FAIRFAX, VIRGINIA — Nearly 30 years ago, in a 1995 paper, the British physician-epidemiologist David Barker, MD, PhD, wrote about his fetal origins hypothesis — the idea that programs to address fetal undernutrition and low birth weight produced later coronary heart disease (BMJ 1995;311:171-4).

His hypothesis and subsequent research led to the concept of adult diseases of fetal origins, which today extends beyond low birth weight and implicates the in utero environment as a significant determinant of risk for adverse childhood and adult metabolic outcomes and for major chronic diseases, including diabetes and obesity. Studies have shown that the offspring of pregnant mothers with diabetes have a higher risk of developing obesity and diabetes themselves.

“It’s a whole discipline [of research],” E. Albert Reece, MD, PhD, MBA, of the University of Maryland School of Medicine (UMSOM), said in an interview. “But what we’ve never quite understood is the ‘how’ and ‘why’? What are the mechanisms driving the fetal origins of such adverse outcomes in offspring?

At the biennial meeting of the Diabetes in Pregnancy Study Group of North America (DPSG), investigators described studies underway that are digging deeper into the associations between the intrauterine milieu and longer-term offspring health — and that are searching for biological and molecular processes that may be involved.

The studies are like “branches of the Barker hypothesis,” said Dr. Reece, former dean of UMSOM and current director of the UMSOM Center for Advanced Research Training and Innovation, who co-organized the DPSG meeting. “They’re taking the hypothesis and dissecting it by asking, for instance, it is possible that transgenerational obesity may align with the Barker hypothesis? Is it possible that it involves epigenetics regulation? Could we find biomarkers?”

The need for a better understanding of the fetal origins framework — and its subsequent transgenerational impact — is urgent. From 2000 to 2018, the prevalence of childhood obesity increased from 14.7% to 19.2% (a 31% increase) and the prevalence of severe childhood obesity rose from 3.9% to 6.1% (a 56% increase), according to data from the U.S. National Health and Nutrition Examination Survey (Obes Facts. 2022;15[4]:560-9).

Children aged 2-5 years have had an especially sharp increase in obesity (Pediatrics 2018;141[3]:e20173459), Christine Wey Hockett, PhD, of the University of South Dakota School of Medicine, said at the DPSG meeting (Figure 1).

Deeper Dives Into Associations, Potential Mechanisms

The EPOCH prospective cohort study with which Dr. Hockett was involved gave her a front-seat view of the transgenerational adverse effects of in utero exposure to hyperglycemia. The study recruited ethnically diverse maternal/child dyads from the Kaiser Permanente of Colorado perinatal database from 1992 to 2002 and assessed 418 offspring at two points — a mean age of 10.5 years and 16.5 years — for fasting blood glucose, adiposity, and diet and physical activity. The second visit also involved an oral glucose tolerance test.

The 77 offspring who had been exposed in utero to GDM had a homeostatic model assessment of insulin resistance (HOMA-IR) that was 18% higher, a 19% lower Matsuda index, and a 9% greater HOMA of β-cell function (HOMA-β) than the 341 offspring whose mothers did not have diabetes. Each 5-kg/m² increase in prepregnancy body mass index predicted increased insulin resistance, but there was no combined effect of both maternal obesity and diabetes in utero.

Exposed offspring had a higher BMI and increased adiposity, but when BMI was controlled for in the analysis of metabolic outcomes, maternal diabetes was still associated with 12% higher HOMA-IR and a 17% lower Matsuda index. “So [the metabolic outcomes] are a direct effect of maternal diabetes,” Dr. Hockett said at the DPSG meeting, noting the fetal overnutrition hypothesis in which maternal glucose, but not maternal insulin, freely passes through the placenta, promoting growth and adiposity in the fetus.

[The EPOCH results on metabolic outcomes and offspring adiposity were published in 2017 and 2019, respectively (Diabet Med. 2017;34:1392-9; Diabetologia. 2019;62:2017-24). In 2020, EPOCH researchers reported sex-specific effects on cardiovascular outcomes, with GDM exposure associated with higher total and LDL cholesterol in girls and higher systolic blood pressure in boys (Pediatr Obes. 2020;15[5]:e12611).]

Now, a new longitudinal cohort study underway in Phoenix, is taking a deeper dive, trying to pinpoint what exactly influences childhood obesity and metabolic risk by following Hispanic and American Indian maternal/child dyads from pregnancy until 18 years postpartum. Researchers are looking not only at associations between maternal risk factors (pregnancy BMI, gestational weight gain, and diabetes in pregnancy) and offspring BMI, adiposity, and growth patterns, but also how various factors during pregnancy — clinical, genetic, lifestyle, biochemical — ”may mediate the associations,” said lead investigator Madhumita Sinha, MD.

“We need a better understanding at the molecular level of the biological processes that lead to obesity in children and that cause metabolic dysfunction,” said Dr. Sinha, who heads the Diabetes Epidemiology and Clinical Research Section of the of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) branch in Phoenix.

The populations being enrolled in the ETCHED study (for Early Tracking of Childhood Health Determinants) are at especially high risk of childhood obesity and metabolic dysfunction. Research conducted decades ago by the NIDDK in Phoenix showed that approximately 50% of Pima Indian children from diabetic pregnancies develop type 2 diabetes by age 25 (N Engl J Med. 1983;308:242-5). Years later, to tease out possible genetic factors, researchers compared siblings born before and after their mother was found to have type 2 diabetes, and found significantly higher rates of diabetes in those born after the mother’s diagnosis, affirming the role of in utero toxicity (Diabetes 2000;49:2208-11).

In the new study, the researchers will look at adipokines and inflammatory biomarkers in the mothers and offspring in addition to traditional anthropometric and glycemic measures. They’ll analyze placental tissue, breast milk, and the gut microbiome longitudinally, and they’ll lean heavily on genomics/epigenomics, proteomics, and metabolomics. “There’s potential,” Dr. Sinha said, “to develop a more accurate predictive and prognostic model of childhood obesity.”

The researchers also will study the role of family, socioeconomics, and environmental factors in influencing child growth patterns and they’ll look at neurodevelopment in infancy and childhood. As of October 2023, almost 80 pregnant women, most with obesity and almost one-third with type 2 diabetes, had enrolled in the study. Over the next several years, the study aims to enroll 750 dyads.
 

The Timing of In Utero Exposure

Shelley Ehrlich, MD, ScD, MPH, of the University of Cincinnati and Cincinnati Children’s Hospital Medical Center, is aiming, meanwhile, to learn how the timing of in utero exposure to hyperglycemia predicts specific metabolic and cardiovascular morbidities in the adult offspring of diabetic mothers.

“While we know that exposure to maternal diabetes, regardless of type, increases the risk of obesity, insulin resistance, diabetes, renal compromise, and cardiovascular disease in the offspring, there is little known about the level and timing of hyperglycemic exposure during fetal development that triggers these adverse outcomes,” said Dr. Ehrlich. A goal, she said, is to identify gestational profiles that predict phenotypes of offspring at risk for morbidity in later life.

She and other investigators with the TEAM (Transgenerational Effect on Adult Morbidity) study have recruited over 170 offspring of mothers who participated in the Diabetes in Pregnancy Program Project Grant (PPG) at the University of Cincinnati Medical Center from 1978 to 1995 — a landmark study that demonstrated the effect of strict glucose control in reducing major congenital malformations.

The women in the PPG study had frequent glucose monitoring (up to 6-8 times a day) throughout their pregnancies, and now, their recruited offspring, who are up to 43 years of age, are being assessed for obesity, diabetes/metabolic health, cardiovascular disease/cardiac and peripheral vascular structure and function, and other outcomes including those that may be amenable to secondary prevention (J Diabetes Res. Nov 1;2021:6590431).

Preliminary findings from over 170 offspring recruited between 2017 and 2022 suggest that in utero exposure to dysglycemia (as measured by standard deviations of glycohemoglobin) in the third trimester appears to increase the risk of morbid obesity in adulthood, while exposure to dysglycemia in the first trimester increases the risk of impaired glucose tolerance. The risk of B-cell dysfunction, meanwhile, appears to be linked to dysglycemia in the first and third trimesters — particularly the first — Dr. Ehrlich reported.

Cognitive outcomes in offspring have also been assessed and here it appears that dysglycemia in the third trimester is linked to worse scores on the Wechsler Abbreviated Scale of Intelligence (WASI-II), said Katherine Bowers, PhD, MPH, a TEAM study coinvestigator, also of Cincinnati Children’s Hospital Medical Center.

“We’ve already observed [an association between] diabetes in pregnancy and cognition in early childhood and through adolescence, but [the question has been] does this association persist into adulthood?” she said.

Preliminary analyses of 104 offspring show no statistically significant associations between maternal dysglycemia in the first or second trimesters and offspring cognition, but “consistent inverse associations between maternal glycohemoglobin in the third trimester across two [WASI-II] subscales and composite measures of cognition,” Dr. Bowers said.

Their analysis adjusted for a variety of factors, including maternal age, prepregnancy and first trimester BMI, race, family history of diabetes, and diabetes severity/macrovascular complications.
 

Back In The Laboratory

At the other end of the research spectrum, basic research scientists are also investigating the mechanisms and sequelae of in utero hyperglycemia and other injuries, including congenital malformations, placental adaptive responses and fetal programming. Researchers are asking, for instance, what does placental metabolic reprogramming entail? What role do placental extracellular vesicles play in GDM? Can we alter the in utero environment and thus improve the short and long-term fetal/infant outcomes?

Animal research done at the UMSOM Center for Birth Defects Research, led by Dr. Reece and Peixin Yang, PhD, suggests that “a good portion of in utero injury is due to epigenetics,” Dr. Reece said in the interview. “We’ve shown that under conditions of hyperglycemia, for example, genetic regulation and genetic function can be altered.”

Through in vivo research, they have also shown that antioxidants or membrane stabilizers such as arachidonic acid or myo-inositol, or experimental inhibitors to certain pro-apoptotic intermediates, can individually or collectively result in reduced malformations. “It is highly likely that understanding the biological impact of various altered in utero environments, and then modifying or reversing those environments, will result in short and long-term outcome improvements similar to those shown with congenital malformations,” Dr. Reece said.

FAIRFAX, VIRGINIA — Nearly 30 years ago, in a 1995 paper, the British physician-epidemiologist David Barker, MD, PhD, wrote about his fetal origins hypothesis — the idea that programs to address fetal undernutrition and low birth weight produced later coronary heart disease (BMJ 1995;311:171-4).

His hypothesis and subsequent research led to the concept of adult diseases of fetal origins, which today extends beyond low birth weight and implicates the in utero environment as a significant determinant of risk for adverse childhood and adult metabolic outcomes and for major chronic diseases, including diabetes and obesity. Studies have shown that the offspring of pregnant mothers with diabetes have a higher risk of developing obesity and diabetes themselves.

“It’s a whole discipline [of research],” E. Albert Reece, MD, PhD, MBA, of the University of Maryland School of Medicine (UMSOM), said in an interview. “But what we’ve never quite understood is the ‘how’ and ‘why’? What are the mechanisms driving the fetal origins of such adverse outcomes in offspring?

At the biennial meeting of the Diabetes in Pregnancy Study Group of North America (DPSG), investigators described studies underway that are digging deeper into the associations between the intrauterine milieu and longer-term offspring health — and that are searching for biological and molecular processes that may be involved.

The studies are like “branches of the Barker hypothesis,” said Dr. Reece, former dean of UMSOM and current director of the UMSOM Center for Advanced Research Training and Innovation, who co-organized the DPSG meeting. “They’re taking the hypothesis and dissecting it by asking, for instance, it is possible that transgenerational obesity may align with the Barker hypothesis? Is it possible that it involves epigenetics regulation? Could we find biomarkers?”

The need for a better understanding of the fetal origins framework — and its subsequent transgenerational impact — is urgent. From 2000 to 2018, the prevalence of childhood obesity increased from 14.7% to 19.2% (a 31% increase) and the prevalence of severe childhood obesity rose from 3.9% to 6.1% (a 56% increase), according to data from the U.S. National Health and Nutrition Examination Survey (Obes Facts. 2022;15[4]:560-9).

Children aged 2-5 years have had an especially sharp increase in obesity (Pediatrics 2018;141[3]:e20173459), Christine Wey Hockett, PhD, of the University of South Dakota School of Medicine, said at the DPSG meeting (Figure 1).

Deeper Dives Into Associations, Potential Mechanisms

The EPOCH prospective cohort study with which Dr. Hockett was involved gave her a front-seat view of the transgenerational adverse effects of in utero exposure to hyperglycemia. The study recruited ethnically diverse maternal/child dyads from the Kaiser Permanente of Colorado perinatal database from 1992 to 2002 and assessed 418 offspring at two points — a mean age of 10.5 years and 16.5 years — for fasting blood glucose, adiposity, and diet and physical activity. The second visit also involved an oral glucose tolerance test.

The 77 offspring who had been exposed in utero to GDM had a homeostatic model assessment of insulin resistance (HOMA-IR) that was 18% higher, a 19% lower Matsuda index, and a 9% greater HOMA of β-cell function (HOMA-β) than the 341 offspring whose mothers did not have diabetes. Each 5-kg/m² increase in prepregnancy body mass index predicted increased insulin resistance, but there was no combined effect of both maternal obesity and diabetes in utero.

Exposed offspring had a higher BMI and increased adiposity, but when BMI was controlled for in the analysis of metabolic outcomes, maternal diabetes was still associated with 12% higher HOMA-IR and a 17% lower Matsuda index. “So [the metabolic outcomes] are a direct effect of maternal diabetes,” Dr. Hockett said at the DPSG meeting, noting the fetal overnutrition hypothesis in which maternal glucose, but not maternal insulin, freely passes through the placenta, promoting growth and adiposity in the fetus.

[The EPOCH results on metabolic outcomes and offspring adiposity were published in 2017 and 2019, respectively (Diabet Med. 2017;34:1392-9; Diabetologia. 2019;62:2017-24). In 2020, EPOCH researchers reported sex-specific effects on cardiovascular outcomes, with GDM exposure associated with higher total and LDL cholesterol in girls and higher systolic blood pressure in boys (Pediatr Obes. 2020;15[5]:e12611).]

Now, a new longitudinal cohort study underway in Phoenix, is taking a deeper dive, trying to pinpoint what exactly influences childhood obesity and metabolic risk by following Hispanic and American Indian maternal/child dyads from pregnancy until 18 years postpartum. Researchers are looking not only at associations between maternal risk factors (pregnancy BMI, gestational weight gain, and diabetes in pregnancy) and offspring BMI, adiposity, and growth patterns, but also how various factors during pregnancy — clinical, genetic, lifestyle, biochemical — ”may mediate the associations,” said lead investigator Madhumita Sinha, MD.

“We need a better understanding at the molecular level of the biological processes that lead to obesity in children and that cause metabolic dysfunction,” said Dr. Sinha, who heads the Diabetes Epidemiology and Clinical Research Section of the of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) branch in Phoenix.

The populations being enrolled in the ETCHED study (for Early Tracking of Childhood Health Determinants) are at especially high risk of childhood obesity and metabolic dysfunction. Research conducted decades ago by the NIDDK in Phoenix showed that approximately 50% of Pima Indian children from diabetic pregnancies develop type 2 diabetes by age 25 (N Engl J Med. 1983;308:242-5). Years later, to tease out possible genetic factors, researchers compared siblings born before and after their mother was found to have type 2 diabetes, and found significantly higher rates of diabetes in those born after the mother’s diagnosis, affirming the role of in utero toxicity (Diabetes 2000;49:2208-11).

In the new study, the researchers will look at adipokines and inflammatory biomarkers in the mothers and offspring in addition to traditional anthropometric and glycemic measures. They’ll analyze placental tissue, breast milk, and the gut microbiome longitudinally, and they’ll lean heavily on genomics/epigenomics, proteomics, and metabolomics. “There’s potential,” Dr. Sinha said, “to develop a more accurate predictive and prognostic model of childhood obesity.”

The researchers also will study the role of family, socioeconomics, and environmental factors in influencing child growth patterns and they’ll look at neurodevelopment in infancy and childhood. As of October 2023, almost 80 pregnant women, most with obesity and almost one-third with type 2 diabetes, had enrolled in the study. Over the next several years, the study aims to enroll 750 dyads.
 

The Timing of In Utero Exposure

Shelley Ehrlich, MD, ScD, MPH, of the University of Cincinnati and Cincinnati Children’s Hospital Medical Center, is aiming, meanwhile, to learn how the timing of in utero exposure to hyperglycemia predicts specific metabolic and cardiovascular morbidities in the adult offspring of diabetic mothers.

