Netherlands. The funders had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript. Dr. Opstal reports no relevant financial relationships. Coauthor disclosures are listed in the original article.

Dr. Tardif has received grant support from Amarin, AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Novartis, Pfizer, RegenXBio, and Sanofi; has received honoraria from AstraZeneca, DalCor Pharmaceuticals, HLS Therapeutics, Pendopharm, and Sanofi; has minor equity interest in DalCor Pharmaceuticals; and is mentioned as an author on submitted patents on pharmacogenomics-guided CETP inhibition, use of colchicine after myocardial infarction, and use of colchicine in COVID-19 (he has waived his rights in the colchicine patents and does not stand to gain financially). Dr. Marquis-Gravel has received research grants from Bayer, has received speaker honoraria from Novartis, and has served on national advisory boards for Servier, JAMP, and Bayer.
 

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

Background: Up to 30 million people in the United States meet criteria for alcohol use disorder. Gabapentin addresses symptoms of protracted withdrawal such as insomnia, irritability, difficulty with attention, dysphoria, and anxiety. It does that by acting on voltage-gated calcium channels and, in turn, influencing GABA and glutamate tone and activity.

A couple of study limitations were a significant noncompletion rate (30% in gabapentin arm and 39% in the placebo arm) and self-reported alcohol withdrawal symptoms prior to entry into the study.

Bottom line: Gabapentin helps in reducing drinking and maintaining alcohol abstinence in individuals with alcohol use disorder, especially those with high–alcohol withdrawal symptoms.

Citation: Anton RF et al. Efficacy of gabapentin for the treatment of alcohol use disorder in patients with alcohol withdrawal symptoms: A randomized clinical trial. JAMA Intern Med. 2020 Mar 9;180(5):728-36.

Dr. Gaddam is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Background: Up to 30 million people in the United States meet criteria for alcohol use disorder. Gabapentin addresses symptoms of protracted withdrawal such as insomnia, irritability, difficulty with attention, dysphoria, and anxiety. It does that by acting on voltage-gated calcium channels and, in turn, influencing GABA and glutamate tone and activity.

A couple of study limitations were a significant noncompletion rate (30% in gabapentin arm and 39% in the placebo arm) and self-reported alcohol withdrawal symptoms prior to entry into the study.

Bottom line: Gabapentin helps in reducing drinking and maintaining alcohol abstinence in individuals with alcohol use disorder, especially those with high–alcohol withdrawal symptoms.

Citation: Anton RF et al. Efficacy of gabapentin for the treatment of alcohol use disorder in patients with alcohol withdrawal symptoms: A randomized clinical trial. JAMA Intern Med. 2020 Mar 9;180(5):728-36.

Dr. Gaddam is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Background: Up to 30 million people in the United States meet criteria for alcohol use disorder. Gabapentin addresses symptoms of protracted withdrawal such as insomnia, irritability, difficulty with attention, dysphoria, and anxiety. It does that by acting on voltage-gated calcium channels and, in turn, influencing GABA and glutamate tone and activity.

A couple of study limitations were a significant noncompletion rate (30% in gabapentin arm and 39% in the placebo arm) and self-reported alcohol withdrawal symptoms prior to entry into the study.

Bottom line: Gabapentin helps in reducing drinking and maintaining alcohol abstinence in individuals with alcohol use disorder, especially those with high–alcohol withdrawal symptoms.

Citation: Anton RF et al. Efficacy of gabapentin for the treatment of alcohol use disorder in patients with alcohol withdrawal symptoms: A randomized clinical trial. JAMA Intern Med. 2020 Mar 9;180(5):728-36.

Dr. Gaddam is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.