“While we know that exposure to maternal diabetes, regardless of type, increases the risk of obesity, insulin resistance, diabetes, renal compromise, and cardiovascular disease in the offspring, there is little known about the level and timing of hyperglycemic exposure during fetal development that triggers these adverse outcomes,” said Dr. Ehrlich. A goal, she said, is to identify gestational profiles that predict phenotypes of offspring at risk for morbidity in later life.

She and other investigators with the TEAM (Transgenerational Effect on Adult Morbidity) study have recruited over 170 offspring of mothers who participated in the Diabetes in Pregnancy Program Project Grant (PPG) at the University of Cincinnati Medical Center from 1978 to 1995 — a landmark study that demonstrated the effect of strict glucose control in reducing major congenital malformations.

The women in the PPG study had frequent glucose monitoring (up to 6-8 times a day) throughout their pregnancies, and now, their recruited offspring, who are up to 43 years of age, are being assessed for obesity, diabetes/metabolic health, cardiovascular disease/cardiac and peripheral vascular structure and function, and other outcomes including those that may be amenable to secondary prevention (J Diabetes Res. Nov 1;2021:6590431).

Preliminary findings from over 170 offspring recruited between 2017 and 2022 suggest that in utero exposure to dysglycemia (as measured by standard deviations of glycohemoglobin) in the third trimester appears to increase the risk of morbid obesity in adulthood, while exposure to dysglycemia in the first trimester increases the risk of impaired glucose tolerance. The risk of B-cell dysfunction, meanwhile, appears to be linked to dysglycemia in the first and third trimesters — particularly the first — Dr. Ehrlich reported.

Cognitive outcomes in offspring have also been assessed and here it appears that dysglycemia in the third trimester is linked to worse scores on the Wechsler Abbreviated Scale of Intelligence (WASI-II), said Katherine Bowers, PhD, MPH, a TEAM study coinvestigator, also of Cincinnati Children’s Hospital Medical Center.

“We’ve already observed [an association between] diabetes in pregnancy and cognition in early childhood and through adolescence, but [the question has been] does this association persist into adulthood?” she said.

Preliminary analyses of 104 offspring show no statistically significant associations between maternal dysglycemia in the first or second trimesters and offspring cognition, but “consistent inverse associations between maternal glycohemoglobin in the third trimester across two [WASI-II] subscales and composite measures of cognition,” Dr. Bowers said.

Their analysis adjusted for a variety of factors, including maternal age, prepregnancy and first trimester BMI, race, family history of diabetes, and diabetes severity/macrovascular complications.
 

Back In The Laboratory

At the other end of the research spectrum, basic research scientists are also investigating the mechanisms and sequelae of in utero hyperglycemia and other injuries, including congenital malformations, placental adaptive responses and fetal programming. Researchers are asking, for instance, what does placental metabolic reprogramming entail? What role do placental extracellular vesicles play in GDM? Can we alter the in utero environment and thus improve the short and long-term fetal/infant outcomes?

Animal research done at the UMSOM Center for Birth Defects Research, led by Dr. Reece and Peixin Yang, PhD, suggests that “a good portion of in utero injury is due to epigenetics,” Dr. Reece said in the interview. “We’ve shown that under conditions of hyperglycemia, for example, genetic regulation and genetic function can be altered.”

Through in vivo research, they have also shown that antioxidants or membrane stabilizers such as arachidonic acid or myo-inositol, or experimental inhibitors to certain pro-apoptotic intermediates, can individually or collectively result in reduced malformations. “It is highly likely that understanding the biological impact of various altered in utero environments, and then modifying or reversing those environments, will result in short and long-term outcome improvements similar to those shown with congenital malformations,” Dr. Reece said.

FAIRFAX, VIRGINIA — Nearly 30 years ago, in a 1995 paper, the British physician-epidemiologist David Barker, MD, PhD, wrote about his fetal origins hypothesis — the idea that programs to address fetal undernutrition and low birth weight produced later coronary heart disease (BMJ 1995;311:171-4).

His hypothesis and subsequent research led to the concept of adult diseases of fetal origins, which today extends beyond low birth weight and implicates the in utero environment as a significant determinant of risk for adverse childhood and adult metabolic outcomes and for major chronic diseases, including diabetes and obesity. Studies have shown that the offspring of pregnant mothers with diabetes have a higher risk of developing obesity and diabetes themselves.

“It’s a whole discipline [of research],” E. Albert Reece, MD, PhD, MBA, of the University of Maryland School of Medicine (UMSOM), said in an interview. “But what we’ve never quite understood is the ‘how’ and ‘why’? What are the mechanisms driving the fetal origins of such adverse outcomes in offspring?

At the biennial meeting of the Diabetes in Pregnancy Study Group of North America (DPSG), investigators described studies underway that are digging deeper into the associations between the intrauterine milieu and longer-term offspring health — and that are searching for biological and molecular processes that may be involved.

The studies are like “branches of the Barker hypothesis,” said Dr. Reece, former dean of UMSOM and current director of the UMSOM Center for Advanced Research Training and Innovation, who co-organized the DPSG meeting. “They’re taking the hypothesis and dissecting it by asking, for instance, it is possible that transgenerational obesity may align with the Barker hypothesis? Is it possible that it involves epigenetics regulation? Could we find biomarkers?”

The need for a better understanding of the fetal origins framework — and its subsequent transgenerational impact — is urgent. From 2000 to 2018, the prevalence of childhood obesity increased from 14.7% to 19.2% (a 31% increase) and the prevalence of severe childhood obesity rose from 3.9% to 6.1% (a 56% increase), according to data from the U.S. National Health and Nutrition Examination Survey (Obes Facts. 2022;15[4]:560-9).

Children aged 2-5 years have had an especially sharp increase in obesity (Pediatrics 2018;141[3]:e20173459), Christine Wey Hockett, PhD, of the University of South Dakota School of Medicine, said at the DPSG meeting (Figure 1).

Deeper Dives Into Associations, Potential Mechanisms

The EPOCH prospective cohort study with which Dr. Hockett was involved gave her a front-seat view of the transgenerational adverse effects of in utero exposure to hyperglycemia. The study recruited ethnically diverse maternal/child dyads from the Kaiser Permanente of Colorado perinatal database from 1992 to 2002 and assessed 418 offspring at two points — a mean age of 10.5 years and 16.5 years — for fasting blood glucose, adiposity, and diet and physical activity. The second visit also involved an oral glucose tolerance test.

The 77 offspring who had been exposed in utero to GDM had a homeostatic model assessment of insulin resistance (HOMA-IR) that was 18% higher, a 19% lower Matsuda index, and a 9% greater HOMA of β-cell function (HOMA-β) than the 341 offspring whose mothers did not have diabetes. Each 5-kg/m² increase in prepregnancy body mass index predicted increased insulin resistance, but there was no combined effect of both maternal obesity and diabetes in utero.

Exposed offspring had a higher BMI and increased adiposity, but when BMI was controlled for in the analysis of metabolic outcomes, maternal diabetes was still associated with 12% higher HOMA-IR and a 17% lower Matsuda index. “So [the metabolic outcomes] are a direct effect of maternal diabetes,” Dr. Hockett said at the DPSG meeting, noting the fetal overnutrition hypothesis in which maternal glucose, but not maternal insulin, freely passes through the placenta, promoting growth and adiposity in the fetus.

[The EPOCH results on metabolic outcomes and offspring adiposity were published in 2017 and 2019, respectively (Diabet Med. 2017;34:1392-9; Diabetologia. 2019;62:2017-24). In 2020, EPOCH researchers reported sex-specific effects on cardiovascular outcomes, with GDM exposure associated with higher total and LDL cholesterol in girls and higher systolic blood pressure in boys (Pediatr Obes. 2020;15[5]:e12611).]

Now, a new longitudinal cohort study underway in Phoenix, is taking a deeper dive, trying to pinpoint what exactly influences childhood obesity and metabolic risk by following Hispanic and American Indian maternal/child dyads from pregnancy until 18 years postpartum. Researchers are looking not only at associations between maternal risk factors (pregnancy BMI, gestational weight gain, and diabetes in pregnancy) and offspring BMI, adiposity, and growth patterns, but also how various factors during pregnancy — clinical, genetic, lifestyle, biochemical — ”may mediate the associations,” said lead investigator Madhumita Sinha, MD.

“We need a better understanding at the molecular level of the biological processes that lead to obesity in children and that cause metabolic dysfunction,” said Dr. Sinha, who heads the Diabetes Epidemiology and Clinical Research Section of the of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) branch in Phoenix.

The populations being enrolled in the ETCHED study (for Early Tracking of Childhood Health Determinants) are at especially high risk of childhood obesity and metabolic dysfunction. Research conducted decades ago by the NIDDK in Phoenix showed that approximately 50% of Pima Indian children from diabetic pregnancies develop type 2 diabetes by age 25 (N Engl J Med. 1983;308:242-5). Years later, to tease out possible genetic factors, researchers compared siblings born before and after their mother was found to have type 2 diabetes, and found significantly higher rates of diabetes in those born after the mother’s diagnosis, affirming the role of in utero toxicity (Diabetes 2000;49:2208-11).

In the new study, the researchers will look at adipokines and inflammatory biomarkers in the mothers and offspring in addition to traditional anthropometric and glycemic measures. They’ll analyze placental tissue, breast milk, and the gut microbiome longitudinally, and they’ll lean heavily on genomics/epigenomics, proteomics, and metabolomics. “There’s potential,” Dr. Sinha said, “to develop a more accurate predictive and prognostic model of childhood obesity.”

The researchers also will study the role of family, socioeconomics, and environmental factors in influencing child growth patterns and they’ll look at neurodevelopment in infancy and childhood. As of October 2023, almost 80 pregnant women, most with obesity and almost one-third with type 2 diabetes, had enrolled in the study. Over the next several years, the study aims to enroll 750 dyads.
 

The Timing of In Utero Exposure

Shelley Ehrlich, MD, ScD, MPH, of the University of Cincinnati and Cincinnati Children’s Hospital Medical Center, is aiming, meanwhile, to learn how the timing of in utero exposure to hyperglycemia predicts specific metabolic and cardiovascular morbidities in the adult offspring of diabetic mothers.

“While we know that exposure to maternal diabetes, regardless of type, increases the risk of obesity, insulin resistance, diabetes, renal compromise, and cardiovascular disease in the offspring, there is little known about the level and timing of hyperglycemic exposure during fetal development that triggers these adverse outcomes,” said Dr. Ehrlich. A goal, she said, is to identify gestational profiles that predict phenotypes of offspring at risk for morbidity in later life.

She and other investigators with the TEAM (Transgenerational Effect on Adult Morbidity) study have recruited over 170 offspring of mothers who participated in the Diabetes in Pregnancy Program Project Grant (PPG) at the University of Cincinnati Medical Center from 1978 to 1995 — a landmark study that demonstrated the effect of strict glucose control in reducing major congenital malformations.

The women in the PPG study had frequent glucose monitoring (up to 6-8 times a day) throughout their pregnancies, and now, their recruited offspring, who are up to 43 years of age, are being assessed for obesity, diabetes/metabolic health, cardiovascular disease/cardiac and peripheral vascular structure and function, and other outcomes including those that may be amenable to secondary prevention (J Diabetes Res. Nov 1;2021:6590431).

Preliminary findings from over 170 offspring recruited between 2017 and 2022 suggest that in utero exposure to dysglycemia (as measured by standard deviations of glycohemoglobin) in the third trimester appears to increase the risk of morbid obesity in adulthood, while exposure to dysglycemia in the first trimester increases the risk of impaired glucose tolerance. The risk of B-cell dysfunction, meanwhile, appears to be linked to dysglycemia in the first and third trimesters — particularly the first — Dr. Ehrlich reported.

Cognitive outcomes in offspring have also been assessed and here it appears that dysglycemia in the third trimester is linked to worse scores on the Wechsler Abbreviated Scale of Intelligence (WASI-II), said Katherine Bowers, PhD, MPH, a TEAM study coinvestigator, also of Cincinnati Children’s Hospital Medical Center.

“We’ve already observed [an association between] diabetes in pregnancy and cognition in early childhood and through adolescence, but [the question has been] does this association persist into adulthood?” she said.

Preliminary analyses of 104 offspring show no statistically significant associations between maternal dysglycemia in the first or second trimesters and offspring cognition, but “consistent inverse associations between maternal glycohemoglobin in the third trimester across two [WASI-II] subscales and composite measures of cognition,” Dr. Bowers said.

Their analysis adjusted for a variety of factors, including maternal age, prepregnancy and first trimester BMI, race, family history of diabetes, and diabetes severity/macrovascular complications.
 

Back In The Laboratory

At the other end of the research spectrum, basic research scientists are also investigating the mechanisms and sequelae of in utero hyperglycemia and other injuries, including congenital malformations, placental adaptive responses and fetal programming. Researchers are asking, for instance, what does placental metabolic reprogramming entail? What role do placental extracellular vesicles play in GDM? Can we alter the in utero environment and thus improve the short and long-term fetal/infant outcomes?

Animal research done at the UMSOM Center for Birth Defects Research, led by Dr. Reece and Peixin Yang, PhD, suggests that “a good portion of in utero injury is due to epigenetics,” Dr. Reece said in the interview. “We’ve shown that under conditions of hyperglycemia, for example, genetic regulation and genetic function can be altered.”

Through in vivo research, they have also shown that antioxidants or membrane stabilizers such as arachidonic acid or myo-inositol, or experimental inhibitors to certain pro-apoptotic intermediates, can individually or collectively result in reduced malformations. “It is highly likely that understanding the biological impact of various altered in utero environments, and then modifying or reversing those environments, will result in short and long-term outcome improvements similar to those shown with congenital malformations,” Dr. Reece said.

Although tubal sterilization is common, especially among those with lower income and education levels, misunderstandings persist about the reversibility of the procedure, and previous studies suggest that many pregnant individuals are not making well-informed decisions, wrote Sonya Borrero, MD, of the University of Pittsburgh, and colleagues.

In a study published in JAMA Network Open, the researchers randomized 350 pregnant individuals with Medicaid insurance to usual care or usual care plus a web-based decision aid in English or Spanish called MyDecision/MiDecisión that included written, audio, and video information about tubal sterilization. The tool also included an interactive table comparing tubal sterilization to other contraceptive options, exercises to clarify patients’ values, knowledge checks, and a final summary report.

The two primary outcomes were knowledge of tubal sterilization based on a 10-question true/false test and decisional conflict about contraceptive choices using the low-literacy Decision Conflict Scale. The participants ranged in age from 21 to 45 years, with a mean age of 29.7 years. Participants were randomized prior to 24 weeks’ gestation, and those in the intervention group completed the intervention immediately using a personal device or a university device in the clinical setting. Further assessments occurred by phone during the third trimester and at 3 months postpartum.

Participants in the decision aid group showed significantly greater knowledge of tubal sterilization compared with controls, with a mean of 76.5% correct responses to the knowledge questions, vs. 55.6% in the control group (P < .001). Decisional conflict scores also were significantly lower in the intervention group compared with controls (mean 12.7 vs. 18.7, P = .002).

The most dramatic knowledge gap related to permanence of tubal sterilization; 90.1% of participants in the intervention group answered correctly that the procedure is not easily reversible, compared to 39.3% of the controls. Similarly, 86.6% of the intervention group responded correctly that the tubes do not “come untied” spontaneously, vs. 33.7% of controls (P < .001 for both).

The findings were limited by several factors including the focus only on pregnant Medicaid patients, the presentation of the decision tool only at a point early in pregnancy, which may have been too soon for some participants to consider tubal sterilization, and a lack of data on long-term satisfaction or regret about tubal sterilization decisions, the researchers noted.

However, the knowledge differences between the intervention and control groups remained significant at the third trimester assessment, they said.

More research is needed in other populations and using other time points, but the current study results suggest that use of the MyDecision/MiDecisión tool in a real-world clinical setting at the actual time of decision-making could improve knowledge and inform patients’ choices, the researchers concluded. Improved patient education also could inform policy decisions about the potential elimination of the 30-day waiting period for sterilization procedures, they said.

The study was supported by the National Institute on Minority Health and Health Disparities. The researchers had no financial conflicts to disclose.

Although tubal sterilization is common, especially among those with lower income and education levels, misunderstandings persist about the reversibility of the procedure, and previous studies suggest that many pregnant individuals are not making well-informed decisions, wrote Sonya Borrero, MD, of the University of Pittsburgh, and colleagues.

In a study published in JAMA Network Open, the researchers randomized 350 pregnant individuals with Medicaid insurance to usual care or usual care plus a web-based decision aid in English or Spanish called MyDecision/MiDecisión that included written, audio, and video information about tubal sterilization. The tool also included an interactive table comparing tubal sterilization to other contraceptive options, exercises to clarify patients’ values, knowledge checks, and a final summary report.

The two primary outcomes were knowledge of tubal sterilization based on a 10-question true/false test and decisional conflict about contraceptive choices using the low-literacy Decision Conflict Scale. The participants ranged in age from 21 to 45 years, with a mean age of 29.7 years. Participants were randomized prior to 24 weeks’ gestation, and those in the intervention group completed the intervention immediately using a personal device or a university device in the clinical setting. Further assessments occurred by phone during the third trimester and at 3 months postpartum.

Participants in the decision aid group showed significantly greater knowledge of tubal sterilization compared with controls, with a mean of 76.5% correct responses to the knowledge questions, vs. 55.6% in the control group (P < .001). Decisional conflict scores also were significantly lower in the intervention group compared with controls (mean 12.7 vs. 18.7, P = .002).

The most dramatic knowledge gap related to permanence of tubal sterilization; 90.1% of participants in the intervention group answered correctly that the procedure is not easily reversible, compared to 39.3% of the controls. Similarly, 86.6% of the intervention group responded correctly that the tubes do not “come untied” spontaneously, vs. 33.7% of controls (P < .001 for both).

The findings were limited by several factors including the focus only on pregnant Medicaid patients, the presentation of the decision tool only at a point early in pregnancy, which may have been too soon for some participants to consider tubal sterilization, and a lack of data on long-term satisfaction or regret about tubal sterilization decisions, the researchers noted.

However, the knowledge differences between the intervention and control groups remained significant at the third trimester assessment, they said.

More research is needed in other populations and using other time points, but the current study results suggest that use of the MyDecision/MiDecisión tool in a real-world clinical setting at the actual time of decision-making could improve knowledge and inform patients’ choices, the researchers concluded. Improved patient education also could inform policy decisions about the potential elimination of the 30-day waiting period for sterilization procedures, they said.

The study was supported by the National Institute on Minority Health and Health Disparities. The researchers had no financial conflicts to disclose.

Although tubal sterilization is common, especially among those with lower income and education levels, misunderstandings persist about the reversibility of the procedure, and previous studies suggest that many pregnant individuals are not making well-informed decisions, wrote Sonya Borrero, MD, of the University of Pittsburgh, and colleagues.

In a study published in JAMA Network Open, the researchers randomized 350 pregnant individuals with Medicaid insurance to usual care or usual care plus a web-based decision aid in English or Spanish called MyDecision/MiDecisión that included written, audio, and video information about tubal sterilization. The tool also included an interactive table comparing tubal sterilization to other contraceptive options, exercises to clarify patients’ values, knowledge checks, and a final summary report.

The two primary outcomes were knowledge of tubal sterilization based on a 10-question true/false test and decisional conflict about contraceptive choices using the low-literacy Decision Conflict Scale. The participants ranged in age from 21 to 45 years, with a mean age of 29.7 years. Participants were randomized prior to 24 weeks’ gestation, and those in the intervention group completed the intervention immediately using a personal device or a university device in the clinical setting. Further assessments occurred by phone during the third trimester and at 3 months postpartum.

Participants in the decision aid group showed significantly greater knowledge of tubal sterilization compared with controls, with a mean of 76.5% correct responses to the knowledge questions, vs. 55.6% in the control group (P < .001). Decisional conflict scores also were significantly lower in the intervention group compared with controls (mean 12.7 vs. 18.7, P = .002).

The most dramatic knowledge gap related to permanence of tubal sterilization; 90.1% of participants in the intervention group answered correctly that the procedure is not easily reversible, compared to 39.3% of the controls. Similarly, 86.6% of the intervention group responded correctly that the tubes do not “come untied” spontaneously, vs. 33.7% of controls (P < .001 for both).

The findings were limited by several factors including the focus only on pregnant Medicaid patients, the presentation of the decision tool only at a point early in pregnancy, which may have been too soon for some participants to consider tubal sterilization, and a lack of data on long-term satisfaction or regret about tubal sterilization decisions, the researchers noted.

However, the knowledge differences between the intervention and control groups remained significant at the third trimester assessment, they said.

More research is needed in other populations and using other time points, but the current study results suggest that use of the MyDecision/MiDecisión tool in a real-world clinical setting at the actual time of decision-making could improve knowledge and inform patients’ choices, the researchers concluded. Improved patient education also could inform policy decisions about the potential elimination of the 30-day waiting period for sterilization procedures, they said.

The study was supported by the National Institute on Minority Health and Health Disparities. The researchers had no financial conflicts to disclose.

TOPLINE:

Treatment of patients with rheumatoid arthritis (RA) with non–tumor necrosis factor inhibitor (TNFi) biologic disease-modifying antirheumatic drugs (bDMARDs) may not pose an increased risk for cancer, compared with TNFis and conventional synthetic DMARDs.

METHODOLOGY:

• Previous research has presented conflicting results on the association between non-TNFi bDMARDs and the risk for cancer, with abatacept drawing particular attention owing to its mode of action.
• By utilizing information from Danish registers (January 2006-December 2020), researchers compared the risk for cancer in 14,944 patients with RA (age > 18 years) who were initiated on non-TNFi bDMARDs (tocilizumab/sarilumab, abatacept, or rituximab), TNFis, or were in the conventional synthetic DMARDs (bDMARD-naive) group.
• The patient population contributed to 21,982 treatment initiations, which corresponded to 1457, 1016, 690, 7458, and 11,361 treatment initiations for the tocilizumab/sarilumab, abatacept, rituximab, TNFi, and bDMARD-naive groups, respectively.
• Patients were followed up until a diagnosis was obtained for cancer, death, emigration, the initiation of a different bDMARD or a targeted synthetic DMARD, or the end of the study, whichever was earlier.
• The primary outcome was defined as any primary cancer diagnosis (except nonmelanoma skin cancer).

TAKEAWAY:

• The risk for overall cancer was not significantly higher in the tocilizumab/sarilumab-, abatacept-, or rituximab-initiated groups than in the TNFi-treated and bDMARD-naive groups.

• The likelihood of cancer appeared to be higher in patients with more than 5 years of exposure to abatacept than in the TNFi-treated (hazard ratio [HR], 1.41; 95% CI, 0.60-2.60) and bDMARD-naive groups (HR, 1.14; 95% CI, 0.51-2.33). However, the results were not statistically significant.
• Treatment with rituximab may be associated with a lower risk for hematologic cancers than for TNFi-treated (HR, 0.09; 95% CI, 0.00-2.06) or bDMARD-naive groups (HR, 0.13; 95% CI, 0.00-1.89), although the findings did not show statistical significance.

IN PRACTICE:

The authors wrote, “bDMARD-associated cancer risk remains a clinically important research question, and more future studies specifically investigating non-TNFi bDMARDs in terms of cancer risk in patients with RA are warranted.”

SOURCE:

The investigation, led by Rasmus Westermann, MD, of Aalborg University Hospital, Aalborg, Denmark, was published online on March 7 in Rheumatology.

LIMITATIONS:

Many patients received more than one type of non-TNFi bDMARD treatment during the study. Because the temporal relationship of DMARD treatment with cancer was not certain, potential carcinogenic treatment effects could not be distinguished. Limited data were available on cancer risk factors.

DISCLOSURES:

The study was supported by the Danish Rheumatism Association and the Danish Cancer Society. Some authors reported financial relationships with pharmaceutical companies outside of the submitted work.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Treatment of patients with rheumatoid arthritis (RA) with non–tumor necrosis factor inhibitor (TNFi) biologic disease-modifying antirheumatic drugs (bDMARDs) may not pose an increased risk for cancer, compared with TNFis and conventional synthetic DMARDs.

METHODOLOGY:

• Previous research has presented conflicting results on the association between non-TNFi bDMARDs and the risk for cancer, with abatacept drawing particular attention owing to its mode of action.
• By utilizing information from Danish registers (January 2006-December 2020), researchers compared the risk for cancer in 14,944 patients with RA (age > 18 years) who were initiated on non-TNFi bDMARDs (tocilizumab/sarilumab, abatacept, or rituximab), TNFis, or were in the conventional synthetic DMARDs (bDMARD-naive) group.
• The patient population contributed to 21,982 treatment initiations, which corresponded to 1457, 1016, 690, 7458, and 11,361 treatment initiations for the tocilizumab/sarilumab, abatacept, rituximab, TNFi, and bDMARD-naive groups, respectively.
• Patients were followed up until a diagnosis was obtained for cancer, death, emigration, the initiation of a different bDMARD or a targeted synthetic DMARD, or the end of the study, whichever was earlier.
• The primary outcome was defined as any primary cancer diagnosis (except nonmelanoma skin cancer).

TAKEAWAY:

• The risk for overall cancer was not significantly higher in the tocilizumab/sarilumab-, abatacept-, or rituximab-initiated groups than in the TNFi-treated and bDMARD-naive groups.

• The likelihood of cancer appeared to be higher in patients with more than 5 years of exposure to abatacept than in the TNFi-treated (hazard ratio [HR], 1.41; 95% CI, 0.60-2.60) and bDMARD-naive groups (HR, 1.14; 95% CI, 0.51-2.33). However, the results were not statistically significant.
• Treatment with rituximab may be associated with a lower risk for hematologic cancers than for TNFi-treated (HR, 0.09; 95% CI, 0.00-2.06) or bDMARD-naive groups (HR, 0.13; 95% CI, 0.00-1.89), although the findings did not show statistical significance.

IN PRACTICE:

The authors wrote, “bDMARD-associated cancer risk remains a clinically important research question, and more future studies specifically investigating non-TNFi bDMARDs in terms of cancer risk in patients with RA are warranted.”

SOURCE:

The investigation, led by Rasmus Westermann, MD, of Aalborg University Hospital, Aalborg, Denmark, was published online on March 7 in Rheumatology.

LIMITATIONS:

Many patients received more than one type of non-TNFi bDMARD treatment during the study. Because the temporal relationship of DMARD treatment with cancer was not certain, potential carcinogenic treatment effects could not be distinguished. Limited data were available on cancer risk factors.

DISCLOSURES:

The study was supported by the Danish Rheumatism Association and the Danish Cancer Society. Some authors reported financial relationships with pharmaceutical companies outside of the submitted work.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Treatment of patients with rheumatoid arthritis (RA) with non–tumor necrosis factor inhibitor (TNFi) biologic disease-modifying antirheumatic drugs (bDMARDs) may not pose an increased risk for cancer, compared with TNFis and conventional synthetic DMARDs.

METHODOLOGY:

• Previous research has presented conflicting results on the association between non-TNFi bDMARDs and the risk for cancer, with abatacept drawing particular attention owing to its mode of action.
• By utilizing information from Danish registers (January 2006-December 2020), researchers compared the risk for cancer in 14,944 patients with RA (age > 18 years) who were initiated on non-TNFi bDMARDs (tocilizumab/sarilumab, abatacept, or rituximab), TNFis, or were in the conventional synthetic DMARDs (bDMARD-naive) group.
• The patient population contributed to 21,982 treatment initiations, which corresponded to 1457, 1016, 690, 7458, and 11,361 treatment initiations for the tocilizumab/sarilumab, abatacept, rituximab, TNFi, and bDMARD-naive groups, respectively.
• Patients were followed up until a diagnosis was obtained for cancer, death, emigration, the initiation of a different bDMARD or a targeted synthetic DMARD, or the end of the study, whichever was earlier.
• The primary outcome was defined as any primary cancer diagnosis (except nonmelanoma skin cancer).

TAKEAWAY:

• The risk for overall cancer was not significantly higher in the tocilizumab/sarilumab-, abatacept-, or rituximab-initiated groups than in the TNFi-treated and bDMARD-naive groups.

• The likelihood of cancer appeared to be higher in patients with more than 5 years of exposure to abatacept than in the TNFi-treated (hazard ratio [HR], 1.41; 95% CI, 0.60-2.60) and bDMARD-naive groups (HR, 1.14; 95% CI, 0.51-2.33). However, the results were not statistically significant.
• Treatment with rituximab may be associated with a lower risk for hematologic cancers than for TNFi-treated (HR, 0.09; 95% CI, 0.00-2.06) or bDMARD-naive groups (HR, 0.13; 95% CI, 0.00-1.89), although the findings did not show statistical significance.

IN PRACTICE:

The authors wrote, “bDMARD-associated cancer risk remains a clinically important research question, and more future studies specifically investigating non-TNFi bDMARDs in terms of cancer risk in patients with RA are warranted.”

SOURCE:

The investigation, led by Rasmus Westermann, MD, of Aalborg University Hospital, Aalborg, Denmark, was published online on March 7 in Rheumatology.

LIMITATIONS:

Many patients received more than one type of non-TNFi bDMARD treatment during the study. Because the temporal relationship of DMARD treatment with cancer was not certain, potential carcinogenic treatment effects could not be distinguished. Limited data were available on cancer risk factors.

DISCLOSURES:

The study was supported by the Danish Rheumatism Association and the Danish Cancer Society. Some authors reported financial relationships with pharmaceutical companies outside of the submitted work.
 

A version of this article appeared on Medscape.com.

TOPLINE:

An earlier diagnosis of psoriatic arthritis (PsA) following symptom onset increases the likelihood of achieving improved clinical outcomes, highlighting the presence of a diagnostic window of opportunity in PsA.

METHODOLOGY:

• A diagnostic delay in PsA leads to increased joint erosions and functional impairment; however, whether a “window of opportunity” (< 12 weeks) exists in PsA requires further evaluation.
• Researchers assessed the impact of diagnostic delay on clinical outcomes in 708 newly diagnosed, disease-modifying antirheumatic drug-naive patients with PsA from the Dutch southwest Early PsA cohort.
• Total diagnostic delay was calculated as the time period between symptom onset and PsA diagnosis made by a rheumatologist.
• On the basis of the total diagnostic delay, patients were categorized into those with a short delay of < 12 weeks (n = 136), intermediate delay of 12 weeks to 1 year (n = 237), and a long delay of > 1 year (n = 335).
• The groups were compared for clinical (Minimal Disease Activity [MDA] and Disease Activity index for Psoriatic Arthritis [DAPSA] remission) and patient-reported outcomes during 3 years of follow-up.

TAKEAWAY:

• The probability of achieving MDA was higher in patients with a short vs long diagnostic delay (odds ratio [OR], 2.55; 95% CI, 1.37-4.76).
• Compared with patients in the long diagnostic delay group, those in the short (OR, 2.35; 95% CI, 1.32-4.19) and intermediate (OR, 1.94; 95% CI, 1.19-3.15) diagnostic delay groups were more likely to achieve DAPSA remission.
• Compared with patients in the long diagnostic delay group, those in the short (estimated mean difference [Δ], −1.09; 95% CI, −1.88 to −0.30) or intermediate (Δ, −0.85; 95% CI, −1.50 to −0.19) groups had slightly less tender joints.

IN PRACTICE:

“A delay of > 1 year is associated with worse clinical outcomes, which includes almost 50% of the PsA population” in this study, wrote the authors, adding that for better long-term outcomes, “it is important that PsA patients are diagnosed by a rheumatologist within 1 year after symptom onset.”

SOURCE:

This study, led by Selinde V.J. Snoeck Henkemans, MD, of the department of rheumatology at Erasmus University Medical Center, Rotterdam, the Netherlands, was published online February 27, 2024, in RMD Open.

LIMITATIONS:

The study’s dropout rates (25%-31% across groups) may have influenced the findings. Patients with a long diagnostic delay might have dropped out owing to treatment dissatisfaction, and those with a short or intermediate delay might have dropped out due to inactive disease.

DISCLOSURES:

This study did not declare any specific source of funding. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

An earlier diagnosis of psoriatic arthritis (PsA) following symptom onset increases the likelihood of achieving improved clinical outcomes, highlighting the presence of a diagnostic window of opportunity in PsA.

METHODOLOGY:

• A diagnostic delay in PsA leads to increased joint erosions and functional impairment; however, whether a “window of opportunity” (< 12 weeks) exists in PsA requires further evaluation.
• Researchers assessed the impact of diagnostic delay on clinical outcomes in 708 newly diagnosed, disease-modifying antirheumatic drug-naive patients with PsA from the Dutch southwest Early PsA cohort.
• Total diagnostic delay was calculated as the time period between symptom onset and PsA diagnosis made by a rheumatologist.
• On the basis of the total diagnostic delay, patients were categorized into those with a short delay of < 12 weeks (n = 136), intermediate delay of 12 weeks to 1 year (n = 237), and a long delay of > 1 year (n = 335).
• The groups were compared for clinical (Minimal Disease Activity [MDA] and Disease Activity index for Psoriatic Arthritis [DAPSA] remission) and patient-reported outcomes during 3 years of follow-up.

TAKEAWAY:

• The probability of achieving MDA was higher in patients with a short vs long diagnostic delay (odds ratio [OR], 2.55; 95% CI, 1.37-4.76).
• Compared with patients in the long diagnostic delay group, those in the short (OR, 2.35; 95% CI, 1.32-4.19) and intermediate (OR, 1.94; 95% CI, 1.19-3.15) diagnostic delay groups were more likely to achieve DAPSA remission.
• Compared with patients in the long diagnostic delay group, those in the short (estimated mean difference [Δ], −1.09; 95% CI, −1.88 to −0.30) or intermediate (Δ, −0.85; 95% CI, −1.50 to −0.19) groups had slightly less tender joints.

IN PRACTICE:

“A delay of > 1 year is associated with worse clinical outcomes, which includes almost 50% of the PsA population” in this study, wrote the authors, adding that for better long-term outcomes, “it is important that PsA patients are diagnosed by a rheumatologist within 1 year after symptom onset.”

SOURCE:

This study, led by Selinde V.J. Snoeck Henkemans, MD, of the department of rheumatology at Erasmus University Medical Center, Rotterdam, the Netherlands, was published online February 27, 2024, in RMD Open.

LIMITATIONS:

The study’s dropout rates (25%-31% across groups) may have influenced the findings. Patients with a long diagnostic delay might have dropped out owing to treatment dissatisfaction, and those with a short or intermediate delay might have dropped out due to inactive disease.

DISCLOSURES:

This study did not declare any specific source of funding. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

An earlier diagnosis of psoriatic arthritis (PsA) following symptom onset increases the likelihood of achieving improved clinical outcomes, highlighting the presence of a diagnostic window of opportunity in PsA.

METHODOLOGY:

• A diagnostic delay in PsA leads to increased joint erosions and functional impairment; however, whether a “window of opportunity” (< 12 weeks) exists in PsA requires further evaluation.
• Researchers assessed the impact of diagnostic delay on clinical outcomes in 708 newly diagnosed, disease-modifying antirheumatic drug-naive patients with PsA from the Dutch southwest Early PsA cohort.
• Total diagnostic delay was calculated as the time period between symptom onset and PsA diagnosis made by a rheumatologist.
• On the basis of the total diagnostic delay, patients were categorized into those with a short delay of < 12 weeks (n = 136), intermediate delay of 12 weeks to 1 year (n = 237), and a long delay of > 1 year (n = 335).
• The groups were compared for clinical (Minimal Disease Activity [MDA] and Disease Activity index for Psoriatic Arthritis [DAPSA] remission) and patient-reported outcomes during 3 years of follow-up.

TAKEAWAY:

• The probability of achieving MDA was higher in patients with a short vs long diagnostic delay (odds ratio [OR], 2.55; 95% CI, 1.37-4.76).
• Compared with patients in the long diagnostic delay group, those in the short (OR, 2.35; 95% CI, 1.32-4.19) and intermediate (OR, 1.94; 95% CI, 1.19-3.15) diagnostic delay groups were more likely to achieve DAPSA remission.
• Compared with patients in the long diagnostic delay group, those in the short (estimated mean difference [Δ], −1.09; 95% CI, −1.88 to −0.30) or intermediate (Δ, −0.85; 95% CI, −1.50 to −0.19) groups had slightly less tender joints.

IN PRACTICE:

“A delay of > 1 year is associated with worse clinical outcomes, which includes almost 50% of the PsA population” in this study, wrote the authors, adding that for better long-term outcomes, “it is important that PsA patients are diagnosed by a rheumatologist within 1 year after symptom onset.”

SOURCE:

This study, led by Selinde V.J. Snoeck Henkemans, MD, of the department of rheumatology at Erasmus University Medical Center, Rotterdam, the Netherlands, was published online February 27, 2024, in RMD Open.

LIMITATIONS:

The study’s dropout rates (25%-31% across groups) may have influenced the findings. Patients with a long diagnostic delay might have dropped out owing to treatment dissatisfaction, and those with a short or intermediate delay might have dropped out due to inactive disease.

DISCLOSURES:

This study did not declare any specific source of funding. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

Cervical manipulations have been associated with vascular complications. While the incidence of carotid dissections does not seem to have increased, the question remains open for vertebral artery injuries. We must remain vigilant!

Resorting to joint manipulation for neck pain is not unusual. Currently, cervical manipulation remains a popular first-line treatment for cervicodynia or headaches. Although evidence exists showing that specific joint mobilization can improve this type of symptomatology, there is a possibility that it may risk damaging the cervical arteries and causing ischemic stroke through arterial dissection.

Epidemiologically, internal carotid artery dissection is a relatively rare event with an estimated annual incidence of 1.72 per 100,000 individuals (those most likely to be diagnosed being obviously those leading to hospitalization for stroke) but represents one of the most common causes of stroke in young and middle-aged adults. Faced with case reports that may raise concerns and hypotheses about an associated risk, two studies have sought to delve into the issue.
 

No Increased Carotid Risk Identified

The first study, of a case-cross design, identified all incident cases of ischemic stroke in the territory of the internal carotid artery admitted to the hospital over a 9-year period using administrative healthcare data, the cases being used as their own control by sampling control periods before the date of the index stroke. Thus, 15,523 cases were compared with 62,092 control periods using exposure windows of 1, 3, 7, and 14 days before the stroke. The study also compared post-medical consultation and post-chiropractic consultation outcomes, knowing that as a first-line for complaints of neck pain or headache, patients often turn to one of these two types of primary care clinicians.

However, data analysis shows, among subjects aged under 45 years, positive associations for both different consultations in cases of subsequent carotid stroke (but no association for those aged over 45 years). These associations tended to increase when analyses were limited to visits for diagnoses of neck pain and headaches. Nevertheless, there was no significant difference between risk estimates after chiropractic or general medical consultation.

A notable limitation of this work is that it did not focus on strokes due to vertebral artery dissections that run through the transverse foramina of the cervical vertebrae.
 

A Screening Test Lacking Precision

More recently, the International Federation of Orthopedic Manual Physical Therapists has looked into the subject to refine the assessment of the risk for vascular complications in patients seeking physiotherapy/osteopathy care for neck pain and/or headaches. Through a cross-sectional study involving 150 patients, it tested a vascular complication risk index (from high to low grade, based on history taking and clinical examination), developed to estimate the risk for the presence of vascular rather than musculoskeletal pathology, to determine whether or not there is a contraindication to cervical manipulation.

However, the developed index had only low sensitivity (0.50; 95% CI, 0.39-0.61) and moderate specificity (0.63; 95% CI, 0.51-0.75), knowing that the reference test was a consensus medical decision made by a vascular neurologist, an interventional neurologist, and a neuroradiologist (based on clinical data and cervical MRI). Similarly, positive and negative likelihood ratios were low at 1.36 (95% CI, 0.93-1.99) and 0.79 (95% CI, 0.60-1.05), respectively.

In conclusion, the data from the case-cross study did not seem to demonstrate an excess risk for stroke in the territory of the internal carotid artery after cervical joint manipulations. Associations between cervical manipulation sessions or medical consultations and carotid strokes appear similar and could have been due to the fact that patients with early symptoms related to arterial dissection seek care before developing their stroke.

However, it is regrettable that the study did not focus on vertebral artery dissections, which are anatomically more exposed to cervical chiropractic sessions. Nevertheless, because indices defined from joint tests and medical history are insufficient to identify patients “at risk or in the process of arterial dissection,” and because stroke can result in severe disability, practitioners managing patients with neck pain cannot take this type of complication lightly.

This story was translated from JIM using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Cervical manipulations have been associated with vascular complications. While the incidence of carotid dissections does not seem to have increased, the question remains open for vertebral artery injuries. We must remain vigilant!

Resorting to joint manipulation for neck pain is not unusual. Currently, cervical manipulation remains a popular first-line treatment for cervicodynia or headaches. Although evidence exists showing that specific joint mobilization can improve this type of symptomatology, there is a possibility that it may risk damaging the cervical arteries and causing ischemic stroke through arterial dissection.

Epidemiologically, internal carotid artery dissection is a relatively rare event with an estimated annual incidence of 1.72 per 100,000 individuals (those most likely to be diagnosed being obviously those leading to hospitalization for stroke) but represents one of the most common causes of stroke in young and middle-aged adults. Faced with case reports that may raise concerns and hypotheses about an associated risk, two studies have sought to delve into the issue.
 

No Increased Carotid Risk Identified

The first study, of a case-cross design, identified all incident cases of ischemic stroke in the territory of the internal carotid artery admitted to the hospital over a 9-year period using administrative healthcare data, the cases being used as their own control by sampling control periods before the date of the index stroke. Thus, 15,523 cases were compared with 62,092 control periods using exposure windows of 1, 3, 7, and 14 days before the stroke. The study also compared post-medical consultation and post-chiropractic consultation outcomes, knowing that as a first-line for complaints of neck pain or headache, patients often turn to one of these two types of primary care clinicians.

However, data analysis shows, among subjects aged under 45 years, positive associations for both different consultations in cases of subsequent carotid stroke (but no association for those aged over 45 years). These associations tended to increase when analyses were limited to visits for diagnoses of neck pain and headaches. Nevertheless, there was no significant difference between risk estimates after chiropractic or general medical consultation.

A notable limitation of this work is that it did not focus on strokes due to vertebral artery dissections that run through the transverse foramina of the cervical vertebrae.
 

A Screening Test Lacking Precision

More recently, the International Federation of Orthopedic Manual Physical Therapists has looked into the subject to refine the assessment of the risk for vascular complications in patients seeking physiotherapy/osteopathy care for neck pain and/or headaches. Through a cross-sectional study involving 150 patients, it tested a vascular complication risk index (from high to low grade, based on history taking and clinical examination), developed to estimate the risk for the presence of vascular rather than musculoskeletal pathology, to determine whether or not there is a contraindication to cervical manipulation.

However, the developed index had only low sensitivity (0.50; 95% CI, 0.39-0.61) and moderate specificity (0.63; 95% CI, 0.51-0.75), knowing that the reference test was a consensus medical decision made by a vascular neurologist, an interventional neurologist, and a neuroradiologist (based on clinical data and cervical MRI). Similarly, positive and negative likelihood ratios were low at 1.36 (95% CI, 0.93-1.99) and 0.79 (95% CI, 0.60-1.05), respectively.

In conclusion, the data from the case-cross study did not seem to demonstrate an excess risk for stroke in the territory of the internal carotid artery after cervical joint manipulations. Associations between cervical manipulation sessions or medical consultations and carotid strokes appear similar and could have been due to the fact that patients with early symptoms related to arterial dissection seek care before developing their stroke.

However, it is regrettable that the study did not focus on vertebral artery dissections, which are anatomically more exposed to cervical chiropractic sessions. Nevertheless, because indices defined from joint tests and medical history are insufficient to identify patients “at risk or in the process of arterial dissection,” and because stroke can result in severe disability, practitioners managing patients with neck pain cannot take this type of complication lightly.

This story was translated from JIM using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Cervical manipulations have been associated with vascular complications. While the incidence of carotid dissections does not seem to have increased, the question remains open for vertebral artery injuries. We must remain vigilant!

Resorting to joint manipulation for neck pain is not unusual. Currently, cervical manipulation remains a popular first-line treatment for cervicodynia or headaches. Although evidence exists showing that specific joint mobilization can improve this type of symptomatology, there is a possibility that it may risk damaging the cervical arteries and causing ischemic stroke through arterial dissection.

Epidemiologically, internal carotid artery dissection is a relatively rare event with an estimated annual incidence of 1.72 per 100,000 individuals (those most likely to be diagnosed being obviously those leading to hospitalization for stroke) but represents one of the most common causes of stroke in young and middle-aged adults. Faced with case reports that may raise concerns and hypotheses about an associated risk, two studies have sought to delve into the issue.
 

No Increased Carotid Risk Identified

The first study, of a case-cross design, identified all incident cases of ischemic stroke in the territory of the internal carotid artery admitted to the hospital over a 9-year period using administrative healthcare data, the cases being used as their own control by sampling control periods before the date of the index stroke. Thus, 15,523 cases were compared with 62,092 control periods using exposure windows of 1, 3, 7, and 14 days before the stroke. The study also compared post-medical consultation and post-chiropractic consultation outcomes, knowing that as a first-line for complaints of neck pain or headache, patients often turn to one of these two types of primary care clinicians.

However, data analysis shows, among subjects aged under 45 years, positive associations for both different consultations in cases of subsequent carotid stroke (but no association for those aged over 45 years). These associations tended to increase when analyses were limited to visits for diagnoses of neck pain and headaches. Nevertheless, there was no significant difference between risk estimates after chiropractic or general medical consultation.

A notable limitation of this work is that it did not focus on strokes due to vertebral artery dissections that run through the transverse foramina of the cervical vertebrae.
 

A Screening Test Lacking Precision

More recently, the International Federation of Orthopedic Manual Physical Therapists has looked into the subject to refine the assessment of the risk for vascular complications in patients seeking physiotherapy/osteopathy care for neck pain and/or headaches. Through a cross-sectional study involving 150 patients, it tested a vascular complication risk index (from high to low grade, based on history taking and clinical examination), developed to estimate the risk for the presence of vascular rather than musculoskeletal pathology, to determine whether or not there is a contraindication to cervical manipulation.

However, the developed index had only low sensitivity (0.50; 95% CI, 0.39-0.61) and moderate specificity (0.63; 95% CI, 0.51-0.75), knowing that the reference test was a consensus medical decision made by a vascular neurologist, an interventional neurologist, and a neuroradiologist (based on clinical data and cervical MRI). Similarly, positive and negative likelihood ratios were low at 1.36 (95% CI, 0.93-1.99) and 0.79 (95% CI, 0.60-1.05), respectively.

In conclusion, the data from the case-cross study did not seem to demonstrate an excess risk for stroke in the territory of the internal carotid artery after cervical joint manipulations. Associations between cervical manipulation sessions or medical consultations and carotid strokes appear similar and could have been due to the fact that patients with early symptoms related to arterial dissection seek care before developing their stroke.

However, it is regrettable that the study did not focus on vertebral artery dissections, which are anatomically more exposed to cervical chiropractic sessions. Nevertheless, because indices defined from joint tests and medical history are insufficient to identify patients “at risk or in the process of arterial dissection,” and because stroke can result in severe disability, practitioners managing patients with neck pain cannot take this type of complication lightly.

This story was translated from JIM using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Adding pembrolizumab (Keytruda) to concurrent chemoradiotherapy in patients with high-risk locally advanced cervical cancer does not harm quality of life, according to patient-reported outcome analyses from the KEYNOTE-A18 trial.

Progression-free survival data from the trial, reported at the 2023 meeting of the European Society for Medical Oncology, showed a 30% reduction in the risk for progression (P =.002) with the addition of pembrolizumab vs placebo, as well as favorable overall survival trends, reported Leslie Randall, MD, with VCU Health in Richmond, Virginia. Now the new analyses bring the “voices of the patients from this large phase 3 study.”

“I think the data can put us at ease and give patients a measure of comfort because there was no detriment in the quality of life,” said Dr. Randall, who presented the data on March 17 at the Society of Gynecologic Oncology (SGO) 2024 conference.

The phase 3 KEYNOTE-A18 trial enrolled 1060 patients new to treatment who had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease. They were randomly allocated to receive pembrolizumab or placebo plus concurrent chemoradiotherapy.

Patient-reported outcome instruments used in the study were the European Organization for Research and Treatment of Cancer (EORTC) 30-item quality-of-life (QOL) core questionnaire (QLQ-C30), the EORTC cervical cancer–specific module (QLQ-CX24), and the EuroQol EQ-5D-5L visual analog scale (VAS). 

Prespecified secondary study endpoints were changes from baseline to week 36 in QLQ-C30 global health status/QOL (GHS/QOL) and physical functioning, and the QLQ-CX24 symptom-experience scale.

At baseline, patient-reported outcome scores were similar between treatment groups. Patients in both treatment groups had an initial decrease in QLQ-C30 GHS/QOL and physical functioning subscale and EQ-5D-5L VAS scores at weeks 3 and 6, but these improved relative to baseline at week 12 and subsequent weeks. 

A similar number of patients in the pembrolizumab and placebo groups had improved or stable scores for QLQ-C30 GHS/QOL (76% vs 75%), QLQ-C30 physical functioning (77% vs 77%), QLQ-CX24 symptom experience (85% vs 85%) and EQ-5D-5L VAS (73% vs 76%). 

Across all QOL instruments evaluated, there were no meaningful differences in patient-reported outcomes among patients who received pembrolizumab compared with those who received placebo, said Dr. Randall.

The improvement in progression-free survival, coupled with the patient-reported outcomes showing no additional harms to quality of life, support pembrolizumab plus concurrent chemoradiotherapy as a “new standard of care” for patients with high-risk locally advanced cervical cancer, she told attendees. 

“We have had stunning success in cervical cancer treatments over the past 10-15 years, and now we see that the addition of pembrolizumab to standard chemotherapy not only improves outcome but very importantly does not significantly impact the quality of life in our patients,” said study discussant R. Wendel Naumann, MD, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

Funding for KEYNOTE-A18 was provided by Merck. Dr. Randall has disclosed relationships with Seagen/Genmab, Merck, GSK, ImmunoGen, AstraZeneca, and On Target Laboratories. Dr. Naumann has no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Adding pembrolizumab (Keytruda) to concurrent chemoradiotherapy in patients with high-risk locally advanced cervical cancer does not harm quality of life, according to patient-reported outcome analyses from the KEYNOTE-A18 trial.

Progression-free survival data from the trial, reported at the 2023 meeting of the European Society for Medical Oncology, showed a 30% reduction in the risk for progression (P =.002) with the addition of pembrolizumab vs placebo, as well as favorable overall survival trends, reported Leslie Randall, MD, with VCU Health in Richmond, Virginia. Now the new analyses bring the “voices of the patients from this large phase 3 study.”

“I think the data can put us at ease and give patients a measure of comfort because there was no detriment in the quality of life,” said Dr. Randall, who presented the data on March 17 at the Society of Gynecologic Oncology (SGO) 2024 conference.

The phase 3 KEYNOTE-A18 trial enrolled 1060 patients new to treatment who had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease. They were randomly allocated to receive pembrolizumab or placebo plus concurrent chemoradiotherapy.

Patient-reported outcome instruments used in the study were the European Organization for Research and Treatment of Cancer (EORTC) 30-item quality-of-life (QOL) core questionnaire (QLQ-C30), the EORTC cervical cancer–specific module (QLQ-CX24), and the EuroQol EQ-5D-5L visual analog scale (VAS). 

Prespecified secondary study endpoints were changes from baseline to week 36 in QLQ-C30 global health status/QOL (GHS/QOL) and physical functioning, and the QLQ-CX24 symptom-experience scale.

At baseline, patient-reported outcome scores were similar between treatment groups. Patients in both treatment groups had an initial decrease in QLQ-C30 GHS/QOL and physical functioning subscale and EQ-5D-5L VAS scores at weeks 3 and 6, but these improved relative to baseline at week 12 and subsequent weeks. 

A similar number of patients in the pembrolizumab and placebo groups had improved or stable scores for QLQ-C30 GHS/QOL (76% vs 75%), QLQ-C30 physical functioning (77% vs 77%), QLQ-CX24 symptom experience (85% vs 85%) and EQ-5D-5L VAS (73% vs 76%). 

Across all QOL instruments evaluated, there were no meaningful differences in patient-reported outcomes among patients who received pembrolizumab compared with those who received placebo, said Dr. Randall.

The improvement in progression-free survival, coupled with the patient-reported outcomes showing no additional harms to quality of life, support pembrolizumab plus concurrent chemoradiotherapy as a “new standard of care” for patients with high-risk locally advanced cervical cancer, she told attendees. 

“We have had stunning success in cervical cancer treatments over the past 10-15 years, and now we see that the addition of pembrolizumab to standard chemotherapy not only improves outcome but very importantly does not significantly impact the quality of life in our patients,” said study discussant R. Wendel Naumann, MD, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

Funding for KEYNOTE-A18 was provided by Merck. Dr. Randall has disclosed relationships with Seagen/Genmab, Merck, GSK, ImmunoGen, AstraZeneca, and On Target Laboratories. Dr. Naumann has no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Adding pembrolizumab (Keytruda) to concurrent chemoradiotherapy in patients with high-risk locally advanced cervical cancer does not harm quality of life, according to patient-reported outcome analyses from the KEYNOTE-A18 trial.

Progression-free survival data from the trial, reported at the 2023 meeting of the European Society for Medical Oncology, showed a 30% reduction in the risk for progression (P =.002) with the addition of pembrolizumab vs placebo, as well as favorable overall survival trends, reported Leslie Randall, MD, with VCU Health in Richmond, Virginia. Now the new analyses bring the “voices of the patients from this large phase 3 study.”

“I think the data can put us at ease and give patients a measure of comfort because there was no detriment in the quality of life,” said Dr. Randall, who presented the data on March 17 at the Society of Gynecologic Oncology (SGO) 2024 conference.

The phase 3 KEYNOTE-A18 trial enrolled 1060 patients new to treatment who had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease. They were randomly allocated to receive pembrolizumab or placebo plus concurrent chemoradiotherapy.

Patient-reported outcome instruments used in the study were the European Organization for Research and Treatment of Cancer (EORTC) 30-item quality-of-life (QOL) core questionnaire (QLQ-C30), the EORTC cervical cancer–specific module (QLQ-CX24), and the EuroQol EQ-5D-5L visual analog scale (VAS). 

Prespecified secondary study endpoints were changes from baseline to week 36 in QLQ-C30 global health status/QOL (GHS/QOL) and physical functioning, and the QLQ-CX24 symptom-experience scale.

At baseline, patient-reported outcome scores were similar between treatment groups. Patients in both treatment groups had an initial decrease in QLQ-C30 GHS/QOL and physical functioning subscale and EQ-5D-5L VAS scores at weeks 3 and 6, but these improved relative to baseline at week 12 and subsequent weeks. 

A similar number of patients in the pembrolizumab and placebo groups had improved or stable scores for QLQ-C30 GHS/QOL (76% vs 75%), QLQ-C30 physical functioning (77% vs 77%), QLQ-CX24 symptom experience (85% vs 85%) and EQ-5D-5L VAS (73% vs 76%). 

Across all QOL instruments evaluated, there were no meaningful differences in patient-reported outcomes among patients who received pembrolizumab compared with those who received placebo, said Dr. Randall.

The improvement in progression-free survival, coupled with the patient-reported outcomes showing no additional harms to quality of life, support pembrolizumab plus concurrent chemoradiotherapy as a “new standard of care” for patients with high-risk locally advanced cervical cancer, she told attendees. 

“We have had stunning success in cervical cancer treatments over the past 10-15 years, and now we see that the addition of pembrolizumab to standard chemotherapy not only improves outcome but very importantly does not significantly impact the quality of life in our patients,” said study discussant R. Wendel Naumann, MD, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

Funding for KEYNOTE-A18 was provided by Merck. Dr. Randall has disclosed relationships with Seagen/Genmab, Merck, GSK, ImmunoGen, AstraZeneca, and On Target Laboratories. Dr. Naumann has no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Primary biliary cholangitis is a rare progressive autoimmune liver disease that specifically targets biliary epithelial cells. In this article, Dr. Kowdley describes prognostic markers of disease, current and investigational medical therapies, liver transplant, and focusing on maximizing favorable long-term outcomes.

Click Here to Read More

Primary biliary cholangitis is a rare progressive autoimmune liver disease that specifically targets biliary epithelial cells. In this article, Dr. Kowdley describes prognostic markers of disease, current and investigational medical therapies, liver transplant, and focusing on maximizing favorable long-term outcomes.

Click Here to Read More

Primary biliary cholangitis is a rare progressive autoimmune liver disease that specifically targets biliary epithelial cells. In this article, Dr. Kowdley describes prognostic markers of disease, current and investigational medical therapies, liver transplant, and focusing on maximizing favorable long-term outcomes.

Click Here to Read More

The number of clinically active rheumatology providers in the United States grew more than 20% from 2009 to 2019, according to a new analysis.

The number of advanced practice providers (APPs) in rheumatology more than doubled during that same time. However, these numerical increases are not enough to meet the projected demand in care, the authors reported.

University of Alabama Medical Center

“Even though we found growth, and if that same growth continued, we’d still be well below the projected needs for the overall aging population of the United States,” lead author Melissa Mannion, MD, MSPH, a pediatric rheumatologist at the University of Alabama at Birmingham, said in an interview.

In a 2015 workforce study by the American College of Rheumatology (ACR), researchers projected that the supply of rheumatologists would decrease by 25% from 2015 to 2030, with an estimated shortage of over 4000 clinical full-time equivalent (cFTE) rheumatology providers.

While the previous study’s findings seem to contrast with this newest analysis, Dr. Dr. Mannion said the findings are complementary, with both studies using different data sources.

The newest findings were published online on February 24 in Arthritis & Rheumatology.

Leveraging Medicare Data

The ACR study estimated the adult rheumatology workforce and cFTEs using both primary and secondary sources, including published data from the American Medical Association and other professional societies, as well as electronic surveys of ACR members and rheumatology fellows in training.

By contrast, this newest study identified rheumatology providers using Medicare administrative data from 2006 to 2020, supplemented by national provider identifier taxonomy codes. Rheumatologists were considered “clinically active” if they provided care for at least five patients in 1 year. To account for rheumatology fellows, who can be categorized as internal medicine physicians, researchers also included internists who prescribed biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) to more than 10 patients a year.

The count also included APPs, both nurse practitioners (NPs) and physician assistants (PAs), who were attached to practices with only rheumatologists, internists, or one other specialty. Like physicians, APPs were included in the count if they prescribed more than 10 patients biologic or targeted synthetic DMARDs in a calendar year and billed at least five patients with a rheumatic condition per year.

Researchers also estimated the number of cFTEs for 2019, using a variety of assumptions to generate an upper and lower range.

Different Numbers, Complementary Conclusions

For the 2019 calendar year, researchers counted 5667 clinically active rheumatologists and 379 NPs/PAs.

This represented a 23% increase in rheumatologists and a 141% increase in the number of APPs in the rheumatology workforce from 2009. The active rheumatology workforce increased by about 100 providers per year over the study period, although growth flattened off in more recent years.

The estimated cFTEs for 2019 ranged from 3457 to 5396, which are “comparable” to the projected 2020 cFTE estimates made in the ACR 2015 workforce study: 3888 to 5777 cFTEs.

American College of Rheumatology

Daniel Battafarano, DO, chair of the ACR Workforce Solutions Committee, agreed with Dr. Mannion that these findings complement each other, telling a similar story “but with different numbers,” he told this news organization. Dr. Battafarano, a professor of medicine at the Uniformed Services University of the Health Sciences, Bethesda, Maryland, led the ACR workforce study.

“Both studies project estimates of rheumatology providers and workforce trends, but neither study can claim accurate numbers of rheumatology providers due to the true limitation of either workforce study model,” he said.

The ACR study began with a higher count of rheumatologists, estimating 6013 practicing providers in 2015, while Dr. Mannion’s team calculated 5474 providers for the same year. The ACR study projected that provider numbers would fall to 5886 by 2020, which was higher than the 2019 count in this most recent study.

Dr. Battafarano noted that the studies also dealt with different time frames: While the ACR study used 2015 data to project trends in 5-year increments, this most recent study looked trends in the previous decade.

“We found an increase over time, although toward the end of our study — from 2019 to 2020 — we did have a drop off in number of providers, so maybe we are finding the beginning of what [the ACR researchers] anticipated, or maybe that will be corrected in the future,” Dr. Dr. Mannion said. “I think that our estimates really coordinate with what they found just using a different data source.”

Geographic Disparities and Solutions

The new study also highlighted the scarcity of rheumatology providers in rural counties, which was also an important take away from the 2015 ACR study. In the new analysis, researchers found that 95% of rheumatology practices were in urban settings, which did not change over the study period. Most counties in the United States had fewer than 30 rheumatologists per 1 million adults, with 93% of rural counties having zero adult rheumatologists. In comparison, 48% of urban counties had no adult rheumatologists.

“There’s not enough people, and they’re in very specific locations,” Dr. Dr. Mannion said. “Both things make it harder for people to get care.”

Dr. Battafarano noted that leveraging APPs would be key to increasing patient access to care moving forward — a resource that has more than doubled in the past decade, according to Dr. Dr. Mannion’s analysis.

“Recruiting a significant number of APPs into rheumatology practice should be a primary goal to increase the rheumatology workforce,” he said. Other potential solutions, he added, include employing telemedicine and educating primary care providers on rheumatic disease to help them comanage these conditions with rheumatologists.

This study was partially funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Mannion was supported by the Rheumatology Research Foundation Norman B. Gaylis, MD Clinical Research Award, paid to her institution. Dr. Battafarano had no relevant disclosures.

A version of this article appeared on Medscape.com.

The number of clinically active rheumatology providers in the United States grew more than 20% from 2009 to 2019, according to a new analysis.

The number of advanced practice providers (APPs) in rheumatology more than doubled during that same time. However, these numerical increases are not enough to meet the projected demand in care, the authors reported.

University of Alabama Medical Center

“Even though we found growth, and if that same growth continued, we’d still be well below the projected needs for the overall aging population of the United States,” lead author Melissa Mannion, MD, MSPH, a pediatric rheumatologist at the University of Alabama at Birmingham, said in an interview.

In a 2015 workforce study by the American College of Rheumatology (ACR), researchers projected that the supply of rheumatologists would decrease by 25% from 2015 to 2030, with an estimated shortage of over 4000 clinical full-time equivalent (cFTE) rheumatology providers.

While the previous study’s findings seem to contrast with this newest analysis, Dr. Dr. Mannion said the findings are complementary, with both studies using different data sources.

The newest findings were published online on February 24 in Arthritis & Rheumatology.

Leveraging Medicare Data

The ACR study estimated the adult rheumatology workforce and cFTEs using both primary and secondary sources, including published data from the American Medical Association and other professional societies, as well as electronic surveys of ACR members and rheumatology fellows in training.

By contrast, this newest study identified rheumatology providers using Medicare administrative data from 2006 to 2020, supplemented by national provider identifier taxonomy codes. Rheumatologists were considered “clinically active” if they provided care for at least five patients in 1 year. To account for rheumatology fellows, who can be categorized as internal medicine physicians, researchers also included internists who prescribed biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) to more than 10 patients a year.

The count also included APPs, both nurse practitioners (NPs) and physician assistants (PAs), who were attached to practices with only rheumatologists, internists, or one other specialty. Like physicians, APPs were included in the count if they prescribed more than 10 patients biologic or targeted synthetic DMARDs in a calendar year and billed at least five patients with a rheumatic condition per year.

Researchers also estimated the number of cFTEs for 2019, using a variety of assumptions to generate an upper and lower range.

Different Numbers, Complementary Conclusions

For the 2019 calendar year, researchers counted 5667 clinically active rheumatologists and 379 NPs/PAs.

This represented a 23% increase in rheumatologists and a 141% increase in the number of APPs in the rheumatology workforce from 2009. The active rheumatology workforce increased by about 100 providers per year over the study period, although growth flattened off in more recent years.

The estimated cFTEs for 2019 ranged from 3457 to 5396, which are “comparable” to the projected 2020 cFTE estimates made in the ACR 2015 workforce study: 3888 to 5777 cFTEs.

American College of Rheumatology

Daniel Battafarano, DO, chair of the ACR Workforce Solutions Committee, agreed with Dr. Mannion that these findings complement each other, telling a similar story “but with different numbers,” he told this news organization. Dr. Battafarano, a professor of medicine at the Uniformed Services University of the Health Sciences, Bethesda, Maryland, led the ACR workforce study.

“Both studies project estimates of rheumatology providers and workforce trends, but neither study can claim accurate numbers of rheumatology providers due to the true limitation of either workforce study model,” he said.

The ACR study began with a higher count of rheumatologists, estimating 6013 practicing providers in 2015, while Dr. Mannion’s team calculated 5474 providers for the same year. The ACR study projected that provider numbers would fall to 5886 by 2020, which was higher than the 2019 count in this most recent study.

Dr. Battafarano noted that the studies also dealt with different time frames: While the ACR study used 2015 data to project trends in 5-year increments, this most recent study looked trends in the previous decade.

“We found an increase over time, although toward the end of our study — from 2019 to 2020 — we did have a drop off in number of providers, so maybe we are finding the beginning of what [the ACR researchers] anticipated, or maybe that will be corrected in the future,” Dr. Dr. Mannion said. “I think that our estimates really coordinate with what they found just using a different data source.”

Geographic Disparities and Solutions

The new study also highlighted the scarcity of rheumatology providers in rural counties, which was also an important take away from the 2015 ACR study. In the new analysis, researchers found that 95% of rheumatology practices were in urban settings, which did not change over the study period. Most counties in the United States had fewer than 30 rheumatologists per 1 million adults, with 93% of rural counties having zero adult rheumatologists. In comparison, 48% of urban counties had no adult rheumatologists.

“There’s not enough people, and they’re in very specific locations,” Dr. Dr. Mannion said. “Both things make it harder for people to get care.”

Dr. Battafarano noted that leveraging APPs would be key to increasing patient access to care moving forward — a resource that has more than doubled in the past decade, according to Dr. Dr. Mannion’s analysis.

“Recruiting a significant number of APPs into rheumatology practice should be a primary goal to increase the rheumatology workforce,” he said. Other potential solutions, he added, include employing telemedicine and educating primary care providers on rheumatic disease to help them comanage these conditions with rheumatologists.

This study was partially funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Mannion was supported by the Rheumatology Research Foundation Norman B. Gaylis, MD Clinical Research Award, paid to her institution. Dr. Battafarano had no relevant disclosures.

A version of this article appeared on Medscape.com.

The number of clinically active rheumatology providers in the United States grew more than 20% from 2009 to 2019, according to a new analysis.

The number of advanced practice providers (APPs) in rheumatology more than doubled during that same time. However, these numerical increases are not enough to meet the projected demand in care, the authors reported.

University of Alabama Medical Center

“Even though we found growth, and if that same growth continued, we’d still be well below the projected needs for the overall aging population of the United States,” lead author Melissa Mannion, MD, MSPH, a pediatric rheumatologist at the University of Alabama at Birmingham, said in an interview.

In a 2015 workforce study by the American College of Rheumatology (ACR), researchers projected that the supply of rheumatologists would decrease by 25% from 2015 to 2030, with an estimated shortage of over 4000 clinical full-time equivalent (cFTE) rheumatology providers.

While the previous study’s findings seem to contrast with this newest analysis, Dr. Dr. Mannion said the findings are complementary, with both studies using different data sources.

The newest findings were published online on February 24 in Arthritis & Rheumatology.

Leveraging Medicare Data

The ACR study estimated the adult rheumatology workforce and cFTEs using both primary and secondary sources, including published data from the American Medical Association and other professional societies, as well as electronic surveys of ACR members and rheumatology fellows in training.

By contrast, this newest study identified rheumatology providers using Medicare administrative data from 2006 to 2020, supplemented by national provider identifier taxonomy codes. Rheumatologists were considered “clinically active” if they provided care for at least five patients in 1 year. To account for rheumatology fellows, who can be categorized as internal medicine physicians, researchers also included internists who prescribed biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) to more than 10 patients a year.

The count also included APPs, both nurse practitioners (NPs) and physician assistants (PAs), who were attached to practices with only rheumatologists, internists, or one other specialty. Like physicians, APPs were included in the count if they prescribed more than 10 patients biologic or targeted synthetic DMARDs in a calendar year and billed at least five patients with a rheumatic condition per year.

Researchers also estimated the number of cFTEs for 2019, using a variety of assumptions to generate an upper and lower range.

Different Numbers, Complementary Conclusions

For the 2019 calendar year, researchers counted 5667 clinically active rheumatologists and 379 NPs/PAs.

This represented a 23% increase in rheumatologists and a 141% increase in the number of APPs in the rheumatology workforce from 2009. The active rheumatology workforce increased by about 100 providers per year over the study period, although growth flattened off in more recent years.

The estimated cFTEs for 2019 ranged from 3457 to 5396, which are “comparable” to the projected 2020 cFTE estimates made in the ACR 2015 workforce study: 3888 to 5777 cFTEs.

American College of Rheumatology

Daniel Battafarano, DO, chair of the ACR Workforce Solutions Committee, agreed with Dr. Mannion that these findings complement each other, telling a similar story “but with different numbers,” he told this news organization. Dr. Battafarano, a professor of medicine at the Uniformed Services University of the Health Sciences, Bethesda, Maryland, led the ACR workforce study.

“Both studies project estimates of rheumatology providers and workforce trends, but neither study can claim accurate numbers of rheumatology providers due to the true limitation of either workforce study model,” he said.

The ACR study began with a higher count of rheumatologists, estimating 6013 practicing providers in 2015, while Dr. Mannion’s team calculated 5474 providers for the same year. The ACR study projected that provider numbers would fall to 5886 by 2020, which was higher than the 2019 count in this most recent study.

Dr. Battafarano noted that the studies also dealt with different time frames: While the ACR study used 2015 data to project trends in 5-year increments, this most recent study looked trends in the previous decade.

“We found an increase over time, although toward the end of our study — from 2019 to 2020 — we did have a drop off in number of providers, so maybe we are finding the beginning of what [the ACR researchers] anticipated, or maybe that will be corrected in the future,” Dr. Dr. Mannion said. “I think that our estimates really coordinate with what they found just using a different data source.”

Geographic Disparities and Solutions

The new study also highlighted the scarcity of rheumatology providers in rural counties, which was also an important take away from the 2015 ACR study. In the new analysis, researchers found that 95% of rheumatology practices were in urban settings, which did not change over the study period. Most counties in the United States had fewer than 30 rheumatologists per 1 million adults, with 93% of rural counties having zero adult rheumatologists. In comparison, 48% of urban counties had no adult rheumatologists.

“There’s not enough people, and they’re in very specific locations,” Dr. Dr. Mannion said. “Both things make it harder for people to get care.”

Dr. Battafarano noted that leveraging APPs would be key to increasing patient access to care moving forward — a resource that has more than doubled in the past decade, according to Dr. Dr. Mannion’s analysis.

“Recruiting a significant number of APPs into rheumatology practice should be a primary goal to increase the rheumatology workforce,” he said. Other potential solutions, he added, include employing telemedicine and educating primary care providers on rheumatic disease to help them comanage these conditions with rheumatologists.

This study was partially funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Mannion was supported by the Rheumatology Research Foundation Norman B. Gaylis, MD Clinical Research Award, paid to her institution. Dr. Battafarano had no relevant disclosures.

A version of this article appeared on Medscape.com.

An advisory panel at the US Food and Drug Administration (FDA) lent support to bids that allow for earlier use of chimeric antigen receptor (CAR-T) therapies in treating multiple myeloma, while also calling for clear disclosure to patients of potential risks of these treatments.

The FDA asked its Oncologic Drugs Advisory Committee (ODAC) to vote on two separate but similar questions at the March 15 meeting. Much of their discussion centered on higher rates of deaths for patients on the CAR-T therapies during early stages of key studies.

ODAC voted 11-0 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for ciltacabtagene autoleucel (cilta-cel, Carvykti, Johnson & Johnson’s Janssen). J&J is seeking approval for use of the drug for adults with relapsed or refractory multiple myeloma (RRMM) who have received at least one prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and are refractory to lenalidomide.

ODAC voted 8-3 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for idecabtagene vicleucel (ide-cel, Abecma, Bristol Myers Squibb). The company is seeking approval of the drug for people with relapsed or refractory multiple myeloma (RRMM) who have received an IMiD, a PI, and an anti-CD38 antibody.

The FDA staff will consider ODAC’s votes and recommendations, but is not bound by them. Janssen’s parent company, J&J, said the FDA’s deadline for deciding on the request to change the cilta-cel label is April 5. Bristol Myers Squibb (BMS) said there is not a PDUFA deadline at this time for its application.

Both CAR-T treatments currently are approved for RRMM after 4 or more prior lines of therapy, including an IMiD, PI and an anti-CD38 monoclonal antibody. Last year BMS and Janssen filed their separate applications, both seeking to have their drugs used earlier in the course of RRMM.

Data provided in support of both requests for expanded use raised alarms at the FDA, with more deaths seen in the early stage of testing among patients given the CAR-T drugs compared to those given standard-of-care regimens, the agency staff said.

The application for cilta-cel rests heavily on the data from the CARTITUDE-4 trial. As reported in The New England Journal of Medicine last year, progression-free survival (PFS) at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group.

But the FDA staff review focused on worrying signs in the early months of this study. For example, the rate of death in the first 10 months post randomization was higher in the cilta-cel arm (29 of 208; 14%) than in the standard therapy arm (25 of 211; 12%) based on an analysis of the intent-to-treat (ITT) population, the FDA said.

In its review of the ide-cel application, the FDA staff said the median PFS was 13.3 months in the ide-cel arm (95% CI: 11.8, 16.1), and 4.4 months (95% CI: 3.4, 5.9) in the standard of care (SOC) arm.

However, the rate of deaths in the first 9 months post randomization was higher in the ide-cel arm (45/254; 18%) than in the comparator standard-of-care group (15/132; 11%) in the ITT population, the FDA staff said. In the safety analysis population, the rate of deaths from adverse events that occurred within 90 days from starting treatment was 2.7% in the ide-cel arm and 1.6 % in the standard-regimen group.

ODAC ultimately appeared more impressed by data indicating the potential benefit, measured as progression-free survival (PFS), of the two drugs under review, than they were concerned about the issues about early deaths raised by FDA staff.

Panelist Jorge J. Nieva, MD, of the University of Southern California said the CAR-T drugs may present another case of “front-loaded risk” as has been noted for other treatments for serious medical procedures, such as allogeneic transplantations and thoracic surgeries.

In response, Robert Sokolic, MD, the branch chief for malignant hematology at FDA, replied that the data raised concerns that did in fact remind him of these procedures.

“I’m a bone marrow transplant physician. And that’s exactly what I said when I saw these curves. This looks like an allogeneic transplant curve,” Dr. Sokolic said.

But there’s a major difference between that procedure and CAR-T in the context being considered at the ODAC meeting, he said.

With allogeneic transplant, physicians “counsel patients. We ask them to accept an upfront burden of increased mortality, because we know that down the line, overall, there’s a benefit in survival,” Dr. Sokolic said.

In contrast, the primary endpoint in the key studies for expansion of CAR-T drugs was progression-free survival (PFS), with overall survival as a second endpoint. The FDA staff in briefing documents noted how overall survival, the gold standard in research, delivers far more reliable answers for patients and doctors in assessing treatments.

In the exchange with Dr. Nieva, Dr. Sokolic noted that there’s far less certainty of benefit at this time when asking patients to consider CAR-T earlier in the progression of MM, especially given the safety concerns.

“We know there’s benefit in PFS. We know there’s a safety concern,” Dr. Sokolic said.“That’s not balanced by an overall survival balance on the tail end. It may be when the data are more mature, but it’s not there yet.”
 

Describing Risks to Patients

ODAC panelists also stressed a need to help patients understand what’s known — and not yet known — about these CAR-T therapies. It will be very challenging for patients to understand and interpret the data from key studies on these medicines, said ODAC panelist Susan Lattimore, RN, of Oregon Health & Science University. She suggested the FDA seek labeling that would be “overtly transparent” and use lay terms to describe the potential risks and benefits.

In its presentations to the FDA and ODAC, J&J noted that the COVID pandemic has affected testing and that the rate of deaths flips in time to be higher in the comparator group.

In its briefing document for the meeting, BMS emphasized that most of the patients in the ide-cel arm who died in the first 6 months of its trial did not get the study drug. There were 9 deaths in the standard-regimen arm, or 6.8% of the group, compared with 30, or 11.8% in the ide-cel group.

In the ide-cel arm, the majority of early deaths (17/30; 56.7%) occurred in patients who never received ide-cel treatment, with 13 of those 17 dying from disease progression, the company said in its briefing document. The early death rate among patients who received the allocated study treatment was similar between arms (5.1% in the ide-cel arm vs 6.8% in the standard regimen arm),the company said.

In the staff briefing, the FDA said the median PFS was 13.3 months in the ide-cel arm, compared with 4.4 months in the standard of care (SOC) arm. But there was a “clear and persistent increased mortality” for the ide-cel group, compared with the standard regimen arm, with increased rates of death up to 9 months. In addition, the overall survival disadvantage persisted to 15 months after randomization, when the survival curves finally crossed, the FDA staff said in its March 15 presentation.

ODAC Chairman Ravi A. Madan, MD, of the National Cancer Institute, was among the panelists who voted “no” in the ide-cel question. He said the risk-benefit profile of the drug does not appear favorable at this time for expanded use.

“There’s a lot of optimism about moving these therapies earlier in the disease states of multiple myeloma,” Dr. Madan said, calling the PFS data “quite remarkable.

“But for me this data at this level of maturity really didn’t provide convincing evidence that ide-cel earlier had a favorable risk benefit assessment in a proposed indication.”

ODAC panelist Christopher H. Lieu, MD, of the University of Colorado, said he struggled to decide how to vote on the ide-cel question and in the end voted yes.

He said the response to the treatment doesn’t appear to be as durable as hoped, considering the significant burden that CAR-T therapy imposes on patients. However, the PFS data suggest that ide-cel could offer patients with RRMM a chance for significant times off therapy with associated quality of life improvement.

“I do believe that the risk-benefit profile is favorable for this population as a whole,” he said. “But it’s a closer margin than I think we would like and patients will need to have in-depth discussions about the risks and benefits and balance that with the possible benefits with their provider.”

An advisory panel at the US Food and Drug Administration (FDA) lent support to bids that allow for earlier use of chimeric antigen receptor (CAR-T) therapies in treating multiple myeloma, while also calling for clear disclosure to patients of potential risks of these treatments.

The FDA asked its Oncologic Drugs Advisory Committee (ODAC) to vote on two separate but similar questions at the March 15 meeting. Much of their discussion centered on higher rates of deaths for patients on the CAR-T therapies during early stages of key studies.

ODAC voted 11-0 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for ciltacabtagene autoleucel (cilta-cel, Carvykti, Johnson & Johnson’s Janssen). J&J is seeking approval for use of the drug for adults with relapsed or refractory multiple myeloma (RRMM) who have received at least one prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and are refractory to lenalidomide.

ODAC voted 8-3 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for idecabtagene vicleucel (ide-cel, Abecma, Bristol Myers Squibb). The company is seeking approval of the drug for people with relapsed or refractory multiple myeloma (RRMM) who have received an IMiD, a PI, and an anti-CD38 antibody.

The FDA staff will consider ODAC’s votes and recommendations, but is not bound by them. Janssen’s parent company, J&J, said the FDA’s deadline for deciding on the request to change the cilta-cel label is April 5. Bristol Myers Squibb (BMS) said there is not a PDUFA deadline at this time for its application.

Both CAR-T treatments currently are approved for RRMM after 4 or more prior lines of therapy, including an IMiD, PI and an anti-CD38 monoclonal antibody. Last year BMS and Janssen filed their separate applications, both seeking to have their drugs used earlier in the course of RRMM.

Data provided in support of both requests for expanded use raised alarms at the FDA, with more deaths seen in the early stage of testing among patients given the CAR-T drugs compared to those given standard-of-care regimens, the agency staff said.

The application for cilta-cel rests heavily on the data from the CARTITUDE-4 trial. As reported in The New England Journal of Medicine last year, progression-free survival (PFS) at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group.

But the FDA staff review focused on worrying signs in the early months of this study. For example, the rate of death in the first 10 months post randomization was higher in the cilta-cel arm (29 of 208; 14%) than in the standard therapy arm (25 of 211; 12%) based on an analysis of the intent-to-treat (ITT) population, the FDA said.

In its review of the ide-cel application, the FDA staff said the median PFS was 13.3 months in the ide-cel arm (95% CI: 11.8, 16.1), and 4.4 months (95% CI: 3.4, 5.9) in the standard of care (SOC) arm.

However, the rate of deaths in the first 9 months post randomization was higher in the ide-cel arm (45/254; 18%) than in the comparator standard-of-care group (15/132; 11%) in the ITT population, the FDA staff said. In the safety analysis population, the rate of deaths from adverse events that occurred within 90 days from starting treatment was 2.7% in the ide-cel arm and 1.6 % in the standard-regimen group.

ODAC ultimately appeared more impressed by data indicating the potential benefit, measured as progression-free survival (PFS), of the two drugs under review, than they were concerned about the issues about early deaths raised by FDA staff.

Panelist Jorge J. Nieva, MD, of the University of Southern California said the CAR-T drugs may present another case of “front-loaded risk” as has been noted for other treatments for serious medical procedures, such as allogeneic transplantations and thoracic surgeries.

In response, Robert Sokolic, MD, the branch chief for malignant hematology at FDA, replied that the data raised concerns that did in fact remind him of these procedures.

“I’m a bone marrow transplant physician. And that’s exactly what I said when I saw these curves. This looks like an allogeneic transplant curve,” Dr. Sokolic said.

But there’s a major difference between that procedure and CAR-T in the context being considered at the ODAC meeting, he said.

With allogeneic transplant, physicians “counsel patients. We ask them to accept an upfront burden of increased mortality, because we know that down the line, overall, there’s a benefit in survival,” Dr. Sokolic said.

In contrast, the primary endpoint in the key studies for expansion of CAR-T drugs was progression-free survival (PFS), with overall survival as a second endpoint. The FDA staff in briefing documents noted how overall survival, the gold standard in research, delivers far more reliable answers for patients and doctors in assessing treatments.

In the exchange with Dr. Nieva, Dr. Sokolic noted that there’s far less certainty of benefit at this time when asking patients to consider CAR-T earlier in the progression of MM, especially given the safety concerns.

“We know there’s benefit in PFS. We know there’s a safety concern,” Dr. Sokolic said.“That’s not balanced by an overall survival balance on the tail end. It may be when the data are more mature, but it’s not there yet.”
 

Describing Risks to Patients

ODAC panelists also stressed a need to help patients understand what’s known — and not yet known — about these CAR-T therapies. It will be very challenging for patients to understand and interpret the data from key studies on these medicines, said ODAC panelist Susan Lattimore, RN, of Oregon Health & Science University. She suggested the FDA seek labeling that would be “overtly transparent” and use lay terms to describe the potential risks and benefits.

In its presentations to the FDA and ODAC, J&J noted that the COVID pandemic has affected testing and that the rate of deaths flips in time to be higher in the comparator group.

In its briefing document for the meeting, BMS emphasized that most of the patients in the ide-cel arm who died in the first 6 months of its trial did not get the study drug. There were 9 deaths in the standard-regimen arm, or 6.8% of the group, compared with 30, or 11.8% in the ide-cel group.

In the ide-cel arm, the majority of early deaths (17/30; 56.7%) occurred in patients who never received ide-cel treatment, with 13 of those 17 dying from disease progression, the company said in its briefing document. The early death rate among patients who received the allocated study treatment was similar between arms (5.1% in the ide-cel arm vs 6.8% in the standard regimen arm),the company said.

In the staff briefing, the FDA said the median PFS was 13.3 months in the ide-cel arm, compared with 4.4 months in the standard of care (SOC) arm. But there was a “clear and persistent increased mortality” for the ide-cel group, compared with the standard regimen arm, with increased rates of death up to 9 months. In addition, the overall survival disadvantage persisted to 15 months after randomization, when the survival curves finally crossed, the FDA staff said in its March 15 presentation.

ODAC Chairman Ravi A. Madan, MD, of the National Cancer Institute, was among the panelists who voted “no” in the ide-cel question. He said the risk-benefit profile of the drug does not appear favorable at this time for expanded use.

“There’s a lot of optimism about moving these therapies earlier in the disease states of multiple myeloma,” Dr. Madan said, calling the PFS data “quite remarkable.

“But for me this data at this level of maturity really didn’t provide convincing evidence that ide-cel earlier had a favorable risk benefit assessment in a proposed indication.”

ODAC panelist Christopher H. Lieu, MD, of the University of Colorado, said he struggled to decide how to vote on the ide-cel question and in the end voted yes.

He said the response to the treatment doesn’t appear to be as durable as hoped, considering the significant burden that CAR-T therapy imposes on patients. However, the PFS data suggest that ide-cel could offer patients with RRMM a chance for significant times off therapy with associated quality of life improvement.

“I do believe that the risk-benefit profile is favorable for this population as a whole,” he said. “But it’s a closer margin than I think we would like and patients will need to have in-depth discussions about the risks and benefits and balance that with the possible benefits with their provider.”

An advisory panel at the US Food and Drug Administration (FDA) lent support to bids that allow for earlier use of chimeric antigen receptor (CAR-T) therapies in treating multiple myeloma, while also calling for clear disclosure to patients of potential risks of these treatments.

The FDA asked its Oncologic Drugs Advisory Committee (ODAC) to vote on two separate but similar questions at the March 15 meeting. Much of their discussion centered on higher rates of deaths for patients on the CAR-T therapies during early stages of key studies.

ODAC voted 11-0 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for ciltacabtagene autoleucel (cilta-cel, Carvykti, Johnson & Johnson’s Janssen). J&J is seeking approval for use of the drug for adults with relapsed or refractory multiple myeloma (RRMM) who have received at least one prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and are refractory to lenalidomide.

ODAC voted 8-3 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for idecabtagene vicleucel (ide-cel, Abecma, Bristol Myers Squibb). The company is seeking approval of the drug for people with relapsed or refractory multiple myeloma (RRMM) who have received an IMiD, a PI, and an anti-CD38 antibody.

The FDA staff will consider ODAC’s votes and recommendations, but is not bound by them. Janssen’s parent company, J&J, said the FDA’s deadline for deciding on the request to change the cilta-cel label is April 5. Bristol Myers Squibb (BMS) said there is not a PDUFA deadline at this time for its application.

Both CAR-T treatments currently are approved for RRMM after 4 or more prior lines of therapy, including an IMiD, PI and an anti-CD38 monoclonal antibody. Last year BMS and Janssen filed their separate applications, both seeking to have their drugs used earlier in the course of RRMM.

Data provided in support of both requests for expanded use raised alarms at the FDA, with more deaths seen in the early stage of testing among patients given the CAR-T drugs compared to those given standard-of-care regimens, the agency staff said.

The application for cilta-cel rests heavily on the data from the CARTITUDE-4 trial. As reported in The New England Journal of Medicine last year, progression-free survival (PFS) at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group.

But the FDA staff review focused on worrying signs in the early months of this study. For example, the rate of death in the first 10 months post randomization was higher in the cilta-cel arm (29 of 208; 14%) than in the standard therapy arm (25 of 211; 12%) based on an analysis of the intent-to-treat (ITT) population, the FDA said.

In its review of the ide-cel application, the FDA staff said the median PFS was 13.3 months in the ide-cel arm (95% CI: 11.8, 16.1), and 4.4 months (95% CI: 3.4, 5.9) in the standard of care (SOC) arm.

However, the rate of deaths in the first 9 months post randomization was higher in the ide-cel arm (45/254; 18%) than in the comparator standard-of-care group (15/132; 11%) in the ITT population, the FDA staff said. In the safety analysis population, the rate of deaths from adverse events that occurred within 90 days from starting treatment was 2.7% in the ide-cel arm and 1.6 % in the standard-regimen group.

ODAC ultimately appeared more impressed by data indicating the potential benefit, measured as progression-free survival (PFS), of the two drugs under review, than they were concerned about the issues about early deaths raised by FDA staff.

Panelist Jorge J. Nieva, MD, of the University of Southern California said the CAR-T drugs may present another case of “front-loaded risk” as has been noted for other treatments for serious medical procedures, such as allogeneic transplantations and thoracic surgeries.

In response, Robert Sokolic, MD, the branch chief for malignant hematology at FDA, replied that the data raised concerns that did in fact remind him of these procedures.

“I’m a bone marrow transplant physician. And that’s exactly what I said when I saw these curves. This looks like an allogeneic transplant curve,” Dr. Sokolic said.

But there’s a major difference between that procedure and CAR-T in the context being considered at the ODAC meeting, he said.

With allogeneic transplant, physicians “counsel patients. We ask them to accept an upfront burden of increased mortality, because we know that down the line, overall, there’s a benefit in survival,” Dr. Sokolic said.

In contrast, the primary endpoint in the key studies for expansion of CAR-T drugs was progression-free survival (PFS), with overall survival as a second endpoint. The FDA staff in briefing documents noted how overall survival, the gold standard in research, delivers far more reliable answers for patients and doctors in assessing treatments.

In the exchange with Dr. Nieva, Dr. Sokolic noted that there’s far less certainty of benefit at this time when asking patients to consider CAR-T earlier in the progression of MM, especially given the safety concerns.

“We know there’s benefit in PFS. We know there’s a safety concern,” Dr. Sokolic said.“That’s not balanced by an overall survival balance on the tail end. It may be when the data are more mature, but it’s not there yet.”
 

Describing Risks to Patients

ODAC panelists also stressed a need to help patients understand what’s known — and not yet known — about these CAR-T therapies. It will be very challenging for patients to understand and interpret the data from key studies on these medicines, said ODAC panelist Susan Lattimore, RN, of Oregon Health & Science University. She suggested the FDA seek labeling that would be “overtly transparent” and use lay terms to describe the potential risks and benefits.

In its presentations to the FDA and ODAC, J&J noted that the COVID pandemic has affected testing and that the rate of deaths flips in time to be higher in the comparator group.

In its briefing document for the meeting, BMS emphasized that most of the patients in the ide-cel arm who died in the first 6 months of its trial did not get the study drug. There were 9 deaths in the standard-regimen arm, or 6.8% of the group, compared with 30, or 11.8% in the ide-cel group.

In the ide-cel arm, the majority of early deaths (17/30; 56.7%) occurred in patients who never received ide-cel treatment, with 13 of those 17 dying from disease progression, the company said in its briefing document. The early death rate among patients who received the allocated study treatment was similar between arms (5.1% in the ide-cel arm vs 6.8% in the standard regimen arm),the company said.

In the staff briefing, the FDA said the median PFS was 13.3 months in the ide-cel arm, compared with 4.4 months in the standard of care (SOC) arm. But there was a “clear and persistent increased mortality” for the ide-cel group, compared with the standard regimen arm, with increased rates of death up to 9 months. In addition, the overall survival disadvantage persisted to 15 months after randomization, when the survival curves finally crossed, the FDA staff said in its March 15 presentation.

ODAC Chairman Ravi A. Madan, MD, of the National Cancer Institute, was among the panelists who voted “no” in the ide-cel question. He said the risk-benefit profile of the drug does not appear favorable at this time for expanded use.

“There’s a lot of optimism about moving these therapies earlier in the disease states of multiple myeloma,” Dr. Madan said, calling the PFS data “quite remarkable.

“But for me this data at this level of maturity really didn’t provide convincing evidence that ide-cel earlier had a favorable risk benefit assessment in a proposed indication.”

ODAC panelist Christopher H. Lieu, MD, of the University of Colorado, said he struggled to decide how to vote on the ide-cel question and in the end voted yes.

He said the response to the treatment doesn’t appear to be as durable as hoped, considering the significant burden that CAR-T therapy imposes on patients. However, the PFS data suggest that ide-cel could offer patients with RRMM a chance for significant times off therapy with associated quality of life improvement.

“I do believe that the risk-benefit profile is favorable for this population as a whole,” he said. “But it’s a closer margin than I think we would like and patients will need to have in-depth discussions about the risks and benefits and balance that with the possible benefits with their provider.”

In 2019, we interviewed Andrea Prince, MD, who was completing her internship in the Inuit village of Puvirnituq, a town of 2000 inhabitants located in Nunavik, in the Canadian Far North. Five years later, still in her position, what perspective does she have on her practice? Have the challenges of practicing medicine in a remote region within the Inuit community affected her vocation? Would she recommend this experience to young doctors?

Question: What position do you currently hold?

Dr. Prince: I am a full-time general practitioner at Puvirnituq Hospital. My responsibilities range from following up on hospitalized patients to those seen in outpatient clinics for chronic illnesses. Within our medical team, I receive patients in the emergency department (day and night shifts), and I travel to smaller dispensaries nearby, especially to the village of Akulivik. So, it’s quite a varied practice.

More recently, I have been involved in remote continuing medical education projects in collaboration with specialists based in Montreal. In this context, we are increasingly trying to collaborate with doctors from other indigenous communities, such as the Grand Council of the Cree, because our practices are quite similar.



Q: What is the patient volume you see?

Dr. Prince: We see approximately 20-30 patients per day in the clinic, plus about 10 by appointment, and dozens of calls from dispensaries, in addition to patients transferred from other villages. There are four daytime doctors (one at night) and about 15 nurses stationed full-time at Puvirnituq Hospital.

Our practice relies heavily on collaboration with the nursing team, which has an expanded role — they can manage certain patients according to the treatment plan established by the doctor and prescribe treatments (eg, antibiotics for uncomplicated otitis).



Q: Access to care in these isolated regions is considered difficult. Have you observed any improvement in the situation over the past 5 years? What about new material and human resources?

Dr. Prince: For the past year, we have had a Starlink internet connection at the hospital, which facilitates telemedicine exchanges with specialists; we can now send data and medical images to Montreal to obtain expertise much more easily. Previously, everything was done by phone or with significant delays. We do not yet have a cellular network, and all records are currently in paper format.

But the challenges remain numerous. Progress is very slow. Like everywhere in the country, we are experiencing a shortage of staff, particularly an insufficient number of nurses. But the impact is even more dramatic in these isolated territories. We have had to close dispensaries on the coast due to a lack of personnel and only offer emergency services. However, patients have no other options; they cannot drive to another hospital. In Nunavik, the road network is practically nonexistent, and travel to other regions is by plane (about a 2.5-hour medical evacuation trip).

So, sometimes, patients do not seek care in time, and when we finally see them, unfortunately, the issue can be quite advanced.



Q: What are the most pressing logistical needs?

Dr. Prince: We still do not have a scanner in the Far North. This has a significant impact on mortality, especially in the case of accidents and trauma, which are very common in these regions. “Residents of Nunavik are four times more likely to suffer trauma than the rest of Quebec’s population and 40 times more likely to die from it,” as recently reported in La Presse.

There has also been much discussion about cancer mortality, with a risk for death about 70% higher following a lung cancer diagnosis (reported by Medscape Medical News). We do not have a mammogram machine to diagnose breast cancer. Before the COVID-19 pandemic, equipped diagnostic teams sometimes traveled to the region, but this is no longer the case. Today, a patient needing a mammogram will have to travel to Montreal. The same goes for colonoscopies, but visits are becoming less frequent. Therefore, campaigns to screen for certain common types of cancer are practically nonexistent.

As for urgent surgeries (appendicitis, cesarean sections, trauma, etc.), patients must be transferred to Montreal by medical evacuation. We have a visiting surgeon twice a year.



Q: What improvement strategies do you foresee despite the lack of resources?

Dr. Prince: The saying “prevention is better than cure” makes perfect sense in such remote regions under extreme conditions (it is impossible to fly a medevac when it is too windy or during a snowstorm!). That’s why my colleagues and I believe that prevention should be the top priority in terms of healthcare intervention. It may seem obvious, but nothing is simple in the Far North.



Q: In which areas should prevention campaigns be prioritized in your opinion?

Dr. Prince: An example is wearing helmets. Practically no one wears this type of protection in the Far North. They use all-terrain vehicles that are dangerous and for which helmet use is crucial. But they are simply not available in stores. So, communication is difficult: We tell people, “you need a helmet for the ATV, another for the bike, for the snowmobile, for playing hockey, etc.” when it is difficult to obtain one. With traumatologists in Montreal, we had a project to create multifunctional helmets for children — to protect them but also to develop a culture of helmet use, which is not common practice in the community — but these are projects that take a lot of time and are more complex than they seem.

Villages still do not have running water. Therefore, it is difficult to give recommendations to patients as they live in sanitary conditions that are unseen elsewhere in Canada. Without clean water, we cannot ensure that wound care is done properly. Not to mention the occurrence of hepatitis A epidemics, like the one we had to face.

Residents also grapple with significant alcohol and smoking problems, but there is no detox center or dedicated psychological help on site. To follow a detox program, patients would have to leave, move away from their families, and that can be psychologically very destabilizing. I try, in my practice, to talk to my patients about this, especially pregnant women — because many continue to smoke or drink during their pregnancy — but we need more resources.



Q: What about women’s health in this region?

Dr. Prince: We are fortunate to have a team of midwives, several of whom are Inuit, who are of great help in accessing contraception, performing cervical cancer screening tests, etc. But some patients with high-risk pregnancies who should be transferred to Montreal refuse to give birth away from their families. Again, if we had the means to allow high-risk women — or those for whom continuous monitoring or a cesarean section may be necessary — to give birth here safely, it would be a big step. As for abortion, it is feasible but remains a very taboo subject in the community.

Regarding violence against women, I have not observed any particularly encouraging developments in the past 5 years, but recently, we met with the mayor about this, hoping that concrete actions will be taken to help victims of violence.
 

Q: What is the predominant feeling in your daily life in a situation that is slow to evolve?

Dr. Prince: I remain hopeful for my patients. We must continue to fight! Initiatives must also come from the communities themselves; they must be involved in developing solutions. Because patients, too, need to have hope. They have the right to be cared for like other inhabitants of Canada.

On my part, I try to find a balance between feeling good about my caregiving profession and not burning out professionally. But burnout is a subject that concerns many doctors around the world and is increasingly being discussed. We should all have psychological support when entering medicine!



Q: Would you recommend colleagues to come and work in the Far North? What would you tell them?

Dr. Prince: I would tell them they will have no regrets! Yes, it’s difficult, but it’s a unique type of practice and very rewarding on a human level.

Professionally, it is a general practice that is no longer seen in the city today. The spectrum is very broad, ranging from neonatology to geriatrics, from the simplest to the most complex. It’s very stimulating. Diagnostically, practice is also very different from what is done in the metropolis. Without a scanner, you really have to question and investigate to evaluate whether a patient should be evacuated by plane to Montreal or not. It’s not trivial. Decisions must be made judiciously and quickly.

The human experience is also unique. Inuit communities are little known, and the aspects relayed in the media are often negative due to their increased risk for addiction. However, they are cheerful and very warm people, with an extraordinary culture. I have learned a lot from them, including reconsidering the notion of time, reviewing my priorities, and approaching life one day at a time.

I am very grateful to them for accepting me. I am sometimes even greeted with a “Welcome home!” when I return from vacation...Being told that in Nunavik, I am also “at home,” touches me immensely. I have seen children grow up, adolescents become adults. A bond of trust has developed.

Of course, all of this comes with sacrifices like being away from family and loved ones. We miss birthdays, weddings, etc. But without hesitation, it’s worth it!



Q: What are the next steps in your career in Nunavik? Will you stay for a long time?

Dr. Prince: I take it one day at a time, especially since I am about to take maternity leave very soon. But if a full-time return to Nunavik is difficult with a newborn, I know that the Nunavummiuts [inhabitants of Nunavik] will always be part of my life and my practice.

I want to remain involved with these communities, whether on-site (by practicing there a few months a year) or in Montreal where many patients are transferred. Coming to be treated in a big city (Montreal, 1.7M inhabitants), in very large hospitals, can be very stressful for them. They express themselves much less verbally than Westerners, so we must know how to listen to them, dedicate the necessary time to them, consider their culture and beliefs. I would like to be the familiar face they will encounter when they are cared for away from home. It’s a bond I want to preserve.

This story was translated from Medscape France using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

In 2019, we interviewed Andrea Prince, MD, who was completing her internship in the Inuit village of Puvirnituq, a town of 2000 inhabitants located in Nunavik, in the Canadian Far North. Five years later, still in her position, what perspective does she have on her practice? Have the challenges of practicing medicine in a remote region within the Inuit community affected her vocation? Would she recommend this experience to young doctors?

Question: What position do you currently hold?

Dr. Prince: I am a full-time general practitioner at Puvirnituq Hospital. My responsibilities range from following up on hospitalized patients to those seen in outpatient clinics for chronic illnesses. Within our medical team, I receive patients in the emergency department (day and night shifts), and I travel to smaller dispensaries nearby, especially to the village of Akulivik. So, it’s quite a varied practice.

More recently, I have been involved in remote continuing medical education projects in collaboration with specialists based in Montreal. In this context, we are increasingly trying to collaborate with doctors from other indigenous communities, such as the Grand Council of the Cree, because our practices are quite similar.



Q: What is the patient volume you see?

Dr. Prince: We see approximately 20-30 patients per day in the clinic, plus about 10 by appointment, and dozens of calls from dispensaries, in addition to patients transferred from other villages. There are four daytime doctors (one at night) and about 15 nurses stationed full-time at Puvirnituq Hospital.

Our practice relies heavily on collaboration with the nursing team, which has an expanded role — they can manage certain patients according to the treatment plan established by the doctor and prescribe treatments (eg, antibiotics for uncomplicated otitis).



Q: Access to care in these isolated regions is considered difficult. Have you observed any improvement in the situation over the past 5 years? What about new material and human resources?

Dr. Prince: For the past year, we have had a Starlink internet connection at the hospital, which facilitates telemedicine exchanges with specialists; we can now send data and medical images to Montreal to obtain expertise much more easily. Previously, everything was done by phone or with significant delays. We do not yet have a cellular network, and all records are currently in paper format.

But the challenges remain numerous. Progress is very slow. Like everywhere in the country, we are experiencing a shortage of staff, particularly an insufficient number of nurses. But the impact is even more dramatic in these isolated territories. We have had to close dispensaries on the coast due to a lack of personnel and only offer emergency services. However, patients have no other options; they cannot drive to another hospital. In Nunavik, the road network is practically nonexistent, and travel to other regions is by plane (about a 2.5-hour medical evacuation trip).

So, sometimes, patients do not seek care in time, and when we finally see them, unfortunately, the issue can be quite advanced.



Q: What are the most pressing logistical needs?

Dr. Prince: We still do not have a scanner in the Far North. This has a significant impact on mortality, especially in the case of accidents and trauma, which are very common in these regions. “Residents of Nunavik are four times more likely to suffer trauma than the rest of Quebec’s population and 40 times more likely to die from it,” as recently reported in La Presse.

There has also been much discussion about cancer mortality, with a risk for death about 70% higher following a lung cancer diagnosis (reported by Medscape Medical News). We do not have a mammogram machine to diagnose breast cancer. Before the COVID-19 pandemic, equipped diagnostic teams sometimes traveled to the region, but this is no longer the case. Today, a patient needing a mammogram will have to travel to Montreal. The same goes for colonoscopies, but visits are becoming less frequent. Therefore, campaigns to screen for certain common types of cancer are practically nonexistent.

As for urgent surgeries (appendicitis, cesarean sections, trauma, etc.), patients must be transferred to Montreal by medical evacuation. We have a visiting surgeon twice a year.



Q: What improvement strategies do you foresee despite the lack of resources?

Dr. Prince: The saying “prevention is better than cure” makes perfect sense in such remote regions under extreme conditions (it is impossible to fly a medevac when it is too windy or during a snowstorm!). That’s why my colleagues and I believe that prevention should be the top priority in terms of healthcare intervention. It may seem obvious, but nothing is simple in the Far North.



Q: In which areas should prevention campaigns be prioritized in your opinion?

Dr. Prince: An example is wearing helmets. Practically no one wears this type of protection in the Far North. They use all-terrain vehicles that are dangerous and for which helmet use is crucial. But they are simply not available in stores. So, communication is difficult: We tell people, “you need a helmet for the ATV, another for the bike, for the snowmobile, for playing hockey, etc.” when it is difficult to obtain one. With traumatologists in Montreal, we had a project to create multifunctional helmets for children — to protect them but also to develop a culture of helmet use, which is not common practice in the community — but these are projects that take a lot of time and are more complex than they seem.

Villages still do not have running water. Therefore, it is difficult to give recommendations to patients as they live in sanitary conditions that are unseen elsewhere in Canada. Without clean water, we cannot ensure that wound care is done properly. Not to mention the occurrence of hepatitis A epidemics, like the one we had to face.

Residents also grapple with significant alcohol and smoking problems, but there is no detox center or dedicated psychological help on site. To follow a detox program, patients would have to leave, move away from their families, and that can be psychologically very destabilizing. I try, in my practice, to talk to my patients about this, especially pregnant women — because many continue to smoke or drink during their pregnancy — but we need more resources.



Q: What about women’s health in this region?

Dr. Prince: We are fortunate to have a team of midwives, several of whom are Inuit, who are of great help in accessing contraception, performing cervical cancer screening tests, etc. But some patients with high-risk pregnancies who should be transferred to Montreal refuse to give birth away from their families. Again, if we had the means to allow high-risk women — or those for whom continuous monitoring or a cesarean section may be necessary — to give birth here safely, it would be a big step. As for abortion, it is feasible but remains a very taboo subject in the community.

Regarding violence against women, I have not observed any particularly encouraging developments in the past 5 years, but recently, we met with the mayor about this, hoping that concrete actions will be taken to help victims of violence.
 

Q: What is the predominant feeling in your daily life in a situation that is slow to evolve?

Dr. Prince: I remain hopeful for my patients. We must continue to fight! Initiatives must also come from the communities themselves; they must be involved in developing solutions. Because patients, too, need to have hope. They have the right to be cared for like other inhabitants of Canada.

On my part, I try to find a balance between feeling good about my caregiving profession and not burning out professionally. But burnout is a subject that concerns many doctors around the world and is increasingly being discussed. We should all have psychological support when entering medicine!



Q: Would you recommend colleagues to come and work in the Far North? What would you tell them?

Dr. Prince: I would tell them they will have no regrets! Yes, it’s difficult, but it’s a unique type of practice and very rewarding on a human level.

Professionally, it is a general practice that is no longer seen in the city today. The spectrum is very broad, ranging from neonatology to geriatrics, from the simplest to the most complex. It’s very stimulating. Diagnostically, practice is also very different from what is done in the metropolis. Without a scanner, you really have to question and investigate to evaluate whether a patient should be evacuated by plane to Montreal or not. It’s not trivial. Decisions must be made judiciously and quickly.

The human experience is also unique. Inuit communities are little known, and the aspects relayed in the media are often negative due to their increased risk for addiction. However, they are cheerful and very warm people, with an extraordinary culture. I have learned a lot from them, including reconsidering the notion of time, reviewing my priorities, and approaching life one day at a time.

I am very grateful to them for accepting me. I am sometimes even greeted with a “Welcome home!” when I return from vacation...Being told that in Nunavik, I am also “at home,” touches me immensely. I have seen children grow up, adolescents become adults. A bond of trust has developed.

Of course, all of this comes with sacrifices like being away from family and loved ones. We miss birthdays, weddings, etc. But without hesitation, it’s worth it!



Q: What are the next steps in your career in Nunavik? Will you stay for a long time?

Dr. Prince: I take it one day at a time, especially since I am about to take maternity leave very soon. But if a full-time return to Nunavik is difficult with a newborn, I know that the Nunavummiuts [inhabitants of Nunavik] will always be part of my life and my practice.

I want to remain involved with these communities, whether on-site (by practicing there a few months a year) or in Montreal where many patients are transferred. Coming to be treated in a big city (Montreal, 1.7M inhabitants), in very large hospitals, can be very stressful for them. They express themselves much less verbally than Westerners, so we must know how to listen to them, dedicate the necessary time to them, consider their culture and beliefs. I would like to be the familiar face they will encounter when they are cared for away from home. It’s a bond I want to preserve.

This story was translated from Medscape France using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

In 2019, we interviewed Andrea Prince, MD, who was completing her internship in the Inuit village of Puvirnituq, a town of 2000 inhabitants located in Nunavik, in the Canadian Far North. Five years later, still in her position, what perspective does she have on her practice? Have the challenges of practicing medicine in a remote region within the Inuit community affected her vocation? Would she recommend this experience to young doctors?

Question: What position do you currently hold?

Dr. Prince: I am a full-time general practitioner at Puvirnituq Hospital. My responsibilities range from following up on hospitalized patients to those seen in outpatient clinics for chronic illnesses. Within our medical team, I receive patients in the emergency department (day and night shifts), and I travel to smaller dispensaries nearby, especially to the village of Akulivik. So, it’s quite a varied practice.

More recently, I have been involved in remote continuing medical education projects in collaboration with specialists based in Montreal. In this context, we are increasingly trying to collaborate with doctors from other indigenous communities, such as the Grand Council of the Cree, because our practices are quite similar.



Q: What is the patient volume you see?

Dr. Prince: We see approximately 20-30 patients per day in the clinic, plus about 10 by appointment, and dozens of calls from dispensaries, in addition to patients transferred from other villages. There are four daytime doctors (one at night) and about 15 nurses stationed full-time at Puvirnituq Hospital.

Our practice relies heavily on collaboration with the nursing team, which has an expanded role — they can manage certain patients according to the treatment plan established by the doctor and prescribe treatments (eg, antibiotics for uncomplicated otitis).



Q: Access to care in these isolated regions is considered difficult. Have you observed any improvement in the situation over the past 5 years? What about new material and human resources?

Dr. Prince: For the past year, we have had a Starlink internet connection at the hospital, which facilitates telemedicine exchanges with specialists; we can now send data and medical images to Montreal to obtain expertise much more easily. Previously, everything was done by phone or with significant delays. We do not yet have a cellular network, and all records are currently in paper format.

But the challenges remain numerous. Progress is very slow. Like everywhere in the country, we are experiencing a shortage of staff, particularly an insufficient number of nurses. But the impact is even more dramatic in these isolated territories. We have had to close dispensaries on the coast due to a lack of personnel and only offer emergency services. However, patients have no other options; they cannot drive to another hospital. In Nunavik, the road network is practically nonexistent, and travel to other regions is by plane (about a 2.5-hour medical evacuation trip).

So, sometimes, patients do not seek care in time, and when we finally see them, unfortunately, the issue can be quite advanced.



Q: What are the most pressing logistical needs?

Dr. Prince: We still do not have a scanner in the Far North. This has a significant impact on mortality, especially in the case of accidents and trauma, which are very common in these regions. “Residents of Nunavik are four times more likely to suffer trauma than the rest of Quebec’s population and 40 times more likely to die from it,” as recently reported in La Presse.

There has also been much discussion about cancer mortality, with a risk for death about 70% higher following a lung cancer diagnosis (reported by Medscape Medical News). We do not have a mammogram machine to diagnose breast cancer. Before the COVID-19 pandemic, equipped diagnostic teams sometimes traveled to the region, but this is no longer the case. Today, a patient needing a mammogram will have to travel to Montreal. The same goes for colonoscopies, but visits are becoming less frequent. Therefore, campaigns to screen for certain common types of cancer are practically nonexistent.

As for urgent surgeries (appendicitis, cesarean sections, trauma, etc.), patients must be transferred to Montreal by medical evacuation. We have a visiting surgeon twice a year.



Q: What improvement strategies do you foresee despite the lack of resources?

Dr. Prince: The saying “prevention is better than cure” makes perfect sense in such remote regions under extreme conditions (it is impossible to fly a medevac when it is too windy or during a snowstorm!). That’s why my colleagues and I believe that prevention should be the top priority in terms of healthcare intervention. It may seem obvious, but nothing is simple in the Far North.



Q: In which areas should prevention campaigns be prioritized in your opinion?

Dr. Prince: An example is wearing helmets. Practically no one wears this type of protection in the Far North. They use all-terrain vehicles that are dangerous and for which helmet use is crucial. But they are simply not available in stores. So, communication is difficult: We tell people, “you need a helmet for the ATV, another for the bike, for the snowmobile, for playing hockey, etc.” when it is difficult to obtain one. With traumatologists in Montreal, we had a project to create multifunctional helmets for children — to protect them but also to develop a culture of helmet use, which is not common practice in the community — but these are projects that take a lot of time and are more complex than they seem.

Villages still do not have running water. Therefore, it is difficult to give recommendations to patients as they live in sanitary conditions that are unseen elsewhere in Canada. Without clean water, we cannot ensure that wound care is done properly. Not to mention the occurrence of hepatitis A epidemics, like the one we had to face.

Residents also grapple with significant alcohol and smoking problems, but there is no detox center or dedicated psychological help on site. To follow a detox program, patients would have to leave, move away from their families, and that can be psychologically very destabilizing. I try, in my practice, to talk to my patients about this, especially pregnant women — because many continue to smoke or drink during their pregnancy — but we need more resources.



Q: What about women’s health in this region?

Dr. Prince: We are fortunate to have a team of midwives, several of whom are Inuit, who are of great help in accessing contraception, performing cervical cancer screening tests, etc. But some patients with high-risk pregnancies who should be transferred to Montreal refuse to give birth away from their families. Again, if we had the means to allow high-risk women — or those for whom continuous monitoring or a cesarean section may be necessary — to give birth here safely, it would be a big step. As for abortion, it is feasible but remains a very taboo subject in the community.

Regarding violence against women, I have not observed any particularly encouraging developments in the past 5 years, but recently, we met with the mayor about this, hoping that concrete actions will be taken to help victims of violence.
 

Q: What is the predominant feeling in your daily life in a situation that is slow to evolve?

Dr. Prince: I remain hopeful for my patients. We must continue to fight! Initiatives must also come from the communities themselves; they must be involved in developing solutions. Because patients, too, need to have hope. They have the right to be cared for like other inhabitants of Canada.

On my part, I try to find a balance between feeling good about my caregiving profession and not burning out professionally. But burnout is a subject that concerns many doctors around the world and is increasingly being discussed. We should all have psychological support when entering medicine!



Q: Would you recommend colleagues to come and work in the Far North? What would you tell them?

Dr. Prince: I would tell them they will have no regrets! Yes, it’s difficult, but it’s a unique type of practice and very rewarding on a human level.

Professionally, it is a general practice that is no longer seen in the city today. The spectrum is very broad, ranging from neonatology to geriatrics, from the simplest to the most complex. It’s very stimulating. Diagnostically, practice is also very different from what is done in the metropolis. Without a scanner, you really have to question and investigate to evaluate whether a patient should be evacuated by plane to Montreal or not. It’s not trivial. Decisions must be made judiciously and quickly.

The human experience is also unique. Inuit communities are little known, and the aspects relayed in the media are often negative due to their increased risk for addiction. However, they are cheerful and very warm people, with an extraordinary culture. I have learned a lot from them, including reconsidering the notion of time, reviewing my priorities, and approaching life one day at a time.

I am very grateful to them for accepting me. I am sometimes even greeted with a “Welcome home!” when I return from vacation...Being told that in Nunavik, I am also “at home,” touches me immensely. I have seen children grow up, adolescents become adults. A bond of trust has developed.

Of course, all of this comes with sacrifices like being away from family and loved ones. We miss birthdays, weddings, etc. But without hesitation, it’s worth it!



Q: What are the next steps in your career in Nunavik? Will you stay for a long time?

Dr. Prince: I take it one day at a time, especially since I am about to take maternity leave very soon. But if a full-time return to Nunavik is difficult with a newborn, I know that the Nunavummiuts [inhabitants of Nunavik] will always be part of my life and my practice.

I want to remain involved with these communities, whether on-site (by practicing there a few months a year) or in Montreal where many patients are transferred. Coming to be treated in a big city (Montreal, 1.7M inhabitants), in very large hospitals, can be very stressful for them. They express themselves much less verbally than Westerners, so we must know how to listen to them, dedicate the necessary time to them, consider their culture and beliefs. I would like to be the familiar face they will encounter when they are cared for away from home. It’s a bond I want to preserve.

This story was translated from Medscape France using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.